Part 2: Infections of Organ Systems

BACTERIAL MENINGITIS

Meningitis, an infection of the subarachnoid space and leptomeninges caused by a variety of pathogenic organisms, continues to be an important source of mortality and morbidity. Despite the introduction of new vaccines that prevent the most severe causes, bacterial or purulent meningitis remains the most important form of meningitis in the United States in terms of incidence, sequelae, and ultimate loss of productive life. Aseptic meningitis, usually caused by viruses, especially enteroviruses, is more common; however, significant sequelae are uncommon, and the disease is usually self-limited. Granulomatous meningitis, caused either by Mycobacterium tuberculosis or fungi, is a major cause of neurologic injury and death in the developing world.

PATHOGENESIS AND EPIDEMIOLOGY

The most common progression of infection in children with bacterial meningitis is hematogenous spread from the nasopharynx followed by bacterial entry into the subarachnoid space where the cerebrospinal fluid (CSF) contains few fixed or circulating scavenger cells to remove bacteria. Different bacteria cross the blood-brain barrier using a variety of cell surface receptors. There is poor opsonic and bactericidal capability in the CSF, so there is not a rapid cellular or humoral immune response, and bacteria can grow to the level of 10⁶ to 10⁷ organisms per milliliter of CSF. Meningitis may also occur as a direct extension from a contiguous focus or as a result of congenital, traumatic, or surgical disruption of normal anatomic barriers. Examples of such disruption include congenital dermal sinuses along the craniospinal axis, basilar skull fractures, and placement of CSF shunts.

Many of the neurologic sequelae of bacterial meningitis are a consequence of altered physiology due to the host’s inflammatory response to the infecting organism (Fig. 226-1). In the subarachnoid space, components of the surface of the multiplying bacteria (lipopolysaccharide, lipo-oligosaccharide, teichoic acid) stimulate generation of proinflammatory cytokines (tumor necrosis factor [TNF]-α, interleukin [IL]-1β, IL-6, platelet activating factor [PAF], and others). These, in turn, increase adhesion of leukocytes to cerebral vascular endothelium, promoting increased blood-brain barrier permeability and migration of leukocytes into the subarachnoid space. White blood cell (WBC) and endothelium-derived reactive oxygen species, and perhaps nitric oxide, then participate in altering cerebrovascular reactivity. Cerebral edema associated with meningitis represents a combination of vasogenic, cytotoxic, and interstitial edema. Cerebral perfusion is reduced in meningitis in approximately 30% of children in whom brain blood-flow studies have been performed. Cerebral edema not only contributes to reduced cerebral perfusion, but may also cause cerebral herniation due to increased intracranial pressure.

Direct cytotoxic neuronal injury, frequently found in postmortem studies, is likely caused by reactive oxygen and nitrogen species (oxygen radical, nitric oxide, peroxynitrite, hydroxyl radical), excitatory amino acids, caspases, and matrix metalloproteinases (MMPs). Experimental animal studies demonstrate improved neuronal survival when specific inhibitors of these compounds are used. Abnormalities of brain metabolism include hypoglycorrhachia and CSF lactic acidosis. Low CSF glucose levels occur by impaired glucose transport across the blood-brain barrier and possibly by increased cerebral glucose utilization. CSF lactic acidosis indicates anaerobic glucose utilization within the central nervous system.

Pathologic changes in meningitis reflect the inflammatory mass in the subarachnoid space, cerebral vasculitis, cerebral edema, and cellular injury. The inflammatory mass usually begins in the basilar cisterns, spreads around the cerebellum, and then spreads over the cerebral convexities. The cranial nerves that traverse the subarachnoid space are particularly prone to injury in meningitis, perhaps due to the surrounding inflammation. Vasculitis of both arteries and veins occurs, particularly in meningitis caused by Streptococcus pneumoniae, resulting in tissue ischemia and arterial and venous infarcts. Direct cellular injury, as a result of bacterial toxins, host factors, or ischemia, is frequently noted in postmortem studies.

The first month after birth represents the period of highest attack rate for meningitis, with likely pathogens including Streptococcus agalactiae (group B Streptococcus), Escherichia coli, other gram-negative enteric organisms, and less commonly, Listeria monocytogenes (Table 226-1). Beyond the neonatal period, the most important pathogens are S pneumoniae and Neisseria meningitidis. In the past, Haemophilus influenzae type B (Hib) was the most common pathogen causing meningitis in toddlers and children, but the incidence has been reduced dramatically by immunization with conjugate vaccines in developed countries. Recent studies of conjugate pneumococcal vaccine, introduced in the United States in 2000, demonstrate that it is effective in preventing pneumococcal meningitis. Similarly, the meningococcal conjugate vaccine first introduced in 2005 as part of the routine vaccination schedule for US adolescents has been effective in reducing meningococcal meningitis due to serogroups A, C, Y, and W135. More recently a vaccine has been approved for serogroup B N meningitidis for at-risk children. Thus, the incidence of infection and prevailing predominant causative organisms vary depending on both the age and the immunization status of the population.

Bacterial meningitis is reported with increased frequency among African Americans, Native Americans, and individuals in rural areas. It is unclear whether environmental or genetic factors are responsible for enhanced susceptibility. Seasonal patterns of disease have been noted to occur, with meningitis caused by N meningitidis and S pneumoniae peaking in the winter months, Hib showing a biphasic distribution with peaks in the early winter and spring, and L monocytogenes occurring most frequently in the summer months. In the “meningitis belt” of sub-Saharan Africa, the shift from the wet to the dry season is associated with an increase in meningitis. These patterns are likely due to the modes for acquiring the organisms, with N meningitidis, S pneumoniae, and Hib spread by the respiratory route in months with increased incidence of common respiratory diseases, and L monocytogenes acquired from contaminated food or contact with farm animals.

Host factors such as asplenia and lack of opsonizing antibody predispose to increased susceptibility to encapsulated organisms such as S pneumoniae and increase the risk of meningitis. Neisseria infections including N meningitidis occur with increased frequency in persons with terminal complement deficiencies. Polymorphisms in toll-like receptor proteins and other adaptor molecules that are integral parts of the innate immune response have also been associated with increased risk for invasive disease caused by N meningitidis.

The emergence of bacteria resistant to commonly prescribed antibiotics has changed empiric treatment of presumed bacterial meningitis. In the past decade, S pneumoniae with reduced susceptibility to penicillins and cephalosporins has been identified in virtually all parts of the world and, in some areas, may compromise the utility of those drugs for empiric therapy. The 13-valent pneumococcal conjugate vaccine (PCV) currently available in the United States is directed at several strains associated with increased antibiotic resistance. According to the Centers for Disease Control and Prevention, in 2013, 30% of invasive infections due to S pneumoniae were caused by pneumococci that were not susceptible to at least 1 drug used for therapy with increased resistance to older β-lactam antibiotics and macrolides. Of children who received the pneumococcal conjugate vaccine, 18.4% of those with invasive pneumococcal disease had strains intermediately susceptible to penicillin, and 19.1% had strains with high-level resistance to penicillin. A serotype (19A) that was not included in the initial 7-valent PCV and was resistant to multiple antibiotics that caused invasive disease has been incorporated in the currently available PCV. Increased antibiotic resistance has also been seen with gram-negative enteric species such as E coli. However, S agalactiae and N meningitidis have remained susceptible to penicillin and third-generation cephalosporins. The clinician must be aware of emerging patterns of antibiotic resistance within the local community and in the hospital setting for patients who develop symptoms suspicious for invasive bacterial disease, including meningitis.

CLINICAL MANIFESTATIONS

The classic triad of symptoms in meningitis includes fever, headache, and stiff neck. However, in children under 2 years of age, and especially in young infants, stiff neck or other signs of meningeal irritation may be absent. Alteration of level of consciousness is usual, occurring in up to 90% of patients. The majority present with irritability, lethargy, or confusion, and 10% to 15% present in coma, a very poor prognostic sign. Physical examination of older children may reveal typical signs of meningeal irritation—stiff neck and positive Kernig and Brudzinski signs. Infants often have a bulging fontanel. Cranial nerve abnormalities, particularly of the sixth cranial nerve, may be the consequence of increased intracranial pressure or of inflammation in the subarachnoid space. Focal neurologic abnormalities are uncommon early in the disease but, when present, may be indicators of cerebral infarct.

Systemic signs may also be present in children with meningitis. The most common occur in the setting of meningococcal disease. The rash in meningococcal sepsis evolves from a transient erythematous, macular eruption to the presence of petechiae, ecchymoses, and purpura. These may lead to frank tissue ischemia and tissue death. Approximately 50% of these patients will have concurrent meningitis. Meningitis due to N meningitidis and gram-negative rods frequently results in hypotension due to the systemic effects of endotoxin. Most other causes of meningitis, including those due to S pneumoniae, Hib, and L monocytogenes, are usually not accompanied by endotoxic shock. Hypotension in the setting of disease caused by these other organisms is most commonly the result of volume depletion or purpura fulminans. Purpura fulminans is a condition associated with overwhelming infections and includes rapidly evolving disseminated intravascular coagulation (DIC), fever, chills, and ecchymotic skin lesions that may ulcerate and progress to peripheral gangrene, shock, and death.

DIAGNOSIS

Once the diagnosis of meningitis is suspected, immediate examination of the CSF is indicated unless there is a strong suspicion of an intracranial mass lesion. Such a mass may be the cause of herniation of the brain through the foramen magnum during the lumbar puncture. Worrisome findings include papilledema or a history of an indolent process with focal neurologic findings. In those instances, lumbar puncture can be delayed until a mass is excluded by cranial computed tomography (CT) or magnetic resonance imaging (MRI) of the brain. CSF abnormalities in bacterial meningitis include elevated numbers of WBCs, elevated protein concentration, hypoglycorrhachia, elevated opening pressure, and bacteria observed on Gram stain. Pleocytosis is typical in bacterial meningitis, with CSF WBC concentrations in the range of 100 to 10,000 cells/μL, although occasionally early in the disease, the WBC concentration may be normal or slightly elevated. In bacterial meningitis, polymorphonuclear cells predominate and usually account for more than 90% of the total. Very high WBC concentrations (> 50,000/μL) raise the possibility of an intracranial abscess that has ruptured into the ventricles.

Hypoglycorrhachia is commonly found in bacterial meningitis, with CSF glucose usually less than 50% of simultaneous serum glucose. Other causes of hypoglycorrhachia include tuberculous and fungal meningitis, subarachnoid hemorrhage, and carcinomatous meningitis. CSF protein concentration is usually elevated, in the range of 100 to 500 mg/dL, but because elevated protein reflects an alteration in the blood-brain barrier, it is not, by itself, diagnostic of bacterial infection.

In contrast to bacterial meningitis, CSF from patients with aseptic (including viral) meningitis is typically characterized by lower WBC counts and a glucose concentration near or within the normal range. Although the percentage of neutrophils may be variable, it is usually much lower in aseptic meningitis where lymphocyte predominance is more common. CSF protein concentration may be normal or elevated in patients with meningitis caused by enterovirus or M tuberculosis.

The Gram stain is positive in more than 90%, and the CSF culture is positive in 70% to 90% of patients with untreated hematogenous bacterial meningitis. The Gram stain must be interpreted by an experienced microbiologist, as errors in interpretation are common. Pneumococci, when overdecolorized, may resemble meningococci, Hib may be thought to be gram-negative enteric organisms or vice versa, and debris may resemble gram-positive cocci. L monocytogenes is frequently difficult to identify on direct smear.

Prior treatment with oral antibiotics substantially reduces the yield of CSF bacterial cultures. More recently, molecular diagnostic methods, including polymerase chain reaction (PCR) of a portion of the bacterial gene encoding the 16S ribosome, have been successful in the early diagnosis and speciation of bacterial meningitis. Novel diagnostic platforms that detect nucleic acid from bacteria, viruses, and fungi that cause meningitis and encephalitis are available, with US Food and Drug Administration (FDA) approval having occurred in 2015 for a platform that detects 14 of the most common central nervous system (CNS) pathogens.

In addition to culture and Gram stain of the CSF, blood culture may be useful in specific etiologic diagnosis. Blood cultures are positive in 40% to 75% of cases of bacterial meningitis, depending on the pathogen, and should be performed routinely.

Studies other than those aimed at making an etiologic diagnosis are indicated as well. Peripheral blood WBC and differential are useful in assessing the likelihood of a serious bacterial infection, and leukopenia may be a poor prognostic sign, indicating failure of the inflammatory response, particularly in the settings of overwhelming meningococcal or pneumococcal disease. Other inflammatory markers such as C-reactive protein and procalcitonin may also be helpful, as high levels correlate with the likelihood of serious bacterial infection, including meningitis, when patients present with symptoms consistent with meningitis. Prolongation of blood coagulation studies in conjunction with thrombocytopenia may indicate DIC, which is often present with serious gram-negative infection. Serum and urine electrolytes and osmolality should be measured routinely to look for the syndrome of inappropriate antidiuretic hormone (SIADH) secretion, marked by hyponatremia in association with increased urine osmolality and increased urine concentration of sodium. Radiologic studies are rarely needed in the diagnosis of meningitis; however, they may be useful in identifying coexisting complicating factors. Cranial CT may indicate cerebral edema early in the infection and later may show subdural effusion or subdural empyema.

TREATMENT

Antimicrobial Therapy

Effective treatment of meningitis depends on early aggressive supportive therapy and selection of empiric antimicrobials appropriate for the likely pathogens. The principles of antimicrobial therapy of meningitis include selection of an antibiotic that is bactericidal against the suspected pathogens and that achieves a concentration in CSF at least 10 times the minimal bactericidal concentration (MBC) for the organism, as this is the concentration that has been shown in animal studies to correlate with most effective sterilization of CSF. Suggested choices for empiric therapy are listed in Table 226-2 and should be based on the likely pathogens for the age group, known exposures, and any unusual risk factors for the patient. Resistance to third-generation cephalosporins is increasing, so empiric therapy with vancomycin as well as ceftriaxone or cefotaxime is warranted when pneumococcal meningitis is suspected. An exception may be in a country or region where monitoring for pneumococcal resistance has shown resistance to be absent.

Definitive antibiotic therapy depends on the antibiotic susceptibility of the causative organism. N meningitidis remains susceptible to penicillin, but ceftriaxone or cefotaxime also can be used. For patients who must avoid all β-lactam antibiotics, meropenem or chloramphenicol would be appropriate. Chloramphenicol is not used in the United States, but in the developing world, it is available, is low cost, can be used intravenously or intramuscularly, can be given orally to complete a course of therapy, and is effective for older children with meningitis due to susceptible organisms. For S pneumoniae strains susceptible to penicillin, penicillin, ceftriaxone, or cefotaxime would be appropriate. If the isolate is nonsusceptible to penicillin but susceptible to ceftriaxone or cefotaxime, 1 of these 2 drugs is recommended, and vancomycin should be discontinued. If the isolate is also nonsusceptible to ceftriaxone or cefotaxime, then vancomycin and ceftriaxone or cefotaxime should be continued for the full course of treatment. In this instance, under selected circumstances, rifampin also may be added if the isolate is susceptible. Hib is uniformly susceptible to ceftriaxone or cefotaxime, but the majority of isolates are susceptible to ampicillin, which is the drug of choice if the isolate is susceptible. Doses of antibiotics used to treat the more common causes of bacterial meningitis in children are shown in Table 226-3.

Duration of antibiotic therapy is 14 to 21 days for neonatal meningitis caused by group B streptococci, and a minimum of 21 days for gram-negative enteric organisms. For meningitis in older infants or children, treatment should be 7 days for N meningitidis, 7 to 10 days for Hib, and 10 to 14 days for S pneumoniae.

Supportive and Adjunctive Therapies

Regarding the possible benefits of adjunctive early corticosteroid treatment, despite numerous studies, there have been inconsistent results in children with bacterial meningitis not caused by Hib. Dexamethasone, 0.15 mg/kg per dose, administered prior to or concurrently with the start of antibiotic treatment and continued every 6 hours for 2 to 4 days is the regimen used in published studies. Some data suggest steroid administration improves mortality in adults with pneumococcal meningitis and improves morbidity and mortality in neonates, but there is insufficient literature to support this as a blanket recommendation for children.

There are supportive measures that address the consequences of serious intracranial pathology. Patients who are comatose or who have impaired gag reflex should have their stomach contents emptied, and intubation should be considered to protect the airway. Hypoxia should be treated with supplemental oxygen. Hypoventilation is particularly worrisome in these patients because elevated Paco₂ may cause cerebral vasodilatation and potentiate increased intracranial pressure. Hypercarbia should be considered another indication for intubation and assisted ventilation.

Fluid management is critically important in patients with meningitis. SIADH occurs in approximately 30% of patients with bacterial meningitis and warrants fluid restriction after restoration of normal blood volume. However, a clinical study has documented the importance of maintaining an adequate cerebral perfusion pressure in this disease. Inappropriate fluid restriction may result in volume depletion, leading to inadequate circulating volume if carried to extremes. If SIADH is present, fluids should be limited to replacement of insensible losses plus urine output (generally, approximately two-thirds of maintenance requirement) until ADH excess resolves. If SIADH is not present, fluids should be administered in an amount appropriate to maintenance requirements plus intercurrent losses, and electrolytes should be carefully monitored.

Therapy of increased intracranial pressure must be directed at maintaining an adequate degree of cerebral perfusion pressure as in other conditions complicated by intracranial hypertension. Available modalities may include elevation of the head of the bed, hyperventilation, withdrawal of CSF through an intraventricular catheter, or possibly the careful use of osmotic diuretic agents.

Mortality rates in bacterial meningitis vary considerably depending on the age of the patient, the pathogen, and the degree of illness at the time of initial evaluation. Individuals with meningococcal meningitis without overwhelming meningococcemia have a fatality rate of 12%, whereas newborns with gram-negative meningitis succumb up to 70% of the time. Death rates from Hib and S pneumoniae are approximately 3% and 6%, respectively, at children’s hospitals in developed countries.

Morbid sequelae occur in approximately 30% of survivors, but there is also an age and pathogen predilection, with the greatest incidence of sequelae occurring among the very young and in those infected with either gram-negative bacteria or S pneumoniae. Although many patients with meningitis have good neurologic outcomes with standard supportive measures and antibiotics, patients with more profound CNS disturbance require more intensive treatment to reduce intracranial pressure in conjunction with supportive care and antimicrobial therapy. In addition to depressed mental status at the time of presentation, other poor prognostic factors include the presence of comorbid conditions, leukopenia, and severe hypoglycorrhachia. The most common neurologic sequelae include deafness in 3% to 25% of patients; cranial nerve palsies in 2% to 7%; and severe injury, such as hemiparesis or global brain injury, in 1% to 2% of patients. More than 50% of patients with neurologic sequelae at discharge from the hospital will improve with time, and recent advances in cochlear implant therapy may provide hope for the child with permanent hearing loss.

PREVENTION

Prevention of meningitis currently takes 2 forms: chemoprophylaxis for susceptible individuals known to be exposed to an index patient and active immunization. Chemoprophylaxis is currently indicated for preventing secondary cases of meningitis due to Hib and N meningitidis. Active immunization with conjugate vaccine against Hib has resulted in a dramatic reduction in invasive disease, with a > 95% reduction in meningitis caused by that organism. Universal infant Hib vaccination is recommended in the United States. The introduction of the conjugate pneumococcal vaccine has also reduced rates of invasive pneumococcal disease such as meningitis, including in high-risk communities, such as Native American communities. Initially, a multivalent polysaccharide vaccine was approved but was not immunogenic for children under 2 years old. This was followed by the first conjugated pneumococcal vaccine, which conferred immunity in infants to the 7 most common pneumococcal serotypes causing invasive disease. This has since been superseded by a conjugated vaccine containing 13 pneumococcal serotypes in the United States as part of the universal infant vaccination.

A quadrivalent conjugate meningococcal vaccine has become available against N meningitidis groups A, C, Y, and W-135. It is administered to all adolescents and to children over 2 years of age who are considered to be at increased risk of meningococcal infection in the United States. The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP) has not recommended the recently licensed group B vaccine for universal immunization but rather for “certain persons aged ≥ 10 years who are at increased risk for meningococcal disease. These persons include persons with persistent complement component deficiencies, persons with anatomic or functional asplenia, microbiologists routinely exposed to isolates of N meningitidis, and persons identified as at increased risk because of a serogroup B meningococcal disease outbreak.”

FUTURE DIRECTIONS

The increasing availability of rapid molecular testing for the early diagnosis of bacterial and viral etiologies of meningitis and encephalitis will potentially have several benefits: (1) early diagnosis of viral disease can reduce the use of empiric antimicrobials that might contribute to increasing microbial resistance; (2) early identification of a bacterial pathogen can direct and narrow antibiotic choices and ensure early appropriate therapy with potential for improved clinical outcomes; and (3) in cases where the Gram stain and culture are negative due to previous antibiotic administration, the rapid identification of a pathogen can help direct therapy.

While much work has gone into adjuvant therapies to improve clinical outcomes for bacterial meningitis, a groundbreaking intervention has proven elusive. While steroids given early may have some clinical benefit, when recommended, it is only in high-income countries and this is not uniformly endorsed. Hypothermia for bacterial meningitis resulted in improved outcomes in animal studies. However, a human trial found it caused more harm than benefit. The use of the antidepressant fluoxetine has had favorable results in animals preventing hippocampal damage during bacterial meningitis, but more data are required to determine if this is a viable therapeutic option. Ongoing studies are examining glycerol as an adjuvant to antibiotic therapy, but results to date have been mixed.

BRAIN ABSCESS

Brain abscess is relatively uncommon yet remains a serious disease. Early diagnosis with neuroradiologic imaging, rapid neurosurgical intervention (including stereotactic brain biopsy and aspiration), and the initiation of broad-spectrum antimicrobial therapy, to cover both anaerobic and aerobic bacteria, provide the best opportunity for a favorable outcome. Nevertheless, because there are no prospective controlled or comparative trials, management relies largely on retrospective studies and clinical experience.

PATHOGENESIS AND EPIDEMIOLOGY

Most abscesses start at the gray-white matter junction. Encapsulation proceeds more rapidly and profusely on the cortical side than on the side facing the white matter. With abscesses in paraventricular sites, rupture into the ventricle may occur at any time, an event that carries a very high mortality.

Investigations of experimental abscesses and correlation of CT scans with both experimental and operative histologic findings have led to a definition of stages in the course of abscess formation. These stages include early and late cerebritis followed by early and late capsule formation. The findings from CT and MRI differ according to the stage of abscess formation. In early cerebritis, there is only patchy enhancement and an ill-defined area of low density or attenuation. As the abscess matures to late cerebritis and early capsule formation, a large enhancing ring is identified. This occurs during the formation of a collagen capsule, and the central portion of the abscess begins to necrose. In the final late capsular stage, there is a well-defined collagen capsule and necrotic center. Contrast images at this stage reveal only a faint thin rim of enhancement.

Brain abscess can arise in association with infection elsewhere in the body or can be caused by penetrating injury or a neurosurgical procedure. Extension and spread of infection via the bloodstream through venous channels to the brain from paranasal, mastoid, or inner ear sites has been reported as the most common cause of brain abscess in many series. However, the incidence of infection from otorhinologic sources has fallen markedly since the introduction of antibiotics. Metastatic abscesses usually originate in either the heart or the lungs, although osteomyelitis, renal infections, and skin abscess (including the scalp) can be the primary source. Anatomic anomalies that predispose children to brain infections include congenital dermoids or dermal sinus tracts. Although treatment of the brain abscess is the primary responsibility, detection and treatment of the infective source must proceed simultaneously. A history of inadequate treatment of an initial source infection, usually with a broad-spectrum antibiotic of insufficient potency, is frequently elicited when patients present with brain abscess. In approximately 6% of patients, the primary source of infection is undetectable.

Material from abscess cavities must be cultured immediately, both aerobically and anaerobically. Anaerobic bacteria, including Bacteroides fragilis, play a prominent role in brain abscess formation, accounting for almost 80% of nontraumatic brain abscesses in some series. Another common isolate is Streptococcus with a predominance of Streptococcus milleri species in the viridans group. Abscesses resulting from trauma most commonly are due to Staphylococcus aureus. Other causative organisms are other Bacteroides species, hemolytic streptococci, Proteus species, H influenzae, E coli, and, rarely, Cryptococcus, Nocardia, Aspergillus, or Corynebacterium species. Still, more than 10% of cultures will be sterile, using the best contemporary culture techniques.

The bacterial spectrum in neonates with brain abscesses differs from that in older infants and children. Brain abscesses in infants less than 3 months of age are often due to gram-negative organisms, such as E coli, Citrobacter species, Proteus species, Chronobacter, or Salmonella species, almost half of the time. The incidence of brain abscess is difficult to evaluate but is probably 2 to 3 per 10,000 general hospital admissions. A preponderance of male patients has been noted in most large series. Nearly one-third of all brain abscesses occur in the pediatric age group. The low incidence of brain abscesses in infants is related to their lack of well-formed frontal or mastoid sinuses.

One risk factor for the development of brain abscesses is cyanosis, caused either by congenital heart disease or by pulmonary arteriovenous shunting. Postmortem studies have indicated that brain abscesses are found in 0.4% of patients dying from all causes, whereas in patients with congenital heart disease, the incidence may be as high as 6%. The incidence of brain abscess in all children with congenital cyanotic heart disease is 2% to 3%. Children with right-to-left intracardiac shunting are deprived of the phagocytic filtering action of the pulmonary capillary bed, and in these children, the cerebral circulation is subject to recurrent bacteremia. These children are also likely to have focal encephalomalacia resulting from hypoxia and decreased cerebral blood flow caused by increased viscosity because of polycythemia. The coincidence of an area of recent infarction and bacteremia will predispose to abscess formation. A relationship has been shown between the severity of hypoxemia and the development of and prognosis for brain abscess in these patients.

Immunosuppressed children are also at risk for brain abscess. This category includes children receiving chemotherapy or radiation therapy for malignancy, a small group who have had transplants, and a smaller group with acquired immunodeficiency syndrome (AIDS). The increased risk in these groups of children is related to their generally high risk for opportunistic infection, rather than to specific CNS factors. The children are usually debilitated, and the abscesses are more likely to be multiple and to contain multiple species, including fungi.

CLINICAL MANIFESTATIONS

The initial symptoms of brain abscess are more likely to be related to its intracranial mass effect than to the infectious nature of the illness. Lethargy, anorexia, and vomiting are noted, and older children will complain of headache. Focal or grand mal seizures may be the first indication of cerebral involvement and may lead to discovery of previously unnoticed neurologic deficits that are due to the abscess. Fever may be low-grade; almost half of children are afebrile on hospital admission, even though there is a history of recent febrile illness. Brain abscesses are usually rapidly progressive; the duration of symptoms is often less than a week and seldom more than a month. Specific neurologic deficits will depend on the area of involvement and may include hemiparesis, sensory impairment, and visual field abnormalities. Posterior fossa abscess will cause ataxia, dysmetria, and cranial nerve palsies.

DIAGNOSIS

Both CT scanning and MRI are useful to diagnose and follow intracranial abscess (Fig. 226-2). MRI will often provide better resolution of the abscess and surrounding edema when compared with CT, but CT imaging is usually more rapidly available in the emergency department. CT and MRI scans should be performed with and without contrast enhancement. Following contrast injection, scans performed both immediately and after delay of 30 to 60 minutes will allow for more precise staging of the abscess. Multiple lesions, which cause high mortality among patients with brain abscesses, are easily diagnosed. Dosages of steroids, antibiotics, and even mannitol may be adjusted according to the changes observed over time.

In patients who receive adjunctive anti-inflammatory therapy, steroids may reduce the contrast enhancement of abscesses, especially during the cerebritis stages. This effect of steroids should not shorten the duration of antibiotic therapy or decrease consideration of surgery if symptoms progress. The results of routine laboratory studies may be normal or may reveal moderate leukocytosis and an elevated erythrocyte sedimentation rate. Skull films may indicate a chronic otorhinologic infection, and rarely, there is evidence of mass effect or increased intracranial pressure.

Many reports have stressed the danger of lumbar puncture in the presence of abscess. If there are indications of increased intracranial pressure or shifting of intracranial structures, lumbar puncture is contraindicated. The information obtained from the CSF in patients with brain abscess is usually nonspecific; often the causative organisms cannot be demonstrated, and lumbar puncture may introduce a potentially fatal risk.

TREATMENT

The initiation of appropriate therapy requires a rapid assessment of the patient’s clinical status and the expertise of an experienced neurosurgeon. An intracerebral abscess can act as a rapidly expanding intracranial mass because of both the purulent collection and the surrounding cerebral edema. Secondary brain stem compression can lead to coma and death in a very short time. Uncal herniation causing midbrain compression is almost uniformly found in fatal brain abscess. For patients who display clinical or radiographic evidence of increased intracranial pressure, initial therapy is aimed at decreasing the intracerebral pressure and mass effect and includes steroids. Periabscess edema derives from both the local mass and the stasis effect and inflammation response that causes a diffuse increase in brain water. Steroids in large doses decrease the endothelial permeability of vessels in the inflammatory area and reduce the excessive edema. Although the restorative effect of steroids on the blood-brain barrier may reduce antibiotic activity in the infected region, this effect is usually of lesser concern than the need to reduce increased intracranial pressure. Patients who do not have evidence of increased intracranial pressure or mass effect may not require steroids or immediate neurosurgical intervention but must have frequent neurologic exams to check for changes in the patient’s status.

Antimicrobial Therapy

Appropriate initial empiric antibiotic therapy for brain abscess is broad to cover the most likely pathogens while awaiting culture data. During the stage of cerebritis, antibiotics with appropriate protein and lipid-binding characteristics can readily diffuse into the area of inflammatory response. Contrast studies have shown that once an abscess has formed, bacteria may still be isolated from the abscess, despite measurable levels of appropriate antibiotics within the abscess. It has been postulated that the intensely acidic environment associated with the necrotic debris may decrease antimicrobial action. This mechanism may explain reported treatment failure despite appropriate antibiotic therapy.

Gram-negative anaerobic organisms (eg, Bacteroides species) often associated with otogenic brain abscesses are susceptible to metronidazole. Metronidazole is bactericidal for most anaerobes; it penetrates into brain abscesses well and is not degraded in purulent debris. Gram-positive cocci such as streptococci usually respond to one of the β-lactam antibiotics or to vancomycin. Vancomycin is increasingly required as the incidence of methicillin-resistant S aureus (MRSA) increases. First-line therapy for gram-negative aerobic bacilli includes the third-generation cephalosporins (cefotaxime, ceftazidime, and ceftriaxone). Bactrim and ciprofloxacin are alternative choices in patients who are unable to tolerate cephalosporins. Thus, empiric therapy might include vancomycin, a third-generation cephalosporin, and metronidazole. Intravenous antibiotic therapy is required intraoperatively and for at least several weeks thereafter. Antimicrobial therapy can be altered as soon as susceptibility testing has been performed on organisms recovered from the purulent material obtained at operation.

Surgical Intervention and Adjunct Therapy

Timing of surgical intervention will depend on the general condition of the child, the location and stage of the abscess, knowledge of the infecting organism, and the response to medical therapy. Patients who have multiple small abscesses are usually best treated medically. Even large areas of cerebritis and early encapsulation may be treated with steroids and appropriate antibiotics if these patients are followed carefully by both clinical observation and serial scanning. However, the process of waiting for abscess stabilization and encapsulation places the patient at risk for abrupt brain herniation or rupture of the abscess. Early aspiration of an abscess in a paraventricular locus is warranted.

Several techniques have been devised for operative treatment of abscesses, and selection of the appropriate procedure will depend on the condition of the patient, abscess location, and degree of abscess encapsulation. The patient’s clinical condition at the time of operation is more important in determining the result than is the choice of operative procedure. Decompression of the mass effect is the primary goal of surgery. Management of children with a brain abscess should be cooperative between experts in infectious diseases and neurosurgery.

Aspiration of the abscess through a burr hole is preferable for severely ill children, as well as for known multiple abscesses and instances where the abscess has a thin or poorly developed wall. CT- and/or MRI-assisted stereotactic equipment is available in most centers. These devices allow for the safe aspiration of even deep abscesses. Abscesses may require 2 or 3 further aspirations in the postoperative period. Total excision can be attempted if the abscess is single, well encapsulated, and away from critically functional cortex. Excision has the advantage of immediately decompressing the mass and decreasing the risk of recurrence from remaining infected material. Excision may be delayed until aspiration and a period of antibiotic and steroid therapy allow stabilization of the cavity and formation of a thick capsule, facilitating total excision. Mortality is highest in children with cyanotic heart disease, and aggressive surgical intervention has been recommended for these patients.

Anticonvulsants should be given to all patients with supratentorial purulent lesions for at least 2 years after surgery. Seizures are frequently present during the preoperative period, and the incidence of seizures after surgery is almost 50%. The choice of operative procedure does not appear to alter the incidence of seizures.

High mortality rates from brain abscess in previous decades have been related to 2 major factors: late diagnosis and the presence of multiple lesions. If diagnosis is delayed until children are obtunded or comatose, the mortality is 65% to 90%. Mortality rates as high as 80% were reported for children with multiple abscesses. With current diagnostic and therapeutic options, a recent case series of 96 patients including both children and adults reported a mortality rate of 6% with an additional 34% of patients suffering moderate to severe sequelae.

SPINAL ABSCESS

Spinal abscesses are rare in children. Infection can occur in any of the intraspinal planes, but most infections occur in the epidural space. Subdural empyema and intramedullary spinal abscesses are even rarer and, when seen, are often associated with a congenital dermal sinus tract or dermoid tumor.

PATHOGENESIS

Spinal epidural abscesses are usually the result of hematogenous seeding. They may be metastatic, from another focus by the veins of the Batson plexus. A minority occur by direct extension, from spondylitis, or from lung or perinephric infections. In adults, there frequently are preexisting systemic illnesses, but children are usually previously normal. If a distant source is identified, it is often a cutaneous furuncle. Local trauma can result in a hematoma, which can provide a nidus for infection. The most common organism is S aureus including MRSA. In S aureus spinal epidural infections, sometimes there is a history of a preceding skin infection, but cases with no risk factors have also been reported. Rarely, spinal epidural abscesses have cultured coagulase-negative staphylococci, gram-negative rods, anaerobes, fungi, and other organisms. Spinal abscesses are most frequent in the midthoracic and lumbar regions.

CLINICAL MANIFESTATIONS

The initial complaint is usually backache, with well-defined localization of tenderness. Initially fever may not be present but usually appears as the condition progresses. As the purulence expands, there is sharp unilateral or bilateral pain at the level of the abscess. As the pain intensifies, the child may refuse to sit or walk. Sensory deficits appear, and weakness of the legs is noted. If untreated, gait difficulty, sphincteric loss, and finally paraplegia follow in rapid order. The chance of recovery after total loss of leg, bladder, and bowel functions is small; therefore, early diagnosis and surgical decompression are of great importance. Surgical consultation should be obtained immediately if an epidural abscess is suspected. Spinal infections in children are generally more acute than are those in adults, and the symptoms may progress rapidly. Infections have been reported in which only several hours have elapsed between the onset of symptoms and the paraplegic state. Differential considerations include spinal and paraspinal tumors such as neuroblastoma or sarcomas, transverse myelitis, discitis, spontaneous hematoma, and Guillain-Barré syndrome.

DIAGNOSIS

Laboratory examination will usually reveal leukocytosis and an elevated erythrocyte sedimentation rate and C-reactive protein. Spine radiographs may show local spondylitis, fracture, or a paraspinal soft tissue mass. Lumbar puncture studies will demonstrate pleocytosis, elevated protein concentration, and decreased glucose concentration. However, it is important to note that lumbar punctures may be contraindicated if a lumbar epidural abscess is suspected because of the potential of seeding the infection into the sterile CSF if the needle traverses the abscess. Therefore, it is best if the diagnosis is made on the basis of history, physical examination, and MRI. Scanning by CT or MRI may diagnose the disorder, and currently, MRI is the imaging study of choice.

TREATMENT

Surgical drainage combined with antibiotics is usually the treatment of choice. Vancomycin is a reasonable empiric choice in communities where MRSA is prevalent. There have been reports of patients treated medically alone with good results when they are a poor operative risk or have a small abscess and lack of neurologic progression. However, there can be no blanket recommendation for medical therapy alone because of the paucity of data. Oral antibiotic treatment (following parenteral) is not advised unless the infecting organism is determined either by a positive blood culture or aspirate. Generally, if an epidural or subdural collection is demonstrated, surgery should be performed immediately. Decompressive laminectomy, removal of the purulent material, and copious irrigation should be done. Antibiotic irrigation has been recommended, but systemically administered antibiotics enter the spinal epidural space easily. In general, the degree of recovery is directly related to the neurologic function at the time of surgery.

INTERVERTEBRAL DISC INFECTION

Discitis is an inflammation of the intervertebral disc or vertebral endplates. It primarily affects children, often in the first 5 years of life, but is also rarely encountered in adults. Although it is considered to be an infectious disease, cultures are often sterile.

PATHOGENESIS

In the young age group, the developing spinal disc has a rich blood supply coming from the vertebrae. It is believed that these vessels provide a pathway to the disc space during bacteremia. In adolescence and into the third decade of life, the disc becomes avascular, and infection in the disc space is secondary to osteomyelitis. Discitis usually affects the lumbar spine, particularly the L3–4 and L4–5 spaces.

Cultures from blood or disc-space material have been positive in less than 50%, leading some to postulate an inflammatory cause rather than an infectious cause in a portion of these children. When cultures are positive, S aureus is usually the cause. Less commonly, Pseudomonas aeruginosa, streptococci, and other gram-negative bacilli have been recovered. Biopsy specimens typically show acute or chronic inflammation.

CLINICAL MANIFESTATIONS

Children usually present with fever and back pain that may be localized. Children may limp or may refuse to stand or walk or may be unable to do so. Severe spinal muscle spasms may lead to splinting, giving the appearance of scoliosis or lordosis, and the physical exam may reveal localized tenderness over the spine and decreased spinal motion. A smaller group of children present with abdominal pain alone, or just irritability, and discitis has been reported to be found in children with prolonged fever of unknown origin. Vertebral osteomyelitis usually occurs in older children, who are more likely to have fever and specific complaints of pain. The differential also includes fracture, epidural abscess, spinal tumors, perinephric or renal infections, transverse myelitis, hematoma, and Guillain-Barré syndrome.

DIAGNOSIS

Discitis is most frequently diagnosed on the basis of diagnostic imaging, although there may be a lag between the radiologic findings and the onset of symptoms. The intervertebral space becomes narrowed, and there is demineralization of adjacent vertebral body margins. CT or MRI scanning is more accurate than plain radiograph in this condition, and the MRI scan usually is the test of choice. A radionuclide scan, with technetium or gallium, is usually positive. The most consistent laboratory finding is an elevation in the erythrocyte sedimentation rate. Culture of the blood may grow a pathogen, and direct aspirates from the disc or vertebral endplate may yield the infecting organism. These cultures are more likely to be positive in vertebral osteomyelitis. In the appropriate clinical setting, biopsy or disc space cultures are not mandatory.

TREATMENT

Treatment is started and usually consists of intravenous administration of antibiotics, usually with antistaphylococcal antibiotics, and immobilization by a brace or body cast. If initial antimicrobial therapy does not include activity against MRSA, failure to respond to therapy may be due to the presence of MRSA, and this would be an indication for obtaining a culture of the involved tissue. If discitis may be associated with MRSA or if MRSA is highly prevalent in the community, it may be necessary to commence empiric therapy with an agent such as vancomycin. Continuation of therapy is best guided by isolation of a pathogen from the blood or disc culture. In the absence of an isolate, there is no one accepted protocol. Four to 6 total weeks of antibiotics with a combination of 2 weeks of intravenous antibiotics followed by a month of oral antibiotics is a common regimen. Failure of the treatment plan to relieve the pain and/or fevers should prompt consideration of needle aspiration or biopsy of the disc space, if this has not already been performed. Open surgery is rarely required, and bracing usually continues until resolution of the symptoms, typically 3 to 4 months. Overall, the outcome for discitis is excellent.

SUGGESTED READINGS

INTRODUCTION

Viral infections of the central nervous system (CNS) may be variously categorized by type of onset (eg, acute, subacute, chronic, or recurrent), by the level of the CNS involved (eg, brain, brain stem, or spinal cord), and by the viral agent causing disease. The approach to diagnosis and management of CNS viral infection depends greatly on the age, immunization history, and immune status of the patient, and also the epidemiologic setting including season, location, and exposure to viruses that are circulating in the community or transmitted by arthropod vectors. Molecular testing techniques continue to evolve to improve identification of viral agents causing CNS diseases.

VIRAL MENINGITIS

ACUTE VIRAL MENINGITIS

Community-acquired viruses and arthropod-borne viruses are the major causes of the acute “aseptic meningitis” syndrome that, by definition, is accompanied by symptoms and signs of meningeal inflammation in the absence of acute bacterial or fungal meningitis. Although meningitis may occur in the course of infection with many viruses (Table 227-1), the human enteroviruses (EVs) have been shown to be responsible for the majority of cases of viral meningitis, most prominently the nonpolio EVs. Other well-known causes of viral meningitis include herpesviruses (herpes simplex virus [HSV], Epstein-Barr virus [EBV], cytomegalovirus [CMV], human herpesvirus [HHV]-6, and varicella-zoster virus [VZV]), mumps virus, lymphocytic choriomeningitis virus (LCMV), influenza virus, and the arthropod-borne viruses (including West Nile virus [WNV], St. Louis encephalitis virus, La Crosse [LAC] virus, and eastern equine encephalitis virus).

Because EVs cause more than 90% of cases, even during periods of peak arbovirus transmission, the epidemiology of viral meningitis usually reflects the trends of EV infection in the population, including seasonal peaks in late summer and fall and a strong inverse correlation between age and observed rates of disease. Overall rates of EV infection are several-fold higher for infants under 12 months of age than older children. The observed rates of meningitis among children with documented EV infection are highest under 4 months of age when approximately 50% of infants undergoing lumbar puncture in the course of an evaluation for fever will have laboratory evidence of meningitis.

Viral meningitis syndrome due to HSV occurs mainly in adolescents and young adults with primary HSV-2 genital infections, but it is also reported in young children (see Chapter 304).

Mumps virus infection, once a common cause of viral meningitis, is now primarily seen in locations where mumps virus circulation is not controlled by immunization (see Chapter 313). However, mumps meningitis has been identified along with or in the absence of clinical mumps infection in the context of outbreaks and is more likely to occur in young adults several years after vaccination. Signs of meningeal irritation occur in approximately 5% of patients identified in mumps outbreaks.

Children acquire LCMV infection from exposure to household environments contaminated by rodent urine. Common house mice are most often implicated; an estimated 5% of these rodents asymptomatically carry LCMV and can transmit the infection throughout their lifetimes. LCMV infection is more common during winter months.

CLINICAL MANIFESTATIONS

The clinical manifestations of EV meningitis vary with age. For young infants, fever and other nonspecific symptoms might be the only manifestations. Older children might first experience a brief prodrome of fever and sore throat followed by headache that is often severe. Signs of meningeal irritation are variable. Children with LCMV infection usually present with an influenza-like systemic illness in addition to headache and signs of meningeal irritation. Complications such as complex seizures, lethargy, coma, and movement disorders that are reported in 5% to 10% of patients with viral meningitis suggest a more precise diagnosis of meningoencephalitis.

DIAGNOSIS

Although the diagnosis of viral meningitis can be suspected based on clinical findings, examination of cerebrospinal fluid (CSF) is necessary when bacterial meningitis must be excluded. The CSF white blood cell (WBC) count typically ranges from 0 to 1000 WBC/mL, but levels > 1000 are also reported in proven cases of viral meningitis. There might be a predominance of neutrophils during the first 1 to 2 days of illness with an inevitable shift to a lymphocyte predominance later. In most cases, the CSF glucose concentration is normal, but values slightly lower than normal are reported in 18% to 33% of cases, and the CSF protein concentration is normal or mildly elevated. Notably, LCMV and mumps infections can be associated with low CSF glucose concentrations. A proportion of children have peripheral leukocytosis, some with a left shift. Confirmation of the diagnosis of EV infection depends on detection of virus in the CSF by polymerase chain reaction (PCR) or by virus isolation. For LCMV, diagnosis usually depends on documentation of seroconversion in paired serum samples. CSF samples from those with HSV infection might reveal lymphocytosis along with an increased number of red blood cells.

TREATMENT

Patients with viral meningitis are given analgesics for headache and are often hospitalized in order to receive intravenous antibiotics until bacterial disease can be ruled out with confidence. Identification of specific agents with available medical therapies should be treated accordingly, including use of acyclovir or valacyclovir for HSV, antiretrovirals for human immunodeficiency virus (HIV) infection, and neuraminidase inhibitors for influenza. However, most viral agents have no specific treatment. The symptoms of acute viral meningitis can be more severe and persist longer in adults compared with young children.

PROGNOSIS

Subtle disturbances of motor function such as limitation of passive motion, muscle spasms, and poor coordination might persist for weeks after resolution of the acute illness but slowly resolve. Despite concern raised by early studies, viral meningitis does not lead to long-term neurologic or cognitive sequelae.

RECURRENT ASEPTIC MENINGITIS

Recurrent aseptic meningitis (Mollaret syndrome) is a rare disease characterized by 3 or more distinct episodes of lymphocytic meningitis of 2 to 5 days in duration, each of which is separated by weeks to years. HSV-2 has been strongly associated with recurrent meningitis by identification of virus in CSF by PCR, but many patients do not have evidence of genital lesions at the time of presentation. A small number of cases are reported to be caused by HSV-1 and EBV, and many have no established etiology. Prophylactic treatment with acyclovir or another anti-HSV drug might suppress recurrent episodes.

ACUTE ENCEPHALITIS

The terms encephalitis, meningoencephalitis, and encephalomyelitis are generally used interchangeably to denote inflammation of the brain, brain stem, and/or spinal cord. The International Encephalitis Consortium defines encephalitis as altered mental status (decreased or altered level of consciousness, lethargy, or personality change) lasting ≥ 24 hours with no alternative cause identified. Additionally, patients must have at least 2 of the following: fever, seizure, focal neurologic findings, CSF pleocytosis, abnormality of brain parenchyma on neuroimaging suggestive of acute encephalitis, or abnormality on electroencephalography (EEG) that is consistent with encephalitis.

Encephalitis causes an estimated 19,000 hospitalizations a year in the United States, with a case fatality rate > 5%. It is a general presumption that most acute encephalitis cases are caused by viral infections, although active surveillance studies are able to identify a specific viral etiology for only 9% to 22% of cases, and the cause of approximately 60% of cases cannot be determined. Important nonviral causes of encephalitis include infections such as bacteria, fungus, and Mycobacterium tuberculosis. Noninfectious causes include autoimmune etiologies such as anti-N-methyl-D-aspartate receptor (NMDAR) and limbic encephalitis, which might present with more psychiatric symptoms than viral causes, but symptom overlap occurs. The list of viruses proven or suspected to cause acute encephalitis is extensive and is prominently represented by herpesviruses, EVs, flaviviruses, togaviruses, bunyaviruses, adenoviruses, mumps virus, LCMV, HIV, and rabies virus that all replicate in neural cells causing neuronal destruction and inflammation, primarily in gray matter (see Table 227-1).

The terms postinfectious encephalitis and acute demyelinating encephalomyelitis (ADEM) are interchangeably applied to acute CNS disease that rarely complicates infection with some common viruses, including measles virus, rubella virus, influenza viruses, and other respiratory viruses. Evidence for CNS viral replication is generally lacking, and immunopathologic mechanisms are considered to be responsible for the characteristic perivascular inflammation and demyelination associated with postinfectious encephalitis.

Overall, children with normal neuroimaging and higher Glasgow Coma Score on presentation have been found to be more likely to recover from acute encephalitis. Neurologic sequelae are associated with younger age at time of illness and presentation with seizure. In particular, children who present with seizures, require more antiepileptic medications for seizure control, and have an abnormal EEG are more likely to develop epilepsy following encephalitis.

HERPES SIMPLEX VIRUS ENCEPHALITIS

HSV causes only 8% to 12% of encephalitis cases of known etiology, but deserves special consideration because HSV is identified in population-based studies as the most common cause of viral encephalitis. The virus affects males and females equally, as well as people of all ages, and has no seasonal variation. Unlike other viral infections, the outcome of HSV encephalitis can be improved with prompt and safe antiviral therapy. HSV-1 and HSV-2 are closely related alpha herpesviruses that share a tropism for mucocutaneous sites and are able to establish latency in neural tissues and reactivate repeatedly, causing recurrent disease. HSV encephalitis is characterized by inflammation with perivascular lymphocytic cuffing, edema, and hemorrhagic necrosis of affected areas of the CNS.

CLINICAL MANIFESTATIONS

Neonates

In neonates, HSV encephalitis can occur as isolated CNS disease or develop in the course of disseminated HSV disease; altogether, about half of infants with neonatal HSV infection develop encephalitis. Viremia probably represents the major route of transmission to the CNS during disseminated neonatal HSV infection, resulting in diffuse, patchy CNS involvement. In contrast, transport to the brain is likely to occur via peripheral sensory neurons in neonates who present with localized CNS disease. In either case, the absence of preexisting immunity and immature T-cell responses permits a high level of virus replication and spread within the immature brain. Both HSV-1 and HSV-2 can be transmitted to the newborn in the perinatal period, but encephalitis occurs more commonly and severely with HSV-2 infection. Infants who survive infection with HSV-2 are likely to have long-term neurologic sequelae. As many as 35% of infants with HSV encephalitis have no skin findings. Overall, infants less than 4 weeks of age are at risk, although disseminated HSV infection typically begins within the first 10 days of life, and infants with disease limited to the CNS are more likely to have onset of disease in the second or third week of life. Neonates with HSV encephalitis typically present with lethargy, poor feeding, and focal and/or generalized seizures. Motor abnormalities in the form of tremors, paresis, and hypo- or hyperreflexia might be noted on exam.

Infants and Children

About one-third of HSV encephalitis cases beyond the newborn period occur in children and adolescents, with an approximate annual incidence of 2 to 4 per 1,000,000. Virtually all are a consequence of sporadic HSV-1 disease that occurs as either a primary or recurrent infection. The hallmark of HSV encephalitis is focal neurologic disease that can affect any part of the brain, brain stem, or spinal cord, but most commonly involves 1 or both temporal lobes. More than 90% of patients present with fever and altered consciousness, and more than two-thirds exhibit headache, personality change, dysphagia, and focal or generalized seizure activity. Other common early findings are memory loss, hemiparesis, ataxia, and cranial nerve palsies. Among children < 4 years of age, presenting symptoms often include febrile seizure.

DIAGNOSIS

The initial evaluation of suspected HSV encephalitis includes brain imaging, EEG, and CSF examination. Diffusion-weighted magnetic resonance imaging (MRI) is reported to be most sensitive, more than standard MRI or computed tomography (CT) for detection of focal brain lesions. The periodic lateralized epileptiform discharges (PLEDs) demonstrated by EEG represent sensitive but relatively nonspecific evidence of HSV encephalitis. At least 90% of patients at presentation will have an abnormal CSF examination with an elevated CSF WBC count and elevated protein concentration.

Confirmation of HSV encephalitis depends on detection of HSV virus in CSF or CNS tissue. PCR detection of viral DNA in CSF is highly sensitive and specific when compared with virus isolation from brain biopsy specimens. Viral culture of the CSF has low sensitivity (< 10%) for HSV, whereas PCR testing is reported to have ≥ 94% sensitivity and ≥ 98% specificity. PCR can be positive as early as 24 hours after symptom onset; however, testing early in the course of HSV encephalitis might produce a false-negative PCR. Repeat testing in cases with an initial false-negative PCR will often reveal a positive PCR by day 4 or later after symptom onset. Despite treatment, HSV DNA has been shown to persist in CSF in virtually all patients who have repeat lumbar punctures up to 7 days after symptom onset. Infectious virus can also be isolated when brain biopsy is performed 4 or more days after the start of antiviral therapy.

TREATMENT

Untreated HSV encephalitis is fatal in more than two-thirds of cases, and only about 10% of survivors recover with normal neurologic function. Intravenous acyclovir given at a dose of 10 mg/kg every 8 hours for 10 days reduces mortality and improves the prognosis for survivors. A higher acyclovir dose of 20 mg/kg every 8 hours for 21 days improves survival for neonates and reduces the risk of poor neurologic outcomes. For those with CNS disease, CSF should again be tested for DNA by PCR near the completion of the parenteral acyclovir course, and if DNA remains present, parenteral acyclovir should be continued for another week, with repeat of this weekly process until DNA is not detected. Continued oral treatment with acyclovir for 6 months following completion of parenteral therapy can improve neurodevelopmental outcomes in those with CNS disease and is recommended for all neonates with HSV disease (CNS or other type). See also the chapter on therapy for perinatal and neonatal infections (Chapter 225).

PROGNOSIS

Delayed initiation of therapy has been associated with poorer outcomes in children. Despite treatment, > 60% of children have neurologic sequelae, particularly seizures or developmental delays. Relapse of CNS disease with recurrent fever, focal neurologic symptoms, and CSF pleocytosis is reported in 10% to 25% of patients with acute HSV encephalitis. Relapse occurs within days to months of discontinuation of antiviral therapy and is associated with similar signs and symptoms compared with the initial episode. Although HSV can be recovered from some cases of recurrent disease, the inability to demonstrate the presence of HSV by virus isolation or PCR in many others suggests a second mechanism that may be immunologically mediated. Relapse with HSV should be distinguished from autoimmune encephalitis since anti-NMDAR encephalitis can be triggered by HSV encephalitis, presumably by triggering an antineuronal autoimmune response.

ENCEPHALITIS CAUSED BY OTHER HERPESVIRUSES

Although HSV is the most common herpes viral agent to cause encephalitis, other herpesviruses have been implicated. Epstein-Barr virus is an important cause of encephalitis, especially among adolescents. Both HHV-6 and HHV-7 have been shown to cause encephalitis in children, although the majority of cases occur among younger or immunocompromised children. Varicella-zoster virus is more likely to cause encephalitis in adults, although cases in children typically present either concurrently with varicella disease or in a postinfectious form. Cytomegalovirus has also been reported to cause encephalitis, particularly in severely immunocompromised children.

ENTEROVIRUS AND PARECHOVIRUS ENCEPHALITIS

Encephalitis is a rare complication of EV infection, but because these infections are ubiquitous, they are a leading cause of encephalitis in children and are responsible for 10% to 15% of encephalitis cases for which an etiology is identified. Children with EV encephalitis tend to be younger and might have a less severe clinical presentation than children with encephalitis caused by other viruses. Additionally, human parechoviruses (HPeV) are an important cause of encephalitis in children younger than 2 years. At least 16 HPeV serotypes have been described to date; many have been associated with encephalitis. For diagnostic workup of suspected EV/HPeV encephalitis, molecular testing of CSF is important. It is important to also test for EV/HPeV in non-CNS sites (throat, stool, and serum) to increase the likelihood of detection.

ARTHROPOD-BORNE ENCEPHALITIS

Several viruses cause acute encephalitis in humans and other mammals following the bite of an infected mosquito or tick, including certain flaviviruses, togaviruses, and bunyaviruses. These taxonomically distinct viruses are often collectively referred to as “arboviruses” due to the common requirement for an arthropod vector, and all exist within diverse ecologic systems that include animal reservoirs in nature. More than 20 arboviruses cause acute encephalitis worldwide; among the most prevalent are Japanese encephalitis virus, responsible for widespread disease throughout East and Southeast Asia, and WNV, the predominant cause of arthropod-borne encephalitis in North America during the past decade. In general, serologic testing with acute and convalescent titers is preferable to molecular testing for arboviruses because viremia precedes symptoms. Molecular testing following symptom onset is often insensitive and fails to detect virus.

JAPANESE ENCEPHALITIS VIRUS

Japanese encephalitis virus, a flavivirus, is the leading cause of vaccine-preventable encephalitis in Asia and the Western Pacific and is responsible for thousands of human encephalitis cases in the region. Culex mosquitoes breed in marshy environments including rice patties, leading to human transmission that primarily occurs in agricultural areas. The ratio of symptomatic to asymptomatic infections is approximately 1:250, and most illness is mild and self-limited. Cases can occur among susceptible people of any age, but in endemic areas, encephalitis primarily occurs among children younger than 15 years. Individuals who develop encephalitis have an estimated mortality of 25%, and 30% to 50% will experience significant neurologic and cognitive sequelae. The spectrum of CNS manifestations includes meningismus, altered consciousness, seizures, extrapyramidal signs, and acute motor neuron disease.

The laboratory diagnosis of Japanese encephalitis virus infection is based on demonstration of specific antibodies in the CSF or serum, which can usually be detected by 4 to 7 days after onset of symptoms. There is no available specific antiviral therapy.

Although the risk of Japanese encephalitis is low for most travelers to endemic areas, immunization is recommended when there is a high risk of exposure, such as travel to rural areas during the rainy season when mosquito activity is high. Vaccines are available in the United States and are approved for children 2 months and older prior to high-risk travel.

WEST NILE VIRUS

WNV is a member of the same flavivirus complex as Japanese encephalitis virus and St. Louis encephalitis virus. Human infections with WNV occur widely in Africa, Europe, South Asia, and Australia, but were unknown in the Americas until 1999 when an outbreak occurred in the New York City metropolitan area caused by a virus with close genetic identity to WNV circulating in Israel and elsewhere in the Middle East. The virus has since spread across the North American continent, causing hundreds to thousands of cases each year. In most locations, human disease coincides with a summer–fall sylvatic cycle that includes viral amplification in birds and transmission via multiple mosquito species. Person-to-person spread might occur via transfusion of blood and blood products, organ transplantation, or rarely from mother to baby during pregnancy, delivery, or while breastfeeding.

Seventy to 80% of people infected by WNV have no symptoms. Approximately 20% of infected persons develop illness that in the majority of patients is limited to fever, malaise, arthralgias, and rash that last for 3 to 10 days. Neurologic disease occurs in a smaller proportion of laboratory-confirmed infections (< 1%) but in a higher percentage of reported cases due to the propensity to test and report cases with serious disease. Overall case fatality rate is 10% for individuals with neurologic disease, although many more deaths occur among individuals with encephalitis compared to meningitis. Children are at lower risk of developing CNS disease than adults, and risk is increased among persons with chronic disease and immunodeficiency, including patients with solid organ transplants and hematologic malignancies. WNV encephalitis can coincide with a number of manifestations indicating different levels of CNS involvement, including seizures, movement disorders (tremor, myoclonus, parkinsonism), cerebellar ataxia, acute motor neuron disease, optic neuritis, chorioretinitis, cranial nerve palsy, radiculopathy, Guillain-Barré syndrome, and demyelinating peripheral neuropathy.

A specific laboratory diagnosis depends on demonstration of WNV IgM antibodies detectable 3 to 8 days after onset, which can persist for several weeks or even months after exposure. Plaque-reduction neutralization tests can help differentiate between flaviviruses and can confirm acute infection when a ≥ 4-fold increase is noted between acute and convalescent samples. Viral RNA can be identified in serum or CSF early in the course of disease but should not be used as the sole test due to insensitivity. There are no specific antiviral therapies for WNV infection, and no vaccine is yet available. Full recovery from WNV neuroinvasive disease occurs in less than half of survivors. Long-term sequelae include fatigue, dizziness, alterations in cognition, inability to concentrate, and residual muscle weakness.

OTHER NORTH AMERICAN ARTHROPOD-BORNE VIRUS DISEASES

La Crosse virus (LAC), eastern equine encephalitis (EEE) virus, western equine encephalitis (WEE) virus, and St. Louis encephalitis (SLE) virus are mosquito-borne viruses that are also important causes of CNS infection. Each of these viruses has a distinct sylvatic cycle, geographic distribution, and spectrum of disease. Each is associated with a high ratio of subclinical infections compared with clinical disease. LAC, EEE, and WEE have higher clinical attack rates among children, and SLE virus, like its close relative WNV, is more often observed in adults.

LAC is the second most common cause of arboviral infections in the United States (after WNV) and the most common cause of neuroinvasive arboviral disease in children. The LAC virus is a bunyavirus transmitted from small mammals by mosquitoes and is endemic in Midwest states. LAC causes approximately 75 cases of encephalitis per year in the United States. In contrast, EEE and WEE viruses are members of the Alphavirus genus (family: Togaviridae) that cause sporadic and unpredictable regional outbreaks of human encephalitis when conditions are optimal for breeding of mosquitoes that maintain these viruses in a natural cycle that includes migratory birds. Compared with other causes of arthropod-borne encephalitis, disease due to LAC virus is relatively mild, and most children recover from infection with minimal or no neurologic sequelae. Disease caused by EEE or WEE viruses is more severe in children, with high rates of death and disability among survivors. EEE has the highest case fatality rate of up to 35%. As of this printing, no human cases of WEE have been reported to the Centers for Disease Control and Prevention (CDC) since 1994.

Virus-specific IgM antibody is present in the serum and CSF at the time of presentation for most arthropod-borne virus encephalitis cases. Serologic testing for regionally prevalent arthropod-borne virus diseases is generally available in state and some local public health laboratories in the United States and Canada. Treatment is limited to supportive measures because no antiviral therapy is available.

OTHER VIRAL CAUSES OF ENCEPHALITIS

Less frequent, but important, viral causes of encephalitis include rabies virus and LCMV.

RABIES

Although rare in the United States, rabies should always be considered in patients with rapidly progressive encephalitis. Rabies is a lyssavirus that spreads from infected animals primarily through bites. Only 1 or 2 cases are generally seen in the United States annually, but worldwide, there are approximately 24,000 to 60,000 deaths each year, with the majority of deaths occurring in Africa and Asia. Paresthesia at the site of a bite is a distinctive feature of rabies and is a relatively common finding, but not uniformly described. Most patients with rabies present with agitation, hydrophobia, delirium, and seizures (“furious form”). A minority of patients present with ascending paralysis, followed by confusion and then coma (“paralytic form”). Fatality is generally 100%, with only a handful of survivors.

LYMPHOCYTIC CHORIOMENINGITIS VIRUS

LCMV is an arenavirus that is acquired from infected house mice, guinea pigs, and hamsters. Humans become infected when saliva, urine, or feces from LCMV-infected rodents is ingested or inhaled. The incidence of LCMV is unknown, but it is likely that infection goes undiagnosed in many instances. Infections occur more frequently in winter months, when rodents are more likely to migrate indoors. Emerging zoonotic viruses associated with encephalitis include Nipah virus, Hendra virus, and Bornavirus.

POSTINFECTIOUS ENCEPHALITIS

Postinfectious encephalitis, or ADEM, is an acute, inflammatory brain disease that is associated with an antecedent or concomitant (often viral) infection. It has also been observed following administration of several vaccines, including smallpox, measles, diphtheria-tetanus-polio, and Japanese B encephalitis. The pathologic features of postinfectious encephalitis are accurately replicated in the experimental allergic encephalomyelitis animal model in which an immune-mediated reaction against myelin protein can be demonstrated. Antimyelin basic protein antibodies can be demonstrated in some patients with postinfectious encephalitis, but evidence of viral replication within the CNS is virtually never demonstrated.

Postinfectious encephalitis is estimated to represent about 10% to 15% of acute encephalitis cases in the United States. Disease is much more common in children than adults, and there is a slightly higher burden of cases in males and during the winter and spring seasons. The current incidence is probably lower than in the past when smallpox vaccines were universally administered. Abrupt onset of fever, altered mental status, seizures, or focal neurologic signs may occur before, during, or, more commonly, within 3 weeks after a respiratory, gastrointestinal, or rash illness, although preceding illness is only reported in about two-thirds of children. The inflammatory changes in the CSF do not distinguish postinfectious encephalitis from other causes of acute encephalitis, but contrast-enhanced MRI examination often reveals characteristic abnormalities on T2 and fluid-attenuated inversion recovery (FLAIR) images in white matter, cerebellum, basal ganglia, and brain stem. Treatments typically include corticosteroids as first-line treatment, with intravenous immunoglobulin or plasma exchange for those who do not respond to corticosteroids. However, the natural course of postinfectious encephalitis is spontaneous resolution, so it is difficult to be certain of the benefits of these treatments. Recovery may be very slow, however. Patients who develop recurrent episodes might ultimately receive a diagnosis of multiple sclerosis.

ACUTE HEMORRHAGIC LEUKOENCEPHALITIS

Acute hemorrhagic leukoencephalitis is a rare form of acute encephalitis of unknown etiology characterized by abrupt onset, a rapid course, and often a fatal outcome. The pathologic changes reflect those of postinfectious encephalitis with edema, demyelination, and perivascular inflammation but also include extensive hemorrhagic lesions within white matter. Compared with postinfectious encephalitis, the CSF findings in acute hemorrhagic encephalitis include elevated opening pressure, relatively high WBC count, predominance of polymorphic leukocytes, and the characteristic presence of red blood cells. Because patients with acute hemorrhagic encephalitis are usually treated with high-dose steroid therapy based on anecdotal experience, it is important to rule out HSV encephalitis that has many similar clinical features.

ACUTE CEREBELLAR ATAXIA

Acute cerebellar ataxia is a common, distinct clinical entity of young children usually caused by acute cerebellitis without evidence of other serious CNS disease. Both direct infection and postinfectious, immunopathologic mechanisms are postulated to occur. Patients typically report recent viral illness. Reported coincident infections include VZV, EV, measles, mumps, rubella, parvovirus, mycoplasma, and EBV. It is also described following vaccinations.

The typical patient is a toddler or young child who develops a truncal ataxia and a wobbly gait 5 to 10 days after onset of the inciting infectious episode, which may have resolved. More severe cases might be accompanied by nausea, vomiting, nystagmus, dysarthria, or dysmetria, but fever and other signs of CNS disease are rare. Disability is often maximal at onset. Even though symptoms resolve slowly over days to weeks, most children recover completely without residual deficits. The most important task of the pediatrician is to rule out a more serious cause for ataxia.

BRAIN STEM ENCEPHALITIS

Enterovirus 71 possesses a unique ability to invade the cerebellum, ventral brain stem, and spinal cord, producing a spectrum of serious neuromotor syndromes including acute flaccid paralysis of 1 or more extremities, cranial nerve paresis, tremors, myoclonus, or ataxia. The majority of cases occur among infants and young children, particularly during outbreaks in Southeast Asia; many children demonstrate rash consistent with hand, foot, and mouth disease prior to the onset of neurologic disease. Although many children recover without deficits, a subset of children develop a devastating, often fatal syndrome of acute neurogenic pulmonary edema and hemorrhage that may result from destruction of medullary vasomotor and respiratory centers. There is some evidence that treatment of pulmonary edema with milrinone improves mortality. Pulmonary hemorrhage often develops rapidly, with most fatalities occurring within 24 hours of admission.

MYELITIS

Acute viral infection of the spinal cord occurs in 2 different forms: segmental (or “transverse”) myelitis of a section of the cord producing motor and sensory dysfunction at a level below the involved segment; and disease limited to gray matter producing acute motor neuron disease.

Acute transverse myelitis (ATM) is a focal inflammatory disorder of the spinal cord, resulting in motor, sensory, and autonomic dysfunction. It occurs at any age, and approximately 20% of cases in the United States occur during childhood. Most children report mild illness during the few weeks prior to neurologic symptoms. Initially, many children report pain later followed by lower extremity weakness (often bilateral), loss of sensation below the level of the lesion, and loss of bladder and bowel control. Transverse myelitis most frequently occurs in the thoracic spinal cord and involves the entire width of the cord within a limited number of segments. Pediatric cases are most often associated with herpesvirus infection, although evidence for infection with other viruses has been presented, and some cases might be caused by immunopathologic mechanisms. Direct infection with HSV1, HSV2, VZV, CMV, and EBV has been demonstrated by detection of virus in CSF by virus isolation or by PCR. HSV is the most common cause of acute transverse myelitis in children, and VZV myelitis is more common in patients who are immunosuppressed. CSF pleocytosis is present in most cases. The presence of oligoclonal immunoglobulin bands on CSF protein electrophoresis in a minority of patients might suggest a diagnosis of multiple sclerosis. Contrast-enhanced MRI is a sensitive and specific technique for demonstrating the inflammatory changes and swelling of the involved cord segments. Anti-herpesvirus drugs and steroids are often administered without clear evidence of benefit or harm. Recovery is slow and often incomplete. Only 30% to 50% of children make a full recovery, while many children experience some permanent disability.

The prototype of acute motor neuron disease is poliomyelitis caused by 1 of 3 poliovirus serotypes. However, other viruses cause acute paralysis by the same pathophysiologic mechanism, including other EVs and flaviviruses. HHV-7 has been detected in immunocompromised individuals, and recent evidence has associated several EVs, including EV71 and EV68, with acute flaccid myelitis. Acute myelitis has also been observed to occur in association with infections due to hepatitis A virus, hepatitis B virus, LCMV, measles virus, mumps virus, rubella virus, and adenovirus. Illness in children often follows a biphasic course over 5 to 12 days with initial nonspecific symptoms including fever, headache, and (for EVs) sore throat followed by a brief period of improvement. The second phase is heralded by onset of intense myalgia, headache, and meningismus, followed by motor weakness that progresses over 1 to 3 days. Paresis ranges from mild weakness to complete flaccid paralysis and characteristically involves 1 or more extremities in an asymmetric manner. Deep tendon reflexes are diminished in the affected extremities, but sensation remains intact. Lumbar puncture reveals a moderate CSF pleocytosis. MRI of the spinal cord demonstrates evidence of acute inflammation in the anterior horns, especially in the regions innervating the arms and legs. Acute motor neuron disease must be differentiated from Guillain-Barré syndrome, which causes symmetrical paralysis and sensory abnormalities in the absence of fever and meningitis.

Most recently, cases of a polio-like syndrome were described in California and then later in other areas of the United States. Many of the affected individuals were children with fever and respiratory or gastrointestinal symptoms prior to onset of neurologic symptoms. Patients had radiologic and neurophysiologic findings of acute motor neuron involvement. This illness is called acute flaccid myelitis (AFM). Preliminary data suggest that at least some of the cases might be associated with EVD68. This apparent increase in AFM cases coincided with a nationwide outbreak of EVD68 respiratory illness.

SUGGESTED READINGS

INTRODUCTION

Sexual activity is common among adolescents. A large ongoing national survey of US high school students reported that 24% of adolescents have had sexual intercourse by ninth grade and 58.1% by 12th grade, based on data collected in 2014 to 2015. Although rates of sexual activity have slowly decreased during 1991 to 2015, the adolescent age group continues to be at the highest risk for common sexually transmitted infections (STIs) compared to other age groups.

This chapter provides an overview of STIs including the common clinical presentations, screening guidelines, and treatment for bacterial, fungal, protozoal, and viral infections. For the most up-to-date clinical guidelines on treatment regimens, readers are strongly advised to refer to the Centers for Disease Control and Prevention (CDC) web site since the optimal treatment regimens are frequently updated based on antibiotic resistance patterns and logistical availability of specific medications in the United States. Table 228-1 summarizes the major points about chlamydia, gonorrhea, human papillomavirus (HPV), Trichomonas, and Candida. Detailed discussions of syphilis, human immunodeficiency virus (HIV), and herpes simplex virus (HSV) infections are found in Chapters 283, 310, and 304, respectively.

EPIDEMIOLOGY

Adolescents and young adults 15 to 24 years of age represent one-quarter of the sexually active population, but they acquire nearly half of the 20 million new STIs each year in the United States. These STIs place our youth at risk for substantial morbidity and mortality, including pelvic inflammatory disease (PID) and its associated sequelae of ectopic pregnancy, infertility, and chronic pelvic pain; HPV-associated genital dysplasia; and HIV-associated immunosuppression and life-threatening complications.

Annual epidemiologic data are published by the CDC, based on state and local STI case reports made from private and public sources. Chlamydia, gonorrhea, and syphilis are reportable infections, whereas other STIs such as HPV, HSV, and Trichomonas are not routinely reported to the public health authorities. In 2014, among women, the highest reported rates of chlamydia infection were found in those age 15 to 24 years (3309.4 cases per 100,000 females), compared to other age groups. The gonorrhea rate is similarly highest in women age 15 to 24 years (484 cases per 100,000 females), and the syphilis rate is highest in women age 20 to 24 years (4.5 cases per 100,000 females). HPV is not a reportable infection, but data from large surveillance studies show that 34% of women age 14 to 24 years have genital HPV, which is roughly 7.5 million females with HPV. Among the men, the highest chlamydia and gonorrhea rates are in those age 20 to 24 years (1368.3 cases per 100,000 males and 485.6 cases per 100,000 males, respectively). Syphilis rates are highest in men age 25 to 29 years (34 cases per 100,000 males), although syphilis rates in men age 20 to 24 years are similarly concerning (31.1 cases per 100,000 males).

The higher STI rates observed in adolescents and young adults are associated with several risk factors. For example, gender is an important factor, as STIs are disproportionately more common among females compared to males, as evidenced from the gender-specific rates discussed above. Among adolescents, those with higher rates of STIs report a younger age of their first sexual encounter, have multiple concurrent sex partners, multiple sequential sex partners, inconsistent use of condoms, or use of injection drugs. Higher risk is also found in certain populations, such as young men who have sex with men (MSM), adolescents evaluated in STI clinics and some adolescent clinics, and those in detention facilities. Race and ethnicity are another important factor to consider for all age groups overall, given the correlation of race and ethnicity to other critical determinants of health, including socioeconomic status, differential educational attainment, and access to quality health care. One challenge in data collection is the missing data on race and ethnicity, since many case reports to public health are submitted without the race and ethnicity information, but population-based studies and national surveys provide clearly confirmatory evidence of the substantial burden of STIs on certain racial and ethnic groups. In 2014, the CDC reported that the overall ratios of chlamydia for African American, Native American, Native Hawaiian/Pacific Islanders, Hispanic, and whites were 6:4:6:2:1. The ratios for gonorrhea were 11:4:3:2:1, and the ratios for primary and secondary syphilis were 5:2:2:2:1. In considering the substantial risk associated with race and ethnicity, it is important to recognize that individuals who reside in geographic areas of high STI prevalence face a greater challenge to reduce their own personal risk for STI exposure. Public health interventions must address not only individual-level risk factors but also community-level risk factors involving social and cultural conditions that impact STI risk.

SCREENING RECOMMENDATIONS

The overall screening recommendations for adolescents and young adults are listed below:

• Sexually active females age < 25 years: Routine annual screening for chlamydia and gonorrhea is recommended, and HIV screening should be offered. The frequency of HIV screening should be based on risk factors. Cervical cancer screening by cervical cytology is recommended to start at age 21 years. Routine screening for other infections (syphilis, HSV, trichomonas, bacterial vaginosis) is not generally recommended in asymptomatic females.

• Sexually active males age < 25 years: Evidence is not sufficient for a broad recommendation for routine screening for all males for chlamydia and gonorrhea, but screening for chlamydia and gonorrhea in high-prevalence settings or men with risk factors should be strongly considered. HIV screening should be offered. The frequency of HIV screening should be based on risk factors.

• Men who have sex with men (MSM): Routine annual screening for HIV and syphilis serology is recommended. For MSM who have had insertive anal intercourse in the preceding year, routine annual screening for urethral chlamydia and gonorrhea is recommended. For MSM who have had receptive anal intercourse in the preceding year, routine annual screening for rectal chlamydia and gonorrhea is recommended. For MSM who have had receptive oral intercourse in the preceding year, routine annual screening for pharyngeal gonorrhea is recommended.

BACTERIAL INFECTIONS

CHLAMYDIA

Chlamydia trachomatis is the most common reported bacterial STI in the United States. Chlamydiae are obligate intracellular bacteria, and disease appears to result from both the destruction of cells during the growth cycle and the body’s immune response to the infection producing inflammation.

CLINICAL MANIFESTATIONS

Uncomplicated endocervicitis is the most common clinical manifestation of chlamydial infection in sexually active female adolescents. However, the majority of chlamydial lower genital infections in women are asymptomatic, thus underscoring the importance of routine screening. When symptomatic, clinical findings may include abnormal vaginal discharge or bleeding, especially after intercourse. Another possible finding is mucopurulent cervicitis (MPC), which presents with a yellow endocervical discharge or by identification of increased polymorphonuclear cells on a Gram stain from the discharge (> 10–30 white blood cells per high-power field). However, MPC is not a sensitive diagnostic indicator of infection because most infected women do not have MPC. The most serious complication of endocervical infection is PID, including a subclinical upper tract infection that can lead to infertility. Routine annual screening for chlamydia has been shown to decrease PID rates in female populations. Patients with multiple risk factors or concern for possible exposures may warrant more frequent screening.

Urethritis is the most common clinical manifestation of chlamydial infection in sexually active male adolescents and occurs commonly in women as well. In men, chlamydia is the most common cause of nongonococcal urethritis (NGU), responsible for 15% to 40% of cases. Chlamydial urethritis is typically identified through testing of symptomatic men (presenting with discharge and dysuria), contact tracing from a chlamydia-positive partner, or routine screening of asymptomatic men. Additionally, 20% to 50% of those with gonococcal urethritis are co-infected with chlamydia.

Extragenital sites represent another clinical presentation, especially in MSM, and most are asymptomatic. In a 2003 study of 6434 MSM seen at an STI clinic, chlamydia prevalence was 7.9% rectal, 5.2% urethral, and 1.4% pharyngeal.

DIAGNOSIS

Diagnosis of chlamydia by direct detection is recommended using US Food and Drug Administration (FDA)–approved nucleic acid amplification tests (NAATs) for both women and men, with or without symptoms. NAATs have demonstrated superior sensitivity and specificity compared to other testing technologies; thus, the older approaches including culture, enzyme immunoassays, nucleic acid probe tests, genetic transformation tests, and serology are not recommended. The exception is the preferred use of culture in cases of suspected sexual abuse in younger children because of the high specificity of culture. Clinicians are advised to refer cases of suspected sexual abuse to centers that are equipped to address the complex medicolegal aspects of these scenarios.

For women, NAATs are available for vaginal, cervical, and urine specimens, with the vagina being the preferred site of collection. Self-collected and clinician-collected vaginal swabs are equivalent in assay performance, and many adolescent women appreciate the convenient option of a self-collected vaginal swab when a pelvic exam is not otherwise indicated, for example in asymptomatic women. In the setting of a pelvic exam, vaginal specimens are still appropriate, but cervical samples are also acceptable. Although a first-catch urine specimen is acceptable in women, urine is less preferred due to lower sensitivity compared to vaginal and cervical specimens.

For men, the preferred detection method is the NAATs using the first-catch urine specimen, which demonstrate equivalent performance to urethral swabs and much higher acceptability from the patient perspective. For MSM, the CDC recommends routine annual screening of extragenital sites (rectal and/or oropharyngeal as indicated by the patient’s history of sexual behaviors) using NAATs, due to superior sensitivity and specificity compared to culture. Since NAATS are not FDA-approved for extragenital sites, rectal and oropharyngeal NAAT testing must be performed by laboratories that meet Clinical Laboratory Improvement Amendments (CLIAs) regulations for assay performance specifications.

TREATMENT

The recommended and alternative treatment regimens are found in Table 228-1. The goals of prompt treatment are to relieve symptoms and to prevent reproductive sequelae and further transmission to partners and neonates. Single-dose azithromycin offers the opportunity for direct administration and observation by clinical staff to ensure adherence. Patient counseling should include advice to abstain from sexual activity for at least 7 days after the single-dose azithromycin or until the other options of 7-day antibiotic courses are completed. Patients should further abstain until all sexual partners are treated. All partners in the past 60 days should ideally receive presumptive treatment and a full STI evaluation. If the patient reports no partners in the past 60 days, then the most recent partner beyond the 60 days should be offered treatment and services. If partners might not be able to access care, expedited partner treatment (EPT) should be offered as an alternative where allowed by state laws. EPT consists of prescription of antibiotic treatment and written counseling, which are delivered by the infected patient to the partner(s). EPT has been shown to decrease rates of recurrent or persistent chlamydia and is endorsed by several national medical societies and public health organizations. Of note, EPT is not ideal for MSM infected with chlamydia because of concern for co-existing STIs in the partners and thus the need for full evaluation in person. All patients diagnosed with chlamydia should also be offered testing for other STIs if not already performed and counseled about consistent condom use for STI prevention. Test-of-cure within a few weeks after treatment is not routinely recommended except in cases of questionable adherence to treatment, persistent symptoms, or repeat exposure to chlamydia. However, it is important to note that a positive result from an NAAT can persist up to 3 weeks after successful treatment due to nonviable chlamydia organisms that cause false-positive results. Rather than conducting routine tests-of-cure, retesting at 3 months after treatment is advised in order to detect reinfection from repeated exposure to an infected partner.

GONORRHEA

Neisseria gonorrhoeae is the second most commonly reported bacterial STI in the United States. N gonorrhoeae is a gram-negative bacterium that has the unique genetic ability to change the antigenic expression of its surface-exposed proteins, making development of a vaccine challenging. Gonorrhea prevalence varies by geographic communities, and clinicians are encouraged to be familiar with public health recommendations for screening in their areas. Additional discussion of N gonorrhoeae can be found in Chapter 269.

CLINICAL MANIFESTATIONS

The majority of gonorrhea infections in men and women are asymptomatic and found on routine screening. Endocervicitis is the most common clinical manifestation of gonorrhea in women, as most gonococcal infections in women affect the lower genital tract with a particular predilection for the columnar cells of the endocervix. When symptomatic, gonorrhea in women leads to vaginal discharge, bleeding, pelvic discomfort, and/or PID. Urethritis is another clinical presentation in women but is often associated with endocervicitis. In men, urethritis is the most common clinical manifestation of gonorrhea. Symptomatic men report dysuria and/or discharge, appearing as soon as 2 to 4 days after urethral exposure. The discharge may be scant, or mucus may be present as a profuse purulent discharge. Approximately 10% of cases progress to acute epididymitis and urethral strictures. Additionally, 5% to 30% of men and 25% to 50% of women with N gonorrhoeae infection have concurrent C trachomatis infection.

Of particular note is the serious condition of disseminated gonococcal infection (DGI), a bloodborne infection that has been classically described as a triad of petechial or pustular skin lesions, polyarthralgia, and tenosynovitis but may also manifest as septic arthritis alone (culture-positive joint fluid in approximately 50% of cases only), which occurs in 2% to 5% of gonorrhea-infected individuals, or involvement of joint and skin alone, known as the arthritis-dermatitis syndrome. Complications of DGI include meningitis and endocarditis, which are very rare. DGI is more common in African Americans than in other race/ethnicity groups. When considering the typical STI risk factors during an evaluation for gonorrhea, clinicians should also inquire about travel history and patients’ sexual exposures outside the United States, given the antimicrobial resistance patterns observed across international geographic regions for gonorrhea in particular.

DIAGNOSIS

Direct diagnosis of gonorrhea by NAATs is the preferred method because NAAT sensitivity is superior to culture but varies by the type of NAAT. FDA-approved NAATs are available for vaginal, endocervical, and urine testing for women, and urine and urethral testing for men. Similar to chlamydia, the vaginal site is recommended for gonorrhea screening for women and the urine for men. As noted, NAATs are not FDA-approved for rectal and oropharyngeal sites but can be used by laboratories that meet CLIA regulations for assay performance specifications. However, culture retains an important role in gonorrhea management due to antimicrobial resistance issues. The US Gonococcal Isolate Surveillance Project (GISP) is a national sentinel surveillance system in place since 1986. Fluoroquinolone-resistant gonorrhea became apparent in 2007, and ongoing concerns for cephalosporin resistance are being monitored in several countries. When treatment failure is suspected, it becomes essential to perform culture and antimicrobial susceptibility testing. Furthermore, similar to chlamydia, culture is preferred in cases of suspected sexual abuse in younger children. Any gonorrhea isolates should be retained for additional testing.

Another diagnostic tool for use only in symptomatic men is the Gram stain of urethral secretions, which is considered diagnostic when polymorphonuclear leukocytes with intracellular gram-negative diplococci are observed. Gram stain is not recommended in asymptomatic men or for endocervical, pharyngeal, or rectal specimens because of low sensitivity in these scenarios.

TREATMENT

The recommended and alternative treatment regimens for uncomplicated gonorrhea of the cervix, urethra, rectum, and pharynx are found in Table 228-1. After fluoroquinolone-resistant gonorrhea emerged in 2007, cephalosporins became the only antibiotics sufficiently effective for gonorrhea treatment. Current guidelines recommend dual therapy using a cephalosporin plus either azithromycin or doxycycline for gonorrhea treatment, regardless of chlamydia test results. Furthermore, rising resistance to cefixime and other oral cephalosporins in several countries as well as concerns about tetracycline resistance have led to the preferred recommended regimen of ceftriaxone and azithromycin as dual treatment administered simultaneously and with direct observation by clinical staff. Of note, the older regimen of azithromycin 2 g orally as monotherapy is no longer recommended in light of concerns for macrolide resistance. In situations of azithromycin allergy, doxycycline may serve as an alternative second antibiotic agent in place of azithromycin. For patients with persistent symptoms 3 to 5 days after treatment, treatment failure should be suspected, and the clinician should perform culture and antimicrobial susceptibility testing, report the case to public health, and work with the CDC to provide isolates for further testing.

The treatment of DGI is not as well-established as is the treatment of uncomplicated cases. The CDC has made recommendations for treatment of DGI cases involving arthritis, arthritis-dermatitis syndrome, meningitis, and endocarditis, as listed in Table 228-1. However, the CDC concurrently advises consultation with an infectious disease specialist and/or the CDC to discuss individual cases, as the optimal treatment regimen for an individual patient may vary. The antibiotic selection and duration of treatment in a particular case are influenced by the specific clinical presentation, antimicrobial susceptibility results, and clinical response to treatment.

Similar to the management of chlamydia, gonorrhea-infected patients should receive counseling about partner treatment, EPT if indicated (cefixime 400 mg and azithromycin 1 g), abstaining from sex until all partners are treated, consistent condom use for future STI prevention, testing for other STIs, and retesting in 3 months to monitor for reinfection.

Treatment for DGI requires hospitalization for parenteral therapy and further evaluation for possible meningitis or endocarditis.

PROTOZOAN AND FUNGAL INFECTIONS

TRICHOMONAS

Trichomonas is the most common nonviral STI in the United States (Fig. 228-1). These organisms are sexually transmitted flagellated protozoans that attach to epithelial cells and can survive for up to 1.5 hours on a wet sponge and 24 hours on a wet cloth. Trichomonas is not reportable to public health authorities, but a US national survey reported an overall prevalence of 3.1%, with the highest prevalence of 13.3% found in non-Hispanic African American women. Similar to other STIs, higher prevalence is observed in populations such as patients with multiple partners, inconsistent condom use, racial/ethnic minorities, those seen in STI clinics, and those in detention facilities, but it is notable that the epidemiology of Trichomonas differs from chlamydia and gonorrhea in that older women also bear the burden of higher prevalence, and lower prevalence is found in MSM.

CLINICAL MANIFESTATIONS

The majority of infected patients are asymptomatic or have minimal symptoms. Untreated infections can persist for months to years. In women, Trichomonas can cause vaginitis, cervicitis, and urethritis. Symptoms include pruritus, vaginal discharge, dyspareunia, postcoital bleeding, lower abdominal pain, dysuria, and frequency. The vulva may appear erythematous, and the vaginal walls may appear granular. The “classical” frothy yellow-green vaginal discharge occurs in only 12% and can be found with other infections. The “strawberry cervix” consisting of punctate hemorrhages on the ectocervix occurs in only 2% and is not pathognomonic for Trichomonas cervicitis. Important implications of Trichomonas infection include the 2- to 3-fold increased risk for HIV acquisition and adverse pregnancy outcomes (eg, preterm birth). In HIV-infected women, Trichomonas carries a higher risk for PID, and thus annual screening is advised in this population. In men, the infection is usually self-limited, and most men are asymptomatic or present with features of nongonococcal urethritis. Infrequently, epididymitis or proctitis may develop.

DIAGNOSIS

In the last several years, new diagnostic assays for Trichomonas have become available. Currently, the most sensitive tests are the FDA-approved NAATs. The APTIMA NAAT (Hologic Gen-Probe, San Diego, CA) can be used for vaginal, endocervical, or urine specimens from women, with both sensitivity and specificity of 95% to 100%. Laboratories fulfilling CLIA regulations can use APTIMA for urine or urethral specimens from men. The BD Probe Tec Q^x Amplified DNA Assay (Becton Dickinson, Franklin Lakes, NJ) is another NAAT available for vaginal, endocervical, or urine specimens from women. Point-of-care assays are also available and FDA-approved for women only. The OSOM Rapid Test (Sekisui Diagnostic, Framingham, MA) is an immunochromatographic capillary flow enzyme immunoassay dipstick that can be used for vaginal specimens, with sensitivity of 82% to 95%, specificity of 97% to 100%, and results in 10 minutes. The Affirm VP III (Becton Dickinson) is a DNA hybridization probe used for vaginal specimens with a sensitivity of 63%, a specificity of 99.9%, and results in 45 minutes.

These newer assays are becoming more widely available, but the traditional wet mount microscopy continues to be commonly used because of convenience, low cost, and immediate results, although sensitivity is only 51% to 65% for vaginal specimens and even lower for specimens from men. Wet mount also requires prompt evaluation for the motile organisms as Trichomonas motility decreases quickly with time. Some clinicians may adopt the option of wet mount first and then NAAT if the wet mount is negative. Culture was traditionally considered the gold standard because of the specificity close to 100%, but it offers sensitivity of only 75% to 96% and is not commonly used currently. Pap cytology sometimes identifies an incidental Trichomonas infection but should not be used for routine testing because of false negatives and false positives.

TREATMENT

The recommended and alternative treatment regimens are found in Table 228-1. For metronidazole and tinidazole, the consumption of alcohol can cause a disulfiram-like reaction. Thus, patients should avoid alcohol-containing drinks until at least 24 hours after metronidazole use or 72 hours after tinidazole use. Metronidazole gel is not recommended because of subtherapeutic levels and insufficient efficacy for the urethra and perivaginal glands.

VULVOVAGINAL CANDIDIASIS

Vulvovaginal candidiasis (VVC) is estimated to occur at least once in 75% of women, and 2 or more episodes are estimated to occur in 40% to 45%. The majority are caused by Candida albicans, but other Candida species are possible. Risk factors include immunocompromise, genetic host factors, medication use, and behavioral factors such as douching. Although sexual transmission of C albicans may occur, the role of such transmission in promoting infection among sexually active women is unclear.

CLINICAL MANIFESTATIONS

Uncomplicated VVC typically presents with nonspecific symptoms of vaginal pruritus, discomfort, or discharge; vulvar edema, fissures, or excoriations; dyspareunia; or dysuria. Approximately 10% to 20% of cases are classified as complicated VVC, including recurrent VVC, severe VVC, or non-albicans species VVC. Recurrent VVC is defined as 4 or more episodes of symptomatic VVC in 1 year. Many of these patients do not have any clear risk factors, and non-albicans species VVC is found in 10% to 20% of recurrent VVC cases. Severe VVC involves extensive vulvar erythema, edema, excoriations, and fissures.

DIAGNOSIS AND TREATMENT

One diagnostic challenge is distinguishing pathogenic infection from nonpathogenic colonization. Accordingly, diagnosis is typically made when a woman has signs and symptoms of vaginitis and either wet mount microscopy that shows budding yeast forms or hyphae (pH is usually < 4.5) or culture that shows yeast species. For patients with signs or symptoms but negative wet mount microscopy, empiric treatment is an option. However, positive culture without signs or symptoms may simply indicate normal colonization because 10% to 20% of women have yeast in the vagina and would not warrant treatment. Treatment regimens are found in Table 228-1.

VIRAL INFECTIONS

HUMAN PAPILLOMAVIRUS

HPV is a member of the papillomavirus family capable of infecting humans. It is a closed, circular, double-stranded DNA virus of approximately 8000 base pairs. The viral genome is enclosed in an icosahedral capsule composed of 2 protein capsomeres (referred to as late [L] 1 and 2 proteins) and lacks the lipid-containing envelope common to many other viruses such as HSV. Unlike other human STIs such as HSV, HPV growth in traditional cell culture has been difficult because its replication is dependent on epithelial cell differentiation and maturation requiring the use of cell raft systems.

PATHOGENESIS AND EPIDEMIOLOGY

For infection, HPV requires access to basal epithelial cells through a wound or inflammation. Sites most vulnerable to infection are those where basal cells are actively dividing including the active squamous metaplasia of the transformation zone of the female cervix and areas of wound healing in the genital area. Although perinatal transmission has been shown to occur, the infections are usually only found in the respiratory tract of the infant. Rarely, genital warts occur in infants from perinatal transmission. Common clinical presentations of HPV include genital warts or condyloma acuminatum. In addition, HPV is the cause of precancerous and cancerous lesions of the genitals, including vulvar, vaginal, cervical, anal, and penile cancers. Genital HPV types are also associated with oropharyngeal cancers. Subclassification of HPV into over 100 types has been based on differences in degree of DNA homology. Of the > 100 types, approximately 40 are considered genital types because they are found predominantly in the genital area only. Genital condyloma are usually associated with HPV type 6 or 11. These types are considered to be low-risk HPV types because they are rarely seen in cancers. Twelve types are considered high risk (HR; 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59), 1 probable HR (68b), and 7 possible HR (66, 26, 53, 67, 70, 73, and 82), The most common type in all anogenital cancers is HPV-16.

Genital HPV infection occurs primarily through sexual behavior and may include genital-to-genital contact or intercourse. The role of hands or sex toys in transmission has not been established, but HPV DNA can be detected on hands and under fingernails. In adolescents and young women, infections are extremely common, with over 50% of young women acquiring the infection within 2 to 4 years after initiating sex. The infections, however, are mostly transient, with 70% to 90% of HPV infections clearing within 1 to 2 years. Persistence of the infection is the key factor in the development of anogenital precancers and cancers. The length of time of persistence required for cancer development is not known. Because HPV is acquired commonly through sexual intercourse during adolescence and cancer is not seen until 2 or 3 decades later, it is thought that years of persistence are required for most individuals before cancer develops. Viral–host protein interactions result in the loss of cell cycle control and are considered crucial steps in the development of the cancers. The roles of other cofactors are less compelling. Those thought to play important roles include cigarette use and immune suppression. More specifically, HIV-infected persons and organ transplant patients are at higher risk for cervical and anal cancers. Other factors with conflicting data include prolonged use of hormonal oral contraceptives, increased parity, and infection with C trachomatis.

CLINICAL MANIFESTATIONS

HPV can cause multicentric disease, including much of the anogenital area, including the vulvar labia minora and majora, clitoris, vaginal introitus, vagina, cervix, urethra, anus, and perineum in women, and the penis (including the prepuce, frenulum, corona, glans, urethra, and shaft), scrotum, and anus in men. The common genital warts, condyloma acuminatum, seen on the skin surfaces present as polypoid masses with fissured and irregular surfaces. They are often multiple and polymorphic and commonly coalesce into large masses. Genital HPV types also often appear as flat, smooth, or pedunculated papules, specifically on mucosal surfaces. These lesions can also occur on conjunctival, nasal, oral, respiratory, gastrointestinal, and bladder mucosa.

Infections with HPV can result in the development of lesions in the anogenital area referred to as low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL). The term low grade refers to benign changes caused by the virus described in cell morphology. These lesions will usually clear spontaneously and require no intervention. High grade refers to changes that are considered truly precancerous (ie, the chance of progression is high and regression less).

DIAGNOSIS

Screening for HPV infections in adolescents and young adult women is currently limited to visual inspection for external genital warts, and for women 21 years and older, cervical cancer screening using cytology is recommended for intraepithelial lesions and invasive cancers. No routine screening recommendations are made for vulvar, anal, and penile precancerous lesions in adolescents and young adults (defined as < 25 years of age) including MSM. This includes immunocompromised individuals.

Diagnosis of genital warts by visual inspection is considered adequate, and HPV testing plays little to no role in confirming the diagnosis unless the diagnosis is questioned. In this case, biopsy is the best confirmation. The differential diagnosis includes bowenoid papulosis, vulvar intraepithelial neoplasia, Bowen disease, condylomata, skin tags, nevocellular nevus, benign tumors, sebaceous glands, seborrheic keratosis, pearly penile papules, molluscum contagiosum, squamous cell carcinoma, vulva papillomatosis, and vestibular papillae.

TREATMENT

Treatment (see Table 228-1) for genital warts includes self-administered and provider-administered options. Provider-administered therapies are primarily ablative including application of trichloroacetic acid (TCA) or bichloroacetic acid (BCA) (85–90%) to the wart. Cryotherapy with liquid nitrogen is also quite effective. Treatments are usually applied weekly for 4 to 6 weeks. If there is no improvement, therapy should be switched, or the diagnosis should be questioned. The current role of podophyllin resin in therapy is questioned because its potency is unpredictable, and it is contraindicated on mucosal surfaces and in pregnancy. Other therapies include cidofovir, intralesion interferon, or 5-fluorouracil/epinephrine gel implant or laser therapy. Surgical removal by experienced clinicians is also an alternative using tangential scissor excision, tangential shave excision, curettage, or electrosurgery. Urethral meatus and vaginal wart treatments include liquid nitrogen or surgical removal. Cervical and intra-anal warts should be treated with cryotherapy with liquid nitrogen, surgical removal, or TCA/BCA. Referral to a trained specialist is recommended for both cervical and anal warts. Cervical warts require biopsy prior to treatment to rule out HSIL.

There are now several options for self-applied therapies. Podofilox is applied directly to the warts twice daily for 3 consecutive days and repeated weekly up to 4 to 6 weeks. Imiquimod (5%), which is a cytokine-inducing agent, is applied directly once daily at bedtime 3 times a week (alternating days) for up to 16 weeks. Sinecatechins is used 3 times daily topically for up to 16 weeks. Disadvantages to all therapies include irritation, inflammation, and ulceration from local applications.

Despite known limitations in sensitivity, cytology remains the primary screening tool for squamous intraepithelial lesions (SIL) and invasive cancers in women age 21 years and older. Although HPV testing assists in triage of borderline abnormal cytology (atypical squamous cells of undetermined significance [ASCUS]) and SIL screening in older women, its role appears less specific in adolescents because of the high rates of HPV infections and LSIL and low rates of HSIL and invasive cancer in this age group. HPV DNA testing in adolescents is not currently recommended under any circumstance. Because HPV is often acquired early after the onset of sexual activity and is likely to be transient, cytology screening is not recommended under 21 years of age unless the patient is immunocompromised. Screening with cytology is then recommended every 3 years. At 25 years of age, primary screening with HPV DNA using the FDA-approved assays is allowed. Immunocompromised adolescent females should be screened within 1 year after the onset of sexual activity.

The cellular changes associated with these lesions can be identified on cytology (cervical cancer screening) and histology. The lesions can usually be visualized with the aid of colposcopy. Typical appearances on colposcopy associated with LSIL, HSIL, and invasive cancers assist in directing biopsy. Final diagnosis is dependent on histologic interpretation of the biopsy, not colposcopic appearance or cytologic diagnosis, specifically in adolescents. HPV DNA detection can be common in women with normal cytology, specifically in young women. Whether these women truly have no lesion remains controversial because cytology alone is an insensitive test to detect SIL. However, most of these infections in women with normal cytology appear transient, as in LSIL, and therefore, detection of HPV DNA in adolescents and young women is not cost-effective as a clinical tool and, as noted, should not be used. There are no treatments available or indicated for HPV DNA detection without abnormal cytology or histology.

PREVENTION

Prevention of HPV types 6, 11, 16, 18 31, 33, 45, 52, and 58 can now be achieved with vaccination prior to exposure. In the United States, the nonavalent (HPV9) vaccine is currently recommended for all females and males age 11 to 12 years. It is also recommended for males and females up to age 26 years, particularly targeting those who are not yet sexually active. In the United States, the HPV vaccine is a 2-dose regimen for those starting the vaccine before their 15th birthday, and a 3-dose regimen for those starting the vaccine after their 15th birthday. The vaccine is not therapeutic and has no effect on women already infected with the HPV types included in the vaccine. A bivalent vaccine for HPV-16 and -18 is also approved for females only. The vaccine can be given starting at 9 years of age. If there is a history of sexual abuse, it is recommended to vaccinate starting at the age of 9 years. Readers should refer to vaccine guidelines frequently updated from the CDC Advisory Committee on Immunization Practices (ACIP).

SYNDROMES

A constellation of symptoms and signs is characteristic of specific STI syndromes. Common lower genital tract syndromes in women include those characterized by vaginal discharge, which include bacterial vaginosis, Trichomonas vaginalis, and candidiasis, as well as endocervicitis and urethritis. In men, urethritis is the most common STI syndrome, but epididymitis also occurs. Proctitis occurs in both females and males.

BACTERIAL VAGINOSIS

The dominant organism (> 95% of organisms) in the normal flora of healthy women is hydrogen peroxide–producing Lactobacillus species. Bacterial vaginosis (BV) results from the replacement of vaginal hydrogen peroxide–producing Lactobacillus species with high concentrations of anaerobic bacteria, including Bacteroides species, Mobiluncus and Prevotella species, and other bacteria such as Gardnerella vaginalis and Mycoplasma hominis. Reported prevalence varies widely from 10% to 50%, depending on the population sampled.

CLINICAL MANIFESTATIONS

BV is the most common cause of abnormal vaginal discharge, although half the women who meet the clinical criteria for the diagnosis have no symptoms. BV is rarely found in non–sexually active women and is associated with multiple sexual partners and lack of condom use as well as douching. However, the cause of the microbial alterations remains unknown. BV has been associated with premature labor, as well as increased risk of acquiring HIV, gonorrhea, chlamydia, HSV, and HPV. Symptoms include pruritus, irritation, and a thin white vaginal discharge with a “fishy” odor.

DIAGNOSIS

Various criteria have been used to diagnose BV. Amsel’s clinical criteria are based on presence of 3 of the following 4 factors: (1) homogenous, thin white discharge that coats the vaginal walls; (2) > 20% of squamous cells with a clue cell appearance (vaginal epithelial cells studded with adherent coccobacilli); (3) pH of vaginal fluid > 4.5; and (4) fishy odor before or after addition of 10% KOH (whiff test). Nugent’s gram stain criteria are used to quantify the absence of lactobacilli, and abundance of gram negative and variable rods and cocci and curved gram negative rods, which are seen in BV. The Nugent score is calculated and categorized as follows: 0 to 3 (normal), 4 to 6 (intermediate abnormal), and 7 to 10 (BV). Newer tests include the Affirm VP III (Becton Dickinson), which detects high concentrations of G vaginalis, and the OSOM BV Blue Test (Sekisui Diagnostics), which detects sialidase activity. Cervical Pap tests should not be used because they have low sensitivity and specificity.

TREATMENT

Treatment of nonpregnant women is linked only to relief of symptoms; male partners of infected women are almost always asymptomatic, and treating men does not affect the woman’s disease course. Treatment may lower risk of other STIs including HIV. Treatment regimens are found in Table 228-1. Additionally, treatment of symptomatic pregnant women is recommended using oral or vaginal treatments as recommended for nonpregnant women. Evidence is insufficient to recommend routine screening and treatment in asymptomatic pregnant women for the prevention of preterm birth.

PELVIC INFLAMMATORY DISEASE

PID is used to describe a variety of inflammatory disorders of the upper female genital tract including endometritis, salpingitis, tubo-ovarian abscess, and peritonitis. PID is thought to reflect ascending infections initiated in the vagina or endocervix. STIs, in particular, C trachomatis and N gonorrhoeae, are often identified, but other vaginal organisms have also been implicated (eg, anaerobes, G vaginalis, Haemophilus influenzae, enteric gram-negative rods, Streptococcus agalactiae, M hominis, Ureaplasma urealyticum, and possibly Mycoplasma genitalium). The notable sequelae of PID include ectopic pregnancy and infertility. Risk factors that may predispose young women to develop acute PID include young age, history of an STI, previous PID diagnosis, greater number of sexual partners, and recent gynecologic interventions (eg, therapeutic abortion or endometrial biopsy). Although the relationship of oral contraceptives to acute PID has been controversial, most current research supports a protective role of oral contraceptives in the development of PID.

DIAGNOSIS

PID is challenging to diagnose because there is no single historical, physical, or laboratory finding that is definitively diagnostic. The clinical diagnosis for PID is imprecise and requires the consideration of multiple possible findings. Although laparoscopy is thought to offer a definitive diagnosis, endometritis and subtle fallopian tube inflammation will be missed. In addition, laparoscopy is frequently unavailable. Since most episodes go undiagnosed because of mild symptoms such as dyspareunia or abnormal vaginal bleeding, it is recommended to have a low threshold for diagnosis. Symptoms and signs of acute PID include lower abdominal pain, vaginal discharge, cervical motion tenderness, and uterine and adnexal tenderness (Table 228-2). The differential diagnosis to be considered in a young woman presenting with acute lower abdominal pain, in addition to PID, includes acute appendicitis, acute cholecystitis, mesenteric lymphadenitis, acute cystitis, acute pyelonephritis, ectopic pregnancy, intrauterine pregnancy, septic abortion, endometriosis, ovarian cyst with or without torsion, hemorrhagic ovarian cyst, ovarian tumor, severe constipation, and trauma.

Principles to remember in the clinical approach to PID include the following: rule out other causes including pregnancy; when in doubt, err on the side of “overdiagnosis” of PID to prevent sequelae, especially in view of the possibility of subclinical infections, while pursuing further workup for other causes; treat with broad-spectrum antibiotics to cover C trachomatis, N gonorrhoeae, and other pathogens discussed earlier and begin the course promptly; and, finally, follow up with clinical evaluations (within 24–48 hours) to confirm the original clinical diagnosis and reevaluate the treatment regimen.

TREATMENT

Treatment regimens are outlined in Table 228-3. Criteria for hospitalization include uncertain diagnosis or the need to rule out surgical emergencies; presence of a pelvic or tubo-ovarian abscess; pregnancy; severe illness, nausea, and vomiting; inability to take oral medications; failure of outpatient therapy within 48 hours; and inability to arrange follow-up within 72 hours of starting antibiotics. Some recommend inpatient treatment for HIV-infected women because of greater sequelae. A serious complication of acute PID is the development of a tubo-ovarian abscess. Although most abscesses can be managed medically, occasional surgical intervention is necessary when medications fail. Screening and treatment of the sexual partner(s) are important parts of PID management, as with any STI. Intrauterine devices (IUDs) do not need to be routinely removed. If no improvement is noted after 48 to 72 hours of treatment, IUD removal should be considered.

FITZ-HUGH-CURTIS SYNDROME

Fitz-Hugh-Curtis (FHC) syndrome results from ascending pelvic infection and inflammation of the liver capsule and/or diaphragm. It presents in females with right upper quadrant pain that can occur without other signs of PID. Bacteria that are typically associated with PID spread from the pelvis along the paracolic gutters to the liver capsule. N gonorrhoeae was the most common cause, but now C trachomatis is causative in about 80% of cases.

The disorder initially presents with acute pain that is similar to cholecystitis and may be referred to the right shoulder. It can then become chronic with persistent, but not severe, right upper quadrant pain. Physical findings are otherwise not specific except for an occasional finding of a friction rub over the right upper quadrant. Diagnosis is most often inferred based on the symptoms and a finding of a positive cervical culture for gonorrhea or chlamydia. Liver function tests are usually normal. Imaging studies may be normal, although ultrasonography or abdominal computed tomography scan may identify perihepatic adhesions. Diagnostic laparoscopy demonstrates the pathognomonic finding of “violin-string” adhesions from the anterior abdominal wall to the liver capsule. Treatment is the same as for PID.

EPIDIDYMITIS

Epididymitis is a clinical syndrome of inflammation of the epididymis caused by infection or trauma. Acute epididymitis is defined as pain and swelling of the epididymis for less than 6 weeks; chronic epididymitis is defined as discomfort in the scrotum, testicle, or epididymis for more than 6 weeks. The patient’s age and sexual history are important in determining the causative agent. C trachomatis and N gonorrhoeae are the most common organisms in sexually active adolescents, being responsible for approximately two-thirds of infections. Enteric organisms such as Escherichia coli must be considered in youth who have engaged in insertive anal intercourse.

CLINICAL MANIFESTATIONS

The patient typically presents with acute onset of unilateral testicular and/or scrotal pain and swelling (hydrocele), often accompanied by asymptomatic urethritis. Urinary frequency, dysuria, and urethral discharge may also occur. Upon examination, the epididymis is swollen and tender. Early in the course of the infection, the epididymis is easily discernible from the testicle, but with progression, the testis becomes involved, producing epididymo-orchitis, thereby making it difficult on examination to differentiate the epididymis from a swollen and tender testicle. The cremasteric reflex may be absent. Fever is a sign of systemic infection.

DIAGNOSIS

Proper STI evaluation is similar to that for urethritis. Epididymitis is often difficult to differentiate from torsion of the spermatic cord. If the diagnosis is unclear, evidence for urethritis is not found, or the pain is very sudden and severe, urgent referral to a urologist should be made since testicular viability is at risk. Diagnosis should include evaluation by 1 of the following point-of-care tests: > 2 white blood cells (WBCs) per oil immersion field on Gram, methylene blue, or gentian violet stain of urethral secretions (this test also allows for the diagnosis of gonococcal infection showing intracellular gram-negative or purple diplococci); positive leukocyte esterase test on first-void urine; or > 10 WBCs per high-power field from a spun first void urine sediment.

Radionucleotide scanning is currently the most accurate method to diagnosis epididymitis. Ultrasound is often unable to distinguish between spermatic cord torsion and epididymitis. Scrotal masses are discussed in other sections. Hospitalization for presumptive acute epididymitis is typically not necessary but should be considered in cases of severe pain when further workup is indicated, when there is fever or concern for systemic disease, or when there is inability to adhere to treatment.

TREATMENT

If chlamydial or gonococcal epididymitis is suspected, empiric treatment should start promptly. The recommended regimen is ceftriaxone 250 mg intramuscularly (IM), plus a 10-day course of doxycycline 100 mg twice daily. For infection likely caused by sexually transmitted chlamydia, gonorrhea, and enteric organisms (men who practice insertive anal intercourse), suggested treatment includes ceftriaxone 250 mg IM plus levofloxacin 500 mg orally once a day for 10 days or ofloxacin 300 mg orally twice a day for 10 days. For infection most likely caused by enteric organisms, suggested treatment is levofloxacin 500 mg orally once a day for 10 days or ofloxacin 300 mg orally twice a day for 10 days. All sexual partners within the prior 60 days should be contacted for evaluation and treatment. If last intercourse was > 60 days, the most recent partner should be evaluated. Additional therapy should include bed rest, scrotal elevation, and analgesics. If there is no improvement within the first 3 days of treatment, the diagnosis and treatment plan should be reconsidered. Other diagnostic possibilities include abscess, tuberculosis, fungal epididymitis, infarction, or tumor. Full resolution of discomfort may take weeks after treatment.

Epididymitis usually resolves without sequelae if treatment is administered promptly. However, there are some indications that oligo- or azoospermia may result, particularly if C trachomatis was the etiologic agent. Other sequelae include atrophy, infarct, or abscess formation.

PROCTITIS, PROCTOCOLITIS, AND ENTERITIS

Proctitis is defined as inflammation of the distal 10 to 12 cm of the rectal mucosa and is associated with anorectal pain, mucus or blood in stools, tenesmus, or rectal discharge. Many infections involve the anus as well and are therefore considered “anorectal” infections. Although STI-related rectal infections are frequently associated with anal intercourse among MSM, they may also occur in heterosexual men and women. Such infections in women are less well defined and, with gonorrhea, are often asymptomatic and associated with endocervical gonorrhea. The most common sexually transmitted anorectal infections among sexually active adolescents include N gonorrhoeae, C trachomatis (including lymphogranuloma venereum [LGV] strains), HSV, and Treponema pallidum (syphilis). HIV-infected persons may also have severe herpes proctitis. Proctocolitis is proctitis with inflammatory extension to the colonic mucosa (> 12 cm above the anus) and is associated with diarrhea or abdominal cramps. Sexually transmitted enteric organisms, most commonly associated with anal intercourse or oral-anal sex, include Entamoeba histolytica, Campylobacter species, Shigella species, and LGV serovars of C trachomatis. Enteritis can present with or without proctitis or proctocolitis and commonly presents with diarrhea and abdominal cramping. It is most commonly associated with oral-anal sex practices. Giardia lamblia is the most common pathogen. Among HIV-infected persons, enteritis may be associated with organisms generally not sexually transmitted, including cytomegalovirus, Mycobacterium avium-intracellulare, Cryptosporidium, Microsporidium, Isospora, and others.

DIAGNOSIS

Diagnostic evaluation for acute proctitis includes a careful sexual history to determine risk (eg, oral-anal sex, anal intercourse); examination including anoscopy; Gram stain of an anal sample; rectal sample tests (NAAT or culture) for N gonorrhoeae, C trachomatis, and HSV (or polymerase chain reaction [PCR]); and T pallidum (and darkfield, if available) serologic testing. If C trachomatis is identified, a molecular PCR test for LGV should be done.

TREATMENT

Empiric treatment is indicated if the examination reveals anorectal exudates or if a Gram stain smear of an anorectal sample reveals polymorphonuclear leukocytes. Ceftriaxone 125 mg IM plus doxycycline 100 mg orally twice daily for 7 days are given while awaiting other test results. Presumptive treatment for HSV in addition to ceftriaxone and doxycycline is indicated for painful perianal or mucosal ulcers found on examination. If symptoms of proctocolitis and enteritis are found in association with oral-anal or anal intercourse, tests for enteric pathogens can be obtained. In the absence of this typical history and findings, other causes of proctitis need to be considered such as non-STI infectious colitis or inflammatory bowel disease (see Chapter 405). Partners of patients with STI-associated (eg, gonorrhea, chlamydia, including LGV) proctitis who had sexual contact within the prior 60 days should be evaluated and treated presumptively.

CHANCROID

The majority of genital ulcers in sexually active youth in the United States are caused by HSV. Syphilis and chancroid are less common. Rates of chancroid have declined in the United States, and chancroid is associated with sporadic outbreaks. Patients infected with chancroid also have a high prevalence of HIV, HSV, and syphilis. Typical signs include painful genital ulcer and tender suppurative inguinal adenopathy.

DIAGNOSIS

Presumptive diagnosis is made when all of the following criteria are present:

1. One or more painful genital ulcers

2. Negative darkfield examination of the ulcer exudate or negative syphilis serology within 7 days

3. Regional inguinal adenopathy

4. Negative HSV test from ulcer exudates

A definitive diagnosis of chancroid requires special culture media that is not widely available in many labs. Currently, there is no FDA-cleared PCR test for Haemophilus ducreyi (the causative agent), but some labs have developed in-house assays.

TREATMENT

Four treatment options are currently recommended: azithromycin 1 g orally once; ceftriaxone 250 mg IM once; ciprofloxacin 500 mg orally twice daily for 3 days; or erythromycin base 500 mg orally 3 times daily for 7 days. Repeat examination should occur within 3 to 7 days of starting treatment in order to confirm improvement. Suppurative inguinal adenopathy may require needle aspiration or incision and drainage if no improvement is seen. Complete healing of larger ulcers may require more than 2 weeks. Patients who are uncircumcised or infected with HIV tend to demonstrate slower healing. All patients infected with chancroid should routinely be tested for HIV and receive repeat testing for syphilis and HIV 3 months later if initial tests were negative. Sex partners should be evaluated and treated if they had sexual contact within 10 days prior to the onset of symptoms.

SUGGESTED READINGS

INTRODUCTION

Bone and joint infections may occur at any age but are more common in children than adults. Optimal management requires early diagnosis and aggressive initial treatment to prevent disabling sequelae. This is best achieved with care provided by a multidisciplinary team of pediatricians and orthopedic surgeons experienced in the specific issues encountered in care of growing children. Soft tissue infections in children, generally less difficult to diagnose and treat than skeletal infections, remain important because of their greater frequency of occurrence and the need for antibiotic therapy, occasionally in conjunction with hospitalization and surgery.

ACUTE HEMATOGENOUS OSTEOMYELITIS

PATHOGENESIS AND EPIDEMIOLOGY

The majority of bone infections in children are of hematogenous origin. The vascular anatomy of long bones in children underlies the predilection for localization of blood-borne bacteria. In children, unlike young infants, the blood supply of the epiphysis is separate from the metaphysis. The nutrient artery to the metaphysis empties into a system of venous sinusoids in which sluggish flow presumably facilitates deposition of bacteria. During the cellulitic phase of acute osteomyelitis, infection originates on the venous side of the system and then spreads to the nutrient artery, causing thrombosis of the nutrient artery. The resultant ischemia prevents host defense mechanisms from reaching the area and allows bacterial proliferation. Formation of an abscess can then occur, which can rupture into the subperiosteal space with subsequent elevation of the periosteum, which is loosely adherent in children. If infection is uncontrolled, purulent material may extend up and down the diaphysis and circumferentially around the bone (Fig. 229-1). In areas in which the metaphysis is intra-articular, such as the hip and shoulder, the intraosseous abscess may rupture into the joint, resulting in septic arthritis. In young infants, blood vessels connect the metaphysis and epiphysis, and rupture of pus into the adjacent joint space is more common.

Thrombosis of blood vessels and elevation of the periosteum deprive the bone of its blood supply, resulting in necrosis, which can be extensive without early surgical drainage. Left untreated, granulation tissue forms around the dead bone, which separates from live bone and becomes a sequestrum. New bone growing around the dead bone is called an involucrum. Sinus tract formation occurs in the involucrum allowing pus to escape and eventually form sinus tracts through the skin. The involucrum is mechanically weak and may become the site of pathologic fractures.

Acute hematogenous osteomyelitis (AHO) is one of the most common and important invasive bacterial infections affecting children. The incidence ranges from 2 to 13 per 100,000 in developed countries, but is considerably higher (up to 200/100,000) in developing countries. Historically, the highest incidence occurred in young children, usually less than 5 years of age. More recent studies, including a large meta-analysis, show the mean age to be 6 to 9 years and the majority of children in multiple series to be in the school-age range, with only 40% being preschool age. There is a consistent male predilection, with males outnumbering females approximately 2:1 in published series. There is frequently a history of some type of minor blunt trauma or illness such as an upper respiratory tract infection. Other risk factors for AHO include immunodeficiency states, sickle cell anemia, and indwelling vascular catheters.

ETIOLOGIC AGENTS

The predominant etiologic organism in AHO in all age groups is Staphylococcus aureus, accounting for 50% to 90% of cases. While methicillin-sensitive S aureus (MSSA) continues to cause the majority of infections, community-acquired methicillin-resistant S aureus (CA-MRSA) has also become a significant pathogen in AHO in particular geographic areas since its emergence in the late 1990s. The majority of strains circulating in the community harbor the genes encoding for the exotoxin panton valentine leukocidin (PVL). This important virulence factor has been associated with severe musculoskeletal infections in children. Studies have shown that osteomyelitis caused by PVL-positive S aureus strains (MSSA or MRSA) are of greater severity and are characterized by more frequent presence of subperiosteal and intraosseous abscesses as well as complications such as multifocal disease and deep venous thrombosis. This may account for the more severe disease seen in patients in certain geographic areas and should be taken into consideration in patient management.

Streptococcus pyogenes osteomyelitis accounts for approximately 10% of cases of AHO and is more prevalent in preschool and early school-aged children. Streptococcus pneumoniae is a less frequent cause of AHO, accounting for 1% to 10% of cases primarily in children less than 3 years of age and immunocompromised patients. Widespread usage of the conjugated pneumococcal vaccine may have resulted in a decline in incidence as it has with other invasive pneumococcal infections.

Kingella kingae, a fastidious gram-negative coccobacillus that colonizes the respiratory tract, has been increasingly recognized as an important pathogen in osteoarticular infections in children younger than 4 years of age. This organism has been reported in more than one series to cause > 50% of cases of AHO. This organism is difficult to recover and requires bone aspirates be inoculated into blood culture bottles, which then need to be incubated longer than many laboratories routinely do or sent for polymerase chain reaction (PCR) for diagnosis. K kingae infections tend to be associated with a less aggressive clinical course than those seen with other bacteria, causing fewer symptoms and less bone destruction.

Streptococcus agalactiae (group B Streptococcus [GBS]) and enteric gram-negative organisms occur almost exclusively in neonates. Salmonella is most commonly isolated in patients with AHO who have sickle cell anemia, although it can occasionally occur in normal hosts. Haemophilus influenzae type b, an important pathogen in older series, is now rarely seen in countries that routinely use the H influenzae type b conjugate vaccine. Less common organisms causing osteomyelitis include Bartonella henselae (the cause of cat scratch disease), Brucella, and Mycobacterium tuberculosis.

Causes of nonhematogenous osteomyelitis in children include Pseudomonas osteochondritis, usually resulting from puncture wounds to the feet through sneakers, and anaerobic, gram-negative, and polymicrobial infections that occur after puncture wounds or open fractures.

CLINICAL MANIFESTATIONS

Early signs of skeletal infection may be subtle, especially in the neonate who may not appear ill. The earliest signs of osteomyelitis in infants may be failure to move the affected extremity (pseudoparalysis), pain on passive movement, or both. Older children typically present with fever, pain at the site of infection, and refusal to use the affected extremity, which usually translates to limping or refusal to bear weight because lower extremity bones are affected more frequently. Nonspecific constitutional symptoms can occur, but are not prominent. There can be intense tenderness over the metaphysis of the bone on palpation, and muscles of the adjacent joint are frequently in spasm. The joint is held in a position of comfort, usually mild flexion, but to a lesser degree than with septic arthritis. Soft tissue changes of swelling, erythema, and heat are generally late findings in osteomyelitis. After several days, a sympathetic sterile effusion may form in a nearby joint, presenting a problem in differentiation from septic arthritis. It is imperative for the evaluating physician to remember that any infant or child with fever and failure to bear weight or use an extremity needs to be carefully evaluated for potential musculoskeletal infection.

Although essentially any bone can be involved, long bones are most often involved in AHO in children. As noted, the majority of infections occur in the lower extremities, and the most common sites of involvement are the distal femoral and proximal tibial metaphyses. Next in frequency are the proximal femoral metaphysis and distal metaphyses of the radius and humerus. Infection in flat bones occurs most often in the pelvis and calcaneus, both of which can present challenges in diagnosis.

The differential diagnosis of osteomyelitis includes cellulitis, septic arthritis, pyomyositis, malignancy, collagen vascular disease, and trauma. In differentiating cellulitis from bone infection, tenderness disproportionate to physical findings suggests osteomyelitis. Septic arthritis may be differentiated from osteomyelitis by its more discrete joint findings and its greater degree of joint immobility, in addition to a lack of metaphyseal tenderness. History, physical examination, clinical scenario, and radiologic studies are helpful in differentiating skeletal infection from other diagnoses. Recovery of the causative organism is best obtained by biopsy or aspiration, which not only establishes the diagnosis but also facilitates susceptibility testing and rules out other pathologic processes.

SPECIAL CLINICAL SITUATIONS

Neonatal Osteomyelitis

Diagnosis of osteomyelitis in an infant who is less than 3 months of age requires a high index of suspicion. Young infants with bone infections often lack fever and other systemic signs of illness. Symptoms may be confined to failure to move an extremity and fussiness or poor feeding. Predisposing factors include a history of any of the following: prematurity, infection, bacteremia, exchange transfusion, or intravascular catheter. GBS, S aureus, and enteric gram-negative bacteria are the most common etiologic agents. Candida must also be considered, especially in the premature infant who has had previous antibiotic therapy or intravascular catheters. As noted, neonates are more likely to have decompression of pus into the adjacent joint, resulting in an associated septic arthritis, and they are also more likely to have multifocal disease.

Pelvic Osteomyelitis

Pelvic osteomyelitis often presents a diagnostic dilemma. Most patients present with fever, limp, or refusal to bear weight. Pain may seem to be localized to the hip, groin, or buttocks, but evaluation of these areas may not reveal the site of infection. Initial diagnostic impressions often include intra-abdominal pathology, other intrapelvic problems, and septic arthritis of the hip joint. In these cases, imaging studies such as computed tomography (CT) or magnetic resonance imaging (MRI) are usually necessary to establish the diagnosis.

Osteomyelitis in Children with Sickle Cell Disease

Aseptic bone infarcts are common in children with sickle cell disease. The signs, symptoms, and radiographic changes may mimic those of acute osteomyelitis, making differentiation between the diagnoses difficult. Neither bone scan nor MRI reliably discriminates between the 2 conditions. Ultrasonography (US) has been reported as a method assisting in differentiation between infarction and infection. A recent case-control study looking at the utility of US in distinguishing between osteomyelitis and vaso-occlusive crisis in sickle cell patients detected periosteal elevation/fluid in 84% of the osteomyelitis patients, whereas in vaso-occlusive crisis, this finding was absent in 91% on initial US and all patients on repeat US. Diagnostic aspiration of the site should be performed in an attempt to recover the organism and confirm the diagnosis. Salmonella species and S aureus are the most frequent causes of bone infection in sickle cell patients depending on the series. A recent meta-analysis showed no evidence favoring one over the other. Aggressive surgery and prolongation of parenteral therapy may be necessary for successful treatment of osteomyelitis in the child with sickle cell disease.

Vertebral Osteomyelitis /Discitis

Vertebral osteomyelitis and discitis are 2 entities that may present similarly, with patients complaining of back pain, limp, or refusal to bear weight. Vertebral osteomyelitis accounts for 1% to 4% of osteomyelitis in children. It is seen in older children and adolescents who are usually febrile on presentation and may have had symptoms for several weeks or months. The lumbosacral area is most commonly involved. S aureus is the predominant organism isolated. Discitis is seen more frequently in children less than 5 years of age when blood supply to intervertebral discs is rich. These patients are seldom ill appearing, and fever is uncommon.

Plain radiographs may show narrowing of the intervertebral space with destruction of vertebral endplates in discitis. Destruction of the vertebrae is seen in vertebral osteomyelitis, but findings may not appear until later in the disease course. MRI has become the modality of choice to differentiate one entity from the other.

DIAGNOSIS

Figure 229-2 outlines an approach to the diagnosis and management of a patient with suspected AHO. No specific laboratory test for the diagnosis of osteomyelitis exists with the exception of isolation of a pathogen from bone.

Bone Aspiration and Biopsy

Bone cultures are positive in 38% to 91% of cases and confirm the diagnosis. Blood cultures are also very useful, demonstrating the organism in 30% to 76% of cases. The highest diagnostic yield occurs when both blood and bone specimens are submitted for culture. Recovery of organisms is enhanced by inoculating bone aspirates into blood culture bottles. This is particularly important when fastidious organisms (eg, Kingella) are suspected, which may require up to a week of incubation before growth is evident. Alternatively, bone aspirates can be submitted for PCR testing when trying to establish a diagnosis in culture-negative osteomyelitis. In multiple studies, PCR testing has been shown to be particularly useful for the diagnosis of Kingella AHO, but when available, can also be used to identify other organisms in cases where conventional cultures are negative.

The ability to recover an organism from blood or bone cultures decreases significantly with prior antimicrobial therapy. Therefore, if the patient is stable, and blood and bone cultures can be done in a timely fashion, it is preferable to delay the initiation of antibiotics until cultures are obtained.

Other Laboratory Studies

Peripheral white blood cell count (WBC) and differential may or may not be abnormal. The erythrocyte sedimentation rate (ESR) rises slowly and initially may be normal or minimally elevated. ESR usually peaks 3 to 5 days after the initiation of therapy and returns to normal in 3 to 6 weeks. Many experts find C-reactive protein (CRP) to be more useful because it rises earlier, peaks within 48 hours of onset of symptoms, and may return to normal after approximately 1 week of effective therapy. Surgical intervention itself increases inflammatory markers; therefore, baseline ESR and CRP values used for monitoring disease progression should be repeated after surgical intervention if such are necessary.

Plain Radiographs

Plain films begin to show destructive changes approximately 7 to 14 days after the onset of bone infection. Subtle osteopenic changes may sometimes be discerned after 5 days. Plain films may be helpful acutely in demonstrating changes in the deep soft tissue adjacent to the affected bone, or joint effusion, as well as excluding other pathology such as fractures. To detect alterations of the soft tissue, identical views of the contralateral limb are recommended.

Radionuclide Scanning

When a bone scan is indicated, radiophosphate bone scintigraphy using technetium (⁹⁹Tc) is most commonly used. Isotope accumulates to a greater degree in areas of increased vascularity and rapid bone turnover, resulting in a hot spot reflected on the scan. Conversely, infected areas may have associated compromise of the vascular supply, causing the area to appear cold or normal, resulting in a false-negative interpretation. Although bone scans have a high degree of sensitivity, they do not make the diagnosis of skeletal infection. Bone scans indicate abnormal areas of bone without revealing whether the abnormality is due to infection, tumor, injury, or other causes. Although the ready availability of MRI in many areas has largely replaced bone scanning, there is still a role in selected cases. Bone scans are particularly helpful in cases where the site of infection is not readily apparent by physical examination or when multiple sites of involvement are suspected. If the site of infection can be localized by physical examination, a bone scan is not necessary. It has been shown experimentally that aspiration of bone (or joint) does not compromise results of subsequent bone scans.

Gallium scans or indium-labeled leukocyte scans are less commonly used techniques in the diagnosis of skeletal infection. Indium-labeled leukocyte scans, which reflect migration of WBCs into areas of inflammation, are useful in the diagnosis of osteomyelitis associated with trauma, recent surgery, or prosthetic devices.

Magnetic Resonance Imaging

MRI has become the most commonly used imaging study for the diagnosis of osteomyelitis. It is an effective modality for imaging bone and is quite sensitive and specific in diagnosis of musculoskeletal infections. It is not recommended as a screening study but is very useful when there is an indication of where the pathology is localized, either from physical examination or radionuclide scanning. It can be especially helpful in cases in which the spine or the pelvis is the site of infection, or conflicting clinical data exist, or in planning surgical intervention. Many orthopedic surgeons request a preoperative MRI because the spatial resolution of MRI is far superior to other modalities. Additionally, conditions requiring surgical intervention such as bone abscesses, subperiosteal abscesses, joint effusions, and pyomyositis are readily determined by MRI.

TREATMENT

Initial antibiotic therapy for osteomyelitis should be based on Gram-stained specimens obtained from bone aspiration, when possible. The importance of obtaining the exact bacteriologic diagnosis by blood or bone culture cannot be overemphasized. In the absence of such data, initial therapy is empiric and must be directed at likely pathogens based on the age of child, considering underlying medical conditions and the clinical presentation of the patient (see Fig. 229-2).

Because S aureus is the major pathogen of AHO, empiric therapy for all age groups should include an appropriate antistaphylococcal agent. Nafcillin, oxacillin, or a first-generation cephalosporin remain the antibiotics of choice for coverage of MSSA and are also effective against K kingae and S pyogenes. However, it is important to know the rates of infection caused by CA-MRSA locally prior to choosing empiric treatment regimens. Multiple studies have proven the effectiveness of clindamycin in the treatment of osteomyelitis. However, S aureus (MSSA or MRSA) may be resistant to this drug, either inherently or induced during treatment. In cases where initial studies show S aureus to be susceptible to clindamycin but resistant to erythromycin, the presence of inducible resistance should be evaluated in vitro with a D-test. When the inherent or inducible resistance rates in the community are greater than 10% to 15%, some experts recommend clindamycin alone not be used for initial treatment. Use of vancomycin, particularly in combination with a β-lactam, can be considered in the critically ill patient or in areas with high rates of MRSA and clindamycin resistance. It is important to recognize that Kingella isolates tend to be resistant to both clindamycin and vancomycin.

In the young infant, GBS and S aureus are the major pathogens, but coverage for enteric gram-negatives must be included. An appropriate initial therapeutic regimen includes an antistaphylococcal agent plus a third-generation cephalosporin, such as cefotaxime.

In children less than 4 years of age, a regimen providing coverage for S aureus, S pyogenes, S pneumoniae, and Kingella should be used. An antistaphylococcal agent plus a third-generation cephalosporin may provide appropriate coverage.

In immunocompromised children or those with underlying medical conditions, broader-spectrum coverage may be appropriate. If Pseudomonas is a consideration, an antipseudomonal agent may be part of the regimen.

Once an organism is identified, therapy should be guided by susceptibilities. If MSSA is identified, nafcillin, oxacillin, or a first-generation cephalosporin is the agent of choice. Cefazolin and other cephalosporins have been shown to reach adequate concentrations in bone tissue, provide convenient dosing schedules, and generally be better tolerated.

Newer antimicrobials have been shown to be acceptable alternatives for the treatment of MRSA osteomyelitis. Linezolid can be used in selected situations. It achieves excellent levels in bone and has equivalent intravenous and oral bioavailability. It has been shown to be effective in step-down therapy of AHO caused by gram-positive organisms but has several disadvantages. It remains expensive, and long-term therapy (> 2 weeks) has been associated with anemia and thrombocytopenia, and thus, weekly blood counts are required when using it. It can also have other serious adverse effects including optic neuritis, peripheral neuropathy, and serotonin syndrome when used in combination with selective serotonin reuptake inhibitors (SSRIs) and sympathomimetic drugs. Daptomycin is another alternative that can be considered in selected situations, but has no oral equivalent and is not approved by the US Food and Drug Administration (FDA) for treatment of osteomyelitis in children. Daptomycin has FDA approval for treatment of pediatric skin and soft tissue infections.

If possible, initiating treatment with a single agent is preferred. If cultures remain sterile, treatment should be continued based on the most common organism for the age group, usually S aureus. If there is no response to treatment, less common organisms may be suspected, although there may be other causes as well (eg, the common etiologic agent is resistant to the chosen antibiotic regimen or there are complications of the infection). In children under 4 years of age with negative cultures, K kingae should strongly be considered.

There are several options for delivery of antibiotic therapy in the treatment of osteomyelitis. Therapy may be completed parenterally through a central venous catheter or a peripherally inserted central catheter (PICC); however, this is much less common today than it was in the past. The most commonly used option currently is to initiate therapy parenterally, followed by orally administered drugs after any necessary surgical procedures have been performed and the clinical condition has stabilized. Oral therapy instituted after an initial course of parenteral therapy is equally effective compared to continued parenteral therapy when the responsible organism and its susceptibilities are defined, although parenteral treatment is associated with more adverse events related to the catheter. The selected option depends on a patient’s particular situation considering factors such as location, extent, and severity of disease, as well as the patient’s ability to tolerate oral therapy and the likelihood of compliance. It is important to recognize that the length of parenteral therapy is dependent on the patient’s response to therapy and may need to be extended in severe disease or in immunocompromised patients. Evidence that a patient can safely be transitioned to oral therapy per some experts has been a combination of subjective and objective clinical findings such as defervescence, increased use of the affected extremity, and a decrease in CRP.

When sequential parenteral/oral therapy is implemented, the oral drug chosen should be active against the identified pathogen, or if the pathogen has not been isolated, when possible, it should be identical in spectrum of activity to the parenteral drug to which the patient has shown clinical response. Contraindications to oral therapy include the inability to swallow or retain medication, lack of an effective oral agent, and failure to demonstrate adequate clinical response to parenteral antibiotics. In older literature, failure to demonstrate the etiologic agent and an inability to monitor the degree of drug absorption were considered contraindications to oral therapy; however, that edict is no longer followed. Especially in young children, palatability of oral suspensions is an important feature. In general, cephalosporins are more palatable than antistaphylococcal penicillins, which are seldom used. Clindamycin is an excellent drug for staphylococcal osteomyelitis in older children, but many young children may not tolerate the taste of the oral solution.

Dosages of oral antibiotics required in sequential intravenous-oral regimens are 2 to 3 times those used for minor infections. It is optimal to monitor absorption of oral antibiotics and compliance by measurement of serum bactericidal levels against the isolated organism or measurement of antibiotic serum levels; however, in practice, these are almost never done.

The minimum or optimum duration of antimicrobial therapy for acute osteomyelitis is unknown. The usual recommended duration is 4 to 6 weeks, but depends on the cause and extent of infection as well as clinical and laboratory response. Older literature suggested that courses of 3 weeks or less were associated with a greater likelihood of relapse or recurrence. However, some newer studies have shown successful outcomes with 3 weeks of therapy. Each patient must be evaluated individually, taking into account the speed of clinical response, whether surgical debridement was done, normalization of CRP or ESR, and radiologic findings.

The need for open surgery in osteomyelitis depends on the extent of the pathologic process in individual patients and likely somewhat on the virulence of the specific pathogen. In children who present early in the “cellulitic phase,” antibiotic therapy alone is usually sufficient for treatment. If pus is encountered during diagnostic aspiration, if a subperiosteal or intramedullary abscess is detected by ultrasound or MRI, or if a bone lesion is evident on plain films, surgical intervention may be warranted. Patients initiated on medical therapy who do not promptly improve should also be evaluated for surgical intervention. Surgical drainage and debridement removes inflammatory products more rapidly than do host defense mechanisms, providing a more effective environment for antibiotic penetration and preventing further bone necrosis. Drainage of an abscess also reduces the inoculum of bacteria present. Any patient with a lytic lesion on plain films should have, in addition to cultures, the bone biopsy sent to pathology for histology and special stains to rule out other pathologic processes such as malignancy and to evaluate for unusual organisms such as fungi or acid-fast bacilli.

It is well accepted that Pseudomonas osteochondritis of the foot following a nail penetrating the foot through a sneaker is mainly a surgical disease. When thorough curettage and debridement are achieved, 10 days of antipseudomonal therapy are usually sufficient.

COMPLICATIONS AND OUTCOMES

Chronic Osteomyelitis

The most common complication of AHO is chronic or recurrent osteomyelitis, which occurs in fewer than 5% of cases. Symptoms may include chronic or recurrent pain, swelling, erythema, or purulent discharge, and in some cases, sinus tract formation. Development of chronic osteomyelitis is more common following nonhematogenous osteomyelitis (eg, following penetrating trauma). The hallmark of chronic osteomyelitis is bone necrosis. Therapy is primarily surgical with adjunctive long-term antibiotics. A bone biopsy should be obtained in chronic osteomyelitis for culture and for histopathology to exclude Langerhans cell histiocytosis, malignancy, and other causes.

With the increase in PVL-positive S aureus strains, especially in CA-MRSA, there has been an increase in cases of severe sepsis in adolescents with the involvement of multiple sites of osteomyelitis and septic arthritis. Deep venous thromboses have also been encountered more frequently in patients with CA-MRSA osteomyelitis but can also occur in patients infected with PVL-positive strains of MSSA. The thrombosis is usually in a vein adjacent to the infected bone site. Septic emboli have been seen in such patients leading to severe respiratory compromise. Patients who have evidence of septic emboli or persistent bacteremia should be evaluated for deep venous thrombosis by Doppler ultrasonography. Those with persistent bacteremia should also be evaluated for other causes such as endocarditis.

Other Complications and Outcomes

Pathologic fractures can occur but are rare. If the bone growth plate is involved, there is a risk of abnormal length of the affected bone. In general, the outcome of well-managed cases of acute osteomyelitis in pediatric patients is favorable.

SEPTIC ARTHRITIS

PATHOGENESIS AND EPIDEMIOLOGY

The anatomy of the synovial joint provides an environment conducive to bacterial infection. The synovial tissue lining the joint lacks a basement membrane and therefore secretes a transudate of serum. The rest of the joint surface is composed of avascular cartilage. Bacteria enter the joint by hematogenous seeding, direct extension from an adjacent focus, or direct inoculation during a joint aspiration, arthrotomy, or trauma. Initially, after bacterial invasion occurs, the synovial membrane swells and produces increased amounts of fluid, distending the joint. If infection persists without treatment, pus accumulates in the area and destruction of cartilage follows. Subluxation or dislocation of the joint may result from increased intra-articular pressure occurring when the joint capsule is distended by purulent fluid. This increased pressure may compromise blood supply in certain areas. In the hip, this may lead to avascular necrosis of the femoral head.

Delayed or inadequate treatment of a septic joint can result in permanent joint damage with subsequent disability. Septic arthritis is most common in children less than 3 years of age. In most cases, a single, large joint is involved, usually in the lower extremity. As with osteomyelitis, males are affected more frequently. There may be a history of trauma or recent infection of the skin or upper respiratory tract. Predisposing factors for the development of septic arthritis vary with age. For example, in neonates, the presence of indwelling catheters including those in the umbilical vessels increases the risk, whereas in older children, risk factors include underlying medical conditions such as immunodeficiencies, diabetes, juvenile idiopathic arthritis (JIA), and hemoglobinopathies.

ETIOLOGIC AGENTS

As in osteomyelitis, etiologic agents of septic arthritis vary by age. S aureus (MSSA and MRSA) is the leading organism in all age groups. In neonates, GBS and enteric gram-negative organisms are also important to consider and may be isolated from an affected joint as a consequence of an adjacent osteomyelitis. S aureus, S pyogenes, K kingae, and S pneumoniae are the most prominent causative pathogens in children less than 4 years of age. H influenzae type b, the most common organism in this age group in the past, is rarely seen now in countries that routinely vaccinate against this agent. In children older than 4 years, S aureus and S pyogenes are the chief pathogens.

Other bacteria reported to cause septic arthritis in children include Neisseria meningitidis, Pseudomonas (eg, following a nail injury through a sneaker), and enteric gram-negative organisms, including Salmonella (eg, sickle cell patients). Neisseria gonorrhoeae is a consideration in neonates and sexually active adolescents. Rat bite fever, an uncommon zoonotic disease caused by Streptobacillus moniliformis usually presents with the triad of fever, rash, and polyarthritis, and may be seen in children with exposure to rats as pets or otherwise.

Fungal septic arthritis is rare but occasionally encountered, especially in the immunocompromised host. Neonates, especially premature infants, who often have indwelling catheters and are exposed to broad-spectrum antibiotics, may develop septic arthritis caused by Candida species. Certain endemic mycoses such as coccidiomycosis, blastomycosis, and histoplasmosis may cause extrapulmonary manifestations in which bones and joints may be involved. The most common joint affected in patients with extrapulmonary blastomycosis is the knee followed by the ankle and elbow joints.

CLINICAL MANIFESTATIONS

Children generally present acutely with a painful, erythematous, warm joint, and refusal to move or bear weight on the affected extremity. Fever, toxicity, and irritability are often accompanying features. The joint is held in the position of most comfort, usually mild flexion. When the hip is involved, erythema or joint swelling is generally not obvious, but the affected hip is held in a position of flexion, abduction, and external rotation. Young children may exhibit the phenomenon of “referred pain,” in which symptoms from an infected hip joint are referred to the ipsilateral knee. The differential diagnosis of septic arthritis includes cellulitis, bursitis, osteomyelitis (including patellar) with or without a sympathetic effusion, reactive arthritis, transient synovitis, arthritis associated with systemic disease such as JIA, or malignancy.

DIAGNOSIS

Because of the risk of long-term orthopedic complications, septic arthritis is an orthopedic emergency. Joint aspiration is the most important component of the diagnostic evaluation. Other laboratory tests and radiologic studies are generally nonspecific, but findings may be useful to direct the evaluation (Fig. 229-3).

Joint Aspiration

For patients in whom the diagnosis of septic arthritis is suspected, aspirating the affected joint can be both diagnostic and in many cases therapeutic. Synovial fluid should be sent for Gram stain, aerobic cultures, and cell count with a leukocyte differential. Anaerobic, fungal, and acid-fast bacilli (AFB) cultures may be considered in some instances (eg, immunocompromised patients, penetrating injuries to the joint, postprocedure septic arthritis). Joint fluid cultures are positive in 30% to 60% of cases. Inoculation of joint fluid into blood culture bottles increases the yield of cultures, particularly when the etiologic agent is fastidious such as in the case of K kingae. Leukocyte counts greater than 50,000 cells/μL, with a predominance of segmented neutrophils, are suggestive of bacterial arthritis, even in the absence of a positive culture. However, it should be recognized that WBCs in infected joint fluid can vary widely, ranging from 2000 to 300,000/μL. Synovial fluid glucose and protein may be measured but are nonspecific.

Other Laboratory Tests

In addition to cultures of joint fluid, it is important to obtain blood cultures, which are positive 30% to 40% of the time. The combination of blood and joint fluid cultures reveals an etiologic agent in approximately 70% of cases. As in osteomyelitis, peripheral WBC, ESR, and CRP may be useful in the workup of the patient with suspected joint infection but are nonspecific. Although frequently abnormal, they do not confirm or exclude the diagnosis. CRP and ESR are valuable adjuncts in gauging response to therapy.

Molecular techniques have improved the diagnosis of culture-negative septic arthritis. PCR techniques are being more frequently utilized, especially when fastidious organisms such as Kingella species are suspected or in patients pretreated with antimicrobial agents. These techniques are currently available only in specialized laboratories, are costly, and may have long turnaround times, limiting their widespread use at this time.

Radiologic Studies

Plain films may demonstrate evidence of soft tissue swelling or widening of the joint space. In the hip, lateral displacement or subluxation of the femoral head may be evident. Normal plain films do not eliminate the possibility of pyogenic arthritis of a joint. Ultrasonography is a reliable method of detecting joint fluid, especially in the hip. It has the advantage of being noninvasive, usually does not require sedation, and generally is more readily available than MRI. MRI is also a sensitive method for detecting joint fluid and may demonstrate abnormalities in adjacent bone or soft tissues. The need for MRI should be discussed with the consulting orthopedic surgeon.

TREATMENT

Figure 229-3 illustrates an approach to the diagnosis and management of septic arthritis. An orthopedic surgeon experienced in the treatment of children should be involved in the management of the child with septic arthritis. The goals of therapy are as follows: decompression of the joint space and removal of inflammatory debris by adequate drainage; sterilization of the joint through the use of appropriate antimicrobial agents; relief of pain; and prevention of joint deformity.

Drainage of the infected joint may require repeated aspiration, arthroscopic lavage, or open drainage with lavage. Repeated aspiration may be appropriate in a setting where no surgeon is readily available to perform arthroscopic or open drainage, but drainage with lavage, either via an arthroscopic or an open procedure, is superior because it allows thorough cleansing and removal of inflammatory debris that cannot be evacuated by aspiration. Arthrotomy may not be necessary for infection of all joints, but is indicated for patients who fail to respond to repeated joint aspirations and in those with infections of the hip (and perhaps the shoulder). Recently, arthroscopic techniques have become more popular and cause less morbidity with similar results.

Antimicrobial therapy should be instituted immediately after blood cultures and joint fluid samples are obtained. Empiric, initial antibiotic choice is based on the likely pathogens at various ages, the results of Gram stain of the joint aspirate, and any special considerations dictated by the patient’s underlying medical problems or clinical situation.

Empiric choice of antimicrobials is similar to that recommended for osteomyelitis, and regimens for all age groups should include an antistaphylococcal agent with coverage for MRSA as dictated by local prevalence. If N gonorrhoeae is a consideration, ceftriaxone or cefotaxime should be used. Parenteral antibiotics are used initially and continued until there is no further need for surgical intervention and the child is afebrile with clinical improvement and improvement of laboratory parameters. Exact length of therapy is dependent on the clinical situation, the patient’s response, and the particular organism. Traditionally, therapy is continued for at least 2 weeks after the patient is afebrile, joint fluid accumulation has resolved, and laboratory parameters have normalized. A prospective, randomized study in Finland showed that shorter courses (3–4 days of intravenous therapy followed by oral therapy to complete 10–14 days) may suffice for MSSA septic arthritis. Clindamycin and oral cephalosporins at high doses were used in the study. In immunocompromised individuals, neonates, and other special populations, therapy should be individualized.

PROGNOSIS AND OUTCOMES

Sequelae of septic arthritis include joint deformity and residual dysfunction, abnormal bone growth, and in the hip, avascular necrosis of the femoral head (Fig. 229-4). Risk factors for subsequent complications include delay in drainage, age < 1 year, involvement of the hip or shoulder, adjacent osteomyelitis, and infection with S aureus.

SKIN AND SOFT TISSUE INFECTIONS

In many areas of the United States, the emergence of CA-MRSA has been accompanied by a marked increase in the incidence of skin and soft tissue infections, which are one of the most common manifestations of this pathogen.

It is important to differentiate uncomplicated cellulitis from other more serious disorders that require more aggressive therapy. For example, it is often difficult to determine if there may be underlying pyomyositis, osteomyelitis, or septic arthritis. Tenderness disproportionate to the soft tissue findings suggests involvement of deeper structures. It is also very important to differentiate uncomplicated cellulitis from the more serious condition of necrotizing fasciitis due to S pyogenes. Single or multiple skin abscesses often develop in conjunction with cellulitis caused by S aureus. In 2014, the Infectious Disease Society of America (IDSA) updated the Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections, which are available at www.idsociety.org.

CELLULITIS, ERYSIPELAS, AND ABSCESSES

Cellulitis is an acute localized infection of the skin involving the subcutaneous tissues. Infection usually develops as a result of a breach in skin integrity or an associated skin lesion. The term has been used interchangeably with “erysipelas,” although for some, the latter refers to an infection limited to the superficial layers of the skin, whereas cellulitis involves deeper structures. Gram-positive organisms, primarily S aureus (including MRSA) and S pyogenes, account for the majority of infections. Other organisms may occasionally be involved, particularly in neonates, in the immunocompromised host, or after trauma. Extremities are frequent sites of infection because they are more subject to minor trauma that may go unnoticed. Cellulitis in certain locations may be associated with an underlying process. Some examples include cellulitis over the buccal area associated with an odontogenic infection or cellulitis behind the ear, which is a common feature of mastoiditis.

The presence of cellulitis is usually easily recognized clinically by findings of erythema, warmth, and edema of an area. Isolating the etiologic agent in the absence of an associated abscess or purulent skin lesion is frequently difficult. Blood cultures are positive in a minority of cases, usually only those with systemic symptoms. If there is an abscess or purulent skin lesion present, material for Gram stain and culture should be obtained during drainage, which should be performed. Some literature discusses skin aspiration of cellulitis; however, in practice this is seldom performed because the yield of these cultures is low. Cultures of the skin via aspiration or punch biopsy is important in patients with malignancies, in patients who develop cellulitis after penetrating trauma, and in immunocompromised patients, as less common organisms may be isolated. Purulent collections within the skin are abscesses, and the most common etiology in children is S aureus.

Therapy in the immunocompetent child should be aimed at S aureus and S pyogenes and based on local susceptibility patterns for them. Incision and drainage constitute the primary therapy for purulent skin and soft tissue infections. Failure to perform incision and drainage has been associated with a lack of clinical response in patients with S aureus skin and soft tissue infections in a recent series. In the afebrile, nontoxic child, drainage alone is sometimes sufficient treatment. Oral therapy for cellulitis alone or as an adjunct to the incision and drainage of abscesses should include agents with coverage for MSSA, MRSA, and S pyogenes. First-generation cephalosporins provide excellent coverage if MRSA is not suspected. Clindamycin is a reasonable choice in areas where most MRSA and S pyogenes are susceptible. Doxycycline is an alternative for older children but may not provide adequate coverage for S pyogenes strains. Trimethoprim/sulfamethoxazole is also an option if S pyogenes is unlikely based on Gram stain results. Parenteral therapy should be used in the febrile patient if progression is rapid or if associated lymphangitis or lymphadenitis is present. Again, initial Gram stain results, if available, can be used to guide selection of therapy. Five to 10 days of therapy are usually sufficient for uncomplicated cellulitis if the infection has improved after 5 days. In more severe infections, treatment can be achieved by sequential parenteral-oral therapy as the patient’s condition warrants.

NECROTIZING SOFT TISSUE INFECTIONS

Some of the most feared skin and soft tissue infections are the necrotizing group: necrotizing fasciitis (NF), gas gangrene, and Fournier necrosis. These infections are life threatening and require a prompt and multidisciplinary approach between the pediatrician, surgeon, and infectious diseases physician. NF is a rare but rapidly progressive condition in which infection spreads to the fascia and subcutaneous tissues causing tissue necrosis. This condition was classically described in patients with varicella complicated by S pyogenes superinfection and subsequent development of NF. Other organisms that have been associated with the development of NF are Pseudomonas species, Aeromonas hydrophila, Vibrio vulnificus, S aureus, and anaerobic streptococci. Initially, NF may be indistinguishable from cellulitis, but usually the patients are toxic and experience pain that is out of proportion to the physical findings. As the disease progresses, bullous lesions, gas in the soft tissues (crepitation), and skin necrosis may become evident. Even though CT and MRI may help establish the diagnosis, the diagnosis is mainly clinical, and obtaining additional imaging may delay prompt initiation of appropriate treatment, which is surgical. It is common for patients to go to the operating room repeatedly until no further debridement is needed. Cultures obtained at the time of surgical intervention usually establish the infecting agent. Initial antibiotic therapy should be broad and should cover S pyogenes, S aureus, and anaerobic organisms. Frequently used antimicrobials include vancomycin or linezolid combined with either piperacillin/tazobactam, a carbapenem, or ceftriaxone plus metronidazole. Once an organism has been identified, then the antimicrobial spectrum should be narrowed. IDSA guidelines recommend continuation of therapy until no further surgical debridement is required, there is clinical improvement, and fever is absent for 48 to 72 hours.

Fournier necrosis is a clinical condition very similar to NF, but is localized to the perineum and external genitalia. It is a rare occurrence in pediatrics; however, cases have been described, especially in premature infants and immunocompromised children. Contrary to adults, the outcome is not as often fatal but necessitates the same aggressive therapy as NF.

Gas gangrene, also known as clostridial myonecrosis, is a rapidly progressive infection of the muscles caused by Clostridium species. When the infection stems from trauma, the usual organism is Clostridium perfringens, whereas when it is a result of seeding from a gastrointestinal source, Clostridium septicum is the most common organism. In the case of trauma, pain ensues 24 hours after the injury, progressing rapidly to necrosis with changes in skin color and the appearance of bullous lesions. Crepitation is a later finding. These patients are very ill, progressing rapidly to multiorgan system failure. In the nontrauma form, it is mainly seen in neutropenic patients (including patients with congenital or cyclic neutropenia) and presents with abrupt onset of severe pain accompanied by fever. The involved extremity may become edematous and change color to a purplish hue. Bacteremia precedes the infection, and therefore, blood cultures are useful. Similar to NF, combination therapy to cover Clostridium species in addition to S aureus, streptococci, and anaerobes is recommended; however, surgery is the mainstay of treatment.

PYOMYOSITIS

Also known as tropical pyomyositis, pyomyositis is an infection of the skeletal muscle characterized by phlegmon or abscess formation within the muscle tissue. Usually nonpenetrating trauma and vigorous activity seem to be predisposing factors in children. The most common symptoms include fever, swelling, and pain over the affected area and limp depending on the involved area. The most common involved sites are the proximal thigh and the hip. S aureus is the most common isolated organism (75%) followed by S pyogenes, S pneumoniae, and occasionally enteric gram-negatives. Laboratory studies usually reveal an elevated WBC, CRP, and ESR, but the creatinine kinase may be normal in the cases of hematogenous spread. The diagnosis is usually established by MRI. Occasionally, pyomyositis is associated with osteomyelitis. The treatment will vary depending whether a drainable abscess is present, in which case incision and drainage should be performed promptly. In patients in whom only a phlegmon is found, prolonged antibiotic therapy should be curative. The length of therapy for pyomyositis is usually 3 to 4 weeks using sequential parenteral-oral therapy.

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ENDOCARDITIS

INTRODUCTION

Infective endocarditis (IE) in pediatric patients is rare (5–12 per 100,000 pediatric admissions) and often associated with an underlying congenital heart defect or, increasingly, central indwelling intravascular catheters. However, structurally normal hearts may also be infected. Premature infants now account for 10% of pediatric IE. Endovascular infections outside the heart and infected thrombi are close cognates of IE.

PATHOGENESIS AND EPIDEMIOLOGY

Establishment of IE results from the interaction of several host and microbial factors. Experimental animal models have demonstrated that damage to the endocardium (as with a plastic catheter or a high-velocity jet of blood) leads to formation of a nonbacterial thrombotic lesion. Following endocardial damage, bacterial access to the bloodstream from elsewhere and subsequent adherence to endocardial surfaces are required for the establishment of IE. It is now thought that the great majority of IE develops as the result of transient bacteremia related to activities of daily life, but not all bacteria are capable of initiating this process. The endocardium appears to be a preferential site of microbial adherence and may have some specificity for binding with certain bacteria. The presence of several factors, including bacterial adhesins, endothelial binding proteins, and agglutinating antibodies that clump bacteria, promotes adherence of organisms to damaged endocardial surfaces. The Venturi effect (the reduction in fluid pressure that results when blood flows through a constricted area) deposits bacterial colonies immediately beyond the orifice that separates high- and low-pressure areas.

Bacteremia in patients with established endocarditis is generally low grade and continuous. As many as 10% of cases of IE yield consistently negative blood cultures, most often as a result of prior antibiotic therapy or organisms that are difficult to culture. Bacteria infecting right-sided heart lesions may be filtered by pulmonary phagocytes, significantly reducing the number of bacteria in a peripheral blood sample.

Classically, viridans streptococci have been the most common cause of IE, progressing along a subacute course in patients with preexisting cardiac lesions in which fever, fatigue, and immune complex–mediated clinical manifestations develop slowly over weeks or months. Enterococci behave in a fashion similar to the viridans streptococci. IE caused by Staphylococcus aureus has historically followed an acute course with rapid progression and poor outcome, including death, often in patients with normal hearts. Prosthetic heart valves within 2 months after implantation are prone to infection with coagulase-negative staphylococci and S aureus, as are neonates who require intensive care and intracardiac central lines. Gram-negative infections of the heart, although infrequent, are increasing in frequency and are most often associated with intravenous drug use, prosthetic or otherwise abnormal valves, invasive procedures, or nosocomial acquisition.

HACEK is an acronym for a group of small, fastidious gram-negative coccobacilli (Haemophilus aphrophilus, Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae). These organisms that normally inhabit the upper respiratory tract are often associated with IE when recovered from the bloodstream. Anaerobic and microaerophilic bacteria as well as polymicrobial infections are responsible for a minority of cases of IE. In adults, these infections occur mostly among intravenous drug users or originate from oropharyngeal, gastrointestinal, or genitourinary sites. Candida IE occurs occasionally, often associated with indwelling catheters. Aspergillus IE has been reported in children following open heart surgery; the blood is always culture-negative. Streptococcus pneumoniae accounts for a small minority of cases of childhood IE in both structurally normal and abnormal hearts. Infections at additional sites (eg, meningitis and pneumonia) often accompany S pneumoniae IE, and despite antibiotic therapy, intracardiac complications are frequent. Culture-negative endocarditis includes infections suppressed by prior courses of antimicrobials as well as poorly cultivable pathogens such as Bartonella, Coxiella, Tropheryma, and Brucella species that are diagnosed serologically or by nucleic acid amplification tests (NAATs). Non–culture-based methods have also identified rare or previously unrecognized organisms in IE of uncertain pathogenicity and significance; consultation with an expert in infectious diseases is advised in this circumstance.

CLINICAL MANIFESTATIONS

The “incubation period” of IE, that is, the time from initial bacteremia to onset of symptoms, is generally less than 2 weeks, although diagnosis may be delayed for weeks or months. Early manifestations may be mild or nonspecific, and patients may not seek medical attention promptly. Improper use of short courses of antibiotics for nonspecific complaints may contribute to delays in diagnosis. Fever (88%), fatigue (60%), gastrointestinal complaints (47%), and weight loss (43%) are common manifestations of IE in children. In a child with underlying congenital heart disease (CHD) and fever, fatigue, or worsening cardiac function, the diagnosis of IE requires a high index of suspicion. Patients with cyanotic CHD with artificial systemic-pulmonary shunts may show declining systemic oxygen saturation due to obstruction of flow. Splenomegaly (48%) is common, while new or changing murmurs are infrequent (24%). Among all pediatric series, extracardiac manifestations of IE are infrequent (all < 4%), including Roth spots (small hemorrhagic retinal lesions with pale centers), Osler nodes (small, tender, reddish-purple nodules typically found on the digital pads), Janeway lesions (painless hemorrhagic macules on the palms or soles), and splinter hemorrhages (linear streaks in the nail beds). Many of the classic manifestations of IE are immunologically mediated. In IE patients with arthralgia and arthritis, splenomegaly, Roth spots, glomerulonephritis, and thrombocytopenia, circulating immune complex levels are significantly higher than in IE patients without these manifestations. Levels of immune complexes decline as these physical manifestations resolve.

Common laboratory findings include anemia (37%) and elevated erythrocyte sedimentation rate (ESR; 75%). The presence of rheumatoid factor (19%) is dependent on the duration of infection. Hematuria and associated hypocomplementemia reflecting immune complex–mediated nephritis occur in 35% of patients, and aseptic meningitis has been reported in a minority of children with IE. Many neonates have neurologic signs (apnea, seizures, and paresis). Some presentations of IE are fulminant, with high fever, rapidly evolving sepsis, metastatic disease, and heart failure. Fulminant IE requires urgent intervention.

DIAGNOSIS

Proper diagnosis is key given the severity of IE and burden of treatment. In evaluating patients for IE, continuous bacteremia is typical; therefore, it is preferable to obtain at least 3 separate blood cultures over a 24- to 48-hour period while antibiotics are withheld if the patient is not acutely ill. Blood should not be drawn through indwelling vascular catheters because contamination may be misleading. If only 1 of several blood cultures of adequate volume is positive, IE is less likely. The blood culture bottles should be filled with their maximal volume using both aerobic and anaerobic bottles. If these are negative, the director of the microbiology laboratory should be alerted and 2 more cultures should be drawn before antibiotic therapy is instituted. Fungal blood cultures are rarely indicated. Commercial NAATs of blood are insensitive and do not detect HACEK organisms. Culture of explanted surgical specimens is poorly specific and should be complemented by NAATs in replicates of the explants and blood cultures.

The subtlety of clinical and laboratory findings in IE necessitates use of complex diagnostic criteria—the modified Duke criteria. In 1994, the Duke University Endocarditis Service developed new diagnostic criteria for IE based on pathologic evidence or on a combination of clinical findings, and these were modified in 2000. According to the Duke criteria, definite IE must meet 2 major criteria, or 1 major and 3 minor criteria, or 5 minor criteria. Major criteria are (1) multiple positive blood cultures for typical IE organisms and (2) evidence of endocardial involvement, either by echocardiography or by the development of a new regurgitant murmur. Minor criteria are a predisposition to IE (eg, CHD), fever, vascular phenomena, immunologic phenomena, and microbiologic or serologic evidence that does not meet major criteria. Each of the major and minor criteria has qualifying details. Modified Duke criteria may be less specific in children than adults.

Echocardiography aids in the diagnosis of IE. Transthoracic echocardiogram (TTE) should be the first-line diagnostic tool. TTE has sensitivities for diagnosis of IE from 59% to 82% in children. Transesophageal echocardiography (TEE) may improve the sensitivity for visualizing prosthetic valves and the aortic outflow tract, but it has more associated risks than TTE in children. Use of TEE should be considered when TTE acoustic window views are inadequate, when suspicion remains high despite negative TTE, when aortic lesions are suspected, for optimal evaluation of prosthetic valves, or for patients > 60 kg.

TREATMENT

Prior to the availability of antibiotics, IE was uniformly fatal. With timely and appropriate medical therapy, IE can be cured and complications minimized. As noted, when patients are clinically stable, specificity of the diagnosis is improved by multiple blood cultures of generous volume collected over a period of 24 to 48 hours before antibiotic therapy is initiated. In patients with severe toxicity, heart failure, or arrhythmias highly suggestive of acute IE, collection of multiple blood cultures over 1 to 2 hours is appropriate, followed by initiation of empiric antibiotic therapy. Following identification of an infecting organism, selection of antibiotics should be based on results of susceptibility testing.

Some basic considerations apply in determining therapy for IE. High doses of parenteral antibiotics are required to exceed the minimum bactericidal concentration for the infecting organism, and synergistic combinations are recommended in some situations (eg, enterococci) to improve effectiveness or to shorten duration of treatment. Oral antibiotics are insufficient unless bioavailability approaches 100%. Antibiotics used should be bactericidal rather than bacteriostatic, because the relatively avascular vegetations of IE offer little access to host defenses. Pediatric and adult guidelines for therapy of specific pathogens, based on susceptibility testing and the presence or absence of prosthetic material, were published by the American Heart Association (AHA) in 2015. Beta-lactams (including penicillins and cephalosporins) and vancomycin are used most frequently. Gentamicin is commonly added for a period of time to achieve synergy with a β-lactam or vancomycin, especially when enterococci or S aureus is the causative organism. Rifampin is useful as an adjunct when S aureus infects prosthetic valves.

Surgical intervention, in addition to medical therapy, is generally indicated in fungal IE, when bacteremia persists despite appropriate antibiotic therapy, when congestive heart failure is uncontrolled by medical therapy, or in the presence of any of the following: abscess of the valve annulus or the myocardium, systemic embolic events, rupture of a valve leaflet or chordae, or acute valvar insufficiency with cardiac failure. Prosthetic valve endocarditis per se is not an indication for surgery, but early surgical intervention may improve the outcome.

The most frequent complications of IE are congestive heart failure and arterial embolization. Intracardiac lesions that may lead to congestive heart failure include valvar insufficiency caused directly by vegetations or by chordal rupture, abscesses of the myocardium or valvar annulus, myocardial infarction, and conduction defects. Arterial emboli occur most frequently when large (> 10 mm) mobile vegetations develop on valves, particularly the anterior leaflet of the mitral valve. Although vegetations slowly regress with effective therapy, sudden disappearance of a vegetation should raise the possibility of embolization.

Emboli originating from left-sided vegetations can affect vascular beds in the systemic or cerebral circulation, whereas right-sided lesions produce pulmonary emboli. Cerebral emboli occur in 30% of left-sided IE and are mostly clinically silent. Head magnetic resonance imaging (MRI) is often considered for detection. Mycotic aneurysms most commonly occur at vessel bifurcations and can involve any artery. Intracranial mycotic aneurysms often require surgery.

Pericarditis may result from bacteremic spread or direct extension of infection. It is usually associated with IE due to S aureus.

PREVENTION

The AHA’s most recent recommendations for prevention of bacterial endocarditis recognize the lack of evidence to support widespread use of antibiotic prophylaxis. Only patients with cardiac conditions with the very highest risk of adverse outcomes from IE should receive prophylaxis for dental procedures (Table 230-1). The importance of good oral hygiene and routine dental care (personal and professional) should be emphasized to all cardiac patients. Table 230-2 provides the AHA’s definition of dental procedures for which prophylactic antibiotics are and are not indicated and antibiotic recommendations for the limited group of qualified patients. Because normal oral flora are altered in patients already taking antibiotic prophylaxis (eg, penicillin for rheumatic fever prophylaxis), a different class of drugs (eg, clindamycin, azithromycin, or clarithromycin) may provide more protection against the patient’s own oral microbes in that circumstance. When patients with cardiac lesions at highest risk of adverse outcomes from endocarditis (see Table 230-1) have established gastrointestinal or genitourinary infections or receive antibiotics for wound or sepsis prophylaxis during a gastrointestinal or genitourinary procedure, their antibiotic regimen should include enterococcal coverage.

ACUTE RHEUMATIC FEVER

INTRODUCTION

Acute rheumatic fever (ARF) is a nonsuppurative sequela of pharyngeal infection with group A Streptococcus (GAS). Target organs of the resultant autoimmune process include the heart, joints, central nervous system, and subcutaneous tissues. Permanent cardiac damage is the most important consequence of this disease.

PATHOGENESIS AND EPIDEMIOLOGY

Antigenic differences among GAS serotypes are related to the bacterial M protein, found within its cell wall. Recent data demonstrated a shift in prevalence from “rheumatogenic” to “nonrheumatogenic” M types in the United States over the past 40 years that parallels the decrease in the incidence of ARF over this period. The 10 days to 3 weeks period between streptococcal pharyngitis and ARF is consistent with a cellular and humoral immune response. Cross-reactivity of streptococcal antigens and human cardiac, synovial, and brain antigens also supports an immune mechanism of ARF.

Pathologic changes are found throughout the body in connective tissue and around small blood vessels. The pathognomonic lesion of rheumatic fever is the Aschoff body, a painless nodular connective tissue lesion consisting of fibrinoid changes and a collection of lymphocytes, plasma cells, and histiocytes. Within the heart, the endocardium and myocardium are most often affected; the pericardium may also be involved by extension or as serositis. Active valvulitis results in variable degrees of valve insufficiency, with chronic changes possibly leading to valvar stenosis. The mitral and aortic valves are affected most commonly, the tricuspid less frequently, and the pulmonary valve rarely.

Pathologic changes in the joints consist of joint effusion, exudation with edema of synovial membranes, focal necrosis in the joint capsule, and edema and inflammation in periarticular tissue. These changes are completely reversible. Subcutaneous nodules seen during the acute phase of the disease histologically resemble Aschoff bodies. “Rheumatic pneumonia” consists of exudative and inflammatory changes without Aschoff bodies. Pathologic changes in patients with chorea are not consistent, and little postmortem information is available because patients with active chorea rarely die.

ARF occurs most often in the winter and spring seasons and in children ages 5 to 15 years. Much less commonly, it has been reported in the preschool age group. There is familial susceptibility to ARF. Asian/Pacific Islander children have recently been identified as a group with possible increased genetic susceptibility. Patients with ARF have a high likelihood of recurrence when reinfected with GAS; this tendency declines with age and with increased time since the last episode. Environmental factors such as nutrition, crowding, and age all appear to influence the incidence of ARF, probably because the same factors influence the incidence of streptococcal pharyngitis.

CLINICAL MANIFESTATIONS

Many of the clinical manifestations of ARF occur in other infectious and inflammatory disorders, and so ARF must meet complex diagnostic criteria. The revised Jones criteria vary for areas of high and low ARF endemicity. Diagnosis requires that an individual have either 2 major criteria or 1 major criterion plus 2 minor criteria along with evidence of streptococcal infection. Exceptions are chorea or indolent carditis, which each may by itself indicate rheumatic fever. The diagnostic criteria are listed in Table 230-3.

Classic ARF presents with acute migratory polyarthritis associated with fever. The joints are red, hot, swollen, exquisitely tender, and painful if moved. In general, the larger joints of the extremities are affected, but arthritis rarely may occur in the spine and other joints such as the temporomandibular and sternoclavicular joints; arthritis of fingers and toes is more common in older than younger patients. Usually, pain and effusion subside in 1 joint as another becomes involved, but several joints may be involved simultaneously. Polyarthritis is the most common of the major criteria and lasts less than 4 to 6 weeks when untreated. Characteristic is a dramatic response to salicylates and nonsteroidal anti-inflammatory drugs (NSAIDs); early use in febrile children may confound diagnosis.

Rheumatic carditis may be asymptomatic. Echocardiography diagnoses 17% more cases of carditis than auscultation. Carditis may affect the endocardium (valves), myocardium, or pericardium. Endocarditis manifested by pathologic murmurs is the hallmark of ARF carditis. The most frequent murmur is an apical regurgitant systolic murmur of mitral regurgitation. With severe mitral regurgitation, the third heart sound may be followed or replaced by a low-pitched mid-diastolic rumble. The early diastolic murmur of aortic regurgitation is the second most common murmur in ARF and generally occurs only in patients who also have mitral regurgitation.

Myocarditis may be manifested by tachycardia disproportionate to the fever, a gallop rhythm, or arrhythmias. Cardiomegaly may be evident on radiograph. Severe myocarditis may result in congestive heart failure with signs including jugular-venous distention, hepatomegaly, and pulmonary edema with rales. Prolongation of the P-R demonstrated on an electrocardiogram interval is common but does not indicate carditis.

Pericarditis may appear suddenly and may be associated with precordial pain and a friction rub. More often, however, patients with pericarditis are asymptomatic. Pericarditis seldom appears without endocarditis and myocarditis, the combination being termed pancarditis. Death may occur during the acute phase of carditis; permanent cardiac damage may result in long-term disability, usually because of mitral or aortic valvar insufficiency and/or stenosis.

Sydenham chorea is characterized by sudden, aimless, irregular movements of the extremities frequently associated with emotional instability and muscle weakness. Whereas carditis and arthritis develop within weeks after an inciting streptococcal infection, chorea presents after several months and is not often associated with other features of ARF except perhaps mild carditis. The onset may be gradual, with complaints that the child is nervous. The child may become clumsy and stumble, fall, or drop objects. Often there are complaints of poor attention and deteriorating handwriting and school performance. Facial grimacing and various speech disorders occur. As chorea becomes more severe, irregular jerking movements can be sufficiently violent to cause injuries. Muscle weakness may be profound. The choreiform movements subside during sleep and are exaggerated by emotion. Characteristically, when the patient is asked to extend the arms, hands, and fingers, flexion of the wrists and hyperextension of the metacarpophalangeal joints (“silver forking”) are observed. The pronator sign may be elicited: after the arms are raised above the head, there is gradual pronation of the hands (apposition of the dorsal aspects of the hands). Other signs are an inability to hold the tongue still when it is protruded and spasmodic contractions of the hands when the patient intentionally grips objects or the examiner’s hand (milkmaid’s grip). Chorea can also be caused by diseases other than ARF, such as systemic lupus erythematosus (SLE) or Wilson disease, and patients who present with chorea as the only manifestation of ARF should undergo a full evaluation.

Subcutaneous nodules are rare and manifest as painless small (0.5–1 cm) swellings over bony prominences, primarily over the extensor tendons of the hands, feet, elbows, scalp, scapulae, and vertebrae. Nodules tend to occur in crops and may persist for days to months after the onset of ARF, generally with severe carditis. Subcutaneous nodules are not specific for ARF and may occur in rheumatoid arthritis as well as SLE.

Erythema marginatum occurs in less than 10% of ARF patients; it may be seen more frequently in children less than 5 years old. The characteristic rash consists of an evanescent, pink, erythematous macule, with a clear center and serpiginous outline (Fig. 230-1). The rash is transient, migratory, and not pruritic; it blanches with pressure, is exacerbated by warmth, and is found primarily on the trunk and proximal extremities, sparing the face.

DIAGNOSIS

Proof of previous streptococcal infection is required in addition to combinations of major and minor criteria. Paired, increasing serum antistreptococcal antibody titers are probably the most specific and reliable proof of previous streptococcal infection. A rising antibody titer to specific streptococcal antigens is more specific than a single elevated value. However, if the patient presents with chorea more than 3 months after the acute streptococcal infection, then antibody titers may be declining or low. The most widely used serologic test is antibody formation against streptolysin O. Titers of at least 333 U in children and 250 U in adults are usually considered elevated. Other available antibody tests are antideoxyribonuclease B, antihyaluronidase, antistreptokinase, and antinicotinamide-adenine-dinucleotidase. A 4-fold rise in titer to 1 or more of the above antigens can be demonstrated in virtually all cases of acute or recurrent rheumatic fever if serum samples are obtained within 2 to 3 months of the streptococcal infection. Titers may remain high for up to a year. Patients who present with fever, rash, arthritis, or carditis should also have studies to exclude SLE and rheumatoid arthritis. These include antinuclear antibodies, anti-deoxyribonucleic acid (DNA) titers, and rheumatoid factor.

Demonstration of GAS by rapid antigen detection, NAATs, or culture of the throat of a patient suspected of having ARF provides strong evidence for the diagnosis. Because of lower sensitivity, negative rapid antigen tests should be followed by culture. Caution is needed, however, as most ARF patients clear their streptococcal pharyngitis without antibiotic therapy, and many children are chronic pharyngeal carriers of GAS unrelated to ARF. Failure to demonstrate GAS in the throat of patients with ARF may be related to prior antibiotic therapy, small numbers of organisms, or improper testing technique, but most often reflects spontaneous clearance.

The 2015 revised Jones criteria recommend use of echocardiography for suspected or confirmed ARF and consideration of serial use in such patients. This should be done even in the absence of auscultatory findings.

Absence of ESR > 60 mm/h and C-reactive protein (CRP) > 3.0 mg/dL argues against ARF. Leukopenia and abnormal urinalysis probably do not occur in rheumatic fever, and if found in a patient with joint and cardiac abnormalities, they are more suggestive of SLE.

TREATMENT

A full course of oral or intramuscular penicillin as given for GAS pharyngitis should be administered to all patients with ARF even if testing for GAS is negative. An oral cephalosporin is an acceptable alternative; macrolide antibiotics, such as erythromycin, clarithromycin, or azithromycin, should be limited to penicillin-allergic patients. Tetracyclines and sulfonamide drugs are not appropriate for treatment of the streptococcal infection.

If a child with ARF is free of clinical carditis, normal activity can be resumed once the pain and fever resolve. If there is mild carditis, a period of 1 to 2 weeks resting at home is reasonable. The murmur may persist indefinitely, and its disappearance is not a requisite for return to activity. The ESR may remain high for weeks, showing gradual decline. Patients with severe carditis, as evidenced by marked cardiomegaly or congestive heart failure, should remain at bed rest for several weeks, until the heart size returns to normal or is at least stable.

Salicylates, NSAIDs, and steroids are beneficial in controlling the acute clinical manifestations of ARF. Arthritis and fever respond dramatically to salicylate therapy, often within hours of initiation. Acetylsalicylic acid is usually used in relatively high doses (50–70 mg/kg/d) for a duration related to the course and severity of the disease; the minimum period is usually 6 weeks. Prior to discontinuation, the dose should be reduced gradually over 2 to 4 weeks. If rebound of rheumatic activity occurs, full therapy may have to be reinstituted for an additional 4 to 6 weeks.

In patients with moderate to severe carditis, neither salicylates nor steroids demonstrate superiority over the other drug in modifying the duration of acute disease or lessening the residual heart damage. However, steroids are indicated in patients who develop congestive heart failure. Current understanding suggests unlikely benefit from digoxin, with the exception of associated arrhythmias. Occasionally, severe incompetence of aortic and/or mitral valves leads to refractory heart failure, which requires surgical implantation of a prosthetic valve.

Specific treatment for chorea is not available. Physical and mental stress should be minimized, and protective measures to prevent injury during severe episodes should be instituted. In very severe cases, steroids, phenobarbital, and valproic acid have been helpful.

Prophylaxis against recurrent ARF should be instituted immediately following acute therapy. The most effective prophylaxis consists of benzathine penicillin G intramuscular injections every 4 weeks; the injection can be painful and may lead to reactions. Alternative therapy consists of either oral penicillin V twice daily or oral sulfisoxazole once daily. Patients without rheumatic heart disease are at lower risk of recurrence than are patients with carditis or valvar disease. In pediatric ARF patients without carditis, prophylaxis should continue for at least 5 years or until age 21, whichever is longer. When ARF includes carditis but no clinical or echocardiographic evidence of residual valvar disease, the duration of prophylaxis should be extended to at least 10 years or well into adulthood, whichever is longer. Patients with persistent valvar disease following ARF with carditis should continue prophylaxis for at least 10 years and until at least age 40. Lifelong prophylaxis should also be considered in this group.

Approximately 75% of patients with ARF are well after 6 weeks. By 6 months, fewer than 5% remain symptomatic with chorea or intractable carditis. Up to 70% of patients who develop carditis during the initial episode of ARF recover without any residual heart disease. Whereas 70% of ARF patients with congestive heart failure and pericarditis develop permanent heart disease, only 20% of patients with mild carditis are permanently affected. When more than 8 weeks have elapsed after stopping treatment, ARF does not recur in the absence of recurrent streptococcal infection. In individual patients, the clinical features of recurrent episodes of ARF tend to be similar to that of the initial episode. The likelihood of permanent residual heart damage following carditis increases with each recurrence. Patients who have had chorea without apparent carditis may present years later with mitral stenosis.

PREVENTION

Most acute pharyngitis is caused by viruses and, less commonly, other bacteria. Only GAS pharyngitis leads to ARF, and ARF is rare in the United States. Well under 3% of confirmed streptococcal pharyngitis infections cause ARF in the United States, while carriers of GAS (with minimal risk of ARF) approximate 10% to 15% of children. The emphasis is therefore on the specificity of diagnosing acute streptococcal pharyngitis to minimize inappropriate therapy and attendant medical risks. The clinical syndrome of streptococcal pharyngitis is variable (abrupt sore throat, cervical adenopathy, fever, headache, often abdominal pain and rash) and not specific; laboratory testing is necessary. Gold standard laboratory testing is by culture. As noted, rapid antigen testing is usually less sensitive than culture, although NAATs approximate culture sensitivity and specificity. The epidemiologic peak of GAS pharyngitis and the risk for developing ARF are between 5 and 15 years of age. Protocols for testing for acute GAS pharyngitis in adults account for the lower GAS prevalence and risk for ARF beyond 15 years of age and are not to be used in children.

Children with compatible clinical presentation, the absence of signs of viral disease (conjunctivitis, coryza, cough, diarrhea, or characteristic viral exanthems or enanthems), and rapid antigen testing, NAAT, or culture detecting GAS in the throat should be treated to prevent ARF (Table 230-4). Preferred regimens include oral penicillin V 2 to 3 times daily or a single daily dose of amoxicillin for 10 days. Parenteral benzathine penicillin is generally reserved for patients with poor compliance. Penicillin-allergic patients should receive a first-generation cephalosporin, clindamycin, or a macrolide. Macrolide resistance by GAS varies geographically. Testing for cure is not generally indicated.

MYOCARDITIS AND PERICARDITIS

INTRODUCTION

The myocardium is specialized muscle and a conduction system that is isolated from the bloodstream by the endocardium; it is perfused by the coronary arteries. The pericardium is made up of 2 layers, which form a sac around the heart, anchored at the origins of the great vessels. The visceral layer is a single layer of mesothelial cells adherent to the myocardium. The parietal layer lies against the mediastinal and pleural spaces and is made up of collagen and elastin fibers. The pericardium is relatively avascular but well innervated.

ACUTE MYOCARDITIS

PATHOGENESIS AND EPIDEMIOLOGY

Acute myocarditis is an acute, patchy inflammation of the heart muscle that accounts for 2% of cases of heart failure. Most pediatric heart failure is due to genetic cardiomyopathies (14%) or is associated with severe CHD (69%) or arrhythmias (15%). In developing countries, nutritional deficiencies and ARF (see above) also contribute to heart failure.

In developed countries, acute myocarditis can be associated with viral infections. Respiratory symptoms are common (56%). The virus infection is usually cleared and then followed by an autoimmune attack and the presence of sarcolemmal antibodies. The myocardium may recover fully from the infection and autoinflammation. If damage is extensive, the heart may dilate chronically. The myocardium is not well innervated, so acute myocarditis often manifests as exertional fatigue, difficulty feeding and abdominal pain, peripheral edema, and palpitations.

The most common organisms infecting the myocardium are enteroviruses (including coxsackieviruses). Adenovirus, Epstein-Barr virus (EBV), herpes simplex virus (HSV), human herpesviruses (HHVs) 6 and 7, cytomegalovirus (CMV), and human immunodeficiency virus (HIV). Many of these are endemic human infections that reactivate commonly. Human parvovirus B19 may be detected for up to a year after primary infection. Genomic material from these persistent or prolonged infections may persist for months to years in tissues. Distinguishing true infection of the myocardium by viruses other than enteroviruses is challenging and best accomplished in population studies that include healthy controls. Acute bacterial myocarditis is rare and most often caused by Mycoplasma pneumoniae, Coxiella burnetii, or Borrelia species. Sepsis, notably pneumococcal, meningococcal, and rickettsial, may lead to severe myocardial dysfunction. Cardiac “stunning” associated with high neurogenic peripheral vascular resistance is a hallmark of enterovirus-71 infection.

CLINICAL MANIFESTATIONS

Acute myocarditis is characterized by reduced ejection fraction of the heart, usually affecting both pulmonary and systemic circulations. In most pediatric patients, the presentation is acute heart failure following a viral prodrome. In infancy, this may manifest by sweating, pallor, tachycardia disproportionate to fever, tachypnea, gastroesophageal reflux and difficulty feeding with consequent growth failure. In older children, there is fatigue (17%), dyspnea, orthopnea, exercise intolerance, cough, nausea, vomiting, and abdominal pain, pericarditis/chest pain (7%), or syncope (5%). Fever, regurgitant murmurs, gallops, jugular venous distension, and peripheral edema or ascites are variable. There may be associated findings of a respiratory or systemic infection, autoinflammatory or autoimmune disorder, or endocrinopathy.

DIAGNOSIS

Echocardiography should be prioritized because it is highly sensitive and specific for acute or fulminant myocarditis. An echocardiogram commonly demonstrates wall motion abnormalities and ventricular dysfunction proportionately less than dilation when compared to myocarditis with dilated cardiomyopathy. Cardiac magnetic resonance (CMR) imaging can provide additional and often superior information to echocardiography. CMR can further assess tissue characteristics such as edema, hyperemia, and fibrosis/scarring of the myocardium. It also can show patchy areas of inflammation and may delineate adjacent pathology in the lung, pleural space, and mediastinum. Chest x-ray is insensitive but may show an enlarged heart. Electrocardiogram is not specific but often abnormal. Electrolytes and renal and hepatic function may be altered. Blood levels of CRP, B-type natriuretic peptides (BNP) or N-terminal (NT)-proBNP, troponin, and creatine kinase-MB concentrations are often elevated. Borrelia and rabies infections are often also associated with progressive heart block. Blood NAAT is highly sensitive for enteroviruses during systemic infection; enteroviruses persist for weeks in respiratory and fecal samples, which may mislead the clinician. NAAT of blood for adenovirus, EBV, HSV, CMV, HHV-6 and -7, and human parvovirus B19 are difficult to interpret. The gold standard for diagnosis and staging of myocarditis (infectious, autoimmune, and chronic forms) is endomyocardial biopsy (EMB). The patchy nature of the disease (evident by CMR), thinner right hearts, and lack of evidence for benefit of standard therapies in children often lead to individualized decisions regarding EMB. Gene panels and metabolic tests for cardiomyopathies are recommended.

TREATMENT

Treatment is mainly supportive and symptomatic care. Therapy involves cardiac monitoring in hospitals capable of electrophysiologic and mechanical circulatory support, diuretics, and inotropes. Use of corticosteroids and intravenous immune globulin (IVIG) is not supported by meta-analyses or large registries. Broad-spectrum antivirals under development (eg, favipiravir) may be useful in the near future. Outcome is generally good, with 66% recovering fully. Paradoxically, patients with the worst ejection fraction acutely often recover the best. Damage in 24% of cases may result in cardiac transplantation or death.

Acute myocarditis may be associated with chest pain and pericarditis (perimyocarditis) and is treated as myocarditis. Pericarditis may be associated with mild myocarditis (myopericarditis) and is treated as pericarditis.

ACUTE PERICARDITIS

PATHOGENESIS AND EPIDEMIOLOGY

Acute pericarditis is an acute inflammation of the pericardial layers. It is most common in early adolescence, particularly in males. Pericarditis in developing countries is usually tuberculous but is viral or idiopathic in industrialized regions. Viral pericarditis often follows a respiratory infection. Enteroviruses, especially the Coxsackie B viruses, are well known to affect the pericardium, with or without associated myocarditis. Sometimes the causative agent can be identified in pericardial fluid by antigen detection tests, NAAT, or viral culture, or may be demonstrated in blood. Detection of viruses from nasopharyngeal or rectal sites often does not correlate with results from pericardial fluid or tissue.

Purulent pericarditis occurs either by hematogenous spread or extension from a septic focus in the lung (pneumonia or empyema), liver abscess, or, rarely, after cardiac surgery. The most common organisms are staphylococci, pneumococci, streptococci, meningococci, and Haemophilus influenzae type B (the latter is much less common in countries with universal childhood vaccination against this pathogen); these organisms can usually be isolated from blood, pleural or pericardial fluid, or other metastatic sites. Fungal pericarditis generally occurs in immunocompromised hosts.

CLINICAL MANIFESTATIONS

Acute pericarditis is most often manifested by pain (85%), irritability, anorexia, and sometimes fever. The pain is precordial or referred to the epigastrium, neck, shoulder, or left arm; it may be relieved by leaning forward and made worse by deep inspiration or coughing. A friction rub (in < 33%) may be heard along the left sternal border as a high-pitched grating sound, similar to the sound of sandpaper rubbing on wood. It is always in phase with the heart sounds, but may vary by respiration or posture and disappears with an enlarging effusion. Tamponade and constrictive pericarditis are rare. Recovery occurs spontaneously in 2 to 4 weeks.

Purulent pericarditis has an acute onset, with high spiking fever, marked blood polymorphonuclear leukocytosis, and severe toxicity. Symptoms may be modified if the patient has received antibiotics.

DIAGNOSIS

There is usually a polymorphonuclear leukocytosis. The electrocardiogram (in < 60%) initially shows elevation of the S-T segments in most leads; after about 1 week, the S-T segments return to normal and are associated with T-wave flattening and then inversion in the same leads. These changes may persist for months after the acute lesion resolves. Echocardiography reveals an effusion (in < 60%) that is usually mild and excludes cardiac tamponade (present in 2%). CMR and computed tomography provide superior visualization of associated chest abnormalities, pericardial thickening, and evidence of inflammation. CRP is recommended in patients with effusion.

ARF, juvenile inflammatory arthritis, SLE, uremia, Kawasaki disease, dissecting aneurysm, hypothyroidism, neoplasm, sarcoidosis, acute myocardial infarction, and acute pancreatitis are rare causes of pericardial disease. Pericardial effusions are also seen with fetal hydrops.

TREATMENT

Treatment for isolated pericarditis is NSAIDs, aspirin, low-dose colchicine, or combinations when response is poor. Corticosteroids may lead to more recurrences and are reserved for specific diseases causing pericarditis (eg, leukemia, tuberculosis, SLE). Risk factors for poor prognosis include fever > 38.0°C, subacute course, large pericardial effusion, and failure to respond within 7 days to NSAIDs.

Specific antibiotic treatment of purulent pericarditis depends on the bacteria identified, but initial empiric antibiotic therapy should include coverage of the usual organisms. Antibiotic therapy should be continued for 3 to 4 weeks. Close observation for tamponade is essential. Surgical drainage of the pericardial cavity is recommended to reduce high mortality and the 25% risk of constrictive pericarditis, which may follow cure; extended follow-up is necessary.

SUGGESTED READINGS

INTRODUCTION

Diarrheal disease due to infectious enteritis remains a significant global health burden, accounting for 1 in 9 child deaths worldwide, and is the second leading cause of mortality in children less than 5 years of age in resource-poor countries. In the United States, it is estimated that young children have 1 to 3 episodes of diarrhea each year, with the highest rates reported in those attending childcare centers. This chapter will focus on common enteric pathogens causing acute diarrhea in children.

PATHOGENESIS AND EPIDEMIOLOGY

Many enteric pathogens cause gastrointestinal (GI) infections in children, especially in those less than 5 years of age (Table 231-1). These pathogens are acquired via the fecal-oral route directly from another person or indirectly following ingestion of food or water contaminated with feces. Person-to-person transmission generally requires only a low-dose inoculum to produce infection and has a short incubation period.

Enteric pathogens cause diarrhea by altering the balance between secretion and absorption of fluids and electrolytes in the GI tract. This can occur by means of a direct effect on enterocyte ion transport and the tight junction barrier or indirectly through virulence factors that cause inflammation. Based on pathophysiology, infectious diarrhea can be categorized as secretory, osmotic, or inflammatory. Secretory diarrhea is the result of active water loss into the GI tract with minimal inflammation, as is classically described with infections such as Vibrio cholerae. Osmotic diarrhea occurs when there is failure to absorb solutes, which then retain water within the GI tract (eg, consuming undiluted concentrated formula). Damage to enterocytes can result in transient lactase deficiency, which in turn results in lactose malabsorption. Inflammatory diarrhea occurs when pathogens, or their enterotoxins, damage enterocytes, leading to villous destruction and impaired water absorption. Infections caused by Salmonella and Clostridium difficile primarily cause inflammatory diarrhea and are characterized by detection of polymorphonuclear white cells in stool.

In cases of suspected infectious enteritis, epidemiologic risk factors may allow consideration of a specific pathogen. Exposures to animals (eg, reptiles), contaminated water, travel to endemic areas, recent receipt of antibiotics, or attendance at a childcare center are important risk factors. For example, Giardia and Cryptosporidium are the most common gastrointestinal infections reported with waterborne outbreaks. Outbreaks of enteric infections in children attending childcare centers have included bacteria (Shigella, Escherichia coli including O157:H7), viruses (adenovirus, astrovirus, norovirus, and rotavirus), and parasites (Cryptosporidium parvum and Giardia lamblia). National outbreaks of infectious bacterial enteritis have followed ingestion of undercooked ground beef, chicken, or pork (E coli O157:H7 and other Shiga-toxin producing E coli [STEC], Salmonella species), raw fish (Salmonella species), milk products (Listeria monocytogenes), nuts (E coli O157:H7, Salmonella species), and raw fruits or vegetables (E coli O157:H7, L monocytogenes, Salmonella species).

In developed countries, viral agents are the most frequent cause of infectious diarrhea in children. In the United States, rotavirus was the most common cause of gastroenteritis before the introduction of routine rotavirus vaccination in 2006. Currently, human caliciviruses such as norovirus are the most frequent cause of infectious enteritis in children < 5 years of age. The most commonly isolated bacteria causing acute infectious enteritis are Campylobacter and Salmonella species, followed by Shigella and E coli O157:H7 and other STEC. An increasing incidence of antimicrobial-associated C difficile–associated diarrhea (CDAD) in hospitalized children has been reported.

CLINICAL MANIFESTATIONS

Most GI infections present with acute diarrhea, defined as 3 or more loose stools per day and generally lasting less than 7 to 14 days. In breastfed and young infants who normally have 3 to 10 stools per day, diarrhea can be defined as an increase in stool frequency to twice the usual number per day. Diarrhea may be accompanied by other signs of enteric involvement including vomiting, abdominal pain or distension, bloody stools, or fever. In children with acute viral gastroenteritis, nausea and vomiting may be the predominant symptoms early in the illness. Enteric fluid losses can lead to dehydration and electrolyte imbalance. In severe cases, children may present with hypovolemic shock with hypotension and altered mental status.

In general, the effects of enteric infections are confined to the intestinal mucosa. Extraintestinal manifestations result from spread of the enteric infection beyond the GI tract or from immune-mediated mechanisms. Young infants and immunocompromised children are at higher risk for extraintestinal invasive disease. Salmonella species can lead to bacteremia or focal infections in susceptible hosts. In the United States, the incidence of invasive Salmonella infections is highest among infants < 3 months of age and can present with bacteremia and/or meningitis. Additional extraintestinal manifestations include osteomyelitis, suppurative arthritis, peritonitis, hepatitis, pneumonia, and endovascular conditions (eg, endocarditis, arteritis, thrombophlebitis). Immune-mediated extraintestinal manifestations tend to occur after the bacterial enteritis has resolved and include reactive arthritis, Guillain-Barré syndrome, hemolytic anemia, erythema nodosum, and renal complications including glomerulonephritis, IgA nephropathy, or hemolytic-uremic syndrome.

DIAGNOSIS

Most cases of infectious enteritis in otherwise healthy children are self-limiting and, as such, do not require diagnostic testing. Clinical practice guidelines recommend diagnostic testing of stool in cases of dysentery (characterized by the presence of frequent, small-volume diarrheal stools that contain mucus or visible blood), moderate to severe disease, patients with prolonged symptoms (lasting > 7–14 days), and those at high risk for complications. Testing is also recommended when there is an outbreak in communities or childcare centers. The combination of fever and bloody stools is highly indicative of a bacterial enteric pathogen such as Campylobacter, Salmonella, Shigella, and E coli 0157:H7 or other STEC. The presence of fecal leukocytes is associated with inflammatory enteroinvasive infections, such Shigella, Salmonella, enteroinvasive E coli, and amoeba, but not with toxin-producing bacteria such as V cholerae or enterotoxigenic E coli. Fecal leukocyte detection by microscopy is approximately 90% specific in differentiating bacterial from nonbacterial causes of diarrhea, but leukocytes can also be identified in noninfectious inflammatory bowel diseases such as Crohn disease or ulcerative colitis. Additional fecal markers of intestinal inflammation include lactoferrin, which has a high sensitivity (95%) but low specificity for infectious enteritis, and fecal calprotectin, which is reported to be 93% sensitive and 88% specific for detection of bacterial infection. In general, use of fecal biomarkers is considered insufficiently reliable for detecting infectious causes of diarrhea, and pathogen-directed diagnostic methods remain the standard of care.

Identification of specific enteric pathogens in some cases may be labor intensive, costly, and time consuming, and require a combination of culture, antigen assay, and nucleic acid detection by polymerase chain reaction (PCR). Recent application of culture-independent methods using broad-range multiplexed molecular assays has allowed for simultaneous testing for multiple pathogens. These syndromic panels detect multiple bacterial, viral, and parasitic pathogens that have been associated with infectious diarrhea, and they offer improved sensitivity over culture. While these assays provide a more rapid means of identifying bacterial enteric pathogens, they may lack specificity for the cause of the current illness and do not detect all potential pathogens. For these reasons, bacterial culture remains an important means of identifying a specific pathogen and performing antibiotic susceptibility testing.

TREATMENT

Because children have greater insensible water loss and limited renal compensation compared with adults, they are at greater risk for fluid depletion and dehydration during an episode of acute diarrhea. As such, they should be assessed for signs of dehydration and hypovolemia on clinical examination and have therapy directed at fluid and electrolyte replacement. In those with severe dehydration and hypovolemic shock, intravenous fluids with isotonic crystalloid should be initiated and continued until circulating blood volume is restored while monitoring the patient’s vital signs and urine output. Electrolyte derangements may occur and require correction in patients with severe diarrhea.

Oral rehydration therapy (ORT) is recommended by the American Academy of Pediatrics and the World Health Organization (WHO) as the preferred treatment for fluid and electrolyte losses in children with mild to moderate dehydration. Commercial ORT solutions are recommended. Fruit juices, sports drinks, and sodas are contraindicated and may aggravate fluid losses in the acute phase due to their high osmolar concentration. Following rehydration, children should be offered an unrestricted age-appropriate diet together with additional oral fluids to replace ongoing stool losses.

Empirical antimicrobials are not recommended for children with suspected infectious gastroenteritis. An exception may be made for children with suspected traveler’s diarrhea as bacterial causes are more frequent than parasitic or viral causes and occur most commonly in the first 2 weeks of travel. Antibiotics effectively shorten the duration of moderate to severe traveler’s diarrhea in adults. Because there are no good data for children in this regard, recommendations are derived from adult studies. Ciprofloxacin and azithromycin as single doses or 3-day therapy regimens are generally the preferred agents, with azithromycin favored in younger children. Nalidixic acid has also been used to treat traveler’s diarrhea in children. The choice of agent also depends on the geographic destination; for example, a high rate of fluoroquinolone resistance in Southeast Asia makes azithromycin a more prudent choice if traveling to these areas. Use of antimotility agents is not recommended for the treatment of acute diarrhea in children.

Antimicrobial therapy may be indicated when certain bacterial and parasitic pathogens are detected in patients with moderate to severe disease, but the benefits and risks of antimicrobial therapy should be carefully considered. Targeted antibiotic therapy is effective in shortening the duration of dysentery and reducing the shedding of Campylobacter and Shigella species in stool. Antimicrobial therapy has proven efficacy against CDAD and most parasitic causes of infectious enteritis, including Giardia and Cryptosporidium. Conversely, antibiotics should be avoided in patients with enterohemorrhagic E coli and STEC because there is some evidence that their use increases the risk for hemolytic-uremic syndrome. Antibiotics are also not indicated in uncomplicated gastroenteritis caused by Salmonella species in otherwise healthy patients as this can lead to prolonged shedding or a chronic carrier state. Antimicrobial therapy against Salmonella species is recommended for children at risk for invasive or complicated disease, including children less than 3 months of age and those with underlying chronic GI tract disease, malignancies, hemoglobinopathies, or other known immunosuppressive illnesses or therapies.

A single dose of ondansetron has been shown to reduce the frequency of vomiting and allow successful rehydration with ORT. The role of other adjunctive therapies such as probiotics for the treatment of infectious enteritis is less clear and requires additional controlled data.

PREVENTION

Because enteric pathogens are acquired via the fecal-oral route, strict hand washing, observing safe food preparation including washing of raw products and thorough cooking of eggs and other foods of animal origin, and access to clean drinking water are imperative to prevent spread of infection. In areas where clean water is not available, use of alcohol-based hand sanitizers containing at least 60% alcohol may be considered, although when hands are heavily soiled, sanitizers may be less effective than handwashing with soap and water for infections caused by C difficile, Cryptosporidium, or norovirus.

Certain bacterial infections (Campylobacter, Cryptosporidium, E coli O157:H7 and other STEC, Shigella, Salmonella, Vibrio species) are reportable to local and state US public health departments given concern for potential epidemic spread. In general, children are considered contagious for as long as the diarrhea is present. However, the risk of transmission of infection persists for as long as an infected person excretes the organism. For example, in children < 5 years of age with nontyphoidal Salmonella species GI infections, 45% will continue to excrete organisms 12 weeks after infection, long after symptoms have resolved.

Since the introduction of routine rotavirus vaccination in the United States in 2006, rates of healthcare utilization and hospitalization for rotavirus gastroenteritis have significantly decreased. As such, the WHO recommended inclusion of rotavirus vaccination in all national immunization programs globally in 2009, with expectations to lower the global burden caused by rotavirus diarrhea. Typhoid vaccine, both as oral live-attenuated and intramuscular polysaccharide formulations, is available for use in patients ≥ 6 years of age and ≥ 2 years of age, respectively. Overall efficacy of these vaccines ranges from 50% to 80%. They do not provide complete protection against Salmonella typhi serovars, do not provide reliable protection against Salmonella paratyphi, and have a variable duration of protection. Use of the oral typhoid vaccine is contraindicated in immunocompromised patients. Currently, recommended indications for typhoid vaccination include travelers to the Indian subcontinent, South and Southeast Asia, Latin America and the Caribbean, the Middle East, and the African continent who will have prolonged exposure to contaminated food and drink and intimate exposure to a household contact known to be a carrier. Typhoid vaccine is not a substitute for careful hand hygiene and safe food and water practices. A live cholera vaccine was recently approved by the US Food and Drug Administration for the prevention of V cholerae caused by serogroup 01 in otherwise healthy patients ≥ 18 years of age traveling to cholera-endemic countries. The single-dose, oral cholera vaccine should be taken at least 10 days before travel and may be shed in the stool of recipients for at least 7 days.

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INTRODUCTION

Patients with infections of the liver generally present with nonspecific symptoms such as fever, fatigue, abdominal pain, or weight loss. The abdominal pain may be diffuse, be confined to the right upper quadrant, or radiate to the shoulder or back. Other symptoms may include headache, arthralgias, and adenopathy. The initial history should focus on geographic location or travel, unprotected sex or drug use, use of hemodialysis or blood products, other recent exposures, vaccination/immune status, chronicity of symptoms, anatomical anomalies or surgery that may affect the biliary tracts, and family history of hepatitis. Physical exam is often normal; some patients will have right upper quadrant or diffuse abdominal tenderness and hepatomegaly. Jaundice or stigmata of chronic liver disease is infrequent. For additional details regarding viral hepatitis, please refer to Table 232-1 and Chapter 303.

Laboratory findings of liver infection often consist of leukocytosis, elevated erythrocyte sedimentation rate (ESR), and variable elevation of bilirubin, aminotransferases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]), alkaline phosphatase, and γ-glutamyl transferase (GGT). Liver ultrasound is useful in initial evaluation of suspected liver infection because it can screen for liver abscess or bile duct anomalies.

BACTERIAL CHOLANGITIS

Cholangitis is an infection of the biliary tracts and is seen most commonly in patients with abnormal biliary tracts such as post-Kasai (portoenterostomy) for biliary atresia. After portoenterostomy, nearly 60% of patients have 1 or more episodes of cholangitis, with decreasing frequency over time. Other conditions that cause functional or mechanical obstruction of the bile ducts such as gallstones, congenital hepatic fibrosis, Caroli syndrome, choledochal cysts, and primary sclerosing cholangitis (PSC) also increase the risk of cholangitis. When these patients present with fever and no other obvious source of infection, they should be evaluated for possible cholangitis. Cholangitis classically presents with fever, jaundice, and right upper quadrant pain (Charcot triad); however, in children, not all symptoms may be present. In patients post-Kasai, fever is seen in nearly 100% of patients with cholangitis, usually with increased bilirubin or acholic stools and laboratory values showing either leukocytosis or leukopenia. Evaluation of cholangitis should include ALT, AST, alkaline phosphatase, GGT, and blood and urine cultures, although blood cultures will be positive in less than 50% of cases. Imaging should also be undertaken by either ultrasound or computed tomography (CT) scan to rule out the presence of abscess, calculi, ductal dilatation, or other anatomic lesions. If concern persists regarding the presence of a stone, a magnetic resonance cholangiogram may be helpful in delineating the location. Liver biopsy can be used to support the diagnosis; however, the diagnostic value of the biopsy should be balanced with the risk of the procedure.

Therapy for cholangitis begins with ensuring that the patient is hemodynamically stable with fluid resuscitation as needed. The patient may require nasogastric suction if an ileus is present. Antibiotics are given parenterally and should cover the most likely pathogens considering local antibiotic sensitivities and have adequate biliary penetration. Cholangitis is most commonly caused by enteric pathogens such as Escherichia coli, Klebsiella, Enterobacter, and Enterococcus; thus, antibiotic coverage often involves a third-generation cephalosporin or broad-spectrum penicillin such as ampicillin-sulbactam in addition to an aminoglycoside. At times, coverage should be expanded to include anaerobic bacteria, with a drug such as metronidazole. If the patient remains febrile, with evidence of obstruction, bile duct decompression is necessary. Available options include endoscopic retrograde cholangiopancreatography (ERCP), percutaneous drainage, or open surgical intervention. The type of intervention depends on clinical stability, anatomy of the lesion, and available procedural expertise. Following therapeutic measures, patients should demonstrate response with defervescence and corresponding decrease in bilirubin, aminotransferases, and white blood cell count. Treatment should continue for 14 to 21 days.

LIVER ABSCESS

Liver abscesses are usually classified as pyogenic or amoebic based on etiology. The distinction is important because treatment varies substantially. Important aspects of the patient’s history that suggest amoebic rather than pyogenic abscess include bloody diarrhea or travel to tropical areas preceding the illness.

Pyogenic Liver Abscess

Pyogenic abscesses may be associated with trauma to the biliary tract or hematogenous spread through the portal vein in conditions such as appendicitis or inflammatory bowel disease. Other risk factors include pelvic inflammatory disease and altered immune status such as chronic granulomatous disease or leukemia. Signs and symptoms are usually nonspecific but commonly include fever, weight loss, abdo­minal pain, right upper quadrant tenderness, and hepatomegaly. A more fulminant presentation associated with septic shock may occur when multiple abscesses or a ruptured abscess occurs. Laboratory findings often demonstrate leukocytosis and an elevated ESR, but aminotransferases, alkaline phosphatase, and bilirubin may be normal or only mildly elevated. Diagnosis requires a high degree of suspicion and appropriate imaging.

Ultrasound may identify focal hypodense lesions and suggest presence of liver abscess. Abdominal CT or magnetic resonance imaging (MRI) scans are used to further define lesions. They may demonstrate abscesses as small as 1 cm. Abscesses appear as areas of hypoattenuation, with surrounding edema. These findings are enhanced through the use of intravenous contrast. A solid appearance should suggest tumor. Pyogenic abscesses are frequently multifocal. Amoebic abscesses, on the other hand, are usually single, most often in the right lobe, near the diaphragm; these findings, however, do not reliably distinguish between pyogenic abscess and amoebic abscess.

Abscess fluid should be obtained by either needle aspiration or placement of a drainage catheter. Indications for open surgery are noted in Figure 232-1. Specimens should be sent for Gram stain and culture. Gram-positive bacteria are most common in children, although gram-negative bacteria and anaerobes are frequently involved, and the specimen may grow more than 1 pathogen. Antibiotic therapy is aimed at covering the most likely pathogens and is then refined based on culture results and susceptibilities. Treatment parenterally for 4 to 6 weeks is generally recommended.

Amoebic Liver Abscess

Amoebic abscess presents similarly to pyogenic liver abscess but is caused by Entamoeba histolytica, which is reported to cause hepatic abscesses in up to 7% of invasive cases (see Chapter 336). Younger children and those living in or traveling from tropical regions such as Southeast Asia or Central or South America are most commonly affected. Jaundice is infrequently seen, and diarrhea may be seen in less than half of patients at the time of presentation; however, a history of dysentery should raise suspicion for this disease.

As with pyogenic liver abscess, the leukocyte count and ESR are usually elevated, and ALT and AST, bilirubin, and alkaline phosphatase are normal to mildly elevated. Imaging studies should include ultrasound or CT of the abdomen. Additional studies include evaluation of the stool for ova and parasites looking for trophozoites or cysts and testing the stool for E histolytica antigen; note that stool tests may be negative in the case of extraintestinal amebiasis and that routine ova and parasite examination does not permit differentiation of E histolytica from nonpathogenic Entamoeba. Serologic testing of the blood is positive in > 90% of patients. Many patients from endemic areas, however, will already have antibodies from previous exposure; the tests can also be falsely negative for the first 7 days of infection. Aspiration of the abscess may also be used to distinguish between pyogenic and amoebic liver abscess. In amoebic liver abscess, the fluid is classically sterile and reddish-brown in color; amoebic organisms will be seen in less than one-third of cases.

Treatment most often begins with metronidazole (50 mg/kg/d divided into 3 doses) for 10 days, with alternatives of tinidazole, ornidazole, and nitazoxanide, which can be given for shorter periods of time. This should then be followed by a luminal amoebicide such as paromomycin or iodoquinol for 10 or 20 days, respectively. This combination is effective at eradication in > 90% of patients. Surgery or invasive therapy usually is not needed. Aspiration may be indicated when fever and abdominal pain persist after 4 to 5 days of treatment and in large abscesses with imminent risk of rupture. In these patients, repeated aspiration may be helpful in improving symptoms and speeding symptom resolution. Complications are generally related to delay in diagnosis or rupture of the abscess, which can cause peritonitis, as well as pulmonary or even cardiac involvement. Mortality is directly related to these findings.

OTHER INFECTIONS OF THE LIVER

A list of nonviral liver pathogens is provided in Table 232-2. Bacterial infections can also result in liver involvement as part of the systemic manifestations. Cat scratch disease (CSD), caused by Bartonella henselae, is most often found in warm, humid climates and, in addition to lymphadenitis, can cause hepatitis, granulomatous hepatitis, hepatosplenomegaly, and hepatic or splenic abscesses. Symptoms are often nonspecific (eg, fever) but may be similar to other liver infections previously discussed; in addition, patients often present with chronic adenopathy. The evaluation, therefore, should focus on a history of cat exposure, adenopathy, and seeking an inoculation site. Imaging studies may show multiple small lesions in both spleen and liver parenchyma, and antibody titers are typically elevated. Antibiotics may not be needed unless the patient is immunosuppressed; complete recovery is expected.

Fitz-Hugh–Curtis syndrome is the common name for perihepatitis in association with salpingitis most often seen in young females. Among adolescents with salpingitis, rates of Fitz-Hugh–Curtis syndrome range from 4% to 12% in most reports, but have been described in up to 27%. Signs and symptoms generally include severe right upper quadrant pain at the lower costal margin with occasional radiation to the back or shoulder that increases with inspiration or deep palpation, in addition to a friction rub over the anterior costal margin. Laboratory values are not typically as helpful as is the clinical picture taken in context. The most common organisms are those that cause pelvic inflammatory disease (Neisseria gonorrhoeae and Chlamydia trachomatis), which can be identified in urine or cervical or rectal swabs. Treatment should cover the most likely bacteria; recommendations for treatment are updated periodically and are available on the Centers for Disease Control and Prevention (CDC) website.

LIVER INFECTIONS IN THE IMMUNOCOMPROMISED

Fungal liver infections are a serious and a significant cause of morbidity and mortality most often seen in immunocompromised patients, especially neutropenic patients undergoing chemotherapy or posttransplant patients. Because the symptoms are nonspecific, this condition should be suspected when a neutropenic patient remains febrile on broad-spectrum antibiotics and blood cultures have shown no growth. Fever, hepatomegaly, and splenomegaly are frequently seen with elevated alkaline phosphatase more often than elevated bilirubin or liver enzymes. Ultrasound appears to be less sensitive than CT in the diagnosis of fungal liver infection. Different etiologies are listed in Table 232-2. Pertinent geographic clues include living or traveling in the southwestern United States or Mexico (Coccidioides) or living or traveling through the Ohio or Mississippi River Valleys in the United States (histoplasmosis).

In the immunocompromised patient, special attention should be given to opportunistic pathogens causing cholangiopathy, a condition with similar clinical and radiologic appearance as PSC. Cholangiopathy is seen in patients with deficient cell-mediated immunity such as those who have acquired immunodeficiency syndrome (AIDS), severe combined immunodeficiency (SCID), common variable immunodeficiency (CVID), Wiskott-Aldrich syndrome, major histocompatibility complex class II deficiency, interferon-γ deficiency, DiGeorge syndrome, or hyper-IgM syndromes. Signs and symptoms are similar to acute cholangitis with abdominal pain and fever, but jaundice is less common. Other findings may include hepatomegaly and diarrhea. Laboratory values often demonstrate an elevated alkaline phosphatase with only mild elevation of bilirubin and mild to no change in liver enzymes. Mild hypoalbuminemia, anemia, or leukopenia may also be noted. Abdominal ultrasound may demonstrate mild dilation of the bile ducts, an enlarged gallbladder, and abnormal liver texture with possible splenomegaly. Detailed evaluation of the bile ducts may require magnetic resonance cholangiogram or ERCP. The most common pathogens include cryptosporidium and cytomegalovirus, but microsporidia and mycobacteria can also cause cholangiopathy. Efforts are more often aimed at prevention rather than treatment of the disease, as cholangiopathy often reflects an advanced disease stage and carries a poor prognosis. Therefore, in patients with AIDS, antiretroviral therapy remains the best option; with the introduction of highly active antiretroviral therapy and subsequent improved immune status, cholangiopathy is seen less frequently in human immunodeficiency virus (HIV)-infected patients. Patients with congenital immunodeficiencies may require bone marrow transplantation.

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INTRODUCTION

Since the introduction of routine immunization against Haemophilus influenzae type b and Streptococcus pneumoniae, urinary tract infections (UTIs) have replaced bacteremia and meningitis as the most common serious bacterial infection in children. Identification and treatment of UTIs are important in managing signs and symptoms such as fever and dysuria, and also for preventing and minimizing the morbidity associated with pyelonephritis and sepsis. The site of infection may be the bladder (cystitis), ureters (ureteritis), pelvis (pyelitis), and/or renal parenchyma (pyelonephritis).

PATHOGENESIS AND EPIDEMIOLOGY

The pathogenesis of UTI depends on a complex interaction between bacterial and host factors. The urinary tract is normally a sterile environment with nearby bacterial reservoirs in the distal urethra, periurethral region, perianal region, perineum, and vagina. With normal hydration and spontaneous voiding, the urinary flow through the distal urethra helps to prevent bacterial ascension into the bladder. Maintenance of normal flora prevents more virulent strains from colonizing the gut and the periurethral area; an individual’s microbiome may be influenced by age, hormones, recent antibiotic use, hygiene, or spermicides.

The majority of UTIs are initiated by bacteria that ascend the urethra and adhere to the mucosal lining of the bladder; a hematogenous source that seeds the urinary tract is much less common but is also possible. The most studied model of bacterial adhesion in the urinary tract is the “P” fimbriae expressed on the surface of uropathogenic Escherichia coli. These bacterial proteins enable adherence of uropathogenic E coli to the bladder. They are referred to as P fimbriae because they can recognize and agglutinate erythrocytes of the P1 blood group. The P blood group antigen is also present on human uroepithelial cells.

Following adhesion, the bacteria may invade across the mucosal barrier and trigger an inflammatory host reaction. White blood cells (WBCs) are then recruited to respond to the bacterial invasion, resulting in leukocytes appearing in the urine (pyuria). The inflammatory response results in the typical symptoms of cystitis including dysuria, urinary frequency, and urgency.

Understanding the pathogenesis of UTI clarifies how certain factors can increase the risk of UTI. For example, bacterial ascension via adherence to the urethra and bladder may be facilitated by infrequent or dysfunctional voiding. Dysfunctional voiding refers to the lack of coordination between 2 processes that are essential for normal voiding to occur—relaxation of the urethral sphincter and contraction of the detrusor muscle of the bladder. The failure of the voluntary sphincter to relax causes an obstruction to the urine outflow during voiding. Coordinated bladder-sphincter control and efficient elimination of urine with a brisk urine outflow across the urethra is a natural defense mechanism against bacterial ascension and adherence. Toilet training is a period during which the risk for UTI rises as the child may inappropriately tighten and relax the sphincter to be socially continent. Children being evaluated for recurrent UTIs will often exhibit dysfunctional voiding on their urologic workup. They will also often have constipation whereby the distended rectum pushes up against the bladder outlet and obstructs the urine flow.

There can be mechanical, anatomic, or structural risk factors that promote UTIs. Indwelling catheters breach the separation between urinary tract and colonized body surface. Congenital genitourinary anomalies indicated by dilation anywhere along the urinary tract often present with UTI because there has been obstruction to normal antegrade urine flow. On the other hand, if during gestational development there was abnormal migration of the Wolffian ducts resulting in laterally displaced ureters, the ureterovesical valve may be faulty, resulting in vesicoureteral reflux (VUR). VUR increases the risk of pyelonephritis by promoting bacterial ascension to the kidneys.

E coli is the most common uropathogen and causes about 80% of all UTIs; other common gram-negative uropathogens include Klebsiella, Proteus, Enterobacter, and Citrobacter. Common gram-positive uropathogens include Staphylococcus saprophyticus, Enterococcus, and rarely, Staphylococcus aureus. According to the American Academy of Pediatrics 2011 guidelines, Lactobacillus species, other coagulase-negative staphylococci, and Corynebacterium species are not considered clinically relevant urine isolates. Factors that affect the incidence of UTIs include gender, age, race, circumcision status, and general health. Throughout childhood, adolescence, and adulthood, females are at higher risk for UTI than males. In contrast, during the early part of the first year of life, boys have a higher incidence of UTI than girls (2.7% vs 0.7%). After the first year of life, the incidence of UTI in males drops to 0.03% to 2% and rises in females to 1% to 3%. Caucasians are at higher risk for UTI than blacks. Uncircumcised boys have up to 12 times the risk of UTI than circumcised boys. Factors such as dysfunctional voiding, constipation, sexual activity, and bladder catheterization increase the risk of UTI.

CLINICAL MANIFESTATIONS

Cystitis is the most common clinical manifestation of infection of the urinary tract. Classic symptoms include urgency, frequency, or dysuria. Children may also have a history of difficulty in initiating the urinary stream. Occasionally, children may complain of abdominal or suprapubic pain. If fever is present, it is usually low grade. The urine may be foul smelling and cloudy.

The clinical presentation of acute pyelonephritis (APN) is more severe; those who have APN have chills, spiking fevers, and complaints of back pain. They may have associated gastrointestinal complaints of diarrhea and especially vomiting. Lower urinary tract symptoms, such as frequency, urgency, dysuria, and suprapubic discomfort, may or may not be present. Other findings vary, such as irritability, poor feeding, vomiting, decreased urinary output, and clinical evidence of dehydration. Infants with APN usually have high fever without other localizing features; since their clinical presentation of UTI tends to be nonspecific, diagnosis relies heavily on laboratory studies outlined below.

Features of the physical examination that should be emphasized include (1) an accurate measurement of blood pressure (hypertension may be present in patients who have chronic renal disease), (2) general growth and development (failure to thrive may be a sign of chronic or recurrent UTI), and (3) a careful abdominal examination (which might reveal tenderness or a mass caused by either an enlarged bladder or an obstructed urinary tract). An effort should be made to elicit the finding of costovertebral angle tenderness in children of all ages. The perineum should be inspected carefully to search for signs of irritation, scars, tears, signs of trauma, labial adhesions, or evidence of vulvovaginitis. A rectal examination should be considered to detect masses or poor sphincter tone, which might be associated with a neurogenic bladder. The lower back should be observed for any lipoma, sinus, pigmentation, or tuft of hair that may be evidence of an occult myelodysplasia.

DIAGNOSIS

In infants or children who are not toilet trained, a sample of urine should be obtained for urinalysis and urine culture via catheterization or suprapubic aspiration (SPA). SPA yields a specimen of urine that completely avoids any contamination from the perineal flora. When urine is obtained via catheterization, the first few drops of urine should not be collected in the sterile container as they may be contaminated by the bacteria in the distal urethra. If the first attempt at catheterization is not successful, a new catheter is required for the next attempt. Urine collected with a bag affixed to the perineum results in a high false-positive rate due to contamination from colonization of the perineum, the vagina in girls, and the prepuce in uncircumcised boys. Bagged specimens are only helpful when the results are negative; if the results from a bagged specimen suggest infection (urine dipstick is positive for leukocyte esterase [LE] or nitrites or microscopic analysis is positive for WBCs or bacteria), then another specimen should be obtained via catheterization or SPA before initiating treatment. In the child who is toilet trained, a freshly voided midstream clean catch urine specimen may be obtained. If the urine is kept at room temperature, it should be analyzed within 1 hour; otherwise the urine should be refrigerated and analyzed within 4 hours.

A diagnosis of UTI requires that there is pyuria (≥ 3 WBCs per high-power field [hpf] or ≥ 10 WBCs/μL or ≥ trace LE on dipstick) and at least 50,000 colony-forming units (CFUs) of a single bacterial species per milliliter of urine when obtained by clean catch or catheter. The presence of pyuria helps to distinguish asymptomatic bacteriuria from true UTI. Asymptomatic bacteriuria occurs in 0.8% of preschool girls and 1% to 2% of school-age girls. Results from the urinalysis will likely be available before the preliminary urine culture, which requires at least 24 hours. In a febrile infant or a child with symptoms suggestive of UTI, a urinalysis suspicious for UTI may include the presence of bacteria or WBCs on microscopy or the presence of LE or nitrites on dipstick (Table 233-1). Nitrites result from the conversion of dietary nitrates to nitrites by gram-negative enteric bacteria such as E coli and require about 4 hours in the bladder. A false-negative nitrite on a dipstick may be due to insufficient bladder time in young children who frequently empty their bladders in less than 4 hours or due to infection with bacteria that do not convert dietary nitrates to nitrites (eg, Enterococcus, Pseudomonas, Acinetobacter, and S saprophyticus). LE is an enzyme found in WBCs and is a surrogate marker for WBCs in the urine. LE has a specificity of about 78%; accordingly, false-positive results may be observed. The presence of bacteria on a Gram stain of a sample of fresh, uncentrifuged urine correlates with 10⁵ CFUs/mL but requires more equipment and expertise than dipsticks.

It should be noted that the definition or threshold of what constitutes a positive urine culture varies according to different guidelines. In general, the varying thresholds take into account the risk of contamination from the distal urethra and periurethral region with a higher threshold used for clean catch specimens and a lower threshold used for urines obtained by catheterization or SPA. The 10⁵ cutoff is based on morning-voided urine samples from adult women with pyelonephritis and applies to clean catch specimens. With the added stipulation that there must be evidence of pyuria, a lower cutoff of 50,000 CFUs/mL is acceptable and is also the general standard for specimens obtained by catheter. Any growth in urine collected by SPA should be considered a positive culture; however, most samples have high colony counts.

TREATMENT

For febrile UTI, the length of treatment should be 7 to 14 days. In an otherwise healthy child with suspected afebrile acute cystitis and without a history of recurrent UTI, a shorter course may be sufficient.

Oral and parenteral antibiotics are equally efficacious treatment for a UTI; the latter is indicated if the patient is either toxic or vomiting or if there are no oral options available (Tables 233-2 and 233-3). Empiric treatment should be based on the local antibiogram, if possible, due to the community variability in resistance and then, if necessary, adjusted according to the antimicrobial susceptibility profile of the uropathogen isolated. Initial oral antibiotic options include cephalosporins, amoxicillin-clavulanate, or trimethoprim-sulfamethoxazole. Sulfonamides should be avoided in premature infants or newborns younger than 4 weeks given the risk of hyperbilirubinemia, jaundice, and kernicterus. Nitrofurantoin does not reach adequate concentrations in tissue, so it is not a good option if pyelonephritis is suspected. Nitrofurantoin should also be avoided in neonates and those with renal insufficiency, liver dysfunction, and glucose-6-phosphate dehydrogenase deficiency.

Infection with Enterococcus is more common during early infancy; accordingly, antibiotic coverage for neonates should include intravenous ampicillin. Broader coverage should also be considered for patients with recent antibiotic exposure, recent hospitalization, or history of genitourinary anomaly because they are at risk for infection with a drug-resistant bacterial species. Increased coverage includes antipseudomonal penicillins, β-lactam/β-lactamase inhibitor combinations, fluoroquinolones, second-, third-, or fourth-generation cephalosporins, and carbapenems. Fluoroquinolones are not a first-line consideration but are an effective choice when Pseudomonas aeruginosa is suspected or proven to be the cause of infection.

The risk of recurrent UTI is highest 3 to 6 months after the index infection. Parents should be educated regarding this possibility and encouraged to seek prompt treatment if a fever or symptomatic UTI develops again. Besides a recent UTI, risk factors for recurrent UTI include bladder and bowel dysfunction (voiding dysfunction and constipation) and congenital anomalies.

A renal and bladder ultrasound is indicated following a first febrile UTI for patients 3 months to 2 years of age; if the ultrasound shows hydronephrosis, a dilated ureter, other evidence of obstructive uropathy, or another significant abnormality, then a voiding cystourethrogram (VCUG) is recommended. A VCUG can also be considered depending on the presence of a family history of VUR; the child’s age, sex, and race; the severity and course of the initial infection; bladder and bowel dysfunction; and importance that parents place on preventing recurrences. The incidence of reflux in girls evaluated after a first UTI is 25% to 40%. If VUR is detected, antibiotic prophylaxis may be considered. A recent large, randomized, placebo-controlled trial (the RIVUR study) showed that antibiotic prophylaxis with trimethoprim-sulfamethoxazole approximately halves the risk of recurrent UTI. The rate of recurrent febrile or symptomatic UTI in these patients with VUR was 24% in the placebo group and 13% in the trimethoprim-sulfamethoxazole group over 2 years. These data can be discussed with parents during shared decision making regarding the use of prophylactic antimicrobials.

PREVENTION

The use of prophylactic antimicrobial agents in order to prevent recurrences of UTIs in patients with VUR is controversial. The RIVUR study showed that although prophylaxis does not prevent renal scarring, it does reduce the risk of recurrence by 50%. Many support the use of prophylactic antimicrobial therapy in patients with grade III to V VUR with the understanding that eventual antimicrobial resistance to the prophylactic agent is likely to develop.

Among preschool and school-age children, bladder and bowel dysfunction are common. A history of dysfunctional voiding can be elicited by inquiring about voiding postponement, urinary incontinence, and constipation. First-line therapy is behavioral modification with more frequent, timed voiding every 2 to 3 hours, increased water intake (1 L/d) in addition to all other fluids consumed, correction of constipation, and improved perineal hygiene if possible. Children who exhibit persistent inability to relax their sphincters may require training that involves relaxation techniques reinforced with biofeedback. Referral to a pediatric urologist may be necessary in some instances.

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INTRODUCTION

Intravascular catheters are used for a wide range of therapies in pediatric patients, such as administering total parenteral nutrition and chemotherapy, providing reliable access for hemodynamic monitoring, blood drawing, and performing interventions such as hemodialysis. No longer limited to the acute care setting, intravascular catheters are also used in outpatient settings. For the purposes of discussing management, complication risks, and preventive strategies, these catheters can be subdivided into short-term, intermediate-term, and long-term devices based on planned duration of use. While there is overlap between catheter types used for given planned durations, it is generally accepted that nontunneled central venous catheters are used for short-term access, peripherally inserted central catheters (PICCs) are often used as intermediate-term catheters, and long-term catheters include tunneled catheters and implantable ports.

PATHOGENESIS AND EPIDEMIOLOGY

Catheter-related bloodstream infections (CR-BSIs) are one of the more common types of healthcare-associated infections and result in increased healthcare costs, increased use of antimicrobials, prolonged hospital stays, morbidity, and death. The pathogenesis of CR-BSI varies. Different types include migration of potential pathogens from the skin at the exit site along the external surface of the catheter to the catheter tip; intraluminal migration of organisms from the catheter hub; contaminated infusates; and rarely, seeding of the catheter hematogenously from a distant focus. Current evidence suggests that migration of pathogens along the external surface of the catheter is more common in CR-BSIs associated with short- and intermediate-term, nontunneled catheters, with a higher rate of extraluminal source of infection in the first 1 to 2 weeks after placement of the central line. In contrast, intraluminal migration of organisms is more commonly seen in CR-BSIs associated with long-term, tunneled catheters. This differential is due in part to mechanical differences in the lines with the presence of a cuff on tunneled catheters acting as a fibrotic dam to migration of organisms along the external lumen. That said, external migration of organisms is possible in tunneled catheters and is associated with tunnel infections. Hematogenous seeding is one proposed mechanism of CR-BSIs in children with dysfunctional bowel; however, the true incidence of bowel translocation of microorganisms with subsequent seeding of the catheter is unknown.

The most commonly reported organisms implicated in CR-BSIs include skin flora such as coagulase-negative Staphylococcus and Staphylococcus aureus, Enterococcus species, enteric gram-negative organisms (particularly in patients with gastrointestinal dysfunction), and Candida species. Of concern is the growing number of CR-BSIs due to multidrug-resistant organisms.

Risk factors for CR-BSIs include prolonged use of systemic antimicrobials, catheter location (short- and intermediate-term lines placed in the femoral vein compared to other sites are more prone to infection in some pediatric studies), infusion of hyperalimentation with lipids, prolonged duration of catheterization (associated with increased formation of pathogenic biofilm), age < 2 years (especially premature infants with immature skin integrity), burn patients, immunocompromised patients, and those with intestinal integrity issues.

CLINICAL MANIFESTATIONS

The clinical manifestations of catheter-related infections are variable and related to the type of infection. Fever is classically associated with CR-BSIs, while erythema, tenderness, and purulent drainage can be seen with exit site, tunnel, and pocket infections. The definitions of different types of catheter-associated infections are presented in Table 234-1.