Part 3: Infections of the Respiratory System

INTRODUCTION

Worldwide, community-acquired pneumonia (CAP) is a leading cause of infectious morbidity and mortality in children. A major clinical challenge persists—determining the role of viral and bacterial pathogens in pediatric pneumonia. Studies that employ blood and respiratory cultures, serology, and molecular detection suggest a small role for bacterial pathogens, while those that rely on pneumococcal conjugate vaccines (PCVs) as a probe to determine the proportion of disease due to Streptococcus pneumoniae suggest that pneumococcus is the major pathogen. Evolving insight from epidemiologic, molecular detection, and vaccine probe studies suggests that viral-bacterial interactions have a substantial role in the pathogenesis of pediatric pneumonia. In addition, the importance of comorbid illness as a risk factor for both increased incidence and poorer outcomes of pneumonia has emerged from recent studies.

EPIDEMIOLOGY

CAP is most frequent in infants and toddlers and remains the most common cause of hospitalization in children. During the period from 2010 to 2012, following the introduction of the 13-valent PCV (PCV13) in the United States, the incidence of CAP requiring hospitalization was 15.7 per 100,000 in those < 18 years of age, with the highest rate among those less than 2 years of age (62 per 100,000). Mortality due to CAP in high-income countries is low, at < 1 per 1000 patient-years in children less than 5 years of age. Males are affected almost twice as commonly as females. Differences in incidence are also reported by socioeconomic status and ethnicity. Rates of pneumococcal pneumonia are higher in native Alaskan children than in nonnatives, as well as in children of African American, Hispanic, and Asian ethnicity compared to Caucasian children. These differences have narrowed, but have not been completely eliminated, in the era of universal immunization with PCVs. The incidence of CAP also varies by season; studies in the United States and Israel report greater frequency in the winter and spring months and in association with annual peaks of respiratory syncytial virus (RSV), influenza A, and, in older children, Mycoplasma pneumoniae. Comorbid illness has been recognized as both predisposing to pneumonia and as being associated with increased severity and morbidity. Children with congenital and acquired immune deficiencies represent a well-known high-risk group, but excess risk and morbidity are also found in children with chronic cardiac and pulmonary disease (including severe asthma), diabetes mellitus, neuromuscular disorders, prematurity, and specific genetic disorders (ie, trisomy 21).

Lower respiratory tract infections (RTIs) are both more frequent and associated with increased mortality in low-income countries. The incidence among children less than 5 years old in 10 low-income countries is estimated to range from 0.2 to 8.1 new episodes per 100 child-weeks. Mortality from pneumonia has become uncommon in high-income countries as noted, yet it remains a major cause of death in low-income countries. The countries with the highest incidence of pneumonia in children are located in Africa and Southeast Asia; case fatality rates for pneumococcal pneumonia are estimated to be 5% globally, with 10 countries accounting for most of the deaths (India, China, Nigeria, Pakistan, Bangladesh, Indonesia, Ethiopia, Democratic Republic of the Congo, Kenya, and the Philippines).

MICROBIAL ETIOLOGY

COMMUNITY-ACQUIRED PNEUMONIA

A large spectrum of pathogens have the capacity to cause CAP in children. In recent studies using routine and molecular methods, potential pathogens are detected in 65% to 80% of cases. Figure 235-1 details the distribution of viral pathogens, bacterial pathogens, neither, and both isolated from hospitalized, radiograph-confirmed cases of pneumonia, and Figure 235-2 details the frequency of various pathogens recovered from these cases. However, in studies comparing pediatric pneumonia cases with asymptomatic controls, only RSV, influenza viruses, and human metapneumovirus (HMPV) were found more frequently and with greater density in the nasopharynx of pneumonia cases, whereas coronavirus and parainfluenza viruses were found more frequently, and rhinoviruses and others were found no more frequently, cautioning the conclusion that recovery from the nasopharynx implies causation of pneumonia.

Studies of vaccine efficacy suggest that the pneumococcus may have a larger role in CAP than revealed through blood or respiratory specimen testing including molecular diagnostics. Such studies report declines of approximately 40% in ambulatory pneumonia and 50% in hospitalization for pneumonia in US children less than 2 years old following universal immunization of infants with the 7-valent PCV (PCV7) and additional declines of approximately 25% following the introduction of PCV13. Black and colleagues have reported a decline of 35% in pneumonia characterized by an abnormal chest radiograph in children immunized with PCV7 compared to unvaccinated controls. Klugman and colleagues observed an approximate 40% decline in children hospitalized for pneumonia associated with influenza, RSV, and HMPV in South African children immunized with 9-valent PCV compared to controls, providing further support for viral-bacterial interaction (specifically S pneumoniae) in the pathogenesis of a large proportion of cases of pneumonia in children. Such interactions are further supported by epidemiologic studies demonstrating an increase in bacteremic pneumococcal pneumonia during the RSV season. These data support a role for S pneumoniae in the etiology of pneumonia beyond those identified by concurrent bacteremia and beyond those with empyema or consolidated lobar pneumonia to include as many as one-third of young children with acutely abnormal chest radiographs and clinical symptoms or signs of RTIs.

Additional bacterial pathogens are also important causes of pneumonia in children. Streptococcus pyogenes is associated with rapid onset of large pleural effusions, significant toxicity, and prolonged fever. Haemophilus influenzae type b (Hib), prior to the introduction of the Hib conjugate vaccine and in countries where Hib vaccination has not been incorporated into national immunization programs, and possibly nontypeable H influenzae (NTHi) strains appear to be associated with prolonged symptoms and are disproportionately found in children with respiratory comorbid illnesses. A substantial role for NTHi is supported by results of lung aspirate studies from Gambia and Papua New Guinea, where NTHi strains are recovered from 25% to 53% of children with Haemophilus pneumonia (Table 235-1). In addition, NTHi has been reported as a major pathogen in children with recurrent CAP undergoing bronchoalveolar lavage (BAL). Most recently, Staphylococcus aureus, specifically community-acquired (CA) methicillin-resistant S aureus (MRSA), has emerged as an important cause of complicated pneumonia. On autopsy, these cases frequently demonstrate microabscesses and hemorrhage. Cavitation, pleural empyema, pneumatocele, bronchopleural fistula, and/or pyopneumothorax also can complicate staphylococcal pneumonia. Karen and colleagues reported S aureus as the most common cause of pleural empyema in children in the decade between 1993 and 2002. However, following the introduction of PCV7, an increase in pneumococcal empyema due to nonvaccine serotypes (those not contained within PCV7) was observed. Following introduction of PCV13, such cases have declined.

The atypical/intracellular pathogens M pneumoniae and Chlamydophila pneumoniae are recognized as important pathogens causing CAP in children. Both are difficult to culture; therefore, most studies rely on nonstandardized serologic tests or molecular detection from the respiratory tract/nasopharynx. Studies of children with ambulatory pneumonia identify M pneumoniae infection in 26.5% to 29.5% of cases and C pneumoniae in 15.0% to 28.5% of cases. These pathogens are found most commonly in children age > 5 years; however, they also occur in younger children. Data from 2222 hospitalized children with radiograph–confirmed pneumonia showed Mycoplasma recovered from 8% of cases overall (see Fig. 235-2), accounting for 19% of the total cases over 5 years old and only 3% of those under the age of 5 years. Mycoplasma should be suspected in children with pneumonia who have headache and wheezing in the setting of a family cluster of lower RTI. Perinatally acquired Chlamydia trachomatis pneumonia, a once common etiology of pneumonia in the first 2 months of life in the United States, has been largely eliminated in high-income countries through the systematic screening and treatment of pregnant women.

Complicated Pneumonia

In children, the microbiology of patients with complicated pneumonia (eg, those with large pleural effusion, empyema, necrotic lung parenchyma, lung abscess, or pneumatocele) differs somewhat from ambulatory patients. In children with complicated bacterial pneumonia with necrosis and/or empyema, S pneumoniae (often serotype 3) and both methicillin-sensitive S aureus (MSSA) and MRSA are dominant. Other less common bacterial pathogens recovered from hospitalized children with pneumonia include group A β-hemolytic streptococci, Hib, and Moraxella catarrhalis. Pneumonia with Group A β-hemolytic streptococci is often rapidly progressive, severe, and associated with sepsis syndrome. Infection with Hib has been virtually eliminated wherever Hib conjugate vaccine has been introduced; however, Hib may still be a significant pathogen in countries where Hib conjugate vaccine has not, as yet, had high penetration in the infant population. Mycobacterium tuberculosis may also present as acute pneumonia with fever, respiratory signs, and alveolar infiltrate with or without pleural effusion. Tuberculosis should be considered in children who recently immigrated to the United States, those returning from travel to countries with endemic tuberculosis, those with human immunodeficiency virus (HIV), and those who have had contact with recently diagnosed individuals. Skin testing for tuberculosis should be a routine part of evaluation of children with pneumonia.

CLINICAL MANIFESTATIONS

Clinical signs and symptoms of bacterial pneumonia overlap with many aspects of viral pneumonia, preventing clear discrimination between the 2. Fever, frequently greater than 102°F (38.9°C), ill appearance, and respiratory and/or abdominal signs are found in the majority of patients with pneumonia due to pneumococcus or RSV (Table 235-2). Tachypnea and rales/crackles are reported in 40% to 50% of such patients. Focal chest pain is uncommon with pneumonia, but when present should strongly suggest bacterial pneumonia. Bacteremic pneumonia is more frequently associated with greater severity of clinical signs and symptoms such as higher fever.

DIAGNOSIS

Determining the etiology of pneumonia in children is challenging because bacteremia is uncommon even in those thought to have bacterial pneumonia; pleural effusion is present in only a small percentage of children, and antimicrobial therapy has often been administered prior to collection of body fluids for culture; nasopharyngeal cultures are not necessarily representative of lower respiratory tract secretions; and the vast majority of children do not produce sputum. More aggressive procedures, such as lung puncture and BAL, may be diagnostic but are generally reserved for hospitalized patients with significant respiratory distress and, therefore, only inform us about a select population of children with pneumonia.

LABORATORY TESTING

Acute-phase reactants such as total and differential white blood cell count, erythrocyte sedimentation rate, C-reactive protein, and procalcitonin have been evaluated for their usefulness in discriminating between viral and bacterial etiologies. In general, these markers of inflammation demonstrate a correlation with bacterial etiology but have limited sensitivity and specificity. Serologic tests have been evaluated for diagnosis of pneumonia due to S pneumoniae, M pneumoniae, and C pneumoniae. Using a number of different techniques, these tests detect immunoglobulin (IgM or IgG) against antigens specific for each of these pathogens. In general, many of the tests are moderately specific, have wide variation in sensitivity, lack reproducibility, and have not been standardized. In addition, serologic tests may provide only retrospective diagnosis because they often require comparison of acute and convalescent serum specimens.

Detection of bacterial antigens in urine and detection of bacterial DNA in nasopharyngeal secretions, sputum, BAL specimens, or blood have been pursued as possible strategies for identifying the etiology of pneumonia. Pneumococcal capsular polysaccharide antigens have been detected in children with pneumococcal pneumonia; however, children with dense nasopharyngeal colonization have also had antigen detected in urine, suggesting the specificity of such assays is limited. Molecular strategies for detection of pneumococcus in blood or nasopharyngeal specimens have received increasing attention. Potentially, DNA from S pneumoniae, M pneumoniae, and C pneumoniae can be detected in clinical samples from children with acute pneumonia. Molecular detection of pneumococcus has proven to be successful in children with culture-negative empyema.

IMAGING

A chest radiograph is often used to confirm the presence of pulmonary infiltrates/consolidation in patients with suspected pneumonia. Lobar consolidation has a high correlation with bacterial pneumonia, while mild interstitial and perihilar changes are considered to be due to viral infection or possibly underlying asthma. While the association of lobar consolidation with pneumococcal disease is well accepted, the role of pneumococcus in cases with interstitial or mixed findings is less certain. Several studies suggest that the presence of alveolar infiltrates is an insensitive but reasonably specific indicator of bacterial infection. In a Finnish study of hospitalized children with pneumonia (n = 254), 71% of those with alveolar infiltrates had bacterial infection. More recent studies (Table 235-3) found no significant correlation between the radiologic picture and the etiologic agent—ie, it was not possible from the chest radiograph alone to predict whether the child had viral infection, bacterial infection, or mixed infection—but rather there was a correlation between age and radiographic findings.

Vaccine probe studies demonstrate that PCV efficacy is greatest in cases with alveolar infiltrates confirming an important role for pneumococcus in such cases. However, efficacy is also demonstrated in children, with interstitial infiltrates and recovery of virus from the nasopharynx strongly suggesting that the pneumococcus, at least in low-income settings, has a significant role in such cases (Table 235-4). Whether its role is direct tissue invasion or to enhance the severity of the viral infection remains uncertain.

SPECIAL POPULATIONS

Despite widespread use of PCVs and an overall decline in rates of all-cause pneumonia and pneumococcal pneumonia in children with high-risk conditions (eg, immunodeficiency, nephrotic syndrome, functional or anatomic asplenia, HIV), the incidence of pneumonia remains disproportionately high compared to otherwise healthy children. Children with chronic heart or lung disease or diabetes mellitus demonstrate a 2- to 3-fold increase in the incidence of pneumonia. Children with comorbid conditions are also at increased risk for treatment failure and poor outcome, making prevention a high priority and requiring additional strategies beyond pneumococcal immunization.

Children with Asthma

A link between RTIs and asthma in children is well established. Recent studies find that those with more severe asthma are at greater risk for all-cause and pneumococcal pneumonia compared to those with mild disease. It has been suggested that asthma exacerbations in children are associated with viral or atypical/intracellular pathogens such as C pneumoniae and M pneumoniae. Both of these agents have also been detected more frequently in children with wheezing than in control subjects (for C pneumoniae, 11.0% vs 4.9%, respectively). In addition, 9 (75%) of 12 children with wheezing and evidence of C pneumoniae infection showed clinical and laboratory improvement of their reactive airways disease after eradication of chlamydial infection with erythromycin or clarithromycin. Furthermore, a history of recurrent wheezing is more common in children with C pneumoniae or M pneumoniae infections than in those without either infection. Some investigators estimate that these organisms may trigger 5% to 30% of wheezing episodes and asthma exacerbations. A recent observation suggested that certain children with recurrent asthma may benefit from azithromycin prophylaxis with a subsequent reduced frequency of exacerbations. Further confirmation is required before this can be widely recommended.

Children with Sickle Cell Disease

The prevalence of pneumonia in children with sickle cell disease (SCD) is significantly higher than in healthy controls. By age 4, children with SCD have a 4 times greater risk of bacterial pneumonia compared with age- and sex-matched controls with normal hemoglobin genotype. Pneumonia in children with SCD also has a more serious clinical course compared to otherwise healthy children. M pneumoniae has been associated with severe pneumonia, including pleural effusion and multilobar infiltrates in children with SCD. Acute chest syndrome (ACS) is a common cause of hospitalization in patients with SCD and is associated with substantial morbidity and mortality (see also Chapter 430). Recent reports indicate that pneumonia may be a common cause of ACS in children with SCD. The report from a 30-center study demonstrated that infection—especially CAP—is a common cause of ACS. In this study, 27 different infectious pathogens as well as pulmonary fat embolism were identified as causes; C pneumoniae and M pneumoniae were the most prevalent infectious agents. Infection was considered a contributing factor in 56% of deaths. Other potential bacterial pathogens include S pneumoniae, S aureus, and H influenzae. The data above support the selection of antibiotics that include activity against atypical/intracellular pathogens when selecting suitable antibacterial coverage for patients with ACS.

Recurrent Community-Acquired Pneumonia

Children with recurrent CAP can be categorized as those with recurrent pneumonia in the same location (on chest radiograph) and those in whom the episodes of pneumonia occur at different locations. In the former situation, anatomical abnormality, foreign body, recurrent aspiration (especially with upper lobe pneumonia), and tracheoesophageal fistula should be considered. In those in whom the pulmonary infiltrate varies in location with each episode, immune deficiency (including cilia dysfunction syndrome) is more likely.

TREATMENT

In 2011, the Pediatric Infectious Diseases Society, in collaboration with the Infectious Diseases Society of America, developed and published guidelines for the management of pneumonia in children. The guidelines address a spectrum of challenges in managing children with pneumonia, including the following: criteria for admission to the hospital or intensive care unit; appropriate diagnostic testing; anti-infectives indicated for ambulatory and inpatient CAP; appropriate duration of therapy; expected response to treatment; management of parapneumonic effusions; management of CAP failing to respond to initial therapy; and prevention of CAP. The guidelines address whether all children with pneumonia require antimicrobial therapy or whether therapy should be limited to those with moderate or severe clinical symptoms and signs. Because a microbiologic diagnosis is not commonly established and the selection of initial antibacterial therapy is primarily empirical, there are no absolutes about which children with CAP require antimicrobial therapy. In addition, the new insights about bacterial-viral interaction in the pathogenesis of CAP and the reduction in hospitalization for “viral” pneumonia in children immunized with PCVs blur the picture.

Most children with CAP can be treated with oral antimicrobial agents. The treatment choice is based on age, clinical severity, and epidemiologic factors. When therapy for CAP is indicated, antibiotics targeting S pneumoniae, the most common bacterial pathogen, should be prescribed. The British Thoracic Society has proposed guidelines for treatment that support withholding antimicrobial therapy in young children presenting with mild symptoms of lower RTIs but do not specifically address whether to treat all children diagnosed with pneumonia. Amoxicillin is the first choice for oral antibiotic therapy in children less than 5 years old. Because β-lactam antibiotics are not active against atypical pathogens, macrolides are often recommended for children age > 5 years or whenever infection with atypical/intracellular pathogens is suspected, such as when headache and wheezing are present. The British Thoracic Society guidelines recommend management in the hospital for children with evidence of more severe disease (Table 235-5). In children hospitalized with severe CAP, initial therapy must include coverage for S pneumoniae, including multidrug-resistant strains in the community and community-acquired MRSA, especially when complicated pneumonia is present (see Chapter 279). The highlights of the Pediatric Infectious Diseases Society guidelines are summarized in Table 235-6.

Impact of Antimicrobial Resistance

As can be seen in Table 235-6, antibacterial resistance has an important influence on the selection of antibacterial therapy for childhood CAP. Multidrug-resistant S pneumoniae has been reported in children with pneumococcal pneumonia. The minimal inhibitory concentration (MIC) for some of these pneumococcal isolates for amoxicillin, amoxicillin clavulanate, azithromycin, and trimethoprim-sulfamethoxazole exceed the pharmacokinetic and pharmacodynamic parameters than can be achieved within the lung with oral administration. Resistance to ceftriaxone (MIC ≥ 4.0 μg/mL) is, however, uncommon among current isolates. Susceptibility to vancomycin and levofloxacin persists among almost all pneumococci isolated from children. Vancomycin or levofloxacin should be considered in children with type I allergy to cephalosporins; however, in 2016, the US Food and Drug Administration (FDA) added a black box warning for adverse events from fluoroquinolones affecting tendons, muscles, nerves, and the central nervous system. The FDA recommended that systemic fluoroquinolones be used only in patients with bacterial sinusitis, chronic bronchitis, and uncomplicated urinary tract infection in the absence other treatment options.

SUGGESTED READINGS

INTRODUCTION

Respiratory viral infections are a major cause of morbidity in children around the world. Healthy infants and preschool children experience between 6 and 10 respiratory illnesses per year, and school-age children and adolescents experience 3 to 5 illnesses annually. Respiratory viral infections are classified into (1) upper respiratory tract infections (URIs), also known as the common cold, rhinitis, pharyngitis, otitis media, and conjunctivitis; and (2) lower respiratory tract infections (LRTIs), namely croup, laryngitis, tracheobronchitis, bronchiolitis, and pneumonia. With molecular techniques becoming the new gold standard for the detection of respiratory viruses, important changes have occurred in our understanding of the role of these viruses in respiratory illnesses in children, particularly in LRTIs. Newly discovered viruses have been identified in the last decade (eg, human bocaviruses, human coronaviruses) that have been associated with respiratory illnesses. In addition, areas that require further research have been uncovered such as the causality between newly discovered viruses and clinical disease, the significance of viral co-detections, and the role of viral quantitation and its correlation with disease severity. Despite these changes, epidemiologic studies have demonstrated that the major associations established by traditional techniques (eg, viral culture, antigen detection, and serology) remain valid. Despite the major advances observed with the development of diagnostic tools, there has been a paucity of major changes in the availability of specific antivirals and vaccines, although many are currently under investigation with the potential to become available in the next few years.

RESPIRATORY SYNCYTIAL VIRUS

Respiratory syncytial virus (RSV) is the leading cause of viral lower respiratory tract disease in infants and toddlers. It accounts for approximately 60% of all LRTIs in preschool-aged children worldwide. In the developing world, RSV is second only to malaria as a cause of death during the first year of life. Severe disease is generally associated with primary infection, although LRTI can also occur upon reinfection. Bronchiolitis, which refers to inflammation of smaller intrapulmonary airways, is the single most distinctive clinical syndrome of RSV infection.

PATHOGENESIS AND EPIDEMIOLOGY

RSV belongs to the genus Pneumovirus within the Paramyxoviridae family. It is an enveloped, single-stranded, negative-sense RNA virus with a diameter spanning 100 to 350 nm. The viral envelope is studded with spike-like projections that include the fusion (F) and attachment (G) surface glycoproteins, but unlike most paramyxoviruses, RSV surface proteins lack both hemagglutinin (HA) and neuraminidase (NA) activity. The G protein initiates the infection, while the F glycoprotein mediates viral penetration by fusing viral and cellular membranes, contributing to syncytia formation. These 2 proteins carry the antigenic determinants that elicit the production of neutralizing antibodies by the host. Nevertheless, the F protein represents the major target for antiviral drug development, especially in its prefusion form (preF), which has been shown to be highly superior at inducing neutralizing antibodies compared to its postfusion (postF) form. Human RSV exists as 2 antigenic subgroups, A and B, which can co-circulate during the same season and exhibit genome-wide sequence divergence.

RSV infection is first established in the upper respiratory tract by infecting the ciliated cells of the nasopharynx, paranasal sinuses, or eustachian tubes of the inner ear. One to 3 days later, 30% of infants who experience their first infection will demonstrate involvement of the lower respiratory tract. In the lower respiratory tract, RSV infects the small bronchial epithelium, spreading to the type 1 and type 2 alveolar pneumocytes. RSV infection is restricted to the respiratory epithelium and rarely spreads outside the respiratory tract. Disseminated disease has been documented in patients with T-cell deficiency.

Infants are more likely to develop severe distal airway disease, because of an immature immune system, the lack of full protection from maternal antibodies, and also the smaller bronchiolar lumen of infants compared with older children and adults. In addition, in infants, collateral ventilation in alveolar regions is not well developed; thus, the impact of obstruction resulting from infection and inflammation is greater.

Histopathologically, airway plugging with mucus, necrosis of the bronchial and bronchiolar epithelium, and peribronchial inflammation with mononuclear cell predominance has been noted. The peribronchial infiltrate may extend into the adjacent pulmonary interstitium. Cytoplasmic inclusion bodies have been described, but syncytia formation is uncommon. Neutrophils are found between small airways and vascular structures and represent the predominant cell type in the bronchoalveolar lavage of RSV-infected infants.

During RSV infection, a number of cytokines and chemokines (eg, interleukin [IL]-8, IL-6, interferon-γ) are released and appear to play a role in the pathogenesis of the disease. Recent data suggest that host innate immune responses are actually inadequately activated or even suppressed in infants with severe RSV disease. With regard to adaptive immunity, the immune response to RSV is neither complete nor long lasting, and reinfections are the rule. Protection against reinfection is greater with homologous than heterologous RSV subtypes. Cellular immunity is not well understood in humans. Nevertheless, the role of CD8+ T cells in viral clearance is highlighted by the fact that patients with profound T-cell deficiency (eg, bone marrow transplantation, severe combined immunodeficiency) often have prolonged viral shedding and develop fatal disease. Regarding humoral immunity, as noted, it appears that antibody responses are important in ameliorating the severity of the disease rather than completely preventing the infection. In addition, passively acquired maternal antibody is not adequate to ensure complete protection from RSV infection and disease. However, children with high titers of maternally derived neutralizing antibody usually have milder symptoms, and the infection is restricted to the upper respiratory tract. These observations have led to use of passive immunoprophylaxis with antibodies as a method for protecting children at highest risk of severe RSV disease.

RSV has a worldwide distribution. In temperate climates, RSV annual midwinter epidemics occur predictably; in the United States, epidemics usually begin in November or December and last until March or April. In the tropics or subtropical areas, RSV activity is present all year long (eg, Florida).

RSV is the single leading cause of infant hospitalization, causing approximately 150,000 hospital admissions per year in children under 2 years of age in the United States. Globally, it is estimated that RSV causes about 34 million episodes of acute LRTIs in children under 5 years of age, resulting in approximately 3.4 million hospitalizations per year. The burden of RSV, however, is significantly larger in the outpatient setting, accounting for 18% of emergency department visits in children less than 5 years of age. In addition, RSV is also a major pathogen in immunocompromised and elderly individuals.

Disease in the immediate neonatal period is uncommon; however, by their first birthday, nearly one-half to two-thirds of infants have been infected with RSV. Seropositivity approaches 100% by 2 years of age. Reinfection with RSV occurs throughout life and may occur even during the same winter season. The annual risk of reinfection falls from between 33% and 75% in the preschool years to approximately 20% among school-age children. The risk of severe LRTI from reinfections also falls with increasing age and number of exposures, likely from the presence of partially neutralizing antibodies following previous infection.

Besides young age (< 6 months) at the start of the RSV season, epidemiologic studies have identified select groups of infants at high risk for severe disease and mortality including premature birth, compromised cardiopulmonary function (chronic lung disease or congenital heart disease [CHD]), trisomy 21, or immunocompromise). Males with severe RSV LRTI outnumber females by 1.6 to 1. Risk factors such as low socioeconomic status and modifiable risk factors such as exposure to secondhand smoke or out-of-home daycare attendance have also been associated with an increased risk for more severe RSV disease.

Humans are the only known reservoir for RSV. Studies of transmission dynamics suggest that infection of infants often follows infection of older siblings. The incubation period ranges from 2 to 8 days, most commonly 4 to 6 days. In infants hospitalized with primary RSV infection, continuous viral shedding for 10 or 11 days detected by polymerase chain reaction (PCR) is commonly observed; young infants and immunocompromised children may shed the virus for 3 to 4 weeks.

Transmission primarily occurs by inoculation of nasopharyngeal or ocular mucous membranes after direct contact with contaminated secretions or fomites. RSV can persist for 30 minutes or more on hands and for several hours on environmental surfaces. Close adherence to infection control policies is critical to limit healthcare-associated transmission. Nosocomial outbreaks of RSV infection in hematopoietic stem cell transplant units and neonatal units have been reported and carry significant morbidity and mortality. Therefore, strict hand-washing and contact precautions using gown and gloves for the duration of the RSV-associated illness must be practiced routinely.

CLINICAL MANIFESTATIONS

The vast majority of infants with RSV infection develop a mild illness with upper respiratory tract symptoms; however, 20% to 30% will develop lower respiratory tract disease (eg, bronchiolitis and/or pneumonia) with the first infection. Of those, 2% to 3% will require hospitalization.

RSV infection is heralded by initial symptoms indistinguishable from those of the common cold. The infant may show rhinitis and cough, and there may be fever. Within 1 to 2 days, the cough becomes more prominent and tachypnea may develop. With increasing respiratory effort, substernal and intercostal retractions are noted along with nasal flaring and abdominal breathing. Grunting can be present in more severe cases. The expiratory phase is prolonged, and the chest is hyperexpanded and hyperresonant, providing further evidence of generalized expiratory airflow obstruction. Crackles or rales with or without diffuse expiratory wheezing are usually heard. In children requiring hospitalization, hypoxemia is typical, reflecting ventilation-perfusion mismatch. Chest radiographs reveal hyperinflation, increased peribronchial markings, and frequently, areas of atelectasis or infiltrate. Densities on chest radiographs are predominantly areas of atelectasis, and although these patients may be labeled as having RSV pneumonia rather than bronchiolitis, this distinction is often arbitrary.

Apnea can be an early manifestation of RSV infection in young infants, particularly infants < 8 weeks old or those with a history of premature birth or apnea of prematurity. Apnea can occur associated with respiratory tract symptoms or may be the only sign at presentation.

Severe bacterial infections, namely bacteremia or meningitis, are extremely rare in infants with RSV bronchiolitis, while urinary tract infections have been documented in approximately 5% of patients. Acute otitis media during or after RSV bronchiolitis occurs in approximately 60% of children. RSV-related fatality rates for hospitalized children in developed countries are < 1%. Although children with underlying conditions such as prematurity or cardiopulmonary disease are at increased risk of death, most fatalities occur in previously healthy infants. The average duration of hospitalization for previously healthy infants without complications is approximately 2 to 3 days. Full recovery may take 2 to 3 weeks. Approximately 50% of infants who develop RSV LRTI will develop recurrent wheezing during childhood. The highest risk for wheezing occurs in the first 6 years of life. It is still unclear whether RSV infection plays a causal role in this pulmonary sequela or whether it is simply a sign of individuals predisposed to asthma. The agent is nevertheless an important precipitant of wheezing in children with reactive airway disease.

DIAGNOSIS

Bronchiolitis is a clinical diagnosis; however, other respiratory viruses also cause bronchiolitis in young children, and clinical features are insufficient to reliably distinguish RSV from these other viral infections. Specific viral diagnosis may be helpful in certain scenarios: when the diagnosis is uncertain; to reduce unnecessary use of antibiotics; or in hospitalized children at risk for severe disease or for infection control purposes. Detection of RSV from nasopharyngeal specimens may be achieved by rapid antigen tests including fluorescence-based methods such as direct fluorescent antibody (DFA: sensitivity 90–95%, specificity 92–97%) or immunoassays such as enzyme immunoassay (EIA: sensitivity 80%, specificity 75–100%). Molecular-based methods such as real-time reverse transcriptase (rt) polymerase chain reaction (PCR) also may be used to detect RSV. The sensitivity of rapid antigen tests may be lower in older children and is poor in adults, because they shed low concentrations of RSV. Detection by viral culture or by serology is not clinically practical for early diagnosis of acute RSV infection. Serology also is challenging to interpret in young infants because of the presence of maternal antibodies.

In cell culture, RSV growth is detected within 5 to 7 days by the typical plaque morphology with syncytium formation. Cell culture was traditionally the gold standard for diagnosis, but this technique has been replaced by the more rapid and sensitive rt-PCR assays, although many outpatient settings still rely on rapid antigen detection by DFA or EIA due to operational challenges and costs. rt-PCR is the most sensitive method for RSV detection and allows the differentiation between A and B subgroups (which is useful for surveillance purposes in cases of respiratory disease outbreaks). Multiplex PCR assays allow the simultaneous detection of several respiratory viruses, including RSV. Recently, an automated real-time molecular station was developed (FilmArray, Biomerieux, Marcy-l’Étoile, France) that performs nucleic acid extraction, then reverse transcription, followed by PCR identification of as many as 20 respiratory pathogens within 1 hour. Using these assays, studies have shown that approximately 30% of children hospitalized with RSV bronchiolitis may be co-infected with another respiratory virus. Whether children with RSV bronchiolitis who are co-infected with another respiratory virus develop more severe disease is still unclear.

TREATMENT

Currently, the primary treatment for RSV infection is supportive and includes nasal suctioning, hydration, and, in hospitalized patients, close cardiorespiratory monitoring and measurement of oxygen saturation. Nasal suctioning may provide relief of upper airway obstruction, but deep suctioning of the nasopharynx is not recommended. Nasogastric or intravenous fluids may be used to maintain hydration or when severe tachypnea is present. Although infants with bronchiolitis are at risk of developing subsegmental atelectasis, chest physiotherapy has not been shown to be of clinical benefit. Humidified oxygen is frequently required when managing hospitalized infants since hypoxemia is common (oxygen saturation < 90%) in more severe illness. The complications associated with hypoxemia and carbon dioxide (CO₂) retention generally begin when the respiratory rate surpasses 60 breaths per minute. Admission to pediatric intensive care units and use of noninvasive or invasive ventilatory support because of severe respiratory distress, hypoxemia, or apnea are required in 10% to 20% of children hospitalized with RSV bronchiolitis.

Inhaled bronchodilators, such as albuterol or racemic epinephrine, or inhaled or systemic corticosteroids are not recommended for the management of children with RSV bronchiolitis. Nebulized hypertonic saline has been shown to increase mucociliary clearance and may be beneficial in infants who are expected to have prolonged hospitalizations (> 72 hours). Last, except for acute otitis media, bacterial infections of the lower respiratory tract are rarely associated with RSV infection; thus, antibiotic treatment is usually not indicated for LRTI.

Ribavirin is a broad-spectrum virostatic antiviral agent with activity against RSV and other RNA viruses. Early on, small, double-blinded, placebo-controlled studies showed a beneficial effect in infants treated with aerosolized ribavirin soon after onset of disease. The required aerosol route of administration, concerns about potential toxic effects among exposed healthcare personnel, possible teratogenicity in pregnant women, conflicting results of efficacy trials, and high cost have led to infrequent use of ribavirin. The American Academy of Pediatrics (AAP) does not recommend its routine use in children but notes that it may be considered for use in selected patients with, or at risk for, life-threatening RSV infection (Table 236-1). It is also important to note that in immunocompromised children at high risk for severe disease, treatment with ribavirin is most helpful during the stage of URI before LRTI has developed. Uncontrolled studies in hematopoietic stem cell transplant recipients using combination therapy with ribavirin and intravenous polyclonal immunoglobulin or monoclonal antibodies (palivizumab) or in lung transplant recipients using ribavirin and intravenous immunoglobulin or corticosteroids have been performed demonstrating potential benefit. There are a number of promising antiviral drugs currently under development, including new monoclonal antibodies with extended half-life, fusion inhibitors, nucleoside analogs, and small molecules. These newer antivirals have the potential to impact both the prevention and treatment of RSV disease in the main target populations. In hospitalized patients, standard and contact precautions are recommended for the duration of the RSV illness, including patients receiving antivirals. Children with RSV should be cared for in single rooms or cohorted with other RSV-infected children.

PREVENTION

Preventive strategies against RSV infection are available. Education of parents and other caregivers on ways to decrease the infant’s exposure not only to RSV but also to factors that may contribute to the severity of the infection must form the basis of any RSV prophylaxis program. Hand hygiene is crucial in all settings. High-risk infants and children should not be exposed to individuals with respiratory infections, and if at all possible, they should not be in settings (eg, childcare centers) where such exposures are likely. Exposure to tobacco smoke must be eliminated since it has been associated with more severe RSV disease. These measures will have the added benefit of decreasing transmission of other respiratory pathogens.

Passive immunoprophylaxis to prevent RSV infection in infants and children at increased risk for severe disease is available in the form of a monoclonal anti-RSV antibody. Palivizumab targets the F surface glycoprotein of RSV, which is highly conserved among RSV isolates. In the original randomized clinical trials, safety and efficacy were established in infants with a history of premature birth (≤ 35 weeks of gestational age), children with chronic lung disease of prematurity (CLD), and children with hemodynamically significant CHD. Mainly because of costs, the AAP has updated the guidance on palivizumab prophylaxis on different occasions. For the specific updated recommendations, see the current edition of the AAP Report of the Committee on Infectious Diseases. The following recommendations are based on the committee’s 2015 report. Palivizumab prophylaxis should be considered at the start of the RSV season for: (1) infants or children with CLD of prematurity born at < 32 weeks of gestation who are younger than 12 months, or younger than 24 months and require medical therapy for their CLD within 6 months before the RSV season; (2) infants born before 29 weeks of gestation who are younger than 12 months at the start of the RSV season; and (3) infants younger than 12 months of age with acyanotic CHD with congestive heart failure and possibly cyanotic CHD. Others to consider palivizumab prophylaxis include children during the first year of life with neuromuscular disorders or pulmonary abnormalities that impair their ability to clear secretions from the lower airway and hematopoietic stem cell transplant patients who are profoundly immunosuppressed during the RSV season.

Palivizumab has a half-life of 28 days, and thus, it is administered once a month during the RSV season intramuscularly. It should be initiated immediately before the RSV season and continued monthly until the end. Although there is significant regional and year-to-year variability in the season onset and offset in the United States, administration of 5 monthly doses starting in November will usually ensure adequate serum concentrations throughout the season. Practitioners outside the United States or in regions with different RSV seasonality should contact their health departments or diagnostic virology laboratories to determine the optimal time to initiate prophylaxis.

Epidemiologic and clinical studies suggest that there are different target populations that will benefit from active immunization with RSV vaccines and that they might require different approaches: young RSV-naïve infants (< 6 months), children > 6 months, pregnant women, and the elderly. Although a safe and effective RSV vaccine has not yet been developed, there are many vaccine candidates currently undergoing testing in preclinical and phase I, II, and III clinical trials.

HUMAN METAPNEUMOVIRUS

First described in 2001, human metapneumovirus (hMPV) is now recognized as a globally distributed respiratory pathogen affecting children and adults. hMPV is one of the causes of bronchiolitis in infants and is also associated with different presentations of URIs and LRTIs in children.

PATHOGENESIS AND EPIDEMIOLOGY

hMPV is an enveloped, single-stranded, negative-sense RNA virus that belongs to the Paramyxoviridae family. Like RSV, which is of the genus Pneumovirus, hMPV has projecting F and G envelope glycoproteins and lacks HA activity. However, differences in its genomic sequence and structure result in its placement in the separate genus Metapneumovirus. There are 2 major groups of hMPV, A and B, which are further divided into 4 clades: A1, A2, B1, and B2. These different subgroups co-circulate each year in different proportions.

The pathogenesis of hMPV is based on limited studies in children, but it appears that the virus causes inflammatory changes of the lower airways once infection has become established. The interaction of hMPV and the immune system is poorly understood. Although humans mount a very robust antibody response to hMPV, immunity wanes over time and provides limited cross-protectivity between genotypes of the virus.

hMPV causes respiratory infections across the globe. Although discovered in 2001, archived sera from the 1950s contain antibodies against this agent, suggesting that this virus has been circulating for at least 60 years. In temperate regions, the virus is present year-round but peaks in late winter and early spring, later than the usual peak of RSV infection. In subtropical areas, hMPV circulation is most prevalent during the spring and summer. It may account for approximately 10% of LRTIs and 3% of URIs in young children. Almost all children are infected at least once by age 5. LRTIs from hMPV are usually associated with primary infection, and the peak age for severe disease and need for hospitalization is older than for RSV, often between 6 and 12 months of age. Studies have demonstrated symptomatic subsequent infections with hMPV from different hMPV subgroups in young children, although most reinfections are generally limited to the upper respiratory tract, which suggests partial immune protection and cross-protection against other hMPV subgroups following natural infection. Limited data suggest that co-circulation of related viruses, such as RSV or parainfluenza virus (PIV), may reduce the incidence of hMPV infections due to the presence of partial cross-protective immunity. Waning immunity is suggested by the fact that hMPV can cause severe respiratory infections in older adults including pneumonia requiring hospitalization. Asymptomatic infections are rare but may be seen in healthy young adults. Humans are the only reservoir, and like RSV, hMPV is thought to be transmitted through direct contact or contact with contaminated secretions. The incubation period is 3 to 5 days, and viral shedding in otherwise immunocompetent infants may last up to 2 weeks. Healthcare-associated infections have been reported.

CLINICAL MANIFESTATIONS

Children infected with hMPV cannot be distinguished clinically from those infected by other respiratory viruses such as RSV or PIVs. URIs with rhinorrhea, cough, or fever are common and can be present in 50% to 90% of cases. Pharyngitis and croup have been described in 40% and 18% of cases, respectively. Acute otitis media is a common complication, occurring in 25% to 50% of children with hMPV infection. Between 5% and 10% of children may also develop a rash during the infection. The most common lower respiratory tract syndromes include bronchiolitis (59%), asthma exacerbation (14%), and pneumonia (8%). When compared to RSV, more children with hMPV are diagnosed with pneumonia versus bronchiolitis, with a higher incidence of radiologic findings such as alveolar disease, focal infiltrates, bronchopneumonic changes, and pleural effusions. Like RSV, prematurity, cardiopulmonary disease, and immunosuppression are associated with more severe infection and higher hospitalization rates.

DIAGNOSIS

In the clinical setting, rt-PCR of respiratory specimens is the most sensitive technique and the gold standard for diagnosis of hMPV. In many clinical laboratories, hMPV is included in the multiplex diagnostic PCR assays, allowing for simultaneous detection of other respiratory pathogens, with a rapid turnaround time. Antigen detection by immunofluorescence using monoclonal antibodies is quite specific, but sensitivity is typically reported as < 75% with these assays. hMPV growth is fastidious in cell culture, with cytopathic effect often not apparent until after 10 to 14 days of incubation, which is not clinically useful. Shell vial culture with immunofluorescence staining improves speed and sensitivity over traditional viral culture but does not reach that of PCR. Serology is useful for epidemiology purposes. A definitive serologic diagnosis requires seroconversion or at least a 4-fold increase in convalescent samples.

TREATMENT

Care for children infected with hMPV is supportive and includes fever control, hydration, and close monitoring of respiratory status and oxygen saturation. Ribavirin is effective against hMPV in vitro and in animal models. In humans, there are a few small studies as well as anecdotal data with conflicting results regarding its benefit. There are also case reports of successful treatment of severe hMPV infection in immunocompromised patients with combined intravenous immunoglobulin and ribavirin. Antibiotics are not indicated for the treatment of hMPV bronchiolitis or pneumonia unless there is evidence of a concurrent bacterial infection.

PREVENTION

In hospitalized patients, standard and contact precautions are warranted for the duration of illness.

PARAINFLUENZA VIRUSES

PIVs are common causes of acute respiratory infections in young children. Croup is the most distinctive clinical syndrome caused by these agents, although bronchiolitis and pneumonia also occur. The initial infection usually occurs in the first few years of life, and reinfections are common.

PATHOGENESIS AND EPIDEMIOLOGY

PIVs are negative-sense, single-stranded, enveloped RNA viruses belonging to the genus Paramyxovirus in the Paramyxoviridae family, which also includes RSV and hMPV. The 4 PIVs have been separated into 2 genera, Respirovirus (serotypes PIV-1 and PIV-3) and Rubulavirus (PIV-2 and PIV-4 with 2 PIV-4 serotypes A and B). The large viral envelope (150–200 nm) is covered with spike-like projections containing 2 glycoproteins, the hemagglutinin-neuraminidase (HN) and fusion (F) proteins. These proteins are important for viral attachment and fusion with host cell membranes and are the major targets for neutralizing antibodies. The serotypes can be distinguished by type-specific antigens, but the viruses also share common antigens, such that infection with one PIV can lead to heterotypic serologic responses to the other serotypes. PIV-3 is the most prevalent serotype, with 90% to 100% of children demonstrating antibody by age 5.

Pathologic studies of children reveal that inflammation as evidenced by necrosis of the epithelium occurs throughout the respiratory tract with primary infection. In croup, the subglottic tissues appear particularly involved, but with primary infection, the airways at all levels, including the alveoli, can be involved. Most children with bronchopneumonia due to PIVs will have cellular necrosis and destruction of bronchial columnar epithelium in addition to diffuse alveolar damage. Infection with PIVs induces initial innate immune responses, serum and mucosal antibody responses, and cellular immune responses (both CD4+ and CD8+). Immunity to reinfections with PIVs is at best incomplete. Naturally acquired serum immunoglobulin (Ig) G provides the most durable protection against reinfection and may protect against LRTIs. However, infection of adult volunteers reveals that mucosal IgA was better correlated with protection from reinfection than serum IgG. After repeated infections, antibodies may develop that cross-neutralize different PIV strains, mostly noted within the genera (PIV-1 and PIV-3, or PIV-2 and PIV-4). Studies of hospital epidemics indicate a high attack rate and implicate shedding of virus before symptom onset.

Although all PIV serotypes are distributed globally and are capable of causing the full spectrum of respiratory illnesses, they tend to occur in distinct epidemiologic and clinical patterns. Humans are the only source of infection. PIV-1 causes the largest, most defined outbreaks of croup. In the United States, these have occurred for several decades during the fall of odd years. PIV-2 produces smaller, less severe epidemics of croup also in the fall months. PIV-1 and PIV-2 infections occasionally result in bronchiolitis or pneumonia. PIV-3 is the most frequently recovered PIV, is endemic, and circulates throughout the year with annual outbreaks typically extending from late spring through summer. It regularly causes bronchiolitis, pneumonia, or croup. The seasonal pattern of PIV-4 has been increasingly recognized with the use of molecular diagnostic tools. PIV-4 has been mainly associated with upper respiratory disease. A large retrospective study conducted in the United States from 2009 to 2012 showed that PIV-4 had year-round prevalence with biennial peaks during the fall of odd-numbered years. PIV infections are associated with substantial morbidity and mortality in immunocompromised hosts. Most PIV outbreaks in transplant units coincide with the peak incidence of these infections in the community.

Most children are infected with all PIV serotypes by age 5. Infection with PIV-1 usually occurs between year 1 and 5, whereas PIV-3 occurs earlier, with up to two-thirds of infants infected before age 1. Acquisition of PIV-4 also occurs during preschool years following the pattern observed with PIV-1 and PIV-2. Reinfection occurs in children and adults with all serotypes and is usually confined to the upper respiratory tract. Person-to-person transmission of PIV occurs via direct contact with large-droplet aerosols or fomites, and illness follows an incubation period of 2 to 6 days. Depending on the serotype, viral shedding can last up to 3 weeks after symptoms resolve.

CLINICAL MANIFESTATIONS

PIVs cause a variety of URIs and LRTIs that may vary based on age and serotype. Most primary infections are symptomatic, and disease prevalence is greater in the outpatient setting. In healthy children, most illnesses involve the upper respiratory tract, and up to 35% are complicated with otitis media. In a subset of children, the infection progresses to the lower respiratory tract causing croup (acute laryngotracheobronchitis), bronchiolitis, or pneumonia. As noted, in general, PIV-1 and PIV-2 are associated with croup, and PIV-4 is associated with mild URI in both children and adults, whereas PIV-3 causes bronchiolitis and pneumonia. Overall, croup is the most common PIV-associated diagnosis. Croup begins with a URI of several days in duration, followed by hoarseness and a “barking seal” croupy cough. Inspiratory stridor and marked retractions are evident in more severe infections. Fever is usually mild. Most children recover after 48 to 72 hours, but some children progress to severe airway obstruction. When croup occurs in children younger than 6 months of age or is prolonged or recurrent, underlying anatomic pathology should be suspected. However, recurrent “spasmodic” (noninfectious) croup can occur in children with normal airway anatomy. The differential diagnosis for severe stridor includes bacterial tracheitis, which may be seen as a secondary bacterial infection following viral croup and is most commonly caused by Staphylococcus aureus, or epiglottitis, which is a life-threatening infection that was usually caused by Haemophilus influenzae type b or diphtheria. These last 2 entities are extremely rare now due to routine immunization. Bronchiolitis and pneumonia caused by PIVs are clinically indistinguishable from those associated with RSV, hMPV, or other respiratory viruses. Rare reports implicate PIVs in cases of aseptic meningitis, encephalitis, myopericarditis, Guillain-Barré syndrome, and parotitis.

DIAGNOSIS

PIV infection should be suspected in a child with compatible symptoms during a known outbreak, but definitive diagnosis requires identification by culture, antigen detection, or PCR from nasopharyngeal or lower respiratory tract specimens. PCR assays for detection of type-specific PIV RNA have the highest sensitivity and specificity, and thus, PCR is currently the preferred method for diagnosis. All 4 PIV serotypes are also included in available multiplex PCR assays, which may allow for simultaneous detection of several other respiratory viruses. Although used less frequently now because of availability of these other tests, if viral culture is performed, as with other respiratory viruses, care must be taken to promptly place specimens in viral transport media and maintain temperature near 4°C during transport due to the lability of these viruses. Antigen detection by immunofluorescent staining or EIA allows rapid diagnosis but is less sensitive than PCR assays. Serologic diagnosis can also be performed but has limited value in patient management.

TREATMENT

In immunocompetent children, treatment of PIV infection is supportive. For the management of croup, nebulized epinephrine and steroids (parenteral, oral, or nebulized) can be used. Close monitoring is needed for those with severe disease, and occasionally, intubation of the airway is necessary. No specific antiviral treatment is currently available for PIV infections. Ribavirin has activity against PIVs in vitro, but retrospective studies in immunocompromised patients have failed to show benefit in preventing progression to the lower respiratory tract. Novel drugs are currently being evaluated in clinical trials. DAS181 is a recombinant sialidase fusion protein with activity against PIV that is currently undergoing phase II clinical trials. DAS181 has been used with success for the treatment of PIV LRTI in lung and stem cell transplant patients, including children, resulting in reductions of viral loads and improvement in clinical symptoms. BCX2798 and BCX2855 (hemagglutinin-neuraminidase inhibitors) have demonstrated antiviral activity against PIV-3 in vitro and in murine models, but no human studies are currently available.

PREVENTION

There is no available PIV vaccine, but many clinical trials are being conducted on vaccine efficacy in healthy infants and children. In addition to standard precautions, contact precautions are recommended for hospitalized infants and young children for the duration of illness.

INFLUENZA VIRUSES

Influenza is an acute respiratory illness typically accompanied by fever and systemic symptoms. Annual global epidemics interspersed with occasional pandemics result in considerable morbidity and mortality in children and adults.

PATHOGENESIS AND EPIDEMIOLOGY

The influenza viruses are members of the Orthomyxoviridae family and are separated into 3 genera: Influenzavirus A, Influenzavirus B, and Influenzavirus C. These viruses contain a negative-sense, single-stranded, segmented RNA genome. Each of the 8 RNA segments codes for 1 or 2 of 11 viral proteins. The segmented nature of the influenza genome allows for exchange of RNA segments when 2 different influenza virions infect the same cell (genetic reassortment). This property is responsible for the antigenic shifts and drifts and has great significance for the epidemiology of influenza including pandemics.

The enveloped virion is about 100 nm in diameter and studded with spike-like projections consisting of its surface glycoproteins HA and NA. Influenza A viruses are further divided into subtypes based on these 2 surface glycoproteins. Major influenza A subtypes circulating in humans have been A (H1N1) and A (H3N2) and, most recently, the pandemic A (H1N1). Protective antibodies directed against particular subtypes of HA or NA are of little or no cross-protective benefit against alternative subtypes. Although human infections with avian influenza viruses are uncommon, they may result in severe lower respiratory tract disease, acute respiratory distress syndrome (ARDS), and death. There are 18 known HA subtypes and 11 NA subtypes of avian influenza viruses, and of those, H5N1 and H7N9 have been associated with severe disease and high mortality rates in humans. Humans are also occasionally infected with swine origin influenza viruses, which usually manifest as the typical influenza-like illness. Influenza B and C have less antigenic variability and are not divided into subtypes. Type C influenza viruses cause sporadic mild influenza-like illness in children, and type C antigens are not included in influenza vaccines.

Influenza infection is initiated by virus inoculation in the upper or lower airways. If present, virus-specific IgG and IgA antibodies against the surface antigens, particularly HA, may block the infection. Neuraminidase facilitates penetration through the sialyloligosaccharide-rich respiratory mucous layer for access to the epithelial cells and later is important for release of newly packaged viruses from cells. The viral HA allows viral attachment and later membrane fusion with respiratory epithelial cells. Upon infection and replication in the respiratory epithelium, virus is shed into respiratory secretions, and local spread ensues, with eventual desquamation. The entire airway from pharynx to alveoli may be involved. Diffuse pneumonia due to alveolar infection can be life threatening. Viral infection usually remains limited to the respiratory tract, although viremia has been described with specific strains and has been associated with enhanced disease severity. Systemic symptoms are mostly due to the high levels of cytokines and chemokines released upon infection. Influenza infection results in damaged mucociliary function, reduced neutrophil function, and impairment of other immune mechanisms that are probably responsible for the increased risk of bacterial superinfections.

The virus type and subtype have an effect on the virulence of the circulating influenza strain. The HA and NA represent the major determinants of immunity. Minor mutations in these enveloped glycoproteins are referred as “antigenic drifts” and occur almost annually. Antigenic drifts are responsible for the circulation of new viral variants to which the individual may be susceptible, perpetuating the annual epidemics of variable extent and severity. At varying intervals, major changes in the HA and NA occur and are referred as “antigenic shifts.” Antigenic shifts are associated with genetic reassortment of RNA segments between human and animal viruses or adaptation of a new animal virus to humans and are responsible for pandemics of influenza A. These events, which occurred 4 times during the 20th century and once in 2009, render antibody to previously circulating influenza A viruses unprotective. Worldwide pandemics associated with considerable excess mortality ensue.

In temperate climates, seasonal influenza epidemics occur during winter months. In the United States, influenza activity usually peaks between January and March, although occasionally, it can occur as early as November or as late as May. Community outbreaks usually last 4 to 8 weeks; however, circulation of 2 or 3 influenza viruses may be associated with a prolonged influenza season of 3 or more months and bimodal peaks in activity. Rates of hospitalization and death associated with influenza vary from year to year because influenza seasons are unpredictable and fluctuate in duration and severity. The severity of the disease is related in part to the presence of preexisting immunity as a result of prior exposure or immunization with a related strain and underlying risk factors (Table 236-2). In the United States, the annual epidemics usually result in more than 200,000 hospitalizations. Hospitalization rates are similarly high for children < 2 years of age and adults age 65 years or older. The number of influenza-associated deaths, which is probably underestimated due to underreporting, can vary from 3000 to 50,000 people annually, with the majority of deaths occurring in adults age 65 years or older. During influenza season, the virus accounts for approximately 20% of outpatient visits for children and adults with acute respiratory infections and fever (influenza-like illness). Surveillance activity is updated weekly during influenza season and available from the Centers for Disease Control and Prevention (CDC).

Young children shed higher concentrations of virus for a longer duration than their older counterparts. The virus is highly contagious and is transmitted person-to-person primarily through contact with respiratory secretions (aerosolized droplets) generated by coughing or sneezing, or through contact with contaminated surfaces. Symptoms follow a 1- to 4-day incubation period, and patients may be infectious 24 hours before symptom onset. Viral shedding lasts for approximately 7 days, although virus can be shed for a longer period of time in young children or in patients with immunodeficiency. Viral shedding and fever are directly correlated.

CLINICAL MANIFESTATIONS

In children, influenza typically presents with sudden onset of fever and respiratory symptoms, but ultimately, the clinical manifestations depend on the age of the child and his or her preexisting immunity. Fever is more prominent than with other viral respiratory infections, occurring in 95% of children, routinely reaching 39°C (102.2°F) to 40°C (104°F), and lasting 3 to 6 days in the absence of complications. In older children, the typical influenza-like illness starts with fever, often accompanied by chills or rigor, headache, myalgias, malaise, sore throat, and dry cough, followed later by a more productive cough and rhinitis. Children under age 5 usually present with a febrile URI, but some manifest severe croup, bronchiolitis, or pneumonia, while neonatal influenza may mimic bacterial sepsis. Tracheitis or tracheobronchitis may be particularly severe or complicated by bacterial superinfection (bacterial tracheitis). Asthma exacerbations are also common in children with influenza infection. The most common complication of influenza is acute otitis media, affecting approximately 10% to 50% of children, followed by pneumonia, especially in high-risk patients. Viral bronchopneumonia is more common in children < 2 years of age and is typically mild, rarely leading to severe disease or death in otherwise healthy children. Bacterial pneumonia has been reported in 2% of hospitalized children and usually manifests as recurrent fever and pulmonary symptoms after 5 to 7 days of influenza illness. The most common causative agents are Streptococcus pneumoniae and Staphylococcus aureus (including methicillin-resistant S aureus [MRSA]). S aureus pneumonia may be particularly severe and rapidly fatal and usually occurs in children with no underlying medical condition.

Other complications of influenza include Reye syndrome in association with aspirin use, toxic shock syndrome due to secondary bacterial infection, myositis or myocarditis and neurologic complications that range from febrile seizures to acute encephalitis, aseptic meningitis, Guillain-Barré syndrome, or transverse myelitis. Postinfectious encephalitis has also been reported.

DIAGNOSIS

Influenza virus infection should be considered when clinically compatible symptoms are present irrespective of the immunization status. However, diagnostic confirmation requires viral isolation or detection of viral antigens or viral RNA in respiratory samples (nasal swab or wash), ideally within the first 3 days of symptoms as viral load decreases afterward. Influenza can be cultured from respiratory secretions upon inoculation into monkey or canine kidney cell cultures or embryonated eggs. Viral growth can be detected after 2 to 6 days by hemadsorption, hemagglutination, or, on occasion, by evidence of cell destruction. However, with the availability of specific antiviral treatment and the need to initiate therapy quickly in high-risk or hospitalized patients, culture methods are not preferred in clinical practice. Similarly, serology testing requires acute and convalescent sampling and thus is not practical for clinical decision making. Rapid antigen detection assays (by immunofluorescence or EIA) are also available, with reported sensitivities of 45% to 97% and specificities of 76% to 100% compared with PCR. Most of these assays cannot differentiate between influenza subtypes, which may be needed for choice of antiviral agents. RNA detection by rt-PCR is the most sensitive and specific diagnostic method and allows for rapid diagnosis, differentiating between influenza types and subtypes. Influenza viruses are included in the commercially available multiplex PCR assays. Diagnostic testing also is helpful because it may reduce additional testing to identify the cause of the child’s influenza-like illness. Treatment should not be withheld in high-risk patients while awaiting rt-PCR test results.

TREATMENT

In general, influenza infection in children is a self-limited condition. Supportive care includes antipyretics to reduce fever (and discomfort). Salicylates should not be used to treat influenza in children or adolescents because of the increased risk of Reye syndrome. Bed rest and maintenance of adequate fluid intake may also provide comfort.

Antiviral therapy is recommended regardless of the immunization status or whether or not symptoms have been present for more than 48 hours for any patient with confirmed or suspected influenza who is hospitalized, has severe or complicated disease, or is at high risk for complications (see Table 236-2). Clinical benefit is greater when antiviral therapy is initiated within 48 hours of symptom onset; however, treatment should be considered even if later in the disease course, especially in hospitalized patients, in whom antiviral therapy has been shown to shorten the duration of hospitalization and decrease mortality. The duration of treatment is 5 days.

Antiviral therapies are discussed in Chapter 240, and use in specific respiratory infections is outlined in Table 236-1. The CDC has a surveillance program in place to identify antiviral resistance each year and updates recommendations for influenza antiviral use accordingly. Two classes of antivirals are approved for treatment and prophylaxis of influenza infections in the United States: NA inhibitors (oseltamivir, zanamivir, and peramivir); and adamantanes (amantadine and rimantadine). NA inhibitors have activity against influenza A and B viruses and can be administered through different routes. Oral oseltamivir is the preferred antiviral and is approved for treatment in children as young as 2 weeks old. Inhaled zanamivir is an alternative, but it is difficult to administer. It is approved for treatment in children over 7 years of age and is not recommended in children with underlying airway disease because of association with bronchospasm. A parenteral form of zanamivir is currently in a phase III clinical trial for patients who cannot tolerate or absorb oseltamivir. Peramivir is another NA inhibitor approved for those over 18 years of age and is also administered intravenously. Dosages are detailed in Table 236-1. Laninamivir is a long-acting inhaled NA inhibitor available only in Japan. Amantadine and rimantadine are active against influenza A only, and levels of resistance in past seasons have been reported to be > 99%; thus, these agents are not recommended for treatment or chemoprophylaxis in the United States.

PREVENTION

Immunoprophylaxis with trivalent and quadrivalent inactivated influenza vaccines (IIVs) or live attenuated, cold-adapted influenza vaccines (LAIVs) and chemoprophylaxis using NA inhibitors are available measures that are effective in reducing the number of influenza virus infections and the impact of influenza disease.

Influenza Vaccines

Since the late 1940s, the vaccination each year prior to the onset of influenza season of individuals at high risk for complications has been the most effective approach for reducing the impact of influenza. Each year, influenza vaccines are modified to contain 3 or 4 antigens (2 for influenza A and 1 or 2 for influenza B) based on the influenza circulation in the Southern Hemisphere, which precedes the circulation in the Northern Hemisphere. From 2005 to 2016, the overall adjusted vaccine effectiveness has varied widely from 10% to 60%. Vaccine effectiveness is highest when the vaccine strains and circulating strains are closely related. The IIVs contain no live virus and are administered either intramuscularly or intradermally. IIVs are available in both trivalent (IIV3) formulations, including a high-dose vaccine for those at least 65 years of age, and quadrivalent (IIV4) formulations. In addition, there are 2 trivalent IIVs that have been developed without using eggs and are available for people older than 18 years with severe egg allergy: recombinant influenza vaccine (RIV3), and cell culture–based influenza vaccine (ccIIV3), which contains trace amounts of ovalbumin. Although intramuscular IIV formulations are licensed for administration in children 6 months and older, the intradermal formulation is only licensed for use in those 18 to 64 years of age.

LAIV4 is a quadrivalent formulation that is administered intranasally and is licensed for healthy children older than 2 years of age and adults less than 50 years old. It is contraindicated in children < 5 years of age with a history of asthma or wheezing in the preceding 12 months, children between 2 and 17 years of age who are receiving chronic aspirin therapy, pregnant women, immunocompromised individuals, and people who have received influenza antiviral treatment within the previous 48 hours. Since 2016, the CDC does not recommend LAIV administration in children because of low effectiveness.

LAIV and most of the IIV formulations are produced in eggs. Except for severe, life-threatening allergic reactions to any ingredient in the vaccine, egg allergy is not a contraindication to influenza vaccination. Recent studies have shown that IIV administered in a single, age-appropriate dose is well tolerated by most recipients with a history of egg allergy. If a child with mild egg allergy (eg, hives) is vaccinated, close observation for 30 minutes and availability of appropriate resuscitation equipment are required. See the CDC recommendations for further information regarding use of influenza vaccines in egg-allergic individuals. The risk of developing Guillain-Barré syndrome is rare (no more than 1–2 cases per million doses).

All children 6 months and older should receive annual influenza vaccination. Children 6 months to 8 years who have not received influenza vaccine previously require 2 doses of vaccine in their first year of influenza vaccination, administered at least 4 weeks apart to boost antibody responses. Children older than 8 years require 1 dose of influenza vaccine regardless of their previous immunization status. Special emphasis for IIV administration should be directed to patients at increased risk (see Table 236-2). Influenza vaccination should be mandatory for healthcare workers. People who care for severely immunocompromised patients (eg, in bone marrow transplant units) should not receive LAIV unless patient contact can be avoided for 7 days following administration. See http://www.cdc.gov/flu for the Public Health Service Advisory Committee on Immunization Practices (ACIP) updated recommendations on influenza vaccine target populations, dosage, administration instructions, and adverse effects. For further discussion of influenza vaccination, see Chapter 239.

Chemoprophylaxis

Chemoprophylaxis should not be substituted for vaccination, even in high-risk patients, but can be considered for prevention of infection in children at high risk of complications during the first 2 weeks following vaccination, children who may not respond to vaccination due to immunosuppression, or children who cannot receive vaccination due to a contraindication. It can also be used during influenza outbreaks for prevention of infection among residents of institutions. Chemoprophylaxis can be administered concomitantly with IIV formulations to provide protection until antibody develops but cannot be administered with LAIV formulations, since antivirals may have activity against vaccine strains. Chemoprophylaxis can be administered before or after exposure in children at high risk for complications. Given the development of resistance to other antiviral agents, the NA inhibitor oseltamivir is now the primary agent recommended for children. It is approved for use in children age 3 months and older. Zanamivir may also be used and is approved as a prophylactic agent for children over age 5. CDC recommendations should be consulted for further information regarding prophylaxis.

Other Preventive Measures

In hospitalized patients, strict infection prevention measures to avoid nosocomial infections should be implemented, and patients should be placed in droplet (and standard) precautions for the duration of illness. Hand washing is essential. Respiratory secretions should be considered infectious.

Other preventive measures that are key when managing children with influenza infection, especially those at increased risk of complications, include influenza vaccination of household contacts and out-of-home caregivers, general infection prevention measures, and avoidance of sick contacts.

ADENOVIRUSES

Adenoviruses account for 5% to 10% of all febrile illnesses in children and are also important causes of ocular, gastrointestinal, and urologic infections. In addition, they are recognized as serious pathogens in immunocompromised hosts in whom fatal disseminated infection can develop following primary infection or viral reactivation.

PATHOGENESIS AND EPIDEMIOLOGY

Adenoviruses are nonenveloped, double-stranded DNA viruses that are icosahedral in shape and measure 70 to 80 nm in diameter. They are members of the Adenoviridae family in the genus Mastadenovirus and are divided into 7 species (A–G) on the basis of their DNA sequence. There are 57 recognized human adenovirus serotypes. Adenoviruses 1 to 5, 7, 14, and 21 are primarily associated with respiratory tract disease, while adenoviruses 40 and 41 mainly cause gastroenteritis. Antigenically important coat proteins include hexon, penton base, and fiber. Infection with one adenovirus type confers type-specific immunity.

In most respiratory disease, the initial infection by adenovirus involves the nose, oropharynx, and conjunctiva, but the severity will vary based on the serotype. In severe pneumonia, total destruction with necrotizing bronchitis, bronchiolitis, and pneumonia has been described. Hyaline membrane and necrosis may be present, whereas cilia and goblet cells may be absent. Often epithelial cells take on a characteristic appearance with adenoviral infection.

Adenoviruses have worldwide distribution, and infections occur throughout the year. Spread is primarily via respiratory droplets, but transmission can also occur by fecal routes or via contact with contaminated fomites. Most children have serologic evidence of prior adenovirus infection by age 10. Care must be taken in associating adenovirus detection with disease entities because these viruses, especially species C, are capable of establishing persistent or latent infection in lymphoid tissues including tonsils, adenoids, and the gut of infected children, and recurrent shedding without acute symptoms can occur. Nevertheless, many epidemics of adenovirus disease including keratoconjunctivitis, pharyngoconjunctival fever, or acute respiratory disease as well as nosocomial transmission have been described. The incubation period ranges from 2 to 14 days for adenoviral respiratory tract infections and 3 to 10 days for gastroenteritis.

CLINICAL MANIFESTATIONS

Adenoviruses are capable of causing a broad spectrum of clinical diseases due to the organ tropism of different species. Species A is primarily associated with respiratory and gastrointestinal infections; species B, C, and E with respiratory infections; species D with ocular and gastrointestinal infections; and species F and G with gastrointestinal infections. The clinical manifestations of adenoviral disease vary based on the age and the host immune status. Severe disease has been reported with types 5, 7, 14, and 21.

Respiratory Illness

Adenoviruses are some of the most common viruses that cause febrile respiratory illnesses in children. The usual duration of illness is 5 to 7 days, although symptomatology can last up to 2 weeks. Infants and children most commonly manifest URI symptoms with conjunctivitis, otitis media, coryza, or pharyngitis, and less commonly with croup or a pertussis-like syndrome. Exudative tonsillitis may be present, and systemic symptoms such as fever, malaise, and headache may be prominent. Respiratory symptoms may be accompanied by a benign follicular conjunctivitis, febrile pharyngitis. and cervical adenitis in a condition termed pharyngoconjunctival fever (adenovirus B types 3 and 7 are the most common isolates). Outbreaks of pharyngoconjunctival fever have been documented in summer camps and in association with public swimming pools. Bronchiolitis or pneumonia occurs in a small percentage of children and can be fatal in neonates and children with underlying medical conditions. The incidence of bronchiolitis obliterans or bronchiectasis is high following adenoviral pneumonia in young children. Although most children recover without complications, some outbreaks caused by species B types 3, 7, 11, 14, and 21 have resulted in fulminate disease with significant mortality.

Epidemic Keratoconjunctivitis

In this more serious form of ocular adenovirus infection, conjunctivitis is followed by bilateral corneal infiltrates and enlargement of preauricular nodes. It has been associated primarily with adenovirus D types 8, 19, and 37 and causes severe pain and blurry vision. Outbreaks of keratoconjunctivitis have been reported in medical facilities.

Extrarespiratory Manifestations

The enteric adenoviruses, species F types 40 and 41 and species G type 52, are important causes of diarrheal illness that may last from 8 to 12 days. Adenoviruses (not necessarily the enteric serotypes) have been recovered from mesenteric lymph nodes of children with intussusception, suggesting a role for these viruses in the pathogenesis of the disease. Adenovirus species B types 11 and 21 are associated with acute hemorrhagic cystitis and hematuria lasting several days to 2 weeks. Adenovirus infection, especially subgroup C type 5, may cause severe hepatitis and liver failure, particularly in infants or immunocompromised patients. Viral myocarditis, meningoencephalitis, hepatitis, and rhabdomyolysis are occasionally associated with adenovirus infection. Severe disseminated adenovirus disease with or without exanthem has been reported in immunocompetent and immunocompromised children, including neonates, and is associated with high mortality.

DIAGNOSIS

Adenoviruses can be identified by PCR in nasopharyngeal, oropharyngeal, and eye secretions, blood, cerebrospinal fluid, urine, stool, and biopsy specimens. Other means less commonly used for adenovirus isolation include traditional culture in primary or permanent cell lines, shell vial culture, and antigen detection that is generally less sensitive than culture but may provide a rapid diagnosis. Serologic evidence of increasing antibody titers could be useful to confirm recent infection.

Because virus shedding from the pharynx may persist for weeks or even recurrently following adenovirus infection, the diagnostic significance of adenovirus detection in respiratory or fecal samples is not as strong as it is with many of the other respiratory viruses. In these cases, measuring viral burden may be useful to confirm acute infection. In immunocompromised patients, quantitative PCR for adenovirus in the blood may be useful for detecting patients at risk of dissemination.

TREATMENT

For most healthy children, treatment is symptomatic. Antiviral therapy is reserved for immunocompromised children and patients with severe disease. Although there are no available controlled trials, the nucleotide analog cidofovir has been used at different doses and intervals for the treatment of adenovirus infection in immunocompromised patients. The major limiting factor of cidofovir is nephrotoxicity. CMX001 (brincidofovir) is a lipid conjugate form of cidofovir with enhanced in vitro activity against adenoviruses, improved bioavailability when administered orally, and lower potential for nephrotoxicity and myelosuppression. Brincidofovir is currently being evaluated in phase III clinical trials, and preliminary results have indicated good safety and efficacy in treating adenoviral infections in transplant recipients. Intravenous immunoglobulin has also been used for the treatment of adenovirus disease in immunocompromised patients. Other emerging therapies include the transfusion of donor-derived adenovirus-specific T lymphocytes, which is currently being used in some centers for stem cell transplant recipients who do not respond to antiviral therapy.

PREVENTION

An effective, live, enteric-coated oral vaccine against serotypes 4 and 7 has been used in military recruits but has not been employed in civilian populations. Hospitalized children with conjunctivitis or gastroenteritis should be placed in contact isolation, and those with respiratory tract disease in contact and droplet isolation for the duration of illness. Adenoviruses are difficult to inactivate with alcohol-based gels and can remain viable on environmental surfaces for prolonged periods; thus, strict hand hygiene and use of disposable gloves are recommended when caring for infected patients.

RHINOVIRUSES AND RESPIRATORY ENTEROVIRUSES

Rhinoviruses have been known to cause the majority of URIs in adults and children, which are also known as the “common cold,” with a generally benign, self-limited course. Currently, they are also increasingly recognized as important triggers of LRTIs and asthma exacerbations.

PATHOGENESIS AND EPIDEMIOLOGY

Rhinoviruses and enteroviruses are small, nonenveloped, single positive-stranded RNA viruses belonging to the Enterovirus genus within the Picornaviridae family. They are divided into 7 species: 3 rhinovirus species (A, B, and C) and 4 non-rhinovirus enterovirus species (A, B, C, and D). There are more than 100 serotypes. Most rhinoviruses replicate optimally at low pH (< 5) and high temperature (> 34°C), the temperature of the upper respiratory tract mucosa. Cross-protection after rhinovirus infection is incomplete and short lasting.

Rhinoviruses infect and replicate in the upper respiratory tract through the intracellular adhesion molecule-1 (ICAM-1), the host receptor for most rhinoviruses. On the other hand, enteroviruses can replicate in different cells, causing clinical syndromes such as febrile illness, viral meningitis and encephalitis, and myopericarditis. Some species of enteroviruses, however, are mainly associated with respiratory tract infections (species C and D) and are clinically indistinguishable from those caused by rhinovirus.

Rhinovirus infections occur year-round, but 2 peaks have been classically reported, 1 between April and May and a second between September and October. Some studies have shown that species C has a different peak of infection, typically over the winter months. Children are the major reservoir for rhinovirus. Transmission occurs primarily by person-to-person contact through self-inoculation with contaminated secretions (hand-to-nose or hand-to-eye). Large-droplet spread is also possible. Viral shedding in respiratory secretions is greatest during the first 2 to 3 days of illness and can last from 10 to 21 days. The incubation period is 2 to 3 days.

Enteroviruses with respiratory tropism, such as species C and D, have a worldwide distribution and can cause respiratory disease with varying degrees of severity ranging from mild URI to pneumonia. Enterovirus D68 was first described in 1962 from children with bronchiolitis and pneumonia, with a few clusters of cases reported over the past decade in different parts of the world. The largest outbreak of enterovirus D68 occurred in the United States in 2014 with over 1000 cases reported in 49 states mainly affecting children with a history of asthma. In addition to its respiratory tropism, enterovirus D68 infection has been associated with neurologic disease including acute flaccid myelitis.

CLINICAL MANIFESTATIONS

Rhinovirus infection can be asymptomatic or symptomatic. The most common manifestation of rhinovirus infection is the common cold—an illness dominated by nasal obstruction or discharge, with accompanying cough, sore throat, and mild or absent fever. It has also been linked to acute otitis media complicating approximately one-third of patients with URI. Rhinoviruses can also cause LRTI, such as bronchiolitis and pneumonia, and are well-established triggers of wheezing in children with asthma.

DIAGNOSIS

rt-PCR is the most sensitive and the preferred test for diagnosis and is the only method available to diagnose rhinovirus C. Commercially available multiplex PCR assays include both rhinoviruses and enteroviruses. Most of these assays target a region that is conserved among both species, making their differentiation difficult. Rhinovirus can be positive by PCR in asymptomatic children, which may indicate residual viral RNA from a prior rhinovirus infection.

TREATMENT

No specific antiviral treatment is currently available for rhinovirus infections. Over-the-counter cough and cold preparations do not provide significant benefit for children with the common cold and are not recommended. Vitamins (ascorbic acid), minerals (zinc), and herbal remedies (Echinacea) are frequently used for the treatment and prevention of the common cold, with limited evidence of any benefit in reducing symptoms. To date, there are no vaccines available or in clinical trials.

PREVENTION

Hand washing and avoidance of hand contact with respiratory secretions of affected individuals reduce viral transmission. For symptomatic hospitalized children, contact and droplet precautions are recommended for the duration of illness.

CORONAVIRUSES

The human coronaviruses are enveloped, pleomorphic, nonsegmented, single-stranded RNA viruses named after their corona or crown-like surface projections that correspond to their surface glycoproteins. Coronaviruses have long been identified as causes of the common cold in adults and children, causing 5% to 18% of childhood respiratory infections. Cases of croup, bronchiolitis, and pneumonia are increasingly recognized. Emergence of 2 highly virulent coronaviruses with zoonotic transmission causing severe LRTI has been described in the past 15 years. In 2003, the SARS coronavirus was identified as a novel virus responsible for the 2002 to 2003 global outbreak that resulted in thousands of cases and more than 700 deaths. Technologies developed during the SARS epidemic contributed to the discovery of additional coronaviruses such that 4 non-SARS coronaviruses (HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1) are currently known to circulate in humans and have been associated with respiratory disease. Non-SARS coronavirus epidemics have also occurred. In 2012, the Middle East respiratory syndrome (MERS) coronavirus (CoV) was identified, and since then, hundreds of people have been affected in different countries. Most people affected with MERS-CoV developed acute febrile respiratory illness, and many died. The incubation period of non-SARS-CoV is approximately 3 days, for SARS-CoV approximately 4 days, and for MERS-CoV approximately 5 days. The growth of CoVs in tissue culture is limited, and rt-PCR has enhanced the ability to detect these viruses. The diagnosis of SARS-CoV or MERS-CoV should not be based on a single test and needs to be confirmed by an approved laboratory. Treatment is supportive, and no vaccines are currently available.

BOCAVIRUSES

Human bocaviruses (HBoVs) of the family Parvoviridae are single-stranded DNA viruses that were discovered in 2005 using novel molecular techniques in children with respiratory infections. HBoVs circulate throughout the year, with peaks in winter and spring months. The virus is most frequently identified in children < 2 years of age. By age 6 years, most children have evidence of previous HBoV infection, with reinfections occurring into adulthood. Four genotypes are included in the Bocavirus genus (HBoV 1–4). HBoV1 is the genotype associated with respiratory disease in children, having been found in approximately 8% of young children with acute respiratory infections including otitis media, pneumonia, bronchiolitis, and wheezing. Although this virus is not commonly found in asymptomatic individuals, its causal role in childhood respiratory infections has been called into question because of the high frequency of co-detection with other respiratory viruses (as high as 80%) and the potential for asymptomatic persistence in some individuals. HBoV1 has also been detected in low levels in the stool of children with gastroenteritis; however, co-pathogens were detected in 100% of the patients, potentially reflecting ingestion of the virus without causation of disease. HBoV2, HBoV3, and HBoV4 seem to be associated with gastrointestinal symptoms, but their prevalence is low. Detection of HBoV1–3 from cerebrospinal fluid in children with encephalitis associated with seroconversion has occasionally been reported. Diagnosis is made mainly with rt-PCR, but serology is also available. Treatment is supportive.

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INTRODUCTION

Fungi are widely distributed in the environment and are uncommon respiratory pathogens in children or adolescents. Fungi causing infection can be viewed as 2 main groups: those that cause endemic mycoses (eg, Histoplasma and Blastomyces species), which can lead to disease in both immunocompetent and immunocompromised hosts; and those considered opportunistic fungal pathogens (eg, Aspergillus and Mucor species), which primarily cause disease in immunocompromised hosts (Fig. 237-1). Although the endemic mycoses can be severe in otherwise healthy hosts, especially when exposed to a large infectious inoculum, infection is more often mild and self-limiting or even subclinical. In contrast, the endemic mycoses and opportunistic fungal pathogens can cause life-threatening pulmonary infections in patients with primary or secondary immunodeficiency. Early diagnosis of respiratory fungal infection is a challenge in both immunocompetent and immunocompromised patients. The initial clinical findings are nonspecific and are similar to other more common bacterial and viral infections. Critical to an early diagnosis is a clinician’s index of suspicion, which is influenced by recognition of the host’s immune status and vulnerability to fungal infections.

THE ENDEMIC MYCOSES

The endemic mycoses are diseases caused by fungi with shared characteristics, including thermal dimorphism (mycelial form in the environment and yeast in tissue), the ability to cause clinically significant disease in otherwise well hosts, and specific geographic distributions.

PATHOGENESIS AND EPIDEMIOLOGY

The respiratory tract serves as the most common primary site of infection and portal of systemic entry for many of the endemic mycoses, including Histoplasma capsulatum, Blastomyces species, Coccidioides species, and Paracoccidioides species. Exposure typically occurs as a result of inhalation of infectious conidia aerosolized from soil disrupted due to wind or human activity. Although Blastomyces species may cause primary cutaneous infection by direct inoculation in children, it most frequently causes primary pulmonary infection. Organisms within the Sporothrix schenckii complex predominantly cause a cutaneous infection acquired through traumatic inoculation and only rarely cause primary respiratory tract disease. The mechanism by which humans become infected with Talaromyces marneffei is incompletely understood, but epidemiologic studies suggest that, similar to these other organisms, inhalation of infectious conidia from disrupted soil is a likely route of acquisition.

After inhalation of conidia, intact cell-mediated immunity appears to be of critical importance for control of infection. Underlying deficiencies in cell-mediated immune function predispose to severe or disseminated disease and to reactivation of latent infection. Examples of medications and conditions that increase risk of severe disease include the acquired immunodeficiency syndrome (AIDS), anticancer chemotherapy, solid organ or hematopoietic stem cell transplantation, chemotherapy, and immunomodulatory medications (including systemic corticosteroids) used for the treatment of rheumatologic and other conditions.

Although cases are documented in patients with apparently normal immunologic function, disseminated histoplasmosis and penicilliosis are considered AIDS-defining illnesses in human immunodeficiency virus (HIV)-infected individuals. Similarly, a diagnosis of penicilliosis in a pediatric patient without a known underlying immunologic deficit may increase the suspicion for a primary or secondary immunodeficiency.

In general, the fungi that cause the endemic mycoses dwell in soil. Each has a specific geographical and environmental predilection (Table 237-1). For this reason, obtaining a careful (past) social history is necessary; it is important to ask patients about travel to endemic regions, occupational activities, and recreational endeavors. Localized outbreaks or disease clusters of endemic mycoses can occur, such as outbreaks of coccidioidomycosis following earthquakes in California.

CLINICAL MANIFESTATIONS

The clinical manifestations of each of the endemic mycoses vary depending on factors such as inoculum burden and host immune competence. In otherwise healthy individuals, infection is commonly subclinical or mild and self-limiting, but on occasions, such as with a large inoculum exposure (eg, cleaning barns), severe clinical disease may develop.

Endemic mycoses, including histoplasmosis, blastomycosis, and coccidioidomycosis, can present with pneumonia. The associated symptoms can range from fever, cough, chest pain, and dyspnea to the acute respiratory distress syndrome. Because symptoms overlap with community-acquired bacterial and viral pneumonias, diagnosis and management of a fungal etiology can be delayed. In endemic areas, lack of clinical improvement following routine treatment of community-acquired pneumonia should raise concern for endemic mycoses.

Pulmonary histoplasmosis typically presents subacutely over the course of weeks with fever, malaise, and progressive cough or dyspnea as a result of lymphadenopathy causing compression of the tracheobronchial tree. Other presentations include mediastinal granulomatous disease, mediastinal lymphadenitis, mediastinal fibrosis, broncholithiasis, and nodular pulmonary disease. Some manifestations are asymptomatic and usually noted incidentally (eg, solitary pulmonary nodules), others produce local respiratory symptoms (eg, mediastinal lymphadenitis or mediastinal fibrosis), and others produce dysphagia, hemoptysis, or the superior vena cava (SVC) syndrome secondary to mass effect or erosion into adjacent structures (eg, mediastinal lymphadenitis). Primary disseminated histoplasmosis, which occurs predominantly in young infants and immunocompromised hosts, can affect any organ system often without any respiratory symptoms.

Pulmonary blastomycosis commonly presents acutely with symptoms of fever, fatigue, chest pain, and cough that mimics typical bacterial pneumonia. In contrast, pulmonary coccidioidomycosis usually presents as a subacute infection with similar symptoms present for weeks to months. Arthralgias, malaise, and skin rashes may also be seen.

Chronic cavitary pulmonary disease has been described following infection with H capsulatum and Coccidioides species in adults, but these indolent forms of disease are rarely encountered in pediatric patients.

Paracoccidioidomycosis and penicilliosis are acquired via the respiratory route, but generalized systemic findings are more common than isolated pulmonary signs and symptoms in pediatric patients. The acute/subacute (or “juvenile”) presentation of paracoccidioidomycosis, more often seen in children, is characterized by a generalized infection involving the reticuloendothelial system and other tissues; pulmonary symptoms are often absent. Attributed to reactivation of disease acquired earlier in life, the chronic (or “adult”) type of paracoccidioidomycosis increases in incidence in early adulthood and usually presents with chronic lung disease, upper respiratory tract ulceration, and local lymphadenopathy. Penicilliosis is characterized by a progressive systemic illness with multisystem involvement that can also include respiratory symptoms in pediatric patients.

Sporotrichosis typically presents with cutaneous lesions, but a pulmonary presentation, including involvement of the nasal mucosa and lower respiratory tract, has been described.

DIAGNOSIS

Pulmonary histoplasmosis produces hilar or mediastinal adenopathy, often with calcification, sometimes associated with diffuse or localized infiltrates. If the diagnosis is delayed or incidental, infiltrates may be absent. In contrast to adults, pleural effusion is rare in children. Cavitary lung lesions may occasionally be seen in chronic pulmonary histoplasmosis. Blastomycosis most frequently causes parenchymal infiltrates, often lobar; pleural effusion is noted in about one-third of cases. Pulmonary coccidioidomycosis commonly produces focal consolidation, often associated with an ipsilateral pleural effusion, with or without adenopathy. Residual findings on thoracic imaging, such as nodules or cavities, may remain following pulmonary coccidioidomycosis in a small number of patients.

Although respiratory signs and symptoms are rare in pediatric paracoccidioidomycosis, abnormal thoracic radiographic findings comparable to pulmonary tuberculosis may be seen during acute disease. Pediatric patients with penicilliosis may have parenchymal infiltrates, nodular lung disease, and pleural effusions.

Pulmonary sporotrichosis produces nonspecific thoracic imaging findings that can include upper lobe cavitary lesions, tracheobronchial lymphadenopathy, and nodular parenchymal lesions.

Histopathology, direct examination of clinical specimens, culture, serology, and antigen-based methods are available to support the diagnosis of an endemic mycosis in the appropriate clinical context (Table 237-2). For many endemic mycoses, the gold standard for diagnosis remains culture or microscopic examination of clinical tissue or body fluid samples. Serologic and antigen-based testing is available to be performed on blood or urine samples for many endemic mycoses. For each of the endemic mycoses, individual tests have their own sensitivity, specificity, advantages, and limitations (see Table 237-2). Molecular diagnostic tests (eg, polymerase chain reaction [PCR]-based tests) are in various stages of development but not currently available for routine clinical use.

TREATMENT

The route, composition, and duration of antifungal treatment for respiratory tract infections caused by endemic mycoses vary with the severity and chronicity of clinical presentation, presence or absence of multisystem organ involvement, and underlying patient characteristics. Clinical practice guidelines for the treatment of histoplasmosis, blastomycosis, coccidioidomycosis, and sporotrichosis, published by the Infectious Diseases Society of America (IDSA), are available to assist management.

Some patients with self-limiting conditions or who present with postinfective symptoms require no antifungal therapy. If therapy is required, active antifungal agents include the various forms of amphotericin and drugs within the azole class. For many of the endemic mycoses, itraconazole has favorable activity and past clinical experience and is the first-line recommended azole antifungal in many cases. Newer extended-spectrum azoles, including voriconazole and posaconazole, may have activity against the fungi that cause the endemic mycoses, but evidence and clinical experience supporting their use as first-line medications are presently limited. Echinocandins (eg, micafungin) demonstrate limited activity against many of the fungi that cause the endemic mycoses, and their use is not routinely recommended.

Ketoconazole and fluconazole can be used for coccidioidomycosis. Trimethoprim-sulfamethoxazole demonstrates effectiveness in the management of paracoccidioidomycosis, although the required treatment duration may be longer than when an azole antifungal is prescribed.

Adjunctive therapy for management of symptomatic lymphadenopathy from histoplasmosis may include surgery or systemic corticosteroids to decompress the SVC or tracheobronchial tree. The role of steroids is still poorly defined, and symptoms often eventually resolve without treatment, but many clinicians prescribe anti-inflammatory doses of corticosteroids for symptomatic hilar or mediastinal lymphadenopathy. If steroids are used, antifungal therapy is often given concurrently.

PREVENTION

Prevention efforts against endemic mycoses are largely focused on minimizing airborne exposure in patients susceptible to severe or disseminated disease. For prevention of histoplasmosis, especially in immunocompromised patients, exposure to soil and dust should be minimized. In contrast to certain adult patients, primary prophylaxis of histoplasmosis in HIV-infected children with antifungal medications is not recommended. Immunocompromised patients residing in or traveling to areas endemic for Coccidioides species should be counseled to avoid exposure to activities that may aerosolize spores in contaminated soil. There are no recommendations for primary antifungal prophylaxis for coccidioidomycosis in patients with AIDS, even in endemic regions. No specific control measures, regarding either exposure avoidance or primary prophylaxis, are recommended for blastomycosis, paracoccidioidomycosis, and sporotrichosis.

THE OPPORTUNISTIC FUNGI

The opportunistic fungi, including yeasts and molds (see Fig. 237-1), lead to disease of the respiratory tract, including sinuses, lower airways, and lung parenchyma, predominantly in immunocompromised hosts. Occasionally, Aspergillus species and other molds cause allergic, saprophytic, or invasive infections in immunocompetent hosts.

PATHOGENESIS AND EPIDEMIOLOGY

Opportunistic fungal infections are the result of the interplay between host susceptibility, the virulence of the pathogen, and inoculum of exposure. Clinical manifestations are related to both the pathogen and the immune response.

Inhalation of airborne fungal conidia is the main route of acquisition for many opportunistic fungal respiratory infections. Phagocytes resident in the respiratory tree provide the first line of defense against fungal pathogens. Conidia that are not contained by this initial response begin mycelial growth, which subsequently triggers a neutrophil response. Compromise of either of these host defense mechanisms allows for further germination into the hyphal form in sinus or lung tissue (in the case of molds), which leads to growth and tissue invasion. Immunologic abnormalities that make patients susceptible to fungal respiratory infections include neutropenia, especially profound neutropenia with an absolute neutrophil count (ANC) less than 100 cells/μL (eg, hematologic malignancies or anticancer chemotherapy), impaired phagocyte function (eg, chronic granulomatous disease), and disruption of cutaneous and mucosal barriers (eg, radiation, chemotherapy, or indwelling catheters).

Defects in cell-mediated immunity, such as those seen in AIDS or therapy for malignancy, also increase the risk of invasive fungal infection and are the primary contributors to the risk of Pneumocystis jirovecii pneumonia (PCP).

Respiratory infections caused by opportunistic fungi are generally not geographically restricted. The incidence, etiology, and presentation of respiratory tract infections secondary to opportunistic fungi can vary from center to center based on differences among centers in immunosuppressive protocols, transplant types (solid organ vs hematopoietic stem cell), and antifungal prophylaxis strategies.

DIAGNOSIS

Persistent fever in an immunocompromised host while on broad-spectrum antibacterials, with or without focal symptoms or signs, is a common presentation of invasive fungal infection. In this setting, pain in the face or chest, mild cough, or visualization of an eschar in the nose may be the first clue to an invasive respiratory fungal infection. A thorough skin exam can also help identify deep-seated invasive fungal infections as skin lesions can be seen in disseminated candidiasis, aspergillosis, and fusariosis and are readily accessible for skin biopsy. When fever persists in a high-risk neutropenic host, computed tomography (CT) of the chest should be performed to pursue a diagnosis of pulmonary infection, even in the absence of local signs or symptoms. A negative CT may need to be repeated after several days or after neutrophil recovery as imaging changes are sometimes absent early in infection during profound neutropenia.

Consensus criteria have been published for the diagnosis of invasive fungal infections. However, many of the recommendations are based on data obtained in adults that are not necessarily directly applicable to pediatrics. As a general construct, the diagnosis requires appropriate patient characteristics (immunocompromising conditions that place the patient at risk of developing a fungal infection) in combination with suggestive radiographic findings or mycologic support (either direct or indirect). Direct mycologic support is provided by histopathology demonstrating fungal forms in association with local tissue damage or by a positive culture for a yeast or mold from a sterile site. Indirect mycologic support is provided by antigen-based testing methods (Table 237-3).

APPROACH TO SPECIFIC ORGANISMS

Yeasts

Candida species may colonize portions of the respiratory tract. As such, identification in sputum or bronchoalveolar lavage (BAL) fluid often represents colonization only. For instance, endotracheal intubation increases the likelihood of airway colonization, and Candida species can be isolated from intubated patients without clinical or radiographic lower respiratory tract disease. However, in immunocompromised or very young patients, Candida species may cause lower respiratory tract disease. Primary pulmonary candidiasis follows aspiration of Candida from the upper respiratory tract, may be associated with oropharyngeal or esophageal candidiasis, and is diagnosed by confirmation of parenchymal disease without candidemia or other organ involvement. The imaging findings differ from secondary pulmonary candidiasis; they consist predominantly of confluent parenchymal opacities that may be multifocal. Secondary pulmonary candidiasis is much more common and represents a component of disseminated candidiasis. Imaging typically reveals a pattern of bilateral innumerable small nodules. Although definitive diagnosis requires biopsy or positive blood cultures, typical imaging and clinical findings in an immunocompromised, typically neutropenic host should lead to presumptive diagnosis and empiric treatment. Most positive cultures from the respiratory tract require no specific therapy. Treatment of confirmed primary pulmonary candidiasis usually involves amphotericin B, an echinocandin, or an azole antifungal drug, depending on organism susceptibility, and duration of therapy is shorter than for disseminated infection. Treatment for secondary pulmonary candidiasis is directed toward disseminated infection. In immunocompromised patients, an echinocandin is the treatment of choice. Azole antifungals and amphotericin may be alternatives depending on organism susceptibility and host factors.

Cryptococcosis is caused by Cryptococcus neoformans and Cryptococcus gattii, which are environmental fungi. C neoformans is associated with exposure to bird droppings; the niche for C gattii is less well understood. Humans are exposed to Cryptococcus species through inhalation of infectious fungal elements from the environment. Secondary dissemination from the lungs with involvement of other organ systems (eg, the central nervous system) may follow. Pulmonary cryptococcosis can present with asymptomatic pulmonary nodules in both healthy and immunocompromised patients, incidentally or as part of a workup for cryptococcal meningitis. Symptomatic pulmonary cryptococcosis presents subacutely with cough, dyspnea, chest pain, and constitutional symptoms. Imaging findings are variable and are a function of the host’s immune status. Nodular, cavitary, and consolidative patterns may all be demonstrated with thoracic imaging. Immunocompromised patients are more likely to have multiple pulmonary nodules, cavitary lung disease, and pleural effusion. A diagnosis of pulmonary cryptococcosis can be made using direct examination of clinical specimens, culture, and antigen detection methods (see Table 237-3). Treatment guidelines have been published by the IDSA and vary with the clinical presentation and host immune status. Azole antifungals (including fluconazole), amphotericin, and flucytosine all have activity against Cryptococcus.

Trichosporonosis is caused by fungi within the Trichosporon genus. They are pathogenic in neonates and patients with compromised skin barriers (eg, skin burns or indwelling central venous lines) or immunologic function (eg, hematologic malignancies or transplant recipients). Infection is typically disseminated and accompanied by pulmonary infiltrates and skin lesions. Diagnosis is made by histopathology and/or culture (can be isolated from blood with disseminated infection). The most active antifungals are the azoles; amphotericin and echinocandins may have little activity.

Molds

Suggestive signs and symptoms of a lower respiratory tract mold infection include fever, cough, dyspnea, and chest pain. Hemoptysis may also be present, especially after neutrophil recovery, and can potentially be life threatening if resulting from erosion into a large blood vessel. However, the only presenting sign of lower respiratory tract infection may be persistent fever despite the provision of broad-spectrum antibacterial agents. For this reason, thoracic imaging is recommended for high-risk neutropenic patients with fever persisting more than 4 days.

Although chest radiograph can identify abnormalities, including nodules and air space consolidation, it has a low sensitivity and specificity for the detection of pulmonary fungal infections in immunocompromised patients. Thoracic CT is more sensitive and specific and provides the advantage of further defining the location, type, and extent of pulmonary lesions to facilitate tissue sampling. Thoracic CT findings may include nodules, cavitary lesions, the “halo” sign, the “reversed halo” sign, and the “air-crescent” sign (Fig. 237-2). The halo sign, classically described in aspergillosis, is a nodule surrounded by a ground-glass opacity thought to be representative of angioinvasion. The reversed halo sign, classically described in zygomycosis, is a rounded area of ground-glass opacity surrounded by consolidation thought to appear as a result of pulmonary infarction. The air-crescent sign is a later finding that may be seen on repeat imaging, especially following neutrophil recovery, and is characterized by air surrounding a radiopaque mass within a cavitary lung lesion. These “typical” CT findings of invasive pulmonary fungal infection are much less common in children, especially those who are less than 5 years old.

Biopsy of areas suspicious for invasive mold infections on thoracic imaging, when possible, is indicated to establish a diagnosis and guide choice of antifungal treatment. Depending on the location of the pulmonary lesion and available expertise, transbronchial, percutaneous radiologically guided (commonly with CT), or open lung biopsies may provide adequate tissue for diagnostic studies. Transbronchial biopsies can be performed in small children if adequate clinical expertise is available. Percutaneous CT-guided biopsy has been demonstrated to have moderate diagnostic yield with relatively low adverse event rates, but utility may be operator-dependent. Open lung biopsy or lobectomy provides the opportunity to sample a larger tissue volume and has the added benefit of removing infected tissue, but is associated with higher perioperative risks. Once acquired, the specimen should be sent for histopathology and culture. Histopathology will show fungal elements in association with local tissue destruction. Although stains (eg, Gomori methenamine silver [GMS] or periodic acid-Schiff [PAS]) can demonstrate characteristic morphologies of an organism (eg, presence or absence of septation and hyphal branching pattern), definitive identification of the underlying etiology is made by culture.

Bronchoscopy with BAL sent for fungal stains, culture, and antigen testing (see Table 237-3) also may provide support for a lower respiratory tract mold infection. However, the diagnostic yield of BAL in immunosuppressed patients, especially those on antifungal agents, is relatively low, so a negative BAL does not necessarily exclude a mold infection. Bronchoscopy with BAL does offer the additional advantage of establishing a diagnosis of alternative infectious processes (eg, viral, bacterial, Pneumocystis).

An enzyme immunoassay (EIA) for the galactomannan antigen, which is found in the cell walls of all Aspergillus species, is available to provide indirect mycologic support of invasive Aspergillus infections and can be performed on serum, plasma, BAL fluid, and cerebrospinal fluid (see Table 237-3). Galactomannan EIA testing has been more rigorously evaluated as a serial prospective surveillance tool for invasive aspergillosis in hematopoietic stem cell transplant recipients; its clinical performance outside this setting has not been as well studied. However, when positive in blood or BAL fluid in an appropriate clinical context, it can help support a diagnosis of invasive pulmonary aspergillosis.

Testing blood for the presence of (1-3)-β-D-glucan, a component of the cell wall in most fungi (excluding the zygomycetes and Cryptococcus species), is also available (see Table 237-3). Based on its favorable performance in adult patients, this test has been included in consensus criteria for the diagnosis of invasive fungal infections. However, performance of this test in children has been less well explored, and preliminary data suggest that the test may be less specific or require a different cutoff in the pediatric population. For this reason, its use as a diagnostic test is not recommended until further clinical data are available.

Once the diagnosis of invasive lower respiratory tract mold infection is suspected or established, antifungal medication should promptly be administered. While awaiting the results of diagnostic tests, amphotericin or voriconazole is usually the drug of choice for initial empirical management. Once identification is made, management guidelines have been published by the IDSA for several of the invasive mold infections, including invasive pulmonary aspergillosis. Long-term therapy, at least 12 weeks and until resolution of profound immunosuppression, is usually required. Adjunctive surgery to remove infected tissue may improve clinical outcomes, especially if the lesion is unifocal or close to large vessels.

Pneumocystis jirovecii

P jirovecii is a globally distributed fungal organism that causes pneumonia (PCP) in immunocompromised hosts. The mode of primary acquisition and habitat are unknown. Exposure to P jirovecii is common in early childhood. Symptomatic disease occurs in patients with compromised cell-mediated immunity (eg, after anticancer chemotherapy, AIDS, or primary immunodeficiencies), so primary prophylaxis with trimethoprim-sulfamethoxazole is recommended in these populations. Signs and symptoms of PCP include nonproductive cough, tachypnea, dyspnea, and hypoxemia. The acuity of presentation varies with the cause and degree of immune suppression and can be acute to subacute with continued progression without treatment. Similarly, the severity of clinical manifestations can be mild to severe. Except for infants less than 4 months of age, who may experience upper and lower respiratory tract disease, infection is commonly subclinical in otherwise well children.

Thoracic imaging most commonly identifies bilateral interstitial infiltrates that may be described as reticular or ground-glass opacities. In less severe disease, chest radiographs may be normal. Thoracic CT is more sensitive and specific than plain chest radiographs for diagnosing PCP.

Because P jirovecii cannot routinely be cultured, the diagnosis relies on identification of the organism in sputum or BAL fluid. Several cytologic stains (eg, GMS), direct fluorescent antibody (DFA) testing, and molecular testing (PCR) are available for clinical use on respiratory samples. Lactate dehydrogenase (LDH) and (1-3)-β-D-glucan may also be elevated in cases of PCP (see Table 237-3). Trimethoprim-sulfamethoxazole is the initial treatment of choice in children over 2 months of age. Alternative agents include pentamidine, atovaquone, dapsone, and clindamycin in combination with primaquine, but these may be less effective. Despite limited evidence, adjunctive corticosteroids are usually administered to patients with significant hypoxemia because response to antimicrobial therapy alone is often delayed.

Aspergilloma and Allergic Bronchopulmonary Aspergillosis

Aspergillus species may cause a noninvasive infection in preexisting pulmonary parenchymal cavities, which is termed a pulmonary aspergilloma. These are composed of fungal hyphae and cellular debris and are most commonly caused by Aspergillus fumigatus. Conditions leading to structural lung abnormalities, including congenital pulmonary malformations, cystic lung disease, or prior tuberculosis, predispose patients to this condition. Patients may be asymptomatic or present with hemoptysis. Characteristically, a cavity containing a rounded mass with a rim of surrounding air and local pleural thickening is seen on thoracic imaging. Aspergillomas do not uniformly necessitate treatment. Surgical resection is commonly the initial treatment of choice; bronchial artery embolization can also be used acutely for patients with life-threatening hemoptysis. No benefit is seen with systemic antifungal administration.

Allergic bronchopulmonary aspergillosis (ABPA) is caused by a hypersensitivity reaction within the respiratory tract to antigens produced by A fumigatus after it becomes trapped in the thick mucus of patients with asthma or cystic fibrosis (CF). The incidence of ABPA in these patient populations increases with age. Signs and symptoms may include fever, productive cough, malaise, and a decrease in pulmonary function test performance. There are diagnostic criteria available for patients with asthma and with CF. Clinical decline, demonstration of hypersensitivity to A fumigatus serologically and by skin testing, and imaging changes are included in the diagnostic schema. The primary treatment is with systemic corticosteroids (eg, prednisone). Azole antifungals (eg, itraconazole) can reduce fungal burden and steroid exposure.

SINUS DISEASE

Owing to their environmental ubiquity, molds frequently colonize the paranasal sinuses. Several distinct clinical diseases, each with unique presentations, pathogenesis, and underlying host risk factors, may be caused by environmental fungi within the paranasal sinuses.

Localized collections of mucous and fungal elements, typically from Aspergillus species, without tissue invasion or inflammatory reaction may develop in an obstructed sinus. Terms have been variably used to describe these collections, including sinus mycetoma and sinus aspergilloma, although these names have been replaced by fungus ball, a more general term. These have not been described in young children, and cases have rarely been diagnosed in adolescence. Affected patients are not usually immunocompromised. The clinical presentation is chronic and includes symptoms of headache and facial pain. Diagnosis is made by clinical history and imaging demonstrating a thickly opacified sinus. Endoscopic sinus surgery is the treatment of choice, and there is no established role for antifungal agents in management.

Allergic fungal sinusitis is a clinical subtype of chronic rhinosinusitis that may be encountered in children and adolescents. It is thought to result from a prolonged IgE-mediated response to antigens expressed by colonizing molds (eg, Alternaria and Curvularia) in the process of noninvasive growth. The presentation is often chronic, and symptoms include nasal congestion, rhinorrhea, and facial pain. Diagnostic criteria include the appropriate clinical findings in an immunocompetent patient, nasal polyposis, suggestive findings on sinus imaging, histopathology of sinus contents demonstrating eosinophilic mucous and fungal elements without mucosal invasion, and type 1 hypersensitivity to fungal antigens. Treatment is both medical and surgical, although the role of antifungal agents in management is unclear.

The most feared form of fungal sinusitis is invasive disease in patients with compromised immune function. This can be disfiguring or fatal if not diagnosed and addressed expediently. Patient characteristics predisposing to invasive fungal sinusitis include neutropenia (eg, anticancer chemotherapy or hematologic malignancy), solid organ or hematopoietic stem cell transplantation, uncontrolled diabetes mellitus, chronic systemic glucocorticoid exposure, and primary or secondary hemochromatosis. Signs and symptoms may include fever, headache, facial pain, periorbital edema, nasal congestion, and epistaxis, although inflammatory findings may be less prominent in patients with significant immunocompromise due to the lack of an associated immune response. Infection may be complicated by invasion into contiguous structures, including the brain, orbits, and local blood vessels. Invasion can result in hemorrhage, infarction, mental status changes, facial paresthesias, proptosis, and diplopia. Molds (eg, Aspergillus species, dematiaceous molds, and the zygomycetes) are most commonly implicated. Suspicion of fungal sinusitis in a susceptible host should prompt immediate endoscopic sinus examination with biopsy of apparently involved nasal or sinus tissue to obtain specimens for histopathology and culture. Imaging with either CT or magnetic resonance imaging (MRI) has limited diagnostic sensitivity and specificity but can define the extent of infection and involvement of adjacent structures. Histopathology typically demonstrates locally invasive fungal hyphae associated with tissue necrosis. An identification of the causal organism may subsequently be made by culture. Surgical consultation, early and repeated debridement, and antifungal therapy are critical to management. Empiric therapy with amphotericin or posaconazole is the treatment of choice for suspected invasive fungal rhinosinusitis while awaiting pathology and culture results. Treatment is subsequently tailored to pathologic and microbiologic findings. These infections are difficult to treat, and significant morbidity often results from repeated surgical intervention or invasion into orbit, eye, or brain.

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INTRODUCTION

Infection of the middle ear, or otitis media (OM), includes acute, nonacute, and chronic types of infections. Acute otitis media (AOM) is defined as an acute illness marked by the presence of middle ear fluid and inflammation of the mucosa that lines the middle ear space. Otitis media with effusion (OME) is defined by the presence of middle ear fluid without signs of acute illness and usually follows AOM but may also occur as a result of viral upper respiratory tract infection (URTI), allergy, or barotrauma. Synonyms for OME include serous otitis, secretory otitis, and glue ear. Less common chronic variations of OM include permanent perforation of the tympanic membrane (TM) and perforation or retraction of the TM with trapped epithelium that is unable to spontaneously clear desquamated debris, forming a cholesteatoma. Both perforations and cholesteatoma may be associated with recurrent foul-smelling otorrhea, termed chronic suppurative otitis media (CSOM). CSOM occurs more commonly after repeated and untreated AOM in low- and middle-income countries. Infection may spread from the middle ear space to contiguous structures such as the inner ear, mastoid air cells, petrous bone, and intracranial structures, leading to infection of the central nervous system.

PATHOGENESIS AND EPIDEMIOLOGY

The middle ear system includes the nasopharynx, the eustachian tube (ET), the middle ear space, and the adjacent structures, including the mastoid air cells and inner ear. The middle ear is an air-filled space between the TM and the inner ear. It has a mucosal lining of respiratory epithelium and contains 3 bony ossicles—malleus, incus, and stapes—that form a lever mechanism important for the conduction of sound. The size of the middle ear cavity and the ossicles is the same at birth as in the adult. The ET originates in the anterior middle ear space and courses anteriorly to empty into the lateral nasopharynx. The normal physiologic functions of the ET include: pressure regulation or ventilation of the middle ear, which equilibrates gas pressure in the middle ear with atmospheric pressure; protection of the middle ear by anatomic, immunologic, and mucociliary defenses; and clearance or drainage of secretions produced within the middle ear via mucociliary activity and muscular clearance. In infancy, the ET is short, wide, and in a straight position, permitting easy access of nasopharyngeal flora into the middle ear space. With increasing age, the ET elongates, narrows, and assumes an oblique position, corresponding to a decrease in the incidence of OM as age increases.

AOM usually occurs concurrently or just after URTI; more than 90% of children with AOM have concurrent URTI symptoms. The 3 most common bacterial otopathogens include Streptococcus pneumoniae, nontypeable Haemophilus influenzae, and Moraxella catarrhalis. These organisms colonize the infant’s nasopharynx from early age and do not infect the respiratory tract or cause symptoms until viral URTI (nasopharyngitis) occurs, causing changes in the nasopharyngeal milieu. Steps in the pathogenesis of AOM are outlined in Table 238-1.

Even when there is no nasopharyngeal colonization by bacterial otopathogens, viral URTI alone may cause AOM through similar mechanisms. URTI may also lead to OME, likely through similar mechanisms, but with less degree of inflammation. In children 6 months to 4 years of age who were closely followed, 37% of viral URTI resulted in AOM, while another 24% resulted in OME. The mean duration of middle ear effusion after an episode of AOM is approximately 3 weeks, with 10% persisting after 12 weeks.

OM is a disease of infancy and early childhood. AOM is the most frequent reason that children visit healthcare facilities in the first 3 years of life and has been one of the most frequent reasons that physicians prescribe antimicrobial agents for infants and children. The peak age-specific attack rate of AOM occurs between 6 and 18 months. Children who have had little or no experience with OM by age 3 years are unlikely to have subsequent severe or recurrent disease. Previous data from the 1980s have shown that, on average, children have 1.2 and 1.1 episodes of AOM in the first and second years of life, respectively. Recent data have shown reduced incidence to 0.67 episodes in the first year. Many factors are likely to contribute to the decline in OM incidence in the past few decades. First, introduction in the United States of the 7-valent conjugate pneumococcal vaccine (PCV7) in 2000, and the 13-valent vaccine (PCV13) in 2010, and later in countries throughout the world, has reduced OM-related healthcare use and the number of episodes of vaccine-type pneumococcal AOM and decreased the incidence of severe and recurrent disease. In addition, routine influenza vaccination was recommended in 2004, 2006, and 2008 for children age 6 to 23 months, 6 months to 5 years, and then all children, respectively. Influenza vaccination has been shown to reduce AOM during yearly influenza epidemics. Second, publication of the Diagnosis and Management Guideline by the American Academy of Pediatrics (AAP) in 2004, which was updated in 2013, presented uniform criteria for diagnosis, choice of antimicrobial agents, and recommendations for use or withholding of antibiotics for children with AOM. Healthcare providers may have felt less pressure to diagnose and treat AOM knowing that observation is an acceptable option. Third, there were programs developed by Centers for Disease Control and Prevention advocacy groups to inform physicians and consumers about the appropriate use of antimicrobial agents to decrease the development of multidrug-resistant bacteria. Last, there has been a decrease in cigarette smoking and an increase in breastfeeding in the United States.

The more severe suppurative complications are infrequent in developed countries, where access to medical care is readily available, although these complications are still a frequent cause of morbidity in developing countries. It is unclear whether early prescribing of antibiotics has been responsible for decreasing the incidence of mastoiditis in developed countries.

OME is even more common than AOM. Up to 90% of school-age children have OME at some time. In the first year of life, > 50% of children experience OME, increasing to > 60% by 2 years of age.

Risk Factors

OM is a multifactorial disease. Risk factors include demographic, prenatal/perinatal, immunologic, anatomic, intrinsic genetic, and environmental risks. Young age at first episode of AOM is significantly associated with recurrent episodes. Males have a higher incidence of single and recurrent episodes of AOM than do females. Selected racial groups, many in developing countries or hostile environments, appear to be otitis prone. Native Americans and Alaskan and Canadian Inuit infants and children have a high incidence of severe AOM and suppurative complications. In an Apache community, a draining ear or perforation was found in 8.4% of patients of all ages. Several studies indicate that African American children have less OM than white children, but it is unclear if this is explained by underdiagnosis in the African American community due to less access to medical care or due to differences in the position of the bony ET among races.

Premature infants and those born with low serum levels of maternally derived pneumococcal antibodies are more prone to OM. Altered host defenses, such as congenital or acquired immune deficiencies, and use of immunosuppressive drugs may play a role in recurrent and severe AOM. Among the anatomic risks are cleft palate, cleft uvula, and submucous cleft. Alteration of normal physiologic defenses (patulous ET) and malignant neoplasms that may alter the anatomy of the upper respiratory tract add to OM risk. An increased incidence of AOM also occurs in children with Down syndrome.

Genetic predisposition to AOM is suggested by the aggregation of cases in families: AOM risk increases if any other member of the family had AOM. There is also a strong genetic component to the amount of time with OME and the number of AOM episodes in monozygotic twins. Severe and recurrent disease may be associated with genetically determined features, such as skull configuration, or with overt or subtle immunologic defects. A range of genes regulating innate and adaptive immunity are associated with predisposition to OM. Some of the heritable risk for OM might result from cytokine gene polymorphisms (eg, tumor necrosis factor [TNF]-α, interleukin [IL]-6), and others such as toll-like receptor (TLR)-2 polymorphisms, affecting signal transduction pathways, have been associated with increased rates of OM and disease severity.

For environmental factors, passive cigarette smoking has been shown to be responsible for structural and physiologic changes in the respiratory tree. Smoke exposure can result in goblet cell hyperplasia and mucus hypersecretion, ciliostasis, and decreased mucociliary transport in the respiratory tract. High concentrations of serum cotinine, a biochemical marker for cigarette smoke exposure, were associated with increased incidence of AOM and increased duration of middle ear effusion (MEE) after AOM. Daycare attendance is an OM risk factor; children in daycare not only have more episodes of AOM than children in home care but also have more resultant surgical procedures. The more children in the daycare group, the more exposures there are to bacterial otopathogens and respiratory viruses and the higher the risk for OM. Similarly, crowded conditions (eg, as seen with low socioeconomic status or a large number of siblings in the household) increase OM risk. On the other hand, breastfeeding of 3 to 6 months in duration has been documented to prevent nasopharyngeal bacterial colonization, as well as URTI and AOM. Among the possible reasons for the beneficial effect of breastfeeding are the presence in breast milk of various immunoglobulins, B and T cells, macrophages and neutrophils, and nonimmune factors including interferon and glycoproteins. Oligosaccharides in breast milk that correspond to the pneumococcal carbohydrate receptor suggest that breast milk may protect against OM by blocking attachment of bacterial pathogens to respiratory mucosa. Thus, lack of breastfeeding is an OM risk factor.

MICROBIOLOGY

Our understanding of the microbiology of AOM is attributed to needle aspiration (tympanocentesis) of the MEE. Results vary depending on the methods used to detect the microorganisms. Bacteria and/or viruses are most commonly detected. AOM is often due to bacterial and viral co-infection.

When only bacterial culture was used to study the MEE, bacterial otopathogens were detected in 70% to 85% of cases. When conventional diagnostic assays including bacterial and viral cultures plus rapid antigen detection for respiratory syncytial virus (RSV) were performed, results showed: bacteria alone in 55% of cases; bacteria and viruses in 15%; viruses alone in 5%; and no pathogens in 25%. Using bacterial culture and polymerase chain reaction (PCR) assays to detect bacteria and viruses, data showed: both bacteria and viruses in 66%; bacteria alone in 27%; viruses alone in 4%; and no pathogen in 4% of cases.

Bacterial Otopathogens

The 3 most common bacterial otopathogens are S pneumoniae, nontypeable H influenzae, and M catarrhalis. Less common bacteria include Streptococcus pyogenes (group A), which causes 2% to 10% of AOM, tends to occur in older children, and is more frequently associated with TM perforation and mastoiditis. Rare pathogens detected in the MEE include Chlamydia, Mycoplasma, Mycobacterium tuberculosis, and fungi.

Bacterial causes of AOM and the diversity of strains within S pneumoniae have been dynamic, with the major contributor to such change being the introduction of PCVs. S pneumoniae is the most important cause of AOM as it often produces the most severe, persistent, or refractory AOM. There are at least 90 distinct serotypes of S pneumoniae, although relatively few types are responsible for most AOM. Before the advent of PCVs, S pneumoniae was the most commonly detected bacteria in MEEs. In the first few years after widespread use of PCV7 (serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) in 2000, there were decreases in frequencies of persistent AOM and AOM associated with early treatment failure, along with an increase in H influenzae AOM. After several years of PCV7 use, vaccine serotypes of S pneumoniae disappeared, but a surge in nonvaccine, multidrug-resistant serotypes, such as 19A, emerged. The widespread use of PCV13 (with added serotypes 1, 3, 5, 6A, 7F, and 19A) since 2010 has been associated with further decline in healthcare use for OM and further decline in AOM caused by serotypes in the PCV13, especially serotypes 19A and 6A.

Nontypeable H influenzae accounts for approximately 45% of AOM; the disease caused by this pathogen is not clinically distinguishable from that caused by S pneumoniae, although AOM caused by H influenzae is more often bilateral than unilateral and particularly associated with older age and recurrent disease. Approximately one-third of strains of H influenzae recovered from MEE produce β-lactamase.

M catarrhalis accounts for approximately 10% of the MEE isolates from children with AOM; it is more often found in polymicrobial AOM. The relative proportion of AOM due to M catarrhalis has been less affected by universal immunization of infants with PCVs. More than 90% of M catarrhalis strains produce β-lactamase.

Respiratory Viruses

Viral URTI is exceedingly common in infants and children and often leads to AOM. It has been suggested that certain viruses are more likely to cause AOM than others. It is likely, however, that any virus that causes URTI is able to induce AOM. A broad spectrum of respiratory viruses cause URTI; rhinoviruses and coronaviruses are the most common among them. Other common URTI viruses are adenoviruses, RSV, parainfluenza viruses, human metapneumovirus, influenza viruses, enteroviruses, and human bocavirus.

Viruses that infect the nasopharynx may enter the middle ear along with bacteria that colonize the nasopharynx. Presence of live virus in the MEE likely indicates AOM causation as it is evidence of viral replication in the middle ear. Ample evidence has shown that live viruses infect the middle ear. First, in experimental animals, virus alone without bacteria can cause AOM; furthermore, the virus interacts with bacteria to generate more severe inflammation. Second, live viruses have been detected in the MEE of children, and their presence interferes with bacteriologic responses to antibiotic. Third, viruses have been found to generate additional cytokines/inflammatory mediators in cases with combined bacterial and viral infection, compared to bacterial infection alone. The presence in MEE of viral nucleic acids alone as detected by PCR has created debate on whether finding nucleic acids suggests that the virus is the pathogen or just a bystander.

Bacterial-Viral Interactions

Due to the wide variety of respiratory viruses and bacterial otopathogens, analyses of viral-bacterial interactions are complex. Interactions between specific viruses and bacteria are the topics of numerous studies in animal models and in vitro. Overall, synergisms between bacteria and viruses are evident and the co-infections increase the degree of inflammation, compared to bacterial infection alone. In infants and children, viral-bacterial interactions during AOM enhance the degree of middle ear inflammation and interfere with the penetration of antibiotic into the middle ear. Recent studies have shown interesting bacterial-viral interactions during URTI. The presence of otopathogens such as S pneumoniae and M catarrhalis increases URTI risk. In addition, specific URI symptoms are associated with the presence of H influenzae or M catarrhalis colonization. These data together suggest that colonizing bacteria may enhance URTI symptoms during viral infection.

ACUTE OTITIS MEDIA

CLINICAL MANIFESTATIONS

Symptoms of AOM are generally nonspecific, including fever, irritability, restless sleep, decreased appetite, vomiting, and diarrhea. Fever occurs in one-third to two-thirds of children with AOM, but temperatures of 40°C or more are unusual unless accompanied by invasive bacterial disease or foci elsewhere. Because AOM most often occurs during URTI, there are also symptoms such as cough, sneezing, runny nose, stuffy nose, and red/watery eyes. Purulent conjunctivitis has been associated with AOM due to nontypeable H influenzae.

Ear pain may manifest as ear tugging in infants. In children 6 months to 3 years of age with URTI, ear tugging does not differentiate children with URTI and AOM from those with only URTI. Earache is not universal in AOM; about one-fifth of children older than age 2 do not complain of ear pain. The ear pain is due to pressure of the increasing suppuration in the middle ear and is relieved when the pressure leads to ischemia of the central vessels in the capillary bed of the TM. Persistent ischemia leads to necrosis of the TM with rupture and discharge of the contents of the middle ear abscess and virtual elimination of the otalgia. Parents often report that a child who had cried with pain was relieved and bloody pus was observed. However, the TM is so vascular that the site of perforation may not be evident even 24 hours later, and the resealed membrane may result in reaccumulation of the purulent MEE.

Hearing loss is a frequent sign in infants. It may be expressed by verbal children or detected by a parent who sees the child not responding to spoken voice.

DIAGNOSIS

Otologic examination should include evaluation of the position, color, and degree of translucency and mobility of the TM. The normal eardrum should be in the neutral position. Mild retraction of the TM usually indicates the presence of negative middle ear pressure, an effusion, or both. Severe retraction of the TM identifies high negative pressure associated with MEE. Fullness or bulging of the TM is caused by increased middle ear pressure or MEE.

The normal TM has a ground-glass appearance and is translucent. The otoscopist should be able to look through the TM and visualize the middle ear landmarks. A blue or yellow color identifies MEE seen through a translucent TM. A red TM may indicate inflammation but may also identify engorgement of the blood vessels of the TM caused by crying, sneezing, or nose-blowing. Adequate examination of the TM to confirm the MEE is sometimes difficult, particularly in infants and small children. Normal and abnormal findings on otoscopic examination are shown in Figure 238-1.

The diagnosis of AOM generally requires: (1) abrupt onset of symptoms; (2) presence of MEE (bulging of the TM, limited or absent mobility of the TM, or otorrhea); and (3) signs or symptoms of middle ear inflammation. As AOM develops, there is a spectrum of signs seen during the progression of TM inflammation and MEE accumulation.

The current Clinical Practice Guideline for the Diagnosis and Management of AOM was published in 2013 by the AAP. The AAP guideline requires bulging TM as evidence for middle ear inflammation. Three degrees of bulging are defined: mild, moderate, and severe. For mild bulging of the TM, intense erythema must also be present. The AAP guideline has tightened the AOM working definition, in order to differentiate AOM from OME, recognizing that the AOM definition likely results in high specificity but less sensitivity as it may exclude less severe presentations of AOM.

Pneumatic otoscopy is the most feasible and cost-effective method for diagnosis of AOM and OME. Mobility of the TM is identified by pressure applied to the rubber bulb attached to the pneumatic otoscope. The normal or air-filled middle ear is identified by a brisk movement inward with slight positive pressure and outward with slight negative pressure. MEE or high negative pressure within the middle ear dampens movement of the TM. Movement of the TM is best seen in the posterosuperior quadrant of the TM.

Tympanometry and acoustic reflectometry can supplement pneumatic otoscopy. Tympanometry involves varying the pressure in the external canal accompanied by a probe tone. A graphic presentation, the tympanogram, provides information on middle ear pressure and the presence of an air-filled or fluid-filled middle ear space. Because tympanometry and pneumatic otoscopy require a seal in the external canal for a few seconds, they may be difficult to perform in the young infant who is irritable due to ear pain. Acoustic reflectometry accompanied by spectral gradient analysis determines the probability of MEE by measuring the response of the eardrum to a frequency sweep in the audible range of 1.8 to 4.4 kHz and provides information on the probability of an air- or a fluid-filled middle ear space.

MEE can also be demonstrated by evidence of pus on the pillow or bedding of the child as a result of TM perforation, observation of fluid in the external canal, needle aspiration (tympanocentesis), or myringotomy (an incision in the TM that drains the MEE).

TREATMENT

Treatment of AOM includes 3 main approaches: pain management and initial observation alone, or when appropriate, antibiotic therapy.

Pain may be a major symptom of AOM due to pressure within the middle ear and can be substantial in the first few days of onset of illness. Antibiotic treatment does not relieve pain within the first 24 hours. Analgesics can relieve pain associated with AOM early in the course. Therefore, the child should be assessed for pain, and if pain is present, treatment for pain should be given. Oral analgesics such as acetaminophen or ibuprofen are the mainstay of AOM pain management; they are effective for mild to moderately severe pain. Narcotic analgesics with codeine or analogs may be prescribed for severe pain; risks and benefits of using these drugs, including potential toxic effects, need to be considered. Topical agents such as benzocaine or lidocaine may offer additional brief benefit over acetaminophen in children older than 5 years.

Numerous studies of AOM, including studies of children younger than age 2 diagnosed with stringent criteria, have shown that AOM may resolve (improvement of symptoms and TM appearance) without antibiotic treatment. While ET dysfunction leads to AOM development, return to normal ET function facilitates drainage of pus from the middle ear; this may take a few to several days.

The 2013 AAP guideline on AOM management suggests the use of 4 factors in deciding whether to choose initial observation or prescribing antibiotics: age, severity of symptoms, presence of otorrhea, and laterality of AOM. Table 238-2 summarizes the recommendations for initial management of uncomplicated AOM. All infants and children with severe AOM, as defined by a toxic-appearing child, persistent otalgia for more than 48 hours, or temperature ≥ 39°C (102.2°F), should receive antibiotic therapy. AOM with otorrhea, presumably with rupture of the TM, also should receive antibiotic therapy. For those with nonsevere symptoms, initial observation is an option for children younger than 2 years of age with unilateral AOM. Children at least 2 years old with unilateral or bilateral AOM may also be observed initially. Initial observation without antibiotic prescription must be a shared decision with the child’s family. If observation is offered, a mechanism must be in place to ensure follow-up and initiation of antibiotics if the child worsens or fails to improve within 72 hours of AOM onset.

The rationale for antibiotic therapy in children with AOM is based on the high rate of positive bacterial cultures of the MEE. However, it has been shown that 19% of children with S pneumoniae and 48% with H influenzae who were not treated with antibiotics had cleared the bacteria cultured from the first tympanocentesis by the time of repeat tympanocentesis 2 to 7 days later. It is estimated that 75% of children infected with M catarrhalis experience bacteriologic cure without antibiotic treatment. Therefore, recommended antibiotics for AOM mostly aim for elimination of S pneumoniae and nontypeable H influenzae. Further considerations for antibiotic selection include cost of the drug, taste, convenience, and adverse effects. Table 238-3 lists recommended antibiotics for (initial or delayed) treatment and for patients who have failed initial antibiotic treatment.

High-dose amoxicillin is recommended as the first-line treatment because of its effectiveness against S pneumoniae and H influenzae, as well as its safety, low cost, acceptable taste, and narrow microbiologic spectrum. In children who have taken amoxicillin in the previous 30 days, those with concurrent conjunctivitis, or those for whom coverage for β-lactamase–positive H influenzae and M catarrhalis is desired, therapy should be initiated with high-dose amoxicillin-clavulanate. Alternative initial antibiotics including cefuroxime and third-generation cephalosporins are less efficacious than the first-line drugs. For penicillin-allergic children, cefdinir, cefuroxime, cefpodoxime, or ceftriaxone may be used as they are unlikely to be associated with cross-reactivity with penicillin; the exceptions are children with severe and/or recent penicillin allergy.

Treatment with an effective antibiotic results in significant resolution of acute signs and symptoms within 48 to 72 hours. Persistent ear pain or systemic signs, including fever after 72 hours of antibiotic therapy, indicate a need for reevaluation for persistent AOM or foci elsewhere. If otologic findings support the diagnosis of persistent AOM, antibiotic treatment should be changed, depending on the initial drug (Table 238-3).

Surgical treatment, including tympanocentesis or myringotomy, results in immediate relief by draining the abscess and should be considered for the child who is toxic, who fails to improve on repeated antibiotic therapy, who has severe suppurative or nonsuppurative complications (eg, mastoiditis or facial nerve palsy), or who has an underlying immunodeficiency. The middle ear fluid should be cultured for bacteriologic diagnosis and susceptibility testing. Presence of multidrug-resistant bacteria in the MEE may necessitate the use of antibiotics that are not approved by the US Food and Drug Administration (FDA) for treatment of AOM, such as levofloxacin or linezolid. Levofloxacin is a quinolone antibiotic that is not approved by the FDA for use in children. Linezolid is a relatively recent and expensive antibiotic that is effective against resistant gram-positive bacteria. Consultation with a pediatric infectious disease expert may help with selection of unconventional drugs.

Duration of antibiotic treatment should be 10 days for children under age 2 years, while a 7-day course should be adequate for AOM in children age 2 to 5 years. For children age 6 years or older with nonsevere symptoms, a 5- to 7-day course is adequate.

Antihistamines have not been shown to be of any value in the management of AOM and may prolong the duration of MEE. Similarly, nasal and oral decongestants are ineffective for treatment of AOM. A 5-day course of systemic corticosteroid therapy, in addition to antibiotics, has not resulted in improvement in treatment failure rate or duration of MEE. Therefore, none of these adjunctive treatments is recommended.

Recurrent Otitis Media

Recurrent AOM is defined as the occurrence of ≥ 3 separate, well-documented AOM episodes in a 6-month period, or ≥ 4 episodes in a 12-month period with at least 1 episode in the preceding 6 months. Antibiotic prophylaxis has been used to prevent recurrent AOM. Studies have shown that an estimated 5 children would have to be given 1 year of antibiotic prophylaxis in order to prevent 1 AOM episode. The modest benefit afforded by a prolonged course of antibiotic prophylaxis does not have longer-lasting benefit after cessation of therapy. Because of the modest benefit and the potential adverse effects associated with prolonged antibiotic use and emergence of resistance, the AAP guideline does not recommend antibiotic prophylaxis.

The use of tympanostomy tubes is recommended for recurrent AOM. Tympanostomy tubes prevent approximately 1.5 episodes of AOM in the 6 months after surgery. The disadvantages of tube placement include the cost, surgical and anesthetic risk, and long-term sequelae such as tympanosclerosis and chronic perforation.

Acute Otitis Media Associated With Tympanostomy Tubes

In a child with tympanostomy tubes, AOM may still occur, presenting as ear discharge, usually without pain or fever. Although this may occur as a result of contaminated water (eg, bath water, pool water) penetrating the tympanostomy tube to enter the middle ear space, it is much more likely to occur as a result of a concurrent URTI. The most common bacterial causes of AOM in children with tympanostomy tubes are S pneumoniae, nontypeable H influenzae, M catarrhalis, Staphylococcus aureus, and Pseudomonas aeruginosa. Treatment with either broad-spectrum antibiotic eardrops that are nontoxic or systemic antibiotics for AOM is recommended. Recent studies have shown that antibiotic ear drops with corticosteroids are superior to systemic antibiotics. However, for antibiotic eardrops to be effective, they must penetrate the tympanostomy tube to reach the middle ear space. A proportion of children with recurrent ear discharge may have bacterial colonization of the tympanostomy tube itself, usually because of bacterial biofilm, which may be extremely resistant to bacterial eradication. In such circumstances, removal of the tympanostomy tube may be required.

OTITIS MEDIA WITH EFFUSION

OME is defined as the presence of fluid in the middle ear without signs and symptoms of acute ear infection. The major concern is resultant hearing loss. Persistent MEE results in decreased mobility of the TM and serves as a barrier to sound conduction. OME may be silent in its presenting symptomatology and may be an incidental finding. There may be subjective symptoms such as mild balance disturbance, especially in younger children, or a change in a child’s behavior. Diagnosis of OME is made by pneumatic otoscopy and/or tympanometry. Many OME episodes resolve spontaneously, but at least 25% of OME persist for ≥ 3 months, and 5% to 10% of episodes last ≥ 1 year. In addition, 30% to 40% of children have repeated OME. Children diagnosed with OME should be assessed for risk for speech, language, or learning problems from MEE because of baseline sensory, physical, cognitive, or behavioral factors.

The American Academy of Otolaryngology–Head and Neck Surgery published the Clinical Practice Guideline: Otitis Media with Effusion in 2016. The guideline recommends watchful waiting for 3 months from the date of effusion onset (if known) or 3 months from the date of diagnosis in the child with OME who is not at risk for developmental difficulties. They recommend against the use of intranasal or systemic steroids, systemic antibiotics, antihistamines, or decongestants. If OME persists for ≥ 3 months in a child or for any duration in an at-risk child, age-appropriate hearing testing should be performed. If bilateral hearing loss is documented, the family should be counseled about the potential impact on speech and language development. The child should be reevaluated for persistent OME at 3- to 6- month intervals until the MEE is no longer present, significant hearing loss is identified, or structural abnormalities of the TM are suspected.

Surgical management for OME primarily aims to restore hearing. Tympanostomy or ventilation tube placement is an option in children with documented hearing difficulties after 3 months. Adenoidectomy as a stand-alone operation or as an adjunct to tube insertion is most beneficial in children age ≥ 4 years. Therefore, surgical management for OME in children ≥ 4 years of age should include adenoidectomy and/or tympanostomy tubes, while tympanostomy tube placement alone is recommended for OME in children < 4 years old.

COMPLICATIONS AND OUTCOMES

Hearing Loss

Hearing loss is the most common complication of OM and can be conductive, sensorineural, or both. Some degree of conductive hearing loss is present whenever fluid fills the middle ear space. In AOM, the loss is usually between 15 and 40 dB; the average loss due to AOM or OME is 27 dB. Reversible or irreversible sensorineural hearing loss can occur during AOM or OME. Reversible sensorineural loss is due to increased tension and stiffness of the round window membrane. Permanent sensorineural hearing loss is most likely due to the spread of infection or products of inflammation through the round window membrane into the labyrinth, development of a perilymphatic fistula in the oval or round window, or suppurative complications such as labyrinthitis or meningitis. Hearing testing is recommended whenever language delay, learning problems, or a significant hearing loss is suspected. Negative pressure in the middle ear, in the absence of MEE, can also be a cause of hearing loss.

Effect of Otitis Media on Child Development

MEE and the resulting conductive hearing loss may lead to decreased perception of language, impaired development of speech and language, lower scores on tests of cognitive abilities, and poor performance in school. Many studies have been performed relating experience with AOM and OME to developmental outcomes, but the differences in design of the studies and inconsistencies of the results limit conclusions about the effect of OM on development. While some studies reported delay in speech and language development related to hearing loss from persistent MEE, others showed that early placement of ventilating tubes in children with prolonged time spent with MEE did not measurably improve developmental outcomes at age 3 years.

Suppurative Complications

CSOM occurs when episodes of recurrent AOM are untreated or inadequately treated; a perforation of the TM persists and there is chronic infection of the middle ear and mastoid. The hallmark of CSOM is a purulent, mucoid, or serous discharge through the persistent perforation. CSOM is a major health problem in many developing countries but is of particular concern in regions and populations with limited access to medical care, including the Inuit of Alaska, Canada, and Greenland; Australian Aborigines; and Native Americans.

Extension of infection from suppurative AOM into the mastoid air cells is frequent; the mastoid infection resolves with treatment of AOM but, in some cases, may progress to an acute periostitis or osteitis. Labyrinthitis may follow the spread of infection from the middle ear into the cochlear and vestibular organs, resulting in sensorineural hearing loss and/or vertigo.

Intracranial complications of OM include meningitis, epidural abscess, subdural empyema, brain abscess, dural sinus thrombosis, and otitic hydrocephalus. Suppurative meningitis and other intracranial complications usually follow bacteremia, but may also occur as a result of spread from the middle ear/mastoid infection through the dura. The pus can accumulate between the dura and the cranial bone (epidural abscess) or the potential space between the dura and the arachnoid (subdural empyema) or progress to the meninges to cause meningitis.

Nonsuppurative Complications

Nonsuppurative complications of AOM include facial paralysis, avascular necrosis of the long process of the incus with an associated conductive hearing loss, atelectasis of the middle ear (with or without a retraction pocket), adhesive OM, tympanosclerosis, and cholesteatoma.

Cholesteatoma consists of keratinized squamous epithelium and may accumulate within the middle ear and expand, resulting in necrosis of surrounding tissues. Cholesteatoma may be a sequela of recurrent OM and may develop from epithelium that has migrated through a perforation of the TM or from epithelium deposited from alternating infection and healing. Cholesteatoma may be due to chronic negative middle ear pressure that retracts a portion of the TM, inhibiting the natural epithelium migration of desquamated squamous debris. This can then become wet and infected, producing foul-smelling otorrhea and/or an expansile mass lesion that can cause local bony erosions. In a patient with a history of chronic otorrhea, pneumatic otoscopy may demonstrate retraction of the TM or granulation tissue or debris within a retraction pocket. However, the diagnosis of cholesteatoma is best made with otomicroscopy using an operating microscope. Computed tomography scanning of the temporal bone may provide further information on the size of the lesion. Aside from otorrhea, symptoms may include conductive hearing loss due to ossicular erosion, sensorineural hearing loss, or disequilibrium due to vestibular involvement. Treatment is surgical.

Although the facial nerve normally travels in a bony canal in its complicated course through the middle ear, up to 55% of individuals have small areas where the bony covering is incomplete, particularly in the area of the oval window. Inflammation may cause edema of the exposed facial nerve as it passes through the middle ear, compromising its venous return within the surrounding bony canal and resulting in peripheral facial nerve palsy. Although full recovery of facial nerve function can be expected in virtually all cases, it is usually recommended that the patient have insertion of a tympanostomy tube and be started on systemic antibiotic therapy. A tympanostomy tube not only serves to drain pus, but also allows for antibiotic and steroid eardrops to be placed directly into the middle ear space.

PREVENTION

Because of the multifactorial nature of OM, there are a variety of prevention strategies. These strategies mainly focus on reducing modifiable risk factors and vaccination against bacterial and viral infections. Chemoprophylaxis using antibiotics to prevent recurrent AOM is currently discouraged due to relative inefficacy, costs, and potential adverse effects. Surgical interventions for recurrent OM prevention are discussed in the earlier section on recurrent OM.

Reducing Environmental Risks

During the OM peak age incidence (6–18 months), avoidance of well-known environmental risks, such as exposure to tobacco smoke, daycare attendance, and use of pacifiers, has been associated with reduction of OM. The benefit of breastfeeding in preventing OM has long been known. Breastfeeding protects against OM until 2 years of age, and protection is greater for exclusive breastfeeding. Based on current data, the AAP Clinical Practice Guideline for the Diagnosis and Management of AOM recommends avoidance of tobacco smoke exposure, and exclusive breastfeeding for at least 6 months. The guideline also discusses other lifestyle changes such as avoiding supine bottle feeding (eg, bottle propping), reducing use of pacifiers, and altering childcare center attendance patterns.

Bacterial Vaccines

The goal of vaccines in this setting is to reduce or eliminate nasopharyngeal colonization of the 3 most common otopathogens: S pneumoniae, nontypeable H influenzae, and M catarrhalis. As noted, PCV7 was first available in 2000. Its use was associated with a 29% reduction in AOM caused by pneumococcal serotypes contained in the vaccines and a 6% to 7% reduction in overall AOM. However, there was subsequent replacement of vaccine serotypes of S pneumoniae in the nasopharynx and as AOM pathogens by nonvaccine serotypes and nontypeable H influenzae. PCV13, available since 2010, has been associated with further reduction of AOM, mastoiditis, and ventilating tube insertion. A 10-valent pneumococcal-nontypeable H influenzae protein D-conjugate vaccine (PHiD-CV) is available in Europe. While effective for pneumococcal OM, PHiD-CV may be less broadly protective for nontypeable H influenzae than originally reported in the earlier prototype vaccine study. Even with serotype replacement phenomenon after new PCVs, there are data suggesting that pneumococcal AOM may continue to decrease with PCV vaccination as the serotypes with greater capacity to cause AOM are replaced by less otopathogenic serotypes. More recent evidence suggests that preventing early OM episodes by PCVs may reduce progression to recurrent/chronic OM, although these conditions are not usually caused by S pneumoniae. However, PCVs do not prevent OM in previously unvaccinated children with a history of recurrent OM. There are no licensed vaccines against nontypeable H influenzae or M catarrhalis, but numerous vaccines are in various stages of development.

Viral Vaccines

AOM is usually preceded by symptomatic viral URTI; therefore, prevention of viral URTI will impact AOM incidence. To date, the only available vaccines against viral respiratory infection are for influenza. Both trivalent, inactivated influenza vaccines and live attenuated influenza vaccines have been shown repeatedly to reduce AOM during influenza seasons. The vaccines work through preventing influenza infection and influenza-associated AOM, which may occur in as many as two-thirds of young children with influenza. The efficacy and effectiveness in AOM prevention vary from year to year depending on the level of influenza activity in the community and how well matched the vaccine strains are with the circulating strains. The higher the level of influenza activity and the better matched the vaccines are, the higher the efficacy/effectiveness in prevention of influenza-associated AOM. Influenza vaccines are currently recommended for all children 6 months of age and older.

Future goals to prevent OM by preventing viral URTI will need to include vaccines against other viruses that are important in AOM development. Vaccines against viruses with high antigenic diversity such as rhinovirus and adenovirus will be difficult to develop. Efforts have been made in RSV vaccine development, mostly to prevent RSV lower respiratory tract infection. Numerous RSV vaccines are in phase I and II clinical trials, some of which are targeting pregnant women to induce maternal immunity for prevention of infection in young infants.

Nonvaccine Approaches to Prevent Viral URTI and AOM

The occurrence of AOM in the course of URTI peaks between days 2 and 5 after URTI onset. Therefore, early administration of antiviral drugs during URTI may prevent AOM development. Currently, antirespiratory viral drugs are available only for influenza. Studies have shown 43% to 85% reduction in AOM development in young children given oseltamivir within 12 to 48 hours of symptom onset. However, a recent meta-analysis of studies in adults and children concluded that neither oseltamivir nor zanamivir significantly reduced OM. Echinacea, a home remedy, immune modulator, and mild antiviral, has been shown to reduce risks of recurrent respiratory infections (including virologically confirmed cases) and OM. Xylitol, a 5-carbon naturally occurring sugar alcohol with antibacterial properties, has been shown to prevent recurrent AOM with some success. However, the successful dose regimens (eg, chewing gum or syrup given 5 times per day) are not practical, while more practical regimens (eg, 3 times per day) are not effective. Probiotics, mostly Lactobacillus and Bifidobacterium, have recently been used to reduce risks of respiratory symptoms and OM in infants and children; results have been encouraging. Further studies are required to identify the most promising probiotic strains and to elucidate the mechanisms by which these probiotics prevent infants and children from developing OM.

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