Fungi can be classified as yeasts, which are unicellular and reproduce by budding; as molds, which are multicellular and consist of tubular structures (hyphae) and grow by elongation and branching; or as dimorphic fungi, which can exist either as yeasts or molds depending on environmental conditions. Categorization according to anatomic and epidemiologic features is shown in Table 43–4. Fungal cells are taxonomically distinct from plant and animal cells. These differences, especially cell wall and cell membrane components, are utilized for diagnosis and are the basis of specific therapy.
Table 43–4.Pediatric fungal infections. ||Download (.pdf) Table 43–4. Pediatric fungal infections.
|Type ||Agents ||Incidence ||Diagnosis ||Diagnostic Tests ||Therapy ||Prognosis |
|Superficial || |
|Very common ||Simple ||KOH prep ||Topical/Oral ||Good |
|Subcutaneous ||Sporothrixa ||Uncommon ||Simpleb ||Culture ||Oral ||Good |
|Systemic: normal host (endemic) || |
|Common: regional ||Often presumptive ||Chest radiograph; serology, antigen detection; tissue biopsy, culture ||Nonec or systemic ||Good |
|Systemic: opportunistic infection || |
|Uncommon ||Difficulte ||Tissue biopsy, culture, antigen/fungal product/DNA detection and NMR for Candida ||Systemic, prolonged ||Poor if therapy is delayed and patient is severely immune compromised |
In the United States, systemic fungal disease in normal hosts is commonly caused by three endemic organisms—Coccidioides, Histoplasma, and Blastomyces—which are restricted to certain geographic areas. Prior residence in or travel to these areas, even for a brief time, is a prerequisite for inclusion in a differential diagnosis. Of these three, Histoplasma most often relapses years later in patients who are immunosuppressed.
Immunosuppression (especially depressed T-cell–mediated immunity), foreign bodies (eg, urinary and central catheters for Candida), ulceration of gastrointestinal and respiratory mucosa, severe burns, broad-spectrum antimicrobial therapy, malnutrition, HIV infection, and neutropenia or neutrophil defects are major risk factors for fungal infections (termed “opportunistic fungal infections”).
Laboratory diagnosis may be difficult because of the small number of fungi present in some lesions, slow growth of some organisms, and difficulty in distinguishing normal colonization of mucosal surfaces from infection. A tissue biopsy with fungal stains and culture is the best method for diagnosing some systemic fungal disease. Repeat blood cultures may be negative even in the presence of intravascular infections. Serologic tests are useful for diagnosing coccidioidomycosis and histoplasmosis, and antigen detection in urine and blood is useful for diagnosing blastomycosis, histoplasmosis, cryptococcosis, and aspergillosis.
The common superficial fungal infections of the hair and skin are discussed in Chapter 15.
LJ: Endemic mycoses: overlooked causes of community acquired pneumonia. Respir Med 2012;106(6):769
N: Diagnostic methods for fungal infections in pediatric patients: microbiological, serological, and molecular methods. Expert Rev Anti Infec Ther 2011;9(3):289
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Residence in, or travel to, an endemic area.
In immunocompetent patients, most often a self-limited flu-like illness; acute pneumonia occurs in a minority of cases.
Complications include progressive pneumonia and disseminated disease (CNS, skin, bone and joints, genitourinary tract).
Diagnosis by culture of specimens from bronchoscopy, skin, or other tissue, or antigen detection.
The causative fungus, Blastomyces dermatitidis, is found in soil primarily in the Mississippi and Ohio River valleys, additional southeastern and south central states, and the states bordering the Great Lakes. Transmission is by inhalation of spores. Subclinical disease is common. Infection rates are similar in both sexes in children, but severe disease is much more common in adults and males.
Primary infection is often unrecognized (> 50%). Clinical disease typically includes cough with purulent sputum, chest pain, headache, weight loss, night sweats, and fever. These occur several weeks to months after inoculation. Infection is most often self-limited in immunocompetent patients, but in some patients an indolent progressive pulmonary disease occurs after an incubation period of 20–100 (median 45) days. Cutaneous lesions (20% of patients) usually represent disseminated disease. Skin lesions are slowly progressive and become ulcers with a sharp, heaped-up border or develop a verrucous appearance. Bone disease resembles other forms of chronic osteomyelitis. Lytic skull lesions in children are typical, but long bones, vertebrae, and the pelvis may be involved. Extrapulmonary disease occurs in 25%–40% of patients with progressive disease. A total body radiographic examination is advisable when blastomycosis is diagnosed in the skin or other extrapulmonary site.
An initial suppurative response is followed by an increase in mononuclear cells and subsequent formation of noncaseating granulomas. Diagnosis requires isolation or visualization of the fungus. Pulmonary specimens (sputum, tracheal aspirates, or lung biopsy) may be positive using conventional or fungal cell wall stains. The budding yeasts have refractile thick walls and are very large and distinctive (figure-of-eight appearance). The fungus can be readily isolated in most laboratories, but a week is often required. Sputum specimens are positive in more than 80% of cases and in almost all bronchial washings, and skin lesions are positive in 80%–100%. Antibody tests are generally not helpful for diagnosis, but an ELISA antigen detection method, similar to that used for histoplasmosis, readily detects Blastomyces antigen in serum, urine, and lung lavage fluids. In this assay, there is cross-reactivity with histoplamosis. Methods based on detecting blastomyces DNA are now available.
Radiographic lobar consolidation and fibronodular interstitial and patchy alveolar infiltrates are typical in cases with progressive pneumonia; effusions, hilar nodes, and cavities are less common. The paucity of cavitation and absence of hilar adenopathy distinguishes acute blastomycosis from histoplasmosis and tuberculosis. Miliary patterns also occur with acute infection. Chronic disease can develop in the upper lobes, with cavities and fibronodular infiltrations similar to those seen in tuberculosis. However, unlike tuberculosis or histoplasmosis, these lesions rarely caseate or calcify.
Primary pulmonary infection resembles acute viral, bacterial, or mycoplasmal infections and is generally confused with atypical community-acquired pneumonia. Blastomycosis should be considered when a significant pulmonary infection in an endemic area fails to respond to antibiotic therapy. Subacute infection mimics tuberculosis, histoplasmosis, and coccidioidomycosis. Chronic pulmonary or disseminated disease must be differentiated from cancer, tuberculosis, or other fungal infections.
One view is that all children with proven blastomyces should receive antifungal therapy. Certainly any patient who is symptomatic at the time of diagnosis with moderately severe or life-threatening blastomycosis (especially if immunocompromised), or has CNS infection, therapy should be initiated with the lipid formulation of amphotericin B (3–5 mg/kg intravenously) for 1–2 weeks or until improved. This is followed by oral itraconazole (5–10 mg/kg/day; divided into two doses [maximum = 400 mg]) for 6 months. Mild to moderate blastomycosis is often treated with oral itraconazole alone for 6–12 months. Bone disease may require a full year of itraconazole therapy. Surgical debridement is required for devitalized bone, drainage of large abscesses, and pulmonary lesions not responding to medical therapy.
Treatment with at least 1 g of amphotericin results in 75%–90% clearance without relapse. Patients initially treated with itraconazole have a 95% cure rate.
J: Blastomycosis in children: analysis of clinical, epidemiologic, and genetic features. J Ped Infect Dis Soc 2017;6:49
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
In normal or immunosuppressed individuals: superficial infections (oral thrush or ulcerations, vulvovaginitis, erythematous intertriginous rash with satellite lesions); fungemia related to intravascular devices.
In immunosuppressed individuals: systemic infections (candidemia with renal, hepatic, splenic, pulmonary, or cerebral abscesses); chorioretinitis; cutaneous nodules.
In either patient population: budding yeast and pseudohyphae are seen in biopsy specimens, body fluids, or scrapings of lesions; positive culture, spectrophotometric and PCR methods for diagnosing candida in body fluids.
Disease due to Candida is caused by C albicans in > 50% of cases in children; severe systemic infection may also be caused by C tropicalis, C parapsilosis, C glabrata, C krusei, and a few other Candida species. Speciation is important because of differences in pathogenicity and response to antifungal therapy.
C albicans is ubiquitous, usually in small numbers, on skin, mucous membranes, or in the intestinal tract. Normal bacterial flora, intact epithelial barriers, neutrophils, and macrophages, in conjunction with antibody and complement and normal lymphocyte function, are factors in preventing invasion. Disseminated infection is almost always preceded by prolonged broad-spectrum antibiotic therapy, instrumentation (including intravascular catheters), and/or immunosuppression. Patients with diabetes mellitus are prone to superficial Candida infection; thrush and vaginitis are most common. Candida is the fourth most common blood isolate in hospitals in the United States and is a common cause of catheter-related urinary tract infection.
1. Oral candidiasis (Thrush)
Adherent creamy white plaques on the buccal, gingival, or lingual mucosa are seen. These may be painful. Lesions may be few and asymptomatic, or they may be extensive, extending into the esophagus. Thrush is very common in otherwise normal infants in the first weeks of life and may last weeks despite topical therapy. Spontaneous thrush in older children is unusual unless they have recently received antimicrobials. Corticosteroid inhalation for asthma predisposes patients to thrush. HIV infection or other immune deficiency should be considered if there is no other reason for oral thrush, especially when it is persistent or recurrent. Angular cheilitis is the name given to painful erythematous fissures caused by Candida at the corners of the mouth, occasionally in association with vitamin or iron deficiencies.
Vulvovaginitis occurs in sexually active girls, in diabetic patients, and in girls receiving antibiotics. Oral contraception and pregnancy are risk factors. Thick, odorless, cheesy discharge with intense pruritus is typical. The vagina and labia are usually erythematous and swollen. Outbreaks are more frequent before menses.
A. DERMATITIS—Diaper dermatitis is often due entirely or partly to Candida. Pronounced erythema with a sharply defined margin and satellite lesions is typical. Pustules, vesicles, papules, or scales may be seen. Weeping, eroded lesions with a scalloped border are common. Any moist area, such as axillae, under breasts, and inguinal or neck folds, may be involved.
B. SCATTERED RED PAPULES OR NODULES—Such findings in immunocompromised patients may represent cutaneous dissemination.
C. PARONYCHIA AND ONYCHOMYCOSIS—These conditions occur in immunocompetent children but are also associated with immunosuppression, hypoparathyroidism, or adrenal insufficiency (Candida endocrinopathy syndrome). The selective absence of specific innate and T-cell responses to Candida can lead to marked, chronic skin and nail infections called chronic mucocutaneous candidiasis.
D. CHRONIC DRAINING OTITIS MEDIA—This may occur in patients who have received multiple courses of antibiotics and are superinfected with Candida.
Esophageal involvement in immunocompromised patients is the most common enteric manifestation, resulting in substernal pain, dysphagia, and painful swallowing. Nausea and vomiting are common in young children. Most patients do not have thrush. Stomach or intestinal ulcers also occur.
Because the organism frequently colonizes the upper respiratory tract, it is commonly isolated from respiratory secretions. Thus, demonstration of tissue invasion is needed to diagnose Candida pneumonia or tracheitis. It is rare, seen mainly in immunosuppressed patients and patients intubated for long periods, usually while taking antibiotics. The infection may cause abscesses, nodular infiltrates, and effusion.
Candiduria may be the only manifestation of disseminated disease. Most often, candiduria is associated with instrumentation, an indwelling catheter, or anatomic abnormality of the urinary tract. Symptoms of cystitis may be present. Masses of Candida may obstruct ureters and cause obstructive nephropathy. Candida casts in the urine suggest renal tissue infection.
Meningitis, and osteomyelitis usually occur only in immunocompromised patients or neonates, generally in those with high-grade candidemia. Endocarditis may occur on an artificial or abnormal heart valve, especially when an intravascular line is present.
8. Disseminated candidiasis
Skin and mucosal colonization precedes but does not predict dissemination. Too often, dissemination is confused with bacterial sepsis. This occurs in neonates—especially premature infants—in an intensive care unit setting and is recognized when a sick infant fails to respond to antibiotics or when candidemia is documented. Invasive disease can occur in > 50% of very low-birth-weight infants. These infants often have unexplained feeding intolerance, cardiovascular instability, apnea, new or worsening respiratory failure, glucose intolerance, thrombocytopenia, or hyperbilirubinemia. A careful search in immunocompromised patients should be carried out for lesions suggestive of disseminated Candida (retinal cotton-wool spots or chorioretinitis; nodular dermal abscesses). If these findings are absent, diagnosis is often based presumptively on the presence of a compatible illness in an immunocompromised patient; a burn patient; or a patient with prolonged postsurgical or intensive care unit course who has no other cause for symptoms and who fails to respond to antimicrobials. Such patients usually have Candida colonization of mucosal surfaces. Treatment for presumptive infection is often undertaken because candidemia is not identified antemortem in some such patients.
Hepatosplenic and renal candidiasis occurs in immunosuppressed patients. The typical case is a severely neutropenic patient who develops chronic fever, variable abdominal pain, and abnormal liver function tests. No causative bacterial pathogen is isolated, and there is no response to antimicrobials. Ultrasound or CT scan of the liver, spleen, and kidney demonstrates multiple round lesions. Biopsy is needed to confirm the diagnosis.
Budding yeast cells are easily seen in scrapings or other samples. A wet mount preparation of vaginal secretions is 40%–50% sensitive; this is increased to 50%–70% with the addition of 10% potassium hydroxide to the sample. The use of a Gram-stained smear is 70%–100% sensitive. Stains for fungal cell walls will increase sensitivity. The presence of pseudohyphae suggests tissue invasion. Positive cultures from nonsterile sites may reflect colonization and need to be carefully evaluated, but Candida should never be considered a contaminant in cultures from normally sterile sites. Candida grows on routine media more slowly than many bacteria; growth is usually evident on agar after 2–3 days and in blood culture within 3, but cultures may remain negative (10%–40%) even with disseminated disease or endocarditis. The ability of yeast to form germ tubes when incubated in human serum gives a presumptive speciation for C albicans. However, newly available NMR (nuclear magnetic resonance) and PCR methods greatly shorten the delay in diagnosis and speciation. Candida in any number in appropriately collected urine suggests true infection.
Thrush may resemble milk or formula (which can be easily wiped away with a tongue blade or swab, revealing normal mucosa without underlying erythema or erosion), other types of ulcers (including herpes), or oral changes induced by chemotherapy. Skin lesions may resemble contact, allergic, chemical, or bacterial dermatitis; miliaria; folliculitis; or eczema. Vulvovaginitis needs to be distinguished from other causes of vaginal discharge and discomfort. Candidemia and systemic infection should be considered in any seriously ill patient with the risk factors previously mentioned.
Arthritis and meningitis occur more often in neonates than in older children, and abscesses can occur in any organ. The greater the length or extent of immunosuppression and the longer the delay before therapy, the more likely that complications will occur.
In infants, oral nystatin suspension (100,000 units four to six times a day in the buccal fold after feeding for 2–3 days after resolution) usually suffices. Nystatin must come in contact with the lesions because it is not absorbed systemically. Older children may use it as a mouthwash (200,000–500,000 units five times a day), although it is poorly tolerated because of its taste. Clotrimazole troches (10 mg) four times a day are an alternative in older children. Prolonged therapy with either agent or more frequent dosing may be needed. Painting the lesions with a cotton swab dipped in gentian violet (0.5%–1%) is visually dramatic and messy but may help refractory cases. Eradication of Candida from pacifiers, bottle nipples, toys, or the mother’s breasts (if the infant is breast-feeding and there is candidal infection of the nipples) may be helpful.
Oral azoles, such as fluconazole (6 mg/kg/day), are effective in older children with candidal infection refractory to nystatin. Discontinuation of antibiotics or corticosteroids is advised when possible. Esophageal candidiasis should be treated with systemic therapy as described later.
Cutaneous infection usually responds to a cream or lotion containing nystatin, amphotericin B, or an imidazole (miconazole, clotrimazole, naftidene, and others). Associated inflammation such as severe diaper dermatitis is helped by concurrent use of a topical low concentration corticosteroid cream, such as 1% hydrocortisone. It may help to keep the involved area dry; a heat lamp and nystatin powder may be used. Suppression of intestinal Candida with nystatin and eradicating thrush may speed recovery and prevent recurrence of diaper dermatitis.
Vulvovaginal candidiasis (see Chapter 44) is treated with clotrimazole, miconazole, triazoles, or nystatin (cheapest if generic is used) suppositories or creams, usually applied once nightly for 3–7 days. A high-dose topical clotrimazole formulation can be given for only a single night. Oral azole therapy is equally effective. A single 150-mg oral dose of fluconazole is effective for vaginitis in older girls. It is more expensive but very convenient. Candida balanitis in sexual partners should be treated, but no controlled study has shown that treating colonization of male sexual partners prevents recurrence in females. Frequent recurrent infections (often with C glabrata) may require elimination of risk factors, the use of oral therapy, or some prophylactic antifungal therapy, such as a single dose of fluconazole weekly for 6 months.
Candiduria in an immunocompetent host with a urinary catheter may respond to catheter removal. Candiduria is treated in all high-risk patients, usually with a 7- to 14-day course of fluconazole (3–6 mg/kg/day), which is concentrated in the urine. Amphotericin B is required for patients with fluconazole-resistant organisms. Renal abscesses or ureteral fungus balls require intravenous antifungal therapy. Removal of an indwelling catheter is imperative.
1. Disseminated Candida infection
Systemic infection is dangerous and resistant to therapy. Surgical drainage of abscesses and removal of all infected tissue (eg, a heart valve) are required for cure. An echinocandin is the preferred therapy. The initial dose and maintenance dosing varies with the drug chosen. Fluconazole may be substituted after 5–7 days if the response to therapy is satisfactory. Fluconazole as initial therapy is an alternative for selected patients who are not critically ill and who are likely to have a sensitive organism. Lipid formulations of amphotericin are alternatives when other drugs are not tolerated or when the isolate has an unfavorable resistance pattern. Hepatosplenic candidiasis should be treated until all lesions have disappeared or calcified.
Fluconazole and itraconazole (best absorbed from the liquid solution) and newer azole drugs, such as voriconazole and posaconazole, or echinocandins, are used interchangeably with or in conjunction with amphotericin. They are often preferred because they are less likely to be toxic than amphotericin. They are acceptable alternatives for serious C albicans infections in nonneutropenic patients and are often effective as first-line therapy in immunocompromised patients. The decision to use systemic azole therapy should include consideration of the local experience with azole-resistant Candida and if the patient had received prophylaxis or treatment with azoles. Fluconazole is well absorbed (oral and intravenous therapy are equivalent), reasonably nontoxic, and effective for a variety of Candida infections. Fluconazole dosage is 8–12 mg/kg/day in a single-daily dose for initial therapy of severely ill children. Selected patients with prolonged immunosuppression (eg, after hematopoietic stem cell transplantation) should receive prophylactic azole or echinocandin prophylaxis. Susceptibility testing for Candida species is available to guide this decision. Candida glabrata and C krusei are common isolates that may be resistant to fluconazole; these are often susceptible to the newer azoles and echinocandins. Candida lusitaniae is usually resistant to amphotericin.
Correction of predisposing factors is important (eg, discontinuing antibiotics and immunosuppressives, improving control of diabetes, and removing infected devices and lines).
Infected central venous lines should be removed immediately; this alone often is curative. If the infection is considered limited to the line and environs, a 14-day course (after the last positive culture) of a systemic antifungal agent following line removal is recommended for nonneutropenic patients. An echinocandin is preferred, with completion of therapy with fluconazole when sensitivity is established. This is because of the late occurrence of focal Candida infection, especially retinal infection in some cases. Persistent fever and candidemia suggest infected thrombus, endocarditis, or tissue infection. All such patients should be examined by an ophthalmologist.
3. Very low-birth-weight infants
In many nurseries rates of severe Candida infection can exceed 5%–10%. Infected infants should receive intravenous amphotericin B (1 mg/kg/day) or fluconazole (12 mg/kg IV or PO) if no prior fluconazole. Treatment should continue until 2 weeks after the last positive culture. Lumbar puncture and eye examination should be performed. Prophylaxis in this setting is fluconazole (3 mg/kg twice weekly) for 6 weeks or until IV therapy is not needed.
Superficial disease in normal hosts has a good prognosis; in abnormal hosts, it may be refractory to therapy. Early therapy of systemic disease is often curative if the underlying immune response is adequate. The outcome is poor when therapy is delayed or when host response is inadequate. Candidemia in the severely premature neonate increases the chance of death and poor neurodevelopmental outcome.
et al: Invasive candidiasis in low birth weight infants: risk factors, clinical course and outcome in a prospective multicenter study of cases and their matched controls. BMC Infect Dis 2014;14:327
M: The current treatment landscape: candidiasis. J Antimicrob Therap Chemother 2016;71(suppl 2):ii13
WT: Fungal prophylaxis in neonates: a review article. Adv Neonatal Care 2014;14(1):17
DR: Executive summary: clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis Feb 15, 2016;62(4):409–417
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Residence in, or travel to, an endemic area.
Primary pulmonary form: fever, chest pain, cough, anorexia, weight loss, and often a macular rash; erythema nodosum or erythema multiforme occurs during the acute phase.
Primary cutaneous form: skin trauma followed in 1–3 weeks by an ulcer and regional adenopathy.
Spherules (endospores in tissue) seen in pus, sputum, CSF, joint fluid; positive culture.
Appearance of precipitating (early) and complement-fixing antibodies (late).
Coccidioidomycosis is caused by the dimorphic fungus Coccidioides (immitis or posadasii), which are endemic in the Sonoran Desert areas of western Texas, southern New Mexico and Arizona, southern California, northern Mexico, and South America. Infection results from inhalation or inoculation of arthrospores (highly contagious and readily airborne in the dry climate). Even brief travel in or through an endemic area, especially during windy seasons, may result in infection. Human-to-human transmission does not occur. More than half of all infections are asymptomatic, and less than 5% are associated with significant pulmonary disease. Chronic pulmonary disease or dissemination occurs in less than 1% of cases.
The incubation period is 10–16 days (range, 7–28 days). Symptoms vary from those of a mild fever and arthralgia to severe influenza-like illness with high fever, nonproductive cough, pleuritic chest pains, arthralgias, headache, and night sweats. Upper respiratory tract signs are uncommon. Most infections are self-limited or minimal in severity. Signs vary from none to rash, rales, pleural rubs, and signs of pulmonary consolidation. Weight loss may occur.
Up to 10% of children develop erythema nodosum or erythema multiforme. These manifestations imply a favorable host response to the organism. Less specific maculopapular eruptions occur in a larger number of children. Skin lesions can occur following fungemia. Primary skin inoculation sites develop indurated ulcers with local adenopathy. Contiguous involvement of skin from deep infection in nodes or bone also occurs. The presence of chronic skin lesions should lead to a search for internal infection.
3. Chronic pulmonary disease
This is uncommon in children. Chronic disease is manifested by chronic cough (occasionally with hemoptysis), weight loss, and radiologic abnormalities.
This is less common in children than adults, and is more common in infants, neonates, pregnant women (especially during the third trimester), African-Americans, Filipinos, American Indians, and patients with HIV or other defective T-cell mediated immunity. More than one organ may be involved. The most common extra-pulmonary sites involved are bone or joint (usually a single bone or joint; subacute or chronic swelling, pain, redness), nodes, meninges (slowly progressive meningeal signs, ataxia, vomiting, headache, and cranial neuropathies), and kidneys (dysuria and urinary frequency). As with most fungal diseases, the evolution of the illness is usually slow.
Direct examination of respiratory secretions, pus, CSF, or tissue may reveal large spherules (30–60 μm) containing endospores germinating in tissue. The organism is detected by using periodic acid–Schiff reagent, methenamine silver, and calcofluor stains. Characteristic colonies grow within 2–5 days on routine fungal and many other media. CSF cultures are often falsely negative.
The sedimentation rate is usually elevated. Eosinophilia may occur, particularly prior to dissemination, and is more common in coccidioidomycosis than in many other conditions with similar symptoms. Meningitis causes a mononuclear pleocytosis (70% contain eosinophils) with elevated protein and mild hypoglycorrhachia.
Antibodies consist of precipitins (usually measurable by 2–3 weeks in 90% of cases and gone by 12 weeks) and complement-fixing antibodies (delayed for several weeks; appear as the precipitins are falling and should disappear by 8 months). Thus, serum precipitins usually indicate acute infection. The extent of the complement-fixing antibody response reflects the severity of infection. Persistent high levels suggest dissemination. ELISA assays, which detect IgM and IgG antibodies against coccidioidal antigens, become positive as early as 1–3 weeks (90% of positive tests) after onset of symptoms. The presence of antibody in CSF indicates CNS infection; CSF and serum antibody titers correlate with disease progression and response to therapy.
Galactomannan antigen from Coccidioides is detected in urine and serum of patients. This occurs more frequently in severe disease compared to moderate disease. Testing both urine and serum should provide a diagnosis in more than 75% of patients.
A skin test with coccidioides antigen can provide evidence of prior infection and conversion implies recent infection. A positive test is a good prognostic sign. Detection of coccidioidal antigen in CSF is useful to establish CNS infection.
Approximately half of symptomatic infections are associated with abnormal chest radiographs—usually infiltrates with hilar adenopathy. Pulmonary consolidation, effusion, and thin-walled cavities may be seen. About 5% of infected patients have asymptomatic nodules or cysts after recovery. Unlike tuberculosis reactivation, apical disease is not prominent. Bone infection causes osteolysis that enhances with technetium. Cerebral imaging may show hydrocephalus and meningitis; intracranial abscesses and calcifications are unusual. Radiographic evolution of all lesions is slow.
Primary pulmonary infection resembles acute viral, bacterial, or mycoplasmal infections; subacute presentation mimics tuberculosis, histoplasmosis, and blastomycosis. Chronic pulmonary or disseminated disease must be differentiated from cancer, tuberculosis, or other fungal infections.
Dissemination of primary pulmonary disease is associated with permissive ethnic background, prolonged fever (> 1 month), a negative skin test, high complement-fixation antibody titer, and marked hilar adenopathy. Local pulmonary complications include effusion, empyema, and pneumothorax. Cerebral infection can cause noncommunicating hydrocephalus due to basilar meningitis.
Mild pulmonary infections in most immune competent patients do not require therapy, although some experts argue for treatment of all infections. Untreated patients should be assessed for 1–2 years to document resolution and to identify any complications. Antifungal therapy is used for prolonged fever, weight loss (> 10%), prolonged duration of night sweats, severe pneumonitis (especially if persisting for 4–6 weeks), or any form of disseminated disease. Neonates, pregnant women, high-risk racial background, and patients with high antibody titers also receive treatment.
Lipid formulation of amphotericin B is used to treat extensive pulmonary or disseminated disease or disease in immunosuppressed patients (2–5 mg/kg/day). In general, the more rapidly progressive the infection, the more compelling the case for amphotericin B therapy. For less severe disease and for meningeal disease, fluconazole or itraconazole are preferred (duration of therapy is 3–6 months or is lifelong for meningeal disease). Measurement of serum levels is suggested to monitor therapy. Chronic fibrocavitary pneumonia is treated for at least 12 months. Itraconazole may be superior to fluconazole. Refractory infection often responds to voriconazle together with caspofungin, and refractory meningitis may require prolonged intrathecal or intraventricular amphotericin B therapy.
Most pulmonary infections require only symptomatic therapy, self-limited activity, and good nutrition. Patients are not contagious.
Excision of chronic pulmonary cavities or abscesses may be needed. Infected nodes, sinus tracts, and bone are other operable lesions. Azole therapy should be given prior to surgery to prevent dissemination and should be continued for 4 weeks arbitrarily or until other criteria for cure are met.
Most patients recover. Even with amphotericin B, however, disseminated disease may be fatal, especially in those racially predisposed to severe disease. A negative skin test or a rising complement-fixing antibody titer is an ominous sign. Individuals who later in life undergo immunosuppressive therapy or develop HIV may experience reactivation of dormant disease. Thus, some transplant, rheumatology, and oncology programs determine prior infection by serology and either provide prophylaxis or observe patients closely during periods of intense immune suppression.
L: Experience from a children’s hospital in an area of endemicity. J Ped Infect Dis Soc 2014;5:89
GR III: Coccidiodomycosis. Infect Dis Clin North Am 2016;30:229
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Acute pneumonitis in immunocompetent individuals.
Immunosuppressed patients especially vulnerable to CNS infection (headache, vomiting, cranial nerve palsies, meningeal signs; mononuclear cell pleocytosis).
Cryptococcal antigen detected in CSF; also in serum and urine in some patients.
Cryptococcus is readily isolated on routine media.
Cryptococcus neoformans is a ubiquitous soil yeast. It survives best in soil contaminated with bird excrement. However, most infections in humans are not associated with a history of significant contact with birds. Inhalation is the presumed route of inoculation. Infections in children are rare, even in heavily immunocompromised patients such as those with HIV infection. Immunocompetent individuals can also be infected, especially by Cryptococcus gattii, which is an emerging pathogen in Canada and the Pacific Northwest. Asymptomatic carriage does not occur.
Pulmonary infection precedes dissemination to other organs. It is frequently asymptomatic (many older children and adults have serologic evidence of prior infection) and often not clinically apparent. Pneumonia is the primary manifestation in one-third of patients; CNS disease is the primary manifestation in 50% of patients. Cryptococcal pneumonia may coexist with CNS involvement. Symptoms are nonspecific and subacute—cough, weight loss, and fatigue.
The most common clinical disease is meningitis, which follows hematogenous spread from a pulmonary focus. This is much more likely to occur in an immunosuppressed patient (especially HIV). Symptoms of headache, vomiting, and fever occur over days to months. Meningeal signs and papilledema are common. Cranial nerve dysfunction and seizures may occur.
Cutaneous disease is usually secondary to dissemination. Papules, pustules, and ulcerating nodules are typical. Bones (rarely joints) may be infected; osteolytic areas are seen, and the process may resemble osteosarcoma. Many other organs, especially the eyes, can be involved with dissemination.
The CSF usually has a lymphocytic pleocytosis; it may be completely normal in immunosuppressed patients with meningeal infection. Direct microscopy may reveal organisms in sputum, CSF, or other specimens. The capsular antigen can be detected by latex agglutination or ELISA, which are both sensitive (> 90%) and specific. False-negative CSF tests are rare. Serum, CSF, and urine should be tested when this infection is suspected. The serum may be negative if the only organ infected is the lung. The organism grows well after several days on many routine media; for optimal culture, collecting and concentrating a large volume of CSF (10 mL) is recommended because the number of organisms may be low. Cryptococcus is included in some multiplex PCR panels for meningitis.
Radiographic findings are usually lower lobe infiltrates or nodular densities; less often effusions; and rarely cavitation, hilar adenopathy, or calcification. Single or multiple focal mass lesions (cryptococcoma) may be detected in the CNS on CT or MRI scan.
Cryptococcal meningitis may mimic tuberculosis, viral meningoencephalitis, meningitis due to other fungi, or a space-occupying CNS lesion. Lung infection is difficult to differentiate from many causes of pneumonia.
Hydrocephalus may be caused by chronic basilar meningitis. Symptomatic and recalcitrant intracranial hypertension is common. Significant pulmonary or osseous disease may accompany the primary infection or dissemination.
Patients with symptomatic pulmonary disease should receive fluconazole for 3–6 months. All immunocompromised patients with cryptococcal pulmonary disease should have a lumbar puncture to rule out CNS infection; this should also be done for immunocompetent patients with cryptococcal antigen in the serum. Severely ill patients should receive amphotericin B deoxycholate (1.0 mg/kg/day). Meningitis is treated with amphotericin B (1 mg/kg/day) and flucytosine (100 mg/kg/day divided into four doses). This combination is synergistic and allows lower doses of amphotericin B to be used. Induction therapy is usually 2 weeks for CNS infections. Fluconazole can be substituted for flucytosine. After this, fluconazole alone (5 mg/kg BID) is maintained for 8 weeks and then continued at a reduced dose for an additional 6–12 months. Some evidence suggests that voriconazole or posaconazole may have greater anticryptococcal activity. Fluconazole remains the preferred maintenance therapy to prevent relapses in high-risk (eg, HIV) patients. CSF antigen levels should be checked after 2 weeks of therapy. Intracranial hypertension is treated by frequent spinal taps or a lumbar drain.
Treatment failure, including death, is common in immunosuppressed patients, especially those with AIDS. Lifelong maintenance therapy may be required in these patients. Poor prognostic signs are the presence of extrameningeal disease, fewer than 20 cells/μL of initial CSF, and initial CSF antigen titer greater than 1:32.
JF: Pulmonary cryptococcosis in the immunocompetent patient—many questions, some answers. Open Forum Infect Dis, 2016;3(3)
JR: Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of America. Clin Infect Dis, 2010;50(3):291–322
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Residence in or travel to an endemic area.
Pneumonia with flu-like illness.
If disseminated, hepatosplenomegaly, anemia, leukopenia.
Histoplasmal antigen in urine, blood, bronchoalveolar lavage fluid or CSF.
Detection by staining the organism in smears or tissue, or by culture.
The dimorphic fungus Histoplasma capsulatum is found in the central and eastern United States (Ohio, Mississippi, and Missouri River valleys), Mexico, and most of South America. Soil contamination is enhanced by the presence of bat or bird feces. Infection is acquired by inhaling spores that transform into the pathogenic yeast form seen in infected tissues, especially within macrophages. Infections in endemic areas are very common at all ages and are usually asymptomatic. Over two-thirds of children are infected in these areas. Reactivation is rare in children, but occurs after treatment with immune suppressive agents, such as biological response modifiers and chemotherapy, even years after primary infection. Reinfection also occurs. The extent of symptoms with primary infection or reinfection is influenced by the size of the infecting inoculum.
Human-to-human transmission does not occur. Infection implies environmental exposure in an endemic area—usually within prior weeks or months. Congenital infection does not occur.
1. Asymptomatic infection (90% of infections)
Asymptomatic histoplasmosis is usually diagnosed by the presence of scattered calcifications in lungs or spleen and a positive skin test or serology. The calcification may resemble that caused by tuberculosis, but may be more extensive than the usual Ghon complex.
Approximately 5% of patients have mild to moderate disease. The cause of this illness is usually not recognized as being histoplasma. Acute pulmonary disease may resemble influenza: fever, malaise, myalgia, arthralgia, and non-productive cough occur 1–3 weeks after a heavy exposure (may be longer with less intense exposure). The subacute form resembles infections such as tuberculosis with cough, weight loss, night sweats, and pleurisy. Chronic disease is unusual in children. Physical examination may be normal, or rales may be heard. A small number of patients may have immune-mediated signs such as arthritis, pericarditis, and erythema nodosum. The usual duration of the disease is less than 2 weeks, followed by complete resolution, but symptoms without antifungal therapy may last several months before resolving.
3. Disseminated infection (5% of infections)
Fungemia during primary infection probably occurs in the first 2 weeks of all infections, including those with minimal symptoms. Transient hepatosplenomegaly may occur, but resolution is the rule in immunocompetent individuals. Heavy exposure, severe underlying pulmonary disease, and immunocompromise are risk factors for progressive infection characterized by anemia, fever, weight loss, organomegaly, CNS or bone marrow involvement, and death. Dissemination may occur in otherwise immunocompetent children; usually they are younger than age 2 years.
Ocular involvement consists of multifocal choroiditis. This usually occurs in immunocompetent adults with other evidence of disseminated disease. Brain, pericardium, intestine, and skin (oral ulcers and nodules) are other sites that can be involved. Adrenal gland involvement is common with systemic disease.
Routine tests are normal or nonspecific in the benign forms. Pancytopenia is present in many patients with disseminated disease. The diagnosis can be made by demonstrating the organism by histology or culture. Tissue yeast forms are small and may be mistaken for artifact. They are usually found in macrophages, occasionally in peripheral blood leukocytes in severe disease, but infrequently in sputum, urine, or CSF. Cultures of infected fluids or tissues may yield the organism after 1–4 weeks of incubation on fungal media, but even cultures of bronchoalveolar lavage or transbronchial biopsy specimens in immunocompromised patients are often negative (15%). Thus, bone marrow and tissue specimens are needed. Detection of histoplasmal antigen in blood, urine, CSF, and bronchoalveolar lavage fluid is the most sensitive diagnostic test (90% positive in the urine with disseminated disease, 75% positive with acute pneumonia), but false-negative results may occur. Cross-reactions occur with other fungal infections. Both urine and serum should be tested for optimal results. The level of antigen correlates with the extent of the infection, and antigen levels can be used to follow the response to therapy and to indicate low-grade infection persisting after completion of therapy (eg, in a child with HIV infection).
Antibodies may be detected by immunodiffusion and complement fixation; the latter rises in the first 2–6 weeks of illness and falls thereafter unless dissemination occurs. Cross-reactions occur with some other endemic fungi. A single high titer or rising titer indicates a high likelihood of disease, but antigen detection has replaced serology as a rapid diagnostic test.
Scattered pulmonary calcifications in a well-child are typical of past infection. Bronchopneumonia (focal mid-lung infiltrates) occurs with acute disease, often with hilar and mediastinal adenopathy, occasionally with nodules, but seldom with effusion. Localized or patchy infiltrates occur in subacute disease. Apical cavitation occurs with chronic infection, often on the background of preexisting pulmonary infection.
Pulmonary disease resembles viral infection, other causes of community acquired pneumonia, tuberculosis, coccidioidomycosis, and blastomycosis. Systemic disease resembles disseminated fungal or mycobacterial infection, leukemia, histiocytosis, or cancer.
Most patients with acute pulmonary disease will benefit from oral itraconazole. Those with subacute disease are generally better when the diagnosis is established, but if still symptomatic should receive oral therapy. Treatment with lipid formulation of amphotericin B (2–5 mg/kg/day) is indicated for severe pulmonary disease (diffuse radiographic involvement); disseminated disease; or when endovascular, CNS, or chronic pulmonary disease is present; and for children younger than age 1 year. Disseminated disease in infants may respond to as few as 10 days of amphotericin B, although 4–6 weeks is usually recommended. Patients with severe disease (especially pulmonary) may benefit from a short course of corticosteroid therapy. Surgical excision of chronic pulmonary lesions is rarely required. Itraconazole (3–5 mg/kg/day for 6–12 weeks; achieve peak serum level of > 1.0 mcg/mL) appears to be equivalent to amphotericin B therapy for mild disease and can be substituted in severe disease after a favorable initial (2 weeks) response to amphotericin B. Chronic pulmonary, CNS, or disseminated disease, should be treated for at least a year after switching to with oral drug.
Quantitation of fungal antigen is useful for directing therapy, and should be monitored for 1 year after successful treatment of severe disease. Relapse may occur in up to 15% of patients with treated chronic disease. Histoplasmosis can reactivate in previously infected individuals who subsequently become immunosuppressed. Chronically immunosuppressed patients may require lifelong maintenance therapy with itraconazole.
Patients with mild and moderately severe infections have a good prognosis. With early diagnosis and treatment, infants with disseminated disease usually recover; the prognosis worsens if the immune response is poor.
CA: Histoplasmosis: up-to-date evidence-based approach to diagnosis and management. Semin Respir Crit Care Med, 2015;36(5):729–745
SM: Improved diagnosis of acute pulmonary histoplasmosis by combining antigen and antibody detection. Clin Infect Dis, 2016;62(7):896–902
LJ: Histoplasmosis. Infect Dis Clin North Am, 2016;30(1):207–227
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Subacute cutaneous ulcers.
New lesions appearing proximal to existing lesions along a draining lymphatic.
Absence of systemic symptoms.
Isolation of Sporothrix schenckii from wound drainage or biopsy.
Sporotrichosis is caused by S schenckii, a dimorphic fungus present as a mold in soil, plants, and plant products from most areas of North and South America. Spores of the fungus can cause infection when they breach the skin at areas of minor trauma. Sporotrichosis has been transmitted from cutaneous lesions of pets.
Cutaneous disease is by far the most common manifestation. Typically at the site of inapparent skin injury, an initial painless papular lesion will slowly become nodular and ulcerate. Subsequent new lesions develop in a similar fashion proximally along lymphatics draining the primary lesion. This sequence of developing painless, chronic ulcers in a linear pattern is strongly suggestive of the diagnosis. Solitary lesions may exist and some lesions may develop a verrucous character. Systemic symptoms are absent and laboratory evaluations are normal, except for acute-phase reactants. The fungus rarely disseminates in immunocompetent hosts. Cavitary pneumonia is an uncommon manifestation when patients inhale the spores. Immunocompromised patients, especially those with HIV infection, may develop disseminated skin lesions and multiorgan disease with extensive pneumonia.
The differential diagnosis of nodular lymphangitis (sporotrichoid infection) includes other endemic fungi and some bacteria, especially atypical mycobacteria and nocardiosis, pyoderma gangrenosum, and syphilis. Diagnosis is made by culture. Biopsy of skin lesions will demonstrate a suppurative response with granulomas and provides the best source for laboratory isolation. Occasionally, the characteristic yeast will be seen in the biopsy.
Treatment is with itraconazole (200 mg/day or 5 mg/kg/day divided BID) for 2–4 weeks after lesions heal, usually 3–6 months. Prognosis is excellent with lymphocutaneous disease in immunocompetent children. Pulmonary or osteoarticular disease, especially in immunocompromised individuals, requires longer therapy. Amphotericin B may be required for disseminated disease, CNS disease, and severe pulmonary disease. Surgical debridement may be required.
VK: Sporotrichosis: an overview and therapeutic options. Dermatol Res Pract 2014
C: Sporotrichosis. Clin Dermatol 2012;30(4):437
PNEUMOCYSTIS & OTHER OPPORTUNISTIC FUNGAL INFECTIONS
The title of this section indicates that fungi that are normally not pathogenic, or do not cause severe disease, may do so when given the opportunity by changes in host defenses. They occur most commonly when patients are treated with corticosteroids, antineoplastic drugs, biological modifiers, or radiation, thereby reducing the number or function of neutrophils and B and T cells. Inborn errors in immune function (such as combined immunodeficiency or chronic granulomatous disease) may also be complicated by these fungal infections. Opportunistic infections are facilitated by altering the normal flora with antibiotics and by disruption of mucous membranes or skin with antineoplastic therapy or indwelling lines and tubes.
Table 43–5 indicates that filamentous fungi are prominent causes of severe systemic fungal disease in immunocompromised patients. Aspergillus species (usually fumigatus) and Zygomycetes (usually Mucorales) cause subacute pneumonia and sinusitis and should be considered when these conditions do not respond to antibiotics in immunocompromised patients. Aspergillus species also commonly cause invasive disease in patients with chronic granulomatous disease. Mucormycosis is especially likely to produce severe sinusitis in diabetics with acidosis when the diabetes is poorly controlled. This fungus may invade the orbit and cause brain infection. Mucormycosis also occurs in patients receiving iron chelation therapy. These fungal infections may disseminate widely. Imaging procedures may suggest the etiology, but they are best diagnosed by aspiration or biopsy of infected tissues. A characteristic CT finding is the “halo sign,” which is a ground-glass opacity surrounding a pulmonary nodule or mass. The “reversed halo sign” is a focal rounded ground-glass opacity surrounded by a crescent or complete ring of consolidation. Detection of galactomannose and β-D-glucan in blood and alveolar fluid is useful for the diagnosis of presumptive of aspergillosis and other opportunistic fungal pathogens.
Table 43–5.Unusual fungal infections in children. ||Download (.pdf) Table 43–5. Unusual fungal infections in children.
|Organism ||Predisposing Factors ||Route of Infection ||Clinical Disease ||Diagnostic Tests ||Therapy and Comments |
|Aspergillus species ||None ||Inhalation of spores ||Allergic bronchopulmonary aspergillosis; wheezing, cough, migratory infiltrates, eosinophilia. ||Organisms in sputum; positive skin test; specific IgE antibody; elevated IgE levels. ||Hypersensitivity to fungal antigens. Use steroids. Antifungals may not be needed. |
| ||Immunosuppression ||Inhalation of spores || |
Progressive pulmonary disease: consolidation, nodules, abscesses.
Disseminated disease: usually lung, brain; occasionally intestine, kidney, heart, bone. Invades blood vessels.
Demonstrate fungus in tissues by stain or culture; septate hyphae branching at 45-degree angle; detecting antigen/fungal components in blood or respiratory samples may be useful; PCR available at some sites.
|Amphotericin B, voriconazole, and oral caspofungin are equally effective; these can be used in combination. |
|Malassezia furfur, M pachydermatis ||Central venous catheter, usually lipid infusion (can occur in the absence of lipid) ||Line infection from skin colonization ||Sepsis; pneumonitis, thrombocytopenia. ||Culture of catheter or blood on lipid-enriched media (for M furfur; M pachydermatis does not need lipid). Fungus may be seen in buffy coat. ||Discontinuation of lipid may be sufficient. Remove catheter. Short-term amphotericin B may be added. Organism ubiquitous on normal skin; requires long-chain fatty acids for growth. |
|Mucorales (Mucor, Rhizopus, Absidia) ||Immunosuppression, diabetic acidosis, iron overload ||Inhalation, mucosal colonization || |
Rhinocerebral: sinus, nose, necrotizing vasculitis; central nervous system spread.
Disseminated: any organ.
Demonstrate broad aseptate hyphae branching at 90-degree angles in tissues by stain
Culture: rapidly growing, fluffy fungus. Detecting antigen/fungal components in blood or respiratory samples may be useful.
|Amphotericin B, surgical debridement; voriconazole and posaconazole also often effective or can be used as a second agent for combined therapy. Poor prognosis. |
|Scedosporium spp ||Immunosuppression ||Inhalation ||Disseminated abscesses (lung, brain, liver, spleen, other). ||Culture of pus or tissue. ||Surgical drainage; voriconazole or caspofungin. |
| ||Minor trauma ||Cutaneous ||Mycetoma (most common). ||Yellow-white granules in pus. Culture. ||Aggressive surgery. |
|Candida and cruptococcus ||See earlier in chapter || || || || |
Although Cryptococcus can cause disease in the immune competent hosts, it is more likely to be clinically apparent or more severe in immunocompromised patients. This yeast causes pneumonia and is a prominent cause of fungal meningitis (see earlier section in this chapter). Candida species in these patients cause fungemia and multiorgan disease, with lungs, esophagus, liver, and spleen frequently affected (see the earlier section on Disseminated Candida Infection).
Opportunistic fungal infections should always be included in the differential diagnosis of unexplained fever or pulmonary infiltrates in immunocompromised patients. These pathogens should be aggressively pursued with imaging studies and with tissue sampling when clues are available. Cryptococcus and Aspergillus may be demonstrated with specific antigen tests. Aspergillus and mucorales can be suspected by detecting fungal cell wall components or by PCR. Interpretation of these results may be difficult, with greater uncertainty in pediatric patients. Opportunistic infections are difficult to treat because of the deficiencies in host immune response. Treatment should be undertaken with consultants who are expert in managing these infections. Voriconazole is the drug of choice for many mold infections, but both echinocandins and amphotericin B formulations are good alternatives. Serum levels of voriconazole should be determined to guide therapy. Combinations of current antifungal drugs are being tested to improve the outcome. Many children who will have depressed phagocytic and T-cell–mediated immune function for long periods (eg, after hematopoietic stem cell transplants) should receive antifungal prophylaxis during the period of severe immune suppression, most often with fluconazole or itraconazole. Very low-birth-weight infants, who are at high risk for systemic Candida infection, often receive similar prophylaxis for prolonged periods.
Malassezia furfur is a yeast that normally causes the superficial skin infection known as tinea versicolor (see Chapter 15). This organism is considered an opportunist when fungemia is associated with prolonged intravenous therapy, especially with central lines used for hyperalimentation. The yeast, which requires skin lipids for its growth, can infect lines when lipids are present in the infusate. Some species will grow in the absence of lipids. Unexplained fever and thrombocytopenia are common. Pulmonary infiltrates may be present. The diagnosis is facilitated by alerting the bacteriology laboratory to add olive oil to culture media. The infection will respond to removal of the line or the lipid supplement. Amphotericin B may hasten resolution.
M: Galactomannan and polymerase chain reaction-based screening for invasive aspergillosis among high-risk hematology patients: a diagnostic meta-analysis. Clin infect Dis 2015;61(8):1263–1272
T: Galactomannan, β-D-Glucan, and polymerase chain reaction-based assays for the diagnosis of invasive fungal disease in pediatric cancer and hematopoietic stem cell transplantation: a systematic review and meta-analysis. Clin Infect Dis 2016;63(10):1340–1348
TF: Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis 2016;63:e1–e60
TT: Breaking the mold: a review of mucormycosis and current pharmacological treatment options. Ann Pharmacother 2016;50(9):747–757
RL: A prospective, international cohort study of invasive mold infections in children. J Pediatric Infect Dis Soc 2015;4(4):313–322
PNEUMOCYSTIS JIROVECI INFECTION
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Fever, tachypnea, cough, dyspnea.
Hypoxemia; diffuse interstitial infiltrates.
Detection of the organism in specimens of pulmonary origin.
Although classified as a fungus on the basis of structural and nucleic acid characteristics, Pneumocystis responds readily to antiprotozoal drugs and antifols. It is a ubiquitous pathogen. Initial infection is presumed to occur asymptomatically via inhalation, usually in early childhood, and to become a clinical problem upon reactivation associated with immune suppression. Person-to-person transmission may contribute to symptomatic disease in immune compromised individuals. In the normal host clinical disease rarely occurs. A syndrome of afebrile pneumonia similar to that caused by Chlamydia trachomatis in normal infants has been described, but its etiology is rarely appreciated. Whether by reactivation or new exposure, severe signs and symptoms occur chiefly in patients with abnormal T-cell function, such as hematologic malignancies and organ transplantation. Pneumocystis also causes severe pneumonia in patients with γ-globulin deficiency and is an AIDS-defining illness for children with advanced HIV infection. Prophylaxis usually prevents this infection (see Chapter 41).
Prolonged, high-dose corticosteroid therapy for any condition is a risk factor; illness beginning as steroids are tapered is a typical presentation. Severely malnourished infants with no underlying illness may also develop this infection, as can those with congenital immunodeficiency. The incubation period is usually at least 1 month after onset of immunosuppressive therapy.
In most patients, a gradual onset of fever, tachypnea, dyspnea, and mild, nonproductive cough occurs over 1–4 weeks. Initially the chest is clear, although retractions and nasal flaring are present. At this stage the illness is nonspecific. Hypoxemia out of proportion to the clinical and radiographic signs is an early finding; however, even minimally decreased arterial oxygen pressure values should suggest this diagnosis in immunosuppressed children. Tachypnea, nonproductive cough, and dyspnea progress. Respiratory failure and death occur without treatment. In some children with AIDS or severe immunosuppression from chemotherapy or organ transplantation, the onset may be abrupt and progression more rapid. Acute dyspnea with pleuritic pain may indicate the complication of pneumothorax.
The general examination is unremarkable except for tachypnea and tachycardia; rales may be absent. There are no upper respiratory signs, conjunctivitis, organomegaly, enanthem, or rash.
Laboratory findings reflect the individual child’s underlying illness and are not specific. Serum lactate dehydrogenase levels may be elevated markedly as a result of pulmonary damage. In moderately severe cases, the arterial oxygen pressure is less than 70 mm Hg or the alveolar-arterial gradient is less than 35 mm Hg.
Early chest radiographs are normal. The classic pattern in later films is bilateral, interstitial, lower lobe alveolar disease starting in the perihilar regions, without effusion, consolidation, or hilar adenopathy. High-resolution CT scanning may reveal extensive ground-glass attenuation or cystic lesions. Older HIV-infected patients present with other patterns, including nodular infiltrates, lobar pneumonia, cavities, and upper lobe infiltrates.
Diagnosis requires finding characteristic round (6–8 mm) cysts in a lung biopsy specimen, bronchial brushings, alveolar washings, induced sputum, or tracheal aspirates. Tracheal aspirates are less sensitive, but are more rapidly and easily obtained. They are more often negative in children with leukemia compared with those with HIV infection; presumably, greater immunosuppression permits replication of a larger numbers of organisms. Because pneumonia in immunosuppressed patients may have many causes, negative results from tracheal secretions in suspected cases should prompt more aggressive diagnostic attempts. Bronchial washing using fiberoptic bronchoscopy is usually well tolerated and rapidly performed.
Several rapid stains—as well as the standard methenamine silver stain—are useful. The indirect fluorescent antibody method is most sensitive. These methods require competent laboratory evaluation, because few organisms may be present and many artifacts may be found. PCR methods are an important alternative.
In immunocompetent infants, C trachomatis pneumonia is the most common cause of the afebrile pneumonia syndrome described for Pneumocystis. In older immunocompromised children, the differential diagnosis includes influenza, respiratory syncytial virus, cytomegalovirus, adenovirus, and other viral infections; bacterial and fungal pneumonia; pulmonary emboli or hemorrhage; congestive heart failure; and Chlamydia pneumoniae and M pneumoniae infections. Lymphoid interstitial pneumonitis, which occurs in older infants with untreated HIV infection, is more indolent and the patient’s lactate dehydrogenase level is normal (see Chapter 41). Pneumocystis pneumonia is rare in children who are complying with prophylactic regimens.
Children at high risk for developing Pneumocystis infection should receive prophylactic therapy. Children at risk include those with hematologic malignancies, children who for other reasons are receiving intensive chemotherapy or high-dose corticosteroids, and children with organ transplants or advanced HIV infection. All children born to HIV-infected mothers should receive prophylaxis against Pneumocystis starting at age 6 weeks unless HIV infection has been ruled out by tests for HIV in serum. HIV-infected infants often receive therapy for the first year of life, or until the patient’s immunologic status is defined sufficiently to determine the need for additional prophylaxis (see Chapter 41). The prophylaxis of choice is trimethoprim-sulfamethoxazole (150 mg/m2/day of trimethoprim and 750 mg/m2/day of sulfamethoxazole) for 3 consecutive days of each week. Alternatives to this prophylaxis regimen include atovaquone, dapsone, or aerosolized pentamidine (https://aidsinfo.nih.gov/guidelines/html/5/pediatric-oi-prevention-and-treatment-guidelines/415/pneumocystis-jirovecii-pneumonia).
Supplemental oxygen and nutritional support may be needed. The patient should be in respiratory isolation.
Trimethoprim-sulfamethoxazole (20 mg/kg/day of trimethoprim and 100 mg/kg/day of sulfamethoxazole in four divided doses intravenously or orally if well tolerated) is the treatment of choice. Improvement may not be seen for 3–5 days. Duration of treatment is 3 weeks in HIV-infected children. Methylprednisolone (2–4 mg/kg/day in four divided doses intravenously) should also be given to patients with moderate to severe infection (partial oxygen pressure < 70 mm Hg or alveolar-arterial gradient > 35) for the first 5 days of treatment. The dosage is reduced by 50% for the next 5 days and further by 50% until antibiotic treatment is completed. If trimethoprim-sulfamethoxazole is not tolerated or there is no clinical response in 5 days, pentamidine isethionate (4 mg/kg once daily by slow intravenous infusion) should be given. Clinical efficacy is similar with pentamidine, but adverse reactions are more common. These reactions include dysglycemia, pancreatitis, nephrotoxicity, and leukopenia. Other effective alternatives utilized in adults include atovaquone, trimethoprim plus dapsone, and primaquine plus clindamycin.
The mortality rate is high in immunosuppressed patients who receive treatment late in the illness.
et al: Pneumocystis jirovecii
pneumonia in the non-HIV-infected population. Ann Pharmacother 2016;50:673
L: Clinical course, radiological manifestations, and outcome of pneumocystis jirovecii
pneumonia in HIV patients and renal transplant recipients. PLoS One Nov 8, 2016;11(11):e0164320
M: High diagnostic value of a new real-time pneumocystis PCR from bronchoalveolar lavage in a real-life clinical setting. Respiration 2016;92(3):144–149