Epidemiology

Histoplasmosis is caused by the organism Histoplasma capsulatum. It is typically found in soil throughout the world and is endemic in the central United States (Ohio and Mississippi River valleys) ( Fig. 31.1 ). This organism thrives in areas with a high concentration of bird or bat excrement in the soil. As a mold, H. capsulatum forms microconidia that can be aerosolized and inhaled by humans. The infection risk is highest when people are exposed to disturbed soil in endemic areas (e.g., construction, farming). Caves and abandoned buildings can also put people at risk of inhalation. Person-to-person transmission is not thought to occur. Skin test reactivity is common in hyperendemic areas, with as many of 80% of the population having a positive skin test by 18 years of age.

Areas endemic for histoplasmosis (CDC reference map).

Etiology

H. capsulatum is a thermally dimorphic fungus that exists as a mold in the environment and as a yeast at human body temperature. At 25°C–30°C, the mold grows as a fluffy colony with spore-bearing aerial mycelia containing small oval microconidia and larger macroconidia. These infectious particles become airborne when soil is disrupted. At 37°C, the spores develop into a budding yeast form over a period of 7 days.

Pathology/Pathogenesis

After inhalation, the microconidia germinate within the alveoli and distal bronchioles and transition to a yeastlike form. The yeast phase can enter and proliferate within macrophages. Similar to tuberculosis, there is early transport to regional lymph nodes with formation of a primary complex. The normal host develops specific T-lymphocyte immunity with proinflammatory cytokine stimulation of the macrophages to kill the fungus. This results in an acute inflammatory reaction in the lungs. The histopathologic features of this process include granulomas and caseous necrosis. As these lesions heal, fibrosis and calcification can develop. Although uncommon in children, an exuberant fibrous response can cause destruction and obstruction of the lung parenchyma and other mediastinal structures.

Symptoms and Physical Findings

The majority of people exposed to H. capsulatum do not develop symptoms. Symptomatic infection occurs in fewer than 5% of infected individuals. The risk of developing disease after exposure depends on inoculum size, degree of immunosuppression, strain-specific virulence factors, and preexisting immunity. The incubation period for the disease is typically 1–3 weeks after exposure. The clinical manifestations of histoplasmosis are classified according to physical location (pulmonary or disseminated), course of disease (acute, subacute or chronic), and whether the disease is a primary infection or due to reactivation of previous infection.

Imaging, Pulmonary Function Testing, Laboratory Findings

Patients with no known history of histoplasmosis can have incidental findings on their chest radiographs showing single or multiple calcified nodules in the lungs as well as mediastinal and hilar lymphadenopathy. Imaging of the chest of those with acute infection is variable and ranges from normal, to focal pneumonitis with mediastinal adenopathy, to extensive interstitial or reticulonodular infiltrates ( Fig. 31.2A ). Chest computed tomography (CT) can be used to better define pericardial involvement, along with bronchial or vascular compression (see Fig. 31.2B ). Calcification of the liver or spleen can also be seen. Chronic pulmonary histoplasmosis with cavitary lesions is rarely seen in children and is more commonly seen in adults with preexisting obstructive pulmonary disease.

(A) Chest x-ray in acute histoplasmosis showing a diffuse interstitial process. (B) Cross-sectional computed tomography with narrowing of the right main stem bronchus attributable to hilar adenopathy in histoplasmosis.

Diagnosis

The diagnosis of histoplasmosis can be challenging. Techniques used in this regard include histopathology, fungal culture, antigen detection, and serologic testing for Histoplasma -specific antibodies. Historically, an intradermal skin test was used, but this has fallen out of favor owing to a high rate of false-positive results in adults from endemic areas.

H. capsulatum can be cultured from sputum, tissue specimens, and bone marrow on standard fungal culture media. Unfortunately the sensitivity is low in acute disease. Growth is seen in 1–6 weeks. Histopathologic examination of biopsy specimens can allow for a rapid diagnosis. Specimens from lung, bronchoalveolar lavage (BAL) fluid, lymph nodes or bone marrow can show intracellular yeast forms using Gomori methenamine silver stains ( Fig. 31.3E and F ).

Panels showing the typical morphology of invasive aspergillosis (A and B), blastomycosis (C and D), and histoplasmosis (E and F). (A, C, and E) Hematoxylin and eosin. (B, D, and F) Gomori’s methenamine silver stain.

Detection of H. capsulatum antigen from serum, urine, or BAL fluid can be done with a commercially available enzyme immunoassay (EIA). This test is most sensitive for severe pulmonary infections or progressive disseminated disease in adults but has a low sensitivity in primary disseminated disease in childhood or in the setting of immunosuppression. When positive, the antigen test can also be helpful in monitoring response to treatment and determining length of treatment. False-positive results are occasionally seen with other endemic fungal infections.

The serologic diagnosis of histoplasmosis also has limitations. Acute pulmonary disease may be missed with this test, as serology does not become positive until 2–6 weeks after infection. Two different types of assays are available: an immunodiffusion test using antibodies to the M and H antigens of H. capsulatum and a complement fixation test that uses antigens from the yeast and mycelial forms. The complement fixation test is slightly more sensitive, while the immunodiffusion test has been found to be more specific. Complement fixation titers equal to or greater than 1 : 32 are highly suggestive of acute or recent infection. In the immunodiffusion test, results are reported as M or H bands. The H band is detectable in less than 20% of cases and is typically found to be positive in cases of disseminated infection or severe acute pulmonary histoplasmosis. Serologic tests are often negative in immunocompromised patients.

Differential Diagnosis

Pulmonary histoplasmosis with mediastinal lymph node involvement can mimic tuberculosis or lymphoma. Disseminated histoplasmosis of infancy can mimic leukemia or sepsis.

Management and Treatment

Histoplasmosis in the normal host is usually a self-limited disease, and antifungal therapy is not required for mild to moderate disease in the immunocompetent host. Children who have persistent symptoms lasting longer than 4 weeks should receive a 6- to 12-week course of oral itraconazole. For severe or disseminated disease, the lipid formulation of amphotericin B is recommended for 1–2 weeks, followed by oral itraconazole for an additional 12 weeks (longer courses may be required for immunocompromised patients). Children being treated for PDH should not be transitioned to oral itraconazole until they have demonstrated clinical improvement and a decline in their serum Histoplasma antigen level. When using oral itraconazole, serum trough concentrations should be checked after 2 weeks of therapy to ensure that levels are greater than 1 µg/mL. Methylprednisolone should also be considered during the first 1–2 weeks of therapy in cases of severe respiratory disease. All children with chronic pulmonary histoplasmosis should be treated with a prolonged course of itraconazole (typically 1–2 years), and severe cases may require an initial course of amphotericin B.

Children with the inflammatory mediastinal manifestations of histoplasmosis (e.g., mediastinal adenitis, pericarditis) may not require antifungal therapy. Mild to moderate cases of pericarditis or rheumatologic syndromes can be treated with nonsteroidal antiinflammatory drugs. In severe cases of mediastinal disease (e.g., adenitis leading to obstruction, severe pericarditis), corticosteroids can be used. In cases where corticosteroids are used, itraconazole should be used concurrently and continued for 6–12 weeks thereafter. General recommendations for the treatment of histoplasmosis in children and adults have been published by the Infectious Disease Society of America (IDSA).

Prevention

Children with impaired cellular immunity should be counseled about the risks of histoplasmosis if they are living in or visiting endemic areas. These patients should avoid activities that increase the risk of exposure, including cleaning household areas with significant dirt or dust (e.g., garages, basements, and barns), cutting firewood, gardening, or exposure to soil contaminated by bird or bat guano. If such activities are unavoidable, an appropriate mask should be worn.

Prognosis

The prognosis of children with histoplasmosis varies greatly based on the clinical scenario. In most children, the disease is unrecognized or self-limited. The cure rate for immunocompetent children with acute disease is high. PDH of infancy was considered uniformly fatal before effective antifungal agents were available, but survival rates are high with modern therapies. Immunocompromised children with disseminated histoplasmosis have a more guarded prognosis.

Epidemiology

Coccidioidomycosis, also known as San Joaquin Valley fever, is a systemic fungal infection caused by Coccidioides immitis and Coccidioides posadasii. Both organisms are found in geographic regions with low rainfall, high summer heat, and alkaline soil. Such geographic locations include the central valleys of California, Arizona, New Mexico, Nevada, and northern Mexico ( Fig. 31.4 ). Children are at greatest risk of disease acquisition during the dry seasons of the year when there is increased exposure to dust. Person-to-person spread does not occur.

Areas endemic for coccidioidomycosis.

Etiology

C. immitis and C. posadasii grow as mycelia in the soil. The mycelia produce hyphae composed of barrel-shaped spores (arthroconidia), which are swept into the air when the soil is disrupted. These arthroconidia are inhaled into the alveolar spaces of the lungs and subsequently develop into round forms known as spherules, which contains multiple endospores. The spherules eventually rupture, releasing endospores into the adjacent tissues.

Pathology/Pathogenesis

The arthroconidia and spherules induce an immune response by neutrophils and macrophages, but phagocytosis is made difficult by the size of the fungal elements. Macrophages and dendritic cells exposed to the coccidioidal antigens stimulate the production of interferon gamma and other cytokines. This leads to further activation of phagosome-lysosome fusion and killing, followed by granulomatous inflammation of the affected area of the lung. Natural infection leads to lifelong immunity.

Clinical Features

Approximately 60% of humans infected with coccidioidomycosis have a subclinical infection. The remainder of infected individuals have symptomatic disease ranging from a self-limited influenza-like illness to more severe disease. After inhalation of arthroconidia, there is an incubation period of 1–4 weeks. This is followed by cough, chest pain, fever, night sweats, arthralgias, and extreme fatigue. About one-third of infected patients will have clinically significant dyspnea. Acute infection can also be accompanied by a papular rash, erythema nodosum, or an erythema multiforme-like eruption. The combination of erythema nodosum, fever, and arthralgia has been described as “desert rheumatism.” Other extrapulmonary manifestations are rare in children and include osteomyelitis and pustules that can ulcerate over time. The most severe manifestation of coccidioidomycosis is meningeal disease, which is seen in less than 1% of patients.

Chronic forms of pulmonary coccidioidomycosis are seen but are uncommon in children. Patients with chronic disease may have had a mild primary infection that was not initially recognized as coccidioidomycosis. Chronic infection can result in cavitary lesions. Hemoptysis may often be the only symptom of a pulmonary cavity infected by Coccidioides spp. Risk factors for chronic pulmonary coccidioidomycosis include diabetes mellitus or an immunocompromising condition.

In one study of 41 children’s hospitals in the United States from 2002 to 2007, Fisher et al. identified 199 children who required hospital admission for coccidioidomycosis. The authors found that 34% of the children had an underlying comorbid condition and 22% required at least one readmission for their disease during the study period.

Imaging, Pulmonary Function Testing, Laboratory Findings

Radiographic findings in pulmonary coccidioidomycosis are variable. Pulmonary nodules and thin-walled cavities can be seen on chest imaging, and some nodules will show calcification over time. Lobar, nodular, and patchy pulmonary infiltrates are all seen in acute disease, with or without hilar lymphadenopathy and pleural effusion. Cavitary lesions and bronchiectasis are all late features of pulmonary Coccidioides infection. In rare cases, rupture of a cavity may lead to severe disease with pyopneumothorax.

Diagnosis

Coccidioidomycosis may not be clinically recognized outside of endemic areas. Children with community-acquired pneumonia, especially with the dermatologic and rheumatologic symptoms already mentioned, should be considered for testing. The diagnosis of coccidioidomycosis is most often made with specific serologic tests utilizing EIA, immunodiffusion, or complement fixation–based tests. Antibody detection of IgG and IgM by EIA is the most sensitive assay and multiple commercially tests are available. Assays that utilize immunodiffusion or complement fixation are more specific. In general, approximately 50% of patients have IgM detected by 1 week of illness, and 90% have IgM detected by 3 weeks of illness. Unlike the case with other infections, IgG returns to normal levels after the infection resolves rather than remaining positive for life. Persistent high titers equal to or greater than 1 : 16 are seen with severe disease or disseminated infection.

A second approach to the diagnosis of coccidioidomycosis is use of an EIA to detect Coccidioides antigens in urine, blood, or BAL fluid. This may prove useful in diagnosing coccidioidomycosis in patients who may not produce Coccidioides -specific antibodies. A small retrospective study of mostly immunocompromised patients found that Coccidioides antigenuria occurred in approximately 70% of patients with culture-proven infection, most of whom had severe disease. The assay proved to have a high negative predictive value except in patients who had infections with another endemic fungal infection. Finally, coccidioidomycosis can be diagnosed by direct identification of the organism in its spherule form in biopsy tissue or BAL fluid. Isolation of Coccidioides from fungal culture is diagnostic. The organism grows rapidly on appropriate artificial media, with visible colonies of mold forming in 5–7 days. There is risk of infection to laboratory workers and the microbiology laboratory should be alerted prior to sending a sample if the disease is suspected.

Differential Diagnosis

Primary pulmonary coccidioidomycosis can resemble viral pneumonia, atypical pneumonia, bacterial pneumonia, tuberculosis, or other endemic fungal infections of the lungs.

Management and Treatment

Treatment is not indicated for all patients. Asymptomatic patients who are found to have a pulmonary nodule from coccidioidomycosis and are otherwise healthy do not require treatment. The benefit of treatment in immunocompetent patients with mild to moderate acute symptomatic infection is controversial. Some experts believe that antifungal therapy may decrease the length of illness or decrease the likelihood of severe infection. Suggested criteria to indicate severe disease include the need for hospitalization, weight loss of greater than 10%, persistent night sweats for greater than 3 weeks, pulmonary infiltrates involving both lungs or greater than half of one lung, prominent hilar lymphadenopathy, symptoms persisting over 2 months, inability to work or attend school, or a complement fixation titer of at least 1 : 16. Treatment should be strongly considered for those of African or Filipino descent, given higher rates of disseminated infection as compared with Caucasians. Although meningitis is uncommon in children with this infection, clinicians should have a low threshold for evaluating for the presence of CNS disease.

When treatment for coccidioidomycosis is indicated, an oral azole such is fluconazole is recommended for 3–6 months, depending on the clinical response. Regardless of whether antifungal therapy is started, patients with coccidioidomycosis should be followed every 1–3 months to document resolution of disease on chest x-ray (CXR) and monitored for new pulmonary or extrapulmonary complications.

Patients with active pulmonary coccidioidomycosis who are at increased risk for severe or disseminated infection should be treated with antifungal therapy. This includes patients with a history of human immunodeficiency virus (HIV) infection, hematopoietic stem cell transplant (HSCT), solid organ transplantation, prolonged exposure to corticosteroids or TNF inhibitors, or those who are pregnant. Treatment in these populations involves fluconazole or amphotericin B, depending on the extent of disease. Patients started on amphotericin B can be switched to oral fluconazole after clinical improvement. General recommendations for treatment of coccidioidomycosis in adults have been published by the IDSA and were last updated in 2016.

Prevention

Patients with impaired cellular immunity who live in or are visiting endemic areas should be counseled about the risks of coccidioidomycosis. This includes children with HIV, those on high-dose corticosteroids, those on anti-TNF therapies, those on antirejection medications after organ transplant, and women in their third trimester of pregnancy. Such patients should avoid activities that increase the risk of exposure, including environments where they would be exposed to large amount of dust from disrupted soil. If such activities are unavoidable, an appropriate mask should be worn. Preemptive therapy for coccidioidomycosis in special at-risk populations is recommended and is described in the IDSA guidelines.

Prognosis

The prognosis of children with coccidioidomycosis varies greatly based on the clinical scenario. The majority of patients have a self-limited disease process with complete recovery in 1–3 weeks. Mortality is low, even in children hospitalized for coccidioidomycosis. In the previously mentioned study by Fisher et al., the authors found that the overall in-house mortality for children admitted with coccidioidomycosis was 3 of 199 patients (1.5%).

Epidemiology

Blastomycosis is another endemic fungal infection that has a geographic localization similar to that of histoplasmosis. This fungus grows best in warm, moist soil, and is endemic in the Ohio and Mississippi River valleys, in addition to the borders of the Great Lakes and the St. Lawrence River ( Fig. 31.5 ). Blastomycosis is uncommon in children, with an estimated 3%–10% of all cases occurring in the pediatric population.

Areas endemic for blastomycosis.

Etiology

Blastomyces dermatitidis is a thermally dimorphic fungus that exists in nature in a mycelial form and converts to a yeast at body temperature. The mycelial form is primarily found in the soil and consists of hyphae that produce conidia. These conidia are released into the air from the soil when it is disrupted and can subsequently be inhaled by humans.

Pathology/Pathogenesis

Blastomycosis can occur in immunocompetent and immunocompromised hosts. Population studies show that the infection is asymptomatic in 50% of children. After B. dermatitidis conidia are inhaled by humans, the organism converts to pathogenic yeast. Alveolar macrophages and neutrophils are capable of phagocytizing and destroying conidia. The adaptive immune response is coordinated by T lymphocytes and is critical in activating a TNF-α response, which further enhances fungicidal activity. Conidia that evade this immune response can convert to the pathogenic yeast form in the lung and may subsequently disseminate.

Clinical Features (Symptoms/Physical Findings)

Blastomycosis is primarily a disease of the lungs. Children typically present with a prolonged illness consisting of fever, fatigue, cough, myalgias, and chest pain. In rare cases, a more severe ARDS presentation is seen. Between 38% and 50% of children with blastomycosis develop disseminated disease, which can manifest as skin lesions (pustular, nodular, or ulcerative lesions), osteomyelitis, septic arthritis, or involvement of the genitourinary tract (prostatitis or epididymitis). Pulmonary blastomycosis can occasionally persist in the chronic form as chronic pulmonary blastomycosis. Symptoms may include productive cough, hemoptysis, and weight loss.

Imaging, Pulmonary Function Testing, Laboratory Findings

Chest imaging can show patchy pneumonitis, nodular lesions or lobar consolidation, which can occur with or without cavitation. Hilar and mediastinal lymphadenopathy is uncommon and should suggest an alternative diagnosis such as tuberculosis or histoplasmosis.

Diagnosis

The diagnosis of blastomycosis is based on visualization of the thick-walled, budding yeast cells on smears from sputum, tracheal aspirates, urine or tissue specimens (see Fig. 31.3C and D ). In cases where the organism cannot be identified by examining sputum, BAL fluid can be cultured on brain/heart infusion or Sabouraud dextrose agar. Serologic testing by immunodiffusion or complement fixation assays lacks sensitivity. A Blastomyces urine antigen test is commercially available, but a high degree of cross-reactivity is seen with other endemic mycoses. Real-time polymerase chain reaction (PCR) assays have been developed that can identify B. dermatitidis in various clinical specimens (e.g., pleural fluid, BAL fluid, sputum) with high sensitivity and specificity.

Differential Diagnosis

Acute pulmonary blastomycosis can mimic bacterial pneumonia, tuberculosis, sarcoidosis, or a malignant neoplasm. Chronic pulmonary blastomycosis can be mistaken for malignancy or tuberculosis. The skin lesions can be misdiagnosed as pyoderma gangrenosum.

Management and Treatment

Unlike acute pulmonary histoplasmosis or coccidioidomycosis, for which treatment is unnecessary in milder forms of disease, treatment of all forms of acute pulmonary blastomycosis is generally recommended. The high rate of disseminated disease in children underscores this recommendation. For mild to moderate acute pulmonary disease, oral itraconazole is recommended for 6–12 months. For patients with moderate to severe pulmonary disease or those with disseminated extrapulmonary disease, amphotericin B (lipid or deoxycholate) should be given for 1–2 weeks or until improvement is noted. This should be followed by oral itraconazole for 6–12 months for pulmonary disease and at least 12 months for disseminated disease. Serum levels of itraconazole should be determined after the patient has received this agent for at least 2 weeks, to ensure adequate drug levels. It is recommended that serum itraconazole levels be greater than 1.0 mg/mL. General recommendations for the treatment of blastomycoses were last published in 2008 by the IDSA.

Prognosis

Overall mortality in adults with blastomycosis is reported to be 4%–6%, with an 18% mortality rate in those with CNS disease. Limited data are available in children, but mortality is thought to be lower in children than in adults due to the presence of less comorbidity.

Epidemiology

Aspergillus species are an important cause of life-threatening infection in immunocompromised children. Humans with normal pulmonary host defenses rarely develop IA, despite routine exposure to airborne conidia. It has been estimated that the average person inhales several hundred Aspergillus conidia spores per day. Hospital construction and renovation have been linked to nosocomial infection in immunocompromised patients. Specific groups of children are at risk of IA. This includes those with leukemia and other malignancies, neutropenia secondary to cytotoxic chemotherapy, HSCT, SOT, inherited or acquired immunodeficiencies, corticosteroid use, as well as low-birth-weight infants. In a retrospective study of pediatric patients with probable or proven IA, 63% had a hematologic malignancy, 38% had a history of a hematopoietic transplant, 11.5% had an inherited immunodeficiency, 6.5% had a history of a SOT and 0.7% had HIV infection.

Of the primary immunodeficiencies, chronic granulomatous disease (CGD) has the best-characterized association with IA. There is a 33% lifetime risk of IA in CGD. Severe combined immune deficiency (SCID) is the other primary immunodeficiency for which the risk of IA is known to be significant. Approximately 4% of children with SCID develop IA, resulting in a high mortality rate.

Of the commonly used immunosuppressive medications, corticosteroids have been identified as an important risk factor for IA. Although the mechanisms are still incompletely understood, corticosteroids have been shown to impair the anticonidial activity of macrophages and suppress neutrophils, both in recruitment and antifungal activity. Newer immunomodulating drugs that inhibit TNF have also been shown to increase the risk of pulmonary and IA. There have also been reports of pulmonary aspergillosis in adults with critical illness secondary to influenza A H1N1.

Aspergillosis has occasionally been described in premature neonates. In this population, risk factors for Aspergillus infection include skin maceration from adhesive tape or venous arm boards, percutaneous catheter insertion sites and necrotizing enterocolitis, all of which reflect mucocutaneous portals of entry.

Etiology

Species within the genus Aspergillus are ubiquitous worldwide; they are found in soil, water, air, and decaying vegetation. The classification of the genus Aspergillus is complex, as there are more than 200 different species that are divided amongst multiple subgenera. Given that some species can be distinguished only by molecular typing, it has been proposed that isolates are referred to as a “species complex.” Aspergillus fumigatus is a species complex that causes the majority of invasive disease in humans, and most of what is known about Aspergillus virulence factors and host immune response comes from research on this organism. Aspergillus flavus is the principal species found in sinusitis and accounts for up to 10% of all invasive isolates. Aspergillus niger, Aspergillus terreus, and Aspergillus nidulans are less common causes of invasive disease. Aspergillus terreus is a notable species given that it is resistant to amphotericin B, and infection from this organism is associated with a high mortality rate. Aspergillus nidulans has been found to occur at an unusually high frequency in children with CGD. The varying pathogenicity of these different species is thought to be related to variables such as the ability to grow at 37°C, conidial size, growth rate, and the production of various virulence factors.

The infective components of the organism are conidia, which are readily aerosolized from the end of hyphal stalks. Inhalation and subsequent germination of conidia leads to the formation of hyphae in the distal airways. These hyphal forms of Aspergillus subsequently invade pulmonary blood vessels and parenchyma, resulting in thrombosis and ischemic necrosis of the affected lung. The time required for this sequence of events to occur is variable; the incubation period of IA is estimated to be as short as 2 days and as long as 3 months. After invasion of pulmonary tissue, spread to contiguous thoracic structures or hematogenous dissemination may occur.

Pathology/Pathogenesis

Anatomic barriers play an important role in the host defense against inhaled Aspergillus conidia. An intact respiratory mucosa, bronchial mucus, surfactant, and ciliated respiratory epithelium eliminate inhaled conidia and prevent germination. Innate immunity is clearly another important part of the host defense. Alveolar macrophages are responsible for the ingestion of conidia. Neutrophil recruitment and activation of cellular immunity also play key roles in the control of invasive hyphae. Once the Aspergillus conidia have germinated into invasive hyphal forms, vascular invasion is seen. One of the histopathologic hallmarks of IA is tissue infarction and necrosis.

Clinical Features (Symptoms/Physical Findings)

IA can be classified into four main clinical presentations: pulmonary aspergillosis, tracheobronchitis, rhinosinusitis, and disseminated disease. Of all these clinical presentations, invasive pulmonary aspergillosis (IPA) is the most common. In a study of aspergillosis in children with cancer, 70% of the 66 children with culture-proven disease had lung involvement. In children with either CGD or HIV/AIDS, pulmonary disease is also the most common manifestation. The classic triad of presenting symptoms for IPA is fever, pleuritic chest pain and hemoptysis, although this triad is seen in only a minority. More often, the presenting symptoms of IPA in children are nonspecific, with the most common complaints being fever, cough, and dyspnea.

Aspergillus tracheobronchitis has been described in lung transplant recipients and those with other immunocompromising conditions. These patients present with cough, dyspnea, and wheezing. Three different patterns of Aspergillus tracheobronchitis have been described: obstructive, ulcerative, and pseudomembranous. Patients with obstructive tracheobronchitis have thick mucus plugs obstructing the airways, which consist of Aspergillus hyphae. These patients often present with expectoration of mucous plugs. Ulcerative tracheobronchitis represents the focal invasion of the mucosa and/or cartilage with Aspergillus hyphae. A final pattern is pseudomembranous tracheobronchitis, which is characterized by diffuse inflammation and invasion of the airway mucosa. This inflammatory process results in a pseudomembrane composed of necrotic debris from Aspergillus hyphae.

Invasive rhinosinusitis due to aspergillosis can cause disease similar to mucormycosis. This can present acutely with fever, facial pain, epistaxis, and visual changes. Extension into the orbits and CNS can be seen. Early nasal endoscopic evaluation by an otolaryngologist is important in the immunocompromised patient, where necrotic lesions are seen from fungal invasion of the mucosal tissues. Disseminated aspergillosis can spread from the respiratory tract to multiple different organs including the skin, CNS, eyes, liver, and kidneys. Aspergillus spp. can also cause endocarditis, particularly in those with prosthetic heart valves.

Imaging, Pulmonary Function Testing, Laboratory Findings

The radiographic appearance of IPA is variable. Overall, the most common findings on plain radiographs of the chest are peripherally distributed lung nodules or masses. Chest radiographs can also be normal early in diagnosis, or they may show a variety of nonspecific findings such as segmental or multilobar consolidation, perihilar infiltrates, pleural effusions or nodular lesions. Chest CT is the imaging modality of choice for early diagnosis and has allowed for earlier preemptive therapy for patients at high risk for IA. Classic CT findings of the “halo sign” (a distinct nodular lesion with surrounding areas of decreased attenuation) and the “air crescent sign” (a late finding of nodular cavitation, usually occurring after recovery of neutrophil counts) are less common in children with IPA than in adults. In a large retrospective study of children with IA, only 11% demonstrated the halo sign and 2.2% showed the air crescent sign.

Diagnosis

The diagnosis of IA involves multiple testing modalities including fungal culture of various clinical specimens, histopathologic examination of tissue, imaging studies and serum biomarkers such as the galactomannan assay. The definitive diagnosis of IA requires the growth of Aspergillus spp. on culture in addition to the visualization of tissue-invasive hyphal forms from biopsy tissue obtained from the same organ (e.g., lung tissue and culture of airway secretions; see Fig. 31.3A and B ). Given that humans are exposed to Aspergillus conidia on a daily basis, a positive culture of Aspergillus spp. from the airways does not necessarily indicate infection. Although lung biopsy is a valuable tool in the diagnosis of IPA, the risks involved in obtaining a biopsy makes this technique unfeasible in some children. For patients at risk of IPA who also have clinical and radiographic findings consistent with the diagnosis, the detection of Aspergillus spp. from respiratory tract secretions has been used as a surrogate method of diagnosis.

When respiratory specimens are obtained from sputum or bronchoalveolar lavage fluid, both direct examination for hyphal elements (via staining with calcofluor or methenamine silver) and fungal culture should be performed. Growth of Aspergillus in the laboratory typically requires 1–3 days of incubation. Once growth is seen, identification of the species requires sporulation so that the spore-bearing structures can be seen on microscopy. If growth of Aspergillus spp. is present in culture and patients are suspected to have an azole-resistant isolate or are unresponsive to initial antifungal agents, susceptibility testing can be performed.

Although a negative culture from sputum or BAL fluid cannot rule out the diagnosis, a positive culture in a neutropenic or bone marrow transplant (BMT) patient with new pulmonary infiltrates is putative evidence of IPA. However, in solid-organ transplant patients, nonneutropenic patients with chronic lung disease, and HIV-infected patients, the positive predictive value of respiratory tract cultures is much lower. There is evidence that the overall culture isolation rate of Aspergillus spp. from BAL or bronchial washing specimens is higher than that from biopsy tissue specimens (8.1% vs. 1.5%).

When lung biopsy is performed, tissue from both the peripheral and central areas of the affected lung should be sampled. Thoracoscopic lung biopsy for diagnosis of IPA has not been systematically studied in children but has been used in this population. Given that biopsy is often not possible, due to comorbidities such as thrombocytopenia, alternative methods of diagnosis are needed in patients at risk of aspergillosis. Despite the angioinvasive nature of Aspergillus spp., positive blood cultures for the mold are rarely reported in IA.

Various biomarker assays have been developed to help in the diagnosis of IA, including the galactomannan assay, PCR-based assays, and tests to detect the (1-3)-β- d -glucan found in the fungal cell wall. The galactomannan antigen assay uses a double-sandwich EIA to detect galactomannan, a polysaccharide cell wall antigen of Aspergillus spp. The assay recognizes circulating galactomannan in patients with IA and was approved in 2003 for use in the United States on serum and BAL specimens. The galactomannan assay is best validated for neutropenic patients with hematologic malignancy and HSCT. In some of the early studies, the galactomannan antigen assay was reported to have a sensitivity as high as 81% and a specificity as high as 89%. Subsequent studies in more diverse populations have shown significantly more variability in test sensitivity, with rates ranging from 30% to 100%. Data on the galactomannan assay in children are limited. In a retrospective study of children receiving chemotherapy or those with a history of HSCT, the galactomannan antigen assay showed poor sensitivity (32%) and positive predictive value (70%), but good specificity (98%) and negative predictive value (92%). Variables such as cutoff values for positivity, specimen treatment, preceding antifungal treatment, pretest probability of IA based on risk factors, and false-positive results in patients receiving piperacillin/tazobactam are thought to contribute to the variability of the results.

Detection of Aspergillus spp. in BAL fluid has been studied using the galactomannan assay and PCR technology, but the precise role of these techniques in diagnosis remains to be seen. In a study of 85 children (59 of whom were immunocompromised), the use of the galactomannan assay on BAL fluid showed a sensitivity of 78% and specificity of 100% for pulmonary aspergillosis. In a study of adult patients with hematologic malignancies, the authors found that the galactomannan assay of BAL fluid had a sensitivity of 92% and specificity 98%. In the same study, PCR of BAL fluid for Aspergillus spp. was compared to the galactomannan assay. The authors found that PCR showed a decreased sensitivity compared with the galactomannan assay but had a similar specificity. Aspergillus PCR from blood specimens of immunocompromised patients has also been studied. In a meta-analysis of 18 primary studies (4 of which included pediatric patients), the authors found that the Aspergillus blood PCR had a mean sensitivity and specificity of 80.5% and 78.5% when tested in patients at high risk of IA. The authors also found a high negative predictive value of 96%.

Several assays (e.g., Fungitel, Fungitec, and Endosafe-PTS) have been developed to detect another component of the fungal cell wall, (1-3)-β- d -glucan (BDG). As a nonspecific marker of invasive fungal infections, BDG assays have varying predictive values in studies of adult patients. However, the assay does not distinguish Aspergillus from the other fungi that contain BDG (various other molds, Candida spp., Pneumocystis ). Furthermore, the performance of the BDG assays in pediatric patients is largely unknown.

Differential Diagnosis

IA can mimic multiple other disease processes depending on the clinical and radiographic features. Pulmonary aspergillosis can be difficult to distinguish from tuberculosis or other invasive fungal infections (e.g., mucormycosis, Fusarium spp.). Rhinosinusitis due to Aspergillus spp. can be clinically and radiographically similar to invasive mucormycosis.

Management and Treatment

Effective treatment of IA involves a combination of antifungal therapy, reversal of immunosuppressing drugs or interventions and in some cases surgery. For over 40 years, amphotericin B was recommended as primary therapy for IA. Monotherapy with amphotericin B has historically had only modest success in the treatment of IA. Mortality with amphotericin B as sole therapy for IA was 65% in one large retrospective review. The toxicity of amphotericin B deoxycholate is well known, with nephrotoxicity being the most common dose-limiting side effect. The newer lipid formulations of amphotericin B offer reduced toxicity, but these compounds have not shown an increase in efficacy relative to the deoxycholate formulation.

In a seminal randomized trial published in 2002, primary therapy with voriconazole was shown to be superior to amphotericin B. Subsequent studies have supported this conclusion, with an estimated 15% improved survival at 12 weeks in patients who received voriconazole compared with other antifungal therapies. The IDSA guideline on the management of aspergillosis published in 2016 recommends that voriconazole be used as the primary treatment of IA in adults and children. The intravenous form should be used for patients with severe illness. When the oral form is used, trough levels should be greater than 1–1.5 µg/mL for efficacy but less than 5–6 µg/mL. Treatment should continue for a minimum of 6–12 weeks, depending on the duration of immunosuppression and evidence of disease improvement. Isavuconazole has shown promise as a treatment option for IA, as it is associated with a lower rate of hepatobiliary and visual disturbances as compared with voriconazole. In a randomized double-blind trial comparing voriconazole with isavuconazole in 527 adults with invasive mold infections (primarily with Aspergillus spp.), isavuconazole was found to be noninferior to voriconazole. Based on these data, isavuconazole was approved by the FDA as an alternative primary therapy for IPA. Amphotericin B should still be used for situations in which hepatic toxicities or drug interactions warrant an alternative to azoles or when voriconazole-resistant molds (e.g., mucormycosis) are still in the differential diagnosis.

Primary therapy with an echinocandin is not recommended for aspergillosis unless the patient is intolerant to both the azoles and amphotericin B or has failed alternative therapy (i.e., salvage therapy). The combination of either voriconazole or amphotericin B with an echinocandin shows some evidence of benefit based on in vitro studies and small nonrandomized clinical trials. The authors of the IDSA guideline recommend that combination antifungal therapy be reserved for severe disease, especially in patients with profound and persistent neutropenia.

Treatment of IA should involve the reduction or elimination of immunosuppressive agents when possible. Adjunctive therapies such as interferon gamma (INF-γ), colony-stimulating factor, and infusions of granulocytes harvested from donors pretreated with granulocyte colony-stimulating factor (GCSF) have a role in the treatment of aspergillosis in certain patients. Although these modalities have not yet been well studied, experience with certain patient populations has led to recommendations for their use. GCSF or granulocyte macrophage colony-stimulating factor (GM-CSF) should be considered in severely neutropenic patients who do not respond to standard therapy. Granulocyte transfusions can be considered for patients with prolonged neutropenia and disease that is refractory to standard therapy. In patients with CGD, recombinant INF-γ is recommended as prophylaxis against IA and other infections.

Therapeutic surgical excision of IPA also has a role in the treatment of certain patients. Surgical resection can provide a definitive diagnosis and can completely eradicate a localized infection of the lung. Patients with IPA that has invaded the great vessels, pericardium, or pleural space may also benefit from surgical intervention. In a retrospective review of 43 pediatric patients with IPA, most of whom were significantly immunosuppressed, the authors found a significantly higher survival rate in the 18 patients who underwent surgical intervention compared with those who received only medical therapy. The retrospective nature of the study, high overall mortality rate in the series (91%) and limitations of medical therapy available at the time of the study (i.e., before the approval of voriconazole) make it difficult to know if such findings can be generalized to current care. In the absence of chest wall extension or uncontrolled bleeding, there is no consensus regarding the benefit of surgical resection prior to HSCT or intensive chemotherapy. General recommendations for the treatment of aspergillosis were published in 2016 by the IDSA.

Prevention

Children with prolonged neutropenia who are at risk of IA should receive prophylaxis with posaconazole or voriconazole. For children previously treated for IA who will require subsequent immunosuppression, antifungal therapy should be restarted to prevent recurrent infection. Children who have had a lung transplant should receive antifungal prophylaxis for 3–4 months after lung transplant with either an azole such as voriconazole or itraconazole or inhaled amphotericin B. Hospitalized allogeneic HSCT recipients should be roomed in a protected environment to reduce exposure to mold. Routine environmental sampling of fungal spores in the hospital is not recommended in the absence of a known outbreak.

Prognosis

In a retrospective analysis of 139 children with IA, the overall mortality rate was found to be 52.5%. The highest mortality rate was seen in patients with allogeneic HSCT, where 78% of the patients had died by 12 weeks or at the end of therapy.

Epidemiology

Invasive infections due to Candida species can cause significant morbidity and mortality in certain populations of children. Candida spp. are the third most common cause of nosocomial bloodstream infections in children. Risk factors include the use of broad-spectrum antibiotics, invasive devices such as central venous catheters, organ transplant, immunosuppressive chemotherapy regimens, and neonates born with very low birth weights. Infections occur primarily via tissue invasion from endogenously acquired strains rather than by person-to-person spread.

Etiology

Candida spp. are yeasts that reproduce by budding. Most members of the genus can produce only pseudohyphae, which are chains of elongated yeast that result from incomplete budding. An exception to this is seen with Candida albicans and Candida dubliniensis, which can produce true hyphae under conditions found in the human host.

Candida spp. commonly colonize the human gastrointestinal tract, genital mucosa and skin. Of the approximately 150 known species of Candida, only 15 species are known to cause human disease. C. albicans is by far the most common species to cause disease and represents about 50% of pediatric invasive candidiasis. Other important Candida species include Candida krusei, glabrata, parapsilosis, tropicalis, lusitaniae and dubliniensis.

Pathology/Pathogenesis

Most studies related to the pathogenicity of Candida spp. have utilized C. albicans. This microorganism has several notable virulence factors including adhesion to host mucosal cells, morphologic switching between the yeast and hyphal forms and the ability to form biofilms. The formation of biofilms plays a significant role in infections of medical devices including central venous catheters and cardiovascular devices. The immune response to Candida is complex and involves the innate and adaptive arms. Neutrophils, macrophages, and monocytes play a particularly important role in preventing disseminated candidiasis, as evidenced by the high risk of disseminated disease in neutropenic patients.

Clinical Features (Symptoms/Physical Findings)

Candida spp. are well known for their ability to cause mucocutaneous infections in normal hosts, including oral-pharyngeal (thrush) infection, diaper rash and paronychia. Immunocompromised patients can develop laryngeal or esophageal candidiasis. Disseminated or invasive candidiasis can occur in almost any organ system or anatomic site. In children with disseminated candidemia, the lungs were found to be involved in 45%–58% of cases. Less common sites of dissemination include the liver, kidney, brain, heart, spleen, and eyes.

When pulmonary candidiasis does occur, three different patterns of disease have been described: primary pneumonia due to tracheobronchial colonization and aspiration, secondary pneumonia in the setting of candidemia with disseminated disease, and secondary pneumonia in the setting of septic emboli. In all of these cases, the clinical manifestations are nonspecific, with fever, cough, and a sepsis-like picture being the most common presentation. Primary candidal pneumonia (i.e., with no evidence of candidemia or other sites of disseminated disease) is rare and is thought to be limited to neutropenic patients and low-birth-weight infants. In patients with disseminated disease, bilateral lung involvement is typical, and microscopic examination of the lung shows pseudohyphae in the pulmonary capillaries. In embolic disease, the lungs (and other organs) are seeded with infected emboli from an endovascular source, resulting in hemorrhagic infarcts at the periphery of the lungs. Invasive candidiasis in neonates differs from disease in older children in that neonates are more likely to present with nonspecific or subtle signs and symptoms of infection.

Imaging, Pulmonary Function Testing, Laboratory Findings

Patterns on chest radiographs have been described most often as patchy consolidations, with larger areas of consolidation limited to severe disease. Nodular lesions with central necrosis can be seen in disseminated disease and are best detected by CT of the lungs. Cavitation and pleural effusions are rare findings.

Diagnosis

Candida grows well on routine agar and does not require specialized fungal media. Culture of Candida spp. from a sterile body site (e.g., blood or CSF) or the demonstration of organisms from tissue biopsy are still the “gold standard” for diagnosis. Growth is typically seen after 2–3 days of incubation, but occasionally >7 days. Automated blood culture systems can allow for earlier detection, but overall sensitivity of candidemia by blood culture is still less than 50%. There are multiple nonculture diagnostics for invasive candidiasis (BDG, antigen/antibody detection assays, PCR), but none are currently recommended by the IDSA guideline for routine use in children.

In immunocompetent children, growth of Candida spp. from the sputum or tracheostomy cultures usually indicates colonization and not infection. In a study of nonneutropenic patients, nearly 90% of bronchoalveolar lavage cultures positive for Candida spp. were judged to be probably or definitely contaminated, despite the fact that the majority of the cultures had been done on protected brush specimens. Candidal pneumonia after aspiration is rare in immunocompetent children.

In immunocompromised patients, growth of Candida from a respiratory tract culture should prompt clinicians to investigate for invasive candidiasis, although it can be difficult to distinguish oropharyngeal or tracheobronchial colonization from invasive pulmonary disease. In a large study of adult cancer patients, the positive predictive value of various cultures for pulmonary candidiasis was determined using histopathology from autopsy specimens as the gold standard. The authors found that the positive predictive value of a sputum culture for pulmonary candidiasis was 42%; from BAL fluid culture it was 29%.

In intubated patients, histologic evidence of candidal invasion of the lung tissue is the only widely accepted definition of pulmonary candidiasis. In patients with candidemia and new respiratory symptoms or radiographic abnormalities, the diagnosis of invasive pulmonary candidiasis should be strongly suspected.

Differential Diagnosis

Invasive candidiasis, depending on the organ system involved or the clinical situation, can mimic multiple disease processes. Candidemia can mimic septic shock. Pulmonary candidiasis can be confused for bacterial or viral pneumonia or other pulmonary mycoses such as aspergillosis or cryptococcosis.

Management and Treatment

The approach to the treatment of invasive candidiasis depends on a variety of factors including the status of the host immune system, source of infection (e.g., medical device–associated, endovascular), identified Candida spp. susceptibility profile, and age of the patient. For neonates with invasive candidiasis, treatment recommendations differ from those for non-neonates given the distinct epidemiology and pathogenesis of the disease in this population as well as the distinct pharmacokinetic and pharmacodynamics of antifungal drugs.

Multiple antifungal drug classes play a role in the treatment of invasive candidiasis, each with strengths and weaknesses based on the clinical scenario. These drug classes include the polyenes (amphotericin B), the azoles, the echinocandins, and flucytosine. Amphotericin B is effective against most Candida species with notable exceptions being resistance in C. lusitaniae and decreased susceptibly in C. krusei and C. glabrata. As mentioned in the section on antifungal drugs at the beginning of this chapter, the lipid preparations of amphotericin B are generally recommended over the deoxycholate form. In the azole family of antifungals, fluconazole should not be used prior to identification of the Candida species, as C. krusei is resistant to fluconazole and increasing rates of resistance have been seen with C. glabrata (~50%) and C. tropicalis. Other drugs in the azole family have broader anticandidal activity than fluconazole, but resistance is still seen in some cases (e.g., voriconazole is often ineffective against C. glabrata ). The echinocandins (caspofungin, micafungin, and anidulafungin) have good activity against almost all Candida species, have a good safety profile, and are approved as first-line agents for severely ill or neutropenic patients. Of note, there is an overall trend of increasing resistance of Candida species to the triazoles and echinocandins. The use of flucyctosine is generally limited to children with candidal infections of the CNS. Therapeutic drug monitoring may be needed in patients on itraconazole, voriconazole, posaconazole, and flucytosine. Standards for susceptibility to the triazole and echinocandin antifungals have been established for Candida spp., and testing is available commercially.

Outside the neonatal population, nonneutropenic children with invasive candidiasis can be treated with fluconazole or an echinocandin. In neutropenic patients or those with critical illness, an echinocandin or liposomal amphotericin B should be used. Voriconazole can be used in children in situations where additional mold coverage is needed. In both of these situations, fluconazole can be used as step-down therapy for patients who have susceptible isolates and documented blood culture clearance.

In patients with a vascular or peritoneal catheter, removal of the catheter is recommended, in addition to antifungal therapy. Full details of management of patients with candidal infection of central venous catheters can be found in guidelines published by the IDSA. In patients with persistent disease despite adequate treatment, a search for a disseminated infection should be conducted. This diagnostic evaluation may need to include evaluation of the liver, spleen, lung, heart, and genitourinary tract. The length of treatment for patients without metastatic complications is generally 2 weeks after clearance of the bloodstream and resolution of symptoms. In disseminated candidiasis, other sites of infection may dictate the type and length of treatment (e.g., endocarditis, meningitis, endophthalmitis). All patients with candidemia should have a dilated fundoscopic evaluation. A lumbar puncture is recommended for all neonates with candidemia.

In neonates with invasive candidemia, amphotericin B deoxycholate is the drug of choice with disseminated disease, including meningitis. The lipid formulations of amphotericin B should be used with caution in neonates, especially if urinary tract involvement is suspected. Oral or IV fluconazole is an alternative to amphotericin B deoxycholate in patients who have not been on fluconazole prophylaxis. The echinocandins should be used with caution in neonates because there are limited data in this population. The IDSA guidelines recommend that this class of antifungals should be limited to salvage therapy or to situations in which resistance or toxicity preclude the use of amphotericin B or fluconazole.

Full details of the treatment of neonatal and nonneonatal candidemia can be found in the guidelines published by the IDSA. These guidelines were last published in 2016 and were endorsed by the American Academy of Pediatrics (AAP) and the Pediatric Infectious Diseases Society (PIDS).

Prevention

Fluconazole prophylaxis is recommended for infants of extremely low birth weights who are admitted to a neonatal intensive care unit with at least moderate rates (≥5%) of invasive candidiasis. Prophylactic fluconazole is also sometimes used in patients with advanced HIV disease, allogenic HSCT, and severe neutropenia.

Prognosis

The mortality rate of invasive Candida infection in neonates is high. In a multicenter study of infants weighing less than 1000 g at birth, the mortality rate was 34% in those with invasive candidiasis, compared to 14% in those without invasive candidiasis. Outside the neonatal period, children with candidemia were also found to have a significant mortality rate. In studies of candidemia in children of all ages, mortality rates range from 10% to 28%.

Epidemiology

C. neoformans and Cryptococcus gattii are two species of Cryptococcus known to be human pathogens. Cryptococcus is an encapsulated yeast that is found worldwide. Exposure to soil that has been contaminated with bird excrement has been found to be associated with infection. In the pre-AIDS era, symptomatic cryptococcal disease (cryptococcosis) was thought to be an uncommon condition, primarily associated in those with hematologic malignancies or recipients of organ transplants. In the HIV era, rates of cryptococcal disease increased significantly. Currently cryptococcosis is most associated with HIV infection, with an estimated 1 million new cases a year worldwide.

Cryptococcosis is an AIDS-defining illness and is seen most often in HIV-infected patients with CD4 ⁺ lymphocyte counts fewer than 100/µL. In adults with AIDS, cryptococcosis occurs in approximately 5% of patients annually. In children with AIDS, this rate is significantly lower, with reported rates of approximately 1% annually. Reasons for the lower incidence in children with AIDS are not known, but potential reasons include a decreased number of lifetime exposures, differences in infecting strains, and inadequate time to reactivate a prior infection. C. neoformans infection in children is also associated with leukemia, lymphoma, prolonged courses of corticosteroids, and SOT as well as in those with congenital immunodeficiencies such as hyperimmunoglobulin M (IgM) and hyperimmunoglobulin (IgE) syndromes.

Cryptococcosis has also been found to occur in immunocompetent children. In a study utilizing a national database of 42 children’s hospitals from the United States, the authors identified 63 children who were hospitalized with cryptococcal disease between 2003 and 2008. Of these children, 64% had an immunocompromising medical condition, 21% were immunocompetent, and 16% had HIV. In another study from Colombia, the authors identified 41 children with the diagnosis of cryptococcosis from 1993 to 2010. Of this cohort, 24.4% had AIDS and 46.3% had no known risk factors.

The incubation period for C. neoformans has not been determined, as infection with this organism often represents reactivation of latent disease. The incubation period for C. gattii is 2–13 months.

Etiology

Cryptococcus is a polyphyletic genus of encapsulated yeasts that compromises more than 70 species. Two of these species, C. neoformans and C. gattii, are known to be pathogenic in humans. C. neoformans primarily causes disease in immunocompromised patients and represents 90% of infections worldwide. C. gattii also causes disease in immunocompromised patients but is more likely than C. neoformans to cause illness in immunocompetent hosts. This phenomenon recently gained attention when C. gattii was found to be the cause of disease in otherwise healthy hosts in the Pacific Northwest of the United States and adjacent parts of Canada.

Cryptococcus has been isolated from soil, trees, and fruit. Dried pigeon droppings have been found to be a particularly effective culture medium for Cryptococcus spp. C. neoformans grows as yeast and replicates by budding. The organism’s sexual state creates basidiospores at the end of the hyphae. The basidiospores are aerosolized and can be inhaled by humans. After inhalation, the organism initially grows in the alveoli without a significant inflammatory response, which is thought to be due in part to the antiphagocytic effect of the polysaccharide capsule. Once within the lung, Cryptococcus may either be contained in a dormant state or disseminate to other organs prior to an adequate host immune response. The CNS is a common site of dissemination for C. neoformans, although the reason for this CNS tropism is not known.

Pathology/Pathogenesis

Both innate and adaptive immune responses are necessary to control infection due to C. neoformans. T cells activate alveolar macrophages via cytokines and promote ingestion of the encapsulated yeast. Humoral immunity plays a role in opsonization, activation of natural killer cells, and clearing of capsular polysaccharide. Conditions associated with defective cellular immunity are at increased risk of symptomatic cryptococcal infections.

Clinical Features (Symptoms/Physical Findings)

Although the most common route of acquisition of cryptococcosis is via inhalation, the pulmonary manifestations of the disease are often mild or asymptomatic. It is estimated that less than 10% of patients with disseminated cryptococcosis have pulmonary symptoms at the time of diagnosis. In individuals with symptomatic pulmonary disease, the typical presentation includes fever, cough, pleuritic chest pain, and weight loss. In cases of disseminated cryptococcosis, virtually any organ system can be involved. The most important sites of extrapulmonary infection include the CNS, skin, prostate and eyes. Cryptococcal meningitis often presents in an indolent manner with progressive symptoms of fever, headache, visual changes, and altered mental status. Isolated cryptococcal fungemia without concurrent organ involvement can occur in adults with HIV but is rare in children.

Imaging, Pulmonary Function Testing, Laboratory Findings

For patients with pulmonary cryptococcal infection, imaging of the chest by plain radiographs and CT is usually nonspecific. An isolated pulmonary nodule, with or without hilar adenopathy, may be the only manifestation of pulmonary cryptococcal infection in immunocompetent individuals. In patients with more severe manifestations of pulmonary cryptococcosis, a variety of imaging findings have been well described, including multiple lung nodules, lobar consolidation with a predilection for the lower lobes, cavitary lesions, pleural effusion, diffuse interstitial infiltrates, and an ARDS-like appearance. If signs of increased intracranial pressure or CNS infection are present, magnetic resonance imaging (MRI) or CT of the head to rule out hydrocephalus and cryptococcomas is indicated. In patients with CNS disease, common CSF indices such as cell count, protein and glucose values can be normal.

Diagnosis

The sensitivity of diagnostic tests for cryptococcal disease are different depending on whether there is isolated pulmonary disease or disseminated disease. For disease isolated to the lungs, noninvasive diagnostic tests have a relatively low sensitivity. Serum cryptococcal antigen testing is usually negative in isolated pulmonary disease. Likewise, sputum culture has a low sensitivity. Bronchoscopy with fungal culture and antigen testing of the lavage fluid can be helpful, although the sensitivity of this approach is variable for patients with isolated pulmonary cryptococcosis. Antibodies to C. neoformans can develop in response to either colonization or infection and are not useful in diagnosis.

Given the limitations of noninvasive methods for isolated pulmonary cryptococcal disease, more invasive procedures such as transthoracic or transbronchial fine-needle aspiration or open lung biopsy may be required to confirm the diagnosis. Direct histopathologic identification of C. neoformans from tissue biopsy specimens is both sensitive and specific for the diagnosis of isolated pulmonary disease. Several different stains can be used to identify the yeast in tissue, including silver stains or stains that target the polysaccharide capsule (e.g., mucicarmine stain). Caution should be used in inter­preting the significance of growth of Cryptococcus from sputum culture, as this may represent colonization.

Cryptococcus can be grown on standard automated blood culturing systems, although growth is best seen with Sabouraud dextrose agar. This media can be used to culture the organism from tissue, sputum, blood, BAL fluid, or CSF. Growth can be slow, sometimes taking up to a week for cultures to become positive. When pleural effusions are present, cultures of thoracentesis fluid are positive in about 40% of AIDS patients. Selective media are available to differentiate C. neoformans and C. gattii. Susceptibility testing for cryptococcal organisms is available, although resistance to antifungals is uncommon.

In contrast to patients with cryptococcal pulmonary disease, the diagnosis of cryptococcal meningitis is less difficult. The latex agglutination test and EIA can be used to provide a rapid diagnosis for those with suspected meningitis. All of these tests detect cryptococcal capsular polysaccharide antigen and are approved for use on serum or cerebrospinal fluid. The sensitivity of these antigen assays in patients with cryptococcal meningitis is greater than 90%. Visualization of encapsulated yeast cells in CSF using India ink has sensitivity ranging from 50% to 80%. Given the frequency of concomitant meningitis, it is generally recommended that a lumbar puncture be performed on patients with pulmonary disease even in the absence of overt signs of CNS infection.

Patients who are severely immunocompromised with cryptococcal disease have been found to have significant incidence of coinfection with other pathogens such as Mycobacterium tuberculosis, nontuberculous mycobacteria, cytomegalovirus, Nocardia spp., and P. jirovecii. For this reason, patients with cryptococcal disease should be tested for additional pathogens as appropriate to the clinical situation.

Differential Diagnosis

The differential diagnosis of a patient with suspected cryptococcal pulmonary disease depends on the clinical scenario and radiographic findings. Patients with an ARDS-like clinical picture and immunodeficiency may present like cases of P. jirovecii infection. Patients with an indolent course of fever, cough, and multiple pulmonary nodules on chest radiograph may be suspected to have a lung malignancy. Children with fever, cough, sputum production, and lobar consolidation are often treated for bacterial pneumonia prior to the diagnosis of pulmonary cryptococcosis.

Management and Treatment

There are no prospective trials in children for the treatment of cryptococcosis. The IDSA guideline on cryptococcosis makes treatment recommendations for both adults and children. For otherwise healthy children with mild-to-moderate pulmonary cryptococcosis, fluconazole is recommended for 6–12 months. If fluconazole cannot be used, itraconazole, voriconazole, and posaconazole are effective alternatives. Echinocandins should not be used as they do not have activity against Cryptococcus spp. Children with severe pulmonary cryptococcosis should be treated similarly to those with CNS disease, regardless of immune status.

All immunocompromised patients and those with CNS cryptococcal infection should be treated aggressively. Corticosteroid treatment may be considered if ARDS is present. Immunocompromised patients with isolated pulmonary cryptococcosis that is mild to moderate in severity (i.e., absence of diffuse pulmonary infiltrates) can be treated with fluconazole orally for 6–12 months. For patients with cryptococcal meningitis, the preferred regimen for induction and consolidation therapy is amphotericin B deoxycholate plus oral or intravenous flucytosine for 2 weeks (or until CSF cultures are negative). This should be followed by oral fluconazole for a minimum of 8 weeks. Lipid formulations of amphotericin B can be substituted for deoxycholate formulations in children with abnormal renal function. After induction and consolidation therapy, maintenance (suppressive) or prophylactic therapy may be indicated depending on the immunosuppressing condition. The IDSA guidelines provided detailed recommendations regarding the length of maintenance and prophylactic therapy for children with HIV and other immunosuppressive conditions.

Prognosis

The prognosis for patients with isolated pulmonary cryptococcosis has not been studied thoroughly, but in the absence of dissemination outcomes appear to be favorable. Prognosis in patients with cryptococcal meningitis is predicted by various CSF parameters, such as organism load, opening CSF pressure, CSF glucose and leukocyte count, and titers of cryptococcal antigen in CSF or blood.

Epidemiology

Mucormycosis is caused by environmental molds found primarily in soil and organic matter. The organism has a near worldwide distribution. The main route of transmission is inhalation of spores from an environmental source. Outbreaks of disease have been linked to construction, excavation, and contaminated air-conditioning filters. Nosocomial clusters of cutaneous infections have been traced to contaminated wooden tongue depressors and various adhesive bandages used in the hospital. Ingestion of spores can also result in gastrointestinal disease. Invasive mucormycosis is typically limited to those with an impaired immune system. Diabetic patients, particularly during ketoacidosis, are known to be at risk for developing rhinocerebral mucormycosis. In nonneutropenic HSCT recipients, mucormycosis can be seen as a late (1–6 months) or very late (>6 months) infection.

Etiology

As with many fungal pathogens, the taxonomy of these organisms has changed. The phylum name Zygomycota has been reorganized based on new molecular phylogenic analyses, and the species that cause human disease are no longer limited to this phylum. For this reason, the term zygomycosis is no longer considered valid. Given that the clinically significant causative agents of mucormycosis belong to the order Mucorales, the term mucormycosis has been proposed as the most valid mycologic reference. Within the family of Mucorales, the most clinically significant genera are Rhizopus and Mucor. Mucorales are filamentous fungi that produce sporangiospores (asexual spores) contained within a saclike structure called a sporangium. When this structure ruptures, the sporangiospores are released and can be inhaled by the human host. Therefore sinus and pulmonary infections are the most common manifestation of this disease.

Pathology/Pathogenesis

Both macrophages and neutrophils are responsible for controlling infection due to mucormycosis. Alveolar macrophages control the germination of inhaled spores through phagocytosis. Neutrophils and mononuclear cells also prevent germination via generation of oxidative metabolites. Dysfunction of macrophage phagocytosis, neutrophil chemotaxis, and oxidative killing by neutrophils have been demonstrated in diabetic ketoacidosis. Other important risk factors include use of corticosteroids, broad-spectrum antibiotics, and hematologic and organ transplantation. One other established at-risk patient group are those receiving iron chelation therapy with deferoxamine. It is thought that this drug acts as a siderophore where it can deliver iron to the fungus, thus promoting growth.

Clinical Features (Symptoms/Physical Findings)

Mucormycosis can be classified into the following forms: rhinocerebral, pulmonary, cutaneous, gastrointestinal, and disseminated disease. Pulmonary disease is the most common clinical manifestation and is found to account for 30% of mucormycosis in a recent series from Europe. The clinical symptoms of pulmonary mucormycosis can initially be subtle or nonspecific in immunocompromised patients. When symptoms are seen, children with pulmonary mucormycosis develop persistent fever, cough, chest pain, and dyspnea. The disease is sometimes found in at-risk patients with pulmonary infiltrates that persist despite treatment for presumed bacterial pneumonia. In advanced disease, hemoptysis can occur because of angioinvasion and hemorrhagic infarction, which characterize this group of infections. Clinicians should be especially alert to the possibility of mucormycosis in children who are receiving antifungal prophylaxis with agents that have activity against Aspergillus but not the Mucorales (e.g., voriconazole or the echinocandins).

Imaging, Pulmonary Function Testing, Laboratory Findings

The radiographic findings of mucormycosis are quite variable. Isolated nodules, lobar consolidation, cavitary lesions, wedge-shaped areas of infarction, and disseminated pulmonary involvement have all been described.

Diagnosis

The diagnosis of invasive mucormycosis is difficult, as the sensitivity of fungal cultures from blood and respiratory tract specimens is low. Testing modalities such as serology and antigen detection are not clinically useful for mucormycosis. PCR assays to detect Mucorales from tissue specimens have shown promise but have not yet become a standardized adjunctive diagnostic test. A tissue-based approach is essential to the diagnosis assuming that the patient can tolerate the necessary procedure. As with Aspergillus spp., histopathology performed on tissue specimens from patients with mucormycosis often shows angioinvasion, with resulting vessel thrombosis and tissue thrombosis. Given these diagnostic limitations, a high index of suspicion is needed in at-risk patients to identify mucormycosis as early as possible. Unfortunately the diagnosis is often made after severe disease or at autopsy.

Differential Diagnosis

Pulmonary mucormycosis can be difficult to distinguish from IPA. In patients with hematologic malignancies, factors that favor the diagnosis of mucormycosis are the presence of concomitant sinusitis, the presence of more than 10 pulmonary nodules, and multiple negative serum Aspergillus galactomannan antigen assays. The diagnosis of mucormycosis is favored if the patient was receiving prophylactic antifungal agents with activity against Aspergillus, such as voriconazole or echinocandins.

Management and Treatment

Treatment of mucormycosis involves a combination of antifungal therapy, aggressive debridement of necrotic lesions, and, when possible, reversal of the predisposing condition that originally led to the infection. Amphotericin B (lipid formulation if available) is the recommended antifungal in patients with mucormycosis. In a study of 70 patients (primarily adults) with hematologic malignancy who had mucormycosis, the authors found that a delay of 6 or more days of an amphotericin B–based therapy resulted in a twofold increase in mortality rate compared with early treatment (82.9% vs. 48.6%).

Most azoles and echinocandins lack significant activity against the organisms that cause mucormycosis, although a few notable exceptions have been found. Both posaconazole and isavuconazole have in vitro activity against the Mucorales. There are multiple published reports of success with posaconazole as part of combination therapy or salvage therapy for mucormycosis. Another exception has been found with caspofungin. Although caspofungin has no activity against the fungi that cause mucormycosis in standard in vitro susceptibility tests, there is some evidence in animal and human studies that caspofungin is synergistic with amphotericin B. In a study of diabetic ketoacidotic mice with disseminated mucormycosis, caspofungin combined with amphotericin B resulted in better outcomes than amphotericin B alone. This combination of caspofungin combined with amphotericin B was also associated with improved outcomes in a retrospective study of primarily diabetic patients with rhino-orbital-cerebral mucormycosis. Isavuconazole has been studied as primary or salvage treatment in adults with mucormycosis. In an open-label trial, the authors found that isavuconazole showed similar efficacy to historical controls who were treated with amphotericin B.

The optimal length of treatment with antifungals has not been studied in patients with pulmonary mucormycosis. Most successfully treated patients require at least 4–6 weeks of therapy, although longer courses may be needed based on clinical response and ability to reverse the underlying immunocompromised state.

Mucormycosis is associated with tissue infarction; therefore antifungal therapy alone may not allow for clinical cure without debridement of devitalized tissue. In a retrospective review of 255 cases of pulmonary mucormycosis, mortality of patients treated with debridement and antifungal therapy was significantly lower than those who received antifungal therapy alone.

Prognosis

Mucormycosis is associated with high mortality, with reported rates of 100% for disseminated disease, 76% for pulmonary disease, and 46% for rhinocerebral disease.

Epidemiology

Sporotrichosis is caused by the fungus Sporothrix schenckii and is seen most commonly in Central America, South America, and the Midwest of the United States. Cutaneous sporotrichosis is the most common form of the disease in both adults and children. Pulmonary sporotrichosis is typically seen in adult males with alcoholism or other chronic medical illnesses such as diabetes mellitus. Disseminated sporotrichosis is rare in children and is typically seen in those who are exposed to immunosuppressive therapy, prolonged treatment with corticosteroids, or in those with AIDS.

Etiology

S. schenckii is a dimorphic fungus with a worldwide distribution in soil and plant products such as straw, wood, and sphagnum moss. Direct inoculation of exposed skin is the most common form of exposure, especially among those working with thorny plants (e.g., florists or rose gardeners). Household transmission has also been attributed to domestic cats. Pulmonary sporotrichosis is thought to be secondary to the inhalation of spores rather than part of disseminated infection. In immunocompromised children, dissemination can occur after cutaneous inoculation or from primary pulmonary infection.

Pathology/Pathogenesis

The immunological mechanisms involved in host control of S. schenckii infections are not well understood. It is thought that both humoral and cellular responses are involved in response to fungal surface and secreted antigens. The factors that influence localized versus disseminated disease include inoculum load, immune status of the host, virulence of the inoculated strain, and depth of traumatic inoculation.

Clinical Features

Sporotrichosis is most commonly a cutaneous or lymphocutaneous infection that manifests as a chronic, papulonodular lesion with or without central ulceration. It is often associated with regional lymphadenopathy. In addition to cutaneous disease, sporotrichosis can occasionally occur as pulmonary, osteoarticular or meningeal infection. The primary pulmonary form of sporotrichosis results in a granulomatous pneumonitis that often cavitates. Signs and symptoms of pulmonary disease include productive cough, fever, weight loss, and hemoptysis. The presentation can be subacute or chronic. Patients with multifocal sporotrichosis are much more likely to be immunocompromised.

Imaging, Pulmonary Function Testing, Laboratory Findings

Radiographs often reveal unilateral or bilateral cavitary lesions with associated parenchymal infiltrate. Hilar lymphadenopathy or pleural effusions are occasionally seen.

Diagnosis

The diagnosis of children with the classic lymphocutaneous form of sporotrichosis is relatively straightforward, given its characteristic pattern of presentation. The diagnosis of pulmonary or disseminated disease can be more difficult given that pulmonary or osteoarticular presentation can mimic other disease processes. The gold standard of diagnosis of sporotrichosis is fungal culture. Tissue biopsy, sputum, or BAL fluid can be inoculated onto Sabouraud’s dextrose agar and incubated at room temperature. Growth typically occurs within 5 days. Fungal staining can be performed on tissue or respiratory specimens, but the small number of fungal organisms may limit visualization. Serology is not used routinely in the diagnosis of sporotrichosis, as the available assays lack adequate sensitivity and specificity. PCR assays have been developed for identifying S. schenckii in tissue specimens, but they are not widely available.

Differential Diagnosis

The skin lesions of sporotrichosis can resemble Nocardia brasiliensis, cutaneous leishmaniasis, or mycobacterial infection. The differential diagnosis of disseminated disease depends on the clinical scenario and location of disease. Pulmonary sporotrichosis can mimic mycobacterial infections, histoplasmosis, or coccidioidomycosis.

Management and Treatment

Treatment of sporotrichosis involves a combination of antifungal therapy and, in some cases, surgical excision. Amphotericin B is the preferred antifungal treatment for life-threatening or extensive pulmonary sporotrichosis. After the patient has shown a favorable response to amphotericin B, therapy can be switched to itraconazole to complete a total course of therapy of at least 12 months. Localized pulmonary disease, particularly cavitary lesions, should be treated with a combination of surgical excision and amphotericin B. In children with less severe pulmonary disease, itraconazole administered for at least 12 months is recommended. Lifelong suppressive therapy with itraconazole may be required for patients with AIDS and other causes of immunosuppression. Serum levels of itraconazole should be measured after the patient has received this medication for at least 2 weeks so as to ensure adequate drug levels. It is recommended that serum itraconazole levels be greater than 1.0 mg/mL.

Prognosis

Cutaneous sporotrichosis responds well to antifungal therapy. Disseminated disease in immunocompromised children can be difficult to treat and is associated with significant morbidity and mortality.

Epidemiology

Trichosporon infections are caused by a group of related fungi that can occasionally cause invasive infections in humans. Trichosporon spp. have been found to colonize the gastrointestinal tract, respiratory tract, skin and vagina. Opportunistic invasive infections are thought to result from preexisting Trichosporon spp. that colonizes these locations. Invasive trichosporonosis can occur in patients with hematologic malignancies and other immunosuppressive states. This pathogen has also been proposed as a cause of severe exacerbations in patients with cystic fibrosis. Immunocompetent patients typically have disease that is limited to the skin, nails or mucosal surfaces.

Etiology

Trichosporon species ( asahii, mucoides, mycotoxinivorans and others) and the closely related Blastoschizomyces capitatus are related fungi that can occasionally cause disease in humans. For the purposes of this chapter, we will refer to these fungi collectively as Trichosporon species. These fungal organisms are commonly found in soil but can colonize the skin, hair shafts, sputum, and mucosal surfaces.

Pathology/Pathogenesis

Invasive infection from Trichosporon spp. is thought to begin with cutaneous and mucosal endogenous flora. Alteration of integrity of these surfaces by an intravascular catheter or chemotherapy-induced mucosal injury may lead to bloodstream infection. Some Trichosporon spp. can form biofilms on implanted devices.

Clinical Features (Symptoms/Physical Findings)

Disease in immunocompetent patients is usually limited to the superficial infections of the skin and hair shafts, particularly in tropical climates. Invasive infections are limited to immunocompromised patients, particularly in those with prolonged neutropenia. The resulting fungemia can lead to subsequent dissemination of the lungs. It is not known how often the lungs are the primary site of disseminated Trichosporon infection, as pulmonary disease is not consistently seen in these cases. In one study of immunocompromised adults with disseminated trichosporonosis, 26.9% were found to have pulmonary involvement. The typical clinical presentation in these cases included fever, dyspnea, cough, and hemoptysis. Renal involvement is also common and may initially manifest as microscopic hematuria or proteinuria. Disseminated Trichosporon infection is also associated with erythematous papules that can progress to bullae and necrotic lesions. Life-threatening disease can occasionally progress rapidly with hypotension, respiratory distress, and renal failure.

Imaging, Pulmonary Function Testing, Laboratory Findings

Chest radiographs in patients with pulmonary trichosporonosis infection typically show diffuse infiltrates with an alveolar pattern, although cavitary lesions and lobar consolidation have been described.

Diagnosis

Trichosporon species grow well on standard fungal media, although differentiating Trichosporon spp. from Candida spp. can be difficult. The importance of distinguishing these two organisms is highlighted by the observation that Trichosporon spp. has shown decreased susceptibility to amphotericin B. Distinguishing between the various Trichosporon species is typically not performed in most clinical laboratories. Disseminated infection can be diagnosed when Trichosporon species is isolated from a sterile site such as blood, CSF or lung tissue. Skin biopsies can be helpful when skin lesions are associated with disseminated infection. Diagnosis can also be made by fungal culture from BAL fluid. Given that Trichosporon species can colonize mucosal surfaces, isolation from sputum and tracheal cultures should be interpreted based on the clinical context. Pseudoinfections due to inadequately sterilized bronchoscopes has also been reported. Given that the genus Trichosporon is closely related to Cryptococcus, the C. neoformans polysaccharide antigen assay may be positive in patients with disseminated Trichosporon infection.

Management and Treatment

Patients with disseminated Trichosporon infection are typically severely immunocompromised. The degree of immunosuppression should be reduced if possible (e.g., GCSF administration, reducing glucocorticoids or other immunosuppressive medications). The azole class of antifungal drugs (particularly voriconazole) has good activity against Trichosporon spp., while significant resistance has been seen with amphotericin B based on in vitro susceptibility studies. The echinocandins are not active against Trichosporon spp.

Prognosis

Pulmonary infections due to disseminated trichosporonosis are associated with a high mortality rate. Patients who recover from their neutropenia have the best prognosis.

Epidemiology and Etiology

Hyalohyphomycosis is caused by a heterogeneous group of filamentous molds that produce hyaline (translucent) hyphae on microscopic examination of clinical tissue specimens. These organisms are ubiquitous molds that are found in the soil and can occasionally cause disease in immunocompromised hosts.

Fusarium spp. ( F. solani, F. oxysporum, and F. moniliforme ) are a group of filamentous fungi that have long been known to cause infections of the nails, skin, and cornea of humans. These organisms have more recently been recognized as an infrequent but important cause of sinusitis, pulmonary disease, and disseminated infection in patients undergoing chemotherapy and HSCT. Corticosteroid therapy has also been found to be an important predisposing factor in developing fusariosis. The respiratory tract is the primary portal of entry for disseminated infection, although access through vascular catheters has also been reported.

Talaromyces (formerly Penicillium ) marneffei is a dimorphic fungus that has been identified as an important opportunistic infection in HIV-infected patients who live in or have traveled to eastern Asia. The lungs are the likely portal of entry, as conidia from the environment convert to the yeast form prior to dissemination. Pulmonary alveolar macrophages are thought to be the primary pulmonary host defense and impaired cell-mediated and alveolar phagocytic function are the main predisposing risk factors in AIDS patients. In more recent years, T. marneffei has been associated with non-HIV immunosuppressive conditions, including various autoimmune diseases, SOTs, HSCT, T lymphocyte–depleting immunosuppressive drugs, and anti-CD20 monoclonal antibodies.

Pseudallescheria boydii and its asexual form, Scedosporium apiospermum, are fungi found in soil as well as polluted and stagnant water. In immunocompetent hosts, these organisms are an important cause of eumycetoma, a chronic granulomatous fungal disease of the subcutaneous tissues. Eumycetoma is rare in children and is typically seen in parts of Southeast Asia, Africa, and Central America. In immunocompromised hosts, disseminated disease can occur, with spread to the lungs or brain.

Pathology/Pathogenesis

The pathogenesis of hyalohyphomycosis has not been well defined, as these organisms are minimally pathogenic in normal hosts.

Clinical and Laboratory Features (Symptoms/Physical Findings)

The clinical features of hyalohyphomycosis are similar to those of IA, with sinus, pulmonary, cutaneous, and disseminated disease being seen. Fusarium spp. are best known as causes of sinusitis, pulmonary infections and fungemia. Chest imaging shows nonspecific alveolar or interstitial infiltrates, nodules, and cavities. Papular skin lesions with necrotic centers are common.

Disseminated T. marneffei infection can present with the clinical syndrome of fever, lymphadenopathy, hepatosplenomegaly, pulmonary infiltrates, weight loss, and anemia. Patients with disseminated infection can also develop a papular rash with central necrosis that can initially be mistaken for molluscum contagiosum. T. marneffei can mimic other infections such as tuberculosis, Pneumocystis jirovecii pneumonia, and cryptococcosis.

P. boydii (and its asexual form S. apiospermum ) are causes of pulmonary disease in immunocompromised patients and are associated with a high mortality rate. Children with CGD are known to be at increased risk of pulmonary infection with S. apiospermum. P. boydii has been reported to be an important cause of pneumonia in children with near-drowning events.

Diagnosis

Fusarium spp. is unusual in that it is the only mold that is commonly associated with fungemia. Fungal blood cultures are positive in 60%–82% of disseminated cases. Diagnosis can be made by isolation of the organism from culture of infected tissues. The diagnosis of T. marneffei and P. boydii is typically made by histopathology or fungal culture of bone, bone marrow, or biopsy tissue from skin or lungs.

The diagnosis of P. boydii (and S. apiospermum ) is also made by culture and histopathologic examination of tissue. The septate hyphae of P. boydii can be indistinguishable from those of Aspergillus hyphae.

Management and Treatment

Treatment for fusariosis includes amphotericin B or voriconazole. Combination antifungal therapy with amphotericin B or voriconazole showed no benefit when compared to those treated with monotherapy. Mortality from disseminated fusariosis has historically been greater than 50% despite antifungal therapy. Amphotericin B is the favored acute treatment of T. marneffei infection. After induction therapy, the patient can be transitioned to itraconazole as maintenance/suppressive therapy. P. boydii and S. apiospermum can be resistant to amphotericin B but are typically susceptible to voriconazole, posaconazole and itraconazole.

Epidemiology and Etiology

Phaeohyphomycosis refers to infections caused by a heterogeneous group of fungi (also known as the dematiaceous molds) that can occasionally cause invasive disease in immunocompromised hosts. More than 150 species have been identified as human pathogens, with the most important species causing invasive disease being S. prolificans, Bipolaris spp., Alternaria spp., Exophiala spp., and Curvularia spp. The agents of phaeohyphomycosis are ubiquitous filamentous molds that are found in the soil and characterized by their darkly pigmented cell walls, which include melanin (the prefix phaeo is derived from Greek meaning “dark”). As with many molds that are responsible for invasive human disease, the respiratory tract is the usual portal of entry for these fungi. Extrapulmonary dissemination is known to occur in immunocompromised patients. This group of organisms is also known to contribute to allergy in humans, including asthma and allergic fungal sinusitis. Various agents of phaeohyphomycosis (e.g., S. prolificans, Exophiala spp.) have been found to colonize the lungs of patients with cystic fibrosis, although it is unclear if these organisms play a role in the progression of this disease.

Clinical and Laboratory Features

Invasive infections are generally limited to immunocompromised hosts and localize to the sinuses, lungs, blood, CNS, skin and eyes. Bipolaris spp., Exophiala spp., Curvularia spp., and S. prolificans have been found to cause the majority of the cases of pneumonia and disseminated disease. The pulmonary manifestations of phaeohyphomycosis include lobar consolidation, asymptomatic solitary pulmonary nodules, and endobronchial lesions. Bipolaris spp. and Curvularia spp. are both known to cause fungal sinusitis.

Diagnosis

The primary method of diagnosis for all agents of phaeohyphomycosis is fungal culture and histopathologic examination of tissue. Microscopic examination is aided using Fontana-Masson stain, which will strongly stain the melanin within the conidia, spores, or hyphae. Even with proper staining, histopathologic interpretation can be difficult and may require referral to a mycology reference laboratory. No commercially available serologic, antigen or PCR assays are available for these organisms.

Management and Treatment

Therapy for invasive phaeohyphomycosis involves antifungal therapy and possible surgical resection of fungal lesions. In addition to diagnosis, isolation of the fungal pathogen allows for susceptibility testing to various antifungal agents. Amphotericin B has activity against many of the fungal organisms responsible for phaeohyphomycosis, although S. prolificans is usually resistant. Other antifungal agents with activity against certain organisms that cause phaeohyphomycosis include voriconazole, itraconazole, and posaconazole. Regardless of antifungal regimen, the mortality of disseminated invasive phaeohyphomycosis is greater than 70%.

Acknowledgments

The authors thank the following collaborators for their roles in obtaining radiographs and pathologic specimens used for the figures in this chapter: Richard M. Heller, Sharon M. Stein, and James D. Chappell. We also would like to thank Dennis O’Connor for his careful review of the manuscript.