Rudolph's Pediatrics, 22nd Ed.

CHAPTER 300. Histoplasmosis

Martin B. Kleiman

Histoplasmosis, the most common endemic fungal infection in the United States, is caused by a thermal dimorphic fungus, Histoplasma capsulatum.1,2 The spore-bearing mold form grows in the environment at temperatures less than 35°C and is commonly found in the Mississippi River and Ohio River basins of the United States (eFig. 300.1 ). The extent and degree of environmental contamination with the mold is augmented by bird and bat droppings; the latter may contain fungal spores as well as provide factors that stimulate mold growth.

Epidemiologic surveys of histoplasmin skin test reactivity in endemic areas show progressive increases with age. Infections occur as sporadic cases in communitywide outbreaks3,4 when dry, windy conditions facilitate aerosolization of spores and as localized clusters caused by disturbance of heavily contaminated microenvironments.5 Such hyperendemic foci include soil in sites of bird roosts; bat-infested caves; rotting logs; and the attics, wall insulation, and fireplaces of old structures6 (eTable 300.1 ).

Infection begins following inhalation of microaeruliospores, which convert in the alveoli to the yeastlike invasive forms of the fungus. This results in a focus of acute pneumonitis and regional hilar adenitis. In addition to this primary focus, yeast forms also disseminate lymphohematogenously to the reticuloendothelial organs; normal cellular immune mechanisms abort further progression in the vast majority of cases. Following the development of specific cellular immunity, inflammatory changes become granulomatous with typical Langhans-type giant cells; fibrosis and calcification may ultimately ensue. Although humoral immunity develops in response to infection, antibody does not play a significant role in recovery and is not protective.

 CLINICAL MANIFESTATIONS

The type and severity of symptoms reflect both the intensity of exposure and the adequacy of the host’s cellular immune response.7 Primary infection is asymptomatic in 99% of normal hosts who are lightly exposed. Most of the remainder develop nonspecific, transient, flulike respiratory symptoms. Infection is symptomatic in about half of otherwise normal patients who are more heavily exposed. In these patients, fever, cough, and chest pain are common symptoms; chest radiographs often show focal pneumonitis and/or hilar adenopathy. Symptoms are almost always self-limited in otherwise healthy patients and resolve within 2 weeks without treatment. Infrequently, the fever, weight loss, and fatigue persist, and antifungal therapy is required. Intense exposure of immunocompetent hosts can cause severe, life-threatening illness characterized by persistent fever, respiratory distress, diffuse reticulonodular chest infiltrates, and sometimes progressive fungal dissemination.7,8

Abnormalities of cellular immune function, whether primary, acquired, or resulting from the relative immaturity of infancy, are risk factors for progressive disseminated histoplasmosis. Patients receiving tumor necrosis factor inhibitors are at high risk for disseminated infections.9 Patients with unreconstituted HIV infection are also at high risk.10-12 Severe and disseminating infection can follow primary exposure or result from reactivation of a previously quiescent focus. An immune reconstitution syndrome, in which symptoms of infection follow the administration of effective highly active antiretroviral therapy, has also been recognized.13 Illness usually begins with isolated fever and weight loss; if untreated, skin lesions, diffuse pulmonary infiltrates, mucosal ulcerations, pancytopenia, and coagulopathy may ensue. This manifestation of histoplasmosis is fatal if untreated.

The relative immaturity of cellular immunity in otherwise normal infants may predispose them to disseminated histoplasmosis of infancy, a rare but life-threatening infection of children younger than 2 years of age.15 In these infants, despite what may be relatively minimal exposure to Histoplasma spores, there is progressive dissemination and heavy parasitization of the reticuloendothelial system. The onset of symptoms is usually insidious with only failure-to-thrive, variable fever, absent toxicity, and progressive hepatosplenomegaly. After about 4 to 6 weeks, pancytopenia and coagulopathy occur. Mucosal and gastrointestinal ulcerations and hemorrhage16 often accompany late symptoms; meningitis15 is common. Chest radiographic abnormalities may remain absent. Disseminated histoplasmosis of infancy is fatal if untreated. Additional manifestations of histoplasmosis are shown in eTable 300.2 .

 DIAGNOSIS

The majority of infections are subclinical or self-limited and do not require laboratory confirmation. The recognition of chest radiographic findings of typical granulomas in otherwise well children who reside in endemic areas infrequently requires laboratory confirmation. Laboratory diagnosis17 is needed to evaluate patients with symptoms that may mimic those caused by other pathogens, especially Mycobacterium tuberculosisBlastomyces dermatitidis, or other causes of granulomatous inflammation. Laboratory diagnosis is also used to noninvasively differentiate histoplasmosis from neoplasm in patients residing in endemic areas who present with hilar or mediastinal adenopathy.18Confirmation of the diagnosis is indicated for patients in whom antifungal therapy is indicated.

Interpretive guidelines for the laboratory evaluation of children with suspected histoplasmosis are summarized in eTable 300.3 . Laboratory tests used to diagnose histoplasmosis include culture, histopathologic examination of biopsy specimens, serologic testing, and histoplasmin detection and quantification.19,20 Direct observation of typical yeast forms in tissue or body fluids and/or isolation of the fungus in culture are diagnostic. The blood, bone marrow, and urine are potential sites from which the organism can be isolated, but cultures are usually negative in mild or moderately severe infections. Disadvantages of these methods are their low sensitivities, a delay of 2 weeks required to isolate the fungus in culture, and the need for an invasive procedure to obtain tissue.19

Table 300-1. Indication for Antifungal Therapy

Definite indication, proven or probable efficacy

Acute diffuse pulmonary infection, moderately severe symptoms, or severe symptoms

Chronic cavitary pulmonary infection

Progressive disseminated infection

Central nervous system infection

Uncertain indication, unknown efficacy

Acute focal pulmonary infection, asymptomatic case, or mild symptoms that persist for < 1 month

Mediastinal lymphadenitis

Mediastinal granuloma

Inflammatory syndromes, treated with corticosteroids

Not recommended, unknown efficacy or ineffective

Mediastinal fibrosis

Pulmonary nodule

Broncholithiasis

Presumed ocular histoplasmosis syndrome

The sensitivity and specificity of antibody and antigen assays are variable. Serologic tests are used most frequently for diagnosis. A single complement-fixation (CF) titer of less than 1:16 to either the yeast or mycelial phase antigen, or the detection of H or M bands by the immunodiffusion method, strongly suggests acute or recent infection. Disadvantages of both serologic tests are that they cross-react with other fungal antibodies, may remain elevated for 18 months or longer following infection, or may be falsely negative in immunocompromised patients. A quantitative enzyme immunoassay (EIA) that measures histoplasmin concentration in urine, serum, and cerebrospinal fluid is an important rapid diagnostic test.20 The EIA is often positive very early in self-limited infection and almost always in serious manifestations,21 especially in progressively disseminating infections. The EIA may also be used to monitor the effectiveness of treatment.

 TREATMENT

Most patients with histoplasmosis improve without antifungal therapy, and the strength of the evidence supporting the use of these agents is strongest for only the most serious manifestations (Table 300-1). Antifungal treatment is required for severe and/or progressively disseminating infections and for patients with primary or acquired cellular immune dysfunction. It is also used for patients with prolonged symptoms (usually exceeding 2–4 weeks); however, evidence for this indication is uncertain. Evidence-based treatment guidelines have been published7 (eTable 300.4 ). Rheumatologic or hypersensitivity symptoms, such as arthritis, pericarditis, or erythema nodosum usually improve with supportive treatment. Pericarditis usually responds promptly to indomethacin.

Amphotericin B is the first antimicrobial agent found effective for treating serious manifestations of histoplasmosis. It is the initial agent used for treating severe infections because it results in more rapid improvement than do newer agents. Itraconazole is also effective for treating histoplasmosis and has the advantages of an oral route of administration and few side effects.

A brief course of steroids is often a useful adjunctive treatment for patients in whom acutely inflamed lymph nodes impinge on or obstruct adjacent structures. Effective antifungal agents should always be used concomitantly and the patient carefully monitored for signs of progressive dissemination while receiving steroids.