Pediatric Histoplasmosis Clinical Presentation

Clinical presentations of histoplasmosis vary depending on the size of the inoculum, the host's immune status, and the presence of underlying lung disease. Overt symptoms occur in 5% of individuals after low-level exposure, but the rate of a clinical disease exceeds 75% after heavy exposure in healthy hosts. The incubation time of acute histoplasmosis in previously nonimmune individuals is 9-17 days.

In a description of a recent large outbreak associated with disturbing soil during school hours at a high school, 77% of all students and staff tested demonstrated evidence of recent infection, and 68% of these developed symptoms of acute pulmonary histoplasmosis. Peak onset of illness occurred 14 days after presumed exposure. ^{[3, 4]}

In 80% of patients, symptoms are nonspecific and include fever, chills, myalgias, nonproductive cough, and chest pain. This acute syndrome can range from mild (lasting 1-5 d) to severe (lasting 10-21 d); the latter is associated with weight loss, fatigue, and night sweats. Fatigue may persist for weeks after the acute symptoms resolve.

• Syndromes in immunocompetent hosts

  • Severe acute pulmonary syndrome: After exposure to a large inoculum, patients may develop severe acute pulmonary syndrome, which is characterized by a flulike prodrome with severe fever, chills, fatigue, cough, and chest pain followed by dyspnea and hypoxemia. This hypoxemia may progress to an adult respiratory distress syndrome (ARDS)–like illness (see the image below).

    Acute pulmonary syndrome in a 16-year-old female adolescent.

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  • Histoplasmoma: Histoplasmosis occasionally manifests as a single pulmonary parenchymal nodule, which is observed as a coin lesion on chest radiographs. This nodule is often asymptomatic.

  • Mediastinal obstructive syndromes (granulomatous mediastinitis)

    • Mediastinal lymph node enlargement occurs in most patients with histoplasmosis (see the image below).

      Hilar lymphadenopathy in an 11-year-old child.

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    • In 5-10% of patients with acute pulmonary syndromes, these nodes may be large enough to obstruct contiguous structures, such as airways, esophagus, and large blood vessels. Airway obstruction can lead to a dry or productive cough and dyspnea. In rare cases, erosion of infected nodes into airway walls can lead to hemoptysis, air leak syndromes, broncholithiasis, or lithoptysis.

    • Esophageal obstruction can cause dysphagia. Airway-esophageal fistulas are reported complications of mediastinal involvement with histoplasmosis. Obstructed pulmonary arteries can produce symptoms of mitral valve obstruction.

    • Fibrosing mediastinitis is a late complication of mediastinal granuloma, in which sustained and exaggerated fibrosis entraps and impinges on mediastinal structures (see the image below), which may result in venous obstruction.

      Fibrosing mediastinitis with mediastinal widening and tracheal deviation.

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    • Fibrosing mediastinitis represents a fibrotic response to a previous episode of histoplasmosis, and some suggest that certain individuals are predisposed to excessive fibrotic responses to Histoplasma antigens. Nonresponses to antifungal treatment and rare isolations of H capsulatum tissue samples indicate that ongoing infection is not likely to play an important role. Presenting symptoms can include cough, dyspnea, wheezing, hemoptysis, dysphagia, and superior vena cava (SVC) obstructive syndrome. In a subset of patients, the process is progressive, leading to death from cor pulmonale or respiratory failure.

  • Pericarditis: Pericarditis usually results from inflammation in contiguous lymph nodes rather than from fungal infection of the pericardial space and occurs in as m any as 10% of patients with symptomatic acute disease. ^[5] Pericarditis with true infection of the pericardium occasionally occurs in disseminated histoplasmosis.

  • Rheumatologic syndrome: A syndrome of arthritis, arthralgias, and erythema nodosum is observed in as many as 10% of patients with acute infection. This syndrome is much more common in women than in men. Joint symptoms can persist for months. In an epidemic in the Midwestern United States that occurred in the 1980s, 24 of 381 (6.3%) patients with symptomatic histoplasmosis had rheumatologic symptoms, primarily arthritis or arthralgia. ^[6] Of these, 46% had erythema nodosum.

• Syndromes in hosts with an underlying illness or immunodeficiency

  • Chronic pulmonary histoplasmosis (CPH): CPH most commonly occurs in adults with underlying lung disease (eg, chronic obstructive pulmonary disease [COPD]) and represents 10% of symptomatic cases. Concurrent neoplasia is not uncommon. CPH is rare in children. The presentation of CPH is similar to that of pulmonary tuberculosis. Most patients have productive cough, dyspnea, or chest pain. Systemic symptoms, such as fatigue, fever, and night sweats, are common. The clinical course of untreated CPH is progressive, with spread to contiguous lung. Complications, such as hemoptysis and bronchopleural fistulae, may ensue. Other infections, such as mycobacterial and other fungal infections (eg, aspergillosis), can coexist.

  • Progressive disseminated histoplasmosis (PDH)

    • PDH can occur in infants who are immunocompetent but is most likely to affect patients with underlying disorders of cell-mediated immunity. In endemic areas, histoplasmosis accounts for 5% of opportunistic infections among individuals with AIDS and may account for 25% in hyperendemic areas. ^[7] The incidence of histoplasmosis among individuals with AIDS in the United States has declined because of widespread use of antiretroviral therapy. Disseminated histoplasmosis in a patient with HIV can be an AIDS-defining illness. PDH also occurs in individuals with Hodgkin disease or lymphoreticular malignancies or in those receiving immunosuppressive therapy.

    • In children, the incidence of disseminated histoplasmosis appears to have decreased over the past 3 decades. The onset of PDH can be insidious, with low-grade fever, weight loss, malaise, and oropharyngeal ulcerations. In patients with severely impaired cellular immunity, the presentation of PDH may be acute and rapidly progressive. Presenting symptoms include severe fever, GI symptoms, hepatosplenomegaly, and pancytopenia. In patients with underlying rheumatic disease, this may mimic Felty Syndrome.

    • Multiorgan system failure and coagulopathy can rapidly ensue. Adrenal involvement is common in PDH (80-90% of patients), and 15% of patients have overt adrenal insufficiency. ^[8]

  • Local manifestations of disseminated disease: Histoplasmosis may include genital ulcers, epididymitis, phimosis, orchitis, cystitis, cholecystitis, pancreatitis, soft-tissue nodules, nodular myositis, panniculitis, carpal tunnel syndrome, osteomyelitis, arthritis, and hypercalcemia. The occurrence of ocular histoplasmosis is controversial because this clinical entity is described in patients who reside exclusively in areas where histoplasmosis in not endemic. ^[9]

  • CNS histoplasmosis: Meningitis is a complication in 10% of patients with disseminated disease but occasionally occurs in patients who are immunocompetent. ^{[5, 10, 11]} Symptoms are usually indolent and chronic; examples include fever, headache, and changes in mental status. Seizures and focal neurologic deficits can occur. Localized lesions in the brain occur in one third of patients with CNS involvement, and isolated spinal cord lesions have been reported.

  • Adrenal disease: This may occur as a manifestation of relapsing histoplasmosis several years after the initial episode. Concurrent CNS involvement is common in patients with adrenal involvement. Histoplasmosis should be excluded in all patients with adrenal insufficiency or adrenal masses, and CT scanning to examine the adrenal glands should be considered in patients with disseminated histoplasmosis.

  • Endocarditis: This is reported in 4% of patients with disseminated histoplasmosis, and mostly presents with embolic episodes. ^[5]

See the list below:

• Syndromes in immunocompetent hosts

  • Severe acute pulmonary syndrome: Physical findings are similar to those of diffuse pneumonitis and include increased work of breathing, nasal flaring, accessory muscle use, and diffuse fine crackles. Pleural involvement can present with pleural friction rub or with diminished breath sounds and dullness to percussion.

  • Mediastinal obstructive syndromes: Obstruction of central airways can produce inspiratory and expiratory wheezes, which may be monophonic and localized. Findings in SVC syndrome include facial swelling, distension of the veins of the neck and upper chest wall, conjunctival injection, and loss of venous pulsations. Pulmonary venous occlusion produces findings consistent with mitral valve stenosis, including a low-pitched diastolic apical murmur.

  • Pericarditis: Physical findings include chest/abdominal pain, pericardial friction rub, and fever. Signs of hemodynamic compromise can be observed in 40% of patients. ^[5]

  • Rheumatologic syndrome: In a subset of patients, symmetric polyarticular arthritis and erythema nodosum may be seen.

• Syndromes in hosts with an underlying illness or immunodeficiency

  • CPH: Crackles, wheezes, and diminished breath sounds may be heard. Other physical findings are similar to those observed in chronic lung disease. Examples are cyanosis and digital clubbing.

  • PDH: Patients usually have respiratory distress, inanition, cachexia, pallor, and hepatosplenomegaly. Subcutaneous nodules may be present, as may signs of localized infection in almost any tissue or organ.

See the list below:

• The spores of H capsulatum (microconidia) become airborne when soil is disturbed.

• High numbers of spores are present in microfoci of soil heavily contaminated with bird or bat droppings, such areas as under bird roosts or in caves (see the image below).

  Starling roost in Alabama.

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• Urban and suburban outbreaks in endemic areas are often associated with large-scale construction or cleaning projects in which soil is disturbed. A recent large outbreak at a high school was associated with roto-tilling soil under a known bird roost during school hours. ^[3]

• The microconidia (1-5 µm in diameter) are easily inhaled and deposited in distal air spaces.

• At body temperature, proliferation of the yeast (infective) form of the organism occurs within 3-5 days.

• Histoplasmosis can occur in almost all mammals. Although the fungus thrives in bird droppings, birds are not infected. However, bats can be infected with H capsulatum. Direct animal-to-human or human-to-human transmissions are not thought to occur.