Current Concepts in the Epidemiology, Diagnosis, and Management of Histoplasmosis Syndromes

Marwan M. Azar, MD; James L. Loyd, MD; Ryan F. Relich, PhD; L. Joseph Wheat, MD; Chadi A. Hage, MD

Disclosures

Semin Respir Crit Care Med. 2020;41(1):13-30. 

In This Article

Pulmonary Histoplasmosis

Acute Pulmonary Histoplasmosis

Clinical Findings. Most individuals exposed to H. capsulatum develop a subclinical or self-limited respiratory illness that does not prompt a health care visit. However, in immunocompromised, older (>50 years) or very young patients (<2 years), or following inhalation of a large inoculum, a flu-like illness comprising fevers, chills, shortness of breath, cough, and pleuritic chest pain ensues at a median of 2 weeks after exposure (Table 3). Given the similarity to community-acquired bacterial and viral pneumonia, antibiotics and antivirals are often prescribed. Lack of response to these antimicrobials should raise the possibility of acute pulmonary histoplasmosis. Acute pulmonary histoplasmosis may also be misdiagnosed as other granulomatous pulmonary processes including mycobacterial disease, lymphoma, and sarcoidosis. In some cases (~5%), rheumatologic, cardiac, and cutaneous manifestations including arthritis, pericarditis, erythema nodosum, and erythema multiforme can occur but these represent a sterile inflammation as part of a systemic response rather than disseminated disease. The most common radiographic pattern of pneumonia is of diffuse bilateral patchy infiltrates along with mediastinal and hilar lymphadenopathy (Figure 5). In cases of dissemination outside of the lungs, laboratory testing may reveal elevated liver function tests, pancytopenia, and lymphocytic pleocytosis on CSF evaluation, suggesting involvement of the liver, bone marrow, and CNS, respectively. In immunocompetent patients, dissemination is usually abrogated by development of a vigorous cellular immune response to H. capsulatum, whereas in frankly immunocompromised hosts, PDH may develop. Unrecognized disease and delays in diagnosis are associated with increases in morbidity and mortality.[66,67]

Figure 5.

Acute Histoplasmosis. A previously healthy middle-aged construction worker presented with fever, arthralgia, dyspnea, and bilateral interstitial infiltrates on chest radiograph, 1 week following demolition of an old building. He rapidly progressed to hypoxic respiratory failure requiring mechanical ventilation. Histoplasma serology was negative, but serum and urine antigen were strongly positive. BAL analysis showed predominant neutrophils and yeast that were consistent with Histoplasma; cultures grew Histoplasma capsulatum. BAL, bronchoalveolar lavage.

Diagnosis. The diagnosis of acute pulmonary histoplasmosis can be rapidly made by cytopathologic examination of BAL for evidence of small narrow-budding yeast though this approach is only 50% sensitive and depends on the burden of disease. Respiratory cultures are sensitive but since H. capsulatum is slow growing (2–6 weeks), this method is not practical for rapid diagnosis. Antigen testing in the urine and/or serum has become increasingly useful for diagnosis due to good sensitivity (83%) and its noninvasive nature.[48,49] When the pretest probability for histoplasmosis is high, sending both urine and serum antigen increases the predictive value of detection. Antigen testing on BAL fluid is an adjunctive test that can identify cases missed by BAL cytopathology and peripheral antigen testing.[33] Serology is usually negative in the acute setting and is therefore less useful for the diagnosis of acute histoplasmosis. Seroconversion on a paired specimen obtained approximately 4 weeks after presentation may establish the diagnosis retrospectively.

Management. Patients with moderate or severe acute histoplasmosis as evidenced by the severity of symptoms and/or radiographic findings and immunocompromised individuals should receive treatment to prevent disseminated disease.[51,68] In patients with acute respiratory distress syndrome, adjunctive corticosteroids (intravenous methylprednisolone at a dose of 0.5–1.0 mg/kg/d) are recommended along with antifungal therapy (Table 4).[69] Liposomal amphotericin B is preferred over the conventional formulation because of better outcomes in patients with HIV/AIDS who had disseminated histoplasmosis.[70] In patients with mild disease, itraconazole alone is appropriate. Most cases of acute histoplasmosis without dissemination can be treated with a 12-week course of antifungals.

Subacute Pulmonary Histoplasmosis

Clinical Findings. This syndrome is characterized by milder respiratory symptoms protracted over weeks to months and usually develops following exposure to smaller inocula. On physical examination, hepatosplenomegaly and oral ulcers may sometimes be noted. Chest X-rays most commonly demonstrate focal opacities along with hilar and mediastinal adenopathy, though diffuse infiltrates also occur (Figure 6). The diagnosis is often overlooked and the syndrome resolves without therapy.

Figure 6.

Subacute Histoplasmosis. A patient presented with cough, exertional dyspnea, low-grade fever, and right lower lobe infiltrates and hilar adenopathy that failed to improve after receiving two courses of antibiotic therapy for community-acquired pneumonia. Fungal serology was positive with H and M bands on immunodiffusion and yeast complement fixation titer of 1:64. Histoplasma antigen was detected in the BAL fluid. BAL, bronchoalveolar lavage.

Diagnosis. Serology is central to the diagnosis of subacute pulmonary histoplasmosis as antibodies are most commonly positive by the time patients present for evaluation. Antigen testing is less sensitive with only 40% of cases positive for antigenuria.[48] Testing of BAL for antigen can be considered. Endobronchial ultrasound (EBUS) with transbronchial needle aspiration can be used to support a diagnosis of subacute pulmonary histoplasmosis in patients with a high degree of clinical suspicion.[71] Lung or mediastinal lymph node biopsies can clinch the diagnosis but are rarely needed in the presence of positive serology.

Management. This form of histoplasmosis is usually self-limited and does not require treatment. If symptoms persist beyond 1 month, itraconazole can be administered for 6 to 12 weeks to prevent development of progressive disseminated disease.

Chronic Pulmonary Histoplasmosis

Clinical Findings. Chronic pulmonary histoplasmosis is a slowly progressive process that most commonly affects older patients (with male predominance) with underlying structural lung disease or a history of smoking. Other risk factors include white race and immunosuppression.[72] The syndrome resembles other chronically destructive pneumonias including tuberculous and nontuberculous mycobacterial infections, and other fungal infections such as semi-invasive chronic pulmonary aspergillosis and chronic pulmonary coccidioidomycosis or blastomycosis (Figure 7). In addition to respiratory symptoms (productive cough, dyspnea, and pleuritic chest pain), constitutional symptoms including fever, night sweats, and weight loss may occur in a progressive or waxing and waning course. Chest imaging demonstrates areas of cavitation, fibrosis, and pleural thickening, which are in a predominantly upper lobe distribution. Infiltrates may surround pre-existing emphysematous bullae mimicking true cavitation, a pattern referred to as a "bullitis." Mediastinal and hilar lymph nodes are often calcified but not necessarily enlarged.[72] With time, volume loss and hilar retraction may ensue as a result of chronic destructive inflammation.[73] The pathophysiology appears to be primarily driven by a maladaptive immune response to fungal antigens, leading to fibrosis, necrosis, and tissue compromise rather than direct fungal virulence.[73]

Figure 7.

Chronic Histoplasmosis. A 68-year-old man active smoker with severe chronic obstructive pulmonary disease presented with 3 months of progressive cough and sputum production that worsened despite antibiotics and steroids. Chest radiograph showed right upper lobe cavitary disease. Fungal cultures of sputum grew H. capsulatum.

Diagnosis. As with acute pulmonary histoplasmosis, testing for antigenemia and antigenuria often clinches the diagnosis. Testing BAL fluid for antigen is a useful adjunctive test.[51] Isolation of H. capsulatum from sputum or BAL specimens is often made. Serology is very useful in this setting and forms the basis for diagnosis in 25% of cases.

Management. All patients with chronic pulmonary histoplasmosis should receive treatment to abrogate progressive destruction of lung tissue. Treatment is associated with fungal clearance from sputum, decreased mortality, and regression of the pulmonary infiltrates in two-thirds of cases.[74] Treatment with itraconazole is indicated for 12 to 24 months but should also be maintained until there is no further improvement on chest imaging, obtained every 6 months. Drug-level monitoring is recommended to ensure therapeutic levels. After treatment completion, patients should be monitored for 1 to 2 years to capture relapsed disease (10–20% of cases).[75]

Pulmonary Nodules

Clinical. Pulmonary nodules seen on chest imaging are common findings among individuals residing in areas endemic for histoplasmosis. The majority are noted incidentally and patients are typically asymptomatic as they represent healed infection that contains no live organisms.[76,77] Histoplasmosis is in fact the most common cause of noncancerous granulomatous nodules and masses in endemic regions.[78]

Diagnosis.: Positron emission tomography (PET) is often used as part of this workup but PET radionuclide uptake is often similarly increased in both malignancy and infection.[79] Newer imaging modalities with modified radionuclide uptake intensity and timing have been developed to differentiate infectious from malignant lung nodules. In a recent study of 72 patients with lung nodules, a delayed radionuclide uptake (1 hour after the initial scan) was highly associated with malignancy (positive predictive value: 80%; negative predictive value: 100%).[80] Application of this imaging technology can be helpful in the workup of lung nodules in patients who reside in endemic areas, sparing them invasive procedures and potentially reducing procedure-related morbidity and cost.

Biopsies of pulmonary nodules via transthoracic fine-needle biopsy or surgical excision are often performed to exclude malignancy[81] (Figure 8), particularly when dealing with larger nodules (>1 cm) and in those with risk factors for cancer such as smoking history. For smaller nodules, serial imaging can be done to follow for enlargement. On histopathology of Histoplasma-associated nodules, both caseating and noncaseating granulomas can be found. Pathologic examination may reveal yeast forms but cultures are rarely positive as the organisms are usually nonviable.[76,77] Anti-Histoplasma antibodies may be detected in some patients, usually at low CF titers (1:8–1:16). Tests for antigen are usually negative.

Figure 8.

Pulmonary nodules. Lung nodule found on a screening chest CT of a 53–year-old man from Indiana. Biopsy showed no malignancy and demonstrated granulomas containing yeast consistent with H. capsulatum. Histoplasma serology via complication fixation was 1:16. CT, computed tomography.

Management. Asymptomatic pulmonary nodules do not require treatment (Table 4). When dealing with nodules that are found in conjunction with acute or chronic pulmonary histoplasmosis, antifungal therapy may be appropriate.

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