Pulmonary Pathology

Acute Pulmonary Histoplasmosis

Sanjay Mukhopadhyay
SUNY Upstate Medical University
Syracuse, NY


Clinical History:
A 45-year-old previously healthy man presented with a 7-day history of daily high fever, severe headache, malaise, nausea, vomiting, myalgia, dyspnea and overwhelming fatigue. On examination, he was found to be febrile and hypoxic. A chest X-ray and subsequent chest CT showed diffuse bilateral reticulonodular infiltrates. Video-assisted wedge biopsies of the right lung were performed.

The patient was one of five construction workers involved in the removal of moldy dry wall, carpet and insulation in a house where the roof had collapsed and sustained water damage from melting snow. The construction work took place over a 5-6 week period, ending 2 days prior to onset of symptoms. All coworkers had presented around the same time period to emergency rooms in the same city with a similar acute illness.

Subsequent cultures from biopsied lung tissue grew Histoplasma capsulatum. Histoplasma serologies were negative in our patient, although one other worker converted to seropositive status and another was seropositive with rising titers. Our patient was treated with itraconazole for 12 weeks. His symptoms resolved within 3 days of initiating therapy. The radiographic abnormalities cleared dramatically within 2 weeks and resolved completely over a 6-week period.


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Diagnosis:
Acute pulmonary histoplasmosis

Discussion:
Lung involvement in histoplasmosis occurs in 4 forms. The diagnosis of a specific form of histoplasmosis is based on clinical and radiographic findings in the presence of serologic, microbiologic or pathologic evidence of Histoplasma infection. The 4 forms of pulmonary histoplasmosis are as follows:
  1. Acute pulmonary histoplasmosis

  2. Chronic pulmonary histoplasmosis

  3. Histoplasmoma

  4. Disseminated histoplasmosis
The type of histoplasmosis that develops in a given individual depends on the number of organisms inhaled, the duration since infection and the immune status of the host. In the vast majority of immunocompetent individuals, inhalation of Histoplasma spores (conidia) results in asymptomatic infection. Inhalation of large numbers of organisms may lead to a flu-like pneumonic illness known as acute pulmonary histoplasmosis. Both asymptomatic infection and acute pulmonary histoplasmosis usually resolve without sequelae. In some patients, however, the organisms are not completely cleared. Instead, they are contained, and usually rendered non-viable, within a well-formed necrotizing granuloma known as a histoplasmoma. In other individuals, usually with underlying structural lung disease, the infection is neither cleared nor contained, but instead progresses to a tuberculosis-like chronic illness known as chronic pulmonary histoplasmosis. Finally, in immunosuppressed individuals, organisms proliferate unhindered within macrophages and disseminate widely through the bloodstream resulting in a potentially fatal condition known as disseminated histoplasmosis.

Most pathologists in the United States are familiar with the classic well-formed necrotizing granuloma that characterizes a histoplasmoma. Chronic pulmonary histoplasmosis is less commonly encountered, but also features well-formed necrotizing granulomas. The Histoplasma-laden histiocytes of disseminated histoplasmosis are also well recognized by most pathologists. However, acute pulmonary histoplasmosis remains poorly recognized, mainly because it is rarely biopsied. For the same reason, there are only a handful of descriptions in the literature on its pathologic findings.

Clinical Presentation
Patients with acute pulmonary histoplasmosis present with an acute flu-like illness characterized by fever, systemic symptoms such as malaise, weakness and headache and non-specific respiratory symptoms such as cough, dyspnea and chest pain. The interval between exposure and development of symptoms is usually 1-3 weeks. The duration of symptoms is short, typically only a few days. In some patients, the source of exposure to Histoplasma organisms may be obvious from a detailed clinical history. Such sources may include a bat-infested cave, construction site, chicken coop, starling roost, golf course or any other site littered with bird or bat droppings. A helpful clinical clue, when present, is a history of an outbreak of a similar illness in other individuals exposed to the same source.

Radiographic Findings
Radiographs in acute pulmonary histoplasmosis show bilateral infiltrates, variously described as "miliary", "reticulonodular", "nodular" or "airspace". Mediastinal lymph nodes are often enlarged. Solitary calcified nodules typical of histoplasmoma or cavitary nodules typical of chronic pulmonary histoplasmosis are not encountered in acute pulmonary histoplasmosis.

Serology
In most cases of acute pulmonary histoplasmosis, serology provides the only evidence of Histoplasma infection. However, since antibodies to Histoplasma form 4-6 weeks after exposure, serology may be negative early in the course of the disease. Titers peak at around 6 weeks. Proof of seroconversion may require measurement of serial titers for up to 12 weeks. In acute pulmonary histoplasmosis, urine antigen is positive in 75-80% of cases, serum antigen in 50% and serum antibodies in 40-90%. A small but significant proportion of patients remain seronegative despite clinical, radiographic and/or microbiologic evidence of infection.

Cultures
The yield of cultures is better in acute pulmonary histoplasmosis than in histoplasmomas, probably because organisms are viable in the former but only rarely so in the latter. Organisms are isolated in approximately 40% of cases of acute pulmonary histoplasmosis. Samples that may yield growth include biopsied lung, sputum, bronchial washings, bronchoalveolar lavage fluid and pleural fluid. Since transient dissemination occurs even in immunocompetent persons, Histoplasma can sometimes be cultured in acute pulmonary histoplasmosis from extrapulmonary sites such as bone marrow or blood.

Pathologic Features
The histologic features of acute pulmonary histoplasmosis have not been adequately described. There are only isolated reports in the literature with any description of the pathologic findings.

Acute pulmonary histoplasmosis is characterized by a lymphohistiocytic (mononuclear) infiltrate that fills the alveolar spaces but also involves alveolar septa (interstitium). At low magnification, the infiltrate may be nodular or diffuse, and consists of an admixture of lymphocytes, histiocytes and fibrin. Intra-alveolar fibrin is always present and may be prominent. At places, histiocytes palisade around foci of necrosis, forming ill-defined necrotizing granulomas. Scattered multinucleated giant cells may be present. Well-formed granulomas are absent. The necrotic foci may be small and scattered or large, extensive and infarct-like. The inflammatory infiltrate may extend into bronchiolar lumens. The interstitium is variably thickened by lymphocytes, histiocytes and occasional plasma cells. There may be an associated vasculitis consisting of lymphocytes and histiocytes, and involving small to medium sized blood vessels. A necrotizing vasculitis is not found. Diagnosis rests on demonstration of Histoplasma yeasts. As with histoplasmomas, organisms are not visible on H&E-stained sections, but can be demonstrated by silver stains such as Grocott's methenamine silver (GMS). The morphology of the organisms is identical to that seen in other forms of histoplasmosis; i.e., they are small, uniform, round to oval yeasts, occasionally with ends that taper to a point (ovate). Narrow-based budding may be present but is difficult to find unless organisms are numerous. The number of organisms varies from case to case, from a few to plentiful. Organisms are scattered within the inflammatory and fibrinous exudate and are more numerous in necrotic areas.

Differential Diagnosis
The differential diagnosis of acute pulmonary histoplasmosis includes other forms of histoplasmosis as well as other disorders characterized by a lymphohistiocytic infiltrate.

In chronic pulmonary histoplasmosis, symptoms are present for months rather than days and pathologic examination shows well-formed necrotizing granulomas in contrast to the diffuse lymphohistiocytic infiltrate of acute pulmonary histoplasmosis. Histoplasmomas usually cause no symptoms, form discrete nodules on radiographs and are characterized pathologically by well-formed necrotizing granulomas. Disseminated histoplasmosis occurs in immunocompromised patients and is characterized by Histoplasma-laden histiocytes. Disseminated histoplasmosis is the only form of histoplasmosis in which organisms are easily seen within histiocytes on H&E-stained sections.

Pneumocystis pneumonia occurs as a granulomatous variant in 1-5% of cases, and the appearance may be reminiscent of acute pulmonary histoplasmosis. A GMS stain may reveal yeast-like fungal forms similar to Histoplasma yeasts within airspaces. The clinical setting is a clue to the diagnosis, since most patients with pneumocystis pneumonia are immunocompromised while acute pulmonary histoplasmosis mainly affects immunocompetent people. On silver stains, pneumocystis organisms show crescent and half-moon shapes while Histoplasma yeasts often taper to a point and may show narrow-based budding.

Lymphomatoid granulomatosis (LYG) is an important entity to consider in the differential diagnosis. It resembles acute pulmonary histoplasmosis because of the presence of a lymphohistiocytic infiltrate with vascular infiltration. Vascular involvement in LYG is more striking than in acute pulmonary histoplasmosis, with numerous cells infiltrating vessel walls. Also, in acute pulmonary histoplasmosis, there are usually foci where histiocytes palisade around areas of necrosis forming identifiable granulomas, while in LYG, the histiocytic infiltrate is more poorly formed and does not aggregate into granulomas. Confirmation of the diagnosis requires demonstration of EBV-infected B-cells (in LYG) or fungal organisms (in acute pulmonary histoplasmosis).

Treatment
Most cases of acute pulmonary histoplasmosis are self-limited and resolve without antifungal therapy. Current guidelines recommend initiation of amphotericin B for patients with moderate to severe disease and itraconazole for those with mild disease who continue to have symptoms for more than a month.

Summary
Acute pulmonary histoplasmosis is the earliest form of symptomatic pulmonary histoplasmosis. It is infrequently biopsied because diagnosis is usually based on clinical and serologic grounds, including acute respiratory and systemic symptoms, diffuse bilateral infiltrates and serologic or microbiologic evidence of Histoplasma infection. The pathologic findings must be distinguished from other forms of histoplasmosis, other infections such as granulomatous pneumocystis pneumonia and non-infectious lung diseases such as lymphomatoid granulomatosis.

Acknowledgments
The author would like to acknowledge Dr. Shea Eckardt (Fellow in the Department of Pulmonology and Critical Care Medicine, State University of New York Upstate Medical University) for graciously providing details of the clinical information.

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