Case 4 -
Acute Pulmonary Histoplasmosis
SUNY Upstate Medical University
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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
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.
Case 4 - Slide 1
Acute pulmonary histoplasmosis
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:
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.
- Acute pulmonary histoplasmosis
- Chronic pulmonary histoplasmosis
- 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
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
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.
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
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
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.
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).
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.
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.
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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