Primary Pulmonary Histoplasmosis
After inhaling the fungus, most normal persons have a mild primary infection with minimal or no symptoms (6
Symptoms, when present, are so nonspecific that isolated sporadic cases of primary histoplasmosis are rarely diagnosed. Knowledge about benign, self-limited primary histoplasmosis comes mostly from the careful study of point source outbreaks in which the clustering of cases facilitates diagnosis. Cough and chest pain are the most common symptoms. The intensity of symptoms varies with the size of the infecting dose. Symptoms are often severe if the infection is acquired in a closed space (inoculum likely to be large) but trivial if the infection is acquired in an open area (inoculum likely to be much smaller). The site of exposure in most early outbreaks was often a closed space (cellar, chicken coop, cave), and many patients had severe symptoms (8
). Chicken coops no longer exist, and small outbreaks today are often related to excavation, cleaning or demolishing old buildings, and cutting downed trees with a chain saw. Most large outbreaks now occur in urban centers, where heavily treed areas populated by blackbirds provide excellent sites for fungal growth (7
). Many outbreaks have occurred in urban areas on the fringe of an area of endemicity where relatively few cases of histoplasmosis were previously recognized, including Mason City, Iowa (10
), and Montreal, Canada (10
). However, the largest known outbreak was in Indianapolis, Indiana (11
), well within the area of endemicity. The usual precipitating event is heavy construction activity, disturbing contaminated soil and creating an infectious aerosol. In community-wide outbreaks, highly symptomatic disease is much less common than in smaller outbreaks associated with heavier exposure in closed spaces. Symptoms, even trivial ones, are reported by fewer than 50% of persons infected in large, open air outbreaks. Asymptomatic patients are identified by the serologic testing of exposed persons and coincidental chest radiography.
The incubation time for acute histoplasmosis is 14 days, with a fairly tight distribution (documented most carefully in open air outbreaks with a well-defined time of exposure). It has been speculated that heavy exposure in a closed space can lead to earlier fever and infiltrates, as can reexposure in previously infected persons.
Symptomatic patients with histoplasmosis have an illness that resembles influenza. The onset is abrupt, with fever, chills, substernal chest pain, and nonproductive cough. Nonspecific headache is common. Myalgias and arthralgias occur in a minority of patients (6
). Although respiratory complaints are extremely common, serious impairment of gas exchange is rare. However, with a large infecting dose, rapid progression of illness may lead to diffuse infiltrates and hypoxemia. In extreme cases, hypoxemia is very severe, and the illness manifests as acute respiratory distress syndrome (ARDS).
Even in symptomatic patients, the chest radiographic findings may be negative. More often, the initial chest radiograph shows one or more areas of pneumonitis, usually in the lower lung fields, presumably because of the higher rate of ventilation in that region. Hilar adenopathy is common and usually ipsilateral (Fig. 19.1
). When a patient in an area where the disease is highly endemic has symptoms of a lower respiratory infection and the chest radiograph shows a focal pulmonary infiltrate with enlarged unilateral hilar nodes, the diagnosis of histoplasmosis is relatively easy. However, parenchymal infiltrates are not always accompanied by hilar adenopathy; in that case, the radiograph is very nonspecific. Alternatively, hilar adenopathy may be present without infiltrate, so that the question of lymphoma or sarcoidosis arises. A variety of invasive diagnostic tests are often considered, depending on the radiographic findings. These tests (bronchoscopy, fine needle aspiration, mediastinoscopy, thoracoscopic video-assisted or traditional open lung biopsy) can usually be avoided if histoplasmosis is considered and diagnosed serologically.
FIGURE 19.1. Primary pulmonary histoplasmosis. Chest radiograph shows massive left hilar adenopathy.
The symptoms of primary histoplasmosis last a few days to a few weeks. In some cases, the chest radiographic manifestations clear completely. In others, the primary parenchymal infiltrate fails to resolve. It rounds up, undergoes central necrosis, and is contained by fibrous tissue. These rounded, densely fibrotic lesions later present as coin lesions that are difficult to differentiate from bronchogenic carcinoma. In the absence of specific benign patterns of calcification, the only absolute way to prove that these nodules are benign is surgical resection. Total calcification, dense central (exactly centered) calcification, and multiple concentric rings of calcification are virtually diagnostic of old granulomas, which are almost always histoplasmomas if the patient has a negative tuberculin skin test and lives or has lived in an
area of endemicity. In contrast, eccentric clumps of calcification can be seen in benign lesions but also in malignant lesions because necrosis and dystrophic calcification can develop as a malignant tumor grows rapidly. Positron emission tomography (PET) can also be used to distinguish cancers (metabolically active) from old granulomas (metabolically inactive). False-negative results are possible with very small malignant lesions (<1 cm), and false-positive results if the infectious process is acute.
The approach to pulmonary nodules is complex. If old chest radiographs prove size stability for 2 years, the lesion is benign and can be ignored. Small lesions in patients younger than 35 years can be followed with a low but not zero chance of malignancy. If any lesion grows under observation, it should be studied further or removed. A positive PET result in an older patient with a significant smoking history, a large or growing nodule, and a low surgical risk is a strong indication for biopsy and resection if the lesion is malignant or indeterminate. Fine needle aspiration for diagnosis is also reasonable for any large or growing lesion, especially in a patient with a moderate to high surgical risk. The diagnosis of a specific benign condition precludes the need for surgery, a nonspecific result decreases the chance of cancer but does not exclude it, and a positive diagnosis of cancer warrants a more aggressive approach despite increased risk.
Chest CT for lung cancer, used increasingly to screen current and remote smokers for lung cancer, detects large numbers of nodules, especially when performed in patients who live or have lived in areas where histoplasmosis is highly endemic. In a study from Rochester, Minnesota, 66% of the patients had one to six noncalcified, mostly very small nodules (12
). The incidence of lung cancer was 1.7%, and the false-positive rate was 98%. These tiny nodules are not fully understood and are not all granulomas. Careful serial follow-up of small and multiple lesions must be undertaken to remove all cancers early and yet avoid thoracotomy for benign disease. The follow-up algorithm recommended by the Mayo Clinic group is very complex (13
). Serial studies are required for most patients, usually at 3- to 6-month intervals. Larger lesions discovered on initial screening should be addressed directly, as previously explained.
Hilar and mediastinal lymph nodes may calcify, as in TB. Foci of calcification in histoplasmosis tend to be larger; the whole node may become densely calcified.
A large infecting dose can cause a diffuse micronodular infiltrate. Healing and subsequent calcification of all these tiny nodules can result in “buckshot” calcifications throughout all lung fields. Often discovered on routine chest radiographs, they are highly characteristic of healed primary histoplasmosis (6
). Many patients have no history of notable respiratory infection. The calcifications have no effect on pulmonary mechanics or gas exchange.
The physical examination findings during the acute phase of histoplasmosis are usually negative. Hepatosplenomegaly suggests disseminated disease (14
). However, several clinical syndromes uncommonly occur with acute histoplasmosis. One is the arthralgia, erythema nodosum, and erythema multiforme complex (13
). Arthralgias, when present, develop during the acute phase of the illness and may be severe enough to interfere with walking. They usually resolve quickly. Rarely, the arthralgias are accompanied by erythema multiforme or erythema nodosum, or both. These skin manifestations often occur in just a few patients in a large outbreak, and they frequently provide a clue that histoplasmosis may be the cause of the outbreak. They are most common in Caucasian women and may develop without other manifestations of histoplasmosis. The incidence is estimated at 1 in 200 infections (9
Pericarditis may develop during the course of acute histoplasmosis. Although rarely mentioned earlier, pericarditis was a relatively common complication of acute histoplasmosis during a large outbreak in Indianapolis (15
). Forty-five (6.3%) of 712 patients had pericarditis. Pericardial effusions are usually sterile and result from inflammation in the adjacent lung or mediastinum rather than direct spread of fungal organisms to the pericardium (15
). Presumably, sporadic cases in the past were not linked to histoplasmosis and were likely diagnosed as benign pericarditis of presumed viral etiology.
Enlarged intrathoracic lymph nodes (called mediastinal granulomas when they are clinically significant) frequently impinge on adjacent mediastinal structures. Enlargement of the peritracheal nodes can cause an irritating cough or dyspnea. Pressure on the esophagus may lead to dysphagia. Enlarged nodes adjacent to the superior vena cava may obstruct the vessel and cause edema of the head and upper extremities. In some patients, the middle lobe syndrome may develop with collapse secondary to compression of the middle lobe bronchus. Large nodes in strategic places can be resected when they are causing severe symptoms, but the back wall of the nodal mass should be left and not dissected off the adjacent structure (overly aggressive attempts to resect the entire nodal mass can injure adherent structures and lead to hemorrhage if the nodal mass is compressing a vascular structure). Although surgery may relieve the symptoms, the natural history tends to be benign, with gradual improvement.
One of the most feared complications of histoplasmosis is exuberant mediastinal fibrosis, which can entrap vital structures and lead to severe functional derangement. The entrapment of bronchi, pulmonary arteries, and pulmonary veins may cause a range of problems, including postobstructive pneumonia, hemoptysis (sometimes from pulmonary venous obstruction), and in the worst cases progressive pulmonary hypertension and death from cor pulmonale. Surgery is dangerous and usually unsuccessful (16
). Case reports and small series have documented stenting of individual narrowed arteries, veins, and bronchi. In a few select individuals with highly favorable focal narrowing of these structures, such procedures can result in clinical improvement (17
Mediastinal fibrosis is a totally different disorder from mediastinal granuloma and does not result from progression of that entity.
Progressive Disseminated Histoplasmosis
During acute pulmonary infection, before the establishment of specific T cell–mediated immunity, the fungus gains access to the circulation through the hilar lymph nodes and spreads hematogenously to RE organs throughout the body. It is likely that benign extrapulmonary spread of the fungus occurs in this manner in most patients. Evidence for such spread comes from careful postmortem studies in Cincinnati, Ohio, in which healed Histoplasma
granulomas were found in the spleen in more than 70% of patients who died of other causes (7
yeast is phagocytosed by cells of the fixed RE system. Initially, rapid intracellular multiplication of the fungus takes place. Only with the onset of specific immunity can the armed macrophages check further replication of the ingested fungus. When T cell–mediated immunity fails to develop or is inadequate, the yeast multiplies unchecked. Heavily parasitized RE cells die, and the yeast particles are released but taken up by other macrophages (fixed cells and cells recruited to the area) that in their turn are destroyed by rapid growth of the fungus. In cases of severe T cell–mediated immune deficiency, whether induced by immunosuppressive drugs or by an underlying illness such as AIDS, a severe, progressive systemic illness develops that without treatment eventually kills the patient. This illness is referred to as progressive disseminated histoplasmosis (PDH)
). The term progressive
is important because it distinguishes unchecked systemic histoplasmosis from the benign extrapulmonary spread that accompanies most primary infections but is quickly limited by the advent of specific immunity (6
PDH is a disease of the RE system in which the organism continues to multiply. Patients with PDH have a high fever and anorexia; this is a rapidly progressive, wasting illness. Respiratory symptoms may or may not be prominent; they are absent in about one third of patients at the onset of the febrile illness. The chest radiographic findings may be entirely normal. The physical examination reveals a febrile, toxic, ill patient. Hepatosplenomegaly is frequently present. Mucocutaneous ulcers may develop (14
). The laboratory evaluation may show pancytopenia, abnormal serum liver chemistries, and, in a minority of patients, severe disseminated intravascular coagulation. None of these abnormalities distinguish histoplasmosis from other systemic infections or processes. Although uncommon, a markedly elevated serum ferritin level (≥10,000 ng/mL) has been reported in AIDS patients with PDH, but also in other clinical conditions (24
The initial chest radiograph may show a variety of patterns, ranging from normal to diffusely abnormal with micronodular infiltrates or even diffuse noncardiac pulmonary edema (Fig. 19.3
). In all patients with normal chest radiographic findings early in the course of the illness, pulmonary infiltrates develop as the illness progresses. Today, most cases of PDH occur in patients with AIDS (25
). PDH also complicates organ transplantation and the glucocorticoid and immunosuppressive treatment now used for a wide variety of malignant and nonmalignant conditions.
FIGURE 19.3. Progressive disseminated histoplasmosis in a patient with AIDS. Chest radiograph shows diffuse infiltrates.
The clinical onset of PDH may be temporally related to the onset of an immunosuppressive illness or the initiation of immunosuppressive therapy, most commonly high-dose glucocorticoids (27
). This temporal relationship suggests that reactivation of previously healed and dormant histoplasmosis may be the mechanism of infection for some patients with PDH, as demonstrated by HIV-infected patients in whom, after many years of residence in areas where histoplasmosis is not endemic, PDH develops under the pressure of severely diminished CD4+
lymphocyte counts (25
). Most AIDS patients in whom PDH is diagnosed who are living in New York City and other cities in the eastern United States where histoplasmosis is not endemic have previously lived in the Caribbean basin, an area where H. capsulatum
infection is endemic (28
). Most AIDS patients in whom PDH is diagnosed who are living in San Francisco and other cities in the far western United States where histoplasmosis is not endemic have previously lived in areas of the central United States where it is highly endemic. H. capsulatum
isolates from specific patients in New York City and San Francisco have been typed and found to be similar to strains from the areas of endemicity where they lived before moving to these cities.
Ample evidence also suggests that primary infections in immunosuppressed persons rapidly disseminate. Most of the patients in whom PDH developed during a community-wide outbreak of histoplasmosis in Indianapolis were severely immunocompromised (29
). These patients acquired new infections during the outbreak that rapidly progressed in the face of well-established T-cell defects. Study of another, more recent outbreak in the same city revealed that PDH developed in an astonishing one fourth or more of HIV-infected patients during the outbreak (26
Some patients with PDH have a milder and more chronic illness. Careful evaluation of these patients after recovery reveals no obvious T-cell dysfunction. It is tempting to speculate that these persons may have had a transient T-cell dysfunction, possibly during an acute viral illness, but this hypothesis is unproven (14
). In some patients, a chronic wasting disease develops that is similar to chronic TB. The main clinical findings are weight loss and low-grade fever. Ulcers of the mucocutaneous junction and mucosa may be seen in the mouth, pharynx, or rectum and on the glans penis. Extensive granulomatous involvement of the adrenal glands may destroy them and cause adrenal insufficiency. Histopathologic examination of involved tissues shows well-formed epithelioid granulomas with few organisms visible (14
). An analogy to leprosy suggests that these patients have better T-cell function, well-developed granulomas, and few organisms (the “tuberculoid” form), whereas patients with severe T-cell deficiency, usually as a consequence of HIV infection, have no granulomas and an extremely high density of organisms in infected tissue (the “lepromatous” form).
Involvement of the central nervous system (CNS) by H. capsulatum
is rare. CNS involvement can present as a space-occupying lesion (e.g., intracranial histoplasmoma) or as chronic meningitis (31
). Endovascular infections may involve the valvular endocardium and abdominal aortic aneurysms (32