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Pathogenesis and clinical features of pulmonary histoplasmosis

Pathogenesis and clinical features of pulmonary histoplasmosis
Literature review current through: Jan 2024.
This topic last updated: Oct 05, 2022.

INTRODUCTION — Histoplasmosis was first described by Samuel Darling, a United States Army physician in Panama in 1906 and subsequently has become recognized as a common and usually asymptomatic infection [1,2]. Histoplasmosis is the most prevalent endemic mycosis in the United States [3]. While most infections are asymptomatic or self-limited, some individuals develop acute pulmonary infections or severe and progressive disseminated infection [4].

The pathogenesis and clinical features of the various pulmonary syndromes that may result from Histoplasma capsulatum infection will be reviewed here. The diagnosis and treatment of pulmonary histoplasmosis, as well as the pathogenesis, clinical manifestations, diagnosis, and treatment of disseminated histoplasmosis are discussed separately. (See "Diagnosis and treatment of pulmonary histoplasmosis" and "Pathogenesis and clinical manifestations of disseminated histoplasmosis" and "Diagnosis and treatment of disseminated histoplasmosis in patients without HIV".)

RESERVOIR — H. capsulatum proliferates best in soil contaminated with bird or bat droppings, which are believed to alter the soil characteristics and increase the nitrogen content, favoring growth of the organism. Sites commonly associated with exposure to H. capsulatum include chicken coops or farm buildings with large accumulations of bird droppings, abandoned buildings, bird roost sites, caves, and wood lots [5].

Activities that have been associated with exposure include excavation, construction, demolition, remodeling, wood cutting and gathering, exploring caves, and cleaning structures that are encrusted with bird or bat guano [6-12]. Heavy exposure usually occurs with activities that disturb a large accumulation of droppings in an enclosed area, such as a cave or an attic. However, in many cases, patients recall no specific exposure.

EPIDEMIOLOGY — H. capsulatum is found worldwide, but is most common in the Midwestern and Central United States, along the Ohio and Mississippi River Valleys [4,13,14]. It is estimated that up to 500,000 new infections occur each year in the United States [15]. Among the endemic mycoses, histoplasmosis is the most common cause for hospitalization.

It has also been recognized that H. capsulatum is observed beyond the Mississippi-Ohio River Valleys, with infections reported in western New York and several mid-Atlantic states [5,16-18]. In addition, H. capsulatum causes disease in Canada, Mexico, Central and South America, as well as in parts of eastern and southern Europe, Africa, eastern Asia, and Australia [19,20]. Increasingly, reports from Latin America have documented the occurrence of histoplasmosis among persons with human immunodeficiency virus (HIV) [21,22].

Although histoplasmosis occurs most commonly in individuals who live in endemic regions, outbreaks have been reported in travelers with exposures to H. capsulatum. As an example, clusters of histoplasmosis have occurred in travelers to Mexico who stayed in a hotel that was undergoing construction [23], and among members of mission groups from the United States that renovated a church in El Salvador [24].

PATHOGENESIS — The lungs provide the portal of entry for H. capsulatum in the vast majority of cases [25], the rare exceptions being transmission from an infected organ in patients who have undergone transplantation [26]. Conidia are inhaled and, if they evade nonspecific lung defenses, cause a localized or patchy bronchopneumonia [27]. The clinical spectrum of acute histoplasmosis varies according to the extent of exposure, presence of underlying lung disease, general immune status, and specific immunity to H. capsulatum. With low-inoculum exposure, most otherwise healthy individuals remain asymptomatic (figure 1). However, patients who inhale a large inoculum can develop severe and potentially fatal acute diffuse pulmonary infection [5,28,29].

Macrophages initially are able to ingest but not kill the fungi (picture 1) [30,31]. Infected macrophages serve to disseminate the infection hematogenously during the first two weeks of infection, before specific immunity has developed [32,33] (see "Pathogenesis and clinical manifestations of disseminated histoplasmosis"). Dissemination is usually clinically silent and may result in the development of H. capsulatum-containing granulomas in the liver and spleen, which may later be discovered incidentally on computed tomography (CT) scan or at autopsy [34]. Progressive, clinically evident dissemination occurs primarily in patients with underlying immunosuppressive disorders, those at the extremes of age, and patients who have experienced an unusually heavy exposure [35].

Cellular immunity to H. capsulatum develops approximately 10 to 14 days after exposure; it is demonstrable first in the lungs and mediastinal lymph nodes and then throughout the reticuloendothelial system [32]. Sensitized T lymphocytes activate macrophages to develop fungicidal properties, and the infection is brought under control in immunocompetent hosts [36,37]. Tumor necrosis factor (TNF) and interferon-gamma play critical roles in defense against H. capsulatum [38]. Progressive illness with both pulmonary and extrapulmonary infection occurs in the absence of intact cellular immunity [35]. Histoplasmosis is the most common fungal infection seen in patients who are treated with TNF-alpha inhibitors [39,40]. The infection tends to be aggressive, and dissemination occurs in most patients. The package inserts for the TNF-alpha inhibitors warn physicians and patients of the heightened risk for development of severe histoplasmosis while taking these agents. (See "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections", section on 'Histoplasmosis'.)

CLINICAL MANIFESTATIONS — Fewer than 5 percent of exposed individuals develop symptomatic disease after a low level exposure to H. capsulatum [41]. Although symptomatic pulmonary histoplasmosis is the most common syndrome following infection [25], a variety of different syndromes can be seen in patients with pulmonary histoplasmosis [42].

Symptomatic pulmonary histoplasmosis — In most patients, the illness presents several weeks following exposure. Symptoms are usually mild, and the events causing the exposure are difficult to identify. Radiographs typically show focal infiltrates and mediastinal or hilar lymphadenopathy [6]. Histoplasmosis often is mistaken as community-acquired pneumonia and only considered after there is no response to empirical antibacterial therapy [43].

Fever, chills, headache, myalgias, anorexia, cough, and chest pain generally develop between two and four weeks after exposure but may be seen within one week in more heavily exposed cases [25,44]. Coryza and sore throat are not typical of histoplasmosis and should suggest alternative diagnoses [44]. Chest pain usually is described as substernal and often is aggravated by deep inspiration; patients may experience pleuritic pain if lesions abut the pleura [25].

On physical examination, fever, rales, and evidence of consolidation have been noted. Symptoms typically resolve within several weeks, but fatigue and asthenia may persist for months, particularly in patients with more severe disease [25,45].

Pathologically, the pulmonary lesion is characterized by a lobular or acinar bronchopneumonia, initially with neutrophilic infiltration [27]. Recruitment of macrophages, lymphocytes, and plasma cells, and the formation of granulomas with conspicuous giant cells occurs at the second week and beyond; central caseous necrosis occurs after several months (picture 2) [25].

Chest radiographs usually show enlarged hilar or mediastinal lymph nodes with focal infiltrates (image 1 and image 2) but may be normal [45]. The pulmonary infiltrates usually are patchy or nodular; cavitation is rarely noted, except in persons with underlying obstructive lung disease [46,47]. Infiltrates may be diffuse following heavy exposure. Nodules measure between 1 and 4 cm in diameter and are often multiple. Of note, diffuse pulmonary infiltrates in an immunosuppressed patient are often one component of disseminated infection [48] (see "Pathogenesis and clinical manifestations of disseminated histoplasmosis"). Pleural effusions are seen in a minority of patients with acute pulmonary histoplasmosis, and organisms are rarely isolated from pleural fluid [25,49,50].

Neither the time course for resolution of radiographic abnormalities nor the effect of antifungal therapy on the rate of clinical or radiographic improvement has been adequately studied. Anecdotal experience suggests that infiltrates clear within two to four months in most persons [25], while adenopathy may persist for years. Calcification of mediastinal nodes or parenchymal lesions may be seen by chest radiography within a few months in children, but calcification usually takes several years to develop in adults.

Acute diffuse pulmonary histoplasmosis — Following extensive exposure, such as occurs with activities that disturb heavily contaminated soil or areas with large amounts of bird or bat droppings, patients can develop acute severe pulmonary infection [6-8]. (See 'Pathogenesis' above.)

Diffuse reticulonodular pulmonary infiltrates are noted (image 3), and the disease can progress to respiratory failure or progressive extrapulmonary dissemination [28,33,51]. Although patients can recover from heavy exposure without treatment, the infection can be severe, and treatment with an antifungal agent is recommended for all patients. (See "Diagnosis and treatment of pulmonary histoplasmosis".)

Following recovery, patients can remain dyspneic and fatigued for months [51].

Chronic pulmonary histoplasmosis — Patients with underlying lung disease are at risk for the development of chronic pulmonary infection following exposure to H. capsulatum [46,52]. Affected patients develop a productive cough, dyspnea, chest pain, fatigue, fevers, weight loss, and sweats and have fibrotic apical infiltrates with cavitation on chest radiographs (image 4) and computed tomography (CT) scans. The clinical and radiographic findings resemble those seen in reactivation tuberculosis; the two syndromes are often confused, and incorrect diagnoses have resulted in inappropriate treatment.

These cavities tend to enlarge, involve new areas of the lung, and may result in the formation of bronchopleural fistulae [46,51,52]. Pathologic examination reveals the presence of underlying emphysema, vascular compromise caused by intimal proliferation in small and medium-sized arteries, tissue necrosis, and fibrosis [52]. Inflammation is disproportionate to the fungal burden, leading to the suggestion that hypersensitivity to fungal antigens may play a role in pathogenesis [52].

Care must be taken to evaluate for both tuberculosis and histoplasmosis in patients who have these findings and who have lived in or been exposed to areas in which histoplasmosis is endemic. Sputum or BAL fluid cultures are required to make this distinction [46,52]. Aspergilloma (ie, fungus ball), atypical mycobacterial infections, and chronic or recurrent pneumonia caused by a variety of bacterial pathogens may develop in areas of lung that have been damaged by chronic pulmonary histoplasmosis.

Most patients with chronic pulmonary histoplasmosis have smoked tobacco for long periods and are therefore at high risk for the development of lung cancer. Lung cancer should be suspected in patients who have nodular lesions that do not respond to treatment or that develop during the course of treatment.

Broncholithiasis — Lymph nodes and pulmonary granulomas calcify within several years of initial infection [25,53-55]. In rare cases, calcified lymph nodes erode into adjacent bronchi, causing symptoms such as chronic cough, wheezing, hemoptysis, fever, chills, and purulent sputum production. Patients may report expectoration of small stones, gravel, or gritty material, and massive hemoptysis may result if the bronchial arteries are involved.

Organisms may be demonstrated in the calcified nodes, but cultures are almost always negative. Broncholiths can be removed bronchoscopically and occasionally may require surgical intervention if massive hemoptysis or a bronchoesophageal fistula has developed. (See "Evaluation and management of life-threatening hemoptysis".)

Mediastinal granuloma and mediastinal lymphadenitis — These two uncommon complications occur within the hilar and mediastinal lymph nodes following acute pulmonary histoplasmosis [25,42]. Differentiation of these two syndromes can be difficult in individual patients. Radiographic findings of calcifications are the most helpful; mediastinal granulomas are frequently characterized by calcifications whereas node calcifications in mediastinal lymphadenitis are uncommon [56].

Mediastinal lymphadenitis − Mediastinal lymphadenitis is a more acute process that occurs when individual lymph nodes enlarge. It occasionally occurs in association with active pneumonia and is most common in children and teenagers. If the lymph nodes enlarge enough, they can compress adjacent mediastinal structures [57].

Mediastinal granuloma − Mediastinal granuloma is a more chronic process that results from coalescence of multiple lymph nodes resulting in a mass-like lesion with a capsule and a caseous necrotic center [58]. This process occurs after the acute pulmonary infection has resolved and can occur at any age. The granulomas are often discovered on radiographs or CT scans performed for another reason, as patients are frequently asymptomatic. However, the mass can compress adjacent structures and sometimes leads to fistula formation with resultant drainage of the necrotic contents into adjacent structures [59,60].

Compression of structures, such as the esophagus, great vessels, and or airways, can result in symptoms that include dysphagia, chest pain, cough, hemoptysis, and dyspnea [25,58]. Young children are at greater risk of airway obstruction than older children and adults.

Fibrosing mediastinitis — This is a rare manifestation of histoplasmosis characterized by extensive fibrosis that can lead to entrapment, distortion, and invasion of structures adjacent to mediastinal lymph nodes, including the great vessels, airways, and the esophagus (image 5). Fibrosing mediastinitis represents an excessive fibrotic response to a prior episode of histoplasmosis; in most cases, the acute episode of histoplasmosis was not clinically diagnosed [61-64]. The most common symptoms are cough, dyspnea, hemoptysis, pleuritic chest pain, and night sweats [62]. This complication of histoplasmosis does not follow mediastinal granuloma or mediastinal lymphadenitis. (See "Mediastinal granuloma and fibrosing mediastinitis".)

Other manifestations

Pericarditis — Pericarditis has been reported in 5 to 10 percent of symptomatic cases of pulmonary histoplasmosis in some series, but is very uncommon in others [45,65]. It is caused by an immunologic reaction to H. capsulatum [45,65] and rarely results from dissemination of organisms into the pericardial space [65]. It is often accompanied by pleural effusions [66]. Findings of pulmonary histoplasmosis may be unrecognized or may precede the development of pericarditis by several weeks or months.

Patients typically present with chest pain and fever, and a pericardial friction rub can be heard [65,66]. Signs of hemodynamic compromise can occur and require urgent pericardiocentesis (image 6) [65,66]. A more detailed discussion of the clinical manifestations of pericarditis is found elsewhere. (See "Acute pericarditis: Clinical presentation and diagnosis".)

Rheumatologic manifestations — Arthritis or arthralgia has been reported in about 5 percent of symptomatic patients with pulmonary histoplasmosis and appears to be more common in women [67]. These manifestations almost always represent a systemic inflammatory reaction to acute pulmonary infection rather than dissemination of the organism to the joints or soft tissues [67].

The arthritis is polyarticular and symmetric in approximately one-half of cases and involves the large or small joints of the upper and lower extremities with similar frequency. Joint radiographs are normal and symptoms usually resolve spontaneously or in response to treatment with non-steroidal anti-inflammatory drugs. Treatment with corticosteroids is sometimes required; careful follow-up is essential in such patients, with monitoring for signs of progressive infection caused by the immunosuppressive effects of the steroids [67].

Nearly one-half of patients with joint pain exhibit erythema nodosum and/or erythema multiforme, and about one-half complain of fever and respiratory symptoms [67-70].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Histoplasmosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topic (see "Patient education: Histoplasmosis (The Basics)")

SUMMARY

Histoplasmosis is the most prevalent endemic mycosis in the United States. Most infections are asymptomatic or self-limited, but some individuals develop acute pulmonary infections or severe and progressive disseminated infection. (See 'Introduction' above.)

Histoplasma capsulatum proliferates best in soil contaminated with bird or bat droppings, which are believed to alter the soil characteristics favoring growth of the organism. Sites commonly associated with exposure to H. capsulatum include chicken coops or farm buildings with large accumulations of chicken droppings, abandoned buildings, bird roost sites, caves, and wood lots. Activities associated with exposure include excavation, construction, demolition, remodeling, wood cutting and gathering, and exploring caves. (See 'Reservoir' above.)

H. capsulatum is found worldwide, particularly in North and Central America. In the United States, H. capsulatum is most prevalent in the midwestern and central states along the Ohio and Mississippi River valleys, but also occurs in microfoci in several states along the East Coast. In addition to the United States, it is also found in Canada, Mexico, Central and South America, as well as in parts of eastern and southern Europe, Africa, eastern Asia, and Australia. (See 'Epidemiology' above.)

The lungs provide the portal of entry for H. capsulatum in the vast majority of cases. Conidia are inhaled and, if they evade nonspecific lung defenses, cause a localized or patchy bronchopneumonia. (See 'Pathogenesis' above.)

Asymptomatic pulmonary histoplasmosis is the most common syndrome following infection. (See 'Clinical manifestations' above.)

Symptomatic pulmonary histoplasmosis typically presents several weeks following exposure. Symptoms are usually mild, and the events causing the exposure are difficult to identify. Radiographs typically show focal infiltrates and mediastinal or hilar lymphadenopathy (image 1 and image 2). (See 'Symptomatic pulmonary histoplasmosis' above.)

Following extensive exposure, such as occurs with activities that disturb heavily contaminated soil or areas with large amounts of bird or bat droppings, patients can develop acute severe pulmonary infection. Diffuse reticulonodular pulmonary infiltrates are noted and the disease can progress to respiratory failure or progressive extrapulmonary dissemination. (See 'Acute diffuse pulmonary histoplasmosis' above.)

Patients with underlying lung disease are at risk for the development of chronic pulmonary infection following exposure to H. capsulatum. Affected patients develop a productive cough, dyspnea, chest pain, fatigue, fevers, and sweats and have fibrotic apical infiltrates with cavitation on chest radiographs or computed tomography (CT) scans (image 4). (See 'Chronic pulmonary histoplasmosis' above.)

Less common pulmonary manifestations include broncholithiasis, mediastinal granuloma (granulomatous mediastinitis), and fibrosing mediastinitis. (See 'Broncholithiasis' above and 'Mediastinal granuloma and mediastinal lymphadenitis' above and 'Fibrosing mediastinitis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Joseph Wheat, MD, who contributed to an earlier version of this topic review.

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