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Histoplasmosis: the radiologic mimic and the disease spectrum--a guide for the practicing radiologist.

Histoplasmosis is caused by a ubiquitous dimorphic fungus that was diagnosed in 1905 by a pathologist named Samuel Darling, MD, while he was working in the Panama Canal Zone. (1) The organism was initially thought to be an encapsulated plasmodium. In 1934, Histoplasma capsulatum was shown to be a dimorphic fungus that exists as a mold in the soil and transforms to a yeast form at normal body temperature. (2) In 1945, Christie and Peterson (3) used a skin-test reagent to demonstrate that tuberculin-negative individuals with pulmonary calcifications were usually histoplasmin-skin-test positive.

Histoplasmosis is usually an asymptomatic, benign, self-limiting illness (Figure 1). The primary infection is acquired through either casual or epidemic exposure. Acute infection may further lead to other manifestations of histoplasmosis--chronic cavitary and disseminated disease. The other sequlae include: histoplasmoma, broncholithiasis, mediastinal granuloma, and mediastinal fibrosis. The secondary effects of mediastinal fibrosis depend on the structures compromised by the disease process and can have a debilitating effect. The diagnosis of the disease is usually made on the basis of complement-fixation testing or an agar gel diffusion test. The histoplasmin skin test is usually not helpful in diagnosis, as it does not provide evidence of the presence of the disease. (4)

Epidemiology

Histoplasmosis is endemic in the central United States, particularly in the Mississippi, Missouri, and Ohio River valleys. The disease is estimated to infect 500,000 persons annually in the United States. The disease has worldwide distribution and, in some regions, up to 30% of the population show positive reaction to histoplasmin. There is a striking association between the occurrence of this disease and the nearby presence of fowl and other birds. Because of their high body temperature, however, the birds do not harbor the organism. The soil, enriched with bird droppings, is conducive to the growth of the organism. The disease can be transmitted by bats, which can harbor the organism in their intestines.

In humans, infections are usually acquired by means of wind-borne spores. The severity of the disease is determined by the immune status of the patient and the amount of exposure to the spores. A large amount of spores in a single exposure or over a short duration can result into a fulminant disease irrespective of the immune status of the patient. (5-7)

Acute histoplasmosis

Acute histoplasmosis is acquired from inhalation of spores. The number of spores necessary to induce infection is unknown. Other routes of infection, such as skin or gastrointestinal tract, are rare portals of entry. (8) The inhaled spores are deposited in the lungs and germinate at human body temperature into yeast forms. The macrophages do not kill the yeast; rather the organism becomes parasitic and multiplies in macrophages. The organism now can disseminate hematogenously after migrating to regional lymph nodes. Specific cellular immunity and hypersensitivity develops in 1 to 2 weeks. Involution, encapsulation, and eventual calcifications become the typical residue of infection.

Radiographically visible calcifications were initially thought to be due to tuberculosis. It was later shown, however, that similar findings could be seen with histoplasmosis. Straub and Schwarz (9) found that pulmonary calcifications larger than 4 mm and lymphnode calcifications larger than 10 mm had an 80% probability of being caused by histoplasmosis. In histoplasmosis, splenic calcifications tend to be numerous and are larger in size than those caused by tuberculosis. (9) It has been suggested that when >5 calcifications are identified in the spleen, they are almost always caused by histoplasmosis (10) (Figures 2 and 3).

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Disseminated disease

Disseminated disease is a rare manifestation of histoplasmosis and is usually encountered in immunocompromised patients. The defective cell-mediated immunity in these patients is unable to control the spread of the organism. (7) The use of cytotoxic drugs, corticosteroids, and immunosuppressive agents after organ transplantation also alters the cell-mediated immunity, as does the human immunodeficiency virus (HIV) in acquired immunodeficiency syndrome (AIDS) patients. The Centers for Disease Control and Prevention include extra-pulmonary histoplasmosis as a defining illness of AIDS. (11) The young (<2 years of age) and elderly (>54 years) are at an increased risk of disseminated disease. (7)

The disease spectrum varies from acute, rapidly fatal illness to chronic, intermittent illness. The most severe form is a rapidly progressive illness, which, if untreated, results in death. Fever, cough, weight loss, anorexia, and malaise are common complaints. Abdominal complaints of nausea, vomiting, diarrhea, and pain may be present. Patients with AIDS may present with disseminated intravascular coagulation with hypotension. Meningitis is more commonly seen in patients with AIDS than in patients without AIDS. Hepatosplenomegaly, bone marrow suppression, and abnormal liver function test results may be seen.

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A variety of radiologic findings are seen. The chest radiograph is frequently normal. The most common findings are diffuse, multiple, small nodular opacities. The opacities are usually <3 mm in diameter. Linear or irregular opacities are the second most common findings. Segmental, lobar, or diffuse air-space opacities or pleural effusions may occur. While lymphadenopathy is commonly seen in immunocompetent patients, such findings are uncommon in immunocompromised patients. (7) The paratracheal or subcarinal masses show areas of low attenuation or enhancing septae, thereby suggesting a granulomatous disease process, such as histoplasmosis or tuberculosis (12) (Figure 4).

Chronic pulmonary disease

Chronic pulmonary histoplasmosis is a progressive, destructive disease process that more commonly involves the apices of the lungs. It is more common in adult, middle-aged white men. Predisposing factors also include cigarette smoking and coexistent emphysema. It is more commonly seen in the apical posterior segments of the upper lobes, especially the right upper lobe. True cavitations are rare. The early manifestation is a segmental, wedge-shaped area of peripheral consolidation that has a moth-eaten appearance from the scattered foci of emphysematous lung. Lymphadenopathy is usually absent.

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Serial chest radiographs are useful in following the course of the disease process and in individualizing the treatment. In one third of patients, the disease resolves spontaneously. A course of antifungal medications is recommended if no radiographic improvement is seen after 3 months. Surgery is rarely necessary and is poorly tolerated. This is because of poor functional reserve in these patients with chronic obstructive pulmonary disease (7) (Figure 5).

Delayed manifestations

Only a minority of patients present with delayed complications. These delayed manifestations are divided into 3 main categories: 1) histoplasmoma, 2) broncholithiasis, and 3) mediastinal granuloma and mediastinal fibrosis. (7)

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Histoplasmoma

Following an asymptomatic infection, the lesions of histoplasmosis often get calcified. A calcified nodule thus remains as the residual evidence of prior infection. In some patients, however, the primary focus may continue to enlarge and is thus termed histoplasmoma. (13,14) The exact etiology of this enlargement is unclear, although various explanations have been theorized. The lesion grows by slow elaboration of the fibrous tissue at the periphery. An abnormal immune reaction may be responsible for this, as was suggested by Goodwin and Snell (14) (Figure 6).

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Histoplasmomas can be found in any lobe; however, they are slightly more common in the posterior aspect of the lower lobes, at the periphery of the lungs close to pleura. They typically show laminated calcific rings (14) (Figure 7). The growth of the lesion is slow, with an estimated doubling time of 14 to 113 months. Because of their peripheral position in the lung parenchyma, histoplasmomas usually do not cause symptoms. (14)

Broncholithiasis

This uncommon condition occurs when the peribronchial calcified lymph nodes produce bronchial obstruction caused by compressive effects or by eroding into the bronchus. Bronchial obstruction can occur because of peribronchial inflammation as well. (15) The common clinical manifestations include hemoptysis, fever, chills, and productive cough. Infrequently, lithoptysis may be seen. The chest radiographs show calcified hilar, paratracheal, or subcarinal lymph nodes. Broncholiths are more common on the right side because of airway anatomy and lymph node distribution. The calcified lesions may show change in position on serial radiographs. Chest CT accurately shows the relationship of the calcified lymph nodes with the bronchial anatomy. Postobstructive atelectasis and bronchiectasis may be present. Although the diagnosis may be apparent on radiologic imaging, bronchoscopy must be performed to exclude an endobronchial neoplasm. (7)

Mediastinal granuloma and fibrosis

Histoplasmosis is considered the most common cause of mediastinal fibrosis and almost always produces a focal disease process. (16) A mediastinal granuloma is composed of enlarged lymph nodes surrounded by a dense fibrous capsule that is 2- to 5-mm thick. It has been suggested that if the capsule of the granuloma is <6 mm thick, it may adhere to the airways of mediastinal vascular structures without interfering with their function. Leakage of the antigenic material from the lymph nodes is presumed to induce the fibrotic reaction. Biopsy specimens rarely grow the organism. (17) The time duration for development of this reaction is not known but is seen more commonly in patients who are 20 to 30 years of age. The subcarinal and right paratracheal nodes are the most common sites for the development of a mediastinal granuloma. The fibrotic process may cause narrowing of the thin-walled structures, such as veins and arteries. Relatively few cases of bronchial tree obstruction have been reported. This has been thought to be because of the relatively thick wall of the bronchial tree. Use of corticosteroids to reduce fibrosis or the use of antifungal medications, such as amphotericin B, has not been successful in the management of mediastinal granuloma. Percutaneous placement of vascular stents has shown promising results in the management of such patients (7,18-20) (Figures 8 through 10).

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Conclusion

Histoplasmosis is a common fungal disease, especially in the United States. Radiologists and other physicians must be familiar with the varying imaging and clinical manifestations of this disease process. With a growing number of immunocompromised patients because of HIV infection and organ transplantation, physicians may see more such patients in their clinical practice. Awareness of the varying manifestations will aid in improved patient management.

REFERENCES

(1.) Darling ST. A protozoan general infection producing pseudotubercles in the lungs and focal necroses in the liver, spleen, and lymph nodes. JAMA. 1906;46: 1283-1285.

(2.) DeMonbreun WA. The cultivation and cultural characteristics of Darling's Histoplasma capsulatum. Am J Trop Med. 1934;14:93-125.

(3.) Christie A, Peterson JC. Pulmonary calcification in negative reactors to tuberculin. Am J Public Health. 1945;35:1131-1147.

(4.) Goodwin RA, Lloyd JE, Des Prez RM. Histoplasmosis in normal hosts. Medicine (Baltimore). 1981;60: 231-266.

(5.) Edwards LB, Acquaviva FA, Livesay VT. Further observations on histoplasmin sensitivity in the United States. Am J Epidemiol. 1973;98:315-325.

(6.) Chase HV. Histoplasmosis. Md State Med J. 1970;19:65-70.

(7.) Gurney JW, Conces DJ. Pulmonary histoplasmosis. Radiology. 1996;199:297-306.

(8.) Goodwin RA Jr, Des Prez RM. State of the art: Histoplasmosis. Am Rev Respir Dis. 1978;117:929-956.

(9.) Straub M, Schwarz J. The healed primary complex in histoplasmosis. Am J Clin Pathol. 1955;25: 727-741.

(10.) Schwarz J, Silverman FN, Adriano SM, et al. The relation of splenic calcification to histoplasmosis. N Engl J Med. 1955;252:887-891.

(11.) Centers for Disease Control. Revision of the case definition of acquired immunodeficiency syndrome for national reporting--United States. MMWR Morb Mortal Wkly Rep. 1985;34:373-375.

(12.) Im JG, Song KS, Kang HS, et al. Mediastinal tuberculous lymphadenitis: CT manifestations. Radiology. 1987;164: 115-119.

(13.) Baum GL, Green RA, Schwarz J. Enlarging pulmonary histoplasmoma. Am Rev Respir Dis. 1960;82: 721-726.

(14.) Goodwin RA Jr, Snell JD Jr. The enlarging histoplasmoma: Concept of a tumor-like phenomenon encompassing the tuberculoma and coccidiodoma. Am Rev Respir Dis. 1969;100:1-12.

(15.) Engleman P, Liebow AA, Gmelich J, Friedman PJ. Pulmonary hyalinizing granuloma. Am Rev Respir Dis. 1977;115:997-1008.

(16.) Sherrick AD, Brown LR, Harms GF, Myers JL. The radiographic findings of fibrosing mediastinitis. Chest. 1994;106:484-489.

(17.) Lai DY, Schwarz J. Cultural and morphologic findings in cervical and mediastinal lymph nodes at necropsy, with reference to fungi. Am J Clin Pathol. 1972; 57:212-214.

(18.) Connell JV, Muhm JR. Radiographic manifestations of pulmonary histoplasmosis: A 10-year review. Radiology. 1976;121:281-285.

(19.) Wieder S, Rabinowitz JG. Fibrous mediastinitis: A late manifestation of mediastinal histoplasmosis. Radiology. 1977;125:305-312.

(20.) Landay MJ, Rollins NK. Mediastinal histoplasmosis granuloma: Evaluation with CT. Radiology. 1989; 172: 657-659.

At the time this article was written, Dr. Gill was a Research Student, Department of Radiology, Louisiana State University (LSU) Health Sciences Center at Shreveport, LA. He is currently a First-Year Resident, Fitchburg Family Medicine Program, University of Massachusetts, Fitchburg, MA. Dr. Malik is an Assistant Professor, Department of Radiology, LSU Health Sciences Center at Shreveport, and a Staff Radiologist, Overton Brooks Veterans Affairs Medical Center, Shreveport, LA. Dr. Lall is an Assistant Professor, Indiana University School of Medicine, Indianapolis, IN.

This article was originally presented as an educational exhibit at the annual conference of the Radiologic Society of North America, Chicago, IL, November 2001.
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Author:Gill, Parveen; Malik, Anil; Lall, Chandana
Publication:Applied Radiology
Date:Sep 1, 2006
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