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 Table of Contents  
Year : 2014  |  Volume : 16  |  Issue : 2  |  Page : 70-76

Histoplasmosis: An emerging infection

Department of Microbiology, Government Medical College, Kozhikode, Kerala, India

Date of Web Publication14-Nov-2014

Correspondence Address:
S Remadevi
Department of Microbiology, Government Medical College, Kozhikode, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0972-1282.144719

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Histoplasmosis is commonly found in US and central America; recently cases were diagnosed from Kerala also. The causative organism Histoplasma capsulatum is found abundant in soil mixed with bird or bat guano. Infection occurs by the inhalation of small oval conidia which can enter the terminal bronchioles and then the alveolar spaces. They multiply inside the macrophages and the cellular immune system of the host decides the outcome. Usually it is a self limiting pulmonary infection, but it can vary from mild pneumonitis to severe acute respiratory distress syndrome. If primary manifestation progresses, disseminated histoplasmosis involving liver, spleen, bone marrow, adrenal gland and mucocutaneous membranes result. Skin test antigen is used in epidemiological studies to find the true extent of infection. Rapid diagnosis is possible with histoplasma antigen detection but serology is useful only in certain cases. Histopathology aids the diagnosis a lot. But the fungal culture remains the gold standard for the confirmation. Histoplasmosis is successfully treated with azoles if it is a mild infection and if severe liposomal Amphotericin B is used initially and then switched over to Itraconazole to be continued for several months.

Keywords: Histoplasma capsulatum , dimorphic fungus, opportunistic infection, progressive disseminated histoplasmosis, immunocompromised

How to cite this article:
Remadevi S. Histoplasmosis: An emerging infection. J Acad Clin Microbiol 2014;16:70-6

How to cite this URL:
Remadevi S. Histoplasmosis: An emerging infection. J Acad Clin Microbiol [serial online] 2014 [cited 2023 Dec 2];16:70-6. Available from: https://www.jacmjournal.org/text.asp?2014/16/2/70/144719

  Introduction Top

Histoplasmosis is a disease caused by the dimorphic fungus, Histoplasma capsulatum. Infection is acquired by inhalation and a vast majority of primary infections go unrecognized medically. The major determinant for the overt illness is likely to be the inoculum size and also the virulence of the strain. [1] It manifests initially as pulmonary histoplasmosis and may progress to disseminated infections. It remains a frequent cause of opportunistic infection among patients who are immunocompromised.

In 1905, Dr. Samuel Taylor Darling, a pathologist from Panama Canal Zone, examined visceral tissues and bone marrow of a young man whose death was originally attributed to military tuberculosis. Seeing small intracellular organisms, he assumed it was a different Leishmania species lacking the kinetoplast and because it exhibited a pseudocapsule, he named it Histoplasma capsulatum[2] and the disease was named Darlings disease. In 1912, da Rocha -Lima suggested that the organism resembled a yeast rather than a protozoan. The disease was thought to be rare and fatal until 1945 when Christie and Peterson established the relationship of histoplasma skin test to pulmonary calcifications in tuberculin-negative patients. According to Loosli (1955), in the United State alone approximately 30 million people living in North Central and South Central States have experienced some form of histoplasma infection. Thanks to the research of the leaders like De Monbreun, Christie, Palmer, Emmons, Furcolow, Ajelloi, Silverman, Baum, Campell, Klite and many others the pathogenesis has been established, clinical picture defined, reliable diagnostics made available and epidemiology worked out. Panja and Sen (1954) from Calcutta claimed the diagnosis of histoplasmosis from India. Skin sensitivity surveys carried out in India by Taneja et al (1955), Edwards (1956), Viswanathan et al (1960) and Pandalai et al (1962) had indicated the possibility of occurrence of infection with this fungus. [3]

Histoplasma was found to produce ascospores and so it was reclassified with the ascomycetes and given the new name Emmonsiella capsulata. However, some traditions die slowly and certain mycologists insisted on retaining the old name because it was familiar in clinical medicine. Mycologists decided to use two names for the fungus; the new name Emmonsiella capsulatum for the sexual stage and the old name Histoplasma capsulatum for the asexual stage. [5] The heterothallic form or sexual form is also known as Ajellomyces capsulatum.

  Epidemiology Top

Endemicity of histoplasmosis particularly that due to Histoplasma capsulatum is notable in certain parts of North, Central and South America, Africa, and Asia. In the USA, it is prevalent over the Ohio and Mississipi river valleys (Ajelloi in 1971). Histoplasma capsulatum var capsulatum is less commonly found in Latin America from Mexico to Argentina, Africa, Malaysia, Indonesia, and Australia. Soil enriched with bird or bat dropping promotes the growth and sporulation of this fungus. Disruption of the soil containing the organism leads to aerosolisation of the microconidia and exposure of humans nearby. People are liable to get infections after travel to areas in America, Africa, and Asia where the disease is endemic. [6] Birds are not infected by the fungus and attempt to isolate Histoplasma capsulatum from their cloaca have been unsuccessful. Bats on the other hand, carry the fungus in their gastrointestinal tract and shed it. [4]

According to one report in 1980, Histoplasmosis is epidemic in West Ban gal and Western India, by performing skin sensitive test to histoplasmin. [11] Three outbreaks of histoplasmosis have been cited. In 1978, it was in conjunction with the demolition of an amusement park, in 1980 related to the building of a swimming pool, and in 1988-1993 during the time of construction of a large tennis complex. During these outbreaks, Williams et al detected antigen in 92%, 21%, and 39% of patients with the disseminated, chronic pulmonary, and self-limited forms, respectively. [22] In 1988, a group of 17 students from an American university crawled into a cave in a national park in Costa Rica to observe the bats. Within 3 weeks, 15 students developed fever, headache, cough, and chest pain, and all were treated for histoplasmosis.

Recently, studies from environmental samples are in progress under the guidance of Dr. Harish C Gugnani, from Dr. B. R. Ambedkar Centre for Biomedical research, University of Delhi, and he had presented a paper at a conference of Mycologists held at Coimbatore in January 2014. Isolation of the fungus is tried from soil enriched with guano (excreta of birds and bats) and also from internal organs of several species of free living bats. He had reported the natural occurrence of Histoplasma capsulatum var. capsulatum after its isolation from soil in an abandoned room of a 350-year-old palatial building, infested with bats of the species Scotophilus heathi in Serampur near Kolkata in West Bengal. [7] The organism is typically found within 20 cm of the surface especially moist soil that is acidic and with a high nitrogen content. In areas where bats roost, the fungus is found most often where the dropping is decaying and mixed with soil. [4]

Disruption of the soil by excavation or construction is the most common means of releasing the organisms, which is subsequently inhaled. Persons at risk include the spelunkers (one who explores wild cave systems - disease is also called spelunkers disease), those who are engaged in agriculture or re-inhabitation of old buildings that have been inhabited by birds or bats. Human-to-human transmission via pulmonary route has not been reported. [2]

Classification: Histoplasmosis is highly diverse at the genetic level because it undergoes sexual recombination in nature. It has 4-7 chromosomes. Restriction Fragment Length Polymorphism (RFLP) of the nuclear genes has segregated histoplasma into six classes. Class 1 is an avirulent strain; the Down's strain. Many isolates recovered from AIDS patients belong to this class. These six classes differ in geographic distribution and virulence. [8]

  Pathogenesis Top

Following inhalation, microconidia enter the terminal bronchioles and alveolar spaces and are rapidly engulfed by the alveolar macrophages. Due to the availability of calcium and iron inside the phagocytes, the microconidia are transformed to budding yeasts. They multiply inside the resting macrophages. Neutrophils and then lymphocytes accumulate in the area. The yeasts use phagosomes as a vehicle for translocation to local draining lymph nodes, from where they spread haematogenously to other internal organs and reticuloendothelial system. After about 2 weeks interferon gamma, interleukin 12 and TNF alpha secreted by T cells assists macrophages in destroying the organism and hence arresting the progress of infection, resulting in a latency state in the most exposed individuals.

In immunocompetent hosts, macrophages, lymphocytes and epithelial cells organize to form a granuloma. These may undergo further fibrosis and calcification. Calcified mediastinal lymph nodes and hepatosplenic calcification are found in healthy individuals in endemic areas. There is some immunity to re-infection.

Progressive disseminated histoplasmosis involves multiple organs and affects liver, spleen, bone marrow, adrenal glands and mucocutaneous membranes. Chronic pulmonary infection occurs in persons with underlying lung disease like emphysema. Chronic infection is similar to tuberculosis with tissue necrosis, fibrosis or even cavity. [6] The similarity is so much that many cases treated for tuberculosis would have actually been undetected histoplasmosis.

  Clinical manifestation Top

Histoplasmosis is usually a self-limiting pulmonary infection, which is asymptomatic or with mild influenza like symptoms. The disease develops in males more frequently than in females by a 4:1 ratio. Manifestations commonly appear by 2 or 3 weeks. Fever, headache, cough, chills and chest pain are the most common symptoms. Pulmonary infection is the primary manifestation varying from mild pneumonitis to severe ARDS. Acute severe pulmonary infection also occurs when a person is exposed to a large inoculum of H. capsulatum. [17] Acute respiratory syndrome can occur within a few days. [18]

Though the usual presentation is a substernal discomfort, in children, it is often located in the anterior chest. [9] Chest pain is believed to be caused by enlargement of either mediastinal or hilar lymph nodes or both. Acute pulmonary infection is accompanied by arthralgia, erythema nodosum or erythema multiforme.

Common X-ray findings are characterized by a patchy pneumonitis that eventually calcifies and a lymphadenopathy [Figure 1]. There may be a granulomatous inflammatory response in mediastinal lymph nodes adjacent to the pericardium and 6% of patients develop a pericarditis also. In all patients who present with mediastinal or hilar lymphadenopathy, histoplasmosis also must be considered in the differential diagnosis, especially if patient comes from an endemic area. Presence of splenic and liver calcifications also indicates the differential diagnosis of past pulmonary tuberculosis or histoplasmosis. [13]
Figure 1: X-ray chest. Histoplasmosis with innumerable miliary calcifications within the lungs- healed. 'snow storm pattern'

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Frequent complications of pulmonary histoplasmosis may be a histoplasmoma resembling a fibroma composed of active inflammation in the periphery and fibrous tissue in the centre and eventually a calcified area that appear as rings. Similar findings may be found in mediastinal granuloma also. Mediastinal fibrosis may be due to reaction to the antigen from histoplasma. Hypoxaemia, shortness of breath and dysphagia may ensue as the fibrotic process progresses. [18]

  Chronic cavitory pulmonary histoplasmosis Top

Patients with pre-existing lung disease are prone to develop cavitory pulmonary histoplasmosis; there will not be any hilar or mediastinal lymphadenopathy. Spontaneous resolution of thin-walled and thick-walled cavities ranges from 10% to 60%. [2] Unique to chronic cavitory histoplasmosis is the so-called "marching cavity", in which necrosis increases the size of the cavity involving the entire lobe. Pleural effusion is uncommon. [17] Differential diagnoses include acute pulmonary blastomycosis and atypical pneumonia such as those due to Mycoplasma, Legionella and Chlamydia. Hilar or mediastinal lymphadenopathy is also seen with Blastomycosis.

Primary mucocutaneous histoplasmosis may present as a non-healing oral ulcer anywhere in the oral cavity like a large and deep tender ulcer on the dorsum of the tongue with oedematous borders and induration [28],[30] [Figure 2]. Differential diagnosis of oral ulcerative lichen planus, squamous cell carcinoma and Mucocutaneous Leishmaniasis are to be considered. Mucocutaneous histoplasmosis is frequently reported in patients with AIDS, but it is rare in immunocompetent hosts. Patients present with asymptomatic swelling or a nodulo-ulcerative lesion of the hard palate and rarely crusted nodules and papules over the extremities, face and trunk. Skin biopsy reveals multiple tiny intracellular round yeast forms with a halo in the dermis. Chest X-ray may show hilar lymphadenopathy.
Figure 2: Commonest manifestation in cases reported from Kerala — lesion on hard palate and sides of oral cavity

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Adrenal involvement is seen in disseminated disease, but sometimes it may be the only site of demonstrable disease and may manifest as adrenomegaly rarely. [27] Early diagnosis and treatment may save the patient from catastrophic adrenal insufficiency. PGIMER, Chandigarh, Punjab, India has reported two cases showing bilateral adrenomegaly on ultrasonography and contrast enhanced CT. [28] Immunostaining with Antihistoplasma antibody can be done in tissues, especially in adrenal tissues. Immunohistochemistry (IHC) is not done routinely.

Genitourinary histoplasmosis is very rare, and to our knowledge, only four cases of epidydimal histoplasmosis and nine cases of prostatic Histoplasmosis have been reported in literature. Post transplant patients may develop fever, pain and swelling in the scrotum. Enlarged epidydimis with prostatic and rectosigmoid abscess can be confirmed as histoplasmosis only by histopathological examination of the epidydimal biopsy. [29]

Gastrointestinal histoplasmosis is common in HIV patients and may be misdiagnosed initially as colonic cancer. Fever, pain in the lower abdomen and weight loss may be the symptom and colonoscopy may reveal stricture and ulcerative growth in the colon. It may present as colonic pseudotumour. Of the gastrointestinal infection, some will have ulcerative lesion in the rectum, ileum and oesophagus, rarely manifest as multiple intestinal haemorrhages. [13]

In Africa, the classical Histoplasma capsulatum var. capsulatum coexists with H. capsulatum var. duboisii. The yeast form of H. capsulatum var. duboisii is typically much larger, up to 15 μm and has a thicker wall. Skin and bones are the most frequent sites affected. In skin, it manifests as a papulonodular and ulcerating lesion or psoriatic like lesion that may spontaneously resolve. Involvement of subcutaneous tissue is seen as a tender nodule similar to cold abscess. Osteolytic bone lesions are also common. Skull and ribs are the frequent bones affected followed by vertebra. Granulomatous lesions within the bone can lead to sinus and cystic lesion. In progressive disease, there is multiorgan involvement including liver, spleen, kidney and lung. There is a combination of granuloma and suppuration. Because of the large size of yeast forms, macrophages cannot clear it by ingestion and so neutrophils also assist the process.

Acute disseminated infections are increasingly reported in HIV patients. Features include fever, pancytopenia, hepatosplenomegaly, lymphadenopathy and often a papular skin eruption.

Progressive Disseminated Histoplasmosis (PDH) is typically seen in immunocompromised individuals who account for 70% of cases. Diabetes mellitus and HIV infection are the most common comorbid conditions in PDH. Progressive Disseminated Histoplasmosis ranges from an acute rapidly fatal course to a subacute course with focal organ involvement. [15]

Osteoarticular infection is an uncommon manifestation. May involve tendons and present as carpel tunnel syndrome or as septic arthritis and rarely osteomyelitis. [19] There is a case report of traumatic fracture of spine leading to weakness of both limbs, then developing a Paraspinal abscess, resulting in non-healing sinuses. [20]

  Scenario in Kerala, South India Top

In Kerala, several cases of histoplasmosis are diagnosed presenting as a nodulo-ulcerative growth on the hard palate. Tender ulcerated lesions may be seen on the soft palate. Bilateral submandibular lymphadenopathy also may be observed. Most of these cases from Kerala are not documented and those reported form only the tip of the iceberg. Out of five cases that were proved by histopathology between 2004 and 2007 at Govt. Medical College, Kottayam, three were confirmed by fungus culture. One was a case of prolonged fever, and the other patient presented with generalized lymphadenopathy (both HIV seronegative).

A manual labourer suspected to have a thyroid swelling and multiple enlarged (4-cm diameter) lymph nodes attended the outpatient clinic on 14th September 2014, at Govt. Medical College, Kozhikode, Fine needle aspiration (FNA) of the lymph node revealed multiple yeast cells in macrophage. The pathologist suspected it to be histoplasma or Penicillium marneffei and sent another sample to the mycology laboratory that grew Histoplasma capsulatum.[10] There were three cases of culture proven mucocutaneous Histoplasmosis, presenting as oral ulcers and whitish plaques on the tongue during previous years.

  Laboratory diagnosis Top

Clinical manifestations and Chest X-ray findings mimic pulmonary tuberculosis and so, laboratory confirmation is mandatory.

Haematology-Blood and bone marrow smears are examined. Giemsa-stained blood smears show organisms within the monocytes and rarely in neutrophils. Histopathology (HPE) and fungal culture for isolation and identification of the fungus is highly essential. On several occasions, FNA from lesions and biopsy samples subjected to HPE gives a clue that is confirmed by culture in the Mycology laboratory.

On direct microscopic examination of smears from clinical specimens, yeast cells are seen as small, ovoid 2-5 micron sized, with a single bud attached by a narrow base, seen extracellularly or within macrophages. [10] Gomori methenamine silver stain (GMS) reveals dark black yeast cells [Figure 3]. Some misshaped or large cells (allomorphs) are also found, which have reduced virulence, and many represent a dormant phase. It can also be demonstrated by H&E and PAS [Figure 4]. PAS stain may not pick up the organism if scanty. GMS should be done in all suspected cases.
Figure 3: GMS stained smear showing small black yeast cells

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Figure 4: Histopathology — H&E stain showing budding yeast cells, both intracellular and extracellular

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Fungal culture remains a gold standard diagnostic test. Cultures are often negative in mild disease. In PDH, culture yield is high for bronchoalveolar lavage (BAL), bonemarrow and blood. Culture is to be done on enriched agar base such as inhibitory mold agar (IMA) or SABHI agar (SDA + Heart infusion agar) or brain heart infusion agar (with cycloheximide and chloramphenicol) must be used. [23]

Addition of 5-10% sheep blood will enhance the growth of the fungus. From such blood-enriched media, subculture is to be done to SDA or potato dextrose agar, to bring out more characteristic colony morphology and modes of sporulation. All the fungal cultures if negative should be incubated for 30 days. Growth starts slowly as delicate cob web-like or hair-like aerial mycelium; initially white but turning grey. Colonies of H. capsulatum may be observed growing on the surface of colonies of C. albicans or on top of contaminating molds [Figure 5]. Lactophenol cotton blue (LPCB) mount should be taken from all such tubes to know whether H. capsulatum has grown in it. The yeast colonies from primary culture or after conversions from the mold form are typically smooth, yellow-white and somewhat glistening with a pasty consistency. Transition to yeast phase can be demonstrated if exposed to 37°C. Shift in the temperature may be sensed by a change in the fluidity of the yeast membrane, and certain genes are upregulated like cdc2, yps-3, and there is increased transcription of genes encoding heat shock protein especially hsp 70. The mold form of H. capsulatum is often difficult to convert to the yeast form. For this reason, the exo-antigen test or the nucleic acid probe test is recommended to confirm the final identification, and it can be made accurately within 1 day after the appearance of initial growth in culture. [23] Using a chemiluminiscent acridium ester-labelled DNA probe, complimentary to the histoplasma rRNA, Padhye et al., identified 103 of 105 H. capsulatum cultures. [24]
Figure 5: Culture on SDA. After 4-5 weeks white cottony mycelial growth appear

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Microscopy on LPCB mount reveals two types of conidia. The thin branching septate hyphae bear small microconidia smooth and oval, ranging from 2 to 5 μm on the sides of delicate hyphae, in a sleeve-like arrangement. This infective form is small enough to lodge in the terminal bronchioles and alveoli. Macroconidia are large, 8-18 μm and help in the identification. Its surface is decorated with slender protrusions referred to as tuberculate or spiked macroconidia [23] [Figure 6].
Figure 6: LPCB mount showing tuberculate/spiked macroconidia

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  Serological Tests for Detecting H. Capsulatum Antibodies Top

Positive results are obtained in over 90% of patients. With cavitory or disseminated histoplasmosis, a delay of 4-6 weeks is there before a sufficiently high titre is achieved. Histoplasma antibodies may be elevated in patients with Blastomycosis, Coccidioidomycosis and Paracoccidioidomycosis. [23]

Complement fixation (CF) test using yeasts and mycelia antigens is more sensitive than the ID test. In acute pulmonary histoplasmosis, the CF test is positive in titres of at least 1:8 in 90% of patients. [26] A single titre of 1:32 or higher or a fourfold increase is diagnostic of active histoplasmosis.

Detection of antigen

Detection of H. capsulatum var. capsulatum circulating antigen is performed with EIA methods. The third generation polyclonal MVista histoplasma antigen EIA allows the quantitative detection of polysaccharide circulating antigen. Urine, serum, BAL or other body fluids can be tested for detection of antigen. The histoplasma antigen EIA has been marketed since 2006. Sensitivity is 71% and specificity is 98% in urine samples. Cross reactions may be there. Recent modifications and development of monoclonal antibodies are very promising. Mycotic Diseases Branch of CDC also has developed an EIA histoplasma antigen detection method from urine of HIV patients and is being evaluated.

Molecular diagnostic methods are in progress to detect H. capsulatum DNA in body fluids and tissue sections particularly to establish a definitive diagnosis of granulomatous disease when fungal stain fail to disclose diagnostic forms. [25] The molecular diagnosis by PCR gives rapid results with good sensitivity and specificity in tissues and body fluids. It is not externally validated and not yet fully commercialized. Recently a Loop-Mediated Isothermal Amplification (LAMP assay) is being validated to detect histoplasma DNA in urine. [21]

  Treatment Top

For mild infections, Itraconazole therapy gives good response. Progressive disseminated histoplasmosis is treated with initial lipid formulation Amphotericin B (3-5 mg/Kg/day) or Amphotericin B 0.7-1 mg/kg/day) for 1-2 weeks.; then Itraconazole (200 mg twice daily) for 12 months. [14] It is found that most of the cases respond well to this regime. [15]

  Prevention Top

People prone for severe disease should avoid high risk areas such as bat or bird inhabited caves. Immunosuppressed patients should not involve in exploring old buildings inhabited by birds or visit areas where disruption of the soil is done by excavation or construction work.

Awareness of pulmonary histoplasmosis among Indian physicians and pulmonologists is very poor. For a definitive diagnosis, the specimens collected from the lesions have to be sent to the pathology laboratory for HPE and microbiology laboratory for fungal culture. So, many such cases, especially pulmonary histoplasmosis, are being missed. In developing countries, tuberculosis is the commonest cause of granuloma formation. Many of the sputum AFB-negative cases are put on empirical anti-tuberculous treatment (ATT). If they do not respond, an alternate diagnosis should be considered and histoplasmosis is to be ruled out.

Regarding the environmental studies, soil surveillance in bat-inhabited areas is not yet introduced in South Indian States, whereas such studies are being conducted in North Indian States like West Bengal and Delhi.

  Acknowledgement Top

Dr. Mini P. N. Faculty in Mycology Division & Dr. Asokan Kuttiyil, Scientific officer Mycology division of Department of Microbology, Medical College, Kozhikode, Kerala, India.

  References Top

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Deepe GS. Mandell, Douglas and Bennett′s principles and practice of infectious diseases. 8 th ed. Philadelphia: Elsevier Churchhill Livingstone; c2005. Vol 2 Chapter 265, Histoplasma capsulatum; p. 2949-62.  Back to cited text no. 2
De Monbreun WA. The cultivation and cultural characteristics of Darlings Histoplasma capsulatum. Am J Trop Med Hyg 1934;14:93-125.  Back to cited text no. 3
Di Salvo AF, Ajello L, Palmer JW Jr, Winkler WG. Isolation of Histoplasma capsulatum from Arizona bats. Am J Epidemiol 1969;89:606-14.  Back to cited text no. 4
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Winn W, Allen S Jr, Janda W, Koneman E, Woods G. Koneman′s color atlas and textbook of diagnostic microbiology. 6 th ed. Philadelphia: Lippincott Williams & Wilkins; 2006. p. 1199.  Back to cited text no. 23
Padhye AA, Smith G, McLaughlin D, Standard PG, Kaufman L. Comparative evaluation of a chemiluminescent DNA probe and an exoantigen test for rapid identification of Histoplasma capsulatum. J Clin Microbiol 1992;30:3108-11.  Back to cited text no. 24
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