Histoplasmosis

Background

This is a fungal infection caused by Histoplasma capsulatum. Infection results when spores of H capsulatum are inhaled into the lung. When this occurs, there is conversion to the pathogenic yeast form. In >90% of cases, infection is asymptomatic.

OUTLINE

Epidemiology

Disease Associations

Pathogenesis

Laboratory/Radiologic/Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Special Stains/Immunohistochemistry/Electron Microscopy

Differential Diagnosis

Prognosis

Treatment

Commonly Used Terms

Internet Links

EPIDEMIOLOGY CHARACTERIZATON

GEOGRAPHY

Worldwide but endemic in certain areas of North and South America

Mississippi and Ohio river valleys

Puerto Rico and other Caribbean islands as well as Central America

DISEASE ASSOCIATIONS CHARACTERIZATION

Bird roosts, chicken coops, and caves

LABORATORY/RADIOLOGIC/OTHER TESTS CHARACTERIZATION

Laboratory Markers
Usually made by culturing the fungus from blood or other clinical specimens or by histopathologic examination of bone marrow aspirate or biopsy material, ravage fluid, or biopsy material from lung or skin lesions

Peripheral blood May show intracellular organisms in white blood cells in up to one half of the patients.

Blood cultures
Especially when collected using the Iysis centrifugation system, are positive in over 90% percent of patients

Cultures may take up to two weeks to become positive

Bone marrow biopsy Performed both for culture and histopathology may be the most rapid method of establishing a definitive diagnosis of invasive infection

Serology
Detection of anti-H capsulatum antibodies by immunodiffusion or complement fixation is positive in about 70 to 80 percent of case

Diagnosis of disseminated histoplasmosis by detection of Histoplasma capsulatum antigen in serum and urine specimens.

Wheat LJ, Kohler RB, Tewari RP.
N Engl J Med 1986 Jan 9;314(2):83-8 Abstract quote
The diagnosis of Histoplasma capsulatum infection by serologic testing for the presence of antibodies is limited by a high rate of false positive and false negative results and by the requirement that the patient have a normal immune response.

We have developed a radioimmunoassay for the detection of H. capsulatum antigen in urine and serum specimens. Antigenuria was noted in 20 of 22 episodes of disseminated histoplasmosis that occurred in 16 patients, in 6 of 32 patients with self-limited infection, in 2 of 32 patients with cavitary histoplasmosis, and in 4 of 8 patients with a sarcoid-like illness caused by H. capsulatum. The detection of antigen in urine was reproducible in 38 of 41 (93 percent) retests of specimens. H. capsulatum antigen was also detected in the serum during 11 of the 22 episodes of disseminated histoplasmosis, in none of the 12 episodes of other types of histoplasmosis in patients with antigenuria, in 1 of the 33 patients with histoplasmosis who lacked the urinary antigen, and in none of the 50 controls. Antigenemia and antigenuria decreased after initiation of antifungal therapy and recurred in patients who had a relapse.

We conclude that this radioimmunoassay for H. capsulatum antigen represents a useful new method for the rapid diagnosis of disseminated histoplasmosis.

PCR

Comparison of staining methods and a nested PCR assay to detect Histoplasma capsulatum in tissue sections.

Bialek R, Ernst F, Dietz K, Najvar LK, Knobloch J, Graybill JR, Schaumburg-Lever G.

Institute for Tropical Medicine, University Hospital Tubingen, Germany.
Am J Clin Pathol 2002 Apr;117(4):597-603 Abstract quote
To optimize diagnosis of histoplasmosis in tissue sections, 30 spleen specimens from mice, experimentally infected with Histoplasma capsulatum, were examined by H&E, Grocott stain, anti-bacille Calmette-Guerin antibody immunostain, Fungiqual A fluorochrome stain (Drs Reinehr and Rembold, Kandern, Germany), and a nested polymerase chain reaction (PCR) assay.

Results were compared with the tissue burden determined by quantitative culture. By applying logistic regression, the nested PCR assay was the most sensitive method, but not significantly more sensitive than the Grocott stain. The 50% quantile to achieve a positive result was determined to be 3 colony-forming units per milligram of spleen tissue for the PCR assay, 11 for the Grocott stain, 27 for the fluorochrome stain, 190 for immunostaining, and 533 for the H&E stain.

The Grocott and fluorochrome stains did not differ significantly in detecting fungal elements. The PCR assay unambiguously identified H. capsulatum in tissue sections.

GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION

General

VARIANTS

LUNG
Acute and chronic disease

BONE MARROW

Histoplasmosis in patients with acquired immunodeficiency syndrome. Hematologic and bone marrow manifestations.

Kurtin PJ, McKinsey DS, Gupta MR, Driks M.

Department of Pathology, Research Medical Center and Infectious Disease Associates of Kansas City, Missouri.

Am J Clin Pathol 1990 Mar;93(3):367-72 Abstract quote
In areas where Histoplasma capsulatum infections are endemic in the United States, there is an increasing frequency of progressive disseminated histoplasmosis (PDH) as an opportunistic infection in patients with acquired immune deficiency syndrome (AIDS).

The bone marrow and peripheral blood (PB) specimens in 13 patients with AIDS and PDH were reviewed. Anemia, leukopenia, and thrombocytopenia were found in 12, 10, and 7 patients, respectively. Circulating organisms were detected in the blood smears or buffy coat preparations from five patients and were associated with PB nRBCs and severe absolute monocytopenia. Morphologically, the marrow specimens showed one of four patterns: (1) no morphologic evidence of infection (two patients, one with a positive marrow culture); (2) discrete granulomas (two patients, both with positive marrow cultures); (3) lymphohistiocytic aggregates (six patients, four with positive marrow cultures); and (4) diffuse macrophage infiltrates (three patients, all with positive marrow cultures).

Morphologic examination of the bone marrow combined with cultures is useful in diagnosing disseminated histoplasmosis in patients with AIDS. However, the morphologic findings in the bone marrow may be different in patients with AIDS compared with non-AIDS patients, and seemingly nondiagnostic morphologic features must be approached with a high degree of suspicion in diagnosing infections with H. capsulatum in this population.

COLON

Colonic histoplasmosis in acquired immunodeficiency syndrome mimicking carcinoma.

Garcia RA, Jagirdar J.

Department of Pathology, New York University/Bellevue Hospital Center, New York, NY.
Ann Diagn Pathol 2003 Feb;7(1):14-9 Abstract quote
Four cases of colonic histoplasmosis in patients with acquired immunodeficiency syndrome mimicking other diseases, primarily colonic adenocarcinoma, are presented.

This topic has been extensively discussed from the medical and radiologic standpoint, but very few publications are found in the pathology literature.

Emphasis is made on the discussion of the clinical manifestations; endoscopic, radiologic, and pathologic characteristics; differential diagnosis; and treatment.

DISSEMINATED
Frequently associated with HIV infection

Disseminated cutaneous histoplasmosis in patients infected with human immunodeficiency virus.

K Ramdial P, Mosam A, Dlova NC, B Satar N, Aboobaker J, Singh SM.

Departments of Anatomical Pathology and *Dermatology, Nelson R. Mandela School of Medicine, Faculty of Health Sciences, University of Natal, Durban, South Africa.

J Cutan Pathol 2002 Apr;29(4):215-25 Abstract quote
Background: In the pre-AIDS era disseminated histoplasmosis was rare and the cutaneous manifestations thereof were reported infrequently. A range of unusual clinical manifestations of disseminated cutaneous histoplasmosis (DCH) in AIDS patients has been documented, but the cutaneous histopathological descriptions are short and incomplete. In addition, the histopathological spectrum of AIDS-associated DCH is poorly recognized.

Methods: This is a prospective 32-month study of all HIV positive patients diagnosed with histoplasmosis in the Departments of Anatomical Pathology and Dermatology, Nelson R. Mandela School of Medicine and King Edward VIII Hospital, Durban, South Africa. Clinical distribution and morphology of the individual skin lesions and CD4+ lymphocyte counts in the peripheral blood were analysed in relation to the histopathological features of biopsied lesional tissue. Ultrastructural examination of tissue retrieved from the wax blocks of three cases that exhibited dermal karyorrhexis and collagen necrosis was undertaken. Fungal culture of lesional skin tissue was undertaken in all patients.

Results: Twenty-one biopsies of papules (7), nodules (4), plaques (5), erythema multiforme-like lesions (2), vasculitic lesions (2) and exfoliative dermatitis (1) from 14 patients were examined. Of four biopsies (CD4 range: 120-128 cells/mm3) one and three demonstrated necrotizing and non-necrotizing granulomatous inflammation with a paucity of intrahistiocytic microorganisms. Seven biopsies (CD4 range: 2-56 cells/mm3) demonstrated diffuse dermal and intravascular accumulation of histiocytes densely parasitized by Histoplasma capsulatum var. capsulatum. Vasculitis, karyorrhexis or collagen necrosis was not present. Ten biopsies (CD4 range: 2-72 cells/mm3) demonstrated diffuse dermal karyorrhexis, collagen necrosis and interstitial, extracellular H. capsulatum var. capsulatum. Histiocytic disintegration and nuclear fragmentation and release of intact microorganisms and intact and ruptured lysosomes were identified ultrastructurally. Leucocytoclastic vasculitis was present in two biopsies of vasculitic clinical morphology. Microbiological culture confirmed histoplasmosis in all cases. Three patients died before treatment was commenced. Two patients died within the first two days of induction of therapy. Nine patients demonstrated dramatic healing of the cutaneous lesions.

Conclusions: Despite the clinicopathological spectrum of DCH and the attendant host immunocompromise, timely and appropriate treatment of DCH may be lifesaving and allows rapid healing of skin lesions. A high index of clinical suspicion and skin biopsies and culture are crucial for accurate diagnosis.

SKIN

Skin lesions in 11% of disseminated disease

Presents as papules and plaques
Punched out ulcers
Purpuric lesions
Local or generalized dermatitis

usually over face, trunk, or extremities

Primary disease is rare usually associated with percutaneous inoculation with erythematous tender nodules or chancre with regional lymphadenopathy

Cutaneous lesions of disseminated histoplasmosis in human immunodeficiency virus-infected patients.

Cohen PR, Bank DE, Silvers DN, Grossman ME.

Department of Dermatology, College of Physicians and Surgeons of Columbia University, New York, New York.
J Am Acad Dermatol 1990 Sep;23(3 Pt 1):422-8 Abstract quote
Disseminated histoplasmosis is being diagnosed more frequently in persons infected with the human immunodeficiency virus and is often the initial manifestation of the acquired immunodeficiency syndrome (AIDS).

Disease-related cutaneous features of HIV-associated disseminated histoplasmosis are defined as mucocutaneous lesions from which fungal organisms were either cultured or demonstrated histopathologically. We report four HIV-seropositive patients with disseminated histoplasmosis who had culture-positive skin or oral lesions of histoplasmosis and review the specific cutaneous manifestations of HIV-associated disseminated histoplasmosis. Including our patients, disease-related skin and/or mucosal lesions were present in 11% of patients (26% of 239) with HIV-associated disseminated histoplasmosis.

The possibility of disseminated histoplasmosis should be considered in all HIV-infected persons and in persons with AIDS risk factors who have fever, weight loss, hepatosplenomegaly, and new cutaneous lesions. An early skin or mucosal biopsy specimen for crushed tissue preparation, histologic evaluation, and fungal culture is a simple, rapid diagnostic procedure.

HISTOLOGICAL TYPES CHARACTERIZATION

General
Intracellular organism that infects macrophages and present within the granulomas

Halo which is present in tissue sections is a fixation artifact and the organism does not have a true capsule

VARIANTS

SKIN

Cutaneous manifestations of histoplasmosis in the acquired immune deficiency syndrome.

Eidbo J, Sanchez RL, Tschen JA, Ellner KM.

Department of Pathology, University of Texas Medical Branch, Galveston 77555-0588.
Am J Surg Pathol 1993 Feb;17(2):110-6 Abstract quote
The clinical and histologic features of cutaneous histoplasmosis in three patients with acquired immunodeficiency syndrome (AIDS) are described. The patients presented with multiple discrete papules on the extremities, trunk, and face, some of which were follicular.

Histologically, the skin biopsies were characterized by a sparse perivascular infiltrate with polymorphonuclear leukocytes, lymphocytes, and occasional histiocytes. Prominent leukocytoclasia and associated dermal necrosis were seen around the superficial blood vessels of the dermis. The Histoplasma capsulatum organisms were for the most part extracellular and difficult to visualize on the hematoxylin and eosin-stained sections. A diagnosis of atypical leukocytoclastic vasculitis was considered.

Histoplasmosis is a relatively common mycosis among AIDS patients, and it is sometimes the first manifestation of the syndrome. The clinical and histologic findings described herein may be relatively common among AIDS patients and are quite different from those of classic disseminated histoplasmosis.

PROGNOSIS AND TREATMENT CHARACTERIZATION

PROGNOSIS

Prospective study of histoplasmosis in patients infected with human immunodeficiency virus: incidence, risk factors, and pathophysiology.

McKinsey DS, Spiegel RA, Hutwagner L, Stanford J, Driks MR, Brewer J, Gupta MR, Smith DL, O'Connor MC, Dall L.

Infectious Disease Associates of Kansas City, University of Missouri-Kansas City School of Medicine, St. Luke's Hospital, USA.
Clin Infect Dis 1997 Jun;24(6):1195-203 Abstract quote
Histoplasmosis is a common opportunistic infection in patients with human immunodeficiency virus (HIV) infection who reside in areas where Histoplasma capsulatum is endemic. We undertook a prospective study of a cohort of 304 HIV-Infected patients in Kansas City from October 1990 through March 1993 to define the incidence-specific risk factors, and pathophysiology of histoplasmosis. The annual incidence of histoplasmosis was 4.7%; 74% of the patients with histoplasmosis were symptomatic (all of whom had disseminated disease).

A history of exposure to chicken coops, a positive baseline serology for complement-fixing antibodies to Histoplasma mycelium antigen, and a baseline CD4+ lymphocyte count of < 150/microL were associated with an increased risk for histoplasmosis. Histoplasmin reactivity and the presence of pulmonary calcifications were not useful markers for patients at high risk.

Symptomatic infection occurred in 9.9% of patients with evidence of prior exposure to H. capsulatum, in 4.0% of patients without documented prior exposure, and in 3.0% of patients who were anergic; these findings suggest that the pathophysiology of histoplasmosis in patients with AIDS involves reactivation of latent infection in some cases and dissemination of exogenously acquired infection in other cases.

TREATMENT

ITRACONAZOLE

Itraconazole treatment of disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome. AIDS Clinical Trial Group.

Wheat J, Hafner R, Korzun AH, Limjoco MT, Spencer P, Larsen RA, Hecht FM, Powderly W.

Department of Medicine, Indiana University, Indianapolis, USA.

Am J Med 1995 Apr;98(4):336-42 Abstract quote
PURPOSE: Amphotericin B has been the treatment of choice for disseminated histoplasmosis in patients with acquired immunodeficiency syndrome (AIDS). Oral antifungal agents would be welcome alternatives to standard treatment of disseminated histoplasmosis in less severe cases. The purpose of this study was to assess the efficacy and safety of itraconazole therapy in patients with AIDS and disseminated histoplasmosis.

PATIENTS AND METHODS: This was a multicenter, open-label, nonrandomized prospective trial conducted in university hospitals of the AIDS Clinical Trial Group. All patients had AIDS and first episodes of disseminated histoplasmosis. Patients with central nervous system involvement or with severe clinical manifestations were excluded. Patients were treated with itraconazole BID by mouth 300 mg for 3 days and then 200 mg BID for 12 weeks. Resolution of clinical findings, clearance of positive cultures, and drug tolerance were the main outcome measurements. A secondary objective was effect of therapy on Histoplasma capsulatum var capsulatum antigen levels.

RESULTS: Of 59 evaluable patients, 50 (85%) responded to therapy. Five patients withdrew because of progressive infection, 1 died of a presumed pulmonary embolus within the first week of therapy without improvement, 2 withdrew because of toxicity, and 1 was lost to follow-up after week 2 of therapy. Patients with moderately severe clinical (fever > 39.5 degrees C or Karnofsky score < 60) or laboratory abnormalities (alkaline phosphatase > 5 times normal or albumin < 3 g/dL) at baseline tended to respond more poorly than did other patients. Resolution of complaints of fever and improvement in fatigue occurred after a median of 3 and 6 weeks, respectively, and weight gain after 2 weeks. Fungemia cleared after a median of 1 week. H capsulatum var capsulatum antigen cleared from the urine and serum at rates of 0.2 and 0.3 units per week, respectively.

CONCLUSIONS: Itraconazole is safe and effective induction therapy for mild disseminated histoplasmosis in patients with AIDS, offering an alternative to amphotericin B in such cases. Patients with moderately severe or severe histoplasmosis should first be treated with amphotericin B and then may be switched to itraconazole after achieving clinical improvement.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.

Commonly Used Terms

Basic Principles of Disease
Learn the basic disease classifications of cancers, infections, and inflammation

Commonly Used Terms
This is a glossary of terms often found in a pathology report.

Diagnostic Process
Learn how a pathologist makes a diagnosis using a microscope

Surgical Pathology Report
Examine an actual biopsy report to understand what each section means

Special Stains
Understand the tools the pathologist utilizes to aid in the diagnosis

How Accurate is My Report?
Pathologists actively oversee every area of the laboratory to ensure your report is accurate

Internet Links

Last Updated 3/27/2003

Send mail to psdermpath@earthlink.net with questions or comments about this web site.
Copyright � 2003 The Doctor's Doctor

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/Immunohistochemistry/Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

DISEASE ASSOCIATIONS	CHARACTERIZATION
Bird roosts, chicken coops, and caves

LABORATORY/RADIOLOGIC/OTHER TESTS	CHARACTERIZATION
Laboratory Markers	Usually made by culturing the fungus from blood or other clinical specimens or by histopathologic examination of bone marrow aspirate or biopsy material, ravage fluid, or biopsy material from lung or skin lesions
Peripheral blood	May show intracellular organisms in white blood cells in up to one half of the patients.
Blood cultures	Especially when collected using the Iysis centrifugation system, are positive in over 90% percent of patients Cultures may take up to two weeks to become positive
Bone marrow biopsy	Performed both for culture and histopathology may be the most rapid method of establishing a definitive diagnosis of invasive infection
Serology	Detection of anti-H capsulatum antibodies by immunodiffusion or complement fixation is positive in about 70 to 80 percent of case
Diagnosis of disseminated histoplasmosis by detection of Histoplasma capsulatum antigen in serum and urine specimens. Wheat LJ, Kohler RB, Tewari RP.	N Engl J Med 1986 Jan 9;314(2):83-8 Abstract quote The diagnosis of Histoplasma capsulatum infection by serologic testing for the presence of antibodies is limited by a high rate of false positive and false negative results and by the requirement that the patient have a normal immune response. We have developed a radioimmunoassay for the detection of H. capsulatum antigen in urine and serum specimens. Antigenuria was noted in 20 of 22 episodes of disseminated histoplasmosis that occurred in 16 patients, in 6 of 32 patients with self-limited infection, in 2 of 32 patients with cavitary histoplasmosis, and in 4 of 8 patients with a sarcoid-like illness caused by H. capsulatum. The detection of antigen in urine was reproducible in 38 of 41 (93 percent) retests of specimens. H. capsulatum antigen was also detected in the serum during 11 of the 22 episodes of disseminated histoplasmosis, in none of the 12 episodes of other types of histoplasmosis in patients with antigenuria, in 1 of the 33 patients with histoplasmosis who lacked the urinary antigen, and in none of the 50 controls. Antigenemia and antigenuria decreased after initiation of antifungal therapy and recurred in patients who had a relapse. We conclude that this radioimmunoassay for H. capsulatum antigen represents a useful new method for the rapid diagnosis of disseminated histoplasmosis.
PCR
Comparison of staining methods and a nested PCR assay to detect Histoplasma capsulatum in tissue sections. Bialek R, Ernst F, Dietz K, Najvar LK, Knobloch J, Graybill JR, Schaumburg-Lever G. Institute for Tropical Medicine, University Hospital Tubingen, Germany.	Am J Clin Pathol 2002 Apr;117(4):597-603 Abstract quote To optimize diagnosis of histoplasmosis in tissue sections, 30 spleen specimens from mice, experimentally infected with Histoplasma capsulatum, were examined by H&E, Grocott stain, anti-bacille Calmette-Guerin antibody immunostain, Fungiqual A fluorochrome stain (Drs Reinehr and Rembold, Kandern, Germany), and a nested polymerase chain reaction (PCR) assay. Results were compared with the tissue burden determined by quantitative culture. By applying logistic regression, the nested PCR assay was the most sensitive method, but not significantly more sensitive than the Grocott stain. The 50% quantile to achieve a positive result was determined to be 3 colony-forming units per milligram of spleen tissue for the PCR assay, 11 for the Grocott stain, 27 for the fluorochrome stain, 190 for immunostaining, and 533 for the H&E stain. The Grocott and fluorochrome stains did not differ significantly in detecting fungal elements. The PCR assay unambiguously identified H. capsulatum in tissue sections.

GROSS APPEARANCE/CLINICAL VARIANTS	CHARACTERIZATION
General
VARIANTS
LUNG	Acute and chronic disease
BONE MARROW
Histoplasmosis in patients with acquired immunodeficiency syndrome. Hematologic and bone marrow manifestations. Kurtin PJ, McKinsey DS, Gupta MR, Driks M. Department of Pathology, Research Medical Center and Infectious Disease Associates of Kansas City, Missouri.	Am J Clin Pathol 1990 Mar;93(3):367-72 Abstract quote In areas where Histoplasma capsulatum infections are endemic in the United States, there is an increasing frequency of progressive disseminated histoplasmosis (PDH) as an opportunistic infection in patients with acquired immune deficiency syndrome (AIDS). The bone marrow and peripheral blood (PB) specimens in 13 patients with AIDS and PDH were reviewed. Anemia, leukopenia, and thrombocytopenia were found in 12, 10, and 7 patients, respectively. Circulating organisms were detected in the blood smears or buffy coat preparations from five patients and were associated with PB nRBCs and severe absolute monocytopenia. Morphologically, the marrow specimens showed one of four patterns: (1) no morphologic evidence of infection (two patients, one with a positive marrow culture); (2) discrete granulomas (two patients, both with positive marrow cultures); (3) lymphohistiocytic aggregates (six patients, four with positive marrow cultures); and (4) diffuse macrophage infiltrates (three patients, all with positive marrow cultures). Morphologic examination of the bone marrow combined with cultures is useful in diagnosing disseminated histoplasmosis in patients with AIDS. However, the morphologic findings in the bone marrow may be different in patients with AIDS compared with non-AIDS patients, and seemingly nondiagnostic morphologic features must be approached with a high degree of suspicion in diagnosing infections with H. capsulatum in this population.
COLON
Colonic histoplasmosis in acquired immunodeficiency syndrome mimicking carcinoma. Garcia RA, Jagirdar J. Department of Pathology, New York University/Bellevue Hospital Center, New York, NY.	Ann Diagn Pathol 2003 Feb;7(1):14-9 Abstract quote Four cases of colonic histoplasmosis in patients with acquired immunodeficiency syndrome mimicking other diseases, primarily colonic adenocarcinoma, are presented. This topic has been extensively discussed from the medical and radiologic standpoint, but very few publications are found in the pathology literature. Emphasis is made on the discussion of the clinical manifestations; endoscopic, radiologic, and pathologic characteristics; differential diagnosis; and treatment.
DISSEMINATED	Frequently associated with HIV infection
Disseminated cutaneous histoplasmosis in patients infected with human immunodeficiency virus. K Ramdial P, Mosam A, Dlova NC, B Satar N, Aboobaker J, Singh SM. *Departments of Anatomical Pathology and Dermatology, Nelson R. Mandela School of Medicine, Faculty of Health Sciences, University of Natal, Durban, South Africa.**	J Cutan Pathol 2002 Apr;29(4):215-25 Abstract quote Background: In the pre-AIDS era disseminated histoplasmosis was rare and the cutaneous manifestations thereof were reported infrequently. A range of unusual clinical manifestations of disseminated cutaneous histoplasmosis (DCH) in AIDS patients has been documented, but the cutaneous histopathological descriptions are short and incomplete. In addition, the histopathological spectrum of AIDS-associated DCH is poorly recognized. Methods: This is a prospective 32-month study of all HIV positive patients diagnosed with histoplasmosis in the Departments of Anatomical Pathology and Dermatology, Nelson R. Mandela School of Medicine and King Edward VIII Hospital, Durban, South Africa. Clinical distribution and morphology of the individual skin lesions and CD4+ lymphocyte counts in the peripheral blood were analysed in relation to the histopathological features of biopsied lesional tissue. Ultrastructural examination of tissue retrieved from the wax blocks of three cases that exhibited dermal karyorrhexis and collagen necrosis was undertaken. Fungal culture of lesional skin tissue was undertaken in all patients. Results: Twenty-one biopsies of papules (7), nodules (4), plaques (5), erythema multiforme-like lesions (2), vasculitic lesions (2) and exfoliative dermatitis (1) from 14 patients were examined. Of four biopsies (CD4 range: 120-128 cells/mm3) one and three demonstrated necrotizing and non-necrotizing granulomatous inflammation with a paucity of intrahistiocytic microorganisms. Seven biopsies (CD4 range: 2-56 cells/mm3) demonstrated diffuse dermal and intravascular accumulation of histiocytes densely parasitized by Histoplasma capsulatum var. capsulatum. Vasculitis, karyorrhexis or collagen necrosis was not present. Ten biopsies (CD4 range: 2-72 cells/mm3) demonstrated diffuse dermal karyorrhexis, collagen necrosis and interstitial, extracellular H. capsulatum var. capsulatum. Histiocytic disintegration and nuclear fragmentation and release of intact microorganisms and intact and ruptured lysosomes were identified ultrastructurally. Leucocytoclastic vasculitis was present in two biopsies of vasculitic clinical morphology. Microbiological culture confirmed histoplasmosis in all cases. Three patients died before treatment was commenced. Two patients died within the first two days of induction of therapy. Nine patients demonstrated dramatic healing of the cutaneous lesions. Conclusions: Despite the clinicopathological spectrum of DCH and the attendant host immunocompromise, timely and appropriate treatment of DCH may be lifesaving and allows rapid healing of skin lesions. A high index of clinical suspicion and skin biopsies and culture are crucial for accurate diagnosis.
SKIN	Skin lesions in 11% of disseminated disease Presents as papules and plaques Punched out ulcers Purpuric lesions Local or generalized dermatitis usually over face, trunk, or extremities Primary disease is rare usually associated with percutaneous inoculation with erythematous tender nodules or chancre with regional lymphadenopathy
Cutaneous lesions of disseminated histoplasmosis in human immunodeficiency virus-infected patients. Cohen PR, Bank DE, Silvers DN, Grossman ME. Department of Dermatology, College of Physicians and Surgeons of Columbia University, New York, New York.	J Am Acad Dermatol 1990 Sep;23(3 Pt 1):422-8 Abstract quote Disseminated histoplasmosis is being diagnosed more frequently in persons infected with the human immunodeficiency virus and is often the initial manifestation of the acquired immunodeficiency syndrome (AIDS). Disease-related cutaneous features of HIV-associated disseminated histoplasmosis are defined as mucocutaneous lesions from which fungal organisms were either cultured or demonstrated histopathologically. We report four HIV-seropositive patients with disseminated histoplasmosis who had culture-positive skin or oral lesions of histoplasmosis and review the specific cutaneous manifestations of HIV-associated disseminated histoplasmosis. Including our patients, disease-related skin and/or mucosal lesions were present in 11% of patients (26% of 239) with HIV-associated disseminated histoplasmosis. The possibility of disseminated histoplasmosis should be considered in all HIV-infected persons and in persons with AIDS risk factors who have fever, weight loss, hepatosplenomegaly, and new cutaneous lesions. An early skin or mucosal biopsy specimen for crushed tissue preparation, histologic evaluation, and fungal culture is a simple, rapid diagnostic procedure.

HISTOLOGICAL TYPES	CHARACTERIZATION
General	Intracellular organism that infects macrophages and present within the granulomas Halo which is present in tissue sections is a fixation artifact and the organism does not have a true capsule
VARIANTS
SKIN
Cutaneous manifestations of histoplasmosis in the acquired immune deficiency syndrome. Eidbo J, Sanchez RL, Tschen JA, Ellner KM. Department of Pathology, University of Texas Medical Branch, Galveston 77555-0588.	Am J Surg Pathol 1993 Feb;17(2):110-6 Abstract quote The clinical and histologic features of cutaneous histoplasmosis in three patients with acquired immunodeficiency syndrome (AIDS) are described. The patients presented with multiple discrete papules on the extremities, trunk, and face, some of which were follicular. Histologically, the skin biopsies were characterized by a sparse perivascular infiltrate with polymorphonuclear leukocytes, lymphocytes, and occasional histiocytes. Prominent leukocytoclasia and associated dermal necrosis were seen around the superficial blood vessels of the dermis. The Histoplasma capsulatum organisms were for the most part extracellular and difficult to visualize on the hematoxylin and eosin-stained sections. A diagnosis of atypical leukocytoclastic vasculitis was considered. Histoplasmosis is a relatively common mycosis among AIDS patients, and it is sometimes the first manifestation of the syndrome. The clinical and histologic findings described herein may be relatively common among AIDS patients and are quite different from those of classic disseminated histoplasmosis.

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSIS
Prospective study of histoplasmosis in patients infected with human immunodeficiency virus: incidence, risk factors, and pathophysiology. McKinsey DS, Spiegel RA, Hutwagner L, Stanford J, Driks MR, Brewer J, Gupta MR, Smith DL, O'Connor MC, Dall L. Infectious Disease Associates of Kansas City, University of Missouri-Kansas City School of Medicine, St. Luke's Hospital, USA.	Clin Infect Dis 1997 Jun;24(6):1195-203 Abstract quote Histoplasmosis is a common opportunistic infection in patients with human immunodeficiency virus (HIV) infection who reside in areas where Histoplasma capsulatum is endemic. We undertook a prospective study of a cohort of 304 HIV-Infected patients in Kansas City from October 1990 through March 1993 to define the incidence-specific risk factors, and pathophysiology of histoplasmosis. The annual incidence of histoplasmosis was 4.7%; 74% of the patients with histoplasmosis were symptomatic (all of whom had disseminated disease). A history of exposure to chicken coops, a positive baseline serology for complement-fixing antibodies to Histoplasma mycelium antigen, and a baseline CD4+ lymphocyte count of < 150/microL were associated with an increased risk for histoplasmosis. Histoplasmin reactivity and the presence of pulmonary calcifications were not useful markers for patients at high risk. Symptomatic infection occurred in 9.9% of patients with evidence of prior exposure to H. capsulatum, in 4.0% of patients without documented prior exposure, and in 3.0% of patients who were anergic; these findings suggest that the pathophysiology of histoplasmosis in patients with AIDS involves reactivation of latent infection in some cases and dissemination of exogenously acquired infection in other cases.
TREATMENT
ITRACONAZOLE
Itraconazole treatment of disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome. AIDS Clinical Trial Group. Wheat J, Hafner R, Korzun AH, Limjoco MT, Spencer P, Larsen RA, Hecht FM, Powderly W. Department of Medicine, Indiana University, Indianapolis, USA.	Am J Med 1995 Apr;98(4):336-42 Abstract quote PURPOSE: Amphotericin B has been the treatment of choice for disseminated histoplasmosis in patients with acquired immunodeficiency syndrome (AIDS). Oral antifungal agents would be welcome alternatives to standard treatment of disseminated histoplasmosis in less severe cases. The purpose of this study was to assess the efficacy and safety of itraconazole therapy in patients with AIDS and disseminated histoplasmosis. PATIENTS AND METHODS: This was a multicenter, open-label, nonrandomized prospective trial conducted in university hospitals of the AIDS Clinical Trial Group. All patients had AIDS and first episodes of disseminated histoplasmosis. Patients with central nervous system involvement or with severe clinical manifestations were excluded. Patients were treated with itraconazole BID by mouth 300 mg for 3 days and then 200 mg BID for 12 weeks. Resolution of clinical findings, clearance of positive cultures, and drug tolerance were the main outcome measurements. A secondary objective was effect of therapy on Histoplasma capsulatum var capsulatum antigen levels. RESULTS: Of 59 evaluable patients, 50 (85%) responded to therapy. Five patients withdrew because of progressive infection, 1 died of a presumed pulmonary embolus within the first week of therapy without improvement, 2 withdrew because of toxicity, and 1 was lost to follow-up after week 2 of therapy. Patients with moderately severe clinical (fever > 39.5 degrees C or Karnofsky score < 60) or laboratory abnormalities (alkaline phosphatase > 5 times normal or albumin < 3 g/dL) at baseline tended to respond more poorly than did other patients. Resolution of complaints of fever and improvement in fatigue occurred after a median of 3 and 6 weeks, respectively, and weight gain after 2 weeks. Fungemia cleared after a median of 1 week. H capsulatum var capsulatum antigen cleared from the urine and serum at rates of 0.2 and 0.3 units per week, respectively. CONCLUSIONS: Itraconazole is safe and effective induction therapy for mild disseminated histoplasmosis in patients with AIDS, offering an alternative to amphotericin B in such cases. Patients with moderately severe or severe histoplasmosis should first be treated with amphotericin B and then may be switched to itraconazole after achieving clinical improvement.