Overview of Histoplasmosis

B. Keith English, M.D.

Chair, Department of Pediatrics

and Human Development\

Nothing to Disclose

Thank You!

Many thanks to my long-time colleague Dr. Sandy Arnold, Chief of Pediatric Infectious Diseases at Le Bonheur Children’s Hospital and the University of Tennessee Health Science Center in Memphis for sharing her slides with me (I have modified them for this presentation)

Diagnosing Pulmonary Histoplasmosis in Children

A child living in Nashville presents with cough for several weeks, low grade fever and dyspnea. The CXR is shown.

What is the best test to confirm the diagnosis of subacute pulmonary histoplasmosis?

A. Histoplasma urine antigen

B. Complement fixation antibody titers

C. BAL and culture

D. Histoplasma serum antigen

E. Cold agglutinins

Treating Mediastinal Histoplasmosis?

A 6 year old boy in Memphis is discovered to have a large right paratracheal mass deviating the trachea on a CXR done during influenza A infection. He became asymptomatic after the flu resolved.

What is the best treatment for this patient?

A. Itraconazole

B. Amphotericin B

C. Steroids

D. Steroids & itraconazole

E. No treatment

Dimorphic Fungi 101

Thermally dimorphic fungi Yeast form at body temperature i.e. isolated from tissues

Mold at lower temps – found in the environment

– Endemic mycoses – geographically distinct and thermally dimorphic

Histoplasmosis

Blastomycosis

Coccidioidomycosis

Exist in nature as spore forming molds

Inhaled spores are infectious

Not contagious from person to person

Histoplasmosis

Caused by the dimorphic fungus Histoplasma capsulatum

Found in soil as mold with microconidia (infectious spores)

Climate and specific soil conditions thought to account for areas of endemnicity

May also be found in higher concentrations in certain microfoci

Histoplasmosis in North and South America

Histo in the U.S.

Epidemiology: high risk activities

          Caves           Spelunking

          Chicken coops           Cleaning, demolition, use of droppings for fertilizer

          Bird roosts           Excavation, camping

          Bamboo canebrakes           Cutting cane, recreation

          School yards           Routine activities, cleaning

          Prison grounds           Routine activities, cleaning

          Decayed wood piles           Transporting or burning wood

          Dead trees           Recreational, cutting wood

          Contaminated chimneys           Cleaning, demolition

          Old building           Demolition, remodeling, cleaning

          Laboratories           Research with H capsulatum

          Ship hatch cover           Cleaning off sea gull guano

Microfocus Activities

Clinical manifestations

In endemic areas, over half of adults have evidence of infection (by histoplasmin skin testing) by young adulthood

Most infections asymptomatic

Severity of disease depends on: Inoculum size (intense exposure in closed space)

Cell-mediated immune function

Virulence of specific strain

Pre-existing immunity 

Pathophysiology

Inhaled microconidia germinate in lungs

Local infection occurs (pneumonitis)

Fungi phagocytosed as part of acute inflammation

Dissemination via lymphohematogenous route occurs early (in first 2 weeks)

Cell mediated immunity required for phagocytic cells to become fungicidal

Granulomatous inflammation develops as cell mediated immunity controls infection

Antibodies produced but not part of effective immune response

Pathophysiology

Re-infection can occur but usually mild due to pre-existing cell-mediated immunity

Most likely to occur in setting of high inoculum exposure

Reactivation/reinfection may also occur in the setting of immunosuppression (HIV, organ transplant)

Clinical manifestations

Clinical syndrome Percent of total

Asymptomatic infection 50–90

Symptomatic infection 10–50

Self-limited syndromes % of symptomatic

Acute pulmonary 60

Rheumatologic 10

Pericarditis 10

Chronic pulmonary 10

Disseminated 10

Histoplasmomas <1

Fibrosing mediastinitis <1

Case

 A 15 year old boy presents with diffuse pneumonitis (CXR on next slide). In the ER he is profoundly hypoxic and is intubated for respiratory failure. His father is at the adult ER for similar symptoms. You suspect histoplasmosis because the mother tells you they were hiking and exploring caves a few weeks ago. 

Diagnosis? Treatment?

What is the best way to make the diagnosis?

What treatment is recommended?

Pulmonary histoplasmosis Flu-like illness with cough, fatigue, fever

CXR findings

– normal to patchy infiltrates or miliary pattern with mediastinal lymph nodes

– "Buckshot" appearance on chest radiograph with subsequent calcification in cases of very heavy exposure

More severe with heavy inoculum, respiratory failure and death can occur without treatment

Disseminated - diffuse reticulonodular pattern (like miliary TB) – no adenopathy

Extrapulmonary disease may coexist as may rheumatologic manifestations: arthritis/arthralgia, erythema nodosum (or these can occur alone)

Histoplasma pneumonia

Subacute Pulmonary Histo

A child living in Nashville presents with cough for several weeks, low grade fever and dyspnea. The CXR is shown.

What is the best test to confirm the diagnosis of subacute pulmonary histoplasmosis?

Mediastinal granuloma

A 6 year old boy in Memphis is discovered to have a large right paratracheal mass deviating the trachea on a CXR done during influenza A infection. He became asymptomatic after the flu resolved.

What is the best treatment for this patient?

Mediastinal histoplasmosis

Exuberant granulomatous response may result in compression of mediastinal structures by lymph nodes

Tracheobronchi, esophagus, pulmonary vessels, SVC

May have associated granulomatous* lesions in lungs, liver, spleen

*Acute histoplasmosis may heal with calcification of granulomata

Mediastinal histoplasmosis

Masses may persist for years but do eventually resolve; may wax and wane over time

Symptoms may develop months or years after infection

Generally treatment for the histoplasmosis is not needed unless there are prolonged symptoms (and even then if of uncertain value)

Post-obstructive pneumonia

Masses have very few organisms so response to antifungal therapy unlikely

Steroids may help – data are limited

For post-obstructive pneumonia, treat for community-acquired pneumonia, not Histoplasma pneumonia

Treatment of mediastinal granuloma?

A. Itraconazole

B. Amphotericin B

C. Steroids

D. Steroids & itraconazole

E.No treatment

histo

Clinical Infectious Diseases 2007; 45:807–25

Disseminated histoplasmosis

Occurs in patients with depressed CMI

Risk correlates with CD4 count in HIV in endemic areas (was once leading “AIDS-defining illness” in certain parts of U.S.)

Also occurs in infants under one year of age with diffuse reticuloendothelial involvement - may cause pneumonitis, hepatosplenomegaly, bone marrow suppression; may be fulminant, fatal

Clinical Infectious Diseases 2007; 45:807–25

Laboratory diagnosis

Culture/Histopathology

Lung biopsy or BAL specimen will be positive in acute pulmonary with high inoculum or disseminated, not mild acute pulmonary

Use lysis centrifugation (Isolator) for blood culture in disseminated disease

May take 4 to 6 weeks to grow

Tissue specimens can be stained for fungus with silver stain or GMS, peripheral blood with Wright’s stain

Laboratory diagnosis

Antigen detection

Detected in urine, serum, CSF, BAL fluid

Most likely to be positive in disseminated disease (90% positive) or severe acute pulmonary (75% positive)

Urine > sensitive than serum

May cross react with blastomyces, paracoccidiodes

Laboratory diagnosis

Serologic testing

For yeast and mycelial antigens

Complement Fixation more sensitive [>1:8 in 90% of acute pulmonary cases; immunodiffusion more specific [76% M band +, 23% H band +]

Develop 2 to 6 weeks after infection

May be elevated from past or asymptomatic infection

Low titer or false negative if immunocompromised

Clinical Infectious Diseases 2007; 45:807–25

Treatment of Histoplasmosis in Children

Antifungal therapy (itraconazole, Ampho B) strongly recommended for severe pulmonary disease, disseminated disease, CNS disease

IDSA guidelines recommend antifungal therapy (with steroids) for severe pericarditis, prolonged or severe symptoms associated with mediastinal granuloma, etc – but evidence supporting this recommendation weak to non-existent

Anecdotal evidence of dramatic response to steroids in patients with bronchial/tracheal obstruction, etc, but weak overall evidence