History: Histoplasmosis was first reported in Panama in 1906
Endemic Area: midsection of US (Mississippi, Louisiana, Arkansas, Tennessee, Kentucky, Ohio, Indiana, Illinois, Missouri)
Incidence: Histoplasmosis is the most common endemic mycosis in the US
About 500k new infections occur annually in the US
Changing Geography of Infections
During 1950’s, may small outbreaks occurred associated with chicken coops
However, since then, with US population moving to urban areas, many current outbreaks occur in urban settings (frequently in areas of low endemicity)
Usually urban outbreaks occur due to soil being disturbed during construction projects
Changing Source of Infections
Previously, chicken coops were a common source of infections
Blackbird (grackles, starlings, red-winged blackbirds) roosts are now a common source, as large numbers of birds aggregate together (with large amounts of droppings)
Tree-lined river banks are common roosting sites
Mobilization of spores during construction leads to community-wide outbreaks involving hundreds-thousands of people
Common Sources:
Cutting up Fallen Trees for Firewood: common source of small outbreaks (chain saws create excellent aerosols)
Cases presented with pulmonary symptoms within 1 wk-6 mo after starting therapy: interstitial infiltrates > disseminated histoplasmosis
All cases were receiving concomitant immunosuppressives
Almost all cases were from a endemic area
Histoplasmosis may be life-threatening in these cases [Tsiodras S, Samonis G, Boumpas DT, et al. Fungal infections complicating tumor necrosis factor-alpha blockade therapy. Mayo Clin Proc 2008; 83:181-194]
Etiology
Histoplasma capsulatum infection
Name derives from fact that organism was first thought to be an encapsulated protozoan (but it actually an unencapsulated fungus)
Organism requires organic nitrogen for growth (this explains its presence in soil contaminated by bat or bird droppings)
Grows as aerial mycelium (with spores on side branches): spores are aerosolized when soil is disturbed
Dimorphic fungus: grows in mycelial phase at RT and yeast phase at body temperature
Coccidioidomycosis and Paracoccidioidomycosis are also dimorphic fungi (but Aspergillus and Cryptococcus are monomorphic fungi)
Physiology
Routes of Transmission
Inhalation of Spores: lung is the portal of entry in almost every case
Direct Inoculation of Spores via Skin: rare, but has been reported
Organ Transplantation with Infected Organ: rare, but has been reported
Incubation Period
9-17 days
Phases of Infection
Inhalation of spores: spores travel to alveoli
Conversion of Spores to Yeast Phase in Lung:
Initial Neutrophilic Response:
Alveolar Macrophage Response:
Ingestion (But Not Killing) of Yeast Forms by Macrophages:
Dissemination of Yeast Forms to Hilar Nodes/Liver/Spleen by Macrophages: transient fungemia (probably occurs) with formation of metastatic foci
Lymphocyte-Mediated Immunity: 2 weeks later
Impaired T-cell immunity may lead to disseminated disease
Granuloma Formation:
Necrosis: may be caseous and indistiguishable from that of TB
Fibrotic Healing with Calcification: calcifications may be seen in lung (as “coin lesions”/lung nodules), hilum, and spleen
Calcification of lung lesions occurs sooner and more quickly in children and young adults
Diagnosis
Sputum GS/Cult+Sens
Acute Histoplasmosis: sputum is not very useful for Acute Histo, because cough usually is not productive
Chronic Pulmonary Histoplasmosis: sputum cultures are usually positive
Sputum 10% KOH
Acute Histoplasmosis: sputum is not very useful for Acute Histoplasmosis, because the organism is intracellular, small, and unlike, Blastomycosis, has no characteristic morphologic features
Chronic Pulmonary Histoplasmosis:
FOB
Acute Histoplasmosis
FOB is diagnostically useful in cases with ARDS
FOB has 60% diagnostic yield for infiltrates in endemic areas
Chronic Pulmonary Histoplasmosis
FOB has 88% diagnostic yield in chronic Histo
Disseminated Histoplasmosis
FOB is useful (especially when using Pap/Silver/PAS stains)
FOB with BAL + fungal stains has 70% diagnostic yield in AIDS patients (this increases to 89% when cultures are also included): the BAL may detect other coinfections or alternative infectious diseases in 22% of these cases
TBB: enhances the diagnostic yield (although organism is difficult to see on H+E stains, so fungal stains are required)
Pleural Fluid
Exudate
Cell Count/Diff: lymphocyte-predominant
Pleural Bx
Non-caseating granulomas
Transthoracic Needle Aspiration
May be used
CXR/Chest CT Patterns
See below
Serology
Acute Histoplasmosis
Serology is important for diagnosis
Complement Fixation (CF): becomes positive >3 weeks after exposure and stays positive for months-years (although in decreasing titers)
A 4-fold rise in titers (or single titer >1:32): suggests recent infection
CF is negative in 30% of Acute Histo cases
Immunodiffusion (ID): more specific than a low-titer CF
Negative in 50% of Acute Histo cases
Does not reach maximum positivity in Acute Histo until 4-6 wks after exposure
Chronic Histoplasmosis
CF: usually have 1:8 or 1:16 titers that do not rise during period of observation
ID:
Disseminated Histoplasmosis
CF: negative in 50% of Disseminated Histo cases
Urine Histoplasma Polysaccharide Antigen Testing: positive in almost all AIDS patients with Disseminated Histo
Urine Histoplasma polysaccharide antigen test is useful to follow course of treatment and to predict relapses
Serum Histoplasma Polysaccharide Antigen Testing: useful to follow course of treatment and to predict relapses
Histoplasmosis Skin Testing
Usually positive in most of population by adulthood in endemic areas -> not diagnostically useful
Disseminated Histo: skin test may be negative -> negative skin test does not rule out disease
CBC
Disseminated Histoplasmosis: pancytopenia
ACE Level
May be elevated
Blood Cult+Sens
Lysis-centrifugation system may increase yields
90% yield in AIDS patients (higher organism load than in other immunocompromised patients)
Peripheral blood smears (buffy coat) are positive in 50% of AIDS patients
Bone Marrow Bx
Disseminated Histoplasmosis: may be diagnostic in these cases (organism is difficult to see on H+E stains, so fungal stains are required)
Shows macrophages full of yeast and/or granulomas
Liver Bx
Disseminated Histoplasmosis: may be diagnostic in these cases (organism is difficult to see on H+E stains, so fungal stains are required)
Clinical Presentations
Pulmonary Manifestations
Asymptomatic Histoplasmosis
Most normal persons are asymptomatic
Acute Histoplasmosis
CXR/Chest CT Pattern
Normal CXR: in many cases (even with symptoms)
Single (or Occasionally Diffuse Micronodular) Infiltrate: predominantly in better ventilated lower lung zones/may be present with or without hilar+mediastinal adenopathy
Ipsilateral Hilar+Mediastinal Adenopathy (common): may be present with or without infiltrate
Pleural Effusion (rare, seen in <1% of cases): usually presents subacutely/effusions usually have coexistent parenchymal infiltrates or subpleural nodule
Clinical
Symptoms may be severe with larger numbers of symptomatic patients (when source of outbreak is an enclosed space, like cave, cellar, etc, with large amount of inhaled spores) or may be mild with <50% of cases having symptoms (when source is in open air, with smaller number of inhaled spores)
Influenzae-Like Symptoms: abrupt onset of malaise/fatigue/myalgias/headache
Arthralgias/Arthritis (Inflammatory, Polyarthritis): arthralgias may be severe and may last days-weeks
Fever:
Dry Cough: harsh
Erythema Nodosum/Erythema Multiforme (only 1% incidence of these in Acute Histo): occur more commonly in women with normal or mildly abnormal CXR’s
Occur at height of cell-mediated immunity
Substernal Chest Pain:
Granulomatous Mediastinitis: enlarged lymph nodes may result in compression of trachea, SVC syndrome, esophageal compression, etc.
Surgical resection of nodes/endovascular stenting may be necessary in some cases (as nodes typically slowly improve without treatment)
Pericarditis (6.3% of cases): usually sterile transudates/probably reactive (not due to direct spread of infection)
Absence of Hepatosplenomegaly: hepatosplenomegaly indicates disseminated infection
[[ARDS]]: rarely occurs
Recovery: normal patients recover from Acute Histoplasmosis 99% of time
Residual Changes (after healing of primary infiltrate and adenopathy)
Lung Nodule: residuum of contracted prior infiltrate, often lower lobe-predominant with central calcification (”target” appearance)
If calcified, makes differentiation from malignancy easier
Satellite lesions are fairly common (seldom exceed 4-5 nodules)
Calcified Hilar/Mediastinal Nodes (often larger than those from TB): after resolution of caseous necrosis in enlarged lymph nodes
Broncholithiasis: due to calcification of nodes with erosion into adjacent structures/patients may present with obstructive symptoms, hemoptysis, lithoptysis (expectoration of stones or gritty material), T-E fistula
Histo is the most common cause of broncholithiasis in US
Fibrosing Mediastinitis: due to fibrotic reaction in mediastinum with encasement of local structures
Splenic Calcifications: seen in 70% of autopsies in endemic areas
Chronic Pulmonary Histoplasmosis
Occurs in patients with pre-existing lung disease (such as smokers with centrilobular emphysema)
Symptoms/Signs: mimic those of TB
Dyspnea:
Low-Grade Fever:
Anorexia:
Weight Loss:
Productive Cough with Mucopurulent Sputum:
Night Sweats: less severe than in TB
CXR/Chest CT Pattern:
Upper Lobe Fibrocavitary Infiltrates: mimics cavitary disease of TB, as it often involves upper lung parenchyma that was previously abnormal (infiltrate outlines the emphysematous airspaces, mimicking cavities)
Recovery
Improvement may occur gradually over time and resolve spontaneously in some cases
However, infection may progress to destroy more lung parenchyma, resulting in fibrotic volume loss in upper lobes
Disseminated Histoplasmosis
T-Cell Dysfunction: almost all cases occur in patients with T-cell impairment (Hodgkin’s, steroids, AIDS, cytotoxics, after anti-TNF therapy)
Most cases now occur in AIDS patients in endemic areas
However, a few cases have been reported with no known T-cell dysfunction (unclear if some transient T-cell dysfunction was etiologic)
Modes of Infection:
Primary Infection (most common): In most cases, infected aerosol exposure occurs while immunocompromised -> Acute Histo -> progression to Disseminated Histo
AIDS patients with Acute Histo almost always progress to Disseminated Histo
Reactivation (less common): during more intense immunosuppression (during progression of AIDS, during steroids, etc.)
Acute, Severe Illness Pattern
Fever:
Hepatosplenomegaly:
Pancytopenia:
DIC:
Chronic Wasting Pattern:
Anorexia:
Weight loss:
Fever:
Mucosal/Mucocutaneous Junction Ulcers: of mouth, oropharynx, rectum, and penis
Itraconazole 200-400 mg/day x 3-24 mo (depending on type of disease)
IV Itraconazole is available (limit use to 2 wks to avoid cyclodextrin nephrotoxicity/avoid with CrCl <30 ml/min)
Alternative: Fluconazole 400-800 mg/day x 6-24 mo
Alternative: Ketoconazole 400 mg/day x 6-24 mo
Alternative: Ampho 0.5-0.7 mg/kg/day (to total dose of 35 mg/kg)(Liposomal Ampho is somewhat more effective)
Maintenance (AIDS patients): Itraconazole 200 mg/day fro life or Ampho 1 mg/kg/wk
Severe Histoplasmosis (Pulmonary, Disseminated, Immunocompromised host)
Ampho 0.7-1 mg/kg/day unil stabilized (Liposomal Ampho is somewhat more effective), then Itraconazole 400 mg/day x 12 mo
IV Itraconazole is available (limit use to 2 wks to avoid cyclodextrin nephrotoxicity/avoid with CrCl <30 ml/min)
Alternative: Ampho 0.5-0.7 mg/kg/day (to total dose of 35 mg/kg), then Itraconazole 400 mg/day x 12 mo
Maintenance (Required for AIDS patients): Itraconazole 200 mg/day for life or Ampho 1 mg/kg/wk
Use of Anti-TNFα Medications in Patients At Risk for Histoplasmosis
Some have suggested that anti-TNFα therapy should be withheld in patients already being treated for Histo
However, if anti-TNFα therapy is necessary, chronic suppression with Itraconazole is probably indicated [Wood KL, Hage CA, Knox KS, et al. Histoplasmosis after treatment with anti-tumor necrosis factor-alpha therapy. Am J Respir Crit Care Med 2003; 167:1279-1282]
References
Newman SL. Cell-mediated immunity to Histoplasma capsulatum. Semin Respir Infect 2001; 16:102-108
Lee JH, Slifman NR, Gershon SK, et al. Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor-alpha
antagonists infliximab and etanercept. Arthritis Rheum 2002; 46:2565-2570
Wood KL, Hage CA, Knox KS, et al. Histoplasmosis after treatment with anti-tumor necrosis factor-alpha therapy. Am J Respir Crit Care Med 2003; 167:1279-1282
