Histoplasmosis

Epidemiology

  • 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)
    • Bat Caves:
    • Storm Cellars:

Risk Factors

  • [[Anti-TNF Therapy]]
    • Relative Risk: infliximab > etanercept > adalimumab
    • 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
    • Adrenal Involvement: may cause Addison’s disease
    • CNS Involvement: chronic meningitis, intracranial histoplasmoma
    • Endocarditis: vegetations occur on native and prosthetic valves/vegetations may be large and may embolize
    • Abdominal Aortic Aneurysm Involvement: few case reports
  • CXR/Chest CT Pattern:
    • Normal or Diffuse Infiltrates:

Histoplasmoma of UA

  • Unlikely to produce significant UA obstruction (see [[Obstructive Lung Disease]])

Dermatologic Manifestations


Treatment

Treatment of Pleural Effusion

  • Usually resolves spontaneously over weeks
  • Antifungal therapy is required for effusions that persist for >3-4 weeks or in immunocompromised host

Mild-Moderate Histoplasmosis (Pulmonary, Disseminated)

  • 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
  • Tsiodras S, Samonis G, Boumpas DT, et al. Fungal infections complicating tumor necrosis factor-alpha blockade therapy. Mayo Clin Proc 2008; 83:181-194
  • 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