Fungal Pneumonia: Causes and Treatments

Fungal Pneumonia Overview

• Fungal pneumonia includes esporotrichosis of subcutaneous mycoses and histoplasmosis of deep or systemic mycoses.

Pulmonary Mycoses Objectives

• Focus on dimorphic, endemic, and pathogenic fungi.
• Includes epidemiology and ecology.
• Focus on clinical manifestations.
• Focus on laboratory diagnosis including direct exam/histopathology, culture identification, and serology
• Includes treatment options.

Systemic Fungal Pathogens

• Opportunistic fungi have a worldwide distribution and include hyaline molds like Aspergillus and Zygomycetes.
• Yeasts/yeast-like fungi like Candida, Cryptococcus neoformans, and Pnemocystis jirovecii are opportunistic.
• Pathogenic endemic dimorphic fungi include Histoplasma capsulatum (unique in PR), Blastomyces dermatitides, Coccidioides immitis, and Paracoccidiodes brasiliensis.
• Opportunistic fungi typically affect Immunocompromised hosts.
• Pathogenic fungi typically affect Immunocompetent hosts.

Causes of Lower Respiratory Tract Infections in Adults

• Lower respiratory tract infections in adults can be caused by inhalation, aspiration (community-acquired or hospital-acquired), or hematogenous spread.
• Fungi in respiratory tracts include Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides immitis.
• These fungi typically cause chronic or subacute pneumonia.

Characteristics of Systemic Mycoses

• Systemic mycoses are acquired by inhalation and are dimorphic.
• They are specific to endemic regions.
• Most cases are asymptomatic or subclinical.
• Initial forms are primary pulmonary similar to TB.
• They are not transmitted from person to person.
• Extra-pulmonary dissemination may occur.
• Disseminated forms are severe.
• Diagnosed by isolation of the etiologic agent.

Endemic-Dimorphic Fungi

• These fungi are filamentous mycelia in nature that form conidia (spores) which are inhaled.
• Coccidioidomycosis: Saprophytic form includes hyaline septate hyphae and arthroconidia (3 x 6 µm).
• Histoplasmosis: Saprophytic form includes hyaline septate hyphae, tuberculate macroconidia (8-16 µm), and small oval microconidia (3-5 µm).
• Blastomycosis: Saprophytic form includes hyaline septate hyphae and short conidiophores bearing single globose to piriform conidia (3-5 µm).
• Paracoccidioidomycosis: Includes hyaline septate hyphae arthroconidia and rare globose conidia (3-5 µm).
• Coccidioidomycosis: The tissue form reaches the lung and is a spherule that has endospores inside.
• Histoplasmosis: The tissue form converts to yeast and grows intracellularly
• Blastomycosis: The tissue form converts to yeast.
• Paracoccidioidomycosis: Small inhaled conidia become yeast and have multiple buds.

Distribution of Endemic Fungi

• Coccidioidomycosis is found in the Southwest USA, Northern Mexico, and parts of South America, in soil that is alkaline and dry.
• Histoplasmosis is found in Ohio and Mississippi river valleys, and in bat and avian habitats (guano).
• Blastomycosis is found in Ohio and Mississippi river valleys, USA-Canada border Great Lakes
• Paracoccidioidomycosis is found in South and Central America

Pathogenesis

• Excreta is a good substrate for Histoplasma, which grows and produces conidia that aerosolize.
• Aerosols are created, inhaled, and small conidia reach the lungs, where they settle and grow at 37 degrees.
• The fungi can resist the host's defenses and grow, forming pneumonia.
• The fungus transforms from a conidia to an intracellular yeast.
• In a normal individual, the person develops immunity and the host wins.
• 99% of infected people are asymptomatic.

Biology of Histoplasmosis

• Murciélagos produce guanos/Bat guano produces conidia, which produce aerosols.
• The tropism of the fungi from most to least is liver, spleen, lymph nodes, and bone marrow.
• In the lung, the fungus becomes an intracellular yeast.
• The fungus disseminates to other parts of the body and travels to lymph nodes.
• The warmer temperature inside the host signals a transformation to an oval, budding yeast (4).
• The yeast are phagocytized by immune cells and transported to regional lymph nodes (5).

Histoplasmosis Epidemiology

• Etiologic agent: Histoplasma capsulatum var. capsulatum (Americas) and Histoplasma capsulatum var. duboisii (Africa) (asexual), and Ajellomyces capsulatum (sexual).
• Has a worldwide distribution with greatest prevalence in temperate zones of the Americas
• The agent is found in the soil of endemic areas.
• Has local outbreaks in relation to caves and birds.
• Disseminated form is common in AIDS patients.
• In PR Histoplasmosis capsulatum is found in Utuado y Aguas Buenas

Histoplasmosis Pathogenesis

• Following lung infection, organisms spread through lymphatics to the regional lymph nodes and hematogenously to other organs.
• In immunocompetent persons, the pathologic findings resemble tuberculosis with granulomas evolving to caseus necrosis.
• Granulomas heal with fibrosis and may calcify.
• Histoplasmosis is a fungus that can infect immunocompetent people.
• The infection resembles tuberculosis with granulomas.
• The body protects itself by making granulomas.

Histoplasmosis Clinical Classification

• Primary pulmonary histoplasmosis can be asymptomatic or subclinical (60-95%).
• Symptomatic (5%) primary pulmonary histoplasmosis can be mild, moderate, or severe (similar to TB).
• Progressive Histoplasmosis can be either Disseminated and Acute or Disseminated and Chronic

Histoplasmosis Primary Pneumonia

• Histoplasmosis primary pneumonia is sporadic in normal hosts.
• It can be asymptomatic or flu-like.
• 90-95% are asymptomatic with normal X-rays.
• Radiologic features are varied.
• Due to Inhalation of conidia
• Causes Conversion to the yeast phase and replication inside Macrophages.
• Shows Patchy pneumonitis (opacities) in one or more lobes often with hilar or mediastinal lymphadenopathy

Histoplasmosis Primary Pneumonia Sporadic in Normal Hosts

• Opacity clear or develop nodule
• Granuloma, caseous necrosis, and calcifications (Ghon lesion)
• Associated with calcification of the draining hilar or mediastinal lymph nodes (Rhanke complex)
• Generally results in "Permanent" immunity
• Does not usually require treatment.

Histoplasmosis Primary Pneumonia in persons with CMI Defects

• More severe than in normal hosts
• Prostration, fever, chills, and sweats are prominent
• Marked dyspnea and hypoxemia can progress to adult respiratory distress syndrome (ARDS)
• Diffuse bilateral infiltrates at the chest radiographs

Histoplasmosis Primary Pneumonia Epidemic

• Caused by exposure to a heavy inoculum.
• An acute severe pulmonary infection known as epidemic histoplasmosis.
• Diffuse reticulonodular pulmonary infiltrates.
• Characterized by High fever, chills, fatigue, dysnea, cough, and chest pain.
• Acute respiratory failure and death may ensue.

Complications of Pulmonary Histoplasmosis

• Patient will rarely experience respiratory symptoms that become severe, with dyspnea and cyanosis.
• Rare sequelae include persistent lymphadenopathy with bronchial obstruction, fibrosing mediastinitis following caseous necrosis of lymph nodes, and pericarditis

Chronic Pulmonary Histoplasmosis

• Chronic pulmonary histoplasmosis affects predominately middle-aged male patients, who may have emphysema or be smokers.
• Common symptoms include cough with purulent and sometimes bloodstained sputum, weight loss, and fever.
• The chest x-ray shows segmental lesions in the upper lobes often with fibrosis and cavitation similar to chronic TB.

Disseminated Histoplasmosis

• Infection beyond the thorax (48% no evidence of lung involvement).
• Infants and patients with defects in CMI (AIDS) may have a disseminated infection.
• Compromise of the RES (liver, spleen, BM), skin & mucous membranes.
• Usually lethal & requires treatment.

Histoplamosis & AIDS Clinical Presentation

• Chronic febrile syndrome.
• Diffuse Interstitial or reticulonodular infiltrates (pneumonia) progress to ARDS.
• Diffuse involvement of multiple organs (Hepatosplenomegaly, Lymphadenopathy, Mucous ulcers, skin lesions).
• Meningitis
• In patients with AIDS Histoplasmosis is a fast acting disease that spreads quickly to other organs.

Disseminated Histoplasmosis Clinical Manifestations

• Progressive disseminated histoplasmosis typically seen in infants, the elderly, and in immunosuppressed patients.
• Chest x-rays may show diffuse interstitial infiltrates and hilar lymph nodes may be enlarged
• Low magnification will show intra alveolar exudates.
• High magnification will show a large number of magenta staining organisms.
• The amount of inflammation can lead to limited respiration.

Histoplasmosis Clinical Manifestations

• Acute pulmonary (Immunocompetent): Fever/chills/headache, non-productive cough, and malaise.
• Chronic pulmonary: Cough, hemoptysis, dyspnea.
• Disseminated (More in infants): Weight loss, enlarged liver/spleen/lymph nodes, mucosal ulceration, adrenal insufficiency, pancytopenia due to bone marrow suppression, ulcers and mass lesions in ileum/colon.

Histoplasmosis Lab Dx Direct Exam

• Look for intracellular small yeasts (1-2 µm) in bone marrow, blood smears, liver tissue, skin, and mucosal lesions.

Histoplasmosis Lab Dx Culture

• Use sputum, blood (Isolator), bone marrow, and tissue biopsy.
• Can be Mycelial phase or Yeast phase
• Mycelial phase: Up to 6 weeks.
• Dimorphism
• Infectious microconidia
• Exo antigen/Anticuerpos
• Genetic probes

Histoplasmosis Lab Dx Serology

• Immunodiffusion M & H bands.
• Inmunodiffusion: 75-85%.
• Look antibodies in the sample.
• Complement fixation: 4X titers or 1:32; 80-90%.
• Histoplasma polysaccharide antigen (HPA) in urine and serum shows 90-97% disseminated cases.
• Prognostic test: relapse is an increase of 2 units.

Histoplasmosis Treatment

• Mild acute pulmonary Histoplasmosis primary therapy is Itraconazole 200 mg daily or bid for 6–12 weeks.
• Mild acute pulmonary Histoplasmosis alternate therapy is Posaconazole 400 mg bid, or voriconazole 200 mg bid, or fluconazole 800 mg daily
• A more effective Histoplasmosis primary therapy but with less toxicity is, Liposomal amphotericin B (3-5 mg/kg/d for 1–2 weeks) followed by itraconazole (200 mg bid for 12 weeks.)
• A more effective Histoplasmosis alternate therapy is, using Amphotericin B lipid complex 3-5 mg/kg/d, or amphotericin B deoxycholate, at (0.7-1.0 mg/kg/d)