Fungal and parasitic respiratory tract infection

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Fungal and Parasitic Respiratory Tract Infections

PART 1: FUNGAL INFECTIONS

Overview

Fungi are eukaryotic organisms that cause respiratory disease via three main mechanisms: direct tissue invasion (opportunistic infections), hypersensitivity reactions (ABPA), or saprophytic colonization. They are classified as:

Yeasts (unicellular, e.g., Candida, Cryptococcus)
Molds - septate hyaline (Aspergillus, Fusarium), aseptate/sparsely septate (Mucor, Rhizopus), or melanized/dematiaceous
Dimorphic fungi - mold at room temperature, yeast at body temperature (endemic fungi: Histoplasma, Blastomyces, Coccidioides)

The epidemiology of opportunistic mycoses is evolving, driven by expanding immunomodulating therapies, more invasive procedures, climate change, and antiretroviral therapy in HIV patients.

Murray & Nadel's Textbook of Respiratory Medicine, p. 1301

1. Aspergillosis

Organism: Aspergillus fumigatus (most common), A. flavus, A. niger, A. terreus (intrinsically amphotericin B-resistant)

Key morphology: Septate, narrow (3-6 µm) hyphae with acute angle (45°) branching in tissue specimens (methenamine silver stain).

Invasive Aspergillosis - septate hyphae with acute angle branching (Methenamine silver stain x450)

Micrograph showing invasive Aspergillus infection: septate hyphae branching at acute 45° angles (Methenamine silver stain, x450 magnification).

Two major pulmonary forms:

a) Invasive Pulmonary Aspergillosis (IPA)

Risk factors: Prolonged neutropenia (AML on chemotherapy), hematologic malignancies, HCT/SOT recipients (especially lung transplant), advanced HIV, chronic granulomatous disease, critical illness (COPD, cirrhosis, DM, renal failure), severe influenza
Pathogenesis: Hyphae invade respiratory mucosa and alveolar capillaries → angioinvasive disease → intravascular thrombosis, hypoxia, coagulative necrosis ("halo sign" on CT)
Imaging: Halo sign (nodule surrounded by ground-glass opacity), air crescent sign, cavitation
Diagnosis: CT chest, serum/BAL galactomannan (sensitivity ~70% in hematologic malignancies), beta-D-glucan, BAL culture, tissue biopsy
Treatment (first-line): Voriconazole (oral/IV) - superior to amphotericin B in landmark trial. Alternative: isavuconazole. Lipid formulations of AmB (ABLC 5 mg/kg/day or liposomal AmB 3-5 mg/kg/day) for refractory/intolerant cases. Echinocandins (caspofungin) as salvage therapy.

b) Chronic Pulmonary Aspergillosis (CPA)

Occurs in patients with underlying structural lung disease (prior TB, COPD, bullae)
Subtypes: simple aspergilloma, chronic cavitary, subacute invasive
Aspergilloma = fungus ball within pre-existing cavity; hemoptysis is the main complication

c) Allergic Bronchopulmonary Aspergillosis (ABPA)

Hypersensitivity to Aspergillus antigens in asthmatics/CF patients
Features: episodic bronchospasm, fleeting pulmonary infiltrates, central bronchiectasis, elevated IgE (total and specific), eosinophilia, positive skin test
Murray & Nadel's Textbook of Respiratory Medicine, pp. 1310-1315

2. Histoplasmosis

Organism: Histoplasma capsulatum (dimorphic fungus) Endemic areas: Ohio and Mississippi River valleys (USA), Latin America; found in soil enriched by bird/bat droppings; exposure in caves (attack rate 50-100%)

Pulmonary syndromes (Fishman's classification):

Syndrome	Age	Course	Imaging	Treatment
Acute	Any	1-2 weeks	Diffuse airspace disease, lymphadenopathy	Only if prolonged or severe
Subacute	Any	Weeks to months	Focal airspace disease, lymphadenopathy	If symptoms >1 month
Chronic	>45, structural lung disease	Months to years	Upper lobe cavitary, thick-walled bullae, emphysema	Yes (itraconazole)
Progressive disseminated (PDH)	Immunocompromised	1-2 weeks	Diffuse airspace opacities	Yes (AmB then itraconazole)

Mediastinal complications: Mediastinal adenitis (young), mediastinal granuloma, fibrosing mediastinitis (most severe - can obstruct airways/vessels)

Diagnostics (sensitivity varies by syndrome):

Histoplasma urinary antigen: 83% acute, 92% PDH (best overall test)
Serology (CF/ID): 95% subacute, 83% chronic
Culture: 42-74% (gold standard but slow)
BAL culture: positive ~50% acute; BAL fungal stain: 70% diffuse PDH in AIDS

Treatment:

Mild/moderate: Itraconazole
Severe/PDH: Liposomal AmB initially, then step-down to itraconazole
Monitor with serial urine antigen levels (declines with treatment, rises with relapse)
Fishman's Pulmonary Diseases and Disorders, pp. 2360-2363

3. Cryptococcosis

Organism: Cryptococcus neoformans (most common, HIV-associated), C. gattii (immunocompetent) Source: Pigeon droppings (C. neoformans); inhalation is the portal of entry

Clinical features:

Portal of entry is the lung, but pulmonary infection is often asymptomatic or minimally symptomatic
Only <5% present with isolated pneumonia
Most dangerous manifestation: cryptococcal meningitis (especially CD4 <100 cells/µL)
Symptoms when present: cough ± hemoptysis, fever, malaise, pleuritic chest pain, dyspnea
Chest radiograph: diffuse bilateral interstitial opacities (65%), hilar adenopathy (27%), pleural effusion (14%), focal consolidation (13%), nodular opacities (11%), cavitation (11%), or normal CXR

Cryptococcal infection - chest X-ray showing solitary cavitary lesion in right lower lung

Frontal chest radiograph: HIV patient with cavitary cryptococcal lesion in the right lower lung field.

Diagnosis:

Cryptococcal antigen (CRAG) test on serum, CSF, urine, BAL - very sensitive and specific
Negative serum CRAG virtually excludes cryptococcal meningitis
India ink stain of CSF (polysaccharide capsule)
Culture of sputum, BAL, or blood

Treatment:

Non-CNS mild-moderate (immunocompetent): Fluconazole
Severe/CNS disease (HIV/immunocompromised): Liposomal AmB + flucytosine (induction) → fluconazole (consolidation/maintenance)
Murray & Nadel's Textbook of Respiratory Medicine, pp. 1835-1838; Frameworks for Internal Medicine, p. 1945

4. Mucormycosis (Zygomycosis)

Organisms: Mucor, Rhizopus, Cunninghamella (order Mucorales) Key morphology: Aseptate (or sparsely septate), broad, ribbon-like hyphae with irregular, wide-angle branching (>90°) - distinguishes from Aspergillus

Forms:

Rhinocerebral (most common, diabetics with DKA)
Pulmonary (neutropenic patients, hematologic malignancy, prolonged steroid use, iron overload/deferoxamine therapy)
Cutaneous, GI, disseminated

Pulmonary mucormycosis:

Presents with fever, cough, chest pain; rapidly progressive consolidation, cavity, "reverse halo sign" (CT)
Angioinvasive → thrombosis and infarction
Mortality very high (>50%)

Diagnosis: Tissue biopsy with culture (serum beta-D-glucan and galactomannan are negative - important distinction from Aspergillus)

Treatment:

Liposomal AmB (first-line, 5-10 mg/kg/day)
Isavuconazole or posaconazole (step-down or salvage)
Surgical debridement essential
Control underlying predisposing condition (glucose control, reduce immunosuppression)
Murray & Nadel's Textbook of Respiratory Medicine, p. 1316

5. Pneumocystis jirovecii Pneumonia (PCP)

Although taxonomically a fungus (formerly thought to be a protozoan), Pneumocystis jirovecii causes a distinct form of opportunistic pneumonia.

Risk factors: CD4 <200 cells/µL (HIV), organ transplant, prolonged corticosteroids, cytotoxic chemotherapy

Clinical features: Subacute onset of progressive dyspnea, dry cough, low-grade fever; hypoxemia disproportionate to clinical examination

Imaging: Bilateral perihilar ground-glass opacities on CT; "bat-wing" pattern on CXR; can be normal in early disease

Diagnosis:

BAL with immunofluorescence (gold standard, sensitivity >90%)
Serum beta-D-glucan elevated
PCR on BAL or sputum

Treatment:

Trimethoprim-sulfamethoxazole (TMP-SMX) - first-line; high-dose IV for severe disease
Adjunctive corticosteroids if PaO2 <70 mmHg or A-a gradient >35 mmHg
Alternatives: Pentamidine, atovaquone, clindamycin + primaquine
Prophylaxis: TMP-SMX when CD4 <200 cells/µL

6. Antifungal Drug Classes (Summary)

Class	Agents	Mechanism	Key Uses
Polyenes	Amphotericin B (lipid formulations preferred)	Binds ergosterol → membrane disruption	Mucormycosis, severe IFI
Azoles	Fluconazole, Itraconazole, Voriconazole, Posaconazole, Isavuconazole	Inhibit ergosterol synthesis (CYP51)	Aspergillosis (voriconazole 1st line), Candida, endemic fungi
Echinocandins	Caspofungin, Micafungin, Anidulafungin	Inhibit beta-1,3-glucan synthase → cell wall disruption	Candida (1st line), salvage in Aspergillus

Murray & Nadel's Textbook of Respiratory Medicine, p. 1301

PART 2: PARASITIC RESPIRATORY INFECTIONS

1. Pulmonary Hydatid Disease (Echinococcosis)

Organism: Echinococcus granulosus (cystic) and E. multilocularis (alveolar)

Life cycle and transmission:

Definitive hosts: carnivores (dogs, foxes)
Intermediate hosts: sheep, cattle
Humans = accidental hosts via faeco-oral transmission
Larvae travel hematogenously → liver first, then lungs (~25%)

Pathology:

Cyst has 3 layers: pericyst (host-derived fibrous), ectocyst (laminar), endocyst (germinal/inner)
Daughter cysts may form within maternal cyst

Clinical features:

Often asymptomatic until cyst enlarges or ruptures
Symptoms: chest pain, cough, dyspnea
Rupture → "hydatid vomica" (expectoration of salty cyst fluid + daughter cysts), anaphylaxis, pleural seeding ("white cancer"), bronchopleural fistula

Imaging:

CT/CXR: round or oval well-defined cyst
"Water lily sign" (floating membranes after partial collapse)
Gharbi classification describes ultrasonographic stages

Diagnosis:

Imaging appearance is characteristic
Serology confirms
Do NOT aspirate - risk of anaphylaxis and seeding

Treatment:

Albendazole (medical treatment, also perioperative to prevent seeding)
Surgical resection (definitive) - avoid spilling cyst contents
PAIR (Puncture, Aspiration, Instillation of 95% alcohol, Re-aspiration) for liver cysts
E. multilocularis: primarily albendazole (often requires prolonged/lifelong therapy)
Rosen's Emergency Medicine, p. 2676; Grainger & Allison's Diagnostic Radiology, p. 1484

2. Pulmonary Paragonimiasis

Organism: Paragonimus westermani (lung fluke) Endemic: Southeast Asia, West Africa, Central/South America Transmission: Ingestion of raw/undercooked crabs or crayfish containing metacercariae

Life cycle: Metacercariae → penetrate intestinal wall → peritoneum → diaphragm → pleura → lung parenchyma → form cysts containing adult flukes

Clinical features:

Chronic cough (can mimic tuberculosis)
Rusty-brown or blood-tinged sputum (hemoptysis)
Pleuritic chest pain
Pleural effusion with high eosinophil count

Imaging: Irregular cystic lesions, "ring shadow," pleural effusion

Diagnosis:

Sputum/stool microscopy - Paragonimus eggs (operculated)
Serology (ELISA)
Peripheral eosinophilia is characteristic

Treatment: Praziquantel (first-line); triclabendazole (alternative)

3. Pulmonary Toxocariasis (Visceral Larva Migrans)

Organism: Toxocara canis or T. cati (dog/cat roundworm larvae) Transmission: Ingestion of contaminated soil with embryonated eggs

Pulmonary manifestation:

Transient pulmonary infiltrates + severe eosinophilia ("Löffler's syndrome")
Wheezing, cough, dyspnea
Affects mainly children

Diagnosis: Serology (ELISA for Toxocara); biopsy shows eosinophilic granuloma with larval fragments

Treatment: Albendazole or mebendazole; corticosteroids for severe pulmonary disease

4. Pulmonary Involvement in Malaria

Plasmodium falciparum can cause acute lung injury/ARDS (pulmonary malaria)
Occurs in ~10% of severe falciparum malaria
Mechanism: sequestration of parasitized RBCs in pulmonary vasculature, cytokine storm
Features: rapid progression to respiratory failure
Treatment: Artesunate IV (preferred over quinine for severe malaria) + respiratory support

5. Pulmonary Strongyloidiasis

Organism: Strongyloides stercoralis Special feature: Can cause hyperinfection syndrome in immunocompromised (especially corticosteroid use) - filariform larvae invade gut wall en masse, disseminate carrying gut bacteria → gram-negative sepsis + pneumonia

Pulmonary features:

Löffler-like syndrome during larval migration
Hyperinfection: bilateral interstitial infiltrates, sometimes respiratory failure
Larvae may be found in sputum/BAL

Treatment: Ivermectin (first-line); albendazole (alternative)

6. Pulmonary Amoebiasis

Organism: Entamoeba histolytica Mechanism: Extension of hepatic amoebic abscess through the diaphragm into the right pleural space/lung base

Clinical features:

Right lower lobe consolidation or pleural effusion
Chocolate-brown ("anchovy sauce") sputum if hepatobronchial fistula forms
"Anchovy sauce" pus is pathognomonic

Treatment: Metronidazole (tissue amoebicide) followed by diloxanide furoate (luminal)

7. Ascariasis - Pulmonary Phase

Organism: Ascaris lumbricoides Pulmonary phase: Larvae migrate through pulmonary capillaries into alveoli → "Löffler's syndrome" (transient eosinophilic pneumonitis, bilateral migratory infiltrates, cough, fever, wheeze)

Treatment: Albendazole or mebendazole (for the intestinal phase); pulmonary phase is typically self-limiting

Key Distinguishing Points Summary

Feature	Aspergillus	Mucormycosis	Cryptococcus	Histoplasma	Hydatid Cyst	PCP
Hyphae	Septate, 45° acute branching	Aseptate, wide-angle	Encapsulated yeast	Dimorphic yeast in tissue	N/A (helminth)	Cysts/trophozoites
Key host	Neutropenic, HCT	DKA, iron overload	CD4 <100 (HIV)	Normal or immunocompromised	Any (endemic area)	CD4 <200
1st-line Rx	Voriconazole	Liposomal AmB + surgery	Fluconazole (mild) or AmB+5FC (CNS)	Itraconazole or AmB	Albendazole + surgery	TMP-SMX
Galactomannan	Positive	Negative	Negative	Negative	N/A	Negative
Beta-D-glucan	Positive	Negative	Positive	Positive	N/A	Elevated

Sources:

Murray & Nadel's Textbook of Respiratory Medicine, 2-Volume Set
Fishman's Pulmonary Diseases and Disorders, 2-Volume Set
Rosen's Emergency Medicine
Frameworks for Internal Medicine
Grainger & Allison's Diagnostic Radiology

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