22.4 Respiratory Mycoses

Respiratory Mycoses

Respiratory mycoses are fungal infections of the lungs and airways. They range from mild, self-limiting illness in healthy people to life-threatening invasive disease in immunocompromised patients. Understanding which fungi cause these infections, how they evade host defenses, and how they're treated is central to this topic.

Common Respiratory Fungal Pathogens

Several fungi are responsible for the major respiratory mycoses. Some are true pathogens (they can infect healthy individuals), while others are opportunistic (they cause disease mainly when the immune system is compromised).

Aspergillus species cause a spectrum of disease collectively called aspergillosis:

• A. fumigatus is the most common cause of invasive aspergillosis in immunocompromised patients. Its small conidia (2–3 µm) reach deep into the alveoli easily.
• A. flavus produces aflatoxins and can trigger allergic responses, including allergic bronchopulmonary aspergillosis (ABPA) and fungal sinusitis.
• A. niger is rarely pathogenic but can cause otomycosis (ear infections) and pneumonia in immunocompromised individuals.
• A. terreus is intrinsically resistant to amphotericin B, which limits treatment options significantly.

Cryptococcus neoformans is an encapsulated yeast found in soil contaminated with pigeon droppings. It causes cryptococcosis, primarily affecting the lungs and central nervous system (cryptococcal meningitis). The polysaccharide capsule is its major virulence factor.

Pneumocystis jirovecii is an atypical fungus that cannot be cultured on standard media. It causes Pneumocystis pneumonia (PCP), one of the most common opportunistic infections in AIDS patients with CD4 counts below 200 cells/µL.

Dimorphic fungi exist as molds in the environment and convert to yeast at body temperature (37°C). This thermal dimorphism is key to their pathogenicity:

• Histoplasma capsulatum causes histoplasmosis. It's found in soil enriched with bat or bird droppings, especially in the Ohio and Mississippi River valleys.
• Coccidioides immitis and C. posadasii cause coccidioidomycosis (Valley Fever), endemic to the arid southwestern U.S. (Arizona, California) and parts of Central and South America. In tissue, they form distinctive spherules filled with endospores rather than typical yeast cells.
• Blastomyces dermatitidis causes blastomycosis, leading to pulmonary infections and characteristic verrucous (wart-like) or ulcerative skin lesions. It's endemic to the Great Lakes region and Ohio/Mississippi River valleys.

Sporothrix schenckii is also dimorphic and primarily causes lymphocutaneous sporotrichosis (a skin infection associated with gardeners and rose thorns), but pulmonary sporotrichosis can occur from inhaling conidia.

Fungal Respiratory Diseases Comparison

• Aspergillosis
  • Symptoms: fever, cough, chest pain, shortness of breath, hemoptysis (coughing up blood)
  • Treatment: voriconazole is first-line therapy; itraconazole for less severe forms; amphotericin B for severe or refractory cases
• Cryptococcosis
  • Symptoms: headache, fever, cough, shortness of breath, skin lesions (cryptococcomas)
  • Treatment: fluconazole for mild-to-moderate pulmonary disease; amphotericin B plus flucytosine (5-FC) for severe cases or CNS involvement, followed by long-term fluconazole maintenance
• Pneumocystis pneumonia (PCP)
  • Symptoms: dry nonproductive cough, progressive dyspnea, fever, chills, fatigue; bilateral ground-glass opacities on chest imaging are characteristic
  • Treatment: trimethoprim-sulfamethoxazole (TMP-SMX) is first-line for both treatment and prophylaxis; pentamidine is the alternative for sulfa-allergic patients. Note that TMP-SMX is an antibacterial, not a traditional antifungal, because P. jirovecii has unique cell membrane composition (it lacks ergosterol, the usual antifungal drug target)
• Histoplasmosis
  • Symptoms: fever, chills, headache, dry cough, chest pain, fatigue (often mimics flu)
  • Treatment: itraconazole for mild-to-moderate cases; amphotericin B for severe or disseminated disease
• Coccidioidomycosis (Valley Fever)
  • Symptoms: fever, cough, chest pain, fatigue, erythema nodosum (painful red skin nodules), joint pain sometimes called "desert rheumatism"
  • Treatment: fluconazole or itraconazole for symptomatic cases; amphotericin B for severe or disseminated disease. About 60% of infections are asymptomatic and self-limiting.
• Blastomycosis
  • Symptoms: fever, cough, chest pain, weight loss, verrucous or ulcerative skin lesions
  • Treatment: itraconazole for mild-to-moderate cases; amphotericin B for severe or life-threatening disease
• Sporotrichosis
  • Symptoms: skin nodules and ulcers along lymphatic channels, lymphadenopathy; pulmonary nodules if inhaled
  • Treatment: itraconazole for lymphocutaneous form; amphotericin B for severe pulmonary or disseminated disease; potassium iodide (SSKI) is a classic alternative for cutaneous disease

Immune Evasion by Fungal Pathogens

Fungi have evolved multiple strategies to survive within the host. These mechanisms explain why fungal infections can be so persistent, especially in immunocompromised patients.

Evasion of innate immune recognition

• Many fungi mask their cell wall $\beta$-glucans beneath layers of other polysaccharides, hiding them from the host receptor dectin-1 that would normally trigger an immune response.
• Aspergillus secretes gliotoxin, an immunomodulatory toxin that suppresses neutrophil function and induces apoptosis in immune cells.

Resistance to phagocytosis and intracellular killing

• The polysaccharide capsule of Cryptococcus neoformans physically prevents engulfment by macrophages and neutrophils. This capsule can also be visualized with an India ink stain, which is diagnostically useful.
• Fungi produce antioxidant molecules like melanin and superoxide dismutase to neutralize the reactive oxygen species (ROS) that phagocytes use to kill ingested microbes.
• Some fungi inhibit phagolysosome formation or prevent acidification of the phagosome, allowing them to survive inside the very cells meant to destroy them.

Modulation of adaptive immune responses

• Fungi can interfere with antigen presentation and T cell activation, blunting the specific immune response.
• They promote production of immunosuppressive cytokines like IL-10, which dampens inflammation.
• Several fungal pathogens skew the immune response toward a Th2 (humoral) profile rather than the protective Th1 (cell-mediated) response. Cell-mediated immunity driven by Th1 cells and activated macrophages is the most effective defense against fungi.

Biofilm formation

• Fungi like Aspergillus and Cryptococcus can form biofilms on tissue surfaces and medical devices. The extracellular matrix of these biofilms shields fungal cells from both immune attack and antifungal drugs, increasing resistance significantly.

Fungal Growth and Infection Mechanisms

The infection process for most respiratory mycoses follows a common pattern:

1. Inhalation of spores (conidia) from the environment is the typical route of entry. Spore size matters: smaller spores penetrate deeper into the lower respiratory tract.
2. Germination and growth occur once spores reach the warm, moist lung environment. For dimorphic fungi, the shift to 37°C triggers conversion from the mold form to the yeast form (or spherules, in the case of Coccidioides). This morphological switch is essential for virulence.
3. Tissue invasion happens through hyphal growth (in Aspergillus) or yeast proliferation (in dimorphic fungi). Hyphae can invade blood vessels, leading to tissue infarction and dissemination to other organs.
4. Opportunistic vs. true pathogens: Dimorphic fungi like Histoplasma and Coccidioides can infect healthy individuals because they are true pathogens. In contrast, Aspergillus, Cryptococcus, and Pneumocystis primarily cause disease in immunocompromised hosts (transplant recipients, AIDS patients, those on corticosteroids or chemotherapy).

Antifungal resistance is a growing concern. Resistance can develop through target modification (e.g., mutations in the ergosterol biosynthesis pathway that reduce azole binding), upregulation of efflux pumps that remove drugs from fungal cells, and biofilm formation. A. terreus is a notable example of intrinsic resistance to amphotericin B.