Lectuer 43: Fungal and Opportunistic Respiratory Infection

Pathogenic

Pathogenic or Opportunistic?

• Blastomyces dermatitidis

• Coccidioides immitis

• Histoplasma capsulatum

Opportunistic

Pathogenic or Opportunistic?

• Cryptococcus neoformans

• Candida albicans

• Aspergillus spp.

• Pneumocystis jirovecii

Opportunistic

Pathogenic or Opportunistic?

• Rhizomucor

• Mycobacterium avium complex

• Mycobacterium kansasii

• Cytomegalovirus

Opportunistic Infection

Infections that are more frequent or more severe in immunocompromised patients

Endemic Mycoses

• Fungal infections with pathogens found in specific areas

• Can cause disease in immunocompetent patients

Blastomycosis, Coccidioidomycosis,

Histoplasmosis

endemic mycoses in US

Paracoccidioidomycosis

endemic mycoses in Central and South America

Talaromycosis

endemic mycoses in Southeast Asia

-Acute self-limited pneumonia

-Chronic Disease

-Disseminated infection

3 basic forms of disease due to fungi

Blastomyces dermatitidis

• Thermally dimorphic fungus: white mold at 25°C, brown yeast at 37°C

• Thick refractile cell wall, single broad based budding

Blastomyces dermatitidis

• Endemic in Ohio and Mississippi River valleys, Great Lakes area, and SE U.S.

• Isolated from soil containing decaying vegetation

• Transmitted by inhaling conidia

Blastomycosis

Acute pneumonia:

• Looks like viral or bacterial pneumonia

• Cough becomes productive as illness progresses

• Fever, SOB, weight loss, night sweats

Chronic pneumonia:

• Looks like tuberculosis or carcinoma

• Diagnosis is delayed

• Fever, productive cough, hemoptysis, chest pain, weight loss

Blastomycosis

Blastomycosis

Blastomycosis

Skin:

• Verrucous lesion with irregular borders

• Ulcerative lesions with well-demarcated

borders

• Subcutaneous nodules

Osteomyelitis:

• Soft tissue swelling or chronic sinus drainage

• Little to no bone pain

Blastomycosis

• Inhaled conidia are phagocytized

• Thick cell wall of yeast form is difficult to phagocytize

• Giant cells and epithelioid granulomas form (pyogranulomatous inflammatory response)

• Glycoprotein BAD-1 facilitates binding to macrophages, allowing dissemination

Blastomycosis

• Sabouraud dextrose agar @ 25-30°C, takes 1-4 weeks

• Conidia found singly at tips of conidiophores; resemble lollipops

• Presumptive diagnosis made by visualization of yeast in a clinical specimen

• KOH wet mount or H&E staining

• May use PAS or Gomori Methenamine Silver stain

Histoplasmosis

aka Darling Disease

Histoplasma capsulatum

• Thermally dimorphic fungus (mold in soil, yeast at body temp)

• Ovoid yeast with narrow based budding

• Survives inside macrophages

Histoplasma capsulatum

• Most common cause for hospitalization among endemic mycoses

• Most common in midwestern and SE U.S., along Ohio and Mississippi River valleys

• Concentrated in soil contaminated with bird/bat droppings

• Transmitted by inhaling spores from soil

Histoplasma capsulatum

Acute Pulmonary Histoplasmosis

• Looks like community-acquired pneumonia

• Radiographs may show focal infiltrates and mediastinal/hilar lymphadenopathy

• Fever, chills, headache, myalgia, cough, substernal chest pain

• Illness is usually self limited

Chronic Cavitary Histoplasmosis

• Seen in older patients with pre-existing lung disease

• Productive cough, dyspnea, chest pain, fatigue, fever, sweats

• Looks like reactivated TB: fibrotic apical infiltrates with cavitation

Disseminated Histoplasmosis

-Histoplasmosis in immunocompromised patients

-fatal if not treated

Acute Histolasmosis

• Fever, fatigue, hepatosplenomegaly, pancytopenia

• Possibly diarrhea and dyspnea

• Severely immunocompromised patients may present with shock and organ failure

Chronic Histoplasmosis

• Pancytopenia, hepatosplenomegaly, oropharyngeal or GI lesions

• May also include skin, brain, and/or adrenal glands

Histoplasmosis

• Macrophages ingest but don't kill fungi; infected macrophages spread fungi

• Cell-mediated immunity is vital for clearing infection

• TNF, IFN-γ, IL-12

Histoplasmosis

-Culture is better in chronic disease, but it's really slow

• Histopathology shows granulomas

• Microscopy can show yeast in specimens

• Detect antigen in serum, urine, or BALF

• Cross reacts with Blastomyces, other fungi

• Serology has limitations

Coccidioidomycosis

AKA San Joaquin Valley fever

Coccidioides immitis

• Dimorphic fungus (mold in soil, spherules in body)

• Septate hyphae with 90° branching; boxcar pattern (thicker arthroconidia alternating with empty cells)

Coccidioides immitis

Primary Coccidioidal Pneumonia

• Looks like community-acquired pneumonia

• Chest pain, cough, fever

• Cutaneous manifestations more common in women

Coccidioidomycosis

• Systemic: fever, night sweats, weight loss

• Desert rheumatism

• Fever, erythema nodosum, arthralgias

• Erythema nodosum, erythema multiforme

Persistent Pulmonary Coccidiodomycosis

• Residual pulmonary nodules

• Coccidioidal cavities

• Usually single, peripheral

• Thin walls

Chronic Fibrocavitary Pneumonia

• When 1° coccidioidal pneumonia doesn't resolve

• More likely in diabetics, immunocompromised, and patients with underlying lung disease

Coccidioidomycosis

Disseminated Coccidioidomycosis

• More common in immunocompromised patients, pregnant women, and patients of African, Filipino, Hispanic, and Native American descent

• Osteomyelitis and synovitis

• Soft tissue infections

• Cutaneous disease

• Meningitis

Coccidioidomycosis

• Arthroconidia are easier to phagocytose

• Spherules are resistant to phagocytosis

• Macrophages can't kill fungi

• Infected macs carry spherules and disseminate pathogen

• Neutrophils and eosinophils are attracted when spherules rupture and release endospores

• Granulomas contain mature unruptured spherules

• Th2 response helps control infection

Coccidioidomycosis

Coccidioidomycosis

• Usually do serology first

• EIA detects IgM or IgG

• May need repeat tests if early in disease

• Stain sputum with KOH or calcofluor white

• Cough is not usually productive

• Stain tissue with H&E, PAS, or Gomori methenamine silver

• Culture takes time and not all labs can do it

Cryptococcosis

• Encapsulated yeast with narrow based budding

• Urease positive, produces melanin

• Found in soil, associated with birds (esp. pigeons and chickens)

• Risk factors: AIDS, glucocorticoids, organ

transplant, cancer, liver disease, sarcoidosis

Cryptococcosis

Pulmonary infection:

• Cough, hemoptysis, chest pain, fever, malaise,

night sweats, weight loss

Cryptococcal Meningitis

• Fever, malaise, headache

• Photophobia, nausea, vomiting

• Cough, dyspnea, rash suggest disseminated disease

• Most patients have CD4 count <100 cells/uL

• Elevated diastolic pressure indicates ↑ intracranial pressure

Cryptococcosis

• Spores inhaled, fungi disseminates hematogenously

• Localizes to CNS

• CSF is favorable to growth

• Dopamine is a substrate for melanin production

• Inflammatory response is milder than bacterial meningoencephalitis

Cryptococcosis

• Methenamine silver stain in histopathology

• Mucicarmine stains both yeast and capsule,

specific for Cryptococcus

• Fontana-Masson stain shows melanin

• Stain CSF with India ink

• Cryptococcal antigen (CrAg)

• Detects glucuronoxylomannan (GXM)

Cryptococcosis

Mucormycosis

AKA zygomycosis

Mucormycosis

• Genera from order Mucorales

• Rhizopus, Mucor, and Rhizomucor

• Broad, irregularly branching hyphae with rare septation

Mucormycosis

• Found in soil and on decaying vegetation

• Causes disease in immunocompromised patients

• Risk factors: diabetes mellitus, hematologic malignancies, organ transplant, burns, deferoxamine

Mucormycosis

Rhinocerebral infection

Rhinocerebral infection

• Most commonly caused by R. oryzae

• Most common risk factor: diabetes, esp. with ketoacidosis

Rhinocerebral infection

• Presents as acute sinusitis with fever, purulent nasal discharge, headache, and sinus pain

• Orbital involvement: periorbital edema, blurred vision, blindness

• Facial numbness

• Usually progresses rapidly

• Black eschar results from necrosis after vascular invasion

Rhinocerebral infection

Pulmonary Mycormycosis

• Bilateral pneumonia, very similar to aspergillosis

• Fever, hemoptysis, dyspnea, cough

• Seen in patients with hematological disease, organ transplants, deferoxamine

• Endobronchial mucormycosis can lead to massive hemoptysis

• Imaging may show reversed halo sign

Mucormycosis

• Inhaled spores become hyphae; hyphae bind to blood vessels and then penetrate

• Angioinvasion leads to infarction, ischemic necrosis

• Ketone reductase allows fungi to survive in acid medium (diabetic ketoacidosis)

Pneumocystis jirovecii

• Now known to be an Ascomycete; originally thought to be protozoa

• Doesn't grow in fungal culture

• Cell wall contains cholesterol

• Worldwide distribution, both humans and animals

• Likely spread person-to-person

• Causes infections in immunocompromised patients

• Cases in AIDS patients have decreased since ART/HAART

Pneumocystis jirovecii

• Pneumocystis pneumonia in HIV+ patients

• Gradual onset of fever, cough, dyspnea that

progresses

• Fatigue, chills, chest pain, weight loss

• AIDS-defining infection

• Hypoxemia at rest or with exertion; increase in

Aa O2 tension gradient

Pneumocystis jirovecii

Pneumocystis jirovecii

• Trophic forms attach to alveolar epithelium

• Beta glucan in cell walls drives inflammation, variations in major surface glycoprotein (MSG) helps evade immune response

• Host inflammatory response causes damage and impairs gas exchange

Pneumocystis jirovecii

• Can't be cultured, so must identify in respiratory samples

• Preferred technique: IF staining with labeled mAbs

• Stains: Giemsa, GMS, PAS, toluidine blue, calcofluor

• PCR of BAL samples is becoming more widespread

C. albicans

the most common Candida spp.

Candida spp.

• Elliptical budding cells; filaments on solid substrate

• Produces germ tubes in serum within 2 hours at 37°C

• Part of normal GI and genitourinary flora

• Causes infections in immunocompromised patients

• More prevalent in infants and elderly

• Cases associated with HIV patients

Primary Pulmonary Candidiasis

-rare

-pts tend to have widespread systemic illness

-hematogenous spread leads to microabscesses throughout parenchyma

Candidemia

-more common

• Immunocompromised and ICU patients at highest risk

• Presentation is variable

• Skin lesions: painless pustules with erythematous base

Candida spp.

• Commensal organism overgrows when host becomes

immunodeficient

• Blood culture

• Scrape and stain skin lesions

• Gram positive

• Punch biopsy of skin or tissue shows microabscesses, budding yeast, and hyphae or pseudohyphae

• Beta-D-glucan is not specific for Candida

Aspergillus

• Mold in nature and in hosts

• Hyphae have 45° branching

• Worldwide distribution, lives in soil and decaying vegetation

• Transmitted by inhaling spores

• Infections in immunocompromised patients

A. fumigatus, A. flavus, A. niger, and A. terreus

most common aspergillus spp. in humans

Aspergillus

Invasive Aspergillosis

• Incidence is increasing

• Classic presentation in neutropenic patients: fever, pleuritic chest pain, hemoptysis

• Dyspnea, chills, headache, arthralgias

• Pulmonary nodules and/or infiltrates

• Prognosis is poor

-vascular invasion with subsequent infarction and necrosis

Allergic Bronchopulmonary Aspergillosis (ABPA)

• Almost always in asthma or CF patients

• Bronchial obstruction, fever, malaise, production of brown mucus plugs, +/- hemoptysis

-IgE-mediated allergic response to Aspergillus colonization of airway

Chronic Pulmonary Aspergillosis

• Presents with chest pain, weight loss, cough, hemoptysis, SOB, fatigue

• Patients are generally immunocompetent, but have prior lung disease/damage

Aspergilloma

a fungal ball generally found in a preformed cavity of the lung, composed of a mass of Aspergillus hyphae

Aspergilloma

• Visualize with air crescent or meniscus sign

• Preexisting cavities are colonized with Aspergillus

Chronic Cavitary Pulmonary Aspergillosis

-regions of consolidation progress to form cavities

• Cavities are thin-walled

• New cavity formation or expansion of existing

cavities over time is characteristic

-prior lung damage leaves places for Aspergillus to grow

Invasive Aspergillus

Diagnosis:

-Galactomannan and beta-D-glucan serum biomarkers

Allergic Bronchopulmonary Aspergillosis (ABPA)

Diagnosis:

-asthma of CF

-elevated IgE

-+aspergillus skin test

Chronic Pulmonary Aspergillosis

Diagnosis:

-negative for TB

-positive for Aspergillus IgG

Nontuberculous Mycobacteria (NTM)

• Acid-fast bacilli, ubiquitous in environment

• Stain with Ziehl-Neelsen or carbol-fuchsin

• Grow on Middlebrook 7H11 or Lowenstein-Jensen agar

• Slow growing; takes 2-4 weeks

M. avium Complex (MAC) and M. kansasii

Most common disease-causing NTM in the US

Mycobacterium Avium Complex (MAC)

• Disease in patients with underlying lung disease (fibro-cavitary disease)

• White males, middle-aged or older, with COPD

• Alcohol abuse or smokers

• CF patients

• Disease in patients without underlying lung disease (nodular bronchiectatic form)

• Nonsmoking females >50 years old

• Disseminated disease

• CD4 count <50 cell/uL

Mycobacterium Avium Complex (MAC)

• taken up by alveolar macrophages

• Bacteria survive inside phagocytes

• Granulomas form to wall off infected cells

• Damage caused by cytolytic enzymes and other cytotoxic proteins leads to necrosis and fibrosis of tissues

• Positive culture from sputum, BAL, or• Positive culture from sputum, BAL, or biopsy

• Biopsy stainin biopsy

• Biopsy staining

Mycobacterium kansasii

• Not found in soil, but is in tap water

• Produces rough colonies that turn bright yellow when exposed to light (photochromogen)

• Unusual beading when stained with acid-fast stains

• More common in southern and central U.S. and urban areas

• May be associated with mining

• Was the most common NTM infection in the 1960-70s, but surpassed by MAC

Mycobacterium kansasii

Mycobacterium kansasii

• Presents like TB

• Productive cough, weight loss, SOB, chest pain, hemoptysis, fever/sweats

• Older age, male, smoking, and underlying lung disease are risk factors

• Causes disseminated disease in HIV+ patients

Cytomegalovirus

-AKA human herpesvirus 5 (HHV-5)

• Herpesviridae

• Enveloped, with dsDNA genome

Cytomegalovirus

• Majority of adults are seropositive

• Transmitted via blood, breastfeeding, perinatally, sex, and close contact

• Reactivation is associated with increased morbidity and mortality

Cytomegalovirus

• If symptomatic, illness presents like infectious mononucleosis

• Fever, rash, fatigue, leukocytosis

• Don't see heterophile antibodies; helps differentiate from EBV infection

• Immunocompromised patients may have specific organ diseases

• Lung transplant patients may have pneumonitis

Cytomegalovirus

Cytomegalovirus

• Lytic infection leads to dramatic cell enlargement

• Virus rearranges cellular protein production to create large perinuclear replication compartment

• Viral load

• Owl's eye appearance of inclusion

bodies

Usually resolves before diagnosis

treatment of acute pulmonary forms of Blastomycosis

Itraconazole for 6-12 months

treatment of mild to moderate forms of Blastomycosis

• Amphotericin B until initial improvement (several weeks)

• Then itraconazole for at least 12 months

treatment of severe forms of Blastomycosis (CNS involvement and immunosuppressed pts)

Steroids

if a pt with Blastomycosis is in respiratory distress, what can you give them?

• Typically resolve spontaneously before diagnosis is made

• If not resolved after 1 month - itraconazole for 6-12 weeks

Treatment of Asymptomatic or mild to moderate forms of primary pulmonary histoplasmosis

Amphotericin B for 1-2 weeks +/- steroids, then itraconazole for 3 months

treatment of severe forms or immunosuppressed pts with primary pulmonary histoplasmosis

Itraconazole (at least 1 year)

treatment for Chronic Cavitary Pulmonary Histoloplasmosis

itraconazole for 12 months or more

treatment for mild to moderate Disseminated Histoplasmosis

Amphotericin B for 1-2 weeks, then itraconazole (up to 2 years)

treatment of moderately severe to severe disseminated histoplasmosis

No treatment

treatment for primary coccidioidomycosis

Itraconazole or fluconazole for at least 1 year

Treatment for Secondary and Disseminated Forms of Coccidioidomycosis