Lecture 40-42: Infectious Agents of the Respiratory Tract

Upper Respiratory Tract Infection (URTI)

• Involve nose, sinuses, larynx, pharynx

• Self-limited irritation and swelling of upper airways with associated cough

• No signs of pneumonia

• Patient has no other condition to account for symptoms (COPD, emphysema, chronic bronchitis)

Lower Respiratory Tract Infection (LRTI)

• Involve trachea, bronchi, bronchioles, lungs

• Generally more severe

• Coughing is primary symptom

Pneumnonia

-inflammation fo the lung parenchyma due to infection

-causes alveoli to fill with fluid or pus

-leading cause of death in children <5

Pneumonia

-pts present with productive cough, dyspnea, chest pain, and possibly hemoptysis

-fever, malaise, myalgias, weight loss

-CXR shows parenchymal opacity

Bacterial

the usual cause of lobar pneumonia is _________________

Staphylococcus

-grape like clusters

-beta hemolytic

-catalase positive

-novobiocin sensitive

-coagulase negative

-located on skin

Streptococcus

-short chains

-requires enriched media

-alpha, beta, or gamma hemolysis

-catalase negative

-coagulase negative

-located in nose and throat

S. pyogenes

1

S. agalactiae

2

S. pneumonaie

3

Streptococcus pneumoniae

most common cause of community-acquired pneumonia

Streptococcus pneumoniae

-fastidious, gram positive, alpha hemolytic, catalase negative

-sensitive to optochin and bile salts

-Quellung reaction

-Common inhabitant of respiratory tract

Streptococcus pneumoniae

-assoc with rust-colored sputum

risk factors:

- >65yo

- <2 yo

-smoking and alcohol abuse

-asthma or COPD

-asplenic

Streptococcus pneumoniae

Virulence Factors:

-capulse

-Pneumolysin

-IgA1 protease

-Neuraminidase

Streptococcus pyogenes

-gram positive cocci in chains

-beta hemolytic

catalase negative

-coagulase negative

-facultative anartobe (Group A)

Streptococcus pyogenes

-Colonizes mucosal membranes

-transmitted by droplets, fomites, direct contact, contaminated food

-diagnosed by culture or rapid antigen detection

Streptococcus pyogenes

• Suppurative: pharyngitis, skin infection, abscess, otitis media

• Toxin-mediated: scarlet fever, toxic shock syndrome

• Autoimmune: rheumatic fever, acute glomerulonephritis, PANDAS (controversial)

Streptococcus pyogenes

Virulence Factors:

-hyaluronic acid capsule

-M proteins

-Streptokinase

-Hyaluronidase

-Hemolytic Toxins: Streptolysin S and O

-C5a peptidase

-Protein F

-Pyrogenic exotoxins

Streptococcus agalactiae

-Gram positive cocci in chains

-catalase negative

-beta hemolytic

-colonizes genital and GI tracts

Streptococcus agalactiae

Important cause of infection in 3 groups:

• Neonates – sepsis, pneumonia, meningitis

• Pregnant women – UTI, chorioamnionitis, postpartum endometriosis, bacteremia

• Nonpregnant adults – sepsis, soft tissue infection, other focal infections

Neonates present with:

• Fever, difficulty feeding, irritability, lethargy

• Respiratory symptoms (tachypnea, grunting, hypoxia, increased work of breathing)

Streptococcus agalactiae

Virulence Factors:

-capsule polysaccharides

-C5a peptidase, beta-hemolysin, superoxide dismutase

-lipoteichoic acid, hyaluronin, pili

Haemophilus influenzae

-Pleomorphic Gram-negative rods, facultative anaerobes, oxidase positive

-Colonizes respiratory tract; humans only known reservoir

• Grows on chocolate agar

-6 typeable strains (a-f) have capsules; nontypeable strains do not

Haemophilus influenzae

• In areas with routine vaccination

• More common to see nontypeable strains; respiratory tract

infections

•causes meningitis and epiglottitis in kids, pneumonia in adults

• Epiglottitis can lead to potentially fatal airway obstruction

• While incidence has decreased since vaccinations, median age at presentation has increased from 3 years to 6-12 years old

Mycoplasma pneumoniae

• Very small, short rod with no cell wall, fastidious; atypical pathogen

• Doesn't Gram stain, difficult to culture

• Lack of cell wall makes bacteria highly pleomorphic

Mycoplasma pneumoniae

• Causes atypical (walking) pneumonia, more commonly in young

children

• Also causes upper respiratory infections and bronchitis

• Transmitted via respiratory droplets; rates rise in the summer

• Associated with autoimmune hemolytic anemia due to cold agglutinins

• M. pneumoniae changes antigen on RBC, leads to IgM autoantibody production

Mycoplasma pneumoniae

Virulence factors:

• Produces hydrogen peroxide and superoxide which injure epithelial cells

• Adherence proteins (P1, P30)

• TLR2 activation leads to inflammatory cytokine production

• CARDS toxin damages epithelial cells

M. tuberculosis

• Human pathogen, no known reservoir

• Latent infection in immunocompetent patients; controlled by cell mediated immune response

• Diagnosed by +PPD skin test

Mycobacterium spp.

• Acid-fast bacilli, slow growing

• Stain with Ziehl-Neelsen or carbol-fuchsin

• Acid-fast bacilli, slow growing

• Stain with Ziehl-Neelsen or carbol-fuchsin

Virulence factors:

• High mycolic acid content makes phagocytosis difficult;

bacteria live inside macrophages

• Cord factor elicits granuloma formation, promotes survival in

macrophages by preventing phagolysosome fusion

• Catalase peroxidase protects from ROS

• Lipoarabinomannan (LAM) is a TLR2 ligand, induces

cytokine production

M. avium complex (MAC)

-M. avium and M. intracellulare

-causes progressive pulmonary disease associated with bronchiectasis or COPD in older patients

-Disseminated infections in AIDS patients

M. avium complex (MAC)

-n opportunistic pathogen, but results from

recent acquisition

• No latent infections

• Can also cause GI and skin/soft tissue infections

-• Biofilm formation, inhibition of cytokine production promote colonization/invasion

M. avium complex (MAC)

Pseudomonas aeruginosa

• Motile, aerobic Gram-negative rod, nonfermenting, ubiquitous in the environment

• Characteristic grape-like odor

• Polar flagellum

• Blue-green pigment (pyocyanin)

Pseudomonas aeruginosa

mportant cause of nosocomial infections:

• Colonization of CF patients

• Wound infections in burn patients

• Ventilator associated pneumonia

• UTI due to indwelling catheters

Pseudomonas aeruginosa

Virulence factors - there are a ton:

• Lives everywhere and forms biofilms (hard to get rid of)

• Exotoxins S, U, and Y (type III secreted toxins)

Klebsiella pneumoniae

Pseudomonas aeruginosa

Klebsiella pneumoniae

• Gram-negative rod, encapsulated, lactose fermenting

• Pink mucoid colonies on MacConkey agar

• Positive Voges-Proskauer (VP) reaction

• Member of Enterbacteriaceae family

Klebsiella pneumoniae

• Infections usually hospital-acquired, in immunocompromised patients

• Pneumonia, UTI, bacteremia

• Red currant jelly sputum

Klebsiella pneumoniae

Virulence factors:

• Capsule protects from phagocytosis

• Biofilms

• LPS acts as endotoxin, provides serum resistance

• Siderophores are iron chelators

• Pili/fimbriae mediate adherence

• Some strains produce ESBL

Bordetella pertussis

• Fastidious Gram-negative coccobacilli

• Humans only known reservoir

• Transmitted by respiratory droplets; risk highest during catarrhal stage

Bordetella pertussis

Cause of whooping cough

Legionella pneumophila

• Pleomorphic Gram-negative rods, fastidious, intracellular pathogen

• Gram stain poorly; can use silver or Giemsa stain

• Culture on buffered charcoal yeast extract (BCYE) agar

• Transmitted by aerosols from contaminated water

Legionella pneumophila

• Cause community-acquired and nosocomial pneumonia (Legionnaire’s disease)

• Diagnosed by looking for antigens in urine

• Can be sporadic infections or outbreaks

• Also causes Pontiac fever

• Acute, self-limited febrile illness

• Short incubation period, rapid recovery

• Thought to be toxin mediated

Legionella pneumophila

Virulence and immune escape:

• Bacteria inhibit phagolysosome fusion, multiply inside macrophages

Rececptor mediated endocytosis

how do naked viruses get into the host cell

Membrane fusion

how do enveloped viruses get into the host cell

Rhinovirus

• Small naked viruses, +ssRNA genome

• Part of Enterovirus genus and Picornaviridae family

• >160 rhinoviruses, classified RV-A, B, and C

• Most common cause of URTI across all age groups

• Host cell receptors: ICAM-1 (CD54): RV-A, RV-B

Rhinovirus

Temperature restrictions:

• _________________ replicates most effectively at 33°C; why they prefer

upper respiratory tract

• Host cell response is more efficient at higher temps

Coronavirus

• Medium enveloped viruses, +ssRNA genome

• Spike proteins extend from capsid, looks like a crown

• Spike proteins bind host receptors; major antigen for neutralizing antibodies

Coronarvirus

• Causes colds; cases increase in winter

• Bind to sugars on glycoproteins (low affinity binding)

SARS virus and MERS virus

• Cause pneumonia

• ACE2 is the SARS receptor, CD26 is the MERS receptor

Adenovirus

• Naked dsDNA virus

• Naked viruses survive longer in the environment; can be transmitted without close contact

• Cause wide range of infections (respiratory, ocular, GI)

• Usually self-limited, but can cause serious illness in immunocompromised patients

Adenovirus

3 major capsid antigens:

• Fiber protein binds CAR (host receptor);

• Can hemagglutinate RBC

• Penton base interacts with host integrins and mediates virus

internalization

• Hexon is the major viral surface protein; contains antigenic

determinants and determines tissue tropism

Paramyxovirus

• Enveloped -ssRNA viruses

-measles and mumps

Paramyxovirus

2 viral proteins are key to infection:

• Hemagglutinin mediates attachment to host

receptor (α2,3 sialic acid); varies among

paramyxoviruses

• Fusion protein causes membrane fusion,

releasing virus into host cell and causing

syncytia formation

Measles

• AKA rubeola

• Fever, malaise, cough, coryza, conjunctivitis, then rash

• Koplik spots are pathognomonic for measles

Measles

• Diarrhea is most common complication

• Pneumonia is most common cause of ________________ assoc death in children

• Encephalitis, acute disseminated encephalomyelitis, subacute sclerosing panencephalitis

• Can lead to immune suppression and secondary infections (bacteremia, pneumonia,

gastroenteritis)

-depletes T and B cells

Mumps

-Presents with fever, headache, myalgia, fatigue, anorexia, then parotitis

• Complications include orchitis, meningitis, encephalitis, and deafness

• Most commonly in school age children and college aged young adults

Mumps

-virus prefers glandular epithelium

-viral replication in parotid gland leads to local inflammtion and infilatration of macrophages and lymphocytes, causing swelling

Croup

• Presents with inspiratory stridor, cough, and hoarseness (laryngotracheitis)

• Infants and young children: barking cough

• Older children and adults: hoarseness

Croup

• URT symptoms first, then LRT symptoms

• Most common in children 6 months-3 years old; usually in fall or winter

• Anatomic hallmark is narrowing of subglottic airway (steeple sign)

Parainfluenza virus type 1

most common cause of croup

Respiratory Syncytial Virus (RSV)

• -ssRNA virus; A and B subtypes

• Can cause severe disease in infants, older and immunocompromised adults

• Risk factors: premature birth, asthma, cardiopulmonary disease, secondhand smoke

• Bronchiolitis in infants

• Pneumonia, bronchitis, asthma/COPD exacerbations in adults

Respiratory Syncytial Virus (RSV)

• Infection doesn't generate immunity to reinfection

• Viral infection can cause inflammatory response that promotes asthma

• Synagis (palivizumab) is a mAb against F protein given monthly during ____________ season

• Only for high-risk infants

• No lasting protection, very expensive

Influenza

• Enveloped virus with segmented, -ssRNA genome; part of Orthomyxoviridae family

• M2 protein is an ion channel that allows intracellular

virus to replicate and exocytose

• Antiviral therapies: Zanamivir, oseltamivir target neuraminidase, Amantidine, rimantadine target M2

Influenza A

-characterized by hemagglutinin (H) and neuraminidase (N) proteins

• H binds to sialic acids on respiratory epithelium

Antigenic drift

• Minor changes in antigens

• Leads to seasonal epidemics

• Occurs as result of error prone replication

• Existing antibodies may be cross-protective

Antigenic Shift

• Completely new antigens

• Leads to pandemics

• Occurs as result of combining RNA segments

from 2 different strains in one host cell

• There are no pre-existing antibodies

Hantavirus

• Enveloped virus with segmented -ssRNA genome, Bunyaviridae family

• Transmitted by inhaling dried rodent urine/feces or by rodent bite

• Most common in SW U.S. and South America

Hantavirus

• Causes hemorrhagic fevers, acute respiratory distress syndrome (ARDS), and renal failure

• GI symptoms may help distinguish HCPS or HPS from other illnesses

Mold; yeast

In relation to fungi:

usually ____________ in environement, and ______________ in host

Pneumocystis jiroveci

• Opportunistic pathogen

• Risk factors: AIDS, glucocorticoids, chemotherapy, cancer,

other immunosuppressive meds

• Interstitial pneumonia with plasma cell infiltrates and

foamy alveolar exudate

• Ground glass on X-ray

• Hypoxemia at rest or with exertion; ↑ A-a O2 gradient

Pneumocystis jiroveci

• LDH may be elevated

• Presence of beta-D-glucan

• PCR of bronchoalveolar lavage fluid

• Visualize fungi with Gomori-methenamine silver or other stains

Aspergillus fumigatus

• Filamentous mold, has narrow septate hyaline hyphae with 45° branching

• Galactomannan is major component of cell walls

• Pulmonary aspergillosis presents with fever, pleuritic chest pain, and hemoptysis

• Also causes aspergilloma, hypersensitivity pneumonitis, rhinosinusitis

Aspergillus fumigatus

• Culture + histopathology showing tissue invasion

• Noninvasive methods: serum galactomannan, staining BAL with Gomori silver or PAS

-Risk factors: Neutropenia, glucocorticoids, immunocompromised

Histoplasma capsulatum

• Thermally dimorphic fungus

• Mold in soil, yeast in host

• Ovoid yeast with narrow based budding

• In the U.S.: Mississippi, Ohio, and St. Lawrence River valleys

• Concentrated in soil contaminated with bird/bat droppings

Histoplasma capsulatum

Suspect in patients with:

• Lung granulomas

• Pneumonia with mediastinal or hilar

lymphadenopathy

• Pulmonary nodules or cavitary lung disease

Coccidioides immitis

• Thermally dimorphic fungus

• Mycelia found in deserts in the southwestern U.S.

• In hosts, spherules contain endospores

• Diagnosed via intradermal antigen injection (similar to PPD for tuberculosis) or serology

Coccidioides immitis

• Coccidioidomycosis (AKA San Joaquin Valley fever)

• Caused by inhaling arthroconidia

• 2nd most common fungal infection in U.S.

Blastomyces dermatitidis

• Thermally dimorphic fungus

• 25°C: fluffy white mold

• 37°C: brown folded yeast with thick refractile cell wall; reproduce with a single broad-based bud

Blastomyces dermatitidis

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

• Found in soil in wooded areas with decaying vegetation

• Extrapulmonary disease is common

• Skin, bones, genitourinary tract

• Can cause disease in immunocompetent patients

• Or infections may be asymptomatic

Cryptococcus neoformans

• Encapsulated yeasts

• Found in soil contaminated with bird droppings, decaying wood, and tree hollows

• Diagnosed by CSF analysis, culture, and staining

• Stain with India ink to show capsule; mucicarmine stain shows both yeast and capsule

• CSF usually shows low WBC, low glucose, ↑ protein, but can be normal in ~30% of patients

• Look for antigen in serum and CSF

Cryptococcus neoformans

• Cryptococcosis (cryptococcal meningitis) occurs mostly in immunosuppressed patients

• Focal pneumonitis (with or without symptoms) in immunocompetent patients

Charcot-Leyden crystals

Ascaris lumbricoides

• Worldwide distribution; most cases in Asia

• Most common in children 2-10 years old

• Highest prevalence in tropics

• Loeffler syndrome (A. pneumonia)

• Nonspecific symptoms (late phase intestinal involvement)

• Abdominal pain, anorexia, nausea/vomiting, diarrhea

• Look for eggs in stool

• Oval with a thick mamillated shell

Ascaris lumbricoides

Life cycle:

• Eggs must embryonate in soil to become infectious

• Humans ingest eggs

• Larvae migrate through intestine into bloodstream and then lungs

• Worms are swallowed and become adults; majority found in the jejunum

Hookworms

• Common in tropics and subtropics

• Risk factors: walking barefoot, poor sanitation

• Ancylostoma duodenale (Mediterranean countries,

Iran, India, Pakistan, Asia)

• Necator americanus (North and South America,

Africa, Indonesia, and South Pacific)

Hookworms

Life cycle

• Filariform larvae penetrate the skin

• Bloodstream carries larvae to the lungs; they migrate

up the bronchial tree and are swallowed

• Develop into adults in small intestine; attach to wall

and feed on blood from capillaries

Hookworms

• Major damage due to blood loss at site of attachment

• Reflects 4 phases of infection

• Ground itch, cutaneous larvae migrans

• Pulmonary symptoms (maybe)

• GI symptoms

• Chronic nutritional impairment

Hookworms

• Stool examination is not helpful before established GI disease

• May see eosinophilia, occult blood in stool

Threadworms

• AKA Strongyloides stercoralis (causes strongyloidiasis)

• Endemic in rural areas in tropics and subtropics

• Sporadic in temperate areas

• Highest rates in US in southeastern states and people who have traveled in endemic areas

Threadworms

• Symptoms depend on site of worm

• Watery diarrhea, pneumonitis, ground itch or larva currens

• Chronic infection: intermittent abdominal pain, fluctuating rash, intermittent eosinophilia

• Find larvae in stool

• Use ELISA to look for antibodies

Clonorchis sinensis and Fasciola hepatica

-liver flukes

-ingesting raw/undercooked fish

-contaminated water in sheep-raising areas

Paragonimus westermani

-lung flukes

• Ingesting raw/undercooked crab or crawfish

• Late infection → chocolate-colored sputum

Entamoeba histolytica

-amebic dysentery

• Ingesting contaminated food/water

• Diarrhea with blood and mucus in stools; trophozoites in stools or tissues

Schistosoma spp.

-blood flukes

• Highest prevalence in sub-Saharan Africa

• Contact with contaminated water; snail hosts

Echinococcus granulosus

-Hydatid Cyst

• Dogs (canids) are definitive hosts; domestic animals are intermediate hosts

• Highest rates of disease in areas where sheep are raised

• Usually a single cyst; symptoms depend on size and location

Tuberculosis

• Present globally, but disease burden is higher in developing nations

• Risk factors: Poverty, malnutrition, incarceration, immunosuppression, occupation

Tuberculosis

• Primary infection is usually asymptomatic

• Chronic cough, weight loss, fever, night sweats

• Hemoptysis is late-stage symptom

• Secondary TB has more severe tissue reaction/hypersensitivity

• Kidney, bone growth plates, lymph nodes, meninges, elbows

• Hip joints (avascular necrosis)

• Vertebrae (Pott's disease)