Respiratory System Infections Chapter 24. Respiratory System Infections Encompass enormous variety of illnesses Trivial to fatal Divided into infections.

Respiratory System Infections

Chapter 24

Respiratory System InfectionsEncompass enormous variety of illnesses

Trivial to fatal

Divided into infections of

Upper respiratory

Head and neck

Uncomfortable but generally not life threatening

Lower respiratory

Chest

More serious

Can be life-threatening

Particularly in the immunocompromised

Normal Flora

Nasal cavity, nasopharynx and pharynx colonized by numerous bacteria

Other sites are sterile

Numerous classes of organisms are present from aerobes to anaerobes

Conjunctiva commonly have no bacteria

Organisms that do invade are swept into the nasolacrimal duct (tear duct) and nasopharynx

Symptoms

Characterized by

Difficulty swallowing

Fever

Red throat with pus patches

Enlarged tender lymph nodes

Localized to neck

Most patients recover uneventfully in approximately a week

Streptococcal Pharyngitis

Streptococcal Pharyngitis

Causative Agent

– Streptococcus pyogenes

Gram-positive

Coccus in chains

β hemolytic

Complete hemolysis of red blood cells

Commonly referred to as group A streptococcus

Due to group A carbohydrate in cell wall

Basis for identification from other organisms

Pathogenesis due to numerous virulence factors

Streptolysin

Protein G

Complications of infection can occur during acute illness

Scarlet fever

Acute glomerulonephritis

Acute rheumatic fever

Treatment

Penicillin is antibiotic of choice

Streptococcal Pharyngitis

Common ColdSymptoms

Malaise

Scratchy mild sore throat

Runny nose

Cough and hoarsness

Nasal secretion

Initially profuse and watery

Later, thick and purulent

No fever

Unless complicated with secondary infection

Symptoms disappear in about a week

Common Cold

Causative Agent

30% to 50% caused by rhinoviruses

More than 100 serotypes of rhinoviruses

Non-enveloped

Single-stranded RNA genome

Common ColdPathogenesis

Virus attach to specific receptors on respiratory epithelial cells and multiply in cells

Large number of viruses released from infected cells

Injured cells cause inflammation which stimulates profuse nasal secretion, sneezing and tissue swelling

Infection is halted by inflammatory response, interferon release, and immune response

Infection can extend to ears, sinuses and lower respiratory tract before stopping

Treatment is supportive with OTC medications

Aka: Pertussis

Symptoms

Runny nose followed by bouts of uncontrollable coughing

Termed paroxymal coughing

Severe cough can cause rupture of small blood vessels in the eyes

Coughing spasm followed by characteristic “whoop”

Sound made by the forceful inspiration of air

Vomiting and seizure may occur

Whooping Cough

Whooping Cough

Causative Agent

– Bordetella pertussis

Small

Encapsulated

Strictly aerobic

Gram-negative

Bacillus

Does not survive long periods outside the host

Pathogenesis

Enters respiratory tract with inspired air and attaches to ciliated cells

Organism colonizes structures of the upper and lower respiratory tract

Mucus secretion increases which causes ciliary action to decrease

Cough reflex is only mechanism for clearing secretions

Whooping Cough

Whooping Cough

Video on web page

Whooping CoughPathogenesis

– B. pertussis produces numerous toxic products

Pertussis toxin - A-B toxin

B portion attaches to cell surface

A portion enters cell and inactivates regulation of cAMP

Causes increased mucus formation

Decreases phagocytic killing

Invasive adenylate cyclase

Increases production of cAMP

Increased mucus formation

Epidemiology

Spreads via infected respiratory droplets

Most infectious during runny nose period

Number of organisms decrease with onset of cough

Classically disease of infants

Milder forms are seen in older children and adults

Often overlooked a persistent cold

Fosters transmission

Whooping Cough

Whooping Cough

Prevention

Vaccine directed at protection of infants

Prevents disease in 70% of individuals

Pertussis vaccine combined with diphtheria and tetanus toxoids (DPT)

Injections given at 6 weeks, 4, 6,and 18 months, 5 years, and now recommended for 12 year olds

Treatment

Erythromycin is effective at reducing symptoms if given early

TuberculosisSymptoms

Chronic illness

Symptoms include

Slight fever with night sweats

Progressive weight loss

Chronic productive cough

Sputum often blood streaked

Causative Agent

Mycobacterium tuberculosis (and M. bovis in AIDS)

Gram-positive cell wall

Slender bacillus

Acid fast due to mycolic acid in cell wall

Slow growing

Generation time 12 hours or more

Resists most prevention methods of control

Pathogenesis

Usually contracted by inhalation of airborne organisms

Bacteria are taken up by pulmonary macrophages in the lungs

Resists destruction within phagocyte

Organism prevents the fusion of phagosome with lysosomes; allows multiplication in protected vacuole

Tuberculosis

Pathogenesis

Organisms are carried to lymph nodes

About 2 weeks post infection intense immune reaction occurs

Macrophages fuse together to make large multinucleated cell

Macrophages and lymphocytes surround large cell and form a tubercle of connective tissue

This is an effort to wall off infected tissue

Activated macrophages release into infected tissue

• Causes death of tissue resulting in formation of “cheesy” material (biofilm)

Tuberculosis

Tuberculosis• Epidemiology

• Estimated 10 million Americans infected

• Rate highest among non-white, elderly, immigrant poor people

• Small infecting dose

• As little as ten inhaled organisms

• Factors important in transmission

• Frequency of coughing, adequacy of ventilation, degree of crowding

Tuberculosis

• Epidemiology

• Tuberculin skin test used to detect those infected

• Small amount of tuberculosis antigen is injected under the skin

• Injection site becomes red and firm if infected

• Positive test does not indicate active disease

Tuberculosis• Prevention

• Vaccination for tuberculosis widely used in many parts of the world

• Vaccine known as Bacillus of Calmette and Guérin

• BCG derived from Mycobacterium bovis

• Gives weak, partial immunity against tuberculosis

• Vaccine not given in United States because it eliminates use of tuberculin test as diagnostic tool

•Treatment

Antibiotic treatment is given in cases of active tuberculosis

Two or more medications are given together to reduce potential antimicrobial resistance

Antimicrobials include Rifampin and Isoniazid (INH)

Both target actively growing organisms and metabolically inactive intracellular organisms

Therapy is pronged, lasting at least 6 months

•Multi-drug resistant strains have arisen in the U. S. and Russia that have spread to other countries

• Symptoms

• Influenza Type A

• Short incubation period

• Averaging 2 days

• Headache

• Fever

• Muscle pain

• Dry cough

• Acute symptoms abate within a week

• Cough, fatigue and generalized weakness may linger

Seasonal Influenza

• Causative Agents• Influenza A virus

• Belong to orthomyxovirus

• Single-stranded RNA genome

• Genome divided into 8 gene segments

• Spiked envelope

• H spike – hemagglutinin (subtypes H1-H16)• Aids in attachment

• Only H1, H2 and H3 viruses circulate in humans

• N spikes – neuraminidase (subtypes N1-N9)

• Cleaves H protein to allow fusion of viral and cellular membranes (i.e., entry into the cell)

• Requires cellular enzyme trypsin to facilitate infection

• Influenza B & C viruses only circulate in humans

Seasonal Influenza

Influenza A Transmission Cycle

Circulates withlimited pathology

Transmission todomestic fowl

Adaptation/reassortment

with swineinfluenza viruses

Transmissionto humans

• Pathogenesis• Acquired through inhalation of infected respiratory

secretions

• Virus attaches to host cells via hemagglutinin spikes

• Once attached viral envelope fuses with host membrane, leading to viral replication within the cell

• Mature viruses bud from host cell

• Budding allows mature virus to pick up envelope

• Infected cells die and slough off

• Host immunity quickly controls viral spread

• Anti-HA neutralizing IgG is protective

• Mortality rate is low

• However, hundreds of thousands or millions of people are infected each year in the U. S.

• On average, about 30,000 Americans, mostly elderly and very young children, die from influenza each year

Seasonal Influenza

• Epidemiology• Outbreaks occur in United States every year

• Vaccines are formulated months in advance using prominent circulating strains

• 2010-2011 vaccine strains

• A/California/7/2009 (H1N1)-like (the same strain as was used for 2009 H1N1 monovalent vaccines)

• A/Perth/16/2009 (H3N2)-like

• B/Brisbane/60/2008-like

• Pandemics occur periodically• Most famous pandemic of 1918 (Spanish flu)

• Spanned the globe in 9 months

• Pandemics have higher than normal morbidity

Seasonal Influenza

Type / Geographic origin / Strain/ Year isolated (H & N genes)

• Epidemiology

• Spread caused by major antigenic changes

• Antigenic drift

• Consists of amino acid changes in spikes (point mutations)

• Particularly hemagglutinin

• Changes minimize effectiveness of immunity to previous strains

• Ensures enough susceptible people are available for continued virus survival

•Antigenic shift

Represent more dramatic changes

Virus strains are drastically antigenically different from previous strains, importantly in the hemagglutinin

New virus comes from genetic re-assortment

Occurs when two different viruses infect a cell at the same time

Genetic mixing results in new virus that is often more virulent

Seasonal Influenza

Seasonal Influenza

• Prevention and Treatment

• Vaccine can be 80% to 90% effective

• New vaccine required every year

• Due to antigenic drift

• Antiviral medications are 70% to 90% effective

• Include amantadine, rimantadine, and Tamiflu

• Must be taken early

• Not a substitute for vaccine

Seasonal Influenza

• There are hundreds, if not thousands, of influenza A viruses circulating in nature

• Seasonal influenza occurs from mammalian viruses

• Pigs in SE Asia are frequently a source of these viruses

• New reassortants arise every year, but most are not pathogenic to humans

• Avian influenza viruses routinely circulate among wild birds

• Some species can be infected without conspicuous pathology

• These species often carry the viruses along migratory routes, exposing other birds

Avian Influenza

• Most avian influenza viruses are highly inefficient at infecting humans

• However, some cultures have domestic birds and pigs in close periodomestic proximity

• This practice increases the chance of

• Reassortment with mammalian influenza viruses

• 1957, 1967 pandemic strains were reasortant mammalian viruses with avian segments (antigenic shift)

• Emergence of mutant avian strains that can infect humans

• 1918 pandemic strain was an avian virus that adapted to efficient human to human transmission (antigenic drift)

Avian Influenza

• Rescue of the 1918 pandemic strain

• Virology did not exist in 1918

• The virus could not be isolated, thus went extinct when the pandemic ended

• In 2005 a group resurrected the 1918 strain from bodies buried in Alaskan permafrost

• Viral genome sequencing indicated it was an avian influenza A virus

• It was also infectious...

Avian Influenza

Avian InfluenzaLungs from Mice Infected with Rescued 1918 H1N1 Pandemic Virus

1918 Strain 1918 Strain

1918 Strain

1918 Strain(HN)/Texa

s 1991 Strain hybrid

1918 Strain with

Texas 1991 Hsegment

Texas 1991 strain

(control)

Tumpey et al., 310:77.

2005

Avian InfluenzaFeature SI1 H5N1 AI2 1918 H1N13

Transmission efficiency High Very low/none High

Replication siteUpper and lower respiratory tract

Lower RT onlyLikely upper &

lower RT

Viral CPE4 Limited Substantial Substantial

Immunopathology Limited Substantial Substantial

Kills embyronated chicken eggs?

No Yes Yes

Requires trypsin for infection of cell cultures?

Yes No No

Vaccine Yes No N/A

Fatality rate 0.03% (U.S.) 57% (global)About 1-2%

(U.S)

DemographicYoung children,

elderlyYoung adults Young adults

1 Seasonal influenza2 Currently circulating H5N1 avian influenza virus3 Rescued 1918 pandemic H1N1 avian influenza virus4 Cytopathic effect (damage directly caused by the virus)

Red - more pathogenic featureGreen - less pathogenic feature

Hantavirus (Cardio)Pulmonary Syndrome• Symptoms

• Early symptoms

• Fever

• Muscle ache

• Especially in the lower back

• Nausea and vomiting

• Diarrhea

• Later symptoms• Unproductive cough

• Increasing shortness of breath

• Capillary leak syndrome in lungs

• Shock and death

•Causative Agents

HantavirusesIncludes Sin Nombre virus found in initial outbreak

Belong to bunyavirus family

Single-stranded RNA genome

Divided into 3 segments

Enveloped

Causes apathogenic, lifetime infection in rodent hosts

Death in humans is caused by cardiac failure from severe hypotension

• Pathogenesis

• Enters body via inhalation of dust contaminated with urine, feces and saliva of infected rodents

• Viremia

• Mechanism unknown

• Carried throughout body

• Infects capillary endothelial cells

• Inflammation causes capillaries to leak fluid into lungs

• Causes hypoxia and hypotension

• Cardiac shock and death occurs in over 36% of patients

Hantavirus Pulmonary Syndrome

• Hantavirus disease is a T cell cytokine-mediated immunopathology

• TNF

• IFNγ

• Interleukin-1

• Interleukin-2

• Lymphotoxin

Hantavirus Pulmonary Syndrome

•Immune cell infiltrates•No viral damage to the lung epithelium

Normal Hantavirus Infection

Proinflammatorycytokines

• Epidemiology

• Emerging disease due to recent discovery

• Most cases in United States occur west of Mississippi River

• Principally caused by Sin Nombre virus

• Deer mice (Peromyscus maniculatus) are the reservoir

• Outbreaks causality with increase rodent populations

• Many, if not all, infected deer mice become persistently infected

• Person-to-person transmission does not occur

• Notable exception: Andes hantavirus in South America (Argentina, Chile)

Hantavirus Pulmonary Syndrome

• Prevention and Treatment

• Prevention is directed towards minimizing exposure

• Keep pet and human food in containers

• Maximal ventilation when cleaning mouse droppings

• Mop with disinfectant

• NEVER use brooms or vacuums

• Wear N-100 HEPA-filtered mask

• Lethal traps and poisons to decrease rodent population

• No effective antiviral treatment (nor would it work anyway)

• Treatment limited to supportive care

• Extracorporeal membrane oxygenation (ECMO)

Hantavirus Pulmonary Syndrome