Diseases of the respiratory

system
Gordon Churchward
3009 Rollins Research Center
ggchurc@microbio.emory.edu
Upper respiratory system
Nose, pharynx, throat
Middle ear, eustachian tube
Ducts from the nasal sinuses and nasolacrimal ducts empty into nasal
cavity, auditory tubes empty into upper portion of throat
Defenses hairs and ciliated mucosa trap particles
Lower respiratory system
Larynx, trachea,bronchial tubes and alveoli (gas exchange)
Lungs enclosed in pleura
Ciliated mucous membrane down to smaller bronchial tubes
Nearly sterile
Case 1
The patient was a 64-year-old retired postal worker with a medical history
of extensive facial reconstruction for squamous cell carcinoma of the head
and neck. He had a 30-year history of smoking. The patient presented with
progressive shortness of breath; a persistent, productive cough; purulent
sputum; and fever to 39.0C 2 days prior to admission.
On physical examination he had a temperature of 37.3C, respiratory rate
of 18/min, pulse rate of 103 beats/min, blood pressure of 154/107 mm Hg,
and pO2 of 92 mm Hg. Chest auscultation revealed coarse breath sounds at
the left lower base with bibasilar fine crackles. He was found to have a left
lower lobe infiltrate on chest radiograph. His admission white blood cell
count was 10,600 with 70% neutrophils, and his hemoglobin was 9.4. Sputum
Gram stain at admission revealed >25 polymorphonuclear cells and >25
squamous epithelial cells. Because of the high numbers of squamous
epithelial cells, the specimen was not processed further. Two blood cultures
obtained at admission revealed the organism seen in Fig. 1. The Gram stain
from the blood culture bottle is shown in Fig. 2. Of note: this was the
patient's third episode of this illness in the past month. Isolates from all
three episodes belonged to the same serotype, type 23.
Case 1
Case 1
Organism? Risk factors
Streptococcus pneumoniae - alpha hemolytic, catalase negative,
optochin-sensitive
Age, immunosuppression, smoking

Populations at risk?
Young children, AIDS, asplenic (sickle cell), cardiovasc., liver,
kidney disease, diabetics, malignancies, immunosuppressed,
connective tissue disease

Virulence factors? Pathogenicity
Polysacharide capsule 7 types responsible for 80-90% invasive
disease
Pneumolysin cytolysin. Fluid accumulation & hemorrhage in
alveoli
Case 1
Prevention? Importance?
Vaccine 7-valent (children), 23-valent (adults)
Conjugate vaccines
Drug prophylaxis in selected populations
Drug resistance

Repeated episodes?
Inadequate treatment
Not susceptible to antimicrobial
Not treated for long enough
Undrained focus of infection
Reinfection with same serotype
Failure to eliminate nasopharyngeal colonization

Two types of respiratory infection
Type Examples Consequences
Restricted to
surface
Common cold viruses
Influenza
Streptocci in throat
Chlamydia (conjunctivitis
Diptheria
Pertussis
Candida albicans
(thrush)

Local spread
Mucosal defenses important
Adaptive immune response too late to be
important
Short incubation period
Spread through
body
Measles, mumps rubella
EBV, CMV
Chlamydia psittaci
Q fever
cryptococcosis
Little or no lesion at entry site
Microbe spreads through body returns to
surface for shedding
e.g. salivary gland (mumps, CMV, EBV)
respiratory tract (measles)
Adaptive immune response important
Longer incubation period
Respiratory invaders
Type Requirement examples
Professional
Infect healthy
respiratory tract
Adhesion to normal mucosal surface
in spite of mucociliary system


Ability to interfere with cilia

Ability to resist destruction in alveolar
macrophage

Ability to damage local mucosal and
submucosal tissues
Respiratory viruses, S. pyogenes (throat)
S. pneumoniae, Mycoplasma pneumoniae
Chlamydia

Bordetella pertussis, M. pneumoniae
S. Pneumoniae (pneumolysin)

Legionella, M. tuberculosis


Corynebacterium diptheriae (toxin), S.
pneumoniae (pneumolysin)
Secondary
invaders
(infect when
host defenses
impaired)
Respiratory virus infection

Local defenses impaired (CF)

Chronic bronchitis
Local foreign body or tumor
Depressed immune system (AIDS)
Depressed resistance (elderly,
alcoholism, renal or hepatic disease)
S. aureus. S. pneumoniae (pneumonia
complicating influenza

S. aureus, Pseudomonas

H. influenzae, S. pneumoniae

Pneumocystis carinii, CMV, M. tuberculosis

S. pneumoniae, S. aureus, H. influenzae
Case 2
The patient was a 5-year-old male who awoke on the day
prior to evaluation with a sore throat and fever. His mother
had him stay home from kindergarten and treated him
symptomatically with Tylenol. He slept well but the next day
awoke still complaining of sore throat and fever, as well as
headache and abdominal pain. He was an only child and
neither parent was ill.

On physical examination, he was noted to have a fever of
38.4C. His physical examination was significant for a 2+ (on
a scale of 1 to 4+) red anterior pharynx, tonsillar region, and
soft palate. His anterior cervical lymph nodes at the angle of
the mandible were slightly enlarged and tender. No skin
lesions or rashes were seen. A culture of the organism
causing this patient's infection is shown in Fig. 1.
Case 2
Case 2
Organism?
Beta-hemolytic, bacitracin-sensitive
Streptococcus pyogenes

Detection important?How? Strengths and
weaknesses?
Viral pharyngitis indistinguishable
Swab
Antibiotic therapy to prevent sequellae
Swabs/culture
Rapid/sensitivity 80-90%

Case 2
Non-infectious sequelae? Pathogenesis?
Rheumatic fever/glomerulonephritis
M protein type M1/M3 / M12/M49
Pharyngitis/ pharyngitis,skin infections
RF - Cross reaction with heart tissue, damage to valves
G- cross reaction with glomerular basement membrane

Antimicrobial resistance
Penicillin resistance hasnt arisen
Penicillin-allergic, macrolides, resistance to erythromycin
Case 2
Sore throat with rash? Virulence factors?
Scarlet fever pyrogenic exotoxins, superantigen

Fatal infections
Streptococcal TSS, necrotizing fasciitis
M1/M3, SpeA superantigen,

Vaccine?
M protein
Many Mtypes, cross reactivity
Streptococcal pharyngitis
Group A -hemolytic streptococci
Streptococcus pyogenes
Produce streptokinases (lyse finbrin clots
Streptolysins ctotoxic to tissues, red blood
cells, leukocytes
Indistinguishable from pharyngitis from other
bacteria and viruses
Inflammation and fever, tonsillitis, involvement
of lymph nodes in neck, otitis media
<80 serological types, immunity is type-specific
Erythrogenic toxin SCARLET FEVER
Toxin production due to lysogenization by
phage


Diptheria
Corynebacerium diptheriae
Sore throat and fever, swelling of neck, grayish membrane (grey
eschar in cutaneous diptheria) forms in throat, can block passage of
air to lungs
Phage lysogenization results in production of powerful toxin
Vaccination with diptheria toxoid
Adaptation to immunized population, relatively non virulent strains
found in many carriers
Few case reported in US, but death rate 5-10%
Effective immune levels in as few as 20% of population
Recent epidemic in former Soviet Union
Epiglottitis
Young children, H. influenza type B
Severe inflammation and edema, w. bacteremia
Difficulty breathing, require intubation

Otitis media
S. pneumoniae 35%
H. influenzae 20-30%
Moraxella catarrhalis 10-15%
S. pyogenes 8-10%
S. aureus 1-2%

Affects 85% of children before age three
7,000,000 case per year
Half of all office visits
Common cold
50% of cases caused by rhinoviruses <100 types (picornovirus ss +strand
RNA env.)
Coxsackie virus A (24 types) (picornoviruses) common cold, oropharyngeal
vesicles
Influenza viruses (orthomyxovirus ms strand RNA env) may invade lower
respiratory tract
Parainfluenza viruses (4 types) (paramyxovirus ss strand RNA env) may
invade larynx
Respiratory syncitial virus (paramyxovirus) may invade lower respiratory
tract
Corona viruses (several types) common cold (ss +strand RNA env)
Adenovirus (42 types) pharyngitis, conjunctivitis, bronchitis (ds DNA
env)
Echoviruses (34 types) (picornoviruse) common cold

Common cold
Sneezing, excessive nasal secretion, congestion
Virus adsorbs to and replicates in epthelial cells
Cell damage, clear fluid outpouring from lamina propria
Host defenses activated
Attraction of phagocytes
Low grade overgrowth by bacterial commensals
Fluid becomes purulent
Recovery, regeneration of epithelium
Case 3
The patient was a 51/2-week-old male who was transferred
to our institution with a 10-day history of choking spells. The
child's spells began with repetitive coughing and progressed
to his turning red and gasping for breath. In the prior 2
days, he also had three episodes of vomiting in association
with his choking spells. His physical examination was
significant for a pulse rate of 160 beats/min and a
respiratory rate of 72/min (both highly elevated). The
child's chest radiograph was clear. There was no evidence of
tracheal abnormalities. His white cell count was 15,500/l
with 70% lymphocytes. The culture from the nasopharyngeal
swab is seen in Fig. 1.
Case 3
Organism?
Bordetella pertussis

Clinical course?
Whooping cough
Abnormal oxygen exchange

Specimens
Binds ciliated epthelial cells, filamentous hemaglutinin,
high yield
Slow culture (10 days)
DFA testing, replaced by PCR
Case 3
Predominance of lymphocytes?
Pertussis toxin lymphocytosis-promoting factor
Distinguishing factor

Vaccination
DTP diptheria, tetanus , pertussis toxoids plus whole cell
Encephalopathy
Vaccine worse than disease
New vaccines

Persistence of cough
Toxin causes ciliostasis and cell death
Bacterial pneumonia
Resistance
Pertussis (whooping cough)
Bordetella pertussis gram- coccus obligate aerobe
Attaches to ciliated cells in trachea
Tracheal cytotoxin damages to ciliated cells
Pertussis toxin enters blood stream causing systemic effects (inhibits signal
transduction)
Adenylate cyclase toxin inhibits defense functions in neutrophils

Catarrhal stage resembles common cold
Paroxysmal stage characteristic cough, severe
Convalescent stage can be prolonged
Complications include CNS anoxia, secondary pneumonia
Tuberculosis
M. tuberculosis inhaled on
microdroplets reach lung, where they
are phagocytosed by alveolar
macrophages

Intaracellular multiplication causes a
chemotactic response attracting
additional macrophages. Many times the
infection is controlled.

If the infection progresses, the disease
is walled off in a tubercle. Arrest at
this point leads to calcification Ghon
complexes
Tuberculosis
In some people a mature tubercle
forms
Caseous center enlarges
liquifaction
Liquifaction continues until the
tubercle ruptures with
dissemination of the mycobacteria
into the airway, cardiovascular and
lymphatic systems milliary
tuberculosis
Acute disease after infection 5%
Latent infection >90%
Reactivation ~ 5%
Tuberculosis
Tuberculin skin test purified
protein derivative injected,
sensitized T cells react giving
delayed hypersensitivity
reaction
BCG vaccine attenutaed strain
Efficacy questionable,
interferes with skin test
Case 4
This 40-year-old male with multisystem failure secondary to
bilateral pneumonia was transferred to our hospital via helicopter.
He had presented to his local physician 3 days previously
complaining of fevers, malaise, and vague respiratory symptoms. He
was given amantadine for suspected influenza. His condition became
progressively worse, with shortness of breath and a fever to
40.5C, and he was admitted to an outside hospital 24 hours prior
to transfer. A laboratory examination revealed abnormal liver and
renal function. Therapy with Timentin (ticarcillin-clavulanic acid)
and trimethoprim-sulfamethoxazole was begun. On admission, he
underwent a bronchoscopic examination that revealed mildly
inflamed airways containing thin, watery secretions. A Gram stain
of bronchial washings obtained at bronchoscopy is shown in Fig. 1.
Based on these findings, he was begun on appropriate antimicrobial
therapy. Culture results are shown in Fig. 2.
Case 4
Case 4
Organisms?
S. pneumoniae, H. influenz, Mycoplasma, Chlamydia, S .
aureus, Klebsiella pneumonia, Legionella, viruses

Bronchial washings?
Bronchioscope bronchial washing, bronchial lavage

Cause?
Legionella
BCYE SPECIAL ORDER
Hepatic and renal dysfunction, thin watery secretions,
dry cough




Case 4
Detection?
Culture slow
DFA 60-70% sensitivity, 2 hours
Urinary antigen 80-90%
PCR?

Epidemiology, infection control?
Aerosols of water
Sporadic more common than nosocomial
Chronic lung disease, immunosuppression, age
Viral infection?
No person-person spread, respiratory isolation unnecessary

Antimicrobial therapy
Erythromycin, also active against Bordetella
Penetrates white cells, Legionella survive and multiply within
macrophages



Pneumonia
Lobar pneumonia: distinct region of lung, polymorph exudate clots in
the alveoli, infection may spread to adjacent alveoli until constrained
by anatomic barriers between segments or lobes of the lung
Bronchopneumonia diffuse, patchy consolidation, spreads through the
airways
Interstitial pneumonia, invasion of lung interstitium, particularly
characteristic of viral pneumonias
Lung abscess, necrotizing pneumonia, cavitation and destruction of
lung parenchyma
Most common cause of death by infection in the elderly

Bacterial pneumonia
Pneumococcal S. pneumoniae, involves both brochi and the alveoli, high
fever, breathing difficulty, chest pain. Can invade bloodstream, pleural
cavity, meninges
H. Influenzae lowered defenses susceptible
Mycoplasma pneumoniae low grade fever headache, cough walking
pneumonia
Legionellosis - Legionella pneumophila high fever, cough
Psittacosis Chlamidia psittacci obligate intracellular bacterium fever,
headache and chills
Chlamidial pneumonia Chlamidia pneumoniae
Q fever Coxiella burnetti obligate intracellular bacterium, can cause
endocarditis years after infection, mainly in western US
S. aureus. Moraxella catarrhalis,S. pyogenes, Pseudomonas, Klebsiella

Case 5
The patient was a 4-month-old female who was admitted to the hospital in
March with severe respiratory distress. Five days prior to admission she
had developed a cough and rhinitis. Two days later she began wheezing and
was noted to have a fever. She was brought to the emergency room when
she became letharagic.
One sibling was reported to be coughing, and her father had a "cold." On
examination she was agitated and coughing. She had a fever of 38.9C,
tachycardia with a pulse rate of 220 beats/min, tachypnea with a
respiratory rate of 80/min, and blood pressure of 90/58 mm Hg. Her
fontanelles were open, soft, and flat. Her throat was clear. She had
subcostal retractions and nasal flaring. On auscultation of her lungs, there
were rhonchi as well as inspiratory and expiratory wheezes.
A chest radiograph revealed interstitial infiltrates and hyperexpansion.
Arterial blood gases on supplemental oxygen revealed a respiratory acidosis
with relative hypoxemia. She was put in respiratory isolation in the pediatric
intensive care unit and was subsequently intubated. Blood and
nasopharyngeal cultures were obtained and sent to the bacteriology and
virology laboratories. A rapid diagnostic test was positive (Fig. 1) and
specific antiviral therapy was begun. She was also given the bronchodilator
aminophylline to treat the bronchospasm that was resulting in her wheezing.
She was extubated 5 days later and discharged home on day 8.
Case 5
Case 5
Differential diagnosis? Viral agent?
Mycoplasma, Bordetella
Parainfluenza, adenovirus, influenza, RSV

Epidemiology
Most important childhood respiratory illness, elderly
Winter, peak Jan, Feb
Droplets, fomites

Diagnostic strategies?
DFA, immunoassay, important to diagnose in children w.
preexisting conditions

Case 5
Treatment strategies
Ribavirin aerosol, controversial efficacy??

Infection control issues?
Respiratory isolation, nosocomial infections hazard.

Prevention
No vaccine inactivated vaccine disastrous
Live attenuated-no success:reversion or no immunity
Subunit vaccine
Human pooled Ig, humanized mouse monoclonal
palivizumab some benefit for children <2 w. chronic
lung disease

Viral pneumonia
Complication of infection influenza, measles, chickenpox


Respiratory syncytial virus (paramyxovirus)
Most common cause of respiratory disease in infants, 100,000
hospitalized, 4500 deaths
Coughing and wheezing lasting for more than a week
Fever with bacterial complications
Influenza
Chills, fever, headache
Virus remains restricted to respiratory
system, no viremia
Inflammatory responses cause bronchitis
and interstitial pneumonia
10,000 - 20,000 deaths per year
Diarrhea not a normal symptom (stomach
flu)

Orthomyxovirus
8 RNA strands, enveloped
Hemaglutinin attachment and membrane
fusion
Neuraminidase release of virus

Influenza
Viral type
Internal
ribonucleoprotein
Antigenic subtype
Hemaglutinin/neuraminidase
Year severity
A
(pandemics)
H3N2 (China)
H1N1 (Spanish)
H2N2 (Asian)
H3N2 (Hong Kong)
1889
1918
1957
1968
Moderate
Severe
Severe
Moderate
B 1940 Moderate
C 1947 Very mild
Antigenic shift genetic recombination between animal and human strains
Antigenic drift accumulation of mutations (no proofreading)
Mortality usually low large numbers of people infected
Predisposition to secondary bacterial infection, staphylococci, pneumococci,
H. influenzae
Histoplasmosis
Histoplasma capsulatum - dimorphic fungus
Spread by bats
Superficial resemblance to
tuberculosis
Disseminated disease in
immunocompromised individuals


Coccidiodomycosis
Coccidiodomycosis immitis
Dimorphic fungus
Geographically restricted valley
fever
Abundant arthrospores spread by
wind
100,000 infections per year
1% of cases progressive disease
resembling tuberculosis spreads
throughout body
50 100 deaths

Aspergillosis
Allergic bronchopulmonary aspergillosis
Patients with asthma
Disseminated disease in immunosuppressed patients
Treatment problematic / amphotericin with reduction in
immunosuppressive therapy if possible
Pneumocystis pneumonia
Pneumocystis carinii related to fungi
Disease in immunocompromised
individuals