Diseases of the respiratory systemGordon Churchward3009 Rollins Research Centerggchurc@microbio.emory.edu

Upper respiratory systemNose, pharynx, throatMiddle ear, eustachian tubeDucts from the nasal sinuses and nasolacrimal ducts empty into nasal cavity, auditory tubes empty into upper portion of throatDefenses hairs and ciliated mucosa trap particles

Lower respiratory systemLarynx, trachea,bronchial tubes and alveoli (gas exchange)Lungs enclosed in pleuraCiliated mucous membrane down to smaller bronchial tubesNearly sterile

Case 1The patient was a 64yearold retired postal worker with a medical history of extensive facial reconstruction for squamous cell carcinoma of the head and neck. He had a 30year 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 1Organism? Risk factorsStreptococcus pneumoniae - alpha hemolytic, catalase negative, optochin-sensitiveAge, immunosuppression, smoking

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

Virulence factors? PathogenicityPolysacharide capsule 7 types responsible for 80-90% invasive diseasePneumolysin cytolysin. Fluid accumulation & hemorrhage in alveoli

Case 1Prevention? Importance?Vaccine 7-valent (children), 23-valent (adults)Conjugate vaccinesDrug prophylaxis in selected populationsDrug resistance

Repeated episodes?Inadequate treatmentNot susceptible to antimicrobialNot treated for long enoughUndrained focus of infectionReinfection with same serotype Failure to eliminate nasopharyngeal colonization

Two types of respiratory infection

TypeExamplesConsequencesRestricted to surfaceCommon cold virusesInfluenzaStreptocci in throatChlamydia (conjunctivitisDiptheriaPertussisCandida albicans (thrush)Local spreadMucosal defenses importantAdaptive immune response too late to be importantShort incubation periodSpread through bodyMeasles, mumps rubellaEBV, CMVChlamydia psittaciQ fevercryptococcosisLittle or no lesion at entry siteMicrobe spreads through body returns to surface for sheddinge.g. salivary gland (mumps, CMV, EBV) respiratory tract (measles)Adaptive immune response importantLonger incubation period

Respiratory invaders

TypeRequirementexamplesProfessionalInfect healthy respiratory tractAdhesion 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 tissuesRespiratory viruses, S. pyogenes (throat)S. pneumoniae, Mycoplasma pneumoniaeChlamydia

Bordetella pertussis, M. pneumoniaeS. 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 tumorDepressed 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 2The patient was a 5yearold 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 2Organism?Beta-hemolytic, bacitracin-sensitiveStreptococcus pyogenes

Detection important?How? Strengths and weaknesses?Viral pharyngitis indistinguishableSwabAntibiotic therapy to prevent sequellaeSwabs/cultureRapid/sensitivity 80-90%

Case 2Non-infectious sequelae? Pathogenesis?Rheumatic fever/glomerulonephritisM protein type M1/M3 / M12/M49Pharyngitis/ pharyngitis,skin infectionsRF - Cross reaction with heart tissue, damage to valvesG- cross reaction with glomerular basement membrane

Antimicrobial resistancePenicillin resistance hasnt arisenPenicillin-allergic, macrolides, resistance to erythromycin

Case 2Sore throat with rash? Virulence factors?Scarlet fever pyrogenic exotoxins, superantigen

Fatal infectionsStreptococcal TSS, necrotizing fasciitisM1/M3, SpeA superantigen,

Vaccine?M proteinMany Mtypes, cross reactivity

Streptococcal pharyngitisGroup A -hemolytic streptococciStreptococcus pyogenesProduce streptokinases (lyse finbrin clotsStreptolysins ctotoxic to tissues, red blood cells, leukocytesIndistinguishable from pharyngitis from other bacteria and virusesInflammation and fever, tonsillitis, involvement of lymph nodes in neck, otitis media

DiptheriaCorynebacerium diptheriaeSore throat and fever, swelling of neck, grayish membrane (grey eschar in cutaneous diptheria) forms in throat, can block passage of air to lungsPhage lysogenization results in production of powerful toxinVaccination with diptheria toxoidAdaptation to immunized population, relatively non virulent strains found in many carriersFew case reported in US, but death rate 5-10%Effective immune levels in as few as 20% of populationRecent epidemic in former Soviet Union

EpiglottitisYoung children, H. influenza type BSevere inflammation and edema, w. bacteremiaDifficulty breathing, require intubation

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

Affects 85% of children before age three7,000,000 case per yearHalf of all office visits

Common cold50% of cases caused by rhinoviruses

Common cold Sneezing, excessive nasal secretion, congestionVirus adsorbs to and replicates in epthelial cellsCell damage, clear fluid outpouring from lamina propriaHost defenses activatedAttraction of phagocytesLow grade overgrowth by bacterial commensalsFluid becomes purulentRecovery, regeneration of epithelium

Case 3The patient was a 51/2weekold male who was transferred to our institution with a 10day 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 3Organism?Bordetella pertussis

Clinical course?Whooping coughAbnormal oxygen exchange

SpecimensBinds ciliated epthelial cells, filamentous hemaglutinin, high yieldSlow culture (10 days)DFA testing, replaced by PCR

Case 3Predominance of lymphocytes?Pertussis toxin lymphocytosis-promoting factorDistinguishing factor

VaccinationDTP diptheria, tetanus , pertussis toxoids plus whole cellEncephalopathyVaccine worse than diseaseNew vaccines

Persistence of coughToxin causes ciliostasis and cell deathBacterial pneumoniaResistance

Pertussis (whooping cough)Bordetella pertussis gram- coccus obligate aerobeAttaches to ciliated cells in tracheaTracheal cytotoxin damages to ciliated cellsPertussis toxin enters blood stream causing systemic effects (inhibits signal transduction)Adenylate cyclase toxin inhibits defense functions in neutrophils

Catarrhal stage resembles common coldParoxysmal stage characteristic cough, severeConvalescent stage can be prolongedComplications include CNS anoxia, secondary pneumonia

TuberculosisM. 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

TuberculosisIn some people a mature tubercle formsCaseous center enlarges liquifactionLiquifaction continues until the tubercle ruptures with dissemination of the mycobacteria into the airway, cardiovascular and lymphatic systems milliary tuberculosisAcute disease after infection 5%Latent infection >90%Reactivation ~ 5%

TuberculosisTuberculin skin test purified protein derivative injected, sensitized T cells react giving delayed hypersensitivity reactionBCG vaccine attenutaed strainEfficacy questionable, interferes with skin test

Case 4This 40yearold 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 (ticarcillinclavulanic acid) and trimethoprimsulfamethoxazole 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 4Organisms?S. pneumoniae, H. influenz, Mycoplasma, Chlamydia, S . aureus, Klebsiella pneumonia, Legionella, viruses

Bronchial washings?Bronchioscope bronchial washing, bronchial lavage

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

Case 4Detection?Culture slowDFA 60-70% sensitivity, 2 hoursUrinary antigen 80-90%PCR?

Epidemiology, infection control?Aerosols of waterSporadic more common than nosocomialChronic lung disease, immunosuppression, ageViral infection?No person-person spread, respiratory isolation unnecessary

Antimicrobial therapyErythromycin, also active against BordetellaPenetrates white cells, Legionella survive and multiply within macrophages

PneumoniaLobar 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 lungBronchopneumonia diffuse, patchy consolidation, spreads through the airwaysInterstitial pneumonia, invasion of lung interstitium, particularly characteristic of viral pneumoniasLung abscess, necrotizing pneumonia, cavitation and destruction of lung parenchymaMost common cause of death by infection in the elderly

Bacterial pneumoniaPneumococcal S. pneumoniae, involves both brochi and the alveoli, high fever, breathing difficulty, chest pain. Can invade bloodstream, pleural cavity, meningesH. Influenzae lowered defenses susceptibleMycoplasma pneumoniae low grade fever headache, cough walking pneumoniaLegionellosis - Legionella pneumophila high fever, coughPsittacosis Chlamidia psittacci obligate intracellular bacterium fever, headache and chillsChlamidial pneumonia Chlamidia pneumoniae Q fever Coxiella burnetti obligate intracellular bacterium, can cause endocarditis years after infection, mainly in western USS. aureus. Moraxella catarrhalis,S. pyogenes, Pseudomonas, Klebsiella

Case 5The patient was a 4monthold 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 5Differential diagnosis? Viral agent?Mycoplasma, BordetellaParainfluenza, adenovirus, influenza, RSV

EpidemiologyMost important childhood respiratory illness, elderlyWinter, peak Jan, FebDroplets, fomites

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

Case 5Treatment strategiesRibavirin aerosol, controversial efficacy??

Infection control issues?Respiratory isolation, nosocomial infections hazard.

PreventionNo vaccine inactivated vaccine disastrousLive attenuated-no success:reversion or no immunitySubunit vaccineHuman pooled Ig, humanized mouse monoclonal palivizumab some benefit for children

Viral pneumoniaComplication of infection influenza, measles, chickenpox

Respiratory syncytial virus (paramyxovirus)Most common cause of respiratory disease in infants, 100,000 hospitalized, 4500 deathsCoughing and wheezing lasting for more than a weekFever with bacterial complications

InfluenzaChills, fever, headacheVirus remains restricted to respiratory system, no viremiaInflammatory responses cause bronchitis and interstitial pneumonia10,000 - 20,000 deaths per yearDiarrhea not a normal symptom (stomach flu)

Orthomyxovirus8 RNA strands, envelopedHemaglutinin attachment and membrane fusionNeuraminidase release of virus

InfluenzaAntigenic shift genetic recombination between animal and human strainsAntigenic drift accumulation of mutations (no proofreading)Mortality usually low large numbers of people infectedPredisposition to secondary bacterial infection, staphylococci, pneumococci, H. influenzae

Viral typeInternal ribonucleoproteinAntigenic subtypeHemaglutinin/neuraminidaseYearseverityA (pandemics)H3N2 (China)H1N1 (Spanish)H2N2 (Asian)H3N2 (Hong Kong)1889191819571968ModerateSevereSevereModerateB1940ModerateC1947Very mild

HistoplasmosisHistoplasma capsulatum - dimorphic fungusSpread by bats Superficial resemblance to tuberculosisDisseminated disease in immunocompromised individuals

CoccidiodomycosisCoccidiodomycosis immitis Dimorphic fungusGeographically restricted valley feverAbundant arthrospores spread by wind100,000 infections per year1% of cases progressive disease resembling tuberculosis spreads throughout body50 100 deaths

AspergillosisAllergic bronchopulmonary aspergillosisPatients with asthmaDisseminated disease in immunosuppressed patientsTreatment problematic / amphotericin with reduction in immunosuppressive therapy if possible

Pneumocystis pneumoniaPneumocystis carinii related to fungiDisease in immunocompromised individuals