Atypical pneumonia

1. Atypical pneumonia 1938, H.A.Reimann, atypical pneumonia : not caused by influenza virus, psittacosis different from other pneumonia Causes of Community-Acquired Atypical Pneumonia Mycoplasma M.pneumoniae Respiratory tract virus Influenza, adenovirus, RSV, parainfluenza virus Other viral agents Varicella-zoster, measles, EBV Rickettsia C. burnetii (Q fever) Chlamydia C.psittaci (psittacosis), C.pneumoniae Bacteria Legionella, F.tularensis, Y.pestis, B.anthracis Fungi Histoplasma, Blastomyces, Coccidioides From Fishman’s pulmonary diseases and disorders. 3rd Ed. Morton NS.

2. Atypical pneumonia Nonzoonotic atypical pneumonia (not spread from animal to human) Mycoplasma pneumonia (M.pneumoniae) Legionnaires’ diseases (Legionella species) Chlamydia pneumonia (Chlamydia pneumoniae) Zoonotic atypical pneumonia (spread from animal to human) Psittacosis(Chlamydia psittaci) Q fever (Coxiella burnetii) Tularemia (Francisella tularensis)

3. Mycoplasma infection • Smallest free living organism(100-300nm) • Lack of cell wall : no Gram staining, resistant to -lactam • M.pneumoniae • M.hominis • Ureaplasma urealyticum : urinary calculi Pathogenesis Adhesion to host cell  induction of ciliostasis Non-specific stimulation of B lymphocyte  trigger autoAb  reactive with brain, heart, muscle, erythrocyte I Ag IgM autoAb(cold agglutinins)  agglutinate human erythrocyte at 4℃

4. Mycoplasma pneumonia Epidemiology • 10-20% of all pneumonia • Common causes of tracheobronchitis, bronchiolitis, pharyngitis • Symptoms persist for weeks or month • Spread by aerosol from person to person • Incubation period 1-3weeks • Common misconception that M.pneumoniae disease is rare among the very young and among older adults has led to a failure of physicians even to consider this conditon in the differential diagnosis.

5. Mycoplasma pneumonia Clinical Features • Tracheobronchitis is the most frequent. • Primary cause of “walking” or “atypical” pneumonia(3-10%). • Sore throat, headache, chills, coryza, general malaise(rigors very rare) • Sometimes myringitis(5%), otitis • Lung abscesses, pneumatoceles, extensive lobar consolidation, respiratory distress and pleural effusion(20%) may develop. • <P/E> • No findings on chest auscultation even if pneumonia is present • Rales, wheeze present later • Sinus tenderness, pharyngeal erythema, erythema or bulla of tympanic membrane, nonprominent cervical adenopathy

6. Mycoplasma pneumonia Extrapulmonary Complication ⑴ Hemolytic anemia antibodies to I Ag on erythrocyte membrane  cold agglutinin response(60%) positive Coombs’ test, reticulocytosis ⑵ Mucocutaneous lesions(25%) erythematous maculopapular and vesicular exanthems ulcerative stomatitis, conjunctivitis ⑶ Gastrointestinal symptoms(25%) nausea, vomiting(common), pancreatitis(rare) ⑷ CNS(0.1%) meningoencephalitis, aseptic meningitis, encephalitis, ascending paralysis, transverse myelitis  slow recovery, permanent neurologic deficit sometimes ⑸ Rheumatologic symptoms arthralgia(common), actual arthritis(rare) ⑹ Cardiac involvement(rare) myopericarditis, hemopericardium, CHF, complete heart block

7. Mycoplasma pneumonia Laboratory Abnormalities ① Routine lab is usually normal. Thrombocytosis Leukocytosis(1/4) ESR(1/3) ② Subclinical hemolytic anemia positive Coombs’ test , reticulocytosis Chest X-ray ① Peribronchial pneumonia : most common thickened bronchial shadow streaks of interstitial infiltration atelectasis ② Pleural effusion(20%) ③ Nodular infiltration ④ Hilar adenopathy uncommon

8. Mycoplasma pneumonia Diagnosis There are no distinguishing clinical or radiologic manifestations that allow a secure diagnosis of mycoplasma pneumonia versus other causes of atypical pneumonia such as chlamydia or legionella. ⑴ Serologic test (IgM and IgG antibody to M.pneumoniae by ELISA or CF test) ① A fourfold or greater increase in titer in paired sera ② A single titer of greater than or equal to 1:32 * Antibody titers rise 7-10 days after infection and peak at 3-4 weeks ⑵ Cold agglutinin test : neither sensitive nor specific for M.pneumoniae ⑶ Antigen capture-enzyme immunoassay (Ag-EIA) ⑷ Direct PCR ⑸ Isolation of M.pneumoniae

9. Mycoplasma pneumonia Treatment of Mycoplasma Pneumonia • No rapid way to make the diagnosis of mycoplasm pneumonia. • Empiric therapy for atypical pneumonia for 14-21 day course ① erythromycin : drug of choice ② tetracyclin, doxycycline : suitable alternatives ③ new drug : clarithromycin, azithromycin

10. Chlamydial infection Chlamydia : obligate intracellular parasites, possess cell wall, both DNA & RNA extracellular elementary body (infective form) intracellular reticulate body • Chlamydia psittaci : pneumonia, psittacosis • Chlamydia trachomatis : STD & perinatal infection • Chlamydia pneumoniae : URI, pneumonia Attack to target cells Rupture of inclusion Enter the cells within phagosome Releasing elementary bodies Reorganize into reticulate bodies Infection of adjacent cells Multiplication in inclusion body

11. Chlamydial infection C. trachomatis inclusion showing a dividing reticulate body, two elementary bodies and an intermediate form with its typical nucleoid Electron micrograph of an inclusion containing C trachomatis cultured for 40hours in L929 cells. Most of the reticulate bodies are at the periphery of the inclusion (X 7500).

12. Chlamydial infection 1. STD Due to C. Trachomatis • At least 20 serotypes for C.trachomatis • LGV(lymphogranuloma venereum) • : more invasive, disease in lymphatic tissue • Non-LGV strains • : superficial infections of eye,genitalia,respiratory tract • Epidemiology • Peak incidence : late teens and early twenties • Prevalence • ① urethritis 3-5% in general medical settings • 10% for asymptomatic soldiers under routine P/E • 15-20% for heterosexual men in STD clinics • ② cervicitis 5% for asymptomatic college students and prenatal patients • 10% in family planning clinics • > 20% in STD clinics

13. Chlamydial infection Clinical Features of STD ⑴ Nongonococcal and postgonococcal urethritis ⑵ Epididymitis ⑶ Reiter’s syndrome ⑷ Proctitis ⑸ Mucopurulent cervicitis ⑹ Pelvic inflammatory disease(PID)

14. Chlamydial infection ㅊ Fig 1. Chlamydial cervicitis with granulation tissue of the zone of transformation

15. Chlamydial infection Fig 2. Colposcopic exam of a cervix. Erythema and mucopurulent discharge coming from the ciervical os

16. Chlamydial infection Fig 3. Unilateral chronic follicular conjunctivitis

17. Chlamydial infection Fig 4. Unilateral follucular conjunctivitis caused autoinoculation from the genital tract

18. Chlamydial infection Fig 5. Fluorescein-conjugated monoclonal antibody detects the EBs in a cervical smear from a patient. EB are apple green, fluorescing,round extracellular particles.

19. Chlamydial infection Fig 6. Iodine stain of a tissue cultures specimen from patient with C. trachomatis infection showing the darkly staining glycogen-containing inclusion

20. Chlamydial infection Fig 7. Chronic salpingitis and obstruction of the distal portion of the tube caused by infection with C.trachomatis

21. Chlamydial infection Fig 8. C. trachomatis epididymitis with unilateral scrotal erythema and edema

22. Chlamydial infection Ulcerated inguinal bubo in a patient with secondary LGV Inguinal bubo Ulcerative lesion

23. Chlamydial infection 2. C. Pneumniae Infections • C.pneumoniae : more difficult to culture than other chlamydiae • Peak incidence : young adults • Secondary episode : older adults • Transmission : from person to person, primarily in schools and family units • Clinical spectrum : acute pharyngitis, sinusitis, bronchitis, pneumonitis • Clinical features • ① resembles that of M.pneumoniae pneumonia • (leukocytosis(-), antecedent URI symptoms, fever, • nonproductive cough,minimal findings on chest auscultaton • small segmental infiltrates on chest x-ray) • ② severe especially in elderly patients • Diagnosis • acute and convalescent-phase sera for chlamydial CF antibody • ( but not distinguish C.pneumoniae from C.trachomatis or C.psittaci) • Treatment • erythromycin or tetracycline 2g/day for 10-14days

24. 3. Psittacosis Chlamydial infection Infectious disease of birds caused by C.psittaci Transmissin from birds to humans -> febrile illness Almost always transmitted to humans by the respiratory route (rarely bite of a pet bird) upper respiratory tract ->bloodstream -> pulmonary alveoli, RES -> lymphocytic inflammation in alveolar walls and interstitium Clinical Features incubation period : 7-14 days more gradual onset with fever, headache, nonproductive cough untreated cases -> sustained or remittent fever for 10days to 3weeks -> gradually abate Diagnosis acute and convalescent-phase sera for chlamydial CF antibody Differential diagnosis Mycoplasma pneumonia, C.pneumoniae pneumonia, legionellosis viral pneumonia, Q fever Treatment tetracycline 2g/day for 7-14days

25. Legionella Infection Legionellosis : two clinical syndromes by genus Legionella Pontiac fever : acute,febrile,self-limited illness by Legionella species Legionnaires’ disease : pneumonia by Legionella species Legionnaires’ disease 1976 outbreak of pneumonia at a hotel in Philadelphia during American Legion Convention  aerobic G(-) bacterium named Legionella pneumophila in lung specimens Etiology Family Legionellaceae : 41 species with 63 serogroups L.pneumophila aerobic G(-) bacilli 80-90% of human infections at least 14 serogroups (most common serogroups 1,4, 6) 17 species other than L.pneumophila associated with human infections L. micdadei, L. bozemanii, L. dumoffii, L. longbeachae

26. Legionella infection Imprint smear of lung in Legionnaires’ disease. The bacilli are red and clustered in alveolar macrophages.

27. Legionella infection L.pneumophilla bacilli are enclosed by envelope,which consists of inner and outer triple-layered membranes.most organisms contain vacuoles.

28. Legionella infection Epidemiology • Transmission • natural habits for L.pneumophila : aquatic bodies(lakes, streams) • enter aquatic reservoirs(cooling towers or water-distribution systems) • grow and proliferate ( enhance colonization in warm temperature 25-42℃) • aerolization, aspiration, direct instillation into the lung Epidemiology 3-15% of community-acquired pneumonia 10-50% of nosocomial pneumonias when a hospital’s water system is colonized with the organisms Most common risk factors cigarette smoking, chronic lung disease, old age, immunosuppression Most often develops in elderly. Surgery is a prominent predisposing factor in nosocomial infection

29. Pathogenesis Legionella infection Enter the lungs via aspiration or direct inhalation Adherence to respiratory tract epithelial cells 1. Conditions that impair mucociliary clearance smoking, lung disease, alcoholism 2. Cell-mediated immunity is the primary mechanism. transplant recipients, HIV patients, patients receiving glucocorticoid hairy cell leukemia(monocyte deficiency and dysfunction) 3. Role of neutrophil : minimal 4. Humoral immune system IgM, IgG witin weeks ofinfection promote killing of legionellae by neutrophils,monocytes,alveolar M neither enhance lysis by complememt nor intracellular multiplication

30. Legionella infection Pontiac Fever Acute, self-limiting, flulike illness with a 24-48h incubation period Pneumonia does not develop. Fever, headache, malaise, fatigue, myalgias : the most frequent symptoms Complete recovery within only a few days without antibiotic therapy Diagnosis by antibody seroconversion

31. Legionella infection Legionnaires’ disease(pneumonia) Clinical Clues suggestive of Legionnaires’ Disease Diarrhea High fever ( > 40℃ ) Numerous neutrophils but no organisms revealed by Gram’s staining of respiratory secretions Hyponatremia (serum sodium level of < 131 meq/L) Failure to respond to -lactam drugs and aminoglycoside antibiotics Occurrence of illness in an environment in which the potable water supply is known by be contaminated with Legionella Onset of symptoms within 10 days after discharge from the hospital

32. Legionella infection

33. Diagnosis Legionella infection Utility of Special laboratory Test for the Diagnosis of Legionnaires’ Disease Specificity,% 100 100 96-99 100 96-99 Test Culture sputum transtracheal aspirate DFA staining of sputum Urinary antigen testing * Antibody serology ** Sensitivity,% 80 90 50-70 70 40-60 * Serogroup 1 only ** IgG and IgM testing of both acute- and convalescent-phase sera. A single titer of ≥ 1:128 is considered presumptive, while a single titer of ≥ 1:256 or fourfold seroconversion is considered definitive.

34. Legionella infection Extrapulmonary Legionellosis Usually result from bloodborne dissemination from the lung Sinusitis, peritonitis, pyelonephritis, cellulitis, pancreatitis : predominantly in immunosuppressed patients The most common extrapulmonary site  Heart : myocarditis, pericarditis, postcardiotomy syndrome, prosthetic-valve endocarditis Most cases hospital-acquired

35. Legionella infection Direct immunofluorescence of L. pneumophila of lung. Numerous bacilli in alveolar macrophages

36. Treatment Legionella infection Antibiotics for 10-14 days * longer period(3 weeks) for immunosuppressed ① Erythromycin ② New macrolides(azithromycin, clarithromycin, roxithromycin, josamycin) ③ Ciprofloxacin : transplanted patient ④ Rifampin + macrolides or quinolone Pontiac fever requires only symptom-based treatment, not antibiotics Prevention Disinfection of the water supply is the ultimate preventive measure. ① Superheat and flush method heating of the water( 70-80℃ ) flushing with hot water for at least 30 min. ② copper and silver ionization method ③ hyperchlorination is no longer recommended