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Emerging Infectious Disease (EID) involving Respiratory Tract

Emerging Infectious Disease (EID) involving Respiratory Tract . Sanit Reungrongrat, MD Pediatrics Department, Faculty of Medicine, Chiang Mai University. Underlying causes for EID. Generalized social changes worldwide urbanization, IV drug abuse, changing sexual practice Demographic changes

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Emerging Infectious Disease (EID) involving Respiratory Tract

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  1. Emerging Infectious Disease (EID) involving Respiratory Tract Sanit Reungrongrat, MD Pediatrics Department, Faculty of Medicine, Chiang Mai University

  2. Underlying causes for EID • Generalized social changes • worldwide urbanization, IV drug abuse, changing sexual practice • Demographic changes • human mobility and refugee population • Medical care • blood transfusion, organ transplant, re-used syringes for antibiotic injections, contamination vaccines and antibiotic resistance Kuiken T, et al. Curr Opin Biotech 2003;14:641

  3. Underlying causes for EID • Economic and commercial trends • intensive food production, extended irrigation, liberalized trading pattern • Climatic changes • global warming and regional changes • Ecosystem disturbance • deforestation, eutrophication of waterways, reduction in predators of disease vector organisms Kuiken T, et al. Curr Opin Biotech 2003;14:641

  4. Human Metapneumovirus(hMPV)

  5. hMPV • Is a pathogen that emerged as a result of increased and tenacious diagnostic efforts rather than through expansion of it range or transmission to a new host species • First identified in 2001 by van den Hoogen BC, et al. (Nat Med 2001;7:719) • Isolated from 28 young children, stored nasopharyngeal aspiration (NPA) with RTI over 20 years in Netherlands • New member of Metapneumovirus genus, Paramyxoviridae family

  6. Paramyxoviridae Pneumovirinae Metapneumovirus Human Metapneumonvirus Classification of Viral Pathogens of Paramyxoviridae Family McIntosh K, McAdam AJ. N Engl J Med 2004;350:431

  7. Pneumoviruses: 3'-NS1-NS2-N-P-M-SH-G-F-M2-L-5' Metapneumoviruses: 3'-N-P-M-F-M2-SH-G-L-5' 13,350 nucleotides Negative-sense, nonsegmented RNA Pneumovirinaesubfamily are distinguished from Paramyxovirinae subfamily by Distantly related amino acid sequences Significant related to F (fusion) and L (polymerase) proteins Pneumovirinae encode more mRNA (8-10 vs. 6-7), and proteins (NS1, NS2, M2-1,M2-2) which not found in Paramyxovirinae Metapneumovirus lack NS1, NS2 and have different positioning of the genes between M, and L Genomic Structure of hMPV Domachowske JB, et al. Clin Microbiol Newsletter 2003;25:17

  8. Electron Micrograph of hMPV • Pleomorphic • Average size 100-600 nm • Nucleocapsids rarely observed • Envelope projections of 13-17 nm Nat Med 2001;7:719

  9. Indirect Immunofluorescence • IDF with polyclonal antibodies to hMPV Richards A, et al Nephrol Dial Transplant2005;20:2848-50

  10. Virus Isolation, Cell Culture and Growth Characteristics of hMPV • Identified by RAP-PCR • Is semi-quantitative reverse transcriptase PCR-based technique (RT-PCR) that is used to compare the entire pool of transcripts • Real-time PCR is rapid (<2hr) • Culture by tertiary monkey kidney cells (tMK), LLC-MK2, Vero cell lines • hMPV grows very slowly (10-14 days) observe by cytopathic effect (CPE) • hMPV replication is trypsin dependent CPE: morphologic characteristics of monolayer change as virions replicate inside the cells Nat Med 2001;7:719

  11. Phylogeny of hMPV • Indicator for the relationship between the newly identified virus isolates and members of Pneumovirinae • Phylogenetic trees were constructed based on the N, P, M and FORFs of these viruses

  12. Heterogeneity of hMPV • Phylogenetic tree analysis of sequence1 • Divided in two genotypes: A and B • Both genotypes can be divided in two subgroups: A1, A2, B1, B2 • The F protein revealed ~95% amino acid sequence identity between virus genotype A and B • the G protein shared only 30% identity • Virus neutralization assays with genotype-specific antibody demonstrated 12- to >100-fold difference between genotype A and B • Genotype A has clinical severity than genotype B2 F gene G gene • Van den Hoogen BG, et al. Pediatr Infect Dis J 2004;23:S25. • Vicente D, et al. Clin Infect Dis 2006;42:e111.

  13. Seroprevalence of hMPV *Sero-archeological analysis using sera collection in 1958 • Serologic studies showed circulating antibodies to the virus in virtually all children age 5 years or older • On the basic antibody prevalence, hMPV has circulate in the human populations at least 45 years and more likely longer Nat Med 2001;7:719

  14. Several epidemiologic studies of hMPV in most parts of the world 36 studies: 2.2-30%

  15. N=601, age<2yr N=488,01-7.7%, 02-19%, 03-2.2%, 2.7%;HIV-infected infant N=10,025, 4mo-79yr, mean 8.2yr, median 1.37yr, 92% <5yr N=97, age<5yr N=381, age<15yr, median age 15 mo N=515 N=166 N=144 N=247 N=126 N=587, age<18yr N=116 N=236,mean age 22 mo (9-38 mo)

  16. N=516, age<5yr N=116, age 3mo-16yr N=63, age<2yr N=214, mean age 10.1 mo N=374 N=132, age 3mo-16yr N=236, median age 12 mo N=90, age<2yr N=1,505, age<15yr N=1,331, age<15yr N=589, age<5yr N=711, all age

  17. N=440, age<5yr N=211, age<1yr N=749, age<2yr N=208, age<3yr N=445, age 2mo-93yr) N=38 N=1,294, all age N=2,384; detect AOM 50% N=248 N=296 N=668, age<5yr

  18. Epidemiology of hMPV • In the community ~2.2% - 5% • In hospitalized children ~5% - 10% • Age <18 years: 2.8% - 17.9% • Age <5 years: 5.5% - 13% • Age <3 years: 4.1% - 6% • Age <2 years: 11% - 25% • Age <1 year: 16.2%

  19. Age and Seasonal Distribution of hMPV (All Age)(Osterhaus A, Fouchier R. Lancet 2003;361:890. (N=115) Number of patient Age range (years) Month Netherland

  20. Age distribution of hMPV-positive children (Age <5 yrs)(Esper F, et al JID 2004;189:1338. N=668) 54 cases (8.1%) No of patients Months USA

  21. Age distribution of hMPV-positive children (Age <3 yrs)(Boivin G, et al Emerg Infect Dis 2003;9:634. N=208) 12 cases (6%) No of patients Months Canada

  22. Epidemiology of hMPV • Year of study – vary by year or location “periodic epidemics” • North America study: more frequent in 2001 than 2000 (7% vs.1.5%) • Italian study: more frequent in 2002 and 2000 than 2001 (43%, 37% vs.7%) • African study: more frequent in 2002 than 2001 and 2003 (19% vs. 7.7%, 2.2%) • Seasonality • Temperate region: late winter to spring • Subtropics region: late spring to summer (HK)

  23. Seasonal incidence of hMPV. Queensland Australia, 2001-2004 (Sloots TP, et al. Emerg Infect Dis 2006;12:1263) N=10,025, All ages Su, summer (Dec-Feb); Au, autumn (Mar-May); W, winter (Jun-Aug); Sp, spring (Sep-Nov)

  24. Epidemiology of hMPV • Asymptomatic infection is rare • Incubation period 4-6 days, duration of symptoms before seeking medical usually <7 days, viral shedding ~ 1-2 weeks • Peak age 6-12 months, male predomonant • 30-85% of hospitalized children have underlying disease • prematurity, chronic lung disease congenital heart disease, cancer, HIV-infected, asthma, renal failure, GERD

  25. Epidemiology of hMPV • Coinfection (5-17%) with virus or bacteria, most common is RSV • Others are influenza, parainfluenza, adenovirus, CMV, rhinovirus, SARS, S pneumoniae, M pneumoniae, C pneumoniae, H influenzae, K pneumoniae, E coli • Cocirculationof different hMPV genotypes in one year

  26. Rates, by year, of each genetypes of hMPVData are from 1982 to 2001 in the Vanderbilt Vaccine Clinic Williams JV, et al. JID 2006;193:387

  27. Distribution of hMPV subtype in Queenland, Australia, 2001-2004 Clinical records: 74.4% admitted, LOS median, 3 days; mean 6.5 day, predominant S&S, cough, rhinorrhea, crackles, fever (N=273 cases) Classification severity: mild 46.8%, moderate 42.5%, severe 10.7% Sloots TP. Et al. Emerg Infect Dis 2006;12:1263

  28. Comparison of hMPV and RSV (1) • Overall, hMPV is less commonly isolated from respiratory specimens than RSV • RSV appears more common than hMPV in infants <6 months • Similar to RSV, majority of hMPV cases occur in young (<5 yrs) and elderly (>65 yrs) • hMPV peaks later (April), where as RSV peaks earlier (December-February) • hMPV and RSV have similarclinical presentation in children and elderly • In 1 study (Greensill J, et al. Emerg Infect Dis 2003;9:372), hMPV/RSV coinfection was detected in 70%

  29. Comparison of hMPV and RSV (2) • While both hMPV and RSV can provokes severe infections, disease severity and hospitalization appears more common with RSV • Compared the clinical symptoms hMPV with age-matched RSV infected children; RSV-infected found more dyspnea, hypoxemia and feeding difficulties • Two studies in hospitalized patients show that hMPV did not need PICU, contrast to some of RSV and Influenza-infected patients1,2 • Pneumonia was more often associated with RSV 1. Viazou S, et al. J Clin Microbiol 2003;41:3043. 2. Boivin G, et al. Emerg Infect Dis 2003;9:634.

  30. Age distribution of hMPV and RSV (Age <2yrs)(Garcia-Garcia ML, et al. Arch Dis Child 2006;91:290. N=749 hMPV 64 cases (14%) RSV 376 cases (76%)

  31. Monthly Distribution of hMPV and RSV (Age <1yr)(Ordas J, et al. J Clin Microbiol 2006:2739. N=211) hMPV 18 cases (16.2%) RSV 96 cases (45.5%)

  32. Clinical Manifestation of hMPV (1) • Fever 57 - 100% • Cough 63 - 100% • Rhinorrhea 46 - 92% • Sore throat 50 - 59.5% • Hoarseness 1 - 6% • Lacrimation 25% • Conjunctivitis 5 - 7% • Influenza-like illness 50 - 53% • Common cold 7 - 52% • Otitis media 12 - 51% • Diarrhea 6 - 37.5% • Vomiting 10 - 48.5% • Febrile seizure 16% • Truncal rash 10 - 19% • Feeding difficulties 36 - 65%

  33. Clinical Manifestation of hMPV (2) • Hypoxia 24 - 47% • Wheeze 0 - 83% • Dyspnea 28 - 83% • Retractions 60 - 92% • Hyperventilation 42% • Cyanosis 4 - 8% • Rhinitis 27 - 80% • Rhinopharyngitis 5% • Pharyngitis 13 - 39% • Laryngitis 5% • Tachycardia 23 - 57% • Pneumonia 8 - 73% • Bronchiolitis 10 - 67% • Asthma exacerbation 14 - 22% • Bronchitis 0 - 60%

  34. Clinical Manifestation of hMPV (3) • Croup 18% • Asthma 14% • Irritability 43% • Apnea 2 - 6% • Noisy breathing 14% • Tachypnea 67% • Rhonchi 20% • Crackles (rales) 8 - 100% • Sneezing 45.5% • Dry mouth 23% • Enlarged liver 6% • Headache 30% • Anorexia 45% • Drowsiness 85% • Lethargy 26%

  35. Lab Investigation • Lymphopenia (<1,500 cumm) 29% • Neutropenia (<1,00 cumm) 6.5% • Elevated transaminase 3.3% • WBC (cumm) 5,930 - 16,500 • LDH (IU/L) 269 - 649 • CRP (mg/dL) 0.76 - 2.54

  36. CXR • Abnormal CXR 28 - 87% • Infiltrates 66% • Air trapping 19% • Atelectasis 40% • Other: peribronchial cuffing, pulmonary edema, cardiomegaly, lobar pneumonia (coinfection with bacteria), pleural thickening

  37. CXR Obtained in a 6-Month-Old Infant with hMPV Bronchiolitis Hyperinflation and diffuse perihilar infiltrates Willaims JV, et al N Engl J Med 2004;350:443-450

  38. Pathology of hMPV • Pathology specimens of hMPV-positive • Exam by light and electron microscopy • BAL • BAL showed • Epithelial degenerative changes and eosinophilic cytoplasmic inclusions within epithelial cells, multinucleated giant cell, histocytosis Red cytoplasmic inclusion Degenerative epithelial cells Multi nucleated giant cell Vargas SO, et al. Pediatr Dev Pathol 2004;7:478

  39. Pathology of hMPV • Lung biopsy showed • Lipoid pneumonia • Chronic airway inflammation • Intraalveolar foamy • Cholesteral clefts • Hemosiderin-laden macrophages Vargas SO, et al. Pediatr Dev Pathol 2004;7:478

  40. Management • Supportive care and managing airway obstruction • Antiviral therapy • Prevention

  41. Supportive Care • Administer humidified oxygen • Nasal suctioning to clear upper airway • Monitor for apnea, hypoxia and impending respiratory failure • Normalize body temperature • Rehydrate with oral or intravenous fluids • Monitor hydration status

  42. Managing Airway Obstruction and Antiviral Therapy • Bronchodilators • Corticosteroids • Ribavirin • Intravenous immunoglobulin

  43. Effect of Ribavirin and Glucocoticoid Treatment in Mouse Model of hMPV infection A. Mean viral titers in lungs of hMPV-infected mice (BALB/c). On day 5 postinfection B. Lung inflammation in hMPV-infected mice evaluation with mean histopathological scores Hamelin ME, et al Antimicrob Agents Chemother2006;50:774

  44. Data of Management • Oxygen administration 24.3 - 34.3% • Bronchodilator 30 - 32.4% • Corticosteroids 8.1 - 17% • Antibiotics 22.2 - 94% • Mechanical ventilation 2% • PICU 2% • Duration of fever: 4 (2-7) days • Duration of hospitalization: 4 (3-7) days • School absence, median (range): 10 (3-15) days 1. Wang SM, et al Clin Microbiol Infect 2006;12:1221, 2. Foulongne V, et al. Pediatr Infect Dis J 2006;25:354, 3. Takao S, et al. Jpn J Infect Dis 2003;56:127, 4. Wolf DG, et al. Pediatr Infect Dis J 2006;25:320

  45. Clinical and Socioeconomic Impact Among Household Contacts • Disease similar to infected child (%) 16 (12.5) • Additional medical visits (%) 16 (12.5) • Antipyretic prescriptions (%) 14 (10.9) • Antibiotic prescriptions (%) 6 (4.7) • Lost working days, median (range) 4 (2-10) • Lost of school days, median (range) 4 (3-15) Bosis S, et al. J med Virol 2005;75:101.

  46. Prevention • Effort to reduce spread include: • Limiting contact with infected patients • Removal from day care and group setting • Proper hygiene: frequent hand washing • Disinfecting surface exposed to infectious secretions • Cohorting hospitalized patients • Vaccination • Immunoprophylaxis

  47. Community-Acquired MRSA(CA-MRSA)

  48. CA-MRSA: Definition • CDC: diagnosis made in the community setting or by culture positive for MRSA within 48 hrs after admission to hospital • It is known that patients may be colonized with HA-MRSA for year before developing infection • Nosocomial outbreak of CA-MRSA have been reports (MMWR Mar 31, 2006;55:329) http://www.cdc.gov/ncidod/hip/ARESIST/mrsa_comm_faq.htm

  49. CA-MRSA: Definition • Molecular marker (Lyon) for definition • The Panton-Valentine leukocidin (PVL) genes • SCC mec IV • Molecular methods • Pulsed-field gel electrophoresis (PFGE) • Multilocus sequence typing (MLST) • PCR-based method CA-MRSA clones; ST1 (USA 400), ST8 (USA 300) Vandenesch F et al. Emerg Infect Dis 2003;9:978

  50. CA-MRSA: History • S aureus is gram-positive coccid bacterium, originally susceptible to penicillin • 1940s: Penicillinase-producing strains appear • 1959: Methicillin introduced • 1961: MRSA emerged as nosocomial pathogen, first at UK • Early 1990s: CA-MRSA infections reported

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