Upload
arthur-barrett
View
222
Download
2
Tags:
Embed Size (px)
Citation preview
Severe viral infections in childhood: Severe viral infections in childhood: recent developmentsrecent developments
Brian Eley
Paediatric Infectious Diseases Unit
Red Cross Children’s Hospital
School of Child and Adolescent Health
University of Cape Town
OverviewOverview
• Measles
• HIV infection in young children
• Severe pneumonia in HIV-infected infants
• Viral sepsis
Measles: annual global cases & Measles: annual global cases & vaccine coverage, 1980-2008vaccine coverage, 1980-2008
WHO. http://whqlibdoc.who.int/hq/2009/WHO_IVB_2009_eng.pdf
Measles vaccine coverage & deaths, Measles vaccine coverage & deaths, 2000-20082000-2008
WHO region Coverage(2000)
Deaths(2000)
Coverage(2008)
Deaths(2008)
African 56% 371,000 73% 28,000
Americas 92% < 1,000 93% < 1,000
Eastern Mediterranean
72% 101,000 83% 7,000
European 91% < 1,000 94% < 1,000
South-East Asia
61% 234,000 75% 126,000
Western Pacific 85% 25,000 93% 2,000
Total 58% 733,000 83% 164,000
Wkly Epidemiol Rec 2009;84:509-516 http://www.who.int/wer/2009/wer8449.pdf
National measles case-based surveillance: National measles case-based surveillance: IgM positive results 1998 - 2009IgM positive results 1998 - 2009
0
100
200
300
400
500
600
700
1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
Nu
mb
er
Months of the year
National Institute For Communicable Diseases, October 2009
Current measles outbreak (2 Feb 2010)Current measles outbreak (2 Feb 2010)
0
5
10
15
20
25
30
< 6 m 6-11 m 1-4 y 5-9 y 10-14 y 15-19 y 20-29 y 30-39 y > 40 y
Age distribution 2009-2010, n=6467
Province EC FS GP KZN LP MP NC NW WC Total
Cases 222 189 4297 567 265 179 75 532 365 6685National Institute For Communicable Diseases, February 2010
Factors contributing to epidemicFactors contributing to epidemic• Vaccine effectiveness & coverage
– After 1 dose at 9 mo: 80-85% seroconversion1
– 1992 epidemic, Cape Town: effectiveness: 79% [CI: 55-90%]2 – After 1 dose at 12-15 mo: 95-98% seroconversion1
– After 2 doses 4 wks apart: seroconversion approaches 99%1 – Coverage in Western Cape (2008):
• MV1: 92.7% [CI: 91-94] & MV2: 60% [CI: 56-64]3
• Kinetics of decline of maternal antibodies4
• Effect of HIV infection– Maternal antibody decay by 6 months of age5
• 91.1%of HIV-infected infants• 83.3%of HIV-exposed but uninfected children• 57.7%of HIV-negative infants
– Vaccine effectiveness: 63% (2003-2005 epidemic, JHB)6
1WHO. Wkly Epidemiol Rec 2009;84:349-3602Coetzee N, et al. S Afr Med J 1994;84:145-1493Corrigall J, et al. S Afr Med J 2008;98:41-45
4Gagneur A, et al. Clin Vaccine Immunol 2008;15:1845-18505R Scott, et al. Clin Infect Dis 2007;45:1417-14246 McMorrow LC, et al. S Afr Med J 2009;99:314-319
Immunisation practiceImmunisation practice
• Mass immunisation campaign– Ro = 15 – 17 in susceptible populations; vaccine
coverage ≥ 95% required to control the circulation of wild-type virus1,2
– National campaign planned for April 2010, targeting all children between 9 months and 15 years
• MV1 at 12-15 months of age
• WHO position on asymptomatic, HIV-infected children3 • 6 months, 9 months & 18 months
3WHO. Wkly Epidemiol Rec 2009;84:349-3601Tang JW, et al. J Hosp Infect 2006;64:100-1142Uzicanin A, et al. Int J Epidemiol 2002;31:968-976
Measles case managementMeasles case managementVariable Placebo
(n=97)Vitamin A
(n=92)RR (95% CI) P value
Death 10 2 0.21 (0.05-0.94) 0.046
Pneumonia duration (d) 12.4 6.5 <0.001
Diarrhoea duration (d) 8.5 5.6 <0.001
Post-measles croup 27 13 0.51 (0.28-0.92) 0.033
Adverse outcome 52 25 0.51 (0.35-0.74) <0.001
Hospital stay (d) 15.2 10.5 0.004
Vitamin A administration on two successive days
Daily dose Age categories
50,000 IU < 6 months
100,000 IU 6 – 11 months
200,000 IU ≥ 12 months
Hussey GD & Klein M. N Engl Med J 1990;323:160-164WHO. Wkly Epidemiol Rec 2009;84:349-360McMorrow LC, et al. S Afr Med J 2009;99:314-319
Cumulative mortality of HIV-infected Cumulative mortality of HIV-infected children in sub-Saharan Africachildren in sub-Saharan Africa
Newell ML et al. Lancet 2004; 364: 1236–43
0.6
0.5
0.4
0.3
0.2
0.1
0
0 100 200 300 400 500 600 700 800 900
Cumulative
probability of death
Age at last visit or death (days)
Not infected (n=2183)
Infected (n=707)
Overall (n=3468)
Unknown HIV status (n=578)
CHER: mortality rates - 32 week analysisCHER: mortality rates - 32 week analysis
Variable Immediate treatment
(n = 252)
Deferred treatment
n = 125
Total
(n = 377)
Death, n (%) 10 (4%) 20 (16%) 30 (8%)Follow-up (person years)
167 79 246
Mortality rate per 100 person years (95% CI)
6.0 (2.9; 10)
25.3(15.5; 39.0)
12.2 (8.2; 17.4)
Hazard Ratio (95% CI)
0.24 (0.11; 0.51)
P-value 0.0002
Violari A, et al. N Engl J Med 2008;359:2233-2244
WHO guideline revision: April 2008WHO guideline revision: April 2008(Strength of recommendation for when to start ART)
Age categories < 12 mo 1 – 4 yrs ≥ 5 yrs
When should ART be started?
All regardless of clinical / CD4
Clinical or CD4 criteria
Clinical or CD4 criteria
Strength of recommendation
Strong Strong Strong
WHO. http://www.who.int/hiv/pub/paediatric/WHO_Paediatric_ART_guideline_rev_mreport_2008.pdf
On World AIDS Day (1 December 2009) President Zuma announced that all children less than 12 months old with HIV infection should commence ART as soon as possible following diagnosis
Recommendations for starting ART Recommendations for starting ART in children (1-3 December 2009) in children (1-3 December 2009)
• Start ART for all infants (< 12 months of age) irrespective of CD4 or clinical stage
(Strong recommendation, moderate quality of evidence)
• Start ART for all children 12-23 months irrespective of CD4 or clinical stage
(conditional/weak recommendation – very low quality evidence)
The acutely hypoxic infantThe acutely hypoxic infant
Weakley M, Vries A, et al S Afr J Child Health 2009;3(2):55-59
Infective causesInfective causes
• Bacteria: S. pneumoniae, S. aureus, H. influenzae, E. coli, K. pneumoniae, Psuedomonas sp., Salmonella sp.
• Viruses: RSV, Influenza, Parainfluenza, Adenovirus, Rhinovirus, metapneumovirus, Cytomegalovirus
• Fungi: Pneumocystis jerovecii, Candida sp., Apergillus sp., Cryptococcus sp, other mycoses
• Mycobacteria: M. tuberculosis, M. avium-intracellulare• Polymicrobial disease:
– McNally: 70% of children irrespective of HIV status, strong predictor of poor outcome
– Utilisation of multiplex PCR technology
– Implication: multi-pronged approach to antimicrobial therapy is required
McNally L, et al. Lancet 2007;369:1440-1451
Approach to acute severe pneumoniaApproach to acute severe pneumonia
• HIV status: Rapid test & HIV DNA PCR • Diagnostic tests: CXR, FBC & differential, Blood
culture, NPA – PJP, respiratory viruses, CMV viral load, ± BAL – viruses & bacteria
• Empiric antimicrobials: ampicillin & gentimicin, co-trimoxazole, gancyclovir, prednisone, ± oseltamavir
• Oxygen: Nasal, Headbox, CPAP, IPPV, HFV• Nutrition & Fluids• ART as soon as diagnosis is confirmed, caregiver
counselled in parallel• Antimicrobial rationalisation
©2005The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. Published by Lippincott Williams & Wilkins, Inc.
2
Goldstein B, et al. Pediatr Crit Care Med 2005;6(1):2-8
Viral sepsisViral sepsis
Do viruses cause clinical presentations Do viruses cause clinical presentations resembling sepsis?resembling sepsis?
• Neonatal sepsis caused by viruses– Herpes simplex virus– Enteroviruses:
• Echoviruses e.g. Serotypes 6 & 11• Parechoviruses 1 & 2 (formally Echoviruses 22 & 23)
– Chikungunya viruses– Dengue virus
• Viral sepsis in infants & children– Dengue viruses– Lassa virus, other viruses causing viral hemorrhagic fevers – Hantavirus– Enteroviruses– Adenovirus in immunocompromised individuals– Respiratory syncytial virus
Argent A & Eley B J Peditr Infect Dis 2009;4(2):161-172
Molecular diagnosisMolecular diagnosis• Application to bacterial sepsis
– Unspecific 16S rRNA gene-targeted generic assays1,2
– Single PCR reactions3
– Real-time, multiplex formats4-6
• Application to fungal sepsis– Unspecific 28S rRNA gene-targeted assays2
– 18S rRNA gene-targeted PCR for Candida infections7
– Multiplex formats4,6,8
• Application to viral pathogens– Multiplex formats for common viral and bacterial pathogens9
– Real-time PCR assays for enteroviruses and parechoviruses10,11
– Real-time PCR for type-specific herpes simplex viruses12
1Wellinghausen N, et al. J Clin Microbiol 2009;47:2759-27652Zhao Y, et al. J Clin Microbiol 2009;47:2067-20783Perchorsky A, et al. J Microbiol Meth 2009;78:325-3394Lehmann LE, et al. Intensive Care Med 2010;36:49-565Bloos F, et al. Intensive Care Med 2010;36:241-2476Avolio M, et al. Shock 2010, Jan 19 [Epub ahead of print]
7Wellinghausen N, et al. Med Microbiol 2009;58(Pt 8):1106-1118 Lau A, et al. J Clin Microbiol 2009, 30 Dec [Epub ahead of print]9Kumar S, et al. J Clin Microbiol 2008;46:3063-307210Noordhoek GT, et al. J Clin Virol 2008;41:75-8011Meylan S, et al. J Clin Virol 2008;41:87-9112Benschop K, et al. J Clin Virol 2008;41:69-74
ConclusionConclusion
• To increase the effectiveness of measles immunisation the age of MV1 should be reconsidered
• The care needs of young HIV-infected children should be prioritised
• Further molecular diagnostic developments are required to advance the concept of viral sepsis, particularly in the setting of neonatology