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