A multicenter study of serious infections in young infants

WHO

Infant mortality in the developing world

126,000,000 live births126,000,000 live births 8,000,000 infant deaths8,000,000 infant deaths 5,000,000 neonatal deaths5,000,000 neonatal deaths 3,300,000 early neonatal deaths3,300,000 early neonatal deaths

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1

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3

4

5

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8

1st week

1-4 weeks

1-12 mths

deaths(millions)

Neonatal deaths

global estimate 5 million per yearglobal estimate 5 million per year 98% in developing countries98% in developing countries 92% in Asia or Africa92% in Asia or Africa data from developing countries, particularly the data from developing countries, particularly the

first week of life likely to be an underestimatefirst week of life likely to be an underestimate

Causes of neonatal mortality

5 million deaths per year5 million deaths per year infection - 1.78 millioninfection - 1.78 million prematurity - 1.15 millionprematurity - 1.15 million birth asphyxia/trauma - 1.38 millionbirth asphyxia/trauma - 1.38 million congenital anomalies - 0.52 millioncongenital anomalies - 0.52 million other perinatal causes - 0.17 millionother perinatal causes - 0.17 million

WHO MSM Programme

Deaths from neonatal infection

1.6 million:1.6 million: 750,000 pneumonia750,000 pneumonia 350,000 tetanus350,000 tetanus 300,000 sepsis300,000 sepsis 150,000 diarrhoea150,000 diarrhoea 50,000 meningitis50,000 meningitis

ie. pneumonia/sepsis/meningitis is responsible for 1.1 million neonatal deaths per year

Views about the causes neonatal sepsis in developing countries in 1989

Most Klebsiella or StaphylococcalMost Klebsiella or Staphylococcal Contribution of pneumococcus or Hib unknownContribution of pneumococcus or Hib unknown Contribution of GBS unknownContribution of GBS unknown Clinical signs are unlikely to be helpful in Clinical signs are unlikely to be helpful in

identifying high risk infants at the primary care levelidentifying high risk infants at the primary care level

Multicentre study objectives

To identify the To identify the bacterial and viral agentsbacterial and viral agents responsible responsible for serious infections in infants under 90 days of age for serious infections in infants under 90 days of age in developing countriesin developing countries

To identify the To identify the simple clinical signssimple clinical signs that best predict that best predict serious infection in infants under 90 days of age serious infection in infants under 90 days of age

WHO multicentre study of pneumonia/sepsis/meningitis in young infants Study Co-ordination: S. Gove, P. Margolis, F. McCaul, S. Parker, C. John; Writing Committee:

K. Mulholland, P. Margolis, K. Mason, S. Gove; Data Management: P. Byass; Statistical Analysis: F. Harrell, K. Mason, J. Carlin; Gambia team: Clinicians: K. Mulholland (PI), O. Ogunlesi, M. Weber, M. Manary, A. Palmer; Laboratory: R. Adegbola, H. Whittle, O. Secka, B. Sam, D. Hazlett, M. Aidoo, Data management: J. Bangali; Director: B. Greenwood; Ethiopia: Clinicians: L. Muhe (PI), M. Tilahun, S. Lulseged, S. Kebede; Laboratory: A. Yohanes*, B. Belete, S. Ringertz; Radiology: T. Desta; Data management: K. Woldeyesus; Director: N. Tafari; Papua New Guinea: Clinicians and nurses: D. Lehmann (PI), G. Saleu, A. Rongap, M. Kakazo, P. Namuigi, S. Lupiwa, R. Sehuko; Laboratory: A. Clegg, R. Sanders , A. Michael, T. Lupiwa, M. Omena, M. Mens, B. Marjen, P. Wai’in, M. Sungu; Data management: D. Lewis; Director: M. Alpers; Philippines: Clinicians: S. Gatchalian (PI), B. Quiambao, A.M. Moreles, L. Abraham; Laboratory: L. Sombrero, F. Palladin, V. Sariano, A.M. Obach; Data management: E. Sunico, T. Cedulla; Study advisors: H. Eichenwald, C. Broome, M.Gratten, P. Margolis, R. Facklam, T. Nolan; Reference Laboratory Support: J. Hendrichsen, P.H. Makela, M. Grandien, J. Schachter, L. Moore, G. Cassell, L. Duffy, R. Facklam, F. Tenover, B. Metchock; Radiology Working Group: H. Tschappeler, M. Hendry, A. Lamont, P. Palmer.

WHO multicentre study of pneumonia/sepsis/meningitis in young infants

4552 sick infants under 90 days of age studied in 4 4552 sick infants under 90 days of age studied in 4 developing countriesdeveloping countries Papua New Guinea, The Gambia, The Papua New Guinea, The Gambia, The

Philippines, EthiopiaPhilippines, Ethiopia full history and examination on every infantfull history and examination on every infant All infants with signs of infection investigatedAll infants with signs of infection investigated outcome of all cases recordedoutcome of all cases recorded

Criteria for investigationPresenting

finding Pulse

oximetry Chest X-ray Blood culture

Lumbar Puncture

T > 37.5C x x T < 37.5C x x x T > 38C x x x cough x x difficulty breathing x x fast breathing x x noisy breathing x x stopped breathing x x child is “very sick” x abnormally irritable x x decreased feeding (< 1/2 normal)

x x

abnormally sleepy/lethargic

x x

seizure x x x extreme irritability x x x bulging fontanel x x x

Positive blood culture isolates

Staph. aureusStaph. aureus 3434 Strep. pneumoniaeStrep. pneumoniae 3333 Group A StreptococcusGroup A Streptococcus 2929 E. coliE. coli 1919 Salmonella spp.Salmonella spp. 1717 other Gram negs.other Gram negs. 2222 H. influenzaeH. influenzae 77 other Streps.other Streps. 6 6

CSF isolates

Age (days) 0-6 7-29 30-59 60-90 total

S. pneumoniae 0 5 10 2 17

H. influenzae 0 0 1 3 4

Gp A Strep. 1 0 2 0 3

E. coli 1 3 2 0 6

other Gm. neg. 4 4 1 1 10

Total 6 13 16 6 41*

* one Group B Streptococcus was isolated

Clinical features

10% of the 2398 infants investigated died:10% of the 2398 infants investigated died: blood culture positive - 31% diedblood culture positive - 31% died blood culture negative - 9% diedblood culture negative - 9% died CSF culture positive - CSF culture positive -

death was associated withdeath was associated with positive CSF or blood culturepositive CSF or blood culture hypoxaemiahypoxaemia major x-ray abnormalitymajor x-ray abnormality abnormal white cell count (<5.5 or >22)abnormal white cell count (<5.5 or >22)

Gram-positive organisms

S. pneumoniaeS. pneumoniae - 33 cases - 33 cases 17 meningitis, 16 pneumonia17 meningitis, 16 pneumonia 11 deaths (33%)11 deaths (33%) mean age 47 daysmean age 47 days

Group A Streptococcus - 29 casesGroup A Streptococcus - 29 cases 4 deaths (14%)4 deaths (14%) mean age 34 daysmean age 34 days

Staph aureusStaph aureus - 34 cases - 34 cases 7 deaths (21%)7 deaths (21%) mean age 33 daysmean age 33 days

Gm negative organisms

Salmonella spp.Salmonella spp. - 17 cases - 17 cases 6 deaths (35%)6 deaths (35%) underweight (mean Z-score -2.4)underweight (mean Z-score -2.4)

E. coliE. coli - 19 cases - 19 cases 10 deaths (53%)10 deaths (53%) 6 meningitis6 meningitis underweight (mean Z-score -2.7)underweight (mean Z-score -2.7)

Viruses

Gambia (n=438) Gambia (n=438) 51 RSV (12%)51 RSV (12%)

peak Sept-Octpeak Sept-Oct 46 Influenza A (11%)46 Influenza A (11%) 22 Influenza B (5%)22 Influenza B (5%) 26 Parainfluenza (6%)26 Parainfluenza (6%)

Philippines (n=685)Philippines (n=685) 101 RSV (15%)101 RSV (15%)

peak Sept-Octpeak Sept-Oct 5 Influenza A5 Influenza A 2 Influenza B2 Influenza B 16 Parainfluenza (2%)16 Parainfluenza (2%)

Clinical signs study

ObjectivesObjectives to identify the best clinical predictors of serious to identify the best clinical predictors of serious

infections in young infants in the hands of infections in young infants in the hands of paediatricianspaediatricians

to identify the simple signs most helpful for the to identify the simple signs most helpful for the identification of infants in need of referral for identification of infants in need of referral for suspected serious infectionsuspected serious infection

Clinical signs study

ProblemsProblems very large amount of clinical data, much very large amount of clinical data, much

overlapping or duplicativeoverlapping or duplicative measured, culture proven endpoint is only a measured, culture proven endpoint is only a

fraction of the infants regarded by clinicians as in fraction of the infants regarded by clinicians as in need of admission and antibioticsneed of admission and antibiotics

how to deal with deaths? how to deal with deaths?

Recorded deaths were Recorded deaths were notnot prevented by appropriate clinical care. prevented by appropriate clinical care.

Clinical signs study

MethodMethod variables analysed as clusters determined by statistical variables analysed as clusters determined by statistical

association and clinical common senseassociation and clinical common sense Ordinal outcome scale:Ordinal outcome scale:

2 = positive blood or CSF culture or SaO2<90% (adj.)2 = positive blood or CSF culture or SaO2<90% (adj.)1 = positive chest x-ray or SaO2 90-95%1 = positive chest x-ray or SaO2 90-95%0 = none of the above0 = none of the above

Proportional odds assumption checkedProportional odds assumption checkedpoor fit for auscultatory findingspoor fit for auscultatory findings

Clinical signs study - full model TemperatureTemperature

Respiratory rateRespiratory rate WAZ scoreWAZ score Bulging fontanelle or convulsionBulging fontanelle or convulsion Drowsy-unconsciousDrowsy-unconscious Signs of respiratory effort (grunting, chest wall indrawing)Signs of respiratory effort (grunting, chest wall indrawing) CrepitationsCrepitations Poor feedingPoor feeding ApneaApnea

Clinical signs study - simplified model

Respiratory rate (0-20 points)Respiratory rate (0-20 points) Temperature PR (0-7 points)Temperature PR (0-7 points) WAZ score (0-6 points)WAZ score (0-6 points) Unable to suck (5 points)Unable to suck (5 points) Crepitations (8 points)Crepitations (8 points) Cyanosis (5 points)Cyanosis (5 points) History of convulsions (4 points)History of convulsions (4 points) Lower chest wall indrawing (3 points)Lower chest wall indrawing (3 points) No arousal with minimal stimulus (2 points)No arousal with minimal stimulus (2 points) History of change in activity (2 points)History of change in activity (2 points)

Probability of culture positive, SaO2<95%, or x-ray abnormal

5 .07 10 .14 15 .27 20 .45 25 .65 30 .80 40 .95

Conclusions Infection, particularly pneumonia, meningitis and Infection, particularly pneumonia, meningitis and

sepsis are major contributors to high mortality sepsis are major contributors to high mortality rates in very young infants in developing countries.rates in very young infants in developing countries.

The most likely bacterial causes are:The most likely bacterial causes are: S. pneumoniaeS. pneumoniae Group A StreptococcusGroup A Streptococcus Staph. aureusStaph. aureus Gram negative enteric organisms, esp. Gram negative enteric organisms, esp. E. coliE. coli

Conclusions - II

Young infants in developing countries are frequently Young infants in developing countries are frequently infected by the usual respiratory viruses, particularly RSV, infected by the usual respiratory viruses, particularly RSV, with much morbidity but little mortalitywith much morbidity but little mortality

Efforts to improve early infant mortality should focus on Efforts to improve early infant mortality should focus on preventing bacterial infections, and early detection and preventing bacterial infections, and early detection and prompt referral of suspected casesprompt referral of suspected cases

Clinical signs can reliably identify those at greatest riskClinical signs can reliably identify those at greatest risk