Karen L. Kotloff, MD on behalf of the VIDA consortium 13 th International Rotavirus Symposium Minsk, Belarus August 2018

Transcription

1 Etiology of diarrheal disease after rotavirus vaccine introduction: The Vaccine Impact on Diarrhea in Africa (VIDA) Study Karen L. Kotloff, MD on behalf of the VIDA consortium 13 th International Rotavirus Symposium Minsk, Belarus August 2018 accine mpact on iarrhea in frica CVD CVD-Mali MRC/The Gambia KEMRI/CDC 1

2 Background: Global Enteric Multicenter Study (GEMS) Matched case-control study of Moderate-to-Severe Diarrhea (MSD) Determine the incidence, etiology and outcomes of MSD 0-59 months old living in censused populations in 7 LDC Key Findings Etiology: 6 pathogens were attributable to 78% of MSD by qpcr (Rotavirus, Cryptosporidium, Shigella, ST-ETEC, Adenovirus 40/41, Campylobacter spp.) Growth Faltering: Cases had significantly more linear growth faltering than controls Mortality: Odds of dying was 8.5 times higher among cases than controls (Kotloff Lancet 2013; 382: ) (Liu Lancet 2016; 388: ) 2

3 Linear Growth of cases vs controls between enrollment and 60-d follow-up HAZ *p<0.05 comparing cases vs controls at follow-up 0-11m 12-23m 24-59m Enrollment * * * Follow-up Cases 0-11m Cases 12-23m Cases 24-59m Controls 0-11m Controls 12-23m Controls 24-59m (adapted from Kotloff Lancet 2013; 382: ) 3

4 60-day growth velocity, by pathogen Girls Boys Est growth velocity (cm/60 days) All other MSD & Rotavirus Girls Age of MSD episode (months) Cryptosporidium, Untreated Shigella, & ST-ETEC All other MSD & Rotavirus Cryptosporidium & ST-ETEC Untreated Shigella Age of MSD episode (months) (unpublished)

5 Vaccine Impact on Diarrhea in Africa (VIDA) VIDA = Three African sites from GEMS after rotavirus vaccine introduced Primary Aim: To investigate the landscape of diarrheal pathogens after rotavirus vaccine introduction to inform future interventions needed in the postrotavirus vaccine era VIDA Sites:

6 Overview of Study Design Demographic Surveillance System (DSS) Sentinel Health Centers MSD Case Enrollment (in 0-11, 12-23, age groups) 60 day follow-up at home HUCS MSD not seeking care at SHC 1-3 Matched controls enrolled at home 10

7 Methods: Case-control enrollment Eligible cases sought healthcare with new onset, acute diarrhea with at least one of the following signs: Sunken eyes Loss of skin turgor History of bloody diarrhea Hospitalization (Actual or recommended) IV rehydration Controls had no diarrhea for 7 days before enrollment Randomly selected from the DSS population, matched to cases by age, gender, residence, and time Each case and control provided: A stool sample, tested for a wide variety of bacterial, viral and protozoal pathogens (conventional assays and quantitative PCR using TaqMan Array Card) 11

8 Preliminary results from first two years of enrollment will be presented Enrollment of MSD cases/controls in VIDA, through 24 months Site 0-11 months months months The Gambia 430/ / /473 Mali 434/ / /425 Kenya 385/ / /449 Total 1249/ / /1347 8

9 Attributable fraction (95% CI) Pathogen-specific MSD attributable fraction by qpcr Rotavirus Cryptosporidium Shigella spp ST-ETEC Adenovirus 40/41 Campylobacter spp Kenya Mali Gambia VIDA GEMS 0-11 months Rotavirus Cryptosporidium Shigella spp ST-ETEC Adenovirus 40/41 Campylobacter spp Rotavirus Cryptosporidium Shigella spp ST-ETEC spp Adenovirus 40/41 Campylobacter spp months months 9

10 Key Findings (qpcr) Top Pathogens (Attributable Fraction) Shigella Rotavirus Adenovirus 40/41 Cryptosporidium ST-producing ETEC Campylobacter spp. 10

11 Median rotavirus case age: GEMS & VIDA = median age of complete vaccination Median: 13 Median: 12 Median: 10 mos Median: 13 mos Median: 9 mos Median: 12 mos Gambia Mali Kenya = GEMS = VIDA In both Mali and Kenya, the median age of a rotavirus case in VIDA is 3 months older than the median age of a rotavirus case in GEMS The median age of a rotavirus case in The Gambia is one month younger in VIDA than in GEMS The scheduled older age of complete vaccination may contribute to this

12 One-week incidence of MSD GEMS VIDA 8 The Gambia 8 Mali 8 Kenya Percent m 12-23m 24-59m m m m m m m 12

13 Pathogen-specific MSD incidence by qpcr Rotavirus Cryptosporidium Shigella spp ST-ETEC Adenovirus 40/41 Campylobacter spp Rotavirus Cryptosporidium Attributable incidence per 100 child years (95% CI) Shigella spp ST-ETEC Adenovirus 40/41 Campylobacter spp Kenya Mali Gambia 0-11 months months Rotavirus Cryptosporidium Attributable incidence per 100 child years (95% CI) Shigella spp ST-ETEC months Adenovirus 40/41 Campylobacter spp Attributable incidence per 100 child years (95% CI) VIDA GEMS 13

14 Annual hospitalizations for severe diarrhea in Banjul, The Gambia, RotaTeq introduction Sanneh B et al Vaccine

15 Progression to persistent diarrhea (PD, lasting >14 days) Diarrhea Normal

16 Changes in progression to persistent diarrhea (PD) between GEMS and VIDA % of MSD cases progressing to persistent diarrhea Age Group GEMS VIDA p-value* The Gambia 7% 11% <0.01 Mali 12% 5% <0.01 Kenya 22% 15% <0.01 *Comparing GEMS vs VIDA PD has become less common in Mali and Kenya since GEMS PD has become more common in The Gambia, possibly due to increased role for Cryptosporidium among infants

17 Growth faltering at follow-up Site Age GEMS Follow-up Case HAZ Control HAZ The Gambia 0-11 m The Gambia m -0.29* -0.14* The Gambia m -0.07* -0.03* Mali 0-11 m -0.28* -0.24* Mali m Mali m Kenya 0-11 m -0.35* -0.21* Kenya m -0.30* -0.10* Kenya m -0.13* * VIDA Follow-up Case HAZ Control HAZ -0.37* -0.30* -0.17* -0.11* -0.08* -0.02* * 0.02* * -0.05* -0.07* 0.03* Adjusted for age, baseline HAZ, and duration of follow-up. *Case status was associated with a significantly lower ΔHAZ, adjusted for baseline HAZ and follow-up time. 17

18 Mortality between enrollment and follow-up GEMS VIDA (2 Years) Cases Controls OR* (95% CI) Cases Controls OR* (95% CI) The Gambia 3.8% (39/1029) 0.6% (7/1569) 7.5 (3-7.5) 1.0% (13/1296) 0% (0/1446) 33.4 ( ) Mali 1.1% (23/2033) 0.2% (5/2064) 4.3 ( ) 0.4% (5/1174) 0% (1/1319) 3.7 ( ) Kenya 3.5% (52/1476) 0.5% (11/1883) 5.3 ( ) 1.5% (15/1036) 0% (1/1390) 12.2 ( ) Total 2.5% (114/4538) 0.4% (23/5493) 5.9 ( ) 0.9% (33/3506) 0% (2/4155) 15.6 ( ) 18 *By conditional logistic regression with Firth s penalized likelihood approach as applicable

19 Summary and Conclusions The landscape of diarrheal incidence and etiologies is changing The incidence of MSD is decreasing The impact of rotavirus vaccine is mostly seen in infants Reduced proportion of visits for rotavirus diarrhea Reduced attributable fraction for rotavirus-associated MSD Reduced incidence of overall and rotavirus-associated MSD Changes in the age of infection In The Gambia, unexplained low impact of vaccine and increases in incidence of diarrhea and MSD - might be improved by vaccinating at younger age. As rotavirus recedes in importance, relative contribution of other pathogens is increasing, e.g., Cryptosporidium, Campylobacter, and Shigella Although baseline rates of mortality and stunting have improved, MSD continues to result in significant growth faltering and increased mortality during the 60 days after an episode. 19

20 Site PIs: Jahangir Hossain (The Gambia) Richard Omore (Kenya) Samba Sow (Mali) Acknowledgments Site investigators, clinical and lab teams, field workers, especially: SMA Zaman, Martin Antonio, Sarwar Golam (The Gambia) Alex Ben Ochieng, Alan Audi, Alex Awuor (Kenya) Doh Sanogo, Boubou Tamboura, Uma Onwuchekwa (Mali) Emmes: Catherine Johnson, Nora Watson PATH: Niranjan Bhat, Joyce Ericson, Devin Groman CVD VIDA Core Team: Clinical/epi/stats: Anna Roose, Dilruba Nasrin, Helen Powell, Diana Lam, Kathy Neuzil, Bill Blackwelder, Yuanyuan Liang Lab: Sharon Tennant, Irene Kasumba Collaborators: UVa: James Platts-Mills, Eric Houpt; U Chile: Roberto Vidal; CDC: Jennifer Verani, Marc-Alain Widdowson, Umesh Parashar, Jackie Tate ISAC Janet Wittes, George Armah, John Clemens, Jim Nataro, Ali Mokdad, Halvor Sommerfelt, & Stéphane Helleringer Bill & Melinda Gates Foundation Anita Zaidi, Carl Kirkwood, Duncan Steele 20

21 Thanks to the families who participated 21 QUESTIONS?

22 Socioeconomic factors VIDA vs. GEMS n Gambia Mali Kenya GEMS VIDA GEMS VIDA GEMS VIDA % caretakers 1 school % with household assets: Electricity Television Telephone Refrigerator Motor/Scooter Radio Bicycle Mean household size (range) (3-125) (2-335) (3-100) (2-179) (2-32) (1-59) = increase = decrease 22

23 Nutritional sequelae of Shigella Change in ΔHAZ ~2 months after episode of shigellosis With WHO-recommended antibiotics Without WHO-recommended antibiotics Delta HAZ months months 0-11 months months months 23

24 Proportion of MSD cases with rotavirus attending study health centers by year, of GEMS and VIDA The % of MSD cases in which rotavirus was identified has decreased among those 0-11 months at all sites In general, this is also true for those months, although results are mixed year-to-year = months = 0-11 months = months

25 Factors associated with persistent diarrhea: Multiple logistic regression model Predictor Odds ratio Site (Baseline = Mali) The Gambia 2.6 ( ) Kenya 3.8 ( ) Age group (Baseline = m) 0-11 months 1.6 ( ) months 1.7 ( ) Pathogens Cryptosporidium spp. 2.0 ( ) Rotavirus 0.4 ( ) Persistent diarrhea more likely among children who are: - Kenyan or Gambian - <2 years of age - Infected with Cryptosporidium Persistent diarrhea less likely among children who are: - Infected with rotavirus

26 Growth faltering at baseline Site Age GEMS Mean HAZ Case Control The Gambia 0-11 m The Gambia m The Gambia m Mali 0-11 m Mali m Mali m Kenya 0-11 m Kenya m Kenya m VIDA Mean HAZ Case Control *p<0.05 in paired t-test 26

27 Growth faltering at baseline Site Age GEMS Mean HAZ Case Control The Gambia 0-11 m The Gambia m The Gambia m Mali 0-11 m -0.60* -0.38* Mali m Mali m Kenya 0-11 m Kenya m Kenya m VIDA Mean HAZ Case Control -0.69* -0.51* * -0.01* -0.92* -0.76* -0.99* -0.77* -0.60* -0.40* *p<0.05 in paired t-test 27

28 GEMS Mortality: Key Findings Odds of dying during 2-month follow-up period was 8.5 times higher among cases relative to controls (statistically significant at all sites but India) (Kotloff Lancet 2013; 382: ) 28 28