Original Studies

Effects of Shigella-, Campylobacter- and ETEC-associated Diarrhea on Childhood Growth Gwenyth Lee, PhD,* Maribel Paredes Olortegui, BS,*† Pablo Peñataro Yori, MPH,*† Robert E. Black, MD,* Laura Caulfield,* Cesar Banda Chavez,† Eric Hall, PhD,‡ William K. Pan, DrPH,§ Rina Meza, BA,¶ and Margaret Kosek, MD*† Background: Studies examining the etiology-specific effects of diarrheal disease on growth are limited and variable in their analytic methods, making comparisons difficult and priority setting based on these findings challenging. A study by Black et al (Black RE, Brown KH, Becker S. Effects of diarrhea associated with specific enteropathogens on the growth of children in rural Bangladesh. Pediatrics. 1984;33:1004–1009.) examined the association between Shigella and enterotoxigenic Escherichia coli-related disease and weight gain and linear growth in Bangladeshi children aged 0–5 years. We estimated similar associations in a 2002 cohort of 0- to 6-year-old children in the Peruvian Amazon. Methods: Diarrheal surveillence was conducted using household visits 3 times per week. Anthropometry was collected monthly. Mixed-effect models were used to estimate the association between Shigella, ETEC and Campylobacter diarrhea and weight gain in a 2-month period and linear growth over a 9-month period. Diarrheal disease burdens and growth intervals were quantified so as to be as comparable as possible to the original report. Results: Shigella- and ETEC-associated diarrhea were not associated with diminished weight gain, although the association between ETEC diarrhea and weight gain (−4.5 g/percent of days spent with ETEC, P = 0.098) was twice that of other etiologic agents, as well as similar in magnitude to the original report. Shigella-associated diarrhea was associated with decreased linear growth (0.055 cm less growth/percent days, P = 0.008), also similar to the original study. Conclusions: Our findings suggest that associations between enteropathogen-specific diarrheal episodes and growth, particularly Shigella, are comparable across geographic and epidemiological contexts. Key Words: diarrhea, ETEC, Shigella, growth, nutritional status (Pediatr Infect Dis J 2014;33:1004–1009)

Accepted for publication March 12, 2014. From the *Department of International Health, the Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; †Asociaciόn Benéfica Proyectos de Informática, Salud, Medicina, y Agricultura (A.B. PRISMA), Iquitos, Peru; ‡Naval Medical Research Center, Bethesda, MD; §Duke Global Health Institute and Nicholas School of Environment, Duke University, Durham, NC; and ¶Department of Bacteriology, US Naval Medical Research Unit Six, Lima, Peru. This work was supported by the National Institutes of Health (K01-TW05717 to M.K.) and a GEIS grant (funding number 847705 82000 25GB0016). G.L. was supported by a National Institutes of Health International Maternal and Child Health Training Grant (T32HD046405; PI Dr. Joanne Katz) and a Proctor and Gamble Doctoral Dissertation Fellowship, awarded by the Johns Hopkins Bloomberg School of Public Health. E.H. is a military service member and R.M. is an employee of the US Government. This work was prepared as part of their official duties. The views expressed in this article are those of the author and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the U.S. Government. The authors have no other funding or conflicts of interest to disclose. Address for correspondence: Margaret Kosek, MD, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St E5545, Baltimore, MD 21205. E-mail: [email protected]. Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 0891-3668/14/3310-1004 DOI: 10.1097/INF.0000000000000351

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D

iarrhea is a common cause of morbidity as well as mortality among children in the developing world. In addition to causing 750,000 deaths per year.1 In the year 2010, it was estimated that the average child <5 in the developing world experiences 2.9 cases per year.2 The effects of diarrheal disease on childhood malnutrition are well-studied,3 having been found to negatively affect both weight gain4 and linear growth,5 and increase a child’s risk of becoming stunted.6 Because undernutrition in the first years of life is associated with poorer cognitive development,7 decreased adult work capacity8 and earnings9 and poorer maternal health outcomes,9 undernutrition is considered to be an important surrogate of human potential loss. It is widely felt that, in impoverished settings, “damage suffered in early life leads to permanent impairment”.9 In many studies relating diarrheal disease and growth, however, it has not been possible to identify diarrheal episodes by etiology. For this reason, the comparative effects of both diarrhea-associated and asymptomatic infections of common gastrointestinal infections remains an important area of study, with the effects of some pathogens better characterized than others. For instance, it has been observed that Cryptosporidium and E. histolytica, although frequently associated with asymptomatic infection or relatively mild diarrheal disease, nevertheless result in decreased linear growth10–12; however, other pathogens frequently associated with severe diarrhea, such as rotavirus, have thus far not been strongly associated with any negative impact on growth.13,14 Effect sizes in these studies are small and the longitudinal models applied differ, making it difficult to compare the results of studies within and between pathogens in a comparative way. ETEC and Shigella are principal causes of bacterial enteritis in children in the developing world. A 1984 study by Black et al13 examined the effects of diarrheal disease associated with Shigella, rotavirus and enterotoxigenic Escherichia coli (ETEC), 3 etiological agents associated with diarrhea in infants and children in the developing world, on the weight gain and linear growth of Bangladeshi children in the first 5 years of life. This study found that greater time spent with ETEC-associated diarrhea was associated with less weight gain over a 2-month period (3 grams less weight gain per percent of days spent with ETEC diarrhea) and that time spent with Shigella-associated diarrhea was associated with poorer changes in linear growth over the course of a year (0.075 cm less linear growth per percent of days spent with ETEC diarrhea). We recently reported that symptomatic Campylobacter, an invasive enteric organism frequently associated with acute but selflimiting diarrhea,15 was associated with poorer growth among children 0–6 years of age living in a peri-urban Peruvian Amazonian community.16 We have now applied a similar statistical methodology to Shigella- and ETEC-associated diarrhea in the same cohort, with adjustments to make our results as directly comparable as possible to the previous study and determine whether the findings are comparable across epidemiologic contexts.

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MATERIALS AND METHODS

Enteropathogens and Growth

Statistical Methods Poisson regression was used to calculate incidence rates of Shigella-associated, Campylobacter-associated and ETEC-associated diarrhea. Smoothed plots of incidence versus age were created (Fig. 1). Baseline characteristics and the incidence of overall diarrheal disease of children who experienced at least 1 case of Shigella, ETEC or Campylobacter-associated diarrhea during the course of the study were compared with children who did not. The final weight gain and linear growth models are shown in Equations (1) and (2), respectively. The effects of Shigella-, ETEC- and Campylobacter-associated diarrhea on weight gain over 2-month intervals was evaluated using the model shown in Equation 1. Two sets of independent variables were considered. Yij − Yi − 2, j = b j + β0 + β1 Dshig + β 2 Dcampy + β3 DETEC + β 4 D0 + ... (1)   + β Age Term 1+ β Age Term 2 + ε 13

14

ij

In Equation (1), j represents child, i represents age in months, Yij the child’s weight or WAZ at age i. Dshig , Dcampy, and DETEC represent, first, the percentage of days in the interval associated with Shigella-, ETEC-, Campylobacter-associated diarrhea and second, the number of incident episodes of Shigella-, ETEC-,Campylobacterassociated diarrhea in the interval (Table 2 Row 2). Similarly D0 represents, first, the percentage of days in the interval associated with diarrhea not associated with Shigella, Campylobacter or ETEC, and second, the number of incident diarrheal episodes not associated with any of the 3 pathogens.

 

Yij − Yi −9, j = b j + β0 + β1 Dshig + β 2 Dcampy + β3 DETEC + β 4 D0 + ... + β12 Age Term 1+ β13 Age Term 2 + ε ij

 (2)

In Equation (2), the effects of Shigella-, ETEC- and Campylobacter-associated diarrhea on linear gain over 9-month intervals is evaluated. Here,Yij represents the child’s length/height at age i, and Dshig , Dcampy and DETEC represent the percentage of days associated with, and the total number of incident episodes of diarrhea associated with these pathogens over the prior 9 months. We chose a 9-month period over a 12-month period to maximize sample size

.4 0

.2

episodes/year

.6

.8

Data were from a prospective, community-based study of 442 children 0–72 months of age from 2002 to 2006 in a community near to Iquitos, Peru. Details of this cohort, including anthropometry and diarrheal surveillance methodology, have previously been reported.17,18 Children were followed up for varying periods because enrollment was ongoing throughout the study and because children aged out of the study at 72 months of age. Few children were lost to follow up when the family permanently migrated outside the study area or if they no longer wished to participate; however, gaps in data collection do exist for individual children because of temporary family migration. In brief, each child’s length/height and weight were measured monthly, on the day of their birth. Children were weighed on Salter scales (Salter Housewares Ltd, Tonbridge, England). Length (children 0–23 months of age) or height (children 24–72 months of age) was measured using a marked platform with a sliding footboard. Data related to socioeconomic status were collected using 2 community censuses during the study period. Participating families were visited 3 times weekly by a trained field worker to document the number and consistency of stools passed by the child over the previous 24-hour period. Diarrhea was defined by 3 or more liquid or semiliquid stools reported over a 24-hour period, with episodes separated by at least 3 symptom-free days. Stool samples were collected as soon as possible after the case definition for diarrhea was met, and not >2 days after the episode ended. One sample was sought for all episodes; however, children who were culture-negative for Campylobacter and Shigella but continued to have diarrhea were asked to provide a sample every fourth day until the episode ended. Fresh stool samples were placed in a Cary-Blair medium and transported in a cooler from the field site for same-day plating. Standard methods were used to isolate Shigella and Campylobacter as described in previous reports.17 Five lactose-positive colonies were additionally selected for polymerase chain reaction for heatlabile and heat-stable toxins for ETEC as per Stacy-Phipps et al.19 Informed consent was obtained and the study protocol was approved by the institutional review boards of Johns Hopkins Bloomberg School of Public Health (Baltimore, MD), US Navy Medical Research Center (Silver Springs, MD), Asociacion Benefica PRISMA (Lima, Peru) and the Regional Health Authority for the Department of Loreto, Peru.

0

12

24

36

48

60

72

Age (months) Campylobacter-associated Diarrhea ETEC-associated Diarrhea Shigella-associated Diarrhea

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FIGURE 1.  Incidence rate of etiologyspecific diarrhea. www.pidj.com | 1005

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RESULTS

TABLE 1.  Diarrheal Episodes, by Pathogen Number of Episodes Shigella only Campylobacter only ETEC only Shigella + Campylobacter Shigella + ETEC ETEC + Campylobacter Shigella + ETEC + Campylobacter Not associated with Shigella, ETEC or Campylobacter Episodes for which no laboratory was performed Total N

260 256 324 25 24 34 5 2783 262 3973

Diarrheal episodes were considered associated with a pathogen when at least 1 stool sample from the episode was culture positive for that pathogen. A stool sample was considered associated with the episode when it was collected during, or up to 1 day after, the episode.

because of the data collection gaps caused by temporary family migration. These models were constructed similar to those previously reported16 and included a random intercept for each study child and a covariance structure that assumed a second-order moving average correlation structure among the residuals for change-inweight models, and a first-order autoregressive correlation structure among the residuals for change-in-height models. Episodes of enteropathogen-associated diarrhea that were ongoing at or near to (≤2 days) the time of anthropometry were excluded from the weight models, to minimize the possibility that results would be influenced by dehydration caused by acute diarrhea. Coinfections (diarrheal episodes associated with 2 or more of the enteropathogens of interest) were double counted (eg, an episode associated with both Shigella and Campylobacter was counted once for each), and sensitivity analyses indicated that this did not bias our results. Age terms were included as fractional polynomials, which is a method to adjust for curvilinear relationships,20 and seasonal 2 dπ ) and effects were considered by including the terms, sine( t 2 dπ cosine( ) to the model, where d is the day of the year and t is t 365.21 Other variables, such as those related to breast-feeding status, birth weight and socioeconomic status, were considered for appropriateness in the analysis and as possible confounding factors. Age, season, birth weight, logged per-capita income and nutritional status (stunting and weight-for-height categorized as >0, 0 to −1, and <−1) were retained in the final weight models, and all except birth weight were retained in the final linear growth models. All analysis was performed using Stata 11 (Statacorp, College Station, TX).

Of 442 children enrolled, 9 were excluded because of limited anthropometric data, defined as fewer than 3 consecutive months of anthropometry, or because they were >72 months of age. Out of a maximum of 11,311 child months of surveillance, the 433 remaining children yielded 838 total child years of surveillance (88.9%) and 10,985 completed monthly anthropometry visits (93.5%). There were 3973 total episodes observed during the surveillance period. Of these, 3711 (93.4%) had at least 1 stool collected and tested in association with the episode. There were 320 Campylobacter-associated, 314 Shigella-associated and 387 ETEC-associated diarrheal episodes (Table 1). The overall incidence of diarrheal disease in the study cohort was 4.8 episodes per child-year, peaking at 9.6 episodes per year among children 12–17 months of age. The mean diarrheal prevalence, defined as the percentage of days in the overall study period spent with diarrhea, was 4.59% for all diarrhea (3.42% for diarrhea other than that caused by Shigella, Campylobacter or ETEC), 0.37% for Shigella-associated diarrhea, 0.45% for ETEC-associated diarrhea and 0.39% for Campylobacter-associated diarrhea. The absolute incidence rates of Shigella-, Campylobacter- and ETEC-associated diarrhea were highest among children approximately 2 years of age (Fig. 1). As a percentage of total diarrhea episodes, however, Shigella and ETEC were most common in older children, whereas Campylobacter made up a larger proportion of diarrheal episodes in younger children (those 13–36 months of age). The mean duration of these episodes was 3.5 days for all episodes of diarrhea, 3.7 days for episodes associated with Shigella, 3.8 for episodes associated with Campylobacter and 3.6 for episodes associated with ETEC. Children who experienced at least 1 diarrheal event associated with these 3 pathogens during the course of the study had a higher incidence of diarrhea overall, were likely to have entered the study at a younger age and have remained in the study for a greater length of time before dropping out. Children who experienced at least 1 episode of Shigella-associated diarrhea were also more likely have experienced at least 1 episode of Campylobacterassociated diarrhea, at least 1 episode of ETEC-associated diarrhea and a greater than 75th percentile diarrheal burden during the study period. In other words, children with these enteropathogens tended to be those with a high burden of diarrhea not attributed to these enteropathogens as well, and this was mostly because of their young age.

Growth Model Outcomes Neither Shigella- or ETEC-associated diarrhea were significantly associated with poorer weight gain over a 2-month period, whether included in the model as incidence or as prevalence (the

TABLE 2.  Impact of Diarrheal Pathogens on Weight Gain Over a 2-month Period

Dependent Variable Change in wt (grams)

Change in wt (grams)

Independent Variables

Coefficients

P Value

Mean values of Significant variables (Range)

% of days with Campylobacter diarrhea % of days with ETEC diarrhea % of days with Shigella diarrhea % of days with other diarrhea Incidence of Campylobacter diarrhea Incidence of ETEC diarrhea Incidence of Shigella diarrhea Incidence of other diarrhea

−2.9 (7.9 to 2.2) −4.5 (−9.8 to 1.0) 1.1 (−4.4 to 6.8) −2.0 (−3.6 to 3.1) −55.3 (−102.1 to −8.4) −25.4 (−69.1 to 18.3) 26.0 (-21.2, 73.1) −31.3 (−46.4 to 16.2)

0.267 0.098 0.689 0.020 0.021 0.255 0.281 <0.001

0.40 (0.00–98.15) 0.46 (0.00–50.00) 0.38 (0.00–78.05) 3.42 (0.00–100.00) 0.05 (0–3) 0.06 (0–2) 0.05 (0–2) 0.48 (0–5)

Adjusting for age, season, birth weight, logged per-capita income and nutritional status (stunting and weight-for-height categorized as >0, 0 to −1 and <−1).

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percentage of days in the interval spent with that diarrhea). Campylobacter-associated diarrheal incidence, as previously reported, was associated with poorer weight gain, as children were estimated to gain 55.3 g less weight per Campylobacter episode; however, no effect on weight gain was found when this was expressed as prevalence (2.9 g/percent, P = 0.267; Table 2). Over 9-month periods, Shigella diarrhea was associated with 0.081 cm less linear growth per diarrheal episode (P = 0.008) or 0.055 cm less linear growth per percent of days spent with Shigella diarrhea (P = 0.002; Table 3). Both ETEC- and Campylobacter-associated episodes of diarrhea were also associated with diminished linear growth when expressed as incidence (number of episodes occurring in the interval) but not as prevalence (percent of days spent with pathogen-associated diarrhea).

CONCLUSIONS In 1984, Black et al13 found that ETEC-associated diarrhea was associated with poorer weight gain over 2-month periods, with an estimated effect of 3 g less weight gain per percent of days with ETEC diarrhea, and Shigella-associated diarrhea was associated with 0.075 cm less gain in length per percent of days with Shigella over a year long period. Surprisingly, there is consistency in our findings with those reported by Black et al.13 Shigella-associated diarrhea was the pathogen most strongly associated with reduced linear growth: we estimated −0.055 cm less linear growth per percent of days with Shigella over a 9-month period (95% confidence interval: −0.089 to −0.020; Table 3). Although we did not find a significant impact of ETEC-associated diarrhea on weight gain (4.5 g less weight gain over 2 months, P = 0.098; Table 2), the magnitude of this coefficient was similar to that previously reported by Black et al. Associations between diarrheal disease and poorer growth have been presented across cohorts and in a variety of epidemiologic contexts. Particularly when discussing pathogen-specific effects, however, the ability to draw conclusions has been hindered by variability in the manner of presentation of results. The retesting of hypotheses across study cohorts with the aim of presenting results in a comparable manner is not only an academic exercise, but also may prove important for priority setting for research and policy. Our models are not the same as those used by Black et al. We did, however, choose the same 2-month interval of analysis to compare associations between enteropathogens and weight gain. A slightly shorter (9 months rather than 1 year) interval was used to test the effects for linear growth, as a longer interval resulted in a diminished quantity of data available for analysis. We also used the same exposure variables (percent of days in the interval with Shigella-associated or ETEC-associated diarrhea) chosen by Black et al.

Enteropathogens and Growth

Our cohort was of similar age (0–6 years) to that of the Black et al’s study (0–5 years). The overall incidence of diarrheal disease peaked at 9.6 episodes/yr in children 12–17 months of age. This was similar to the Bangladeshi cohort, in which the overall incidence peaked at approximately 7 episodes/child-year in children 2–11 months of age.22 In the Bangladeshi cohort, the incidence of E. coli-associated diarrhea was about 2 per child-year, and incidence of Shigella-associated diarrhea was <1 episode per childyear.22 Our rates of enteropathogen-specific diarrhea were slightly lower (<1 per year). The most significant contrast between the 2 cohorts was in the prevalence of diarrheal episodes, rather than in their incidence. The mean duration of episodes in our Peruvian cohort was 3.5 days, and only 2.4% of episodes became persistent (≥14 days duration). The original Bangladeshi cohort had a reported median duration of 4–5 days for overall diarrhea, and 8.0% lasted 20 days or more.22 This trend was even more pronounced for shigellosis, which had a median duration of 7 days, with 16% of Shigella episodes lasting 20 days or more.22 As a result of this difference, and in spite of a slightly less stringent diarrheal definition (≥3 liquid or semiliquid stools vs. ≥4 liquid stools/d), the mean percent of days with Shigella-associated and ETEC-associated diarrhea in our cohort was much lower than what was reported by Black (0.4% vs. 2.8% of days with Shigella, 0.5% vs. 3.8% of days with ETEC, and 3.4% vs. 12.8% of days with other-cause diarrheas; 4.6% of days with overall diarrhea). As undernutrition is more strongly associated with diarrheal duration than with incidence,23,24 it is also relevant that our study population appears to have had less acute malnutrition than the previous cohort.25 Further, only 11.6% of children in our cohort were reported to weigh <2.5 kg at birth, whereas studies in South Asia frequently report a high incidence of low birth weight and intrauterine growth retardation.26 For instance, Roy27 found that between 30 and 40% of newborns in Bangladesh weighed <2.5 kg at birth. As a result, despite our replication of the association between specific enteropathogens and growth, the cumulative impact of enteropathogen-specific diarrheal disease and growth might be expected to vary between the 2 cohorts. If calculated based on disease prevalence, the Bangladeshi cohort spent many more days with diarrhea than did the Peruvian cohort, and therefore, the expected cumulative impact of these infections on growth would be greater in the earlier cohort. At least 1 study has found that the longitudinal prevalence of diarrhea is more predictive of weight gain than is diarrheal incidence.28 In our own data, however, comparisons of model fit suggested that diarrheal incidence explained more of the variability in weight gain and linear growth than did prevalence. However, for the sake of comparability, we present both prevalence and incidence models here.

TABLE 3.  Impact of Diarrheal Pathogens on Linear Growth Over a 9-Month Period Dependent Variable Change in ht (cm)

Change in ht (cm)

Independent Variables

Coefficients

P Value

Mean Values of Significant Variables (Range)

% of days with Campylobacter diarrhea % of days with ETEC diarrhea % of days with Shigella diarrhea % of days with other diarrheas Incidence of Campylobacter diarrhea Incidence of ETEC diarrhea Incidence of Shigella diarrhea Incidence of other diarrheas

−0.029 (−0.058 to 0.001) −0.029 (−0.060 to 0.002) −0.055 (−0.089 to −0.020) −0.013 (−0.023 to −0.002) −0.067 (−0.127 to −0.007) −0.057 (−0.112 to −0.002) −0.081 (−0.141 to −0.021) −0.041 (−0.060 to −0.021)

0.052 0.065 0.002 0.015 0.029 0.041 0.008 <0.001

0.39 (0.00–28.19) 0.45 (0.00–27.37) 0.39 (0.00–25.76) 3.22 0.00–72.00) 0.25 (0–6) 0.32 (0–5) 0.26 (0–3) 2.17 (0–15)

Adjusting for age, season, logged per-capita income and nutritional status (stunting and weight-for-height categorized as >0, 0 to −1 and <−1).

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There are other relevant differences between the 2 cohorts. The etiologies of diarrhea in the “other-cause” diarrhea category are likely to have been distinct. Rotavirus was a common enteropathogen considered alongside Shigella and E. coli in the Bangladeshi study. In our cohort, most samples were not tested for rotavirus, although national estimates from the same period suggest that it is likely to have been common.29 Other bacterial causes of diarrhea including Aeromonas, Salmonella and Vibrio cholerae were tested for but found to be rare and can also be excluded as frequent enteropathogens in the Peruvian cohort. In a subset of stools, norovirus was found in 21.3% of diarrheal stool samples and 3% of non-diarrheal stools30 making this also a likely significant cause of diarrhea in this setting. According to study protocol, for cases in which the child was still symptomatic when bacteriological culture confirmed a positive enteropathogen result, appropriate antibiotic therapy was administered. The exception to this was where dysentery was reported, in which case an antibiotic was given as soon as the specimen was received (before the result of cultures), in which case the therapy was guided by known patterns of antibiotic resistance of Shigella isolates in the community. As a result, the likelihood of treatment across the 3 pathogens was not similar. Nearly 40% [39.8% (125)] of Shigella-associated diarrheal episodes were treated with effective antibiotics, as opposed to only 18.9% of Campylobacter and 5.2% of ETEC-associated episodes. For this reason, it should be considered that the effects of Shigella may also be less severe in this population than in circumstances in which a smaller percentage of diarrheal episodes are correctly and promptly treated. The serogroups of Shigella present were similar to what was reported in the Bangladeshi cohort, as 67.1% of Shigella isolates were flexneri, 11.8% sonnei, 11.4% boydii and 2.4% dysenteriae31; in the Bangladeshi community, 67% were flexneri and the other 3 serogroups “were each responsible from 9 to 12%” of Shigella episodes.22 Risk factors for Shigellaassociated diarrhea in Peru have been previously reported and include less maternal education, the lack of a piped water supply and lower weight-for-age.17 Our findings reinforce the relative importance of Shigella-associated diarrhea as a cause of growth faltering. Clinical dysentery syndrome is associated with damage to the intestinal structure and function and greater endogenous protein loss than non-dysentery diarrheas,32 and Shigella is the most common cause of endemic dysentery in this and in most epidemiological contexts. Poor linear growth in early childhood is associated with cognitive deficits, lower adult work capacity and poor maternal outcomes and is therefore a marker for human potential lost.8,33,34 The consistent and diferential long-term effects attributable to select enteropathogens provide support for prioritization of accelerated vaccines, diagnostics and treatments targeted at those pathogens causing the greatest degree of long-term morbidity, as well as those causing acute mortality.

ACKNOWLEDGMENTS The authors would like to thank Matilda Bustos Aricara, Victora Lopez Manuyama, Marla Judith Aricari Huanari and Lleny Amasifuen Llerena for their hard work and thoughtful contributions in the field, as well as all the study families for their generosity with their time and support of the project. REFERENCES 1. Liu L, Johnson HL, Cousens S, et al. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet 2012; 379:2151–61.

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2. Fischer-Walker CL, Perin J, Aryee MJ, Boschi-pinto C, Black RE. Diarrhea incidence in low- and middle-income countries in 1990 and 2010: a systematic review. BMC Public Health 2012; 12:220. 3. Rice AL, Sacco L, Hyder A, et al. Malnutrition as an underlying cause of childhood deaths associated with infectious diseases in developing countries. Bull World Health Organ. 2000;78:1207–1221. 4. Becker S, Black RE, Brown KH. Relative effects of diarrhea, fever, and dietary energy intake on weight gain in rural Bangladeshi children. Am J Clin Nutr. 1991;53:1499–1503. 5. Checkley W, Epstein LD, Gilman RH, et al. Effects of acute diarrhea on linear growth in Peruvian children. Am J Epidemiol. 2003;157:166–175. 6. Checkley W, Buckley G, Gilman RH, et al.; Childhood Malnutrition and Infection Network. Multi-country analysis of the effects of diarrhoea on childhood stunting. Int J Epidemiol. 2008;37:816–830. 7. Walker SP, Grantham-Mcgregor SM, Powell CA, et al. Effects of growth restriction in early childhood on growth, IQ, and cognition at age 11 to 12 years and the benefits of nutritional supplementation and psychosocial stimulation. J Pediatr. 2000;137:36–41. 8. Haas JD, Murdoch S, Rivera J, et al. Early nutrition and later physical work capacity. Nutr Rev. 1996;54(2 pt 2):S41–S48. 9. Victora CG, Adair L, Fall C, et al.; Maternal and Child Undernutrition Study Group. Maternal and child undernutrition: consequences for adult health and human capital. Lancet. 2008;371:340–357. 10. Checkley W, Gilman RH, Epstein LD, et al. Asymptomatic and symptomatic cryptosporidiosis: their acute effect on weight gain in Peruvian children. Am J Epidemiol. 1997;145:156–163. 11. Checkley W, Epstein LD, Gilman RH, et al. Effects of Cryptosporidium parvum infection in Peruvian children: growth faltering and subsequent catchup growth. Am J Epidemiol. 1998;148:497–506. 12. Mondal D, Petri WA Jr, Sack RB, et al. Entamoeba histolytica-associated diarrheal illness is negatively associated with the growth of preschool children: evidence from a prospective study. Trans R Soc Trop Med Hyg. 2006;100:1032–1038. 13. Black RE, Brown KH, Becker S. Effects of diarrhea associated with specific enteropathogens on the growth of children in rural Bangladesh. Pediatrics. 1984;73:799–805. 14. Feller AJ, Zaman K, Lewis KD, et al. Malnutrition levels among vaccinated and unvaccinated children between 2 and 3 years of age following enrollment in a randomized clinical trial with the pentavalent rotavirus vaccine (PRV) in Bangladesh. Vaccine. 2012;30(suppl 1):A101–A105. 15. Janssen R, Krogfelt KA, Cawthraw SA, et al. Host-pathogen interactions in Campylobacter infections: the host perspective. Clin Microbiol Rev. 2008;21:505–518. 16. Lee G, Pan W, Peñataro Yori P, et al. Symptomatic and asymptomatic Campylobacter infections associated with reduced growth in Peruvian children. PLoS Negl Trop Dis. 2013;7:e2036. 17. Kosek M, Yori PP, Pan WK, et al. Epidemiology of highly endemic multiply antibiotic-resistant shigellosis in children in the Peruvian Amazon. Pediatrics. 2008;122:e541–e549. 18. Lee G, Yori P, Olortegui MP, et al. Comparative effects of vivax malaria, fever and diarrhoea on child growth. Int J Epidemiol. 2012;41:531–539. 19. Stacy-Phipps S, Mecca JJ, Weiss JB. Multiplex PCR assay and simple preparation method for stool specimens detect enterotoxigenic Escherichia coli DNA during course of infection. J Clin Microbiol. 1995;33:1054–1059. 20. Royston P, Ambler G, Sauerbrei W. The use of fractional polynomi als to model continuous risk variables in epidemiology. Int J Epidemiol. 1999;28:964–974. 21. Stolwijk AM, Straatman H, Zielhuis GA. Studying seasonality by using sine and cosine functions in regression analysis. J Epidemiol Community Health. 1999;53:235–238. 22. Black RE, Brown KH, Becker S, et al. Longitudinal studies of infectious diseases and physical growth of children in rural Bangladesh. II. Incidence of diarrhea and association with known pathogens. Am J Epidemiol. 1982;115:315–324. 23. Black RE, Brown KH, Becker S. Malnutrition is a determining factor in diarrheal duration, but not incidence, among young children in a longitudinal study in rural Bangladesh. Am J Clin Nutr. 1984;39:87–94. 24. Guerrant RL, Schorling JB, McAuliffe JF, et al. Diarrhea as a cause and an effect of malnutrition: diarrhea prevents catch-up growth and malnutrition increases diarrhea frequency and duration. Am J Trop Med Hyg. 1992;47(1 pt 2):28–35.

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25. Brown KH, Black RE, Becker S. Seasonal changes in nutritional status and the prevalence of malnutrition in a longitudinal study of young children in rural Bangladesh. Am J Clin Nutr. 1982;36:303–313. 26. Black RE, Allen LH, Bhutta ZA, et al.; Maternal and Child Undernutrition Study Group. Maternal and child undernutrition: global and regional exposures and health consequences. Lancet. 2008;371:243–260. 27. Roy NC. Use of mid-upper arm circumference for evaluation of nutritional status of children and for identification of high-risk groups for malnutrition in rural Bangladesh. J Health Popul Nutr. 2000;18:171–180. 28. Morris SS, Cousens SN, Kirkwood BR, et al. Is prevalence of diarrhea a better predictor of subsequent mortality and weight gain than diarrhea incidence? Am J Epidemiol. 1996;144:582–588. 29. Ehrenkranz P, Lanata CF, Penny ME, et al. Rotavirus diarrhea disease burden in Peru: the need for a rotavirus vaccine and its potential cost savings. Rev Panam Salud Publica. 2001;10:240–248.

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Enteropathogens and Growth

30. Yori PP, Schwab K, Gilman RH, et al. Norovirus highly prevalent cause of endemic acute diarrhea in children in the peruvian Amazon. Pediatr Infect Dis J. 2009;28:844–847. 31. Kosek M, Yori PP, Pan WK, et al. Epidemiology of highly endemic multiply antibiotic-resistant shigellosis in children in the Peruvian Amazon. Pediatrics. 2008;122:e541–e549. 32. Alam DS, Marks GC, Baqui AH, et al. Association between clinical type of diarrhoea and growth of children under 5 years in rural Bangladesh. Int J Epidemiol. 2000;29:916–921. 33. Grantham-McGregor S. A review of studies of the effect of severe malnutrition on mental development. J Nutr 1995; 125:2233. 34. Black RE, Allen LH, Bhutta ZA, et al.; Maternal and Child Undernutrition Study Group. Maternal and child undernutrition: global and regional exposures and health consequences. Lancet. 2008;371:243–260.

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