Are young and older children with diarrhea presenting in the same way?

Sharika Nuzhat; Baharul Alam; S M Tafsir Hasan; Shamsun Nahar Shaima; Mohammod Jobayer Chisti; A S G Faruque; Rina Das; Tahmeed Ahmed

doi:10.1371/journal.pone.0300882

. 2024 May 13;19(5):e0300882. doi: 10.1371/journal.pone.0300882

Are young and older children with diarrhea presenting in the same way?

Sharika Nuzhat ¹, Baharul Alam ¹, S M Tafsir Hasan ², Shamsun Nahar Shaima ², Mohammod Jobayer Chisti ¹, A S G Faruque ², Rina Das ^2,^3,^‡,^*, Tahmeed Ahmed ^2,^4,^5,^6,^‡

Editor: Sanjoy Kumer Dey⁷

PMCID: PMC11090295 PMID: 38739609

Abstract

Background

Diarrhoea is a global health problem. More than a quarter of diarrhoeal deaths occur among children less than five years. Different literatures analyzed presentation and outcomes of less than five diarrhoeal children. The world has made remarkable progress in reducing child mortality. So, older children are growing in number. Our aim was to identify clinical differentials and variations of pathogens among younger (less than five) and older (five to nine years) diarrhoeal children.

Method

Data were extracted from the diarrhoeal disease surveillance system (DDSS) of Dhaka Hospital (urban site) and Matlab Hospital (rural site) of the International Centre for Diarrhoeal Disease Research, Bangladesh for the period of January 2012 to December 2021. Out of 28,781 and 12,499 surveillance patients in Dhaka and Matlab Hospital, 614 (2.13%) and 278 (2.22%) children were five to nine—years of age, respectively. Among under five children, 2456 from Dhaka hospital and 1112 from Matlab hospital were selected randomly for analysis (four times of five to nine years age children, 1:4).

Results

Vomiting, abdominal pain, and dehydrating diarrhoea were significantly higher in older children in comparison to children of less than five years age (p-value <0.05) after adjusting study site, gender, antibiotic use before hospitalization, diarrhoeal duration < 24 hours, intake of oral rehydration fluid at home, parental education, WASH practice and history of cough. Vibrio. cholerae, Salmonella, and Shigella were the common fecal pathogen observed among older children compared to under five after adjusting for age, gender and study site.

Conclusion

Although percentage of admitted diarrhoeal children with five to nine years is less than under five years children but they presented with critical illness with different diarrhoeal pathogens. These observations may help clinicians to formulate better case management strategies for children of five to nine years that may reduce morbidity.

Introduction

Diarrhoea is a global health problem. In 2016, diarrhea was the eighth leading cause of mortality among the total population, responsible for more than 1·6 million deaths [1]. More than a quarter (26·93%) of diarrhoeal deaths occurred among children younger than five years, and about 90% (89·37%) of diarrhoeal deaths occurred in South Asia and sub-Saharan Africa [1]. A systematic review of diarrhoea morbidity and mortality [2], suggested that diarrhoea morbidity rates have remained constant in all ages since the 1980s in both developed and developing countries, also estimated more than 2.8 billion episodes of diarrhoea per year in children aged more than five years, adolescents, and adults [2]. Older children and adolescents are responsible for large burden of communicable disease [3].

Globally, diarrhoea is the second leading cause death among under five children [4]. In Asia, this risk remains high from ages 5–14 and reaches a low and constant plateau throughout adolescence and adulthood. At the same time, it declines less dramatically in Africa among more than five years old children and remains relatively stable throughout the lifespan [2]. In Bangladesh Demographic and Health Survey (BDHS) 2017–18, information was obtained from under five children about their experience of having an episode of diarrhoea in the two weeks before the survey. Overall, 5% of children under age of five years had diarrhoea during last two weeks period [5]. Prevalance remained the same in BDHS 2022 survey. But limited data were found on older children suffering from diarrhoea. Children in the age group of 5–14 years are regarded as school-age. This period lays the foundation for good health and sound mind in children, which persists throughout their lifetime [6]. The first growth spurt, the preadolescent or mid-growth spurt, is seen at around six to eight years of age. This is followed by the adolescent growth spurt between 10–17 years of age. There are many factors present in children’s day-to-day household settings which make them vulnerable to undernutrition.

Infectious disease morbidity was associated with lower weight gains in Bangladeshi children aged 5 to 11 years [7]. Global diarrhoea mortality among individuals older than five years was dominated by Shigella [8] and nearly 70% occurred in children more than five years [8]. Vibrio cholerae (cholera) was the third leading cause of diarrhoea mortality among all ages, responsible for 0.11 million deaths [8]. In Bangladesh, diarrhoea mortality rates decreased among children under five from 15.1 to 6.0 per 1000 live births between 1980 and 2015 [9, 10].

In recent decades, little is known about the burden of diarrhoeal disease in children under five and in older children aged five to nine years. Hence, to address the existing knowledge gap and share research findings with policymakers and clinicians to formulate better case management strategies, we undertook this comparative assessment of the clinical features and etiology of diarrhoea among older children of five to nine years with that among under five years old children.

Materials and methods

Ethical statements

For this study, data were extracted from the electronic database of the hospital-based diarrhoeal disease surveillance system (DDSS) of Dhaka hospital and Matlab hospital of the International Center for Diarrhoeal Disease Research, Bangladesh (icddr,b). The DDSS has the approval from the institutional review board of icddr,b (Research Review Committee and Ethical Review Committee) for data analysis. Ethical Review Committee was also pleased with the voluntary participation, maintenance of rights of the participants, and confidential handling of personal information by the hospital doctors and accepted this consenting procedure. At the time of enrolment into DDSS, verbal consent was obtained from the parents or the attending caregivers of each child, following hospital policy. The verbal consent was recorded by keeping a checkmark in the questionnaire that was again assured by showing the mark to parents or caregivers.

Study population and study site

Diarrhoeal Disease Surveillance System (DDSS) is routine ongoing surveillance in hospitals of icddr,b located in Dhaka and Matlab, Bangladesh. In the Surveillance system of Dhaka Hospital, systematically (from every 50^th patient according to their hospital ID number) collects information including age, sex, socio-demographic characteristics, clinical features, and identifies common bacterial and viral isolates from fecal samples. In Matlab Hospital, patients from the Matlab HDSS (Health and Demographic Surveillance System) area are included in the hospital surveillance system.

For the present study, we used 10 years data limited to 0–9 years of children enrolled in the DDSS from January 2012 to December 2021. In this study period, 28,781 and 12,499 diarrhoeal patients were enrolled in Dhaka and Matlab Hospital surveillance systems, respectively. Of them, 614 and 278 children aged five to nine years from Dhaka and Matlab, separately, were included in the analyses (Fig 1). We considered randomly selected children aged less than 5 years as the comparison group (controls) in a 1:4 ratio to increase the statistical power for analyses using SPSS [11], Dhaka Hospital was considered an urban study site, and Matlab Hospital was a rural study site.

Study design

In this retrospective study, five to nine years of diarrhoeal children were considered as cases and compared with under five diarrhoeal children. The study period was from 2012 to 2021. Fig 1 shows the flow chart for selecting the cases and comparison groups.

614, five to nine years old children and 2456 under-five children were selected from Dhaka hospital. 278, five to nine years children and 1112 under-five children were selected from Matlab hospital.

Stool microbiology

After collection, fresh stool specimens from DDSS-enrolled patients were sent to icddr,b central laboratories for routine screening of the aforementioned enteric pathogens. The details of the laboratory procedures for detecting entero-pathogens in stool samples have been described elsewhere [12–14]. In brief, Vibrio cholera was isolated by growth on tellurite taurocholate gelatin agar (TTGA) media with enrichment in bile peptone broth. Salmonella spp. and Shigella spp. were isolated by growth on MacConkey agar and Salmonella-Shigella (SS) agar with enrichment in selenite broth followed by antisera panel testing (Denka Seiken Co., Ltd.). Campylobacter spp. was isolated by growth on Brucella agar. Aeromonas spp. were isolated by growth on TTGA and gelatin agar followed by phenotypic characterization of long-sugar metabolism. For the detection of ETEC, fresh stool specimens were plated onto MacConkey agar. The plates were incubated at 37˚C for 18 hours. Six lactose fermenting individual colonies morphologically resembling E. coli were isolated and tested for the presence of heat-stable and heat-labile toxins using ganglioside GM1 ELISA and multiplex PCR [15, 16]. Antimicrobial susceptibility was checked for each of the isolated bacteria. The presence of Group, A rotavirus-specific VP6 antigen in stool samples, was detected using the ProSpect Rotavirus kit (Oxoid Ltd, Basingstoke, UK), which utilizes a polyclonal antibody in a solid phase sandwich-type enzyme immunoassay according to the manufacturer’s instructions [17].

Statistical analysis

We summarized the characteristics of children using percentages and mean with standard deviation (SD) as appropriate. Bivariable and multivariable binary logistic regression models were used to assess the association of outcome variables (dehydration status, presented with fever, presence of watery stool, abdominal pain, convulsion, death, and infection with rotavirus, Vibrio. Cholerae, Salmonella, and Shigella) with age groups (five to nine years compared to less than five years). The number of observations in one cell was less than five for the convulsion and death variable, so we could not include these two variables in the final model. Each of the clinical outcome variables was analyzed as a separate model adjusting for potential available covariates, such as study site, age, sex, use of antibiotics prior hospitalization, diarrhoeal duration, use of oral rehydration fluid at home, parent’s education, WASH practice, and history of cough. Isolated pathogens were adjusted for study site, age, and sex. We expressed the strength of association as odds ratio (OR) and adjusted odds ratio (aOR) with a 95% confidence interval (95% CI) with a <0.05 p value. All statistical tests were two-sided. Data analysis were done in Stata v15.1 (Stata Corp, College Station, TX, USA).

Results

In Dhaka hospital, there were 28,781 surveillance patients during the period 2012 to 2021. Out of them 614, five to nine years old children and 2456, under five children were included in analysis. (Fig 1). From 2012 to 2021in Matlab Hospital total surveillance patients were 12,499. Among them, we included 278, five to nine years old children and 1112 under five children for analysis (Fig 1). Yearly admission of the children of both groups in both study sites was comparable though it showed the rise of younger children during the COVID pandemic 2020–2021. In the COVID period, older children presenting with diarrhea were lower in percentage than younger children (Fig 2).

Tables 1 and 2 show the comparison of demographic and clinical characteristics of five to nine years children and less than five years children. Parents of older children were illiterate compared to younger children in both study areas. Five to nine years children of urban and rural sites more commonly presented with short duration of diarrhoea (<24 hours), some/severe dehydration, vomiting, and abdominal pain. On the other hand, these children were less likely to present with a history of fever and cough. No death was observed among the older children in both hospitals.

Table 1. Characteristics of five to nine years and under five diarrhoeal children admitted in urban site (Dhaka hospital), icddr,b from 2012–2021.

		5–9 years (n = 614) (%)	0- <5 years (n = 2456) (%)
Sex	Female	246 (40.07)	944 (38.44)
Sex	Male	368 (59.93)	1512 (61.56)
Paternal education	Literate	446 (72.64)	2143/2455 (87.29)
Paternal education	Illiterate	168 (27.36)	312/2455 (12.71)
Maternal education	Literate	483 (78.66)	2265/2455 (92.26)
Maternal education	Illiterate	131(21.34)	190/2455 (7.74)
Sources of drinking water	Non-tube well	378 (61.56)	1254 (51.08)
Sources of drinking water	Tube well water	236 (38.44)	1201/2455 (48.92)
Water treatment method used	No	343/613 (55.95)	1475 (60.06)
Water treatment method used	Yes	270/613 (44.05)	981 (39.94)
Toilet facility	Non-sanitary latrine	78 (12.70)	303 (12.34)
Toilet facility	Sanitary/semi-sanitary latrine	536 (87.30)	2152/2455 (87.66)
Use of oral rehydration fluid at home	Yes	592 (96.42)	2369/2455 (96.50)
Use of oral rehydration fluid at home	No	22 (3.58)	86/2455 (3.50)
Use of Antibiotic prior to hospitalization	No	232/366 (63.39)	578/1454 (39.75)
Use of Antibiotic prior to hospitalization	Yes	134/366 (36.61)	876/1454 (60.25)
Diarrheal duration < 24 hours	No	259 (42.18)	1689 (68.80)
Diarrheal duration < 24 hours	Yes	355 (57.82)	766/2455 (31.20)
Stool consistency	Non-watery	43 (7.00)	208 (8.47)
Stool consistency	Watery	571 (93.00)	2247/2455 (91.53)
Presence of vomiting	No	104 (16.94)	673 (25.94)
Presence of vomiting	Yes	510 (83.06)	1819 (74.06)
Presence of abdominal Pain	No	220 (35.83)	1317 (53.65)
Presence of abdominal Pain	Yes	394 (64.17)	1138/2455 (46.35)
Dehydration status	No	124 (20.20)	1673/2454 (68.17)
	Some	240 (39.09)	699 (28.48)
	Severe	250 (40.72)	82/2454 (3.34)
Presence of fever	No	397/594 (66.84)	1430 (60.21)
Presence of fever	Yes	197/594 (33.16)	945/2375 (39.79)
Presence of cough	No	500 (81.43)	1426/2455 (58.09)
Presence of cough	Yes	114 (18.57)	1029/2455 (41.91)
Presence of convulsion	No	588 (95.77)	2454/2455 (99.96)
Presence of convulsion	Yes	26(4.23)	1/2455 (0.40)
Outcome	Alive	614 (100.00)	2449/2453 (99.84)
Outcome	Death	0	4/2453 (0.31)

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Table 2. Characteristics of 5–9 years and under five diarrhoeal children admitted in rural site (Matlab hospital), icddr,b from 2012–2021.

characteristics		5–9 years (n = 278) (%)	0-<5 years (n = 1112) (%)
Sex	Female	107 (38.49)	450 (40.47)
Sex	Male	171 (61.51)	662 (59.53)
Paternal education	Literate	236 (84.89)	1022 (91.99)
Paternal education	Illiterate	42 (15.11)	89/1111 (8.01)
Maternal education	Literate	247 (88.85)	1,073 (96.49)
Maternal education	Illiterate	31 (11.15)	39 (3.51)
Sources of drinking water	Non-tube well	4 (1.44)	36 (3.24)
Sources of drinking water	Tube well water	274 (98.56)	1076 (96.76)
Water treatment method used	No	269 (96.76)	1,025 (92.18)
Water treatment method used	Yes	9 (3.24)	87 (7.82)
Toilet facility	Non-sanitary latrine	186 (66.91)	711 (63.94)
Toilet facility	Sanitary/semi-sanitary latrine	92 (33.09)	401 (36.06)
Use of oral rehydration fluid at home	Yes	248 (89.21)	964 (86.69)
Use of oral rehydration fluid at home	No	30 (10.79)	148 (13.31)
Use of Antibiotic prior to hospitalization	No	107/193 (55.44)	347/723 (47.99)
Use of Antibiotic prior to hospitalization	Yes	86/193 (44.56)	376/723 (52.01)
Diarrheal duration < 24 hours	No	151 (54.32)	790 (71.04)
Diarrheal duration < 24 hours	Yes	127 (45.68)	322 (28.96)
Stool consistency	Non-watery	65 (23.38)	211 (18.97)
Stool consistency	Watery	213 (76.62)	901 (81.03)
Presence of vomiting	No	48 (17.27)	278 (25.00)
Presence of vomiting	Yes	230 (82.73)	834 (75.00)
Presence of abdominal Pain	No	60 (21.58)	553 (49.73)
Presence of abdominal Pain	Yes	218 (78.42)	559 (50.27)
Dehydration status	No	203 (73.02)	1064 (95.68)
	Some	68 (24.46)	45 (4.05)
	Severe	7 (2.52)	3 (0.27)
Presence of fever	No	70/240 (29.17)	186/1000 (18.60)
Presence of fever	Yes	170/240 (70.83)	814/1000 (81.40)
Presence of cough	No	234 (84.17)	668 (60.07)
Presence of cough	Yes	44 (15.83)	444 (39.93)
Presence of convulsion	No	99/100 (99.00)	450/453 (99.34)
Presence of convulsion	Yes	1/100 (1.00)	3/453 (0.66)
Outcome	Alive	277 (100.00)	1112 (100.00)
Outcome	Death	0	0

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Table 3 shows that in logistic regression analysis after adjusting for study site, sex, use of antibiotics before hospitalization, diarrhoeal duration, use of fluid at home, parent’s education, source of drinking water, use of water treatment, use of improved latrine, h/o cough, five to nine years old diarrhoeal children were significantly associated with some /severe dehydration, vomiting, and abdominal pain.

Table 3. Association of clinical characteristics with children aged five to nine years in logistic regression.

	Unadjusted OR (95%CI)	P value	Adjusted OR (95%CI)	P value
Some /severe dehydration	5.70 (4.88–6.67)	0.000	6.50 (5.07–8.35)	0.000
Fever	0.72 (0.62–0.84)	0.000	0.73 (0.58–0.92)	0.007
Watery stool	0.97 (0.77–1.21)	0.765	0.86 (0.63–1.16)	0.325
Presence of vomiting	1.68 (1.39–2.03)	0.000	1.55 (1.21–1.99)	0.000
Abdominal Pain	2.41 (2.06–2.81)	0.000	2.60 (2.10–3.21)	0.000

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Each model was adjusted for study site, sex, use of antibiotics before hospitalization, diarrhoeal duration, use of fluid at home, parents education, source of drinking water, use water treatment, use of improved latrine, and history of cough seperately.

Table 4 shows isolated organisms among the study group in both the study sites. All microorganisms were not tested in the rural study site. Isolation of V. Cholerae, Shigella, and Salmonella was significantly higher in the study areas among five to nine years children than under five children. On the other hand, Rotavirus predominance was observed among the young children group. After adjusting the study site, age, and sex, V. Cholerae, Shigella, and Salmonella were significantly associated with five to nine years children than under-five children. At the same time, rotavirus was substantially lower in older children.

Table 4. Isolated fecal organisms in diarrhoeal children admitted in urban site (Dhaka hospital) and rural site (Matlab hospital), icddr,b from 2012–2021 and independent association of organisms with five to nine years group.

Organisms	Dhaka Hospital				Matlab hospital				Overall
Organisms	5–9 years (n = 239)	0-<5 years (n = 1104)	Crude OR (95% CI)	P Value	5–9 years (n = 109)	0-<5 years (n = 469)	Crude OR (95% CI)	P Value	Study site and sex adjusted OR (95% CI)	P value
Rotavirus	45/239 (18.83)	838/1104 (75.91)	0.07 (0.05–0.10)	0.000	13/109 (11.93)	397/469 (84.65)	0.02 (0.01–0.05)	0.000	0.05 (0.04–0.07)	0.000
ETEC	13/236 (5.51)	80/1103 (7.25)	0.75 (0.41–1.36)	0.339	Not done	Not done
V. Cholerae	103/239 (43.10)	39/1104 (3.53)	20.68 (13.73–31.14)	0.000	34/109 (31.19)	14/469 (2.99)	14.73 (7.55–28.75)	0.000	18.93 (13.34–26.86)	0.000
*Shigella*	22/239 (9.21)	25/1104 (2.26)	4.38 (2.42–7.90)	0.000	52/109 (47.71)	50/469 (10.66)	7.64 (94.75–12.31)	0.000	6.14 (4.24–8.89)	0.000
*Campylobacter*	14/239 (5.86)	57/1104 (5.16)	1.14 (0.63–2.09)	0.663	No isolates	No isolates
*Aeromonas*	29/239 (12.13)	56/1104 (5.07)	2.58 (1.61–4.14)	0.000	No isolates	No isolates
*Salmonella*	7/239 (2.93)	8/1104 (0.72)	4.13 (1.48–11.51)	0.003	10/109 (9.17)	8/469 (1.71)	5.82 (2.24–15.12)	0.000	4.97 (2.48–9.97)	0.000

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aOR: adjusted odds ratio, each of the pathogens was adjusted for study site, and sex

Discussion

To our knowledge, this is the first study that investigated the clinical presentation and etiology of diarrhoea among five to nine years old children of Bangladesh and compared it with younger children. Though the percentage of five to nine years diarrhoeal children has been limited in number in the last 10 years in both urban and rural sites, these older children presented with critical illnesses.

The world has made remarkable progress in reducing child mortality. The global U5MR decreased by 59% (90% uncertainty interval [UI] 56–61) from 93·0 (91·7–94·5) deaths per 1000 live births in 1990 to 37·7 (36·1–40·8) in 2019 [18]. If all countries met the SDG target on under five mortality, 11 million under five deaths could be averted between 2020 and 2030 [18]. With more young children now surviving, improving the survival of older children is an increasing area of focus nowadays. Globally, mortality rates among older children declined by 40% during this period [19]. Every region of the world has made progress in reducing more older child mortality rates, with the most significant percentage reductions occurring in Southeast Asia (65%), Africa (60%), and European (40%) LMICs (lower and middle income countries) [19]. In 2016, about 1 million children died, mainly from preventable causes like pneumonia, diarrhoea and malaria [20]. Globally, the top five causes of death among older children were diarrhoeal diseases (10%), lower respiratory infections (10%), road traffic injuries (8%), malaria (7%), and meningitis (6%) in 2016 [19]. Despite absolute reductions in mortality rates, African LMICs had substantially higher older child mortality rates than all other regions due to the continued burden of infectious diseases, including diarrhoeal diseases, lower respiratory infections, and malaria [19]. Southeast Asian LMICs, in contrast, had the fastest progress of any region. This success was mainly achieved by reducing mortality rates from the exact infectious causes that continue to burden the African continent [19].

The focus on the diarrhoeal disease was on under-five children. In our study, we have found that older children are more likely to be associated with dehydrating diarrhoea, vomiting, and abdominal pain in the adjusted model compared to younger children. Several studies have assessed the accuracy of the WHO, CDS, and DHAKA methods of dehydration assessment in different contexts, none have been validated for assessing dehydration in patients over five years with acute diarrhoea [21–24]. Differences in both adult physiology and diarrhoea etiology may compromise the accuracy of clinical diagnostic models initially developed for use in young children [25, 26]. NIRUDAK is the first study to empirically derive clinical diagnostic models for assessing dehydration severity in patients over five years of age [27]. A systematic review reported the estimates of duration and severity outcomes [28]. Due to the lack of studies reporting results for children 5–15 years of age, they could not directly estimate the burden of diarrhoea on this age group [28]. Dehydration in younger children is associated with poor intake, and amount of purging in comparison to low body weight [29], but for older children lack of knowledge regarding ORS intake, negligence probably the factor associated with their presentation. A study conducted on determinants of dehydrating diarrhoea reported that risk of severe dehydration in diarrhoea increases abruptly from zero to ten years of age and Vibrio cholerae is identified as contributing organism for dehydration [12]. But this study did not differentiate other clinical features between young and older children.

Childhood morbidity status, especially diarrhoea, has been reported in other studies to impair the growth of children, specifically in weight gain [30] which in the long run halts the development of the children. A study conducted in a neighboring country found a significant association between being underweight and episodes of diarrhoea in the last year among school-aged children [31]. This follows the findings of Torres et al. [7], who reported that diarrhoea correlates significantly with retarded weight gain among children above preschool age. So, diarrhoeal illness among these older children needs to be appropriately treated, and proper nutrition counseling is also required for post-diarrhoeal days.

Another study conducted for older children, adolescents, and adults revealed that the most frequently isolated pathogens among patients hospitalized for diarrhoea are ETEC and Vibrio cholerae O1/O139 [25]. Rotavirus, which is known to be a leading cause of death among young children, was not found to be as important among older persons providing additional evidence suggesting immunity with increasing age [25]. In outpatient settings, Salmonella spp., Shigella spp., and E. histolytica were the most frequently isolated pathogens in the older age group [25]. In our study, we analyzed our hospitalized diarrhoeal children where rotaviral diarrhoea is less likely associated with more than five years of children. This is similar to other studies suggesting better protection with older age [32]. But Salmonella spp. and Shigella spp. were significantly higher in percentage among older age group compared to younger children.

Irrespective of the scientific pertinence of the abovementioned findings on five to nine years children, our study has some limitations. We included only the diarrhoeal children who visited the hospital. Lack of data related to caregivers’ s knowledge regarding the management of diarrhoeal along with data regarding follow-up of such children was not available. We could not evaluate the effect of the Rota viral vaccine as this is yet to incorporate into the EPI schedule of Bangladesh. Although this study had been conducted in the largest diarrhoeal disease facility in the world and also focused on both urban and rural communities, such data as mentioned above along with nationwide data on the disease severity and fatality among older children would have enhanced the reliability of our observation. In addition to that the areas where the burden of Cholera is insignificant might show different presentation.

Conclusion

Our study suggested that children over five might get benefit from greater attention to controlling diarrhoeal diseases, thereby reducing their morbidity. International initiatives targeting child mortality have focused on children under five years of age [7]. Including older children in the program, management would help to reduce morbidity and mortality in this age group who are neglected. High-quality prospective community- and facility-based studies on the etiology of diarrhoeal illness among children aged five to nine years old are needed, ideally, ones that cover an entire 12-month period to account for diarrhoea seasonality.

Acknowledgments

This research was supported by core donors who provide unrestricted support to icddr,b for its operations and research. Current donors providing unrestricted support include the Governments of Bangladesh and Canada. We gratefully acknowledge our core donors for their support and commitment to icddr,b’s research efforts.

Data Availability

It is the policy of our centre (icddr,b) that the data, which contain identifying patient information, are not to be made available. However, data related to this paper are available upon request. Researchers who meet the criteria for access to confidential data may contact with Armana Ahmed (armana@icddrb.org) at the Research Administration of icddr,b (http://www.icddrb.org/).

Funding Statement

The author(s) received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0300882.r001

Decision Letter 0

Sanjoy Kumer Dey

8 Dec 2023

PONE-D-23-25038Are young and older children with diarrhea presenting in the same way?PLOS ONE

Dear Dr. Das.

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Comments to the Author

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Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

**********

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Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: No

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This is an understudied and important topic given most research on diarrhea has focused on the under-5 group in LMICs. This is a straightforward but well done dataset analysis of older children at two hospitals in bangladesh that helps provide an understanding of the presentation and epidemiology of this older group for those working in the region.

General comments:

- how was the 5-9 age group decided to be the focus of this study as presumably other age groups (particularly adolescents) were part of the datasets? Adolescents are another highly understudied group, and one might consider including these patients in analysis, or discuss whether there may be plans to include in a future study which would be greatly needed

- suggest that the authors revise the discussion for improved clarity and flow, to focus on how this study's results fits in with the prior literature and give recommendations on how the authors would like to see their results applied to improve patient care and public health policies. additionally what are the highest priority areas for research in this older child group that are needed?

- suggest plos one team assist with english grammar due to minor errors throughout - for instance

"5-9 years of children" should be rephrased to "children 5-9 years of age" etc

specific edits:

Line 55-7: please cite the mortality rates from diarrhea in older children globally as well as in bangladesh/asian region if these exist

Study population/study site:

- Please include more details on inclusion/exclusion criteria. Also how was diarrhea defined? Did this include acute/chronic diarrhea? What about other disease in which diarrhea was just one presenting symptom?

- Clarify how random selection for controls was performed, what were inclusion/exclusion criteria for the 0-5 year group?

- Please also give some more details about icddrb and the Dhaka and Matlab hospitals for readers who are unaware. what types of patients are served, differences between matlab/dhaka, cholera seasonality, etc.

- Do patients with the most critical illness get transferred? I note that it is later mentioned there were no deaths in this age group at either hospital - is this due to transfer for more severe cases to other facilities perhaps? Would give some context and data if available, or cite as a limitation if not available.

Statistical analysis

- how were the outcome variable and covariates selected from those available in the datasets? Please provide rationale and citations whenever possible

Line 151: what was suspected reason for demographic change during covid? How would this impact interpretation of your results?

Line 161: a the authors expand on their speculations why these variables (parental illiteracy, shorter duration, more dehydration, etc) were associated with the older child group? shorter duration perhaps to higher presence of cholera/less rotavirus? Or other explanation? Can add this in discussion. also how might these findings be used to improve care by clinicians who treat these patients?

Line 171: h/o should be spelled out

Line 216: spell out abbreviations such as CDS at first use

Discussion section:

- In general this section needs to be more focused and to emphasize the most interesting findings of THIS study. there is relatively little discussion of the actual findings from the current study. additionally there is quite a bit of discussion on general child mortality however this should be reframe to focus on diarrheal mortality and how this study findings fit into the existing literature.

- There is no comment on the findings of those variables associated with older groups - parental literacy, short duration of symptoms, cough, fever, convulsions, etc. these are interesting findings and would like the authors to expand on why these were associated in this patient population. Particularly how to frame the understanding of how parental literacy and diarrheal presentation in older children are associated in Bangladesh context.

Line 221-22 - need more details about this review, what it studied, the main findings. Details are lacking and hard to understand how this current study results fit with this

Reviewer #2: Comments

Major comments:

1) Your manuscript requires major revision of % writing

2) First of all, your outcome (dependent variable) should be “diarrhea” for your Table 1 and Table 2. Therefore, you have to re-construct Table 1 and Table 2 using ‘Diarrhea’ as outcome variable and all the variables listed in both tables as independent variables using bivariable logistic regression to calculate the unadjusted odds ratio. Later on, those variables socring p-value < 0.25 to take them to the final model (Multivariable logistic regression).

3) Your Table 3 is incorrect. You have to construct another Table 3 which mainly focuses on multivariable logistic regression by taking those variables from Table 1 and Table 2 (after incorporating the comments given in the above 2nd major comments) which scored p-values less than or equal to 0.25. Mind you, you have to analyses both unadjusted odds ratio and adjusted odds ratio in Table 3 after including those variables with a score of p-value < 0.25. Therefore, all your Tables (Table 1, Table 2, and Table 3) are incorrect. With these incorrect analyses you cannot, discuss, you cannot conclude and you cannot recommend. Therefore, I will stop reviewing your manuscript now. This is because, all your results, discussions, conclusion and recommendations will definitely be changed after complying with the comments given above. Mind you, this is your major of major revisions. Therefore, I will review your second manuscript after incorporating all what has been commented above.

Minor comments:

1) Avoid unnecessary open space between title and authors name and between authors name and affiliation. Example, line number 2 and 5 have nothing to indicate

2) Your Table 4 may be correct, but I will see it after you incorporated all the major comments given above.

Sections

Page-2

Abstract

Rewrite your abstract using the structured way of abstract writing i.e. divide it into sub-sections Background, Method, Results, and Conclusion

L25: every single digit number should be written in word. Therefore, write <5 in word “less than five” and do the same correction throughout the document

L26: delete “children” and replace it by “diseases”

L26 – L27: the sentence “More young children are now surviving and improving the survival of older children” is meaningless. Re-write it meaningfully!!!

L33: Every time the word “respectively” should be preceded by comma. Therefore, add comma after the word “age”

L38: Don’t start a sentence with abbreviation; rather write in full form as “Vibrio cholerae”

Page-3

Introduction

L75 – L76: The justification “In recent decades, little is known about the burden of diarrheal disease in older children and adolescents” doesn’t go in line with your title. Therefore, modify it as “In recent decades, little is known about the burden of diarrheal disease in children under five and in older children five to nine years”

Page-4

L81: add ‘s’ to statement and make it “Statements”

L86: Don’t start a sentence with abbreviation ‘ERC’. Rather, write the full form ‘Ethical Review Committee’

Page-5

L93: Same comment as above, write the full form of DDSS

L104: the 11th reference should be placed between SPSS and the full stop

L108: Delete ‘0-<5’ and replace it by ‘under five’

Page-6

L110 – L111: Delete all the (%) from the two lines

Page-7

L133: Delete ‘simple’ and replace it by ‘bivariable’

L136: Delete ‘< 0-5 years’ and replace it by ‘less than five years’

L146: Delete colon from ‘Result:’

L147 – L148: the sentence “From 2012 to 2021, in Dhaka Hospital, out of a total of 28,781 surveillance patients, 5 to 9 years of children were 614 (%), randomly selected 2456 (%) children from 14,684 under -5 children (Figure 1).” is non-sense. Please re-write it meaningfully

L149 – L151: still the sentence “During the study period, in Matlab Hospital, out of 12,499 surveillance patients, 5 to 9 years children were 278 (%), and we randomly selected 1112 (%) children from 6,460 under-five children (Fig 1).” is non-sense. Re-write it meaningfully

Page-8

L160: Don’t start a sentence with number. Write it as “Five to nine years”

L164 – L 166: From Table 1 delete ‘Ref’ and replace it by ‘1’. This is because you are taking that option as a reference, so it will have an Odds Ratio of 1. Furthermore, italicize CI and p from p-value. Similarly, do the same correction throughout the manuscript.

In this Table 1 please enclose the CIs of the variables ‘The water treatment method used’ and ‘Toilet facility’. Moreover, where are the ORs with the CI for the variables ‘Presence of convulsion’ and ‘Outcome’?

From Table 2 for the variable ‘Maternal education’ you have to take the option ‘Literate’ as a reference; therefore, delete the OR with its CI and replace it by 1

Comments on References

Reference #3: It is too old data in 2008, it doesn’t describe the current situation. Therefore, remove it and replace it by the most recent one

Reference #4: It is too old data in 2008, it doesn’t describe the current situation. Therefore, remove it and replace it by the most recent one

Reference #9: Lacks page number. Therefore, include the page number after going back to the original article

I will continue evaluating the references in your second draft after addressing the major comments given above!!!

**********

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Reviewer #1: No

Reviewer #2: No

**********

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Attachment

Submitted filename: Reviewer comments.docx

pone.0300882.s001.docx^{(17.3KB, docx)}

PLoS One. 2024 May 13;19(5):e0300882. doi: 10.1371/journal.pone.0300882.r002

Author response to Decision Letter 0

16 Jan 2024

Reviewer's comments to the authors:

Major comments:

Comment:

1) Your manuscript requires major revision of % writing

Response: Thank you for your comment. We have revised the write up.

Comment:

Response: Thank you very much for your suggestion. As our hospital is a diarrheal disease hospital all patients were with diarrhea. There is no scope to consider diarrhea as outcome variable. So, we compared the prevalence of different clinical presentation between two age group of population in two different study sites (Urban-Dhaka hospital and Rural-Matlab hospital) (Table 1 and Table 2). Later we have analyzed each of the clinical features of diarrhea which are our outcome variables (dehydration status, presented with fever, presence of watery stool, abdominal pain). Each outcome variable was analyzed considering with separate models (Table 3) with similar adjusted variables as our target is to find out the differentiating feature for older children for early detection of ill cases.

Response: Thank you for your comments. All of our study children are with diarrhea, so there is no scope to consider diarrhea as outcome variable. In table 1 and table 2, we compared the prevalence of different demographic and clinical presentation between two age group of population in two different study sites (Urban-Dhaka hospital and Rural-Matlab hospital). We have removed OR, CI and p value for table 1 and 2 as all of those are not our outcome variables. In table 3, we have analyzed our outcome variables (dehydration status, presented with fever, presence of watery stool, abdominal pain). Each outcome variable was analyzed considering as separate model (Table 3) with similar adjusted variables as our target is to find out the differentiating feature for older children for early detection of ill cases.

Minor comments:

Comment:

1) Avoid unnecessary open space between title and authors name and between authors name and affiliation. Example, line number 2 and 5 have nothing to indicate

Response: Thank you, we have reduced the spaces in title page.

Comment:

2) Your Table 4 may be correct, but I will see it after you incorporated all the major comments given above.

Response: Thank you for your comment. As our outcome variables for table 4 are organisms, so we have included both crude and adjusted OR for all the organisms in different sites. As all of our children are with diarrhea culture positive organisms were included in table 4.

Sections

Page-2

Abstract

Comment: Rewrite your abstract using the structured way of abstract writing i.e. divide it into sub-sections Background, Method, Results, and Conclusion

Response: Thank you for your suggestion. We organized the abstract as per journal policy. We have added sub-headings as per your suggestion.

Comment: L25: every single digit number should be written in word. Therefore, write <5 in word “less than five” and do the same correction throughout the document

Response: Thank you for your comment. We have revised single digits with texts.

Comment: L26: delete “children” and replace it by “diseases”

Response: We revised this.

Comment: L26 – L27: the sentence “More young children are now surviving and improving the survival of older children” is meaningless. Re-write it meaningfully!!!

Response: Thank you for your comment. We have rewritten the line.

Comment: L33: Every time the word “respectively” should be preceded by comma. Therefore, add comma after the word “age”

Response: Thank you. We have included comma after “age”.

Comment: L38: Don’t start a sentence with abbreviation; rather write in full form as “Vibrio cholerae”

Response: Thank you for your suggestion. We have revised it accordingly.

Page-3

Introduction

Comment: L75 – L76: The justification “In recent decades, little is known about the burden of diarrheal disease in older children and adolescents” doesn’t go in line with your title. Therefore, modify it as “In recent decades, little is known about the burden of diarrheal disease in children under five and in older children five to nine years”

Response: Thank you for your suggestion. We have revised it accordingly

Page-4

Comment: L81: add ‘s’ to statement and make it “Statements”

Response: We have included “s” for “statement”.

Comment: L86: Don’t start a sentence with abbreviation ‘ERC’. Rather, write the full form ‘Ethical Review Committee’

Response: We have incorporated “Ethical Review Committee” in place of ERC.

Page-5

Comment: L93: Same comment as above, write the full form of DDSS

Response: Thank you. We have incorporated elaborated form.

Comment: L104: the 11th reference should be placed between SPSS and the full stop

Response: We have incorporated full stop after reference.

Comment: L108: Delete ‘0-<5’ and replace it by ‘under five’

Response: Thank you for your comment. We have revised it.

Page-6

Comment: L110 – L111: Delete all the (%) from the two lines

Response: Thank you. We have removed these.

Page-7

Comment: L133: Delete ‘simple’ and replace it by ‘bivariable’

Response: we have revised it.

Comment: L136: Delete ‘< 0-5 years’ and replace it by ‘less than five years’

Response: We have revised it as text.

Comment: L146: Delete colon from ‘Result:’

Response: Thank you for your comment, we have removed colon.

Comment: L147 – L148: the sentence “From 2012 to 2021, in Dhaka Hospital, out of a total of 28,781 surveillance patients, 5 to 9 years of children were 614 (%), randomly selected 2456 (%) children from 14,684 under -5 children (Figure 1).” is non-sense. Please re-write it meaningfully

Response: Thank you for your suggestion. We have revised the sentence.

Comment: L149 – L151: still the sentence “During the study period, in Matlab Hospital, out of 12,499 surveillance patients, 5 to 9 years children were 278 (%), and we randomly selected 1112 (%) children from 6,460 under-five children (Fig 1).” is non-sense. Re-write it meaningfully.

Response: Thank you. We have revised the sentence.

Page-8

Comment: L160: Don’t start a sentence with number. Write it as “Five to nine years”

Response: We have revised the number with texts.

Comment: L164 – L 166: From Table 1 delete ‘Ref’ and replace it by ‘1’. This is because you are taking that option as a reference, so it will have an Odds Ratio of 1. Furthermore, italicize CI and p from p-value. Similarly, do the same correction throughout the manuscript.

Response: Thank you for your comment. We have removed OR and CI and p value from both table 1 and 2 as all of these are not our outcome variables, these are derailing readers insight.

Comment: In this Table 1 please enclose the CIs of the variables ‘The water treatment method used’ and ‘Toilet facility’. Moreover, where are the ORs with the CI for the variables ‘Presence of convulsion’ and ‘Outcome’?

Response: Thank you for your comment. We have removed OR and CI and p value from both table 1 and 2 as all of these are not our outcome variables, these are derailing readers insight.

Comment: From Table 2 for the variable ‘Maternal education’ you have to take the option ‘Literate’ as a reference; therefore, delete the OR with its CI and replace it by 1

Response: Thank you for your comment. We have removed OR and CI and p value from both table 1 and 2 as all of these are not our outcome variables, these are derailing readers insight.

Comments on References

Comment: Reference #3: It is too old data in 2008, it doesn’t describe the current situation. Therefore, remove it and replace it by the most recent one

Response: Thank you for your suggestion. We have replaced the reference with the article published in 2023.

Comment: Reference #4: It is too old data in 2008, it doesn’t describe the current situation. Therefore, remove it and replace it by the most recent one

Response: Thank you for your observation. We have replaced the reference with the article published in 2023.

Comment: Reference #9: Lacks page number. Therefore, include the page number after going back to the original article

Response: Thank you for your observation. We have revised the reference.

Comment:

I will continue evaluating the references in your second draft after addressing the major comments given above!!!

Response: Thank you for your kind support.

Comments to the author:

In this instance, it seems there may be acceptable restrictions in place that prevent the public sharing of your minimal data. However, in line with our goal of ensuring long-term data availability to all interested researchers, PLOS’ Data Policy states that authors cannot be the sole named individuals responsible for ensuring data access (http://journals.plos.org/plosone/s/data-availability#loc-acceptable-data-sharing-methods).

Data requests to a non-author institutional point of contact, such as a data access or ethics committee, helps guarantee long term stability and availability of data. Providing interested researchers with a durable point of contact ensures data will be accessible even if an author changes email addresses, institutions, or becomes unavailable to answer requests. Before we proceed with your manuscript, please also provide non-author contact information (phone/email/hyperlink) for a data access committee, ethics committee, or other institutional body to which data requests may be sent. If no institutional body is available to respond to requests for your minimal data, please consider if there any institutional representatives who did not collaborate in the study, and are not listed as authors on the manuscript, who would be able to hold the data and respond to external requests for data access? If so, please provide their contact information (i.e., email address). Please also provide details on how you will ensure persistent or long-term data storage and availability.

Response:

Thank you for your valuable comment. In the methodology section of the manuscript, we added the data availability statement. We also provide non-author contact information from icddr,b Research Administration as “Data Availability: This data set contains some personal information of the study patients (such as name, admission date, month, area of residence). Our IRB has required that the personal information of the participants is not disclosed. Thus, the policy of our centre (icddr,b) is that we should not make the availability of the whole data set in the manuscript, the supplemental files, or a public repository. However, data related to this manuscript are available upon request and researchers who meet the criteria for access to confidential data may contact Armana Ahmed (armana@icddrb.org) to the Research Administration of icddr,b (http://www.icddrb.org/).”

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