Experience with Clinically Diagnosed Down Syndrome Children Admitted with Diarrhea in an Urban Hospital in Bangladesh

There is lack of information in the medical literature on clinically diagnosed Down syndrome children presenting with diarrhea. Our aim was to describe our experience with Down syndrome patients admitted with diarrhea by evaluating the factors associated with Down syndrome presenting with diarrheal illness. In this retrospective chart analysis, we enrolled all the diarrheal children aged 0–59 months admitted to the Dhaka Hospital of the International Centre for Diarrheal Disease Research, Bangladesh (icddr, b), from March 2011 to February 2013. Down syndrome children with diarrhea constituted cases and randomly selected threefold diarrheal children without Down syndrome constituted controls. Among 8422 enrolled children 32 and 96 were the cases and the controls, respectively. Median age (months) of the cases and the controls was comparable (7.6 (4.0, 15.0) versus 9.0 (5.0, 16.8); p = 0.496). The cases more often presented with severe acute malnutrition, developmental delay, congenital heart disease, hypothyroidism, sepsis, hypocalcemia, developed hospital acquired infection (HAI) during hospitalization, and required prolonged stay at hospital compared to the controls (for all p < 0.05). Thus, diarrheal children with clinically diagnosed Down syndrome should be investigated for these simple clinical parameters for their prompt management that may prevent HAI and prolonged hospital stay.


Introduction
Down syndrome is popularly known as trisomy 21, because it is a genetic disorder caused by a presence of all or part of a third copy of chromosome 21, Patterson [1]. Globally, as of 2010, Down syndrome occurs in about 1 per 1000 live births [2] and results in about 17,000 deaths [3]. Most of the hospitals in Bangladesh do not have any facilities to confirm the diagnosis of Down syndrome using genetic sequencing. Thus, we often rely on clinical diagnosis of Down syndrome. Children with Down syndrome are more likely to have multiple health problems than the general population. Some of these problems are associated with failure to thrive leading to life threatening serious illness [3]. There is an increased incidence of gastrointestinal problems among people with Down syndrome [3]. It is therefore important to be aware of conditions involved and of their presenting symptoms and management. Although diarrhea may be a common comorbidity in Down syndrome children under 5 years, little is known about such population. Like other hospitals of Bangladesh and in other developing countries, the caseload of clinically diagnosed Down syndrome children having diarrhea is not uncommon at the Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr, b), the only international organization that works on diarrhea disease research. However, there is no published data on the factors associated with clinically diagnosed Down syndrome children having diarrhea. Identification of factors associated with clinically diagnosed Down syndrome and diarrhea in such population may help to reduce morbidity and deaths in resource poor settings. Thus, the aim of our study was to describe our experience with Down syndrome 2 International Scholarly Research Notices patients admitted with diarrhea by identifying the factors associated with clinically diagnosed Down syndrome in diarrheal children.

Ethics Statement.
In this chart review, data were analyzed anonymously; thus, no parental or ethical consent was required.

Study
Design. This was a retrospective chart review that was conducted at the Dhaka Hospital of icddr, b using electronic database of the hospital (SHEBA). We used an unmatched case control design and enrolled 8422 diarrheal children of both sexes, aged 0-59 months, who were admitted to the Intensive Care Unit (ICU), High Dependency Unit (HDU), or Longer Stay Ward (LSW) of the hospital from March 2011 to February 2013. Children with clinically diagnosed Down syndrome presenting with diarrhea constituted the cases and randomly selected diarrheal children without Down syndrome constituted controls. Controls were randomly selected by computer randomization using SPSS (version 17.0; SPSS Inc., Chicago) from a computerized data source of icddr, b. We used 1 : 3 unmatched case control ratio to increase the statistical power of our analyses. We defined Down syndrome clinically if a child had at least seven of the following clinical features: mental impairment, stunted growth, low muscle tone, depressed nasal bridge, slanted eyes, large protruding tongue, abnormal outer ears, wide gap between first and second toes, shortened head and neck, Simian crease, and high arch palate [4]. Diarrhea was defined if a child had three or more abnormally loose or watery stools per 24 hours, and status of dehydration was defined by "Dhaka Methods" of assessment of dehydration that is almost similar to WHO method and approved by WHO [5].

Study Site.
The description of the study site (Dhaka Hospital of icddr, b) has been described in our previously published article [6].

Patient Management.
Management of the diarrheal children with Down syndrome was done symptomatically; that is, management of pneumonia, sepsis, severe cholera, dysentery, severe malnutrition, and other bacterial infections was done following the hospital's guidelines [7]. The babies with Down syndrome were referred to Shishu Bikash Kendro of Dhaka Shishu Hospital or Bangabandhu Sheikh Mujib Medical University Hospital for further management and developmental rehabilitation.

Measurements.
Case report forms (CRF) were developed and finalized for data acquisition. Characteristics analyzed included sociodemographic (age, gender, height and weight, type of residence, source of drinking water, and formula feeding), clinical signs (dehydration and temperature), clinical diagnosis (sepsis, pneumonia, chronic lung disease, pulmonary TB, severe acute malnutrition, congenital heart diseases (CHD), motor developmental delay within 0-59 months (neck control, sitting, standing with or without support, and walking) [8], hypothyroidism, hospital acquired infection (HAI) [9,10]), and outcome during discharge. Sepsis was defined as presence or presumed presence of infection with hypothermia (≤35.0 ∘ C) or hyperthermia (≥38.5 ∘ C), tachycardia, tachypnea, and abnormal WBC count (>11 × 10 9 /L or <4 × 10 9 /L or band and neutrophil ratio ≥0.10) [11,12]. Additionally, there may have been altered organ function such as altered mental status and bounding pulse in absence of clinical dehydration or after correction of dehydration. Pneumonia was initially diagnosed clinically following the World Health Organization recommended classification of pneumonia [13] and was confirmed with radiologic evidence of consolidation or patchy opacities [14]. Chronic lung disease was defined if there was moist cough for more than 4 weeks with recurrent chest infections, exertional dyspnea, and growth failure with or without the presence of clubbing, chest wall deformity, adventitious sounds on chest auscultation, and/or hyperinflation [15]. Severe acute malnutrition was defined as severe wasting ( score for weight for height/length, < −3 of the median of the WHO anthropometry), severe underweight ( score for weight for age, < −3 of the median of the WHO anthropometry), or nutritional edema. Pulmonary tuberculosis was diagnosed with supportive evidence such as positive tuberculin skin test or a positive contact history with a sputum positive tuberculosis patient plus if there was no improvement of signs of pneumonia or status of severe malnutrition following standard treatment plus even without microbiological confirmation of tuberculosis follow-up improvement with antitubercular therapy [6]. CHD was clinically diagnosed with auscultatory murmur heard by using stethoscope over cardiac area of the chest and was confirmed by echocardiography. Common CHD were atrioventricular septal defect or ventricular septal defect, mitral valve problems, tetralogy of Fallot, and patent ductus arteriosus [16]. Hypothyroidism was initially diagnosed clinically with any five of the following: history of feeding difficulties, failure to thrive, history of prolonged jaundice after birth, history of constipation, floppiness, large fontanelles, macroglossia, and cold mottled skin in the extremities and the diagnosis was confirmed by measuring TSH or thyroxine level in blood [17][18][19]. The identification of blood isolates and the susceptibility testing were done with the routine methods at the microbiological laboratory. Blood culture and serum electrolyte were processed in the Dhaka Hospital, icddr, b [20].
2.6. Analysis. All data were entered into SPSS for Windows (version 17.0; SPSS Inc., Chicago) and Epi-Info (version 6.0, USD, Stone Mountain, GA). Differences in proportions were compared by the Chi-square test. In normally distributed data differences of means were compared by Student'stest and Mann-Whitney test was used for comparison of data that were not normally distributed. A probability of less than 0.05 was considered statistically significant. Strength of  association was determined by calculating odds ratio (OR) and their 95% confidence intervals (CIs).

Results
There were 32 cases and 96 controls. The cases more often presented with developmental delay, congenital heart disease, hypothyroidism, severe acute malnutrition (SAM), sepsis, and lower serum calcium level compared to the controls. During hospitalization the cases more often developed HAI and required prolonged stay at hospital compared to the controls. All other variables among the cases and the controls shown in Table 1 were comparable.

Discussion
This study, though weakened by limited sample size, was able to describe our experience with Down syndrome patients admitted with diarrhea by identifying different associated factors for clinically diagnosed Down syndrome in diarrheal patients aged 0-59 months. Our observation of association of severe acute malnutrition, developmental delay, congenital heart disease, sepsis, hypothyroidism, and hypocalcemia on admission and prolonged hospital stay and HAI during hospitalization with Down syndrome in diarrheal patients is not surprising but needs to be reported for the better clinical management of such children. Down syndrome is often associated with failure to thrive [21]. In our study, developmental delay was found to be strongly associated with Down syndrome in diarrheal children and the finding is consistent with previous study conducted in children without diarrhea [21]. Although there is a lack of evidence on the relationship between diarrhea and CHD, in this study, we have found strong association between CHD and Down syndrome in diarrhea patients. In our study we found 53% babies had CHD among Down syndrome and the observation is consistent with previous data which showed that the prevalence of CHD in children with Down syndrome involving nondiarrheal children was 40-50% [22,23]. Thus, developmental delay, failure to thrive, and CHD might have an impact in contributing to SAM.
Our observation of association of sepsis and other infections (such as diarrhea and pneumonia) with Down syndrome in diarrheal children compared to those without Down syndrome is also understandable. This is probably due to the fact that children with Down syndrome in developing countries invariably present with SAM [24], that is, associated with immunosuppression, and often become prone to severe form of infection such as pneumonia, diarrhea, and sepsis [25,26].

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Our observation of the association of hypothyroidism with the diarrheal children having Down syndrome is also understandable. In our study we found 9.3% babies had thyroid dysfunction among Down syndrome whereas the prevalence of thyroid disease with Down syndrome in previous studies involving nondiarrheal children was 4-18% [17-19, 23, 27-29]. Down syndrome was also found to be significantly associated with hypocalcemia. Hypocalcemia used to occur mostly in children suffering from diarrhea and/or SAM [30] as in our study.
Although no published data were found on the association of HAI and prolonged hospitalization with Down syndrome in diarrheal children, the observation is quite understandable. In our study, diarrheal children with Down syndrome were observed to have had association with severe acute malnutrition, developmental delay, sepsis and various infections. Due to management of their multiple ailments, these children required to stay in the hospital for longer period which is strongly associated with HAI [31,32].
The limitation of the study is the lack of genetic sequencing in diagnosing the children with Down syndrome. Another limitation is the small sample that might have an impact of the lesser association of other factors.

Conclusion
Our data of Down syndrome in diarrheal children and the published data in nondiarrheal children suggest that the presentations of Down syndrome are almost similar in diarrheal and nondiarrheal children. Down syndrome in diarrheal children was found to have an association with severe acute malnutrition, congenital heart disease, hypothyroidism, developmental delay, sepsis, and hypocalcemia on admission. These children often required prolonged hospitalization and were prone to develop hospital acquired infection. Thus, clinicians may look for these simple clinical parameters in clinically diagnosed Down syndrome children with diarrhea for their prompt management that may prevent prolonged hospitalization as well as hospital acquired infection.

Disclosure
Mohammod Jobayer Chisti is the senior author.