BMJ Open. Secondary Subject Heading: Infectious diseases, Paediatrics, Respiratory medicine

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1 Follow up of severe pneumonia children at day-care clinic/hospital after an observational and randomized controlled study in Bangladesh Journal: BMJ Open Manuscript ID: bmjopen Article Type: Research Date Submitted by the Author: 0-Feb-0 Complete List of Authors: Ashraf, Hasan; International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Clinical Sciences Division (CSD); Centre for Nutrition and Food Security (CNFS) Alam, Nur; International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Clinical Sciences Division (CSD); Centre for Nutrition and Food Security (CNFS) Chisti, Md.; International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Clinical Sciences Division (CSD); Centre for Nutrition and Food Security (CNFS) Salam, Mohammed; International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Clinical Sciences Division (CSD); Centre for Nutrition and Food Security (CNFS) Ahmed, Tahmeed; International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Clinical Sciences Division (CSD); Centre for Nutrition and Food Security (CNFS) Gyr, Niklaus; University of Basel, Department of Internal Medicine <b>primary Subject Heading</b>: Paediatrics Secondary Subject Heading: Infectious diseases, Paediatrics, Respiratory medicine Keywords: Respiratory infections < THORACIC MEDICINE, INFECTIOUS DISEASES, PAEDIATRICS

2 Page of BMJ Open children enrolled in uncontrolled day-care pneumonia study [0] 0 children enrolled in RCT pneumonia study [] Therefore, a total of children received day-care management for severe pneumonia Acute phase management at the day-care clinic (n=) discontinued treatment left Dhaka stayed at long distance mother had a sick child at home mother had job insecurity mother had personal reason referred to hospitals 0 had severe pneumonia with hypoxemia had very severe pneumonia with VSD with heart failure had lobar pneumonia with sepsis had difficult and rapid breathing had pneumothorax Major events during the months follow up period at the day-care clinic (n=) were successfully managed and discharged from the daycare clinic and advised for follow-up visits Deaths and referral during follow-up period death during -month follow-up period died of very severe pneumonia with hypoxemia at Dhaka Hospital of icddr,b died of hospital-acquired sepsis at Dhaka Hospital of icddr,b died of unknown causes referred to hospital during -months follow-up period had severe pneumonia with hypoxemia had severe pneumonia had dehydrating diarrhoea had bronchiolitis had VSD with cyanosis had pulmonary TB had severe pallor had vesical calculus had pneumonia with SAM had severe respiratory difficulty 0 children allocated to the day-care management for severe pneumonia Randomized to either day-care, or hospital-care 0 children allocated to the hospitalcare and received hospital-care management for severe pneumonia Acute phase management at the hospital (n=0) discontinued treatment left Dhaka mothers had personal reasons referred to other specialized hospitals had pulmonary tuberculosis had dehydrating diarrhoea had heart failure had heart failure with hospital acquired sepsis Major events during the months follow up period at the hospital (n=) successfully managed and discharged from the hospital and advised for follow-up visits Deaths and referral during follow-up period deaths during -month follow-up period died of tubercular meningitis (TBM) died of dehydrating diarrhea died of unknown cause readmissions to hospital during -months follow-up period had severe pneumonia with hypoxemia had severe pneumonia had bronchiolitis had severe respiratory difficulty had TBM

3 Page of Follow up of severe pneumonia children at day-care clinic/hospital after an observational and randomized controlled study in Bangladesh Hasan Ashraf a, Nur H Alam a, Mohammod J Chisti a, Mohammed A Salam a, Tahmeed Ahmed a and Niklaus Gyr b a Clinical Sciences Division; Centre for nutrition and Food Security, icddr,b (International Centre for Diarrhoeal Disease Research, Bangladesh) b Department of Internal Medicine, University of Basel, Switzerland Short Title: Short-term follow-up of children with pneumonia Key Words: Follow-up Morbidity Mortality Relapse Pneumonia Financial Disclosure: The authors have no financial relationships relevant to disclosure of this article Conflict of interest: None of the authors has any conflict of interest Corresponding Author: Dr. Hasan Ashraf, Scientist, Clinical Sciences Division, icddr,b Shaheed Tajuddin Ahmed Sarani, Mohakhali, Dhaka, Bangladesh Tel: 0--0-/Ext. Fax: ashrafh@icddrb.org Word Count: Abstract Objectives: To determine relapse, morbidity, mortality and referral of childhood pneumonia during follow-up period. Design: An observational followed by a RCT comparing day-care with hospital-care. Setting: Day-care was provided at Radda Clinic and hospital-care at Mirpur Paediatric Hospital. Participants: Children aged - months with severe pneumonia. Interventions: The day-care group received antibiotics, feeding and supportive care from 0:00-:00 daily while hospital-care group received similar antibiotics, food and supportive care for hours daily until resolution and followed-up. Primary and secondary outcome measures: The primary outcome measures were proportion of successes of day-care at follow-up visits as determined by estimating OR with % CI in comparison with hospital-care. The secondary outcome measures were proportion (with % CI) requiring referral to hospitals and proportion (with % CI) with relapse and fatal outcome. Results: Enrolled children with a mean (SD) age of. (.) months, % were infants, and % were male. The follow-up compliance dropped from % at first to % at sixth visit. The common morbidities included cough (%), rapid breathing (%) and diarrhoea (%) with higher rate in day-care children. Four [0.% (% CI, 0.-.%)] day-care and two [.% (% CI, 0.-%)] hospital-care children died. More day-care children [n= [.% (% CI,.-0.%)] required referral to hospital compared to hospital-care children [n=[.% (% CI,.-0.%)]. There were no significant differences in major outcomes in relation to success, death, referral and hypoxaemia. Conclusions: Children following treatment of severe pneumonia experienced considerable morbidities due to cough, rapid breathing and diarrhea. The findings indicate importance of follow-up for early detection of medical problems and their management to reduce risks of death. Establishment of an effective community follow-up would be ideal to address problem of non-compliance with follow-up. Trial registration: The original RCT comparing day-care with hospital-care was registered at (identifier NCT00).

4 Page of BMJ Open Article summary Article Focus As there is little information about what happens after recovery from pneumonia and whether this recovery is sustained in their homes over longer period, the main focus of the studies were to assess the success and feasibility of the Day-care model of treatment of severe childhood pneumonia, especially during the -months follow-up period To compare the Day-care model of treatment of severe childhood pneumonia with the standard hospitalized care during the -months follow-up period To record the events following discharge of children, such as to determine relapse of pneumonia, monitor nutritional changes, and record morbidities and deaths during the -months follow-up period including the compliance to follow up visits Key messages Children following apparently effective treatment of severe pneumonia experienced considerable morbidities due to cough, fever, rapid breathing, chest indrawing, feeding difficulty, and diarrhoea during follow-up period Day-care children experienced significantly more from all of the above morbidities except fever during their follow-up period compared to the hospital-care children Follow-up of children with severe pneumonia is very important for early detection of medical problems for reducing the risk of morbidities and death Strengths of the study Although the follow-up compliance reduced over time, still the compliance rates of severe childhood pneumonia were significantly better than those recovering from SAM. Despite the reduced follow-up compliance rates, it was still impressive (%) even at the end of -months. Moreover, this impressive rate of follow-up was spontaneous and around % children were brought by their parents and the spontaneous follow-ups were not due to any incentive. Minor illnesses (%) developed during follow-up

5 Page of period in pneumonia study is less than that observed in SAM children (%). Similarly, the requirement of medication following recovery from severe pneumonia (%) was less than those recovering from SAM (%). Limitations of the study There were a few important limitations of the study. First, we did not have sufficient data for comparing cost effectiveness of two different approaches of management of childhood pneumonia. Second, we could not assess the sustainability for -months follow-up visits at the respective health facilities where children had received their initial treatment. Third, we did not assess the feasibility of community follow-up. Introduction Pneumonia is one of the leading causes of morbidity and mortality in under-five children causing about. million deaths every year globally []. According to a recent report published in 00, % of the total. million global deaths among under- children in 00 were due to pneumonia []. In terms of magnitude of problem, there is an estimated incidence of million new cases of childhood pneumonia each year globally, including million cases in southeast Asia, and -0 million (-%) are severe enough requiring hospitalization in developing countries [-]. An estimated. million (% CI. to. million) children died from Acute Respiratory Infection (ARI) globally in 000 and 0% of these deaths occurred in Africa and Southeast Asia [, ]. In Bangladesh, Acute Lower Respiratory Infections (ALRI) account for % of under- and 0% of infantile deaths []. World Health Organization (WHO) s guidelines for case management of pneumonia recommend that children with severe pneumonia require facility-based management with parenteral antibiotics [] but inadequate paediatric beds limits hospitalcare in Bangladesh. We, therefore, developed the concept of a Day-care model [-] through establishment of facilities at outpatient clinics for management of common childhood illnesses, such as severe acute malnutrition (SAM) [] and severe pneumonia [0, ] hoping to provide greater public health benefits to Bangladeshi children and thus reducing morbidities and deaths. Objectives

6 Page of BMJ Open As there is little information about what happens after recovery from pneumonia and whether this recovery is sustained in their homes over longer period, the objective of the follow-up studies were to assess the success and feasibility of the Day-care model of treatment of severe childhood pneumonia by comparing the findings with standard hospitalized care, and to record events following discharge of children from both models such as determine relapse of pneumonia, monitor nutritional changes, and record morbidities and deaths during follow-up period as well as compliance to follow up visits, which is not routinely done in Bangladesh. Study design We first assessed the efficacy and feasibility of the Day-care model for the management of severe pneumonia in a prospective, but uncontrolled pilot study [0]. It was followed by a randomized controlled trial (RCT) comparing the day-care based management with hospital management []. Settings The day-care was provided at the Radda Clinic, which is operated by a non-governmental organization (NGO) that has been providing maternal and child health (MCH) services in the Mirpur area of the metropolitan Dhaka City Corporation (DCC) since covering a population of around.0 million. The hospital-care was provided at the Institute of Child Health and Shishu Sasthya Foundation Hospital (ICHSH). This institution has been providing health care to children through outpatient facilities, attended by 0 children each day, and -bed inpatient facilities for pediatric medicine, pediatric surgery and neonatology since. Participants In the above mentioned original reference studies [0, ], we compared the day-care management with hospital management of children of either sex, aged - months, with severe pneumonia according to WHO criteria []. They had been enrolled to receive either day-care management at a clinic or hospitalized management from June 00-November 00. Children with tuberculosis, congenital heart disease and Down s syndrome and also those with associated co-morbidities such as

7 Page of SAM, sepsis, hypoglycemia, and convulsion were excluded. The studies were approved by the Research and Ethical Review Committees (RRC and ERC) of International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b). Interventions The day-care children were treated at the Radda Clinic with antibiotics, food and supportive care from 0:00-:00 hours on each day and then sent home [0, ]. Oxygen was administered via nasal cannulae to all hypoxemic children with oxygen saturation of less than % in room air [0,,, ], as recorded by the pulse oximeter. All children received a once daily intramuscular injection of ceftriaxone in a dose of -00 mg/kg for at least days [0, ], as it has been used successfully for outpatient treatment of the most severe bacterial pneumonia in children and because of its single daily dose which can easily be administered during daily clinic visits []. Infants (- months) and children received a locally produced milk-based diet (milk-suji; kcal/00 ml and. g protein/00 ml) every h between 0:00-:00. Breast feeding was continued and infant formula ( kcal/00 ml and. g protein/00 ml) was given to non-breastfed infants aged - months. Mothers were provided with - feeds of milksuji/infant formula in a hot pot to feed their children in home during night and they were educated and encouraged to continue the care of their children in home. The same management continued on each day until there was clinical improvement, defined as no fever, no fast breathing, no lower chest wall indrawing, no danger signs, no rales on auscultation, and no hypoxemia [], when children were discharged. Children randomized to hospital management received the same antibiotic therapy, food and supportive care for hours every day (compared to hours/day at the clinic) at the ICHSH from the time of admission until discharge. Follow up study: After discharge from the clinic/hospital, parents were advised to visit the respective clinic or hospital for follow-up assessment of their children every weeks for months when they were examined by study physicians. At each follow up visit, the study physician interviewed the attending

8 Page of BMJ Open mothers/caregivers about the signs and symptoms of specific morbidities since the previous visit. Morbidity data like respiratory (e. g. cough, fever, running nose, difficulty in breathing, chest indrawing), diarrheal, or others (e. g. eye, ear, nose, and skin infection, thrush, passage of worms) were recorded on a Case Report Forms (CRFs). We also recorded events such as relapses, morbidities, deaths, unscheduled extra-visits, and referrals to hospitals. Any child developing pneumonia, diarrhea, or other complications requiring hospitalization during follow-up period were referred to the Dhaka Hospital of icddr,b or, to the ICHSH for appropriate management. Other minor illnesses were treated by the study physician. Children who failed to attend the clinic/hospital on scheduled follow-up dates were visited in their homes by a health care worker who encouraged the parents to comply with follow-up visits. Data analysis including primary and secondary outcome measures All data were collected on pre-designed CRFs, edited, entered onto a personal computer, and analysed using statistical software e.g. Statistical Package for Social Sciences (SPSS version 0; SPSS Inc, Chicago, Illinois, USA); EPI Info version.0; and CIA. The primary outcome measures were proportion of successes of day-care management at follow-up visits as determined by estimating Odds Ratios (OR) with their % confidence intervals (% CI) in comparison with hospital-care results. The secondary outcome measures were proportion (with % CI) of children requiring referral to hospitals, and proportions (with % CI) of children developing relapses and having fatal outcome during follow-up. Results In total, children living in the Mirpur, Dhaka, Bangladesh with severe pneumonia had been enrolled into two successive original studies: one uncontrolled [0] study followed by another RCT protocol [] and thus a total of children were assigned to day-care management in both studies [0, ] and another 0 children to the hospital-care management in the RCT only [] (Figure ). The children were followed-up for -months after improvement and discharge from their primary treatment sites. The mean

9 Page of age [standard deviation (SD)] of the children was. (.) months, 0 (%) were infants (- months), (%) were males, and (%) were breast-fed (Table ). Most of the children were well nourished without any wasting, but only with mild degree of under-nutrition (Table ). About half of the children belonged to poor families (%) with a monthly income of about US$ 0, while % of the fathers were day labourer or rickshaw-puller, and % of the mothers were housewives. Compliance to follow up visits gradually reduced with time following discharge: %, %, 0%, %, %, and % for the first, second, third, fourth, fifth, and sixth visits, respectively (Table ). The common symptoms and signs noted during follow-up visits included cough (%), fever (%), rapid breathing (%), and diarrhea (%), while less common symptoms were chest indrawing (%), feeding difficulties (%), and difficulty in breathing (%) (Table ). About % children reported some minor illnesses such as poor appetite, otitis media, conjunctivitis, oral moniliasis (thrush), scabies, and other skin infections, and thus % children also required medication during follow-up period (Table ). The sustainability of -months follow up in the study group after discharge from the day-care clinic is similar ( %) to that of control group after discharge from the hospital (Table ). A significantly higher number of day-care children reported cough, rapid breathing, chest indrawing, feeding difficulty, and diarrheal illnesses compared to hospital-care children (Table ). Failure to both day-care and hospital management were associated with the following conditions: (i) positive history of chest wall indrawing at home; (ii) presence of tachycardia, defined as pulse rate of more than 0 beats per minute and hypoxaemia with an oxygen saturation of less than % as recorded by the pulse oximetry [, ], both on admission; and (iii) prolongation of duration of clinic/hospital stay of more than 0 days (Table ). There were no deaths during acute phase care of children in day-care and hospital-care; however, four [0.% (% CI, 0.% to.%)] children in day-care group and two [.% (% CI, 0.% to %)] children in hospital-care group died during -month follow-up period (Table ) and another child [0.% (% CI, 0.% to.%)] in hospital-care group died after follow-up period. Amongst day-care children, one each child died of severe pneumonia with hypoxemia and hospital-acquired sepsis, both at the Dhaka

10 Page 0 of BMJ Open Hospital of icddr,b, but the cause could not be ascertained in remaining two children. Amongst hospitalcare children, one died during the follow-up period due to tubercular meningitis (TBM) about two weeks after discharge; another died of dehydrating diarrhoea in his village home, about six weeks after discharge; the only child died after -months follow-up period, about one year after discharge in village home, and the cause of death could not be ascertained. During follow-up period, a higher number of day-care children (n=) required referral to specialized hospital compared to hospital-care children (n=) (OR., p=0.0), although not significant (Table ). Of all day-care children, [.% (% CI,.% to 0.%)] required referral to hospital during - months follow-up period (Table ): for severe pneumonia with hypoxemia, for severe pneumonia without hypoxemia, for bronchiolitis, for VSD with cyanosis, one each for pulmonary TB, severe pallor, vesical calculus, pneumonia with SAM, and severe pneumonia with severe respiratory difficulty, and the remaining were referred to Dhaka Hospital of icddr,b for dehydrating diarrhea (Figure ). Of all hospital-care children, [.% (% CI,.% to 0.%)] required re-admission to the ICHSH/referred to DSH during -months follow-up period (Table ): for severe pneumonia with hypoxemia, for severe pneumonia without hypoxemia, for bronchiolitis, for severe pneumonia with severe respiratory difficulty, and the only remaining child was referred to DSH for tubercular meningitis (TBM) (Figure ). Similarly, significantly higher number of children with hypoxemia (n=) required referral/re-admission to a hospital compared to children without hypoxemia (n=) during follow-up period (OR.; p=0.00) (data not shown here) []. There were no significant differences in major outcomes between study and control group of children during -months follow-up period in relation to success, death, referral to hospitals and development of hypoxemia (Table ). Discussion In both of these studies, we noted great importance of follow-up since some cases relapsed or developed morbidities, or needed unscheduled extra-clinic/hospital visits, and a few died during this period. Results

11 Page of of our studies suggest the need for establishment of routine follow-up of children following successful management of severe pneumonia at health care facilities for early detection of medical problems and their appropriate management, and for preventing deaths. Such follow-ups should be ideally done at health facilities where children had received initial treatment but a community follow-up system may be possible, if trained and motivated community health workers and adequate resources are available [, ]. In our studies, follow-up compliance reduced over time, but the compliance rates of these children recovering from severe pneumonia were significantly better than those recovering from SAM (OR.; p<0.0) []. Despite the reduced follow-up compliance rates, it was still impressive (%) even at the end of -months (Table ) a finding of considerable importance. Moreover, this impressive rate of follow-up was spontaneous around % children were brought by their parents and the remaining few came after health workers made home visits encouraging them to come. The spontaneous follow-ups were not due to any incentive, except that the study supported the conveyance costs to very poor families (%) with a monthly income of about US$ 0 only. The findings that more day-care children suffered from cough, rapid breathing, chest indrawing, feeding difficulty, and diarrhea during follow-up period might be explained by presence of relatively more severe illness amongst day-care group, such as more children with hypoxaemia with lower oxygen saturation compared to hospital-care group (Table ). Minor illnesses (%) developed during follow-up period in pneumonia study is less than that observed in SAM children (%) [], having poor nutritional status with depressed immunity. Similarly, the requirement of medication following recovery from severe pneumonia (%) was less than those recovering from SAM (%) [], as more medications are needed by SAM children because of their relatively more minor illnesses. Children with a positive history of lower chest wall indrawing and those presenting with tachycardia and hypoxaemia on admission should be carefully monitored and aggressively treated, as they are unlikely to improve with routine therapy leading to prolongation of their clinic/hospital stay. There were a few important limitations of our studies. First, we did not have sufficient data for comparing cost effectiveness of two different approaches of management of childhood pneumonia. Second, we could

12 Page of BMJ Open not assess sustainability for -months follow-up visits at respective health facilities where children had received their initial treatment. Third, we did not assess the feasibility of community follow-up. However, we have planned to provide detailed cost effective analysis after completion of one ongoing study. Conclusions: Children following apparently effective treatment of severe pneumonia experienced considerable morbidities due to cough, fever, rapid breathing, chest indrawing, feeding difficulty, and diarrhea following discharge and day-care children experienced significantly more from all of the above morbidities except fever during their follow-up period compared to hospital-care children. The findings indicate the importance of follow-up of children with severe pneumonia irrespective of their primary site of management (day-care clinic or hospital) for early detection and efficient management of medical problems reducing the risk of death. Establishment of an effective community follow-up of non-compliant children, whenever possible, would be ideal to address the problem of non-compliance with follow-up. Trial registration The original RCT comparing the day-care management with hospital management [] has been registered at (identifier NCT00). Funding statement This work was supported by the Eagle Foundation (Geneva, Switzerland) (Grant GR-00). Authors contributions HA, NHA, NG conceived the idea; HA, NHA, MAS contributed to the study data interpretation; HA, MAS, NG wrote the paper. HA, NHA, MJC, MAS, TA, NG critically analyzed and approved the final manuscript. Figure legend Figure Trial profile of children with severe pneumonia 0

13 Page of Table Comparison of baseline characteristics of study children Characteristics Total (n=) Day-care (n=) Hospitalcare (n=0) P value Male; n (%) () () 0 () 0. Age in month; mean (SD). (.). (.). (.) 0. Infants (- months); n (%) 0 () () () months; n (%) 0 () () () 0.0 Breast-fed; n (%) () () () 0. Weight, mean ± SD, kg. (.0). (.). (.) 0. Height, mean ± SD, cm. (.). (.).0 (.) 0. Weight-for-age Z score (WAZ); mean (SD) Weight-for-height Z score (WHZ); mean (SD) Presence of hypoxemia (oxygen saturation of <%); n (%) Oxygen saturation (%) on admission; mean (SD) Oxygen saturation (%) after oxygen therapy; mean (SD) Values are number (%), or mean (SD) -. (.) -. (.) -. (.) (.) -0. (.0) -0. (.) 0.0 () (0) () 0.0. (.0).0 (.).0 (.) (.). (.). (.) 0.

14 Page of BMJ Open Table Compliance rates, morbidities, and medications during each of the follow-up visits of study children (n=) Follow-up compliance st followup visit nd followup visit rd followup visit () Cough () () (0) Fever () () Rapid breathing Chest indrawing Feeding difficulty Difficult breathing 0 (0) () 0 () th followup visit () () () th followup visit th followup visit () 0 () () () 0 () 00 () () () (0) () () () () () () () () 0 () () () () () () 0 () () () () () () () 0 () () () () Diarrhea () () () () () () 0 () Minor illnesses Medicine taken Values are number (%) () 0 () Total 0 () 00 () 0 () () () 0 () () () 0 () () () () 00 () () ()

15 Page of Table Comparison of compliance rates, morbidities and medications during three-month follow up period Morbidity Day-care visits (n=) Hospital-care visits (00) follow- visits Total up () OR p-value Compliance to () () all six follow-up visits Cough () () Fever () () Rapid breathing 0 (0) (0). <0.0 Chest indrawing (0) (0). <0.0 Feeding () () 0. <0.0 difficulty Difficult 0 () (). 0. breathing Diarrhea () () 0 0. <0.0 Minor illnesses () 0 () Medicine taken 0 () 0 () 0. <0.0 Values are number (%)

16 Page of BMJ Open Table Comparison of study in relation to their success and failure Characteristic Success(n=) Failure (n=) Total(n=) p-value Male, n (%) () () () 0. Age months, mean ± SD. (.0). (.). (.) 0.0 Infants (- months), n (%) () () 0 () 0. Children (- months), n 0 () () 0 () 0. (%) Breast-fed, n (%) () () () 0. History of Cough, n (%) () () 0 () 0. History of Fever, n (%) 0 (0) () (0) 0. History of difficulty () () () 0. breathing, n (%) History of chest wall 0 () () () indrawing, n (%) Weight, mean ± SD, kg.0 (.). (.). (.) 0.0 Height, mean ± SD, cm. (.0). (.) () 0.0 Weight-for-age z score, -.(.) -.(.0) -.(.) 0.0 mean ± SD Weight-for-height z score -0.(.) -0.0(0.) -0.(.) 0.0 mean ± SD Temp. of > 0 C, n (%) () () (0) 0. Pulse rate, mean ± SD, beats () () () 0. per min Pulse rate of >0 beats per () () 0 () 0.00 min, n (%) Respiratory rate, mean ± SD, () () () 0. breaths per min Respiratory rate 0 breaths (00) (00) (00) NA per min Rales/crepitation on () () 0 () 0. auscultation, n (%)

17 Page of Hepatomegaly (liver () 0 () () 0.0 palpable for > cm), n (%) Dur. of stay (day-care/. (.). (.0) (.) 0. hospital), days, mean ± SD Dur. of stay > 0 days, n (%) 0 () () () 0.0 Duration of antibiotic (Ceftriaxone) therapy, days, mean ± SD Hypoxemia at admission (oxygen sat. <%), n (%) Oxygen saturation at admission, mean ± SD (.). (.) (.) 0. Values are number (%), or mean (SD) 0 () () () 0.0. (.) () () 0. Table Outcome for study children during follow up period Characteristic Day-care (n=) Successful follow-up visits [.% (% CI.% to %)] Death* [0.% (% CI 0.% to.%)] Referred/re-admission hospital Development hypoxemia Values are number (%) NB: to of [.% (% CI.% to 0.%)] [.% (% CI.% to.%)] Hospital-care (n= 0) [0.% (% CI.% to %)] ** [.% (% CI 0.% to.%)] [.% (% CI.% to 0.%)] [.% (% CI 0.% to.%)] *no infants died during the day-care/hospital-care study period **only one child died after three months follow up period Total (n=) 0 [.% (% CI.% to 0.%)] ** [.% (% CI 0.% to.%)] [.% (% CI.% to.%)] [.% (% CI.% to.%)] OR p Value

18 Page of BMJ Open References. Black RE, Cousens S, Johnson HL, et al. Global, regional, and national causes of child mortality in 00: a systematic analysis. Lancet 00;:-.. Rudan I, Tomaskovic L, Boschi-Pinto C, et al. WHO Child Health Epidemiology Reference Group. Global estimate of the incidence of clinical pneumonia among children under five years of age. Bull World Health Organ 00;:-0.. Rudan R, Boschi-Pinto C, Biloglav Z, et al. Epidemiology and etiology of childhood pneumonia. Bull World Health Organ 00;:0-.. Ashraf H, Chisti MJ, Alam NH. Treatment of childhood pneumonia in developing countries. In: Health Management, eds. Krzysztof Smigorski ISBN SCIYO 00:-.. Mulholland K. Magnitude of the problem of childhood pneumonia. Lancet ;:0-.. Williams BG, Gouws E, Boschi-Pinto C, et al. Estimates of world-wide distribution of child deaths from acute respiratory infections. Lancet Infect Dis 00;:-.. Baqui AH, Black RE, Arifeen SE, et al. Causes of childhood deaths in Bangladesh: results of a nationwide verbal autopsy study. Bull World Health Organ ;:-.. World Health Organization. Acute respiratory infections in children: case management in small hospitals in developing countries. A manual for doctors and other senior health workers. WHO/ARI/0.. Geneva: WHO, 0.. Ashraf H, Ahmed T, Hossain MI, et al. Day-care management of children with severe malnutrition in an urban health clinic in Dhaka, Bangladesh. J Trop Pediatr 00;:-. 0. Ashraf H, Jahan SA, Alam NH, et al. Day-care management of severe and very severe pneumonia, without associated co-morbidities such as severe malnutrition, in an urban health clinic in Dhaka, Bangladesh. Arch Dis Child 00;:0-.. Ashraf H, Mahmud R, Alam NH, et al. Randomized controlled trial of day care versus hospital care of severe pneumonia in Bangladesh. Pediatr 00 Oct;():e0-.. Ashraf H, Alam NH, Salam MA, et al. A follow-up experience of months after treatment of children with severe acute malnutrition in Dhaka, Bangladesh. J Trop Pediatr 0;October (epub ahead of print).. Jurban A. Pulse oximetry. Crit Care ;:R-R.

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20 Follow up of severe pneumonia children at day-care clinic/hospital after a randomized controlled trial in Dhaka, Bangladesh Journal: BMJ Open Manuscript ID: bmjopen r Article Type: Research Date Submitted by the Author: 0-Apr-0 Complete List of Authors: Ashraf, Hasan; International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Clinical Sciences Division (CSD); Centre for Nutrition and Food Security (CNFS) Alam, Nur; International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Clinical Sciences Division (CSD); Centre for Nutrition and Food Security (CNFS) Chisti, Md.; International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Clinical Sciences Division (CSD); Centre for Nutrition and Food Security (CNFS) Salam, Mohammed; International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Clinical Sciences Division (CSD); Centre for Nutrition and Food Security (CNFS) Ahmed, Tahmeed; International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Clinical Sciences Division (CSD); Centre for Nutrition and Food Security (CNFS) Gyr, Niklaus; University of Basel, Department of Internal Medicine <b>primary Subject Heading</b>: Paediatrics Secondary Subject Heading: Infectious diseases, Paediatrics, Respiratory medicine Keywords: Respiratory infections < THORACIC MEDICINE, INFECTIOUS DISEASES, PAEDIATRICS

21 Page of BMJ Open Follow up of severe pneumonia children at day-care clinic/hospital after a randomized controlled trial in Dhaka, Bangladesh Hasan Ashraf a, Nur H Alam a, Mohammod J Chisti a, Mohammed A Salam a, Tahmeed Ahmed a and Niklaus Gyr b a Clinical Sciences Division; Centre for Nutrition and Food Security, icddr,b (International Centre for Diarrhoeal Disease Research, Bangladesh) b Department of Internal Medicine, University of Basel, Switzerland Short Title: Short-term follow-up of children with pneumonia Key Words: Follow-up Morbidity Mortality Relapse Pneumonia Financial Disclosure: The authors have no financial relationships relevant to disclosure of this article Conflict of interest: None of the authors has any conflict of interest Corresponding Author: Dr. Hasan Ashraf, Scientist, Clinical Sciences Division, icddr,b Shaheed Tajuddin Ahmed Sarani, Mohakhali, Dhaka, Bangladesh Tel: 0--0-/Ext. Fax: ashrafh@icddrb.org Word Count: Abstract Objectives: To compare the relapse, morbidity, mortality, and re-hospitalization rates between a daycare group and a hospital group for children with severe pneumonia. Design: An observational study following two cohorts of children with severe pneumonia for months after discharge from hospital/clinic. Setting: Day-care was provided at the Radda Clinic and hospital-care at a hospital in Dhaka, Bangladesh. Participants: Children aged - months with severe pneumonia attending the clinic/hospital who survived to discharge. Interventions: Children received antibiotics, feeding and supportive cares from 0:00-:00 daily in day-care group or similar treatment in hospitalized group were followed up for -months. Primary and secondary outcome measures: The primary outcome measures were the proportion of successes and failures of day-care at follow-up visits as determined by estimating the OR with % CI in comparison to hospital-care. The secondary outcome measures were the proportion requiring re-hospitalization, relapse and fatal outcome. Results: We enrolled 0 children with a mean (SD) age of () months, % were infants, and % were males. The follow-up compliance dropped from % at first to % at sixth visit. The common morbidities during the follow-up period included cough (%), fever (%), diarrhoea (%) and rapid breathing (%). During the follow-up period, significantly more day-care children [n= [. (.-.)] required re-hospitalization after completion of initial day-care, compared to initial hospital-care group [n=[. (.-0.)]. Failure of both day-care and hospital management was associated with tachycardia, tachypnoea and hypoxaemia on admission. Conclusions: There are considerable morbidities in children discharged following treatment of severe pneumonia like cough, fever, rapid breathing and diarrhea during -months period. The findings indicate the importance of follow-up for early detection of medical problems and their management to reduce the risk of death. Establishment of an effective community follow-up would be ideal to address the problem of non-compliance with follow-up. Trial registration: The original RCT comparing day-care with hospital-care was registered at (identifier NCT00).

22 Page of Article summary Article Focus The main focus of the article is to describe the features of relapse, morbidity, mortality and rehospitalization following successful discharge for severe pneumonia in <-year-old children in urban Dhaka, Bangladesh To compare the compliance, relapse, morbidity, mortality and re-hospitalization rates between an outpatient managed day-care group and a hospital-managed group over months To identify risk factors for poor outcome Key messages Children following apparently effective treatment of severe pneumonia experienced considerable morbidity due to cough, fever, rapid breathing, and diarrhoea during the follow-up period The risk factors for poor outcome include the presence of tachycardia, tachypnoea, and hypoxaemia on admission and prolonged duration of stay Follow-up of children with severe pneumonia is very important for early detection of medical problems for reducing the risk of morbidity and death Strengths of the study Although the follow-up compliance reduced over time, it was still impressive (%) even at the end of - months. Moreover, this impressive rate of follow-up was spontaneous, around % of the children were brought by their parents and no incentives were given. The identification of risk factors for poor outcomes including the presence of tachycardia, tachypnoea, and hypoxaemia on admission, and prolonged duration of stay are very important strengths of the study. The number of minor illnesses developed during the follow-up period was low (only %) and the requirement for medication following recovery was also low (%). Limitations of the study

23 Page of BMJ Open There were some important limitations in this study. First, we could not assess the sustainability of - month follow-up visits at the respective health care facilities where children had received their initial treatment. Second, we did not assess the feasibility of community follow-up, which can be done in future studies. Introduction Pneumonia is one of the leading causes of morbidity and mortality in under-five children causing about. million deaths every year globally []. According to a recent report published in 00, % of the total. million global deaths among under- children in 00 were due to pneumonia []. There is an estimated incidence of million new cases of childhood pneumonia each year globally, including million cases in southeast Asia, and -0 million (-%) are severe enough to require hospitalization in developing countries [-]. An estimated. million children died from Acute Respiratory Infection (ARI) globally in 000 and 0% of these deaths occurred in Africa and Southeast Asia [, ]. In Bangladesh, Acute Lower Respiratory Infection (ALRI) accounts for % of <-year-old child deaths and 0% of infantile deaths []. World Health Organization (WHO) s guidelines for case management of pneumonia recommend that children with severe pneumonia require facility-based management with parenteral antibiotics [] but an inadequate number of paediatric beds limits hospital-care in Bangladesh. We, therefore, developed the concept of a Day-care model [-] through establishment of facilities at outpatient clinics for management of common childhood illnesses, such as severe acute malnutrition (SAM) [] and severe pneumonia [0, ] hoping to provide greater curative or case management benefits to Bangladeshi children and thus reducing morbidity and deaths. Objectives As there is little information about what happens after recovery from pneumonia and whether this recovery is sustained in their homes over a longer period, the objectives of the study were: ) to describe the features of relapse, morbidity, mortality and re-hospitalization following successful discharge after severe pneumonia in <-year-old children in urban Dhaka, Bangladesh; ) to compare the compliance,

24 Page of relapse, morbidity, mortality and re-hospitalization rates between an outpatient managed day-care group and a hospital-managed group over months; and ) to explore the predictors of failures for -months of follow-up. Study design An observational study following two cohorts of children with severe pneumonia who were discharged either from the outpatient day-care clinic or from the hospital after recovery from their primary illness during the long-term post management follow-up of children enrolled in another RCT (). Settings The day-care was provided at the Radda Clinic, which is operated by a non-governmental organization (NGO) that has been providing maternal and child health (MCH) services in the Mirpur area of the metropolitan Dhaka City Corporation (DCC), Dhaka, Bangladesh since covering a population of around.0 million. The hospital-care was provided at the Institute of Child Health and Shishu Sasthya Foundation Hospital (ICHSH), Mirpur, Dhaka, Bangladesh. This institution provides health care to children at its outpatient facility, attended by 0 children each day, and -bed inpatient facility for pediatric medicine, pediatric surgery and neonatology since. Participants In the above mentioned original reference study [], we compared the outpatient day-care management with inpatient hospitalized management of children of either sex, aged - months, with severe pneumonia according to WHO criteria []. From September 00 through November 00 they were randomized to receive either outpatient day-care management at a clinic or inpatient hospitalized management. Children with tuberculosis, congenital heart disease and Down s syndrome and also those with associated co-morbidities such as SAM, sepsis, hypoglycemia, and convulsion were excluded. The study was approved by the Research and Ethical Review Committees (RRC and ERC) of the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b). A written informed consent was obtained from the parents of each child before enrollment into the study.

25 Page of BMJ Open Interventions The day-care children were treated at the outpatient clinic (Radda Clinic) with antibiotics, food and supportive care from 0:00-:00 hours on each day and then sent home [0, ]. Oxygen was administered to all hypoxemic children with oxygen saturation of less than % in room air [0,,, ], and they received injection ceftriaxone for days [0,, ]. Infants (- months) and children received a locally produced milk-based diet, breast feeding was continued, and infant formula was given to non-breastfed infants aged - months. The same management continued on each day until there was clinical improvement followed by discharge []. Children randomized to hospital management received the same antibiotic therapy, food and supportive care for hours every day (compared to hours/day at the clinic) at the hospital (ICHSH) from the time of admission until discharge. Follow up study: After discharge from the clinic/hospital, parents were advised to visit the respective clinic or hospital for follow-up assessment by study physicians of their children every weeks for months. At each follow up visit, the study physician interviewed the attending mothers/caregivers about the signs and symptoms of specific morbidities since the previous visit. Morbidity data like respiratory (e. g. cough, fever, running nose, difficulty in breathing, chest indrawing, rales on auscultation), diarrheal, or others (e. g. eye, ear, nose, and skin infection, thrush, passage of worms) were recorded on a Case Report Form (CRF). The vital signs (pulse, respiration, temperature, body weight, length/height, and oxygen saturation) were recorded at each follow-up visit. The Z-scores for weight-for-age (ZWA) and weight-forheight (ZWH) were calculated during each follow up visit to assess changes in nutritional status. We also recorded events such as relapses, deaths, unscheduled extra-visits, and re-hospitalizations. Any child developing pneumonia, diarrhea, or other complications requiring re-hospitalization during the follow-up period was referred to the Dhaka Hospital of icddr,b/ichsh for appropriate management. Other minor illnesses were treated by the study physician. Children who failed to attend the clinic/hospital on

26 Page of scheduled follow-up dates were visited in their homes by a health care worker who encouraged the parents to comply with follow-up visits. Data analysis including primary and secondary outcome measures All data were collected on pre-designed CRFs, edited, entered onto a personal computer, and analysed using statistical software e.g. Statistical Package for Social Sciences (SPSS version.; SPSS Inc, Chicago, Illinois, USA); EPI Info version.0; and CIA. The primary outcome measures were expressed as the proportion of successes and failures of day-care management at follow-up visits as determined by estimating Odds Ratios (ORs) with their % confidence intervals (% CIs) in comparison with hospital-care results. The secondary outcome measures were expressed as the proportion (with % CIs) of children requiring re-hospitalizations, and proportion (with % CIs) of children who relapsed or died during follow-up. The study groups were compared at the time of discharge from the clinic/hospital and during the follow-up period. The continuous variables were compared between the groups using Student s t-test and non-parametric tests. Dichotomous variables were compared using the x -test or Fisher s exact test, as appropriate. A probability of <0.0 was considered statistically significant. Results In total, 0 children living in the Mirpur, Dhaka, Bangladesh with severe pneumonia were enrolled into the original RCT study [] and were equally (0 in each) assigned randomly to the outpatient day-care or inpatient hospital care (Figure ). The children were then followed-up for -months after discharge from their primary treatment sites. The health status of the study children at the time of discharge from the clinic/hospital is shown in Table. The mean age [standard deviation (SD)] of the children was () months, (%) were infants (- months), 0 (%) were males, and 0 (%) were breast-fed with significantly more infants receiving the hospital-care (Table ). Most of the children were well nourished without any wasting, but only with a mild degree of under-nutrition (Table ). About half of

27 Page of BMJ Open the children belonged to poor families (%) with a monthly income of about US$ 0, while % of the fathers were day labourers or rickshaw-pullers, and % of the mothers were housewives. Compliance with follow up visits after discharge from the clinic/hospital gradually reduced over time following discharge: %, %, %, %, %, and % for the first, second, third, fourth, fifth, and sixth visits, respectively (Table ). The common symptoms and signs noted during follow-up visits included cough (%), fever (%), diarrhea (%), and rapid breathing (%), while less common symptoms were chest indrawing (%), feeding difficulties (%), and difficulty in breathing (%) (Table ). About % of the children reported minor illnesses such as poor appetite, otitis media, conjunctivitis, oral moniliasis (thrush), scabies, and other skin infections, but % of the children required medication during follow-up period (Table ). The sustainability of -months follow up in the study group after discharge from the day-care clinic is similar ( 0%) to that of control group after discharge from the hospital (Table ). A significantly higher number of hospital-care children reported cough, diarrhea, and feeding difficulty compared to day-care children and needed more medication during the follow-up period (Table ). However, a significantly higher number of day-care children reported respiratory problems such as rapid breathing and chest indrawing compared to hospital-care children (Table ). Failure of both day-care and hospital management were associated with the following: (i) the presence of tachycardia defined as pulse rate of more than 0 beats per minute; tachypnoea defined as respiratory rate of more than 0 breaths per minute; and hypoxaemia with an oxygen saturation of less than % as recorded by pulse oximetry [, ], all on admission; and (ii) prolonged duration of clinic/hospital stay for more than 0 days (Table ). During the follow-up period, a significantly higher number of day-care children (n=) required rehospitalization compared to hospital-care children (n=) (OR., p=0.0) (Table ), as more day-care children had severe hypoxaemia compared to the hospital-care group (n= vs. ) (OR., p=0.0) (Table ). Similarly, a significantly higher number of children with hypoxemia (n=) required rehospitalization compared to children without hypoxemia (n=) during follow-up period (OR.;