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1 RSV-Related Healthcare Burden: A Prospective Observational Study in a Resource-Constrained

2 Setting
3
4 Senjuti Saha PhD1#, Sudipta Saha SM1,2, Naito Kanon MSc1, Yogesh Hooda PhD1, Mohammad Shahidul
5 Islam PhD1, Shuborno Islam BSc1, Zabed Bin Ahmed MSc1, Md Jahangir Alam FCPS3, Ataul Mustufa Anik
6 MSc1, Probir K Sarkar FCPS3, Mohammed Rizwanul Ahsan, DCH4, Md. Ruhul Amin FCPS1, Samir K Saha
7 PhD1,5
8
9 1. Child Health Research Foundation, Dhaka, Bangladesh
10 2. Department of Social and Behavioural Sciences, Harvard T. H. Chan School of Public Health, Boston,
11 USA
12 3. Department of Pediatric Respiratory Medicine (Pulmonology), Bangladesh Shishu Hospital and
13 Institute, Dhaka, Bangladesh
14 4. Department of Emergency, Observatory and Referral, Bangladesh Shishu Hospital and Institute,
15 Dhaka, Bangladesh
16 5. Department of Microbiology, Bangladesh Shishu Hospital and Institute, Dhaka, Bangladesh
17
18 Correspondence to
19
20 Senjuti Saha, PhD
21 Deputy Executive Director
22 Child Health Research Foundation
23 23/3 Khilji Road, Mohammadpur
24 Dhaka 1207, Bangladesh
25 Email: [email protected]
26

NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

27 Abstract
28 Background: Respiratory syncytial virus (RSV) is a leading cause of pediatric hospitalizations globally,
29 impacting overstretched health systems. Comprehensive data is vital for informing RSV vaccination
30 policies.
31
32 Methods: From January to December 2019, a prospective study was conducted at Bangladesh's largest
33 pediatric hospital to evaluate RSV's burden on the health system. We analyzed hospitalization rates,
34 lengths of stay, and outcomes for children under five using WHO criteria and qPCR testing. We also
35 examined survival probability for children denied admission due to bed shortages, compared with
36 those admitted using the Kaplan-Meier method, and estimated the effects of a maternal vaccine using
37 Monte-Carlo simulations.
38
39 Findings: Out of 40,664 children admitted, 31,692 were under five. Of these, 19,940 were eligible for
40 study inclusion with 7,191 meeting inclusion criteria; 6,149 (86%) had samples taken, with 1,261 (21%)
41 testing positive for RSV. The hospital incidence rate was 465 per 10,000 admissions. The median age of
42 RSV patients was 3 months, with a median stay of 5 days. RSV accounted for 8,274 bed days of the
43 total 151,110 observed bed days. In-hospital mortality was 1.9%, increasing to 9.9% during a 90-day
44 follow-up over telephone. Additionally, 9,169 children were denied admission during the study period;
45 of these, 5,969 under-five children were approached, and outcomes of 2,850 admitted versus 3,928
46 refused were followed. The hazard ratio for death was 1.37 for refused versus admitted children,
47 highest within neonates at 1.7. A 70% efficacious vaccine would equate to adding 50 hospital beds and
48 averting 195 deaths.
49
50 Interpretation: RSV significantly contributes to pediatric hospitalizations in Bangladesh, exacerbating
51 healthcare burdens and increasing mortality risks. Maternal vaccination could significantly reduce both
52 direct and indirect RSV burdens, enhancing healthcare capacity and benefiting overall child health in
53 resource-limited settings.
54
55 Funding: Bill and Melinda Gates Foundation
 medRxiv preprint doi: https://doi.org/10.1101/2024.04.29.24306491; this version posted May 24, 2024. The copyright holder for this preprint
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56 Introduction
57
58 Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infection in young
59 children. Annually, RSV infections are estimated to result in 33 million episodes, 3.6 million
60 hospitalizations, and 26,300 deaths 1. Low- and middle-income countries (LMICs) bear a
61 disproportionate burden of the disease, where over 95% of RSV infections and more than 97% of RSV-
62 attributable deaths occur 1.
63
64 Emerging interventions, such as maternal vaccines and long-acting monoclonal antibodies, promise to
65 reduce RSV-related morbidity and mortality 2–4. There is also growing evidence suggesting that these
66 interventions might have broader benefits, like reducing respiratory illnesses caused by other
67 pathogens, decreasing recurrent hospitalizations, and improving lung health 5–7. Policymakers across
68 countries are grappling with decisions about introduction, and which groups should be prioritized for
69 these interventions. Making informed decisions necessitates up-to-date and locally relevant
70 epidemiological data. However, there exist large data gaps from LMICs.
71
72 In Bangladesh, a densely populated lower-middle income country, with a birth cohort of almost 3
73 million8 the healthcare system faces unique challenges due to the high burden of communicable and
74 non-communicable diseases9. Data from the country’s largest pediatric hospital indicate that
75 approximately 20% of children needing hospitalization—whether for communicable or non-
76 communicable diseases—have to be turned away due to bed shortages 10. Timely and appropriate care
77 is vital for child survival and well-being. In settings where healthcare resources are stretched thin, a
78 high RSV burden can exacerbate capacity issues, potentially leading to adverse health outcomes for
79 children who cannot be admitted for various reasons. Thus, it is imperative to consider both the direct
80 and indirect effects of RSV infections on child health and the broader health system when making
81 informed policy decisions.
82
83 Two prominent multi-country studies, Aetiology of Neonatal Infections in South Asia (ANISA) 11, and
84 Pneumonia Etiology Research for Child Health (PERCH) 12, have highlighted RSV as a primary etiological
 medRxiv preprint doi: https://doi.org/10.1101/2024.04.29.24306491; this version posted May 24, 2024. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
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85 agent in sepsis and respiratory tract infections in Bangladesh and other countries in Asia and Africa.
86 While these studies underscore RSV's role in community-based child morbidity, gaps remain in
87 understanding the extent of RSV-associated hospitalizations and the broader impact on the healthcare
88 capacity in resource-constrained settings.
89
90 To address the current gaps in data and estimate the potential impact of RSV vaccines, we conducted a
91 prospective, observational study at Bangladesh's largest pediatric hospital. We aimed to quantify RSV-
92 associated hospitalizations, bed usage, and outcomes. We also assessed the wider health implications
93 for children denied admission due to bed shortages, providing crucial data to inform policy and
94 intervention strategies.
95
96 Methods
97
98 Ethical considerations
99 This study was approved by the ethical review board of the Bangladesh Shishu Hospital and Institute
100 (BSHI). We obtained written informed consent from guardians of children admitted in the hospital
101 from whom nasopharyngeal samples were collected. We obtained informed verbal consent from
102 caregivers when they were registered in the study after hospital admission refusal for telephone follow
103 up. We also obtained informed verbal consent from caregivers of admitted patients selected for
104 follow-up over telephone.
105
106 Study Design and Setting
107 From January to December 2019, we conducted a prospective observational surveillance at the BSHI,
108 previously known as Dhaka Shishu Hospital (DSH), located in Dhaka, Bangladesh. BSHI, with its 653-bed
109 capacity (2019), is Bangladesh's largest pediatric hospital. It offers primary to tertiary care for patients
110 up to 18 years old. Admission decisions for the in-patient department (IPD) are made by physicians in
111 the Emergency Room (ER).
112
113 This study had two main components: (i) active surveillance within the IPD to detect RSV infections;
 medRxiv preprint doi: https://doi.org/10.1101/2024.04.29.24306491; this version posted May 24, 2024. The copyright holder for this preprint
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114 and (ii) active surveillance of health outcomes of patients who had to be denied hospitalization due to
115 bed shortages in the IPD, despite needing hospitalization, and a control group of patients who were
116 admitted in the IPD.
117
118 RSV Surveillance in the IPD
119 Children aged 0–59 months admitted to the wards selected for the study with 414 beds were
120 evaluated by study physicians using the WHO RSV hospital-based surveillance case definition 13 (Text
121 S1, appendix page 3). The remaining 239 beds of the total 653 were not selected because they were in
122 wards that do not admit patients with possible infectious diseases (surgery, nephrology, oncology and
123 cardiology wards). Eligible children were enrolled in the study after obtaining written consent from
124 caregivers and obtaining a nasopharyngeal swab sample. Nasopharyngeal swabs were collected by
125 trained nurses and tested using established qPCR methods (Text S2, appendix page 3).
126
127 Refusal Surveillance in the ER
128 Upon arrival at BSHI, families with children potentially needing hospitalization are triaged to the
129 Emergency Room (ER). Here, a physician evaluates the child's condition to determine if immediate
130 hospitalization is necessary. Beds are available on a first come first serve basis. If the physician decides
131 that the child requires hospitalization, but no beds are available, families are referred or advised to
132 seek care elsewhere. During this study, when a child was refused admission due to bed shortages
133 despite requiring hospitalization, trained research assistants documented the ER physician's diagnosis
134 for the patients, and upon obtaining verbal consent from the caregiver, they collected basic details,
135 including the child's age, family address, and contact numbers.
136
137 Health Outcome Follow-Up
138 Among the <5 y children refused admission due to shortage of beds and whose contact information
139 was obtained, families were selected using a computer-based randomization algorithm, and contacted
140 via telephone approximately 2 weeks after hospital-refusal, and the child's health status (“alive” or
141 “deceased”), and date of death (if applicable) was recorded based on caregivers’ response. If the child
142 was alive during the 2-week follow-up, a second follow-up call was made three months post refusal. In
 medRxiv preprint doi: https://doi.org/10.1101/2024.04.29.24306491; this version posted May 24, 2024. The copyright holder for this preprint
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143 parallel, from the cohort of children <5 years who were admitted during the same time, children were
144 randomly chosen for follow-up in the same manner. Additional information on in-hospital mortality
145 was obtained from hospital records.
146
147 Survival curves were computed using the Kaplan-Meier method. Date of death was collected during
148 follow-up, or from hospital records for admitted cases. Conservative censoring assumptions were
149 made – children refused admission and not followed-up at 14-days were considered censored at day 0,
150 and those not followed up at 90-days were considered censored at 14-days (last successful contact).
151 Admitted children’s censoring time was dealt with similarly, except that hospital discharge (either alive
152 or through mortality) was additional information. Multivariate Cox Proportional-Hazards models were
153 used to estimate hazard ratios adjusted for diagnosis cluster (Table S1, appendix page 5), age in
154 months, and sex. We also obtained stratified estimates of hazard ratios.
155
156 Estimated impact of RSV maternal vaccine impact analysis (Monte Carlo Simulation)
157
158 A Monte Carlo simulation was conducted to estimate the direct and indirect effects of RSV vaccination
159 on hospital admissions and 90-day mortality. The simulation used empirical data on the total number
160 of children requiring admission in 2019 across all age groups and diagnoses, length of stay, and
161 estimated 90-day survival probabilities among refused and admitted cases based on follow-up. We
162 explored the impact on total deaths within 3 months of hospital admission or refusal when a fixed
163 number of beds were occupied under a baseline scenario reflecting the empirical data. Additionally,
164 scenarios with various reductions in the number of RSV cases were simulated. The median value across
165 1000 simulations and the 95% prediction intervals are reported. Further methodological details are
166 provided in Text S3, appendix page 4.
167
168 Role of funding source
169 The funder had no role in study design, data collection, data analysis, data interpretation, writing of
170 the report, or the decision to submit this manuscript. The corresponding authors had full access to all
171 the data in the study and had final responsibility for the decision to submit for publication.
 medRxiv preprint doi: https://doi.org/10.1101/2024.04.29.24306491; this version posted May 24, 2024. The copyright holder for this preprint
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172
173 Results
174
175 Cases Hospitalized with RSV:
176
177 In 2019, a total of 49,833 children sought care at BSHI and were advised admission, of whom 40,664
178 could be admitted based on the available beds (Figure 1, Table 1). 31,692 of them were <5, and of
179 them 19,940 were admitted in the screening wards. Of them, 7,191 met the inclusion criteria of the
180 study, and a sample was successfully collected from 6,149 (86%) of these children. Samples could not
181 be collected from the remaining 1,042 eligible cases due to various reasons including the guardian’s
182 refusal to participate in the study, use of oxygen mask, and discharge before enrollment or sample
183 collection (Table S2, appendix page 5)). 92% (5658/6149) of all samples were collected within 72 hours
184 of hospitalization (Table S3, appendix page 6).
185
186 All 6,149 samples were tested for the presence of RSV using qPCR, and of them 1,261 (21%) samples
187 tested positive. Assuming 1,042 untested eligible cases among 7191 had the same positivity as those
188 tested, the overall proportion of all hospital admissions that were RSV positive was 4.65% or 465 RSV
189 cases per 10,000 <5 hospitalizations (95% CI: 443 to 489).
 medRxiv preprint doi: https://doi.org/10.1101/2024.04.29.24306491; this version posted May 24, 2024. The copyright holder for this preprint
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Hospital study Follow-up study

49,833 children required

admission at BSHI

9,169 children
refused admission

2,324 night
refusals

40,664 children 6,845 children

admitted at BSHI screened for follow-up

8,972 >5 876 >5

children children

31,692 <5 children 5,969 <5 refused

admitted children eligible
11,752 in 2,041 children
non-study not followed-up
wards (random)

19,940 <5 children 2,850 admitted children 3,928 refused children

admitted in study wards selected for follow-up approached for follow-up

12,749 323 could 503 could

non-eligible not reached not reached

7,191 <5 children 2,527 admitted children 3,435 refused children

eligible and enrolled followed up at 14 days followed up at 14 days
Alive = 2,302 Alive = 2,931
1,042
Deceased = 225 Deceased = 504
samples
not collected

6,149 samples 337 could 300 could

collected not reached not reached

4,888 RSV
negative 1,965 admitted children 2,631 refused children
followed up at 90 days followed up at 90 days
Alive = 1,883 Alive = 2,525
1,261 RSV positive Deceased = 82 Deceased = 106

190
191 Figure 1. Flowchart of sample collection and patient follow-up. The figure illustrates the process of
192 sample collection and subsequent patient follow-up for children under five admitted to BSHI or refused
193 admission due to unavailability of bed. Reasons for failures of sample collection and details on those
194 lost to follow-up are provided in Supplementary Appendix Tables S2, S4 - S7.
195
196
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197 The highest number of patients were enrolled in the study between June and September (Figure 2A),
198 and these four months accounted for over 70% of the total RSV-positive cases (882/1261) (Figure 2B).
199 During July, August and September, more than 20% of the 414 beds were due to RSV positive cases
200 (Figure 2C).
201
202 Table 1: Clinical attributes study participants enrolled in the study stratified by RSV status.
203
Overall RSV NegaJve/ RSV PosiJve p
Not Tested
Number of PaJents 19940 18679 1261
Sex - Female (%) 7582 (38.0) 7196 (38.5) 386 (30.6) <0.001
Age in months (median [IQR]) 5.00 [0.00, 5.00 [0.00, 3.00 [1.00, <0.001
16.00] 17.00] 8.00]
< 2 wks 5364 (26.9) 5293 (28.3) 71 ( 5.6)
2 wks - 3 mnths 4039 (20.3) 3413 (18.3) 626 (49.6)
4 - 6 mnths 1648 ( 8.3) 1464 ( 7.8) 184 (14.6)
7 mnths - 2 yrs 5693 (28.6) 5381 (28.8) 312 (24.7)
2 - 5yrs 3196 (16.0) 3128 (16.7) 68 ( 5.4)
In-hospital mortality (%) 1266 ( 6.3) 1242 ( 6.6) 24 ( 1.9) <0.001
Length of Stay (median [IQR]) 4.00 [2.00, 4.00 [2.00, 5.00 [4.00, <0.001
7.00] 7.00] 8.00]
Diagnosis Cluster (%) <0.001
Respiratory ManifestaJon 5026 (25.2) 4065 (21.8) 961 (76.2)
GastrointesJnal 2192 (11.0) 2178 (11.7) 14 ( 1.1)
ManifestaJon
Perinatal Asphyxia 2178 (10.9) 2164 (11.6) 14 ( 1.1)
Febrile Illness 1464 ( 7.3) 1445 ( 7.7) 19 ( 1.5)
Systemic InfecJons 1421 ( 7.1) 1352 ( 7.2) 69 ( 5.5)
Preterm low-birth weight 899 ( 4.5) 887 ( 4.7) 12 ( 1.0)
Other 6758 (33.9) 6586 (35.3) 172 (13.6)
204
205 Of the positive cases, 30.6% were females. The median age of PCR-confirmed RSV cases was 3 months
206 (IQR 1.3, 8.3 days) and 70% (881 of 1261) of the cases were within the first six months (Fig 3A, Table
207 1)). Notably, 17% of infections occurred in the first 4 weeks of life, highlighting the vulnerability of very
208 young babies to RSV. Median hospital stay of RSV cases was 5 days (IQR 4 – 8), and medial stay of all
209 RSV-negative cases and non-tested cases were 4 days (IQR 2 – 7). Throughout the year, RSV cases
210 accounted for 8,274 (5.5%) of the total 151,110 bed days observed.
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A 800

Eligible Cases

700 Samples Collected

Number of patients
600

500

400

B
40

30
% RSV Positive

20

10

0
C 25
% of Occupied Beds RSV Cases

20

15

10

0
Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec
Month
211
212 Figure 2. RSV Infections and Bed Occupancy in BSHI in 2019. A. The total number of patients enrolled
213 into the study each month, and the number of samples collected from these patients. B. Percentage of
214 RSV positive cases detected each month. C. Percentage of occupied beds with RSV positive cases across
215 different months. The dip in bed occupancy seen in mid-August is because of Eid-ul-Adha holidays.
 medRxiv preprint doi: https://doi.org/10.1101/2024.04.29.24306491; this version posted May 24, 2024. The copyright holder for this preprint
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216 In total, 24 cases (1.9%) of all positive cases died during their stay at the hospital (Table 1). Median age
217 of these cases was 130 days (IQR 77 - 175) and died between 0 - 26 days of hospitalization.
218

A B
200
60 40

RSV Test Positivity

RSV Cases

Frequency
150
30
40
100
20

20
10 50

0 0 0
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 0 5 10 15 20 25 30

Age (Weeks) Length of Hospital Stay (days)

219
220 Figure 3. Age distribution of RSV cases and length of hospital stay. A. Age distribution of RSV cases (n
221 = 1,261) in weeks, where the green line represents RSV test positivity in different age groups, the solid
222 orange line indicates the median age, and the dotted orange line shows the mean age. B. Length of
223 hospital stay in days of RSV cases (n = 1,261), with the solid orange line representing the median length
224 of stay and the dotted orange line the mean.
225
226
227 Impact of Bed Shortages on Non-Admitted Patients
228
229 During the study period, of the total 49,833 children requiring hospitalization, the hospital was unable
230 to admit 9,169 (18.4%) patients requiring admission due to lack of beds (Figure 1). Of them, we were
231 able to approach and collect contact information of 5,969 families for follow-up; 3,200 patients were
232 not approached because they either came to the hospital at night when the study research assistants
233 were absent (n = 2,324) or were >5 years of age (n = 876). Of the families who provided verbal consent
234 and contact information for telephone follow-up, a random selection of 3,928 (43%) patients were
235 chosen for follow-up. Out of these, 3,435 (87%) could be successfully contacted and followed up at 2
236 weeks. The primary reasons for missing follow-up included switched-off mobile phones, incorrect
237 phone numbers, or no response to the call (Table S4, appendix page 6). During the first follow up, 2931
238 (85.3%) children were reported to be alive by their guardian, and 504 (14.7%) were reported to have
239 died. Of the 2,931 patients alive, 2631 (89.8%) could be subsequently contacted during the 3-month
 medRxiv preprint doi: https://doi.org/10.1101/2024.04.29.24306491; this version posted May 24, 2024. The copyright holder for this preprint
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240 follow up, and 2525 (96%) were reported to be alive, and an additional 106 (4%) had died. The survival
241 probability at the end of follow up was 0.805 [95% CI: 0.791, 0.819] for refused patients (Figure 4a).
242

A B + RSV Positive Cases

+ Admitted + Refused Admission
1.0 + 1.0 ++++++
++ +++++
+++
+++ +++++++++++

Survival probability
Survival probability

+++ +++ +
+++++ +++++++ +
+++++
0.9 ++++++++++ 0.9 ++++++++
++++++ +
+ +++++++++++++
+
+++++++ ++ ++++++++++++++
0.8 0.8

0.7 0.7
0 25 50 75 100 0 25 50 75 100
Time (days) Time (days)
243
244
245 Figure 4. Survival Analysis of Patients followed-up. A. Survival probabilities of patients who were
246 refused admission with those who were admitted. Cases were censored at discharge if there was no
247 follow-up or at the last successful follow-up. B. Survival curve for only RSV-positive cases: the 24 cases
248 that resulted in in-hospital deaths, alongside the additional 205 cases that were followed up, of whom
249 18 subsequently died.
250
251 2,850 admitted <5-year children were randomly selected for follow-up during the same time. Of them,
252 2,527 (89%) were successfully followed up at 2 weeks. Reasons for unsuccessful follow up included
253 those above, in addition to missing contact information in the hospital records (Supplementary table
254 6). During the first follow up, 2302 (91.1%) children were reported to be healthy, and 225 (8.9%) were
255 reported to have died (Table 2). Of the 2,302 patients alive 1,965 (85.3%) could be subsequently
256 contacted during the 3-month follow up, of which 1,883 (95.8%) were alive, and an additional 82
257 (4.2%) had died (Figure 4). The survival probability at the end of follow up was 0.874 [95% CI: 0.861,
258 0.887] among those admitted (Figure 4a).
259
260
261
262
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263 Table 2: Clinical attribute and outcome of participants admitted or refused admissions who were
264 followed-up. The table represents data of participants for whom data could be collected. Diagnoses
265 was could not be collected for 18% of participants, 14-day mortality was missing for 12% and 90-day
266 mortality was missing for 21%.
267
Overall Admi`ed Refused p-value
Number of PaJents 6772 2845 3927
Sex - Female (%) 2582 (38.1) 1071 (37.6) 1511 (38.5) 0.502
Age in months (median 3.00 [0.00, 4.00 [0.00, 3.00 [0.00, 0.006
[IQR]) 12.00] 15.00] 11.00]
< 2 wks 2017 (29.8) 804 (28.3) 1213 (30.9) <0.001
2 wks - 3 mnths 1430 (21.1) 600 (21.1) 830 (21.1)
4 - 6 mnths 622 ( 9.2) 226 ( 7.9) 396 (10.1)
7 mnths - 2 yrs 1869 (27.6) 764 (26.9) 1105 (28.1)
2 - 5yrs 834 (12.3) 451 (15.9) 383 ( 9.8)
ER Diagnosis Cluster (%)
Respiratory 1463 (26.5) 351 (20.1) 1112 (29.4)
ManifestaJon
GastrointesJnal 475 ( 8.6) 182 (10.4) 293 ( 7.8)
ManifestaJon
Perinatal Asphyxia 702 (12.7) 211 (12.1) 491 (13.0)
Febrile Illness 207 ( 3.7) 101 ( 5.8) 106 ( 2.8) <0.001
Systemic InfecJons 496 ( 9.0) 145 ( 8.3) 351 ( 9.3)
Preterm low-birth 382 ( 6.9) 78 ( 4.5) 304 ( 8.0)
weight
Other 1799 (32.6) 677 (38.8) 1122 (29.7)
14-day Mortality (%) 729 (12.2) 225 ( 8.9) 504 (14.7) <0.001

90-day Mortality (%) 917 (17.2) 307 (14.0) 610 (19.4) <0.001
268
269
270 Overall comparison between the two groups revealed a hazard ratio (HR) of 1.69 (CI 1.48 - 1.94) of
271 death in children who were refused admission compared to children who were admitted (Table 3). The
272 HR was 1.37 (CI 1.56 - 1.79) in models adjusted for age, diagnosis and sex. Models stratified by age
273 groups showed that HR of death was significantly greater for refused cases among babies in their first
274 month of life (neonates) (HR 1.93 [CI 1.62 - 2.30]) but not in other age groups. When stratified by
 medRxiv preprint doi: https://doi.org/10.1101/2024.04.29.24306491; this version posted May 24, 2024. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

275 diagnosis, HR of death was significantly greater among those with perinatal asphyxia (HR 2.22 [1.68,
276 2.92]), systemic infections (HR 1.79 [1.13, 2.85]), and preterm low-birth weight 1.85 [1.32, 2.59].
277
278 Table 3: Hazard ratio (HR) of refused vs admitted participants adjusted by age, sex, and diagnosis.
279
Adjusted by Strata HR [95% CI]
1.69 [1.48, 1.69]
Age, Sex, Diagnosis 1.56 [1.36, 1.79]
Sex, Diagnosis < 1 mnth 1.93 [1.62, 2.3]
Sex, Diagnosis 2-3 mnths 1.19 [0.89, 1.58]
Sex, Diagnosis 4 mnths - 1 yr 1.47 [0.87, 2.48]
Sex, Diagnosis 1-5 yrs 1.05 [0.66, 1.68]
Age, Diagnosis Male 1.59 [1.34, 1.9]
Age, Diagnosis Female 1.49 [1.2, 1.84]
Age, Sex Respiratory Manifestaton 0.96 [0.7, 1.31]
Age, Sex Perinatal Asphyxia 2.22 [1.68, 2.92]
Age, Sex Systemic Infectons 1.79 [1.13, 2.85]
Age, Sex Preterm low-birth weight 1.85 [1.32, 2.59]
Age, Sex Febrile Illness 0.79 [0.14, 4.37]
Age, Sex Gastrointestnal Manifestaton 1.37 [0.51, 3.71]
Age, Sex Other 1.32 [1.02, 1.71]
280
281
282 Post-hospitalization RSV-associated mortality
283 While the study was not designed to specifically follow-up RSV positive cases, of the 2,527 admitted
284 children randomly selected and successfully followed up, there were 205 RSV positive cases. Of these,
285 18 children died within the 90-day follow-up period. Their median age was 107.5 days (IQR 44.75 - 157)
286 Considering both in-hospital mortality of all RSV admissions and mortality during follow-up of a subset
287 of cases revealed that survival decreased substantially over time, with a 90-day survival probability of
288 0.901 [95% CI: 0.865, 0.938] at the end of the follow-up period (Figure 4b).
289
290
291
292
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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

293 Potential Impact of Maternal RSV Vaccination

294
295 In a Monte Carlo simulation of hospital admissions and refusals for the baseline scenario, based on the
296 empirical data and a 650-bed capacity, on average, 49,968 children required admissions (95%
297 prediction intervals (PI): 49,500, 50,379), and 9,221 (95% PI: 8,869, 9,760) cases were refused
298 admission over the course of the year. This was in concordance with the true burden of total cases
299 requiring admission and refusals – 49,833 and 9,169 respectively. In the vaccine scenario with 70%
300 reduction in RSV cases requiring admission, 48,895 (95% PI: 48,514, 49,315) cases required admission,
301 and 8,103 cases were refused (7,728, 8.695) – a 16.6% refusal rate. Even though total cases requiring
302 admissions in this scenario remained as high as 97.9% (48895/49968) of the baseline scenario, the
303 number of refused cases was 87.8% (8103/9221), due to the freeing up of bed spaces. Figure 5
304 demonstrates the effects of a 70% reduction in RSV admissions through vaccination, showing its impact
305 on deaths and hospital bed utilization. The plot compares mortality with increase in available beds,
306 demonstrating how reducing RSV cases is akin to increasing bed capacity. Overall, there were 7,002
307 deaths (6829, 7167) in the baseline scenario, and 6807 deaths (6629, 6930) in the vaccine scenario, a
308 difference of 195 deaths. A reduction in RSV cases was found to decrease both hospital RSV incidence
309 and the overall number of RSV cases seeking admission at the hospital. The estimated reduction in
310 deaths with the 70% efficacious vaccine would be equivalent of adding roughly 50 beds to the hospital
311 although, there is considerable overlap of the variability in the estimates from the different scenarios.
312
 medRxiv preprint doi: https://doi.org/10.1101/2024.04.29.24306491; this version posted May 24, 2024. The copyright holder for this preprint
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313
314 Figure 5. Impact of RSV Vaccination on Hospital Utilization and 90-day Mortality Rates of all children
315 who require admission at BSHI. Effects of a 70% reduction in RSV admissions through vaccination,
316 showing its impact on deaths and hospital bed utilization among children under five. The plot
317 compares mortality against the effective increase in available beds, demonstrating how reducing RSV
318 cases is akin to increasing bed capacity.
319
320 Discussion
321 Informed decision-making on interventions to prevent RSV infections in young infants requires
322 contemporary and locally relevant epidemiological data. Our study demonstrates the significant impact
323 of RSV on healthcare resources in Bangladesh, a country characterized by a high burden of infectious
324 diseases and a substantial demand for pediatric care amidst resource limitations.
325
326 Our study recorded an overall RSV positivity rate of 21% among the 6,149 patients admitted to the
327 largest pediatric hospital of Bangladesh with respiratory illnesses, corresponding to an RSV hospital
328 incidence of 465 per 10,000 <5 admissions. The median age of confirmed RSV cases was 3 months.
329 These findings are concordant with those of the PERCH study that reported that in Bangladesh 31.2%
330 of children hospitalized with respiratory tract infections tested positive for RSV 12.
331
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332 The in-hospital mortality rate for RSV-positive cases was 1.6%, which escalated to 9.9% during the 90-
333 day follow-up of discharged patients. The median age of recorded RSV-associated deaths was 4.2
334 months. These data are comparable to a Zambian study that found RSV in 9% of community deaths
335 and 5% of in-hospital deaths 14. In Child Health and Mortality Prevention Surveillance (CHAMPS) study,
336 RSV was found in 5.5% of all deaths, with variability across countries: 9.7% in Mali, 10.7% in Ethiopia,
337 and a lower 2% in Bangladesh 15. Half of the deaths in the CHAMPS study occurred in infants younger
338 than six months.
339
340 These findings underscore the critical need for maternal immunization strategies, such as vaccines like
341 ABRYSVO™, which has demonstrated 81.8% efficacy in preventing RSV infections within the first three
342 months of life 16. Our estimates suggest that maternal immunization could potentially reduce the
343 hospital incidence from 465 to 140 cases per 10,000 <5 admissions.
344
345 Beyond the direct impact of RSV infections, our findings also demonstrate the considerable burden
346 infections impose on the healthcare system. For a minimum of three months during the study year,
347 RSV cases occupied more than 20% of the beds under observation, with a median hospital stay for RSV-
348 positive cases at 5 days—longer than the overall median length of stay of 4 days for all admitted
349 patients. In 2019, RSV cases accounted for 8,274 of the total 151,110 bed days observed. As the largest
350 pediatric tertiary hospital in Bangladesh, BSHI, even with its total of 653 beds, is insufficient.
351 Consequently, clinicians often must refuse admission due to bed unavailability 10. We followed over
352 5,000 admitted and refused children up to 90 days to determine the difference in health outcomes and
353 the wider effects of high-burden infections like RSV on the healthcare system. The cumulative
354 mortality proportion for children denied admission was 19.4%, significantly higher than the 14% among
355 those admitted. This discrepancy in mortality risk is quantified by a hazard ratio (HR) of 1.69 across all
356 children under five.
357
358 The HR for death was 1.37 among children refused admission compared to those admitted, adjusted
359 for age, diagnosis, and sex. The highest mortality risk was observed in neonates requiring
360 hospitalization within their first month of life, with a HR of 1.93 . This disparity highlights the essential
 medRxiv preprint doi: https://doi.org/10.1101/2024.04.29.24306491; this version posted May 24, 2024. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

361 role of healthcare access in determining child survival outcomes. Monte Carlo simulation using a 70%
362 efficacious vaccine is estimated to be equivalent to adding approximately 50 beds to the hospital, and
363 averting 195 deaths in only one hospital, each year.
364
365 The issue of bed shortages, a prevalent concern across many LMICs, is pressing. In Bangladesh, the rate
366 of 0.8 beds per 1,000 population is markedly lower than in developed nations such as 2.9 in the USA
367 and 2.5 in the UK 17. With limited infrastructure, preventative strategies become even more vital. Over
368 the past decades, the introduction of multiple vaccines in Bangladesh and improved health systems
369 have led to a decrease in under-5, yet the rate 33 death in 1,000 live birth remain high, underscoring
370 the need for further disease prevention measures 18. Given the considerable proportion of hospital
371 beds occupied by RSV cases during peak periods, introducing an RSV vaccine could significantly impact
372 bed availability for critically ill infants. Other interventions like administration of monoclonal antibodies
373 in neonates and infants can also be considered. However, the cost and logistical hurdles associated
374 with monoclonal antibody treatments, such as nirsemivab, highlight the need for affordable, scalable,
375 and equitable solutions, particularly in LMICs like Bangladesh where 69% of health expenditures are
376 out-of-pocket 19.
377
378 While our 2019 study centered on RSV, a significant dengue outbreak during the same period
379 compounded the strain on hospital resources 20. In addition, other infectious etiologies of respiratory
380 infections remain to be explored, as evidenced by the high number of cases meeting the inclusion
381 criteria for RSV October to December, despite the absence of RSV detection.
382
383 The findings of this study must be viewed considering certain limitations. Primary among them is the
384 necessity to conduct the study in a single hospital due to the high volume of cases and the extensive
385 follow-up required for thousands of patients. While the authors' lived experiences suggest that similar
386 circumstances are likely in other resource-limited settings, a multi-site research would be helpful in
387 developing a more detailed understanding of the RSV burden among children throughout Bangladesh
388 and potentially the wider region. Furthermore, the study's duration was constrained to one year,
389 shortened by the COVID-19 pandemic in the following year. A longitudinal study spanning multiple
 medRxiv preprint doi: https://doi.org/10.1101/2024.04.29.24306491; this version posted May 24, 2024. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

390 years could provide more information on the patterns of RSV seasonality, but previous reports from
391 Bangladesh suggest an unpredictable pattern of RSV seasonality 21. And the overall high burden of RSV
392 in the study hospital aligns with previous studies 11,12. This study also did not investigate concurrent
393 infections alongside RSV, nor was it set up to confirm deaths directly attributable to RSV. Lastly,
394 potential biases due to human factors may have influenced the clinicians' admissions decisions during
395 times of resource scarcity, even though such decisions should theoretically be unaffected by bed
396 availability constraints.
397
398 The broader context and global health implications of our study are significant. The challenges
399 highlighted related to shortage of hospital beds in places with high burden of disease are common in
400 many LMICs and the global health community can learn from these findings particularly regarding
401 resource allocation and estimate potential impact of preventive strategies like vaccination. This study
402 also contributes to the growing body of evidence supporting the development and distribution of RSV
403 vaccines or other interventions, which could significantly impact child health globally, specifically in
404 low-resource countries where burden is the highest.
405
406 Declaration of Interests
407 The authors declare no conflict of interest.
408
409 Author contributions
410 S.S. contributed to conceptualization, funding acquisition, study design, implementation, monitoring,
411 data analysis, drafting the initial manuscript, and preparation of figures. S.Sa. was involved in data
412 analysis, preparation of figures, and manuscript editing. N.K. contributed to data analysis and editing.
413 Y.H. participated in data analysis, preparation of figures, and manuscript editing. M.S.I. was responsible
414 for analysis and coordination of the study, and also contributed to editing. S.I. carried out specimen
415 extraction and PCR testing. Z.B.A. coordinated and trained doctors and nurses, assisted in the
416 implementation of the study, in addition to contributing to manuscript editing. M.J.A. was involved in
417 monitoring and management activities, as well as editing. A.M.A. performed data cleaning. P.K.S.
418 contributed to management and patient data analysis. M.R.A. was involved in implementation and
 medRxiv preprint doi: https://doi.org/10.1101/2024.04.29.24306491; this version posted May 24, 2024. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

419 management. M.R.A. contributed to editing. S.K.S. contributed to conceptualization, funding

420 acquisition, study design, implementation, monitoring, and manuscript editing. All authors reviewed
421 the manuscript and agreed on the contents.
422
423 Declaration of Generative AI and AI-assisted technologies in the writing process
424 During the preparation of this work the authors used ChatGPT to check grammar, spellings, and
425 improve readability of the manuscript. After using this tool/service, the authors reviewed and edited
426 the content as needed and take full responsibility for the content of the publication.
427
428
429 References

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