Clinical signs of possible serious infection and associated mortality among young infants presenting at first-level health facilities.

BACKGROUND: The World Health Organization recommends inpatient hospital treatment of young infants up to two months old with any sign of possible serious infection. However, each sign may have a different risk of death. The current study aims to calculate the case fatality ratio for infants with individual or combined signs of possible serious infection, stratified by inpatient or outpatient treatment.
METHODS: We analysed data from the African Neonatal Sepsis Trial conducted in five sites in the Democratic Republic of the Congo, Kenya and Nigeria. Trained study nurses classified sick infants as pneumonia (fast breathing in 7-59 days old), severe pneumonia (fast breathing in 0-6 days old), clinical severe infection [severe chest indrawing, high (> = 38°C) or low body temperature (<35.5°C), stopped feeding well, or movement only when stimulated] or critical illness (convulsions, not able to feed at all, or no movement at all), and referred them to a hospital for inpatient treatment. Infants whose caregivers refused referral received outpatient treatment. The case fatality ratio by day 15 was calculated for individual and combined clinical signs and stratified by place of treatment. An infant with signs of clinical severe infection or severe pneumonia was recategorised as having low- (case fatality ratio ≤2%) or moderate- (case fatality ratio >2%) mortality risk.
RESULTS: Of 7129 young infants with a possible serious infection, fast breathing (in 7-59 days old) was the most prevalent sign (26%), followed by high body temperature (20%) and severe chest indrawing (19%). Infants with pneumonia had the lowest case fatality ratio (0.2%), followed by severe pneumonia (2.0%), clinical severe infection (2.3%) and critical illness (16.9%). Infants with clinical severe infection had a wide range of case fatality ratios for individual signs (from 0.8% to 11.0%). Infants with pneumonia had similar case fatality ratio for outpatient and inpatient treatment (0.2% vs. 0.3%, p = 0.74). Infants with clinical severe infection or severe pneumonia had a lower case fatality ratio among those who received outpatient treatment compared to inpatient treatment (1.9% vs. 6.5%, p<0.0001). We recategorised infants into low-mortality risk signs (case fatality ratio ≤2%) of clinical severe infection (high body temperature, or severe chest indrawing) or severe pneumonia and moderate-mortality risk signs (case fatality ratio >2%) (stopped feeding well, movement only when stimulated, low body temperature or multiple signs of clinical severe infection). We found that both categories had four times lower case fatality ratio when treated as outpatient than inpatient treatment, i.e., 1.0% vs. 4.0% (p<0.0001) and 5.3% vs. 22.4% (p<0.0001), respectively. In contrast, infants with signs of critical illness had nearly two times higher case fatality ratio when treated as outpatient versus inpatient treatment (21.7% vs. 12.1%, p = 0.097).
CONCLUSIONS: The mortality risk differs with clinical signs. Young infants with a possible serious infection can be grouped into those with low-mortality risk signs (high body temperature, or severe chest indrawing or severe pneumonia); moderate-mortality risk signs (stopped feeding well, movement only when stimulated, low body temperature or multiple signs of clinical severe infection), or high-mortality risk signs (signs of critical illness). New treatment strategies that consider differential mortality risks for the place of treatment and duration of inpatient treatment could be developed and evaluated based on these findings. CLINICAL TRIAL REGISTRATION: This trial was registered with the Australian New Zealand Clinical Trials Registry under ID ACTRN 12610000286044.

Introduction

An estimated 2.4 million neonatal deaths occurred globally in 2019, representing 47% of under-five deaths [1]. The neonatal period in the first 28 days of life after birth is the most vulnerable time for survival. Each day 6700 neonatal deaths occur, one-third on the first day of birth, and three-quarters in the first week of life [1]. The global neonatal mortality rate decreased by 52% from 37 deaths per 1000 live births in 1990 to 17 deaths per 1000 live births in 1990 [1]. Bacterial infections, including sepsis, meningitis and pneumonia, account for 37% of neonatal deaths in the low-resource settings of South Asia and sub-Saharan Africa [2]. An estimated 9.8% died of the 6.9 million cases of possible serious bacterial infection (PSBI) in neonates and young infants up to two months of age in 2012 [3]. A recent systematic review of 26 studies from 14 countries estimated the neonatal sepsis incidence as 2824 per 100,000 live births with a mortality of 17.6%. However, the review also highlighted the variations in the definition of sepsis [4].

Early diagnosis requires recognition of clinical signs of bacterial sepsis [5-7]. Serious bacterial and viral infections are difficult to differentiate clinically in neonates and young infants up to two months of age. World Health Organization (WHO) recommends that young infants with any sign of possible serious infection should be managed at a hospital with injectable antibiotics and supportive care [8]. Unfortunately, in many low-resource settings, families may not accept referral advice, and sick young infants are not taken to hospital [9-12]. Common barriers for not accepting referral advice are distance to the hospital, availability of transport and other logistical reasons such as lack of child care, cost of travel and treatment, lack of permission from the husband or family elders, concerns around quality of care, a previous negative experience or poor attitudes of health workers at the hospital, cultural or religious beliefs and the absence of referral protocols/algorithms [13-17]. WHO launched a guideline for managing PSBI in young infants when referral is not feasible in 2015 [18], based on evidence from high-quality randomised controlled trials [19-22]. The WHO guideline recommends that if a referral is not feasible, young infants with signs of clinical severe infection can be managed with a simplified antibiotic regimen of injectable gentamicin plus oral amoxicillin on an outpatient basis [18]. The critically ill young infants should be treated at a hospital because they require other supportive care apart from antibiotics, and most will be unable to take an oral antibiotic. In contrast, those infants aged 7–59 days with only fast breathing should be treated with oral amoxicillin on an outpatient basis without referral [18].

The updated WHO Integrated Management of Childhood Illness (IMCI) chart booklet for young infants [23] based on WHO guideline [18], recommends seven signs for urgent referral to hospital: not feeding well/not able to feed at all; convulsions; fast breathing; severe chest indrawing; high body temperature (≥ 38°C); low body temperature (< 35.5°C); movement only when stimulated or no movement at all [23]. WHO recommendations [18, 23] assumed a similar mortality risk for all signs of possible serious infection. However, individual signs may have variable mortality risks, which may have implications for treatment strategies [24]. Therefore, we conducted an analysis using the African Neonatal Sepsis Trial (AFRINEST) [19, 20] data to calculate the case fatality ratio (CFR) for young infants with individual or combined signs of possible serious infection, stratified by inpatient or outpatient treatment.

Methods

Study data

We used AFRINEST [19, 20] data for this analysis. Young infants less than two months of age were classified based on the updated IMCI chart booklet [23] as pneumonia [fast breathing (respiratory rate ≥ 60 breaths per minute) in 7–59 days old], severe pneumonia (fast breathing in 0–6 days old), clinical severe infection [stopped feeding well, severe chest indrawing, high body temperature (≥ 38°C), low body temperature (< 35.5°C), or movement only when stimulated] or critical illness (convulsions, not able to feed at all, or no movement at all). The study was conducted at one site, each in the Democratic Republic of Congo (DRC) and Kenya, and three sites in Nigeria (Ibadan, Ile-Ife and Zaria) and followed the same protocol, quality control, and coordination. Trial design and methods of AFRINEST have been described in detail elsewhere [25-27]. Briefly, young infants with any sign of infection were identified by trained community-level health workers (CLHW) in the community and referred to first-level health facilities in the study catchment area for further management. At the first-level health facilities, nurses trained in IMCI assessed infants for signs of possible serious infection. All young infants with any sign of possible serious infection were referred to a hospital. Those infants whose caregivers accepted referral to a hospital were followed up on day 15 of the initial assessment to collect information on their survival status. Those whose caregivers refused referral were offered simplified antibiotic treatment on an outpatient basis at the first-level health facility after consent was obtained and followed until day 15 to collect their survival status [19, 20]. In the DRC, the distance between the health centre (primary health care facility) and the Health Zone General Referral Hospital is approximately 50–55 kilometres (km) in the study area. Since there is no public transportation system available in the study area, people typically walk or ride a bicycle to reach the hospital. The time to reach the hospital can take up to 12 hours by foot or seven hours by bicycle, depending upon the weather, as in the rainy season, it takes a much longer time. In Kenya, the distance between the health centres and the district hospital is around 30 km in the study area. It usually takes several hours on foot and about 50 minutes by a motorized vehicle. In Ibadan, Nigeria, the secondary level referral hospital is approximately 40 km from the Primary Health Centres (PHC) in the study area. It usually takes 90 minutes to reach the hospital through public transport. In Ile-Ife, Nigeria, the referral hospital is situated 50 km away from the PHCs in the study area. The duration of travel time varies from 30 minutes to an hour, depending on the mode of transportation. In Zaria, Nigeria, the Gambo Sawaba General Hospital is at a distance of 15 km from the PHCs in the study area and the Ahmadu Bello University teaching hospital is over 30 km away. Most families walk, while only a few have the privilege of using motorized vehicles as most feeder roads are not motorable, especially during the rainy season. For this analysis, we selected 7129 young infants who presented at the first-level health facilities in the study catchment area, and IMCI trained nurses classified these infants as pneumonia, severe pneumonia, clinical severe infection, or critical illness.

Outcomes and exposure

The study outcome was the survival status of a young infant with any sign of possible serious infection by day 15 after an initial assessment. CFR was defined as the number of deaths divided by the number of young infants with a specific clinical sign(s) by day 15. The main exposure variable was the clinical sign(s) at the time of presentation. Clinical signs considered in this analysis were fast breathing only, signs of clinical severe infection alone or in combination, or signs of critical illness alone or a combination [18, 23]. The place of treatment was categorised into either inpatient or outpatient.

Statistical analysis

Stata 14.2 (Stata-Corp, College Station, TX, USA) was used for analysis. We calculated the prevalence of each clinical sign–alone or in combination—defined as the number of young infants with a specific clinical sign(s) divided by the total number of young infants with any sign of possible serious infection, expressed as a percent. CFR is reported with a 95% confidence interval (CI), calculated for IMCI classification of infants with possible serious infection as well as for each clinical sign–alone or in combination. Additionally, the CFR for IMCI classification and each clinical sign–alone or in combination, was compared between those who received outpatient and those who received inpatient treatment. Based on CFRs, infants with signs of clinical severe infection or severe pneumonia were recategorised for mortality risk into two groups, those who had low-mortality risk signs (defined as CFR of ≤ 2% for any sign), or those with moderate-mortality risk signs (defined as CFR of > 2% for any sign). The CFR for infants with signs of clinical severe infection or severe pneumonia with a low- or moderate-mortality risk sign was calculated and compared between outpatient and inpatient treatment and between the two age groups (0–6 days and 7–59 days) also. A Chi-square test was used to compare the CFR between outpatient and inpatient treatment groups, and p-values were reported. Cases with missing information about the survival status were excluded from the analysis. Infants were classified as outpatient or inpatient treatment group based on the initial treatment they received.

Consent and ethical approval

The protocol was approved by the local institutional review boards at each site and by the WHO Ethical Review Committee. We obtained the site-specific ethics approvals from the University of Kinshasa School of Public Health Ethics Committee, DRC; the Moi University and Moi University Teaching Hospital Institutional Research and Ethics Committee, Eldoret, Kenya; the University of Ibadan/University College Ibadan Hospital Ethics Committee, Ibadan, Nigeria; the Obafemi Awolowo University Teaching Hospitals Complex Ethics Committee, Ile-Ife, Nigeria and the Ahmadu Bello University Teaching Hospital Ethics Committee, Zaria, Nigeria before the enrolment took place. Written and witnessed informed consent was obtained from parents/caregivers of infants before recruitment.

Results

IMCI-trained nurses at the first-level health facilities assessed 18420 young infants 0–59 days old who were identified and referred by the CLHWs from the community at all five study sites. Of these, 7129 (38.7%) infants had any sign of possible serious infection, and they were followed up to day 15 after the initial assessment to document their survival status. The mean age of young infants with possible serious infection was 14.5 days (standard deviation 13.6). Out of 7129 young infants who had any sign of possible serious infection, 6040 (84.7%) were less than 28 days, and 3893 (54.6%) were males. We excluded 83 young infants from the analysis for whom information on survival status was missing. Thus data for 7046 young infants were analysed for CFR. About 89% (6269/7046) of young infants received outpatient treatment.

Amongst 7129 sick young infants, fast breathing (in 7–59 days old) was the most prevalent sign (26%), followed by high body temperature (20%) and severe chest indrawing (19%). More than one sign of clinical severe infection was reported in 8%, while signs of critical illness showed a relatively low prevalence (≤ 1%) in young infants (Fig 1).

Fig 1

Prevalence of clinical signs of possible serious infection in young infants 0–59 days old (n = 7129).

The prevalence of low body temperature sign was 10 times higher in young infants 0–6 days of age (6.8%) than 7–59 days olds (0.7%). The prevalence of severe chest indrawing was 2.4 times higher in young infants 7–59 days old (23.8%) than those 0–6 days olds (10.5%) (Table 1).

Table 1

Distribution of signs of IMCI* classification stratified by age categories in young infants presenting with any sign of possible serious infection (n = 7129).

IMCI* classification	Age 0–6 days (N = 2752) n (%)	Age 7–59 days (N = 4377) n (%)
Pneumonia
Fast breathing† in 7–59 days old‡	Not applicable	1866 (42.6%)
Severe pneumonia
Fast breathing† in 0–6 days old‡	1317 (47.9%)	Not applicable
Clinical severe infection§
High body temperature (≥ 38°C) ‡	601 (21.8%)	811 (18.5%)
Severe chest indrawing‡	290 (10.5%)	1041 (23.8%)
Movement only when stimulated‡	12 (0.4%)	19 (0.4%)
Stopped feeding well‡	83 (3.0%)	170 (3.9%)
Low body temperature (< 35.5°C) ‡	162 (6.9%)	31 (0.7%)
Multiple signs of clinical severe infection§	187 (6.8%)	359 (8.2%)
Critical illness¶
Convulsions‡	62 (2.2%)	43 (1.0%)
Unable to feed at all‡	14 (0.5%)	24 (0.5%)
No movement at all‡	8 (0.3%)	7 (0.2%)
Multiple signs of critical illness¶	16 (0.6%)	6 (0.4%)

*IMCI: Integrated management of childhood illnesses.

† Fast breathing is defined as a respiratory rate of ≥ 60 breaths per minute.

‡ Young infant presenting with a single sign.

§ Clinical severe infection is defined as the presence of any one of the following signs: severe chest indrawing, high body temperature (≥ 38°C), low body temperature (< 35.5°C), stopped feeding well, or movement only when stimulated.

¶ Critical illness is defined as the presence of any one of the following signs: convulsions, unable to feed at all, or no movement at all.

Infants with pneumonia had the lowest CFR (0.2%), while those with any sign of critical illness had the highest CFR (16.9%) (Table 2). In terms of individual signs of clinical severe infection, infants with high body temperature had the lowest CFR (0.8%), whereas low body temperature had the highest CFR (11.0%). The CFRs of infants with any sign of critical illness ranged from 11.3% to 27.3% (Table 2).

Table 2

Number of deaths, cases and case fatality ratio (CFR) of sick young infants by IMCI* classification [23] (n = 7046).

IMCI* classification of sick infants	Deaths/young infants	CFR† % (95% CI)
Pneumonia
Fast breathing‡ in 7–59 days old§	4/1843	0.2 (0.1, 0.6)
Severe pneumonia
Fast breathing‡ in 0–6 days old§	26/1291	2.0 (1.3, 2.9)
Clinical severe infection¶	85/3746	2.3 (1.8, 2.8)
High body temperature (≥ 38°C) §	11/1409	0.8 (0.4, 1.4)
Severe chest indrawing§	12/1329	0.9 (0.5, 1.6)
Movement only when stimulated§	1/31	3.2 (0.1, 16.7)
Stopped feeding well§	10/251	4.0 (1.9, 7.2)
Low body temperature (< 35.5°C)§	20/182	11.0 (6.8, 16.5)
Multiple signs of clinical severe infection¶	31/544	5.7 (3.9, 8.0)
Critical illness#	28/166	16.9 (11.5, 23.4)
Convulsions§	11/97	11.3 (5.8, 19.4)
Unable to feed at all§	8/35	22.9 (10.4, 40.1)
No movement at all§	3/12	25.0 (5.5, 57.2)
Multiple signs of critical illness#	6/22	27.3 (10.7, 50.2)

*IMCI: Integrated management of childhood illnesses.

† CFR: Case fatality ratio.

‡ Fast breathing is defined as a respiratory rate of ≥ 60 breaths per minute.

§ Young infant presenting with a single sign.

¶ Clinical severe infection is defined as the presence of any one of the following signs: severe chest indrawing, high body temperature (≥ 38°C), low body temperature (< 35.5°C), stopped feeding well, or movement only when stimulated.

#Critical illness is defined as the presence of any one of the following signs: convulsions, unable to feed at all, or no movement at all.

Compared to inpatient hospital treatment, young infants who received outpatient treatment had a CFR 1.5 times lower for pneumonia (p = 0.74), 3.4 times lower for clinical severe infection or severe pneumonia (p < 0.0001) but 1.8 times higher for critical illness (p = 0.097) (Table 3). Infants with low-mortality risk signs of clinical severe infection or severe pneumonia had a CFR of 1% with outpatient treatment versus 4% with inpatient treatment (p<0.0001). Infants with moderate-mortality risk signs of clinical severe infection had a CFR of 5.3% with outpatient treatment versus 22.4% with inpatient treatment (p<0.0001) (Table 3).

Table 3

Case fatality ratio (CFR) comparison by the place of treatment and by IMCI* classification [23] and recategorisation of signs of clinical severe infection or severe pneumonia on mortality risk (n = 7046).

	Young infants who received outpatient treatment		Young infants who received inpatient treatment		p-value
	Deaths/young infants	CFR† % (95% CI)	Deaths/young infants	CFR† % (95% CI)
A. IMCI* classification
Pneumonia‡	3/1501	0.2 (0.1, 0.6)	1/342	0.3 (0.1, 1.6)	0.738
Clinical severe infection§ or severe pneumonia¶	88/4685	1.9 (1.5, 2.3)	23/352	6.5 (4.2, 9.6)	<0.0001
Critical illness#	18/83	21.7 (13.4, 32.1)	10/83	12.1 (5.9, 21.0)	0.097
B. Recategorisation of signs of clinical severe infection§ or severe pneumonia¶ based on mortality risk
Low-mortality risk signs**	37/3726	1.0 (0.7, 1.4)	12/303	4.0 (2.1, 6.8)	<0.0001
High body temperature (≥ 38°C)††	11/1383	0.8 (0.4, 1.4)	0/26	-
Severe chest indrawing††	10/1310	0.8 (0.4, 1.4)	2/19	10.5 (1.3, 33.1)
Only fast breathing in 0–6 days old††	16/1033	1.5 (0.9, 2.5)	10/258	3.9 (1.9, 7.0)
Moderate-mortality risk signs‡‡	51/959	5.3 (4.0, 6.9)	11/49	22.4 (11.8, 36.6)	<0.0001
Movement only when stimulated††	1/30	3.3 (0.1, 17.2)	0/1	-
Stopped feeding well††	9/243	3.7 (1.7, 6.9)	1/8	12.5 (0.3, 52.7)
Low body temperature††	15/161	9.3 (5.3, 14.9)	5/21	23.8 (8.2, 47.2)
Multiple signs of clinical severe infection§	26/525	4.9 (3.3, 7.2)	5/19	26.3 (9.1, 51.2)

*IMCI: Integrated management of childhood illnesses.

†CFR: Case fatality ratio.

‡ Pneumonia is defined as fast breathing (respiratory rate of ≥ 60 breaths per minute) in 7–59 days old infants.

§ Clinical severe infection is defined as the presence of any one of the following signs: severe chest indrawing, high body temperature (≥ 38°C), stopped feeding well, movement only when stimulated, or low body temperature (< 35.5°C).

¶ Severe pneumonia is defined as fast breathing (respiratory rate of ≥ 60 breaths per minute) in 0–6 days old infants.

# Critical illness is defined as the presence of any one of the following signs: convulsions, unable to feed at all, or no movement at all. For the current analysis, only these three common signs of critical illness were considered.

** Low-mortality risk signs are defined as infants with a case fatality ratio for any sign ≤ 2.0%.

†† Young infant presenting with a single sign.

‡‡ Moderate-mortality risk signs are defined as infants with a case fatality ratio for any sign >2.0%.

The CFR was higher for both 0–6 days and 7–59 days age groups among severe pneumonia and clinical severe infection categories in inpatient versus outpatient treatment groups (Table 4). In contrast, among 0–6 days old infants with a critical illness, the CFR was more than twice in the outpatient treatment group compared to the inpatient treatment group. In the 0–6 days old age group, both low- and moderate-mortality risk signs had over twice the CFR for those who received inpatient treatment than those who received outpatient treatment. In contrast, CFR was nine times higher in 7–59 days old with moderate-mortality risk signs amongst those who received inpatient treatment than those who received outpatient treatment, although the numbers are relatively small (Table 4).

Table 4

Case fatality ratio (CFR) with the place of treatment by age and by IMCI* classification and recategorisation of signs of clinical severe infection or severe pneumonia on mortality risk (n = 7046).

	Age 0–6 days (n = 2707)		Age 7–59 days (n = 4339)
	Outpatient treatment	Inpatient treatment	Outpatient treatment	Inpatient treatment
	Deaths/ infants (CFR†)	Deaths/ infants (CFR†)	Deaths/ infants (CFR†)	Deaths/ infants (CFR†)
A. IMCI* classification
Pneumonia‡	Not applicable	Not applicable	3/1501 (0.2%)	1/342 (0.3%)
Clinical severe infection§ or severe pneumonia¶	62/2300 (2.7%)	20/316 (6.3%)	26/2385 (1.1%)	3/36 (8.3%)
Critical illness#	12/44 (27.3%)	6/47 (12.8%)	6/39 (15.4%)	4/36 (11.1%)
B. Recategorisation of signs of clinical severe infection§ or severe pneumonia¶ based on mortality risk
Low-mortality risk signs**	27/1902 (1.4%)	12/279 (4.3%)	10/1824 (0.5%)	0/24 (0.0%)
High body temperature (≥ 38°C)††	8/588 (1.4%)	0/12 (0.0%))	3/795 (0.4%)	0/14 (0.0%)
Severe chest indrawing††	3/281 (1.1%)	2/9 (22.2%)	7/1029 (0.7%)	0/10 (0.0%)
Only fast breathing in 0–6 days old††	16/1033 (1.5%)	10/258 (3.9%)	NA	NA
Moderate-mortality risk signs‡‡	35/398 (8.8%)	8/37 (21.6%)	16/561 (2.8%)	3/12 (25.0%)
Movement only when stimulated††	1/11 (9.1%)	0/1 (0.0%)	0/19 (0.0%)	0/0
Stopped feeding well††	5/79 (6.3%)	1/4 (25.0%)	4/164 (2.4%)	0/4 (0.0%)
Low body temperature††	13/134 (9.7%)	4/19 (21.0%)	2/27 (7.4%)	1/2 (50.0%)
Multiple signs of clinical severe infection§	16/174 (9.2%)	3/13 (23.1%)	10/351 (2.8%)	2/6 (33.3%)

*IMCI: Integrated management of childhood illnesses.

†CFR: Case fatality ratio.

‡Pneumonia is defined as fast breathing (respiratory rate of ≥ 60 breaths per minute) in 7–59 days old infants.

§Clinical severe infection is defined as the presence of any one of the following signs: severe chest indrawing, high body temperature (≥ 38°C), stopped feeding well, movement only when stimulated, or low body temperature (< 35.5°C).

¶ Severe pneumonia is defined as fast breathing (respiratory rate of ≥ 60 breaths per minute) in 0–6 days old infants.

#Critical illness is defined as the presence of any one of the following signs: convulsions, unable to feed at all, or no movement at all. For the current analysis, only these three common signs of critical illness were considered.

** Low-mortality risk signs are defined as infants with a case fatality ratio for any sign ≤ 2.0%.

†† Young infant presenting with a single sign.

‡‡ Moderate-mortality risk signs are defined as infants with a case fatality ratio for any sign >2.0%.

We did not see any significant differences in the study sites separately in the outpatient and inpatient treatment groups by IMCI categories or by mortality risks (S1 Table).

Discussion

Key findings

Four key findings emerged from our analysis. First, infants with pneumonia (fast breathing in 7–59 days old) had the lowest CFR, and it was almost the same whether they received either outpatient or inpatient treatment. Second, infants with severe pneumonia had a relatively higher CFR than pneumonia but lower than those with a clinical severe infection or critical illness. Third, infants with any sign of critical illness had the highest CFR, and those treated as outpatients had it nearly twice as high compared to the ones treated as inpatients. Finally, in infants with signs of clinical severe infection, the CFR for individual signs showed substantial variation. This variation provided us with an opportunity to recategorise young infants with clinical severe infection or severe pneumonia into those with low- or moderate-mortality risk signs. Both categories had four times lower mortality among those who received outpatient treatment compared to inpatient treatment. This finding could be due to several reasons, such as delay in reaching the hospital after accepting referral advice, relatively sicker patients accepting referral advice, delay in getting appropriate treatment after reaching the hospital or inadequate quality of care, and development of hospital infections [16, 28–30]. These findings add support to the body of evidence suggesting a need to further improve the management of sick young infants in low resource settings where the quality of care and referral feasibility are a problem [15, 31–35].

Like the AFRINEST, two simplified antibiotic therapy trials (SATT) were conducted in Bangladesh and Pakistan. These trials showed that the simplified antibiotic regimen for young infants with clinical severe infection when referral to a hospital is not feasible was as efficacious as the standard regimen [21, 22]. AFRINEST and SATT studies [19-22] contributed evidence to the WHO guideline for managing PSBI in young infants when a referral is not feasible [18], but they did not report mortality for individual or combination of clinical signs. Hibberd et al. [24] reported CFR for some individual signs of PSBI in young infants in a multi-centre study from low resource settings; 0.8% for high fever, 5.7% for a breathing problem, 15.3% for feeding problem/stopped suckling/feeding, 18% for convulsions and 18.4% for hypothermia. However, they did not calculate it for all signs of infection and did not report it for the place of treatment [24]. In contrast, we reported mortality for individual clinical signs and compared it both for outpatient and inpatient treatment.

Research and policy implications

These findings have important research and policy implications for developing and evaluating new management strategies for young infants aged 0–59 days with any sign of possible serious infection. First, infants with any sign of critical illness cannot be safely managed on an outpatient basis because apart from antibiotics, they also require supportive care such as oxygen, fluid therapy, nutrition, management of hypothermia and hypoglycaemia. Second, a young infant with pneumonia had a very low mortality risk and, therefore, can be effectively and safely treated on an outpatient basis as recommended by WHO [18, 23]. Third, young infants having low-mortality risk signs can be treated on an outpatient basis without referral to a hospital, as demonstrated in the previous trials, in which most of them were cured [19, 21, 22]. Fourth, it has been demonstrated in the AFRINEST and SATT studies that most young infants with signs of clinical severe infection were cured with outpatient simplified antibiotics regimens [19, 21, 22]. However, there were around 10% treatment failures, including about 3% deaths or those who deteriorated clinical. We hypothesize that these young infants with a clinical severe infection who did not benefit from simplified antibiotic regimens on an outpatient basis (having moderate-mortality risk signs) might benefit from a shorter duration of inpatient treatment, compared to critically ill young infants who would need a longer inpatient treatment [8]. Thus, our findings provide research hypotheses to improve the current treatment strategies for sick young infants in low-resource settings.

Strengths and limitations

The strengths of this study included the analysis of data from a large, high-quality, multi-centre trial. Large sample size from five clinical sites representing east, central, and west Africa increased the external generalizability of the study. This prospective study utilized trained and well-supervised health workers to collect data during follow-up, reducing the risk of selection and misclassification bias often encountered in retrospective chart-review studies [27]. Finally, the outcome was assessed by independent outcome assessors who were not linked with the treatment. There were a few limitations also. First, the diagnosis was based on only clinical signs, and microbiology or radiology was not used. Second, we did not collect information on comorbidities in this study. Finally, a potential limitation could be that the health centre nurses referred critically ill young infants more strongly than the other sick young infants. Although it is a possibility, we believe that because the health workers were very well trained in the study methods and were supervised, it did not happen on a scale to cause a referral bias [27, 36]. Also, ones who were treated on an outpatient basis were randomised to various treatments [37].

Conclusion

The mortality risk differs with different clinical signs. The young infants with a possible serious infection can be grouped into those with low-mortality risk signs (high body temperature, or severe chest indrawing or severe pneumonia); moderate-mortality risk signs (stopped feeding well, movement only when stimulated, low body temperature or multiple signs of clinical severe infection), or high-mortality risk signs (critical illness). New treatment strategies that consider differential mortality risks for the place of treatment and duration of inpatient hospital treatment could be developed and evaluated based on these findings.

Case fatality ratio (CFR) with the place of treatment by study site and by IMCI* classification and recategorisation of signs of clinical severe infection or severe pneumonia on mortality risk (n = 7046).

(DOCX)

Click here for additional data file.

(PDF)

Click here for additional data file.

17 Feb 2021

PONE-D-20-17173

Clinical signs of possible serious infection and associated mortality among young infants presenting at first-level health facilities

PLOS ONE

Dear Dr. Nisar,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Specifically, both reviewers have asked for additional methodological details and further information and clarification of some of the results and observations from the study. In addition, they have provide suggestions to better place your submission in context of previously published work.

Please submit your revised manuscript by Apr 01 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Nicola Stead

Senior Editor

PLOS ONE

Journal requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

3. Thank you for stating the following in the Competing Interests section:

"YBN and RB are WHO employees. All other authors declare no competing interests."

Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to  PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests).  If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

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

Reviewer #1: Thank you for the invitation to review the study „Clinical signs of possible serious infection and associated mortality among young infants presenting at first-level health facilities“. The study estimates the case fatality rate of different signs of possible severe bacterial infections in infants. The authors found that the mortality risk differs with clinical signs and young infants with serious infection can be grouped into those with lower mortality risk signs; higher mortality risk signs; or signs of critical illness and that only for more severely ill children, inpatient treatment is advantageous compared to outpatient treatment. This is a clinically relevant work that can inform future guidelines on management of PSBI and a well-written manuscript.

I have the following comments:

1. Introduction: “Unfortunately, in many low-resource settings families may not accept referral advice, and sick young infants are not taken to hospital (9-12).” Is refusal by families the major reason for which young infants are not admitted or are there any further barriers to be considered?

2. Methods: „For this analysis, 7129 young infants classified as pneumonia, severe pneumonia, clinical severe infection, or critical illness by IMCI trained nurses at first-level health facilities were selected“ Patients were selected in the outpatient setting and IMCI nurses were trained at first-level health facilities, correct? This sentence is somewhat confusing and the setting of patient inclusion should be better specified.

3. Methods – Statistical analyses: Please be more specific on the analyses conducted, e.g. which tests were used for between-group comparisons? How was missing data handled? Were infants that were initially treated in the outpatient and later admitted to an inpatient facility excluded or counted as in- or outpatient treated cases?

4. Results: “A total of 18420 young infants 0-59 days old were assessed by IMCI-trained nurses at first-level health facilities at five study sites.” Again this may be misleading in terms of setting of patient screening (community vs first-level health facilities).

5. Results: How was the age and sex distribution of young infants with signs of PSBI? Did the authors collect any data on underlying comorbidity? E.g. add a demographics table.

6. Results: Did the distribution of signs of PSBI differ between <7, >= days old?

7. Results: „Of the 7129 young infants, fast breathing (in 7-59 days old)“. Another 18% had fast breathing (in <7d old) according to Fig. 2. I think it would be clearer to refer the proportions to the infants at risk, which means the <7, >=7 day olds or to report a combined proportion of fast breathing.

8. Results: „Compared to inpatient treatment, young infants who received outpatient treatment had a CFR 1.5 times lower for pneumonia (p = 0.74), 3.4 times lower for clinical severe infection or severe pneumonia (p < 0.0001) and 1.8 times higher for critical illness (p = 0.097).“ Were there any differences by study site, level of health facility, underlying comorbidity (if such data is available) or age group of infants (<7 days, >=7 days)? I think it would be important looking a bit deeper into this as this finding may have important implications for care.

9. Discussion: „This finding could be due to several reasons, such as delay in reaching the hospital after accepting referral advice, relatively sicker patients accepting referral advice, delay in getting appropriate treatment after reaching the hospital or inadequate quality of care, and development of nosocomial infections (23-25).“

9.a. Are there any other studies from LMIC with similar results?

9.b. Is there a way to adjust for severity of disease and comorbidities in the data? I think if the authors consider differences in disease severity as a possible explanation of their findings, it would be important to control for this confounder. Otherwise the results should be presented with more caution and this issue should be more prominently included in the discussion.

9.c. Where there any other signs detected by the trained nurses that can help to distinguish infants likely to benefit from hospital admissions vs. infants that may have better outcomes if treated in the outpatient setting?

10. Discussion: Fourth, infants categorized as having higher mortality risk signs, who are not as sick as critically ill, could benefit from a shorter stay in the hospital when they accept referral instead of the recommended seven days (8).

Based on which data was this conclusion made? Please underpin this hypothesis with data or references.

11. Can any conclusions on the definition of sepsis in LMIC be drawn from this data?

Reviewer #2: Abstract page 2:

1) The authors should avoid using abbreviations in the abstract (see Submission Guidelines of the Journal).

Introduction:

1) The authors state on page 4 row 1-6: “Neonatal mortality has decreased…for case fatality rate (CFR) of 9.8% (4).” Please try to supply the reader with more recent data about neonatal mortality, incidence of bacterial infections / sepsis and who they are defined!!! Some of the references are from 2009 and 2012.

2) There is discrepancy between the objective mentioned in the end of the introduction part of the manuscript (page 5 row 7-10) and the objective mentioned in the abstract in the background (page 2, row 3-4) part. The authors should give us consistent description of the “objective of the study”!!!

See the following information which should be integrated in your paper.

Neonatal Mortality ( Reference: data.unicef.org)

The first 28 days of life – the neonatal period – is the most vulnerable time for a child’s survival. Children face the highest risk of dying in their first month of life at an average global rate of 17 deaths per 1,000 live births in 2019, down by 52 per cent from 38 deaths per 1,000 in 1990.

In comparison, the probability of dying after the first month and before reaching age 1 was estimated at 11 deaths per 1,000 and the probability of dying after reaching age 1 and before reaching age 5 was estimated at 10 deaths per 1,000 in 2019.

Globally, 2.4 million children died in the first month of life in 2019 – approximately 6,700 neonatal deaths every day – with about a third of all neonatal deaths occurring within the first day after birth, and close to three-quarters occurring within the first week of life.

Definitions of indicators: Neonatal mortality rate:Probability of dying during the first 28 days of life, expressed per 1,000 live births. Infant mortality rate: Probability of dying between birth and exactly 1 year of age, expressed per 1,000 live births. Under-five mortality rate:Probability of dying between birth and exactly 5 years of age, expressed per 1,000 live births.

Methods:

1) The authors should explain why they defined outcome (“survival status”) on “day 15 after the initial assessment” and not in the end of the neonatal period day 28?

2) Page 6 row 18-21: “CFR, was defined at the…..alone or in combination” This description of CFR definition should be better placed in the Methods part of the manuscript but not in the section of “statistical analysis”.

Results:

1) The authors should decide how they want to present their results. It is unnecessary to present the same information in the text with a written description and a Figure which presents the same information. Therefore, I would suggest to omit Figure 1 from the manuscript.

2) The authors mentioned that 7086 children were included to the study. But on page 7, row 17; “Of the 7192 young infants….” Please clarify this discrepancy in the numbers of patients.

3) The authors should decide once again, how they want to present their results. It is unnecessary to present the same information in the text with a written description (page 7, row 21-23 and page 8, row 1-4) and a table (Table 1) which presents the same information. In this case I would suggest to leave Table 1 which supplies well-arranged information and only “refer the reader” to this table in the results part without presenting the same result in written way.

Discussion:

1) The authors state on page 9, row 1-2 that there was a higher CFR in outpatients compaired to inpatients with the same signs of critical illness this should be more in detail elaborated.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

26 Feb 2021

Point by point to reviewers' comments is attcahed

Submitted filename: Response to reviewers_26 Feb 2021.docx

Click here for additional data file.

4 May 2021

PONE-D-20-17173R1

Clinical signs of possible serious infection and associated mortality among young infants presenting at first-level health facilities

PLOS ONE

Dear Dr. Nisar,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jun 18 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Emma Sacks

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments (if provided):

Thank you for your careful revisions and an overall impactful analysis with important practice implications.

In addition to the final additional comments from one reviewer, can you also please address the following?

-Can you provide a bit more information about the distances, especially from first level facilities to hospitals? This might give more context about why families refuse referral and why the journey itself might be more dangerous for critically ill neonates. It might be important for understanding the differences between the 5 sites as well, which would be nice to include in the paper.

-I believe what you describe is actually a case fatality RATIO, not a rate (as it has no time component) ? But I leave it to your judgement

-Please be more specific about the exclusion criteria as related to "missing values" - was this any value, a certain indicator, a set of variables?

-In the ethical approval section, please list the IRBs at each site/country

-Unlike AFRNIEST, which is explained, SATT is not described (nor is the acronym spelled out). If references to SATT are included in the discussion, please give a bit more detail about the SATT trial.

-In the discussion, please include something about the potential of referral bias (or, why you believe there was none?). Could it be possible that nurses more strongly encourage referral of young infants who are more critically ill? These potential biases should also be alluded to in the limitations.

-Please add captions to figures (it looks like there are 2 figure 1s?)

-The paper would benefit from a careful read - there are a few sentences where the technical writing could be improved and abbreviations (such as "neonates up to 28 days were 6040" which is unclear or the contraction "we didn't" could be written out)

-In the future, please use line numbers to assist reviewers in providing feedback.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

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

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

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

Reviewer #1: I thank the authors for considering my comments and this good revision. The additional analyses increase the value of the study and help to better understand the data. I have only minor comments:

Introduction: The focus of the study is on infants and neonates, thus I would suggesting adding also some epidemiological data on deaths due to infectious diseases/PSBI infection in infants to the first paragraph, which is now presenting data exclusively on neonates.

Methods: „Place of treatment was categorized into either hospitalized or outpatient.“ Place of treatment should be hospital not hospitalized from my point of view.

Table 4: Low body temperature – age 7-59 day, hospitalized treatment: 1/1 should be 100%?

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

23 May 2021

Rebuttal letter

Point by point response to academic editor and reviewers' comments

PONE-D-20-17173R1: Clinical signs of possible serious infection and associated mortality among young infants presenting at first-level health facilities

Academic editor

Comment#1

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article's retracted status in the References list and also include a citation and full reference for the retraction notice.

Authors' response

We have updated the reference list as per journal requirements in the revised manuscript.

Comment#2

Can you provide a bit more information about the distances, especially from first-level facilities to hospitals? This might give more context about why families refuse the referral and why the journey itself might be more dangerous for critically ill neonates. It might be important for understanding the differences between the 5 sites as well, which would be nice to include in the paper.

Authors' response

Thank you for this comment. We have added the following information in the revised manuscript:

"In the Democratic Republic of Congo (DRC), the distance between the health centre (primary health care facility) and the Health Zone General Referral Hospital is approximately 50-55 kilometres (km) in the study area. Since there is no public transportation system available in the study area, people typically walk or ride a bicycle to reach the hospital. The time to reach the hospital can take up to 12 hours by foot or seven hours by bicycle, depending upon the weather, as in the rainy season, it takes a much longer time. In Kenya, the distance between the health centres and the district hospital is around 30 km in the study area. It usually takes several hours on foot and about 50 minutes by a motorized vehicle. In Ibadan, Nigeria, the secondary level referral hospital is approximately 40 km from the Primary Health Centres (PHC) in the study area. It usually takes 90 minutes to reach the hospital through public transport. In Ile-Ife, Nigeria, the referral hospital is situated 50 km away from the PHCs in the study area. The duration of travel time varies from 30 minutes to an hour, depending on the mode of transportation. In Zaria, Nigeria, the Gambo Sawaba General Hospital is at a distance of 15 km from the PHCs in the study area and the Ahmadu Bello University teaching hospital is over 30 km away. Most families walk, while only a few have the privilege of using motorized vehicles as most feeder roads are not motorable, especially during the rainy season.

Comment#3

I believe what you describe is actually a case fatality RATIO, not a rate (as it has no time component)? But I leave it to your judgement

Authors' response

Thank you for pointing out this. We have changed it to case fatality ratio in the revised manuscript.

Comment#4

Please be more specific about the exclusion criteria as related to "missing values" - was this any value, a certain indicator, a set of variables?

Authors' response

We have revised this statement in the revised manuscript as given below:

"Cases with missing information about the survival status were excluded from the analysis."

Comment#5

In the ethical approval section, please list the IRBs at each site/country

Authors' response

We have added the following sentence in the revised manuscript:

"We obtained the site-specific ethics approvals from the University of Kinshasa School of Public Health Ethics Committee, DRC; the Moi University and Moi University Teaching Hospital Institutional Research and Ethics Committee, Eldoret, Kenya; the University of Ibadan/University College Ibadan Hospital Ethics Committee, Ibadan, Nigeria; the Obafemi Awolowo University Teaching Hospitals Complex Ethics Committee, Ile-Ife, Nigeria and the Ahmadu Bello University Teaching Hospital Ethics Committee, Zaria, Nigeria before the enrolment took place."

Comment#6

Unlike AFRNIEST, which is explained, SATT is not described (nor is the acronym spelled out). If references to SATT are included in the discussion, please give a bit more detail about the SATT trial.

Authors' response

Thank you, and we agree with the academic editor. We have mentioned the following two sentences in the discussion section of the revised manuscript and spelled out SATT acronym.

"Like the AFRINEST, two simplified antibiotic therapy trials (SATT) were conducted in Bangladesh and Pakistan. These trials showed that the simplified antibiotic regimen for young infants with clinical severe infection when referral to a hospital is not feasible was as efficacious as the standard regimen."

Comment#7

In the discussion, please include something about the potential of referral bias (or, why you believe there was none?). Could it be possible that nurses more strongly encourage referral of young infants who are more critically ill? These potential biases should also be alluded to in the limitations.

Authors' response

Thank you for this suggestion. We have added the following text in the limitation section to address it.

Finally, a potential limitation could be that the health centre nurses referred critically ill young infants more strongly than the other sick young infants. Although it is a possibility, but we believe that because the health workers were very well trained in the study methods and were supervised, it did not happen on a scale to cause a referral bias [27, 36]. Also, ones who were treated on an outpatient basis were randomised to various treatments [37].

Comment#8

Please add captions to figures (it looks like there are 2 figure 1s?)

Authors' response

We have added the appropriate captions to the figures it in the revised manuscript.

Comment#9

The paper would benefit from a careful read - there are a few sentences where the technical writing could be improved and abbreviations (such as "neonates up to 28 days were 6040" which is unclear or the contraction "we didn't" could be written out)

Authors' response

Thank you for this comment. We have read the manuscript carefully and made the necessary corrections to the revised manuscript.

Comment#10

In the future, please use line numbers to assist reviewers in providing feedback.

Authors' response

We have added line numbers in the revised manuscript.

Reviewer's comments

Reviewer #1: I thank the authors for considering my comments and this good revision. The additional analyses increase the value of the study and help to better understand the data. I have only minor comments:

Comment#1

Introduction: The focus of the study is on infants and neonates; thus, I would suggesting adding also some epidemiological data on deaths due to infectious diseases/PSBI infection in infants to the first paragraph, which is now presenting data exclusively on neonates.

Authors' response

We had given the following sentence in the first paragraph of the manuscript, “An estimated 9.8% died of the 6.9 million neonatal cases of possible serious bacterial infection (PSBI) in 2012”, which we have modified as follows:

“An estimated 9.8% died of the 6.9 million cases of possible serious bacterial infection (PSBI) in neonates and young infants up to two months of age in 2012”.

Comment#2

Methods: "Place of treatment was categorized into either hospitalized or outpatient. "Place of treatment should be hospital not hospitalized from my point of view.

Authors' response

Thank you for pointing out this. We had used the term ‘hospitalized’ because one could be treated in a hospital as an inpatient or an outpatient basis both. We have modified the place of treatment throughout the revised manuscript as either inpatient or outpatient.

Comment#3

Table 4: Low body temperature – age 7-59 days, hospitalized treatment: 1/1 should be 100%?

Authors' response

Thank you for this comment. It was a typo error as there were 2 cases of low body temperature in young infants 7-59 days old. We have corrected this in the revised manuscript.

Submitted filename: Response to reviewers_26 Feb 2021.docx

Click here for additional data file.

31 May 2021

Clinical signs of possible serious infection and associated mortality among young infants presenting at first-level health facilities

PONE-D-20-17173R2

Dear Dr. Nisar,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Emma Sacks

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thank you for your thorough revisions. I believe the findings of this study are actually very important for guiding practice and policy, and I am enthusiastic to see it published. Thank you again for your patience during the review process.

Reviewers' comments:

16 Jun 2021

PONE-D-20-17173R2

Clinical signs of possible serious infection and associated mortality among young infants presenting at first-level health facilities

Dear Dr. Nisar:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Emma Sacks

Academic Editor

PLOS ONE