case study of neonatal pneumonia

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Neonatal Pneumonia

, MD, University of Rochester School of Medicine and Dentistry

• Symptoms and Signs

Chlamydial Pneumonia

Neonatal pneumonia is lung infection in a neonate. Onset may be within hours of birth and part of a generalized sepsis syndrome or after 7 days and confined to the lungs. Signs may be limited to respiratory distress or progress to shock and death. Diagnosis is by clinical and laboratory evaluation for sepsis. Treatment is initial broad-spectrum antibiotics changed to organism-specific drugs as soon as possible.

(See also Overview of Pneumonia Overview of Pneumonia Pneumonia is acute inflammation of the lungs caused by infection. Initial diagnosis is usually based on chest x-ray and clinical findings. Causes, symptoms, treatment, preventive measures, and... read more in adults and Overview of Neonatal Infections Overview of Neonatal Infections Neonatal infection can be acquired In utero transplacentally or through ruptured membranes In the birth canal during delivery (intrapartum) From external sources after birth (postpartum) Common... read more .)

Pneumonia is the most common invasive bacterial infection after primary sepsis. Early-onset pneumonia is part of generalized sepsis that first manifests at or within hours of birth ( see Neonatal Sepsis Neonatal Sepsis Neonatal sepsis is invasive infection, usually bacterial, occurring during the neonatal period. Signs are multiple, nonspecific, and include diminished spontaneous activity, less vigorous sucking... read more ). Late-onset pneumonia usually occurs after 7 days of age, most commonly in neonatal intensive care units among infants who require prolonged endotracheal intubation because of lung disease (called ventilator-associated pneumonia).

Etiology of Neonatal Pneumonia

Symptoms and Signs of Neonatal Pneumonia

Late-onset hospital-acquired pneumonia manifests with unexplained worsening of the patient's respiratory status and increased quantities and a change in the quality of the respiratory secretions (eg, thick and brown). Infants may be acutely ill, with temperature instability and neutropenia.

Diagnosis of Neonatal Pneumonia

Chest x-ray

Evaluation includes chest x-ray, pulse oximetry, blood cultures, and Gram stain and culture of tracheal aspirate.

If Gram stain of tracheal aspirate shows a significant number of polymorphonuclear leukocytes and a single organism that is consistent with the one that grows from culture of the tracheal aspirate, the likelihood increases that this organism is the cause of the pneumonia. Because bacterial pneumonia in neonates may disseminate, a full evaluation for sepsis Diagnosis Neonatal sepsis is invasive infection, usually bacterial, occurring during the neonatal period. Signs are multiple, nonspecific, and include diminished spontaneous activity, less vigorous sucking... read more , including a lumbar puncture, should also be done. However, blood cultures are positive in only 2 to 5% of cases of hospital-acquired pneumonia.

Treatment of Neonatal Pneumonia

Usually vancomycin and a broad-spectrum beta-lactam drug

Treatment of Chlamydial Pneumonia

Erythromycin or azithromycin

The diagnosis of pneumonia secondary to Chlamydia trachomatis should prompt an evaluation of the mother and her partner because untreated maternal chlamydial infection may have complications such as pelvic inflammatory disease and sterility.

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INTRODUCTION

The epidemiology, microbiology, clinical manifestations, diagnosis, and treatment of neonatal pneumonia are reviewed here. Neonatal sepsis is discussed separately:

● (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates" .)

● (See "Management and outcome of sepsis in term and late preterm neonates" .)

● (See "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation" .)

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• Published: 12 July 2023

Short-course antibiotic therapy for pneumonia in the neonatal intensive care unit

• Zachery S. Lewald   ORCID: orcid.org/0009-0006-2711-7841 1 , 2 , 3 , 4 ,
• Pavel Prusakov   ORCID: orcid.org/0000-0001-5787-5623 5 ,
• Jacqueline K. Magers   ORCID: orcid.org/0000-0001-8422-8157 5 ,
• Matthew J. Kielt   ORCID: orcid.org/0000-0002-4568-9070 2 , 3 ,
• Concepción de Alba Romero   ORCID: orcid.org/0000-0003-0794-2466 2 , 3 , 6 ,
• Natalie O. White 7 ,
• Randy R. Miller   ORCID: orcid.org/0000-0003-1524-6129 7 ,
• Richard Moraille 8 ,
• Anthony R. Theile 8 ,
• Pablo J. Sánchez   ORCID: orcid.org/0000-0003-2437-1247 2 , 3 , 4 &

Nationwide Children’s Hospital Neonatal Antimicrobial Stewardship Program (NEO-ASP)

Journal of Perinatology volume  43 ,  pages 1145–1151 ( 2023 ) Cite this article

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• Outcomes research
• Respiratory tract diseases

To determine the adherence and safety outcomes of a 5-day antibiotic course with a “time-out” for treatment of “blood culture-negative” pneumonia in the NICU.

Study design

Prospective surveillance of all infants diagnosed with pneumonia at 7 NICUs from 8/2020-12/2021. Safety outcomes were defined a priori by re-initiation of antibiotic therapy within 14 days after discontinuation and overall and sepsis-related mortality.

128 infants were diagnosed with 136 episodes of pneumonia; 88% ( n  = 119) were treated with 5 days of definitive antibiotic therapy. Antibiotics were restarted within 14 days in 22 (16%) of the 136 pneumonia episodes. However, only 3 (3%) of the 119 episodes of pneumonia treated for 5 days had antibiotics restarted for pneumonia. Mortality was 5% (7/128); 5 of the 7 deaths were assessed as sepsis-related.

Adherence to the 5-day definitive antibiotic treatment for “culture-negative” pneumonia was high and the intervention seemed safe.

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Data availability

The de-identified dataset generated from the study is available from the corresponding author on reasonable request and following approval by the Institutional Review Board of Nationwide Children’s Hospital.

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Acknowledgements

The study was presented in part as poster presentations at the Pediatric Academic Societies Meeting, Denver, CO on 4/25/2022, Midwest Society for Pediatric Research, Chicago, IL on 9/29/2022, and St. Jude/PIDS Pediatric Infectious Diseases Research Conference, Memphis, TN, on 3/2/2023.

ZSL received a Pediatric Infectious Diseases Society Summer Research Scholar Award (SUMMERS) for his work on this study.

Author information

A full list of members and their affiliations appears in the Supplementary Information.

Authors and Affiliations

The Ohio State University, Columbus, OH, USA

Zachery S. Lewald

Department of Pediatrics, Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, OH, USA

Zachery S. Lewald, Matthew J. Kielt, Concepción de Alba Romero & Pablo J. Sánchez

Division of Neonatology, Nationwide Children’s Hospital, Center for Perinatal Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, OH, USA

Division of Pediatric Infectious Diseases, Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, OH, USA

Zachery S. Lewald & Pablo J. Sánchez

Department of Pharmacy, Nationwide Children’s Hospital, Columbus, OH, USA

Pavel Prusakov, Jacqueline K. Magers, Caitlyn Schwirian, Wai-Yin Mandy Tam & Alexandra F. Burton

Division of Neonatology, Hospital 12 de Octubre, Madrid, Spain

Concepción de Alba Romero

Pediatrix Medical Group of Ohio, Columbus, OH, USA

Natalie O. White, Randy R. Miller & Maclain J. Magee

Central Ohio Newborn Medicine, Columbus, OH, USA

Richard Moraille & Anthony R. Theile

Department of Pediatrics, Division of Neonatology, Nationwide Children’s Hospital, Center for Perinatal Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, OH, USA

Pablo J. Sánchez, Alexandra K. Medoro, Maria Jebbia & Roopali Bapat

Department of Pediatrics, Division of Pediatric Infectious Diseases, Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, OH, USA

Pablo J. Sánchez, Alexandra K. Medoro, Joshua R. Watson & Katia C. Halabi

Department of Neonatal Nurse Practitioners, Nationwide Children’s Hospital, The Ohio State Wexner Medical Center, Columbus, OH, USA

Melinda Albertson & Tommy Nathaniel Johnson-Roddenberry

Department of Clinical Outcomes, Nationwide Children’s Hospital, Columbus, OH, USA

Malak Abdel-Hadi

You can also search for this author in PubMed   Google Scholar

• Pablo J. Sánchez
• , Jacqueline K. Magers
• , Pavel Prusakov
• , Natalie O. White
• , Randy R. Miller
• , Richard Moraille
• , Anthony R. Theile
• , Alexandra K. Medoro
• , Joshua R. Watson
• , Melinda Albertson
• , Caitlyn Schwirian
• , Wai-Yin Mandy Tam
• , Alexandra F. Burton
• , Tommy Nathaniel Johnson-Roddenberry
• , Maria Jebbia
• , Maclain J. Magee
• , Katia C. Halabi
• , Malak Abdel-Hadi
•  & Roopali Bapat

Contributions

ZSL collected and analyzed the data, assisted with the analyses, wrote the first draft of the manuscript, and reviewed and revised the manuscript. PP conceptualized and designed the study, designed the data collection instruments, collected data, assisted with the analyses, and reviewed and revised the manuscript. JKM conceptualized and designed the study, collected data, and reviewed and revised the manuscript. MJK assisted with the analyses, reviewed and revised the manuscript. CdAR collected and helped to analyze the data, reviewed and revised the manuscript, and approved the final manuscript as submitted. NOW conceptualized and designed the study, reviewed and revised the manuscript. RRM conceptualized and designed the study, reviewed and revised the manuscript. RM conceptualized and designed the study, reviewed and revised the manuscript. ART conceptualized and designed the study, reviewed and revised the manuscript. PJS conceptualized and designed the study, coordinated and supervised data collection, analyzed the data, and critically reviewed and revised the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Pablo J. Sánchez .

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Competing interests.

PP received grant funding from Merck & Co. unrelated to this study. Other authors have no conflicts of interest relevant to this article to disclose.

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Lewald, Z.S., Prusakov, P., Magers, J.K. et al. Short-course antibiotic therapy for pneumonia in the neonatal intensive care unit. J Perinatol 43 , 1145–1151 (2023). https://doi.org/10.1038/s41372-023-01720-6

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Received : 22 April 2023

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Published : 12 July 2023

Issue Date : September 2023

DOI : https://doi.org/10.1038/s41372-023-01720-6

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Volume 11 Supplement 3

Technical inputs, enhancements and applications of the Lives Saved Tool (LiST)

• Open access
• Published: 13 April 2011

Effect of case management on neonatal mortality due to sepsis and pneumonia

• Anita K M Zaidi 1 ,
• Hammad A Ganatra 1 ,
• Sana Syed 1 ,
• Simon Cousens 2 ,
• Anne CC Lee 3 ,
• Robert Black 3 ,
• Zulfiqar A Bhutta 1 &
• Joy E Lawn 4  

BMC Public Health volume  11 , Article number:  S13 ( 2011 ) Cite this article

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Each year almost one million newborns die from infections, mostly in low-income countries. Timely case management would save many lives but the relative mortality effect of varying strategies is unknown. We have estimated the effect of providing oral, or injectable antibiotics at home or in first-level facilities, and of in-patient hospital care on neonatal mortality from pneumonia and sepsis for use in the Lives Saved Tool (LiST).

We conducted systematic searches of multiple databases to identify relevant studies with mortality data. Standardized abstraction tables were used and study quality assessed by adapted GRADE criteria. Meta-analyses were undertaken where appropriate. For interventions with biological plausibility but low quality evidence, a Delphi process was undertaken to estimate effectiveness.

Searches of 2876 titles identified 7 studies. Among these, 4 evaluated oral antibiotics for neonatal pneumonia in non-randomised, concurrently controlled designs. Meta-analysis suggested reductions in all-cause neonatal mortality (RR 0.75 95% CI 0.64- 0.89; 4 studies) and neonatal pneumonia-specific mortality (RR 0.58 95% CI 0.41- 0.82; 3 studies). Two studies (1 RCT, 1 observational study), evaluated community-based neonatal care packages including injectable antibiotics and reported mortality reductions of 44% (RR= 0.56, 95% CI 0.41-0.77) and 34% (RR =0.66, 95% CI 0.47-0.93), but the interpretation of these results is complicated by co-interventions. A third, clinic-based, study reported a case-fatality ratio of 3.3% among neonates treated with injectable antibiotics as outpatients. No studies were identified evaluating injectable antibiotics alone for neonatal pneumonia. Delphi consensus (median from 20 respondents) effects on sepsis-specific mortality were 30% reduction for oral antibiotics, 65% for injectable antibiotics and 75% for injectable antibiotics on pneumonia-specific mortality. No trials were identified assessing effect of hospital management for neonatal infections and Delphi consensus suggested 80%, and 90% reductions for sepsis and pneumonia-specific mortality respectively.

Oral antibiotics administered in the community are effective for neonatal pneumonia mortality reduction based on a meta-analysis, but expert opinion suggests much higher impact from injectable antibiotics in the community or primary care level and even higher for facility-based care. Despite feasibility and low cost, these interventions are not widely available in many low income countries.

This work was supported by the Bill & Melinda Gates Foundation through a grant to the US Fund for UNICEF, and to Saving Newborn Lives Save the Children, through Save the Children US.

Deaths occurring in the neonatal period each year account for 41% (3.6 million) of all deaths in children under 5 years [ 1 ]. The majority of these deaths occur in low income countries and almost 1 million of these deaths are attributable to infectious causes including neonatal sepsis, meningitis and pneumonia [ 1 ]. These deaths occur because of lack of preventive care (clean birth care, breastfeeding) and appropriate case management [ 2 ]. Delays in treating neonatal infections of even a few hours may be fatal. Delays in illness recognition and care seeking, a dearth of primary health care providers, and limited access to facility care contribute to these deaths [ 3 ]. Recent trials have demonstrated the effect of community-based packages for prevention and treatment of neonatal bacterial infections, with the potential to save many lives [ 4 , 5 ].

Therapy with appropriate antibiotics and supportive management in neonatal nurseries is the cornerstone of management of neonatal sepsis and pneumonia, with strong biological plausibility that such therapy saves lives. Yet the quality of evidence is understandably affected by the ethical impossibility of undertaking randomized trials of antibiotic management compared with no antibiotic management. Nevertheless, given the limited access to care for sick neonates in low income countries, it is important to assess the potential mortality effect of oral antibiotics and injectable antibiotics delivered in domiciliary or primary care settings. Case management for hospitalized neonates is more expensive, but to guide policy and program investments we also need to know how much more effective it is compared to care delivered at home or in primary care settings.

The objective of this review is to provide estimates of the effectiveness of three interventions in preventing neonatal deaths from severe infection: (i) case management with oral antibiotic therapy alone for pneumonia and sepsis; (ii) case management with injectable antibiotics (± oral antibiotics) as an outpatient or at home for neonatal sepsis /meningitis and pneumonia; and (iii) hospital-based case management, including injectable antibiotics, intravenous fluids, oxygen therapy, second line injectable antibiotics if needed, and other supportive therapy (Table 1 ). These mortality effect estimates are used in the Lives Saved Tool (LiST) software, a user-friendly tool that estimates the number of lives saved by scaling up key interventions and helps in child survival planning in low income countries [ 6 , 7 ].

We searched all published literature as per CHERG systematic review guidelines[ 7 ]. Databases searched were PubMed, Cochrane Libraries and WHO regional databases from 1990 until April 2009 and included publications in any language (Figure 1 ). Search terms included various combinations of: sepsis, meningitis and pneumonia. For sepsis and pneumonia management at a hospital level we conducted two parallel searches (Figures 2 and 3 ). These were broader as we also wanted to identify studies reporting incidence and case fatality ratios (CFR) for a related study on global burden of neonatal sepsis. Titles and abstracts were reviewed and studies were included if data on one of the following outcomes was provided: all-cause mortality, sepsis/meningitis/pneumonia mortality and/or CFR. Furthermore, extensive efforts were made to contact investigators and program managers for unpublished data.

Searches and screening for community based management of sepsis and pneumonia.

Searches and screening for hospital management of sepsis

Searches and screening for hospital management of pneumonia.

Inclusion/exclusion criteria, abstraction

We reviewed all available observational studies, randomized controlled trials, systematic reviews, and meta-analyses, which included neonates and principally involved the management of serious neonatal infections. The search was limited to “humans”. We examined studies published from 1990 until April 2009.

We included randomized controlled trials, studies with concurrent controls, and observational studies with no control group if mortality outcomes were reported. All studies meeting final inclusion criteria were double data abstracted into a standardized form. We abstracted key variables with regard to the study identifiers and context, study design and limitations, intervention specifics, and mortality outcomes. We assessed the quality of each of these studies using a standard table employing an adapted version of GRADE[ 8 ] developed by the Child Health Epidemiology Reference Group (CHERG) [ 7 ]. For studies which reported mortality outcomes that were not neonatal specific, we contacted the authors to request the neonatal-specific data. All studies that were coded are included in Additional File 1 .

Case definition of sepsis

During our review of selected studies we were unable to find a standard definition for clinical neonatal sepsis or pneumonia (Table 2 ). Each study used different criteria although most are a variation on WHO IMCI approach. We therefore decided to accept authors’ definitions of sepsis and pneumonia, recognizing that these non-specific definitions lower mortality outcome estimates as many “non-sepsis” cases are included in an effort to maximize sensitivity.

Analyses and summary measures

All studies reporting mortality data for pneumonia and sepsis management, in community and hospital settings, were summarized according to the overall quality of evidence for each outcome and each data input type using an adapted version of the GRADE 21 protocol table [ 7 ]. When appropriate, we conducted meta-analyses to obtain pooled estimates of the risk ratios, using either the Mantel-Haenzsel or, when there was evidence of heterogeneity, the DerSimonian-Laird random effects estimator. 95% confidence intervals (CI) were also calculated. Statistical analyses were performed using STATA 10.0 ( http://www.stata.com ).

Delphi Process for Establishing Expert Consensus

For intervention-outcome combinations for which we did not identify moderate quality evidence, we sought expert consensus via the Delphi method. Individuals invited to participate were experts in newborn health and sepsis representing six WHO regions (South Asia, Africa, Western Europe, Eastern Europe, North America, Australia), and including multiple disciplines - international health, pediatric infectious diseases, clinical neonatology, and general pediatrics. Twenty (of twenty-three experts invited) agreed to participate in the Delphi process. The questionnaire was developed by JL, AZ, SC and SS, and refined after several rounds of pilot testing. The questionnaire was sent by email and included the background and aims of the Delphi and estimates of effect that were available from the literature for different scenarios. The median response and range were determined for each question. Consensus was defined a priori as an interquartile range in responses of not more than 30% for each question. For those estimates not reaching consensus, the plan was for results to be electronically distributed to the panel, virtual discussion allowed, and a second round of email questionnaires sent. However, consensus was achieved after one round of questionnaires and subsequent rounds were not necessary.

Studies identified

Our systematic searches for community management of sepsis and pneumonia identified 2876 titles (Figure 1 ) and after screening of titles, abstracts and relevant full texts, we located 7 studies of interest (reported in 8 papers) [ 9 – 16 ]. We identified 4 non randomised concurrently controlled studies, which evaluated oral antibiotics for pneumonia (Table 5 ) [ 10 , 14 – 16 ]. Three of these studies did not report disaggregated neonatal outcomes in the primary papers, but neonatal outcomes were available through abstracted forms from an earlier meta-analysis by Sazawal et al [ 17 ]. For management of neonatal sepsis using injectable antibiotics, we located 3 studies (reported in 4 papers) [ 9 , 11 – 13 ]. There was one observational primary clinic-based study without a control group [ 13 ], one RCT [ 12 ] and one non-randomised, concurrently controlled study [ 9 ]. The fourth paper reported observational data from individual infants evaluated during the RCT mentioned above and was not a separate study [ 11 ]. All the studies were from high neonatal mortality regions.

In our search for hospital-based studies of sepsis we found 55 studies from a total pool of 13998 studies which reported sepsis and/or meningitis mortality outcomes (Figure 2 ) [ 18 – 70 ]. For pneumonia, we found two studies from a total pool of 94 studies (Figure 3 ) [ 71 , 72 ].

The details of each study and quality assessment using GRADE are summarised in Tables 3 , 4 , 5 , and 6 .

Evidence for effectiveness of oral antibiotic therapy alone

Unpublished neonatal data were obtained from the principal investigators of the four studies identified and a new meta-analysis was done to update that of Sazawal et al[ 17 ]. We performed meta analyses for two outcomes: oral antibiotics were associated with reductions in both all-cause mortality (4 studies [ 10 , 14 – 16 ]: RR 0.75 95% CI 0.64- 0.89) (Figure 4 ) and pneumonia-specific mortality (3 studies [ 10 , 15 , 16 ]: RR 0.58 95% CI 0.41- 0.82) (Figure 5 ). Limitations included non-randomization, estimation of intervention coverage as precise coverage estimates were not available;and variability between studies of the intensity of co-interventions. We found no studies of the effect of oral antibiotics on sepsis-specific mortality. The Delphi consensus (median) was for a 28% reduction in sepsis-specific mortality with an interquartile range of 20% to 36.25% (Figure 6 ).

Meta-analysis of observational studies comparing oral antibiotics versus none in the community setting for babies: All cause mortality. Legend: Heterogeneity chi-squared = 1.17 (d.f. = 3) p = 0.760 I-squared (variation in RR attributable to heterogeneity) = 0.0% Test of RR=1 : z= 3.32 p = 0.001

Meta-analysis of observational studies comparing oral antibiotics versus none in the community setting for babies: Pneumonia mortality. Legend: Heterogeneity chi-squared = 2.16 (d.f. = 2) p = 0.339 I-squared (variation in RR attributable to heterogeneity) = 7.5% Test of RR=1: z= 3.06 p = 0.002

Box plot of Delphi expert opinion estimates of reduction in neonatal cause specific mortality due to pneumonia and sepsis/meningitis

Evidence for effectiveness of injectable antibiotic therapy (±oral antibiotics)

Three studies reported in four papers, were identified (Table 6 ) [ 9 , 11 – 13 ]. One, an RCT[ 12 ] evaluated the impact of a perinatal care package which included the administration of injectable antibiotics in domiciliary settings in situations where referral to hospital was not possible. This trial reported a reduction in all-cause neonatal mortality of 34% (RR=0.66, 95%CI 0.47-0.93). A second paper from the same study reported that the CFR for neonates who were evaluated and actually treated with injectable antibiotics was 4.4% [ 11 ]. A non-randomized, concurrently controlled study [ 9 ] also evaluated the impact of a home-based neonatal care package in which septic neonates were treated with injectable antibiotics when referral to hospital was not possible. The overall mortality reduction in the intervention arm of the trial was calculated to be 44% (RR=0.56 95% CI 0.41-0.77). A third, uncontrolled study [ 13 ] based in a primary care clinic reported a CFR of 3.3% among septic children treated with injectable antibiotics.

In both of the community-based studies [ 9 , 12 ] injectable antibiotics were only one component of comprehensive community-based newborn care packages, and therefore the effectiveness of injectable antibiotics alone in the community cannot be reliably estimated. The Delphi consensus for the effect of injectable antibiotics was for a 65% reduction (interquartile range of 50-70%) in sepsis-specific mortality and 75% reduction (interquartile range of 70-81.25%) in pneumonia-specific mortality in community-based settings (Figure 6 ).

Evidence for effectiveness of inpatient hospital case management

We found no trials assessing the impact of hospital-based case management and the observational studies of hospital management showed wide variation in effect. Searches conducted for studies reporting CFRs in neonates with pneumonia in health facilities revealed very few data. Two studies were identified with author-defined neonatal pneumonia; both were from low income, non-industrialised settings and reported CFRs of 14.4% [ 72 ] and 30.8% [ 71 ].

CFRs for neonatal sepsis, adjusted for the proportion of very low birth weight babies in the study, were plotted against national percentage skilled delivery, as a proxy for access to hospital-based case management of neonatal sepsis. In countries with a high proportion of births attended by skilled attendants, the predicted CFR for sepsis was 9.5%, whereas in countries with a low proportion (<30%) skilled birth attendance, the predicted CFR for sepsis with hospital care is 20-30% (Figure 7 ). A 68% reduction in the CFR for neonatal sepsis is predicted as one moves from 0% to100% skilled birth attendance. This reduction is likely to under estimate the effect of hospital-based case management since skilled birth attendance is likely to be a poor surrogate for effective facility case management of neonatal infections, but was used in the absence of coverage data for case management

Plot of neonatal sepsis CFR versus percent skilled delivery as a marker of access to facility care. Model fitted: outcome = log(CFR) Covariates = Skilled attendant coverage and % babies vLBW Fitted line is predicted CFR for settings with % VLBW<30%. Predicted CFR at 0% skilled attendance is 30%. Predicted CFR at 100% skilled attendance is 9.5%. % reduction = 68.5% Coefficient skilled attendance is 0.12 on the log scale (95% CI -0.02 to -0.007); i.e. for each 1% increase in skilled attendance rate CFR is reduced by 1.1% (95% CI: 0.7% to 1.6%)

Although the quality of evidence is low according to GRADE criteria, the recommendation for case management of neonatal infections is strong, and this is standard practice globally. Table 7 provides a summary of the effect of case management on neonatal sepsis and pneumonia cause specific mortality, and GRADE of the estimate. Therefore the Delphi process was used to provide estimates for the effect of hospital care. The Delphi consensus was for a 80% reduction in sepsis-specific mortality (interquartile range 75% to 85%), and a 90% reduction in pneumonia-specific mortality (interquartile range 88.75% to 95%) (Figure 6 ).

Infections including sepsis, meningitis and pneumonia are responsible for almost a million neonatal deaths annually. Neonates are more susceptible to severe infections and the progression of disease is more rapid due to developmental immunodeficiency, resulting in high CFRs. Also, a significant proportion of infections may arise early, after vertical transmission from the mother [ 73 ]. Therefore, timely identification and appropriate management with antibiotics is an important strategy to reduce the burden of neonatal mortality due to infections. We have previously reported the evidence from observational and experimental studies in low income countries for community-based management of neonatal infections (pneumonia and sepsis) with oral and injectable antibiotics [ 74 – 76 ]. We have now undertaken a systematic review of available evidence, including from industrialized countries and facility settings, and where the quality of evidence is low we have undertaken a Delphi expert process to estimate the cause-specific mortality effect.

This review of effectiveness of the interventions is shaped in large part by the needs of the LiST model. In that model, increasing coverage of an intervention results in a reduction in deaths due to one or more specific causes or in reduction of a risk factor. Therefore the reviews and the GRADE process used were designed to develop estimates of the effect of an intervention in reducing death due to specific causes. For more details of the review methods, the adapted GRADE approach or the LiST model see related publications [ 6 , 7 ].

To our knowledge, this is the first review providing effectiveness estimates for case management options to reduce neonatal deaths due to neonatal sepsis/meningitis and pneumonia, in both community and facility settings. Theodoratou et al have previously estimated effectiveness of pneumonia case management in children under 5 years but they did not disaggregate neonatal mortality data from later child mortality [ 77 ]. The estimated effect of community case management on pneumonia mortality in children under 5 years of age in the analysis by Theodoratou et al is 70% (77). Oral antibiotics in community settings for neonatal pneumonia in our analysis were associated with a 42% reduction in pneumonia-specific mortality and a 25% reduction in all-cause neonatal mortality based on a meta-analysis of available trials. There is no evidence to estimate the effect of oral antibiotics on sepsis-specific mortality, but our Delphi process suggested a 28% reduction. Delphi-derived estimates for the effects of management using injectable antibiotics delivered in home or primary care settings came out at 65% for sepsis-specific mortality and 75% for pneumonia-specific mortality. These estimates are biologically plausible and consistent with published studies [ 9 , 12 ] which reported reductions in all-cause neonatal mortality (sepsis plus other causes) of 34% and 44% respectively with community-based packages including injectable antibiotics. CFRs reported from observational studies of hospital case management varied widely, from 6.7 to 67%. Our Delphi estimates suggested an 80% mortality reduction in sepsis deaths and a 90% reduction in pneumonia deaths with hospital case management.

There were 4 effectiveness trials assessing the impact of oral antibiotics on pneumonia-specific mortality in the community. Only one of these studies was randomized and the programmatic coverage of the intervention had to be estimated as coverage data were not routinely assessed or reported. The selection and intensity of co-interventions was not uniform between the studies. An additional limitation was the lack of clearly defined cause-of-death definitions by the authors. However, the effect sizes were remarkably consistent with each other, and therefore the evidence level was upgraded to moderate.

GRADE guidelines rank the evidence relating to the effect of injectable antibiotics on sepsis-specific mortality as low quality. The 3 studies identified were not uniform with respect to study designs; one was an effectiveness RCT, one was a non-randomized concurrent trial and the third was an observational study describing the experience from primary care clinic without a control group. Both the RCT [ 12 ] and the non-randomized concurrent trial[ 9 ], involved concurrent co-interventions alongside the administration of injectable antibiotics. This made it impossible to assess the impact of injectable antibiotics alone on sepsis mortality. Neither study reported the change in the sepsis-specific mortality rate in the intervention arm compared to control arm, and reported the impact on all-cause neonatal mortality only. The absence of randomization in one of the trials is a further limitation [ 9 ]. The main limitation to the observational study in a primary care clinic [ 13 ] was the absence of a control arm in the study.

We identified no controlled trials assessing the effect of hospital-based case management of neonatal infections. Such studies would be difficult or impossible to implement in an ethical fashion. Thus studies were limited to reporting CFRs for neonatal sepsis and meningitis. The studies were from varied settings, from both industrialized and low income countries, and reported widely varying CFRs. Only 2 of these observational studies reported CFRs for pneumonia. One of these studies reported a very high CFR for pneumonia due, we believe, to the high proportion of LBW babies in the sample (60%).

We found some moderate quality evidence for intervention packages including antibiotics in community settings but ironically data are most lacking at facility level, and district hospital level is a critical gap [ 78 ]. Unlike the LiST review on neonatal resuscitation which identified several before-after studies of facility based neonatal resuscitation reporting mortality data, we were unable to find similar before-after studies on the effect of hospital-based case management of sepsis/meningitis/pneumonia. An understandable reason for this might be the ethical constraints precluding such studies. However, historical reviews from the pre-antibiotic era provide an insight into the CFR associated with untreated sepsis in facility settings. The best available evidence comes from the series of papers from Yale Medical Center reporting time trends for neonatal sepsis. These data show that in the 1920s and 1930s the CFR for blood culture confirmed sepsis stood at 90% [ 79 , 80 ]. With the introduction of antibiotics, the CFR decreased to 45% by 1965 [ 81 ], and with the subsequent introduction of intensive care units and advanced life support it came down to 16% by 1988[ 82 ], and 3% by 2003[ 83 ]. Such data highlight the effectiveness of hospital-based management in preventing neonatal mortality from sepsis.

As evident from our results, even oral or injectable antibiotics alone are highly effective in reducing deaths from neonatal sepsis or pneumonia. These interventions hold great potential to reduce the 1 million neonatal deaths each year. If substantial reduction in neonatal mortality is desired, both, community and facility-based interventions are required, linked by functioning referral systems, giving the potential to prevent hundreds of thousands of avoidable newborn deaths every year.

This work was supported in part by a grant to the US Fund for UNICEF for Child Health Epidemiology Reference Group from the Bill &Melinda Gates Foundation (grant 43386) to “Promote evidence-based decision making in designing maternal, neonatal and child health interventions in low- and middle-income countries”, and by a grant to Save The Children USA from the Bill & Melinda Gates Foundation (Grant 50124) for "Saving Newborn Lives".

Abbreviations

Case Fatality Rate

Child Health Epidemiology Reference Group

Integrated Management of Childhood Illnesses

Lives Saved Tool

Randomized Controlled Trial.

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Acknowledgements

We are grateful to Rajiv Bahl for insightful review of an earlier draft of this paper. We are also grateful to the members of the Delphi Expert Panel including Rajiv Bahl, Abhay Bang, Abdullah Baqui, Zulfiqar Bhutta, Robert Black, Simon Cousens, Gary Darmstadt, Mike English, Luis Huicho, David Isaacs, Joy Lawn, Patrick Mark, Kim Mulholland, David Osrin, Vinod Paul, Igor Rudan, Cindy Stephen, Barbara Stoll, Steven Wall and Anita Zaidi.

This article has been published as part of BMC Public Health Volume 11 Supplement 3, 2011: Technical inputs, enhancements and applications of the Lives Saved Tool (LiST). The full contents of the supplement are available online at http://www.biomedcentral.com/1471-2458/11?issue=S3 .

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Anita K M Zaidi, Hammad A Ganatra, Sana Syed & Zulfiqar A Bhutta

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AZ and JL planned the review, SS and AZ undertook the searches and abstraction with input from JL and HG. SC undertook the meta-analyses. RB provided unpublished data from a previous investigator working group. JL, AZ and ACCL planned the Delphi. All authors contributed to the manuscript.

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Zaidi, A.K.M., Ganatra, H.A., Syed, S. et al. Effect of case management on neonatal mortality due to sepsis and pneumonia. BMC Public Health 11 (Suppl 3), S13 (2011). https://doi.org/10.1186/1471-2458-11-S3-S13

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Clinical characteristics of hospitalized term and preterm infants with community-acquired viral pneumonia

• Xinxian Guan 1   na1 ,
• Shasha Gao 1   na1 ,
• He Zhao 2 ,
• Huiting Zhou 2 ,
• Yan Yang 1 ,
• Shenglin Yu 1 &
• Jian Wang 2  

BMC Pediatrics volume  22 , Article number:  452 ( 2022 ) Cite this article

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Pneumonia is a serious problem that threatens the health of newborns. This study aimed to investigate the clinical characteristics of hospitalized term and preterm infants with community-acquired viral pneumonia.

This was a retrospective analysis of cases of community-acquired viral pneumonia in the Neonatal Department. Nasopharyngeal aspirate (NPA) samples were collected for pathogen detection, and clinical data were collected. We analysed pathogenic species and clinical characteristics among these infants.

RSV is the main virus in term infants, and parainfluenza virus (PIV) 3 is the main virus in preterm infants. Patients infected with PIV3 were more susceptible to coinfection with bacteria than those with respiratory syncytial virus (RSV) infection ( p  < 0.05). Preterm infants infected with PIV3 were more likely to be coinfected with bacteria than term infants ( p  < 0.05), mainly gram-negative bacteria (especially Klebsiella pneumonia). Term infants with bacterial infection were more prone to fever, cyanosis, moist rales, three concave signs, elevated C-reactive protein (CRP) levels, respiratory failure and the need for higher level of oxygen support and mechanical ventilation than those with simple viral infection ( p  < 0.05). The incidence of hyponatremia in neonatal community-acquired pneumonia (CAP) was high.

Conclusions

RSV and PIV3 were the leading causes of neonatal viral CAP. PIV3 infection is the main cause of viral CAP in preterm infants, and these individuals are more likely to be coinfected with bacteria than term infants, mainly gram-negative bacteria. Term infants with CAP coinfected with bacteria were more likely to have greater disease severity than those with single viral infections.

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Introduction

Pneumonia is one of the most common infectious diseases in the neonatal period and accounts for 46% of all neonatal diseases [ 1 ]. Moreover, the mortality rate of pneumonia is 1.2%, which ranks highest among all neonatal infectious diseases; thus, pneumonia is a serious problem that threatens the health of newborns [ 2 ]. The main pathogens of neonatal pneumonia are bacteria, viruses, and fungi [ 3 ]. In recent years, many studies of bacterial pneumonia in neonates have been published [ 4 ], but information on viral pneumonia in neonates is limited. Many viruses can damage the airway epithelial layer, thus increasing the likelihood of both adherence to the respiratory tract and bacterial translocation, two of the critical first steps in causing infection [ 5 ]. Viruses can also lead to dysfunction of the immune system, thereby promoting bacterial infection [ 6 ]. We retrospectively analysed all preterm and term neonates with community-acquired viral pneumonia over a 5-year period to study the aetiology and clinical features of these infants.

Materials and methods

The present study was a retrospective analysis of newborn patients with community-acquired viral pneumonia. The general clinical data, clinical signs and symptoms, auxiliary examination results, complications and prognoses were collected and analysed from the hospital medical records system.

The inclusion criteria were as follows: the patients were hospitalized in the Neonatal Department of Children’s Hospital of Soochow University (Suzhou, China) between January 2017 and December 2021 and were diagnosed with community-acquired pneumonia (CAP); and the aetiology of these cases must be positive for respiratory syncytial virus (RSV), adenovirus, influenza virus (Inf) A, Inf B, or parainfluenza virus (PIV1, PIV2, and PIV3).

The exclusion criteria were as follows: patients with incomplete clinical data and severe basic diseases, such as congenital heart disease, congenital immunodeficiencies and incomplete medical data [ 7 , 8 ].

Diagnostic criteria and data collection

CAP refers to clinical signs and symptoms of pneumonia acquired outside a hospital setting [ 9 ] and is diagnosed based on clinical findings (fever, cough, and difficulty in breathing), physical examination findings (tachypnoea, chest retraction, and decreased breath sounds or rales), and radiological findings [ 10 ]. Chest radiographs were evaluated by a radiologist trained in reading and interpreting radiographs according to the World Health Organization’s (WHO) guidelines [ 11 ]. Respiratory failure is defined as the failure to maintain either normal delivery of oxygen to the tissues or normal removal of carbon dioxide from the tissues. Respiratory failure occurs when there is an imbalance between the respiratory workload and ventilatory strength and endurance. The suggested cutoffs for diagnosing respiratory failure include two or more of the following: PaCO2 > 60 mmHg, PaO2 < 50 mmHg or O2 saturation < 80% with an FiO2 of 1.0 and pH < 7.25 [ 12 ]. Heart failure (HF) is defined as the failure of the heart when it supplies blood to either systemic or pulmonary circulation at an appropriate rate of flow, or to receive venous return at an appropriate filling pressure, but produces adverse effects on the heart, the circulation, and the patient [ 13 ]. The diagnosis and treatment of HF are based on Canadian Cardiovascular Society Guidelines [ 13 ]. Pulmonary air leak syndrome (PALS) comprises several different clinical conditions, such as pulmonary interstitial emphysema (PIE), pneumomediastinum, pneumothorax and pneumopericardium, which all results from alveolar over distension and air leakage outside the lungs [ 14 ]. In this study, PALS is comprised of pneumothorax and pneumomediastinum. The treatment of mechanical ventilation (MV) in this research includes invasive MV and non-invasive ventilation (NIV), and invasive MV includes high frequency oscillatory ventilation (HFOV) and conventional mechanical ventilation (CMV).

Pathogen testing

Nasopharyngeal aspirates (NPA) were collected under strict aseptic operations within 24 h from all hospitalized patients ( n  = 375) to identify the pathogen. The samples were divided into three subsamples for pathogen detection. One subsample was used to detect seven common respiratory viruses as previously described by direct immunofluorescence analysis, and the remaining two subsamples were used to detect and identify bacteria using bacterial culture and Mycoplasma by using PCR analysis. The study period overlapped with coronavirus disease 2019 (COVID-19) pandemic, COVID-19 real-time polymerase chain reaction (RT-PCR) test was performed by nasopharyngeal swab method for the infants from March 2020 to December 2021( n  = 89).

Immunofluorescence analysis for respiratory virus pathogen detection

A total of 1–2 mL of NPA was mixed with PBS and centrifuged at (400–600) × g for 15 min. Then, the supernatant was discarded, and the remaining sample was washed three times with PBS (5 mL). PBS (0.5 to 1 mL) was added after centrifugation to make the cell suspension. Subsequently, seven wells (25 μL/well) were spotted on the slide, air-dried at room temperature, and fixed in cold acetone for 10 min. Then, 20 μL of immunofluorescent reagent (containing fluorescein-FITC-labelled monoclonal antibody) was added to each of the wells. After incubation at 37 °C for 30 min and rinsing 3 times with PBS, the glycerol buffer solution was air-dried and ready for further analysis. Seven common respiratory viruses (including RSV, adenovirus, InfA, Inf B, PIV1, PIV2, and PIV3) were detected by direct immunofluorescence analysis. A positive negative control is provided by the kit (D3 Ultra DFA respiratory virus screening and identification kit, Athens, Ohio, USA). Bright yellow–green fluorescence and/or fluorescent spots in the nucleus/cytoplasm were considered positive.

RT-PCR for COVID-19

Laboratory confirmation of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) RNA was performed by RT-PCR. Briefly, according to the manufacturer’s instruction, we extracted the nucleic acid from nasopharyngeal swab samples by using the Viral Nucleic Acid Kit (Health, Ningbo, China). We also used COVID-19 detection kits (Bioperfectus, Taizhou, China) in detecting the ORF1ab and the N genes. At the same time, we adopted the procedure of RT-PCR assay from the WHO protocol (2020b). A positive test was defined as a cycle threshold value (Ct value) less than 35 and laboratory confirmation of COVID-19 was based on the positive results for both ORF1ab and the N genes.

Bacterial culture for bacterial detection

Bacteria were tested by inoculating NPA samples on blood plates that were read after incubating for 18–20 h. If bacterial growth was > 10 4 colony forming units/mL, it was considered significant. Morphology selection depended on experienced clinical laboratory physicians.

PCRs for Mycoplasma

Mycoplasma pneumoniae were detected by PCR. NPA samples were centrifuged at 12,000 × g for 5 min. DNA was obtained from the NPA samples (200 μL) using DNA-EZ Reagents (Sangon Biotech, Shanghai, China) in accordance with the manufacturer’s instructions. A final volume of 100 μL containing DNA was eluted for detection of Mycoplasma pneumoniae gene amplification via real-time PCR.

Statistical analysis

Statistical analysis was performed using SPSS v.17.0 for Windows (SPSS Inc., Chicago, IL). Normally distributed data are expressed as the mean ± standard deviation, and nonnormally distributed data are expressed as the median and interquartile range. Normally distributed data were compared using the independent samples t test, and nonnormally distributed data were compared using the Kruskal–Wallis test. Categorical data are presented as numbers and percentages. The chi-square and Fisher exact tests were used to compare categorical data. All tests were two-tailed, and P  < 0.05 was considered statistically significant.

Three hundred seventy-five newborns were enrolled and retrospectively analysed in this study. No deaths were reported. There were 248 males and 127 females. Of the 375 patients, 344 were term infants, and 31 were preterm infants. All term infants were younger than 28 days old at admission. The postmenstrual age (PMA) of all preterm infants was less than 44 weeks after birth.

Comparison of pathogens in preterm and term infants

Of the 375 community-acquired viral pneumonia cases, 140 patients were coinfected with bacteria, 3 patients were coinfected with mycoplasma. The types of bacteria included Staphylococcus aureus ( n  = 42), Escherichia coli ( n  = 32), Klebsiella pneumoniae ( n  = 22), Streptococcus viridans ( n  = 20), Moraxella catarrhalis ( n  = 13), Aerobacter cloacae ( n  = 5), Enterobacter aerogenes ( n  = 3) , Haemophilus influenzae ( n  = 2) and Proteus mirabilis ( n  = 1). All admitted infants through the pandemic were tested negative for COVID-19.

Full-term infants were more likely to be infected with RSV than preterm infants ( p  < 0.001). Preterm infants were more likely to be infected with PIV3 than term infants ( p  < 0.001). In addition, preterm infants were more likely to be coinfected with bacteria than term infants ( p  < 0.001), especially Gram-negative bacteria ( p  < 0.001), such as Klebsiella pneumoniae ( p  < 0.001) (Table 1 ).

In all cases of community-acquired viral pneumonia, regardless of the viral infection, newborns with coinfection, especially bacterial infection, were more prone to respiratory failure (43/140). The probability of respiratory failure in children with simple virus infection (30/232) was lower (χ2 = 17.51, p  < 0.001) than in those coinfected with bacteria (Table 2 ).

The distribution of virus species and monthly distribution of respiratory virus detection

Among the 375 enrolled patients, 322 were infected with RSV alone (85.9%), 2 were infected with both RSV and Inf A (0.5%), 1 was infected with both RSV and PIV3 (0.3%), 35 were infected with PIV3 alone (9.3%), 10 were infected with Inf A alone (2.7%) and 5 were infected with Inf B alone (1.3%). No patient was infected with adenovirus, PIV1 or PIV2. RSV infection mainly occurred in January, February, November and December, which showed obvious seasonal prevalence. However, PIV3 infection did not show significant seasonal prevalence (Fig.  1 ).

Monthly distribution of CAP in neonates with RSV and PIV3 infection

Patients infected with PIV3 were more prone to co-infection with bacteria than those with RSV infection. Preterm infants were more susceptible to co-infection with bacteria than term infants

In all children with community-acquired viral pneumonia, their combined bacterial infection was compared. One child with mixed infection of RSV and PIV3 was excluded because he had no bacterial infection. The prevalence of RSV pneumonia complicated with bacterial infection was 33.0% (107/324), and the prevalence of PIV3 pneumonia complicated with bacterial infection was 60% (21/35). Because the total number of children with other types of viral (Inf A and Inf B) pneumonia was small, statistical analysis was carried out together, and the prevalence of combined bacterial infection was 80% (12/15). Statistical analysis showed that patients infected with PIV3 and other viruses were more likely to be coinfected with bacteria than patients infected with RSV ( p  < 0.05). Among RSV-infected patients, preterm infants were more likely to be complicated ( p  < 0.01) with bacterial infection than term infants. The same trend was found in PIV 3-infected infants ( p  < 0.05) (Fig.  2 ) .

The proportion of coinfection with bacteria of different viruses in preterm and term infants

Clinical characteristics of coinfected with bacteria in term infants and premature infants with viral pneumonia

Of the 375 patients with community-acquired viral pneumonia, two cases of coinfection with mycoplasma in term infants and one case of coinfection with mycoplasma in preterm infants were excluded from the analysis. Therefore, the clinical features of coinfection with bacteria among term infants (342 cases) and premature infants (30 cases) with viral pneumonia are summarized in Table 2 . The percentage of coinfection with bacteria was different between term and preterm infants ( p  < 0.05). There were 117 term infants coinfected with bacteria (117/342), and there were 23 preterm infants coinfected with bacteria (23/30). Our results suggested that premature infants are more likely to be complicated with bacterial infection.

For laboratory tests, the white blood cell (WBC) count was not affected by coinfection with bacteria in term or preterm infants. The proportion of neutrophils to WBCs was not different between term infants with coinfection with bacteria and those with simple virus infection. However, in preterm infants, the prevalence of neutrophils to WBCs was different between those with coinfection with bacteria and those with simple virus infection. The level of C-reactive protein (CRP) in term infants was different between those with coinfection with bacteria and those with simple virus infection. The level of CRP was not affected in preterm infants with co-infection with bacteria and those with simple virus infection.

In the term infant group, children with bacterial infection are more likely to have fever and cyanosis symptoms than children with simple virus infection. The three concave signs are more obvious among term infants with bacterial infection, their CRP values are higher ( p  < 0.01), they are more likely to be complicated with respiratory failure, and they are more likely to need oxygen support and mechanical ventilation treatment, including invasive and non-invasive mechanical ventilation. The signs of pulmonary moist rales in children with simple virus infection were significantly more common than those in children with bacterial infection.

In the preterm infant group, the hospitalization time of infants with bacterial infection was longer than that of infants with simple virus infection, and the prevalence of neutrophils to WBC was lower ( p  < 0.014) than that of infants with simple virus infection.

Neonatal immune dysfunction, as well as neonatal lung development, is not fully developed and vulnerable to the invasion of external pathogens [ 15 ]. Pathogens can be transmitted to newborns through droplets and contact [ 16 ]. Because of the complexity of the community environment and the variation in regions and seasons, the distribution of pathogens also differs. In addition, the incidence of disease increases rapidly, which is the focus of current research [ 17 ].

In our study, the peak incidence of RSV pneumonia occurred during the winter and early spring. Similar results were reported in our previous study with a subtropical climate [ 18 , 19 ], and the peak of RSV activity was in the winter and spring seasons [ 19 ].

In Suzhou, China, the infection rate of COVID-19 was low, epidemic data is obtained from the Sina Real-Time Epidemic website ( https://news.sina.cn/zt_d/yiqing0121 ) [ 20 ]. We had tested hospitalized children for SARS-CoV-2 and there were no positive cases during study period. The current research showed that RSV and PIV3 were the major viral pathogens in neonatal community-acquired viral pneumonia, especially RSV. Few patients were infected with InfA or InfB. RSV was the main virus in term newborns. PIV3 was the main virus in preterm infants. Unfortunately, there are currently no vaccines available against pathogens (RSV, PIVs, influenza virus) for infants under 6 months of age [ 21 ]. In newborns, especially in preterm infants, palivizumab is the only licenced treatment to help reduce the burden of RSV [ 22 ]. Unfortunately, palivizumab use is limited in the Suzhou area. Additionally, Preterm infants are more likely to co-infect with bacteria than term infants, especially gram-negative bacteria, such as Klebsiella pneumoniae . Therefore, in clinical work, we can preliminarily distinguish potential pathogens for newborns with CAP based on whether they are preterm or term infants and thus select the targeted treatment schemes.

In the present study, patients with PIV3 infection were more likely to be infected with bacteria than patients with RSV infection (60.0% vs. 33.0%). Additionally, patients with other virus (InfA, InfB) infections were more likely to be infected with bacteria than patients with RSV infections (80.0% vs. 33.0%). Among RSV-infected patients, preterm infants were more likely to be complicated with bacterial infection than term infants, and the same trend was found in PIV3-infected infants. This result suggested that preterm infants are more susceptible to coinfection with bacteria than term infants. Therefore, in the clinic, when treating patients with PIV3 and other virus (InfA, InfB) infections or preterm infants, we should be alert to the possibility of combined bacterial infection and relax the indications for the use of antibiotics on the basis of support and symptomatic treatment. For patients with RSV infection, antibiotics should be used as soon as a concurrent bacterial infection is detected.

Not everyone with neonatal viral pneumonia will have prodromal symptoms, as the incidence of these symptoms usually varies between 30 and 65% depending on the pathogen [ 23 ]. In this study, patients with mild infections only showed symptoms of mild cough and low fever, while patients with severe infections had serious cough, high fever, apnoea, cyanosis, tachypnoea, refusal to feed, vomit or diarrhoea, three concave signs, increased moist rales, wheezing in the lungs, and complications with respiratory failure, HF and PALS.

This study also showed that preterm infants are more susceptible to coinfection, especially for bacteria, which is related to the lower immune function of preterm infants than that of term infants [ 24 , 25 ]. The trachea of premature infants is narrow, and the wall of the trachea easily collapses. The abundant capillaries and weak ciliary movement function provide a good environment for the attachment and reproduction of pathogenic bacteria [ 26 ]. Because the immune system of premature infants is not fully developed, their immune function is low [ 27 , 28 ]. Neonatal immune function, especially that of the local airway, is also underdeveloped with lower levels of secretory IgA, which serves an anti-infectious role [ 29 ]. Foetal immunoglobulins are mostly transmitted from the mother, but this physiological process mainly occurs in the middle and late stages of pregnancy. The IgG level of full-term newborns can reach the maternal level [ 30 ]. Respiratory virus infection is often accompanied by bacterial infection [ 31 ]. Because the humoral and cellular immunity of premature infants at small gestational age are at a low level [ 24 ], the damaged respiratory mucosa and inhibited immune function by respiratory viruses induce the risk of bacterial infection. Therefore, newborns are more easily infected by a variety of pathogens. Therefore, targeted measures, such as perinatal detection and health care, should be taken to reduce the birth of premature infants. When pneumonia occurs in premature infants, corresponding treatment measures, including respiratory support, immune support, enteral nutrition, parenteral nutrition support and sodium supplements, should be actively adopted.

Hyponatremia is relatively common in pneumonia, with one large Italian series reporting a rate of 45% [ 32 ]. In our study, the overall incidence of hyponatremia was 30.9% (116/375); however, hyponatremia was mild in the majority of cases, from 130 mmol/l to 135 mmol/l. Studies in developing countries have shown this to be associated with increasing severity of pneumonia and risk of death. Factors increasing the risk of dehydration and potentially hyponatremia include reduced nutrient/water intake and increased evaporative losses as a result of both increased respiratory rate and increased core temperature. Sometimes it may be a result of additional losses from vomiting and diarrhoea. Pneumonia is widely cited as a potential cause of syndrome of inappropriate antidiuretic hormone secretion (SIADH) [ 33 ], but no studies have examined the biochemistry and pathophysiology of hyponatremia in children with pneumonia with sufficient rigor to be able to differentiate adequately between SIADH and salt depletion; therefore, hyponatremia has frequently been ascribed to SIADH. Some scholars suspect that hyponatremia principally occurs secondarily to dehydration in most children considered to have SIADH. This has major implications for acute patient management, as SIADH is managed with fluid restriction, and dehydration clearly requires rapid volume replacement. Further studies are urgently required to address this question in the future.

In all patients involved in this study, the main pathogens that were co-infected were Staphylococcus aureus , Escherichia coli , Klebsiella pneumoniae and Streptococcus viridans , which was similar to other reports [ 34 ]. In addition, this article also found that in term infants with concurrent bacterial infections, the symptoms are more severe and more likely to have respiratory failure. Some of these patients require not only oxygen support but also NIV or invasive MV. Therefore, term infants with viral and bacterial infections are more severe than those with pure viral infections [ 35 ,  36 ], and more attention should be devoted to respiratory management [ 37 , 38 ] and supportive care. Once the results of NPA culture are confirmed (before those of drug sensitivity testing are clear), appropriate antibiotics for common bacteria can be empirically selected. After the report of bacterial drug sensitivity tests, the type of antibiotics should be adjusted according to the treatment effect.

Neutrophils play an important and active role in the body's nonspecific immunity. In the present study, the total number of leukocytes in preterm infants combined with bacterial infection was numerically higher than that in preterm patients with simple virus infection; although the difference was not statistically significant, the prevalence of neutrophils to WBC was lower than that in patients with simple virus infection ( p  < 0.05). The hospital stay in preterm infants with bacterial infection is also longer than that in preterm patients with simple virus infection. When bacteria and other microbial pathogens invade and inflammatory reactions occur, they can reach the inflammatory site under the influence of chemokines, devour bacteria and tissue fragments, and prevent the diffusion of pathogenic microorganisms in the body [ 39 ]. When the inflammatory reaction is strong, a large number of neutrophils stored in bone marrow are released into the blood, and the level of neutrophils increases. However, neutrophils were depleted in bone marrow when the infection was very serious, resulting in a decrease in neutrophil expression levels [ 40 ]. Therefore, when the prevalence of neutrophils to WBC is reduced in preterm infants, the risk of bacterial infection may increase, resulting in a prolonged hospital stay.

RSV and PIV3 are the main pathogens of neonatal viral pneumonia. It is necessary to consider the possibility of RSV infection in neonates with viral CAP in winter and early spring. In PIV3-infected newborns and premature infants, we should be alert to the possibility of combined bacterial infection. Preterm infants are more prone to PIV3 infection and coinfection with bacteria. Term infants are more prone to be infected with RSV. Term infants with bacterial infection are more prone to respiratory failure than simple virus infection. Patients with respiratory failure should be closely monitored and supported in a timely manner by inhaling oxygen and ventilation. When the prevalence of neutrophils to WBCs in preterm infants is reduced, it is easily complicated by bacterial infection. Additionally, hyponatremia cannot be ignored in children with pneumonia.

However, this study also has some shortcomings: the number of patients involved, especially preterm infants, was small. In the future, we will conduct more joint research with hospitals and communities in multiple regions. We will expand the inclusion criteria and include some children with insignificant performance in the study.

Availability of data and materials

The datasets generated and/or analysed during the current study are not publicly available due to the datasets need to be kept confidential, but they are available from the corresponding author upon reasonable request.

Abbreviations

Nasopharyngeal aspirates

Community-acquired pneumonia

Respiratory syncytial virus

Parainfluenza virus

Influenza virus

C-reactive protein

World Health Organization

Postmenstrual age

Syndrome of inappropriate antidiuretic hormone secretion

Real-time polymerase chain reaction

Severe Acute Respiratory Syndrome Coronavirus 2

Coronavirus disease 2019

Heart failure; PALS: pulmonary air leak syndrome

Pulmonary interstitial emphysema

Mechanical ventilation

High frequency oscillatory ventilation

Conventional mechanical ventilation

Non-invasive ventilation

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Acknowledgements

This work was supported by Jiangsu maternal and child health research project [Shenglin Yu, grant number F202021].

Financial support for this study was provided by the Foundation of Jiangsu Province Health Committee (F202021).

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Xinxian Guan and Shasha Gao contributed equally to this work.

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Department of Neonatology, Children’s Hospital of Soochow University, Suzhou, China

Xinxian Guan, Shasha Gao, Yan Yang & Shenglin Yu

Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, China

He Zhao, Huiting Zhou & Jian Wang

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Xinxian Guan and Shasha Gao wrote the main manuscript text and analysed the data. He Zhao and Huiting Zhou collected laboratory data and prepared Figs. 1 and 2 . Yan Yang collected clinical data and prepared Tables 1 and 2 . Shenglin Yu and Jian Wang have made substantial contributions to the conception and design. All authors reviewed the manuscript. All authors read and approved the final manuscript.

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Correspondence to Shenglin Yu or Jian Wang .

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All procedures performed in studies involving human participants were carried out in accordance with the Committee on Publication Ethics and the International Committee of Medical Journal Editors. This study was approved by the Ethics Committee of Children’s Hospital of Soochow University (under number 2020CS004). The study was retrospective, and the data were anonymous, so the requirement for informed consent was waived by the Ethics Committee of Children’s Hospital of Soochow University.

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Guan, X., Gao, S., Zhao, H. et al. Clinical characteristics of hospitalized term and preterm infants with community-acquired viral pneumonia. BMC Pediatr 22 , 452 (2022). https://doi.org/10.1186/s12887-022-03508-7

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• Coinfection

BMC Pediatrics

ISSN: 1471-2431

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Effect of case management on neonatal mortality due to sepsis and pneumonia

Affiliation.

• 1 Department of Paediatrics and Child Health, the Aga Khan University, Karachi, Pakistan. [email protected]
• PMID: 21501430
• PMCID: PMC3231886
• DOI: 10.1186/1471-2458-11-S3-S13

Background: Each year almost one million newborns die from infections, mostly in low-income countries. Timely case management would save many lives but the relative mortality effect of varying strategies is unknown. We have estimated the effect of providing oral, or injectable antibiotics at home or in first-level facilities, and of in-patient hospital care on neonatal mortality from pneumonia and sepsis for use in the Lives Saved Tool (LiST).

Methods: We conducted systematic searches of multiple databases to identify relevant studies with mortality data. Standardized abstraction tables were used and study quality assessed by adapted GRADE criteria. Meta-analyses were undertaken where appropriate. For interventions with biological plausibility but low quality evidence, a Delphi process was undertaken to estimate effectiveness.

Results: Searches of 2876 titles identified 7 studies. Among these, 4 evaluated oral antibiotics for neonatal pneumonia in non-randomised, concurrently controlled designs. Meta-analysis suggested reductions in all-cause neonatal mortality (RR 0.75 95% CI 0.64- 0.89; 4 studies) and neonatal pneumonia-specific mortality (RR 0.58 95% CI 0.41- 0.82; 3 studies). Two studies (1 RCT, 1 observational study), evaluated community-based neonatal care packages including injectable antibiotics and reported mortality reductions of 44% (RR = 0.56, 95% CI 0.41-0.77) and 34% (RR = 0.66, 95% CI 0.47-0.93), but the interpretation of these results is complicated by co-interventions. A third, clinic-based, study reported a case-fatality ratio of 3.3% among neonates treated with injectable antibiotics as outpatients. No studies were identified evaluating injectable antibiotics alone for neonatal pneumonia. Delphi consensus (median from 20 respondents) effects on sepsis-specific mortality were 30% reduction for oral antibiotics, 65% for injectable antibiotics and 75% for injectable antibiotics on pneumonia-specific mortality. No trials were identified assessing effect of hospital management for neonatal infections and Delphi consensus suggested 80%, and 90% reductions for sepsis and pneumonia-specific mortality respectively.

Conclusion: Oral antibiotics administered in the community are effective for neonatal pneumonia mortality reduction based on a meta-analysis, but expert opinion suggests much higher impact from injectable antibiotics in the community or primary care level and even higher for facility-based care. Despite feasibility and low cost, these interventions are not widely available in many low income countries.

Funding: This work was supported by the Bill & Melinda Gates Foundation through a grant to the US Fund for UNICEF, and to Saving Newborn Lives Save the Children, through Save the Children US.

Publication types

• Meta-Analysis
• Research Support, Non-U.S. Gov't
• Anti-Bacterial Agents / therapeutic use*
• Case Management
• Controlled Clinical Trials as Topic
• Infant Mortality*
• Infant, Newborn
• Pneumonia / drug therapy*
• Pneumonia / mortality
• Sepsis / drug therapy*
• Sepsis / mortality
• Treatment Outcome
• Anti-Bacterial Agents

• Case report
• Open access
• Published: 25 March 2024

Stenotrophomonas maltophilia neonatal sepsis: a case report

• Williams Oluwatosin Adefila   ORCID: orcid.org/0000-0002-1928-4862 1 ,
• Isaac Osie 1 , 2 ,
• Modou Lamin Keita 1 ,
• Baleng Mahama Wutor 1 ,
• Abdulsalam Olawale Yusuf 1 ,
• Ilias Hossain 1 ,
• Minteh Molfa 1 ,
• Ousman Barjo 1 ,
• Rasheed Salaudeen 1 &
• Grant Mackenzie 1 , 2 , 3 , 4  

Journal of Medical Case Reports volume  18 , Article number:  180 ( 2024 ) Cite this article

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Stenotrophomonas maltophilia is a gram-negative bacteria known for causing opportunistic and nosocomial infections in humans. S. maltophilia is an emerging pathogen of concern due to it’s increasing prevalence, diverse disease spectrum, intrinsic multi-drug resistance and high mortality rates in immunocompromised individuals. S. maltophilia is a rare cause of neonatal sepsis associated with significant morbidity and mortality. The bacterium’s multi-drug resistance poses a considerable challenge for treatment, with various mechanisms contributing to its resistance.

Case presentation

We report a case involving a 40-h-old male African neonate who exhibited symptoms of neonatal sepsis. The blood culture revealed Stenotrophomonas maltophilia , which was sensitive to ciprofloxacin and gentamicin but resistant to other antibiotics. Lumbar puncture for CSF could not be done because the father declined.

We treated the newborn with the empirical first-line antibiotics as per the national guideline intravenous ampicillin and gentamicin for six days, and the child recovered fully with a repeated negative blood culture.

Conclusions

This report describes a neonatal sepsis case caused by S. maltophilia, a multi-drug resistant bacteria and a rare cause of neonatal sepsis. We report that early detection of the bacterial and antimicrobial management based on local antibiogram data may be essential for successful patient’s management.

Peer Review reports

Stenotrophomonas maltophilia  causes human infections ranging from bacteremia, sepsis, endocarditis, pneumonia, and meningitis. It is a gram-negative, glucose non-fermentative aerobic rod with low virulence. The bacteria was described in 1961 by Hugh and Ryschenkow [ 1 ].

S. maltophilia is often pathogenic in immunocompromised and hospitalized patients, especially in the intensive care unit (ICU) [ 2 ]. It can also produce biofilms on prosthetic devices, such as catheters, mechanical ventilators, and feeding tubes [ 3 ]. The mortality rate of an S. maltophilia infection is high, primarily when associated with pneumonia (or bacteremia) and antibiotic resistance [ 4 ]. The resistance can be intrinsic, or the bacteria can develop resistance to antibiotics over time. The increasing use of antibiotics, especially broad-spectrum antibiotics, has contributed to the rise of multidrug-resistant (MDR) strains of S. maltophilia . MDR strains are resistant to a wide range of antibiotics, making them difficult to treat [ 5 ]. The outbreak of SARS-CoV-2 may have contributed to the increase in the prevalence of MDR bacteria, including S. maltophilia , because of the increased irrational use of antibiotics to treat COVID-19 [ 6 ].

A 40-h-old male African neonate was brought by the mother to our health facility, Bansang Hospital, at 7:30 am. Bansang Hospital (a secondary care facility) is in rural Gambia. It is the main referral centre for the country’s two largest regions (Central and Upper River Region). The mother complained of a persistently high fever that started about a day after delivery. She also complained of the child’s refusal to breastfeed with poor suckling ability, and was highly irritable. The mother also complained that the child had multiple episodic jerky movements, clenching the fist, lip-smacking, upward eye rolling, and limb stiffness during each episode. She noticed that the child had abnormal rapid breathing and a gradual decline in the child’s alertness. There was no history of vomiting or passage of loose, watery stool. There was no history of yellowish discolouration of the eye or the skin.

The mother was a primigravid, carrying the pregnancy to term with only two antenatal visits. She was not a known diabetic or hypertensive. She was not on any long-term medication. She was HIV-negative and received the required prenatal tetanus toxoid vaccination.

The pregnancy was carried to term. There was a history of premature membrane rupture and liquor drainage for more than two days before the onset of labour. The draining amniotic fluid was not blood-stained but had a foul odour. The mother also complained of a foul-smelling whitish-brown vaginal discharge with no associated itching two weeks before the delivery. The mother did not receive any antibiotics before delivery. She delivered in the hospital through spontaneous vaginal delivery after more than 18 h of prolonged labour. The child’s birth weight was 3kg, and the newborn did not cry immediately after birth, necessitating further resuscitation. Apgar score in the first minute was three, and at ten minutes, it was seven. After a successful resuscitation, the child was allowed to breastfeed, and the mother described the suckling reflex as weak. They were discharged home less than 24 h after delivery.

The parents noticed the newborn having a persistent high-grade fever that started the following day after birth, not feeding, and becoming weak at home. The grandmother gave the newborn some undetermined syrups to reduce the fever. The newborn was not improving; hence, the mother brought him to the hospital.

Physical examination revealed an acutely ill-looking newborn with hyperpyrexia (temperature of 39.1 degrees Celsius), not pale, anicteric, not cyanosed, responsive to pain only and having seizures. The child weighed 3kg.

The central nervous system examination showed a newborn with poor suckling reflex, unresponsive except to pain, poor Moro reflex, normal fontanelles, normal tones globally and lethargic.

The respiratory rate was 65 breaths per minute, hypoxia with oxygen saturation of 80%, absent subcostal retraction, nil dullness to chest percussion, and broncho-vesicular breath sounds.

His heart rate was 153 beats per minute, with no abnormal heart sounds on auscultation.

The rest of the physical examination was unremarkable.

The random blood sugar was 5.1 mmol/l (91.8 mg/dl). We requested a blood culture, microscopy, and sensitivity, and a chest x-ray.

We counselled the parents for lumbar puncture for cerebrospinal fluid analysis, but the father declined.

A diagnosis of early-onset neonatal sepsis with a differential diagnosis of neonatal meningitis and perinatal asphyxia was made.

The newborn was started on empirical first-line antibiotics as per the national guideline: IV ampicillin 50mg/kg every 6 h and IV gentamicin 5mg/kg daily. Also, we put the child on nil per oral, intravenous maintenance fluid 34mls every three hours and a stat dose of IV phenobarbitone. Moreover, we placed the child on humidified oxygen, one litre per minute, through a nasal prong and monitored the vital signs, including random blood sugar.

Results of investigation

The chest x-ray findings were essentially normal. The blood culture yielded glucose non-fermenting colonies, and the Gram stain showed gram-negative rods. We processed the bacterium for identification using the Analytical Profile Index (API) 20E. The identification number 1202000 on the API is consistent with Stenotrophomonas maltophilia. Antibiotic susceptibility testing of the pathogen using the disc diffusion method showed sensitivity to ciprofloxacin and gentamicin. The organism was resistant to ceftriaxone, tetracycline, chloramphenicol, and ampicillin.

Progress report

After 48 h of admission, the fever subsided, and the child had one episode of convulsion. He was alert but had a poor suckling reflex. After 72 h of hospital admission, he had no seizures in the previous 36 h, had started breastfeeding, and no complaints or abnormalities were noted. After four days of hospital admission, he had a normal suckling reflex, and the mother had adequate lactation. No anomaly was detected, and we stopped the intravenous maintenance fluid. We did not change the antibiotic regimen because the child improved well clinically on the initial antibiotics administered. There were no observed adverse effects or complications during the treatment. After six days on admission, the newborn was discharged home for a follow-up in one week. The mother had no complaints at follow-up, and the child was feeding well with no abnormal signs.

Discussion and conclusions

The prevalence of Stenotrophomonas maltophilia isolation described from different hospitals ranged from 7.1 to 37.7 cases per 10,000 discharges or 18.3 cases per 1,000 patient days. The majority of these reports were investigated after a perceived increase in the incidence and prevalence of the organism[ 7 ].

Neonatal sepsis is a leading cause of death in newborns in sub-Saharan Africa. It is estimated that 380,000 to 2 million cases of neonatal sepsis occur in sub-Saharan Africa each year and that 270,000 are fatal [ 7 ]. Neonatal resuscitation, low birth weight, and prematurity are risk factors for neonatal sepsis. Prolonged and premature membrane rupture, multiple vaginal examinations, meconium-stained amniotic fluid, and intrapartum fever are maternal risk factors for neonatal sepsis [ 8 ]. Gram-positive bacteria (Staphylococcus aureus , Streptococcus pyogenes, group B streptococcus, and group D streptococcus ) and gram-negative bacteria ( Klebsiella, Escherichia coli, Pseudomonas, Enterobacter spp, and Salmonella spp.) are the most common causes of neonatal sepsis in sub-Saharan Africa [ 9 , 10 , 11 ].

S . maltophilia is a rare cause of neonatal sepsis globally and in sub-Saharan Africa, but its emergence has significant implications for patient management due to antimicrobial resistance [ 12 ]. S. maltophilia is categorized by the World Health Organization (WHO) categorized as a primary multi-drug-resistant bacteria in hospital settings [ 13 ]. The prevalence of S. maltophilia infections increased in the general population, with more cases in the Western Pacific regions (from 6% to 18.6%) and lower prevalence in the American regions (from 3.2% to 5.7%) in 1991 and 2019 [ 13 ]. S. maltophilia has exhibited an increasing tendency towards drug resistance through multiple mechanisms. These mechanisms include the expression of resistance genes acquired from the environment, reduced outer membrane permeability, and transposons encoded within the chromosome and plasmids [ 14 ]. Furthermore, other mechanisms of antimicrobial resistance include the production of β-lactamase enzymes, integrons, biofilms, and multi-drug efflux [ 15 , 16 , 17 ].

Our patient’s mother had prolonged prelabour rupture of membranes and prolonged labour. These risk factors predisposed the neonate to acquire sepsis with S. maltophilia. Also, the neonate had perinatal asphyxia and needed to be resuscitated. This was another avenue through which the neonate may have acquired the infection.

Even though prematurity and low birth weight have been reported as risk factors for S. maltophilia infection in the newborn , our case was term and had a normal birth weight but with significant other risk factors for sepsis [ 17 , 18 ]. Since 1977, the first case of S. maltophilia was documented, and only very few cases of meningitis associated with S. maltophilia have been documented [ 19 , 20 ]. The management of S. maltophilia infection is challenging due to the bacterium’s resistance to multiple antimicrobials used to treat Gram-negative infections [ 10 ]. Trimethoprim-sulfamethoxazole and flouroquininolones are typically effective against S. maltophilia strains, but due to its unfavourable side effects, it is not recommended for use in newborns [ 21 ]. In our patient, we found that the pathogen was susceptible to ciprofloxacin and gentamicin and resistant to ceftriaxone, tetracycline, chloramphenicol, and ampicillin. The organism’s resistance to commonly available antibiotics such as ampicillin and ceftriaxone, poses a challenge to effective clinical management. It increases the chances of neonatal mortality and morbidity, especially in resource-limited settings.

Neonatal sepsis can be devastating due to its high mortality and potential long-term consequences and the risk is further amplified when S. maltophilia is indicated [ 22 ]. However, this can be prevented through early detection. Early detection of S. maltophilia and management is critical because of its aggressive nature as an opportunistic pathogen, non-specific neonatal symptoms, rapid progression, and improved treatment outcomes [ 23 ].

The index newborn responded well to the first-line empirical treatment combination of ampicillin and gentamicin, and the child recovered fully. Hence, it is essential to note that the chosen antibiotic combination had a high success rate despite the organism’s inherent multi-drug resistance. Furthermore, this case has highlighted the role of S. maltophilia as an emerging cause of nosocomial infections in vulnerable patients such as neonates in resource limited settings. Clinicians should have a high suspicion to identify patients at high risk for S. maltophilia infections. Early detection and prompt management using clinical and microbiological evidence are paramount to successfully managing S. maltophilia neonatal sepsis.

Due to the parents’ refusal to perform a lumbar puncture to confirm our suspicion of meningitis, a blood culture was essential for diagnosing S. maltophilia infection in our patient. We had other limitations in conducting further crucial diagnostic investigations like complete blood count and C-reactive protein because our laboratory is under-equipped.

This report shows that although S. maltophilia is a rare cause of neonatal sepsis, early detection and management based on local antibiogram data is essential for excellent patient outcomes. The lack of microbiology services in many settings in sub-Saharan Africa will mean that infections with S. maltophilia are under-detected and often inadequately treated.

Availability of data

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Abbreviations

Intravenous

Intensive care unit

Multi-drug resistant

Analytical Profile Index

World Health Organization

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Acknowledgements

We appreciate the paediatric team of the Bansang Hospital, the microbiology team and the haematology department for the excellent communication and management of this patient.

No funds were used to produce this manuscript.

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Medical Research Council Unit The Gambia at London, School of Hygiene and Tropical Medicine, West Africa, PO Box 273, Fajara, The Gambia

Williams Oluwatosin Adefila, Isaac Osie, Modou Lamin Keita, Baleng Mahama Wutor, Abdulsalam Olawale Yusuf, Ilias Hossain, Minteh Molfa, Ousman Barjo, Rasheed Salaudeen & Grant Mackenzie

Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK

Isaac Osie & Grant Mackenzie

Murdoch Children’s Research Institute, Melbourne, Australia

Grant Mackenzie

Department of Paediatrics, University of Melbourne, Melbourne, Australia

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OB, MM, and RS provided the microbiology laboratory work results and assisted in drafting the case report. BMW and AOY assisted in the drafting of the case report. MLK assisted in the patient’s management and also in writing the manuscript. IO and GM provided clinical work support, supervision, and writing of the case report manuscript.

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Adefila, W.O., Osie, I., Keita, M.L. et al. Stenotrophomonas maltophilia neonatal sepsis: a case report. J Med Case Reports 18 , 180 (2024). https://doi.org/10.1186/s13256-024-04479-2

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Effect of case management on neonatal mortality due to sepsis and pneumonia

Anita k m zaidi.

1 Department of Paediatrics and Child Health, the Aga Khan University, Karachi, Pakistan

Hammad A Ganatra

Simon cousens.

2 London School of Tropical Medicine and Hygiene, London, UK

Anne CC Lee

3 Johns Hopkins Bloomberg School of Public Health, International Health, Baltimore MD, USA

Robert Black

Zulfiqar a bhutta.

4 Saving Newborn Lives/Save the Children, Cape Town, South Africa

Associated Data

Each year almost one million newborns die from infections, mostly in low-income countries. Timely case management would save many lives but the relative mortality effect of varying strategies is unknown. We have estimated the effect of providing oral, or injectable antibiotics at home or in first-level facilities, and of in-patient hospital care on neonatal mortality from pneumonia and sepsis for use in the Lives Saved Tool (LiST).

We conducted systematic searches of multiple databases to identify relevant studies with mortality data. Standardized abstraction tables were used and study quality assessed by adapted GRADE criteria. Meta-analyses were undertaken where appropriate. For interventions with biological plausibility but low quality evidence, a Delphi process was undertaken to estimate effectiveness.

Searches of 2876 titles identified 7 studies. Among these, 4 evaluated oral antibiotics for neonatal pneumonia in non-randomised, concurrently controlled designs. Meta-analysis suggested reductions in all-cause neonatal mortality (RR 0.75 95% CI 0.64- 0.89; 4 studies) and neonatal pneumonia-specific mortality (RR 0.58 95% CI 0.41- 0.82; 3 studies). Two studies (1 RCT, 1 observational study), evaluated community-based neonatal care packages including injectable antibiotics and reported mortality reductions of 44% (RR= 0.56, 95% CI 0.41-0.77) and 34% (RR =0.66, 95% CI 0.47-0.93), but the interpretation of these results is complicated by co-interventions. A third, clinic-based, study reported a case-fatality ratio of 3.3% among neonates treated with injectable antibiotics as outpatients. No studies were identified evaluating injectable antibiotics alone for neonatal pneumonia. Delphi consensus (median from 20 respondents) effects on sepsis-specific mortality were 30% reduction for oral antibiotics, 65% for injectable antibiotics and 75% for injectable antibiotics on pneumonia-specific mortality. No trials were identified assessing effect of hospital management for neonatal infections and Delphi consensus suggested 80%, and 90% reductions for sepsis and pneumonia-specific mortality respectively.

Oral antibiotics administered in the community are effective for neonatal pneumonia mortality reduction based on a meta-analysis, but expert opinion suggests much higher impact from injectable antibiotics in the community or primary care level and even higher for facility-based care. Despite feasibility and low cost, these interventions are not widely available in many low income countries.

This work was supported by the Bill & Melinda Gates Foundation through a grant to the US Fund for UNICEF, and to Saving Newborn Lives Save the Children, through Save the Children US.

Deaths occurring in the neonatal period each year account for 41% (3.6 million) of all deaths in children under 5 years [ 1 ]. The majority of these deaths occur in low income countries and almost 1 million of these deaths are attributable to infectious causes including neonatal sepsis, meningitis and pneumonia [ 1 ]. These deaths occur because of lack of preventive care (clean birth care, breastfeeding) and appropriate case management [ 2 ]. Delays in treating neonatal infections of even a few hours may be fatal. Delays in illness recognition and care seeking, a dearth of primary health care providers, and limited access to facility care contribute to these deaths [ 3 ]. Recent trials have demonstrated the effect of community-based packages for prevention and treatment of neonatal bacterial infections, with the potential to save many lives [ 4 , 5 ].

Therapy with appropriate antibiotics and supportive management in neonatal nurseries is the cornerstone of management of neonatal sepsis and pneumonia, with strong biological plausibility that such therapy saves lives. Yet the quality of evidence is understandably affected by the ethical impossibility of undertaking randomized trials of antibiotic management compared with no antibiotic management. Nevertheless, given the limited access to care for sick neonates in low income countries, it is important to assess the potential mortality effect of oral antibiotics and injectable antibiotics delivered in domiciliary or primary care settings. Case management for hospitalized neonates is more expensive, but to guide policy and program investments we also need to know how much more effective it is compared to care delivered at home or in primary care settings.

The objective of this review is to provide estimates of the effectiveness of three interventions in preventing neonatal deaths from severe infection: (i) case management with oral antibiotic therapy alone for pneumonia and sepsis; (ii) case management with injectable antibiotics (± oral antibiotics) as an outpatient or at home for neonatal sepsis /meningitis and pneumonia; and (iii) hospital-based case management, including injectable antibiotics, intravenous fluids, oxygen therapy, second line injectable antibiotics if needed, and other supportive therapy (Table ​ (Table1). 1 ). These mortality effect estimates are used in the Lives Saved Tool (LiST) software, a user-friendly tool that estimates the number of lives saved by scaling up key interventions and helps in child survival planning in low income countries [ 6 , 7 ].

Definitions of interventions reviewed

We searched all published literature as per CHERG systematic review guidelines[ 7 ]. Databases searched were PubMed, Cochrane Libraries and WHO regional databases from 1990 until April 2009 and included publications in any language (Figure ​ (Figure1). 1 ). Search terms included various combinations of: sepsis, meningitis and pneumonia. For sepsis and pneumonia management at a hospital level we conducted two parallel searches (Figures ​ (Figures2 2 and ​ and3). 3 ). These were broader as we also wanted to identify studies reporting incidence and case fatality ratios (CFR) for a related study on global burden of neonatal sepsis. Titles and abstracts were reviewed and studies were included if data on one of the following outcomes was provided: all-cause mortality, sepsis/meningitis/pneumonia mortality and/or CFR. Furthermore, extensive efforts were made to contact investigators and program managers for unpublished data.

Searches and screening for community based management of sepsis and pneumonia.

Searches and screening for hospital management of sepsis

Searches and screening for hospital management of pneumonia.

Inclusion/exclusion criteria, abstraction

We reviewed all available observational studies, randomized controlled trials, systematic reviews, and meta-analyses, which included neonates and principally involved the management of serious neonatal infections. The search was limited to “humans”. We examined studies published from 1990 until April 2009.

We included randomized controlled trials, studies with concurrent controls, and observational studies with no control group if mortality outcomes were reported. All studies meeting final inclusion criteria were double data abstracted into a standardized form. We abstracted key variables with regard to the study identifiers and context, study design and limitations, intervention specifics, and mortality outcomes. We assessed the quality of each of these studies using a standard table employing an adapted version of GRADE[ 8 ] developed by the Child Health Epidemiology Reference Group (CHERG) [ 7 ]. For studies which reported mortality outcomes that were not neonatal specific, we contacted the authors to request the neonatal-specific data. All studies that were coded are included in Additional File 1 .

Case definition of sepsis

During our review of selected studies we were unable to find a standard definition for clinical neonatal sepsis or pneumonia (Table ​ (Table2). 2 ). Each study used different criteria although most are a variation on WHO IMCI approach. We therefore decided to accept authors’ definitions of sepsis and pneumonia, recognizing that these non-specific definitions lower mortality outcome estimates as many “non-sepsis” cases are included in an effort to maximize sensitivity.

Varying definitions of neonatal sepsis used by investigators and clinicians

Analyses and summary measures

All studies reporting mortality data for pneumonia and sepsis management, in community and hospital settings, were summarized according to the overall quality of evidence for each outcome and each data input type using an adapted version of the GRADE 21 protocol table [ 7 ]. When appropriate, we conducted meta-analyses to obtain pooled estimates of the risk ratios, using either the Mantel-Haenzsel or, when there was evidence of heterogeneity, the DerSimonian-Laird random effects estimator. 95% confidence intervals (CI) were also calculated. Statistical analyses were performed using STATA 10.0 ( http://www.stata.com ).

Delphi Process for Establishing Expert Consensus

For intervention-outcome combinations for which we did not identify moderate quality evidence, we sought expert consensus via the Delphi method. Individuals invited to participate were experts in newborn health and sepsis representing six WHO regions (South Asia, Africa, Western Europe, Eastern Europe, North America, Australia), and including multiple disciplines - international health, pediatric infectious diseases, clinical neonatology, and general pediatrics. Twenty (of twenty-three experts invited) agreed to participate in the Delphi process. The questionnaire was developed by JL, AZ, SC and SS, and refined after several rounds of pilot testing. The questionnaire was sent by email and included the background and aims of the Delphi and estimates of effect that were available from the literature for different scenarios. The median response and range were determined for each question. Consensus was defined a priori as an interquartile range in responses of not more than 30% for each question. For those estimates not reaching consensus, the plan was for results to be electronically distributed to the panel, virtual discussion allowed, and a second round of email questionnaires sent. However, consensus was achieved after one round of questionnaires and subsequent rounds were not necessary.

Studies identified

Our systematic searches for community management of sepsis and pneumonia identified 2876 titles (Figure ​ (Figure1) 1 ) and after screening of titles, abstracts and relevant full texts, we located 7 studies of interest (reported in 8 papers) [ 9 - 16 ]. We identified 4 non randomised concurrently controlled studies, which evaluated oral antibiotics for pneumonia (Table ​ (Table5) 5 ) [ 10 , 14 - 16 ]. Three of these studies did not report disaggregated neonatal outcomes in the primary papers, but neonatal outcomes were available through abstracted forms from an earlier meta-analysis by Sazawal et al [ 17 ]. For management of neonatal sepsis using injectable antibiotics, we located 3 studies (reported in 4 papers) [ 9 , 11 - 13 ]. There was one observational primary clinic-based study without a control group [ 13 ], one RCT [ 12 ] and one non-randomised, concurrently controlled study [ 9 ]. The fourth paper reported observational data from individual infants evaluated during the RCT mentioned above and was not a separate study [ 11 ]. All the studies were from high neonatal mortality regions.

Summary of community-based studies for case management with oral antibiotics for and effect on cause specific neonatal mortality due to pneumonia

In our search for hospital-based studies of sepsis we found 55 studies from a total pool of 13998 studies which reported sepsis and/or meningitis mortality outcomes (Figure ​ (Figure2) 2 ) [ 18 - 70 ]. For pneumonia, we found two studies from a total pool of 94 studies (Figure ​ (Figure3) 3 ) [ 71 , 72 ].

The details of each study and quality assessment using GRADE are summarised in Tables ​ Tables3, 3 , ​ ,4, 4 , ​ ,5, 5 , and ​ and6 6 .

GRADE assessment of studies of effect of case management on cause specific neonatal mortality due to pneumonia

GRADE assessment of studies of case management on cause specific neonatal mortality due to neonatal sepsis

*NMR LEVELs (1=NMR <5 per 1000 live births, 2=NMR 6 to 15 per 100 live births, 3= NMR 15 to 30 per 100 live births, 4=NMR 31-45 per 100 live births 5=NMR >45 per 100 live births

Summary of community-based studies including injectable antibiotics for case management of neonatal sepsis (observational, quasi experimental, and RCT)

* Combined data from years 2 and 3 of trial i.e. 1996-1997 and 1997-1998.

**Observational data on individual infants evaluated during the cluster randomized trial by Baqui et al. Control group is families unable to comply with referral and were not offered treatment with injectable antibiotics at home.

Evidence for effectiveness of oral antibiotic therapy alone

Unpublished neonatal data were obtained from the principal investigators of the four studies identified and a new meta-analysis was done to update that of Sazawal et al[ 17 ]. We performed meta analyses for two outcomes: oral antibiotics were associated with reductions in both all-cause mortality (4 studies [ 10 , 14 - 16 ]: RR 0.75 95% CI 0.64- 0.89) (Figure ​ (Figure4) 4 ) and pneumonia-specific mortality (3 studies [ 10 , 15 , 16 ]: RR 0.58 95% CI 0.41- 0.82) (Figure ​ (Figure5). 5 ). Limitations included non-randomization, estimation of intervention coverage as precise coverage estimates were not available;and variability between studies of the intensity of co-interventions. We found no studies of the effect of oral antibiotics on sepsis-specific mortality. The Delphi consensus (median) was for a 28% reduction in sepsis-specific mortality with an interquartile range of 20% to 36.25% (Figure ​ (Figure6 6 ).

Meta-analysis of observational studies comparing oral antibiotics versus none in the community setting for babies: All cause mortality. Legend: Heterogeneity chi-squared = 1.17 (d.f. = 3) p = 0.760 I-squared (variation in RR attributable to heterogeneity) = 0.0% Test of RR=1 : z= 3.32 p = 0.001

Meta-analysis of observational studies comparing oral antibiotics versus none in the community setting for babies: Pneumonia mortality. Legend: Heterogeneity chi-squared = 2.16 (d.f. = 2) p = 0.339 I-squared (variation in RR attributable to heterogeneity) = 7.5% Test of RR=1: z= 3.06 p = 0.002

Box plot of Delphi expert opinion estimates of reduction in neonatal cause specific mortality due to pneumonia and sepsis/meningitis

Evidence for effectiveness of injectable antibiotic therapy (±oral antibiotics)

Three studies reported in four papers, were identified (Table ​ (Table6) 6 ) [ 9 , 11 - 13 ]. One, an RCT[ 12 ] evaluated the impact of a perinatal care package which included the administration of injectable antibiotics in domiciliary settings in situations where referral to hospital was not possible. This trial reported a reduction in all-cause neonatal mortality of 34% (RR=0.66, 95%CI 0.47-0.93). A second paper from the same study reported that the CFR for neonates who were evaluated and actually treated with injectable antibiotics was 4.4% [ 11 ]. A non-randomized, concurrently controlled study [ 9 ] also evaluated the impact of a home-based neonatal care package in which septic neonates were treated with injectable antibiotics when referral to hospital was not possible. The overall mortality reduction in the intervention arm of the trial was calculated to be 44% (RR=0.56 95% CI 0.41-0.77). A third, uncontrolled study [ 13 ] based in a primary care clinic reported a CFR of 3.3% among septic children treated with injectable antibiotics.

In both of the community-based studies [ 9 , 12 ] injectable antibiotics were only one component of comprehensive community-based newborn care packages, and therefore the effectiveness of injectable antibiotics alone in the community cannot be reliably estimated. The Delphi consensus for the effect of injectable antibiotics was for a 65% reduction (interquartile range of 50-70%) in sepsis-specific mortality and 75% reduction (interquartile range of 70-81.25%) in pneumonia-specific mortality in community-based settings (Figure ​ (Figure6 6 ).

Evidence for effectiveness of inpatient hospital case management

We found no trials assessing the impact of hospital-based case management and the observational studies of hospital management showed wide variation in effect. Searches conducted for studies reporting CFRs in neonates with pneumonia in health facilities revealed very few data. Two studies were identified with author-defined neonatal pneumonia; both were from low income, non-industrialised settings and reported CFRs of 14.4% [ 72 ] and 30.8% [ 71 ].

CFRs for neonatal sepsis, adjusted for the proportion of very low birth weight babies in the study, were plotted against national percentage skilled delivery, as a proxy for access to hospital-based case management of neonatal sepsis. In countries with a high proportion of births attended by skilled attendants, the predicted CFR for sepsis was 9.5%, whereas in countries with a low proportion (<30%) skilled birth attendance, the predicted CFR for sepsis with hospital care is 20-30% (Figure ​ (Figure7). 7 ). A 68% reduction in the CFR for neonatal sepsis is predicted as one moves from 0% to100% skilled birth attendance. This reduction is likely to under estimate the effect of hospital-based case management since skilled birth attendance is likely to be a poor surrogate for effective facility case management of neonatal infections, but was used in the absence of coverage data for case management

Plot of neonatal sepsis CFR versus percent skilled delivery as a marker of access to facility care. Model fitted: outcome = log(CFR) Covariates = Skilled attendant coverage and % babies vLBW Fitted line is predicted CFR for settings with % VLBW<30%. Predicted CFR at 0% skilled attendance is 30%. Predicted CFR at 100% skilled attendance is 9.5%. % reduction = 68.5% Coefficient skilled attendance is 0.12 on the log scale (95% CI -0.02 to -0.007); i.e. for each 1% increase in skilled attendance rate CFR is reduced by 1.1% (95% CI: 0.7% to 1.6%)

Although the quality of evidence is low according to GRADE criteria, the recommendation for case management of neonatal infections is strong, and this is standard practice globally. Table ​ Table7 7 provides a summary of the effect of case management on neonatal sepsis and pneumonia cause specific mortality, and GRADE of the estimate. Therefore the Delphi process was used to provide estimates for the effect of hospital care. The Delphi consensus was for a 80% reduction in sepsis-specific mortality (interquartile range 75% to 85%), and a 90% reduction in pneumonia-specific mortality (interquartile range 88.75% to 95%) (Figure ​ (Figure6 6 ).

Effect of case management on neonatal sepsis and pneumonia cause specific mortality, and GRADE of the estimate

Infections including sepsis, meningitis and pneumonia are responsible for almost a million neonatal deaths annually. Neonates are more susceptible to severe infections and the progression of disease is more rapid due to developmental immunodeficiency, resulting in high CFRs. Also, a significant proportion of infections may arise early, after vertical transmission from the mother [ 73 ]. Therefore, timely identification and appropriate management with antibiotics is an important strategy to reduce the burden of neonatal mortality due to infections. We have previously reported the evidence from observational and experimental studies in low income countries for community-based management of neonatal infections (pneumonia and sepsis) with oral and injectable antibiotics [ 74 - 76 ]. We have now undertaken a systematic review of available evidence, including from industrialized countries and facility settings, and where the quality of evidence is low we have undertaken a Delphi expert process to estimate the cause-specific mortality effect.

This review of effectiveness of the interventions is shaped in large part by the needs of the LiST model. In that model, increasing coverage of an intervention results in a reduction in deaths due to one or more specific causes or in reduction of a risk factor. Therefore the reviews and the GRADE process used were designed to develop estimates of the effect of an intervention in reducing death due to specific causes. For more details of the review methods, the adapted GRADE approach or the LiST model see related publications [ 6 , 7 ].

To our knowledge, this is the first review providing effectiveness estimates for case management options to reduce neonatal deaths due to neonatal sepsis/meningitis and pneumonia, in both community and facility settings. Theodoratou et al have previously estimated effectiveness of pneumonia case management in children under 5 years but they did not disaggregate neonatal mortality data from later child mortality [ 77 ]. The estimated effect of community case management on pneumonia mortality in children under 5 years of age in the analysis by Theodoratou et al is 70% (77). Oral antibiotics in community settings for neonatal pneumonia in our analysis were associated with a 42% reduction in pneumonia-specific mortality and a 25% reduction in all-cause neonatal mortality based on a meta-analysis of available trials. There is no evidence to estimate the effect of oral antibiotics on sepsis-specific mortality, but our Delphi process suggested a 28% reduction. Delphi-derived estimates for the effects of management using injectable antibiotics delivered in home or primary care settings came out at 65% for sepsis-specific mortality and 75% for pneumonia-specific mortality. These estimates are biologically plausible and consistent with published studies [ 9 , 12 ] which reported reductions in all-cause neonatal mortality (sepsis plus other causes) of 34% and 44% respectively with community-based packages including injectable antibiotics. CFRs reported from observational studies of hospital case management varied widely, from 6.7 to 67%. Our Delphi estimates suggested an 80% mortality reduction in sepsis deaths and a 90% reduction in pneumonia deaths with hospital case management.

There were 4 effectiveness trials assessing the impact of oral antibiotics on pneumonia-specific mortality in the community. Only one of these studies was randomized and the programmatic coverage of the intervention had to be estimated as coverage data were not routinely assessed or reported. The selection and intensity of co-interventions was not uniform between the studies. An additional limitation was the lack of clearly defined cause-of-death definitions by the authors. However, the effect sizes were remarkably consistent with each other, and therefore the evidence level was upgraded to moderate.

GRADE guidelines rank the evidence relating to the effect of injectable antibiotics on sepsis-specific mortality as low quality. The 3 studies identified were not uniform with respect to study designs; one was an effectiveness RCT, one was a non-randomized concurrent trial and the third was an observational study describing the experience from primary care clinic without a control group. Both the RCT [ 12 ] and the non-randomized concurrent trial[ 9 ], involved concurrent co-interventions alongside the administration of injectable antibiotics. This made it impossible to assess the impact of injectable antibiotics alone on sepsis mortality. Neither study reported the change in the sepsis-specific mortality rate in the intervention arm compared to control arm, and reported the impact on all-cause neonatal mortality only. The absence of randomization in one of the trials is a further limitation [ 9 ]. The main limitation to the observational study in a primary care clinic [ 13 ] was the absence of a control arm in the study.

We identified no controlled trials assessing the effect of hospital-based case management of neonatal infections. Such studies would be difficult or impossible to implement in an ethical fashion. Thus studies were limited to reporting CFRs for neonatal sepsis and meningitis. The studies were from varied settings, from both industrialized and low income countries, and reported widely varying CFRs. Only 2 of these observational studies reported CFRs for pneumonia. One of these studies reported a very high CFR for pneumonia due, we believe, to the high proportion of LBW babies in the sample (60%).

We found some moderate quality evidence for intervention packages including antibiotics in community settings but ironically data are most lacking at facility level, and district hospital level is a critical gap [ 78 ]. Unlike the LiST review on neonatal resuscitation which identified several before-after studies of facility based neonatal resuscitation reporting mortality data, we were unable to find similar before-after studies on the effect of hospital-based case management of sepsis/meningitis/pneumonia. An understandable reason for this might be the ethical constraints precluding such studies. However, historical reviews from the pre-antibiotic era provide an insight into the CFR associated with untreated sepsis in facility settings. The best available evidence comes from the series of papers from Yale Medical Center reporting time trends for neonatal sepsis. These data show that in the 1920s and 1930s the CFR for blood culture confirmed sepsis stood at 90% [ 79 , 80 ]. With the introduction of antibiotics, the CFR decreased to 45% by 1965 [ 81 ], and with the subsequent introduction of intensive care units and advanced life support it came down to 16% by 1988[ 82 ], and 3% by 2003[ 83 ]. Such data highlight the effectiveness of hospital-based management in preventing neonatal mortality from sepsis.

As evident from our results, even oral or injectable antibiotics alone are highly effective in reducing deaths from neonatal sepsis or pneumonia. These interventions hold great potential to reduce the 1 million neonatal deaths each year. If substantial reduction in neonatal mortality is desired, both, community and facility-based interventions are required, linked by functioning referral systems, giving the potential to prevent hundreds of thousands of avoidable newborn deaths every year.

List of abbreviations used

CFR: Case Fatality Rate; CHERG: Child Health Epidemiology Reference Group; IMCI: Integrated Management of Childhood Illnesses; LiST: Lives Saved Tool; RCT: Randomized Controlled Trial.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

AZ and JL planned the review, SS and AZ undertook the searches and abstraction with input from JL and HG. SC undertook the meta-analyses. RB provided unpublished data from a previous investigator working group. JL, AZ and ACCL planned the Delphi. All authors contributed to the manuscript.

This work was supported in part by a grant to the US Fund for UNICEF for Child Health Epidemiology Reference Group from the Bill &Melinda Gates Foundation (grant 43386) to “Promote evidence-based decision making in designing maternal, neonatal and child health interventions in low- and middle-income countries”, and by a grant to Save The Children USA from the Bill & Melinda Gates Foundation (Grant 50124) for "Saving Newborn Lives".

Supplementary Material

Study identifiers and context

Acknowledgements

We are grateful to Rajiv Bahl for insightful review of an earlier draft of this paper. We are also grateful to the members of the Delphi Expert Panel including Rajiv Bahl, Abhay Bang, Abdullah Baqui, Zulfiqar Bhutta, Robert Black, Simon Cousens, Gary Darmstadt, Mike English, Luis Huicho, David Isaacs, Joy Lawn, Patrick Mark, Kim Mulholland, David Osrin, Vinod Paul, Igor Rudan, Cindy Stephen, Barbara Stoll, Steven Wall and Anita Zaidi.

This article has been published as part of BMC Public Health Volume 11 Supplement 3, 2011: Technical inputs, enhancements and applications of the Lives Saved Tool (LiST). The full contents of the supplement are available online at http://www.biomedcentral.com/1471-2458/11?issue=S3 .

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