ABSTRACT
Introduction
Ventilator-associated pneumonia (VAP) is one of the most common healthcare-associated infections (HAI) in neonates admitted in neonatal intensive care units (NICUs).
Methods
We did a systematic review using PRISMA methodology to identify the main etiological agents in Brazilian NICUs. Eligible studies published without period restriction were identified in PUBMED, SCIELO, LILACS and DOAJ. Studies were included if they were conducted in neonates hospitalized at NICU. Studies done in outpatient care, neonates outside NICU, emergency department, primary care, long-term care facilities or a combination of these were excluded.
Results
We identified 6384 articles in the initial search and four papers met the inclusion criteria. In all studies included, rates of device-associated infections were described, including VAP rates. The VAP incidence density, in exclusively Brazilian NICU, ranged from 3.2 to 9.2 per 1000 ventilator-days. Pneumonia was described as the main HAI in NICU in one article, as the second type of HAI in two other articles and as the fourth type of HAI in the last one. The main pathogens causing all HAI types were described in three of four articles, but, none of the articles reported which pathogens were related or associated to VAP.
Conclusion
Etiological agents causing VAP in Brazilian NICUs are, until the present time, not known.
Keywords:
Systematic reviews; Ventilator-associated pneumonia; Newborn; Etiological agents
Introduction
Surveillance, prevention and control of healthcare-associated infections (HAI) in intensive care units, including pediatric intensive care units (PICU) and neonatal intensive care units (NICU) are a global concern, mainly due to high prevalence of multi-drug resistant bacteria in many of these units.11 Global action plan on antimicrobial resistance. WorldHealth Organization; 2015. Available at: http://apps.who.int/iris/bitstream/10665/193736/1/9789241509763_eng.pdf?ua=1 [accessed 14.02.17].
http://apps.who.int/iris/bitstream/10665...
In 2017, World Health Organization (WHO) published a list of antibiotic-resistant "priority pathogens". The most critical group of all includes Acinetobacter, Pseudomonas and various Enterobacteriaceae (including Klebsiella, E. coli, Serratia, and expanded), carbapenem-resistant or extended-spectrum beta-lactamase (ESBL) producers. They are frequently related to severe bloodstream and pneumonia infections in intensive care units.22 WHO publishes list of bacteria for which new antibiotics are urgently needed. Geneve: WHO; 2017. Available at: http://www.who.int/mediacentre/news/releases/2017/bacteria-antibiotics-needed/en/ [accessed 13.12.17].
http://www.who.int/mediacentre/news/rele...
Pneumonia is one of the most common HAI in neonates which is diagnosed using a combination of imaging, clinical and laboratory criteria.33 Dudeck MA, Horan TC, Peterson KD, et al. National Healthcare Safety Network report, data summary for 2011, device-associated module. Am J Infect Control. 2013;41:286-300. Ventilator-associated pneumonia (VAP) occurs when the patient is on mechanical ventilation for more than two calendar days on the date of diagnosis and the ventilator was in place on the date of event or the day before.44 Critérios Diagnósticos de Infecção Relacionada à Assistência à Saúde Neonatologia. Série Segurança do Paciente e Qualidade em Serviços de Saúde. Brasil: ANVISA; 2013. Available at: https://www20.anvisa.gov.br/segurancadopaciente/index.php/publicacoes/item/criterios-diagnosticos-de-infeccoes-relacionadas-a-assistencia-a-saude-neonatologia [accessed 17 December.
https://www20.anvisa.gov.br/segurancadop...
VAP accounts for up to 32.2 % of HAI among neonates.55 Azab SFA, Sherbiny HS, Saleh SH, et al. Reducing ventilator-associated pneumonia in neonatal intensive care unit using "VAP prevention Bundle": a cohort study. BMC Infect Dis. 2015;15:314.
A recent meta-analysis of observational studies identified 10 variables as independent risk factors for the development of VAP, including length of stay in NICU (OR 23.45), reintubation (OR 9.18), enteral feeding (OR 5.59), mechanical ventilation (OR 4.04), transfusion (OR 3.32), low birth weight (OR 3.16), premature infants (OR 2.66), parenteral nutrition (OR 2.30), bronchopulmonary dysplasia (OR 2.21), and tracheal intubation (OR 1.12).66 Tan B, Zhang F, Zhang X, et al. Risk factors for ventilator-associated pneumonia in the neonatal intensive care unit: a meta-analysis of observational studies. Eur J Pediatr. 2014;173:427-34.
Several surveillance systems VAP rates in neonates around the world are NEO-KISS (Nosocomial infection surveillance system for preterm infants on neonatology departments and ICUs) in Germany, neonIN Surveillance Network in UK, and National Healthcare Safety Network (NHSN) in USA.77 NEO-KISS (Nosocomial infection surveillance system for preterm infants on neonatology departments and ICUs). Available at: http://www.nrz-hygiene.de/en/surveillance/hospital-infection-surveillance-system/neo-kiss/ [accessed 09.12.17].
http://www.nrz-hygiene.de/en/surveillanc...
8 neonIN Surveillance Network. Available at: https://www.neonin.org.uk/#/home [accessed 09.12.17].
https://www.neonin.org.uk/#/home...
-99 National Healthcare Safety Network (NHSN). Available at: https://www.cdc.gov/nhsn/index.html [accessed 09.12.17].
https://www.cdc.gov/nhsn/index.html...
In a recent report of a national electronic surveillance of VAP rates in neonates, covering 376 hospitals from all Brazilian regions, the incidence density was found to be 7.7, 8.4, 7.5, 7.8, and 8.1 for neonates <750 g, 751-1000 g, 1000-1500 g, 1501-2500 g, and >2500 g, respectively. Despite these important data, no information was available concerning the etiology of VAP in neonates.1010 Boletim Segurança do Paciente e Qualidade em Serviços de Saúde nº 16: Avaliação dos indicadores nacionais das Infecções Relacionadas à Assistência à Saúde (IRAS) e Resistência microbiana do ano de 2016. ANVISA, Brasil. Available at: https://www20.anvisa.gov.br/segurancadopaciente/index.php/publicacoes/item/boletim-seguranca-do-paciente-e-qualidade-em-servicos-de-saude-n-16-avaliacao-dos-indicadores-nacionais-das-infeccoes-relacionadas-a-assistencia-a-saude-iras-e-resistencia-microbiana-do-ano-de-2016 [accessed 28.03.18].
https://www20.anvisa.gov.br/segurancadop...
VAP rates vary in different regions of Brazil. In Rio de Janeiro state, the reported VAP incidence density in 2016 was 5.7 cases per 1000 ventilator days in neonates born with more than 2500 g, with no description of etiological agents.1111 Informativo da Coordenação Estadual de Controle de Infecção Hospitalar. CECIH, Rio de Janeiro, Setembro de 2017. Available at: http://www.aeciherj.org.br/publicacoes/Informativos-CCIH/Informativo_IRAS-2017-v2.pdf [accessed 09.12.17].
http://www.aeciherj.org.br/publicacoes/I...
Knowledge about VAP rates in neonates and the respective causal agents is critical to define which strategies should be prioritized by infection control committees to reduce morbidity and mortality.
The aim of this systematic review was to identify studies reporting the etiological agents causing VAP, in Brazilian NICU.
Materials and methods
This systematic review was conducted according to recommendations of the PRISMA guidelines for reporting systematic reviews.1212 Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700.
Search strategy
The search was carried out for publications in PUBMED, SCIELO, LILACS and DOAJ using the search term: "ventilator associated pneumonia", without period restriction, limiting results by age (newborns) and English and Portuguese languages (Fig. 1).
Eligibility criteria
Inclusion criteria
Studies were eligible for full-text review if they were conducted in hospitalized newborns in NICU setting and reported the etiological agents. Study designs included review studies, multicenter studies, cohort studies, case series, and retrospective studies.
Exclusion criteria
Letters, notes, conference abstracts, and opinion articles were excluded. Studies conducted in outpatient care, newborns outside NICU setting, emergency department, primary care, long-term care facilities, or a combination of the above were also excluded.
Study selection
First-round: Exclusion of duplicate articles.
Second-round: Exclusion of papers based on type of article.
Third round: Reading of the full-text articles.
After the third round, relevant papers cited as references of full-text articles were included for analysis, if they fulfilled the eligibility criteria.
Data collection
Data were extracted using a standardized data-extraction form which summarized the study details including authors, year of publication, place where the study was conducted, and time frame of the study.
Quality of articles and risk of bias
Quality of articles was assessed using the integrated quality criteria for systematic review of multiple study designs (ICROMS) tool.1313 Zingg W, Castro-Sanchez E, Secci FV, et al. Innovative tools for quality assessment: integrated quality criteria for review of multiple study designs (ICROMS). Public Health. 2016;133:19-37. In this methodology, it is possible to analyze and integrate studies of different designs using the following criteria. In summary, the tool consists of two parts: the first is a list of quality criteria specific for each study design, as well as criteria applicable across all study designs by using a scoring system and the second is a ‘decision matrix’, which specifies the robustness of the study by identifying minimum requirements according to the study type and the relevance of the study to the review question. Only studies with minimum scores and mandatory criteria, according the ICROMS methodology were included in the final analysis (Annex Annex. Decision matrix of mandatory criteria and minimum score for study type to be included in the review Study designa Mandatory criteriab Minimum score RCT, cRCT 1A, 2A, 2B, and 3A 22 CBA 1A, 2D, 3B and 3C 18 CITS 1A, 3D and 6A 18 NCITS 1A, 1B, 2C and 5D 22 NCBA 1A, 1B, 2C and 5D 22 Cohort 1A, 2E, 3G and 4C 18 Qualitative 1A, 1E and 2F 16 a Study Designs: RCT = randomized controlled trial; CBA = controlled before-after; CITS = controlled interrupted time series; cRCT = cluster-randomized controlled trial; NCITS = noncontrolled interrupted time series; NCBA = non-controlled before-after. b Scores applicable to each criterium: Yes (criterion met) = 2 points; Unclear (unclear whether or not the criterion is met) = 1 point; No (criterion not met) = 0 points. Adapted from Zingg W et al. Innovative tools for quality assessment: integrated quality criteria for review of multiple study designs (ICROMS). Public Health 2016;133:19-37. ). For cohort studies, a minimum score of 18 points was necessary to be included in the review.
Results
According to the systematic review criteria we identified 6384 articles in the initial search and just four papers met the inclusion criteria for the final analysis (Fig. 2).
All four reports included were cohort studies, and two of them were multicenter studies (one including NICUs from Brazil and other countries, and one including only Brazilian NICUs). In all studies, device-associated infection rates were described, including VAP rates. VAP incidence density in the studies ranged from 2.4 to 13.2 per 1000 ventilator-days in all NICUs and from 3.2 to 9.2 per 1000 ventilator-days in studies that included only Brazilian NICUs
Pneumonia was described as the main HAI in NICU in one article, the second type of HAI in two other studies, and the fourth type of HAI in the last study.
The main pathogens causing the HAI were described in three of the four articles, but, none reported which pathogens were related or associated to VAP.
The study design, setting, number of subjects, country, study period, aim, interventions applied, and summary of key findings design of articles included are shown in Table 1. All studies included reached at least 18 points according ICROMS methodology.
Discussion
This review highlighted the absence of data on the causative agents related to VAP in Brazilian NICU. VAP is one of most prevalent infections within NICU in many countries. For example, Tan et al. studied the epidemiology of neonatal VAP in China. In an analysis of 16,587 newborns, the incidence and case fatality rates were 42.8% and 16.4%, respectively. Gram-negative bacteria were detected in 77.6% of cultures, followed by Gram-positive bacteria (18.8%) and fungi (3.7%). Gram-negative bacteria were resistant to meropenem, imipenem, and ciprofloxacin in rates of 1.5-25.0%, 4.9-29.0%, and 8.5-24.7%, respectively. Gram-positive bacteria have resistance rates as high as 80.3-91.9% to oxacillin.66 Tan B, Zhang F, Zhang X, et al. Risk factors for ventilator-associated pneumonia in the neonatal intensive care unit: a meta-analysis of observational studies. Eur J Pediatr. 2014;173:427-34. Other study conducted in 304 NICU of USA analyzed device-associated infections, including VAP. Pooled mean incidence rates of VAP by birth weight category (750 g or less, 751-1000 g, 1001-1500 g, 1501-2500 g, and more than 2500 g) were 2.36, 2.08, 1.28, 0.86, and 0.72, respectively. The frequencies of isolated pathogens were 16% of Pseudomonas species, 15% S. aureus, and 14% Klebsiella species.1818 Hocevar SN, Edwards JR, Horan TC, Morrell GC, Iwamoto M, Lessa FC. Device-associated infections among neonatal intensive care unit patients: incidence and associated pathogens reported to the National Healthcare Safety Network, 2006-2008. Infect Control Hosp Epidemiol. 2012;33:1200-6. New methods for rapid detection of pathogens related to VAP (Unyvero multiplex PCR) could provide additional information for clinical decision making, especially in neonates and in the setting of nosocomial pneumonia, also contributing to reduce inappropriate antimicrobial therapy.1919 Papan C, Meyer-Buehn M, Laniado G, Nicolai T, Griese M, Huebner J. Assessment of the multiplex PCR‑based assay Unyvero pneumonia application for detection of bacterial pathogens and antibiotic resistance genes in children and neonates. Infection. 2018;46:189-96.
In our review, just one study specified the agents causing HAI, but the description referred to all infections, failing to single out the etiology of VAP. Coagulase-negative staphylococci was the main pathogen identified, possibly related to bloodstream infections rather than VAP.1515 Pessoa-Silva CL, Richtmann R, Calil R, et al. Healthcare-associated infections among neonates in Brazil. Infect Control Hosp Epidemiol. 2004;25:772-7.
Despite these relevant epidemiological data included in final analysis, no studies carried out in Brazilian NICU reporting the pathogens related to VAP could be identified. Probably, the etiologic agents are similar to those reported in Latin America, but the resistance profile could be different in each country.2020 Versporten A, Bielicki J, Drapier N, Sharland M. Goossens H on behalf of ARPEC project. The Worldwide Antibiotic Resistance and Prescribing in European Children (ARPEC) point prevalence survey: developing hospital-quality indicators of antibiotic prescribing for children. J Antimicrob Chemother. 2016;71:1106-17. This information is mandatory to guide governmental policies and regional and local actions that should be implemented to prevent VAP in neonates. To our knowledge, this is the first systematic review in Brazil studying agents causing VAP in NICU.
Data of VAP rates in, exclusively, Brazilian NICU were described in two reports, with incidence density ranging from 3.2 to 9.2/1000 ventilator-days. These data are higher than those reported for NHSN surveillance, but similar to rates reported by Wójkowska-Mach et al. in six Polish NICU (3.1/1000 NICU patient days) between 2009 and 2011 and by Tekin et al. in a 4-year device-associated nosocomial infections surveillance in a single NICU of Turkey (6.4 per 1000/ventilator days).2121 Wójkowska-Mach J, Merritt TA, Borszewska-Kornacka M, et al. Device-associated pneumonia of very low birth weight infants in Polish Neonatal Intensive Care Units. Adv Med Sci. 2016;61:90-5.,2222 Tekin R, Dal T, Pirinccioglu H, Oygucu SE. A 4-year surveillance of device-associated nosocomial infections in a neonatal intensive care unit. Pediatr Neonatol. 2013;54:303e308. In another study included in our analysis, Rosenthal et al described VAP rates in 30 NICU from a multicenter study and included two Brazilian NICU, but it was not possible to determine the exact rate in these two units.
There are some limitations in our review. Studies reporting VAP etiological agents that could have been reported in others sources of research such as congress abstracts and regional governmental reports, were not included in this research. Usually these reports come from single healthcare institutions but provide useful information about local data.
In conclusion, etiological agents causing VAP in Brazilian NICU are, until the present time, not known. We suggest inclusion of VAP etiological agents in systematic reports of Brazilian National system surveillance as well more studies including epidemiology data from all Brazilian regions.
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FundingThe author(s) received no financial support for the research, authorship, and/or publication of this article.
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Peer review statementNot commissioned; blind peer-reviewed.
Acknowledgments
The authors thank all members of Laboratory of Teaching of Prevention and Control of Healthcare-Associated Infections (Cristiane Henriques Teixeira, Lucia Santos Werneck, Andreia Medeiros and Patricia Ribeiro) for support.
Appendix A Annex. Quality criteria for application per study design. Integrated quality criteria for review of multiple study designs (ICROMS)
b
Annex. Decision matrix of mandatory criteria and minimum score for study type to be included in the review
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4Critérios Diagnósticos de Infecção Relacionada à Assistência à Saúde Neonatologia. Série Segurança do Paciente e Qualidade em Serviços de Saúde. Brasil: ANVISA; 2013. Available at: https://www20.anvisa.gov.br/segurancadopaciente/index.php/publicacoes/item/criterios-diagnosticos-de-infeccoes-relacionadas-a-assistencia-a-saude-neonatologia [accessed 17 December.
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» http://www.nrz-hygiene.de/en/surveillance/hospital-infection-surveillance-system/neo-kiss/ -
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» https://www.cdc.gov/nhsn/index.html -
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» https://www20.anvisa.gov.br/segurancadopaciente/index.php/publicacoes/item/boletim-seguranca-do-paciente-e-qualidade-em-servicos-de-saude-n-16-avaliacao-dos-indicadores-nacionais-das-infeccoes-relacionadas-a-assistencia-a-saude-iras-e-resistencia-microbiana-do-ano-de-2016 -
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12Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700.
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13Zingg W, Castro-Sanchez E, Secci FV, et al. Innovative tools for quality assessment: integrated quality criteria for review of multiple study designs (ICROMS). Public Health. 2016;133:19-37.
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15Pessoa-Silva CL, Richtmann R, Calil R, et al. Healthcare-associated infections among neonates in Brazil. Infect Control Hosp Epidemiol. 2004;25:772-7.
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16Rosenthal VD, Lynch P, Jarvis WR, et al. International Nosocomial Infection Control Consortium members. Socioeconomic impact on device-associated infections in limited-resource neonatal intensive care units: findings of the INICC. Infection. 2011;39:439-50.
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17Urzedo JE, Levenhagen MM, Pedroso RS, Abdallah VO, Sabino SS, Brito DV. Nosocomial infections in a neonatal intensive care unit during 16 years: 1997-2012. Rev Soc Bras Med Trop. 2014;47:321-6.
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18Hocevar SN, Edwards JR, Horan TC, Morrell GC, Iwamoto M, Lessa FC. Device-associated infections among neonatal intensive care unit patients: incidence and associated pathogens reported to the National Healthcare Safety Network, 2006-2008. Infect Control Hosp Epidemiol. 2012;33:1200-6.
-
19Papan C, Meyer-Buehn M, Laniado G, Nicolai T, Griese M, Huebner J. Assessment of the multiplex PCR‑based assay Unyvero pneumonia application for detection of bacterial pathogens and antibiotic resistance genes in children and neonates. Infection. 2018;46:189-96.
-
20Versporten A, Bielicki J, Drapier N, Sharland M. Goossens H on behalf of ARPEC project. The Worldwide Antibiotic Resistance and Prescribing in European Children (ARPEC) point prevalence survey: developing hospital-quality indicators of antibiotic prescribing for children. J Antimicrob Chemother. 2016;71:1106-17.
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21Wójkowska-Mach J, Merritt TA, Borszewska-Kornacka M, et al. Device-associated pneumonia of very low birth weight infants in Polish Neonatal Intensive Care Units. Adv Med Sci. 2016;61:90-5.
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22Tekin R, Dal T, Pirinccioglu H, Oygucu SE. A 4-year surveillance of device-associated nosocomial infections in a neonatal intensive care unit. Pediatr Neonatol. 2013;54:303e308.
Publication Dates
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Publication in this collection
Jul-Aug 2018
History
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Received
29 Mar 2018 -
Accepted
15 June 2018 -
Published
05 July 2018