Rethink Respiratory Rate for Diagnosing Childhood Pneumonia

One in six childhood deaths is caused by pneumonia, making it the largest infectious cause of death for children worldwide [[1]United Nations Inter-agency Group for Child Mortality Estimation, (UN IGME) Levels and trends in child mortality: Report 2017. United Nations Children's Fund, New York2017 Oct 26Google Scholar], particularly in low and middle-income countries (LMIC) where timely pneumonia diagnosis is a much greater challenge because of limited resources [[2]McAllister D.A. Liu L. Shi T. Chu Y. Reed C. Burrows J. et al.Global, regional, and national estimates of pneumonia morbidity and mortality in children younger than 5 years between 2000 and 2015: a systematic analysis.Lancet Glob Health. 2019; 7 (Jan): e57Summary Full Text Full Text PDF Scopus (250) Google Scholar]. The World Health Organization (WHO) defines pneumonia as the presence of fast breathing and/or chest indrawing in children who present with cough or cold and/or difficulty breathing. If diagnosed early, antibiotic therapy can be initiated to effectively treat pneumonia [[3]Drake D.E. Cohen A. Cohn J. National hospital antibiotic timing measures for pneumonia and antibiotic overuse.Qual Manag Health Care. 2007; 16 (Apr): 113-122Crossref PubMed Scopus (27) Google Scholar]. Fast breathing had long been considered a sensitive clinical sign of pneumonia in a child with cough or difficulty breathing [[4]Palafox M. Guiscafré H. Reyes H. Munoz O. Martínez H. Diagnostic value of tachypnoea in pneumonia defined radiologically.Arch Dis Child. 2000; 82 (Jan): 41-45Crossref PubMed Scopus (96) Google Scholar], particularly in LMIC. The WHO has recommended that community health workers (CHWs) use the respiratory rate (RR) for diagnosis and that they treat pneumonia in children according to specific case-management algorithms [[5]World Health Organization Integrated management of childhood illness: Caring for newborns and children in the community.2011Google Scholar]. There are numerous technologies for measuring RR by detecting changes in selected parameters, such as exhaled carbon dioxide, air temperature, humidity and chest wall movement [6AL-Khalidi F.Q. Saatchi R. Burke D. Elphick H. Tan S. Respiration rate monitoring methods: a review.Pediatr Pulmonol. 2011; 46 (Jun): 523-529Crossref PubMed Scopus (325) Google Scholar, 7Daw W. Medical devices for measuring respiratory rate in children: a review.Journal of Advances in Biomedical Engineering and Technology. 2016; 3 (May 31)Crossref Google Scholar]. Each method has strengths and limitations, and most of them are not suitable for LMIC [[8]UNICEF supply division Pneumonia diagnostics: Current outlook and perspectives. UNICEF, 2013https://Www.unicef.org/supply/files/pneumonia_diagnostics_aid_devices_and_prespective.PDFGoogle Scholar]. In this journal, Baker et al. [[9]Baker K. Alfvén T. Mucunguzi A. wharton-smith A. dantzer E. habte T. et al.Performance of four respiratory rate counters to support community health workers to detect the symptoms of pneumonia in children in low resource settings: a prospective, multicentre, hospital-based, single-blinded, comparative trial.EClinicalMedicine. 2019; https://doi.org/10.1016/j.eclinm.2019.05.013Summary Full Text Full Text PDF PubMed Scopus (18) Google Scholar] report the outcome of a clinical study that assessed the performance of four non-contact relatively simple manual RR counters for use by CHWs in screening for pneumonia among 454 sick children in LMIC settings. Those methods included the Mark Two ARI timer (MK2 ARI), counting beads with an ARI timer, the Rrate Android phone, and the Respirometer feature phone applications. The development of the protocol and methods are nicely described in a video produced by the authors (https://www.malariaconsortium.org/resources/video-library/927/protocol-film-implementing-a-trial-to-evaluate-pneumonia-diagnostic-devices). All four devices were compared to an automated RR counter using Masimo capnography reference measurements. The results showed that while CHWs were able to obtain RRs from children in the majority of cases, the agreement of their measurements with the reference standard was low for all devices tested. Counting RRs using the four devices, albeit simple, was also associated with a huge inter-observer variability, thus characterizing “human counting” as being subjective and unreliable. Accurate and reliable counting in young infants was especially difficult, with only 8–20% of the assessments being in agreement with the reference standard, regardless of the RR device used. Though this was the first large, multicenter evaluation of the use of RR counting aids to diagnose pneumonia by CHW in children <5 y, the results of this study agree with previous studies. For example, CHWs correctly diagnosed and treated only 40% of all cases of childhood pneumonia by counting the RR in two Ugandan studies [10Källander K. Tomson G. Nsabagasani X. Sabiiti J.N. Pariyo G. Peterson S. Can community health workers and caretakers recognise pneumonia in children? Experiences from western Uganda.Trans R Soc Trop Med Hyg. 2006; 100: 956-963Summary Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 11Mukanga D. Babirye R. Peterson S. Pariyo G.W. Ojiambo G. Tibenderana J.K. et al.Can lay community health workers be trained to use diagnostics to distinguish and treat malaria and pneumonia in children? Lessons from rural Uganda.Trop Med Int Health. 2011; 16 (Oct): 1234-1242Crossref PubMed Scopus (94) Google Scholar]. In our more recent study in the Democratic Republic of Congo [[12]Amirav I. Masumbuko C.K. Hawkes M.T. Poor agreement and imprecision of respiratory rate measurements in children in a low-income setting.Am J Respir Crit Care Med. 2018; 198 (Dec 1,): 1462-1463Crossref PubMed Scopus (10) Google Scholar], we observed that movement, crying, and stranger anxiety, particularly in children <3 y, were significant impediments to accurate assessment of RR. Ginsburg et al.'s systematic review provided an overview of the RR measurement tools that have undergone clinical evaluations of accuracy against a reference standard among spontaneously breathing children <5 y [[13]Ginsburg A.S. Lenahan J.L. Izadnegahdar R. Ansermino J.M. A systematic review of tools to measure respiratory rate in order to identify childhood pneumonia.Am J Respir Crit Care Med. 2018; 197 (May 1,): 1116-1127Crossref PubMed Scopus (43) Google Scholar]. Unfortunately, most of those accuracy studies were not done and/or validated in LMIC. There are also concerns about the validity of the various reference standards used in such studies, including the one used by Baker et al. An editorial by Ansermino et al. [[14]Ansermino J.M. Dumont G. Ginsburg A.S. How 'uncertain' is our reference standard for respiratory rate measurement?.Am J Respir Crit Care Med. 2019; 199 (Jan 23,): 1036-1037Crossref PubMed Scopus (8) Google Scholar] suggested that the tolerance level should be an order of magnitude greater than the random variation observed with the reference device when comparing reference and investigational medical devices. Thus, they argue that “RR measurement studies would benefit from an uncertainty (probabilistic) approach to the reference standard, including procedures to measure and reduce this uncertainty”. The reference issue notwithstanding, the measurement of RR in children remains challenging. Non-contact devices, such as those employed in the Baker et al. study, are thought to cause less distress to the child and therefore are less likely to alter the child's RR. However, they still rely on the CHW to count the RR or to tap the screen of a phone, and both CHW-based methods are prone to error and lead to overdiagnosis and/or underdiagnosis and inappropriate treatment. Baker et al. state that “counting RR manually, with breaths being difficult to see and count being hard to maintain without interruptions that require the count to be repeated, is a difficult procedure to do accurately and more is required of a device than simply supporting the health workers to keep count of the number of breaths a patient takes over 60 seconds.” We agree entirely. We believe that there is an urgent need to re-think our existing dogmas about using RR as a stand-alone or sole diagnostic criterion for diagnosing pneumonia. Detecting work of breathing (WOB), for example, has recently emerged as being useful and even superior to breath counting in the diagnosis of pneumonia, particularly in severe cases [15Rambaud-Althaus Clotilde Althaus Dr Fabrice, MD|Genton, Blaise, Prof|D'Acremont, Valérie, MD. Clinical features for diagnosis of pneumonia in children younger than 5 years: a systematic review and meta-analysis.Lancet Infectious Diseases, The. 2015; 15: 439-450Summary Full Text Full Text PDF PubMed Scopus (129) Google Scholar, 16Naydenova E, Tsanas A, Howie S, Casals-Pascual C, De Vos M. The power of data mining in diagnosis of childhood pneumonia. J R Soc Interface 2016 Jul;13(120):20160266.Google Scholar, 17Shah S.N. Bachur R.G. Simel D.L. Neuman M.I. Does this child have pneumonia?: the rational clinical examination systematic review.JAMA. 2017; 318 (Aug 1,): 462-471Crossref PubMed Scopus (107) Google Scholar], and it warrants further investigation. Accumulating literature suggests that the use of a combination of signs and symptoms and potential point of care (POC) markers may be better than RR as a stand-alone tool. A systematic review by Rambaud-Althaus et al. concluded that any decision tree based solely on a single clinical sign is unlikely to increase diagnostic precision of childhood pneumonia [[15]Rambaud-Althaus Clotilde Althaus Dr Fabrice, MD|Genton, Blaise, Prof|D'Acremont, Valérie, MD. Clinical features for diagnosis of pneumonia in children younger than 5 years: a systematic review and meta-analysis.Lancet Infectious Diseases, The. 2015; 15: 439-450Summary Full Text Full Text PDF PubMed Scopus (129) Google Scholar]. In accordance with that review, a set of carefully designed machine learning tools combining four quantifiable vital signs (RR, heart rate, O2 saturation, and temperature) was shown to support multi-faceted diagnoses of childhood pneumonia [[16]Naydenova E, Tsanas A, Howie S, Casals-Pascual C, De Vos M. The power of data mining in diagnosis of childhood pneumonia. J R Soc Interface 2016 Jul;13(120):20160266.Google Scholar]. Similar conclusions were reached by another systematic review by Shah et al. in 2017 [[17]Shah S.N. Bachur R.G. Simel D.L. Neuman M.I. Does this child have pneumonia?: the rational clinical examination systematic review.JAMA. 2017; 318 (Aug 1,): 462-471Crossref PubMed Scopus (107) Google Scholar]. The latter review suggested that WOB is a better predictor than RR for diagnosing pneumonia. This year, a study from Tanzania suggested an interesting combination of clinical signs (RR and WOB) coupled with POC (e.g., C-reactive protein levels) to increase diagnostic yield of pneumonia and reduce antibiotic prescription [[18]Keitel K. Samaka J. Masimba J. Temba H. Said Z. Kagoro F. Mlaganile T. Sangu W. Genton B. D’Acremont V. Safety and Efficacy of C-reactive Protein–guided Antibiotic Use to Treat Acute Respiratory Infections in Tanzanian Children: A Planned Subgroup Analysis of a Randomized Controlled Noninferiority Trial Evaluating a Novel Electronic Clinical Decision Algorithm (ePOCT).Clin Infect Dis. 2019; (Published on line 2019 Feb 2)PubMed Google Scholar]. Finally, a large study from Malawi challenged the role of RR in the management of nonsevere fast-breathing pneumonia [[19]Ginsburg A.S. Mvalo T. Nkwopara E. McCollum E.D. Ndamala C.B. Schmicker R. et al.Placebo vs amoxicillin for nonsevere fast-breathing pneumonia in malawian children aged 2 to 59 months: a double-blind, randomized clinical noninferiority trial.JAMA Pediatr. 2018; 173 (Nov 12): 21Crossref Scopus (37) Google Scholar]. This was a double-blind, 2-arm, randomized clinical noninferiority trial on 1343 children aged 2 to 59 months with pneumonia with a follow-up of 14 days. There was no significant difference in outcome between children who received antibiotics or placebo by day 14. The authors cite a 2016 Cochrane review that found that there is insufficient evidence for antibiotic use as a means of preventing suppurative complications, such as pneumonia [[20]. Alves Galvão MG, Rocha Crispino Santos, Marilene Augusta, Alves da Cunha, Antonio J L. Antibiotics for preventing suppurative complications from undifferentiated acute respiratory infections in children under five years of age. Cochrane Database Syst Rev 2016 Feb 29,;2:CD007880.Google Scholar]. In line with previous studies [[21]Muro F. Mtove G. Mosha N. Wangai H. Harrison N. Hildenwall H. et al.Effect of context on respiratory rate measurement in identifying non-severe pneumonia in african children.Trop Med Int Health. 2015; 20 (Jun): 757-765Crossref PubMed Scopus (22) Google Scholar], the 2019 study from Malawi suggest that the diagnostic yield of fast breathing among children with true bacterial pneumonia appeared to have been low, implying that fast breathing might be neither an appropriately sensitive nor a specific sign of bacterial pneumonia, thus challenging the role of RR in the diagnosis of pneumonia. In summary, the Baker et al. study as well as emerging literature calls for a radically different approach to better diagnose pneumonia in children. We need to think out of the box as we approach the 3rd decade of the 21st century. Conception, design, and drafting of the manuscript: I.A., M.L. None declared. Performance of Four Respiratory Rate Counters to Support Community Health Workers to Detect the Symptoms of Pneumonia in Children in Low Resource Settings: A Prospective, Multicentre, Hospital-Based, Single-Blinded, Comparative TrialNone of the four devices evaluated performed well based on agreement with the reference standard. The ARI timer currently recommended for use by CHWs should only be replaced by more expensive, equally performing, automated RR devices when aspects such as usability and duration of the device significantly improve the patient-provider experience. Full-Text PDF Open Access

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