You are here

  • Home
  • Archive
  • Volume 14, Issue 8
  • Influence of HIV status on outcomes of children admitted with sepsis at a paediatric hospital in Zambia: protocol for a prospective longitudinal study

Article Text

Article menu

Download PDFPDF

HIV/AIDS
Protocol
Influence of HIV status on outcomes of children admitted with sepsis at a paediatric hospital in Zambia: protocol for a prospective longitudinal study
  1. Jonathan Gwasupika1,2,
  2. Davidson Hamer3,4,
  3. Victor Daka5,
  4. Ruth L Mfune5,
  5. Choolwe Jacobs2
  1. 1Department of Clinical Sciences, Tropical Diseases Research Centre, Ndola, Zambia
  2. 2Department of Epidemiology and Biostatistics, University of Zambia, Lusaka, Zambia
  3. 3Department of Global Health, Boston University, Boston, Massachusetts, USA
  4. 4Department of Medicine, Boston University, Boston, Massachusetts, USA
  5. 5Public Health Department, The Copperbelt University, Kitwe, Copperbelt, Zambia
  1. Correspondence to Mr Victor Daka; dakavictorm{at}gmail.com

Abstract

Introduction Sepsis, a condition of global public health concern, is a major cause of morbidity and mortality, especially in patients with underlying HIV infection. This study aims to determine outcomes, aetiology and antibiotic resistance patterns among children with HIV exposure or infection admitted with a clinical presentation suggestive of sepsis who have confirmed bloodstream infections at Arthur Davison Children’s Hospital (ADCH) in Ndola, Zambia.

Methods and analysis This will be a prospective longitudinal study of 200 children aged <2 years admitted with sepsis at ADCH with two of the following conditions: temperature of 38.0°C, respiratory rate ≥20 breaths per minute and pulse rate ≥90 beats per minute. About 2–5 mL of blood collected from each participant will be inoculated into BACTEC culture bottles and incubated for 5–7 days. Positive cultures will be inoculated onto culture media for subculture followed by species identification followed by antibiotic susceptibility testing. Time-to-event outcomes such as hospital readmission and mortality will be analysed using Kaplan-Meier and Cox proportional hazards. Predictors will be identified using regression methods. All statistical tests will use a 5% significance level with a 95% confidence level. STATA V.16 will be used for statistical analysis.

Ethics and dissemination Ethical clearance and approval have been granted by the Tropical Diseases Research Centre Ethics Committee (TDRC-EC 092/07/23). Caregiver consent will be obtained verbally for participants presenting as medical emergencies, and written informed consent will be obtained once stable. Findings from this study will be shared with the Ministry of Health Zambia and will be disseminated to the scientific community through peer-reviewed scientific journals.

  • PAEDIATRICS
  • MICROBIOLOGY
  • INFECTIOUS DISEASES
  • Diagnostic microbiology
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjopen-2023-080607

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    STRENGTHS AND LIMITATIONS OF THIS STUDY

    • This study will investigate sepsis in children infected with HIV and exposed to HIV, a high-risk population.

    • This study will generate critical data on antibiotics suitable for children exposed to HIV, infected with HIV or not infected with HIV, information that is currently lacking in our setting.

    • To enable targeted interventions, our study will investigate risk factors for resistant bacterial species causing bloodstream infections in children at Arthur Davison Children’s Hospital (ADCH).

    • Due to the integration of this study into the routine operations of the facility, study staff may be limited in their control of participants and clinicians who will be responsible for interventions and clinical outcomes in this population.

    • Despite the selection of a referral facility for this study, our generalisation of this data may be limited to only the catchment population ADCH.

    Introduction

    Background

    Sepsis, a condition of global public health concern,1 is a major cause of morbidity and mortality, especially in patients with underlying HIV infection.2 Sepsis can be defined as a life-threatening organ dysfunction caused by an infectious agent.3 The defining features of sepsis include at least two of the following: a white blood cell count of more than 12 x ×109/L or less than 4 x 109/L, temperature equal to or more than 38°C, heart rate more than 90 beats per minute and a respiratory rate more than 20 breaths per minute.4 Bacterial organisms, the major causes of sepsis, can enter the bloodstream via the nasopharynx, lungs, gastrointestinal tracts and genitourinary tracts.5 Sepsis is among the most common opportunistic infections in children infected with HIV.6 Sepsis in children infected with HIV results from the invasion of extrinsic-resistant bacterial normal flora.7 Despite microorganisms differing from place to place, clinical syndromes rather than specific bacteria are managed in the absence of an accompanying microbiological profile.8

    In recent years, sepsis has increasingly been caused by multi-drug-resistant (MDR) bacteria,9 resulting from antibiotic misuse, low-dose prescriptions and the incomplete intake of a prescribed dosage.10 Bacteraemia is becoming more prevalent in patients infected with HIV.11 Antibiotic administration in patients suspected of sepsis is encouraged, ideally immediately after blood collection for culture to determine the causative agent.12 However, sepsis diagnosis is provisional in most children infected with HIV in many low- and middle-income countries,13 and antibiotics are administered empirically at admission prior to blood culture.14 The types of bacteria causing sepsis depend on the patient’s age and premorbid conditions such as HIV.15 The prevalence of HIV in Zambian children is approximately 1.1%,16 with about 64% of children infected with HIV being on antiretroviral therapy.17

    According to the Zambia Demographic Health Survey 2020 (ZDHS), over 30% of children presenting with fever are administered antibiotics despite not knowing the cause.18 There is little known about the epidemiology and outcomes of sepsis and antibacterial resistance among infants infected with HIV.19 A previous study done at ADCH in neonates showed resistance to the first-line and second-line treatments used as empirical treatment in children exposed to HIV and not exposed to HIV.20 However, if no action is taken towards resistant bacteria, there will be continuous pressure on broad-spectrum antibiotics, increasing the likelihood of bacteria becoming resistant and causing sepsis in children.21 While the ultimate cause of death is not identified in these patients, it is likely that a large proportion will succumb to severe sepsis.19

    Despite a high mortality rate in childhood associated with sepsis, there is limited evidence on the causes and outcomes of paediatric bloodstream infections (BSI), especially in the context of HIV infection. In addition, there is a paucity of data on antibiotic susceptibility patterns in children infected with HIV admitted to hospitals with sepsis in Zambia.

    Study rationale

    The identification of pathogens in blood cultures has great diagnostic and prognostic value. Frequent information on common microorganisms and their antimicrobial susceptibility patterns is essential in formulating treatment guidelines for patients. According to WHO 2018 surveillance data, there are high levels of antibiotic resistance to a number of serious bacterial infections in both high- and low-income countries.22

    This study will determine whether the antibiotics administered to children empirically for suspected sepsis in the HIV-infected, the HIV-exposed (children born to mothers infected with HIV) and the HIV-non-exposed and not infected are likely to be effective based on bacterial culture and sensitivity testing and, if not, to develop improved empiric treatment algorithms. The study will highlight the current status of antibiotic resistance in the infant population, bacterial resistance to commonly used antibiotics and the most common bacteria causing infections in infants infected with HIV, exposed to HIV or infants not exposed to or infected with HIV seen at ADCH.

    Methods and analysis

    Main objective

    To determine the outcome, aetiology and antibiotic resistance patterns among children with HIV exposure or infection and those without HIV exposure or infection admitted to Arthur Davison Children’s Hospital (ADCH) in Ndola, Zambia, with sepsis.

    Specific objectives

    1. To evaluate adverse outcomes (duration of hospitalisation, complications of hospitalisation and mortality) among children exposed to or infected with HIV and those without exposure to or infected with HIV admitted with sepsis.

    2. To investigate the common bacteria responsible for BSIs among children admitted with sepsis who are exposed to or infected with HIV and those without exposure to or infected with HIV.

    3. To determine patterns of antibiotic susceptibility among children exposed to or infected with HIV and those who are not exposed to or infected, admitted with sepsis.

    4. To determine factors associated with MDR bacterial infections among children exposed to or infected with HIV and those without exposure or infected with HIV, admitted with sepsis.

    5. To determine factors associated with adverse outcomes in children admitted with sepsis among children exposed to or infected with HIV and those without exposure or infected with HIV, admitted with sepsis.

    Hypothesis

    We hypothesise that there is no difference in children with BSI, MDR bacteria and adverse outcomes (defined as prolonged hospitalisation and/or rehospitalisation during the follow-up period) identified among HIV exposed, HIV infected and HIV uninfected and unexposed.

    Study design and time period

    This will be a prospective longitudinal study of all infants admitted with suspected sepsis from November 2023 to June 2024 at ADCH in Ndola, Zambia.

    Study site

    ADCH is the largest tertiary hospital in the Copperbelt Province of Zambia, with a bed capacity of about 250–300 beds, and it is the only specialised paediatric hospital in the Northern region of Zambia. The majority of infants needing critical medical attention in the province as well as in the nearby provinces of North Western, Luapula, Muchinga and Northern provinces are referred to ADCH. More than 10 infants are admitted to ADCH daily and the majority of the admissions are due to infectious causes.

    Study population

    The study will be conducted on all infants admitted to ADCH with suspected sepsis.

    Inclusion criteria

    For infants to be included in the study, they will need to meet the following criteria:

    1. Less than 2 years of age presenting with a temperature of ≥38.0°C and either a heart rate ≥90 beats per minute or a respiratory rate ≥20 breaths per minute.

    2. Signs and symptoms of a possible bacterial infection according to WHO IMNCI criteria.

    Exclusion criteria

    Children whose parents will not provide consent for their child to participate in the study will be excluded.

    Outcomes

    Primary outcomes

    1. All-cause mortality (both in and out of the hospital during the 90-day follow-up).

    2. Blood culture and drug sensitivity results at admission

    Secondary outcomes

    1. Length of hospital stay >72 hours.

    2. Mortality for days 30 and 90

    3. Unplanned readmission within 30 days and 90 days after discharge

    4. Bacteria causing bloodstream infections.

    Sample size

    To calculate the sample size, we assumed to detect about 53.0% of confirmed bloodstream infection in children exposed to or infected with HIV23 and about 26.0% in children not exposed to or infected with HIV.24 A 95% CI was used with a ratio of 1:1 between the exposed and the unexposed group with the outcome being a positive blood culture for bacteria. Taking a potential loss to follow-up rate of 20% into consideration and 80% power, a sample size of 200 participants was calculated using Stata V.16.

    Sampling strategy

    Due to the success of option B+ for the prevention of mother-to-child transmission, many fewer children in Zambia are HIV infected. Although we originally planned to have differential recruitment (with recruitment of HIV-positive children only on Mondays and Wednesdays), the protocol has been amended to have daily recruitment of all three categories of children. The sampling strategy is shown in figure 1.

    Figure 1
    Figure 1

    Sampling strategy.

    Data collection procedure

    Confirmation of HIV infection in exposed children is done at 6 weeks of age by DNA PCR.25 However, the HIV status of the child will be obtained from the under-five card and confirmation will be done with the guardian or caregiver. After obtaining written informed consent from the child’s caregiver, demographic and clinical information obtained at admission will be entered in electronic case report forms on a mobile application installed with REDCap. The phone number of the guardian or caregiver for the participant will be obtained for follow-up contact. The duration of hospitalisation will be determined for all children from the date of admission to an outcome event, which can either be discharge or death.26 Discharged participants will be contacted at day 30 after discharge via a phone interview to determine the well-being of the child and whether the child was later re-hospitalised or died. Table 1 outlines the schedule of activities during the course of the study.

    View this table:
    Table 1

    Schedule of study activities

    Sample collection

    To determine the causative bacteria and antibiotic susceptibilities, blood samples will be collected at admission for bacterial culture. The skin will be cleaned with a disinfectant solution before the withdrawal of blood. Thereafter, 3–5 mL of blood will be drawn aseptically from a peripheral vein and injected into a BACTEC Peds Plus (Becton Dickinson, Ireland) culture bottle.

    Sample analysis

    The blood sample will be sent to the microbiology laboratory at ADCH. Incubation in an automated machine at 37°C will be done immediately on receipt of the specimen for 5–7 days. After the automated BACTEC machine detects a positive culture within 24–72 hours, inoculation onto different culture media for subculture and organism identification will be performed using gram stain and biochemical tests. Thereafter, antibiotic susceptibility testing will be done using the Kirby-Bauer disc diffusion method, as per the Clinical and Laboratory Standards Institute guidelines.27 Commonly used antibiotics, namely amoxicillin, cotrimoxazole, ceftriaxone and erythromycin, will be used for antibiotic susceptibility testing depending on the gram stain and biochemical results. The growth of multiple bacterial organisms will be considered contaminants.28 However, if a pathogen and a common contaminant are isolated from the same culture, this will be classified as BSI with the pathogen.29

    Data management and analysis

    Collected data will be cleaned using data cleaning scripts in REDCap and then exported to STATA software V.16 SE (STATA Corp) for statistical analysis. Continuous variables will be compared univariably between HIV infected (n=67), HIV exposed (n=66), and HIV non-infected or non-exposed (n=67) in children admitted with sepsis using means and SDs (or median and IQR where non-normal), and categorical variables using χ2 or Fisher’s exact tests. To test for any difference in means between two continuous variables, a t test will be used for normally distributed data and a non-parametric Wilcoxon rank-sum (Mann-Whitney) test will be used for skewed data to find differences between medians. Time-to-event outcomes such as hospital readmission and mortality will be analysed and compared between HIV infected, HIV exposed, and HIV non-exposed or non-infected using Kaplan-Meier and Cox proportional hazards. Predictors of these outcomes will be identified using regression methods to identify an exploratory model with adequate control of confounding. The interpretation of effects will focus on those with p<0.05. Survival and logistic regression methods will be used to determine the relationship between the outcome and explanatory variables. All statistical tests will be tested at a 5% significance level with a 95% confidence level.

    Patient and public involvement

    The study results will be shared with ADCH management to bridge the gap between the study findings and the management of the patients. Patients and the public will not be directly involved in the conduct of the study.

    Ethics and dissemination

    Ethical clearance and approval for the study have been granted by the Tropical Diseases Research Centre Ethics Committee (TDRC-EC 092/07/23) and the National Health Research Authority. Permission to carry out the study and access patient information at ADCH has been obtained from ADCH hospital management. Confidentiality of patient information will be maintained as study data will be restricted to the principal investigator or designated study staff. Names of study participants will not be displayed on the data collection tool; instead, serial numbers will be used to identify the patients.

    Consent

    Verbal consent will be sought from parents or guardians whose children present as emergencies and written informed consent obtained once the child is stabilised. Written consent will be sought from the parent or guardian after they have been given information about the study, an information leaflet offered or read out and time allowed for consideration. The right of the participant to refuse to participate without giving reasons will be respected. All participants will be free to withdraw at any time from the study without giving reasons and without prejudicing further management or treatment.

    Publication policy and dissemination plans

    All publications and presentations relating to the study will be authorised by the principal investigator (PI) and will include at least the study PI, local mentor and international mentor. The PI will be the custodian of the data and specimens generated from the study. Study data will not be the property of the participating healthcare facility where the data were generated but upon request, the data can be shared with the respective institutions. Study findings will be presented at ADCH and at local and international conference or scientific symposia. Additionally, the findings from the study will be shared with the Ministry of Health and will be disseminated to the scientific community through peer-reviewed scientific journals.

    Ethics statements

    Patient consent for publication

    Acknowledgments

    The authors would like to thank the management of the TDRC for their support in the development of the protocol. They would also like to thank Harvard, Boston and the North Western University of New Mexico (HBNU) for their continued support.

    References

    1. ↵
      1. Rudd KE,
      2. Johnson SC,
      3. Agesa KM, et al
      . Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet 2020;395:200–11. doi:10.1016/S0140-6736(19)32989-7
      OpenUrlCrossRefPubMed
    2. ↵
      1. Huson MAM,
      2. Grobusch MP,
      3. van der Poll T
      . The effect of HIV infection on the host response to bacterial sepsis. Lancet Infect Dis 2015;15:95–108. doi:10.1016/S1473-3099(14)70917-X
      OpenUrlCrossRefPubMedWeb of Science
    3. ↵
      1. Reinhart K,
      2. Daniels R,
      3. Kissoon N, et al
      . Recognizing Sepsis as A Global Health Priority - A WHO Resolution. N Engl J Med 2017;377:414–7. doi:10.1056/NEJMp1707170
      OpenUrlCrossRefPubMed
    4. ↵
      1. Cassini A,
      2. Högberg LD,
      3. Plachouras D, et al
      . Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis. Lancet Infect Dis 2019;19:56–66. doi:10.1016/S1473-3099(18)30605-4
      OpenUrlCrossRefPubMed
    5. ↵
      1. Okomo U,
      2. Akpalu ENK,
      3. Le Doare K, et al
      . Aetiology of invasive bacterial infection and antimicrobial resistance in neonates in sub-Saharan Africa: a systematic review and meta-analysis in line with the STROBE-NI reporting guidelines. Lancet Infect Dis 2019;19:1219–34. doi:10.1016/S1473-3099(19)30414-1
      OpenUrlCrossRefPubMed
    6. ↵
      1. Nesheim SR,
      2. Balaji A,
      3. Hu X, et al
      . Opportunistic Illnesses in Children With HIV Infection in the United States, 1997-2016. Pediatr Infect Dis J 2021;40:645–8. doi:10.1097/INF.0000000000003154
      OpenUrl
    7. ↵
      1. Sampane-Donkor E,
      2. Badoe EV,
      3. Annan JA, et al
      . Colonisation of antibiotic resistant bacteria in a cohort of HIV infected children in Ghana. Pan Afr Med J 2017;26:60. doi:10.11604/pamj.2017.26.60.10981
      OpenUrl
    8. ↵
      1. Bernabé KJ,
      2. Langendorf C,
      3. Ford N, et al
      . Antimicrobial resistance in West Africa: a systematic review and meta-analysis. Int J Antimicrob Agents 2017;50:629–39. doi:10.1016/j.ijantimicag.2017.07.002
      OpenUrlCrossRef
    9. ↵
      1. Folgori L,
      2. Bielicki J
      . Future Challenges in Pediatric and Neonatal Sepsis: Emerging Pathogens and Antimicrobial Resistance. J Pediatr Intensive Care 2019;8:17–24. doi:10.1055/s-0038-1677535
      OpenUrl
    10. ↵
      1. Naylor NR,
      2. Atun R,
      3. Zhu N, et al
      . Estimating the burden of antimicrobial resistance: a systematic literature review. Antimicrob Resist Infect Control 2018;7:58. doi:10.1186/s13756-018-0336-y
      OpenUrl
    11. ↵
      1. Japiassú AM,
      2. Amâncio RT,
      3. Mesquita EC, et al
      . Sepsis is a major determinant of outcome in critically ill HIV/AIDS patients. Crit Care 2010;14:R152. doi:10.1186/cc9221
    12. ↵
      1. Tavaré A,
      2. O’Flynn N
      . Recognition, diagnosis, and early management of sepsis: NICE guideline. Br J Gen Pract 2017;67:185–6. doi:10.3399/bjgp17X690401
      OpenUrlFREE Full Text
    13. ↵
      1. Olaru ID,
      2. Tacconelli E,
      3. Yeung S, et al
      . The association between antimicrobial resistance and HIV infection: a systematic review and meta-analysis. Clin Microbiol Infect 2021;27:846–53. doi:10.1016/j.cmi.2021.03.026
      OpenUrlCrossRef
    14. ↵
      1. Zar HJ,
      2. Workman L,
      3. le Roux SM, et al
      . A randomized controlled trial of intermittent compared with daily cotrimoxazole preventive therapy in HIV-infected children. AIDS 2010;24:2225–32. doi:10.1097/QAD.0b013e32833d4533
      OpenUrlCrossRefPubMedWeb of Science
    15. ↵
      1. Alebachew G,
      2. Teka B,
      3. Endris M, et al
      . Etiologic Agents of Bacterial Sepsis and Their Antibiotic Susceptibility Patterns among Patients Living with Human Immunodeficiency Virus at Gondar University Teaching Hospital, Northwest Ethiopia. Biomed Res Int 2016;2016:5371875. doi:10.1155/2016/5371875
    16. ↵
      ZAMBIA POPULATION-BASED HIV IMPACT ASSESSMENT ZAMPHIA. 2016.
    17. ↵
      1. Mutanga JN,
      2. Mutembo S,
      3. Ezeamama AE, et al
      . Long-term survival outcomes of HIV infected children receiving antiretroviral therapy: an observational study from Zambia (2003-2015). BMC Public Health 2019;19:115. doi:10.1186/s12889-019-6444-7
    18. ↵
      1. ZSA
      2. MOH
      3. UTHVL
      4. et al
      . Zambia demographic and health survey 2018. 2020.
    19. ↵
      1. Jacob ST,
      2. Moore CC,
      3. Banura P, et al
      . Severe sepsis in two Ugandan hospitals: a prospective observational study of management and outcomes in a predominantly HIV-1 infected population. PLoS ONE 2009;4:e7782. doi:10.1371/journal.pone.0007782
    20. ↵
      1. Gwasupika J,
      2. Kaonga P,
      3. Jacobs C
      . Antibiotic Resistance and Associated Factors for Neonatal Sepsis at a Selected Children’s Hospital in Zambia. Int J Heal Sci Res 2021;11:295–303.
      OpenUrl
    21. ↵
      1. Murray CJ,
      2. Ikuta KS,
      3. Sharara F
      . Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 2022;399:629–55. doi:10.1016/S0140-6736(21)02724-0
      OpenUrlCrossRefPubMed
    22. ↵
      1. WHO
      . WHO report on surveillance of antibiotic consumption: 2016-2018 early implementation. World Health Organization; 2018.128.
    23. ↵
      1. Jaspan HB,
      2. Huang LC,
      3. Cotton MF, et al
      . Bacterial disease and antimicrobial susceptibility patterns in HIV-infected, hospitalized children: a retrospective cohort study. PLoS ONE 2008;3:e3260. doi:10.1371/journal.pone.0003260
    24. ↵
      1. Weiss SL,
      2. Fitzgerald JC,
      3. Pappachan J, et al
      . Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study. Am J Respir Crit Care Med 2015;191:1147–57. doi:10.1164/rccm.201412-2323OC
      OpenUrlCrossRefPubMed
    25. ↵
      1. Ministry of Health
      . Zambia guidelines for treatment and prevention of hiv infection. 2020.138.
    26. ↵
      1. Boeddha NP,
      2. Schlapbach LJ,
      3. Driessen GJ, et al
      . Mortality and morbidity in community-acquired sepsis in European pediatric intensive care units: a prospective cohort study from the European Childhood Life-threatening Infectious Disease Study (EUCLIDS). Crit Care 2018;22:143. doi:10.1186/s13054-018-2052-7
    27. ↵
      1. Clinical ana laboratry Standard Institute
      . M100 Performance Standards for Antimicrobial Susceptibility Testing A CLSI Supplement for Global Application. 28th edn.
    28. ↵
      1. Hossain B,
      2. Weber MW,
      3. Hamer DH, et al
      . Classification of Blood Culture Isolates Into Contaminants and Pathogens on the Basis of Clinical and Laboratory Data. Pediatr Infect Dis J 2016;35:S52–4. doi:10.1097/INF.0000000000001107
      OpenUrlPubMed
    29. ↵
      1. Mwananyanda L,
      2. Pierre C,
      3. Mwansa J, et al
      . Preventing Bloodstream Infections and Death in Zambian Neonates: Impact of a Low-cost Infection Control Bundle. Clin Infect Dis 2019;69:1360–7. doi:10.1093/cid/ciy1114
      OpenUrlPubMed

    Footnotes

    • X @vmdaka

    • Contributors JG conceptualised the study, wrote the first draft and acted as the guarantor. VD and RLM reviewed and edited the manuscript. CJ and DH performed the editing, reviewed the manuscript and supervised the conduct of the study.

    • Funding This work was supported by Fogarty International Center and National Institute of Mental Health of the National Institutes of Health—Award Number D43 TW010543.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.