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IMPACT OF INTEGRATED COMMUNITY CASE MANAGEMENT ON SEVERE MALARIA IN A HIGH TRANSMISSION AREA IN NORTHERN ZAMBIA by Ben Kussin-Shoptaw A thesis submitted to Johns Hopkins University in conformity with the requirements for the degree of Master of Science Baltimore, Maryland April 2020 i Abstract Background: Mortality due to severe malaria remains elevated in rural, high transmission areas despite more than a decade of control measures. Progression from uncomplicated to severe malaria is rapid, with death occurring within one to two days after symptom onset if no treatment is given. Individuals living farther away from healthcare facilities have higher odds of death from severe malaria than those living closer, suggesting that inaccessibility to care may be a key driver of mortality within these populations. To alleviate this distance-related barrier to care, community health workers in northern Zambia were trained to diagnose, treat, and refer severe malaria cases to the nearest health center or hospital as part of a rollout of an integrated community case management program (iCCM). This thesis assessed the impact of iCCM in Nchelenge District, Luapula Province, Zambia on severe malaria metrics. Methods: The study population was a before-and-after cross sectional study of children ≤15 years old admitted for severe malaria (N=1,115) to the children’s ward of St. Paul’s General Hospital from October 2017 - May 2019. Patient demographics, inpatient registry diagnoses, and hematological data were collated and examined for associations with severe malaria and severe malaria mortality in a pre-post analysis. A multivariable logistic model was constructed to look for potential changes in these associations over time. Time-matched case-control data (N=107 per group) were fitted to conditional logistic regression models to account for unmeasured confounders potentially obscuring the relationship between distance and severe malaria death. Finally, kriging models were generated and mapped to visualize the relationship between Euclidean distance to the hospital and in-hospital mortality. Results: Of the 1,119 children hospitalized during the study period, a total of 1,115 had available outcome data. Demographically they were similar across the entire time period, with a median ii age of 1.9 years (interquartile range [IQR] 1.1-3.0), 53% were male, and 10% were refugees from the Democratic Republic of Congo residing in the Kenani Transit Camp (pre) or Mantapala Refugee Settlement (post) in Nchelenge District, Zambia. Case fatality did not significantly differ between the periods before and after iCCM implementation (13% vs. 15%, p=0.24). The most frequent complication of severe malaria was severe anemia (N=257, 23%), which was slightly reduced in the post-iCCM period from 25% to 20%. Consistent with this, the median hemoglobin concentration was higher after iCCM implementation (7.4 g/dL, IQR 4.1-9.8) than before (6.0 g/dL, IQR 4.1-8.7). The proportions of patients with sepsis physiology and thrombocytopenia followed a similar trend. Children admitted during the post-implementation period resided a median distance from the hospital of 11 km (IQR 2.3-25 km), a trending increase from the pre-iCCM median of 7 km (IQR 2.5-18 km). When controlling for age, sex, refugee status, and concomitant diagnoses (severe anemia, sepsis, pneumonia, gastroenteritis, meningitis, protein-calorie malnutrition), increased distance was no longer associated with severe malaria death after iCCM implementation (adjusted odds ratio [aOR] 1.01, 95% CI 0.99-1.04, p=0.18) despite being strongly associated with the outcome in the overall model (aOR 1.02, 95% CI 1.01-1.02, p=0.003). In the case-control study, patients were being admitted from more distant villages in the post-iCCM period, with cases coming from villages a median of 17 km (IQR 5-25 km) away from the hospital compared to 4 km (IQR 2-15 km) for controls (p=0.049). Kriged maps visually depicted a reduction in case fatality at further distances from the hospital in the post- compared to pre-iCCM period and identified temporally changing hotspots of severe malaria mortality throughout the district. Conclusions: Although no difference was seen in severe malaria mortality before and after iCCM implementation, findings support that iCCM led to earlier diagnosis and referral overall, iii and a greater number of referrals of children from more distant villages. Clinicians may begin to see more severe patients as iCCM continues its rollout and previously hard to reach patients have access to the health system. Continual monitoring of this patient population will elucidate further the true impact of iCCM and its effectiveness in limiting severe malaria mortality. iv Primary Reader and Advisor: William J. Moss Secondary Ready: Matthew M. Ippolito Acknowledgements I would first and foremost like to thank the people of Nchelenge District and St. Paul’s General Hospital for being so welcoming and helpful during my time there—natotela sana. I would also like to thank Dr. Jean-Bertin Kabuya, Dr. Mike Chaponda, Clifford Tende, and the rest of the Tropical Diseases Research Centre Team for allowing me the opportunity to work, live, and play alongside them in Kashikishi. In particular I’d like to extend my gratitude to James Lupiya, who made me feel like a member of the village by the time of my departure. I thank Dr. Clive Shiff for starting me on this pathway and sharing enough wonderful stories, life lessons, and inspiration to fuel my passion for years to come. I want to thank Dr. Matthew Ippolito for guiding me throughout the data collection, analysis, and writing processes while allowing me an opportunity to present this work at the highest levels of science. I thank him also for his constant support and advice—both professional and philosophical. I am eternally grateful to Dr. Bill Moss for allowing me the opportunity to go conduct this research and his guidance throughout my graduate school experience. I want to thank my partner Marissa Hetrich for her faith in me, her endless patience as I wrote deep into the night and into early morning hours, and most of all for her love. Finally, I would like to thank my mom, Jody Kussin, dad, Steve Shoptaw, my siblings, and the rest of my family and friends for their support of me throughout both this thesis process and my life in general. v Table of Contents Abstract .......................................................................................................................................... ii Acknowledgements ....................................................................................................................... v Glossary ....................................................................................................................................... vii List of Tables .............................................................................................................................. viii List of Figures ............................................................................................................................... ix I. Introduction ........................................................................................................................... 1 1.1 Clinical and Epidemiologic Background ............................................................................. 1 1.2 Barrier of Distance and Integrated Community Case Management ................................. 4 1.3 Objectives and Aims ............................................................................................................... 6 II. Patient Characterization and Risk Factor Analysis ........................................................... 9 2.1 Introduction ........................................................................................................................... 9 2.2 Methods .................................................................................................................................. 9 2.3 Results ................................................................................................................................... 13 2.4 Conclusions........................................................................................................................... 25 III. Before-and-After Case-Control Study of iCCM Impact .................................................. 29 3.1 Introduction ......................................................................................................................... 29 3.2 Methods ................................................................................................................................ 29 3.3 Results ................................................................................................................................... 31 3.4 Conclusions........................................................................................................................... 37 IV. Geospatial Analysis of iCCM Impact ................................................................................ 38 4.1 Introduction ......................................................................................................................... 38 4.2 Methods ................................................................................................................................ 39 4.3 Results ................................................................................................................................... 40 4.4 Conclusions..........................................................................................................................
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