key: cord-0902754-fkkxsd07
authors: Hussein, Rasha; Guedes, Murilo Henrique; Ibraheim, Nada; Ali, Mazin M.; El-Tahir, Amal; Allam, Nahla; Abuakar, Hussain; Pecoits-Filho, Roberto; Kotanko, Peter
title: Impact of COVID-19 and malaria Coinfection on Clinical Outcomes: A Retrospective Cohort Study
date: 2022-03-31
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2022.03.028
sha: fd3e8d55f404fe76524ffce270e279b52dc7be60
doc_id: 902754
cord_uid: fkkxsd07

OBJECTIVES: Despite the possibility of concurrent infection with COVID-19 and malaria, little is known about the clinical course of coinfected patients. We analysed the clinical outcomes of patients with concurrent COVID-19 and malaria infection. METHODS: We conducted a retrospective cohort study that assessed prospectively collected data of all patients who were admitted between May and December 2020 to the Universal COVID-19 treatment center (UCTC), Khartoum, Sudan. UCTC compiled demographic, clinical, laboratory (including testing for malaria), and outcome data in all patients with confirmed COVID-19 hospitalized at that clinic. The primary outcome was all-cause mortality during the hospital stay. We built proportional hazard Cox models with malaria status as the main exposure and stepwise adjustment for age, gender, cardiovascular comorbidities, diabetes, and hypertension. RESULTS: We included 591 patients with confirmed COVID-19 diagnosis who were also tested for malaria. Mean (SD) age was 58 (16.2) years, 446/591 (75.5%) were males. Malaria was diagnosed in 270/591 (45.6%) patients. Most malaria patients were infected by Plasmodium falciparum (140/270; 51.9%), 121/270 (44.8%) were coinfected with Plasmodium falciparum and Plasmodium vivax. Median follow-up was 29 days. Crude mortality rates were 10.71 and 5.87 per 1,000 person-days for patients with and without concurrent malaria, respectively. In the fully adjusted Cox model, patients with concurrent malaria and COVID-19 had a greater mortality risk (hazard ratio 1.43, 95% confidence interval 1.21-1.69). CONCLUSION: Coinfection with COVID-19 and malaria is associated with increased all-cause in-hospital mortality compared to monoinfection with SARS-CoV-2.

Objectives: Despite the possibility of concurrent infection with COVID-19 and malaria, little is 24 known about the clinical course of coinfected patients. We analysed the clinical outcomes of 25 patients with concurrent COVID-19 and malaria infection. 26

Methods: We conducted a retrospective cohort study that assessed prospectively collected data 27 of all patients who were admitted between May and December 2020 to the Universal COVID-19 28 treatment center (UCTC), Khartoum, Sudan. UCTC compiled demographic, clinical, laboratory 29 (including testing for malaria), and outcome data in all patients with confirmed COVID-19 30 hospitalized at that clinic. The primary outcome was all-cause mortality during the hospital stay. 31

We built proportional hazard Cox models with malaria status as the main exposure and stepwise 32 adjustment for age, gender, cardiovascular comorbidities, diabetes, and hypertension. Plasmodium vivax. Median follow-up was 29 days. Crude mortality rates were 10.71 and 5.87 38 per 1,000 person-days for patients with and without concurrent malaria, respectively. In the fully 39 adjusted Cox model, patients with concurrent malaria and COVID-19 had a greater mortality risk 40 (hazard ratio 1.43, 95% confidence interval 1.21-1.69).

The COVID-19 pandemic disproportionally affects low-and middle income countries (LMIC). 1, 2 In 46 Sudan, a Sub-Saharan LMIC, poor health care literacy and the spread of false information further 47 centers, and home isolation. All admitted patients had either COVID-19 confirmed by reverse 67 transcription-polymerase chain reaction (RT-PCR), or suspected by clinical presentation and chest 68 computer tomography. On admission, all patients without previously confirmed COVID-19 were 69 tested by SARS-CoV-2 RT-PCR from nasopharyngeal and/or oropharyngeal swabs. 70

Malaria infection was screened by both an antigen-based rapid diagnostic test (RDT) and 71 microscopic confirmation of Plasmodium falciparum (PF) and/or Plasmodium vivax (PV). 72

The Ecotest® Malaria PF/Pan Rapid Test Device -MAL-W23M is a chromatographic immunoassay 73 (CIA) for rapid qualitative determination of antigen in whole blood. This test depends on the 74 presence of PF histidine-rich protein II (HRP-II) specific to PF and plasmodium lactate 75 dehydrogenase (pLDH) specific to PV in human blood sample; it has been applied with thin or 76 thick microscopy on clinical samples. The results showed sensitivity and specificity of 99.9% and 77 over 99%, respectively, relative to microscopy. All RDTs were maintained at room temperature 78 until first use. RDTs were labelled with a sample identification number and the date on which the 79 test was performed. Tests were conducted per manufacturer's instructions. 80

All patients with confirmed COVID-19 who were tested for malaria were included in this study. 81

Patients who were diagnosed with malaria before admission (N=13), were re-tested using RDT 82 and microscopy. Per our laboratory's experience, the Ecotest® is accurate and performs well 83 even in low parasite density. 84

Demographic, clinical, laboratory, and outcome data were extracted from the medical records 85 and entered into an electronic, study-specific data base. Steps to ensure data integrity and 86 privacy were implemented. 87 J o u r n a l P r e -p r o o f (MOH), Khartoum. Expedited review was conducted by the MOH Ethics Review Committees and 90 approval was granted (protocol COVID-19/001/2020). 91

The primary exposure was coinfection with malaria and SARS-CoV-2, as defined above. We use generalized estimating equations (GEE) with independence working covariance structure 120 to estimate the associations between malaria on survival. GEE models are used to estimate 121 population average effects in the presence of correlations between analysis units. In this study, 122 we use geographical location as the cluster. 123

Proportional hazards assumptions are tested by inspection of Kaplan-Meier curves and testing 124 log(time) interaction with malaria status. Effect modification of the Khartoum region on the 125 malaria exposure is tested by including an interaction term between region and malaria in the 126 fully adjusted model. Additionally, effect modification by age is tested by an interaction term 127 between median age and malaria in the fully adjusted model. Missingness is assumed to be 128 completely at random (MCAR) and a complete case analysis is performed. 129 estimated in models including age, gender, hypertension, diabetes, and cardiovascular diseases 131 as covariates. Sensitivity analysis according to malaria severity is performed. 132

All analyses are performed using R software 4. 1 (Tables S4 and S5 ). More patients in the severe malaria group needed oxygen support 160 (95%) as compared to non-severe malaria (91%) and to those without malaria diagnosis (89%). 161

Oxygen flow rates for were 11.3 (± 4.6), 9.3 (± 4.7) and 10.5 (±4.8) L/min for severe malaria, non-162 severe malaria and non-malaria groups, respectively. 163

Median follow-up was 29 days. Crude mortality rates were 10.71 and 5.87 per 1,000 person-days 164 in the malaria and non-malaria groups, respectively (Figure 2) . Median length of hospital stay 165 was 21 days (IQR: 14-28) for the malaria group and 20 days (IQR: 15-28) for the non-malaria group 166 (p=0.49; Wilcoxon test). The median period between symptom onset and hospital admission was 167 six days (IQR: 5-9) in the malaria group and eight days (IQR: 5-11) in the non-malaria group 168 (p=0.005; Wilcoxon test). 169 outcomes among coinfected subjects. A meta-analysis of observational data and case series 217 however, clinical outcomes have not been addressed. 10 The impact of coinfection on 220 hematological and hepatic outcomes was reported in 12 patients with coinfection: 221 hyperbilirubinemia and mild anemia were seen in four (33%) and two (17%) patients, 222 respectively 15 . The rates of jaundice (2.1%) and severe anemia (3.8%) were lower in our cohort. 223

Our study has several strengths, first and foremost the availability of detailed health records and 225 a well organized, systematic and robust testing strategy for both COVID-19 and malaria. Almost 226 93% of patients admitted to UCTC were tested for COVID-19 and malaria, mitigating bias by 227

indication. In addition, the study population comprises patients from urban and rural areas. 

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