current malaria infection previous malaria exposure and clinical profiles and outcomes CORD-Papers-2022-06-02 (Version 1)

Title: Current malaria infection previous malaria exposure and clinical profiles and outcomes of COVID-19 in a setting of high malaria transmission: an exploratory cohort study in Uganda
Abstract: BACKGROUND: The potential effects of SARS-CoV-2 and Plasmodium falciparum co-infection on host susceptibility and pathogenesis remain unknown. We aimed to establish the prevalence of malaria and describe the clinical characteristics of SARS-CoV-2 and P falciparum co-infection in a high-burden malaria setting. METHODS: This was an exploratory prospective cohort study of patients with COVID-19 who were admitted to hospital in Uganda. Patients of all ages with a PCR-confirmed diagnosis of SARS-CoV-2 infection who had provided informed consent or assent were consecutively enrolled from treatment centres in eight hospitals across the country and followed up until discharge or death. Clinical assessments and blood sampling were done at admission for all patients. Malaria diagnosis in all patients was done by rapid diagnostic tests microscopy and molecular methods. Previous P falciparum exposure was determined with serological responses to a panel of P falciparum antigens assessed using a multiplex bead assay. Additional evaluations included complete blood count markers of inflammation and serum biochemistries. The main outcome was overall prevalence of malaria infection and malaria prevalence by age (including age categories of 020 years 2140 years 4160 years and >60 years). The frequency of symptoms was compared between patients with COVID-19 with P falciparum infection versus those without P falciparum infection. The frequency of comorbidities and COVID-19 clinical severity and outcomes was compared between patients with low previous exposure to P falciparum versus those with high previous exposure to P falciparum. The effect of previous exposure to P falciparum on COVID-19 clinical severity and outcomes was also assessed among patients with and those without comorbidities. FINDINGS: Of 600 people with PCR-confirmed SARS-CoV-2 infection enrolled from April 15 to Oct 30 2020 597 (>99%) had complete information and were included in our analyses. The majority (502 [84%] of 597) were male individuals with a median age of 36 years (IQR 2847). Overall prevalence of P falciparum infection was 12% (95% CI 94146; 70 of 597 participants) with highest prevalence in the age groups of 020 years (22% 87448; five of 23 patients) and older than 60 years (20% 102341; nine of 46 patients). Confusion (four [6%] of 70 patients vs eight [2%] of 527 patients; p=0040) and vomiting (four [6%] of 70 patients vs five [1%] of 527 patients; p=0014] were more frequent among patients with P falciparum infection than those without. Patients with low versus those with high previous P falciparum exposure had a increased frequency of severe or critical COVID-19 clinical presentation (16 [30%] of 53 patients vs three [5%] of 56 patients; p=00010) and a higher burden of comorbidities including diabetes (12 [23%] of 53 patients vs two [4%] of 56 patients; p=00010) and heart disease (seven [13%] of 53 patients vs zero [0%] of 56 patients; p=00030). Among patients with no comorbidities those with low previous P falciparum exposure still had a higher proportion of cases of severe or critical COVID-19 than did those with high P falciparum exposure (six [18%] of 33 patients vs one [2%] of 49 patients; p=0015). Multivariate analysis showed higher odds of unfavourable outcomes in patients who were older than 60 years (adjusted OR 87 95% CI 10755; p=0049). INTERPRETATION: Although patients with COVID-19 with P falciparum co-infection had a higher frequency of confusion and vomiting co-infection did not seem deleterious. The association between low previous malaria exposure and severe or critical COVID-19 and other adverse outcomes will require further study. These preliminary descriptive observations highlight the importance of understanding the potential clinical and therapeutic implications of overlapping co-infections. FUNDING: Malaria Consortium (USA).
Published: 2021-10-25
Journal: Lancet Microbe
DOI: 10.1016/s2666-5247(21)00240-8
DOI_URL: http://doi.org/10.1016/s2666-5247(21)00240-8
Author Name: Achan Jane
Author link: https://covid19-data.nist.gov/pid/rest/local/author/achan_jane
Author Name: Serwanga Asadu
Author link: https://covid19-data.nist.gov/pid/rest/local/author/serwanga_asadu
Author Name: Wanzira Humphrey
Author link: https://covid19-data.nist.gov/pid/rest/local/author/wanzira_humphrey
Author Name: Kyagulanyi Tonny
Author link: https://covid19-data.nist.gov/pid/rest/local/author/kyagulanyi_tonny
Author Name: Nuwa Anthony
Author link: https://covid19-data.nist.gov/pid/rest/local/author/nuwa_anthony
Author Name: Magumba Godfrey
Author link: https://covid19-data.nist.gov/pid/rest/local/author/magumba_godfrey
Author Name: Kusasira Stephen
Author link: https://covid19-data.nist.gov/pid/rest/local/author/kusasira_stephen
Author Name: Sewanyana Isaac
Author link: https://covid19-data.nist.gov/pid/rest/local/author/sewanyana_isaac
Author Name: Tetteh Kevin
Author link: https://covid19-data.nist.gov/pid/rest/local/author/tetteh_kevin
Author Name: Drakeley Chris
Author link: https://covid19-data.nist.gov/pid/rest/local/author/drakeley_chris
Author Name: Nakwagala Fredrick
Author link: https://covid19-data.nist.gov/pid/rest/local/author/nakwagala_fredrick
Author Name: Aanyu Helen
Author link: https://covid19-data.nist.gov/pid/rest/local/author/aanyu_helen
Author Name: Opigo Jimmy
Author link: https://covid19-data.nist.gov/pid/rest/local/author/opigo_jimmy
Author Name: Hamade Prudence
Author link: https://covid19-data.nist.gov/pid/rest/local/author/hamade_prudence
Author Name: Marasciulo Madeleine
Author link: https://covid19-data.nist.gov/pid/rest/local/author/marasciulo_madeleine
Author Name: Baterana Byarugaba
Author link: https://covid19-data.nist.gov/pid/rest/local/author/baterana_byarugaba
Author Name: Tibenderana James K
Author link: https://covid19-data.nist.gov/pid/rest/local/author/tibenderana_james_k
sha: d0a050f08cd22ad64818d693fc185826f19f3be0
license: no-cc
license_url: [no creative commons license associated]
source_x: Elsevier; Medline; PMC; WHO
source_x_url: https://www.elsevier.com/https://www.medline.com/https://www.ncbi.nlm.nih.gov/pubmed/https://www.who.int/
pubmed_id: 34723228
pubmed_id_url: https://www.ncbi.nlm.nih.gov/pubmed/34723228
pmcid: PMC8545833
pmcid_url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8545833
url: https://www.sciencedirect.com/science/article/pii/S2666524721002408 https://api.elsevier.com/content/article/pii/S2666524721002408 https://www.ncbi.nlm.nih.gov/pubmed/34723228/ https://doi.org/10.1016/s2666-5247(21)00240-8
has_full_text: TRUE
Keywords Extracted from Text Content: heart p=0·014 people p=0·0030 8·7-44·8 Oct high P falciparum p=0·049 p=0·0010 serum biochemistries patients participants individuals COVID-19 blood p=0·040 co-infections SARS-CoV-2 Patients dobutamine heart epinephrine infants CIs FN TGF-β1 [13] [14] [15] gamma-glutamyl transferase oral DNA Th2 cytokines kit liver p=0·55 p=0·026 Oct intravenous heparin GEXP18 Plasmodium falciparum Agape p=0·042 p=0·0010 serum biochemistries highexposure participants n/N blood BD FACSCalibur flow cytometer × children Puteaux Novartis Oct 8 microscopist low-exposure UK 5·8 Patient appendix p 6 Serum appendix pp 10-11 azithromycin 125-250 PubMed 5·4 merozoite surface protein 1.19 apical membrane antigen 1 early-transcribed membrane protein (Etramp5.Ag1) blood samples p=0·0090 appendix p 4 CRP oral warfarin appendix p 5 IL-6 blood cells France ProXL trations 13·9 border Patients JA intravenous artesunate Th) 1 transforming growth factor β lungs TNF-α IL-10 COVID-19 patient p=0·0040 malariaendemic AMA-1 IL-2 162·9 glutamate-rich protein region 2 BD WBCs vitamin D serum albumin IL-7 paracetamol appendix p=0·049 p=0·52 patients chest p=0·0080 COVID-19 renal GLURP.R2 interleukin (IL)-2 oxygen lowexposure anticoagulants COVID-19 case-management appendix p 3 platelet p<0·1 IL-8 malaria-disease intravenous HA 5·9 human T-helper cell OR P falciparum Burkina Faso cellular p=0·029 Rh2.2030 Shanghai, China JKT kin patient appendix p 2 artemetherlumefantrine tablets case-management 7·7 co-infections p=0·077 SARS-CoV-2 Achan patients COVID-19 UK
Extracted Text Content in Record: First 5000 Characters:Methods This was an exploratory prospective, cohort study of patients with COVID-19 who were admitted to hospital in Uganda. Patients of all ages with a PCR-confirmed diagnosis of SARS-CoV-2 infection who had provided informed consent or assent were consecutively enrolled from treatment centres in eight hospitals across the country and followed up until discharge or death. Clinical assessments and blood sampling were done at admission for all patients. Malaria diagnosis in all patients was done by rapid diagnostic tests, microscopy, and molecular methods. Previous P falciparum exposure was determined with serological responses to a panel of P falciparum antigens assessed using a multiplex bead assay. Additional evaluations included complete blood count, markers of inflammation, and serum biochemistries. The main outcome was overall prevalence of malaria infection and malaria prevalence by age (including age categories of 0-20 years, 21-40 years, 41-60 years, and >60 years). The frequency of symptoms was compared between patients with COVID-19 with P falciparum infection versus those without P falciparum infection. The frequency of comorbidities and COVID-19 clinical severity and outcomes was compared between patients with low previous exposure to P falciparum versus those with high previous exposure to P falciparum. The effect of previous exposure to P falciparum on COVID-19 clinical severity and outcomes was also assessed among patients with and those without comorbidities. Of 600 people with PCR-confirmed SARS-CoV-2 infection enrolled from April 15, to Oct 30, 2020, 597 (>99%) had complete information and were included in our analyses. The majority (502 [84%] of 597) were male individuals with a median age of 36 years (IQR 28-47). Overall prevalence of P falciparum infection was 12% (95% CI 9·4-14·6; 70 of 597 participants), with highest prevalence in the age groups of 0-20 years (22%, 8·7-44·8; five of 23 patients) and older than 60 years (20%, 10·2-34·1; nine of 46 patients). Confusion (four [6%] of 70 patients vs eight [2%] of 527 patients; p=0·040) and vomiting (four [6%] of 70 patients vs five [1%] of 527 patients; p=0·014] were more frequent among patients with P falciparum infection than those without. Patients with low versus those with high previous P falciparum exposure had a increased frequency of severe or critical COVID-19 clinical presentation (16 [30%] of 53 patients vs three [5%] of 56 patients; p=0·0010) and a higher burden of comorbidities, including diabetes (12 [23%] of 53 patients vs two [4%] of 56 patients; p=0·0010) and heart disease (seven [13%] of 53 patients vs zero [0%] of 56 patients; p=0·0030). Among patients with no comorbidities, those with low previous P falciparum exposure still had a higher proportion of cases of severe or critical COVID-19 than did those with high P falciparum exposure (six [18%] of 33 patients vs one [2%] of 49 patients; p=0·015). Multivariate analysis showed higher odds of unfavourable outcomes in patients who were older than 60 years (adjusted OR 8·7, 95% CI 1·0-75·5; p=0·049). Interpretation Although patients with COVID-19 with P falciparum co-infection had a higher frequency of confusion and vomiting, co-infection did not seem deleterious. The association between low previous malaria exposure and severe or critical COVID-19 and other adverse outcomes will require further study. These preliminary descriptive observations highlight the importance of understanding the potential clinical and therapeutic implications of overlapping co-infections. SARS-CoV-2 has caused considerable morbidity and mortality globally, with more than 236 million cases and 4·83 million deaths reported by Oct 8, 2021 . 1 Since the first reported cases in Africa on Feb 14, 2020, SARS-CoV-2 has spread to all countries in the continent and has caused unprecedented socio economic and health-care system disruptions. 2 Although sub-Saharan Africa has a relatively low global proportion of COVID-19 cases and deaths compared with other continents, 3 it has a disproportionately higher burden of other infectious diseases, including malaria, HIV/AIDS, and tuberculosis. [4] [5] [6] The potential effects of COVID-19 on the control of these diseases and the potential implications of any clinical interactions between COVID-19 and these diseases therefore remains a major public health concern in Africa, especially when geographical overlap results in high levels of co-infection. However, despite the global spread of SARS-CoV-2, our understanding of the epidemiology and clinical course of COVID-19 in countries with substantial burdens of other infectious diseases is limited. The magnitude of clinical overlap between these diseases and COVID-19 and the potential consequences of co-infection also remains largely unknown. Whereas previous predictive models suggest possibly lower mortality from COVID-19 in Africa than in high-income countries, 7 several modelling studies and reports indicate that a
Keywords Extracted from PMC Text: renal serum biochemistries Plasmodium falciparum p=0·047 Serum 41–60 anticoagulants infants AMA-1 merozoite surface protein 1.19 patients vitamin D azithromycin HA liver Burkina Faso serum albumin p=0·042 appendix p 5 Rh2.2030 TNF-α COVID-19 case-management guidelines 5·4 Novartis outcomes,26 participants TGF-β1 artemether-lumefantrine intravenous dexamethasone blood samples early-transcribed membrane protein low-exposure appendix p 2 described.21 appendix p 6 apical membrane antigen 1 BD IL-8 transforming growth factor β p=0·0080 IL-2 BD FACSCalibur flow cytometer heart p=0·55 COVID-19.17 p=0·0090 MSP1.19 intravenous malaria13 ProXL liver-enzyme Oct 8 " case-management p<0·1 diagnosis.25 blood cells COVID-19 CRP CIs children Africa).4 blood France Th2 cytokines kit patient appendix p 7 −43·2 GEXP18 appendix pp 10–11 microscopist IL-7 DNA oral warfarin platelet disruptions.2 −3·0 guidelines.19 Blood-sample Patient −0·9 SARS-CoV-2 p=0·0040 oral high-malaria-burden 162·9 paracetamol 5·9 appendix p 8) p=0·019 p=0·077 p=0·0050 Th) 1 interleukin (IL)-2 oxygen 213·6 dobutamine IL-10 human T-helper cell epinephrine gamma-glutamyl transferase cellular FN appendix p 3).20 −65344·4 mortality.33 COVID-19 pandemic.8 Agape co-infections Puteaux p=0·52 −4283·4 appendix p 4 lungs WBCs UK intravenous heparin appendix p 9 −8·2 Oct 7·7 intravenous artesunate chest p=0·026 p=0·029 P falciparum antigens 5·8 Achan COVID-19 patient IL-6 border p=0·049 kin 13·9 malaria-disease −4·9 × −6·3 Patients p=0·036 p=0·0010
Extracted PMC Text Content in Record: First 5000 Characters:SARS-CoV-2 has caused considerable morbidity and mortality globally, with more than 236 million cases and 4·83 million deaths reported by Oct 8, 2021.1 Since the first reported cases in Africa on Feb 14, 2020, SARS-CoV-2 has spread to all countries in the continent and has caused unprecedented socioeconomic and health-care system disruptions.2 Although sub-Saharan Africa has a relatively low global proportion of COVID-19 cases and deaths compared with other continents,3 it has a disproportionately higher burden of other infectious diseases, including malaria, HIV/AIDS, and tuberculosis.4, 5, 6 The potential effects of COVID-19 on the control of these diseases and the potential implications of any clinical interactions between COVID-19 and these diseases therefore remains a major public health concern in Africa, especially when geographical overlap results in high levels of co-infection. However, despite the global spread of SARS-CoV-2, our understanding of the epidemiology and clinical course of COVID-19 in countries with substantial burdens of other infectious diseases is limited. The magnitude of clinical overlap between these diseases and COVID-19 and the potential consequences of co-infection also remains largely unknown. Whereas previous predictive models suggest possibly lower mortality from COVID-19 in Africa than in high-income countries,7 several modelling studies and reports indicate that a large number of excess cases and deaths from HIV/AIDs, tuberculosis, and malaria could occur as a consequence of the COVID-19 pandemic.8, 9, 10, 11, 12 However, the assumptions in some of these models that one disease does not directly influence the transmission or severity of the other and that COVID-19 only affects these diseases by disrupting control measures and affecting health systems have not been verified. Of particular interest among these infections is malaria, which causes substantial morbidity and mortality, with an estimated 229 million cases and 409 000 deaths reported globally in 2019 (>90% in sub-Saharan Africa).4 If co-infections with SARS-CoV-2 and agents such as Plasmodium falciparum should cause increased complications, then the burden of COVID-19 in low-income and middle-income countries could be substantially worse than predicted. Whether immunomodulation caused by malaria13, 14 is beneficial or harmful in the context of co-infection with SARS-CoV-2 is also unclear. Malaria-induced immunomodulation has been shown to be protective against severe manifestations of some respiratory viruses such as influenza,15 by suppressing production of cytokines and decreasing recruitment of cellular inflammatory components to the lungs, leading to milder clinical symptoms and inflammation.16 Previous malaria exposure or pre-existing infection with malaria could therefore plausibly lead to changes in susceptibility and severity of COVID-19.17 However, despite these observations, the effects of malaria and SARS-CoV-2 co-infection on host susceptibility and pathogenesis remain unclear. This preliminary descriptive investigation was conducted in this context to better characterise COVID-19 cases in a setting with a high burden of malaria, and to assess the prevalence and clinical characteristics of SARS-CoV-2 and P falciparum co-infection. This study was an exploratory, prospective, cohort study carried out from April 15, to Oct 30, 2020, at COVID-19 treatment centres in eight tertiary hospitals in Uganda. These included three hospitals in central Uganda, two hospitals in north Uganda, one hospital in east Uganda, one hospital in south Uganda, and one hospital in northwest Uganda (appendix p 2). Using consecutive sampling, we included patients with COVID-19 of all ages who were admitted to hospital, with PCR-confirmed COVID-19 diagnosis, and who had provided informed consent or assent. Written informed consent was obtained from adult patients or their next of kin (for patients who were unconscious or critically ill). Written parental or guardian consent was obtained for all children (aged <18 years) and assent was obtained from patients aged 8–17 years. If a patient could not read or write, a literate adult impartial witness (a member of the clinical team not involved in the study) was present throughout the consenting process and signed and dated the consent form, with a thumb print from the patient. Patients were followed up daily on the wards until discharge or death. The study was approved by the Mulago National Referral Hospital Research and Ethics committee and the Uganda National Council for Science and Technology. The study was also listed on the MESA Track database under the name "Evaluating the impact of COVID-19 on malaria and other infectious diseases in Uganda: Understanding comorbidities". Demographic and clinical information collected included age, sex, presenting complaints, underlying medical conditions, duration of illness, clinical examination findings, diagnosis, and medications prescribed
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