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Post-mortem examination of Hospital Inpatient COVID-19 Deaths in Lusaka, Zambia - A Descriptive Whole-body Autopsy Series

Open AccessPublished:June 16, 2021DOI:https://doi.org/10.1016/j.ijid.2021.06.013

      Highlights

      • Whole body autopsies define pathology of COVID-19 hospital deaths in Africa.
      • A spectrum of pathological manifestations of COVID-19 are seen in all organs.
      • Common findings are Pulmonary thromboembolism, Diffuse Alveolar Damage and Pneumonia.
      • Common comorbidities of TB and HIV, in the younger age group requires further study.

      Abstract

      Background

      Since information on the pathology of COVID-19 from sub-Saharan Africa (SSA) remains scarce, the objective of our study was to define the gross pathology and histological features of COVID-19. We report data from 29 whole-body autopsies of COVID-19 deaths occurring in hospitals in Lusaka, Zambia - the first large autopsy case series from Africa.

      Methods

      We performed a descriptive post-mortem examination study of inpatient COVID-19 related deaths at two hospitals in Lusaka, Zambia. Whole-body autopsies were conducted according to Standard Operating Procedures. Gross and histopathological examinations of all organs were performed. Patient demographics, history, co-morbidities, autopsy gross and microscopic findings, and cause(s) of death were recorded and analyzed using STATA version 14. Variables were grouped and presented as frequencies and percentages.

      Findings

      Autopsies were performed on 29 decedents (mean age = 44 ± 15.8years; age range = 19-82; 17/29 [58.8%] males). 22/29 [75.9%] cases were <55 years of age. A spectrum of pathological manifestations of COVID-19 were seen in all organs. The commonest causes of death were pulmonary thromboembolism (13/29, 45%), Diffuse Alveolar Damage (9/29, 31%), and COVID-19 pneumonia (7/29, 25%). 22/29 (76%) had co-morbidities. Common co-morbidities included HIV (8/29, 28%), Hypertension (6/29, 20%) Tuberculosis (3/29, 10%), Diabetes (3/29, 10%).

      Conclusions

      A spectrum of gross anatomical and histopathological findings are seen in COVID-19 deaths in hospitalized decedents. These appear broadly similar to those reported from China, Europe and USA. Differences include a younger age group, and co-morbidities of HIV and TB co-infection which require further investigation.

      Keywords

      Introduction

      The SARS-CoV-2 pandemic has caused 171,292,827 confirmed COVID-19 cases with 3,687,589 deaths globally as of June 4th, 2021. Of these 3,530,845 cases occurred in sub-Saharan Africa (SSA) with 131,630 deaths (

      WHO Coronavirus dashboard 2021. https://covid19.who.int/ -accessed June 4th, 2021.

      ;

      Africa CDC - Coronavirus Disease 2019 (COVID-19). Latest updates on the COVID-19 crisis from Africa CDC. https://africacdc.org/COVID-19/ -accessed June 4th, 2021.

      ). Zambia reported its first COVID-19 case in March 2020 and has since recorded 96, 563 cases with 1,284 deaths as of June 4th, 202 (

      World Health Organisation, Zambia, https://www.who.int/countries/zmb/ -accessed June 4th, 2021.

      ). Eighteen months after the first COVID-19 cases were reported from Wuhan, China, several major knowledge gaps on COVID-19 pathology and pathogenesis remain, particularly in SSA. The case-fatality ratio (CFR) for COVID-19 in Africa appears lower than the Case Fatality Rate in western countries, indicating that COVID-19 may manifest less severe disease and that the pathogenesis of COVID-19 in SSA may be different (
      • Lawal Y.
      Africa’s low COVID-19 mortality rate: A paradox?.
      ,
      • Bamgboye E.L.
      • Omiye J.A.
      • Afolaranmi O.J.
      • et al.
      COVID-19 Pandemic: Is Africa Different?.
      ).
      An area of continuing neglect and missed opportunities for COVID-19 research in SSA is that of accurately defining the pathological features of COVID-19 and ascertaining the underlying cause(s) of death from COVID-19 in hospitals (
      • Bamgboye E.L.
      • Omiye J.A.
      • Afolaranmi O.J.
      • et al.
      COVID-19 Pandemic: Is Africa Different?.
      ,
      • Mawalla W.F.
      The contribution of autopsy in COVID-19 pandemic: Missed opportunity in Sub-Saharan Africa.
      ,
      • Mucheleng’anga L.
      • Himwaze C.
      The role of forensic pathology in the COVID-19 pandemic in Zambia.
      ). Whilst several reports of whole body autopsy case series and organ specific pathology have been published from China, Europe and USA (
      • Maiese A.
      • Manetti A.C.
      • La Russa R.
      • et al.
      Autopsy findings in COVID-19-related deaths: a literature review.
      ), there is little information on post-mortem examination and the pathology of COVID-19 in SSA. There remains scanty information on the actual causes of death and pathogenesis of COVID-19 from the African continent. There are only two individual case reports of whole body autopsies and lung biopsy studies of four South African ICU patients obtained after death (
      • Mulale U.K.
      • Kashamba T.
      • Strysko J.
      • Kyokunda L.T.
      Fatal SARS-CoV-2 and Mycobacterium tuberculosis coinfection in an infant: insights from Botswana.
      ,
      • Khaba M.C.
      • Ngale T.C.
      • Madala N.
      COVID-19 in an HIV-infected patient. Lessons learned from an autopsy case.
      ,
      • Bruce-Brand C.
      • Allwood B.W.
      • Koegelenberg C.F.N.
      • Lalla U.
      • Louw E.
      • Diacon A.H.
      • et al.
      Postmortem lung biopsies from four patients with COVID-19 at a tertiary hospital in Cape Town, South Africa.
      ). Several reports have emphasized the need for rekindling and revamping autopsy and post-mortem studies in SSA (
      • Mawalla W.F.
      The contribution of autopsy in COVID-19 pandemic: Missed opportunity in Sub-Saharan Africa.
      ,
      • Mucheleng’anga L.
      • Himwaze C.
      The role of forensic pathology in the COVID-19 pandemic in Zambia.
      ,
      • Maiese A.
      • Manetti A.C.
      • La Russa R.
      • et al.
      Autopsy findings in COVID-19-related deaths: a literature review.
      ,
      • Mulale U.K.
      • Kashamba T.
      • Strysko J.
      • Kyokunda L.T.
      Fatal SARS-CoV-2 and Mycobacterium tuberculosis coinfection in an infant: insights from Botswana.
      ,
      • Khaba M.C.
      • Ngale T.C.
      • Madala N.
      COVID-19 in an HIV-infected patient. Lessons learned from an autopsy case.
      ,
      • Bruce-Brand C.
      • Allwood B.W.
      • Koegelenberg C.F.N.
      • Lalla U.
      • Louw E.
      • Diacon A.H.
      • et al.
      Postmortem lung biopsies from four patients with COVID-19 at a tertiary hospital in Cape Town, South Africa.
      ,
      • Mudenda V.
      • Malyangu E.
      • Sayed S.
      • et al.
      Addressing the shortage of pathologists in Africa: Creation of a MMed Programme in Pathology in Zambia.
      ), to determine the underlying pathology and causes of COVID-19 deaths occurring in hospital inpatients.
      Whole-body autopsies in general, and on confirmed or suspected SARS-CoV-2 cases in Africa have not been forthcoming due to scarcity of pathologists, inadequate infrastructure, and difficulties in obtaining consent for autopsies (
      • Mawalla W.F.
      The contribution of autopsy in COVID-19 pandemic: Missed opportunity in Sub-Saharan Africa.
      ,
      • Mucheleng’anga L.
      • Himwaze C.
      The role of forensic pathology in the COVID-19 pandemic in Zambia.
      ,
      • Khaba M.C.
      • Ngale T.C.
      • Madala N.
      COVID-19 in an HIV-infected patient. Lessons learned from an autopsy case.
      ,
      • Rampatige R.
      • Gilks C.F.
      Autopsies and better data on causes of death in Africa.
      ). In addition, performing autopsies in environments where infectious pathogens such as SARS-CoV-2 are suspected or confirmed, requires optimal biosafety facilities (
      • World Health Organization
      Infection prevention and control for the safe management of a dead body in the context of COVID-19.
      ,
      • Baj J.
      • Ciesielka M.
      • Buszewicz G.
      • Maciejewski R.
      • Budzyńska B.
      • Listos P.
      • Teresiński G.
      • et al.
      COVID-19 in the autopsy room–requirements, safety, recommendations and pathological findings.
      ,
      • Liang T.
      • Cai H.
      • Chen Y.
      • et al.
      Handbook of COVID-19 prevention and treatment: The First Affiliated Hospital, Zhejiang University School of Medicine, complied according to clinical experience.
      ), which are unavailable in most African countries.
      The objective of our case series study was to present the histopathological findings following whole-body autopsies in COVID-19 inpatients. We present post-mortem examination data from 29 whole-body autopsies of COVID-19 deaths occurring in hospitals, in Lusaka, Zambia - the first large autopsy case series study from Africa.

      Methods

      Study design and sites

      We conducted a retrospective descriptive study of reports of 29 whole body autopsies we had perfomed of COVID-19 inpatient deaths whose proximate cause of death was SARS-CoV-2 infection (positive SARS-CoV-2 reverse transcriptase-polymerase chain reaction (RT-PCR). The hospital deaths occurred between March 2020 and March 2021 in the COVID-19 isolation wards at the University Teaching Hospital (UTH) and Levy Mwanawasa University Teaching Hospital (LMUTH), Lusaka, Zambia. Selection for autopsy was based according to request by physician

      Ethics permission

      Informed consent from the next-of-kin was obtained to conduct the autopsy and publish the findings. The Office of State Forensic Pathology (OSFP) granted permission to access postmortem data.

      Pre-autopsy procedures

      All staff involved underwent safety training procedures. Clinical case notes were reviewed prior to autopsy. The two autopsy pathologists had rehearsed on how they were to work together, classify and define the autopsy findings. Placement and handling of equipment was also planned. The manner in which the pathologists’ assistant would operate was also discussed and practiced.
      The mortuary and autopsy rooms used to perform the autopsy are had a working refrigeration system and good lighting and water reticulation system, but have no negative pressure ventilation. The bodies were well preserved as the refrigeration was in working condition. The bodies were placed in the mortuary two to three hours after death. The timing of autopsy was between 24 to 72 hours after death. The body was washed using chlorine before autopsy.

      Autopsy procedures

      Whole body autopsies were performed in accordance with the Practice Manual for Medicolegal Death Investigations. The practice manual for medicolegal death investigation is used in Zambia as a local guideline for conducting forensic postmortem examinations. It covers processes to follow for autopsies on bodies infected with category three and four infectious organisms including SARS-CoV-2. In all cases, we followed universal precautions using personal protective equipment (PPE) (hair caps, eye protection, goggles), long sleeved, non-waterproof gown, covered by a water-proof apron. Double pair of standard disposable surgical latex gloves were used. Cut resistant gloves were also used. We used guidance in place with regards to dressing and undressing of PPE when dealing with infected bodies as in the practice manual for medicolegal death investigations.

      Tissues sampled and histological examination

      Representative samples were obtained from the various organs (Brain, Lungs, Heart, Liver, Spleen, Kidneys) and other tissues as required and submitted in standard tissue cassettes and fixed in 10% neutral buffered formalin for 72 hours. The samples were processed, embedded in paraffin, sectioned, mounted onto glass slides, and stained using hematoxylin and eosin (H&E) staining according to the Standard Operating Procedure Manual at the UTH histopathology Laboratory. All slides were examined together by the two forensic and anatomical pathologists.
      The cause of death was formulated within the context of the history, clinical findings, circumstances of death, autopsy findings, and ancillary studies.

      Data collection and analyses

      Data on the decedents’ demographics, history, circumstances, autopsy findings, and opinion of the cause of death was entered in excel and analyzed using STATA version 14. The variables were grouped and presented as frequencies and percentages.

      Results

      Decedent demographics

      Demographics of the autopsied cases are given in Table 1.
      Table 1Demographic characteristics of COVID-19 hospital decedents autopsied.
      Characteristic/VariableHospital Decedents autopsied
      GenderN (%)
      Male17 (58.8)
      Female12 (41.4)
      Total No. decedents autopsied29
      Mean Age (years)44
      Age range19-82
      Age group
      15-252 (6.9)
      26-355 (17.2)
      36-459 (31.0)
      46-556 (20.7)
      56-654 (13.8)
      66-752 (6.9)
      76-851 (3.5)
      Autopsies were performed on 29 decedents (mean age = 44 ± 15.8years; age range = 19-82; 17/29 [58.8%] males).

      Symptoms and Co-morbidities

      The symptoms and comorbidities of the 29 decedents are given in Table 2. Common symptoms observed were; difficulty breathing (n = 24/29, 83%), cough (n = 9/29, 31%), fever (n = 11/29, 38%), headache (n = 6/29, 21%), general body weakness (n = 4/29, 14%).
      Table 2Symptoms and Comorbidities of 29 decedents autopsied.
      SYMPTOM(S) AT ADMISSIONNumber (%)
      Difficulty breathing24(82.8)
      Cough9(31.0)
      Fever11(37.9)
      Headache6(20.7)
      General Body Weakness4(13.8)
      Vomiting2(6.9)
      Diarrhea2(6.9)
      Oral Thrush1(100)
      Abdominal Pain1(3.4)
      CO-MORBIDITIES AT ADMISSION
      HIV positive8(27.6)
      Hypertension6(20.7)
      Tuberculosis3(10.3)
      Diabetes3(10.3)
      Pregnancy2(6.9)
      Cerebral Vascular Accident1(3.4)
      Malaria1(3.4)
      Leprosy1(3.4)
      Atherosclerotic heart disease1(3.4)
      Paraquat toxicity1(3.4)
      Sickle Cell Anaemia1(3.4)
      Overall, 22/29 (76%) decedents had comorbidities. Co-morbidities were present in 22/29 (76%) of decedents. Common co-morbities included HIV (8/29, 27%), Hypertension (6/29, 21%) Tuberculosis (3/29, 10%), Diabetes (3/29, 10%).

      Autopsy findings

      The main gross pathology and microscopic autopsy findings, and cause(s) of death, are given in Table 3.
      Table 3Main autopsy findings and causes of death.
      Autopsy findingsNumber (%)
      Diffuse Alveolar Damage12/29 (41.4)
      Emboli10/29 (34.5)
      Saddle Emboli6/29 (20.7)
      Shower Emboli4/29 (13.8)
      Pneumonia9/29 (31)
      Granular kidneys5/29 (17.2)
      Deep Venous Thrombosis3/29 (10.3)
      Disseminated Thrombi4/29 (13.8)
      Tuberculosis1/29 (3.4)
      Anaemia1/29 (3.4)
      Kaposi Sarcoma1/29 (3.4)
      Colorectal adenocarcinoma1/29 (3.4)
      Main Autopsy Causes of Death
      Pulmonary Thromboembolism13/29 (44.8)
      Diffuse Alveolar Damage9/29 (31.0)
      Pneumonia7/29 (24.2)
      The commonest causes of death were pulmonary thromboembolism (13/29, 45%), Diffuse Alveolar Damage (DAD) (9/29, 31%), and COVID-19 pneumonia (7/29, 25%).

      Gross pathology and Microscopic Findings

      A selection of images representative gross and microscopic autopsy findings are given. Figure 1 (Figures 1A to G) show gross pathology findings.
      Figure 1
      Figure 1A: Brain: Gross appearance showing hyperaemia (white arrow heads).
      B: Lung: Pulmonary thrombus in the pulmonary artery (white arrow head).
      C: Lung: Shower thrombo-emboli and grey hepatisation (white arrow head and bent white arrow up).
      D: Leg: Deep venous thrombosis (white arrow head).
      E: Liver: Thromboemboli in the liver in a case with disseminated thrombosis (white arrow head).
      F: Kidney: Granular surfaces of the kidneys in a case with hypertension.
      G: Kidney: Infarction due to disseminated thrombosis (white arrow heads).
      Figure 1
      Figure 1A: Brain: Gross appearance showing hyperaemia (white arrow heads).
      B: Lung: Pulmonary thrombus in the pulmonary artery (white arrow head).
      C: Lung: Shower thrombo-emboli and grey hepatisation (white arrow head and bent white arrow up).
      D: Leg: Deep venous thrombosis (white arrow head).
      E: Liver: Thromboemboli in the liver in a case with disseminated thrombosis (white arrow head).
      F: Kidney: Granular surfaces of the kidneys in a case with hypertension.
      G: Kidney: Infarction due to disseminated thrombosis (white arrow heads).
      Figure 2 (Figures 2A-F) shows microscopic histopathological findings.
      Figure 2
      Figure 2A: Brain: Micrograph (X 40) of the brain parenchyma showing hemorrhage (white arrow head), around a vessel.
      B: Micrograph (X 20) of lung showing acute (white arrow head) and organising pneumonia (bent white arrow up), and squamous metaplasia (triangle).
      C: Micrograph (X 20) of lung showing a thrombus (white arrow head) and organising pneumonia (bent white arrow up).
      D: Micrograph (X 40) of lung tissue showing diffuse alveolar damage within the lung. The hyaline membranes (blue arrow head) are observed to line the alveolar walls. The alveolar space is indicated by the bent white arrow up.
      E: Micrograph (X 40) of a vessel (bent white arrow up) showing a thrombus (white arrow head).
      F: Micrograph (X 20) of an infarcted kidney showing disseminated thrombus (white arrow head) and neutrophils in the parenchyma in a case (bent white arrow up).
      Figure 2
      Figure 2A: Brain: Micrograph (X 40) of the brain parenchyma showing hemorrhage (white arrow head), around a vessel.
      B: Micrograph (X 20) of lung showing acute (white arrow head) and organising pneumonia (bent white arrow up), and squamous metaplasia (triangle).
      C: Micrograph (X 20) of lung showing a thrombus (white arrow head) and organising pneumonia (bent white arrow up).
      D: Micrograph (X 40) of lung tissue showing diffuse alveolar damage within the lung. The hyaline membranes (blue arrow head) are observed to line the alveolar walls. The alveolar space is indicated by the bent white arrow up.
      E: Micrograph (X 40) of a vessel (bent white arrow up) showing a thrombus (white arrow head).
      F: Micrograph (X 20) of an infarcted kidney showing disseminated thrombus (white arrow head) and neutrophils in the parenchyma in a case (bent white arrow up).

      Overall individual decedent characteristics and autopsy findings

      Table 4 depicts demographic, clinical and autopsy characteristics of each of the 29 decedents that were autopsied.
      Table 4Summary: demographic, clinical and autopsy characteristics of each individual decedent autopsied.
      Case #Sex/AgeSymptomsDuration of illnessComorbiditiesGross pathology and microscopic findingsCause(s) of death
      1M/38Cough, Oral thrush, Diarrhea, Fever, Difficulty in breathing7 daysLeprosy

      Pneumonia
      Heavy lungs (>1000 g each), consolidation of lungs and neutrophils in alveolar spaces and DADPulmonary thromboembolism due to COVID-19
      2M/37Cough

      Difficulty in breathing
      6 daysHIVConsolidation of lungs and neutrophils in alveolar spacesPneumonia due to COVID-19
      3M/40Difficulty in breathing

      Headache, Fever
      14 daysNoneHeavy lungs (>1000 g each), and DADDiffuse Alveolar Damage due to COVID-19
      4M/29Difficulty in breathing5 daysDisseminated Kaposi Sarcoma HIV/AIDSHeavy lungs (>1000 g each), Kaposi sarcoma lesions in the esophagus, stomach, bowel, lungs, skin and DADDiffuse Alveolar Damage due to COVID-19
      5F/40General body weakness Vomiting, Fever7 daysHIV

      Malaria
      Consolidation of lungs and neutrophils in alveolar spacesPneumonia due to COVID-19
      6M/62Cough

      Difficulty in breathing, Fever
      4 daysDiabetes, HypertensionHeavy lungs (>1000 g each), shower thromboemboli, thromboemboli in the heart, granular kidneys, and DADPulmonary thromboembolism due to COVID-19
      7F/47Cough

      Difficulty in breathing, Fever
      5 daysHIVConsolidation of lungs and organising pneumoniaPneumonia due to COVID-19
      8M/55Cough, Fever120 daysHIV

      Disseminated Tuberculosis
      Heavy lungs (>1000 g each) and DADDiffuse Alveolar Damage due to COVID-19
      933/FDifficulty in breathing, cough, Pregnant on claxane5 daysNoneHeavy lungs (>1000 g each), shower thromboemboli, iliac artery thromboembolic, thromboemboli in the heart, and DADPulmonary thromboembolism due to COVID-19
      1038/MCough

      Difficulty in breathing, Fever
      14 daysColorectal adenocarcinoma

      HIV
      Heavy lungs (>1000 g each), colorectal adenocarcinoma, and DADDiffuse Alveolar Damage due to COVID-19
      1137/FCough

      Difficulty in breathing

      Diarrhea and on claxane
      5 daysHypertensionHeavy lungs (>1000 g each), shower thromboemboli, iliac artery thromboembolic, thromboemboli in the heart, and DADPulmonary thromboembolism due to COVID-19
      1248/FDifficulty in breathing, headache8 daysHypertensive heart disease

      HIV
      Consolidation of lungs, granular kidneys, large heart (700 g) and neutrophils in alveolar spaces, glomerular sclerosisPneumonia due to COVID-19
      13M/62Difficulty in breathing3 daysHypertension,

      Diabetes
      Consolidation of lungs, granular kidneys and neutrophils in alveolar spacesPneumonia due to COVID-19
      1432/MGeneral body pains, vomiting14 daysDiabetesHeavy lungs (>1000 g each) and DADDiffuse Alveolar Damage due to COVID-19
      1527/FDifficulty in breathing in pregnancy3 daysSickle cell anemiaHeavy lungs (>1000 g each), and DAD. No sickle cells identifiedDiffuse Alveolar Damage due to COVID-19
      1642/FDifficulty in breathing

      Palpitations
      7 daysPulmonary tuberculosisConsolidation of lungs, and neutrophils in alveolar spacesPneumonia due to COVID-19
      1747/FDifficulty in breathing5 daysNoneSaddle emboli, heavy lungs (>1000 g each), deep venous thrombosis, and DADPulmonary thromboembolism due to Deep Venous Thrombosis due to COVID-19
      1865/MDifficulty in breathingNoneCerebral Vascular AccidentSaddle emboli.Pulmonary thromboembolism due to COVID-19
      1958/MDifficulty in breathing, Headache, Fever on claxane5 daysHypertension

      Obese
      Heavy lungs (>1000 g each), shower emboli, deep venous thrombosis, myocarditis, kidney and brain infarcts and DADPulmonary thromboembolism due to Deep Venous Thrombosis due to COVID-19
      2019/FDifficulty in breathing and Fever3 daysParaquat toxicity treated for 14 daysHeavy hemorrghic lungs (>1000 g each), and DADDiffuse Alveolar Damage due to COVID-19
      2182/MDifficulty in breathing1 dayDiabetes, Atherosclerotic coronary artery heart diseaseHeavy lungs (>1000 g each) and DADDiffuse Alveolar Damage due to COVID-19
      2266/MDifficulty in breathing14 daysHypertensionHeavy lungs (>1000 g each), granular kidneys, and DADDiffuse Alveolar Damage due to COVID-19
      2370/FCough

      Difficulty in breathing on claxane. Death on operation table
      6 daysHypertensionHeavy lungs (>1000 g each), deep venous thrombosis, thrombosed mesenteric vessels, saddle emboli, and DADPulmonary thromboembolism due to COVID-19
      2433/MDifficulty in Breathing, Fever6 daysHIVSaddle emboli, heavy lungs (>1000 g each), consolidated lungs, and neutrophils in alveolar spaces and DADPulmonary thromboembolism due to COVID-19
      2536/MDifficulty in in breathing, Abdominal pains14 daysAbdominal TBMultiples abdominal caseating nodules, saddle thromboembolismPulmonary thromboembolism due to COVID-19
      2620/FHeadache, general body weakness3 daysNoneHeavy lungs (>1000 g each), shower emboli, and DADPulmonary thromboembolism due to COVID-19
      2743/MDifficulty in in breathing1 dayNoneDisseminated thrombi in lungs, liver, iliac vesselsPulmonary thromboembolism due to COVID-19
      2850/MGeneral body weakness, headache1 dayNoneHeavy lungs (>1000 g each), bilateral shower emboli, and DADPulmonary thromboembolism due to COVID-19
      2947/FDifficulty in in breathing, fever, headache6 daysNoneShower emboli, heavy lungs (>1000 g each), organising pneumonia and DADPulmonary thromboembolism due to COVID-19
      Abbreviations: DAD = Diffuse Alveolar Damage.

      Discussion

      To our knowledge, this is the first large COVID-19 whole-body autopsy series of hospital inpatient deaths to be reported from sub-Saharan Africa (SSA) to date. Autopsy studies and data on the pathology of COVID-19 from SSA is scanty and has been restricted only to examination of tissue samples obtained through minimally invasive post-mortem examination of 4 cases in South Africa (
      • Bruce-Brand C.
      • Allwood B.W.
      • Koegelenberg C.F.N.
      • Lalla U.
      • Louw E.
      • Diacon A.H.
      • et al.
      Postmortem lung biopsies from four patients with COVID-19 at a tertiary hospital in Cape Town, South Africa.
      ) and two autopsy reports, one of a COVID-19 and HIV co-infected person (
      • Khaba M.C.
      • Ngale T.C.
      • Madala N.
      COVID-19 in an HIV-infected patient. Lessons learned from an autopsy case.
      ) and another of an infant co-infected with SARS-CoV-2 and Mycobacterium tuberculosis (
      • Mulale U.K.
      • Kashamba T.
      • Strysko J.
      • Kyokunda L.T.
      Fatal SARS-CoV-2 and Mycobacterium tuberculosis coinfection in an infant: insights from Botswana.
      ). Our study provides data from 29 autopsies of hospital COVID-19 deaths. Our descriptions of symptoms ante-mortem, comorbidities, the extent of disease, the cause(s) of death, fill an important knowledge gap on COVID-19 pathology in Africa.
      There were more males than females in our autopsied cases. Published reports suggest that males may be more susceptible to SARS-CoV-2 infection due to their higher plasma Acetylcholinesterase Enzyme 2 (ACE2) levels, less effective antiviral immune defenses than women (
      • Gadi N.
      • Wu S.C.
      • Spihlman A.P.
      • et al.
      What’s Sex Got to Do With COVID-19? Gender-Based Differences in the Host Immune Response to Coronaviruses.
      ). Understanding COVID-19 the gender differences in Africa will require larger cohort studies and include biopsychosocial and immunological investigations (
      • Griffith D.M.
      • Sharma G.
      • Holliday C.S.
      • et al.
      Men and COVID-19: A Biopsychosocial Approach to Understanding Sex Differences in Mortality and Recommendations for Practice and Policy Interventions.
      ).
      The age of our study decedents ranged from 19-82 years, with a mean age of 44. Notably, 22/29 (76.0%) were below the age of 55 years. This is at variance with reported autopsy studies from Europe, China and North America, where the deaths were commonly observed in those above 65 years old (
      • Edler C.
      • Schröder A.S.
      • Aepfelbacher M.
      • et al.
      Dying with SARS-CoV-2 infection-an autopsy study of the first consecutive 80 cases in Hamburg, Germany.
      ,
      • Falasca L.
      • Nardacci R.
      • Colombo D.
      • et al.
      Postmortem Findings in Italian Patients With COVID-19: A Descriptive Full Autopsy Study of Cases With and Without Comorbidities.
      ,
      • Bryce C.
      • Grimes Z.
      • Pujadas E.
      • et al.
      Pathophysiology of SARS-CoV-2: the Mount Sinai COVID-19 autopsy experience.
      ,
      • Bian Xiu-Wu
      • The COVID-19 Pathology Team
      Autopsy of COVID-19 patients in China.
      ). The comparatively younger age may be attributed to Zambia's age structure, where people above the age of 55 are less than 6% of the entire population (

      Index Mundi, Zambia Age structure, https://www.indexmundi.com/zambia/age_structure.html. Accessed on 14/03/2021.

      ). It could also due to HIV being more prevalent in people less than 55 years (
      • Himwaze C.
      • Mucheleng’anga L.
      • Siyumbwa S.
      • et al.
      Prevalence of Human Immunodeficiency Virus, Hepatitis B, and Hepatitis C Viral Infections among Forensic Autopsy Cases at the University Teaching Hospital in Lusaka, Zambia.
      ). HIV may also play a role since it is considered a risk factor for acquiring SARS-CoV-2 infection and is associated with a higher risk of mortality from COVID-19 (
      • Ssentongo P.
      • Heilbrunn E.S.
      • Ssentongo A.E.
      • et al.
      Epidemiology and outcomes of COVID-19 in HIV-infected individuals: a systematic review and meta-analysis.
      ).
      As reported from autopsy studies from outside Africa (
      • Edler C.
      • Schröder A.S.
      • Aepfelbacher M.
      • et al.
      Dying with SARS-CoV-2 infection-an autopsy study of the first consecutive 80 cases in Hamburg, Germany.
      ,
      • Falasca L.
      • Nardacci R.
      • Colombo D.
      • et al.
      Postmortem Findings in Italian Patients With COVID-19: A Descriptive Full Autopsy Study of Cases With and Without Comorbidities.
      ,
      • Bryce C.
      • Grimes Z.
      • Pujadas E.
      • et al.
      Pathophysiology of SARS-CoV-2: the Mount Sinai COVID-19 autopsy experience.
      ,
      • Bian Xiu-Wu
      • The COVID-19 Pathology Team
      Autopsy of COVID-19 patients in China.
      ), difficulty in breathing, cough, fever, and headache were the most common symptoms. This may reflect admission criteria, which selected patients with moderate and severe respiratory symptoms (

      COVID CONTINENT HUB, Interim Clinical Guidance for Management of Patients with Coronavirus Disease 2019 (COVID-19). https://www.c19hub.io/interim-clinical-guidance-for-management-of-patients-with-coronavirus-disease-2019-COVID-19/. -Accessed on 24/03/2021.

      ,
      • Grant M.C.
      • Geoghegan L.
      • Arbyn M.
      • et al.
      The prevalence of symptoms in 24,410 adults infected by the novel coronavirus (SARS-CoV-2; COVID-19): A systematic review and meta-analysis of 148 studies from 9 countries.
      ) and assessment of temperatures during admission (
      • Bian Xiu-Wu
      • The COVID-19 Pathology Team
      Autopsy of COVID-19 patients in China.
      ).
      HIV infection and hypertension co-morbidities were common among our study group and these comorbidities are important compared to the observations made in other autopsy studies from outside Africa (
      • Maiese A.
      • Manetti A.C.
      • La Russa R.
      • et al.
      Autopsy findings in COVID-19-related deaths: a literature review.
      ,
      • Edler C.
      • Schröder A.S.
      • Aepfelbacher M.
      • et al.
      Dying with SARS-CoV-2 infection-an autopsy study of the first consecutive 80 cases in Hamburg, Germany.
      ,
      • Falasca L.
      • Nardacci R.
      • Colombo D.
      • et al.
      Postmortem Findings in Italian Patients With COVID-19: A Descriptive Full Autopsy Study of Cases With and Without Comorbidities.
      ,
      • Bryce C.
      • Grimes Z.
      • Pujadas E.
      • et al.
      Pathophysiology of SARS-CoV-2: the Mount Sinai COVID-19 autopsy experience.
      ,
      • Bian Xiu-Wu
      • The COVID-19 Pathology Team
      Autopsy of COVID-19 patients in China.
      ).
      The range of macroscopic and microscopic pathological features of COVID-19 in hospital deaths in Lusaka, Zambia, greatly resemble those seen in autopsy case series from China, Europe, and USA (
      • Maiese A.
      • Manetti A.C.
      • La Russa R.
      • et al.
      Autopsy findings in COVID-19-related deaths: a literature review.
      ,
      • Edler C.
      • Schröder A.S.
      • Aepfelbacher M.
      • et al.
      Dying with SARS-CoV-2 infection-an autopsy study of the first consecutive 80 cases in Hamburg, Germany.
      ,
      • Falasca L.
      • Nardacci R.
      • Colombo D.
      • et al.
      Postmortem Findings in Italian Patients With COVID-19: A Descriptive Full Autopsy Study of Cases With and Without Comorbidities.
      ,
      • Bryce C.
      • Grimes Z.
      • Pujadas E.
      • et al.
      Pathophysiology of SARS-CoV-2: the Mount Sinai COVID-19 autopsy experience.
      ,
      • Bian Xiu-Wu
      • The COVID-19 Pathology Team
      Autopsy of COVID-19 patients in China.
      ). Diffuse Alveolar Damage (DAD), pulmonary thromboembolism, and pneumonia were the most prevalent autopsy findings, respectively.
      Pulmonary thromboembolism due to SARS-CoV-2 was the most common cause of death in our series. It is now known that thrombosis in decedents with SARS-CoV-2 infection is part of the microangiopathic changes observed in COVID-19 (
      • Maiese A.
      • Manetti A.C.
      • La Russa R.
      • et al.
      Autopsy findings in COVID-19-related deaths: a literature review.
      ). We observed that four patients on anticoagulant therapy (enoxaparin) had died of pulmonary thromboembolism with disseminated thrombosis. Further studies are required to establish the reason why coagulopathy occurs despite anticoagulant preventive therapy. Thromboembolic disease is not uncommon in Zambia at autopsy, however the occurrence of deep vein thrombosis, pulmonary embolism and microthrombi in smaller pulmonary vessels should alert the physician to the possibility of COVID-19 and perform a SARS-CoV-PCR test to confirm of rule out COVID-19.
      Nonetheless, It is important to emphasize that deep vein thrombosis and pulmonary embolism, and microthrombi in the small pulmonary vessels should alert clinicians that they may be pathognomonic signs of COVID-19, especially in SSA.
      DAD due to SARS-CoV-2 was the second most common cause of death. SARS-CoV-2 enters the epithelial lining cells of the respiratory tract using the ACE2 enzyme as a viral receptor leading to DAD and eventually death (
      • Mohanty S.K.
      • Satapathy A.
      • Naidu M.M.
      • et al.
      Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and coronavirus disease 19 (COVID-19) - anatomic pathology perspective on current knowledge.
      ). Pneumonia due to COVID-19 was the third most common cause of death. Patients admitted to the hospital were empirically treated with ceftriaxone and azithromycin (
      COVID-19 rapid guideline: antibiotics for pneumonia in adults in hospital.
      ) to cover the possibility of bacterial pneumonia. Pneumonia due to SARS-CoV-2 was a common finding and thus empiric use of antibiotics may not be appropriate in these cases and needs further study and discussion.
      Autopsies provide the most accurate data about cause of death, but remain operationally difficult and expensive. The World Health Organisation (WHO) recommended that autopsy rooms must be adequately ventilated (
      • World Health Organization
      Infection prevention and control for the safe management of a dead body in the context of COVID-19.
      ). Maximal infection prevention should be provided using full-body suits with air-purifying respirators (
      • Baj J.
      • Ciesielka M.
      • Buszewicz G.
      • Maciejewski R.
      • Budzyńska B.
      • Listos P.
      • Teresiński G.
      • et al.
      COVID-19 in the autopsy room–requirements, safety, recommendations and pathological findings.
      ,
      • Liang T.
      • Cai H.
      • Chen Y.
      • et al.
      Handbook of COVID-19 prevention and treatment: The First Affiliated Hospital, Zhejiang University School of Medicine, complied according to clinical experience.
      ). Autopsies were conducted in a mortuary with inadequate ventilation, and 2 cases were conducted in a well-ventilated mortuary. Although there is no evidence of transmission of SARS-CoV-2 from decedents, we washed the bodies with chlorine and used standard personal protective equipment during the autopsy (
      • World Health Organization
      Infection prevention and control for the safe management of a dead body in the context of COVID-19.
      ,
      • Baj J.
      • Ciesielka M.
      • Buszewicz G.
      • Maciejewski R.
      • Budzyńska B.
      • Listos P.
      • Teresiński G.
      • et al.
      COVID-19 in the autopsy room–requirements, safety, recommendations and pathological findings.
      ,
      • Liang T.
      • Cai H.
      • Chen Y.
      • et al.
      Handbook of COVID-19 prevention and treatment: The First Affiliated Hospital, Zhejiang University School of Medicine, complied according to clinical experience.
      ). The autopsy team members were tested for COVID-19 every two months (or when they became symptomatic) by reverse transcriptase-polymerase chain reaction (RT-PCR) on nasopharyngeal swabs. None of our pathologists or the assistants have tested positive for SARS-CoV-2 indicating that optimal infection control practice reduces risk of acquiring SARS-CoV-2 during autopsies.
      There are several limitations to our study which are inherent to all autopsy studies, including selection bias and the relatively small numbers. However, our study illustrates that autopsies during the COVID-19 era are possible to conduct on SARS-CoV-2 infected subjects in Zambia. There is a need to revive clinical and research autopsies througout sub-Saharan African countries (
      • Mawalla W.F.
      The contribution of autopsy in COVID-19 pandemic: Missed opportunity in Sub-Saharan Africa.
      ,
      • Mucheleng’anga L.
      • Himwaze C.
      The role of forensic pathology in the COVID-19 pandemic in Zambia.
      ,
      • Bruce-Brand C.
      • Allwood B.W.
      • Koegelenberg C.F.N.
      • Lalla U.
      • Louw E.
      • Diacon A.H.
      • et al.
      Postmortem lung biopsies from four patients with COVID-19 at a tertiary hospital in Cape Town, South Africa.
      ,
      • Mudenda V.
      • Malyangu E.
      • Sayed S.
      • et al.
      Addressing the shortage of pathologists in Africa: Creation of a MMed Programme in Pathology in Zambia.
      ,
      • Rampatige R.
      • Gilks C.F.
      Autopsies and better data on causes of death in Africa.
      ,
      • Barth R.F.
      • Xu X.
      • Buja L.M.
      A Call to Action: The Need for Autopsies to Determine the Full Extent of Organ Involvement Associated With COVID-19.
      ,
      • Yi E.S.
      • Cecchini M.J.
      • Bois M.C.
      Pathologists in pursuit of the COVID-19 culprit.
      ) to add to the provisional information provided by our study. Further autopsies with accurate data are required to conjure a more comprehensive picture of the pathogenesis and impact of COVID-19 in SSA.
      Our autopsy study serves as a pivotal starting point for conversations around future autopsy studies in SSA and worldwide, to further understand factors which influence expression of clinical spectrum of disease and the impact on other co-morbidities such as HIV, tuberculosis, malaria, hypertension, and diabetes. The COVID-19 pandemic serves as a reminder to authorities responsible for health care and policy formulation to invest more into autopsy pathology services (
      • Yi E.S.
      • Cecchini M.J.
      • Bois M.C.
      Pathologists in pursuit of the COVID-19 culprit.
      ). Furthermore, with new SARS-CoV-2 variants in circulation and decedents dying after re-infection, sequencing data will need to be aligned to autopsy studies to better understand the full scope of COVID-19 in Zambia and the rest of Africa. Further investments are required to improve the accuracy of diagnosis, recording and reporting of all causes of death and to ascertain the generic validity of our findings, An international COVID-19 postmortem platform is required for gathering uniform autopsy and postmortem data, and for enabling comparisons between countries.

      Conflicts of interest

      All authors declare no conflict of interest.

      Authors contributions

      Conceptualization: Luchenga Adam Mucheleng’anga, Cordelia Maria Himwaze and Alimuddin Zumla.
      Methodology: Luchenga Adam Mucheleng’anga and Cordelia Maria Himwaze.
      Software and formal analysis: Amos Hamukale.
      Validation: Viktor Telendiy, Fred Maate, Mupeta Songwe, Lunda Shibemba, Chitalu Chanda, Duncan Chanda, Peter Julius, Chibamba Mumba, Clemence Marimo, Amos Hamukale, Llyod Mulenga, and Alimuddin Zumla.
      Data curation : Luchenga Adam Mucheleng’anga, Cordelia Maria Himwaze, Viktor Telendiy
      Writing: First and final drafts: Cordelia Maria Himwaze, Alimuddin Zumla and Luchenga Adam Mucheleng’anga. Review and editing: All authors contributed to writing of the manuscript.
      Visualization: Luchenga Adam Mucheleng’anga, Cordelia Maria Himwaze, Amos Hamukale, Peter Julius and Alimuddin Zumla.
      Supervision: Alimuddin Zumla and Luchenga Adam Mucheleng’anga.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Acknowledgements

      We are indebted to Dr. Chitalu Chanda, who campaigned for the idea of all deaths in the isolation wards at UTH to be autopsied and counseled the next-of-kin about the importance of autopsies in these deaths. We thank our brave pathologist’s assistants, Mr. Mwanza Rabson and Mr. Chanda Brain, without whom the autopsies would have been impossible to conduct. Our gratitude goes to our hard-working biomedical scientists Ms. Lomeo Chifunda, Ms. Alice Chibondwe, and Mr. Chrispin Chiyabi. We also thank Dr. Suwilanji Sivile and Dr. Francis Mupeta for supporting autopsy work on hospital Inpatient COVID-19 Deaths.
      Sir Prof Alimuddin Zumla, is a co-Principal Investigator of the (PANDORA-ID-NET), the Pan-African Network For Rapid Research, Response, Relief and Preparedness for Infectious Disease Epidemics, supported by the EDCTP. He is in receipt of a UK National Institutes of Health Research, Senior Investigator Award and is a Mahathir Foundation Science Award laureate.

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