In 2019, the world was struck by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which caused the coronavirus disease 2019 (COVID-19).^1,2 The resulting COVID-19 pandemic continues to pose challenges to healthcare systems. Compared to previous pandemics, the COVID-19 pandemic has exhibited a cyclical nature and unique manifestation in different geographical areas.²

Various aspects of the disease have been reported from epidemiology to mortality.^3,4,5,6,7 Studies on mortality do not report on other causes of death within the pandemic,^1,6,7 although these are equally important in the fight against the SARS-CoV-2. Autopsies are indispensable in clarifying the cause of death, as well as for quality control and audit in medical practice. It is an established fact that a clinically determined cause of death is not as reliable as an autopsy-determined cause of death.^8,9

Real-time reverse transcription polymerase chain reaction (rRT-PCR) is the standard laboratory technique for testing for SARS-CoV-2 and can be used for samples taken at autopsy.¹⁰ Identifying pathological consequence of SARS-CoV-2 at autopsy can be a useful addition to rRT-PCR.

Surveillance has remained a cornerstone in the management of the COVID-19 pandemic. Different types of surveillance systems have been used during the COVID-19 pandemic, such as the hospital-based mortality surveillance and routine surveillance.¹¹ As part of its expanded surveillance protocol, the 37 Military Hospital in Accra, Ghana, screened all deceased patients received at the Department of Anatomical Pathology morgue for SARS-CoV-2 and cause of death in May 2020. The aim of the study was to determine the underlying causes of death and the presence of SARS-CoV-2 using rRT-PCR for all cases admitted to the Department of Anatomical Pathology during the study period.

The study identified three categories of deaths that occurred during the pandemic. There were a significant number of undiagnosed SARS-CoV-2 infections among deceased individuals received by the Anatomical Pathology Department of the 37 Military Hospital with unique histopathological features of SARS-CoV-2 induced deaths. The potential for community spread of the virus from handling of unsuspected SARS-CoV-2 deceased individuals without personal protective equipment, as well as the SARS-CoV-2 cases found during autopsy, are a missing link in efforts to control the pandemic. There are other documented missing links affecting overall SARS-CoV-2 control such as non-uniform data collection, vaccine hesitancy and non-reliable energy infrastructure in low-resource environments.^13,14,15 In an Italian multicentre study conducted in 2020, the presence of SARS-CoV-2 in bronchoalveolar samples was 32.7% of suspected cases with 76% having a double negative nasopharyngeal test.¹⁶ Our study also found SARS-CoV-2 in the bronchopulmonary specimens of cases with negative nasopharyngeal tests and in cases who died from other conditions. These findings need to be factored into the current health policy on SARS-CoV-2.

The underlying cause of death is critical in accurate reporting and documentation for better epidemic surveillance and effective planning of control measures.¹⁷ This is the first reported post-mortem study data for Ghana that has categorised underlying causes of death into three groups: non-SARS-CoV-2 related (85.1%), SARS-CoV-2 associated (12.4%) and SARS-CoV-2 induced (2.5%). The case fatality rate in Ghana for SARS-CoV-2 infection was reported to be an average of 0.5% in July 2020.¹⁸ This did not include deaths due to SARS-CoV-2 as identified by post-mortem examinations. The presence of post-mortem-diagnosed cases of SARS-CoV-2-induced deaths in this study implies that the overall case count is higher than reported for Ghana. The need to include cases identified by pathology departments during post-mortem examinations in defining all case mortality has been emphasised.¹⁹ This highlights the importance of post-mortem examination in understanding the natural history of diseases and defining a true mortality rate.

Accurate reporting is a requirement in the documentation of cause of death. In its guidelines for certification and classification of COVID-19 as a cause of death, the WHO requires a distinction between underlying cause of death and immediate cause of death in the completion of Part I of the International Form of the Medical Certificate of Cause of Death.²⁰ This was to encourage uniformity of data collection to guide health policy, but differences in classification are emerging.^20,21 The evolution of the pandemic and the understanding of the disease requires a simple categorisation of underlying of causes of death. The categorisation adopted in this study is useful for determining accurate case counts during clinical audits of deaths.

Identifying subgroups of COVID-19 case mortality is useful in managing the pandemic.²² Of particular interest were the 20 SARS-CoV-2-associated deaths in our study. These cases were categorised as having died from their underlying medical conditions, rather than from SARS-CoV-2. The prioritisation of care for SARS-CoV-2 infections by the health system, rather than the underlying condition, might have contributed to their mortality. Most deaths during the pandemic have been reported as being related to underlying conditions.^8,23 This raises the question as to whether SARS-CoV-2 has the potential to delay care among patients with underlying medical conditions. The presence of SARS-CoV-2 among the BIDs patients in our study suggests a high community transmission of the disease. Such cases may be asymptomatic and likely to result in an increased disease burden in the absence of strict protocols.

Interestingly, our study found a high proportion (85.1%) of deaths not attributable to SARS-CoV-2. The impact of the pandemic on health systems and the lack of provision of optimum care are attributable causes to the phenomenon of high proportions of non-SARS-CoV-2-related deaths.²⁴ Among the BID cases in our study not attributable to SARS-CoV-2, hypertension, infection, liver cirrhosis, diabetes mellitus and pulmonary embolism-related complications were the leading causes of death. Causes of death not attributable to SARS-CoV-2 for cases from the hospitals (in descending order) included hypertension, tumours, accident and trauma, diabetes mellitus and infections. In Ghana, the prevalence of major non-communicable diseases, especially hypertension, and their risk factors has increased and contributes significantly to the disease burden.²⁵ Hypertension and its related complications were the leading causes of death in both groups of patients. Non-communicable metabolic diseases, tumours and trauma-related deaths rank high in the study. This emphasises the need for aggressive clinical care for non-communicable diseases even in the face of a positive SARS-CoV-2 test.

Our study found an overall SARS-CoV-2 case positivity rate of 14.90% among deceased patients received by the Anatomic Pathology Department; these are not included in Ghana’s national data on SARS-CoV-2. The study found a mean age of 55 years for male patients and 53 years female patients with an equal gender ratio. This is a different demographic pattern from the reported increased susceptibility to COVID-19 among the elderly, those with severe comorbidities and among male patients.²⁶ While our study found a high proportion of comorbidities among the elderly, the deaths were not directly from SARS-CoV-2, but from the associated cormorbidities.²³ It can be extrapolated that, in the context of an underlying medical condition, the primary disease possess more risk than the SARS-CoV-2 infection.

Severe acute respiratory syndrome corona virus 2 has been known to survive longer in cold temperatures and on fomites, with guidelines emerging for the handling of an autopsy in suspected cases.^27,28 In our study, the pathology department discovered 24 SARS-CoV-2-infected deceased patients, of which 20 were previously undiagnosed. The absence of appropriate personal protective equipment and standard protocols predisposed staff to a high risk of infection. It is recommended that there should be a national protocol for the safe performance of autopsies during the pandemic.

The site of sample collection has a direct correlation with the sensitivity of rRT-PCR tests, and bronchopulmonary samples give the highest viral yield.^29,30,31 In our study, bronchopulmonary specimens gave a higher positivity rate than nasopharyngeal specimens, implying that our bronchopulmonary specimens also had a higher viral load. The higher level of virus in bronchial secretions should be a recognised risk for medical staff during oropharyngeal endoscopic procedures and anaesthesia. The necessary awareness and preventive practices to avoid contracting the virus should be in place.

The analysis of the histology of specimens from COVID-19 cases provides useful information about the disease. Our study found inflammatory features in the lungs and thrombus formation in the arterial systems of major organs. This combination of pulmonary congestion with peri-vascular lymphocytic infiltrates, interstitial/intra-alveolar fibrosis, type 2 pneumocyte hyperplasia, DAD with hyaline membrane formation, as well as arterial thrombosis, are likely to result in the rapid and severe hypoxemia noticed among COVID-19 patients. An ensuing cellular response in the presence of an underlying medical disease could contribute to the high mortality in these patients. A higher proportion of such patients in our study had cardiovascular disease. The role of the thrombus formation and subsequent hypoxia on vascular endothelium need to be investigated.

In our study, there were two cases with the clinical and histopathological features of acute respiratory distress syndrome/DAD that had negative SARS-CoV-2 rRT-PCR test results. There were no definitive diagnoses at the time of autopsy. Even though both patients had comorbid conditions, evidence at post-mortem did not attribute their deaths to the comorbid conditions. A recent case series report ascribed such situations to a ‘probable’ case of COVID-19 as the cause of death.³⁰ Such cases, who test negative for SARS-CoV-2 but have clinical features suggestive of COVID-19, should be considered as a subgroup of COVID-19 to help in case management and prevention protocols, considering the high mortality associated with the disease. The negative PCR results of these two cases are most likely to be false-negative results. Such false-negative errors may be the result of pre-analytical issues,³² such as poorly collected samples, mislabelling, improper storage or transport, or interference from medications. That notwithstanding, there are other causes of acute respiratory distress syndrome/DAD that should be considered, and an autopsy should therefore be encouraged to distinguish between SARS-CoV-2-induced deaths and SARS-CoV-2-associated deaths.

The study showed that a significant number of clinically diagnosed cases of COVID-19 may be false. Deaths could have been wrongly labelled as due to COVID-19, because of a positive SARS-CoV-2 test by the nasopharyngeal route and presence of respiratory difficulty. Such patients would have been denied dignified burials by their relatives, instead of the practice of mass burial as mandated by national policy at the beginning of the pandemic. These findings are a useful addition to Ghana’s national data to determine which deceased patients can be safely released to families and which require supervised burials. The importance of routine screening in high-risk clinical practice among asymptomatic patients and guidelines to protect staff must be emphasised.