Spatially resolved single-cell atlas of the lung in fatal Covid19 in an African population reveals a distinct cellular signature and an interferon gamma dominated response (preprint)

Postmortem single-cell studies have transformed understanding of lower respiratory tract diseases (LRTD) including Covid19 but there is almost no data from African settings where HIV, malaria and other environmental exposures may affect disease pathobiology and treatment targets. We used histology and high-dimensional imaging to characterise fatal lung disease in Malawian adults with (n=9) and without (n=7) Covid19, and generated single-cell transcriptomics data from lung, blood and nasal cells. Data integration with other cohorts showed a conserved Covid19 histopathological signature, driven by contrasting immune and inflammatory mechanisms: in the Malawi cohort, by response to interferon-gamma (IFN-{gamma}) in lung-resident alveolar macrophages, in USA, European and Asian cohorts by type I/III interferon responses, particularly in blood-derived monocytes. HIV status had minimal impact on histology or immunopathology. Our study provides data resources and highlights the importance of studying the cellular mechanisms of disease in underrepresented populations, indicating shared and distinct targets for treatment.

Genomically informed clinical comparison of three epidemic waves of COVID-19 in Malawi (preprint)

Background Compared to the abundance of clinical, molecular, and genomic information available on patients hospitalised with COVID-19 disease from high-income countries, there is a paucity of data from low-income countries. Methods We enrolled a cohort of patients with PCR confirmed COVID-19 disease at Queen Elizabeth Central Hospital, the main hospital for southern Malawi, between July 2020 and September 2021. The recruitment period covered three waves of SARS-CoV-2 infections in Malawi. Clinical and diagnostic data were collected using the ISARIC clinical characterization protocol for COVID-19. The viral material from PCR-positive swabs was amplified with a tiling PCR scheme and sequenced using the MinION sequencer in Malawi. Consensus genomes were generated using the ARTIC pipeline and lineage assignment was performed using Pangolin. Results Sequencing data showed that wave one was predominantly B.1 (8/11 samples), wave two consisted entirely of Beta variant of concern (VOC) (6/6), and wave three was predominantly Delta VOC (25/26). Patients presenting in the second and third waves had progressively fewer underlying chronic conditions, and patients in the third wave had a shorter time to presentation (2 days vs 5 in the original wave). Multivariable logistic regression demonstrated increased mortality in wave three, dominated by the Delta VOC, compared to previous waves (OR 6.6 [CI 1.1-38.8]). Conclusions Patients hospitalised with COVID-19 in Blantyre during the Delta wave had more acute symptom onset; fewer underlying conditions; and were more likely to die. Whilst we demonstrate the value of linking virus sequence data with clinical outcome data in a low-income setting, this study also highlights the considerable barriers to establishing sequencing capacity in a setting heavily affected by disruptions in supply chain and inequity of resource distribution.