In an add-on study of the WHO Solidarity trial, Norwegian investigators examined the effect of remdesivir and hydroxychloroquine on the degree of clinical respiratory failure, on SARS-CoV-2 viral load in the oropharynx, and on levels of inflammatory variables in plasma or serum.

Neutrophils are essential innate immune cells that extrude chromatin in the form of neutrophil extracellular traps (NETs) when they die. This form of cell death has potent immunostimulatory activity. We show that heme-induced NETs are essential for malaria pathogenesis. Using patient samples and a mouse model, we define two mechanisms of NET-mediated inflammation of the vasculature: activation of emergency granulopoiesis via granulocyte colony-stimulating factor production and induction of the endothelial cytoadhesion receptor intercellular adhesion molecule–1. Soluble NET components facilitate parasite sequestration and mediate tissue destruction. We demonstrate that neutrophils have a key role in malaria immunopathology and propose inhibition of NETs as a treatment strategy in vascular infections.

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BackgroundCo-infection with falciparum malaria and HIV-1 increases the severity and mortality of both infections in unstable malaria-transmission areas. In contrast, in stable transmission areas, HIV co-infection increases the severity of both infections but has not been found to influence malaria mortality.MethodsIn a prospective cross-sectional study, clinical and laboratory data were consecutively collected for all adults admitted with fever and/or suspected malaria to the medical department of the Central Hospital of Maputo, Mozambique, during two malaria seasons from January 2011. Malaria and HIV PCRs were performed, and risk factors for fatal outcomes were analysed. The impact of HIV on the clinical presentation and mortality of malaria was assessed.FindingsA total of 212 non-pregnant adults with fever and/or suspected malaria and 56 healthy controls were included in the study. Of the 131 patients with confirmed falciparum malaria, 70 were co-infected with HIV-1. The in-hospital mortality of the co-infected patients was 13.0% (9/69) compared with 1.7% (1/59) in the patients without HIV (p = 0.018). Malaria severity (p = 0.016) and co-infection with HIV (p = 0.064) were independent risk factors for death although the association with HIV did not reach statistical significance. The co-infected patients had significantly more frequent respiratory distress, bleeding disturbances, hypoglycaemia, liver and renal failure and high malaria parasitemia compared with the patients with malaria alone.InterpretationsHIV co-infection is associated with increased disease severity in and mortality from malaria in an area of stable malaria transmission. This finding was not observed earlier and should motivate doctors working in malaria-endemic areas to consider early HIV testing and a closer follow-up of patients with malaria and HIV co-infection.

Background During the coronavirus disease 2019 (COVID-19) pandemic, many countries experienced infection in healthcare workers (HCW) due to overburdened healthcare systems. However, whether infected HCW acquire protective immunity against SARS-CoV-2 is unclear. Here, we characterized SARS-CoV-2-specific antibody responses in Norwegian HCW in a prospective cohort study. Methods We enrolled 607 HCW pre- and post-the first COVID-19-pandemic wave. Exposure history, COVID-19-like symptoms and serum samples were collected. SARS-CoV-2-specific antibodies were characterized by spike-protein IgG/IgM/IgA enzyme-linked immunosorbent and live-virus neutralization assays. Results Spike-specific IgG, IgM, and IgA antibodies increased after the first pandemic wave in HCW with COVID-19-patient exposure, but not in HCW without patient exposure. Thirty-two HCW (5.3%) had spike-specific antibodies (11 seroconverted with ≥4-fold increase, 21 were seropositive at baseline). Neutralizing antibodies were found in 11 HCW that seroconverted, of whom 4 (36.4%) were asymptomatic. Ninety-seven HCW were tested by reverse-transcriptase-polymerase chain reaction (RT-PCR) during follow-up, 8 were positive (7 seroconverted and 1 had undetectable antibodies). Conclusions We found increases in SARS-CoV-2-neutralizing antibodies in infected HCW, especially after COVID-19-patient exposure. Our data show a low number of SARS-CoV-2-seropositive HCW in a low prevalence setting, however, the proportion of seropositivity was higher than RT-PCR positivity, highlighting the importance of antibody testing.

The association between pulmonary sequelae and markers of disease severity, as well as pro-fibrotic mediators, were studied in 108 patients 3 months after hospital admission for COVID-19. The COPD assessment test (CAT-score), spirometry, diffusion capacity of the lungs (DLCO), and chest-CT were performed at 23 Norwegian hospitals included in the NOR-SOLIDARITY trial, an open-labelled, randomised clinical trial, investigating the efficacy of remdesivir and hydroxychloroquine (HCQ). Thirty-eight percent had a CAT-score ≥ 10. DLCO was below the lower limit of normal in 29.6%. Ground-glass opacities were present in 39.8% on chest-CT, parenchymal bands were found in 41.7%. At admission, low pO2/FiO2 ratio, ICU treatment, high viral load, and low antibody levels, were predictors of a poorer pulmonary outcome after 3 months. High levels of matrix metalloproteinase (MMP)-9 during hospitalisation and at 3 months were associated with persistent CT-findings. Except for a negative effect of remdesivir on CAT-score, we found no effect of remdesivir or HCQ on long-term pulmonary outcomes. Three months after hospital admission for COVID-19, a high prevalence of respiratory symptoms, reduced DLCO, and persistent CT-findings was observed. Low pO2/FiO2 ratio, ICU-admission, high viral load, low antibody levels, and high levels of MMP-9 were associated with a worse pulmonary outcome.

Background: The potential impact of HIV-1 on falciparum malaria has been difficult to determine because of diagnostic problems and insufficient epidemiological data.

Background Although coronavirus disease 2019 (COVID‐19) is primarily a respiratory infection, mounting evidence suggests that the gastrointestinal tract is involved in the disease, with gut barrier dysfunction and gut microbiota alterations being related to disease severity. Whether these alterations persist and are related to long‐term respiratory dysfunction remains unknown. Methods Plasma was collected during hospital admission and after 3 months from the NOR‐Solidarity trial (n = 181) and analyzed for markers of gut barrier dysfunction and inflammation. At the 3‐month follow‐up, pulmonary function was assessed by measuring the diffusing capacity of the lungs for carbon monoxide (DLCO). Rectal swabs for gut microbiota analyses were collected (n = 97) and analyzed by sequencing the 16S rRNA gene. Results Gut microbiota diversity was reduced in COVID‐19 patients with respiratory dysfunction, defined as DLCO below the lower limit of normal 3 months after hospitalization. These patients also had an altered global gut microbiota composition, with reduced relative abundance of 20 bacterial taxa and increased abundance of five taxa, including Veillonella, potentially linked to fibrosis. During hospitalization, increased plasma levels of lipopolysaccharide‐binding protein (LBP) were strongly associated with respiratory failure, defined as pO2/fiO2 (P/F ratio) <26.6 kPa. LBP levels remained elevated during and after hospitalization and were associated with low‐grade inflammation and respiratory dysfunction after 3 months. Conclusion Respiratory dysfunction after COVID‐19 is associated with altered gut microbiota and persistently elevated LBP levels. Our results should be regarded as hypothesis generating, pointing to a potential gut–lung axis that should be further investigated in relation to long‐term pulmonary dysfunction and long COVID.