Infant mortality remains a major global concern. Sudden unexpected death in infancy (SUDI) is reported globally and an infant mortality rate of 23.129 per 1 000 live births has been reported in the Western Cape, South Africa, in 2024. Infections are often confirmed in SUDI cases admitted to the Tygerberg Medico-legal Mortuary in Cape Town, but molecular diversity in respiratory viruses is underreported. A total of 162 previously confirmed polymerase chain reaction (PCR)-positive trachea and / or lung samples from SUDI cases collected between 2015 and 2019 were retested for either rhinovirus or human respiratory syncytial virus (RSV). Sixty-four samples were positive for rhinovirus and 15 for RSV. Results from 5 of all positive samples were outside the PCR assay amplification limits determined by the cycle threshold (Ct) value and were excluded. Another 4 samples did not amplify, and the remaining 70 underwent subsequent sequencing, but successful sequences could only be obtained in 53 samples. All three rhinovirus (A, B and C) genotypes were identified, with RV-A most prevalent, followed by RV-C and RV-B. RSV-A and RSV-B were detected equally, and after amino acid alignment, 20 amino acid duplication and nine substitutions were found that confirmed two RSV-BA9 genotypes. This study describes the molecular and phylogenetic characterisation of specific respiratory viruses in SUDI cases in South Africa. However, the rapid decline in viral viability in post-mortem samples does not allow correlation between viral genotypes and cause of death or disease severity. Future prospective studies should therefore investigate temporality and associations between specific viral strains and clinical disease severity and mortality.

The clinical evolution of patients infected with the Severe Acute Respiratory Coronavirus type 2 (SARS-CoV-2) depends on the complex interplay between viral and host factors. The evolution to less aggressive but better-transmitted viral variants, and the presence of immune memory responses in a growing number of vaccinated and/or virus-exposed individuals, has caused the pandemic to slowly wane in virulence. However, there are still patients with risk factors or comorbidities that put them at risk of poor outcomes in the event of having the coronavirus infectious disease 2019 (COVID-19). Among the different treatment options for patients with COVID-19, virus-targeted measures include antiviral drugs or monoclonal antibodies that may be provided in the early days of infection. The present expert consensus is based on a review of all the literature published between 1 July 2021 and 15 February 2022 that was carried out to establish the characteristics of patients, in terms of presence of risk factors or comorbidities, that may make them candidates for receiving any of the virus-targeted measures available in order to prevent a fatal outcome, such as severe disease or death. A total of 119 studies were included from the review of the literature and 159 were from the additional independent review carried out by the panelists a posteriori. Conditions found related to strong recommendation of the use of virus-targeted measures in the first days of COVID-19 were age above 80 years, or above 65 years with another risk factor; antineoplastic chemotherapy or active malignancy; HIV infection with CD4+ cell counts < 200/mm³; and treatment with anti-CD20 immunosuppressive drugs. There is also a strong recommendation against using the studied interventions in HIV-infected patients with a CD4+ nadir <200/mm³ or treatment with other immunosuppressants. Indications of therapies against SARS-CoV-2, regardless of vaccination status or history of infection, may still exist for some populations, even after COVID-19 has been declared to no longer be a global health emergency by the WHO.

Clinical information on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with inborn errors of immunity (IEI) during the current Coronavirus disease 2019 (COVID-19) pandemic is still limited. Proper DNA repair machinery is required for the development of the adaptive immune system, which provides specific and long-term protection against SARS-CoV-2. This review highlights the impact of SARS-CoV-2 infections on IEI patients with DNA repair disorders and summarizes susceptibility risk factors, pathogenic mechanisms, clinical manifestations and management strategies of COVID-19 in this special patient population.

The vast interindividual clinical variability observed in any microbial infection-ranging from silent infection to lethal disease-is increasingly being explained by human genetic and immunological determinants. Autoantibodies neutralizing specific cytokines underlie the same infectious diseases as inborn errors of the corresponding cytokine or response pathway. Autoantibodies against type I IFNs underlie COVID-19 pneumonia and adverse reactions to the live attenuated yellow fever virus vaccine. Autoantibodies against type II IFN underlie severe disease caused by environmental or tuberculous mycobacteria, and other intra-macrophagic microbes. Autoantibodies against IL-17A/F and IL-6 are less common and underlie mucocutaneous candidiasis and staphylococcal diseases, respectively. Inborn errors of and autoantibodies against GM-CSF underlie pulmonary alveolar proteinosis; associated infections are less well characterized. In individual patients, autoantibodies against cytokines preexist infection with the pathogen concerned and underlie the infectious disease. Human antibody-driven autoimmunity can interfere with cytokines that are essential for protective immunity to specific infectious agents but that are otherwise redundant, thereby underlying specific infectious diseases.

The severe acute respiratory syndrome (SARS)-coronavirus 2 (CoV2)/COVID-19 pandemic has reminded us of the fundamental and nonredundant role played by the innate and adaptive immune systems in host defense against emerging pathogens. The study of rare 'experiments of nature' in the setting of inborn errors of immunity (IEI) caused by monogenic germline variants has revealed key insights into the molecular and cellular requirements for immune-mediated protection against infectious diseases. This review will provide an overview of the discoveries obtained from investigating severe COVID-19 in patients with defined IEI or otherwise healthy individuals.

Genetic, serological and cohort studies have provided key findings regarding host defense against SARS-CoV2 infection, and mechanisms of disease pathogenesis. Remarkably, the risk factors, severity of disease, and case fatality rate following SARS-CoV2 infection in patients with IEI were not too dissimilar to that observed for the general population. However, the type I interferon (IFN) signaling pathway - activated in innate immune cells in response to viral sensing - is critical for anti-SARS-CoV2 immunity. Indeed, genetic variants or autoAbs affecting type I IFN function account for up to 20% of all cases of life-threatening COVID-19.

The analysis of rare cases of severe COVID-19, coupled with assessing the impact of SARS-CoV2 infection in individuals with previously diagnosed IEI, has revealed fundamental aspects of human immunology, disease pathogenesis and immunopathology in the context of exposure to and infection with a novel pathogen. These findings can be leveraged to improve therapies for treating for emerging and established infectious diseases.

We established the COVID Human Genetic Effort (www.covidhge.com) to discover the human genetic and immunological bases of the vast interindividual clinical variability between humans infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We found that about 3% of patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia were ill because of inborn errors of genes controlling type I interferon (IFN)-dependent immunity (which controls influenza virus), and at least 10% of patients with life-threatening COVID-19 pneumonia had neutralizing auto-Abs against some of the 17 individual type I IFNs. These findings indicate that impaired type I IFN immunity underlies life-threatening COVID-19 pneumonia in at least 13% of patients. These discoveries pave the way for further research into unexplained severe cases, and provide a rationale for preventing and treating the disease in individuals at risk, with recombinant type I IFNs.

All of humans and other mammalian species are colonized by some types of microorganisms such as bacteria, archaea, unicellular eukaryotes like fungi and protozoa, multicellular eukaryotes like helminths, and viruses, which in whole are called microbiota. These microorganisms have multiple different types of interaction with each other. A plethora of evidence suggests that they can regulate immune and digestive systems and also play roles in various diseases, such as mental, cardiovascular, metabolic and some skin diseases. In addition, they take-part in some current health problems like diabetes mellitus, obesity, cancers and infections. Viral infection is one of the most common and problematic health care issues, particularly in recent years that pandemics like SARS and COVID-19 caused a lot of financial and physical damage to the world. There are plenty of articles investigating the interaction between microbiota and infectious diseases. We focused on stimulatory to suppressive effects of microbiota on viral infections, hoping to find a solution to overcome this current pandemic. Then we reviewed mechanistically the effects of both microbiota and probiotics on most of the viruses. But unlike previous studies which concentrated on intestinal microbiota and infection, our focus is on respiratory system's microbiota and respiratory viral infection, bearing in mind that respiratory system is a proper entry site and residence for viruses, and whereby infection, can lead to asymptomatic, mild, self-limiting, severe or even fatal infection. Finally, we overgeneralize the effects of microbiota on COVID-19 infection. In addition, we reviewed the articles about effects of the microbiota on coronaviruses and suggest some new therapeutic measures.

Antimicrobial peptides (AMPs) are produced by neutrophils, monocytes, and macrophages, as well as epithelial cells, and are an essential component of innate immunity system against infection, including several viral infections. AMPs, in particular the cathelicidin LL-37, also exert numerous immunomodulatory activities by inducing cytokine production and attracting and regulating the activity of immune cells. AMPs are scarcely expressed in normal skin, but their expression increases when skin is injured by external factors, such as trauma, inflammation, or infection. LL-37 complexed to self-DNA acts as autoantigen in psoriasis and lupus erythematosus (LE), where it also induces production of interferon by plasmocytoid dendritic cells and thus initiates a cascade of autocrine and paracrine processes, leading to a disease state. In these disorders, epidermal keratinocytes express high amounts of AMPs, which can lead to uncontrolled inflammation. Similarly, LL-37 had several favorable and unfavorable roles in virus replication and disease pathogenesis. Targeting the antiviral and immunomodulatory functions of LL-37 opens a new approach to limit virus dissemination and the progression of disease.

Multicellular eukaryotes emerged late in evolution from an ocean of viruses, bacteria, archaea, and unicellular eukaryotes. These macroorganisms are exposed to and infected by a tremendous diversity of microorganisms. Those that are large enough can even be infected by multicellular fungi and parasites. Each interaction is unique, if only because it operates between two unique living organisms, in an infinite diversity of circumstances. This is neatly illustrated by the extraordinarily high level of interindividual clinical variability in human infections, even for a given pathogen, ranging from a total absence of clinical manifestations to death. We discuss here the idea that the determinism of human life-threatening infectious diseases can be governed by single-gene inborn errors of immunity, which are rarely Mendelian and frequently display incomplete penetrance. We briefly review the evidence in support of this notion obtained over the last two decades, referring to a number of focused and thorough reviews published by eminent colleagues in this issue of Human Genetics. It seems that almost any life-threatening infectious disease can be driven by at least one, and, perhaps, a great many diverse monogenic inborn errors, which may nonetheless be immunologically related. While the proportions of monogenic cases remain unknown, a picture in which genetic heterogeneity is combined with physiological homogeneity is emerging from these studies. A preliminary sketch of the human genetic architecture of severe infectious diseases is perhaps in sight.