Protecting the vulnerable: addressing the COVID-19 care needs of people with compromised immunity

Limited knowledge is available on the relationship between antigen-specific immune responses and COVID-19 disease severity. We completed a combined examination of all three branches of adaptive immunity at the level of SARS-CoV-2-specific CD4+ and CD8+ T cell and neutralizing antibody responses in acute and convalescent subjects. SARS-CoV-2-specific CD4+ and CD8+ T cells were each associated with milder disease. Coordinated SARS-CoV-2-specific adaptive immune responses were associated with milder disease, suggesting roles for both CD4+ and CD8+ T cells in protective immunity in COVID-19. Notably, coordination of SARS-CoV-2 antigen-specific responses was disrupted in individuals > 65 years old. Scarcity of naive T cells was also associated with ageing and poor disease outcomes. A parsimonious explanation is that coordinated CD4+ T cell, CD8+ T cell, and antibody responses are protective, but uncoordinated responses frequently fail to control disease, with a connection between ageing and impaired adaptive immune responses to SARS-CoV-2.

Long COVID is an often debilitating illness that occurs in at least 10% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. More than 200 symptoms have been identified with impacts on multiple organ systems. At least 65 million individuals worldwide are estimated to have long COVID, with cases increasing daily. Biomedical research has made substantial progress in identifying various pathophysiological changes and risk factors and in characterizing the illness; further, similarities with other viral-onset illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome have laid the groundwork for research in the field. In this Review, we explore the current literature and highlight key findings, the overlap with other conditions, the variable onset of symptoms, long COVID in children and the impact of vaccinations. Although these key findings are critical to understanding long COVID, current diagnostic and treatment options are insufficient, and clinical trials must be prioritized that address leading hypotheses. Additionally, to strengthen long COVID research, future studies must account for biases and SARS-CoV-2 testing issues, build on viral-onset research, be inclusive of marginalized populations and meaningfully engage patients throughout the research process. Long COVID is an often debilitating illness of severe symptoms that can develop during or following COVID-19. In this Review, Davis, McCorkell, Vogel and Topol explore our knowledge of long COVID and highlight key findings, including potential mechanisms, the overlap with other conditions and potential treatments. They also discuss challenges and recommendations for long COVID research and care.

To the Editor: A 45-year-old man with severe antiphospholipid syndrome complicated by diffuse alveolar hemorrhage, 1 who was receiving anticoagulation therapy, glucocorticoids, cyclophosphamide, and intermittent rituximab and eculizumab, was admitted to the hospital with fever (Fig. S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). On day 0, Covid-19 was diagnosed by SARS-CoV-2 reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay of a nasopharyngeal swab specimen, and the patient received a 5-day course of remdesivir (Fig. S2). Glucocorticoid doses were increased because of suspected diffuse alveolar hemorrhage. He was discharged on day 5 without a need for supplemental oxygen. From day 6 through day 68, the patient quarantined alone at home, but during the quarantine period, he was hospitalized three times for abdominal pain and once for fatigue and dyspnea. The admissions were complicated by hypoxemia that caused concern for recurrent diffuse alveolar hemorrhage and was treated with increased doses of glucocorticoids. SARS-CoV-2 RT-PCR cycle threshold (Ct) values increased to 37.8 on day 39, which suggested resolving infection (Table S1). 2,3 On day 72 (4 days into another hospital admission for hypoxemia), RT-PCR assay of a nasopharyngeal swab was positive, with a Ct value of 27.6, causing concern for a recurrence of Covid-19. The patient again received remdesivir (a 10-day course), and subsequent RT-PCR assays were negative. On day 105, the patient was admitted for cellulitis. On day 111, hypoxemia developed, ultimately requiring treatment with high-flow oxygen. Given the concern for recurrent diffuse alveolar hemorrhage, the patient’s immunosuppression was escalated (Figs. S1 through S3). On day 128, the RT-PCR Ct value was 32.7, which caused concern for a second Covid-19 recurrence, and the patient was given another 5-day course of remdesivir. A subsequent RT-PCR assay was negative. Given continued respiratory decline and concern for ongoing diffuse alveolar hemorrhage, the patient was treated with intravenous immunoglobulin, intravenous cyclophosphamide, and daily ruxolitinib, in addition to glucocorticoids. On day 143, the RT-PCR Ct value was 15.6, which caused concern for a third recurrence of Covid-19. The patient received a SARS-CoV-2 antibody cocktail against the SARS-CoV-2 spike protein (Regeneron). 4 On day 150, he underwent endotracheal intubation because of hypoxemia. A bronchoalveolar-lavage specimen on day 151 revealed an RT-PCR Ct value of 15.8 and grew Aspergillus fumigatus. The patient received remdesivir and antifungal agents. On day 154, he died from shock and respiratory failure. We performed quantitative SARS-CoV-2 viral load assays in respiratory samples (nasopharyngeal and sputum) and in plasma, and the results were concordant with RT-PCR Ct values, peaking at 8.9 log10 copies per milliliter (Fig. S2 and Table S1). Tissue studies showed the highest SARS-CoV-2 RNA levels in the lungs and spleen (Figs. S4 and S5). Phylogenetic analysis was consistent with persistent infection and accelerated viral evolution (Figures 1A and S6). Amino acid changes were predominantly in the spike gene and the receptor-binding domain, which make up 13% and 2% of the viral genome, respectively, but harbored 57% and 38% of the observed changes (Figure 1B). Viral infectivity studies confirmed infectious virus in nasopharyngeal samples from days 75 and 143 (Fig. S7). Immunophenotyping and SARS-CoV-2–specific B-cell and T-cell responses are shown in Table S2 and Figures S8 through S11. Although most immunocompromised persons effectively clear SARS-CoV-2 infection, this case highlights the potential for persistent infection 5 and accelerated viral evolution associated with an immunocompromised state.