SARS-CoV-2 Reinfections and Long COVID in the Post-Omicron Phase of the Pandemic

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Abstract

We are reviewing the current state of knowledge on the virological and immunological correlates of long COVID, focusing on recent evidence for the possible association between the increasing number of SARS-CoV-2 reinfections and the parallel pandemic of long COVID. The severity of reinfections largely depends on the severity of the initial episode; in turn, this is determined both by a combination of genetic factors, particularly related to the innate immune response, and by the pathogenicity of the specific variant, especially its ability to infect and induce syncytia formation at the lower respiratory tract. The cumulative risk of long COVID as well as of various cardiac, pulmonary, or neurological complications increases proportionally to the number of SARS-CoV-2 infections, primarily in the elderly. Therefore, the number of long COVID cases is expected to remain high in the future. Reinfections apparently increase the likelihood of long COVID, but less so if they are mild or asymptomatic as in children and adolescents. Strategies to prevent SARS-CoV-2 reinfections are urgently needed, primarily among older adults who have a higher burden of comorbidities. Follow-up studies using an established case definition and precise diagnostic criteria of long COVID in people with or without reinfection may further elucidate the contribution of SARS-CoV-2 reinfections to the long COVID burden. Although accumulating evidence supports vaccination, both before and after the SARS-CoV-2 infection, as a preventive strategy to reduce the risk of long COVID, more robust comparative observational studies, including randomized trials, are needed to provide conclusive evidence of the effectiveness of vaccination in preventing or mitigating long COVID in all age groups. Thankfully, answers not only on the prevention, but also on treatment options and rates of recovery from long COVID are gradually starting to emerge.

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Extrapulmonary manifestations of COVID-19

Aakriti Gupta, Mahesh Madhavan, Kartik Sehgal … (2020)

Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.

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Multiorgan and Renal Tropism of SARS-CoV-2

Victor G. Puelles, Marc Lütgehetmann, Maja T Lindenmeyer … (2020)

To the Editor: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) preferentially infects cells in the respiratory tract, 1,2 but its direct affinity for organs other than the lungs remains poorly defined. Here, we present data from an autopsy series of 27 patients (see the clinical data in Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org) that show that SARS-CoV-2 can be detected in multiple organs, including the lungs, pharynx, heart, liver, brain, and kidneys. We first quantified the SARS-CoV-2 viral load in autopsy tissue samples obtained from 22 patients who had died from Covid-19. Seventeen patients (77%) had more than two coexisting conditions (Figure 1A), and a greater number of coexisting conditions was associated with SARS-CoV-2 tropism for the kidneys (Table S2), even in patients without a history of chronic kidney disease (Table S3). The highest levels of SARS-CoV-2 copies per cell were detected in the respiratory tract, and lower levels were detected the kidneys, liver, heart, brain, and blood (Figure 1B). These findings indicate a broad organotropism of SARS-CoV-2. Since the kidneys are among the most common targets of SARS-CoV-2, we performed in silico analysis of publicly available data sets of single-cell RNA sequencing. This analysis revealed that RNA for angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2), and cathepsin L (CTSL) — RNA of genes that are considered to facilitate SARS-CoV-2 infection 3 — is enriched in multiple kidney-cell types from fetal development through adulthood (Fig. S1). This enrichment may facilitate SARS-CoV-2–associated kidney injury, as previously suggested. 4 We also quantified the SARS-CoV-2 viral load in precisely defined kidney compartments obtained with the use of tissue microdissection from 6 patients who underwent autopsy (1 patient who was included in the previously mentioned 22 patients as an internal negative control, plus 5 additional patients). Three of these 6 patients had a detectable SARS-CoV-2 viral load in all kidney compartments examined, with preferential targeting of glomerular cells (Fig. S2). We also detected viral RNA and protein with high spatial resolution using in situ hybridization and indirect immunofluorescence with confocal microscopy (Figure 1C). Data on additional controls are provided in Figures S3 and S4. On the basis of these findings, renal tropism is a potential explanation of commonly reported new clinical signs of kidney injury in patients with Covid-19, 5 even in patients with SARS-CoV-2 infection who are not critically ill. Our results indicate that SARS-CoV-2 has an organotropism beyond the respiratory tract, including the kidneys, liver, heart, and brain, and we speculate that organotropism influences the course of Covid-19 disease and, possibly, aggravates preexisting conditions.

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Evolution of antibody immunity to SARS-CoV-2

Christian Gaebler, Zijun Wang, Julio C C Lorenzi … (2021)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected 78 million individuals and is responsible for over 1.7 million deaths to date. Infection is associated with the development of variable levels of antibodies with neutralizing activity, which can protect against infection in animal models1,2. Antibody levels decrease with time, but, to our knowledge, the nature and quality of the memory B cells that would be required to produce antibodies upon reinfection has not been examined. Here we report on the humoral memory response in a cohort of 87 individuals assessed at 1.3 and 6.2 months after infection with SARS-CoV-2. We find that titres of IgM and IgG antibodies against the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 decrease significantly over this time period, with IgA being less affected. Concurrently, neutralizing activity in plasma decreases by fivefold in pseudotype virus assays. By contrast, the number of RBD-specific memory B cells remains unchanged at 6.2 months after infection. Memory B cells display clonal turnover after 6.2 months, and the antibodies that they express have greater somatic hypermutation, resistance to RBD mutations and increased potency, indicative of continued evolution of the humoral response. Immunofluorescence and PCR analyses of intestinal biopsies obtained from asymptomatic individuals at 4 months after the onset of coronavirus disease 2019 (COVID-19) revealed the persistence of SARS-CoV-2 nucleic acids and immunoreactivity in the small bowel of 7 out of 14 individuals. We conclude that the memory B cell response to SARS-CoV-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence.