Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic, which has resulted in global healthcare crises and strained health resources. As the population of patients recovering from COVID-19 grows, it is paramount to establish an understanding of the healthcare issues surrounding them. COVID-19 is now recognized as a multi-organ disease with a broad spectrum of manifestations. Similarly to post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are increasing reports of persistent and prolonged effects after acute COVID-19. Patient advocacy groups, many members of which identify themselves as long haulers, have helped contribute to the recognition of post-acute COVID-19, a syndrome characterized by persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. Here, we provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae. Finally, we discuss relevant considerations for the multidisciplinary care of COVID-19 survivors and propose a framework for the identification of those at high risk for post-acute COVID-19 and their coordinated management through dedicated COVID-19 clinics.

Objective T cells play a key role in the pathogenesis of early systemic sclerosis. This study was undertaken to assess the safety and efficacy of abatacept in patients with diffuse cutaneous systemic sclerosis (dcSSc). Methods In this 12‐month, randomized, double‐blind, placebo‐controlled trial, participants were randomized 1:1 to receive either subcutaneous abatacept 125 mg or matching placebo, stratified by duration of dcSSc. Escape therapy was allowed at 6 months for worsening disease. The coprimary end points were change in the modified Rodnan skin thickness score (MRSS) compared to baseline and safety over 12 months. Differences in longitudinal outcomes were assessed according to treatment using linear mixed models, with outcomes censored after initiation of escape therapy. Skin tissue obtained from participants at baseline was classified into intrinsic gene expression subsets. Results Among 88 participants, the adjusted mean change in the MRSS at 12 months was −6.24 units for those receiving abatacept and −4.49 units for those receiving placebo, with an adjusted mean treatment difference of −1.75 units (P = 0.28). Outcomes for 2 secondary measures (Health Assessment Questionnaire disability index and a composite measure) were clinically and statistically significantly better with abatacept. The proportion of subjects in whom escape therapy was needed was higher in the placebo group relative to the abatacept group (36% versus 16%). In the inflammatory and normal‐like skin gene expression subsets, decline in the MRSS over 12 months was clinically and significantly greater in the abatacept group versus the placebo group (P < 0.001 and P = 0.03, respectively). In the abatacept group, adverse events occurred in 35 participants versus 40 participants in the placebo group, including 2 deaths and 1 death, respectively. Conclusion In this phase II trial, abatacept was well‐tolerated, but change in the MRSS was not statistically significant. Secondary outcome measures, including gene expression subsets, showed evidence in support of abatacept. These data should be confirmed in a phase III trial.

ObjectivesDetermine global skin transcriptome patterns of early diffuse systemic sclerosis (SSc) and how they differ from later disease.MethodsSkin biopsy RNA from 48 patients in the Prospective Registry for Early Systemic Sclerosis (PRESS) cohort (mean disease duration 1.3 years) and 33 matched healthy controls was examined by next-generation RNA sequencing. Data were analysed for cell type-specific signatures and compared with similarly obtained data from 55 previously biopsied patients in Genetics versus Environment in Scleroderma Outcomes Study cohort with longer disease duration (mean 7.4 years) and their matched controls. Correlations with histological features and clinical course were also evaluated.ResultsSSc patients in PRESS had a high prevalence of M2 (96%) and M1 (94%) macrophage and CD8 T cell (65%), CD4 T cell (60%) and B cell (69%) signatures. Immunohistochemical staining of immune cell markers correlated with the gene expression-based immune cell signatures. The prevalence of immune cell signatures in early diffuse SSc patients was higher than in patients with longer disease duration. In the multivariable model, adaptive immune cell signatures were significantly associated with shorter disease duration, while fibroblast and macrophage cell type signatures were associated with higher modified Rodnan Skin Score (mRSS). Immune cell signatures also correlated with skin thickness progression rate prior to biopsy, but did not predict subsequent mRSS progression.ConclusionsSkin in early diffuse SSc has prominent innate and adaptive immune cell signatures. As a prominently affected end organ, these signatures reflect the preceding rate of disease progression. These findings could have implications in understanding SSc pathogenesis and clinical trial design.

Objective Many transplant programs are hesitant to offer lung transplantation to patients with systemic sclerosis (SSc) due to concerns about extrapulmonary involvement that might affect survival. The aim of this study was to determine whether adults with SSc have higher 1‐year mortality rates after lung transplantation compared to those with interstitial lung disease (ILD) or pulmonary arterial hypertension (PAH) not due to SSc. Methods Using data provided by the United Network for Organ Sharing, we performed a retrospective cohort study of 229 adults with SSc, 201 with PAH, and 3,333 with ILD who underwent lung transplantation in the US between May 4, 2005 and September 14, 2012. We examined associations between diagnosis and 1‐year survival after lung transplantation using stratified Cox models adjusted for recipient, donor, and procedure factors. Results Adults with SSc undergoing lung transplantation in the US had a multivariable‐adjusted 48% relative increase in the 1‐year mortality rate compared to those with non–SSc‐related ILD (hazard ratio 1.48 [95% confidence interval 1.01–2.17]). However, we did not detect a difference in the risk of death at 1 year between those with SSc and those with non–SSc‐related PAH (hazard ratio 0.85 [95% confidence interval 0.50–1.44]). Conclusion A diagnosis of SSc may confer an increased risk of death 1 year following lung transplantation compared to a diagnosis of ILD, but this risk is similar to that of PAH, a widely accepted indication for lung transplantation. Future work should identify modifiable risk factors that can improve transplant outcomes in this population.

Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examinedHLAassociations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestry-predominantHLA-DRB1*08:04andHLA-DRB1*11:02alleles were associated with overall SSc risk, and theHLA-DRB1*08:04allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestry-predominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, theHLA-DPB1*13:01andHLA-DRB1*07:01alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance ofHLAin defining autoantibody subtypes. The association of theHLA-DPB1*13:01allele with the ATA+subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence andHLA-DPB1*13:01allele frequency in multiple populations was observed (r= 0.98,P= 3 × 10−6). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA α/β allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link betweenHLAalleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.