Thrombocytopenia in the Course of COVID-19 Infection.

We report three cases of severe thrombocytopenia during COVID-19 infection associated with either cutaneous purpura or mucosal bleeding. The initial investigations ruled out other causes of thrombocytopenia. Two of the patients were treated with intravenous immunoglobulins and eltrombopag, while the third recovered spontaneously. A good clinical and biological response was achieved in all patients leading to hospital discharge. LEARNING POINTS: Immune thrombocytopenia should be considered in COVID-19-infected patients presenting with thrombocytopenia.Coronavirus-related thrombocytopenia can be severe and life-threatening.Despite the severity of coronavirus-related immune thrombocytopenia, recovery may be spontaneous or achieved following immunoglobulin or platelet growth factor administration.

ERN ReCONNET points to consider for treating patients living with autoimmune rheumatic diseases with antiviral therapies and anti-SARS-CoV-2 antibody products.

Recent studies have shown that people who are immunocompromised may inadvertently play a role in spurring the mutations of the virus that create new variants. This is because some immunocompromised individuals remain at risk of getting COVID-19 despite vaccination, experience more severe disease, are susceptible to being chronically infected and remain contagious for longer if they become infected and considering that immunocompromised individuals represent approximately 2% of the overall population, this aspect should be carefully considered. So far, some autoimmune rheumatic disease (ARD) patients with COVID-19 have been treated with antiviral therapies or anti-SARS-CoV-2 antibody products. However, there is no homogeneous approach to these treatment strategies. This issue was addressed within the European Reference Network (ERN) on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ReCONNET) in a discussion among experts and patient's representatives in the context of the rare and complex connective tissue diseases (rCTDs) covered by the Network. ERN ReCONNET is one of the 24 ERNs launched by the European Commission in 2017 with the aim of tackling low prevalence and rare diseases that require highly specialised treatment and promoting concentration of knowledge and resources through virtual networks involving healthcare providers (HCPs) across the European Union (EU). Considering the urgent need to provide guidance not only to the rCTDs community, but also to the whole ARDs community, a multidisciplinary Task Force, including expert clinicians and European Patient Advocacy Group (ePAG) Advocates, was created in the framework of ERN ReCONNET with the aim of developing overarching principles (OP) and points-to-consider (PtC) on a homogenous approach to treat immunocompromised patients with ARDs (with a particular focus on CTDs) affected by COVID-19 using antiviral therapies and anti-SARS-CoV-2 antibody products. The present work reports the final OP and PtC agreed by the Task Force.

Tolerance and efficacy of targeted therapies prescribed for off-label indications in refractory systemic autoimmune diseases: data of the first 100 patients enrolled in the TATA registry (TArgeted Therapy in Autoimmune Diseases).

OBJECTIVES: To assess the tolerance and efficacy of targeted therapies prescribed off-label in refractory low-prevalence autoimmune and inflammatory systemic diseases. METHODS: The TATA registry (TArgeted Therapy in Autoimmune Diseases) is a prospective, observational, national and independent cohort follow-up. The inclusion criteria in the registry are as follows: age >18 years; low-prevalence autoimmune and inflammatory systemic disease treated with off-label drugs started after 1 January 2019. RESULTS: Hundred (100) patients (79 women) were enrolled. The median age was 52.5 years (95% CI 49 to 56) and the median disease duration before enrolment was 5 years (3 to 7). The targeted therapies at enrolment were as follows: Janus kinase/signal transducers and activators of transcription inhibitors (44%), anti-interleukin (IL)-6R (22%), anti-IL-12/23, anti-IL-23 and anti-IL-17 (9%), anti-B cell activating factor of the tumour necrosis factor family (5%), abatacept (5%), other targeted treatments (9%) and combination of targeted treatments (6%). 73% of patients were receiving corticosteroid therapy at enrolment (median dose 10 mg/day). The current median follow-up time is 9 months (8 to 10).Safety: 11 serious infections (incidence rate of 14.8/100 patient-years) and 1 cancer (1.3 cancers/100 patient-years) were observed. Two patients died from severe COVID-19 (2.7 deaths/100 patient-years).Efficacy: the targeted treatment was considered effective by the clinician in 56% of patients and allowed, in responders, a median reduction of oral corticosteroids of 15 (9 to 21) mg/day, below 7.5 mg/day in 76% of patients, while 28% discontinued. CONCLUSION: These initial results of the TATA registry confirm the diversity of targeted treatments prescribed off-label in refractory autoimmune diseases and their corticosteroid-sparing effect when effective. Tolerance was acceptable in these refractory patients with a long history of treatment with immunosuppressive drugs.

Long Term Follow-Up of Sarcopenia and Malnutrition after Hospitalization for COVID-19 in Conventional or Intensive Care Units.

BACKGROUND: The post-COVID-19 condition, defined as COVID-19-related signs and symptoms lasting at least 2 months and persisting more than 3 months after infection, appears now as a public health issue in terms of frequency and quality of life alterations. Nevertheless, few data are available concerning long term evolution of malnutrition and sarcopenia, which deserve further attention. METHOD: Sarcopenia was investigated prospectively, together with weight evolution, at admission and at 3 and 6 months after hospital discharge in 139 COVID-19 patients, using the European Working Group on Sarcopenia in Older People (EWGSOP2) criteria, associating both decreased muscle strength and muscle mass, assessed, respectively, with hand dynamometer and dual-energy X-ray absorptiometry. RESULTS: Of the 139 patients, 22 presented with sarcopenia at 3 months; intensive care units (ICU) length of stay was the sole factor associated with sarcopenia after multivariate analysis. Although the entire group did not demonstrate significant weight change, weight decreased significantly in the sarcopenia group (Five and eight patients, showing, respectively, >5 or >10% weight decrease). Interestingly, at 6 months, 16 of the 22 patients recovered from sarcopenia and their weight returned toward baseline values. CONCLUSIONS: Sarcopenia and malnutrition are frequently observed in patients hospitalized for COVID-19, even 3 months after infection occurrence, but can largely be reversed at 6 months after discharge. Enhanced patient care is needed in sarcopenic patients, particularly during long stays in an ICU.

Incidence and predictors of COVID-19 and flares in patients with rare autoimmune diseases: a systematic survey and serological study at a national reference center in France.

BACKGROUND: The risk of severe COVID-19 and its determinants remain largely unknown in patients with autoimmune and inflammatory rheumatic diseases. The objective of this study was to assess the prevalence of COVID-19 infection in patients followed for rare autoimmune diseases as well as the predictors of COVID-19 and disease flare-ups. METHODS: Cross-sectional phone survey from April 9, 2020, to July 2, 2020, during which patients with autoimmune diseases followed at the National Reference Center for Rare Autoimmune diseases of Strasbourg were systematically contacted by phone and sent a prescription for a SARS-CoV-2 serology. RESULTS: One thousand two hundred thirty-two patients were contacted. One thousand fifty-five patients with a confirmed diagnosis of systemic autoimmune disease were included (4 unreachable, 4 moves abroad, 5 deaths before pandemic, 50 without consent, and 114 without autoimmune disease). Among them, 469 (44.5%) patients were tested for SARS-CoV-2 serology. Thirty-nine patients (7.9%) had SARS-CoV-2 infection (either through chest CT-scan [n = 5], RT-PCR on nasopharyngeal swab [n = 14], or serology [n = 31]) among the 496 who underwent at least one of those 3 diagnosis modalities. Of the 39 proven cases, 33 had clinical manifestations (6 asymptomatic patients were diagnosed through systematic serology testing), 31 were managed by home care, 3 were hospitalized due to a need for oxygenation, two required admission to an intensive care unit, and one died. Among patients with confirmed SARS-CoV-2 infection, reported flares were more frequent than in uninfected patients (26.3% [10/38] vs. 7.0% [32/457], p < 0.0001). Preventive sick leave had no significant impact on the prevalence of SARS-CoV-2 infection (5.8% [3/53]) compared to work continuation (7.6% [30/397], p = 0.64). Overall, the seroprevalence of SARS-CoV-2 was 6.6% (31/469) which was numerically lower to the Grand-Est general population estimated to be 9.0%. CONCLUSIONS: This systematic survey of more than 1000 patients with rare systemic autoimmune diseases reports a low prevalence of proven SARS-CoV-2 infection and very rare severe infections, probably related to good compliance with prophylactic measures in these patients.

Reduced Flow-Mediated Dilatation Is Not Related to COVID-19 Severity Three Months after Hospitalization for SARS-CoV-2 Infection.

The coronavirus disease 2019 (COVID-19) pandemic has spread rapidly worldwide, with more than two million deaths. Evidence indicates the critical role of the vascular endothelium in its pathophysiology but, like potential changes in functional vasodilation, the vascular effect of SARS-CoV-2 at a given distance from the acute infection is largely unknown. We assessed brachial artery flow-mediated dilatation (FMD) in 27 COVID-19 patients needing conventional or intensive care unit hospitalization, three months after SARS-CoV-2 infection diagnosis and in nine age- and sex- matched control subjects. Interestingly, the FMD was lower in COVID-19 patients as compared to controls (8.2 (7.2-8.9) vs. 10.3 (9.1-11.7)); p = 0.002, and half of the hospitalized COVID-19 survivors presented with a reduced FMD < 8% at three months of COVID-19 onset. Impaired FMD was not associated with severe or critical SARS-CoV-2 infection, reflected by ICU hospitalization, total hospitalization duration, or severity of lung damage. In conclusion, reduced FMD is often observed even three months after hospitalization for SARS-CoV-2 infection, but such alteration predominantly appears to not be related to COVID-19 severity. Longer and larger follow-up studies will help to clarify the potential prognosis value of FMD among COVID-19 patients, as well as to further determine the mechanisms involved.

The impact of COVID-19 on rare and complex connective tissue diseases: the experience of ERN ReCONNET.

During the COVID-19 pandemic, the need to provide high-level care for a large number of patients with COVID-19 has affected resourcing for, and limited the routine care of, all other conditions. The impact of this health emergency is particularly relevant in the rare connective tissue diseases (rCTDs) communities, as discussed in this Perspective article by the multi-stakeholder European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ERN ReCONNET). The clinical, organizational and health economic challenges faced by health-care providers, institutions, patients and their families during the SARS-CoV-2 outbreak have demonstrated the importance of ensuring continuity of care in the management of rCTDs, including adequate diagnostics and monitoring protocols, and highlighted the need for a structured emergency strategy. The vulnerability of patients with rCTDs needs to be taken into account when planning future health policies, in preparation for not only the post-COVID era, but also any possible new health emergencies.

Autophagy in T cells from aged donors is maintained by spermidine and correlates with function and vaccine responses.

Vaccines are powerful tools to develop immune memory to infectious diseases and prevent excess mortality. In older adults, however vaccines are generally less efficacious and the molecular mechanisms that underpin this remain largely unknown. Autophagy, a process known to prevent aging, is critical for the maintenance of immune memory in mice. Here, we show that autophagy is specifically induced in vaccine-induced antigen-specific CD8+ T cells in healthy human volunteers. In addition, reduced IFNγ secretion by RSV-induced T cells in older vaccinees correlates with low autophagy levels. We demonstrate that levels of the endogenous autophagy-inducing metabolite spermidine fall in human T cells with age. Spermidine supplementation in T cells from old donors recovers their autophagy level and function, similar to young donors' cells, in which spermidine biosynthesis has been inhibited. Finally, our data show that endogenous spermidine maintains autophagy via the translation factor eIF5A and transcription factor TFEB. In summary, we have provided evidence for the importance of autophagy in vaccine immunogenicity in older humans and uncovered two novel drug targets that may increase vaccination efficiency in the aging context.