Clinical trials on the pharmacological treatment of long COVID: A systematic review.

The postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC), also known as post-acute coronavirus disease 19 (COVID-19) or the long COVID syndrome (long COVID) is an emerging public health concern. A substantial proportion of individuals may remain symptomatic months after initial recovery. An updated review of published and ongoing trials focusing on managing long COVID will help identify gaps and address the unmet needs of patients suffering from this potentially debilitating syndrome. A comprehensive literature search was conducted on the international databases and clinical trial registries from inception to 31 July 2022. This review included 6 published trials and 54 trial registration records. There is significant heterogeneity in the characterization of long COVID and ascertainment of primary outcomes. Most of the trials are focused on individual symptoms of long COVID or isolated organ dysfunction, classified according to cardiovascular, respiratory and functional capacity, neurological and psychological, fatigue, and olfactory dysfunction. Most of the interventions are related to the mechanisms causing the individual symptoms. Although the six published trials showed significant improvement in the symptoms or organ dysfunction studied, these initial studies lack internal and external validity limiting the generalizability. This review provides an update of the pharmacological agents that could be used to treat long COVID. Further standardization of the diagnostic criteria, inclusion of participants with concomitant chronic cardiometabolic diseases and standardization of outcomes will be essential in future clinical trials.

Hypercoagulability, endotheliopathy, and inflammation approximating 1 year after recovery: Assessing the long-term outcomes in COVID-19 patients.

Sustained hypercoagulability and endotheliopathy are present in convalescent COVID-19 patients for up to 4 months from recovery. The hemostatic, endothelial, and inflammatory profiles of 39 recovered COVID-19 patients were evaluated up to 16 months after recovery from COVID-19. These values were compared with a control group of healthy volunteers (n = 124). 39 patients (71.8% males, median age 43 years) were reviewed at a mean of 12.7 ± 3.6 months following recovery. One patient without cardiovascular risk factors had post COVID-19 acute ischaemic limb. Elevated D-dimer and Factor VIII levels above normal ranges were noted in 17.9% (7/39) and 48.7% (19/39) of patients respectively, with a higher median D-dimer 0.34 FEU µg/mL (IQR 0.28, 0.46) (p < .001) and Factor VIII 150% (IQR 171, 203) (p = .004), versus controls. Thrombin generation (Thromboscreen) showed a higher median endogenous thrombin potential (ETP) of 1352 nM*min (IQR 1152, 1490) (p = .002) and a higher median peak height of 221.4 nM (IQR 170.2, 280.4) (p = 0.01) and delayed lag time 2.4 min (1.42-2.97) (p = 0.0002) versus controls. Raised vWF:Ag and ICAM-1 levels were observed in 17.9% (7/39) and 7.7% (3/39) of patients respectively, with a higher median VWF:Ag 117% (IQR 86, 154) (p = 0.02) and ICAM-1 54.1 ng/mL (IQR 43.8, 64.1) (p = .004) than controls. IL-6 was noted to be raised in 35.9% (14/39) of patients, with a higher median IL-6 of 1.5 pg/mL (IQR 0.6, 3.0) (p = 0.004) versus controls. Subgroup analysis stratifying patients by COVID-19 severity and COVID-19 vaccination preceding SARS-CoV-2 infection did not show statistically significant differences. Hypercoagulability, endothelial dysfunction, and inflammation are still detectable in some patients approximately 1 year after recovery from COVID-19.

SARS-CoV-2 mRNA Vaccination and Graves' Disease: A Report of 12 Cases and Review of the Literature.

CONTEXT AND OBJECTIVE: Thyroid autoimmunity has been reported to be associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the SARS-CoV-2 vaccination recently. We report a series of patients who presented with new onset or relapse of Graves' disease-related hyperthyroidism shortly after receiving the SARS-CoV-2 messenger RNA (mRNA) vaccine at a single tertiary institution in Singapore. METHODS AND RESULTS: We describe 12 patients who developed hyperthyroidism within a relatively short interval (median onset, 17 [range, 5-63] days) after receiving the SARS-CoV-2 mRNA vaccine. The majority were females (11/12) with median age of 35.5 (range, 22-74) years. Six patients had new-onset hyperthyroidism, whereas the other 6 had relapse of previously well-controlled Graves' disease. TSH receptor antibody concentrations ranged from 2.4 to 32 IU/L. The majority of the patients were able to go for the second dose of the vaccine without any further exacerbations. Literature review revealed 21 other similar cases reported from across the world. CONCLUSION: Our case series provides insight into the characteristics of individuals in whom Graves' disease was triggered by the SARS-CoV-2 vaccination. Clinicians need to be vigilant of precipitation or exacerbation of autoimmune thyroid disorders in predisposed individuals after exposure to the SARS-CoV-2 vaccination. Further epidemiological and mechanistic studies are required to elucidate the possible associations between the SARS-CoV-2 vaccines and the development of thyroid autoimmunity.

Diabetes Care During COVID-19 Pandemic in Singapore Using a Telehealth Strategy.

Singapore currently has one of highest number of confirmed COVID-19 cases in Southeast Asia. To curb the further spread of COVID-19, Singapore government announced a temporary nationwide lockdown (circuit breaker). In view of restrictions of patients' mobility and the enforcement of safe distancing measures, usual in-person visits were discouraged. Here we describe how diabetes care delivery was ad hoc redesigned applying a telehealth strategy. We describe a retrospective assessment of subjects with diabetes, with and without COVID-19 infection, during the circuit breaker period of 7th April to 1st June 2020 managed through Tan Tock Seng Hospital's telehealth platform. The virtual health applications consisted of telephone consultations, video telehealth visits via smartphones, and remote patient monitoring. The TTSH team intensively managed 298 diabetes patients using a telehealth strategy. The group comprised of (1) 84 inpatient COVID-19 patients with diabetes who received virtual diabetes education and blood glucose management during their hospitalisation and follow-up via phone calls after discharge and (2) 214 (n=192 non-COVID; n=22 COVID-positive) outpatient subjects with suboptimal glycaemic control who received intensive diabetes care through telehealth approaches. Remote continuous glucose monitoring was applied in 80 patients to facilitate treatment adjustment and hypoglycaemia prevention. The COVID-19 pandemic situation mooted an immediate disruptive transformation of healthcare processes. Virtual health applications were found to be safe, effective and efficient to replace current in-person visits.

Statin use is associated with lower disease severity in COVID-19 infection.

We aim to study the association of hyperlipidemia and statin use with COVID-19 severity. We analysed a retrospective cohort of 717 patients admitted to a tertiary centre in Singapore for COVID-19 infection. Clinical outcomes of interest were oxygen saturation ≤ 94% requiring supplemental oxygen, intensive-care unit (ICU) admission, invasive mechanical-ventilation and death. Patients on long term dyslipidaemia medications (statins, fibrates or ezetimibe) were considered to have dyslipidaemia. Logistic regression models were used to study the association between dyslipidaemia and clinical outcomes adjusted for age, gender and ethnicity. Statin treatment effect was determined, in a nested case-control design, through logistic treatment models with 1:3 propensity matching for age, gender and ethnicity. All statistical tests were two-sided, and statistical significance was taken as p < 0.05. One hundred fifty-six (21.8%) patients had dyslipidaemia and 97% of these were on statins. Logistic treatment models showed a lower chance of ICU admission for statin users when compared to non-statin users (ATET: Coeff (risk difference): - 0.12 (- 0.23, - 0.01); p = 0.028). There were no other significant differences in other outcomes. Statin use was independently associated with lower ICU admission. This supports current practice to continue prescription of statins in COVID-19 patients.

The ACE-2 in COVID-19: Foe or Friend?

COVID-19 is a rapidly spreading outbreak globally. Emerging evidence demonstrates that older individuals and people with underlying metabolic conditions of diabetes mellitus, hypertension, and hyperlipidemia are at higher risk of morbidity and mortality. The SARS-CoV-2 infects humans through the angiotensin converting enzyme (ACE-2) receptor. The ACE-2 receptor is a part of the dual system renin-angiotensin-system (RAS) consisting of ACE-Ang-II-AT1R axis and ACE-2-Ang-(1-7)-Mas axis. In metabolic disorders and with increased age, it is known that there is an upregulation of ACE-Ang-II-AT1R axis with a downregulation of ACE-2-Ang-(1-7)-Mas axis. The activated ACE-Ang-II-AT1R axis leads to pro-inflammatory and pro-fibrotic effects in respiratory system, vascular dysfunction, myocardial fibrosis, nephropathy, and insulin secretory defects with increased insulin resistance. On the other hand, the ACE-2-Ang-(1-7)-Mas axis has anti-inflammatory and antifibrotic effects on the respiratory system and anti-inflammatory, antioxidative stress, and protective effects on vascular function, protects against myocardial fibrosis, nephropathy, pancreatitis, and insulin resistance. In effect, the balance between these two axes may determine the prognosis. The already strained ACE-2-Ang-(1-7)-Mas in metabolic disorders is further stressed due to the use of the ACE-2 by the virus for entry, which affects the prognosis in terms of respiratory compromise. Further evidence needs to be gathered on whether modulation of the renin angiotensin system would be advantageous due to upregulation of Mas activation or harmful due to the concomitant ACE-2 receptor upregulation in the acute management of COVID-19.

Is DPP4 inhibition a comrade or adversary in COVID-19 Infection

Hypertension and Diabetes are the most common comorbid conditions in patients with COVID-19 and has been shown to adversely impact prognosis globally. It has been shown that hyperglycemia is one of the factors that increases the risk of poor outcomes in these patients . These patients are usually on multiple medications and recently a series of discussion on how Dipeptidyl peptidase 4 inhibitors (DPP4i) may be beneficial in these patients has been presented. This commentary presents a nuanced debateon why the DPP4i may not bebeneficial in COVID-19 and that caution needs to be addressed in making any judgementsuntil real world data is available.