Sensitivity and specificity of 14 SARS-CoV-2 serological assays and their diagnostic potential in RT-PCR negative COVID-19 infections.

BACKGROUND: Molecular detection of SARS-CoV-2 in respiratory samples is the gold standard for COVID-19 diagnosis but it has a long turnaround time and struggles to detect low viral loads. Serology could help to diagnose suspected cases which lack molecular confirmation. Two case reports are presented as illustration. OBJECTIVES: The aim of this study was to evaluate the performance of several commercial assays for COVID-19 serology. We illustrated the added value of COVID-19 serology testing in suspect COVID-19 cases with negative molecular test. STUDY DESIGN: Twenty-three sera from 7 patients with a confirmed molecular diagnosis of SARS-CoV-2 were tested using 14 commercial assays. Additionally, 10 pre-pandemic sera and 9 potentially cross-reactive sera were selected. We calculated sensitivity and specificity. Furthermore, we discuss the diagnostic relevance of COVID-19 serology in a retrospective cohort of 145 COVID-19 cases in which repetitive molecular and serological SARS-CoV-2 tests were applied. RESULTS: The interpretation of the pooled sensitivity of IgM/A and IgG resulted in the highest values (range 14-71% on day 2-7; 88-94% on day 8-18). Overall, the specificity of the assays was high (range 79-100%). Among 145 retrospective cases, 3 cases (2%) remained negative after sequential molecular testing but positive on final SARS-CoV-2 serology. CONCLUSION: Sensitivity of COVID-19 serological diagnosis was variable but consistently increased at >7 days after symptom onset. Specificity was high. Our data suggest that serology can complement molecular testing for diagnosis of COVID-19, especially for patients presenting the 2nd week after symptom onset or later.

Effect of anti-interleukin drugs in patients with COVID-19 and signs of cytokine release syndrome (COV-AID): a factorial, randomised, controlled trial.

BACKGROUND: Infections with SARS-CoV-2 continue to cause significant morbidity and mortality. Interleukin (IL)-1 and IL-6 blockade have been proposed as therapeutic strategies in COVID-19, but study outcomes have been conflicting. We sought to study whether blockade of the IL-6 or IL-1 pathway shortened the time to clinical improvement in patients with COVID-19, hypoxic respiratory failure, and signs of systemic cytokine release syndrome. METHODS: We did a prospective, multicentre, open-label, randomised, controlled trial, in hospitalised patients with COVID-19, hypoxia, and signs of a cytokine release syndrome across 16 hospitals in Belgium. Eligible patients had a proven diagnosis of COVID-19 with symptoms between 6 and 16 days, a ratio of the partial pressure of oxygen to the fraction of inspired oxygen (PaO2:FiO2) of less than 350 mm Hg on room air or less than 280 mm Hg on supplemental oxygen, and signs of a cytokine release syndrome in their serum (either a single ferritin measurement of more than 2000 µg/L and immediately requiring high flow oxygen or mechanical ventilation, or a ferritin concentration of more than 1000 µg/L, which had been increasing over the previous 24 h, or lymphopenia below 800/mL with two of the following criteria: an increasing ferritin concentration of more than 700 µg/L, an increasing lactate dehydrogenase concentration of more than 300 international units per L, an increasing C-reactive protein concentration of more than 70 mg/L, or an increasing D-dimers concentration of more than 1000 ng/mL). The COV-AID trial has a 2 × 2 factorial design to evaluate IL-1 blockade versus no IL-1 blockade and IL-6 blockade versus no IL-6 blockade. Patients were randomly assigned by means of permuted block randomisation with varying block size and stratification by centre. In a first randomisation, patients were assigned to receive subcutaneous anakinra once daily (100 mg) for 28 days or until discharge, or to receive no IL-1 blockade (1:2). In a second randomisation step, patients were allocated to receive a single dose of siltuximab (11 mg/kg) intravenously, or a single dose of tocilizumab (8 mg/kg) intravenously, or to receive no IL-6 blockade (1:1:1). The primary outcome was the time to clinical improvement, defined as time from randomisation to an increase of at least two points on a 6-category ordinal scale or to discharge from hospital alive. The primary and supportive efficacy endpoints were assessed in the intention-to-treat population. Safety was assessed in the safety population. This study is registered online with ClinicalTrials.gov (NCT04330638) and EudraCT (2020-001500-41) and is complete. FINDINGS: Between April 4, and Dec 6, 2020, 342 patients were randomly assigned to IL-1 blockade (n=112) or no IL-1 blockade (n=230) and simultaneously randomly assigned to IL-6 blockade (n=227; 114 for tocilizumab and 113 for siltuximab) or no IL-6 blockade (n=115). Most patients were male (265 [77%] of 342), median age was 65 years (IQR 54-73), and median Systematic Organ Failure Assessment (SOFA) score at randomisation was 3 (2-4). All 342 patients were included in the primary intention-to-treat analysis. The estimated median time to clinical improvement was 12 days (95% CI 10-16) in the IL-1 blockade group versus 12 days (10-15) in the no IL-1 blockade group (hazard ratio [HR] 0·94 [95% CI 0·73-1·21]). For the IL-6 blockade group, the estimated median time to clinical improvement was 11 days (95% CI 10-16) versus 12 days (11-16) in the no IL-6 blockade group (HR 1·00 [0·78-1·29]). 55 patients died during the study, but no evidence for differences in mortality between treatment groups was found. The incidence of serious adverse events and serious infections was similar across study groups. INTERPRETATION: Drugs targeting IL-1 or IL-6 did not shorten the time to clinical improvement in this sample of patients with COVID-19, hypoxic respiratory failure, low SOFA score, and low baseline mortality risk. FUNDING: Belgian Health Care Knowledge Center and VIB Grand Challenges program.

The Role of Patient-Reported Outcomes in Sleep Measurements.

Several questionnaires aka patient-reported outcome measures (PROMs) have been developed for specific use in sleep medicine. Some PROMS are "disease-specific," that is, related to a specific sleep disorder, whereas others are generic. These PROMS constitute a valuable add-on to the conventional history taking. They can be used in the areas of research, clinical practice, and quality of health care appraisal. Still, these instruments have inherent limitations, requiring proficient application in the various areas of interest. Disease-specificity includes a risk for nosologic bias that may confound diagnostic and therapeutic results. Future research should provide solutions for shortcomings of presently available questionnaires.

Sex differences in the association between arterial hypertension, blood pressure, and sleep apnea in the general population.

STUDY OBJECTIVES: To assess sex-related differences in the relationship between hypertension (HT), blood pressure (BP), and sleep apnea in the general population. METHODS: We performed home polygraphy in a cohort of 1809 men and women in the general population. Office BP was measured. Presence of HT (drug-treated, physician-diagnosed, or high BP during study visit) was also recorded. HT rate and BP were assessed over a range of 7 sleep apnea severity categories based on the respiratory event index (REI). RESULTS: The age-adjusted HT prevalence rate increased with higher REI in both sexes. After additional adjustment for obesity the association remained significant in women but not in men. In participants not treated with antihypertensive medications, age-adjusted BP increased with REI. Remarkably, the association was already significant within the normal range (REI < 5 events/h). The REI threshold for higher BP was situated at a distinctly lower cutoff point in women compared to men. After additional adjustment for obesity, the associations remained significant for diastolic but not systolic BP. CONCLUSIONS: Significant increases in the age-adjusted BP and HT rate in the general population were present at lower REI cutoffs in women compared to men. Even a very low number of respiratory events was associated with higher BP and HT prevalence. Adjustment for obesity attenuated these associations, especially in men. Sex differences in BP susceptibility across the sleep apnea spectrum may be present.

Myotonic dystrophy type 1 as a major risk factor for severe COVID-19?

The coronavirus disease 2019 (COVID-19) pandemic is challenging health care systems worldwide. People with myotonic dystrophy type 1 (DM1) represent a high-risk population during infectious disease outbreaks, little is known about the potential impact of COVID-19 on patients with DM1. We studied the clinical course of COVID-19 in three hospitalized patients with myotonic dystrophy type 1 or Steinert's disease, between April 1, 2020-April 30-2020. All three had advanced Steinert's disease receiving non-invasive nocturnal home ventilatory support. Two of them lived in a residential care centre. Two patients had a limited respiratory capacity, whereas one patient had a rather preserved functional capacity but more comorbidities. Two out of three patients were obese, none of them had diabetes mellitus. Two patients received hydroxychloroquine. Despite maximal supportive care with oxygen therapy, antibiotics, intensive respiratory physiotherapy and non-invasive positive pressure ventilation, all three patients eventually died due to COVID-19. Our case series of three patients with DM1 admitted for COVID-19 confirms that they are at high risk for severe disease and poor outcome. Clinical trials are needed to define best practices and determinants of outcomes in this unique population.

Sex-specific sleep apnea screening questionnaires: closing the performance gap in women.

BACKGROUND: The availability of poly(somno)graphy [P(S)G] for sleep apnea (SA) diagnosis is limited, making pre-test case evaluation an important challenge. The Neck, Obesity, Snoring, Age, Sex (NoSAS) and STOP-Bang (SBQ) scores are accepted screening tests, but their sex-specific performance in the general population is unknown. OBJECTIVE: To compare the sex-specific diagnostic characteristics of the NoSAS and SBQ scores, and to optimize the performance of these tools for men and women. METHODS: Participants from a population-based cohort (n = 2205) underwent clinical evaluation, including NoSAS, SBQ, and home polygraphy. RESULTS: We obtained successful polygraphy in 1809 participants. Moderate-to-severe SA was present in 11.7%. Diagnostic performance indices of NoSAS and the SBQ calculated on the overall group (men + women) overestimated the performance in both sexes separately. The sensitivity of NoSAS for an apnea/hypopnea index (AHI) ≥15 h-1 was acceptable in men (87.1%), but low in women (55.3%). The reverse was true for the specificity (39.9% in men, 87.4% in women). A similar sex-specific difference in diagnostic performance was seen with the SBQ. Using women-specific cut-offs for the scores (NoSAS ≥6 or SBQ ≥2) and neck circumference (>35 cm) increased the sensitivity in women to levels similar to men (88.5 and 87.2%). Although specificity decreased, it still remained higher than in men. CONCLUSION: In women, the sensitivity of NoSAS and the SBQ is too low for SA screening in the general population. Sex-specific cut-offs reverse this imbalance and achieve test sensitivities in women similar to those in men, whilst still retaining higher specificities than in men. Sleep questionnaires performance reporting should be sex-stratified.

Phenotype and Risk Burden of Sleep Apnea: A Population-Based Cohort Study.

Sleep apnea (SA) prevalence had increased. The socioeconomic burden is significant because of healthcare-related costs and adverse outcome, especially in moderate-to-severe SA. However, the population impact is unclear, particularly for mild SA. We aimed to assess the current prevalence and the cardiovascular risk associates of SA in the general population. We performed home polygraphy and extensive clinical, sociodemographic, and cardiovascular assessment in 2205 eligible subjects from a population-based cohort. Successful polygraphy was obtained in 1809 subjects (mean age, 56.0; SD, 5.9 years; 52.3% women). The prevalence was 41.0%, 11.8%, and 6.5% for mild, moderate, and severe SA in men and 26.6%, 4.4%, and 1.2% in women. Male sex, age, increasing BMI, and snoring were independently associated with SA, whereas sleepiness or tiredness were not. Compared with those without SA, mild SA was associated with (age- and sex-adjusted OR; 95% CI): diabetes mellitus (2.40; 1.52-3.80), hypertension (1.76; 1.42-2.19), left ventricular hypertrophy (1.36; 1.03-1.79), arterial plaques (1.19; 0.94-1.52), and increased IL-6 (interleukin-6) levels (1.37; 1.10-1.72). These associations were more pronounced in moderate-to-severe SA. To conclude, SA is highly prevalent in the middle-aged general population. It is largely undetected and undetectable using a symptom-based strategy. Yet, even the large group with mild SA shows a manifestly higher metabolic, inflammatory, and cardiovascular risk factor burden, with potential public health implications.

Sleep apnea and the impact on cardiovascular risk in patients with Marfan syndrome.

BACKGROUND: Marfan syndrome (MFS) is an inherited connective tissue disorder characterized by ectopia lentis, aortic root dilation and dissection and specific skeletal features. Obstructive sleep apnea (OSA) in MFS has been described earlier but the prevalence and its relation with the cardiovascular risk is still controversial. This study aimed to further investigate these aspects. METHODS: In this prospective longitudinal study, we performed an attended polysomnography in 40 MFS patients (60% women, 37 ± 12.8 years) and evaluated several cardiovascular parameters through echocardiography, resting electrocardiogram, 24 hr-Holter monitoring and serum NT-ProBNP measurements. RESULTS: We found that OSA was present in 42.5% of the patients and that higher body mass index was the most important factor associated with the presence of OSA. We observed that overweight was present in 27.5% of the patients in the whole cohort and in 55.6% if >40 years. Furthermore, when evaluating the impact of OSA on the cardiovascular system, we observed that patients with OSA tended to have higher systolic blood pressure, larger distal aortic diameters and a higher prevalence of ventricular arrhythmia. These differences were, however, not significant after adjusting for confounders. CONCLUSIONS: Our study shows a high prevalence of OSA and a high prevalence of overweight in MFS patients. We found some trends between OSA and cardiovascular features but we could not establish a solid association. Our study, however might be underpowered, and a multicenter collaborative study could be very useful to answer some important open questions.

The Link Between Obstructive Sleep Apnea and Cardiovascular Disease.

Obstructive sleep apnea (OSA) is common in the general population and highly prevalent in patients with cardiovascular disease. In this paper, we review (1) the pathophysiological mechanisms of OSA that may causally contribute to cardiovascular disease; (2) current evidence regarding the association between OSA and hypertension, stroke, ischemic heart disease, heart failure, atrial fibrillation, and cardiovascular mortality; and (3) the impact of continuous positive airway pressure (CPAP) treatment on cardiovascular risk factors and outcomes. We emphasize the importance of obesity as a comorbidity of OSA and a confounder in the association between OSA and cardiovascular disease. We also discuss the importance of addressing obesity in patients with OSA, as a strategy to reduce the burden of cardiovascular risk factors in this population. Implications for the approach of patients' OSA in clinical practice and future research directions are discussed.

Neomacrolides in the treatment of patients with severe asthma and/or bronchiectasis: a retrospective observational study.

RATIONALE: Previous studies have demonstrated that long-term low-dose macrolides are efficacious in cystic fibrosis (CF) and diffuse panbronchiolitis, two chronic neutrophilic airway diseases. AIMS: The aims of this study were to evaluate the efficacy and safety of low-dose neomacrolides as add-on therapy in patients with severe asthma and/or bronchiectasis and to identify predictors for therapeutic response. METHODS: In a retrospective observational cohort study, we examined 131 adult, non-CF patients with severe asthma and/or bronchiectasis, receiving low-dose neomacrolides as add-on treatment. Pulmonary function tests and symptom scores were assessed at baseline and after 3 to 8 weeks of therapy. RESULTS: After 3-8 weeks of treatment with low-dose neomacrolides, 108 patients were available for evaluation. In asthma patients (n = 47), pulmonary function tests and symptom scores improved significantly. Responders (≥7% forced expiratory volume in one second predicted [FEV(1)%] improvement) were older (55 vs. 47 years; p = 0.042) and had a longer duration of asthma (29 vs. 9 years; p = 0.052). In patients with bronchiectasis only (n = 61), symptom scores improved significantly. Responders (≥60% symptom score improvement) were older (61 vs. 53 years; p = 0.004), more frequently male (53% vs. 27%; p = 0.043), and there was a nonsignificant trend towards higher high-resolution CT (HRCT) score for bronchiectasis in responders (6.4 vs. 4.6; p = 0.053). In multivariate logistic regression analysis, age and male gender were independent predictors for improvement in this group. CONCLUSION: The results of this retrospective study suggest that neomacrolides may be useful as an add-on therapy in patients with severe asthma and/or bronchiectasis. Older age may predict good response in patients with severe asthma, whereas older age, male gender and a higher HRCT score for bronchiectasis may predict therapeutic response in patients with bronchiectasis only. Prospective controlled trials of neomacrolides in patients with severe asthma are needed to confirm these observations.

The value of auto-adjustable CPAP devices in pressure titration and treatment of patients with obstructive sleep apnea syndrome.

In moderate to severe obstructive sleep apnea syndrome (OSAS), the use of Continuous Positive Airway Pressure (CPAP) is the gold standard therapy. In the last decade, new technologies such as auto-adjustable CPAP (APAP) have been promoted as having an added advantage over CPAP, because of their ability to adapt the pressure level to the patient's need at all times. This could logically result in the deliverance of lower pressures, which was hypothesized to improve patient acceptance and compliance for therapy. Several clinical trials have been performed with APAP in different modalities, as a titration tool in attended or unattended conditions, or as a treatment device for chronic use. Comparison of these trials is challenging, since APAP technology is evolving promptly and devices differ not only in how sleep-disordered breathing is detected, but also in how the operational algorithm responds accordingly. Although the question remains whether proof has yet been delivered of the superiority of this technology over CPAP, there is a tendency to accept it as common standard practice in OSAS titration and treatment. This review will bring available evidence on this subject into perspective.