European Respiratory Society Statement on Long COVID-19 Follow-Up

Patients diagnosed with COVID-19 associated with SARS-CoV-2 infection frequently experience symptom burden post-acute infection or post-hospitalisation. We aim to identify optimal strategies for follow-up care that may positively impact the patient's quality-of-life (QOL).A European Respiratory Society (ERS) Task Force (TF) convened and prioritised eight clinical questions. A targeted search of the literature defined the time line of long COVID-19 as one to six months post infection and identified clinical evidence in the follow-up of patients. Studies meeting the inclusion criteria report an association of characteristics of acute infection with persistent symptoms, thromboembolic events in the follow-up period and evaluations of pulmonary physiology and imaging. Importantly, this statement reviews QOL consequences, symptom burden, disability and home care follow-up. Overall, the evidence for follow-up care for patients with long COVID-19 is limited

Treatment outcome definitions in nontuberculous mycobacterial pulmonary disease: an NTM-NET consensus statement

Nontuberculous mycobacterial pulmonary diseases (NTM-PD) are increasingly recognised as opportunistic infections of humans. These chronic pulmonary infections have two main presentations. The first is a fibro-cavitary disease, that occurs in patients with pre-existing pulmonary diseases, such as chronic obstructive pulmonary disease, bronchiectasis, previous tuberculosis or other structural lung disease. The second presentation is a nodular- bronchiectatic disease of primarily the lingula and middle lobe that tends to affect a middle- aged and elderly female population [1]. Treatment of NTM-PD requires long-term administration of complex multidrug therapies that are species-specific. Currently recommended regimens are supported by a very limited evidence base [2, 3]. The increasing incidence of NTM-PD has sparked increased interest in performing prospective randomised clinical trials [4]. One of the drawbacks of the existing case series and clinical trials is that they have applied different outcome measures [5]. This hampers meta-analyses, which are important in these still understudied infectious diseases. To enhance the quality and interpretability of the results of future trials and retrospective cohort studies, we aimed to formulate clear and broadly acceptable outcome definitions for NTM-PD treatment

Evidence of mycobacterial disease in COPD patients with lung volume reduction surgery; the importance of histological assessment of specimens: a cohort study

Background Patients with COPD are at risk of non-tuberculous mycobacterial infection (NTM). This study examined the histology of lung tissue from COPD patients following lung volume reduction with particular focus on evidence of mycobacterial infection. Methods Retrospective histological study of 142 consecutive lung volume reduction surgical specimens (126 separate patients) at Royal Brompton Hospital between 2000 – 2013, with prospectively collected preoperative data on exacerbation rate, lung function and body mass index. Results 92% of patients had at least one other histological diagnosis in addition to emphysema. 10% of specimens had histological evidence of mycobacterial infection, one with co-existent aspergilloma. Mycobacteria were only identified in those patients with granulomas that were necrotising. These patients had higher exacerbation rates, lower TLCO and FEV1. Conclusion A proportion of severe COPD patients will have evidence of mycobacterial infection despite lack of clinical and radiological suspicion. This may have implications for long-term management of these patients

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men

Clinical standards for diagnosis, treatment and prevention of post-COVID-19 lung disease

BACKGROUND: The aim of these clinical standards is to provide guidance on ‘best practice’ care for the diagnosis, treatment and prevention of post-COVID-19 lung disease. METHODS: A panel of international experts representing scientific societies, associations and groups active in post-COVID-19 lung disease was identified; 45 completed a Delphi process. A 5-point Likert scale indicated level of agreement with the draft standards. The final version was approved by consensus (with 100% agreement).RESULTS: Four clinical standards were agreed for patients with a previous history of COVID-19: Standard 1, Patients with sequelae not explained by an alternative diagnosis should be evaluated for possible post-COVID-19 lung disease; Standard 2, Patients with lung function impairment, reduced exercise tolerance, reduced quality of life (QoL) or other relevant signs or ongoing symptoms ≥4 weeks after the onset of first symptoms should be evaluated for treatment and pulmonary rehabilitation (PR); Standard 3, The PR programme should be based on feasibility, effectiveness and cost-effectiveness criteria, organised according to local health services and tailored to an individual patient’s needs; and Standard 4, Each patient undergoing and completing PR should be evaluated to determine its effectiveness and have access to a counselling/health education session. CONCLUSION: This is the first consensus-based set of clinical standards for the diagnosis, treatment and prevention of post-COVID-19 lung disease. Our aim is to improve patient care and QoL by guiding clinicians, programme managers and public health officers in planning and implementing a PR programme to manage post-COVID-19 lung disease

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population