Autoantibodies Neutralizing Type I IFNs in the Bronchoalveolar Lavage of at Least 10% of Patients During Life-Threatening COVID-19 Pneumonia.

Autoantibodies (auto-Abs) neutralizing type I interferons (IFNs) are found in the blood of at least 15% of unvaccinated patients with life-threatening COVID-19 pneumonia. We report here the presence of auto-Abs neutralizing type I IFNs in the bronchoalveolar lavage (BAL) of 54 of the 415 unvaccinated patients (13%) with life-threatening COVID-19 pneumonia tested. The 54 individuals with neutralizing auto-Abs in the BAL included 45 (11%) with auto-Abs against IFN-α2, 37 (9%) with auto-Abs against IFN-ω, 54 (13%) with auto-Abs against IFN-α2 and/or ω, and five (1%) with auto-Abs against IFN-ß, including three (0.7%) with auto-Abs neutralizing IFN-α2, IFN-ω, and IFN-ß, and two (0.5%) with auto-Abs neutralizing IFN-α2 and IFN-ß. Auto-Abs against IFN-α2 also neutralize the other 12 subtypes of IFN-α. Paired plasma samples were available for 95 patients. All seven patients with paired samples who had detectable auto-Abs in BAL also had detectable auto-Abs in plasma, and one patient had auto-Abs detectable only in blood. Auto-Abs neutralizing type I IFNs are, therefore, present in the alveolar space of at least 10% of patients with life-threatening COVID-19 pneumonia. These findings suggest that these auto-Abs impair type I IFN immunity in the lower respiratory tract, thereby contributing to hypoxemic COVID-19 pneumonia.

No increased prevalence of autoantibodies neutralizing type I IFNs in idiopathic pulmonary fibrosis patients.

SARS-CoV2 infection has a poor prognosis in patients affected of idiopathic pulmonary fibrosis (IPF). Autoantibodies (auto-Abs) neutralizing type I interferons (IFNs) are found in the blood of at least 15% of patients with life-threatening COVID-19 pneumonia. Because of the elevated prevalence of some auto-Abs in IPF patients, we hypothesize that the prevalence of auto-Abs neutralizing type I IFNs might be increased in the IPF population and then explained specific poor outcome after COVID-19. We screened the plasma of 247 consecutive IPF patients for the presence of auto-Abs neutralizing type I IFNs. Three patients displayed auto-Abs neutralizing type I IFNs. Among them, the only patient with documented SARS-CoV-2 infection experienced life threatening COVID-19 pneumonia. The prevalence of auto-Abs neutralizing type I IFNs in this cohort of IPF patients was not significantly different from the one of the general population. Overall, this study did not suggest any association between auto-Abs neutralizing type I IFNs and IPF.

Interstitial lung disease following coronavirus disease 2019.

PURPOSE OF REVIEW: The aim of this review was to summarize the recent data concerning interstitial lung disease after COVID-19, a field where knowledge is evolving very quickly. RECENT FINDINGS: It has been found that a proportion of patients displayed fibrotic-like pattern on chest computed tomography shortly after COVID-19 pneumonia. Those lesions can potentially represent precursors of fibrosis, although most of them will resolve until 1 year postinfection. There was a wide range of the prevalence of post-COVID-19 interstitial lung disease detected in the literature, which can be attributed to the heterogeneous definition of lung abnormalities and the discrepancy of study design. The severity of acute COVID-19 disease has been linked to increased risk of residual imaging and functional abnormalities, while reduced DLco was the most common functional abnormality in long-term survivors. Studies indicated that pathophysiology of post-COVID interstitial lung disease shares common mechanisms with idiopathic pulmonary fibrosis. Regarding therapeutic strategies of post-COVID-19 interstitial lung disease, the role of immunosuppressive and antifibrotic treatment is currently under investigation. SUMMARY: We still need to learn about the natural history of COVID-19 disease, allowing for a better targeting of therapeutic interventions through a multidisciplinary approach.

COVID-19 in patients with pulmonary alveolar proteinosis: a European multicentre study.

Adult PAP patients experience similar #COVID19 rates to the general population, and high rates of hospitalisation and deaths, underscoring their vulnerability and the need for measures to prevent infection. The impact of iGM-CSF must be considered. https://bit.ly/3M0wKnZ.

COVID-19 acute respiratory distress syndrome promotes a specific alternative macrophage polarization.

Acute respiratory distress syndrome (ARDS) alveolar environment induced a pro-repair anti-inflammatory macrophage polarization. However, patients with coronavirus disease 2019 (COVID-19) ARDS frequently exhibit a huge lung inflammation and present pulmonary scars and fibrosis more frequently than patients with non-COVID-19 ARDS, suggesting that the COVID-19 ARDS alveolar environment may drive a more inflammatory or pro-fibrotic macrophage polarization. This study aimed to determine the effect of the COVID-19 ARDS alveolar environment on macrophage polarization. The main finding was that broncho-alveolar lavage fluids (BALF) from patients with early COVID-19 ARDS drove an alternative anti-inflammatory polarization in normal monocyte-derived macrophages; characterized by increased expressions of CD163 and CD16 mRNA (3.4 [2.7-7.2] and 4.7 [2.6-5.8] fold saline control, respectively - p = 0.02), and a secretory pattern close to that of macrophages stimulated with IL-10, with the specificity of an increased production of IL-6. This particular alternative pattern was specific to early ARDS (compared with late ARDS) and of COVID-19 ARDS (compared with moderate COVID-19). The early COVID-19 ARDS alveolar environment drives an alternative anti-inflammatory macrophage polarization with the specificity of inducing macrophage production of IL-6.

COVID-19 in patients with Pulmonary Alveolar Proteinosis A European multicenter study

Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) signaling is essential in both alveolar macrophages (AMs) differentiation and activation of lung immune cells [1]. Differentiated AMs are crucial in both the elimination of alveolar microbes and surfactant clearance. The disruption of the GM-CSF axis in alveolar macrophages leads to the development of pulmonary alveolar proteinosis (PAP) [1]. In the majority of patients this relates to the presence of autoantibodies against GM-CSF autoimmune (a)PAP but there are multiple other causes [1, 2, 3]. GM-CSF deficient animals may have impaired lung inflammatory response to commensal microbes and humans with PAP may occasionally develop opportunistic lung infections [4]. The mainstay of pharmacological treatment in aPAP is inhaled GM-CSF which is off-label but increasingly used worldwide [5, 6, 7, 8, 9].

European Respiratory Society statement on long COVID follow-up.

Patients diagnosed with coronavirus disease 2019 (COVID-19) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection frequently experience symptom burden post-acute infection or post-hospitalisation. We aimed 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 convened and prioritised eight clinical questions. A targeted search of the literature defined the timeline of "long COVID" as 1-6 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 is limited.

Blood fibrocytes are associated with severity and prognosis in COVID-19 pneumonia.

Increased blood fibrocytes are associated with a poor prognosis in fibrotic lung diseases. We aimed to determine whether the percentage of circulating fibrocytes could be predictive of severity and prognosis during coronavirus disease 2019 (COVID-19) pneumonia. Blood fibrocytes were quantified by flow cytometry as CD45+/CD15-/CD34+/collagen-1+ cells in patients hospitalized for COVID-19 pneumonia. In a subgroup of patients admitted in an intensive care unit (ICU), fibrocytes were quantified in blood and bronchoalveolar lavage (BAL). Serum amyloid P (SAP), transforming growth factor-ß1 (TGF-ß1), CXCL12, CCL2, and FGF2 concentrations were measured. We included 57 patients in the hospitalized group (median age = 59 yr [23-87]) and 16 individuals as healthy controls. The median percentage of circulating fibrocytes was higher in the patients compared with the controls (3.6% [0.2-9.2] vs. 2.1% [0.9-5.1], P = 0.04). Blood fibrocyte count was lower in the six patients who died compared with the survivors (1.6% [0.2-4.4] vs. 3.7% [0.6-9.2], P = 0.02). Initial fibrocyte count was higher in patients showing a complete lung computed tomography (CT) resolution at 3 mo. Circulating fibrocyte count was decreased in the ICU group (0.8% [0.1-2.0]), whereas BAL fibrocyte count was 6.7% (2.2-15.4). Serum SAP and TGF-ß1 concentrations were increased in hospitalized patients. SAP was also increased in ICU patients. CXCL12 and CCL2 were increased in ICU patients and negatively correlated with circulating fibrocyte count. We conclude that circulating fibrocytes were increased in patients hospitalized for COVID-19 pneumonia, and a lower fibrocyte count was associated with an increased risk of death and a slower resolution of lung CT opacities.

Observer agreement and clinical significance of chest CT reporting in patients suspected of COVID-19.

OBJECTIVES: To assess interobserver agreement and clinical significance of chest CT reporting in patients suspected of COVID-19. METHODS: From 16 to 24 March 2020, 241 consecutive patients addressed to hospital for COVID-19 suspicion had both chest CT and SARS-CoV-2 RT-PCR. Eight observers (2 thoracic and 2 general senior radiologists, 2 junior radiologists, and 2 emergency physicians) retrospectively categorized each CT into one out of 4 categories (evocative, compatible for COVID-19 pneumonia, not evocative, and normal). Observer agreement for categorization between all readers and pairs of readers with similar experience was evaluated with the Kappa coefficient. The results of a consensus categorization were correlated to RT-PCR. RESULTS: Observer agreement across the 4 categories was good between all readers (κ value 0.61 95% CI 0.60-0.63) and moderate to good between pairs of readers (0.54-0.75). It was very good (κ 0.81 95% CI 0.79-0.83), fair (κ 0.32 95% CI 0.29-0.34), moderate (κ 0.56 95% CI 0.54-0.58), and moderate (0.58 95% CI 0.56-0.61) for the categories evocative, compatible, not evocative, and normal, respectively. RT-PCR was positive in 97%, 50%, 31%, and 11% of cases in the respective categories. Observer agreement was lower (p < 0.001) and RT-PCR positive cases less frequently categorized evocative in the presence of an underlying pulmonary disease (p < 0.001). CONCLUSION: Interobserver agreement for chest CT reporting using categorization of findings is good in patients suspected of COVID-19. Among patients considered for hospitalization in an epidemic context, CT categorized evocative is highly predictive of COVID-19, whereas the predictive value of CT decreases between the categories compatible and not evocative. KEY POINTS: • In patients suspected of COVID-19, interobserver agreement for chest CT reporting into categories is good, and very good to categorize CT "evocative." • Chest CT can participate in estimating the likelihood of COVID-19 in patients presenting to hospital during the outbreak, CT categorized "evocative" being highly predictive of the disease whereas almost a third of patients with CT "not evocative" had a positive RT-PCR in our study. • Observer agreement is lower and CTs of positive RT-PCR cases less frequently "evocative" in presence of an underlying pulmonary disease.

Arterial Thrombotic Events in Adult Inpatients With COVID-19.

OBJECTIVE: To evaluate the clinical course of and risk factors for arterial thrombotic events in adult inpatients with coronavirus disease 2019 (COVID-19). METHODS: All consecutive adult patients admitted for COVID-19 infection in a referral center in France and discharged from the hospital between April 1 and April 30, 2020, were included. All arterial thrombotic events that occurred through discharge were considered for analysis. Epidemiologic, demographic, clinical, laboratory, treatment, and outcome data were extracted from electronic medical records with use of a standardized data collection form. RESULTS: Overall, 531 COVID-19+ patients were analyzed. Among them, 30 (5.6%) experienced arterial thrombotic events. Arterial thrombotic events in the setting of COVID-19 infection happened at a median of 11 (5-20) days after the first symptoms of infection; occurred in high-risk patients according to traditional cardiovascular risk factors; had an atypical pattern, such as thrombosis of the aorta, upper limb, or renal arteries or cerebral microvasculopathy in 7 (23.3%) cases; and were associated with an in-hospital mortality rate of 40%. Arterial thrombotic events increased the risk of death by 3-fold in COVID-19+ patients (hazard ratio, 2.96; 95% CI, 1.4 to 4.7; P=.002). A subdistribution survival hazard model showed that a concentration of D-dimer above 1250 ng/mL increased the risk of arterial thrombotic events in COVID-19+ patients by more than 7 (subdistribution hazard ratio, 7.68; 95% CI, 2.9 to 20.6; P<.001). CONCLUSION: A dramatically high rate of in-hospital death was observed in patients who suffered arterial thrombotic events in the setting of COVID-19 infection. A D-dimer level above 1250 ng/mL at entry may identify COVID-19+ patients at risk for arterial thrombotic events.

Glucocorticoids with low-dose anti-IL1 anakinra rescue in severe non-ICU COVID-19 infection: A cohort study.

BACKGROUND: The optimal treatment for patients with severe coronavirus-19 disease (COVID-19) and hyper-inflammation remains debated. MATERIAL AND METHODS: A cohort study was designed to evaluate whether a therapeutic algorithm using steroids with or without interleukin-1 antagonist (anakinra) could prevent death/invasive ventilation. Patients with a ≥5-day evolution since symptoms onset, with hyper-inflammation (CRP≥50mg/L), requiring 3-5 L/min oxygen, received methylprednisolone alone. Patients needing ≥6 L/min received methylprednisolone + subcutaneous anakinra daily either frontline or in case clinical deterioration upon corticosteroids alone. Death rate and death or intensive care unit (ICU) invasive ventilation rate at Day 15, with Odds Ratio (OR) and 95% CIs, were determined according to logistic regression and propensity scores. A Bayesian analysis estimated the treatment effects. RESULTS: Of 108 consecutive patients, 70 patients received glucocorticoids alone. The control group comprised 63 patients receiving standard of care. In the corticosteroid±stanakinra group (n = 108), death rate was 20.4%, versus 30.2% in the controls, indicating a 30% relative decrease in death risk and a number of 10 patients to treat to avoid a death (p = 0.15). Using propensity scores a per-protocol analysis showed an OR for COVID-19-related death of 0.9 (95%CI [0.80-1.01], p = 0.067). On Bayesian analysis, the posterior probability of any mortality benefit with corticosteroids+/-anakinra was 87.5%, with a 7.8% probability of treatment-related harm. Pre-existing diabetes exacerbation occurred in 29 of 108 patients (26.9%). CONCLUSION: In COVID-19 non-ICU inpatients at the cytokine release phase, corticosteroids with or without anakinra were associated with a 30% decrease of death risk on Day 15.