Immunoglobulin signature predicts risk of post-acute COVID-19 syndrome.

Following acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) a significant proportion of individuals develop prolonged symptoms, a serious condition termed post-acute coronavirus disease 2019 (COVID-19) syndrome (PACS) or long COVID. Predictors of PACS are needed. In a prospective multicentric cohort study of 215 individuals, we study COVID-19 patients during primary infection and up to one year later, compared to healthy subjects. We discover an immunoglobulin (Ig) signature, based on total IgM and IgG3 levels, which - combined with age, history of asthma bronchiale, and five symptoms during primary infection - is able to predict the risk of PACS independently of timepoint of blood sampling. We validate the score in an independent cohort of 395 individuals with COVID-19. Our results highlight the benefit of measuring Igs for the early identification of patients at high risk for PACS, which facilitates the study of targeted treatment and pathomechanisms of PACS.

Rituximab therapy in a patient with steroid-refractory bird fancier's lung.

A 62-year-old woman presented with a 3-month history of shortness of breath on exertion and dry cough. On examination, she was noted to have fine end-inspiratory crepitations over the upper zone of the lungs. Pulmonary function tests (PFTs) showed a restrictive defect. Initial chest radiography revealed diffuse reticular interstitial shadowing while high-resolution CT scan of the thorax showed fibrotic changes. Avian precipitins were also highly positive for pigeons, parrots and budgerigars. Taking into account these results, the patient was diagnosed with hypersensitivity pneumonitis. Antigen avoidance, oral glucocorticoids and azathioprine achieved an initial improvement in PFTs and symptoms; however, the patient still deteriorated, requiring long-term oxygen therapy. While working the patient up for lung transplantation, rituximab was given to good effect (acting as a bridging therapy) as it achieved symptomatic relief and stabilisation of her PFTs.

Prognostic performance of the FACED score and bronchiectasis severity index in bronchiectasis: a systematic review and meta-analysis.

BACKGROUND: Bronchiectasis is a multidimensional lung disease characterized by bronchial dilation, chronic inflammation, and infection. The FACED (Forced expiratory volume in 1 s (FEV1), Age, Chronic colonization, Extension, and Dyspnea) score and Bronchiectasis Severity Index (BSI) are used to stratify disease risk and guide clinical practice. This meta-analysis aimed to quantify the accuracy of these two systems for predicting bronchiectasis outcomes. METHODS: PubMed, Embase, and the Cochrane Database of Systematic Reviews were searched for relevant studies. Quality of included studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) criteria. Pooled summary estimates, including sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were calculated. Summary receiver operating characteristic curves were constructed, and the area under the curve (AUC) was used to evaluate prognostic performance. RESULTS: We analyzed 17 unique cohorts (6525 participants) from ten studies. FACED scores with a cut-off value ≥ 5 predicted all-cause mortality better than BSI with a cut-off value ≥ 9, based on pooled sensitivity (0.34 vs 0.7), specificity (0.94 vs 0.66), PLR (4.76 vs 2.05), NLR (0.74 vs 0.48), DOR (6.67 vs 5.01), and AUC (0.87 vs 0.75). Both FACED scores with a cut-off value ≥ 5 (AUC = 0.82) and BSI scores with a cut-off value ≥ 5 or 9 (both AUC = 0.80) help to predict hospitalization. CONCLUSIONS: At a cut-off value ≥ 5, FACED scores can reliably predict all-cause mortality and hospitalization, while BSI scores can reliably predict hospitalization with a cut-off of ≥5 or ≥9. Further studies are essential to validate the prognostic performance of these two scores.

Usefulness of bronchoalveolar lavage in a French pediatric cohort with hypersensitivity pneumonitis.

BACKGROUND: Hypersensitivity pneumonitis (HP) is a rare interstitial lung disease in children, and very little data are available on the frequency, diagnosis, and outcomes of HP. In a pediatric cohort with HP, the characteristics of the CD4/CD8 lymphocyte ratio are often described as nonspecific. METHODS: We used the National French Database (RespiRare) to collect data from the last decade on HP. The diagnosis of HP was defined by the presence of a relevant exposure, clinical symptoms, and compatible lung imaging radiology and was usually defined by positive precipitins antibodies. RESULTS: A total of 16 children with a mean age of 10 years (4-13) presented with HP. All children presented with dyspnea on exertion. Diffuse ground-glass opacity was present in all computed tomography (CT) scans. Research guided by a questionnaire and precipitins antibodies against the corresponding antigens showed that patients were positive for contact with birds with or without fungi. Bronchoalveolar lavage (BAL) was performed in 12 children. The total cell counts were elevated in BAL fluid, with a mean value of 36% lymphocytes. The CD4/CD8 lymphocyte ratio was below one for all children. CONCLUSION: BAL in our pediatric cohort with HP had the same characteristics as that of adults with HP. An HP diagnosis must be considered when dyspnea on exertion and diffuse ground-glass opacity are observed. Carrying out BAL and serological tests can help diagnose and avoid lung biopsy.

Interstitial pneumonia with autoimmune features and platypnea-orthopnea syndrome.

Interstitial pneumonia with autoimmune features (IPAF) is a recently proposed terminology for interstitial lung disease (ILD) with evidence of autoimmunity that does not meet the criteria for a defined connective tissue disease (CTD). Although ILD is well recognised in patients with established CTD, it is rarely the sole presenting feature of CTD. We report a case of 22-year-old male patient, who presented with progressive shortness of breath for 2 months and had features suggestive of platypnea-orthodeoxia syndrome (POS). Imaging revealed ILD with usual interstitial pneumonia pattern. Patient had features of autoimmune disorder but did not fulfil the criteria for any CTD and hence was labelled as IPAF. His POS was attributed predominantly to the lower lobe disease. The patient responded well to immunosuppressive treatment. A systematic review of literature of all cases with POS due to pulmonary parenchymal involvement has also been done.

IgG4-related disease in a patient with HIV infection.

A 47-year-old HIV-positive man with good immune and virological status presented with chronic multiple enlarged lymph nodes, lung disease and eosinophilia. Radiologic tests showed enlarged cervical, thoracic and axillary lymph nodes, with interstitial lung damage. After several non-specific histologic studies, an elevated serum IgG4 level led us to request immunohistochemistry of a lymph node sample. The test confirmed the diagnosis of IgG4-related disease.

Chest tightness is relieved with the use of asthma drugs except bronchodilators.

Objective: Many patients with a chief complaint of chest tightness are examined in medical facilities, and a lack of diagnosis is not uncommon. We have reported that these patients often include those with chest tightness relieved with bronchodilator use (CTRB) and those with chest tightness relieved with the use of asthma drugs except bronchodilators (CTRAEB). The purpose of this study was to demonstrate the clinical characteristics of the patients with CTRAEB and compare them with data from patients with CTRB. Methods: Patients with CTRB (n = 13) and CTRAEB (n = 7) underwent a bronchodilator test, assessments of airway responsiveness to methacholine, bronchial biopsy, and bronchial lavage under fiberoptic bronchoscopy before receiving treatment. In all, 10 healthy subjects, 11 bronchial biopsy control patients, and 10 asthmatic patients were recruited for comparison. Results: Inhalation of a short-acting ß2-agonist (SABA) increased the forced expiratory volume in one second (FEV1) by 5.1% ± 4.0% in patients with CTRB and by 1.3% ± 3.5% in patients with CTRAEB, and the difference was statistically significant (p = 0.0449). The bronchial biopsy specimens from the patients with CTRB and CTRAEB exhibited significant increases in T cells (p < .05) compared with those of the control subjects. The bronchial responsiveness to methacholine was increased in only a minor portion of patients with CTRB and CTRAEB. Conclusions: We hypothesized that the clinical condition of patients with CTRAEB involves chest tightness arising from inflammation alone, and this chest tightness is mostly associated with airway T cells, without constriction of the airways. There is little to distinguish CTRAEB from CTRB aside from the response to bronchodilator treatment. This clinical trial is registered at www.umin.ac.jp (UMIN13994, 13998, and 16741).

Prevalence and spectrum of symptomatic pulmonary involvement in primary Sjögren's syndrome.

OBJECTIVES: The present cross-sectional study aimed to estimate the prevalence of chronic respiratory symptoms in primary Sjögren's syndrome (pSS) and define the clinical, functional and imaging characteristics of symptomatic pulmonary disease in pSS. METHODS: Four hundred and fourteen consecutive pSS patients were interviewed for the presence of chronic respiratory complaints (cough and/or dyspnea). Symptomatic pSS patients without respiratory or other comorbidities underwent further investigation with clinical evaluation and assessment with pulmonary functional testing (PFTs) and chest high resolution CT (hrCT) on inspiratory and expiratory phase. Comparison of clinical and laboratory features between symptomatic and asymptomatic pSS patients was also performed. RESULTS: Prevalence of chronic respiratory symptoms in pSS was estimated at 21.5% (89/414). Symptoms were attributed to underlying comorbidities in approximately one third of cases (30/89). Thirty nine of the remaining 59 patients were finally assessed with PFTs and hrCT. Small airway disease was diagnosed in 20 individuals with an obstructive pattern in PFTs and/or compatible radiological signs. Seven patients were diagnosed with interstitial lung disease, while in the remaining 12 pSS patients, with normal PFTs and hrCT, symptoms were attributed to xerotrachea. Raynaud's phenomenon occurred more frequently in symptomatic than asymptomatic patients (p=0.024). CONCLUSIONS: Approximately one fifth of a large cohort of pSS patients presented chronic respiratory symptoms. Small airway disease was the most commonly recognized pulmonary disorder among symptomatic pSS patients, followed by xerotrachea and interstitial lung disease.

Lung cancer-associated pulmonary hypertension: Role of microenvironmental inflammation based on tumor cell-immune cell cross-talk.

Dyspnea is a frequent, devastating, and poorly understood symptom of advanced lung cancer. In our cohort, among 519 patients who underwent a computed tomography scan for the diagnosis of lung cancer, 250 had a mean pulmonary artery diameter of >28 mm, indicating pulmonary hypertension (PH). In human lung cancer tissue, we consistently observed increased vascular remodeling and perivascular inflammatory cell accumulation (macrophages/lymphocytes). Vascular remodeling, PH, and perivascular inflammatory cell accumulation were mimicked in three mouse models of lung cancer (LLC1, KRasLA2 , and cRaf-BxB). In contrast, NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ immunodeficient xenograft and dominant-negative IKK2 mutant triple transgenic (Sftpc-rtTA/Tet-O-Ikk2DN) mice did not develop PH. Coculturing human lung cancer cells with macrophages and lymphocytes strongly up-regulated cytokine release, provoking enhanced migration, apoptosis resistance, and phosphodiesterase 5 (PDE5)-mediated up-regulation of human lung vascular cells, which are typical features of PH. The PDE5 inhibitor sildenafil largely suppressed PH in the LLC1 model. We conclude that lung cancer-associated PH represents a distinct PH category; targeting inflammation in the microenvironment and PDE5 offers a potential therapeutic option.

Exercise-modulated epigenetic markers and inflammatory response in COPD individuals: A pilot study.

The study investigated the effects of exercise on epigenetic signals and systemic cytokine levels in chronic obstructive pulmonary disease (COPD) individuals. Ten participants of a pulmonary rehabilitation program were submitted to 24 sessions of a supervisioned exercise protocol thrice-weekly (90min/session). Blood samples were collected at baseline, after the 1st session, before and after the 24th session. A DNA hypomethylation status was observed after the 1st session when compared at baseline, while global histone H4 acetylation status was unaltered in any time-points evaluated. No significant changes were observed on cytokine levels after the 1st session. A significant enhancement on interleukin 6 (IL-6) and a decrease on transforming growth factor-beta (TGF-ß) levels were found after the 24th session when compared to the pre 24th session. Moreover, 23 sessions of exercise were able to diminish significantly the basal levels of IL-6 and interleukin 8 (IL-8). These data suggest a potential role of epigenetic machinery in mediating the anti-inflammatory effects of exercise in COPD patients.

Infusion reactions during infliximab treatment are not associated with IgE anti-infliximab antibodies.

OBJECTIVES: Controversy exists on the role of IgE antidrug antibodies (IgE-ADA) in infusion reactions (IR) on infliximab treatment, partly due to the lack of a positive control used for assay validation. We sought to (1) develop a robust assay to measure IgE-ADA, including a positive control, (2) determine the association between IgE-ADA and IR and (3) determine the incidence of IgE-ADA in infliximab treated patients. METHODS: A recombinant human IgE anti-infliximab monoclonal antibody was developed as standard and positive control. With this antibody, we set up a novel robust assay to measure IgE-ADA. IgE-ADA was determined in three retrospective cohorts (n=159) containing IR+ (n=37) and IR- (n=39), and longitudinal sera of 83 spondyloarthritis. RESULTS: IgE-ADA was found in 0/39 IR-, whereas 4/37 (11%) IR+ showed low levels (0.1-0.3 IU/mL, below the 0.35 IU/mL threshold associated with elevated risk of allergic symptoms). All patients who were IgE-ADA positive also had (very) high IgG-ADA levels. The incidence of IgE-ADA in patients with infliximab-treated spondyloarthritis was estimated at less than approximately 1%. CONCLUSIONS: IgE-ADA is rarely detected in infliximab-treated patients. Moreover, the absence of IgE-ADA in the majority of IR+ patients suggests that IgE-ADA is not associated with infusion reactions.

The Neutrophil to Lymphocyte Ratio Is Related to Disease Severity and Exacerbation in Patients with Chronic Obstructive Pulmonary Disease.

Objective Although chronic obstructive pulmonary disease (COPD) is characterized by systemic inflammation, the association between the neutrophil to lymphocyte ratio (NLR; an indicator of inflammation) and the clinical status of COPD has not been well studied. We hypothesized that the NLR is associated with disease severity and exacerbation in COPD patients. Methods We performed blood testing, pulmonary function testing, chest computed tomography, a body composition analysis, and a 6-minute walk test and applied the modified Medical Research Council (MMRC) dyspnea scale for 141 stable COPD patients. In addition, we calculated the body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index to evaluate the disease severity. Finally, we examined the association between the NLR and clinical parameters in stable COPD patients, and we further investigated changes in the NLR between exacerbation and the stable state. Results The NLR was positively correlated with the BODE index, extent of emphysema, and MMRC score (p<0.001 for all), while inversely correlated with airflow obstruction (p<0.001), body mass index (p<0.001), fat-free mass index (p=0.001), and the 6-minute walk distance (p<0.001). We obtained the NLR during exacerbation from 49 patients. The NLR was significantly higher at exacerbation compared to the stable state (p<0.001). Conclusion The NLR was associated with disease severity and exacerbation in COPD patients. Therefore, the usefulness of the NLR in COPD patients should be elucidated in clinical settings in future investigations.

Azithromycin for episodes with asthma-like symptoms in young children aged 1-3 years: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Bacteria and viruses are equally associated with the risk of acute episodes of asthma-like symptoms in young children, suggesting antibiotics as a potential treatment for such episodes. We aimed to assess the effect of azithromycin on the duration of respiratory episodes in young children with recurrent asthma-like symptoms, hypothesising that it reduces the duration of the symptomatic period. METHODS: In this randomised, double-blind, placebo-controlled trial, we recruited children aged 1-3 years, who were diagnosed with recurrent asthma-like symptoms from the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort; a birth cohort consisting of the general Danish population of Zealand, including Copenhagen. Exclusion criteria were macrolide allergy, heart, liver, neurological, and kidney disease, and, before each treatment, one or more clinical signs of pneumonia (respiratory frequency of ≥50 breaths per min; fever of ≥39°C; C-reactive protein concentration of ≥476·20 nmol/L [≥50 mg/L]). Each episode of asthma-like symptoms lasting at least 3 days was randomly allocated to a 3-day course of azithromycin oral solution of 10 mg/kg per day or placebo after thorough examination by a study physician at the Copenhagen Prospective Studies on Asthma research unit. Each episode was randomly allocated independently of previous treatment from a computer-generated list of random numbers in blocks of ten (generated at the Pharmacy of Glostrup). Investigators and children were masked until the youngest child turned 3 years of age and throughout the data validation and analysis phases. The primary outcome was duration of the respiratory episode after treatment, verified by prospective daily diaries and analysed with Poisson regression. Analyses were per protocol (excluding those without a primary outcome measure or who did not receive treatment). This trial is registered with ClinicalTrials.gov, number NCT01233297. FINDINGS: Between Nov 17, 2010, and Jan 28, 2014, we randomly allocated 158 asthma-like episodes in 72 children (79 [50%] to azithromycin and 79 [50%] to placebo). The mean duration of the episode after treatment was 3·4 days for children receiving azithromycin compared with 7·7 days for children receiving placebo. Azithromycin caused a significant shortening of the episode of 63·3% (95% CI 56·0-69·3; p<0·0001). The effect size increased with early initiation of treatment, showing a reduction in episode duration of 83% if treatment was initiated before day 6 of the episode compared with 36% if initiated on or after day 6 (p<0·0001). We noted no differences in clinical adverse events between the azithromycin (18 [23%] of 78 episodes included in final analysis) and placebo (24 [30%] of 79) groups (p=0·30), but we did not investigate bacterial resistance patterns after treatment. INTERPRETATION: Azithromycin reduced the duration of episodes of asthma-like symptoms in young children, suggesting that this drug could have a role in acute management of exacerbations. Further research is needed to disentangle the inflammatory versus antimicrobial aspects of this relation. FUNDING: Lundbeck Foundation, Danish Ministry of Health, Danish Council for Strategic Research, Capital Region Research Foundation.

Prevalence of myasthenia gravis and associated autoantibodies in paraneoplastic pemphigus and their correlations with symptoms and prognosis.

BACKGROUND: Paraneoplastic pemphigus (PNP) involves multiple organs, but little is known about its neurological involvement. OBJECTIVES: To investigate the symptoms, prognosis and profiles of associated autoantibodies in myasthenia gravis (MG), and their correlations in patients with PNP. METHODS: Fifty-eight patients with PNP were assessed for myasthenic symptoms and laboratory evidence. Serum autoantibodies against acetylcholine receptor (AChR), acetylcholinesterase (AChE), titin, ryanodine receptor (RyR) and muscle-specific kinase (MuSK) were measured by enzyme-linked immunosorbent assay. Patients with pemphigus vulgaris (PV), pemphigus foliaceus (PF), connective tissue disease (CTD) and non-PNP MG (NP-MG), and healthy donors, served as controls. These autoantibodies in PNP were also compared in the presence or absence of dyspnoea or muscle weakness. Cox regression and log-rank tests were used for survival analysis. RESULTS: Overall 39% of patients with PNP experienced muscle weakness, and 35% were diagnosed with MG. Moreover, 35% had positive anti-AChR and 28% had anti-AChE antibodies, similarly to NP-MG (33% and 17%, respectively, P > 0·05). However, both were negative in all patients with PV, PF and CTD and healthy donors (P < 0·005). No other antibodies showed significant differences among groups. Anti-AChR and anti-AChE antibody levels were significantly increased in patients with PNP with dyspnoea, while anti-AChR, anti-titin and anti-RyR were significantly increased in patients with PNP with muscle weakness (P < 0·05). Nevertheless, levels and positive rates of these autoantibodies showed no significant differences between PNP with Castleman disease and thymoma. Although anti-AChE levels impacted survival duration (P  =  0·027, odds ratio 3·14), MG complications did not affect the overall survival percentage in PNP. CONCLUSIONS: MG is a complication of PNP. Anti-AChR and anti-AChE antibodies are prominent in patients with PNP, especially those with dyspnoea.