Distinguishing features of long COVID identified through immune profiling.

Post-acute infection syndromes may develop after acute viral disease1. Infection with SARS-CoV-2 can result in the development of a post-acute infection syndrome known as long COVID. Individuals with long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions2-4. However, the biological processes that are associated with the development and persistence of these symptoms are unclear. Here 275 individuals with or without long COVID were enrolled in a cross-sectional study that included multidimensional immune phenotyping and unbiased machine learning methods to identify biological features associated with long COVID. Marked differences were noted in circulating myeloid and lymphocyte populations relative to the matched controls, as well as evidence of exaggerated humoral responses directed against SARS-CoV-2 among participants with long COVID. Furthermore, higher antibody responses directed against non-SARS-CoV-2 viral pathogens were observed among individuals with long COVID, particularly Epstein-Barr virus. Levels of soluble immune mediators and hormones varied among groups, with cortisol levels being lower among participants with long COVID. Integration of immune phenotyping data into unbiased machine learning models identified the key features that are most strongly associated with long COVID status. Collectively, these findings may help to guide future studies into the pathobiology of long COVID and help with developing relevant biomarkers.

Differences in Mortality Among Patients With Asthma and COPD Hospitalized With COVID-19.

BACKGROUND: It remains unclear whether patients with asthma and/or chronic obstructive pulmonary disease (COPD) are at increased risk for severe coronavirus disease 2019 (COVID-19). OBJECTIVE: Compare in-hospital COVID-19 outcomes among patients with asthma, COPD, and no airway disease. METHODS: A retrospective cohort study was conducted on 8,395 patients admitted with COVID-19 between March 2020 and April 2021. Airway disease diagnoses were defined using International Classification of Diseases, 10th Revision codes. Mortality and sequential organ failure assessment (SOFA) scores were compared among groups. Logistic regression analysis was used to identify and adjust for confounding clinical features associated with mortality. RESULTS: The median SOFA score in patients without airway disease was 0.32 and mortality was 11%. In comparison, asthma patients had lower SOFA scores (median 0.15; P < .01) and decreased mortality, even after adjusting for age, diabetes, and other confounders (odds ratio 0.65; P = .01). Patients with COPD had higher SOFA scores (median 0.86; P < .01) and increased adjusted odds of mortality (odds ratio 1.40; P < .01). Blood eosinophil count of 200 cells/µL or greater, a marker of type 2 inflammation, was associated with lower mortality across all groups. Importantly, patients with asthma showed improved outcomes even after adjusting for eosinophilia, indicating that noneosinophilic asthma was associated with protection as well. CONCLUSIONS: COVID-19 severity was increased in patients with COPD and decreased in those with asthma, eosinophilia, and noneosinophilic asthma, independent of clinical confounders. These findings suggest that COVID-19 severity may be influenced by intrinsic immunological factors in patients with airway diseases, such as type 2 inflammation.

Proteomic profiling demonstrates inflammatory and endotheliopathy signatures associated with impaired cardiopulmonary exercise hemodynamic profile in Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome.

Approximately 50% of patients who recover from the acute SARS-CoV-2 experience Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome. The pathophysiological hallmark of PASC is characterized by impaired system oxygen extraction (EO2) on invasive cardiopulmonary exercise test (iCPET). However, the mechanistic insights into impaired EO2 remain unclear. We studied 21 consecutive iCPET in PASC patients with unexplained exertional intolerance. PASC patients were dichotomized into mildly reduced (EO2peak-mild) and severely reduced (EO2peak-severe) EO2 groups according to the median peak EO2 value. Proteomic profiling was performed on mixed venous blood plasma obtained at peak exercise during iCPET. PASC patients as a group exhibited depressed peak exercise aerobic capacity (peak VO2; 85 ± 18 vs. 131 ± 45% predicted; p = 0.0002) with normal systemic oxygen delivery, DO2 (37 ± 9 vs. 42 ± 15 mL/kg/min; p = 0.43) and reduced EO2 (0.4 ± 0.1 vs. 0.8 ± 0.1; p < 0.0001). PASC patients with EO2peak-mild exhibited greater DO2 compared to those with EO2peak-severe [42.9 (34.2-41.2) vs. 32.1 (26.8-38.0) mL/kg/min; p = 0.01]. The proteins with increased expression in the EO2peak-severe group were involved in inflammatory and fibrotic processes. In the EO2peak-mild group, proteins associated with oxidative phosphorylation and glycogen metabolism were elevated. In PASC patients with impaired EO2, there exist a spectrum of PASC phenotype related to differential aberrant protein expression and cardio-pulmonary physiologic response. PASC patients with EO2peak-severe exhibit a maladaptive physiologic and proteomic signature consistent with persistent inflammatory state and endothelial dysfunction, while in the EO2peak-mild group, there is enhanced expression of proteins involved in oxidative phosphorylation-mediated ATP synthesis along with an enhanced cardiopulmonary physiological response.

"Long Haulers".

Post-COVID conditions continue to afflict patients long after acute severe acute respiratory syndrome-coronavirus-2 (SARS CoV-2) infection. Over 50 symptoms across multiple organ systems have been reported, with pulmonary, cardiovascular, and neuropsychiatric sequelae occurring most frequently. Multiple terms have been used to describe post-COVID conditions including long COVID, long-haul COVID, postacute coronavirus disease 2019 (COVID-19), postacute sequelae of SARS-CoV-2 infection, long-term effects of COVID, and chronic COVID-19; however, standardized assessments and treatment algorithms for patients have generally been lacking. This review discusses the epidemiology and risk factors for post-COVID conditions and provides a general overview of the diagnostic assessment and treatment of specific manifestations. Data derived from the multitude of observational studies and scientific investigations into pathogenesis are providing a clearer understanding of the distinct phenotypes of post-COVID conditions. Insight gained from these studies and ongoing interventional trials continues to lead to the development of clinical protocols directed toward improving COVID-19 survivors' quality of life and preventing or reducing long-term morbidity.

Persistent Exertional Intolerance After COVID-19: Insights From Invasive Cardiopulmonary Exercise Testing.

BACKGROUND: Some patients with COVID-19 who have recovered from the acute infection after experiencing only mild symptoms continue to exhibit persistent exertional limitation that often is unexplained by conventional investigative studies. RESEARCH QUESTION: What is the pathophysiologic mechanism of exercise intolerance that underlies the post-COVID-19 long-haul syndrome in patients without cardiopulmonary disease? STUDY DESIGN AND METHODS: This study examined the systemic and pulmonary hemodynamics, ventilation, and gas exchange in 10 patients who recovered from COVID-19 and were without cardiopulmonary disease during invasive cardiopulmonary exercise testing (iCPET) and compared the results with those from 10 age- and sex-matched control participants. These data then were used to define potential reasons for exertional limitation in the cohort of patients who had recovered from COVID-19. RESULTS: The patients who had recovered from COVID-19 exhibited markedly reduced peak exercise aerobic capacity (oxygen consumption [VO2]) compared with control participants (70 ± 11% predicted vs 131 ± 45% predicted; P < .0001). This reduction in peak VO2 was associated with impaired systemic oxygen extraction (ie, narrow arterial-mixed venous oxygen content difference to arterial oxygen content ratio) compared with control participants (0.49 ± 0.1 vs 0.78 ± 0.1; P < .0001), despite a preserved peak cardiac index (7.8 ± 3.1 L/min vs 8.4±2.3 L/min; P > .05). Additionally, patients who had recovered from COVID-19 demonstrated greater ventilatory inefficiency (ie, abnormal ventilatory efficiency [VE/VCO2] slope: 35 ± 5 vs 27 ± 5; P = .01) compared with control participants without an increase in dead space ventilation. INTERPRETATION: Patients who have recovered from COVID-19 without cardiopulmonary disease demonstrate a marked reduction in peak VO2 from a peripheral rather than a central cardiac limit, along with an exaggerated hyperventilatory response during exercise.

A Clinic Blueprint for Post-Coronavirus Disease 2019 RECOVERY: Learning From the Past, Looking to the Future.

The severe acute respiratory syndrome coronavirus 2 pandemic poses extraordinary challenges. The tremendous number of coronavirus disease 2019 (COVID-19) cases in the United States has resulted in a large population of survivors with prolonged postinfection symptoms. The creation of multidisciplinary post-COVID-19 clinics to address both persistent symptoms and potential long-term complications requires an understanding of the acute disease and the emerging data regarding COVID-19 outcomes. Experience with severe acute respiratory syndrome and Middle East respiratory syndrome, post-acute respiratory distress syndrome complications, and post-intensive care syndrome also informs anticipated sequelae and clinical program design. Post-COVID-19 clinical programs should be prepared to care for individuals previously hospitalized with COVID-19 (including those who required critical care support), nonhospitalized individuals with persistent respiratory symptoms following COVID-19, and individuals with preexisting lung disease complicated by COVID-19. Effective multidisciplinary collaboration models leverage lessons learned during the early phases of the pandemic to overcome the unique logistical challenges posed by pandemic circumstances. Collaboration between physicians and researchers across disciplines will provide insight into survivorship that may shape the treatment of both acute disease and chronic complications. In this review, we discuss the aims, general principles, elements of design, and challenges of a successful multidisciplinary model to address the needs of COVID-19 survivors.

Pulmonary Complications of Immunotherapy.

Immune checkpoint inhibitor (ICI) therapy represents a paradigm shift in the treatment of patients with locally advanced and metastatic lung cancer. Although immunotherapy generally has a more favorable safety profile when compared with chemotherapy, immune-related adverse events represent important, but incompletely understood, treatment-limiting complications associated with significant morbidity and mortality risk. Current guidelines for diagnosis and management are derived from consensus experience, highlighting that further prospective investigation in this area is needed. As ICI-related pneumonitis is a clinically and radiographically diverse toxidrome, clinical vigilance is important while treating patients with lung cancer.

Knowledge Gaps and Research Priorities in Immune Checkpoint Inhibitor-related Pneumonitis. An Official American Thoracic Society Research Statement.

Rationale: Immune checkpoint inhibitors (ICIs) have revolutionized cancer care but are associated with unique adverse events, including potentially life-threatening pneumonitis. The diagnosis of ICI-pneumonitis is increasing; however, the biological mechanisms, clinical and radiologic features, and the diagnosis and management have not been well defined.Objectives: To summarize evidence, identify knowledge and research gaps, and prioritize topics and propose methods for future research on ICI-pneumonitis.Methods: A multidisciplinary group of international clinical researchers reviewed available data on ICI-pneumonitis to develop and refine research questions pertaining to ICI-pneumonitis.Results: This statement identifies gaps in knowledge and develops potential research questions to further expand knowledge regarding risk, biologic mechanisms, clinical and radiologic presentation, and management of ICI-pneumonitis.Conclusions: Gaps in knowledge of the basic biological mechanisms of ICI-pneumonitis, coupled with a precipitous increase in the use of ICIs alone or combined with other therapies, highlight the importance in triaging research priorities for ICI-pneumonitis.

A Young Man With Hemoptysis and Cavitary Lung Lesions.

CASE PRESENTATION: A man in his 20s presented with 2 months of mild fatigue and intermittent hemoptysis of less than a tablespoon per episode. He was previously healthy and was on no medications. He denied fevers, night sweats, weight loss, wheezing, dyspnea, musculoskeletal symptoms, and rashes. He had emigrated from a South American country to the United States 3 years earlier. He worked as a groundskeeper but had no exposures to animals, mold, or dusts. He reported rare prior cigarette smoking with no history of alcohol or drug use. He was unsure whether he had received the Bacillus Calmette-Guérin vaccine.

Sarcoidosis Following Anti-PD-1 and Anti-CTLA-4 Therapy for Metastatic Melanoma.

Immune checkpoint inhibitors represent the newest treatment for stage IV melanoma. These agents are generally well tolerated, however severe immune-related adverse effects have been noted in a small, but clinically significant percentage of patients. Specifically, sarcoidosis is a known potential complication following anti-CTLA-4 therapy. We present 2 cases of pulmonary and cutaneous sarcoidosis developing in patients with stage IV melanoma. Both patients were treated with ipilimumab and anti-PD-1 therapy, and both experienced good oncologic responses to treatment; neither had evidence of preexisting sarcoidosis. Of note, both patients developed sarcoidosis only after undergoing immune checkpoint inhibitor therapy. In 1 patient, sarcoidosis developed after initiation of anti-PD-1 therapy, 3 months after the last dose of anti-CTLA-4 monotherapy, suggesting a synergistic immune dysmodulating effect of both checkpoint inhibitors. Ultimately, both patients' symptoms and radiologic findings resolved with corticosteroid treatment, and both patients have tolerated retreatment with PD-1 inhibitors. Sarcoidosis is a rare complication of immune checkpoint inhibitors and can manifest with severe pulmonary manifestations. However, sarcoidosis in this setting is responsive to corticosteroids and does not necessarily recur with retreatment. It is yet unclear whether the development of sarcoidosis in these patients represents unmasking of preexisting autoimmune tendencies or is a marker of oncologic response.

Pulmonary Toxicities from Checkpoint Immunotherapy for Malignancy.

Checkpoint immunotherapy with agents targeting PD-1 and CTLA-4 has transformed the landscape of oncologic therapy. Immune-related adverse events (IRAEs), including significant pulmonary toxicities, have been observed in patients treated with these agents. The incidence, timing, clinical features, and outcomes of pulmonary IRAEs are quite variable, emphasizing the importance for clinical vigilance as these therapies become more ubiquitous in the treatment of a spectrum of malignancies. Outcomes are generally favorable when toxicity is recognized early and treated promptly.

Pneumococcal Vaccination Strategies. An Update and Perspective.

Streptococcus pneumoniae is an important global pathogen that causes a wide range of clinical disease in children and adults. Pneumococcal pneumonia is by far the common presentation of noninvasive and invasive pneumococcal disease and affects the young, the elderly, and the immunocompromised disproportionately. Patients with chronic pulmonary diseases are also at higher risk for pneumococcal infections. Substantial progress over the century has been made in the understanding of pneumococcal immunobiology and the prevention of invasive pneumococcal disease through vaccination. Currently, two pneumococcal vaccines are available for individuals at risk of pneumococcal disease: the 23-valent pneumococcal polysaccharide vaccine (PPV23) and the 13-valent pneumococcal protein-conjugate vaccine (PCV13). The goal of pneumococcal vaccination is to stimulate effective antipneumococcal antibody and mucosal immunity response and immunological memory. Vaccination of infants and young children with pneumococcal conjugate vaccine has led to significant decrease in nasal carriage rates and pneumococcal disease in all age groups. Recent pneumococcal vaccine indication and schedule recommendations on the basis of age and risk factors are outlined in this Focused Review. As new pneumococcal vaccine recommendations are being followed, continued efforts are needed to address the vaccine efficacy in the waning immunity of the ever-aging population, the implementation of vaccines using two different vaccines under very specific schedules and their real world clinical and cost effectiveness, and the development of next generation pneumococcal vaccines.

Effect of variation in CHI3L1 on serum YKL-40 level, risk of asthma, and lung function.

BACKGROUND: The chitinase-like protein YKL-40 is involved in inflammation and tissue remodeling. We recently showed that serum YKL-40 levels were elevated in patients with asthma and were correlated with severity, thickening of the subepithelial basement membrane, and pulmonary function. We hypothesized that single-nucleotide polymorphisms (SNPs) that affect YKL-40 levels also influence asthma status and lung function. METHODS: We carried out a genomewide association study of serum YKL-40 levels in a founder population of European descent, the Hutterites, and then tested for an association between an implicated SNP and asthma and lung function. One associated variant was genotyped in a birth cohort at high risk for asthma, in which YKL-40 levels were measured from birth through 5 years of age, and in two populations of unrelated case patients of European descent with asthma and controls. RESULTS: A promoter SNP (-131C-->G) in CHI3L1, the chitinase 3-like 1 gene encoding YKL-40, was associated with elevated serum YKL-40 levels (P=1.1 x 10(-13)), asthma (P=0.047), bronchial hyperresponsiveness (P=0.002), and measures of pulmonary function (P=0.046 to 0.002) in the Hutterites. The same SNP could be used to predict the presence of asthma in the two case-control populations (combined P=1.2 x 10(-5)) and serum YKL-40 levels at birth (in cord-blood specimens) through 5 years of age in the birth cohort (P=8.9 x 10(-3) to 2.5 x 10(-4)). CONCLUSIONS: CHI3L1 is a susceptibility gene for asthma, bronchial hyperresponsiveness, and reduced lung function, and elevated circulating YKL-40 levels are a biomarker for asthma and decline in lung function.