A 77-Year-Old Woman With Capillary Hypoxia and Perioral Cyanosis.

CASE PRESENTATION: A 77-year-old woman with asthma, hypothyroidism, irritable bowel syndrome, overactive bladder, and multiple rheumatologic conditions was sent from the clinic to the ED for evaluation of hypoxia. In the clinic, she reported dizziness without shortness of breath and was noted to have perioral cyanosis with an oxygen saturation measured by pulse oximetry (Spo2) of 80%. She was given a nonrebreather mask delivering oxygen at 8 L/min, but the Spo2 remained at 77% to 82%. In the ED, the patient reported intermittent shortness of breath, 2 to 3 days of mild left lower extremity swelling, and a brief episode of lightheadedness earlier in the day that had since resolved. She denied fevers/chills, upper respiratory symptoms, and chest pain. She had been referred to the pulmonology clinic 3 years earlier to evaluate mild hypoxia with Spo2 readings in the low 90% range, but pulmonary function testing failed to identify an etiology. There was no history of VTE. Her rheumatologic conditions included osteoarthritis, rheumatoid arthritis, Sjögren's syndrome, and fibromyalgia.

Anti-Granulocyte-Macrophage Colony-Stimulating Factor Monoclonal Antibody Gimsilumab for COVID-19 Pneumonia: A Randomized, Double-Blind, Placebo-controlled Trial.

Rationale: GM-CSF (granulocyte-macrophage colony-stimulating factor) has emerged as a promising target against the hyperactive host immune response associated with coronavirus disease (COVID-19). Objectives: We sought to investigate the efficacy and safety of gimsilumab, an anti-GM-CSF monoclonal antibody, for the treatment of hospitalized patients with elevated inflammatory markers and hypoxemia secondary to COVID-19. Methods: We conducted a 24-week randomized, double-blind, placebo-controlled trial, BREATHE (Better Respiratory Education and Treatment Help Empower), at 21 locations in the United States. Patients were randomized 1:1 to receive two doses of intravenous gimsilumab or placebo 1 week apart. The primary endpoint was all-cause mortality rate at Day 43. Key secondary outcomes were ventilator-free survival rate, ventilator-free days, and time to hospital discharge. Enrollment was halted early for futility based on an interim analysis. Measurements and Main Results: Of the planned 270 patients, 225 were randomized and dosed; 44.9% of patients were Hispanic or Latino. The gimsilumab and placebo groups experienced an all-cause mortality rate at Day 43 of 28.3% and 23.2%, respectively (adjusted difference = 5% vs. placebo; 95% confidence interval [-6 to 17]; P = 0.377). Overall mortality rates at 24 weeks were similar across the treatment arms. The key secondary endpoints demonstrated no significant differences between groups. Despite the high background use of corticosteroids and anticoagulants, adverse events were generally balanced between treatment groups. Conclusions: Gimsilumab did not improve mortality or other key clinical outcomes in patients with COVID-19 pneumonia and evidence of systemic inflammation. The utility of anti-GM-CSF therapy for COVID-19 remains unclear. Clinical trial registered with www.clinicaltrials.gov (NCT04351243).

Mavrilimumab in patients with severe COVID-19 pneumonia and systemic hyperinflammation (MASH-COVID): an investigator initiated, multicentre, double-blind, randomised, placebo-controlled trial.

BACKGROUND: In patients with COVID-19, granulocyte-macrophage colony stimulating factor (GM-CSF) might be a mediator of the hyperactive inflammatory response associated with respiratory failure and death. We aimed to evaluate whether mavrilimumab, a monoclonal antibody to the GM-CSF receptor, would improve outcomes in patients with COVID-19 pneumonia and systemic hyperinflammation. METHODS: This investigator-initiated, multicentre, double-blind, randomised trial was done at seven hospitals in the USA. Inclusion required hospitalisation, COVID-19 pneumonia, hypoxaemia, and a C-reactive protein concentration of more than 5 mg/dL. Patients were excluded if they required mechanical ventilation. Patients were randomly assigned (1:1) centrally, with stratification by hospital site, to receive mavrilimumab 6 mg/kg as a single intravenous infusion, or placebo. Participants and all clinical and research personnel were masked to treatment assignment. The primary endpoint was the proportion of patients alive and off supplemental oxygen therapy at day 14. The primary outcome and safety were analysed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT04399980, NCT04463004, and NCT04492514. FINDINGS: Between May 28 and Sept 15, 2020, 40 patients were enrolled and randomly assigned to mavrilimumab (n=21) or placebo (n=19). A trial of 60 patients was planned, but given slow enrolment, the study was stopped early to inform the natural history and potential treatment effect. At day 14, 12 (57%) patients in the mavrilimumab group were alive and off supplemental oxygen therapy compared with nine (47%) patients in the placebo group (odds ratio 1·48 [95% CI 0·43-5·16]; p=0·76). There were no treatment-related deaths, and adverse events were similar between groups. INTERPRETATION: There was no significant difference in the proportion of patients alive and off oxygen therapy at day 14, although benefit or harm of mavrilimumab therapy in this patient population remains possible given the wide confidence intervals, and larger trials should be completed. FUNDING: Kiniksa Pharmaceuticals.

Occult Colonic Perforation in a Patient With Coronavirus Disease 2019 After Interleukin-6 Receptor Antagonist Therapy.

BACKGROUND: Interleukin-6 blockade (IL-6) has become a focus of therapeutic investigation for the coronavirus disease 2019 (COVID-19). METHODS: We report a case of a 34-year-old with COVID-19 pneumonia receiving an IL-6 receptor antagonist (IL-6Ra) who developed spontaneous colonic perforation. This perforation occurred despite a benign abdominal exam and in the absence of other known risk factors associated with colonic perforation. RESULTS: Examination of the colon by electron microscopy revealed numerous intact severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virions abutting the microvilli of the colonic mucosa. Multiplex immunofluorescent staining revealed the presence of the SARS-CoV-2 spike protein on the brush borders of colonic enterocytes that expressed angiotensin-converting enzyme 2. However, no viral particles were observed within the enterocytes to suggest direct viral injury as the cause of colonic perforation. CONCLUSIONS: These data and absence of known risk factors for spontaneous colonic perforation implicate IL-6Ra therapy as the potential mediator of colonic injury in this case. Furthermore, this report provides the first in situ visual evidence of the virus in the colon of a patient presenting with colonic perforation adding to growing evidence that intact infectious virus can be present in the stool.

Targeting GM-CSF in COVID-19 Pneumonia: Rationale and Strategies.

COVID-19 is a clinical syndrome ranging from mild symptoms to severe pneumonia that often leads to respiratory failure, need for mechanical ventilation, and death. Most of the lung damage is driven by a surge in inflammatory cytokines [interleukin-6, interferon-γ, and granulocyte-monocyte stimulating factor (GM-CSF)]. Blunting this hyperinflammation with immunomodulation may lead to clinical improvement. GM-CSF is produced by many cells, including macrophages and T-cells. GM-CSF-derived signals are involved in differentiation of macrophages, including alveolar macrophages (AMs). In animal models of respiratory infections, the intranasal administration of GM-CSF increased the proliferation of AMs and improved outcomes. Increased levels of GM-CSF have been recently described in patients with COVID-19 compared to healthy controls. While GM-CSF might be beneficial in some circumstances as an appropriate response, in this case the inflammatory response is maladaptive by virtue of being later and disproportionate. The inhibition of GM-CSF signaling may be beneficial in improving the hyperinflammation-related lung damage in the most severe cases of COVID-19. This blockade can be achieved through antagonism of the GM-CSF receptor or the direct binding of circulating GM-CSF. Initial findings from patients with COVID-19 treated with a single intravenous dose of mavrilimumab, a monoclonal antibody binding GM-CSF receptor α, showed oxygenation improvement and shorter hospitalization. Prospective, randomized, placebo-controlled trials are ongoing. Anti-GM-CSF monoclonal antibodies, TJ003234 and gimsilumab, will be tested in clinical trials in patients with COVID-19, while lenzilumab received FDA approval for compassionate use. These trials will help inform whether blunting the inflammatory signaling provided by the GM-CSF axis in COVID-19 is beneficial.

Implementation of a Professional Society Core Curriculum and Integrated Maintenance of Certification Program.

Medical professional societies exist to foster collaboration, guide career development, and provide continuing medical education opportunities. Maintenance of certification is a process by which physicians complete formal educational activities approved by certifying organizations. The American Thoracic Society (ATS) established an innovative maintenance of certification program in 2012 as a means to formalize and expand continuing medical education offerings. This program is unique as it includes explicit opportunities for collaboration and career development in addition to providing continuing medical education and maintenance of certification credit to society members. In describing the development of this program referred to as the "Core Curriculum," the authors highlight the ATS process for content design, stages of curriculum development, and outcomes data with an eye toward assisting other societies that seek to program similar content. The curriculum development process described is generalizable and positively influences individual practitioners and professional societies in general, and as a result, provides a useful model for other professional societies to follow.

Prognostic significance of infections in critically ill adult patients with acute liver injury: a retrospective cohort study.

BACKGROUND AND AIMS: Patients with acute liver failure have high rates of infections, likely from defects in immune function. Whether infections are independently associated with poor outcomes is unclear. We hypothesized that patients with acute liver injury who developed infections were at increased risk of adverse outcomes. METHODS: We conducted a retrospective analysis of 150 critically ill adult patients admitted with acute liver dysfunction at a single academic institution between 2005 and 2011. We excluded patients with immunocompromised states, patients with chronic liver disease and patients who died or were discharged within 48 h of admission. Our primary endpoint was a 30-day event-free survival, with events defined as either death or liver transplantation. Our secondary endpoint was length of stay. Univariate and multivariate analyses were performed to determine associations between presence of infection and our primary and secondary endpoints. RESULTS: Of our cohort of 150 patients, 62 (41%) were infected and 88 (59%) were not infected. Of the infected patients, 45% died or underwent transplantation, compared to 22% for the non-infected patients (P = 0.003). Univariate and multivariate analyses demonstrated that infections in patients with acute liver dysfunction were an independent predictor of poor outcome (i.e. death or transplantation). In addition, specific types of infection, including pneumonia, independently led to a 48% increase in length of stay (P = 0.002). CONCLUSIONS: Infections in patients with acute liver dysfunction are associated with increased risk of death or transplant and increased hospital length of stay.

Pneumothorax ex-vacuo or "trapped lung" in the setting of hepatic hydrothorax.

BACKGROUND: Hepatic hydrothorax is a major pulmonary complication of liver disease occurring in up to 5-10% of patients with cirrhosis. CASE PRESENTATION: We report four observations of the development of pneumothorax ex-vacuo or trapped lung in the setting of hepatic hydrothorax. The diagnosis of trapped lung was made based on the presence of a hydropneumothorax after evacuation of a longstanding hepatic hydrothorax with failure of the lung to re-expand after chest tube placement in three of the four cases. Two patients underwent surgical decortication with one subsequent death from post-operative bleeding. The other two patients remarkably had spontaneous improvement of their "trapped lung" without surgical intervention. CONCLUSIONS: While pneumothorax ex-vacuo is a known phenomenon in malignant effusions, to our knowledge, it has never been described in association with hepatic hydrothoraces. The pathophysiology of this phenomenon remains unclear but could be related to chronic inflammation with development of a fibrous layer along the visceral pleura.

Sleep disorders in chronic liver disease.

Sleep-related complaints and disturbances are increasingly recognized in the setting of chronic liver disease and have recently been shown to be an important prognostic factor in patients with advanced chronic liver disease. This article reviews the literature surrounding sleep disturbances and disorders in a variety of types of chronic liver disease. This includes the association of sleep disturbances with hepatitis C and antiviral therapy, primary biliary cirrhosis, and Wilson disease as well as the circadian rhythm abnormalities present in cirrhosis and hepatic encephalopathy. The association between chronic liver disease, particularly nonalcoholic fatty liver disease, and sleep-disordered breathing is also reviewed in detail.

Molecular and cellular aspects of sepsis-induced immunosuppression.

Sepsis is a significant cause of death worldwide. Although the prevailing theory of the sepsis syndrome has been that of a condition of uncontrolled inflammation in response to infection, sepsis is increasingly being recognized as an immunosuppressive state. The immune modulations of sepsis result in altered innate and adaptive immune responses, thereby rendering the septic host susceptible to secondary infections. In this review, we present an overview of the clinical and experimental evidence for sepsis-induced immunosuppression and outline the mechanisms that underlie this phenotype. With an improved understanding of how host immune states may be altered during sepsis, better immunomodulatory therapies may be developed to address the immune derangements observed in patients with sepsis.