Secretory Cells Are the Primary Source of pIgR in Small Airways.

Loss of secretory IgA (SIgA) is common in chronic obstructive pulmonary disease (COPD) small airways and likely contributes to disease progression. We hypothesized that loss of SIgA results from reduced expression of pIgR (polymeric immunoglobulin receptor), a chaperone protein needed for SIgA transcytosis, in the COPD small airway epithelium. pIgR-expressing cells were defined and quantified at single-cell resolution in human airways using RNA in situ hybridization, immunostaining, and single-cell RNA sequencing. Complementary studies in mice used immunostaining, primary murine tracheal epithelial cell culture, and transgenic mice with secretory or ciliated cell-specific knockout of pIgR. SIgA degradation by human neutrophil elastase or secreted bacterial proteases from nontypeable Haemophilus influenzae was evaluated in vitro. We found that secretory cells are the predominant cell type responsible for pIgR expression in human and murine airways. Loss of SIgA in small airways was not associated with a reduction in secretory cells but rather a reduction in pIgR protein expression despite intact PIGR mRNA expression. Neutrophil elastase and nontypeable H. influenzae-secreted proteases are both capable of degrading SIgA in vitro and may also contribute to a deficient SIgA immunobarrier in COPD. Loss of the SIgA immunobarrier in small airways of patients with severe COPD is complex and likely results from both pIgR-dependent defects in IgA transcytosis and SIgA degradation.

Logistical Considerations and Clinical Outcomes Associated With Converting Operating Rooms Into an Intensive Care Unit During the Coronavirus Disease 2019 Pandemic in a New York City Hospital.

BACKGROUND: Coronavirus disease 2019 (COVID-19) emerged as a public health crisis that disrupted normal patterns of health care in the New York City metropolitan area. In preparation for a large influx of critically ill patients, operating rooms (ORs) at NewYork-Presbyterian/Columbia University Irving Medical Center (NYP-Columbia) were converted into a novel intensive care unit (ICU) area, the operating room intensive care unit (ORICU). METHODS: Twenty-three ORs were converted into an 82-bed ORICU. Adaptations to the OR environment permitted the delivery of standard critical care therapies. Nonintensive-care-trained staff were educated on the basics of critical care and deployed in a hybrid staffing model. Anesthesia machines were repurposed as critical care ventilators, with accommodations to ensure reliable function and patient safety. To compare ORICU survivorship to outcomes in more traditional environments, we performed Kaplan-Meier survival analysis of all patients cared for in the ORICU, censoring data at the time of ORICU closure. We hypothesized that age, sex, and obesity may have influenced the risk of death. Thus, we estimated hazard ratios (HR) for death using Cox proportional hazard regression models with age, sex, and body mass index (BMI) as covariables and, separately, using older age (65 years and older) adjusted for sex and BMI. RESULTS: The ORICU cared for 133 patients from March 24 to May 14, 2020. Patients were transferred to the ORICU from other ICUs, inpatient wards, the emergency department, and other institutions. Patients remained in the ORICU until either transfer to another unit or death. As the hospital patient load decreased, patients were transferred out of the ORICU. This process was completed on May 14, 2020. At time of data censoring, 55 (41.4%) of patients had died. The estimated probability of survival 30 days after admission was 0.61 (95% confidence interval [CI], 0.52-0.69). Age was significantly associated with increased risk of mortality (HR = 1.05, 95% CI, 1.03-1.08, P < .001 for a 1-year increase in age). Patients who were ≥65 years were an estimated 3.17 times more likely to die than younger patients (95% CI, 1.78-5.63; P < .001) when adjusting for sex and BMI. CONCLUSIONS: A large number of critically ill COVID-19 patients were cared for in the ORICU, which substantially increased ICU capacity at NYP-Columbia. The estimated ORICU survival rate at 30 days was comparable to other reported rates, suggesting this was an effective approach to manage the influx of critically ill COVID-19 patients during a time of crisis.

Monocyte-derived dendritic cells link localized secretory IgA deficiency to adaptive immune activation in COPD.

Although activation of adaptive immunity is a common pathological feature of chronic obstructive pulmonary disease (COPD), particularly during later stages of the disease, the underlying mechanisms are poorly understood. In small airways of COPD patients, we found that localized disruption of the secretory immunoglobulin A (SIgA)-containing mucosal immunobarrier correlated with lymphocyte accumulation in airway walls and development of tertiary lymphoid structures (TLS) around small airways. In SIgA-deficient mice, we observed bacterial invasion into the airway epithelial barrier with lymphocytic infiltration and TLS formation, which correlated with the progression of COPD-like pathology with advanced age. Depletion of either CD4+ or CD8+ T lymphocytes reduced the severity of emphysema in SIgA-deficient mice, indicating that adaptive immune activation contributes to progressive lung destruction. Further studies revealed that lymphocyte infiltration into the lungs of SIgA-deficient mice was dependent on monocyte-derived dendritic cells (moDCs), which were recruited through a CCR2-dependent mechanism in response to airway bacteria. Consistent with these results, we found that moDCs were increased in lungs of COPD patients, along with CD4+ and CD8+ effector memory T cells. Together, these data indicate that endogenous bacteria in SIgA-deficient airways orchestrate a persistent and pathologic T lymphocyte response through monocyte recruitment and moDC differentiation.

Anesthetic management of donor nephrectomy for a recipient with history of malignant hyperthermia: avoiding a transferred trigger.

We describe a case of living unrelated renal transplantation from a non-malignant hyperthermia (MH) susceptible donor to an MH-susceptible recipient, along with its intraoperative and perioperative considerations. The renal transplant recipient reported a personal history of MH requiring intensive care unit admission. A nontriggering anesthetic was therefore chosen for the unrelated donor to avoid possible triggering via the transplanted kidney to the MH-susceptible recipient. This case provides a unique opportunity to review the concepts of antigen transfer related to transplant anesthesia, as well as the importance of communication among anesthesia and surgical teams to promote patient safety.

Methylene Blue for Vasoplegia When on Cardiopulmonary Bypass During Double-Lung Transplantation.

Vasoplegia syndrome, characterized by hypotension refractory to fluid resuscitation or high-dose vasopressors, low systemic vascular resistance, and normal-to-increased cardiac index, is associated with increased morbidity and mortality after cardiothoracic surgery. Methylene blue inhibits inducible nitric oxide synthase and guanylyl cyclase, and has been used to treat vasoplegia during cardiopulmonary bypass. However, because methylene blue is associated with increased pulmonary vascular resistance, its use in patients undergoing lung transplantion has been limited. Herein, we report the use of methylene blue to treat refractory vasoplegia during cardiopulmonary bypass in a patient undergoing double-lung transplantation.

The basis of the immunomodulatory activity of malaria pigment (hemozoin).

The most common and deadly form of the malaria parasite, Plasmodium falciparum, is responsible for 1.5-2.7 million deaths and 300-500 million acute illnesses annually [Bremen in J. Trop. Med. Hyg. 64:1-11 (2001); World Health Organization (2002)]. Hemozoin, the biomineral formed to detoxify the free heme produced during parasitic hemoglobin catabolism, has long been suspected of contributing to the pathological immunodeficiencies that occur during malarial infection. While there is a growing consensus in the literature that native hemozoin maintains immunosuppressive activity, there is considerable controversy over the reactivity of the synthetic form, beta-hematin (BH). Given the emerging importance of hemozoin in modulating a host immune response to malarial infection, a careful examination of the effects of the constitutive components of the malaria pigment on macrophage response has been made in order to clarify the understanding of this process. Herein, we present evidence that BH alone is unable to inhibit stimulation of NADPH oxidase and inducible nitric oxide synthase, the key enzymes involved in oxidative burst, and is sensitive to the microbicidal agents of these enzymes both in vitro and in vivo. Further, by systematically examining each of the malaria pigment's components, we were able to dissect their impact on the immune reactivity of a macrophage model cell line. Reactions between BH and red blood cell (RBC) ghosts effectively reconstituted the observed immunomodulatory reactivity of native hemozoin. Together, these results suggest that the interaction between hemozoin and the RBC lipids results in the generation of toxic products and that these products are responsible for disrupting macrophage function in vivo.