key: cord-0923127-1188u9nw authors: Batarseh, Einas; Kersten, Brian P.; Pinelo, Anna C.; Vertalino, Vincent; Nadler, Jamie N.; Schwartz, Stanley A. title: Reply to Chan and Majluf-Cruz: Is the Angioedema Associated with COVID-19 a Real Entity, a Mimic, or Both? date: 2021-03-01 journal: Am J Respir Crit Care Med DOI: 10.1164/rccm.202012-4365le sha: dd1b145891825d4768f734adb20044cebd64d61c doc_id: 923127 cord_uid: 1188u9nw nan Multiple risk factors are believed to increase the incidence of ACE (angiotensin-converting enzyme) inhibitor (ACEI)-induced angioedema through various pathways, including polymorphisms in the genes encoding NEP and APP, medications that inhibit DPP4, and autoantibodies against C1-INH. Although we hypothesize similarities between ACEI-induced angioedema and COVID-19-associated angioedema, there is a wide window for the development of angioedema after the onset of COVID-19 symptoms and it can still be related to the kallikrein-kinin system for the following reasons: First, the timeline for COVID-19 phases and clinical manifestations continues to evolve because of complex multisystem activities. Studies have noted that the onset of the COVID-19 hyperinflammatory state has ranged between 2 and 5 weeks (2) . Second, the presentation of ACEI-induced angioedema can range between weeks and months after starting and discontinuing the medication. Thus, we can anticipate a similar variability in angioedema onset in patients hospitalized for COVID-19 (3). Third, ACE2 does not inhibit BK but mainly inhibits DABK and Lys-DABK, which are downstream in the systemic and tissue kallikrein pathway, leading to a later onset in their signaling activity. Fourth, BK binds primarily to b2R, which is expressed on endothelial cells and does not rely on the inflammatory cascade to induce angioedema. In contrast, DABK and Lys-DABK bind primarily to b1R, which is only upregulated in the setting of inflammation. Therefore, accumulation of DABK and Lys-DABK would not induce angioedema until the establishment of the inflammatory state. Regarding proning the patients, patients 1, 2, and 3 developed angioedema 6-7 days after the last time they were proned. Patient 4 was never proned. The swelling involved the whole face, tongue, lips, upper airway edema, and laryngeal edema. For those patients who were proned, they were positioned in reverse Trendelenburg position when proned. Therefore, proning was not believed to be related to angioedema. Although the patient with angioedema described by Cohen, referenced in our original letter, had an elevated functional concentration of C1-INH, it may not necessarily prevent angioedema. This is evidenced by data showing that many patients with ACEI angioedema do not respond to C1-INH concentrate. Also, C1-INH is a potent inhibitor of BK release from HMWK (high-molecular-weight kininogen) but it does not directly affect the metabolism of LMWK (low-molecularweight kininogen) to Lys-BK and subsequently to Lys-DABK, which can precipitate angioedema in the setting of dysfunctional ACE2. However, it is important to note that the rapid improvement in the patient's angioedema may be related to the inactivation of BK by the elevated C1-INH concentration Regarding the issue of LMWH enhancing C1-INH activity, Chan and colleagues raise an interesting point. All of our patients were on deep venous thrombosis prophylaxis; two were receiving heparin and two were receiving LMWH. Current literature suggests that autoimmune phenomena may be increased during COVID-19 and in the post-COVID-19 syndrome (4) . Consequently, one can speculate that autoantibodies to C1-INH can develop during COVID-19, increasing the risk of angioedema. Thus, the suggestion by Chan and colleagues to use LMWH to augment the activity of C1-INH bears consideration and could become a potential Angioedema in African American patients hospitalized for COVID-19 Angioedema in COVID-19 The pragmatics of prone positioning Isolated lower lip edema: a rare complication of prone positioning Long-term follow up analysis of nadroparin for hereditary angioedema: a preliminary report Angioedema in African American patients hospitalized for COVID-19 A systematic review of pathological findings in COVID-19: a pathophysiological timeline and possible mechanisms of disease progression Lisinopril-induced angioedema in a patient with plasma prekallikrein deficiency The triggering of post-COVID-19 autoimmunity phenomena could be associated with both transient immunosuppression and an inappropriate form of immune reconstitution in susceptible individuals Angioedema and urticaria in a COVID-19 patient: a case report and review of the literature Acute urticaria with angioedema in the setting of coronavirus disease 2019 Idiopathic nonhistaminergic acquired angioedema in a patient with coronavirus disease 2019 ACE inhibitor and COVID-19 Copyright © 2021 by the American Thoracic Society Apparent Increase in Chronic Obstructive Pulmonary Disease Mortality Is Likely an Artifact of Changes in Documentation and Coding As the developers of the Centers for Medicare and Medicaid Services' Chronic Obstructive Pulmonary Disease (COPD) Hospital Mortality and Readmission measures, we read with interest the recent paper by Neira and colleagues (1) . The authors document a substantial increase in 30-day mortality for patients hospitalized for COPD between the years 2006-2010, 2010-2014, and 2014-2017, corresponding with the period before, in the run-up to, and after the implementation of Medicare's Hospital Readmissions Reduction Program. Over this same period, 30-day readmission rates were observed to decline, raising concerns that hospital efforts intended to prevent readmissions might have inadvertently led to harm. As part of their analysis, the authors estimate that some 1,196 deaths might be attributable to this federal program.Although unintended consequences of the Hospital Readmissions Reduction Program are one potential explanation for the apparent increase in 30-day mortality, our own analysis of Medicare claims data for this same period suggests that the increase was an artifact of recent changes in hospital documentation and coding practices. In 2016, hospitals received updated coding instructions for cases in which a patient is admitted for a COPD exacerbation complicated by pneumonia. In such instances, hospitals were guided to use COPD-rather than pneumonia-as the principal diagnosis (2) . Within the span of 1 year, we observed a large increase (both in absolute and relative terms) in patients entering the COPD Measure Cohort who carried a secondary diagnosis of pneumonia. Between 2015-2016 and 2016-2017, the COPD cohort grew by approximately 47,000 cases, a figure almost entirely accounted for by an additional 48,000 cases with pneumonia who previously would have been counted in the pneumonia measure ( Figure 1 ).