key: cord-0975792-veml6v97 authors: Ziehr, David R.; Alladina, Jehan; Petri, Camille R.; Maley, Jason H.; Moskowitz, Ari; Medoff, Benjamin D.; Hibbert, Kathryn A.; Thompson, B. Taylor; Hardin, C. Corey title: Respiratory Pathophysiology of Mechanically Ventilated Patients with COVID-19: A Cohort Study date: 2020-06-15 journal: Am J Respir Crit Care Med DOI: 10.1164/rccm.202004-1163le sha: dd20ae7c4ee1bade059da50f62e85cb5eac052d8 doc_id: 975792 cord_uid: veml6v97 nan against the routine use of high-flow nasal cannula or noninvasive positive-pressure ventilation. Data collection and definitions. Data were collected from the electronic medical records. ARDS was defined according to the Berlin criteria (7) . We estimated the physiological dead-space fraction using the unadjusted Harris-Benedict estimate of resting energy expenditure and the rearranged Weir equation for CO 2 production (8) . We calculated the ventilatory ratio as previously described (9) . Statistical analysis. We used descriptive statistics to summarize the clinical data. The results are reported as medians and interquartile ranges (IQRs). Categorical variables are reported as counts and percentages. We report all available data without imputation. We performed analyses with GraphPad Prism v7.0 software. Demographic and clinical characteristics. From March 11 to March 30, 2020, 66 patients with laboratory-confirmed COVID-19 were intubated and admitted to ICUs at Massachusetts General Hospital and Beth Israel Deaconess Medical Center. The patients' demographics, clinical characteristics, therapies, and outcomes are summarized in Table 1 . The median age was 58 years (range, 23-87 yr), and 43 patients (65%) were male. Eight patients (12%) had preexisting pulmonary disease, and 22 patients (34%) were current or former smokers. Respiratory failure and respiratory system indices. Gas exchange and respiratory system mechanics are shown in Figure 1 . On ICU admission, 56 patients (85%) met the Berlin criteria for ARDS, and most patients had mild-to-moderate ARDS (7) . On intubation, the median PEEP was 10 6, 8, 10) . The patients exhibited a spectrum of impaired gas exchange and respiratory system mechanics, and very few patients had nearnormal compliance (Figure 1 ). Improvements in oxygenation and compliance with prone positioning were consistent with prior studies of prone ventilation in early ARDS (10) . Prone ventilation improves gas exchange in ARDS by increasing aerated areas of the lung, among other mechanisms (11) . Our findings thus differ from earlier series describing nearnormal respiratory system compliance and a lack of recruitability in early presentations of COVID-19 respiratory failure (4, 5) . The patients in our cohort were managed with established ARDS therapies, including low VT ventilation, conservative fluid administration, and, in many cases, prone ventilation. With a minimum follow-up of 30 days, overall mortality was 16.7% and the majority of the patients were successfully extubated and discharged from the ICU. Our study has important limitations. The limited duration of patient follow-up in this retrospective study was driven by a focus on respiratory pathophysiology as opposed to clinical outcomes. Furthermore, it is possible that some patients were not intubated for reasons related to goals and preferences, and thus were not included in our cohort. Patients with COVID-19 respiratory failure in our series exhibited gas exchange values, respiratory system mechanics, and responses to prone ventilation similar to those observed in large cohorts of patients with ARDS. Although further study is needed to elucidate the biology and unique features of this disease, our findings provide a pathophysiologic justification for the use of established ARDS therapies, including low VT and early prone ventilation, for COVID-19 respiratory failure. n The three group A drugs should be complemented by one or two of the group B drugs, clofazimine (CFZ) and D-cycloserine (DCS)/terizidone, for the design of MDR/RR-TB treatment regimens (4) . This recommendation has also been adopted in the recent official clinical practice guideline on treatment of drugresistant tuberculosis jointly published by the American Thoracic Society, the CDC, the European Respiratory Society, and the Infectious Diseases Society of America (5) . BDQ inhibits the mycobacterial ATP synthase by targeting its c-ring AtpE (ATP synthase subunit c, Mycobacterium tuberculosis), leading to rapid depletion of intracellular ATP levels (6) . Accordingly, mutations in atpE, which to date have very rarely been observed in clinical isolates, can confer BDQ resistance (7) . In addition, mutations in rv0678, a transcriptional repressor of the MmpS5-MmpL5 efflux pump, have been described after exposure to BDQ in clinical isolates and in in vitro selection experiments (8) . Mutations in rv0678 also affect CFZ and result in minimum inhibitory concentrations (MICs) ranging around the critical concentrations (CCs) (8) . In light of the new WHO recommendations, concerns have been raised regarding the global preparedness to detect resistance to BDQ, CFZ, and companion drugs (4, 9) . In the present study, we investigated BDQ/CFZ resistance in a cohort of consecutive patients with MDR-TB. We aimed to 1) determine the incidence of BDQ/CFZ resistance, 2) identify the underlying mechanisms, and 3) describe patients at risk for developing resistance under therapy. In June 2018, BDQ and CFZ were added to the second-line phenotypic drug susceptibility testing (pDST) panel at the National and WHO Supranational Reference Center for Mycobacteria in Borstel, Germany, which processes about three-fourths of all new MDR-TB cultures in Germany annually. In addition to all initial MDR-MTBC isolates, selected follow-up isolates were tested in patients treated with BDQ or CFZ at least every 2 months to monitor the emergence of resistance under therapy. Testing was performed using a mycobacteria growth indicator tube (MGIT) 960 system (Becton Dickinson) with CC of 1 mg/ml for both BDQ and CFZ, which corresponds to the tentative epidemiological cutoff value for both agents; that is, isolates with MIC greater than CC are phenotypically non-wild type (pNWT) and assumed to be resistant (7) . For all isolates showing growth at the CC, BDQ and CFZ MICs were determined by testing at 0.125, 0.25, 0.5, 0.75, 1.0, 2.0, 4.0, and 8.0 mg/ml in MGITs using EpiCenter TB eXiST software (Becton Dickinson). In addition, selected preceding and follow-up isolates were subjected to MIC testing. MIC data for all isolates showing resistance to BDQ and/or CFZ and for a subset of susceptible isolates were reproduced at the WHO Supranational Reference Laboratory in Munich-Gauting, Germany. Whole-genome sequencing of all drug-resistant isolates and, if available, at least one preceding susceptible isolate was performed as previously described (10) . In addition to routine molecular drug resistance testing (mDST), each genome was investigated for mutations in atpE, rv0678, mmpS5, mmpL5, Rv1979c, pepQ, and serB2, including 30-180 bp of the respective upstream regions (10) . 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Prone positioning in severe acute respiratory distress syndrome Prone position augments recruitment and prevents alveolar overinflation in acute lung injury Author disclosures are available with the text of this letter at www.atsjournals.org.