Patients with coronavirus disease 2019 (COVID-19) can develop rapidly progressive respiratory failure. Ventilation strategies during the COVID-19 pandemic seek to minimize patient mortality. In this study we examine associations between the availability of emergency department (ED)-initiated high-flow nasal cannula (HFNC) for patients presenting with COVID-19 respiratory distress and outcomes, including rates of endotracheal intubation (ETT), mortality, and hospital length of stay.We performed a retrospective, non-concurrent cohort study of patients with COVID-19 respiratory distress presenting to the ED who required HFNC or ETT in the ED or within 24 hours following ED departure. Comparisons were made between patients presenting before and after the introduction of an ED-HFNC protocol.Use of HFNC was associated with a reduced rate of ETT in the ED  and decreased the cumulative proportion of patients who required ETT within 24 hours of ED departure  or during their entire hospitalization . Using HFNC was also associated with a trend toward increased survival to hospital discharge; however, this was not statistically significant . There was no impact on intensive care unit or hospital length of stay. Demographics, comorbidities, and illness severity were similar in both cohorts.The institution of an ED-HFNC protocol for patients with COVID-19 respiratory distress was associated with reductions in the rate of ETT. Early initiation of HFNC is a promising strategy for avoiding ETT and improving outcomes in patients with COVID-19. Global healthcare resources have been tested by the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leading to increased prevalence of the infectious syndrome known as coronavirus disease 2019 (COVID-19). Patients with COVID-19 can develop rapidly progressive respiratory failure over a period of hours to days.2Contemporary concerns regarding the risk of bio-aerosol dispersion during the use of non-invasive ventilation methods led to hospital policies and approaches that favored ETT with closed ventilatory circuits and viral filters over non-invasive ventilation to limit infectious spread to medical professionals.7Ventilation strategies during the COVID-19 pandemic seek to minimize patient mortality while also reducing infectious risk to medical professionals. With limited supplies of ventilators, negative pressure rooms and personal protective equipment (PPE), the rapid spread of COVID-19 within communities experiencing severe outbreaks can quickly overwhelm hospital resources.At the beginning of the COVID-19 pandemic, our institution restricted the use of HFNC in the ED for COVID-19 patients; however, after noting improved outcomes in patients receiving HFNC in our medical intensive care unit (ICU), our ED instituted the use of HFNC in select negative pressure rooms. The timeline of institutional policies supporting early ETT of COVID-positive patients in the ED and subsequent implementation of ED-initiated HFNC provided a natural before-and-after experiment of two patient cohorts whose outcomes could be studied.The objective of this retrospective cohort study was to determine the potential impact of ED-initiated HFNC for the treatment of COVID-19 respiratory failure by looking at patient outcomes before and after its availability. We hypothesized that the availability of HFNC in the ED would be associated with a decreased proportion of patients intubated in the ED, decreased proportion of patients intubated within the first 24 hours of hospitalization, decreased hospital and ICU length of stay, and improved survival.This retrospective, non-concurrent cohort study was approved by the University of Chicago Institutional Review Board (IRB20-0781) and conducted at the University of Chicago Medical Center, a large, urban, quaternary, academic medical center and Level I trauma center. According to the hospital’s 2018–2019 Community Health Needs Assessment, the population of the 12 ZIP code service area is 625,707, and is 76.7% non-Hispanic Black/African American, 12.3% Hispanic/Latino, and 7.8% non-Hispanic. Annual ED volume was 108,188 as of June 2020, 68.9% of which were adult visits. On January 24, 2020, the University of Chicago Hospital Incident Command System (HICS) was activated and travel-screening for COVID-19 was initiated. On March 18, 2020, in response to international reports of healthcare worker SARS-CoV-2 transmission following aerosolizing procedures, HICS restricted the use of all aerosol-generating procedures including nebulizers and non-invasive positive pressure ventilation (NIPPV) in all non-ICU settings, including the ED. All patients requiring greater than six liters per minute of supplemental oxygen by nasal cannula, those with severe respiratory fatigue, hypercarbia, or those unable to protect their airways received ETT in the ED.2). The flow rate was titrated up to 60 liters per minute as needed to decrease work of breathing and maintain a respiratory rate of less than 30 breaths per minute. FiO2 was titrated to maintain an oxygen saturation between 92–96%. Decisions about which patients needed ETT rather than HFNC prior to ED departure were made by the bedside emergency physician. Some patients were transiently placed on HFNC while in the ED but were able to be de-escalated to nasal cannula prior to ED departure. Results of this study are reported in accordance with the STROBE Guidelines .11On April 6, institutional policies changed to allow for the use of high-flow nasal cannula (HFNC) in the ED for COVID-positive patients requiring greater than six liters of oxygen per minute by nasal cannula. Patients receiving HFNC were required to be placed in a negative pressure room with an anteroom to limit the spread of aerosolized virus. The HFNC was initiated at a flow rate of 40 liters per minute and 100% fraction of inspired oxygen  or Cepheid Xpert Xpress  SARS-CoV-2 qualitative reverse transcriptase polymerase chain reaction assays. Testing may have occurred at an outpatient clinic or curbside locations prior to visiting the ED, in the ED, or after admission. Patients were considered positive during their hospital encounter if they had a positive result within 14 days prior to ED arrival or prior to hospital discharge. The study was approved by the University of Chicago Institutional Review Board (IRB20-0781), and the need for informed consent was waived as all patient data were obtained through a de-identified data mart.All data provided for this study were obtained through a de-identified COVID-19 data mart created and maintained by the University of Chicago Center for Research Informatics (CRI). The CRI data mart comprised multiple tables, including the following: patient demographic information; admit/discharge/transfer (ADT) events, encounters, flowsheets, diagnosis and problem lists; smoking history; lab values; inpatient diagnosis-related groups (DRG); de-identified notes; and medication administrations.International Classification of Diseases, 10th Revision (ICD-10) codes from their diagnosis and problem lists. We mapped ICD-10 codes using methods previously described by Charlson, Elixhauser, and van Walraven.Patient ages were calculated for each encounter using the number of years between patient birth date and the ADT timestamp of ED arrival. The timing of respiratory interventions was determined by grouping respiratory flowsheet events by patient ID and oxygen delivery method. The earliest timestamps for HFNC and intubation during each encounter were saved for each patient where applicable. Patient comorbidities were determined using 2/FiO2) ratio within the first 24 hours of hospitalization, as well as initial sequential organ failure assessment (SOFA) score upon arrival to the ICU. The labs/biomarkers that were selected to ensure similarities between patient cohorts are those that have been previously associated with increased mortality, including complete blood counts, serum bicarbonate, blood urea nitrogen, serum creatinine, glucose, alanine aminotransferase (ALT), lactate dehydrogenase, creatinine kinase, troponin, prothrombin time, D-dimer, ferritin, interleukin-6 and C-reactive protein.19To assess for potential confounding bias due to patient-level differences in the composition of each cohort, we compared the cohorts to one another regarding patient age, gender, race, ethnicity, comorbidities, ED vital signs, illness severity, and lab values/biomarkers. Comorbidities controlled for included those previously associated with increased mortality in COVID-19 , as well as those that comprise the Charlson and Elixhauser scoring systems, which have strong prior validity evidence to predict inpatient mortality for both COVID and non-COVID patients.Additional details regarding variable transformation are available in the The primary outcome variables were the maximum levels of respiratory support at ED departure, within the first 24 hours after ED departure, and through the entire duration of hospitalization, as well as survival at hospital discharge. Secondary outcome variables included total inpatient and ICU lengths of stay.a priori sample size calculation to detect a 50% decrease in the proportion of patients requiring ETT within 24 hours of hospitalization, from 90% prior to the availability of ED HFNC to 45% following the availability of ED HFNC, resulting in a minimum sample size of 42 patients, using alpha of 0.05 and a power of 90% . The decision to power our study to detect a 50% reduction in ETT was based upon our personal experiences in caring for patients during the time periods prior to and following the availability of ED HFNC. We performed all data extraction, transformation, and analysis using RStudio version 1.2.5001 running R version 3.5.1 and tidyverse 1.2.1 . We mapped ICD-10 codes for each patient to individual comorbidities using the comorbidity package.explore package,arsenal package.missForest, a non-parametric, random forest-based method.P-values less than 0.05 were considered to be statistically significant.We performed an , & Lang 09). The There were 771 encounters with COVID-19-positive patients greater than or equal to 18 years old seen in the adult ED resulting in hospital admission. A total of 134 patients required HFNC or ETT within 24 hours of admission. We excluded eight patients who underwent operative procedures during hospitalization and three patients who were started on ED-HFNC but de-escalated to nasal cannula prior to ED departure. Of the 123 patients meeting both the inclusion and exclusion criteria, 28 were seen prior to the availability of ED-HFNC and 95 were seen following the availability of ED-HFNC. See The median age of the study population was 65 years (IQR 57–75). Patients were predominantly Black/African-American (85.4%) and non-Hispanic (90.2%). Participants were 52.0% male. There were no statistically significant differences between the demographics of each group.The median body mass index was 31.4 . The median weighted Charlson score was 4 (IQR 2–6), and the median van Walraven (Elixhauser) score was 17 (IQR 9.0–26.5). There were no differences in Charlson or van Walraven scores or any of their component comorbidities between the two groups.When comparing the worst ED vital signs for each patient, as defined by the maximum recorded heart rate, temperature, and respiratory rate, and minimum recorded systolic blood pressure and oxygen saturation, we found no statistically significant differences between the two cohorts. Similarly, there were no statistically significant differences between the two cohorts in terms of illness severity, as defined by the median PaO2/FiO2 ratio during the first 24 hours of hospitalization and the SOFA score upon ICU admission. There were no differences in lab values between the two groups. Overall, 34.1% of patients received remdesivir after admission. There was no statistical difference in the rate of treatment with remdesivir between the two groups. P <0.001). The availability of ED-HFNC was also associated with a significant decrease in the cumulative proportion of patients who required ETT within 24 hours of hospitalization  and throughout their entire admission .For patients with COVID-19 respiratory distress requiring ETT/HFNC within the first 24 hours of hospitalization, the introduction of ED-initiated HFNC was associated with a reduced rate of ETT in the ED  and decreased ICU length of stay (median 8.6 days [IQR 5.1–10.9] vs. 6.0 days [IQR 2.9–13.5]), these findings were not statistically significant. There was no difference in the median total inpatient length of stay between the two study periods. See Overall, our study suggests that making HFNC available as a treatment option in the ED for patients experiencing respiratory distress due to COVID-19 was associated with a significantly reduced rate of ETT in the ED and reduced intubation through the entire period of hospitalization. While there were trends toward improved survival and decreased ICU length of stay, these findings were not statistically significant.A prior case series evaluating the use of HFNC for patients with severe H1N1 influenza pneumonitis found that 45% of patients receiving HFNC (9/20) never required intubation, suggesting that HFNC may play a role in the treatment of infectious severe hypoxemic respiratory failure.242, has recently been developed to help predict which patients will succeed with HFNC or progress to needing ETT; While the results of this study support the use of ED-initiated HFNC for COVID-19-associated respiratory distress, there are some risks and limitations of HFNC that must be considered. Given the potential for aerosolization of the SARS-CoV-2 virus,Some studies have shown that HFNC causes minimal bio-aerosol dispersion,31Although not formally included as part of our study, we did not see an increased rate of COVID-19 among healthcare workers as a result of treating COVID-positive patients with HFNC. During the period before ED-HFNC two physicians and four nurses working in our ED tested positive for SARS-CoV-2; in the time period following ED-HFNC, no physicians and six nurses tested positive, none of whom were found to have provided direct patient care to any COVID-19-positive patient on HFNC.We hypothesize that the two primary mechanisms by which HFNC might improve patient outcomes include the following: 1) earlier respiratory support for patients who need it; and 2) decreased complications associated with ETT. When the only available option to emergency physicians is ETT or no ETT, we observed that nearly half of all patients who ultimately required ETT/HFNC within 24 hours of ED departure did not have these interventions in the ED. This finding indicates that there may have been an opportunity to provide earlier respiratory support and prevent later decompensation, a trajectory that may have ultimately impacted survival. The widely known FLORALI trial showed that HFNC did not reduce the risk of intubation in patients with acute hypoxemic respiratory failure but was associated with improved 90-day mortality9The risks of ETT are numerous, including increased risk of ventilator-associated infections, barotrauma, extended ICU stays, and adverse reactions to sedation.34While these data provide compelling support for the use of ED-HFNC in the treatment of COVID-19 pneumonitis, it will be important to consider which patients are at high risk of HFNC-failure as determined by their ROX index, as well as other treatments that could be initiated in the ED that could augment patient outcomes. A recent study of early self-proning in awake, non-intubated, COVID-19-positive patients in the ED found significant improvements in oxygen saturation within five minutes,This study has several limitations. As part of a retrospective cohort study, patients were not randomized with respect to which interventions they received and thus causation could not be established. We also recognize the risk of chronology bias in studying non-concurrent cohorts during a pandemic where practice is likely to quickly evolve in response to emerging literature in ways that were not captured by our analyses. Such unmeasured changes in practice would likely have the most impact upon distal outcomes such as hospital discharge. The sample size for this study was calculated to detect a 50% reduction in the rate of ETT; therefore, it was underpowered to detect differences in mortality rates associated with ED-HFNC. Also, as a study of a single, urban, academic medical center with a predominately African-American/Black patient population, our results may not be entirely generalizable, although given the increased incidence of COVID-19 in Black communities, these results may be of particular importance for this population., Additionally, analysis was performed using de-identified information contained within a data mart rather than having the ability to review individual patient charts directly in the electronic health record, which limited the ability to control for certain potential confounders, such as prone positioning and traditional or radiographic-based pneumonia severity scores, since these were not included in the data mart.While it may seem surprising that patients requiring HFNC or ETT did not have higher temperatures, this may be related to the use of infrared forehead thermometers, which have previously been shown not to be as accurate as other measurement methods.Given our findings, we believe that despite early recommendations against its use, high-flow nasal cannula is a treatment option that should be considered for patients with COVID-19. We encourage hospital systems and emergency departments to closely evaluate their internal resources and consider deploying HFNC as a front-line treatment for patients with suspected or confirmed COVID-19 presenting with respiratory distress.What do we already know about this issue?Patients diagnosed with coronavirus disease 2019 (COVID-19) frequently develop severe respiratory distress requiring significant ventilatory support.What was the research question?Does the availability of ED-initiated high flow nasal cannula (HFNC) reduce the rate of endotracheal intubation (ETT) for patients with COVID-related respiratory distress?What was the major finding of the study?For patients with severe COVID, the availability of ED-HFNC reduced the rate of ETT in the ED, within the first 24 hours of hospitalization, and throughout their entire hospitalization.How does this improve population health?The use of ED-HFNC reduces the need for ETT, allowing efficient allocation of ventilators, which may be a scarce resource, while also reducing exposure to ventilator-associated complications.


Findings for risk perceptions were largely in directions that contradict the HBM. Circumstances surrounding behavior change during the pandemic are complex and may be especially complex for nicotine addiction.During the COVID-19 pandemic, studies have documented increased and decreased cigarette smoking among adults. Individual differences in the perceived susceptibility and seriousness of the virus, for people who smoke in general and for oneself personally, may relate to changes in smoking. Using the Health Belief Model (HBM) as a theoretical framework, we examined associations with self-reported increasing and decreasing smoking a lot during the COVID-19 stay-at-home period. Adults in 30 large U.S. cities who smoked cigarettes daily completed an online survey between 14 July and 30 November 2020. The analytic sample (N = 2768) was 54.0% male and 68.3% white with 23.7% reporting increasing and 11.3% decreasing smoking (6% reported both). Younger age, a diagnosis of COVID-19, and greater pandemic-related stress were associated with greater odds of both increased and decreased smoking. Increased smoking also was associated with heavier nicotine dependence, greater desire to quit, and greater perceived susceptibility and lower perceived seriousness of COVID-19 for people who smoke, while pandemic-related job-loss, lower nicotine dependence, and greater self-efficacy were associated with decreased smoking. Among respondents who had not contracted COVID-19 ( The COVID-19 pandemic has resulted in unprecedented global mortality and morbidity and represents a major source of stress and disruption to daily life. As of June 2021, the World Health Organization has reported over 177 million confirmed cases of COVID-19, including nearly 4 million deaths . In the The COVID-19 pandemic has had different effects on smoking behavior. A cross-sectional survey of U.S. adults who use cigarettes and/or e-cigarettes found that compared to pre-pandemic, 28.3% of participants reported decreasing their smoking, while 30.3% reported increasing . In a U.Individual differences in risk perceptions may be related to smoking behavior during the pandemic. The Health Belief Model (HBM) was developed in the 1950s by social psychologists working in the U.S. Public Health Service to explain why people did not participate in a free and accessible tuberculosis screening program. According to the HBM, individuals’ likeliness to engage in a behavior is largely determined by their perceived susceptibility to the health threat and perceived seriousness of the health threat . Over tiDuring the COVID-19 pandemic, most studies of the HBM focused on behavioral intentions , and adherence to COVID-19 mitigation behaviors , with mixed results. Perceived susceptibility and seriousness were positively associated with intention to obtain a vaccination in three studies ,22,23, bThe present study is an online survey of adults in 30 U.S. cities who smoke cigarettes daily, conducted July through November 2020, when COVID-19 infections and hospitalizations were rising in most parts of the U.S. Analyses examined associations between perceived susceptibility and perceived seriousness of COVID-19 with reported changes in smoking behavior during COVID-19 stay-at-home restrictions. Because smoking behavior could vary during the stay-at-home period, we measured increased and decreased smoking separately. We assessed COVID-19 threat perceptions (susceptibility and seriousness) for oneself  and for people who smoke . Based on the tenets of the HBM, we hypothesized that greater perceived susceptibility to and seriousness of COVID-19 would be negatively associated with increased smoking and positively associated with decreased smoking during the pandemic. Our models adjusted for relevant modifying variables  and examined the association of self-efficacy with changes in smoking.n = 2185) of the analytic sample were new respondents and 21.1% (n = 583) were returning respondents.The participants were adults who smoked cigarettes daily, resided in one of 30 large U.S. cities see Table A1n = 2447) who had not had COVID-19  reported personal susceptibility and seriousness. Among all participants, two items assessed susceptibility to and seriousness of COVID-19, respectively, for people who smoke: “Smoking cigarettes _____ the risk of getting COVID-19” and “Smoking cigarettes ______ the risk of dying from COVID-19” .Personal susceptibility was assessed with, “How likely do you think it is that you will be diagnosed with COVID-19 within the next year?” . Personal seriousness was measured with, “How serious do you think infection with COVID-19 would be to your health?” . Only participants . Instructions defined this period as a time in which “many U.S. residents were asked to limit their activities and stay at home” and noted that for most people, these restrictions were in place for the entire month of April 2020 but may have started earlier and/or ended later in the respondent’s city.Participants reported whether they suspected having had COVID-19 . Participants with a positive test or medical diagnosis were considered to have had COVID-19. Participants reported whether they lost their job permanently during the pandemic (yes/no) and changes in income as a result of the pandemic . The four-item Perceived Stress Scale  , race , and Hispanic/Latinx ethnicity (yes/no). Participants provided demographic data at their baseline wave of survey completion (Wave 1 or Wave 2). Due to small sample sizes, some demographic groups were combined in analyses. Participant gender was categorized as “man”  or “womxn” . Race and ethnicity were combined into non-Hispanic white or other race/ethnicity; “not known” was treated as missing data. Based on the observed distributions, personal susceptibility and seriousness were categorized as low (1–2), moderate (3), or high (4–5). General susceptibility and seriousness were categorized as low  or high (smoking greatly increases or increases risk). Chi-square tests examined associations between personal and general susceptibility and seriousness measures. Participants who reported increasing (decreasing) smoking “a lot” were categorized as “increasing” (“decreasing”). All other responses  were categorized as not increasing (decreasing).GEE models, adjusted for covariates and the clustering of participants within 30 cities, examined the association of changes in smoking during the stay-at-home period with perceived susceptibility and seriousness of COVID-19. With the full sample, two GEE models examined the likelihood of increased smoking and decreased smoking as a function of general COVID-19 susceptibility and seriousness for people who smoke. Two additional GEE models, restricted to participants who had not gotten COVID-19, examined the likelihood of increased smoking and decreased smoking as a function of both personal and general susceptibility and seriousness of COVID-19. All four GEE models adjusted for age , gender (man vs. womxn), race/ethnicity (non-Hispanic White vs. other race/ethnicity), job loss (vs. no job loss), income loss (vs. no income loss or not known), time coded as weeks elapsed since the survey was first fielded (14 July 2020), stress during COVID-19, heaviness of smoking (an indicator of nicotine dependence), self-efficacy for quitting smoking, and desire to quit smoking. The analyses were conducted using IBM SPSS Statistics 27 .Participants in the analytic sample were those who provided complete data on increased smoking, decreased smoking, general susceptibility, general seriousness, and all covariates. Among participants who had not had COVID-19, complete data on personal susceptibility and personal seriousness were also required for inclusion in the analytic sample. Of the 3435 participants who completed the survey, 2768 were retained in analyses.Participant characteristics are presented in Most participants reported low (60.9%) to moderate (25.6%) personal susceptibility to COVID-19, but moderate (25.6%) to high (48.1%) personal seriousness of COVID-19. About half reported that smoking increases susceptibility to (53.8%) and seriousness of (62.3%) COVID-19. Crosstabulations between personal and general susceptibility and seriousness measures are presented in For the 2418 participants who did not report COVID-19 and who completed measures of general and personal susceptibility and seriousness, In a convenience sample of U.S. adults who smoked cigarettes daily and lived in one of 30 cities, perceived susceptibility to and seriousness of COVID-19 for oneself personally and for people who smoke generally were significantly associated with self-reported changes in smoking behavior during the stay-at-home period of the COVID-19 pandemic. The direction of associations varied, such that increasing smoking during the stay-at-home period was associated with significantly greater perceptions of COVID-19 personal susceptibility, personal seriousness, and general susceptibility, but with lower perceptions of COVID-19 general seriousness. Decreasing smoking was significantly associated with greater perceptions of COVID-19 personal susceptibility and with lower perceptions of COVID-19 general seriousness. When participants who had had COVID-19 were included in the analysis, however, perceived general seriousness was no longer significantly associated with decreased smoking. The measures of personal and general susceptibility and seriousness were significantly related to one another, suggesting that viewing COVID-19 as a threat was reflected in all four measures of perceived risk. However, a substantial proportion of participants (26.3%) perceived low-to-moderate personal seriousness, yet high general seriousness, as well as low-to-moderate personal susceptibility, yet high general susceptibility (40.9%). Despite their own smoking, many participants seemed to believe that while smoking increases risk for COVID-19, they were at low risk. This finding may have been attributable, in part, to measurement. Participants reported their personal risk perceptions in terms of absolute risk and general risk perceptions in terms of relative risk . Alternatively, this finding may reflect comparative optimism . Comparative optimism is driven by both motivated  and nonmotivated processes  . It is aBased on the HBM, we hypothesized that participants with greater perceptions of personal and general susceptibility and seriousness would be less likely to increase their smoking and more likely to decrease their smoking during the COVID-19 stay-at-home period. Consistent with the HBM and our hypotheses, participants who did not believe that smoking increased the risk of getting seriously ill from COVID-19  were more likely to increase their smoking during the stay-at-home period. Participants who believed that they were at high risk of contracting COVID-19  were more likely to decrease their smoking. However, other associations for the measures of COVID-19 threat perceptions were not in the expected direction. Importantly, the HBM was developed to predict volitional behaviors, such as obtaining a tuberculosis test or a vaccine. Rational choice theories, like the HBM, rely on assumptions that people are motivated chiefly by self-interest and that their preferences are fairly stable and based upon their judgments of available information. Such assumptions of choice discount the role of addiction . In adulIn the context of nicotine dependence, rational choice is further impeded by the tobacco-saturated media and retail environments in which people live. Even during the COVID-19 stay-at-home period, many tobacco specialty shops remained open, some in direct opposition of state orders mandating them to close . Prior cThe unique circumstances of the pandemic, including stress, isolation, and economic hardship, also bring complexity. The COVID-19 stay-at-home period was marked by significant uncertainty and rapid changes in available information, making it difficult for people to accurately assess threat. Additionally, the COVID-19 pandemic has produced unprecedented disruption in every facet of daily life. Participants who lost their job during the pandemic were significantly more likely to decrease their smoking, suggesting that they may have tried to save money by purchasing fewer cigarettes during financial hardship. Perceived stress from the pandemic was significantly associated with both increased smoking and decreased smoking. Prior research has also documented both increased and decreased smoking during the pandemic ,12, withIn the current secondary analysis, we were unable to examine all constructs of the HBM. Perceived benefits and barriers to behavior change, which were not assessed, are often stronger predictors of behavior than susceptibility and seriousness  and may Lastly, items of interest  were focused on temporally distinct time periods. If COVID-19 risk perceptions changed during the pandemic, smoking behavior during the stay-at-home period would have preceded measured risk perceptions, and it is plausible that participants who changed their smoking subsequently changed their risk perceptions. For example, participants who increased their smoking during the stay-at-home period may have increased their perceived personal susceptibility and seriousness to COVID-19 due to their increased smoking. Additionally, they may have viewed smoking as increasing susceptibility because their heavier smoking raised the personal salience of a potential link between smoking and COVID-19 risk. Other variables in the model, such as heaviness of smoking, which is dependent on the number of cigarettes smoked per day, may have been influenced by changes in smoking behavior during the stay-at-home period. Regardless of the temporal order of changes in smoking and COVID-19 risk perceptions, some results contradict the HBM. Relationships may be bidirectional, and this cross-sectional study did not enable causal inference. Future research could use methodology more sensitive to short-term changes in perceptions and behavior, such as ecological momentary assessment, to further examine the relationships between risk perceptions and smoking behavior.The COVID-19 pandemic created a multitude of stressors and concerns and changes in daily schedules that may affect smoking behavior. Among U.S. adults smoking daily in 30 U.S. cities, the threat of COVID-19, perceived personally and for people who smoke generally, was associated with changes in smoking behavior, however, largely in directions that contradict the HBM. The circumstances surrounding behavior change during the pandemic are complex and may be especially complex for nicotine addiction. Future research should consider whether the same complexities are evident for other addictive behaviors.


Coronavirus disease 2019 (COVID-19) is known to manifest with bilateral pneumonia and acute respiratory distress syndrome. This infection with severe acute respiratory syndrome coronavirus 2 (SAR-CoV-2) is alarming because it not only affects the respiratory system but may also cause thromboembolic events. Multiple studies have reported procoagulation/hypercoagulable complications in COVID-19. This case series is a valuable addition to the literature because it reflects unique presentations of thrombotic events in COVID-19 patients. We report two cases in which patients presented with thromboembolic complications secondary to COVID-19 infection: one with severe bowel ischemia and the other with blue toe syndrome. To formulate management strategies to prevent fatal outcomes for patients with COVID-19, physicians must be vigilant in identifying life-threatening thromboembolic complications from this disease. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes an aggressive infection with potentially serious health consequences, coronavirus disease 2019 (COVID-19). Although COVID-19 primarily causes respiratory infection, recent studies have shifted their attention to vascular complications of this disease, including alarming thromboembolism [Case 1A 66-year-old man presented to the hospital with a two-day history of abdominal pain, nausea, vomiting, cough, and shortness of breath. He was tested positive for COVID-19 before hospitalization. Physical examination was normal except for diminished breath sounds on auscultation; his oxygen saturation was 98% on room air. A therapeutic dose of enoxaparin was initiated for an elevated D-dimer (3.12 mg/L).Computed tomography (CT) of the abdomen and pelvis on presentation demonstrated no abnormal gastrointestinal findings. Chest CT angiography (CTA) was obtained to evaluate for pulmonary embolism in the setting of an elevated D-dimer. Chest CTA was negative for acute pulmonary embolism but visualized patchy bilateral ground-glass consolidation with a peripheral predominance, compatible with COVID-19 pneumonia.On hospital day 2, the patient reported worsening abdominal pain associated with nausea and vomiting. His D-dimer continued to be elevated and was increased to 7.24 mg/L. Repeat CT of the abdomen and pelvis with intravenous contrast showed acute intraluminal thrombus involving the superior mesenteric artery (SMA) and left colic artery in the setting of abnormally dilated loops of small bowel with air-fluid levels, compatible with ischemic ileus Figure . The patOn arrival, the patient was evaluated for SMA thrombectomy and stent placement. A hyperemic loop of the small bowel was identified in the left lower quadrant, and a bowel perforation was discovered. There was clear evidence of full-thickness small bowel ischemia, with evidence of extensive transmural necrosis. He underwent SMA mechanical thrombectomy followed by damage control laparotomy and small bowel resection. On postoperative day 2, he underwent reopening of laparotomy and was found to have patchy ischemia throughout most of the small bowel as well as a segment of ischemic bowel with perforation. At that time, his abdomen was washed out, small bowel resection was performed, and two small bowel anastomoses were created with the placement of ABTHERA™ negative-pressure wound therapy. On postoperative day 4 following the initial procedure, staged relaparotomy was performed. During abdomen exploration, distal small bowel anastomosis breakdown was identified and the bowel was resected. The patient was taken to the operating room for restoration of the abdominal continuity and abdominal closure. The patient’s postoperative course was complicated by new-onset atrial fibrillation with a rapid ventricular rate, in addition to deterioration of the anastomoses with stool leakage. The family declined further surgical intervention and approved transfer to hospice care, and the patient died on day 10.Case 2A 62-year-old man with a history of chronic obstructive pulmonary disease, tobacco use, chronic respiratory failure, and Parkinson's disease presented to the hospital with progressive weakness, dyspnea, and cough. He tested positive for COVID-19. Physical examination was normal except for diminished breath sounds on auscultation. Chest CTA in the setting of elevated D-dimer (4.4 mg/L) was negative for acute pulmonary embolism but demonstrated patchy bilateral ground-glass consolidation, compatible with COVID-19 pneumonia. He was started on dexamethasone, a therapeutic dose of enoxaparin, and remdesivir.The patient had tachypnea with a respiratory rate of 34 breaths per minute and was using accessory muscles of respiration. He was transferred to the critical care unit where he was intubated and placed on mechanical ventilatory support. His D-dimer continued to be elevated and increased to 9.2 mg/L. Repeat chest CTA demonstrated new findings of many intraluminal aortic thrombi  microvascular thrombosis and inflammation of the endothelium and (2) microvascular thrombosis in the lungs, which causes ventilation/perfusion mismatch and results in hypoxemia. The inflammatory component further enhances the thrombotic process in all organs. Imaging CT in combination with assessment of D-dimer levels provides biomarkers to diagnose and monitor these prothrombotic and embolic processes of COVID-19 [In case 1, results of the abdominal and pelvic CTA at presentation were normal despite the patient having abdominal symptoms. His D-dimer level continued to rise with ongoing abdominal symptoms, which prompted us to repeat imaging, yielding a diagnosis of acute SMA thrombosis. As a life-threatening condition that may result from atherosclerotic or embolic disease, the mortality rate in SMA thrombosis ranges from 28% to 90% ,4. The cIn case 2, the chest CTA at presentation did not show emboli. Repeat chest CTA was performed in the setting of an elevated D-dimer, which showed aortic thrombi. The patient later presented with blue toe syndrome, which is characterized by tissue ischemia secondary to atherothrombotic or cholesterol crystal embolization. These embolic/thrombotic events lead to the occlusion of small vessels, limiting distal arterial perfusion and thus causing tissue ischemia ,8. The cThe optimal medical management of blue toe syndrome consists of anticoagulant therapy with either low-dose subcutaneous heparin or combination therapy with aspirin and dipyridamole antiplatelet therapy. However, with embolic causes, optimal management of blue toe syndrome is still uncertain. Some clinician-researchers recommend early surgery to remove the embolic source to spare the risk of further tissue or limb loss. Other clinicians suggest that surgical management is often unnecessary, and medical management with antiplatelet therapy is satisfactory in a subset of patients as well . CurrentBased on the literature review, there are a great number of studies that addressed the association between COVID-19 and bowel ischemia. Acute mesenteric ischemia does seem to be a rare complication of COVID-19, and elevated D-dimer levels can be considered while assessing a patient of COVID-19 with abdominal pain for mesenteric ischemia . HoweverAs noted in both of our cases, it is crucial to repeat imaging based on elevated D-dimer levels in COVID-19 patients. Further studies are needed to define the specific correlation between markers of coagulopathy such as D-dimer in patients with COVID-19 and outcomes after thrombotic events. Available evidence indicates that a dysfunctional coagulation pathway in COVID-19 patients results in embolic events; however, specific studies concerning vascular complications are lacking. It is crucial to have large multicenter studies to investigate vascular complications in COVID-19 and to formulate management strategies with good patient outcomes.


Is treatment with full, multiagent chemotherapy regimens associated with better survival compared with less-aggressive regimens in older adults with Hodgkin lymphoma?In this population-based cohort study of 2686 patients aged 65 years or older with Hodgkin lymphoma, variability in the magnitude of the association between treatment intensity and mortality by stage and cause-specific mortality was found, possibly reflecting competing risks of death. However, full chemotherapy regimens tended to have the lowest mortality from any cause.These findings suggest that full, multiagent chemotherapy regimens may be associated with better survival in older adults who can tolerate them. This cohort study examines the association between treatment intensity and cause-specific mortality among older adults with Hodgkin lymphoma. Hodgkin lymphoma is an aggressive blood cancer that is highly curable in younger patients who receive multiagent chemotherapy. Worse survival in older patients may reflect less-aggressive treatment, competing risks of death, or different disease biological factors.To examine the association between treatment intensity and cause-specific mortality among older adults with Hodgkin lymphoma.This was a population-based cohort study of patients aged 65 years or older with Medicare Part A and B fee-for-service coverage who received a diagnosis of Hodgkin lymphoma from 2000 to 2013. The association between treatment intensity and cause-specific mortality was estimated separately for early-stage and advanced-stage disease with Cox proportional hazards models. Multivariable adjustment and propensity score weighting helped control for confounding. Data are from the 1999 to 2016 Surveillance, Epidemiology, and End Results Medicare database. Data analysis was performed from April 2020 to June 2021.First-line treatment categorized as (1) full chemotherapy regimen, (2) partial chemotherapy regimen, (3) single chemotherapy agent or radiotherapy, or (4) no treatment.The main outcome was 3-year Hodgkin lymphoma–specific and other-cause mortality.Among 2686 patients , 1307 had early-stage disease and 1379 had advanced-stage disease. For Hodgkin lymphoma–specific mortality in patients with early-stage disease, hazard ratios (HRs) were higher for partial regimens  or no treatment  than for full regimens; there was no difference between single-agent chemotherapy or radiotherapy and full regimens. For other-cause mortality in patients with early-stage disease, HRs were higher for partial regimens , single-agent chemotherapy or radiotherapy , or no treatment  than for full regimens. For Hodgkin lymphoma–specific mortality in patients with advanced-stage disease, HRs were higher for partial regimens , single-agent chemotherapy or radiotherapy , or no treatment  than for full regimens. For other-cause mortality in patients with advanced-stage disease, HRs were higher for partial regimens , single-agent chemotherapy or radiotherapy , or no treatment  than for full regimens.This cohort study found variability in the magnitude of the association between treatment intensity and mortality by stage and cause-specific mortality, possibly reflecting competing risks of death. However, full chemotherapy regimens were associated with lower mortality and could be considered for older adults who can tolerate them. In addition, older adults, particularly those with comorbidities, may not tolerate multiagent chemotherapy regimens and may be treated with partial chemotherapy regimens or palliative approaches.12Hodgkin lymphoma (HL) is an aggressive hematologic cancer with increased incidence during adolescence and young adulthood and a second increase during late adulthood (age 70-80 years).13 National registries, such as Surveillance, Epidemiology and End Results (SEER)–Medicare, provide real-world data as an alternative to clinical trials. Therefore, we examined the association between treatment intensity and cause-specific mortality among older adults with HL using SEER-Medicare data. We hypothesized that in unadjusted analyses, treatment with full chemotherapy regimens would have better survival, whereas those receiving no treatment would have worse survival. We hypothesized that adjustment for confounding would attenuate these associations.Although survival in older patients with HL may not achieve the levels of younger patients, opportunities exist to select treatments that optimize survival. However, studying the association between treatment intensity and survival in older adults is challenging because they are typically excluded from clinical trials.12 Patients with only 1 to 10 claims within 6 months of diagnosis were required to have 1 or more HL-related claim.This cohort study used SEER-Medicare data from 1999 to 2016. Patients were aged 65 years or older at diagnosis with incident classic HL, as defined by SEER registry histological data. Patients had to be eligible for at least 3 years of follow-up in the SEER registry to capture 3-year survival data. The cohort was restricted to patients with Medicare Part A and B fee-for-service coverage for 6 months before and 1 year after diagnosis (or until date of death) to fully capture treatment claims, thereby restricting diagnoses to 2000 to 2013. Exclusion criteria were missing diagnosis month, unknown diagnostic confirmation, diagnosis reported only from autopsy or death certificate, another cancer diagnosis less than 6 months before HL diagnosis, no claims within 6 months of diagnosis, and unknown stage.STROBE) reporting guideline.14 The institutional review board at Tufts Medical Center deemed this study exempt from review because data were publicly available and deidentified. Therefore, consent was not required in accordance with 45 CFR §46.This study followed the Strengthening the Reporting of Observational Studies in Epidemiology  was calculated, with censoring at 3 years after diagnosis.19 Although the number of recommended chemotherapy cycles varied by disease stage, we categorized treatment on the basis of the first 2 cycles, which corresponded to the fewest number of cycles recommended for early stage HL and the fewest number of cycles before response-based treatment adaptation.10 In addition, using 2 cycles reduces immortal time bias and time-varying confounding . To be classified as receiving a full regimen, patients had to receive all drugs for 2 cycles, except orally administered drugs , which were available only as Medicare Part D pharmacy claims for part of the study period. In light of research showing that bleomycin should be used cautiously in older adults,20 ABVD both with and without bleomycin was considered a full regimen. Partial regimens included any multiagent chemotherapy regimen that did not meet full regimen criteria . Single agent or RT included patients treated with 1 chemotherapy agent at a time or RT. No treatment was defined by no claims for these treatments within 4 months of diagnosis.First-line treatment initiated within 4 months of diagnosis was determined from inpatient, outpatient, and physician or supplier claims using chemotherapy J codes, Healthcare Common Procedure Coding System codes, and Diagnosis Related Group codes and was categorized as (1) full chemotherapy regimens , (2) partial chemotherapy regimen , (3) single chemotherapy agent or RT (referred to hereafter as single agent or RT), or (4) no treatment. Full regimens were based on National Comprehensive Cancer Network guidelines and established chemotherapy regimens used during the study window, with a focus on older patients.22 Medicaid dual eligibility was defined using the state buy-in indicator. Frailty and comorbidity in the 6 months before HL diagnosis were defined using claims-based algorithms.24 Frailty, a probability score, was converted to 1 to 100, where higher scores indicate higher probability of frailty. The current HL cancer was excluded from the comorbidity index. Using the comorbidity index, a separate cardiac comorbidity indicator was created for myocardial infarction or congestive heart failure, according to their association with treatment.25 Prior cancer was defined as having a SEER-Medicare entry for any cancer more than 6 months before HL diagnosis.Potential confounders of the association between treatment and mortality included patient, disease, and geographical characteristics. Diagnosis date, age at diagnosis, gender, race or ethnicity , marital status, HL histology, Ann Arbor stage, and B symptoms were defined from SEER registry data. Race and ethnicity were assessed in this study because disparities in cancer treatment and outcomes by race and ethnicity have been observed elsewhere.26Geographical characteristics included region, population density, and presence of a hospital providing chemotherapy within the health service area. Region and population density were determined from the Medicare enrollment file. Population density was dichotomized as more populated  and less populated . Regions included Northeast, Midwest, South, and West based on SEER registry data. The 2017 to 2018 Area Health Resources Files Access System was used to determine whether there was a hospital providing chemotherapy in the health service area during the year of HL diagnosis.27 Analyses were conducted in R statistical software version 4.0.3 and RStudio statistical software version 1.4.1103 . Two-sided α was set to .05.Analyses were done separately for early-stage (I and II) and advanced-stage (III and IV) disease because of differences in treatment and outcomes. Patient, disease, and geographical characteristics were described. Cell counts less than 11 were suppressed to avoid reidentification of patients.28To address missing data in stage (160 patients), marital status (116 patients), race (12 patients), and B symptoms (665 patients), we created 10 multiply imputed data sets using the mice (multivariable imputation by chained equations) R package. Predictive mean matching with 10 iterations was done. Imputations were assessed for plausibility and convergence. The Rubin rule was used to pool results from multiply imputed data sets.31 This shifted time 0 from diagnosis to 2 months after diagnosis, thereby removing patients who died within 2 months of diagnosis. We compared characteristics of those included and excluded in the landmark analysis to understand generalizability of our findings.To reduce the effect of immortal time bias, which could be caused by requiring patients to survive to the completion of all chemotherapy cycles to be classified as receiving full regimens, we conducted a landmark analysis.32 Multivariable adjustment and propensity score weighting were used to adjust for confounding. The multivariable analysis adjusted for all covariates. The propensity score was fit using a generalized boosted model, which allowed for the 4 treatment categories  and 95% CIs for the association between first-line treatment and 3-year cause-specific hazard of mortality (HL specific or other-cause specific).38 E-values were computed on the basis of whichever level of treatment had a HR that was closest to the null, but still significant, which provided a conservative estimate.An E-value was computed to quantify the minimum strength of association that an unmeasured confounder would need to have with both treatment and cause-specific mortality to completely explain away a significant association between treatment and cause-specific mortality based on the multivariable model.39 Linearity of continuous covariates was assessed with plots of Martingale residuals. Data analysis was performed from April 2020 to June 2021.The proportional hazards assumption for the Cox models was assessed using correlations between Schoenfeld residuals and time, plots of Schoenfeld residuals over time, and interactions with step functions of time.The cohort included 2686 patients , of whom 1307 (49%) had early-stage disease and 1379 (51%) had advanced-stage disease. Patient and geographical characteristics were similar across disease stage, but there were some differences in disease and treatment characteristics by disease stage . CompareBy 3 years, 228 patients had died from HL, 281 from other causes, and 798 were still alive. For both causes of death, results from multivariable and propensity score–weighted models had attenuated HRs compared with unadjusted models ; resultsBy 3 years, 357 patients had died from HL, 380 from other causes, and 642 were still alive. For HL-specific mortality, the multivariable model was attenuated from unadjusted models, whereas the propensity score–weighted model was similar to unadjusted models. For other-cause mortality, results from multivariable and propensity score–weighted models were similar, both with attenuated HRs compared with unadjusted models . Results The observed HR of 1.62 for single agent or RT and other-cause mortality among patients with early-stage disease could be explained by an unmeasured confounder that was associated with both treatment and other-cause mortality with a HR of 2.14, above and beyond measured confounders. See the eFigure in the In this large, population-based cohort study of older patients with HL, we found a significant association between treatment intensity and 3-year cause-specific mortality, even after adjustment for confounders such as age, comorbidity, and frailty. Patients with early-stage and advanced-stage disease generally had lower HL-specific and other-cause mortality when treated with full chemotherapy regimens than partial regimens, single agent or RT, or no treatment.40 comparing different treatment intensities in older patients with HL . Although treatment-related toxic effects were not assessable in this study, they likely are associated with both treatment selection and mortality.For early-stage disease, HRs for single agent or RT and no treatment (compared with full regimens) were higher for other-cause mortality than HL-specific mortality. These differences could be reflecting competing causes of death; furthermore, less-aggressive treatment may have been selected because of competing risks, which may not have been fully accounted for in our models. For advanced-stage disease, HRs for partial regimens, single agent or RT, and no treatment (compared with full regimens) were higher for HL-specific mortality than other-cause mortality. This suggests that some older patients could minimize their mortality, especially HL-specific mortality, with more-intensive chemotherapy if they are able to tolerate it. Interestingly, the HRs for less-intensive chemotherapy for advanced-stage disease were larger than those for early-stage disease, suggesting that treatment intensity matters more for advanced-stage disease. Of note, the magnitude of our HRs is similar to those observed in another study11 and are associated with worse outcomes.21 Higher stage disease was associated with worse HL-specific mortality in both early-stage and advanced-stage disease. Interestingly, older age was associated with worse other-cause mortality only in early-stage disease, whereas older age was associated with worse HL-specific mortality in advanced-stage disease. One explanation is that older patients with early-stage disease are dying from other causes, whereas older patients with advanced-stage disease are dying from HL. For advanced-stage disease, more comorbidities were associated with worse HL-specific and other-cause mortality. Our results support prior research41 that found a high prevalence of comorbidities in older patients with HL and worse outcomes in patients with comorbidities. Differences in mortality by Medicaid dual eligibility and region may reflect disparities in care or outcomes,44 whereas differences by gender and histology support previous research in HL.45 Lower other-cause mortality for Black non-Hispanic patients with advanced disease was unexpected, but may be associated with adjustment for factors contributing to racial and ethnic disparities.46Aside from treatment, other factors were associated with mortality, with some differences by stage and cause of death. B symptoms were associated with worse HL-specific and other-cause mortality in early-stage and advanced-stage models. Prior research shows that B symptoms are common in older patients50 We observed that patients also experience competing risks of death from non-HL causes. Although not assessed here, treatment preferences likely are associated with treatment intensity and survival. For example, some patients may prefer length of life vs treatment-related toxic effects or quality of life, or vice versa, but data about preferences among older patients with HL are scarce.51 These findings highlight the importance of patient-physician discussion about treatment-related toxic effects, quality of life, and treatment goals.47 Finally, recently approved novel agents, such as immune checkpoint inhibitors, may offer alternatives to full chemotherapy regimens among older, frail patients.52These findings have implications for clinical practice. Even after adjustment for confounders, patients receiving full regimens had the best survival. Therefore, full regimens could be considered for patients who can tolerate them and for whom full regimens align with treatment preferences. Age should not be the only deciding factor in treatment. Older patients without comorbidity or frailty may tolerate intense chemotherapy regimens. Integration of frailty and geriatric assessment into clinical care could inform treatment decisions.55 We did observe attenuation of treatment effect sizes after multivariable adjustment, indicating successful adjustment for measured confounders. Improved balance across measured confounders after propensity score weighting also indicates reduced confounding. Although unmeasured confounders  may explain the remaining association, the E-value analysis found that any unmeasured confounder would need to have a stronger association with treatment and survival than most measured confounders. On the basis of the International Prognostic Score in HL, the strongest factor associated with risk of disease progression  had a risk ratio of 1.49,45 indicating that although confounding could explain this association, it is unlikely. We addressed immortal time bias using a landmark analysis, which required patients to survive at least 2 months from diagnosis. Although this excluded older and sicker patients, they were likely part of a different population for whom treatment was not considered; therefore, these results generalize to patients surviving at least 2 months.Limitations of our study design include confounding by indication and possible immortal time bias. We sought to address confounding with multivariable adjustment and propensity score weighting. Despite planned analysis, we were unable to conduct an instrumental variable analysis based on naturally occurring geographical variations in physician treatment preferences because the available geographical regions were either too large (SEER registry) or too small .56 To determine first-line treatment using claims data, patients were limited to those with Medicare Part A and B fee-for-service, thus limiting generalizability by excluding patients with Medicare Advantage who tend to be healthier, low-to-middle income, and from more populated areas.57 Our treatment definition was based on the first 2 cycles of chemotherapy. Although this allowed us to capture the fewest number of recommended cycles and to reduce time-varying confounding and immortal time bias, the definition may not align with what clinicians and guidelines considered full chemotherapy regimens, especially for advanced disease.10 In addition, given that SEER-Medicare data do not include information on chemotherapy dosages or treatment-related toxic effects, we were unable to consider dose modifications and were unable to adjust for potential confounding by time-varying treatment-related toxic effects. No treatment was assumed on the basis of the lack of any treatment-related claims, which could result in treatment misclassification. However, the following evidence indicates this was not a major issue: all patients were required to have medical claims at the time of their HL diagnosis, patients not receiving treatment because they died within 2 months of diagnosis were excluded from the landmark analysis, and our prior work12 found an explanation for why most patients did not receive treatment .We acknowledge this study’s other limitations. SEER-Medicare is the largest longitudinal population-based database of older adults with cancer in the US, but patients in the database are not necessarily representative of all older patients with HL.We present a large population-based analysis examining treatment intensity and survival among older patients with newly diagnosed HL. We found variability in the magnitude of the association between treatment intensity and mortality by stage and cause-specific mortality, possibly reflecting competing risks of death. Full chemotherapy regimens may be associated with better survival in older adults who can tolerate them. Consideration of patient age, competing risks of death, and geriatric assessment (including both frailty and comorbidity), as well as discussion of treatment preferences, can better inform treatment selection and likely translate to improved outcomes.


Background: Primary spontaneous pneumothorax is potentially life-threatening, and its recurrence is always a serious problem. Pathological examination provides molecular insights into the pathophysiology of primary spontaneous pneumothorax.Objectives: To investigate the association of histopathologic features of primary spontaneous pneumothorax with matrix metalloproteinase expression and their relevance to the recurrence.Methods: A total of 217 tissue section slides in 172 adolescent patients with primary spontaneous pneumothorax were retrospectively reviewed from January 2001 to June 2020. All histopathologic features were recorded and pathologic findings related to ipsilateral recurrence and second surgery were analyzed. Serum levels of matrix metalloproteinases were prospectively measured in 25 primary spontaneous pneumothorax patients receiving surgery and 18 healthy controls. Their relevance to the histopathologic features of primary spontaneous pneumothorax related to its recurrence was also examined.Results: The major presenting histopathologic findings of primary spontaneous pneumothorax were bleb/bulla (98%) followed by fibrosis (68%). Low prevalence of the pathologic findings of granulation tissue and macrophage accumulation were significantly associated with recurrent primary spontaneous pneumothorax, whereas fibrosis was significantly higher in patients receiving more than once surgery. Furthermore, the ratios of matrix metalloproteinase-2/tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 were significantly higher in theses pathological findings as well as multinucleated giant cells and mesothelial cell hyperplasia in comparison with healthy controls.Conclusions: Low prevalence of macrophage accumulation and granulation tissue related to the overexpression of matrix metalloproteinase-2 and−9 activities may contribute to healing impairment and primary spontaneous pneumothorax recurrence. Primary spontaneous pneumothorax (PSP), characterized by the presence of air in the pleural space without apparent lung disease, affects adolescents and young adults with a significant recurrence rate , 2. PSP Pathological examination provides direct and powerful evidence of pathological changes and molecular insights into the pathophysiology of diseases. PSP occurs mainly from the pleural porosity of blebs or bullae. Several factors including distal airway anomaly or inflammation, apical ischemia, or abnormal connective tissue are related to the formation of blebs/bullae . A recenThis study aimed to determine the histopathologic features involved in the pathogenesis of PSP and its recurrence through histological analysis of tissue slides obtained from surgery. It also aimed to determine the association of these pathologic findings with MMPs expression for PSP recurrence.Adolescent patients aged 15–20 years with PSP underwent video-assisted thoracoscopic surgery (VATS) wedge resection were retrospectively enrolled from January 2001 to June 2020. PSP was defined as pneumothorax occurring in a patient without apparent underlying lung disease, trauma or inherited disorder. Clinical details including age, sex, body mass index (BMI), smoking habits, location, and recurrent side of pneumothorax were recorded and analyzed. The first VATS lung resection was considered if patients had recurrent ipsilateral pneumothorax or large size of pneumothorax with prolonged air leak over 4 days in the first episode of pneumothorax . The secAdolescent PSP patients were also enrolled prospectively to investigate the pathologic findings of PSP related to matrix metalloproteinases (MMPs) serum levels. All blood samples were collected within 72 h of admission in PSP patients before the first time VATS surgery. Healthy adolescents aged <20 years from a general health check-up program without personal history of pneumothorax or other inherent pulmonary conditions were enrolled as healthy controls.All standard hematoxylin and eosin (H&E) stained histologic sections from lung tissues of PSP patients were reviewed using light microscopy. Each tissue slide was evaluated in obvious histologic lesions and was read by the same specialist in pulmonary pathology. Pathological findings including lung tissue features  and cell features  were recorded. Tissue pathologic images were taken and analyzed using the Olympus fluorescent microscope  equipped with DP71 CCD camera image capture system.TM Human MMP panel, 9-plex assay kit , including MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-12, and MMP-13, according to the manufacturer's instructions. Briefly, 50 ul of sample was incubated with antibody-coupled beads and biotinylated detection antibodies at room temperature. The beads were eventually re-suspended in 125 ul assay buffer and read on the Bio-Plex suspension array system. Data were analyzed using Bio-Plex Manager software version 6.0. The lower detection limit was 1.0 pg/mL with the coefficient of variation (CV) <10%.Serum were isolated from whole blood by centrifugation at 3,000 rpm for 10 min (Eppendorf centrifuge 5810R) and stored at −80°C until further use. MMPs measurement was performed simultaneously for the Bio-Plex ProMMPs associated with PSP were selected for further ELISA assay. Serum levels of MMP-2, MMP-3, MMP-9, and tissue inhibitors of metalloproteinases 1 (TIMP-1) were measured using ELISA kits  according to the manufacturer's instructions. The ratio of MMPs/TIMP-1 was calculated as a measure of the biological activities of MMPs.2–test, or Fisher exact test was used to compare the nominal data of histopathological findings in PSP. Differences in continuous variables with non-normal distribution between PSP patients and healthy controls were tested using the Mann-Whitney test. Statistical analysis was performed using the Statistical Package for the Social Sciences  and graphs were drawn using GraphPad Prism Version 5.01 software . All statistical hypothesis tests were 2-tailed and a P-value < 0.05 was considered to be significant.The Chi-square test, χA total of 217 tissue section slides (101 right-sided and 116 left-sided) in 172 adolescent PSP patients with more than one pathology slide at the same time of VATS surgery were retrospectively reviewed. Among them, 19 (11%) patients had an ipsilateral recurrence after the first VATS surgery. Eighty-eight (41%) pathology slides were obtained from PSP patients with recurrence. Among them, 46 (52%) slides were right-sided recurrence, whereas 42 (48%) slides were left-sided recurrence. Pathology slides obtained from the first and second VATS on the same side were found in 192 and 25 slides, respectively .P < 0.05). A further logistic analysis also revealed that macrophage accumulation  and granulation tissue  were significantly associated with right side and left side recurrent PSP, respectively. Furthermore, fibrosis (P < 0.01) (The major presenting histopathologic features of PSP were bleb/bulla (98%) followed by fibrosis (68%), mesothelial cell hyperplasia (43%) and macrophage accumulation (40%). The differences in pathologic findings between adolescent PSP with and without recurrence are shown in fibrosis  was sign < 0.01) .To evaluate the relationships between histopathologic features of PSP and MMPs, a total of forty-three subjects were prospectively enrolled, including 25 PSP patients with VATS and 18 healthy controls . All subP < 0.05), but not with MMP-3/TIMP-1 ratio.The ratios of MMP-2/TIMP-1, MMP-3/TIMP-1, and MMP-9/TIMP-1 were further linked to the pathologic findings of PSP. There were no statistically significant differences in MMPs activity between histological changes of PSP. However, compared with healthy controls, MMP-2/TIMP-1 and MMP-9/TIMP-1 ratios were significantly associated with macrophage accumulation  and granPSP recurrence is a serious complication and that needs to be addressed. Histopathological examination provides unique insights into the pathogenesis and recurrence of PSP. This study has demonstrated an association between the decreased macrophage accumulation and granulation tissue formation and PSP recurrence. Overexpression of MMP-2 and MMP-9 activities appear to be associated these pathologic findings contributing to healing impairment and recurrence of PSP.The histopathologic findings corresponding to the most common cause of pneumothorax are blebs and bullae as in this study . SpontanFibrosis, a pathological process occurring after insult to tissue injury, is characterized by the accumulation of excess ECM components with scant capillaries . RepeateSome pathologic changes are reactive and reflect responses to the injury produced by the pneumothorax. An exuberant hyperplasia of mesothelial cells in serous membranes or pneumocytes lining pulmonary alveoli is frequently related to localized atelectasis or acute lung injury . MultinuPSP is associated with diffuse abnormalities within the pleura, a thin tissue covered by a layer of mesothelial cells surrounding the lungs . MesotheGranulation tissue is characterized by fibrovascular proliferation, which participates in tissue repair mechanism through the production of connective tissue protein matrix and growth of microscopic blood vessels . FurtherMMPs are proteolytic enzymes that participate in injury and repair mechanisms by regulating immune cell influx, facilitating the migration of fibroblasts and keratinocytes, and remodeling scar tissue . HoweverA major limitation of our study is its retrospective review of tissue section slides, which may show associations among variables but can rarely establish causal relationships. The relatively small sample size for the correlations between MMPs and pathologic findings of PSP may also not be representative of the entire population. Clinically, it is hindered to obtain lung tissue from adolescent healthy volunteers as controls and serum levels of MMPs and TIMPs may not reflect lung tissue levels and/or action. However, a comprehensive histological analysis of lung tissue from PSP patients with a link to the biological role of serum MMPs provides novel insights into the pathogenesis of PSP and its recurrence.A combination of histopathological examination of the lung tissues and biological activities of MMP analysis highlights the importance of an imbalance in cell-ECM interactions associated with PSP. A low prevalence of macrophage accumulation and granulation tissue is associated with increased risk of PSP recurrence. Overexpression of MMP-2 and MMP-9 activities may particularly play a role in healing impairment, leading to subsequent recurrence. However, further studies are warranted to address cause-effect relationships in studies of impact.The original contributions presented in the study are included in the article/This study was approved by the Institutional Review Board of Chang Gung Memorial Hospital (No. 103-6472C). Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the minor(s)' legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.C-YC, T-PC, and T-YH designed and supervised the study. J-RC and S-YY provided samples and expert assistance in pathology analysis. C-JW performed experiments and analyzed the data. All authors contributed to the article and approved the submitted version.This work was supported by CMRPG2D0331-2 and CMRPG2B0391-2 from the Chang Gung Medical Foundation, Chang Gung University, Taiwan.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


During February 2021, an opening event was held indoors at a rural Illinois bar that accommodates approximately 100 persons. The Illinois Department of Public Health (IDPH) and local health department staff members investigated a COVID-19 outbreak associated with this opening event. Overall, 46 COVID-19 cases were linked to the event, including cases in 26 patrons and three staff members who attended the opening event and 17 secondary cases. Four persons with cases had COVID-19–like symptoms on the same day they attended the event. Secondary cases included 12 cases in eight households with children, two on a school sports team, and three in a long-term care facility (LTCF). Transmission associated with the opening event resulted in one school closure affecting 650 children  and hospitalization of one LTCF resident with COVID-19. These findings demonstrate that opening up settings such as bars, where mask wearing and physical distancing are challenging, can increase the risk for community transmission of SARS-CoV-2, the virus that causes COVID-19. As community businesses begin to reopen, a multicomponent approach should be emphasized in settings such as bars to prevent transmissionOn February 17, 2021, IDPH was notified through the state’s outbreak reporting system of a possible COVID-19 outbreak  in persons who attended an opening event at a bar in a rural Illinois county. The event had occurred indoors, with no outside air flow, approximately 2 weeks earlier in a 2,800-sq-ft bar during normal operating hours (4:00 p.m. to 1:00 a.m.). Six employees staffed the bar. Although the total number of bar patrons who attended the event is unknown, the bar accommodates approximately 100 persons. Before the event, IDPH reported a 7-day average daily COVID-19 incidence of 41–42 cases per 100,000 persons in the county; 14 days after the event, the 7-day average daily incidence had more than doubled, to 86–87 cases per 100,000 persons (A bar attendee case was defined as the onset of COVID-19–like symptoms or receipt of a positive SARS-CoV-2 test result within 14 days of the bar opening event in a bar patron or employee who reported attending the event and who had no previous identified epidemiologic link to a COVID-19 case outside that setting. A confirmed case was defined as receipt of a positive SARS-CoV-2 nucleic acid amplification test (NAAT) or antigen test result by a person who attended the event, and a probable case was defined as COVID-19–like symptoms in a person who attended the event but had no laboratory confirmation of infection.Local health department staff members, per standard practice, conducted case investigations within 48 hours of receipt of a positive SARS-CoV-2 test result in the county using a standardized questionnaire; demographic data, symptoms, and symptom onset date were entered into an electronic contact tracing platform. Through routine case investigation, local health department investigators identified a cluster of cases linked to the bar opening event through case reports indicating that persons attended the event or were close contacts of a person with an event-associated case during the 14 days before symptom onset or the testing date. All persons with a bar attendee case or secondary case of COVID-19 were interviewed by local health department staff members. This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy.Bar patrons and employees. By February 16, 2021, 29 bar attendee cases had been identified among persons who reported attending the opening event  received testing, 17 (45.9%) of whom received a positive test result within 14 days of the contact. Two persons with secondary COVID-19 cases were school-related contacts of persons with bar attendee COVID-19, three were LTCF contacts, and 12 were household contacts. Among the 17 persons with secondary cases of confirmed COVID-19, 13 were symptomatic, with symptom onset dates ranging from 3 to 11 days after the event. Median age was 28 years (range = 10–71 years), and nine persons were female.One bar attendee with COVID-19 reported the onset of a runny nose 2 days after the event and reported 26 close contacts at school during indoor sports practice and in-person school instruction. Two student athletes who were close contacts of this person subsequently received COVID-19 diagnoses 8 and 13 days after the event. Local health department officials were notified by a school official that the school district would close for 2 weeks beginning February 18 because 13 staff members were in isolation, in quarantine, or absent because their own child was quarantined.One bar attendee who worked at an LTCF as a certified nursing assistant was asymptomatic and received a positive test result during routine COVID-19 testing at the facility 4 days after the event. After receipt of the positive test result, all LTCF residents and staff members in the facility were tested; three secondary cases (one in a staff member and two in residents) in persons who were close contacts of the bar attendee with COVID-19 were identified in the facility 5–9 days after the event. One resident with a secondary case was hospitalized on February 20, within 14 days of the positive test result, and was discharged the same day. None of the four persons in the LTCF with bar attendee or secondary COVID-19 had received a COVID-19 vaccination; all LTCF staff members and residents had been previously offered the vaccine.By February 26, 12 household contacts in eight different households had received positive SARS-CoV-2 test results, including five school-aged children. Local health department staff members interviewed household contacts to assess exposures. Secondary household cases were linked to nine (31.0%) of 29 bar attendee cases. Eleven persons were symptomatic, and cases were confirmed by NAAT or antigen testing. No household contacts with COVID-19 were hospitalized.An event held to celebrate a bar opening led to an outbreak among bar patrons and employees and was the likely source of subsequent COVID-19 transmission among household members, LTCF residents and staff members, and school athletes, leading to 46 cases, hospitalization of an LTCF resident, and a school closure affecting 650 children. Attendees included one person with an asymptomatic infection who received a COVID-19 diagnosis the day before the event and four symptomatic persons who subsequently received a COVID-19 diagnosis after the event. Asymptomatic persons are estimated to account for approximately 40%–45% of infections (Similar gatherings that involve eating or drinking, such as on-premises dining at restaurants, weddings, and night clubs, have been associated with increased risk for acquiring COVID-19 and have the potential to become super-spreading events for SARS-CoV-2 infection (The findings in this report are subject to at least four limitations. First, interviews were voluntary, and many community members were reluctant to disclose contacts or additional details about themselves, including their occupation. Therefore, the number of cases described in this report is likely lower than the actual number of bar attendee and secondary cases associated with the event. Second, it is unlikely that all asymptomatic cases were counted, and not all contacts were tested; therefore, some infected contacts might have been missed. Third, information on individual-level behaviors such as wearing masks and physical distancing was not collected from persons with cases. Finally, specimens were not available for whole genome sequencing; thus, the relationship among strains was not documented, and whether the increase in county-level incidence might be attributed to variants that spread more easily than the original SARS-CoV-2 strain cannot be determined.Bars can play a role in community spread of COVID-19 because of limited mask use while eating or drinking and lack of consistent physical distancing. These findings show that SARS-CoV-2 transmission originating in a business such as a bar not only affects the patrons and employees of the bar but can also affect an entire community. As community businesses begin to reopen, considering additional prevention measures is important, such as limiting building occupancy levels and improving ventilation, especially in locations where consistent and correct mask wearing and physical distancing are difficult to enforce. Businesses can work with local health officials to promote behaviors and maintain environments that reduce the risk for SARS-CoV-2 transmission and develop strategies for reopening safely to prevent outbreaks in the community, such as modifying layouts and operating procedures (Gatherings in settings where mask wearing and physical distancing do not occur are known to increase the spread of COVID-19.Forty-six cases of COVID-19 were linked to an indoor bar opening event that occurred during February 2021 in a rural Illinois county. Event patrons were linked to secondary cases among household, long-term care facility, and school contacts, resulting in one hospitalization and one school closure affecting 650 students.Opening up settings such as bars, where mask wearing and physical distancing are challenging, can affect the community. As community businesses reopen, prevention measures should be emphasized, including limiting building occupancy, improving ventilation, prioritizing outdoor seating, enforcing correct mask wearing and physical distancing, staying home when ill, and encouraging COVID-19 vaccination to reduce transmission on site and within the community.