Cardiopulmonary exercise testing in younger patients with persistent dyspnea following acute, outpatient COVID-19 infection.

Studies using cardiopulmonary exercise testing (CPET) to evaluate persistent dyspnea following infection with COVID-19 have focused on older patients with co-morbid diseases who are post-hospitalization. Less attention has been given to younger patients with post-COVID-19 dyspnea treated as outpatients for their acute infection. We sought to determine causes of persistent dyspnea in younger patients recovering from acute COVID-19 infection that did not require hospitalization. We collected data on all post-COVID-19 patients who underwent CPET in our clinic in the calendar year 2021. Data on cardiac function and respiratory response were abstracted, and diagnoses were assigned using established criteria. CPET data on 45 patients (238.3 ± 124 days post-test positivity) with a median age of 27.0 (22.0-40.0) were available for analysis. All but two (95.6%) were active-duty service members. The group showed substantial loss of aerobic capacity-average VO2 peak (L/min) was 84.2 ± 23% predicted and 25 (55.2%) were below the threshold for normal. Spirometry, diffusion capacity, high-resolution computed tomography, and echocardiogram were largely normal and were not correlated with VO2 peak. The two most common contributors to dyspnea and exercise limitation following comprehensive evaluation were deconditioning and dysfunctional breathing (DB). Younger active-duty military patients with persistent dyspnea following outpatient COVID-19 infection show a substantial reduction in aerobic capacity that is not driven by structural cardiopulmonary disease. Deconditioning and DB breathing are common contributors to their exercise limitation. The chronicity and severity of symptoms accompanied by DB could be consistent with an underlying myopathy in some patients, a disorder that cannot be differentiated from deconditioning using non-invasive CPET.

Obesity-related Changes in Diffusing Capacity and Transfer Coefficient of the Lung for Carbon Monoxide and Resulting Patterns of Abnormality across Reference Equations.

Rationale: In 2017, an American Thoracic Society/European Respiratory Society Task Force report recommended further research on the effects that body mass index (BMI) has on diffusing capacity of the lung for carbon monoxide (DlCO), the transfer coefficient (Kco), and the alveolar volume (VA). Objectives: Our goals were to 1) quantify the magnitude and direction of change to measured and predicted DlCO values as BMI increases in patients free of cardiopulmonary disease and 2) identify how BMI and obesity-related changes differ by reference set. Methods: Using data from a prospective cohort study of service members free of cardiopulmonary disease, we modeled the effect that BMI has on measured values of DlCO, Kco, and VA, after adjusting for age, sex, hemoglobin (Hgb), and height. We then referenced DlCO, Kco, and VA to normal values using four different reference equations. Results: There were 380 patients with data available for analysis, and 130 had a BMI ⩾ 30 kg/m2 (87.7% class I obesity). After controlling for age, sex, Hgb, and height, increased BMI was significantly associated with Kco (ß = 0.09, P < 0.01) and VA (ß = -0.15, P < 0.01) but not DlCO. After adjustment for Hgb, for every 5-kg/m2 increase in BMI, the mean increase in percent predicted (PPD) values ranged from 4.2% to 6.5% and from 5.0% to 7.5% for DlCO and Kco, respectively; and the mean decrease in VA PPD was 3.2-4.0%. In the presence of obesity (BMI ⩾ 30 kg/m2), the prevalence of DlCO and Kco abnormalities dropped by 4.1-12.1% and 0.4-16.3%, respectively, across equations, whereas VA abnormalities increased from 7.7% to 9.9%. Eliminating 163 patients with abnormal trans-thoracic echocardiogram (TEE), high-resolution computed tomographic (HRCT) scan, or Hgb altered the magnitude of relationships, but significance was preserved. Conclusions: In an otherwise healthy population with predominantly class I obesity and normal TTE, HRCT scan, and Hgb, we found that Kco and VA were more affected by BMI than DlCO. Increases in PPD values varied across equations and were modest but significant and could change clinical decision making by reducing sensitivity for detecting gas-exchange abnormalities. BMI and obesity had the smallest effect on Global Lung Function Initiative PPD values.

Deconstructing the Treatment Effect of Remdesivir in the Adaptive Coronavirus Disease 2019 (COVID-19) Treatment Trial-1: Implications for Critical Care Resource Utilization.

BACKGROUND: The Adaptive Coronavirus Disease 2019 (COVID-19) Treatment Trial-1 (ACTT-1) found that remdesivir therapy hastened recovery in patients hospitalized with COVID-19, but the pathway for this improvement was not explored. We investigated how the dynamics of clinical progression changed along 4 pathways: recovery, improvement in respiratory therapy requirement, deterioration in respiratory therapy requirement, and death. METHODS: We analyzed trajectories of daily ordinal severity scores reflecting oxygen requirements of 1051 patients hospitalized with COVID-19 who participated in ACTT-1. We developed competing risks models that estimate the effect of remdesivir therapy on cumulative incidence of clinical improvement and deterioration, and multistate models that utilize the entirety of each patient's clinical course to characterize the effect of remdesivir on progression along the 4 pathways above. RESULTS: Based on a competing risks analysis, remdesivir reduced clinical deterioration (hazard ratio [HR], 0.73; 95% confidence interval [CI]: .59-.91) and increased clinical improvement (HR, 1.22; 95% CI: 1.08, 1.39) relative to baseline. Our multistate models indicate that remdesivir inhibits worsening to ordinal scores of greater clinical severity among patients on room air or low-flow oxygen (HR, 0.74; 95% CI: .57-.94) and among patients receiving mechanical ventilation or high-flow oxygen/noninvasive positive-pressure ventilation (HR, 0.73; 95% CI: .53-1.00) at baseline. We also find that remdesivir reduces expected intensive care respiratory therapy utilization among patients not mechanically ventilated at baseline. CONCLUSIONS: Remdesivir speeds time to recovery by preventing worsening to clinical states that would extend the course of hospitalization and increase intensive respiratory support, thereby reducing the overall demand for hospital care.

Evaluation of Supranormal Spirometry Values With an Obstructive Ratio for Airway Hyperreactivity.

BACKGROUND: Published guidelines on spirometry interpretation suggest an elevated FVC and FEV1 > 100% of predicted with an obstructive ratio may represent a physiological variant. Further evidence is needed on whether this finding indicates symptomatic airways obstruction and what additional evaluation should be done. METHODS: Participants were prospectively enrolled to undergo additional testing for a technically adequate spirometry study with an FEV1 > 90% of predicted, and FEV1/FVC below the lower limit of normal, based on 95th percentile confidence intervals. Further testing consisted of full pulmonary function testing, impulse oscillometry (IOS), post-bronchodilator testing, fractional exhaled nitric oxide (FeNO), and methacholine challenge testing (MCT). RESULTS: A total of 49 patients meeting entry criteria enrolled and completed testing. Thirty-three were considered symptomatic based on clinical indications for initial testing and 16 were considered asymptomatic. Baseline pulmonary function test values were not different between groups while IOS R5 values (% predicted) were higher in the symptomatic group (126.5 ± 0.37 vs 107.1 ± 0.31). Bronchodilator responsiveness on PFT or IOS was infrequent in both groups. There was a 29% positivity rate for MCT in the symptomatic group compared to one borderline study in asymptomatic participants. FeNO was similar for symptomatic, 26.17 ± 31.3 ppb, compared to asymptomatic, 22.8 ± 13.5 ppb (p = 0.93). The dysanapsis ratio was higher in the symptomatic (0.15 ± 0.03) compared to the asymptomatic (0.13 ± 0.02) (p < 0.05). CONCLUSION: Normal FEV1 > 90% of predicted and obstructive indices may not represent a normal physiological variant in all patients. In symptomatic patients, a positive MCT and elevated baseline IOS values were more common than in asymptomatic patients with similar PFT characteristics. These findings suggest that clinicians should still evaluate for airway hyperresponsiveness in patients with exertional dyspnea with airway obstruction and FEV1 > 90% of predicted and consider alternative diagnoses to include a normal physiologic variant if non-reactive.

Post-COVID-19 Pulmonary Fibrosis: Novel Sequelae of the Current Pandemic.

Since the initial identification of the novel coronavirus SARS-CoV-2 in December 2019, the COVID-19 pandemic has become a leading cause of morbidity and mortality worldwide. As effective vaccines and treatments begin to emerge, it will become increasingly important to identify and proactively manage the long-term respiratory complications of severe disease. The patterns of imaging abnormalities coupled with data from prior coronavirus outbreaks suggest that patients with severe COVID-19 pneumonia are likely at an increased risk of progression to interstitial lung disease (ILD) and chronic pulmonary vascular disease. In this paper, we briefly review the definition, classification, and underlying pathophysiology of interstitial lung disease (ILD). We then review the current literature on the proposed mechanisms of lung injury in severe COVID-19 infection, and outline potential viral- and immune-mediated processes implicated in the development of post-COVID-19 pulmonary fibrosis (PCPF). Finally, we address patient-specific and iatrogenic risk factors that could lead to PCPF and discuss strategies for reducing risk of pulmonary complications/sequelae.

Isolated Small Airway Dysfunction and Ventilatory Response to Cardiopulmonary Exercise Testing.

BACKGROUND: The effect of isolated small airway dysfunction (SAD) on exercise remains incompletely characterized. We sought to quantify the relationship between isolated SAD, identified with lung testing, and the respiratory response to exercise. METHODS: We conducted a prospective evaluation of service members with new-onset dyspnea. All subjects underwent plethysmography, diffusing capacity of the lung for carbon monoxide (DLCO), impulse oscillometry, high-resolution computed tomography (HRCT), and cardiopulmonary exercise testing (CPET). In subjects with normal basic spirometry, DLCO, and HRCT, SAD measures were analyzed for associations with ventilatory parameters at submaximal exercise and at maximal exercise during CPET. RESULTS: We enrolled 121 subjects with normal basic spirometry (ie, FEV1, FVC, and FEV1/FVC), DLCO, and HRCT. Mean age and body mass index were 37.4 ± 8.8 y and 28.4 ± 3.8 kg/m2, respectively, and 110 (90.9%) subjects were male. The prevalence of SAD varied from 2.5% to 28.8% depending on whether FEV3/FVC, FEF25-75%, residual volume/total lung capacity, and R5-R20 were used to identify SAD. Agreement on abnormal SAD across tests was poor (kappa = -0.03 to 0.07). R5-R20 abnormalities were related to higher minute ventilation ([Formula: see text]) and higher [Formula: see text]/maximum voluntary ventilation (MVV) during submaximal exercise and to lower [Formula: see text] during maximal exercise. After adjustment for differences at baseline, there remained a trend toward a relationship between R5-R20 and an elevated [Formula: see text]/MVV during submaximal exercise (ß = 0.04, 95% CI -0.01 to 0.09, P = .10), but there was no significant association with [Formula: see text] during submaximal exercise or with [Formula: see text] during maximal exercise. No other SAD measures showed a relationship with ventilatory parameters. CONCLUSIONS: In 121 subjects with normal basic spirometry, DLCO, and HRCT, we found poor agreement across tests used to detect SAD. Among young, healthy service members with postdeployment dyspnea, SAD as identified by lung function testing does not predict changes in the ventilatory response to exercise.

Intermittent gastric feeds lower insulin requirements without worsening dysglycemia: A pilot randomized crossover trial.

INTRODUCTION: We hypothesized that critically ill medical patients would require less insulin when fed intermittently. METHODS: First, 26 patients were randomized to receive intermittent or continuous gastric feeds. Once at goal nutrition, data were collected for the first 4-hr data collection period. Next, the enteral feed type was switched, goal nutrition was repeated, and a second 4-h data collection period was completed. The primary endpoint was the total amount of insulin infused; secondary endpoints were glucose concentration mean, maximum, minimum, and standard deviation, as well as episodes of hypoglycemia. RESULTS: Sixteen of the 26 patients successfully completed the protocol. One patient experienced a large, rapid, and sustained decline in insulin requirement from liver failure, creating a bias of lesser insulin in the intermittent arm; this patient was removed from the analysis. For the remaining 15 patients, the average total amount of insulin infused was 1.4 U/patient/h less following intermittent feeds: P =0.027, 95% confidence interval (0.02, 11.17), and effect size 0.6. Secondary endpoints were statistically similar. CONCLUSIONS: Critically ill medical patients who require an insulin infusion have a reduced insulin requirement when fed intermittently, whereas dysglycemia metrics are not adversely affected. A larger clinical study is required to confirm these findings.

Comparison of Forced and Slow Vital Capacity Maneuvers in Defining Airway Obstruction.

BACKGROUND: Obstructive lung disease is diagnosed by a decreased ratio of FEV1 to the vital capacity (VC). Although the most commonly used VC is FVC, American Thoracic Society guidelines suggest alternative VCs, for example, slow VC (SVC), may offer a more-accurate evaluation of breathing capacity. There is recent evidence that using only FEV1/FVC underrecognizes obstruction in subjects at high risk and who are symptomatic. Previous studies have indicated that healthy individuals show a minimum difference between FVC and SVC; however, testing of individuals with asthma and who are symptomatic indicates that SVC can be markedly larger than FVC. OBJECTIVE: To evaluate the differences among SVC, FVC, and SVC-based measurements in the diagnosis of symptomatic obstructive lung disease. METHODS: A retrospective analysis was performed of spirometry and plethysmography measurements from studies conducted between 2011 to 2015. We established a pulmonary function database that incorporated predictive equations from the National Health and Nutrition Examination Survey III (NHANES III). The SVC to FVC difference was calculated. FEV1/SVC was compared with FEV1/FVC by using NHANES III lower limit of normal values. RESULTS: A total of 2,710 studies with 2,244 subjects were reviewed. Spirometric obstruction, as defined by NHANES III, was identified in 26.1% of the studies (707/2,710). The mean (± SD) difference between SVC and FVC was 375.0 ± 623.0 mL and 258.8 ± 532.5 mL in those with and those without obstruction, respectively. Subgroup and multivariate analysis demonstrated age, body mass index, and FEV1 associated contributions to the difference between SVC and FVC. By using FEV1/SVC, the prevalence of obstruction increased from 26.1 to 45.0% (1,219/2,710) and identified 566 additional studies of subjects with obstruction. Fifty-four percent of the subjects with newly-identified obstructive lung disease (305/566) had smoking histories, and 67.4% (345/512) received medications for obstructive lung disease. CONCLUSIONS: The isolated use of FVC-based diagnostic algorithms did not recognize individuals with symptomatic obstructive lung disease. Recognizing the difference between SVC and FVC measurements in subjects will improve testing and diagnosis of obstructive lung disease.

A Comparison of Global Lung Initiative 2012 with Third National Health and Nutrition Examination Survey Spirometry Reference Values. Implications in Defining Obstruction.

RATIONALE: Obstructive lung disease is diagnosed by a decreased ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC); however, there is no universally accepted lower limit of normal for the FEV1/FVC ratio. Current established reference values use the Third National Health and Nutrition Examination Survey (NHANES III) database. In 2012, the Global Lung Initiative (GLI) introduced GLI12, which is a compilation reference set that uses standard deviation values to define normal spirometry. OBJECTIVES: To evaluate the changes in classification of obstructive spirometry with use of GLI12 compared with NHANES III in a heterogeneous, multiracial population. METHODS: We evaluated the spirometry studies conducted in our pulmonary function laboratory between January 2005 and December 2015. NHANES III reference equations were calculated to predict lower limits of normal for FEV1, FVC, and FEV1/FVC. GLI12 values were established using European Respiratory Society published computer software. FEV1 severity was graded using 2005 American Thoracic Society guidelines for NHANES III and using z-score-based criteria for GLI12. Asymmetric partition analysis evaluated agreement between the reference sets. RESULTS: A total of 11,888 studies were evaluated. Obstruction was diagnosed in 2,857 studies using NHANES III versus 2,489 studies using GLI12. Agreement regarding the presence or absence of obstruction occurred in 2,483 of studies with obstruction and 9,025 studies without obstruction (agreement, 96.8%; κ = 0.91). Of the studies with obstruction, 1,595 had agreement in severity grading. Overall, agreement regarding obstruction and severity grading occurred in 10,620 studies, representing 89.3% of all studies. A total of 380 studies (3.2%) had discordance regarding the presence or absence of obstruction, 34.0% (844 of the 2,483 obstruction studies) had a one-degree of change in FEV1 disease severity scoring, with 44 cases (1.8%) that had changes of two categories in FEV1 severity scores. No studies had greater than two degrees of change. Asymmetric partition analysis suggested that the highest clinically significant changes were seen in older individuals, particularly African American men older than 65. CONCLUSIONS: Our evaluation suggests that there is moderate overall agreement between NHANES III and GLI12. We found a 3.2% change in classification of obstruction when transitioning from NHANES III to GLI12. When incorporating a z-score-based FEV1 and GLI12 reference set, 10.7% of the spirometry studies had a change in their categorization. The disagreement between the two datasets was most pronounced in elderly subjects. Although we cannot endorse one reference set over the other, we highlight the potential implications of adopting the GLI12 reference sets and suggest caution when interpreting spirometry in the elderly.

Salvage extracorporeal membrane oxygenation in induction-associated acute respiratory distress syndrome in acute leukemia patients: A case series.

BACKGROUND:: The prognosis of hematologic malignancies has improved over the past three decades. However, the prognosis in hematologic malignancies with severe acute respiratory distress syndrome has remained poor. Initial reports regarding the utility of extracorporeal membrane oxygenation in hematologic malignancies have been controversial, with limited evaluations of acute leukemia patients supported by extracorporeal membrane oxygenation. METHODS:: We conducted a retrospective review of patients with acute leukemia who developed acute respiratory distress syndrome requiring veno-venous extracorporeal membrane oxygenation support at our facility from July 2015 through August 2017. RESULTS:: Four cases of acute myelogenous leukemia with respiratory failure and acute respiratory distress syndrome treated with veno-venous extracorporeal membrane oxygenation while undergoing induction chemotherapy were identified. All patients completed induction therapy with addition of extracorporeal membrane oxygenation support, with two patients dying secondary to their acute leukemia and the other two surviving to allogeneic hematopoietic stem cell transplant. Overall, 75% (three of four) survived to decannulation with a 1-year survival rate following extracorporeal membrane oxygenation of 50% (two of four). CONCLUSION:: Currently, the use of extracorporeal membrane oxygenation in patients with hematologic malignancies who develop severe acute respiratory distress syndrome remains controversial. Although extracorporeal membrane oxygenation in post-allogeneic hematopoietic stem cell transplant is associated with poorer outcomes, our data suggest that salvage extracorporeal membrane oxygenation support is a viable option to manage moderate to severe acute respiratory distress syndrome while completing therapeutic chemotherapy and following in the peri-induction phase of acute leukemia.

Non-traumatic Pulmonary Emergencies in the Deployed Setting.

PURPOSE OF REVIEW: Pulmonary disorders accounted for up to 8% of the over 70,000 medical evacuations conducted from Iraq and Afghanistan in the past 15 years. This review of non-traumatic pulmonary emergencies provides an overview of deployed military medical treatment capabilities and highlights pulmonary emergencies requiring aeromedical evacuation from theater. RECENT FINDINGS: Recent studies have improved the epidemiologic evaluation of non-traumatic pulmonary disease, highlighted specific parenchymal diseases, and revealed infection pathologies unique to the deployed setting. Literature regarding possible chemical exposures in the current deployed environment remains limited. SUMMARY: Respiratory disorders requiring medical evacuation represent a wide variety of diseases. Complications such as pulmonary emboli, infectious pathogens, and hazardous chemical exposures threaten the deployed warfighter. Adequate medical care requires an understanding of these potential environmental exposures. This review serves as a general overview of this topic; however, more research regarding epidemiologic and environmental exposures is required.