Pulmonology: What You May Have Missed in 2023.

The field of pulmonology saw significant advances in 2023. The publications highlighted in this article address advances and changes in practice related to asthma, chronic obstructive pulmonary disease (COPD), interstitial lung disease, pleural disorders, and sleep-disordered breathing. One article reviews data examining the efficacy of vaccination against respiratory syncytial virus, a respiratory viral illness that has had devastating effects globally. Four studies evaluate the role of various therapies in COPD, including dupilumab, ensifentrine, pulmonary rehabilitation programs, and lung volume reduction versus endobronchial valves. Another study explores the effect on vascular events of positive-pressure ventilation in patients with sleep-disordered breathing and recent stroke. The use of combination therapy with rituximab and mycophenolate mofetil on progression-free survival in patients with nonspecific interstitial pneumonia is the topic of another study. We also highlight an update of clinical recommendations for the evaluation of patients with pleural disorders and a systematic review analyzing the effectiveness of inhaled corticosteroids as a supplement to dual therapy for COPD.

Disparities in Unilateral Do Not Resuscitate Order Use During the COVID-19 Pandemic.

OBJECTIVES: A unilateral do-not-resuscitate (UDNR) order is a do-not-resuscitate order placed using clinician judgment which does not require consent from a patient or surrogate. This study assessed how UDNR orders were used during the COVID-19 pandemic. DESIGN: We analyzed a retrospective cross-sectional study of UDNR use at two academic medical centers between April 2020 and April 2021. SETTING: Two academic medical centers in the Chicago metropolitan area. PATIENTS: Patients admitted to an ICU between April 2020 and April 2021 who received vasopressor or inotropic medications to select for patients with high severity of illness. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The 1,473 patients meeting inclusion criteria were 53% male, median age 64 (interquartile range, 54-73), and 38% died during admission or were discharged to hospice. Clinicians placed do not resuscitate orders for 41% of patients ( n = 604/1,473) and UDNR orders for 3% of patients ( n = 51/1,473). The absolute rate of UDNR orders was higher for patients who were primary Spanish speaking (10% Spanish vs 3% English; p ≤ 0.0001), were Hispanic or Latinx (7% Hispanic/Latinx vs 3% Black vs 2% White; p = 0.003), positive for COVID-19 (9% vs 3%; p ≤ 0.0001), or were intubated (5% vs 1%; p = 0.001). In the base multivariable logistic regression model including age, race/ethnicity, primary language spoken, and hospital location, Black race (adjusted odds ratio [aOR], 2.5; 95% CI, 1.3-4.9) and primary Spanish language (aOR, 4.4; 95% CI, 2.1-9.4) had higher odds of UDNR. After adjusting the base model for severity of illness, primary Spanish language remained associated with higher odds of UDNR order (aOR, 2.8; 95% CI, 1.7-4.7). CONCLUSIONS: In this multihospital study, UDNR orders were used more often for primary Spanish-speaking patients during the COVID-19 pandemic, which may be related to communication barriers Spanish-speaking patients and families experience. Further study is needed to assess UDNR use across hospitals and enact interventions to improve potential disparities.

Correction: Next-generation multimodality of nutrigenomic cancer therapy: sulforaphane in combination with acetazolamide actively target bronchial carcinoid cancer in disabling the PI3K/Akt/mTOR survival pathway and inducing apoptosis.

[This corrects the article DOI: 10.18632/oncotarget.28011.].

Mortality Risk From COVID-19 Among Unvaccinated Subjects With Autoimmune Phenotypes of Interstitial Lung Disease.

BACKGROUND: The impact of the severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2) virus on patients with interstitial lung disease (ILD) remains poorly understood. As patients with ILD often have severe underlying lung parenchymal involvement, and immunosuppressive therapy is common in this population, they are presumed to be at high risk for severe coronavirus disease 2019 (COVID-19) pneumonitis. Our aim was to explore demographic and clinical differences between those with ILD who tested positive for the SARS-CoV-2 virus compared to those with ILD who did not. METHODS: In this retrospective cohort study, we identified adult, unvaccinated patients evaluated at the University of Chicago in 2020 who were enrolled in the ILD registry, and stratified by SARS-CoV-2 seropositive status. We then compared baseline clinical characteristics between SARS-CoV-2 seropositive and SARS-CoV-2 seronegative patients and assessed immunosuppressive therapy that the patient may have been on since ILD diagnosis. C-reactive protein and leukocyte subsets were evaluated at COVID diagnosis compared to the time of baseline ILD evaluation as were pulmonary function testing. Variable comparisons were determined by two-sided t-tests or chi-square tests as appropriate, and logistic regression models were fitted to assess the odds of death from COVID-19 using generalized linear models with maximum-likelihood estimation. RESULTS: Of the 309 individuals with ILD in our cohort, 6.8% (n=21) tested positive for SARS-CoV-2. Those who were SARS-CoV-2 positive were younger (57 years vs 66 years; P=0.002), had baseline higher total lung capacity (81% vs 73%, P=0.045), similar forced vital capacity (71% vs. 67%, P=0.37), and similar diffusion capacity of carbon monoxide (71% vs. 62%, P=0.10) at baseline. Among patients with ILD and COVID-19, 67% had received immunosuppressive therapies compared to 74% of those with ILD without COVID-19. Those with ILD and COVID-19 were also more likely to have had a diagnosis of autoimmune-related ILD (connective tissue disease-ILD or interstitial pneumonia with autoimmune features) (62% vs 38%, P=0.029). Overall, the mortality hazard was highest among unvaccinated subjects with autoimmune-related ILD who had COVID-19 (OR=9.6, 95% CI=1.7-54.0; P=0.01). DISCUSSION: SARS-CoV-2 is prevalent in ILD, and may put unvaccinated adults who are younger, with autoimmune ILD, and on immunosuppressive therapy at higher risk. This suggests a need for COVID-19 vaccinations and therapy (inpatient and outpatient) for this group of patients at high risk for COVID-19. Larger studies are needed to fully explore the relationship between ILD and immunosuppressive therapy in COVID-19.

High-titer rheumatoid factor seropositivity predicts mediastinal lymphadenopathy and mortality in rheumatoid arthritis-related interstitial lung disease.

Rheumatoid arthritis-related interstitial lung disease (RA-ILD) is a common connective tissue disease-related ILD (CTD-ILD) associated with high morbidity and mortality. Although rheumatoid factor (RF) seropositivity is a risk factor for developing RA-ILD, the relationship between RF seropositivity, mediastinal lymph node (MLN) features, and disease progression is unknown. We aimed to determine if high-titer RF seropositivity predicted MLN features, lung function impairment, and mortality in RA-ILD. In this retrospective cohort study, we identified patients in the University of Chicago ILD registry with RA-ILD. We compared demographic characteristics, serologic data, MLN size, count and location, and pulmonary function over 36 months among patients who had high-titer RF seropositivity (≥ 60 IU/ml) and those who did not. Survival analysis was performed using Cox regression modeling. Amongst 294 patients with CTD-ILD, available chest computed tomography (CT) imaging and serologic data, we identified 70 patients with RA-ILD. Compared to RA-ILD patients with low-titer RF, RA-ILD patients with high-titer RF had lower baseline forced vital capacity (71% vs. 63%; P = 0.045), elevated anti-cyclic citrullinated peptide titer (122 vs. 201; P = 0.001), CT honeycombing (50% vs. 80%; P = 0.008), and higher number of MLN ≥ 10 mm (36% vs. 76%; P = 0.005). Lung function decline over 36 months did not differ between groups. Primary outcomes of death or lung transplant occurred more frequently in the high-titer RF group (HR 2.8; 95% CI 1.1-6.8; P = 0.028). High-titer RF seropositivity was associated with MLN enlargement, CT honeycombing, and decreased transplant-free survival. RF titer may be a useful prognostic marker for stratifying patients by pulmonary disease activity and mortality risk.

Next-generation multimodality of nutrigenomic cancer therapy: sulforaphane in combination with acetazolamide actively target bronchial carcinoid cancer in disabling the PI3K/Akt/mTOR survival pathway and inducing apoptosis.

OBJECTIVE: Aberrations in the PI3K/AKT/mTOR survival pathway in many cancers are the most common genomic abnormalities. The phytochemical and bioactive agent sulforaphane (SFN) has nutrigenomic potential in activating the expression of several cellular protective genes via the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 is primarily related to mechanisms of endogenous cellular defense and survival. The efficacy of SFN in combination with acetazolamide (AZ) was investigated in reducing typical H727 and atypical H720 BC survival, migration potential, and apoptosis in vitro and in vivo preclinical xenograft tissues. MATERIALS AND METHODS: Microscopic imaging, immunocytochemistry, wound healing assay, caspase-cleaved cytokeratin 18 (M30, CCK18) CytoDeath ELISA assay, immunofluorescence labeling assays for apoptosis, hypoxia, Western Blotting, Tunnel assay, measurement of 5-HT secretion by carbon fiber amperometry assay, quantitative methylation-specific PCR (qMSP), morphologic changes, cell viability, apoptosis activity and the expression levels of phospho-Akt1, Akt1, HIF-1α, PI3K, p21, CAIX, 5-HT, phospho-mTOR, and mTOR in xenografts derived from typical H727 and atypical H720 BC cell lines. RESULTS: Combining AZ+SFN reduced tumor cell survival compared to each agent alone, both in vitro and in vivo xenograft tissues. AZ+SFN targeted multiple pathways involved in cell cycle, serotonin secretion, survival, and growth pathways, highlighting its therapeutic approach. Both H727 and H720 cells were associated with induction of apoptosis, upregulation of the p21 cell cycle inhibitor, and downregulation of the PI3K/Akt/mTOR pathway, suggesting that the PI3K/Akt/mTOR pathway is a primary target of the AZ+SFN combination therapy. CONCLUSIONS: Combining SFN+AZ significantly inhibits the PI3K/Akt/mTOR pathway and significantly reducing 5-HT secretion in carcinoid syndrome.

Implementation and Assessment of a Proning Protocol for Nonintubated Patients With COVID-19.

INTRODUCTION: The COVID-19 pandemic has caused over 1,250,000 deaths worldwide. With limited therapeutic options, proning nonintubated patients emerged as a safe and affordable intervention to manage hypoxemia. METHODS: A proning protocol to identify and prone eligible patients was implemented. Patients were encouraged to self-prone for 2-3 hours, 3 times daily. Investigators created educational materials for nurses and patients and developed a COVID-19-specific proning order within the electronic health record (EHR). Investigators completed an 800-person retrospective chart review to study the implementation of this protocol. RESULTS: From March 22, 2020, to June 5, 2020, 586 patients were admitted to the COVID-19 floor. Of these patients, 42.8% were eligible for proning. Common contraindications were lack of hypoxia, altered mental status, and fall risk. The proning protocol led to a significant improvement in provider awareness of patients appropriate for proning, increasing from 12% to 83%, as measured by placement of a proning order into the EHR. There was a significant improvement in all appropriate patients documented as proned, increasing from 18% to 45% of eligible patients. CONCLUSIONS: The creation of an effective hospital-wide proning protocol to address the exigencies of the COVID-19 pandemic is possible and may be accomplished in a short period of time.

Implementing Prone Positioning for COVID-19 Patients Outside the Intensive Care Unit.

BACKGROUND: Proning intubated intensive care unit patients for the management of acute respiratory distress syndrome is an accepted standard of practice. We examined the nursing climate in 4 units and its impact on implementing a novel self-proning protocol to treat COVID-19 patients outside the intensive care unit. LOCAL PROBLEM: Nursing units previously designated for medical/surgical populations had to adjust quickly to provide evidence-based care for COVID-19 patients attempting self-proning. METHODS: Nurses from 4 nursing units were surveyed about the implementation process on the self-proning protocol. Their perception of unit implementation was assessed via the Implementation Climate Scale. INTERVENTIONS: A new self-proning nursing protocol was implemented outside the intensive care unit. RESULTS: Consistent education on the protocol, belief in the effectiveness of the intervention, and a strong unit-based climate of evidence-based practice contributed to greater implementation of the protocol. CONCLUSIONS: Implementation of a new nursing protocol is possible with strong unit-based support, even during a pandemic.

Treatment for lymphedema following head and neck cancer therapy: A systematic review.

OBJECTIVE: To perform the first systematic review evaluating all established treatment modalities of head and neck lymphedema resulting from head and neck cancer therapy. Since craniofacial lymphedema treatment represents unique challenges not addressed by extremity lymphedema therapies, a systematic review and evaluation of treatment modalities specific to this area is needed to guide clinical management and further research. DATA SOURCES: Four electronic databases were searches from inception to September 2018. These included Scopus (Embase), PubMed (Medline), Clinicaltrials.gov, and Cochrane Databases. REVIEW METHODS: A search string was developed, and all databases queried for keywords on three subjects: head and neck cancer, lymphedema, and therapy. Results were uploaded to an EndNote database where relevant items were identified by hand-searching all titles and abstracts. Subsequently results were combined, duplicates removed, and full papers screened according to eligibility criteria. RESULTS: Of a total 492 search results, twenty-six items met eligibility criteria for this review. These included fourteen cohort studies, seven case reports, two randomized controlled trials, two systematic reviews, and one narrative review totaling 1018 study subjects. The manual lymph drainage group had the largest number of studies and participants, with fewer studies investigating selenium, liposuction, and lymphaticovenular anastomosis. CONCLUSION: Evidence for the efficacy of all types of lymphedema therapy is limited by paucity of large randomized controlled trials. While manual lymph drainage is best studied, liposuction and surgical treatments have also been effective in a small number of patients.