Jaime Rosenberg

It’s been established that coughing serves as an indicator of 

 (COPD) exacerbation. Probing the importance of cough reflex sensitivity specifically, researchers have found that cough reflex sensitivity is heightened during exacerbation of COPD and falls after recovery.

However, the researchers were able to show that continued cough reflex hypersensitivity at recovery can help serve as a predictor for future exacerbations.

While hospitalized for COPD exacerbation during the 2017-2018 winter seasons, 20 patients participated in inhaled capsaicin challenge in which thresholds to elicit 5 coughs were documented. Patients continued the challenge for 6 weeks following their recovery. Analyzing at the results, the researchers found that the capsaicin cough thresholds were significantly lower while patients had their exacerbation than when they were 6 weeks post recovery (1.76 vs 809 μmol L−1, respectively).

“Capsaicin is a selective agonist of transient receptor potential vanilloid 1 ion channel receptors (TRPV1), which are expressed on C-fibre sensory nerves. Bronchopulmonary C fibres are relatively quiescent in health and can be sensitised or activated by inflammatory mediators,” 

. “Exposure to ozone, lactic acid, cationic proteins and prostaglandin-E2 are known to enhance pulmonary C-fibre responses to mechanical and chemical stimuli in a reversible fashion. Airway inflammation in exacerbation of COPD could therefore lead to sensitisation or activation of C fibres.”

Notably, there was no association between the change in the doubling dosing from the time of exacerbation to recovery and age, forced expiratory volume in 1 second, or history of COPD exacerbations prior to the study exacerbation.

Seventeen patients were followed for 12 months to monitor any future exacerbations. The year of follow-up revealed that persistence of cough reflex hypersensitivity at recovery was linked with the frequency of future exacerbations, which are commonly characterized by increased cough and/or sputum volume or purulence.

“Such episodes are associated with impaired quality of life, accelerated decline in lung function and increased health care utilisation,” wrote the researchers, who added, “The identification of individuals with COPD who are more susceptible to exacerbation may lead to targeted preventive therapies.”

During the year of follow-up, 15 of the 17 patients had a mean 2.5 subsequent exacerbations. Of the 42 total exacerbations, 30 led to seeking out primary care services, 12 led to emergency department visits, and 9 led to hospital admissions. According to the researchers, subsequent exacerbations were more common in patients who had a lower reduction in cough reflex sensitivity at 6 weeks following the initial exacerbation.

Cho P, Fletcher H, Turner R, Patel I, Jolley C, Birring S. The relationship between cough reflex sensitivity and exacerbation frequency in chronic obstructive pulmonary disease. 

. Published June 19, 2020. doi: 10.1007/s00408-020-00366-x

Articles

Researchers found that cough reflex sensitivity is amplified during chronic obstructive pulmonary disease (COPD) exacerbation and reduces after recovery, while its persistence can help serve as a predictor for future exacerbations.

Continued Cough Reflex Hypersensitivity After COPD Exacerbation Predicts More Attacks

 examining DC-mediated differentiation of alloreactive donor CD4+ T cells during exacerbation of acute gut 

 (GVHD) has led researchers to suggest that the findings could aid in examining T cell differentiation in patients undergoing allogeneic hematopoietic stem cell transplantation (alloSCT).

While alloSCT is a curative therapy for an array of acute leukemias through its graft-versus-leukemia (GVL) effect, the procedure can also cause GVHD when donor T cells damage noncancerous host tissue, including in the gastrointestinal (GI) tract. Previous research has established acute GVHD in the GI tract as the primary cause of both GVHD severity and mortality, and as a result, emphasis is placed on preventing acute gut GVHD while still preserving the GVL effect of alloSCT.

According to the researchers, the key to this is determining the spatial and temporal differences between GVL and GVHD.

Through droplet-based scRNA-Seq and computational modeling, the researchers observed an emergence of pathogenic and regulatory states along a single developmental trajectory in mesenteric lymph nodes (mLNs). Unexpectedly, the researchers also observed a second trajectory with little proliferation or cytokine expression, reduced glycolysis, and high 

“We previously showed in preclinical models that donor CD4+ T cells are initially activated by recipient nonhematopoietic antigen-presenting cells (APCs) within the gut, including epithelial cells that upregulate class II MHC molecules,” explained the researchers. “Donor-derived colonic DCs also prime donor CD4+ cells in mesenteric lymph nodes (mLNs) and trigger Th cell differentiation, which serves to amplify and exacerbate GVHD.”

From the preclinical model, the researchers were able to determine that cytokines like IL-17A, IFN-γ, and granulocyte-macrophage colony-stimulating factor created by alloreactive Th1 and Th17 cells in the GI tract promote GVHD. On the other hand, IL-10 produced by Tr1 and iTreg cells offer protection from the disease.

In the current study, the researchers sampled transcriptomes from thousands of alloreactive CD4+ T cells of a single specificity from both lymphoid and nonlymphoid gut-associated tissue. In doing this, they found cellular states expressing canonical Th1/Th17 cytokine genes 

regulatory genesat frequencies similar to that expressed by flow cytometry. Of note, there was significant similarity between the transcriptomes of the lymphoid tissue but also in the gut.

“Subtle differences became more evident among gut-trafficked TEa cells that had stopped proliferating, with 

,” explained the researchers. “Given that Tea cells can upregulate T-bet and IFN-γ but not IL-17A or Foxp3 in the complete absence of the class II MHC presentation, our data are broadly consistent with a Th1-like state being a default program in the gut, which may be countered by alloantigen presentation via class II MHC molecule toward iTreg or Th17-like states.”

According to the researchers, a main takeaway from the study was that proinflammatory states were not readily distinguished from immune-suppressive iTreg states.

They added: “One question, however, is whether our inability to separate proinflammatory and regulatory states was attributed to reliance on droplet-based scRNA-Seq, without supplementing this with high-dimensional protein assessment via flow or mass cytometry, single-cell epigenomic assessment via scATAC-Seq, or scRNA-Seq at higher sequencing depths.”

Engel J, Lee H, Williams C, et al. Single-cell transcriptomics of alloreactive CD4+ T cells over time reveals divergent fates during gut graft-versus-host disease. 

. 2020;5(13):e137990. doi: 10.1172/jci.insight.137990.

Previous research has established acute graft-versus-host disease (GVHD) in the gastrointestinal tract as the primary cause of both GVHD severity and mortality, and as a result, emphasis is placed on preventing acute gut GVHD while still preserving the graft-versus-leukemia effect of allogeneic hematopoietic stem cell transplantation.

Research Offers Clues Into T Cell Differentiation in Worsening of Acute Gut GVHD 

In order to achieve optimal treatment delivery in chronic obstructive pulmonary disease (

), it’s important for patients to have the respiratory strength to overcome the internal resistance of their dry powder inhaler (DPI) so as to disaggregate the powdered drug into fine particles for lung deposition. To this end, peak inspiratory flow (PIF) has been touted as a measure of a patient’s ability to use DPIs.

Despite this importance, a gap in knowledge exists when it comes to having robust quality criteria for determining a repeatability limit for measuring PIF. In search of this, researchers were able to determine the PIF repeatability limit, as well as show that the 2 highest of 3 values of PIF met the repeatedly limit.

The 

, and according to researchers, provide guidance for measuring PIF against the simulated resistance of DPIs in both clinical practice and research studies.

The analysis used data from a phase 3 study (study 0149) in which patients took 3 measures of PIF, including before and after using the inhaled study drug, within 1 session. From there, researchers determined the repeatability limit by using each unique combination of 2 assessments, which they defined as the absolute difference between 2 measurements under identical conditions.

The researchers also used study 0149, in addition to a second phase 3 trial (study 0128), to determine the relationship between PIF measured by the In-Check DIAL device at 2 resistances:

They found repeatability limits of PIF (10 L/min against the resistance of the Diskus and 5 L/min against the resistance of the HandiHaler) were achieved by the overwhelming majority of patients (95%).

Importantly, researchers also determined that a PIFD of 60 L/min is roughly equivalent to a PIFHH value of 40 L/min after controlling for covariates including sex, weight, body mass index, forced vital capacity, and percent predicted forced expiratory volume in the first second.

“Based on these data, we recommend that at least 3 measures of PIF be undertaken, using the In-Check DIAL device, until the two highest measurements meet the repeatability limits, which is similar to the recommendations for spirometry,” researchers said. They added, “Although we cannot comment on the total number of measurements that might be performed, our data demonstrate a tendency for the highest PIF value to be obtained in the first 2 efforts.”

Investigators saw in study 0128 the average values for PIF at 0 resistance and PIFHH were 84.6 L/min and 57.3 L/min, respectively. In study 0149, average values for PIFD and PIFHH were 42.4 L/min and 29.0 L/min, respectively. According to the researchers, the lower PIFHH in study 0149 is likely due to its inclusion of patients with suboptimal PIF, defined as <60 L/min set to Diskus resistance.

Looking at the average difference between the 2 measurements from the same patients and averaged over all patients, researchers found “the mean difference between measurement attempts for PIFD and PIFHH was small, <5 L/min and <3 L/min, respectively.”




Barnes CN, Mahler DA, Ohar JA, Lombardi DA, Crater GD. Peak inspiratory flows: defining repeatability limits and a predictive equation for different inhalers. 

. Published online April 25, 2020. doi: 10.1016/j.chest.2020.03.072


Using data from 2 phase 2 trials, researchers were able to determine the peak inspiratory flow (PIF) repeatability limit, and show that the 2 highest of 3 PIF values met the repeatedly limit.


Researchers Determine Repeatability Limits, Predictive Equation for COPD Inhalers

Historically, few studies have focused on what implications spontaneous pneumothorax has on patients with 

connective tissue disease-associated interstitial disease

 (CTD-ILD). A new study is now putting a spotlight on these implications, finding that the complication does not bode well for disease prognosis.

, the onset of spontaneous pneumothorax is strongly indicative of a poor outcome for patients. In fact, these patients were more than 20 times more likely to have a poor prognosis compared with patients who did not develop pneumothorax (HR 22.0; 95% CI 10.3—46.9; 

“The study highlights the clinical importance of pneumothorax as a serious complication associated with poor outcomes in patients with CTD-ILD, of which clinicians should be aware in the clinical course of CTD-ILD,” stressed the researchers.

According to the researchers, this complication was common among the 140 patients who received a CTD-ILD diagnosis between January 2000 and December 2014. Over the course of the study, 18 had developed pneumothorax. The cumulative incidence was 6.5% at 1 year, 8.7% at 3 years, and 11.3% at 5 years following diagnosis. Fifty percent of patients who developed pneumothorax had developed the complication within 1 year of their CTD-ILD diagnosis.

Throughout the study, 33 patients died, with the mortality rate falling significantly higher among patients who developed pneumothorax than those who did not (66.7% vs 17.2%, respectively). Consequently, patients with pneumothorax also had worse 10-year survival rates. Patients with the complication had a 10-year survival rate of just under 30% (29.6%) compared to a rate of 81.3% among patients without the complication.

“It was important to elucidate the predictive factors for the onset of pneumothorax as our findings demonstrated that pneumothorax was significantly associated with poorer outcomes in patients with CTD-ILD,” noted the researchers. “In the present study, we found that a lower BMI was associated with the onset of pneumothorax in patients with CTD-ILD, which is consistent with previous reports regarding primary spontaneous pneumothorax and secondary pneumothorax in patients with [idiopathic pulmonary fibrosis].”

Aside from BMI, greater extent of reticular abnormalities (

Grade 2) and the administration of methylprednisolone pulse therapy were heavily associated with the onset of pneumothorax. Among all patients, 37.1% received intravenous methylprednisolone pulse therapy. Patients receiving the treatment were more than 3 times more likely to develop the complication.

Other therapies used in the study included prednisolone alone and prednisolone in combination with immunosuppressive agents.

Nishimoto K, Fujisawa T, Yoshimura K, et al. Pneumothorax in connective tissue disease-associated interstitial lung disease. 

. Published online July 7, 2020. doi: 10.1371/ journal.pone.0235624

According to a new study, patients with connective tissue disease-associated interstitial disease (CTD-ILD) had significantly higher mortality rates and worse 10-year survival rates than patients who did not develop the complication.

Author | Jaime Rosenberg

Articles

Continued Cough Reflex Hypersensitivity After COPD Exacerbation Predicts More Attacks

Research Offers Clues Into T Cell Differentiation in Worsening of Acute Gut GVHD

Researchers Determine Repeatability Limits, Predictive Equation for COPD Inhalers

Onset of Pneumothorax Carries Poor Prognosis for Patients With CTD-ILD