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June 15, 2021

Transforming medicine for patients with respiratory diseases

By Elizabeth Zimmermann
decorative photo: table top computer image of lungs and blood vessels

The Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery provides a unique service for Mayo Clinic. Embedded in the medical practice, its objective is to transform the practice of medicine – from the inside out. Center researchers work within multidisciplinary teams to identify areas for improvement within individual practice areas. These teams investigate ways to improve health outcomes and manage the cost of care. They also work to enhance the experience of patients, caregivers and staff within health care.

Recently several studies were published in collaboration with center researchers, addressing various questions surrounding patients with respiratory diseases.

The World Health Organization reports that respiratory disease are leading causes of death and disability in the world.

"Lungs are critical organs. Without breath, we have no life," says Andrew Limper, M.D., Robert D. and Patricia E. Kern Associate Dean of Practice Transformation. "Lung cancer and chronic respiratory diseases – most commonly asthma or chronic obstructive pulmonary disease, or COPD, disable or kill 10s of millions of people each year, including our own patients. So yes, finding ways to improve the health of people with these and other respiratory concerns is a priority."

In addition to leading the Mayo Clinic Kern Center for the Science of Health Care Delivery, Dr. Limper is a pulmonology and critical care physician at Mayo Clinic as well as a biomedical researcher. He is also the Walter and Leonore Annenberg Professor of Pulmonary Medicine. Not surprisingly, he has a special interest in this vein of research.

He offers some comment on the recent studies, some of which he co-authored, and all of which address some aspect of care for patients with respiratory disease.

Text box containing: Citation 1 -- Journal
Ann Am Thorac Soc. 2021 Mar;18(3):468-476. doi: 10.1513/AnnalsATS.202003-267OC. 
Authors 
Kelly M Pennington  1   2, Hayley J Dykhoff  2, Xiaoxi Yao  2   3   4, Lindsey R Sangaralingham  2   5, Nilay D Shah  2   3, Steve G Peters  1   6, Jason N Barreto  7, Raymund R Razonable  6   8, Cassie C Kennedy  1   2   6 
Affiliations 
1 Division of Pulmonary and Critical Care Medicine, Department of Medicine
2 Robert D. and Patricia E. Kern Center for the Science of Healthcare Delivery
3 Department of Health Sciences Research
4 Department of Cardiovascular Medicine
5 OptumLabs, Cambridge, Massachusetts.
6 William J. von Liebig Center for Transplantation and Clinical Regeneration
7 Department of Pharmacy
8 Division of Infectious Diseases, Department of Medicine
All Mayo Clinic, Rochester, Minnesota, USA, except (5) .

When lungs no longer function due to disease or injury, a lung transplant can restore both quality of life and longevity. However, patients who receive a lung transplant are particularly susceptible to invasive fungal infections, which can substantially reduce the new lungs' function, and potentially lead to death.

"More than 2,500 people received a lung transplant in 2018 in the U.S. alone," says Dr. Limper. "Oftentimes treatment guidelines are developed within professional societies that proscribe best practices for a particular group of patients, type of procedure, or in consideration of other factors. However, no such guidelines exist for the proactive use of antifungals to prevent fungal infection in new lung transplant recipients."

Research that supports guideline development, implementation and dissemination of best practices is critical to improving patient outcomes, and a theme around which center researchers often work. Therefore, 2019-2020 Kern Scholar Kelly Pennington, M.D., along with her primary mentor Cassie Kennedy, M.D., designed a scholar year focused on summarizing available evidence, administering a clinical practice survey, and ultimately conducting this project. 

The investigators used the OptumLabs Data Warehouse to examine the records of 662 patients who received a transplant between 2005 and 2018. They looked for evidence of prophylactic antifungal use, and outcomes for patients who did, or did not, receive antifungal medication. They also sought to identify an average duration of treatment. This latter question is important because long-term antifungal treatment can cause or exacerbate a number of serious medical concerns, is expensive, and requires very close, regular monitoring.

They found that 387 received prophylaxis and 275 did not. Death from any cause within the first year following transplant was significantly lower (about 50%) among those who received the antifungal prophylaxis.

"Using administrative claims data to answer clinical questions is a relatively new concept," says Dr. Limper. "However, without this rich data set, our researchers could not have answered this clinically important question."

In addition to quantifying the life-extending value of antifungal prophylaxis for lung transplant recipients, the investigators were able to make some other observations. Patients receiving any prophylactic antifungal treatment were a little less likely to contract an invasive fungal infection.

The authors report Aspergillus species — these are mold, a type of fungus — infections accounted for 92% and 82% of the infections in the non-prophylaxis and prophylaxis groups, respectively. Looking only at those patients who received mold-specific antifungal treatment, the team found these patients had slightly fewer invasive fungal infections than patients without any sort of prophylaxis. However, the findings were not significant enough to indicate benefits in a particular type of antifungal medication.

Text box containing: Citation 2 -- Journal
BMJ Open. 2021 Mar 17;11(3):e044010. doi: 10.1136/bmjopen-2020-044010. 
Authors 
Molly Moore Jeffery  1   2, Nathan W Cummins  3, Timothy M Dempsey  4, Andrew H Limper  5   6, Nilay D Shah  7   6, Fernanda Bellolio  2 
Affiliations 
1 Division of Health Care Delivery Research
2 Emergency Medicine
3 Department of Medicine, Division of Infectious Diseases
4 Pulmonary Critical Care Medicine, David Grant Medical Center, Travis AFB, California, USA.
5 Division of Pulmonary and Critical Care Medicine 
6 Robert D and Patricia E Kern Center for the Sciences of the Health Care Delivery
7 Division of Health Care Delivery Research, 
All Mayo Clinic, Rochester, Minnesota, USA, except (4) .

In the next study, another team of researchers — also using the OptumLabs Data Warehouse — sought clarity for some urgent questions emerging from the COVID-19 pandemic.

Early in 2020, concerns surfaced among health care providers about the effects of various conditions and associated medications on the outcomes of patients contracting COVID-19. SARS-CoV-2, which causes COVID-19, uses the angiotensin converting enzyme 2 (ACE2) receptor to infect airway cells. Some anti-hypertensive medications, such as ACE inhibitors (ACEis) and angiotensin receptor blockers (ARBs), alter ACE2 expression, and there was concern that patients taking these medications for hypertension might have worse COVID-19 outcomes.

"SARS-CoV-2 is a new virus, and COVID-19 is a new type of infection," says Dr. Limper, who co-authored this study. "To understand it and treat the new illness, we start by examining similar viruses and illnesses that looked much like those caused by a COVID-19 infection."

The authors commenced a retrospective study, examining a cohort of 202,629 individuals who had contracted one or more acute viral respiratory illnesses during the 2018-2019 influenza season (Sept. 30, 2018, through March 18, 2019). These patients were already diagnosed with hypertension, and most were receiving ACEis, ARBs, or some other anti-hypertensive medication.

Of these, outpatient use of ARBs was associated with lower risk of death within the first weeks following their illness. ARBs also appeared to contribute to less risk of hospitalization, including intensive or critical care, as well as less chance of acute respiratory distress. All were better outcomes compared to ACEis or other anti-hypertensive medications.

Patients taking ACEis had a reduced risk of death in comparison to non-ARB anti-hypertensive medications. However, patients receiving ACEis did not experience any substantial effects on other complications.

"Our findings reinforce guidance for patients to remain on ACEis or ARBs as prescribed by their doctors," says Dr. Limper. "Really, this is true for all medications. We always want patients to discuss any medication concerns with their physicians, and to play an active role in deciding course of treatment."

Although their findings appear positive, the researchers cite several confounding factors which prevent them from proving causal relationships between ACEis or ARBs and better outcomes for people with an acute viral respiratory illness.

Text box containing: Citation 3 -- Journal
ERJ Open Res. 2021 Mar 8;7(1):00011-2021. doi: 10.1183/23120541.00011-2021. eCollection 2021 Jan. 
Authors 
Teng Moua  1, Aahd Kubbara  1, Paul Novotny  2, Jennifer L Ridgeway  3, Andrew H Limper  1   3, Jay H Ryu  1, Matthew M Clark  4, Roberto Benzo  1 
Affiliations 
1 Division of Pulmonary and Critical Care Medicine
2 Dept of Health Sciences Research
3 Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery
4 Dept of Psychiatry and Psychology
All Mayo Clinic, Rochester, Minnesota, USA.

In this article, the researchers explore the value of patient-reported quality of life outcomes for more than just a measure of individual well-being. The multidisciplinary team reported the results of a cross-sectional prospective study in which they sought to determine "the degree to which two previously unassessed patient reported quality of life outcomes in fibrotic interstitial lung disease correlate with clinical and functional parameters, and a respiratory-related quality of life instrument applied in a novel manner."

"It seems almost disingenuous to not have included patient-reported outcomes in formal prognostic observations, as we know that a person's level of physical and emotional resiliency are linked to overall health," says Dr. Limper. "We wanted to improve on existing methods and get more specific intellectual and emotional inputs from patients to help better manage their care."

Typically, an assessment of a patient with fibrotic interstitial lung disease focuses on objective improvement or stabilization of lung function decline measured by forced vital capacity — the amount of air exhaled during a breathing test.

In the trial, the investigators consented and enrolled 167 patients between January 2019 and February 2020. They were asked to complete four questionnaires, assessing, among other things, emotional affect or mood, and self-management ability.

"Our findings suggest that some more subjective, patient reported outcomes, are able to clarify the disease picture for a particular patient," says Dr. Limper. "In particular we hope to gain further validation on the utility of patient reported fatigue, self-management and mood."

In the paper, the authors encourage synergistic alignment of interventions to address both traditional measurements of diseases status and progression such as lung function and more intrinsic measurements such as patient-reported symptom burden and health care utilization.

Text box containing: Citation 4 -- Journal
Respir Med. 2021 Mar;178:106309. doi: 10.1016/j.rmed.2021.106309. Epub 2021 Jan 22. 
Authors 
Misbah Baqir  1, Amit Vasirreddy  2, Ann N Vu  3, Teng Moua  3, Alanna M Chamberlain  4, Ryan D Frank  4, Jay H Ryu  3 
Affiliations 
1 Division of Pulmonary and Critical Care Medicine
2 Department of Internal Medicine, Berkshire Medical Center, Pittsfield, MA, USA.
3 Division of Pulmonary and Critical Care Medicine
4 Department of Health Sciences Research
All Mayo Clinic, Rochester, Minnesota, USA, except (2).

Idiopathic pulmonary fibrosis (IPF) is scarring in the lungs for which doctors have not been able to identify a cause. This is a progressive condition, leading to chronic, debilitating health issues

Many factors can cause or exacerbate scarring in the lungs, making it difficult to breathe, or to obtain enough oxygen to live.

"We have seen that many people with IPF also have gastroesophageal reflux disease, or GERD," says Dr. Limper, "enough so that we can no longer call it a coincidence, and therefore is something we need to examine to see if one causes the other."

In this study, the research team examined the question of whether GERD is a risk factor or consequence of idiopathic pulmonary fibrosis. Using the medical records linkage system of the Rochester Epidemiology Project, they were able to compare outcomes for 113 patients with idiopathic pulmonary fibrosis to those of 226 patients with an identified interstitial lung disease (i.e. not IPF), and 226 additional patients without lung disease. These patient cohorts were selected from between January 1, 1997, and June 30, 2017. The control cohorts each included two individuals matched to a patient with IPF, by sex, age (within 5 years) and diagnosis (within 5 years).

They found that the odds of having GERD were 1.78 times higher for people with IPF, than a person in the community with no known lung disease.. However, people with IPF were less likely to have GERD than patients with non-IPF fibrotic lung disease.

The authors noted that slightly different study designs may have contributed to the latter finding, as other studies have typically shown patients with IPF more likely to experience GERD than those with non-IPF lung disease.

"Our researchers also noted that patients with IPF were much more likely to be a smoker now, or at some point, than the patients without lung disease," says Dr. Limper.

"For our practice, these findings should prompt me and my fellow clinicians to determine whether there is a history of acid reflux in our patients with pulmonary fibrosis or to do definitive testing and treat for it."

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Tags: Aahd Kubbara, acute respiratory illness, Alanna Chamberlain, Andrew Limper, Ann Vu, antifungal, biomedical research, Cassie Kennedy, Center for the Science of Health Care Delivery, chronic obstructive pulmonary disease, COPD, COVID-19, fibrosis, Findings, gastroesophageal reflux, GERD, hypertension, idiopathic pulmonary fibrosis, Jason Barreto, Jay Ryu, Kelly Pennington, Kern Health Care Delivery Scholars, lung disease, lung transplant, M. Fernanda Bellolio, Matthew Clark, medical research, Misbah Baqir, Molly Jeffery, Nathan Cummins, News, Nilay Shah, OptumLabs, patient experience, patient reported outcomes, practice improvement, Progress Updates, pulmonary and critical care medicine, pulmonology, Raymund Razonable, respiratory disease, Roberto Benzo, Rochester Epidemiology Project, Steve Peters, Teng Moua, Timothy Dempsey, Xiaoxi Yao

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