Critical Care Network

Nonrespiratory Critical Care Section

Goals-of-care discussions are essential to management of the intensive care unit (ICU) patient. Racial inequities in end-of-life decision making have been documented for many years, with literature demonstrating that marginalized populations are less likely to have EHR-documented goals-of-care discussions and more likely to have concerns regarding clinician communication.

A recently published randomized control trial in JAMA highlights an intervention that offers promise in addressing disparities in goals-of-care conversations. Curtis, et al. studied whether priming physicians with a communication guide advising on discussion prompts and language for goals-of-care could improve the rate of documented goals-of-care discussions among hospitalized older adults with serious illness. The study found that for patients in the intervention arm, there was a significant increase in proportion of goals-of-care discussions within 30 days. Notably, the difference in documented goals-of-care discussions between arms was greater in the subgroup of patients from underserved groups (Curtis JR, et al. JAMA. 2023;329[23]:2028-37).

Nevertheless, while interventions may help increase the rate of goals-of-care discussions, it is also important to address the content of discussions themselves. You and colleagues recently published a mixed-methods study assessing the impact of race on shared decision-making behaviors during family/caregiver meetings. The authors found that while ICU physicians approached shared decision making with White and Black families similarly, Black families felt their physicians provided less validation of the family role in decision making than White families did (You H, et al. Ann Am Thorac Soc. 2023 May;20[5]:759-62). These findings highlight the importance of ongoing work that focuses not only on quantity but also on quality of communication regarding goals-of-care for patients from diverse backgrounds.

Divya Shankar MD
Section Fellow-in-Training

Muhammad Hayat-Syed MD
Section Vice Chair

Critical Care Network

Nonrespiratory Critical Care Section

Goals-of-care discussions are essential to management of the intensive care unit (ICU) patient. Racial inequities in end-of-life decision making have been documented for many years, with literature demonstrating that marginalized populations are less likely to have EHR-documented goals-of-care discussions and more likely to have concerns regarding clinician communication.

A recently published randomized control trial in JAMA highlights an intervention that offers promise in addressing disparities in goals-of-care conversations. Curtis, et al. studied whether priming physicians with a communication guide advising on discussion prompts and language for goals-of-care could improve the rate of documented goals-of-care discussions among hospitalized older adults with serious illness. The study found that for patients in the intervention arm, there was a significant increase in proportion of goals-of-care discussions within 30 days. Notably, the difference in documented goals-of-care discussions between arms was greater in the subgroup of patients from underserved groups (Curtis JR, et al. JAMA. 2023;329[23]:2028-37).

Nevertheless, while interventions may help increase the rate of goals-of-care discussions, it is also important to address the content of discussions themselves. You and colleagues recently published a mixed-methods study assessing the impact of race on shared decision-making behaviors during family/caregiver meetings. The authors found that while ICU physicians approached shared decision making with White and Black families similarly, Black families felt their physicians provided less validation of the family role in decision making than White families did (You H, et al. Ann Am Thorac Soc. 2023 May;20[5]:759-62). These findings highlight the importance of ongoing work that focuses not only on quantity but also on quality of communication regarding goals-of-care for patients from diverse backgrounds.

Divya Shankar MD
Section Fellow-in-Training

Muhammad Hayat-Syed MD
Section Vice Chair

Critical Care Network

Nonrespiratory Critical Care Section

Goals-of-care discussions are essential to management of the intensive care unit (ICU) patient. Racial inequities in end-of-life decision making have been documented for many years, with literature demonstrating that marginalized populations are less likely to have EHR-documented goals-of-care discussions and more likely to have concerns regarding clinician communication.

A recently published randomized control trial in JAMA highlights an intervention that offers promise in addressing disparities in goals-of-care conversations. Curtis, et al. studied whether priming physicians with a communication guide advising on discussion prompts and language for goals-of-care could improve the rate of documented goals-of-care discussions among hospitalized older adults with serious illness. The study found that for patients in the intervention arm, there was a significant increase in proportion of goals-of-care discussions within 30 days. Notably, the difference in documented goals-of-care discussions between arms was greater in the subgroup of patients from underserved groups (Curtis JR, et al. JAMA. 2023;329[23]:2028-37).

Nevertheless, while interventions may help increase the rate of goals-of-care discussions, it is also important to address the content of discussions themselves. You and colleagues recently published a mixed-methods study assessing the impact of race on shared decision-making behaviors during family/caregiver meetings. The authors found that while ICU physicians approached shared decision making with White and Black families similarly, Black families felt their physicians provided less validation of the family role in decision making than White families did (You H, et al. Ann Am Thorac Soc. 2023 May;20[5]:759-62). These findings highlight the importance of ongoing work that focuses not only on quantity but also on quality of communication regarding goals-of-care for patients from diverse backgrounds.

Divya Shankar MD
Section Fellow-in-Training

Muhammad Hayat-Syed MD
Section Vice Chair

Diffuse Lung Disease & Transplant Network

Lung Transplant Section

Frailty, a concept that originated in the geriatric population, is a state of vulnerability resulting from a decline in reserve and function across physiological systems. While it is more commonly observed in older adults, some aging-associated syndromes, such as sarcopenia, impaired cognition, inflammation, and malnutrition, may be present in younger patients with end-stage organ disease. These syndromes can be associated with biological age, as opposed to chronological age, which explains why younger patients with end-stage organ disease can develop frailty (Schaenman JM, et al. Am J Transplant. 2021 Jun;21[6]:2018-24). Frailty in the lung transplant population is associated with increased morbidity and mortality while on the waitlist and post-transplant (Montgomery E, et al. J Transplant. 2020 Aug 7:3239495). In 2021, the International Society of Heart and Lung Transplantation recommended including a frailty assessment to complete a patient’s transplant evaluation. The committee cautioned using current assessment tools, as they are not yet accepted as the standard of care (Leard, et al. J Heart Lung Transplant. 2021 Nov;40[11]:1349-79). Existing tools being used evolved from studies of community-dwelling older adults with no predilection for distinct organ disease, which include the Fried Physical Frailty Phenotype (FPFP) and the Short Physical Performance Battery (SPPB). Along with physical limitations, frail patients tend to have abnormal biomarkers including higher inflammatory cytokines, such as plasma IL-6 and tumor necrosis factor receptor 1, and lower insulin-like growth factor I and leptin (Singer JP, et al. Am J Respir Crit Care Med. 2015;192[11]1325-34). The concept of a lung-focused approach to frailty, which considers biomarkers and body composition, is currently being researched (Singer JP, et al. J Heart Lung Transplant. 2023;S1053-S2498[23]00049-9). This disease-specific frailty scale would identify lung transplant candidates who may benefit from targeted interventions, and such frailty would also be expected to improve after transplant.

Erin Meier, MD
Section Fellow-in-Training

Anupam Kumar, MD, FCCP
Section Member-at-Large

Diffuse Lung Disease & Transplant Network

Lung Transplant Section

Frailty, a concept that originated in the geriatric population, is a state of vulnerability resulting from a decline in reserve and function across physiological systems. While it is more commonly observed in older adults, some aging-associated syndromes, such as sarcopenia, impaired cognition, inflammation, and malnutrition, may be present in younger patients with end-stage organ disease. These syndromes can be associated with biological age, as opposed to chronological age, which explains why younger patients with end-stage organ disease can develop frailty (Schaenman JM, et al. Am J Transplant. 2021 Jun;21[6]:2018-24). Frailty in the lung transplant population is associated with increased morbidity and mortality while on the waitlist and post-transplant (Montgomery E, et al. J Transplant. 2020 Aug 7:3239495). In 2021, the International Society of Heart and Lung Transplantation recommended including a frailty assessment to complete a patient’s transplant evaluation. The committee cautioned using current assessment tools, as they are not yet accepted as the standard of care (Leard, et al. J Heart Lung Transplant. 2021 Nov;40[11]:1349-79). Existing tools being used evolved from studies of community-dwelling older adults with no predilection for distinct organ disease, which include the Fried Physical Frailty Phenotype (FPFP) and the Short Physical Performance Battery (SPPB). Along with physical limitations, frail patients tend to have abnormal biomarkers including higher inflammatory cytokines, such as plasma IL-6 and tumor necrosis factor receptor 1, and lower insulin-like growth factor I and leptin (Singer JP, et al. Am J Respir Crit Care Med. 2015;192[11]1325-34). The concept of a lung-focused approach to frailty, which considers biomarkers and body composition, is currently being researched (Singer JP, et al. J Heart Lung Transplant. 2023;S1053-S2498[23]00049-9). This disease-specific frailty scale would identify lung transplant candidates who may benefit from targeted interventions, and such frailty would also be expected to improve after transplant.

Erin Meier, MD
Section Fellow-in-Training

Anupam Kumar, MD, FCCP
Section Member-at-Large

Diffuse Lung Disease & Transplant Network

Lung Transplant Section

Frailty, a concept that originated in the geriatric population, is a state of vulnerability resulting from a decline in reserve and function across physiological systems. While it is more commonly observed in older adults, some aging-associated syndromes, such as sarcopenia, impaired cognition, inflammation, and malnutrition, may be present in younger patients with end-stage organ disease. These syndromes can be associated with biological age, as opposed to chronological age, which explains why younger patients with end-stage organ disease can develop frailty (Schaenman JM, et al. Am J Transplant. 2021 Jun;21[6]:2018-24). Frailty in the lung transplant population is associated with increased morbidity and mortality while on the waitlist and post-transplant (Montgomery E, et al. J Transplant. 2020 Aug 7:3239495). In 2021, the International Society of Heart and Lung Transplantation recommended including a frailty assessment to complete a patient’s transplant evaluation. The committee cautioned using current assessment tools, as they are not yet accepted as the standard of care (Leard, et al. J Heart Lung Transplant. 2021 Nov;40[11]:1349-79). Existing tools being used evolved from studies of community-dwelling older adults with no predilection for distinct organ disease, which include the Fried Physical Frailty Phenotype (FPFP) and the Short Physical Performance Battery (SPPB). Along with physical limitations, frail patients tend to have abnormal biomarkers including higher inflammatory cytokines, such as plasma IL-6 and tumor necrosis factor receptor 1, and lower insulin-like growth factor I and leptin (Singer JP, et al. Am J Respir Crit Care Med. 2015;192[11]1325-34). The concept of a lung-focused approach to frailty, which considers biomarkers and body composition, is currently being researched (Singer JP, et al. J Heart Lung Transplant. 2023;S1053-S2498[23]00049-9). This disease-specific frailty scale would identify lung transplant candidates who may benefit from targeted interventions, and such frailty would also be expected to improve after transplant.

Erin Meier, MD
Section Fellow-in-Training

Anupam Kumar, MD, FCCP
Section Member-at-Large

Airway Disorders Network

Bronchiectasis Section

Bronchiectasis is a chronic inflammatory lung disease characterized by the progressive destruction of the airways and persistent inflammation. In bronchiectasis, excessive neutrophil accumulation in the airways leads to release of neutrophil serine proteases (NSPs), which contributes to tissue damage and perpetuates the inflammatory process in the lungs. The three main NSPs include neutrophil elastase (NE), proteinase3, and cathepsin G. Elevations in NE activity in sputum in NCFBE are associated with increased exacerbations and declines in lung function. Dipeptidyl peptidase 1 (DPP1), an enzyme primarily found in neutrophils, is responsible for activating NSPs during neutrophil maturation. In bronchiectasis, increased DPP1 activity results in an augmented production of active NSPs, exacerbating lung damage and inflammation.

Brensocatib, an oral, reversible inhibitor of DPP1 is currently being developed as a novel approach to managing bronchiectasis. Brensocatib was evaluated in a phase 2 clinical trial (WILLOW), a randomized, double-blind, placebo-controlled trial involving adults with non–cystic fibrosis bronchiectasis (NCFBE). Treatment with brensocatib for 24 weeks significantly prolonged the time to the first exacerbation at both the 10 mg and 25 mg doses and lowered the risk of exacerbation by 40% relative to placebo. The treatment was well tolerated, with no significant safety concerns. Results of a recent post hoc analysis from the WILLOW study show that brensocatib effectively reduces exacerbations and slows lung function decline across different severities of bronchiectasis. These findings suggest that brensocatib holds potential as the 1st new therapeutic option for patients with NCFBE, with currently no FDA-approved drugs. Results of a larger-scale phase 3 trial are awaited later this year, which will hopefully confirm these results and ascertain the long-term safety.

Shyamsunder Subramanian, MD, MBBS, FCCP
Section Chair

Airway Disorders Network

Bronchiectasis Section

Bronchiectasis is a chronic inflammatory lung disease characterized by the progressive destruction of the airways and persistent inflammation. In bronchiectasis, excessive neutrophil accumulation in the airways leads to release of neutrophil serine proteases (NSPs), which contributes to tissue damage and perpetuates the inflammatory process in the lungs. The three main NSPs include neutrophil elastase (NE), proteinase3, and cathepsin G. Elevations in NE activity in sputum in NCFBE are associated with increased exacerbations and declines in lung function. Dipeptidyl peptidase 1 (DPP1), an enzyme primarily found in neutrophils, is responsible for activating NSPs during neutrophil maturation. In bronchiectasis, increased DPP1 activity results in an augmented production of active NSPs, exacerbating lung damage and inflammation.

Brensocatib, an oral, reversible inhibitor of DPP1 is currently being developed as a novel approach to managing bronchiectasis. Brensocatib was evaluated in a phase 2 clinical trial (WILLOW), a randomized, double-blind, placebo-controlled trial involving adults with non–cystic fibrosis bronchiectasis (NCFBE). Treatment with brensocatib for 24 weeks significantly prolonged the time to the first exacerbation at both the 10 mg and 25 mg doses and lowered the risk of exacerbation by 40% relative to placebo. The treatment was well tolerated, with no significant safety concerns. Results of a recent post hoc analysis from the WILLOW study show that brensocatib effectively reduces exacerbations and slows lung function decline across different severities of bronchiectasis. These findings suggest that brensocatib holds potential as the 1st new therapeutic option for patients with NCFBE, with currently no FDA-approved drugs. Results of a larger-scale phase 3 trial are awaited later this year, which will hopefully confirm these results and ascertain the long-term safety.

Shyamsunder Subramanian, MD, MBBS, FCCP
Section Chair

Airway Disorders Network

Bronchiectasis Section

Bronchiectasis is a chronic inflammatory lung disease characterized by the progressive destruction of the airways and persistent inflammation. In bronchiectasis, excessive neutrophil accumulation in the airways leads to release of neutrophil serine proteases (NSPs), which contributes to tissue damage and perpetuates the inflammatory process in the lungs. The three main NSPs include neutrophil elastase (NE), proteinase3, and cathepsin G. Elevations in NE activity in sputum in NCFBE are associated with increased exacerbations and declines in lung function. Dipeptidyl peptidase 1 (DPP1), an enzyme primarily found in neutrophils, is responsible for activating NSPs during neutrophil maturation. In bronchiectasis, increased DPP1 activity results in an augmented production of active NSPs, exacerbating lung damage and inflammation.

Brensocatib, an oral, reversible inhibitor of DPP1 is currently being developed as a novel approach to managing bronchiectasis. Brensocatib was evaluated in a phase 2 clinical trial (WILLOW), a randomized, double-blind, placebo-controlled trial involving adults with non–cystic fibrosis bronchiectasis (NCFBE). Treatment with brensocatib for 24 weeks significantly prolonged the time to the first exacerbation at both the 10 mg and 25 mg doses and lowered the risk of exacerbation by 40% relative to placebo. The treatment was well tolerated, with no significant safety concerns. Results of a recent post hoc analysis from the WILLOW study show that brensocatib effectively reduces exacerbations and slows lung function decline across different severities of bronchiectasis. These findings suggest that brensocatib holds potential as the 1st new therapeutic option for patients with NCFBE, with currently no FDA-approved drugs. Results of a larger-scale phase 3 trial are awaited later this year, which will hopefully confirm these results and ascertain the long-term safety.

Shyamsunder Subramanian, MD, MBBS, FCCP
Section Chair

After much anticipation, the inaugural issues of both CHEST^®Critical Care and CHEST^®Pulmonary officially launched in late June. These new open access additions to the journal CHEST^® portfolio feature content that is permanently and freely available online for all – promoting transparency, inclusiveness, and collaboration in research – and offer authors more avenues to share their practice-changing research.

The first issue of CHEST Critical Care featured research into ICU mortality across prepandemic and pandemic cohorts in resource-limited settings in South Africa, an exploration into symptom trajectory in recipients of hematopoietic stem-cell transplantation, a narrative review of post-intensive care syndrome, and an investigation into early echocardiographic and ultrasonographic findings in critically ill patients with COVID-19.

In addition, an editorial from Hayley Gershengorn, MD, Editor in Chief of CHEST Critical Care, offers readers more insights into the need for a publication focused on the breadth of clinical topics in critical care and her goals for the new publication.

“I’m ecstatic for this launch. We are grateful to our authors for the trust they put in us and are excited to share their work with our critical care colleagues around the world,” Dr. Gershengorn said. “The editorial team and the American College of Chest Physicians staff have worked tirelessly on this journal, and it’s incredibly gratifying to see the first issue publish.”

Read the full issue and new research from the journal at www.chestcc.org.

In his own editorial featured in the inaugural issue of CHEST Pulmonary, Editor in Chief Matthew Miles, MD, MEd, FCCP, shares how the flagship journal’s proud heritage of sharing impactful clinical research – and the need to target areas of pulmonary and sleep medicine research not covered by other journals – inspired the creation of this new publication.

The issue also includes research into mobile health opportunities for asthma management, an exploration into telemedicine for patients with interstitial lung diseases, an in-depth review into the rare and often underdiagnosed disorder primary ciliary dyskinesia, research on the impact of the social vulnerability index on pulmonary embolism mortality, and an investigation into pneumothorax complications after percutaneous lung biopsy.

“I am deeply grateful to our authors, reviewers, editorial board, and staff who have contributed to the launch of our first issue,” Dr. Miles said. “The journal CHEST is known for excellence in clinically relevant research and patient management guidance. CHEST Pulmonary expands the CHEST portfolio with additional opportunity for researchers to share their work in an exclusively open access format to reach the broadest possible audience. I know our readers will enjoy learning from the research and reviews in issue one.”

Review the full issue and new articles from CHEST Pulmonary at www.chestpulmonary.org.

After much anticipation, the inaugural issues of both CHEST^®Critical Care and CHEST^®Pulmonary officially launched in late June. These new open access additions to the journal CHEST^® portfolio feature content that is permanently and freely available online for all – promoting transparency, inclusiveness, and collaboration in research – and offer authors more avenues to share their practice-changing research.

The first issue of CHEST Critical Care featured research into ICU mortality across prepandemic and pandemic cohorts in resource-limited settings in South Africa, an exploration into symptom trajectory in recipients of hematopoietic stem-cell transplantation, a narrative review of post-intensive care syndrome, and an investigation into early echocardiographic and ultrasonographic findings in critically ill patients with COVID-19.

In addition, an editorial from Hayley Gershengorn, MD, Editor in Chief of CHEST Critical Care, offers readers more insights into the need for a publication focused on the breadth of clinical topics in critical care and her goals for the new publication.

“I’m ecstatic for this launch. We are grateful to our authors for the trust they put in us and are excited to share their work with our critical care colleagues around the world,” Dr. Gershengorn said. “The editorial team and the American College of Chest Physicians staff have worked tirelessly on this journal, and it’s incredibly gratifying to see the first issue publish.”

Read the full issue and new research from the journal at www.chestcc.org.

In his own editorial featured in the inaugural issue of CHEST Pulmonary, Editor in Chief Matthew Miles, MD, MEd, FCCP, shares how the flagship journal’s proud heritage of sharing impactful clinical research – and the need to target areas of pulmonary and sleep medicine research not covered by other journals – inspired the creation of this new publication.

The issue also includes research into mobile health opportunities for asthma management, an exploration into telemedicine for patients with interstitial lung diseases, an in-depth review into the rare and often underdiagnosed disorder primary ciliary dyskinesia, research on the impact of the social vulnerability index on pulmonary embolism mortality, and an investigation into pneumothorax complications after percutaneous lung biopsy.

“I am deeply grateful to our authors, reviewers, editorial board, and staff who have contributed to the launch of our first issue,” Dr. Miles said. “The journal CHEST is known for excellence in clinically relevant research and patient management guidance. CHEST Pulmonary expands the CHEST portfolio with additional opportunity for researchers to share their work in an exclusively open access format to reach the broadest possible audience. I know our readers will enjoy learning from the research and reviews in issue one.”

Review the full issue and new articles from CHEST Pulmonary at www.chestpulmonary.org.

After much anticipation, the inaugural issues of both CHEST^®Critical Care and CHEST^®Pulmonary officially launched in late June. These new open access additions to the journal CHEST^® portfolio feature content that is permanently and freely available online for all – promoting transparency, inclusiveness, and collaboration in research – and offer authors more avenues to share their practice-changing research.

The first issue of CHEST Critical Care featured research into ICU mortality across prepandemic and pandemic cohorts in resource-limited settings in South Africa, an exploration into symptom trajectory in recipients of hematopoietic stem-cell transplantation, a narrative review of post-intensive care syndrome, and an investigation into early echocardiographic and ultrasonographic findings in critically ill patients with COVID-19.

In addition, an editorial from Hayley Gershengorn, MD, Editor in Chief of CHEST Critical Care, offers readers more insights into the need for a publication focused on the breadth of clinical topics in critical care and her goals for the new publication.

“I’m ecstatic for this launch. We are grateful to our authors for the trust they put in us and are excited to share their work with our critical care colleagues around the world,” Dr. Gershengorn said. “The editorial team and the American College of Chest Physicians staff have worked tirelessly on this journal, and it’s incredibly gratifying to see the first issue publish.”

Read the full issue and new research from the journal at www.chestcc.org.

In his own editorial featured in the inaugural issue of CHEST Pulmonary, Editor in Chief Matthew Miles, MD, MEd, FCCP, shares how the flagship journal’s proud heritage of sharing impactful clinical research – and the need to target areas of pulmonary and sleep medicine research not covered by other journals – inspired the creation of this new publication.

The issue also includes research into mobile health opportunities for asthma management, an exploration into telemedicine for patients with interstitial lung diseases, an in-depth review into the rare and often underdiagnosed disorder primary ciliary dyskinesia, research on the impact of the social vulnerability index on pulmonary embolism mortality, and an investigation into pneumothorax complications after percutaneous lung biopsy.

“I am deeply grateful to our authors, reviewers, editorial board, and staff who have contributed to the launch of our first issue,” Dr. Miles said. “The journal CHEST is known for excellence in clinically relevant research and patient management guidance. CHEST Pulmonary expands the CHEST portfolio with additional opportunity for researchers to share their work in an exclusively open access format to reach the broadest possible audience. I know our readers will enjoy learning from the research and reviews in issue one.”

Review the full issue and new articles from CHEST Pulmonary at www.chestpulmonary.org.

Dr. Hossri and Dr. Ivashchuk are with UTHealth Houston –Texas Medical Center, Department of Internal Medicine; Division of Pulmonary, Critical Care, and Sleep Medicine.

As new treatments for specific moderate to severe asthma phenotypes have been developed, management decisions have grown more complicated. The treatment indications for asthma are clear; however, there is overlap with certain therapeutics that target the same pathway with similar end results. In the past decade, research to help providers decide which biologic therapy to use for defined cases has increased. It is now customary to call such treatment “tailored therapy” because it is not a one-size-fits-all approach that follows a rigid algorithm. Instead, it is a customized treatment plan that accounts for patient-specific risk factors and comorbidities.

Comorbidities commonly associated with asthma include atopic dermatitis, chronic rhinosinusitis with nasal polyposis, eosinophilic granulomatosis with polyangiitis, eosinophilic esophagitis, bronchiectasis and allergic bronchopulmonary aspergillosis. While we lack consensus or a universally accepted treatment algorithm for treating asthma when these comorbidities are present, recent evidence helps guide us to which therapies work best.
 

Atopic dermatitis

There is a higher prevalence of asthma in patients with atopic dermatitis. A concept called the “atopic march” refers to the progression of childhood atopic dermatitis to manifestations such as asthma, food allergies, and hay fever. The more severe the atopic dermatitis is in childhood, the higher the risk for asthma later on in life. The data on the biologic pathogenesis of atopic dermatitis point to the involvement of interleukins – interleukin (IL)-4 and IL 13 (Silverberg JI. Ann Allergy Asthma Immunol. 2019;123[2]:144-51).

CHEST

These same interleukins are active in what is called “Th2-high” asthma. The activation of Th2 cells in the inflammatory pathway occurs in atopic dermatitis and asthma irrespective of immunoglobulin E levels. Preliminary data show therapies that target IL-13 alone are effective for treating asthma with comorbid atopic dermatitis but those blocking both IL-4 and IL-13, like dupilumab, are superior. Both interleukins are considered pivotal in the Th-2 pathway. This suggests that dual inhibition is an integral component in the treatment of moderate to severe atopic dermatitis with asthma. Analysis of other Th2 mediators, such as mepolizumab (IL-5 antagonist) and omalizumab (anti-IgE) have shown minimal efficacy, further supporting the use of dupilumab (Guttman-Yassky E, et al. J Allergy Clin. Immunol. 2019 Jan;143[1]:155-72).

Chronic rhinosinusitis with nasal polyposis

The “unified airway” concept holds that because the upper airways (nasal mucosa, pharynx, and larynx) are in direct communication with the lower airways (bronchi and bronchioles). This would explain the correlation between chronic rhinosinusitis with nasal polyposis (CRSwNP) and asthma. Many studies also show the severity of one disease increases the severity of the other.

CHEST

Patients with both CRSwNP and asthma typically experience a more treatment-resistant course characterized by higher rates of corticosteroid dependence and nasal polyposis recurrences when compared with asthma alone (Laidlaw TM, et al. J Allergy Clin Immunol. 2021 Mar;9[3]:1133-41). They typically have Th2-high asthma and are usually eosinophilic. The optimal treatment approach is mindful of the unified airway concept. Large-scale studies demonstrate significant benefit when targeting IL-5, especially in those with bilateral nasal polyps, need for systemic steroids in the past 2 years, significant impairment in quality of life, loss of smell, and a concomitant diagnosis of asthma (Fokkens WJ, et al. Allergy. 2019 Dec;74[12]:2312). Although data are inconsistent, there is enough evidence to suggest dupilumab be considered for those with eosinophilic asthma and CRSwNP along with atopy, atopic dermatitis, and/or high FeNO levels. In those without atopic symptoms, an anti-IL5/anti-IL5R (mainly mepolizumab and benralizumab) is preferred. Having said this, direct comparative analyses between biologics are lacking, and the above approach relies on an indirect assessment of existing data coupled with clinical experience. The approach may change as new data become available.

Eosinophilic granulomatosis with polyangiitis

Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by disseminated necrotizing eosinophilic granulomas. EGPA is driven by a response similar to that seen in Th2-high asthma. Adult-onset asthma with sinusitis and allergic rhinitis is the most common EGPA presentation. Of all the biologics, mepolizumab has been best studied as treatment for those with EGPA and asthma symptoms. One small study demonstrated disease remission in 8 of 10 cases (Moosig F, et al. Ann Intern Med. 2011 Sep 6;155[5]:341-3). However, many of these patients relapsed after discontinuing therapy.

Eosinophilic esophagitis

Recent reports demonstrated a large portion of adults with a

diagnosis of eosinophilic

esophagitis (EoE) also have a history of asthma. Currently, standard treatment is proton pump

inhibitors and diet modifications. The prevalence of EoE has increased with growing awareness of the disease. Unrecognized and untreated EoE can lead to devastating complications such as esophageal fibrosis, strictures, and food impaction. Similar to some of the above-mentioned syndromes,

EoE is also driven by a Th2 response and eosinophilic inflammation. A recent study in 2022 showed that 31% to 38% of

people with EoE had concomitant asthma (Dellon ES, et al. N Engl J Med. 2022 Dec 22;387 [25]:2317-30). In this population, a weekly dose of dupilumab, 300 mg, led

to a significant improvement in dysphagia symptoms and

histology when compared with placebo.

Allergic bronchopulmonary aspergillosis

Despite its low prevalence worldwide, allergic bronchopulmonary aspergillosis (ABPA) is frequently encountered when managing severe asthma. Current treatment is long-term, relatively high dose systemic corticosteroids. In light of their unfavorable side effect profile, steroid-sparing approaches are being sought. Dupilumab, omalizumab, mepolizumab, and benralizumab have all been tested for their effects on ABPA. Thus far, mepolizumab has the most convincing evidence to support its use for asthma with concomitant ABPA, mainly because it has the most rapid onset of action. Up to 90% of patients with ABPA were able to stop systemic steroids between 2 and 14 months after starting mepolizumab (Schleich F, et al. J Allergy Clin Immunol. 2020 Jul-Aug;8[7]:2412-3.e2).

Bronchiectasis

Asthma and bronchiectasis can coexist in up to 77% of patients. Typically, the pathophysiology behind bronchiectasis is focused around neutrophilic inflammation. New evidence suggests some patients with bronchiectasis, usually in the setting of comorbid adult-onset asthma, demonstrate an eosinophilic Th-2 response. The association is seen more commonly in female patients, the elderly, and nonsmokers. A small prospective study with four patients with severe asthma and bronchiectasis showed significant improvement with less exacerbations, increased pre-bronchodilator FEV₁, and a reduction of serum and sputum eosinophils after starting mepolizumab treatment (Carpagnano GE, et al. J Asthma Allergy. 2019 Mar 5;12:83-90). Clinical trials designed to clarify the role for biologics for asthma with co-morbid bronchiectasis are currently underway.

Dr. Hossri and Dr. Ivashchuk are with UTHealth Houston –Texas Medical Center, Department of Internal Medicine; Division of Pulmonary, Critical Care, and Sleep Medicine.

As new treatments for specific moderate to severe asthma phenotypes have been developed, management decisions have grown more complicated. The treatment indications for asthma are clear; however, there is overlap with certain therapeutics that target the same pathway with similar end results. In the past decade, research to help providers decide which biologic therapy to use for defined cases has increased. It is now customary to call such treatment “tailored therapy” because it is not a one-size-fits-all approach that follows a rigid algorithm. Instead, it is a customized treatment plan that accounts for patient-specific risk factors and comorbidities.

Comorbidities commonly associated with asthma include atopic dermatitis, chronic rhinosinusitis with nasal polyposis, eosinophilic granulomatosis with polyangiitis, eosinophilic esophagitis, bronchiectasis and allergic bronchopulmonary aspergillosis. While we lack consensus or a universally accepted treatment algorithm for treating asthma when these comorbidities are present, recent evidence helps guide us to which therapies work best.
 

Atopic dermatitis

There is a higher prevalence of asthma in patients with atopic dermatitis. A concept called the “atopic march” refers to the progression of childhood atopic dermatitis to manifestations such as asthma, food allergies, and hay fever. The more severe the atopic dermatitis is in childhood, the higher the risk for asthma later on in life. The data on the biologic pathogenesis of atopic dermatitis point to the involvement of interleukins – interleukin (IL)-4 and IL 13 (Silverberg JI. Ann Allergy Asthma Immunol. 2019;123[2]:144-51).

CHEST

These same interleukins are active in what is called “Th2-high” asthma. The activation of Th2 cells in the inflammatory pathway occurs in atopic dermatitis and asthma irrespective of immunoglobulin E levels. Preliminary data show therapies that target IL-13 alone are effective for treating asthma with comorbid atopic dermatitis but those blocking both IL-4 and IL-13, like dupilumab, are superior. Both interleukins are considered pivotal in the Th-2 pathway. This suggests that dual inhibition is an integral component in the treatment of moderate to severe atopic dermatitis with asthma. Analysis of other Th2 mediators, such as mepolizumab (IL-5 antagonist) and omalizumab (anti-IgE) have shown minimal efficacy, further supporting the use of dupilumab (Guttman-Yassky E, et al. J Allergy Clin. Immunol. 2019 Jan;143[1]:155-72).

Chronic rhinosinusitis with nasal polyposis

The “unified airway” concept holds that because the upper airways (nasal mucosa, pharynx, and larynx) are in direct communication with the lower airways (bronchi and bronchioles). This would explain the correlation between chronic rhinosinusitis with nasal polyposis (CRSwNP) and asthma. Many studies also show the severity of one disease increases the severity of the other.

CHEST

Patients with both CRSwNP and asthma typically experience a more treatment-resistant course characterized by higher rates of corticosteroid dependence and nasal polyposis recurrences when compared with asthma alone (Laidlaw TM, et al. J Allergy Clin Immunol. 2021 Mar;9[3]:1133-41). They typically have Th2-high asthma and are usually eosinophilic. The optimal treatment approach is mindful of the unified airway concept. Large-scale studies demonstrate significant benefit when targeting IL-5, especially in those with bilateral nasal polyps, need for systemic steroids in the past 2 years, significant impairment in quality of life, loss of smell, and a concomitant diagnosis of asthma (Fokkens WJ, et al. Allergy. 2019 Dec;74[12]:2312). Although data are inconsistent, there is enough evidence to suggest dupilumab be considered for those with eosinophilic asthma and CRSwNP along with atopy, atopic dermatitis, and/or high FeNO levels. In those without atopic symptoms, an anti-IL5/anti-IL5R (mainly mepolizumab and benralizumab) is preferred. Having said this, direct comparative analyses between biologics are lacking, and the above approach relies on an indirect assessment of existing data coupled with clinical experience. The approach may change as new data become available.

Eosinophilic granulomatosis with polyangiitis

Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by disseminated necrotizing eosinophilic granulomas. EGPA is driven by a response similar to that seen in Th2-high asthma. Adult-onset asthma with sinusitis and allergic rhinitis is the most common EGPA presentation. Of all the biologics, mepolizumab has been best studied as treatment for those with EGPA and asthma symptoms. One small study demonstrated disease remission in 8 of 10 cases (Moosig F, et al. Ann Intern Med. 2011 Sep 6;155[5]:341-3). However, many of these patients relapsed after discontinuing therapy.

Eosinophilic esophagitis

Recent reports demonstrated a large portion of adults with a

diagnosis of eosinophilic

esophagitis (EoE) also have a history of asthma. Currently, standard treatment is proton pump

inhibitors and diet modifications. The prevalence of EoE has increased with growing awareness of the disease. Unrecognized and untreated EoE can lead to devastating complications such as esophageal fibrosis, strictures, and food impaction. Similar to some of the above-mentioned syndromes,

EoE is also driven by a Th2 response and eosinophilic inflammation. A recent study in 2022 showed that 31% to 38% of

people with EoE had concomitant asthma (Dellon ES, et al. N Engl J Med. 2022 Dec 22;387 [25]:2317-30). In this population, a weekly dose of dupilumab, 300 mg, led

to a significant improvement in dysphagia symptoms and

histology when compared with placebo.

Allergic bronchopulmonary aspergillosis

Despite its low prevalence worldwide, allergic bronchopulmonary aspergillosis (ABPA) is frequently encountered when managing severe asthma. Current treatment is long-term, relatively high dose systemic corticosteroids. In light of their unfavorable side effect profile, steroid-sparing approaches are being sought. Dupilumab, omalizumab, mepolizumab, and benralizumab have all been tested for their effects on ABPA. Thus far, mepolizumab has the most convincing evidence to support its use for asthma with concomitant ABPA, mainly because it has the most rapid onset of action. Up to 90% of patients with ABPA were able to stop systemic steroids between 2 and 14 months after starting mepolizumab (Schleich F, et al. J Allergy Clin Immunol. 2020 Jul-Aug;8[7]:2412-3.e2).

Bronchiectasis

Asthma and bronchiectasis can coexist in up to 77% of patients. Typically, the pathophysiology behind bronchiectasis is focused around neutrophilic inflammation. New evidence suggests some patients with bronchiectasis, usually in the setting of comorbid adult-onset asthma, demonstrate an eosinophilic Th-2 response. The association is seen more commonly in female patients, the elderly, and nonsmokers. A small prospective study with four patients with severe asthma and bronchiectasis showed significant improvement with less exacerbations, increased pre-bronchodilator FEV₁, and a reduction of serum and sputum eosinophils after starting mepolizumab treatment (Carpagnano GE, et al. J Asthma Allergy. 2019 Mar 5;12:83-90). Clinical trials designed to clarify the role for biologics for asthma with co-morbid bronchiectasis are currently underway.

Dr. Hossri and Dr. Ivashchuk are with UTHealth Houston –Texas Medical Center, Department of Internal Medicine; Division of Pulmonary, Critical Care, and Sleep Medicine.

As new treatments for specific moderate to severe asthma phenotypes have been developed, management decisions have grown more complicated. The treatment indications for asthma are clear; however, there is overlap with certain therapeutics that target the same pathway with similar end results. In the past decade, research to help providers decide which biologic therapy to use for defined cases has increased. It is now customary to call such treatment “tailored therapy” because it is not a one-size-fits-all approach that follows a rigid algorithm. Instead, it is a customized treatment plan that accounts for patient-specific risk factors and comorbidities.

Comorbidities commonly associated with asthma include atopic dermatitis, chronic rhinosinusitis with nasal polyposis, eosinophilic granulomatosis with polyangiitis, eosinophilic esophagitis, bronchiectasis and allergic bronchopulmonary aspergillosis. While we lack consensus or a universally accepted treatment algorithm for treating asthma when these comorbidities are present, recent evidence helps guide us to which therapies work best.
 

Atopic dermatitis

There is a higher prevalence of asthma in patients with atopic dermatitis. A concept called the “atopic march” refers to the progression of childhood atopic dermatitis to manifestations such as asthma, food allergies, and hay fever. The more severe the atopic dermatitis is in childhood, the higher the risk for asthma later on in life. The data on the biologic pathogenesis of atopic dermatitis point to the involvement of interleukins – interleukin (IL)-4 and IL 13 (Silverberg JI. Ann Allergy Asthma Immunol. 2019;123[2]:144-51).

CHEST

These same interleukins are active in what is called “Th2-high” asthma. The activation of Th2 cells in the inflammatory pathway occurs in atopic dermatitis and asthma irrespective of immunoglobulin E levels. Preliminary data show therapies that target IL-13 alone are effective for treating asthma with comorbid atopic dermatitis but those blocking both IL-4 and IL-13, like dupilumab, are superior. Both interleukins are considered pivotal in the Th-2 pathway. This suggests that dual inhibition is an integral component in the treatment of moderate to severe atopic dermatitis with asthma. Analysis of other Th2 mediators, such as mepolizumab (IL-5 antagonist) and omalizumab (anti-IgE) have shown minimal efficacy, further supporting the use of dupilumab (Guttman-Yassky E, et al. J Allergy Clin. Immunol. 2019 Jan;143[1]:155-72).

Chronic rhinosinusitis with nasal polyposis

The “unified airway” concept holds that because the upper airways (nasal mucosa, pharynx, and larynx) are in direct communication with the lower airways (bronchi and bronchioles). This would explain the correlation between chronic rhinosinusitis with nasal polyposis (CRSwNP) and asthma. Many studies also show the severity of one disease increases the severity of the other.

CHEST

Patients with both CRSwNP and asthma typically experience a more treatment-resistant course characterized by higher rates of corticosteroid dependence and nasal polyposis recurrences when compared with asthma alone (Laidlaw TM, et al. J Allergy Clin Immunol. 2021 Mar;9[3]:1133-41). They typically have Th2-high asthma and are usually eosinophilic. The optimal treatment approach is mindful of the unified airway concept. Large-scale studies demonstrate significant benefit when targeting IL-5, especially in those with bilateral nasal polyps, need for systemic steroids in the past 2 years, significant impairment in quality of life, loss of smell, and a concomitant diagnosis of asthma (Fokkens WJ, et al. Allergy. 2019 Dec;74[12]:2312). Although data are inconsistent, there is enough evidence to suggest dupilumab be considered for those with eosinophilic asthma and CRSwNP along with atopy, atopic dermatitis, and/or high FeNO levels. In those without atopic symptoms, an anti-IL5/anti-IL5R (mainly mepolizumab and benralizumab) is preferred. Having said this, direct comparative analyses between biologics are lacking, and the above approach relies on an indirect assessment of existing data coupled with clinical experience. The approach may change as new data become available.

Eosinophilic granulomatosis with polyangiitis

Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by disseminated necrotizing eosinophilic granulomas. EGPA is driven by a response similar to that seen in Th2-high asthma. Adult-onset asthma with sinusitis and allergic rhinitis is the most common EGPA presentation. Of all the biologics, mepolizumab has been best studied as treatment for those with EGPA and asthma symptoms. One small study demonstrated disease remission in 8 of 10 cases (Moosig F, et al. Ann Intern Med. 2011 Sep 6;155[5]:341-3). However, many of these patients relapsed after discontinuing therapy.

Eosinophilic esophagitis

Recent reports demonstrated a large portion of adults with a

diagnosis of eosinophilic

esophagitis (EoE) also have a history of asthma. Currently, standard treatment is proton pump

inhibitors and diet modifications. The prevalence of EoE has increased with growing awareness of the disease. Unrecognized and untreated EoE can lead to devastating complications such as esophageal fibrosis, strictures, and food impaction. Similar to some of the above-mentioned syndromes,

EoE is also driven by a Th2 response and eosinophilic inflammation. A recent study in 2022 showed that 31% to 38% of

people with EoE had concomitant asthma (Dellon ES, et al. N Engl J Med. 2022 Dec 22;387 [25]:2317-30). In this population, a weekly dose of dupilumab, 300 mg, led

to a significant improvement in dysphagia symptoms and

histology when compared with placebo.

Allergic bronchopulmonary aspergillosis

Despite its low prevalence worldwide, allergic bronchopulmonary aspergillosis (ABPA) is frequently encountered when managing severe asthma. Current treatment is long-term, relatively high dose systemic corticosteroids. In light of their unfavorable side effect profile, steroid-sparing approaches are being sought. Dupilumab, omalizumab, mepolizumab, and benralizumab have all been tested for their effects on ABPA. Thus far, mepolizumab has the most convincing evidence to support its use for asthma with concomitant ABPA, mainly because it has the most rapid onset of action. Up to 90% of patients with ABPA were able to stop systemic steroids between 2 and 14 months after starting mepolizumab (Schleich F, et al. J Allergy Clin Immunol. 2020 Jul-Aug;8[7]:2412-3.e2).

Bronchiectasis

Asthma and bronchiectasis can coexist in up to 77% of patients. Typically, the pathophysiology behind bronchiectasis is focused around neutrophilic inflammation. New evidence suggests some patients with bronchiectasis, usually in the setting of comorbid adult-onset asthma, demonstrate an eosinophilic Th-2 response. The association is seen more commonly in female patients, the elderly, and nonsmokers. A small prospective study with four patients with severe asthma and bronchiectasis showed significant improvement with less exacerbations, increased pre-bronchodilator FEV₁, and a reduction of serum and sputum eosinophils after starting mepolizumab treatment (Carpagnano GE, et al. J Asthma Allergy. 2019 Mar 5;12:83-90). Clinical trials designed to clarify the role for biologics for asthma with co-morbid bronchiectasis are currently underway.

Cardiogenic shock (CS) is being recognized more often in critically ill patients. This increased prevalence is likely due to a better understanding of CS and the benefit of improving cardiac output (CO) to ensure adequate oxygen delivery (DO₂). There is no one specific definition of CS; rather, CS describes a clinical condition in which a patient is suffering from cellular hypoperfusion due to an ineffective CO with normal or elevating intravascular filling pressures.

CS is often, but not always, caused by a cardiac dysfunction. The heart is not able to provide adequate DO₂ to the tissues. Hypoperfusion ensues. The body attempts to compensate for the poor perfusion by increasing heart rate, vasoconstriction, and shunting blood flow to vital organs. These compensatory mechanisms worsen perfusion by increasing myocardial ischemia which further worsens cardiac dysfunction. This is known as the downward spiral of CS (Ann Intern Med. 1999 Jul 6;131[1]).

There is a number of different etiologies for CS. Historically, acute myocardial infarctions (AMI) was the most common cause. In the last 20 years, AMI-induced CS has become less prevalent due to more aggressive reperfusion strategies. CS due to etiologies such as cardiomyopathy, myocarditis, right ventricle failure, and valvular pathologies have become more common. While the overarching goal is to restore DO₂ to the tissue, the optimal treatment may differ based on the etiology of the CS. The Society for Cardiovascular Angiography and Intervention (SCAI) published CS classification stages in 2019 and then updated the stages 2022 (J Am Coll Cardiol. 2022 Mar 8;79[9]:933-46). In addition to the stages, there is now a three-axis model to address risk stratification. These classifications are a practically means of identifying and treating patients presenting with or concern for acute CS.

Stage A (At Risk) patients are not experiencing CS, but they are the at risk population. The patient’s hemodynamics, physical exam, and markers of hypoperfusion are normal. Stage A includes patients who have had a recent AMI or have heart failure.

Stage B (Beginning) patients have evidence of hemodynamic instability but are able to maintain tissue perfusion. These patients will have true or relative hypotension or tachycardia (in an attempt to maintain CO). Distal perfusion is adequate, but signs of ensuing decompensation (eg, elevated jugular venous pressure [JVP]) are present. Lactate is <2.0 mmol/L. Clinicians must be vigilant and treat these patients aggressively, so they do not decompensate further. It can be difficult to identify these patients because their blood pressure may be “normal,” but upon investigation, the blood pressure is actually a drop from the patient’s baseline.

Chronic heart failure patients with a history of depressed cardiac function will often have periods of cardiac decompensation between stages A and B. These patients are able to maintain perfusion for longer periods of time before further decompensation with hypoperfusion. If and when they do decompensate, they will often have a steep downward trajectory, so it is advantageous to the patient to be aggressive early.

Stage C (Classic) patients have evidence of tissue hypoperfusion. While these patients will often have true or relative hypotension, it is not a definition of stage C. These patients have evidence of volume overload with elevated JVP and rales throughout their lung fields. They will have poor distal perfusion and cool extremities that may become mottled. Lactate is ≥ 2 mmol/L. B-type natriuretic peptide (BNP) and liver function test (LFTs) results are elevated, and urine output is diminished. If a pulmonary arterial catheter is placed (highly recommended), the cardiac index (CI) is < 2.2 L/min/m² and the pulmonary capillary wedge pressure (PCWP) is > 15 mm Hg. These patients look like what many clinicians think of when they think of CS.

These patients need better tissue perfusion. Inotropic support is needed to augment CO and DO₂. Pharmacologic support is often the initial step. These patients also benefit from volume removal. This is usually accomplished with aggressive diuresis with a loop diuretic.

Stage D (Deteriorating) patients have failed initial treatment with single inotropic support. Hypoperfusion is not getting better and is often worsening. Lactate is staying > 2 mmol/L or rising. BNP and LFTs are also rising. These patients require additional inotropes and usually need vasopressors. Mechanical cardiac support (MCS) is often needed in addition to pharmacologic inotropic support.

Stage E (Extremis) patients have actual or impending circulatory collapse. These patients are peri-arrest with profound hypotension, lactic acidosis (often > 8 mmol/L), and unconsciousness. These patients are worsening despite multiple strategies to augment CO and DO₂. These patients will likely die without emergent veno-arterial (VA) extracorporeal membrane oxygenation (ECMO). The goal of treatment is to stabilize the patient as quickly as possible to prevent cardiac arrest.

In addition to the stage of CS, SCAI developed the three-axis model of risk stratification as a conceptual model to be used for evaluation and prognostication. Etiology and phenotype, shock severity, and risk modifiers are factors related to patient outcomes from CS. This model is a way to individualize treatment to a specific patient.

Shock severity: What is the patient’s shock stage? What are the hemodynamics and metabolic abnormalities? What are the doses of the inotropes or vasopressors? Risk goes up with higher shock stages and vasoactive agent doses and worsening metabolic disturbances or hemodynamics.

Phenotype and etiology: what is the clinical etiology of the patient’s CS? Is this acute or acute on chronic? Which ventricle is involved? Is this cardiac driven or are other organs the driving factor? Single ventricle involvement is better than bi-ventricular failure. Cardiogenic collapse due to an overdose may have a better outcome than a massive AMI.

Risk modifiers: how old is the patient? What are the comorbidities? Did the patient have a cardiac arrest? What is the patient’s mental status? Some factors are modifiable, but others are not. The concept of chronologic vs. physiologic age may come into play. A frail 40 year old with stage 4 cancer and end stage renal failure may be assessed differently than a 70 year old with mild hypertension and an AMI.

The SCAI stages of CS are a pragmatic way to assess patients with an acute presentation of CS. These stages have defined criteria and treatment recommendations for all patients. The three-axis model allows the clinician to individualize patient care based on shock severity, etiology/phenotype, and risk modification. The goal of these stages is to identify and aggressively treat patients with CS, as well as identify when treatment is failing and additional therapies may be needed.

Dr. Gaillard is Associate Professor in the Departments of Anesthesiology, Section on Critical Care; Internal Medicine, Section on Pulmonology, Critical Care, Allergy, and Immunologic Diseases; and Emergency Medicine; Wake Forest School of Medicine, Winston-Salem, N.C.

Cardiogenic shock (CS) is being recognized more often in critically ill patients. This increased prevalence is likely due to a better understanding of CS and the benefit of improving cardiac output (CO) to ensure adequate oxygen delivery (DO₂). There is no one specific definition of CS; rather, CS describes a clinical condition in which a patient is suffering from cellular hypoperfusion due to an ineffective CO with normal or elevating intravascular filling pressures.

CS is often, but not always, caused by a cardiac dysfunction. The heart is not able to provide adequate DO₂ to the tissues. Hypoperfusion ensues. The body attempts to compensate for the poor perfusion by increasing heart rate, vasoconstriction, and shunting blood flow to vital organs. These compensatory mechanisms worsen perfusion by increasing myocardial ischemia which further worsens cardiac dysfunction. This is known as the downward spiral of CS (Ann Intern Med. 1999 Jul 6;131[1]).

There is a number of different etiologies for CS. Historically, acute myocardial infarctions (AMI) was the most common cause. In the last 20 years, AMI-induced CS has become less prevalent due to more aggressive reperfusion strategies. CS due to etiologies such as cardiomyopathy, myocarditis, right ventricle failure, and valvular pathologies have become more common. While the overarching goal is to restore DO₂ to the tissue, the optimal treatment may differ based on the etiology of the CS. The Society for Cardiovascular Angiography and Intervention (SCAI) published CS classification stages in 2019 and then updated the stages 2022 (J Am Coll Cardiol. 2022 Mar 8;79[9]:933-46). In addition to the stages, there is now a three-axis model to address risk stratification. These classifications are a practically means of identifying and treating patients presenting with or concern for acute CS.

Stage A (At Risk) patients are not experiencing CS, but they are the at risk population. The patient’s hemodynamics, physical exam, and markers of hypoperfusion are normal. Stage A includes patients who have had a recent AMI or have heart failure.

Stage B (Beginning) patients have evidence of hemodynamic instability but are able to maintain tissue perfusion. These patients will have true or relative hypotension or tachycardia (in an attempt to maintain CO). Distal perfusion is adequate, but signs of ensuing decompensation (eg, elevated jugular venous pressure [JVP]) are present. Lactate is <2.0 mmol/L. Clinicians must be vigilant and treat these patients aggressively, so they do not decompensate further. It can be difficult to identify these patients because their blood pressure may be “normal,” but upon investigation, the blood pressure is actually a drop from the patient’s baseline.

Chronic heart failure patients with a history of depressed cardiac function will often have periods of cardiac decompensation between stages A and B. These patients are able to maintain perfusion for longer periods of time before further decompensation with hypoperfusion. If and when they do decompensate, they will often have a steep downward trajectory, so it is advantageous to the patient to be aggressive early.

Stage C (Classic) patients have evidence of tissue hypoperfusion. While these patients will often have true or relative hypotension, it is not a definition of stage C. These patients have evidence of volume overload with elevated JVP and rales throughout their lung fields. They will have poor distal perfusion and cool extremities that may become mottled. Lactate is ≥ 2 mmol/L. B-type natriuretic peptide (BNP) and liver function test (LFTs) results are elevated, and urine output is diminished. If a pulmonary arterial catheter is placed (highly recommended), the cardiac index (CI) is < 2.2 L/min/m² and the pulmonary capillary wedge pressure (PCWP) is > 15 mm Hg. These patients look like what many clinicians think of when they think of CS.

These patients need better tissue perfusion. Inotropic support is needed to augment CO and DO₂. Pharmacologic support is often the initial step. These patients also benefit from volume removal. This is usually accomplished with aggressive diuresis with a loop diuretic.

Stage D (Deteriorating) patients have failed initial treatment with single inotropic support. Hypoperfusion is not getting better and is often worsening. Lactate is staying > 2 mmol/L or rising. BNP and LFTs are also rising. These patients require additional inotropes and usually need vasopressors. Mechanical cardiac support (MCS) is often needed in addition to pharmacologic inotropic support.

Stage E (Extremis) patients have actual or impending circulatory collapse. These patients are peri-arrest with profound hypotension, lactic acidosis (often > 8 mmol/L), and unconsciousness. These patients are worsening despite multiple strategies to augment CO and DO₂. These patients will likely die without emergent veno-arterial (VA) extracorporeal membrane oxygenation (ECMO). The goal of treatment is to stabilize the patient as quickly as possible to prevent cardiac arrest.

In addition to the stage of CS, SCAI developed the three-axis model of risk stratification as a conceptual model to be used for evaluation and prognostication. Etiology and phenotype, shock severity, and risk modifiers are factors related to patient outcomes from CS. This model is a way to individualize treatment to a specific patient.

Shock severity: What is the patient’s shock stage? What are the hemodynamics and metabolic abnormalities? What are the doses of the inotropes or vasopressors? Risk goes up with higher shock stages and vasoactive agent doses and worsening metabolic disturbances or hemodynamics.

Phenotype and etiology: what is the clinical etiology of the patient’s CS? Is this acute or acute on chronic? Which ventricle is involved? Is this cardiac driven or are other organs the driving factor? Single ventricle involvement is better than bi-ventricular failure. Cardiogenic collapse due to an overdose may have a better outcome than a massive AMI.

Risk modifiers: how old is the patient? What are the comorbidities? Did the patient have a cardiac arrest? What is the patient’s mental status? Some factors are modifiable, but others are not. The concept of chronologic vs. physiologic age may come into play. A frail 40 year old with stage 4 cancer and end stage renal failure may be assessed differently than a 70 year old with mild hypertension and an AMI.

The SCAI stages of CS are a pragmatic way to assess patients with an acute presentation of CS. These stages have defined criteria and treatment recommendations for all patients. The three-axis model allows the clinician to individualize patient care based on shock severity, etiology/phenotype, and risk modification. The goal of these stages is to identify and aggressively treat patients with CS, as well as identify when treatment is failing and additional therapies may be needed.

Dr. Gaillard is Associate Professor in the Departments of Anesthesiology, Section on Critical Care; Internal Medicine, Section on Pulmonology, Critical Care, Allergy, and Immunologic Diseases; and Emergency Medicine; Wake Forest School of Medicine, Winston-Salem, N.C.

Cardiogenic shock (CS) is being recognized more often in critically ill patients. This increased prevalence is likely due to a better understanding of CS and the benefit of improving cardiac output (CO) to ensure adequate oxygen delivery (DO₂). There is no one specific definition of CS; rather, CS describes a clinical condition in which a patient is suffering from cellular hypoperfusion due to an ineffective CO with normal or elevating intravascular filling pressures.

CS is often, but not always, caused by a cardiac dysfunction. The heart is not able to provide adequate DO₂ to the tissues. Hypoperfusion ensues. The body attempts to compensate for the poor perfusion by increasing heart rate, vasoconstriction, and shunting blood flow to vital organs. These compensatory mechanisms worsen perfusion by increasing myocardial ischemia which further worsens cardiac dysfunction. This is known as the downward spiral of CS (Ann Intern Med. 1999 Jul 6;131[1]).

There is a number of different etiologies for CS. Historically, acute myocardial infarctions (AMI) was the most common cause. In the last 20 years, AMI-induced CS has become less prevalent due to more aggressive reperfusion strategies. CS due to etiologies such as cardiomyopathy, myocarditis, right ventricle failure, and valvular pathologies have become more common. While the overarching goal is to restore DO₂ to the tissue, the optimal treatment may differ based on the etiology of the CS. The Society for Cardiovascular Angiography and Intervention (SCAI) published CS classification stages in 2019 and then updated the stages 2022 (J Am Coll Cardiol. 2022 Mar 8;79[9]:933-46). In addition to the stages, there is now a three-axis model to address risk stratification. These classifications are a practically means of identifying and treating patients presenting with or concern for acute CS.

Stage A (At Risk) patients are not experiencing CS, but they are the at risk population. The patient’s hemodynamics, physical exam, and markers of hypoperfusion are normal. Stage A includes patients who have had a recent AMI or have heart failure.

Stage B (Beginning) patients have evidence of hemodynamic instability but are able to maintain tissue perfusion. These patients will have true or relative hypotension or tachycardia (in an attempt to maintain CO). Distal perfusion is adequate, but signs of ensuing decompensation (eg, elevated jugular venous pressure [JVP]) are present. Lactate is <2.0 mmol/L. Clinicians must be vigilant and treat these patients aggressively, so they do not decompensate further. It can be difficult to identify these patients because their blood pressure may be “normal,” but upon investigation, the blood pressure is actually a drop from the patient’s baseline.

Chronic heart failure patients with a history of depressed cardiac function will often have periods of cardiac decompensation between stages A and B. These patients are able to maintain perfusion for longer periods of time before further decompensation with hypoperfusion. If and when they do decompensate, they will often have a steep downward trajectory, so it is advantageous to the patient to be aggressive early.

Stage C (Classic) patients have evidence of tissue hypoperfusion. While these patients will often have true or relative hypotension, it is not a definition of stage C. These patients have evidence of volume overload with elevated JVP and rales throughout their lung fields. They will have poor distal perfusion and cool extremities that may become mottled. Lactate is ≥ 2 mmol/L. B-type natriuretic peptide (BNP) and liver function test (LFTs) results are elevated, and urine output is diminished. If a pulmonary arterial catheter is placed (highly recommended), the cardiac index (CI) is < 2.2 L/min/m² and the pulmonary capillary wedge pressure (PCWP) is > 15 mm Hg. These patients look like what many clinicians think of when they think of CS.

These patients need better tissue perfusion. Inotropic support is needed to augment CO and DO₂. Pharmacologic support is often the initial step. These patients also benefit from volume removal. This is usually accomplished with aggressive diuresis with a loop diuretic.

Stage D (Deteriorating) patients have failed initial treatment with single inotropic support. Hypoperfusion is not getting better and is often worsening. Lactate is staying > 2 mmol/L or rising. BNP and LFTs are also rising. These patients require additional inotropes and usually need vasopressors. Mechanical cardiac support (MCS) is often needed in addition to pharmacologic inotropic support.

Stage E (Extremis) patients have actual or impending circulatory collapse. These patients are peri-arrest with profound hypotension, lactic acidosis (often > 8 mmol/L), and unconsciousness. These patients are worsening despite multiple strategies to augment CO and DO₂. These patients will likely die without emergent veno-arterial (VA) extracorporeal membrane oxygenation (ECMO). The goal of treatment is to stabilize the patient as quickly as possible to prevent cardiac arrest.

In addition to the stage of CS, SCAI developed the three-axis model of risk stratification as a conceptual model to be used for evaluation and prognostication. Etiology and phenotype, shock severity, and risk modifiers are factors related to patient outcomes from CS. This model is a way to individualize treatment to a specific patient.

Shock severity: What is the patient’s shock stage? What are the hemodynamics and metabolic abnormalities? What are the doses of the inotropes or vasopressors? Risk goes up with higher shock stages and vasoactive agent doses and worsening metabolic disturbances or hemodynamics.

Phenotype and etiology: what is the clinical etiology of the patient’s CS? Is this acute or acute on chronic? Which ventricle is involved? Is this cardiac driven or are other organs the driving factor? Single ventricle involvement is better than bi-ventricular failure. Cardiogenic collapse due to an overdose may have a better outcome than a massive AMI.

Risk modifiers: how old is the patient? What are the comorbidities? Did the patient have a cardiac arrest? What is the patient’s mental status? Some factors are modifiable, but others are not. The concept of chronologic vs. physiologic age may come into play. A frail 40 year old with stage 4 cancer and end stage renal failure may be assessed differently than a 70 year old with mild hypertension and an AMI.

The SCAI stages of CS are a pragmatic way to assess patients with an acute presentation of CS. These stages have defined criteria and treatment recommendations for all patients. The three-axis model allows the clinician to individualize patient care based on shock severity, etiology/phenotype, and risk modification. The goal of these stages is to identify and aggressively treat patients with CS, as well as identify when treatment is failing and additional therapies may be needed.

Dr. Gaillard is Associate Professor in the Departments of Anesthesiology, Section on Critical Care; Internal Medicine, Section on Pulmonology, Critical Care, Allergy, and Immunologic Diseases; and Emergency Medicine; Wake Forest School of Medicine, Winston-Salem, N.C.

As part of the 300+ educational sessions attendees will find at CHEST 2023 in Hawai’i, ticketed sessions are available for learners looking to attend smaller group sessions or experience hands-on learning.

CHEST

Explore the many ticketed sessions, and sign up early in case they sell out.
 

Simulation sessions

If you’re looking to gain hands-on exposure to equipment and tools that may not be available at your home institution, look no further than these simulation sessions. Choose from 25 different sessions offering firsthand experience with procedures relevant to your clinical practice.

“It’s a great opportunity to teach higher stakes procedures in a very low stakes environment where everybody’s comfortable and everybody’s learning from each other,” said Live Learning Subcommittee Chair, Nicholas Pastis, MD, FCCP.

CHEST 2023 simulation sessions will address clinical topics, including endobronchial ultrasound, cardiopulmonary exercise testing (CPET), intubation and cricothyrotomy, bronchoscopy management, and more. These sessions are taught by experts who use these real-world strategies in their daily practice.

CHEST 2022 attendee, Weston Bowker, MD, found value in the simulation courses he was able to attend in Nashville.

“It’s fantastic just to work with some of the leading experts in the field, especially from an interventional pulmonology standpoint. And, you truly get a different experience than maybe what your home institution offers,” he said.
 

Problem-based learning sessions

Exercise your critical thinking skills by working to resolve real-world clinical problems during these small group sessions. Refine your expertise on topics like lung cancer screening and staging, biologics in asthma, pneumonia, and more.

“Problem-based learning courses take a clinical problem or case study that is somewhat controversial to create a learning environment where the problem itself drives the learning with participants,” said CHEST 2023 Scientific Program Committee Chair, Aneesa Das, MD, FCCP. “These are small group sessions where learners can actively participate and collaborate to discuss various perspectives on the issue and work toward potential solutions.”

This year’s problem-based learning courses were chosen based on common controversies in chest medicine and current hot topics in medicine.

Dr. Das is excited for the Using CPET to Solve Your Difficult Cases course. “Cardiopulmonary exercise tests can sometimes be difficult even for seasoned physicians. This is always an amazing problem-based learning topic,” she added.
 

Meet the Professor sessions

Connect with leading chest medicine experts during these limited-capacity discussions capped at 24 registrants per session. Meet the Professor attendees will have the opportunity to engage in stimulating conversations on bronchiectasis, central airway obstructions, obesity hypoventilation, and sublobar resection.

“Meet the Professor sessions are a unique opportunity to interact and learn from a leader in the field in a very small group setting on a high-yield topic,” said Dr. Das. “These sessions allow for a learning environment that is personalized and intimate.”

As part of the 300+ educational sessions attendees will find at CHEST 2023 in Hawai’i, ticketed sessions are available for learners looking to attend smaller group sessions or experience hands-on learning.

CHEST

Explore the many ticketed sessions, and sign up early in case they sell out.
 

Simulation sessions

If you’re looking to gain hands-on exposure to equipment and tools that may not be available at your home institution, look no further than these simulation sessions. Choose from 25 different sessions offering firsthand experience with procedures relevant to your clinical practice.

“It’s a great opportunity to teach higher stakes procedures in a very low stakes environment where everybody’s comfortable and everybody’s learning from each other,” said Live Learning Subcommittee Chair, Nicholas Pastis, MD, FCCP.

CHEST 2023 simulation sessions will address clinical topics, including endobronchial ultrasound, cardiopulmonary exercise testing (CPET), intubation and cricothyrotomy, bronchoscopy management, and more. These sessions are taught by experts who use these real-world strategies in their daily practice.

CHEST 2022 attendee, Weston Bowker, MD, found value in the simulation courses he was able to attend in Nashville.

“It’s fantastic just to work with some of the leading experts in the field, especially from an interventional pulmonology standpoint. And, you truly get a different experience than maybe what your home institution offers,” he said.
 

Problem-based learning sessions

Exercise your critical thinking skills by working to resolve real-world clinical problems during these small group sessions. Refine your expertise on topics like lung cancer screening and staging, biologics in asthma, pneumonia, and more.

“Problem-based learning courses take a clinical problem or case study that is somewhat controversial to create a learning environment where the problem itself drives the learning with participants,” said CHEST 2023 Scientific Program Committee Chair, Aneesa Das, MD, FCCP. “These are small group sessions where learners can actively participate and collaborate to discuss various perspectives on the issue and work toward potential solutions.”

This year’s problem-based learning courses were chosen based on common controversies in chest medicine and current hot topics in medicine.

Dr. Das is excited for the Using CPET to Solve Your Difficult Cases course. “Cardiopulmonary exercise tests can sometimes be difficult even for seasoned physicians. This is always an amazing problem-based learning topic,” she added.
 

Meet the Professor sessions

Connect with leading chest medicine experts during these limited-capacity discussions capped at 24 registrants per session. Meet the Professor attendees will have the opportunity to engage in stimulating conversations on bronchiectasis, central airway obstructions, obesity hypoventilation, and sublobar resection.

“Meet the Professor sessions are a unique opportunity to interact and learn from a leader in the field in a very small group setting on a high-yield topic,” said Dr. Das. “These sessions allow for a learning environment that is personalized and intimate.”

As part of the 300+ educational sessions attendees will find at CHEST 2023 in Hawai’i, ticketed sessions are available for learners looking to attend smaller group sessions or experience hands-on learning.

CHEST

Explore the many ticketed sessions, and sign up early in case they sell out.
 

Simulation sessions

If you’re looking to gain hands-on exposure to equipment and tools that may not be available at your home institution, look no further than these simulation sessions. Choose from 25 different sessions offering firsthand experience with procedures relevant to your clinical practice.

“It’s a great opportunity to teach higher stakes procedures in a very low stakes environment where everybody’s comfortable and everybody’s learning from each other,” said Live Learning Subcommittee Chair, Nicholas Pastis, MD, FCCP.

CHEST 2023 simulation sessions will address clinical topics, including endobronchial ultrasound, cardiopulmonary exercise testing (CPET), intubation and cricothyrotomy, bronchoscopy management, and more. These sessions are taught by experts who use these real-world strategies in their daily practice.

CHEST 2022 attendee, Weston Bowker, MD, found value in the simulation courses he was able to attend in Nashville.

“It’s fantastic just to work with some of the leading experts in the field, especially from an interventional pulmonology standpoint. And, you truly get a different experience than maybe what your home institution offers,” he said.
 

Problem-based learning sessions

Exercise your critical thinking skills by working to resolve real-world clinical problems during these small group sessions. Refine your expertise on topics like lung cancer screening and staging, biologics in asthma, pneumonia, and more.

“Problem-based learning courses take a clinical problem or case study that is somewhat controversial to create a learning environment where the problem itself drives the learning with participants,” said CHEST 2023 Scientific Program Committee Chair, Aneesa Das, MD, FCCP. “These are small group sessions where learners can actively participate and collaborate to discuss various perspectives on the issue and work toward potential solutions.”

This year’s problem-based learning courses were chosen based on common controversies in chest medicine and current hot topics in medicine.

Dr. Das is excited for the Using CPET to Solve Your Difficult Cases course. “Cardiopulmonary exercise tests can sometimes be difficult even for seasoned physicians. This is always an amazing problem-based learning topic,” she added.
 

Meet the Professor sessions

Connect with leading chest medicine experts during these limited-capacity discussions capped at 24 registrants per session. Meet the Professor attendees will have the opportunity to engage in stimulating conversations on bronchiectasis, central airway obstructions, obesity hypoventilation, and sublobar resection.

“Meet the Professor sessions are a unique opportunity to interact and learn from a leader in the field in a very small group setting on a high-yield topic,” said Dr. Das. “These sessions allow for a learning environment that is personalized and intimate.”

Migraine is well known as a vascular phenomenon, but research over time has shown that vasodilation is a secondary feature of headache rather than the cause of headache pain. Calcitonin gene-related peptide (CGRP) and other vasoactive inflammatory proteins transmit nociceptive signals through the trigeminal system, and although vasodilation occurs, it is not essential for migraine attacks to occur. White matter changes on MRI are a common finding in people with migraine, and the burden of migraine often correlates with the amount of white matter changes seen. This connection highlights the indirect connection between migraine and vascular risks factors, and this study attempts to better quantify this, specifically with respect to stroke and myocardial infarction (MI).

The study by Fuglsang and colleagues was a registry-based nationwide population-based cohort study that included over 200,000 individuals with migraine, using data collected from 1996 to 2018. Participants were differentiated as having or not having migraine on the basis of prescriptions of preventive or acute migraine medications. Male and female participants were further subdivided, and these groups were compared to healthy controls. The primary endpoints were hazard ratio and absolute risk differences for developing hemorrhagic or ischemic stroke or MI among all groups.

The researchers found an increased risk for ischemic stroke that was equal among male and female participants. Hemorrhagic stroke and MI were seen to be increased in migraine, but primarily among women with migraine. This study specifically investigated what the researchers termed "premature" stroke and MI, and there remains a likelihood that estrogen could be the differentiating factor between the difference in risk between male and female participants with migraine. I have recently highlighted a number of studies investigating vascular risk factors associated with migraine; this study will help clinicians appropriately educate their patients with migraine regarding vascular risk.

The first medications reported as helpful preventively for migraine were antihypertensives, specifically beta-blockers (BB). A number of other medications in other antihypertensive subclasses have also subsequently been shown to be helpful for migraine prevention. These include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), calcium channel blockers (CCB), and alpha-blockers (AB). Carcel and colleagues conducted a meta-analysis that investigated a wide variety of antihypertensive medications in multiple classes and compared the reduction in headache frequency as defined as headache days per month.

This analysis reviewed 50 studies involving over 4000 participants. The majority of the studies (35 out 50 [70%]) had a cross-over design. The medications evaluated included clonidine (an alpha agonist), candesartan (an ARB), telmisartan (an ARB), propranolol (a BB), timolol (a BB), pindolol (a BB), metoprolol (a BB), bisoprolol (a BB), atenolol (a BB), alprenolol (a BB), nimodipine (a CCB), nifedipine (a CCB), verapamil (a CCB), nicardipine (a CCB), enalapril (an ACE inhibitor), and lisinopril (an ACE inhibitor). For each class of antihypertensive, there was a lower number of monthly headache days with treatment compared with placebo; the greatest reduction was for the CCB with a mean difference of about 2 days per month. BB on average decreased headache days per month by 0.7 days. For BB, there was no clear trend to increased efficacy with increased dose. Only six trials reported the difference in blood pressure: On average, there was a 9.3 mm Hg drop in systolic and 3.0 mm Hg drop in diastolic pressure.

The authors showed that there is statistical significance for the use of antihypertensive medications for decreasing migraine days per month, and this was statistically significant separately for numerous specific drugs within the classes: clonidine, candesartan, atenolol, bisoprolol, propranolol, timolol, nicardipine, and verapamil. Antihypertensive medications remain some of the most popular first-line preventive options for migraine, and although the benefit of this class as a whole is mild (slightly more than 1 day per month), it can be an excellent option for many patients

The relationship between migraine and caffeine is necessarily controversial. Caffeine is included as a component of many over-the-counter migraine treatments, and the beneficial effect of caffeine as an acute treatment for migraine has been documented for decades. Reduction in caffeine, however, has also been established as a helpful lifestyle modification for prevention of migraine attacks. Zhang and colleagues used data from the National Health and Nutrition Examination Survey database, a program conducted by the Centers for Disease Control and Prevention to assess the health and nutritional status of adults and children in the United States.

This study sought to quantify the relationship between dietary caffeine and "severe headache." For this study, "severe headache" was defined as answering yes to the question: During the past 3 months, did you have severe headaches or migraines? Dietary caffeine intake was collected through two 24-hour dietary recall interviews, one in person and one 3-10 days later via telephone. The amount of caffeine consumed was estimated in mg/day from all caffeine-containing foods and beverages, including coffee, tea, soda, and chocolate, using the US Department of Agriculture's Food and Nutrient Database. Each participant's mean caffeine intake was defined as the difference between the first and second dietary recalls.

A large number of covariates were assessed as well, including age, race/ethnicity, body mass index, poverty-income ratio, educational level, marital status, hypertension, cancer, energy intake, protein intake, calcium intake, magnesium intake, iron intake, sodium intake, alcohol status, smoking status, and triglyceride level. A total of 8993 participants were included. Caffeine intake was divided into four groups: ≥ 0 to < 40 mg/day, ≥ 40 to < 200 mg/day, ≥ 200 to < 400 mg/day, and ≥ 400 mg/day. After adjusting for confounders, a significant association between dietary caffeine intake and severe headaches or migraines was detected.

Curiously, in this study, only male participants were included. The authors found a clear correlation between the amount of caffeine consumed over a 24-hour period and severe migraine attacks. Further evaluation should investigate the frequency of attacks rather than just individual experience over a 3-month period. Although caffeine is helpful acutely, higher dose consumption is a risk factor for worsening migraine.

Migraine is well known as a vascular phenomenon, but research over time has shown that vasodilation is a secondary feature of headache rather than the cause of headache pain. Calcitonin gene-related peptide (CGRP) and other vasoactive inflammatory proteins transmit nociceptive signals through the trigeminal system, and although vasodilation occurs, it is not essential for migraine attacks to occur. White matter changes on MRI are a common finding in people with migraine, and the burden of migraine often correlates with the amount of white matter changes seen. This connection highlights the indirect connection between migraine and vascular risks factors, and this study attempts to better quantify this, specifically with respect to stroke and myocardial infarction (MI).

The study by Fuglsang and colleagues was a registry-based nationwide population-based cohort study that included over 200,000 individuals with migraine, using data collected from 1996 to 2018. Participants were differentiated as having or not having migraine on the basis of prescriptions of preventive or acute migraine medications. Male and female participants were further subdivided, and these groups were compared to healthy controls. The primary endpoints were hazard ratio and absolute risk differences for developing hemorrhagic or ischemic stroke or MI among all groups.

The researchers found an increased risk for ischemic stroke that was equal among male and female participants. Hemorrhagic stroke and MI were seen to be increased in migraine, but primarily among women with migraine. This study specifically investigated what the researchers termed "premature" stroke and MI, and there remains a likelihood that estrogen could be the differentiating factor between the difference in risk between male and female participants with migraine. I have recently highlighted a number of studies investigating vascular risk factors associated with migraine; this study will help clinicians appropriately educate their patients with migraine regarding vascular risk.

The first medications reported as helpful preventively for migraine were antihypertensives, specifically beta-blockers (BB). A number of other medications in other antihypertensive subclasses have also subsequently been shown to be helpful for migraine prevention. These include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), calcium channel blockers (CCB), and alpha-blockers (AB). Carcel and colleagues conducted a meta-analysis that investigated a wide variety of antihypertensive medications in multiple classes and compared the reduction in headache frequency as defined as headache days per month.

This analysis reviewed 50 studies involving over 4000 participants. The majority of the studies (35 out 50 [70%]) had a cross-over design. The medications evaluated included clonidine (an alpha agonist), candesartan (an ARB), telmisartan (an ARB), propranolol (a BB), timolol (a BB), pindolol (a BB), metoprolol (a BB), bisoprolol (a BB), atenolol (a BB), alprenolol (a BB), nimodipine (a CCB), nifedipine (a CCB), verapamil (a CCB), nicardipine (a CCB), enalapril (an ACE inhibitor), and lisinopril (an ACE inhibitor). For each class of antihypertensive, there was a lower number of monthly headache days with treatment compared with placebo; the greatest reduction was for the CCB with a mean difference of about 2 days per month. BB on average decreased headache days per month by 0.7 days. For BB, there was no clear trend to increased efficacy with increased dose. Only six trials reported the difference in blood pressure: On average, there was a 9.3 mm Hg drop in systolic and 3.0 mm Hg drop in diastolic pressure.

The authors showed that there is statistical significance for the use of antihypertensive medications for decreasing migraine days per month, and this was statistically significant separately for numerous specific drugs within the classes: clonidine, candesartan, atenolol, bisoprolol, propranolol, timolol, nicardipine, and verapamil. Antihypertensive medications remain some of the most popular first-line preventive options for migraine, and although the benefit of this class as a whole is mild (slightly more than 1 day per month), it can be an excellent option for many patients

The relationship between migraine and caffeine is necessarily controversial. Caffeine is included as a component of many over-the-counter migraine treatments, and the beneficial effect of caffeine as an acute treatment for migraine has been documented for decades. Reduction in caffeine, however, has also been established as a helpful lifestyle modification for prevention of migraine attacks. Zhang and colleagues used data from the National Health and Nutrition Examination Survey database, a program conducted by the Centers for Disease Control and Prevention to assess the health and nutritional status of adults and children in the United States.

This study sought to quantify the relationship between dietary caffeine and "severe headache." For this study, "severe headache" was defined as answering yes to the question: During the past 3 months, did you have severe headaches or migraines? Dietary caffeine intake was collected through two 24-hour dietary recall interviews, one in person and one 3-10 days later via telephone. The amount of caffeine consumed was estimated in mg/day from all caffeine-containing foods and beverages, including coffee, tea, soda, and chocolate, using the US Department of Agriculture's Food and Nutrient Database. Each participant's mean caffeine intake was defined as the difference between the first and second dietary recalls.

A large number of covariates were assessed as well, including age, race/ethnicity, body mass index, poverty-income ratio, educational level, marital status, hypertension, cancer, energy intake, protein intake, calcium intake, magnesium intake, iron intake, sodium intake, alcohol status, smoking status, and triglyceride level. A total of 8993 participants were included. Caffeine intake was divided into four groups: ≥ 0 to < 40 mg/day, ≥ 40 to < 200 mg/day, ≥ 200 to < 400 mg/day, and ≥ 400 mg/day. After adjusting for confounders, a significant association between dietary caffeine intake and severe headaches or migraines was detected.

Curiously, in this study, only male participants were included. The authors found a clear correlation between the amount of caffeine consumed over a 24-hour period and severe migraine attacks. Further evaluation should investigate the frequency of attacks rather than just individual experience over a 3-month period. Although caffeine is helpful acutely, higher dose consumption is a risk factor for worsening migraine.

Migraine is well known as a vascular phenomenon, but research over time has shown that vasodilation is a secondary feature of headache rather than the cause of headache pain. Calcitonin gene-related peptide (CGRP) and other vasoactive inflammatory proteins transmit nociceptive signals through the trigeminal system, and although vasodilation occurs, it is not essential for migraine attacks to occur. White matter changes on MRI are a common finding in people with migraine, and the burden of migraine often correlates with the amount of white matter changes seen. This connection highlights the indirect connection between migraine and vascular risks factors, and this study attempts to better quantify this, specifically with respect to stroke and myocardial infarction (MI).

The study by Fuglsang and colleagues was a registry-based nationwide population-based cohort study that included over 200,000 individuals with migraine, using data collected from 1996 to 2018. Participants were differentiated as having or not having migraine on the basis of prescriptions of preventive or acute migraine medications. Male and female participants were further subdivided, and these groups were compared to healthy controls. The primary endpoints were hazard ratio and absolute risk differences for developing hemorrhagic or ischemic stroke or MI among all groups.

The researchers found an increased risk for ischemic stroke that was equal among male and female participants. Hemorrhagic stroke and MI were seen to be increased in migraine, but primarily among women with migraine. This study specifically investigated what the researchers termed "premature" stroke and MI, and there remains a likelihood that estrogen could be the differentiating factor between the difference in risk between male and female participants with migraine. I have recently highlighted a number of studies investigating vascular risk factors associated with migraine; this study will help clinicians appropriately educate their patients with migraine regarding vascular risk.

The first medications reported as helpful preventively for migraine were antihypertensives, specifically beta-blockers (BB). A number of other medications in other antihypertensive subclasses have also subsequently been shown to be helpful for migraine prevention. These include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), calcium channel blockers (CCB), and alpha-blockers (AB). Carcel and colleagues conducted a meta-analysis that investigated a wide variety of antihypertensive medications in multiple classes and compared the reduction in headache frequency as defined as headache days per month.

This analysis reviewed 50 studies involving over 4000 participants. The majority of the studies (35 out 50 [70%]) had a cross-over design. The medications evaluated included clonidine (an alpha agonist), candesartan (an ARB), telmisartan (an ARB), propranolol (a BB), timolol (a BB), pindolol (a BB), metoprolol (a BB), bisoprolol (a BB), atenolol (a BB), alprenolol (a BB), nimodipine (a CCB), nifedipine (a CCB), verapamil (a CCB), nicardipine (a CCB), enalapril (an ACE inhibitor), and lisinopril (an ACE inhibitor). For each class of antihypertensive, there was a lower number of monthly headache days with treatment compared with placebo; the greatest reduction was for the CCB with a mean difference of about 2 days per month. BB on average decreased headache days per month by 0.7 days. For BB, there was no clear trend to increased efficacy with increased dose. Only six trials reported the difference in blood pressure: On average, there was a 9.3 mm Hg drop in systolic and 3.0 mm Hg drop in diastolic pressure.

The authors showed that there is statistical significance for the use of antihypertensive medications for decreasing migraine days per month, and this was statistically significant separately for numerous specific drugs within the classes: clonidine, candesartan, atenolol, bisoprolol, propranolol, timolol, nicardipine, and verapamil. Antihypertensive medications remain some of the most popular first-line preventive options for migraine, and although the benefit of this class as a whole is mild (slightly more than 1 day per month), it can be an excellent option for many patients

The relationship between migraine and caffeine is necessarily controversial. Caffeine is included as a component of many over-the-counter migraine treatments, and the beneficial effect of caffeine as an acute treatment for migraine has been documented for decades. Reduction in caffeine, however, has also been established as a helpful lifestyle modification for prevention of migraine attacks. Zhang and colleagues used data from the National Health and Nutrition Examination Survey database, a program conducted by the Centers for Disease Control and Prevention to assess the health and nutritional status of adults and children in the United States.

This study sought to quantify the relationship between dietary caffeine and "severe headache." For this study, "severe headache" was defined as answering yes to the question: During the past 3 months, did you have severe headaches or migraines? Dietary caffeine intake was collected through two 24-hour dietary recall interviews, one in person and one 3-10 days later via telephone. The amount of caffeine consumed was estimated in mg/day from all caffeine-containing foods and beverages, including coffee, tea, soda, and chocolate, using the US Department of Agriculture's Food and Nutrient Database. Each participant's mean caffeine intake was defined as the difference between the first and second dietary recalls.

A large number of covariates were assessed as well, including age, race/ethnicity, body mass index, poverty-income ratio, educational level, marital status, hypertension, cancer, energy intake, protein intake, calcium intake, magnesium intake, iron intake, sodium intake, alcohol status, smoking status, and triglyceride level. A total of 8993 participants were included. Caffeine intake was divided into four groups: ≥ 0 to < 40 mg/day, ≥ 40 to < 200 mg/day, ≥ 200 to < 400 mg/day, and ≥ 400 mg/day. After adjusting for confounders, a significant association between dietary caffeine intake and severe headaches or migraines was detected.

Curiously, in this study, only male participants were included. The authors found a clear correlation between the amount of caffeine consumed over a 24-hour period and severe migraine attacks. Further evaluation should investigate the frequency of attacks rather than just individual experience over a 3-month period. Although caffeine is helpful acutely, higher dose consumption is a risk factor for worsening migraine.

TOPLINE:

Most patients who receive antibiotics rather than surgical treatment for appendicitis have successful long-term outcomes, but some may require surgery up to 20 years later.

METHODOLOGY:

• Follow-up on 292 patients involved in two randomized controlled trials conducted in the 1990s by the Swedish National Patient Registry
• Both trials divided patients into two groups: those who underwent appendectomy and those who received antibiotic treatment for appendicitis.
• Researchers looked at rates of recurrent appendicitis that required surgery later in life.

TAKEAWAY:

• 29% of patients in the nonoperative group who were discharged successfully during the initial study eventually underwent surgery.
• Some patients who initially received antibiotics required surgery up to 20 years later.
• 9.5% of patients who didn’t undergo surgery went to a surgical outpatient clinic for abdominal pain, compared with 0.01% of those who had surgery.

IN PRACTICE:

“More than half of the patients treated nonoperatively did not experience recurrence and avoided surgery over approximately 2 decades. There is no evidence for long-term risks of nonoperative management other than that of recurrence of appendicitis,” the authors report.

SOURCE:

Simon Eaton, PhD, of UCL Great Ormond Street Institute of Child Health in London, was the corresponding author of the study, published online in JAMA Surgery. The study was funded by the NIHR Biomedical Research Centre at Great Ormond Street Hospital and the Swedish Research Council.

LIMITATIONS:

The data were retrospective, so the researchers could not track how patients’ circumstances and characteristics changed over time. Most patients were male, and the researchers lacked histopathology results for patients for whom nonsurgical treatment succeeded initially but who later required appendectomy. They also relied on diagnostic standards used in the 1990s, when the initial studies were performed; these were less sophisticated and accurate than recent standards.

DISCLOSURES:

Coauthor Jan Svensson, MD, PhD, reported receiving grants from the Lovisa Foundation during the conduct of the study. No other disclosures were reported.

A version of this article first appeared on Medscape.com.

TOPLINE:

Most patients who receive antibiotics rather than surgical treatment for appendicitis have successful long-term outcomes, but some may require surgery up to 20 years later.

METHODOLOGY:

• Follow-up on 292 patients involved in two randomized controlled trials conducted in the 1990s by the Swedish National Patient Registry
• Both trials divided patients into two groups: those who underwent appendectomy and those who received antibiotic treatment for appendicitis.
• Researchers looked at rates of recurrent appendicitis that required surgery later in life.

TAKEAWAY:

• 29% of patients in the nonoperative group who were discharged successfully during the initial study eventually underwent surgery.
• Some patients who initially received antibiotics required surgery up to 20 years later.
• 9.5% of patients who didn’t undergo surgery went to a surgical outpatient clinic for abdominal pain, compared with 0.01% of those who had surgery.

IN PRACTICE:

“More than half of the patients treated nonoperatively did not experience recurrence and avoided surgery over approximately 2 decades. There is no evidence for long-term risks of nonoperative management other than that of recurrence of appendicitis,” the authors report.

SOURCE:

Simon Eaton, PhD, of UCL Great Ormond Street Institute of Child Health in London, was the corresponding author of the study, published online in JAMA Surgery. The study was funded by the NIHR Biomedical Research Centre at Great Ormond Street Hospital and the Swedish Research Council.

LIMITATIONS:

The data were retrospective, so the researchers could not track how patients’ circumstances and characteristics changed over time. Most patients were male, and the researchers lacked histopathology results for patients for whom nonsurgical treatment succeeded initially but who later required appendectomy. They also relied on diagnostic standards used in the 1990s, when the initial studies were performed; these were less sophisticated and accurate than recent standards.

DISCLOSURES:

Coauthor Jan Svensson, MD, PhD, reported receiving grants from the Lovisa Foundation during the conduct of the study. No other disclosures were reported.

A version of this article first appeared on Medscape.com.

TOPLINE:

Most patients who receive antibiotics rather than surgical treatment for appendicitis have successful long-term outcomes, but some may require surgery up to 20 years later.

METHODOLOGY:

• Follow-up on 292 patients involved in two randomized controlled trials conducted in the 1990s by the Swedish National Patient Registry
• Both trials divided patients into two groups: those who underwent appendectomy and those who received antibiotic treatment for appendicitis.
• Researchers looked at rates of recurrent appendicitis that required surgery later in life.

TAKEAWAY:

• 29% of patients in the nonoperative group who were discharged successfully during the initial study eventually underwent surgery.
• Some patients who initially received antibiotics required surgery up to 20 years later.
• 9.5% of patients who didn’t undergo surgery went to a surgical outpatient clinic for abdominal pain, compared with 0.01% of those who had surgery.

IN PRACTICE:

“More than half of the patients treated nonoperatively did not experience recurrence and avoided surgery over approximately 2 decades. There is no evidence for long-term risks of nonoperative management other than that of recurrence of appendicitis,” the authors report.

SOURCE:

Simon Eaton, PhD, of UCL Great Ormond Street Institute of Child Health in London, was the corresponding author of the study, published online in JAMA Surgery. The study was funded by the NIHR Biomedical Research Centre at Great Ormond Street Hospital and the Swedish Research Council.

LIMITATIONS:

The data were retrospective, so the researchers could not track how patients’ circumstances and characteristics changed over time. Most patients were male, and the researchers lacked histopathology results for patients for whom nonsurgical treatment succeeded initially but who later required appendectomy. They also relied on diagnostic standards used in the 1990s, when the initial studies were performed; these were less sophisticated and accurate than recent standards.

DISCLOSURES:

Coauthor Jan Svensson, MD, PhD, reported receiving grants from the Lovisa Foundation during the conduct of the study. No other disclosures were reported.

A version of this article first appeared on Medscape.com.

Smokers with extreme phenotypes of high and low risk of developing tobacco-associated lung cancer have different genetic profiles, according to a multidisciplinary study conducted by specialists from the Cancer Center at the University of Navarra Clinic (CUN). The results were presented at the annual meeting of the American Society for Clinical Oncology. 

Ana Patiño García, PhD, director of the genomic medicine unit at the CUN and a coordinator of the research, explained in an interview the main reason why this study was conducted. “This study came straight out of the oncology clinic, where we are constantly encountering patients with lung cancer who have never smoked or who have smoked very little, while we also all know people who have smoked a lot throughout their lifetime and have never developed cancer. This observation has led us to ask whether there are genetic factors that increase or decrease the risk of cancer and protect people against this disease.”

José Luis Pérez Gracia, MD, PhD, oncologist, coordinator of the oncology trials department at the CUN and another of the individuals responsible for this research, said: “This is the first study to validate genetic factors associated with people who appear to be resistant to developing tobacco-related lung cancer or who, on the other hand, are at high risk of developing this disease.”
 

Pioneering approach 

Earlier evidence showed that some smokers develop cancer, and others don’t. “This is a very well-known fact, since everyone knows about some elderly person who has been a heavy smoker and has never developed lung cancer,” said Dr. Pérez. “Unfortunately, we oncologists encounter young smokers who have been diagnosed with this disease. However, despite the importance of understanding the causes behind these phenotypes, it is a question that has never been studied from a genetic standpoint.”

The study was conducted using DNA from 133 heavy smokers who had not developed lung cancer at a mean age of 80 years, and from another 116 heavy smokers who had developed this type of cancer at a mean age of 50 years. This DNA was sequenced using next-generation techniques, and the results were analyzed using bioinformatics and artificial intelligence systems in collaboration with the University of Navarra Applied Medical Research Center and the University of Navarra School of Engineering.

When asked how this methodology could be applied to support other research conducted along these lines, Dr. Patiño said, “The most novel thing about this research is actually its approach. It’s based on groups at the extremes, defined by the patient’s age at the time of developing lung cancer and how much they had smoked. This type of comparative design is called extreme phenotypes, and its main distinguishing characteristic – which is also its most limiting characteristic – is choosing cases and controls well. Obviously, with today’s next-generation sequencing technologies, we achieve a quantity and quality of data that would have been unattainable in years gone by.”

Speaking to the role played by bioinformatics and artificial intelligence in this research, Dr. Patiño explained that they are fairly new techniques. “In fact, these technologies could be thought of as spearheading a lot of the biomedical research being done today. They’ve also somewhat set the stage for the paradigm shift where the investigator asks the data a question, and in the case of artificial intelligence, it’s the data that answer.”
 

Pinpointing genetic differences

In his analysis of the most noteworthy data and conclusions from this research, Dr. Pérez noted, “The most significant thing we’ve seen is that both populations have genetic differences. This suggests that our hypothesis is correct. Of course, more studies including a larger number of individuals will be needed to confirm these findings. For the first time, our work has laid the foundation for developing this line of research.” 

“Many genetic variants that we have identified as differentials in cases and controls are found in genes relevant to the immune system (HLA system), in genes related to functional pathways that are often altered in tumor development, and in structural proteins and in genes related to cell mobility,” emphasized Dr. Patiño.

Many of the genetic characteristics that were discovered are located in genes with functions related to cancer development, such as immune response, repair of genetic material, regulation of inflammation, etc. This finding is highly significant, said Dr. Pérez. “However, we must remember that these phenotypes may be attributable to multiple causes, not just one cause.”

Furthermore, the specialist explained the next steps to be taken in the context of the line opened up by this research. “First, we must expand these studies, including more individuals with, if possible, even more extreme phenotypes: more smokers who are older and younger, respectively. Once the statistical evidence is stronger, we must also confirm that the alterations observed in lab-based studies truly impact gene function.”
 

Earlier diagnosis 

The clinician also discussed the potential ways that the conclusions of this study could be applied to clinical practice now and in the future, and how the conclusions could benefit these patients. “The results of our line of research may help in early identification of those individuals at high risk of developing lung cancer if they smoke, so that they could be included in prevention programs to keep them from smoking or to help them stop smoking,” said Dr. Pérez. “It would also allow for early diagnosis of cancer at a time when there is a much higher chance of curing it. 

“However, the most important thing is that our study may allow us to better understand the mechanisms by which cancer arises and especially why some people do not develop it. This [understanding] could lead to new diagnostic techniques and new treatments for this disease. The techniques needed to develop this line of research (bioinformatic mass sequencing and artificial intelligence) are available and becoming more reliable and more accessible every day. So, we believe our strategy is very realistic,” he added.

Although the line of research opened up by this study depicts a new scenario, the specialists still must face several challenges to discover why some smokers are more likely than others to develop lung cancer.

“There are many lines of research in this regard,” said Dr. Pérez. “But to name a few, I would draw attention to the need to increase the number of cases and controls to improve the comparison, study patients with other tumors related to tobacco use, ask new questions using the data we have already collected, and apply other genomic techniques that would allow us to perform additional studies of genetic variants that have not yet been studied. And, of course, we need to use functional studies to expand our understanding of the function and activity of the genes that have already been identified.” 

Dr. Patiño and Dr. Pérez declared that they have no relevant financial conflicts of interest.

This article was translated from the Medscape Spanish Edition. A version appeared on Medscape.com.

Smokers with extreme phenotypes of high and low risk of developing tobacco-associated lung cancer have different genetic profiles, according to a multidisciplinary study conducted by specialists from the Cancer Center at the University of Navarra Clinic (CUN). The results were presented at the annual meeting of the American Society for Clinical Oncology. 

Ana Patiño García, PhD, director of the genomic medicine unit at the CUN and a coordinator of the research, explained in an interview the main reason why this study was conducted. “This study came straight out of the oncology clinic, where we are constantly encountering patients with lung cancer who have never smoked or who have smoked very little, while we also all know people who have smoked a lot throughout their lifetime and have never developed cancer. This observation has led us to ask whether there are genetic factors that increase or decrease the risk of cancer and protect people against this disease.”

José Luis Pérez Gracia, MD, PhD, oncologist, coordinator of the oncology trials department at the CUN and another of the individuals responsible for this research, said: “This is the first study to validate genetic factors associated with people who appear to be resistant to developing tobacco-related lung cancer or who, on the other hand, are at high risk of developing this disease.”
 

Pioneering approach 

Earlier evidence showed that some smokers develop cancer, and others don’t. “This is a very well-known fact, since everyone knows about some elderly person who has been a heavy smoker and has never developed lung cancer,” said Dr. Pérez. “Unfortunately, we oncologists encounter young smokers who have been diagnosed with this disease. However, despite the importance of understanding the causes behind these phenotypes, it is a question that has never been studied from a genetic standpoint.”

The study was conducted using DNA from 133 heavy smokers who had not developed lung cancer at a mean age of 80 years, and from another 116 heavy smokers who had developed this type of cancer at a mean age of 50 years. This DNA was sequenced using next-generation techniques, and the results were analyzed using bioinformatics and artificial intelligence systems in collaboration with the University of Navarra Applied Medical Research Center and the University of Navarra School of Engineering.

When asked how this methodology could be applied to support other research conducted along these lines, Dr. Patiño said, “The most novel thing about this research is actually its approach. It’s based on groups at the extremes, defined by the patient’s age at the time of developing lung cancer and how much they had smoked. This type of comparative design is called extreme phenotypes, and its main distinguishing characteristic – which is also its most limiting characteristic – is choosing cases and controls well. Obviously, with today’s next-generation sequencing technologies, we achieve a quantity and quality of data that would have been unattainable in years gone by.”

Speaking to the role played by bioinformatics and artificial intelligence in this research, Dr. Patiño explained that they are fairly new techniques. “In fact, these technologies could be thought of as spearheading a lot of the biomedical research being done today. They’ve also somewhat set the stage for the paradigm shift where the investigator asks the data a question, and in the case of artificial intelligence, it’s the data that answer.”
 

Pinpointing genetic differences

In his analysis of the most noteworthy data and conclusions from this research, Dr. Pérez noted, “The most significant thing we’ve seen is that both populations have genetic differences. This suggests that our hypothesis is correct. Of course, more studies including a larger number of individuals will be needed to confirm these findings. For the first time, our work has laid the foundation for developing this line of research.” 

“Many genetic variants that we have identified as differentials in cases and controls are found in genes relevant to the immune system (HLA system), in genes related to functional pathways that are often altered in tumor development, and in structural proteins and in genes related to cell mobility,” emphasized Dr. Patiño.

Many of the genetic characteristics that were discovered are located in genes with functions related to cancer development, such as immune response, repair of genetic material, regulation of inflammation, etc. This finding is highly significant, said Dr. Pérez. “However, we must remember that these phenotypes may be attributable to multiple causes, not just one cause.”

Furthermore, the specialist explained the next steps to be taken in the context of the line opened up by this research. “First, we must expand these studies, including more individuals with, if possible, even more extreme phenotypes: more smokers who are older and younger, respectively. Once the statistical evidence is stronger, we must also confirm that the alterations observed in lab-based studies truly impact gene function.”
 

Earlier diagnosis 

The clinician also discussed the potential ways that the conclusions of this study could be applied to clinical practice now and in the future, and how the conclusions could benefit these patients. “The results of our line of research may help in early identification of those individuals at high risk of developing lung cancer if they smoke, so that they could be included in prevention programs to keep them from smoking or to help them stop smoking,” said Dr. Pérez. “It would also allow for early diagnosis of cancer at a time when there is a much higher chance of curing it. 

“However, the most important thing is that our study may allow us to better understand the mechanisms by which cancer arises and especially why some people do not develop it. This [understanding] could lead to new diagnostic techniques and new treatments for this disease. The techniques needed to develop this line of research (bioinformatic mass sequencing and artificial intelligence) are available and becoming more reliable and more accessible every day. So, we believe our strategy is very realistic,” he added.

Although the line of research opened up by this study depicts a new scenario, the specialists still must face several challenges to discover why some smokers are more likely than others to develop lung cancer.

“There are many lines of research in this regard,” said Dr. Pérez. “But to name a few, I would draw attention to the need to increase the number of cases and controls to improve the comparison, study patients with other tumors related to tobacco use, ask new questions using the data we have already collected, and apply other genomic techniques that would allow us to perform additional studies of genetic variants that have not yet been studied. And, of course, we need to use functional studies to expand our understanding of the function and activity of the genes that have already been identified.” 

Dr. Patiño and Dr. Pérez declared that they have no relevant financial conflicts of interest.

This article was translated from the Medscape Spanish Edition. A version appeared on Medscape.com.

Smokers with extreme phenotypes of high and low risk of developing tobacco-associated lung cancer have different genetic profiles, according to a multidisciplinary study conducted by specialists from the Cancer Center at the University of Navarra Clinic (CUN). The results were presented at the annual meeting of the American Society for Clinical Oncology. 

Ana Patiño García, PhD, director of the genomic medicine unit at the CUN and a coordinator of the research, explained in an interview the main reason why this study was conducted. “This study came straight out of the oncology clinic, where we are constantly encountering patients with lung cancer who have never smoked or who have smoked very little, while we also all know people who have smoked a lot throughout their lifetime and have never developed cancer. This observation has led us to ask whether there are genetic factors that increase or decrease the risk of cancer and protect people against this disease.”

José Luis Pérez Gracia, MD, PhD, oncologist, coordinator of the oncology trials department at the CUN and another of the individuals responsible for this research, said: “This is the first study to validate genetic factors associated with people who appear to be resistant to developing tobacco-related lung cancer or who, on the other hand, are at high risk of developing this disease.”
 

Pioneering approach 

Earlier evidence showed that some smokers develop cancer, and others don’t. “This is a very well-known fact, since everyone knows about some elderly person who has been a heavy smoker and has never developed lung cancer,” said Dr. Pérez. “Unfortunately, we oncologists encounter young smokers who have been diagnosed with this disease. However, despite the importance of understanding the causes behind these phenotypes, it is a question that has never been studied from a genetic standpoint.”

The study was conducted using DNA from 133 heavy smokers who had not developed lung cancer at a mean age of 80 years, and from another 116 heavy smokers who had developed this type of cancer at a mean age of 50 years. This DNA was sequenced using next-generation techniques, and the results were analyzed using bioinformatics and artificial intelligence systems in collaboration with the University of Navarra Applied Medical Research Center and the University of Navarra School of Engineering.

When asked how this methodology could be applied to support other research conducted along these lines, Dr. Patiño said, “The most novel thing about this research is actually its approach. It’s based on groups at the extremes, defined by the patient’s age at the time of developing lung cancer and how much they had smoked. This type of comparative design is called extreme phenotypes, and its main distinguishing characteristic – which is also its most limiting characteristic – is choosing cases and controls well. Obviously, with today’s next-generation sequencing technologies, we achieve a quantity and quality of data that would have been unattainable in years gone by.”

Speaking to the role played by bioinformatics and artificial intelligence in this research, Dr. Patiño explained that they are fairly new techniques. “In fact, these technologies could be thought of as spearheading a lot of the biomedical research being done today. They’ve also somewhat set the stage for the paradigm shift where the investigator asks the data a question, and in the case of artificial intelligence, it’s the data that answer.”
 

Pinpointing genetic differences

In his analysis of the most noteworthy data and conclusions from this research, Dr. Pérez noted, “The most significant thing we’ve seen is that both populations have genetic differences. This suggests that our hypothesis is correct. Of course, more studies including a larger number of individuals will be needed to confirm these findings. For the first time, our work has laid the foundation for developing this line of research.” 

“Many genetic variants that we have identified as differentials in cases and controls are found in genes relevant to the immune system (HLA system), in genes related to functional pathways that are often altered in tumor development, and in structural proteins and in genes related to cell mobility,” emphasized Dr. Patiño.

Many of the genetic characteristics that were discovered are located in genes with functions related to cancer development, such as immune response, repair of genetic material, regulation of inflammation, etc. This finding is highly significant, said Dr. Pérez. “However, we must remember that these phenotypes may be attributable to multiple causes, not just one cause.”

Furthermore, the specialist explained the next steps to be taken in the context of the line opened up by this research. “First, we must expand these studies, including more individuals with, if possible, even more extreme phenotypes: more smokers who are older and younger, respectively. Once the statistical evidence is stronger, we must also confirm that the alterations observed in lab-based studies truly impact gene function.”
 

Earlier diagnosis 

The clinician also discussed the potential ways that the conclusions of this study could be applied to clinical practice now and in the future, and how the conclusions could benefit these patients. “The results of our line of research may help in early identification of those individuals at high risk of developing lung cancer if they smoke, so that they could be included in prevention programs to keep them from smoking or to help them stop smoking,” said Dr. Pérez. “It would also allow for early diagnosis of cancer at a time when there is a much higher chance of curing it. 

“However, the most important thing is that our study may allow us to better understand the mechanisms by which cancer arises and especially why some people do not develop it. This [understanding] could lead to new diagnostic techniques and new treatments for this disease. The techniques needed to develop this line of research (bioinformatic mass sequencing and artificial intelligence) are available and becoming more reliable and more accessible every day. So, we believe our strategy is very realistic,” he added.

Although the line of research opened up by this study depicts a new scenario, the specialists still must face several challenges to discover why some smokers are more likely than others to develop lung cancer.

“There are many lines of research in this regard,” said Dr. Pérez. “But to name a few, I would draw attention to the need to increase the number of cases and controls to improve the comparison, study patients with other tumors related to tobacco use, ask new questions using the data we have already collected, and apply other genomic techniques that would allow us to perform additional studies of genetic variants that have not yet been studied. And, of course, we need to use functional studies to expand our understanding of the function and activity of the genes that have already been identified.” 

Dr. Patiño and Dr. Pérez declared that they have no relevant financial conflicts of interest.

This article was translated from the Medscape Spanish Edition. A version appeared on Medscape.com.