Pulmonary arterial hypertension (PAH) is a rare disease associated with abnormally elevated pulmonary pressures and right heart failure resulting in high morbidity and mortality. Although the prognosis for patients with PAH has improved with the introduction of pulmonary vasodilators, disease progression remains a major problem. Given that available therapies are inadequate for preventing small-vessel loss and obstruction, there is active interest in identifying drugs capable of targeting angiogenesis and mechanisms involved in the regulation of cell growth and fibrosis. Among the mechanisms linked to PAH pathogenesis, preclinical studies have identified promising compounds that are currently being tested in clinical trials. These drugs target seven of the major mechanisms associated with PAH pathogenesis: bone morphogenetic protein signaling, tyrosine kinase receptors, estrogen metabolism, extracellular matrix, angiogenesis, epigenetics, and serotonin metabolism. In this review, we discuss the preclinical studies that led to prioritization of these mechanisms, and discuss completed and ongoing phase 2/3 trials using novel interventions such as sotatercept, anastrozole, rodatristat ethyl, tyrosine kinase inhibitors, and endothelial progenitor cells, among others. We anticipate that the next generation of compounds will build on the success of the current standard of care and improve clinical outcomes and quality of life for patients with PAH.

Patients admitted to the ICU with critical COVID-19 often require prolonged periods of mechanical ventilation. Difficulty weaning, lack of progress, and clinical deterioration are commonly encountered. These conditions should prompt a thorough evaluation for persistent or untreated manifestations of COVID-19, as well as complications from COVID-19 and its various treatments. Inflammation may persist and lead to fibroproliferative changes in the lungs. Infectious complications may arise including bacterial superinfection in the earlier stages of disease. Use of immunosuppressants may lead to the dissemination of latent infections, and to opportunistic infections. Venous thromboembolic disease is common, as are certain neurologic manifestations of COVID-19 including delirium and stroke. High levels of ventilatory support may lead to ventilator-induced injury to the lungs and diaphragm. We present diagnostic and therapeutic considerations for the mechanically ventilated patient with COVID-19 who shows persistent or worsening signs of critical illness, and we offer an approach to treating this complex but common scenario.

Nontuberculous mycobacterial pulmonary disease (NTM-PD) continues to impose a significant clinical burden of disease on susceptible patients. The incidence of NTM-PD is rising globally, but it remains a condition that is challenging to diagnose and treat effectively. This review provides an update on the global epidemiologic features, risk factors, and diagnostic considerations associated with the management of NTM-PD.

Asthma-COPD overlap (ACO) is a heterogeneous condition that describes patients who show persistent airflow limitation with clinical features that support both asthma and COPD. Although no single consensus definition exists to diagnose this entity, common major criteria include a strong bronchodilator reversibility or bronchial hyperreactivity, a physician diagnosis of asthma, and a ≥ 10-pack-year cigarette smoking history. The prevalence of ACO ranges from 0.9% to 11.1% in the general population, depending on the diagnostic definition used. Notably, patients with ACO experience greater symptom burden, worse quality of life, and more frequent and severe respiratory exacerbations than those with asthma or COPD. The underlying pathophysiologic features of ACO have been debated. Although emerging evidence supports the role of environmental and inhalational exposures in its pathogenesis among patients with a pre-existing airway disease, biomarker profiling and genetic analyses suggest that ACO may be a heterogeneous condition, but with definable characteristics. Early-life factors including childhood-onset asthma and cigarette smoking may interact to increase the risk of airflow obstruction later in life. For treatment options, the population with ACO historically has been excluded from therapeutic trials; therefore strong, evidence-based recommendations are lacking beyond first-line inhaler therapies. Advanced therapies in patients with ACO are selected according to disease phenotypes and are based on extrapolated data from asthma and COPD. Research focused on defining biomarkers and evidence-based treatment options for ACO is needed urgently.

Although long neglected, the right side of the heart (RH) is now widely accepted as a pivotal player in heart failure (HF) either with reduced or preserved ejection fraction. The chronic overload of the pulmonary microcirculation results in an initial phase characterized by right ventricular (RV) hypertrophy, right atrial dilation, and diastolic dysfunction. This progresses to overt RH failure when RV dilation and systolic dysfunction lead to RV-pulmonary arterial (RV-PA) uncoupling with low RV output. In the context of its established relevance to progression of HF, clinicians should consider assessment of the RH with information from clinical assessment, biomarkers, and imaging. Notably, no single parameter can predict prognosis alone in HF. Assessments simultaneously should encompass RV systolic function, pulmonary pressures, an estimation of RV-PA coupling, and RH morphologic features. Despite a large volume of evidence indicating the relevance of RH function to the clinical syndrome of HF, evidence-based management strategies are lacking. Targeting RH dysfunction in HF should be an objective of future investigations, being an unmet need in the current management of HF.

Severe forms of pulmonary embolism (PE) in children, althought rare, cause significant morbidity and mortality. We review the pathophysiologic features of severe (high-risk and intermediate-risk) PE and suggest novel pediatric-specific risk stratifications and an acute treatment algorithm to expedite emergent decision-making. We defined pediatric high-risk PE as causing cardiopulmonary arrest, sustained hypotension, or normotension with signs or symptoms of shock. Rapid primary reperfusion should be pursued with either surgical embolectomy or systemic thrombolysis in conjunction with a heparin infusion and supportive care as appropriate. We defined pediatric intermediate-risk PE as a lack of systemic hypotension or compensated shock, but with evidence of right ventricular strain by imaging, myocardial necrosis by elevated cardiac troponin levels, or both. The decision to pursue primary reperfusion in this group is complex and should be reserved for patients with more severe disease; anticoagulation alone also may be appropriate in these patients. If primary reperfusion is pursued, catheter-based therapies may be beneficial. Acute management of severe PE in children may include systemic thrombolysis, surgical embolectomy, catheter-based therapies, or anticoagulation alone and may depend on patient and institutional factors. Pediatric emergency and intensive care physicians should be familiar with the risks and benefits of each therapy to expedite care. PE response teams also may have added benefit in streamlining care during these critical events.

Prerecorded video content in medical education has become more common. Increasingly accessible technology coupled with the COVID-19 pandemic and subsequent need for distanced learning has greatly increased the interest in and need for high-quality video content. The use of short educational videos to augment other teaching methods has been shown to improve learners' experiences, knowledge retention, and understanding of content. Multiple studies have demonstrated that video education can be a highly effective tool for learning, particularly for hard-to-visualize processes and for procedural education. Videos allow learners to view content at their own pace and revisit materials on demand. In addition, well-designed videos can be repurposed by educators, ultimately reducing time needed to create high-quality educational content. Currently available technology allows educators to create high-quality videos at minimal cost and with a modest investment of time. This article details practical tips for creating high-yield educational videos.

In December 2019, the command of a US Army Advanced Individual Training battalion on Fort Eustis, Virginia, was briefed on the results of tobacco and nicotine use surveys distributed to trainee soldiers and subsequently decided to ban tobacco and nicotine products in this population. The policy implementation process was thoroughly planned in a joint effort between battalion leadership and the installation military health facility. Data were collected throughout the process that evaluated nicotine product use among trainee soldiers, instructors, and leaders. Preferences on assistance with quitting and views on policy implementation processes also were collected. Comprehensive and multimodal resources and therapy to assist with treatment of dependence of tobacco and nicotine were offered. Although more data are needed on outcomes of this type of intervention, addressing tobacco and nicotine use in the military is long overdue, and our intervention offers a reproducible model to do so. It incorporates education, behavioral resources, and medication therapy with the aim to improve long-term quit rates and to improve the health of soldiers throughout and after their careers.

Asthma is a common chronic airways disease with significant impact on patients, caregivers, and the health care system. Although most research and novel interventions mainly have focused on patients with uncontrolled severe asthma, most patients with asthma have mild disease. Epidemiologic studies suggest that many patients with mild asthma report frequent exacerbations of the disease and uncontrolled symptoms. However, despite its impact, mild asthma does not have either a uniformly agreed on definition for or a consensus on its clinical and pathophysiologic progression. More recently, the approach to treatment of patients with mild asthma has undergone significant changes primarily based on emerging evidence that airway inflammation in this population is important. This led to clinical research studies that explored the efficacy of as-needed inhaled corticosteroids along with the rescue medications that traditionally have been the mainstay of treatment. Despite some advancement in the field in recent years, many controversies and unmet needs remain. In this review, we examine the current understanding of the pathophysiologic features and management of mild asthma. In addition, we outline unmet needs for future research. We conclude that mild asthma contributes significantly to the morbidity and mortality of asthma and should be the focus of future research.

Cystic fibrosis (CF) is a progressive monogenetic disorder that causes persistent pulmonary disease, but also affects other organ systems, including the digestive tract. Recent advances in treatment and care of patients with CF, including the use of new and highly effective CF transmembrane conductance regulator modulators, have led to a dramatic increase in survival. Young patients with CF now can expect to live to or beyond middle age, when cancer is more frequent. Patients with CF now are known to face an increased risk of digestive tract cancer, particularly cancer of the colon. The risk, which could be triggered by associated CF-related conditions or other genetic mechanisms, is even greater in patients who received a transplant. Also some evidence suggests that adenomatous polyps develop more frequently in patients with CF and at an earlier age than in patients without CF. To reduce the excess risk of intestinal cancer in patients with CF, the Cystic Fibrosis Foundation has developed colonoscopy-based guidelines. For nontransplanted patients, colonoscopy should begin at 40 years of age, with rescreening at 5-year intervals; the screening interval should be shortened to 3 years if adenomatous polyps are discovered. For transplanted patients, screening should start at 30 years of age, or within 2 years of the transplant operation. Before colonoscopy, it is essential for patients with CF to undergo a special, more intensive bowel preparation than normally used for those without CF. Whether the new drugs that have dramatically improved morbidity and mortality for patients with CF will alter the risk of cancer is unknown and needs to be assessed in future studies.

Considering the COVID-19 pandemic where concomitant occurrence of ARDS and severe acute brain injury (sABI) has increasingly coemerged, we synthesize existing data regarding the simultaneous management of both conditions. Our aim is to provide readers with fundamental principles and concepts for the management of sABI and ARDS, and highlight challenges and conflicts encountered while managing concurrent disease. Up to 40% of patients with sABI can develop ARDS. Although there are trials and guidelines to support the mainstays of treatment for ARDS and sABI independently, guidance on concomitant management is limited. Treatment strategies aimed at managing severe ARDS may at times conflict with the management of sABI. In this narrative review, we discuss the physiological basis and risks involved during simultaneous management of ARDS and sABI, summarize evidence for treatment decisions, and demonstrate these principles using hypothetical case scenarios. Use of invasive or noninvasive monitoring to assess brain and lung physiology may facilitate goal-directed treatment strategies with the potential to improve outcome. Understanding the pathophysiology and key treatment concepts for comanagement of these conditions is critical to optimizing care in this high-acuity patient population.

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Novel, highly effective, modulator therapies correcting and potentiating CFTR function are changing the course of this disease. We present an ethical dilemma involving an 11-year-old child with CF and end-stage lung disease. Shortly after starting treatment with elexacaftor-tezacaftor-ivacaftor, the family received notification that a matched donor lung had been allocated. Clinical decision-making in this case is challenging as definitive data to medically support one treatment option over the other are limited. A survey of CF center team members was conducted for the purpose of this article. Ethical principles that may guide us in these situations are discussed. Overall, results of the survey present a lack of agreement as to the best approach in this situation. Physicians, when compared with other team members, are more likely to provide a specific recommendation vs presenting the information to the family and letting them decide (OR, 4.0; 95% CI, 1.2-12.8; P = .021). A shared decision-making model, stressing our moral obligation as physicians to respect autonomy by appreciating family values, while offering to participate in the decision-making process and ensuring nonmaleficence, is presented. In summary, CFTR modulators affect the outcomes of CF disease and influence clinical decision-making. The current lack of data on long-term outcomes, in young patients with CF receiving effective modulator therapy, should not preclude CF team participation in decision-making. Shared decision-making, which is focused on respecting autonomy, is our preferred approach in these situations.

Time-limited trials (TLTs) are used in the management of critical care patients undergoing potentially nonbeneficial interventions to improve prognostication and build trust and consensus between family and intensivists. When these trials are not well defined and executed, discordant views of the patient's prognosis, conflict, and continuation of nonbeneficial care can arise. The mnemonic TIME (truth about uncertainty in prognosis, interval of time, measurement of improvement, and end or extend) can help facilitate clear communication surrounding TLTs. This framework allows physicians and families to deal more effectively with the inherent uncertainty and required flexibility needed in caring for complex critical care patients. This can lead to patient-centered decision-making that improves patient-physician relationships and goal-concordant care and also potentially reduces nonbeneficial treatments at the end of life.

ARDS is an inflammatory condition of the lungs and is a common condition in adult ICUs. The resources required and costs of care for patients with ARDS are significant because of the severity of the illness and extended ICU lengths of stay.

The practice of using race or ethnicity in medicine to explain differences between individuals is being called into question because it may contribute to biased medical care and research that perpetuates health disparities and structural racism. A commonly cited example is the use of race or ethnicity in the interpretation of pulmonary function test (PFT) results, yet the perspectives of practicing pulmonologists and physiologists are missing from this discussion. This discussion has global relevance for increasingly multicultural communities in which the range of values that represent normal lung function is uncertain. We review the underlying sources of differences in lung function, including those that may be captured by race or ethnicity, and demonstrate how the current practice of PFT measurement and interpretation is imperfect in its ability to describe accurately the relationship between function and health outcomes. We summarize the arguments against using race-specific equations as well as address concerns about removing race from the interpretation of PFT results. Further, we outline knowledge gaps and critical questions that need to be answered to change the current approach of including race or ethnicity in PFT results interpretation thoughtfully. Finally, we propose changes in interpretation strategies and future research to reduce health disparities.

Timely care is an important dimension of health care quality, but the impact of delays in care on lung cancer outcomes is unclear. Quantifying the impact of delays in cancer treatment on survival is necessary to inform resource allocation, quality improvement initiatives, and lung cancer guidelines. Review of the available literature demonstrated significant heterogeneity between studies in terms of the impact of delay. Frequently paradoxical results were reported, with delay being associated with improved survival in patients with advanced disease. However, significant methodologic flaws were identified in many studies, which probably is the reason for the paradoxical results. The most significant methodologic limitations identified were incorrectly controlling for final pathologic stage (a mediator in the causal chain from delay to survival), failure to control for confounding by acuity of cancer presentation, and failure to consider effect measure modification. The effect of delay on survival probably varies by stage. The impact of delays is lowest for subcentimeter nodules, probably highest in stage II disease, and low in patients who are only eligible for palliative care. Precise quantification of the impact of delay is not currently possible. Given the available evidence, quality metrics for the timeliness of lung cancer care should focus on local barriers to care. These metrics should be carefully designed to take into account clinical-radiographic stage at initial presentation.

Critically ill adults are at increased risk of VTE, including DVT, and pulmonary embolism. Various agents exist for venous thromboprophylaxis in this population.

The COVID-19 pandemic has caused acute lung injury in millions of individuals worldwide. Some patients develop COVID-related acute respiratory distress syndrome (CARDS) and cannot be liberated from mechanical ventilation. Others may develop post-COVID fibrosis, resulting in substantial disability and need for long-term supplemental oxygen. In both of these situations, treatment teams often inquire about the possibility of lung transplantation. In fact, lung transplantation has been successfully employed for both CARDS and post-COVID fibrosis in a limited number of patients worldwide. Lung transplantation after COVID infection presents a number of unique challenges that transplant programs must consider. In those with severe CARDS, the inability to conduct proper psychosocial evaluation and pretransplantation education, marked deconditioning from critical illness, and infectious concerns regarding viral reactivation are major hurdles. In those with post-COVID fibrosis, our limited knowledge about the natural history of recovery after COVID-19 infection is problematic. Increased knowledge of the likelihood and degree of recovery after COVID-19 acute lung injury is essential for appropriate decision-making with regard to transplantation. Transplant physicians must weigh the risks and benefits of lung transplantation differently in a post-COVID fibrosis patient who is likely to remain stable or gradually improve in comparison with a patient with a known progressive fibrosing interstitial lung disease (fILD). Clearly lung transplantation can be a life-saving therapeutic option for some patients with severe lung injury from COVID-19 infection. In this review, we discuss how lung transplant providers from a number of experienced centers approach lung transplantation for CARDS or post-COVID fibrosis.

Cardiopulmonary determination of death is a mainstay of the practice of internal medicine and pulmonary physicians. Despite this, there is considerable variability in death examinations. This article tracks the evolution of the tripartite death examination, initially developed in the middle of the 19th century to protect against premature burial. Although the societal context for controversies about death determination has shifted to discussions about end-of-life care in ICUs and organ transplantation, the cardiopulmonary death examination has largely remained unchanged from its original formulation. The recognition of coma dépassé and brain death has further pushed the focus of the death examination onto the neurological system. Despite advancing diagnostics and legislative attempts to standardize the definition of death, cardiopulmonary death determination largely remains an ad hoc process.

Pulmonary arterial hypertension (PAH) is a progressive incurable condition that is characterized by extensive remodeling of the pulmonary circulation, leading to severe right-sided heart failure and death. Similar to other vascular contractile cells, pulmonary arterial smooth muscle cells play central roles in physiological and pathologic vascular remodeling because of their remarkable ability to dynamically modulate their phenotype to ensure contractile and synthetic functions. The dysfunction and molecular mechanisms underlying their contribution to the various pulmonary vascular lesions associated with PAH have been a major focus of research. The aim of this review is to describe the medial and nonmedial origins of contractile cells in the pulmonary vascular wall and present evidence of how they contribute to the onset and progression of PAH. We also highlight specific potential target molecules and discuss future directions that are being explored to widen the therapeutic options for the treatment of PAH.