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Older adults suffering from chronic pulmonary diseases, such as chronic obstructive pulmonary disease and interstitial lung disease, and critical illnesses, such as sepsis and acute respiratory failure, are more vulnerable to adverse outcomes like disability and greater side effects from treatments. In this update, we discuss recent practice-changing clinical trials and observational studies in PulmonaryCritical Care Medicine that have advanced our understanding of the diagnosis or management of older adults with chronic lung diseases or critical illnesses.

Idiopathic pulmonary fibrosis is a fatal interstitial lung disease characterized by the TGF-β (transforming growth factor-β)–dependent differentiation of lung fibroblasts into myofibroblasts, which leads to excessive deposition of collagen proteins and progressive scarring. We have previously shown that synthesis of collagen by myofibroblasts requires de novo synthesis of glycine, the most abundant amino acid found in collagen protein. TGF-β upregulates the expression of the enzymes of the de novo serine–glycine synthesis pathway in lung fibroblasts; however, the transcriptional and signaling regulators of this pathway remain incompletely understood. Here, we demonstrate that TGF-β promotes accumulation of ATF4 (activating transcription factor 4), which is required for increased expression of the serine–glycine synthesis pathway enzymes in response to TGF-β. We found that induction of the integrated stress response (ISR) contributes to TGF-β–induced ATF4 activity; however, the primary driver of ATF4 downstream of TGF-β is activation of mTORC1 (mTOR Complex 1). TGF-β activates the PI3K-Akt-mTOR pathway, and inhibition of PI3K prevents activation of downstream signaling and induction of ATF4. Using a panel of mTOR inhibitors, we found that ATF4 activation is dependent on mTORC1, independent of mTORC2. Rapamycin, which incompletely and allosterically inhibits mTORC1, had no effect on TGF-β–mediated induction of ATF4; however, Rapalink-1, which specifically targets the kinase domain of mTORC1, completely inhibited ATF4 induction and metabolic reprogramming downstream of TGF-β. Our results provide insight into the mechanisms of metabolic reprogramming in myofibroblasts and clarify contradictory published findings on the role of mTOR inhibition in myofibroblast differentiation.

Coronavirus disease 2019 (COVID-19) continues to impact older adults disproportionately with respect to serious consequences ranging from severe illness and hospitalization to increased mortality risk. Concurrently, concerns about potential shortages of healthcare professionals and health supplies to address these issues have focused attention on how these resources are ultimately allocated and used. Some strategies, for example, misguidedly use age as an arbitrary criterion that disfavors older adults in resource allocation decisions. This is a companion article to the American Geriatrics Society (AGS) position statement, "Resource Allocation Strategies and Age-Related Considerations in the COVID-19 Era and Beyond." It is intended to inform stakeholders including hospitals, health systems, and policymakers about ethical considerations that should be considered when developing strategies for allocation of scarce resources during an emergency involving older adults. This review presents the legal and ethical background for the position statement and discusses these issues that informed the development of the AGS positions: (1) age as a determining factor, (2) age as a tiebreaker, (3) criteria with a differential impact on older adults, (4) individual choices and advance directives, (5) racial/ethnic disparities and resource allocation, and (6) scoring systems and their impact on older adults. It also considers the role of advance directives as expressions of individual preferences in pandemics. J Am Geriatr Soc 68:1143-1149, 2020.

RationaleChronic obstructive pulmonary disease (COPD) predominantly affects older adults. However, the co-morbid occurrence of geriatric conditions has been understudied.ObjectiveCharacterize the prevalence of geriatric conditions among community-dwelling U.S. older adults with self-reported COPD.MethodsWe conducted a nationally representative, cross-sectional study of 3,005 U.S. community-dwelling older adults (ages 57–85 years) from the National Social Life, Health, and Aging Project (NSHAP). We evaluated the prevalence of select geriatric conditions (multimorbidity, functional disability, impaired physical function, low physical activity, modified frailty assessment, falls, polypharmacy, and urinary incontinence) and psychosocial measures (frequency of socializing, sexual activity in the last year, loneliness, cognitive impairment, and depressive symptoms) among individuals with self-reported COPD as compared to those without. Using multivariate logistic and linear regressions, we investigated the relationships between COPD and these geriatric physical and psychosocial conditions.Main ResultsSelf-reported COPD prevalence was 10.7%, similar to previous epidemiological studies. Individuals with COPD had more multimorbidity [modified Charlson score 2.6 (SD 1.9) vs. 1.6 (SD 1.6)], more functional disability (58.1 vs. 29.6%; adjusted OR 3.1, 95% CI 2.3, 4.3), falls in the last year (28.4 vs. 20.8%; adjusted OR 1.4, 95% CI 1.01, 2.0), impaired physical function (75.8 vs. 56.6%; adjusted OR 2.1, 95% CI 1.1, 3.7), more frequently reported extreme low physical activity (18.7 vs. 8.1%; adjusted OR 2.3, 95% CI 1.5, 3.5) and higher frailty prevalence (16.0 vs. 2.7%; adjusted OR 6.3, 95% CI 3.0,13.0) than those without COPD. They experienced more severe polypharmacy (≥10 medications, 37.5 vs. 16.1%; adjusted OR 2.9, 95% CI 2.0, 4.2). They more frequently reported extreme social disengagement and were lonelier, but the association with social measures was eliminated when relationship status was accounted for, as those with COPD were less frequently partnered. They more frequently endorsed depressive symptoms (32.0 vs. 18.9%, adjusted OR 1.9, 95% CI 1.4, 2.7). There was no noted difference in cognitive impairment between the two populations.ConclusionsGeriatric conditions are common among community-dwelling older adults with self-reported COPD. A “beyond the lung” approach to COPD care should center on active management of geriatric conditions, potentially leading to improved COPD management, and quality of life.

Idiopathic pulmonary fibrosis (IPF) is characterized by the transforming growth factor (TGF)-β-dependent differentiation of lung fibroblasts into myofibroblasts, leading to excessive deposition of extracellular matrix proteins, which distort lung architecture and function. Metabolic reprogramming in myofibroblasts is emerging as an important mechanism in the pathogenesis of IPF, and recent evidence suggests that glutamine metabolism is required in myofibroblasts, although the exact role of glutamine in myofibroblasts is unclear. In the present study, we demonstrate that glutamine and its conversion to glutamate by glutaminase are required for TGF-β-induced collagen protein production in lung fibroblasts. We found that metabolism of glutamate to α-ketoglutarate by glutamate dehydrogenase or the glutamate-pyruvate or glutamate-oxaloacetate transaminases is not required for collagen protein production. Instead, we discovered that the glutamate-consuming enzymes phosphoserine aminotransferase 1 (PSAT1) and aldehyde dehydrogenase 18A1 (ALDH18A1)/Δ1-pyrroline-5-carboxylate synthetase (P5CS) are required for collagen protein production by lung fibroblasts. PSAT1 is required for de novo glycine production, whereas ALDH18A1/P5CS is required for de novo proline production. Consistent with this, we found that TGF-β treatment increased cellular concentrations of glycine and proline in lung fibroblasts. Our results suggest that glutamine metabolism is required to promote amino acid biosynthesis and not to provide intermediates such as α-ketoglutarate for oxidation in mitochondria. In support of this, we found that inhibition of glutaminolysis has no effect on cellular oxygen consumption and that knockdown of oxoglutarate dehydrogenase has no effect on the ability of fibroblasts to produce collagen protein. Our results suggest that amino acid biosynthesis pathways may represent novel therapeutic targets for treatment of fibrotic diseases, including IPF.

Background: The morbidity and mortality of interstitial lung disease (ILD) is high, despite novel therapeutics. Recognizing unmet needs for symptom management, advance care planning (ACP), and supp...

Coronavirus disease 2019 (COVID-19) continues to impact older adults disproportionately, from severe illness and hospitalization to increased mortality risk. Concurrently, concerns about potential shortages of healthcare professionals and health supplies to address these needs have focused attention on how resources are ultimately allocated and used. Some strategies misguidedly use age as an arbitrary criterion, inappropriately disfavoring older adults. This statement represents the official policy position of the American Geriatrics Society (AGS). It is intended to inform stakeholders including hospitals, health systems, and policymakers about ethical considerations to consider when developing strategies for allocating scarce resources during an emergency involving older adults. Members of the AGS Ethics Committee collaborated with interprofessional experts in ethics, law, nursing, and medicine (including geriatrics, palliative care, emergency medicine, and pulmonology/critical care) to conduct a structured literature review and examine relevant reports. The resulting recommendations defend a particular view of distributive justice that maximizes relevant clinical factors and deemphasizes or eliminates factors placing arbitrary, disproportionate weight on advanced age. The AGS positions include (1) avoiding age per se as a means for excluding anyone from care; (2) assessing comorbidities and considering the disparate impact of social determinants of health; (3) encouraging decision makers to focus primarily on potential short-term (not long-term) outcomes; (4) avoiding ancillary criteria such as "life-years saved" and "long-term predicted life expectancy" that might disadvantage older people; (5) forming and staffing triage committees tasked with allocating scarce resources; (6) developing institutional resource allocation strategies that are transparent and applied uniformly; and (7) facilitating appropriate advance care planning. The statement includes recommendations that should be immediately implemented to address resource allocation strategies during COVID-19, aligning with AGS positions. The statement also includes recommendations for post-pandemic review. Such review would support revised strategies to ensure that governments and institutions have equitable emergency resource allocation strategies, avoid future discriminatory language and practice, and have appropriate guidance to develop national frameworks for emergent resource allocation decisions. J Am Geriatr Soc 68:1136-1142, 2020.

Organ fibrosis, including idiopathic pulmonary fibrosis, is associated with significant morbidity and mortality. Because currently available therapies have limited effect, there is a need to better understand the mechanisms by which organ fibrosis occurs. We have recently reported that transforming growth factor (TGF)-β, a key cytokine that promotes fibrogenesis, induces the expression of the enzymes of the de novo serine and glycine synthesis pathway in human lung fibroblasts, and that phosphoglycerate dehydrogenase (PHGDH; the first and rate-limiting enzyme of the pathway) is required to promote collagen protein synthesis downstream of TGF-β. In this study, we investigated whether inhibition of de novo serine and glycine synthesis attenuates lung fibrosis in vivo. We found that TGF-β induces mRNA and protein expression of PHGDH in murine fibroblasts. Similarly, intratracheal administration of bleomycin resulted in increased expression of PHGDH in mouse lungs, localized to fibrotic regions. Using a newly developed small molecule inhibitor of PHGDH (NCT-503), we tested whether pharmacologic inhibition of PHGDH could inhibit fibrogenesis both in vitro and in vivo. Treatment of murine and human lung fibroblasts with NCT-503 decreased TGF-β–induced collagen protein synthesis. Mice treated with the PHGDH inhibitor beginning 7 days after intratracheal instillation of bleomycin had attenuation of lung fibrosis. These results indicate that the de novo serine and glycine synthesis pathway is necessary for TGF-β–induced collagen synthesis and bleomycin-induced pulmonary fibrosis. PHGDH and other enzymes in the de novo serine and glycine synthesis pathway may be a therapeutic target for treatment of fibrotic diseases, including idiopathic pulmonary fibrosis.

© 2016 Elsevier Ltd Background Azathioprine is a commonly prescribed therapy for connective tissue disease-associated interstitial lung disease (CTD-ILD). Combination therapy that included azathioprine was recently shown to increase the risk of death and hospitalization in patients with idiopathic pulmonary fibrosis. Whether azathioprine increases the risk of adverse outcomes in patients with fibrotic CTD-ILD, including those with CTD-associated usual interstitial pneumonia (UIP), remains unknown. Methods A retrospective cohort analysis was performed to determine the combined incidence rate of death, transplant and respiratory hospitalization associated with azathioprine exposure. A fibrotic CTD-ILD cohort treated with mycophenolate mofetil served as a comparator group. Incidence rates were compared with an incidence rate ratio (IRR) generated by negative binomial regression. Longitudinal pulmonary function response was then assessed using mixed effects linear regression models. Results Fifty-four patients were treated with azathioprine and forty-three with mycophenolate. Medication discontinuation due to non-respiratory side effects occurred in 27% and 5% of the azathioprine and mycophenolate cohorts, respectively. The combined incidence rate of adverse outcomes was 0.015 and 0.013 for azathioprine and mycophenolate, respectively (IRR 1.23; 95% CI 0.49-3.12; p = 0.66). Similar incidence rates were observed among those with CTD-UIP (IRR 0.83; 95% CI 0.21-3.31; p = 0.79). Both groups demonstrated pulmonary function stability over time, with the azathioprine group demonstrating a marginal improvement. Conclusions A significant minority of patients could not tolerate azathioprine due to non-respiratory side effects. Of those who did tolerate azathioprine, a similar incidence of adverse outcomes was observed as those treated with mycophenolate. Both therapies were associated with stability in pulmonary function.

Purpose: Terminal oncology intensive care unit (ICU) hospitalizations are associated with high costs and inferior quality of care. This study identifies and characterizes potentially avoidable terminal admissions of oncology patients to ICUs. Methods: This was a retrospective case series of patients cared for in an academic medical center’s ambulatory oncology practice who died in an ICU during July 1, 2012 to June 30, 2013. An oncologist, intensivist, and hospitalist reviewed each patient’s electronic health record from 3 months preceding terminal hospitalization until death. The primary outcome was the proportion of terminal ICU hospitalizations identified as potentially avoidable by two or more reviewers. Univariate and multivariate analysis were performed to identify characteristics associated with avoidable terminal ICU hospitalizations. Results: Seventy-two patients met inclusion criteria. The majority had solid tumor malignancies (71%), poor performance status (51%), and multiple encounters with the health care system. Despite high-intensity health care utilization, only 25% had documented advance directives. During a 4-day median ICU length of stay, 81% were intubated and 39% had cardiopulmonary resuscitation. Forty-seven percent of these hospitalizations were identified as potentially avoidable. Avoidable hospitalizations were associated with factors including: worse performance status before admission (median 2 v 1; P = .01), worse Charlson comorbidity score (median 8.5 v 7.0, P = .04), reason for hospitalization (P = .006), and number of prior hospitalizations (median 2 v 1; P = .05). Conclusion: Given the high frequency of avoidable terminal ICU hospitalizations, health care leaders should develop strategies to prospectively identify patients at high risk and formulate interventions to improve end-of-life care.

Anti-synthetase syndrome is an autoimmune condition, characterized by antibodies directed against an aminoacycl transfer RNA synthetase along with clinical features that can include interstitial lung disease, myositis, Raynaud’s phenomenon, and arthritis. There is a higher prevalence and increased severity of interstitial lung disease in patients with anti-synthetase syndrome, as compared to dermatomyositis and polymyositis, inflammatory myopathies with which it may overlap phenotypically. Diagnosis is made by a multidisciplinary approach, synthesizing rheumatology and pulmonary evaluations, along with serologic, radiographic, and occasionally muscle and/or lung biopsy results. Patients with anti-synthetase syndrome often require multi-modality immunosuppressive therapy in order to control the muscle and/or pulmonary manifestations of their disease. The long-term care of these patients mandates careful attention to the adverse effects and complications of chronic immunosuppressive therapy, as well as disease-related sequelae that can include progressive interstitial lung disease necessitating lung transplantation, pulmonary hypertension, malignancy and decreased survival. It is hoped that greater awareness of the clinical features of this syndrome will allow for earlier diagnosis and appropriate treatment to improve outcomes in patients with anti-synthetase syndrome.

We evaluated the safety and effectiveness of adjunctive tacrolimus therapy with conventional immunosuppression in patients with severe connective tissue disease-related interstitial lung disease (CTD-ILD). We included patients from our interstitial lung disease (ILD) registry with CTD-ILD, in whom tacrolimus was added to corticosteroids and an additional immunosuppressive agent. Demographic data, clinical features, lung function, radiographic images, and pathologic findings were reviewed. Effectiveness was assessed by comparing pulmonary function tests (PFTs) closest to tacrolimus initiation to PFTs approximately 6-12 months later. Corticosteroid dose at these time points was also evaluated. We report adverse events attributed to tacrolimus. Seventeen patients with CTD-ILD were included in adverse event analysis; twelve were included in efficacy analysis. Length of tacrolimus therapy ranged from 6 to 110 months (mean 38.8 months ± 31.4). The mean improvement in percent predicted total lung capacity was 7.5% ± 11.7 (p = 0.02). Forced vital capacity mean improvement was 7.4% ± 12.5 (p = 0.06). The average decrease in corticosteroid dose at follow-up was 20.3 mg ± 25.2 (p = 0.02) with complete discontinuation in six patients. No patients experienced a life-threatening adverse event attributed to tacrolimus. Tacrolimus can be effective and is well tolerated as an adjunctive therapy and allows tapering of corticosteroids.

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown etiology. The genes TOLLIP and MUC5B play important roles in lung host defense, which is an immune process influenced by oxidative signaling. Whether polymorphisms in TOLLIP and MUC5B modify the effect of immunosuppressive and antioxidant therapy in individuals with IPF is unknown.To determine whether single-nucleotide polymorphisms (SNPs) within TOLLIP and MUC5B modify the effect of interventions in subjects participating in the Evaluating the Effectiveness of Prednisone, Azathioprine, and N-Acetylcysteine in Patients with Idiopathic Pulmonary Fibrosis (PANTHER-IPF) clinical trial.SNPs within TOLLIP (rs5743890/rs5743894/rs5743854/rs3750920) and MUC5B (rs35705950) were genotyped. Interaction modeling was conducted with multivariable Cox regression followed by genotype-stratified survival analysis using a composite endpoint of death, transplantation, hospitalization, or a decline of ≥ 10% in FVC.Significant interaction was observed between N-acetylcysteine (NAC) therapy and rs3750920 within TOLLIP (P interaction = 0.001). After stratifying by rs3750920 genotype, NAC therapy was associated with a significant reduction in composite endpoint risk (hazard ratio, 0.14; 95% confidence interval, 0.02-0.83; P = 0.03) in those with a TT genotype, but a nonsignificant increase in composite endpoint risk (hazard ratio, 3.23; 95% confidence interval, 0.79-13.16; P = 0.10) was seen in those with a CC genotype. These findings were then replicated in an independent IPF cohort.NAC may be an efficacious therapy for individuals with IPF with an rs3750920 (TOLLIP) TT genotype, but it was associated with a trend toward harm in those with a CC genotype. A genotype-stratified prospective clinical trial should be conducted before any recommendation regarding the use of off-label NAC to treat IPF.

Background Mortality is similarly high among individuals with usual interstitial pneumonia (UIP) due to idiopathic pulmonary fibrosis (IPF) and interstitial pneumonia with autoimmune features (IPAF). Circulating anti-nuclear antibodies (ANA) are commonly found in this patient population, suggesting possible aberrant immune activation. Because an environment of oxidative stress can result from immunologic activation, we hypothesized that ANA positive patients with UIP would have improved outcome when exposed to the antioxidant N-acetylcysteine (NAC) compared to ANA negative patients. Methods A single center, retrospective cohort analysis was performed. Patients with UIP due to IPF and IPAF were stratified according to ANA status to and NAC exposure. Transplant-free survival (TFS) was assessed using the Kaplan-Meier estimator and multivariable Cox regression adjusted for diagnosis, gender/age/physiology score, immunosuppressant exposure and anti-fibrotic exposure. Results Of 293 individuals with UIP due to IPF (74%) or IPAF (26%), NAC exposure was documented in 58 (19.8%). Among NAC exposed individuals, 33 (56.9%) were ANA seropositive and 25 (43.1%) were seronegative. NAC exposure was associated with improved TFS survival among ANA seropositive individuals in unadjusted analysis (plogrank = 0.02) and after multi-variable adjustment (HR 0.51, 95% CI 0.30–0.87; p = 0.01). There was no association between NAC exposure and TFS in ANA seronegative individuals (HR 1.26, 95% CI 0.69–2.32; p = 0.45). Formal interaction testing confirmed NAC*ANA interaction (p = 0.04) and sensitivity analysis demonstrated an increasing effect size associated with NAC therapy as ANA titer increased. Among patients with available genetic data, a marginally higher proportion of ANA positive patients (p = 0.08) carried the rs3750920 (TOLLIP) genotype previously shown to predict favorable outcome in NAC exposed patients. Conclusion NAC exposure is associated with improved transplant-free survival ANA positive patients with UIP. These findings support the prospective collection of ANA data in in future NAC clinical trials performed in patients with UIP. Electronic supplementary material The online version of this article (10.1186/s12890-018-0599-3) contains supplementary material, which is available to authorized users.

Hemodynamic forces regulate vascular functions. Disturbed flow (DF) occurs in arterial bifurcations and curvatures, activates endothelial cells (ECs), and results in vascular inflammation and ultimately atherosclerosis. However, how DF alters EC metabolism, and whether resulting metabolic changes induce EC activation, is unknown. Using transcriptomics and bioenergetic analysis, we discovered that DF induces glycolysis and reduces mitochondrial respiratory capacity in human aortic ECs. DF-induced metabolic reprogramming required hypoxia inducible factor-1α (HIF-1α), downstream of NAD(P)H oxidase-4 (NOX4)-derived reactive oxygen species (ROS). HIF-1α increased glycolytic enzymes and pyruvate dehydrogenase kinase-1 (PDK-1), which reduces mitochondrial respiratory capacity. Swine aortic arch endothelia exhibited elevated ROS, NOX4, HIF-1α, and glycolytic enzyme and PDK1 expression, suggesting that DF leads to metabolic reprogramming in vivo. Inhibition of glycolysis reduced inflammation suggesting a causal relationship between flow-induced metabolic changes and EC activation. These findings highlight a previously uncharacterized role for flow-induced metabolic reprogramming and inflammation in ECs. DOI: http://dx.doi.org/10.7554/eLife.25217.001, eLife digest Atherosclerosis is the build-up of fatty material inside the blood vessels, and is one of the leading causes of heart disease and stroke. The blood vessels affected are typically inflamed for many years before the condition develops, and the condition often occurs at sites where blood vessels branch or turn. The cells that line the inside of the blood vessels are known as endothelial cells. Flowing blood exerts a force upon the endothelial cells, named “shear force”, which is similar to how wind bends plants. When the blood flows in one direction, the shear forces are high, the endothelial cells are tightly held together, and the vessels are less likely to become inflamed. However, the flow of blood is disturbed around turns or branch points. This means thatthe shear forces are lower and that the gaps between the endothelial cells are bigger. Low shear forces also mean that the endothelial cells release chemical signals that promote the inflammation and ultimately leads to atherosclerosis. Though low shear forces play an important role in “activating” endothelial cells to promote inflammation, it was not clear how this happens. Wu et al. now show that when shear forces inside blood vessels are low, endothelial cells promote inflammation by modifying their own metabolism. The experiments involved applying either high or low shear forces to endothelial cells that had originally been collected from a major blood vessel of human donors, and then grown in the laboratory. Wu et al. then analyzed the gene activity of these endothelial cells and discovered that low shear forces activate a selected pool of genes. The activated genes are mainly responsible for two cellular processes: glycolysis and the response to hypoxia. Glycolysis is a process that releases energy by breaking down the sugar glucose, while hypoxia refers to the situation when cells do not receive enough oxygen. Further molecular analyses revealed that low shear forces stabilize a particular protein involved in the response to hypoxia, named HIF-1α, and that this protein is responsible for stimulating glycolysis. Finally, Wu et al. showed that increasing glycolysis in endothelial cells was enough to cause the blood vessels to become inflamed. Going forward, a better understanding of how low shear forces modify the metabolism of endothelial cells in blood vessels and consequently promote inflammation will help scientists to tackle new questions about how atherosclerosis begins and develops. In the longer-term, these findings might also lead to the development of new treatments to atherosclerosis and similar diseases. DOI: http://dx.doi.org/10.7554/eLife.25217.002

Patients with interstitial lung disease (ILD) may have features of connective tissue disease (CTD), but lack findings diagnostic of a specific CTD. A recent European Respiratory Society/American Thoracic Society research statement proposed criteria for patients with interstitial pneumonia with autoimmune features (IPAF).We applied IPAF criteria to patients with idiopathic interstitial pneumonia and undifferentiated CTD-ILD (UCTD). We then characterised the clinical, serological and morphological features of the IPAF cohort, compared outcomes to other ILD cohorts and validated individual IPAF domains using survival as an endpoint.Of 422 patients, 144 met IPAF criteria. Mean age was 63.2 years with a slight female predominance. IPAF cohort survival was marginally better than patients with idiopathic pulmonary fibrosis, but worse than CTD-ILD. A non-usual interstitial pneumonia pattern was associated with improved survival, as was presence of the clinical domain. A modified IPAF cohort of those meeting the clinical domain and a radiographic or histological feature within the morphological domain displayed survival similar to those with CTD-ILD.IPAF is common among patients with idiopathic interstitial pneumonia and UCTD. Specific IPAF features can identify subgroups with differential survival. Further research is needed to replicate these findings and determine whether patients meeting IPAF criteria benefit from immunosuppressive therapy.