Endoscopic treatment for pancreatic fluid collections: Is active intervention always the optimal option?

Good patient vitality and activity levels at the first visit positively affect clinical decision-making, particularly in the selection of diagnostic work-ups and treatments across various medical fields. Several indicators of patient vitality, such as frailty (measured by the “Frailty Risk Score”),¹ sarcopenia (assessed using the psoas muscle mass index/area/density), and comorbidity index,² have been reported in recent literature and are closely associated with disease prognosis. Gilbert et al. reported that among 202,718 patients, those with the highest Hospital Frailty Risk Scores had significantly increased odds of 30-day mortality (odds ratio [OR] 1.71, 95% confidence interval [CI] 1.68–1.75), prolonged hospital stays (OR 6.03, 95% CI 5.92–6.10), and 30-day readmissions (OR 1.48, 95% CI 1.46–1.50) in older patients in acute care settings.¹ Furthermore, Farooq et al. found that frailty in adult patients with acute pancreatitis was associated with higher rates of local complications, such as pseudocyst and walled-off necrosis, and systemic complications including acute respiratory distress syndrome and sepsis, based on a large national database of the United States.³ It is widely acknowledged that frailty and comorbidity are interrelated in the progression of many diseases. For instance, during the COVID-19 pandemic, all measures of frailty and comorbidity were associated with higher COVID-19 mortality risk, even after adjusting for age and sex, according to data from the UK Biobank, which included 2812 COVID-19 inpatients.⁴ Furthermore, in an emergency department study of two Dutch hospitals, older adults with polypharmacy resulting from comorbidities and frailty had an increased risk of mortality (OR 2.62 and 3.92, 95% CI 1.39–4.93 and 1.95–7.90 for excessive polypharmacy).⁵ This association is not surprising, as scoring systems for both frailty and comorbidity often include overlapping factors such as cognitive function and mobility.^{1, 2, 5}

Pancreatic fluid collections (PFCs), such as pseudocysts, walled-off necrosis, or postoperative pancreatic fistulas, can develop after acute pancreatitis or pancreatic resection. In some cases, these complications are refractory and potentially fatal despite multidisciplinary approaches. The treatment strategy for PFCs depends on the patient's condition, which is often influenced by the severity and number of comorbidities, as well as the characteristics of the PFC itself. To date, no studies have investigated the impact of comorbidity accumulation on the clinical outcomes of minimally invasive endoscopic ultrasound (EUS)-guided treatments for PFCs. However, Hamada et al. demonstrated that the Charlson Comorbidity Index (CCI), a measure of comorbidity burden, was significantly associated with in-hospital mortality in patients undergoing EUS-guided drainage of PFCs. The adjusted ORs for mortality compared to patients with a CCI of 0 were 0.76 (95% CI 0.22–2.54) for patients with a CCI of 1–2, 5.39 (95% CI 1.74–16.7) for those with a CCI of 3–5, and 8.77 (95% CI 2.36–32.6) for those with a CCI of ≥6 (P_trend <0.001).⁶ This association persisted after controlling for age, sex, type of PFC (pseudocyst, walled-off necrosis, or postoperative PFC), drainage route, and stent type (plastic or metal). The study was further validated by a large national cohort data in Japan for more comprehensive findings. Notably, bleeding complications after the EUS-guided procedure were not significantly increased in patients with higher CCI scores (P_trend >0.34), despite a high likelihood of many participants being on antithrombotic medications (details not provided).⁶ Future research should explore the relationship between bleeding risks and the type or number of antithrombotic agents used in these patients.

As Hamada et al. noted, the biological mechanisms underlying the high mortality observed in patients with higher CCI remain unclear.⁶ Several studies offer potential insights. Jones et al. conducted a genome-wide meta-analysis and found that muscle weakness may be associated with genetic susceptibility.⁷ Among 256,523 Europeans aged 60 years and older, they identified 15 loci associated with muscle weakness, including genes involved in autoimmune disease (HLA-DQA1), osteoarthritis (GDF5, ALDH1A2, TGFA, BRSK1), cell cycle and cancer protection (TGFA), transcription regulation (RBBP6, ZBTB38), and musculoskeletal development (GDF5, DYM) (European Working Group on Sarcopenia in Older People definition). Furthermore, the concept of “inflammaging” – a chronic, low-grade inflammation associated with aging – has been proposed to explain increased susceptibility to chronic morbidity, disability, frailty, and premature death in older adults.⁸ Mechanisms behind inflammaging may include genetic factors, central obesity, increased gut permeability, altered microbiota, cellular senescence, inflammasome activation, oxidative stress, immune dysregulation, and chronic infections.⁸ Inflammaging, frailty, and comorbidity burden can share common features, such as genetic susceptibility, chronic stress, infection, and cancer development. Notably, Hamada et al.⁶ reported that approximately 20% of patients with a CCI ≥3 died from cancer when receiving EUS-guided treatment of PFCs. This finding aligns with genetic studies linking single nucleotide polymorphisms related to cellular senescence and inflammation with age-related diseases, including cancer, cardiovascular disease, and type 2 diabetes.⁹ Furthermore, Zeng et al.¹⁰ discovered that a single nucleotide polymorphism in the IL-6 gene was significantly associated with extreme longevity, supporting the role of IL-6 in regulating morbidity and mortality, particularly in older adults.

Elucidating the underlying mechanisms linking comorbidity burden to mortality can lead to the construction of novel treatment algorithms, not only for PFCs but also for a range of diseases influenced by inflammaging. Establishing a national biobank to systematically collect clinical data and biological specimens would facilitate multidisciplinary research on this topic, leading to more comprehensive and precise treatment strategies.

Author declares no conflict of interest for this article.

None.