CHARACTERIZATION OF CYTOKINE STORM SYNDROME AND SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN PATIENTS WITH EARLY SEVERE ACUTE PANCREATITIS: A PROSPECTIVE COHORT STUDY

Background
Germline genetic testing is recommended for younger patients with idiopathic pancreatitis, but there is no consensus recommendation for those over age 35. We aimed to analyze the results of genetic testing for pancreatic genetic mutations using a large dataset including all ages.

Methods
Individuals (ages 0-90) who underwent germline multigene testing for pancreatitis susceptibility genes (CASR, CFTR, CPA1, CTRC, PRSS1, SPINK1) through a large commercial laboratory between 2017 and 2022 for any cause were selected. Test results and information collected from requisition forms were evaluated. Multivariable logistic regression models were performed to identify factors associated with a positive pancreatitis panel result (defined as at least one pathogenic, likely pathogenic, and/or increased risk variant in a pancreatitis-related gene). Clinically significant results were defined as positive results in PRSS1, biallelic CFTR or SPINK1, or polygenic (i.e., CFTR and CASR).

Results
Overall, 2,468 subjects with primary indication of acute pancreatitis (AP; n=401), chronic pancreatitis (CP; n=631), pancreatic cancer (n=128), or other indications (n=1,308) completed panel testing. Among subjects with AP or CP (n=1,032), the most common variants were monoallelic CFTR (18.8%), monoallelic SPINK (6.9%), PRSS1 (4.5%), polygenic (2.0%), CTRC (1.6%), and biallelic CFTR (1.3%). The frequency of pathogenic variants varied according to age at the time of testing (Figure 1, 2). Variants in CASR contributed to polygenic results (with SPINK1) in 3 subjects. Among patients with pancreatic cancer, 10.2% had monoallelic variants in CFTR, but none had biallelic variants in CFTR.

Among subjects with AP or CP, the frequency of an abnormal result was significantly greater for those <35 versus ≥35 years of age (32.1% vs 24.5%, p=0.007). Similarly, the frequency of a clinically significant result was higher for those <35 vs ≥35 years of age (10.8% vs 5.4%, p=0.001). After adjusting for age, sex, race/ethnicity, primary indication for testing, and family history of pancreatitis, a positive family history of pancreatitis was associated with increased odds ratio (OR) of 8.59 (95% confidence interval (CI) 2.92-25.25) for a clinically significant panel result while each 5-year increase in age at test completion had lower odds (OR 0.89, 95% CI 0.83-0.95).

Discussion
The yield of germline genetic testing is highest in younger individuals with a positive family history of pancreatitis, which supports current recommendations for testing. However, a clinically significant result was found in approximately 5% of older adults. Therefore, we suggest that genetic counseling and germline testing should be considered for patients of all ages with acute or chronic pancreatitis.

Background: Development of organ failure (OF) within the first week of acute pancreatitis (AP) is characterized as early severe acute pancreatitis (ESAP) and has a mortality of up to 40%. The pathophysiology of OF in ESAP is not well understood. Our aim was to characterize cytokine storm syndrome (CSS) and secondary hemophagocytic lymphohistiocytosis (HLH) in AP.

Methodology: In this prospective observational cohort study, all consecutive patients with AP presenting within 14 days of onset of abdominal pain were included. Serum cytokines and chemokines were measured in all patients on day 3, 7, 14, 21 and 28 or till hospital discharge. The diagnosis of CSS was made in the presence of (i) elevated levels of serum IL-6 >160 pg/ml, (ii) presence of systemic inflammation such as systemic inflammatory response syndrome >48 hours and (iii) OF grade ≥2 persisting for ≥48 hours in the absence of sepsis. Secondary HLH was diagnosed as per 2004 HLH criteria or a H-score >169. CSS was correlated with clinical outcomes such as OF and mortality.

Results: From February 2021 till August 2022, 152 consecutive patients hospitalized for AP were screened and 98 patients were included in the study: 23 (23.5%) had mild, 24 (24.5%) moderate and 51 (52%) had severe AP as per revised Atlanta Classification. Of the 98 patients, 40 (40.8%) developed CSS with higher admission IL-6 levels [median 278 (IQR 207.5-450) pg/ml vs. 93.75 (43.1-154) pg/ml, p <0.01], modified Marshall OF score [Median 4 (IQR 3-5) vs. 0 (0-2), p <0.01] and higher in-hospital mortality [16 (40%) vs. 6 (10.3%), p=0.001] as compared to no CSS group (N=58). Serum TNF-a (r= 0.878, p=0.009), IL-6 (r=0.85, p=0.015), IL-8 (r=0.772, p=0.042), IL-10 (r=0.832, p=0.02), and IL-1b(r=0.884, p=0.008) showed statistically significant positive correlation with modified Marshall OF score on day 3 in CSS, while CCL-5 (r= 0.875, p=0.01) showed statistically significant negative correlation. Serial change in levels of IL-1b, IL-2, IL-6, IL8, IL-17 and IL-18 correlated with modified Marshalls OF score and mortality (Fig 1). Of the 51 patients with ESAP, 15 patients developed secondary HLH after a median of 9 (IQR 8-14) days from onset of AP HLH resolved on day 20 (15-27) of illness in patients who survived (n=8). Onset and resolution of HLH was in parallel with the onset and resolution of OF (Fig 2). No specific therapy for HLH was given [MOU1] and 6/15 (40%) died in HLH group.

Conclusion: Development of CSS in early phase of AP portended poor outcomes with higher OF and mortality. A proportion of patients with ESAP developed secondary HLH. These entities need to be recognized early to develop therapies targeting exaggerated dysregulated immune responses and improve outcomes in severe AP.