A broadly neutralizing monoclonal antibody overcomes the mutational landscape of emerging SARS-CoV-2 variants of concern.

The emergence of new variants of SARS-CoV-2 necessitates unremitting efforts to discover novel therapeutic monoclonal antibodies (mAbs). Here, we report an extremely potent mAb named P4A2 that can neutralize all the circulating variants of concern (VOCs) with high efficiency, including the highly transmissible Omicron. The crystal structure of the P4A2 Fab:RBD complex revealed that the residues of the RBD that interact with P4A2 are a part of the ACE2-receptor-binding motif and are not mutated in any of the VOCs. The pan coronavirus pseudotyped neutralization assay confirmed that the P4A2 mAb is specific for SARS-CoV-2 and its VOCs. Passive administration of P4A2 to K18-hACE2 transgenic mice conferred protection, both prophylactically and therapeutically, against challenge with VOCs. Overall, our data shows that, the P4A2 mAb has immense therapeutic potential to neutralize the current circulating VOCs. Due to the overlap between the P4A2 epitope and ACE2 binding site on spike-RBD, P4A2 may also be highly effective against a number of future variants.

Trends of humoral immune responses to heterologous antigenic exposure due to vaccination & omicron SARS-CoV-2 infection: Implications for boosting.

Background & objectives: Vaccination and natural infection can both augment the immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but how omicron infection has affected the vaccine-induced and hybrid immunity is not well studied in Indian population. The present study was aimed to assess the durability and change in responses of humoral immunity with age, prior natural infection, vaccine type and duration with a minimum gap of six months post-two doses with either ChAdOx1 nCov-19 or BBV152 prior- and post-emergence of the omicron variant. Methods: A total of 1300 participants were included in this observational study between November 2021 and May 2022. Participants had completed at least six months after vaccination (2 doses) with either ChAdOx1 nCoV-19 or an inactivated whole virus vaccine BBV152. They were grouped according to their age (≤ or ≥60 yr) and prior exposure of SARS-CoV-2 infection. Five hundred and sixteen of these participants were followed up after emergence of the Omicron variant. The main outcome was durability and augmentation of the humoral immune response as determined by anti-receptor-binding domain (RBD) immunoglobulin G (IgG) concentrations, anti-nucleocapsid antibodies and anti-omicron RBD antibodies. Live virus neutralization assay was conducted for neutralizing antibodies against four variants - ancestral, delta and omicron and omicron sublineage BA.5. Results: Before the omicron surge, serum anti-RBD IgG antibodies were detected in 87 per cent participants after a median gap of eight months from the second vaccine dose, with a median titre of 114 [interquartile range (IQR) 32, 302] BAU/ml. The levels increased to 594 (252, 1230) BAU/ml post-omicron surge (P<0.001) with 97 per cent participants having detectable antibodies, although only 40 had symptomatic infection during the omicron surge irrespective of vaccine type and previous history of infection. Those with prior natural infection and vaccination had higher anti-RBD IgG titre at baseline, which increased further [352 (IQR 131, 869) to 816 (IQR 383, 2001) BAU/ml] (P<0.001). The antibody levels remained elevated after a mean time gap of 10 months, although there was a decline of 41 per cent. The geometric mean titre was 452.54, 172.80, 83.1 and 76.99 against the ancestral, delta, omicron and omicron BA.5 variants in the live virus neutralization assay. Interpretation & conclusions: Anti-RBD IgG antibodies were detected in 85 per cent of participants after a median gap of eight months following the second vaccine dose. Omicron infection probably resulted in a substantial proportion of asymptomatic infection in the first four months in our study population and boosted the vaccine-induced humoral immune response, which declined but still remained durable over 10 months.

Pancreatic hemorrhage contributes to late mortality in patients with acute necrotizing pancreatitis.

OBJECTIVES: The frequency, risk factors, and impact on survival of hemorrhage into (peri)pancreatic collections in patients with acute pancreatitis (AP) has not been well studied. The study was designed to evaluate the risk factors for hemorrhage, successful hemostasis and its effect on in-hospital mortality. METHODS: In a prospective cohort study for prediction of severity of AP, the incidence, risk factors, and outcomes of pancreatic hemorrhage were analyzed. Patients with significant hemorrhage were managed according to a predefined protocol including endovascular intervention. RESULTS: Out of 363 patients hospitalized during the study-period, 33(9%) patients developed hemorrhage. Median time from onset of AP to hemorrhage was 59(45-68) days. The cause of hemorrhage was arterial in 19(57.5%) patients and unlocalized in 14(42.5%) patients. Hemorrhage was managed by conservative approach in 7 (21.2%), radiographic angioembolisation in 16 (48.5%), radiographic angioembolisation followed by surgery in 3 (9.1%), and surgery in 7 (21.2%) patients. Persistent organ failure [aHR 2.3 (1.1-5.1), p = 0.03], use of large bore (>20 Fr) catheter for initial drainage [aHR 3.9 (1.7-9.1), p = 0.001] and extensive (>50%) necrosis [aHR 3.1 (1.4-6.9), p = 0.005] were significant risk factors for hemorrhage. Hemorrhage was an independent predictor of mortality [aHR 2.0 (1.2-3.4), p = 0.008] in addition to persistent organ failure (aHR 12.1 (5.7-25.8), p < 0.001). In-hospital mortality in patients with hemorrhage was 22/33 (66.7%) vs. 81/330 (25%) in no hemorrhage group [p <0.001]. CONCLUSION: Pancreatic hemorrhage occurs later in the course of acute pancreatitis in relatively sicker group of patients with organ failure and extensive necrosis, and is independently associated with a higher risk of in-hospital mortality.

Early Versus Delayed Cholecystectomy for Acute Biliary Pancreatitis: A Systematic Review and Meta-Analysis.

BACKGROUND: Recommendations regarding the timing of cholecystectomy for acute biliary pancreatitis (ABP) require a systematic summary of current evidence to guide clinical practice. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing early cholecystectomy (EC) versus delayed cholecystectomy (DC) in patients with ABP. METHODS: We searched databases Medline, Embase, SCOPUS, Web of Science and Cochrane CENTRAL for randomized controlled trials addressing this question. Pairs of reviewers abstracted data and assessed the risk of bias in included studies. A random-effects meta-analysis was done to study the effect of the timing of cholecystectomy on outcomes of interest in patients with ABP. GRADE methodology was used to rate the quality in the body of evidence for each outcome as high, moderate, low, or very low. RESULTS: 11 randomized trials (1176 participants) were included. High-quality evidence from seven RCTs (867 participants) showed a statistically significant reduction in the risk for recurrent biliary events in favour of early cholecystectomy (RR 0.10, 95% CI 0.05 to 0.19, I2 = 0%). High-quality evidence from five trials was in favour of early cholecystectomy with a significant reduction in the risk 7of recurrent pancreatitis (RAP) in comparison to delayed cholecystectomy (RR 0.21, 95% CI 0.09 to 0.51, I2 = 0%). CONCLUSION: This review showed that EC has definite advantages over DC in terms of reducing recurrent pancreaticobiliary events and LOS following mild ABP. However, more RCTs are required to study the role of EC in patients with moderately-severe and severe ABP. Trial Registration Protocol registered on Prospero (CRD42020192823).

Clinical Course of Chronic Pancreatitis During Pregnancy and its Effect on Maternal and Fetal Outcomes.

INTRODUCTION: There are limited data on the effect of chronic pancreatitis (CP) on pregnancy outcomes and vice versa. Our aim was to evaluate the clinical trajectory of CP during pregnancy and its effect on pregnancy outcomes. METHODS: All female patients of child-bearing age (≥15 years) diagnosed with CP were studied from January 2004 to July 2019. The change in frequency of painful episodes was assessed before, during, and after pregnancy. Maternal and fetal outcomes were compared between pregnant women (early onset) and women presenting with CP after completion of all pregnancies (late onset). RESULTS: Of 187 women with CP, pregnancy outcomes and clinical course were assessed in 99 patients. The frequency of painful exacerbations was significantly lower during pregnancy compared with prepregnancy and postpregnancy periods (P < 0.001). The median pain score decreased significantly to 0 (0-2) during pregnancy from 3 (0-6) before conception and increased to 4 (0-8) after pregnancy (P = 0.002). Women with early onset CP (n = 57) had their first child later and had fewer pregnancies compared with those with late onset CP (n = 42). There was no difference in maternal outcomes such as gestational diabetes, hypertension, and preterm delivery, and fetal outcomes such as abortion, low birth weight, and still birth between the groups. There was no reported congenital anomaly. DISCUSSION: Younger patients with CP had later and fewer pregnancies, but there was no increased risk of adverse maternal and fetal outcomes. The clinical course of CP was usually benign during pregnancy with decreased frequency and severity of pain.

Endoscopic transmural drainage tailored to quantity of necrotic debris versus laparoscopic transmural internal drainage for walled-off necrosis in acute pancreatitis: A randomized controlled trial.

BACKGROUND AND AIMS: Both endoscopic and laparoscopic transmural internal drainage are practiced for drainage of walled-off necrosis (WON) following acute pancreatitis (AP) but the superiority of either is not established. Our aim was to compare transperitoneal laparoscopic drainage with endoscopic drainage using either lumen apposing metal stents (LAMS) or plastic stents tailored to the amount of necrotic debris in WON. METHODS: In a randomized controlled trial, adequately powered to exclude the null hypothesis, patients with symptomatic WON were randomized to either endoscopic or laparoscopic drainage. In the endoscopy group, two plastic stents were placed if the WON contained <1/3rd necrotic debris and a LAMS was placed if it was >1/3rd. Primary outcome was resolution of WON within 4 weeks without re-intervention for secondary infection. Secondary outcome was overall success (resolution of WON at 6 months) and adverse events. RESULTS: Forty patients were randomized: 20 to each group. Baseline characteristics were comparable between the groups. Primary outcome was similar between the groups [16 (80%) in laparoscopy and 15 (75%) in endoscopy group; p = 0.89]. The overall success was similar [18 (90%) in laparoscopy vs. 17 (85%) in endoscopy; p = 0.9]. Median duration of hospital stay was shorter in endoscopy group [4 (4-8) vs. 6 days (5-9); p = 0.03]. Adverse events were comparable between the groups. CONCLUSION: Laparoscopic drainage was not superior to endoscopic transmural drainage with placement of multiple plastic stent or LAMS depending on the amount of necrotic debris for symptomatic WON in AP. The hospital stay was shorter with the endoscopic approach.

Immediate and Long-Term Outcomes of Percutaneous Radiological Interventions for Hemorrhagic Complications in Acute and Chronic Pancreatitis.

PURPOSE: To evaluate and compare the immediate and long-term outcomes of radiological interventions for hemorrhagic complications in patients with acute and chronic pancreatitis. MATERIALS AND METHODS: This retrospective study, conducted between January 2014 and June 2020, included all patients with acute and chronic pancreatitis presenting with hemorrhagic complications who underwent angiography and/or embolization. Their clinical, angiographic, and embolization details were evaluated and correlated with procedure success, complications, recurrence, and mortality. The patients were subgrouped into groups A (acute pancreatitis) and C (chronic pancreatitis), and comparisons were made. RESULTS: The study included 141 patients (mean age, 36.3 ± 11.2 years; 124 men), of whom 106 patients had abnormal angiography findings and underwent embolization. Of them, group A had 50 patients (56 lesions) and group C had 56 patients (61 lesions). All the patients in group A had severe acute pancreatitis, with a mean computed tomography severity index of 7.6. The technical and clinical success rates of embolization, complications, recurrence, and long-term outcomes were not significantly different between the groups. Group A had significantly higher mortality due to sepsis and organ failure. Embolic agents did not have any significant association with complications, recurrence, and mortality. After a mean follow-up of 2 years, 72.5% of the patients were asymptomatic, and none had symptoms attributable to embolization. CONCLUSIONS: Success, complications, and recurrence after embolization for hemorrhagic complications were comparable between acute and chronic pancreatitis. Acute pancreatitis was associated with significantly higher mortality. Embolic agents did not significantly influence the outcomes. None had long-term adverse effects attributable to embolization.

Acute pancreatitis and nosocomial COVID-19: Cause specific host responses may determine lung injury.

BACKGROUND: Coronavirus disease 2019 (COVID-19) presents with myriad extra-pulmonary manifestation and a high mortality in patients with comorbidities. Its effect on patients with pre-existing acute pancreatitis is not known. METHODS: We hereby, present 3 cases with severe acute pancreatitis with persistent respiratory failure who acquired nosocomial COVID-19 during their hospital stay after recovery from respiratory failure. Their clinical course is highlighted which reflects on pathophysiology of organ dysfunction in these 2 disease states. RESULTS: None of the 3 patients with severe acute pancreatitis who developed nosocomial COVID-19 redeveloped respiratory failure due to COVID-19 despite having recently recovered from pancreatitis induced acute hypoxemic respiratory failure. Only one patient developed SARS-CoV2 induced moderate pneumonia. CONCLUSION: These cases highlight that host responses and mechanisms of lung injury might be different in severe acute pancreatitis and COVID-19.

Percutaneous Endoscopic Step-Up Therapy Is an Effective Minimally Invasive Approach for Infected Necrotizing Pancreatitis.

BACKGROUND: Infected pancreatic necrosis (IPN) is a major complication of acute pancreatitis (AP), which may require necrosectomy. Minimally invasive surgical step-up therapy is preferred for IPN. AIM: To assess the effectiveness of percutaneous endoscopic step-up therapy in patients with IPN and identify predictors of its success. METHODS: Consecutive patients with AP hospitalized to our tertiary care academic center were studied prospectively. Patients with IPN formed the study group. The treatment protocol for IPN was percutaneous endoscopic step-up approach starting with antibiotics and percutaneous catheter drainage, and if required necrosectomy. Percutaneous endoscopic necrosectomy (PEN) was performed using a flexible endoscope through the percutaneous tract under conscious sedation. Control of sepsis with resolution of collection(s) was the primary outcome measure. RESULTS: A total of 415 patients with AP were included. Of them, 272 patients had necrotizing pancreatitis and 177 (65%) developed IPN. Of these 177 patients, 27 were treated conservatively with antibiotics alone, 56 underwent percutaneous drainage alone, 53 required underwent PEN as a step-up therapy, 1 per-oral endoscopic necrosectomy, and 52 required surgery. Of the 53 patients in the PEN group, 42 (79.2%) were treated successfully-34 after PEN alone and 8 after additional surgery. Eleven of 53 patients died due to organ failure-7 after PEN and 4 after surgery. Independent predictors of mortality were > 50% necrosis and early organ failure. CONCLUSION: Percutaneous endoscopic step-up therapy is an effective strategy for IPN. Organ failure and extensive pancreatic necrosis predicted a suboptimal outcome in patients with infected necrotizing pancreatitis.

Endoscopic versus laparoscopic drainage of pseudocyst and walled-off necrosis following acute pancreatitis: a randomized trial.

BACKGROUND: Pancreatic fluid collections (PFC) may develop following acute pancreatitis (AP). Endoscopic and laparoscopic internal drainage are accepted modalities for drainage of PFCs but have not been compared in a randomized trial. Our objective was to compare endoscopic and laparoscopic internal drainage of pseudocyst/walled-off necrosis following AP. PATIENTS AND METHODS: Patients with symptomatic pseudocysts or walled-off necrosis suitable for laparoscopic and endoscopic transmural internal drainage were randomized to either modality in a randomized controlled trial. Endoscopic drainage comprised of per-oral transluminal cystogastrostomy. Additionally, endoscopic lavage and necrosectomy were done following a step-up approach for infected collections. Surgical laparoscopic cystogastrostomy was done for drainage, lavage, and necrosectomy. Primary outcome was resolution of PFCs by the intended modality and secondary outcome was complications. RESULTS: Sixty patients were randomized, 30 each to laparoscopic and endoscopic drainage. Both groups were comparable for baseline characteristics. The initial success rate was 83.3% in the laparoscopic and 76.6% in the endoscopic group (p = 0.7) after the index intervention. The overall success rate of 93.3% (28/30) and 90% (27/30) in the laparoscopic and endoscopic groups respectively was also similar (p = 1.0). Two patients in the laparoscopic group required endoscopic cystogastrostomy for persistent collections. Similarly, two patients in the endoscopic group required laparoscopic drainage. Postoperative complications were comparable between the groups except for higher post-procedure infection in the endoscopic group (19 vs. 9; p = 0.01) requiring endoscopic re-intervention. CONCLUSIONS: Endoscopic and laparoscopic techniques have similar efficacy for internal drainage of suitable pancreatic fluid collections with < 30% debris. The choice of procedure should depend on available expertise and patient preference.

Pentazocine, a Kappa-Opioid Agonist, Is Better Than Diclofenac for Analgesia in Acute Pancreatitis: A Randomized Controlled Trial.

OBJECTIVES: The ideal analgesic is not known for patients with acute pancreatitis (AP). Concerns have been raised about serious adverse effects of opioid analgesics increasing the severity of AP. We hypothesized that nonsteroidal anti-inflammatory drugs might be better analgesics because of their anti-inflammatory effect. Our objective was to compare pentazocine, an opioid, and diclofenac, a nonsteroidal anti-inflammatory drug, for adequate analgesia in patients with AP. METHODS: In a double-blind randomized controlled trial, patients with AP were randomized to either intravenous diclofenac 75 mg or pentazocine 30 mg. Fentanyl was given as a rescue analgesic through a patient-controlled analgesia pump. Primary outcome was pain relief measured objectively by the dose of fentanyl required as the rescue analgesic, pain-free period, and numbers of effective and ineffective demands of fentanyl. Secondary outcome was adverse events. RESULTS: Fifty patients were randomized, 24 to the pentazocine group and 26 to the diclofenac group. Baseline characteristics were comparable between the groups. Pentazocine was found to be better than diclofenac in terms of significantly lower dose of the rescue analgesic (fentanyl) required (126 µg (interquartile range (IQR) 65-218 µg) vs 225.5 µg (IQR 133-427 µg); P = 0.028) and longer pain-free period (31.1 ± 8.2 vs 27.9 ± 6.6 hours, P = 0.047). The number of effective and ineffective demands was lower in the pentazocine group compared with the diclofenac group (11.5 (IQR 8-15) vs 16 (IQR 13-20), P = 0.098) although not statistically significant. Adverse events were similar between the groups. CONCLUSIONS: Pentazocine, a kappa-opioid receptor agonist, was significantly better than diclofenac for pain relief in AP (Trial registration number: CTRI/2016/09/007326).

Interleukin-6 significantly improves predictive value of systemic inflammatory response syndrome for predicting severe acute pancreatitis.

BACKGROUND: Predicting severe acute pancreatitis (AP) is important for triage, prognosis, and designing therapeutic trials. Persistent systemic inflammatory response syndrome (SIRS) predicts severe AP but its diagnostic accuracy is suboptimal. Our objective was to study if cytokine levels could improve the predictive value of clinical variables for the development of severe AP. METHODS: Consecutive patients with AP were included in a prospective cohort study at a tertiary care center. Serum levels of IL-6, TNF-α, IL-10, MCP-1, GM-CSF and IL-1ß were measured at day 3 of onset of AP. Variables such as age, co-morbidity, etiology, SIRS, and cytokines were modeled to predict severe AP by multivariable regression analysis. Genotyping was done to correlate IL-6, TNF-α and MCP-1 gene polymorphisms with cytokine levels. RESULTS: Of 236 patients with AP, 115 patients admitted within 7 days of onset formed the study group. 37 of the 115 (32%) patients developed organ failure. Independent predictors of organ failure were persistent SIRS (OR 34; 95% CI: 7.2-159) and day 3 serum IL-6 of >160 pg/ml (OR 16.1; 95% CI:1.8-142). IL-6 gene (-174 G/C) GG genotype was associated with significantly higher levels of IL-6 compared to CC/CG genotype. Serum IL-6 >160 pg/ml increased the positive predictive value of persistent SIRS from 56% to 85% and specificity from 64% to 95% for predicting OF without compromising its sensitivity and negative predictive value. CONCLUSION: Serum IL-6 of >160 ng/ml added significantly to the predictive value of SIRS for severe AP.

Increased oxidative stress and deficient antioxidant levels may be involved in the pathogenesis of idiopathic recurrent acute pancreatitis.

BACKGROUND: Increased Oxidative Stress (OS) is implicated in the pathogenesis of Chronic Pancreatitis (CP). Whether or not OS contributes to disease progression through the stages of Recurrent Acute Pancreatitis(RAP), to CP is not known. Increased OS, if present in RAP could be an important therapeutic target in preventing progression of RAP to CP. OBJECTIVE: To assess the oxidative stress and antioxidant status in patients with idiopathic RAP. METHODS: 50 consecutive patients with Idiopathic Recurrent Acute Pancreatitis (IRAP) were included. Markers of OS [4-hydroxynonenol (4-HNE), malondialdehyde (MDA) and serum SOD (S-SOD)] and antioxidant status [ferric reducing the ability of plasma (FRAP), Glutathione peroxidase (GPX) and Vitamin C (Vit C)] were measured in quiescent phase and during an episode of pancreatitis. Their levels were compared with those in age and sex matched healthy controls and patients with CP. RESULTS: The mean age of patients with IRAP was 22.2 ± 7.7 years and 39 (78%) were males. Levels of 4-HNE were significantly increased in patients with IRAP compared with healthy controls (3.03 ± 2.35 vs. 2.12 ± 1.29 ng/ml; p = 0.03) and were even higher during an episode of acute pancreatitis (5.21 ± 3.51 ng/ml; p = 0.03). Antioxidant levels were reduced in IRAP compared with healthy controls as measured by FRAP (707.0 ± 144.9 vs. 528.8 ± 120.0 µmol/Fe2+liberated; p = 0.0001) and GPX (1472 ± 375.7 vs. 910.0 ± 558.5 pg/ml; p = 0.001). OS and antioxidant profiles were similar in IRAP and CP with no significant difference. CONCLUSION: OS is increased in patients with IRAP, more so during an acute episode. Antioxidant levels are also reduced suggesting that OS may play a role in the pathogenesis of IRAP and its progression to CP.

Long-term pain relief with optimized medical treatment including antioxidants and step-up interventional therapy in patients with chronic pancreatitis.

BACKGROUND AND AIM: Abdominal pain is difficult to treat in patients with chronic pancreatitis (CP). Medical therapy including antioxidants has been shown to relieve pain of CP in the short-term. Our aim was to study the long-term results of optimized medical and interventional therapy for pain relief in patients with CP with a step-up approach. METHODS: All consecutive patients with CP were included prospectively in the study. They were treated medically with a well-balanced diet, pancreatic enzymes, and antioxidants (9000 IU beta-carotene, 0.54 g vitamin C, 270 IU vitamin E, 600 µg organic selenium, and 2 g methionine). Endoscopic therapy and/or surgery were offered if medical therapy failed. Pain relief was the primary outcome measure. RESULTS: A total of 313 patients (mean age 26.16 ± 12.17; 244 males) with CP were included; 288 (92%) patients had abdominal pain. The etiology of CP was idiopathic in 224 (71.6%) and alcohol in 82 (26.2%). At 1-year follow-up, significant pain relief was achieved in 84.7% of patients: 52.1% with medical therapy, 16.7% with endoscopic therapy, 7.6% with surgery, and 8.3% spontaneously. The mean pain score decreased from 6.36 ± 1.92 to 1.62 ± 2.10 (P < 0.001). Of the 288 patients, 261, 218, 112, and 51 patients were followed up for 3, 5, 10, and 15 years, respectively; 54.0%, 57.3%, 60.7%, and 68.8% of them became pain free at those follow-up periods. CONCLUSION: Significant pain relief is achieved in the majority of patients with optimized medical and interventional treatment.

Novel and Experimental Therapies in Chronic Pancreatitis.

Chronic pancreatitis (CP) is a progressive inflammatory disease of the pancreas. The currently available treatment of CP is aimed at controlling symptoms and managing complications. Unfortunately, no specific treatment is available to halt the progression of the disease process because the pathophysiological perturbations in CP are not well understood. In this review, we discuss various therapeutic targets and investigational agents acting on these targets. Among these, therapies modulating immune cells and those acting on pancreatic stellate cells appear promising and may translate into clinical benefit in near future. However, these experimental therapies are mostly in animal models and they do not recapitulate all aspects of human disease. Still they may be beneficial in developing effective therapeutic modalities to curb inflammation in chronic pancreatitis.