1.1 Acute pancreatitis in CF

Acute pancreatitis is a known but less common manifestation in the CF population as it exclusively tends to occur in pwCF-PS. A recent study demonstrated that 2.9% of included patients with PS developed AP versus 0.9% of patients with EPI developed pancreatitis.⁶ Overall, 20% of PS CF patients develop AP. Recurrent AP seems to be related to the degree of severity in relation to the CFTR gene but has also been reported to be greater in individuals who carry mutations in both CFTR and SPINK1 genes, likely due to a synergistic effect of multiple disease-producing genetic mutations. A retrospective chart review mentioned comprehensive data from the INSPIRE (INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE) study, which included those with at least one CFTR mutation who developed the diagnosis of AP and/or CP (34% and 23%, respectively). CFTR mutations were the most common in those with RAP. This emphasizes the importance of CFTR functional testing and genetic analysis in those patients with RAP or a severe episode of AP.^{7, 8} The functional severity of the CFTR mutation was related to the balance between the degree of pancreatic acinar preservation and the extent of ductal plugging due to inspissated secretions. The functional severity of the mutations was determined from a calculation of a pancreatic insufficiency prevalence score (PIP). Eventually, it was found that those with mild genotypes had a greater risk of pancreatitis, but since not all that carried the genotype had greater pancreatitis risk, there was a suggestion of influences on phenotype by non-CFTR modifier factors. Among the 62 patients who developed AP, only 11 had a single AP event, 37 had RAP, and 14 had chronic pancreatitis (CP). In many of these patients, the onset of pancreatitis preceded the diagnosis of CF.³

The original Atlanta classification system for AP, first established in 1992, created a worldwide consensus for the terminology of AP types, severity, and complications.⁹ In 2012, the classification was revised to update terms, clarify definitions, and incorporate an updated understanding of pancreas physiology.¹⁰ The diagnosis of AP requires the presence of at least 2 of 3 criteria: abdominal pain consistent with classic pancreatitis such as epigastric abdominal pain radiating to the back, amylase and/or lipase greater than 3 times the upper limit of normal, and characteristic findings on imaging among ultrasound (US), computed tomography (CT), or magnetic resonance imaging (MRI).

AP is divided into two types: interstitial edematous, and necrotizing. Interstitial edematous AP is the more common subtype and presents with enlargement of the pancreas due to inflammatory edema. On CT, the parenchyma shows homogeneous enhancement, peripancreatic fat shows inflammatory changes by haziness or stranding, and there may be peripancreatic fluid. The necrotizing type develops in about 5–10% of patients and can occur in the parenchyma or peripancreatic tissue. CT may underestimate the extent of the disease, as necrosis can evolve over several days based on the impairment of pancreatic perfusion. These may be variable as they can remain solid or liquefy, remain sterile or become infected, persist, or disappear over time. Importantly, most evidence does not show the correlation between the extent of necrosis and the risk of infection.¹⁰

The revised Atlanta classification further specifies the early and late phases of the disease. The early phase usually lasts a week and results from host response to local pancreatic injury including cytokine cascades that manifest clinically as the systemic inflammatory response syndrome, which increases the risk of organ failure. Organ failure focuses on the respiratory, renal, and cardiovascular systems in a modified Marshall scoring system. The late phase only occurs in those with moderately severe or severe AP as they are more likely to develop local complications.¹⁰

Severity is classified as mild, moderately severe, or severe. Mild AP is the most common subtype, is defined as having no organ failure nor local or systemic complications and tends to resolve within the first week. Moderately severe disease presents with transient organ failure (with a duration of 48 hours post-onset of AP) along with local complications or exacerbation of comorbid disease. Severe AP occurs with organ failure, either single or multiple, which persists for at least 48 hours post-AP onset.¹⁰

1.2 Management of acute pancreatitis

The initial management of AP in children parallels that in adults, with minor differences in the classification of AP severity and the rate of intravenous fluid administration. The inflammatory state induced by AP results in significant extravasation of proteinaceous intravascular fluid into the extracellular space, leading to intravascular hemoconcentration. Low intravascular volume reduces organ perfusion such as that of the pancreas, increasing the risk of pancreatic necrosis, acute kidney injury, respiratory failure, and other organ dysfunction.¹¹ Therefore, treatment begins by an assessment of AP severity through an assessment of organ function, hemodynamic stability, and the presence or absence of the systemic inflammatory response syndrome, followed by triage to the appropriate level of care.¹²

Early intravenous fluid resuscitation with a crystalloid is the foundation of therapy and the most important initial treatment, especially in cases with high admission hematocrit levels ( > 44%).^{13, 14} While there was lacking evidence to support a preference for crystalloid type Lactated Ringer's (LR) versus normal saline in the past,^13-15 evolving evidence is now suggesting LR may be the preferred fluid type in both adults and children.^16-19 Although direct evidence in children is lacking, the data can be extrapolated to pediatric cases as has been done previously.¹⁴ The recent pivotal WATERFALL randomized controlled trial by de-Madaria et al. has now favored a moderate rather than aggressive rate of intravenous fluid administration.²⁰ Lactated Ringer's at a rate of 1.5 mL/kg is recommended, preceded by a bolus of 10 mL per kilogram in hypovolemic patients. The rate in children has been suggested to be 1.5–2 times the rate of maintenance fluids, however, based on the new data from the WATERFALL Trial, less aggressive rates could be considered.^{14, 21} Less aggressive fluid hydration has been shown to significantly reduce volume overload, which could be treated with reduction of hydration and with the use of diuretics. The WATERFALL Trial also highlights the importance of continual reassessment of fluid response, volume status, and ideally, goal-directed therapy including vital signs and urine output. Although it is prudent to frequently monitor vitals, urine output, electrolytes, renal function, and volume status, neither the hematocrit nor any other parameter have been found to serve as a goal metric to effectively adjust fluid resuscitation.^{14, 22} In the WATERFALL trial, intravenous fluid therapy was discontinued once oral feeding was tolerated for 8 hours and as early as 20 hours from the start of intravenous fluid resuscitation; while in children, early refeeding has been recommended within 48 hours for mild AP, and within 72 hours for severe cases.^{20, 23}

Early enteral refeeding by oral or nasogastric access is recommended and does not negatively affect the course of AP in both children and adults, and may reduce the risk of infectious complications by maintaining tight junctions in the intestine thereby limiting bacterial translocation.^{14, 20, 24-27} Antibiotic prophylaxis should be avoided in the absence of infection.¹⁴ Repeat imaging with pancreas protocol contrast-enhanced MRI or CT should be deferred unless there is a clinical deterioration or a lack of clinical improvement, and, if necessary, should be delayed to 4 days after symptom onset to better detect complications such as necrosis.^{14, 16} Pain can be managed with narcotics if nonsteroidal anti-inflammatory medications are insufficient to control pain, although this is based on limited data.¹⁴

Next, any underlying contributing etiology of the episode of AP should be identified and treated to prevent recurrence or exacerbation of AP. Biliary, medication, anatomic, and systemic illness etiologies are the most common causes of pediatric AP and should first be investigated with a detailed personal history, with the benefit of including toxic etiologies such as alcohol in older pediatric and adult patients.¹⁴ Less common causes of AP could be elicited by a history focusing on abdominal trauma, infections, recent procedures such as endoscopic retrograde cholangiopancreatography (ERCP), and family history of pancreatic disease for genetic causes.^{16, 28} Extensive counselling regarding the cessation of alcohol, marijuana, and smoking should be completed if appropriate. For alcohol use-related AP, alcohol intervention during admission has been suggested by the American Gastroenterological Association.¹³ Any potential offending medications should be discontinued when possible.

A thorough evaluation for biliary causes should be pursued by laboratory hepatic function testing and imaging. Ultrasound abdomen may have a role in cases with negative CT imaging to account for non-calcified stones that are less well visualized on CT.

Biliary pancreatitis determined by visible cholelithiasis/sludge, choledocholithiasis, or elevated transaminases (particularly ALT > 150 within 48 h after onset of symptoms) without visible biliary stones on imaging should be treated with cholecystectomy on index admission to reduce risk of RAP.^{13, 14, 16, 29-31} Presence of even a small amount of sludge/microlithiasis can be sufficient to cause AP, and in most situations, sludge is more common as an AP etiology than large choledocholithiasis with sludge refluxing from the common bile duct into the pancreatic duct via the common channel to then trigger an AP episode. ERCP can be performed non-urgently for choledocholithiasis, unless there is concurrent cholangitis, where urgent ERCP would be indicated.^{13, 14, 32}

Every case of AP should also have serum triglyceride levels evaluated at, or near the time of admission to evaluate for hypertriglyceridemia as a cause for AP, seen in familial lipid disorders and other chronic medical conditions. False negative triglyceride levels can occur if tested substantially after admission in a patient who is kept nil per os. Causative hypertriglyceridemia should be treated with insulin, noting that some medications administered following admission, such as propofol, may increase triglyceride levels following the onset of the.

Autoimmune pancreatitis (AIP) should be considered with the typical laboratory, imaging, and/or histologic findings. Type 1 AIP is suspected in adults based on a pattern of presentation with other organ involvement and elevation in serum IgG4 levels but is unusual in children.³³ Children tend to present with Type 2 AIP where no other organ involvement is present (IgG4 negative), especially in the setting of concurrent inflammatory bowel disease due to the marked association with Type 2 AIP.^33-35 Therefore, IgG4 is rarely positive in children, and its measurement is not as useful in excluding or diagnosing AIP. Due to less well-defined criteria and the difficulty in obtaining tissue specimens in children, the diagnosis of AIP should be based on high clinical suspicion and steroid responsiveness.³⁴ Treatment with a time-limited course of oral prednisone at doses of 1–1.5 mg/kg/day is usually sufficient for Type 2 AIP and pediatric cases.^{34, 35}

Idiopathic AP/RAP with no identifiable cause should have endoscopic ultrasound evaluation for structural abnormalities when available and genetic testing for PRSS1, SPINK1, and CFTR mutations.

Finally, local complications of AP such as fluid collections, pseudocysts, necrotic fluid collections and walled-off necrosis can be drained endoscopically by EUS-guided transluminal drainage and necrosectomy, procedures which have been successfully also performed in children or by percutaneous interventional radiology drainage, with surgical drainage and debridement reserved for only the most severe of cases that are nonresponsive to a progressive step-up approach in either children or adults.^36-38

1.3 AP/RAP chronic management: Longitudinal effects of modulator therapies

Acute recurrent pancreatitis manifests as individual episodes of pancreatitis but between these episodes there is a lack of structural changes or abnormalities found on imaging to suggest chronic, irreversible pancreatic damage, as seen in chronic pancreatitis. Imaging modalities to evaluate for such findings would include transabdominal and endoscopic ultrasound, MRI, as well as CT. ARP may be seen in genetic etiologies such as CF. Historically, noninvasive, long-term treatment options for ARP have focused on supportive care, including pain control and lifestyle modifications (i.e. alcohol abstinence in a patient with alcoholic RAP) to prevent further attacks. CFTR modulators have been shown to be an effective drug therapy for reducing pancreatitis episodes as well as improving exocrine pancreatic function.

Improvement in exocrine function has been described to occur because of better duct cell function and subsequent acinar cell function.³⁹ By improving CFTR function, modulators alter the luminal environment within the pancreas by increasing alkalinization and lowering secretion viscosity allowing better pancreatic drainage and thereby lessening the recurrence of AP.

Ramsey et al. performed a recent systematic review including 41 of 630 studies meeting inclusion criteria and found that with modulator use, pancreatitis events decreased by 85%, which was most significant in the pancreatic-sufficient subgroup. These cases included both ivacaftor use as well as combination therapy. This review also noted that 21% of individuals who had been exocrine insufficient at the time of modulator initiation converted to sufficiency during the treatment course. These individuals tended to be younger than those who remained pancreatic insufficient, potentially supporting the theory of chronic ongoing pancreatic damage due to CF even in those who are already pancreatic insufficient.³⁹ A case series by Emery et al. reported that some individuals on ivacaftor (IVA) tolerated a decrease in pancreatic enzyme dosing after IVA initiation, and that IVA could improve pediatric patients' body mass index, fecal elastase levels, and blood glucose suggesting improvements in both exocrine and endocrine pancreatic function.⁴⁰

In addition to pwCF, individuals with CFTR-related disorder (CFTR-RD) who do not meet clinical criteria for CF (sweat chloride values < 60 mmol/L) are still at risk for AP given the presence of CFTR dysfunction. CFTR modulators could also be used as an early and effective treatment for those with CFTR-RD suffering from AP or RAP to avoid sequelae and complications seen with chronic pancreatic damage.⁴¹

CFTR modulators have also been reported to potentially increase the risk of AP in certain individuals. Restoration of acinar and ductal function by modulators could lead to a more optimal environment for AP to occur, depending on the extent of fibrosis and damage already developed that is seen in CF-PI individuals.⁴² Modulators restore enough acinar function to allow for acinar injury and inflammation from enzyme auto-activation as previously described, and therefore providers should be aware of this potential but thankfully infrequent complication of modulator therapy.⁴²

1.4 AP/RAP chronic management of pain: A focus on non-opioid analgesics

Both centrally acting opioid and/or peripherally acting non-opioid analgesics can be used for pain management in AP. There is no specific ideal pain management regimen in pediatric AP patients, nor difference in risk of developing complications of AP based on the pain management regimen used (opioid vs. non-opioid analgesics).^{14, 26} Nevertheless, preference for non-opioid regimens is suggested to decrease adverse sequelae of opioid use.

Non-opioid medications including acetaminophen and ibuprofen are used as first-line for mild pain, with opioids reserved for management of moderate to severe pain.⁴³ In CP, the aim is to treat the neuropathic nature of pancreatic pain, with medications such as selective serotonin reuptake inhibitors, pregabalin, and gabapentin, but no studies evaluated the efficacy of these medications in children with CP.⁴³ This is similar to pain management strategies in adults with CP where the data is extrapolated from.

¹⁴Opioid-sparing analgesics like NSAIDS have been used to control AP-associated pain despite being uncommonly responsible for the development of AP. Epidural analgesics have been used to decrease pain in patients with AP by blocking sympathetic nerve mediated redistribution of splanchnic blood flow to nonperfused areas of the pancreatic.¹⁴ Procaine has also been used locally and systemically as a basic analgesic for AP. However, neither epidural analgesics nor procaine specifically are commonly used as pain management options in AP, with celiac plexus blockade more commonly employed as a pain management strategy in CP patients.⁴³

In CP, non-opioid analgesics including medications to address neuropathic pain are the foundations of therapy, and opioid analgesics are reserved for either cases refractory to non-opioid analgesics or on an as-needed basis in the case of pain flares. Pancreatic enzyme replacement therapy (PERT) is not used for pain control in CP as it has been shown to be ineffective, though patients on PERT may report an improvement of discomfort secondary to maldigestion or bloating that may be treated by PERT.⁴³

1.5 Surgical management of acute recurrent and chronic pancreatitis

The pain of CP is thought to originate from both dilated ducts (“plumbing”) and neural pathways (“wiring”). Surgical intervention is considered when persistent pain negatively impacts the quality of life and is not adequately controlled by medications, celiac plexus nerve block, or endoscopic interventions including sphincterotomy, stone extraction, and stricture dilation.^44-46 A multidisciplinary approach selects among pancreatic drainage, resection, and total pancreatectomy with islet cell auto transplantation (TPIAT), or supportive care. The advantage of TPIAT is the radical treatment of underlying diffuse structural pancreatic damage or RAP as can be seen with genetic etiologies, a variably dilated pancreatic duct with a lack of a discrete pancreatic head mass, or a failed prior procedure.^{44, 47, 48} Limited surgical resection techniques can be considered for more focal diseases. For Cases with a uniformly dilated duct ≥ 7 mm, a Frey (preferred) or Modified Peustow decompress the ductal system without resecting the pancreatic head. Otherwise, if a pancreatic head mass requires a wider resection of the pancreatic head, a duodenum-preserving Frey, Beger or Berne is preferred over a Whipple.^{44, 49, 50} The surgical option for a variably dilated duct and/or pancreatic duct less than 7 mm would be a TPIAT if there is no head mass accounting for the ductal changes. TPIAT is performed only when patients are nondiabetic at baseline given expected islet loss. In patients with pre-existing diabetes, total pancreatectomy can be considered but the islet autotransplantation component would be of limited benefit. TPIAT should be considered carefully due to the complexity of the surgery, but durable pain relief has been reported in approximately 90% of patients at 15 years, with a 20% insulin independence rate.⁵¹ The conventional operations involving drainage and/or partial resection have also had lasting benefit in adults, and lasting pain relief in children ranging 78–91% over several years.^52-55

Exocrine pancreatic insufficiency can develop following an episode of severe AP, extensive chronic injury to the pancreatic parenchyma, and also postoperatively when all or a significant portion of the pancreas is resected. There is a higher incidence of EPI in CF-related CP, suggesting underlying ongoing chronic damage to the gland even in the absence of discrete AP episodes.⁵⁶ Management begins with appropriate nutrition, diet, vitamin supplementation, enzyme replacement, and monitoring for complications of EPI. In contrast to non-CF CP where a normal diet is recommended, a high-fat diet accompanied by PERT is recommended in pediatric patients with CF to meet the appropriate nutritional and caloric needs. Growth should be followed closely to allow early dietary intervention if necessary. Fat-soluble vitamins A, D, E, and K are frequently deficient, and levels should be tested at regular intervals, usually every 12 months or at shorter intervals if deficiencies are present. Symptomatic or subclinical EPI is likely with a single fecal elastase level of less than 100 μg/g of formed stool, but treatment with PERT can be initiated also at indeterminate/moderate EPI elastase levels of 100–200 μg/g formed stool.^{56, 57} Dosing of PERT in pediatrics is similar to that in adults and can be based on weight, fat consumption, or feeding volume.⁵⁶ Weight-based dosing begins at 1000 lipase units/kg/meal and can be increased to 3000 lipase units/kg/meal. A maximum dose of 10,000 lipase units/kg/meal is advised due to the risk of fibrosing colonopathy, as occurs in adults.⁵⁸ PERT dosing in adults is less commonly weight-based.

The major sequelae of CP are EPI with its associated complications, diabetes mellitus (DM), fluid and necrotic collections, and pancreatic cancer. Fluid and necrotic collections can usually be monitored for spontaneous resolution unless the development of symptoms such as abdominal pain, nausea, vomiting, or early satiety indicates the need for drainage. The prevalence of DM in children with CP is reported to be 4-9% and therefore screening with yearly A1c and fasting blood glucose level is recommended.⁵⁶ Pancreatogenic diabetes (Type 3c) in children should be treated by a pediatric endocrinologist and usually requires insulin. Chronic pancreatitis is also known to increase the risk of pancreatic cancer in adults up to a relative risk of 13.3, especially with concurrent smoking or alcohol use.^{59, 60} However, genetic causes of chronic pancreatitis such as PRSS1 and CFTR mutations are also associated with pancreatic cancer and are the most common etiologies of CP in children, raising the possibility of at least a theoretically increased risk of pancreatic cancer development long-term though seemingly more likely in adulthood if at all.^{56, 61, 62}