Logo American Journal of Case Reports

Call: 1.631.629.4328
Mon-Fri 10 am - 2 pm EST

Contact Us

Logo American Journal of Case Reports Logo American Journal of Case Reports Logo American Journal of Case Reports

12 February 2022: Articles  USA

Autologous Islet Transplantation After Total Pancreatectomy in a Patient Recovered from SARS-CoV-2: A Case Report

Unknown etiology, Clinical situation which can not be reproduced for ethical reasons

Rachel P. Tindall1AE, Suzanne Bertera2ACEF*, Tadahiro Uemura1A, Molly Vincent1BE, Michael F. Knoll2BCEF, Carmela A. Knoll1AB, Rita Bottino2AD, Harry Williams3AD, Massimo Trucco24AEF, Ngoc Thai1A

DOI: 10.12659/AJCR.935142

Am J Case Rep 2022; 23:e935142

0 Comments

Abstract

BACKGROUND: SARS-CoV-2 infection or COVID-19 disease has been linked to the onset of diabetes and metabolic dysregulation because it has been suggested that viral entry proteins, specifically ACE2 and TMPRSS2, are expressed in the exocrine cells and ductal epithelium of the pancreas. Because of the unknown effect this can have on islet function, there can be doubt that patients with previous SARS-CoV-2 infections are good candidates for autologous islet transplantation after total pancreatectomy (TPAIT).

CASE REPORT: A patient with a history of chronic pancreatitis and previous non-surgical interventions was presented as a viable candidate for TPAIT at our institution. Approximately 1 month later, the patient contracted a SARS-CoV-2 infection, resulting in a mild case of COVID-19. The infection resolved without the need for hospitalization. At the time of this occurrence, COVID-19 was primarily considered a respiratory ailment, and little was known of the potential association between metabolic dysfunction and SARS-CoV-2. Islet isolation and surgery proceeded in a textbook manner with no surgical complications. The patient was weaned off exogenous insulin within 3 months after transplantation.

CONCLUSIONS: Favorable outcomes after surgery included pain reduction, islet function, and improved quality of life for the patient in the first 6 months after the procedure. These successful results demonstrate that SARS-CoV-2 infection did not prevent the patient from achieving good glucose regulation after auto-islet transplantation. This outcome suggests that, at least in this instance of mild infection, there were no long-lasting negative COVID-19-associated effects on the transplanted islets that might impact islet function.

Keywords: Islets of Langerhans Transplantation, Pancreatectomy, Pancreatitis, Chronic, SARS-CoV-2

Background

Total pancreatectomy (TP) is the final therapeutic option to alleviate intractable pain associated with chronic pancreatitis (CP) or recurrent acute pancreatitis that remains unresolved after less invasive procedures fail to bring relief [1]. Excision of the pancreatic organ results in type 3c or surgically induced diabetes unless it is combined with autologous islet transplantation (AIT), in which insulin-producing beta cells isolated from the pancreas are returned to the patient’s liver, with a mitigating effect on diabetes. Type 3c diabetes is often regarded as “brittle” or difficult to control [2]. Alternatively, after TP with AIT (TPAIT), about 2 in 3 patients either become insulin independent or require relatively small doses of insulin to maintain glycemic control [3]. Since 2008, most patients undergoing TP for CP have undergone TPAIT rather than TP alone [4]. TPAIT offers a lower mortality rate for the patient, shorter time in the hospital, improved quality of life, and lower adjusted cost than TP alone [4] in addition to the metabolic advantages offered by the islet transplantation itself [3]. Establishing metabolic control after islet transplantation provides health benefits to recipients who would otherwise experience insulin-dependent diabetes after TP or from the association with the progression of the CP itself.

There is a growing recognition of a connection between SARSCoV-2 and pancreatic dysfunction [5,6], with some evidence showing that the virus can physiologically alter insulin-producing beta cells, resulting in impaired ex vivo function [7]. It is not yet known whether pathological damage to endocrine cells occurs, is transient, or would potentially have a deleterious effect on islet function after clinical islet transplantation. This case report represents a first look at a patient undergoing TPAIT with a medical history including a prior infection of SARS-CoV-2 that was resolved at the time of surgery.

Case Report

SURGICAL TECHNIQUE:

The TP was undertaken by laparotomy. The extirpative phase included dissection off the retroperitoneum, with care to isolate and preserve the splenic artery, gastroduodenal artery, and splenic vein. In the final steps, the gastroduodenal artery was serially ligated and sharply divided, and then the splenic artery was ligated proximally and sharply divided. The splenic vein was stapled to the left of the inferior mesenteric vein, and the specimen was immediately removed. The splenic artery was flushed antegrade on the back table with cold lactated ringers solution and retrograde through the splenic vein until it flushed clear. It was packaged and delivered immediately to the isolation laboratory. The warm ischemia time was 3 min. During islet isolation, the reconstructive phase of the surgery proceeded, including placement of a portal vein catheter via the splenic vein stump for infusion, hepaticojejunostomy, and retrocolic gastrojejunostomy. Following isolation, the patient was infused with 5675 IEQ/kg islets. The estimated blood loss for the procedure was 50 mL. The length of the entire procedure was 519 min. The start of case to flushing of pancreas was approximately 210 min, and during the processing phase, the reconstruction was performed and the cannula was placed into the portal vein for infusion. Since processing of islet cells was done on site, the patient remained in the operating room for the entire time, which was around 180 min. The infusion time for islets was 43 min.

ISLET ISOLATION AND INFUSION: The pancreas with the attached duodenum and spleen were transported to the islet isolation facility inside the hospital with 22 min cold ischemia time. The pancreas measured 18×4.5×2 cm3 and weighed 107.8 g. The organ was visibly inspected, and it was found that the fat deposition was average, there was no edema, the texture was firm (normal for CP pancreata), and it was well flushed with ringer’s lactate solution in the operating room via the splenic artery. The pancreas was prepared by removing the duodenum and spleen (Figure 2A), cleaned of remaining fat (11.0 g), and bisected at the neck. Catheters (14G) were inserted into the pancreatic duct in the head and body and sutured in place (Figure 2B). Islet isolation was based on a previously published approach used in our laboratory [9,10]. Collagenase NB 1 GMP grade (15 PZ U/g) combined with neutral protease NB GMP grade (1.5 DMC U/g) was perfused through the pancreas for 15 min at 28°C in a Rajotte recirculation device (Figure 2B). At this point, the head and body/tail sections had inflated and taken on a glossy sheen associated with successful infusion, before deflating slightly. The pancreas was then placed in a Ricordi chamber with 7 marbles and manually disrupted by shaking. Tissue was collected from the temperature-controlled chamber for 33 min (10 min of warm collection followed by 23 min of cold collection). After collection, 30.8 g (out of initial 107.8 g, or 28.6%) of tissue remained undigested in the chamber; only 10% of the remaining tissue was determined to be non-fibrotic pancreatic parenchyma, the remainder being ductal system fragments, blood vessels, and fibrotic pancreatic parenchyma. A total of 20 mL of tissue was collected after digestion, then islets were separated on a discontinuous polysucrose gradient using a COBE cell separator, resulting in a more concentrated (purer) islet mass in a pellet volume of 7.2 mL. The purity of islets infused back to the patient was 30% to 40% (Figure 2C), and viability was >90%, based on representative samples. Islets were counted using IEQ, defined as a hypothetical islet of 150 μm in diameter [11]. The total number of islets returned to the patient was 401 775 IEQ, equaling 5675 IEQ/kg. The endotoxin level of the cell product was 0.34 U/kg, the Gram stain was negative, and follow-up microbiology showed no contamination at 30 days after surgery.

POSTOPERATIVE CARE:

The patient was transferred to the Intensive Care Unit on an insulin drip and D5 ½ NS for strict blood glucose management. Our protocol continues this therapy until postoperative day 3, when long-acting insulin (Lantus) and sliding-scale insulin are started and the drip is discontinued. Nutrition can be initiated with liquids at this time, and D5 fluids are continued until reliable oral intake. In our patient’s case, delayed gastric emptying occurred and required a post-anastomotic nasoenteric feeding tube for nutrition. C-peptide levels were checked daily and goal glucose levels were less restrictive than at postoperative days 1 to 3. The patient was discharged upon becoming clinically stable and returned home with a glucometer, basal and sliding-scale insulin, and instructions for monitoring blood glucose levels. The delayed gastric emptying resolved after discharge, with complete oral intake by 4 to 5 weeks after surgery and normal-consistency food by 8 weeks, at which time the patient had restarted pancreas enzyme supplementation.

ISLET FUNCTION AND PAIN RESOLUTION:

In the immediate hospital postoperative period, the patient’s pain was managed well with a patient-controlled analgesia pump. This was transitioned to oral medication with sips of water when oral intake was tolerated. The patient subjectively felt that the preoperative back pain had resolved and the postsurgical pain felt different in location and quality. As an outpatient, she had almost complete pain resolution. The patient’s pain physician titrated the oxycodone dose down over the course of 2 months to 20 mg a day from an initial dose of 9 mg long-acting oxycodone twice daily, with breakthrough 10 mg oxycodone/acetaminophen every 6 h. At 6 months after surgery, she is on 5 mg hydrocodone every 12 h with a plan to cease this over the next few months.

Small amounts of long-acting insulin were maintained in the recovery period for islet cell support. At 3 months after islet transplantation, the patient came off exogenous insulin completely. The hemoglobin A1c level at 8 weeks after surgery was 5.9%, with an average glucose of 123 mg/dL, and fasting C-peptide 0.52 ng/mL. At 6 months, the hemoglobin A1c level was 5.8%, non-fasting blood glucose was 96 mg/dL, and C-peptide was 1.33 ng/mL, while the patient was still remaining off exogenous insulin.

Discussion

In this patient, mild SARS-CoV-2 infection did not appear to impact islet function following islet auto-transplant after pancreatectomy. Islets were isolated successfully in a volume predictive of metabolic control after TPAIT. Transplantation of >5000 IEQ/kg is strongly associated with insulin independence in recipients [10,12,13]. Approximately 4 weeks after surgery, the patient was taking 4 units of long-acting insulin (Lantus) per day, which was discontinued after 3 months. Typically, patients, including those who become insulin independent, receive insulin for a period of time (up to 3 months, depending on the transplantation center) after TPAIT to support islet engraftment without over-taxing their function [14].

The patient did not test positive for SARS-CoV-2 until approximately 1 month after undergoing a pre-procedure MMTT. At that time, relatively little was known about metabolic dysfunction potentially associated with SARS-CoV-2, which was primarily thought to be a disease of the respiratory system, and so there was no cause to consider a follow-up metabolic test to determine functional capacity of the islets after the infection had run its course. Immediate preoperative laboratory tests showed a normal fasting blood glucose of 87 mg/dL, which did not prompt further testing after SARS-CoV-2 infection.

In the early stage after TPAIT, the patient’s recovery was good. The patient remained in the hospital 15 days after surgery before returning home. The length of stay was related to delayed gastric emptying and oral intolerance. There was a subsequent admission to the hospital once for a nasojejunal feeding tube replacement while she was still receiving distal feeds for delayed gastric emptying. This is a fairly common occurrence after TP with or without islet transplantation. It should be noted here that the eventual likely consequences of CP progression are exocrine insufficiency and diabetes because viable endocrine and exocrine tissue is replaced with fibrosis. When it becomes necessary to relieve the pain of CP with the excision of the pancreas, both conditions are assured. Exogenous digestive enzymes can assist with digestion, while AIT can mitigate the severity of diabetes or even result in exogenous insulin independence.

Our experience with TPAIT during the pandemic era (beginning in March 2020) consists of isolating islets for 17 patients who underwent TPAIT at Allegheny General Hospital (Pittsburgh, PA), the Cleveland Clinic (Cleveland, OH), and the University of Pittsburgh Medical Center (Pittsburgh, PA). Our data show that there are no significant statistical differences between key outcome parameters of islet isolation/transplantation, IEQ, and IEQ/kg between the patient and pandemic era patients and a cohort consisting of the 17 previous patients (standard t test calculated on graphpad.com, P=0.2955 and P=0.0728, respectively). Other than the patient in this case study, to the best of our knowledge, no patients in this analysis had contracted COVID-19 prior to TPAIT. The patient in this study received 401 775 IEQ and 5675 IEQ/kg.

Now that vaccines for COVID-19 are readily available in the US, several hospital groups are requiring prospective surgical patients to be vaccinated; however, vaccination remains voluntary at this time for patients in the health systems in which we are affiliated. Recognizing the detrimental effects of patients being unable to receive a full range of health care to meet their needs during the pandemic, which can either be due to hospitals temporarily suspending elective surgeries as they prepare for an influx of COVID-19 patients or through patients being unwilling to risk exposure in medical settings, we continue to support TPAIT for suitable patients without delay whenever possible, when there is not an active SARSCoV-2 infection. It is well known that as CP progressively destroys the endocrine pancreas, fewer islets can be rescued at the time of surgery, resulting in a lower islet mass for transplantation and a less likely chance of insulin independence. Vaccinations are a primary tool that has helped return many sectors of society to near normalcy and should be strongly encouraged for prospective candidates for TPAIT. It allows a comfort level to patients to reengage in their medical treatments. COVID-19 testing should be mandatory for the safety of all involved with the procedure, which is placed on hold until any detected infection is resolved. After resolution (as defined by best guidance at the time), MMTT and cardiac testing should be retaken if they had already occurred; however, except in the case of significant changes since the prior testing, TPAIT should proceed after the delay. If scores are low, but the patient otherwise remains a good candidate for TPAIT, another MMTT should be considered after a period of several months to see if there is a rebound of islet function. Because the effect of SARS-CoV-2 on human islets already under attack by ongoing severe CP is not known and the potential consequences of delays in treatment are well understood, we continue to recommend TPAIT for all suitable patients with as little delay as medically possible.

Conclusions

In light of recent research that has associated even mild cases of SARS-CoV-2 with pancreatitis [5], new onset diabetes, and demonstrated changes (at least ex vivo) to the islets, resulting in a less efficient stimulated glucose response [7], we thought that it was important to demonstrate in a clinical setting that prior SARS-CoV-2 infection did not necessarily disqualify patients as candidates for TPAIT.

References:

1.. Bellin MD, Forlenza GP, Majumder K, Total pancreatectomy with islet autotransplantation resolves pain in young children with severe chronic pancreatitis: J Pediatr Gastroenterol Nutr, 2017; 64; 440-45

2.. Ewald N, Kaufmann C, Raspe A, Kloer HU, Prevalence of diabetes mellitus secondary to pancreatic disease (type 3c): Diabetes Metab Res Rev, 2012; 28; 338-42

3.. Walsh RM, Aguilar Saavedra JR, Lentz G, Improved quality of life following total pancreatectomy and auto-islet transplantation for chronic pancreatitis: J Gastrointest Surg, 2012; 16; 1469-77

4.. Lara LF, Bellin MD, Ugbarugba E, A study on the effect of patient characteristics, geographical utilization, and patient outcomes for total pancreatectomy alone and total pancreatectomy with islet autotransplantation in patients with pancreatitis in the United States: Pancreas, 2019; 48; 1204-11

5.. Lakshmanan S, Malik A, Acute Pancreatitis in Mild COVID-19 Infection: Cureus, 2020; 12; e9886

6.. Wang F, Wang H, Fan J, Pancreatic injury patterns in patients with coronavirus disease 19 pneumonia: Gastroenterology, 2020; 159; 367-70

7.. Müller JA, Groß R, Conzelmann C, SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas: Nat Metab, 2021; 3; 149-65

8.. Lundberg R, Beilman GJ, Dunn TB, Metabolic assessment prior to total pancreatectomy and islet autotransplant: Utility, limitations and potential: Am J Transplant, 2013; 13; 2664-71

9.. Bottino R, Bertera S, Grupillo M, Isolation of human islets for autologous islet transplantation in children and adolescents with chronic pancreatitis: J Transplant, 2012; 2012; 642787

10.. Johnston PC, Lin YK, Walsh RM, Factors associated with islet yield and insulin independence after total pancreatectomy and islet cell autotrans-plantation in patients with chronic pancreatitis utilizing off-site islet isolation: Cleveland Clinic experience: J Clin Endocrinol Metab, 2015; 100; 1765-70

11.. Ricordi C, Gray DW, Hering BJ, Islet isolation assessment in man and large animals: Acta Diabetol Lat, 1990; 27; 185-95

12.. Ali KF, San Martin VT, Walsh RM, Change in functional beta cell capacity with time following autologous islet transplantation: Pancreas, 2019; 48; 656-61

13.. Sutherland DE, Gruessner AC, Carlson AM, Islet autotransplant outcomes after total pancreatectomy: A contrast to islet allograft outcomes: Transplantation, 2008; 86; 1799-802

14.. Bellin MD, Balamurugan AN, Pruett TL, Sutherland DE, No islets left behind: Autotransplantation for surgery-induced diabetes: Curr Diab Rep, 2012; 12; 580-86

SARS-CoV-2/COVID-19

19 May 2022 : Case report  Serbia

Bilateral Emphysematous Pyelonephritis Associated with COVID Pneumonia: A Case Report

Am J Case Rep In Press; DOI: 10.12659/AJCR.936370  

17 May 2022 : Case report  USA

High-Frequency Oscillatory Ventilation for Refractory Hypoxemia in Severe COVID-19 Pneumonia: A Small Case ...

Am J Case Rep In Press; DOI: 10.12659/AJCR.936651  

13 May 2022 : Case report  Japan

A case of exacerbation of haloperidol-induced rhabdomyolysis following the onset of COVID-19

Am J Case Rep In Press; DOI: 10.12659/AJCR.936589  

13 May 2022 : Case report  USA

Acute Disseminated Encephalomyelitis After SARS-CoV-2 Vaccination

Am J Case Rep In Press; DOI: 10.12659/AJCR.936574  

In Press

26 May 2022 : Case report  USA

Cardiac Tamponade as Initial Presentation of Systemic Lupus Erythematous in Third-Trimester Pregnancy

Am J Case Rep In Press; DOI: 10.12659/AJCR.936273  

25 May 2022 : Case report  Mexico

Acute Mitral Regurgitation Due to Chordae Tendineae Rupture: A Rare Presentation of Cardiac Amyloidosis

Am J Case Rep In Press; DOI: 10.12659/AJCR.936545  

25 May 2022 : Case report  USA

Pleural Effusion as the Initial Presentation of Gastric Adenocarcinoma: A Case Report

Am J Case Rep In Press; DOI: 10.12659/AJCR.935434  

24 May 2022 : Case report  USA

Adalimumab Mitigates Lumbar Radiculopathy in a Case of Ankylosing Spondylitis

Am J Case Rep In Press; DOI: 10.12659/AJCR.936600  

Most Viewed Current Articles

23 Feb 2022 : Case report  USA

Penile Necrosis Associated with Local Intravenous Injection of Cocaine

DOI :10.12659/AJCR.935250

Am J Case Rep 2022; 23:e935250

17 Feb 2022 : Case report  Oman

Myocarditis, Pulmonary Hemorrhage, and Extensive Myositis with Rhabdomyolysis 12 Days After First Dose of P...

DOI :10.12659/AJCR.934399

Am J Case Rep 2022; 23:e934399

06 Dec 2021 : Case report  Brazil

Lipedema Can Be Treated Non-Surgically: A Report of 5 Cases

DOI :10.12659/AJCR.934406

Am J Case Rep 2021; 22:e934406

19 Feb 2022 : Case report  USA

A Rare Case of Coronavirus Disease 2019 Vaccine-Associated Cerebral Venous Sinus Thrombosis Treated with Me...

DOI :10.12659/AJCR.935355

Am J Case Rep 2022; 23:e935355

Your Privacy

We use cookies to ensure the functionality of our website, to personalize content and advertising, to provide social media features, and to analyze our traffic. If you allow us to do so, we also inform our social media, advertising and analysis partners about your use of our website, You can decise for yourself which categories you you want to deny or allow. Please note that based on your settings not all functionalities of the site are available. View our privacy policy.

American Journal of Case Reports eISSN: 1941-5923
American Journal of Case Reports eISSN: 1941-5923