Candida glabrata infection of a pancreatic pseudocyst in a COVID-19 patient: A case report and review of the literature

Introduction Pancreatic pseudocysts remain a feared complication of acute or chronic pancreatitis and are often characterized by collections of fluids due to underlying damage to the pancreatic ducts, culminating in a walled-off region bereft of an epithelial layer but surrounded by granulation tissue. While fungal infections of pancreatic pseudocysts are rarely encountered, candida albicans remains the most frequently implicated organism. Case presentation A 55-year-old male presented with pain in the left-hypochondriac region, accompanied by non-bilious emesis and nausea. Interestingly, the patient also tested positive for a COVID-19 infection. Investigative workup divulged enhancing pancreatic walls with a radiologic impression consistent with a pancreatic pseudocyst. An ultrasound-guided external drainage was performed; the drainage was conducted unremarkably, with the resultant fluid collection revealing the presence of Candida Glabrata. The patient was commenced on antifungal therapy and continues to do well to date. Discussion Infectious ailments of pancreatic pseudocysts remain a widely known complication of acute pancreatitis. While it is rare, fungal infection is a crucial consideration for patients with pancreatic pseudocysts, especially in the context of a lack of an adequate response to antibiotics, deterioration, comorbidities, and immunocompromised states. Conclusion Rapid identification of the microbe responsible for pancreatic pseudocyst infection is vital for time-sensitive treatment and a more rapid recovery, curbing associated morbidity and mortality.


Introduction
Pancreatic pseudocysts remain a feared complication of acute or chronic pancreatitis. They are often characterized by collections of fluids due to underlying damage to the pancreatic ducts, culminating in a walled-off region bereft of an epithelial layer but surrounded by granulation tissue [1]. The reported incidence rate of acute pseudocysts as post-pancreatitis complications hovers around 6-18%, with chronic pseudocyst reported in upwards of 20-40% of cumulative cases [2]. They frequently present with a vague constellation of symptoms, typified by abdominal pain, distension, covert bleeding, nausea, and vomiting [3]. Clinically, pseudocysts pose a diagnostic conundrum and are often mistaken for recurrent or chronic pancreatitis [3]. Infectious ailments of pseudocysts present an additional challenge, with the mainstay of treatment being endoscopic or external drainage [1][2][3]. While fungal infections of pancreatic pseudocysts are rarely encountered, candida albicans remains the most frequently implicated organism [4]. Nevertheless, infection with candida glabrata remains exceedingly rare. In the present paper, we elucidate the case of a 55-year-old male who presented with pain in the left-hypochondriac region, accompanied by non-bilious emesis and nausea. Interestingly, the patient also tested positive for a COVID-19 infection. Investigative workup by employing a computed tomography (CT) scan divulged enhancing pancreatic walls with a radiologic impression consistent with a pancreatic pseudocyst. An ultrasound-guided external drainage was performed; the drainage was conducted unremarkably, with the resultant fluid collection sent for further culture and sensitivity examination, revealing the presence of Candida Glabrata. The patient was commenced on antifungal therapy and continues to do well to date.

Case Presentation
A 55-year-old male presented to the emergency department with a three-day history of dull aching, gradually worsening left hypochondriac region pain accompanied by non-bilious emesis and profound nausea. Pertinently, the patient reported that the pain had no temporal association with eating or drinking, and further stated that physical activity would exacerbate the pain intensity, resulting in immobility and ambulatory dysfunction over the past three days.
The patient initially sustained an episode of acute pancreatitis of unknown etiology 18-months ago, which promptly responded to conservative medical management. Consequently, the patient developed a pancreatic pseudocyst as a complication of his recurrent bouts of pancreatitis. The pseudocyst continued to enlarge in size until the patient presented to the emergency department three months prior to the current presentation. Gastroenterology was consulted at the time and a cystogastrostomy was performed to facilitate drainage into the stomach cavity. A computed tomography (CT) scan at the time divulged enhancing pancreatic walls with a radiologic impression consistent with a pancreatic pseudocyst. Radiological imaging at the time further revealed an unremarkable liver and a gallbladder replete with gallstones within the gallbladder lumen. The gallbladder otherwise appeared normal and no biliary ductal dilation was noted; however, there was appreciable fatty infiltration of the pancreas along with wall thickening consistent with a pancreatic pseudocyst in the setting of recurrent bouts of acute pancreatitis. Interestingly, the patient had tested positive for a COVID-19 infection four days prior to the onset of his symptoms.
In order to better elucidate the etiology underlying the patient's current presentation, amylase and tumor marker levels, including CEA and CA-19-9, were ordered to exclude an underlying malignancy process. All tumour markers and amylase levels were unremarkable. Following cystogastrostomy, the patient was discharged in a stable state. However, two days later, the patient returned with a constellation of symptoms including spiking fevers to 101.3 • fahrenheit, dull aching pain in the right upper quadrant, and nausea and vomiting. Considering the presence of an infectious process, intravenous antibiotics were started and resulted in downtrending C-reactive protein levels from 420 μg/mL to 322 μg/mL over three days. Concurrently, the leukocytosis also abated, resulting in downtrending levels of 16000 cells/mL on day 1-11000 cells/mL on day 3 of admission. Given the patient's history of pancreatitis, a CT scan of the abdomen was performed and revealed a large pancreatic pseudocyst (Fig. 1).
The upper and lower limits of the pancreatic pseudocyst were also delineated by the CT scan and reveal exorbitant proportions consistent with a diagnosis of a huge infected pseudocyst (Fig. 4, Fig. 5).
A multidisciplinary team meeting was thus conjured in order to facilitate optimal management. Input from the infectious disease, general surgery, gastroenterology, and interventional radiology teams was considered and a decision to proceed with ultrasound (US)-guided external drainage was made. The drainage was conducted unremarkably, with the hemorrhagic fluid collection sent for further culture and sensitivity examination. Following US-guided drainage, the patient returned to his baseline afebrile state, and the CRP downtrended to 130 μg/mL. Interestingly, the culture turned out positive for heavy growth of Candida glabrata, which was noted to be susceptible to fluconazole and amphotericin B; however, it was intermediately resistant to caspofungin. At this point, the differentials included an infected pseudocyst, pancreatic abscess, and various subcategories of neoplasms. Thereafter, a decision to commence fluconazole and meropenem in order to curb residual infection was made. The drain output continued to drain 200-300 mL of fluid. Post-operatively, the patient continued to do well with thorough abatement of his symptoms after surgery. The present paper was reported in accordance with the SCARE guidelines [5]. The patient received supportive treatment postoperatively within the hospital for three days thereafter, with regular inflammatory parameters and routine laboratory workup showing resolution in derangement.
In another case report, a 45-year-old man was hospitalized for a constellation of symptoms, characterized by early satiety, worsening epigastric pain, hypoglycemia, and altered mental status three weeks after his hospitalization for acute pancreatitis [7]. He began experiencing these symptoms while at a rehabilitation facility, as his acute pancreatitis episode was presumed secondary to alcohol abuse. A day two abdominal computed tomography (CT) scan revealed a mass consistent with a pancreatic pseudocyst, and blood cultures revealed Burkholderia cepacia resistant to amikacin, cefepime, ciprofloxacin, gentamicin and piperacillin-tazobactam and sensitive to ceftazidime, meropenem, and trimethoprim-sulfamethoxazole (TMP-SMX). By day 10 of ceftazidime treatment, the patient continued to experience spiking fevers [7]. A CT-guided drainage of the pseudocyst with culture revealed multidrug-resistant (MDR) B. cepacia, Candida dubliniensis, and Candida glabrata. Micafungin was added to his regimen. On day 15, a cyst gastrostomy was performed with stent placement using endoscopic ultrasound. However, a biliary stricture prevented adequate endoscopic retrograde pancreatography (ERCP), and an AXIOS stent was placed. The drained fluid continued to grow MDR B. cepacia. Two weeks later, repeat ERCP with sphincterotomy and stent removal was performed. Repeated CT after two weeks showed a dwindling pseudocyst. Despite these measures and the continuation of ceftazidime and micafungin for 10 weeks, the patient experienced recurring symptoms and growth of the cyst. Finally, four months after his diagnosis, surgical intervention with explorative laparotomy and open cystogastrostomy revealed a pus-filled pseudocyst and necrotic pancreas. This intervention proved definitive, with improvement and infection elimination [7].
Another case report from Germany implicated a 34-year-old woman suffering from alcoholic hepatitis and an acute-on-chronic pancreatitis who developed Candida infection of a pseudocyst 12 days post-ERCP [8]. She successfully recovered after US-guided percutaneous drainage followed by IV and intracavity amphotericin B and obliterative therapy using a tetracycline [8]. Another case report detailed the successful treatment of a 48-year-old man's pancreatic pseudocyst infected with Candida albicans using a Roux-en-Y cystojejunostomy and amphotericin B as an adjuvant [9]. Other cases of pancreatic pseudocyst fungal infections have been discussed in the literature, including one in a postpartum woman [10,11].
Fungal infection of a pancreatic pseudocyst has proven to be rapidly fatal. A 40-year-old man with a history of diabetes mellitus, congestive heart failure, alcoholic cirrhosis, and acute-on-chronic pancreatitis was determined to be septic despite negative blood cultures [12]. After appropriate treatment, multiple antibiotic therapy, and total parenteral nutrition, the patient slowly improved. However, imaging revealed the development of a phlegmon that transformed into pseudocysts, and percutaneous aspiration and culture revealed Candida albicans infection, which led to dissemination [12]. Treatment with amphotericin B and aggressive supportive care proved insufficient, and the patient deteriorated and expired due to multiple organ system failure [12].
A retrospective study of patients with walled-off pancreatic necrosis between 2005 and 2013 fungal infection was documented in 57 of 123 patients (46%) [13]. The most common pathogen implicated was Candida albicans (55%) followed by Candida glabrata (20%) [13]. Moreover, there was no significant difference in mortality between those treated with antifungals after the first confirmation of fungal infection versus those not treated or treated inadequately [13]. A total of 10 patients (18%) with fungal infection died, three with concomitant fungemia and seven with isolated walled-off necrosis. In another similar retrospective study, 54 patients of 136 (40%) were found to have Candida-infected pancreatic necrosis, of which seven developed candidemia [14]. Here, patients with concomitant candidemia boasted a significantly higher mortality rate (57.1% vs 20.2%, p = 0.042) [14].
While it is rare, fungal infection is a crucial consideration for patients with pancreatic pseudocysts, especially in the context of a lack of an    [15]. In its exacerbated forms, pseudocysts can culminate in additional sinister complications such as secondary pleural effusions [15]. Retrospective analysis of patients with pancreatic pseudocysts in Germany divulged that patients with fungal infection of pseudocysts had longer hospital stays, required more aggressive treatment strategies, and had lower 1-year survival when compared to those afflicted with bacterial etiologies [16].
In the present paper, fluconazole-and amphotericin B-susceptible Candida glabrata was isolated, and fluconazole was thus used in combination with meropenem to thwart the potential for residual infection. The patient recovered with prompt eradication of infection and his symptoms subsequently abated. Finally, the patient's confirmed COVID-19 infection poses the question surrounding a possible link to his susceptibility to this rare pseudocyst infection. Not uncommonly, COVID-19 has been reported to induce a cytokine storm and susceptibility to secondary infections. In this case, admittedly, we cannot ascertain whether concurrent COVID-19 infection played any major role in the development of this Candida glabrata infected pancreatic pseudocyst. Further studies with similar patient populations are therefore warranted in order to better inform the debate on what constitutes optimal medical and surgical management.

Future direction
The results of this study are interesting as it showcases the rare case of the incidence of pancreatic pseudocysts with concurrent infection by COVID-19. This raises the question whether infection from COVID-19 potentially plays a mediating role in developing complications to a pre-existing medical condition. Prior data and research in this area are sparse which warrants further investigation. Future studies should investigate the relationship between fungal infections of pancreatic pseudocysts and COVID-19, if one exists. We propose the implementation of double blinded placebo randomized control trials to fully elucidate the link between complications of pancreatitis and COVID-19. Not only will this inform us of the role COVID-19 plays in the development of complications or side effects for pancreatic pseudocysts, but also open the doors to investigating how other rare diseases may be affected by concurrent infection with COVID-19.

Conclusion
Fungal infections of pancreatic pseudocysts remain a rare but wellstudied complication of acute pancreatitis. While pancreatic pseudocysts can spontaneously remit, percutaneous, endoscopic, or even surgical intervention may eventually be warranted. Telltale signs of an infected pancreatic pseudocyst include a patient with worsening symptoms and positive blood cultures. Rapid identification of the responsible microbe is vital for time-sensitive treatment and a more rapid recovery. Especially in the case of fungal species, predominantly Candida spp, aggressive treatment with antifungal agents is warranted to curb the risk of disseminated candidemia. Further studies with similar patient populations are warranted to further explore the possible link between Covid-19 and development of fungal pseudocyst infection.

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Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

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Declaration of competing interest
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