Acute Acalculous Cholecystitis and COVID-19


Acute acalculous cholecystitis (AAC) was first delineated by Duncan in 1884. It signifies a form of cholecystitis that occurs without the formation of gallstones, accounting for approximately 5–10% of all acute cholecystitis cases in adults. Predominantly observed in critically ill patients, AAC is associated with risk factors such as trauma, surgery, shock, burns, sepsis, total parenteral nutrition (TPN), and mechanical ventilation. Despite its rarity compared to calculous cholecystitis, AAC harbors a grim prognosis with a mortality rate nearing 30%, often exacerbated by complications like necrosis, perforation, and empyema. Interestingly, AAC can also manifest in otherwise healthy individuals, frequently attributed to infectious etiologies.

COVID-19 Pandemic and Gastrointestinal Implications

The emergence of COVID-19, instigated by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in Wuhan, China, in December 2019, escalated into a global pandemic. Over three years, it has inflicted over 300 million infections and led to more than 5 million fatalities worldwide. The mechanism of SARS-CoV-2 involves its spike protein binding to angiotensin-converting enzyme 2 (ACE2) receptors, predominantly found in lung alveolar and gastrointestinal (GI) tract epithelial cells. This receptor distribution elucidates the respiratory and GI manifestations observed in COVID-19 patients.

Intersecting Pathways: AAC in the Context of COVID-19

This review aims to dissect the interrelation between AAC and COVID-19, delving into pathogenesis, diagnostics, management, and patient outcomes. A comprehensive literature survey across platforms like MEDLINE/PubMed, Scopus, and Google Scholar has been conducted to amalgamate current findings and case reports linking AAC with COVID-19.

Gastrointestinal Manifestations and Complications of COVID-19

The GI tract, rich in ACE2 receptors, is susceptible to direct damage by SARS-CoV-2, leading to a wide range of symptoms. The prevalence of these symptoms varies, with anorexia, diarrhea, nausea/vomiting, and abdominal pain being the most common. Severe COVID-19 can precipitate critical conditions like ileus and mesenteric ischemia in a significant fraction of hospitalized patients. Chronic GI disorders and certain medications have been identified as risk enhancers for severe COVID-19 outcomes.

Biliary Manifestations in COVID-19

AAC is notably prevalent among severely ill COVID-19 patients, often linked to gallbladder motility reduction and complications in the biliary system. The extensive presence of ACE2 receptors in biliary tissues suggests a potential pathway for SARS-CoV-2 to incite cholecystitis. Additional factors like cytokine storm-induced inflammation, hypercoagulability leading to ischemia, and thrombotic microangiopathy further compound the risk of AAC in COVID-19 patients.

Typology and Aetiology of Acute Acalculous Cholecystitis

AAC can manifest in various forms: from simple inflammation to more severe conditions like suppurative, gangrenous, or perforative cholecystitis. The etiological spectrum of AAC spans mechanical, chemical, and bacterial origins, illustrating the complex interplay of factors that precipitate this condition.

Pathogenesis of AAC

AAC’s development is a multifactorial process, particularly influenced by the patient’s overall health status. The disease mechanism varies between critically ill patients and those with non-critical conditions, emphasizing the need for tailored approaches in understanding and managing AAC.

Future Perspectives

While the nexus between COVID-19 and AAC is supported by clinical observations and theoretical models, robust empirical data is requisite for establishing a definitive causal relationship. Continued research and case study compilations are imperative to unravel the complexities of AAC in the setting of COVID-19, aiming to enhance diagnostic accuracies, therapeutic strategies, and overall patient prognoses. As the pandemic evolves, so does our understanding of its multifaceted impacts on various health conditions, including AAC, necessitating a dynamic and informed medical response.

Pathogenesis of Acute Acalculous Cholecystitis (AAC) in the Context of Infectious Agents

The development of Acute Acalculous Cholecystitis (AAC) is multifaceted, influenced by a range of pathological processes. Its occurrence can be stratified into two principal categories, based on the patient’s condition: AAC in critically ill patients and AAC in non-critically ill patients.

AAC in Critically Ill Patients

  • Bile Stasis: A pivotal factor in AAC’s pathogenesis among critically ill patients is bile stasis. Conditions such as total parenteral nutrition (TPN), prolonged fasting, volume depletion, and the use of opioid analgesics, certain hormones, and drugs can impair gallbladder motility and viscosity, leading to cholestasis. Other contributing factors include altered lipid metabolism in type II diabetes, cerebrovascular diseases, and mechanical ventilation with positive end-expiratory pressure (PEEP) exceeding 7 cm H2O. Bile stasis can cause direct injury to the gallbladder mucosa through chemical composition changes, like increased lysophosphatidylcholine.
  • Gallbladder Ischemia–Reperfusion Injury: The cystic artery, being a terminal artery, makes the gallbladder particularly susceptible to ischemia. This can result from various conditions including septic shock, hypovolemic shock, trauma, burns, and cardiovascular surgeries. Microangiography studies reveal a poor and irregular capillary network in AAC, contrasting with the dense vessel network in acute calculous cholecystitis (ACC).

AAC in Non-Critically Ill Patients

  • Direct Invasion: AAC can result from the direct invasion of the gallbladder epithelium by microorganisms, identifiable through histopathology, molecular techniques, electron micrographs, and bile cultures. Factors like opioid use in GI surgeries, injury to the sphincter of Oddi, and procedures like ERCP increase the risk of bacterial infection, leading to AAC. Systemic infections can induce AAC through blood circulation, affecting the gallbladder.
  • Vasculitis: Immune-mediated necrotizing vasculitis, often caused by viral infections, can induce gallbladder injury by causing localized ischemia, cell death, and necrosis. Mechanisms include antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity, leading to endothelial destruction, fluid extravasation, and gallbladder wall edema.
  • Obstruction: AAC can also arise from the obstruction of the biliary tract due to intrinsic or extrinsic factors. Conditions like echinococciasis and infectious diseases, such as EBV, can cause extrinsic compression, leading to increased intraluminal pressure, gallbladder wall tension, ischemia, and AAC.
  • Anatomical Abnormalities: Congenital abnormalities in the biliary system can predispose to AAC by impairing bile duct emptying, leading to cholestasis and increased AAC risk.
  • Other Risk Factors: AAC risk is heightened by factors like immunodeficiencies, atherosclerosis, vasculitis, diabetes mellitus, stroke, arterial hypertension, reduced vagal tone, bone marrow transplantation, interleukin-2 therapy, and lymphokine-activated killer cell therapy.
  • Sequestration: Particularly in Plasmodium falciparum infections, erythrocyte deformation leads to microcirculatory obstruction and ischemia, elucidating AAC’s pathogenesis during malaria.
  • Epstein–Barr Virus (EBV): EBV is a common infectious cause of AAC, with proposed mechanisms including direct invasion, vasculitis, and extrinsic cystic duct blockage by inflamed lymph nodes. However, the exact pathophysiological process remains elusive, as the virus may not always be detectable post-cholecystectomy in the affected tissue.

AAC’s pathogenesis is complex and varies based on the patient’s health status, with distinct mechanisms in critically and non-critically ill patients. Understanding these processes is vital for effective diag

Pathogenesis of Acute Acalculous Cholecystitis in COVID-19

The pathogenesis of Acute Acalculous Cholecystitis (AAC) during COVID-19 infection remains largely enigmatic, with critical illness, mechanical ventilation, and prolonged total parenteral nutrition (TPN) being the recognized triggers. The intricate interaction between the SARS-CoV-2 virus and the human body, particularly through the angiotensin-converting enzyme 2 (ACE2) receptors, plays a pivotal role in the suspected mechanisms of AAC in COVID-19 patients.

Direct Invasion and Systemic Effects

ACE2 receptors, abundantly present in the biliary tract and the vascular endothelium of the gallbladder, are potential gateways for the virus, hinting at direct invasion as a pathophysiological pathway. Furthermore, SARS-CoV-2’s ability to infect small intestinal enterocytes, which also express ACE2 receptors, and its potential entry into the gallbladder via bile recirculation, presents another route for gallbladder involvement. Although the virus has rarely been detected in bile or tissue samples from AAC patients, the few instances of such detections underscore the need for more research to understand these mechanisms fully.

Immune Response and Coagulopathy

The systemic inflammation and immune alterations triggered by SARS-CoV-2 infection could activate proinflammatory pathways, leading to late-onset cholecystitis. Additionally, the virus-induced coagulopathy and prothrombotic state might contribute to small-vessel thrombosis, resulting in gallbladder wall ischemia. Histopathological findings in some studies, like those by Bozada-Gutiérrez et al., have shown ischemia, necrosis due to thrombosis, hemorrhagic changes, and acute inflammatory infiltrates in the gallbladder wall, often associated with acute peritonitis.

Clinical Observations and Management

Worldwide case reports and series have documented acute cholecystitis in COVID-19 patients, with several instances of gangrenous AAC noted. Studies like the ChoCO-W prospective observational study found no significant difference in AAC incidence between COVID-19 and non-COVID-19 patients, but a higher prevalence of necrosis/gangrene and increased mortality in COVID-19 cases. These observations highlight the severity of AAC when it co-occurs with COVID-19.

Management strategies for acute cholecystitis in COVID-19 patients have varied from antibiotics and percutaneous cholecystostomy to urgent laparoscopic or open cholecystectomy, depending on the severity and response to initial treatments.

Conclusion and Future Directions

While direct invasion by SARS-CoV-2 and subsequent systemic inflammatory responses are theorized pathways for AAC in COVID-19 patients, conclusive evidence is scarce, necessitating further research. The rarity of virus detection in gallbladder samples and the diverse clinical outcomes observed suggest a complex interplay of factors contributing to AAC’s pathogenesis in COVID-19. Continuous study and documentation of such cases are crucial for unraveling the specific mechanisms and improving the management and outcomes of AAC in the context of COVID-19.

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