|Year : 2021 | Volume
| Issue : 2 | Page : 83-91
Novel infectious causes of acute pancreatitis: A comprehensive review
Saurabh Gaba1, Monica Gupta1, Ruchi Gaba2, Sarabmeet Singh Lehl1
1 Department of General Medicine, Government Medical College and Hospital, Chandigarh, India
2 Department of Paediatrics, All India Institute of Medical Sciences, New Delhi, India
|Date of Submission||27-Jan-2021|
|Date of Acceptance||25-Nov-2021|
|Date of Web Publication||24-Dec-2021|
Dr. Monica Gupta
Department of General Medicine, Level 4 D Block, Government Medical College and Hospital, Sector 32, Chandigarh - 160 030
Source of Support: None, Conflict of Interest: None
Acute pancreatitis can result from a variety of infections. The causative pathogens have been well established to be certain viruses and parasites. However, certain infections fail to find mention in standard literature and have been overlooked due to the trivial number of cases of pancreatitis that result from them. Among these are influenza, leptospirosis, acute viral hepatitis, and certain tropical infections such as dengue, chikungunya, scrub typhus, malaria, and typhoid. In this narrative review, we have conducted a literature search on PubMed and EMBASE databases for cases of pancreatitis occurring in these diseases and compiled the data. Most of these infections are prevalent in the developing world, and consequently, more cases are reported from these regions. The pathogenesis, predictors of outcome, and the response to antimicrobial therapy have not been studied extensively. The actual incidence is probably higher than what is reported, and this subject deserves more attention.
Keywords: Acute pancreatitis, chikungunya, coronavirus disease 2019, dengue, infections, influenza, leptospirosis, malaria, scrub typhus, viral hepatitis
|How to cite this article:|
Gaba S, Gupta M, Gaba R, Lehl SS. Novel infectious causes of acute pancreatitis: A comprehensive review. Indian J Community Fam Med 2021;7:83-91
|How to cite this URL:|
Gaba S, Gupta M, Gaba R, Lehl SS. Novel infectious causes of acute pancreatitis: A comprehensive review. Indian J Community Fam Med [serial online] 2021 [cited 2022 Jan 23];7:83-91. Available from: https://www.ijcfm.org/text.asp?2021/7/2/83/333666
| Introduction|| |
Acute pancreatitis (AP) is characterized by abrupt onset of inflammation that is often reversible and resolves with conservative management alone. The damage caused by the initial insult is propagated by activation of digestive proenzymes or zymogens within the pancreas, rather than the duodenum, leading to autodigestion. The diagnosis is made by the presence of any two of the following three criteria – the characteristic abdominal pain, elevation of serum amylase and/or lipase to more than three times the upper limit of normal, and imaging evidence of inflammation. The causes of AP are mentioned in [Table 1].
The classic clinical symptoms are nausea, vomiting, and epigastric pain that is continuous, radiates to the back, is exacerbated by food intake, and is partially relieved on bending forward. Third space fluid loss and systemic inflammation lead to hypotension. The clinical course can be complicated by certain local and systemic complications. The management involves bowel rest and early resuscitation with intravenous fluids. Early enteral feeding is preferred, and close monitoring for complications is needed. Antibiotics are indicated only when there is definite evidence of infection. Fluid collections may require drainage if they are infected or cause mass effects. This can be done by percutaneous, endoscopic, or surgical approach.
Among infections, the causes of AP have conventionally been started to include viruses such as Cytomegalovirus, mumps, coxsackievirus, and human immunodeficiency virus and parasites such as Toxoplasma and Ascaris. Apart from these, there are certain infections that have failed to find recognition in standard literature. These are mostly tropical infections, and occur predominantly in developing countries and in travelers who return from these regions. The data available is confined to isolated case reports or small series. We have provided an overview of the infectious causes of AP, which are mentioned in [Table 2].
| Material and Methods|| |
A search was conducted for articles indexed in PubMed and EMBASE databases using the keywords “specific infection + pancreatitis” and “specific infection + acute pancreatitis” to compile the available evidence of AP caused by influenza, chikungunya, viral hepatitis, dengue, malaria, fungi, leptospirosis, scrub typhus, typhoid, and coronavirus disease 2019 (COVID-19).
| Results|| |
People infected with HIV have a higher incidence of AP than the general population, and the risk is higher in advanced stages with lower CD4+ count. The etiology is diverse and may result from direct inflammation due to HIV itself, or from opportunistic infections such as Cytomegalovirus, Toxoplasma gondii, and Cryptosporidium. Drug-induced AP can result from antiretroviral drugs such as nucleoside reverse transcriptase inhibitors (didanosine, stavudine, and lamivudine) and nonnucleoside reverse transcriptase inhibitors (efavirenz and nevirapine). Didanosine has consistently been shown to confer the highest risk, among the antiretroviral drugs, in a dose-dependent manner. The mechanism is not completely identified, but it may be related to mitochondrial toxicity. The protease inhibitors are less commonly implicated. Drugs used in conjunction with antiretroviral therapy, such as corticosteroids, pentamidine, and trimethoprim-sulfamethoxazole, can also lead to AP. There are numerous case reports implicating herpes simplex, coxsackievirus, Epstein–Barr virus, and varicella-zoster virus in AP.,,
It has been shown that H5N1 influenza A can bind to pancreatic cells and induce apoptosis. The infected pancreatic cells also produce pro-inflammatory cytokines. Human H1N1 and H3N2 and avian H7N1 and H7N3 influenza virus can also infect human pancreatic islet cells. Damage to the pancreatic beta-cells by H1N1 influenza virus and precipitation of diabetes has also been documented., Baran et al. have reported the case of a 19-year-old male who presented with abdominal pain, fever, and upper respiratory symptoms. He was found to have H1N1 influenza, and no alternate cause of AP was found. He was treated with oseltamivir for 5 days and recovered quickly. Another case of AP has been reported in an 86-year-old male with untreated chronic lymphocytic leukemia. Severe AP with acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI) has been reported in a 42-year-old woman. She was also treated with oseltamivir and recovered after a week. Possible association has also been reported by Sánchez Bautista et al. in a 12-year-old girl.
During a chikungunya outbreak in French Guiana, two patients with underlying chronic pancreatitis developed AP. One was a 54-year-old man, and the other was a 55-year-old man who also developed Guillain–Barré syndrome and encephalitis.
AP can occur in acute viral hepatitis due to the hepatotropic viruses. The pathogenesis has been proposed to be related to the edema of the ampulla of Vater, which impedes the normal flow of pancreatic secretions into the duodenum. Direct injury of the pancreatic cells by virus is under investigation. The presence of hepatitis B DNA and surface antigen has been documented in the acinar cells of a patient of liver transplant suffering from AP due to acute-on-chronic hepatitis B. If viral hepatitis is associated with acute liver failure, AP may also result from sepsis or pancreatic ischemia due to hypotension and disseminated intravascular coagulation.
In their review, Haffar et al. have reported the incidence of AP in acute hepatitis A to be <0.1%. They found that 6% of the cases of AP were associated with acute liver failure. The median interval between appearance of clinical jaundice and the onset of abdominal pain was 4 days. Mostly young patients (median age of 16 years) were affected, and most of the documented cases were from Asia. The mortality rate was noted to be similar to other causes of AP. In a retrospective analysis of 790 cases of AP over 6 years at an institution in India, 16 cases (2.1%), with a mean age of 25 years, were attributed to acute hepatitis E. One patient had acute liver failure. From another center in India, Bhagat et al. have documented AP in four and three cases of acute hepatitis E and A, respectively. All of them recovered with conservative management. Jain et al. have documented the incidence of AP in acute viral hepatitis to be as high as 5.6% (7 cases out of 124). Hepatitis E, A, and B were implicated in four, two, and one case, respectively. The clinical course was uncomplicated, and all the patients recovered. The six cases of AP due to hepatitis E studied by Mishra et al. also recovered completely with conservative management. Severe AP complicated by multi-organ dysfunction and local complications has also been documented in hepatitis E., To the best of our knowledge, only one case of AP associated with hepatitis C (genotype 1b) has been published. The patient was a 70-year-old female from Brazil, and AP was mild.
After the mosquito bite, dengue virus enters the Langerhans cells via membrane receptors, and replicates using its cellular machinery. The new viruses are released by exocytosis, and they infect other cell types. Migration of the Langerhans cells to the lymph nodes accelerates the spread to other parts of the body. AP is a very rare complication since the number of reported cases is miniscule compared to the incidence of dengue. Most of the data are from India [Table 3]. The pathogenesis may involve direct invasion of the pancreatic acinar cells by the dengue virus, obstruction to bile flow due to edema of the ampulla of Vater, or as a part of multi-organ dysfunction in dengue shock syndrome (DSS). The clinical course is comprised of three phases. The febrile phase, which lasts for 3–7 days, is followed by the critical phase in which plasma leakage occurs that can lead to shock and organ dysfunction. The critical phase lasts for up to 2 days, but it can lead to certain complications that can be long lasting and determine the outcome of the illness. In the convalescent phase, complete defervescence occurs and the general well-being of the patient gradually improves. Clinically, dengue can present as dengue fever, dengue hemorrhagic fever (DHF), and DSS. DHF is characterized by thrombocytopenia, evidence of increased vascular permeability, and hemorrhagic manifestations. DHF complicated by shock results in DSS that is often refractory to treatment. There is no specific antimicrobial drug, and the treatment is supportive. It is worth noting that AP can develop during both the febrile and critical periods of illness.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing COVID-19 pandemic that has led to unprecedented health and social and economic desolation. It was first identified in the Wuhan city of China in December 2019 and quickly spread to the rest of the world. The coronavirus family consists of certain RNA viruses that have spikes on their surface and typically cause respiratory illness. The SARS and Middle East respiratory syndrome pandemics were also caused by coronaviruses. SARS-CoV-2 has a probable zoonotic origin (bats or pangolins), and human-to-human transmission occurs by respiratory droplets. Spread can also occur from a contaminated environment.,, Its entry into the host cells is mediated by the angiotensin-converting enzyme 2 (ACE2) receptors and facilitated by transmembrane protease serine 2. So far, only dexamethasone has been shown to reduce mortality in the severely ill patients. Well-designed randomized controlled trials have either failed to establish a clear-cut benefit, have not been conducted, or are underway with regard to other drugs such as hydroxychloroquine, ivermectin, azithromycin, tocilizumab, remdesivir, and favipiravir.,,,,, The use of convalescent plasma is also being tried. Supportive management and anticoagulation form the mainstay of therapy. Human trials for the vaccine are underway. In a retrospective study on 52 patients with COVID-19 pneumonia, evidence of pancreatic injury in the form of elevation of amylase and lipase was found in 17.3% of the cases. In their study on 121 patients, Liu et al. found that pancreatic injury was more common in patients with severe COVID-19 infection. Elevation of amylase or lipase was seen in 17.91% of the patients with severe disease, while it was seen in only 1.85% of those with mild disease. It might be related to the systemic inflammatory response or direct cell injury as the ACE-2 receptor is expressed both in the pancreatic islets and acinar glands. The reported cases of AP are compiled in [Table 4].
|Table 4: Cases of acute pancreatitis reported in Coronavirus disease 2019|
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Ascaris is a well-known cause of AP, and the burden is highest in developing countries. The pathogenesis involves obstruction of the bile flow when the worm enters the ampulla of Vater from the duodenum, or by irritating the Sphincter of Oddi More Details leading to its spasm. Cryptosporidium is a very rare cause of AP both in immunocompetent and immunodeficient individuals. Toxoplasmosis can cause AP in patients with HIV. Ahuja et al. and Hofman et al. have reported the presence of Toxoplasma cysts in the pancreatic acini on autopsy of patients with known AIDS., Similar finding has been reported by Garcia et al., but the patient was found to have HIV after presentation with AP.
Malaria is caused by five species of the parasite Plasmodium. These are Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, and Plasmodium knowlesi. It is transmitted by the bite of female Anopheles mosquitoes which transmit sporozoites to the host while taking blood meal. The parasite reproduces asexually in the liver and red blood cells (RBCs). The disease is a major public health problem in Sub-Saharan Africa and South Asia, and lower incidence is seen in some South American countries. It poses a significant danger to the travelers too, who are advised to take chemoprophylaxis when traveling to the endemic regions. Severe disease results from P. falciparum and less commonly P. vivax. Features of severe malaria are ARDS, shock, encephalopathy and seizures (cerebral malaria), AKI, hypoglycemia, acidemia, hemoglobinuria, severe anemia (hemoglobin <5 gm/dL), and hyperparasitemia (infection of >5% of RBCs). For sensitive vivax malaria, chloroquine is the drug of choice. Falciparum malaria, chloroquine-resistant vivax malaria, and complicated malaria are always treated with artemisinin-based therapy or quinine. AP is reported in falciparum, and less commonly in vivax malaria [Table 5]. It has not been included in the criteria for severe malaria, and the pathogenesis has not been elucidated yet, but it may involve cytoadherence of the infected RBCs to the endothelium of the pancreatic vasculature with resultant ischemia. It can be seen that AP occurs mostly in association with other complications.
AP can occur as a part of disseminated fungal disease. It has been reported in invasive aspergillosis. The mechanism may be related to direct invasion of the pancreas and its vasculature or microvascular thrombosis secondary to disseminated intravascular coagulation.
Cases of AP in Mycoplasma pneumoniae have been described in few studies., The pathogenesis may be multifactorial. There is hematogenous dissemination of the bacteria and production of inflammatory cytokines locally in the affected organs. Vasculitis and immune modulation due to the phagocytosed macrophages may play a role. Sporadic isolated reports of AP due to Campylobacter jejuni, Yersinia More Details enterocolitica, and Yersinia pseudotuberculosis More Details also exist., One author has suggested that AP in campylobacter disease may be due to direct invasion of the pancreatic duct, or due to the host immune response.
Leptospirosis is a zoonotic disease caused by spirochetal bacteria of the genus Leptospira. The disease is distributed worldwide, but the incidence in tropics is ten times higher than other regions. It can be controlled but not eradicated by improved sanitation. Humans are incidental hosts, and the infection is acquired by exposure of contaminated soil or excreta of infected animals to damaged skin, mucosa, or conjunctiva. Consequently, the disease is sporadic, and farmers, sewer workers, and animal handlers are at a higher risk. Less commonly, infection can also occur by ingestion of contaminated food or inhalation of aerosols. It commonly causes a mild and self-limiting febrile illness, but occasionally, it can be severe. Leptospirosis complicated by jaundice and AKI is commonly referred to as Weil's disease. High-quality literature is available on reports of AP from America, Europe, Asia, and Africa [Table 6]. AP is very rare and has been seen in severe disease with multiple complications, but the outcome is good. The possible mechanisms are ischemia and vasculitis.
Scrub typhus is caused by Orientia tsutsugamushi, a bacterium of the genus Rickettsia which comprises Gram-negative, obligate intracellular parasites. Humans are accidental end hosts for the pathogen, which is transmitted by the bite of Leptotrombidium mites. Scrub typhus is a resurging zoonotic infection occurring in parts of Asia and Oceania. Its pathogenesis involves infection of the endothelial cells which leads to a vasculitic type of reaction with microvascular injury and thrombosis. The same mechanism is probably responsible for AP. Many cases with AP have been reported from India [Table 7].
Typhoid or enteric fever is a bacterial infection caused by Salmonella More Details typhi. It is a specter of the developing countries that are battling with overcrowding and poor sanitation. Contrariwise, a single case in the affluent countries is sufficient to make the public health authorities vigilant. Most of the cases in the developed country have a history of travel to the endemic regions. The infection is acquired by oral route. Resistance to gastric acid enables the bacterium to establish infection in the Peyer's patches of the small intestine from where lymphatic and hematogenous dissemination occurs. Further replication occurs within the reticuloendothelial system. Carriers can release the bacilli via feces or urine for prolonged periods. The hypertrophy and necrosis of the Peyer's patches can lead to intestinal hemorrhage and subsequent perforation. The clinical features in an untreated patient follow a stereotypical timeline with fever, malaise, chills, nausea, abdominal pain, diarrhea, or constipation in the 1st week; hepatomegaly, spleenomegaly, salmon rash (rarely seen in dark-skinned individuals), and abdominal pain in the 2nd week; and intestinal bleeding, intestinal perforation, delirium, sepsis, and shock in the 3rd week. The mechanism of AP has been postulated to reflux of S. typhi containing bile into the pancreatic duct, leading to direct injury. The other possibilities include the effect of bacterial toxin and the host immune response. Patients with typhoid may have elevations of amylase and lipase without any clinical evidence of AP. This was confirmed by Hermans et al., who studied 14 adult patients and found that while seven patients had elevated serum enzyme levels, only four had AP, and this complication did not adversely affect the outcome. The data published on AP in culture-proven typhoid are mentioned in [Table 8].
We speculate that the true incidence of pancreatitis in the infections discussed in this review is higher than what is suggested by the available data. The reasons for this are manifold. Firstly, there may be significant under-reporting. Since most of the cases are from developing countries and a majority of the patients are treated at peripheral centers, there is little impetus for the clinicians to publish their experience. Secondly, the lack of diagnostic facilities at such centers can be an impediment. Thirdly, the symptoms of abdominal pain and vomiting may be attributed to the disease per se, or to other pathologies, such as gastritis, hepatitis, cholecystitis, or adverse drug reactions. The possibility of AP may not even be considered. Fourthly, the pancreatitis may be mild and have little symptoms, so the specific investigations required to diagnose it may not be done. Conversely, the patient may have severe pancreatitis and present in such sick condition that he is not able to give the history. Finally, pancreatitis may be attributed to other causes, such as gall stones, drugs, and alcohol, if there is a history of their intake. It is also possible that some patients in the endemic regions who present with a primary diagnosis of AP may have actually developed it as a complication of some infection. The antibiotics that they receive during their care resolve the underlying infection, precluding an accurate diagnosis.
| Conclusion|| |
The current understanding of the infectious etiology of AP is incomplete. Although some causes are well established, AP is also a rare complication of infections such as dengue, malaria, scrub typhus, leptospirosis, typhoid, chikungunya, influenza, acute viral hepatitis, and COVID-19. Physicians should be wary of its possibility before attributing the symptoms to another abdominal pathology. The data available are limited and confined to case reports or case series. An attempt to investigate the pathogenesis has not been made yet. Due to the dearth of data and absence of a well-planned study, no statistical conclusions can be drawn at the moment, and it is currently not possible to comment on how its severity compares to AP caused by other causes, the effect of antimicrobial treatment, and the long-term outcome. The subject provides an opportunity for future studies and research.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]