Plasmodium vivax is the most geographically widespread of the human malaria parasites, responsible for roughly 40 percent of malaria cases outside sub-Saharan Africa and imposing a heavy burden across South Asia, including Bangladesh. For much of medical history it was labeled benign tertian malaria, a description that reflected its typically lower mortality compared with Plasmodium falciparum. That reputation has been steadily dismantled. Systematic reviews have documented severe and fatal vivax complications including acute liver failure, acute respiratory distress syndrome, acute kidney injury, profound anemia, and coagulopathy. The biological basis for this severity lies in cytokine-mediated immune dysregulation, activation of the endothelial cells lining blood vessels, and microvascular dysfunction driven by rosetting and cytoadherence, in which infected red blood cells clump together and stick to vessel walls, choking off blood flow to tissues.

The patient arrived at a tertiary referral center in Dhaka after five days of high-grade fever with rigors and chills, generalized weakness, and upper abdominal pain accompanied by nausea and vomiting. She had no significant medical, surgical, or family history, took no regular medications, and had never traveled outside the Dhaka metropolitan area. On admission she was acutely ill and hemodynamically unstable, with a temperature of 39.8 degrees Celsius, a heart rate of 112 beats per minute, a blood pressure of 96 over 60 millimeters of mercury, and a respiratory rate of 22 breaths per minute. She was conscious and fully oriented, but examination revealed yellowing of the sclerae, pallor, tenderness in the right upper abdomen, a spleen palpable about three centimeters below the left costal margin, and ascites, free fluid in the abdominal cavity, confirmed by shifting dullness.

Laboratory results painted an alarming picture. She had pancytopenia, a collapse of all three blood cell lineages, with platelets down to 18 billion per liter, hemoglobin of 9.6 grams per deciliter, and white cells at 3.3 billion per liter. Ferritin, an inflammatory marker, was measured at a staggering 28,839 nanograms per milliliter, while lactate dehydrogenase reached 1,178 units per liter and triglycerides 332 milligrams per deciliter. Liver tests showed severe injury, with AST of 522 units per liter and total bilirubin of 5.65 milligrams per deciliter, predominantly of the conjugated type, pointing to hepatocellular and cholestatic damage from systemic hyperinflammation. Coagulation studies revealed a prolonged prothrombin time of 19.5 seconds, fibrinogen depleted to 91 milligrams per deciliter, and a D-dimer of 7.83 micrograms per milliliter, a combination fulfilling the International Society on Thrombosis and Haemostasis criteria for overt DIC. Serum lipase of 584 units per liter, more than three times the upper limit of normal, alongside characteristic abdominal pain, satisfied the revised Atlanta criteria for acute pancreatitis.

Imaging and further workup helped assemble the diagnosis. Abdominal ultrasonography showed hepatosplenomegaly, moderate ascites, bilateral mild pleural effusions, and increased renal cortical echogenicity consistent with acute nephropathy. Notably, the pancreas appeared normal, which the authors emphasize does not exclude pancreatitis, since ultrasound has limited sensitivity in early or mild disease. Analysis of the ascitic fluid found inflammatory cells, elevated protein, and a markedly raised adenosine deaminase level of 69.74 units per liter, which initially raised concern for tuberculous peritonitis in this endemic setting. However, cultures, malignant cytology, and GeneXpert testing for tuberculosis were all negative, and the fluid’s mixed inflammatory profile, the absence of chronic constitutional symptoms, and the rapid resolution without antitubercular therapy indicated the ascites was part of the systemic inflammatory response to severe malaria. A rapid diagnostic test was positive for the P. vivax-specific parasite lactate dehydrogenase antigen, although the peripheral blood smear was negative, likely reflecting low-density parasitemia or partial prior treatment.

The immunological diagnosis rested on established scoring systems. The patient fulfilled six of the eight HLH-2004 diagnostic criteria: persistent fever, splenomegaly, bicytopenia, hyperferritinemia, hypertriglyceridemia, and hypofibrinogenemia, where five or more criteria are required. Because NK cell function and soluble interleukin-2 receptor assays were unavailable due to resource constraints, the team also applied the HScore, a validated probability calculator for reactive HLH, retrospectively. Her score of 264 corresponded to a greater than 99 percent probability of reactive HLH. Ferritin concentrations above 20,000 nanograms per milliliter are uncommon in uncomplicated malaria, the authors note, and should prompt active evaluation for secondary HLH. Bone marrow examination was not performed, since hemophagocytosis is neither mandatory nor pathognomonic under the HLH-2004 framework, and the absence of lymphadenopathy, malignancy, or autoimmune disease, together with rapid resolution on antimalarials, supported an infection-triggered process.

HLH itself is a syndrome of catastrophic immune dysregulation in which macrophages and cytotoxic T lymphocytes escape normal control, flooding the body with inflammatory cytokines including interleukin-6, tumor necrosis factor alpha, interferon gamma, and interleukin-18. In malaria-associated secondary HLH, persistent antigenic stimulation by parasitized erythrocytes is thought to drive this aberrant activation, promoting hemophagocytosis, the consumption of blood cells by macrophages, in the bone marrow, liver, spleen, and lymph nodes, which produces the characteristic cytopenias, extreme hyperferritinemia, and hypertriglyceridemia. DIC, meanwhile, arises from endothelial injury, monocyte and macrophage activation, impaired anticoagulant pathways, and fibrinolytic dysregulation, leading to widespread microvascular thrombosis with consumption of clotting factors. Although best documented in falciparum malaria, DIC is increasingly recognized in vivax infection. Acute pancreatitis remains a rare malaria complication, proposed to result from microvascular ischemia caused by sequestration of parasitized cells in pancreatic capillaries and direct cytokine-mediated injury.

Treatment followed World Health Organization guidelines for severe malaria: intravenous artesunate at 2.4 milligrams per kilogram at zero, 12, and 24 hours, then once daily. Critically, the team deliberately deferred HLH-directed immunosuppressive therapy with dexamethasone or etoposide, consistent with expert recommendations that treating the underlying infection is often sufficient in infection-associated HLH when an effective antimicrobial exists. Intravenous immunoglobulin was considered but judged unlikely to add benefit given her rapid improvement. DIC was managed conservatively without transfusions, and pancreatitis was managed with bowel rest and nutritional support. Fever resolved by day five, abdominal pain and pancreatic enzymes normalized in parallel, and platelets climbed from 18 to 80 billion per liter by day nine. After stabilization she switched to oral artemether-lumefantrine, and with confirmed normal G6PD activity received primaquine for 14 days to eradicate dormant hepatic hypnozoites, the vivax-specific reservoir that can reactivate weeks to months later. She was discharged on day 12 and remained asymptomatic with fully normalized inflammatory markers at follow-up.

The authors are candid about limitations. Species confirmation rested solely on the rapid diagnostic test, since PCR was unavailable, and cross-reactivity with Plasmodium knowlesi, which can also cause severe malaria, cannot be excluded. Broader viral screening for alternative HLH triggers such as Epstein-Barr virus, cytomegalovirus, and HIV was not performed, and NK cell activity, soluble interleukin-2 receptor, and bone marrow biopsy were all unavailable. Even so, the case joins a small but growing international literature, including reports from Korea, other South Asian settings, and pediatric practice, establishing vivax-associated HLH as a reproducible entity in which prompt antimalarial therapy determines outcome. For clinicians in endemic regions, the message is pointed: extreme hyperferritinemia, coagulopathy, or elevated pancreatic enzymes in a malaria patient should trigger systematic evaluation beyond routine workup, because recognizing these hyperinflammatory and thrombotic complications early, and treating the parasite decisively, may be enough to save a life without resorting to immunosuppression.

Subject of Research: Severe Plasmodium vivax malaria complicated by secondary hemophagocytic lymphohistiocytosis, disseminated intravascular coagulation, and acute pancreatitis

Article Title: Severe Plasmodium vivax Malaria Complicated by Secondary Hemophagocytic Lymphohistiocytosis, Disseminated Intravascular Coagulation, and Acute Pancreatitis: A Case Report

Article References: Nafian, T., Azad, M. A. K., Murshed, K. M., Aftab, K. A., Shahriar, R., & Faisal, A. A. (2026). Severe Plasmodium vivax Malaria Complicated by Secondary Hemophagocytic Lymphohistiocytosis, Disseminated Intravascular Coagulation, and Acute Pancreatitis: A Case Report. Clinical Case Reports, 14(10), Article e73581. https://doi.org/10.1002/ccr3.73581

Image Credits: AI Generated

DOI: 10.1002/ccr3.73581

Keywords: Plasmodium vivax, malaria, hemophagocytic lymphohistiocytosis, disseminated intravascular coagulation, acute pancreatitis, artesunate, cytokine storm, hyperferritinemia, Bangladesh, HLH-2004 criteria, HScore, severe malaria

A new prospective clinical study published in the Journal of Cellular and Molecular Medicine offers a fresh molecular angle on this problem by examining a family of proteins that has rarely been studied in human pancreatitis: the ATP-binding cassette, or ABC, transporters. These transporters form a large protein superfamily that functions as ATP-dependent pumps, moving a wide range of endogenous and exogenous compounds across cell membranes. In doing so, they help maintain cellular barrier functions, preserve cellular homeostasis and regulate cellular stress responses. Importantly, their expression is known to be modulated by inflammatory signalling and various forms of cellular stress, which makes them plausible players in a disease defined by exactly those processes. Yet, until now, the expression levels of ABC transporter genes in acute pancreatitis and their relationship to clinical and radiological severity had not been sufficiently clarified.

The research team, working at the University of Health Sciences Sancaktepe Şehit Prof. Dr. İlhan Varank Training and Research Hospital in Türkiye, focused on two specific members of the transporter family. The first, ABCG2, located on chromosome 4q22, mediates the efflux of diverse substrates out of the cell through an ATP-dependent mechanism and has been linked to protection against oxidative stress in experimental systems. The second, ABCC2, also known as MRP2, is expressed not only in the liver but also in human pancreatic tissue, particularly on the apical membrane of ductal cells, where it contributes to the export of toxic metabolites and inflammatory mediators. Given these functional profiles, both genes were considered candidates for involvement in the inflammatory and cellular stress pathways that underpin acute pancreatitis.

The study enrolled 80 patients hospitalized with acute pancreatitis between December 2023 and January 2025, alongside 96 healthy controls matched for age and sex who had no acute or chronic inflammatory disease, infection, rheumatologic condition, or chronic liver or kidney disease. Diagnosis followed standard criteria, requiring at least two of three features: typical abdominal pain, serum amylase or lipase at least three times the upper limit of normal, or compatible imaging findings. Clinical severity was assessed with the Ranson score at admission and at 48 hours, while radiological severity was classified using computed tomography in strict accordance with the revised Atlanta classification, distinguishing mild disease from moderately severe disease with transient organ failure or local complications and severe disease with persistent organ failure beyond 48 hours.

The molecular workflow was straightforward but rigorous. Peripheral venous blood samples were collected from all participants, and after routine biochemical analyses were completed, remaining blood was centrifuged, separated and stored at minus 80 degrees Celsius. Total RNA was extracted from whole blood using a TRIzol-based method, with concentration and purity verified spectrophotometrically. Complementary DNA was synthesized and the expression levels of ABCG2 and ABCC2 were quantified by quantitative real-time polymerase chain reaction, with β-actin serving as the internal control. All reactions were run in triplicate and relative gene expression was calculated using the 2^(−ΔΔCt) method, a standard approach that normalizes target gene signals to a stable reference gene.

The demographic picture of the cohort reflected the typical profile of acute pancreatitis. The mean age of patients was 49.74 years, statistically indistinguishable from the control group’s 47.96 years, and 60 percent of patients were male. Gallstones were by far the most common cause of the disease, accounting for 52.5 percent of cases, followed by alcohol use at 15 percent, hyperlipidemia at 5 percent, medication-related causes at 3.75 percent and other etiologies at 23.75 percent. Clinically, the median total Ranson score was 3, and 57.5 percent of patients were classified as having severe disease by that score. Radiologically, however, 83.7 percent of patients showed mild disease on computed tomography, with only 16.3 percent classified as moderate or severe. Pleural effusion occurred in 11.3 percent of patients, 7.5 percent needed supplemental oxygen, 5 percent required intensive care, and the median hospital stay was six days.

The central molecular findings were striking. ABCG2 expression was significantly lower in patients with acute pancreatitis than in healthy controls, with a median expression of 0.29 in the patient group versus 0.58 in controls, a difference that reached statistical significance at p = 0.025. ABCC2, by contrast, showed no significant difference between patients and controls, with a median of 1.54 in patients versus 0.89 in controls and a p-value of 0.172. When the researchers stratified patients by Ranson score, neither gene distinguished mild from severe clinical disease; ABCG2 showed a non-significant trend toward higher expression in severe cases at p = 0.098, while ABCC2 showed no relationship at all. The picture changed, however, when severity was assessed radiologically: ABCG2 expression was significantly higher in the moderate and severe group defined by computed tomography, with a median of 1.05 versus 0.21 in mild cases, a difference that was statistically significant at p = 0.038.

Receiver operating characteristic analysis added further nuance. The area under the curve for ABCG2 as a discriminator of acute pancreatitis was 0.598, with a 95 percent confidence interval of 0.515 to 0.682, a statistically significant but modest discriminatory performance. The authors interpret this carefully: the fact that ABCG2 expression is lower in patients overall suggests it is unlikely to serve as a stand-alone diagnostic marker. Instead, they argue, the gene may function as a dynamic indicator of the underlying inflammatory and cellular stress biology. They propose a plausible mechanism: the intense cytokine response and cellular stress during the acute inflammatory phase may initially suppress ABCG2 expression, while a compensatory upregulation emerges in more severe cases as oxidative burden and cellular injury accumulate. This interpretation is consistent with prior experimental work showing that ABCG2 can reduce oxidative stress and apoptosis, and with evidence that reactive oxygen species, disrupted calcium homeostasis, mitochondrial dysfunction and ATP depletion drive acinar cell necrosis in pancreatitis.

The findings also align with earlier animal data. In a rat model of chronic pancreatitis, researchers including members of the same team had previously observed changes in ABCG2 and ABCC2 expression in the setting of chronic inflammation, with melatonin administration influencing oxidative and endoplasmic reticulum stress parameters tied to these genes. The present human study, however, reveals a different pattern: suppression of ABCG2 overall but elevation in radiologically severe cases. The authors attribute these differences to the distinct biology of acute versus chronic inflammation, interspecies variation and the use of peripheral blood rather than pancreatic tissue. Notably, the stronger association of ABCG2 with radiological rather than clinical severity may reflect the fact that computed tomography more directly demonstrates morphological injury, including necrosis and local complications, whereas clinical scores may under-capture severity in the early phase. The study’s limitations include its single-centre design, modest sample size and reliance on blood samples, but its strengths are considerable: it is the first study to evaluate ABCG2 and ABCC2 expression in human acute pancreatitis, and by linking molecular data to both clinical scores and imaging classifications it provides original evidence that ABCG2 may be a dynamically regulated candidate biomarker of inflammatory and cellular stress in this unpredictable disease.

Subject of Research: ABCG2 and ABCC2 transporter gene expression and its relationship to disease severity in acute pancreatitis

Article Title: ABCG2 and ABCC2 Expression Levels and Their Relationship With Disease Severity in Acute Pancreatitis

Article References: Baş, S., Güzel Tanoğlu, E., Tanoğlu, A., Karahan, H. T., Gökçe, M. S., Yeniçeri, M., Şenoymak, M. C., & Arslan, K. (2026). ABCG2 and ABCC2 Expression Levels and Their Relationship With Disease Severity in Acute Pancreatitis. Journal of Cellular and Molecular Medicine, 30(18), Article e71368. https://doi.org/10.1111/jcmm.71368

Image Credits: AI Generated

DOI: 10.1111/jcmm.71368

Keywords: acute pancreatitis, ABCG2, ABCC2, ABC transporters, gene expression, Ranson score, revised Atlanta classification, computed tomography, oxidative stress, biomarkers, qRT-PCR, inflammation

The research, conducted by a team at Semmelweis University in Budapest along with collaborators in Romania and Hungary, took the form of a systematic review and meta-analysis published in the journal Gut Pathogens. Rather than relying on any single centre’s experience, the investigators systematically searched the medical literature for studies reporting on the microbiological profile of patients undergoing endoscopic or percutaneous drainage for infected walled-off necrosis or pancreatic pseudocysts. These two types of pancreatic fluid collections represent distinct pathological entities. Walled-off necrosis arises when areas of dead pancreatic or surrounding tissue become encapsulated by a wall of inflammatory tissue, typically four or more weeks after the onset of necrotising pancreatitis. Pancreatic pseudocysts, by contrast, are fluid-filled cavities bounded by fibrous tissue that lack the solid necrotic component. Both can become infected, and both are increasingly managed through minimally invasive drainage rather than open surgery, making the organisms they harbour directly relevant to treatment decisions.

After screening the available literature according to a protocol registered in advance on the PROSPERO international prospective register of systematic reviews, the team identified thirty-one eligible studies encompassing one thousand two hundred and eighty-six patients with culture-positive infections of pancreatic fluid collections. The pooled analysis revealed a microbial ecosystem dominated by organisms that originate in the gastrointestinal tract, which makes anatomical sense given that the pancreas lies adjacent to the duodenum and that pancreatic fluid collections frequently communicate with the gut either through the pancreatic duct or through erosion into adjacent bowel. Escherichia coli emerged as the single most prevalent bacterium in infected walled-off necrosis, detected in twenty-one percent of cases with a ninety-five percent confidence interval spanning thirteen to thirty-one percent. Enterococcus species followed closely at twenty percent, with a wider confidence interval of twelve to thirty-three percent reflecting the heterogeneity of the underlying studies.

Perhaps the most striking finding was the prominence of Candida species, detected in twenty percent of infected walled-off necrosis cases with a confidence interval of eleven to thirty-three percent. The presence of this fungal genus at rates comparable to the leading bacterial pathogens challenges the traditional assumption that bacterial organisms alone drive the majority of these infections. Candida is a normal inhabitant of the gastrointestinal tract, and its appearance in pancreatic collections likely reflects translocation from the gut across compromised mucosal barriers. The finding has important therapeutic implications because standard empiric antibiotic regimens for intra-abdominal infections typically do not cover fungi, meaning that clinicians who rely on broad-spectrum antibacterial agents alone may miss a substantial proportion of causative organisms.

The analysis also quantified the burden of antimicrobial resistance in these collections, finding that multidrug-resistant organisms were present with a pooled prevalence of twenty-four percent among infected patients, with a confidence interval stretching from ten to fifty percent. This wide range reflects significant variability across the included studies, likely driven by differences in local antibiotic prescribing practices, infection control infrastructure, and patient populations. Nevertheless, the central estimate is alarming because it means that approximately one in four patients with an infected pancreatic fluid collection harbours organisms resistant to multiple first-line antimicrobial agents. The authors noted that the spectrum of resistance includes extended-spectrum beta-lactamase producing Enterobacteriaceae, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus, each of which demands specific therapeutic agents that may not be part of standard empiric protocols.

One of the most clinically valuable contributions of the study lies in its regional stratification, which exposed dramatic geographical variation in pathogenic distribution. In European patients, Candida species predominated at thirty-eight percent with a confidence interval of twenty-three to fifty-six percent, followed by Enterococcus species at thirty-five percent. In Asian populations, the picture shifted markedly, with Escherichia coli leading at twenty-nine percent and Klebsiella species rising to twenty-seven percent. This east-west divide has tangible implications for how empiric antibiotic therapy should be selected. A clinician in Budapest or Bucharest facing a patient with suspected infected pancreatic necrosis might reasonably weight antifungal and anti-enterococcal coverage more heavily, while a counterpart in Seoul or Mumbai would need to ensure robust coverage against gram-negative organisms including Klebsiella, which in many Asian centres carries elevated rates of carbapenem resistance.

When the researchers turned their attention specifically to infected pancreatic pseudocysts rather than walled-off necrosis, they found a somewhat different hierarchy. Escherichia coli was again the leading pathogen at twenty-nine percent, though with a very wide confidence interval of eight to sixty-five percent that underscores the smaller number of studies and patients available for this subgroup. Staphylococcus species followed at twenty-five percent, and Klebsiella species came in at eighteen percent. The broader confidence intervals for pseudocyst-associated infections reflect the relative rarity of infected pseudocysts compared with infected necrosis, since pseudocysts are less likely to harbour solid necrotic debris that serves as a nutrient-rich medium for bacterial proliferation. Nevertheless, the finding that Staphylococcus species rank second in pseudocyst infections is noteworthy because it suggests a possible role for skin flora or healthcare-associated contamination in these collections, particularly when interventions such as fine-needle aspiration or drainage have been performed.

The technical challenges of obtaining reliable microbiological data from pancreatic fluid collections deserve careful consideration. Culture results can be influenced by the sampling method employed, whether by endoscopic ultrasound-guided fine-needle aspiration, direct puncture during drainage, or percutaneous catheter placement. Prior antibiotic exposure, which is nearly universal in these patients by the time drainage is attempted, can suppress the growth of susceptible organisms and lead to false-negative cultures or an overrepresentation of resistant species. The heterogeneity of sampling modalities across the thirty-one included studies represents a limitation that the authors acknowledged, noting that marked variation across regions and sampling techniques contributed to the wide confidence intervals observed for many organisms. The researchers also pointed out that the retrospective and observational nature of most included studies means that temporal trends in resistance patterns could not be reliably assessed, and that the findings warrant further prospective evaluation.

The clinical implications of this work extend beyond the choice of individual antibiotics. The authors argue that recognition of regional pathogenic distribution should inform antimicrobial stewardship programmes, which aim to optimise antibiotic use to preserve efficacy and limit the emergence of resistance. In the context of infected pancreatic fluid collections, stewardship involves a delicate balance. Empiric coverage must be broad enough to address the likely pathogens, including consideration of fungal coverage in European settings, yet targeted de-escalation based on culture results is essential to avoid selecting for multidrug-resistant organisms. The finding that nearly a quarter of infections involve multidrug-resistant organisms adds urgency to calls for rapid diagnostic methods that can identify pathogens and their resistance profiles within hours rather than days, allowing clinicians to narrow therapy sooner and spare patients the toxicities and costs of unnecessarily broad regimens.

This study represents a significant step forward in understanding the microbiological underpinnings of one of the most feared complications of acute pancreatitis. By synthesising data from thirty-one studies and over twelve hundred patients across multiple continents, it provides clinicians with evidence-based benchmarks against which to judge their local microbiology results and to calibrate empiric therapy. The dominance of enteric organisms confirms that the gut serves as the primary reservoir for infection in these collections, while the unexpected prominence of Candida species and the substantial burden of antimicrobial resistance highlight gaps in current treatment paradigms. As the authors conclude, a diverse microbial profile with enteric organisms, fungal pathogens, and significant heterogeneity across regions characterises infected pancreatic fluid collections, and integrating this knowledge into clinical practice may ultimately translate into better outcomes for patients facing these life-threatening complications.

Subject of Research: Microbiological profile of infected walled-off pancreatic necrosis and pseudocysts

Article Title: The microbiological landscape of infected walled-off necrosis and pancreatic pseudocysts: a systematic review and meta-analysis

Article References: Brand, T., Marchis, A., Grigorovici, R., Aviv, K., Tóth, R., Bunduc, S., Mihály, E., Obeidat, M., Erőss, B., Hegyi, P., & Hegyi, P. J. (2026). The microbiological landscape of infected walled-off necrosis and pancreatic pseudocysts: a systematic review and meta-analysis. Gut Pathogens. https://doi.org/10.1186/s13099-026-00883-9

Image Credits: AI Generated

DOI: 10.1186/s13099-026-00883-9

Keywords: acute pancreatitis, walled-off necrosis, pancreatic pseudocyst, pancreatic fluid collections, Escherichia coli, Enterococcus, Candida, multidrug resistance, antimicrobial stewardship, endoscopic drainage, meta-analysis, microbiology