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