Secondary hemophagocytic lymphohistiocytosis mimicking sepsis in hepatitis A–E coinfection: spontaneous recovery with supportive care

ABSTRACT

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome caused by dysregulated immune activation. Viral infections, particularly Epstein–Barr virus, are well-known triggers; however, HLH associated with acute viral hepatitis is rare, especially in the setting of hepatitis A (HAV) and hepatitis E (HEV) coinfection. A 30-year-old man presented with fever following the onset of jaundice, along with fatigue and dyspnea. Laboratory evaluation revealed severe hyperbilirubinemia, markedly elevated transaminases, anemia, hyperferritinemia, and hypertriglyceridemia. He also had hemolysis due to glucose 6 phosphate dehydrogenase(G6PD) deficiency. Bone marrow examination demonstrated hemophagocytosis. Viral m arkers confirmed HAV and HEV coinfection. Although he fulfilled five out of eight HLH-2004 criteria, sepsis markers like raised procalcitonin and leukocytosis posed diagnostic challenge. He was managed with supportive care alone, and showed spontaneous clinical and biochemical improvement without immunosuppressive therapy. This case highlights a probable HLH spectrum disorder triggered by HAV–HEV coinfection. It underscores the importance of considering HLH in patients with acute viral hepatitis who develop persistent fever and cytopenia, while also recognizing that selected patients may improve with supportive care alone.

INTRODUCTION

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome characterized by uncontrolled activation of cytotoxic T lymphocytes and macrophages leading to cytokine storm and multiorgan dysfunction. It may be primary (genetic) or secondary to infections, malignancies or autoimmune disorders [1]. Among infectious triggers, viral etiologies such as Epstein–Barr virus (EBV), Cytomegalovirus (CMV) and herpesviruses (HSV) are most frequently implicated [2]. HLH usually presents as an acute febrile illness with multisystemic involvement. Laboratory findings, viz., cytopenia and hyperferritinemia, are often nonspecific. Therefore, diagnosis becomes challenging due to the variable presentations, rarity of the disease and absence of dedicated tests like IL-2 receptor activity in resource-limited settings. HLH carries a high mortality rate ranging from 50 to 70%. Hence, prompt diagnosis and management are crucial [3].

Acute viral hepatitis due to hepatitis A virus (HAV) and hepatitis E virus (HEV) constitutes a major global health burden. However, their association with HLH is uncommon and likely under-recognized. Damaged hepatocytes release intracellular contents known as damage associated molecular patterns (DAMPs). These stimulate resident liver macrophages and circulating immune cells to produce a cascade of inflammatory cytokines, viz, TNF-α, IL-1β and IL-6. These trigger a positive feedback loop precipitating ongoing systemic inflammation. HLH is often difficult to distinguish from sepsis as both conditions present with fever, hemodynamic instability, elevated procalcitonin and multiorgan dysfunction. Immunosuppression is a key component in the management of cytokine storm syndromes; however, it may be detrimental in the presence of an uncontrolled active bacterial infection. Therefore, accurate identification of the underlying etiology remains the primary clinical challenge [4].

We report a case of HLH triggered by HAV–HEV coinfection with spontaneous resolution without immunosuppressive therapy.

CASE PRESENTATION:

A 30-year-old man presented with generalized body ache and fatigue for 14 days followed by jaundice and dark urine. Four days after onset of jaundice, he developed high-grade fever with chills and rigors along with shortness of breath.

On clinical examination he was icteric, tachycardic and tachypneic. There was hepatomegaly. Baseline investigations comprised conjugated hyperbilirubinemia with total bilirubin 540.4 umol/L, direct bilirubin 490.8 umol/L, hypertransaminasemia with aspartate aminotransferase (AST) 2657 IU/L, alanine aminotransferase (ALT) 3389 IU/L, alkaline phosphatase (ALP) 157 IU/l, gamma glutamyl transpeptidase (GGT) 188 IU/L. His complete hemogram showed anemia with Hb of 93 g/L, leukocytosis with total count 14.4x10⁹ cells/mm³ and relatively normal platelet count of 124x10⁹ /L. C-reactive protein was borderline (14.7 mg/l) but procalcitonin levels were high i.e., 2.26 mg/L. He also had coagulopathy (INR 1.54). Abdominal ultrasonography revealed hepatosplenomegaly with liver measuring 16.9 cm and spleen 13.6cm. He was managed initially as acute liver injury with possible sepsis and started on broad-spectrum antibiotics along with vitamin K parenteral supplementation. Also, the need for therapeutic plasma exchange as a rescue option was explained to the attendants.

In the next 24 hrs his INR improved to 1.3, hemoglobin continued to drop to 6.9 g%. At the same time, he had intermittent high-grade fever. Urine culture was sterile and blood culture showed no interim growth. Peripheral blood showed anisopoikilocytosis, polychromatophilic red blood cells and nRBCs suggestive of hemolysis. Lactate Dehydrogenase levels were also markedly elevated. However direct antiglobulin test (DAT) and indirect antiglobulin test (IAT) were negative which ruled out immune mediated hemolysis. Further hemolytic work-up during hospitalization revealed glucose 6-phosphate dehydrogenase (G6PD) deficiency. He had elevated serum ferritin levels (>10,000 ng/ml). In view of high-grade fever, hepatosplenomegaly and elevated serum ferritin with anemia, possibility of HLH was considered. His fasting triglycerides too were elevated i.e., 667 mg/dl. Subsequently, bone marrow aspiration revealed hemophagocytes with increased histiocytic activity (Figure 1) along with erythroid hyperplasia and dyserythropoiesis. Plasma cell, megakaryocytes and granulopoiesis were normal. Serum fibrinogen level was just above the lower limit of normal i.e. 2.1 g/l. However, as five out of eight HLH 2004 criteria were fulfilled, a HLH-like hyperinflammatory state was considered. Corticosteroids or intravenous immunoglobulins were considered as probable treatment options. He was given one unit of packed RBC. His fever spikes reduced and procalcitonin levels also normalized. Antibiotics were discontinued after negative cultures and normalization of procalcitonin. Subsequently fever subsided, hemoglobin stabilized and liver function gradually improved. At follow-up, he remained clinically stable with improving hemoglobin and declining bilirubin levels (Table 1).

Fig. 1.

Bone marrow aspirate showing hemophagocytes (blue arrows) (May–Grünwald Giemsa stain, magnification ×400).

Table 1.

Trends in hematological and biochemical parameters.

Parameters (In SI units)	Normal range	At admission	48 hours after admission	At discharge	1 week follow up	2 weeks follow up
Hb (g/L)	130-160	91	65	98	101	116
TLC (x109/L)	4-11	14.4	18.6	6.6	4.7	6.6
Platelet (x109/L)	150-400	126	135	194	340	220
Blb (Direct) (umol/L)	5.13-22.3	540.4 (490.8)	767.8 (711.4)	340.3 (306)	285.6 (253)	94.6 (59.5)
AST (U/L)	20-50	2657	2146	85	106	142
ALT (U/L)	20-50	3389	2950	238	150	147
SAP (U/L)	40-120	157	138	221	327	203
INR	0.8-1.2	1.54	1.52	0.99	1.05	1.18
CRP (mg/L)	<10	39.7	------	14.7	------	------
Procalcitonin (ug/L)	<0.5	2.2	------	0.46	------	------
Serum ferritin (ug/L)	30-150	------	>10,000	------	------	1,675
Fasting Triglyceride (mmol/L)	<200	------	754	------	------	------
Serum Fibrinogen (g/L)	2-4	------	2.1	------	------	------

DISCUSSION

HLH is characterized by inappropriate activation of cytotoxic T lymphocytes and natural killer (NK) cells. In a healthy immune system, these cells produce two cytolytic enzymes: perforin and granzyme; packaged into granules and discharged into the immunological synapse between the effector cell and the target cell. In HLH this synergy is disrupted leading to a vicious cycle of inflammation. As cytotoxic cells accumulate, there is a massive increase in circulating cytokines [5]. This cytokine storm leads to widespread activation of macrophages resulting in hemophagocytosis and excessive inflammation causing organ damage.

In adults' malignancies, autoimmune disorders and infections are the common precipitants of HLH. Among infections, EBV, HSV, CMV and intracellular pathogens like leishmaniasis and tuberculosis are commonly implicated. Hepatitis A and E are accountable for global burden of acute viral hepatitis but they are rarely associated with HLH. Giri et al. published a case series of HAV induced HLH comprising five cases. All the cases had similar presenting features i.e., high grade fever after onset of jaundice. There was anemia in four patients while leukopenia in one patient and one patient had leukocytosis. Two patients had thrombocytopenia. LDH was found elevated in four patients. Three patients had low fibrinogen levels. One patient improved spontaneously without treatment. All other patients required dexamethasone and one expired among them [6]. In another case report of HAV associated HLH, the patient had drop in Hb from 10 to 5.5g%, while platelet counts and TLC remained normal. LDH level was very high (1540 IU/l), suggestive of hemolysis. He had high serum ferritin and triglyceride but normal fibrinogen levels. Bone marrow revealed increased number of histiocytes with hemophagocytes. He developed subsequent fungal pneumonia warranting mechanical ventilation and was managed successfully with intravenous antimicrobials and intravenous immunoglobulin [7]. Desai et al, reported a case of HEV infection associated HLH. This patient had pancytopenia with high serum ferritin (21,900 ug/L) and serum triglyceride of 660 mg/dl. Accordingly on bone marrow aspiration, hemophagocytes were demonstrated. Thereafter he was started on dexamethasone and within 72 hours there was resolution of fever along with improvement in LFT and blood counts [8].

The diagnosis of HLH is always challenging in the absence of specific signs and symptoms. For instance, hyperferritinemia may be evident in any acute inflammatory state. Moreover, bone marrow aspiration may not show hemophagocytes in the early stage. Further the tests like fibrinogen, soluble CD 25 marker assay and NK cell activity assays are not always available in resource limited settings. As for example in our patient, we could not do the NK cell activity and soluble CD 25 marker assay due to logistic issues. The diagnosis should follow the HLH 2004 criteria, requiring five out of eight criteria, viz., fever, splenomegaly, cytopenia of two or more lineages, hypertriglyceridemia and/or hypofibrinogenemia, decreased or absent NK cell activity, elevated ferritin, hemophagocytes visualized in bone marrow, spleen or lymph nodes [9].

The management strategy in HLH has three components: supportive care, identification and treatment of underlying trigger and suppression of cytokine storm. In the absence of a universal consensus, multiple immunosuppressants have been tried for secondary HLH. In contrast to primary HLH where Etoposide is highly effective, in secondary HLH it is reserved for refractory cases. Either corticosteroids alone or in combination with IVIg, etanercept and plasma exchange are first line treatment options for secondary HLH [10].

Our patient had HAV and HEV co-infection. High-grade fever after onset of jaundice and fall in Hb prompted us to suspect HLH. In complete hemogram there was anemia with leukocytosis and normal platelet count. As per a systematic review, thrombocytopenia is the commonest feature followed by leukopenia and rarely anemia [11]. However, only anemia was observed in the hemogram unlike other reported cases with bicytopenia or pancytopenia. The presence of G6PD deficiency likely contributed to hemolysis. However, it does not explain the persistent fever, marked hyperferritinemia and hemophagocytosis indicating an underlying HLH-like hyperinflammatory state. The patient fulfilled five HLH-2004 criteria—fever, hepatosplenomegaly, hyperferritinemia (>10,000 ng/mL), hypertriglyceridemia and bone marrow hemophagocytosis—supporting a diagnosis within the HLH spectrum despite atypical hematological findings. The drop in hemoglobin was stabilized after stopping antibiotics which indicates probable cessation of antibiotic induced oxidative stress related hemolysis. Notably, spontaneous resolution without immunosuppressive therapy (as observed in our case) has been infrequently described [6,12,13] (Table 2). Despite initial elevation of procalcitonin, persistently negative cultures, absence of clinical deterioration and rapid improvement after discontinuation of antibiotics argued against sepsis. It is speculated that procalcitonin, often used as a marker of bacterial sepsis, can be significantly elevated in HLH. The hyperinflammatory state and macrophage activation lead to high circulating levels of cytokines (especially IL-6 and TNF-α), prompting non-thyroidal tissues (like the liver) to release procalcitonin [14]. Also, the spontaneous recovery from HLH was noteworthy. It is hypothesized that as the immune system successfully clears the virus, the inflammatory signals naturally subside allowing the hyperactive immune response to calm down and the patient to recover.

Table 2.

Summary of reported cases of HLH associated with viral hepatitis.

Ref No	Precipitating factor	Clinical presentation	Cytopenia	Treatment	Outcome
Giri et al. 2025 [6]	HAV infection	Fever	Leukopenia	Dexamethasone	Improved
Giri et al. 2025 [6]	HAV infection	Fever with altered sensorium	Pancytopenia	Supportive care	Expired
Giri et al. 2025 [6]	HAV infection	Fever	Anemia and Thrombocytopenia	Dexamethasone	Improved
Giri et al. 2025 [6]	HAV infection	Fever	Anemia and Leukopenia	Supportive care	Improved
Giri et al. 2025 [6]	HAV infection	Fever	Anemia and Thrombocytopenia	Dexamethasone	Improved
Mallick et al. 2019 [7]	HAV infection	Fever with type 1 respiratory failure	Pancytopenia	IVIg	Improved
Watanabe et al. 2002 [12]	HAV infection	Fever	Thrombocytopenia	Supportive care	Improved
Desai et al. 2024 [13]	HEV infection	Fever, pain abdomen	Leukopenia	Dexamethasone	Improved
Present case	HAV/HEV coinfection	Fever with severe anemia	Anemia	Supportive care	Improved

To our knowledge, reports of HLH occurring in the setting of concomitant HAV and HEV infection are scarce. Although HAV-associated HLH has been described previously, HEV-associated HLH remains uncommon in the literature. In addition, our patient presented with isolated anemia as the only cytopenia, whereas most reported cases have documented thrombocytopenia and leukopenia. Another notable feature was spontaneous recovery with supportive care alone, without the requirement for HLH-directed immunosuppressive therapy, an outcome that has only occasionally been reported.

CONCLUSION

This case highlights the importance of considering HLH or HLH-like hyperinflammatory syndromes in patients with acute viral hepatitis presenting with persistent fever and laboratory evidence of systemic inflammation. Importantly, it emphasizes that selected clinically stable patients with probable infection-associated HLH spectrum disorders may improve with close monitoring and supportive care, while individualized therapeutic decisions remain essential.

Funding

This study received no external funding.

Informed Consent Statement

Written informed consent was obtained from the patient for publication of his clinical data and imaging findings. A copy of the signed consent form is available upon reasonable request.