Acute hepatitis A infection‐associated hemophagocytic lymphohistiocytosis in adult presenting as impending acute liver failure: A case report and literature review

Abstract Hemophagocytic lymphohistiocytosis has been reported as a severe complication of various viral infections but unusual for the hepatitis A virus. We report a case of 25‐year‐old man with hepatitis A infection‐associated hemophagocytic lymphohistiocytosis and impending acute liver failure to emphasize the importance of early diagnosis and treatment of this condition.


| INTRODUCTION
Hemophagocytic lymphohistiocytosis (HLH) is a rare, lifethreatening condition characterized by clinical and laboratory evidence of extreme systemic inflammation resulting from uncontrolled immune activation. 1 Diagnosis of HLH required any five of eight criteria based on the HLH-2004 guidelines, which consist of fever, splenomegaly, at least two lineages of cytopenia, hypertriglyceridemia and/or hypofibrinogenemia, elevated ferritin, low or absent NK cell activity, elevated soluble CD25, and hemophagocytosis in bone marrow, spleen, or lymph nodes. 2 HLH was categorized into familial and acquired. Acquired HLH usually arises in association with malignancy, infection, and autoimmune disease. Among infectious etiology, virus is the major contributor including the Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus (HHV). 3,4 Nevertheless, HLH has been rarely reported as the consequence of acute hepatitis A infection. Delayed diagnosis and treatment in unrecognized cases has resulted in high mortality. 5 Herein, we present a case of 25-year-old man with acute high-grade fever, hepatomegaly, thrombocytopenia, and rapidly progressive hepatic dysfunction. Acute hepatitis A infection-associated HLH with impending acute liver failure was diagnosed and treated successfully with corticosteroid and intravenous immunoglobulin. A 25-year-old man presented with high-grade fever for one day without any significant organ-specific symptoms. His past medical history was unremarkable. He denied alcohol consumption, herbal intake, and illicit drug use. A physical examination revealed body temperature (BT) of 39.5°C, non-tender hepatomegaly (liver span of 14 cm) without icterus, signs of chronic liver stigmata, ascites, and splenomegaly.

| CASE REPORT
On admission, laboratory tests were significant for aspartate aminotransferase (AST) 303 unit/L (normal range , and alanine aminotransferase (ALT) 374 unit/L (normal range 0-55). The bilirubin level, alkaline phosphatase, complete blood count (CBC), and coagulogram were unremarkable ( Table 1). The hepatitis panel was positive for hepatitis A IgM. Whereas hepatitis A IgG, hepatitis E IgM/IgG, dengue NS1 antigen, dengue IgM/IgG, EBV IgM/IgG, hepatitis B surface antigen, hepatitis B core IgM/ IgG, hepatitis C antibody, anti-nuclear antibody (ANA), and HIV antibody were negative. An abdominal ultrasonography showed hepatomegaly without space-occupying lesions. The visualized hepatic vein, portal vein, and biliary system were also unremarkable. Therefore, acute hepatitis A infection became the diagnosis based on his clinical presentation and initial laboratory findings.
During admission, he had persistent high-grade fever (BT: 39-39.5°C) with rapid deterioration of the liver biochemistry (Table 1). Serial blood tests revealed mild thrombocytopenia along with international normalized ratio (INR) prolongation, elevated serum lactate dehydrogenase (LDH), and hyperferritinemia. Given the rapidly progressive hepatic dysfunction and severe systemic inflammation, impending acute liver failure due to acute hepatitis A infection-associated HLH was suspected. The differential diagnosis of this condition included severe sepsis due to complicated bacterial septicemia, severe leptospirosis and rickettsial infection. Thus, hemoculture for bacteria and indirect immunofluorescent (IFA) test for Leptospira and rickettsia were sent and became negative.
A bone marrow study was urgently performed to establish the diagnosis. Increased histiocytes with multiple foci of hemophagocytosis were demonstrated on aspiration smears (Figure 1). Pulse intravenous dexamethasone at a dose of 40 mg/day was immediately started resulting in defervescence and marked improvement of the liver biochemistry, inflammatory markers, and thrombocytopenia within 72 h ( Table 1). The bone marrow biopsy confirmed hemophagocytosis without any histologic and immunohistochemical evidence of lymphoma and EBV. Abdominal and chest computer tomography (CT) unrevealed lymphadenopathy that could suggest lymphoma. Intravenous immunoglobulin (IVIG) at a dose of 400 mg/ kg/day for five days was then administered at Day 7 of the illness with a satisfactory result. Oral dexamethasone was tapered off over the next four weeks. There was no evidence of clinical and laboratory recurrence after a fivemonth follow-up.

| DISCUSSION
Hepatitis A virus (HAV), the RNA virus in the Picornaviridae family, is one of the most common causes of acute hepatitis worldwide. 6 Primary transmission of HAV is the fecal-oral route via contaminated food and water. The incidence of HAV infection tends to be higher in low socio-economic and poor sanitation areas. Furthermore, the high-risk population includes males who have sex with males, HIV-infected patients, close contact of HAVinfected cases, and illicit drug users. 7 Non-specific viral illness is the most common presenting symptom and usually self-limited. 7,8 However, 0.5% of acute HAV-infected patients were complicated with acute fulminant hepatitis causing a high mortality rate up to 80%. 8,9 In addition to acute fulminant hepatitis, hemophagocytic lymphohistiocytosis (HLH) has been reported as a rare complication of acute HAV infection. HLH is the catastrophic hyperinflammatory condition caused by overstimulation of hemophagocytic activity of the macrophage in reticuloendothelial organs. For HAV-associated HLH, the virus triggers T-lymphocytes to release the inflammatory cytokines and stimulate massive hemophagocytosis. 10,11 Delayed diagnosis and treatment of acute HAV infection-associated HLH result from the rarity of the disease entity and non-specific clinical presentation. Thus, the authors conducted a literature review from the PubMed, Google Scholar, and Cochrane databases till September 2021, using the following terms: "hepatitis A"; "hepatitis A virus"; "HAV"; "hemophagocytosis"; "haemophagocytosis"; "hemophagocytic lymphohistiocytosis"; "haemophagocytic lymphohistiocytosis"; and "HLH." The publications were extracted only for the case report in adults (aged over 15 years at diagnosis). A total of 20 case reports (including the current patient) were reviewed, and the clinical data comprising the baseline characteristics, laboratory findings, clinical progression, treatment, and outcomes were obtained ( Table 2).
The clinical characteristics of the reported cases from the literature review were analyzed using SPSS software for Windows, version 18 (SPSS, Inc.,) and delineated in Table 3. The mean age at diagnosis was 30.5 ± 11.2 years (range from 15 to 50 years), and 12 patients (60%) were male. The most common presenting symptoms were fever (95%) and jaundice (50%). On physical examination, hepatomegaly and splenomegaly accounted for 91.6% and 81.3%, respectively. In comparison with the study of MacKinney-Novelo et al., 7 the presenting symptoms among uncomplicated acute HAV infection and HAVassociated HLH based on the reviewed data were comparable. However, hepatosplenomegaly was the predominant physical sign in HAV-associated HLH compared to those without HLH (81.3%-91.6% vs. 7%-78%). 7,12,13 Acute hepatitis A infection was diagnosed by HAV IgM in all reported cases. The test usually positive at the onset of the symptoms gave a high diagnostic sensitivity and specificity of more than 99%. 14,15 Therefore, delayed diagnosis for acute uncomplicated HAV infection was not observed, and the diagnosis was usually made on their first admission of viral illness in the reviewed data. In contrast to HAV-associated HLH, four cases were diagnosed at 15-30 days after the improvement of their first episode of acute hepatitis A infection causing a delay in treatment and high mortality. 5,[16][17][18] The explanation for the delayed onset of HLH in these four cases was unclear. Nonetheless, it could be a result of delayed immune activation or a relapse of acute HAV infection ("relapsing hepatitis") causing an immunologic rebound and trigger more severe systemic inflammation.
Thrombocytopenia was the initial hematologic abnormality in HAV-associated HLH based on the reviewed data (Table 3). In childhood HAV infection, thrombocytopenia is usually caused by immune thrombocytopenia (ITP). 19,20 However, in adult HAV infection, thrombocytopenia could be the early sign of HLH and usually progress to pancytopenia at the maximal disease activity. Thus, the superimposed HLH should be considered in acute HAV-infected patients who have thrombocytopenia on the initial presentation. Moreover, cytopenia of at least two lineages was required to complete the diagnostic criterion according to the HLH-2004 guidelines. 2 Nevertheless, only 45% of HAV-associated HLH patients exhibited two lineages of cytopenia based on the reviewed data (Table 3). Thus, this criterion was ineligible to contribute to the early HLH diagnosis since more than two cytopenia usually occurred in the latter course of HLH.
Among uncomplicated HAV-infected patients, liver biochemical changes usually manifested as a mixed Died hepatocellular and cholestatic pattern. The average peak of total bilirubin (TB) was 7-9 mg/dL, whereas the mean AST and ALT levels could be higher than 1000 IU/L, which were similar to those with HAVassociated HLH based on the reviewed data. 7,12 However, the patient of the current report had rapidly progressive hepatic dysfunction characterized by the increase of the AST and ALT levels above twentyfold of the upper normal limit within 48 h along with the INR prolongation ( Table 1). All of these findings postulated the impending acute liver failure and raised suspicion of superimposed HLH. Liver injury in HLH typically occurs in the early phase as a result of a cytokines storm and could rapidly progress to acute liver failure and death. 21 Hepatic dysfunction would lead to various biochemical alterations, including hypertriglyceridemia (due to impaired lipoprotein lipase activity), hypofibrinogenemia causing subsequent coagulopathy, disseminated intravascular coagulation (DIC), and multiorgan dysfunction. 21 The elevation of the LDH and serum ferritin was a result of cellular injury and severe systemic inflammation. Nonetheless, hypofibrinogenemia and hypertriglyceridemia were not observed in the patient of the current report, as the HLH was diagnosed in the early course.
Bone marrow aspiration and/or biopsy usually demonstrates hemophagocytosis in most reported cases. Bedside microscopic evaluation of aspiration smears provided prompt HLH diagnosis in the patient of the current report even though there were only three compatible diagnostic criteria including fever, hyperferritinemia, and bone marrow hemophagocytosis. The presence of at least five of eight criteria for the HLH diagnosis was observed only in seven patients (36.8%) based on the reviewed data (Table 3). Thus, the combination of the clinical findings, laboratory evidence of systemic inflammation, organ damage, and bone marrow hemophagocytosis was crucial for the HLH diagnosis even though there were incomplete HLH-2004 criteria. The HLH diagnostic criteria were usually fulfilled in the later course of the disease and could delay the diagnosis and treatment.
Standard treatment protocol for acute HAV-associated HLH was not well-established. Various treatment regimens for HAV-associated HLH have been reported, including corticosteroid, intravenous immunoglobulin (IVIG), and chemotherapeutic agent either single or combination therapy ( Table 2). Twelve patients (63.2%) and eight patients (42.1%) in the reviewed data were treated with corticosteroid and IVIG, respectively. A chemotherapeutic agent was prescribed in three patients (15.8%) and usually combined with corticosteroid and/or IVIG. A granulocyte colony-stimulating factor (G-CSF) was used as an adjunctive treatment in three reported cases. 5

T A B L E 2 (Continued)
Nonetheless, three patients (15.8%) were spontaneously resolved without treatment.
The patient of the current report was successfully treated with intravenous high-dose dexamethasone and IVIG without any evidence of clinical and laboratory recurrence at a 5 months follow-up. However, three reported cases of HAV-associated HLH died upon corticosteroid and/or IVIG treatment due to acute liver failure and superimposed infection. 16,17,24 Although corticosteroid and IVIG seemed to be the effective treatment options in HAVassociated HLH, treatment initiation in the latter disease course eventually contributed to the poor treatment outcomes, especially in those who already had significant organ failure. A chemotherapeutic agent was not initiated in the patient of the current report, as he was in clinical and laboratory remission after corticosteroid and IVIG treatment.
The overall mortality rate of HAV-associated HLH was 20%, whereas the 30 days mortality and overall mortality of adult HLH were 20%-44% and 50%-75%, respectively. [25][26][27] The cause of death in the reported cases of HAVassociated HLH was acute liver failure and superimposed disseminated fungal infection. 16,17,24 Delayed immunosuppressive therapy and presence of acute liver failure at treatment initiation might be associated with death according to the reviewed data ( Table 2).
In conclusion, this case report emphasized the importance of early diagnosis and treatment of HAV-associated HLH. Thus, clinical, laboratory, and hemophagocytic evidence is crucial for diagnosis and would encourage prompt treatment even with incomplete HLH diagnostic criteria. Although the standard treatment approach in adult HAVassociated HLH is not well-defined, early immunosuppressive therapy would be the cornerstone for improving survival and evading fatal complications. Hence, further clinical studies could elaborate a more effective treatment paradigm for HAV-associated HLH.