Herpes Simplex Virus Hepatitis in Patients Requiring Intensive Care Unit Admission: A Retrospective, Multicenter, Observational Study

Abstract The clinical features and short-term prognosis of patients admitted to the intensive care unit for herpes hepatitis are lacking. Of 33 patients admitted between 2006 and 2022, 22 were immunocompromised, 4 were pregnant women, and 23 died. Sixteen patients developed a hemophagocytic syndrome. Acyclovir was initiated a median (interquartile range) of 1 (0–3) day after admission.

Acute liver failure is a rare but life-threatening critical illness [1,2].One of the least reported causes is severe herpes simplex virus (HSV) hepatitis (HH).Its pathophysiology is not fully understood.Although primary infection is a major cause of herpes hepatitis [3][4][5][6], a few cases of HH associated with HSV reactivation, defined by immunoglobulin G (IgG) serology positivity, have been reported in immunocompromised patients [7].The prevalence of HH appears to be around 0.8% of cases of severe hepatitis [8,9].
Most of the available data consist of case reports with literature reviews [7,10].The clinical picture of HH is a febrile hepatic insufficiency with cutaneous signs and marked serum transaminase and lactate dehydrogenase elevation occurring in immunocompromised or pregnant patients, and to a lesser extent in the postoperative setting [3][4][5][6][7]9].The prognosis of HH has been reported to be poor, with a mortality rate of up to 60%, compared with 19%-36% for other causes of severe acute hepatitis.A diagnostic delay has been frequently reported, with only 30% of patients receiving early antiviral treatment with acyclovir [9].
There are to our knowledge no previous studies describing the clinical characteristics, management, and short-term outcomes of patients admitted to the intensive care unit (ICU) for HH.We conducted a large multicenter retrospective cohort study in adult patients admitted to French ICUs for acute hepatitis and proven HSV infection and aimed at describing their clinical and biological features, management, and ICU mortality.

Patients
We performed a 16-year multicenter retrospective observational cohort study in 27 adult ICUs located throughout metropolitan France.All consecutive patients hospitalized in participating ICUs between 2006 and 2022 with a compatible history and a proven HSV infection (positive polymerase chain reaction [PCR] in blood or liver biopsy) were included (Supplementary Method 1).

Ethical Considerations
This observational, noninterventional analysis of medical records was approved by the Institutional Review Board of the French Intensive Care Society in December 2021 (CE SRLF 21-108).

Collection of Data
Data pertaining to demographics, comorbidities, clinical examinations, laboratory findings, microbiological investigations, and therapeutic management at ICU admission and during ICU stay were collected.Duplex HSV PCR methods were used in most centers and were qualitative for half the patients.Quantitative assessment of circulating HSV DNA was provided when available and expressed as log DNA copy numbers/mL of serum.Simplified Acute Physiology Score II (SAPS II) and Sequential Organ Failure Assessment (SOFA) scores were computed using the worst values recorded within the first 24 hours of admission.Missing data were retrieved by queries to the investigators.

Statistical Analysis
Quantitative data were expressed as mean (SD) or median (interquartile range [IQR]) and compared using a Student t test or nonparametric Mann-Whitney test, as appropriate.Qualitative data were compared by χ 2 test or Fisher exact test.Factors associated with ICU mortality were analyzed by univariable logistic regression.The tests were 2-tailed, and a value of P < .05 was considered statistically significant.Statistical analysis was performed using the software R 4.2.2(The R Foundation for Statistical Computing, Vienna, Austria).

Control Group
A bicentric control group cohort of ICU acetaminophen hepatitis patients was assembled to explore the specificity of the features of hemophagocytic syndrome observed in patients with HH (Supplementary Method 2).

RESULTS
Among the 27 participating ICUs, 15 identified a total of 33 patients during the study period.

Clinical and Biological Features
The median age (IQR) was 55 (37-65) years, with 15 patients (45.4%) of male gender.Risk factors for HH commonly reported in the literature included 22 (66.7%)immunosuppressed patients and 4 (12.1%)pregnant patients (3 were in the third trimester and 1 in the second trimester) (Table 1 1).HH diagnosis was confirmed in all cases by a blood PCR, and a liver biopsy was performed in 16 (48.5%)patients, confirming diagnosis in all cases when performed (Table 2).When available, HSV IgG was negative for 94.1% of patients (n = 16/17; data missing for 16 patients) (Table 2).

Treatment
The vast majority of patients (n = 32/33, 97%) received acyclovir during their hospital stay (Table 2).The median time from symptom onset to initiation of acyclovir (IQR) was 8 (5-10) days, and the median time from ICU admission to initiation of acyclovir (IQR) was 1 (0-3) day.
Unexpectedly, 16 (48.5%)patients developed hemophagocytic syndrome (HS) [13] during the course of their ICU stay.Hemophagocytosis was present on myelogram in 12 (41%) patients (Table 2).In order to establish whether HS was related to the severity of liver failure or a specific feature of severe HSV hepatitis, we compared patients from the current cohort with a control cohort of patients with severe acetaminophen hepatitis with regard to HS features (Supplementary Table 1).There were significantly fewer immunosuppressed patients and pregnant women in the acetaminophen hepatitis group than in the HH group (P < .001),with no fever (P < .001)and no cytopenia (P < .001).The HScore [12] was significantly lower, with no hemophagocytic syndrome diagnosed in the acetaminophen group, suggesting that HS was not related to the severity of liver failure itself.

Factors Associated With ICU Death
Factors associated with mortality in univariable analysis included severity of illness scores (SAPS 2 and SOFA scores), an altered mental status and serum creatinine at ICU admission, and need for vasopressor support, occurrence of hepatic encephalopathy or DIC, and PT nadir during ICU stay (Supplementary Table 2).

DISCUSSION
We describe the largest multicenter cohort of patients admitted to the ICU for herpetic hepatitis.The main findings of our study are as follows: (1) the 2 main causes of ICU admission were multivisceral and acute liver failure; (2) 67% of patients were immunocompromised and 12% were pregnant women; (3) clinical presentation was associated with frank fever in 91% of patients, cutaneous signs in 39% of patients, and marked transaminase elevation predominating on AST; and (4) ICU mortality was 70%.
As expected, the factors associated with ICU mortality included severity of illness scores and hepatic encephalopathy, which are indicative of liver and other organ failures.We found no statistically significant association between time to initiation of acyclovir and mortality.Nevertheless, the high mortality observed in our series suggests that clinicians should consider initiating empiric treatment with acyclovir in patients admitted for acute febrile hepatitis with a compatible clinical history.Importantly, studies comparing acyclovir with placebo in mechanically ventilated, critically ill patients have reported no statistically significant excess risk of renal failure [14].For the most severe patients, liver transplantation may be considered [9].However, in our series, only 4 patients required transplantation, and, regrettably, they eventually died.
As previously reported [11,15], there was a significant proportion (48.5%) of patients developing hemophagocytic syndrome, confirmed on myelogram in most cases, during the course of ICU stay.In our series, the diagnosis was made on the basis of severe fever, almost constant immunosuppression, profound thrombocytopenia, hepatic abnormalities, and coagulation disorders (eg, DIC; 42.4%).Hemophagocytic syndrome in a patient at risk is a supplemental feature that should lead clinicians to suspect herpetic hepatitis.
Our study certainly has limitations, related to its retrospective and observational design and the long duration of the inclusion period, required by the rareness of HH.
The strengths of this study lie in its national multicenter design, involving liver and general ICUs throughout France.The relatively high number of cases, considering the rarity of the disease, makes it the largest worldwide series to our knowledge.The number of cases with histologic evidence (n = 16/33, 48.5%) also limits the subjectivity of the diagnosis.
Among the perspectives of this work, the delay in diagnosis leads to a reflection on diagnostic criteria.Whether patients with negative HSV PCR may have been missed in the current series cannot be excluded and raises the question of the best diagnostic and therapeutic strategy in this setting (eg, repeated PCR testing and empiric acyclovir initiation).Given the extreme rarity of this disease, national prospective registries would probably be needed to validate diagnostic criteria, reassess the prevalence of the disease, and evaluate more aggressive therapeutic strategies.

CONCLUSIONS
HH in patients admitted to the ICU is an extremely rare entity associated with very high mortality.Despite known risk factors (immunodepression and pregnancy) and a clinico-biologic picture of febrile hepatitis, characterized by a marked transaminase elevation predominating on AST, with cutaneous signs and cytopenias, diagnosis remains difficult.Early acyclovir treatment is recommended.