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Herpes simplex virus sepsis and acute liver failure
Abstract
Acute liver failure is a life threatening disease mostly triggered by drug-induced or toxic liver damage or viral hepatitis. Herpes Simplex virus (HSV) hepatitis is rare and accounts for only 1% of all acute liver failures. The importance of HSV-induced acute liver failure is based on its extremely severe clinical course with lethality rates of almost 75%. HSV hepatitis is just one of several clinical manifestations of HSV sepsis leading more frequently to encephalitis, pneumonia and esophagitis. Local herpes infection or recurrence of dermal lesions (herpes labialis, herpes genitalis), however, is common and account for the high prevalence of HSV-1 or HSV-2 infection in adults. Another rare entity is visual dissemination, which mostly affects immunocompromised patients. Compromised cellular immunity is a major risk factor for HSV sepsis because of either primary infection or reactivation of occult chronic HSV infection. Delayed diagnosis without antiviral therapy significantly contributes to the unfavorable outcome. Typically, anicteric hepatitis is seen in patients with HSV hepatitis. Because of its low incidence, however, and the lack of dermal manifestations, HSV hepatitis is rarely considered in the context of acute liver failure. In addition, diagnostic tests might not always be available. Therefore, it is a generally accepted consensus to begin antiviral therapy pre-emptively with acyclovir in cases of acute liver failure of unknown origin, in which high urgency (HU) liver transplantation remains the only therapeutical option. Even in the case of early specific therapy, sepsis may prevail and the indication for HU transplantation must be evaluated carefully. The outcome after liver transplantation for HSV-induced liver failure with reported survival rates of more than 40% is good. Because of the risk of recurrence, lifelong prophylaxis with acyclovir is recommended.
... Only 1% of all cases of acute liver failure are caused by HSV hepatitis [2]. HSV hepatitis mainly occurs in immunocompromised patients, including solid organ transplant (SOT) recipients, patients receiving immunosuppressive medications or chemotherapy, patients with immunodeficiency syndrome or HIV infection, pregnant patients, patients after thymectomy, or even immunocompetent hosts [3][4][5][6][7]. Post-transplant HSV hepatitis usually occurs in the early post-transplant period as reactivation of latent infection or primary donor-derived infection and, only in rare instances, occurs de novo [8][9][10]. ...
... In our case, the patient did not have mucocutaneous lesions. When left untreated, HSV can cause different types of complications, such as aseptic meningitis and transverse myelitis, or rarely, hepatitis, which is more commonly seen in immunosuppressed patients and pregnant patients in their third trimester [3]. Hepatitis related to HSV has a characteristic of rapid progression, leading to acute liver failure in 74% of patients [4] and high mortality of up to 90% [12]. ...
... Encephalopathy is considered a late manifestation. The most common laboratory findings are transaminitis (100-1000-fold above normal), with low to normal total bilirubin, known as "anicteric transaminitis", leukopenia, thrombocytopenia, coagulopathy, and disseminated intravascular coagulation [3]. Liver imaging is nonspecific and can show different signs of liver enlargement and periportal edema [14]. ...
Patient: Male, 60-year-old
Final Diagnosis: Herpes simplex virus 2 hepatitis
Symptoms: Generalized weakness • chills • fever
Clinical Procedure: —
Specialty: Infectious Diseases • General and Internal Medicine
Objective
Rare disease
Background
Herpes simplex virus (HSV) is a rare cause of hepatitis. HSV hepatitis can be life-threatening due to its rapid progression to liver failure if not treated on time. It affects primarily immunocompromised individuals but can also present in immunocompetent hosts. HSV hepatitis in solid organ transplant recipients usually occurs in the early post-transplant period as fulminant hepatitis. We present a rare case of febrile anicteric HSV2 hepatitis occurring late in the post-transplant period, with only mild elevation in transaminase levels.
Case Report
A 60-year-old man presented to the Emergency Department with generalized weakness, chills, and fever for 1 day. His medical history included Crohn’s disease, primary sclerosing cholangitis, liver transplantation, and cholangiocarcinoma. Initial laboratory findings revealed leukocytosis. Extensive workup did not reveal a clear etiology of persistent fever. Liver enzymes peaked to aspartate transaminase 198 U/L and alanine transaminase 135 U/L, suggesting possible hepatitis. Liver biopsy showed focal areas of necrosis with vague histiocyte collections. Liver biopsy tissue was positive for HSV2 by polymerase chain reaction; therefore, HSV2 hepatitis diagnosis was made. Intravenous acyclovir was initiated for treatment of HSV2 hepatitis, which resulted with fever resolution within 48 h of initiation and return of liver enzymes to normal levels.
Conclusions
This case highlights the importance of having a high suspicion of HSV hepatitis as a rare cause of persistent fevers in immunosuppressed, post-transplant patients even in the late post-transplant period and in the absence of mucocutaneous lesions. Prompt recognition of this disease is crucial to start prompt treatment and decrease mortality.
... Due to its nonspecific symptoms and rarity, HSV hepatitis is often a delayed or missed diagnosis, leading to treatment delays that result in a poor prognosis. Screening for IgM and IgG antibodies in the serum for an early diagnosis of the disease often yields nonspecific findings, is time consuming and impractical [12,13]. Liver biopsy is the most reliable method for diagnosing HSV hepatitis. ...
... Liver biopsy is the most reliable method for diagnosing HSV hepatitis. Although transvenous biopsy is preferred over percutaneous biopsy, there remains a risk of bleeding with this method in patients with liver failure [12,[14][15][16][17][18]. Therefore, a PCR test for HSV-DNA is recommended in these patients [12,14,16,17]. ...
... Although transvenous biopsy is preferred over percutaneous biopsy, there remains a risk of bleeding with this method in patients with liver failure [12,[14][15][16][17][18]. Therefore, a PCR test for HSV-DNA is recommended in these patients [12,14,16,17]. In our case, liver biopsy was difficult to perform due to the patient's general condition; however, a diagnosis was made on the basis of the skin lesions and results of immunological tests. ...
Background
The incidence of acute liver failure from herpes simplex virus is rare.
Case presentation
A 71-year-old Japanese man was diagnosed with acute liver failure and was transferred to our hospital. Steroid therapy, plasma exchange, and hemodiafiltration were started for liver failure, and antimicrobial therapy was initiated for pneumonia. Staphylococcus epidermidis was detected in blood culture. Skin rash appeared; a positive anti-herpes simplex virus result led to the diagnosis of acute liver failure from herpes simplex virus. Hence, acyclovir was started. After blood tests improved, treatments for acute liver failure were discontinued. Antimicrobial therapy was continued; however, he died. In this case, persistent bacteremia and drug-induced liver damage due to acyclovir may have contributed to his death.
Conclusions
Acute liver failure can lead to complications and death. Thus, careful observation is crucial, even if the patient has shown some improvements.
... Our case is of particular interest given the rarity of viral hepatitis secondary to disseminated HSV-2 in an immunocompetent host. Viral hepatitis accounts for only 1-2% of all viral causes of acute liver failure [6][7][8][9][10]. Risk factors for disseminated disease include immunodeficiency, immunocompromised state, posttransplantation, and pregnancy (primarily in the third trimester); however, up to 25% of cases occur in immunocompetent patients [8]. ...
... HSV hepatitis remains difficult to diagnose given the nonspecific nature of presenting signs and symptoms. Most commonly, patients present in an anicteric state with elevated aminotransferases, low bilirubin, leukopenia, and thrombocytopenia with concurrent fever or abdominal pain [9][10][11][12][13][14]. Although peak aminotransferases are often greater than 1000, values less than 1000 can be seen [15]. ...
... We also highlight that only 30-50% of patients present with, or develop, characteristic herpetic lesions, further emphasizing that clinicians should not rely on classic cutaneous findings in diagnosing disseminated HSV [9]. Early diagnosis and treatment with intravenous acyclovir remains essential as 74% of cases progress to acute liver failure, with mortality rates as high as 90% [7][8][9][10]12,13,17]. ...
Patient: Male, 57-year-old
Final Diagnosis: Hepatitis • herpes
Symptoms: Fever
Medication: —
Clinical Procedure: —
Specialty: General and Internal Medicine
Objective
Challenging differential diagnosis
Background
Herpes simplex virus-2 (HSV-2) affects nearly 1 in 5 adults in the United States. Complications such as viral hepatitis and dissemination are rare in immunocompetent hosts. In this report, we describe a case of viral hepatitis secondary to disseminated HSV-2 in an immunocompetent patient with recurrent fevers and elevated aminotransferases.
Case Report
A 57-year-old man with a history of type 2 diabetes and hypertension was admitted with a right index finger lesion concerning for an abscess. He underwent successful incision and drainage and was started on ampicillin-sulbactam. On Day 2 of hospitalization, he developed recurrent fevers and elevated aminotransferases and inflammatory markers. An extensive infectious, rheumatologic, and malignancy workup were pursued without immediate findings. Imaging demonstrated cirrhotic morphology of the liver and splenomegaly, but lab markers were intact for liver synthetic function. On Day 7 of hospitalization, fever frequency decreased, and HSV-2 titers resulted, with positive IgM and negative IgG. He subsequently developed erythematous, raised lesions in multiple dermatomes. Nucleic acid amplification testing of biopsied lesions was positive for HSV-2, confirming viral hepatitis secondary to disseminated HSV-2. He was started on intravenous acyclovir and discharged on valacyclovir following improvement in symptoms.
Conclusions
We report a case of viral hepatitis secondary to disseminated HSV-2 in an immunocompetent host. Up to 25% of cases occur in immunocompetent hosts and many patients do not develop characteristic skin lesions. Early diagnosis and treatment of viral hepatitis secondary to disseminated HSV remains vital to minimize morbidity and mortality.
... 19 In the absence of characteristic clinical findings, the antemortem diagnosis of HSV hepatitis is essentially based on liver biopsy. Liver biopsy, although considered a gold standard for diagnosing HSV hepatitis, 3,6,8,14,19,20 is often times not performed due to the presence of significant coagulopathy associated with the disease. 6,19,20 Histological sections demonstrate extensive necrosis with adjacent congestion and minimal inflammatory infiltrates. ...
... Liver biopsy, although considered a gold standard for diagnosing HSV hepatitis, 3,6,8,14,19,20 is often times not performed due to the presence of significant coagulopathy associated with the disease. 6,19,20 Histological sections demonstrate extensive necrosis with adjacent congestion and minimal inflammatory infiltrates. Due to extensive necrosis or ballooning degeneration, the characteristic cytopathic changes associated with HSV infection (including viral inclusions) may not be appreciated. ...
... 6,19 Viral serology is nonspecific for diagnosing HSV infections. [6][7][8]19,20 HSV DNA polymerase chain reaction testing can, however, be a useful diagnostic tool. 3,6,8,19,20 HSV hepatitis is associated with high mortality, which is often rapid, in up to 90% of the cases. ...
Herpes simplex virus (HSV) hepatitis is an uncommon cause of fulminant hepatic failure, seen mostly in immunocompromised patients. Conventional treatment modalities for inflammatory bowel disease (IBD), such as steroids and azathioprine, have been known to cause HSV hepatitis. However, the reported incidence of HSV hepatitis in IBD patients undergoing tumor necrosis factor (TNF)-α inhibitor therapy is very rare. In this case report, we describe a rare case of fulminant HSV hepatitis that developed in a patient with Crohn’s disease after treatment with the TNF-α inhibitor, adalimumab.
... 11 HSV sepsis can lead to encephalitis, pneumonia, and esophagitis. 12 It also has a rare manifestation causing fulminant hepatitis in immunocompetent and immunosuppressed patients. It accounts for 1% of acute liver failure cases and has mortality rates reaching 90%. ...
... It accounts for 1% of acute liver failure cases and has mortality rates reaching 90%. 6,12 Diagnosing HSV hepatitis can be difficult due to the nonspecific clinical features. Most HSV infections are asymptomatic or only produce mild nonspecific viral symptoms. ...
Herpes simplex virus (HSV) is a rare cause of acute hepatitis in patients with chronic immunosuppression, including Crohn’s disease. HSV hepatitis has the propensity to cause acute liver failure and death. The presenting signs and symptoms can be nonspecific, thereby causing the diagnosis to go overlooked with inadequate management, leading to a high mortality rate. We report a case of a 31-year-old male on chronic prednisone treatment for Crohn’s disease who unexpectedly died. Subsequently, an autopsy showed HSV hepatitis as the cause of death. Thus, although a rare complication, HSV hepatitis should always be kept in mind as a fatal complication in patients with acute hepatitis and chronic immunosuppression.
Keywords:
Herpes Simplex Virus; Hepatitis; Crohn’s Disease; Prednisone
... Most cases are mucocutaneous infections, however, in a lower percentage they develop systemic infections. The acute liver failure (ALF) due to primary or reactivated infection is an extremely rare and potentially fatal entity [3]. We report 3 solid-organ transplantation patients who developed ALF due to HSV-1 primary infection in the immediate post-transplant period. ...
... It has been reported an incidence of herpes infection (HSV and herpes zoster virus) of 8% in the first month posttransplant, 10% in the first 6 months and 16% at 6 months' posttransplant [4]. The prevalence of herpes simplex virus seropositivity in SOT is 75% with an incidence of primary infection of 6.7% at the first year [3], the majority of them are mild infections and less frequently severe systemic infections. HSV hepatitis is a rare and fatal entity that could be a donor-derived infection. ...
Herpes virus infections is not uncommon in solid organ transplantation patients. We report 3 cases with primary Herpes simplex virus type-1 (HSV1) infection with acute liver failure (ALF). This is a rare and potentially fatal entity that could be a donor-derived infection. Although the initial clinical presentation is non-specific, it should be considered as a differential diagnosis in HSV-negative serology patients with liver failure and empirical treatment must be started in combination with a drastic reduction of immunosuppression. A strategy of HSV prophylaxis for pre-transplant HSV seronegative patients must be stablished in order to reduce the risk of clinical disease.
... In particular, HSV hepatitis can cause fatal acute liver failure even in immunocompetent hosts if it is not diagnosed in time [7]. Compromised cellular immunity after transplantation is a major risk factor for reinfection with and the recurrence of HSV [12]. One study reported that 42% of patients with positive HSV IgG before transplantation experienced changes of HSV polymerase chain reaction from negative to positive early after liver transplantation [13]. ...
... However, considering the clinical course, in which liver failure occurred several days after the aggravation of skin lesions, HSV hepatitis was thought to be secondary vis-ceral dissemination. Further, the HSV infection in our case report was likely to involve other organs as well as the skin and liver because the typical clinical presentations of HSV hepatitis are anicteric hepatitis without skin lesions [12]. ...
... In immunocompetent patients, HVS hepatitis is a particularly rare condition, with few reported cases, (5,6) progression to acute liver failure in 74% and a mortality rate up to 90%. (1) Due to its rarity, there are no widely accepted guidelines for its diagnosis; thus patient history, physical examination, and blood tests with a high degree of suspicion are critical to adequate management. ...
... He also did not show typical mucocutaneous lesions of herpes infection, however absence of this lesions are described in half of the patients. (6) In the article published by Little L et al., the authors retrospectively analyzed all the HSV hepatitis-related cases within the Acute Liver Failure Study Group database, the median AST level was nearly 7800 U/l as compared to much lower levels in non-HSV hepatitis. (8) In fact, clinical sings of HSV hepatitis can include the so called "anicteric hepatitis" or "transaminitis", characterized by normal or slightly elevated bilirubin with transaminases levels 100-1000x the upper normal limit, in association with leucopenia and thrombocytopenia. ...
Herpes simplex virus (HSV) are challenging eti-ologic agents with a wide range of clinical manifestations. We present a case of a 34-year-old im-munocompetent male who was brought to the Emergency Department (ED) with fever and prostration. In the first approach, blood tests revealed an acute hepatitis without an identified etiology. Besides the use of N-acetylcysteine, he. became worse and evolved to acute liver failure and coma. HSV deoxyribonucleic acid (DNA) was identified in the cerebrospinal fluid (CSF) and blood. Although acyclovir was started on day 3, he developed cardiovascular shock with multiple organ failure and died on the 7th day of hospitalization. A high index of suspicion is needed, and early diagnosis should be promoted between clinicians.
... Редко, но встречаются случаи заболевания и у иммунокомпетентных взрослых людей. Факторами риска фульминантного герпетического гепатита являются: большая доза инокулята при первичном инфицировании, активация латентной инфекции, реинфекция вторым штаммом вируса герпеса и/или гепатотропным штаммом вируса [43]. ...
... В большинстве случаев герпетический гепатит диагностируется посмертно, на секции. В идеале его диагностика должна включать в себя серологическое обследование и ПЦР [43]. «Золотым стандартом» диагностики герпетического гепатита является биопсия печени, но подход к этому исследованию должен быть осторожным из-за повышенного риска возникновения осложнений (кровотечений) [44]. ...
The review deals with the problem of liver affection by viruses that traditionally are not referred to hepatotropic ones, but present a great threat to the group of newborn children, immunosuppressed individuals and patients with histories of transplantation of organs. The authors describe liver lesions in infections caused by viruses of the herpetic group, enteroviruses, parvovirus В19, paromyxovirus, rubella virus. Special attention is paid to the histological picture of these lesions.
... In recent years, real-time PCR has been increasingly applied to simplify the overall procedure and reduce performance time in detecting and quantifying virus in clinical samples [15,16]. Multiplex qPCR has been suggested as an efficient alternative for simultaneous detection of HCMV, HHV-6 and HHV-7 within the same reaction [9,17]. In the current study, the incidence of betaherpesvirus infection in patients with ALF of unknown etiology was investigated using the multiplex qPCR approach. ...
... One major reason for delayed diagnosis is the lack of specific symptoms. Typical mucocutaneous lesions are absent in half of the patients developing hepatitis [3,17], highlighting the need for early diagnosis for optimizing therapy. In this study, 23.6% samples from ALF patients displayed positivity for at least one of the betaherpesviruses. ...
Background:
The etiology of acute liver failure (ALF) is often unknown and reported to be associated with herpesviruses in a number of cases. In this study, we examined for betaherpesviruses infections in patients with ALF of unknown etiology using a multiplex qPCR to Betaherpesviruses subfamily.
Methods:
Liver explant and serum samples from 27 patients with ALF of unknown etiology were analyzed with the aid of multiplex qPCR to identify betaherpesviruses. All positive samples were sequenced to confirm herpes infection and liver enzyme levels evaluated.
Results:
Betaherpesviruses infection was effectively detected using multiplex qPCR. Six (22%) HHV-6, one (3%) HCMV and two (7%) dual infections (one with HHV-7/HHV-6, and the other with HHV-7/ HCMV). Interestingly, HHV-7 was only detected in the presence of other betaherpesviruses. Sequencing information confirmed betaherpesviruses infection. High hepatic enzyme levels and INR values> 1.5 were determined in all betaherpesvirus-positive patients.
Conclusions:
Multiplex qPCR facilitated efficient quantification, indicating that differentiation between betaherpesviruses is possible with the sole use of real-time PCR. Liver explant and serum samples were positive for some betaherpesviruses, and coinfection of HHV-7 with HHV-6 and HCMV was additionally detected. Based on these results, we propose that ALF patients should be screened for the presence of betaherpesviruses.
... Die verschiedenen Erkennungsstrukturen sind sehr unterschiedlich in ihrer Größe. So sind kleine Moleküle und Peptide im unteren einstelligen Nanometer-Bereich, ebenso Antikörper (≈ 5 nm), Viren ein bis zwei Größenordnung größer (≈ 26 nm bei AAVs [15] und 100 -200 nm bei Herpesviren [16]). Zellen hingegen sind von der Dicke im Mikrometerbereich (≈ 10 µm) [17]. ...
... HSV is another virus of concern, with reactivation being a notable issue not limited to tocilizumab but applicable to immunosuppressive states in general. HSV remains latent in immunocompetent individuals but can cause mucosal lesions or, in severe cases, liver damage and encephalitis when host immunity is compromised [5]. IL-6 plays a role in infection control through various mechanisms [6], and its inhibition can impair HSV control, potentially leading to viral reactivation. ...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been linked to severe pneumonia and systemic deterioration in humans. When antiviral drugs and antibodies are not available, it is preferable to choose early treatment methods to suppress cytokine storms. While an interleukin-6 receptor antagonist has proven effective in controlling cytokine storms in coronavirus disease 2019 (COVID-19) pneumonia, it can also increase susceptibility to secondary infections, such as herpes simplex virus (HSV). HSV hepatitis can progress rapidly and be fatal, posing a significant therapeutic challenge. We present the case of a patient with chronic liver disease who developed severe hepatitis following a COVID-19 infection. Despite initial clinical improvement, the patient experienced a relapse marked by high fever, mucosal ulcerations, and deteriorating liver function, eventually leading to acute liver failure and death. Histopathological analysis confirmed HSV hepatitis as the cause of the liver damage. This case underscores the risks associated with HSV reactivation in immunosuppressed patients and highlights the necessity for prompt antiviral treatment and preventive measures. Continuous vigilance is crucial for managing prolonged immunosuppressive states to mitigate severe complications and enhance patient outcomes.
... However, in many instances, especially with Herpes Simplex Virus (HSV) infections, they can mimic symptoms of bacterial sepsis and should be considered in antibiotic-resistant sepsis. [30][31][32] In addition to vertically transmitted HSV, Cytomegalovirus (CMV) and other TORCH infections and enteroviruses are also among the viral agents implicated in sepsis or sepsis-like syndromes of the newborn. 33,34 CMV, for example, although itself a significant cause of congenital hearing loss and other neonatal morbidities, is also linked to and found in bacterial neonatal sepsis. ...
Neonatal sepsis, a bloodstream infection in the first 28 days of life, is a leading cause of morbidity and mortality among infants in both developing and developed countries. Additionally, sepsis is distinguished in neonates by unique pathophysiological and presentational factors relating to its development in immature neonatal immune systems. This review focuses on the current understanding of the mechanics and implications of neonatal sepsis, providing a comprehensive overview of the epidemiology, aetiology, pathophysiology, major risk factors, signs and symptoms and recent consensus on the diagnosis and management of both early-onset and late-onset neonatal sepsis. It also includes a discussion on novel biomarkers and upcoming treatment strategies for the condition as well as the potential of COVID-19 infection to progress to sepsis in infants.
... HSV hepatitis is a rare entity with one literature review citing only 137 cases from 1969 to 2006 [1]. HSV hepatitis more often affects immunocompromised patients and pregnant women, but in a study of patients with acute liver failure related to HSV, one fourth of the patients were immunocompetent [2]. Presentation varies and usually includes a documented fever as well as myalgias and abdominal pain, but only 30%-50% present with skin lesions. ...
... For HSV-sepsis, the high mortality is largely due to the non-specific clinical presentation, lack of awareness, delay in diagnosis and therapy. [2] Our report suggested that NGS might be helpful in identification of certain microbial pathogens in sepsis as etiologic agents and subsequently beneficially impact patient care. [3] Fulminant HSV hepatitis with liver failure should be considered in this patient for international normalized ratio 2.01 and status epilepticus. ...
... Around 74% of HSV hepatitis cases result in acute liver failure. This can result in emergent need for liver transplantation with high mortality rates of >80% in untreated patients and >50% in those treated with acyclovir, making timely diagnosis essential [4]. In patients receiving liver transplantation, HSV reactivation occurs more commonly during the first month after transplantation, making a diagnosis of HSV difficult owing to overlapping features of acute organ rejection during this time period [5]. ...
Disseminated herpes simplex virus (HSV) is mainly seen in immunocompromised individuals. Atypical lesions can be present in both primary infection and reactivation disease. Compared with the general population, inmunocompromised hosts are at greater risk of increased persistency and severity of clinical manifestations, including severe systemic involvement such as esophagitis, meningitis, and hepatitis. Herein, we report the case of a liver transplant recipient with atypical disseminated herpes simplex virus-1 complicated by HSV-related hepatitis. Dermatological consultation and histological assessment were crucial for a correct diagnosis and treatment.
... In recent years, real-time PCR has been increasingly applied to simplify the overall procedure and reduce performance time in detecting and quantifying virus in clinical samples (15,16). Multiplex qPCR has been suggested as an e cient alternative for simultaneous detection of HCMV, HHV-6 and HHV-7 within the same reaction (9,17). In the current study, the incidence of betaherpesvirus infection in patients with ALF of unknown etiology was investigated using the multiplex qPCR approach. ...
Background: The etiology of acute liver failure (ALF) is often unknown and reported to be associated with herpesviruses in a number of cases. In this study, we examined for betaherpesviruses infections in patients with ALF of unknown etiology using a multiplex qPCR to Betaherpesviruses subfamily. Methods: Liver explant and serum samples from 27 patients with ALF of unknown etiology were analyzed with the aid of multiplex qPCR to identify betaherpesviruses. All positive samples were sequenced to confirm herpes infection and liver enzyme levels evaluated. Results: Betaherpesviruses infection was effectively detected using multiplex qPCR. Six (22%) HHV-6, one (3%) HCMV and two (7%) dual infections (one with HHV-7/HHV-6, and the other with HHV-7/ HCMV). Interestingly, HHV-7 was only detected in the presence of other betaherpesviruses. Sequencing information confirmed betaherpesviruses infection. High hepatic enzyme levels and INR values>1.5 were determined in all betaherpesvirus-positive patients. Conclusions: Multiplex qPCR facilitated efficient quantification, indicating that differentiation between betaherpesviruses is possible with the sole use of real-time PCR. Liver explant and serum samples were positive for some betaherpesviruses, and coinfection of HHV-7 with HHV-6 and HCMV was additionally detected. Based on these results, we propose that ALF patients should be screened for the presence of betaherpesviruses.
... In recent years, real-time PCR has been increasingly applied to simplify the overall procedure and reduce performance time in detecting and quantifying virus in clinical samples (15,16). Multiplex qPCR has been suggested as an e cient alternative for simultaneous detection of HCMV, HHV-6 and HHV-7 within the same reaction (9,17). In the current study, the incidence of betaherpesvirus infection in patients with ALF of unknown etiology was investigated using the multiplex qPCR approach. ...
Background: The etiology of acute liver failure (ALF) is often unknown and reported to be associated with herpesviruses in a number of cases. In this study, we examined for betaherpesviruses infections in patients with ALF of unknown etiology using a multiplex qPCR to Betaherpesviruses subfamily. Methods: Liver and serum samples from 27 patients with ALF of unknown etiology were analyzed with the aid of multiplex qPCR to identify betaherpesviruses. All positive samples were sequenced to confirm herpes infection and liver enzyme levels evaluated. Results: Betaherpesviruses infection was effectively detected using multiplex qPCR. Seven (26%), two (7%) and three (11%) cases were positive for HHV-6, HHV-7 and HCMV, respectively. Two cases of dual infection (HHV-7/HHV-6 and HHV-7/HCMV) were additionally identified. Interestingly, HHV-7 was only detected in the presence of other betaherpesviruses. Sequencing information confirmed betaherpesviruses infection. High hepatic enzyme levels and INR values>1.4 were determined in all betaherpesvirus-positive patients. Conclusions: Multiplex qPCR facilitated efficient quantification, indicating that differentiation between betaherpesviruses is possible with the sole use of real-time PCR. Liver and serum samples were positive for some betaherpesviruses, suggesting an association with ALF. Coinfection of HHV-7 with HHV-6 or HCMV was additionally detected, suggesting that the precursor betaherpesviruses infection can trigger HHV-7 infection. Based on these results, we propose that ALF patients should be screened for the presence of betaherpesviruses.
... In recent years, real-time PCR has been increasingly applied to simplify the overall procedure and reduce performance time in detecting and quantifying virus in clinical samples (15,16). Multiplex qPCR has been suggested as an e cient alternative for simultaneous detection of HCMV, HHV-6 and HHV-7 within the same reaction (9,17). In the current study, the incidence of betaherpesvirus infection in patients with ALF of unknown etiology was investigated using the multiplex qPCR approach. ...
Background: The etiology of acute liver failure (ALF) is often unknown and reported to be associated with herpesviruses in a number of cases. In this study, we examined for betaherpesviruses infections in patients with ALF of unknown etiology using a multiplex qPCR to Betaherpesviruses subfamily. Methods: Liver and serum samples from 27 patients with ALF of unknown etiology were analyzed with the aid of multiplex qPCR to identify betaherpesviruses. All positive samples were sequenced to confirm herpes infection and liver enzyme levels evaluated. Results: Betaherpesviruses infection was effectively detected using multiplex qPCR. Seven (26%), two (7%) and three (11%) cases were positive for HHV-6, HHV-7 and HCMV, respectively. Two cases of dual infection (HHV-7/HHV-6 and HHV-7/HCMV) were additionally identified. Interestingly, HHV-7 was only detected in the presence of other betaherpesviruses. Sequencing information confirmed betaherpesviruses infection. High hepatic enzyme levels and INR values>1.4 were determined in all betaherpesvirus-positive patients. Conclusions: Multiplex qPCR facilitated efficient quantification, indicating that differentiation between betaherpesviruses is possible with the sole use of real-time PCR. Liver and serum samples were positive for some betaherpesviruses, suggesting an association with ALF. Coinfection of HHV-7 with HHV-6 or HCMV was additionally detected, suggesting that the precursor betaherpesviruses infection can trigger HHV-7 infection. Based on these results, we propose that ALF patients should be screened for the presence of betaherpesviruses.
... In recent years, real-time PCR has been increasingly applied to simplify the overall procedure and reduce performance time in detecting and quantifying virus in clinical samples (15,16). Multiplex qPCR has been suggested as an e cient alternative for simultaneous detection of HCMV, HHV-6 and HHV-7 within the same reaction (9,17). In the current study, the incidence of betaherpesvirus infection in patients with ALF of unknown etiology was investigated using the multiplex qPCR approach. ...
Background: The etiology of acute liver failure (ALF) is often unknown and reported to be associated with herpesviruses in a number of cases. In this study, we examined for betaherpesviruses infections in patients with ALF of unknown etiology using a multiplex qPCR to Betaherpesviruses subfamily. Methods: Liver explant and serum samples from 27 patients with ALF of unknown etiology were analyzed with the aid of multiplex qPCR to identify betaherpesviruses. All positive samples were sequenced to confirm herpes infection and liver enzyme levels evaluated. Results: Betaherpesviruses infection was effectively detected using multiplex qPCR. Six (22%) HHV-6, one (3%) HCMV and two (7%) dual infections (one with HHV-7/HHV-6, and the other with HHV-7/ HCMV). Interestingly, HHV-7 was only detected in the presence of other betaherpesviruses. Sequencing information confirmed betaherpesviruses infection. High hepatic enzyme levels and INR values>1.5 were determined in all betaherpesvirus-positive patients. Conclusions: Multiplex qPCR facilitated efficient quantification, indicating that differentiation between betaherpesviruses is possible with the sole use of real-time PCR. Liver explant and serum samples were positive for some betaherpesviruses, and coinfection of HHV-7 with HHV-6 and HCMV was additionally detected. Based on these results, we propose that ALF patients should be screened for the presence of betaherpesviruses.
... Moreover, the global incidence of HSV-2 was estimated to be about 417 million in 2012 [5]. Sometimes, the incidence of HSV infection leads to other diseases like the Alzheimer's disease and liver failure [6,7]. ...
Herpes Simplex Virus (HSV) is an infectious virus that is responsible for various types of orofacial and genital infections. Two types of HSV viruses, HSV-1 and HSV-2, are the most dangerous HSV viruses. Every year, millions of people get infected with this menacing virus, however, no satisfactory treatment or vaccine has not yet been discovered to fight against HSV. Although there are some anti-viral therapies, however, studies have showed that such anti-viral therapies may also fail to provide good impact. In this study, a possible subunit vaccine against HSV-1, strain-17, was designed using the tools and reverse vaccinology and bioinformatics. Three potential antigenic envelope glycoproteins were selected from nine envelope glycoproteins, for possible vaccine construction. Potential epitopes capable of inducing high immunogenic response and at the same time have non-allergenicity and conservancy across other strains and species, were selected by some robust analysis, for vaccine construction. Finally, three possible vaccines were designed. Each of the vaccine construct differ from each other only in their adjuvant sequences and based on molecular docking analysis, one best vaccine construct was selected for molecular dynamics simulation study and in silico codon adaptation. The experiment showed that the selected best vaccine should be good candidate against HPV-1, strain-17. However, wet lab study should be conducted on the suggested vaccine(s) for confirming their potentiality, safety and efficacy.
... In septic patients, liver dysfunction can vary from subclinical injury to overt failure. [12] Sepsis-associated liver dysfunction can roughly be categorized as hypoxic hepatitis and sepsis-induced cholestasis, but acknowledged diagnostic tools to detect early liver dysfunction are still lacking. Kramer et al [13] defined hepatic dysfunction as a bilirubin concentration of greater than 2 mg/dL (>34 mmol/L) within 48 h of admission in a large cohort study, while Bakker et al [14] defined acute liver failure using the following criteria: bilirubin >2.5 mg/dL (>43 mmol/L), serum ALT concentration more than twice the upper limit, and prothrombin time of greater than 1.5 times the control value or an international normalized ratio of greater than 1.5. ...
Rationale:
Sepsis-associated liver failure is characterized by increased bilirubin levels and coagulation disorders, which has a significant impact on mortality due to the insufficient understanding of its complicated pathogenesis pathophysiology and a lack of standardized treatment.
Patient concerns:
A 56-year-old woman presented signs of sepsis on the 2nd day after undergoing ureteroscopy for left ureter and laparoscopy for lysis of adhesions around left ureter due to hydronephrosis. Her condition seemed to have been improved after treatment, but the bilirubin levels suddenly increased drastically with presence of coagulation disorders.
Diagnosis:
Laboratory tests combined with her medical history confirmed the diagnosis as sepsis-associated liver failure.
Interventions:
Plasma exchange was applied after hepatoprotective drugs, and other supportive therapies were given which did not significantly improve the condition.
Outcomes:
Laboratory liver function tests indicated the restoration of damaged liver function after plasma exchange was performed and the patient was soon transferred from intensive care unit back to the general ward.
Lessons:
Plasma exchange might be a vital and effective therapy to improve outcome of sepsis associated liver failure especially when conventional support therapy is ineffective.
... Treatment of HSV hepatitis, and subsequent prognosis, is highly contingent on time. Rapidly progressive acute liver failure occurs in 74% of cases, with mortality rates reaching 90% [17]. Studies have demonstrated better clinical outcomes in patients who were started on acyclovir early in their hospital course. ...
Herpes simplex virus (HSV) is a rarely reported cause of viral hepatitis. Aggressive in nature, most cases of HSV hepatitis rapidly progress to fulminant hepatic failure. Present day, its pathogenesis is yet to be elucidated, but its complications and associated high mortality rate are clear. Clinically, its symptoms mimic those of other causes of acute hepatic failure thus making the diagnosis of HSV hepatitis a precarious task. Although treatment in the form of acyclovir is readily available, most cases have a poor prognosis due to late initiation of therapy. This makes the early identification of HSV essential in improving outcomes and potentially preventing mortality.
... В условиях наших опытов внутрибрюшинное заражение мышей вызывало серьёзные неврологические симптомы и гибель 90% животных. Высокий уровень летальности (около 75%) наблюдается и при острых заболеваниях ВПГ-этиологии у людей [13]. Стратегии лечения, направленные на подавление функций вирусных генов, имеют ряд известных ограничений [14]. ...
The objective of this study was to evaluate immunoregulatory and protective potential of mesenchymal stem cells (MSC) in a mouse model of lethal HSV1 infection. MSC were isolated from bone marrow of DBA mice and cultured in flasks with DMEM containing 10% FBS, insulin, transferrin, selenite, fbroblast growth factor, glutaminе and gentamicin. Antiviral activity was tested on HSV1-infected Vero cells. In vivo experiments were performed on DBA mice divided into 5 groups (10 animals each): group 1, intact (naïve) mice; group 2, intravenous (iv) MSC injection; group 3, ntraperitoneal infection with 20 LD50 HSV1 followed by MSC injection; group 4, HSV1 infection followed by acyclovir (ACV) injection; group 5, HSV1 infection and iv injection of saline. Isolated cells were consistent with MSC morphologically, by adhesive ability and surface receptors. Conditioned media from MSC collected after 4-5 passages inhibited HSV1 infection in vitro by 64-70% and contained IL-6 and TNF-α, whose concentrations were 5- and 20-fold higher, respectively, than in the control. MSC and ACV injections protected 70% and 60% of DBA mice, respectively, compared with the control (group 5, 10% survival). High activity of virus neutralizing anti-HSV1 antibodies and activation of T cell proliferation were observed in survived mice from group 3. Serum levels of IL-6 and TNF-α in these mice were lower and that of INF-γ much higher than in agonizing animals of this group (Р<0.05). These fndings indicate that MSC therapy is a prospective approach to the development of new effective management of generalized HSV1 infection.
... LFUE could have an autoimmune etiology, as evidenced by concurrent development of aplastic anemia in some cases [35]. Among viruses, hepatitis E, adenovirus, echovirus, herpes simplex virus (HSV), and influenza virus, along with rarer causes, such as dengue virus and yellow fever virus, have been implicated in liver failure [36][37][38][39]. Metagenomic next-generation sequencing has been used to identify possible viral etiologies in 187 adult patients in the Acute Liver Failure Study Group, and found viruses including HSV-1, parvovirus B19, and human herpesvirus-7. ...
Background:
Liver failure of unknown etiology (LFUE) has a transplant-free survival rate of less than 25%. Human herpesvirus 6 (HHV-6) may be associated with LFUE, but existing studies are limited by small sample size.
Methods:
We identified all children who underwent liver transplant for LFUE at a single quaternary children's hospital. 51/65 cases were able to be age-matched with controls (children who underwent liver transplant for metabolic liver disease). Quantitative polymerase chain reaction (PCR) for HHV-6 was performed on DNA from formalin-fixed paraffin-embedded liver explant tissue. Results: HHV-6 was detected in 34/51 cases (66.7%), and 19/51 controls (37.3%) (p=0.005). Average HHV-6 viral load was 213,207 copies/10 6 cells in positive cases (range: 7,293-1,102,030), and 38,115 copies/10 6 cells in positive controls (range: 1,382-122,375) (p=0.0008). HHV-6 was present significantly more often in cases compared to controls in patients less than 6 years in age; in particular, in patients less than 3 years in age, HHV-6 was present in 13/27 cases (48.1%), and 2/27 controls (7.4%) (p=0.0009).
Conclusions:
HHV-6 was detected in liver explants significantly more often and in higher quantities in children transplanted for LFUE compared to controls. This suggests HHV-6 should be evaluated for in young children who present with LFUE.
... Результати ПЦР та ІФА часто не співпадають [12], а верифікація результатів біопсії (зокрема імуногістохімії печінки) у пацієнтів з печінковою недостатністю не завжди виявляє ВПГ [7]. Між тим несвоєчасне виявлення інфекції і відсутність противірусної терапії в значній мірі визначають несприятливий результат [8,9]. ...
... Одним з найбільш частих органів -мішеней вірусу простого герпесу у новонароджених є печінка. Вірусний герпетичний гепатит характеризується нейтропенією, тромбоцитопенією, підвищенним рівнем трансаміназ, прямою гіпербілірубінемією з подальшим приєднанням ДВЗсиндрому, асциту та розвитком гострої печінкової недостатності, що потребує трансплантації печінки [26,31]. Нерідко супроводжується ураженням інших органів, а саме геморагічним пневмонітом, менінгоенцефалітом та ознаками некротичного ентероколіту. ...
Herpes infection in neonates leads to significant morbidity and adverse long-term effects. Currently, the level of herpes
simplex virus infection among pregnant women is rather high (30-65%), therefore, all children are potentially susceptible to
the risk of neonatal herpes infection. Frequency of neonatal herpes according to the world literature data ranges from
1:2500 to 1:60000 live births. So, it is necessary to study the current epidemiological data, the modes of transmission,
maternal immune status, peculiarities of clinical signs and management of infants with confirmed or suspected neonatal HSV
infection according to the latest international guiderlines, and implement them in the national practice.
Key words: herpes infection, the newborn, diagnosis, treatment, acyclovir.
... Viral DNA is present in brain, liver and lungs in moribund wild type and IL-36β KO mice. In humans HSV can disseminate to internal organs such as the brain, liver and lungs, where it causes organ damage leading to significant morbidity and mortality [2][3][4][5][6] . We previously showed that in the HSV-1 flank model the virus disseminates to internal organs such as the brain, liver and lungs 12 . ...
Interleukin-36 (IL-36) represents three cytokines, IL-36α, IL-36β and IL-36γ, which bind to the same receptor, IL-1RL2; however, their physiological function(s) remain poorly understood. Here, the role of IL-36 in immunity against HSV-1 was examined using the flank skin infection mouse model. Expression analyses revealed increased levels of IL-36α and IL-36β mRNA in infected skin, while constitutive IL-36γ levels remained largely unchanged. In human keratinocytes, IL-36α mRNA was induced by HSV-1, while IL-1β and TNFα increased all three IL-36 mRNAs. The dominant alternative splice variant of human IL-36β mRNA was isoform 2, which is the ortholog of the known mouse IL-36β mRNA. Mice deficient in IL-36β, but not IL-36α or IL-36γ, succumbed more frequently to HSV-1 infection than wild type mice. Furthermore, IL-36β−/− mice developed larger zosteriform skin lesions along infected neurons. Levels of HSV-1 specific antibodies, CD8⁺ cells and IFNγ-producing CD4⁺ cells were statistically equal in wild type and IL-36β−/− mice, suggesting similar initiation of adaptive immunity in the two strains. This correlated with the time at which HSV-1 genome and mRNA levels in primary skin lesions started to decline in both wild type and IL-36β−/− mice. Our data indicate that IL-36β has previously unrecognized functions protective against HSV-1 infection.
... [3][4][5][6] In healthy, immunocompetent persons at any age, EBV and herpes simplex virus (HSV) infection are usually self-limiting, rarely lead to complications and are both uncommon causes of acute liver failure (ALF). [7][8][9][10][11] The case presented in this report highlights the possibility of a synergistic effect of these two closely succeeding viral primary infections in the development of a severe systemic disease in an immunocompetent person. In addition, it emphasises that SHLH should be suspected routinely when severe systemic illness with multiorgan failure develops following a viral infection and that the diagnosis should be confirmed rapidly by laboratory and histopathological investigations. ...
We present a case of severe fatal hepatitis in a young patient presumably triggered by two ubiquitous viral diseases which occurred in close succession. This case is unusual because of the exceptional chronological sequence of primary Epstein–Barr virus and herpes simplex virus type 1 infection causing systemic immune dysregulation associated with rapidly developing liver failure and consecutive multiorgan failure. Clinical, laboratory and histopathological findings indicated the development of secondary haemophagocytic lymphohistiocytosis triggered by these closely succeeding viral primary infections.
... 18 There are only a small number of cases of ACV-resistant treatment for HSV hepatitis. 6,19,20 In conclusion, our case illustrates an unusual presentation of HSV hepatitis. Diagnosis requires a high index of clinical suspicion. ...
Herpes simplex virus (HSV) hepatitis is a rare cause of acute liver failure (ALF). It carries a mortality rate of 80% if untreated, thus early identification and treatment are critical. Without high clinical suspicion, HSV hepatitis is difficult to diagnose. A 48-year-old Hispanic female presented with a 4-day history of abdominal pain and a vaginal cuff tear requiring laparoscopic repair. She subsequently developed postsurgical disseminated HSV, resulting in ALF. Acyclovir was initiated, but she was resistant to treatment. She was given additional foscarnet and responded without requiring a liver transplant.
Acute liver failure (ALF) is a rare cause of liver-related mortality worldwide, with an estimated annual global incidence of more than one million cases. While drug-induced liver injury, including acetaminophen toxicity, is the leading cause of ALF in the Western world, viral infections remain a significant cause of ALF and the most common cause in many developing nations. Given the high mortality rates associated with ALF, healthcare providers should be aware of the broad range of viral infections that have been implicated to enable early diagnosis, rapid treatment initiation when possible, and optimal management, which may include liver transplantation. This review aims to provide a summary of viral causes of ALF, diagnostic approaches, treatment options, and expected outcomes.
Background: Improvements in liver transplant (LT) outcomes are attributed to advances in surgical techniques, use of potent immunosuppressants, and rigorous pre-LT testing. Despite these improvements, post-LT infections remain the most common complication in this population. Bacteria constitute the most common infectious agents, while fungal and viral infections are also frequently encountered. Multi-drug-resistant bacterial infections develop because of polymicrobial overuse and prolonged hospital stays. Immediate post-LT infections are commonly caused by viruses. Conclusions: Appropriate vaccination, screening of both donor and recipients before LT and antiviral prophylaxis in high-risk individuals are recommended. Antimicrobial drug resistance is common in high-risk LT and associated with poor outcomes; epidemiology and management of these cases is discussed. Additionally, we also discuss the effect of coronavirus disease 2019 (COVID-19) infection and monkeypox in the LT population.
Introduction:
Severe acute hepatitis (SAH) is defined by a severe inflammation of hepatocytes in the liver parenchyma which can lead to an acute liver failure, a clinical condition with high mortality rate that can be triggered by several factors but is usually associated to hepatotropic viruses' infection. In 2022, cases of children with severe acute hepatitis of unknown origin hospitalized in Glasgow, Scotland, were reported. Possible causes of this condition include, but are not limited to, undiagnosed viral (and non-viral) infections, autoimmune hepatitis, drug and/or chemical toxicity, mitochondrial chain respiratory and metabolic disorders.
Areas covered:
Herpesviruses can cause severe acute hepatitis, but little is known about the role and the mechanisms of herpesviruses as a causative agent of this type of hepatitis. We review the role of herpesviruses as causative agent of SAH in children and other possible mechanisms involved in this disease.
Expert opinion:
Differential diagnosis for herpesvirus in SAH should be implemented in all settings. Alternative fluids, such as saliva and dried blood, could be used in the diagnosis to overwhelm the availability of biological specimens at sufficient volume. In the future, genetic studies could also be added to increase the knowledge about severe acute hepatitis in children.
Acute liver failure (ALF) is a rare, acute, potentially reversible condition resulting in severe liver impairment and rapid clinical deterioration in patients without preexisting liver disease. Due to the rarity of this condition, published studies are limited by the use of retrospective or prospective cohorts and lack of randomized controlled trials. Current guidelines represent the suggested approach to the identification, treatment, and management of ALF and represent the official practice recommendations of the American College of Gastroenterology. The scientific evidence was reviewed using the Grading of Recommendations, Assessment, Development and Evaluation process to develop recommendations. When no robust evidence was available, expert opinions were summarized using Key Concepts. Considering the variety of clinical presentations of ALF, individualization of care should be applied in specific clinical scenarios.
Liver failure can develop as either acute liver failure in the absence of preexisting liver disease, or as acute-on-chronic liver failure in a patient with underlying chronic liver disease or cirrhosis. A timely liver biopsy is helpful to distinguish acute and chronic liver disease, identify precipitating factors, provide prognostic information based on pathologic changes, and aid in making appropriate decisions for patient management. This article will discuss the pathologic features of acute and acute-on-chronic liver failure. Developing an appreciation for the histopathologic patterns of injury observed in these entities is essential for a practical understanding of the diagnostic process.
Orthotopic liver transplant (LT) represents an important treatment strategy for end-stage liver disease. While transplant recipient survival has improved dramatically, greater than two-thirds of LT patients suffer from infectious complications within the first year after transplant. LT patients are at risk for infections originating from donor organs, surgical complications, hospital and community exposures, and from their own latent infections. A patient’s risk for infection by specific pathogens is related to their net state of immunosuppression—the collective effect of all patient, medication, and disease-related factors on the immune system’s ability to combat infection. Temporal variations in immunosuppression and pathogen exposure produce predictable trends in infection type. Early infections are most often related to surgical complications or latent infection. Opportunistic infections become prevalent during the intermediate phase, against which microbial prophylaxis regimens are utilized. The late phase is characterized by a return to a community-acquired infection profile, although patients with graft dysfunction/rejection episodes remain at risk for opportunistic infections. The understanding of these factors is critical for effective diagnosis and management of infection in post-LT patients.
Sepsis is responsible for the highest economic and mortality burden in critical care settings around the world, prompting the World Health Organization in 2018 to designate it as a global health priority. Despite its high universal prevalence and mortality rate, a disproportionately low amount of sponsored research funding is directed toward diagnosis and treatment of sepsis, when early treatment has been shown to significantly improve survival. Additionally, current technologies and methods are inadequate to provide an accurate and timely diagnosis of septic patients in multiple clinical environments. For improved patient outcomes, a comprehensive immunological evaluation is critical which is comprised of both traditional testing and quantifying recently proposed biomarkers for sepsis. There is an urgent need to develop novel point‐of‐care, low‐cost systems which can accurately stratify patients. These point‐of‐critical‐care sensors should adopt a multiplexed approach utilizing multimodal sensing for heterogenous biomarker detection. For effective multiplexing, the sensors must satisfy criteria including rapid sample to result delivery, low sample volumes for clinical sample sparring, and reduced costs per test. A compendium of currently developed multiplexed micro and nano (M/N)‐based diagnostic technologies for potential applications toward sepsis are presented. We have also explored the various biomarkers targeted for sepsis including immune cell morphology changes, circulating proteins, small molecules, and presence of infectious pathogens. An overview of different M/N detection mechanisms are also provided, along with recent advances in related nanotechnologies which have shown improved patient outcomes and perspectives on what future successful technologies may encompass.
This article is categorized under: Diagnostic Tools > Biosensing
Herpes Simplex Virus (HSV) is a highly infectious virus that is responsible for various types of orofacial and genital infections. Two types of HSV exist i.e. HSV-1 and HSV-2, that are infecting millions of people around the world. However, no satisfactory treatment or counter-measure has yet been discovered to fight against the HSV infections. In this study, three possible polyvalent subunit vaccines against multiple strains of HSV-1 and HSV-2, targeting the envelope glycoproteins- E, B, and D, were designed using the tools of reverse vaccinology and immunoinformatics. The highly antigenic, non-allergenic, non-toxic, non-homolog (to the human proteome), and 100% conserved epitopes across the selected strains and species (eight epitopes from each of the CTL, HTL, and BCL epitope groups), were selected for vaccine construction. These designed vaccines are expected to be effective against the selected viral types simultaneously (as a polyvalent vaccine), without producing any unwanted adverse reaction within the body. Finally, from the three vaccine constructs, one best vaccine was determined by molecular docking analysis and thereafter, the MD simulation and immune simulation studies of the best vaccine construct also yielded satisfactory results, pointing towards quite good stability of the complex. Finally, in silico cloning was performed for analyzing the effective mass production strategy of the best vaccine construct. However, wet lab-based study should be conducted on the suggested vaccines for validating their potentiality, safety, and efficacy.
Communicated by Ramaswamy H. Sarma
Infections involving the hepatobiliary tract contribute to significant morbidity and mortality in solid-organ transplant recipients, particularly recipients of a hepatic allograft. Bacteria within the gastrointestinal tract may colonize a dysfunctional biliary system, thereby increasing the risk for ascending cholangitis. Additionally, infections such as cytomegalovirus or Epstein-Barr virus may trigger life-threatening acute illness and foster risk for other opportunistic infections and malignancies, respectively during the posttransplant period. Fungal and protozoal pathogens may also find refuge within the biliary tract of immunosuppressed host, and approach toward such infections often requires a combined medical and surgical intervention. Screening for clinical, subclinical, and latent infections, early institution of prophylactic drug therapy, and appropriate immunization form the central tenet for evaluation of patients being considered for allograft transplantation. A high level of suspicion for biliary tract infections or infections involving the liver in at risk allograft recipients may assist in early diagnosis and prompt initiation of effective antimicrobial therapy. Risk mitigation by lowering drug-induced immune suppression, when possible, is important for effective management of such infections. In this chapter, a comprehensive review of hepatobiliary tract infections is presented with an emphasis on complications in patients undergoing solid-organ transplantation.
Herpes Simplex Virus (HSV) hepatitis in liver transplant patients is a rarely reported infective complication of HSV with severe consequences, often leading to fulminant hepatitis if left untreated. The clinical signs are often atypical, leading to under-reporting in the literature and potential delays in treatment. Our case report describes such atypical mucocutaneous lesions in a liver transplant recipient. We highlight the need for further reports, especially those with images, in order to aid the diagnosis of HSV infection, and to allow prompt treatment to prevent complications such as HSV hepatitis.
Background:
An 11-year old girl with DOCK8 deficiency was proposed for potentially curative hematopoietic stem cell transplantation (HSCT), the donor being her haploidentical mother. However, end-stage liver disease, caused by chronic Cryptosporidium infection required liver transplantation before HSCT.
Methods:
Consequently, a staged approach of a sequential liver transplant followed by a HSCT was planned, with her mother as the donor for both liver and HSCT.
Results:
The patient successfully underwent a left lobe orthotopic liver transplant, however, she developed a biliary leak delaying the HSCT. Notably, the recipient demonstrated 3 percent donor lymphocyte chimerism in her peripheral blood immediately prior to HSCT. Haploidentical related donor HSCT performed two months after liver transplantation was complicated by the development of acyclovir-resistant HSV viremia, primary graft failure, and sinusoidal obstruction syndrome (SOS). The patient died from SOS associated multiorgan failure with Candida sepsis on day +40 following HSCT.
Conclusions:
We discuss the many considerations inherent to planning for HSCT preceded by liver transplant in patients with primary immunodeficiencies, including the role of prolonged immunosuppression and the risk of infection prior to immune reconstitution. We also discuss the implications of potential recipient sensitization against donor stem cells precipitated by exposure of the recipient to the donor lymphocytes from the transplanted organ.
Herpes virus hepatitis varies in presentation, ranging from asymptomatic to acute liver failure, in both immunocompetent and immunocompromised individuals. Hepatitis caused by herpes viridae family is uncommon and usually results in mild diseases. It is also often self‐limited, although in certain populations especially immunosuppressive patients it can cause severe infections, leading to acute to fulminant hepatic failure. In addition, some isolated cases of fulminant disease in immunocompetent individuals have been reported. As the presentation is frequently non‐specific, it is important to keep a high suspicion for these viral etiologies, and start empiric therapy sooner than later with antiviral agents. Liver transplantation is the last resort. Mortality remains high in fulminant hepatic failure caused by herpes viridae without liver transplantation. In this article, we reviewed the current literatures on hepatitis caused by three members of the herpes viridae family, cytomegalovirus, Epstein–Barr virus and herpes simplex virus to discuss the epidemiology, diagnostic methods, clinical features and current management in literatures, and also to determine which aspects need to be investigated in further detail. Herpes viridae‐mediated acute liver failure is rare, but is associated with a poor prognosis even with early treatment.
This article is protected by copyright. All rights reserved.
Hepatitis is an unusual manifestation of herpesvirus infection. Herpes simplex virus hepatitis is a difficult diagnosis to
establish, and the infection is often fatal. We report one case of herpes simplex virus hepatitis and review 51 cases in the
literature. Impaired immunity resulting from pregnancy, malignancy, immunosuppression, or inhalational anesthetics may be
predisposing factors. Fever, nausea, vomiting, abdominal pain, leukopenia, thrombocytopenia, coagulopathy, and a marked rise
in serum transaminase levels are invariably present. Liver biopsy is the procedure of choice for diagnosis. The liver appears
mottled and has a minimal inflammatory response. Mortality rates associated with herpes simplex virus hepatitis are high,
and early diagnosis and treatment with acyclovir or vidarabine may produce a favorable outcome.
We determined the prevalence of herpes simplex virus (HSV) and cytomegalovirus (CMV) antibodies in a cohort of adolescents
12 to 22 years of age in anticipation of the development of vaccines to control HSV and CMV infections. For the overall study
population, we found that 62% were seropositive for HSV type 1 (HSV-1), 12% were seropositive for HSV type 2 (HSV-2), and
65% were seropositive for CMV. Race was not related to HSV-1 seropositivity, but African-American adolescents were more likely
than Caucasian adolescents to be seropositive for HSV-2 and CMV. Girls also were more likely than boys to be seropositive
for HSV-2 and CMV. For boys, history of a sexually transmitted disease was identified as a risk factor for HSV-2 seropositivity;
for girls, a greater number of sexual partners increased the risk of being seropositive for HSV-2. Our data demonstrating
a high prevalence of infection during adolescence suggest that immunization for HSV-1, HSV-2, and CMV may need to occur in
childhood.
Five cases of fulminant hepatitis due to herpes simplex virus were identified among patients admitted to the Thomas E. Starzl Transplantation Institute between January 1991 and September 1994. The diagnosis was established in three of the five patients on the basis of transjugular liver biopsy specimen results. These three patients were treated with acyclovir; two survived and one required liver transplantation. Early histologic diagnosis, specific antiviral treatment, and liver transplantation in selected patients may improve the clinical outcome of this almost uniformly fatal disease.
Because acute liver failure is rare, related data have been sparse. Studies have suggested that viral hepatitis is the most common underlying cause of this condition.
To describe the clinical features, presumed causes, and short-term outcomes of acute liver failure.
Prospective cohort study.
17 tertiary care centers participating in the U.S. Acute Liver Failure Study Group.
308 consecutive patients with acute liver failure, admitted over a 41-month period.
Detailed clinical and laboratory data collected during hospitalization, including outcome 3 weeks after study admission.
73% of patients were women; median age was 38 years. Acetaminophen overdose was the most common apparent cause of acute liver failure, accounting for 39% of cases. Idiosyncratic drug reactions were the presumptive cause in 13% of cases, viral hepatitis A and B combined were implicated in 12% of cases, and 17% of cases were of indeterminate cause. Overall patient survival at 3 weeks was 67%. Twenty-nine percent of patients had liver transplantation, and 43% survived without transplantation. Short-term transplant-free survival varied greatly, from 68% for patients with acetaminophen-related liver failure to 25% and 17% for those with other drug reactions and liver failure of indeterminate cause, respectively. Coma grade at admission appeared to be associated with outcome, but age and symptom duration did not.
Acetaminophen overdose and idiosyncratic drug reactions have replaced viral hepatitis as the most frequent apparent causes of acute liver failure. Apparent cause and coma grade at admission were associated with outcome. Although transplantation may improve patient survival, it was unavailable or unnecessary for most patients.
A panel of 23 real-time PCR assays based on TaqMan technology has been developed for the detection and monitoring of 16 different viruses and virus families including human polyomaviruses BK virus and JC virus, human herpesviruses 6, 7, and 8, human adenoviruses, herpes simplex viruses 1 and 2, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, parvovirus B19, influenza A and B viruses, parainfluenza viruses 1 to 3, enteroviruses, and respiratory syncytial virus. The test systems presented have a broad dynamic range and display high sensitivity, reproducibility, and specificity. Moreover, the assays allow precise quantification of viral load in a variety of clinical specimens. The ability to use uniform PCR conditions for all assays permits simultaneous processing and detection of many different viruses, thus economizing the diagnostic work. Our observations based on more than 50,000 assays reveal the potential of the real-time PCR tests to facilitate early diagnosis of infection and to monitor the kinetics of viral proliferation and the response to treatment. We demonstrate that, in immunosuppressed patients with invasive virus infections, surveillance by the assays described may permit detection of increasing viral load several days to weeks prior to the onset of clinical symptoms. In virus infections for which specific treatment is available, the quantitative PCR assays presented provide reliable diagnostic tools for timely initiation of appropriate therapy and for rapid assessment of the efficacy of antiviral treatment strategies.
Hepatitis due to herpes simplex virus (HSV) is a potentially fatal disorder that is often not considered in the differential diagnosis of acute hepatitis. This disease occurs most often in patients with impaired immunity and is very uncommon in healthy patients. HSV hepatitis presents with a wide clinical spectrum, and the clinical diagnosis is difficult. We describe a case of disseminated herpes virus infection with fulminant hepatitis mimicking an acute human immunodeficiency virus infection in a 33-year-old healthy man. Preliminary studies suggest that early treatment of HSV hepatitis with acyclovir may be beneficial in these patients. A high index of suspicion and the availability of early diagnostic tools, such as HSV DNA detection, may dramatically improve the clinical outcome of severe HSV hepatitis.
Fulminant hepatic dysfunction in the third trimester of pregnancy accompanied by fever may result from disseminated herpes simplex virus.Since 1969, 24 cases of herpes simplex hepatitis, including the current case, have been reported. Mucocutaneous lesions are present in only half of cases; therefore, suspicion for diagnosis of this disease is low. Twenty-five percent of cases were not diagnosed until autopsy. Maternal and perinatal mortality are high, approaching 39 percent for both mother and fetus. Early recognition with initiation of antiviral therapy appears to be most important in maximizing survival. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader will be able to understand the typical presentation of HSV hepatitis during pregnancy and the other conditions that can resemble HSV hepatitis, to be aware of the mortality of the disease in pregnancy, and to know which is the most appropriate therapy for HSV hepatitis during pregnancy.
Viral hepatitis has previously been the major cause of acute liver failure (ALF) in the United States. We aimed to determine the incidence of viral hepatitis-related ALF and to compare the outcome and clinical and biochemical variables in patients with hepatitis A and B.MethodsA total of 354 patients with ALF from multiple centers were screened for possible acute viral etiology.ResultsForty-three patients (12.1% of all ALF cases) had acute viral hepatitis: hepatitis A (n = 16), hepatitis B (n = 26), and herpes simplex virus infection (n = 1). There was no difference between groups with regard to age, gender, body mass index, admission or peak coma grade, symptom duration, admission mean arterial pressure, temperature, or biochemical liver tests, creatinine, arterial pH, or rate of infections. Platelet count was significantly higher in hepatitis A patients than in hepatitis B patients. The transplantation-free (spontaneous) survival rate was significantly higher for hepatitis A patients (69%) than for hepatitis B patients (19%, p = 0.007), whereas the liver transplantation rate was higher in hepatitis B patients (62%) than in hepatitis A patients (19%, p = 0.017). Spontaneous survivors had significantly higher mean arterial pressure, higher platelet count, and lower AST/ALT ratio than patients who did not survive spontaneously.Conclusions
Viral hepatitis now comprises only one-eighth of all ALF cases in the United States. The marked difference in spontaneous survival between hepatitis A and B cannot be explained by the severity of hepatic dysfunction on admission but may rather be an inherent feature of the infections or a bias toward transplanting patients with hepatitis B.
Fulminant hepatic failure (FHF) is defined by the appearance of severe liver injury with hepatic encephalopathy in a previously healthy person. There are an estimated 2,000 cases of FHF in the United States yearly, representing 0.1% of all deaths and, perhaps, 6% of liverrelated deaths. The causes of FHF are many, the chief ones in the United States being hepatitis A; B; non-A, non-B and drug induced liver disease. There are no specific therapies for FHF, however, liver transplantation is recommended for situations in which spontaneous recovery appears unlikely. Factors that are valuable in assessing the likelihood of spontaneous recovery are static features such as patient age and etiology of FHF and dynamic features including encephalopathy grade, prothrombin time, and serum bilirubin. Presently, approximately 7% of all liver transplants are done for FHF and the 1-year patient survival rates average 63%, somewhat less than survival rates for nonfulminant liver disease, averaging 78%. The management of patients with FHF is challenging, particularly important being monitoring and early treatment of infections, hemodynamic abnormalities, and brain edema. Innovative approaches to management and therapy include use of cytoprotective or antiviral medications, hepatic support systems, extracorporeal liver support, hepatocyte transplantation, auxiliary liver transplantation, and xenotransplantation. None of these are of proven benefit, but many are promising as a means to support the patient with FHF until spontaneous recovery occurs or a suitable liver graft is available for transplantation. (Hepatology 1995;21:240–252).
We report our results with orthotopic liver transplantation in children with fulminant liver failure. Thirty-five children with fulminant liver failure were evaluated for liver transplantation. The main causes of liver failure were viral hepatitis (54.2%), drug-induced liver injury (14.2%) and Wilson's disease (11.4%). Children were considered as candidates for liver transplantation only if hepatic encephalopathy was associated with a decrease in the level of factor V to below 25%. Seven children (20%) did not meet this criterion and recovered spontaneously. Six children (17.1%) had contraindications for liver transplantation and died. In three of these six children, contraindications included irreversible brain damage at the time of admission. Twenty-two children (62.8%) met the criteria for liver transplantation and were placed on the emergency transplant list. Three of them died awaiting grafts. Nineteen children underwent liver transplantation; 13 of them (68.4%) are alive without sequelae, after 6 mo to 4 yr of follow-up, at this writing. Four of the children who died after surgery had severe encephalopathy on admission that did not improve after liver transplantation. In conclusion, emergency liver transplantation appears to be an effective treatment for children with fulminant liver failure. Nevertheless, irreversible brain damage developed in 10 patients, and they died before or after surgery. We postulate that many of these deaths could have been avoided if children had been transferred to a liver transplantation facility and had undergone transplantation earlier. We emphasize that children with acute liver failure should be transferred to a center that performs liver transplantation before the development of hepatic encephalopathy. (HEPATOLOGY 1992;16:1156–1162.)
Percutaneous liver biopsy is the procedure of choice for most patients because of its simplicity and the high percentage of adequate biopsies obtained. It is a bedside procedure that does not require specialized equipment or the services of a highly trained angiographer. Nevertheless, complications are not uncommon unless strict contraindications are observed. It is usually recommended that patients be excluded who present with ascites, a prothrombin time less than 50%, a partial thromboplastin time greater than 10 s, or a platelet count less than 50 000. Mahal et al (1979) cite lack of attention to the contraindications as the most important factor in 22 bleeding episodes which occurred following 3800 percutaneous biopsies (0.7%). It is these contraindications that are the main indication for transjugular biopsy. Despite the highly selective nature of the patients who have undergone transjugular biopsy, the frequency of post-biopsy bleeding is only 0.35% and of death 0.13% (Table 1). These figures include the earliest experiences with this technique and can be expected to improve with increased experience and the development of new instruments that make the procedure safer and easier. Transjugular liver biopsy should be an essential procedure in every hospital that is involved in treating patients with liver disease. Unfortunately, although Lebrec et al (1982) estimated that approximately 30% of patients are rejected for percutaneous biopsy because of the presence of contraindications, relatively few centres have adopted this technique. This may be in part due to the reluctance of clinicians to subject their patients to a procedure they perceive as stressful, although a study by Poynard and Lebrec (1982) showed patients rated transjugular biopsy as less painful and inconvenient than percutaneous biopsy.
Disseminated herpes simplex virus (HSV) infection may lead to acute liver failure (ALF) and the need for emergency liver transplantation (LT). The primary aim of this study was to determine the utility of HSV serological testing and HSV DNA testing by polymerase chain reaction (PCR) in the diagnosis and management of indeterminate, pregnancy-related, and known HSV-related ALF. Stored sera obtained on study day 1 or 2 from patients enrolled in the United States ALF Study Group with indeterminate (n = 51), pregnancy-related (n = 12), and HSV-related (n = 4) ALF were screened for HSV DNA by PCR and serology. While 7 of the indeterminate and pregnant patients had positive anti-HSV immunoglobulin M, none had detectable HSV DNA. The 4 known HSV cases all had high-titer HSV DNA on presentation (range: 3.5 to 36 x 10(8) copies/mL). Two HSV patients underwent LT but developed posttransplant extrahepatic HSV infection despite suppression of HSV DNA with acyclovir treatment, and one of them eventually died. The 2 other fulminant HSV patients died within 48 hours of presentation. In conclusion, serum HSV DNA indicative of occult HSV infection was not detected in 51 indeterminate and 12 pregnancy-related ALF patients. The 4 patients with known HSV-related ALF all had high HSV DNA levels at presentation, and despite the rapid use of antiviral therapy and emergency LT, substantial morbidity and mortality were encountered, highlighting the poor prognosis with severe disseminated HSV infection.
A healthy 20-year-old woman developed herpes simplex virus (HSV) hepatitis. The diagnosis was made by needle biopsy of the liver, and the patient was intravenously treated with acyclovir for 15 consecutive days (total dose, 21 g). The liver biopsy specimen and liver tissue obtained at autopsy were processed for immunoperoxidase staining with rabbit anti-HSV and for DNA-DNA in situ hybridization. The liver biopsy tissue revealed massive necrosis of hepatocytes, which were strongly positive for HSV with both immunoperoxidase and in situ hybridization methods. The liver tissue obtained at autopsy showed regenerative nodules of hepatocytes, surrounded by connective tissue stroma. Within the connective tissue there were completely necrotic hepatocytes, which were positive for HSV with the immunoperoxidase method but almost completely negative with the in situ hybridization method, except for a very few HSV DNA-positive hepatocytic nuclei. It was concluded that immunoperoxidase staining with anti-HSV is a sensitive method with which to detect ongoing and previous HSV infection, whereas the in situ hybridization method is specific for HSV-DNA from viable HSV.
Although transjugular liver biopsy requires the availability of trained personnel, takes more time than percutaneous biopsy and is moderately expensive, it is a safe alternative technique for obtaining adequate liver tissue for diagnosis in special clinical situations. The usual indications for transjugular rather than percutaneous liver biopsy are (a) coagulation disorder (prothrombin time greater than 3 sec over control value and/or platelet count less than 60,000/cm3), (b) massive ascites and (c) desire to perform ancillary procedures, such as measurement of pressures or opacification of the hepatic veins and inferior vena cava. Less common indications for transjugular liver biopsy include failed percutaneous biopsy, massive obesity, small cirrhotic liver (increased risk and lower success rate) and suspected vascular tumor or peliosis hepatis. Results from several centers indicate that adequate or diagnostic liver tissue is obtained in 81% to 97% of cases. The typical length of the biopsy core ranges from 0.3 cm to 2.0 cm. Modification of the classic technique, particularly the adaptation of a Tru-Cut needle, shows promise in yielding longer cores of tissue with less fragmentation. Transjugular liver biopsy is performed with an acceptable complication rate that ranges 0% to 20%. The reported mortality of transjugular liver biopsy was 0 in three major centers and ranged from 0.1% to 0.5% in three other centers. Transjugular liver biopsy may be useful in obtaining diagnostic liver tissue not only in advanced chronic liver disease with coagulopathy, ascites or both, but also in patients with fulminant hepatic failure to better determine prognosis and the need for liver transplantation.
Eight cases of hepatitis due to herpes simplex virus (HSV) (five “confirmed,” three “possible”) were identified among marrow-transplant
recipients at the Fred Hutchinson Cancer Research Center between 1975 and 1988. The clinical and pathological characteristics
of these patients are described and compared with published findings for non-marrow-transplant recipients with HSV hepatitis.
Clinical syndromes in the marrow-transplant recipients ranged from fever associated with abdominal pain and elevations in
serum aminotransferase levels to fulminant hepatitis. Evidence of hepatic infection appeared before day 20 following transplantation
unless prophylaxis with acyclovir was given, in which case HSV hepatitis did not appear until after day 40. All patients died,
although the one patient who was given early, empirical high-dose acyclovir therapy clearly improved with antiviral therapy
and may have died of other causes. Involvement of multiple organs with HSV was found in three of four patients with confirmed
HSV hepatitis who underwent autopsy. In all cases, reactivation of latent HSV was the presumed source of the HSV hepatitis.
HSV hepatitis should be considered when HSV-seropositive recipients of marrow transplants develop abdominal pain, fever, and
elevations in aminotransferase levels.
Herpes simplex virus (HSV) hepatitis is rare in adults, usually occurring in immunocompromised individuals and in otherwise healthy women in the third trimester of pregnancy. Three cases of HSV hepatitis occurring in pregnant women were diagnosed at our institution between 1981 and 1990. This diagnosis was not suspected clinically, and in each case was made on the basis of histology, immunoperoxidase studies, and viral cultures of liver tissue. Clinically, the patients had severe anicteric liver failure with markedly elevated serum aspartate aminotransferase and alanine aminotransferase levels; two of the three patients died. None had mucocutaneous lesions at the time of diagnosis. Histologically, two distinct patterns of necrosis and inflammation were seen. Two of the cases had well-demarcated foci of necrosis scattered randomly throughout the lobules with neutrophilic infiltration, giving the impression of abscess formation. Hepatocytes at the periphery of these areas of necrosis had enlarged nuclei with "ground-glass" inclusions; however, no Cowdry type A inclusions were seen. Rare multinucleated cells were present. Immunoperoxidase staining using antibodies to HSV was positive primarily in the hepatocytes with inclusions. The third case had diffuse, almost total hepatic necrosis with no viral inclusions and virtually no inflammatory response. This histologic pattern is similar to that seen in neonates with HSV infection. Immunoperoxidase studies in this case were negative; however, viral cultures were positive. While HSV hepatitis may be suspected or diagnosed on the basis of histology alone, viral cultures are an important adjunct since viral inclusions may be absent. Prompt diagnosis is important since antiviral therapy is now available.
Herpes simplex hepatitis is a rare disease in adults and with high mortality (81%). Most cases are seen in immunocompromised hosts or in the third trimester of pregnancy. A 43-year-old woman with psoriatic arthritis, treated with prednisone and methotrexate (MTX), presented with an acute abdomen and elevated liver enzymes. The diagnosis was made by liver biopsy. MTX was stopped and acyclovir was started. The patient survived. The diagnosis of Herpes simplex should be suspected in immunocompromised hosts and established by liver biopsy and viral cultures. Treatment includes parenteral acyclovir and discontinuation or reduction of immunosuppressive therapy.
Two cases of herpes simplex virus hepatitis in pregnancy are presented. Each case was characterized by extremely high serum aminotransferase levels with minimal bilirubin elevation. In both cases, liver biopsy was instrumental in arriving at the diagnosis. In addition, computed tomography showed a radiographic appearance of the liver not characteristically seen in other hepatic disorders of pregnancy. A high index of suspicion in the second case led to early recognition and treatment. Despite the presence of fulminant liver failure and evidence of herpes encephalitis in the other case, institution of therapy with acyclovir was associated with complete recovery in both patients. The present cases are compared and contrasted with the literature. The incidence of two cases within a 6-month period suggests that herpes simplex virus hepatitis in pregnancy may occur more frequently than previously reported.
We report three cases of neonatal herpes simplex virus (HSV) infection presenting as fulminant hepatitis. None of the patients had clear risk factors for HSV infection and they all died. Antiviral treatment for HSV is currently available but must be administered early in the course of the disease before irreversible liver tissue damage is present. Since the diagnosis may be difficult to establish, we wish to draw the attention of clinicians to the presentation of neonatal HSV infection and suggest that in such cases viral cultures, including culture of liver tissue, should be obtained early and antiviral treatment administered while awaiting the culture results.
A pathological study was carried out in 200 autopsied cases experienced in our department from 1981 to 1988. Eight patients (4.0%) had herpes simplex virus (HSV) infections in their visceral organs. Another one patient was diagnosed as HSV hepatitis through necropsy of liver. The nine patients (five of them were male) ranged in age from 34 to 70 years (mean, 58). Four patients had non-Hodgkin's lymphoma, and the other included one with adult T-cell leukemia, one with multiple myeloma, one with idiopathic interstitial pneumonia and one with bronchial asthma, however, one did not have any underlying disease. Two patients died of HSV fulminant hepatitis and one died of HSV diffuse interstitial pneumonia. The most commonly involved organ was esophagus (7/8), followed by tongue (5/8), liver (3/9), spleen, pancreas, lymph node (2/8), and lung, adrenal, tonsil (1/8). Typical herpetic changes such as ballooning degeneration of cells, multinucleated giant cells, ground-glass nuclei and Cowdry type A intranuclear inclusions were observed at the margin of the ulcer or coagulation necrosis. Indirect immunoperoxidase stain revealed HSV-1 antigen in all of the 9 cases, HSV particles were demonstrated in 2. Seven patients had concomitant infections with one or more pathogens in addition to HSV, which included cytomegalovirus in 5, aspergillus in 4, candida in 3 and bacteria in 3.
A 16 year old girl with ulcerative colitis developed hepatitis with a high fever, leukopenia and a marked rise in serum transaminases without jaundice. There were no skin, oral, or genital lesions. Liver biopsy was precluded by abnormalities in coagulation. Postmortem examination of the liver by light and electron microscopy, culture, immunoperoxidase and immunofluorescent staining confirmed the diagnosis of hepatitis due to type 1 herpes simplex virus. Despite the rarity, this viral aetiology should be included in the differential diagnosis of all patients with severe hepatitis. The absence of mucocutaneous lesions should not exclude the diagnosis, especially when other clinical features are compatible.
Herpes simplex viral (HSV) hepatitis is uncommon in adults. Two new cases are reported herein; a literature review revealed
an additional 33 patients. Ages ranged from 13 to 87 years; the mean age was 32.6 years, and the median was 28 years. HSV
hepatitis usually occurs as part of disseminated HSV infection and is characterized by fulminant hepatic necrosis with serum
transaminase levels frequently elevated 100- to 1,000-fold. Disseminated intravascular coagulation was present in 90% of the
cases. Outcome was poor; 86% of the patients died. Eighty-six percent of the patients had an underlying condition associated
with impaired host defenses. Renal transplantation (26%), steroid use other than in renal transplant patients (26%), and pregnancy
(23%) were the most frequent underlying conditions. Early recognition and prompt initiation of antiviral therapy may offer
a chance for improved survival rates.
Herpes simplex virus hepatitis in pregnancy was first reported in 1969. Seven other cases have since been reported, and this communication describes two additional cases. The clinical presentation and laboratory profiles of these two cases parallel those described. Unreported, however, is the sharp contrast between the presentation of pregnant patients with herpes simplex virus hepatitis and the presentation of pregnant patients with other life-threatening forms of hepatitis. Nine of ten patients reported to date have been anicteric with peak total bilirubin levels of less than 1.3 mg/dL before cesarean section or laparotomy. That this presentation may not be unique to pregnancy is suggested by three case reports of fatal, anicteric herpes simplex virus hepatitis in previously healthy, nonpregnant adults. The cause of this phenomenon is unknown.
A case is described of herpetic hepatitis in a pregnant woman with primary herpetic stomatitis. Intranuclear inclusion bodies and virus particles were found in hepatocytes, and herpes virus was isolated from a liver biopsy and from oral swabs but not from blood. From rising titres of neutralizing and complement-fixing antibody it is concluded that the oral infection was a primary one. Factors predisposing to the hepatitis are discussed.
In this article the authors attempt to explain the immunologic alterations occuring in the mother with regard to the immunology of the maternal-fetal interaction. A number of mechanisms have been proposed to explain the nonrejection of the fetus and placenta, recently summarized by Beer et al.
To determine whether abnormalities in T-cell subsets might help to explain the immunodeficient state in pregnancy, we used monoclonal antibodies to enumerate the proportion and absolute number of subsets of T cells and other peripheral-blood mononuclear cells from normal pregnant women, post-partum women, and newborns. We found a significant decrease in relative and absolute numbers of helper T lymphocytes (T4+ cells) throughout pregnancy. Normalization of T4+ cells occurred during the third to fifth month post partum. Our findings support previous evidence of maternal immunodeficiency during pregnancy and indicate that it may occur because of a reduction in the population of helper T cells.
During the last 31 months, 50 children between 3 months and 15 years of age have undergone living related liver transplantation (LRLT) for end-stage liver diseases (39 biliary atresia, 2 Budd-Chiari syndrome, 2 progressive intrahepatic cholestasis, 3 liver cirrhosis, 1 Wilson disease, 1 protoporphyria, 1 tyrosinemia, and 1 fulminant hepatitis). Combined FK-506 and low-dose steroids were routinely used for immunosuppression. There were seven deaths, two of which were related to infection (Candida pneumonia and Epstein-Barr virus [EBV]-associated lymphoproliferative syndrome [LPS]). Five patients had a bacterial infection, all of which were associated with surgical complications. Three patients had Candida infection, all of which were malnourished, had biliary atresia, and had been managed with prolonged antibiotics against obstinate ascending cholangitis. There were 14 symptomatic viral infections (1 herpes simplex virus, 1 herpes zoster virus, 5 cytomegalovirus [CMV], 6 EBV, and 1 EBV-associated LPS). Three of the five CMV infections appeared in patients whose graft was ABO-incompatible, who were managed with prophylactic OKT-3. Most of the viral infections (except 1 EBV-associated LPS) were minor and were treated successfully. The low incidence and successful treatment of CMV infection are related to the high compatibility and low incidence of allograft rejection in LRLT. Bacterial and fungal infections can be decreased by greater refinement of surgical technique and more aggressive preoperative management. Treatment of EBV infection is still an unsolved problem.
Hepatitis due to herpes simplex virus (HSV) developed in a pregnant women at 38 weeks' gestation. She delivered a live-born infant who had serologically documented HSV 2 infection but did well with acyclovir therapy. The mother, however, died five days postpartum from fulminant hepatic failure despite antiviral treatment, and HSV was demonstrated in the liver. Twenty-three reported cases clearly establish pregnancy as a condition that can predispose to disseminated HSV infection. The majority of cases have been due to HSV 2, and primary infection in the latter part of pregnancy appears to constitute the greatest risk. The major disease manifestations appear to be hepatitis and encephalitis. Historically, maternal and fetal mortality rates have been high, but there is a trend toward improved survival in the acyclovir era.
Fulminant hepatitis due to herpes simplex virus (HSV) in adults is a rare and deadly disease. We describe a 23-year-old woman with a 20-year history of Crohn's disease (CD) who was hospitalized with an acute febrile illness and diarrhea. A computed tomography (CT) scan of the abdomen demonstrated an intramural sigmoid colon abscess and multiple abscesses in the liver. Despite high-dose parenteral corticosteroids and broad-spectrum antibiotics, the patient remained acutely ill, with high fever and markedly elevated serum transaminase levels, but no jaundice. Sigmoid resection and wedge liver biopsy were performed at laparotomy. Histologic examination documented HSV-type intranuclear inclusions and inflammation with necrosis in both the sigmoid colon and liver specimens. The patient subsequently died despite parenteral acyclovir treatment. Although rare, fulminant hepatitis due to HSV simplex virus should be considered in the differential diagnosis of all patients with severe hepatitis. Of special note, the necrotizing liver lesions may be mistaken for pyogenic abscesses on CT scan.
With the aim of evaluating liver disturbances after BMT in 76 patients, the hepatic venous pressure gradient was measured and a transvenous liver biopsy was performed through the jugular vein. Catheterization was successful in 71 patients (93%). In 11 cases the procedure was performed twice, yielding a total number of 82 studies. In five (6%) liver biopsies were non-evaluable. Complications were rare (7%), minor and reversible. As a result of this procedure, the diagnosis was modified in 45%, with both the diagnosis and treatment being modified in 30% of patients. Veno-occlusive disease (VOD) was histologically demonstrated in 15 out of 26 patients (58%) in whom this complication was suspected and in two out of 33 (6%) in whom it was not. Acute GVHD of the liver was confirmed in 15 out of the 35 patients (43%) in whom this complication was suspected and in four of 24 (17%) in whom it was not. The hepatic venous pressure gradient was significantly higher in VOD than in liver GVHD. Whereas 14/17 (82%) patients with VOD had a gradient pressure higher than 9 mmHg, no patient with GVHD had a gradient above this value. We conclude that transjugular liver biopsy is an effective, safe, and useful technique to evaluate BMT related liver dysfunction.
Liver transplantation is the therapeutic choice for fulminant hepatic failure in children.
All 66 cases of fulminant hepatic failure in the pediatric population seen at UCLA from May, 1985 to November, 1993 were reviewed to determine changes in survival rates since the advent of liver transplantation. We evaluated the clinical course and events leading to the exclusion of surgical management of nonsurvivors, who otherwise would have benefited from a liver transplant. We also compared the latter's clinical course with the nontransplant survivors to determine parameters for screening patients for liver transplantation.
Fifty-one patient (77%) were put on the transplant list initially but eventually, only 38 (58%) patients underwent orthotopic liver transplantation (OLT) and of these 30 (79%) patients survived. Of the remaining 29 (42%) patients who did not undergo liver transplantation, only 10 (36%) patients survived. Nine patients died while waiting for a donor liver secondary to complications of hepatic failure. The majority of nonsurvivors in the OLT and no-OLT groups succumbed because of irreversible neurologic deterioration. In the no-OLT group, comparisons between survivors and non-survivors were made. There were no significant demographic differences. It took a mean of 8 days (+/-8) versus 22 days (+/-15), (p = 0.009), from onset of illness to first hospital admission for survivors and nonsurvivors, respectively. Time to reach stage II encephalopathy was a mean of 5 days (+/-5) for survivors versus 18 days (+/-16), (p = 0.05) for nonsurvivors. Nonsurvivors were transferred to the transplant center at a mean of 12.2 days (+/-12) after being first admitted elsewhere as compared to a mean of 1.9 days (+/-18) for survivors, (p = 0.02). Mean prothrombin time decreased by a mean of 13.4 s/day (+/-16) for survivors as against 2.25 s/day (+/-6) for nonsurvivors, (p = 0.06). Mean peak total bilirubin for nonsurvivors was 460 mumol/L (27 mg/dl) versus 220 mumol/L (13 mg/dl) for survivors, (p = 0.06). Nonsurvivors died at a mean of 30 days (+/-19) from onset and survivors' liver tests started to improve at a mean of 11 days (+/-9) from onset.
From these studies, we conclude that liver transplantation remains the therapeutic choice for fulminant hepatic failure in children. Early referral and closer follow-up is necessary for timely admission to liver transplant centers to enable screening and proper preparation of these patients for liver transplantation.
Hepatitis due to Herpes Simplex Virus (HSV) is a rare and severe infection in patients with impaired immunity, as bone marrow transplanted. The antemortem diagnosis is often difficult to establish because the clinical features are nonspecific. We report an uncommon cause of fulminant hepatic failure in a neutropenic patient, 14 days after bone marrow transplantation. HSV-2 fulminant hepatitis occurred during acyclovir prophylactic treatment. No observation of HSV hepatitis in this context has been reported since prophylaxis is used. Because of the extremely high apparent mortality associated with HSV hepatitis, and the improved survival noted among the non-marrow-transplant recipients and prolonged survival seen in one marrow transplant recipient, it seems reasonable to urge early and aggressively acyclovir therapy. A liver biopsy seems to be indispensable in the case of hepatic failure in post-marrow-transplantation in order to make rapidly a diagnosis.
Herpes simplex virus (HSV) hepatitis is a rare complication of HSV infection with a high reported mortality rate in untreated patients. The authors present a case of HSV hepatitis in a 26-year-old female with focal proliferative lupus nephropathy who was status post one cycle of pulse high-dose (1 gm/ m2) cyclophosphamide. Treatment with parenteral acyclovir was successful. A meta analysis of well-documented cases of HSV hepatitis treated with acyclovir, excluding those that omit initial serum concentrations of hepatic transaminases, suggests that the early administration of parenteral acyclovir may have been instrumental in the achievement of a successful outcome, and that a patient's serum levels of hepatic transaminases at the time of treatment initiation may predict outcome. This is the first reported case of successful parenteral acyclovir treatment of HSV hepatitis in a patient with lupus nephritis who has recently undergone cyclophosphamide immunosuppression, and includes a meta analysis to examine the hypothesis that initial markers of hepatic injury may predict outcome of acyclovir treatment.
Herpes simplex virus hepatitis (HSV hepatitis) is an uncommon and severe complication of HSV type 1 and HSV type 2 infection. HSV hepatitis affects mostly immunocompromised patients. We report the case of a young man without any previous known immunodeficiency who developed fatal HSV hepatitis in the first 8 days of oral corticotherapy given for ulcerative colitis. A prompt diagnosis was possible because HSV was recovered from peripheral blood leukocytes.
Hepatitis due to herpes simplex virus (HSV) is a potentially fatal disorder that is often not considered in the differential diagnosis of acute hepatitis. This disease occurs most often in patients with impaired immunity and is very uncommon in healthy patients. HSV hepatitis presents with a wide clinical spectrum, and the clinical diagnosis is difficult. We describe a case of disseminated herpes virus infection with fulminant hepatitis mimicking an acute human immunodeficiency virus infection in a 33-year-old healthy man. Preliminary studies suggest that early treatment of HSV hepatitis with acyclovir may be beneficial in these patients. A high index of suspicion and the availability of early diagnostic tools, such as HSV DNA detection, may dramatically improve the clinical outcome of severe HSV hepatitis.
Fulminant hepatic dysfunction in the third trimester of pregnancy accompanied by fever may result from disseminated herpes simplex virus. Since 1969, 24 cases of herpes simplex hepatitis, including the current case, have been reported. Mucocutaneous lesions are present in only half of cases; therefore, suspicion for diagnosis of this disease is low. Twenty-five percent of cases were not diagnosed until autopsy. Maternal and perinatal mortality are high, approaching 39 percent for both mother and fetus. Early recognition with initiation of antiviral therapy appears to be most important in maximizing survival.
Although exceedingly rare, fulminant hepatic failure (FHF) in immunocompetent patients can develop with primary or recurrent infection due to herpes simplex virus (HSV). The diagnosis is frequently obscured by the absence of mucocutaneous involvement. Elevated transaminase values with leukopenia and a relatively low bilirubin level may provide clues to the diagnosis. We describe an immunocompetent woman who died of FHF before a definitive diagnosis of HSV type 2 hepatitis was established. Herpes simplex virus hepatitis is one of the few causes of FHF for which potentially effective therapy is available. Thus, early diagnosis is paramount and usually requires liver biopsy. Recent studies suggest that transjugular liver biopsy is safe and effective in establishing the cause of FHF. Since the diagnosis and management of FHF are frequently influenced by the results of transjugular liver biopsy, it may become a standard diagnostic tool for managing FHF in centers where such expertise exists.
Herpes simplex-induced fulminant hepatitis is an infrequently reported cause of hepatitis in adults. Pregnant females and patients with impaired cellular immunity may be at increased risk, although healthy adults have been affected. The diagnosis may be underrecognized due to nonspecific presenting symptoms and lack of typical cutaneous herpes lesions. We present three cases of fatal herpes simplex fulminant hepatitis. Our review of case reports of herpes simplex hepatitis in adults demonstrates improved survival with intravenous acyclovir therapy. We believe that empiric use of acyclovir should be considered while the diagnostic evaluation of non-acetaminophen-induced fulminant hepatitis is underway. Recognition of characteristic liver function abnormalities seen with fulminant herpes simplex hepatitis include marked elevation of transaminases with AST > ALT and a mild hyperbilirubinemia (anicteric hepatitis), and they should prompt acyclovir therapy. This is especially true when there are no obvious risk factors for other forms of hepatitis.
Liver transplantation is now accepted as effective therapy in the treatment of acute and chronic hepatic failure. Improvements in surgical techniques and immune suppression have led to 5-year survival rates that exceed 70% in most centers. The success of transplantation has led to a dramatic increase in the number of candidates to over 14,000 places on the national waiting list. While the number of patients in need of transplantation increases, there has been little growth in the supply of available cadaveric organs, resulting in an organ shortage crisis. With waiting times often exceeding 1 to 2 years, the waiting list mortality now exceeds 10% in most regions. Several novel approaches have been developed to address the growing disparity between the limited supply and excessive demand for suitable organs.
Nucleoside analogues such as acyclovir and ganciclovir have been the mainstay of therapy for alphaherpesviruses (herpes simplex virus (HSV) and varicella-zoster virus (VZV)) and cytomegalovirus (CMV) infections, respectively. Drug-resistant herpesviruses are found relatively frequently in the clinic, almost exclusively among severely immunocompromised patients receiving prolonged antiviral therapy. For instance, close to 10% of patients with AIDS receiving intravenous ganciclovir for 3 months excrete a drug-resistant CMV isolate in their blood or urine and this percentage increases with cumulative drug exposure. Many studies have reported that at least some of the drug-resistant herpesviruses retain their pathogenicity and can be associated with progressive or relapsing disease. Viral mutations conferring resistance to nucleoside analogues have been found in either the drug activating/phosphorylating genes (HSV or VZV thymidine kinase, CMV UL97 kinase) and/or in conserved regions of the viral DNA polymerase. Currently available second line agents for the treatment of herpesvirus infections--the pyrophosphate analogue foscarnet and the acyclic nucleoside phosphonate derivative cidofovir--also inhibit the viral DNA polymerase but are not dependent on prior viral-specific activation. Hence, viral DNA polymerase mutations may lead to a variety of drug resistance patterns which are not totally predictable at the moment due to insufficient information on specific drug binding sites on the polymerase. Although some CMV and HSV DNA polymerase mutants have been found to replicate less efficiently in cell cultures, further research is needed to correlate viral fitness and clinical outcome.
Viral hepatitis has previously been the major cause of acute liver failure (ALF) in the United States. We aimed to determine the incidence of viral hepatitis-related ALF and to compare the outcome and clinical and biochemical variables in patients with hepatitis A and B.
A total of 354 patients with ALF from multiple centers were screened for possible acute viral etiology.
Forty-three patients (12.1% of all ALF cases) had acute viral hepatitis: hepatitis A (n = 16), hepatitis B (n = 26), and herpes simplex virus infection (n = 1). There was no difference between groups with regard to age, gender, body mass index, admission or peak coma grade, symptom duration, admission mean arterial pressure, temperature, or biochemical liver tests, creatinine, arterial pH, or rate of infections. Platelet count was significantly higher in hepatitis A patients than in hepatitis B patients. The transplantation-free (spontaneous) survival rate was significantly higher for hepatitis A patients (69%) than for hepatitis B patients (19%, p = 0.007), whereas the liver transplantation rate was higher in hepatitis B patients (62%) than in hepatitis A patients (19%, p = 0.017). Spontaneous survivors had significantly higher mean arterial pressure, higher platelet count, and lower AST/ALT ratio than patients who did not survive spontaneously.
Viral hepatitis now comprises only one-eighth of all ALF cases in the United States. The marked difference in spontaneous survival between hepatitis A and B cannot be explained by the severity of hepatic dysfunction on admission but may rather be an inherent feature of the infections or a bias toward transplanting patients with hepatitis B.
Acute hepatitis with severe hepatic failure is an uncommon manifestation of herpes simplex virus (HSV) infection. It has been described in both immunocompromised and immunocompetent patients and is usually fatal. Due to the better survival after acyclovir treatment in a few reported cases, physicians need to be aware of the characteristic clinical abnormalities so that early diagnosis and treatment can be implemented. The authors describe an adolescent diagnosed with Hodgkin disease who developed fatal hepatic failure secondary to acute HSV. Typical signs and symptoms in patients at risk, when there is no other obvious cause of fulminant hepatitis, should lead to early empirical treatment with acyclovir.
Herpes virus hepatitis (HSV) represents a form of acute necrotizing hepatitis, which most frequently develops in immunocompromised patients. Therapeutic options include high-dose intravenous acyclovir and liver transplantation. We report the first case of recurrent HSV hepatitis after liver retransplantation, which occurred despite continuous administration of high-dose intravenous antiviral therapy. Because explant histology pointed to initial therapy response, we thought that the reason for recurrence might be due to acyclovir resistance. Most acyclovir resistance is caused by inactivating mutations in the herpes virus thymidine kinase gene. HSV infection was detected by histology and proofed by immunohistochemistry. PCR amplification of the herpes virus thymidine kinase gene was performed on histology specimens to demonstrate the course of viral infection in liver tissue. Genotypic resistance testing of the herpes virus was performed by sequencing the thymidine kinase amplicon. In serial biopsy, HSV-DNA sequences were only detectable when histology revealed herpes hepatitis. Whereas the primary explant exhibited the wild-type thymidine kinase gene, a biopsy of the second graft one month after retransplantation, which showed recurrent herpes virus hepatitis, had a single base insertion within a homopolymeric cytosine stretch. This mutation causes a frame shift leading to a premature stop codon and results in a known acyclovir-resistant herpes strain. In conclusion, we believe that testing for acyclovir-resistant herpes strains should be considered in high-risk patients in whom viral clearance is not achieved serologically to prevent fatal recurrence of disease by using antiviral drugs such as inhibitors of HSV-DNA polymerase or viral helicase primase inhibitors.
We report 5 cases of acute liver failure related to herpes simplex (HSV) infection in 1 immunocompetent and 4 immunosuppressed patients. One patient was too ill for liver transplantation indication. Three patients, among the 4 listed, underwent liver transplantation. Three patients died 11 days to 1 year after transplantation and 2 patients died 2 to 3 days after admission. All presented with fever and none with skin lesions. The diagnosis of HSV-related hepatitis was made antemortem in only 2 patients on the basis of positive blood cultures and/or immunohistochemic findings. In the remaining patients, HSV diagnosis was made retrospectively on further histologic and virologic investigations. Primary HSV infection was certain or likely in all cases, including an HSV2 superinfection of an anti-HSV1-positive patient and two HSV superinfections of hepatitis B virus (HBV)-related chronic liver disease. In these latter patients, HSV diagnosis was totally unsuspected, despite fever. HSV superinfection has significantly contributed to liver dysfunction aggravation and death. In conclusion, the diagnosis of HSV hepatitis is difficult to establish in the absence of specific clinical signs. This may suggest the need for early administration of acyclovir in patients with suspected HSV hepatitis, without waiting for virologic confirmation. Diagnosis methods providing fast results (real-time polymerase chain reaction [PCR]) should be implemented.
Herpes simplex virus (HSV) is seen throughout the world and can be treated with acyclovir. We present a case of fulminant hepatic failure (FHF) as a result of disseminated HSV infection in a pregnant patient during the second trimester.
The medical records of a patient suffering from HSV-related fulminant hepatic failure were collected. A review of the literature was collected and reported.
A previously healthy female presented with fulminant hepatic failure at a local emergency room complaining of a 5-day history of fever, nausea, vomiting, and right side abdominal pain that radiated to the back. She was diagnosed with fulminant hepatic failure and progressed into a coma. The patient underwent orthotopic liver transplantation (OLT) prior to the diagnosis of HSV and then treated successfully with acyclovir.
Treatment of HSV fulminant hepatitis is dependent up on early suspicion and prompt intervention. In addition, antiviral therapy may need to be lifelong.
Following thorascopic thymectomy performed because of myasthenia gravis, a 25-year-old man was affected by fulminant hepatic failure (FHF) of unknown etiology. He was then transferred to our department, where his clinical situation worsened with the onset of renal failure, shock, coagulopathy and coma. Given the young age of the patient, the immediate availability of a donor, and the absence of a definite diagnosis of sepsis at the time, it was decided to proceed with liver transplantation. The results of a polymerase chain reaction (PCR) test (a technique that was unavailable at the referring hospital), which arrived only a few hours later, indicated the presence of herpes simplex virus (HSV) DNA in several of the patient's samples; this led to the formulation of a diagnosis of FHF due to HSV. It is worth noting that HSV-IgM and HSV-IgG assays had always been negative in this patient. Despite acyclovir therapy with initially encouraging clinical results, the patient died several days later because the viral infection had spread to the graft, lungs, heart, spleen, stomach and kidneys. Since evaluating antibody response is not always useful in diagnosing HSV infection, and particularly if PCR methodology is unavailable, it is worth initiating early empiric antiviral therapy when the etiology of FHF is indeterminate This is because the timeliness of treatment while awaiting virological confirmation may be critical to survival. If a liver transplantation becomes mandatory, careful consideration should be given to the extent of the viral infection and its response to therapy because of the possibility of viral spread to the graft.
Hepatitis is a rare complication of herpes simplex virus (HSV), often leading to acute liver failure (ALF), liver transplantation (LT), and/or death. Our aim was to identify variables associated with either survival or progression (death/LT), based on an analysis of cases in the literature and our institution. A total of 137 cases (132 literature, 5 institutional) of HSV hepatitis were identified. The main features at clinical presentation were fever (98%), coagulopathy (84%), and encephalopathy (80%). Rash was seen in less than half of patients. Most cases (58%) were first diagnosed at autopsy and the diagnosis was suspected clinically prior to tissue confirmation in only 23%. Overall, 74% of cases progressed to death or LT, with 51% in acyclovir-treated patients as compared to 88% in the untreated subjects (P=0.03). Variables on presentation associated with death or need for LT compared to spontaneous survival: male gender, age>40 yr, immunocompromised state, ALT>5,000 U/L, platelet count<75x10(3)/L, coagulopathy, encephalopathy, and absence of antiviral therapy. In conclusion, HSV hepatitis has a high mortality and is often clinically unsuspected. Patients who are male, older, immunocompromised, and/or presenting with significant liver dysfunction are more likely to progress to death and should thus be evaluated for LT early. Based on the frequent delay in HSV diagnosis, low risk-benefit ratio, and significantly improved outcomes, empiric acyclovir therapy for patients presenting with ALF of unknown etiology is recommended until HSV hepatitis is excluded.