Liver Disease Associated with Non-Hepatitis Viruses

Introduction

The liver is a highly perfused organ and the first filter for blood coming from the intestines. Thus, the liver is particular prone to become involved in blood-borne infections. Apart from the so-called hepatitis viruses, many other viruses, primarily targeting other extrahepatic tissues, also lead to liver damage and hepatitis. Damage can range from asymptomatic elevations of aminotransferases to fulminant hepatic failure depending on the virus and the host's immune response. When the immune system controls infection poorly, direct infection of hepatocytes and liver necrosis may occur. This situation applies to patients under severe immunosuppression or infections with particularly virulent agents such as the viruses that cause hemorrhagic fevers.

Alternatively, liver cells may become victims of collateral damage without direct infection when cytolytic CD8 + T effector lymphocytes are expanded outside the liver and then recruited via liver-resident macrophages such as Kupffer cells presenting viral antigens ( Polakos et al., 2006 ; Schumann et al., 2000 ). This type of liver damage is particularly associated with respiratory viruses such as influenza virus. However, since many viral infections expand CD8 + T lymphocytes, this by-stander mechanism may affect the liver more often ( Murali-Krishna et al., 1998 ).

Here, we provide a brief overview over viral infections primarily not designated as hepatitis viruses which may lead to liver disease and hepatic complications. This overview will largely focus on the hepatic aspects of viral infections. Thus, readers interested in more detailed information should consult a comprehensive textbook in microbiology or clinical infectious diseases.

Virus-Induced Liver Necrosis and Viral Hemorrhagic Fevers

General Comments

Approximately 8% of travelers to the developing world require medical care during or after travel, and fever is the underlying problem in 28% of them ( Wilson et al., 2007 ). Physicians evaluating returned travelers frequently suspect rare or exotic diagnoses. Although exotic diseases, in particular viral hemorrhagic fevers are a severe threat in certain regions of the world, liver disease due to exotic infections such as Ebola virus, Rift valley fever or Lassa fever have been reported only sporadically but do not represent a frequent health problem in returning travelers.

Viral hemorrhagic fevers share some epidemiological and clinical features and cause rather similar liver pathology. Most viruses are transmitted via arthropod vectors. The viruses cause small vessel damage in multiple organs resulting in overt hemorrhage. The spectrum of diseases and their geographical distribution are listed in Table 1 . Much attention has been paid to abnormal liver function and altered hepatic pathology. Nevertheless, clinically significant liver disease or death from liver failure are rare complications except in yellow fever. Table 1 Viral hemorrhagic fevers affecting the liver Table 1 Disease Virus family Geographical regions Dengue fever Flaviviridae Africa, Asian, tropical America Yellow fever Flaviviridae Africa, Southern America Lassa fever Arenaviridae Western Africa Argentinian hemorrhagic fever Arenaviridae (Junin virus) Argentina Ebola Fever Filoviridae Central and Western Africa Marburg fever Filoviridae Central and South Africa Rift Valley fever Bunyaviridae Eastern and Central Africa Kongo-Krim Hemorrhagic fever Bunyaviridae Former Soviet union, Central and Western Asia Africa Hemorrhagic fever with renal failure Bunyaviridae Northern Europe and Asia Chikungunya fever Togaviridae Western Africa, Southeast Asia, Oceania, Southern, Europe

Dengue fever is among the top three etiological agents, accounting for approximately 6% of febrile illnesses in the traveler ( Wilson et al., 2007 ). Of note, although malaria is the leading cause of systemic febrile illness worldwide, apart from Sub-Saharan Africa and Central America travelers returning from tropical or sub-tropical regions had Dengue fever more frequently than malaria. Chikungunya fever is an emerging novel virus infection recently expanding in Asia and Africa, which also causes fever, myalgia, arthralgia and skin rash in increasing numbers of patients.

Dengue-Fever

Risk factors and epidemiology

The dengue virus complex comprises four antigenically related but distinct Flaviviruses termed dengue virus serotypes 1 through 4 (DEN-1 to DEN-4). Dengue viruses are transmitted by Aedes aegypti mosquitos in epidemic and endemic outbreaks and cause acute infections. Three to six days after a mosquito bite the virus spreads via the blood-stream, and among the various organs it can be isolated frequently from liver samples ( Rosen and Khin, 1989 ).

Clinical presentation

Dengue virus infection usually causes a flu-like illness with a rash—dengue fever ( Fig. 1 ). Hepatomegaly and elevated serum aminotransferases, which are usually mild, are common in dengue virus infections ( Wahid et al., 2000 ). Clinically more severe diseases, for example, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) can follow from secondary infection with dengue virus of different serotype. In 2009, the World Health Organization issued new guidelines and introduced a revised classification scheme consisting of the following categories: dengue without warning signs, dengue with warning signs, and severe dengue ( World Health Organization, 2009 ). However, there are no reliable warning signs for severe dengue. Fig. 1 Dengue virus infection. Hyperemic rash in a patient with dengue fever. Fig. 1

In DHF there are widespread petechial hemorrhages together with multiple organ damage; in DSS, which mostly affects children below the age of 15, there is extensive capillary leakage and severe fluid depletion leading to hypovolemic shock. If untreated, mortality approaches 50%. In fatal cases of DHF the liver is enlarged, pale from steatosis and shows multifocal hemorrhages.

Diagnosis

Laboratory diagnosis of dengue virus infection is done by detection of viral components, for example, PCR in serum or indirectly by serology. The sensitivity of each approach depends on the duration and course of the patient's illness when the patient presents for evaluation.

Therapy

Currently vaccines against dengue virus are being developed but have not become licensed, yet. There is no direct antiviral therapy available against the dengue viruses. Thus, treatment is supportive, requiring meticulous fluid management and intensive care in DSS. Details for treatment are summarized in recent WHO guidelines ( World Health Organization, 2012 ).

Chikungunya-Fever

Risk factors and epidemiology

Chikungunya is an arthropod-borne Toga virus initially endemic to West Africa, which next spread to the Indian Ocean islands and Southeast Asia ( Charrel et al., 2007 ). Chikungunya fever was originally considered a disease of tropical and subtropical regions, until an outbreak in Northern Italy was recorded in 2007 ( Rezza et al., 2007 ). Since then chikungunya infections have become exported to other Western countries, the Americas and Caribbean region via international travel. Of note, dengue and Zika viruses are transmitted by the same mosquito vectors as chikungunya. Thus, the viruses can co-circulate in the same geographic region, and coinfections have been documented. Transmission of chikungunya via blood products has been reported in France, where a nurse was infected by exposure to blood from an infected patient. Chikungunya, might also be transmitted inadvertently by organ transplantation since viremia can exceed high levels prior to onset of symptoms.

Clinical presentation

The infection begins abruptly with high fever, symmetric polyarthralgia and macular or maculopapular skin rash ( Taubitz et al., 2007 ). Pruritus and bullous skin lesions have also been described. Previously chikungunya fever has been considered a self-limited disease. However, severe complications also comprising acute viral hepatitis and deaths have been reported in the recent outbreaks; particularly in elderly patients (> 65 years) and people with pre-existing chronic medical problems. Some patients have persisting symptoms for a variable length of time after the acute illness. Manifestations include arthritis/arthralgia, edematous polyarthritis of fingers and toes, morning pain and stiffness, and severe tendosynovitis.

Diagnosis

Clinically chikungunya fever must be differentiated from dengue fever, which shares many symptoms and features. The diagnosis of chikungunya virus infection should be suspected in a patient with acute onset of fever and polyarthralgia who had possible exposure by travel to or residency in an epidemiological risk area. The diagnosis of chikungunya is established by detection of Chikungunya viral RNA via real-time reverse-transcription polymerase chain reaction (RT-PCR) or Chikungunya virus serology ( Pan-American Health Organisation, 2017 ). Chikungunya IgM antibodies become detectable by ELISA 5 days after the onset of symptoms. For certain regions simultaneous testing for dengue and Zika virus infection is recommended.

Therapy

There exists no specific antiviral therapy for acute chikungunya virus infection. Treatment consists of supportive care and includes rest, fluid replacement, and eventually the use of nonsteroidal antiinflammatory drugs (NSAIDs) or acetaminophen to relieve pain and fever. In patients suspected to have dengue virus coinfection NSAIDs should be avoided before the patient becomes afebrile for > 2 days, in order to avoid bleeding complications associated with severe dengue virus infection. Chikungunya infection cannot be prevented by vaccination.

Hanta-Viruses

Risk factors and epidemiology

Hanta viruses are examples of emerging viruses, which belong to the genus Hantavirus within the Bunyaviridae family. They are negative-sense single-stranded RNA viruses, primarily harbored in rodents and shed in rodent urine, saliva and feces. The virus is inhaled by man as aerosols from dried rodent excreta, or in unusual circumstances, transmitted by bites ( Nichol et al., 2000 ). Hantaviruses exist in multiple serotypes worldwide, which differ in their virulence. Some are considered apathogenic, while certain isolates can produce two distinct severe syndromes in humans: the Hanta virus cardiopulmonary syndrome, mostly due to isolates in the Americas; and the hemorrhagic fever with renal syndrome caused by isolates (Seoul virus, Dobrava virus, Puumala virus, Hantaan virus) in Europe and Asia ( Plyusnin et al., 2001 ).

Clinical presentation

In some instances, patients with Hanta virus hemorrhagic fever suffered from severe acute hepatitis, whereas renal damage was rather mild (Wong et al., 1987; Chan et al., 1987 ; Lledó et al., 2003 ). Hanta virus has also been incriminated as a potential cause of cryptogenic hepatitis in Southwestern China. However, this hypothesis has not been confirmed by antibody studies in Japan. Hanta viruses, however, may still play some role, because Hanta virus infection has been observed to trigger autoimmune liver disease ( Yotsuyanagi et al., 1998 ). Thus, this mechanism may contribute to community-acquired hepatitis ( Martin et al., 2008 ). Nevertheless, the precise role of Hanta virus infections for human liver disease still awaits clarification.

Diagnosis

By the time symptoms are evident, patients uniformly have antiviral IgM antibodies and most have IgG antibodies. Diagnostic assays to detect Hanta virus antibodies include enzyme-linked immunosorbent assay (ELISA), immunoblot test (SIA), Western blot, indirect immunofluorescence (IFA), complement fixation, and hemagglutinin inhibition as well as neutralization assays.

Therapy

Hanta virus strains associated with hemorrhagic fever and hepatorenal syndrome are sensitive to ribavirin in vitro. A prospective, randomized, double-blind, placebo-controlled trial in the People's Republic of China reported a sevenfold decrease in mortality among ribavirin-treated patients with serologically confirmed Hanta virus disease ( Huggins et al., 1991 ). However, ribavirin appeared to be less effective in Hanta virus cardiopulmonary syndrome. Thus, it has not yet been approved, but nevertheless may be tried as rescue treatment in emergency situations ( Sidwell and Smee, 2003 ).

Yellow Fever Virus

Risk factors and epidemiology

Yellow fever is a member of the Flaviviridae family and constitutes a single-stranded plus strand RNA virus. It comprises a single conserved serotype and seven major genotypes reflecting distinct regions in West Africa, Central-East Africa and South America ( Vasconcelos et al., 2004 ; Barnett, 2007 ). Yellow fever virus is transmitted by a variety of different Aedes vectors and causes endemic and epidemic outbreaks in Africa and South America. Yellow fever can be prevented by vaccination, and thus, has become rare in travelers.

Clinical presentation

The spectrum of yellow fever virus infection ranges from subclinical infection to a life-threatening disease with fever, jaundice, renal failure and hemorrhage. Usually yellow fever initially presents as an acute, flu-like illness of sudden onset with fever, myalgia and headache, which cannot be distinguished easily from other acute infections such as severe malaria, leptospirosis, fulminant viral hepatitis or Dengue hemorrhagic fever.

Between 48 and 72 h after onset, aminotransferases start to rise in blood heralding the development of jaundice. The degree of liver abnormalities at this stage predicts the severity of liver disease during the course of the illness later on. Next, a period of apparent remission lasting up to 48 h may follow the initial infection. Patients with abortive infection recover at this stage. About 15% of patients will enter the third stage of intoxication characterized by the return of fever, prostration and organ dysfunction. Patients suffer from nausea, vomiting, or epigastric pain, and develop jaundice and oliguria. Bleeding can occur from the mouth, nose, eyes or stomach. Serum aspartate transferase (AST) levels usually exceed those of alanine transferase (ALT).

The outcome of yellow fever infection is determined during the second week after onset, when many patients either rapidly recover, while between 20% and 50% of the patients, who have progressed to the stage of intoxication, will ultimately die from circulatory shock. Convalescence may be associated with fatigue over several weeks, and occasionally jaundice and elevated aminotransferases may persist for months.

Diagnosis

The diagnosis of yellow fever is confirmed by demonstration of specific IgM by ELISA, by PCR or by isolating the virus from the blood. Polymerase chain reaction (PCR) testing in blood and urine can detect the virus in early stages of the disease. In later stages, testing to identify antibodies is recommended. Liver biopsies should be avoided due to a high risk of bleeding complications.

Therapy

There is currently no specific anti-viral drug to treat yellow fever but specific care to manage dehydration, liver and kidney failure as well as fever improves outcomes. Ribavirin inhibits yellow fever virus in vitro. However, the extremely high concentrations of the drug needed cannot be achieved in vivo. Recently there have been attempts to treat liver failure resulting from yellow fever infection by high urgency liver transplantation ( Song et al., 2019 ). However, outcomes after liver transplantation were mixed and the few survivors had frequent postoperative bacterial and cytomegalovirus infections.

A highly active attenuated live-vaccine is available, which induces seroconversion rates > 95% and provides a high level of protection. Due to potential risks associated with a live virus vaccine children below the age of 9 months, pregnant women and immunosuppressed individuals should not receive the vaccine, nor should subjects be vaccinated who are allergic to egg proteins. Infrequently two serious vaccine-related complications may occur: a form of encephalitis termed yellow fever-associated neurotropic disease and a syndrome resembling natural infection designated as yellow fever vaccine-associated viscerotropic disease.

Adenoviruses

Risk factors and epidemiology

Adenoviruses have a worldwide distribution and cause febrile diseases. Over 50 serotypes can be distinguished which are further subdivided into the six subgoups A through F. Typical syndromes comprise conjunctivitis, upper respiratory tract infections such as pharyngitis and coryza, pneumonia and otitis media. In young children an acute diarrheal illness is caused by subgroup F type 40 and 41 adenoviruses. Adenoviruses can persist in human tissue over prolonged periods ( Garnett et al., 2009 ), and can cause a variety of clinical syndromes in immunocompromised individuals including severe hepatitis ( Kojaoghlanian et al., 2003 ). In particular, transmission of latent adenovirus with the donated organ is a risk factor for adenoviral hepatitis in pediatric liver transplantation ( Michaels et al., 1992 ).

Clinical presentation

Adenoviral hepatitis occurs in congenital and acquired immunodeficiency syndromes and resembles severe necrotizing hepatitis associated with Herpes simplex virus infection. Patients develop extensive areas of liver cell necrosis ( Fig. 2 ), massively elevated aminotransferases, and a severe coagulopathy ( South et al., 1982 ; Janner et al., 1990 ; Krilov et al., 1990 ). Ultimately, outcomes may be fatal. Fig. 2 Adenoviral hepatitis. (A) Areactive necrosis of liver tissue in a HIV-positive patient with hepatitis. Hämatoxylin-Eosin (HE) stain. (B) Detection of adenovirus particles in the liver tissue by electron microscopy. (C) Necrotic tissue was visualized by computerized tomography in this patient. Fig. 2

Diagnosis

Liver biopsy specimens may reveal typical intranuclear inclusion bodies in necrotic areas of the liver, but biopsies carry an extremely high bleeding risk. Viral isolation and PCR techniques help to identify the causative viral strain.

Therapy

To date a proven therapy or vaccine to prevent adenoviral hepatitis does not exist, but ribavirin may be helpful in selected cases ( Wulffraat et al., 1995 ).

Liver Damage Associated With Respiratory Viruses

General Comments

Liver damage in fatal influenza has been considered immune-mediated, because high cytokine levels were detected ( Murali-Krishna et al., 1998 ; Peiris et al., 2004 ). Moreover, volunteers infected experimentally with intranasal influenza A/Kawasaki/86 (H1N1) transiently developed elevated aminotransferases ( Polakos et al., 2006 ). Since the rise in liver enzymes occurred after pyrexia had settled, it was concluded that the host's immune responses rather than viral infection caused damage to the liver. Immune mediated liver damage may also be the cause for elevated aminotransferases in other viral respiratory infections such as respiratory syncytial virus ( Peiris et al., 2004 ). However, cardiovascular failure and hepatic ischemia must be considered in as alternative factors in patients with severe respiratory infections ( Fig. 3 ) ( Eisenhut et al., 2004 ). Fig. 3 Ischemic damage of the biliary system resulting from hypoxia in severe influenza virus pneumonia. (A) Cytokeratin 7 staining reveals damaged intrahepatic bile ducts in patient who developed progressive intrahepatic cholestasis after severe influenza virus pneumonia requiring respiratory support. (B) Several weeks later ischemic type biliary damage (biliary strictures and sludge) becomes apparent in ERCP. Fig. 3

Influenza Viruses

Risk factors and epidemiology

Influenza viruses represent three genera in the Orthomyxoviridae family. Generally influenza A viruses is associated with more severe disease in humans than influenza viruses B and C. Influenza A is further subdivided with respect to genetic variation in its hemagglutinin (H) and neuraminidase (N) genes.

Clinical presentation

Influenza viruses commonly cause a self-limited acute respiratory infection with fever, rhinorrhea, sore throat and occasionally gastrointestinal symptoms. Therefore, aminotransferases are not monitored routinely. In the 2004 H1N5 influenza outbreak, however, about 60% of patients with pneumonia had deranged liver function tests with gastrointestinal symptoms such as vomiting, abdominal pain and diarrhea on initial presentation ( Yuen and Wong, 2005 ). Although molecular evidence for viral liver disease was not found, autopsy revealed hepatic centro-lobular necrosis in some cases ( To et al., 2001 ).

Diagnosis

In influenza virus infection the clinical presentation is dominated by fever and respiratory symptoms. The diagnosis be established by detecting viral antigen or antibodies, but nowadays the gold standard has become detection of viral RNA in throat washings by PCR.

Therapy

Influenza virus infection can be treated and prevented by neuraminidase inhibitors such as oseltamivir and zanamivir, which have been recommended especially for treatment in influenza H1N5 infection by the WHO in 2010 ( Schünemann et al., 2007 ). However, their benefit is limited due to the appearance of resistant isolates in recent outbreaks. A preventive vaccine is adapted annually to the circulating strains.

Coronaviruses

Risk factors and epidemiology

Severe acute respiratory syndrome (SARS) is caused by a novel coronavirus (SARS-coronavirus, SARS-CoV), which caused outbreaks of severe infections of the lung and gastrointestinal tract in the Far East and Canada ( Ksiazek et al., 2003 ; Drosten et al., 2003 ; Lee et al., 2003 ; Poutanen et al., 2003 ). There was also other organ involvement. Middle East Respiratory Syndrome Coronavirus (MERS-CoV) first appeared in the Arabian peninsula and meanwhile has occasionally been observed also in few travelers returning from risk areas. Apart from viral pneumonia other internal organs may become affected including hepatitis ( Alsaad et al., 2018 ), particularly when MERS-CoV hits patients with concomitant diseases, for example, diabetes mellitus. Sars-CoV and MERS-CoV have been detected in masked palm civets, dogs and cats as well as camel and thus represent zoonotic infections in man.

Clinical presentation

Approximately 25% of patients with SARS had elevated liver enzymes at the onset of infection, and further 45% of patients with normal liver enzymes at initial presentation developed elevated aminotransferases later on, so that overall up to 70% of patients showed elevated liver enzymes during their illness ( Booth et al., 2003 ; Choi et al., 2003 ; Wong et al., 2003 ; Chan et al., 2005 ). Jaundice was observed in < 10% of cases. In most patients aminotransferases started to rise toward the end of the first week and peaked at the end of the second week. With resolution of SARS aminotransferases normalized spontaneously in the majority of patients. Severe liver damage (ALT > 5 times the upper limit of normal) was observed more frequently in male patients, and those with significant other comorbidities or elevated serum creatinine levels ( Chan et al., 2005 ).

Diagnosis

Diagnosis of SARS-CoV and MERS-CoV infection is suspected in persons with typical symptoms who had contact to risk areas. The diagnosis is confirmed in certified specialized microbiology labs by PCR from respiratory fluids. Hygienic prevention measures have to be respected when handling samples and caring for patients with suspected coronavirus pneumonia.

Therapy

During SARS outbreaks both ribavirin and Kaletra (baby dose ritonavir/lopinavir) were tested as experimental therapy but showed limited success.

Infections by Herpesviruses

General Comments

Herpesviruses form a large family of DNA viruses, which comprises eight members that can cause disease in man ( Table 2 ). Herpes simplex virus (HSV), varizella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV) and Human Herpesvirus type 6 or 7 (HHV6, HHV7) can directly affect the liver and are infections in the human population usually acquired during childhood or adolescence. HHV8 can be transmitted sexually and presumeably also vertically from mother to child but has a more limited prevalence. In severely immunosuppressed patients HHV8 can cause Kaposi sarcoma and body cavity lymphoma. Herpesviruses persist life-long and can reactivate liver disease in immunosuppressed patients later on. Table 2 Human herpesviruses Table 2 Systematic name Common name Herpesvirus subfamily Estimated prevalence Route of transmission Human herpesvirus 1 Herpes simplex virus (HSV)-1 Alphaherpesvirinae 75%–>95% Oral secretions, close contact Human herpesvirus 2 HSV-2 Alphaherpesvirinae 4%–95% Genital secretions, close contact Human herpesvirus 3 Varicella zoster virus (VZV) Alphaherpesvirinae > 90% Aerosole, close contact Human herpesvirus 4 Epstein-Barr virus (EBV) Gammaherpesvirinae 70%–95% Oral secretions Human herpesvirus 5 Human Cytomegalovirus (CMV) Betaherpesvirinae 40%–95% Oral secretions, genital secretions Human herpesvirus 6 Human Herpes virus 6 (HHV6) Betaherpesvirinae > 85% Oral secretions Human herpesvirus 7 Human Herpes virus 7 (HHV7) Betaherpesvirinae > 85% Oral secretions Human herpesvirus 8 Kaposi Sarcoma associated Herpesvirus Gammaherpesvirinae 10%–25% Oral secretions, genital secretions

Herpesviruses Types 1–3 (Herpes simplex Virus, Varicella-Zoster Virus)

Risk factors and epidemiology

Primary herpes simplex infection produces characteristic oral (HSV-1) or genital (HSV-2) vesicular lesions. Symptoms can be severe with fever and malaise but primary infections are frequently asymptomatic. Fulminant hepatitis is a complication both of HSV-1 and HSV-2 infection ( Pinna et al., 2002 ). Organ transplantation and treatment for hematological malignancies are the most frequent underlying predispositions ( Johnson et al., 1992 ). Further individuals at risk include neonates, patients on steroids, HIV-infected patients, and patients with cancer or myelodysplastic syndromes ( Pinna et al., 2002 ; Johnson et al., 1992 ; Kusne et al., 1991 ; Zimmerli et al., 1988 ; Frederick et al., 2002 ). Rarely fatal HSV-hepatitis has also been reported in immunocompetent adults ( Goodman et al., 1986 ).

Varicella zoster virus (Herpesvirus type 3) causes chicken pox; and shingles when latent infection is reactivated. After primary infection there is replication of varicella zoster virus in the epithelia of gut, respiratory tract, liver and endocrine glands. Secondary viraemia then leads to infection of the skin and causes the typical rash. Liver disease is rare and limited to patients with severe immunodeficiency.

Clinical presentation

HSV-related hepatitis has a high (> 80%) mortality and resembles septic endotoxic shock; jaundice is not always present ( Kusne et al., 1991 ). Patients suffer from fever, anorexia, nausea, vomiting, abdominal pain, leucopenia, and coagulopathy. Typical oral or genital vesicular lesions may be present in only about 30% of patients ( Pinna et al., 2002 ). Some patients have disseminated further extrahepatic involvement, for example, lung, lymphnodes, spleen, and adrenal glands.

In severe varicella zoster virus infection hepatic lesions are similar to herpes simplex hepatitis. Varicella zoster virus has also been reported to trigger severe autoimmune type hepatitis ( Al-Hoamoudi, 2009 ).

Diagnosis

The diagnosis of HSV-related hepatitis must be rapidly established. Serologic assays are of little use. Herpes simplex and varicella zoster viruses are detected preferentially by the polymerase chain reaction ( Finström et al., 2009 ), or occasionally by viral isolation or immunofluorescence staining.

Therapy

Prompt systemic treatment with acyclovir reduces HSV-associated morbidity and serious complications in HIV-infected patients. Antiviral acyclovir prophylaxis has markedly reduced HSV re-activation after organ transplantation ( Seale et al., 1985 ; Pettersson et al., 1985 ). Acyclovir resistance occurs in about 5% of immunocompromised patients and is negligible (< 0.5%) in immunocompetent subjects ( Tyring et al., 2002 ). Valacyclovir is a prodrug of acyclovir, and famciclovir a prodrug of penciclovir, which have similar antiviral mechanisms as acyclovir. Thus HSV isolates resistant to acyclovir are also resistant to these drugs ( Levin et al., 2004 ). Cidofovir and foscarnet are alternative choices to treat acyclovir-resistant HSV but are less well tolerated ( Safrin et al., 1991 ). Treatment and prophylaxis of varicella zoster hepatitis is similar to herpes simplex viruses because acyclovir also inhibits replication of varicella zoster virus.

Cytomegalovirus (CMV)

Risk factors and epidemiology

In immunocompetent hosts cytomegalovirus (CMV) infection may be rather asymptomatic but occasionally causes transient minimally symptomatic acute disease. Congenital cytomegalovirus infection occurs in < 2% of newborns and is encountered in mothers with primary CMV infection or CMV re-activation during pregnancy. Approximately 10% of neonates with congenital CMV-infection show hepatosplenomegaly and jaundice at birth ( Kylat et al., 2006 ). When newborns or immunocompromised patients, for example, HIV infection, cancer, solid organ or bone marrow transplantation become CMV-infected, they may develop serious disease. CMV-related liver disease represents the commonest cause of viral hepatitis after organ transplantation. Infection may result from re-activation of endogenous virus under immunosuppression, infection from the transplanted organ or blood transfusion of a CMV-positive donor. In liver transplantation, most CMV disease occurs at 1–4 months after transplantation. CMV infection is also a potential factor triggering acute and chronic rejection. Vice versa, rejection therapy with corticosteroid boluses may induce endogenous CMV reactivation.

Although CMV re-activation is a frequent complication also in HIV-positive patients with advanced immunodeficiency (CD4 counts < 200/μL), involvement of the liver seems to be rather rare ( Palmer et al., 1987 ), but CMV occasionally causes bile-duct necrosis and a so-called HIV-cholangiopathy, a sclerosing cholangitis encountered in patients with terminal HIV-immunodeficiency ( Bonacini, 1992 ).

Clinical presentation

In about 10% of immunocompetent subjects primary cytomegalovirus infection produces an infectious mononucleosis-like syndrome, which is associated with elevated aminotransferases and a mild hepatitis ( Fig. 4 ). Liver histology may show focal hepatocyte and bile duct damage with lymphocytic infiltration into the sinusoids and occasionally epithelioid granulomas without necrosis, while CMV inclusion bodies or CMV immunostaining are only rarely seen ( Snover and Horwitz, 1984 ). Fetal CMV infection has also been associated with obstructive biliary disease and neonatal hepatitis with giant cell transformation, cholestasis and viral inclusion bodies ( Finegold and Carpenter, 1982 ). Fig. 4 Cytomegalovirus (CMV) hepatitis. (A) Activated monocyte-like lymphocytes in the blood in a 25-year-old patient with hepatitis. (B) Non-necrotic granuloma in the liver biopsy (HE-stain) from another patient with CMV hepatitis. (C) Detection of CMV inclusion bodies (“owl's eye”) in CMV hepatitis. Fig. 4

Diagnosis

In liver biopsies hepatocytes are swollen and may contain basophilic granules in the cytoplasm. A typical intranuclear amphophilic inclusion body can be present, resembling an “owl's eye” ( Fig. 3 C). Both nuclear and cytoplasmic inclusions are full of virions ( Desmet, 1983 ). However, in posttransplantation CMV hepatitis cytomegalovirus inclusion bodies are scanty. Instead small foci of necrosis and inflammation (microabscesses) may be present ( Fig. 3 B).

De novo appearance of CMV IgM antibodies or a fourfold rise in IgG antibodies herald CMV infection in immunocompetent individuals. However, serology is unreliable in immunocompromised patients and is replaced by quantitative molecular DNA amplification assays ( Humar et al., 1999 ; Caliendo et al., 2003 ). Meanwhile most transplant centers perform CMV surveillance by weekly quantitative determination of CMV DNA.

Therapy

In most transplant units organ recipients at high risk for acquiring CMV disease receive immune prophylaxis with CMV-hyperimmune antibodies and antiviral drugs ( Paya, 2001 ). However, CMV infection and disease may still develop. CMV hepatitis should be treated promptly in patients with immunodeficiency. Intravenous ganciclovir or oral valganciclovir over 3 weeks is the treatment of choice. Drugs must be continued in reduced doses as chemoprophylaxis, if prolonged immunosuppression is anticipated ( Crumpacker, 1996 ). Fortunately, ganciclovir resistance is still rare ( Martin et al., 2008 ), so that the more toxic alternatives cidofovir and foscarnet are rarely needed.

Epstein-Barr Virus (EBV)

Risk factors and epidemiology

Epstein-Barr virus (EBV) is shedded in oral secretions, and most primary EBV infections occur in adolescents. EBV accounts for 90% acute infectious mononucleosis syndromes. It persists life-long in a latent state, which results from a dynamic interplay between viral evasion strategies and the host's immune responses. While—unlike other herpesviruses—EBV reactivation-associated liver disease is not a prominent feature of persistent EBV infection, this herpesvirus is a potent cause for various malignancies such B- and T cell lymphomas, Hodgkin lymphoma, and nasopharyngeal carcinoma. EBV has also been associated with an aggressive lymphoproliferative disease after liver transplantation. EBV intrauterine infection may lead to diverse congenital anomalies also comprising biliary atresia ( Goldberg et al., 1981 ). However, only few pregnant women are susceptible, thus intrauterine EBV infection is rare.

Clinical presentation

In infants and young children primary infection is frequently asymptomatic, while in adults it results in the infectious mononucleosis syndrome. Patients develop malaise, headache, low-grade fever, before the more specific symptoms such as pharyngitis/tonsillitis, swelling of cervical lymphnodes and moderate to high-grade fever occur. Nausea, vomiting, and anorexia are frequent findings. A mild clinical hepatitis accompanies infectious mononucleosis in approximately 90% of patients ( Fig. 5 ). Splenomegaly is found in about half of patients, but hepatomegaly and jaundice are infrequent findings. Patients show peripheral blood lymphocytosis with characteristic large abnormal lymphocytes in their blood smears. The vast majority of patients recover over 2–4 weeks, but fatigue may persist over several months after infection. EBV does not infect hepatocytes but lymphoid tissue. Thus, liver damage is due to immune-mediated pathology and—when exceptionally done—biopsy specimens show diffuse lymphocytic infiltrates in the sinusoids but only occasionally focal apoptotic hepatocytes ( Fig. 3 A) ( Purtilo and Sakamoto, 1981 ). Moreover, EBV-related immune activation can lead to several complications: Fig. 5 Infectious mononucleosis (EBV-infection). (A) Rash in a patient with acute EBV infection. (B) “Hepatitis” in EBV infection. Note the lymphocytes are located in the sinusoids and do not seem to directly attack hepatocytes. Fig. 5

Patients with X-linked lymphoproliferative disease (XLP) caused by a mutation in the SH2D1A gene on the X chromosome are particularly vulnerable to the Epstein-Barr virus and may suffer fatal infections with extensive liver necrosis ( Seemayer et al., 1995 ).

In patients with severe immunodeficiency lymphomatoid granulomatosis is a further unusual complication of Epstein-Barr virus infection leading to granuloma formation in multiple organs including the liver, which may require interferon-alpha antiviral therapy ( Wilson et al., 1996 ).

In patients with HIV infection an EBV-associated lymphoproliferative disorder with hepatic infiltration of immunoblasts ( Beissner et al., 1987 ), and a hemophagocytic syndrome have been reported ( Albrecht et al., 1997 ).

Epstein-Barr virus is also the major causative agent for the so-called posttransplant lymphoproliferative disease (PTLD), which after organ transplantation may result in lymphocytic infiltration of the liver and other organs ranging from benign polyclonal B cell proliferation to malignant B cell lymphoma ( Hanto, 1995 ). PTLD occurs more commonly in children than in adults, depending on the degree of immunosuppression. It is primarily a complication in EBV-negative organ recipients, who develop primary EBV infection under immunosuppression owing to a graft from an EBV-positive donor.

Finally, EBV is a potent risk factor to develop lymphoma in later life even in patients without overt immunosuppression ( Fig. 6 ). Fig. 6 EBV-associated lymphoma (Hodgkin's disease). (A) CD30 expression in the lymphoid tissue from a liver biopsy of a patient with Hodgkin's disease (Peroxidase stain). (B) In situ hybridization reveals expression of EBER—an EBV-associated marker—in the lymphoma tissue. Fig. 6

Diagnosis

The clinical suspicion of Epstein-Barr virus infection is confirmed by detection of heterophilic or EBV-specific antibodies in infectious mononucleosis and quantitative polymerase chain reaction assays in patients with lymphoproliferative disorders ( Bruu et al., 2000 ; Weinberger et al., 2004 ). Liver biopsy is not recommended for routine diagnostics.

Therapy

Treatment of Epstein-Barr virus infection is primarily supportive. Corticosteroid therapy can ameliorate symptoms. However, this option should be only considered in individuals with immune-mediated life-threatening complications, for example, imminent liver failure. Because of theoretical concerns to suppress the immune system in an infection with a potentially oncogenic virus, corticosteroids are not recommended in general. Acyclovir inhibits the EBV DNA polymerase, and antiviral therapy with this drug has shortened virus shedding but failed to demonstrate a convincing clinical benefit even in severe acute Epstein-Barr virus infection ( Torre and Tambini, 1999 ). Acyclovir antiviral therapy is not effective against latent EBV-infection. Thus, reduction in immunosuppression, anticancer chemotherapy, and B-cell depleting antibodies are needed to treat EBV-related lymphoproliferative disorders.

Human Herpesviruses Types 6 (HHV6) and 7 (HHV7)

Risk factors and epidemiology

HHV-6 exists in two variants, HHV6-A and HHV-6B, which infect T cells and various other cells types expressing the CD46 receptor ( Santoro et al., 1999 ). Although genetically clearly distinct from HHV-6, HHV-7 is another β-herpesvirus that shares many features with HHV-6. Primary infection with either virus commonly occurs at young age and can lead to a febrile illness known as exanthema subitum or roseola infantum ( Leach, 2000 ). Pityriasis rosea reflects primary infection with HHV-7. HVV-6 also integrates into the host's genome and is transmitted via the germline. HHV6 and HHV-7 can reactivate each other ( Tanaka-Taya et al., 2000 ) as well as cytomegalovirus leading to symptomatic CMV-disease in liver transplantation ( Humar et al., 2000 ).

Clinical presentation

The full spectrum of diseases caused by chronic HHV-6 and -7 infection is still unclear, but these viruses are putatively involved in a variety of different syndromes such as encephalitis, multiple sclerosis, pneumonitis, an infectious mononucleosis-like syndrome, postinfectious drug hypersensitivity as well as lymphoproliferative disorders and systemic disease in immunocompromised patients ( Stoeckle, 2000 ). HHV-6 can cause severe and fatal hepatitis in neonates, children and adults ( Mendel et al., 1995 ; Chevret et al., 2008 ; Härmä et al., 2003 ). Hepatitis due to infection and reactivation of HHV-6 and HHV-7 can also complicate organ transplantation ( Dockrell and Paya, 2001 ; Härmä et al., 2006 ; Ohashi et al., 2008 ). In addition, HHV-6 has been associated with autoimmunity and giant-cell hepatitis and giant-cell transformation of bile duct cells ( Potenza et al., 2008 ).

Diagnosis

HHV6-IgM antibodies develop within a week after infection but are an unreliable marker, because false-positive test results in about 5% of healthy controls. Beyond that serology does not distinguish between HHV-6A and HHV-6B variants and may cross-react with HHV7. The preferred method to diagnose HHV-6 and -7 infection is by quantitative DNA amplification assays ( Deback et al., 2008 ). Detecting high viral loads in liver specimens or HHV-6 viremia is associated with approximately twofold increased mortality after liver transplantation ( Pischke et al., 2012 ).

Therapy

In immunocompetent patients HHV-6 and -7 cause a benign self-limited infection, which does not require specific antiviral treatment. Unlike HHV-6B both HHV-6A and HHV-7 are relatively resistant against ganciclovir, while foscarnet acts against all three viruses ( Yoshida et al., 1998 ; De Clercq et al., 2001 ). Cidofovir may be a therapeutic alternative, but some resistant HHV-6 isolates have been identified ( Bonnafous et al., 2008 ).

Human Herpesvirus Type 8 (HHV8)

Risk factors and epidemiology

Human herpesvirus 8 is a γ-herpesvirus, which has potential for malignant transformation. Although primary HHV-8 infection can cause rash and fever in children and immunocompromised individuals, the onset of HHV-8-related diseases usually occurs several years after HHV-8 acquisition: Kaposi sarcoma, body cavity lymphoma, and multicentric Castleman's disease are the typical presentations of HHV-8 infection but bone marrow aplasia and multiple myeloma has also been described in association with HHV-8 infection ( Lee and Henderson, 2001 ).

Clinical presentation

In autopsy studies Kaposi sarcoma involved the liver in approximately 20% of patients with AIDS and was usually part of a widespread cutaneous and visceral disease. Due to highly active antiretroviral combination therapy, Kaposi sarcoma has become a rare complication of HIV infection. However, fulminant hepatic Kaposi sarcoma may occur after organ transplantation ( Cahoon et al., 2018 , Fig. 7 ). Macroscopically there are dark-red tumors on the skin, the liver capsule and the parenchyma. Under the microscope the typical lesion is a mesh of spindle-cell-like tumor cells and dilated thin-walled vessels ( Glasgow et al., 1985 ). Fig. 7 Kaposi sarcoma after liver transplantation. (A) Brownish nodules appear in the abdominal scars 12 weeks after liver transplantation. (B) Histology reveals a spindle-cell rich tumor confirming the clinical diagnosis of Kaposi sarcoma. (C) In situ detection of human herpesvirus 8 (HHV) in the Kaposi tissue. Fig. 7

Hepatosplenomegaly, fever, and weight loss are typical features of multicentric Castleman's disease, a pre-malignant proliferation of B-lymphocytes ( Fig. 8 A). Lymphocytes in multicentric Castleman's disease and Kaposi sarcoma seem to cooperate with each other, and thus the two HHV-8-related lesions occasionally occur within the same lymphnode ( Naresh et al., 2008 ). Fig. 8 Rare tumor entities associated with persistent HHV8 infection. (A) Castleman's disease in a lymphnode of HIV-positive patient who developed malaise, fever and cutaneous Kaposi sarcoma. Castleman's disease is a HHV8-associated pre-malignant lymphoproliferative disorder, which can progress to B-cell lymphoma. (B) Tumor cells of HHV8-associated body cavity lymphoma found in ascites from a HIV-positive patient. Fig. 8

Ascites and pleural effusions are the hallmark of HHV-8-related body cavity lymphoma possibly giving rise to a false initial diagnosis of decompensated liver cirrhosis. However, abundant lymphoma cells in the aspirated fluids provide a pivotal diagnostic hint ( Fig. 8 B). HHV-8 can also cause solid organ lymphoma involving the liver ( Cesarman and Knowles, 1999 ).

Diagnosis

The diagnosis of HHV-8 associated malignancies is established from biopsies via their characteristic histopathological features. The virus itself is detected by various antibody assays or polymerase chain reaction (PCR) assays ( Chiereghin et al., 2017 ).

Therapy

Reconstitution of immune function is the primary goal for treatment of HHV-8 associated diseases. This can be achieved by highly active antiretroviral therapy in HIV infection and alternatively by antiproliferate m-TOR (mammalian target of rapamycin) inhibitors for immune suppression in transplantation ( Barozzi et al., 2009 ). Immune stimulation with imiquimod and interferon-alpha ( Babel et al., 2008 ; Van der Ende et al., 2007 ) has been attempted. Oncological therapy with liposomal anthracyclines or paclitaxel in Kaposi sarcoma ( Di Trolio et al., 2006 ; Stebbing et al., 2003 ), or rituximab in the case of Castleman's disease and lymphoma are further potent treatment options ( Bower et al., 2007 ). Ganciclovir, cidofovir, foscarnet, adefovir and lobucavir but not acyclovir can block HHV-8 replication in vitro, and in a controlled crossover trial valganciclovir reduced oropharyngeal shedding of HHV-8 by 80% ( Casper et al., 2008 ).

Outlook

This overview addresses the currently most relevant viral infections involving the liver. However, it provides only an outline and is in far not exhaustive. In rare instances, hepatitis occurred in the context of infections with enteroviruses ( Sun and Smith, 1966 ), measles ( Khatib et al., 1993 ) and rubella viruses ( McLellan and Gleiner, 1982 ) as well as Parvovirus B19 ( Yoto et al., 1996 ; Hayakawa et al., 2007 ). The reader will find details of these rare infections in microbiology textbooks. Beyond that, international travel and global warming are likely to introduce new exotic infections, which must be considered in the differential diagnosis of severe hepatitis. This problem is illustrated by the recent autochthonous Crimean–Congo hemorrhagic fever (CCHF) virus infections in Spain ( Negredo et al., 2017 ), which did not occur in this country before. Thus, hepatologists must be constantly prepared to face new challenges.

Acknowledgments

Histology slides were kindly provided by Prof. Dr. Hans-Peter Fischer, Department of Pathology, Rheinische Friedrich-Wilhelms University of Bonn, Germany.

References

Albrecht H. Schäfer H. Stellbrinck H.-J. Greten H. Epstein-Barr-virus-associated hemophagocytic syndrome. A cause of fever of unknown origin in HIV infection Archives of Pathology & Laboratory Medicine 121 1997 853 858 9278614

Al-Hoamoudi W.K. Severe autoimmune hepatitis triggered by varicella zoster infection World Journal of Gastroenterology 15 2009 1004 1006 19248202 10.3748/wjg.15.1004 PMC2653401

Alsaad K.O. Hajeer A.H. Al Balwi M. Al Moaiqel M. Al Oudah N. Al Ajlan A. AlJohani S. Histopathology of Middle East respiratory syndrome coronovirus (MERS-CoV) infection—Clinicopathological and ultrastructural study Histopathology 72 2018 516 524 28858401 10.1111/his.13379 PMC7165512

Babel N. Eibl N. Ulrich C. Development of Kaposi's sarcoma under sirolimus-based immunosuppression and successful treatment with imiquimod Transplant Infectious Disease 10 2008 59 62 17428275 10.1111/j.1399-3062.2007.00239.x

Barnett E.D. Yellow fever: Epidemiology and prevention Clinical Infectious Diseases 44 2007 850 856 17304460 10.1086/511869

Barozzi P. Riva G. Vallerini D. Indirect antitumor effects of mammalian target of rapamycin inhibitors against Kaposi sarcoma in transplant patients Transplantation 88 2009 597 598 19696647 10.1097/TP.0b013e3181b15d56

Beissner R.S. Rappaport E.S. Diaz J.A. Fatal case of Epstein-Barr virus-associated lymphoproliferative disorder associated with a human immunodeficiency virus infection Archives of Pathology & Laboratory Medicine 111 1987 250 253 3030225

Bonacini M. Hepatobiliary complications in patients with human immunodeficiency virus infection The American Journal of Medicine 92 1992 404 411 1558086 10.1016/0002-9343(92)90271-c

Bonnafous P. Boutolleaus D. Naesens L. Characterization of a cidofovir-resistant HHV-6 mutant obtained by in vitro selection Antiviral Research 77 2008 237 240 18241936 10.1016/j.antiviral.2007.12.004

Booth C.M. Matukas L.M. Tonlinson G.A. Clinical features and short term outcome of 144 patients with SARS in the greater Toronto area JAMA 289 2003 2801 2809 12734147 10.1001/jama.289.21.JOC30885

Bower M. Powles T. Williams S. Brief communication: Rituximab in HIV-associated multicentric Castleman disease Annals of Internal Medicine 147 2007 836 839 18087054 10.7326/0003-4819-147-12-200712180-00003

Bruu A.L. Hjetland R. Holter E. Evaluation of 12 commercial tests for detection of Epstein-Barr virus-specific and heterophile antibodies Clinical and Diagnostic Laboratory Immunology 7 2000 451 456 10799460 10.1128/cdli.7.3.451-456.2000 PMC95893

Cahoon E.K. Linet M.S. Clarke C.A. Pawlish K.S. Engels E.A. Pfeiffer R.M. Risk of Kaposi sarcoma after solid organ transplantation in the United States International Journal of Cancer 143 2018 2741 2748 29987894 10.1002/ijc.31735 PMC10655926

Caliendo A.M. Yen-Lieberman B. Baptista J. Comparison of molecular tests for detection and quantification of cell-associated cytomegalovirus DND Journal of Clinical Microbiology 41 2003 3509 3513 12904347 10.1128/JCM.41.8.3509-3513.2003 PMC179805

Casper C. Krantz E.M. Corey L. Valganciclovir for suppression of human herpesvirus-8 replication: A randomized, double-blind, placebo-controlled, crossover trial The Journal of Infectious Diseases 198 2008 23 30 18491970 10.1086/588820 PMC2700177

Cesarman E. Knowles D.M. The role of Kaposi's sarcoma-associated herpesvirus (HSHV/HHV8) in lymphoproliferative diseases Seminars in Cancer Biology 9 1999 165 174 10343068 10.1006/scbi.1998.0118

Chan Y.C. Wong T.W. Yap E.H. Haemorrhagic fever with renal syndrome involving the liver The Medical Journal of Australia 147 1987 248 249 2890086 10.5694/j.1326-5377.1987.tb133422.x

Chan H.L.-Y. Kwan A.C.-P. To K.F. Clinical significance of hepatic derangement in severe acute respiratory syndrome World Journal of Gastroenterology 11 2005 2148 2153 15810082 10.3748/wjg.v11.i14.2148 PMC4305785

Charrel R.N. de Lamballerie X. Raoult D. Chikungunya outbreaks—The globalization of vectorborne diseases New England Journal of Medicine 356 2007 769 771 10.1056/NEJMp078013 17314335

Chevret L. Boutolleau D. Halimi-Idri N. Human herpesvirus-6 infection: A prospective study evaluating HHV-6 DNA levels in liver from children with acute liver failure Journal of Medical Virology 80 2008 1051 1057 18428148 10.1002/jmv.21143

Chiereghin A. Barozzi P. Petrisli E. Piccirilli G. Gabrielli L. Riva G. Potenza L. Multicenter prospective study for laboratory diagnosis of HHV8 infection in solid organ donors and transplant recipients and evaluation of the clinical impact after transplantation Transplantation 101 2017 1935 1944 28333859 10.1097/TP.0000000000001740

Choi K.w. Chau T.N. Tsang O. Outcomes and prognostic factors in 267 patients with severe acute respiratory syndrome in Hong Kong Annals of Internal Medicine 139 2003 715 723 14597455 10.7326/0003-4819-139-9-200311040-00005

Crumpacker C.S. Ganciclovir The New England Journal of Medicine 335 1996 721 729 8786764 10.1056/NEJM199609053351007

De Clercq E. Naesens L. De Bolle L. Antiviral agents against human herpesviruses HHV-6, HHV-7 and HHV-8 Reviews in Medical Virology 11 2001 381 395 11747000 10.1002/rmv.336

Deback C. Agbalika F. Scieux C. Detection of human herpesviruses HHV-6, HHV-7 and HHV-8 in whole blood by real-time PCR using the new CMV, HHV-6, 7, 8 R-gene kit Journal of Virological Methods 149 2008 285 291 18329730 10.1016/j.jviromet.2008.01.026

Desmet M.-J.V.V.J. Cytomegalovirus hepatitis: A histological and immunohistochemical study Applied Pathology 1 1983 41 49 6331473

Di Trolio R. Di Lorenzo G. Delfino M. De Placido S. Role of pegylated liposomal doxorubicin (PLD) in systemic Kaposi's sarcoma: A systematic review International Journal of Immunopathology and Pharmacology 19 2006 253 263 16831292 10.1177/039463200601900202

Dockrell D.H. Paya C.V. Human herpesvirus-6 and -7 in transplantation Reviews in Medical Virology 11 2001 23 36 11241800 10.1002/rmv.299

Drosten C. Gunther S. Preiser W. Identification of a novel coronavirus in patients with severe acute respiratory syndrome The New England Journal of Medicine 348 2003 1967 1976 12690091 10.1056/NEJMoa030747

Eisenhut M. Thorburn K. Ahmed T. Transaminase levels in ventilated children with respiratory syncytial virus bronchiolitis Intensive Care Medicine 30 2004 931 934 15024569 10.1007/s00134-004-2236-2

Finegold M.J. Carpenter R.J. Obliterative cholangitis due to cytomegalovirus: A possible precursor of paucity of intrahepatic bile ducts Human Pathology 13 1982 662 665 6282733 10.1016/s0046-8177(82)80011-7

Finström N. Bergsten K. Ström H. Analysis of varicella-zoster virus and herpes simplex virus in various clinical samples by the use of different PCR assays Journal of Virological Methods 150 2009 193 196 10.1016/j.jviromet.2009.04.035 19433110

Frederick D.M. Bland D. Gollin Y. Fatal disseminated herpes simplex virus infection in a previously healthy pregnant woman The Journal of Reproductive Medicine 47 2002 591 596 12170540

Garnett C.T. Talekar G. Mahr J.A. Latent species C adenoviruses in human tonsil tissues Journal of Virology 83 2009 2417 2428 19109384 10.1128/JVI.02392-08 PMC2648257

Glasgow B.J. Anders K. Layfield L.J. Clinical and pathologic findings of the liver in acquired immune deficiency syndrome (AIDS) American Journal of Clinical Pathology 83 1985 482 588 10.1093/ajcp/83.5.582 2986450

Goldberg G.N. Fulginti V.A. Ray C.G. In utero Epstein-Barrvirus (infectious mononucleosis) infection JAMA 246 1981 1579 1581 6268854

Goodman Z.D. Ishak K.G. Sesterhenn I.A. Herpes simplex hepatitis in apparently immunocompetent adults American Journal of Clinical Pathology 85 1986 694 699 3518404 10.1093/ajcp/85.6.694

Hanto D.W. Classification of Epstein-Barr virus associated posttransplant lymphoproliferative diseases: Implications for understanding their pathogenesis and developing rational treatment strategies Annual Review of Medicine 36 1995 381 394 10.1146/annurev.med.46.1.381 7598473

Härmä M. Höckerstedt K. Lautenschlager I. Human herpesvirus-6 and acute liver failure Transplantation 76 2003 536 539 12923440 10.1097/01.TP.0000069233.13409.DF

Härmä M. Höckerstedt K. Krogerus L. Lautenschlager I. Pre-transplant human herpesvirus 6 infection of patients with acute liver failure is a risk factor for post-transplant human herpesvirus 6 infection of the liver Transplantation 81 2006 367 372 16477222 10.1097/01.tp.0000195771.83614.0b

Hayakawa H. Tara M. Niina K. Osame M. A clinical study of adult human parvovirus B 19 infection Internal Medicine 41 2007 295 299 10.2169/internalmedicine.41.295 11993790

Huggins J.W. Hsiang C.M. Cosgriff T.M. Prospective, double-blind, concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome The Journal of Infectious Diseases 164 1991 1119 1683355 10.1093/infdis/164.6.1119

Humar A. Gregson D. Caliendo A.M. Clinical utility of quantitative cytomegalovirus viral load determination for predicting cytomegalovirus disease in liver transplant recipients Transplantation 68 1999 1305 1311 10573068 10.1097/00007890-199911150-00015

Humar A. Malkan G. Moussa G. Human herpesvirus-6 is associated with cytomegalovirus reactivation in liver transplant recipients The Journal of Infectious Diseases 181 2000 1450 1453 10762575 10.1086/315391

Janner D. Petru A.M. Belchis D. Azimi P.H. Fatal adenovirus infection in a child with acquired immunodeficiency syndrome Pediatric Infectious Disease 9 1990 434 436 10.1097/00006454-199006000-00013 2164186

Johnson J.R. Egaas S. Gleaves C.A. Hepatitis due to herpes simplex virus in marrow-transplant recipients Clinical Infectious Diseases 14 1992 38 45 1571460 10.1093/clinids/14.1.38

Khatib R. Siddique M. Abbass M. Measles associated hepatobiliary disease: An overview Infection 21 1993 112 114 8491519 10.1007/BF01710744

Kojaoghlanian T. Flomenberg P. Horwitz M.S. The impact of adenovirus infection on the immunocompromised host Reviews in Medical Virology 13 2003 155 171 12740831 10.1002/rmv.386

Krilov L.R. Rubin L.G. Frogel M. Disseminated adenovirus infection with hepatic necrosis in patients with human immunodeficiency virus infection and other immunodeficiency states Reviews of Infectious Diseases 12 1990 303 307 2158668 10.1093/clinids/12.2.303

Ksiazek T.G. Erdman D. Goldsmith C.S. A novel coronavirus in patients with severe acute respiratory syndrome The New England Journal of Medicine 348 2003 1953 1966 12690092 10.1056/NEJMoa030781

Kusne S. Schwartz M. Breining M.K. Herpes simplex virus hepatitis after solid organ transplantation The Journal of Infectious Diseases 163 1991 1001 1007 1850439 10.1093/infdis/163.5.1001 PMC2956417

Kylat R.I. Kelly E.N. Ford-Jones E.L. Clinical findings and adverse outcome in neonates with symptomatic congenital cytomegalovirus (SCCMV) infection European Journal of Pediatrics 165 2006 773 778 16835757 10.1007/s00431-006-0172-6

Leach C.T. Human herpesvirus-6 and -7 infections in children: Agents of roseola and other syndromes Current Opinion in Pediatrics 51 12 2000 269 274 10.1097/00008480-200006000-00017 10836165

Lee L.M. Henderson D.K. Emerging viral infections Current Opinion in Infectious Diseases 14 2001 467 480 11964867 10.1097/00001432-200108000-00012

Lee N. Hui D. Wu A. A major outbreak of severe acute respiratory syndrome in Hong Kong The New England Journal of Medicine 348 2003 1986 1994 12682352 10.1056/NEJMoa030685

Levin M.J. Bacon T.H. Leary J.J. Resistance of herpes simplex virus infections to nucleoside analogues in HIV-infected patients Clinical Infectious Diseases 39 suppl 5 2004 S248 S257 15494896 10.1086/422364

Lledó L. Klingström J. Gegúndez M.I. Hantavirus infections in Spain: Analysis of sera from the general population and from patients with pneumonia, renal disease and hepatitis Journal of Clinical Virology 27 2003 296 307 12878094 10.1016/s1386-6532(02)00228-7

Martin B.K. Ricks M.O. Forman M.S. Jabs D.A. Change over time in incidence of ganciclovir resistance in patients with cytomegalovirus retinitis Clinical Infectious Diseases 44 2008 1001 1008 10.1086/512368 17342657

McLellan R.K. Gleiner J.A. Acute hepatitis in an adult with rubeola JAMA 247 1982 2000 2001 7062506

Mendel I. de Matteis M. Bertin C. Fulminant hepatitis in neonates with human herpesvirus 6 infection The Pediatric Infectious Disease Journal 14 1995 993 997 8584368 10.1097/00006454-199511000-00013

Michaels M.G. Green M. Walde E.R. Starzl T.E. Adenovirus infection in pediatric liver transplant recipients The Journal of Infectious Diseases 165 1992 170 174 1727887 10.1093/infdis/165.1.170 PMC2954762

Murali-Krishna K. Altmann J.D. Suresh M. Counting antigen-specific CD8 T cells: A reevaluation of bystander activation during viral infection Immunity 8 1998 177 187 9491999 10.1016/s1074-7613(00)80470-7

Naresh K.N. Rice A.J. Bower M. Lymphnodes involved by multicentric Castleman disease among HIV-positive individuals are often involved by Kaposi sarcoma The American Journal of Surgical Pathology 32 2008 1006 1012 18469709 10.1097/PAS.0b013e318160ed97

Negredo A. de la Calle-Prieto F. Palencia-Herrejón E. Mora-Rillo M. Astray-Mochales J. Sánchez-Seco M.P. Bermejo Lopez E. Autochthonous Crimean–Congo hemorrhagic fever in Spain The New England Journal of Medicine 377 2017 154 161 28700843 10.1056/NEJMoa1615162

Nichol T.S. Aikawa J. Kawacka Y. Emerging viral diseases Proceedings of the National Academy of Sciences of the United States of America 97 2000 12411 12412 11035785 10.1073/pnas.210382297 PMC34064

Ohashi M. Sugata K. Ihira M. Human herpesvirus 6 infection in adult living related liver transplant recipients Liver Transplantation 14 2008 100 109 18161770 10.1002/lt.21304

Palmer M. Braly L.F. Schaffner F. The liver in AIDS disease Seminars in Liver Disease 7 1987 192 202 3317858 10.1055/s-2008-1040576

Pan-American Health Organisation Tool for the diagnosis and care of patients with suspected arboviral diseases 2017 Pan-American Health Organisation Washington DC http://iris.paho.org/xmlui/bitstream/handle/123456789/33895/9789275119365_eng.pdf

Paya C. Prevention of cytomegalovirus disease in recipients of solid-organ transplants Clinical Infectious Diseases 32 2001 596 603 11181123 10.1086/318724

Peiris J.S. Yu W.C. Leung C.w. Re-emergence of fatal human influenza a subtype H5N1 disease Lancet 363 2004 617 619 14987888 10.1016/S0140-6736(04)15595-5 PMC7112424

Pettersson E. Hovi T. Ahonen J. Prophylactic oral acyclovir after renal transplantation Transplantation 39 1985 279 281 2983461 10.1097/00007890-198503000-00014

Pinna A.D. Rakela J. Demetris A.J. Fung J.J. Five cases of fulminant hepatitis due to herpes simplex virus in adults Digestive Diseases and Sciences 47 2002 750 754 11991604 10.1023/a:1014779614525

Pischke S. Gösling J. Engelmann I. Schlue J. Wölk B. Jäckel E. High intrahepatic HHV-6 virus loads but neither CMV nor EBV are associated with decreased graft survival after diagnosis of graft hepatitis Journal of Hepatology 56 2012 1063 1069 22245897 10.1016/j.jhep.2011.12.017

Plyusnin A. Krüger D.H. Lundkvist A. Hantavirus infections in Europe Advances in Virus Research 57 2001 105 136 11680383 10.1016/s0065-3527(01)57002-5

Polakos N.K. Cornejo J.C. Murray D.A. Kupffer cell-dependent hepatitis occurs during influenza infection The American Journal of Pathology 168 2006 1169 1178 16565492 10.2353/ajpath.2006.050875 PMC1606556

Potenza I. Luppi M. Barozzi P. HHV-6A in syncytial giant-cell hepatitis The New England Journal of Medicine 359 2008 583 602 10.1056/NEJMoa074479 18687640

Poutanen S.M. Low D.E. henry B. Identification of severe acute respiratory syndrome in Canada The New England Journal of Medicine 348 2003 1995 2005 12671061 10.1056/NEJMoa030634

Purtilo D.T. Sakamoto K. Epstein-Barr virus and human disease: Immune response determines the clinical and pathological expression Human Pathology 12 1981 677 679 6269987 10.1016/s0046-8177(81)80162-1

Rezza G. Nicoletti L. Angelini R. Infection with chikungunya virus in Italy: An outbreak in a temperate region Lancet 370 2007 1840 1846 18061059 10.1016/S0140-6736(07)61779-6

Rosen L. Khin M.M. UT. Recovery of virus from the liver of children with fatal dengue: Reflections on the pathogenesis of the disease and its possible analogy with that of yellow fever Research in Virology 140 1989 351 360 2772416 10.1016/s0923-2516(89)80115-3

Safrin S. Crumpacker C. Chatis P. A controlled trial comparing foscarnet with vidarabine for acyclovir-resistant mucocutaneous herpes simplex infection in the AIDS patient The New England Journal of Medicine 325 1991 551 555 1649971 10.1056/NEJM199108223250805

Santoro F. Kennedy P.E. Locatelli G. CD46 is a cellular receptor for human herpesvirus 6 Cell 99 1999 817 827 10619434 10.1016/s0092-8674(00)81678-5

Schumann J. Wolf D. Pahl A. Importance of Kupffer cells for T-cell-dependent liver injury in mice The American Journal of Pathology 157 2000 1671 1683 11073826 10.1016/S0002-9440(10)64804-3 PMC1885735

Schünemann S.R. Hill M. WHO rapid advice guidelines for pharmacological management of sporadic human infection with avian influenza A (H5N1) virus The Lancet Infectious Diseases 7 2007 21 31 17182341 10.1016/S1473-3099(06)70684-3 PMC7106493

Seale L. Jones C.J. Kathpalia S. Prevention of herpesvirus infections in renal allograft recipient JAMA 254 1985 3435 3438 2999455

Seemayer T.A. Gross T.G. Egeler M. X-linked lymphoproliferative disease: Twenty-five years after discovery Pediatric Research 38 1995 471 478 8559596 10.1203/00006450-199510000-00001

Sidwell R.W. Smee D.F. Viruses of the Bunya- and Togaviridae families: Potential as bioterrorism agents and means of control Antiviral Research 57 2003 101 111 12615306 10.1016/s0166-3542(02)00203-6

Snover D.C. Horwitz C.A. Liver disease in cytomegalovirus mononucleosis: A light microscopical and immunoperoxidase study of six cases Hepatology 4 1984 408 412 6327485 10.1002/hep.1840040309

Song A.T.W. Abdala E. de Martino R.B. Malbouisson L.M.S. Tanigawa R.Y. Andrade G.M. Ducatti L. Doi A.M. Liver transplantation for fulminant hepatitis due to yellow fever Hepatology 69 3 2019 1349 1352 10.1002/hep.30273 30218577

South M.A. Dolen J. Beach D.K. Fatal adenovirus hepatic necrosis in severe combined immune deficiency Pediatric Infectious Disease 1 1982 416 419 6298755 10.1097/00006454-198211000-00012

Stebbing J. Wildfire A. Portsmouth S. Paclitaxel for anthracycline-resistant AIDS-related Kaposi's sarcoma: Clinical and angiogenic correlations Annals of Oncology 14 2003 1660 1666 14581275 10.1093/annonc/mdg461

Stoeckle M.Y. The spectrum of human herpesvirus 6 infection: From roseola infantum to adult disease Annual Review of Medicine 51 2000 423 430 10.1146/annurev.med.51.1.423 10774474

Sun N.C. Smith V.M. Hepatitis associated with myocarditis. Unusual manifestation of infection with Coxsackie virus group B, type 3 The New England Journal of Medicine 274 1966 190 193 5902617 10.1056/NEJM196601272740405

Tanaka-Taya K. Kondo T. Nakgawa N. Reactivation of human herpesvirus 6 by infection of human herpesvirus 7 Journal of Medical Virology 60 2000 284 289 10630960 10.1002/(sici)1096-9071(200003)60:3<284::aid-jmv6>3.0.co;2-8

Taubitz W. Cramer J.P. Kapaun A. Chikungunya fever in travelers: Clinical presentation and course Clinical Infectious Diseases 45 2007 e1 e4 17554689 10.1086/518701

To K.F. Chan P.K. Chan K.F. Pathology of fatal human infection associated with avian influenza A H5N1 virus Journal of Medical Virology 63 2001 242 246 11170064 10.1002/1096-9071(200103)63:3<242::aid-jmv1007>3.0.co;2-n

Torre D. Tambini R. Acyclovir for treatment of infectious mononucleosis: A metaanalysis Scandinavian Journal of Infectious Diseases 31 1999 543 547 10680982 10.1080/00365549950164409

Tyring S.K. Baker D. Snowden W. Valacyclovir for herpes simples virus infection: Long-term safety and sustained efficacy after 20 years’ experience with acyclovir The Journal of Infectious Diseases 186 suppl 1 2002 S40 S46 12353186 10.1086/342966

Van der Ende M. Mulder J.W. van den Berge M. Complete clinical and virological remission of refractory HIV-related Kaposi's sarcoma with pegylated interferon alpha AIDS 21 2007 1661 1662 17630571 10.1097/QAD.0b013e32827035a4

Vasconcelos P.F. Bryant J.E. da Rosa T.P. Genetic divergence and dispersal of yellow fever virus, Brazil Emerging Infectious Diseases 10 2004 1578 1584 15498159 10.3201/eid1009.040197 PMC3320275

Wahid F. Sanusi S. Zawawi M.M. Ali R.A. A comparison of the pattern of liver involvement in dengue hemorrhagic fever with classic dengue fever Southeast Asian Journal of Tropical Medicine and Public Health 31 2000 259 263 11127322

Weinberger B. Plentz A. Weinberger K.M. Quantitation of Epstein-Barr virus mRNA using reverse transcription and real-time PCR Journal of Medical Virology 74 2004 612 618 15484273 10.1002/jmv.20220

Wilson W.H. Kingma D.W. Raffeld M. Association of lymphomatoid granulomatosis with Epstein-Barr viral infection of B lymphocytes and response to interferon-alpha 2b Blood 87 1996 4531 4537 8639820

Wilson M.E. Weld L.H. Boggild A. Fever in returned travelers: Results from the GeoSentinel surveillance network Clinical Infectious Diseases 44 2007 1560 1568 17516399 10.1086/518173

Wong W.M. Ho J.C. Hung I.F. Temporal pattern of hepatic dysfunction and disease severity in patients with SARS JAMA 290 2003 2663 2665 14645306 10.1001/jama.290.20.2663

World Health Organization (2009) Dengue: Guidelines for diagnosis, treatment, prevention and control , new edition. WHO: Geneva. http://www.who.int/tdr/publications/documents/dengue-diagnosis.pdf 23762963

World Health Organization Handbook for clinical management of dengue 2012 WHO Geneva http://www.wpro.who.int/mvp/documents/handbook_for_clinical_management_of_dengue.pdf

Wulffraat N.M. Geelen S.P. van Dijken P.J. Recovery from adenovirus pneumonia in a severe combined immunodeficiency patient with intravenous ribavirin Transplantation 59 1995 927 7701598

Yoshida M. Yamada M. Tsukazaki T. Comparison of antiviral compounds against human herpesvirus 6 and 7 Antiviral Research 40 1998 73 84 9864048 10.1016/s0166-3542(98)00049-7

Yoto Y. Kudoh T. Haseyama K. Human parvovirus B19 infection associated with acute hepatitis Lancet 347 1996 868 869 8622394 10.1016/s0140-6736(96)91348-3

Yotsuyanagi H. Koike K. Meng G. Acute exacerbation of autoimmune liver disease associated with hantaviral infection Scandinavian Journal of Infectious Diseases 30 1998 81 83 9670364 10.1080/003655498750002358

Yuen K.Y. Wong S.S.Y. Human infection by avian influenza A H5N1 Hong Kong Medical Journal 11 2005 189 199 15951584

Zimmerli W. Bianchi L. Gudat F. Disseminated herpes simplex type 2 and systemic Candida infection in a patient with previous asymptomatic HIV infection The Journal of Infectious Diseases 157 1988 597 598 3343529 10.1093/infdis/157.3.597