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Human Herpesvirus 6 Infection of the Gastroduodenal Mucosa

  1. Leena Halme1,
  2. Johanna Arola2,
  3. Krister Höckerstedt1, and
  4. Irmeli Lautenschlager1,3
  1. 1Department of Transplantation and Liver Surgery, Transplant Unit Research Laboratory, Helsinki University Hospital, Helsinki, Finland
  2. 2Department of Pathology, Helsinki University Hospital (HUSLAB) and University of Helsinki, Helsinki, Finland
  3. 3Department of Virology, Helsinki University Hospital (HUSLAB) and University of Helsinki, Helsinki, Finland
  1. Reprints or correspondence: Dr. Leena Halme, Dept. of Transplantation and Liver Surgery, Helsinki University Hospital, Box 263, FIN-00029 Helsinki, Finland (leena.halme{at}hus.fi).
 
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Abstract

Background.Human herpesvirus 6 (HHV-6) infections are usually asymptomatic reactivations in adult liver transplant recipients, but they may also cause fever or graft dysfunction. HHV-6 infection can also present symptoms of gastroenteritis. In this study, we investigated the presence of HHV-6 in the gastroduodenal mucosa of liver transplant recipients and in immunocompetent patients undergoing gastroscopic examination because of dyspeptic symptoms.

Methods.HHV-6 and cytomegalovirus (CMV) examinations were performed on gastroduodenal biopsy specimens obtained during upper gastrointestinal endoscopic examinations from 90 liver transplant recipients and from 31 immunocompetent patients with upper gastrointestinal symptoms. In the gastroduodenal mucosa, HHV-6 and CMV was demonstrated by immunohistochemistry in frozen sections using monoclonal antibodies against HHV-6– and CMV-specific antigens.

Results.HHV-6–positive cells were found in biopsy specimens from 21 (23%) of the liver transplant recipients and 6 (19%) of the immunocompetent patients, CMV-positive cells were found in specimens from 55 (61%) of the transplant recipients and 7 (23%) of the immunocompetent patients, and 12 transplant recipients were found to have both HHV-6 and CMV infection. Fifteen transplant recipients with positive HHV-6 findings in the gastroduodenal mucosa also had HHV-6 antigenemia, whereas 30 patients with HHV-6 antigenemia did not have gastroduodenal involvement. Endoscopic findings in these patients included biliary complications in 10 patients and gastritis in 2 patients. Histopathological findings were nonspecific and included very mild inflammation. A total of 30 (94%) of the transplant recipients with biliary complications also had HHV-6 or CMV detected in the duodenal mucosa.

Conclusions.HHV-6–positive cells and CMV-positive cells were frequently found in the gastroduodenal mucosa of liver transplant recipients and of immunocompetent patients undergoing gastroscopic examination because of dyspeptic symptoms.

Human herpesvirus 6 (HHV-6) is a lymphotropic virus that belongs to the β-herpesviruses, together with its close relatives cytomegalovirus (CMV) and human herpesvirus 7. In infants, HHV-6 infection may present either as excanthema subitum or as nonspecific infection, or it may not involve any clinical symptoms [1]. Seroconversion mostly occurs before the age of 2 years, and the seroprevalence in the adult population is universally >95% [2]. Two major subgroups of HHV-6 variant A and variant B have been identified. Clinical isolates from transplant recipients are predominantly of variant B [3].

As is the case with other herpesviruses, HHV-6 persists in the host in a latent form after primary infection and can reactivate during immunosuppression. In liver transplant recipients, reactivations caused by variant B are common [4]. Although HHV-6 is a lymphotropic virus, it uses CD46 as a receptor and may also infect other cell types, such as monocytes and endothelial and epithelial cells [2]. HHV-6 can infect liver allografts and cause graft dysfunction [4–6]. We, as well as others, have demonstrated that HHV-6 is frequently detected by the antigenemia test, culture, or PCR in peripheral blood samples from liver transplant recipients [4, 7–9]. In addition to graft dysfunction, invasive HHV-6 infection in liver transplant recipients has also been associated with fever, interstitial pneumonitis, skin rash, and encephalitis [5, 6, 10].

Primary HHV-6 infection in children can also present symptoms resembling gastroenteritis, diarrhea, and nausea [1]. In stem cell transplant recipients with gastrointestinal symptoms, HHV-6 DNA has been detected by PCR in gastroduodenal and colorectal mucosa [11] and by in situ hybridization in large bowel mucosa [12]. We wanted to investigate the presence of HHV-6 infection in the gastroduodenal mucosa of liver transplant recipients who underwent endoscopic examination because of upper gastrointestinal symptoms or suspicion of biliary complication and of immunocompetent patients with dyspeptic symptoms.

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Patients and Methods

Tests for HHV-6 and CMV were performed on gastroduodenal biopsy specimens obtained during upper gastrointestinal endoscopic examinations from 90 liver transplant recipients (in a group of 100 endoscopic examinations, the examination was performed a median of 0.23 years [range, 7 days to 12 years] after liver transplantation) and from 31 immunocompetent patients with dyspeptic symptoms. Indications for endoscopic examination are presented in table 1. Indications for receipt of a liver transplant were acute liver disease (23 patients), alcoholic liver disease (10), biliary cirrhosis (34), hepatitis C virus infection (2), hepatitis B virus infection (1), cryptogenic cirrhosis (15), and hepatocellular carcinoma (5).

Figure 1
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Figure 1

The gastric mucosa of a 36-year-old patient with primary sclerosing cholangitis and intense human herpesvirus 6 infection in the gastroduodenal mucosa. A, Hematoxylin-eosin stain (original magnification, ×20) showing histological characteristics, with inset (original magnification, ×100). B, Human herpesvirus 6–positive cells in the gastric mucosa demonstrated by immunohistochemistry (original magnification, ×20), with inset (original magnification, ×100).

Table 1
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Table 1

Indications for upper gastrointestinal endoscopic examination.

The main immunosuppressive medication was cyclosporine for 83% of the patients and tacrolimus for 17%. These agents were used in combination with azathioprine or mycophenolate mofetil and methylprednisolone. Transplant rejections were treated with high-dose methylprednisolone and, if this treatment failed, with the monoclonal antibody OKT 3. The transplant recipients with symptomatic CMV antigenemia were treated with intravenous ganciclovir (5 mg/kg twice daily) for at least 2 weeks. None of these transplant recipients received routine antiviral prophylaxis, except for ganciclovir prophylaxis (5 mg/kg administered twice daily for 5–10 days intravenously), which was administered when acute rejection was treated with high-dose steroids. The patients were regularly screened for bacterial, fungal, and viral infections according to the routine posttransplantation follow-up scheme.

HHV-6 and CMV antigenemia.The patients were monitored for HHV-6 antigenemia in parallel with CMVpp65 antigenemia. Blood samples were obtained weekly during the patients' hospitalization and thereafter, according to our clinical protocol, at 1, 2, 3, 6, 9, and 12 months after transplantation or in case of clinical symptoms and were also obtained at every posttransplantation visit to the hospital. The standard CMVpp65 test was performed as described elsewhere [13]. HHV-6 infections were diagnosed with use of the HHV-6 antigenemia test, which detects HHV-6–specific antigens in PBMCs [3]. First, the PBMCs were isolated by Ficoll-Paque density gradient centrifugation and cytocentrifuged onto microscope slides. The presence of viral antigens in the cytopreparations was demonstrated by indirect immunoperoxidase staining and by monoclonal antibodies against an early HHV-6–specific antigen and an HHV-6 variant B virion protein (MAB8533 and MAB8535; Chemicon), detecting both variants A and B, as described elsewhere [4]. The specificity of the antibodies has been described by Chemicon. Normal mouse IgG was used as a negative control for nonspecific binding. A peroxidase-conjugated rabbit antimouse (Dako) and a peroxidase-conjugated goat antirabbit antibody (Zymed) were used as second and third antibodies. The reaction was revealed by 3-amino-9-ethyl carbazole solution containing hydrogen peroxide, and Mayer's hemalum was used for counterstaining.

Histological examination of biopsy specimens.In all patients, 2 biopsy specimens from the second portion of the duodenum and 2 biopsy specimens from the antrum of the stomach were obtained for CMV and HHV-6 analysis. Biopsy specimens for histopathological analysis, including hematoxylin-eosin, Alcian blue, periodic acid-Schiff, and Giemsa stainings, were obtained routinely at the first endoscopic examination of the patient and thereafter from macroscopic findings.

Demonstration of CMV and HHV-6 in the biopsy speci mens.For HHV-6 and CMV antigen detection, the gastroduodenal biopsy material was snap-frozen, and sections (3–4 microns in diameter) were cut, acetone-fixed, and stored at -20°C until used. The presence of HHV-6 viral antigens was demonstrated by an indirect 3-layer immunoperoxidase staining and monoclonal antibodies against HHV-6–specific antigens, as described above for PBMCs and as described elsewhere for tissue sections [4, 6]. The CMV-specific antigens (pp65 matrix protein; Biotest AG) were demonstrated in the biopsy specimens as described elsewhere [14]. Before staining, the sections were treated with chloroform to eliminate nonspecific reactions caused by endogenous peroxidase. The intensity of HHV-6 and CMV infections was graded as negative, mild (1–3 positive cells per high-power visual field), moderate (4–6 positive cells per high-power visual field), or intense (⩾7 positive cells per high-power visual field).

Ethics.The study was approved by the Ethics Committee of Helsinki University Hospital (Helsinki, Finland), and all patients and control subjects gave their informed consent.

Statistics.The variables were compared using the nonparametric Mann-Whitney U test.

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Results

HHV-6 antigens were detected in the gastroduodenal mucosa of biopsy samples obtained from 21 (23%) of the liver transplant recipients (in 23 endoscopic examinations) and from 6 (19%) of the immunocompetent patients with dyspeptic symptoms (table 2). In 17 endoscopic examinations performed for 15 transplant recipients with an HHV-6–positive finding in the gastroduodenal mucosa, the patients also had HHV-6 antigenemia, whereas in 31 endoscopic examinations performed for patients with HHV-6 antigenemia, the biopsy specimens were HHV-6 negative. In 2 (9.5%) of the patients with positive HHV-6 findings in the gastroduodenal mucosa, no preceding or simultaneous HHV-6 antigenemia was detected. All HHV-6 strains were variant B. The median time from liver transplantation to examination was 0.24 years (range, 16 days to 4.0 years) in patients with gastroduodenal HHV-6 involvement, 0.19 years (range, 7 days to 5.2 years) in patients with HHV-6 antigenemia without gastroduodenal involvement, and 0.24 years (range, 8 days to 12 years) in patients without HHV-6 antigenemia or gastroduodenal involvement (not statistically significant). Among transplant recipients, the duodenal mucosa was affected in 20 (87%) of HHV-6–positive cases, and the gastric mucosa was affected in 15 (65%), whereas among immunocompetent patients with dyspeptic symptoms, both gastric and duodenal mucosa were affected in 50% of HHV-6–positive cases. The HHV-6 antigens were located in the PBMCs infiltrating the mucosa. The intensity of HHV-6 infection in the gastroduodenal mucosa was graded, on the basis of the number of cells that were positive for viral antigens, as intense in 4 transplant recipients, moderate in 4 transplant recipients, and mild in all immunocompetent patients (3). Histopathologic findings in the HHV-6–positive mucosa were nonspecific and included very mild inflammation (figure 1).

Table 2
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Table 2

No. (%) of patients with positive human herpesvirus 6 (HHV-6) or cytomegalovirus (CMV) findings in gastroduodenal biopsy specimens.

Table 3
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Table 3

Intensity of human herpesvirus 6 (HHV-6) and cytomegalovirus (CMV) positivity in gastroduodenal biopsy specimens.

Indications for endoscopic examination in transplant recipients with HHV-6–positive findings in the gastroduodenal mucosa were biliary complications (10 patients), control of brush cytology (in a patient with primary sclerosing cholangitis and high-grade dysplasia in the common bile duct), dyspeptic symptoms (6 patients), suspicion of gastrointestinal bleeding (2 patients), and to control earlier findings (2 patients). Endoscopic findings were biliary complications in 10 patients (leak in 3 and stricture in 7) and gastritis in 2 patients. Indications for endoscopic examination in immunocompetent control subjects with HHV-6–positive findings in the gastroduodenal mucosa were dyspepsia (3), suspicion of bleeding (2), and ulcer control (1), and endoscopic findings were gastric ulcer in 1 control subject.

Only 1 (1%) of 90 transplant recipients and 5 (16%) of the patients with dyspeptic symptoms had Helicobacter pylori–positive findings in previously or simultaneously obtained histopathological samples of gastric mucosa. None of these patients had gastric CMV or HHV-6 infection at the time that the sample was obtained. During the routine follow-up of the transplant recipients, no other possible gastrointestinal infections, such as rotavirus or adenovirus infections, were diagnosed.

Among transplant recipients, gastroduodenal CMV infection was found in 55 (61%) of the patients, including 12 patients who were coinfected with HHV-6; among immunocompetent patients with dyspeptic symptoms, duodenal CMV infection was found in 7 patients, none of whom had HHV-6 coinfection (table 2). A total of 15 transplant recipients (17%) had simultaneous CMV antigenemia, and 13 (87%) of them had CMV-positive findings in the gastroduodenal mucosa. Simultaneous HHV-6 and CMV antigenemia were detected in 10 transplant recipients, 4 of whom had gastroduodenal HHV-6 and CMV coinfection. The gastroduodenal biopsy specimens were obtained during ganciclovir therapy for CMV antigenemia in 9 patients. Five of these patients had HHV-6 antigenemia, and 2 had HHV-6–positive cells in the gastroduodenal mucosa. The intensity of gastroduodenal CMV infection is shown in 3. Histopathological findings in the CMV-positive mucosa were also nonspecific and mild.

Biliary complications were diagnosed in 32 patients. In 7 patients, endoscopic retrograde cholangiopancreatography with gastroduodenal biopsies were performed twice. During the first endoscopic retrograde cholangiopancreatographic examination (performed a median of 66 days [range, 14 days to 4 years] after liver transplantation), gastroduodenal biopsy specimens were CMV positive in 21 patients (66%) and HHV-6 positive in 9 patients (28%). In 7 patients (22%), gastroduodenal biopsy specimens were both HHV-6 and CMV negative, but 5 of these patients had simultaneous HHV-6 (3 patients) or CMV (2 patients) antigenemia. The 2 patients without positive HHV-6 and CMV findings had early biliary complications (1 leak on the fourteenth pod and 1 stricture on the twenty-third pod).

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Discussion

HHV-6–positive cells were found in 21 (23%) of the gastroduodenal biopsy specimens obtained at a median of 3 months after liver transplantation and in 6 (19%) of the specimens obtained from immunocompetent patients who underwent upper gastrointestinal endoscopic examination because of dyspeptic symptoms. A total of 15 (74%) of the transplant recipients with positive findings in the gastroduodenal mucosa had simultaneous HHV-6 antigenemia. HHV-6 is considered to be a harmless β-herpesvirus that may, however, cause hepatitis and graft dysfunction in liver transplant recipients, although the cause-and-effect relationship often is lacking [5]. Although primary HHV-6 infection of infants can cause gastroenteritis-like symptoms, most of the adult patients in our study with test results positive for HHV-6 had no or only mild upper gastrointestinal symptoms. Unfortunately, gastroduodenal biopsy specimens from healthy persons without gastrointestinal symptoms were not available because of ethical reasons.

Herpes simplex virus infection has been found to be associated with chronic gastric erosions [15, 16]. CMV infection can cause ulceration, erosions, and mucosal hemorrhage in the gastrointestinal tract [17, 18]. Upper gastrointestinal and ileocolonic HHV-6 infection detected by PCR has been described in a series of 228 stem cell transplant recipients [11]. A total of 5 of 23 patients with HHV-6–positive findings in the gastroduodenal mucosa and 3 of 17 patients with such findings in the colorectal mucosa were considered to have an association between symptoms and HHV-6 antigenemia, because they had histological signs of inflammation that were consistent with viral infection. However, those patients were also reported to have coinfection with other microorganisms, including Epstein-Barr virus, CMV, adenovirus, herpes simplex virus, rotavirus, and Candida albicans. In a case report describing a 4-patient series of stem cell transplant recipients with severe diarrhea, HHV-6 DNA was detected in goblet cells and histiocytes of the submucous region of the large intestine, suggesting that HHV-6 may infect and reactivate in those cells [12]. In the present series, histopathological findings of HHV-6 were nonspecific and included mild inflammation, suggesting that HHV-6 is an innocent bystander in the gut, located in the mononuclear cell infiltration, rather than in the tissues cells.

The principal indirect effect of HHV-6 infection in association with organ transplantation is found to result from its potential to exacerbate other herpesvirus infections, especially CMV infection [19–21], as well as from its influence on the occurrence of other opportunistic infections, such as fungal disease [22, 23]. In this series, CMV-positive cells were found simultaneously with HHV-6–positive cells in 61% of the transplant recipients and 23% of the immunocompetent patients with gastroduodenal HHV-6 infection. In most cases, the CMV infection was mild. In addition, 10 transplant recipients had simultaneous HHV-6 and CMV antigenemia.

We have previously found a strong association between CMV antigenemia, as well as duodenal CMV infection, and biliary complications in liver transplant recipients [13]. In the present series, 32 patients had a biliary complication after liver transplantation. A total of 23 (72%) of them had CMV antigenemia or CMV-positive findings in the duodenal mucosa. Seven additional patients had simultaneous HHV-6 antigenemia and/or HHV-6–positive findings in the duodenal mucosa, suggesting that HHV-6 infection may also predispose to biliary com plications.

In conclusion, HHV-6–positive cells were found in gastro duodenal biopsy specimens obtained from 6 (19%) of immunocompetent patients with dyspeptic symptoms and from 21 (23%) of immunosuppressed patients a median of 3 months after liver transplantation. Among transplant recipients with positive findings in the gastroduodenal mucosa, 15 (74%) had simultaneous HHV-6 antigenemia. Further studies are needed to confirm whether HHV-6 infection of the gastroduodenal mucosa causes gastrointestinal symptoms or predisposes to biliary complications, as seen in CMV infection.

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Acknowledgments

We thank Marjatta Palovaara, for technical assistance, and Stephen Venn, for correcting the English text.

Financial support.The Sigrid Juselius Foundation and Helsinki University Hospital Funds (to E.V.O.).

Potential conflicts of interest.All authors: no conflicts.

  • Received June 22, 2007.
  • Accepted September 28, 2007.
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  1. Clin Infect Dis. (2008) 46 (3): 434-439. doi: 10.1086/525264
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