Fatal adenovirus hepatitis during standard chemotherapy for childhood acute lymphoblastic leukemia

Fulminant hepatitis is a rare complication of adenoviral infection that has not previously been reported in children receiving standard chemotherapy for acute leukemia. The authors have observed fatal adenovirus hepatitis in three children receiving first-line chemotherapy for acute lymphoblastic leukemia (ALL). The patients presented 10, 17, and 8 months into therapy according to the UKALL XI (third intensification), UKALL 97/99 (maintenance), and pilot UKALL 2003 (delayed intensification II) protocols, respectively. All patients received aggressive supportive care and intravenous immunoglobulins. The second and third patients were also treated with intravenous cidofovir. Despite these measures, all three children deteriorated rapidly and died of fulminant liver failure. Although rare, adenovirus infection should be considered in the differential diagnosis of acute hepatitis in children receiving standard chemotherapy for ALL.     

Adenovirus Ascending Cholangiohepatitis

Three children, two with liver transplants and one with acquired human immunodeficiency virus (HIV) infection, presented with hepatitis accompanied by elevated gamma glutamyl transpeptidase. Biopsies revealed cholangiohepatitis caused by adenovirus infection. There was a progressive loss of interlobular bile ducts in two of the patients. In one patient, infection of the biliary tree was marked by a necrotizing cholangitis, with adenoviral inclusions noted in the biliary epithelium. In each patient, there was evidence of adenovirus gastrointestinal infection. This is the first report of adenoviral infection of the biliary tree in humans. It is hypothesized that adenovirus cholangiohepatitis occurs as a result of ascending infection from the gastrointestinal tract to the biliary tree.     

Adenoviral infections in pediatric transplant recipients: a hospital-based study

OBJECTIVE: To assess the disease burden and outcomes resulting from adenoviral infections among pediatric transplant recipients. METHODS: This was a retrospective study of adenoviral infections among pediatric transplant recipients who were hospitalized at our center between 1993 and 2003. Patients were defined as having adenoviral infection if the virus was demonstrated in stool, urine, respiratory, blood, or biopsy tissue samples in the presence of attributable clinical findings. Data were obtained from the hospital's medical records and laboratory databases. RESULTS: There were 55 patients with single episodes of adenovirus infection: 28 (50.9%) solid organ transplant (SOT) and 27 (49.1%) hematopoietic stem cell transplant (HSCT) recipients. The prevalence rates among SOT and HSCT recipients were 1 per 16 and 1 per 24 transplants performed, respectively. The median age of patients with adenovirus infections was 3.66 years (range, 0.25-17.25). Infection occurred at a median of 1.6 months posttransplantation (range, 0.03-153.). Adenovirus was most frequently demonstrated from the gastrointestinal tract (78%). Other sites infected included the respiratory tract, liver, blood and urinary tract. Overall mortality was 14.6%. All deaths occurred among HSCT recipients (mortality, 29.6%). Deaths were more likely among patients with adenovirus identified at >or=2 sites than in those having localized disease (P < 0.01). CONCLUSION: Mortality from adenoviral infection was a greater risk for HSCT than SOT recipients. Early onset of infection after transplantation suggests the possibility of reactivation of adenovirus rather than new acquisition in at least of proportion of cases. This is important for surveillance of this infection in transplant recipients.     

Treatment of adenovirus hepatitis with cidofovir in a pediatric liver transplant recipient

AdV hepatitis is a rarely reported complication after pediatric liver transplantation that is associated with high rates of morbidity, mortality and graft failure. Successful treatment of AdV relies on early diagnosis of disease by quantitative PCR measurement of adenoviral DNA in blood and histological evidence in tissue biopsy. Pharmacologic treatment largely consists of antiviral therapy with CDV, an acyclic nucleoside phosphonate analog and reduction in immunosuppression. This report describes a case of AdV hepatitis in a pediatric liver transplant recipient successfully treated with a modified, renal sparing dosing of CDV.     

Correlation between serum interleukin 6 and C-reactive protein concentrations in patients with adenoviral respiratory infection

OBJECTIVE: To characterize adenoviral respiratory infection, we evaluated clinical features, laboratory findings and serum cytokine concentrations in patients with adenoviral infection and compared them with those in patients with influenza virus and respiratory syncytial virus (RSV) infections. METHODS: We enrolled 106 patients who had been diagnosed with acute viral respiratory infection caused by adeno-, influenza and respiratory syncytial viruses from January, 1995, through December, 1998. Forty-nine patients had adenovirus infection, 19 patients had influenza virus infection and 38 patients had RSV infection. Etiologic diagnosis was made based on the antigen detection by enzyme immunoassay (influenza virus, RSV), and viral isolation was done by tissue culture (adenovirus, influenza virus) from nasopharyngeal specimens. We evaluated clinical manifestations, laboratory findings (white blood cell count, C-reactive protein, erythrocyte sedimentation rate) and serum cytokine [interleukin (IL)-1-beta, IL-6, IL-8, interferon gamma and tumor necrosis factor alpha] concentrations. RESULTS: We observed prolonged fever, strong inflammatory response such as leukocytosis with neutrophilia and high C-reactive protein values in patients with adenoviral respiratory infection compared with those in patients with influenza virus and RSV infections. Serum IL-6 concentrations in patients with adenoviral respiratory infection were higher than those in patients with influenza virus and RSV infections. Other cytokine (IL-1-beta, IL-2, interferon gamma and tumor necrosis factor alpha) values did not differ among adenovirus, influenza virus and RSV infections. CONCLUSIONS: Patients with adenoviral respiratory infection have high grade and prolonged fever, strong inflammatory response and higher serum IL-6 than in influenza and RSV infection.     

A rare case of adenoviral fulminant hepatic necrosis after chemotherapy

The authors report a rare case of fulminant adenoviral hepatic necrosis occurring after chemotherapy in a patient with a second relapse of acute myeloid leukemia. The literature is reviewed and the a role of rapid viral diagnosis in the clinical management of this complication is discussed. A 10-year-old girl with relapsed acute myeloid leukemia after allogeneic bone marrow transplant underwent re-induction chemotherapy with high-dose cytosine arabinoside and amsacrine. During induction she developed diarrhea and a marked coagulopathy, followed by fulminant hepatic failure and acute pre-renal failure. She rapidly deteriorated and died. A limited autopsy was performed. Adenovirus type 5 was cultured from ante mortem clinical samples and detected by polymerase chain reaction in postmortem samples of heart blood, lung, trachea, spleen, and liver. At autopsy, the liver demonstrated massive hepatic necrosis with positive immunofluorescence for adenovirus. Electron microscopy demonstrated intranuclear inclusions, typical of adenovirus. There was no evidence of pneumonia. Adenovirus can cause fulminant hepatic necrosis following chemotherapy in a nontransplant setting. If adenoviral disease is suspected, appropriate rapid viral studies should be undertaken, because early intervention with ribavirin or cidofovir may prevent rapid fulminant progression. Further studies on the role of antiviral therapy in this setting are warranted.     

A RARE CASE OF ADENOVIRAL FULMINANT HEPATIC NECROSIS AFTER CHEMOTHERAPY

The authors report a rare case of fulminant adenoviral hepatic necrosis occurring after chemotherapy in a patient with a second relapse of acute myeloid leukemia. The literature is reviewed and the a role of rapid viral diagnosis in the clinical management of this complication is discussed. A 10-year-old girl with relapsed acute myeloid leukemia after allogeneic bone marrow transplant underwent re-induction chemotherapy with high-dose cytosine arabinoside and amsacrine. During induction she developed diarrhea and a marked coagulopathy, followed by fulminant hepatic failure and acute pre-renal failure. She rapidly deteriorated and died. A limited autopsy was performed. Adenovirus type 5 was cultured from ante mortem clinical samples and detected by polymerase chain reaction in postmortem samples of heart blood, lung, trachea, spleen, and liver. At autopsy, the liver demonstrated massive hepatic necrosis with positive immunofluorescence for adenovirus. Electron microscopy demonstrated intranuclear inclusions, typical of adenovirus. There was no evidence of pneumonia. Adenovirus can cause fulminant hepatic necrosis following chemotherapy in a nontransplant setting. If adenoviral disease is suspected, appropriate rapid viral studies should be undertaken, because early intervention with ribavirin or cidofovir may prevent rapid fulminant progression. Further studies on the role of antiviral therapy in this setting are warranted.     

Adenovirus infection and treatment with cidofovir in children after liver transplantation

Abstract:  In a retrospective study, serum samples from 21 pediatric liver transplant recipients were analysed by quantitative real-time PCR for ADV infection up to 24 wk after Tx. ADV DNA was detected in serum of eight children after Tx, one of whom developed life-threatening fulminant hepatitis and sepsis. None of these children were symptomatic at the time of first detection of ADV DNA in serum after Tx. Seven children with positive ADV PCR had low adenoviral loads, showed no increase in viral load and remained clinically asymptomatic in the follow-up period of 24 wk. After 10 wk under immunosuppression one child presented clinically with adenoviral sepsis and severe necrotizing hepatitis. This patient revealed a dramatic increase of ADV from baseline titers up to 1.3 × 10⁹ copies/mL serum within 10 wk after Tx. ADV was also detected in a liver biopsy of this child at 1.2 × 10⁴ copies/cell and typed by sequence analysis as human ADV species C, type 6, a rarely detected ADV type and first described in a liver transplant patient. Immunosuppression was reduced in this patient immediately and the antiviral drug cidofovir administered intravenously followed by viral suppression and clinical improvement of the child.     

ADENOVIRUS AND MARROW TRANSPLANTATION IN CHILDREN

Adenovirus disease is a major cause of morbidity and mortality among recipients of marrow transplants. Recent advances have contributed to a finer understanding of the biological basis for viral persistence in the normal host as well as disseminated disease in the immunocompromised patient. However, these insights have not yielded new, effective therapeutic interventions. Currently, there are no proven antiviral therapies available for treating adenoviral disease. Anecdotal reports have indicated that combinations of ribavirin, intravenous immunoglobulin, and donor T cells are efficacious in cases with limited infection. We anticipate that the incidence of adenoviral infections in marrow transplant recipients will continue to increase because the pool of transplant recipients continues to enlarge and more immunosuppressive preparative regimens, including T-cell depletion, are more commonly used. This review summarizes the clinical manifestations of adenovirus in the bone marrow transplant population including such common complications as hemorrhagic cystitis and rarer manifestations of disseminated infection, such as nephritis, gastroenteritis, pneumonia, hepatitis, pancreatitis, and encephalitis.     

The differentiation of classic Kawasaki disease, atypical Kawasaki disease, and acute adenoviral infection: use of clinical features and a rapid direct fluorescent antigen test

OBJECTIVE: To compare the clinical and laboratory features of children with Kawasaki disease with those with acute adenoviral infection, which may mimic Kawasaki disease. DESIGN: We retrospectively compared the medical records of children with Kawasaki disease and atypical Kawasaki disease with those of children with acute adenoviral infection. All children included were initially evaluated because their primary care physicians were concerned that they might have Kawasaki disease. The utility of a rapid direct fluorescent antigen test for adenovirus was evaluated. Thirty-six children with Kawasaki disease (23 with classic and 13 with atypical presentations) and 7 patients with acute adenoviral infection were studied. SETTING: A tertiary care pediatric hospital. RESULTS: Children with Kawasaki disease were more likely to have conjunctivitis (36 of 36 vs 4 of 7), strawberry) tongues (23 of 36 vs 1 of 7), perineal peeling (19 of 36 vs 0 of 7), and distal extremity changes (22 of 36 vs 0 of 7) than those with acute adenoviral infection. Children with acute adenoviral infection were more likely to have purulent conjunctivitis (3 of 7 vs 1 of 36) and exudative pharyngitis (3 of 7 vs 1 of 35). In addition to pyuria (13 of 26 vs 0 of 6), patients with Kawasaki disease had higher mean white blood cell counts (15.3 +/- 3.5 vs 11.5 +/- 6.0 x 10(9)/L), erythrocyte sedimentation rates (56 vs 42 mm/h), platelet counts (426 vs 259 x 10(9)/L), and levels of alanine aminotransferase (101 vs 18 U/L) than those with acute adenoviral infection. Children with Kawasaki disease had lower mean albumin levels (32 vs 36 g/L). A rapid antigen test for adenovirus had a specificity and sensitivity of 100% compared with viral culture. CONCLUSIONS: Kawasaki disease and acute adenoviral infection can present with many of the same clinical characteristics. A rapid direct fluorescent antigen assay for adenovirus may be a helpful adjunctive test for distinguishing acute adenoviral infection from Kawasaki disease.     

Chronic hepatitis B surface antigen-negative hepatitis after treatment of malignancy.

We reviewed the records of all patients with a diagnosis of malignancy who were treated at our center and who had not had chemotherapy for at least 18 months, to assess the prevalence of chronic hepatitis B surface antigen (HBsAg)-negative hepatitis, to assess the prevalence of a marker of hepatitis C virus infection, and to determine the severity of chronic liver disease. Of 557 eligible patients, 38 (6.8%) had chronic HBsAg-negative hepatitis. Of these 38 patients, 20 (52.6%) had a marker of hepatitis C virus infection. The prevalence of chronic HBsAg-negative hepatitis was higher in patients previously treated for leukemia than in patients treated for another malignancy (11.8% vs 4.6%; p = 0.004). The liver biopsy revealed chronic active hepatitis or cirrhosis or both in 8 (28%) of 28 patients with clinical chronic HBsAg-negative hepatitis. Four patients without hepatitis C virus infection who underwent liver biopsy had hepatitis B virus antigen in the liver, confirmed by immunohistochemistry studies. One patient uninfected with hepatitis C virus had hemochromatosis. We conclude that infection with hepatitis C virus was the major cause of chronic HBsAg-negative hepatitis in pediatric patients previously treated for malignancy; the cause remained unidentified in 30% of the patients.     

Adenovirus infection within stromal cells in a pediatric small bowel allograft.

Adenovirus infection is not uncommon in pediatric small bowel transplant recipients. Histopathologic findings include characteristic epithelial changes of intranuclear inclusions and smudging of nuclei. We present a case of adenovirus within stromal cells of the lamina propria in a biopsy from a small bowel allograft. Immunohistochemistry and double-labeled immunofluorescence were performed using antibodies against adenovirus, CD31, vimentin, cytokeratin, and CD163 on the allograft intestinal biopsy. Electron microscopy was done to confirm the presence of viral particles and to attempt to confirm the origin of the infected cells. The index biopsy showed scant cells within the lamina propria double-labeled with vimentin and adenovirus. Several cells showed predominantly cytoplasmic staining for adenoviral antigen. Intranuclear adenoviral particles were found in several cells of the lamina propria by electron microscopy. A subsequent biopsy showed typical adenoviral intranuclear inclusions within surface enterocytes. Adenovirus may infect stromal cells within the lamina propria. Although the typical location of adenoviral inclusions in small bowel is the surface epithelial cell nuclei, some cases may show inclusions within stromal cells. This observation may be important in the pathobiology of adenoviral infection, especially in the setting of pediatric transplantation. This finding should alert pathologists examining small bowel transplant biopsies, particularly those biopsies with extensive ulceration, to include careful surveillance of the lamina propria.     

Clinical utility of liver biopsy in children with acquired immunodeficiency syndrome

BACKGROUND: Little is known about hepatic histology in children with AIDS, although the liver is frequently involved in the course of HIV infection. The clinical utility of liver biopsy in these patients is not well-defined. We reviewed retrospectively the results of this procedure in a group of infected children better to delineate its indications. PATIENTS AND METHODS: Eighteen children with AIDS underwent liver biopsy in our institution. The indications were unexplained fever in eight children, six of whom had an elevated erythrocyte sedimentation rate and clinical suspicion of mycobacterial infection; jaundice in four; suspicion of drug toxicity (dideoxyinosine) in two; discussion of treatment for chronic hepatitis B in three; suspicion of cytomegalovirus infection in one who had also AIDS cholangiopathy. RESULTS: Of the six children thought to have mycobacterial infection, two had the disease on biopsy, both of whom had abnormal liver enzymes. The children with unexplained fever had nonspecific findings, except for one with lymphoid interstitial pneumonitis who had a dense lymphoid infiltrate. Of the four with jaundice two had extensive necrosis caused by adenovirus infection in one and suspected herpes simplex infection in the other. The other two with jaundice had unexplained findings, severe necrosis and fibrosis in one case and hemophagocytosis in the other one; both improved clinically. Both children with suspected dideoxyinosine hepatotoxicity had nonspecific findings. The three children with chronic hepatitis B had mild lesions that were not an indication for treatment. CONCLUSIONS: Liver biopsy appeared to be useful in two groups of selected children with AIDS: when there is strong clinical suspicion of mycobacterial infection; and when the child is jaundiced.     

Quantitation of adenovirus genome during acute infection in normal children

BACKGROUND: Adenovirus infection causes a wide range of clinical illness in normal children. New molecular techniques allow quantitation of viral genome to study the natural history of adenovirus infection and viral load in normal children. METHODS: Clinical samples were collected from 38 previously healthy, febrile children, and viral cultures were performed. Quantitative polymerase chain reaction (PCR) was used to detect adenovirus genome and to determine viral load. Adenovirus isolates were genotyped with a PCR-based assay. RESULTS: Adenovirus culture was positive in 6 children who were diagnosed with acute adenovirus infection. Throat swabs contained high copy numbers of adenovirus genome (1.6 x 10(6)-6 x 10(7) copies/swab) from 4 of 4 adenovirus culture-positive children. Only 2 of 32 adenovirus culture-negative children had detectable adenovirus genome from throat swabs, but with a lower copy number (8 x 10(2) copies/swab). Adenovirus genome was not detected in blood samples from 5 of 6 adenovirus culture-positive children with uncomplicated upper respiratory tract infection and from all adenovirus culture-negative children. High level viremia (1.8 x 10(8)/ml) was detected in an adenovirus culture-positive 6-month-old infant with fever, pneumonia, conjunctivitis and hepatitis. Subsequent reduction in viral load paralleled her clinical recovery. Adenovirus viruria (1 x 10(9) copies/ml) with normal urinanalysis was detected in another adenovirus culture-positive child. All 6 adenovirus isolates were genotyped as adenovirus type 7h. CONCLUSION: Viral load assessment in clinical samples determined by quantitative PCR can be useful in the diagnosis of adenovirus infection in immunocompetent, febrile children.     

Adenoviral diseases in children: a study of 105 hospital cases

The clinical findings for 105 children hospitalized with adenoviral infection were studied prospectively. In 82 children, the diagnosis was based on the detection of adenovirus antigen in the nasopharyngeal specimens and in 17 children in the feces. In the remaining six patients, findings from nasopharyngeal specimens were negative but a significant increase in CF (complement fixation) titers was detected. The clinical picture of adenoviral infection was characterized by high-grade (mean 39.4 degrees C) and prolonged fever (mean duration 5.4 days). Tonsillitis, otitis, and gastroenteritis were the most common illnesses. In 17% of the patients, no identifiable focus of infection could be demonstrated; nine children with no identifiable focus of infection had febrile convulsions. The WBC count and ESR varied from normal values to values seen in bacterial infections; thus it was difficult to distinguish adenoviral disease from a bacterial disease. Forty-five children were referred to the hospital due to infection unresponsive to antimicrobial therapy. The rapid detection of adenovirus antigen in nasopharyngeal specimens or feces proved to have a great clinical value in the diagnosis of adenoviral infections.     

Adenovirus necrotizing hepatitis complicating atypical teratoid rhabdoid tumor

Adenovirus‐induced fulminant hepatitis is rare. It has been reported in children with primary immunodeficiency, following transplantation or while receiving chemotherapy for hematological malignancy. We present the case of an infant recovering from chemotherapy for atypical teratoid rhabdoid tumor (ATRT) in whom a diagnosis of hepatic necrosis due to adenovirus was made.     

Delta Virus and Childhood Leukemia

We studied 145 children with acute lymphocytic leukemia (ALL) in remission who had been off chemotherapy for at least 2 years, to assess the prevalence of hepatitis delta virus (HDV) infection, and to determine whether HD V infection was associated with more severe chronic liver disease. The prevalence of chronic HBV infection was 41.5% (60/145). The prevalence of HDV infection among these patients with chronic HBV infection was 50% (30/60). Eighty-five patients were HBsAg-negative. There was evidence that HDV-infected children had more severe chronic liver disease than did HBsAg-positive, anti-HDV-negative patients: (1) their serum ALT levels were significantly more likely to be elevated at long-term follow-up (27/30 vs. 10/26, p = 0.0001); (2) their mean ALT levels were significantly higher 3 years after the cessation of chemotherapy (128 vs. 84 IU/L, p = 0.001); and (3) they were more likely to have either chronic acute hepatitis or cirrhosis when liver biopsy was done (18/23 vs. 6/18, p = 0.0038). Children who were HBsAg-negative had the lowest alanine aminotransferase (ALT) levels and were least likely to have chronic active hepatitis or cirrhosis (3/31).

We conclude that infection with HDV in children with ALL is associated with serious chronic liver disease. In long-term survivors, HDV infection is a major cause of morbidity and an adverse prognostic factor in terms of leukemia-free survival.     

Severe adenovirus bronchiolitis in children

Severe adenoviral infections such as the necrotizing adenovirus bronchiolitis occur sporadically in infants. Ascertaining the etiologic role of adenovirus in cases of lung disease can pose a diagnostic problem. We present two cases of severe bronchiolitis in previously healthy children in which adenovirus could be shown to be the causing agent. Both children received immunosuppressive therapy with steroids and Cyclosporin for 3 mo and a course of intravenous Ribavirin for 10 d. The results were conflicting: despite therapy Patient 1 died due to respiratory failure, Patient 2 improved notably. Conclusions: Adenovirus can cause severe bronchiolitis in previously healthy children. Diagnosis may be difficult to achieve. The role of antiviral therapy in the treatment of adenoviral infections remains to be cleared.     

Acute adenovirus hepatitis in liver transplant recipients.

An acute or fulminant adenovirus hepatitis developed in 5 of 224 pediatric patients who were recipients of orthotopic liver transplants. All had received prednisolone, azathioprine, and cyclosporine as basal immunosuppression, and four received monoclonal (OKT3) or polyclonal (antithymocyte globulin) antibodies for steroid-resistant rejection episodes. These patients initially had high fever and a worsening condition for a mean of 73 days after transplantation (range 44 to 140 days). Results of biochemical tests showed very high serum levels of lactate dehydrogenase. Aspartate aminotransferase values were always markedly more elevated than those of alanine aminotransferase. Two patients had severe leukopenia. Results of histologic studies of the liver showed extensive areas of confluent necrosis and targetlike hepatocyte nuclei. Typical intranuclear viral inclusions were observed on electron microscopy. Adenovirus was cultured in all patients and in two relatives. Two patients died of liver failure; others recovered after cessation of immunosuppression. We conclude that adenovirus hepatitis can be fatal in liver transplant recipients. There is no specific treatment, and immunosuppression must be discontinued.     

The impact of RSV,adenovirus, influenza,and parainfluenza infection in pediatric patients receiving stem cell transplant,solid organ transplant,or cancer chemotherapy

RVIs are a significant cause of morbidity and mortality in immunocompromised children. We analyzed the characteristics and outcomes of infection by four respiratory viruses (RSV, adenovirus, influenza, and parainfluenza) treated at a pediatric tertiary care hospital in a retrospective cohort of patients who had received cancer chemotherapy, hematopoietic stem cell, or SOT. A total of 208 infections were studied among 166 unique patients over a time period of 1993–2006 for transplant recipients, and 2000–2005 for patients with cancer. RSV was the most common respiratory virus identified. There were 17 (10% of all patients) deaths overall, of which 12 were at least partly attributed to the presence of a RVI. In multivariate models, LRT symptoms in the absence of upper respiratory symptoms on presentation (OR 10.2 [2.3, 45.7], p = 0.002) and adenoviral infection (OR 3.7 [1.1, 12.6], p = 0.034) were significantly associated with poor outcome, defined as death or disability related to RVI. All of the deaths occurred in patients who had received either solid organ or HSCT. There were no infections resulting in death or disability in the cancer chemotherapy group.