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Biomedical subjects

Kathleen B Schwarz

Publications and source records attributed to Kathleen B Schwarz.

18 recordsLinked to original sources
PubMed2006

Modulation of the IL-12/IFN-gamma axis by IFN-alpha therapy for hepatitis C.

Although IFN-alpha forms the foundation of therapy for chronic hepatitis C, only a minority of patients has a sustained response to IFN-alpha alone. The antiviral activities of IFN-alpha formed the rationale for its use in viral hepatitis. However, IFN-alpha and the other Type I IFNs are also pleiotropic immune regulators. Type I IFNs can promote IFN-gamma production by activating STAT4 but can also inhibit production of IL-12, a potent activator of STAT4 and IFN-gamma production. The efficacy of IFN-alpha in the treatment of hepatitis C may therefore depend in part on the balance of IFN-gamma-inducing and IL-12-suppressing effects. We characterized the effects of pegylated IFN-alpha therapy for hepatitis C on the capacity of patients' PBMC to produce IL-12 and IFN-gamma ex vivo. Cells from patients with a sustained virological response to therapy had significantly greater levels of IFN-alpha-driven IFN-gamma production prior to treatment than those from nonresponding patients. No differences in pretreatment IL-12 productive capacity were seen between patient groups. However, therapy with IFN-alpha led to suppression of inducible IL-12 production throughout the course of therapy in both groups of patients.

CD4-Positive T-Lymphocytes↗
PubMed2006

Long-term lamivudine therapy for children with HBeAg-positive chronic hepatitis B.

One year of lamivudine treatment results in increased hepatitis B e antigen (HBeAg) seroconversion and serum hepatitis B virus (HBV) DNA negativity in children with chronic hepatitis B and high serum alanine aminotransferase concentrations. Two hundred seventy-six children who participated in a 1-year randomized, placebo-controlled study of lamivudine were enrolled in a 24-month, open-label extension. Patients were stratified into two groups based on HBeAg status at week 48 of the previous study: 213 HBeAg-positive children were entered into a treatment arm, and 63 HBeAg-negative children were entered into an observation arm to evaluate durability of HBeAg loss. In the treatment arm, 28 of 133 (21%) children previously treated with lamivudine and 23 of 77 (30%) children who previously received placebo achieved the primary end point: virological response (VR) (HBeAg loss and HBV DNA negativity) at month 24. The incidence of YMDD (tyrosine, methionine, aspartate, aspartate) mutations at month 24 was 64% (66/103) in the children previously treated with lamivudine and 49% (34/70) in those previously treated with placebo. The incidence of VR at month 24 was 5% (5/100) for patients with YMDD mutant HBV and 54% (39/72) for patients without. The durability of response in the observation arm was 89% (48/54) at month 24. In conclusion, further clinical response was seen over the 24-month open-label study period in children who had not initially achieved a VR after 12 months of lamivudine treatment. However, the incidence of YMMD mutations increased over time and resulted in lower response rates. VR was maintained in most patients who had initially responded to lamivudine in the first 12 months.

Adolescent↗
PubMed2006

Safety, efficacy and pharmacokinetics of peginterferon alpha2a (40 kd) in children with chronic hepatitis C.

Chronic hepatitis C virus (HCV) infection in children is a problem affecting thousands of children worldwide. Although standard interferon (INF) has better efficacy in pediatric patients than in adults, results in children with genotype 1 are poor; response rates to combination treatment with standard INF and ribavirin are better but the treatment requires thrice-weekly injections. The improved antiviral efficacy of weekly pegylated interferons relative to standard interferons in adults with chronic HCV infection suggests that pegylated interferons may also improve antiviral efficacy in children. We therefore investigated the pharmacokinetics, efficacy and safety of peginterferon alpha2a (pegINF-alpha2a) (40 kd) in 14 children ages 2 to 8 years with chronic hepatitis C (13 genotype 1, 1 non-1 genotype). Drug dose was calculated from each patient's body surface area (BSA) according to the formula BSA (m2)/(1.73 m2) x 180 microg, and patients were administered once-weekly subcutaneous injections for 48 weeks. Viral load and pharmacokinetic parameters were determined from blood drawn throughout the study and during follow-up. At week 24, the mean trough concentration was about 20% below values obtained from adults treated with pegINF-alpha2a, and the area under the curve from 0 to 168 hours was about 20% above adult values, suggesting that drug doses calculated from BSA achieved therapeutically adequate concentrations. Six of 14 patients (43%), all infected with genotype 1, achieved a sustained virological response. Adverse events were those commonly associated with INF-based treatment, and none was deemed serious. In conclusion, our findings provide a basis for larger studies evaluating the efficacy and safety of pegINF-alpha2a as monotherapy as well as in combination with ribavirin in pediatric patients with chronic hepatitis C.

Antiviral Agents↗
PubMed2006

Treatment options for chronic hepatitis B and C infection in children.

There has been a dramatic increase in treatment options for both chronic hepatitis B (CHB) and chronic hepatitis C (CHC) infection in adults over the past 5-10 years, resulting in standardized regimes for initial treatment, relapsers and even infection in the setting of recurrence post-liver transplantation. These regimes have resulted in the halting of the disease progression, reduction in the risk of hepatocellular carcinoma and removal of these infections as a contraindication for liver transplantation. However, treatment in children must be considered carefully in the context of the natural history of these infections and host factors, particularly the immunological mileu, which may affect response to therapy. The as yet unknown long-term effects of medications must also be balanced with the probability of significant life-long morbidity or mortality from chronic hepatitis and its complications. Furthermore, the development of drug resistance, particularly in the case of CHB, has significant implications for the pediatric patient who may exhaust effective therapeutic options at a relatively young age. For these reasons, initiation of therapy must be based on sound criteria. Based on the current data, we recommend that therapy should be offered to children with CHB who have an elevation in alanine aminotransferase (>2-3 x upper limit of normal) for more than 6 months. Therapy with interferon-alpha should be offered in the majority of cases with the aim of immune clearance as measured by early antigen seroconversion. By contrast, treatment indication for CHC in children remains controversial. If used, combination therapy with pegylated interferon and ribavirin is likely to produce the highest rates of sustained viral response.

Antiviral Agents↗
PubMed2005

Primary liver carcinoma arising in people younger than 30 years.

Primary liver carcinomas in children and young adults are uncommon and poorly described. We examined primary liver carcinomas in people younger than 30 years and performed immunostains for markers of biliary (cytokeratin [CK] 7, CK19, CD56) and hepatocellular (HepPar) differentiation. We found 23 primary liver carcinomas were found: 13 hepatocellular carcinomas (HCCs), 9 fibrolamellar carcinomas (FLCs), and 1 cholangiocarcinoma. Most HCCs showed compact (n = 7) or trabecular (n = 4) growth patterns. The Edmondson grades were as follows: 1, 3 tumors; 2, 8 tumors; and 3, 2 tumors). All HCCs and FLCs were HepPar(+). All FLCs and 7 of 9 HCCs were CK7(+). In contrast, a control group of 65 adult HCCs showed less CK7 positivity (24 [37%]; P = .03). CK19 was positive in 2 HCCs and CD56 in 1 HCC. No chronic background liver disease was seen, although 3 cases showed foci of altered hepatocytes. HCCs are the most common primary liver carcinoma in children and young adults followed by FLCs. They are morphologically similar to adult HCC, but more likely to be CK7(+).

Adolescent↗
PubMed2004

Autoimmune hepatitis.

Autoimmune hepatitis affects all ages with a peak incidence in preadolescent girls. The pathogenesis of autoimmune hepatitis has not been defined. Susceptibility, clinical manifestations, and treatment outcomes are affected by environmental factors, individual immunoregulatory responses, genetic factors, age and gender. An international panel has developed diagnostic criteria for autoimmune hepatitis, and a scoring system to assess the strength of the diagnosis has also been proposed. This article discusses the diagnosis and treatment of the three types of autoimmune hepatitis proposed based on characteristic autoantibody profiles, as well as de novo autoimmune hepatitis, a new type of autoimmune hepatitis that has been recently described in liver transplant recipients without previous autoimmune disease.

Adolescent↗
PubMed2003

Pediatric issues in new therapies for hepatitis B and C.

Two antiviral treatments have been approved for hepatitis B virus (HBV) infection by the US Food and Drug Administration (FDA) for use in children: interferon (IFN)-alpha, 6 MU/m(2) three times a week subcutaneously for 6 months, and lamivudine, 3 mg/kg/d orally for 12 months. Twenty-six percent to 58% of children treated with IFN become HBV DNA negative, and up to 38% become negative to hepatitis B e antigen (HBeAg). Lamivudine, a nucleoside analogue that blocks viral replication by inhibition of the HBV polymerase, has been associated with comparable rates of seroconversion of HBeAg to anti-HBe. Loss of surface antigen occurs in less than 5% of patients treated with lamivudine, compared with 3% to 33% in those treated with IFN-alpha. Fifty percent to 65% of children treated with lamivudine clear HBV DNA after 12 months of therapy, but relapse rates have not been clarified. Patients treated with lamivudine develop drug-resistant (YMDD) mutants in the HBV polymerase at the rate of 16% to 32% per year. No treatments for children with hepatitis C virus (HCV) have been approved by the FDA. However, published reports describe treatment with IFN monotherapy and combination therapy with IFN and ribavirin. Trials of PEG-IFN alone or in combination with ribavirin are in progress. Given the lack of data regarding treatment of HCV in children, it is generally agreed among pediatric hepatologists that the optimal treatment is within the context of randomized, controlled trials.

Adolescent↗
PubMed2003

Epidemiology of primary hepatic malignancies in U.S. children.

The epidemiology of primary hepatic malignancies in U.S. children is poorly characterized. We analyzed the incidence, mortality, and characteristics of primary hepatic malignancies in U.S. residents less than 20 years of age. Fatal primary hepatic malignancies in persons less than 20 years of age, between 1979 and 1996, were identified using the multiple-cause-of-death database (National Center for Health Statistics). Histologically confirmed primary hepatic malignancies occurring between 1973 and 1997 were identified using the Surveillance, Epidemiology, and End Results (SEER) database. Between 1979 and 1996, 918 primary hepatic malignancy deaths (average, 0.7/1,000,000/year) were reported nationally among persons less than 20 years of age; rates were higher among Asians and among foreign-born children. Between 1973 and 1997, 271 primary hepatic malignancy cases were reported to SEER among persons less than 20 years of age, of which 184 (67%) and 83 (31%) were hepatoblastoma and hepatocellular carcinoma, respectively. Among children less than 5 years of age, hepatoblastoma accounted for 91% of primary hepatic malignancy cases, whereas among those 15 to 19 years of age, hepatocellular carcinoma accounted for 87% of cases. Five-year survival for hepatoblastoma was 52%, compared with 18% for hepatocellular carcinoma. In the SEER sites, between 1973 and 1977 and 1993 and 1997, hepatoblastoma rates increased (0.6 to 1.2/1,000,000, respectively), while hepatocellular carcinoma rates decreased (0.45 to 0.29/1,000,000, respectively). In conclusion, histologically confirmed hepatocellular carcinoma was reported in children less than 5 years of age, also, where hepatoblastoma is the predominant primary hepatic malignancy. Hepatocellular carcinoma has worse survival rates than hepatoblastoma, and its incidence has not increased. Better maintenance of databases may provide information about associated factors behind this unexpected occurrence.

Adolescent↗
PubMed2003

Plasma markers of platelet activation in cystic fibrosis liver and lung disease.

BACKGROUND: Transforming growth factor beta 1 (TGFbeta1) is a major fibrogenic cytokine, the expression of which is increased in the livers of children with cystic fibrosis liver disease (CFLD) and in the bronchoalveolar lavage fluid of patients with cystic fibrosis pulmonary disease (CFPD). The purpose of our study was to investigate the usefulness of plasma TGFbeta1 as a noninvasive marker of CFLD and CFPD, or both and to investigate the contribution of platelet-derived TGFbeta1 to plasma TGFbeta1 by correlating the latter with platelet factor 4 (PF4). METHODS: Three groups of patients with cystic fibrosis were studied: 1) those with CFLD, 2) those with CF and no liver disease (CFNLD), and 3) those with CFPD. Controls were healthy adolescents and adults. Plasma TGFbeta1 was assayed using the R and D Quantikine quantitative sandwich enzyme immunoassay technique and PF4 (American Bioproducts ELISA kit). RESULTS: Plasma TGFbeta1 was markedly increased in CFPD (15 +/- 3 ng/mL) versus healthy adults (1 +/- 0 ng/mL; P < 0.004. The PF4 values followed a similar pattern: 105 +/- 8 ng/mL in CFPD versus 12 +/- 4 ng/mL (P < 0.0001). Plasma TGFbeta1 values in CFLD did not differ from CFNLD patients of comparable age nor from values for healthy adolescents. Plasma TGFbeta1 values were strongly correlated with values for PF4: r = 0.543, P < 0.0001. CONCLUSIONS: Plasma TGFbeta1 is not a useful marker of CFLD. The increased plasma TGFbeta1 and PF4 in CFPD patients are of interest both as possible noninvasive markers of pulmonary fibrosis and because the increased values suggest that platelet activation may play a pathogenetic role in CFPD.

Adult↗
PubMed2003

Fractures in biliary atresia misinterpreted as child abuse.

Bone fractures in children without a history of injury are highly suspicious for child abuse. Biliary atresia is a disorder associated with metabolic bone disease, and there are numerous reports of osteopenia, rickets, and/or fractures in this population. We report 3 cases of children with biliary atresia who had bony fractures as well as osteopenia whose caretakers were investigated for child abuse. Pediatricians should be aware of an increased incidence of fractures and overall prevalence of bone disease in this population.

Biliary Atresia↗
PubMed2002

Clinical trial of lamivudine in children with chronic hepatitis B.

BACKGROUND: Lamivudine therapy is effective for chronic hepatitis B infection in adults. We evaluated the efficacy and tolerability of lamivudine as a treatment for chronic infection with hepatitis B virus (HBV) in children. METHODS: Children with chronic hepatitis B were randomly assigned in a 2:1 ratio to receive either oral lamivudine (3 mg per kilogram of body weight; maximum, 100 mg) or placebo once daily for 52 weeks. The primary end point was virologic response (defined by the absence of serum hepatitis B e antigen and serum HBV DNA) at week 52 of treatment. RESULTS: Of the 403 children screened, 191 were randomly assigned to receive lamivudine and 97 to receive placebo. The rate of virologic response at week 52 was higher among children who received lamivudine than among those who received placebo (23 percent vs. 13 percent, P=0.04). Lamivudine therapy was well tolerated and was also associated with higher rates of seroconversion from hepatitis B e antigen to hepatitis B e antibody, normalization of alanine aminotransferase levels, and suppression of HBV DNA. CONCLUSIONS: In children with chronic hepatitis B, 52 weeks of treatment with lamivudine was associated with a significantly higher rate of virologic response than was placebo.

Adolescent↗
PubMed2002

An analysis of published trials of interferon monotherapy in children with chronic hepatitis C.

BACKGROUND: Although no therapeutic regimen has received Food and Drug Administration approval for treating children with chronic hepatitis C viral infection (CHC), there have been a number of pediatric interferon-alpha (IFN-alpha) trials. The purpose of this study was to perform a critical review of these trials to determine 1) end-of-treatment (ETR) and sustained-response (SR) rates, 2) predictors of response to therapy, and 3) safety of and tolerance to IFN-alpha in children with CHC. METHODS: Relevant studies in the English-language medical literature and abstracts (January 1990 through November 2000) were identified by searching for manuscripts that contained the key words "children," "hepatitis C," and "interferon." Trials were considered eligible for inclusion in this analysis if criteria for treatment included positive serum polymerase chain reaction for hepatitis C virus RNA (HCV PCR). RESULTS: Twenty published manuscripts of the use of IFN-alpha in children with CHC were found, of which 12 met our inclusion criteria. Twenty-two abstracts, of which seven met our inclusion criteria, were identified. In the 19 included trials, 366 treated and 105 untreated children were observed; five countries were represented. Average ETR was 54% (0%-91%) and average SR was 36% (0%-73%). The SR in children with genotype 1 was 27% versus 70% for nongenotype 1 ( P = 0.001). Five of 105 (5%) untreated controls exhibited spontaneous viral clearance. CONCLUSIONS: To date, there is no published large-scale, multicenter, prospective, placebo-controlled randomized trial of the use of IFN-alpha in children with CHC. The data in this review suggest that IFN-alpha in children with CHC does have reasonable efficacy and safety. This review highlights the need for a more systematic design of future pediatric CHC trials. Ideally, such trials would be large scale, prospective, and controlled, and would include HCV genotype and viral load, histology, quality of life measures, and systematic recording of adverse events and of effects of therapy on growth and development.

Adolescent↗
PubMed2002

Viral hepatitis.

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Child↗