Israel Medical Association Journal

Background: Hepatitis C virus (HCV) is a leading cause of cirrhosis and hepatocellular carcinoma worldwide. Several viral and host factors related to viral response have been reported in the era of treatment with pegylated (PEG)-interferon and ribavirin.

Objectives: To quantify histological findings from patients with chronic HCV using computerized morphometry and to investigate whether the results can predict response to medical treatment with peg-interferon and ribavirin.

Methods: We followed 58 patients with chronic HCV infection with METAVIR score F1 and F2 in our liver unit who were grouped according to treatment response sustained viral response (SVR) and non-SVR. Liver needle biopsies from these patients were evaluated and histological variables, such as inflammatory cells, collagen fibers and liver architecture, were quantified using computerized morphometrics. The pathologist who performed the histomorphometric analysis was blinded to previous patient clinical and histological information.

Results: Histomorphometric variables including the density of collagen fibers were collected. The number of inflammatory cells in the portal space and textural variable were found to be statistically significant and could be used together in a formula to predict response to treatment, with a sensitivity of 93% and a 100% specificity.

Conclusions: Histomorphometry may help to predict a patient's response to treatment at an early stage.

The major route of hepatitis C virus (HCV) infection in the pediatric age group is vertical, with infection occurring in up to 5% of infants born to mothers positive for HCV-RNA. The natural course of pediatric HCV infection is characterized by a high rate of spontaneous clearance, an asymptomatic clinical course, and normal or mild histologic changes. Cirrhosis is reported in 1–2% of children and progression to severe chronic liver disease and HCC occurs 20–30 years after infection. Treatment with pegylated interferon (Peg-IFN) + ribavirin results in a sustained viral response (SVR) of up to 100% in children with HCV genotypes 2 or 3 but only 45–55% in those infected with genotypes 1 or 4. Treatment is associated with adverse effects ranging from flu-like symptoms, myalgia, anemia and thrombocytopenia, to less commonly observed thyroid-related symptoms, alopecia, neuropsychiatric manifestations and possible long-term effects on growth. Ongoing trials with direct-acting antiviral agents in adults show promising results with treatment regimens of shorter duration and high tolerance. The next few years will likely see these advances introduced to the pediatric population as well. In the meantime, in children with HCV an expectant approach is advocated and treatment should be offered only to those at high risk for more severe, progressive disease. 

Background: Determining the accuracy of interferon gamma-releasing assays (IGRAs) is difficult due to the lack of a gold standard test for diagnosing latent tuberculosis (LTB). 

Objectives: To analyze the guidelines used for interpreting IGRAs in determining prophylactic treatment management for latent tuberculosis (LTB) in Israel.

Methods: We analyzed the retrospective data of 367 subjects who were referred to our laboratory during the period 2007–2011 for QuantiFERON Test-Gold In Tube (QFT-GIT) tests because of suspected LTB. Demographics and clinical data were retrieved from a questionnaire at enrollment, and 166/367 (45%) were further interviewed by phone in order to complete follow-up information on prophylactic TB treatment. 

Results: The majority of subjects (116/166, 69.9%, P < 0.0001) were spared prophylactic treatment subsequent to QFT-GIT testing. Subjects with negative QFT-GIT and positive tuberculin skin test (TST) results who were BCG-vaccinated had the lowest treatment rates (6/68, 8.8%, P < 0.0001). Most BCG-vaccinated subjects with positive TST and negative QFT-GIT test results received treatment with anti-tumor necrosis factor-alpha (TNFα) (17/19, 89.5%, P = 0.004). We found more negative QFT-GIT test results in subjects who were receiving anti-TNFα or steroid and other immunosuppressive treatment prior to testing (11/11, 100%, P = 0.029; 22/26, 84.6%, P = 0.06; 15/17, 88%, P = 0.06, respectively). 

Conclusions: Deciding on LTB prophylactic treatment in Israel is highly influenced by QFT-GIT test results. QFT-GIT findings contribute to clinical decisions, but their interpretation must also consider the patient’s medical history and clinical characteristics. 

 

Abstract

Background: The mass influx of immigrants from tuberculosis-endemic countries into Israel was followed by a considerable increase in the incidence of tuberculosis (TB). All contacts of active TB patients are obliged to be screened by tuberculin skin tests (TST) and, if found positive, prophylactic treatment is considered.

Objectives: To assess the utility of interferon-gamma (IFNγ)-release assay with a prolonged follow-up in preventing unnecessary anti-TB therapy in individuals with suspected false positive results.

Methods: Between 2008 and 2012 the QuantiFERON TB gold-in-tube test (QFT-G) was performed in 278 sequential individuals who were mostly TST-positive and/or were in contact with an active TB patient. In all, whole blood was examined by the IFNγ-release assay. We correlated the TST diameter with the QFT-G assay and followed those patients with a negative assay.

Results: The QFT-G test was positive in only 72 (42%) of all 171 TST-positive individuals. There was no correlation between the diameter of TST and QFT-G positivity. Follow-up over 5 years was available in 128 (62%) of all QFT-G-negative individuals. All remained well and none developed active TB.

Conclusions: A negative QFT-G test may obviate the need for anti-TB therapy in more than half of those with a positive TST.

Background: Multiple drug allergy syndrome is a rarely reported clinical condition characterized by an adverse reaction to more than one different class of pharmacologically and structurally unrelated drugs. The pathogenesis may involve immediate-type or delayed-type hypersensitivity.

Objectives: To further characterize patients with MDA[1] in terms of the type of CADR, drug intake and clinical drug suspicion.

Methods: The study group comprised 12 patients (6 males, 6 females) with CADRs[2] showing in vitro drug-induced IFNγ[3] release for multiple drugs, suggesting the presence of MDA. The diagnostic role of in vitro IFNγ release in identifying the culprit drugs was evaluated in terms of clinical data and the results of in vivo tests (withdrawal and/or challenge tests) with the offending drugs.

Results: Clinical relevance was attributed to in vitro drug-induced IFNγ release towards multiple drugs in this series of 12 patients with a variety of CADRs, implying MDA. The results of in vivo tests for the offending drugs confirmed the diagnosis. The main causative agents responsible were antibiotics and non-steroidal anti-inflammatory drugs.

Conclusions: The study further supports the role of a T cell-mediated mechanism in the pathogenesis of MDA. The in vitro drug-induced IFNγ release test may serve as a laboratory tool to identify the culprit drugs associated with this allergy.  

Background Drug-specific CD8+ TH1 lymphocytes have been found in the peripheral blood and involved skin of patients with drug-induced bullous exanthems.

Objectives To determine whether the interferon-gamma release test can identify culprit drugs in pemphigus patients.

Methods Clinical and laboratory workup for pemphigus was performed in 14 pemphigus vulgaris patients who had been exposed to drugs, and the IFNl[1] release test was conducted on their lymphocytes from heparinized venous blood cultured with medium, phytohemagglutinin and one of 32 drugs, or medium and phytohemagglutinin alone.

Results Ten of the patients and 13 of the 32 drugs exhibited a positive response to the test. Eight of the 10 patients with positive IFNl test results had a less severe course of the disease, with fast reduction in steroid dosage.

Conclusions The findings demonstrate both the ability of the IFNl release test to identify drugs that can induce pemphigus, and its usefulness in the diagnostic workup of pemphigus patients.

Background: The cognitive impairment (frontal, parietal) in many patients with multiple sclerosis does not correlate with the degree of neurological disability and disease duration. Frontal/prefrontal cognitive impairment requires neuropsychological diagnostic tools.

Objectives: To evaluate the clinical effect of IFNβ-1b[1] (Betaferon®) treatment on cognitive function and event-related potential as compared to the clinical course (EDSS[2]) in MS patients during 1 year of follow-up.

Methods: This prospective open-label design study included 16 consecutive patients with relapsing forms of MS attending the MS outpatient clinic. Mean EDSS score was calculated prior to starting treatment. Parietal lobe event-related potential P300 was elicited using an auditory physical stimulus to an alert subject. Mean P300 amplitude and latency were calculated for the group before treatment. The Wisconsin Card Sorting Test, which measures frontal lobe functions, was performed before the treatment. After 1 year of treatment a second P300 and Wisconsin Card Sorting Test were performed and the mean change between visit 1 and baseline was calculated for each parameter. Correlation between the change in P300 and the Wisconsin Card Sorting Test score at baseline was measured using the paired t-test.

Results: There was a significant reduction in P300 amplitude and latency after 1 year of treatment with IFNβ-1b: from 20.3 ± 8.3 μv to 13.1 ± 10.6 μv (P = 0.026) for amplitude, and from 312.9 ± 15.6 msec to 302.0 ± 17.0 msec (P = 0.002) for latency. The Perseverative Response (raw score) and the Perseverative Response U.S. Census age-matched standard score showed a significant improvement – from 20.7 ± 30.7 to 13.1 ± 10.6 (P = 0.001) and 96.7 ± 15.7 to 100.1 ± 11.1 (P = 0.0025) respectively – after 1 year of treatment. A mild but not significant improvement was observed on the EDSS after 1 year of treatment: 2.9 ± 0.5 to 2.8 ± 1.1.

Conclusions: A cognitive decline in MS patients may have a negative impact on the quality of life, affecting all active daily living domains. IFNβ-1b, a disease-modifying therapy, has demonstrated a positive therapeutic effect on cognitive dysfunction, unrelated to its effect on the EDSS score and course of the disease.

Background: Drug-induced thyrotoxicosis is not uncommon. It may worsen life-threatening arrhythmias and may be refractory to medical treatment. Near-total thyroidectomy presents a valid alternative to medical therapy and should be considered early in the management of the disease.

Objectives: To assess whether near-total thyroidectomy was a viable approach for our patients.

Methods: Twelve patients – 7 men and 5 women, aged 63 to 82 years – presented with drug-induced fulminant thyrotoxicosis following 1 to 12 months of amiodarone treatment (11 patients, mean 7 months) and after a 6 months course of interferon-alpha treatment (one patient). Medical therapy included propylthiouracil in doses up to 1200 mg/day in all patients and a beta-receptor antagonist in seven. Five patients had to stop amiodarone treatment and start high doses of steroids. A thyroid scan was performed in all patients using 5 mCi of Tc-99m pertechnetate. The thyroid scan showed absent uptake of the tracer in the thyroid bed in all patients, precluding the use of radioablation.

Results: Four patients (three with AIT[1] and one with interferon therapy) who did not respond to 3 months of medical therapy required surgical thyroidectomy due to severe unremitting thyrotoxicosis. A near-total thyroidectomy resulted in rapid correction of thyrotoxicosis, enabling continuation of the anti-arrhythmic drug. There were no intraoperative or postoperative arrhythmias. Subsequently, all patients recovered rapidly and remained well and euthyroid on thyroxine replacement therapy.

Conclusions: Since surgery results in rapid control of thyrotoxicosis and permits continued therapy with amiodarone, we suggest that near-total thyroidectomy warrants consideration as a definitive treatment for resistant amiodarone or interferon-induced thyrotoxicosis.