Israel Medical Association Journal

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.

Abstract

Background: Scleroderma lung disease (ILD-SSc) is treated mainly with cyclophosphamide (CYC). The effectiveness of CYC was judged after 12–24 months in most reports.

Objectives: To analyze the effect of monthly intravenous CYC on pulmonary function tests including forced vital capacity (FVC) and diffusing lung capacity (DLCO), as well as Rodnan skin score (mRSS), during long-term follow-up.

Methods: We retrospectively collected the data on 26 ILD-SSc patients who began CYC treatments before 2007. Changes in FVC, DLCO and mRSS before treatment, and at 1, 4 and 7 years after completion of at least six monthly intravenous CYC treatments for ILD-SSc were analyzed.

Results: Mean cumulative CYC dose was 8.91 ± 3.25 G. More than 30% reduction in FVC (0%, 8%, and 31% of patients), DLCO (15%, 23%, 31%), and mRSS (31%, 54%, 62%) at years 1, 4 and 7 was registered. During the years 0–4 and 4–7, annual changes in FVC, DLCO and mRSS were 3.2 vs. 0.42% (P < 0.040), 4.6 vs. 0.89% (P < 0.001), and 1.8 vs. 0.2 (P = 0.002). The greatest annual FVC and DLCO reduction over the first 4 years correlated with mortality (P = 0.022). There were no differences in the main variables regarding doses of CYC (< 6 G and > 6 G).

Conclusions: In patients with ILD-SSc, CYC stabilized the reduction of FVC during treatment, but this effect was not persistent. The vascular characteristic of ILD-SSc (DLCO) was not affected by CYC treatment. CYC rapidly improved the mRSS. This effect could be achieved with at least 6 G of CYC. Higher rates of annual reduction in FVC and DLCO in the first 4 years indicate the narrow window of opportunity and raise the question regarding ongoing immunosuppression following CYC infusions.

 

Background: The activated NLRP3 inflammasome is associated with the etiology of fibrotic diseases. The role of inflammasomes in SSc is still poorly understood.

Objectives: To determine the expression of NLRP3 (nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3) in the skin of patients with systemic sclerosis (SSc) and its relationship with pro-inflammatory cytokines and vascular mediators expression.

Methods: Skin biopsies were taken from 42 patients with either limited or diffuse SSc (21 lcSSc and 21 dcSSc), and from 13 healthy individuals. Using real-time polymerase chain reaction (PCR), the relative expression of caspase-1, IL-1β, IL-18, IL-33, TGF-β, ET-1, iNOS and eNOS genes, were measured. The location of NLRP3 and IL-1β were also determined by immunohistochemistry. Clinical characteristics were evaluated.

Results: The mean age of the patients was 49.3 ± 12.9 (lcSSc), 44.6 ±1 3.8 (dcSSc), and 45 ± 14.1 (healthy individuals). Compared to healthy individuals, the skin of both subtypes of SSc showed a significant increase (P < 0.05) in NLRP3, caspase-1, IL-1β, IL-18 and ET-1. Samples of lcSSc also showed a significant increase of eNOS (P < 0.029), iNOS (P < 0.04) and TGF-β (P < 0.05). Dermal fibrosis evaluated by modified Rodnan skin score (MRSS) had significant correlation with NLRP3, IL-1β, IL-18, and ET-1. Immunohistochemical analysis showed stronger staining of NLRP3 and IL-1β cytoplasmic expression in the keratinizing squamous epithelium of skin from SSc patients compared to controls.

Conclusions: This study identified NLRP3 over-expression in skin of patients with SSc. Skin thickness correlates positively with the NLRP3 inflammasome gene expression and with the vascular mediator and pro-fibrotic ET-1, suggesting that NLRP3 inflammasome plays a role in the pathophysiology of skin fibrosis in human SSc.

Objectives: To examine the proliferative index, as expressed by Ki67, in various subtypes of basal cell carcinoma, and to assess its relationship to various histological and clinical variables.

Methods: In this retrospective study 51 lesions of BCC were examined. In each case, the following data were gathered: demographic (age and gender), anatomic location, size of the lesion, and clinical follow-up.  Each case was stained immunohistochemically with anti-Ki67 antigen (MIB-1), and the proliferative index was determined. Histologic analysis was performed for the following data: presence of an ulcer, intensity of inflammatory infiltrate, histologic subtype, mitotic count, and the presence of perineural invasion.

Results: Basal cell carcinoma exhibited a wide variation of proliferative indices, ranging from 1% to 61%. A significant statistical correlation was observed between the proliferative index and the mitotic activity, tumor ulceration and brisk tumor-infiltrating lymphocytes.

Conclusions: The wide variation in the degree of proliferation (from almost no activity to highly proliferative tumors) suggests that basal cell carcinoma exhibits a wide spectrum of biological characteristics. Ulcerated lesions were characterized by high proliferative index. No true correlation was demonstrated between the proliferative index and the aggressive histologic subtypes, implying that other factors were more biologically significant. The degree of proliferation also showed significant statistical correlation with the degree of tumor infiltration by lymphocytes. The significance of this proliferation-associated increased immunogenicity needs to be further studied.

Background: Skin-prick tests (SPT), food-specific immunoglobulin E level (sIgE) and clinical history have limited value individually in predicting the severity of outcome of the oral food challenge (OFC). 

Objectives: To develop a score that accounts for SPT, sIgE and clinical history to predict the risk of severe reaction to the OFC. 

Methods: A 5 year retrospective chart review was performed on 983 children who underwent OFC to egg, milk and peanut. 

Results: Using multilogistic regression, four major indicators were found to be independently associated with failed OFC: sIgE (odds ratio = 1.04, P < 0.0001) , wheal size of the SPT (OR = 1.23, P < 0.0001), a history of any prior reaction to the food (OR = 1.13, P < 0.01), and a history of a prior non-cutaneous reaction (OR = 1.99, P < 0.01)  and three were independently associated with anaphylaxis: wheal size (OR = 1.16, P < 0.001), a history of a prior non-cutaneous reaction (OR = 4.24, P < 0.01), and age (OR = 1.07, P < 0.03). A Food Challenge Score (0–4) was developed which accounted for SPT wheal, sIgE, a history of a prior non-cutaneous reaction, and age. A score of 0–1 had a negative predictive value for multisystem reaction to the OFC: 95% for milk, 91% for egg and 93% for peanut. A score of 3–4 had a positive predictive value for anaphylaxis:  62% for milk, 92% for egg and 86% for peanut.

Conclusions: Severe reaction to milk, egg and peanut OFC can be predicted using a simple score that takes into account clinical data that are commonly available prior to the challenges.