On-Field Test of Tuberculosis Diagnosis through Exhaled Breath Analysis with a Gas Sensor Array.

Tuberculosis (TB) is among the more frequent causes of death in many countries. For pulmonary TB, early diagnosis greatly increases the efficiency of therapies. Although highly sensitive tests based on nucleic acid amplification tests (NAATs) and loop-mediated isothermal amplification (TB-LAMP) are available, smear microscopy is still the most widespread diagnostics method in most low-middle-income countries, and the true positive rate of smear microscopy is lower than 65%. Thus, there is a need to increase the performance of low-cost diagnosis. For many years, the use of sensors to analyze the exhaled volatile organic compounds (VOCs) has been proposed as a promising alternative for the diagnosis of several diseases, including tuberculosis. In this paper, the diagnostic properties of an electronic nose (EN) based on sensor technology previously used to identify tuberculosis have been tested on-field in a Cameroon hospital. The EN analyzed the breath of a cohort of subjects including pulmonary TB patients (46), healthy controls (38), and TB suspects (16). Machine learning analysis of the sensor array data allows for the identification of the pulmonary TB group with respect to healthy controls with 88% accuracy, 90.8% sensitivity, 85.7% specificity, and 0.88 AUC. The model trained with TB and healthy controls maintains its performance when it is applied to symptomatic TB suspects with a negative TB-LAMP. These results encourage the investigation of electronic noses as an effective diagnostic method for future inclusion in clinical practice.

Unemployment Status Subsequent to Cancer Diagnosis and Therapies: A Systematic Review and Meta-Analysis.

The purpose of our study is to examine whether cancer and treatments are associated with job loss or changes in employment status. Eight prospective studies were included in the systematic review and meta-analysis, with a population aged 18-65 years, analyzing treatment regimen and psychophysical and social status in post-cancer follow-up of at least 2 years. In the meta-analysis, a comparison was made between recovered unemployed cases and cases from a standard reference population. Results are summarized graphically using a forest plot. We showed that cancer and subsequent treatment are risk factors for unemployment with an overall relative risk of 7.24 (lnRR: 1.98, 95% CI: 1.32-2.63) or for change in employment status. Individuals undergoing chemotherapy and/or radiation treatment and those with brain and colorectal cancers are more likely to develop disabilities that negatively affect the risk of unemployment. Finally, variables such as low level education, female sex, older age, and being overweight before starting therapy are associated with higher risk of unemployment. In the future, it will be necessary for people with cancer to have access to specific health, social welfare, and employment support programs. In addition, it is desirable that they become more involved in their choice of therapeutic treatment.

Systematic review and meta-analysis of recent high-quality studies on exposure to particulate matter and risk of lung cancer.

BACKGROUND: Several aspects of the association between exposure to air pollution and risk of lung cancer remain unclear. OBJECTIVE: We aimed at performing a meta-analysis of high-quality cohort studies on exposure to particulate matter (PM) 10 and PM2.5 and risk of lung cancer. METHODS: We identified cohort studies published since 2004, that reported risk estimates of lung cancer for exposure to PM2.5 and PM10 adjusted for tobacco smoking and socioeconomic status, and conducted a meta-analysis based on random-effects models, including stratification by outcome, sex, country, tobacco smoking, and age. RESULTS: Results on PM2.5 exposure were available from 15 studies; the summary relative risk (RR) for an increase of 10 µg/m3 was 1.16 (95% confidence interval [CI] 1.09, 1.23). The corresponding RR for PM10 exposure was 1.23 (95 CI 1.05, 1.40; seven studies). A higher risk was suggested in studies based on lung cancer mortality and in studies conducted in East Asia, while no difference was shown according to sex, smoking status or age. There was no suggestion of publication bias. CONCLUSIONS: Our meta-analysis supported the hypothesis of an association between exposure to PM2.5 or PM10 and risk of lung cancer, and provided evidence that the magnitude of the risk might be higher than previously estimated, and might be modified by outcome and geographic region.

Delay in Breast Cancer Treatments During the First COVID-19 Lockdown. A Multicentric Analysis of 432 Patients.

BACKGROUND/AIM: Extraordinary restrictions aimed to limit Sars-CoV-2 spreading; they imposed a total reorganization of the health-system. Oncological treatments experienced a significant slowdown. The aim of our multicentric retrospective study was to evaluate screening suspension and surgical treatment delay during COVID-19 and the impact on breast cancer presentation. PATIENTS AND METHODS: All patients who underwent breast surgery from March 11, 2020 to May 30, 2020 were evaluated and considered as the Lockdown group. These patients were compared with similar patients of the previous year, the Pre-Lockdown group. RESULTS: A total of 432 patients were evaluated; n=223 and n=209 in the Lockdown and Pre-lockdown-groups, respectively. At univariate analysis, waiting times, lymph-nodes involvement and cancer grading, showed a statistically significant difference (p<0.05). Multivariate analysis identified waiting-time on list (OR=1.07) as a statistically significant predictive factor of lymph node involvement. CONCLUSION: Although we did not observe a clinically evident difference in breast cancer presentation, we reported an increase in lymph node involvement.

Effect of Lockdown in Surgical Emergency Accesses: Experience of a COVID-19 Hospital.

BACKGROUND/AIM: SARS-CoV-2 pandemic imposed extraordinary restriction measures and a complete reorganization of the Health System. The aim of the study was to evaluate the impact of COVID-19 on emergency surgical department accesses. PATIENTS AND METHODS: Patients admitted to surgical emergency departments was retrospectively recorded during the Lockdown (March 11, 2020-May 3, 2020) and compared with the same number of days in 2019 and immediately before Lockdown (January 16, 2020-March 10, 2020). Diagnoses, priority levels, modes of patient's transportation, waiting times and outcomes were analysed. RESULTS: During the lockdown phase, we ob-served a reduction in the access to emergency surgical departments of 84.45% and 79.78%, com-pared with the Pre-Lockdown2019 and Pre-Lockdown2020 groups, respectively. Patient's transportation, hospitalization and patients discharge with indications to an outpatient visit, waiting and total times exhibited a significant difference during the lockdown (p<0.005). CONCLUSION: We observed a reduction of surgical emergency accesses during the lockdown. Implementing the use of the regional systems and preventing overcrowding of emergency departments could be beneficial for reducing waiting times and improving the quality of treatments for patients.

Lockdown of Breast Cancer Screening for COVID-19: Possible Scenario.

BACKGROUND/AIM: Coronavirus disease is spreading worldwide. Due to fast transmission and high fatality rate drastic emergency restrictions were issued. During the lockdown, only urgent medical services are guaranteed. All non-urgent services, as breast cancer (BC) screening, are temporarily suspended. The potential of breast cancer screening programs in increasing the survival rate and decreasing the mortality rate has been widely confirmed. Suspension could lead to worse outcomes for breast cancer patients. Our study aimed to analyse the data and provide estimates regarding the temporary BC screening suspension. PATIENTS AND METHODS: Data regarding breast cancer and respective screening programs were achieved through literature research and analysis. RESULTS: Considering three different scenarios with respect to the lockdown's impact on breast cancer screening, we estimate that approximately 10,000 patients could have a missed diagnosis during these 3 months. Considering a 6-month period, as suggested by the Imperial college model, the number of patients who will not receive a diagnosis will rise to 16,000. CONCLUSION: Breast cancer screening should be resumed as soon as possible in order to avoid further breast cancer missed diagnosis and reduce the impact of delayed diagnosis.

A novel approach for geographical risk mapping of morbidity and mortality rates: the case of Val D'Agri, Italy.

While associations between exposure to air pollutants and increased morbidity and mortality are well established, few rigorous studies on this issue are available. The aim of the current study is to implement a new approach to the spatial analysis of mortality and morbidity, based on testing for the presence of the same association in other areas of similar size. Additionally, we perform a case study in Val d'Agri (VA), an area of Basilicata Region, Southern Italy, where oil and natural gas extraction began in 1998. In order to examine the spatial distribution of morbidity and mortality in the region of interest, Hospital discharge (2001-2013) and mortality (2003-2014) rates for the main environment-related diseases were calculated. In addition, a comparison between the period 1980-1998 and the period 1999-2014 was performed for cardiovascular disease mortality. For the period under study, a neutral scenario emerged for cancer and respiratory diseases, where we found no differences in morbidity and mortality as compared to the national benchmark. In some cases significantly lower values (as compared to the nation-wide benchmark) were found. Conversely, a slight excess in morbidity and mortality (as compared to the nation-wide benchmark) emerged for cardiovascular diseases. Still, this excess was common to a number of municipalities in the surroundings of VA, and appeared to be already present in 1980. Higher rates of cardiovascular diseases, lower rates of neoplastic disorders no differences in mortality for respiratory causes (as compared to the nation-wide benchmark) were found in multiple areas of the region, and were therefore not specific to VA. In summary, our data do not support the hypothesis of a role of industrial activities related to oil extraction in VA in determining mortality and morbidity patterns and trends.

Frailty as the Future Core Business of Public Health: Report of the Activities of the A3 Action Group of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA).

Background: The prevalence of frailty at population-level is expected to increase in Europe, changing the focus of Public Health. Here, we report on the activities of the A3 Action Group, focusing on managing frailty and supporting healthy ageing at community level. Methods: A three-phased search strategy was used to select papers published between January 2016 and May 2018. In the third phase, the first manuscript draft was sent to all A3-Action Group members who were invited to suggest additional contributions to be included in the narrative review process. Results: A total of 56 papers were included in this report. The A3 Action Group developed three multidimensional tools predicting short⁻medium term adverse outcomes. Multiple factors were highlighted by the group as useful for healthcare planning: malnutrition, polypharmacy, impairment of physical function and social isolation were targeted to mitigate frailty and its consequences. Studies focused on the management of frailty highlighted that tailored interventions can improve physical performance and reduce adverse outcomes. Conclusions: This review shows the importance of taking a multifaceted approach when addressing frailty at community level. From a Public Health perspective, it is vital to identify factors that contribute to successful health and social care interventions and to the health systems sustainability.

Evaluation of the Usefulness of FDG-PET/CT for Nodal Staging of Breast Cancer.

BACKGROUND/AIM: Positron emission tomography/computed tomography (PET/CT) with 18F-fluorodeoxyglucose (18F-FDG) has recently been used to investigate lymph node (LN) metastases and several predictive features in patients with breast cancer (BC). The aim of this study was to assess the value of this non-invasive imaging procedure for axillary staging. PATIENTS AND METHODS: Fifty patients with early primary unilateral, locally advanced, or recurrent invasive operable BC were enrolled. All patients underwent preoperative 18F-FDG PET/CT, and the results were compared with the histopathology of dissected axillary LNs and their biological and immunohistochemical characteristics. The diagnostic performance of 18F-FDG PET/CT in detecting LN metastases from primary or recurrent BC was analyzed. The mean values of the initial PET/CT parameters, including the primary tumour (SUV T) and ipsilateral axillary LNs (SUV LN), were compared with the clinicopathological features of patients to determine their usefulness for predicting clinical interactions. RESULTS: The sensitivity, specificity, overall accuracy, positive predictive value, and negative predictive value of 18F-FDG PET/CT for axillary LN staging were 87%, 90%, 88%, 93%, and 82%, respectively. Bivariate analyses showed strong interactions of nuclear grade (p=0.05), progesterone receptor expression (p=0.001), Ki-67 index (0.027), and local relapse with the SUV T. A high SUV LN value was significantly correlated with a higher nuclear grade score (p=0.05), oestrogen receptor negativity (p=0.001), progesterone receptor negativity (p=0.014), a high Ki-67 index (>20%; p=0.048), LN metastasis (p<0.001), a basal tumour (p=0.04), and locoregional recurrence (p<0.001). CONCLUSION: PET/CT is a reproducible, non-invasive imaging modality that is useful for evaluating a primary BC mass and its relationship with metastatic axillary LNs, thereby predicting tumour behaviour and guiding clinical practice.

Additional Nodal Disease Prediction in Breast Cancer with Sentinel Lymph Node Metastasis Based on Clinicopathological Features.

AIM: The standard-of-care in breast cancer (BC) with positive sentinel lymph node (SLN) metastasis includes complete axillary lymph node dissection (ALND); however, almost half of such cases have no further tumor burden. This study aimed to assess the clinicopathological factors that predict non-SLN metastasis to define subgroups of SLN-positive patients in whom the axilla may be staged by SLN biopsy alone, while avoiding unnecessary overtreatment. PATIENTS AND METHODS: The records of 191 patients with histologically-proven primary BC who underwent a positive (SLN) biopsy between 2005 and 2017 were reviewed. Patients with at least one tumor-involved SLN who underwent completion ALND were enrolled. Demographic and clinicopathological characteristics, including age, primary tumor size and histological grade, lymphovascular invasion, ratio of positive SLNs to the harvested SLNs, SLN metastasis size, and molecular subtype classification according to immunohistochemical biomarker status [estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)], were evaluated. Data were collected retrospectively and analyzed using the Mann-Whitney and Chi-square tests (statistical significance: p<0.05). RESULTS: The incidence of non-SLN metastasis associated with positive SLN was 48.6% (93/191). The risk of additional nodal spread correlated with high sentinel nodal ratio >0.67 [odds ratio (OR)=2.55, p=0.032], luminal BC subtype (OR=2.67, p=0.06), HER2 overexpression (OR=0.4, p=0.016), and ER+PR-HER2- profile (OR=2.95, p=0.027). There was a tendency (statistically insignificant; p>0.05) toward higher incidence of non SLN metastasis with increasing age and histological grade, which could be attributed to the small sample size. CONCLUSION: According to this study, sentinel nodal ratio and BC subtypes as per ER, PR, and HER2 status significantly predicted the likelihood of additional lymphatic involvement. Validation of these parameters in prospective studies is indicated, and may help individualize treatment modalities.

Biomarkers for predicting spontaneous preterm birth: an umbrella systematic review.

OBJECTIVE: To identify all systematic reviews investigating the role of maternal and fetal biomarkers for predicting spontaneous preterm birth (SPTB). METHODS: Medline and Web of Sciences databases were searched electronically. Studies exploring the association between maternal biomarkers and spontaneous delivery were considered suitable for inclusion. A synthesis of the systematic reviews was performed with the umbrella methodology. Statistical measures of association (Odd ratio, OR, relative risk, RR) and predictive accuracy (sensitivity, specificity, positive and negative likelihood ratios were used to synthesize results of the included studies. RESULTS: 21,614 articles were identified, 542 were assessed with respect to their eligibility for inclusion and 14 systematic reviews included. Cervical fibronectin was the biomarkers which showed the highest strength of association with the occurrence of SPTB (delivery within 24 h OR 7, 95%CI 3-17; delivery <7 days (OR 12, 95%CI 8-16). Maternal serum alpha fetoprotein, was associated with an OR of 4 and 3 for early and late SPTB. C-reactive protein had an OR of 2 (95%CI 1-2) and 8 (95%CI 4-16) when detected in maternal plasma and amniotic fluid, respectively. Among cytokines, interleukin-6 had an OR and an LR + for SPTB of 2 and 12 when detected in maternal serum. CONCLUSIONS: Cervical fetal fibronectin, alpha fetoprotein, C- reactive protein and interleukin 6 can have an overall good diagnostic accuracy in identifying pregnancies at risk of SPTB. Large prospective studies in different sub-set of women are needed to ascertain whether the combination of different serological and imaging marker can improve antenatal prediction of this condition.

New insights into the metastatic behavior after breast cancer surgery, according to well-established clinicopathological variables and molecular subtypes.

Despite advances in treatment, up to 30% of patients with early breast cancer (BC) experience distant disease relapse. However, a comprehensive understanding of tumor spread and site-specific recurrence patterns remains lacking. This retrospective case-control study included 103 consecutive patients with metastatic BC admitted to our institution (2000-2013). Cases were matched according to age, tumor biology, and clinicopathological features to 221 patients with non-metastatic BC (control group). The median follow-up period among the 324 eligible patients was 7.3 years. While relatively low values for sensitivity (71%) and specificity (56%) were found for axillary lymph node (ALN) involvement as an indicator of risk and pattern of distant relapse, nodal status remained the most powerful predictor of metastases (OR: 3.294; CL: 1.9-5.5). Rates of dissemination and metastatic efficiency differed according to molecular subtype. HER2-positive subtypes showed a stronger association with systemic spread (OR: 2.127; CL: 1.2-3.8) than other subgroups. Classification as Luminal or Non-Luminal showed an increased risk of lung and distant nodal recurrence, and a decreased risk in bone metastases in the Non-Luminal group (OR: 2.9, 3.345, and 0.2, respectively). Tumors with HER2 overexpression had a significantly high risk for distant relapse (OR: 2.127) compared with HER2-negative tumors and also showed higher central nervous system (CNS) and lung metastatic potential (OR: 5.6 and 2.65, respectively) and low risk of bone disease progression (OR: 0.294). Furthermore, we found significant associations between biological profiles and sites of recurrence. A new process of clinical/diagnostic staging, including molecular subtypes, could better predict the likelihood of distant relapses and their anatomical location. Recognition and appreciation of clinically distinct molecular subtypes may assist in evaluation of the probability of distant relapses and their sites. Our analysis provides new insights into management of metastatic disease behavior, to lead to an optimal disease-tailored approach and appropriate follow-up.

Assessment of frailty in community-dwelling older adults residents in the Lazio region (Italy): A model to plan regional community-based services.

PURPOSE OF THE STUDY: The prevalence of frailty is expected to increase worldwide in parallel with demographic ageing. Despite this, little is known about the prevalence in different populations particularly community-based samples. This cross-sectional study evaluates the prevalence of frailty in a community-dwelling older adult population and describes a methodology to plan community-based interventions. METHODOLOGY: A random sample of 1331 older adults, resident in the Lazio-Region of Italy, were screened by trained public health nurses (PHNs) by administering a validated questionnaire (the Functional Geriatric Evaluation questionnaire). Prevalence of frailty was calculated using the Final Synthetic Score derived from the questionnaire's Final Score. Variables associated with frailty were selected through univariate and multivariate statistical analysis. RESULTS: Prevalence of frail (FS≥10,≤50) and very frail (FS<10) individuals was 13.9% and 7.6% respectively. Variables associated with frailty were age (older than 85 years), disability, living alone or the presence of a paid carer, lower education and neurological disorders like stroke, dementia, Parkinson disease and other neuropsychiatric diseases; Anaemia or cancer were also associated with a higher prevalence of frailty. DISCUSSION: The study provide a comprehensive picture of the prevalence of frailty and factors associated to this condition in community-dwelling older adults. On the basis of the study results, a plan of community-based services could address the needs of care of the elderly population. A trained team of PHNs may be the most appropriate personnel to carry out multidimensional frailty assessment in this setting.

Levels of bone markers in a population of infants exposed in utero and during breastfeeding to tenofovir within an Option B+ programme in Malawi.

OBJECTIVES: No data are available on bone metabolism in infants exposed to tenofovir during breastfeeding. We investigated bone metabolism markers in the first year of life in infants from mothers who received tenofovir, lamivudine and efavirenz during pregnancy and 12 months of breastfeeding in a national Option B+ programme in Malawi. METHODS: Serum samples collected at 6 and 12 months in tenofovir-exposed infants and in a small sample of tenofovir-unexposed infants from the same clinical centre were analysed in batches for levels of bone-specific alkaline phosphatase (BAP; marker of bone formation) and of C-terminal telopeptide of type I collagen (CTX; marker of bone resorption). RESULTS: Overall, 136 tenofovir-exposed infants were evaluated. No infant had at either timepoint CTX values above the upper normal limit, while most of them had at 6 and 12 months levels of BAP above the upper normal limit for the age range. Levels of bone markers showed no differences by gender and no association with growth parameters. Tenofovir-unexposed and -exposed children had similar mean levels of bone markers at 6 months (CTX: 0.62 versus 0.55 ng/mL, P = 0.122; BAP: 384 versus 362 U/L, P = 0.631). CONCLUSIONS: No significant association between treatment with tenofovir and CTX or BAP levels was found. The high levels of BAP, coupled to the normal levels observed for CTX, might reflect primarily skeletal growth. Potential negative effects of prolonged exposure to tenofovir through breastfeeding cannot however be excluded and longitudinal studies that evaluate bone mineralization status in children enrolled in Option B+ programmes are warranted.

Minimalist video-assisted thoracic surgery biopsy of mediastinal tumors.

BACKGROUND: Mediastinal tumors often require surgical biopsy to achieve a precise and rapid diagnosis. However, subjects with mediastinal tumors may be unfit for general anesthesia, particularly when compression of major vessels or airways does occur. We tested the applicability in this setting of a minimalist (M) uniportal, video-assisted thoracic surgery (VATS) strategy carried out under locoregional anesthesia in awake patients (MVATS). METHODS: We analyzed in a comparative fashion including propensity score matching, data from a prospectively collected database of patients who were offered surgical biopsy for mediastinal tumors through either MVATS or standard VATS. Tested outcome measures included feasibility, diagnostic yield, and morbidity. RESULTS: A total of 24 procedures were performed through MVATS. Diagnostic yield was 100%. Median hospital stay and time interval to oncologic treatment were 2 days (IQR, 2-3 days) and 7 days (IQR, 5.5-11.5 days), respectively. At overall comparison (MVATS, N=24 vs. VATS, N=23), there was a significant difference in both frequency and severity of postoperative complication as measured by Clavien-Dindo classification (P<0.006). In a propensity score matched comparison (8 patients per group), grade 3 or 4 complications requiring aggressive management were found only in the general anesthesia group. Global time spent in the operating room was shorter in the MVATS group (P=0.05). Time interval to oncological treatment was the same between groups. Other differences were also found in SIRS score (P=0.05) and PaO2/FiO2 (P=0.04) thus suggesting better adaption to perioperative stress. CONCLUSIONS: MVATS biopsy appears to be a reliable tool to optimize diagnostic assessment in patients with mediastinal tumors. It can offer high diagnostic accuracy due to large tissue samples, while reducing morbidity rate compared to the same operation under general anesthesia. More robust evaluation is needed to define the appropriateness of MVATS in this specific clinical setting.

Drug resistance mutations 18 months after discontinuation of nevirapine-based ART for prevention of mother-to-child transmission of HIV in Malawi.

OBJECTIVES: The objective of this study was to determine the prevalence of drug resistance mutations among HIV-positive women in Malawi 18 months after discontinuing nevirapine-based ART for the prevention of mother-to-child transmission. PATIENTS AND METHODS: HIV-infected antiretroviral-naive (except for single-dose nevirapine) pregnant Malawian women receiving a nevirapine-based triple antiretroviral regimen from Week 25 of gestation until 6 months of breastfeeding were included in this analysis. Drug resistance was assessed in HIV-DNA 24 months post-partum and at baseline (before the initiation of treatment). In patients with resistance, the presence of mutations was also evaluated in the corresponding plasma samples. RESULTS: Seven out of 42 (16.7%) women studied had archived drug resistance at Month 24 [six cases had NNRTI-associated mutations and two cases the M184I mutation]. In four cases, resistance mutations were already present at baseline (all NNRTI mutations). In three cases, there was an emergence of 'new' resistance (also present in the plasma in one case). Of the 35 women without resistance mutations at Month 24, only one subject had resistance mutations at baseline. Baseline resistance was significantly more common among women with mutations at 24 months compared with those harbouring a WT virus (4/7 versus 1/35, P < 0.001). CONCLUSIONS: Among women who had discontinued drugs 6 months post-partum, only 3/42 (7.1%) had accumulated new resistance mutations in HIV-DNA 2 years after delivery. These findings are reassuring in terms of the safety of the Option B strategy for the prevention of HIV mother-to-child transmission.

The complex care of severe emphysema: role of awake lung volume reduction surgery.

The resectional lung volume reduction surgery (LVRS) procedure entailing nonanatomic resection of destroyed lung regions through general anesthesia with single-lung ventilation has shown to offer significant and long-lasting improvements in respiratory function, exercise capacity, quality of life and survival, particularly in patients with upper-lobe predominant emphysema and low exercise capacity. However mortality and morbidity rates as high as 5% and 59%, respectively, have led to a progressive underuse and have stimulated investigation towards less invasive surgical and bronchoscopic nonresectional methods that could assure equivalent clinical results with less morbidity. We have developed an original nonresectional LVRS method, which entails plication of the most severely emphysematous target areas performed in awake patients through thoracic epidural anesthesia (TEA). Clinical results of this ultra-minimally invasive procedure have been highly encouraging and in a uni-center randomized study, intermediate-term outcomes paralleled those of resectional LVRS with shorter hospital stay and fewer side-effects. In this review article we analyze indications, technical details and results of awake LVRS taking into consideration the available data from the literature.

A pharmacogenetics study in Mozambican patients treated with nevirapine: full resequencing of TRAF3IP2 gene shows a novel association with SJS/TEN susceptibility.

Steven-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are severe adverse drug reactions, characterized by extensive epidermal detachment and erosions of mucous membrane. SJS/TEN is one of the most serious adverse reactions to Nevirapine (NVP) treatment, commonly used in developing countries as first-line treatment of human immunodeficiency virus infection. In the last years TRAF3IP2 gene variants had been described as associated with susceptibility to several diseases such as psoriasis and psoriatic arthritis. We hypothesized that this gene, involved in immune response and in NF-κB activation, could also be implicated in the SJS/TEN susceptibility. We performed a full resequencing of TRAF3IP2 gene in a population of patients treated with NVP. Twenty-seven patients with NVP-induced SJS/TEN and 78 controls, all from Mozambique, were enrolled. We identified eight exonic and three intronic already described variants. The case/control association analysis highlighted an association between the rs76228616 SNP in exon 2 and the SJS/TEN susceptibility. In particular, the variant allele (C) resulted significantly associated with a higher risk to develop SJS/TEN (p = 0.012 and OR = 3.65 (95% CI 1.33-10.01)). A multivariate analysis by logistic regression confirmed its significant contribution (p = 0.027, OR = 4.39 (95% CI 1.19-16.23)). In conclusion, our study suggests that a variant in TRAF3IP2 gene could be involved in susceptibility to SJS/TEN.