Leïla Belkhir

Pneumococcal septic arthritis in adults: clinical analysis and review.

Abstract Background: Septic arthritis (SA) is a rheumatological emergency that can lead to rapid joint destruction and irreversible loss of function. The most common pathogen causing SA is Staphylococcus aureus which is responsible for 37–65% of cases. Streptococcus pneumoniae is traditionally described as an uncommon cause of SA of a native joint. The objective of our study was to analyse clinical characteristics, treatment, and outcome of all cases of pneumococcal septic arthritis treated in our institution, and to compare them with other series published in the literature. Materials and methods: We conducted a retrospective study of pneumococcal SA identified among all cases of SA diagnosed in a teaching hospital of one thousand beds between 2004 and 2009. Diagnosis was based on culture of joint liquid or by the presence of pneumococcal bacteraemia and purulent (more than 50 000/mm3 white blood cells with more than 90% neutrophils) joint fluid aspiration. Results: Among 266 cases of SA, nine patients (3·3%) were diagnosed as having pneumococcal SA. The median age was 75 years. The main affected joint was the knee (7/9). No patient had more than one joint involved. Four patients suffered from concomitant pneumonia. Joint culture and blood cultures were positive in 7/9 and 5/9, respectively. Median (range) length of stay was 18 days (3–47 days). One patient with associated pneumococcal bacteraemia died 19 days after admission. Seven patients recovered completely. Conclusions: Streptococcus pneumoniae is now being increasingly recognized as a common agent of SA. This organism is frequently associated with pneumococcal pneumonia or bacteraemia, particularly in patients with advanced age and comorbidities. Direct inoculation of joint fluid into blood culture medium BACTEC system increases the probability of microbiological diagnosis. The prognosis is usually favourable if the disease is promptly recognized and treated (antibiotic therapy combined with joint drainage).

Tigecycline-induced acute pancreatitis: about two cases and review of the literature

Abstract Tigecycline (formerly GAR-936, Tygacyl®) is the first glycylcycline antibiotic available for clinical use. It has an expanded broad-spectrum antibiotic activity. Phase III studies have identified gastrointestinal side-effects, especially nausea and vomiting. as the most common adverse events. Few cases of acute pancreatitis (AP) have been described in the literature. We report two new cases of mild tigecycline-induced pancreatitis. Tigecycline was given for soft-tissue infection in both cases. Symptoms such as nausea, vomiting and mostly abdominal pain occurred within 5 days after starting Tigecycline. Pancreatic enzymes elevation occurred five to six days after initiation of treatment, and resolved within a week after drug-discontinuation. Diagnosis of mild pancreatitis was confirmed after performing CT-Scan of the abdomen in both cases. We take this opportunity to review the literature about this potentially serious side-effect induced by tigecycline.

Late presentation for human immunodeficiency virus HIV diagnosis results of a Belgian single centre

Abstract Background Antiretroviral therapy reduces mortality and morbidity in HIVinfected individuals, most markedly when initiated early, before advanced immunodeficiency has developed. Although the international guidelines recommend starting antiretroviral therapy ART with a high CD4 cell count level, in the practice, this is particularly challenging to achieve, especially in late presentation of HIV diagnosis. The aim of this study was to determine the frequency and the demographic features associated with late presentation for HIV diagnosis in our Centre. Methods All newly diagnosed patients with HIV between January 2007 and December 2011 in our AIDS Reference Centre, were included. Late presenter patient was defined as patient with CD4 count 350mm3 at the time of diagnosis. Demographic age, sex, ethnicity, migration and clinical characteristics transmission mode, CD4 cell count, viral load were collected. We also collected data on outcome median day of hospitalization, mortality, virological response to ART and lost to followup LTFU. LTFU was defined as patient without any medical contact and viral load measurements during two consecutive years in our centre. Results From 2007 to 2011, 154 429 out of 359 patients newly diagnosed with HIV were late presenters. According to univariate analysis, age 50, female gender, migrant from subSaharan Africa and heterosexual contact were associated with late presentation for HIV diagnosis. In the multivariate analysis, age 50, heterosexual contact and migrant status particularly women were the only independent risk factors for late presentation. Late presenters tend to have a worse outcome than nonlate presenters. Conclusion A considerable proportion of patients continue to be diagnosed with advanced HIV disease, despite the fact that risk factors for late presentation have been clearly identified. Despite high testing rate for HIV in Belgium, highrisk population like migrant, heterosexual contact, remain under tested. In order to be able to detect and treat all patients with high CD4 cell count as recommended by all international guidelines, we recommend developing testing policies specifically focused on these categories at high risk for late presentation.

High FDG uptake on FDG-PET scan in HIV-1 infected patient with advanced disease

Abstract We report the case of a 48-year-old Caucasian male positive for HIV-1 who was admitted in our clinic for a fever of unknown origin with weight loss. The CD4 cell count was 99/mm3 and the viral load (VL) was 836500 copies/ml. A first FDG-PET-CT showed abnormal hypermetabolism of multiple lymp nodes, of the bone marrow and of the spleen. Tuberculosis and lymphoma were excluded by a lymph node biopsy and a culture. Six months after the start of a highly active anti-retroviral therapy (HAART) containing lamuvidine, tenofovir, atazanavir boosted by ritonavir, a new FDG-PET-CT showed a complete normalisation of the metabolism in the regions previously described as having a high FDG uptake. The VL was < 37 copies/ml and his CD4 cell count was 399 /mm3. In conclusion: in patients with advanced HIV infections presenting with FUO, high uptake in 18FDG-PET-CT can be the marker of advanced disease reflecting the areas of viral replication.

IMPORTED MALARIA IN A TERTIARY HOSPITAL IN BELGIUM: EPIDEMIOLOGICAL AND CLINICAL ANALYSIS

Abstract Background and objective: There has been a marked increase in tourism, immigration, and business travel to malaria-endemic areas. Non-immune individuals (western travellers) or immigrants living for more than one year in non-endemic areas who visit friends and relatives (VFR) are particularly susceptible to developing severe malaria when travelling to areas with high levels of transmission. In this study, epidemiological, clinical and biological features of malaria in travellers returning from endemic areas were analysed. This may help clinicians unfamiliar with malaria not to overlook this disease in its early stage, and to initiate prompt treatment. Patients and methods: we retrospectively analysed all cases of patients who presented with malaria in our institution between 2003 and 2008. Results: Eighty patients were included. Most patients visited Africa (93.6%). Accordingly, P. falciparum was the main species identified (67/77 patients i.e. 87%). Sixty-five patients (65/78 i.e. 83.3%) had not taken any prophylaxis and 13 (16.7%) had taken it inadequately. Common clinical features were fever (80/80, 100%), influenza-like symptoms (16/80, 20.1%), respiratory symptoms (5/80, 6.3%), neurological symptoms (2/80, 2.5%) or digestive symptoms (15/80, 18.8%). Digestive symptoms were predominant in children < 16 y.o. (60% of these patients). Conclusion: Imported malaria cases are mostly related to the lack of adequate use of chemoprophylaxis. Plasmodium falciparum is the main species responsible for imported cases of malaria in our institution. Clinical features vary, but fever is universally present at presentation. As such, all cases of fever upon return from a malaria-endemic area must be considered as malaria until proven otherwise, at least during the first three months after the return.

Quantification of darunavir and etravirine in human peripheral blood mononuclear cells using high performance liquid chromatography tandem mass spectrometry (LC–MS/MS), clinical application in a cohort of 110 HIV-1 infected patients and evidence of a potential drug–drug interaction

OBJECTIVES To describe the validation of a sensitive high performance liquid chromatography tandem mass spectrometry (LC-MS/MS) method allowing the simultaneous quantification of darunavir (DRV) and etravirine (ETR) in peripheral blood mononuclear cells (PBMCs) and its application in a cohort of HIV-1 infected patients. METHODS Blood samples were obtained from 110 patients. PMBCs were isolated using density gradient centrifugation. Drug extraction from PBMCs was performed with a 60:40 methanol-water (MeOH-H2O) solution containing deuterated IS (DRV-d9 and ETR-d8). The chromatographic separation was performed on a RP18 XBridge™ column. RESULTS The geometric mean (GM) of cell associated concentration ([DRV]CC) and plasmatic concentration ([DRV]plasma) were 360.5ng/mL (CI95%:294.5-441.2) and 1733ng/mL (CI95%:1486-2021), respectively. A geometric mean intracellular (IC)/plasma ratio (GMR) of 0.21 (CI95%:0.18-0.24) was calculated. Adjusted for dose/body surface area and post-intake time, a statistically significant correlation was observed between [DRV]Plasma and the eGFR (p=0.002) and between [DRV]Plasma and the concomitant use of ETR (p=0.038). For the 10 patients receiving ETR in addition to DRV, the GM of [ETR]Plasma (available for 8 out of 10 patients) and [ETR]CC were 492.3ng/mL and 2951ng/mL respectively. The GMR of ETR was 7.6 (CI95%: 3.61-13.83). CONCLUSIONS A handy and sensitive high performance LC-MS/MS method allowing the simultaneous quantification of DRV and ETR in PBMCs has been described and successfully applied in the largest cohort of DRV-treated patients reported to date. ETR accumulates more efficiently in PBMCs compared to DRV. We have also highlighted a possible impact of ETR on DRV plasma concentrations requiring further investigations.

Interaction between Darunavir and Etravirine Is Partly Mediated by CYP3A5 Polymorphism.

Objectives To assess the impact of the loss-of-function CYP3A5*3 allele (rs776746, 6986A>G SNP) on darunavir (DRV) plasma concentrations. Methods 135 HIV-1 infected patients treated with DRV-based therapy were included in the study and plasma samples were obtained immediately before drug intake in order to determine DRV trough concentrations using an ultra performance liquid chromatography method (UPLC) with diode-array detection (DAD). Noteworthy is the fact that in 16 (11.9%) patients, etravirine (ETR) was combined with DRV. CYP3A5 genotypes were determined using real time PCR method (TaqMan® genotyping assay). The patients were then classified into CYP3A5 expressors (CYP3A5*1 allele carriers) and non-expressors (CYP3A5*3 homozygous). Subsequently, the association between DRV plasma trough concentration ([DRV]plasma) and CYP3A5 genotype-based expression status was analyzed. Results 45% of the patients were classified as CYP3A5 expressors. In the whole cohort, mean [DRV]plasma was not different between CYP3A5 expressors and non-expressors (1894ng/ml [CI95%: 1566–2290] versus 1737ng/ml [CI95%: 1468–2057], p = 0.43). However, in the subgroup of the 16 patients receiving DRV combined with ETR, a significantly lower [DRV]plasma was observed for CYP3A5 expressors when compared to non-expressors (1385ng/ml [CI95%:886.3–2165] versus 3141ng/ml [CI95%:2042–4831], p = 0.007). Conclusions Interaction between DRV and ETR is partly mediated by CYP3A5 polymorphism with lower DRV plasma trough concentrations in CYP3A5 expressors suggesting a specific ETR-driven CYP3A5 activation only in CYP3A5 expressors. Consequently, these patients might be more at risk of infra-therapeutic [DRV]plasma. This potentially important observation is a good illustration of a genotype-based drug interaction, which could also have considerable consequences if translated to other CYP3A5-metabolized drugs. Further investigations are thus needed to confirm this association and to explore its clinical impact, mainly in the African population among whom CYP3A5 expressors are more frequent, before recommending systematic CYP3A5 pre-emptive genotyping for DRV-ETR co-administration.

Time trend of clinical cases of Lyme disease in two hospitals in Belgium, 2000–2013

BackgroundAs several studies indicated an increase in Lyme disease (LD), notably in neighbouring countries, concerns have arisen regarding the evolution of Lyme disease in Belgium. In order to confirm or infirm the increase of LD in Belgium, we focused on hospital admissions of patients diagnosed with LD between 2000 and 2013 based on hospital admission databases from two hospitals in Belgium.MethodsHospital databases are a stable recording system. We did a retrospective analysis of the medical files of patients hospitalized with Lyme disease in two Belgian hospitals between 2000 and 2013.ResultsThe annual number of cases of LD for the two studied Belgian hospitals remained stable between 2000 and 2013, ranging from 1 for the Cliniques universitaires Saint-Luc to 15 for the the Clinique Saint-Pierre. No increasing trend were noted in the estimated annual incidence rate but the average estimated annual incidence rate was higher for the hospital Saint-Pierre (8.1 ± 3.7 per 100,000 inhabitants) than Saint-Luc (2.2 ± 1.5 per 100,000 inhabitants). The number of hospital cases of LD peaked between June and November.ConclusionsBased on hospital admissions with LD, no increasing trend was observed for the period 2000–2013 in the two studied Belgian hospitals. This is in line with other studies carried out in Belgium.

Nevirapine-associated liver toxicity and hypersensitivity reactions in a cohort of HIV-1-infected patients,clinical analysis

Antiretroviral drug-related liver injury is a common cause of morbidity and treatment discontinuation in HIV-infected patients. Nevirapine is incriminated as one of the liver toxicity inducer especially in patients with high CD4-cells count. The purpose of our study was to analyze the role of CD4 cell count at treatment initiation and that of several co-factors (Hepatitis C or Hepatitis B virus co-infection, concurrent use of protease inhibitors) on the incidence of liver toxicity and hypersensivity reactions induced by Nevirapine in our HIV1-infected patients.

Impact of UGT1A1 polymorphisms on Raltegravir and its glucuronide plasma concentrations in a cohort of HIV-1 infected patients.

The aim of this study was to evaluate the effect of UGT1A1 polymorphisms on Raltegravir (RAL) and its metabolite RAL-glucuronide trough plasma concentrations ([RAL]plasma and [RAL-glu]plasma) and on the metabolic ratio (MR): [RAL-glu]plasma/[RAL]plasma. UGT1A1 genotyping was performed on 96 patients. 44% (n = 42) were homozygous UGT1A1*1/*1 while 50% (n = 48) and 6% (n = 6) were UGT1A1*28 and UGT1A1*36 carriers, respectively. The median concentration and interquartile range (IQR) of [RAL]plasma were 88.5 ng/ml (41.0–236), 168 ng/ml (85.8–318) and 92.5 ng/ml (36.4–316) for UGT1A1*1/*1, UGT1A1*28 and UGT1A1*36 carriers, respectively. Only the difference between UGT1A1*1/*1 and *28 carriers was statistically significant (p = 0.022). The median MR (IQR) were 5.8 (3–10), 2.9 (1.6–5.3) and 3.2 (1.7–5.9) for UGT1A1*1/*1, UGT1A1*28 and UGT1A1*36 carriers, respectively. Only the difference between UGT1A1*1/*1 and *28 carriers was statistically significant (p = 0.004) with an allele-dependent effect: UGT1A1*28 homozygous having lower MR than heterozygous carriers who show lower MR compared to *1/*1. Except for the sensation of fatigue, this PK effect did not correlate with clinical adverse events or biological abnormalities. In Conclusion, we demonstrate that UGT1A1*28 polymorphism has a significant impact on RAL metabolism: UGT1A1*28 carriers being characterized by higher [RAL]plasma and lower MR.