Diagnostic Prediction Model for Tuberculous Meningitis: An Individual Participant Data Meta-Analysis.

No accurate and rapid diagnostic test exists for tuberculous meningitis (TBM), leading to delayed diagnosis. We leveraged data from multiple studies to improve the predictive performance of diagnostic models across different populations, settings, and subgroups to develop a new predictive tool for TBM diagnosis. We conducted a systematic review to analyze eligible datasets with individual-level participant data (IPD). We imputed missing data and explored three approaches: stepwise logistic regression, classification and regression tree (CART), and random forest regression. We evaluated performance using calibration plots and C-statistics via internal-external cross-validation. We included 3,761 individual participants from 14 studies and nine countries. A total of 1,240 (33%) participants had "definite" (30%) or "probable" (3%) TBM by case definition. Important predictive variables included cerebrospinal fluid (CSF) glucose, blood glucose, CSF white cell count, CSF differential, cryptococcal antigen, HIV status, and fever presence. Internal validation showed that performance varied considerably between IPD datasets with C-statistic values between 0.60 and 0.89. In external validation, CART performed the worst (C = 0.82), and logistic regression and random forest had the same accuracy (C = 0.91). We developed a mobile app for TBM clinical prediction that accounted for heterogeneity and improved diagnostic performance (https://tbmcalc.github.io/tbmcalc). Further external validation is needed.

Incarceration history is associated with HIV infection among community-recruited people who inject drugs in Europe: A propensity-score matched analysis of cross-sectional studies.

AIMS: We measured the association between a history of incarceration and HIV positivity among people who inject drugs (PWID) across Europe. DESIGN, SETTING AND PARTICIPANTS: This was a cross-sectional, multi-site, multi-year propensity-score matched analysis conducted in Europe. Participants comprised community-recruited PWID who reported a recent injection (within the last 12 months). MEASUREMENTS: Data on incarceration history, demographics, substance use, sexual behavior and harm reduction service use originated from cross-sectional studies among PWID in Europe. Our primary outcome was HIV status. Generalized linear mixed models and propensity-score matching were used to compare HIV status between ever- and never-incarcerated PWID. FINDINGS: Among 43 807 PWID from 82 studies surveyed (in 22 sites and 13 countries), 58.7% reported having ever been in prison and 7.16% (n = 3099) tested HIV-positive. Incarceration was associated with 30% higher odds of HIV infection [adjusted odds ratio (aOR) = 1.32, 95% confidence interval (CI) = 1.09-1.59]; the association between a history of incarceration and HIV infection was strongest among PWID, with the lowest estimated propensity-score for having a history of incarceration (aOR = 1.78, 95% CI = 1.47-2.16). Additionally, mainly injecting cocaine and/or opioids (aOR = 2.16, 95% CI = 1.33-3.53), increased duration of injecting drugs (per 8 years aOR = 1.31, 95% CI = 1.16-1.48), ever sharing needles/syringes (aOR = 1.91, 95% CI = 1.59-2.28) and increased income inequality among the general population (measured by the Gini index, aOR = 1.34, 95% CI = 1.18-1.51) were associated with a higher odds of HIV infection. Older age (per 8 years aOR = 0.84, 95% CI = 0.76-0.94), male sex (aOR = 0.77, 95% CI = 0.65-0.91) and reporting pharmacies as the main source of clean syringes (aOR = 0.72, 95% CI = 0.59-0.88) were associated with lower odds of HIV positivity. CONCLUSIONS: A history of incarceration appears to be independently associated with HIV infection among people who inject drugs (PWID) in Europe, with a stronger effect among PWID with lower probability of incarceration.

Long-Term Longitudinal Evaluation of Six Commercial Immunoassays for the Detection of IgM and IgG Antibodies against SARS CoV-2.

The number of serological assays for SARS-CoV-2 has skyrocketed in the past year. Concerns have been raised regarding their performance characteristics, depending on the disease severity and the time of the analysis post-symptom onset (PSO). Thus, independent validations using an unbiased sample selection are required for meaningful serology data interpretation. We aimed to assess the clinical performance of six commercially available assays, the seroconversion, and the dynamics of the humoral response to SARS-CoV-2 infection. The study included 528 serum samples from 156 patients with follow-up visits up to six months PSO and 161 serum samples from healthy people. The IgG/total antibodies positive percentage increased and remained above 95% after six months when chemiluminescent immunoassay (CLIA) IgG antiS1/S2 and electro-chemiluminescent assay (ECLIA) total antiNP were used. At early time points PSO, chemiluminescent microparticle immunoassay (CMIA) IgM antiS achieved the best sensitivity. IgM and IgG appear simultaneously in most circumstances, and when performed in parallel the sensitivity increases. The severe and the moderate clinical forms were significantly associated with higher seropositivity percentage and antibody levels. High specificity was found in all evaluated assays, but the sensitivity was variable depending on the time PSO, severity of disease, detection method and targeted antigen.

Healthcare-associated Clostridioides difficile infection during the COVID-19 pandemic in a tertiary care hospital in Romania.

Introduction. Information on healthcare-associated C.difficile infection (HA-CDI) in COVID-19 patients is limited. We aimed to assess the characteristics of HA-CDI acquired during and before the COVID-19 pandemic. Methods. We conducted a retrospective study in a tertiary care hospital, in which since March 2020 exclusively COVID-19 patients are hospitalized. We compared HA-CDI adult patients hospitalized in March 2020-February 2021 with those hospitalized during the same period in 2017-2018. Results. We found 51 cases during 2020-2021 (COVID-19 group), incidence 5.6/1000 adult discharge and 99 cases during 2017-2018 (pre-COVID-19 group), incidence 6.1/1000 adult discharge (p=0.6). The patients in COVID-19 group compared to pre-COVID-19 group were older (median age 66 vs 62 years), with similar rate of comorbidities, but with higher rate of cardiovascular diseases (62.7% vs 42.4%) and less immunosuppression (21.6% vs 55.6%), they had a higher proton pump inhibitors use (94.1% vs 32.3%), and a longer hospitalization (median 19 vs 14 days). Eighty-five (85.9%) patients in pre-COVID-19 group versus 44 (86.3%) patients in COVID-19 group received antimicrobial treatment - mainly cephalosporins (34,1%), quinolones (22,3%) and glycopeptides (21,1%) in pre-COVID-19 group and mainly cephalosporins and macrolides (63,6% each) in COVID-19 group. We found four HA-CDI-related deaths in pre-COVID-19 group and none in the COVID-19 group. Conclusions. The HA-CDI incidence in COVID-19 group did not change versus the same period of time during 2017-2018. The antibiotic use was the most important factor associated with HA-CDI. We identified a high use of broad-spectrum antibiotics despite the lack of empirical antimicrobial recommendations in COVID-19.

Exhaustion and senescence of CD4 and CD8 T cells that express co-stimulatory molecules CD27 and CD28 in subjects that acquired HIV by drug use or by sexual route.

INTRODUCTION: The human immunodeficiency virus (HIV) infection leads to immune activation, senescence and exhaustion of T cells. Co-stimulatory molecules play important roles in controlling these processes. The CD28 signaling triggers efficient T cell activation, while CD27 provides survival signals to CD28- T cells. Loss of these molecules was associated with senescent phenotype and resistance to checkpoint inhibitors.Romania has faced an HIV outbreak among people who inject drugs (PWID), most of them chronically infected with hepatitis C virus (HCV). HIV/HCV co-infection was associated with increased immune activation and rapid disease progression. METHODS: We evaluated by flow cytometry the expression of CD27, CD28, CD38, HLA-DR, CD57 and PD-1 on CD4 and CD8 T cells from 34 subjected infected with HIV (22 PWID and 12 people who acquired HIV by sexual route - PWHS) and 18 HIV-negative individuals (controls). RESULTS: We found that as compared to controls, HIV patients, regardless of infection route, have high percentages of intermediately differentiated (CD27+CD28-) and low percentages of less differentiated (CD27+CD28+) CD8 T cells. Significantly higher levels of CD8+CD27+CD28- T cells were found in PWHS than in PWID. A lower percentage of intermediately and highly differentiated (CD27-CD28-) CD8 T cells express CD57 in people living with HIV (PLWH) than in controls. Increased levels of less and intermediately differentiated CD4 and CD8 T cells expressing PD-1 were identified in PLWH, especially in PWID; these directly correlated with HIV viral load and T cell activation and negatively correlated with CD4 counts. CONCLUSIONS: Our data show that induction of PD-1 on T cells expressing co-stimulatory molecules CD27 and/or CD28 might contribute to poor control of HIV infection and to immune activation.

Treatment initiation or switch to BIC/FTC/TAF - real-world safety and efficacy data from two HIV centers in Romania.

INTRODUCTION: Development of highly active antiretroviral therapy marked an important step forward in the management of people living with HIV and fixed dose combinations are now available to be used as modern antiretroviral regimens. The single-tablet regimen bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) was recently approved in Europe and included in international guidelines and recommendations. It became available in Romania in early 2021. We present the real-world results from a retrospective analysis of patients initiating BIC/FTC/TAF in two HIV centers in Romania. METHODS: This retrospective analysis included patients treated with BIC/FTC/TAF (first-line or switch) in two HIV centers in Romania, one in Bucharest and one in Iași. We collected data on baseline patient characteristics, reasons for initiation of BIC/FTC/TAF and preliminary clinical and laboratory efficacy, safety and tolerability data. All assessments had been performed according to local practice. Statistical analyses were mostly descriptive and association analysis was performed to assess changes in laboratory parameters from baseline to data cut-off (October 2021). RESULTS: In total, 122 patients were initiated on BIC/FTC/TAF in routine clinical practice from February to October 2021 in the two HIV centers, either as first-line or switch. The majority of patients were male (71%). The median age at baseline was 35.0 years (IQR 32.0-50.8 years). Overall, 91 patients (75%) were treatment-experienced and the most frequent reason for switch was treatment simplification (79%). The mean ± standard deviation follow-up duration on treatment with BIC/FTC/TAF was 101.6 ± 64.2 days until the cut-off date for this analysis. We found no significant changes in lipid values, blood glucose or liver enzymes, coupled with a significant decrease in viral load (p=0.001). A low number of adverse events occurred during the treatment period (n=4): two cases of fatigue and two gastrointestinal reactions. No patient discontinued BIC/FTC/TAF and the overall tolerability was good. CONCLUSIONS: The insights of the first report on BIC/FTC/TAF use in routine clinical practice in Romania provide an overview of effectiveness and safety to local clinicians treating this patient population.

HIV outbreaks among people who inject drugs in Europe, North America, and Israel.

During 2011-16, HIV outbreaks occurred among people who inject drugs (PWID) in Canada (southeastern Saskatchewan), Greece (Athens), Ireland (Dublin), Israel (Tel Aviv), Luxembourg, Romania (Bucharest), Scotland (Glasgow), and USA (Scott County, Indiana). Factors common to many of these outbreaks included community economic problems, homelessness, and changes in drug injection patterns. The outbreaks differed in size (from under 100 to over 1000 newly reported HIV cases among PWID) and in the extent to which combined prevention had been implemented before, during, and after the outbreaks. Countries need to ensure high coverage of HIV prevention services and coverage higher than the current UNAIDS recommendation might be needed in areas in which short acting drugs are injected. In addition, monitoring of PWID with special attention for changing drug use patterns, risk behaviours, and susceptible subgroups (eg, PWID experiencing homelessness) needs to be in place to prevent or rapidly detect and contain new HIV outbreaks.

Rapid Clinical Score for the Diagnosis of Tuberculous Meningitis: A Retrospective Cohort Study.

OBJECTIVE: The aim of our study was to retrospectively validate a previously described rapid clinical score (RCS) in distinguishing tuberculous meningitis (TBM) from viral meningitis (VM) in people who are at increased risk of tuberculosis, as well as from cryptococcal meningitis (CM) in HIV-infected patients. METHODS: We performed a retrospective study of patients admitted with a diagnosis of aseptic meningitis between January 2012 and December 2015, to a referral hospital for infectious diseases. The variables included in RCS were duration of symptoms before admission, neurological stage, cerebrospinal fluid (CSF) to blood glucose ratio, and CSF protein. We included in this retrospective study 31 patients with definite or probable TBM including 14 HIV-infected patients, 62 HIV-noninfected patients with VM, and 18 HIV-infected patients with CM. RESULTS: The sensitivity of RCS to distinguish TBM from VM was 96.7%, with a specificity of 81.1% and the area under the receiver operating characteristic (ROC) curve was 0.949 (0.90-0.99). When all four criteria from the RCS were present, the specificity increased at 100%. In HIV-infected patients, the sensitivity and specificity of RCS in differentiating TBM from CM were 86.6% and 27.7%, respectively, and the area under the ROC curve was 0.669 (0.48-0.85). CONCLUSION: This easy-to-use RCS was found to be helpful in differentiating TBM from VM, with a better sensitivity than molecular amplification techniques and a relatively good specificity. However, the RCS was not useful to differentiate between TBM and CM in HIV-infected patients.

Epidemic dispersion of HIV and HCV in a population of co-infected Romanian injecting drug users.

Co-infections with HIV and HCV are very frequent among people who inject drugs (PWID). However, very few studies comparatively reconstructed the transmission patterns of both viruses in the same population. We have recruited 117 co-infected PWID during a recent HIV outbreak in Romania. Phylogenetic analyses were performed on HIV and HCV sequences in order to characterize and compare transmission dynamics of the two viruses. Three large HIV clusters (2 subtype F1 and one CRF14_BG) and thirteen smaller HCV transmission networks (genotypes 1a, 1b, 3a, 4a and 4d) were identified. Eighty (65%) patients were both in HIV and HCV transmission chains and 70 of those shared the same HIV and HCV cluster with at least one other patient. Molecular clock analysis indicated that all identified HIV clusters originated around 2006, while the origin of the different HCV clusters ranged between 1980 (genotype 1b) and 2011 (genotypes 3a and 4d). HCV infection preceded HIV infection in 80.3% of cases. Coincidental transmission of HIV and HCV was estimated to be rather low (19.65%) and associated with an outbreak among PWID during detention in the same penitentiary. This study has reconstructed and compared the dispersion of these two viruses in a PWID population.

Immune reconstitution inflammatory syndrome in central nervous system tuberculosis.

BACKGROUND: Immune reconstitution inflammatory syndrome (IRIS) related to tuberculosis (TB) is an exacerbation of an inflammatory response that most often occurs in HIV-infected patients but it has also been observed in non-HIV immunocompromised hosts. We describe two cases of TB associated IRIS with CNS involvement, one in a patient diagnosed with HIV infection and the other in a patient with immunosuppression due to anti tumor necrosis factor treatment. CASE REPORT; The first case was a 40-year-old man, newly diagnosed with HIV infection, who developed right hemiplegia and expressive aphasia. Lumbar puncture and MRI sustained the diagnosis of TB meningoencephalitis. He initially improved understandard antituberculous therapy (ATT). After 6 weeks of ATT antiretroviral treatment (ART) was initiated and one week later the patient experienced worsening of his symptoms (left hemiparesis and mixed aphasia), of CSF and MRI changes. He improved after he was starting on corticosteroids in tapering doses, with clinical deterioration at lower doses over a 5-month period. The second case was a 56-year-old male, treated for 3 years with Infliximab for ankylosing spondylitis. He was diagnosed with disseminated TB (CNS tuberculomas and pulmonary TB), histological and bacteriological confirmed the diagnosis. His neurological symptoms improved after starting ATT but after 2 weeks of therapy he presented with diplopia and generalized tonic-clonic seizures. These symptoms improved only after corticosteroids were added (tapering doses during the next 6 months). CONCLUSION: TB-associated IRIS with CNS involvement is potentially life threatening. Corticosteroids should be used to control the IRIS symptoms in those patients. The dosing and duration should be tailored to each patient.

Co-infections and co-morbidities among injecting drug users versus sexually infected patients in Bucharest.

INTRODUCTION: After the 2008 introduction of new psychoactive substances (NPS) in Romania, the number of newly diagnosed HIV infections showed significant increase among injecting drug users (IDUs). Our objective was to analyze the differences between co-infections related to the HIV infection, based on the way of transmission (IDUs versus sexually infected). MATERIALS AND METHODS: A retrospective transversal study was carried out, analyzing 245 adult HIV-positive patients, diagnosed between January 2013 and December 2013 in our hospital. We collected socio-demographic, epidemiological and laboratory data at the diagnosis and analyzed them using SPSS version 20. RESULTS: Most patients (71%, 174/245) were men and the median age was 32 years (IQR: 26-38). 91 patients (37%) were former/active IDUs (most of them injecting both opioids and NPS), while 154 patients (63%) were sexually infected, with 84% being heterosexuals and 16% men having sex with men (MSM). The median CD4 count, at the moment of diagnosis, was 294 cells/mm(3) (IQR: 119-483). CONCLUSION: Heterosexual transmission was the most common way of HIV transmission in 2013 in contrast with EU/CEE, where MSM accounted for the majority of cases of HIV epidemics in 2012 [1]. Sexually transmitted HIV infection was associated with late presentation, stage C and syphilis. We noted a high percentage of IDU transmission, which was associated with stage A and hepatitis C infection.

Characteristics of late presenters in Bucharest.

INTRODUCTION: Late presentation is associated with increased healthcare costs, rates of HIV transmission and poor outcome. In Romania, in 2012, one third of individuals with new HIV diagnosis were late presenters (LP). OBJECTIVE: The aim of the study was to evaluate the epidemiological and clinical characteristics associated with late presentation. METHODS: We retrospectively studied patients over 18 years old, notified in our institution between January 2012 and December 2013, including 499 out of 727 newly diagnosed patients in Bucharest. LP were defined as patients presenting with CD4 T-cell count below 350 cells/mm(3) or with an AIDS defining event. Patients with advanced HIV disease (AHD) were defined as persons with a CD4 T-cell count below 200 cells/mm(3). Differences between groups were analyzed using the Mann-Whitney U test for continuous variables and the chi-square test for dichotomous variables. Multivariable analysis was performed using binary logistic regression. RESULTS: Out of 499 patients included, 362 (72%) were male. The median age was 30 (IQR 26-36). A total of 302 (61%) were LP and 184 (37%) were patients with AHD. A total of 170 (34%) were asymptomatic and 114 (23%) presented with an AIDS-defining event. The median CD4 count was 293 cells/mm(3) (IQR 125-471) and the median HIV viral load was 100,191 copies/mL (IQR 34,560-272,936). Characteristics of LP compared with non-LP are shown in Table 1. Stage C disease has been shown by multivariable analysis to be associated with LP (p<0.001, OR=11.56, 95% CI 4.94-27.03). CONCLUSIONS: More than half of newly HIV diagnosed patients in Bucharest were LP. The proportion of LP was highest among heterosexually acquired cases. Although most our patients were young, late presentation was associated with age over 35 years. The lower proportion of LP among IVDU compared with those heterosexually infected could be explained by a higher proportion of HIV screening tests among IVDU.