Factors Associated With Genotypic Resistance and Outcome Among Solid Organ Transplant Recipients With Refractory Cytomegalovirus Infection.

Genotypically resistant cytomegalovirus (CMV) infection is associated with increased morbi-mortality. We herein aimed at understanding the factors that predict CMV genotypic resistance in refractory infections and disease in the SOTR (Solid Organ Transplant Recipients) population, and the factors associated with outcomes. We included all SOTRs who were tested for CMV genotypic resistance for CMV refractory infection/disease over ten years in two centers. Eighty-one refractory patients were included, 26 with genotypically resistant infections (32%). Twenty-four of these genotypic profiles conferred resistance to ganciclovir (GCV) and 2 to GCV and cidofovir. Twenty-three patients presented a high level of GCV resistance. We found no resistance mutation to letermovir. Age (OR = 0.94 per year, IC95 [0.089-0.99]), a history of valganciclovir (VGCV) underdosing or of low plasma concentration (OR= 5.6, IC95 [1.69-20.7]), being on VGCV at infection onset (OR = 3.11, IC95 [1.18-5.32]) and the recipients' CMV negative serostatus (OR = 3.40, IC95 [0.97-12.8]) were independently associated with CMV genotypic resistance. One year mortality was higher in the resistant CMV group (19.2 % versus 3.6 %, p = 0.02). Antiviral drugs severe adverse effects were also independently associated with CMV genotypic resistance. CMV genotypic resistance to antivirals was independently associated with a younger age, exposure to low levels of GCV, the recipients' negative serostatus, and presenting the infection on VGCV prophylaxis. This data is of importance, given that we also found a poorer outcome in the patients of the resistant group.

Specificities of Meningitis and Meningo-Encephalitis After Kidney Transplantation: A French Retrospective Cohort Study.

Kidney transplant recipients develop atypical infections in their epidemiology, presentation and outcome. Among these, meningitis and meningoencephalitis require urgent and adapted anti-infectious therapy, but published data is scarce in KTRs. The aim of this study was to describe their epidemiology, presentation and outcome, in order to improve their diagnostic and management. We performed a retrospective, multicentric cohort study in 15 French hospitals that included all 199 cases of M/ME in KTRs between 2007 and 2018 (0.9 case per 1,000 KTRs annually). Epidemiology was different from that in the general population: 20% were due to Cryptococcus neoformans, 13.5% to varicella-zoster virus, 5.5% to Mycobacterium tuberculosis, and 4.5% to Enterobacteria (half of which produced extended spectrum beta-lactamases), and 5% were Post Transplant Lymphoproliferative Disorders. Microorganisms causing M/ME in the general population were infrequent (2%, for Streptococcus pneumoniae) or absent (Neisseria meningitidis). M/ME caused by Enterobacteria, Staphylococci or filamentous fungi were associated with high and early mortality (50%-70% at 1 year). Graft survival was not associated with the etiology of M/ME, nor was impacted by immunosuppression reduction. Based on these results, we suggest international studies to adapt guidelines in order to improve the diagnosis and the probabilistic treatment of M/ME in SOTRs.

Human pegivirus identified in severe myelitis and optic neuritis in immunocompromised patients: A pathogenic role for a forgotten virus?

The role of Human pegivirus (HPgV) in patients with encephalitis has been recently questioned. We present cases of 4 patients with similar clinical, biological, and radiological characteristics, including a past history of transplantation with long-term immunosuppression and a progressive course of severe and predominantly myelitis, associated in 3 cases with optic neuropathy causing blindness. Extensive workup was negative but analysis of the CSF by use of pan-microorganism DNA- and RNA-based shotgun metagenomics was positive for HPgV. This case series further supports the hypothesis of HPgV CNS infection and highlights the utility of metagenomic next-generation sequencing of CSF in immunocompromised patients.

What do the changing patterns of comorbidity burden in people living with HIV mean for long-term management? Perspectives from European HIV cohorts.

Undoubtedly, comorbidities complicate long-term HIV management and have significant cost implications for healthcare systems. A better understanding of these comorbidities and underlying causes would allow for a more considered and proactive approach to the long-term management of HIV. This review examines cross-sectional analyses of six European cohort studies (Athens Multicenter AIDS Cohort Study, Aquitaine Cohort, EuroSIDA Cohort study, French claims EGB, German InGef Cohort and the Italian Cohort of Individuals, Naïve for Antiretrovirals), which included individuals with HIV followed over a certain period of time. Based on these cohorts, we examined how comorbidities have changed over time; how they compromise HIV management; and how much of a financial burden they impart. These data also provided a framework to explore the major issues of ageing and HIV and the practical implications of managing such issues in real-life practice.

COVID-19-related encephalopathy: a case series with brain FDG-positron-emission tomography/computed tomography findings.

AIM: The aim of this paper is to describe the clinical features of COVID-19-related encephalopathy and their metabolic correlates using brain 2-desoxy-2-fluoro-D-glucose (FDG)-positron-emission tomography (PET)/computed tomography (CT) imaging. BACKGROUND AND PURPOSE: A variety of neurological manifestations have been reported in association with COVID-19. COVID-19-related encephalopathy has seldom been reported and studied. METHODS: We report four cases of COVID-19-related encephalopathy. The diagnosis was made in patients with confirmed COVID-19 who presented with new-onset cognitive disturbances, central focal neurological signs, or seizures. All patients underwent cognitive screening, brain magnetic resonance imaging (MRI), lumbar puncture, and brain 2-desoxy-2-fluoro-D-glucose (FDG)-positron-emission tomography (PET)/computed tomography (CT) (FDG-PET/CT). RESULTS: The four patients were aged 60 years or older, and presented with various degrees of cognitive impairment, with predominant frontal lobe impairment. Two patients presented with cerebellar syndrome, one patient had myoclonus, one had psychiatric manifestations, and one had status epilepticus. The delay between first COVID-19 symptoms and onset of neurological symptoms was between 0 and 12 days. None of the patients had MRI features of encephalitis nor significant cerebrospinal fluid (CSF) abnormalities. SARS-CoV-2 RT-PCR in the CSF was negative for all patients. All patients presented with a consistent brain FDG-PET/CT pattern of abnormalities, namely frontal hypometabolism and cerebellar hypermetabolism. All patients improved after immunotherapy. CONCLUSIONS: Despite varied clinical presentations, all patients presented with a consistent FDG-PET pattern, which may reflect an immune mechanism.

What are the infectious risks with disease-modifying drugs for multiple sclerosis and how to reduce them? A review of literature.

Patients with multiple sclerosis taking immunosuppressive therapy may be at risk of reactivating latent pathogens, community-acquired infections, worsening asymptomatic chronic infections, and contracting de novo infections. This risk was evaluated mainly in short-term clinical trials and few studies have investigated this risk in real-life settings. In clinical practice, this infectious risk should be evaluated when a multiple sclerosis diagnosis is made in order to propose specific follow-up or immunization as soon as possible and thus avoid contraindications or risk of lowered vaccination responses. Systematic screening should also be proposed for each patient before second-line therapy to ensure the risk is in line with the treatment plan. This systematic screening must include HIV and hepatitis B and C for all patients before treatment. The immunization schedule needs to be updated and influenza vaccine could be proposed each year for patients receiving disease-modifying drugs. Prevention is preferable to treatment, reducing both infectious morbidity and mortality, as well as interruptions in multiple sclerosis therapy. Therefore, preventive approaches should be tailored to individual patient and treatment risk factors. In this review, we describe the infectious risk with immunossuppressive therapies and propose minimal screening recommendations to evaluate the risk and adapt the prevention and strategy of immunization to each case at multiple sclerosis diagnosis and at specific follow-up visits to avoid difficulties using live-attenuated vaccines or risk reduced immune responses.

Routine screening for HIV, hepatitis B virus and hepatitis C virus in individuals undergoing oral and maxillofacial surgery.

OBJECTIVES: Given the effectiveness of treatment of HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, there are considerable benefits associated with determining HIV/HBV/HCV status. We evaluated the feasibility and acceptability of systematic screening and subsequent care in an oral and maxillofacial surgery department. METHODS: The anaesthesiologists proposed screening for HIV, HBV and HCV to all individuals of unknown infection status undergoing surgery between 19 April 2016 and 19 April 2017. The endpoints were the rates of test offer, acceptance/refusal and new diagnoses. Seropositive individuals were referred to infectious disease specialists. Associations between age, sex or surgery type and test offer (eligible individuals) or acceptance/refusal (those offered testing) were investigated. RESULTS: Of the 1407 individuals attending the department, 1322 were eligible for inclusion in the study. Testing was proposed to 899 individuals [68%; 95% confidence interval (CI) 65-71%], 831 of whom accepted the offer (92.4%; 95% CI 90.5-94.1%). Results were obtained for 787 individuals (41 samples were uncollected and three were invalid). Age was the only factor associated with test offer in multivariable analysis [odds ratio (OR) 0.90; 95% CI 0.84-0.97, per additional 10 years], and no factor was associated with acceptance. Of the five, three and eight individuals testing positive for HIV, HBV and HCV, four, two and one patient, respectively, reported prior knowledge of seropositivity. The new diagnosis rate was 0.13% (95% CI 0-0.7%) for HIV and HBV, and 0.89% (95% CI 0.36-1.82%) for HCV [three positive polymerase chain reaction (PCR) tests]. All individuals newly diagnosed with HIV or HCV infection received specific antiviral treatment. CONCLUSIONS: Rates of screening offer and acceptance were high. Substantial screening resources are required to decrease the impact of the hidden epidemics of HIV, HBV and HCV infections.

Invasive cervical cancer in HIV-infected women: risk and survival relative to those of the general population in France. Results from the French Hospital Database on HIV (FHDH)-Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (ANRS) CO4 cohort study.

OBJECTIVES: We examined trends in the incidence rates of invasive cervical cancer (ICC) and in the rate of survival after ICC among women living with HIV (WLHIV) in France and compared them to those of the general population. METHODS: Histologically validated incident cases of ICC in the period 1992-2009 from the French Hospital Database on HIV (FHDH-ANRS CO4) were included in the study. Age-standardized incidence rates were estimated for FHDH and the general population in France for 1992-1996 [pre-combination antiretroviral therapy (cART) period], 1997-2000 (early cART period), 2001-2004 (intermediate cART period), and 2005-2009 (late cART period). Age-standardized incidence ratios (SIRs) were calculated. Five-year survival was compared with that of the general population for ICC diagnosed in 2005-2009 after standardization for age. RESULTS: Among 28 977 WLHIV, 60 incident ICCs were histologically validated. There was a nonsignificant decreasing trend for the incidence across the cART periods (P = 0.07), from 60 to 36/100 000 person-years. The risk of ICC was consistently significantly higher in WLHIV than in the general population; the SIR was 5.4 [95% confidence interval (CI) 3.0-8.9] during the pre-cART period and 3.3 (95% CI 2.2-4.7) in 2005-2009. Survival after ICC did not improve across periods (log-rank P = 0.14), with overall estimated 5-year survival of 78% (95% CI 0.67-0.89%). Five-year survival was similar for WLHIV and the general population for women diagnosed with ICC in 2005-2009, after standardization (P = 0.45). CONCLUSIONS: ICC risk is still more than three times higher in WLHIV than in the general population. Survival after ICC did not improve over time and was similar to that of the general population during the most recent period. Such results call for promotion of the uptake of screening in WLHIV.

Expression pattern of the CXCL12/CXCR4-CXCR7 trio in Kaposi sarcoma skin lesions.

BACKGROUND: Recent studies have independently implicated the chemokine CXCL12 and its receptors, CXCR4 and CXCR7, in the pathophysiology of Kaposi sarcoma (KS). OBJECTIVES: We investigated whether the CXCL12/CXCR4-CXCR7 protein trio could constitute KS biomarkers. METHODS: Endothelial and spindle cells positive for CXCL12/CXCR4-CXCR7, human herpesvirus-8 latency-associated nuclear antigen (LANA), Ki67 antigen (proliferation) and vascular endothelial growth factor (VEGF) were quantitated in skin lesions from patients with AIDS-associated KS, patients with classic KS and patients with angiomas, using immunohistochemistry and quantitative image analysis (16, 21 and 20 skin lesions, respectively). Plasma CXCL12 concentrations were measured by enzyme-linked immunosorbent assay from 20 patients with AIDS-KS, 12 HIV-infected patients without KS and 13 healthy donors' samples. RESULTS: Cells positive for CXCL12, CXCR4, CXCR7, LANA, Ki67 and VEGF were significantly enriched in patients with AIDS-associated KS and classic KS vs. angiomas (P < 0·001), and in nodular vs. macular/papular KS lesions (P < 0·05). CXCL12, CXCR4 and CXCR7 detection correlated with LANA, Ki67 and VEGF detection (r > 0·4; P < 0·05). However, plasma CXCL12 concentrations did not differ between patients with AIDS-associated KS, HIV-infected patients without KS, and healthy donors. CONCLUSIONS: The CXCL12/CXCR4-CXCR7 trio is upregulated in KS and correlates with KS pathophysiological markers and the severity of skin lesions. Histological assessment of the CXCL12 axis could serve as a valuable biomarker for KS diagnosis and progression.

COPEDOL: A two-year observational study in pretreated HIV-1-infected patients switching to a dolutegravir-based regimen.

OBJECTIVES: Dolutegravir is a second-generation integrase strand transfer inhibitor of particular interest as a rescue treatment for people living with HIV (PLWHIV) who develop resistance to multiple antiretrovirals (ART). We assessed the virological treatment response in patients switched to a dolutegravir-based regimen following failure of previous ART treatment in a real-world treatment setting. PATIENTS AND METHODS: This was a multicenter, longitudinal, observational study with retrospective patient enrolment. Patients were enrolled between February 2017 and January 2018. Patients starting dolutegravir treatment between February 2014 and September 2016 were retrospectively included. Patients were followed up for 24 months after dolutegravir initiation. During this period, treatment with dolutegravir could be discontinued at any time at the physician's discretion. Treatment failure was either defined as a viral load≥50 copies/mL at two consecutive blood samples or as clinical or biological safety issues. Overall, 459 patients were enrolled and 329 completed 24 months of treatment. The primary study outcome measures were treatment response and time to treatment response. RESULTS: 346/440 patients (78.6%) achieved a treatment response; 86 patients discontinued dolutegravir treatment (of whom 17 for failure to achieve or maintain viral suppression and 38 for tolerability issues). Acquired dolutegravir-resistance mutations were identified in five patients. CONCLUSIONS: A sustained treatment response can be obtained with a dolutegravir-based treatment regimen in PLWHIV experiencing treatment failure, even in vulnerable patients with a long history of previous ART failure, infected with multidrug-resistant HIV strains, and with multiple comorbidities.

Long COVID-19 symptoms: Clinical characteristics and recovery rate among non-severe outpatients over a six-month follow-up.

BACKGROUND: To describe persistent symptoms in long COVID-19 non-severe outpatients and report the 6-month clinical recovery (CR) rate. METHODS: Observational study enrolling outpatients (≥ 18 years) with confirmed non-severe COVID-19 (positive nasopharyngeal RT-PCR or presence of SARS-CoV-2 antibodies) who consulted for persistent symptoms after the first pandemic wave (March-May 2020). CR was assessed at the 6-month visit and defined as complete (no symptom), partial (persistent symptoms of lower intensity) or lack of recovery (no improvement). RESULTS: Sixty-three patients (79% women, mean age: 48 years) enrolled; main symptoms (mean 81 days after acute infection): asthenia/myalgia (77%), dyspnea (51%), headaches (35%), cough (33%). At 6 months (n=56), 30% had complete, 57% partial, and 13% lack of recovery. The proportion of patients with>2 persistent symptoms was 26% at 6 months (main symptoms: dyspnea [54%] and asthenia/myalgia [46%]). CONCLUSION: We observed a slow but high recovery rate at 6 months among these outpatients.

Prevalence and factors associated with symptom persistence: A prospective study of 429 mild COVID-19 outpatients.

INTRODUCTION: Persistent symptoms have recently emerged as a clinical issue in COVID-19. We aimed to assess the prevalence and risk factors in symptomatic non-hospitalized individuals with mild COVID-19. METHODS: We performed a prospective cohort study of symptomatic COVID-19 outpatients, from March to May 2020, with weekly phone calls from clinical onset until day 30 and up to day 60 in case of persistent symptoms. The main outcomes were the proportion of patients with complete recovery at day 30 and day 60 and factors associated with persistent symptoms. RESULTS: We enrolled 429 individuals mostly women (72.5%) and healthcare workers (72.5%), with a median age of 41.6 years [IQR 30-51.5]. Symptoms included: cough (69.7%), asthenia (68.8%), anosmia (64.8%), headaches (64.6%), myalgia (62.7%), gastrointestinal symptoms (61.8%), fever (61.5%), and ageusia (60.8%). Mean duration of disease was 27 days (95%CI: 25-29). The rate of persistent symptoms was 46.8% at day 30 and 6.5% at day 60 consisting in asthenia (32.6%), anosmia (32.6%), and ageusia (30.4%). The probability of complete recovery was 56.3% (95%CI: 51.7-61.1) at day 30 and 85.6% (95%CI: 81.2-89.4) at day 60. Factors associated with persistent symptoms were age>40 (HR 0.61), female sex (HR 0.70), low cycle threshold (HR 0.78), and ageusia (HR 0.59). CONCLUSIONS: COVID-19 - even in its mild presentation - led to persistent symptoms (up to one month) in nearly half of individuals. Identification of risk factors such as age, gender, ageusia and viral load is crucial for clinical management and argues for the development of antiviral agents.

Comparison of HIV-Infected and Noninfected Patients Undergoing Bariatric Surgery: The ObeVIH Study.

OBJECTIVE: The aim of this study was to compare clinical characteristics and adipose/liver tissue histology analysis in HIV-infected and HIV-uninfected subjects undergoing bariatric surgery. DESIGN: This was a cross-sectional study of HIV-infected subjects undergoing single-port sleeve gastrectomy with prospective enrolment and frequency age (±5 years), sex, and body mass index (BMI, ± 5 kg/m2) matched on HIV-uninfected subjects. METHODS: This study was conducted at a single clinical site at Pitié-Salpêtrière hospital-Paris-France comprising 19 HIV-uninfected and 21 HIV-infected subjects with plasma VL < 20 copies/mL, all with a BMI > 40 kg/m2 or >35 kg/m2 with comorbidities. Histology of subcutaneous and visceral abdominal adipose tissue (SCAT/VAT) and liver biopsies was collected during single-port sleeve gastrectomy. Outcomes included anthropometric characteristics, comorbidities, cardiovascular parameters, adipose tissue, and liver histology. RESULTS: The age of HIV-infected participants was (median, interquartile range IQR) 48 y (42-51), with 76.2% females, a BMI of 41.4 kg/m2 (37.3-44.4), an antiretroviral duration of 16 y (8-21), current integrase strand transfer inhibitor (INSTI)-based regimen in 15 participants and non-INSTI regimen in 6 participants, and a CD4 count of 864/mm3 (560-1066). The age of controls was 43 y (37-51), with 78.9% females and a BMI of 39.2 kg/m2 (36.3-42.6). Anthropometric characteristics, comorbidities, and cardiovascular parameters did not differ according to HIV status and INSTI treatment. The number of macrophage crown-like structures in SCAT was lower in INSTI-treated participants than in HIV-uninfected participants (P = 0.02) and non-INSTI-treated HIV-infected subjects (P = 0.07). Hepatic steatosis and liver disease severity global score were lower in INSTI-treated participants than in non-INSTI-treated HIV-infected participants (P = 0.05 and P = 0.04, respectively). CONCLUSIONS: HIV-infected and HIV-uninfected subjects undergoing bariatric surgery presented a similar profile regarding anthropometric measures, cardiovascular parameters, and comorbidities. However, INSTI-treated participants presented milder SCAT and liver alterations than non-INSTI-treated participants.

Cerebral aspergillosis in the era of new antifungals: The CEREALS national cohort study Nationwide CEREbral Aspergillosis Lesional study (CEREALS).

BACKGROUND: Cerebral aspergillosis (CA) is a life-threatening disease for which diagnosis and management remain challenging. Detailed analyses from large cohorts are lacking. METHODS: We included 119 cases of proven (n = 54) or probable (n = 65) CA diagnosed between 2006 and 2018 at 20 French hospitals. Data were collected at baseline and during follow-up. Cerebral imaging was reviewed centrally by two neuroradiologists. RESULTS: The most frequent underlying conditions were hematological malignancy (40%) and solid organ transplantation (29%). Galactomannan was detected in the serum of 64% of patients. In 75% of cases, at least one of galactomannan, Aspergillus PCR, and ß-d-glucan was positive in the cerebrospinal fluid. Six-week mortality was 45%. Two distinct patterns of disease were identified according to presumed route of dissemination. Presumed haematogenous dissemination (n = 88) was associated with a higher frequency of impaired consciousness (64%), shorter time to diagnosis, the presence of multiple abscesses (70%), microangiopathy (52%), detection of serum galactomannan (69%) and Aspergillus PCR (68%), and higher six-week mortality (54%). By contrast, contiguous dissemination from the paranasal sinuses (n = 31) was associated with a higher frequency of cranial nerve palsy (65%), evidence of meningitis on cerebral imaging (83%), macrovascular lesions (61%), delayed diagnosis, and lower six-week mortality (30%). In multivariate analysis and in a risk prediction model, haematogenous dissemination, hematological malignancy and the detection of serum galactomannan were associated with higher six-week mortality. CONCLUSION: Distinguishing between hematogenous and contiguous dissemination patterns appears to be critical in the workup for CA, as they are associated with significant differences in clinical presentation and outcome.

Infective endocarditis due to Neisseria elongata: A case report and literature review.

INTRODUCTION: Neisseria elongata (NE), a Gram-negative, rod-shaped organism, was previously thought to be non-pathogenic. However, in recent years it has become increasingly recognized as a rare cause of infective endocarditis. In this paper, we report a case of NE infective endocarditis and provide a review of the literature. OBJECTIVES: To describe a case of NE endocarditis, and to review the literature in search of any similar cases of this rare condition. CASE REPORT: Our patient is a 77-year-old, otherwise healthy female patient who was found to have mitral valve endocarditis with valve regurgitation. DISCUSSION: NE endocarditis is a rare condition that typically affects the left cardiac chambers and is associated with high risk of embolization. A literature review retrieved 35 other cases. CONCLUSIONS: Our report underlines the rarity of NE endocarditis, insofar as relatively few cases have been reported. The bacterium presents similarities with HACEK organisms and can potentially cause infective endocarditis.

Increased risk of IRIS-associated tuberculosis in HIV-infected patients receiving Integrase Inhibitors.

BACKGROUND: Tuberculosis is associated with a risk of immune reconstitution inflammatory syndrome (IRIS) after ART initiation. METHODS: Data from all patients with newly diagnosed tuberculosis disease and uncontrolled HIV infection from 1997 to 2017 in a French center were retrospectively collected. We evaluated the incidence of tuberculosis-IRIS in patients initiating ART with or without integrase inhibitors (INSTI) RESULTS: Fifty-five patients were included: 21 receiving an INSTI regimen and 34 a non-INSTI regimen. Except with regard to ART regimen, the two groups were comparable (median CD4 of 85/mm3). The overall percentage of IRIS was 34% (19/55), with 52% IRIS in INSTI regimen and 23% in non-INSTI regimen respectively (P=0.04). In a multivariate logistic model, we observed an increased risk of IRIS in the INSTI regimen compared to the non-INSTI, with an OR at 3.33 [95% CI, 1.01-11.1] (P=0.05) CONCLUSIONS: ART containing integrase inhibitors could be associated with increased incidence of TB-associated IRIS.