Expert Narrative Review of the Safety of Cladribine Tablets for the Management of Relapsing Multiple Sclerosis.

Cladribine tablets (CladT) is a highly active oral disease-modifying therapy (DMT) for the management of relapsing multiple sclerosis (RMS). CladT acts as an immune reconstitution therapy, in that two short courses of treatment 1 year apart have been shown to suppress disease activity for a prolonged period in most patients, without need for continued DMT. Each course of CladT induces a profound reduction in B lymphocytes that recovers over months, and serious lymphopenia (Grade 3-4) is uncommon. Smaller reductions in levels of T lymphocytes occur slightly later: on average, these remain within the normal range and repopulate progressively. A larger effect occurs on CD8 vs. CD4 cells. Reactivation of latent or opportunistic infections (e.g. varicella zoster, tuberculosis) is mostly associated with very low lymphocyte counts (< 200/mm3). Screening and managing pre-existing infections, vaccinating non-exposed patients and delaying the 2nd year of treatment with CladT to allow lymphocytes to recover to > 800/mm3 (if necessary) are important for avoiding infections and higher-grade lymphopenia. There was no demonstrable or apparent effect of CladT on the efficacy of vaccinations, including against Covid-19. Adverse events consistent with drug-induced liver injury (DILI) represent a rare but potentially serious complication of CladT therapy in spontaneous adverse event reporting; patients should be screened for liver dysfunction before starting treatment. Ongoing hepatic monitoring is not required, but CladT must be withdrawn if signs and symptoms of DILI develop. There was a numerical imbalance for malignancies when comparing cladribine to placebo in the clinical programme, particularly in short-term data, but recent evidence shows that the risk of malignancy with CladT is similar to the background rate in the general population and to that with other DMTs. Overall, CladT is well tolerated with a favorable safety profile appropriate for the management of RMS.

Decrease in CD4 T-Cell Count and Risk of Severe Morbid Conditions in People With Human Immunodeficiency Virus Infection With Controlled Viral Load After Initiating Combination Antiretroviral Therapy Between 2006 and 2018.

BACKGROUND: A previous study showed an association between CD4 T-cell count decline in people with human immunodeficiency virus infection (PWH) with viral suppression and an increased risk of severe morbid conditions. We aimed to assess the risk of CD4 T-cell count decline (hereafter, CD4 decline), determine associated factors, and evaluate the association of this decline with the risk of severe morbid conditions (cardiovascular disease and cancer) or death. METHODS: From the Agence Nationale de Recherches sur le SIDA et les hépatites virales (ANRS) CO4 French Hospital Database on HIV cohort, we selected PWH >18 years old who had been followed up for ≥2 years after viral suppression following the initiation of combination antiretroviral therapy (cART) between 2006 and 2018. CD4 decline was defined as 2 consecutive relative differences ≥15%. Among participants with such decline, we modeled CD4, CD8, and total lymphocyte counts before and after CD4 decline, using spline regression. The remaining objectives were assessed using Poisson regression, with the association between CD4 decline and the risk of severe morbid conditions or death evaluated during or after 6 months of decline. RESULTS: Among 15 714 participants (75 417 person-years), 181 presented with CD4 decline (incidence rate, 2.4/1000 person-years (95% confidence interval, 2.1-2.8). CD8 and total lymphocyte counts also showed a similar decline. Older current age and lower viral load at treatment initiation were associated with the risk of CD4 decline. The risk of severe morbid conditions or death was 11-fold higher during the first 6 months for participants who presented with CD4 decline versus those who did not (incidence rate ratio, 10.8 [95% confidence interval, 5.1-22.8]), with no significant difference after 6 months. CONCLUSIONS: In PWH with viral suppression, CD4 decline was rare and related to global lymphopenia. It was associated with a higher risk of severe morbid conditions or death during the first 6 months.

Antibiotics in mastoid and epitympanic obliteration with S53P4 bioactive glass: A retrospective study.

Objective: The role of antibiotics in ear surgery is still controversial. The aim of this study was to assess their need in cholesteatoma surgery when performing obliteration with S53P4 bioactive glass, a biocompatible material with antibacterial properties. Methods: This retrospective cohort study was conducted in a tertiary referral center between January 2017 and May 2019. Sixty-nine consecutive patients, who underwent surgery for cholesteatoma removal and/or rehabilitation of canal-wall-down mastoidectomy with mastoid and epitympanic obliteration using S53P4 granules were included. Before 2019, antibiotics were routinely used (group "w/AB"). Patients received intravenous antibiotics during surgery, oral treatment was continued for 7 days and topical antibiotics for 1 month. After 2019, no antibiotics were administered (group "w/oAB"). The primary outcome was the occurrence of early surgical site infection. Secondary outcomes were late infection, anatomic and functional results at 3 and 12 months. Results: Twenty-three patients were included in group "w/oAB" and 46 in group "w/AB", with no significant differences in demographics, medical history or follow-up. Five ears (22%) in group "w/oAB" developed an early infection compared with 2 (4%) in group "w/AB" (p = .03). The relative risk was 6.11, 95CI%[1.09;31.96]. Infections were successfully treated with antibiotics, and no patient underwent surgical removal of the granules. No late infections or complications were observed. There was no difference in graft failure or air-bone gap closure at 1 year. Conclusion: Peri-/post-operative antibiotics prevent early infection in obliteration surgery with S53P4 granules. Infections can be treated medically without complications or require removal of the implanted material. Level of evidence: 4.

Pearls & Oy-sters: Spinal Cord Candidiasis Linked to CARD9 Deficiency Masquerading as a Longitudinally Extensive Transverse Myelitis.

Candida spp. myelopathies are very rare. We report a case of subacute longitudinally extensive transverse myelitis in an apparently immunocompetent 55-year-old man. After a negative infectious workup, corticosteroids and plasma exchange were initiated. Although there was a transient initial improvement, symptoms then worsened, and the lumbar puncture was repeated. Candida albicans was isolated in the CSF, and a diagnosis of spinal cord candidiasis was made. Gene panel sequencing for inborn immune deficiencies identified a homozygous disease-causing CARD9 variant. Despite antifungal treatment, necrotic myelitis, meningoencephalitis, and cerebral vasculitis developed. Fungal spinal cord infections can mimic inflammatory myelitis, and beta-D-glucan testing of both serum and CSF may help narrow down the diagnosis. In cases of severe or unexpected invasive Candida spp. infection, even adults and apparently immunocompetent patients should be screened for inborn immune deficiencies and CARD9 deficiency in particular.

Clinical Features and Outcome of Multidrug-Resistant Osteoarticular Tuberculosis: A 12-Year Case Series from France.

The optimal treatment for osteoarticular infection due to multidrug-resistant tuberculosis strains (MDR-OATB) remains unclear. This study aims to evaluate the diagnosis, management and outcome of MDR-OATB in France. We present a case series of MDR-OATB patients reviewed at the French National Reference Center for Mycobacteria between 2007 and 2018. Medical history and clinical, microbiological, treatment and outcome data were collected. Twenty-three MDR-OATB cases were reported, representing 3% of all concurrent MDR-TB cases in France. Overall, 17 were male, and the median age was 32 years. Six patients were previously treated for TB, including four with first-line drugs. The most frequently affected site was the spine (n = 16). Bone and joint surgery were required in 12 patients. Twenty-one patients (91%) successfully completed the treatment with a regimen containing a mean of four drugs (range, 2-6) for a mean duration of 20 months (range, 13-27). Overall, high rates of treatment success were achieved following WHO MDR-TB treatment guidelines and individualized patient management recommendations by the French National TB Consilium. However, the optimal combination of drugs, duration of treatment and role of surgery in the management of MDR-OATB remains to be determined.

Cerebral vasculitis due to Aspergillus spp. in immunocompromised patients: literature review.

OBJECTIVES: Invasive aspergillosis is a threat for immunocompromised patients. We present a case series of aggressive cerebral vasculitis caused by Aspergillus spp. infection in immunocompromised patients. METHODS: We present a retrospective case series of three autopsy-proven invasive cerebral aspergillosis with diffuse vasculitis affecting large caliber cerebral vessels. RESULTS: Three patients were immunosuppressed: one on rituximab, one on corticosteroids, and one with a renal transplant. Two of these patients were diagnosed with cerebral aspergillosis on postmortem. CONCLUSION: Aspergillus cerebral vasculitis is a rare form of invasive aspergillosis that should be considered in an immunocompromised individual with suggestive lesions on imaging. It should be suspected as a possible cause of aseptic neutrophil meningitis.

Cumulative incidence of SARS-CoV-2 infection and associated risk factors among frontline health care workers in Paris: the SEROCOV cohort study.

With the COVID-19 pandemic, documenting whether health care workers (HCWs) are at increased risk of SARS-CoV-2 contamination and identifying risk factors is of major concern. In this multicenter prospective cohort study, HCWs from frontline departments were included in March and April 2020 and followed for 3 months. SARS-CoV-2 serology was performed at month 0 (M0), M1, and M3 and RT-PCR in case of symptoms. The primary outcome was laboratory-confirmed SARS-CoV-2 infection at M3. Risk factors of laboratory-confirmed SARS-CoV-2 infection at M3 were identified by multivariate logistic regression. Among 1062 HCWs (median [interquartile range] age, 33 [28-42] years; 758 [71.4%] women; 321 [30.2%] physicians), the cumulative incidence of SARS-CoV-2 infection at M3 was 14.6% (95% confidence interval [CI] [12.5; 16.9]). Risk factors were the working department specialty, with increased risk for intensive care units (odds ratio 1.80, 95% CI [0.38; 8.58]), emergency departments (3.91 [0.83; 18.43]) and infectious diseases departments (4.22 [0.92; 18.28]); current smoking was associated with reduced risk (0.36 [0.21; 0.63]). Age, sex, professional category, number of years of experience in the job or department, and public transportation use were not significantly associated with laboratory-confirmed SARS-CoV-2 infection at M3. The rate of SARS-CoV-2 infection in frontline HCWs was 14.6% at the end of the first COVID-19 wave in Paris and occurred mainly early. The study argues for an origin of professional in addition to private life contamination and therefore including HCWs in the first-line vaccination target population. It also highlights that smokers were at lower risk.Trial registration The study has been registered on ClinicalTrials.gov: NCT04304690 first registered on 11/03/2020.

Anti-PD-1 immune-related adverse events are associated with high therapeutic antibody fixation on T cells.

Immune checkpoint inhibitors (ICI) widely improved the treatment of solid and hematologic malignancies. Yet, a remarkable proportion of patients receiving ICI develop immune related adverse events (irAEs) which are difficult to define as treatment-related. This underlines the need to develop a biomarker to guide irAE diagnosis. We developed a novel flow cytometry assay combining measurement of anti-PD-1 (programmed cell death protein-1) occupancy and evaluation of remaining PD-1 receptor availability with anti-IgG4 PE and anti-PD-1 BV421. We prospectively collected blood and biological fluids samples from patients treated by IgG4 anti-PD-1 therapy (nivolumab or pembrolizumab), with (n=18) or without (n=12) current irAE. We analyzed PD-1+ and IgG4+ staining pattern and MFI values of these parameters on CD4 and CD8 T cells, and IgG4+/PD-1+ MFI ratios are calculated. A higher mean fluorescence intensity IgG4+/PD-1+ ratio was measured on peripheral CD4+ T cells of irAE cases, when compared to controls (p=0.003). ICI-related toxicity is therefore associated with increased therapeutic antibody occupancy of PD-1 receptors on CD4+ T cells. Furthermore, in one case of ICI-related pneumonitis, binding of therapeutic antibody was stronger on lung CD4+ T cell than in blood. In another case of ICI-related encephalitis, the PD-1 receptor occupancy was total on CSF CD4 T cells, but only partial on peripherical CD4 T cells. Our results suggest that flow cytometry monitoring of ICI occupancy can be used in patients treated with monoclonal ICI to guide irAE diagnosis.

AA Amyloidosis in the Course of HIV Infection: A Report of 19 Cases Including 4 New French Cases and a Comprehensive Review of Literature.

INTRODUCTION: HIV infection has been recently retained as an unclear cause of AA amyloidosis. Our aim was to investigate cases of AA amyloidosis associated with HIV infection to understand if it could be considered as a cause of AA amyloidosis. METHODS: A comprehensive literature review was conducted as well as retrospective study from French cases collected from our national reference center for AA amyloidosis. RESULTS: Altogether, 19 patients with AA amyloidosis and HIV infection were found with 68% of men and median age at amyloidosis diagnosis of 38 years (range 28-75 years). Clinical presentation was nephrotic syndrome in 94% (n = 17/18). Among patients with renal involvement and assessable outcome (n = 17), 11 (64.7%) progressed to chronic kidney disease, with 6 (35%) end-stage renal disease. Seventy-five percent of patients had uncontrolled HIV infection and 71.4% CD4 counts <400/mm3 at amyloidosis diagnosis. Repeated or chronic bacterial or fungal infection was found in 47% of cases and a history of parenteral drug use in 55% of patients. Three patients had no classical or at least no suspected AA amyloidosis cause found or reported. CONCLUSIONS: AA Amyloidosis is a rare condition in HIV patients with common renal involvement and significant risk of progression to chronic renal insufficiency. Because of the frequency related to other inflammatory conditions in this population, HIV is probably not an independent risk factor for AA amyloidosis.

Immune activation and chronic inflammation: Is there an additional effect of HIV in a geriatric population?

ABSTRACT: HIV infection has become a chronic disease, with a lower mortality, but a consequent increase in age-related noninfectious comorbidities. Metabolic disorders have been linked to the effect of cART as well to the effects of immune activation and chronic inflammation. Whereas it is known that aging is intrinsically associated with hyperinflammation and immune system deterioration, the relative impact of chronic HIV infection on such inflammatory and immune activation has not yet been studied focusing on an elderly HIV-infected population.The objectives of the study were to assess 29 blood markers of immune activation and inflammation using an ultrasensitive technique, in HIV-infected patients aged ≥75 years with no or 1 comorbidity (among hypertension, renal disease, neoplasia, diabetes mellitus, cardiovascular disease, stroke, dyslipidemia, and osteoporosis), in comparison with age-adjusted HIV-uninfected individuals to identify whether biomarkers were associated with comorbidities. Wilcoxon nonparametric tests were used to compare the levels of each marker between control and HIV groups; logistic regression to identify biomarkers associated to comorbidity in the HIV group and principal component analysis (PCA) to determine clusters associated with a group or a specific comorbidity.A total of 111 HIV-infected subjects were included from the Dat'AIDS cohort and compared to 63 HIV-uninfected controls. In the HIV-infected group, 4 biomarkers were associated with the risk of developing a comorbidity: monocyte chemoattractant protein-1 (MCP-1), neurofilament light chain (NF-L), neopterin, and soluble CD14. Six biomarkers (interleukin [IL]-1B, IL-7, IL-18, neopterin, sCD14, and fatty acid-binding protein) were significantly higher in the HIV-infected group compared to the control group, 11 biomarkers (myeloperoxydase, interleukin-1 receptor antagonist, tumor necrosis factor receptor 1, interferon-gamma, MCP-1, tumor necrosis factor receptor 2, IL-22, ultra sensitivity C-reactive protein, fibrinogen, IL-6, and NF-L) were lower. Despite those differences, PCA to determine clusters associated with a group or a specific comorbidity did not reveal clustering nor between healthy control and HIV-infected patients neither between the presence of comorbidity within HIV-infected group.In this highly selected geriatric HIV population, HIV infection does not seem to have an additional impact on age-related inflammation and immune disorder. Close monitoring could have led to optimize prevention and treatment of comorbidities, and have limited both immune activation and inflammation in the aging HIV population.

Human papillomavirus lesions in 16 MS patients treated with fingolimod: Outcomes and vaccination.

Few cases of human papillomavirus (HPV) diseases have been reported in multiple sclerosis (MS) patients treated with fingolimod. We describe a case series of 16 MS patients (11 women, 5 men) developing HPV lesions after the onset of fingolimod, without previous HPV history. Fingolimod had to be discontinued in six patients. Six patients received vaccination for HPV, with good tolerance. Our report highlights that systematic HPV screening and discussion about HPV vaccination before fingolimod onset are crucial. In case of occurrence of HPV lesions during fingolimod treatment, a comprehensive workup of HPV disease is necessary, with discussion of HPV vaccination to prevent secondary lesions. Prevalence studies of HPV lesions are needed in MS patients with the different disease-modifying therapies.

SARS-CoV-2 infection in patients with primary central nervous system lymphoma.

BACKGROUND: Cancer patients may be at higher risk for severe coronavirus infectious disease-19 (COVID-19); however, the outcome of Primary Central Nervous System Lymphoma (PCNSL) patients with SARS-CoV-2 infection has not been described yet. METHODS: We conducted a retrospective study within the Lymphomes Oculo-Cérébraux national network (LOC) to assess the clinical characteristics and outcome of SARS-CoV-2 infection in PCNSL patients (positive real-time polymerase chain reaction of nasopharyngeal swab or evocative lung computed tomography scan). We compared clinical characteristics between patients with severe (death and/or intensive care unit admission) and mild disease. RESULTS: Between March and May 2020, 13 PCNSL patients were diagnosed with SARS-CoV-2 infection, 11 (85%) of whom were undergoing chemotherapy at the time of infection. The mortality rate was 23% (3/13), and two additional patients (15%) required mechanical ventilation. Two patients (15%) had no COVID-19 symptoms. History of diabetes mellitus was more common in severe patients (3/5 vs 0/8, p = 0.03). Two patients recovered from COVID-19 after mechanical ventilation during more than two weeks and resumed chemotherapy. In all, chemotherapy was resumed after COVID-19 recovery in nine patients (69%) after a median delay of 16 days (range 3-32), none of whom developed unusual chemotherapy complication nor SARS-Cov2 reactivation. CONCLUSION: This preliminary analysis suggests that, while being at higher risk be for severe illness, PCNSL patients with COVID-19 might be treated maximally especially if they achieved oncological response at the time of SARS-CoV-2 infection. Chemotherapy might be resumed without prolonged delay in PCNSL patients with COVID-19.

Immune checkpoint inhibitors for progressive multifocal leukoencephalopathy: a new gold standard?

OBJECTIVES: Progressive multifocal leukoencephalopathy (PML) is a very rare and opportunistic encephalitis caused by JC polyomavirus that is linked to profound immunosuppression and is usually fatal unless immune function can be restored. Immune checkpoint inhibitors (ICI) are monoclonal antibodies (mAbs) that block either CTLA-4 or PD-1 inhibitor receptors, thus enhancing antiviral T-cell activity. Successful treatment of PML by ICI has recently generated some enthusiasm in case reports/small series of patients. However, the initial enthusiasm was mitigated by some individual case reports that did not show any benefit. More data are thus warranted about efficacy of immune checkpoint inhibitors in the specific context of PML. METHODS AND RESULTS: We report here the outcomes of six PML patients treated by ICI between 2017 and 2019. Underlying causes of immunosuppression consisted in hematologic malignancies (n = 4), primary immune deficiency (n = 1) and use of immunosuppressive therapies for myasthenia gravis (n = 1). Three patients were alive with a mean follow-up of 21 months (14-33) after first ICI infusion, including one patient with frank clinical response, one with stabilization, and one with initial worsening and further stabilization of PML. The three other patients rapidly died from PML. CONCLUSIONS: Our data suggest that ICI may be effective for PML treatment but were less impressive than the ones previously reported. Larger studies are thus warranted to confirm this efficacy and to identify the predictive factors of response.