Safety of hydroxychloroquine and darunavir or lopinavir in COVID-19 infection.

BACKGROUND: Combination therapy with hydroxychloroquine and darunavir/ritonavir or lopinavir/ritonavir has been suggested as an approach to improve the outcome of patients with moderate/severe COVID-19 infection. OBJECTIVES: To examine the safety of combination therapy with hydroxychloroquine and darunavir/ritonavir or lopinavir/ritonavir. METHODS: This was an observational cohort study of patients hospitalized for COVID-19 pneumonia treated with hydroxychloroquine and darunavir/ritonavir or lopinavir/ritonavir. Clinical evaluations, electrocardiograms and the pharmacokinetics of hydroxychloroquine, darunavir and lopinavir were examined according to clinical practice and guidelines. RESULTS: Twenty-one patients received hydroxychloroquine with lopinavir/ritonavir (median age 68 years; 10 males) and 25 received hydroxychloroquine with darunavir/ritonavir (median age 71 years; 15 males). During treatment, eight patients (17.4%) developed ECG abnormalities. Ten patients discontinued treatment, including seven for ECG abnormalities a median of 5 (range 2-6) days after starting treatment. All ECG abnormalities reversed 1-2 days after interrupting treatment. Four patients died within 14 days. ECG abnormalities were significantly associated with age over 70 years, coexisting conditions (such as hypertension, chronic cardiovascular disease and kidney failure) and initial potential drug interactions, but not with the hydroxychloroquine concentration. CONCLUSIONS: Of the patients with COVID-19 who received hydroxychloroquine with lopinavir or darunavir, 17% had ECG abnormalities, mainly related to age or in those with a history of cardiovascular disease.

Central nervous system candidiasis beyond neonates: Lessons from a nationwide study.

Though candidiasis is the most frequent invasive fungal infection, Candida spp. central nervous system (CNS) infections are rare but severe. To further describe clinico-patho-radiological presentations of this entity, we report a retrospective study from January 2005 to December 2018 including patients aged ≥ 28 days with proven or probable CNS candidiasis in France. Twenty-four patients were included. Seventeen patients (70%) had CNS localization secondary to disseminated candidiasis (10 with hematologic malignancies [HM]; the seven other patients had infective endocarditis [IE]). Among patients with HM, seven previously had lumbar puncture for intrathecal chemotherapy, the three others had IE. Among patients with disseminated infection, magnetic resonance imaging (MRI) evidenced meningitis (17%), micro-abscesses (58%), or vascular complications (67%). Seven patients (30%) had isolated CNS involvement related to neurosurgery (n = 2), CARD9 deficiency (n = 2), intravenous drug use, diabetes mellitus, or no identified predisposing condition (n = 1 each). All evaluated patients with isolated CNS involvement had meningitis on cerebrospinal fluid (CSF) and intracranial hypertension. For the latter patients, MRI evidenced meningitis (71%) or abscesses (57%). Among all patients, cerebrospinal fluid (CSF) culture grew Candida spp. in 31% of cases. CSF ßDGlucan or mannan Ag were positive in respectively 86% and 80% of cases. Mortality attributed to CNS candidiasis was 42%: 53% in case of disseminated infection (70% for HM) and 14% in case of localized infection. CNS candidiasis are isolated or occur during disseminated infection in patients with HM and lumbar puncture for intrathecal chemotherapy or during IE. Clinical, radiological finding and outcome highly vary according to CNS localized versus disseminated candidiasis. LAY SUMMARY: Candida is a yeast and is the most common cause of fungal infections worldwide. Candida central nervous system (CNS) infections are rare, severe, and poorly described. We report a retrospective study from January 2005 to December 2018 including patients aged ≥ 28 days with proven or probable CNS candidiasis in France. Twenty-four patients were included (14 men, median age 51 years). Seventeen patients had CNS localization secondary to disseminated candidiasis from blood to CNS (10 with hematologic malignancies [HM], the seven other patients had infective endocarditis [IE]). Seven patients had isolated CNS involvement related to neurosurgery (n = 2), CARD9 deficiency (n = 2), intravenous drug use (n = 1), diabetes mellitus (n = 1), or no identified risk factor (n = 1).During Candida CNS infections, brain lesions were meningitis abscesses or vascular complications. Cerebrospinal fluid (CSF) culture grew Candida spp. in 31% of cases. Forty-two percent of patients died from infection: 53% in case of disseminated infection (70% for HM) and 14% in case of localized infection.

Prosthetic Valve Candida spp. Endocarditis: New Insights Into Long-term Prognosis-The ESCAPE Study.

Background: Prosthetic valve endocarditis caused by Candida spp. (PVE-C) is rare and devastating, with international guidelines based on expert recommendations supporting the combination of surgery and subsequent azole treatment. Methods: We retrospectively analyzed PVE-C cases collected in Spain and France between 2001 and 2015, with a focus on management and outcome. Results: Forty-six cases were followed up for a median of 9 months. Twenty-two patients (48%) had a history of endocarditis, 30 cases (65%) were nosocomial or healthcare related, and 9 (20%) patients were intravenous drug users. "Induction" therapy consisted mainly of liposomal amphotericin B (L-amB)-based (n = 21) or echinocandin-based therapy (n = 13). Overall, 19 patients (41%) were operated on. Patients <66 years old and without cardiac failure were more likely to undergo cardiac surgery (adjusted odds ratios [aORs], 6.80 [95% confidence interval [CI], 1.59-29.13] and 10.92 [1.15-104.06], respectively). Surgery was not associated with better survival rates at 6 months. Patients who received L-amB alone had a better 6-month survival rate than those who received an echinocandin alone (aOR, 13.52; 95% CI, 1.03-838.10). "Maintenance" fluconazole therapy, prescribed in 21 patients for a median duration of 13 months (range, 2-84 months), led to minor adverse effects. Conclusion: L-amB induction treatment improves survival in patients with PVE-C. Medical treatment followed by long-term maintenance fluconazole may be the best treatment option for frail patients.

Parental consanguinity is associated with a severe phenotype in common variable immunodeficiency.

The DEFI study has collected clinical data and biological specimens from kindreds with CVID. Patients with demonstrated parental consanguinity (cCVID group) were compared to patients without parental consanguinity (ncCVID). A total of 24 of the 436 patients with CVID had consanguineous parents. Age at first symptoms and age at diagnosis were comparable in the two groups. Some complications were more frequent in cCVID patients: splenomegaly (62.5% vs. 29%; p = 0.001), granulomatous disease (29% vs. 12%; p = 0.02), and bronchiectasis (58% vs. 29%; p = 0.003). A high incidence of opportunistic infections was also observed in this population (29% vs. 5%; p < 0.001). Distribution of B-cell subsets were similar in the two groups. Naïve CD4+ T cells were decreased in cCVID patients (15% vs. 28%; p < 0.001), while activated CD4 + CD95+ (88% vs. 74%; p = 0.002) and CD8 + HLA-DR + T cells (47% vs. 31%; p < 0.001) were increased in these patients when compared to ncCVID patients. Parental consanguinity is associated with an increased risk of developing severe clinical complications in patients with CVID. Most of these patients presented with severe T-cell abnormalities and should be considered with a diagnosis of late-onset combined immune deficiency (LOCID). Systematic investigation for parental consanguinity in patients with CVID provides useful information for specific clinical care and genetic screening.

Covichem: A biochemical severity risk score of COVID-19 upon hospital admission.

Clinical and laboratory predictors of COVID-19 severity are now well described and combined to propose mortality or severity scores. However, they all necessitate saturable equipment such as scanners, or procedures difficult to implement such as blood gas measures. To provide an easy and fast COVID-19 severity risk score upon hospital admission, and keeping in mind the above limits, we sought for a scoring system needing limited invasive data such as a simple blood test and co-morbidity assessment by anamnesis. A retrospective study of 303 patients (203 from Bordeaux University hospital and an external independent cohort of 100 patients from Paris Pitié-Salpêtrière hospital) collected clinical and biochemical parameters at admission. Using stepwise model selection by Akaike Information Criterion (AIC), we built the severity score Covichem. Among 26 tested variables, 7: obesity, cardiovascular conditions, plasma sodium, albumin, ferritin, LDH and CK were the independent predictors of severity used in Covichem (accuracy 0.87, AUROC 0.91). Accuracy was 0.92 in the external validation cohort (89% sensitivity and 95% specificity). Covichem score could be useful as a rapid, costless and easy to implement severity assessment tool during acute COVID-19 pandemic waves.

Paradoxical anti-TNF-associated TB worsening: Frequency and factors associated with IRIS.

OBJECTIVES: Paradoxical tuberculosis (TB) worsening, an example of the immune reconstitution inflammatory syndrome (IRIS), is an increasing phenomenon now described in several settings, including anti-tumor necrosis factor (TNF) discontinuation during biotherapy-induced TB. To better recognize it, we analyzed the frequency and factors associated with anti-TNF-induced TB-IRIS. METHODS: Case-control study on anti-TNF-associated TB patients. IRIS cases, defined with the following consensus criteria, were matched to two controls (anti-TNF-associated TB without IRIS). IRIS frequency was based on the French RATIO registry. Conditional logistic-regression identified IRIS risk factors. RESULTS: Fourteen patients developed anti-TNF-associated TB-IRIS within medians of 45 [IQR 22-131] days after starting anti-TB therapy and 110 [IQR 63-164] days after the last anti-TNF infusion. Each case was matched to two controls by year of TB diagnosis. IRIS-associated factors were (odds ratio [95% CI]): disseminated TB (11.4 [1.4-92.2], P=0.03), history of Mycobacterium tuberculosis exposure (12.7 [1.6-103.0], P=0.02) and steroid use at the time of TB diagnosis (4.6 [1.2-17.2], P=0.02). The RATIO registry IRIS frequency was 7%. CONCLUSION: After stopping biotherapy, paradoxical anti-TNF-associated TB worsening occurred most often in patients with disseminated TB. Although diagnosis remains difficult, physicians must be aware of IRIS because prolonged anti-TB treatment is not needed but, paradoxically, immunosuppressant reintroduction may be.

Thymic Epithelial Tumor-Associated Cytopenia: A 10-Year Observational Study in France.

INTRODUCTION: Thymic epithelial tumor (TET)-associated cytopenia is rare but difficult to treat. METHODS: We performed a multicenter, retrospective study of TET and associated forms of cytopenia in France. Cases were collected by the French National Reference Center for Autoimmune Cytopenia and the French National Thymic Malignancy Interest Group (Réseau Tumeurs Thymiques et Cancer) and through a call for cases by the French Society of Internal Medicine. RESULTS: Thirty-six cases were recorded between 2002 and 2014 and followed up for a median of 38 months (interquartile range, 23-106 months). Thirty-two patients underwent surgery for TET, and 14 of the latter were in complete remission at last follow-up. Cytopenia can occur before, simultaneously, or after diagnosis of TET. The most common types of cytopenia were pure red cell aplasia (in 30% of cases) and Good syndrome (GS) (also in 30% of cases). Eleven patients displayed two or more episodes of cytopenia. Eighteen patients received steroids as their first-line treatment, leading to a complete response in nine. Other first-line treatments (cyclosporine and rituximab) were less effective but should be considered as treatment options. Infections developed in 84% of the patients with GS; this did not appear to be related to the presence or absence of immunosuppressive treatment or chemotherapy. Eight patients died during the follow-up period (two died of cytopenia and five of infections). CONCLUSIONS: The optimal treatment for TET-associated cytopenia has not been clearly defined and the outcome does not appear to be correlated with TET progression. For GS, prophylactic immunoglobulin replacement therapy and prophylactic antibiotic therapy can be recommended.

Melioidosis in a European traveler without comorbidities: a case report and literature review.

Melioidosis is an endemic disease in Southeast Asia and northern Australia. It habitually affects immune-depressed hosts and may have a wide range of clinical manifestations. The use of positron emission tomography-computed tomography (PET-CT) has not been described previously for this disease. We report the case of a European traveler without comorbidities who developed melioidosis with pulmonary and bone marrow involvement 1 year after exposure. Antibiotic treatment was managed by taking into account the evolution on PET-CT. We review the literature and suggest the use of PET-CT for the initial evaluation of melioidosis, especially to look for a bone location, and to manage the length of antibiotic therapy.

Paradoxical exacerbation of tuberculosis after TNFα antagonist discontinuation: beware of immune reconstitution inflammatory syndrome.

Paradoxical worsening of tuberculosis associated with immune reconstitution during antiretroviral therapy in patients with HIV infection is known as the immune reconstitution inflammatory syndrome (IRIS). Here, we report a case of paradoxical worsening of IFN-alpha induced tuberculosis in a patient experiencing reconstitution of pathogen-specific immune responses after discontinuing TNFα antagonist therapy. This case serves to alert clinicians that complications such as tuberculosis may worsen after TNFα antagonist discontinuation. This situation may paradoxically require readministration of the immunosuppressive drug in some patients.

Circulation of multiple patterns of unique recombinant forms B/CRF02_AG in France: precursor signs of the emergence of an upcoming CRF B/02.

BACKGROUND: HIV-1 group M is characterized by substantial genetic diversity, and includes nine subtypes, more than 45 circulating recombinant forms (CRFs), and numerous unique recombinant forms (URFs). In France, the epidemic is characterized by predominance of subtype B strains, increasing prevalence of non-B subtypes (CRF02_AG being the most prevalent) and increasing at-risk behaviour in the MSM population. The high prevalence and co-circulation of B and CRF02_AG strains in this population raise the possibility that recombinant forms might emerge and spread. METHODS: Samples from seven patients (five being MSM) were selected on the basis of subtyping discordances in different regions. The pattern of each near full-length genome of the viruses was characterized. The relationships between the newly and previously described B/CRF02_AG URFs were analysed using phylogenetic networks. Single genome amplification was used to search for the parental strains and confirmation of the breakpoints. RESULTS: Seven unique recombination patterns were identified, breakpoints being found throughout the genomes, with hotspots in pol and accessory genes. No link was observed with the previous forms, but the CRF02 regions of two new viruses indicated that they are phylogenetically associated, suggesting a common ancestral strain. No evidence of circulating parental strains was found. CONCLUSION: This description of seven URFs involving subtype B and CRF02_AG highlights the growing complexity of HIV molecular epidemiology in France. These multiple patterns, found mostly in MSM, and the hypothesis of a better fitness of some recombinant strains, argue for a context that could lead to the genesis of CRFB/02_AG strains in France.

Tenosynovitis as a possible feature of immune reconstitution syndrome during highly active antiretroviral treatment (HAART).

An immune reconstitution syndrome (IRS) occurs in between 10% and 25% of patients starting highly active antiretroviral treatment (HAART). A 49-year-old patient presents a tenosynovitis 6 weeks after HAART initiation. In our patient, exhaustive tests for infectious, inflammatory and drug-related causes of tenosynovitis were negative. The improvement obtained with high-dose Non-steroidal anti-inflammatory-drug (NSAID) therapy and the patient's immunovirologic profile, supported a diagnosis of tenosynovitis associated with immune reconstitution, a form of IRS that has not previously been described. This original case increase the broad spectrum of inflammatory rheumatologic disorders associated with HIV infection.