Concurrent cerebral aspergillosis and abdominal mucormycosis during ibrutinib therapy for chronic lymphocytic leukaemia

Comment on Invasive aspergillosis with pulmonary and central nervous system involvement during ibrutinib therapy for relapsed chronic lymphocytic leukaemia: case report. [Clin Microbiol Infect. 2018]International audienceWe read with great interest the article from Peri et al. describing a case report of invasive aspergillosis (IA) with primary pulmonary involvement followed by central nervous system (CNS) involvement in a patient treated for chronic lymphocytic leukaemia (CLL) with ibrutinib [1]. The clinical outcome has been favourable with a combination of voriconazole and liposomal amphotericin B (L-AmB). This case highlights the need for systematic screening of CNS involvement in patients receiving ibrutinib therapy for CLL and concurrent invasive fungal infection, which was not performed during the initial course of pulmonary aspergillosis in the case reported by Peri et al. To complement Peri et al.'s work, we would like to report a case with primary CNS involvement that has benefited from a systematic screening for extra-neurological involvement and additional invasive tissue biopsies. As ibrutinib-associated fungal infections are an emerging syndrome, we would like to describe clinical issues in the management of these infections. A 52-year-old woman presented with a 5-year history of CLL. In 2015 she received a combination of rituximab, fludarabine and cyclophosphamide with complete remission. She relapsed in September 2017 when a treatment with ibrutinib was started. At that time, she experienced neutropenia (between 0.4 and 0.6 G/L). She presented to the hospital on 16 March 2018 with a 2-week history of confusion, behaviour disorders and aggression. The pa-tient's temperature was 38.3 C. Cerebral computed tomography (CT) demonstrated a well-defined rim-enhancing lesion with a hypodense centre surrounded by oedema in the left external capsule region complicated by a mass effect on the left ventricle and a subfalcine herniation (Fig. 1a). A stereotaxic biopsy was performed, and mycological cultures were positive for Aspergillus fumigatus with negative direct examination. Antifungal susceptibility tests showed the following MICs (EUCAST method): vor-iconazole 0.19 mg/L; isavuconazole 0.25 mg/L; posaconazole 0.094 mg/L; itraconazole 0.36 mg/L; caspofungin 0.094 mg/L. Bacterial cultures were also positive for Propionibacterium acnes. No tumour cell was detected on pathological examination. After the biopsy was performed, she subsequently received cefotaxime and metronidazole for 7 days and a single dose of prednisolone of 1 mg/kg. Intravenous voriconazole (400 mg/12 h at day one then 200 mg/12 h) was started after the result of fungal cultures. Serum galactomannan antigen was negative. (1,3)-b-D-glucan serum titres were 84 pg/mL. Aspergillus fumigatus PCR in serum was negative. Sinus and chest CT scans were normal. A systematic abdominal CT scan revealed a lesion of the upper pole of the left kidney and a lesion of the spleen both consistent with abscesses (Fig. 1c). A CT-guided biopsy was performed of the kidney lesion. The histopathological examination showed ischaemic ne-crosis associated with non-septate broad hyphae. Fungal culture

Doravirine plus lamivudine two-drug regimen as maintenance antiretroviral therapy in people living with HIV: a French observational study

International audienceBackground: Two-drug regimens based on integrase strand transfer inhibitors (INSTIs) and boosted PIs have entered recommended ART. However, INSTIs and boosted PIs may not be suitable for all patients. We aimed to report our experience with doravirine/lamivudine as maintenance therapy in people living with HIV (PLWH) followed in French HIV settings.Methods: This observational study enrolled all adults who initiated doravirine/lamivudine between 1 September 2019 and 31 October 2021, in French HIV centres participating in the Dat'AIDS cohort. The primary outcome was the rate of virological success (plasma HIV-RNA < 50 copies/mL) at Week (W)48. Secondary outcomes included: rate of treatment discontinuation for non-virological reasons, evolution of CD4 count and CD4/CD8 ratio over follow-up.Results: Fifty patients were included, with 34 (68%) men; median age: 58 years (IQR 51-62), ART duration: 20 years (13-23), duration of virological suppression: 14 years (8-19), CD4 count: 784 cells/mm3 (636-889). Prior to switching, all had plasma HIV-RNA < 50 copies/mL. All but three were naive to doravirine, and 36 (72%) came from a three-drug regimen. Median follow-up was 79 weeks (IQR 60-96). Virological success rate at W48 was 98.0% (95% CI 89.4-99.9). One virological failure occurred at W18 (HIV-RNA = 101 copies/mL) in a patient who briefly discontinued doravirine/lamivudine due to intense nightmares; there was no resistance at baseline and no resistance emergence. There were three strategy discontinuations for adverse events (digestive disorders: n = 2; insomnia: n = 1). There was no significant change in CD4/CD8 ratio, while CD4 T cell count significantly increased.Conclusions: These preliminary findings suggest that doravirine/lamivudine regimens can maintain high levels of viral suppression in highly ART-experienced PLWH with long-term viral suppression, and good CD4+ T cell count

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old