Intestinal Candida albicans overgrowth in IgA deficiency.

BACKGROUND: Secretory IgA interacts with commensal bacteria, but its impact on human mycobiota ecology has not been widely explored. In particular, whether human IgA-deficiency is associated with gut fungal dysbiosis remains unknown. OBJECTIVES: Our goal was to study the impact of IgA on gut mycobiota ecology. METHODS: The Fungi-Flow method was used to characterize fecal, systemic, and maternal IgA, IgM, and IgG responses against 14 representative fungal strains (yeast/spores or hyphae forms) in healthy donors (HDs) (n = 34, 31, and 20, respectively) and to also compare gut mycobiota opsonization by secretory antibodies in HDs (n = 28) and patients with selective IgA deficiency (SIgAd) (n = 12). Stool mycobiota composition was determined by internal transcribed spacer gene sequencing in HDs (n = 23) and patients with SIgAd (n = 17). Circulating CD4+ T-cell cytokine secretion profiles were determined by intracellular staining. The impact of secretory IgA, purified from breast milk (n = 9), on Candidaalbicans growth and intestinal Caco-2 cell invasion was tested in vitro. RESULTS: Homeostatic IgA binds commensal fungi with a body fluid-selective pattern of recognition. In patients with SIgAd, fungal gut ecology is preserved by compensatory IgM binding to commensal fungi. Gut Calbicans overgrowth nevertheless occurs in this condition but only in clinically symptomatic patients with decreased TH17/TH22 T-cell responses. Indeed, secretory IgA can reduce in vitro budding and invasion of intestinal cells by Calbicans and therefore exert control on this pathobiont. CONCLUSION: IgA has a selective impact on Calbicans ecology to preserve fungal-host mutualism.

Extensive Dermatophytosis Caused by Terbinafine-Resistant Trichophyton indotineae, France.

Extensive dermatophytosis caused by terbinafine-resistant Trichophyton indotineae harboring Phe397Leu and Leu393Ser substitutions in the squalene epoxidase enzyme was diagnosed in France. Analysis of internal transcribed spacer sequences revealed the wide spread of this species in Asia and Europe. Detection of T. indotineae in animals suggests their possible role as reservoirs.

Myeloproliferative neoplasms and clonal haematopoiesis in patients with giant cell arteritis: a case-control and exploratory study.

OBJECTIVES: GCA is a large vessel vasculitis for which triggering factors remain unknown. Clonal haematopoiesis (CH) was associated with atherosclerosis through the induction of inflammation in myeloid cells, and data suggest that CH expansion and inflammation may support each other to induce a pro-inflammatory loop. Our objective was to describe the impact of JAK2p.V617F-mutated myeloproliferative neoplasms (MPNs) on GCA and to screen MPN-free patients for CH mutations. METHODS: We performed a retrospective case-control study comparing the characteristics of 21 GCA patients with MPN and 42 age- and gender-matched GCA patients without MPN. Also, 18 GCA patients were screened for CH through next-generation sequencing (NGS). RESULTS: The most frequent associated MPN was essential thrombocythaemia (ET; n = 11). Compared with controls, GCA patients with MPN had less-frequent cephalic symptoms (71.4 vs 97.6%; P = 0.004) and higher platelet counts at baseline [485 × 109/l (interquartile range 346-586) vs 346 (296-418); P = 0.02]. There was no difference between groups for other clinical features. Overall survival was significantly shorter in patients with MPN compared with controls [hazard ratio 8.2 (95% CI 1.2, 56.6); P = 0.03]. Finally, screening for CH using NGS in 15 GCA patients without MPN revealed CH in 33%. CONCLUSION: GCA patients with MPN display higher platelet counts and shorter overall survival than controls. This association is not fortuitous, given the possible pathophysiological relationship between the two diseases. CH was found in one-third of GCA patients, which may be higher than the expected prevalence for a similar age, and should be confirmed in a larger cohort.

Overexpression of IgG2 in patients resembling IgG4-related disease with normal IgG4.

IgG4-Related Disease (IgG4-RD) results from tissue infiltration by IgG4-expressing plasma cells and lymphocytes, leading to fibrosis and organomegaly. Clinical presentation is remarkably variable according to organ involvement, and high IgG4 serum concentration, initially considered a diagnostic hallmark of IgG4-RD, tends to be forgone as an indispensable criterion for its diagnosis; it can indeed be absent in some patients, highlighting the diversity of presentation of this dysimmune condition. Nevertheless, elevation of IgG4 serum concentration in suggestive settings remains an argument in favour of IgG4-RD, and while other IgG subclasses can be elevated, this biological feature lacks any diagnostic value. We retrospectively studied 9 patients (5 females, 4 males, 31-81 years old) for whom a diagnosis of IgG4-RD had been considered, based on clinical, imaging or histological criteria, but appeared to display abnormally high serum IgG2 while IgG4 levels were normal. Increased serum IgG1 in one case and increased IgG3 in another one were also noticed. Immunohistochemical analyses of intracellular immunoglobulins could be performed on tissue lymph node biopsies from 2 patients, which demonstrated strong infiltration with IgG2-expressing plasma cells. Thus, overexpression of IgG2 subclass may highlight cases of dysimmune disorders resembling IgG4-RD, although the disease trigger might be different, notably infectious. We suggest measuring all serum IgG subclass levels in patients with features consistent with IgG4-RD.

Severe onychomycosis management with oral terbinafine in a kidney transplantation setting: Clinical follow-up by image analysis.

BACKGROUND: Severe onychomycosis treatment in kidney transplant recipients (KTR) is challenging because of drug interactions and adverse events. Tacrolimus remains the antirejection treatment (ART) of choice in kidney transplantation but tolerance with systemic terbinafine for the management of severe onychomycosis has not been studied. OBJECTIVE: This study illustrates severe onychomycosis management in a kidney transplantation setting and investigates systemic terbinafine tolerance profile in KTR. PATIENTS/METHODS: We retrospective analysed clinical data of KTR with a confirmed diagnosis of severe onychomycosis. RESULTS: We retrieved a total of 29 KTR with severe onychomycosis needing an oral treatment to manage onychomycosis. In 55.1% (16/29) KTR, altered renal biological parameters or lack of guidelines to manage severe onychomycosis were the main reasons to deterring clinicians from prescribing oral treatments. 13 patients received an oral terbinafine treatment (9, 3 and 1 with a tacrolimus, cyclosporine and everolimus-based ART, respectively). Clinical and biological follow-up did not reveal severe drug interactions. ART blood levels showed significant variations in 2 patients without clinical consequences in renal graft. Two patients reported mild adverse events but after only one dose of terbinafine. Using an open-source image analysis program, clinical evolution of onychomycosis could be retrospectively quantified and followed up. CONCLUSIONS: The results presented here suggest that oral terbinafine can be proposed to treat severe onychomycosis with an acceptable tolerance profile in KTR with different ART such as tacrolimus and highlight the need of multicentric studies to establish guidelines for onychomycosis treatment in KTR.

Persistent deficiency of mucosal-associated invariant T cells during dermatomyositis.

OBJECTIVES: Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that are important for antibacterial immunity and may have regulatory roles. MAIT cells are decreased during SLE. However, their frequencies and phenotype have not been investigated in DM. We studied MAIT cell frequencies and phenotype in DM patients with active and inactive disease (after treatment). METHODS: Peripheral blood flow cytometry analysis of MAIT cells was compared between DM (n = 22), SLE (n = 10), psoriasis (n = 7) and atopic dermatitis (n = 5) patients, and healthy controls (n = 19). RESULTS: A dramatic decrease of circulating MAIT cell frequency was observed in active DM and SLE patients compared with healthy controls and other inflammatory skin diseases [active DM: median = 0.25% (interquartile range 0.19-0.6%), P < 0.0001; active SLE: median = 0.61 (0.55-0.77), P < 0.0001 vs healthy controls: 2.32% (1.18-4.45%)]. MAIT cells from active DM patients had an abnormal phenotype including increased expression of CD25 and cytotoxic T-lymphocyte-associated protein 4 that correlated with their low frequency in the blood. CONCLUSION: In DM, peripheral blood MAIT cells are dramatically reduced and have an activated/exhausted phenotype that may be linked to increased activation-induced cell death.

Plasma histamine elevation in a large cohort of sickle cell disease patients.

The role of mast cells has been questioned in sickle cell disease (SCD). We performed a prospective study evaluating plasma histamine and tryptase levels in a cohort of paediatric and adult patients, in steady state (n = 132) and during vaso-occlusive crisis (VOC) (n = 121). Histamine level was elevated in 18% of patients in steady state and in 61% during VOC. Median histamine level was significantly higher during VOC than in steady state (24·1 [7·0-45·0] vs 9·6 [6·2-14·4] nmol/l, P < 0·0001). Tryptase level was slightly increased during VOC without reaching pathological values. These results suggest a role of mast cell activation in SCD pathophysiology.

Cardiac manifestations in sickle cell disease varies with patient genotype.

Cardiac involvement is well characterized in sickle cell anaemia (SCA) but cardiac features associated with Haemoglobin SC (HbSC) disease are mostly unknown. We compared 60 patients with HbSC disease (median age 31 years, 25 men) to 60 SCA patients and 60 controls matched for age and gender. Left ventricular ejection fraction (LVEF), left ventricle (LV) mass index (LVMi), cardiac index and peak tricuspid regurgitation velocity (TRV) were measured using echocardiography. LV filling pressures were assessed using the ratio of early diastolic transmitral velocity to tissue velocity (E/e' ratio). The LVMi was higher in both genotypes compared to controls. However, whereas LV hypertrophy was observed only in 3(5%) HbSC patients, this condition was diagnosed in 27(45%) SCA patients (P < 0·0001). While cardiac index and TRV were similar in HbSC compared to controls, SCA patients exhibited elevated cardiac output and TRV. LVEF was similar in the 3 groups. However, both genotypes had a higher E/e' ratio compared to controls. Cardiac involvement in SCA was related to anaemia and haemolysis, while LV diastolic dysfunction and TRV in HbSC disease patients were related to arterial hypertension and overweight comorbidities. In summary, cardiac involvement and its determinants are different in HbSC disease and SCA. Patient's genotype should be considered with regard to the echocardiographic indications and findings.

Cutaneous Arteriolosclerosis Is Not Specific to Ischemic Hypertensive Leg Ulcers.

BACKGROUND: The histological characteristic of hypertensive leg ulcers (HLU) is the presence of "arteriolosclerosis." The pertinence of performing a skin biopsy to diagnose HLU is questionable, as cutaneous arteriolosclerosis may be related to patient comorbidities. The objective here was to evaluate the frequency of arteriolosclerosis in skin leg biopsies performed in patients without ulcer and in control patients with HLU. METHODS: We performed a retrospective study between January 2013 and July 2014. Patients were included if they had undergone a deep skin biopsy on the lower limbs, in the absence of any leg ulcer. Controls were patients with typical HLU. RESULTS: Fifty-eight patients and 6 controls were included. Hypertension was present in 25 patients (43%). Arteriolosclerosis, defined as fibrous endarteritis, was present in 35 out of 58 patients (60%) and in all of the controls. No hyalinosis or hyperplastic proliferative arteriolosclerosis was observed in the patients or controls. Only age was an independent factor associated with the presence of cutaneous arteriolosclerosis (p &x#3c; 0.0001). CONCLUSION: Cutaneous arteriolosclerosis is significantly and independently associated with age. Thus, skin biopsy seems not to be necessary for the diagnosis of HLU but only for a differential diagnosis.