High Heterogeneity of Multidrug-Resistant Enterobacteriaceae Fecal Levels in Hospitalized Patients Is Partially Driven by Intravenous ß-Lactams.

Multidrug-resistant Enterobacteriaceae (MRE) colonize the intestine asymptomatically from where they can breach into the bloodstream and cause life-threatening infections, especially in heavily colonized patients. Despite the clinical relevance of MRE colonization levels, we know little about how they vary in hospitalized patients and the clinical factors that determine those levels. Here, we conducted one of the largest studies of MRE fecal levels by tracking longitudinally 133 acute leukemia patients and monitoring their MRE levels over time through extensive culturing. MRE were defined as Enterobacteriaceae species that acquired nonsusceptibility to ≥1 agent in ≥3 antimicrobial categories. In addition, due to the selective media used, the MRE had to be resistant to third-generation cephalosporins. MRE were detected in 60% of the patients, but their fecal levels varied considerably among patients and within the same patient (>6 and 4 orders of magnitude, respectively). Multivariate analysis of clinical metadata revealed an impact of intravenous beta-lactams (i.e., meropenem and piperacillin-tazobactam), which significantly diminished the fecal MRE levels in hospitalized patients. Consistent with a direct action of beta-lactams, we found an effect only when the patient was colonized with strains sensitive to the administered beta-lactam (P < 0.001) but not with nonsusceptible strains. We report previously unobserved inter- and intraindividual heterogeneity in MRE fecal levels, suggesting that quantitative surveillance is more informative than qualitative surveillance of hospitalized patients. In addition, our study highlights the relevance of incorporating antibiotic treatment and susceptibility data of gut-colonizing pathogens for future clinical studies and in clinical decision-making.

CD1d-mediated lipid presentation by CD11c+ cells regulates intestinal homeostasis.

Intestinal homeostasis relies on a continuous dialogue between the commensal bacteria and the immune system. Natural killer T (NKT) cells, which recognize CD1d-restricted microbial lipids and self-lipids, contribute to the regulation of mucosal immunity, yet the mechanisms underlying their functions remain poorly understood. Here, we demonstrate that NKT cells respond to intestinal lipids and CD11c+ cells (including dendritic cells (DCs) and macrophages) are essential to mediate lipid presentation within the gut ultimately controlling intestinal NKT cell homeostasis and activation. Conversely, CD1d and NKT cells participate in the control of the intestinal bacteria composition and compartmentalization, in the regulation of the IgA repertoire and in the induction of regulatory T cells within the gut. These changes in intestinal homeostasis require CD1d expression on DC/macrophage populations as mice with conditional deletion of CD1d on CD11c+ cells exhibit dysbiosis and altered immune homeostasis. These results unveil the importance of CD11c+ cells in controlling lipid-dependent immunity in the intestinal compartment and reveal an NKT cell-DC crosstalk as a key mechanism for the regulation of gut homeostasis.

Sweet syndrome and differentiation syndrome in a patient with acute promyelocytic leukemia.

The differentiation syndrome is an inflammatory reaction with increased capillary permeability that occurs in up to 25% of patients with acute promyelocytic leukemia treated with all-trans retinoic acid. A 50-year-old man with acute promyelocytic leukemia underwent chemotherapy with idarubicin and all-trans retinoic acid. On day +21 the patient developed pruritic prepatelar papules as well as several 10 mm subcutaneous nodules in both thighs accompanied by persistent fever. On the day +25 the patient presented with bilateral pulmonary crackles, infiltrates in the right lower lobe and severe hypotension which required dopamine infusion. Biopsy of one of the thighs nodules was performed. A Sweet syndrome associated to a differentiation syndrome was suspected. All-trans retinoic acid therapy was discontinued and dexamethasone was administered. In 48 h the patient showed remission of the fever and the infiltrates and the skin lesions acquired a residual aspect. It is debatable whether these two syndromes are distinct entities with common mechanisms or whether they are poles of the same spectrum. Dermatologists and hematologists must be aware of these two syndromes and its pathophysiologic association.

Comedonal graft-vs-host disease: a distinct clinical expression of a lichenoid follicular GVHD.

We report two cases of chronic follicular graft-vs-host disease (GVHD) that resemble closed and open acne-like comedones. We propose the term 'comedonal GVHD' for this variant. A 47-year-old man presented with multiple 2-4-mm acne-like follicular papules in facial areas on day 82 status post bone marrow transplantation. A biopsy showed follicular infundibular dilation with keratotic plugs, hypergranulosis and vacuolar alteration (hydropic degeneration) of the basal layer, with dyskeratotic (apoptotic) keratinocytes, scattered lymphocytes and vascular ectasia of the superficial dermal plexus. We diagnosed chronic follicular lichenoid GVHD. The second patient was a 53-year-old female. On day 420 after transplantation, she presented with generalized dark to grayish, confluent, indurated lesions with confluent papules and unevenly distributed comedo-like lesions. Skin biopsy showed sclerotic dermis and also dilated follicular infundibula with keratotic plugging, hypergranulosis and vacuolar alteration (hydropic degeneration) of the basal layer of the epidermis. We established the diagnosis of chronic sclerodermoid GVHD with follicular lichenoid involvement. The presence of open and closed comedones on the trunk and facial region of an adult raises several differential diagnosis but in our patients, histopathologic study demonstrated typical features of GVHD, which led to this diagnoses despite the peculiar clinical findings.

Outcome of patients with serology suggestive of past hepatitis B virus infection during antitumor necrosis factor therapy for psoriasis.

BACKGROUND: Recently, the reactivation during treatment with tumor necrosis factor (TNF) blockers has exceptionally been described in patients with hepatitis B virus (HBV) antigen-negative (HBsAg). The objective was to evaluate the influence of anti-TNF agents in patients with psoriasis and serology suggesting past hepatitis B state. METHODS: The inclusion criteria were chronic plaque psoriasis treated with anti-TNF therapy, HBsAg-negative, and HBcAb-positive. We gathered the demographic data and type and duration of anti-TNF agent. Serum aminotransferase levels and HBV serologic status were requested at baseline and during follow-up. RESULTS: We have included 13 patients (four women, nine men) (mean age of 62.1 years). The agent was etanercept in seven cases, infliximab in four patients, and adalimumab in the other two. The mean duration of TNF therapy was 28.6 months. None of them became HBsAg-positive. Neither signs nor symptoms of acute hepatitis were reported. CONCLUSION: The management of HBsAg-negative patients is unresolved. Only nine cases of HBV reactivation during treatment with TNF blockers have been reported. Despite the low risk of reactivation in these patients, we recommend the monitoring of serum aminotransferase levels, HBsAb titers, HBsAg and, if possible, viral load.

Targeting miR-21 to treat psoriasis.

Psoriasis is a common inflammatory skin disease with limited treatment options that is characterized by a complex interplay between keratinocytes, immune cells, and inflammatory mediators. MicroRNAs (miRNAs) are regulators of gene expression and play critical roles in many human diseases. A number of miRNAs have been described to be up-regulated in psoriasis, but their causal contribution to disease development has not been demonstrated. We confirm that miR-21 expression is increased in epidermal lesions of patients with psoriasis and that this leads to reduced epidermal TIMP-3 (tissue inhibitor of matrix metalloproteinase 3) expression and activation of TACE (tumor necrosis factor-α-converting enzyme)/ADAM17 (a disintegrin and metalloproteinase 17). Using patient-derived skin samples and mouse models of psoriasis, we demonstrate that increased miR-21 may be a consequence of impaired transcriptional activity of Jun/activating protein 1 (AP-1), leading to activation of the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (Stat3) pathway. Inhibition of miR-21 by locked nucleic acid (LNA)-modified anti-miR-21 compounds ameliorated disease pathology in patient-derived psoriatic skin xenotransplants in mice and in a psoriasis-like mouse model. Targeting miR-21 may represent a potential therapeutic option for the treatment of psoriasis.