Self-application of aminoglycoside-based creams to treat cutaneous leishmaniasis in travelers.

BACKGROUND: In endemic foci, the use of an aquaphilic cream containing paromomycin with/without gentamicin to treat cutaneous leishmaniasis (CL) is safe, painless and cures 78-82% of patients with New and Old World CL. Self-application in travelers requires evaluation. METHODS: Travelers with 1-10 lesions of confirmed CL were prospectively treated with the paromomycin-gentamicin formulation (WR279396, 2012-2017, Group 1) and carefully follow up, or treated with a locally produced paromomycin-only cream (2018-2022, Group 2). The cream was applied once under supervision, then self-applied daily for 20-30 days. A cured lesion was defined as 100% re-epithelialization at day 42 without relapse at three months. RESULTS: Medical features were similar in Group 1 (17 patients), and Group 2 (23 patients). Patients were infected with either Leishmania major, L. infantum, L. killicki, L. guyanensis, L. braziliensis, or L. naiffi. Intention-to-treat and per-protocol cure rates were 82% (95% confidence interval (CI) [64.23;100.00]) and 87% (95% CI [71,29;100.00]) in Group 1, and 69% (95% CI [50.76; 88.37]) and 76% (95% CI [57.97; 94.41]) in Group 2. In the pooled Group 1&2, 75% (95% CI [61.58;88.42]) (30/40) and 81% (95% CI [68,46;93.6]) (30/37) of patients were cured in intention-to-treat and per-protocol, respectively. There were no significant differences observed in the success rates between Old World and New World CL (83.3% vs. 60%, p = 0.14). Prospective observations in Group 1 showed that adverse events were mainly pruritus (24%) and pain (18%) on lesions (all mild or moderate). No mucosal involvement was observed in either group. DISCUSSION: In this representative population of travelers who acquired CL either in the Old or New World, the 81% per-protocol cure rate of a self-applied aminoglycoside cream was similar to that observed in clinical trials.

Treatment outcome of imported cutaneous leishmaniasis among travelers and migrants infected with Leishmania major and Leishmania tropica: a retrospective study in European centers 2013 to 2019.

OBJECTIVES: Cutaneous leishmaniasis (CL) in Asia, Northern, and Sub-Saharan Africa is mainly caused by Leishmania major and Leishmania tropica. We describe and evaluate the treatment outcome of CL among travelers and migrants in Europe. METHODS: We conducted a retrospective study of parasitological confirmed CL cases caused by L. major and L. tropica during 2013-2019 in Europe. Data were collected from medical records and databases within the LeishMan network. RESULTS: Of 206 included cases of CL, 75 were identified as L. major and 131 as L. tropica. Of patients with L. tropica infection, 80% were migrants, whereas 53% of patients with L. major infection had been visiting friends and relatives. Among patients with L. tropica, 48% were younger than 15 years. Pentavalent antimony cured 73% (L. major) and 78% (L. tropica) of patients. The cure rate for intralesional administration was 86% and 67% for systemic, on L. tropica. Liposomal amphotericin B had a cure rate of 44-63%. CONCLUSION: L. major infections were mostly found in individuals visiting friends and relatives, whereas L. tropica were mainly identified in migrants. No patients with L. major relapsed. Pentavalent antimony, liposomal amphotericin B, and cryotherapy had cure rates in accordance with previous studies.

Surveillance of leishmaniasis cases from 15 European centres, 2014 to 2019: a retrospective analysis.

BackgroundSurveillance of human leishmaniasis in Europe is mostly limited to country-specific information from autochthonous infections in the southern part. As at the end of 2021, no integrated analysis has been performed for cases seen across centres in different European countries.AimTo provide a broad perspective on autochthonous and imported leishmaniasis cases in endemic and non-endemic countries in Europe.MethodsWe retrospectively collected records from cutaneous, mucosal and visceral leishmaniasis cases diagnosed in 15 centres between 2014 and 2019. Centres were located in 11 countries: Belgium, France, Germany, Italy, the Netherlands, Norway, Portugal, Spain, Sweden, Switzerland and the United Kingdom. Data on country of infection, reason for travelling, infecting species, age and sex were analysed.ResultsWe obtained diagnostic files from 1,142 cases, of which 76%, 21% and 3% had cutaneous, visceral, and mucosal disease, respectively. Of these, 68% were men, and 32% women, with the median age of 37 years (range: 0-90) at diagnosis. Visceral leishmaniasis was mainly acquired in Europe (88%; 167/190), while cutaneous leishmaniasis was primarily imported from outside Europe (77%; 575/749). Sixty-two percent of cutaneous leishmaniasis cases from outside Europe were from the Old World, and 38% from the New World. Geographic species distribution largely confirmed known epidemiology, with notable exceptions.ConclusionsOur study confirms previous reports regarding geographic origin, species, and traveller subgroups importing leishmaniasis into Europe. We demonstrate the importance of pooling species typing data from many centres, even from areas where the aetiology is presumably known, to monitor changing epidemiology.

Clinical diversity and treatment results in Tegumentary Leishmaniasis: A European clinical report in 459 patients.

BACKGROUND: Cutaneous leishmaniasis (CL) is frequent in travellers and can involve oro-nasal mucosae. Clinical presentation impacts therapeutic management. METHODOLOGY: Demographic and clinical data from 459 travellers infected in 47 different countries were collected by members of the European LeishMan consortium. The infecting Leishmania species was identified in 198 patients. PRINCIPAL FINDINGS: Compared to Old World CL, New World CL was more frequently ulcerative (75% vs 47%), larger (3 vs 2cm), less frequently facial (17% vs 38%) and less frequently associated with mucosal involvement (2.7% vs 5.3%). Patients with mucosal lesions were older (58 vs 30 years) and more frequently immunocompromised (37% vs 3.5%) compared to patients with only skin lesions. Young adults infected in Latin America with L. braziliensis or L. guyanensis complex typically had an ulcer of the lower limbs with mucosal involvement in 5.8% of cases. Typically, infections with L. major and L. tropica acquired in Africa or the Middle East were not associated with mucosal lesions, while infections with L. infantum, acquired in Southern Europe resulted in slowly evolving facial lesions with mucosal involvement in 22% of cases. Local or systemic treatments were used in patients with different clinical presentations but resulted in similarly high cure rates (89% vs 86%). CONCLUSION/SIGNIFICANCE: CL acquired in L. infantum-endemic European and Mediterranean areas displays unexpected high rates of mucosal involvement comparable to those of CL acquired in Latin America, especially in immunocompromised patients. When used as per recommendations, local therapy is associated with high cure rates.

Poor outcome and high prevalence of invasive fungal infections in patients with adult T-cell leukemia/lymphoma exposed to zidovudine and interferon alfa.

Patients treated for adult T-Cell leukemia/lymphoma (ATL) have a poor prognosis and are prone to infectious complications which are poorly described. As the French reference center for ATL, we retrospectively analyzed 47 consecutive ATL (acute, n = 23; lymphoma, n = 14; chronic, n = 8; smoldering, n = 2) patients between 2006 and 2016 (median age 51 years, 96% Afro-Caribbean origin). The 3-year overall survival (OS) was 15.8%, 11.3%, and 85.7% for acute, lymphoma, and indolent (chronic and smoldering) forms respectively. Among aggressive subtypes, 20 patients received, as frontline therapy, high dose of zidovudine and interferon alfa (AZT-IFN⍺) resulting in an overall response rate (ORR) of 39% (complete response [CR] 33%) and 17 chemotherapy resulting of an ORR of 59% (CR 50%). Ninety-five infections occurred in 38 patients, most of whom had an acute subtype (n = 73/95; 77%). During their follow-up, patients receiving frontline chemotherapy or frontline AZT-IFNα developed infections in 74% (n = 14/19) and 89% (n = 24/27) of the cases respectively. Sixty-four (67%) of infections were microbiologically documented. Among them, invasive fungal infections (IFI, n = 11) included 2 Pneumocystis jirovecii pneumonia, 5 invasive aspergillosis, and 4 yeast fungemia. IFI exclusively occurred in patients with acute subtype mostly exposed to AZT-IFNα (n = 10/11) and experiencing prolonged (> 10 days) grade 4 neutropenia. Patients with aggressive subtype experiencing IFI had a lower OS than those who did not (median OS 5.4 months versus 18.4 months, p = 0.0048). ATL patients have a poor prognosis even in the modern era. Moreover, the high rate of infections impacts their management especially those exposed to AZT-IFNα.

"Chronic Disseminated Aspergillosis," a Novel Fungal Immune Reconstitution Inflammatory Syndrome.

We report a case of chronic hepatosplenic aspergillosis following immune reconstitution complicating colic aspergillosis in an AIDS patient with multicentric Castleman disease. Symptoms mimicked the clinical presentation of chronic disseminated candidiasis and responded to corticosteroid. This emerging entity enlarges the spectrum of fungal immune reconstitution inflammatory syndrome in the HIV setting.

Voriconazole topical cream formulation: evidence for stability and antifungal activity.

Systemic use of voriconazole (VCZ) might be restricted by adverse events, such as hepatotoxicity and neurotoxicity, or drug-drug interactions. Topical VCZ application to skin may help to treat local infection more effectively and limit unwanted whole-body exposure. Topical VCZ cream was stable for 90 days when refrigerated. A patient with cutaneous Fusarium solani infection on his right forearm was successfully treated with topical 1% VCZ cream after failure of oral VCZ treatment.

Failure of multiplex meningitis/encephalitis (ME) NAT during cryptococcal meningitis in solid organ recipients.

Cryptococcal meningitis is a severe cause of central nervous system infections among immunocompromised solid organ transplant (SOT) patients. While new diagnostic methods as multiplex meningitis/encephalitis (ME) NAT (nucleic acid test) are increasingly used as a first-line tool in hospital practice, data in HIV-negative patients including SOT remain scarce. We report here false-negative results of multiplex NAT among SOT patients with proven cryptococcal meningitis.

Pseudomonas aeruginosa bloodstream infections in children: a 9-year retrospective study.

P. aeruginosa bloodstream infection (BSI) is associated with high hospital mortality. Empirical combination therapy is commonly used, but its benefit remains debated. The purpose of this study was to describe in a paediatric population, demographical characteristics and outcome of children treated for P. aeruginosa BSI receiving either a combined or single antibacterial therapy. We performed a retrospective, single-centre, cohort study of hospitalized children with P. aeruginosa BSI from 2007 to 2015. A total of 118 bloodstream infections (BSI) were analysed (102 (86.4%) hospital-acquired, including 52 (44.1%) hospitalized in intensive care unit). In immunocompromised children, 52% of BSI episodes were recorded. Recent medical history revealed that 68% were hospitalized, 31% underwent surgery and 67% had a prior antibiotic therapy within the last 3 months. In-hospital mortality was similar for patients receiving single or combined anti-Pseudomonas therapy (p = 0.78). In multivariate analysis, independent risk factors for in-hospital mortality were neutropenia (OR = 6.23 [1.94-20.01], hospitalization in ICU (OR = 5.24 [2.04-13.49]) and urinary tract infection (OR = 4.40 [1.02-19.25]).Conclusion: P. aeruginosa BSI mainly occurred in immunocompromised children. Most infections were hospital-acquired and associated with high mortality. Combination therapy did not improve survival. What is Known: • P. aeruginosa bloodstream infection (BSI) is associated with high hospital mortality. Empirical combination therapy is commonly used but its benefit remains debated. What is New: • This is the largest cohort of Pseudomonas aeruginosa bacteraemia in children ever published. P. aeruginosa Bloodstream mainly occurred in immunocompromised children. Most infections were hospital-acquired and associated with high mortality. Combination therapy did not improve survival.

Smoking as a Risk Factor of Invasive Fungal Disease: Systematic Review and Meta-Analysis.

To investigate the association between smoking and invasive fungal disease (IFD), we searched MEDLINE and Web of Science for studies published until September 2018. Two authors independently performed study selection and data extraction. Relative risks (RRs) were pooled using random-effects meta-analysis. We included 25 studies (18 171 participants; 2527 IFD cases). The meta-analysis showed an increased risk of IFD in smokers (RR 1.41 [95% confidence interval 1.09-1.81]; P = .008). The risk of IFD was higher in retrospective than in prospective studies (RR 1.93 [1.28-2.92] vs. 1.02 [0.78-1.34]; P = .04), in studies with multivariate adjustment compared to studies with univariate analysis (RR 2.15 [1.27-3.64] vs. 1.15 [0.88-1.51]; P = .06), and in studies published after 2002 (RR 2.08 [1.37-3.15] vs. 0.95 [0.75-1.22]; P = .008); other subgroup characteristics did not significantly influence the association in metaregression. Smoking cessation strategies should be implemented, especially in patients who are already at risk for IFD.

Aspergillus felis in Patient with Chronic Granulomatous Disease.

We report a case of Aspergillus felis infection in a patient with chronic granulomatous disease who had overlapping features of invasive pulmonary aspergillosis and allergic bronchopulmonary aspergillosis. Identifying the species responsible for aspergillosis by molecular methods can be crucial for directing patient management and selection of appropriate antifungal agents.

Isavuconazole Diffusion in Infected Human Brain.

We report the cases of a 39-year-old woman with chronic lymphocytic leukemia and a 21-year-old man with chronic granulomatous disease treated for cerebral aspergillosis. The patients required radical surgery for infection progression despite adequate isavuconazole plasma concentration or neurological complication. We thus decided to measure the brain isavuconazole concentration. These results suggest that the concentrations of isavuconazole obtained in the infected brain tissue clearly differ from those obtained in the normal brain tissue and the cerebrospinal fluid.

Understanding Pathogenesis and Care Challenges of Immune Reconstitution Inflammatory Syndrome in Fungal Infections.

Immune deficiency of diverse etiology, including human immunodeficiency virus (HIV), antineoplastic agents, immunosuppressive agents used in solid organ recipients, immunomodulatory therapy, and other biologics, all promote invasive fungal infections. Subsequent voluntary or unintended immune recovery may induce an exaggerated inflammatory response defining immune reconstitution inflammatory syndrome (IRIS), which causes significant mortality and morbidity. Fungal-associated IRIS raises several diagnostic and management issues. Mostly studied with Cryptococcus, it has also been described with other major fungi implicated in human invasive fungal infections, such as Pneumocystis, Aspergillus, Candida, and Histoplasma. Furthermore, the understanding of IRIS pathogenesis remains in its infancy. This review summarizes current knowledge regarding the clinical characteristics of IRIS depending on fungal species and existing strategies to predict, prevent, and treat IRIS in this patient population, and tries to propose a common immunological background to fungal IRIS.

Severe, non specific symptoms in non-typhoidal Salmonella infections in adult patients with sickle cell disease: a retrospective multicentre study.

BACKGROUND: Non-typhoidal salmonellosis (NTS) often occurs in children with sickle-cell disease (SCD) and remains a significant cause of mortality in developing countries. However, there is lack of reports on the clinical presentation, outcome and complications of NTS in adults with SCD. METHODS: We performed a chart review between 2006 and 2016 of adults SCD diagnosed with NTS in 3 referral centers monitoring approximately 3500 SCD adults. RESULTS: Twenty-three episodes of NTS were diagnosed among 22 SCD adults. Diagnosis was challenging: 65% (n = 15/23) of patients presented with vaso-occlusive crisis (VOC) and 30% had no fever. Isolated serotypes were: ser. Enteritidis (n = 8), ser. Typhimurium (n = 6), others (n = 3). We identified two patterns of infections: (1) bacteremic NTS (n = 15) with (n = 9) or without secondary foci of infections (n = 6); (2) non-bacteremic NTS with extra-intestinal foci of infection (n = 8), including primary bones/joints infections (n = 5). Half of patients with osteo-articular localization (n = 6/13) had a previous history of osteonecrosis (n = 2) or osteomyelitis (n = 4) at the same site. Morbidity was high, 6 patients (26%) were admitted to the intensive care unit, 14 patients (61%) required RBC transfusion for VOC. Half of the episodes (n = 12) required surgery (n = 10) or interventional radiology (n = 2) to control the infection. One patient presented a relapse of NTS bacteraemia one year after the first episode. CONCLUSIONS: Besides bloodstream infections, clinical presentation of NTS in adults with SCD is non-specific at admission. A triad including bacteraemia, secondary focis of infection and bone localizations was observed in 30% of cases.

Is It Time for Systematic Voriconazole Pharmacogenomic Investigation for Central Nervous System Aspergillosis?

Voriconazole is the standard treatment for invasive aspergillosis but requires therapeutic drug monitoring to optimize therapy. We report two cases of central nervous system aspergillosis treated with voriconazole. Because of low trough plasma concentrations, we identified gain-of-function mutations in CYP2C19 that were partially responsible for the therapeutic failure of voriconazole. We suggest that systematic voriconazole pharmacogenomic investigation of cerebral aspergillosis be performed to avoid effective therapy delay in this life-threatening disease.

A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity.

Heterozygosity for human signal transducer and activator of transcription 3 (STAT3) dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341 ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the STAT3 promoter. The patients' cells have low basal levels of STAT3 mRNA and protein. The autoinduction of STAT3 production, activation, and function by STAT3-activating cytokines is strongly impaired. Like patients with STAT3 DN mutations, ZNF341-deficient patients lack T helper 17 (TH17) cells, have an excess of TH2 cells, and have low memory B cells due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341 dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the STAT3 transcription-dependent autoinduction and sustained activity of STAT3.

Liposomal amphotericin B in travelers with cutaneous and muco-cutaneous leishmaniasis: Not a panacea.

BACKGROUND: Complex cutaneous and muco-cutaneous leishmaniasis (CL and MCL) often requires systemic therapy. Liposomal amphotericin B (L-AmB) has a strong potential for a solid clinical benefit in this indication. METHODS: We conducted a retrospective analysis of data from a French centralized referral treatment program and from the "LeishMan" European consortium database. All patients with parasitologically proven CL or MCL who received at least one dose of L-AmB were included. Positive outcome was based on ulcer closure as per recent WHO workshop guidelines. RESULTS: From 2008 through 2016, 43 travelers returning from 18 countries (Old World n = 28; New World n = 15) were analyzed with a median follow-up duration of 79 days [range 28-803]. Main clinical forms were: localized CL with one or multiple lesions (n = 32; 74%) and MCL (n = 8; 19%). As per published criteria 19 of 41 patients (46%) were cured 90 days after one course of L-AmB. When the following items -improvement before day 90 but no subsequent follow-up, delayed healing (>3 months) and healing after a second course of L-AmB- were included in the definition of cure, 27 of 43 patients (63%) had a positive outcome. Five patients (MCL = 1; CL = 4) experienced a relapse after a median duration of 6 months [range 3-27] post treatment and 53% of patients (23/43) experienced at least one adverse event including severe hypokalaemia and acute cardiac failure (one patient each). In multivariate analysis, tegumentary infection with L. infantum was associated with complete healing after L-AmB therapy (OR 5.8 IC 95% [1.03-32]) while infection with other species had no impact on outcome. CONCLUSION: In conditions close to current medical practice, the therapeutic window of L-AmB was narrow in travellers with CL or MCL, with the possible exception of those infected with L. infantum. Strict follow-up is warranted when using L-AmB in patients with mild disease.