Successful Allogenic Stem Cell Transplantation in Patients with Inherited CARD9 Deficiency.

Autosomal recessive (AR) CARD9 (caspase recruitment domain-containing protein 9) deficiency underlies invasive infections by fungi of the ascomycete phylum in previously healthy individuals at almost any age. Although CARD9 is expressed mostly by myeloid cells, the cellular basis of fungal infections in patients with inherited CARD9 deficiency is unclear. Therapy for fungal infections is challenging, with at least 20% premature mortality. We report two unrelated patients from Brazil and Morocco with AR CARD9 deficiency, both successfully treated with hematopoietic stem cell transplantation (HSCT). From childhood onward, the patients had invasive dermatophytic disease, which persisted or recurred despite multiple courses of antifungal treatment. Sanger sequencing identified homozygous missense CARD9 variants at the same residue, c.302G>T (p.R101L) in the Brazilian patient and c.301C>T (p.R101C) in the Moroccan patient. At the ages of 25 and 44 years, respectively, they received a HSCT. The first patient received a HLA-matched HSCT from his CARD9-mutated heterozygous sister. There was 100% donor chimerism at D + 100. The other patient received a T cell-depleted haploidentical HSCT from his CARD9-mutated heterozygous brother. A second HSCT from the same donor was performed due to severe amegakaryocytic thrombocytopenia despite achieving full donor chimerism (100%). At last follow-up, more than 3 years after HSCT, both patients have achieved complete clinical remission and stopped antifungal therapy. HSCT might be a life-saving therapeutic option in patients with AR CARD9 deficiency. This observation strongly suggests that the pathogenesis of fungal infections in these patients is largely due to the disruption of leukocyte-mediated CARD9 immunity.

Mast cells' involvement in inflammation pathways linked to depression: evidence in mastocytosis.

Converging sources of evidence point to a role for inflammation in the development of depression, fatigue and cognitive dysfunction. More precisely, the tryptophan (TRP) catabolism is thought to play a major role in inflammation-induced depression. Mastocytosis is a rare disease in which chronic symptoms, including depression, are related to mast cell accumulation and activation. Our objectives were to study the correlations between neuropsychiatric features and the TRP catabolism pathway in mastocytosis in order to demonstrate mast cells' potential involvement in inflammation-induced depression. Fifty-four patients with mastocytosis and a mean age of 50.1 years were enrolled in the study and compared healthy age-matched controls. Depression and stress were evaluated with the Beck Depression Inventory revised and the Perceived Stress Scale. All patients had measurements of TRP, serotonin (5-HT), kynurenine (KYN), indoleamine 2,3-dioxygenase 1 (IDO1) activity (ratio KYN/TRP), kynurenic acid (KA) and quinolinic acid (QA). Patients displayed significantly lower levels of TRP and 5-HT without hypoalbuminemia or malabsorption, higher IDO1 activity, and higher levels of KA and QA, with an imbalance towards the latter. High perceived stress and high depression scores were associated with low TRP and high IDO1 activity. In conclusion, TRP metabolism is altered in mastocytosis and correlates with perceived stress and depression, demonstrating mast cells' involvement in inflammation pathways linked to depression.

Decreased tryptophan and increased kynurenine levels in mastocytosis associated with digestive symptoms.

The main metabolism pathway of tryptophan is protein formation, but it can also be metabolized into serotonin and kynurenine. Indoleamine 2,3-dioxygenase (IDO) is the enzyme that catalyzes the degradation of tryptophan into kynurenine. Mastocytosis is a heterogeneous disease characterized by mast cell accumulation in various tissues with 57% of patients having gastrointestinal involvement. We studied tryptophan metabolism in mastocytosis patients displaying or not gastrointestinal features and healthy subjects (n = 26 in each group). Mastocytosis patients with digestive symptoms displayed significantly increased kynurenine level and IDO activity as compared to healthy controls and mastocytosis patients without digestive symptoms. This could be linked to mast cell-mediated digestive inflammation among patients with mastocytosis. This work is the first focusing on kynurenine pathway in a mast cell disease and could help to understand the pathogenesis of digestive features in mastocytosis as well as in other mast cell-mediated diseases.

Mycobacterium avium complex disseminated infection in a kidney transplant recipient.

Mycobacterium avium-intracellulare complex (MAC) infections are well known in immunocompromised patients, notably in human immunodeficiency virus infection, but remain scarcely described in kidney transplantation. Moreover, cutaneous involvement in this infection is very unusual. We describe here a disseminated infection caused by MAC in a kidney transplant recipient revealed by cutaneous lesions. This case highlights the need for an exhaustive, iterative microbiologic workup in the context of an atypical disease presentation in a renal transplant patient, regardless of the degree of immunosuppression.

Induction therapy with linezolid/clarithromycin combination for Mycobacterium chelonae skin infections in immunocompromised hosts.

BACKGROUND: The optimal management of Mycobacterium chelonae disease in immunocompromised patients remains unclear. A combination of antimicrobial agents is recommended as monotherapy with clarithromycin has been associated with clinical failures due to acquired resistance. OBJECTIVES: We aim to report the efficacy and tolerability of linezolid in association with clarithromycin for the treatment of M. chelonae infections in immunocompromised patients. METHODS: We describe four immunocompromised patients treated by linezolid and clarithromycin for cutaneous M. chelonae disease. RESULTS: This combination was associated with rapid clinical efficacy in all patients with no relapse observed after a median follow-up of 2.25 years (1.4 years). However, this treatment was responsible for frequent adverse events including thrombocytopaenia, myalgia and mitochondrial toxicity. All adverse effects were reversible after linezolid discontinuation. CONCLUSIONS: We therefore suggest linezolid/clarithromycin combination as the initial therapeutic strategy for M. chelonae skin infections in immunocompromised patients.

Dramatic improvement of severe cryptococcosis-induced immune reconstitution syndrome with adalimumab in a renal transplant recipient.

In solid organ transplant recipients, immune reconstitution inflammatory syndrome (IRIS) is a rare complication of cryptococcosis, which may require steroids in its most severe forms. Here, we report the case of a renal transplant recipient who developed severe cryptococcal meningitis-associated IRIS 1 week after immunosuppression reduction. High-dose steroids failed to improve the disease. Finally, a recombinant human monoclonal tumor necrosis factor-α (TNF-α) antagonist, adalimumab, was prescribed, and the patient rapidly experienced dramatic neurological improvement. No IRIS relapse occurred within 14 months following adalimumab discontinuation.

Prospective pilot study of high-dose (10 mg/kg/day) liposomal amphotericin B (L-AMB) for the initial treatment of mucormycosis.

BACKGROUND: Mucormycosis incidence is increasing and is associated with a high rate of mortality. Although lipid-based formulations of amphotericin B are the recommended first-line treatment, only one prospective trial in a limited number of patients has been performed to evaluate this regimen. METHODS: Patients with proven or probable mucormycosis were included between June 2007 and March 2011. Patients were scheduled to receive 10 mg/kg/day liposomal amphotericin B (L-AMB) monotherapy for 1 month and surgery was performed when appropriate. The primary outcome was response rate at week 4 or at the end of treatment (EOT) if before week 4, evaluated by an independent committee. ClinicalTrials.gov Identifier: NCT00467883. RESULTS: Forty patients were enrolled. Response was analysed in 33 patients at week 4. Most patients had a haematological malignancy as their primary underlying disease (53%). Seventy-one percent of patients underwent therapeutic surgery. The response rate at week 4 or at EOT was 36%, with 18% partial responses and 18% complete responses. The response rate at week 12 was 45%, with 13% partial responses and 32% complete responses. Overall mortality was 38% at week 12 and 53% at week 24. Serum creatinine doubled in 16 (40%) patients and returned to normal levels within 12 weeks in 10/16 (63%). CONCLUSIONS: High-dose L-AMB for mucormycosis, in combination with surgery in 71% of cases, was associated with an overall response rate of 36% at week 4 and 45% at week 12 and creatinine level doubling in 40% of patients (transient in 63%). These results may serve as the basis for future clinical trials.

Update on the safety profile of certolizumab pegol in rheumatoid arthritis: an integrated analysis from clinical trials.

OBJECTIVE: To report the long-term safety data of certolizumab pegol (CZP) in rheumatoid arthritis (RA) accumulated as of 30 November 2011. DESIGN: Data from 10 completed randomised controlled trials (RCT) of CZP in RA and several open-label extensions (OLE) were pooled across all doses. Reported adverse events (AE) occurred between the first dose and 84 days after the last dose. All deaths, serious infectious events (SIE) and malignancies were reviewed by external experts, classified according to predefined rules, and validated by an external steering committee. Incidence rates (IR) and event rates (ER) per 100 patient-years (PY) are presented. RESULTS: 4049 RA patients who received CZP were included in the safety pooling; total exposure 9277 PY, mean exposure 2.1 years (range 0.04-7.6). SIE, most frequently pneumonia (IR 0.73/100 PY), were the most common serious AE, occurring more frequently in CZP compared to placebo-treated patients in RCT (IR 5.61/100 PY vs 1.35/100 PY, odds ratio (OR) 4.35, 95% CI 0.65 to 29.30). SIE rates were lower in the CZP-treated population including OLE (ER 4.33/100 PY). 44 patients developed tuberculosis (IR 0.47/100 PY), 39 from high endemic regions. 58 deaths occurred in CZP-exposed patients (IR 0.63/100 PY) and 70 developed malignancies excluding non-melanoma skin cancer (IR 0.76/100 PY), including five lymphomas (IR 0.05/100 PY). CONCLUSIONS: No new or unexpected safety signals associated with CZP emerged in this updated long-term safety analysis. While SIE rates were higher for CZP than for placebo in RCT, the rate decreased with continued exposure to CZP. These rates are consistent with data previously reported for CZP and other tumour necrosis factor inhibitors.

Opportunistic infections and biologic therapies in immune-mediated inflammatory diseases: consensus recommendations for infection reporting during clinical trials and postmarketing surveillance.

No consensus has previously been formed regarding the types and presentations of infectious pathogens to be considered as 'opportunistic infections' (OIs) within the setting of biologic therapy. We systematically reviewed published literature reporting OIs in the setting of biologic therapy for inflammatory diseases. The review sought to describe the OI definitions used within these studies and the types of OIs reported. These findings informed a consensus committee (infectious diseases and rheumatology specialists) in deliberations regarding the development of a candidate list of infections that should be considered as OIs in the setting of biologic therapy. We reviewed 368 clinical trials (randomised controlled/long-term extension), 195 observational studies and numerous case reports/series. Only 11 observational studies defined OIs within their methods; no consistent OI definition was identified across studies. Across all study formats, the most numerous OIs reported were granulomatous infections. The consensus group developed a working definition for OIs as 'indicator' infections, defined as specific pathogens or presentations of pathogens that 'indicate' the likelihood of an alteration in host immunity in the setting of biologic therapy. Using this framework, consensus was reached upon a list of OIs and case-definitions for their reporting during clinical trials and other studies. Prior studies of OIs in the setting of biologic therapy have used inconsistent definitions. The consensus committee reached agreement upon an OI definition, developed case definitions for reporting of each pathogen, and recommended these be used in future studies to facilitate comparison of infection risk between biologic therapies.

FDG-PET/CT findings in systemic mastocytosis: a French multicentre study.

INTRODUCTION: Mastocytosis is a clonal haematological disease characterized by uncontrolled proliferation and the activation of mast cells. The value of FDG-PET/CT (FDG-PET) in mastocytosis has yet to be determined. METHODS: We retrospectively identified patients with an established diagnosis of systemic mastocytosis (SM), according to the WHO criteria, who underwent PET using the French Reference Centre for Mastocytosis database. Semi-quantitative and visual analysis of FDG-PET was performed and compared to the clinico-biological data. RESULTS: Our cohort included 19 adult patients, median age 65 years [range 58-74], including three with smouldering SM (SSM), three with aggressive SM (ASM), 10 with an associated clonal haematological non-mast-cell lineage disease (SM-AHNMD), and three with mast cell sarcoma (MCS). FDG-PET was performed at the time of the SM diagnosis (15/19), to evaluate lymph node (LN) activity (3/19) or the efficacy of therapy (1/19). FDG uptake was observed in the bone marrow (BM) (9/19, 47%), LN (6/19, 32%), spleen (12/19, 63%), or liver (1/19, 5%). No significant FDG uptake was observed in the SSM and ASM patients. A pathological FDG uptake was observed in the BM of 6/10 patients with SM-AHNMD, appearing as diffuse and homogeneous, and in the LN of 5/10 patients. All 3 MCS patients showed intense and multifocal BM pathological uptake, mimicking metastasis. No correlation was found between the FDG-PET findings and serum tryptase levels, BM mast cell infiltration percentage, and CD30 and CD2 expression by mast cells. CONCLUSIONS: FDG uptake does not appear to be a sensitive marker of mast cell activation or proliferation because no significant FDG uptake was observed in most common forms of mastocytosis (notably purely aggressive SM). However, pathological FDG uptake was observed in the SM-AHNMD and in MCS cases, suggesting a role of FDG-PET in their early identification and as a tool of therapeutic assessment in this subgroup of patients.

Nocardiosis in transplant recipients.

Nocardiosis is a rare opportunistic infection caused by Nocardia spp., an aerobic actinomycete, that mainly affects patients with cell-mediated immunity defects, such as transplant recipients. Despite recent progress regarding Nocardia identification and changes in taxonomic assignment, many challenges remain for the diagnosis or management of nocardiosis. This opportunistic infection affects 0.04 to 3.5 % of patients with solid organ or hematopoietic stem cell transplantation, depending on the organ transplanted, cytomegalovirus (CMV) infection, corticosteroids dose and calcineurin inhibitors level. Nocardiosis diagnosis relies on appropriate clinical, radiological and microbiological workup that includes the sampling of an accessible involved site and molecular microbiology tools. In parallel, extensive clinical and radiological evaluations are mandatory, including brain imaging, even in the absence of neurological signs. In transplanted patients, differential diagnosis is challenging, with co-infections reported in 20 to 64 % of cases. As the antibiotic susceptibility pattern varies among species, the antimicrobial regimen before species identification should rely on the association of antibiotics active on all species of Nocardia. Bactericidal antibiotics are required in cases of severe or disseminated disease. Furthermore, in transplant recipients, combination therapy is difficult to manage because of cumulative toxicity and interactions with immunosuppressive agents. Because of a high recurrence rate, antibiotic therapy should be prescribed for 6 to 12 months.

Dimorphic fungal osteoarticular infections.

The objective of this investigation was to review the clinical manifestations, management, and outcome of osteoarticular infections caused by dimorphic fungi. We exhaustively reviewed reports of bone and joint infections caused by dimorphic fungi published between 1970 and 2012. Underlying conditions, microbiological features, histological characteristics, clinical manifestations, antifungal therapy, and outcome were analyzed in 222 evaluable cases. Among 222 proven cases (median age 41 years [interquartile range (IQR) 26-57]), 73 % had no predisposing condition. Histopathology performed in 128 (57 %) cases and culture in 170 confirmed diagnosis in 63 % and 98 % of the cases, respectively. Diagnosis was obtained from an extra-osteoarticular site in 16 cases. The median diagnostic time was 175 days (IQR 60-365). Sporothrix schenckii was the most frequent pathogen (n = 84), followed by Coccidioides immitis (n = 47), Blastomyces dermatitidis (n = 44), Histoplasma capsulatum (n = 18), Paracoccidioides brasiliensis (n = 16), and Penicillium marneffei (n = 13). Arthritis occurred in 87 (58 %) cases and osteomyelitis in 64 (42 %), including 19 vertebral osteomyelitis. Dissemination was reported in 123 (55 %) cases. Systemic antifungal agents were used in 216 (97 %) patients and in combination with surgery in 129 (60 %). Following the Infectious Diseases Society of America (IDSA) guidelines, a successful initial medical strategy was observed in 97/116 (84 %) evaluable cases. The overall mortality was 6 %, and was highest for P. marneffei (38.5 %). This study demonstrates that dimorphic osteoarticular infections have distinctive clinical presentations, occur predominantly in apparently immunocompetent patients, develop often during disseminated disease, and may require surgical intervention.

Determinants of radiological patterns and severity in immunocompromised adults with Metapneumovirus infection.

BACKGROUND: Human Metapneumovirus (HMPV) belongs to the Pneumoviridae family and is responsible for respiratory infections. Mild infections are well-recognized in children, while its precise impact in various categories of immunocompromised adults has not been well addressed. RESEARCH QUESTION: We retrospectively studied HMPV infections in immunocompromised adults followed in two large French university medical centers. STUDY DESIGN AND METHODS: We identified immunocompromised adults with positive HMPV Polymerase Chain Reaction (PCR) for 36 months and reviewed their medical charts. For lung transplant recipients (LTR), FEV1 was collected at baseline, during and after infection. Imaging was centralized and chest involvement was categorized by dominant CT patterns. We compared severe patients (requiring oxygen or ventilation) and non hypoxemic patients. RESULTS: Seventy-two patients were included, 27 were LTR, 25 had a hematological malignancy or were hematopoietic stem cell recipients, 20 had another immunocompromised status. Twenty patients (28%) presented a hypoxemic infection, requiring hospitalization and intensive care units transfers in 50/72 (69.4%) and 9/72 (12.5%) respectively, with only one death. Hypoxemia was less pronounced in LTRs (p = 0.014). Finally, age and dyspnea remained independent factors associated with hypoxemia (p < 0.005). The most frequent radiological patterns were bronchopneumonia (34.2%) and bronchiolitis (39.5% and 64.3% in the overall population and in LTRs respectively, p = 0.045). FEV1 improved in LTRs at one month and 85% had recovered their baseline FEV1 within 6 months. INTERPRETATIONS: In immunocompromised adults, HMPV infections required frequent hospitalizations and ICU transfers, while mortality is low. In LTRs, bronchiolitis pattern was predominant with short and long-term favorable outcome.

[Pulmonary complications of Chronic Granulomatous Disease]. / Complications pulmonaires de la granulomatose septique chronique.

Chronic Granulomatosis Disease (CGD) is an inherited immune deficiency due to a mutation in the genes coding for the subunits of the NADPH oxidase enzyme that affects the oxidative capacity of phagocytic cells. It is characterized by increased susceptibility to bacterial and fungal infections, particularly Aspergillus, as well as complications associated with hyperinflammation and granulomatous tissue infiltration. There exist two types of frequently encountered pulmonary manifestations: (1) due to their being initially pauci-symptomatic, possibly life-threatening infectious complications are often discovered at a late stage. Though their incidence has decreased through systematic anti-bacterial and anti-fungal prophylaxis, they remain a major cause of morbidity and mortality; (2) inflammatory complications consist in persistent granulomatous mass or interstitial pneumoniae, eventually requiring immunosuppressive treatment. Pulmonary complications recurring since infancy generate parenchymal and bronchial sequelae that impact functional prognosis. Hematopoietic stem cell allograft is a curative treatment; it is arguably life-sustaining and may limit the morbidity of the disease. As a result of improved pediatric management, life expectancy has increased dramatically. That said, new challenges have appeared with regard to adults: difficulties of compliance, increased inflammatory manifestations, acquired resistance to anti-infectious therapies. These different developments underscore the importance of the transition period and the need for multidisciplinary management.

Enterobacter cloacae pyomyositis complicating chronic granulomatous disease and review of gram-negative bacilli pyomyositis.

Pyomyositis is a primary purulent infection of skeletal muscles mostly described in tropical areas. Staphylococcus aureus is by far the main causative microorganisms. In temperate areas, pyomyositis more frequently affects male adults with immunodeficiency. Gram-negative bacilli pyomyositis are uncommon and occur mainly in this context of immunodeficiency. Only one case of Enterobacter cloacae pyomyositis has been reported so far. Chronic Granulomatous Disease (CGD) is a rare inherited immunodeficiency characterized by a loss of NADPH oxidase activity in phagocytic cells that favors infections due to catalase-positive microorganisms. Pyomyositis has only been described once as a complication of CGD. We report here a case of Enterobacter cloacae-associated pyomyositis of the left thigh in a patient with CGD, and review the literature on Gram-negative pyomyositis.

Disseminated toxoplasmosis in non-allografted patients with hematologic malignancies: report of two cases and literature review.

Toxoplasmosis can be a severe opportunistic infection in patients with acquired immunodeficiency syndrome (AIDS), and also among solid organ transplant and allogeneic hematopoietic stem cell transplant (HSCT) patients. Patients with low-grade or chronic hematologic malignancies are treated with increasing immunosuppressive regimens and, therefore, represent an emerging population at risk for opportunistic diseases. We report here two cases of disseminated toxoplasmosis occurring in non-allografted hematologic patients with chronic lymphoproliferations. A review of 44 cases from the literature reveals that toxoplasmosis occurs increasingly in indolent B cell lymphoproliferative disorders. Aggressive lymphoproliferations, adenosine analogs, autologous HSCT, and the absence of chemoprophylaxis are the main risk factors for opportunistic toxoplasmosis. The central nervous system is the main organ involved. Fever is only present in half of all cases. Latent Toxoplasma cysts reactivation (LTCR) is the most common, but primary infection occurs in about 20% of cases. Global mortality is over 50%.

The efficacy of voriconazole in 24 ocular Fusarium infections.

PURPOSE: We examined, retrospectively, the efficacy of voriconazole in Fusarium eye infections. METHODS: Voriconazole-treated patients with proven or probable keratitis or endophthalmitis from the voriconazole database (9 patients) and six French ophthalmology departments (15 patients) were included. Sociodemographic features, predisposing factors, history of corneal trauma, associated ocular conditions, other diseases and prior therapies were analysed. Investigator-determined success was defined as infection resolution with medical treatment. Failure was no response or persistent infection and required surgery. RESULTS: Most patients were Caucasian (83 %) and male (71 %). The infection was keratitis (63 %) or endophthalmitis (37 %) and proven in 23 (96 %). Prior therapy included topical and/or systemic amphotericin (46 %), fluconazole (17 %) or others (33 %), often in combination. Causative fungi were Fusarium solani (14, 58 %), Fusarium moniliforme (1), Fusarium oxysporum (1) and Fusarium spp. (8). Voriconazole was administered systemically, topically and/or by intraocular injection, and 16 patients (67 %) received salvage and eight primary therapy. The overall response was 67 % (73 % keratitis and 56 % endophthalmitis) but seven patients required adjunctive surgery. However, response was 63 % for eight primary therapy patients and 69 % for 16 salvage therapy patients. Response by species was Fusarium solani 64 % (9/14) and all others 80 % (8/10). In 13 patients (77 %), voriconazole was used in combination (response 69 vs. 64 % alone) with topical [amphotericin B 10/24 (42 %), caspofungin 5 (21 %), natamycin 1 (4 %)] and systemic agents [caspofungin 3 (13 %), amphotericin 2 (8 %)]. CONCLUSIONS: Topical and systemic voriconazole appears to be effective alone or in combination with other agents for treating severe Fusarium keratitis or endophthalmitis.

Mucormycosis as a rare cause of severe gastrointestinal bleeding after multivisceral transplantation.

Mucormycosis, an emerging fungal infection in solid organ transplant patients, is mostly located in rhino-orbito-cerebral, pulmonary, and cutaneous areas, or disseminated with poor prognosis. A 4-year-old girl with chronic intestinal pseudo-obstruction syndrome underwent a modified multivisceral transplantation, including half of the stomach, the duodeno-pancreas, the small bowel, and the right colon. On postoperative day 5, a digestive perforation was suspected. Surgical exploration found a small necrotic area on the native stomach, which was externally drained. The next day, massive gastric bleeding occurred. During the emergency laparotomy, 2 hemorrhagic ulcers were found and resected from the transplanted stomach. Pathology and fungal culture showed mucormycosis caused by Lichtheimia (formerly Absidia) ramosa in both the transplanted and native stomach. High-dose intravenous liposomal amphotericin B was immediately started. No other site of fungal infection was found. The child recovered, and 3 years after transplantation, is alive and well, off parenteral nutrition. The originality of this case is the very early presentation after transplantation, the unusual site, and the complete recovery after rapid medico-surgical management. The origin of the fungus and treatment are discussed.