Pierre Jean Weiller

Q fever 1985-1998. Clinical and epidemiologic features of 1,383 infections.

In order to describe the clinical features and the epidemiologic findings of 1,383 patients hospitalized in France for acute or chronic Q fever, we conducted a retrospective analysis based on 74,702 sera tested in our diagnostic center, National Reference Center and World Health Organization Collaborative Center for Rickettsial Diseases. The physicians in charge of all patients with evidence of acute Q fever (seroconversion and/or presence of IgM) or chronic Q fever (prolonged disease and/or IgG antibody titer to phase I of Coxiella burnetii > or = 800) were asked to complete a questionnaire, which was computerized. A total of 1,070 cases of acute Q fever was recorded. Males were more frequently diagnosed, and most cases were identified in the spring. Cases were observed more frequently in patients between the ages of 30 and 69 years. We classified patients according to the different clinical forms of acute Q fever, hepatitis (40%), pneumonia and hepatitis (20%), pneumonia (17%), isolated fever (17%), meningoencephalitis (1%), myocarditis (1%), pericarditis (1%), and meningitis (0.7%). We showed for the first time, to our knowledge, that different clinical forms of acute Q fever are associated with significantly different patient status. Hepatitis occurred in younger patients, pneumonia in older and more immunocompromised patients, and isolated fever was more common in female patients. Risk factors were not specifically associated with a clinical form except meningoencephalitis and contact with animals. The prognosis was usually good except for those with myocarditis or meningoencephalitis as 13 patients died who were significantly older than others. For chronic Q fever, antibody titers to C. burnetii phase I above 800 and IgA above 50 were predictive in 94% of cases. Among 313 patients with chronic Q fever, 259 had endocarditis, mainly patients with previous valvulopathy; 25 had an infection of vascular aneurysm or prosthesis. Patients with endocarditis or vascular infection were more frequently immunocompromised and older than those with acute Q fever. Fifteen women were infected during pregnancy; they were significantly more exposed to animals and gave birth to only 5 babies, only 2 with a normal birth weight. More rare manifestations observed were chronic hepatitis (8 cases), osteoarticular infection (7 cases), and chronic pericarditis (3 cases). Nineteen patients were observed who experienced first a documented acute infection, then, due to underlying conditions, a chronic infection. To our knowledge, we report the largest series of Q fever to date. Our results indicate that Q fever is a protean disease, grossly underestimated, with some of the clinical manifestations being only recently reported, such as Q fever during pregnancy, chronic vascular infection, osteomyelitis, pericarditis, and myocarditis. Our data confirm that chronic Q fever is mainly determined by host factors and demonstrate for the first time that host factors may also play a role in the clinical expression of acute Q fever.

Prevalence and clinical significance of IgG isotype anti-β2-glycoprotein I antibodies in antiphospholipid syndrome: A comparative study w

To investigate the prevalence, significance, and specificity of IgG isotype anti-β2-Glycoprotein I antibodies (a-β2-GPI) in antiphospholipid syndrome (APS), we developed an enzyme-linked immunosorbent assay (ELISA) for the detection of IgGa-β2-GPI and tested sera from 61 patients with autoimmune disorders (AID), 39 patients with APS and 22 patients with systemic lupus erythematosus without APS, 139 patients with various infectious diseases (hepatitis C virus infection, human immunodeficiency virus infection, Q fever, Mediterranean spotted fever, syphilis) and 97 healthy control subjects. Using irradiated plates coated with human β2-GPI, we showed that in the sera of patients with AID, optical densities from the coated wells were significantly higher than those from the noncoated ones (p = 0.0001). In this assay, intra-assay and inter-assay variation coefficients ranged between 4% and 10%. Clinical evaluation showed that IgG-a-β2-GPI were found in 23 of 61 patients with AID but in only one patient with an infectious disease. The presence of the IgG-a-β2-GPI in association with APS (p = 0.005) was statistically significant with high specificity (98%) and positive predictive value (87.5%) but with low sensitivity (54%), and was significantly associated with venous thrombosis (p = 0.0025). In addition, the IgG-a-β2-GPI levels were highly correlated with those of anticardiolipin antibodies (aCL) (p < 0.001). In contrast to a-β2-GPI, aCL were found with a high prevalence (40%) in patients with infectious diseases. Because of their high specificity, anti-β2-GPI antibodies appear to be useful tools in the evaluation of the risk of APS. However, because of their low sensitivity, their detection needs to be associated with that of aCL.

Haploidentical T Cell-Replete Transplantation with Post-Transplantation Cyclophosphamide for Patients in or above the Sixth Decade of Age Compared with Allogeneic Hematopoietic Stem Cell Transplantation from an Human Leukocyte Antigen-Matched Related or Unrelated Donor.

It has recently been shown that a T cell-replete allogeneic (allo) hematopoietic stem cell transplantation (HSCT) from a haploidentical donor (haplo-ID) could be a valid treatment for hematological malignancies. However, little data exist concerning older populations. We provided transplantation to 31 patients over the age of 55 years from a haplo-ID and compared their outcomes with patients of the same ages who underwent transplantation from a matched related (MRD) or an unrelated donor (UD). All 3 groups were comparable, except for their conditioning. Patients in haplo-ID group received 2 days of post-transplantation high-dose cyclophosphamide followed by cyclosporine A and mycophenolate mofetil, whereas patients in other groups received pretransplantation antithymocyte globulin, cyclosporine A, and additional mycophenolate mofetil in case of 1-antigen mismatch. All patients but 1 in the haplo-ID group engrafted. The incidence of grades 2 to 4 acute graft-versus-host disease (GVHD) was not statistically different between recipients from haplo-ID (cumulative incidence, 23%) and MRD (cumulative incidence, 21%) transplantations but it was lower than after UD HSCT (cumulative incidence, 44%). No patient in the haplo-ID group developed severe chronic GVHD, compared with cumulative incidences of 16% and 14% after MRD (P = .02) and UD (P = .03) grafts, respectively. The cumulative incidences of relapse were similar in the 3 groups, whereas nonrelapse mortality after UD HSCT was 3-fold higher than after haplo-ID or MRD HSCT. Overall, 2-year overall survival (70%), progression-free survival (67%), and progression and severe chronic GVHD-free survival (67%) probabilities after haplo-ID did not statistically differ from MRD transplantation (78%, 64%, and 51%, respectively), although they were higher than after UD transplantation (51% [P = .08], 38% [P = .02], and 31% [P = .007]). We conclude that T cell-replete haplo-ID HSCT followed by post-transplantation high-dose- cyclophosphamide in patients over 55 years is associated with promising results, similar to MRD HSCT, and is deserving prospective evaluation.

Contribution of anti-β2glycoprotein I IgA antibodies to the diagnosis of anti-phospholipid syndrome: potential interest of target domains to discriminate thrombotic and non-thrombotic patients

OBJECTIVES Although the last international guidelines for aPL recommended determination of IgA aCL and anti-β2glycoprotein I (aβ2GPI) antibodies for the evaluation of APS in the absence of conventional IgG or IgM aCL and aβ2GPI antibodies, the clinical value of these antibodies remains controversial. We evaluated the clinical utility of IgA aPL and of the determination of target domains of aβ2GPI IgA antibodies. METHODS A retrospective analysis was performed on sera from 439 patients referred for routine detection of aPL IgA by in-house ELISA. Sera positive for aβ2GPI IgA were subsequently tested for aβ2GPI domain 1 (D1) and domain 4/5 (D4/5) antibodies using ELISAs. RESULTS The prevalence of aβ2GPI IgA antibodies was 16% in patients, significantly different from controls (1%, P < 0.0001). These antibodies were associated with clinical contexts related to APS as thrombosis (28.6% vs. 15%, P = 0.009) and SLE (42% vs. 15%, P < 0.0001). Interestingly, determination of their target domains revealed a significant association between aβ2GPI IgA directed against D4/5 and SLE without thrombosis (66.7 vs. 16.7%, P = 0.002). In contrast, aCL IgA were not more prevalent in patients than in controls. CONCLUSION Our study confirmed the interest of aβ2GP1 IgA in the exploration of APS and suggests that identification of target domains of aβ2GP1 IgA may be useful in the evaluation of thrombotic risk in SLE patients.

Lack of interaction between hepatitis C virus and alcohol in the pathogenesis of cirrhosis. A statistical study

BACKGROUND/AIMS In several studies markers of hepatitis C virus infection have been shown to be present in alcoholic patients with cirrhosis. Our work was designed to test the likely hypothesis that this association is due to an interaction between hepatitis C virus and alcohol in the pathogenesis of cirrhosis. METHODS We compared alcohol consumption and repartition of anti-HCV antibodies detected by an immunoblot recombinant assay in 101 male patients with cirrhosis and in 120 male controls. Interactions between anti-hepatitis C virus, alcohol and cirrhosis were calculated using log linear hierarchical models for frequency data. The basis of the method is that an interaction between hepatitis C virus and alcohol implies that a model built on the hypothesis of a role of hepatitis C virus and alcohol in the disease should be improved by a coefficient associated with multiplicative effects of hepatitis C virus and alcohol. RESULTS In patients with cirrhosis the mean alcohol consumption (148 +/- 100 g per day) and the incidence of positivity for anti-HCV antibodies (45%) were significantly higher than in controls. The results were consistent with a theoretical model built with the hypothesis of an independent role of both alcohol and hepatitis C virus. The goodness of fit between this model and the actual distribution of alcohol consumption and hepatitis C virus markers was not improved by introduction of an interaction between hepatitis C virus and alcohol. CONCLUSIONS In alcoholic subjects with hepatitis C virus infection, the probability to have cirrhosis seemed to be explained by additive effects of alcohol and hepatitis C virus. From a purely statistical point of view, no interaction between hepatitis C virus and alcohol consumption on a multiplicative scale could be demonstrated.

CLINICAL FEATURES AND FOLLOW-UP OF FOUR NEW CASES OF FACIAL-ONSET SENSORY AND MOTOR NEURONOPATHY

In this study we report three patients with facial‐onset sensory and motor neuronopathy (FOSMN), including the first female to be described. A fourth rather atypical case of a pyramidal syndrome with a fast rate of progression is also described. These cases raise the question as to whether upper motor neuron impairment is involved in FOSMN and whether there is a link between this syndrome and amyotrophic lateral sclerosis. The existence of this syndrome suggests that it may be wise to monitor all patients with isolated idiopathic trigeminal sensory neuropathy to ensure that this type of motor neuron disease is not overlooked. Muscle Nerve, 2011

Low incidence of chronic GVHD after HLA-haploidentical peripheral blood stem cell transplantation with post-transplantation cyclophosphamide in older patients

erated, without any adverse events. In an on-going phase I study, data on another anti-PD-1 antibody, nivolumab, were reported in 23 patients with relapsed Hodgkin lymphoma, 18 having failed brentuximab vedotin treatment (Ansell et al, 2015). After a median of 16 (6–37) doses, the response rate was 87% (CR: 17%; PR: 70%). Adverse events occurred in 78% of patients. In another on-going phase I study, data on pembrolizumab were reported in 15 patients with relapsed Hodgkin lymphoma, all of who had failed brentuximab vedotin (Moskowitz et al, 2014). Pembrolizumab was used at a high dose of 10 mg/kg, given every 2 weeks. After six courses, the response rate was 53% (CR: 20%; PR: 33%). At such frequent high doses of pembrolizumab, 67% of patients experienced one or more adverse events. Notably, three patients developed pneumonitis, which resulted in drug withdrawal in one patient. Our findings are unique, as low-dose pembrolizumab has hitherto not been used to treat Hodgkin lymphoma. We showed that pembrolizumab administered at a much lower dose (cumulatively only 6 mg/kg at interim assessment) resulted in very good response. To minimize adverse events and cost, the use of low-dose pembrolizumab in refractory Hodgkin lymphoma warrants further investigation. Author contributions

The efficacy and safety of a new reduced-toxicity conditioning with 4 days of once-daily 100 mg/m2 intravenous busulfan associated with fludarabine and antithymocyte globulins prior to allogeneic stem cell transplantation in patients with high-risk myelodysplastic syndrome or acute leukemia

Abstract The optimal intensity of myeloablation associated with a reduced-toxicity conditioning (RTC) regimen in order to decrease the relapse rate without increasing non-relapse mortality (NRM), is not well established yet. This retrospective analysis was done on 30 patients with hematological malignancies. The aim was to assess the safety of a RTC regimen based on the busulfan at a dose of 100 mg/m2/d intravenously for 4 d, fludarabine at a dose of 30 mg/m2/d for 5 d, and anti-thymoglobulins at a dose of 2.5 mg/kg/d for 2 d. The cumulative incidences of grade 2–4 acute graft-versus-host disease (GVHD) and all grades chronic GVHD were 37% and 42%, respectively. Median 1-year overall survival and disease-free survival were 66% and 50%, respectively. At 1 year, the cumulative incidence of relapse/disease progression was 33%. NRM was 3% and 17% at day 100 and 1 year, respectively. This RTC conditioning regimen can lead to a long-term disease control. Moreover, it appears to be safe with a low NRM rate among high-risk patients.

Fasciite avec éosinophilie : discussion de la responsabilité d'un inhibiteur de l'enzyme de conversion de l'angiotensine

Resume Dans le cadre des syndromes neuro-eosinophiliques, les atteintes les plus peripheriques portent surtout sur les fascias et sur les muscles. Elles apparaissent le plus souvent spontanement, mais peuvent parfois etre consecutives a un effort. Nous rapportons le cas d’une patiente âgee de 43 ans qui a presente un angio-œdeme dans les suites immediates d’un traitement par Ranipril (Triatec ® ) suivi sans discontinuer d’une fasciite avec eosinophilie. L’evolution spontanee sans aucun traitement a ete favorable. L’imputabilite de cet inhibiteur de l’enzyme de conversion a ete jugee plausible. A notre connaissance, cet effet secondaire n’a jamais ete signale anterieurement.

Rosai-Dorfman disease initially misdiagnosed as sarcoidosis.

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