[Sinonasal polyposis associated with a deficiency subclass immunoglobulin G: Place of substitution immunoglobulins]. / Polypose nasosinusienne associée à un déficit en sous-classes d'Immunoglobuline G: place de la substitution en immunoglobulines polyvalentes.

PURPOSE: To study the effect of the introduction of a substitution by intravenous Immunoglobulins (Ig IV) at patients with immunoglobulins G (IgG) subclasses deficiency and nasal polyposis. MATERIAL AND METHODS: Prospective study concerning five patients with IgG subclasses deficiency and nasal polyposis treated by Ig IV. Rhinologic, otologic and pulmonary symptoms, exacerbations of nasal polyposis, chronic otitis and asthma as well as the number of antibiotics and corticoids treatments were counted during the Ig IV substitution. OBJECTIVES: To study the association between IgIV substitution and the number of exacerbations of nasal polyposis, chronic otitis, asthma and the number of antibiotics and corticoids treatments in patients with IgG subclasses deficiency and nasal polyposis. RESULTS: Five patients with a IgG subclass deficiency and nasal polyposis were substituted. The number of antibiotics and corticoids cures increased at one patient and remained stable at four others. The number of sinus, ear and lung infections as well as the global rhinologic score of symptoms and the endoscopic stage of the nasal polyposis remained stable. In the absence of efficiency of the treatment, this one was interrupted at the end of 6 months for patients n° 1 and n° 3, 24 months for patient n° 4 and 42 months for patient n° 5. CONCLUSION: The current study failed to highlight clinical improvement in patients wih IgG subclasses deficiency and nasal polyposis treated by Ig IV. A previous study had not allowed to find a link between IgG subclasses deficiency and severity of nasal polyposis, what seems to be confirmed by the absence of improvement brought during the substitution of this deficit in the current study.

Perturbation of CD4+ and CD8+ T-cell repertoires during progression to AIDS and regulation of the CD4+ repertoire during antiviral therapy.

The T-cell antigen receptor (TCR) repertoire was studied longitudinally by analyzing the varying lengths of the beta chain CDR3 hypervariable region during the course of HIV-1 infection and following combination antiretroviral therapy. Drastic restrictions in CD8+ T-cell repertoire usage were found at all stages of natural progression and persisted during the first six months of treatment. In contrast, significant CD4+ T-cell repertoire perturbations were not found in early stages of infection but correlated with progression to AIDS. Out of ten patients presenting with pretreatment perturbations, normalization of the CD4+ repertoire was observed in eight good responders, but not in two cases of unsuccessful therapy. These results indicate that, besides CD4+ cell count rise, an efficient control of HIV replication may allow qualitative modifications of the CD4+ repertoire balance.

Liver-related deaths in HIV-infected patients between 1995 and 2005 in the French GERMIVIC Joint Study Group Network (Mortavic 2005 study in collaboration with the Mortalité 2005 survey, ANRS EN19).

BACKGROUND: More than 10 years after the introduction of combination antiretroviral therapy (cART), we examined the trend in the proportion of deaths caused by end-stage liver disease (ESLD) in HIV-infected adults in France between 1995 and 2005. DESIGN AND METHODS: In 2005, 34 departments prospectively recorded all deaths in HIV-infected patients who were followed in those departments (around 24 000). RESULTS: were compared with those of four previous cross-sectional surveys conducted since 1995 using the same methodology. Results Among 287 reported deaths in 2005, 100 (35%) were related to AIDS, and 48 (17%) to ESLD. Three out of four patients who died from ESLD-related causes had chronic hepatitis C. Excessive alcohol consumption was reported in approximately half of the patients (48%). At death, 62% of patients had undetectable HIV viral load and the median CD4 count was 237 cells/microL. From 1995 to 2005, the proportion of deaths caused by ESLD increased from 2 to 17% (P<0.001). The proportion of deaths caused by hepatocellular carcinoma increased from 5% in 1995 to 25% in 2005 (P=0.0337). CONCLUSIONS: Over the 10 years from 1995 to 2005, the proportion of deaths caused by hepatitis C virus-related ESLD has increased in HIV-infected patients. ESLD is currently a leading cause of death in this population, with hepatocellular carcinoma representing a quarter of liver-related deaths. Recommendations for the detection of hepatocellular carcinoma should be strictly applied in these patients.

Drug resistance profiles for the HIV integrase gene in patients failing raltegravir salvage therapy.

OBJECTIVES: Recent data showed the selection of mutations in the integrase gene, mainly involving position 148 or 155, in patients displaying virological failure (VF) on raltegravir (RAL) therapy. Here, we describe the development of RAL resistance, in both plasmatic and cellular compartments, in three heavily pretreated HIV-infected patients failing RAL-containing regimens. METHODS: Three of 17 patients receiving RAL displayed VF. The entire integrase gene, isolated from plasma and peripheral blood mononuclear cells (PBMC), was sequenced. A clonal analysis was performed in one patient at the time of VF. RESULTS: At the time of VF, RAL-resistance mutations were selected: (i) Q148R in patients 1 and 3; (ii) T66A and E92Q in patient 2. A gradual accumulation of new mutations was observed in all patients, including G140S, Q148H and N155H in patient 1, L74I in patient 2, and G140S in patient 3. Clonal analysis showed the coexistence, in patient 1, of the two common resistance pathways (mutations Q148R/H and N155H) found in distinct quasi-species. In addition, RAL-resistance mutations were detected in HIV DNA in all patients. CONCLUSIONS: Having rapidly established, resistance to RAL evolves and diversifies, and is likely to impact the efficacy of subsequently used second-generation integrase inhibitors. Moreover, RAL-resistance mutations can be archived early in PBMC.

Discrepant responses to triple combination antiretroviral therapy in advanced HIV disease.

OBJECTIVES: To determine the clinical, virological and immunological outcome in a cohort of unselected patients receiving triple combination therapy for more than 1 year. METHODS: Prospective follow-up of a cohort of 162 unselected, protease inhibitor-naive, antiretroviral-experienced patients with advanced HIV disease, treated with indinavir combined with two nucleoside analogues. RESULTS: The mean CD4 cell count and plasma HIV RNA level in the study group at baseline were 69+/-5 x 10(6)/l and 4.75+/-0.07 log10 copies/ml, respectively. Five per cent of patients died prematurely or were lost to follow-up. Fifty-seven per cent of patients responded to therapy, as assessed by a sustained increase in CD4 cell counts above 50 x 10(6)/l and a decrease in plasma HIV RNA greater than 1 log10 copies/ml, throughout 12.1 months of follow-up. Seventeen per cent of patients were immunological and virological non-responders. Twenty-one per cent of patients exhibited discrepant virological and immunological responses to treatment, of whom one-half failed to exhibit significant increases in CD4 cells despite a virological response to therapy and one-half exhibited increased CD4 cell counts in the absence of significant decrease in plasma viral load. The incidence of AIDS-defining events in the latter group of patients was similar to that of responder patients, whereas their incidence was higher in patients who failed to exhibit a virological and immunological response and those who failed to increase CD4 cells despite a significant decrease in viral load. CONCLUSION: Our observations of discrepant immunological and virological responses to treatment raise the issue of the significance of persistent elevated levels of plasma HIV RNA and of the relevance of measurements of plasma viral load for assessing the efficacy of antiretroviral therapy in patients whose CD4 cell counts increase despite the absence of significant decrease in plasma HIV viral load.

Plasma levels of thrombomodulin in pulmonary hypertension.

BACKGROUND: Long-standing pulmonary hypertension (PH) leads to structural alterations of the pulmonary vasculature and its endothelium, and occlusion of small vessels by microthrombi. In patients with PH, the search for factors inducing or worsening endothelium damage and in situ thrombi is still ongoing. Thrombomodulin (TM), an endothelial cell membrane protein, is a receptor for thrombin and a major anticoagulant proteoglycan. PURPOSE: To analyze plasma TM levels in patients with different forms of severe PH. PATIENTS: We prospectively studied 32 consecutive patients with PH referred for heart, lung, or heart-lung transplantation: 11 patients with primary PH (group 1), 11 patients with secondary precapillary PH (Eisenmenger's syndrome, group 2) and 10 patients with secondary postcapillary PH due to congestive heart failure (group 3). Thirty-eight healthy subjects were also studied as a control group. METHODS: Plasma concentrations of TM were measured by an immunoenzymatic technique that uses two anti-TM monoclonal antibodies that have a strong avidity and react with different epitopes of the molecule. RESULTS: Thrombomodulin plasma levels decreased in all patients with precapillary PH, and this decrease was highly significant compared with controls (26 +/- 2 versus 44 +/- 2 ng/mL, P = 0.0001). In primary PH, the TM decrease was only significant in males whereas in the Eisenmenger's syndrome TM values were the lowest of all the patients studied, with mean values twice as low as controls (22 +/- 2 versus 44 +/- 2 ng/mL, P = 0.0001). In contrast, in postcapillary PH, studied only in males, TM levels were increased (85 +/- 17 versus 54 +/- 3 ng/mL, P = 0.02). Patients with precapillary PH had more severe disease than patients with postcapillary PH, with higher pulmonary artery pressure and pulmonary vascular resistance (P < 0.001). There was no correlation between TM plasma levels and all hemodynamic variables. CONCLUSION: We found low levels of plasma TM in patients with precapillary PH but not in postcapillary PH compared with healthy controls. This may be related to the severity of PH and may contribute to the initiation or worsening of in situ thromboses frequently found in pulmonary hypertension. Further studies should analyze whether other markers of endothelial cell damage are correlated with plasma TM levels in patients with precapillary pulmonary hypertension.

The cumulative occurrence of resistance mutations in the HIV-1 protease gene is associated with failure of salvage therapy with ritonavir and saquinavir in protease inhibitor-experienced patients.

Salvage therapy with ritonavir (RTV) and saquinavir (SQV) failed to achieve virological and immunological improvement in 24 HIV-infected patients who discontinued triple therapy with RTV or indinavir (IDV) because of failure or intolerance to treatment. Changes in the HIV-1 protease gene sequence were analyzed prospectively in 14 patients. No primary protease mutation was found prior to the use of protease inhibitors. After 7 months of treatment with IDV or RTV, primary resistance mutations at codons pol 46 and/or pol 82 were observed in 11 of 13 patients. After 16 weeks on RTV-SQV, novel primary mutations related to SQV emerged in 7 of 13 patients, together with an increase in the number of secondary resistance mutations. Our observations indicate that the cumulative occurrence of resistance mutations in the protease gene was associated with failure of antiretroviral therapy. The presence of mutations to a first protease inhibitor may represent a risk factor for the failure of a subsequent treatment with a second line protease inhibitor.

Imbalanced "memory" T lymphocyte subsets and analysis of dendritic cell precursors in the peripheral blood of adult patients with Langerhans cell histiocytosis.

OBJECTIVES: To investigate the phenotype of lymphocytes and dendritic cell precursors in the peripheral blood of adult patients with histiocytosis X. METHODS: Data were obtained on patients with histiocytosis X treated in La Pitié-Salpetrière Hospital. Peripheral blood mononuclear cells from 10 patients (4 with unifocal and 6 with disseminated disease) were studied by flow cytometry. A method was set up to detect circulating Langerhans cells, dendritic cells and their precursors. RESULTS: An abnormal repartition of "memory" T lymphocyte subsets was observed, with a significant decrease of CD4CD45RO and CD8CD45RO and a reciprocal increase of CD4CD45RA "naive" cells, while CD4+ cells displaying the accessory molecule CD28 were decreased in some patients. These abnormalities disappeared in vitro after triggering of the CD3 and CD28 molecules in the absence of antigen presenting cells, hence demonstrating that there was no constitutive defect in the capacity of CD4+ and CD8+ T cells to convert from the CD45RO- to the CD45RO+ isoform. Langerhans cells were undetectable in the peripheral blood, and dendritic cells and their precursors were present in normal proportions (0.5 +/- 0.2% and 2.8 +/- 1.2%, respectively), but the latter were more numerous (4% and 6% of the PBMC) in the two patients with the more severe form of the disease. CONCLUSIONS: We found in these patients some T lymphocyte phenotype abnormalities which suggest alterations in antigen-driven activation processes. The number of dendritic precursor cells was not consistently elevated in the peripheral blood from histiocytosis X patients.

Antiphosphatidylethanolamine antibody as the sole antiphospholipid antibody in systemic lupus erythematosus with thrombosis.

A previously healthy 34-year-old woman, was diagnosed as having systemic lupus erythematosus (SLE), with membranous glomerulopathy which improved rapidly. Neither lupus anticoagulant nor anticardiolipin antibodies were detected in her plasma. After three months of total remission, she developed a severe pulmonary thromboembolism for which no specific biological cause was found. Her plasma was analysed for different antiphospholipid antibodies: lupus anticoagulant and anticardiolipin antibodies were again negative. Using an ELISA prepared with either five different anionic phospholipids or zwitterionic phosphatidylethanolamine, solely an anti-phosphatidylethanolamine IgG was discovered in her plasma. In lupus patients, the presence of antiphospholipid antibodies is now well recognized as a high risk factor for repeated thrombosis and/or recurrent abortions. This case suggests that the presence of antiphosphatidylethanolamine antibody should be investigated in cases of unexplained thrombosis in SLE, where the usual clinical and biological investigations have failed to shed light.

Intramedullary abscess resulting from disseminated cryptococcosis despite immune restoration in a patient with AIDS.

We report on a case of cryptococcal intramedullary abscess, which occurred three years after a disseminated cryptococcosis and two years after a lymph node cryptococcal recurrence in a HIV-infected patient who exhibited a long-standing immune restoration. At the time of diagnosis, CD4(+) lymphocyte-count was 640x10(6)/l and HIV viral load was undetectable. Spinal involvement is rare during cryptococcosis of the central nervous system. As far as we are aware, there is only one case of proven intramedullary cryptococcal abscess reported in the literature and this case is then the second one. The significant and sustained increase in CD4 count following effective antiretroviral therapy was probably associated with only a partial immune restitution that did not allow to avoid the occurrence of the cryptococcal medullar abscess. Finally, this case raises the question of when to stop secondary prophylaxis of cryptococcal disease after increase in CD4 cell count under antiretroviral therapy.

[Human parvovirus B19 infection. Update]. / Infection humaine par le parvovirus B19. Mise au point.

Pathogenicity of parvovirus B19 has been demonstrated. The spectrum of clinical manifestations varies according to the age and immune status of affected patients. Parvovirus B19 is the aetiologic agent of erythema infectiosum in children. In normal adults, it is responsible for acute, bilateral and symmetrical arthritis, although chronic arthritis can develop. Parvovirus B19 has a particular tropism for erythroid precursors: in patients with underlying hemolysis, it induces transient aplastic crisis; in immunosuppressed patients the virus can lead to chronic pure red cell aplasia. Hydrops fetalis is one of the most severe manifestation of the infection. Diagnosis of recent parvovirus B19 infection is based upon serology and PCR, especially in immunosuppressed patients in whom polyvalent intravenous immunoglobulins must be started. The link between parvovirus B19 and systemic vasculitis is questioned.

[Thrombomodulin: physiology and clinical applications (excluding systemic diseases)]. / La thrombomoduline: physiologie et applications cliniques (en dehors des maladies systémiques).

Thrombomodulin (TM) is a proteoglycan present on the surface of endothelial and mesothelial cells where it acts as a strong anticoagulant. TM is also located in other cells (keratinocytes, osteoblasts, mononuclear phagocytes...) where it might be involved in cell differentiation or inflammatory processes. The damage of endothelial cells releases cleavage fragments. Plasma TM appears to be a marker of endothelium damage. Plasma TM has been investigated in several disorders: it is usually increased in the case of diffuse endothelial damage.

[Primary pulmonary hypertension in human immunodeficiency virus infection. Study of 9 cases amd review of the literature]. / Hypertension artérielle pulmonaire primitive au cours de l'infection par le virus de l'immunodéficience humaine. Etude de neuf observations et revue de la littérature.

PURPOSE: In medical literature, primary pulmonary hypertension occurs in 0.5% of human immunodeficiency virus (HIV)-infected patients, irrespective of the stage of the HIV disease, and is more frequent in drug users. Plexogenic arteriopathy is the most frequent histological lesion. METHODS: We retrospectively report on nine cases of primary pulmonary hypertension during HIV infection. RESULTS: The subjects were four women and five men, mean age 38 years old. Four of them had been sexually contaminated and five had contracted the disease through intravenous drug use. At the time primary pulmonary hypertension was diagnosed, mean CD4 cell count was 234 +/- 217/mm3 and the viral load was low or undetectable. Primary pulmonary hypertension has been diagnosed an average of 7 months after the first cardiovascular clinical signs had started. Despite anti-coagulant (7/9 cases), vasodilatator (4/9 cases) and/or diuretic (7/9 cases) therapy, the progression of the disease quickly turned out to be negative (seven deaths). CONCLUSION: Diagnosis of primary pulmonary hypertension should be considered when unexplained dyspnea occurs in an HIV-positive patient. At initial evaluation, alterations of hemodynamic parameters are usually less severe than during idiopathic primary pulmonary hypertension, but their progression is quicker and more severe, independent of the patient's immune status. Current data do not allow the determination of whether antiretroviral therapy is active in primary pulmonary hypertension evolution. Therapeutic evaluation with prostacyclin is currently being carried out. While the life expectancy of HIV-infected patients extends, primary pulmonary hypertension occurrence could increase and call for early diagnosis, thus allowing for specific care.

[Episcleritis and brucellosis. Apropos of a case]. / Episclérite et brucellose. A propos d'un cas.

A 35-year-old man presented a case of recurrent episcleritis revealing brucellosis. No concurrent diagnosis other than brucellosis could account for the episcleritis. Moreover his status was dramatically improved by specific antibiotherapy. A review of the literature showed that uveitis and optic neuropathies are the most common ocular manifestations of brucellosis. To the best of our knowledge, this is the first case of episcleritis associated with brucellosis.

[Efficacy of intravenous immunoglobulin in the treatment of Birdshot retinochoroiditis]. / Efficacité et tolérance des immunoglobulines intraveineuses dans le traitement de la rétinochoroïdopathie de type Birdshot.

AIM: To evaluate the efficacy of intravenous immunoglobulin (IVIg) in the treatment of Birdshot retinochoroiditis. PATIENTS AND METHODS: Eighteen patients were followed-up prospectively in a total number of 37 patients recorded. Inclusion criteria were birdshot retinochoroiditis (BRC) according to the criteria defined by Ryan et al., and a decrease in visual acuity (VA). Efficacy was assessed by measurements of visual acuity and a decrease in inflammation and macular edema on fluorescein angiograms. RESULTS: Sex ratio=1, mean age was 51 (range 29 to 72 years), HLA A29 was positive in 100% of the patients. VA at baseline was 0.6+/-2.4 (range 0.25 to 0.9). Angiography showed retinal vasculitis in 32 patients (86.48%) and cystoid macular edema in 16 patients (43.24%). IVIg was administered at a dosage of 0.4g/kg/d for 4 days then 0.6g/kg/d for 2 days every 4 weeks. Follow-up lasted a mean of 2.7+/-2.0 years (range, 4 months to 5.6 years). Visual acuity of 35 out of 66 eyes (53%) increased by 2.6+/-1.5 (range 1 to 5). In 19 eyes out of 66 (29%), VA remained stable and in 12 eyes out of 66 (18%), VA decreased by -1.8+/-0.8 (ranges-4 to -1). Inflammation on fluorescein angiography improved in 17 patients (81%) and cystoid macular edema decreased in 65% of the cases. Side effects were rare. Treatment was discontinued for side effects in only 3 patients. DISCUSSION: BRC is a chronique disease threatening vision. Treatments including systemic corticosteroids and cyclosporin A may result in severe long-term side effects. IVIg is well tolerated and may be therapeutic alternative for the treatment of BRC.

[The glomerulopathies of cirrhosis of the liver]. / Les glomérulopathies des cirrhoses du foie.

Since 1970, the types of glomerulopathy encountered in patients with cirrhosis of the liver have been accurately determined. In alcoholic cirrhosis IgA glomerulonephritis is frequent, usually non-proliferative and latent, sometimes membranoproliferative. Defective elimination of circulating immune complexes made up of bacterial or food antigens and IgA antibodies is thought to play a part in the pathogenesis of this type of glomerulonephritis. Extramembranous or membranoproliferative glomerulonephritis, occasionally containing the viral antigen, may complicate post-hepatitis cirrhosis, in which case an antiviral treatment might be effective against the renal disease.

[Transmission modes of hepatitis C virus]. / Modes de transmission du virus de l'hépatite C.

SITUATION IN FRANCE: The prevalence of hepatitis C virus (HCV) infection in the French population is estimated at 1%, a level similar to that in other western countries. USUAL CONTAMINATION ROUTES: Epidemiological studies, together with gene typing, have made it possible to distinguish transmission modes. A history of intravenous drug abuse or transfusion is found in 60 to 80% of all subjects infected by the HCV. Other documented modes of contamination include hemodialysis, organ transplantation, accidental occupational-related puncture and mother-infant transmission. OTHER ROUTES: Sexual or intra-familial nonsexual transmission is uncommon and related to the length of exposure and the stage of HCV infection in the "source" subjects. Cases of HCV transmission have been reported during medical procedures. Currently the mode of of transmission is unknown in 20 to 40% of the cases.

[Antiphospholipid antibodies: cause of thrombosis or an epiphenomenon?]. / Anticorps antiphospholipides: cause des thromboses ou épiphénomène?

Antiphospholipid antibodies (aPL) present in systemic lupus erythematosus and the primary antiphospholipid syndrome are a well-known risk factor for thrombosis. Most of them require the presence of a cofactor, beta 2-glycoprotein I for anticardiolipin antibodies, prothrombin for lupus anticoagulant. These aPL are of the "immune" type. APL are also found in various non-immunological conditions, in which repeated endothelial or membranous damages appear to be frequent, but thromboses are rare. Most of these aPL are cofactor-independent, except those induced by chlorpromazine, and might belong to "natural" antibodies.

[Antiphospholipid syndrome. 20 cases]. / Syndrome des antiphospholipides. 20 observations.

OBJECTIVES: We analyzed the clinical and biological characteristics as well as the clinical course and outcome observed in 20 patients with antiphospholipid antibodies and clinical signs including thrombosis or repeated spontaneous abortion to better identify the recently described antiphospholipid syndrome. METHODS: We retrospectively studied all patients observed in our unit from 1981 to 1992 who fulfilled the following inclusion criteria: a) at least one episode of arterial or venous thrombosis and/or repeated spontaneous abortions, b) positive for antiphospholipid antibodies. RESULTS: Twenty patients were included, 3 with systemic lupus erythematosus (according to the American Rheumatism Association criteria). Arterial or venous thrombosis occurred in 9 and 16 respectively, including exceptional cases of cerebral phlebitis and thrombosis of dermal capillaries. High blood pressure was recorded in 8. Only 1 or 2 types of antiphospholipid antibodies were found in most patients. Anticardiolipin, a circulating anticoagulant and a false-positive Bordet-Wassermann reaction were found together in only 3 out of 16. In addition, the antibody level varied independently from the thrombotic events. There was no case with a clinical course from primary antiphospholipid syndrome to systemic erythromatosus lupus. The effect to treatment on occurrence of new thrombotic events was studied. Three patients suffered one or more haemorrhagic events during antivitamin K treatment. CONCLUSION: It is difficult to establish a differentiation between primary antiphospholipid syndrome, systemic lupus erythematosus and lupus-like syndromes, and precise methods of identifying antiphospholipid antibodies should be further developed.

[Antiphospholipid syndrome and the pneumologist]. / Le syndrome des antiphospholipides et le pneumologue.

The antiphospholipid syndrome (APS) is usually defined by the association of a clinical manifestation (venous or arterial thrombosis or miscarriage) with the presence of antiphospholipid antibodies (lupus anticoagulant and/or anticardiolipin antibodies). It frequently occurs in the course of systemic lupus erythematosus but is also encountered as a "primary" disease. APS is responsible for diverse respiratory manifestations. Pulmonary embolism is common. The site of the causal venous thrombosis is frequently unusual. Pulmonary hypertension may be a consequence of repeated embolism or may belong to the primary idiopathic variety. Pulmonary manifestations may also result from left-sided heart failure due to mitral or aortic valve abnormalities, myocardial infarction or a specific myocardiopathy. APS is probably involved in the occurrence of some cases of adult respiratory distress syndrome. Long term secondary prevention of recurrent thrombosis is a central point in the management of APS.