High prevalence of infectious events in thrombotic thrombocytopenic purpura and genetic relationship with toll-like receptor 9 polymorphisms: experience of the French Thrombotic Microangiopathies Reference Center.

BACKGROUND: Infectious events have been reported as major environmental triggers of thrombotic thrombocytopenic purpura (TTP). We detail here the potential association between infections and TTP. STUDY DESIGN AND METHODS: We recruited randomly and prospectively a cohort of 280 consecutive TTP patients during a 9-year period. Features of infection were systematically recorded. RESULTS: Features consistent with an infectious event were observed in 114 patients (41%) at time of TTP diagnosis. Infectious agents were documented in 34 cases and were mainly Gram-negative bacilli. At time of diagnosis infected patients more frequently had fever (p < 0.001). Infections at diagnosis did not impact prognosis and outcome. Thirty-six percent of patients experienced an infectious event during hospitalization, which resulted in more exacerbation of TTP (p = 0.02). Infections were not overrepresented during treatment in patients who received steroids and/or rituximab. Further genetic analysis of toll-like receptor (TLR)-9 functionally relevant polymorphisms revealed that TLR-9 +2848 G and TLR-9 +1174 A genotypes were more frequent in TTP patients than in controls (p = 0.04 and p = 0.026, respectively) and more particularly in patients negative for the Class II human leukocyte antigen system susceptibility allele DRB1*11 (p = 0.001 and p = 0.002, respectively). Haplotypes estimation showed that 1174A-2848G haplotype was significantly more frequent in TTP (p = 0.004), suggesting a primary role for this haplotype variation in conferring a predisposition for acquired TTP. CONCLUSION: Infections should be considered as an aggravating factor during the course of TTP. Particular polymorphisms in TLR-9 gene may represent risk factors for TTP.

Intravitreal ranibizumab and/or dexamethasone implant for macular edema secondary to retinal vein occlusion.

PURPOSE: To investigate the outcome of intravitreal ranibizumab and/or dexamethasone implant treatment for treatment of macular edema (ME) secondary to central or branch retinal vein occlusion (CRVO or BRVO) in a clinical setting. METHODS: Retrospective analysis of consecutive patients followed for at least 6 months. Data recorded included the type of occlusion, initial and final visual acuity, and number of injections. RESULTS: Sixty-five patients were included, 26 had CRVO and 39 BRVO. Mean (± SD) follow-up duration was 16 (± 7.7) months. Twenty-four (36.9%) patients received ranibizumab in monotherapy, 19 patients (29.3%) dexamethasone in monotherapy, and 22 patients (33.8%) received successively both treatments. In dexamethasone-treated patients, mean (± SD) visual acuity gain was 5.8 ± 10.7 letters for BRVO and 16.8 ± 15.6 letters for CRVO. In ranibizumab-treated patients, mean (± SD) visual acuity gain was 9.2 ± 10 letters for BRVO and 18.2 ± 20.5 letters for CRVO. CONCLUSION: Both intravitreal ranibizumab and dexamethasone intravitreal implant could be used as first-line therapy for patients with ME secondary to retinal vein occlusion.

Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center.

OBJECTIVE: To assess the efficacy and safety of rituximab in adults responding poorly to standard treatment for severe autoimmune thrombotic thrombocytopenic purpura. DESIGN: Open-label prospective study. Outcomes in the survivors were compared to those of 53 historical survivors who were given therapeutic plasma exchange alone or with vincristine. SETTING: Hospitals belonging to the Reference Network for Thrombotic Microangiopathies in France. PATIENTS: Twenty-two adults with either no response or a disease exacerbation when treated with intensive therapeutic plasma exchange. INTERVENTION: Add-on rituximab therapy, four infusions over 15 days. MEASUREMENTS AND MAIN RESULTS: One patient died despite two rituximab infusions. In the rituximab-treated patients, the time to a durable remission was significantly shortened (p = .03), although the plasma volume required to achieve a durable remission was not significantly different compared to the controls. Platelet count recovery occurred within 35 days in all 21 survivors, compared to only 78% of the historical controls (p < .02). Of the rituximab-treated patients, none had a relapse within the first year but three relapsed later on. In patients treated with rituximab, a rapid and profound peripheral B-cell depletion was produced, lasting for 9 months and correlating with higher a disintegrin and metalloproteinase with thrombospondin-13 activity and lower anti-a disintegrin and metalloproteinase with thrombospondin-13 antibody titers. These differences were no longer significant after 12 months. No severe side effects occurred. CONCLUSIONS: Adults with severe thrombocytopenic purpura who responded poorly to therapeutic plasma exchange and who were treated with rituximab had shorter overall treatment duration and reduced 1-yr relapses than historical controls.

Development and validation of a predictive model for death in acquired severe ADAMTS13 deficiency-associated idiopathic thrombotic thrombocytopenic purpura: the French TMA Reference Center experience.

BACKGROUND: Acquired thrombotic thrombocytopenic purpura is still associated with a 10-20% death rate. It has still not been possible to clearly identify early prognostic factors of death. This study involved thrombotic thrombocytopenic purpura patients with acquired severe (<10% of normal activity) ADAMTS13 deficiency and aimed to identify prognostic factors associated with 30-day death. DESIGN AND METHODS: The study involved a prospective cohort of patients and was carried out between October 2000 and August 2010. A validation cohort of patients was set up from September 2010 to August 2011. Altogether, 281 (analysis cohort) and 66 (validation cohort) consecutive adult thrombotic thrombocytopenic purpura patients with acquired severe ADAMTS13 deficiency were enrolled. The study evaluated 30-day mortality after treatment initiation according to characteristics at inclusion. RESULTS: Non-survivors (11%) were older (P=10(-6)) and more frequently presented arterial hypertension (P=5.10(-4)) and ischemic heart disease (P=0.013). Prognosis was increasingly poor with age (P=0.004). On presentation, cerebral manifestations were more frequent in non-survivors (P=0.018) and serum creatinine level was higher (P=0.008). The most significant independent variables determining death were age, severe cerebral involvement and LDH level 10 N or over. A 3-level risk score for early death was defined and confirmed in the validation cohort using these variables, with higher values corresponding to increased risk of early death. CONCLUSIONS: A risk score for early death was defined in patients with thrombotic thrombocytopenic purpura and validated on an independent cohort. This score should help to stratify early treatment and identify patients with a worse prognosis.

Splenectomy and/or cyclophosphamide as salvage therapies in thrombotic thrombocytopenic purpura: the French TMA Reference Center experience.

BACKGROUND: The objective was to assess the efficacy and safety of splenectomy and cyclophosphamide as salvage therapies in severe thrombotic thrombocytopenic purpura (TTP). STUDY DESIGN AND METHODS: During a 10-year period, patients who did not improve with plasma exchanges, steroids, vincristine, and/or rituximab were considered for splenectomy or cyclophosphamide. Patients with a documented severe (<10% of normal value) acquired ADAMTS13 deficiency are reported here. RESULTS: Eighteen patients with a severe acquired ADAMTS13 deficiency required a salvage therapy. Thirteen patients had a splenectomy 19 (interquartile range [IQR], 10-51) days after TTP diagnosis. One patient died the day after splenectomy. The remaining patients improved platelets (PLTs) until Day 6, along with a rapid and major lactate dehydrogenase improvement. Six patients, however, subsequently experienced a transient worsening. Durable PLT count recovery in survivors was observed within 13 (IQR, 11.5-25.5) days. Postoperative complications included thromboembolic events (two cases) and infections (five cases). Five patients received pulses of cyclophosphamide 12 (IQR, 12-15) days after TTP diagnosis. All patients recovered PLTs 10 (IQR, 9-24) days after the first pulse and two experienced a transient worsening. Three patients experienced infections. Three relapses occurred 5 months, 2.5 years, and 4.5 years after splenectomy and one relapse occurred 3.5 years after cyclophosphamide. After a 2.5 (IQR, 0.75-6.2)-year follow-up, the overall survival was 94%. CONCLUSION: Cyclophosphamide and splenectomy provide comparable high remission rates in severe TTP with acceptable side effects and should be considered in the more severe patients who do not improve with other therapies.

Cancer awareness in atypical thrombotic microangiopathies.

OBJECTIVE: To specify the clinical and biological characteristics of thrombotic microangiopathies (TMAs) associated with a recent diagnosis of cancer. PATIENTS AND Methods. Multicenter study involving 14 national centers. Cross-sectional analysis of 20 patients with cancer-associated TMAs included in our national registry from October 2000 to July 2007. Patients were also compared with 134 adult patients with an acquired idiopathic TMA by univariate analysis. RESULTS: Patients with a cancer-associated TMA typically displayed severe weight loss, dyspnea, bone pain, as well as disseminated intravascular coagulopathy and massive erythromyelemia (75%, 55%, 50%, 41%, and 85% of cases, respectively). By contrast, these features were observed with a much lower incidence in patients with an idiopathic TMA (8.9%, 19.7%, 0.8%, 7.1%, and 17.5%, respectively). Moreover, median platelet count was higher (48 x 10(9)/l; range, 21-73 x 10(9)/l versus 19 x 10(9)/l; range, 10-38 x 10(9)/l, respectively) and median serum creatinine level was lower (74 microM [range, 68-102] versus 113 microM [range, 80-225], respectively). The activity of the specific von Willebrand factor-cleaving proteinase ADAMTS13 was detectable in 14/17 studied patients. Platelet count improvement was observed in only seven patients and paralleled the response to chemotherapy. Prognosis of patients with cancer-associated TMAs was very poor, with a 30-day and 2-year mortality rate of 50% and 95%, respectively. CONCLUSION: Cancer-associated TMAs display specific features at onset that should prompt investigation of an underlying disseminated malignancy. In this context, chemotherapy rather than plasma is mandatory since TMA prognosis parallels that of cancer.

Two cases of cellulitis in the course of African tick bite fever: a fortuitous association?

In African tick bite fever (ATBF), inoculation eschar - resulting from disruption of the cutaneous barrier - may be a risk factor for cellulitis. We report 2 cases of ATBF associated with cellulitis. A 77-year-old woman was referred for severe leg cellulitis upon returning from sub-Saharan Africa. She developed erythematous macules. Rickettsia africae was detected by PCR assay from a skin biopsy specimen, and ATBF diagnosis was confirmed. A 75-year-old man was hospitalized after his return from Zimbabwe for a maculopapular exanthema and erysipelas-like rash of the leg. The diagnosis of cellulitis associated with ATBF was confirmed by PCR and serological methods. Both patients were treated for ATBF and cellulitis by a combination of doxycycline and beta-lactam antibiotics, and both had a good recovery. Inoculation eschar may be a risk factor for cellulitis; thus, we hypothesize a non-fortuitous association between ATBF and cellulitis.

Study of persistence and recurrence rates in 106 patients with condyloma and intraepithelial neoplasia after CO2 laser treatment.

Our aim was to evaluate remission and relapse rates and the number of laser sessions necessary for treatment. Among the relapses observed, we sought to differentiate between the persistence and recurrence of an HPV-induced lesion. This retrospective study was performed in patients, immunocompetent or not, treated with CO2 laser for condylomatous or neoplastic anogenital lesions by the same operator over a period of 12 months. 106 treated patients were followed for 6 months. Three groups of patients were analysed: HIV(+) patients, patients with therapeutic immunosuppression (ImST) and immunocompetent patients (ImC). Twenty-seven (25.5%) patients presented with high-grade intraepithelial neoplasms (IEN III). IEN III lesions were more common in the HIV(+) group than in immunocompetent patients (47.4% versus 20.2%, p = 0.015). The development of HPV-induced lesions at several sites on the body was also more common in HIV(+) patients. Post-laser controls at one month demonstrated a clinical absence of HPV-induced lesions in 81.2% of cases, recurrence in 12.6% of cases and persistence in 6.6% of cases. Remission rates at one month did not differ significantly between the three groups. 93% of patients in remission at one month were still in remission at three months. IEN III neoplasms in remission at one month remained so at six months. ImC and ImST patients presented more frequently with recurrence than persistence, when compared with HIV(+) patients. At six months, 83% of patients were in remission after 1.4 laser treatments. The excision of HPV-induced anogenital lesions using CO2 laser remains an efficient treatment, even if it needs to be repeated if lesions recur or persist. CO2 laser treatment under colposcopic guidance can achieve remission in both immunocompromised and non-compromised patients with longstanding lesions.

Scurvy in liver transplant patients.

We report on scurvy in 3 liver transplant recipients. Clinical presentation was limited to ecchymotic purpura and mild follicular keratosis with no mucosal involvement. Skin biopsies suggest vitamin C deficiency, which was confirmed by a low level of vitamin C in both sera and leukocyte specimens. Skin lesions dramatically improved within a few weeks after supplementation with ascorbic acid.

Mitochondrial DNA depletion in adipose tissue of HIV-infected patients with peripheral lipoatrophy.

BACKGROUND: NRTI-induced host toxicity is proposed to involve cellular mitochondrial DNA (mtDNA) depletion. Determinants of cellular mtDNA copy number from HIV-infected patients receiving HAART and HIV-seronegative controls were investigated from subcutaneous fat samples, and relation with antiretroviral regimen was studied. STUDY DESIGN: HIV-infected patients receiving HAART (n = 50), HIV-infected patients not currently under HAART regimen (n = 2) and HIV-seronegative controls (n = 9) of similar age and BMI were enrolled prospectively when undergoing Coleman's lipostructure for correction of facial lipoatrophy or plastic surgery, respectively. After centrifugation, abdominal fat tissue was collected and stored at -80 degrees C. MtDNA analysis was blindly performed after a total DNA extraction from adipose tissue, followed by a real-time PCR quantification. The log of mtDNA copies/cell in adipose tissue [log(DNA)] was compared between groups by means of analysis of variance. RESULTS: The log(DNA) in adipose tissue of HIV-infected patients was significantly lower than in the HIV-seronegative control group (P < 0.0001). In HIV-infected patients, log(DNA) was significantly reduced in the 50 NRTI-treated patients (P < 0.01), but not when considering mtDNA level according to the use of PI or NNRTI in current HAART regimen. In NRTI-treated patients, only stavudine (n = 20) and didanosine (n=14) were significantly and independently associated with reduced mtDNA level (P < 0.0001 and <0.05, respectively). Currently stavudine or didanosine-treated patients had a significant reduced mtDNA level compared to past users (P < 0.0001 and <0.05, respectively). Other clinical, biological, and immuno-virological variables than NRTI did not correlate significantly to adipocyte mtDNA level. CONCLUSION: This study supports that current treatment by NRTI is a main determinant of mtDNA depletion in adipose tissue of HIV-seropositive patients with peripheral fat wasting. Stavudine or didanosine current intake is significantly associated with mtDNA depletion in vivo, that could be reversible after the discontinuation of these molecules, when considering mtDNA level according to current use versus past use of these molecules.

Mycosis fungoides-type cutaneous T-cell lymphoma and neutrophilic dermatosis.

BACKGROUND: Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL). Patients with limited patch and/or plaque disease have a normal life expectancy. Neutrophilic dermatosis (ND) may be associated with various hematologic disorders. However, its association with CTCL is exceptional and has been reported only twice with leukemic forms of CTCL. OBSERVATIONS: Three patients with MF developed ND resistant to conventional therapies and responsible for an impaired quality of life due to constitutional symptoms and painful cutaneous lesions. All patients underwent an aggressive treatment course despite their varying initial clinical stages of MF, and all experienced a fatal outcome less than 18 months after the onset of ND. CONCLUSIONS: The association of MF with ND is exceptional and carries a poor prognosis, but the pathophysiologic nature of this association remains unclear. It may involve neutrophil chemoattractant cytokine production by tumor cells. A triggering role of interferon alfa is also possible.

Evaluation of Coleman lipostructure for treatment of facial lipoatrophy in patients with human immunodeficiency virus and parameters associated with the efficiency of this technique.

OBJECTIVE: To evaluate the efficiency of Coleman lipostructure in patients infected with human immunodeficiency virus (HIV). DESIGN: Open-label study and survey. SETTING: Ambulatory dermatosurgery department of a university hospital. PATIENTS: Thirty-three consecutive HIV-infected patients undergoing Coleman lipostructure between 2000 and 2001. INTERVENTIONS: Clinical examination, blood tests, and standardized photographs at baseline and 1 year after the lipostructure. MEAN OUTCOME MEASURES: Efficiency was assessed by the agreement of 3 independent medical specialists on facial lipodystrophy improvement after surgery and by patient satisfaction. RESULTS: Facial lipoatrophy was improved in 12 patients (36%; 95% confidence interval, 20%-52%) as judged by all 3 evaluators. Quantity of fat injected (P = .01) and a low serum triglyceride level before surgery (P = .03) were significantly associated with improvement of facial lipoatrophy. Of the 33 patients, 14 (43%) were very satisfied, 17 (50%) were partly satisfied, and 27 (81%) had a better quality of life. The most common comment was that the patient looked better and appeared less ill. CONCLUSION: Our 1-year evaluation of Coleman lipostructure for correction of facial lipoatrophy in HIV-infected patients proved the efficiency of this treatment when measured conservatively by agreement on improvement by 3 independent specialists and demonstrated a patient satisfaction rate of 93%.

Cutaneous Waldenstrom's macroglobulinemia with "deck-chair" sign treated with cyclophosphamide.

Specific skin lesions are rare in Waldenstrom's macroglobulinemia (WM). We report a case of a 58-year-old man who presented macules, papules, and an erythema of the trunk with the "deck-chair" sign revealing the relapse of WM. Histologic and immunohistochemical examinations confirmed that cutaneous lesions were related to specific infiltration with neoplastic cells. Remission of both skin lesions and immunological abnormalities was obtained with oral cyclophosphamide.

HIV and antiretroviral drug distribution in plasma and fat tissue of HIV-infected patients with lipodystrophy.

OBJECTIVE: To determine HIV and antiretroviral drug distribution in plasma and fat tissue of HIV-infected patients with lipodystrophy. METHODS: Twenty-three consecutive HIV-infected patients (median age, 43 years; male:female ratio, 18:5; median CD4 cell count, 419 x 10(6)/l) undergoing Coleman's lipostructure were enrolled prospectively in this study. HIV-1 RNA and plasma concentration of antiretroviral drugs were determined blindly in plasma and adipocyte lysate samples. HIV-1 proviral DNA was detected by nested PCR in fresh frozen adipocytes. RESULTS: Mean plasma HIV-1 RNA was significantly higher than that in adipocyte lysate samples (this was below the limit of detection in all patients tested). HIV-1 proviral DNA was positive in two out of 18 adipocyte samples with a level between 2 and 5 copies; the distribution seemed to be specific and comparable within each therapeutic class--protease inhibitors (PI) or non-nucleoside reverse transcriptase inhibitors (NNRTI). NNRTI concentrations in adipocyte lysates were approximately 100-fold higher than those of PI. Efavirenz may accumulate in fat tissue as a function of treatment duration. CONCLUSION: Our results suggest that HIV does not replicate and does not integrate its genome in fat tissue in patients with fat redistribution abnormalities. In patients with effective nadir plasma concentrations of PI and NNRTI, determination of concentration in adipocyte lysates suggests that PI may diffuse in fat tissue with the same pattern of distribution for all structurally related components tested. NNRTI present a high affinity for fat tissue and may accumulate in this compartment.

Detection and quantification of Mycoplasma genitalium in male patients with urethritis.

Detection and quantification of Mycoplasma genitalium were evaluated in 83 patients with urethritis (group 1), 60 patients with urethral symptoms but no urethritis (group 2), and 50 asymptomatic men (group 3). Quantification of M. genitalium was carried out using real-time polymerase chain reaction (PCR) analysis of first-pass urine samples. The rate of detection of M. genitalium was significantly higher in group 1 than in groups 2 and 3 (P<.0001). The mean observed concentration of M. genitalium was 1.2x10(4) equivalent genomes/mL of urine (range, 50 to 8x10(4) equivalent genomes/mL). Analysis of M. genitalium load in serial urine samples collected before and after the administration of antibacterial treatment showed an association between clinical and microbiological responses, with a shift to negative PCR results in symptom-free patients. Our results illustrate the usefulness of monitoring the M. genitalium load in evaluating the susceptibility of M. genitalium to antibacterial treatment.

[Buschke-Lowenstein penile tumor]. / Tumeur pénienne de Buschke-Löwenstein.

The Buschke-Löwenstein genital tumour is a poorly defined, uncommon tumour. The distinction between benign lesions, potentially malignant lesions and carcinomatous lesions is difficult. The authors report a case of Human Papillomavirus (HPV) 11-associated Buschke-Löwenstein tumour with an area of micro-invasive carcinoma on histological examination of the surgical resection specimen. A 34-year-old patient was operated for recurrent condylomatous lesions of the penis with scrotal extension. Histological examination of the complete operative specimen confirmed the presence of Buschke-Löwenstein tumour as well as an area of dermal micro-invasion on one section. Molecular hybridization revealed the presence of HPV 11 DNA and immunohistochemistry showed basal cells weakly expressing mutant p53. The classification of Buschke-Löwenstein tumours is controversial. Some authors consider these tumours to be benign tumours or giant condylomata (non-metastatic, associated with HPV 6-11), while others consider these tumours to be borderline malignant (local extension and risk of progression to invasive carcinoma). The role of HPV as cofactor involved in carcinomatous transformation also remains controversial. The authors emphasize the need for surgical resection of this type of tumour with histological examination of the entire operative specimen looking for areas of micro-invasion. In the presence of micro-invasion with healthy resection margins and staging by clinical examination and complementary investigations, treatment essentially consists of regular surveillance.

[Polyclonal CD8+/CD57+ T cell expansions: clinical significance]. / Signification clinique des expansions polyclonales lymphocytaires T CD8+/CD57+.

Polyclonal CD8(+)/CD57(+)T cell lymphocytosis can be observed in various conditions such as chronic viral infections, autoimmune cytopenias, connective tissue diseases, chronic graft-versus-host disease and primary or secondary immune deficiencies. This population results from the chronic stimulation of CD8(+)/CD28(+)/CD57(-)lymphocytes by exogenous (mostly infection-related), autologous or allogeneic antigens. Paralleling chronic antigen stimulation, these CD8(+) T cells acquire a poor capacity to proliferate in standard conditions in relation with the loss of CD28, whereas CD57 antigen becomes expressed at their surface. CD8(+)/CD57(+)T cells represent activated cytotoxic T lymphocytes at a terminal stage of their differentiation with evidence of immunological senescence, which have usually lost their cytotoxic properties to become "regulatory" T cells. Patients with a CD8(+)/CD57(+)T cell lymphocytes expansion can display features of organ infiltration, as well as chronic idiopathic neutropenia. The search of this population has therefore a diagnostic value in clinical practice. A CD8(+)/CD57(+)T cell lymphocytes expansion must be suggested in patients with an organomegaly or organ(s) infiltration, particularly in patients infected by the human immunodeficiency virus or in the setting of allogeneic hematopoietic stem cell transplantation, as well as in patients with a neutropenia of unexplained origin. The identification of a CD8(+)/CD57(+)T cell lymphocytes expansion also has therapeutical consequences since patients with an organ infiltration or a neutropenia may respond remarkably to immunomodulatory therapies. The search of a CD8(+)/CD57(+) T cell expansion thus represents a useful and still poorly known diagnostic tool which clinical interest deserves further evaluation.

Cutaneous macroglobulinosis: a report of 2 cases.

BACKGROUND: Specific cutaneous lesions of Waldenström macroglobulinemia are rare and include neoplastic cell infiltrates, IgM bullous disease, and so-called IgM-storage papules, which characterize cutaneous macroglobulinosis (CM). OBSERVATIONS: We report 2 patients with CM. In patient 1, CM started as small papules, as reported in most of the previously published case studies of CM. In patient 2, lesion evolution was remarkable by its severity, with large ulcerated nodules, and the disease progressed rapidly. As mentioned for half the previously described patients, peripheral neuropathy was suspected in patient 2 and demonstrated in patient 1, with production of antibodies to myelin-associated glycoprotein. CONCLUSIONS: To the best of our knowledge, rituximab treatment of Waldenström macroglobulinemia associated with CM has not been described previously. Rituximab caused complete remission of the lesions in patient 1, whereas disease rapidly progressed in patient 2, and the patient died. These observations suggest that evolution of the cutaneous IgM-storage lesions reflects that of the underlying Waldenström macroglobulinemia, and CM is not a prognostic marker.