Annette Schaeffer

Zidovudine-induced mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion

Zidovudine is known to be responsible for a mitochondrial myopathy with ragged-red fibres and mitochondrial DNA depletion in muscle. Lactic acidosis alone or associated with hepatic abnormalities has also been reported. A single report mentioned the concomitant occurrence of muscular and hepatic disturbances and lactic acidosis in a patient receiving zidovudine, but muscle and liver tissues were not studied. A 57-year-old man with AIDS, who had been treated with zidovudine for 3 years, developed fatigue and weight loss. Serum creatine kinase and hepatic enzyme levels were high. Lactic acidosis was present. Liver biopsy showed diffuse macrovacuolar and microvacuolar steatosis. After withdrawal of zidovudine, creatine kinase, aspartate aminotransferase, and alanine aminotransferase levels normalised within 5 days, and lactacidaemia decreased. Acidosis persisted. The patient became confused and febrile and died 8 days after detection of high blood lactic acid. A muscle sample obtained at autopsy showed mitochondrial abnormalities with ragged-red fibres and lipid droplet accumulation. Southern blot analysis showed depletion of mitochondrial DNA, affecting skeletal muscle and liver tissue. No depletion was found in myocardium and kidney. This case emphasises that zidovudine treatment can induce mitochondrial multisystem disease, as revealed in our case by myopathy, liver steatosis and lactic acidosis.

Autoimmune thrombocytopenic purpura and common variable immunodeficiency: Analysis of 21 cases and review of the literature

Abstract: To describe the main characteristics and outcome of autoimmune thrombocytopenic purpura (AITP) in patients with common variable immunodeficiency (CVID), we analyzed data from 21 patients and reviewed additional cases from the literature. To be included in this study, patients had to have CVID and a previous history of AITP with a platelet count ≤50 × 109/L at onset. A complete response to treatment was defined by a platelet count ≥150 × 109/L, and a partial response by a platelet count >50 × 109/L with an increase of at least twofold the initial level. The median platelet count at AITP diagnosis was 20 × 109/L (range, 2-50 × 109/L). The median age at AITP diagnosis was 23 years (range, 1-51 yr), whereas the median age at CVID diagnosis was 27 years (range, 10-74 yr). CVID was diagnosed before the onset of AITP in only 4 patients (19%), 3 of whom were being treated with intravenous immunoglobulin (IVIg) replacement therapy. CVID was diagnosed more than 6 months after AITP in 13 cases (62%), and the 2 conditions were diagnosed concomitantly in 4 cases. Eleven patients (52%) had at least 1 autoimmune manifestation other than AITP, among which autoimmune hemolytic anemia (7 cases) and autoimmune neutropenia (5 cases) were preeminent. Seventeen of the 21 patients (80%) received at least 1 treatment for AITP; 13 patients received corticosteroids alone and 7 (54%) achieved at least a partial response; 8 patients received IVIg at 1-2 g/kg alone or in combination with steroids, leading to a short-term response rate of 50%. Four patients underwent a splenectomy (2 complete responses, 2 failures); 2 additional splenectomies were performed for associated autoimmune hemolytic anemia. With a mean follow-up of 5.6 years after the surgical procedure, none of the 6 splenectomized patients had a life-threatening infection. With a median follow-up after AITP onset of 12 years, 13/21 patients (62%) were in treatment-free remission (7 complete responses, 6 partial responses), 7 patients (23%) were in remission while on prednisone ≤20 mg/day with or without azathioprine, and only 1 patient still had a platelet count <50 × 109/L. Five patients had died at the time of the analysis; none of the deaths was related to a hemorrhage. Severe infections including 3 fatal bacterial infections and 2 opportunistic infections occurred in 6 patients during or after treatment of AITP. In conclusion, AITP, alone or in combination with autoimmune hemolytic anemia (Evans syndrome) and/or autoimmune neutropenia, is frequent in patients with CVID, and is not prevented by IVIg substitutive therapy. Since AITP frequently precedes the diagnosis of CVID, testing for immunoglobulin levels should be performed in every patient diagnosed with AITP. Steroids and splenectomy seem to have the same efficacy as in idiopathic AITP, but the increased risk of severe infections must be taken into consideration. Abbreviations: AITP = autoimmune thrombocytopenic purpura, CVID = common variable immunodeficiency, IVIg = intravenous immunoglobulin.

Autoimmune Thrombocytopenic Purpura and Helicobacter pylori Infection

BACKGROUND The mechanisms triggering the production of platelet autoantibodies in autoimmune thrombocytopenic purpura (AITP) are poorly understood. Recently, marked improvements in platelet counts have been reported in patients with AITP and concurrent Helicobacter pylori infection after eradication of H pylori by a standard antibiotic regimen. We looked for an association between H pylori infection and AITP in adults. METHODS Fifty-one adults of white French origin, negative for human immunodeficiency virus (mean +/- SD age, 40 +/- 19.8 years), with AITP and a platelet count of less than 50 x 10(3)/microL at onset were included. Thirty-five consecutive nonthrombocytopenic patients (mean +/- SD age, 43 +/- 22 years) of the same origin and with unknown H pylori status served as control subjects. Antibodies against H pylori were detected by means of an agglutination method in both patients and control subjects. Sex ratio, mean age, hemorrhagic manifestations, response to corticosteroid therapy, and final outcome were compared in H pylori-negative and H pylori-positive patients with AITP. To test for a possible molecular mimicry mechanism, we also used an immunoblot assay to look for specific H pylori antibodies in platelet eluates from 3 H pylori-positive patients with AITP. RESULTS Seroprevalence of H pylori in patients with AITP (15 [29%]) was not significatively different from that in control subjects (10 [29%]). The H pylori-positive and H pylori-negative patients with AITP did not differ in main characteristics at AITP onset, response rate to corticosteroids, and final outcome. None of the 3 patients investigated had H pylori antibodies in platelet eluates. CONCLUSION Although the role of H pylori in a subgroup of patients with AITP cannot be excluded, we found no evidence of an association between H pylori infection and AITP.

Dapsone for chronic autoimmune thrombocytopenic purpura: a report of 66 cases

Sixty‐six adults with chronic autoimmune thrombocytopenic purpura AITP and platelet count <50 ×109 l were treated with dapsone (75–100 mg orally). A response was observed in 33 patients. The median duration of treatment required to obtain a response was 21 d (range 8–90). The median maximal platelet count on treatment was 130 × 109 l (range 71–355). Dapsone was continued in 20/33 responders for a median of 12.5 months (range 1–48) and the response persisted in 19. Treatment was intentionally withdrawn in the other 13 responders and thrombocytopenia immediately recurred in 12. Reversible side‐effects required cessation of treatment in seven patients. These results demonstrate that dapsone is an effective, inexpensive, and well‐tolerated treatment for chronic AITP.

Intravenous immunoglobulin for adults with autoimmune thrombocytopenic purpura: results of a randomized trial comparing 0.5 and 1 g/kg b.w.

Since the first reports demonstrating the ability of a total dose of 2 g/kg body weight (b.w.) of intravenous immunoglobulin (IVIg) to increase the platelet count in patients with autoimmune thrombocytopenic purpura (AITP), the optimal dose has remained controversial. We report the results of a randomized study which compared two low doses of IVIg (0.5 g/kg b.w., group A, n = 19, and 1 g/kg b.w., group B, n = 18) in 37 adults with AITP and platelet count <50 × 109/l, in preparation for surgery or in a situation with a risk of bleeding. On day 4 the proportion of responses, defined by a platelet count > 80 × 109/l and at least twice the initial platelet count, was significantly higher in the group receiving 1 g/kg b.w. (12/18 in group B versus 4/19 in group A, P = 0.005). All but one of the day 4 responders had already responded on day 3. The daily changes in the platelet count from the beginning of IVIg treatment were larger in group B, with a significant difference relative to group A on day 3 (92 × 109/l in group B versus 50 × 109/l in group A, P = 0.03) and on day 4 (106 × 109/l in group B versus 55 × 109/l in group A, P = 0.03). Patients who had not responded by day 4 subsequently received 1.5 g IVIg/kg b.w. (group A) or 1 g IVIg/kg b.w. (group B). A response was observed in 11/13 initial non‐responders in group A, and in 2/6 initial non‐responders in group B. Finally, on day 8, the proportion of responders was 78% (29/37) in the entire group and was similar in the two subgroups. In conclusion, (1) initial treatment with 1 g/kg b.w. of IVIg appeared to be more effective than 0.5 g/kg b.w. in adults with AITP; (2) infusion of a low dose of IVIg did not jeopardize the efficacy of IVIg reinfusion; (3) some adults who did not respond to 1 g IVIg/kg b.w. responded to a higher dose.

Specific antiplatelet glycoprotein autoantibodies are associated with the thrombocytopenia of primary antiphospholipid syndrome

Thrombocytopenia is a frequent complication of primary antiphospholipid syndrome (PAPL) and has been attributed to antibodies directed against platelet glycoproteins (Gp) and also to antiphospholipid antibodies. We tested patients with PAPL with and without thrombocytopenia for specific antiplatelet autoantibodies. Platelet autoantibodies were detected by means of platelet immunoassays which included MAIPA with a panel of monoclonal antibodies directed against all the platelet Gps known to be possible targets for platelet autoantibodies. A high prevalence of serum platelet antibodies was found in patients with thrombocytopenia (73%, 11/15 patients) whereas antiplatelet antibody was detected in only one of the 10 control patients (P < 0.01). The antibodies mainly recognized GpIIbIIIa (n = 7), but also CD9 (n = 5), GpIaIIa (n = 4), GpIbIX (n = 3) and GpIV (n = 3). Platelet‐Gp antibodies eluted from the platelet surface had the same reactivity as those found in the original sera from three of the four patients tested, whereas no anticardiolipin activity was found in the platelet eluates, suggesting the absence of cross‐reactivity between anticardiolipin and antiplatlet antibodies. The MAIPA assay was also performed with F(ab′)2 fragments obtained by pepsin digestion of serum IgG from four patients. The same results were obtained with F(ab′)2 fragments and the original serum, demonstrating that platelet antibodies specifically bind in vivo to platelet Gps via their F(ab′)2 fragments. Our results suggest a link between specific platelet antibodies and the thrombocytopenia of PAPL.

acute Arterial Obliteration: A New Feature of the Poems Syndrome?

The POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammapathy, and skin changes) syndrome is a rare variant of plasma cell dyscrasia with multisystemic manifestations. We present 4 cases with arterial symptoms typical of acute arterial obliteration (AAO) and review 9 similar cases in the literature. The clinical course of AAO was unusual and particularly severe when affecting the lower limbs; recurrent events required amputations. As demonstrated by angiographic and histologic studies, thrombotic and atheromatous lesions were the main pathologic features of AAO. Atherosclerotic risk factors were absent or moderate in 3 of our cases, and no cause of thrombosis other than the POEMS syndrome was found. A high production of cytokines was found in all cases, with elevated serum levels of interleukin-1 beta (9/9 samples), interleukin-6 (7/9 samples), and tumor necrosis factor-alpha (6/9 samples). We suggest that arterial manifestations should be added to the spectrum of manifestations of the POEMS syndrome. Cytokines may mediate the POEMS syndrome-associated AAO, as previously proposed for the other systemic manifestations of this disorder.

Costs and benefits of measures to prevent needlestick injuries in a university hospital.

OBJECTIVE To document the costs and the benefits (both in terms of costs averted and of injuries averted) of education sessions and replacement of phlebotomy devices to ensure that needle recapping did not take place. DESIGN The percentage of recapped needles and the rate of needlestick injuries were evaluated in 1990 and 1997, from a survey of transparent rigid containers in the wards and at the bedside and from a prospective register of all injuries in the workplace. Costs were computed from the viewpoint of the hospital. Positive costs were those of education and purchase of safer phlebotomy devices; negative costs were the prophylactic treatments and follow-up averted by the reduction in injuries. SETTING A 1,050-bed tertiary-care university hospital in the Paris region. RESULTS Between the two periods, the proportion of needles seen in the containers that had been recapped was reduced from 10% to 2%. In 1990, 127 needlestick (12.7/100,000 needles) and 52 recapping injuries were reported versus 62 (6.4/100,000 needles) and 22 in 1996 and 1997. When the rates were related to the actual number of patients, the reduction was 76 injuries per year. The total cost of information and preventive measures was

The response to high-dose intravenous immunoglobulin or steroids is not predictive of outcome after splenectomy in adults with autoimmune thrombocytopenic purpura.

325,927 per year. The cost-effectiveness was

Platelet autoantibodies and lupus-associated thrombocytopenia

4,000 per injury prevented. CONCLUSION Although preventive measures taken to ensure reduction of needlestick injuries appear to have been effective (75% reduction in recapping and 50% reduction in injuries), the cost of the safety program was high.