Intravenous immunoglobulin in the treatment of human immunodeficiency virus-related thrombocytopenia.код для вставкиСкачать
American Journal of Hematology 38:261-266 (1991) Intravenous Immunoglobulin in the Treatment of Human Immunodeficiency Virus-Related Thrombocytopenia Mark U. Rarick, Terri Montgomery, Susan Groshen, Jane Sullivan-Halley, Denise Jamin, Amitabha Mazumder, Parkash S. Gill, Carmen Loureiro, and Alexandra M. Levine Departmentsof Internal Medicine (M.U.R., T.M., A.M., P.S.G., C.L., A.M.L.), Section of Hematology, Preventive Medicine (S.G., J.S.-H.), and Pharmacology (D.J.), University of Southern California School of Medicine, Los Angeles, California Fourteen patients with sexually transmitted human immunodeficiency virus (HIV)-related immune thrombocytopenia were treated with intravenous gammaglobulin (IVIG). The patients were treated with a uniform program consisting of 1g/kg of IVlG on day 1and day 2, followed by 1 g/kg on day 15. Most patients had pretreatment bleeding symptoms, which included petechiae, spontaneous and traumatic ecchymoses, gum bleeding, and epistaxis. Median baseline platelet count was 17,000/mm3(range 3-61 ,000/mm3). After the infusion of the IGIV, all patients had a resolution of their bleeding by day 8. The median maximum platelet count achieved with the IGlV was 220,000/mm3 (range 76-426,000/ mm3). No patient achieved either a sustained complete or partial remission after the conclusion of the IVlG therapy. Toxicities were minimal with the majority being headache and nausea. In conclusion, patients with sexually transmitted HIV infection and immune thrombocytopenia respond favorably to WIG. This treatment should be considered as first-line therapy for patients with HIV-related immune thrombocytopenia who require immediate but temporary increase in their platelet count, attributable to symptoms or signs of clinical bleeding or because of the need for an invasive procedure. Key words: thrombocytopenia, HIV infection, intravenous gammaglobulin INTRODUCTION Infection by the human immunodeficiency virus (HIV) is manifest by a spectrum of clinical diseases. Hematologic abnormalities include anemia, leukopenia, thrombocytopenia, and coagulation abnormalities [ 1-71. Thrombocytopenia may be the initial manifestation of HIV disease in up to 1 1 % of infected patients . The etiology of thrombocytopenia is multifactorial, including immune-mediated peripheral destruction, splenic sequestration, decreased megakaryocytopoiesis, and in some instances, drug-related causes as well [9-141. Most patients may be asymptomatic or may present with only minor manifestations of bleeding. Only rarely do patients exhibit severe bleeding, but cranial hemmorhage or symptomatic gastrointestinal bleeding can be seen "7 ,9,141. The treatment of immune associated HIV thrombocytopenia is not well established. Corticosteroids will produce a rise in platelet count in most patients [15,16] but rarely produce a sustained remission; furthermore, long-term use of steroids may complicate the underlying HIV-induced immunodeficiency. Splenectomy may also 0 1991 Wiley-Liss, Inc. induce short-term remissions in up to 90% of the patients , but late relapses may occur 1181. A more rapid progression of the HIV infection in splenectomized patients has been seen by some investigators [ 191 but not by others . The use of vincristine results in a minor response rate but the neuropathic toxicity may limit its clinical value 1211. Danazol has had only minor activity in patients with HIV-related thrombocytopenia . The protein A immunoadsorption column 1231 and anti-Rh antibodies  have also been used to treat patients with HIV-related thrombocytopenia, although data are rather limited. Recently, zidovudine (ZDV) has been shown to improve the thrombocytopenia in up to 90% of HIVinfected patients [25-301. Intravenous gammaglobulin (IVIG) has been used widely in patients with classic autoimmune thrombocy- Received for publication January 2, 1991; accepted May 16, 1991. Address reprint requests to Dr. Mark U. Rarick, USC School of Medicine, Norris Cancer Hospital, 1441 Eastlake Ave., Rrn. 162, Los Angeles, CA 90033. 262 Rarick et al. topenia. Most patients will respond to gammaglobulin, and long-term remissions occasionally can be seen [31341. IVIG has also been used successfully in patients with HIV-related thrombocytopenia [35,36]. These reports have included patients with thrombocytopenia who consist of a spectrum of groups at risk of HIV infection, including homosexual and bisexual men, hemophiliacs, and IV drug users. Since preliminary evidence suggests that the mechanism of HIV-thrombocytopenia may differ depending on the risk factor for HIV infection, it is possible that response rates to IVIG in these groups may also differ [ 141. In the current study, a uniform group of patients with sexually transmitted HIV infection and severe thrombocytopenia (<30,000/mm3) were treated with IVIG in order to ascertain the response rate, toxicities, and long-term efficacy in this subgroup of patients. MATERIAL AND METHODS Patients For the purpose of this study, patients were included if they had documented HIV infection via sexual transmission and severe thrombocytopenia, as defined by a platelet count of <30,000/mm3 on two occasions at least 1 week apart. All patients underwent bone marrow aspirate and biopsy, the results of which were required to be consistent with immune thrombocytopenia, without evidence of other underlying pathologic process. Patients with vitamin deficiencies (B 12 and folate) were excluded, as were those with opportunistic infections or neoplasms requiring cytotoxic drug therapy. Patients were required to have received no therapy for thrombocytopenia for at least 4 weeks. At the time of the study, the effect of ZDV on thrombocytopenia was unknown. Therefore, patients who met the licensed indicators for ZDV at the time of the study (previous episode of Pneumocystis carinii pneumonia or CD4+ lymphocyte count of <200/mm3) and met the above entrance criteria were eligible for study inclusion. Drug Regimen and Definition of Response A treatment cycle of intravenous gammaglobulin (IVIG), (Gamimune-N, 5 % , Cutter Biologic, pH 4.25) was defined as 1 g/kg IVIG administered intravenously on day 1 and day 2, followed by 1 g/kg on day 15. Maintenance therapy followed, consisting of 1 g/kg IVIG every 3 weeks for three additional treatments. The infusion rate of IVIG did not exceed 0.4 ml/kg/min. A complete remission was defined as development of a platelet count of >150,000/mm3, sustained for 1 month. Partial remission was defined as a rise in platelet count to >50,000, but <150,000, sustained for 1 month. A relapse of thrombocytopenia was defined as development of a platelet count of <50,000/mm3 at any time. Since the initial seven patients had all relapsed by the time of the first 3-week maintenance dose, the schedule of IVIG was changed for the subsequent seven patieqts to 1 g/kg IVIG on the first and second day of their treatment, followed by 1 g/kg every 2 weeks for four doses (total of six doses of IVIG). Patients were then followed once a month for 3 months and assessed for sustained response and toxicity. Laboratory Monitoring Platelet counts were obtained at baseline and prior to each dose of IVIG. Platelet bound IgG and IgM were measured by direct immunofluorescence . Serum anti-platelet IgG was measured by indirect immunofluorescence. The number of peripheral blood CD4+ lymphocytes was analyzed by flow cytometry . Quantitative IgG, IgA, and IgM were measured at baseline and prior to each treatment cycle, as were circulating immune complexes, determined by the pethyethylene glycol (PEG) method . Statistical Methods The response variable was the platelet count at day 15, maximum value over baseline, and day of last follow-up. The explanatory variables were baseline platelet count, CD4+ lymphocyte count at baseline and D15, platelet antibody titers at baseline and D15, and quantitative immunoglobulins also at baseline and D15. Platelet counts were plotted as a function of time. Scatter plots were drawn to display any possible associations between the response and the explanatory variables. To evaluate quantitatively the association of the explanatory variables with the response, the WilcoxonMann-Whitney test was used . All P values were two-sided. RESULTS Fourteen patients with HIV infection were enrolled and received a total of 104 doses of IVIG. Patient characteristics are demonstrated in Table I. There were 13 males and 1 female, with a median age of 27 years (range 23-37 years). The risk factor for HIV infection was through sexual transmission in all cases. The majority of the patients had a history of relatively minor bleeding, consisting of petechiae in 64%, spontaneous ecchymoses in 29%, traumatic ecchymoses in 7 I %, gum bleeding in 64%, and epistaxis in 36%. One patient had history of headaches; a computed tomographic (CT) scan revealed a possible intracranial bleed, although a magnetic resonance imaging (MRI) scan was normal. One patient had no bleeding history. Ten of the patients (72%) had received no prior therapy for immune thrombocytopenia. Three patients (21%) had received IVIG in the past for thrombocytopenia, and one lGlV Use in HIV-Related Immune Thrombocytopenia 263 TABLE 1. Patient Characteristics* Patient Prior TCP treatment HIV stage 5 Mild headache 1 31 M Danazol [I1 1. 2. 3. 4. 2 26 M IVIG 3 months prior I11 1. Petechiae 2. Gum bleeding PGL 11 Mild diarrhea for 24 hr after infusion 3 21 M IVIG 4 months prior 111 Nausea, mild headache 25 M None 111 PGL Petechiae Ecchymoses PGL 13 4 1. 2. 3. 1. 2. 3. 5 26 M None IVA 1. Petechiae 2. Spontaneous ecchymoses 3. Gum bleeding PGL Hairy leukoplakia 10 6 25 M IVIG 2 months prior I11 6 Headache 33 None PGL 6 None None I 11 111 Petechiae Post-traumatic ecchymoses Gum bleeding Post-traumatic ecchymoses PGL Ecchymoses I 1. 2. 3. I. I. 2. 1. 2. Post-traumatic ecchymoses Epistaxis PGL 9 None PGL 6 Mild phlebitis PGL 6 None 8 31 9 33 M None 111 10 26 F None I11 Petechiae Traumatic ecchymoses Gum bleeding Epistaxis Petechiae Traumatic ecchymoses Gum bleeding Petechiae Post-traumatic bruises Headache with questionable intracranial hemorrhage by CT scan; MRI negative Petechiae Post-traumatic ecchymoses 3. Gum bleeding + spontaneous 1 . Ecchymoses: spontaneous, P.E. Toxicity Sex M M Bleeding # Doses ( I g/kg) Age PGL Petechiae 6 None Nausea traumatic 2. Epistaxis IVA 1. Petechiae 2. Post-traumatic ecchymoses 3. Gum bleeding PGL Petechiae, gum bleeding 6 None M AZT stopped prior to Rx 1 wk restarted D43 of protocol None 111 1. Petechiae 2. Ecchymoses, post-traumatic, spontaneous 3. Gum bleeding 4. Epistaxis PGL Petechiae, ecchymoses 6 Pruritis X5 min mild headache 23 M None I11 None PGL 9 Mild swelling at injection site Transient disorientation Mild headache <24 hr 32 M None 111 1. Gum bleeding 2. Epistaxis PGL 9 Headache X2 11 26 M 12 36 13 14 * TCP, thrombocytopenia; PGL, persistent generalized lymphadenopathy. Rarick et al. 264 P L A 1 E L E T C 0 U n T X 1 0 0 0 - l i 5 8 *MEDIAN 29 36 CYCS DAY f MAX + MIN Fig. 1. Median platelet count cycle 1. Days 1, 2, 5,8,15,29, and 36. patient (7%) had received Danazol. There was only one patient who had received ZDV. This patient had stage IVA HIV infection with T4 cells <200/mm3. He had discontinued the ZDV one week prior to study entry because of symptomatic ZDV toxicity consisting of nausea and headache. On physical examination, generalized lymphadenopathy was seen in all (100%) patients. The only other HIV related abnormality was hairy leukoplakia in one patient. Other abnormalities on exam consisted of petechiae in four patients (29%), mild ecchymoses in three patients (21%), and active gum bleeding in one patient (7%)). Figure 1 demonstrates the median platelet count at baseline and throughout the first two treatment cycles. As shown, the median baseline platelet count was 17,000/ mm3 (range 3-61 ,000/mm3), the median maximum platelet count achieved was 220,000/mm3 (range 7 6 426,000/mm3), at a median time of day 8 (range D3D29). Although none of the patients achieved a formal complete or partial remission, all patients experienced a platelet count rise of 55 ,00W07,000/mm3 (median rise of 158,000/mm3).Clinical bleeding present at baseline resolved in all patients by day 8. One patient underwent extraction of two wisdom teeth while on therapy, with no bleeding complications from the surgical procedure. No patient achieved a sustained complete or partial remission of thrombocytopenia after 1 month off therapy. Toxicities experienced from the IVIG were minima1 and consisted of headache during the infusion in five (36%), nausea in two (14%),and one episode each of diarrhea, phlebitis, pruritis, swelling at the injection site, and mild disorientation. Five patients (36%) experienced no toxicity whatsoever. In comparison to baseline, there was no statistical change in CD4+ lymphocyte count, platelet antibody titers, or quantitative immunoglobulins, as shown in Table 11, although there was a tendency toward a greater rise in platelet count in patients who had lower baseline levels of platelet bound antibody and immunoglobulins ( P = 0.09). TABLE 11. Clinical Values of Study Patients Median platelet count (/mm3) X lo3 (range) CD4 lymphocyte count (/mm3) (range) Platelet-bound IgG (RF)" (range) Platelet-bound IgM (RF)" (range) Serum antiplatelet ATB (RF)a (range) PEG immune complexb (/*g/ml) IgG' (mg/dl) Range IgA' (mg/dl) Range lgMC(mg/dl) Range Baseline Dav 15 17 (3-61) 377 (154-909) 2.7 (1.5-13.9) 3.35 (0.8-14.8) 1.2 (0.7-5.4) 40 (19-217) 105 (30-470) 2,120 (1 ,460-5,270) 2.50 (14 1-694) 207 ( I 14-634) "RF, reference range; normal <1.5. bNormal <30 pg/ml. 'Normal IgG, 600-2,000 mg/dl; IgM, 50-400 mg/dl; IgA, 40-250 mg/dl. 3.5 (1.3-22.7) 4.8 (1.3-19.5) 1 .o (0.4-5.3) 56 (30-980) 2,890 (2.330-4,690) 275 (1 19-675) 219 (95-676) IGlV Use in HIV-Related Immune Thrombocytopenia DISCUSSION The optimal therapy for thrombocytopenia in an HIVinfected patient must incorporate the state of underlying immunodeficiency. Previously, corticosteroids were often used in this setting. However, with the known immunosuppressive effects of corticosteroids, and the recent evidence indicating an association of Kaposi’s sarcoma with glucocorticoids , the use of this modality may not be optimal. Short-term follow-up of patients undergoing splenectomy for HIV-related immune thrombocytopenia has shown a response rate of 90% . However, long-term study is needed to understand fully the impact of splenectomy on the subsequent course of these immunocompromised patients, since earlier development to acquired immunodeficiency syndrome (AIDS) has been reported after splenectomy. In the present study, all patients with sexually transmitted HIV-related thrombocytopenia responded within 8 days to IVIG infusion. Although the response was short-lived, it is apparent that patients requiring an immediate increase in platelet count may be well managed with IVIG infusion. The long-term response rate of IVIG is disappointing, however. Interestingly, patients with non-HIV-related immune thrombocytopenia may achieve long-term remissions with the use of IVIG infusions. The reason that patients with HIV immunothrombocytopenia relapse quickly after IVIG is unknown but may include the severity of persistent immunodeficiency, sustained elevated levels of circulating immune complexes, and/or persistent B-cell dysregulation with production of high titers of antiplatelet antibodies. The mechanism of action of IVIG in each of the immune-related thrombocytopenias may include interference with the reticuloendothelial system or macrophage Fc receptor, inactivation of antiplatelet antibodies, decrease in natural killer (NK) cell activity, and decrease in platelet antibody synthesis . In our study, we did not observe changes in platelet bound antibodies or circulating immune complexes. Recent reports indicating the efficacy of ZDV [24-291 and interferon-y (IFN-a) [48,49] in patients with HIVrelated immune thrombocytopenia are encouraging. Combined therapy using IVIG with ZDV or IFN-a may ameliorate the early relapse seen in patients treated with IVIG alone. 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