Clinical Features Related to Antiphospholipid Syndrome in Patients with Chronic Viral Infections (Hepatitis C Virus/HIV Infection): Description of 82 Cases

Clinical Infectious Diseases, Apr 2004

Ramos-Casals, Manuel, Cervera, Ricard, Lagrutta, Mariana, Medina, Francisco, García-Carrasco, Mario, de la Red, Gloria, Bové, Albert, Ingelmo, Miguel, Font, Josep

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Clinical Features Related to Antiphospholipid Syndrome in Patients with Chronic Viral Infections (Hepatitis C Virus/HIV Infection): Description of 82 Cases

Clinical Features Related to Antiphospholipid Syndrome in Patients with Chronic Viral Infections (Hepatitis C Virus/HIV Infection): Description of 82 Cases Manuel Ramos-Casals 1 Ricard Cervera 1 Mariana Lagrutta 1 Francisco Medina 0 Mario Garc´ıa-Carrasco 1 Gloria de la Red 1 Albert Bov e´ 1 Miguel Ingelmo 1 Josep Font 1 0 Department of Rheumatology, Hospital de Especialidades, Centro Me ́dico Nacional Siglo XXI , Mexico DF , Mexico 1 Department of Autoimmune Diseases, Institut d'Investigacions Biome`diques We analyzed the spectrum of clinical features related to antiphospholipid syndrome (APS) in patients with chronic viral infections, such as hepatitis C virus (HCV) infection and human immunodeficiency virus (HIV) infection. We selected patients from the HISPAMEC registry who repeatedly tested positive for antiphospholipid antibodies (aPL) and who had features of APS, and we searched the MEDLINE database for additional cases. A total of 82 patients were included (45 had chronic HCV infection, 32 had HIV infection, and 5 had HCVHIV coinfection). The main features of APS were avascular bone necrosis (20 patients), peripheral thrombosis (17), thrombocytopenia (15), neurologic features (13), cardiac manifestations (12), pulmonary embolism (9), gastrointestinal manifestations (8), and cutaneous manifestations (8). The main APS-related features in HCVinfected patients were intraabdominal thrombosis and myocardial infarction, whereas, in HIV-infected patients, the main features were avascular bone and cutaneous necrosis. These viruses might act in some patients as chronic triggering agents that induce a heterogeneous, atypical presentation of APS. - Antiphospholipid syndrome (APS) is an autoimmune disease characterized by arterial or venous thrombosis and often by multiple fetal losses and (usually moderate) thrombocytopenia, in association with presence of antiphopholipid antibodies (aPLs) (mainly anticardiolipin antibodies [aCLs] and lupus anticoagulant [LA]) [ 1 ]. aPLs have also been detected in patients with acute and chronic infections and malignant diseases, and their presence has been associated with use of some medications [ 2 ]. Infectious agents have recently been implicated in the pathogenesis of APS, particularly in its catastrophic form, and intercurrent bacterial infections might constitute one of the main precipitating factors of the catastrophic response in some patients [ 3 ]. However, the etiopathogenic role of chronic viral diseases, such as hepatitis C virus (HCV) infection and HIV infection, has been little studied in association with APS. HCV infection has been associated with some systemic autoimmune diseases, such as Sjo¨gren syndrome [ 4 ], rheumatoid arthritis [ 5 ], and systemic lupus erythematosus [ 6 ]. Nevertheless, its association with APS is controversial [ 7 ], and although the presence of aPLs in patients with chronic HCV infection is common, it is rarely associated with thrombotic events [ 8 ]. HCV HCV HCV HCV HCV HCV HCV HCV Study, patient Buskila et al. [ 17 ]: 59 Puri et al. [ 33 ]: 60 Baid et al. [ 14 ] 61 62 63 64 65 Orbea-Rios et al. [ 31 ]: 66 Cailleux et al. [ 18 ]: 67 Gonzalez et al. [ 23 ]: 68 Fickert et al. [ 22 ]: 69 Hernandez et al. [ 24 ]: 70 Leder et al. [ 26 ]: 71 Turhal et al. [ 37 ] 72 73 74 75 Brown et al. [ 16 ] 76 77 78 Panuk et al. [ 32 ]: 79 Calza et al. [ 19 ] 80 81 82 HCV HCV HCV HCV HCV HCV HCV HIV HIV HIV HCV HCV HIV HIV HIV HIV HIV HIV HIV HIV HCV HIV HIV HIV Similarly, a high prevalence of aPLs with a low frequency of associated thrombosis has also been noted among patients with HIV infection [ 3 ]. We report 21 new cases of chronic viral infection with APSrelated clinical or hematological manifestations. In addition, we review the literature for additional cases, with the aim of characterizing the spectrum of clinical manifestations related to APS in patients with HCV and/or HIV infection. PATIENTS AND METHODS In 2001, several reference centers from Spain and Latin American countries with substantial experience in the management of autoimmune diseases associated with chronic viral infection constituted the Hispanoamerican Study Group of Autoimmune Manifestations of Chronic Viral Disease (HISPAMEC), with the aim of creating a registry of patients with coexisting systemic autoimmune diseases and HCV and/or HIV infection. From the HISPAMEC registry, we selected patients who presented with repeated test results positive for aPLs together with clinical features of APS. The diagnosis of APS was based on the preliminary classification criteria proposed in 1999 by Wilson et al. [ 9 ], although some patients who received diagnoses before 1999 met the criteria proposed by Harris et al. [ 10 ], which included thrombocytopenia. A diagnosis of catastrophic APS was considered when a patient presented with acute devastating APS with multiple organ involvement (13 organs), as recently defined [ 11 ]. We defined the different clinical and analytical manifestations on the basis of the largest published clinical description of APS [ 12 ]. HIV/AIDS • CID 2004:38 (1 April) • 1011 In addition, we searched the MEDLINE database for articles published during the period of January 1980 through August 2003 using the search terms “antiphospholipid syndrome,” “antiphospholipid antibodies,” “anticardiolipin antibodies,” “lupus anticoagulant,” “thrombosis,” “infarction,” “thrombocytopenia,” “fetal loss,” “HCV,” “HTLV-III,” “retroviruses,” and “HIV.” We identified additional articles through an exhaustive hand search of the bibliographies of the retrieved articles. Only well-documented cases were finally included in our study. RESULTS Characteristics of HISPAMEC patients. We identified 21 patients (12 of whom had chronic HCV infection, 6 of whom had HIV infection, and 3 of whom had HCV-HIV coinfection) who presented with repeated test results positive for aPLs and APS-related clinical features. Thirteen patients (62%) were men, and 8 (38%) were women, with a mean age at the time of APS diagnosis of 40.8 years (range, 29–73 years). Three patients presented with HCV-associated SLE. APS was diagnosed in 20 patients with a previously known HCV-HIV infection, with the main clinical features leading to APS diagnosis being thrombotic phenomena (n p 9), thrombocytopenia (n p 3), detection of aPLs in a patient with a past history of miscarriages (n p 1), and other causes (n p 7). In the remaining patient, APS was diagnosed before HCV infection, which was detected on the basis of elevated transaminase levels. The clinical manifestations of APS were peripheral venous thrombosis in 5 patients, avascular bone necrosis in 5, pulmonary embolism in 4, fetal loss in 4, severe cytopenia in 4, stroke in 2, myocardial infarction in 2, optic neuropathy in 2, digital ischemia in 1, and portal/splenic venous thrombosis in 1. One patient presented with catastrophic APS with multiorgan thrombotic manifestations (cardiac, pancreatic, splenic, hematological, and renal). Other clinical features were malar rash (n p 2), oral ulcers (n p 2), cutaneous vasculitis (n p 2), CNS involvement (n p 2), articular involvement (n p 1), glomerulonephritis (n p 1), and serositis (n p 1). Hematological features included anemia (hemoglobin level, !10 g/dL; 6 patients [29%]), leukopenia (leukocyte count, !4 109 leukocytes/L; 3 patients [14%]), and thrombocytopenia (platelet count, !150 109 platelets/L; 9 patients [43%]), which was severe (!30 109 platelets/L) in 4 patients. Nineteen patients tested positive for aCLs at medium/high titers, and 10 tested positive for LA. Characteristics of all identified patients. Table 1 shows the main characteristics of 82 patients with chronic viral infections presenting APS-related manifestations (the aforementioned cases plus 61 well-defined cases identified in the literature search) [ 7, 13–38 ]. Forty-five patients (55%) presented with chronic HCV infection, 32 (39%) presented with HIV 1012 • CID 2004:38 (1 April) • HIV/AIDS infection, and 5 (6%) presented with HCV-HIV coinfection. Seven patients presented with associated autoimmune diseases, such as systemic lupus erythematosus (4 patients), vasculitis (2 patients; polyarteritis nodosa and leukocytoclastic vasculitis), and Crohn disease (1 patient). Epidemiological data were available for 65 patients: 41 patients (63%) were male, and 24 (27%) were female, with a mean age of 37.4 years (range, 4–77 years). APS-related features are summarized in table 2 and included avascular bone necrosis (20 patients [24%]), fetal losses (5 [21%] of 24 female patients), peripheral thrombosis (17 patients [21%]; deep vein thrombosis in 15 patients, superficial thrombophlebitis in 2, and arterial thrombosis in 2), thrombocytopenia (15 patients [20%]), neurologic features (13 patients [16%], including stroke in 10 patients, migraine in 4, transient ischemic attack in 2, and epilepsy in 2), cardiac manifestations (12 patients [15%]; myocardial infarction in 11 patients and valvular vegetations in 1), pulmonary embolism (9 patients [11%]), gastrointestinal manifestations (8 patients [10%]; splachnic venous thrombosis in 5 patients, mesenteric ischemia in 1, splenic infarction in 1, and splenic vein thrombosis in 1), cutaneous manifestations (8 patients [10%]; cutaneous necrosis in 5 patients, livedo reticularis in 2, and digital gangrene in 1), renal manifestations (5 patients [6%]; renal thrombotic microangiopathy in 5 patients, renal vein thrombosis in 2, and renal artery thrombosis in 1), ophthalmic manifestations (4 patients [5%]; optic neuropathy in 3 patients and retinal vein thrombosis in 1), and hepatic manifestations (3 patients [4%]; portal thrombosis in 2 patients and Budd-Chiari syndrome in 1). Other features included testicular thrombosis in one patient and catastrophic APS in another. aCLs were present in 80 patients (97%), and LA was present in 17 (57%) of 30 patients. Compared with HIV-infected patients (table 3), HCV-infected patients had a higher mean age (44 vs. 31 years; P p .001) and were more often female (50% vs. 27%; P p .063). HCV-infected patients also had a higher prevalence of cardiac manifestations (27% vs. 0%; P ! .001) and abdominal manifestations (29% vs. 3%; P p .004), as well as a trend toward a higher prevalence of thrombocytopenia (22% vs. 6%; P p .057). In contrast, HCV-infected patients had no bone involvement (0% vs. 59%; P ! .001) and showed a trend toward a lower prevalence of skin involvement (4% vs. 16%; P p .092). DISCUSSION HCV and HIV are considered the causes of the 2 major epidemic viral infections in the past 2 decades, with a recent phenomenon being the increasing description of autoimmune features in HCV- and HIV-infected patients. On the one hand, chronic HCV infection has been associated with detection of autoantibodies and systemic autoimmune diseases [ 4–6 ]. On the other hand, the use of HAART therapy is giving rise to a substantial change in the clinical spectrum of HIV infection, in which, as in chronic HCV infection, an increasing frequency of associated autoimmune and lymphomatous processes is being described [ 39 ]. The persistent stimulation of the immune system triggered by these chronic viral infections may favor the development of autoimmune manifestations. Historically, aPLs have always being closely associated with infectious agents: they were first detected in serum samples obtained from patients with syphilis [ 40 ]. Later, in a review of APS cases in patients with viral infections, Uthman and Gharavi [ 41 ] identified isolated cases associated with such viruses as cytomegalovirus, varicella zoster virus, and Epstein-Barr virus. Recently, the possible association of APS with chronic viral infections (e.g., HCV and/or HIV infection) has generated growing interest, but this is still controversial. In spite of the infrequent association of APS with HCV infection [ 42 ], we describe a total of 45 HCV-infected patients with APS, a number that has allowed the clinical characterization of this small subset of patients with APS. In comparison with patients in general studies of APS [ 12 ], the HCV-infected patients with APS in our study had a higher mean age and a differentiated clinical spectrum of thrombotic involvement; furthermore, they had a lower frequency of the more typical features of APS, such as peripheral thrombosis and neurological features, and, in contrast, a higher prevalence of atypical or infrequent features of APS, such as myocardial infarction and intraabdominal thrombotic events. In addition, in patients with APS and HCV infection, we observed a higher frequency of positive immunological markers that are often detected in chronic HCV infection, such as antinuclear antibodies (77% of our patients and 46% of the total patients), cryoglobulins, hypocomplementemia, and rheumatoid factor (75%, 58%, and 50% of our patients, respectively). Cryoglobulinemia is closely associated with HCV infection, but its possible role in the development of APS-related features has been little studied [ 6, 37 ]. The higher presence of LA in patients with APS and HCV infection (80%) may well explain the occurrence of thrombotic events in this subset of HCV-infected patients, because its prevalence in unselected series of HCV-infected patients is extremely low (!1%). We also present data on 31 HIV-infected patients with APS, 5 (16%) of whom had HIV-HCV coinfection. Analysis of APSrelated features in HIV infection shows a similar pattern to those in HCV infection, with a higher frequency of test results positive for aPLs combined with a very infrequent rate of thrombotic events and APS [ 40 ]. The first evidence of APSHIV/AIDS • CID 2004:38 (1 April) • 1013 related features in HIV infection came from the studies of thennamed HTLV-III infection in the United States in the 1980s [ 43–45 ]. However, the few reports of thrombotic events in HIVinfected patients are mostly related to extrinsic causes, such as opportunistic infections and metabolic disturbances after HAART therapy [ 40 ]. Other factors, such as decreased levels of functional protein C or acquired protein S deficiency, have also been implicated [ 3 ], showing a multifactorial origin of HIV-related thrombosis, with aPLs playing a limited role, as evidenced by the 31 HIV-infected patients with APS features presented in this study. Clinical characterization of HIV-related APS includes a predominance of male patients, with a mean age of 30 years and, like HCV-related APS, with a more heterogeneous clinical presentation than that observed in large studies of unselected APS patients. However, the pattern of clinical expression of APS in HIV-infected patients is different from that in HCV-infected patients, with a higher frequency of bone and cutaneous involvement and a lower frequency of cardiac and intraabdominal features. Noteworthy is the description of 14 HIV-infected patients with aPL-associated avascular bone necrosis (ABN), given that Tektonidou et al. [ 46 ], using resonance imaging, have recently demonstrated a higher prevalence of asymptomatic ABN in patients with primary APS, suggesting that clinicians should be alert to the possibility of this unusual manifestation of APS in patients with both primary and HIV-related APS. Only 1 (1.3%) of the 76 patients with APS associated with chronic viral infection developed the catastrophic form of APS, whose pathogenesis involves several triggering factors, with infections being increasingly described as a major precipitator. The first evidence came from Rojas-Rodrı´guez et al. [ 47 ], who found that bacterial infections were triggering factors for the development of catastrophic APS in 6 of 8 patients, whereas Asherson et al. [ 48 ] found infections (mainly acute) in 28 (35%) of 80 patients with catastrophic APS. This important role of bacterial agents as triggering factors for catastrophic APS may be associated with the acute nature of the infection, which might induce a disproportionate immune response involving superantigen-related mechanisms [ 47 ]. Asherson and Shoenfeld [ 3 ] recently raised the possibility of a molecular mimicry between the infectious agent and some autoantigen, such as b2-GPI. This study has demonstrated a broad spectrum of APSrelated features in patients with chronic viral infections such as HCV and HIV, most of which are considered atypical or are infrequently detected in general series of APS. Compared with the largest published series of unselected patients with APS [ 12 ], HCV-HIV–coinfected patients have a higher frequency of specific APS-related features, such as myocardial infarction, cutaneous necrosis, renal microangiopathy, avascular bone necrosis, and optic neuropathy, and, in contrast, a lower frequency 1014 • CID 2004:38 (1 April) • HIV/AIDS of more typical features of APS, such as peripheral thrombosis, neurological features, livedo reticularis, or thrombocytopenia (table 4). It may be hypothesized that 2 opposite etiopathogenic situations occur in patients with APS and chronic viral infections. On one hand, several autoimmune phenomena related to HCV/ HIV infections, such as the presence of aPLs, thrombocytopenia, digital ischemia, or cutaneous necrosis, might mimic APS in some patients, or, because of the frequent detection of aPLs in HCV-HIV–coinfected patients, a casual association with thrombotic events might lead to the fulfillment of the APS classification criteria. On the other hand, HCV and HIV might act as etiopathogenic agents for the development of a true APS in a small subset of patients. To differentiate both etiopathogenic associations, determination of b2-GPI antibodies in these patients might play a key role in distinguishing the pathogenic or b2-GPI–dependent aCLs (etiopathogenic association) from the nonpathogenic b2-GPI–independent aCLs (mimicry or casual association). The data presented in this study suggested that APS is infrequently observed in patients with chronic viral diseases in comparison with other systemic autoimmune diseases, such as Sjo¨gren syndrome or systemic lupus erythematosus [ 4, 6 ]. Nevertheless, the progressive use of antiviral therapies will lead to increased chronicity of both these viral infections, with a probable increase in the number of patients presenting with autoimmune features. In the near future, diagnosis and treatment of these processes will present an important clinical challenge in the treatment of patients with chronic HCV and HIV infections. In conclusion, we describe a subset of patients with chronic viral infections (HCV and HIV infections) who presented a specific clinical picture of APS. The main APS-related features in HCV-infected patients were intraabdominal thrombosis and myocardial infarction, whereas, in HIV-infected patients, they were avascular bone and cutaneous necrosis. Infectious agents may play an etiopathogenic role in the clinical expression of some patients with APS, with bacterial infections probably acting as acute triggering agents of a devastating, multiorgan form of APS (catastrophic APS), whereas viruses, such as HCV and HIV, might act in some patients as chronic triggering agents that induce a heterogeneous, atypical presentation of APS. MEMBERS OF THE HISPANOAMERICAN STUDY GROUP OF AUTOIMMUNE MANIFESTATIONS OF CHRONIC VIRAL DISEASE (HISPAMEC) Manuel Ramos-Casals (Coordinator), Mario Garcı´a-Carrasco, Ricard Cervera, Miguel Ingelmo and Josep Font (Department of Autoimmune Diseases, Hospital Clinic, IDIBAPS, School of Medicine, University of Barcelona, Barcelona, Spain); Xavier Forns and Jose Ma Sanchez-Tapias (Department of Hepatology, Hospital Clinic, Barcelona); Armando Lo´ pez-Guillermo (Department of Hematology, Hospital Clinic, Barcelona); Jose Rosas and Gregorio Santos (Rheumatology Unit, Hospital de la VilaJoiosa, Vila-Joiosa, Alacant, Spain); Francisco Medina (Department of Rheumatology, Hospital de Especialidades, Centro Me´dico Nacional Siglo XXI, Mexico DF, Mexico); Luis Javier Jara (Department of Rheumatology, Hospital de Especialidades, Centro Me´dico Nacional La Raza, Mexico DF, Mexico); Juan Manuel Anaya, Rheumatology Unit (Corporacio´ n para Investigaciones Biolo´ gicas and Clı´nica Universitaria Bolivariana, School of Medicine, Universidad Pontificia Bolivariana, Medellı´n, Colombia); and Juan Carlos Restrepo (Hospital Pablo Tobo´ n Uribe and University of Antioquia, Medellı´n, Colombia). 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Ramos-Casals, Manuel, Cervera, Ricard, Lagrutta, Mariana, Medina, Francisco, García-Carrasco, Mario, de la Red, Gloria, Bové, Albert, Ingelmo, Miguel, Font, Josep. Clinical Features Related to Antiphospholipid Syndrome in Patients with Chronic Viral Infections (Hepatitis C Virus/HIV Infection): Description of 82 Cases, Clinical Infectious Diseases, 2004, 1009-1016, DOI: 10.1086/382537