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Systemic Vasculitis With Gastrointestinal Involvement in an HIV-Infected Adult
Systemic Vasculitis With Gastrointestinal Involvement in an HIV-Infected Adult HELEN SAMBATAKOU, MD; DIMITRIS TSIACHRIS, MD; STAMATIA STAMOULI, MD; PANAGIOTIS GARGALIANOS, MD; ATHANASIOS ARCHIMANDRITIS, MD
ABSTRACT: Several types of human immunodeficiency virus (HIV)-associated vasculitides, including polyarteritis nodosa–like syndromes have been reported in patients with HIV infection. The pathogenic mechanism is thought to be related to either circulating immune complexes or direct endothelial involvement by HIV per se. In HIVrelated necrotizing systemic vasculitis, affected arteries are smaller than those seen in classic polyarteritis nodosa, and it rarely becomes a multisystem and life-threatening disease with the exception of cases with heart, kidney, central nervous system, or gut involvement. We describe a case of
systemic necrotizing vasculitis in an HIV-infected individual presented with fever, purpuric rash, and polyarthritis who eventually had development of mesentery artery thrombosis and nephrotic syndrome. The patient, solely under triple antiretroviral therapy, remains symptom free, with no evidence of his multisystem disease and no progression of his HIV infection after 10 years of follow-up. All patients with a vasculitis of unidentified etiology should be evaluated for HIV infection. KEY INDEXING TERMS: Human immunodeficiency virus; Systemic vasculitis; Polyarteritis nodosa; Gastrointestinal tract. [Am J Med Sci 2008;335(3):237–238.]
V
posterior aspects of both legs below the knees (Figure 1), polyarthritis of the knees and ankles, and intermittent fever. Blood tests showed a leukocyte count of 8400 cells/mm3, with 87% segmented neutrophils and a normal platelet count and bleeding times. At the same time, he was found to have 1.07 g of protein excreted in the urine per 24 hours. During the second week of hospitalization, he became acutely ill with severe abdominal pain and rectal bleeding. An abdominal CT scan was negative, and colonoscopy revealed mucosal erosions in rectal and sigmoid colon. He subsequently required a laparotomy with resection of 125 cm of the ileum, and the diagnosis of a mesenteric artery thrombosis was considered at operation. Histological examination revealed a necrotizing vasculitis of small and medium-sized vessels of the gut with ischemia and ulceration without evidence of CMV inclusion bodies (Figure 2). His postoperative course was uneventful. Laboratory investigation revealed positive serology for HIV infection (stage B2, oropharyngeal candidiasis), whereas coinfections such as herpes, hepatitis viruses, CMV and Parvo B19, which could be responsible for vasculitis, were excluded. Funduscopic examination was also negative, although the probability of CMV disease was low with a CD4 count ⬎100 mm3 (CD4 cell count was 142 cells/mm3 and plasma viral load was 217.400 copies/mL). A full immunology screen showed normal immunoglobulin and complement levels, negative ANCA titer, and lupus associated immunology and a mildly elevated ESR of 55 mm/1 h. He had not received any drugs before the initiation of the symptoms. His skin rash was also biopsied and showed a typical leukocytoclastic vasculitis. Immunoperoxidase studies revealed fibrin and C3 deposits in the skin vessels, but of great importance was that there was no evidence of IgA. His renal disease appeared to worsen, developing 12.3 g of proteinuria with a rise in plasma creatinine up to 2 mg/dL but with no requirement of renal dialysis. Renal biopsy revealed findings consistent with Henoch-Schonlein purpura, such as segmental glomerulopathy with crescent formation and areas of necrosis, but no evidence of any vasculitis affecting the vessels. Immunoperoxidase studies revealed IgG and IgA deposits in the capillary walls; some C3 deposit was present but no C4. He initially received 3 pulses of 0.5 g intravenous cyclophosphamide at 3 weekly intervals and was started on relatively high doses of steroids and triple antiretroviral therapy. Six months later, prednisone was permanently discontinued. The patient remained symp-
asculitic syndromes have been reported in 0.4% of patients with human immunodeficiency virus (HIV) infection and are among the disimmunitymediated disorders seen in this group of patients.1 Several types of HIV-associated vasculitides, including necrotizing systemic vasculitis, primary angiitis of the central nervous system, and angiocentric immunoproliferative disorders have been reported.2 The pathogenic mechanism is thought to be related to either circulating immune complexes or direct endothelial involvement by HIV per se.3 In contrast to vasculitides in the general population, little clinical data exist concerning the clinical course, prognosis, and management of these disorders in HIVpositive individuals. Target organ involvement predominantly includes muscles, skin, and nerves and only rarely the gastrointestinal tract. We describe a case of systemic necrotizing vasculitis in an HIV-infected individual who presented with fever, purpuric rash, and polyarthritis, who eventually had development of mesentery artery thrombosis and nephrotic syndrome. Case Report A 33-year-old homosexual man was admitted to the hospital in March 1996 because of purpuric rash affecting both anterior and
From the University of Athens, Second Department of Internal Medicine (HS, DT, AA), Hippokration Hospital, Athens, Greece; and the Department of Internal Medicine (SS, PG), General Hospital of Athens, Athens, Greece. Submitted April 9, 2007; accepted in revised form May 7, 2007. Correspondence: Dr. Dimitris Tsiachris, Second Department of Internal Medicine, Hippokration General Hospital, 114 Vas. Sophias Avenue, 11527 Athens, Greece (E-mail: [email protected]). THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
237
HIV-Related Systemic Vasculitis
Figure 1. Palpable maculopapular rash and ankle arthritis of the right leg.
tom free, with no evidence of multisystem disease and no progression of HIV infection for a period of more than 10 years of follow-up. It is clear that he had some form of systemic vasculitis affecting skin, gut, and to a lesser extent, his kidneys. We suggest that HIV-1 virus is the major etiologic factor for the systemic vasculitis described here, although we cannot formally exclude another infectious etiology such as CMV. Additionally, the clinical and histopathologic findings appear to be compatible with those of Henoch-Schonlein purpura, though the lack of IgA deposition ruled out that diagnosis.
Discussion Polyarteritis nodosa–like syndromes and nonspecific necrotizing vasculitides are the most commonly described entities in HIV-positive patients. Classic polyarteritis nodosa (c-PAN) is a multisystem necrotizing vasculitis of small and medium-sized muscular arteries with characteristic involvement of renal and visceral arteries. In HIV-associated PAN, affected arteries tend to be smaller than those seen in c-PAN, and muscles, nerves, and skin are the major target organs.2,3 The usual clinical course of c-PAN, characterized either by fulminant deterioration or by relentless progression with acute flare-ups, is not typically seen in the HIV population.4 In fact, it seems that HIV-related PAN rarely becomes a multisystem and life-threatening disease, with the ex-
Figure 2. Histology of sections of small intestine showing marked infiltration of lymphocytes, neutrophils, and histiocytes and lesions of necrotizing vasculitis with fibrinoid necrosis of the vessel wall.
238
ception of some cases with heart, kidney, central nervous system, or gut involvement.5 Pathogenic mechanisms for HIV-associated vasculitic syndromes include direct action of HIV on endothelial cells (isolation of HIV-RNA and p24 antigen on vascular lesions), an excess of CD8 T-cells, and/or immune complexes, possibly involved at different stages of the disease.2,6,7 In particular, immunohistopathologic studies on specimens in HIV-associated PAN showed CD8 T-cell infiltrate in the center of the lesions and macrophages in the periphery, whereas the direct immunofluorescence revealed deposition of IgM immune complexes in the vessel walls.6 Interestingly, serology for HBV is invariably negative despite its high prevalence in HIV patients, minimizing the role of HBV in the development of PAN in this setting.2 Corticosteroid therapy alone or with a cytotoxic drug, especially in cases with renal or abdominal vessels involvement, seems to be the treatment of choice. Intravenous gamma globulin and plasmapheresis may also be effective alternative treatments. Initiation of antiretroviral therapy in HIVpositive patients with PAN, not already on highly active antiretroviral therapy, is of great importance. The co-occurrence of vasculitis and HIV infection, 2 diseases affecting the immune system, is an opportunity to gain specific insight into the pathogenesis as well as also a challenge to the clinician to diagnose and treat the combined diseases instead of each disorder singly. Because of the relatively good prognosis and the broad spectrum of nonspecific clinical manifestations commonly reported from HIV individuals without underlying vasculitis, some cases of HIV-related vasculitis could remain underdiagnosed, because histopathological examination is rarely carried out. All patients with a vasculitis of unidentified etiology should be evaluated for HIV infection. References 1. Munoz Fernandez S, Cardenal A, Balsa A, et al. Rheumatic manifestations in 556 patients with human immunodeficiency virus infection. Semin Arthritis Rheum 1991;21:30–9. 2. Calabrese L. Vasculitis and infection with the human immunodeficiency virus. Rheum Dis Clin North Am 1991;17:131–47. 3. Gherardi RK, Mhiri C, Baudrimont M, et al. Iron pigment deposits, small vessel vasculitis, and erythrophagocytosis in the muscle of human immunodeficiency virus-infected patients. Hum Pathol 1991;22:1187–94. 4. Libman BS, Quismorio FP, Stimmler MM. Polyarteritis nodosa-like vasculitic in human immunodeficiency virus infection. J Rheumatol 1995;22:351–5. 5. Font C, Miro O, Pedrol E, et al. Polyarteritis nodosa in human immunodeficiency virus infection: report of four cases and review of the literature. Br J Rheumatol 1996;35:796–9. 6. Gherardi R, Belec L, Mhiri C, et al. The spectrum of vasculitis in human immunodeficiency virus-infected patients: a clinicopathologic evaluation. Arthritis Rheum 1993;36:1164–74. 7. Massari M, Salvarani C, Portioli I, et al. Polyarteritis nodosa and HIV infection: no evidence of a direct pathogenic role of HIV. Infection 1996;24:159–61.
March 2008 Volume 335 Number 3
ABSTRACT: Several types of human immunodeficiency virus (HIV)-associated vasculitides, including polyarteritis nodosa–like syndromes have been reported in patients with HIV infection. The pathogenic mechanism is thought to be related to either circulating immune complexes or direct endothelial involvement by HIV per se. In HIVrelated necrotizing systemic vasculitis, affected arteries are smaller than those seen in classic polyarteritis nodosa, and it rarely becomes a multisystem and life-threatening disease with the exception of cases with heart, kidney, central nervous system, or gut involvement. We describe a case of
systemic necrotizing vasculitis in an HIV-infected individual presented with fever, purpuric rash, and polyarthritis who eventually had development of mesentery artery thrombosis and nephrotic syndrome. The patient, solely under triple antiretroviral therapy, remains symptom free, with no evidence of his multisystem disease and no progression of his HIV infection after 10 years of follow-up. All patients with a vasculitis of unidentified etiology should be evaluated for HIV infection. KEY INDEXING TERMS: Human immunodeficiency virus; Systemic vasculitis; Polyarteritis nodosa; Gastrointestinal tract. [Am J Med Sci 2008;335(3):237–238.]
V
posterior aspects of both legs below the knees (Figure 1), polyarthritis of the knees and ankles, and intermittent fever. Blood tests showed a leukocyte count of 8400 cells/mm3, with 87% segmented neutrophils and a normal platelet count and bleeding times. At the same time, he was found to have 1.07 g of protein excreted in the urine per 24 hours. During the second week of hospitalization, he became acutely ill with severe abdominal pain and rectal bleeding. An abdominal CT scan was negative, and colonoscopy revealed mucosal erosions in rectal and sigmoid colon. He subsequently required a laparotomy with resection of 125 cm of the ileum, and the diagnosis of a mesenteric artery thrombosis was considered at operation. Histological examination revealed a necrotizing vasculitis of small and medium-sized vessels of the gut with ischemia and ulceration without evidence of CMV inclusion bodies (Figure 2). His postoperative course was uneventful. Laboratory investigation revealed positive serology for HIV infection (stage B2, oropharyngeal candidiasis), whereas coinfections such as herpes, hepatitis viruses, CMV and Parvo B19, which could be responsible for vasculitis, were excluded. Funduscopic examination was also negative, although the probability of CMV disease was low with a CD4 count ⬎100 mm3 (CD4 cell count was 142 cells/mm3 and plasma viral load was 217.400 copies/mL). A full immunology screen showed normal immunoglobulin and complement levels, negative ANCA titer, and lupus associated immunology and a mildly elevated ESR of 55 mm/1 h. He had not received any drugs before the initiation of the symptoms. His skin rash was also biopsied and showed a typical leukocytoclastic vasculitis. Immunoperoxidase studies revealed fibrin and C3 deposits in the skin vessels, but of great importance was that there was no evidence of IgA. His renal disease appeared to worsen, developing 12.3 g of proteinuria with a rise in plasma creatinine up to 2 mg/dL but with no requirement of renal dialysis. Renal biopsy revealed findings consistent with Henoch-Schonlein purpura, such as segmental glomerulopathy with crescent formation and areas of necrosis, but no evidence of any vasculitis affecting the vessels. Immunoperoxidase studies revealed IgG and IgA deposits in the capillary walls; some C3 deposit was present but no C4. He initially received 3 pulses of 0.5 g intravenous cyclophosphamide at 3 weekly intervals and was started on relatively high doses of steroids and triple antiretroviral therapy. Six months later, prednisone was permanently discontinued. The patient remained symp-
asculitic syndromes have been reported in 0.4% of patients with human immunodeficiency virus (HIV) infection and are among the disimmunitymediated disorders seen in this group of patients.1 Several types of HIV-associated vasculitides, including necrotizing systemic vasculitis, primary angiitis of the central nervous system, and angiocentric immunoproliferative disorders have been reported.2 The pathogenic mechanism is thought to be related to either circulating immune complexes or direct endothelial involvement by HIV per se.3 In contrast to vasculitides in the general population, little clinical data exist concerning the clinical course, prognosis, and management of these disorders in HIVpositive individuals. Target organ involvement predominantly includes muscles, skin, and nerves and only rarely the gastrointestinal tract. We describe a case of systemic necrotizing vasculitis in an HIV-infected individual who presented with fever, purpuric rash, and polyarthritis, who eventually had development of mesentery artery thrombosis and nephrotic syndrome. Case Report A 33-year-old homosexual man was admitted to the hospital in March 1996 because of purpuric rash affecting both anterior and
From the University of Athens, Second Department of Internal Medicine (HS, DT, AA), Hippokration Hospital, Athens, Greece; and the Department of Internal Medicine (SS, PG), General Hospital of Athens, Athens, Greece. Submitted April 9, 2007; accepted in revised form May 7, 2007. Correspondence: Dr. Dimitris Tsiachris, Second Department of Internal Medicine, Hippokration General Hospital, 114 Vas. Sophias Avenue, 11527 Athens, Greece (E-mail: [email protected]). THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
237
HIV-Related Systemic Vasculitis
Figure 1. Palpable maculopapular rash and ankle arthritis of the right leg.
tom free, with no evidence of multisystem disease and no progression of HIV infection for a period of more than 10 years of follow-up. It is clear that he had some form of systemic vasculitis affecting skin, gut, and to a lesser extent, his kidneys. We suggest that HIV-1 virus is the major etiologic factor for the systemic vasculitis described here, although we cannot formally exclude another infectious etiology such as CMV. Additionally, the clinical and histopathologic findings appear to be compatible with those of Henoch-Schonlein purpura, though the lack of IgA deposition ruled out that diagnosis.
Discussion Polyarteritis nodosa–like syndromes and nonspecific necrotizing vasculitides are the most commonly described entities in HIV-positive patients. Classic polyarteritis nodosa (c-PAN) is a multisystem necrotizing vasculitis of small and medium-sized muscular arteries with characteristic involvement of renal and visceral arteries. In HIV-associated PAN, affected arteries tend to be smaller than those seen in c-PAN, and muscles, nerves, and skin are the major target organs.2,3 The usual clinical course of c-PAN, characterized either by fulminant deterioration or by relentless progression with acute flare-ups, is not typically seen in the HIV population.4 In fact, it seems that HIV-related PAN rarely becomes a multisystem and life-threatening disease, with the ex-
Figure 2. Histology of sections of small intestine showing marked infiltration of lymphocytes, neutrophils, and histiocytes and lesions of necrotizing vasculitis with fibrinoid necrosis of the vessel wall.
238
ception of some cases with heart, kidney, central nervous system, or gut involvement.5 Pathogenic mechanisms for HIV-associated vasculitic syndromes include direct action of HIV on endothelial cells (isolation of HIV-RNA and p24 antigen on vascular lesions), an excess of CD8 T-cells, and/or immune complexes, possibly involved at different stages of the disease.2,6,7 In particular, immunohistopathologic studies on specimens in HIV-associated PAN showed CD8 T-cell infiltrate in the center of the lesions and macrophages in the periphery, whereas the direct immunofluorescence revealed deposition of IgM immune complexes in the vessel walls.6 Interestingly, serology for HBV is invariably negative despite its high prevalence in HIV patients, minimizing the role of HBV in the development of PAN in this setting.2 Corticosteroid therapy alone or with a cytotoxic drug, especially in cases with renal or abdominal vessels involvement, seems to be the treatment of choice. Intravenous gamma globulin and plasmapheresis may also be effective alternative treatments. Initiation of antiretroviral therapy in HIVpositive patients with PAN, not already on highly active antiretroviral therapy, is of great importance. The co-occurrence of vasculitis and HIV infection, 2 diseases affecting the immune system, is an opportunity to gain specific insight into the pathogenesis as well as also a challenge to the clinician to diagnose and treat the combined diseases instead of each disorder singly. Because of the relatively good prognosis and the broad spectrum of nonspecific clinical manifestations commonly reported from HIV individuals without underlying vasculitis, some cases of HIV-related vasculitis could remain underdiagnosed, because histopathological examination is rarely carried out. All patients with a vasculitis of unidentified etiology should be evaluated for HIV infection. References 1. Munoz Fernandez S, Cardenal A, Balsa A, et al. Rheumatic manifestations in 556 patients with human immunodeficiency virus infection. Semin Arthritis Rheum 1991;21:30–9. 2. Calabrese L. Vasculitis and infection with the human immunodeficiency virus. Rheum Dis Clin North Am 1991;17:131–47. 3. Gherardi RK, Mhiri C, Baudrimont M, et al. Iron pigment deposits, small vessel vasculitis, and erythrophagocytosis in the muscle of human immunodeficiency virus-infected patients. Hum Pathol 1991;22:1187–94. 4. Libman BS, Quismorio FP, Stimmler MM. Polyarteritis nodosa-like vasculitic in human immunodeficiency virus infection. J Rheumatol 1995;22:351–5. 5. Font C, Miro O, Pedrol E, et al. Polyarteritis nodosa in human immunodeficiency virus infection: report of four cases and review of the literature. Br J Rheumatol 1996;35:796–9. 6. Gherardi R, Belec L, Mhiri C, et al. The spectrum of vasculitis in human immunodeficiency virus-infected patients: a clinicopathologic evaluation. Arthritis Rheum 1993;36:1164–74. 7. Massari M, Salvarani C, Portioli I, et al. Polyarteritis nodosa and HIV infection: no evidence of a direct pathogenic role of HIV. Infection 1996;24:159–61.
March 2008 Volume 335 Number 3