Vasculitis due to infection may occur as a consequence of the inflammation of vessel walls due to direct or contiguous infection, type II or immune complex-mediated reaction, cell-mediated hypersensitivity, or inflammation due to immune dysregulation triggered by bacterial toxin and/or superantigen production. As immunosuppressive therapy administered in the absence of antimicrobial therapy may increase morbidity and fail to effect the resolution of infection-associated vascular inflammation, it is important to consider infectious entities as potential inciting factors in vasculitis syndromes. The causality between infection and vasculitis has been established in hepatitis B-associated polyarteritis nodosa (HBV-PAN) and hepatitis C-associated (cryoglobulinemic) vasculitis (HCV-CV). The review summarizes the recent literature on the pathophysiological mechanisms and the approaches to the management of HBV-PAN and HCV-CV. Roles of other viral and microbial infections, which either manifest as vasculitic syndromes or are implicated in the pathogenesis of primary vasculitides, are also discussed.
Clinical trials are needed to assess the efficacy and safety of steroids and other immunosuppressive agents, for example, biologics, to improve the treatment of severe HBV-PAN and HCV-CV.
Viral and microbial etiologies should be considered in any vasculitic syndrome.
Testing for HBV and HCV should be performed in the evaluation of small-to medium-sized vessel vasculitis, in particular PAN and CV.
Treatment of infection-related vasculitis requires eradicating the infective agent as well as using immunosuppressive drugs as needed to control vascular inflammation/damage.
Viral and microbial etiologies should be considered in any vasculitic syndrome.
Testing for HBV and HCV should be performed in the evaluation of small-to medium-sized vessel vasculitis, in particular PAN and CV.
Treatment of infection-related vasculitis requires eradicating the infective agent as well as using immunosuppressive drugs as needed to control vascular inflammation/damage.
Infection is a well-recognized trigger of vasculitis. The mechanisms may involve the direct infection of vascular wall or via indirect immunological effects such as type II, III, or IV hypersensitivity reactions . Many infectious agents including viral, bacterial, or fungal agents, or microbial antigens have been reported in the literature to be associated with vasculitis ( Table 1 ). However, a causal relationship has only been firmly established in a few instances of vasculitis, such as chronic hepatitis B virus (HBV)-associated polyarteritis nodosa (PAN) and hepatitis C virus (HCV) with cryoglobulinemic vasculitis. These two entities are included as “vasculitis associated with probable etiology” in the 2012 Chapel Hill Consensus Conference on the Nomenclature of Vasculitides . It is crucial to evaluate for infective etiologies in any workup of vasculitis so that appropriate antimicrobial/viral therapies can be given as the etiology-based treatment, as immunosuppressants alone may not be sufficient and may even be detrimental.
|Giant cell arteritis; aortitis
|Coxiella burnetii , Parvovirus B19, Cytomegalovirus, Varicella zoster
|Central nervous system vasculitis
|Mycoplasma pneumoniae , Varicella zoster
|Hepatitis B Virus, Hepatitis C Virus, Epstein–Barr virus, Cytomegalovirus, Parvovirus B19, Ehrlichiae
|Mycoplasma pneumoniae , Epstein–Barr virus, Parvovirus B19
|Granulomatosis with polyangiitis
|Staphylococcus , Epstein–Barr virus, Parvovirus B19
|Mycoplasma pneumonia , Parvovirus B19, Cytomegalovirus
While a vasculitic syndrome may be readily identified in a patient with an established diagnosis of HBV or HCV, vasculitis may present as an uncommon feature of a ubiquitous infection. Therefore, a heightened suspicion for temporal and epidemiological clues is necessary. This review article primarily addresses HBV- and HCV-related vasculitis, and, briefly, it covers vasculitis associated with other microorganisms.
Characterized by arteritis of medium/small arteries without small-vessel involvement, glomerulonephritis, or antineutrophil cytoplasmic antibodies (ANCAs), PAN is classified as an idiopathic primary systemic vasculitis . However, ≥30% of PAN cases are secondary to HBV infection , with HBV positivity being the single most important criterion in confirming the diagnosis of PAN, in the setting of compatible clinical and angiographic features . In recent decades, the incidence of PAN has significantly declined in the context of HBV vaccination programs and blood transfusion screening . Clinical manifestations of PAN appear usually within the 6–12 months of silent chronic hepatitis, and 60% have a documented HBV exposure prior to PAN onset . In the largest cohort of PAN ( n = 348) from the French Vasculitis Study Group Database, although the same clinical manifestations were commonly present in the HBV-PAN and the non-HBV-related groups, patients with HBV-PAN were often younger than 40 years, and peripheral neuropathy (mononeuritis multiplex), malignant hypertension, orchitis, cardiomyopathy, and gastrointestinal (GI) ischemia were more frequently observed . Patients with HBV-PAN also had a higher prevalence of liver enzyme elevation and GI microaneurysms and/or stenoses on angiography . GI disease requiring laparotomy carries high mortality, and it is the most feared complication of PAN. Further, HBV-PAN presents more acutely, and it portends more severe disease course by Five Factor Score and Birmingham Vasculitis Activity Score when compared with the nonviral PAN . Generally, HBV is a monophasic disease once treated to remission. Over a follow-up of 5.7 years, HBV-PAN had a higher mortality rate (34%) but less relapses (11%) compared with the nonviral PAN (20% and 22%, respectively) . Although HBV-PAN is believed to be an immune complex (IC) deposition disease, glomerulonephritis and pulmonary alveolitis/capillaritis (except in cases of pulmonary artery aneurysms) typically do not occur, and hypocomplementemia is rare. Renal complications may include hypertension from renal artery stenosis as well as rupture of renal microaneurysms causing silent renal infarction, presenting clinically with hematuria, proteinuria, and/or acute kidney injury. Renal biopsy is contraindicated in the setting where microaneurysms are suspected or confirmed.
Several hypotheses have been proposed to explain the pathogenesis of HBV extrahepatic manifestations . Most evidence supports a type III hypersensitivity injury whereby vascular damage is produced by ICs with viral antigens (add a recent ref). ICs that are formed or deposited within the vessel lumen may cause a serum sickness reaction seen occasionally in the pre-icteric phase of acute HBV infection. PAN and membranous nephropathy develop at later stages as a consequence of sustained HBV antigenemia. ICs detected by solid-phase radioimmunoassay, electron microscopy, passive hemagglutination, and other methods were correlated with the clinical course of the disease . Presumably, ICs activate the classic complement pathway, leading to the recruitment of neutrophils. HBsAg with immunoglobulins (Igs) and complement have been identified by immunofluorescence in the hyaline and fibrinoid lesions of affected vessel walls . HBeAg and pre-S1 Ag have also been implicated. Seroconversion is associated with improved prognosis.
Viral replication within the blood vessels with direct endothelial injury may also engender vascular lesions as detectable HBV RNA, replicative intermediates of HBV, HBsAg, and HBcAg localized to the mesenteric endothelium have been identified in HBV-PAN . Although viral induction of host autoantibodies reactive to vasculature was postulated, anti-endothelial cell antibodies (AECA) implicated in a number of vasculitis (including PAN) are rarely found in HBV patients, and they are similar among HBV-infected patients with or without PAN as well as among healthy controls . There have been anecdotal reports of chronic HBV infection associated with other forms of vasculitis such as eosinophilic granulomatosis with polyangiitis (GPA) or HBV vaccination preceding the onset of vasculitis . It remains unclear whether these reports are coincidental or causal.
Although potentially fatal, the outcome of PAN has improved with early and aggressive treatment along with better understanding of the pathophysiology. Antiviral therapy may successfully treat HBV-PAN by inhibiting viral replication, even without concomitant immunosuppressive treatment . Guillevin et al. proposed a stepwise strategy with initial prompt and rapid control of severe life-threatening manifestations of the vasculitis using systemic glucocorticoid, and then plasmapheresis aimed at removing the ICs, followed by antiviral therapy to inhibit HBV replication and abrupt cessation of glucocorticoid after 1–2 weeks to enhance immunological clearance of HBV-infected hepatocytes and to facilitate seroconversion of HBeAg to anti-HBeAb .
In a single-arm prospective study of 10 patients with HBV-PAN, 2 weeks of glucocorticoid followed by plasmapheresis and lamivudine led to recovery in nine subjects with 66% HBe seroconversion rate and suppression of HBV DNA to undetectable levels .
Conventional glucocorticoid and cyclophosphamide regimens without antiviral therapy are contraindicated due to the risk of continued viremia, progression of chronic hepatitis or cirrhosis, and, more ominously, reactivation of HBV with fulminant hepatitis. Ultimately, treatment needs to be individualized according to severity, titration of the dose, and duration of corticosteroid, and for patients with life-threatening disease, the use of cyclophosphamide may be warranted.
Current strategies for the treatment of HBV-PAN involve the use of nucleos(t)ide analogues, which work by directly inhibiting viral replication. The use of lamivudine and telbivudine has been superseded by newer, more effective first-line agents such as tenofovir and entecavir . Interferon-α (IFNα) has been used either alone (ref) with anecdotal success for HBV-PAN or in combination with antivirals for refractory cases. There is one case report of the use of antitumor necrosis factor, etanercept, for refractory cutaneous HBV-PAN, albeit in a HBV carrier status, without any untoward side effects .
Hepatitis C-associated (cryoglobulinemic) vasculitis
Chronic hepatitis virus C infection produces extrahepatic manifestations among which mixed cryoglobulinemia (MC) is the most frequent. HCV-associated cryoglobulins are typically type II and type III, referred to as MCs, consisting of IgM with rheumatoid factor (RF) activity that forms complexes with the (Fc) portion of polyclonal IgG. The RF may be monoclonal (in type II) or polyclonal (in type III) Ig. MCs are also linked to various autoimmune and lymphoproliferative diseases, but HCV infection accounts for an overwhelming 90% of MC . Although MC is prevalent (40–70%) in patients with HCV infection, it is usually asymptomatic with cryoglobulinemic vasculitis (CV) occurring in only 5% of patients with HCV-associated MC .
The pathogenesis underpinning of HCV-MC is the clonal expansion of B cells triggered and sustained by persistent immune stimulation from the inability to eradicate the infection . The mechanism(s) whereby autoreactive RF develops in chronic HCV infection remain unclear. HCV RNA encodes for a capsid protein core and the two envelope glycoproteins (E1 and E2), which are essential components for viral entry and fusion, and multiple nonstructural regulatory proteins. HCV is lymphotrophic, and binding of its E2 envelope glycoprotein to the CD81 receptor (a HCV putative receptor) of B cells and the innate Toll-like receptor (TLR) 7 activates B cells . Engagement of CD81 by E2 results in multiple cellular effects, including c-Jun N-terminal kinase (JNK) pathway activation leading to the proliferation of naïve (CD 27−) B cells and upregulation of cytidine deaminase causing hypermutation in the V H genes of B cells . The N-terminal region of E2 of HCV, which has a similar structure to human Ig variable domain, has been shown to be one of the antigens driving the production of IgM-RF in HCV-MC-associated cryoprecipitate . IgM-RF cross-reacting with nonstructural proteins such as NS3 has also been isolated as cryoprecipitates. Mutations in the N-terminal hypervariable regions 1 and 2 (HVR1 and HVR2) of the E2 envelope glycoprotein were initially thought to predispose to MC via CD81-activated proliferation of peripheral B cells . However, viral genotyping studies have overall failed to demonstrate correlations between viral sequences and development of MC or progression of MC to symptomatic disease .
B-cell clonal expansion
MCs are produced by marginal zone B cells of lymphoid aggregates in hepatic portal tracts primarily, but bone marrow, lymph nodes, and peripheral mononuclear cells where HCV RNA has been demonstrated may be other sources . In the majority of patients with HCV-associated MC, there is a selective expansion of specific B cells expressing VH1-69 and Ig κV κ 3 heavy-chain gene segments that encode RF of the WA idiotype, binding both IgG Fc and viral protein NS3, suggesting a cross-reactivity between a virus-associated epitope and an IgG autoantigen . It is postulated that IgG-bound HCV drives the clonal expansion of VH1-69 + B cells , which upon chronic antigenic exposure results in a gradual selection from an initial polyclonal type III cryoglobulin toward monoclonal RF. The monoclonal B cells are similar to the mature marginal zone B cells by the co-expression of IgM and CD27, undergoing tremendous expansion as a defense mechanism against HCV infection, but with the attendant risk of progression to autoimmunity and malignant transformation. B-cell clonal proliferation correlates with a high intrahepatic viral load , but the total number of B cells in patients with cryoglobulins is not more than those without cryoglubulins .
B-lymphocyte stimulator (BlyS), also known as B-cell-activating factor (BAFF), a tumor necrosis factor (TNF)-α family member required for B-cell survival, has been implicated in the sustenance of B-cell proliferation in HCV-associated MC. Higher serum BAFF levels have been demonstrated in chronic HCV with MC compared with those without MC or patients with chronic HBV infection . Recent studies showed that −871T allelic mutations of the BAFF promoter were correlated with higher BAFF mRNA levels in vivo, and they are significantly more prevalent in patients with HCV-MC compared with those without MC . Paradoxically, antiviral therapy and/or treatment with rituximab may lead to the upregulation of BAFF that may account for the persistence or incidence of symptomatic MC despite HCV RNA being rendered negative , suggesting that the B-cell proliferation may become independent of the triggering viral agent.
Cryoprecipitation and vascular injury
HCV-CV is an IC disorder with cryoprecipitate containing viral antigens, IgM RF bound to polyclonal anti-HCV IgG, and complement . The ICs are localized to small vessels of internal organs, although preferentially to the colder extremities. In addition to temperature and size of the IC, a wide range of other physical and biochemical factors contribute to the insolubility of the IC . The most important factor appears to be the interaction of the IgM fraction with IgG specific for core viral antigen . Although a recent study showed that HCV cryoprecipitates had IgG activity against the core as well as NS3 and NS4 epitopes , it is the core protein that was directly correlated with the amount of cryoprecipitate .
The complement system plays an important role in the composition of cryoprecipitating ICs. IgM RF is capable of activating the complement system through the binding of the globular domain of the C1q protein . C1q receptors (gC1q-R) are widely expressed on the surface of blood cells and endothelial cells, and they bind to large ICs containing HCV core protein, facilitating subsequent vascular inflammation. It has been shown that levels of soluble gC1q-R, which circulates as a ligated form containing both C1q and HCV core protein, are significantly higher in HCV-MC compared with HCV without MC. The HCV core–gC1q-R interaction promotes inflammatory responses by the activation of the complement cascades, leading to subsequent infiltration of the vascular tissue by proinflammatory cells and vasculitic damage .
Clinical manifestations of CV
CV is characterized most commonly by cutaneous vasculitis (purpura and/or leg ulcers), membranoproliferative glomerulonephritis (MPGN), and peripheral neuropathy. Table 2 shows the preliminary classification criteria of CV proposed by the Italian Group for the Study of Cryoglobulinemia (GISC) . The classification criteria set has a high specificity of 93.6% and a sensitivity of 88.5% for CV, and it allows the distinction of patients with CV from (i) those with cryoglobulinemia without CV and (ii) those with clinical features of CV but who lack positive cryoglobulins (such as the connective tissue diseases). The determination of cryoglobulin is notoriously difficult, and it may be false negative due to low cryocrit, poor blood handling/processing, or tissue IC sequestration, thus causing a dilemma when faced with a suspected CV with negative cryoglobulin. In this setting, repeated testing for cryoglobulin is warranted .
a De Vita S, Soldano F, Isola M, Monti G, Gabrielli A, Tzioufas A, et al. Preliminary classification criteria for the cryoglobulinaemic vasculitis. Annals of the Rheumatic Diseases 2011 Jul; 70(7):1183–1190.
Barring the different diagnostic criteria previously used for study inclusion, survival from CV appears to have recently improved from a 10-year survival of <50%–80% . Although renal failure used to be the most common cause of mortality , in a more recent French cohort study ( n = 85, 23 deaths), infection (35%) was the most common cause of death followed by liver disease (30%) and heart disease (17%). Only a small proportion of patients died of renal failure or vasculitis. Most deaths occur within the first 4 years, and immunosuppressive treatment was associated with increased mortality, despite adjusting for disease severity (ref). The improved prognosis of HCV-CV may be attributed to the better identification of HCV and advances in anti-HCV and renal replacement therapies.
Therapeutic aims for managing HCV-associated CV should include controlling vascular inflammation and B-cell proliferation, and viral eradication. The treatment is best individualized based on organ involvement, severity, previous therapies, and comorbidities. While there is concern that prolonged immunosuppression may impair viral clearance, high-dose steroids, plasmapheresis, and/or cyclophosphamide may be lifesaving in the context of diffuse alveolar hemorrhage or GI ischemia or central nervous system (CNS) involvement. The current standard of care with PEGylated INFα and ribavirin results in the sustained remission of CV in a majority who achieve sustained virologic response (SVR) . However, in 10–20% of patients, the combination is poorly tolerated due to toxicities, or it is contraindicated. Furthermore, patients infected with HCV genotype 1, the most prevalent genotype worldwide (60%), fail to achieve SVR, and recurrence of MC and clinical symptoms are associated with HCV RNA relapse. Recently available antiviral combination agents such as ledipasvir–sofosbuvir or simeprevir–sofosbuvir that have a high activity against HCV genotype 1 now offer better options for effecting IFN-free viral clearance in this population of affected patients.
It is important to recognize that CV may persist even with the clearance of HCV. Rituximab, which targets RF-producing B-cell clones, has emerged as an optimal choice for severe CV. A recent phase III, randomized controlled trial demonstrated the superiority of rituximab monotherapy (1 g, 2 weeks apart) compared with conventional therapy with corticosteroids, azathioprine, cyclophosphamide, or plasmapheresis for the treatment of skin ulcers, active glomerulonephritis, or refractory peripheral neuropathy related to HCV-CV following failure with antiviral agents or contraindication to antiviral therapy . Response to rituximab was evident within 2–6 months, and it was accompanied by the reduction of glucocorticoid dose, a decrease in RF level, and a rise in C4 levels.
Endovascular microbial infection
Bacterial endocarditis may trigger the development of systemic vasculitis . Vascular injury simulating vasculitis of various-sized intracranial vessels has been demonstrated on routine cranial angiography and on cranial magnetic resonance imaging (MRI) studies in patients with bacterial endocarditis and meningitis , with mycotic aneurysm, retinal vasculitis, brain infarcts, and brain hemorrhage being dire consequences . In addition to directed antibiotic therapy, early adjunctive use of dexamethasone in selected patients may reduce vascular inflammation and neurological sequelae .
Bacterial infection should be considered in patients presenting with aortitis, as infective aortitis is fatal if untreated. Septic aortitis most commonly occurs in older men with atherosclerosis, with prolonged fever, abdominal or back pain, palpable abdominal mass, and leukocytosis as the common presenting features . Infection may arise either as a direct extension of a local infection, traumatic contamination, and septic embolism from infective endocarditis or as a hematogenous seeding from a distant source of bacteremia. Complications may include mycotic aneurysm, aortic rupture, aortoduodenal fistula, and vertebral osteomyelitis. Staphylococcus aureus and enteric gram-negative bacteria (especially Salmonella ) are the main causative organisms seeding atheromatous vessels ; enterococci , Clostridium septicum, and Listeria monocytogenes, and fungi such as Candida and Aspergillus are pathogens identified in immunosuppressed patients . Although systemic lupus erythematosus, liver cirrhosis, human immunodeficiency virus (HIV) infection, and solid organ cancers have been shown to be independent risk factors for Salmonella bacteremia , the only independent positive predictor of Salmonella endovascular infection appears to be atherosclerosis .
Computed tomographic angiography is the most useful imaging modality for evaluating suspected infectious aortitis. MRI with gadolinium enhancement should be considered when the use of iodinated contrast media is contraindicated. In clinicopathologic studies of surgical repair of infected aortic aneurysms, acute inflammation superimposed on severe chronic atherosclerosis was most prevalent. In a number of cases, purulent inflammation is absent with just chronic inflammatory changes and lymphoplasmacytic inflammation and fibrosis being present in the lesion. The causative organism can usually be recovered from either blood cultures (positive in 50–85%) or excised aortic tissue in up to 76% of cases . Optimal treatment with early surgery, with excision of infected aorta and bypass grafting, in combination with prolonged antibiotic administration has improved outcomes .
Rickettsiae are arthropod-borne (ticks), gram-negative, obligate intracellular bacteria, which primarily infect endothelial cells resulting in Rocky Mountain spotted fever (RMSF, caused by Rickettsia rickettsii ), boutonneuse fever (caused by Rickettsia conorii ), and other spotted fevers . Following skin inoculation, Rickettsia spread via lymphatics into the circulation, infecting and replicating in the cytoplasm of target endothelial cells. The outer membrane proteins and cell surface antigens (e.g., Omps, Sca-2, and Sca-4) are capable of eliciting protective immune responses in experimental animals , and facilitating attachment to and entry into the endothelial cell membrane via vinculin activation and actin organization . Following phagocytosis of the pathogen, host cell immune responses follow, including the expression of adhesion molecules, proinflammatory cytokines and chemokines, and procoagulants . Cell damage has been associated with rickettsial phospholipase A2 and protease activities and free-radical-induced injury . The organisms then traverse cell to cell utilizing RickA protein-induced actin polymerization for directional intracellular movements and intercellular spread . The net effect is a lymphohistocytic response with widespread vasculitis, most importantly in the brain and lungs, causing increased vascular permeability, edema, hypotension, and multiorgan failure .
RMSF is frequently fatal if not adequately treated with antibiotics early during the course of the illness. Symptoms usually commence 2–14 days after the tick bite with fever, headache, myalgias, nausea with or without vomiting, and abdominal pain . The characteristic rash appears after 3–5 days, and it evolves from macular to maculopapular to petechial, on the ankles and wrists and then spreads centrally and to the palms and soles. Azotemia, skin necrosis, thrombocytopenia (true disseminated intravascular coagulation is rare), retinal vasculitis, and multifocal rhabdomyolysis are other complications. Non-cardiogenic pulmonary edema may evolve; meningoencephalitis and neurological involvement are associated with high mortality as is the absence of the typical rash (“viscerotropic” RMSF), due to frequent delays in diagnosis . The presence of glucouse-6-posphate dehydrogenase deficiency is associated with fulminant RMSF, whereby death occurs within the first 5 days of symptom onset .
Culture is difficult for rickettsiae, but genetic tools including real-time polymerase chain reaction (PCR) analysis for genes of major surface proteins and immunohistochemical analysis of skin-biopsy specimens for R. rickettsii antigen have adequate sensitivity, and they provide timely diagnosis of emerging as well as established rickettsioses . PCR of rickettsial DNA in blood samples is not sufficiently sensitive; serologic analysis may confirm diagnosis retrospectively when antibodies begin to appear during convalescence, but they are not useful during initial management, and antibody cross-reactivity may result in false-positive test results. Prompt treatment with tetracycline class antibiotics is prudent when the diagnosis is suspected in the context of a relevant travel history coupled with a clinical prodrome consistent with RMSF.
Endovascular complications, particularly of the aorta, may occur as a complication of infection with Coxiella burnetii ; aortitis in Q fever most commonly occurs in the context of preexisting atheromatous disease . Inflammatory lesions of other large vessels, including temporal arteries, have been reported . Favorable outcomes require prolonged antibiotic therapy combined with surgical resection/repair of involved aortic aneurysms .
Ehrlichiae, most notably Ehrlichia chaffeensis , are tick-borne intracellular pathogens capable of inciting multisystem disease with severe hepatic dysfunction, coagulopathy, and acute cardiomyopathy. The organisms have tropism for a variety of tissues, including endothelial cells. Endothelial cells support the growth of E. chaffeensis in culture, and recent reports of murine models of Ehrlichial infection also confirm infection and replication of the organisms in vascular endothelium . Biopsy reports of cutaneous lesions in infected humans have been reported to be consistent with polyarteritis . Ehrlichiosis is best diagnosed in the acute setting by positive PCR assay and confirmation of E. chaffeensis DNA, identification of morulae in leukocytes and a positive immunofluorescence titer to E. chaffeensis antigen, or immunostaining of E. chaffeensis antigen in a biopsy sample. Most patients will respond to treatment with doxycycline, although fulminant disease with refractory cardiomyopathy and/or severe macrophage activation syndrome may occur despite therapy, even in otherwise immunocompetent hosts .
In avian studies, Mycoplasma species have been shown to have tropism for the arterial walls . Human infection with Mycoplasma pneumoniae may be associated with cutaneous vasculitis syndromes including leukocytoclastic vasculitis and urticarial vasculitis . Henoch–Schonlein purpura (HSP) with or without associated nephritis has been reported in the context of acute mycoplasma infection . CNS vasculopathy consistent with vasculitis and/or thrombosis has been observed in association with antecedent mycoplasma infection . M. pneumoniae is among the purported microbial pathogens associated with Kawasaki’s disease (KD) .
Although complications of infection with Toxoplasma gondii most commonly occur, and they are most severe in immunocompromised patients (such as those with advanced HIV disease), vasculitis involving the retinal arteries may occur in immunocompetent individuals . The typical clinical manifestations of ocular toxoplasmosis include recurrent unilateral posterior uveitis with necrotizing retinitis and secondary choroiditis occurring adjacent to pigmented retinochoroidal lesions with associated retinal vasculitis. The diagnosis of toxoplasmosis vasculitis of the retina is usually established by its characteristic clinical appearance, but ocular fluid testing with DNA PCR studies for Toxoplasma gene sequences or intraocular production of specific antibody may be helpful for the confirmation of the diagnosis in atypical cases . Treatment regimens incorporate systemic corticosteroid with oral pyrimethamine and sulfadiazine, although toxicity of this antibiotic combination may require intraocular forms of drug delivery or the use of alternative antimicrobials such as trimethoprim–sulfamethoxazole .
Viral (non-HBV/HCV) -induced vasculitides
Viremia is frequently associated with circulating ICs that may engender vascular inflammation, and a number of viruses have tropism for vascular endothelium. Viruses may also engender cell transformation events that may culminate in vascular inflammation syndromes. As the role of viruses in vasculitis becomes better understood, treatment regimens incorporating therapies targeting specific viruses are therefore playing a greater role in the management of vasculitis.
Parvovirus B19 (PVB19) has tropism for a variety of cell types, including endothelial cells, that possess the P blood group antigen globoside and α5β1 integrins, the main receptor complex for PVB19 entry into the cell . The target cells include endothelium as well as erythroid progenitors, megakaryocytes, fetal myocytes, and placental trophoblasts. Acute PVB19 infection has been associated with clinical features suggestive of vasculitis; these include intestinal ischemia , papular-purpuric “glove and stocking” syndrome , mononeuritis multiplex , IC glomerulonephritis , and dermal infarction .
The known endothelial tropism of PVB19 has prompted numerous investigations for the potential role of the virus in the pathogenesis of other established vasculitic disorders ( Table 1 ). Through serologic and immunohistochemistry studies as well as DNA amplification in blood, skin, and endothelial tissue samples, human PVB19 infection has been implicated in the pathogenesis of PAN and GPA , Behcet’s disease , and HSP . A pathogenetic role for PVB19 has also been implicated in the vasculopathy associated with systemic sclerosis , dermatomyositis , and systemic lupus erythematosus .
Parvovirus DNA has also been detected by PCR amplification in temporal artery biopsy specimens of patients with giant cell arteritis (GCA), suggesting a possible role for the virus in the development of large vessel vasculitis , particularly in cases with a high viral load . However, other larger studies have not corroborated this initial observation , with a similar frequency of PVB19 DNA localization found in arterial surgical specimens obtained from age-matched controls with atherosclerotic carotid/aortic disease . An association of PVB19 with KD remains uncertain .
Although mild cases of PVB19 infection may spontaneously resolve, severe disease warrants the use of intravenous immunoglobulin (IVIG) and occasionally corticosteroids. It should be recognized that acute parvovirus infection may complicate the clinical course of other medium–small-vessel vasculitides. In one series of patients with GPA who became infected with PVB19, the patients appeared to have GPA relapses or poor response to conventional immunosuppressive therapy, only to improve following courses of high-dose IVIG .
Cytomegalovirus (CMV) is capable of infecting endothelial cells, resulting in clinical presentations consistent with small-to medium-sized vessel vasculitis and possibly aortitis . CMV vasculitis most commonly presents as retinal, skin, or gut lesions; neurologic deficits due to CNS or peripheral nervous system infarcts may also appear . Although most commonly seen in immunosuppressed patients, CMV-induced vasculitis involving small- or medium-sized arteries with enteric vasculitis, HSP, and classic PAN have been reported to occur in immunocompetent patients . Pulmonary septal capillary injury and alveolar hemorrhage without classic inclusion body cytopathic change that is morphologically indistinguishable from small-vessel vasculitis involving the lungs have also been described .
CMV infection has been associated with other vascular complications including venous thrombosis and accelerated atherogenesis. In a meta-analysis, thrombosis (splanchnic vein thrombosis, deep vein thrombosis, and pulmonary embolism) associated with CMV infection was more prevalent in immunocompetent hosts, particularly those with inherited thrombophilia in the setting of CMV mononucleosis . CMV infection has been implicated in the development of atheromatous lesions in cerebral arteries with the development of stroke , as well as in the afferent arterioles of renal allografts .
The diagnosis of CMV vasculitis is best established by the biopsy of lesions to identify cytomegalic endothelia and macrophages with intranuclear inclusions. If biopsy is not feasible, a presumptive diagnosis of CMV vasculitis can be made in the context of confirmed viremia (by PCR studies of peripheral blood) and characteristic morphologic lesions of vasculitis on vascular imaging studies. A diagnostic and therapeutic challenge arises when CMV-induced vasculitis occurs in patients who are on immunosuppressive therapy for the treatment of other vasculitides, for example, GPA as manifestations of CMV infection may mimic recrudescence of the underlying vasculitis. As such, primary CMV infection or reactivation should be suspected in a setting of clinical worsening of established autoimmune vasculitis despite traditional immunosuppression. Appropriate cultures, PCR studies, and mucosal biopsy specimens to rule out CMV infection should be procured in previously stable patients who develop new lesions involving the skin, lungs, glomeruli, gut, or CNS.
Necrotizing arteritis due to CMV may require glucocorticoid treatment initially, but appropriate antiviral therapy should be instituted concurrently and promptly in patients with CMV-associated vasculitis. Early recognition of CMV-induced vasculitis in immunosuppressed patients is critical; favorable outcomes in this setting are associated with prompt institution of antiviral therapy and a decrease in the immunosuppression . For patients with CMV vasculitis, particularly when there is gut involvement, the preferred initial treatment is ganciclovir, with dose adjustment for renal insufficiency. For patients with severe disease, the administration of CMV immunoglobulin (CytoGam) should be considered. Foscarnet can be used in patients with confirmed ganciclovir resistance.
Varicella zoster virus
Varicella zoster virus (VZV) has been implicated as a cause of granulomatous vasculitis in the CNS, resulting from the direct viral infection of large and small cerebral vessels following either primary varicella infection (varicella) or reactivation (zoster) . Clinical features may manifest within a month following primary VZV infection. However, VZV vasculopathy involving the cerebral arteries may evolve over many months following herpes zoster ophthalmicus or zoster that may have occurred anywhere in the body, with the duration of disease manifestations occurring up to 2 years before the diagnosis is confirmed . Not uncommonly, cutaneous or ophthalmic manifestations of herpes zoster are absent, with some patients noting only herpetic neuralgia . Indeed, VZV DNA and/or antigens with multinucleate giant cells have been identified in the affected arterial tissues in patients with segmental granulomatous angiitis of the CNS in the absence of antecedent cutaneous or ophthalmic zoster .
The clinical CNS manifestations associated with VZV vasculopathy can be either unifocal or multifocal, presenting as acute hemiplegia, transient ischemic attacks, and/or other various stroke syndromes including intranuclear opthalmoplegia and rapidly progressive multi-infarct dementia . Complications may include cerebral aneurysms, arterial dissection, and/or subarachnoid and intracerebral hemorrhages . Extracranial involvement of the temporal arteries and optic neuritis have also been reported . VZV vasculitis occurs in immunocompetent as well as in immunocompromised patients including those with organ transplant, cancer, or HIV/acquired immune deficiency syndrome (AIDS), or those on treatment with immune-modulatory/immunosuppressive agents . As such, VZV infection should be considered in the differential diagnosis of patients with idiopathic primary angiitis of the CNS and all strokes of unclear etiology, particularly in HIV-positive and other immunocompromised patients.
Ischemic or hemorrhagic infarction with gray or white matter lesions, particularly gray–white matter junctions, on MRI provides a clue to the diagnosis of VZV vasculitis . Angiography demonstrates the segmental narrowing of a mix of large- and small-vessel involvement, often with post-stenotic dilatation . VZV meningitis and myelitis are often concurrent with VZV vasculitis; cerebrospinal fluid (CSF) studies show pleocytosis and frequently red blood cells. The diagnosis of VZV vasculopathy can be confirmed by the presence of VZV DNA using appropriate primers for PCR studies or anti-VZV IgG antibody in the CSF with the determination of the serum/CSF VZV IgG index. CSF VZV IgG is reportedly a more sensitive test in patients with a longer disease duration, and the diagnosis should not be excluded unless both VZV PCR studies and VZV IgG antibody studies are negative. Suspected cases should be treated immediately with intravenous acyclovir for at least 2 weeks and a short course (5–7 days) of corticosteroids to control the inflammation of the cerebral arteries .
Herpes simplex virus
Infection with herpes simplex virus (both HSV-1 and HSV-2) has been associated with cerebral vasculitis complicated by hemorrhage and/or cerebral infarction . Diagnosis is best established by the presence of characteristic angiographic appearance and/or post-contrast vessel wall enhancement, and by the evidence of viral replication on PCR studies for HSV gene sequences on CSF or peripheral blood .
Human T-cell lymphotropic virus-1
Human T-cell lymphotropic virus-1 (HTLV-1) is one of several retroviruses capable of directly or indirectly inducing vascular lesions, and it has been identified as a causative factor in a number of nonmalignant inflammatory lesions, most notably a myelopathy classically described as tropical spastic paraparesis in endemic areas. Vascular complications of HTLV-1 infection also include the inflammation of the uveal tract with anterior uveitis and retinal vasculitis . HTLV-1 infection is diagnosed by the presence of elevated serum or CNS antibody titers to HTLV-1 in an appropriate clinical setting.
Epstein–Barr virus (EBV) infection may present with an IC vasculitis involving small-caliber vessels and renal glomeruli with hepatosplenomegaly and HSP-like features of palpable purpura, hematuria, and arthritis . EBV infection has been implicated in the pathogenesis of PAN , as well as in studies of patients with granulomatous angiitis involving medium- and large-sized arteries whereby EBV DNA sequences have been found in intimal and medial tissues . Associations between infection with EBV and coronary artery aneurysms and other inflammatory lesions of the aorta reminiscent of KD have also been reported , with a greater prevalence of EBV DNA sequences demonstrated in circulating mononuclear cells of patients with KD and coronary artery aneurysms compared with age-matched controls .
By virtue of its tropism for and ability to transform lymphoid cells and engender atypical immune responses, EBV may furthermore be associated with an unusual variety of vascular and perivascular syndromes during acute or chronic EBV infection. Transformation of EBV-infected B-cell lymphocytes and natural killer (NK) cells may result in vascular syndromes associated with angiocentric lymphoid proliferation, as seen in lymphomatoid granulomatosis (LG), which leads to tissue necrosis. Due to its propensity for multiorgan involvement, most frequently the lungs, and the histological features of granulomatous angiitis, LG often mimics systemic vasculitis, most notably GPA . LG occurs most commonly in immunodeficiency states, such as AIDS, Wiskott–Aldrich syndrome, and posttransplantation immunodeficiency . LG has also been associated with autoimmune disorders including Sjögren’s syndrome, rheumatoid arthritis, and systemic lupus erythematosus, perhaps related to immunosuppression employed to manage these disorders .
The vascular lesions in LG constitute mature CD3/CD4-positive T cells responding to EBV-infected B cells in and around the vasculature that are CD20 positive, occasionally CD30 positive and CD15 negative, with EBV-encoded RNA present . EBV DNA sequences enriched in the lesional B cells are not typically found in the large numbers of non-clonally related T cells, findings that distinguish LG from angiocentric T-cell lymphomas, where there is evidence of clonal T-cell expansion . EBV transformation of NK cells resulting in multisystem vascular infiltration by clonally expanded large granular lymphocytes has also been reported , further adding to the spectrum of EBV-associated vasculopathies. As with posttransplant lymphoproliferative disorder, the reduction of immunosuppression is advisable. Data on success with the use of anti-CD20 (rituximab) for the management of LG are emerging .
West Nile virus
Implicated in seasonal meningitis/encephalitis syndromes, West Nile virus (WNV) has been associated with cerebral vasculitis complicated by stroke . Most commonly occurring in the context of antecedent meningitis/encephalitis, the development of posterior uveitis with retinal vasculitis including branch artery occlusions and microaneurysms has recently been identified as an ocular complication of WNV .