PATHOGENESIS Known infectious causes of vasculitis in man STANLEY J. NAIDES, MD n array of pathogens is known to cause vasculi- and our ability to intervene in disease processes, have ren- tis in man.1,2 For several of these agents, vas- dered some causes of vasculitis far less common. culitis is the major manifestation of disease. The Amajority, however, typically present as infec- ■ VIRAL CAUSES OF VASCULITIS tious processes in which vasculitis is an occasional mani- Our knowledge of viral pathogenesis has exploded in the festation of disease. For many, vasculitis may be a compo- last quarter of the twentieth century, accelerated in large nent of disease pathogenesis but is not a prominent feature part by epidemics of “emerging” viral diseases. Hepatitis C of the clinical presentation. The various agents—viruses, virus, discovered in 1989, has worldwide prevalence.3 The bacteria, and fungi—share a common target, blood vessels. 10- to 20-year latent period before hepatic or rheumatic The involvement of vessels may be direct, with vascular manifestations of disease explains the increasing number structures serving as targets. Many infectious pathogens of cases of hepatitis C virus–mediated vasculitis currently have tissue tropism that includes endothelium. Other being seen in the United States following the epidemic of agents may bind to the vessel wall because the vascular en- new infections in the 1980s.4 Prior to the discovery and dothelium expresses specific receptors for the pathogen or characterization of hepatitis C virus in the late 1980s, the another moiety with which the pathogen travels. Even triad of arthritis, palpable purpura, and type II cryoglobu- when the agent does not enter the endothelial cell, the im- linemia was given the sobriquet “essential mixed cryo- mune response to the agent may be focused at the vessel globulinemia” and considered an idiopathic vasculitis. wall because the pathogen is adherent to the endothelial Availability of diagnostic testing for hepatitis C virus cell surface, thereby promoting innocent by-stander injury demonstrated that almost all of these cases were associat- to the vessel. Processes that target the endothelium direct- ed with hepatitis C virus infection. Immune response to ly are usually acute in nature. Innocent bystander injury is the virus elicits a response to the Fc portion of im- often chronic and may be insidious in onset. munoglobulin with the majority of elicited antibody hav- Demonstration of infectious agents as the cause of ing the Wa idiotype.5,6 Immune complexes of anti–Fc Wa some cases of vasculitis fuels interest in searching for in- idiotypic antibody and pre-existing antibody, and virus fectious etiologies of idiopathic vasculitis. The advent of have the peculiar physical property of precipitating out of highly sensitive molecular techniques has encouraged solution in the cold (“cryoglobulins”). Presumably, Wa id- searches for various known pathogens in idiopathic vas- iotype recognizes a cross-reactive epitope found on he- culitis. Recognition that infectious agents are dynamic patitis C virus and immunoglobulin. Extremities and skin populations of organisms prompts us to search for emerg- are sufficiently cold so as to explain a predilection for ing pathogens as previously unknown causes of vasculitis. small-vessel leukocytoclastic vasculitis of the skin; gravity Such pathogens “emerge” as new species or strains devel- enhances vascular injury in dependent distal vessels, giv- op from older species in their traditional host population. ing rise to palpable purpura predominantly in the lower Others may emerge due to spread into a new host popula- extremities. More severe cases may manifest visceral organ tion. The new, previously non-susceptible population may involvement including membranoproliferative glomeru- become infected because the pathogen adapts to the new lonephritis and bowel involvement. Small- and medium- host species. Alternatively, the agent may spread to a new sized arteries may be involved as well, especially in the susceptible host population as a consequence of changes kidneys. in the physical environment or human or vector behavior Hepatitis B virus (HBV) infection provides the classic that promotes geographical spread. In mirror fashion, example of virally mediated immune complex disease. A changes in the behavior of pathogens, vectors, and hosts, lymphocytic venulitis or neutrophilic vasculitis of small vessels with leukocytoclastic or fibrinoid changes presents typically as an “urticaria-arthritis syndrome.”7 Immune From the Division of Rheumatology, Penn State Milton S. Hershey complexes of hepatitis B virus surface antigen (HBsAg) Medical Center, Hershey, PA. Address correspondence to S.J.N., Thomas B. Hallowell Professor of and antibodies to hepatitis B virus surface antigen Medicine, Professor of Microbiology and Immunology, Professor of (HBsAb) circulate in the blood and are found deposited in 8,9 Pharmacology, and Chief, Division of Rheumatology, Penn State vessels in association with complement. The long laten- Milton S. Hershey Medical Center, Hershey, PA 17033. cy period of HBV allows time for an immune response to E-mail: [email protected]. occur. Viral replication increases HBsAg load, and is tem- VOLUME 69 • SUPPLEMENT II CLEVELAND CLINIC JOURNAL OF MEDICINE SII-15 Downloaded from www.ccjm.org on September 27, 2021. For personal use only. All other uses require permission. CAUSES OF VASCULITIS ■ NAIDES porally associated with jaundice.10 The immune complex- Staphylococcus and streptococcus infections are common es eventually no longer form in antigen excess, and the causes. Gram-negative organisms, other gram-positive serum sickness-like illness resolves. HBV has also been as- cocci, fungi, and parasites may be causative as well, and sociated with large-vessel polyarteritis nodosa-like ill- their occurrence depends on the clinical setting.60-66 ness.11 Onset is early in the course of chronic HBV he- Mycotic aneurysms resulting from septic emboli are com- patitis. Immune complexes containing HBsAg, HBsAb, mon with staphylococcus, streptococcus, and Salmonella and complement are found in the vessel wall.12 The de- species.67-69 Patients with subacute infections may devel- terminants of small vessel versus larger vessel disease in op cryoglobulins.70-72 Bacteremia may present as leukocy- the two syndromes of HBV infection are unknown. toclastic vasculitis.73,74 Small-vessel vasculitis may be as- Human immunodeficiency virus (HIV) patients may sociated with post-streptococcal infection, distinct from present with a variety of vasculitides. However, it is diffi- endocarditis.75,76 The Rickettsiae are a group of obligate in- cult to specifically attribute the various vasculitides seen tracellular bacteria with tropism for vascular endotheli- to HIV because of frequent co-infections with other um.77 Infection results in widespread microvascular leak, agents that may cause vasculitis in the absence of HIV in- local thrombosis, and ultimately multisystem failure if un- fection. Human T lymphotropic virus l infection may treated.78,79 cause retinal, cutaneous, or central nervous system vas- In the lung, necrosis of vessels may occur from septic culitis.13-16 emboli or from contiguous spread in primary pneumonias. The herpesviruses (cytomegalovirus, varicella-zoster, In the latter setting, Pseudomonas aeruginosa and Legionella herpes simplex viruses 1 and 2, and herpes hominis) may pneumophila often cause direct necrosis via contiguous be associated with retinal vasculitis in immunocompro- spread.80 The presentation, however, is that of pneumo- mised patients.17-23 Varicella-zoster may also cause a dif- nia. Mycobacterial or fungal pulmonary infections may fuse central nervous system small arterial granulomatous mimic Wegener’s granulomatosis or Churg-Strauss vas- vasculitis, or a small- and/or large-artery vasculopathy.24-27 culitis in eliciting a granulomatous reaction in vessels.81 Herpes simplex viruses 1 and 2 have been associated with Spread of Mycobacterium tuberculosis to the aorta may be cutaneous vasculitis and necrotizing arteritis of small and seen as a cause of tuberculous aortitis, coronary arteritis, medium vessels.28-30 Epstein-Barr virus has been suggested and mycotic aneurysm.82-84 Aspergillus aeruginosa, as a cause of both small- and large-vessel disease in a num- Aspergillus fumigatus, and Mucor may be characterized by ber of cases and short series.31-36 However, the ability to direct vessel invasion and necrosis.68,85,86 demonstrate causality in many instances is made all the Coccidioides immitis meningitis may be associated with more difficult by the latency of herpesvirus infection. vasculitis that can be confused with central nervous sys- Parvovirus B19 has been suggested as the causative tem angiitis.87,88 Coccidioides immitis may also present as agent of Wegener’s granulomatosis and polyarteritis no- an immune-complex–mediated disease with erythema no- dosa in a number of cases and short series.37-42 However, dosum, periarthritis predominantly of the ankles, and bi- the issue of latency and the failure to eliminate B19 from hilar lymphadenopathy.89,90 This presentation is often pooled blood products provides a cautionary note when confused with Löfgren’s syndrome of sarcoidosis. While considering causality.43-46 Rare cases of vasculitis have sarcoidosis as a cause of Löfgren’s syndrome is more preva- similarly been reported following rubella virus, aden- lent in eastern United States populations,