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Infectious etiologies of cutaneous vasculitis
Infectious Etiologies of Cutaneous Vasculitis LARRY E. MILLIKAN, MD TIMOTHY C. FLYNN, MD
V
asculitis remains an enigma for most physicians in practice. Because it is, by definition, a secondary phenomenon and not a disease suis generis, symptomatic treatment remains the primary goal until we come to the point where we are more likely to pick up probable etiologies and treat accordingly. The case presented here provides a good example of the direction we are going in our understanding of the infectious causes of vasculitis.
Case Report A 75-year-old woman noted the onset of an erythematous papular pruritic eruption on the knees and flexural aspects of the arms. An eczematous dermatitis was diagnosed, and oral antibiotics were prescribed by her primary-care physician. Betamethasone valerate ointment improved the patient’s dermatitis, and the patient was given oral prednisone. Elevated liver enzymes were noted on a serum chemistry panel. The AGT was elevated at 210 (nl 0 – 40) and alkaline phosphatase at 270 (nl 25–120). Hepatitis serology tests for hepatitis A, B, and C were negative. One month later, the patient experienced a widespread eruption consisting of edematous papules and vesicles (Fig 1). Some coalescence of the papules occurred, forming plaques on the trunk and thighs. Worsening of the dermatitis occurred over the next several weeks. Large areas of oozing and crusting developed. The patient’s liver functions improved with an ALT of 126 U/L (nl 5– 40) and AST 54 (nl 5– 40). Alkaline phosphatase was elevated to 328 U/L (nl 38 –126). Hepatitis C antibodies were detected in the patient’s serum a month after the initial negative hepatitis serologies. Skin biopsy revealed inflammation along the superficial and middle reticular dermis. Neutrophils and eosinophils were present in subcorneal and subepidermal blisters. A perivascular neutrophilic infiltrate with vasculitis was seen. The patient was treated with local Diprolene ointFrom the Department of Dermatology, Tulane University Medical Center, New Orleans, Louisiana USA. Address correspondence to Larry Millikan, M.D., Department of Dermatology, Tulane University Medical Center, New Orleans, LA 70112 USA. © 1999 by Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
ment with saran wrap occlusion intermittently over the next 5 months. Improvement was seen with topical therapy, and over the next 6 months the patient experienced only occasional outbreaks. Her liver functions have returned to normal, and PCR RNA quantitation of hepatitis C virus is within normal limits.
Mechanisms of Infectious Vasculitis Over the years, certain infections have been characterized with findings of purpuric or palpable purpuric lesions, often acral, the so-called hallmark signs of vasculitis. Perhaps the best examples relate to the infection in meningococcemia, Rocky Mountain spotted fever, and the related condition Henoch-Schoenlein purpura. The widespread sepsis that occurs in meningococcal and gram-negative infections, and the subsequent vascular reactions in many instances, is a septic vasculitis, but often is limited to the areas of septic vessel involvement, which is usually acral. In other cases the infection is remote from the infection (ie, herpes simplex, hepatitis B or C) when more widespread vascular involvement occurs. Traditional concepts in vasculitis center most frequently around the traditional Coombs and Gell classification of immunologic reactions. Of the four types of reactions, Type 3 seems to be still the leading contender in the study of vasculitis. As understanding expands, the possibility of very specific Type 2 reactions directed at the vascular epithelium cannot be ruled out entirely. A Type 3 or immune-complex reaction has always been the most likely possibility in those patients with vasculitis. This can be carried over into the concept of vasculitis associated with infections, wherein the antigens often are the infectious agents. As the host develops increasing immunity, the similarities to serum sickness become quite apparent. The size of immune complexes has bearing on the extent of AG/AB interaction as the zone of equivalence is reached. The resultant large immune complexes can become trapped in vessels, simulating an immune response that results in what microscopically appears as a vasculitis (Table 1). The antigen can be whole organisms, with IgM and IgG antibodies to same, forming the large lattice that then becomes an area of vascular compromise with subsequent inflam0738-081X/99/$–see front matter PII S0738-081X(99)00061-9
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Figure 1. Infectious vasculitis most prominent on the distal extremities.
Figure 2. “Classical vasculitis” related to the rickettsial organisms of Q fever.
matory reaction, chemotaxis of inflammatory polymorphonuclear and phagocytic cells, infiltrating the vessel wall giving the picture of vasculitis. The antigen can be an entire organism or antigenic portions of the infectious agents resulting from destruction and inflammation of those organisms (see alternate complement pathway below). Another pathway is the formation of cryoglobulins to infectious agents and other monoclonal antibody (rather than usual IgM or IgG antibodies) production that in smaller vessels can stimulate the sequence of vasculitis. This seems to be the case often in many patients with viral infections such as hepatitis C, as mentioned in the Case Report. Vasculitis from complement activation by the Pillemer pathway is another direct process associated with several infectious organisms (see Table 2). The alternate pathway of complement provides direct activation of the complement components (Table 2) by various microorganisms, whole or partial, and their antigens. Direct activation from candida polysaccharides, and fragments of gram-positive and gram-negative organisms can rapidly activate the alternate pathway, which allows a rapid response by the host, thus
circumventing the recruitment and expansion of the B-cell clone to produce antibodies against the specific organism. The direct involvement of certain organisms and their effect on endothelial cells and vessels in the early steps of vasculitis may be mediated by such pathways, resulting in evolution of early complement components to the C5, C6, and C7 chemotaxic factors that cause the microscopic and ultimately clinical vasculitic process. Table 1.
Infectious Mechanisms in Vasculitis
I Classical Coombs/Gel reactions II Cytotoxic III Immune complexes IGG, IGM, IGA Cryoglobulins Alternate pathway complement activation Polysaccharides gram (⫺) organism Bacterial products Superantigens Gamma/delta T cells Heat shock proteins
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The traditional pathway of complement activation is involved in the traditional response to antigen-antibody immune complexes stimulating the first components of complement C1, C4, and C2 with the amplification loop of C3. The complement activation with the immense amplification at the C3 step greatly enhances the inflammatory response of the host, and is an essential defense that develops from microbial antigens reacting with host antibodies or microbial antigen or fragments activating directly the alternative pathway. As alluded to above, the classical studies of Dixon in serum sickness provided the groundwork for our understanding of Type III reactions and the subsequent vasculitis and clinical signs of dermatitis, urticaria, and arthritis. As our understanding of immune and inflammatory reactions has expanded beyond the traditional concepts into the proliferating area of cytokines, other mechanisms are now being proposed and studied. Some newer concepts involving our increased understanding of the various cytokines are under close scrutiny. Such cytokines as tumor necrosis factor and various interleukins may be very significant in the evolution of vasculitis, and such cytokines may be produced directly by the stimulation from various infectious agents. This results in recruitment of polymorphonuclear cells into the peripheral small vessels, with a small-vessel vasculitis giving the clinical picture of palpable purpura. There are very intriguing reports suggesting virtually all types of infectious agents as playing a role in the development of vasculitis. These range from common organisms, both gram-positive and gram-negative including Staphylococcus, Streptococcus, and meningococcus. Under these circumstances, a widespread vasculitis can occur as is seen with the toxic shock syndrome related to Staphylococcus or Streptococcus.1 Cytokine formation and inflammatory cell infiltration that result are the mechanisms presumed for infectious vasculitis occurring with these organisms. Intriguing also is a recent case where HenochSchoenlein purpura was found to respond to treatment for Helicobacter pylori.2 We and others have seen the same thing occur in some patients with Sweet’s syndrome. Here again is an inflammatory process in which vasculitis is a major component, and is intriguing to think that H. Pylori is only the first of many infectious agents that can stimulate this characteristic reaction. With newer polymerase chain reaction (PCR) technology, identification of other infectious organisms as a cause of vasculitis seems certain. The vasculitis occurring with certain granulomas also adds emphasis to the need for evaluation in patients with vasculitis to determine whether a granulomatous infection is an underlying agent or whether an unusual “presumed” infectious disorder such as sarcoidosis is a cause. Viral infections represent perhaps the current area of greatest interest in elucidation of the infectious causes
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for vasculitis. Hepatitis C results in many cutaneous signs and symptoms including vasculitis, erythema multiforme, erythema nodosum, Behcet’s syndrome, urticaria and pruritus—all with some aspects of vasculitis. Additionally Lichen planus, porphyria cutanea tarda and malacoplakia have been similarly reported.3 The case mentioned above is an example of many reports in the literature of vasculitis occurring in association with hepatitis C.4,5 The problem with hepatitis C infections often is proving the association because there remains in many patients no good therapeutic approach to completely clear the infection.6 If the hypothesis of hepatitis C as a cause of the vasculitis were true, one should see clearing of the vasculitic process with treatment as reported by various investigators.7,8 Two decades ago, the broadening interest in hepatitis B and its cutaneous manifestations initiated some of the earliest studies of the role of viral infections as a cause of vasculitiis.4 This indeed was a possible cause of an urticarial syndrome as well as vasculitis; the primary pathology of urticaria, urticarial vasculitis, and vasculitis alone occurred in the incubation process when the antibody response had surpassed the zone of equivalence, resulting in the formation of large immune complexes that, when positive in the smaller vessels, progressed to vasculitis. The viremia that caused this series of events was early on in the infection, prior to the severe involvement of the hepatoctyes and the subsequent clinical picture of icterus and clinical hepatitis. This process could occur in some patients with a milder involvement, resulting in anicteric hepatitis. The extensive studies in hepatitis B infection the 1970s are now supplanted by a similar flurry of studies of the full spectrum of cutaneous signs of hepatitis C in the mid1980s to the 1990s. A great number of patients with hepatitis C also may manifest the nontraditional mechanism in the formation of the vasculitic process. Cryoglobulins are a common association with hepatitis C infection,5,6 and proliferation of other monoclonal antibodies may also be significant in the evolution of the vasculitic process. Only recently, with the use of various agents such as plasmapheresis and interferons,7,8 have we been able to provide even a minimum treatment regimen for these patients. Hence, without any definitive or consistent curative therapy for any of these viral disorders, the fulfillment of Koch’s postulates is not possible. The impetus to aggressively pursue the direct association of the virus and the vasculitis in these cases is most important. If it is impossible to clear the viral infection, then one cannot establish with full confidence the real association. A possible indirect approach would be the use of viral antigen levels (by PCR—as is now done with HIV) and comparison of the clinical picture with intensity of the viral load. This is particularly a problem in some viruses that tend to have had a long and close
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Table 2. 1.
2.
Treatment of Infectious Vasculitis
Determine Etiology PCR AB response Culture Biochemical sequelae Address agent with specific therapy Antibacterial Antiviral Supportive Therapy Relates to severity of syndrome Severe Corticosteroid therapy Anti-fibrinolytic merger Anti-H1/H2 histamine therapy Depsone (as a steroid-sparing modality) Pheresis Immunoabsorption Routine Antihistamines H1/H2
association with mankind, such as the herpes group of viruses. Following the flurry of studies in the evolution of vasculitis in patients with hepatitis (involving urticaria and erythema multiforme as intermediate steps), similar work was done looking at herpes simplex, when newer techniques became available to identify easily and early on particles and specifically viral antigen antibody complexes. Researchers reported severe necrotizing vasculitis in neonatal herpes simplex infections,9 and traditional leuckocytoclastic vasculitis associated with herpes was reported in 1984.10 With the herpes group of viruses, this number of identifiable subsets has grown rapidly through herpes virus I through herpes virus VIII. Historically, the erythema multiforme (EM) seen with HSV-I/II has been previously well defined. The vasculitis in EM links the herpes virus as a cause of vasculitis.10,11 In comparative epidemiology, there is a vasculitic process seen with infection from the gazelle herpes virus (which is the same as the equine herpes) IX.12 As many of these patients are in remote areas, especially sub-Saharan Africa, better diagnosis and optimal therapy still elude us because of the local conditions in these areas. Recent research findings are perhaps the most promising explorations into the interaction of cytokines and other molecules in the vasculitis process. Studies on leukocytoclastic vasculitis has highlighted the role of eosinophils, tumor necrosis factor-alpha, IL-5, VCAM-1, and other factors often resulting in the picture of a Type 3 drug reaction.13 Researchers have also studied superantigens, and gamma/delta T lymphocytes in vasculitis.14 It is intriguing to consider the possibility that coexistence of initiating viral infections can set off this cascade. The role of the herpes virus in this process with such agents as HHV-7 and -8 is an area of very active research at the present time, with
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promise for a fruitful evolution of our understanding in the near future. Additionally, the chronic infection with some of these herpes viruses can be susceptible to reactivation, and further may be cofactors in several pathologic processes, involving the vessels. The most significant prototype is the association of herpes virus 8 with Kaposi’s sarcoma.14 The understanding of the exact role of herpes viruses 6, 7, and 8 at the present time is not totally clear because of the omnipresence of some of these organisms, the chronicity of the infection in the body, and the inability with all the tools available at the present time to sort out a primary etiological role from a passenger role or even an associated epi-phenomenon. The antibody response to the infectious organism, however, can be manifest with a clonal proliferation of lymphocytes and sometimes a monoclonal gammopathy, which are the preliminary steps that ultimately result in vasculitis. Other reactions can similarly start the pathway of cryoglobulin production, which then affects the smaller peripheral vessels, producing a leukoctyoclastic vasculitis. A complement cascade after primary infection in various types of viruses can result in activation of cytokines, giving the ultimate picture of vasculitis, or the direct stimulation of antibodies, some of which are cryoglobulins, with similar results. The production of significant levels of cryoglobulins that persist for a certain amount of time can result in flare-ups of the vasculitis from seeming inconsequential co-infections. In the animal world, it was previously mentioned about the equine herpes viruses and their ability to cause a vasculitis. Similarly, zoonotic infection with Brucella has been reported to result in the production of a vasculitic picture, clinically and microscopically.15 Additionally, the path to clinical vasculitis can be initiated directly by infectious organisms through the alternative or pillemer pathway of complement activation (Table 2). This can be directly activated through various surface receptors, sugars, and so forth, and can be done so directly through gram-negative organisms as well as many yeasts. Nonimmunologic activation occurs from bacterial debris, lipopolysaccharides, enzymes, and polysaccharides from plants and bacteria. This may be a major role for the vasculitis and septic shock seen in gram-negative septicemia and also the severe systemic signs and symptoms associated with candidemia. The organism’s less well understood because of the gravity of the clinical situation and the acute nature. The high level of mortality has limited full investigation and limited animal models for such are available. Other organisms of significance in the vasculitic process include the intermediate organisms such as Rickettsia and Mycoplasma. As mentioned above, the acral purpura, which is one of the hallmarks of spotted fever,
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was found in the 1970s to be accompanied microscopically with rickettsial debris in the peripheral vessels, stimulating both the vasculitic process and the purpuric picture, which is typical of the syndrome.16 Similar clinical pictures can occur accompanying Mycoplasma infections, which can result in anaphylactoid purpura and clinically a picture of vasculitis.17 Among yeast and fungal organisms, candida is perhaps the foremost example of infectious-associated vasculitis. Here, in many instances, it is presumed that the candida polysaccharides directly turn on the alternative pathway of complement as organisms get trapped in the peripheral small vessels. This subsequently activates complement components that cause the C5, C6, and C7 steps stimulating chemotaxis as well as the terminal C8, C9 activation steps that result in cell membrane destruction. Importantly, the earlier steps of complement may also be essential in agglutination of these organisms to facilitate the host’s clearance of them through phagolysosomal uptake or direct membrane attack through the terminal complement C8, C9 steps. Although the immune complexes can be deleterious to the host in their effect, as they do produce clinical vasculitis. These steps are, however, an essential one to allow the body’s recticuloendothelial system to clear these organisms, whether they be bacterial, fungal, yeast, or viral. Finally, in the role of infectious etiologies, some studies have reported Senus Cryptococcus as the cause of vasculitis in patients, some of which have congenital immune deficiency disease, and others (HIV, transplant patients) who have chronic cryptococcosis and other fungal infections.18 Many of the very florid infections that result in a clonal proliferation of B cells with a subsequent antibody production, especially production of monoclonal antibodies (m proteins), can give this picture. This becomes even a greater likelihood in patients in whom HIV infection has played a major role in alteration of the innate immune system. Regulation of the antibody response after exposure to infectious organisms is suppressed in the patient with florid HIV infection because of the changes in the T-helper/suppressor type that would normally be effective in fighting the infection and regulating the antibody response to same.19 The immunosuppressed patient, especially those with HIV-1, are unique examples of the potential for a cascade of infections in which a similar response with cytokines and antibodies can give a clinical picture of vasculitis. Further, many infectious agents that would normally be easily suppressed in the normal host proliferate in the HIV-positive patients, and this can result in the initiation of many of these immunologic pathways that can predispose the patient to a fulminant vasculitis, with dramatic cutaneous findings including necrosis.19
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Treatment The usual principles of therapy for all types of vasculitis pertain here; the key is early identification of the infectious agent and appropriate treatment. As one can see from the Case Report, many new approaches are being developed to address the situation with hepatitis C. With other infections, the appropriate antimicrobial is essential, and in severe/acute episodes, antimicrobials plus steroids are appropriate. Plasmapheresis and immunoabsorption have been useful in some of these chronic infections that lack adequate therapy. This will diminish the accumulation of various proteins that precipitate the inflammatory process through complement activation and other activities. Table 2 outlines the appropriate therapy for infectious vasculitis.
Conclusions Perhaps the best examples of infection-associated vasculitis today are some of the more traditional bacterial infections (streptococcus and meningococcus), but of growing significance in the literature is the association of hepatitis C with this similar process. Indeed, many patients in the past with a leukocytoclastic vasculitis may have had an association with hepatitis B and/or C, but this occurred at a time when sensitive testing to identify the infection in most hosts was not feasible or easily done. With better techniques such as PCR and various immunodiagnostic techniques, looking at characteristic antibodies with certain infections now offers us an ability to sort out and determine the true incidence of vasculitis related to the myriad of infectious agents. If one is liberal in interpretation of vasculitis to include some of the acute erythemas such as erythema multiforme, a major cause having a vasculitis as a significant portion of immunologic findings could extend the association of infectious agents from other categories of vasculitis. The literature in regards to bullous erythema multiforme encompasses many agents, including drugs, infectious agents, and other precipitating factors. The exact steps going from mycoplasma as an asymptomatic infection to mycoplasma causing pneumonia, to erythema multiforme of a minor or major category still remains to be worked out. This, however, is an excellent example of a reactive process, vasculitis-like so to speak, that can be eloquently treated if one includes perseverance in the study techniques. As our detection tools increase in sensitivity we are finding more associations of infections precipitating clinical vasculitis. This increasing precision in identification, coupled with newer and more effective antimicrobial therapy, promises more effective and faster therapy for these patients.
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References 1. Mandes ST. Toxin-mediated streptococcal and staphylococcal disease. J Am Acad Dermatol 1998;39:383–98. 2. Mozrzymas R, d’Amore ES, Montini G, et al. SchoenleinHenoch vasculitis and chronic Helicobacter pyloris associated gastritis and duodenal ulcer: A case report. Ped Med Clin 1997;19:467– 8. 3. Gower RG, Saysker WF, Komler FP, et al. Small-vessel vasculitis caused by hepatitis B virus immune complexes. J Allergy Clin Immunol 1978;62:222– 8. 4. Parson ME, Russo GG, Millikan LE. Dermatologic disorders associated with viral hepatitis infections. Int J Dermatol 1996;35(2):77– 81. 5. Hadziyannis SJ. Skin diseases associated with hepatitis C virus infection. J Eur Acad Dermatol Venereol 1998;10(1): 12–21. 6. Daoud MS, Gibson LE, Daoud S, et al. Chronic hepatitis C and skin diseases: A review. Mayo Clin Proc 1995;70: 559 – 64. 7. von Kobyletzki G, Stucker M, Hoffman K, et al. Severe therapy-resistant necrotizing vasculitis associated with hepatitis C virus infection: Successful treatment of the vasculitis with extracorporeal immunoadsorption. Br J Dermatol 1998;138:926 –7. 8. Limaye AP, Schmidt RA, Glenny RW, et al. Successful treatment of severe hepatitis C-associated pulmonary vasculitis in a liver transplant recipient. Transplantation 1998; 65:9989 –1000. 9. Phinney PR, Higiel S, Bryson VJ, et al. Necrotizing vasculitis in a case of neonatal herpes simplex infection. Arch Pathol Lab Med 1982;106:64 –7. 10. Cohen C, Trapuckol S. Leucocytoclastic vasculitis associated with cutaneous infection by herpes viruses. Am J Dermatopathol 1984;6:561–5.
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11. Dupin N, Maralin A, Gorin I, et al. Prevalence of human herpes virus 8 infection measured by antibodies to later nuclear antigen in patients with various dermatologic diseases. Arch Dermatol 1998;134:700 –7. 12. Yanai T, Sarac T, Fubushih, et al. Neuropathological study of gazelle herpes virus 1 (equine herpes virus 9) infection in Thomasons gazelles. J Comp Pathol 1998; 119:159 – 68. 13. Comacchi C, Ghersetich I, Lotti T. Gamma-delta T lymphocytes in leucocytoclastic cutaneous necrotizing vasculitis: Clue to the infective etiology. Int J Immunopathol Pharmacol 1992;10:53– 6. 14. Cattani P, Capuano M, Lesnoni I, et al. Human herpes virus 8 in Italian HIV seronegative patients with Kaposi sarcoma. Arch Dermatol 1998;134:695–9. 15. Nagore E, Sanchez-Motilla J, Navarro V, et al. Leukocytoclastic vasculitis as a cutaneous manifestation of systemic infection caused by Brucella melitises. Cutis 1999;63: 25–7. 16. Walker DH, Cain BG, Olmstead PM. Laboratory diagnosis of Rocky Mountain spotted fever by immunofluorescent demonstration of Rickettsia in cutaneous lesions. Am J Clin Pathol 1978;69:619 –23. 17. Sussman M, Jones JH, Almida JD, et al. Deficiency of the second component of complement associated with anaphylactoid purpura and the presence of mycoplasma in the serum. Clin Exp Immunol 1973;14:531–9. 18. Kovacs JA, Kovacs AA, Polis M, et al. Cryptococcosis in the acquired immune deficiency syndrome. Ann Intern Med 1985;103:533– 8. 19. Roh SS, Gertner L. Digital necrosis in acquired immune deficiency syndrome vasculopathy treated with recombinant tissue plasmogen activator. J Rheumatol 1997;24: 2258 – 61.
V
asculitis remains an enigma for most physicians in practice. Because it is, by definition, a secondary phenomenon and not a disease suis generis, symptomatic treatment remains the primary goal until we come to the point where we are more likely to pick up probable etiologies and treat accordingly. The case presented here provides a good example of the direction we are going in our understanding of the infectious causes of vasculitis.
Case Report A 75-year-old woman noted the onset of an erythematous papular pruritic eruption on the knees and flexural aspects of the arms. An eczematous dermatitis was diagnosed, and oral antibiotics were prescribed by her primary-care physician. Betamethasone valerate ointment improved the patient’s dermatitis, and the patient was given oral prednisone. Elevated liver enzymes were noted on a serum chemistry panel. The AGT was elevated at 210 (nl 0 – 40) and alkaline phosphatase at 270 (nl 25–120). Hepatitis serology tests for hepatitis A, B, and C were negative. One month later, the patient experienced a widespread eruption consisting of edematous papules and vesicles (Fig 1). Some coalescence of the papules occurred, forming plaques on the trunk and thighs. Worsening of the dermatitis occurred over the next several weeks. Large areas of oozing and crusting developed. The patient’s liver functions improved with an ALT of 126 U/L (nl 5– 40) and AST 54 (nl 5– 40). Alkaline phosphatase was elevated to 328 U/L (nl 38 –126). Hepatitis C antibodies were detected in the patient’s serum a month after the initial negative hepatitis serologies. Skin biopsy revealed inflammation along the superficial and middle reticular dermis. Neutrophils and eosinophils were present in subcorneal and subepidermal blisters. A perivascular neutrophilic infiltrate with vasculitis was seen. The patient was treated with local Diprolene ointFrom the Department of Dermatology, Tulane University Medical Center, New Orleans, Louisiana USA. Address correspondence to Larry Millikan, M.D., Department of Dermatology, Tulane University Medical Center, New Orleans, LA 70112 USA. © 1999 by Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
ment with saran wrap occlusion intermittently over the next 5 months. Improvement was seen with topical therapy, and over the next 6 months the patient experienced only occasional outbreaks. Her liver functions have returned to normal, and PCR RNA quantitation of hepatitis C virus is within normal limits.
Mechanisms of Infectious Vasculitis Over the years, certain infections have been characterized with findings of purpuric or palpable purpuric lesions, often acral, the so-called hallmark signs of vasculitis. Perhaps the best examples relate to the infection in meningococcemia, Rocky Mountain spotted fever, and the related condition Henoch-Schoenlein purpura. The widespread sepsis that occurs in meningococcal and gram-negative infections, and the subsequent vascular reactions in many instances, is a septic vasculitis, but often is limited to the areas of septic vessel involvement, which is usually acral. In other cases the infection is remote from the infection (ie, herpes simplex, hepatitis B or C) when more widespread vascular involvement occurs. Traditional concepts in vasculitis center most frequently around the traditional Coombs and Gell classification of immunologic reactions. Of the four types of reactions, Type 3 seems to be still the leading contender in the study of vasculitis. As understanding expands, the possibility of very specific Type 2 reactions directed at the vascular epithelium cannot be ruled out entirely. A Type 3 or immune-complex reaction has always been the most likely possibility in those patients with vasculitis. This can be carried over into the concept of vasculitis associated with infections, wherein the antigens often are the infectious agents. As the host develops increasing immunity, the similarities to serum sickness become quite apparent. The size of immune complexes has bearing on the extent of AG/AB interaction as the zone of equivalence is reached. The resultant large immune complexes can become trapped in vessels, simulating an immune response that results in what microscopically appears as a vasculitis (Table 1). The antigen can be whole organisms, with IgM and IgG antibodies to same, forming the large lattice that then becomes an area of vascular compromise with subsequent inflam0738-081X/99/$–see front matter PII S0738-081X(99)00061-9
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Figure 1. Infectious vasculitis most prominent on the distal extremities.
Figure 2. “Classical vasculitis” related to the rickettsial organisms of Q fever.
matory reaction, chemotaxis of inflammatory polymorphonuclear and phagocytic cells, infiltrating the vessel wall giving the picture of vasculitis. The antigen can be an entire organism or antigenic portions of the infectious agents resulting from destruction and inflammation of those organisms (see alternate complement pathway below). Another pathway is the formation of cryoglobulins to infectious agents and other monoclonal antibody (rather than usual IgM or IgG antibodies) production that in smaller vessels can stimulate the sequence of vasculitis. This seems to be the case often in many patients with viral infections such as hepatitis C, as mentioned in the Case Report. Vasculitis from complement activation by the Pillemer pathway is another direct process associated with several infectious organisms (see Table 2). The alternate pathway of complement provides direct activation of the complement components (Table 2) by various microorganisms, whole or partial, and their antigens. Direct activation from candida polysaccharides, and fragments of gram-positive and gram-negative organisms can rapidly activate the alternate pathway, which allows a rapid response by the host, thus
circumventing the recruitment and expansion of the B-cell clone to produce antibodies against the specific organism. The direct involvement of certain organisms and their effect on endothelial cells and vessels in the early steps of vasculitis may be mediated by such pathways, resulting in evolution of early complement components to the C5, C6, and C7 chemotaxic factors that cause the microscopic and ultimately clinical vasculitic process. Table 1.
Infectious Mechanisms in Vasculitis
I Classical Coombs/Gel reactions II Cytotoxic III Immune complexes IGG, IGM, IGA Cryoglobulins Alternate pathway complement activation Polysaccharides gram (⫺) organism Bacterial products Superantigens Gamma/delta T cells Heat shock proteins
Clinics in Dermatology
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1999;17:509 –514
The traditional pathway of complement activation is involved in the traditional response to antigen-antibody immune complexes stimulating the first components of complement C1, C4, and C2 with the amplification loop of C3. The complement activation with the immense amplification at the C3 step greatly enhances the inflammatory response of the host, and is an essential defense that develops from microbial antigens reacting with host antibodies or microbial antigen or fragments activating directly the alternative pathway. As alluded to above, the classical studies of Dixon in serum sickness provided the groundwork for our understanding of Type III reactions and the subsequent vasculitis and clinical signs of dermatitis, urticaria, and arthritis. As our understanding of immune and inflammatory reactions has expanded beyond the traditional concepts into the proliferating area of cytokines, other mechanisms are now being proposed and studied. Some newer concepts involving our increased understanding of the various cytokines are under close scrutiny. Such cytokines as tumor necrosis factor and various interleukins may be very significant in the evolution of vasculitis, and such cytokines may be produced directly by the stimulation from various infectious agents. This results in recruitment of polymorphonuclear cells into the peripheral small vessels, with a small-vessel vasculitis giving the clinical picture of palpable purpura. There are very intriguing reports suggesting virtually all types of infectious agents as playing a role in the development of vasculitis. These range from common organisms, both gram-positive and gram-negative including Staphylococcus, Streptococcus, and meningococcus. Under these circumstances, a widespread vasculitis can occur as is seen with the toxic shock syndrome related to Staphylococcus or Streptococcus.1 Cytokine formation and inflammatory cell infiltration that result are the mechanisms presumed for infectious vasculitis occurring with these organisms. Intriguing also is a recent case where HenochSchoenlein purpura was found to respond to treatment for Helicobacter pylori.2 We and others have seen the same thing occur in some patients with Sweet’s syndrome. Here again is an inflammatory process in which vasculitis is a major component, and is intriguing to think that H. Pylori is only the first of many infectious agents that can stimulate this characteristic reaction. With newer polymerase chain reaction (PCR) technology, identification of other infectious organisms as a cause of vasculitis seems certain. The vasculitis occurring with certain granulomas also adds emphasis to the need for evaluation in patients with vasculitis to determine whether a granulomatous infection is an underlying agent or whether an unusual “presumed” infectious disorder such as sarcoidosis is a cause. Viral infections represent perhaps the current area of greatest interest in elucidation of the infectious causes
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for vasculitis. Hepatitis C results in many cutaneous signs and symptoms including vasculitis, erythema multiforme, erythema nodosum, Behcet’s syndrome, urticaria and pruritus—all with some aspects of vasculitis. Additionally Lichen planus, porphyria cutanea tarda and malacoplakia have been similarly reported.3 The case mentioned above is an example of many reports in the literature of vasculitis occurring in association with hepatitis C.4,5 The problem with hepatitis C infections often is proving the association because there remains in many patients no good therapeutic approach to completely clear the infection.6 If the hypothesis of hepatitis C as a cause of the vasculitis were true, one should see clearing of the vasculitic process with treatment as reported by various investigators.7,8 Two decades ago, the broadening interest in hepatitis B and its cutaneous manifestations initiated some of the earliest studies of the role of viral infections as a cause of vasculitiis.4 This indeed was a possible cause of an urticarial syndrome as well as vasculitis; the primary pathology of urticaria, urticarial vasculitis, and vasculitis alone occurred in the incubation process when the antibody response had surpassed the zone of equivalence, resulting in the formation of large immune complexes that, when positive in the smaller vessels, progressed to vasculitis. The viremia that caused this series of events was early on in the infection, prior to the severe involvement of the hepatoctyes and the subsequent clinical picture of icterus and clinical hepatitis. This process could occur in some patients with a milder involvement, resulting in anicteric hepatitis. The extensive studies in hepatitis B infection the 1970s are now supplanted by a similar flurry of studies of the full spectrum of cutaneous signs of hepatitis C in the mid1980s to the 1990s. A great number of patients with hepatitis C also may manifest the nontraditional mechanism in the formation of the vasculitic process. Cryoglobulins are a common association with hepatitis C infection,5,6 and proliferation of other monoclonal antibodies may also be significant in the evolution of the vasculitic process. Only recently, with the use of various agents such as plasmapheresis and interferons,7,8 have we been able to provide even a minimum treatment regimen for these patients. Hence, without any definitive or consistent curative therapy for any of these viral disorders, the fulfillment of Koch’s postulates is not possible. The impetus to aggressively pursue the direct association of the virus and the vasculitis in these cases is most important. If it is impossible to clear the viral infection, then one cannot establish with full confidence the real association. A possible indirect approach would be the use of viral antigen levels (by PCR—as is now done with HIV) and comparison of the clinical picture with intensity of the viral load. This is particularly a problem in some viruses that tend to have had a long and close
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Table 2. 1.
2.
Treatment of Infectious Vasculitis
Determine Etiology PCR AB response Culture Biochemical sequelae Address agent with specific therapy Antibacterial Antiviral Supportive Therapy Relates to severity of syndrome Severe Corticosteroid therapy Anti-fibrinolytic merger Anti-H1/H2 histamine therapy Depsone (as a steroid-sparing modality) Pheresis Immunoabsorption Routine Antihistamines H1/H2
association with mankind, such as the herpes group of viruses. Following the flurry of studies in the evolution of vasculitis in patients with hepatitis (involving urticaria and erythema multiforme as intermediate steps), similar work was done looking at herpes simplex, when newer techniques became available to identify easily and early on particles and specifically viral antigen antibody complexes. Researchers reported severe necrotizing vasculitis in neonatal herpes simplex infections,9 and traditional leuckocytoclastic vasculitis associated with herpes was reported in 1984.10 With the herpes group of viruses, this number of identifiable subsets has grown rapidly through herpes virus I through herpes virus VIII. Historically, the erythema multiforme (EM) seen with HSV-I/II has been previously well defined. The vasculitis in EM links the herpes virus as a cause of vasculitis.10,11 In comparative epidemiology, there is a vasculitic process seen with infection from the gazelle herpes virus (which is the same as the equine herpes) IX.12 As many of these patients are in remote areas, especially sub-Saharan Africa, better diagnosis and optimal therapy still elude us because of the local conditions in these areas. Recent research findings are perhaps the most promising explorations into the interaction of cytokines and other molecules in the vasculitis process. Studies on leukocytoclastic vasculitis has highlighted the role of eosinophils, tumor necrosis factor-alpha, IL-5, VCAM-1, and other factors often resulting in the picture of a Type 3 drug reaction.13 Researchers have also studied superantigens, and gamma/delta T lymphocytes in vasculitis.14 It is intriguing to consider the possibility that coexistence of initiating viral infections can set off this cascade. The role of the herpes virus in this process with such agents as HHV-7 and -8 is an area of very active research at the present time, with
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promise for a fruitful evolution of our understanding in the near future. Additionally, the chronic infection with some of these herpes viruses can be susceptible to reactivation, and further may be cofactors in several pathologic processes, involving the vessels. The most significant prototype is the association of herpes virus 8 with Kaposi’s sarcoma.14 The understanding of the exact role of herpes viruses 6, 7, and 8 at the present time is not totally clear because of the omnipresence of some of these organisms, the chronicity of the infection in the body, and the inability with all the tools available at the present time to sort out a primary etiological role from a passenger role or even an associated epi-phenomenon. The antibody response to the infectious organism, however, can be manifest with a clonal proliferation of lymphocytes and sometimes a monoclonal gammopathy, which are the preliminary steps that ultimately result in vasculitis. Other reactions can similarly start the pathway of cryoglobulin production, which then affects the smaller peripheral vessels, producing a leukoctyoclastic vasculitis. A complement cascade after primary infection in various types of viruses can result in activation of cytokines, giving the ultimate picture of vasculitis, or the direct stimulation of antibodies, some of which are cryoglobulins, with similar results. The production of significant levels of cryoglobulins that persist for a certain amount of time can result in flare-ups of the vasculitis from seeming inconsequential co-infections. In the animal world, it was previously mentioned about the equine herpes viruses and their ability to cause a vasculitis. Similarly, zoonotic infection with Brucella has been reported to result in the production of a vasculitic picture, clinically and microscopically.15 Additionally, the path to clinical vasculitis can be initiated directly by infectious organisms through the alternative or pillemer pathway of complement activation (Table 2). This can be directly activated through various surface receptors, sugars, and so forth, and can be done so directly through gram-negative organisms as well as many yeasts. Nonimmunologic activation occurs from bacterial debris, lipopolysaccharides, enzymes, and polysaccharides from plants and bacteria. This may be a major role for the vasculitis and septic shock seen in gram-negative septicemia and also the severe systemic signs and symptoms associated with candidemia. The organism’s less well understood because of the gravity of the clinical situation and the acute nature. The high level of mortality has limited full investigation and limited animal models for such are available. Other organisms of significance in the vasculitic process include the intermediate organisms such as Rickettsia and Mycoplasma. As mentioned above, the acral purpura, which is one of the hallmarks of spotted fever,
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was found in the 1970s to be accompanied microscopically with rickettsial debris in the peripheral vessels, stimulating both the vasculitic process and the purpuric picture, which is typical of the syndrome.16 Similar clinical pictures can occur accompanying Mycoplasma infections, which can result in anaphylactoid purpura and clinically a picture of vasculitis.17 Among yeast and fungal organisms, candida is perhaps the foremost example of infectious-associated vasculitis. Here, in many instances, it is presumed that the candida polysaccharides directly turn on the alternative pathway of complement as organisms get trapped in the peripheral small vessels. This subsequently activates complement components that cause the C5, C6, and C7 steps stimulating chemotaxis as well as the terminal C8, C9 activation steps that result in cell membrane destruction. Importantly, the earlier steps of complement may also be essential in agglutination of these organisms to facilitate the host’s clearance of them through phagolysosomal uptake or direct membrane attack through the terminal complement C8, C9 steps. Although the immune complexes can be deleterious to the host in their effect, as they do produce clinical vasculitis. These steps are, however, an essential one to allow the body’s recticuloendothelial system to clear these organisms, whether they be bacterial, fungal, yeast, or viral. Finally, in the role of infectious etiologies, some studies have reported Senus Cryptococcus as the cause of vasculitis in patients, some of which have congenital immune deficiency disease, and others (HIV, transplant patients) who have chronic cryptococcosis and other fungal infections.18 Many of the very florid infections that result in a clonal proliferation of B cells with a subsequent antibody production, especially production of monoclonal antibodies (m proteins), can give this picture. This becomes even a greater likelihood in patients in whom HIV infection has played a major role in alteration of the innate immune system. Regulation of the antibody response after exposure to infectious organisms is suppressed in the patient with florid HIV infection because of the changes in the T-helper/suppressor type that would normally be effective in fighting the infection and regulating the antibody response to same.19 The immunosuppressed patient, especially those with HIV-1, are unique examples of the potential for a cascade of infections in which a similar response with cytokines and antibodies can give a clinical picture of vasculitis. Further, many infectious agents that would normally be easily suppressed in the normal host proliferate in the HIV-positive patients, and this can result in the initiation of many of these immunologic pathways that can predispose the patient to a fulminant vasculitis, with dramatic cutaneous findings including necrosis.19
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Treatment The usual principles of therapy for all types of vasculitis pertain here; the key is early identification of the infectious agent and appropriate treatment. As one can see from the Case Report, many new approaches are being developed to address the situation with hepatitis C. With other infections, the appropriate antimicrobial is essential, and in severe/acute episodes, antimicrobials plus steroids are appropriate. Plasmapheresis and immunoabsorption have been useful in some of these chronic infections that lack adequate therapy. This will diminish the accumulation of various proteins that precipitate the inflammatory process through complement activation and other activities. Table 2 outlines the appropriate therapy for infectious vasculitis.
Conclusions Perhaps the best examples of infection-associated vasculitis today are some of the more traditional bacterial infections (streptococcus and meningococcus), but of growing significance in the literature is the association of hepatitis C with this similar process. Indeed, many patients in the past with a leukocytoclastic vasculitis may have had an association with hepatitis B and/or C, but this occurred at a time when sensitive testing to identify the infection in most hosts was not feasible or easily done. With better techniques such as PCR and various immunodiagnostic techniques, looking at characteristic antibodies with certain infections now offers us an ability to sort out and determine the true incidence of vasculitis related to the myriad of infectious agents. If one is liberal in interpretation of vasculitis to include some of the acute erythemas such as erythema multiforme, a major cause having a vasculitis as a significant portion of immunologic findings could extend the association of infectious agents from other categories of vasculitis. The literature in regards to bullous erythema multiforme encompasses many agents, including drugs, infectious agents, and other precipitating factors. The exact steps going from mycoplasma as an asymptomatic infection to mycoplasma causing pneumonia, to erythema multiforme of a minor or major category still remains to be worked out. This, however, is an excellent example of a reactive process, vasculitis-like so to speak, that can be eloquently treated if one includes perseverance in the study techniques. As our detection tools increase in sensitivity we are finding more associations of infections precipitating clinical vasculitis. This increasing precision in identification, coupled with newer and more effective antimicrobial therapy, promises more effective and faster therapy for these patients.
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