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Henoch-Schoenlein Syndrome
1
Symposium on Pediatric Hematology
Henoch-Schoenlein Syndrome
David L. Silber, M.D.*
Based on current knowledge, one might dispute the inclusion of a discussion on Henoch-Schoenlein's purpura (anaphylactoid purpura) in a volume devoted to pediatric hematology on the grounds that no abnormalities of blood or the blood-forming tissues have been demonstrated in this fascinating disease. However, the protean manifestations of anaphylactoid purpura and their similarities to the signs of several genuine hematologic diseases cause this disorder to appear frequently in the differential diagnosis of patients with hematologic abnormalities. These similarities suggest that continued study will one day reveal a specific hematologic defect in this disease. The terms "anaphylactoid purpura" and "Henoch-Schoenlein's purpura" have prevailed while a host of synonyms have become obsolete (peliosis rheumatica coined by Henoch, hemorrhagic capillary toxicosis, purpura rheumatica, non thrombocytopenic purpura, allergic purpura, primary purpura, Osler's syndrome, vascular anaphylactoid purpura, acute vascular purpura). Credit for the original description of the disease probably belongs to Willan45 (1808), but Schoenlein35 was the first to recognize the association between purpura and joint symptoms (1837); Henoch 20 reported the first cases in children (1874) and emphasized the abdominal symptoms. Frank13 first applied the term "anaphylactoid" in 1915 and this nomenclature was supported by numerous authqrs, as a variety of allergenic agents ranging from foods to bee stings to specific bacteria were implicated etiologically. As will be noted below, evidence for most of these theories has been less than firm and one wonders if Frank suspected as much when he wrote of "anaphylactoid" rather than "anaphylactic" purpura. Lastly, since this disorder may occur without purpura or with purpura limited to internal organs and thus not visible, many have settled on Henoch-Schoenlein syndrome (HSS) as the most appropriate nomenclature. The full picture of HSS includes non thrombocytopenic purpura, arthralgia, abdominal pain, and abnormalities of urinary sediment simi" Associate Professor. Department of Pediatrics, University of Iowa College of Medicine, Iowa City, Iowa Pediatric Clinics of North America- Vol. 19, No.4, November 1972
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lar to those in post-streptococcal glomerulonephritis. The above manifestations may appear in variable time sequence and in a variety of combinations. Likewise, there may be marked differences in severity of the several manifestations in the same patient. Studies on HSS3.41 have illustrated a predilection of the disease for children and young adults. Among children, HSS has been reported as early as 6 months of age with peak incidence between 4 and 5 years. Boys are affected more frequently than girls and there appears to be a seasonal incidence, with more cases in spring and fall months.
CLINICAL MANIFESTATIONS Skin and Subcutaneous Tissues Obvious involvement of the skin usually, but not always, is present and generally precedes the appearance of other manifestations. Typically, HSS begins with the appearance of a localized ot generalized urticarial rash which becomes maculopapular and progresses from pale pink to red (Fig. 1). Petechiae soon appear in the same general distribution as the rash. In some patients, the eruption is maculopapular from the beginning and urticaria is not observed. Petechiae may coalesce to form ecchymotic or purpuric areas which may become quite large. The petechial eruption appears to be gravity-dependent, as indicated by its
Figure 1. Early eruption of Henoch-Schoenlein syndrome showing urticarial lesions, some with central areas of hemorrhage.
Figures 2 and 3. Typical distribution of petechiae in HenochSchoenlein syndrome over buttocks and lower extremitie£.
Figure 3.
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Figure 4. Marked facial edema in Henoch-Schoenlein syndrome. Note also urticarial lesions on face and arm.
predilection for the buttocks and lower extremities (Figs. 2 and 3), and its tendency to disappear if the patient is confined to bed, then reappear upon ambulation. Epistaxis and bleeding from the gums occur rarely. The rash of HSS may persist for several weeks or may be transient and recurrent for several months or even years. In one series,3 40 per cent of patients had one or more recurrences within 6 weeks of onset of the disease. Recurrence of the rash may be unassociated with other symptoms even though multiple systems were involved in the patient's initial episode. Edema, especially of the hands and feet, may be present. In young patients, especially under 3 years of age, scalp edema is common and may be massive with extension to and closure of the eyelids (Fig. 4). Infants with HSS may have edema as the only cutaneous manifestation, possibly because they ambulate little or not at all and thereby avoid the abovementioned gravitational effect. In some patients the edematous areas are painful and tender.
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Vernier et al. 4 have demonstrated abnormalities in the dermis of patients with HSS. They have included perivascular infiltration and thrombi in small vessels. Joints Arthralgia usually is present in HSS. Ankle and knee involvement are more common than wrist or digit changes. Findings may be limited to slight puffiness of one or two joints or may include warm painful swelling of several joints. Pain may be moderately severe even in the absence of objective findings. Swelling is due to periarticular involvement and not bleeding or effusion within the joint. While joint findings may resemble those of acute rheumatic fever, response to aspirin, unlike that expected in rheumatic fever, is not impressive. Joint involvement also may be recurrent but eventually resolves completely with no permanent damage. 37 Gastrointestinal Manifestations Gastrointestinal symptoms presumably result from petechial hemorrhage and/or edema in the bowel wall although this cannot always be verified. When severe, gross or occult blood can be identified in the stool; the frequency of this finding obviously depends on the thoroughness of one's search. Symptoms associated with bleeding consist of variably severe abdominal pain, usually colicky in nature, and usually closely related in time to cutaneous purpura. Vomiting is common and occasionally is associated with hematemesis. Over half the patients with HSS can be expected to have gastrointestinal symptoms. 3 , 14 The most dramatic and important gastrointestinal manifestation is intussusception. While a relatively small percentage of patients with HSS develop radiographically and/or surgically proven intussusception, the possibility exists that the severe intermittent colicky pain in other patients stems from intermittent intussusception which undergoes spontaneous reduction. In patients who undergo surgery for intussusception it often is possible to demonstrate a localized area of hemorrhage and/or edema which has provided a leading point for the intussusception. Diagnosis is facilitated by the occurrence of the classic symptoms (sudden severe pain, shock-like state, and so-called currant jelly stool) in an older child since the peak incidence of intussusception is in infancy. Such an event occasionally permits the diagnosis of HSS even before skin or joint manifestations have appeared.
Renal Signs The renal manifestations of HSS are potentially the most serious, as well as the only aspect of the syndrome likely to become chronic. Usually the clinical picture most closely resembles acute post-streptococcal glomerulonephritis with edema, hematuria, proteinuria, hypertension, and occasionally azotemia and hypoalbuminen,ria. Beyond this, there are important differences between post-streptococcal nephritis and the renal manifestations of HSS, especially with respect to renal biopsy findings and, of course, etiology. Evidence from renal biopsy studies on children with HSS indicates that some degree of renal involvement may occur in as many as 80 per
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cent,18 although the proportion of patients showing clinical evidence is smaller (40 to 62 per cent).3,4D Among those with hematuria and/or proteinuria, an estimated 6 to 36 per cent will develop progressive chronic renal disease. 31 This group will include a few patients who progress to renal failure. While deaths from renal failure in HSS are rare, they represent the chief mortality from the disease. 21
Uncommon Features or Complications A variety of unusual to rare complications has been reported. Kaplan27 described facial nerve palsy in a child with HSS who had marked facial edema. Headache, with or without hypertension, frequently is described. Convulsions, hemiparesis, and coma have been reported with HSS, and while most of these have been attributed to hypertensive encephalopathy, both subarachnoid and intracerebral hemorrhages have been observed. 3D Gastrointestinal complications have included chronic intestinal obstruction from adhesions presumably resulting from bowel ischemia,46 bowel perforation,31 massive gastrointestinal hemorrhage,16 and massive necrosis of the bowel. 15 Fatal pulmonary hemorrhage has been described,23 and Fitzsimmons reported two boys with HSS in whom testicular pain and scrotal swelling developed. 12 Progression of purpuric lesions to gangrene has been described; I!, 14, 28 however, some 9 feel these cases should be categorized as purpura fulminans. One patient with the classic manifestations of HSS without hematuria but with severe hypertension has been described;ID however, the diagnosis of renal involvement in this patient was not supported by biopsy evidence. Cardiac involvement resembling rheumatic carditis associated with the clinical picture of HSS has been reported rarely. 14, 22
LABORATORY STUDIES While there may be some abnormalities in laboratory studies on patients with HSS, these generally reflect secondary changes, such as anemia from gastrointestinal blood loss, and none is diagnostic of the disease. As implied above, gross or occult blood may be found in the stool. Cellular elements and protein may appear in the urine and should be sought diligently with repeated and careful microscopic examination of urine sediments. Less frequently, azotemia may be found. Platelet counts, by definition, are normal, or in some cases elevated. Bleeding and clotting studies invariably are normal,37 as is bone marrow examination. Data on erythrocyte sedimentation rate are conflicting; in some reported series elevated ESR has been the rule, in others, the exception. Eosinophilia is rare. The tourniquet test is positive in about 25 per cent of patients with HSS.7 Serum proteins and recently immunoglobulins in HSS have received some attention. J ones 26 reported hypoalbuminemia in several patients with HSS whose urinary protein losses apparently were trivial and who
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displayed evidence of protein-losing enteropathy on studies with radioactive tracer substances. Trygstad and Stiehm38 found elevated levels of IgA globulin in 10 of 20 children with HSS seen within 3 months of onset of the skin rash, but normal levels in 7 children seen one or more years after onset of their disease. No explanation of these findings is yet available and measuring IgA levels would appear to have little value as a means of establishing the diagnosis of HSS. Much has been written about streptococcal antibody titers, particularly in attempts to support the role of streptococcal infection in the etiology of the disease (see below). While results have varied somewhat, careful studies 4 indicate that the incidence of elevated streptococcal antibodies (ASO, anti-DNaseB, anti-NA Dase) in patients with HSS does not differ from that of the general population. One laboratory procedure which, while not diagnostic of HSS, may facilitate differentiating between post-streptococcal nephritis and the nephritis of HSS is measurement of serum complement or Blc-globulin. Normal values have been reported consistently in HSS4. 17 in contrast to consistently depressed values associated with post-streptococcal nephritis. 17. 44 Usually one can exclude post-streptococcal nephritis on the basis of the presence of other manifestations of HSS and absence of streptococcal antibodies; when this is not possible, percutaneous renal biopsy'usually permits an experienced pathologist to establish the diagnosis. A detailed discussion of electron and light microscopic features is beyond the scope of this paper, especially since reported findings have not been entirely consistent. In general, however, the picture is one of focal glomerulitis rather than the diffuse changes seen with post-streptococcal nephritis, although diffuse changes have been observed in occasional patients with HSS.8. 39
ETIOLOGY To date the etiology of HSS is unknown. The similarity of some of the manifestations of HSS to those of certain hypersensitivity reactions has given rise to sustained strong suspicion that the same mechanisms are operating. Children with HSS have a higher incidence of major allergic conditions than the general population. 3 Cause and effect relationships with certain antigenic substances have been demonstrated consistently in some patients. These substances have included various foods such as chocolate, milk, eggs, and beans,!' 2 various drugs such as aspirin, antibiotics, and penicillin,24 and insect bites. 5 In practice, however, the patient in whom such an antigenic substance can be identified is exceptional. Peters and Horton 33 described a patient who developed "allergic purpura" without renal manifestations on exposure to cold and, recently, Rogers et al,34 have reported an adult with the full picture of HSS including renal involvement which occurred on several occasions after exposure to cold temperatures. Our experience includes one child who had repeated episodes of abdominal pain and petechiae over the lower extremities immediately following ingestion of ice cold food or drink but
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not after ingesting the same substances at room temperature. Her most dramatic episode followed ingestion of snow. Gairdner14 was the first to suggest the possible etiologic role of streptococcal infection and this suspicion was heightened by the frequent association of renal manifestations resembling post-streptococcal glomerulonephritis. Earlier studies supported this hypothesis but, as mentioned earlier, more recent studies employing controls and streptococcal antibody titers have failed to confirm previous findings. A history of recent presumably viral respiratory infection is common 9 in HSS patients but this is more difficult to interpret in the absence of appropriate post hoc studies such as those used to confirm recent streptococcal infection. HSS has been observed following rubella and rubeola and on several occasions following vaccination for smallpox. 6 , 25, 29
TREATMENT Therapy is essentially supportive or symptomatic. In the occasional patient who shows evidence of concomitant bacterial infection, appropriate antibiotic therapy obviously is advisable. This most often involves the recovery of beta-hemolytic streptococci from the pharynx because the persistent suspicion that an etiologic relationship exists causes clinicians to perform throat cultures on HSS patients almost routinely. Although a positive culture from such a patient probably reflects only a carrier state, treatment with penicillin is in order, unless, of course, there is reason to suspect that the patient's HSS may be penicillin related. The urticarial phase of the rash and the frequent appearance of edema have led to the administration of antihistaminic agents, but there is no evidence that the course of the disease is altered by these drugs. 3 Similarly, experience with salicylates in rheumatic fever and rheumatoid arthritis occasionally leads to aspirin therapy for the arthritis of HSS. This not only fails to yield a response but also carries with it the risk of gastric ulceration 43 and superimposed platelet dysfunction,32, 36, 42 either of which can produce confusion of the clinical picture or even significant additional risk to the patient. Steroid therapy has received considerable study after initial experience produced some enthusiasm. It is now clear that while steroids usually will produce dramatic improvement in some of the signs of the disease, particularly scalp and facial edema, and in some of the symptoms, especially abdominal discomfort and joint pain, this is the limit of their benefits and sustained therapy is inappropriate.3 Some feel the reduction in abdominal pain after steroid therapy signals reduced bowel edema and thus a lessened risk of intussusception but this is purely speculative. That steroids fail to influence the course of the renal manifestations, including the probability of chronic renal disease, is now accepted. Bed rest often results in disappearance of petechiae and favors sore joints but probably accomplishes little else. Otherwise therapy is directed at specific problems; e.g., antihypertensive agents for the occasional patient with the full picture of
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nephritis. Chronic nephritis from HSS, as chronic nephritis from other causes, is a difficult management problem with a limited outlook. Some of the reported favorable results from therapy with immunosuppressants have involved children with HSS nephritis. I6 • 19
PROGNOSIS Prognosis for survival in HSS is good; mortality rate is estimated at 2 per cent9 and this is due almost entirely to renal failure. For many children, however, morbidity is significant because of severity of symptoms, need for surgical intervention, and the high rate of annoying recurrences mentioned previously.
REFERENCES 1. Ackroyd, J. F.: Allergic purpura, including purpura due to foods, drugs, and infections. Amer. J. Med., 14:605, 1953. 2. Alexander, H. L., and Eyermann, E. H.: Food allergy in Henoch's purpura. Arch. Dermat. Syph., 16:322, 1927. 3. Allen, D. M., Diamond, L. K., and Howell, D. A.: Anaphylactoid purpura in children (SchOnlein-Henoch Syndrome). Amer. J. Dis. Child., 99:833, 1960. 4. Ayoub, E. M., and Hoyer, J.: Anaphylactoid purpura: Streptococcal antibody titers and Bglobulin levels. J. Pediat., 75:193, 1969. 5. Burke, D. M., and Jellinek, H. L.: Nearly fatal case of Schiinlein-Henoch syndrome following insect bite. Amer. J. Dis. Child., 88:772, 1954. 6. Casteles-Van Daele, M.: Vaccination and Henoch-Schoenlein purpura. New Eng. J. Med., 279:1171,1969. 7. Davis, E.: The Schoenlein-Henoch syndrome of vascular purpura. Blood, 3:129,1948. 8. Dodge, W. F., Daeschner, C. W., Brennan, J. C., et al.: Percutaneous renal biopsy in children. II. Acute glomerulonephritis, chronic glomerulonephritis, and nephritis of anaphylactoid purpura. Pediatrics, 30:297, 1962. 9. Dodge, W. R., Travis, L. B., and Daeschner, C. W.: Anaphylactoid purpura, polyarteritis nodosa and purpura fulminans. PEDIAT. CLIN. N. AMER., 10:879, 1963. 10. DuBois, D. R.: Severe hypertension in Schoenlein-Henoch purpura without hematuria. (Letter.) J. Pediat., 75:731, 1969. 11. Elefant, E., Jeklerova, J., and Trapl, J.: Henoch's fulminating purpura causing cutaneous necroses in a four months old infant. Ann. Paediat., 197:452, 1961. 12. Fitzsimmons, J. S.: Uncommon complication of anaphylactOid purpura. Brit. Med. J., 4:431, 1968. 13. Frank, E.: Bed. Klin. Wchnschr., 52:454, 1915. 14. Gairdner, D.: The Schiinlein-Henoch syndrome (anaphylactoid purpura). Quart. J. Med., 17:95, 1948. 15. Gilbert, E. F., and DaSilva, A. Q.: Henoch-Schoenlein purpura. Report of a fatal case with gastrointestinal hemorrhage and necrosis. Clin. Pediat., 5:181, 1966. 16. Goldbloom, R. B., and Drummond, K. N.: Anaphylactoid purpura with massive gastrointestinal hemorrhage and glomerulonephritis. Amer. J. Dis. Child., 116:97, 1968. 17. Gotoff, S. P., Fellers, F. X., Vawter, G. F., et aI.: The Blc-globulin in childhood nephrotic syndrome. Laboratory diagnosis of progressive glomerulonephritis. New Eng. J. Med., 273:524, 1965. 18. Greifer, I., Bernstein, J., Kikkawa, Y., and Edelmann, C. A., Jr.: Histologic evidence of nephritis in patients with Henoch-Schonlein syndrome without clinical evidence of renal disease. Abstracts of The Third International Congress of Nephrologists (Free Communications) Washington, D.C. September 25-30, 1966, p. 203. 19. Grupe, W. E., and Heymann, W.: Cytotoxic drugs in steroid-resistant renal disease. Amer. J. Dis. Child., 112:448, 1966. 20. Henoch, E.: Uber eine eigenthumliche form von purpura. Beri. Klin. Wchnschr., 11 :641, 1874. 21. Hughes, L. A., and Wenzl, J. E.: Anaphylactoid purpura nephritis in children. Data from a follow-up study. Clin. Pediat., 8:594, 1969. 22. Imai, T., and Matsumoto, S.: Anaphylactoid purpura with cardiac involvement. Arch. Dis. Child., 45:727,1970 .
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23. Jacome, A. F.: Pulmonary hemorrhage and death complicating anaphylactoid purpura. Southern Med. J., 60:1003, 1967. 24. Jensen, B.: Schiinlein-Henoch's purpura. Three cases with fish or penicillin as antigen. Acta Med. Scand., 152:61,1955. 25. Jimenez, E. L., and Dorrington, H. J.: Vaccination and Henoch-Schoenlein purpura. New Eng. J. Med., 279:1171,1968. 26. Jones, N. F., Creamer, B., and Gimlette, T. M. D.: Hypoproteinaemia in anaphylactoid purpura. Brit. Med. J., 2:1166, 1966. 27. Kaplan, J. M., Quintana, P., and Samson, J.: Facial nerve palsy with anaphylactoid purpura. Amer. J. Dis. Child., 119:452, 1970. 28. Kisker, C. T., Glueck, H., and Kauder, E.: Anaphylactoid purpura progressing to gangrene and its treatment with heparin. J. Pediat., 73:748, 1968. 29. Lane, J. M.: Vaccination and Henoch-Schoenlein purpura. New Eng. J. Med., 280:781, 1969. 30. Lewis, I. C., and Philpott, M. G.: Neurological complications in the Schoenlein-Henoch syndrome. Arch. Dis. Child., 31 :369, 1956. 31. Lindenauer, S. M., and Tank, E. S.: Surgical aspects of Henoch-Schiinlein's purpura Surgery, 59:982, 1966. 32. O'Brien, J. R: Effects of salicylates on human platelets. Lancet, 1 :779, 1968. 33. Peters, G. A., and Horton, B. T.: Allergic purpura with special reference to hypersensitiveness to cold. Mayo Clin. Proc., 16:631, 1941. 34. Rogers, P. W., Bunn, S. M., Jr., Kurtzman, N. A., and White, M. G.: Schoenlein-Henoch syndrome associated with exposure to cold. Arch. Int. Med., 128:782, 1971. 35. Schonlein, J. L.: Allgemeine und specielle Pathologie und Therapie. Herisou, L.t. Compt., 3rd ed., 1837, p. 48. . 36. Schwartz, A. D., and Pearson, H. A.: Aspirin, platelets, and bleeding. J. Pediat., 78:558, 1971. 37. Smith, C. H.: Blood Diseases of Infancy and Childhood. St. Louis, Missouri, C. V. Mosby Company, 2nd ed., 1966, p. 725. 38. Trygstad, C. W., and Stiehm, E. R: Elevated serum IgA globulin in anaphylactoid purpura. Pediatrics, 47:1023, 1971. 39. Urizar, R E., and Herdman, R C.: Anaphylactoid purpura III. Early morphologic glomerular changes. Amer. J. Clin. Path., 53:258, 1970. 40. Vernier, R L., Worthen, H. G., Peterson, RD., et al.: Anaphylactoid purpura. I. Pathology of the skin and kidney and frequency of streptococcal infection. Pediatrics, 27:181, 1961. 41. Wedgwood, R. J. P., and Klaus, M. H.: Anaphylactoid purpura (Schiinlein-Henoch Syndrome). A long term follow-up study with special reference to the renal lesion. Pediatrics, 16:196, 1955. 42. Weiss, H. J., Aledort, L. M., and Kochwa, S.: The effect of salicylates on the hemostatic properties of platelets. J. Clin.Invest., 47:2169, 1968. 43. Weiss, A., Pitman, E. R, and Graham, E. C.: Aspirin and gastric bleeding. Gastroscopic observations with review of literature. Amer. J. Med., 31 :266, 1961. 44. West, C. D., Northway, J. D., and Davis, N. C.: Serum levels of Blc-globulin, a complement component, in the nephritides, lipoid nephrosis, and other conditions. J. Clin. Invest., 43:1507, 1964. 45. WilIan, R: Cutaneous Diseases. London, 1808. 46. Young, D. G.: Chronic intestinal obstruction following Henoch-Schiinlein disease. Clin. Pediat., 3:737, 1964. Department of Pediatrics University of Iowa College of Medicine Iowa City, Iowa 52240
Symposium on Pediatric Hematology
Henoch-Schoenlein Syndrome
David L. Silber, M.D.*
Based on current knowledge, one might dispute the inclusion of a discussion on Henoch-Schoenlein's purpura (anaphylactoid purpura) in a volume devoted to pediatric hematology on the grounds that no abnormalities of blood or the blood-forming tissues have been demonstrated in this fascinating disease. However, the protean manifestations of anaphylactoid purpura and their similarities to the signs of several genuine hematologic diseases cause this disorder to appear frequently in the differential diagnosis of patients with hematologic abnormalities. These similarities suggest that continued study will one day reveal a specific hematologic defect in this disease. The terms "anaphylactoid purpura" and "Henoch-Schoenlein's purpura" have prevailed while a host of synonyms have become obsolete (peliosis rheumatica coined by Henoch, hemorrhagic capillary toxicosis, purpura rheumatica, non thrombocytopenic purpura, allergic purpura, primary purpura, Osler's syndrome, vascular anaphylactoid purpura, acute vascular purpura). Credit for the original description of the disease probably belongs to Willan45 (1808), but Schoenlein35 was the first to recognize the association between purpura and joint symptoms (1837); Henoch 20 reported the first cases in children (1874) and emphasized the abdominal symptoms. Frank13 first applied the term "anaphylactoid" in 1915 and this nomenclature was supported by numerous authqrs, as a variety of allergenic agents ranging from foods to bee stings to specific bacteria were implicated etiologically. As will be noted below, evidence for most of these theories has been less than firm and one wonders if Frank suspected as much when he wrote of "anaphylactoid" rather than "anaphylactic" purpura. Lastly, since this disorder may occur without purpura or with purpura limited to internal organs and thus not visible, many have settled on Henoch-Schoenlein syndrome (HSS) as the most appropriate nomenclature. The full picture of HSS includes non thrombocytopenic purpura, arthralgia, abdominal pain, and abnormalities of urinary sediment simi" Associate Professor. Department of Pediatrics, University of Iowa College of Medicine, Iowa City, Iowa Pediatric Clinics of North America- Vol. 19, No.4, November 1972
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lar to those in post-streptococcal glomerulonephritis. The above manifestations may appear in variable time sequence and in a variety of combinations. Likewise, there may be marked differences in severity of the several manifestations in the same patient. Studies on HSS3.41 have illustrated a predilection of the disease for children and young adults. Among children, HSS has been reported as early as 6 months of age with peak incidence between 4 and 5 years. Boys are affected more frequently than girls and there appears to be a seasonal incidence, with more cases in spring and fall months.
CLINICAL MANIFESTATIONS Skin and Subcutaneous Tissues Obvious involvement of the skin usually, but not always, is present and generally precedes the appearance of other manifestations. Typically, HSS begins with the appearance of a localized ot generalized urticarial rash which becomes maculopapular and progresses from pale pink to red (Fig. 1). Petechiae soon appear in the same general distribution as the rash. In some patients, the eruption is maculopapular from the beginning and urticaria is not observed. Petechiae may coalesce to form ecchymotic or purpuric areas which may become quite large. The petechial eruption appears to be gravity-dependent, as indicated by its
Figure 1. Early eruption of Henoch-Schoenlein syndrome showing urticarial lesions, some with central areas of hemorrhage.
Figures 2 and 3. Typical distribution of petechiae in HenochSchoenlein syndrome over buttocks and lower extremitie£.
Figure 3.
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Figure 4. Marked facial edema in Henoch-Schoenlein syndrome. Note also urticarial lesions on face and arm.
predilection for the buttocks and lower extremities (Figs. 2 and 3), and its tendency to disappear if the patient is confined to bed, then reappear upon ambulation. Epistaxis and bleeding from the gums occur rarely. The rash of HSS may persist for several weeks or may be transient and recurrent for several months or even years. In one series,3 40 per cent of patients had one or more recurrences within 6 weeks of onset of the disease. Recurrence of the rash may be unassociated with other symptoms even though multiple systems were involved in the patient's initial episode. Edema, especially of the hands and feet, may be present. In young patients, especially under 3 years of age, scalp edema is common and may be massive with extension to and closure of the eyelids (Fig. 4). Infants with HSS may have edema as the only cutaneous manifestation, possibly because they ambulate little or not at all and thereby avoid the abovementioned gravitational effect. In some patients the edematous areas are painful and tender.
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Vernier et al. 4 have demonstrated abnormalities in the dermis of patients with HSS. They have included perivascular infiltration and thrombi in small vessels. Joints Arthralgia usually is present in HSS. Ankle and knee involvement are more common than wrist or digit changes. Findings may be limited to slight puffiness of one or two joints or may include warm painful swelling of several joints. Pain may be moderately severe even in the absence of objective findings. Swelling is due to periarticular involvement and not bleeding or effusion within the joint. While joint findings may resemble those of acute rheumatic fever, response to aspirin, unlike that expected in rheumatic fever, is not impressive. Joint involvement also may be recurrent but eventually resolves completely with no permanent damage. 37 Gastrointestinal Manifestations Gastrointestinal symptoms presumably result from petechial hemorrhage and/or edema in the bowel wall although this cannot always be verified. When severe, gross or occult blood can be identified in the stool; the frequency of this finding obviously depends on the thoroughness of one's search. Symptoms associated with bleeding consist of variably severe abdominal pain, usually colicky in nature, and usually closely related in time to cutaneous purpura. Vomiting is common and occasionally is associated with hematemesis. Over half the patients with HSS can be expected to have gastrointestinal symptoms. 3 , 14 The most dramatic and important gastrointestinal manifestation is intussusception. While a relatively small percentage of patients with HSS develop radiographically and/or surgically proven intussusception, the possibility exists that the severe intermittent colicky pain in other patients stems from intermittent intussusception which undergoes spontaneous reduction. In patients who undergo surgery for intussusception it often is possible to demonstrate a localized area of hemorrhage and/or edema which has provided a leading point for the intussusception. Diagnosis is facilitated by the occurrence of the classic symptoms (sudden severe pain, shock-like state, and so-called currant jelly stool) in an older child since the peak incidence of intussusception is in infancy. Such an event occasionally permits the diagnosis of HSS even before skin or joint manifestations have appeared.
Renal Signs The renal manifestations of HSS are potentially the most serious, as well as the only aspect of the syndrome likely to become chronic. Usually the clinical picture most closely resembles acute post-streptococcal glomerulonephritis with edema, hematuria, proteinuria, hypertension, and occasionally azotemia and hypoalbuminen,ria. Beyond this, there are important differences between post-streptococcal nephritis and the renal manifestations of HSS, especially with respect to renal biopsy findings and, of course, etiology. Evidence from renal biopsy studies on children with HSS indicates that some degree of renal involvement may occur in as many as 80 per
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cent,18 although the proportion of patients showing clinical evidence is smaller (40 to 62 per cent).3,4D Among those with hematuria and/or proteinuria, an estimated 6 to 36 per cent will develop progressive chronic renal disease. 31 This group will include a few patients who progress to renal failure. While deaths from renal failure in HSS are rare, they represent the chief mortality from the disease. 21
Uncommon Features or Complications A variety of unusual to rare complications has been reported. Kaplan27 described facial nerve palsy in a child with HSS who had marked facial edema. Headache, with or without hypertension, frequently is described. Convulsions, hemiparesis, and coma have been reported with HSS, and while most of these have been attributed to hypertensive encephalopathy, both subarachnoid and intracerebral hemorrhages have been observed. 3D Gastrointestinal complications have included chronic intestinal obstruction from adhesions presumably resulting from bowel ischemia,46 bowel perforation,31 massive gastrointestinal hemorrhage,16 and massive necrosis of the bowel. 15 Fatal pulmonary hemorrhage has been described,23 and Fitzsimmons reported two boys with HSS in whom testicular pain and scrotal swelling developed. 12 Progression of purpuric lesions to gangrene has been described; I!, 14, 28 however, some 9 feel these cases should be categorized as purpura fulminans. One patient with the classic manifestations of HSS without hematuria but with severe hypertension has been described;ID however, the diagnosis of renal involvement in this patient was not supported by biopsy evidence. Cardiac involvement resembling rheumatic carditis associated with the clinical picture of HSS has been reported rarely. 14, 22
LABORATORY STUDIES While there may be some abnormalities in laboratory studies on patients with HSS, these generally reflect secondary changes, such as anemia from gastrointestinal blood loss, and none is diagnostic of the disease. As implied above, gross or occult blood may be found in the stool. Cellular elements and protein may appear in the urine and should be sought diligently with repeated and careful microscopic examination of urine sediments. Less frequently, azotemia may be found. Platelet counts, by definition, are normal, or in some cases elevated. Bleeding and clotting studies invariably are normal,37 as is bone marrow examination. Data on erythrocyte sedimentation rate are conflicting; in some reported series elevated ESR has been the rule, in others, the exception. Eosinophilia is rare. The tourniquet test is positive in about 25 per cent of patients with HSS.7 Serum proteins and recently immunoglobulins in HSS have received some attention. J ones 26 reported hypoalbuminemia in several patients with HSS whose urinary protein losses apparently were trivial and who
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displayed evidence of protein-losing enteropathy on studies with radioactive tracer substances. Trygstad and Stiehm38 found elevated levels of IgA globulin in 10 of 20 children with HSS seen within 3 months of onset of the skin rash, but normal levels in 7 children seen one or more years after onset of their disease. No explanation of these findings is yet available and measuring IgA levels would appear to have little value as a means of establishing the diagnosis of HSS. Much has been written about streptococcal antibody titers, particularly in attempts to support the role of streptococcal infection in the etiology of the disease (see below). While results have varied somewhat, careful studies 4 indicate that the incidence of elevated streptococcal antibodies (ASO, anti-DNaseB, anti-NA Dase) in patients with HSS does not differ from that of the general population. One laboratory procedure which, while not diagnostic of HSS, may facilitate differentiating between post-streptococcal nephritis and the nephritis of HSS is measurement of serum complement or Blc-globulin. Normal values have been reported consistently in HSS4. 17 in contrast to consistently depressed values associated with post-streptococcal nephritis. 17. 44 Usually one can exclude post-streptococcal nephritis on the basis of the presence of other manifestations of HSS and absence of streptococcal antibodies; when this is not possible, percutaneous renal biopsy'usually permits an experienced pathologist to establish the diagnosis. A detailed discussion of electron and light microscopic features is beyond the scope of this paper, especially since reported findings have not been entirely consistent. In general, however, the picture is one of focal glomerulitis rather than the diffuse changes seen with post-streptococcal nephritis, although diffuse changes have been observed in occasional patients with HSS.8. 39
ETIOLOGY To date the etiology of HSS is unknown. The similarity of some of the manifestations of HSS to those of certain hypersensitivity reactions has given rise to sustained strong suspicion that the same mechanisms are operating. Children with HSS have a higher incidence of major allergic conditions than the general population. 3 Cause and effect relationships with certain antigenic substances have been demonstrated consistently in some patients. These substances have included various foods such as chocolate, milk, eggs, and beans,!' 2 various drugs such as aspirin, antibiotics, and penicillin,24 and insect bites. 5 In practice, however, the patient in whom such an antigenic substance can be identified is exceptional. Peters and Horton 33 described a patient who developed "allergic purpura" without renal manifestations on exposure to cold and, recently, Rogers et al,34 have reported an adult with the full picture of HSS including renal involvement which occurred on several occasions after exposure to cold temperatures. Our experience includes one child who had repeated episodes of abdominal pain and petechiae over the lower extremities immediately following ingestion of ice cold food or drink but
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not after ingesting the same substances at room temperature. Her most dramatic episode followed ingestion of snow. Gairdner14 was the first to suggest the possible etiologic role of streptococcal infection and this suspicion was heightened by the frequent association of renal manifestations resembling post-streptococcal glomerulonephritis. Earlier studies supported this hypothesis but, as mentioned earlier, more recent studies employing controls and streptococcal antibody titers have failed to confirm previous findings. A history of recent presumably viral respiratory infection is common 9 in HSS patients but this is more difficult to interpret in the absence of appropriate post hoc studies such as those used to confirm recent streptococcal infection. HSS has been observed following rubella and rubeola and on several occasions following vaccination for smallpox. 6 , 25, 29
TREATMENT Therapy is essentially supportive or symptomatic. In the occasional patient who shows evidence of concomitant bacterial infection, appropriate antibiotic therapy obviously is advisable. This most often involves the recovery of beta-hemolytic streptococci from the pharynx because the persistent suspicion that an etiologic relationship exists causes clinicians to perform throat cultures on HSS patients almost routinely. Although a positive culture from such a patient probably reflects only a carrier state, treatment with penicillin is in order, unless, of course, there is reason to suspect that the patient's HSS may be penicillin related. The urticarial phase of the rash and the frequent appearance of edema have led to the administration of antihistaminic agents, but there is no evidence that the course of the disease is altered by these drugs. 3 Similarly, experience with salicylates in rheumatic fever and rheumatoid arthritis occasionally leads to aspirin therapy for the arthritis of HSS. This not only fails to yield a response but also carries with it the risk of gastric ulceration 43 and superimposed platelet dysfunction,32, 36, 42 either of which can produce confusion of the clinical picture or even significant additional risk to the patient. Steroid therapy has received considerable study after initial experience produced some enthusiasm. It is now clear that while steroids usually will produce dramatic improvement in some of the signs of the disease, particularly scalp and facial edema, and in some of the symptoms, especially abdominal discomfort and joint pain, this is the limit of their benefits and sustained therapy is inappropriate.3 Some feel the reduction in abdominal pain after steroid therapy signals reduced bowel edema and thus a lessened risk of intussusception but this is purely speculative. That steroids fail to influence the course of the renal manifestations, including the probability of chronic renal disease, is now accepted. Bed rest often results in disappearance of petechiae and favors sore joints but probably accomplishes little else. Otherwise therapy is directed at specific problems; e.g., antihypertensive agents for the occasional patient with the full picture of
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nephritis. Chronic nephritis from HSS, as chronic nephritis from other causes, is a difficult management problem with a limited outlook. Some of the reported favorable results from therapy with immunosuppressants have involved children with HSS nephritis. I6 • 19
PROGNOSIS Prognosis for survival in HSS is good; mortality rate is estimated at 2 per cent9 and this is due almost entirely to renal failure. For many children, however, morbidity is significant because of severity of symptoms, need for surgical intervention, and the high rate of annoying recurrences mentioned previously.
REFERENCES 1. Ackroyd, J. F.: Allergic purpura, including purpura due to foods, drugs, and infections. Amer. J. Med., 14:605, 1953. 2. Alexander, H. L., and Eyermann, E. H.: Food allergy in Henoch's purpura. Arch. Dermat. Syph., 16:322, 1927. 3. Allen, D. M., Diamond, L. K., and Howell, D. A.: Anaphylactoid purpura in children (SchOnlein-Henoch Syndrome). Amer. J. Dis. Child., 99:833, 1960. 4. Ayoub, E. M., and Hoyer, J.: Anaphylactoid purpura: Streptococcal antibody titers and Bglobulin levels. J. Pediat., 75:193, 1969. 5. Burke, D. M., and Jellinek, H. L.: Nearly fatal case of Schiinlein-Henoch syndrome following insect bite. Amer. J. Dis. Child., 88:772, 1954. 6. Casteles-Van Daele, M.: Vaccination and Henoch-Schoenlein purpura. New Eng. J. Med., 279:1171,1969. 7. Davis, E.: The Schoenlein-Henoch syndrome of vascular purpura. Blood, 3:129,1948. 8. Dodge, W. F., Daeschner, C. W., Brennan, J. C., et al.: Percutaneous renal biopsy in children. II. Acute glomerulonephritis, chronic glomerulonephritis, and nephritis of anaphylactoid purpura. Pediatrics, 30:297, 1962. 9. Dodge, W. R., Travis, L. B., and Daeschner, C. W.: Anaphylactoid purpura, polyarteritis nodosa and purpura fulminans. PEDIAT. CLIN. N. AMER., 10:879, 1963. 10. DuBois, D. R.: Severe hypertension in Schoenlein-Henoch purpura without hematuria. (Letter.) J. Pediat., 75:731, 1969. 11. Elefant, E., Jeklerova, J., and Trapl, J.: Henoch's fulminating purpura causing cutaneous necroses in a four months old infant. Ann. Paediat., 197:452, 1961. 12. Fitzsimmons, J. S.: Uncommon complication of anaphylactOid purpura. Brit. Med. J., 4:431, 1968. 13. Frank, E.: Bed. Klin. Wchnschr., 52:454, 1915. 14. Gairdner, D.: The Schiinlein-Henoch syndrome (anaphylactoid purpura). Quart. J. Med., 17:95, 1948. 15. Gilbert, E. F., and DaSilva, A. Q.: Henoch-Schoenlein purpura. Report of a fatal case with gastrointestinal hemorrhage and necrosis. Clin. Pediat., 5:181, 1966. 16. Goldbloom, R. B., and Drummond, K. N.: Anaphylactoid purpura with massive gastrointestinal hemorrhage and glomerulonephritis. Amer. J. Dis. Child., 116:97, 1968. 17. Gotoff, S. P., Fellers, F. X., Vawter, G. F., et aI.: The Blc-globulin in childhood nephrotic syndrome. Laboratory diagnosis of progressive glomerulonephritis. New Eng. J. Med., 273:524, 1965. 18. Greifer, I., Bernstein, J., Kikkawa, Y., and Edelmann, C. A., Jr.: Histologic evidence of nephritis in patients with Henoch-Schonlein syndrome without clinical evidence of renal disease. Abstracts of The Third International Congress of Nephrologists (Free Communications) Washington, D.C. September 25-30, 1966, p. 203. 19. Grupe, W. E., and Heymann, W.: Cytotoxic drugs in steroid-resistant renal disease. Amer. J. Dis. Child., 112:448, 1966. 20. Henoch, E.: Uber eine eigenthumliche form von purpura. Beri. Klin. Wchnschr., 11 :641, 1874. 21. Hughes, L. A., and Wenzl, J. E.: Anaphylactoid purpura nephritis in children. Data from a follow-up study. Clin. Pediat., 8:594, 1969. 22. Imai, T., and Matsumoto, S.: Anaphylactoid purpura with cardiac involvement. Arch. Dis. Child., 45:727,1970 .
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23. Jacome, A. F.: Pulmonary hemorrhage and death complicating anaphylactoid purpura. Southern Med. J., 60:1003, 1967. 24. Jensen, B.: Schiinlein-Henoch's purpura. Three cases with fish or penicillin as antigen. Acta Med. Scand., 152:61,1955. 25. Jimenez, E. L., and Dorrington, H. J.: Vaccination and Henoch-Schoenlein purpura. New Eng. J. Med., 279:1171,1968. 26. Jones, N. F., Creamer, B., and Gimlette, T. M. D.: Hypoproteinaemia in anaphylactoid purpura. Brit. Med. J., 2:1166, 1966. 27. Kaplan, J. M., Quintana, P., and Samson, J.: Facial nerve palsy with anaphylactoid purpura. Amer. J. Dis. Child., 119:452, 1970. 28. Kisker, C. T., Glueck, H., and Kauder, E.: Anaphylactoid purpura progressing to gangrene and its treatment with heparin. J. Pediat., 73:748, 1968. 29. Lane, J. M.: Vaccination and Henoch-Schoenlein purpura. New Eng. J. Med., 280:781, 1969. 30. Lewis, I. C., and Philpott, M. G.: Neurological complications in the Schoenlein-Henoch syndrome. Arch. Dis. Child., 31 :369, 1956. 31. Lindenauer, S. M., and Tank, E. S.: Surgical aspects of Henoch-Schiinlein's purpura Surgery, 59:982, 1966. 32. O'Brien, J. R: Effects of salicylates on human platelets. Lancet, 1 :779, 1968. 33. Peters, G. A., and Horton, B. T.: Allergic purpura with special reference to hypersensitiveness to cold. Mayo Clin. Proc., 16:631, 1941. 34. Rogers, P. W., Bunn, S. M., Jr., Kurtzman, N. A., and White, M. G.: Schoenlein-Henoch syndrome associated with exposure to cold. Arch. Int. Med., 128:782, 1971. 35. Schonlein, J. L.: Allgemeine und specielle Pathologie und Therapie. Herisou, L.t. Compt., 3rd ed., 1837, p. 48. . 36. Schwartz, A. D., and Pearson, H. A.: Aspirin, platelets, and bleeding. J. Pediat., 78:558, 1971. 37. Smith, C. H.: Blood Diseases of Infancy and Childhood. St. Louis, Missouri, C. V. Mosby Company, 2nd ed., 1966, p. 725. 38. Trygstad, C. W., and Stiehm, E. R: Elevated serum IgA globulin in anaphylactoid purpura. Pediatrics, 47:1023, 1971. 39. Urizar, R E., and Herdman, R C.: Anaphylactoid purpura III. Early morphologic glomerular changes. Amer. J. Clin. Path., 53:258, 1970. 40. Vernier, R L., Worthen, H. G., Peterson, RD., et al.: Anaphylactoid purpura. I. Pathology of the skin and kidney and frequency of streptococcal infection. Pediatrics, 27:181, 1961. 41. Wedgwood, R. J. P., and Klaus, M. H.: Anaphylactoid purpura (Schiinlein-Henoch Syndrome). A long term follow-up study with special reference to the renal lesion. Pediatrics, 16:196, 1955. 42. Weiss, H. J., Aledort, L. M., and Kochwa, S.: The effect of salicylates on the hemostatic properties of platelets. J. Clin.Invest., 47:2169, 1968. 43. Weiss, A., Pitman, E. R, and Graham, E. C.: Aspirin and gastric bleeding. Gastroscopic observations with review of literature. Amer. J. Med., 31 :266, 1961. 44. West, C. D., Northway, J. D., and Davis, N. C.: Serum levels of Blc-globulin, a complement component, in the nephritides, lipoid nephrosis, and other conditions. J. Clin. Invest., 43:1507, 1964. 45. WilIan, R: Cutaneous Diseases. London, 1808. 46. Young, D. G.: Chronic intestinal obstruction following Henoch-Schiinlein disease. Clin. Pediat., 3:737, 1964. Department of Pediatrics University of Iowa College of Medicine Iowa City, Iowa 52240