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Home , Protein S deficiency, Purpura fulminans

CPJXXX10.1177/0009922815590116Clinical PediatricsWampole et al research-article5901162015

Brief Report

Clinical 4–­1 A Case of Postinfectious S © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav Deficiency Masquerading as Henoch– DOI: 10.1177/0009922815590116 Schönlein cpj.sagepub.com

Anthony J. Wampole, MD1, Halie M. Anderson, MD1, and Ellen R. Wald, MD1

Case Report (Presentation) inability to urinate brought him back to the ED. His exam was notable for tachycardia; he had scattered pete- The patient is a previously healthy 4-year-old male who chiae on chest and arms and diffuse “nonpalpable” pur- is admitted for a purpuric rash. Ten days before admis- pura on legs, buttocks, perineum, and penis with sion he experienced mild, transient cold symptoms. Four surrounding edema. His scrotum was purpuric and days before admission he developed hives on his lower grossly edematous, with overlying bullae. Urine was abdomen and mild swelling of his feet; symptoms grossly bloody. Repeat laboratory studies were notable improved with diphenhydramine. Two days later the pri- for leukocytosis, anemia, and . mary care provider (PCP) was informed of slight perior- Complete metabolic panel, including electrolytes, kid- bital puffiness and ongoing swelling (with a slight ney function, and transaminases, was notable for a “bluish-hue”) on the dorsum of his feet bilaterally. He mildly low CO (21 mEq/L) and albumin (2.8 g/L). 2 was otherwise well, without fever or discomfort, except studies were grossly abnormal with PT/ for mild itching between doses of diphenhydramine. INR = 8.0, partial thromboplastin time (PTT) = 70.2, Family was instructed to seek medical care if he devel- <40, and D-dimer >10 000. Blood cultures oped joint pain or swelling, difficulty with mobility, were obtained; he was given a dose of ceftriaxone, nor- blue-purple rash, or fever. Twelve hours later, a dark mal saline bolus, and and trans- purple rash evolved over his legs. He was taken to a ferred to our critical care unit. On arrival he was local emergency department (ED) where he was afebrile hemodynamically stable but showed ongoing, severe with normal vital signs. He was documented to have . He had deep purple plaques over thighs purpuric lesions on his lower extremities and scattered and lower extremities, including lateral hips and penis. hives on his torso. Laboratory studies were remarkable Feet were relatively spared with some purple discolor- for a low normal count and prothrombin time ation of toes. There were no petechiae or purpura above (PT)/international normalized ratio (INR) = 1.4 (see the waistline. His penis and scrotum were extremely Table 1 for timeline of presentation, including vital swollen and deeply ecchymotic, with overlying bullae signs, pertinent labs, and physical exam findings). He (see Figure 1). He had a normal blood gas, with a lactate was discharged home with a presumptive diagnosis of of 2.1 mEq/l. He was diagnosed with Henoch–Schönlein purpura (HSP). His PCP saw him the (PF) and disseminated intravascular coagulation of following day; his vital signs were normal and he was uncertain etiology. noted to have swelling and redness of his penis, as well Further diagnostic workup was undertaken to deter- as “deep bruising” of the posterior thighs and buttock. mine the etiology of the PF. Blood drawn on the day of Urinalysis did not show hematuria. The PCP agreed admission (before receiving any blood products) was with the diagnosis of HSP; the patient was sent home retrospectively found to have suppressed with anticipatory guidance. That night, he developed activity (49%; reference range = 75% to 140%). After worsening bruising and swelling and progressive penile the initiation of plasmapheresis, the DIC stabilized and pain that inhibited his ability to void. The escalation of pain prompted a second visit to his local ED. He 1University of Wisconsin School of and , remained afebrile without vital sign changes. His exam Madison, WI, USA was notable for progressive ecchymoses of the lower extremities and buttocks. His penile shaft was described Corresponding Author: Anthony J. Wampole, Department of Pediatrics, University of as “moderately to severely edematous and ecchymotic.” Wisconsin School of Medicine and Public Health, Box 4108, 600 No laboratory studies were obtained. He was started on Highland Avenue, Madison, WI 53792, USA. oral prednisone and discharged. Unremitting pain and Email: [email protected]

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Table 1. Timeline and Associated Laboratory Findings.

First ED Visit (2 days PCP Office (1.5 days Second ED Visit (1 day PTA) PTA) PTA) Third ED Visit Admission to PICU

Vital signs Afebrile; HR 139; BP Afebrile; HR 128; BP Afebrile; HR 121; BP Afebrile; HR 154; BP Afebrile; HR 145; BP 108/59; RR 24 104/50; RR 24 106/68; RR 26 106/73; RR 28 114/68; RR 22 Examination Purpuric lesions on Swelling and redness of Ecchymoses of the Scattered petechiae Deep purple plaques lower extremities; his penis, as well as lower extremities on chest and arms; over thighs and scattered hives on “deep bruising” of the and buttocks; penile diffuse “nonpalpable” lower extremities. torso posterior thighs and shaft was described purpura on legs, Feet relatively spared buttock as “moderately to buttocks, perineum, with some purple severely edematous and penis with discoloration of and ecchymotic” surrounding edema; toes. No petechiae scrotum purpuric and or purpura above grossly edematous, the waistline. with overlying bullae Penis and scrotum were extremely swollen and deeply ecchymotic, with overlying bullae. WBC (K/µL) 10.3; 70% PMNs, — — 16.7; 87% PMNs; 11% 10.5; 81% PMNs; 16 24% lymphs lymphs lymphs Hgb (g/dL)/Hct (%) 12.5/35.6 — — 9.5/27.9 5.3/15 (K/µL) 152 — — 41 17 CO (mEq/L) 22 — — 21 23 2 BUN (mg/dL) 13 — — 18 20 Creatinine (mg/dL) 0.35 — — 0.47 0.43 Urinalysis Unable to be (+) ketones; 2-5 WBCs — Grossly bloody — obtained PT/INR 1.4 — — 8 1.3 Diagnosis HSP HSP HSP DIC Purpura fulminans Intervention Anticipatory Anticipatory guidance Prednisone (1 mg/kg, Blood products, fluids, guidance BID) transfer to PICU

Abbreviations: ED, emergency department; PTA, prior to admission; PCP, primary care ; PICU, pediatric intensive care unit; HR, heart rate; BP, blood pressure; RR, respiratory rate; WBC, white blood cell count; PMN, neutrophils; lymphs, lymphocytes; Hgb, hemoglobin; Hct, hematocrit; BUN, blood urea nitrogen; PT, prothrombin time; INR, international normalized ratio; HSP, Henoch–Schönlein purpura; DIC, disseminated intravascular dissemination.

the protein S activity normalized rapidly, supporting the Henoch–Schönlein Purpura diagnosis of a postinfectious acquired antibody to pro- tein. He underwent a series of debridements and cadav- HSP is the most common small vessel in childhood, affecting approximately 20/100 000 children eric grafts, but ultimately required bilateral 1 below-knee . His scrotum re-epithelialized; annually. It is the most common cause of petechiae and a urinary catheter was placed for urethral patency and he purpura in children (more common than idiopathic had suprapubic catheter placement for urinary diversion. [ITP] and childhood leuke- Pain and agitation were management issues throughout mias). HSP can occur anytime in childhood with a peak his hospitalization. He experienced several skin and uri- incidence at 4 to 5 years. It is preceded by a viral upper nary tract infections. He will ultimately require penile respiratory tract infection in more than half of cases. The reconstruction and bladder augmentation procedures. hallmark of HSP is palpable purpura, classically involv- His total hospital stay was 84 days. ing pressure-dependent areas of the lower extremities and buttocks. The rash can initially appear as urticarial- like lesions and often progresses to varying-sized pete- Discussion chiae and coalesced, raised purpura. Other commonly associated findings include edema, abdominal pain The patient’s initial presentation seemed most consistent (75%), migratory arthralgias/arthritis affecting joints of with HSP; however, his clinical trajectory diverged sub- lower extremities (80%), renal involvement (30% to stantially from the expected course. He was diagnosed 50%), and, more rarely, scrotal involvement and intus- to have postinfectious PF, which ultimately threatened susception. HSP is generally a self-limited illness. Most his life and compromised his limbs. children have complete resolution of symptoms within

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Figure 1. Physical exam findings. Exam findings on presentation (top photo and left photo) and evolution over first 12 hours of inpatient admission (right photo). He had purple plaques over thighs and lower extremities, including lateral hips and penis. Feet were relatively spared with some purple discoloration of toes. There were no petechiae or purpura above the waistline. His penis and scrotum were extremely swollen and deeply ecchymotic, with overlying bullae.

4 to 6 weeks with about one third of patients experienc- general pediatricians in our community to determine ing relapse of symptoms within the first year. Renal their typical diagnostic evaluation for patients present- involvement and risk for hypertension and chronic kid- ing with presumed HSP. Responses of 36 pediatricians ney disease are the most significant long-term sequelae demonstrated that urinalysis was the most frequently that require ongoing monitoring and management. obtained laboratory test obtained by providers (97%). A HSP is diagnosed clinically without specific or con- complete blood count and basic metabolic panel were firmatory laboratory studies with the exception of a skin the next most popular tests, 63% and 29%, respectively; biopsy (rarely performed). None of the major pediatric only 10% to 13% obtained an INR or PTT. textbooks provide strong recommendations regarding the initial evaluation of a patient with a new diagnosis of 2-5 Purpura Fulminans HSP. Most pediatric resources only recommend uri- nalysis to determine whether hematuria is present. PF is a descriptive term that encompasses a variety of However, some recent articles have recommended more disorders that culminate in the rapid development of extensive preliminary testing, including complete blood progressive skin lesions that may ultimately lead to count, erythrocyte sedimentation rate, prothrombin time extensive skin and gangrene, all in the context or INR, basic metabolic panel, antistreptolysin antibody of a consumptive coagulopathy.7 In children, PF most testing, urine dipstick with protein/creatinine ratio, and often occurs as a component of overwhelming , blood culture.6 This testing evaluates for diagnoses that usually caused by or may be masquerading as HSP. pneumoniae.8 Rarely, PF is caused by Based on the lack of recommendations from classic inherited deficiencies of coagulation factors ( textbooks and our experience with this case, we polled or S deficiencies) or is deemed idiopathic. It has recently

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been recognized that a preceding illness was present in Author Contributions 90% of pediatric patients who have been categorized as Each author contributed to the writing, research and editing of having idiopathic PF. Based on these observations, some this article. propose that the term “idiopathic” is better characterized as “postinfectious” and may be immune-mediated. A Declaration of Conflicting Interests small case series, in which patients with postinfectious The author(s) declared no potential conflicts of interest with PF have absent protein S levels, has substantiated this respect to the research, authorship, and/or publication of this 7 claim. Absent protein S levels may be mediated by the article. development of an autoantibody against protein S (ie, an acquired ). Interestingly, the patients Funding in this series with PF, thought to be secondary to an anti– The author(s) received no financial support for the research, protein S antibody, first developed erythematous mac- authorship, and/or publication of this article. ules, which rapidly progressed to sharply defined purpura, primarily affecting the buttocks and lower References extremities. 1. Reid-Adam J. Henoch–Schönlein purpura. Pediatr Rev. Distinguishing HSP and postinfectious PF may be 2014;35:447-449. difficult. In both entities, the distribution of purpuric 2. Miller ML, Pachman LM. Vasculitis syndromes: Henoch– lesions is similar. Unfortunately, there is no description Schönlein purpura. In: Kliegman RM, Behrman RE, Jenson in the literature about the precise appearance of the pur- HB, Stanton BF, eds. Nelson Textbook of Pediatrics. puric skin demarcation in HSP versus postinfectious PF, Philadelphia, PA: Saunders; 2007:1043-1045. with the exception that HSP is typically described as 3. Higuchi LM, Sundel RP. Henoch–Schönlein syndrome. In: palpable purpura and is generally nonscarring. Multiple McMilllan JA, Feigin RD, DeAngelis CD, Jones MD, eds. features appear distinctive in our patient, including (a) Oski’s Pediatrics: Principles and Practice. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:2559-2562. presentation with ecchymoses involving his penis and 4. Barron KS. Vasculitides: Henoch–Schönlein purpura (ana- scrotum, which is atypical for HSP; (b) complaints of phylactoid purpura). In: Rudolph CD, Rudolph AM, Lister severe leg pain, which were qualitatively different than GE, First LR, Gershon AA, eds. Rudolph’s Pediatrics. the arthralgias experienced more frequently in HSP; and New York, NY: McGraw-Hill; 2011:810-812. (c) flat, cutaneous lesions that became deep purple and 5. Adrogué HE, Flores FX. Henoch–Schönlein purpura. sharply demarcated from the surrounding normal skin. In: McInerny TK, Adam HM, Campbell DE, Kamat In our case an abnormal INR was documented nearly DM, Kelleher KJ, eds. American Academy of Pediatrics 48 hours before admission but was not further evaluated. Textbook of Pediatric Care. Elk Grove Village, IL: A low-normal platelet count on presentation might also American Academy of Pediatrics; 2009:2112-2115. have been unexpected in the context of illness and/or 6. McCarthy HJ, Tizard EJ. Clinical practice: diagnosis and . Recognition of the prolonged INR may management of Henoch–Schönlein purpura. Eur J Pediatr. 2010;169:643-650. have altered his disease course. Although laboratory 7. Levin M, Eley BS, Louis J, Cohen H, Young L, Heyderman studies in patients suspected to have HSP are generally of RS. Postinfectious purpura fulminans caused by an auto- low yield, the benefit of identifying a case of postinfec- antibody directed against protein S. J Pediatr. 1995;127: tious PF, with abnormal coagulation studies as the distin- 355-363. guishing factor, seems compelling. Accordingly, we 8. Chalmers E, Cooper P, Forman K, et al. Purpura fulminans: recommend the performance of screening blood counts recognition, diagnosis and management. Arch Dis Child. and an INR in children presenting with presumed HSP. 2011;96:1066-1071.

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