Background

A 20-year-old active-duty male soldier presents to the emergency department (ED) of a military hospital complaining of a 3-day history of a dark-red "burning rash." The rash started at his sock line and, over the course of the past 2 days, has spread proximally up his thighs. It is not present on his abdomen or back, but it has spread to his hands over the past day. The patient also developed a sore throat and a scratchy voice the day before presentation, without odynophagia. He was in the North Carolina woods as part of his infantry training, which is supplemental training after boot camp. He reports having spent 20+ hours per day for the past several days in a foxhole (a hole in the ground that soldiers use for protection). The patient reports fatigue only related to his level of activity and lack of sleep during training. He is not taking any medications, he has no allergies, and he has smoked 5-10 cigarettes daily for the past year. He also reports drinking approximately 5-10 beers with his comrades 1-2 times per month before starting his training. The patient notes some right ankle swelling and pain that started after a 12.43 mi (20 km) field hike with a 60 lb (27.22 kg) rucksack on his back. The pain and swelling began 1 month before admission and has worsened in the past few days. He has had no pruritus, fevers, chills, abdominal pain, diarrhea, changes in urine color, or dysuria, as well as no new sexual contacts and no recent animal or insect bites. No one else in his military unit has reported similar skin findings. The patient had a minor motorcycle accident 18 months ago, with a right leg laceration that required suture repair. He has no significant family history.
On physical examination, his vital signs demonstrate a strong pulse, with a regular rhythm and a rate of 58 bpm, blood pressure of 123/60 mm Hg, weight of 165.3 lb (75 kg), and oral temperature of 98.1°F (36.7°C). He is a very fit, well-developed white male in no apparent distress. The pharynx shows no erythema or exudate, and the neck examination demonstrates no tenderness to palpation or lymphadenopathy. The cardiac examination is notable for a point of maximum intensity at the 5th left interspace, but no murmurs, gallops, or rubs are appreciated. The patient's pulses are strong bilaterally. The respiratory examination reveals lungs clear to auscultation bilaterally. The abdominal examination is unremarkable, and the stool test is negative for occult blood. The skin examination show lesions ranging in diameter from 2 mm to 10 cm (see Figures 1-3). The macules and plaques are nonblanchable, and most of them are concentrated in the posterior calves, the palms, and the soles of the feet. No macules or plaques are noted on the face, chest, or back. The lesions are not tender to palpation or warm to the touch. His hands and right ankle exhibit 1+ nonpitting edema. The patient has a scar on his right leg from his motorcycle accident that is well-healed, with no fluctuance or erythema. The neurologic examination is unremarkable.
A urinalysis shows 2+ protein and 2+ blood, with 25-50 red blood cells (RBCs) per high-power field on microscopy. His coagulation studies at admission include a prothrombin time (PT) of 12.3 s, an international normalized ration (INR) of 1.08, and a partial thromboplastin time (PTT) of 25.5 s. The patient's blood urea nitrogen (BUN) is 24 mg/dL (8.59 mmol/L) and his creatinine value is 1.1 mg/dL (97.2 µmol/L). The complete blood count (CBC) shows a white blood cell (WBC) count of 7.4 × 103/µL (7.4 × 109/L), a hemoglobin (HGB) of 12.4 g/dL (124 g/L), a hematocrit (HCT) of 37.1% (0.371), and a platelet count of 195 × 103/µL (195 × 109/L), with a normal smear. Skin punch biopsies of 2 of the lesions are obtained that demonstrate small-vessel leukocytoclastic vasculitis. Immunofluorescence of the skin biopsies demonstrates a weak linear pattern at the dermal-epidermal junction for immunoglobulin G (IgG), immunoglobulin A (IgA), and complement 3 (C3).

What is the diagnosis?

Hint: The patient is presenting with nonblanchable lesions after reporting an antecedent sore throat.
Henoch-Schönlein purpura (HSP)
Mixed cryoglobulinemia
Polyarteritis nodosum
Systemic lupus erythematosus
Hemolytic uremic syndrome (HUS)

Your Colleagues Responded:
Henoch-Schönlein purpura (HSP) Correct Answer 62%
Mixed cryoglobulinemia 6%
Polyarteritis nodosum 7%
Systemic lupus erythematosus 6%
Hemolytic uremic syndrome (HUS) 17%

Discussion

Figure 1. Figure 2. Figure 3.

There exist several guidelines for the diagnosis of Henoch-Schönlein purpura.[1] The American College of Rheumatology (ACR) requires 4 criteria (published in 1990) for diagnosing Henoch-Schönlein purpura[2]: palpable purpura, patient age of 20 years or less at onset, bowel angina, and the presence of granulocytes in the vessel walls. More recently, in 2006, the European League Against Rheumatism (EULAR) and the Pediatric Rheumatology Society published their own Henoch-Schönlein purpura criteria. These include palpable purpura as a mandatory criterion, with at least one of the following conditions: diffuse abdominal pain, predominant IgA deposition (confirmed on biopsy), acute arthritis in any joint, and renal involvement (as evidenced by hematuria and/or proteinuria).[3] According to the older ACR criteria, the diagnosis of Henoch-Schönlein purpura for our patient could be called into question, as he exhibited no bowel angina; however, according to the more recent EULAR criteria, our patient fits the diagnosis of Henoch-Schönlein purpura quite well, as he has palpable purpura, predominant IgA deposition confirmed on biopsy, a monoarticular arthralgia in his right ankle, and renal involvement.
The sine qua non for the diagnosis of Henoch-Schönlein purpura is a skin biopsy finding of IgA deposition at the dermal-epidermal junction. A skin biopsy with immunofluorescence studies is recommended if clinical suspicion of Henoch-Schönlein purpura exists.[4] The etiology of the disease remains unknown, but it is understood to be an autoimmune response (usually to an upper respiratory infection).
Other items in the differential diagnosis include many of the etiologies of palpable purpura. An algorithmic attempt has been made (see Table 1) to delineate these etiologies, but classification remains difficult.[5] Palpable purpura is a classic skin manifestation of cutaneous vasculitis, but there are many other entities that can cause it.[6] Additional information can be gleaned from the pathologic diagnosis of small vessel vasculitis, which also carries its own differential (see Table 2).[7] The intersection of these 2 differentials consists of the following set of diagnoses: mixed cryoglobulinemia, vasculitis associated with collagen vascular disease (ie, systemic lupus erythematosus, rheumatoid arthritis), and Henoch-Schönlein purpura.
Mixed cryoglobulinemia was easily ruled out, as the patient's serum cryoglobulin test and complement levels were a C3 of 118 mg/dL (1.18 g/L; normal range, 79-152 mg/dL), a C4 of 26 mg/dL (0.26 g/L; normal range, 16-38 mg/dL), complement CH50 of 53.0 U/mL (53 kU/L; normal range 22-60 U/mL), and a negative serum cryoglobulin examination. Another diagnosis that was readily excluded was systemic lupus erythematosus. Our patient had only 1 arthralgia, but no fevers, myalgia, or malaise were noted; only 1/11 American Rheumatologic Association criteria for the diagnosis of lupus were met.[8] To satisfy the clinical diagnosis of systemic lupus erythematosus, 4/11 American Rheumatologic Association criteria are required.[8] Although the patient meets the histopathologic criteria for solitary IgA nephropathy, as the renal biopsy showed diffuse proliferative endocapillary glomerulonephritis with increased mesangial matrix and cellularity, capillary wall thickening, and lobular accentuation on light and electron microscopy with strong (3+) mesangial staining for IgA and fibrinogen, as well as lappa and lambda light chains (2-3+) present on immunofluorescence microscopy, he also exhibited some of the cardinal clinical features of Henoch-Schönlein purpura at presentation. He denied having had blood in his urine on prior urinalyses or a history of gross blood urine, lessening the possibility of IgA nephropathy. After further inquiry, it was confirmed that the patient had no family history of renal disease and, as such, it is unlikely that he has familial IgA nephropathy. Polyarteritis nodosum (PAN) could be considered in the differential diagnosis, but this patient displayed none of the classic signs or symptoms of fever, abdominal pain, nausea, and weight loss. Also common to PAN is the is involvement of small- and medium-sized arteries, as well as subcutaneous nodules (not palpable purpura). Joint pain, however, is very common in PAN. PAN may be associated with hepatitis B or C, but this patient's hepatitis panel was negative. A hemorrhagic diathesis was quickly ruled out with the normal coagulation studies. Lyme disease, in contrast to Henoch-Schönlein purpura, more commonly presents with the typical target lesions of erythema migrans and a positive Lyme titer (and not with a purpuric rash). This patient had a negative Lyme antibody examination, although this finding alone does not exclude the possibility of the disease. Multiple arthralgias are more common in Lyme disease, and they seldom present with abdominal pain. Hemolytic uremic syndrome (HUS) should be considered in the differential diagnosis, but it can be easily recognized by the presence of microangiopathic anemia and is distinguished from Henoch-Schönlein purpura by the absence of purpura and arthralgias.
Henoch-Schönlein purpura is an autoimmune, self-limited IgA-mediated vasculitis that most commonly presents in children 5 years of age. In fact, 95% of cases present in children <10 years of age.[9] There is a 2:1 distribution between males and females.[10] The overall incidence is 0.14 cases per 1000 population in children aged 2-14.[10] This patient is in a relatively uncommon demographic for the disease. The most common signs and symptoms of the disease are palpable purpura (100%), abdominal pain (63%), gastrointestinal bleeding (33%), arthralgia (82%), nephritis (40%), and hematuria.[11] Risk factors associated with a poor prognosis for renal survival include nephrotic syndrome, decreased factor XIII activity, hypertension, and renal failure at onset.[9] It is known that severe Henoch-Schönlein purpura–associated nephritis and progression to nephrotic syndrome are associated with a poorer prognosis.[9]
The mainstays of treatment for Henoch-Schönlein purpura are observation, intravenous hydration, and steroid therapy. Most cases are self-limited and resolve within 4 weeks.[12,13] Cyclophosphamide is usually reserved for severe, systemic forms of vasculitis, and appropriate consultation with a nephrologist is recommended.[16] Chronic kidney disease and end-stage renal disease are known complications of Henoch-Schönlein purpura, with incidence rates of 5% and 1.5%, respectively.[12] It should be noted that corticosteroids should only be instituted after consultation with a nephrologist, as they are of questionable benefit.[13,14] In fact, only 1 randomized controlled clinical trial has been performed evaluating the use of corticosteroids in treating Henoch-Schönlein purpura as renal protective agents. Huber et al found that early prednisone therapy initiation did not ward off chronic kidney disease at 1 year[14]; however, there has been a case report of successful treatment of an adult patient with crescentic glomerulonephritis (from Henoch-Schönlein purpura) with 9 rounds of double-filtration plasmapheresis and concomitant plasma replacement.[15]
Our patient was admitted to the hospital ward and vigorously volume-expanded with normal saline at 250 cc/h. His creatinine clearance was 182.7 mL/min (3.05 mL/s; this is within normal limits). Also notable was his antistreptolysin O (ASO) titer of 722 Todd U/mL (normal range, 0-117 Todd U/mL). Even with his severe skin manifestations, the severity of our patient's Henoch-Schönlein purpura nephritis on admission was low. The patient's positive ASO titer pointed to a recent presumed streptococcal pharyngitis. The skin biopsy report was significant for small-vessel leukocytoclastic vasculitis. The immunofluorescence study of the sample demonstrated a weak linear pattern at the dermal-epidermal junction, with IgG, IgA, and C3, which was consistent with the diagnosis of Henoch-Schönlein purpura. On admission, the patient's protein-to-creatinine ratio was 5.5, consistent with nephrotic-range proteinuria, or >3.5 grams of protein per day. A normal protein-to-creatinine ratio is <0.2.[17] Although the nephrology service was consulted early in the clinical course and the patient was started on high dose intravenous methylprednisolone therapy at 1 gram divided twice a day on hospital day 1, his condition rapidly worsened. By hospital day 4, the patient's serum creatinine was 1.1 mg/dL (97.2 µmol/L) and his protein-to-creatinine ratio had increased to 15.1. His urine volume was 1850 mL on that day, with 24 h protein and creatinine excretion totaling 35.8 grams and 2384 mg, respectively. The patient, while still normotensive, had developed prominent edema consistent with nephrotic syndrome. As his renal status had worsened significantly, he was transferred to a tertiary care center for further nephrology care. A subsequent renal biopsy demonstrated diffuse proliferative endocapillary glomerulonephritis consistent with IgA nephropathy, or Henoch-Schönlein purpura. Mild chronic tubulointerstitial disease and mild hyaline arteriolar sclerosis were noted as well. A regimen of cyclophosphamide was initiated, and the patient deteriorated to end-stage renal disease by the time this case was compiled.

Table 1: Etiology of Purpura

• Intravascular (usually nonpalpable) Alterations in platelet formation, destruction, or function
• Drugs (aspirin, methyldopa)
• Idiopathic thrombocytopenic purpura
• Thrombotic thrombocytopenic purpura
• Disseminated intravascular coagulation
• Infection (especially Neisseria, Rickettsia, Staphylococcus)
• Splenic sequestration
• Radiation therapy
• Myelofibrosis
• Myeloproliferative disorders
Vascular (usually palpable) Inflammatory vascular causes
• Cutaneous vasculitis
• Purely cutaneous vasculitis (eg, secondary to medications)
• Henoch-Schönlein purpura
• Polyarteritis nodosa
• Granulomatous vasculitis (Wegener granulomatosis, Churg-Strauss vasculitis)
• Cutaneous vasculitis associated with a collagen
• Vascular disease (eg, systemic lupus erythematosus, rheumatoid arthritis)
• Giant cell arteritis
• Mixed cryoglobulinemia
• Hyperglobulinemic purpura
Noninflammatory vascular causes
• Trauma
• Subacute bacterial endocarditis
• Other embolic diseases
• Amyloidosis
• Extravascular and miscellaneous (may be palpable or nonpalpable) Corticosteroids
• Toxins and venoms
• Senile purpura
• Scurvy
• Valsalva maneuver
• Pseudopurpura (Sweet syndrome, cherry angiomas, angiokeratoma, Kaposi sarcoma)
Derived from: Schreiner DT. Purpura. Dermatol Clin. 1989;7(3):481-90

Table 2: Clinical Signs of Necrotizing Vasculitis with Respect to Vessel Size Involved

Small Vessels
Signs Diseases
• Urticaria Hypersensitivity vasculitis
• Palpable Purpura Henoch-Schönlein purpura
• Essential Mixed Cryoglobulinemia
• Vasculitis associated with connective tissue disease
• Vasculitis associated with malignancy
• Serum sickness and serum sickness-like reactions
• Nodules, bullae, or ulcers Chronic urticaria (urticarial vasculitis)
• Urticarial prodrome of acute hepatitis type B infection
Large Vessels
Signs Diseases
• Subcutaneous nodules, ulceration, and, ecchymoses Polyarteritis nodosa
• Churg-Strauss syndrome
• Wegener granulomatosis
• Giant cell (temporal) arteritis
Derived from: Habif, TP. Clinical Dermatology: A Color Guide to Diagnosis and Therapy. 4th ed. St. Louis: Mosby; 2004.

Test

If the clinician is clinically suspicious of Henoch-Schönlein purpura in a patient, which test is most likely to give a definitive diagnosis?
Urine protein electrophoresis
Skin biopsy
Serum complement levels
24 h urine protein
CBC

Which of the following statements about Henoch-Schönlein purpura is true?
Henoch-Schönlein purpura treatment requires corticosteroids.
Henoch-Schönlein purpura treatment requires dialysis.
Henoch-Schönlein purpura treatment requires plasmapheresis.
Most cases of Henoch-Schönlein purpura spontaneously resolve within 1 month.
Most cases of Henoch-Schönlein purpura treatment are steadily progressive and typically manifest significant renal pathology.

If the clinician is clinically suspicious of Henoch-Schönlein purpura in a patient, which test is most likely to give a definitive diagnosis?
Your Colleagues Responded:
Urine protein electrophoresis 5%
Skin biopsy Correct Answer 81%
Serum complement levels 7%
24 h urine protein 3%
CBC 2%
Which of the following statements about Henoch-Schönlein purpura is true?
Your Colleagues Responded:
Henoch-Schönlein purpura treatment requires corticosteroids. 17%
Henoch-Schönlein purpura treatment requires dialysis. 0%
Henoch-Schönlein purpura treatment requires plasmapheresis. 2%
Most cases of Henoch-Schönlein purpura spontaneously resolve within 1 month. Correct Answer 70%
Most cases of Henoch-Schönlein purpura treatment are steadily progressive and typically manifest significant renal pathology. 7%