Rash, Pedal Edema, and Severe Anemia in a 17-year-old Male

A 17-year-old boy presents to a rural emergency department for several months of foot swelling, lower extremity rash, and fatigue. Three months earlier, the patient was seen in the clinic for 3 days of polyarthralgia and swelling of his left wrist, right elbow, and bilateral feet, with a "red dot" rash on his legs. He was noted to have a nonblanching, mixed palpable and purpuric rash on his lower extremities (Fig); arthritis of his right elbow; and edema and pain of the bilateral feet, ankles, and wrists. Laboratory tests revealed a creatinine level of 1.2 mg/dL (106.08 µmol/L), a hemoglobin level of 10.4 g/dL (104 g/L), a C-reactive protein level of 5.0 mg/dL (50 mg/L), and an erythrocyte sedimentation rate of 68 mm/hr. Urinalysis showed hematuria and proteinuria. The patient was diagnosed presumptively as having IgA vasculitis, discharged with supportive care, and advised to follow up in 1 week.The patient did not follow up for outpatient care. Now, in the emergency department, he complains of ongoing pain in his elbows and hands, lower extremity swelling and rash similar to his initial presentation, and worsening fatigue. He denies fevers, weight loss, abdominal pain, change in stooling, hematochezia or hemoptysis, cough, or history of sinusitis or asthma. He denies any known exposures to hazardous chemicals, rats, or other animals, and he has not traveled recently.His vital signs show a heart rate of 112 beats/min, a blood pressure of 161/79 mm Hg, and normal pulse oximetry, respiratory rate, and temperature. His weight is stable at his baseline of 176 lb (80 kg). Physical examination reveals a pale male with bilateral lower extremity edema extending from foot to mid-shin and a scattered, nonblanching mixed petechial and purpuric rash from the tops of his feet to his knees without ulcerations, vesicles, or plaques. The patient has full range of motion, with mild pain with movement in both ankles. All other large and small joints appear normal, without erythema, edema, or warmth on examination. Cardiac examination is notable for tachycardia but is otherwise negative for rubs, murmurs, or gallops; lungs are clear to auscultation bilaterally, with no increased work of breathing; and abdominal examination shows a soft, nontender abdomen with normal bowel sounds and no hepatosplenomegaly, masses, rebound pain, or guarding. Examination of the head, oropharynx, and neck is normal, with no tonsillar erythema or exudates and no cervical lymphadenopathy. A genitourinary examination is not performed at this time.Laboratory studies are notable for a hemoglobin level of 2.8 g/dL (28 g/L), a mean corpuscular volume of 80 μm3 (80 fL), a platelet count of 453 × 103/μL (453 × 109/L), and a WBC count of 0.00946 × 103/μL (0.00946 × 109/L), with 79% neutrophils. His creatinine level is 1.7 mg/dL (150.28 µmol/L), blood urea nitrogen level is 19 mg/dL (6.78 mmol/L), sodium level is 138 mEq/L (138 mmol/L), potassium level is 3.4 mEq/L (3.4 mmol/L), chloride level is 104 mEq/L (104 mmol/L), and carbon dioxide level is 20 mEq/L (20 mmol/L), with an albumin level of 2.5 g/dL (25 g/L). Liver function test results are otherwise normal. Brain natriuretic peptide level is 1,337 pg/mL (1,337 ng/L) (reference range, 0–125 pg/mL [0–125 ng/L]), and urine shows 100 mg/dL (1 g/L) of protein, a large amount of blood, and 6 to 10 white and red blood cells per high-power field. Lactate dehydrogenase level is normal. Iron serum level is 15 μg/dL (2.69 µmol/L) (reference range, 49–181 μg/dL [8.77–32.40 µmol/L]), with a normal direct iron binding capacity and an elevated reticulocyte percentage of 13.2.The patient presented with severe anemia, hypertension, arthralgias, a mixed petechial and purpuric rash, lower extremity edema, and laboratory work indicative of glomerulonephritis.The differential diagnosis for anemia includes decreased red blood cell production (from inflammation, bone marrow suppression, and iron deficiency), blood loss, and hemolysis. Common causes of anemia of inflammation include malignancy, acute or chronic infection, and chronic autoimmune inflammatory disease. (1)Petechiae and purpura, nonblanching erythematous rashes due to hemorrhage of blood into the skin or mucosa, may be benign or may be the result of more serious conditions, including platelet dysfunction or deficiency (thrombocytopenia), abnormalities of hemostasis and the coagulation cascade, or abnormalities of the vascular system, including vascular fragility or inflammation. (2)(3) Anemia may be seen with purpura in cases of blood loss, hemolysis, and bone marrow infiltration or failure (leukemia, aplastic anemia). (2)Primary causes of glomerulonephritis in children and adolescents include IgA nephropathy (previously Berger disease), membranoproliferative glomerulonephritis, hereditary nephritis (previously Alport syndrome), and postinfectious glomerulonephritis. Secondary causes are often associated with other systemic illnesses, including systemic lupus erythematosus, IgA vasculitis (previously Henoch-Schonlein purpura), Goodpasture syndrome, hemolytic uremic syndrome, and antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides (granulomatosis with polyangiitis [GPA], microscopic polyangiitis, and eosinophilic GPA). (4)(5) Postinfectious glomerulonephritis, minimal change disease, and IgA vasculitis are the most common sources of glomerular disease in younger children in the United States. (6)The patient was given 1 U of packed red blood cells and transferred to a PICU, where he received an additional 5 U. Due to his elevated brain natriuretic peptide level, echocardiography was performed, which was normal. The patient was seen by rheumatology and nephrology services and underwent a renal biopsy showing focal necrotizing and crescentic glomerulonephritis, pauci-immune type. Blood work showed ANCAs with serine protease 3 antibodies, consistent with GPA. C3 and C4 complement levels were both low at 75 mg/dL (0.75 g/L) (reference range, 84–177 mg/dL [0.84–1.77 g/L]) and 8.2 mg/dL (0.08 g/L) (reference range, 12–45 mg/dL [0.12–0.45 g/L]), respectively.Computed tomography (CT) of the patient's chest was notable for ground glass opacities in multiple lobes in an asymmetrical distribution without cavitating lung nodules or pulmonary masses. CT sinus showed an isolated mucous retention cyst without other findings.GPA, formerly called Wegener granulomatosis, is a systemic autoimmune necrotizing vasculitis that mainly affects small vessels. It often results in granulomatous inflammation of the upper and lower respiratory tracts, although blood vessels in the skin, gastrointestinal tract, and peripheral nerves are frequently involved as well. (7)(8) Renal involvement is common in children, with pauci-immune necrotizing and crescentic glomerulonephritis often leading to chronic kidney disease. (9)The incident rate of US patients with GPA is 1.8 per million per year in the pediatric group and 12.8 per million per year in working-age adults (19–65 years old). Most pediatric patients (79.8%) are 12 to 18 years of age at diagnosis, with a slight female predominance. (10)ANCAs against either proteinase 3 or myeloperoxidase are the classic pathologic finding of GPA and are central to the disease. (9) Other ANCA-associated vasculitides include microscopic polyangiitis and eosinophilic GPA. (9) These diseases often result in severe clinical presentations, frequent recurrences, and high morbidity. (9) Data show that the mortality rate associated with GPA can be as high as 80% in untreated patients. (10)Anemia is common in patients with ANCA-associated renal vasculitis. (7) In a series of 45 adult patients with this diagnosis treated from 2003 to 2014 at a large Japanese referral hospital, 100% of patients presented with anemia at the time of diagnosis, and more than half presented with a hemoglobin level less than 7.5 g/dL (<75 g/L). Anemia severity directly correlated with degree of renal failure and overall survival rates. (8)The etiology of primary systemic vasculitis remains unclear. Some studies have reported a significant association with farming and exposure to silica, (11) or a raised odds ratio for exposure to assorted metals and welding fumes, whereas other studies have not observed any association with occupational metal exposure. (12) Nasal carriage of Staphylococcus aureus by patients with GPA has been linked to a higher risk of relapse. (12)Initial classification criteria for pediatric GPA were developed by the American College of Rheumatology in 1990. A new set of criteria was endorsed/published by the European League Against Rheumatism, the Paediatric Rheumatology International Trials Organisation, and the Paediatric Rheumatology European Society (EULAR/PRINTO/PReS) in 2010, (9) and requires the presence of 3 of 6 criteria for the diagnosis of GPA: 1) granulomatous inflammation in the wall of an artery or in the perivascular or extravascular area on pathology; 2) upper airway involvement, including chronic nasal or sinus symptoms; 3) laryngotracheobronchial involvement; 4) pulmonary involvement (chest radiograph or CT showing nodules, cavities, or fixed infiltrates); 5) ANCA positivity by immunofluorescence or enzyme-linked immunosorbent assay; and 6) renal involvement, including proteinuria, hematuria, or necrotizing pauci-immune glomerulonephritis on biopsy. (13)Although IgA vasculitis and GPA share overlapping symptoms, palpable purpura with lower limb predominance is more common in IgA vasculitis than in GPA (89% versus 15% of patients in the EULAR/PRINTO/PRES data set). Proteinuria and hematuria are less common in IgA vasculitis (33% of patients) than in GPA, where rates of renal involvement approach 65%. Abdominal pain is present in greater than 60% of patients with IgA vasculitis but is not associated with GPA. More than 70% of patients with GPA have upper airway, laryngotracheobronchial, or pulmonary involvement by examination or imaging compared with less than 10% in other vasculitides. (13)Guidelines for the treatment and management of ANCA-associated vasculitis were last revised in 2021 and recommend rituximab, a B-cell–depleting anti-CD20 monoclonal antibody, as the preferred medication for induction for active, severe GPA. (14)(15) Cyclophosphamide, a cytotoxic alkylating drug that inhibits both T- and B-cell lymphocyte proliferation and decreases their synthesis of antibodies, is recommended in patients with severe disease refractory to rituximab. (16) In patients with life-threatening manifestations such as diffuse alveolar hemorrhage or rapidly progressive glomerulonephritis with severe kidney injury, plasma exchange is often administered in addition to standard induction therapy, (17)(18) although its use remains controversial. (19) Maintenance therapy includes lower doses of corticosteroids (reduced to minimize toxicities associated with long-term high-dose glucocorticoids [14]) and azathioprine or methotrexate or mycophenolate mofetil. (9) Despite treatment, relapses are common. (7)(14)When looking at adult cohorts with GPA, older age and organ involvement were independent predictors of mortality. The European Vasculitis Study Group found that, in general, patients with predominant upper respiratory tract disease had improved survival (hazard ratio, 0.31) and those with predominant renal disease had worse survival (hazard ratio, 4.45). (20)Data regarding pediatric mortality are limited. In Panupattanapong et al's (10) cohort of 94 children with GPA from 2007 to 2014, 17 (18.1%) progressed to end-stage renal disease, all within 1 year of diagnosis, with 5 children dying during the observation period. Severe infections remain a major cause of complications/hospitalizations, with 2 to 3 times higher rates of leukopenia, neutropenia, and hypogammaglobulinemia among pediatric patients with GPA compared with adults. (10)The patient was started on prednisone and cyclophosphamide and was discharged with outpatient follow-up (the patients' initial presentation preceded the release of the 2021 guidelines). Unfortunately, the patient developed severe diarrhea due to cyclophosphamide and required readmission for electrolyte repletion and intravenous hydration. He was subsequently switched to rituximab and continues to receive maintenance rituximab infusions every 6 months.The presence of a vasculitic rash with glomerulonephritis, although also seen in IgA vasculitis, should be highly concerning for an antineutrophil cytoplasmic antibody–associated vasculitis.Lack of abdominal pain and palpable purpura, in addition to severe anemia in patients older than 10 years, should prompt the clinician to consider etiologies for glomerulonephritis other than IgA vasculitis. Anemia is frequent at the time of diagnosis of granulomatosis with polyangiitis (GPA), and its severity has been linked to the degree of patients' renal dysfunction and survival rates.The European League Against Rheumatism, Paediatric Rheumatology International Trials Organisation, and Paediatric Rheumatology European Society criteria require the presence of 3 of 6 features to make a diagnosis of GPA.GPA can be associated with severe clinical presentations, frequent recurrences, and a high morbidity rate.New treatment guidelines consist of a reduced corticosteroid regimen and rituximab induction therapy. Cyclophosphamide is considered for patients with severe disease and/or those refractory to treatment with rituximab.