This is a five year old boy who presents to the Emergency Department with acute right ankle arthritis. His ankle is red, hot, tender, and obviously swollen. His mother states that he refuses to bear weight on that leg. She further notes that he complained of left knee pain the previous day and that he has not been himself since an upper respiratory infection a week previously. He is anorexic and has lost 2-3 pounds over the past week, thought to be due to recurrent, crampy abdominal pain.
Past medical history and family history are noncontributory.
Exam: VS T 39, HR 160, RR 24, BP 130/90. He is ill-appearing, irritable, and febrile. HEENT exam is positive for mild pharyngitis. His neck is supple. His chest shows some pre-sternal edema with clear lungs and a gallop rhythm. Abdomen: His liver is tender to deep palpitation and percussion. Borborygmus is auscultated. Genitalia: Circumcised male with bilaterally descended testes. There are extensive ecchymoses on his scrotum with swollen, weeping red involvement of the corona of the glans penis. He may have a borderline effusion of his left knee and 2+ swelling, erythema, tenderness, pain-on-motion and limitation-of-motion of the right ankle. His skin exam is positive for slightly raised petechial rash on his legs, most prominent on his ankles, posterior thighs and buttocks. Some lesions have coalesced into ecchymotic purpura.
Laboratory: CBC WBC 36,600, Hgb 8.2, Hct 26, platelet count 750,000. UA: cloudy, amber; sp gr 1.029, blood 3+, protein 2+, rbc casts 2-3 per hpf, and granular casts 1-2 per hpf. Erythrocyte sedimentation rate, 90 mm/hr. ANA, negative, RF, negative, ASO 250 Todd units, IgG 1280, IgM 280, IgA 600 mg/dl. Blood and urine cultures were negative. Stool guaiac 2+. Uric acid 6.5mg/dl, BUN 30mg/dl, Cr 1.3mg/dl, SGOT 90, SGPT 110. A skin biopsy demonstrates leukocytoclastic vasculitis on light microscopy and IgA staining of the vascular endothelium on fluorescent microscopy.
This patient has perhaps the most common vasculitis of childhood, namely Henoch-Schonlein purpura (HSP, also called anaphylactoid purpura or rheumatoid purpura).
The vasculitides of childhood are a complex and poorly understood group of inflammatory conditions whose etiologies appear to be on an immune basis. Several classification schema have been proposed based on: 1) vessel size, 2) presumed immunopathophysiology, or 3) organ involvement. The more common vasculitides are listed below:
I. Small and Medium Vessel Vasculitis
. . . . A. Immune Complex Mediated
. . . . . . . . 1. Henoch-Schonlein Purpura
. . . . . . . . 2. Hypersensitivity vasculitis
. . . . . . . . 3. Polyarteritis nodosa (PAN)
. . . . . . . . 4. Urticarial vasculitis
. . . . . . . . 5. Cryoglobulinemia
. . . . . . . . 6. Connective tissue diseases (SLE, JRA, dermatomyositis, scleroderma, Behcet disease)
. . . . B. Antineutrophil Cytoplasmic Antibody (ANCA) Associated Disorders:
. . . . . . . . 1. Wegener's granulomatosis*
. . . . . . . . 2. Microscopic polyarteritis
. . . . . . . . 3. Churg-Strauss syndrome*
. . . . . . . . 4. Drug-induced vasculitis
. . . . C. Miscellaneous
. . . . . . . . 1. Erythema elevatum diutinum
. . . . . . . . 2. Paraneoplastic*
. . . . . . . . 3. Infection
. . . . . . . . 4. Inflammatory bowel disease
II. Large vessel vasculitis
. . . . A. Temporal arteritis*
. . . . B. Takayasu arteritis
*rare in childhood
Henoch-Schonlein purpura (HSP) is characterized by a tetrad including: palpable purpura, arthritis, abdominal pain and glomerulonephritis. The rash of HSP has been described as palpable purpura. Certainly petechiae are very common early and often tend to coalesce. Target lesions, ecchymosis, lymphangitic streaks and purple or bloody suffusions are sometimes seen. The distribution of the rash is typically from the waist down. Occasionally the rash involves the upper extremities and I have seen the rare child with a generalized rash of the entire body to include involvement of palms, soles, and even the scalp. Histopathologically, leukocytoclastic vasculitis is observed and immunopathologically, IgA is deposited in involved vessel walls and the renal glomerulus. In spite of there being two subtypes of IgA (i.e., IgA1, IgA2) only IgA1 is involved in HSP. Arthritis is often extremely acute and may be quite inflammatory. Large joints of the lower extremities are most commonly involved, especially ankles and knees. The arthritis is much like that of acute rheumatic fever, often very acute, sometimes migratory and often, exceedingly responsive to nonsteroidal anti-inflammatory drugs (NSAIDs). Hypertension usually responds to diuretic therapy and judicious fluid management. Renal involvement is relatively mild to moderate and is of the nephritic type. Occasionally, a nephrotic syndrome may occur instead. The gastrointestinal tract is commonly affected and most often, crampy abdominal pain is the primary manifestation. Diffuse bleeding from the GI tract is treated medically. Rarely intussusception complicates the picture and obstruction or perforation may necessitate emergency surgery. Testicular vasculitis maybe confused with testicular torsion. Corticosteroids must be reserved for serious complications of the disease and should not be instituted for treatment of the rash or arthritis. Mild recurrent abdominal pain likewise is best managed conservatively.
Polyarteritis nodosa (PAN) was the first described vasculitis and it is a prime example of medium vessel vasculitis. Although occasionally seen in children, it is distinctly far more common in adults. Infantile polyarteritis nodosa (IPAN) is a rare and often lethal inflammatory disease of small and medium-sized arteries. Clinically, IPAN is often considered part of the spectrum of Kawasaki Disease (KD), in spite of the fact that IPAN was described nearly 130 years ago. Specifically, IPAN, with aneurysmal involvement of major coronary arteries and fatal KD are clinically and pathologically indistinguishable. Indeed, the primary distinction between KD and IPAN is that the diagnosis of KD is based entirely on clinical criteria while the diagnosis of IPAN is based on histologic findings. Additionally, a major distinction between polyarteritis and KD is the profound difference in prognosis; much worse for IPAN.
Microscopic polyarteritis is a necrotizing vasculitis, which affects small vessels (capillaries, venules and arterioles) in the kidneys and lungs. It is commonly associated with the presence of circulating antineutrophil cytoplasmic antibody (ANCA). Clinically, necrotizing glomerulonephritis occurs in the majority of patients. Hemoptysis and life-threatening pulmonary hemorrhage may supervene. This vasculitis is distinguishable from Wegener's granulomatosis in that respiratory tract symptoms are less and granulomatous inflammation is not present in microscopic polyarteritis.
Hypersensitivity vasculitis: Cutaneous involvement includes palpable purpura, papules, urticaria, erythema multiforme vesicles, pustules, ulcers and necrosis. Typically the rash involves dependent regions and occurs in crops. The patient is usually asymptomatic, but occasionally complains of burning/tingling. With regard to treatment, one must: 1) exclude systemic involvement, and 2) identify and remove offending allergens/agents, most often medications.
Urticarial vasculitis is an entity with three subtypes which have been described: normocomplementemic; hypocomplementemic, and the hypocomplementemic urticarial vasculitis syndrome (HUVS). The latter disease resembles systemic lupus erythematosus (SLE). The skin involvement is by definition, urticarial. Those patients with the lupus-like syndrome may require corticosteroid treatment and those with normal complement levels are usually self-limited.
Cryoglobulins are antibodies that precipitate in the cold and resolubalize on warming. Cryoglobulinemic vasculitis is associated with autoimmune conditions in childhood. Cryoglobulins may contain IgA, IgG or IgM, some have rheumatoid factor activity and they have been classified into types I, II and III. Types II and III may be associated with vasculitic syndromes. Immune complexes of mixed cryoglobulins, deposit in vessel walls, activate complement and produce recurrent palpable purpura with cutaneous ulceration. Hepatis C virus infections account for the majority of cases.
Vasculitis complicates several of the connective tissue diseases of childhood. These would include systemic lupus erythematosus juvenile rheumatoid arthritis, dermatomyositis, scleroderma, and Behcet disease. Clinically the vasculitic manifestations may be as minimal as a purpuric skin rash in SLE to telangiectasis of the nail beds in dermatomyositis to necrosis and gangrene of one or more digits to life threatening central nervous system vasculitis.
Wegener's granulomatosis or lethal midline granuloma is a rare vasculitis characterized by a triad of necrotizing vasculitis of the upper respiratory tract, the lower respiratory tract and focal segmental glomerulonephritis. Patients present with fever, malaise, weight loss, arthralgias, myalgias, rhinitis, sinusitis, nasal and oral ulceration. Pulmonary symptoms include dyspnea, chest pain, bloody sputum, and hemoptysis. A majority of patients develop antineutrophil cytoplasmic antibodies (ANCA) have been recognized since 1985 and are classified as cytoplasmic (c) or perinuclear (p) depending on the fluorescence location. ANCAs may have some diagnostic and prognostic significance. A tissue diagnosis is required to differentiate this condition from another rare vasculitis, lymphomatoid granulomatosis, perhaps more prevalent in children than Wegener's.
Churg-Strauss syndrome was initially reported under the descriptive title of allergic granulomatosis and angiitis. Churg-Strauss syndrome is virtually non-existent in children.
Takayasu arteritis is the prototype vasculitis involving large vessels. Takayasu arteritis (also known as pulseless disease of Japan) involves the aorta and its branches. It is exceedingly uncommon in children; however it is seen in teenagers from Micronesia and should always be considered in an adolescent girl with severe hypertension and a peripheral or abdominal bruit. Non-specific symptoms such as malaise and arteralgia (pain over blood vessels) are seen early on as the disease progresses. The involved vessels progressively narrow producing inequality in pulses, claudication and ischemia. The diagnosis should be suspected in young women with a systemic inflammatory illness, altered arterial pulses, or bruits. The diagnosis is confirmed by angiography and in our recent experience, treatment is often accomplished by interventional radiology/angiography procedures such as angioplasty.
The terms "purpura", "petechiae", and "ecchymosis" are frequently used in the clinical descriptions of vasculitic and other conditions. Note that in HSP, the term purpura is preferred over ecchymosis although the dictionary definition of these terms are the same or almost the same. The implied difference is that purpura have a sharply demarcated border and imply that vasculitis is the etiology, while ecchymosis has a diffuse border which implies that trauma or a hemorrhagic diathesis is the etiology. In HSP, the lesions are sharply demarcated (i.e., a vasculitis) which clinically appears as petechia (smaller lesions) and purpura (larger lesions). Compare this to idiopathic thrombocytopenic purpura (ITP), in which these lesions can be sharply demarcated resembling petechia and purpura, but ultimately, they develop frank bruising (i.e., ecchymosis). HSP is a vasculitis, while ITP is not.
Questions
1. Which immunoglobulin is prominently involved with the lesions of Henoch-Schonlein purpura?
2. What is the tetrad of Henoch-Schonlein purpura?
3. What histopathological term is used to describe the light microscopic findings in the skin biopsy of HSP?
4. Infantile polyarteritis nodosa (IPAN) is considered by some to be the severe end of the spectrum of which other vasculitis of childhood?
5. Name three connective tissue diseases of childhood, which are sometimes complicated by vasculitis.
References
1. Person DA. Infantile Polyarteritis Nodosa. e-Medicine Textbook of Pediatrics, 2001. http://www.emedicine.com/
2. Primer on the Rheumatic Diseases, 12th edition. 2001, Atlanta, GA: Arthritis Foundation.
Answers to questions
1. IgA.
2. purpura, arthritis, abdominal pain and glomerulonephritis.
3. leukocytoclastic vasculitis.
4. Kawasaki disease.
5. JRA, SLE, dermatomyositis, scleroderma and Behcet disease.