Childhood Polyarteritis Nodosa

The Viennese pathologist Karl von Rokitansky is credited with the first description of polyarteritis nodosa (PAN) in 1852. The drawing that accompanied his original description of PAN clearly showed multiple aneurysms of varying size in the mesenteric artery of the index case. In 1866, Kussmaul and Maier reported the case of a 27-year-old man who, over a period of approximately 2 months, developed a multisystem disease characterized by fever, myalgias, abdominal pain, mononeuritis multiplex, and proteinuria. A few days before his death he developed palpable subcutaneous nodules. At autopsy, nodules involving the coronary, gastric, renal, splenic, mesenteric, hepatic, bronchial, and phrenic arteries were obvious.

Microscopic studies demonstrated that the intima of the affected arteries was completely intact and that the media and adventitia were severely inflamed and disrupted. For these reasons, Kussmaul and Maier termed this condition periarteritis nodosa. Their paper included a drawing of their patient's heart showing numerous coronary artery aneurysms. The first case of CPAN reported in the English-language literature may be that of a 7-year-old boy who, in 1870, died of "scarlet fever" at St. Bartholomew Hospital in London. Samuel Gee noted that 3 coronary artery aneurysms were present at autopsy and were filled with fresh thrombi.

More recently, Sarah Long suggested that perhaps one of the first documented cases of KD in the United States was that of a 9-month-old infant reported as 1 in a series of 5 cases of Stevens-Johnson syndrome in the Journal of Pediatrics in 1949. The infant had fever, irritability, cervical adenopathy, a polymorphous rash, and conjunctival suffusion. Cardiac arrest supervened, and, at autopsy, hemopericardium secondary to a ruptured coronary artery aneurysm was discovered. This author submits that this infant had CPAN. Other similar case reports appeared in Europe and the United States in the late 19th and early 20th centuries.

Much has been written in the past 2 decades with regard to the classification of the systemic vasculitides. In an attempt to put PAN into proper perspective, the classification promulgated by an international consensus conference held in Chapel Hill, NC, and published in 1994[2] is included here. Large-vessel vasculitis includes giant cell (temporal) arteritis and Takayasu arteritis. Medium-vessel vasculitis includes PAN and KD. Small-vessel vasculitis includes Wegener granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis (microscopic polyarteritis), Henoch-Schönlein purpura, essential cryoglobulinemic purpura, and cutaneous leukocytoclastic angiitis.

An infectious etiology for polyarteritis nodosa (PAN) has been considered for years. Early observers considered streptococci or Staphylococcus aureus to be likely candidates. In 1970, Gocke et al[3]  demonstrated Australia antigen (hepatitis B surface antigen) and immunoglobulin M (IgM) antibody in an arterial lesion of PAN in a woman who had been transfused with contaminated blood several weeks previously. These remarkable and serendipitous observations by Gocke et al clearly linked hepatitis B surface antigen to the etiology of PAN. Hepatitis B surface antigenemia is associated with approximately 20% of patients with PAN.[4]

Other investigators have suggested various bacterial etiologies, but none has been confirmed independently. Viruses other than hepatitis B, such as hepatitis A and C, human immunodeficiency virus (HIV), cytomegalovirus (CMV), human T-cell lymphotropic virus-1 (HTLV-1), and parvovirus, have been reported to have etiologic associations with PAN, but none has been repeatedly isolated from patients with PAN.

Considerable evidence supports the notion that PAN is an immune complex disease. However, the elusive antigen or antigens involved remain unknown, with the exception of hepatitis B.

The cause of childhood polyarteritis nodosa (CPAN) is not known. Almost since Kawasaki first described acute febrile mucocutaneous lymph node syndrome (MCLNS) of childhood, investigators have attempted to link it with infectious agents or antigens. Rickettsia species, Propionibacterium acnes, a feline virus, retroviruses, Epstein-Barr virus (EBV), a dust mite antigen, streptococci, and a "super antigen" were proposed as etiologic; however, no explanation has stood the test of time. Clinically, MCLNS has features of an infectious disease, perhaps viral. Similarly, it has many features of a rheumatic disease.

Taken together, the evidence suggests that MCLNS/Kawasaki disease (KD) is the final common clinical pathway resulting from any of a number of infecting or inciting agents or antigens. The author has treated 2 children with CPAN and hepatitis B surface antigenemia.

United States statistics

The incidence and prevalence of childhood polyarteritis nodosa (CPAN) is not known, perhaps because of problems with the nosology of vasculitis syndromes, the rarity of the condition, and the lack of reported cases. The incidence of classic Kawasaki disease (KD) seems to be decreasing in the United States, as well as worldwide, with atypical or forme fruste cases becoming more common.

International statistics

The incidence, prevalence, and distribution of childhood polyarteritis nodosa (CPAN) are not known.

A population-based study from southern Sweden reported that the annual incidence for polyarteritis nodosa was 0.7 per million children.[5]

Race-, sex-, and age-related demographics

Race

Sufficient worldwide data are lacking, but individuals of Asian descent appear to have a disproportionately high incidence of vasculitis.

Sex

Males are affected more commonly than females, with a male-to-female ratio approaching 2:1.

Age

Polyarteritis nodosa (PAN) most often affects persons aged 40-60 years, although all ages are represented. By definition, childhood polyarteritis nodosa (CPAN) refers to cases occurring in childhood.

Overall prognosis is guarded. The 10-year mortality rate, even in aggressively treated patients, exceeds 20%. However, some cases remit without treatment. These statistics relate primarily to adult polyarteritis nodosa (PAN) and not childhood polyarteritis nodosa (CPAN).

Morbidity/mortality

Adult polyarteritis nodosa (PAN) is an often fatal disease. Before the modern treatment era, the 5-year mortality was approximately 90%. The disease course is highly variable in individual patients. Some may have rapidly progressive disease, leading to death in days or weeks, whereas others may have more subacute disease. Other patients experience waxing and waning of symptoms, leading to chronic disability. In still others, the disease apparently remits with little or no treatment.

Childhood polyarteritis nodosa (CPAN) is perhaps more variable; however, rapidly progressive cases involving the coronary arteries may be highly lethal. With the widespread recognition of Kawasaki disease (KD) and its effective treatment, CPAN has almost disappeared. Most cases of isolated coronary arteritis observed today are considered incorrectly (in the author's opinion) to be atypical KD.

Complications

Complications are related to the extent of disease and include digital necrosis and amputation, bowel infarction, myocardial infarction, stroke, renal failure, hepatic failure, and death. (See the image below.) These complications relate primarily to adult polyarteritis nodosa (PAN).

 

Presenting symptoms of childhood polyarteritis nodosa (CPAN) are nonspecific and include fever, malaise, anorexia, weight loss, and abdominal pain. In decreasing order of frequency, the organs most often affected are the kidney, heart, and liver.

Clinical manifestations of childhood polyarteritis nodosa (CPAN) are a reflection of the organ systems involved.

Kidney

Renal disease in polyarteritis nodosa (PAN) is rarely symptomatic but results in impaired renal function with abnormal urinary sediment, hematuria, proteinuria, and elevated blood pressure.

Occasionally, patients develop rapidly progressive renal failure and end-stage kidney disease.

Renal artery vasculitis with aneurysm formation is the primary lesion.

Heart

Coronary artery aneurysms are relatively common in CPAN. See the image below.

Clinical manifestations of cardiac involvement are infrequent. Congestive heart failure, pericarditis, and myocardial infarction (often silent) are observed in variable frequencies.

Transmural biopsy results of patients with Kawasaki disease (KD) suggest that PAN-related pancarditis is present in virtually all patients.

Cardiac abnormalities are present in 90% of adults with PAN at autopsy.

Gastrointestinal tract

Abdominal pain is common in patients with PAN.

When bleeding is present, PAN may be mistaken for inflammatory bowel disease.

Massive hemorrhage, infarction, and perforation of the bowel may be fatal.

Involvement of the liver, gallbladder, or pancreas is not uncommon. Hydrops of the gallbladder has been reported in KD.

Hypertransaminasemia is common, and, in cases associated with hepatitis B surface antigenemia, chronic aggressive hepatitis complicates the clinical picture.

Vasculitis of the appendix has been reported in adults and children.

Nervous system

Peripheral neuritis, manifested as mononeuritis multiplex, is the most common neurologic complication. Distal lesions occur more commonly than proximal lesions, and upper and lower extremities are affected equally.

Vasculitis of the vasa nervorum with vascular occlusion appears to be responsible for patients' symptoms and occurs early in the course of the disease. CNS involvement, including encephalopathy, focal defects, and seizures, occurs later in the disease course.[6]

Strokes are a leading cause of death. Cerebral artery aneurysms have been observed in CPAN.

Skin

Rashes occur in nearly one half of patients with PAN. Nonspecific maculopapular lesions, urticarial rashes, livedo reticularis, and vasculitic ulcers occur in various patients.[7]

Raynaud phenomenon, digital vasculitis, ecchymosis, and subcutaneous nodules, so-called nodose lesions are observed in some patients.

Palpable arterial aneurysms are occasionally striking, particularly in the inguinal areas or axillae.

Testes

Testicular pain or tenderness occurs commonly in males with PAN. Testicular biopsy results reveal vasculitis in 25% of patients.

For diagnostic purposes, blind testicular biopsy sometimes is recommended, even in male children with CPAN.

Musculoskeletal system

Approximately one half of patients complain of myalgias and arthralgias.

Myositis is demonstrable in some patients.

Frank arthritis may occur early in the disease course and is clinically quite similar to that observed in acute rheumatic fever.

Rarely, a chronic destructive arthritis similar to rheumatoid arthritis may evolve.

As with other systemic rheumatic diseases, the basic laboratory tests in childhood polyarteritis nodosa (CPAN) should include the following:

• Complete blood cell (CBC) count

• Urinalysis

• Serum chemistry panel

• Erythrocyte sedimentation rate

• Antinuclear antibody determination

• Rheumatoid factor test and tests for hepatitis B

• Quantitative immunoglobulins

• Tests for circulating immune complexes (eg, Raji cell radioimmune assay, C1q binding test)

Other tests are selected on the basis of the clinical examination.

Appropriate cultures are obtained if the patient's condition warrants.

Routine laboratory tests help support the diagnosis and are used to monitor the effects of potentially toxic therapy.

Antineutrophil cytoplasmic antibodies (ANCA) have been detected in the circulation of some patients with necrotizing vasculitis and are directed toward proteinase 3 (PR3) and associated with circulating ANCA (cANCA) and myeloperoxidase (MPO) associated with perinuclear ANCA (pANCA). The antibodies are detected in some patients with certain forms of polyarteritis nodosa (PAN), but these antibodies have not been associated with CPAN.

After a basic posteroanterior (PA) and lateral chest radiograph (see image below), imaging studies are directed at involved organ systems.

Echocardiography (ECHO) is used extensively to evaluate the coronary arteries in children with Kawasaki disease (KD) and to monitor children with documented coronary artery aneurysms.

Arteriography (see image below) is extremely helpful in evaluating patients with polyarteritis nodosa (PAN) or childhood polyarteritis nodosa (CPAN).

CT scan or MRI studies may be required depending on the patient's signs and symptoms.

The criteria for a diagnosis of polyarteritis nodosa (PAN) include histopathologic changes consistent with necrotizing arteritis; thus, by definition, a biopsy is indicated. However, demonstration of characteristic renal aneurysms on arteriography is considered diagnostic.

Electromyography and nerve conduction tests may be indicated in some patients.

Electroencephalography sometimes is helpful.

Polyarteritis nodosa (PAN) affects medium and small arteries and, to a lesser extent, arterioles and venules. Focal segmental involvement of the vessels is characteristic. Often the coexistence of acute and healed lesions as well as normal and affected vessels and microaneurysms is observed. Visceral, cutaneous, cerebral, and pulmonary vessels are affected, in decreasing frequency. Histopathologic findings include necrotizing arteritis with a mixed cellular infiltrate with few eosinophils. Rarely, granulomatous changes are observed. The vascular lesions of childhood polyarteritis nodosa (CPAN) are indistinguishable from those in fatal cases of Kawasaki disease (KD).

See the slide below.

Medical care of the patient with polyarteritis nodosa (PAN) is individualized. In the acute phase, hospitalization usually is required. Diagnostic tests, imaging studies, and biopsies as appropriate are carried out expeditiously. Intensive care often is necessary to provide for frequent monitoring and emergency medical or surgical treatment.

Inpatient and outpatient care in childhood polyarteritis nodosa (CPAN) is individualized for each patient. Medications are tailored to the patient's needs and disease course.

Patients with polyarteritis nodosa (PAN) may develop acute abdominal emergencies, including intractable GI bleeding, bowel infarction, and viscus or aneurysmal rupture. These complications are associated with significant mortality. The author has treated a preadolescent boy who underwent coronary artery bypass surgery for the management of myocardial ischemia and necrosis secondary to PAN.

Histologic confirmation is necessary to make the diagnosis of PAN. Biopsies of muscle, sural nerve, kidney, liver, testis, and rectum have been used to confirm PAN and are preferred to biopsies of skin, which are less diagnostic and do not necessarily indicate the extent of systemic involvement.

Specialty consultations depend on the individual patient's disease onset and course. A pediatric rheumatologist experienced in the treatment of children with systemic vasculitis should head the team and direct the overall care of infants and children with childhood polyarteritis nodosa (CPAN). Pediatric cardiologists, critical care specialists, neurologists, surgeons, physiatrists, pulmonologists, gastroenterologists, and nephrologists may need to be consulted at times.

Diet

Diet is dictated by the extent and involvement of the disease and by its therapy.

Activity

Activity is based on the patient's tolerance. In general, the child is encouraged to increase physical activity.

In 2021, the American College of Rheumatology (ACR) and the Vasculitis Foundation (VF) released joint guidelines on the management of polyarteritis nodosa (PAN).[8]

Imaging

The guidelines offer the following conditional recommendations:

• Abdominal vascular imaging can aid in establishing a diagnosis and determining the extent of disease
• Follow-up abdominal vascular imaging can be used for patients with a history of severe abdominal PAN who become asymptomatic
• A deep-skin biopsy is preferred over a superficial skin punch biopsy to aid in establishing a diagnosis of PAN involving the skin
• A combined nerve and muscle biopsy is preferred over a nerve biopsy alone to aid in establishing a diagnosis of peripheral neuropathy and suspected PAN
• Serial neurologic examinations instead of repeated electromyography/nerve conduction studies (eg, every 6 months) should be used to monitor disease activity in patients with a history of peripheral motor neuropathy secondary to PAN

Treatment

Conditional recommendations for patients with newly diagnosed severe active disease include the following:

• Initiating treatment with IV pulse glucocorticoids (GCs) over high-dose oral GCs
• Initiating treatment with cyclophosphamide and high-dose GCs over high-dose GCs alone
• Initiating treatment with cyclophosphamide and GCs over rituximab and GCs
• Treat with other non-GC immunosuppressive agents and GCs over GCs alone for patients unable to tolerate cyclophosphamide
• The use of plasmapheresis combined with cyclophosphamide and GCs is NOT recommended

For patients with newly diagnosed nonsevere active disease, the guidelines conditionally recommend treatment with non-GC immunosuppressive agents and GCs over GCs alone. For patients with PAN in remission who are receiving non-GC immunosuppressive therapy, discontinuation of non-GC immunosuppressive agents after 18 months over continued (indefinite) treatment is conditionally recommended.

Physical therapy is conditionally recommended for patients with nerve and/or muscle involvement.

The guidelines strongly recommend treatment with tumor necrosis inhibitors over GCs alone for patients with deficiency of adenosine deaminase 2.

Current standard of care for Kawasaki disease (KD) includes slow intravenous immune globulin (IVIG). When considering this treatment, risks must be compared with benefits in atypical or questionable cases, since IVIG is a human blood product and possesses potential infectious hazards. Additionally, a nonsteroidal anti-inflammatory drug (NSAID) or aspirin is administered orally. The author prefers one of the NSAIDs, such as naproxen in anti-inflammatory doses or ibuprofen in antipyretic doses, because of their safety profiles. Low-dose aspirin may be continued for months for its antiplatelet effects. Dipyridamole may be prescribed for patients with coronary artery aneurysms.

The treatment of children with polyarteritis nodosa (PAN) must be individualized. Often, corticosteroids are required to reduce inflammation. High-dose IV pulse methylprednisolone is administered judiciously over 1 hour with appropriate monitoring (blood pressure q15min) to treat organ- or life-threatening disease. This treatment may be repeated daily for 3-6 days or on alternate days depending on the patient's response. Aggressive treatment with cytotoxic drugs must be individualized and may be lifesaving. Plasma exchange therapy, with or without hemodialysis, may be required. Because of the high fatality rate, a pediatric rheumatologist experienced in caring for the critically ill child with necrotizing vasculitis must direct and coordinate care.

Biologic agents have been used in the treatment of patients with severe and/or refractory PAN.[1, 9, 10]

Class Summary

Immune globulin is purified preparation of gamma globulin derived from large pools of human plasma and composed of 4 subclasses of antibodies, approximating the distribution of human serum. One blood product, immunoglobulin, has documented efficacy in childhood polyarteritis nodosa (CPAN).

Immunoglobulin, intravenous (Gamimune N, Gammagard, Sandoglobulin)

Neutralizes circulating myelin antibodies through anti-idiotypic antibodies. Also down-regulates proinflammatory cytokines, including INF-γ, blocks Fc receptors on macrophages, suppresses inducer T and B cells, and augments suppressor T cells. Blocks complement cascade and promotes remyelination. May increase CSF IgG (10%).

In controlled studies, IVIG rapidly decreases fever, shortens hospitalization, and decreases coronary aneurysms in patients with KD.

Class Summary

These agents have anti-inflammatory, antipyretic, and antiplatelet activities. Their mechanism of action inhibits cyclooxygenase activity and prostaglandin synthesis. Other mechanisms also may exist, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell-membrane functions.

Naproxen (Naprosyn)

Anti-inflammatory, antipyretic, and antiplatelet activities all therapeutic in this disease. Because of relatively long serum half-life, can be used twice daily.

Ibuprofen (Motrin, Advil)

Excellent antipyretic activity. Because of short plasma half-life, must be administered qid.

Class Summary

These agents have potent anti-inflammatory effects. Intermittent high doses (ie, pulse therapy) of intravenous methylprednisolone inhibit antibody production.

Prednisone (Deltasone, Orasone, Liquid Pred)

Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocyte and antibody production. Effective in reducing severe inflammation in vasculitis.

Methylprednisolone (Solu-Medrol)

Decreases inflammation by suppressing migration of PMNs and reversing increased capillary permeability. High-dose pulse IV methylprednisolone has been lifesaving in patients with systemic vasculitis.

Class Summary

Patients with immune dysregulation and autoimmunity often benefit from immunosuppression. One immunosuppression agent, cyclophosphamide, may be lifesaving in patients with severe vasculitis.

Cyclophosphamide (Cytoxan)

Has probably best risk-to-benefit ratio in systemic vasculitis of all antineoplastic agents.