Clinically, IPAN often is part of the spectrum of Kawasaki disease (KD). However, it was described nearly 130 years ago. IPAN with aneurysmal involvement of major coronary arteries and KD are clinically and pathologically indistinguishable. Indeed, the major 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. This article explores the similarities and differences between these entities with the focus on the current understanding of IPAN.

Viennese pathologist Karl Rokitansky is credited with the first description of polyarteritis nodosa (PAN) in 1852. The drawing that accompanied his 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 PAN 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.

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. The authors submit that this infant had IPAN. 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 decade 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 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 vasculitis, and cutaneous leukocytoclastic angiitis.

Pathophysiology: PAN is an inflammatory disease of small and medium muscular arteries. It can involve any organ but most commonly involves the kidneys, joints, muscles, peripheral nerves, GI tract, and skin. Classic PAN is restricted to medium and small arteries without involvement of smaller vessels. Patients with arteriolitis, venulitis, or capillaritis (including glomerular capillaritis) are by definition excluded from this diagnostic category. The pathophysiologic association between IPAN and PAN and between both these entities and KD is unclear. Mucocutaneous changes must be present to make a diagnosis of KD, but the diagnosis of IPAN or PAN is based solely on the pathologic findings.

Frequency:

History: Presenting symptoms 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.

Physical: Clinical manifestations are a reflection of the organ systems involved.

• Kidney

• Renal disease in 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 IPAN.

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

• 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.
• 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 groin or axilla.

• 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.

• 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.

Causes: An infectious etiology for PAN has been considered for years. Early observers considered streptococci or Staphylococcus aureus to be likely candidates. In 1970, Gocke et al 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.

• Other investigators have suggested various bacterial etiologies, but none have 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 have 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.

• The cause of IPAN 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/KD is the final common clinical pathway resulting from any of a number of infecting or inciting agents or antigens. The senior author has treated 2 children with PAN and hepatitis B surface antigenemia.

Lab Studies:

• As with other systemic rheumatic diseases, the basic laboratory tests should include the following:

• CBC

• Urinalysis

• Serum chemistry panel

• Erythrocyte sedimentation rate

• Antinuclear antibody determination

• Rheumatoid factor test and hepatitis B serologies

• Quantitative immunoglobulins

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

• Other tests are selected on the basis of the patient’s systemic involvement.

• 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) associated with cANCA and myeloperoxidase (MPO) associated with pANCA. The antibodies are detected in some patients with certain forms of PAN, but these antibodies have not been associated with IPAN.

Imaging Studies:

• After a basic posteroanterior and lateral chest radiograph, imaging studies are directed at involved organ systems.

• Echocardiography is used extensively to evaluate the coronary arteries in children with KD and to monitor children with documented coronary artery aneurysms.

• Arteriography is extremely helpful in evaluating patients with PAN or IPAN.

• Traditional criteria for the diagnosis of PAN have included arteriographic abnormalities (ie, aneurysms, occlusions) of visceral arteries.

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

Procedures:

• The criteria for a diagnosis of 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.

Histologic Findings: 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 IPAN are indistinguishable from those in fatal cases of KD.

Medical Care: Medical care of the patient with 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.

Surgical Care:

• Patients with 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 senior 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.

Consultations: 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 IPAN. 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.

Current standard of care for KD includes slow IV administration of 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) such as aspirin is administered orally. The senior author prefers one of the newer 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 is prescribed for patients with coronary artery aneurysms.

The treatment of children with 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.
Drug Category: Immune globulin -- 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 IPAN.

Drug Category: Nonsteroidal anti-inflammatory drugs -- 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.

Drug Category: Corticosteroids -- These agents have potent anti-inflammatory effects. Intermittent high doses (ie, pulse therapy) of IV methylprednisolone inhibit antibody production.

Drug Category: Immunosuppressive agents -- Patients with immune dysregulation and autoimmunity often benefit from immunosuppression. One immunosuppression agent, cyclophosphamide, may be lifesaving in patients with severe vasculitis.

Further Inpatient Care:

• Inpatient care is individualized for each patient.

Further Outpatient Care:

• Outpatient care is individualized for each patient.

In/Out Patient Meds:

• Medications are tailored to the patient’s needs and disease course.

Transfer:

• Definitive treatment of children with systemic vasculitis must be performed in the setting of a full-service medical center.

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. These complications relate primarily to adult PAN.

Prognosis:

• 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 PAN and not IPAN.

Patient Education:

• Patient and parent education must be individualized and coordinated by a multidisciplinary team, including a nurse, social worker, occupational therapist, physical therapist, and rheumatologist.