eMedicine Specialties > Pediatrics: General Medicine > Rheumatology

Infantile Polyarteritis Nodosa

Author: Donald A Person, MD, Medical Director, Senior Scientist, Department of Clinical Investigation, Tripler Army Medical Center, Honolulu; Professor of Pediatrics, F Edward Herbert School of Medicine, USUHS, John A Burns School of Medicine, University of Hawaii at Manoa
Contributor Information and Disclosures

Updated: Jun 15, 2006

Introduction

Background

Infantile polyarteritis nodosa (IPAN) is a rare and often fatal inflammatory disease of small and medium arteries. Polyarteritis has been described worldwide, although vasculitic diseases tend to be more common in individuals of Asian descent.

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

United States

The incidence and prevalence of IPAN is not known, perhaps because of problems with the nosology of vasculitis syndromes. Data are available for KD (see Pediatrics, Kawasaki Disease).

International

The incidence and prevalence of IPAN are not known.

Mortality/Morbidity

Adult PAN is a highly fatal disease. Before the modern treatment era, the 5-year mortality rate 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. IPAN is perhaps more variable; however, rapidly progressive cases involving the coronary arteries may be highly lethal. With the widespread recognition of KD and its effective treatment, IPAN virtually has disappeared. Most cases of isolated coronary arteritis observed today are considered incorrectly (in the author's opinion) to be atypical KD.

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

PAN most often affects males aged 40-60 years, although all ages are represented. By definition, IPAN is restricted to infants.

Clinical

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 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 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 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.
• 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, with the exception of hepatitis B.
• 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 author has treated 2 children with PAN and hepatitis B surface antigenemia.

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