Pediatric Wegener Granulomatosis 

Wegener granulomatosis (WG) is a clinicopathologic entity that is very rare in children. Much of the information presented in this article is derived from adult literature. Strictly defined, the Wegener triad for generalized Wegener granulomatosis is necrotizing granulomatous lesions of the upper or lower respiratory tract, generalized necrotizing vasculitis involving both arteries and veins, and focal necrotizing glomerulonephritis (GN). Regional Wegener granulomatosis can occur when sinopulmonary disease occurs in the absence of renal disease. The largest historical series of patients with Wegener granulomatosis included those with compatible clinical histories and histologic evidence of either vasculitis or granulomatous inflammation. This more inclusive definition of Wegener granulomatosis used in the 1970s and 1980s has been defined more strictly in the 1990s.

The Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis more strictly defined Wegener granulomatosis, distinguishing it from other forms of vasculitis with similar clinical features.^[1] Additionally, antineutrophil cytoplasmic autoantibodies (ANCA), which are associated with Wegener granulomatosis, can now be routinely tested and have provided clinicians an additional diagnostic tool.^[2]

Newer reports adhere to stricter criteria, requiring one of the following to be classified as Wegener granulomatosis: histologic evidence of granulomatous inflammation, presence of pulmonary nodules, cavitary pulmonary lesions, or invasive bony disease in the upper respiratory tract. In this newer, more rigorous scheme, patients with clinical evidence of ANCA positive small vessel vasculitis, who lack granulomatous inflammation, are classified as having microscopic polyangiitis (MPA). These changing definitions of Wegener granulomatosis complicate the interpretation of earlier studies.

Because the various forms of ANCA-associated small vessel vasculitis (ie, Wegener granulomatosis, MPA, Churg-Strauss syndrome) respond to similar treatments, newer trials in patients with ANCA (+) small vessel vasculitis can be applied to patients who would previously have been classified as having Wegener granulomatosis. In this article, Wegener granulomatosis is used as a clinical diagnosis. ANCA-associated small vessel vasculitis and Wegener granulomatosis are used interchangeably unless otherwise indicated.

In 1939, Wegener initially described a group of patients with necrotizing granulomatous arteritis involving the upper and lower respiratory tracts, sinuses, middle ear, and nasopharynx. Before the institution of effective therapy, the mean survival of adults with untreated Wegener granulomatosis was only 5 months, with 82% of patients dying within the first year and 90% of patients dying within the second year. Despite improvement with the use of corticosteroids, the mean survival time was increased only to 12.5 months. With the advent of cytotoxic therapy for Wegener granulomatosis, patient survival has markedly improved. In 1983, Fauci et al reported a 93% complete remission rate in 85 patients (mean age 43.6 y, range 14-75 y) treated with prednisone and oral cyclophosphamide.^[3]

The hallmark lesion is necrotizing vasculitis of small arteries and veins together with granuloma formation that can be either intravascular or extravascular. Lung involvement is typically bilateral nodular cavitary infiltrates, which, on biopsy findings, demonstrate necrotizing granulomatous vasculitis. The renal biopsy lesion is that of a pauci-immune necrotizing and crescentic GN. The pathogenesis of Wegener granulomatosis is still unknown, but the role of environmental exposures have been questioned by some authors.

Hogan et al reported an odds ratio of silica dust exposure that was 4.4 times greater for patients with ANCA (+) small vessel vasculitis when compared with controls.^[4] The role of ANCA in the pathogenesis of small vessel vasculitis has been studied by the development of several animal models. In humans, Schlieben et al reported that a newborn developed a pulmonary-renal syndrome associated with transplacental passage of myeloperoxidase (MPO) ANCA immunoglobulin (Ig)G from a mother with ANCA disease who developed a clinical and serologic flare of disease during pregnancy.^[5] Others believe that respiratory infections may be part of the inciting event in either the onset of the disease or its relapses.

Frequency

United States

The incidence of Wegener granulomatosis is difficult to determine, but it is known to occur much more frequently in adults. One study analyzed the national mortality data from the National Center for Health Statistics, hospitalization data from the National Hospital Discharge Survey of nonfederal short stay hospitals, and data from the Statewide Planning and Research Cooperative System of New York State. Based on analysis of these data, the prevalence of Wegener granulomatosis was estimated to be at least 3 cases per 100,000 persons. A higher percentage (3.3%) of individuals younger than 20 years appeared in the New York data than in the national data (0.1%).

International

An approximate 5-year incidence rate of 1.3 cases per 100,000 persons is observed in the United Kingdom.

Mortality/Morbidity

During the 10-year period from 1979-1988, Wegener granulomatosis was listed as the cause of death on 1784 death certificates; 22 of these deaths were of children younger than 15 years.^[6]

According to the 2008 US Renal Data Systems (USRDS) Annual Data Report, from 2002-2006, Wegener granulomatosis was the underlying cause of ESRD in 54 (0.9%) children (0-19 y) with incidental ESRD.^[7] The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) 2007 Annual Report lists the causes of renal failure in their pediatric dialysis database encompassing 1992-2006.^[8] Of the more than 9500 children transplanted in the registry, Wegener granulomatosis was listed as the primary disease in 52 cases (0.5%). Permanent morbidity from disease or its treatment occurs in 87% of patients. Newer regimens should improve morbidity. The first year mortality for children in the United States with Wegener granulomatosis and ESRD was 3.7%.^[7]

Race

In 1992, Hoffman et al described 158 patients cared for at the National Institutes of Health (NIH); 97% percent of patients were white.^[9] Of the pediatric patients with Wegener granulomatosis who developed ESRD in the United States, 82% were white.

Sex

Essentially, the condition occurs equally in adult males and females. Of the 135 patients older than 19 years at the NIH, the male-to-female ratio was 70:65. Rottem et al (1993) studied 23 patients from the NIH who were younger than 19 years and had childhood-onset Wegener granulomatosis.^[10] Unlike adults, a female preponderance was found. The male-to-female ratio was 7:16. ESRD developed in roughly equal numbers of males and females with Wegener granulomatosis. In all, the male-to-female ratio was 19:21. The NAPRTCS 2007 annual report reported a slight female preponderance of 58% females in the 52 patients with Wegener granulomatosis who have been transplanted.

Age

Most patients with Wegener granulomatosis are adults. Of the patients studied at the NIH, 85% were older than 19 years.

Rottem et al (1993) studied 23 patients from the NIH who were younger than 19 years and had childhood-onset Wegener granulomatosis.^[10] The mean age of onset of clinical disease in the pediatric group was 15.4 years (range 9.3-19.4 y), and a median of 8 months passed from onset of symptoms until a definitive diagnosis was secured. The median age of patients with Wegener granulomatosis who developed ESRD in the United States was 15 years.^[7]