eMedicine Specialties > Pediatrics: General Medicine > Pulmonology

Wegener Granulomatosis

Author: Rudolph P Valentini, MD, Director of Dialysis Services, Associate Professor, Department of Pediatrics, Division of Pediatric Nephrology, Wayne State University; Vice Chief of Staff, Children's Hospital of Michigan
Coauthor(s): Debbie S Toder, MD, Director of Cystic Fibrosis Center, Department of Pediatrics, Division of Pulmonary Medicine, Assistant Professor, Wayne State University and Children's Hospital of Michigan
Contributor Information and Disclosures

Updated: Mar 5, 2009

Introduction

Background

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

Pathophysiology

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

Clinical

History

Patients with Wegener granulomatosis (WG) can have a multitude of symptoms, depending on the organ systems involved. These symptoms are listed by organ systems.

• Ear, nose, and throat findings
  • The symptoms causing pediatric patients to seek medical care are usually attributable to the upper and lower respiratory tract.
  • Rottem et al (1993) reported that 87% of their pediatric patients presented with ear, nose, and throat (ENT) pathology that included sinusitis (61%), nasal disease (48%), otitis media (39%), hearing loss (26%), and ear pain (22%).¹⁰ Ultimately, 91% of pediatric patients developed upper respiratory problems, with sinus involvement occurring in 83% of pediatric patients.
  • When patients with Wegener granulomatosis present with nasal and sinus disease, constitutional symptoms may seem severe relative to the physical findings.
• Central airway findings
  • Wegener granulomatosis may involve the larynx, subglottic space, trachea, and mainstem bronchi.
  • Subglottic stenosis was reported in 4% of pediatric patients at presentation and ultimately developed in 48% of pediatric patients. This was significantly greater than the 10% occurrence of subglottic stenosis in adults reported by Hoffmann et al.⁹
  • In a series of 51 adults with Wegener granulomatosis, all patients presenting with symptoms such as persistent cough, stridor, or dyspnea on exertion were found to have tracheobronchial lesions. Interestingly, unsuspected tracheobronchial lesions were found in 37% of patients undergoing bronchoscopy for evaluation of parenchymal disease.
  • Ulcerative tracheobronchitis was the most frequently observed lesion and was found in 35% of patients.
  • An additional 9.8% of patients had subglottic stenosis.
  • Four patients had cicatricial tracheal or bronchial narrowing at the site of previous inflammation.
• Pulmonary manifestations
  • Pulmonary involvement can be asymptomatic, insidious in onset, or severe and fulminant.
  • In Rottem et al's (1993) series, lung disease occurred in 22% of patients at presentation and eventually developed in 74% of patients.¹⁰
  • Pulmonary infiltrates (61%), pulmonary nodules (43%), and hemoptysis (26%) were the most common abnormalities.
  • Radiographic abnormalities may occur in the absence of symptoms. Patients with Wegener granulomatosis may present with life-threatening diffuse alveolar hemorrhage, which is often accompanied by progressive glomerulonephritis (GN). Radiographically, patients with alveolar hemorrhage present with infiltrates, usually bilateral as shown in Media file 1.
    
    

    

    Shown is a chest radiograph of an 11-year-old girl who presented with an upper respiratory tract infection, myalgias, and arthralgias for 1 month followed by an abrupt presentation with pallor, hemoptysis, and hypertension. Her bilateral fluffy infiltrates are suggestive of a pulmonary hemorrhage. She had an antineutrophil cytoplasmic autoantibodies (ANCA)–positive pauci-immune necrotizing and crescentic glomerulonephritis (GN) associated with her pulmonary hemorrhage. Supportive therapy consisted of mechanical ventilation and hemodialysis along with immunosuppressive therapy. Her anti–glomerular basement membrane antibody test result was negative. Nearly 2 years later, she had a serum creatinine of 0.7 mg/dL and no residual pulmonary disease.

    [ CLOSE WINDOW ]

    

    Shown is a chest radiograph of an 11-year-old girl who presented with an upper respiratory tract infection, myalgias, and arthralgias for 1 month followed by an abrupt presentation with pallor, hemoptysis, and hypertension. Her bilateral fluffy infiltrates are suggestive of a pulmonary hemorrhage. She had an antineutrophil cytoplasmic autoantibodies (ANCA)–positive pauci-immune necrotizing and crescentic glomerulonephritis (GN) associated with her pulmonary hemorrhage. Supportive therapy consisted of mechanical ventilation and hemodialysis along with immunosuppressive therapy. Her anti–glomerular basement membrane antibody test result was negative. Nearly 2 years later, she had a serum creatinine of 0.7 mg/dL and no residual pulmonary disease.

    
    These infiltrates rapidly clear, as shown in Media file 2.
    
    

    

    An 11-year-old girl presented with an upper respiratory tract infection, myalgias, and arthralgias for 1 month followed by an abrupt presentation with pallor, hemoptysis, and hypertension. She had an antineutrophil cytoplasmic autoantibodies (ANCA)–positive pauci-immune necrotizing and crescentic glomerulonephritis (GN) associated with her pulmonary hemorrhage. A follow-up chest radiograph obtained several days later shows a complete resolution of her pulmonary infiltrates. This rapid resolution is more consistent with hemorrhage than with pneumonia.

    [ CLOSE WINDOW ]

    

    An 11-year-old girl presented with an upper respiratory tract infection, myalgias, and arthralgias for 1 month followed by an abrupt presentation with pallor, hemoptysis, and hypertension. She had an antineutrophil cytoplasmic autoantibodies (ANCA)–positive pauci-immune necrotizing and crescentic glomerulonephritis (GN) associated with her pulmonary hemorrhage. A follow-up chest radiograph obtained several days later shows a complete resolution of her pulmonary infiltrates. This rapid resolution is more consistent with hemorrhage than with pneumonia.

• Renal manifestations
  • GN was present in only 9% of patients at presentation but ultimately developed in 61% (14 of 23) of patients at some point during the course of the disease. GN manifests as hematuria, proteinuria (in most cases), and renal insufficiency. Hypertension and gross hematuria are typically uncommon.
  • Of note, 8 of Rottem et al's (1993) 23 patients (35%) developed chronic renal insufficiency, with 2 patients requiring dialysis.¹⁰ Alternatively, 57% of the 14 patients with renal involvement developed chronic renal insufficiency, and 14% of patients required dialysis.
  • When one observes children with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis and GN who often present with more indolent disease, the incidence of end-stage renal disease (ESRD) can be significantly higher. In the United States, Ellis et al (1995) reported a 60% incidence of ESRD in 5 children treated at 2 centers,¹¹ and Valentini et al (1998) found an incidence of 14% in 7 pediatric patients in a single center series.¹² In a multicenter review from Japan, Hattori et al reported a 29% incidence of ESRD and 19% incidence of reduced renal function in 31 children with ANCA-associated glomerulonephritis (median age 12 y).¹³
  • These various reports support the need to maintain a high index of suspicion for renal disease in children with vasculitis in an effort to reduce long-term morbidity from late disease recognition.
• Ocular manifestations
  • Eye disease occurred in 13% of Rottem et al's (1993) patients at the outset of disease and 48% of patients overall.¹⁰
  • Dacryocystitis, proptosis, eye pain, and episcleritis were the most common abnormalities.
  • Retroorbital pseudotumor causes proptosis and eye pain.
  • In a series of 13 adult and pediatric patients presenting with ocular involvement, 11 patients had nasal, sinus, or ear symptoms in the months preceding presentation. Ocular symptoms typically developed subacutely and then rapidly progressed. Only 5 of these patients had constitutional symptoms, and, during the period of follow-up, only 1 patient developed renal disease. All patients developed an orbital mass, and all but 2 patients eventually developed bilateral eye disease.
  • Disease remission generally occurred in response to corticosteroids and immunosuppression, but treatment was not standardized. Some patients were left with visual impairment.
  • Because of both the risk of ocular disease and the potential ophthalmologic adverse effects of corticosteroids, pediatric patients should have an ophthalmologic examination at diagnosis and yearly thereafter, should symptoms develop.
• General manifestations
  • Rottem et al's (1993) study revealed that systemic symptoms, including arthralgia/arthritis (30%), fever (22%), weight loss (13%), and rash (9%), were present at disease onset in numerous instances.¹⁰
  • During follow-up, musculoskeletal symptoms occurred in 78% of patients, fever in 43% of patients, weight loss in 26% of patients, and rash in 52% of patients.
• Other organ involvement
  • Neurologic and cardiovascular systems can be involved as well.
  • Literature on adults states that 4% of patients present with nervous system involvement, but nervous system involvement eventually develops in 10-34% of patients.
  • A peripheral neuropathy, such as mononeuritis multiplex, has been the most frequent neurologic manifestation described in adult patients.
  • Cardiac involvement is rarely detected antemortem but includes pericarditis and coronary arteritis in 10-20% of cases. Necrotizing vasculitis of the coronary vessels can result in a myocardial infarction or sudden death.

Physical

Physical examination findings are listed in a head-to-toe manner. Because patients may have involvement of only a few organ systems, many of the physical findings listed may not be present.

• Head, ears, eyes, nose, and throat findings
  • Eyes - Conjunctivitis, scleritis, or proptosis
  • Ears - Chronic otitis media
  • Nose - Persistent rhinorrhea, epistaxis, nasal crusting, mucosal ulceration, or septal perforation; occasionally, saddle nose deformity
  • Throat -Pharyngitis with possible ulcerations
• Neck findings
  • Stridor can be present with tracheal involvement.
  • Distended neck veins can be observed in cardiac involvement and manifest in congestive heart failure (CHF).
• Chest findings
  • Tachypnea may be noted in patients with significant anemia, airway disease, or lung parenchymal involvement.
  • Wheezing may be noted.
• Cardiovascular manifestations: Heart sounds may be distant if pericardial effusion is present.
• Abdominal findings
  • Abdominal pain can be observed.
  • Rarely, GI bleeding can occur.
• Manifestations in the extremities
  • Findings of arthritis can be observed.
  • Edema from fluid retention can be noted in patients with significant GN leading to renal failure.
• Neurologic manifestations
  • A sensory, motor, or mixed sensory/motor peripheral neuropathy can be present. These are manifestations of mononeuritis multiplex, which is the most common form of neurologic involvement in Wegener granulomatosis.
  • Cranial nerve involvement can occur but is rare.
• Skin findings
  • Rashes are present in approximately 50% of patients (adult or children).
  • Rashes vary from palpable purpura, ulcers, vesicles, papules, and subcutaneous nodules.
• Clinical assessment: Various scoring systems have been used in an attempt to objectively assess the vasculitis disease activity. The Birmingham Vasculitis Activity Scoring system, which was first reported in 1994, has been favorably adopted by the rheumatology and nephrology community.¹⁴ This scoring system evaluates signs and symptoms in 9 organ systems and has been used in numerous treatment studies in an attempt to objectively measure differences in disease activity after the addition of an investigational agent (eg, etanercept).

Causes

The pathogenesis is still unknown.

• Some researchers have speculated that the ANCAs may have a role in the development of small vessel vasculitis.
  • One hypothesis is that an infection results in the production of proinflammatory cytokines, such as tumor necrosis factor–alpha (TNF-alpha) or interleukin-1.
  • These cytokines induce resting neutrophils (ie, polymorphonuclear neutrophils [PMNs]) to express ANCA antigens (ie, myeloperoxidase, proteinase 3) that are normally contained within cytoplasmic granules, on their cell surfaces.
  • These local cytokines also increase expression of adhesion molecules, allowing activated PMNs to attach to vascular endothelial cells.
  • Circulating ANCA bind to these primed PMNs, leading to activation and degranulation with production of oxygen radicals that induce endothelial injury.
  • This hypothesis is derived from in vitro data and has not been documented in vivo. Nonetheless, it is an attractive hypothesis, because relapses of WG are usually triggered by a respiratory infection. Furthermore, prophylactic antibiotics that reduce respiratory relapses may reduce systemic relapses, as well.
  • The role of B cells are also being investigated in trials with rituximab.¹⁵
• From a genetic predisposition standpoint, an increased association of Wegener granulomatosis and the human leukocyte antigen (HLA)-B8 and HLA-DR2 gene loci is observed. Data have revealed that a functional polymorphism, 620W, in the gene encoding for an intracellular tyrosine phosphatase (PTPN22) is a risk factor for the development of Wegener granulomatosis. Patients with ANCA (+) Wegener granulomatosis were found to have a significantly higher frequency of the PTPN22 620W allele when compared with healthy controls (p<0.001).

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