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DEFINITION: Granulomatous inflammation involving the upper and lower respiratoyr tract, and necrotizing vasculitis affecting small to medium-sized vessels. Necrotizing glomerulonephritis is common. (Chapel Hill Consensus Conference, 1994)
CLASSIFICATION CRITERIA: •Nasal or oral inflammation (includes painful/painless oral ulcers, or purulent or bloody nasal discharge)
•CXR evidence of nodules, infiltrates or cavities
•Microscopic hematuria or red cell casts
•Granulomatous inflammation on biopsy
> 2 of 4 reported to have 88% sensitivity and 92% specificity for correctly classifying cases in adults.
(American College of Rheumatology, 1990)
However, there are problems with the above definition and criteria. First, nasal and oral inflammation is not unique to Wegener's Granulomatosis (WG), and can occur in up to 20% of cases of microscopic polyangitis (the main differential diagnosis, with different treatment and prognosis). Also, the Chapel Hill definition requires a biopsy showing granulomata, and does not acknowledge clinical or laboratory surrogates for other essential elements of the disease. By the ACR criteria, patients with non-granulomatous disease could be classified as WG. Neither scheme includes ANCA studies which have now become a very common investigative tool. Both were designed to define cases for studies, and are not validated as diagnostic criteria, though they are often used in this manner. Finally, and perhaps most importantly for our purposes, both only apply to adult patients. Because the ACR criteria were validated in adults, and pediatric control cases would differ (even if patients were similar, which often they are not), the sensitivity and specificity of these criteria would be different in children.
In order to address these issues, the European League Against Rheumatism (EULAR) and the Pediatric Rheumatology Society (PReS) met in November 2005 to devise a new classification system for childhood vasculitides. Their purpose was to include those diseases that occur only in childhood (ex. Kawasaki disease) and exclude those that occur only in adulthood (ex. temporal arteritis). As well, they sought to highlight differences in the pediatric presentation of other diseases such as Polyarteritis nodosa and Wegener's Granulomatosis. They based their system on the CCHC classification by vessel size, modified for children.
The EULAR/PReS classification requires 3 of the following 6 criteria:
•Abnormal urinalysis (hematuria or proteinuria)
•Granulomatous inflammation on biopsy of the respiratory tract (renal biopsy typically shows necrotizing pauci-immune glomerulonephritis)
•Subglottic, tracheal or endobronchial stenosis
•Abnormal CXR or CT
•PR3 ANCA or c-ANCA staining
(EULAR/PReS, Ann Rheum Dis, 2006)
Airway stenosis was added in recognition of its greater frequency in children compared to adults. Again, it is important to remember that these criteria were developed by consensus, and studies are required to validate them as a case definition using patient and control groups, then further evaluate them prospectively to judge their utility as diagnostic criteria.
EPIDEMIOLOGY: Wegener's granulomatosis is rare in adults, but even more so in children. While the incidence in adults is reported to range from 7.9-8.5/million/year, in children it has been estimated at < 0.5/million/year. The prevalence of WG in adults is reported as 30-53/million, while this information is not available for the pediatric population.
ETIOLOGY: The etiology of WG is currently unknown. The recognition that chronic nasal carriage of Staph aureus is associated with relapses, whereas treatment with trimethoprim-sulfamethoxazole may reduce relapse rates, has led to the theory of an infectious component. The suggestion of a seasonal variation in incidence, with more cases occurring in winter and spring, has lent some support to this theory. In addition, it is been found that heterozygosity for a1-anti-trypsin deficiency is associated with an increased risk for WG, as well as with increased morbidity, suggesting the contribution of a genetic predisposition.
PATHOPHYSIOLOGY: The pathophysiology of WG involves an autoimmune inflammatory process, mediated by TNF-a-primed neutrophils and monocytes which express taret antigens of ANCA, especially proteinase-3. Activation of the neutrophils and monocytes by ANCA causes them to adhere to the endothelial wall, express and secret pro-inflammatory cytokines (including TNF-a and IL-8), and undergo a respiratory burst. This ultimately results in swelling and necrosis of the vascular endothelium.
CLINICAL FEATURES: Overall, the age of onset of WG is usually between 25 and 50 years of age. In childhood, it can occur from infancy to adolescence. The classic triad of WG is involvement of the upper airways, lower respiratory tract and kidneys - 90% of patients initially seek care because of upper or lower airway symptoms.
Upper airway symptoms are varied, and include epistaxis, sinusitis and otitis with or without hearing loss. Chronic nasal involvement can lead to the classic deformity known as a "saddle nose" (Fig. 7) which is reported to occur in up to 40-50% of pediatric patients, twice as common as in adults. Finally, subglottic, tracheal and endobronchial stenosis can occur in up to 50% of pediatric patients (5 times more common than adults), and often occurs independently of other features of active WG. If systemic symptoms are absent at presentation, these airway symptoms may be mistaken as being secondary to allergy or infection.
Involvement of the lower airways presents nonspecifically with cough, wheeze, dyspnea or hemoptysis. It is important to obtain imaging (CXR and/or CT) in all patients suspected to have WG, a up to 30% of patients with CXR abnormalities (infiltrates, nodules, etc.) will be asymptomatic.
The prevalence of renal involvement varies in pediatric case series from 10-20% of patients, up to 50-100%, though renal involvement developed in 60-80% of patients in the series with lower prevalence at onset. The prevalence increases with age. Renal manifestations include hematuria, proteinuria and necrotizing glomerulonephritis. Renal involvement may be asymptomatic. A patient with WG is considered to have "limited" disease if there is no evidence of renal involvement.
Many organ systems other than the classic triad can be affected in WG. Ocular manifestations include scleritis (may be nodular, Fig. 8), conjunctivitis and uveitis. Optic neuritis can also occur, as well as proptosis, with or without retro-orbital pseudotumour (Fig. 9). Ocular involvement can occur at all ages, in up to 10-15% or patients, and can seriously threaten vision.
Nervous system involvement has been described in up to 10% of patients, most commonly in the form of central or peripheral nerve palsies. While intracranial bleeding and structural anomalies are rare in WG compared to other vasculitides, they should be considered in any case of altered level of consciousness or seizures.
As with other vasculitides, joint involvement is common, occurring in up to 50% of patients. This typically consists of arthralgias of the large joints including hips, knees, ankles and wrists. Objective arthritis is found only in a minoritiy.
Finally, skin involvement is common (30-50% of patients) and varies widely. Erythematous or purpuric macules (Fig.10), massive nodules, necrotizing vasculitic ulcerations and gangrene have all been reported. In fact, there are reports of patients initially being diagnosed as having Henoch-Schonlein Purpura, and had poor response to standard treatment.
DIFFERENTIAL DIAGNOSIS:
The differential diagnosis really depends on the constellation of symptoms evident at presentation. In general however, there are 3 other vasculitides that form the major differential diagnoses. Microscopic polyangitis (MPA) is another necrotizing small vessel vasculitis with pulmonary and renal involvement, that is ANCA positive, however usually shows p-ANCA staining with anti-MPO positivity. Polyarteritis nodosa (PAN) is a medium vessel vasculitis with pulmonary and renal involvement that is ANCA negative. Finally, Churg-Strauss Syndrome (CSS) is a granulomaous, small vessel necrotizing vasculitis involving the respiratory tract, but that has predominant features of asthma and allergy.
DIAGNOSIS:
Diagnosis of WG is made by the pattern of symptoms and organ involvement and histopathology showing vasculitis, granulomatous inflammation and necrosis. Figure 11 depicts a pulmonary lesion of WG showing a central rounded area outlined by green arrows with a central defect containing neutrophils. This central area is interpreted as a vessel that has been mostly destroyed by the suppurative necrosis of WG. The neighboring lung shows interstitial fibrosis with a reduction in the size of air spaces. If renal biopsy is performed, it typically shows a segmental necrotizing glomerulonephritis.
Pulmonary imaging can lend support to the diagnosis. Computed tomography can show any combination of ground glass attenuation, bronchial wall thickening, traction bronchiectasis, and bilateral subpleural or peribronchovascular nodules (Fig. 12).
Finally, serology in the form of antinuclear cytoplasmic antibody (ANCA) is a relatively non-invasive test that can help steer towards performing a biopsy to confirm a diagnosis of WG, or towards another diagnosis. ANCA ws first described in 1982 and found to have a high association with active WG. Immunofluorescence is used to describe the staining pattern of ANCA, being either cytoplasmic (c-ANCA) as in WG, or perinuclear (p-ANCA) as in MPA. ELISA can determine the exact antigen to which the ANCA is directed. C-ANCAs are typically directed against proteinase-3 (therefore are anti-PR3), while ANCAs directed against myeloperoxidase (anti-MPO) are more usually perinuclear (p-ANCA) in staining, though anti-MPO has slightly greater variability in staining than anti-PR3. C-ANCA is reported to have been detected in 70-90% of patients with active WG, with a specificity of 80-100%, though this was carried out in adults, with no information for pediatric cases. It is important to remember than other ANCA-positive diseases occur in childhood (ex. juvenile idiopathic arthritis - p-ANCA, cystic fibrosis - c-ANCA). Because of this, ANCA serology cannot replace biopsy. Some studies have shown that an increase in ANCA titres precedes an increase in clinical disease activity, with titre-based treatment preventing relapses, though this has not been confirmed in larger studies.
TREATMENT:
Treatment in pediatric WG is based on case reports, adult regimens, and treatment for other vasculitides - its rarity has made treatment studies difficult. There are no standard guidelines, evidence-based or by consensus. The mainstay of treatment, as with most vaculitides, is immunosuppressve therapy.
Initial trials in adults of glucocorticoids (ex. prednisolone) alone showed improvement in systemic and upper-airway symptoms, with an increase in median survival from 5 months untreated, to 12.5 months. However, steroids alone are inadequate for treatment of pulmonary and renal involvement.
Cyclophosphamide is no routinely used, in combination with high-dose steroid. In an NIH study of adults, the use of this combination provided marked improvement in 90% of patients, with complete remission in 75% and a 5-year survival rate of 80%. However, 50% of patients experience relapses, and drug-related toxicity complicated the course in 40%. Cyclophosphamide-related toxicities include infertility, hemorrhagic cystitis, bladder carcinoma, lymphoma, bone marrow suppression and myelodysplasia. Intravenous pulse therapy (rather than daily oral therapy) ahs been studied in an attempt to reduce drug-related toxicity, and has been shown to have similar survival and remission rates, with a significant reduction in side effect, in particular gonadal toxicity. The few studies of cyclophosphamide in children have shown similar improvements, but with less toxicity (only 20% of patients), and in particular no malignancies after similar periods of treatment and follow-up.
Methotrexate has also been used in combination with steroids with 75% remission, but a time to relapse of 29 months. While it isn't sufficient to treat significant renal disease, when used as initial treatment in adults withWG-related glomerulonephritis but normal serum creatining, there was no long-term decline in renal function. It has also been found to maintain remission in patients initially treated with cyclophosphamide. Finally, it has been used to continue treatment in patients with significant cyclophosphamide toxicity. To summarize, methotrexate is generally considered to be a reasonable alternative for initial treatment in select groups of patients, such as those with limited or non-life-threatening disase, normal serum creatinine, or cyclophosphamide toxicity.
Other, adjunctive treatments include azathioprine, used for maintenance of remission as a cyclophosphamide and steroid-sparing agent, and trimethoprim-sulfamethoxazole (TMP-SMX). As mentioned earlier, some studies have shown a reduction in relapse rates with TMP-SMX treatment. There have also been a few case reports of TMP-SMX as monotherapy in disease limited to the upper airway. Finally, it has been used as PCP prophylaxis during immunosuppressive therapy, especially with methotrexate.
COURSE AND PROGNOSIS:
For WG in general, there is now a >80% 5-year survival, with survival increasing with younger age (among adults) and lower serum creatinine. Mortality is mainly related to renal involvement, and is 80% if left untreated. Complete remission is more likely if disease activity was high at presentation, but less likely if organ damage was present. Disease-free remission is rare, and up to 80% of children relapse in a median of 28 months (range 4 months to 10 years). Higher rates of relapse are associated with less intensive initial therapy, with respect to lower cyclophosphamide doses and shorter duration of high-dose steroid treatment.
Rates of permanent disease-related morbidity are high and can vary with age. For example, nasal deformity is seen in 48% of children compared to 25% of adults. A similar pattern is seen for subglottic stenosis, occurring in 35% of children and only 9% of adults. Rates of other morbidities however are similar between the two groups: permanent hearing loss in 17%, visual loss in 9%, renal insufficiency in 35% with ESRD in 9%, chronic sinus disease in 48% and pulmonary disease in 14%.
As mentioned above, treatment-related morbidity can be significant, but is less common in children than in adults (22% of patients compared to 45%). The morbidities that occur with greatest frequency include cystitis (up to 50%), infertility (at least 30%) and serious infections (40%).
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DISCUSSION
DEFINITION: Granulomatous inflammation involving the upper and lower respiratoyr tract, and necrotizing vasculitis affecting small to medium-sized vessels. Necrotizing glomerulonephritis is common. (Chapel Hill Consensus Conference, 1994)
CLASSIFICATION CRITERIA: •Nasal or oral inflammation (includes painful/painless oral ulcers, or purulent or bloody nasal discharge)
•CXR evidence of nodules, infiltrates or cavities
•Microscopic hematuria or red cell casts
•Granulomatous inflammation on biopsy
(American College of Rheumatology, 1990)
However, there are problems with the above definition and criteria. First, nasal and oral inflammation is not unique to Wegener's Granulomatosis (WG), and can occur in up to 20% of cases of microscopic polyangitis (the main differential diagnosis, with different treatment and prognosis). Also, the Chapel Hill definition requires a biopsy showing granulomata, and does not acknowledge clinical or laboratory surrogates for other essential elements of the disease. By the ACR criteria, patients with non-granulomatous disease could be classified as WG. Neither scheme includes ANCA studies which have now become a very common investigative tool. Both were designed to define cases for studies, and are not validated as diagnostic criteria, though they are often used in this manner. Finally, and perhaps most importantly for our purposes, both only apply to adult patients. Because the ACR criteria were validated in adults, and pediatric control cases would differ (even if patients were similar, which often they are not), the sensitivity and specificity of these criteria would be different in children.
In order to address these issues, the European League Against Rheumatism (EULAR) and the Pediatric Rheumatology Society (PReS) met in November 2005 to devise a new classification system for childhood vasculitides. Their purpose was to include those diseases that occur only in childhood (ex. Kawasaki disease) and exclude those that occur only in adulthood (ex. temporal arteritis). As well, they sought to highlight differences in the pediatric presentation of other diseases such as Polyarteritis nodosa and Wegener's Granulomatosis. They based their system on the CCHC classification by vessel size, modified for children.
The EULAR/PReS classification requires 3 of the following 6 criteria:
•Abnormal urinalysis (hematuria or proteinuria)
•Granulomatous inflammation on biopsy of the respiratory tract (renal biopsy typically shows necrotizing pauci-immune glomerulonephritis)
•Subglottic, tracheal or endobronchial stenosis
•Abnormal CXR or CT
•PR3 ANCA or c-ANCA staining
(EULAR/PReS, Ann Rheum Dis, 2006)
Airway stenosis was added in recognition of its greater frequency in children compared to adults. Again, it is important to remember that these criteria were developed by consensus, and studies are required to validate them as a case definition using patient and control groups, then further evaluate them prospectively to judge their utility as diagnostic criteria.
EPIDEMIOLOGY: Wegener's granulomatosis is rare in adults, but even more so in children. While the incidence in adults is reported to range from 7.9-8.5/million/year, in children it has been estimated at < 0.5/million/year. The prevalence of WG in adults is reported as 30-53/million, while this information is not available for the pediatric population.
ETIOLOGY: The etiology of WG is currently unknown. The recognition that chronic nasal carriage of Staph aureus is associated with relapses, whereas treatment with trimethoprim-sulfamethoxazole may reduce relapse rates, has led to the theory of an infectious component. The suggestion of a seasonal variation in incidence, with more cases occurring in winter and spring, has lent some support to this theory. In addition, it is been found that heterozygosity for a1-anti-trypsin deficiency is associated with an increased risk for WG, as well as with increased morbidity, suggesting the contribution of a genetic predisposition.
PATHOPHYSIOLOGY: The pathophysiology of WG involves an autoimmune inflammatory process, mediated by TNF-a-primed neutrophils and monocytes which express taret antigens of ANCA, especially proteinase-3. Activation of the neutrophils and monocytes by ANCA causes them to adhere to the endothelial wall, express and secret pro-inflammatory cytokines (including TNF-a and IL-8), and undergo a respiratory burst. This ultimately results in swelling and necrosis of the vascular endothelium.
CLINICAL FEATURES: Overall, the age of onset of WG is usually between 25 and 50 years of age. In childhood, it can occur from infancy to adolescence. The classic triad of WG is involvement of the upper airways, lower respiratory tract and kidneys - 90% of patients initially seek care because of upper or lower airway symptoms.
Upper airway symptoms are varied, and include epistaxis, sinusitis and otitis with or without hearing loss. Chronic nasal involvement can lead to the classic deformity known as a "saddle nose" (Fig. 7) which is reported to occur in up to 40-50% of pediatric patients, twice as common as in adults. Finally, subglottic, tracheal and endobronchial stenosis can occur in up to 50% of pediatric patients (5 times more common than adults), and often occurs independently of other features of active WG. If systemic symptoms are absent at presentation, these airway symptoms may be mistaken as being secondary to allergy or infection.
Involvement of the lower airways presents nonspecifically with cough, wheeze, dyspnea or hemoptysis. It is important to obtain imaging (CXR and/or CT) in all patients suspected to have WG, a up to 30% of patients with CXR abnormalities (infiltrates, nodules, etc.) will be asymptomatic.
The prevalence of renal involvement varies in pediatric case series from 10-20% of patients, up to 50-100%, though renal involvement developed in 60-80% of patients in the series with lower prevalence at onset. The prevalence increases with age. Renal manifestations include hematuria, proteinuria and necrotizing glomerulonephritis. Renal involvement may be asymptomatic. A patient with WG is considered to have "limited" disease if there is no evidence of renal involvement.
Many organ systems other than the classic triad can be affected in WG. Ocular manifestations include scleritis (may be nodular, Fig. 8), conjunctivitis and uveitis. Optic neuritis can also occur, as well as proptosis, with or without retro-orbital pseudotumour (Fig. 9). Ocular involvement can occur at all ages, in up to 10-15% or patients, and can seriously threaten vision.
Nervous system involvement has been described in up to 10% of patients, most commonly in the form of central or peripheral nerve palsies. While intracranial bleeding and structural anomalies are rare in WG compared to other vasculitides, they should be considered in any case of altered level of consciousness or seizures.
As with other vasculitides, joint involvement is common, occurring in up to 50% of patients. This typically consists of arthralgias of the large joints including hips, knees, ankles and wrists. Objective arthritis is found only in a minoritiy.
Finally, skin involvement is common (30-50% of patients) and varies widely. Erythematous or purpuric macules (Fig.10), massive nodules, necrotizing vasculitic ulcerations and gangrene have all been reported. In fact, there are reports of patients initially being diagnosed as having Henoch-Schonlein Purpura, and had poor response to standard treatment.
DIFFERENTIAL DIAGNOSIS:
The differential diagnosis really depends on the constellation of symptoms evident at presentation. In general however, there are 3 other vasculitides that form the major differential diagnoses. Microscopic polyangitis (MPA) is another necrotizing small vessel vasculitis with pulmonary and renal involvement, that is ANCA positive, however usually shows p-ANCA staining with anti-MPO positivity. Polyarteritis nodosa (PAN) is a medium vessel vasculitis with pulmonary and renal involvement that is ANCA negative. Finally, Churg-Strauss Syndrome (CSS) is a granulomaous, small vessel necrotizing vasculitis involving the respiratory tract, but that has predominant features of asthma and allergy.
DIAGNOSIS:
Diagnosis of WG is made by the pattern of symptoms and organ involvement and histopathology showing vasculitis, granulomatous inflammation and necrosis. Figure 11 depicts a pulmonary lesion of WG showing a central rounded area outlined by green arrows with a central defect containing neutrophils. This central area is interpreted as a vessel that has been mostly destroyed by the suppurative necrosis of WG. The neighboring lung shows interstitial fibrosis with a reduction in the size of air spaces. If renal biopsy is performed, it typically shows a segmental necrotizing glomerulonephritis.
Pulmonary imaging can lend support to the diagnosis. Computed tomography can show any combination of ground glass attenuation, bronchial wall thickening, traction bronchiectasis, and bilateral subpleural or peribronchovascular nodules (Fig. 12).
Finally, serology in the form of antinuclear cytoplasmic antibody (ANCA) is a relatively non-invasive test that can help steer towards performing a biopsy to confirm a diagnosis of WG, or towards another diagnosis. ANCA ws first described in 1982 and found to have a high association with active WG. Immunofluorescence is used to describe the staining pattern of ANCA, being either cytoplasmic (c-ANCA) as in WG, or perinuclear (p-ANCA) as in MPA. ELISA can determine the exact antigen to which the ANCA is directed. C-ANCAs are typically directed against proteinase-3 (therefore are anti-PR3), while ANCAs directed against myeloperoxidase (anti-MPO) are more usually perinuclear (p-ANCA) in staining, though anti-MPO has slightly greater variability in staining than anti-PR3. C-ANCA is reported to have been detected in 70-90% of patients with active WG, with a specificity of 80-100%, though this was carried out in adults, with no information for pediatric cases. It is important to remember than other ANCA-positive diseases occur in childhood (ex. juvenile idiopathic arthritis - p-ANCA, cystic fibrosis - c-ANCA). Because of this, ANCA serology cannot replace biopsy. Some studies have shown that an increase in ANCA titres precedes an increase in clinical disease activity, with titre-based treatment preventing relapses, though this has not been confirmed in larger studies.
TREATMENT:
Treatment in pediatric WG is based on case reports, adult regimens, and treatment for other vasculitides - its rarity has made treatment studies difficult. There are no standard guidelines, evidence-based or by consensus. The mainstay of treatment, as with most vaculitides, is immunosuppressve therapy.
Initial trials in adults of glucocorticoids (ex. prednisolone) alone showed improvement in systemic and upper-airway symptoms, with an increase in median survival from 5 months untreated, to 12.5 months. However, steroids alone are inadequate for treatment of pulmonary and renal involvement.
Cyclophosphamide is no routinely used, in combination with high-dose steroid. In an NIH study of adults, the use of this combination provided marked improvement in 90% of patients, with complete remission in 75% and a 5-year survival rate of 80%. However, 50% of patients experience relapses, and drug-related toxicity complicated the course in 40%. Cyclophosphamide-related toxicities include infertility, hemorrhagic cystitis, bladder carcinoma, lymphoma, bone marrow suppression and myelodysplasia. Intravenous pulse therapy (rather than daily oral therapy) ahs been studied in an attempt to reduce drug-related toxicity, and has been shown to have similar survival and remission rates, with a significant reduction in side effect, in particular gonadal toxicity. The few studies of cyclophosphamide in children have shown similar improvements, but with less toxicity (only 20% of patients), and in particular no malignancies after similar periods of treatment and follow-up.
Methotrexate has also been used in combination with steroids with 75% remission, but a time to relapse of 29 months. While it isn't sufficient to treat significant renal disease, when used as initial treatment in adults withWG-related glomerulonephritis but normal serum creatining, there was no long-term decline in renal function. It has also been found to maintain remission in patients initially treated with cyclophosphamide. Finally, it has been used to continue treatment in patients with significant cyclophosphamide toxicity. To summarize, methotrexate is generally considered to be a reasonable alternative for initial treatment in select groups of patients, such as those with limited or non-life-threatening disase, normal serum creatinine, or cyclophosphamide toxicity.
Other, adjunctive treatments include azathioprine, used for maintenance of remission as a cyclophosphamide and steroid-sparing agent, and trimethoprim-sulfamethoxazole (TMP-SMX). As mentioned earlier, some studies have shown a reduction in relapse rates with TMP-SMX treatment. There have also been a few case reports of TMP-SMX as monotherapy in disease limited to the upper airway. Finally, it has been used as PCP prophylaxis during immunosuppressive therapy, especially with methotrexate.
COURSE AND PROGNOSIS:
For WG in general, there is now a >80% 5-year survival, with survival increasing with younger age (among adults) and lower serum creatinine. Mortality is mainly related to renal involvement, and is 80% if left untreated. Complete remission is more likely if disease activity was high at presentation, but less likely if organ damage was present. Disease-free remission is rare, and up to 80% of children relapse in a median of 28 months (range 4 months to 10 years). Higher rates of relapse are associated with less intensive initial therapy, with respect to lower cyclophosphamide doses and shorter duration of high-dose steroid treatment.
Rates of permanent disease-related morbidity are high and can vary with age. For example, nasal deformity is seen in 48% of children compared to 25% of adults. A similar pattern is seen for subglottic stenosis, occurring in 35% of children and only 9% of adults. Rates of other morbidities however are similar between the two groups: permanent hearing loss in 17%, visual loss in 9%, renal insufficiency in 35% with ESRD in 9%, chronic sinus disease in 48% and pulmonary disease in 14%.
As mentioned above, treatment-related morbidity can be significant, but is less common in children than in adults (22% of patients compared to 45%). The morbidities that occur with greatest frequency include cystitis (up to 50%), infertility (at least 30%) and serious infections (40%).
Next page /