Bazan-Socha, Stanisława

Głodzik, Izabela

Ignacak-Popiel, Maria

Kosałka-Węgiel, Joanna

Lis, Grzegorz

Musiał, Jacek

Tkaczyk, Marcin

Zachwieja, Katarzyna

Zugaj, Anna

Żuber, Zbigniew

English

Jagiellonian Univeristy Repository

5FOLIA MEDICA CRACOVIENSIA Vol. LIV, 1, 2014: 5–12 PL ISSN 0015-5616Joanna KosałKa1, stanisława Bazan-socha1, Maria ignacaK2, anna zugaJ2, Katarzyna zachwieJa3, izaBella głodziK4, grzegorz lis4, Marcin tKaczyK5,  zBigniew ŻuBer6, JaceK Musiał1CLINICAL MANIFESTATION OF PEDIATRIC GRANULOMATOSIS WITH POLYANGIITIS — THE EXPERIENCE OF TWO REGIONS  IN POLANDAbstract: B a c k g r o u n d: The purpose of this study was to describe clinical manifestations, labo-ratory findings and outcome of granulomatosis with polyangiitis (GPA) in pediatric patients living in two regions (Southern and Central) of Poland.M e t h o d s: Retrospective analysis of patient hospital records from four large hospitals during a period from 1995 to 2013. Patients with confirmed diagnosis of GPA according to American College of Rheumatology (ACR) and EULAR/PRINTO/PRES criteria for GPA were analyzed. All patients were subjected to clinical, laboratory, radiological and immunological assessment.R e s u l t s: During this 18-year period only 9 children with confirmed diagnosis of GPA (6 girls, 3 boys) were identified. The average age of the disease onset was 12 years (range: 8–16 years). Average delay between first symptoms and diagnosis was approx. 20 months (range: 0–84 months). Organ system involvement at presentation included: kidneys 88.8% (8/9), lungs 77.7% (7/9), ear/nose/throat 55.5% (5/9), gastrointestinal tract 55.5% (5/9), skin 44.4% (4/9), joints 22.2% (2/9), eyes 11.1% (1/9) and nervous system 11.1% (1/9). In 5 children disease course was progressive (constant progression of sinusitis in one case, end-stage renal disease in two, chronic kidney disease stage IV in one and one child died due to alveolar hemorrhage).C o n c l u s i o n: The majority of our patients were females. Clinical features of pediatric GPA were similar to those described in adults. None of our patients developed subglottic stenosis and in only 2 children saddle-nose deformity was observed. Although GPA was treated according to contemporary standards care, disease progression was observed in more than a half of children. Key words: granulomatosis with polyangiitis, Wegener’s granulomatosis, vasculitis, children, childhood.INTRODUCTIONGranulomatosis with polyangiitis (GPA; formerly Wegener’s granulomatosis) is a systemic, necrotizing vasculitis affecting small and medium-sized blood vessels, associated with granulomatous inflammation [1, 2]. Clinically, this disease mani-fests itself mainly through constitutional symptoms together with the involvement of respiratory tract and kidneys [3]. The disease was first described in 1936 by 6a German pathologist — Friedrich Wegener [4]. Nowadays it was proposed to abandon eponyms and use the name of granulomatosis with polyangiitis [4]. Reported annual incidence of GPA varies between 0.5 and 10 cases per one million [5–7]. This disease usually manifests itself in the 6th and 7th decade of life, with similar frequency between genders in adult age [5]. Its occurrence in childhood has also been reported [2, 8–11], with one case diagnosed as early as in the second week of life [12]. The incidence of pediatric GPA is not well estab-lished with boys to girls ratio from 1:1 to 1:4 [9]. Disease course in adulthood and childhood can differ [1]. It was suggested that GPA in childhood is more frequently complicated by a subglottic stenosis and nasal deformity [13]. On the other hand, treatment related morbidity and disease progression might be less common in children [13]. GPA in both children and adults is fatal if left untreat-ed. Induction treatment and chronic therapy is crucial for going into remission and maintaining relapse-free disease. Early medical data, obtained before imple-mentation of effective treatment showed mean survival of about 5 months, with more than 90% of patients dying within the first 2 years after diagnosis [7]. The aim of our study was to provide data on pediatric GPA in four major hospitals from Central and Southern Poland [12] and to compare this experience with the limited (mainly case reports) literature.PATIENTS AND METHODSWe retrospectively analyzed paper medical records of children hospitalized in two large pediatric hospitals (Polish-American Children’s Hospital and St. Louis Children Hospital, both in Cracow), one department of internal medicine compri-sing systemic vasculitis reference center (2nd Department of Internal Medicine, Jagiellonian University Medical College) also in Cracow (administrative region of Southern Poland — 3.3 million inhabitants) and one pediatric reference center in a central region of the country (Nephrology Division, Department of Paediatrics and Immunology Polish Mother Memorial Hospital Research Institute in Łódź). We systematically collected organ specific clinical, laboratory and imaging features at presentation, and at any time, and measures of outcome, such as remission, progression and refractory disease. Analyzed records came from the period of 1995–2013. Patients were entered into the study, if they had at least 2 out of the 4 criteria according to the ACR or at least 3 out of the 6 criteria according to the EULAR/PRINTO/PRES [11, 14]. However, there are no precise and unequivocal diagnostic criteria and it’s important to base the diagnosis on clinical symptoms (such as epistaxis, haemoptysis with cough and dyspnoe, haematuria, general edema, skin lesions), histopathological picture of affected organ (s) and the pre-sence of anti-neutrophil cytoplasmic antibodies (ANCA) [6, 10–12]. In follow-up these signs can also be observed as indicators of GPA relapse. 7RESULTSIn all four hospitals, during the period of 18 years, diagnosis of GPA was esta-blished in only nine children (6 girls and 3 boys). The average age of disease onset was 12 years (range: 8–16 years). The average delay between first symptoms and diagnosis was approx. 20 months (range: 0–84 months) (Table 1). At presenta-tion the most common symptoms were constitutional ones: weight loss, fever or arthralgia. They were presented in all children except for one. Organ involvement at presentation included: kidneys 88.8% (8/9), lungs 77.7% (7/9), ear/nose/si-nuses/throat 55.5% (5/9), gastrointestinal tract 55.5% (5/9), skin 44.4% (4/9), joints 22.2% (2/9), eyes 11.1% (1/9) and nervous system 11.1% (1/8) (Table 2). Later, in the course of the disease, upper and lower airway and kidney involve-ment prevailed (Table 2). Anti-neutrophil cytoplasmic antibodies (ANCA) were po-sitive in all patients. Their presence, however, is not absolutely necessary for a clinical diagnosis of GPA. Other common laboratory abnormalities at diagnosis included: proteinuria 100% (9/9), hematuria 88.8% (8/9) and abnormal chest X-ray 77.7% (7/9) or chest CT scan 77.7% (7/9). Six children reported chronic rhinitis, but sinusitis in CT or X-ray was confirmed in only four. Our analysis included 18 years of medical history. During this time recommendations for GPA treatment have been constantly changing. Moreover, new immunosuppression re-gimens were invented. For this reason, and due to delayed diagnosis, each child was treated in a different way. All patients received glucocorticosteroids (GCS) Number Gender Age at diagnosis Age of onset Diagnosis delay (years)Patient 1 W 11 11 0Patient 2 W 20 13 7Patient 3 W 13 12 1Patient 4 M 15 15 0Patient 5 W 11 11 0Patient 6 M 10 8 2Patient 7 W 13 9 4Patient 8 W 16 16 0Patient 9 M 14 13 1Average     13.66 12     1.66T a b l e  1Demographic data, delay in diagnosis, treatment at diagnosis of GPA and disease activity score  at presentation.8T a b l e  2Clinical manifestation at diagnosis GPA and at any time after diagnosis of GPA.At presentation At any timeConstitutional symptoms 8 9 Fever 5 7 Arthralgias 3 3 Weight loss 5 6Renal involvement 8 8 Glomerulonephritis 8 8 Requirement for dialysis 2 3 Kidney tranplatation 0 1Ear, nose,  throat involvement5 8 Rhinitis 4 6 Sinusitis 4 4 Epistaxis 2 2 Oral ulcers 2 2 Otitis media 1 3 Nasal ulcers 0 0 Conductive/sensorineural deafness 1 1 Saddle nose 0 2 Subglottic stenosis 0 0 Nasal septal perforation 0 4Pulmonary involvement 7 8 Alveolar hemorrhage 3 4 Nodules 3 4 Fixed infiltrates 2 2 Required ventilation 0 1 Pleuritis 2 2Eye involvement 1 19At presentation At any time Conjunctivitis 1 1 Scleritis/episcleritis 0 0 Proptosis 0 0Skin involvement 4 4 Petechiae/palpable purpura 4 4 Urticaria 1 1 Panniculitis/erythematous nodules 1 1Arthritis 2 3Hypertension 1 2Gastrointestinal involvement 5 5 Abdominal pain 5 5 Gastrointestinal bleeding 2 3Venous thrombotic event 1 1 Deep vein thrombosis 1 1 Pulmonary embolus 0 0Nervous system involvement 1 2and cyclophosphamide (CTX). In addition, mycophenolate mofetil was used in four children and cyclosporine in one. In four children plasmapheresis was used and two children required chronic hemodialysis. In five patients disease course was progressive in spite of treatment with cyclophosphamide and corticosteroids (constant progression of sinusitis in one case, end-stage renal disease in two, chronic kidney disease stage IV in one, one child died due to alveolar hemorrhage). The child, who died was the youngest of our patients at the time of the first GPA symptoms (8 years of age with 2 years delay in diagnosis). In all five children progression was observed after steroid withdrawal. Progression of sinusitis was mainly a consequence of delayed diagnosis and a very low maintenance dose of corticosteroid (on average 0.1 mg per kg every other day). In one child progres-sion (renal failure) developed on mycophenolate mofetil combined with low-dose steroids. Three (out of four) children who achieved stable and long lasting disease remission were diagnosed and treated without delay. Their remission induction treatment included oral prednisone (0.5 mg/per kg/per day), or periodic infusion 10of intravenous high-doses of methyloprednisolone, and intravenous cyclophospha-mide. In our group of patients, apart from increased risk of infections, no other important clinical side effects of immunosuppressive therapy were observed. DISCUSSIONBased on our material we are not able to precisely specify the prevalence of pe-diatric GPA in Poland. Our estimation, however, indicates approximate frequency of about 0.05 per 100 000 children per year in analysed region, which is proba-bly less than the real. In the available literature GPA incidence among children is also not well established, but estimated between 0.03 and 3.2 per 100 000 children per year, with boys to girls ratio from 1:1 to 1:4 [9, 7, 12, 15]. Recen-tly, the number of newly diagnosed cases of GPA constantly increases. This is possibly due to increased awareness of its existence [6, 7, 9]. The median of age at first symptoms in our study was 12 years (range: 8–16 years); higher than that reported by Belostotsky et al. (6 years) [12], but lower than those published by Stegmayr et al. (17.8 years) [16], Akikusa et al. (14.5 years) [2] and Cabral et al. (13.975 years) [11]. The adult literature and pediatric study performed by Stegmayr et al. suggested an equal male/female ratio or male predominance [16]. However, in our study, similarly to those performed by Belostotsky et al. [16], Cabral et al. [11] and Akikusa et al. [2] predominance of girls was evident. Cli-nical manifestations of pediatric GPA is usually different than that observed in adults and this is probably the most important reason for delayed diagno-sis [1]. In our group of patients the diagnosis was also significantly delayed (by 20 months on average) even though 7 of 9 children at presentation had co-existence of symptoms from upper and/or lower airways and kidneys. This relates to poor awareness of this disease in children among family doctors and pedia-tricians in the Polish health system, probably because of its rarity in children. Other reasons may include variable course, sometimes limited to constitutional symptoms only [17], which may lead to wrong diagnosis and mistreatment of GPA in children. As an example — two of our patients were initially diagnosed with Schoenlein-Henoch purpura. This caused a substantial delay in the institution of a proper immunosuppressive therapy and in effect in severe and irreversible organ damage (kidney failure and destruction of parasinusal bones, respectively). Constitutional symptoms in children GPA are always presented at the time of diagnosis, accompanied by rhinitis (87%) and kidney involvement (86%) [2, 17]. Frequency of rhinitis and sinusitis may continue to grow during the further course of the disease [2, 12]. Based on the data from 23 GPA children Rottem et al. reported that this form of disease is five times more often complicated by subglottic stenosis and two times more often by nasal deformity. Belostotsky et al. made a similar observation in their group of 17 children with GPA [12]. In con-11trast, none of our patients developed subglottic stenosis and only in two children saddle-nose deformity was observed. A reason for rare occurrence of above-men-tioned symptoms lies probably in a higher age at first symptoms. Ophthalmologic complications and peripheral neuropathy was presented in 11% and 22% of our patients, respectively. This roughly corresponds to the available literature [13].In summary, even though GPA affects mainly adult patients, pediatricians must be aware of this possibility. Diagnosis should be made as quickly as possi-ble to avoid irreversible organ damage or even death. Especially, when there are symptoms from upper and/or lower respiratory tract and kidneys, GPA should be always considered. We can describe these signs as a diagnostic “red flag”.ABBREVIATIONS AND ACRONYMSACR  — American College of Rheumatology ANCA  — anti-neutrophil cytoplasmic antibodies EULAR/PRINTO/PRES — European League Against Rheumatism/Paediatric Rheumatology Interna-    tional Trials Organisation/Paediatric Rheumatology European Society CTX  — cyclophosphamide GCS  — glucocorticosteroids GPA  — granulomatosis with polyangiitis MMF  — mycophenolate mofetil WG   — Wegener’s granulomatosisREFERENCES1. Pełkowska A., Sancewicz-Pach K., Słowiaczek E., et al.: Diagnostic difficulties in 15-year-old boy with Wegener granulomatosis. Przegl Pediatr. 2005; 35: 174–177. — 2. Akikusa J.D., Schneider R., Har-vey E.A., et al.: Clinical features and outcome of pediatric Wegener’s granulomatosis. Arthritis Rheum. 2007; 57: 837–844. — 3. Wong S.N., Shah V., Dillon M.J.: Antineutrophil cytoplasmic antibodies in Wegener’s granulomatosis. Arch Dis Child. 1998; 79: 246–250. — 4. Kucharz E.J., Majdan M., Kotuls- ka A.: Ziarniniakowatość z zapaleniem naczyń — nowa nazwa ziarniniakowatości Wegenera i potrzeba jej upowszechnienia. Reumatologia. 2012; 50: 541–542. — 5. Morales-Angulo C., García-Zornoza R., Obe-so-Agüera S., et al.: Ear, nose and throat manifestations of Wegener’s granulomatosis (granulomatosis with polyangiitis). Acta Otorrinolaringol Esp. 2012; 63: 206–211. — 6. Rodrigues C.E., Callado M.R., No-bre C.A., et al.: Wegener’s granulomatosis: prevalence of the initial clinical manifestations—report of six cases and review of the literature. Rev Bras Reumatol. 2010; 50: 150–164. — 7. Takwoingi Y.M., Dempster J.H.: Wegener’s granulomatosis: an analysis of 33 patients seen over a 10-year period. Clin Otolaryngol Allied Sci. 2003; 28: 187–194. — 8. Ziakas N.G., Boboridis K., Gratsonidis A., et al.: Wegener’s granulomatosis of the orbit in a 5-year-old child. Eye (Lond). 2004; 18: 658–660. — 9. Ludwichowska A., Cieszyńska J., Piotrowski S., et al.: Otological manifestations of Wege-ner’s granulomatosis in 14-year boy — case study. Forum Medycyny Rodzinnej. 2012; 6: 175–181. — 10. Siomou E., Tramma D., Bowen C., et al.: ANCA-associated glomerulonephritis/systemic vasculitis in childhood: clinical features-outcome. Pediatr Nephrol. 2012; 27: 1911–1920.11. Cabral D.A., Uribe A.G., Benseler S., et al.: Classification, presentation, and ini-tial treatment of Wegener’s granulomatosis in childhood. Arthritis Rheum. 2009; 60: 3413–123424. — 12. Belostotsky V.M., Shah V., Dillon M.J.: Clinical features in 17 paediatric patients with Wegener granulomatosis. Pediatr Nephrol. 2002; 17: 754–761. — 13. Frosch M., Foell D.: Wegener granulomatosis in childhood and adolescence. Eur J Pediatr. 2004; 163: 425–434. — 14. Ozen S., Pistorio A., Iusan S.M., et al.: EULAR/PRINTO/PRES criteria for Henoch-Schön-lein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria. Ann Rheum Dis. 2010; 69: 798–806. — 15. Smolewska E., Biernacka-Zielińska M., Szadkowska A., et al.: Wegener’s granulomatosis in a 14-year-old boy — a multidisciplinary approach. Przegl Pediatr. 2005; 35: 234–240. — 16. Steg- mayr B.G., Gothefors L., Malmer B., et al.: Wegener granulomatosis in children and young adults. A case study of ten patients. Pediatr Nephrol. 2000; 14: 208–213. — 17. Jóźwiakowska M., Tuszkiewicz-Misztal E., Górnicka G.: Wegener granulomatosis — case report. Przegl Pediatr. 2005; 35: 234–240. 1 2nd Department of Internal Medicine Unit of Allergy and Clinical Immunology Jagiellonian University, Medical College  Kraków, Poland2 University Hospital Unit of Allergy and Clinical Immunology  Kraków, Poland3 University Children’s Hospital Unit of Nephrology and Hypertension  Kraków, Poland4 University Children’s Hospital Unit of Pulmonology, Allergy and Dermatology  Kraków, Poland5 Polish Mother Memorial Hospital Research Institute Nephrology Division,  Department of Paediatrics and Immunology  Łódź, Poland6 St. Luis Children’s Hospital Unit of Older Children with Subunit of Neurology,  Rheumatology and Rehabilitation Kraków, Poland  Corresponding author:Joanna Kosałka MD 2nd Department of Internal Medicine Unit of Allergy and Clinical Immunology Jagiellonian University Medical College ul. Skawińska 8, 31-066 Kraków, Poland Phone: +48 669 233 755  Fax: +48 12 430 52 03 E-mail: joanna.kosalka@gmail.com

Clinical manifestation of pediatric granulomatosis with polyanglitis : the experience of two regions in Poland

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Clinical manifestation of pediatric granulomatosis with polyanglitis : the experience of two regions in Poland

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