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Diffuse alveolar hemorrhage in childhood-onset systemic lupus erythematosus: a severe disease flare with serious outcome

Diffuse alveolar hemorrhage in childhood-onset systemic lupus erythematosus: a severe disease... Objective: To evaluate prevalence, clinical manifestations, laboratory abnormalities and treatment in a multicenter cohort study including 847 childhood-onset systemic lupus erythematosus (cSLE) patients with and without diffuse alveolar hemorrhage (DAH), as well as concomitant parameters of severity. Methods: DAH was defined as the presence of at least three respiratory symptoms/signs associated with diffuse interstitial/alveolar infiltrates on chest x-ray or high-resolution computer tomography and sudden drop in hemoglobin levels. Statistical analysis was performed using Bonferroni correction (p < 0.0022). Results: DAH was observed in 19/847 (2.2%) cSLE patients. Cough/dyspnea/tachycardia/hypoxemia occurred in all cSLE patients with DAH. Concomitant parameters of severity observed were: mechanical ventilation in 14/19 (74%), hemoptysis 12/19 (63%), macrophage activation syndrome 2/19 (10%) and death 9/19 (47%). Further analysis of cSLE patients at DAH diagnosis compared to 76 cSLE control patients without DAH with same disease duration [3 (1–151) vs. 4 (1–151) months, p = 0.335], showed higher frequencies of constitutional involvement (74% vs. 10%, p < 0.0001), serositis (63% vs. 6%, p < 0.0001) and sepsis (53% vs. 9%, p < 0.0001) in the DAH group. The median of disease activity score(SLEDAI-2 K) was significantly higher in cSLE patients with DAH [18 (5–40) vs. 6 (0–44), p < 0.0001]. The frequencies of thrombocytopenia (53% vs. 12%, p < 0.0001), intravenous methylprednisolone (95% vs. 16%, p < 0.0001) and intravenous cyclophosphamide (47% vs. 8%, p < 0.0001) were also significantly higher in DAH patients. Conclusions: This was the first study to demonstrate that DAH, although not a disease activity score descriptor, occurred in the context of significant moderate/severe cSLE flare. Importantly, we identified that this condition was associated with serious disease flare complicated by sepsis with high mortality rate. Keywords: Diffuse alveolar hemorrhage, Childhood, Systemic lupus erythematosus, Multicenter study * Correspondence: clovisaasilva@gmail.com Pediatric Rheumatology Unit, Children’s Institute, Faculdade de Medicina da Universidade de São Paulo (FMUSP), Av. Dr. Eneas Carvalho Aguiar, 647 - Cerqueira César, São Paulo, SP 05403-000, Brazil Pediatric Pulmonology Unit, Children’s Institute, FMUSP, Av. Dr. Eneas Carvalho Aguiar, 647 - Cerqueira César, São Paulo, SP 05403-000, Brazil Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Blay et al. Advances in Rheumatology (2018) 58:39 Page 2 of 6 Introduction HRCT, and sudden drop in hemoglobin level at least of Systemic lupus erythematosus (SLE) is a multisystemic 1.5 g/dL [7, 10, 11]. Bronchoalveolar lavage with autoimmune disease characterized by the involvement of hemosiderin-laden macrophages evidence was also several organs and systems [1–3]. Pleuropulmonary recorded [14]. Patients were divided in two groups with manifestations were described as initial feature from 17 similar disease duration: cSLE patients with DAH to 42% childhood-onset SLE (cSLE) patients, particularly (assessed at DAH diagnosis) and cSLE patients without mild to moderate pleuritis [1, 3–5]. These respiratory DAH (assessed at last visit). complications may be classified as acute or chronic [6]. Descriptors and definitions of SLE Disease Activity Of note, diffuse alveolar hemorrhage (DAH) is an Index 2000 (SLEDAI-2 K) score were used to acute, rare and life-threatening pulmonary manifestation characterize disease parameters and to calculate disease characterized by sudden onset of respiratory symptoms, activity score [19]. Custom definitions were defined as such as dyspnea; hypoxemia; hemoptysis; tachycardia previously reported [3, 18]. Neuropsychiatric lupus and/or cough; associated with new lung infiltrates on included 19 syndromes according to ACR classification chest x-ray (CXR) or high-resolution computer tomog- criteria [20]. Antiphospholipid syndrome was diagnosed raphy (HRCT); and sudden drop in serum hemoglobin taking into account the presence of arterial and/or levels [7, 8]. venous thrombosis concomitant to high titers of anti- Data of DAH in cSLE patients are limited due to the phospholipid antibodies [21]. Macrophage activation small representation of this complication in previous syndrome was diagnosed considering the preliminary case series or the focus on the comparison to adult SLE, cSLE diagnostic guidelines, requiring the presence of at precluding an accurate analysis of associated factors and least one clinical plus two laboratorial criteria [22]. outcomes in patients with and without this severe Laboratorial assessment included complete blood cell complication [4, 7–15]. count and urine test. Anti-double-stranded DNA Therefore, the objective of the present multicenter (anti-dsDNA), IgG and IgM anticardiolipin antibodies cohort study was to assess the prevalence and the (aCL) were carried out at each center and the cutoff possible DAH association with demographic, clinical values were considered valid. Lupus anticoagulant was manifestations, laboratory abnormalities, disease activity detected according to the guidelines of the International score, treatments and outcomes in a large cSLE Society on Thrombosis and Hemostasis [23]. population. Drug treatment data (prednisone, intravenous methyl- prednisolone, chloroquine diphosphate, hydroxychloro- Methods quine sulfate, methotrexate, azathioprine, cyclosporine, This was a retrospective multicenter cohort study mycophenolate mofetil, intravenous cyclophosphamide including 1017 patients followed in 10 Pediatric and intravenous gammaglobulin) were also recorded. Rheumatology tertiary referral services in São Paulo state, Brazil. One hundred and sixty five patients were Statistical analysis excluded due to: incomplete medical charts (n = 96), Results were presented as an absolute number undifferentiated connective tissue disorder with 3 or (frequency) for categorical variables and median (range) fewer American College of Rheumatology (ACR) criteria or mean ± standard deviation (SD) for continuous vari- (n = 43), isolated cutaneous lupus erythematosus (n =11), ables. Categorical variables comparisons were assessed neonatal lupus erythematosus (n = 8), drug-induced lupus by Pearson χ-Square or Fisher’s exact test. Continuous (n = 5) and mixed connective tissue disease (n =2). variables from cSLE patients with and without DAH Therefore, this study group comprised 852 cSLE patients. were compared by Mann-Whitney test or t test as All of them fulfilled the ACR criteria for SLE [16], with appropriate. Statistical analysis was performed using disease onset before the age of 18 [17]. Bonferroni correction (p < 0.0022). An investigator meeting was held for protocol training according to the clinical parameters definitions and dis- Results ease activity tool scoring, as previously reported [3, 18]. DAH was observed in 19/847 (2.2%) cSLE patients. Patient’s medical charts were systematically reviewed Cough, dyspnea, tachycardia and hypoxemia occurred in according to demographic data, clinical characteristics, all 19 cSLE patients with DAH; hemoptysis in 12/19 and DAH features, laboratorial abnormalities, therapies and endotracheal tube bleeding in 14/19. New infiltrates on outcomes. CXR or HRCT and hemoglobin drop at least of 1.5 g/dL DAH was defined as the presence of at least three were evidenced in all cSLE patients with DAH (Table 1). respiratory symptoms and signs (dyspnea, hypoxemia, Bronchoalveolar lavage was performed in two cSLE hemoptysis, tachycardia and/or cough) associated with patients and hemosiderin-laden macrophage was diffuse interstitial and/or alveolar infiltrates on CXR or observed in both of them. Blay et al. Advances in Rheumatology (2018) 58:39 Page 3 of 6 Table 1 Demographic, clinical manifestations and imaging in 19 childhood-onset systemic lupus erythematosus (cSLE) patients with diffuse alveolar hemorrhage Patient Disease duration, Months Cough Dyspnoea Tachycardia Hypoxemia Hemoptysis/bleeding in New Infiltrates Drop Hbg/dL endotracheal tube CXR or HRCT 1 60 + + + + + / + + 1.8 2 151 + + + + + / + + 1.5 3 5 + + + + + / + + 2.0 4 0 + + + + + / + + 1.6 5 33 + + + + + / + + 1.9 6 0 + + + + + / + + 2.7 7 3 + + + + + / + + 1.7 8 90 + + + + + / - + 2.5 9 42 + + + + + / + + 4.5 10 4 + + + + + / + + 3.0 11 0 + + + + - / - + 3.2 12 47 + + + + - / + + 1.5 13 5 + + + + - / + + 1.5 14 0 + + + + + / - + 2.0 15 0 + + + + - / + + 7.0 16 0 + + + + - / - + 2.0 17 3 + + + + - / + + 2.0 18 1 + + + + - / - + 1.7 19 0 + + + + + / + + 8.0 CXR Chest x-ray, HRCT High resolution computer tomography, Hb Hemoglobulin, ND Not done Regarding outcomes, hospitalization in pediatric inten- The frequencies of thrombocytopenia (53% vs. 12%, sive care unit occurred in 17/19 cSLE patients with p < 0.0001), intravenous methylprednisolone (95% vs. DAH and mechanical ventilation in 14/19. DAH associ- 16%, p < 0.0001) and intravenous cyclophosphamide ated with sepsis was observed in 10/19 cSLE patients. (47% vs. 8%, p < 0.0001) were also significantly higher Concomitant macrophage activation syndrome was evi- in the former group. The median of prednisone dose denced in 2/19 patients. Death was observed in 9/19 was higher in cSLE patients with DAH compared to cSLE patients. The median duration between DAH onset those without DAH [1.4 (0.3–2) vs. 0.5 (0.03–3) mg/Kg, and death was 2 days (0.5–25). Blood erythrocyte trans- p < 0.0001] (Table 4). fusion and broad-spectrum antibiotics were adminis- tered in all cSLE patients with DAH. Intravenous Discussion methylprednisolone pulse therapy was used in 18/19 This is the largest study to evaluate DAH, a rare and cSLE and intravenous cyclophosphamide in 9/19 acute life-threatening pulmonary manifestation, in cSLE (Table 2). None of them had recurrence of DAH. population. Further comparison between cSLE patients with DAH The multicenter study design with a large cohort of compared to 76 cSLE control patients without DAH children and adolescents patients allowed a more precise with same disease duration [3 (1–151) vs. 4 (1–151) assessment of this rare and severe cSLE respiratory months, p = 0.335], showed significantly higher fre- complication. An investigator meeting was also taken in quencies of constitutional involvement (74% vs. 10%, place to standardize the protocol study in all centers. p < 0.0001), serositis (63% vs. 6%, p < 0.0001) and However, the limitation was the retrospective design sepsis (53% vs. 9%, p < 0.0001) in the former group. with potential missing data. The median of SLEDAI-2 K was significantly higher The prevalence of DAH in cSLE patients in the in cSLE patients with DAH compared to cSLE present study was similar to other reports, varying from patients without this complication [18 (5–40) vs. 6 2to 5% [6, 7, 24]. Diagnosis of this condition included (0–44), p < 0.0001]. Frequencies of nephritis and the typical respiratory symptoms and signs, drop in neuropsychiatric involvements were similar in both hemoglobin levels and the radiographic evidence of groups (p > 0.0022) (Table 3). pulmonary infiltrates, as well as the assessment of Blay et al. Advances in Rheumatology (2018) 58:39 Page 4 of 6 Table 2 Outcomes and immunosuppressive treatment in 19 childhood-onset systemic lupus erythematosus (cSLE) patients with diffuse alveolar hemorrhage Patient ICU Mechanical ventilation Sepsis MAS Death IV methylprednisolone IV cyclophosphamide pulse therapy 1+ + + – ++ – 2+ + + –– ++ 3+ + + – ++ – 4+ + + –– ++ 5+ + –– ++ – 6+ + –– – ++ 7+ + + – ++ + 8+ – + – ++ + 9+ + –– ++ – 10 + + –– – ++ 11 + –– – – + – 12 + + – ++ + – 13 + + –– + –– 14 + – + –– ++ 15 + + + + – ++ 16 –– + –– + – 17 + + + –– ++ 18 –– – – – + – 19 + + –– ++ – ICU Intensive care unit, MAS Macrophage activation syndrome, IV Intravenous Table 3 Demographic data, clinical manifestations and disease activity score in childhood-onset systemic lupus erythematosus (cSLE) patients according to the presence of diffuse alveolar hemorrhage (DAH) Variables With DAH (at diagnosis) Without DAH (at last visit) P (n = 19) (n = 76) Demographic data Female gender 14 (74) 66 (87) 0.172 Disease duration, months 3 (1–151) 4 (1–151) 0.335 Current age, years 13 (9–18) 13 (3–23) 0.889 Current clinical manifestations Constitutional 14 (74) 8 (10) < 0.0001* Mucocutaneous 9 (47) 31 (41) 0.614 Musculoskeletal 5 (26) 8 (10) 0.127 Serositis 12 (63) 5 (6) < 0.0001* Neuropsychiatric 4 (21) 11 (14) 0.491 Nephritis 16 (84) 42 (55) 0.033 Current autoimmune thrombosis (APS), n = 90 0/16 (0) 1/74 (1) 1.000 Sepsis 10 (53) 7 (9) < 0.0001* Macrophage activation syndrome 2 (10) 2 (3) 0.113 Death, n = 94 9 (47) 15/75 (20) 0.020 Current disease activity SLEDAI-2 K, n =82 18 (5–40) 6 (0–44) < 0.0001* *P-value according to Bonferroni correction for multiple comparisons (p < 0.0022). Results are presented in n (%) and median (range), APS Antiphospholipid syndrome, SLEDAI-2 K Systemic Lupus Erythematosus Disease Activity Index 2000 Blay et al. Advances in Rheumatology (2018) 58:39 Page 5 of 6 Table 4 Current laboratory tests and drug therapy of childhood-onset systemic lupus erythematosus (cSLE) according to the presence of diffuse alveolar hemorrhage (DAH) Variables With DAH (at diagnosis) Without DAH (at last visit) P (n = 19) (n = 76) Current laboratory exams Autoimmune hemolytic anemia 5 (26) 8 (10) 0.127 Thrombocytopenia, < 150,000/mm , n = 93 10 (52) 9/74 (12) < 0.0001* Anti-ds-DNA, n = 75 8/13 (61) 30/62 (48) 0.544 Drug therapy Prednisone current dose, mg/Kg, n = 82 1.4 (0.3–2) 0.5 (0.03–3) < 0.0001* Intravenous methylprednisolone 18 (95) 12 (15) < 0.0001* Antimalarial drugs 14 (74) 41 (54) 0.193 Azathioprine 2 (10) 16 (21) 0.513 Mycophenolate mofetil 1 (5) 5 (6) 1.000 Intravenous cyclophosphamide 9 (47) 6 (8) < 0.0001* *P-value according to Bonferroni correction for multiple comparisons (p < 0.0022). Results are presented in n (%) and median (range), anti-ds-DNA – anti-double- stranded DNA antibodies hypoxemia due to acute respiratory distress [7]. In empirical antibiotics and mechanical ventilation are addition, in two of our cSLE patients the presence of therefore essential to improve cSLE outcome [6, 7]. haemosiderin-laden macrophages in the absence of bloody fluid suggested recent bleeding [6], analyzed by Conclusion the bronchoalveolar lavage. This was the first study to demonstrate that DAH, We demonstrated that DAH, although not a disease although not a disease activity score descriptor, occurs activity score descriptor of SLEDAI-2 K [19], was associ- in the context of significant moderate/severe cSLE flare. ated with high moderate or severe disease activity scores, Importantly, we identified that this condition is associ- particularly thrombocytopenia, serositis and constitu- ated with serious disease flare complicated by sepsis and tional involvement. In contrast to previous reports DAH high mortality rate. was not associated with lupus nephritis [13]. Acknowledgements Of note, we identified that DAH was a severe Our gratitude to Ulysses Doria-Filho for the statistical analysis. The authors manifestation requiring pediatric intensive care unit thank the following Pediatric Rheumatology Divisions and colleagues for including their patients: Children’s Institute, FMUSP (Marco F. Silva, Mariana hospitalization and mechanical ventilation for the vast Ferriani, Roberta C. Gomes, Victor L. Marques, Gabriella E. Lube, Sandra R. M. majority of our patients. We extended previous observa- Lopes, Glaucia V. Novak, Beatriz C. Molinari, Clarissa C. Valões, Verena Balbi, tion of high frequency of severe infection in adults/cSLE João D. Montoni, Laila P. Coelho, Luciana S. Henriques, Pedro Anuardo, Monica Verdier, Juliana B. Brunelli, Adriana A. Jesus, Antonio C. Pastorino, patients with DAH [7], thus demonstrating the cata- Heloisa H. Marques, Andrea Watanabe, Benita G. Schvartsman, Maria H. strophic nature of DAH, since more than half of cSLE Vaisbich, Werther B. Carvalho, Magda Carneiro-Sampaio, Vicente Odone- patients developed concomitant sepsis. Filho); Division of Rheumatology, FMUSP (Juliane A. Paupitz, Glauce L. Lima, Ana Paula L. Assad); UNIFESP (Maria O. E. Hilário, Andreia S. Lopes, Aline Reinforcing this finding of poor outcome, 10% of the Alencar, Daniela P. Piotto, Giampaolo Faquin); UNESP (Priscila R. Aoki, Juliana cSLE patients were diagnosed with concomitant O. Sato, Silvana P. Cardin); Irmandade da Santa Casa de Misericórdia de São macrophage activation syndrome. In fact, this is a rare Paulo (Andressa Guariento, Eunice Okuda, Maria Carolina dos Santos); UNICAMP (Maraísa Centeville, Renata Barbosa, Simone Appenzeller); Ribeirão condition characterized by an excessive activation and Preto Medical School, FMUSP (Paola P. Kahwage, Gecilmara Pileggi, Francisco proliferation of T lymphocytes and macrophages with Hugo Gomes, Virginia Ferriani), Hospital Infantil Darcy Vargas (Jonatas Libório, massive hypersecretion of proinflammatory cytokines, Cássia Barbosa, Luciana T. P. Paulo); Hospital Municipal Infantil Menino Jesus (Simone Lotufo). and may induce severe hemorraghae [25, 26]. We observed a high mortality rate in cSLE patients Funding with DAH, as also observed in other studies [6, 10, 11]. This study was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq 301805/2013–0 to RMRP, This unfavorable outcome revealed that sepsis and 303752/2015–7 to MTT, 301479/2015–1 to CSM, 305068/2014–8 to EB and macrophage activation syndrome may have 303422/2015–7 to CAS), Federico Foundation (to EB, RMRP and CAS) and by contributed to the death of more than half of the Núcleo de Apoio à Pesquisa “Saúde da Criança e do Adolescente” da USP (NAP-CriAd) to CAS. patients. Early detection of this severe pulmonary complication, Availability of data and materials prompt immunosuppressive agents treatment [9, 15, 27], Not applicable. Blay et al. Advances in Rheumatology (2018) 58:39 Page 6 of 6 Authors’ contributions 12. Koh WH, Thumboo J, Boey ML. Pulmonary haemorrhage in oriental patients All authors analyzed and interpreted the patient data regarding autoimmune with systemic lupus erythematosus. Lupus. 1997;6:713–6. hepatitis in childhood onset systemic lupus erythematosus. GB, EB and CAS 13. Shen M, Zeng X, Tian X, Zhang F, Zeng X, Zhang X, et al. Diffuse alveolar were the major contributor in writing the manuscript. All authors read and hemorrhage in systemic lupus erythematosus: a retrospective study in approved the final manuscript. China. Lupus. 2010;19:1326–30. 14. Martinez-Martinez MU, Sturbaum AK, Alcocer-Varela J, Merayo-Chalico J, Gómez-Martin D, Gómez-Bañuelos Jde J, et al. Factors associated with Ethics approval and consent to participate mortality and infections in patients with systemic lupus erythematosus with This study was approved by our Ethics Committee. diffuse alveolar hemorrhage. J Rheumatol. 2014;41:1656–61. 15. Kimura D, Shah S, Briceno-Medina M, Sathanandam S, Haberman B, Zhang J, Consent for publication et al. Management of massive diffuse alveolar hemorrhage in a child with Not applicable. systemic lupus erythematosus. J Intensive Care. 2015;7(3):10. 16. Hochberg MC. Updating the American College of Rheumatology revised Competing interests criteria for the classification of systemic lupus erhytematosus. Arthrits The authors declare that they have no competing interests. Rheum. 1997;40:1725. 17. Silva CA, Avcin T, Brunner HI. Taxonomy for systemic lupus erythematosus with onset before adulthood. Arthritis Care Res (Hoboken). 2012;64:1787–93. Publisher’sNote 18. Marques VL, Gormezano NW, Bonfá E, Aikawa NE, Terreri MT, Pereira RM, Springer Nature remains neutral with regard to jurisdictional claims in et al. Pancreatitis subtypes survey in 852 childhood-onset systemic lupus published maps and institutional affiliations. erythematosus patients. J Pediatr Gastroenterol Nutr. 2016;62:328–34. 19. Gladman DD, Ibañez D, Urowitz MB. Systemic lupus erythematosus disease Author details activity index 2000. J Rheumatol. 2002;29:288–91. Pediatric Rheumatology Unit, Children’s Institute, Faculdade de Medicina da 20. American College of Rheumatology Ad Hoc committee on neuropsychiatric Universidade de São Paulo (FMUSP), Av. Dr. Eneas Carvalho Aguiar, 647 - Lupus Syndromes. The American College of Rheumatology nomenclature Cerqueira César, São Paulo, SP 05403-000, Brazil. Pediatric Pulmonology Unit, and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum. Children’s Institute, FMUSP, Av. Dr. Eneas Carvalho Aguiar, 647 - Cerqueira 1999;42:599–608. César, São Paulo, SP 05403-000, Brazil. Division of Rheumatology, FMUSP, 21. Avcin T, Cimaz R, Rozman B. The Ped-APS Registry: the antiphospholipid Sao Paulo, Brazil. Pediatric Rheumatology Unit, Universidade Federal de São syndrome in childhood. Lupus. 2009;18:894–9. Paulo, Sao Paulo, Brazil. São Paulo State University (UNESP), Faculdade de 22. Parodi A, Davì S, Pringe AB, Pistorio A, Ruperto N, Magni-Manzoni S, et al. Medicina de Botucatu, Sao Paulo, Brazil. São Paulo State University of Lupus Working Group of the Paediatric Rheumatology European Society. A Campinas (UNICAMP), Sao Paulo, Brazil. Irmandade da Santa Casa de macrophage activation syndrome in juvenile systemic lupus erythematosus: Misericórdia de São Paulo, Sao Paulo, Brazil. Ribeirão Preto Medical School – a multinational multicenter study of thirty-eight patients. Arthritis Rheum. University of São Paulo, Sao Paulo, Brazil. 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Diffuse alveolar hemorrhage in childhood-onset systemic lupus erythematosus: a severe disease flare with serious outcome

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Medicine & Public Health; Rheumatology
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Abstract

Objective: To evaluate prevalence, clinical manifestations, laboratory abnormalities and treatment in a multicenter cohort study including 847 childhood-onset systemic lupus erythematosus (cSLE) patients with and without diffuse alveolar hemorrhage (DAH), as well as concomitant parameters of severity. Methods: DAH was defined as the presence of at least three respiratory symptoms/signs associated with diffuse interstitial/alveolar infiltrates on chest x-ray or high-resolution computer tomography and sudden drop in hemoglobin levels. Statistical analysis was performed using Bonferroni correction (p < 0.0022). Results: DAH was observed in 19/847 (2.2%) cSLE patients. Cough/dyspnea/tachycardia/hypoxemia occurred in all cSLE patients with DAH. Concomitant parameters of severity observed were: mechanical ventilation in 14/19 (74%), hemoptysis 12/19 (63%), macrophage activation syndrome 2/19 (10%) and death 9/19 (47%). Further analysis of cSLE patients at DAH diagnosis compared to 76 cSLE control patients without DAH with same disease duration [3 (1–151) vs. 4 (1–151) months, p = 0.335], showed higher frequencies of constitutional involvement (74% vs. 10%, p < 0.0001), serositis (63% vs. 6%, p < 0.0001) and sepsis (53% vs. 9%, p < 0.0001) in the DAH group. The median of disease activity score(SLEDAI-2 K) was significantly higher in cSLE patients with DAH [18 (5–40) vs. 6 (0–44), p < 0.0001]. The frequencies of thrombocytopenia (53% vs. 12%, p < 0.0001), intravenous methylprednisolone (95% vs. 16%, p < 0.0001) and intravenous cyclophosphamide (47% vs. 8%, p < 0.0001) were also significantly higher in DAH patients. Conclusions: This was the first study to demonstrate that DAH, although not a disease activity score descriptor, occurred in the context of significant moderate/severe cSLE flare. Importantly, we identified that this condition was associated with serious disease flare complicated by sepsis with high mortality rate. Keywords: Diffuse alveolar hemorrhage, Childhood, Systemic lupus erythematosus, Multicenter study * Correspondence: clovisaasilva@gmail.com Pediatric Rheumatology Unit, Children’s Institute, Faculdade de Medicina da Universidade de São Paulo (FMUSP), Av. Dr. Eneas Carvalho Aguiar, 647 - Cerqueira César, São Paulo, SP 05403-000, Brazil Pediatric Pulmonology Unit, Children’s Institute, FMUSP, Av. Dr. Eneas Carvalho Aguiar, 647 - Cerqueira César, São Paulo, SP 05403-000, Brazil Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Blay et al. Advances in Rheumatology (2018) 58:39 Page 2 of 6 Introduction HRCT, and sudden drop in hemoglobin level at least of Systemic lupus erythematosus (SLE) is a multisystemic 1.5 g/dL [7, 10, 11]. Bronchoalveolar lavage with autoimmune disease characterized by the involvement of hemosiderin-laden macrophages evidence was also several organs and systems [1–3]. Pleuropulmonary recorded [14]. Patients were divided in two groups with manifestations were described as initial feature from 17 similar disease duration: cSLE patients with DAH to 42% childhood-onset SLE (cSLE) patients, particularly (assessed at DAH diagnosis) and cSLE patients without mild to moderate pleuritis [1, 3–5]. These respiratory DAH (assessed at last visit). complications may be classified as acute or chronic [6]. Descriptors and definitions of SLE Disease Activity Of note, diffuse alveolar hemorrhage (DAH) is an Index 2000 (SLEDAI-2 K) score were used to acute, rare and life-threatening pulmonary manifestation characterize disease parameters and to calculate disease characterized by sudden onset of respiratory symptoms, activity score [19]. Custom definitions were defined as such as dyspnea; hypoxemia; hemoptysis; tachycardia previously reported [3, 18]. Neuropsychiatric lupus and/or cough; associated with new lung infiltrates on included 19 syndromes according to ACR classification chest x-ray (CXR) or high-resolution computer tomog- criteria [20]. Antiphospholipid syndrome was diagnosed raphy (HRCT); and sudden drop in serum hemoglobin taking into account the presence of arterial and/or levels [7, 8]. venous thrombosis concomitant to high titers of anti- Data of DAH in cSLE patients are limited due to the phospholipid antibodies [21]. Macrophage activation small representation of this complication in previous syndrome was diagnosed considering the preliminary case series or the focus on the comparison to adult SLE, cSLE diagnostic guidelines, requiring the presence of at precluding an accurate analysis of associated factors and least one clinical plus two laboratorial criteria [22]. outcomes in patients with and without this severe Laboratorial assessment included complete blood cell complication [4, 7–15]. count and urine test. Anti-double-stranded DNA Therefore, the objective of the present multicenter (anti-dsDNA), IgG and IgM anticardiolipin antibodies cohort study was to assess the prevalence and the (aCL) were carried out at each center and the cutoff possible DAH association with demographic, clinical values were considered valid. Lupus anticoagulant was manifestations, laboratory abnormalities, disease activity detected according to the guidelines of the International score, treatments and outcomes in a large cSLE Society on Thrombosis and Hemostasis [23]. population. Drug treatment data (prednisone, intravenous methyl- prednisolone, chloroquine diphosphate, hydroxychloro- Methods quine sulfate, methotrexate, azathioprine, cyclosporine, This was a retrospective multicenter cohort study mycophenolate mofetil, intravenous cyclophosphamide including 1017 patients followed in 10 Pediatric and intravenous gammaglobulin) were also recorded. Rheumatology tertiary referral services in São Paulo state, Brazil. One hundred and sixty five patients were Statistical analysis excluded due to: incomplete medical charts (n = 96), Results were presented as an absolute number undifferentiated connective tissue disorder with 3 or (frequency) for categorical variables and median (range) fewer American College of Rheumatology (ACR) criteria or mean ± standard deviation (SD) for continuous vari- (n = 43), isolated cutaneous lupus erythematosus (n =11), ables. Categorical variables comparisons were assessed neonatal lupus erythematosus (n = 8), drug-induced lupus by Pearson χ-Square or Fisher’s exact test. Continuous (n = 5) and mixed connective tissue disease (n =2). variables from cSLE patients with and without DAH Therefore, this study group comprised 852 cSLE patients. were compared by Mann-Whitney test or t test as All of them fulfilled the ACR criteria for SLE [16], with appropriate. Statistical analysis was performed using disease onset before the age of 18 [17]. Bonferroni correction (p < 0.0022). An investigator meeting was held for protocol training according to the clinical parameters definitions and dis- Results ease activity tool scoring, as previously reported [3, 18]. DAH was observed in 19/847 (2.2%) cSLE patients. Patient’s medical charts were systematically reviewed Cough, dyspnea, tachycardia and hypoxemia occurred in according to demographic data, clinical characteristics, all 19 cSLE patients with DAH; hemoptysis in 12/19 and DAH features, laboratorial abnormalities, therapies and endotracheal tube bleeding in 14/19. New infiltrates on outcomes. CXR or HRCT and hemoglobin drop at least of 1.5 g/dL DAH was defined as the presence of at least three were evidenced in all cSLE patients with DAH (Table 1). respiratory symptoms and signs (dyspnea, hypoxemia, Bronchoalveolar lavage was performed in two cSLE hemoptysis, tachycardia and/or cough) associated with patients and hemosiderin-laden macrophage was diffuse interstitial and/or alveolar infiltrates on CXR or observed in both of them. Blay et al. Advances in Rheumatology (2018) 58:39 Page 3 of 6 Table 1 Demographic, clinical manifestations and imaging in 19 childhood-onset systemic lupus erythematosus (cSLE) patients with diffuse alveolar hemorrhage Patient Disease duration, Months Cough Dyspnoea Tachycardia Hypoxemia Hemoptysis/bleeding in New Infiltrates Drop Hbg/dL endotracheal tube CXR or HRCT 1 60 + + + + + / + + 1.8 2 151 + + + + + / + + 1.5 3 5 + + + + + / + + 2.0 4 0 + + + + + / + + 1.6 5 33 + + + + + / + + 1.9 6 0 + + + + + / + + 2.7 7 3 + + + + + / + + 1.7 8 90 + + + + + / - + 2.5 9 42 + + + + + / + + 4.5 10 4 + + + + + / + + 3.0 11 0 + + + + - / - + 3.2 12 47 + + + + - / + + 1.5 13 5 + + + + - / + + 1.5 14 0 + + + + + / - + 2.0 15 0 + + + + - / + + 7.0 16 0 + + + + - / - + 2.0 17 3 + + + + - / + + 2.0 18 1 + + + + - / - + 1.7 19 0 + + + + + / + + 8.0 CXR Chest x-ray, HRCT High resolution computer tomography, Hb Hemoglobulin, ND Not done Regarding outcomes, hospitalization in pediatric inten- The frequencies of thrombocytopenia (53% vs. 12%, sive care unit occurred in 17/19 cSLE patients with p < 0.0001), intravenous methylprednisolone (95% vs. DAH and mechanical ventilation in 14/19. DAH associ- 16%, p < 0.0001) and intravenous cyclophosphamide ated with sepsis was observed in 10/19 cSLE patients. (47% vs. 8%, p < 0.0001) were also significantly higher Concomitant macrophage activation syndrome was evi- in the former group. The median of prednisone dose denced in 2/19 patients. Death was observed in 9/19 was higher in cSLE patients with DAH compared to cSLE patients. The median duration between DAH onset those without DAH [1.4 (0.3–2) vs. 0.5 (0.03–3) mg/Kg, and death was 2 days (0.5–25). Blood erythrocyte trans- p < 0.0001] (Table 4). fusion and broad-spectrum antibiotics were adminis- tered in all cSLE patients with DAH. Intravenous Discussion methylprednisolone pulse therapy was used in 18/19 This is the largest study to evaluate DAH, a rare and cSLE and intravenous cyclophosphamide in 9/19 acute life-threatening pulmonary manifestation, in cSLE (Table 2). None of them had recurrence of DAH. population. Further comparison between cSLE patients with DAH The multicenter study design with a large cohort of compared to 76 cSLE control patients without DAH children and adolescents patients allowed a more precise with same disease duration [3 (1–151) vs. 4 (1–151) assessment of this rare and severe cSLE respiratory months, p = 0.335], showed significantly higher fre- complication. An investigator meeting was also taken in quencies of constitutional involvement (74% vs. 10%, place to standardize the protocol study in all centers. p < 0.0001), serositis (63% vs. 6%, p < 0.0001) and However, the limitation was the retrospective design sepsis (53% vs. 9%, p < 0.0001) in the former group. with potential missing data. The median of SLEDAI-2 K was significantly higher The prevalence of DAH in cSLE patients in the in cSLE patients with DAH compared to cSLE present study was similar to other reports, varying from patients without this complication [18 (5–40) vs. 6 2to 5% [6, 7, 24]. Diagnosis of this condition included (0–44), p < 0.0001]. Frequencies of nephritis and the typical respiratory symptoms and signs, drop in neuropsychiatric involvements were similar in both hemoglobin levels and the radiographic evidence of groups (p > 0.0022) (Table 3). pulmonary infiltrates, as well as the assessment of Blay et al. Advances in Rheumatology (2018) 58:39 Page 4 of 6 Table 2 Outcomes and immunosuppressive treatment in 19 childhood-onset systemic lupus erythematosus (cSLE) patients with diffuse alveolar hemorrhage Patient ICU Mechanical ventilation Sepsis MAS Death IV methylprednisolone IV cyclophosphamide pulse therapy 1+ + + – ++ – 2+ + + –– ++ 3+ + + – ++ – 4+ + + –– ++ 5+ + –– ++ – 6+ + –– – ++ 7+ + + – ++ + 8+ – + – ++ + 9+ + –– ++ – 10 + + –– – ++ 11 + –– – – + – 12 + + – ++ + – 13 + + –– + –– 14 + – + –– ++ 15 + + + + – ++ 16 –– + –– + – 17 + + + –– ++ 18 –– – – – + – 19 + + –– ++ – ICU Intensive care unit, MAS Macrophage activation syndrome, IV Intravenous Table 3 Demographic data, clinical manifestations and disease activity score in childhood-onset systemic lupus erythematosus (cSLE) patients according to the presence of diffuse alveolar hemorrhage (DAH) Variables With DAH (at diagnosis) Without DAH (at last visit) P (n = 19) (n = 76) Demographic data Female gender 14 (74) 66 (87) 0.172 Disease duration, months 3 (1–151) 4 (1–151) 0.335 Current age, years 13 (9–18) 13 (3–23) 0.889 Current clinical manifestations Constitutional 14 (74) 8 (10) < 0.0001* Mucocutaneous 9 (47) 31 (41) 0.614 Musculoskeletal 5 (26) 8 (10) 0.127 Serositis 12 (63) 5 (6) < 0.0001* Neuropsychiatric 4 (21) 11 (14) 0.491 Nephritis 16 (84) 42 (55) 0.033 Current autoimmune thrombosis (APS), n = 90 0/16 (0) 1/74 (1) 1.000 Sepsis 10 (53) 7 (9) < 0.0001* Macrophage activation syndrome 2 (10) 2 (3) 0.113 Death, n = 94 9 (47) 15/75 (20) 0.020 Current disease activity SLEDAI-2 K, n =82 18 (5–40) 6 (0–44) < 0.0001* *P-value according to Bonferroni correction for multiple comparisons (p < 0.0022). Results are presented in n (%) and median (range), APS Antiphospholipid syndrome, SLEDAI-2 K Systemic Lupus Erythematosus Disease Activity Index 2000 Blay et al. Advances in Rheumatology (2018) 58:39 Page 5 of 6 Table 4 Current laboratory tests and drug therapy of childhood-onset systemic lupus erythematosus (cSLE) according to the presence of diffuse alveolar hemorrhage (DAH) Variables With DAH (at diagnosis) Without DAH (at last visit) P (n = 19) (n = 76) Current laboratory exams Autoimmune hemolytic anemia 5 (26) 8 (10) 0.127 Thrombocytopenia, < 150,000/mm , n = 93 10 (52) 9/74 (12) < 0.0001* Anti-ds-DNA, n = 75 8/13 (61) 30/62 (48) 0.544 Drug therapy Prednisone current dose, mg/Kg, n = 82 1.4 (0.3–2) 0.5 (0.03–3) < 0.0001* Intravenous methylprednisolone 18 (95) 12 (15) < 0.0001* Antimalarial drugs 14 (74) 41 (54) 0.193 Azathioprine 2 (10) 16 (21) 0.513 Mycophenolate mofetil 1 (5) 5 (6) 1.000 Intravenous cyclophosphamide 9 (47) 6 (8) < 0.0001* *P-value according to Bonferroni correction for multiple comparisons (p < 0.0022). Results are presented in n (%) and median (range), anti-ds-DNA – anti-double- stranded DNA antibodies hypoxemia due to acute respiratory distress [7]. In empirical antibiotics and mechanical ventilation are addition, in two of our cSLE patients the presence of therefore essential to improve cSLE outcome [6, 7]. haemosiderin-laden macrophages in the absence of bloody fluid suggested recent bleeding [6], analyzed by Conclusion the bronchoalveolar lavage. This was the first study to demonstrate that DAH, We demonstrated that DAH, although not a disease although not a disease activity score descriptor, occurs activity score descriptor of SLEDAI-2 K [19], was associ- in the context of significant moderate/severe cSLE flare. ated with high moderate or severe disease activity scores, Importantly, we identified that this condition is associ- particularly thrombocytopenia, serositis and constitu- ated with serious disease flare complicated by sepsis and tional involvement. In contrast to previous reports DAH high mortality rate. was not associated with lupus nephritis [13]. Acknowledgements Of note, we identified that DAH was a severe Our gratitude to Ulysses Doria-Filho for the statistical analysis. The authors manifestation requiring pediatric intensive care unit thank the following Pediatric Rheumatology Divisions and colleagues for including their patients: Children’s Institute, FMUSP (Marco F. Silva, Mariana hospitalization and mechanical ventilation for the vast Ferriani, Roberta C. Gomes, Victor L. Marques, Gabriella E. Lube, Sandra R. M. majority of our patients. We extended previous observa- Lopes, Glaucia V. Novak, Beatriz C. Molinari, Clarissa C. Valões, Verena Balbi, tion of high frequency of severe infection in adults/cSLE João D. Montoni, Laila P. Coelho, Luciana S. Henriques, Pedro Anuardo, Monica Verdier, Juliana B. Brunelli, Adriana A. Jesus, Antonio C. Pastorino, patients with DAH [7], thus demonstrating the cata- Heloisa H. Marques, Andrea Watanabe, Benita G. Schvartsman, Maria H. strophic nature of DAH, since more than half of cSLE Vaisbich, Werther B. Carvalho, Magda Carneiro-Sampaio, Vicente Odone- patients developed concomitant sepsis. Filho); Division of Rheumatology, FMUSP (Juliane A. Paupitz, Glauce L. Lima, Ana Paula L. Assad); UNIFESP (Maria O. E. Hilário, Andreia S. Lopes, Aline Reinforcing this finding of poor outcome, 10% of the Alencar, Daniela P. Piotto, Giampaolo Faquin); UNESP (Priscila R. Aoki, Juliana cSLE patients were diagnosed with concomitant O. Sato, Silvana P. Cardin); Irmandade da Santa Casa de Misericórdia de São macrophage activation syndrome. In fact, this is a rare Paulo (Andressa Guariento, Eunice Okuda, Maria Carolina dos Santos); UNICAMP (Maraísa Centeville, Renata Barbosa, Simone Appenzeller); Ribeirão condition characterized by an excessive activation and Preto Medical School, FMUSP (Paola P. Kahwage, Gecilmara Pileggi, Francisco proliferation of T lymphocytes and macrophages with Hugo Gomes, Virginia Ferriani), Hospital Infantil Darcy Vargas (Jonatas Libório, massive hypersecretion of proinflammatory cytokines, Cássia Barbosa, Luciana T. P. Paulo); Hospital Municipal Infantil Menino Jesus (Simone Lotufo). and may induce severe hemorraghae [25, 26]. We observed a high mortality rate in cSLE patients Funding with DAH, as also observed in other studies [6, 10, 11]. This study was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq 301805/2013–0 to RMRP, This unfavorable outcome revealed that sepsis and 303752/2015–7 to MTT, 301479/2015–1 to CSM, 305068/2014–8 to EB and macrophage activation syndrome may have 303422/2015–7 to CAS), Federico Foundation (to EB, RMRP and CAS) and by contributed to the death of more than half of the Núcleo de Apoio à Pesquisa “Saúde da Criança e do Adolescente” da USP (NAP-CriAd) to CAS. patients. 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