Azathioprine hypersensitivity syndrome in anti-myeloperoxidase anti-neutrophil cytoplasmic antibody-associated vasculitis

Azathioprine hypersensitivity syndrome in anti-myeloperoxidase anti-neutrophil cytoplasmic... Clinical Kidney Journal, 2018, 1–3 doi: 10.1093/ckj/sfy038 Exceptional Case EX C EPT I O NA L C A S E Azathioprine hypersensitivity syndrome in anti-myeloperoxidase anti-neutrophil cytoplasmic antibody-associated vasculitis 1, 1, 2 Robert Greite *, Konstantin Deutsch *, Jan Hinrich Bra ¨ sen and Sibylle von Vietinghoff Department of Internal Medicine, Division of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany and Institute for Pathology, Hannover Medical School, Hannover, Germany Correspondence and offprint requests to: Sibylle von Vietinghoff; E-mail: vonVietinghoff.Sibylle@mh-hannover.de *These authors contributed equally to this work ABSTRACT Two patients with anti-neutrophil cytoplasmic antibody–associated vasculitis (AAV) and rapid onset of high fever, tachycardia and systemic hypotension accompanied by elevated laboratory markers of infection were diagnosed with azathioprine hypersensitivity syndrome only after repeat exposure. Azathioprine hypersensitivity can closely mimic sepsis and/or vasculitis activity and should be considered in AAV, a condition with frequent use of this drug. We discuss the pitfalls in diagnosis and the possible pathophysiologic background. Keywords: ANCA vasculitis, azathioprine, fever, relaps, sepsis cancer, arterial hypertension, aortic aneurysm and plaque psoria- BACKGROUND sis was diagnosed with renal anti-myeloperoxidase AAV Infectious complications of immunosuppressive therapy and [Figure 1A, initial Birmingham Vasculitis Activity Score (BVAS) vasculitis activity are the main causes of death in patients early 14]. Therapy with intravenous cyclophosphamide (cumulative after diagnosis of anti-neutrophil cytoplasmic antibody–associ- dose 6.2 g) stabilized the glomerular filtration rate (GFR) ated vasculitis (AAV) [1]. Azathioprine is part of the standard (Figure 1B). His course was complicated by a spinal fracture sus- maintenance regimen in this condition [2]. We here report two tained when jumping from a burning building, necessitating in- cases where azathioprine hypersensivity syndrome closely sertion of foreign materials for stabilization. Two weeks after he mimicked complications of vasculitis leading to intensive care was started on azathioprine maintenance therapy, he presented unit (ICU) admissions and significant disease burden. in the emergency room (ER) with diarrhoea. He admitted to not regularly taking either azathioprine or corticosteroid. On exami- nation, he was incompletely oriented to time and situation and Case 1 febrile (38.4 C), with blood pressure of 90/50 mmHg, heart rate A 64-year-old man with acute renal failure and known chronic 193/min and arrhythmic. A papular, indolent rash was noted on kidney disease (CKD) after partial nephrectomy for renal cell all limbs. Physical examination of the lungs and spinal column Received: 7.2.2018. Editorial decision: 2.4.2018 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy038/5001771 by Ed 'DeepDyve' Gillespie user on 12 July 2018 2| R. Greite et al. FIGURE 1: Clinical course and results of renal biopsy. (A–C) Patient 1 received a diagnosis of AAV from a renal biopsy showing necrotizing crescentic glomerulonephritis [(A) Jones haematoxylin and eosin stain, 60 original magnification] and was subsequently treated with cyclophosphamide boli (B). Repeat biopsy at the time of acute clinical presentation yielded persistent vasculitis activity and additionally aggressive tubulointerstitial disease [(C) periodic acid–Schiff stain, 40 and 60 original magnification]. Major elevations of creatinine and CRP were noted at the times of azathioprine exposure and clinical hypersensitivity. (D) Patient 2 similarly responded with CRP and creatinine elevations to azathioprine exposure. was unremarkable; neither meningism nor focal neurological ab- patient presented with fever (40.7 C), tachycardia (105/min) and normalities were noted. Laboratory values showed an elevated tachypnoea (24/min) in the ER. CRP and procalcitonin (3.6 mg/L) relative neutrophil count (88.7%), C-reactive protein (CRP) and were significantly elevated. Acute renal failure was diagnosed procalcitonin (204 mg/L). Serum creatinine had risen markedly (Figure 1D). Antibiotic treatment with piperacillin-tazobactam (Figure 1B). The patient was admitted to the ICU for circulatory and moxifloxacin was started and azathioprine was held for a management and received antibiotic therapy with piperacillin/ suspected bacterial infection. Chest X-ray, abdominal ultra- tazobactam and metronidazole for suspected enteral infection sound and echocardiography showed no signs of infection. On and sepsis plus high-dose steroids for a suspected relapse of vas- Day 2 he developed generalized exanthema. Microbiological culitis. He improved rapidly and was transferred to the general testing remained negative and he was discharged 1 week later. ward, where he underwent repeat renal biopsy 4 days later Azathioprine was restarted on Day 17. Approximately 2 (Figure 1C). Active vasculitis and aggressive tubulointerstitial in- h later he was readmitted to the ER with nausea, thoracic wall flammation were seen. Cyclophosphamide was administered exanthema, fever (39 C), hypotension (98/52 mmHg), tachycar- along with five courses of plasma exchange. Renal function im- dia (99/min) and tachypnoea (19/min). He was in acute renal proved while receiving monthly intravenous cyclophosphamide failure. CRP and procalcitonin (384 mg/L) were again markedly el- and de-escalation of therapy was planned. One day after taking evated. The patient was transferred to the ICU and received re- the first dose of azathioprine he was found by his sister in a con- nal replacement therapy for hyperkalaemia. Microbiological fused and dishevelled state and admitted to the ER for suspected testing was again negative. A diagnosis of azathioprine hyper- intoxication. On examination, he was aphasic and disoriented sensitivity was made. After a 5-month follow-up period, he is without meningism. Atrial fibrillation with a heart rate up to 180/ well with rituximab maintenance therapy and his renal func- min was noted, his blood pressure was 147/100 mmHg and his tion has returned to baseline (Figure 1D). temperature was mildly elevated at 37.8 C. Laboratory results showed no ethanol, elevated CRP, procalcitonin (31.5 mg/L) and an increase in creatinine (Figure 1B). Cerebral computed tomogra- DISCUSSION phy, magnetic resosnance imaging and electroencephalography yielded no pathologic results. He was admitted to the stroke unit Idiosyncratic effects of azathioprine therapy occur indepen- and treated with ampicillin/sulbactam for suspected infection. dently of dose with an incidence of one in six (5%) [3]. His rhythm spontaneously converted to normofrequent sinus Azathioprine hypersensitivity is independent of hepato- and rhythm and he regained the ability to speak and write over the myelotoxicity, which were absent in our patients and others ensuing 48 h. A diagnosis of azathioprine hypersensitivity syn- (Supplementary data, Table S1). Diagnosis is by exclusion of drome was made. Maintenance immunosuppression was other causes and improvement after drug withdrawal [4]. switched to mycophenolate, then rituximab, with limited suc- Azathioprine is initially metabolized into 6-mercaptopurine cess. He died 6 months later at home. (6-MP) and methylnitroimidazole. The 6-MP is further metabo- lized by hypoxanthine phosphoribosyl transferase to 6-thiogua- Case 2 nine nucleotides [5]. These nucleotides are responsible for drug action and the dose-dependent side effects. Further metabolism A 49-year-old man diagnosed with rapid progressive glomerulo- of 6-MP by thiopurine methyltransferase (TPMT) and xanthine nephritis due to anti-MPO AAV on kidney biopsy (initial BVAS oxidase (XO) results in inactive metabolites. Low TPMT activity 16) was started on azathioprine for maintenance therapy or XO inhibition are associated with increased toxicity. TPMT (100 mg/d) after six courses of intravenous cyclophosphamide polymorphisms can be determined prior to treatment. However, (cumulative dose 7 g). His past medical history was significant for excessive leg swelling after insect stings. After 7 days, the hypersensitivity has been linked to the imidazole side chain Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy038/5001771 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Azathioprine hypersensitivity syndrome | 3 rather than TPMT, as 6-MP lacking the imidazole side chain has not yet not caused such reactions [5, 6]. Azathioprine hypersensitivity in AAV is frequently diag- nosed only after re-exposure to the drug (Supplementary data, Table S1), also because of overlapping features with both active vasculitis and sepsis, two very common conditions during the first year after diagnosis of vasculitis [1]. Table 1 shows some characteristics that may aid in discriminating these entities. Features that favour hypersensitivity include onset within days of azathioprine administration, marked elevation of laboratory markers of sepsis in the absence of a clinical focus or positive bacterial cultures and stable or declining ANCA titres. However, there is no diagnostic test for azathioprine hypersensitivity. Even renal biopsy may not always determine the diagnosis and indeed, in our first patient, even suggested coexistence of vas- culitis activity and hypersensitivity. However, increased aware- ness of this rare side effect of azathioprine may improve the care of patients with this condition. SUPPLEMENTARY DATA Supplementary data are available at ckj online. CONFLICT OF INTEREST STATEMENT None declared. REFERENCES 1. Flossmann O, Berden A, de Groot K et al. Long-term patient survival in ANCA-associated vasculitis. Ann Rheum Dis 2011; 70: 488–494 2. Jennette JC, Nachman PH. ANCA glomerulonephritis and vas- culitis. Clin J Am Soc Nephrol 2017; 12: 1680–1691 3. de Boer NK, van Bodegraven AA, Jharap B et al. Drug insight: pharmacology and toxicity of thiopurine therapy in patients with IBD. Nat Clin Pract Gastroenterol Hepatol 2007; 4: 686–694 4. Bidinger JJ, Sky K, Battafarano DF et al. The cutaneous and sys- temic manifestations of azathioprine hypersensitivity syn- drome. J Am Acad Dermatol 2011; 65: 184–191 5. LiuY-P, XuH-Q, LiM et al. Association between thiopurine S-methyltransferase polymorphisms and azathioprine-induced adverse drug reactions in patients with autoimmune diseases: a meta-analysis. PLoS One 2015; 10: e0144234 6. Godeau B, Paul M, Autegarden JE et al. Hypersensitivity to aza- thioprine mimicking gastroenteritis. Absence of recurrence with 6-mercaptopurine. Gastroenterol Clin Biol 1995; 19: 117–119 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy038/5001771 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 1. Clinical constellations that may aid differential diagnosis of vasculitis activity, sepsis and azathioprine hypersensitivity Clinical signs Laboratory values Acute renal Serum markers Time of onset failure Nausea and Atrial Urinary Bacterial (typical) Fever (histology) vomiting Rash fibrillation Leucocytosis sediment cultures CRP PCT ANCA Vasculitis activity After reduction of (") Frequent Rare Common Rare Rare, Red cell " – ¼/" immunosuppression (crescentic (petechial, usually casts, glomerulonephritis) vasculitic) mild acanthocytes Sepsis During induction " Frequent Infrequent Infrequent Rare "" Unspecific Frequentlyþ"" " ¼/# therapy (prerenal, findings acute tubular necrosis) Azathioprine Days after start of " Frequent Common Common Frequent "" Unspecific "" "" ¼/# hypersensitivity azathioprine therapy, (acute interstitial (neutrophilic findings within hours after nephritis) dermatitis) re-exposure PCT, procalcitonin. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Kidney Journal Oxford University Press

Azathioprine hypersensitivity syndrome in anti-myeloperoxidase anti-neutrophil cytoplasmic antibody-associated vasculitis

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Abstract

Clinical Kidney Journal, 2018, 1–3 doi: 10.1093/ckj/sfy038 Exceptional Case EX C EPT I O NA L C A S E Azathioprine hypersensitivity syndrome in anti-myeloperoxidase anti-neutrophil cytoplasmic antibody-associated vasculitis 1, 1, 2 Robert Greite *, Konstantin Deutsch *, Jan Hinrich Bra ¨ sen and Sibylle von Vietinghoff Department of Internal Medicine, Division of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany and Institute for Pathology, Hannover Medical School, Hannover, Germany Correspondence and offprint requests to: Sibylle von Vietinghoff; E-mail: vonVietinghoff.Sibylle@mh-hannover.de *These authors contributed equally to this work ABSTRACT Two patients with anti-neutrophil cytoplasmic antibody–associated vasculitis (AAV) and rapid onset of high fever, tachycardia and systemic hypotension accompanied by elevated laboratory markers of infection were diagnosed with azathioprine hypersensitivity syndrome only after repeat exposure. Azathioprine hypersensitivity can closely mimic sepsis and/or vasculitis activity and should be considered in AAV, a condition with frequent use of this drug. We discuss the pitfalls in diagnosis and the possible pathophysiologic background. Keywords: ANCA vasculitis, azathioprine, fever, relaps, sepsis cancer, arterial hypertension, aortic aneurysm and plaque psoria- BACKGROUND sis was diagnosed with renal anti-myeloperoxidase AAV Infectious complications of immunosuppressive therapy and [Figure 1A, initial Birmingham Vasculitis Activity Score (BVAS) vasculitis activity are the main causes of death in patients early 14]. Therapy with intravenous cyclophosphamide (cumulative after diagnosis of anti-neutrophil cytoplasmic antibody–associ- dose 6.2 g) stabilized the glomerular filtration rate (GFR) ated vasculitis (AAV) [1]. Azathioprine is part of the standard (Figure 1B). His course was complicated by a spinal fracture sus- maintenance regimen in this condition [2]. We here report two tained when jumping from a burning building, necessitating in- cases where azathioprine hypersensivity syndrome closely sertion of foreign materials for stabilization. Two weeks after he mimicked complications of vasculitis leading to intensive care was started on azathioprine maintenance therapy, he presented unit (ICU) admissions and significant disease burden. in the emergency room (ER) with diarrhoea. He admitted to not regularly taking either azathioprine or corticosteroid. On exami- nation, he was incompletely oriented to time and situation and Case 1 febrile (38.4 C), with blood pressure of 90/50 mmHg, heart rate A 64-year-old man with acute renal failure and known chronic 193/min and arrhythmic. A papular, indolent rash was noted on kidney disease (CKD) after partial nephrectomy for renal cell all limbs. Physical examination of the lungs and spinal column Received: 7.2.2018. Editorial decision: 2.4.2018 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy038/5001771 by Ed 'DeepDyve' Gillespie user on 12 July 2018 2| R. Greite et al. FIGURE 1: Clinical course and results of renal biopsy. (A–C) Patient 1 received a diagnosis of AAV from a renal biopsy showing necrotizing crescentic glomerulonephritis [(A) Jones haematoxylin and eosin stain, 60 original magnification] and was subsequently treated with cyclophosphamide boli (B). Repeat biopsy at the time of acute clinical presentation yielded persistent vasculitis activity and additionally aggressive tubulointerstitial disease [(C) periodic acid–Schiff stain, 40 and 60 original magnification]. Major elevations of creatinine and CRP were noted at the times of azathioprine exposure and clinical hypersensitivity. (D) Patient 2 similarly responded with CRP and creatinine elevations to azathioprine exposure. was unremarkable; neither meningism nor focal neurological ab- patient presented with fever (40.7 C), tachycardia (105/min) and normalities were noted. Laboratory values showed an elevated tachypnoea (24/min) in the ER. CRP and procalcitonin (3.6 mg/L) relative neutrophil count (88.7%), C-reactive protein (CRP) and were significantly elevated. Acute renal failure was diagnosed procalcitonin (204 mg/L). Serum creatinine had risen markedly (Figure 1D). Antibiotic treatment with piperacillin-tazobactam (Figure 1B). The patient was admitted to the ICU for circulatory and moxifloxacin was started and azathioprine was held for a management and received antibiotic therapy with piperacillin/ suspected bacterial infection. Chest X-ray, abdominal ultra- tazobactam and metronidazole for suspected enteral infection sound and echocardiography showed no signs of infection. On and sepsis plus high-dose steroids for a suspected relapse of vas- Day 2 he developed generalized exanthema. Microbiological culitis. He improved rapidly and was transferred to the general testing remained negative and he was discharged 1 week later. ward, where he underwent repeat renal biopsy 4 days later Azathioprine was restarted on Day 17. Approximately 2 (Figure 1C). Active vasculitis and aggressive tubulointerstitial in- h later he was readmitted to the ER with nausea, thoracic wall flammation were seen. Cyclophosphamide was administered exanthema, fever (39 C), hypotension (98/52 mmHg), tachycar- along with five courses of plasma exchange. Renal function im- dia (99/min) and tachypnoea (19/min). He was in acute renal proved while receiving monthly intravenous cyclophosphamide failure. CRP and procalcitonin (384 mg/L) were again markedly el- and de-escalation of therapy was planned. One day after taking evated. The patient was transferred to the ICU and received re- the first dose of azathioprine he was found by his sister in a con- nal replacement therapy for hyperkalaemia. Microbiological fused and dishevelled state and admitted to the ER for suspected testing was again negative. A diagnosis of azathioprine hyper- intoxication. On examination, he was aphasic and disoriented sensitivity was made. After a 5-month follow-up period, he is without meningism. Atrial fibrillation with a heart rate up to 180/ well with rituximab maintenance therapy and his renal func- min was noted, his blood pressure was 147/100 mmHg and his tion has returned to baseline (Figure 1D). temperature was mildly elevated at 37.8 C. Laboratory results showed no ethanol, elevated CRP, procalcitonin (31.5 mg/L) and an increase in creatinine (Figure 1B). Cerebral computed tomogra- DISCUSSION phy, magnetic resosnance imaging and electroencephalography yielded no pathologic results. He was admitted to the stroke unit Idiosyncratic effects of azathioprine therapy occur indepen- and treated with ampicillin/sulbactam for suspected infection. dently of dose with an incidence of one in six (5%) [3]. His rhythm spontaneously converted to normofrequent sinus Azathioprine hypersensitivity is independent of hepato- and rhythm and he regained the ability to speak and write over the myelotoxicity, which were absent in our patients and others ensuing 48 h. A diagnosis of azathioprine hypersensitivity syn- (Supplementary data, Table S1). Diagnosis is by exclusion of drome was made. Maintenance immunosuppression was other causes and improvement after drug withdrawal [4]. switched to mycophenolate, then rituximab, with limited suc- Azathioprine is initially metabolized into 6-mercaptopurine cess. He died 6 months later at home. (6-MP) and methylnitroimidazole. The 6-MP is further metabo- lized by hypoxanthine phosphoribosyl transferase to 6-thiogua- Case 2 nine nucleotides [5]. These nucleotides are responsible for drug action and the dose-dependent side effects. Further metabolism A 49-year-old man diagnosed with rapid progressive glomerulo- of 6-MP by thiopurine methyltransferase (TPMT) and xanthine nephritis due to anti-MPO AAV on kidney biopsy (initial BVAS oxidase (XO) results in inactive metabolites. Low TPMT activity 16) was started on azathioprine for maintenance therapy or XO inhibition are associated with increased toxicity. TPMT (100 mg/d) after six courses of intravenous cyclophosphamide polymorphisms can be determined prior to treatment. However, (cumulative dose 7 g). His past medical history was significant for excessive leg swelling after insect stings. After 7 days, the hypersensitivity has been linked to the imidazole side chain Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy038/5001771 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Azathioprine hypersensitivity syndrome | 3 rather than TPMT, as 6-MP lacking the imidazole side chain has not yet not caused such reactions [5, 6]. Azathioprine hypersensitivity in AAV is frequently diag- nosed only after re-exposure to the drug (Supplementary data, Table S1), also because of overlapping features with both active vasculitis and sepsis, two very common conditions during the first year after diagnosis of vasculitis [1]. Table 1 shows some characteristics that may aid in discriminating these entities. Features that favour hypersensitivity include onset within days of azathioprine administration, marked elevation of laboratory markers of sepsis in the absence of a clinical focus or positive bacterial cultures and stable or declining ANCA titres. However, there is no diagnostic test for azathioprine hypersensitivity. Even renal biopsy may not always determine the diagnosis and indeed, in our first patient, even suggested coexistence of vas- culitis activity and hypersensitivity. However, increased aware- ness of this rare side effect of azathioprine may improve the care of patients with this condition. SUPPLEMENTARY DATA Supplementary data are available at ckj online. CONFLICT OF INTEREST STATEMENT None declared. REFERENCES 1. Flossmann O, Berden A, de Groot K et al. Long-term patient survival in ANCA-associated vasculitis. Ann Rheum Dis 2011; 70: 488–494 2. Jennette JC, Nachman PH. ANCA glomerulonephritis and vas- culitis. Clin J Am Soc Nephrol 2017; 12: 1680–1691 3. de Boer NK, van Bodegraven AA, Jharap B et al. Drug insight: pharmacology and toxicity of thiopurine therapy in patients with IBD. Nat Clin Pract Gastroenterol Hepatol 2007; 4: 686–694 4. Bidinger JJ, Sky K, Battafarano DF et al. The cutaneous and sys- temic manifestations of azathioprine hypersensitivity syn- drome. J Am Acad Dermatol 2011; 65: 184–191 5. LiuY-P, XuH-Q, LiM et al. Association between thiopurine S-methyltransferase polymorphisms and azathioprine-induced adverse drug reactions in patients with autoimmune diseases: a meta-analysis. PLoS One 2015; 10: e0144234 6. Godeau B, Paul M, Autegarden JE et al. Hypersensitivity to aza- thioprine mimicking gastroenteritis. Absence of recurrence with 6-mercaptopurine. Gastroenterol Clin Biol 1995; 19: 117–119 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy038/5001771 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Table 1. Clinical constellations that may aid differential diagnosis of vasculitis activity, sepsis and azathioprine hypersensitivity Clinical signs Laboratory values Acute renal Serum markers Time of onset failure Nausea and Atrial Urinary Bacterial (typical) Fever (histology) vomiting Rash fibrillation Leucocytosis sediment cultures CRP PCT ANCA Vasculitis activity After reduction of (") Frequent Rare Common Rare Rare, Red cell " – ¼/" immunosuppression (crescentic (petechial, usually casts, glomerulonephritis) vasculitic) mild acanthocytes Sepsis During induction " Frequent Infrequent Infrequent Rare "" Unspecific Frequentlyþ"" " ¼/# therapy (prerenal, findings acute tubular necrosis) Azathioprine Days after start of " Frequent Common Common Frequent "" Unspecific "" "" ¼/# hypersensitivity azathioprine therapy, (acute interstitial (neutrophilic findings within hours after nephritis) dermatitis) re-exposure PCT, procalcitonin.

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Clinical Kidney JournalOxford University Press

Published: May 23, 2018

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