- Email: [email protected]
Association of Autism with Cancer
Translating Best Evidence into Best Care EDITOR’S NOTE: Studies for this issue were identified using the Clinical Queries feature of PubMed, “hand” searching JAMA Pediatrics, Pediatrics, and The Journal of Pediatrics, and from customized EvidenceUpdates alerts. EBM PEARL: STANDARDIZED INCIDENCE RATIO (SIR) AND EXCESS ABSOLUTE RISK: The SIR is the number of people with a particular disease in a specific population relative to what would be the number with that disease expected in a similar population (age, sex, calendar year, over a specific period of time). The expected number is calculated by multiplying the number of affected individuals in the general population per person-years of follow-up time, by the person-years of follow-up time in the cohort. In the study by Chiang et al (J Pediatr 2015;166:418-23), there were 20 patients with autistim disorder with cancer. The expected number, adjusted for the number of person years of follow-up was 10.31. The ratio of these two numbers, 20/ 10.31=1.94 is the SIR. The excess absolute risk is the difference of 20 and 10.31 divided by the personyears of follow-up time in the cohort: (20-10.31)/76,332 = 0.13 cancers/1000 person-years (see the piece by Blatt on page 208). LITERATURE SEARCH PEARL: SLIDER INTERFACE FOR MEDLINE (SLIM): SLIM is quick way to search PubMed (http://www.ncbi.nlm.nih.gov/pubmed) by allowing for easy limit adjustment employing a slide-rule interface for each adjustment. The standard limits are represented, such as age, publication date, and citations to display. In addition, the methodologic quality filters have been included (the same ones as in the “clinical queries” section of PubMed), as well as one’s choice of MeSH term application to the search. A “preview count” button gives quick feedback on how many citations were retrieved, without actually loading the citations until the “search” button is pressed. The SLIM search engine may be found at https://pmi.nlm.nih.gov/slim/ and is a quick approach to a methodologically high-level search with limits. —Jordan Hupert, MD
Association of Autism with Cancer Chiang HL, Liu CJ, Hu YW, Chen SC, Hu LY, Shen CC, et al. Risk of cancer in children, adolescents, and young adults with autistic disorder. J Pediatr. 2015;166:418-23. Question Among children and adolescents, what is the association of autistic disorder (AD) with cancer? Design Retrospective cohort study. Setting Taiwan National Health Insurance Research Database, Registry for Catastrophic Illness Patients. Participants Children and adolescents with AD enrolled in the databases from 1997 through 2011 at ages 1-20 years. Intervention Analysis of database and registry. Outcomes Number of cancers in patients with AD compared with the expected number. Main Results Cancer occurred more frequently in patients with AD than the total number of expected cancers, with a standardized incidence ratio (SIR) estimate (number of AD patients with cancer divided by the expected number) of 1.94 (95% CI 1.18-2.99). Conclusions Patients with AD have an increased risk of cancer. Commentary This ambitious look at over 8000 children with AD benefited from sample size. However, anonymized
208
database studies can be flawed by the quality of even stringently defined coding diagnoses. Validation of AD can be difficult, with both under- and overdiagnosis, leading to inaccuracies in calculating relative risks of comorbidities.1 Cancer coding is suspect when pathology reports are not reviewed, even if they were the basis for database inclusion. Anatomic coding may have obscured associations with specific tumor types (eg, “ovarian cancers” could have been lymphomas or soft tissue sarcomas). Some histologically benign brain tumors may not have been identified, which may have contributed to the lack of association between these tumors and AD as has been suggested by a prior report.2 Patients in whom a cancer diagnosis preceded that of AD were excluded and may have masked an association in young children. Even assuming that all AD and cancer designations were correct, the high SIR of a child with AD developing cancer did not convey a high excess absolute risk, which was only 0.13/1000 years of subject follow-up more than for population controls.3 Results should be reassuring to families of children with AD, and should not trigger routine surveillance. Julie Blatt, MD University of North Carolina School of Medicine Chapel Hill, North Carolina
Vol. 167, No. 1 July 2015
References 1. Fisch GS. Nosology and epidemiology in autism: classification counts. Am J Med Genet C Semin Med Genet 2012;160C:91-103. 2. Lauritsen MB, Mors O, Mortensen PB, Ewald H. Medical disorders among inpatients with autism in Denmark according to ICD-8: a nationwide register-based study. J Autism Dev Disord 2002;32:115-9. 3. Friedman DL, Whitton J, Leisenring W, Mertens AC, Hammond S, Stovall M, et al. Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst 2010; 102:1083-95.
Early peanut consumption is protective against peanut allergy development Du Toit G, Roberts G, Sayre PH, Bahnson HT, Radulovic S, Santos AF, et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med. 2015;372:80313. Question Among infants at high risk of peanut allergy, what is the therapeutic efficacy of early, compared with late peanut introduction, in the development of peanut allergy? Design Stratified, randomized controlled trial. Setting Single site in the United Kingdom. Participants Infants, 4-10 months of age, at high risk for peanut allergy. Intervention Consume or avoid peanuts until 60 months of age. Outcomes Peanut allergy at 60 months of age. Main Results Peanut allergy decreased among infants who consumed peanuts: number needed to treat, 9 (95% CI, 7 to 14) and 4 (95% CI, 3 to 12), for pre-study skin-prick negative and positive infants, respectively. Conclusions Early introduction of peanuts significantly decreased allergy development. Commentary This trial addresses an observation previously made by the authors,1 that the rate of peanut allergy was 10-fold higher among Jewish children in the UK where peanut generally is avoided in the first year of life, compared with Israeli infants who ingest peanuts routinely. The compelling evidence in the current study supports the hypothesis that earlier introduction is protective. However, the translation of the findings into practice requires reflection. Participants were infants already having illnesses associated with developing peanut allergy, excluding those with stronger positive peanut allergy tests. Indeed, some infants reacted at the medically-supervised first exposure. Should physicians wish to recapitulate the study, attention must be paid to the following: (1) decisions regarding allergy skin testing; (2) supervising the first feeding; (3) instructions for dosing (the impact of different regimens are unknown); (4) addressing whether infants are “dependent” upon regimented peanut ingestion to remain tolerant; and (5) instructions about feeding, as peanuts and peanut butter are choking hazards.
How the results apply to healthy infants is unknown. One could extrapolate that the study supports prior American Academy of Pediatrics2 and American Academy of Allergy, Asthma and Immunology3 conclusions that there is no evidence for avoiding any particular foods, including allergens such as peanut, to healthy infants at risk for allergy who are developmentally ready to ingest solids. Expert panels are working on recommendations based on this study. Scott H. Sicherer, MD Icahn School of Medicine at Mount Sinai New York, New York
References 1. Du Toit G, Katz Y, Sasieni P, Mesher D, Maleki SJ, Fisher HR, et al. Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy. J Allergy Clin Immunol 2008;122:984-91. 2. Greer FR, Sicherer SH, Burks AW. Effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas. Pediatrics 2008;121: 183-91. 3. Fleischer DM, Spergel JM, Assa’ad AH, Pongracic JA. Primary Prevention of Allergic Disease Through Nutritional Interventions. J Allergy Clin Immunology Pract 2013;1:29-36.
Prolonged postconcussive rest is not superior to usual care Thomas DG, Apps JN, Hoffmann RG, McCrea M, Hammeke T. Benefits of strict rest after acute concussion: a randomized controlled trial. Pediatrics 2015;135:213-23. Question Among children and adolescents with concussion, what is the therapeutic benefit of strict rest, compared with the currently recommended moderate stepwise rest approach, in significant post-concussive symptoms? Design Randomized controlled trial. Unclear if outcome assessment was blinded. Setting University of Wisconsin emergency department with follow-up at home or University. Participants Children 11 – 22 years of age diagnosed with concussion, presenting to the emergency department within 24 hours of injury. Intervention Strict rest for 5 days or usual care (stepwise return to activity after symptom resolution). Outcomes Neurocognitive and balance assessments. Main Results There were no clinically significant differences in neurocognitive or balance outcomes. However, the intervention group reported more daily postconcussive symptoms. Conclusions Strict rest immediately after concussion offered no benefit over usual care. Commentary The use of rest as a treatment tool in concussion remains the standard of care1; however, the most 209
THE JOURNAL OF PEDIATRICS
www.jpeds.com
appropriate duration of rest is unclear. This important study examines this issue in patients aged 11-22 years, presenting to a major hospital emergency department. The finding that strict rest for 5 days did not improve outcomes, and may have delayed recovery in some domains, is not surprising, and is consistent with the evolving understanding of concussion. It is now understood that concussion is not necessarily a single entity, but rather a spectrum of conditions, and that symptoms correlate with the primary pathophysiology, such as vestibular, cervical, autonomic, ocular, migrainous or cognitive dysfunction.2 The mainstay of treatment in concussion is a paradigm based on an individualized approach to symptoms and signs. A blanket rest period is inappropriate. Rest should be instituted in the first hours/ days postinjury, with the understanding that symptom evolution commonly occurs during this period. Then, an individualized rehabilitation and recovery program should be developed. Whether this paradigm requires significant modification in children is unresolved, particularly in young children ages 5-10 years. The primary goals in children are symptom management and return to school. Return to play is a secondary goal. To what extent this depends upon rest, rather than physical rehabilitation, is yet to be established. Gavin Davis, MBBS Cabrini Medical Centre, Malvern Victoria, Australia
References 1. McCrory P, Meeuwisse W, Aubry M, Cantu B, Dvorak J, Echemendia R, et al. Consensus statement on concussion in sport: the 4th International Conference on Concussion in Sport held in Zurich, November 2012. Br J Sports Med 2013;47:250-8. 2. Collins MW, Kontos AP, Reynolds E, Murawski CD, Fu FH. A comprehensive, targeted approach to the clinical care of athletes following sport-related concussion. Knee Surg Sports Traumatol Arthrosc 2014; 22:235-46.
Propanolol effectively treats significant infantile hemangiomas Leaute-Labreze C, Hoeger P, Mazereeuw-Hautier J, Guibaud L, Baselga E, Posiunas G, et al. A randomized, controlled trial of oral propranolol in infantile hemangioma. N Engl J Med. 2015;372:735-46. Question Among children with hemangiomas requiring systemic treatment, what is the therapeutic efficacy of propranolol, compared with placebo, in resolution of the hemangioma? Design Randomized control trial. Setting 30 centers in Europe and North America. Participants Infants with hemangiomas requiring therapy. Intervention Oral propranolol versus placebo. 210
Vol. 167, No. 1 Outcomes Resolution or near resolution of the hemangioma after 6 months of treatment. Main Results The frequency of successful treatment was higher with propanolol than with placebo (number needed to treat 2, 95% confidence interval 2, 3). Conclusions Propranolol was effective at a dose of 3 mg per kilogram per day for 6 months in the treatment of infantile hemangioma. Commentary This well-designed, pharmacy-sponsored study enrolled 460 subjects from 30 centers in 16 countries and provided the evidence necessary for Pierre-Fabre Pharmaceuticals, Inc to gain Food and Drug Administration approval of Hemangeol (propranolol hydrochloride; Pierre Fabre Pharmaceuticals, Inc, Parsippany, New Jersey). Several precautions in this study interpretation are notable. Investigators expanded inclusion criteria mid-study to include subjects with asymptomatic, nonfacial infantile hemangiomas in order to improve enrollment. This nonstringent indication should not be expanded to clinical practice and only infants with symptomatic or cosmetic-threatening lesions should be treated. Propranolol is an antiproliferative agent that also may affect replicating nonhemangioma cells in developing infants. Long-term detrimental effects of propranolol may become apparent in the future, in a similar fashion to infants with hemangiomas treated with interferon who later developed spastic diplegia.1 The significance of impaired shortterm memory in propranolol-treated mice is one such potential risk warranting further investigation.2 Clearly, propranolol is efficacious in treating hemangiomas. Whether it merely hastens involution or actually improves the ultimate outcome of involution remains a critical question, as Hemangeol is expensive and not without risk. The investigators of this remarkable study can substantially advance our understanding of hemangioma treatment with a follow-up study of the same subjects comparing the involuted-hemangioma outcome of treated versus untreated patients. Nancy M. Bauman, MD Children’s National Medical Center Washington, DC
References 1. Michaud AP, Bauman NM, Burke DK, Manaligod JM, Smith RJ. Spastic diplegia and other motor disturbances in infants receiving interferonalpha. Laryngoscope 2004;114:1231-6. 2. Sun H, Mao Y, Wang J, Ma Y. Effects of beta-adrenergic antagonist, propranolol, on spatial memory and exploratory behavior in mice. Neurosci Ltr 2011;498:133-7.
Obstructive sleep apnea syndrome is associated with delayed growth Zhang XM, Shi J, Meng GZ, Chen HS, Zhang LN, Wang ZY, et al. The effect of obstructive sleep apnea syndrome on
CURRENT BEST EVIDENCE
July 2015 growth and development in nonobese children: a parallel study of twins. J Pediatr. 2015;166:646-50. Question Among young children, what is the association of growth delay in those with obstructive sleep apnea syndrome (OSAS), versus children without OSAS? Design Identical-twin-sibling case-control. Setting Xinhua Hospital, China. Participants Twins, 3-12 years of age, one of each twin pair with OSAS. Intervention Tonsillectomy and adenoidectomy (T&A) in the affected twin. Outcomes Height and weight before and after (up to 12 months). Main Results The height and weight of the OSAS group before T&A was lower than the control group. During the follow-up period, height and weight increased but were lower than the control group. Serum insulin–like growth factor 1 levels in the OSAS group before T&A were lower than the control group. The level was significantly increased 3 months after T&A. Conclusions OSAS impairs growth. Commentary In children with sleep disordered breathing but without contributing comorbid conditions, T&A can improve and sometimes resolve nocturnal respiratory symptoms, as well as improve daytime symptoms (behavior, cognition, and growth) – though not in all cases. Establishing consequences of untreated sleep disordered breathing and the potential benefits of treatment are complicated by incon-
sistent definitions and criteria for intervention. With growing interest in this area, large multi-institutional studies have been pursued. Marcus et al evaluated 464 children ages 5-9 years with OSAS and found improvement in behavior and quality of life, without significant differences in primary neurocogntive outcomes (executive function and attention) in patients receiving immediate T&A compared with delayed T&A controls.1 Subsequent investigation demonstrated a low risk of postsurgical complications (7% of 221 cases).2 Though a smaller cohort, the twin study by Zhang et al offers strong methodology controlling for potential environmental and genetic contributing factors, and concisely evaluates the impact of OSAS’ on growth through height, weight, and insulin–like growth factor 1 levels. Overall, this study strongly supports T&A to treat pediatric OSAS, thereby improving short-term growth. Pallavi P. Patwari, MD University of Illinois at Chicago Chicago, Illinois
References 1. Marcus CL, Moore RH, Rosen CL, Giordani B, Garetz SL, Taylor HG, et al. A randomized trial of adenotonsillectomy for childhood sleep apnea. N Engl J Med 2013;368:2366-76. 2. Konstantinopoulou S, Gallagher P, Elden L, Garetz SL, Mitchell RB, Redline S, et al. Complications of adenotonsillectomy for obstructive sleep apnea in school-aged children. Int J Pediatr Otorhinolaryngol 2015;79:240-5.
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Association of Autism with Cancer Chiang HL, Liu CJ, Hu YW, Chen SC, Hu LY, Shen CC, et al. Risk of cancer in children, adolescents, and young adults with autistic disorder. J Pediatr. 2015;166:418-23. Question Among children and adolescents, what is the association of autistic disorder (AD) with cancer? Design Retrospective cohort study. Setting Taiwan National Health Insurance Research Database, Registry for Catastrophic Illness Patients. Participants Children and adolescents with AD enrolled in the databases from 1997 through 2011 at ages 1-20 years. Intervention Analysis of database and registry. Outcomes Number of cancers in patients with AD compared with the expected number. Main Results Cancer occurred more frequently in patients with AD than the total number of expected cancers, with a standardized incidence ratio (SIR) estimate (number of AD patients with cancer divided by the expected number) of 1.94 (95% CI 1.18-2.99). Conclusions Patients with AD have an increased risk of cancer. Commentary This ambitious look at over 8000 children with AD benefited from sample size. However, anonymized
208
database studies can be flawed by the quality of even stringently defined coding diagnoses. Validation of AD can be difficult, with both under- and overdiagnosis, leading to inaccuracies in calculating relative risks of comorbidities.1 Cancer coding is suspect when pathology reports are not reviewed, even if they were the basis for database inclusion. Anatomic coding may have obscured associations with specific tumor types (eg, “ovarian cancers” could have been lymphomas or soft tissue sarcomas). Some histologically benign brain tumors may not have been identified, which may have contributed to the lack of association between these tumors and AD as has been suggested by a prior report.2 Patients in whom a cancer diagnosis preceded that of AD were excluded and may have masked an association in young children. Even assuming that all AD and cancer designations were correct, the high SIR of a child with AD developing cancer did not convey a high excess absolute risk, which was only 0.13/1000 years of subject follow-up more than for population controls.3 Results should be reassuring to families of children with AD, and should not trigger routine surveillance. Julie Blatt, MD University of North Carolina School of Medicine Chapel Hill, North Carolina
Vol. 167, No. 1 July 2015
References 1. Fisch GS. Nosology and epidemiology in autism: classification counts. Am J Med Genet C Semin Med Genet 2012;160C:91-103. 2. Lauritsen MB, Mors O, Mortensen PB, Ewald H. Medical disorders among inpatients with autism in Denmark according to ICD-8: a nationwide register-based study. J Autism Dev Disord 2002;32:115-9. 3. Friedman DL, Whitton J, Leisenring W, Mertens AC, Hammond S, Stovall M, et al. Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst 2010; 102:1083-95.
Early peanut consumption is protective against peanut allergy development Du Toit G, Roberts G, Sayre PH, Bahnson HT, Radulovic S, Santos AF, et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med. 2015;372:80313. Question Among infants at high risk of peanut allergy, what is the therapeutic efficacy of early, compared with late peanut introduction, in the development of peanut allergy? Design Stratified, randomized controlled trial. Setting Single site in the United Kingdom. Participants Infants, 4-10 months of age, at high risk for peanut allergy. Intervention Consume or avoid peanuts until 60 months of age. Outcomes Peanut allergy at 60 months of age. Main Results Peanut allergy decreased among infants who consumed peanuts: number needed to treat, 9 (95% CI, 7 to 14) and 4 (95% CI, 3 to 12), for pre-study skin-prick negative and positive infants, respectively. Conclusions Early introduction of peanuts significantly decreased allergy development. Commentary This trial addresses an observation previously made by the authors,1 that the rate of peanut allergy was 10-fold higher among Jewish children in the UK where peanut generally is avoided in the first year of life, compared with Israeli infants who ingest peanuts routinely. The compelling evidence in the current study supports the hypothesis that earlier introduction is protective. However, the translation of the findings into practice requires reflection. Participants were infants already having illnesses associated with developing peanut allergy, excluding those with stronger positive peanut allergy tests. Indeed, some infants reacted at the medically-supervised first exposure. Should physicians wish to recapitulate the study, attention must be paid to the following: (1) decisions regarding allergy skin testing; (2) supervising the first feeding; (3) instructions for dosing (the impact of different regimens are unknown); (4) addressing whether infants are “dependent” upon regimented peanut ingestion to remain tolerant; and (5) instructions about feeding, as peanuts and peanut butter are choking hazards.
How the results apply to healthy infants is unknown. One could extrapolate that the study supports prior American Academy of Pediatrics2 and American Academy of Allergy, Asthma and Immunology3 conclusions that there is no evidence for avoiding any particular foods, including allergens such as peanut, to healthy infants at risk for allergy who are developmentally ready to ingest solids. Expert panels are working on recommendations based on this study. Scott H. Sicherer, MD Icahn School of Medicine at Mount Sinai New York, New York
References 1. Du Toit G, Katz Y, Sasieni P, Mesher D, Maleki SJ, Fisher HR, et al. Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy. J Allergy Clin Immunol 2008;122:984-91. 2. Greer FR, Sicherer SH, Burks AW. Effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas. Pediatrics 2008;121: 183-91. 3. Fleischer DM, Spergel JM, Assa’ad AH, Pongracic JA. Primary Prevention of Allergic Disease Through Nutritional Interventions. J Allergy Clin Immunology Pract 2013;1:29-36.
Prolonged postconcussive rest is not superior to usual care Thomas DG, Apps JN, Hoffmann RG, McCrea M, Hammeke T. Benefits of strict rest after acute concussion: a randomized controlled trial. Pediatrics 2015;135:213-23. Question Among children and adolescents with concussion, what is the therapeutic benefit of strict rest, compared with the currently recommended moderate stepwise rest approach, in significant post-concussive symptoms? Design Randomized controlled trial. Unclear if outcome assessment was blinded. Setting University of Wisconsin emergency department with follow-up at home or University. Participants Children 11 – 22 years of age diagnosed with concussion, presenting to the emergency department within 24 hours of injury. Intervention Strict rest for 5 days or usual care (stepwise return to activity after symptom resolution). Outcomes Neurocognitive and balance assessments. Main Results There were no clinically significant differences in neurocognitive or balance outcomes. However, the intervention group reported more daily postconcussive symptoms. Conclusions Strict rest immediately after concussion offered no benefit over usual care. Commentary The use of rest as a treatment tool in concussion remains the standard of care1; however, the most 209
THE JOURNAL OF PEDIATRICS
www.jpeds.com
appropriate duration of rest is unclear. This important study examines this issue in patients aged 11-22 years, presenting to a major hospital emergency department. The finding that strict rest for 5 days did not improve outcomes, and may have delayed recovery in some domains, is not surprising, and is consistent with the evolving understanding of concussion. It is now understood that concussion is not necessarily a single entity, but rather a spectrum of conditions, and that symptoms correlate with the primary pathophysiology, such as vestibular, cervical, autonomic, ocular, migrainous or cognitive dysfunction.2 The mainstay of treatment in concussion is a paradigm based on an individualized approach to symptoms and signs. A blanket rest period is inappropriate. Rest should be instituted in the first hours/ days postinjury, with the understanding that symptom evolution commonly occurs during this period. Then, an individualized rehabilitation and recovery program should be developed. Whether this paradigm requires significant modification in children is unresolved, particularly in young children ages 5-10 years. The primary goals in children are symptom management and return to school. Return to play is a secondary goal. To what extent this depends upon rest, rather than physical rehabilitation, is yet to be established. Gavin Davis, MBBS Cabrini Medical Centre, Malvern Victoria, Australia
References 1. McCrory P, Meeuwisse W, Aubry M, Cantu B, Dvorak J, Echemendia R, et al. Consensus statement on concussion in sport: the 4th International Conference on Concussion in Sport held in Zurich, November 2012. Br J Sports Med 2013;47:250-8. 2. Collins MW, Kontos AP, Reynolds E, Murawski CD, Fu FH. A comprehensive, targeted approach to the clinical care of athletes following sport-related concussion. Knee Surg Sports Traumatol Arthrosc 2014; 22:235-46.
Propanolol effectively treats significant infantile hemangiomas Leaute-Labreze C, Hoeger P, Mazereeuw-Hautier J, Guibaud L, Baselga E, Posiunas G, et al. A randomized, controlled trial of oral propranolol in infantile hemangioma. N Engl J Med. 2015;372:735-46. Question Among children with hemangiomas requiring systemic treatment, what is the therapeutic efficacy of propranolol, compared with placebo, in resolution of the hemangioma? Design Randomized control trial. Setting 30 centers in Europe and North America. Participants Infants with hemangiomas requiring therapy. Intervention Oral propranolol versus placebo. 210
Vol. 167, No. 1 Outcomes Resolution or near resolution of the hemangioma after 6 months of treatment. Main Results The frequency of successful treatment was higher with propanolol than with placebo (number needed to treat 2, 95% confidence interval 2, 3). Conclusions Propranolol was effective at a dose of 3 mg per kilogram per day for 6 months in the treatment of infantile hemangioma. Commentary This well-designed, pharmacy-sponsored study enrolled 460 subjects from 30 centers in 16 countries and provided the evidence necessary for Pierre-Fabre Pharmaceuticals, Inc to gain Food and Drug Administration approval of Hemangeol (propranolol hydrochloride; Pierre Fabre Pharmaceuticals, Inc, Parsippany, New Jersey). Several precautions in this study interpretation are notable. Investigators expanded inclusion criteria mid-study to include subjects with asymptomatic, nonfacial infantile hemangiomas in order to improve enrollment. This nonstringent indication should not be expanded to clinical practice and only infants with symptomatic or cosmetic-threatening lesions should be treated. Propranolol is an antiproliferative agent that also may affect replicating nonhemangioma cells in developing infants. Long-term detrimental effects of propranolol may become apparent in the future, in a similar fashion to infants with hemangiomas treated with interferon who later developed spastic diplegia.1 The significance of impaired shortterm memory in propranolol-treated mice is one such potential risk warranting further investigation.2 Clearly, propranolol is efficacious in treating hemangiomas. Whether it merely hastens involution or actually improves the ultimate outcome of involution remains a critical question, as Hemangeol is expensive and not without risk. The investigators of this remarkable study can substantially advance our understanding of hemangioma treatment with a follow-up study of the same subjects comparing the involuted-hemangioma outcome of treated versus untreated patients. Nancy M. Bauman, MD Children’s National Medical Center Washington, DC
References 1. Michaud AP, Bauman NM, Burke DK, Manaligod JM, Smith RJ. Spastic diplegia and other motor disturbances in infants receiving interferonalpha. Laryngoscope 2004;114:1231-6. 2. Sun H, Mao Y, Wang J, Ma Y. Effects of beta-adrenergic antagonist, propranolol, on spatial memory and exploratory behavior in mice. Neurosci Ltr 2011;498:133-7.
Obstructive sleep apnea syndrome is associated with delayed growth Zhang XM, Shi J, Meng GZ, Chen HS, Zhang LN, Wang ZY, et al. The effect of obstructive sleep apnea syndrome on
CURRENT BEST EVIDENCE
July 2015 growth and development in nonobese children: a parallel study of twins. J Pediatr. 2015;166:646-50. Question Among young children, what is the association of growth delay in those with obstructive sleep apnea syndrome (OSAS), versus children without OSAS? Design Identical-twin-sibling case-control. Setting Xinhua Hospital, China. Participants Twins, 3-12 years of age, one of each twin pair with OSAS. Intervention Tonsillectomy and adenoidectomy (T&A) in the affected twin. Outcomes Height and weight before and after (up to 12 months). Main Results The height and weight of the OSAS group before T&A was lower than the control group. During the follow-up period, height and weight increased but were lower than the control group. Serum insulin–like growth factor 1 levels in the OSAS group before T&A were lower than the control group. The level was significantly increased 3 months after T&A. Conclusions OSAS impairs growth. Commentary In children with sleep disordered breathing but without contributing comorbid conditions, T&A can improve and sometimes resolve nocturnal respiratory symptoms, as well as improve daytime symptoms (behavior, cognition, and growth) – though not in all cases. Establishing consequences of untreated sleep disordered breathing and the potential benefits of treatment are complicated by incon-
sistent definitions and criteria for intervention. With growing interest in this area, large multi-institutional studies have been pursued. Marcus et al evaluated 464 children ages 5-9 years with OSAS and found improvement in behavior and quality of life, without significant differences in primary neurocogntive outcomes (executive function and attention) in patients receiving immediate T&A compared with delayed T&A controls.1 Subsequent investigation demonstrated a low risk of postsurgical complications (7% of 221 cases).2 Though a smaller cohort, the twin study by Zhang et al offers strong methodology controlling for potential environmental and genetic contributing factors, and concisely evaluates the impact of OSAS’ on growth through height, weight, and insulin–like growth factor 1 levels. Overall, this study strongly supports T&A to treat pediatric OSAS, thereby improving short-term growth. Pallavi P. Patwari, MD University of Illinois at Chicago Chicago, Illinois
References 1. Marcus CL, Moore RH, Rosen CL, Giordani B, Garetz SL, Taylor HG, et al. A randomized trial of adenotonsillectomy for childhood sleep apnea. N Engl J Med 2013;368:2366-76. 2. Konstantinopoulou S, Gallagher P, Elden L, Garetz SL, Mitchell RB, Redline S, et al. Complications of adenotonsillectomy for obstructive sleep apnea in school-aged children. Int J Pediatr Otorhinolaryngol 2015;79:240-5.
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