Inova Children's Hospital

The objective of this practice guideline is to provide recommendations for the accurate diagnosis and optimal treatment of group A streptococcal pharyngitis in children and adults. The desired outcomes are prevention of acute rheumatic fever, prevention of suppurative complications, improvement of clinical symptoms and signs, reduction in transmission of group A β-hemolytic streptococci to close contacts of patients, and minimization of potential adverse effects of inappropriate antimicrobial therapy. This statement is an update of the practice guideline published in 1997 [1] and takes into account relevant research published since that time. A major substantive change is the acceptance of negative results of rapid antigen detection testing (RADT) for exclusion of acute streptococcal pharyngitis, without the previously mandated confirmation with a negative culture result, provided certain criteria are met, as detailed below. Diagnosis. Acute pharyngitis is one of the most frequent illnesses for which pediatricians, internists, and other primary care physicians are consulted. Although the group A streptococcus is the most common bacterial cause of acute pharyngitis, only a small percentage of patients with this condition are infected by group A streptococci. Moreover, group A streptococcal pharyngitis is the only commonly occurring form of acute pharyngitis for which antibiotic therapy is definitely indicated. Therefore, for a patient with acute pharyngitis, the clinical decision that usually needs to be made is whether the pharyngitis is attributable to group A streptococci. The signs and symptoms of group A streptococcal and other (most frequently viral) pharyngitides overlap broadly. Therefore, unless the physician is able with confidence to exclude the diagnosis of streptococcal pharyngitis on epidemiological and clinical grounds, a laboratory test should be done to determine whether group A streptococci are present in the pharynx. The test may be either culture of a throat swab specimen or an RADT, which detects the presence of group A streptococcal carbohydrate on a throat swab. A positive result of throat culture or RADT for a patient with signs and symptoms of acute pharyngitis is considered, for clinical purposes, to establish the diagnosis of “strep throat.” However, because some RADTs appear to be considerably less sensitive than is culture of a throat swab specimen, a negative RADT result for a child or adolescent should be confirmed by performance of a throat culture, unless the physician has ascertained in his or her practice that the RADT being used is comparable in sensitivity to a throat culture. Because of the epidemiological features of acute pharyngitis in adults (e.g., low incidence of streptococcal infection and extremely low risk of rheumatic fever), diagnosis of this infection in adults on the basis of the results of an RADT, without confirmation of negative RADT results by negative results of culture, is an acceptable alternative to diagnosis on the basis of throat culture results (figure 1). The generally high specificity of RADTs should minimize overprescription of antimicrobials for treatment of adults. Diagnosis and management of acute pharyngitis. The algorithm applies to uncomplicated cases of acute pharyngitis. Additional diagnostic and therapeutic measures may be necessary for patients with suppurative complications (e.g., peritonsillar abscess or cervical lymphadenitis) or infection with uncommon pharyngeal bacterial pathogens (e.g., Corynebacterium diphtheriae, Neisseria gonorrhoeae) is suspected. *See the discussion in Diagnosis of Group A Streptococcal Pharyngitis. Neg., negative result; pos., positive result. Therapy. Patients with acute streptococcal pharyngitis should receive therapy with an antimicrobial agent in a dose and for a duration that is likely to eradicate the infecting organism from the pharynx. A number of antibiotics have been shown to be effective in treating group A streptococcal pharyngitis. These include penicillin and its congeners (such as ampicillin, amoxicillin, and the semisynthetic penicillins), as well as numerous cephalosporins and macrolides and clindamycin. Penicillin, however, remains the agent of choice because of its proven efficacy, safety, narrow spectrum, and its low cost. Amoxicillin is often used in place of oral penicillin V to treat young children; the efficacy appears to be equal. This choice is primarily related to acceptance of the taste of the suspension. Preliminary investigations have demonstrated that once-daily amoxicillin therapy is effective in the treatment of group A β-hemolytic streptococcal pharyngitis [2, 3]. If these results are confirmed by additional investigations, once-daily amoxicillin therapy, because of its low cost and relatively narrow spectrum, could become an alternative regimen to treat group A β-hemolytic streptococcal pharyngitis. Intramuscular administration of benzathine penicillin G is preferred for patients who are unlikely to complete a full 10-day course of oral therapy. Erythromycin is a suitable alternative for patients allergic to penicillin. First-generation cephalosporins are also acceptable for patients who do not exhibit immediate-type hypersensitivity to β-lactam antibiotics. Most oral antibiotic therapy must be administered for the conventional 10 days to achieve maximal rates of pharyngeal eradication of group A streptococci, but certain newer agents have been reported to achieve comparable rates of bacteriologic and clinical cure of streptococcal pharyngitis when administered for <5 days. However, no definitive results from comprehensive studies are available to allow final evaluation of these proposed shorter courses of oral antibiotic therapy [4], which, therefore, cannot be recommended at this time. Moreover, these antibiotics have a much broader spectrum than does penicillin, and most, even when administered for short courses, are more expensive. Except under bacteriologic testing or of patients who are a course of antimicrobial therapy testing of contacts of a patient with group A streptococcal pharyngitis is A small percentage of patients have a of acute pharyngitis with results of throat culture or RADT that are positive for group A streptococci a short of a course of antimicrobial therapy. may be with an antimicrobial agent for treatment of the If the treatment with an oral agent and is in a course of benzathine penicillin G therapy should be the course of or may be to pharyngitis in a from group A streptococcal pharyngitis. with certain antimicrobial as and may be because have been shown to high rates of eradication of streptococci from the under these Group A streptococcal pharyngitis is an acute infection of the that is by The objective of this practice guideline is to provide recommendations for the accurate diagnosis and optimal treatment of group A streptococcal pharyngitis in children and in adults. The physician for a patient with acute pharyngitis must a diagnosis and determine which, should be clinical and laboratory evaluation result in a diagnosis of group A β-hemolytic streptococcal pharyngitis, penicillin remains the of choice for the patient allergic to penicillin, alternative antimicrobial agents are The desired outcomes are as prevention of acute rheumatic prevention of suppurative complications (e.g., peritonsillar cervical and improvement in clinical symptoms and rapid in to transmission of group A β-hemolytic streptococci to and other close contacts of the and to allow the rapid of and minimization of potential adverse effects of inappropriate antimicrobial therapy. A number of clinical of diagnostic and treatment for group A streptococcal pharyngitis The for of of for for of streptococcal to treatment from duration and of and recommendations and the of the and of the are by of an of 1). A of the of a and the the of the These are in of for recommendations in clinical of diagnostic a high on the diagnostic test with the in acute pharyngitis to group A β-hemolytic streptococci from that to other evaluation of high to proven clinical and bacteriologic efficacy, safety, spectrum of antimicrobial and cost. and Group A β-hemolytic streptococcus is the most common bacterial cause of acute pharyngitis diagnosis by antimicrobial therapy is for the the Although acute pharyngitis is one of the most frequent illnesses for which and other primary care physicians are only a relatively small percentage of patients with this condition are infected by group A streptococci. Moreover, the signs and symptoms of group A streptococcal and pharyngitis overlap that accurate diagnosis on clinical is usually the of by certain other pharyngeal bacterial pathogens (e.g., Corynebacterium and Neisseria antimicrobial therapy is of no proven as treatment for acute pharyngitis to other than group A streptococci. Therefore, is extremely that physicians exclude the diagnosis of group A streptococcal pharyngitis to inappropriate administration of antimicrobials to of patients with pharyngitis. only does therapy patients to the and of antimicrobial therapy, to the of which is being reported with in the and of acute pharyngitis. If the clinical of group A streptococcal pharyngitis is by of the organism in from the the should the most antimicrobial therapy, from a number of antimicrobial agents to be effective group A streptococci. Because the cost to the patient may as much as on the recommendations are on safety, and cost. are the most common cause of acute pharyngitis as and frequently cause acute pharyngitis. agents of acute pharyngitis include and is a frequent cause of acute pharyngitis that is often by the other clinical features of (e.g., and with and a number of other agents may be with acute pharyngitis. as and are uncommon of acute pharyngitis. Group A β-hemolytic streptococci are the most common cause of bacterial pharyngitis, but other also cause acute pharyngitis These include and G β-hemolytic streptococci and is a cause of acute pharyngitis that may be with a to that in cases of fever, in cause acute pharyngitis in and with other as and and with (e.g., are of acute pharyngitis. is from this of potential group A β-hemolytic streptococcal pharyngitis is the only commonly occurring form of acute pharyngitis for which antibiotic therapy is definitely indicated. Therefore, for a patient with acute pharyngitis, the clinical decision that usually needs to be made is whether the pharyngitis is attributable to group A β-hemolytic streptococci. Acute group A β-hemolytic streptococcal pharyngitis has certain epidemiological and clinical features The is primarily a of children of in usually in the and Patients with group A β-hemolytic streptococcal pharyngitis commonly present with throat of on and and may also be in children patients have with or without and cervical may include a on the in and a However, of these is for group A β-hemolytic streptococcal pharyngitis. the of or the presence of clinical features as and a than a streptococcal and epidemiological and diagnosis of pharyngitis to group A β-hemolytic streptococci should be for group A β-hemolytic streptococcal whether to a test for a patient with acute pharyngitis, the clinical and epidemiological should be A of close with a of streptococcal pharyngitis is as is an of a high of group A β-hemolytic streptococcal in the usually not be done for patients with acute pharyngitis that has clinical and epidemiological features not of a group A streptococcal of diagnostic studies for group A β-hemolytic streptococci not only the of positive test results but also the percentage of cases in which patients have positive test results and are than have been made to the clinical and epidemiological features of acute pharyngitis into that to the that a is by group A β-hemolytic streptococci These clinical are in patients who are at low risk of streptococcal infection that performance of a throat culture or an RADT is usually However, the signs and symptoms of streptococcal and pharyngitis overlap for diagnosis to be made with the diagnostic on clinical The clinical diagnosis of group A β-hemolytic streptococcal pharyngitis cannot be made with even by the most and bacteriologic confirmation is in the diagnosis of acute pharyngitis in adults. Group A streptococci cause of cases of acute pharyngitis in patients but only of illnesses in adults However, the risk of acute pharyngitis to group A streptococci is for of children and adults into close with The risk of a of acute rheumatic is extremely low in even should have an and of streptococcal pharyngitis. Because of these epidemiological the of a clinical algorithm without confirmation has been recommended as an acceptable alternative basis for diagnosis of infection in adults this algorithm a positive result of group A streptococcal throat culture with an of on the number of clinical features present of this diagnostic result in treatment of an number of adults with that is an result in this which has a low of streptococcal pharyngitis and low risk of rheumatic or rheumatic However, because of the features of acute pharyngitis in exclusion of the diagnosis on the basis of negative RADT without confirmation by negative culture is an acceptable alternative to diagnosis on the basis of throat culture The generally high specificity of RADT should minimize overprescription of antimicrobials for treatment of adults. This is of in of that the more for of adults who primary care physicians because of a throat culture. of a throat swab on a remains the for the of the presence of group A streptococci in the and for the confirmation of the clinical diagnosis of acute streptococcal pharyngitis If done culture of a throat swab on a has a sensitivity of for the detection of the presence of group A β-hemolytic streptococci in the the of throat culture the in which the swab is has an on the of streptococci from the culture swab should be from the of and the pharyngeal of the oral and are not acceptable and these should not be with the swab or the have been care who in to a throat swab from an child may a specimen that is results may be the patient has antibiotics or at the the throat swab is has also been reported that the of and culture may the of positive culture results However, are with to the of the of and the culture in the of a the cost and with of and culture are to for physicians who throat in that the of the throat culture is the duration of the swab is a culture should be at for additional at however, a number of positive throat culture results that not have been therapeutic may be made on the basis of an culture, is to that negative results at at The clinical of the number of group A β-hemolytic streptococcal present on the throat culture is Although patients with acute group A streptococcal pharyngitis are likely to have positive than are patients who are is much overlap in the of of throat culture results that the cannot be made on this basis the most used test for of group A streptococci from other β-hemolytic streptococci in is the This test a on the basis of that of group A streptococci a of a of of A streptococci do not this alternative and of streptococcal is by detection of the carbohydrate antigen in bacterial are available for this are for by clinical but most physicians throat to the additional for the improvement in provided by with an antigen detection test A of a throat swab on is the or in the result. RADTs have been for the of group A β-hemolytic streptococci from throat Although these rapid are more than culture, provide results and treatment of patients with streptococcal pharyngitis the risk of the of group A β-hemolytic streptococci, the patient to to or and the acute with the The of RADTs for certain (e.g., patients in has been shown to the number of patients who are for streptococcal pharyngitis, with of throat The of the RADTs that are available have an specificity of with culture This that test results are therefore, therapeutic be made with confidence on the basis of a positive test result. the sensitivity of most of these is or even with culture has been that most of the RADT results for patients who are and are not However, studies of RADTs demonstrated that a of patients with RADT results infected with group A β-hemolytic streptococci and not The RADTs used relatively and on sensitivity and a more RADTs that and have become These may be more sensitive than other RADTs and even as sensitive as throat culture on However, in of the RADT and other available as well as the of studies the physicians who RADT for diagnosis in children and and who do not culture to negative results should do only in practice that the RADT has a sensitivity to that of throat culture Moreover, the should be for some of these the of does not the for of that are not of the conventional throat culture RADTs infected from with pharyngitis. allow physicians to antibiotics from the of patients with for results of culture or RADT are This is of of patients with who are in primary care receive for antimicrobials and not present and are of no in the diagnosis of acute pharyngitis. are for confirmation of streptococcal in patients of acute rheumatic or acute also are in epidemiological for patients with acute infection from patients who are The diagnosis of acute group A streptococcal pharyngitis should be on clinical and epidemiological and by performance of a laboratory A positive result of either throat culture or RADT confirmation of the presence of group A β-hemolytic streptococci in the pharynx. However, for children and a negative RADT result should be confirmed with a throat culture result, unless the physician has ascertained in his or her practice that the RADT used is comparable to a throat culture. Because of the epidemiological features of acute pharyngitis in adults (e.g., low incidence of streptococcal infection and extremely low risk of rheumatic fever), diagnosis of this infection in adults on the basis of the results of an RADT, without confirmation of negative RADT results by negative results of culture, is an acceptable alternative to diagnosis on the basis of throat culture The generally high specificity of RADTs should minimize overprescription of antimicrobials for treatment of adults to of diagnostic the of patients who have group A β-hemolytic streptococci in a course of antimicrobial therapy are Therefore, culture of throat is not for patients who have a complete course of therapy for group A streptococcal pharyngitis however, in which should have of throat should be for patients with a of rheumatic and should also be for patients who acute pharyngitis of either acute rheumatic or acute as well as of group A streptococcal pharyngitis in or throat may also be when of group A streptococci has been occurring a throat are not for patients who have a complete course of therapy for group A streptococcal pharyngitis. therapy is for with pharyngitis the presence of the organism in the throat is confirmed by culture or RADT (figure 1). If is clinical or epidemiological that results in a high of antimicrobial therapy be the physician is for laboratory provided that the therapy is the diagnosis of streptococcal pharyngitis is not confirmed by results of a laboratory of antimicrobial therapy results in of signs and symptoms However, should be group A streptococcal pharyngitis is usually a and symptoms days of even without antimicrobial therapy This objective of clinical improvement with therapy even more therapy be for to days the of symptoms and the of the major acute rheumatic These allow the in antimicrobial therapy the evaluation of an patient with group A streptococcal pharyngitis. the therapeutic studies numerous antimicrobial agents have been in clinical and have been shown to be of eradication of group A streptococci from the However, the only recommended antimicrobial therapy that has been in studies and has been shown to of rheumatic is therapy These studies done with penicillin G in a that has since been by benzathine penicillin this no in are Although are not are that benzathine penicillin G is effective in primary prevention of rheumatic prevention of an of rheumatic group A streptococcal penicillin G has also been shown to the of cases of rheumatic streptococcal in Moreover, benzathine penicillin G has been proven effective in prevention of rheumatic in patients who have a of the as antimicrobials eradicate group A streptococci from the and is that eradication is a for in primary prevention of rheumatic for antimicrobial therapy for group A streptococcal pharyngitis. has not been a in the treatment of group A streptococcal pharyngitis in the clinical of group A in the has been to be to penicillin. Although relatively high of to and antibiotics have been reported from of group A streptococci in the have been shown to be to Although have been of in the is no that this is at the present time. However, the of macrolides and for and physicians should be of of antimicrobial and are not recommended for treatment of group A streptococcal pharyngitis because of the rates of antimicrobial to these agents group A streptococci and the frequent of these agents to eradicate even from the pharynx. an antimicrobial for treatment of group A streptococcal pharyngitis, to include efficacy, safety, antimicrobial spectrum with therapy and cost. These the of antimicrobial therapy. A number of antibiotics have been shown to be effective in treating group A streptococcal pharyngitis. These include penicillin and its congeners (such as and as well as numerous cephalosporins and macrolides and clindamycin. Penicillin, however, remains the treatment of choice because of its proven efficacy and safety, and its narrow spectrum and low cost Amoxicillin is often used in place of penicillin V as oral therapy for young children; the efficacy appears to be equal. This choice is primarily related to acceptance of the taste of the suspension. Erythromycin is a suitable alternative for patients allergic to penicillin. First-generation cephalosporins are also acceptable for patients allergic to penicillin who do not immediate-type hypersensitivity to β-lactam antibiotics. the patient infected with an of group A who is to β-lactam is an Most oral antibiotics must be administered for the conventional 10 days to achieve maximal rates of pharyngeal eradication of group A streptococci. has been reported that and are effective in group A streptococci from the when administered for <5 only the are for a course of therapy by the and at this However, studies of therapy include no of with therapy, and do not include for which treatment and the of these antibiotics are much broader than is the spectrum of penicillin, even when the antibiotics are administered for short courses, are more Therefore, of these shorter courses of oral antimicrobial therapy cannot be at this to treat pharyngitis to group A β-hemolytic streptococci with a dose of penicillin have been have demonstrated that once-daily and once-daily of cephalosporins (e.g., and are effective in pharyngeal streptococci. only and are as once-daily therapy for streptococcal pharyngitis in Preliminary investigations have demonstrated that once-daily amoxicillin therapy is effective treatment for group A β-hemolytic streptococcal pharyngitis [2, 3]. If its is confirmed by additional investigations, once-daily amoxicillin therapy, because of its low cost and relatively narrow spectrum, could become an alternative regimen for the treatment of group A β-hemolytic streptococcal pharyngitis. for group A streptococcal may be either or recommended for antimicrobials proven to be effective for the treatment of uncomplicated group A streptococcal pharyngitis and for the of the and the on which the recommendations are Intramuscular benzathine penicillin G therapy is preferred for patients unlikely to complete a full 10-day course of oral therapy. Patients with acute streptococcal pharyngitis should receive therapy with an antimicrobial agent at a dose and for a duration that is likely to eradicate the infecting organism from the pharynx. the basis of its narrow spectrum of antimicrobial the with which adverse and its penicillin is the of choice for treatment of patients who are not allergic to of in the of patient group A streptococci in however, is not necessary to test these contacts for group A streptococcal or to treat have positive test in which testing of an patient is the in Diagnosis of Group A Streptococcal is recommended that culture be for contacts and treatment be administered to with positive culture contacts of patients with group A streptococcal as or may be at risk of or infection with the of contacts the of this guideline and has been in Except in in which is risk of frequent or of streptococcal culture of throat swab from or treatment of contacts of patients with group A streptococcal pharyngitis is not recommended performance of throat culture for have a course of antibiotic therapy is not necessary in the in Diagnosis of Group A Streptococcal Because is no only patients who have signs and symptoms of acute pharyngitis that in the of therapy are likely to patients have culture or RADT results positive for group A streptococci, are of in the of infection with the antimicrobial regimen or a infection with group A streptococci from the or A of pharyngitis by the infecting of group A treatment cannot be but this do not antimicrobial therapy. have group A β-hemolytic streptococci present in but have no of to the organism the and in as as of children may be may be by group A β-hemolytic streptococci for that may of pharyngitis. may that these patients have group A β-hemolytic streptococci in and appear to have acute streptococcal pharyngitis. are unlikely to the organism to close contacts and are at low for suppurative complications or complications (e.g., acute rheumatic Moreover, is much more to eradicate group A streptococci from the of than from patients with acute This has been shown to be for penicillin therapy and may also be for some other clinical and epidemiological in of the published studies that penicillin has relatively high rates for group A streptococci from the the patient likely with is to a with an infection from a patient with acute streptococcal pharyngitis. include patient of the (e.g., the of and the of the signs and symptoms however, the may not be able to from acute infection and to course of of pharyngitis that are with laboratory confirmation of group A streptococci and that of a course of antimicrobial therapy, treatment with of the agents in is Because patient with oral antimicrobial therapy often is an a regimen of benzathine penicillin G should be these is not necessary to additional throat swab for culture the course of therapy unless the patient remains or or unless are present the in Diagnosis of Group A Streptococcal even more clinical is the a child or a of to of acute pharyngitis for which culture or RADT results are positive for group A streptococci. is likely that most of these patients are a patient with frequent the clinical to antibiotic therapy and the presence or of group A streptococci in of throat is in from of acute pharyngitis. or of streptococcal from from an patient may also in at this but studies are available only from research If a physician that of is the for of group A streptococcal in a may be to from contacts and treat for culture results are positive is no that are for group A streptococci or that to antimicrobial is not recommended to the of rheumatic in patients who have a of rheumatic of the may be for the patient do not in and for no alternative for the pharyngitis is may the number of of pharyngitis in some patients, but only for a have been no definitive studies of treatment of of acute pharyngitis in the However, the in have been reported to result in low rates of bacteriologic A small percentage of patients have a of acute pharyngitis with results of throat culture positive for group A streptococci a short of a course of antimicrobial therapy. A may be with the in the course of or may be to in a from group A streptococcal antimicrobial agents have been shown to high rates of pharyngeal eradication of streptococci under these that these agents are in for treatment of with of pharyngitis proven by culture or rapid antigen detection of the of care of patients with acute pharyngitis include the for patients of group A streptococcal pharyngitis, performance of throat or for patients with acute pharyngitis and positive for group A streptococci, of one of the antimicrobial recommended in for patients with negative test results for group A streptococci, or of antimicrobial for patients who have an course of antimicrobial therapy, of performance of or for contacts of patients with group A streptococcal pharyngitis, of throat or and of of antimicrobial to of acute pharyngitis for patients with a of rheumatic

We recently identified mutations of ARX in nine genotypic males with X-linked lissencephaly with abnormal genitalia (XLAG), and in several female relatives with isolated agenesis of the corpus callosum (ACC). We now report 13 novel and two recurrent mutations of ARX, and one nucleotide change of uncertain significance in 20 genotypic males from 16 families. Most had XLAG, but two had hydranencephaly and abnormal genitalia, and three males from one family had Proud syndrome or ACC with abnormal genitalia. We obtained detailed clinical information on all 29 affected males, including the nine previously reported subjects. Premature termination mutations consisting of large deletions, frameshifts, nonsense mutations, and splice site mutations in exons 1 to 4 caused XLAG or hydranencephaly with abnormal genitalia. Nonconservative missense mutations within the homeobox caused less severe XLAG, while conservative substitution in the homeodomain caused Proud syndrome. A nonconservative missense mutation near the C-terminal aristaless domain caused unusually severe XLAG with microcephaly and mild cerebellar hypoplasia. In addition, several less severe phenotypes without malformations have been reported, including mental retardation with cryptogenic infantile spasms (West syndrome), other seizure types, dystonia or autism, and nonsyndromic mental retardation. The ARX mutations associated with these phenotypes have included polyalanine expansions or duplications, missense mutations, and one deletion of exon 5. Together, the group of phenotypes associated with ARX mutations demonstrates remarkable pleiotropy, but also comprises a nearly continuous series of developmental disorders that begins with hydranencephaly, lissencephaly, and agenesis of the corpus callosum, and ends with a series of overlapping syndromes with apparently normal brain structure.

The therapeutic approach to childhood nephrotic syndrome is based on a series of studies that began with an international collaborative effort sponsored by the International Study of Kidney Disease in Children in 1967. The characteristics of children presenting with nephrotic syndrome have changed over recent decades with greater frequency of the challenging condition focal segmental glomerulosclerosis and a greater prevalence of obesity and diabetes mellitus, which may be resistant to glucocorticoids in the former and exacerbated by long-term glucocorticoid therapy in the latter 2 conditions. The Children's Nephrotic Syndrome Consensus Conference was formed to systematically review the published literature and generate a children's primary nephrotic syndrome guideline for use in educational, therapeutic, and research venues.

BACKGROUND: 7-Valent pneumococcal conjugate vaccine (PCV7 [Prevnar, Wyeth Pharmaceuticals Inc, Philadelphia, PA], serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) is effective in preventing vaccine-serotype pneumococcal disease. 13-Valent pneumococcal conjugate vaccine (PCV13) (PCV7 serotypes plus 1, 3, 5, 6A, 7F, and 19A) was designed to provide broader pneumococcal disease coverage. We evaluated the immunogenicity and safety of PCV13 compared with PCV7. METHODS: Infants received PCV13 or PCV7 at ages 2, 4, 6, and 12 to 15 months with routine pediatric vaccinations. Pneumococcal anticapsular polysaccharide-binding immunoglobulin G responses and functional antipneumococcal opsonophagocytic activity were assessed 1 month after dose 3, before the toddler dose, and 1 month after the toddler dose. Safety and tolerability were also assessed. RESULTS: For the 7 common serotypes, PCV13-elicited immunoglobulin G titers were noninferior to those elicited by PCV7, although PCV13 responses were generally somewhat lower. PCV13 also elicited functional opsonophagocytic activity comparable with that elicited by PCV7. For the 6 additional serotypes in PCV13, PCV13 elicited binding and functional antibody levels notably greater than those in PCV7 recipients. After PCV13 immunization, concordance between antipolysaccharide and opsonophagocytic responses was noted for all 13 serotypes. The PCV13 toddler dose resulted in higher immune responses compared with infant-series doses. Safety and tolerability were comparable; reactogenicity was generally mild. CONCLUSIONS: PCV13 will be as effective as PCV7 in the prevention of pneumococcal disease caused by the 7 common serotypes and could provide expanded protection against the 6 additional serotypes. The PCV13 safety profile was comparable to that of PCV7.

We undertook a retrospective chart review of 37 neonates who received fentanyl by continuous infusion while undergoing extracorporeal membrane oxygenation (ECMO) between May 1986 and October 1988. We quantified the doses of all sedatives utilized, determined the incidence of neonatal abstinence syndrome (NAS), and identified risk factors associated with NAS. We determined peak fentanyl infusion rate, mean fentanyl infusion rate, total fentanyl dose, and duration of ECMO therapy. NAS was observed in 21 of 37 neonates (57%). In both the NAS and non-NAS neonates, mean infusion rate increased steadily during ECMO therapy, from a mean of 11.6 +/- 6.9 (SD) micrograms.kg-1.h-1 on day 1 to a mean of 52.5 +/- 19.4 (SD) micrograms.kg-1.h-1 by day 8. Total fentanyl dose and duration of ECMO were significantly greater in neonates with NAS. We found that neonates with a total dose greater than 1.6 mg/kg or an ECMO duration greater than 5 days had a significantly greater incidence of NAS (chi-squared test, P less than 0.01 and P less than 0.005; odds ratios = 7.0 and 13.9, respectively). With multiple logistic regression, ECMO duration was found to be the most powerful predictor of the occurrence of NAS. We also measured plasma fentanyl concentrations in a separate group of 5 neonates receiving fentanyl by continuous infusion for sedation. Fentanyl concentrations increased steadily during the period of infusion, suggesting the development of tolerance to the sedating effects. We conclude that continuous administration of fentanyl for sedation is associated with the uniform development of tolerance and a significant incidence of dependence. Alternative approaches to sedation should be investigated.

Germline mutations are the source of evolution and contribute substantially to many health-related processes. Here we use whole-genome deep sequencing data from 693 parents-offspring trios to examine the de novo point mutations (DNMs) in the offspring. Our estimate for the mutation rate per base pair per generation is 1.05 × 10(-8), well within the range of previous studies. We show that maternal age has a small but significant correlation with the total number of DNMs in the offspring after controlling for paternal age (0.51 additional mutations per year, 95% CI: 0.29, 0.73), which was not detectable in the smaller and younger parental cohorts of earlier studies. Furthermore, while the total number of DNMs increases at a constant rate for paternal age, the contribution from the mother increases at an accelerated rate with age.These observations have implications related to the incidence of de novo mutations relating to maternal age.

Mutations of LAMB2 typically cause autosomal recessive Pierson syndrome, a disorder characterized by congenital nephrotic syndrome, ocular and neurologic abnormalities, but may occasionally be associated with milder or oligosymptomatic disease variants. LAMB2 encodes the basement membrane protein laminin beta2, which is incorporated in specific heterotrimeric laminin isoforms and has an expression pattern corresponding to the pattern of organ manifestations in Pierson syndrome. Herein we review all previously reported and several novel LAMB2 mutations in relation to the associated phenotype in patients from 39 unrelated families. The majority of disease-causing LAMB2 mutations are truncating, consistent with the hypothesis that loss of laminin beta2 function is the molecular basis of Pierson syndrome. Although truncating mutations are distributed across the entire gene, missense mutations are clearly clustered in the N-terminal LN domain, which is important for intermolecular interactions. There is an association of missense mutations and small in frame deletions with a higher mean age at onset of renal disease and with absence of neurologic abnormalities, thus suggesting that at least some of these may represent hypomorphic alleles. Nevertheless, genotype alone does not appear to explain the full range of clinical variability, and therefore hitherto unidentified modifiers are likely to exist.

OBJECTIVES: Unintended variation in the care of patients with Crohn disease (CD) and ulcerative colitis (UC) may prevent achievement of optimal outcomes. We sought to improve chronic care delivery and outcomes for children with inflammatory bowel disease by using network-based quality improvement methods. METHODS: By using a modified Breakthrough Series collaborative structure, 6 ImproveCareNow Network care centers tested changes in chronic illness care and collected data monthly. We used an interrupted time series design to evaluate the impact of these changes. RESULTS: Data were available for 843 children with CD and 345 with UC. Changes in care delivery were associated with an increase in the proportion of visits with complete disease classification, measurement of thiopurine methyltransferase (TPMT) before initiation of thiopurines, and patients receiving an initial thiopurine dose appropriate to their TPMT status. These were significant in both populations for all process variables (P < .01) except for measurement of TPMT in CD patients (P = .12). There were significant increases in the proportion of CD (55%-68%) and UC (61%-72%) patients with inactive disease. There was also a significant increase in the proportion of CD patients not taking prednisone (86%-90%). Participating centers varied in the success of achieving these changes. CONCLUSIONS: Improvements in the outcomes of patients with CD and UC were associated with improvements in the process of chronic illness care. Variation in the success of implementing changes suggests the importance of overcoming organizational factors related to quality improvement success.

In the past few years, drug-facilitated sexual assaults have received widespread media coverage. In addition to alcohol, the most frequently used date-rape drug, flunitrazepam (Rohypnol), a fast-acting benzodiazepine, and gamma-hydroxybutyrate (GHB) and its congeners are among the most popular drugs used for this purpose. The latter drug is easily procured at some gymnasiums, popular bars, discos, and rave clubs, as well as over the Internet. Perpetrators choose these drugs because they act rapidly, produce disinhibition and relaxation of voluntary muscles, and cause the victim to have lasting anterograde amnesia for events that occur under the influence of the drug. Alcoholic beverages potentiate the drug effects. We review several date-rape drugs, provide information on laboratory testing for them, and offer guidelines for preventing drug-facilitated sexual assault.

BACKGROUND AND OBJECTIVES: Doxorubicin, effective against many malignancies, is limited by cardiotoxicity. Continuous-infusion doxorubicin, compared with bolus-infusion, reduces early cardiotoxicity in adults. Its effectiveness in reducing late cardiotoxicity in children remains uncertain. We determined continuous-infusion doxorubicin cardioprotective efficacy in long-term survivors of childhood acute lymphoblastic leukemia (ALL). METHODS: The Dana-Farber Cancer Institute ALL Consortium Protocol 91-01 enrolled pediatric patients between 1991 and 1995. Newly diagnosed high-risk patients were randomly assigned to receive a total of 360 mg/m(2) of doxorubicin in 30 mg/m(2) doses every 3 weeks, by either continuous (over 48 hours) or bolus-infusion (within 15 minutes). Echocardiograms at baseline, during, and after doxorubicin therapy were blindly remeasured centrally. Primary outcomes were late left ventricular (LV) structure and function. RESULTS: A total of 102 children were randomized to each treatment group. We analyzed 484 serial echocardiograms from 92 patients (n = 49 continuous; n = 43 bolus) with ≥1 echocardiogram ≥3 years after assignment. Both groups had similar demographics and normal baseline LV characteristics. Cardiac follow-up after randomization (median, 8 years) showed changes from baseline within the randomized groups (depressed systolic function, systolic dilation, reduced wall thickness, and reduced mass) at 3, 6, and 8 years; there were no statistically significant differences between randomized groups. Ten-year ALL event-free survival rates did not differ between the 2 groups (continuous-infusion, 83% versus bolus-infusion, 78%; P = .24). CONCLUSIONS: In survivors of childhood high-risk ALL, continuous-infusion doxorubicin, compared with bolus-infusion, provided no long-term cardioprotection or improvement in ALL event-free survival, hence provided no benefit over bolus-infusion.

OBJECTIVES: Selection of relevant patient safety interventions for the pediatric intensive care (PICU) requires identification of the types and severity of adverse events (AEs) and adverse drug events (ADEs) that occur in this setting. The study's objectives were to: 1) determine the rates of AEs/ADEs, including types, severity, and preventability, in PICU patients; 2) identify population characteristics associated with increased risk of AEs/ADEs; 3) develop and test a PICU specific trigger tool to facilitate identification of AEs/ADEs. DESIGN, SETTING, PATIENTS: Retrospective, cross-sectional, randomized review of 734 patient records who were discharged from 15 U.S. PICUs between September and December 2005. INTERVENTION: A novel PICU-focused trigger tool for AE/ADE detection. MEASUREMENTS AND RESULTS: Sixty-two percent of PICU patients had at least one AE. A total of 1488 AEs, including 256 ADEs, were identified. This translates to a rate of 28.6 AEs and 4.9 ADEs per 100 patient-days. The most common types of AEs were catheter complications, uncontrolled pain, and endotracheal tube malposition. Ten percent of AEs were classified as life-threatening or permanent; 45% were deemed preventable. Higher adjusted rates of AEs were found in surgical patients (p = .02), patients intubated at some point during their PICU stay (p = .002), and patients who died (p < .001). Surgical patients had higher preventable adjusted AE (p = .01) and ADE rates (p = .02). The adjusted cumulative risk of an AE per PICU day was 5.3% and 1.6% for an ADE alone. There was a 4% increase in adjusted ADEs rates for every year increase in age. CONCLUSIONS: AEs and ADEs occur frequently in the PICU setting. These data provide areas of focus for evidence-based prevention strategies to decrease the substantial risk to this vulnerable pediatric population.

FOR many years surgeons have felt the need for some technical procedure that would help in bridging gaps of the arterial system when a large vessel has been destroyed by trauma or has become thrombosed because of degenerative disease or embolism, or when certain cardiovascular abnormalities require operative correction. Extensive investigations have been conducted to further the work of other experimenters and to determine the feasibility of transferring a segment of large artery from one animal to another of the same species. Full reports of these studies will be published elsewhere.1 2 3 In the laboratory for surgical research sections of abdominal . . .

BACKGROUND: Practical and objective instruments to assess pediatric Crohn's disease (CD) activity are required for observational research and quality improvement. The objectives were: 1) to determine the feasibility of completing the Pediatric Crohn's Disease Activity Index (PCDAI) and the Abbreviated PCDAI (APCDAI); and 2) to create a Short PCDAI by retaining and reweighting the most practical and informative components. METHODS: Physicians in the ImproveCareNow Collaborative for pediatric inflammatory bowel disease (IBD) were asked to record components of the PCDAI and assign a Physician Global Assessment (PGA) of disease severity at each patient encounter. We assessed the feasibility of the PCDAI, the APCDAI, and the individual index components by determining the proportion of visits in which data were recorded. We created a short index by retaining and reweighting components of the PCDAI completed in ≥80% of visits. The feasibility of the Short PCDAI and its ability to discriminate between PGA categories were evaluated using descriptive statistics. RESULTS: This study population included 1355 subjects with CD (6373 visits). The PCDAI and APCDAI were complete in 16.7% and 44.1% of visits, respectively. A Short PCDAI, including general well-being, abdominal pain, stools, weight, abdominal exam, and extraintestinal manifestations were completed in 66.5% of visits. The correlation between the Short PCDAI and PGA was similar to that of the PCDAI (r = 0.60, P < 0.001 versus 0.61, P < 0.001). CONCLUSIONS: The Short PCDAI is a practical and valid tool to measure pediatric CD activity. Its use should facilitate quality improvement and observational research.

BACKGROUND: Obesity and attention difficulties are known complications following surgical treatment for craniopharyngioma. Treatments to date have been largely disappointing. OBJECTIVE: To examine the use of the central nervous system stimulant dextroamphetamine sulfate to regulate appetite and subsequent weight gain in children treated for craniopharyngioma. SETTING: A multidisciplinary clinic specializing in pediatric brain tumors. PATIENTS: Five consecutive patients with significant weight gain and poor attention following surgical treatment for craniopharyngioma were selected for the study. INTERVENTION: Children enrolled in the study were treated with dextroamphetamine, and growth, laboratory, and behavioral assessments were conducted for 24 months. RESULTS: Mean +/- SD body mass index (weight in kilograms divided by height in meters squared) increased from 21 +/- 3.5 before the operation to 32 +/- 2.8 by the start of the protocol. Body mass indices remained stable throughout the protocol. No changes were observed in insulin levels or caloric intake, but the children were more active when taking dextroamphetamine. Parents noted a significant improvement in hyperactivity (mean +/- SD, 1.2 +/- 0.4 to 0.6 +/- 0.2; P =.05), scored with the Conners Parent and Teacher Rating Scales. Teachers noted a similar improvement. CONCLUSIONS: During dextroamphetamine treatment, weight gain stabilized in children who had experienced obesity following surgical resection for craniopharyngioma. In addition, parents and teachers noted significant improvements in children's overall activity and attention. Further studies are needed to determine if the improvements are stable and if earlier intervention can prevent the initial obesity.

PURPOSE: To assess the potential of whole-genome sequencing (WGS) to replicate and augment results from conventional blood-based newborn screening (NBS). METHODS: Research-generated WGS data from an ancestrally diverse cohort of 1,696 infants and both parents of each infant were analyzed for variants in 163 genes involved in disorders included or under discussion for inclusion in US NBS programs. WGS results were compared with results from state NBS and related follow-up testing. RESULTS: NBS genes are generally well covered by WGS. There is a median of one (range: 0-6) database-annotated pathogenic variant in the NBS genes per infant. Results of WGS and NBS in detecting 28 state-screened disorders and four hemoglobin traits were concordant for 88.6% of true positives (n = 35) and 98.9% of true negatives (n = 45,757). Of the five infants affected with a state-screened disorder, WGS identified two whereas NBS detected four. WGS yielded fewer false positives than NBS (0.037 vs. 0.17%) but more results of uncertain significance (0.90 vs. 0.013%). CONCLUSION: WGS may help rule in and rule out NBS disorders, pinpoint molecular diagnoses, and detect conditions not amenable to current NBS assays.

INVESTIGATIONS of serum complement in clinical and experimental renal disease have suggested an immune mechanism in certain forms of nephritis. In the two laboratory models for glomerulonephritis, nephrotoxic nephritis and foreign protein nephritis, serum complement titers have been shown to fall at the time the renal lesions develop.1 , 2 Observations of complement in human nephritis date back to 1915, when Gunn3 found low levels in acute glomerulonephritis. Subsequently, other investigators have confirmed these findings and reported diminished complement titers in subacute glomerulonephritis, in systemic lupus erythematosus and in some cases of the nephrotic syndrome. In contrast, complement titers were normal in . . .

BACKGROUND: The tenet that children with acute purulent rhinitis need not be treated with antibiotics unless drainage persists for 7 to 10 days is taught to medical students and residents in primary care specialties but may not be adhered to in actual clinical practice. Because of the global increase in bacterial resistance stemming largely from the overuse of antibiotics, we sought to determine how acute purulent rhinitis is managed in the primary care setting. METHODS: We surveyed all 450 pediatricians (PD) and family practitioners (FP) in northern Virginia who were in active practice in 1994. The survey instrument was a questionnaire containing two clinical vignettes followed by a series of multiple choice or fill-in-the-blanks questions. Initial nonresponders received up to three additional mailings of the same questionnaire. RESULTS: There were 346 (77%) evaluable responses. Seventy-one percent of FP and 53% of PD (P = 0.001) immediately prescribed antibiotics for infants with scant, green nasal mucopurulent secretions of 1 day duration; fewer treated an older child immediately (50% FP vs. 24% PD, P < 0.00001). Only 15% of FP vs. 23% of PD (P = 0.07) waited for 7 to 10 days of persistent purulent nasal drainage in infants before prescribing antibiotics. Ninety-four percent of FP and 95% of PD (P = 0.8) indicated that they would prescribe antibiotics immediately for infants with acute purulent rhinitis who attended day care. For otitis-prone children who were not in day care, 86% of FP and 78% of PD (P = 0.02) would also treat without delay. The reasons given for prompt antibiotic therapy were (1) the belief that many untreated patients would develop persistent purulent nasal drainage, (2) concern that acute otitis media would develop, (3) pressure from mothers to prescribe an antibiotic and/or (4) the desire to allow employed parents to return to work earlier. Amoxicillin was the initial choice for 89% of FP vs. 76% of PD (P = 0.003). Most FP (89%) and PD (97%) were concerned about the increase in bacterial resistance rates arising from unnecessary antibiotic prescribing (P = 0.01). CONCLUSIONS: Most infants and children with acute purulent rhinitis of short duration were treated with antibiotics despite professed concerns over the spread of bacterial resistance; the practice was more prevalent among FP.

Phototherapy is the use of visible light for the treatment of hyperbilirubinemia in the newborn. This relatively common therapy lowers the serum bilirubin level by transforming bilirubin into water-soluble isomers that can be eliminated without conjugation in the liver. The dose of phototherapy is a key factor in how quickly it works; dose in turn is determined by the wavelength of the light, the intensity of the light (irradiance), the distance between the light and the baby, and the body surface area exposed to the light. Commercially available phototherapy systems include those that deliver light via fluorescent bulbs, halogen quartz lamps, light-emitting diodes, and fiberoptic mattresses. Proper nursing care enhances the effectiveness of phototherapy and minimizes complications. Caregiver responsibilities include ensuring effective irradiance delivery, maximizing skin exposure, providing eye protection and eye care, careful attention to thermoregulation, maintaining adequate hydration, promoting elimination, and supporting parent-infant interaction.

INTRODUCTION: Incorporation of clinical decision support systems (CDSSs) into computerized physician order entry assists prescribers with medication dosing, identification of duplicate therapies, drug-allergy alerts and drug-drug interactions (DDIs). The generation of DDI alerts is one aspect of CDSS that may improve patient safety and reduce adverse drug events. AREAS COVERED: Currents issues with the generation of DDI alerts, such as alert fatigue, unclear clinical significance and database inconsistencies are a few of the problems that have been identified with DDI alerting. Research has shown that DDI alerting may be improved through the tiering of alerts, generation of patient-specific alert and directing some alerts to clinicians other than physicians. More research in this area, such as how to decrease the variability of database rating systems, improve the identification of clinically significant alerts and increase the patient specificity of the generated DDI alerts, should be conducted. EXPERT OPINION: DDI knowledgebases need to take into account more patient-specific information. Strategies to avoid alert fatigue, such as DDI tiering and reducing signal:noise ratios, are important areas for future study. End-user participation and clinician feedback should be incorporated in the development of DDI knowledgebases to increase alert compliance.

OBJECTIVE: Our goal was to conduct a prospective, multicentered, comparative study that would objectively verify and explain observed differences in short-term neurodevelopmental outcomes after inflicted versus noninflicted head trauma. METHODS: Children <36 months of age who were hospitalized with acute head trauma confirmed by computed tomography imaging were recruited at multiple sites. Extensive clinical data were captured prospectively, subjects were examined, cranial imaging studies were blindly reviewed, and caregivers underwent scripted interviews. Follow-up neurodevelopmental evaluations were completed 6 months after injury. Head-trauma etiology and mechanisms were categorized by using objective a priori criteria. Thereafter, subject groups with inflicted versus noninflicted etiologies were compared. RESULTS: Fifty-four subjects who met the eligibility criteria were enrolled at 9 sites. Of 52 surviving subjects, 27 underwent follow-up assessment 6 months after injury. Etiology was categorized as noninflicted in 30 subjects, inflicted in 11, and undetermined in 13. Compared with subjects with noninflicted head trauma, subjects with inflicted head trauma (1) more frequently experienced noncontact injury mechanisms, (2) sustained greater injury depth, (3) more frequently manifested acute cardiorespiratory compromise, (4) had lower initial Glasgow Coma Scale scores, (5) experienced more frequent and prolonged impairments of consciousness, (6) more frequently demonstrated bilateral, hypoxic-ischemic brain injury, (7) had lower mental developmental index scores 6 months postinjury, and (8) had lower gross motor quotient scores 6 months postinjury. CONCLUSIONS: Compared with infants with noninflicted head trauma, young victims of inflicted head trauma experience more frequent noncontact injury mechanisms that result in deeper brain injuries, cardiorespiratory compromise, diffuse cerebral hypoxia-ischemia, and worse outcomes.