miércoles, 17 de julio de 2013

Obesidad y cefalea


Obesity in Children With Headaches

Headache. 2013;53(6):954-961. © 2013  Blackwell Publishing

Abstract and Introduction

Abstract

Objective
To examine the association between obesity and the different types of primary headaches, and the relation to headache frequency and disability

Background
The association between obesity and headache has been well established in adults, but only a few studies have examined this association in children, in particular, the relationship between obesity and different types of primary headaches.

Methods
 The authors retrospectively evaluated 181 children evaluated for headaches as their primary complaint between 2006 and 2007 in their Pediatric Neurology Clinic. Data regarding age, gender, headache type, frequency, and disability, along with height and weight were collected. Body mass index was calculated, and percentiles were determined for age and sex. Headache type and features were compared among normal weight, at risk for overweight, and overweight children.

Results
A higher prevalence (39.8%) of obesity was found in our study group compared with the general population. The diagnosis of migraine, but not of tension-type headache, was significantly associated with being at risk for overweight (odds ratio [OR] = 2.37, 95% confidence interval 1.21– 4.67, P = .01) or overweight (OR = 2.29, 95% confidence interval 0.95– 5.56, P = .04). A significant independent risk for overweight was present in females with migraine (OR = 4.93, 1.46– 8.61, P = .006). Regardless of headache type, a high body mass index percentile was associated with increased headache frequency and disability, but not with duration of attack.

Conclusions
Obesity and primary headaches in children are associated. Although obesity seems to be a risk factor for migraine more than for tension-type headache, it is associated with increased headache frequency and disability regardless of headache type.

Introduction
Headaches are a common complaint in children and adolescents, with prevalence ranging from 40% to 75%.[1] Similarly, childhood obesity has become a serious public health problem, and increases in obesity rates have been observed in children of all ages.[2, 3] Recent studies indicate that approximately 20% of school-age children in European countries are overweight or obese and 5% are obese. In North America, these figures are 30% and 15%, respectively.[4] In Israel, cross-sectional data from school-based surveys conducted in 1997 and 1998[5] showed that approximately 16– 20% of school children could be classified as overweight or obese (body mass index [BMI] >85th percentile). A higher obesity rate of up to 26% was described in the 2010 Organization for Economic Co-operation and Development (OECD) report.[6]
Chronic headaches in children are associated with school impairment, a decrease in the amount of free time spent with peers or engaging in after-school activities, and other factors that significantly impair quality of life, such as appetite and sleep.[7, 8] Overweight and obese children are at a higher risk for developing chronic diseases such as hypertension, dyslipidemia, diabetes, heart disease, and stroke.[9] Both conditions have also been associated with psychiatric comorbidity; obesity is related most notably to depression, eating disorders especially loss of control over eating, and attention deficit hyperactivity disorder,[10] while children and adolescents with primary headaches were found to suffer more readily from depression, anxiety, and attachment disorders.[11]
The association between obesity and headache has been well established in adults. Population-based studies have found that individuals with episodic headaches who were obese had over 5-fold increased odds of developing chronic daily headaches (CDHs).[12]This association occurred primarily with chronic migraine and not with chronic tension-type headache (TTH).[13] Increased odds of developing migraine-type headaches was found in obese premenopausal women.[14] In patients with migraine, a high BMI was associated with more frequent and severe migraine attacks.[15] Only a few studies have examined this association in children. In a multicenter study by Hershey et al[16] on children with primary headaches, obesity was associated with headache frequency and disability, with significant improvement after weight loss. Similarly, adolescents with recurrent headaches were more overweight and obese than those without headaches.[17] In a recent study by Pinhas-Hamiel et al,[18] overweight adolescent females had an almost 4-fold excess risk of headache when compared with normal-weight girls.The purpose of the present study was to examine the association between obesity and the different types of primary headaches, and the relation to headache frequency and impairment.
The association between obesity and headache has been well established in adults. Population-based studies have found that individuals with episodic headaches who were obese had over 5-fold increased odds of developing chronic daily headaches (CDHs).[12]This association occurred primarily with chronic migraine and not with chronic tension-type headache (TTH).[13] Increased odds of developing migraine-type headaches was found in obese premenopausal women.[14] In patients with migraine, a high BMI was associated with more frequent and severe migraine attacks.[15] Only a few studies have examined this association in children. In a multicenter study by Hershey et al[16] on children with primary headaches, obesity was associated with headache frequency and disability, with significant improvement after weight loss. Similarly, adolescents with recurrent headaches were more overweight and obese than those without headaches.[17] In a recent study by Pinhas-Hamiel et al,[18] overweight adolescent females had an almost 4-fold excess risk of headache when compared with normal-weight girls.The purpose of the present study was to examine the association between obesity and the different types of primary headaches, and the relation to headache frequency and impairment.

Methods
Patients
This retrospective study included children up to 18 years of age who were evaluated for headaches as their primary main complaint between 2006 and 2007. All patients were referred by their primary physician to our Pediatric Neurology Clinic and were identified retrospectively from the clinic database. Children with developmental delay, seizure disorder, major psychiatric disorders, hydrocephalus, or different systemic diseases such as hypertension were excluded from the study.

Chart Review
During their initial and follow-up visits to the Clinic, all patients and parents completed a semistructured history form. The forms and personal interviews focused on the main characteristics of the headaches, including age at onset, location, quality, frequency, duration, aura, associating symptoms, and family history. A headache-related disability was measured using the Pediatric Migraine Disability Assessment (PedMIDAS) questionnaire,[19] a 6-item questionnaire assessing the level of impairment in school, home, and social activities in the previous 3 months. Consumption of medications for acute treatment in the last 3 months was also assessed. All children underwent thorough physical and neurological assessments, and weight and height measurements. Additional blood tests or neuroimaging studies were carried out as required. The final diagnosis of the headache typed was based on 2004 International Classification of Headache Disorders 2nd Edition (ICHD-II) criteria.[20] BMI was calculated as the weight in kilograms divided by the height in meters squared. At risk for overweight was defined as BMI 85th to <95th percentile for age and gender. Overweight was defined as BMI ≥95th percentile for age and gender according to the Centers for Disease Control and Prevention health data.[21] These growth charts have been reported to be appropriate for assessing Israeli children.[22] Children with BMI <5th percentile (n = 7) were defined as underweight and were excluded from the study.
The associations between BMI and headache type, duration, frequency, and disability were assessed.

Statistical Evaluation
Categorical data were summarized as proportions (percentages), and continuous variables as means and standard deviations (SDs). For group comparison, chi-square analysis and Fisher's exact tests were used for qualitative variables, and Student's t-test and Kruskal–Wallis test were used for quantitative variables.Multivariate analyses of the associations between BMI and headache type and disability were conducted using logistic regressions with odds ratio (OR) and 95% confidence interval (CI). Analyses for the total sample were adjusted for age and gender.For all comparisons and analyses, all P values refer to 2-tailed tests. P value of <.05 was used as the cut-off point of statistical significance.The study was approved by an institutional review board committee.

Results
Subject Clinical Features and Headache Diagnosis
The cohort consisted of 181 children aged 4– 18 years (mean 10.14, SD = 3.36), with 81 (44.8%) males and 100 (55.2%) females. Follow up lasted 2.2– 6 years (mean 4.3, SD = 1.26). All children had normal physical and neurological examinations, and unremarkable growth and developmental milestones.The baseline headache diagnosis and subclassifications were made according to the 2004 ICHD-II criteria.[16] A migraine headache, including all subtypes such as migraine with and without aura, chronic and probable migraine, was diagnosed in 44.7% of patients, and a TTH was diagnosed in 48.1%. Thirteen (7%) children had unclassified headaches. Episodic and chronic headaches were not distinguished in separate groups because the numbers of patients within each group were too small to give reasonable interpretations.

BMI and Headache Diagnosis
Of the 181 study participants, 109 (60.2%) were of normal weight, 48 (26.5%) were categorized as at risk for overweight, and 24 (13.3%) as overweight. Overall, 39.8% of the study population had BMI ≥85th percentile. This value is significantly higher than the recent estimates of pediatric obesity rate in Israel 26% (P = .05) reported in the 2010 OECD report.[6] The mean age of children in the 3 weight groups was similar: 10.2 ± 3.08 years, 10.4 ± 3.12 years, and 10.3 ± 2.9 years in the normal, at risk for overweight, and overweight groups, respectively. A significantly greater proportion of females was found in the at risk for overweight (68.8%) and overweight (70.8%) groups compared with the normal-weight group (45.9%, P = .02). The diagnosis of migraine was more common in the at risk for overweight (60.4%) and overweight (62.4%) groups compared with the normal-weight group (34%, P = .01) (Table 1).When adjusted for age and gender, the diagnosis of migraine but not of TTH was significantly associated with being at risk for overweight (OR = 2.37, 95% CI 1.21– 4.67, P = .01) or overweight (OR = 2.29, 95% CI 0.95– 5.56, P = .04). A significant independent risk for overweight was present in females with migraine (OR = 4.93, 1.46– 8.61, P = .006) compared with males (OR = 0.77, 0.41– 4.28, P = .56) (Table 2).

BMI and Headache Frequency and Disability
Patients were subdivided into 3 groups according to attack frequency: (1) 4 or less attacks per month; (2) 5– 15 attacks per month; and (3) more than 15 attacks per month. A high frequency of headaches was associated with obesity. Frequent headaches (more than 15 attacks per month) were significantly more common in the obese children compared with the normal-weight children, 23% vs 12%, P < .01. Headache duration was not significantly different in the 2 groups, lasting less than 2 hours in 35% vs 38% of patients, 2– 4 hours in 55% vs 49%, and longer than 4 hours in 10% vs 13% (P = not significant). When asked, "How many days per month are you using medications for acute headache?" 43% of the obese children vs 17% of the normal-weight children reported using analgesic medications more than 15 days per month (Table 3).
A percentage of children with some level of disability (PedMIDAS grades II-IV) was assessed in relation to BMI and headache type, and adjusted for age and gender (Table 4). For the total study population, 14.7% of those with normal weight had some level of disability compared with 20.3% of the at risk for overweight group (OR = 1.7; CI 1.4– 2.2, P < .001) and 33.3% in the overweight group (OR = 3.1; CI 1.9– 5.8, P < .0001). Similar results were measured for both migraine and TTH. For children with migraine, 12.5% of those with normal weight had some level of disability compared with 17.8% of the at risk for overweight group (OR = 1.9; CI 1.5– 2.4, P < .0001) and 30.7 in the overweight group (OR = 3.7; CI 2.2– 6.1, P < .0001). For children with TTH, 15.2% of those with normal weight had some level of disability compared with 22.2% of the at risk for overweight group (OR = 1.6; CI 1.3– 2.0, P < .0001) and 30% in the overweight group (OR = 2.9; CI 1.7– 4.9, P < .0001).

Discussion
The main findings of the present study are the high rate of obesity in our population of children with primary headaches, and the correlation of BMI percentile to headache diagnosis, frequency, and disability. Overall, 39.8% of the study population had BMI ≥85th percentile (26.5% were categorized as at risk for overweight and 13.3% as overweight). This value is significantly higher than the recent estimates of pediatric obesity rates in Israel 26% (P = .05). These results are similar to some previous adult studies that showed a significant association between BMI >30 and prevalence and incidence of headaches.[12, 23] The results differ, however, from a large multicenter study by Hershey et al[16] that found the same obesity rate in pediatric headache sufferers and the general pediatric population. In another recent study, Pakalnis and Kring[24] evaluated 925 children from their pediatric headache clinic. They found that although obesity seemed to be more prevalent in their series of patients compared with population-based norms, significant differences were noted only in patients with CDH and in the subgroup of chronic TTH.
In our study, the strongest association with obesity was found for females and for children with migraine headache. In the obese group, 59.7% of headaches were reported as migraine, whereas among normal-weight subjects 34.8% had migraine and 54.1% had TTHs. Females with migraine had an almost 5-fold risk for overweight when compared with males. These results are in accordance with other recent studies in adults that found a significant association between obesity and migraine progression and frequency.[25] In a large population study by Bigal et al,[15] obesity was found to be an exacerbating factor for migraine, but not for other types of episodic headache. A high prevalence of migraine was found in obese patients undergoing corrective obesity surgery.[26] Horev et al found a high incidence of migraine with aura in morbidly obese women and suggested high estrogen levels produced by adipose tissue as a possible explanation.[27] Recent studies in children also reported a strong association between overweight and migraine headache.[28, 29] In a recent study of 273 children and adolescents, 50% of obese patients suffered from migraine compared with only 25% in the normal-weight group.[18]
Several possible mechanisms that may account for the association between obesity and frequent migraine have been suggested.[30] Obesity is recognized as a pro-inflammatory state. Markers of inflammation, including leukocyte count, tumor necrosis factor-α, and interleukin-6, increase in obesity and may be associated with neurovascular inflammation in patients with migraine.[31] Plasma calcitonin gene-related peptide levels, an important post-synaptic mediator of trigeminovascular inflammation in migraine, are elevated in obese individuals, particularly in women.[32] Finally, recent data suggest that dismodulation in hypothalamic neuropeptides orexin in obese persons may be associated with increased susceptibility to neurogenic inflammation causing migraine attacks.[30, 33] Information regarding the association between obesity and headache-related disability in children is limited. In his study on 913 children with headache, Hershey et al found a significantly positive correlation between BMI percentile and headache frequency and headache-related disability scores. At follow up, a reduction in BMI was associated with a reduction in headache frequency, but not with headache-related disability.[16] In another recent study on 124 children with migraine, obesity was associated with frequency, but not severity of migraine attacks.[28]
Headache frequency, duration, and disability were considered in trying to assess the headache-related burden in our study. Obese children in our study had a significantly higher rate of very frequent headaches (more than 15 attacks per month) as well as higher disability grades compared with normal-weight children. The association between BMI percentile and higher disability grades was similar for both migraine and TTH. There was no significant difference in duration of attacks between obese and normal-weight children. Additionally, we found a significantly higher rate of acute drug treatment in our patients with obesity compared with normal-weight children, similar for both migraineurs and children with TTH. This may also reflect the more frequent and disabling attacks among the obese children. These results are compatible with prior results in adult studies.[15, 23] In their population study of adults with CDH, Bigal and Lipton found that obese patients not only had a higher rate of headache, but also suffered from increased severity of headaches and missed more school and work days than non-obese patients.[13] It was hypothesized that increased attack frequency may cause neuronal sensitization that reduces response to therapy and that obesity contributed toward the development of this sensitivity. In adults with episodic headaches, obesity was associated with higher disability grades only in patients with migraine, but not in those with other types of episodic headaches.[41]
Some caution is required in assessing the type of relationship between obesity and headache frequency and disability in children. Current data are not sufficient to establish a significant causal relation, and both physiological and environmental factors are probably playing a role. Obesity was found to be associated with increased prevalence and severity of other chronic pain disorders besides headache, such as musculoskeletal and abdominal pain.[35, 36] Both conditions are associated with psychiatric comorbidities, such as depression and anxiety,[10, 37] that can further increase headache frequency and disability.[38] Lifestyle may have an impact on both weight and headache. In a population-based study by Molarius et al,[39] physical inactivity was strongly associated with headache disorders independent of economic and psychosocial factors. On the other hand, recurrent headaches were found to be associated with low physical activity[40] that can further contribute to overweight and further increase headache frequency.[17] Sleep problems such as short sleep duration and poor sleep quality may also play a role in both obesity and recurrent headaches.[41, 42]
No matter what the leading explanations for the correlation between obesity and headaches are, given our evidence as well as others, weight is a modifiable risk factor for recurrent headaches in children. Weight and BMI should be measured and calculated in all children presenting with headache, and weight control should be part of the treatment of chronic headache in children.Some limitations should be considered in the present study. First, our sample cannot be considered as representative of pediatric headache patients because of selection bias. Subjects who are referred to a hospital clinic might have more health-related problems compared with children with headaches treated within the community. Second, stratification of data according to headache diagnosis and gender resulted in relatively small groups that could underpower the analyses. Finally, as mentioned before, we cannot infer causality between obesity and headache frequency and disability.
In summary, our data show a high rate of obesity in children with primary headaches compared with the general population. The strongest association with obesity was found for females and for children with migraine headaches. In all the children with primary headaches, a high BMI percentile was associated with increased headache frequency and disability. Although we were unable to adequately address the question of causal relationship, we believe in and emphasize the importance of obesity prevention and treatment in children with headaches.References

Headache. 2013;53(6):954-961. © 2013  Blackwell Publishing






martes, 16 de julio de 2013

7ma Promoción de Residentes de Pediatria




Promoción "Pedro E. San Martín Howard"
Los integrantes de la 7ma promoción de residentes de pediatría de la sede del Hospital Nacional Dos de Mayo 2010-2013 con sus tutores, padrinos, residentes e internos en develado de placa recordatoria y emotiva despedida.

lunes, 15 de julio de 2013

Nuevas drogas anti epilépticas



Recent Literature on Pediatric Antiepileptic Drugs
Pediatr Pharm. 2012;18(12) © 2012  Children's Medical Center, University of Virginia
With the addition of over a dozen new antiepileptic drugs (AEDs) in the United States over the past 20 years, there has been a steady increase in the number of papers published describing alternatives to traditional therapy with phenobarbital, phenytoin, carbamazepine, and valproic acid. Among them are papers addressing the use of newer AEDs in the prevention and treatment of seizures in infants, children, and adolescents. This issue of Pediatric Pharmacotherapy provides an overview of pediatric AED research published during 2012.Open-label Extension Studies of LevetiracetamMany of the papers published this year describe the use of levetiracetam in different settings. An effective therapy for partial-onset, generalized tonic-clonic, and myoclonic seizures, levetiracetam also offers the advantages of a mild adverse effect profile, few drug interactions, and no requirement for serum concentration monitoring. The results from several extension studies became available this year which support the safety and efficacy of levetiracetam in pediatric clinical practice.[1,2] Delanty and colleagues published the findings from a manufacturer-sponsored phase III open-label study which included children and adults who participated in two earlier clinical trials.[1] The study was conducted at 69 institutions in 16 countries over a 5-year period. A total of 217 patients (4–64 years of age) were enrolled, with 125 completing the study. All but one patient were taking one or more concomitant AEDs. The average levetiracetam dose was 2,917.5 mg/day (range 788.2–3,993 mg/day). The median treatment period was 2.1 years, with a maximum of 4.6 years. The median reduction in seizure frequency from baseline was 91.4%. Eighty-five percent of patients achieved a 50% or greater reduction in seizures. Overall, 56.2% of patients experienced at least one seizure-free period lasting at least 6 months. Of those patients, 22.6% had no seizures during the evaluation period. The results were consistent among all seizure types. Adverse effects were reported by 165 patients (76%), most commonly headache, dizziness, or depression.A second manufacturer-sponsored levetiracetam extension study was conducted in children 4 to 16 years of age.[2] This 48-week study was conducted over a 4-year period at 33 centers in five countries. A total of 103 patients were enrolled, with 89 completing the study. The majority (73.8%) were less than 13 years of age. The mean levetiracetam dose during the study was 50.2 ± 15.6 mg/kg/day (range 9–85.8 mg/kg/day). The median duration of treatment was 11 months. Mean scores on tests of memory and cognitive functioning remained consistent during treatment, demonstrating no detrimental effects on cognition. Changes in the Child Behavior Checklist syndrome scores showed statistically significant improvement from baseline. The median percentage reduction in seizure frequency from baseline was 86.4% (range 23.2–100%). Sixty-nine percent achieved a 50% or greater reduction in seizure frequency, with 33.4% of patients remaining seizure-free. Adverse effects were reported by 91.3% of patients, with headache, irritability, aggression, and fatigue occurring most often. The authors concluded that levetiracetam provided effective, sustained seizure control in children, with stable cognitive functioning and improved behavior.Levetiracetam for Status EpilepticusBased on its safety and efficacy profile and the availability of an injectable formulation, levetiracetam has become an alternative treatment for status epilepticus in many hospitals. A recent paper by Misra and colleagues described the results of a randomized, open-label pilot study comparing levetiracetam to lorazepam for the initial management of children and adults with status epilepticus.[3] Seventy-nine patients (1–75 years of age) received either levetiracetam 20 mg/kg given IV over 15 minutes or lorazepam 0.1 mg/kg over 2–4 minutes. Those who did not achieve seizure control within 10 minutes were treated with the alternate agent. Seizure control was achieved in a similar percentage of patients, 76.3% of those given levetiracetam and 75.6% of those given lorazepam. Of the patients who failed to respond to the initial drug, the percentage responding to alternate agent was 79.3% for levetiracetam and 88.9% for lorazepam. Seizure control at 24 hours was also comparable between the groups: 79.3% in those given levetiracetam initially and 67.7% in those given lorazepam. The only statistically significant difference between the groups was a higher need for mechanical ventilation in the lorazepam group (10 patients versus 4 in the levetiracetam group, p = 0.03).Additional clinical experience in this setting comes from McTague and colleagues who conducted a 2-year open-label observational study of IV levetiracetam in 51 children with acute repeated seizures or status epilepticus.[4] Patients ranged in age from 0.2 to 18.8 years, with a mean age of 7.1 years. The median starting dose was 14.4 mg/kg (range of 5–30 mg). Twenty-three children with repetitive seizures (59%) became seizure-free and four of five children had termination of their status epilepticus. Forty-two patients (81%) were started on maintenance levetiracetam. Three children developed aggressive behavior, with one child requiring discontinuation of the drug. These two studies, while limited by their small sample size, lend support to the consideration of levetiracetam as an alternative therapy for the management of pediatric status epilepticus.Seizure Prophylaxis With LevetiracetamPhenytoin has traditionally been given in the immediate period following head injury to protect against the development of early post-traumatic seizures. The 2012 Guidelines for the Acute Management of Severe Traumatic Brain Injury in Infants, Children, and Adolescents give the use of phenytoin prophylaxis a level III recommendation (the lowest category) based on the lack of quality research demonstrating its efficacy.[5] While phenytoin may be beneficial, it has several disadvantages, including the risk for arrhythmias and necrosis after extravasation, as well as potential drug interactions and the need for serum concentration monitoring.Some hospitals have begun using levetiracetam for prophylaxis of both early and late seizures after trauma, with a variety of treatment protocols ranging from 7 to 30 days. Klein and colleagues recently published the results of an open-label phase II study of levetiracetam added to phenytoin in patients at risk for post-traumatic epilepsy.[6] A total of 126 patients (86 adults and 40 children) completed the study at two level 1 trauma centers. All patients received phenytoin for one week after injury as standard care for prevention of early post-traumatic seizures. Sixty-six patients also received levetiracetam (55 mg/kg/day) for 30 days, while the remainder served as controls. Only two patients stopped treatment due to an adverse effect (somnolence). At 2 years post-injury, 9.1% of the patients given levetiracetam had developed post-traumatic seizures, compared to 13.3% of the controls. Although the study was too small to demonstrate statistical significance, the authors suggest that levetiracetam may be useful addition to phenytoin for the prevention of late post-traumatic epilepsy.Levetiracetam has also been suggested as an alternative to phenytoin for seizure prophylaxis in patients undergoing craniotomy. A group of investigators from the University Medical Center at Regensburg, Germany recently published a retrospective study of 235 adults and children (9 years of age and older) who received prophylactic perioperative phenytoin or levetiracetam.[7] The primary outcome was the development of seizures during the first week after surgery. Patients treated with phenytoin received 750 mg IV prior to surgery, followed by an infusion of 30 mg/hr for 24 hours. Phenytoin was continued for another 4 days, tapered from 100 mg three times daily down to 50 mg once daily. The levetiracetam group received 1,000 mg IV prior to and following surgery, with 1,000 mg given twice daily on day 2, 500 mg twice daily on day 3, and 500 mg daily on days 4 and 5. The incidence of seizures was no different between the two groups: 7/154 patients (4.5%) treated with phenytoin and 2/81 patients (2.5%) in the levetiracetam group (p = 0.66).While these studies suggest that levetiracetam may be an acceptable alternative to phenytoin for seizure prophylaxis, much more work is needed before it can be adopted as standard practice. Larger multicenter prospective studies, likely requiring the utilization of collaborative research networks, will be necessary to determine the clinical significance of AED prophylaxis in the trauma and postoperative settings.Levetiracetam Pharmacokinetics in NeonatesLevetiracetam has also become a popular choice for treatment of neonatal seizures that fail to respond to benzodiazepines or phenobarbital. Several studies, both prospective and retrospective, have been published within the past five years describing the safety and efficacy of levetiracetam in the neonatal population. In the July issue of Pediatric Research, Sharpe and colleagues published a study defining the pharmacokinetic profile of IV levetiracetam during the first week of life.[8] Eighteen term neonates with seizures failing to respond to phenobarbital received a 20 or 40 mg/kg loading dose, followed by 5–10 mg/kg/day for one week. The authors identified an increase in clearance, from a mean of 0.7 ± 0.27 mL/min/kg on day 1 to 1.33 ± 0.35 mL/min/kg on day 7. The corresponding half-life decreased from 18.5 ± 7.1 hrs to 9.1 ± 2 hrs. Values at day 7 were similar to those reported by other investigators in neonates up to 1 month of age. This rapid increase in clearance is not easily explained. Levetiracetam is eliminated primarily in the urine as unchanged drug. The reduced glomerular filtration rate of neonates would be expected to result in a slower clearance immediately after birth, with a gradual increase over time. The authors suggest that their findings may be explained by a reduced capacity for tubular reabsorption of levetiracetam in the neonatal kidney and suggest that more frequent dosing may be necessary during the first week of life.Rufinamide use in Lennox Gastaut SyndromeAn open-label observational trial of rufinamide was published earlier this year demonstrating the utility of this agent as adjunctive therapy in children with Lennox Gastaut syndrome (LGS).[9] A total of 128 children (1.8–19.9 years) underwent a 4-week titration, beginning at 10 mg/kg/day, followed by a 12-week maintenance phase. The average dose after titration was 31.7 ± 8.7 mg/kg/day. Forty-six of the 112 patients completing the study (35.9%) experienced at least a 50% reduction in seizure frequency. Ten children (7.8%) became seizure-free. Twenty-one children (16.4%) had an increase in seizure frequency. Over a third of patients experienced adverse effects; fatigue was reported by 11.7% and poor appetite by 7% of patients. The 31.7% overall response rate for rufinamide in patients not controlled with an average of 3 other AEDs demonstrates the potential for this agent in the treatment of refractory LGS.Sweat Chloride Concentrations With TopiramateOligohidrosis occurs in a small number of patients taking topiramate, but the mechanism underlying this adverse effect is not well understood. Although numerous cases of topiramate-induced hyperthermia and heat stroke have been reported in the literature, only one recent report describes an elevated sweat chloride concentration in the affected patient. To further characterize the mechanism for topiramate-induced oligohidrosis, Guglani and colleagues at the Children's Hospital of Pittsburgh conducted sweat chloride testing in 21 children on therapy for at least 6 months.[10] Twenty-one children (mean age 11.7 ± 4.1 years, range 6 months-18 years) were enrolled, as well as 20 healthy children (mean age 11.3 ± 4.2 years) who served as controls. Sweat chloride concentrations were significantly higher in the topiramate group, with a mean of 37.7 ± 18.8 mmol/L compared to a mean of 15.9 ± 6.9 mmol/L in the controls (p = 0.0001). Mean sweat volume was significantly lower in the children receiving topiramate (29.1 ± 17.4 μL compared to 41.2 ± 17.5 μL in the controls, p = 0.037). This study demonstrates that not only is sweat production altered in patients taking topiramate, but the chloride concentration of the sweat is abnormal as well. These differences were consistent among patients and occurred in a controlled environment, without the presence of hyperthermia. The authors suggest that future studies of topiramate-induced oligohidrosis include assessment for a dose-response relationship, correlation with topiramate serum concentrations, and evaluation of potential pharmacogenomic differences.Propylene Glycol-associated ApoptosisAlthough an international survey published earlier this year in Pediatric Neurology found that phenobarbital remains the most common choice for management of neonatal seizures among neurologists and neonatologists,[11] there are growing concerns over its potential for toxicity. Phenobarbital injection contains 68% propylene glycol and 10% ethanol as solvents. While the risk for these compounds to produce cardiotoxicity has long been known, new data suggests the potential for neurotoxicity as well.In a recent study from Washington University, Lau and colleagues examined the effects of phenobarbital and propylene glycol on the developing central nervous system of immature mice.[12] Tissue from mice exposed to propylene glycol demonstrated widespread apoptotic neurodegeneration. After 24 hours, there was evidence of apoptosis, destruction of axons and dendrites, and residual cellular debris. The greatest damage was documented 7 days after exposure. Administration of phenobarbital dissolved in propylene glycol produced greater damage than propylene glycol alone, suggesting a potentiation of apoptosis with the combination. This information, combined with the low efficacy of phenobarbital in terminating neonatal seizures and increasing interest in levetiracetam and topiramate in this population, has the potential to trigger a change in prescribing patterns.Behavioral Adverse EffectsOne of the most important issues when selecting an AED for a pediatric patient is the likelihood for adverse effects on learning and behavior. An in-depth review of the behavioral adverse effects of AEDs was published in the June issue of the Journal of Clinical Psychopharmacology.[13] Eddy and colleagues summarize the literature on 15 AEDs, including both older and newer drugs, with data from children and adults. Tables for the more commonly used AEDs provide a quick summary of the available studies and make this article a useful resource for any health care provider caring for children with seizures. In addition to presenting information on adverse effects, the authors point out studies describing the positive effects of some AEDs on learning and behavior. They also provide recommendations for future research, including the need for better age-based assessment tools.Efficacy of Perampanel in AdolescentsTwo new AEDs, perampanel and ezogabine, were approved by the Food and Drug Administration during 2012. Perampanel, a noncompetitive α–amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist, is indicated for use as adjunctive therapy in patients 12 years of age and older with partial-onset seizures. In the August issue of Neurology, French and colleagues published the results of a multicenter, double-blind, placebo-controlled phase III trial in 388 adolescents and adults.[14] Patients received 8 mg or 12 mg perampanel or placebo once daily for 13 weeks, after an initial 6-week titration period. The median percent change in seizure frequency was -21%, -26.3%, and -34.5% for the placebo, 8 mg, and 12 mg perampanel treatment groups (p = 0.0261 and p = 0.0158 for the 8 mg and 12 mg groups compared to placebo). The percentages of patients achieving a 50% reduction in seizure frequency during the 13-week maintenance period were 26.4%, 37.6%, and 36.1% for the three groups. The most frequent adverse effects were dizziness, somnolence, irritability, headaches, falls, and ataxia. Based on their results, the authors concluded that perampanel is an effective therapy for patients whose epilepsy has not been controlled with other AEDs.SummarySeveral important papers have been published on the use of AEDs in infants, children, and adolescents during the past year, ranging from extension studies assessing long-term efficacy and safety to reports of their use in new patient settings or new descriptions of adverse effects. These papers add a great deal to our understanding of the role these drugs can play in the treatment of seizures in the pediatric population.ReferencesAcknowledgments
The editors would like to thank Dr. Howard Goodkin for serving as a guest editor this month.

Many of the papers published this year describe the use of levetiracetam in different settings. An effective therapy for partial-onset, generalized tonic-clonic, and myoclonic seizures, levetiracetam also offers the advantages of a mild adverse effect profile, few drug interactions, and no requirement for serum concentration monitoring. The results from several extension studies became available this year which support the safety and efficacy of levetiracetam in pediatric clinical practice.[1,2] Delanty and colleagues published the findings from a manufacturer-sponsored phase III open-label study which included children and adults who participated in two earlier clinical trials.[1] The study was conducted at 69 institutions in 16 countries over a 5-year period. A total of 217 patients (4–64 years of age) were enrolled, with 125 completing the study. All but one patient were taking one or more concomitant AEDs. The average levetiracetam dose was 2,917.5 mg/day (range 788.2–3,993 mg/day). The median treatment period was 2.1 years, with a maximum of 4.6 years. The median reduction in seizure frequency from baseline was 91.4%. Eighty-five percent of patients achieved a 50% or greater reduction in seizures. Overall, 56.2% of patients experienced at least one seizure-free period lasting at least 6 months. Of those patients, 22.6% had no seizures during the evaluation period. The results were consistent among all seizure types. Adverse effects were reported by 165 patients (76%), most commonly headache, dizziness, or depression.A second manufacturer-sponsored levetiracetam extension study was conducted in children 4 to 16 years of age.[2] This 48-week study was conducted over a 4-year period at 33 centers in five countries. A total of 103 patients were enrolled, with 89 completing the study. The majority (73.8%) were less than 13 years of age. The mean levetiracetam dose during the study was 50.2 ± 15.6 mg/kg/day (range 9–85.8 mg/kg/day). The median duration of treatment was 11 months. Mean scores on tests of memory and cognitive functioning remained consistent during treatment, demonstrating no detrimental effects on cognition. Changes in the Child Behavior Checklist syndrome scores showed statistically significant improvement from baseline. The median percentage reduction in seizure frequency from baseline was 86.4% (range 23.2–100%). Sixty-nine percent achieved a 50% or greater reduction in seizure frequency, with 33.4% of patients remaining seizure-free. Adverse effects were reported by 91.3% of patients, with headache, irritability, aggression, and fatigue occurring most often. The authors concluded that levetiracetam provided effective, sustained seizure control in children, with stable cognitive functioning and improved behavior.Levetiracetam for Status EpilepticusBased on its safety and efficacy profile and the availability of an injectable formulation, levetiracetam has become an alternative treatment for status epilepticus in many hospitals. A recent paper by Misra and colleagues described the results of a randomized, open-label pilot study comparing levetiracetam to lorazepam for the initial management of children and adults with status epilepticus.[3] Seventy-nine patients (1–75 years of age) received either levetiracetam 20 mg/kg given IV over 15 minutes or lorazepam 0.1 mg/kg over 2–4 minutes. Those who did not achieve seizure control within 10 minutes were treated with the alternate agent. Seizure control was achieved in a similar percentage of patients, 76.3% of those given levetiracetam and 75.6% of those given lorazepam. Of the patients who failed to respond to the initial drug, the percentage responding to alternate agent was 79.3% for levetiracetam and 88.9% for lorazepam. Seizure control at 24 hours was also comparable between the groups: 79.3% in those given levetiracetam initially and 67.7% in those given lorazepam. The only statistically significant difference between the groups was a higher need for mechanical ventilation in the lorazepam group (10 patients versus 4 in the levetiracetam group, p = 0.03).Additional clinical experience in this setting comes from McTague and colleagues who conducted a 2-year open-label observational study of IV levetiracetam in 51 children with acute repeated seizures or status epilepticus.[4] Patients ranged in age from 0.2 to 18.8 years, with a mean age of 7.1 years. The median starting dose was 14.4 mg/kg (range of 5–30 mg). Twenty-three children with repetitive seizures (59%) became seizure-free and four of five children had termination of their status epilepticus. Forty-two patients (81%) were started on maintenance levetiracetam. Three children developed aggressive behavior, with one child requiring discontinuation of the drug. These two studies, while limited by their small sample size, lend support to the consideration of levetiracetam as an alternative therapy for the management of pediatric status epilepticus.Seizure Prophylaxis With LevetiracetamPhenytoin has traditionally been given in the immediate period following head injury to protect against the development of early post-traumatic seizures. The 2012 Guidelines for the Acute Management of Severe Traumatic Brain Injury in Infants, Children, and Adolescents give the use of phenytoin prophylaxis a level III recommendation (the lowest category) based on the lack of quality research demonstrating its efficacy.[5] While phenytoin may be beneficial, it has several disadvantages, including the risk for arrhythmias and necrosis after extravasation, as well as potential drug interactions and the need for serum concentration monitoring.Some hospitals have begun using levetiracetam for prophylaxis of both early and late seizures after trauma, with a variety of treatment protocols ranging from 7 to 30 days. Klein and colleagues recently published the results of an open-label phase II study of levetiracetam added to phenytoin in patients at risk for post-traumatic epilepsy.[6] A total of 126 patients (86 adults and 40 children) completed the study at two level 1 trauma centers. All patients received phenytoin for one week after injury as standard care for prevention of early post-traumatic seizures. Sixty-six patients also received levetiracetam (55 mg/kg/day) for 30 days, while the remainder served as controls. Only two patients stopped treatment due to an adverse effect (somnolence). At 2 years post-injury, 9.1% of the patients given levetiracetam had developed post-traumatic seizures, compared to 13.3% of the controls. Although the study was too small to demonstrate statistical significance, the authors suggest that levetiracetam may be useful addition to phenytoin for the prevention of late post-traumatic epilepsy.Levetiracetam has also been suggested as an alternative to phenytoin for seizure prophylaxis in patients undergoing craniotomy. A group of investigators from the University Medical Center at Regensburg, Germany recently published a retrospective study of 235 adults and children (9 years of age and older) who received prophylactic perioperative phenytoin or levetiracetam.[7] The primary outcome was the development of seizures during the first week after surgery. Patients treated with phenytoin received 750 mg IV prior to surgery, followed by an infusion of 30 mg/hr for 24 hours. Phenytoin was continued for another 4 days, tapered from 100 mg three times daily down to 50 mg once daily. The levetiracetam group received 1,000 mg IV prior to and following surgery, with 1,000 mg given twice daily on day 2, 500 mg twice daily on day 3, and 500 mg daily on days 4 and 5. The incidence of seizures was no different between the two groups: 7/154 patients (4.5%) treated with phenytoin and 2/81 patients (2.5%) in the levetiracetam group (p = 0.66).While these studies suggest that levetiracetam may be an acceptable alternative to phenytoin for seizure prophylaxis, much more work is needed before it can be adopted as standard practice. Larger multicenter prospective studies, likely requiring the utilization of collaborative research networks, will be necessary to determine the clinical significance of AED prophylaxis in the trauma and postoperative settings.Levetiracetam Pharmacokinetics in NeonatesLevetiracetam has also become a popular choice for treatment of neonatal seizures that fail to respond to benzodiazepines or phenobarbital. Several studies, both prospective and retrospective, have been published within the past five years describing the safety and efficacy of levetiracetam in the neonatal population. In the July issue of Pediatric Research, Sharpe and colleagues published a study defining the pharmacokinetic profile of IV levetiracetam during the first week of life.[8] Eighteen term neonates with seizures failing to respond to phenobarbital received a 20 or 40 mg/kg loading dose, followed by 5–10 mg/kg/day for one week. The authors identified an increase in clearance, from a mean of 0.7 ± 0.27 mL/min/kg on day 1 to 1.33 ± 0.35 mL/min/kg on day 7. The corresponding half-life decreased from 18.5 ± 7.1 hrs to 9.1 ± 2 hrs. Values at day 7 were similar to those reported by other investigators in neonates up to 1 month of age. This rapid increase in clearance is not easily explained. Levetiracetam is eliminated primarily in the urine as unchanged drug. The reduced glomerular filtration rate of neonates would be expected to result in a slower clearance immediately after birth, with a gradual increase over time. The authors suggest that their findings may be explained by a reduced capacity for tubular reabsorption of levetiracetam in the neonatal kidney and suggest that more frequent dosing may be necessary during the first week of life.Rufinamide use in Lennox Gastaut SyndromeAn open-label observational trial of rufinamide was published earlier this year demonstrating the utility of this agent as adjunctive therapy in children with Lennox Gastaut syndrome (LGS).[9] A total of 128 children (1.8–19.9 years) underwent a 4-week titration, beginning at 10 mg/kg/day, followed by a 12-week maintenance phase. The average dose after titration was 31.7 ± 8.7 mg/kg/day. Forty-six of the 112 patients completing the study (35.9%) experienced at least a 50% reduction in seizure frequency. Ten children (7.8%) became seizure-free. Twenty-one children (16.4%) had an increase in seizure frequency. Over a third of patients experienced adverse effects; fatigue was reported by 11.7% and poor appetite by 7% of patients. The 31.7% overall response rate for rufinamide in patients not controlled with an average of 3 other AEDs demonstrates the potential for this agent in the treatment of refractory LGS.Sweat Chloride Concentrations With TopiramateOligohidrosis occurs in a small number of patients taking topiramate, but the mechanism underlying this adverse effect is not well understood. Although numerous cases of topiramate-induced hyperthermia and heat stroke have been reported in the literature, only one recent report describes an elevated sweat chloride concentration in the affected patient. To further characterize the mechanism for topiramate-induced oligohidrosis, Guglani and colleagues at the Children's Hospital of Pittsburgh conducted sweat chloride testing in 21 children on therapy for at least 6 months.[10] Twenty-one children (mean age 11.7 ± 4.1 years, range 6 months-18 years) were enrolled, as well as 20 healthy children (mean age 11.3 ± 4.2 years) who served as controls. Sweat chloride concentrations were significantly higher in the topiramate group, with a mean of 37.7 ± 18.8 mmol/L compared to a mean of 15.9 ± 6.9 mmol/L in the controls (p = 0.0001). Mean sweat volume was significantly lower in the children receiving topiramate (29.1 ± 17.4 μL compared to 41.2 ± 17.5 μL in the controls, p = 0.037). This study demonstrates that not only is sweat production altered in patients taking topiramate, but the chloride concentration of the sweat is abnormal as well. These differences were consistent among patients and occurred in a controlled environment, without the presence of hyperthermia. The authors suggest that future studies of topiramate-induced oligohidrosis include assessment for a dose-response relationship, correlation with topiramate serum concentrations, and evaluation of potential pharmacogenomic differences.Propylene Glycol-associated ApoptosisAlthough an international survey published earlier this year in Pediatric Neurology found that phenobarbital remains the most common choice for management of neonatal seizures among neurologists and neonatologists,[11] there are growing concerns over its potential for toxicity. Phenobarbital injection contains 68% propylene glycol and 10% ethanol as solvents. While the risk for these compounds to produce cardiotoxicity has long been known, new data suggests the potential for neurotoxicity as well.In a recent study from Washington University, Lau and colleagues examined the effects of phenobarbital and propylene glycol on the developing central nervous system of immature mice.[12] Tissue from mice exposed to propylene glycol demonstrated widespread apoptotic neurodegeneration. After 24 hours, there was evidence of apoptosis, destruction of axons and dendrites, and residual cellular debris. The greatest damage was documented 7 days after exposure. Administration of phenobarbital dissolved in propylene glycol produced greater damage than propylene glycol alone, suggesting a potentiation of apoptosis with the combination. This information, combined with the low efficacy of phenobarbital in terminating neonatal seizures and increasing interest in levetiracetam and topiramate in this population, has the potential to trigger a change in prescribing patterns.Behavioral Adverse EffectsOne of the most important issues when selecting an AED for a pediatric patient is the likelihood for adverse effects on learning and behavior. An in-depth review of the behavioral adverse effects of AEDs was published in the June issue of the Journal of Clinical Psychopharmacology.[13] Eddy and colleagues summarize the literature on 15 AEDs, including both older and newer drugs, with data from children and adults. Tables for the more commonly used AEDs provide a quick summary of the available studies and make this article a useful resource for any health care provider caring for children with seizures. In addition to presenting information on adverse effects, the authors point out studies describing the positive effects of some AEDs on learning and behavior. They also provide recommendations for future research, including the need for better age-based assessment tools.Efficacy of Perampanel in AdolescentsTwo new AEDs, perampanel and ezogabine, were approved by the Food and Drug Administration during 2012. Perampanel, a noncompetitive α–amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist, is indicated for use as adjunctive therapy in patients 12 years of age and older with partial-onset seizures. In the August issue of Neurology, French and colleagues published the results of a multicenter, double-blind, placebo-controlled phase III trial in 388 adolescents and adults.[14] Patients received 8 mg or 12 mg perampanel or placebo once daily for 13 weeks, after an initial 6-week titration period. The median percent change in seizure frequency was -21%, -26.3%, and -34.5% for the placebo, 8 mg, and 12 mg perampanel treatment groups (p = 0.0261 and p = 0.0158 for the 8 mg and 12 mg groups compared to placebo). The percentages of patients achieving a 50% reduction in seizure frequency during the 13-week maintenance period were 26.4%, 37.6%, and 36.1% for the three groups. The most frequent adverse effects were dizziness, somnolence, irritability, headaches, falls, and ataxia. Based on their results, the authors concluded that perampanel is an effective therapy for patients whose epilepsy has not been controlled with other AEDs.SummarySeveral important papers have been published on the use of AEDs in infants, children, and adolescents during the past year, ranging from extension studies assessing long-term efficacy and safety to reports of their use in new patient settings or new descriptions of adverse effects. These papers add a great deal to our understanding of the role these drugs can play in the treatment of seizures in the pediatric population.ReferencesAcknowledgments
The editors would like to thank Dr. Howard Goodkin for serving as a guest editor this month.

Pediatr Pharm. 2012;18(12) © 2012  Children's Medical Center, University of Virginia
Recent Literature on Pediatric Antiepileptic Drugs

jueves, 11 de julio de 2013

Protracted Bacterial Bronchitis

Archives of Disease in Childhood Protracted Bacterial Bronchitis Reinventing And old disecase Vanessa Craven, Mark L EverardDisclosures Arch Dis Child. 2013;98(1):72-76. Abstract and Introduction Abstract Chronic cough is common in the paediatric population, yet the true prevalence of this condition remains difficult to define. Protracted bacterial bronchitis (PBB) is a disease caused by the chronic infection of the conducting airways. In many children the condition appears to be secondary to impaired mucociliary clearance that creates a niche for bacteria to become established, probably in the form of biofilms. In others, immunodeficiencies, which may be subtle, appear to be a factor. PBB causes persistent coughing and disturbed sleep, and affects exercise tolerance, causing significant levels of morbidity. PBB has remained largely unrecognised and is often misdiagnosed as asthma. Introduction Unlike 'wheeze', persistent cough in childhood has received very little attention in the literature over the past four decades. Reviewing the relatively sparse literature relating to chronic cough in children suggests that its prevalence (coughing every day for many weeks or months) may be in the region of 8%, although some studies quote much higher figures.[1,2] This represents a huge unrecognised level of morbidity,[3] and for parents is a source of great frustration as clinicians frequently dismiss their concerns with statements such as 'it's just another cold' or 'it's his asthma cough'. It is common for children to be seen more than 20 times because of their cough before being referred.[4] As well as there being relatively few studies exploring the prevalence of persistent cough among children in the community, even fewer have attempted to determine its causes. Of those referred to one tertiary centre with a cough for at least 3 weeks, 54.5% were referred with a primary diagnosis of asthma. After investigations that included a bronchoscopy, the most common primary diagnosis (40%) was protracted bacterial bronchitis (PBB), with only 2% having this diagnosis at referral. The diagnosis of asthma was rarely substantiated,[5] findings that are very similar to those observed in our clinic. It should be noted that the few studies in primary care generate a different pattern of causes, including a higher prevalence of asthma (because most asthmatics are not referred to secondary care) and unrecognised pertussis infection in school age children. Despite PBB being an important cause of chronic morbidity, it is notable that this 'disease' did not feature in paediatric or even respiratory paediatric textbooks until very recently. Work highlighting the importance of this condition has led to its inclusion in national and international cough guidelines[6,7] and the recent Scottish Intercollegiate Guidelines Network (SIGN) and the British Thoracic Society (BTS) asthma guidelines, as an alternative diagnosis in a wheezy child who has a wet cough.[8] Much scepticism regarding the existence of PBB arises from the concept that a chronic bacterial infection would not be able to affect the lungs, an organ that has been traditionally thought of as sterile, unless the patient has a significant underlying disease such as cystic fibrosis, primary ciliary dyskinesia or an immunodeficiency. Recent advances in our understanding of the way bacteria behave in different settings are providing an opportunity to develop new conceptual models that permit us to understand the interaction of bacterial pathogens within the normal host bacterial flora in the upper and lower airways, thus challenging these beliefs. What is PBB? Historically, PBB[9] has been labelled in a variety of ways, including 'chronic bronchitis of childhood',[10] nomenclature that reflected the clinical phenotype. More recently terms have been used that describe the pathological process and the site of infection, namely persistent endobronchial infection and chronic suppurative lung disease.[11] In essence the condition is, as these names suggest, a protracted or persistent infection of the conducting airways by pathogenic bacteria, most commonly by non-typable Haemophilus influenzae (NTHi), Streptococcus pneumoniae and less commonly Moraxella catarrhalis. In PBB it is often found that more than one organism is identified in bronchoalveolar lavage (BAL) samples, and viral pathogens including rhinovirus, adenovirus, respiratory syncytial virus (RSV) and parainfluenza virus are also commonly detected by PCR.[12] It would appear that this condition, that was probably prevalent in the pre-antibiotic era and frequently led to bronchiectasis over time, is again becoming more common, having largely been forgotten for several decades. Over the past few years there has been a relative explosion of publications relating to this disease. Clinically the diagnosis is based on typical features suggestive of a persistent infection of the conducting airways by pathogenic bacteria, most noticeably a persistent 'wet' cough in the absence of signs indicative of an alternative specific cause, that resolves with appropriate antibiotics. This is analogous to the diagnosis of asthma that is based on a suggestive history and an unequivocal response to therapy. PBB Appears to be a Biofilm Disease An improved understanding of bacterial behaviour has provided us with a means to explain how some bacteria are able to persist so effectively within the conducting airways and in other related sites such as the middle ear and sinuses.[13] Their ability to remain in potentially hostile environments has been linked to the production of biofilms. A biofilm is a matrix secreted by some bacteria that is thought to enhance attachment, facilitate access to nutrients and decrease antibiotic penetration, thus providing substantial protection against antibiotics and making the bacteria difficult to eradicate with standard length courses of antibiotics.[14] In those with cystic fibrosis, the eradication of mucoid Pseudomonas aeruginosa is extraordinarily difficult once biofilms are established,[15] providing the rationale for the early, aggressive use of antibiotics in order to eliminate it from the airways before it becomes part of a biofilm structure. Biofilm production by NTHi has been seen in patients with cystic fibrosis[16] as well as in those with chronic otitis media[17] and chronic obstructive pulmonary disease.[18] It is important to recognise that there are two compartments within the lungs—the respiratory spaces (alveoli and respiratory bronchioles) and the conducting airways—each having very different structures and functions. The respiratory compartment has a huge cross-sectional area, with the thin wall of an alveolar epithelial cell and a capillary endothelial cell being all that separates pulmonary capillaries and the alveolar space. The conducting airways are much more complex structures, with multiple branches providing the structure for the large surface area, enabling gaseous exchange more peripherally while also protecting the fragile respiratory zone from pathogens and particulates. Organisms behave quite differently in the two regions. S pneumoniae and H influenzae can cause acute life threatening pneumonias when they rapidly divide in the respiratory compartment of the lung. In the majority of cases, response to antibiotics is prompt and dramatic. S pneumoniae and NTHi can also cause an acute bronchitis in the conducting compartment; if not cleared, the bacteria appear to form biofilms in which they replicate slowly and are able to persist for prolonged periods, being difficult to eradicate. This is attributable to their slow replication, together with the structural and biological adaptations of organisms protected within biofilms. What is the Role of the Host–Pathogen Interaction in PBB? It is now recognised that we encounter NTHi, S pneumoniae and M catarrhalis frequently and regularly. Prospective studies show a high prevalence of these organisms 'colonising' the upper airway in infancy and childhood, with them being detected in some from as early as the neonatal period.[19,20] It now appears that the 'normal' lower airways are not sterile, but also have their own resident microbiota consisting of large numbers of organisms, the majority of which are not able to be cultured using traditional microbiological techniques designed to isolate known pathogens.[21] Establishing a presence, even transiently, involves potential pathogens interacting with the host's microbiota as well as its physical and immunological defences. The organisms use different strategies to deal with these various challenges. An example of the complexity of these interactions is studies in vitro suggesting that S pneumoniae will out compete NTHi using, for example, hydrogen peroxide to displace it.[22] Conversely, in vivo, the neutrophilic inflammation induced by NTHi appears to confer an advantage over S pneumoniae. Both organisms appear to provide some protection against colonisation with Staphlococcus aureus.[23] Furthermore, external factors such as antibiotic therapy and smoking can disrupt the normal flora of the upper and lower airways and may predispose to the emergence of potential pathogens, a process well described in ventilator acquired pneumonia.[24] The Importance of Impaired Mucociliary Clearance Stasis in any system enables pathogens to thrive, and the most common reason for these organisms to become established in the lower airway appears to be the opportunity provided by impaired mucociliary clearance. This might be due to specific diseases such as cystic fibrosis and primary ciliary dyskinesia, or airway problems such as tracheobronchomalacia.[25] In asthma, particularly poorly controlled asthma, there may be poor mucociliary clearance and epithelial damage resulting from inflammation and mucus plugging. It appears that the loss of cilia and delayed recovery of normal function occurring with viral lower respiratory tract infections in early childhood may be a common predisposing factor permitting potential pathogens to exploit this opportunity.[26] What are the Clinical Features of PBB? Typically children with PBB are young, the majority of studies describing children less than 6 years old,[5,27] although it can commence at any time including into adulthood. Without carefully exploring the reported symptoms, the initial history given by parents can appear to be typical of asthma, with night-time coughing, shortness of breath with exercise, 'wheezing' and exacerbations with upper respiratory tract infections being typical. Affected children characteristically have a persistent 'wet' cough as opposed to the 'dry' nocturnal cough of asthma, although parents often find it difficult to make this distinction; the question 'does he sound like a 60 a day smoker first thing in the morning?' is often more helpful. The cough is typically persistent, with the question 'when did he last not have a cough?' being useful to distinguish a frequent intermittent cough from a persistent cough. Again the cough is typically worse when changing posture, just after lying down in bed and first thing in the morning, but can be present all night as occurs in asthma. Parents often describe their child becoming short of breath and coughing with exercise. Children with PBB typically cough so much that they appear to be gasping for breath, while the shortness of breath observed in asthmatics is not directly related to coughing and hence a simple report such as 'he gets short of breath and coughs with exercise' needs to be explored in more detail. It is also common to report that a child has a 'wheeze', although in one study, on closer questioning, this almost always represented a ruttle (a coarse, non-musical noise generated in the larger airways as a result of secretions that can be felt on the chest).[27] A viral infection will exacerbate both asthma and PBB. In PBB this is likely to be due to the release of planktonic forms of bacteria from biofilms, presumably in response to the associated inflammation which may help disseminate the organism as has been seen in cystic fibrosis.[28] As with exacerbations of asthma, children with PBB who have a viral respiratory tract infection, and indeed those with symptoms due to other causes such as pertussis, will experience increased symptoms for a period and then improve as they 'regress to the mean'. In these cases almost any intervention may be perceived to have been helpful, hence a very critical assessment of the response to treatment at the appropriate time is an essential part of the diagnostic process; one cannot simply provide 2 weeks of antibiotics and see the patient again several weeks later. In an area where response to treatment is a large component of the diagnostic process, this phenomenon can, and frequently does, lead to misdiagnoses. Unequivocal improvement following the introduction of a treatment such as an inhaled corticosteroid for a child with probable asthma or antibiotics for PBB is necessary to help confirm a presumptive diagnosis. One looks for a dramatic improvement that transforms the child's health; 'he is a new child', not simply 'he is coughing less'. Children with PBB generally do not look unwell, yet the morbidity resulting from disturbed sleep for both the child and their parents and the impact on their general well being is frequently significant if the right history is sought.[29] When the condition is treated effectively, parents do report that the cough resolves for the first time, but more importantly for them, they generally say that they have 'a new child' because of the impact on their general health and activity. Anecdotally PBB has become far more prevalent over the past 15 years, a period that has seen a progressive fall in antibiotic use.[30] In primary care, treating suspected viral respiratory tract infections with antibiotics has been discouraged, but perhaps the caveat that a persistent cough may need treatment has been forgotten. Quite when antibiotics should be given is unclear, but a persistent wet cough (in contrast to the dry 'post-viral' or 'non-specific' cough frequently seen in primary care) that is not improving after 2–3 weeks might be a reasonable compromise. At this stage, a traditional 5–7-day course is probably effective; when later, such courses may have little impact. Parents often report that antibiotics have not helped, which is interpreted as making PBB unlikely, but on closer questioning it may be that the cough was improving, with symptoms worsening quickly when the antibiotics were stopped. The role of defects in the immunological aspects of the host response remains unclear. In the majority of patients there are no identifiable major immunodeficiencies, but relatively minor or transient development defects may play a role in some.[31] When and How to Diagnose PBB? An increasing number of clinical pathways and investigation guidelines for chronic cough in childhood exist.[6,29,32,33] Chest radiographs are often normal or may have only minor abnormalities such as peribronchial wall thickening, findings consistent with other conditions such as viral lower respiratory tract infections, poorly controlled asthma and recurrent minor aspirations. Hyperinflation is uncommon and should again raise the question of asthma alone or the co-existence of PBB with asthma.[29] Cough swabs can be useful but have a relatively low sensitivity.[27] The definitive investigation, although invasive, is fibreoptic bronchoscopy with BAL, although care is needed when interpreting results. Timing of this is dependent on discussions with parents, and generally we reserve this for those who continue to relapse after three courses of antibiotics, but some parents prefer to have a definitive diagnosis at the outset. Identifying a significant cause such as mild variant cystic fibrosis or an immunodeficiency is uncommon, thus we generally treat patients with two or three courses of antibiotics before proceeding to bronchoscopy and undertaking immunological investigations. In cases where there are concerning features or parental desire for a 'definitive' test, we may proceed directly to these, but this is influenced by the severity of symptoms. Typically we find secretions and oedematous collapsible bronchi that collapse during suctioning while undertaking a BAL. Antibiotic usage within a month often results in a negative culture, even in a child with significant symptoms, hence the timing of bronchoscopy in relation to recent antibiotic courses is important although positive cultures can be obtained despite recent antibiotic use.[34] How is PBB Treated? This is largely an evidence-free zone. A meta-analysis studying the treatment of 'prolonged' cough (greater than 10 days) in the absence of a diagnosis or an isolated infective cause, found only two small, randomised controlled trials that included a placebo or a control group. They both studied children under 7 years old and neither study was deemed of high quality. Their conclusion was that treatment with antibiotics was beneficial, with one clinical cure for every three children treated. The review supported the use of antibiotics in children with a prolonged wet cough, although called for further randomised controlled trials using a better study design and validated outcome measures.[35] A more recent double blind study involving 50 children found that 2 weeks of co-amoxiclav, led to resolution of cough in 48% of children with a 'wet' cough lasting more than 3 weeks compared with 16% of those receiving placebo.[36] None of the studies undertook longer follow-up. The aim of treatment is to eradicate bacteria and to allow regeneration of the epithelium in the absence of infection. Two weeks of high dose antibiotics such as co-amoxiclav (40 mg/kg/day amoxicillin content) would normally lead to resolution of the cough and a dramatic improvement in the child's quality of life, however recurrence of symptoms is described, and repeated courses of antibiotics may be necessary to achieve clinical improvement. In a recent study, more than 70% of those treated with antibiotics for 2 weeks or longer relapsed.[25] As the epithelium is likely to be damaged and impaired mucociliary clearance will persist beyond clearance of organisms, we empirically use prolonged courses of 6–8 weeks, but the optimal treatment remains to be determined. By definition the cough must resolve with a course of appropriate antibiotics; usually the effect of treatment is dramatic, with the child's family reporting a significant improvement in their symptoms. Shorter courses of antibiotics tend to result in a partial resolution of the cough or a cough that will relapse after a few days off treatment, differing from community acquired pneumonias for which 5–7 days' treatment is usually sufficient. Donnelly found over half (51%) of their cohort were completely symptom-free after two courses of antibiotics, with only 13% requiring six or more courses or needing continuous prophylactic antibiotics for at least one winter.[27] Unfortunately we do not know the best therapeutic approach, and there is a need to review the balance of the undoubted benefits to the individual in terms of quality, with potential problems resulting from development of antibiotic resistance, although anecdotally we observe a very low instance of apparent resistance. Inevitably prevention is always going to be better than cure, so early intervention with short courses of antibiotics would appear desirable, but is difficult to implement in the current climate without good diagnostic techniques. Whether vaccines against NTHi will ever prove to be effective is unclear. The use of pneumococcal conjugate vaccines has not reduced the incidence of this condition. In our cohort non-vaccine serotypes are predominantly isolated, although this does appear to be in part attributable to serotype replacement following the introduction of conjugate pneumococcal vaccines.[37] Whether the less virulent non-vaccine serotypes are better suited to a biofilm existence is unclear. What is the Natural History of PBB? The 'vicious circle hypothesis' is generally accepted as the most plausible explanation for the development of bronchiectasis in most patients.[38] Implicit in this hypothesis is the development of impaired mucociliary clearance and chronic endobronchial infection, leading to inflammation and damage to the wall of the conducting airways that is eventually evident on high resolution computerised tomograph (HRCT) scans. Attempts to break this circle and permit full recovery of the epithelium include antibiotics to treat infection, physiotherapy to improve clearance, and in the case of cystic fibrosis, anti-inflammatory agents such as macrolides, DNAse and osmotic agents to help restore mucociliary clearance. The treatment of many viral upper respiratory tract infections with antibiotics possibly prevented the development of PBB and thus bronchiectasis in the years when cases appeared less, although this may also be secondary to an under-appreciation of the problem. The progression to bronchiectasis may take many years or even decades. The progression from a 'wet' cough, to producing purulent sputum without radiological evidence of bronchiectasis, to established bronchiectasis was well described in the pre-antibiotic days when the term 'pre-bronchiectasis' was used.[39] The rate of deterioration is thought to be determined by the extent and type of infection, the frequency of exacerbations, the nature of any underlying conditions, and the use, efficacy and adherence to medical therapy. What is the Danger of Recognising This New/Old Diagnosis? PBB is a real and significant cause of morbidity. Its prevalence in the community is unclear, but is likely to be growing with changes in antibiotic usage and possibly as a result of the H influenzae type B and pneumococcal conjugate vaccines.[37] PBB accounts for nearly half of the referrals to our 'general' respiratory clinics at present, the majority of asthma being diagnosed and managed in primary care. Despite this, it must not be forgotten that asthma is the commonest cause of significant respiratory symptoms in childhood and we must guard against returning to mistreating asthma with antibiotics. For those who are new to the area and who see the dramatic impact that antibiotics can have on the lives of children with PBB, there is a danger that we misdiagnose mild asthmatics as having PBB and begin to over-use antibiotics again to treat exacerbations of asthma. It is also important to recognise that asthma per se predisposes to PBB, particularly if poorly controlled, and hence in a patient with definite asthma who has a persistent wet cough, antibiotics may have an important role but they should not be used to treat exacerbations of asthma mislabelled as 'chest infections'. Paediatric respiratory medicine continues to rely on accurate history taking and assessing the response to therapies. Asthma, recurrent wheezy bronchitis (wheezing due to a viral bronchitis without significant bronchospasm), frequent viral respiratory tract infections and PBB share many clinical features, and hence accurate assessment in the absence of diagnostic tests remains difficult. Many children and their families continue to experience unnecessary morbidity due to medical models of respiratory disease that do not embrace the complexities of the host's interactions with microorganisms, pollutants and allergens. Summary In a child in whom a persistent 'wet' cough is a prominent feature, the diagnosis of a persistent bacterial bronchitis should be considered, either alone or as a co-morbidity with asthma (antibiotics should not be used to treat exacerbations of asthma but may have a role in an asthmatic with a persistent wet cough). In recognising the existence of this condition, it is important that we do not go full circle and treat exacerbations of asthma with antibiotics; careful history taking and a robust approach to reviewing the response to therapy at the appropriate time are key components of the diagnostic process for asthma and alternative diagnoses. If the response is not as anticipated, the diagnosis must be revisited in order to try to minimise the morbidity associated with misdiagnosis, but if improvement is seen, the result is often a dramatic improvement in the child's and their parents' quality of life. References Faniran AO, Peat JK, Woolcock AJ. Measuring persistent cough in children in eEpidemiological studies—development of a questionnaire and assessment of prevalence in two countries. Chest 1999;115:434–9. Cook DG, Strachan DP. Parental smoking and prevalence of respiratory symptoms and asthma in school age children. Thorax 1997;52:1081–94. Newcombe PA, Sheffield JK, Juniper EF, et al. Development of a parent-proxy quality-of-life chronic cough-specific questionnaire. Chest 2008;133:386–95. Marchant JM, Newcombe PA, Juniper EF, et al. What is the burden of chronic cough for families? Chest 2008;134:303–9. Marchant JM, Masters IB, Taylor SM, et al. Evaluation and outcome of young children with chronic cough. Chest 2006;129:1132–41. Shields MD, Bush A, Everard ML, et al. Recommendations for the assessment and management of cough in children. Thorax 2008;63:1–15. Gibson PG, Chang AB, Glasgow NJ, et al. CICADA: Cough in Children and Adults: Diagnosis and Assessment. Australian cough guidelines summary statement. Med J Aust 2010;192:265–71. British Thoracic Society Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. Thorax 2008;63(Suppl 4):iv1–21. Chang AB, Landau LI, Van Asperen PP, et al. Cough in children: definitions and clinical evaluation—position statement of the thoracic society of Australia and New Zealand. Med J Aust 2006;184:398–403. Field CE. Bronchiectasis in childhood.3. Prophylaxis, treatment and progress with a follow-up study of 202 cases of established bronchiectasis. Pediatrics 1949;4:355–72. Chang AB, Boyce NC, Masters IB,, et al. Bronchoscopic findings in children with non-cystic fibrosis and chronic suppurative lung disease. Thorax 2002;57:935–8. Algar VE, Choi G, Douros K, et al. Neutrophil count trends in BAL samples from children being investigated for chronic cough. Eur Resp J 2012;In press. Bakaletz L. Bacterial biofilms in the upper airway—evidence for role in pathology and implications for treatment of otitis media. Pediatr Respir Rev 2012;13:154–9. Stewart PS. Mechanisms of antibiotic resistance in bacterial biofilms. Int J Med Microbiol 2002;292:107–13. Bjarnsholt T, Jensen PO, Fiandaca MJ, et al. Pseudomonas aeruginosa biofilms in the respiratory tract of cystic fibrosis patients. Pediatr Pulm 2009;44:547–58. Starner TD, Zhang N, Kim G, et al. Haemophilus influenzae forms biofilms on airway epithelia—implications in cystic fibrosis. Am J Resp Crit Care 2006;174:213–20. Hall-Stoodley L, Hu FZ, Gieseke A, et al. Direct detection of bacterial biofilms on the middle-ear mucosa of children with chronic otitis media. JAMA 2006;296:202–11. Kyd JM, McGrath J, Krishnamurthy A. Mechanisms of bacterial resistance to antibiotics in infections of COPD patients. Curr Drug Targets 2011;12:521–30. Pelton S. Regulation of bacterial trafficking in the nasopharynx. Pediatr Respir Rev 2012;13:150–3. Aniansson G, Alm B, Andersson B, et al. Nasopharyngeal colonization during the first year of life. J Infect Dis 1992;165:S38–42. Hilty M, Burke C, Pedro H, et al. Disordered microbial communities in asthmatic airways. Plos One 2010;5:e8578. Pericone CD, Overweg K, Hermans PWM, et al. Inhibitory and bactericidal effects of hydrogen peroxide production by Streptococcus pneumoniae on other inhabitants of the upper respiratory tract. Infect Immun 2000;68:3990–7. Pettigrew MM, Gent JF, Revai K, et al. Microbial interactions during upper respiratory tract infections. Emerg Infect Dis 2008;14:1584–91. Trouillet JL, Chastre J, Vuagnat A, et al. Ventilator-associated pneumonia caused by potentially drug-resistant bacteria. Am J Resp Crit Care 1998;157:531–9. Kompare M, Weinberger M. Protracted bacterial bronchitis in young children: association with airway malacia. J Pediatr 2012;160:88–92. Everard M. Recurrent lower respiratory tract infections: going around in circles, respiratory medicine style. Pediatr Respir Rev 2012;13:139–43. Donnelly D, Critchlow A, Everard ML. Outcomes in children treated for persistent bacterial bronchitis. Thorax 2007;62:80–4. Chattoraj SS, Ganesan S, Jones AM, et al. Rhinovirus infection liberates planktonic bacteria from biofilm and increases chemokine responses in cystic fibrosis airway epithelial eells. Thorax 2011;66:333–9. Chang AB, Redding GJ, Everard ML. Chronic wet cough: protracted bronchitis, chronic suppurative lung disease and bronchiectasis. Pediatr Pulmon 2008;43:519–31. Gulliford M, Latinovic R, Charlton J, et al. Selective decrease in consultations and antibiotic prescribing for acute respiratory tract infections in UK primary care up to 2006. J Pub Health 2009;31:512–20. Nikolaizik WH, Warner JO. Etiology of chronic suppurative lung disease. Arch Dis Child 1994;70:141–2. Bailey EJ, Morris PS, Kruske SG, et al. Clinical pathways for chronic cough in children. Cochrane Database Syst Review 2008;2:CD006595. Chang AB, Robertson CF, van Asperen PP, et al. Can a management pathway for chronic cough in children improve clinical outcomes: protocol for a multicentre evaluation. Trials 2010;11:103. De Schutter I, De Wachter E, Crokaert F, et al. Microbiology of bronchoalveolar lavage fluid in children with acute nonresponding or recurrent community-acquired pneumonia: identification of nontypeable Haemophilus influenzae as a major pathogen. Clin Infect Dis 2012;52:1437–4. Marchant JM, Morris P, Gaffney JT, et al. Antibiotics for prolonged moist cough in children. Cochrane Database Syst Review 2005;4:CD004822. Marchant J, Masters IB, Champion A,, et al Randomised controlled trial of amoxycillin clavulanate in children with chronic wet cough. Thorax 2012;67:689–93. Prifits K, Slack M, Anthracopoulos MB, et al. Streptococcus pneumoniae and non-typable Haemophilus influenzae causing bacterial bronchitis in children and the impact of vaccination. Chest 2012;In press. Cole PJ. Inflammation—a two-edged-sword—the model of bronchiectasis. Eur J Resp Dis 1986;69:6–15. Field CE. Bronchiectasis in childhood 2. Aetiology and pathogenesis, including a survey of 272 cases of doubtful irreversible bronchiectasis. Pediatrics 1949;4:231–48.

Clostridium dificile

From the American Academy of Pediatrics Policy Statement Clostridium difficile Infection in Infants and Children COMMITTEE ON INFECTIOUS DISEASES. 2013 Next Section ABSTRACT Infections caused by Clostridium difficile in hospitalized children are increasing. The recent publication of clinical practice guidelines for C difficile infection in adults did not address issues that are specific to children. The purpose of this policy statement is to provide the pediatrician with updated information and recommendations about C difficile infections affecting pediatric patients. KEY WORDS Clostridium difficile Clostridium difficile infections antibiotic-associated diarrhea Abbreviations: CCCA — cell culture cytotoxicity assay CDI — Clostridium difficile infection EIA — enzyme immunoassay FDA — Food and Drug Administration NAAT — nucleic acid amplification test NAP1 — North American pulsed field type 1 PCR — polymerase chain reaction Previous Section Next Section INTRODUCTION Clostridium difficile is a spore-forming, obligate anaerobic, Gram-positive bacillus and is acquired from the environment or by the fecal-oral route. Toxins A and B are responsible for intestinal disease. C difficile is the most common cause of antimicrobial-associated diarrhea and is a common health care-associated pathogen. Clinical symptoms vary widely, from asymptomatic colonization to pseudomembranous colitis with bloody diarrhea, fever, and severe abdominal pain. The incidence of C difficile infections (CDIs) among hospitalized children has been increasing across the United States since 1997.1–3 Kim et al evaluated the annual incidence of C difficile–associated disease from 2001 to 2006 at 22 freestanding children’s hospitals and found increases in the number of admissions (2.4 to 4.0/1000 admissions; P = .04) as well as the number of cases per patient-days in the hospital (4.4 to 6.5 cases/10 000 patient-days; P = .06).1 Nylund et al evaluated data from 1997, 2000, 2003, and 2006 and demonstrated an increase in the number of CDIs, from 3565 cases in 1997 to 7779 cases in 2006 (total cases, 21 274; P < .01).2 Zilberberg et al also demonstrated an increase of hospitalizations attributable to C difficile, from 7.24 to 12.80/10 000 hospitalizations.3 The emergence of the epidemic strain of toxin-producing C difficile (North American pulsed field type 1 [NAP1]) in recent years may have changed the epidemiology in children. Published guidelines for managing CDI in adults affirm that there are gaps in the knowledge surrounding CDIs in infants and children.4 Disease in the Neonate/Infant/Young Child 0 to 3 Years of Age Although testing of infants is not recommended, recent data have shown that 26% of children hospitalized with CDIs were infants younger than 1 year, and 5% were neonates.1 What cannot be determined from these data are whether the rates of hospitalization for CDIs represent true disease or asymptomatic carriage. The intestine of the newborn infant is sterile, but by 12 months of age, an infant’s intestine has flora similar to that of an adult.5C difficile carriage rates average 37% for infants 0 to 1 month of age and 30% between 1 and 6 months of age.5 Vaginal delivery, premature rupture of membranes, and previous administration of antimicrobial agents have little effect on carriage rates, but exposure to environments where C difficile is present (eg, ICUs) is important.6–8 The organism has been recovered from the hands of hospital personnel, baby baths, oximeters, electronic thermometers, and hospital floors. Breastfed infants have lower carriage rates than do formula-fed infants (14% vs 30%, respectively).9 At 6 to 12 months of age, approximately 14% of children are colonized with C difficile, and by 3 years of age, the rate is similar to that of nonhospitalized adults (0% to 3%).5 Recognized risk factors for older children acquiring CDI included antimicrobial therapy, use of proton pump inhibitors, repeated enemas, use of diapers, prolonged nasogastric tube insertion, gastrostomy and jejunostomy tubes, underlying bowel disease, gastrointestinal tract surgery, renal insufficiency, and impaired humoral immunity. Carriage rates in hospitalized children and adults approximate 20%.4 Many of these risk factors are common among hospitalized children; the presence of risk factors does not necessarily prove causation of CDI in an individual patient. Clinical illness is rarely reported before 12 to 24 months of age. It is possible that neonates/infants may lack the cellular machinery to bind and process the toxins of Clostridium species.10 There have been relatively few studies of C difficile with diarrhea that include control groups. In an emergency department treating children, 7% of patients with diarrhea and 15% of controls were colonized with C difficile.11 In 2 studies of inpatients 0 to 2 years of age, 11% to 59% of patients with diarrhea and 24% to 33% of controls were colonized with C difficile.12,13 Among inpatients 0 to 34 months of age, 21% of those with diarrhea and 33% of controls carried C difficile.14 Among patients 0 to 12 years of age, 2.9% of outpatients, 4.6% of inpatients, and 6.6% of controls were colonized with C difficile.15 In the setting of a high prevalence of asymptomatic carriage, detection of C difficile toxin cannot be assumed to be the causative agent for diarrhea in children before adolescence, particularly young children.16 The NAP1 Isolate of C difficile The NAP1 strain of C difficile has been described as causing severe disease, including an increased incidence of symptomatic infection relative to colonization, recurrent disease, sepsis, toxic megacolon, bowel perforation, and mortality.17 The NAP1 strain has entered the pediatric population at lower rates (10%–19% of C difficile isolates) than reported for adults (>50%).18,19 NAP1-associated CDIs occur in children without exposure to health care facilities and/or to antimicrobial agents.20,21 Whether the NAP1 strain is truly responsible for more severe disease in children requires further investigation. Newer strains of C difficile have also been isolated (eg, NAP7, NAP8), and their role in human disease has yet to be elucidated completely.22 Detection of the NAP1 strain of C difficile is not possible in most laboratories and, in most situations, would not influence the clinical care of an individual patient. DIAGNOSTIC TESTING The diagnosis of C difficile disease is based on the presence of diarrhea and of C difficile toxins in a diarrheal stool specimen. Diarrhea is often defined as 3 or more stools that take the shape of their container in a 24-hour period. Because of a slow turnaround time, isolation of the organism from stool is not a clinically useful diagnostic test, nor is testing of stool from asymptomatic patients. The cell culture cytotoxicity assay (CCCA) has been replaced by more sensitive diagnostics. The most common testing method used today for C difficile toxins is the commercially available enzyme immunoassay (EIA), which detects toxins A and/or B. Mean test sensitivities range from 72% to 82%, with mean specificities of 97% to 98%, compared with the CCCA.23 With low prevalence rates of disease in children, sensitivities and specificities such as these lead to an unacceptably low positive predictive value, thus limiting the usefulness of such testing.11–15 Testing for glutamine dehydrogenase produced by C difficile should only be used as part of a 2-step algorithm with a confirmation of positive results by using either a toxin assay A/B EIA or a CCCA.4 Molecular assays using nucleic acid amplification tests (NAATs) are approved by the US Food and Drug Administration (FDA) and are now preferred by many laboratories. NAATs combine good sensitivity and specificity, have turnaround times comparable to EIAs, and are not required to be part of a 2- or 3-step algorithm.24 In a recent study, the sensitivities of the real-time polymerase chain reaction (PCR) assay for toxin A/B compared with EIA for toxin A/B were superior (95% vs 35%, respectively), and the specificity was equal (100%).25 With the use of the PCR, the positivity rates for stool samples doubled, from 7.9% to 8.3% with EIA to 14.9% to 18.1% with PCR, and the numbers of repeated samples decreased. Many children’s hospitals are converting to NAAT technology to diagnose CDIs, but more data are needed before NAATs can be used routinely.4 Because carriage is so common, it is prudent to avoid routine testing for C difficile in children younger than 1 year. Testing for C difficile can be considered in children 1 to 3 years of age with diarrhea, but testing for other causes of diarrhea, particularly viral, is recommended first.19 For children older than 3 years, testing can be performed in the same manner as for older children and adults. Endoscopic findings of pseudomembranes and hyperemic, friable rectal mucosa suggest pseudomembranous colitis and are sufficient to diagnose a CDI at any age. A common mistake is to use EIAs and NAATs as tests of cure after treatment of CDIs. C difficile, its toxins, and genome are shed for long periods after resolution of diarrheal symptoms. None of the assays are licensed or recommended for tests of cure. Excretion of toxin approximates 13% to 24% at 2 weeks and 6% at 4 weeks after therapy.26,27 Given that NAAT testing is more sensitive than toxin assays, an interval greater than 4 weeks since last testing should be used for testing with a recurrence. TREATMENT Discontinuation of antimicrobial agents is the first step in treating CDI and may suffice in most instances. For patients with moderate or severe disease, proper empirical antibiotic treatment should be started as soon as the diagnosis is suspected. Antiperistaltic medications should be avoided because they may obscure symptoms and precipitate complications, such as toxic megacolon. Although orally administered vancomycin is still the only agent approved by the US FDA for the treatment of CDI in children, it was replaced as the drug of choice in the 1990s in response to concerns over the emergence of vancomycin-resistant enterococcus. Metronidazole is currently the drug of choice for the initial treatment of children and adolescents with mild to moderate disease on the basis of efficacy, cost, and antimicrobial stewardship. Oral vancomycin or vancomycin administered by enema with or without intravenous metronidazole is indicated as initial therapy for patients with severe disease and for patients who do not respond to oral metronidazole.4 Severe or fatal disease is more likely to occur in neutropenic children with leukemia, in children with intestinal stasis (eg, Hirschsprung disease), and in patients with inflammatory bowel disease. Prospective trials for therapy longer than 10 days have not been performed for either drug. Historically, metronidazole resistance in C difficile was rare, and there is no evidence that the new epidemic isolates, NAP1, is more resistant to metronidazole compared with the nonepidemic isolates. A recent randomized controlled trial evaluating a subgroup of patients with severe disease suggested that vancomycin treatment was superior to metronidazole even in patients infected with the NAP1 isolate.28 Extrapolating these data to treatment with infants and children is difficult, and more data are required. Up to 30% of patients treated for CDIs experience a recurrence after discontinuing therapy. Recurrences represent either relapse with the original isolate or reinfection with a new isolate. In clinical practice, the distinction cannot be made. Patients with a recurrence will usually respond to a second course of the same treatment. Metronidazole should not be used for the treatment of the second recurrence (third episode) or for chronic therapy (because of possible neurotoxicity4), and tapered or pulsed regimens of vancomycin are recommended for this situation. Vancomycin therapy is recommended in adults with the first recurrence if the patient has a white blood cell count of 15 000/μL or higher or has an increasing serum creatinine concentration, because they are at a higher risk of developing complications from CDI. No data exist for children. Other antimicrobial agents with activity against C difficile include nitazoxanide, fidaxomicin (FDA approved for treatment of CDI in adults in 2011), and rifaximin; criteria for optimal use of these drugs in children are unknown. Because there is a lack of controlled studies in children, probiotics are not recommended for either the prevention or the treatment of CDI. In rare instances, severely ill patients may require cecostomy for irrigation or a colectomy. Fecal transplantation (enteric administration of donor stool flora) is used anecdotally.29 CONTROL Transmission is via the fecal-oral route, and CDI is transmitted to others by contact with the patient or the patients’ contaminated environment. Control of C difficile in the environment is essential to the control of CDIs in health care facilities. People with C difficile–associated diarrhea should be placed in standard plus contact precautions for the duration of their diarrhea. Test of cure is not recommended; the patient may be removed from isolation once the diarrhea has resolved. Use of gloves is the best proven method for preventing patient-to-patient transmission via the hands of health care personnel. Hand-washing with soap and water is more effective for the removal of spores than is alcohol-based hand sanitizer. Germicidal wipes with 10% sodium hypochlorite are good adjuncts for cleaning the environment, especially in an outbreak situation. RECOMMENDATIONS Testing for C difficile colonization or toxin should only be performed in children with diarrhea who meet the clinical and age-related conditions listed in the following recommendations. Testing in infants (younger than 12 months of age) is complicated by a high rate of asymptomatic colonization. Testing of these infants should be limited to those with Hirschsprung disease or other severe motility disorders or in an outbreak situation. Alternative etiologies should be sought even in those with a positive test result for C difficile. Testing in the second and third year of life is difficult to interpret; alternative etiologies should be sought. A positive test result indicates possible CDI. A positive test result after the third year of life indicates probable CDI. Risk factors increasing the probability of CDI include antimicrobial therapy, use of proton pump inhibitors, underlying bowel disease, renal insufficiency, or impaired humoral immunity. Endoscopic or histologic test results positive for pseudomembranous colitis indicate definite CDI. Test of cure is not recommended. Testing for recurrences less than 4 weeks after initial testing is only useful when the results of repeat testing are negative. Discontinuation of antimicrobial agents is the first step in treating CDI and may suffice in most instances. Antiperistaltic medications should be avoided. When antimicrobial treatment is indicated for moderate disease, metronidazole (30 mg/kg/day in 4 divided doses, orally; maximum, 2 g/day) is the drug of choice for initial treatment of first episode of CDI and for first recurrence. Oral vancomycin (40 mg/kg/day in 4 divided doses; maximum, 2 g/day), with or without metronidazole, is recommended for severe disease and second recurrence. Use of gloves with symptomatic patients, washing of hands with soap and water, and environmental decontamination using chlorine products are key control measures. Contact isolation may be removed once the diarrhea has resolved. REFERENCES ↵ Kim J, Smathers SA, Prasad P, Leckerman KH, Coffin S, Zaoutis T. 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