Current Pediatric Reviews (v.7, #3)

Dedication to Dr. Raffaella Rosso (Late) by Bentham Science Publishers (i-i).
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About 30 years ago the first cases of AIDS among adults were reported in MMWR [1]. It was soon clear that the HIVepidemic was affecting not only adults but also children [2].The search for a treatment started almost immediately and the first drug identified for antiretroviral treatment (ART) waszidovudine for both adults and children [3, 4]. In less than ten years the time of Highly Active Antiretroviral Treatment(HAART) came for adults [5]. It took some more time to have a triple combination of antiretroviral drugs as the standard ofcare in children, too [6]. Excellent results arrived soon, but it rapidly became clear that ART management presented severalchallenges [7, 8]. Nowadays, we are facing a pediatric HIV epidemic that has virtually stopped expanding in developed countries. Conversely,in developing countries there is still an ongoing epidemic, although progressing slower than in the past [9]. In particular, themajority of new pediatric cases of HIV infection are concentrated in this latter area of the world. When planning for this special issue it was considered interesting to collect updated information that could supportpediatricians working where most cases of HIV infection in children are (i.e. first- and second-line ART in resource-limitedsettings; TB/HIV co-infection). Nevertheless, issues not strictly related to developing countries, but also challenges forpediatric ART that could be relevant for all settings (i.e. adherence; pharmacokinetics; immune recovery) were addressed.This special issue could not necessarily cover all possible issues of pediatric HIV-infection management in all possiblesettings. However, it can surely provide a source of highly qualified information for those who want to improve management ofHIV-infected children in their Institutions.

Feasibility and Challenges in Providing Antiretroviral Treatment to Children in Sub-Saharan Africa by Janneke H. van Dijk, William J. Moss, Catherine G. Sutcliffe (154-165).
The scale-up of pediatric antiretroviral therapy (ART) in sub-Saharan Africa over the past decade involvedunprecedented political and donor commitment. These pediatric ART programs have demonstrated they can provide ARTto human immunodeficiency virus (HIV)-infected children and that these children achieve treatment outcomescomparable to children in high-resource settings. Several obstacles, however, have hindered program implementation andimpacted treatment outcomes. Challenges particularly affecting children include shortages of properly trained healthcareproviders, lack of laboratory capacity for infant diagnosis and pediatric treatment monitoring, poor adherence, disclosureof HIV infection status and attrition. Innovative solutions to these challenges have been developed and programs aredemonstrating they can successfully expand services to increase ART coverage in affected communities. As programsoptimize the care and treatment of children, and more efficiently provide HIV services within the health care system, newchallenges arise, including integration of child and family health services, use of electronic health records and thepotential need for rationing antiretroviral drugs. Further evaluation of innovative solutions to these challenges and barriersto care, as well as continued commitment on the part of governments and donors, will be required if all HIV-infectedchildren are to receive proper care.

Current Research Issues in the Pharmacokinetics of Antiretroviral Drugs in Children by Natella Y. Rakhmanina, Edmund V. Capparelli (166-172).
Modern pediatric combination antiretroviral therapy faces a difficult challenge of preserving the focus on anindividual child while addressing the globalization of antiretroviral exposure. While the gains from pediatric antiretroviraltherapies have been tremendous, minimizing the lag between the approval of new antiretroviral agents in adults andgetting these therapies into infants and children, using appropriate formulations and dosages, has been challenging.Fortunately, the development of antiretroviral therapies has coincided with several important initiatives designed toenhance the drug approval process in children. With increased antiretroviral therapy exposure among pediatric patientsworldwide, the concerns for long-term adherence, antiretroviral drug resistance and long-term antiretroviral therapyassociated toxicities, some of which are only now beginning to be investigated in children, have arisen. This manuscriptreviews the major milestones in the evolution and changes in the design of the clinical trials of antiretroviral drugs inHIV-infected children throughout the development of pediatric antiretroviral therapy. It further investigates the role oftherapeutic drug monitoring in the clinical trials and clinical practice and discusses challenges of pediatric HIV therapyand antiretroviral drug development.

Antiretroviral and Antituberculosis Therapy in HIV-TB Co-Infected Children by Amy L. Slogrove, Helena Rabie, Mark F. Cotton (173-179).
HIV-infected children experience a high burden of tuberculosis. With recent advances in international pediatricHIV treatment guidelines significant numbers of infants and children will require simultaneous treatment for both TB andHIV. This article attempts to concisely outline strategies for effective co-treatment of both infections. Rifamycins, anessential component of short course TB chemotherapy, alter the metabolism of a number of antiretroviral drugs. Theseinteractions and their consequences are considered. Options for antiretroviral therapy and the optimal timing of itsinitiation in the presence of antituberculosis therapy are discussed.

Pediatric antiretroviral treatment programs have been rolled out in resource limited settings, providing lifesavingtreatment to approximately 300,000 HIV-infected children. The standard first-line antiretroviral regimen is a nonnucleosidereverse transcriptase plus 2 nucleoside reverse transcriptase inhibitors (NRTIs). A meta-analysis showed that70% of children achieved virologic suppression after 12 months of first line therapy. This article presents thechallenges in diagnosis of treatment failure in resource limited settings and reviews the current guidelines formanagement of HIV-infected children with second-line antiretroviral therapy. The details of antiretroviral drugsrecommended for second line regimens are summarized. The current standard second-line regimen is a boostedproteaseinhibitor-based regimen plus recycling NRTIs. The potential role of new ARV drug classes for second-lineregimen is addressed.

Recent Achievements in Understanding Immune Recovery of Children Treated with HAART by Mª Angeles Munoz-Fernandez, Rafael Correa-Rocha (188-198).
The natural course of HIV infection causes a severe depletion of CD4+ T cells, phenotypic alterations of T-cellsubsets and a decline in thymic function, which in turn produces a progressive impairment of the immune function. HIVinfectedchildren present some distinct features when compared to adults mainly due to the immaturity of immune systemand the preserved capacity of thymic renewal of immune cells. The introduction of highly active antiretroviral therapy(HAART) decreased mortality rates in HIV-infected children, and proved to be effective in suppressing plasma viral loadsand increasing CD4+ T-cell counts and T-cell rearrangement excision circles (TREC) levels in young HIV-infectedpatients. These findings indicate that recovery of thymic function is a pivotal event in immune reconstitution. Among thecytokines and hormones identified as possible regulators of thymopoiesis, IL-7 may play an essential role promoting thedifferentiation of thymocytes into mature T cells that will leave the thymus and move to the periphery in response to Tcelldepletion. HAART provides appropriate functional immune reconstitution in children to withdraw prophylaxisagainst some opportunistic infections, but a revaccination or antigenic reexposure could be required to restore theprotective immunity to some vaccine-preventable diseases. The immune reconstitution associated to HAART could alsoproduce an immune reconstitution inflammatory syndrome (IRIS). In conclusion, HAART treatment in HIV-infectedchildren has shown to be effective in decreasing viral load (VL) and recovering the T-cell population due to a preservedthymic function as well as the homeostatic mechanisms of IL-7.

Combination antiretroviral therapy (ART) for the treatment of HIV infection requires sustained adherence tomaintain its efficacy. Adherence to ART presents several challenges for children receiving it and for their caregivers andpediatricians. Many factors can affect adherence to ART; they can be divided into: 1) Factors related to the patient and thefamily; 2) Factors related to the drug/medication; and 3) Factors related to the health care system. Different strategies canbe employed to overcome some of the obstacles identified in these three groups. Some of these strategies are of provenefficacy; others have been proposed and tested only in small cohorts. Tailoring ART regimen on the daily activities of thechild and his/her family, coupled with an intensive education programme on adherence for child and caregivers, prior tostarting the treatment is probably one of the most effective interventions. Specific medication-related problems(depending on drug pharmacokinetic and pharmacodynamic, taste and palatability, food restrictions, etc.) exist; suchproblems cannot be solved solely by clinicians or by families. In this area, greater commitment of the pharmaceuticalindustry is still needed, and innovative solutions have to be identified by clinicians in partnership with drugmanufacturers. Furthermore, an “adherence strategy/programme” should be a key component of the ART delivery strategyof any institution treating HIV-infected children. Most of the necessary interventions to be included in such programmescan be easily implemented, but they require trained and committed staff (and institutions), and time to be spent withpatients and their caregivers.

When a child is having difficulty listening in noisy situations e.g. classroom, a hearing test should be considered as a firstdiagnostic step. If however, the hearing test is normal and the symptom persists, the pediatrician should consider requesting anauditory processing assessment. Hearing loss in childhood is known to interfere with communication, learning, languageacquisition, social life and academic achievements. Similarly Auditory Processing Disorder (APD) may affect a child’s abilityto communicate, normally acquire reading skills and it may interfere with social life and academic achievements. An estimated5% of school aged children may be affected by the disorder, which in many cases remains undiagnosed.This is a monothematic issue on pediatric (Central) Auditory Processing Disorder (APD or CAPD). The word monothematic iscompound and of Greek origin, “mono” meaning only one and “thematic” meaning topic. It focuses on raising awareness ofthis disorder and providing evidence and data on speech perception in noise, comorbidity of APD and reading disabilities(Dyslexia), the neural substrate of the disorder and objective biological measures as a supplement for assessment andmonitoring of management outcome. The aim is to provide a well-structured overview of presenting symptomatology,comorbidity and neurobiological origin. It should be noted that APD is too complex for all its features and controversies to bepresented in a single issue. Nevertheless, authors in this issue are presenting this disorder mainly from the clinician’s point ofview largely incorporating current research.The core deficit in APD is difficulty perceiving speech in noise in the presence of a normal hearing test (audiogram). A keypoint to be remembered by the general practice pediatrician is as Bantwal & Hall state “A normal audiogram does not rule out ahearing deficit. Indeed, we really hear with our brains, not our ears”. Both parental and child’s concern about hearing should beadequately addressed. Diagnosis of normal hearing sensitivity does not exclude the possibility of APD being present. As aresult of this core deficit a child's ability to communicate and learn may be impaired and comorbidity with reading disabilitiesmay present. These impairments have been shown to be associated with anxiety, low self-esteem and difficulty in acquiringfriends as possible presenting psychosocial problems and may ultimately lead to academic failure.30-50% of children with reading disabilities and/or learning disorders present with APD. Causality of this comorbidity is notconclusively defined at the present time. In this issue, preliminary results by Veuillet, Bouilhol & Thai-Van, are presentedshowing on one end differences in developmental trajectories of auditory descending pathway function between normal readingand dyslexic children and on the other end deficient high level process. Hearing is a sensation requiring bottom-upfunctionality, which is information conveyed and decoded from the peripheral auditory organ to the central auditory nervoussystem and the brain cortex. However, cognitive elements play a significant role accelerating information processing and this isdenoted as top-down functionality. Top-down and bottom-up functioning in the auditory system are synergistically processinginformation accomplishing auditory perception. Even though this mentioned relation exists, yet “Too rarely to this day, healthprofessionals faced with children with learning difficulties ask whether an APD is present” as noted in the conclusion paragraphof Veuillet et al.....

Pediatric Speech Perception in Noise by Anuradha R. Bantwal, James W. Hall III (214-226).
An acceptable acoustical environment is necessary for effective communication and learning. Children whoexperience abnormally poor speech perception in noise, including those with normal hearing sensitivity, are at risk forspeech and language delay, reading disorders, psychosocial problems, and academic failure. The biological bases ofspeech perception in noise are complex and include processes at cortical as well as sub-cortical levels of the auditorynervous system. In children, the ability to perceive speech in degraded listening conditions improves significantly withage in parallel with developmental changes in the auditory nervous system. Difficulty in listening to speech in noisysurroundings is a common symptom associated with auditory processing disorders (APD). Clinical assessment of speechperception in noise quantifies potential problems that a child might face in daily listening situations. Optimally, pediatricspeech in noise tests are designed to meet minimal psychometric criteria. A speech in noise test should be appropriate forthe child’s age and native language so as to minimize the role of linguistic factors. A diagnosis of APD should not bemade based solely on a speech in noise test but, rather, on a battery of tests, each exploring a different suprathresholdauditory process. Speech in noise tests should be used and interpreted with extreme caution when assessing auditoryprocessing in children with co-existing peripheral hearing loss. Children with normal hearing sensitivity, whoseperformance on tests using competing acoustic signals is below normal, can benefit from specific intervention and the useof signal enhancing devices such as FM systems.

Co-Morbidity of APD and Reading Disabilities by Evelyne Veuillet, Caroline Bouilhol, Hung Thai-Van (227-240).
Auditory processing disorders (APDs) are associated with an inability to process auditory information whichcannot be explained by abnormal hearing thresholds. This review focuses on APDs that are liable to be found in subjectswith language-based learning disabilities such as dyslexia. Although the causal relationship between the presence of anAPD and reading deficits is still poorly understood, it is clear that in many cases (estimated range between 30-50%) thepresence of an APD may serve as a marker of language-based learning problems. While some dyslexic children can becharacterized by poor performances in auditory temporal processing (resolution, masking, ordering, integration) they canalso experience hearing difficulties with competing or degraded acoustic signals (for example, during dichotic listening orin the presence of a noisy background). Behavioural hearing deficits are not always found in dyslexic children; whenpresent they may be explained, at least partly, by the task complexity which induces strong cognitive load. However, thereis no doubt that the co-morbidity of APD and dyslexia can create difficulties in communication and academic skills. Inaddition to these behavioural indices of APD, evidence for abnormal function of the descending auditory pathway isprovided in dyslexia. We here present preliminary results showing 1) differences in the developmental trajectories whennormal reading and dyslexic children are compared for auditory descending pathway function and 2) deficient high levelprocess (attention) which appears in literacy problems and auditory processing deficits (dichotic listening) throughfeedback connections from higher to lower areas. These abnormalities, in turn, may be accompanied by differentbehavioural manifestations of APD.

Central auditory processing deficits and central auditory processing disorder (CAPD) has been linked to anumber of different etiological bases. Reports document CAPD in children stemming from neurological abnormalities,including seizure disorders, neoplasms, degenerative processes, traumatic brain injury, cerebrovascular accidents,metabolic disorders, and genetic disorders across a variety of sites of lesion at all levels of the central auditory nervoussystem (CANS). Also documented is the efficiency of central auditory behavioral tests and electrophysiologicalprocedures in evaluating pediatric patients with known or suspected neurological involvement. All regions of the CANScan be assessed using auditory evoked potentials, electoacoustic procedures, and central auditory behavioral tests after acareful assessment of the peripheral auditory system. Multidisciplinary evaluation is crucial to both diagnosis andintervention given the potential for multiple system involvement, complex clinical profiles, and frequent co-morbidities inchildren with neurological problems. The patterns of performance deficits seen in children with documented CANSlesions are comparable to those patterns seen in adult patients with documented CANS lesions. Moreover, central auditorytest battery deficit patterns seen in children with auditory-related complaints but with no identifiable lesions of the CANSmirror those patterns seen in pediatric and adult populations with circumscribed disorders of the CANS, and these deficitpatterns correlate with neuroimaging results. These common patterns indicate that lesion studies of adult (or pediatric)patients can serve to approximate a ‘gold standard’ for CAPD in children with no identifiable CANS lesion. Whether thesource of CANS dysfunction is benign or the result of neurological lesion or compromise, the underlying source of theresulting CAPD is neurobiological, originating in the central nervous system.

Auditory processing impairments negatively impact language learning, the ability to listen effectively in noisyenvironments, and the development of reading skills. Behavioral assessments of auditory processing provide valuableinsight into auditory function but lack information about the biological health of the auditory pathway, and can becomplicated by comorbid disorders, alertness, and motivation. The speech-evoked auditory brainstem response hasrecently been linked to communication skills such as speech-in-noise perception and reading ability and providesadditional insight for the diagnosis and management of auditory processing disorders. This paper reviews how objectivebiological measures of auditory function can be used to reveal auditory system dysfunction in the absence of hearing loss.