Ilya Petrou, MD

	Citing poor efficacy, the Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) recently voted down the use of the live attenuated influenza vaccine (LAIV) for the 2016-2017 flu season. However, the committee further recommended annual flu vaccinations using either the inactivated influenza vaccine (IIV) or recombinant influenza vaccine (RIV) for everyone aged 6 months and older.

	Having been approved by the US Food and Drug Administration (FDA) for persons aged between 2 and 49 years, the LAIV, also known as the “nasal spray” flu vaccine, was introduced into the market over a decade ago as an alternative to the injectable influenza vaccines such as the IIV and RIV options. The LAIV, on account of its painless mode of delivery, is clearly a preferred route of vaccine administration and was promoted and touted as a viable influenza vaccination option to the IIV and RIV. However, the recently available interim data demonstrating poor or relatively lower efficacy of the LAIV from the 2013 through 2016 flu seasons has led to the ACIP’s dissuasion to implement the nasal spray vaccine in patients.

	“We agree with the ACIP’s decision to recommend healthcare providers and parents use only the inactivated vaccine for this influenza season,” says Benard P Dreyer, MD, professor of Pediatrics, director of Developmental-Behavioral Pediatrics, New York University School of Medicine, director of Pediatrics, Bellevue Hospital Center, and president of the American Academy of Pediatrics (AAP), New York.

	The ACIP recently reviewed the preliminary data from the US Influenza Vaccine Effectiveness Network concerning the LAIV’s efficacy among children aged between 2 and 17 years during the 2015-2016 flu season and found that the nasal spray vaccine could provide only 3% protection against any flu virus in that patient cohort, a dismal record by any standard. In stark contrast, however, data also showed that the IIV flu vaccination option demonstrated a 63% protection against any virus in the same cohort.

	This poor performance of LAIV protection during the 2015-2016 flu season was preceded by poor and/or lower-than-expected LAIV efficacy during the 2013-2014 and 2014-2015 flu seasons. The consecutively poor performances of the LAIV during the last few flu seasons has befuddled researchers, as the efficacy data of the LAIV before and soon after the FDA approval and licensure suggested it to be either comparable to, or better than, the IIV option.

	It remains unclear as to why the LAIV fared so poorly in the last few flu seasons, and experts are still trying to figure this out. Current theories for the LAIV’s poor efficacy revolve around the strain in the vaccine being less effective when administered through the nose, or perhaps a change in the population that makes some persons more resistant to responding to the vaccine.

	According to Dreyer, the news with the LAIV may be somewhat of a setback for those needle-phobic individuals who prefer to receive the flu vaccination painlessly via nasal spray. Fortunately, however, the IIV and RIV options appear to be working well. The AAP strongly recommends parents to annually immunize all children aged older than 6 months and, apparently, the superior flu vaccination options currently appear to be the IIV and RIV alternatives.

	“It is absolutely paramount that people receive their annual flu shot, as the flu virus is an unpredictable and dangerous virus. The flu vaccine is the best way to protect children from the flu virus and, at present, it appears that the IIV and RIV injection vaccines are the most effective options currently available to achieve that goal,” Dreyer says.

	Dr Petrou is a freelance medical writer based in Budapest, Hungary. He has nothing to disclose in regard to affiliations with or financial interests in any organizations that may have an interest in any part of this article.

Articles

Recent data has revealed the live attenuated influenza vaccine (LAIV), also known as the “nasal spray” vaccine, to be grossly ineffective, leading to the ACIP’s decision not to recommend its usage. As such, healthcare providers must be judicious in their choice of influenza vaccine with their patients.

Live attenuated influenza vaccine “shelved” for poor efficacy

 found that although vaccines are associated with an increased potential risk of febrile seizure in young children, the overall risk is small, suggesting that following the currently recommended immunization schedule may be the optimal approach in managing appropriate vaccination of young children of immunization age.

	The childhood immunization schedule in the United States is put forth by the Centers for Disease Control and Prevention (CDC) based upon recommendations made by the Advisory Committee on Immunization Practices (ACIP). According to the current recommendations, influenza vaccine should be administered annually to everyone aged 6 months or older; children should receive 5 doses of diphtheria, tetanus, and acellular pertussis (DTaP) vaccine, which are recommended to be given at ages 2, 4, and 6 months, between 15 to 18 months, and between 4 to 6 years; and children should receive 4 doses of pneumococcal conjugate vaccine (PCV), which are recommended to be given at ages 2, 4, and 6 months, and between 12 to 15 months.

	One of the long-standing issues with administering these vaccines is that they can cause fever, which in young children can lead to febrile seizures. The question returns to many wary practitioners and concerned parents as to whether the benefits of a timely administration of recommended vaccines outweigh the risk of developing febrile seizure.

	“These vaccines prevent infections that can sometimes be severe or life threatening. The benefits of timely vaccination are likely much greater than the small risk of febrile seizure. Febrile seizures are relatively benign and do not cause lasting harm. Influenza vaccine, when needed, should still be given at the same time as these other vaccines,” says Jonathan Duffy, MD, MPH, Immunization Safety Office, CDC, Atlanta, Georgia, and lead author of the recent vaccination study.

	In the study, Duffy and colleagues used the Vaccine Safety Datalink to assess whether certain vaccines if given alone or in combination with other vaccines can be associated with febrile seizures. Data examined included the risk of febrile seizure 0 to 1 day postvaccination for all routinely recommended vaccines (influenza, PVC, and DTaP) among children aged 6 to 23 months during a period encompassing 5 influenza seasons (2006-2007 through 2010-2011). It was found that only PVC vaccine was associated with an increased rate of febrile seizure when given alone, but whereas influenza vaccine had no independent risk, the risk for febrile seizure was increased when given together with PVC or DTaP.

	The study also found that the concomitant administration of influenza, PVC, and DTaP vaccines can lead to febrile seizures at a rate of up to 30 in 100,000 children immunized. For the average pediatrician, who may annually see 1000 children aged younger than 5 years, including 3 to 500 aged between 6 and 24 months, one could expect to see at most 1 child who experiences a febrile seizure every 5 to 10 years because of administration of these vaccines together in the first 2 years of life. That would be a risk of 1 febrile seizure per pediatric practice every 5 to 10 years.

	According to Duffy, upon review of the results of this study as well as others concerning fever and febrile seizures following childhood vaccines, the ACIP decided that the small risk of febrile seizure following PCV vaccine and the vaccine combinations studied were outweighed by the benefits of the vaccines. These vaccines can prevent serious and life-threatening infections, Duffy says, and the ACIP continues to recommend that these vaccines be given and that they can be given together when needed.

	“Febrile seizures are known to occur at a low rate following certain vaccines, however, there are currently no evidence-based methods recommended to prevent febrile seizures following vaccination. The potential benefit of vaccination to prevent febrile seizure over longer periods is less readily apparent than the short-term risk of febrile seizure in the first few days immediately after vaccination. Over the long-term, vaccination might reduce the risk of febrile seizure, although additional study would be needed to quantify this for each type of vaccine. We hope the results of our current study will help doctors and parents make informed decisions about vaccination for individual children,” Duffy says.

	More information about the ACIP and current vaccine recommendations can be found online at: 

	1. Duffy J, Weintraub E, Hambidge SJ, et al; Vaccine Safety Datalink. Febrile seizure risk after vaccination in children 6 to 23 months. 

Maintaining the currently recommended vaccination schedule of influenza, pneumococcal conjugate, and diphtheria/tetanus/acellular pertussis vaccines in young children as put forth by the Centers for Disease Control and Prevention is likely the best way to manage immunization in this patient population despite the slightly increased risk for febrile seizure.

Febrile seizure risk and vaccines

	Although the diagnostic value of nasal cytology has long been established, widespread systematic implementation of this very simple, quick, and safe procedure in the pediatric population is still lacking. A recent review paper evaluating the advantages of using the nasal cytology procedure in the pediatric population

 once again reinforced the clinical importance of nasal cytology as an adjunct diagnostic tool, and underscores its great utility in the optimization of the treatment and management of nasal disorders in the pediatric population.

Matteo Gelardi, MD“Contrary to all the cytologic procedures performed in other parts of the human body such as the thyroid, breast, salivary glands, and lymph nodes, nasal cytology is not an invasive procedure and does not require any anesthesia. The technique does not require a histological sample but instead only a simple surface cytological collection performed with a little spoon (Rhino-probe) or a tampon (similar to the oropharyngeal tampon), which is inserted in the corresponding inferior turbinate. As the procedure is painless, quick, and safe, it can be viewed as an ideal adjunct diagnostic procedure to further help in the treatment and management of patients with nasal disorders,” says Matteo Gelardi, MD, Section of Otolaryngology, Department of Basic Medical Science, Neuroscience and Sensory Organs, University of Bari, Italy.

	Nasal cytology has been proven time and again to be a very useful diagnostic procedure for nasal disorders and diseases, being able to detect both the cellular modifications of the nasal epithelium caused by allergen exposure, irritative stimuli (physical or chemical), or inflammation. In addition to elucidating the fine differences and nuances among newly identified disorders including nonallergic rhinitis with eosinophils (NARES), nonallergic rhinitis with mast cells (NARMA), and nonallergic rhinitis with neutrophils (NARESMA), Gelardi says that the technique also can help to distinguish between the different forms of allergic rhinitis, thereby assisting clinicians to more quickly home in on an appropriate therapy, whether anti-inflammatory agents or allergen immunotherapy.

	Several different diagnostic tests are currently being used in the field of otolaryngology, including macroscopic (nasal endoscopy), microscopic (nasal cytology), allergological (prick test), and functional tests (rhinomanometry), and each procedure opens up a diagnostic window that gives clinicians a better overall picture of the disease under investigation. Unfortunately, however, Gelardi says that nasal cytology still isn’t being used enough in the pediatric field or in other specialties. Historically, one of the main reasons is suspected to be the lack of standardization of the cytological procedures related to the sampling and interpreting of nasal cytograms. Gelardi says that the literature created over the last years has been very specific in helping to put these issues to rest, opening the door for a newly found trust and reliance in the procedure. Gelardi also recently published a theoretical aid to help further clarify all the cytomorphological aspects of the normal and pathologic nasal mucosa.

	Children are frequently affected by nasal pathologies, particularly during the early childhood period in which infectious diseases and allergies are generally overlapped. As such, Gelardi says that nasal cytology can be very useful in differentiating among these diseases, allowing clinicians to initiate an appropriate and exacted therapy. For instance, the cytology of bacterial rhinitis is microscopically characterized by the presence of numerous bacteria and neutrophils, and traces of biofilm often can be observed in the cytogram as an expression of the chronicity of the existing rhinopathy. In acute allergic diseases, the cytogram is always characterized by the presence of partially degranulated eosinophils and mast cells. Such “characteristic” cytograms can quickly help clinicians classify the disease in question and commence with appropriate therapy.

	After performing the cytogram, the clinical and therapeutic follow-up plays an important role, Gelardi says, because it allows the physician to personalize the treatment according to the cytological representation of the individual patient (ie, bacteria persistence, presence of biofilm, as well as status of the eosinophils and mast cells degranulation).

	“Nasal cytology turns indispensable when the presence of an allergic rhinitis is suspected, even if all of the tests previously performed (ie, prick test, [radioallergosorbent test], etc) demonstrated negative results. In these cases, in fact, nasal cytology is the only diagnostic tool able to identify those rhinopathies usually defined as vasomotor, nonspecific, idiopathic, or cryptogenic. Fortunately, there is a growing interest for pediatricians, allergists, and [ear, nose, and throat] specialists to develop the skills to perform standardized nasal cytology exams in their patients, a trend that we hope will continue for the benefit of our patients,” Gelardi says.

	1. Gelardi M, Iannuzzi L, Quaranta N, Landi M, Passalacqua G. Nasal cytology: practical aspects and clinical relevance. 

Atlas of Nasal Cytology for the Differential Diagnosis of Nasal Diseases

Although still underused among available diagnostic procedures, nasal cytology is viewed by many specialists as an indispensable adjunctive diagnostic exam that clinicians can and should use more often to optimally diagnose, treat, and manage the myriad of nasal disorders and diseases occurring in pediatric patients.

Nasal cytology: An untapped diagnostic tool

	When large-particle inhaled corticosteroids (ICS) used as a monotherapy fail to control asthma, the current asthma guidelines recommend “stepping up” therapy by adding long-acting beta 2 agonists (LABAs) to the regimen as a first-line alternative treatment approach. Recent research, however, has shown that pediatric patients with uncontrollable asthma would not only benefit more from the administration of small-particle ICS used as a monotherapy in this scenario, but that small-molecule ICS treatment should be considered as the foundation of the management of asthma in children, heralding a potential paradigm shift from traditional asthma therapy.

David Price, MD“The treatment of asthma in children can be challenging and the choices of treatment are often complex. Standard size-particle ICS has already been established as an effective first-line treatment approach for acute episodes of asthma. However, this approach can sometimes fall short of its therapeutic goal. In still uncontrollable asthma, stepping up therapy with the addition of LABAs to the ICS regimen has shown to be effective where standard size-particle ICS therapy used as a monotherapy fails. The use of small-particle ICS, however, has gained favor among clinicians and their patients in part due to the simplification of the dose regimen for asthma management in this patient population, coupled with at least equivalent efficacy in observational studies,” says David Price, MD, professor of Primary Care Respiratory Medicine, Academic Primary Care, University of Aberdeen, United Kingdom.

	The most commonly used small-particle ICS agents in the United States include beclomethasone dipropionate and fluticasone dipropionate. One of the main advantages of small-particle ICS is that these agents have an improved total lung deposition and, therefore, lower daily doses are required to achieve an effective control of asthma when compared with large-particle ICS drugs. In addition, small-particle ICS agents are able to reach the small airways, which may result in an increased treatment efficacy leading to a quicker resolution of symptoms.

	Price and colleagues recently conducted an electronic records review study of children with asthma aged 5 to 11 years comparing the efficacy between small-particle ICS treatment and standard size-particle ICS treatment when initiating or stepping up ICS treatment for their disease, as well as small-particle ICS and standard size-particle ICS with the addition of LABA to the regimen.

 Variables were measured during 2 consecutive years (1 baseline year for confounder definition and 1 outcome year), including risk-domain asthma control and rate of severe exacerbations.

	In the initiation population cohort, those children who were prescribed small-particle ICS (n=797) experienced greater odds of asthma control as well as a lower severe exacerbation rate when compared with those who received standard size-particle ICS therapy (n=797). Similarly, it was found that step-up treatment outcomes were significantly more favorable in the small-particle ICS cohort compared with the standard size-particle ICS cohort.

	Results also showed that the number needed to treat with small-particle ICS to achieve 1 additional child with asthma control was 17 for the initiation cohort and 5 for the step-up cohort. The data did not show any significant differences in outcome between those patients who received stepped-up small-particle ICS treatment (n=185) when compared with those who received ICS plus LABA combination therapy (n=185).

	The results not only clearly speak in favor of using small-particle ICS therapy for acute bouts of asthma, but they also suggest that small-particle ICS could be considered as the drug of choice for the long-term management of this disease in the pediatric population. Moreover, the use of small-particle ICS appears to be more practical and can result in lower overall healthcare costs for this patient population because there is no need to have a combination inhaler at the ready or a prescription for ICS plus LABA should the patient require stepping up treatment.

	Clinicians frequently rely on evidence from randomized controlled trials (RCT) for guidance in their choice of asthma therapy. Unfortunately, however, such trials are few and far between mostly because of the large costs associated with RCTs. Moreover, RCTs do not always represent a complete cross-section of the asthma patient population under scrutiny, says Price, and they can often exclude those patients with milder disease who are also more prone to disease exacerbations. As such, the outcomes of observational design studies can often prove to be very valuable in helping clinicians optimally treat and manage their patients.

	“According to the evidence, small-particle ICS should be the treatment of choice for acute asthma episodes in pediatric patients, a notion that challenges the status quo of current asthma therapy in children,” says Price. “Although further studies need to be performed to confirm these results, we believe that our data firmly supports small-particle ICS as the optimal treatment approach for asthma in the pediatric population,” he adds.

	1. van Aalderen WM, Grigg J, Guilbert TW, et al. Small-particle inhaled corticosteroid as first-line or step-up controller therapy in childhood asthma. 

	Dr. Price has received research support from Teva; is a member of the following boards for which fees were paid to RiRL: Aerocrine, Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Meda, Mundipharma, Napp, Novartis, and Teva; has received consultancy fees paid to RiRL from Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Meda, Mundipharma, Napp, Novartis, Pfizer, and Teva; has received research support for which fees were paid to RiRL from UK National Health Service, British Lung Foundation, Aerocrine, AstraZeneca, Boehringer Ingelheim, Chiesi, Eli Lilly, GlaxoSmithKline, Meda, Merck, Mundipharma, Novartis, Orion, Pfizer, Respiratory Effectiveness Group, Takeda, Teva, and Zentiva; has received fees (paid to RiRL) for manuscript preparation from Mundipharma and Teva; has received travel reimbursement from Aerocrine, Boehringer Ingelheim, Mundipharma, Napp, Novartis, and Teva; has received funding paid to RiRL for patient enrollment or completion of research from Almirall, Chiesi, Teva, and Zentiva; has received unrestricted funding, paid to RiRL, for investigator-initiated research from Aerocrine, AKL Ltd, Almirall, Boehringer Ingelheim, Chiesi, Meda, Mundipharma, Napp, Novartis, Orion, Takeda, Teva, and Zentiva; has a pending patent for Phytopharmaceuticals with AKL Ltd; has shares in AKL Ltd, which produces phytopharmaceuticals; and owns 80% of RiRL Ltd and its subsidiary social enterprise Optimum Patient Care; and is peer reviewer for grant committees: Medical Research Council (2012), Efficacy and Mechanism Evaluation programme (2012), and HTA (2012).

New research suggests that the use of small-particle inhaled corticosteroids as a first-line or step-up therapy for uncontrollable asthma in children would be more helpful in clearing symptoms and preventing exacerbations than traditional treatment approaches such as large-particle inhaled corticosteroids with or without the addition of long-acting beta 2 agonists.

Author | Ilya Petrou, MD

Articles

Live attenuated influenza vaccine “shelved” for poor efficacy

Febrile seizure risk and vaccines

Nasal cytology: An untapped diagnostic tool

Small-particle inhaled corticosteroids: Paradigm shift in asthma treatment