Influenza vaccination in children with asthma

Every year, outbreaks of in.uenza appear across the world and cause substantial morbidity and mortality in the general population, particularly in persons with underlying conditions including asthma. Because the in.uenza virus changes constantly, man’s acquired immunity is usually only partial and therefore the population will always to a greater or lesser extent be susceptible. In asthmatics, in.uenza causes upper respiratory tract infections that frequently trigger exacerbations. Large population-based studies have estimated the morbidity and the risk of developing clinical complications in people with asthma. During in.uenza periods, hospitalisation, drug prescriptions and visits to physicians increase, and asthma exacerbations and pneumonia have been reported as the most common complications. Children with asthma are at a higher risk for complications than adults. Reasons to vaccinate asthmatics are the prevention of in.uenza-related illness and complications, including asthma exacerbations and death. However, the protective effect of in.uenza vaccination in asthmatic patients is still disputed. So far no unequivocal bene.cial effect of in.uenza vaccination in asthmatics was found in observational and experimental studies in the sense of reduction of asthma exacerbations and of other complications. Although opinions on the clinical effectiveness of in.uenza vaccination in asthmatic patients are currently based on consensus and indirect evidence, the guidelines of most Western countries advise to vaccinate patients with asthma. As a result, in asthma care, in.uenza vaccination is considered to be a cornerstone for quality of care. Despite these recommendations only a minority of asthma patients is vaccinated worldwide. Reasons for this are fear among patients that vaccination could cause in.uenza, and doubts about bene.ts and effectiveness of in.uenza vaccination amongst physicians and patients. Aim of this thesis is to provide evidence to either support or modify the policy of vaccinating asthmatic patients as is described in most western guidelines. I will focus on children, because in children asthma is the most important reason for in.uenza vaccination and asthma is the most frequent chronic disease in childhood. In chapter 2 we report on the available knowledge of the incidence of in.uenza, the natural course and the burden of disease. Incidence .gures are a prerequisite to reliably forecast the impact of preventive measures for in.uenza and calculate the number needed to treat in order to prevent one additional case of in.uenza. Likewise, incidence .gures are also needed to estimate the number of participants for preventive or therapeutic trials. We conducted a systematic review to estimate the incidence of in.uenza and concomitant morbidity and mortality in children 0 through 19 years (0-19 years). We searched for observational studies and placebo or non treated arms of experimental studies for information on laboratory proven in.uenza illness. From a total of 2758 papers, 356 papers were reviewed on the basis of abstract or title. Sixteen papers were added searching the reference list of these papers. Finally 28 studies met inclusion criteria. They showed a varying incidence of in.uenza with .gures up to 46%. However, when looking at two long term observational studies and averaging seasonal .uctuations, the overall incidence of in.uenza in children was found to be between 5% (children aged 0-19 years) and 9.5% (children aged 0-5 years) per year. Serious morbidity was seldom reported. In the studies selected we found no cases of mortality. Our conclusion is that, given the average incidence for in.uenza found, the self­limited character of the disease, the mild associated morbidity and the rare cases of mortality in children, one can question if in.uenza in children at a population level is a major public health problem. As a result of this outcome we advise that preventive strategies for children should be reconsidered. When investigating preventive strategies for in.uenza one should be led by the average incidence and include more seasons. In chapters 3-6 we present various results of our randomised double-blind placebo-controlled trial in 696 children with asthma, aged 6-18 years. Parenteral vaccination with inactivated in.uenza vaccine or placebo took place approximately November 1st, and children were followed until April 1st of the next year. Local and systemic symptoms, possibly as a result of vaccination, and airway symptoms were reported in a diary. Symptoms scored during the .rst week after vaccination were considered to be adverse effects of the vaccination. When symptom scores reached a prede.ned level, a pharyngeal swab was taken and spirometry was performed. One week later a quality of life questionnaire was administered. Primary outcome was the number of asthma exacerbations associated with virologically proven in.uenza infection. Three hundred forty-nine children were assigned placebo, and 347 were assigned vaccine. In chapter 3, we address the adverse effects of in.uenza vaccination, especially on asthma. Because there is a constant debate that in.uenza vaccination may provoke an asthma exacerbation, a decisive answer to these doubts may affect vaccination rate. During the .rst week after vaccination, participants recorded local, in.uenza like and asthma symptoms as well as use of medication, health care use and absenteeism. As reported in previous studies, vaccine recipients reported redness and stiffness of the arm much more often than placebo recipients. For symptoms of in.uenza like illness, fever, headache and myalgia showed smaller though signi.cant differences during the .rst season, as did hoarseness during the second season, all favouring placebo. These differences may be an expression of the difference between strains used in the vaccine during the two seasons or may be a result of a difference between populations studied in the two in.uenza seasons. Except for cough during the day in the .rst season, favouring placebo, there were no differences indicating that vaccination exacerbates asthma. We conclude that in.uenza vaccination does not seem to exacerbate asthma and can be given safely to asthmatic children. In the literature there is little evidence that in.uenza vaccination reduces asthma exacerbations. In chapter 4 we report the main results of our randomised double­blind placebo-controlled trial in asthmatic children regarding the preventive effect of in.uenza vaccination on clinical illness, notably asthma exacerbations. Children reported, as described above, airway symptoms in a diary. When symptom scores reached a prede.ned level, a pharyngeal swab was taken. Primary outcome was the number of asthma exacerbations associated with virologically proven in.uenza infection. We considered a reduction in asthma exacerbations of at least 50% as clinically relevant. Three hundred forty-nine children were assigned placebo, and 347 were assigned vaccine. Pharyngeal swabs positive for in.uenza were related to 42 asthma exacerbations, 24 in the vaccine group and 18 in the placebo group, a difference of 33% favouring placebo (31% after adjustment for confounders; 95% con.dence interval, –34% to 161%). In.uenza-related asthma exacerbations were of similar severity in both groups; they lasted 3.1 days shorter in the vaccine group (95% con.dence interval, –6.2 to -0.002 days, p=0.06). We conclude that in.uenza vaccination did not result in a signi.cant reduction of the number, severity, or duration of asthma exacerbations caused by in.uenza. We think additional studies, using in.uenza proven clinical illness as an endpoint, are warranted to justify routine in.uenza vaccination of children with asthma. Health-related quality of life (physical, social and emotional impairments) should be an important measure in evaluations of the management of childhood asthma. Therefore, in chapter 5, the Pediatric Asthma Quality of Life Questionnaire (PAQLQ), a questionnaire in English to de.ne quality of life in asthmatic children, is validated for the Dutch translation. We assessed psychometric properties, responsiveness, and longitudinal and cross­sectional construct validity of the Dutch PAQLQ version. The study group consisted of 238 children (6–18 years) with asthma, a subset of children from our trial on in.uenza vaccination, with complete respiratory symptom diaries in the course of one winter season; each child had one (or more) PAQLQ measurement(s) concerning one (or more) week(s) with relatively many symptoms (n=238). Each child also had one PAQLQ measurement concerning another week with relatively few symptoms. The PAQLQ scores of these weeks were compared. Additionally, in a subgroup of the study group that had experienced two or more ‘weeks with many symptoms’ (n=101), we compared the PAQLQ scores for two different weeks with many symptoms of these children. All Cronbach’s a’s of the PAQLQ total score and domains were above 0.70, except for Activities (a=0.54), indicating that the internal consistency of the questions in the questionnaire is moderate to good. Mean PAQLQ scores were signi.cantly different (p 0.05) between a week with many symptoms and another week with many symptoms. These results indicate responsiveness of the instrument. Changes in lower respiratory tract symptoms, indicative of asthma severity, correlated better with changes in PAQLQ scores than changes in upper respiratory tract symptoms, which supports the longitudinal and cross-sectional construct validity. The assessed properties of the translation into Dutch were similar to those originally established for the PAQLQ in Canada. This study showed that the Dutch PAQLQ has adequate psychometric properties, excellent responsiveness, and that its longitudinal and cross-sectional construct validity is supported. As this questionnaire has been translated and validated in several languages it is an excellent tool for international and trans-cultural asthma research. In chapter 6 we show the effect of in.uenza vaccination on the well being of asthmatic children. Using PAQLQ, we measured the effects of in.uenza vaccination on physical, emotional and social impairments in asthmatic children. Supplementary we assessed whether in.uenza vaccination has an effect on the corresponding respiratory symptoms and spirometric parameters as well as on all their symptoms throughout the season. Compared to placebo, vaccination improved health-related quality of life in the weeks of illness related to in.uenza-positive swabs. However, no effect was found for respiratory symptoms recorded in the diaries during those weeks. Similarly, no differences were found for quality of life in all weeks of illness or for respiratory symptoms throughout the seasons. Our conclusion is that in.uenza vaccination has a moderate bene.cial effect on quality of life in in.uenza-positive weeks of illness in children with asthma. In chapter 7 we re.ect on our .ndings and conclude that, given the available information on the effectiveness of airway medication; the low overall incidence of in.uenza; the absence of direct evidence for serious complications of in.uenza infection in asthmatic children; the absence of evidence for the clinical effectiveness of in.uenza vaccination in asthmatic children; the absence of adverse effects of in.uenza vaccination and the doubts about cost-effectiveness of this preventive intervention in asthmatic children, guidelines on in.uenza vaccination should be revised and, despite the safety of vaccination, should reconsider the advice to vaccinate children with mild to moderate asthma. Future research should .rst of all focus on long term observational research, spanning more seasons, to determine the real impact of in.uenza in children with and without asthma. Whereas sentinel stations, in cooperation with national in.uenza centres, nowadays provide information on the number of in.uenza like illnesses per number of physicians consultations or at a population level, they could deliver information based on culture con.rmed illness and the burden of disease due to in.uenza in a well de.ned population at risk. Secondly, experiments in which populations in certain regions, covered by sentinel stations, would be asked to participate in vaccination trials, could measure the effect of in.uenza vaccination in the different age and disease categories, including asthma, for which vaccination is advocated but for which insuf.cient evidence for its effectiveness is currently available. In any case, experimental designs should take symptoms of patients on an individual level and symptom based measurements, such as PAQLQ, as an outcome. In this way, the updating of recommendations can be guided by medicine-based evidence wich in turn may improve the effectiveness of recommendations.Over de gehele wereld zijn er ieder jaar uitbraken van in.uenza die substantiële morbiditeit en mortaliteit teweeg brengen onder de bevolking, in het bijzonder bij personen met een onderliggend lijden zoals astma. Omdat het in.uenzavirus constant verandert is de bescherming die men na een infectie opbouwt slechts gedeeltelijk, hierdoor zal de bevolking altijd in meerdere of mindere mate ontvankelijk zijn voor het in.uenzavirus. Een in.uenza-infectie veroorzaakt bij patiënten met astma een ontsteking van de bovenste luchtwegen die vaak een astma-aanval uitlokt. Er zijn grote studies gedaan waarbij onderzocht is hoeveel ziekte er veroorzaakt wordt door in.uenza en wat de kans is op klinische complicaties bij patiënten met astma. Het aantal ziekenhuisopnames, medicijnvoorschriften en bezoeken aan een arts stijgt tijdens griepperiodes en als meest voorkomende complicaties treden astma­aanvallen en longontsteking op. Kinderen met astma lopen een groter risico op complicaties dan volwassenen. Patiënten met astma worden gevaccineerd ter voorkoming van door in.uenza veroorzaakte ziekte en de bijbehorende complicaties, waaronder astma-aanvallen en overlijden. Het beschermende effect van in.uenzavaccinatie is echter nog steeds onderwerp van discussie. Tot nu toe is in observationele en experimentele studies niet ondubbelzinnig aangetoond dat in.uenzavaccinatie het aantal astma-aanvallen of andere complicaties van in.uenza gunstig beïnvloedt. Hoewel de ideeën over de klinische effectiviteit van in.uenzavaccinatie bij patiënten met astma op dit moment zijn gebaseerd op consensus en indirect bewijs, wordt in de richtlijnen van de meeste Westerse landen geadviseerd patiënten met astma te vaccineren tegen in.uenza. Griepvaccinatie wordt dan ook gezien als een hoeksteen van de kwaliteit van de zorg bij patiënten met astma. Ondanks de genoemde aanbevelingen wordt wereldwijd slechts een minderheid van de astmapatiënten gevaccineerd. Bij patiënten bestaat er angst dat vaccinatie juist in.uenza veroorzaakt en bij patiënten én artsen blijven er twijfels bestaan over de voordelen en de effectiviteit van in.uenzavaccinatie. Dit proefschrift wil bewijs leveren ter ondersteuning of aanpassing van het in de meeste westerse landen gevoerde beleid om patiënten met astma te vaccineren tegen in.uenza. Ik beperk me daarbij tot kinderen: bij hen is astma de meest voorkomende chronische ziekte en tevens de belangrijkste reden voor griepvaccinatie. In hoofdstuk 2 beschrijven we de kennis die op dit moment aanwezig is met betrekking tot de incidentie, het natuurlijke verloop en de ziektelast van in.uenza. Incidentiecijfers zijn onontbeerlijk om de gevolgen van preventieve maatregelen tegen in.uenza te kunnen voorspellen en te berekenen hoeveel mensen gevaccineerd moeten worden om één geval van in.uenza te voorkomen. Deze cijfers zijn ook een voorwaarde om het aantal benodigde deelnemers voor preventieve of therapeutische trials te kunnen schatten. We voerden een systematische review uit om te bepalen wat de incidentie van in.uenza en de daardoor veroorzaakte morbiditeit en mortaliteit is bij kinderen van 0 tot en met 19 jaar (0-19 jaar). Daarbij zochten we naar informatie over, middels laboratoriumonderzoek bewezen, door in.uenza veroorzaakte ziekte in observationele studies en experimentele studies met een placebo arm of een arm waarin geen behandeling plaatsvond. Van in totaal 2758 artikelen werden 356 artikelen, op basis van het abstract of de titel, door de beoordelaars besproken. Zestien artikelen werden toegevoegd op basis van de referentielijsten van deze artikelen. Uiteindelijk voldeden 28 artikelen aan de inclusiecriteria. De incidentiecijfers van in.uenza varieerden nogal met als hoogste cijfer een incidentie van 46%. Als we echter kijken naar de twee gevonden langjarige observationele studies, bleek de gemiddelde jaarsincidentie van in.uenza bij kinderen te liggen tussen 5% (0-19 jaar) en 9.5% (0-5 jaar). Ernstige morbiditeit werd zelden beschreven en in de geselecteerde studies werd mortaliteit niet genoemd. Als we kijken naar de gemiddelde incidentie van in.uenza, het zichzelf beperkende karakter van de ziekte, de milde bijkomende morbiditeit en de zeldzaamheid van mortaliteit bij kinderen, is het de vraag of in.uenza bij kinderen op bevolkingsniveau een groot maatschappelijk gezondheidsprobleem is. Op basis van onze uitkomsten is ons advies de huidige preventieve maatregelen te heroverwegen. Daarnaast vinden we dat bij onderzoek van preventieve strategieën voor in.uenza men zich moet laten leiden door de gemiddelde incidentie én meerdere seizoenen in beschouwing moet nemen. In hoofdstuk 3-6 presenteren we de resultaten van ons gerandomiseerde dubbelblinde placebogecontroleerde onderzoek bij 696 kinderen met astma in de leeftijdsgroep van 6 tot en met 18 jaar. Rondom 1 november ontvingen de kinderen een injectie met geïnactiveerd in.uenzavaccin of placebo, de kinderen werden daarna gevolgd tot 1 april van het daaropvolgende jaar. Zij noteerden locale en algemene klachten ten gevolge van de vaccinatie en luchtwegklachten in een dagboekje. De genoteerde klachten in de eerste week beschouwden we als bijwerking van de vaccinatie. Als, na de eerste week, de gescoorde luchtwegklachten een van tevoren afgesproken grens bereikten, werd een keelwat afgenomen en vond een longfunctiemeting plaats. Een week later werd een kwaliteit van levenvragenlijst afgenomen. Van de deelnemende kinderen ontvingen 349 het placebovaccin en 347 het in.uenzavaccin. In hoofdstuk 3 onderzochten we de bijwerkingen van griepvaccinatie vooral met betrekking tot de gevolgen voor het astma. Omdat er al lang discussie is over de vraag of in.uenzavaccinatie een astma-aanval kan uitlokken is een duidelijk antwoord op deze vraag van belang. Dit kan belangrijke gevolgen hebben voor de vaccinatiegraad. Gedurende de eerste week na de vaccinatie noteerden de deelnemers aan de trial klachten op de plaats van de prik, griepachtige klachten en astmaklachten en tevens medicatiegebruik, gezondheidszorggebruik en afwezigheid. Conform eerdere studies rapporteerden de deelnemers die het echte vaccin ontvingen veel vaker roodheid en een stijve arm dan zij die met placebo gevaccineerd waren. Wat betreft griepachtige symptomen waren er kleinere maar wel signi.cante verschillen, ten voordele van de placebogevaccineerden, voor koorts, hoofdpijn en spierpijn in het eerste seizoen en heesheid in het tweede seizoen. Het verschil tussen de seizoenen zou te maken kunnen hebben met het verschil tussen de in het vaccin gebruikte stammen gedurende de twee seizoenen, maar kan ook een gevolg zijn van een verschil tussen de in de twee seizoenen deelnemende kinderen. Behalve een verschil voor hoesten overdag in het eerste seizoen ten voordele van de placebogevaccineerden waren er geen aanwijzingen dat vaccinatie astma-aanvallen uitlokte. Onze conclusie is daarom dat griepvaccinatie geen astma-aanvallen lijkt uit te lokken en veilig toegediend kan worden aan kinderen met astma. In de wetenschappelijke literatuur is er weinig bewijs dat griepvaccinatie astma­aanvallen voorkómt. In hoofdstuk 4 doen we verslag van de belangrijkste resultaten van ons gerandomiseerde dubbelblinde placebogecontroleerde onderzoek bij kinderen met astma naar het effect van in.uenzavaccinatie, waarbij we in het bijzonder naar astma-aanvallen keken. De deelnemende kinderen noteerden, zoals hiervoor beschreven, luchtwegklachten in een dagboekje. Als de gescoorde luchtwegklachten een van tevoren afgesproken grens bereikten, werd een keelwat afgenomen. Onze primaire uitkomstmaat was het aantal astma-aanvallen dat in verband gebracht kon worden met een virologisch bewezen in.uenza-infectie. We beschouwden een reductie van tenminste 50% van het aantal astma-aanvallen als klinisch relevant. Van de deelnemende kinderen ontvingen 349 het placebovaccin en 347 het in.uenzavaccin. Van de gerapporteerde astma-aanvallen waren er 42 gerelateerd aan een in.uenzapositieve keelwat, 24 in de gevaccineerde groep en 18 in de placebogroep. Een verschil van 33% ten voordele van de placebogroep (31% na correctie voor ‘confounders’; 95% betrouwbaarheidsinterval –34% tot 161%). In.uenzagerelateerde astma­aanvallen waren even ernstig in beide groepen; ze duurden 3,1 dag korter in de vaccingroep (95% betrouwbaarheidsinterval, –6,2 tot –0,002 dag, p=0,06). Onze conclusie is dat in.uenzavaccinatie niet resulteerde in een signi.cante vermindering van het aantal, de ernst en de duur van in.uenzagerelateerde astma-aanvallen. We zijn van mening dat aanvullende studies, waarbij ziekte in combinatie met bewijs voor in.uenza als eindpunt gebruikt wordt, no

Opinions of the Dutch public on palliative sedation: A mixed-methods approach

Background: Palliative sedation is defined as deliberately lowering a patient's consciousness, to relieve intolerable suffering from refractory symptoms at the end of life. Palliative sedation is considered a last resort intervention in endof-life care that should not be confused with euthanasia. Aim: To inform healthcare professionals about attitudes of the general public regarding palliative sedation. Design and setting: A cross-sectional survey among members of the Dutch general public followed by qualitative interviews. Method: One thousand nine hundred and sixty members of the general public completed the question

Prevalence and “red flags” regarding specified causes of back pain in older adults presenting in general practice

Background. In a small proportion of patients experiencing unspecified back pain, a specified underlying pathology is present. Objective. The purposes of this study were: (1) to identify the prevalence of physician specified causes of back pain and (2) to assess associations between “red flags” and vertebral fractures, as diagnosed by the patients’ general practitioner (GP), in older adults with back pain. Methods. The Back Complaints in the Elders (BACE) study is a prospective cohort study. Patients (aged >55 years) with back pain were included when consulting their GP. A questionnaire was administered and a physical examination and heel bone densitometry were performed, and the results determined back pain and patient characteristics, including red flags. Participants received a radiograph, and reports were sent to their GP. The final diagnoses established at 1 year were collected from the GP’s patient registry. Results. Of the 669 participants included, 6% were diagnosed with a serious underlying pathology during the 1-year follow-up. Most of these participants (n=33, 5%) were diagnosed with a vertebral fracture. Multivariable regression analysis showed that age of ≥ 75 years, trauma, osteoporosis, a back pain intensity score of ≥ 7, and thoracic pain were associated with a higher chance of getting the diagnosis of a vertebral fracture. Of these variables, trauma showed the highest positive predictive value for vertebral fracture of 0.25 (95% confidence interval=0.09, 0.41) and a positive likelihood ratio of 6.2 (95% confidence interval=2.8, 13.5). A diagnostic prediction model including the 5 red flags did not increase these values. Limitations. Low prevalence of vertebral fractures could have led to findings by chance. Conclusions. In these older adults with back pain presenting in general practice, 6% were diagnosed with serious pathology, mainly a vertebral fracture (5%). Four red flags were associated with the presence of vertebral fracture

Defining trajectories in older adults with back pain presenting in general practice.

although back pain is a frequently recurring disorder, the course of back pain remains uncertain

Influenza vaccination in children with asthma: randomized double-blind placebo- controlled trial.

There is little evidence that influenza vaccination reduces asthma exacerbations. We determined whether influenza vaccination is more effective than placebo in 6-18-year-old children with asthma. We performed a randomized, double-blind, placebo-controlled trial. Parenteral vaccination with inactivated influenza vaccine or placebo took place approximately November 1, and children were followed until April 1 of the next year. Airway symptoms were reported in a diary. When symptom scores reached a predefined level, a pharyngeal swab was taken. Primary outcome was the number of asthma exacerbations associated with virologically proven influenza infection. Three hundred forty-nine children were assigned placebo, and 347 were assigned vaccine. Pharyngeal swabs positive for influenza were related to 42 asthma exacerbations, 24 in the vaccine group and 18 in the placebo group, a difference of 33% favoring placebo (31% after adjustment for confounders; 95% confidence interval, -34% to 161%). Influenza-related asthma exacerbations were of similar severity in both groups; they lasted 3.1 days shorter in the vaccine group (95% confidence interval, -6.2 to 0.002 days, p = 0.06). We co