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Three Part Question

Do children with JIA [patient] who become infected with influenza [intervention] have a more prolonged illness [outcome] than healthy children [comparison]? In children with JIA [patient], should flu vaccinations be given [intervention] to prevent flu [outcome]? Do children with JIA respond to flu vaccination [does the vaccination have the required effect]? Does flu vaccination [intervention] cause a flare of JIA [adverse event]?

Clinical Scenario

A 12-year-old girl with rheumatoid factor negative polyarticular juvenile idiopathic arthritis (JIA) attends an outpatient appointment with her mother. Her disease has been controlled by subcutaneous methotrexate, but over the past month, she has stopped taking medication because of adverse effects—in particular, nausea and vomiting after administration of methotrexate injection. On examination, she is found to have a flare of her disease with 10 swollen inflamed joints and early morning stiffness for 2 h/day. You apply for funding for anti-tumour necrosis factor (TNF) treatment and, in the meantime, plan to treat her disease flare with a course of prednisolone. On discussion during the consultation, her mother tells you that she has had a letter from the general practitioner asking her child to attend for a flu vaccination and asks your advice.

Search Strategy

Medline via Pubmed, Embase search date 13 September 2006
{vaccine OR vaccination} AND {arthritis}, AND {child OR childhood OR children or juvenile} AND {influenza}.

Search Outcome

Medline via Pubmed; 20 papers identified, 3 relevant. Embase: 58 articles identified, 6 relevant to vaccination but only 3 specific to influenza vaccine in JIA
Secondary sources: Cochrane Library. Nil relevant. One review identified for influenza vaccination in healthy children (2006), but not for children immunosuppressed by disease or drugs. TRIP: 59 evidence-based articles identified, 1 relevant. Twelve guidelines were identified, 1 of which was relevant. Ten query answers, 3 e-textbooks and 1 patient information leaflet were identified, but none of these were relevant. Seventy Medline articles were identified through TRIP, but duplicated primary searches.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Malleson et al, 1993	34 patients with JIA, age 3–22 years Active arthritis in 25/34 (74%) Deterioration of JIA in 3 children after vaccine, but overall, more patients better than worse Adequate response to vaccination Prednisolone used in 7/34 (21%) and DMARD used in 9/34 (26%) Compared with 13 (presumed) healthy children 1991–1992 flu season	Prospective open-cohort study (level 4)	No adverse effects except increased length of time of feeling unwell in the JIA group compared with controls	Increased number of days of feeling unwell in children with JIA (p = 0.015) Significance lost when corrected for number of comparisons Number of flares: pre-vaccine: 4 flares/145 patient; months post-vaccine: 3 flares/34 patient months	Clearly focused study Healthy control group All patients accounted for at end of trial Follow-up complete Applicable to UK patient groups Non-randomised Small numbers
			Increased flares after vaccine but flares easy to control	No statistical difference between mean clinical evaluation before and after vaccination
Olsen et al, 1994	14 children with JIA, aged 5–20 years 6 with oligo JIA, 5 poly JIA, 3 systemic onset JIA Suggests all 14 children were vaccinated, although randomisation method unclear 7 controls: 5 with asthma, and 2 siblings Abstract published in 1990 No significant difference in laboratory values in the two groups	Prospective open study: letter and abstract (level 4)	Patients with JIA may have a flare of disease or adverse effects from influenza vaccination 2 patients felt they improved after vaccination	Preimmunisation and seroresponsiveness comparable in all groups No effect of prednisolone or DMARD 2/14 patients with JIA had joint pain/systemic symptoms for 7–10 days No control patients had joint pain	Control group Randomised Examiner blinded Very small numbers No raw data shown, thus unable to analyse results Trial design unclear with poor description of methods and results
Kanakoudi Tsakalidou et al, 2001,	70 children, aged 4–17 years 49 JIA 11 SLE 10 other rheumatic conditions At the time of vaccination, 17/70 had active disease All children on immunosuppressants Divided into four groups according to therapeutic regimen 5 healthy children also vaccinated but did not act as a control group 1999–2000 flu season	Prospective open-cohort study (level 4)	No significant adverse effects identified from influenza vaccination Any effects that did occur were short lasting	5 patients (7%) reported adverse effects. 3 had local reactions and 2 systemic reactions. 9 patients had upper respiratory tract symptoms	Clearly focused Follow-up complete Applicable to UK children Discusses issues of immunosuppression and different disease types No control group Not randomised or blinded Small numbers
			Influenza vaccine did not seem to affect disease activity	No patients had deterioration in disease activity, flare of disease, or change in laboratory parameters at review, 1, 3 and 6–8 months after taking vaccine Most patients developed a protective serological response to all 3 strains of influenza virus. No patients had a flu-like illness in the 6-month follow-up period

Comment(s)

Currently, there is variation in practice regarding immunisation of children with JIA owing to a lack of available published evidence (Davis, Minder). Existing guidelines suggest that influenza may cause severe disease in patients immunocompromised by disease or drugs, and predisposes to bacterial infection.(RCPCH, BSR, Dept of Health Immunization, AAP). It is therefore recommended that, each autumn, influenza vaccination should be given widely to this patient population, their family contacts and their care givers. The decision as to whether children with JIA should be vaccinated against influenza currently rests with individual doctors who balance the risk of influenza and influenza vaccination in individual patients with JIA. The present threat of an influenza pandemic, and government pressure on general practitioners to vaccinate against influenza in target groups, provides a good reason to review available evidence. Complications of influenza infection that can be avoided by vaccination include bronchitis or secondary bacterial pneumonia, otitis media, and meningitis or encephalitis. An increased risk of complications is found in children with chronic illness and in those who are immunocompromised.(Dept of Health Immunization). Risks of infection need to be balanced with any adverse effects of vaccination. Common adverse effects are usually mild and short lasting, such as pain, swelling and redness at the injection site, formation of a small painless nodule, or low grade fever, shivering, headache, myalgia and arthralgia. Other rare adverse effects such as neuralgia, paraesthesia, convulsions, transient thrombocytopenia, Guillain—Barré syndrome, vasculitis and encephalomyelitis have been reported (Dept of Health Immunization). Contraindications for vaccination include a previous anaphylactic reaction to the vaccine or component of the vaccine, or a confirmed anaphylactic reaction to egg products. Several types of influenza vaccination are available. In the UK, inactivated types are most commonly used (whole virion vaccine, subunit vaccine or split virion vaccine) (Smith). There is evidence that inactivated vaccines are effective in healthy adults, and vaccination between September and November is said to offer 70–80% protection for 1 year (Dept of Health Immunization). Children <13 years of age may need two doses, and there may possibly be a suboptimal response in immunocompromised patients (Smith). There are no randomised controlled trials addressing the issue of vaccination against influenza in patients with JIA. Two small prospective open-cohort studies (table) suggest that vaccination is safe, and that children with JIA are able to develop a protective response to vaccination equivalent to that of healthy children (Malleson, Kanakoudi). Vaccination does not seem to have a noticeable effect on disease activity. Another small study suggests that children can have short-lasting but significant adverse effects after vaccination including a flare of their arthritis, although the study methodology is poorly documented (Olsen). All studies occurred before 2000 and therefore do not address the issue of effect of immunosuppression with anti-TNF treatments, but there is documentation of seroconversion despite immunosuppression with other disease-modifying anti-rheumatic drugs such as methotrexate, ciclosporin and azathioprine, in addition to prednisolone. Influenza vaccination changes each year to reflect changes in influenza strain, and hence some influenza strains may be more rheumatogenic and thereby more likely to precipitate a flare of arthritis. However, there is no evidence for this. In fact, evidence from other vaccinations, such as hepatitis B vaccination in children with JIA, suggests that children develop an adequate response without aggravation of their arthritis (Kasapçopur). Evidence in adults with rheumatoid arthritis, including adults treated with anti-TNF medication, suggests that influenza vaccination is safe, effective and generates a good antibody response (Fomin, Herron, Chalmers). In the absence of a large double-blind, placebo-controlled trial, it is impossible to be certain that influenza vaccination does not cause a flare of arthritis in some children. However, the current available evidence suggests that children with arthritis are not at a significantly increased risk of adverse reactions or disease flare after inactivated influenza vaccination. Children with JIA seem to be able to produce an antibody response similar to healthy children after vaccination, even when they are taking steroids or disease-modifying drugs. No children were taking anti-TNF medication, and therefore the effect of immunosuppression by these newer medicines on seroconversion after vaccination has not been addressed. However, evidence from adult studies indicates adequate seroconversion in rheumatoid arthritis. Evidence from cohort studies in healthy children suggests that inactivated vaccines have a reasonable efficacy (up to 64%) and effectiveness (57%) in children over 6 years of age (Smith). The current evidence does not indicate whether influenza vaccination is actually protective against developing symptoms of influenza illness, or whether children with JIA are more at risk of developing severe influenza infection with secondary complications. Until this is addressed, the risk:benefit ratio of influenza vaccination in patients with JIA is uncertain. However, available evidence suggests that influenza vaccination is safe in children with JIA and produces a satisfactory protective response.

Editor Comment

DMARD, disease-modifying anti-rheumatic drug; JIA, juvenile idiopathic arthritis; SLE, systemic lupus erythematosus.

Clinical Bottom Line

There is an increased risk of secondary bacterial infections from influenza disease in patients immunocompromised by disease or drugs (grade C). Flu vaccination seems to be safe in children with JIA; it is unlikely to cause a flare of disease (grade C). Flu vaccination may be effective in JIA; children seem to produce an adequate antibody response (grade C). Flu vaccination should be given in all children with JIA (grade C).

References

1. Malleson PN, Tekano JL, Scheifele DW, et al. Influenza immunisation in children with chronic arthritis: a prospective study. J Rheumatol 1993;20:1769–73.
2. Olson NY, Lindsley CB, Page-Goertz S. Influenza immunization in children with chronic arthritis [letter]. J Rheumatol 1994;21:1581.
3. Kanakoudi Tsakalidou F, Trachana M, Pratsidou-Gertsi P, et al. Influenza vaccination in children with chronic rheumatic diseases and long-term immunosuppressive therapy. Clin Exp Rheumatol 2001;19:589–94.
4. Davies K, Woo P. Immunization in rheumatic diseases of childhood: an audit of the clinical practice of British Paediatric Rheumatology Group members and a review of the evidence. Rheumatology 2002;41:937–41.
5. Minder K, Niewerth M, Singendonk W, et al. Vaccination coverage among children with juvenile idiopathic arthritis (JIA) [abstract]. Rheumatology 2005;44:i91.
6. The Royal College of Paediatrics and Child Health. Immunisation of the immunocompromised. Child Best practice statement, 2002.
7. British Society of Rheumatology (BSR). Vaccinations in the immuno-compromised person. Guidance for patients taking immunosuppressants, steroids and new biologic therapies. London: BSR, 2002.
8. Department of Health Immunisation against infectious Disease. The Green Book. Edited by D Salisbury, M Ramsay, K Noakes, DOH, 2006.
9. American Academy of Pediatrics (AAP) Committee on infectious diseases. Recommendations for influenza vaccination of children. Chicago, USA:AAP, 2004.
10. Smith S, Demicheli V, Harnden A, et al. Vaccines for preventing influenza in healthy children (Protocol). Cochrane collaboration. Oxford: Update Software, 2005. Issue 3.
11. Kasapçopur Ö, Çullu F, Kamburoòlu-Goksel A, et al. Hepatitis B vaccination in children with juvenile idiopathic arthritis. Ann Rheum Dis 2004;63:1128–30.
12. Fomin I, Caspi D, Levy V, et al. Vaccination against influenza in rheumatoid arthritis: the effect of disease modifying drugs including TNF blockers. Ann Rheum Dis 2006;65:191–4.
13. Herron A, Dettlett G, Hixon, et al. Influenza vaccination in patients with rheumatic diseases. Safety and efficacy. JAMA 1979;242:53–6.
14. Chalmers A, Scheifele D, Patterson C, et al. Immunisation of patients with rheumatoid arthritis against influenza: a study of vaccine safety and immunogenicity. J Rheumatol 1994;21:1203–6.
15. Smith S, Demicheli V, Di Pietrantonj C, et al. Vaccines for preventing influenza in healthy children [Review]. The Cochrane Library Issue 3. (accessed 5 Jan 2006). Oxford: Update Software, 2006.