Department of Rheumatology, Great Ormond Street Hospital, London WC1N 3EJ, UK
Abstract
Objectives. To establish opinion and clinical practice of senior clinicians working with children with rheumatic diseases with regard to immunization and to determine whether or not this is in accordance with current recommendations. To review published guidelines on the subject and examine the evidence base supporting them.
Methods. A questionnaire was sent to all consultant members of the British Paediatric Rheumatology Group. Information on a variety of issues relating to immunization practice in children with rheumatic diseases was collected. A review of published guidelines and the medical literature on the subject was undertaken to assess current recommendations for immunization in patients on immunosuppressive agents and the evidence supporting these.
Results. A number of different sources of information are being used to decide whether or not to immunize patients with rheumatic diseases. Clinical practice varies between individuals. Areas of discordance include the doses of corticosteroids and disease-modifying drugs at which significant immunosuppression is felt likely to occur, the level of immunosuppression conferred by rheumatological diseases themselves and whether or not vaccination should be deferred in the presence of active disease. There was also variation in policy with regard to immunizations not part of the routine recommended schedule.
Conclusions. There is variation in both opinion and clinical practice regarding immunization in children with rheumatic diseases amongst senior clinicians working in the field of paediatric rheumatology. This reflects the lack of consistency between various sets of published guidelines and their non-specificity for rheumatic diseases and their treatment, and the lack of published evidence on the safety and efficacy of different vaccines in these situations. Further research is indicated in the hope that more specific guidelines may be developed for this not uncommonly encountered area of uncertainty.
KEY WORDS: Immunization, Paediatric rheumatology, Audit, Clinical practice.
Whether or not a child with a rheumatological disorder should receive a certain vaccine is an issue not uncommonly encountered by medical professionals working with children. The safety and efficacy of the vaccine in question need to be considered and weighed against the risks to the individual of not being immunized and subsequently contracting the infection. Immunosuppressive effects of both the underlying disease and its treatment can affect both the safety and efficacy of certain vaccines. Widely available guidelines on immunization practice in children have little specific information with regard to rheumatological diseases and their treatment.
We aimed to establish the clinical practice and opinions of specialists working with children with rheumatic diseases, to establish which sources of information they are using to help make decisions and to determine whether clinical practice was consistent throughout the UK.
Subjects and methods
A three-part postal questionnaire was designed. The first part was concerned with detailed sources of information used when faced with an immunization issue.
The second part asked whether or not the respondent would administer particular vaccines in patients with juvenile idiopathic arthritis (JIA) on a given variety of treatment dosages and combinations, in both stable and unstable disease. The third part of the questionnaire was designed to determine how immunosuppressive respondents considered a selection of disease-modifying anti-rheumatic drugs (DMARDs) and corticosteroids at varying doses. The questionnaires were sent to all 24 consultant British Paediatric Rheumatology Group members working within the UK: 16 were paediatric rheumatologists, six adult rheumatologists with a paediatric interest and two general paediatricians with an interest in rheumatology.
Results
Of the 24 questionnaires sent out, 23 were returned (96%). Only three respondents (13%) had written guidelines within their department. Respondents were using a variety of guidelines and other sources of information. Twelve (54%) mentioned the Department of Health publication Immunisation against Infectious Disease and one each the RCPCH publication Medicines for Children, the American Academy of Pediatrics Web guidelines and the British National Formulary.
All respondents said they would recommend immunization with a live vaccine to a patient with JIA if they were on NSAIDs alone (Table 1) although four (17%) would defer this in the presence of unstable, active disease. Three respondents would recommend live vaccines in patients taking long-term corticosteroids. Although the majority of respondents would withhold live vaccines in a patient on methotrexate, three (13%) would be confident to immunize in this situation and a further two (9%) felt that it would probably be safe.
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A small proportion of respondents would withhold non-live vaccines in patients on corticosteroids and/or DMARDs. Reluctance increased with greater levels of immunosuppressive therapy. Respondents were far more likely to withhold the meningococcal C conjugate vaccine than other non-live vaccines.
With regard to how immunosuppressive different doses and combinations of steroids and DMARDs were considered, opinion differed widely in some cases, particularly regarding methotrexate (Table 2). The dose of systemic corticosteroid felt to be immunosuppressive varied widely, the generally agreed cut-off point being 0.5 mg/kg/day however, above which all respondents felt it had at least some clinically significant immunosuppressive properties.
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Discussion
The incidence of inflammatory rheumatological disorders in childhood is of the order of 1:10 000 [1]. Many of these patients are on corticosteroid medication and a significant and increasing proportion are prescribed one or more DMARDs. As potentially immunocompromised individuals, a high priority must be therefore given to the prevention of potentially dangerous infections, including immunization where appropriate. The benefits of immunization, however, need to be weighed against the potential risks in each case: there are a number of reports in the literature describing the development of disseminated disease after the administration of live vaccines to immunocompromised patients (although none specifically immunocompromised by rheumatic disease or its treatment). There are also a number of isolated case reports linking administration of vaccines to the development of rheumatological conditions or worsening of pre-existing disease.
While there is no doubt that treatment with high-dose systemic corticosteroids results in increased vulnerability to infections, particularly viruses such as measles and chickenpox, there is no consensus on the minimum dose likely to cause clinically significant immunosuppression. This is due to a lack of studies to determine this and is reflected in the various published guidelines where doses felt to be immunosuppressive and live vaccines consequently contra-indicated vary between 0.2 and 1 mg/kg/day. Similarly, with methotrexate there is no published data on the dose at which immunosuppression is likely to occur. This lack of evidence forces manufacturers to advise caution and recommend that live vaccines should be withheld in any patient on methotrexate regardless of dose.
Guidelines for immunization in paediatric rheumatic disease
No specific guidelines have to date been compiled for children with rheumatic disorders.
The Department of Health document Immunisation against Infectious Disease has a short section on contraindications to live vaccines [2]. It states that live vaccines should not be given to patients undergoing treatment for malignant disease, organ transplant recipients on immunosuppressive treatment and patients who have undergone bone marrow transplant in the last 6 months. No specific reference to rheumatic or other inflammatory disorders or DMARDs is made. Live vaccines are contraindicated if a patient is on a prednisolone equivalent of 2 mg/kg/day for more than a week or 1 mg/kg/day for more than 1 month. It is stated that patients on lower doses of steroid either in combination with other immunosuppressant drugs, or because of their underlying disease process may be immunosuppressed. In such cases professionals are advised to seek specialist advice. The British Society for Rheumatology have published guidelines on the administration of vaccines in patients taking cytotoxic immunosuppressants and/or steroid therapy [3]. These state that live vaccines are contraindicated in all patients taking cytotoxic drugs and on moderate or high-dose steroids for 2 weeks or more. They state, however, that there is no consensus on the dose low enough to be defined as safe, suggesting 10 mg/day (in adults) as a sensible compromise. After cessation of steroid or cytotoxic therapy it is recommended that live vaccines be withheld for a minimum of 3 months.
The British Society for Rheumatology (BSR) actively recommend the use of Influenza A, meningococcus C, Haemophilus B, Hepatitis B and tetanus vaccines in patients with rheumatic disease but state that immunization response may be sub-optimal and boosters may be required.
The American Academy of Pediatrics Committee on Infectious Disease guidelines vary slightly from those of the BSR, recommending for example that live vaccines may be given with up to 2 mg/kg/day of prednisolone [4].
Anti-rheumatic drugs: evidence for immunosuppressive effect
Cytotoxic drugs used in rheumatological conditions include methotrexate, azathioprine, cyclosporin A, cyclophosphamide and chlorambucil. The immunosuppressive effects of these drugs have been assessed in patients taking them in the doses used to treat malignant conditions. The doses used in rheumatic diseases tend to be much lower, however, and there is little or no published evidence on the degree of immunosuppression conferred at these doses. In the one prospective study, adults with rheumatoid arthritis taking methotrexate had a mildly increased susceptibility to infections [5].
There are several case-reports in the literature of disseminated and occasionally lethal disseminated varicella and measles infections in immunocompromised patients, including those on steroids and or cytotoxic drugs. This study showed that British paediatric rheumatologists are well aware of this potential riskalthough only a handful of respondents routinely immunize susceptible patients for varicella, all were aware of their patients varicella status and prepared to give specific immunoglobulin where necessary.
Live vaccines in the immunocompromised host
There are a number of publications in the medical literature reporting serious adverse events following live vaccine administration in immunocompromised hosts although, interestingly, none relating to patients with rheumatic disease [621]. These risks, however, need to be balanced against the risks of the infection itself. Measles remains a significant cause of mortality in patients with malignancy [22]. Measles deaths in children with AIDS have been dramatically reduced by the now widespread practice of routinely immunizing HIV-positive patients against measles [23].
There have been no reported cases of fatality from varicella following immunization (Pasteur Merieux MSD Ltd, personal communication). Two prospective studies found a favourable riskbenefit relationship of immunizing cancer patients against varicella [24, 25] leading directly to the routine immunization of oncology patients against varicella in several countries. There may in some cases be a window of opportunity before starting a patient on immunosuppressive drugs when live vaccines could be administered (2 weeks prior if BSR guidelines are followed) and this should be considered. Despite this there are a large number of patients already on immunosuppressive drugs with no immunity to varicella who remain at-risk.
Efficacy of vaccination in patients with rheumatic disease
A number of studies have attempted to assess the efficacy of certain vaccines in patients on immunosuppressive drugs [2630]. For obvious reasons these studies have focused on inactive vaccines and those not part of the primary immunization schedule. The reported development of protective antibody titres in response to pneumococcal vaccine in patients on immunosuppressive therapy ranges from 56 to 96% [2730]. Influenza A vaccine appears to be less effective [30].
Although inactive vaccines are clearly safe in immunocompromised patients, the possibility of inadequate response must be borne in mind. It would seem prudent to routinely check vaccine titres in such patients in case further doses are indicated.
Do vaccines cause and/or exacerbate autoimmune disease?
Although there are sporadic reports in the medical literature describing the development of autoimmune disease following vaccination, population-based data are not available and it is consequently impossible to determine whether or not the associations are true [3143]. Two prospective trials failed to find evidence of an association between the vaccination and increased disease activity [29, 44].
Conclusions
Immunization practice varies between centres and individuals caring for children with rheumatic diseases, which reflects a lack of published evidence on the subject.
More research in this field is clearly indicated in order to allow the development of clear, comprehensive guidelines to aid the management of increasing number of patients with rheumatic and other autoimmune diseases requiring treatment with immunosuppressive agents.
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