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Keywords:

  • AAAAI;
  • ESID;
  • IVIg;
  • primary immunodeficiency;
  • prophylactic antibiotics

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results and discussion
  6. Conclusion
  7. Acknowledgements
  8. Disclosure
  9. References
  10. Appendices

Primary immunodeficiency diseases (PIDs) comprise a heterogeneous group of rare disorders. This study was devised in order to compare management of these diseases in the northern hemisphere, given the variability of practice among clinicians in North America. The members of two international societies for clinical immunologists were asked about their management protocols in relation to their PID practice. An anonymous internet questionnaire, used previously for a survey of the American Academy of Allergy, Asthma and Immunology (AAAAI), was offered to all full members of the European Society for Immunodeficiency (ESID). The replies were analysed in three groups, according to the proportion of PID patients in the practice of each respondent; this resulted in two groups from North America and one from Europe. The 123 responses from ESID members (23·7%) were, in the majority, very similar to those of AAAAI respondents, with > 10% of their practice devoted to primary immunodeficiency. There were major differences between the responses of these two groups and those of the general AAAAI respondents whose clinical practice was composed of < 10% of PID patients. These differences included the routine use of intravenous immunoglobulin therapy (IVIg) for particular types of PIDs, initial levels of IVIg doses, dosing intervals, routine use of prophylactic antibiotics, perceptions of the usefulness of subcutaneous immunoglobulin therapy (SCIg) and of the risk to patients' health of policies adopted by health-care funders. Differences in practice were identified and are discussed in terms of methods of health-care provision, which suggest future studies for ensuring continuation of appropriate levels of immunoglobulin replacement therapies.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results and discussion
  6. Conclusion
  7. Acknowledgements
  8. Disclosure
  9. References
  10. Appendices

Primary immunodeficiency diseases (PIDs) comprise a group of more than 150 distinct diseases arising from 120 different genetic abnormalities that affect development and/or function of the immune system [1]. Despite the heterogeneity of PIDs, impairment of immunity results in the common hallmark of susceptibility to infection. While once thought to be exceedingly rare, symptomatic primary immunodeficiencies are now appreciated to range from 1:500–1:500 000 in the general population in the United States and Europe [2,3]. A random digit dialling telephone survey in 2007 estimated that one in 1200 people within the United States are diagnosed with an immunodeficiency [4], although this included selective immunoglobulin A deficiency (IgAD), which is not usually clinically significant. These diseases have been considered rare, thus controlled studies investigating clinical interventions are scarce. In an effort to address these issues, several regions have created national registries for PIDs to enable epidemiological studies.

In the absence of controlled studies of therapeutic interventions for patients with PIDs, efforts have been organized to describe expert practice in order to ascertain consistencies, differences and outstanding questions. In the United States a recent survey of expert practice has been performed of the members of the American Academy of Allergy, Asthma and Immunology (AAAAI) [5]. In the majority of centres in the United States, immunology is a subspeciality with combined training in allergy and certifying examinations covering both clinical disciplines. In Europe, clinical immunology is sometimes, although not always, a distinct and separate subspeciality; in many other countries, PID patients are managed by physicians or paediatricians working in related specialities. With this difference in mind, we sought to compare the expert practice of PID between members of the European Society for Immunodeficiencies (ESID) and the AAAAI.

Due to the paucity of epidemiological research regarding their management, patient treatment plans are often created based on physician experience, past experience or expert opinion. One aim was to try to identify expert practice as applied to PID, while another was to understand the impact of experience upon such practice.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results and discussion
  6. Conclusion
  7. Acknowledgements
  8. Disclosure
  9. References
  10. Appendices

Survey subjects

We conducted a cross-sectional study among members of ESID and the AAAAI. Individuals who were full members of ESID in 2006 and members of AAAAI in 2005 were eligible for inclusion in this study. Members of the AAAAI were included as described [5], and those of ESID who met eligibility were sent the study questionnaire with an accompanying covering letter.

Survey design and administration

A close replica of the questionnaire administered to the members of the AAAAI in 2005 was designed to be self-administered via the internet [5]. The aim was to collect the specialist perspectives on therapy for PIDs from members of ESID, for comparison with the findings from members of the AAAAI. Changes made prior to distribution were only minor, related mainly to European compared to American English, as the goal was to keep the two questionnaires as similar as possible. All changes made to the survey instrument were approved by the ESID Board to ensure applicability to a European audience. A print format reproduction of the survey instrument is available as Appendix A and the original AAAAI survey is available as a supplement to the previous publication [5]. Some of the topics addressed in this survey instrument included utilization of IVIg for specific diseases, dosing and frequency of IVIg administration, utility of subcutaneous immunoglobulin therapy (SCIg), use of prophylactic antibiotics and health-care concerns.

A covering letter from ESID, explaining the purpose of the questionnaire, was sent via e-mail to full members of ESID, approximately 450 physicians or paediatricians with a link to a non-incentivized, web-based questionnaire. Three follow-up e-mails were sent as reminders to help increase survey participation, which was also conducted for the AAAAI members. Responses were collected electronically from July 2006 to September 2006 in a database. Each member of ESID was allowed to respond once to the questionnaire.

Data analysis

Duplicate responses were identified by careful analysis of name, e-mail and location fields. These repeated responses were examined closely and if the response pattern was the same in each entry, only one entry was preserved and the rest were removed. If there were multiple responses with different response patterns, all entries from the physician were removed as there was no way to determine which entry was the desired response. The original data from the AAAAI survey were analysed again for the purposes of this paper and duplicate entries treated in the same fashion to allow for optimal comparison between the two data sources.

AAAAI respondents were categorized into two groups as before [5]: a ‘focused’ group that reported that > 10% of their practice was devoted to patients with PID, and a ‘general’ group where ≤10% of their practice was devoted to patients with PID. Each response item was analysed separately.

Statistical analyses compared responses between (1) ESID and focused AAAAI respondents and (2) ESID and general AAAAI respondents. The comparison between focused and general AAAAI respondents has been reported previously [5]. Differences in responses between groups were assessed using χ2 and Fisher's exact tests for categorical data where appropriate. All data were analysed using STATA version 11·0 (Stata Corp., College Station, TX, USA). Statistical significance was declared with P-values < 0·05.

Results and discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results and discussion
  6. Conclusion
  7. Acknowledgements
  8. Disclosure
  9. References
  10. Appendices

Survey response

There were 123 responses to our questionnaire, which was a 27·3% response rate and therefore higher than the 13·5% response rate to the AAAAI survey, although the total number of respondents was greater in the AAAAI survey, in keeping with the larger membership [5]. The higher response rate may be due, in part, to a smaller community of immunologists within ESID or a greater sense of commitment to PID among the ESID membership. In both instances, the questionnaires had relatively low response rates overall. This reflects the general finding that there are lower responses to e-mail and internet surveys than postal mail surveys [6]. The covering letter from an organizational leader that accompanied the ESID survey may, in part, account for the higher response rate. The disadvantage of low response rates is the risk of substantial non-response bias, but this is likely to be the same for each group.

Demographic characteristics of respondents

In order to understand the nature of individual respondents generally, information on the length of time since medical graduation and on geographical location of respondents was requested. ESID respondents had a very similar distribution to the AAAAI respondents (Table 1), in terms of age or length of medical practice. ESID is an international organization and although it was a requirement to be a member of ESID to participate in this questionnaire, there are ESID members located outside Europe. Among the 123 ESID respondents, 105 (85·4%) were located within Europe (Table 2 and Appendix B); the United Kingdom had the largest representation (26 respondents, 21·1%), reflecting the relatively high number of PID centres in the United Kingdom. In addition, six respondents (4·9%) were from the Middle East and 11 (8·9%) from other countries (Table 2 and Appendix B).

Table 1.  Comparison between European Society for Immunodeficiency (ESID) and American Academy of Allergy, Asthma and Immunology (AAAAI) respondents with regard to their year of graduation from medical school.
CharacteristicsESIDFocused AAAAIGeneral AAAAI
# (%)# (%)# (%)
Total respondents12365329
Year of graduationMissing response9 (7·3)6 (9·2)34 (10·3)
1990 or later43 (35)24 (36·9)97 (29·5)
1975–8955 (44·7)26 (40)135 (41)
Earlier than 197516 (13)9 (13·8)63 (19·1)
Table 2.  Percentage of total respondents by country.
 CountryESID respondents
# (%)
  1. ESID: European Society for Immunodeficiencies.

EuropeBelgium6 (4·9)
Croatia1 (0·8)
Czech Republic3 (2·4)
Denmark1 (0·8)
Estonia1 (0·8)
Finland3 (2·4)
France2 (1·6)
Germany12 (9·8)
Greece4 (3·3)
Ireland2 (1·6)
Italy8 (6·5)
Lithuania1 (0·8)
Netherlands9 (7·3)
Norway1 (0·8)
Poland1 (0·8)
Portugal2 (1·6)
Romania1 (0·8)
Russia4 (3·3)
Slovakia1 (0·8)
Slovenia1 (0·8)
Spain3 (2·4)
Sweden3 (2·4)
Turkey8 (6·5)
Ukraine1 (0·8)
United Kingdom26 (21·1)
Total105 (85·4)
Middle EastEgypt1 (0·8)
Israel3 (2·4)
Oman1 (0·8)
Saudi Arabia1 (0·8)
Total6 (4·9)
Rest of the worldArgentina1 (0·8)
Australia1 (0·8)
Brazil3 (2·4)
Costa Rica1 (0·8)
Japan1 (0·8)
Mexico1 (0·8)
South Africa1 (0·8)
United States2 (1·6)
Total11 (8·9)
No response 1 (0·8)
Total 123

Solutions to study limitations

Non-response bias is a limitation of this present study, as so few questionnaires were returned for analysis. We attempted to minimize response bias by ensuring anonymous responses, as respondents may have otherwise felt pressured to answer with the more ‘socially acceptable’ answer rather than their true beliefs, especially when it comes to patient care and following guidelines. Because the mode of administration was an internet questionnaire, it is conceivable that younger members might have been more apt to respond. However, our demographics show that the largest proportion of respondents were not actually in the group that had graduated medical school most recently, but rather the group that graduated from 1975 to 1989 (Table 1). In addition, those who responded may have been more motivated to respond because they had differing practices that they wanted expressed to the immunology community anonymously, or they actually are well versed in practice guidelines and wanted to portray this fact by responding to our survey. Those who did not respond may have differed in their comfort level in caring for immunodeficient patients or believed that they had nothing novel to contribute by responding. Given that clinical immunology is sometimes a separate subspeciality within parts of Europe, the majority of those who received the questionnaire should have been equally comfortable in caring for PID patients with a similar familiarity in practice guidelines, so this bias would be expected to be minimal. This might have explained the small but measurable difference in response rate between ESID and the AAAAI.

Use of IVIg for specific PID

IVIg is well documented to decrease infection rates within specific PIDs [7,8]. The recommendation of IVIg as therapy for patients with PID varies with specific disease and there was agreement between ESID and focused AAAAI respondents in most diagnoses (Fig. 1). For example, all three subgroups agreed in their recommendation of IVIg for X-linked agammaglobulinaemia. For common variable immune deficiency (CVID), 96·9% of ESID respondents recommended treating most to all patients with IVIg compared with 90·5% of general AAAAI respondents, although this difference was not statistically significant (P = 0·057). Hyper-IgM (HIGM) syndrome presented a more dramatic difference, where 92·9% of ESID respondents recommended use of IVIg to treat the majority of these patients, whereas only 51% of general AAAAI respondents agreed (P < 0·001). These differences were not apparent when ESID and focused AAAAI respondents were compared (Fig. 1). In addition, ESID respondents recommended IVIg more frequently than general AAAAI respondents for severe combined immune deficiency (SCID) (P < 0·001), whereas the responses of the focused AAAAI respondents were statistically indistinguishable from those of ESID. The differences were largely the same as those identified previously between the general and focused AAAAI members [5]. These findings are likely to indicate a need for increased awareness of practice parameters and guidelines for the treatment of PID among subspecialists who divide their effort among immunology and other disciplines, as well as increased education in PID. A substantial proportion of general AAAAI members practice in a community-based setting that further distinguishes this group from ESID, and creates a potentially unique set of educational needs and challenges.

image

Figure 1. Recommendation of immunoglobulin replacement for specific primary immunodeficiencies. (a) Percentage of immunologists recommending intravenous immunoglobulin (IVIg) for more than 50% of patients with the specific primary immunodeficiency disease (PID) listed. (b) Percentage of immunologists recommending IVIg for at least some (5–50%) patients with the listed diagnosis. P-values test the comparisons marked by the brackets. Comparisons were tested via χ2 or Fisher's exact test (marked by *). The European Society for Immunodeficiency (ESID) is represented in black, focused American Academy of Allergy, Asthma and Immunology (AAAAI) members in dark grey, general AAAAI members in light grey. Agam: agammaglobulinaemia; AT: ataxia telangectasia; CGD: chronic granulomatous disease; CMC: chronic mucocutaneous candidiasis; CVID: common variable immune deficiency; Comp: complement deficiency; DGS: DiGeorge syndrome; HIGM: hyper-IgM syndrome; HIES: hyper-IgE syndrome; IgGSD: IgG subclass deficiency; IgAD: IgA deficiency; SCID: severe combined immunodeficiency; SCN: severe congenital neutropenia; SAD: specific antibody deficiency; IFN: interferon-gamma/interleukin-12 cytokine axis defect; WAS: Wiskott–Aldrich syndrome; XLP : X-linked lymphoproliferative syndrome.

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There are complex PID diseases where guidelines are less clear regarding use of IVIg therapy [9], and in these cases responses varied more within the experienced groups. The ESID and focused AAAAI groups (52–64% of respondents) perceived that most patients with Wiskott–Aldrich syndrome (WAS) or X-linked lymphoproliferative disease (XLP) required IVIg to maintain good health, whereas only 26–30% of respondents in the general AAAAI group reported this. Recommendations regarding patients with WAS or XLP have evolved over the last two decades, and it is hypothesized that only those attending advanced PID meetings, or avidly consuming subspeciality literature, might be aware of these changes.

In those diseases in which IVIg usage is more controversial, there were similar differences. For example, for immunoglobulin G subclass deficiencies (IgGSD), 62·4% of ESID respondents recommended IVIg for at least some patients with this particular PID and an additional 17·1% would recommend it for most/all of their patients. This response was more common in ESID than it was in the general AAAAI group, where 62·4% (ESID) compared to 49·6% (general AAAAI) would recommend IVIg for some of their patients with IgGSD and 17·1% (ESID) compared to 12% (general AAAAI) would recommend it for most to all patients with this PID. Similarly, there was a small subset of respondents in all three subgroups who would recommend IVIg for patients with IgAD, even though guidelines in the vast majority of countries do not recommend immunoglobulin replacement for this diagnosis [10]. ESID recommended this more commonly (11·8%) than did general AAAAI respondents (4·3%, P = 0·012). This may reflect a lack of clarity regarding the questionnaire, as definitions, and therefore treatment implications, of IgAD with IgGSD and IgGSD alone vary between countries and continents.

Dosing and infusion interval of IVIg therapies

Interestingly, ESID respondents were equally likely (Fig. 2a) to recommending infusion frequencies of every 3 (45·6%) or 4 weeks (49·1%). Within the AAAAI membership, the vast majority (87%) recommended every 4 weeks as the most commonly recommended infusion interval for IVIg infusions for their patients [5]. This difference between ESID and both the AAAAI respondent groups was statistically significant (P < 0·001). This may reflect the greater use of self-infusion of IVIg by patients at home in Europe, which provides greater flexibility regarding infusion interval (although specific data do not exist to substantiate this hypothesis). More population-based databases need to be utilized to determine measures of outcome in PID patients receiving IVIg every 3 versus every 4 weeks, as the efficacy of every 3-week dosing is currently unclear. Initial dosing of IVIg for PID patients naive to IVIg (Fig. 2b), however, showed strong agreement between all three subgroups (64·4–65·6%) that 400 mg/kg of IVIg should be used.

image

Figure 2. Intravenous immunoglobulin (IVIg) usage parameters. Comparison of current practice within immunologists of IVIg usage for treatment of antibody disorders. (a) Interval between IVIg infusions, (b) level of initial dosing of IVIg and (c) desired maintenance IgG trough levels (pre-infusion). P-values test the comparisons marked by the brackets. Comparisons were tested via χ2 or Fisher's exact test (marked by *). The European Society for Immunodeficiency (ESID) is represented in black, focused American Academy of Allergy, Asthma and Immunology (AAAAI) members in dark grey, general AAAAI members in light grey.

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Regarding IgG trough levels, recent literature supports that IgG troughs levels higher than those recommended previously can reduce the incidence of pneumonia [11] or bacterial infections [7]. Both ESID and focused AAAAI respondents tended to recommend higher IgG troughs for their patients than general AAAAI respondents (Fig. 2c). Whereas 43·8% of general AAAAI respondents recommended trough levels of 501–600 mg/dl, only 25·2% of ESID respondents recommended these levels (P = 0·001). The converse was true: 26·9% of ESID respondents recommended higher trough levels of 751–900 mg/dl, whereas only 11·7% of general AAAAI respondents recommended this higher trough level (P < 0·001). Because IgG trough levels required to keep antibody deficiency patients infection-free have been identified as variable, spanning the normal range as in the general population [7], the specific utility of these values may change with time.

Perceptions regarding SCIg replacement therapy for PID

SCIg replacement has been used as a therapy for PID in Europe for more than 20 years [2]. SCIg replacement was only approved by the Food and Drug Administration (FDA) in the United States in 2006. Despite this difference in availability, ESID and focused AAAAI respondents were similar in their responses, with the majority agreeing that SCIg replacement was equally as effective as IVIg in treating their PID patients (Fig. 3). General AAAAI respondents, however, were not as confident in the equality of SCIg replacement compared with IVIg. Only 44·6% considered it equally as effective compared with 66·7% of ESID respondents (P < 0·001). Almost four times as many ESID respondents (19·8%) than general AAAAI respondents (5·2%) thought that SCIg was even more effective than IVIg replacement. Strikingly, there were no ESID respondents who thought that SCIg replacement was less effective than IVIg replacement for their patients, compared to 10·9% of focused AAAAI and 24·3% of general AAAAI respondents.

image

Figure 3. Perceived efficacy of subcutaneous immunoglobulin therapy (SCIg). Comparison of immunologists' opinions regarding the efficacy of subcutaneous versus intravenous immunoglobulin replacement. P-values test the comparisons marked by the brackets. Comparisons were tested via χ2 or Fisher's exact test (marked by *). The European Society for Immunodeficiency (ESID) is represented in black, focused American Academy of Allergy, Asthma and Immunology (AAAAI) members in dark grey, general AAAAI members in light grey.

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Use of prophylactic antibiotics in patients with PIDs

Apart from chronic granulomatous disease (CGD) [12,13] and complement deficiencies [6], there are no rigorous studies evaluating the effect of prophylactic antibiotics and their usefulness in patients with PIDs [14]. Given the widespread use of prophylaxis for pulmonary infection with pneumocystis in severe T cell deficiencies [9], we sought to query how often immunologists were using prophylaxis for the prevention of other types of infections aside from pulmonary infection with pneumocystis. We asked respondents if they used prophylactic antibiotic therapy for some of their patients with PID to prevent infection (excluding Pneumocystis prophylaxis), and 93·1% of ESID respondents reported the use of prophylactic antibiotics. To detail this use further, we found that prophylaxis is also used in practice as an adjunct to IVIg (Fig. 4). More ESID respondents (49·1%) would use prophylaxis as an adjunct in 11–50% of their patients than general AAAAI respondents (26·9%) (P < 0·001).

image

Figure 4. Use of adjunct prophylactic antibiotics in primary immunodeficiency diseases (PIDs). Percentage of immunologists who use prophylactic antibiotics as adjunct therapy to intravenous immunoglobulin (IVIg) in given proportions of their patients with antibody deficiencies. P-values test the comparisons marked by the brackets. Comparisons were tested via χ2 or Fisher's exact test (marked by *). The European Society for Immunodeficiency (ESID) is represented in black, focused American Academy of Allergy, Asthma and Immunology (AAAAI) members in dark grey, general AAAAI members in light grey.

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When separated by specific PID, there were several differences between the three subgroups of respondents who perceived antibiotic prophylaxis as moderately to extremely useful in these patients (Fig. 5a). Given the body of literature supporting use of prophylaxis in CGD, it was not surprising that 96·1% of ESID respondents perceived antibiotic prophylaxis as beneficial in this diagnosis, whereas only 73·5% of general AAAAI respondents agreed (P < 0·001). ESID and focused AAAAI respondents differed in this regard in only two disease categories: IgAD and SCID. Only 28·1% of ESID respondents perceived moderate to extreme utility in prophylaxis in IgAD, whereas 54·4% of focused AAAAI respondents held this opinion (P = 0·002); again, this may be the result of different definitions of IgAD between the two groups [9,15]. In SCID, 78·7% of ESID compared to 55·3% of focused AAAAI respondents found moderate to extreme utility in prophylaxis for these patients (P = 0·002). The other statistically significant differences were between ESID and general AAAAI respondents across a wide range of fairly rare conditions (Fig. 5a, P < 0·05 for all comparisons), where the perceived utility of antibiotic prophylaxis was greater among ESID members.

image

Figure 5. Perceived utility of prophylactic antibiotics within specific primary immunodeficiency diseases (PIDs). (a) Percentage of immunologists who believe prophylactic antibiotics (excluding Pneumocystis prophylaxis) are moderately to extremely useful in particular PIDs. (b) Comparison of how often immunologists rotate prophylactic antibiotics. P-values test the comparisons marked by the brackets. Comparisons were tested via χ2 or Fisher's exact test (marked by *). The European Society for Immunodeficiency (ESID) is represented in black, focused American Academy of Allergy, Asthma and Immunology (AAAAI) members in dark grey, general AAAAI members in light grey. Agam: agammaglobulinaemia; AT: ataxia telangectasia; CGD: chronic granulomatous disease; CMC: chronic mucocutaneous candidiasis; CVID: common variable immune deficiency; Comp: complement deficiency; DGS: DiGeorge syndrome; HIGM: hyper-IgM syndrome; HIES: hyper-IgE syndrome; IgGSD: IgG subclass deficiency; IgAD: IgA deficiency; SCID: severe combined immunodeficiency; SCN: severe congenital neutropenia; SAD: specific antibody deficiency; IFN: interferon-gamma/interleukin-12 cytokine axis defect; WAS: Wiskott–Aldrich syndrome; XLP : X-linked lymphoproliferative syndrome.

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The use of rotating prophylactic antibiotics is also controversial, as there are no supporting studies. More ESID respondents (58·7%) than focused AAAAI respondents (41·8%) reported that they do not rotate antibiotics (P = 0·043). Conversely, more AAAAI respondents overall would rotate the prophylactic antibiotic on a monthly basis compared with ESID respondents (focused P = 0·023, general P = 0·002). Why ESID members were less likely to rotate antibiotics when used as prophylaxis remains unclear, but represents an important direction for future interventional clinical research.

Health-care concerns

There was little variability in the chosen interval for follow-up for healthy PID patients; all three subgroups agreed that every 6 months was the most appropriate (Fig. 6a). ESID respondents more frequently recommended quarterly evaluations (35·7%) compared with the general AAAAI respondents (23·6%, P = 0·015), and were less likely to recommend annual follow-up (P = 0·021). The fact that clinical immunology has been a separate subspeciality in several countries in Europe may explain the trend towards more regular routine PID patient evaluations than in the United States, where immunology is combined most typically with a large allergy practice.

image

Figure 6. Recommended immunology follow-up and perceived reimbursement risks. (a) Comparison of follow-up intervals recommended for patients with primary immunodeficiency disease (PID) if they are in good health. (b) Comparison of risk level perceived by immunologists concerning current reimbursement standards for intravenous immunoglobulin (IVIg). P-values test the comparisons marked by the brackets. Comparisons were tested via χ2 or Fisher's exact test (marked by *). The European Society for Immunodeficiency (ESID) is represented in black, focused American Academy of Allergy, Asthma and Immunology (AAAAI) members in dark grey, general AAAAI members in light grey.

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The most striking difference across the entire questionnaire, however, arose when providers were asked to assess the risk to their patients of reimbursement policies for IVIg therapies. Within the ESID respondents, there was a general trend towards no or slight perceived risk, whereas there was a strong concern among AAAAI respondents, with the majority reporting extreme or serious risk (Fig. 6b). While this is due probably to the differences in health-care models that exist between Europe and the United States, it underscores a need for the collection of clinical outcome data on newly diagnosed patients in both continents and standardized quality of life information for existing patients; these will enable health technology assessments to be made to inform payers – whether insurers or government agencies – and to ensure appropriate health-care provisions. Furthermore, there is a need for advocacy on behalf of PID patients in both continents, particularly in the face of changing health-care economies and to ensure adequate access for optimal life-saving therapies and management. The present survey of practice demonstrates important areas of consensus that should be viewed as integral care standards, as well as indicating areas in which further interventional research should be focused to improve patient management.

Conclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results and discussion
  6. Conclusion
  7. Acknowledgements
  8. Disclosure
  9. References
  10. Appendices

Overall, the comparison of these surveys of practice in Europe and America demonstrate remarkable similarities in the care applied to patients with PID. The differences, while few, represent areas for future research and potentially practice improvement. The greater similarity between focused American immunologists and ESID immunologists compared to general allergy and immunology physicians within the United States demonstrates a continued role for specialized practitioners as well as a sustained need for dissemination of information.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results and discussion
  6. Conclusion
  7. Acknowledgements
  8. Disclosure
  9. References
  10. Appendices

Funding for this survey was provided by the American Academy of Allergy, Asthma and Immunology, the European Society for Immunodeficiencies and the Immune Deficiency Foundation. This study was also supported by the Federal Ministry of Education and Research (BMBF 01 EO 0803).

Disclosure

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results and discussion
  6. Conclusion
  7. Acknowledgements
  8. Disclosure
  9. References
  10. Appendices

Authors H.S. Hernandez-Trujillo, H. Chapel, V. Lo Re III, L.D. Notarangelo, B. Gathmann, B. Grimbacher, J.M. Boyle, C. Scalchunes and M.L. Boyle have no disclosures to report. V.P. Hernandez-Trujillo MD – Merck Claritin Council Member; Baxter Advisory Group, Speaker and IFIR attendee; CSL Speaker. J.S. Orange – Consultant to: CSL Bhering, Talecris Biotherapeutics, Griffols, Baxter Healthcare; Research grant review committee: Octapharma USA.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results and discussion
  6. Conclusion
  7. Acknowledgements
  8. Disclosure
  9. References
  10. Appendices

Appendices

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results and discussion
  6. Conclusion
  7. Acknowledgements
  8. Disclosure
  9. References
  10. Appendices

Appendix A

American Academy of Allergy Asthma and Immunology Immune Deficiency Foundation

ID NUMBER: _______ (for internal purposes only)

SPECIALIST PHYSICIAN PERSPECTIVES ON PRIMARY IMMUNODEFICIENCY DISEASES (PID) IN EUROPE 2006

  • 1
    How much of your clinical practice is devoted to patients with PID or suspected of having PID?
    • • 
      < 1%
    • • 
      1–5%
    • • 
      6–10%
    • • 
      11–25%
    • • 
      26–50%
    • • 
      51–75%
    • • 
      > 75%
  • 2
    In what type of outpatient setting do you spend MOST of your patient care time?
    • • 
      General practice
    • • 
      Single-speciality practice in a general hospital
    • • 
      Single-speciality practice in a university hospital
    • • 
      Private practice
    • • 
      Private hospital
    • • 
      Other, please specify below
    • _____________________________

  • 3
    In an average month, about how many patients overall do you see on an out-patient basis? (Your best estimate is fine.)
    • __________ patients per week

  • 4
    Have you ever treated patients with the following diagnoses?
    • MARK AS MANY AS APPLY

    • • 
      Agammaglobulinaemia
    • • 
      Ataxia telangiectasia
    • • 
      Chronic granulomatous disease
    • • 
      Chronic mucocutanous candidiasis
    • • 
      Common variable immunodeficiencies (CVIDs)
    • • 
      Complement deficiencies
    • • 
      DiGeorge syndrome
    • • 
      Hyper-IgM syndromes
    • • 
      Hyper-IgE syndrome
    • • 
      IgG subclass deficiencies
    • • 
      Selective IgA deficiency
    • • 
      Severe combined immunodeficiencies (SCID)
    • • 
      Severe congenital neutropenia
    • • 
      Specific antibody deficiency
    • • 
      IFN-γ/IL-12 cytokine axis defect
    • • 
      Wiskott–Aldrich syndrome
    • • 
      X-linked lymphoproliferative syndrome (XLP)
    • • 
      None of these ever
    • IF NONE EVER, SKIP TO Q30a on Page 4

  • 5
    Do you currently follow any patients with the following diagnoses?
    • MARK AS MANY AS APPLY

    • • 
      Agammaglobulinaemia
    • • 
      Ataxia telangiectasia
    • • 
      Chronic granulomatous disease
    • • 
      Chronic mucocutanous candidiasis
    • • 
      Common variable immunodeficiencies (CVIDs)
    • • 
      Complement deficiencies
    • • 
      DiGeorge syndrome
    • • 
      Hyper-IgM syndromes
    • • 
      Hyper-IgE syndrome
    • • 
      IgG subclass deficiencies
    • • 
      Selective IgA deficiency
    • • 
      Severe combined immunodeficiencies (SCID)
    • • 
      Severe congenital neutropenia
    • • 
      Specific antibody deficiency
    • • 
      Wiskott–Aldrich syndrome
    • • 
      X-linked lymphoproliferative syndrome (XLP)
    • • 
      None of these currently
  • 6
    In counselling a PID patient about to start immunoglobulin (IG) therapy, how would you present their risk of contracting the following diseases as a result of treatment?
    • NO RISK (A)

    • LOW RISK (B)

    • MODERATE RISK (C)

    • HIGH RISK (D)

    • HIV

    • Hepatitis B

    • Hepatitis C

    • Prion disease

    • Rotavirus

    • Yet to be discovered pathogens

  • 7
    Would you recommend intravenous IG therapy for all, most, some or few to no patients with0ellip;
    • FEW TO NONE (< 5%) (A)

    • SOME (5–50%) (B)

    • MOST (> 50%) (C)

    • ALL OR ALMOST ALL (> 95%) (D)

    • Agammaglobulinaemia XLA

    • Ataxia telangiectasia

    • Chronic granulomatous disease

    • Chronic mucocutanous candidiasis

    • CVIDs complement deficiencies

    • DiGeorge syndrome

    • Hyper-IgM syndromes

    • Hyper-IgE syndrome

    • IgG subclass deficiencies

    • Selective IgA deficiency

    • SCID

    • Severe congenital neutropenia

    • Specific antibody deficiency

    • IFN-γ/IL-12 cytokine axis defect

    • Wiskott–Aldrich syndrome

    • XLP

  • 8
    About how many PID patients do you follow who are maintained on IG therapy to prevent infection?
  • ____________ NUMBER

    • If zero skip to question 18

  • Questions 9–14 refer specifically to IG administered intravenously.

  • 9
    What percentage of your patients receives their IG therapy at following sites?
    • FEW TO NONE (< 5%) (A)

    • SOME (5–50%) (B)

    • MOST (> 50%) (C)

    • ALL OR ALMOST ALL (> 95%) (D)

    • Primary care/GP surgery

    • Hospital out-patient infusion

    • Hospital in-patient

    • Home with nurse

    • Home via self-infusion

  • 10a.
    What is the usual interval with which you recommend patients with antibody disorders receive their IVIg therapy (on average)?
    • • 
      Every week
    • • 
      Every 2 weeks
    • • 
      Every 3 weeks
    • • 
      Every 4 weeks
    • • 
      Every 5 weeks
    • • 
      Every 6 or more weeks
  • 10b.
    What is the usual interval with which you recommend patients with antibody disorders receive their SCIg (on average)?
    • • 
      Every week
    • • 
      Every 2 weeks
    • • 
      Every 3 weeks
    • • 
      Every 4 weeks
    • • 
      Every 5 weeks
    • • 
      Every 6 or more weeks
  • 11
    What is the usual initial IG dosage per kilogram of body weight that you typically recommend for patients with antibody disorders (given at the interval in question 10)?
    • • 
      ≤200 mg/kg
    • • 
      300 mg/kg
    • • 
      400 mg/kg
    • • 
      500 mg/kg
    • • 
      600 mg/kg
    • • 
      > 600 mg/kg
    • • 
      I do not consider mg/kg when dosing IG
  • 12
    What percentage of your patients receiving IG therapy is premedicated with the following to facilitate infusions?
    • FEW TO NONE (< 5%) (A)

    • SOME (5–50%) (B)

    • MOST (> 50%) (C)

    • ALL OR ALMOST ALL (> 95%) (D)

    • Paracetamol

    • Antihistamine

    • Corticosteroid

    • Non-steroidal anti-inflammatory

    • Saline i.v.

  • 13
    How many of your PID patients receiving IVIg therapy have surgically implanted (indwelling) access devices to facilitate IG infusions?
    • • 
      > 75%
    • • 
      51–75%
    • • 
      26–50%
    • • 
      5–25%
    • • 
      < 5%
    • • 
      None
  • 14
    What pre-infusion IgG trough do you try to achieve in your hypogammaglobulinaemic patients?
    • • 
      3·00–5·00 g/l
    • • 
      5·00–6·00 g/l
    • • 
      6·00–7·50 g/l
    • • 
      7·50-9·00 g/l
    • • 
      > 9·00 g/l
    • • 
      I do not consider pre-infusion IgG levels.
  • 15
    How effective overall do you believe subcutaneous immunoglobulin therapy is compared to IVIG for patients with antibody deficiencies?
    • • 
      Much more effective
    • • 
      Somewhat more effective
    • • 
      Equally effective
    • • 
      Somewhat less effective
    • • 
      Much less effective
    • • 
      Not sure
  • 16
    What proportion of your patients who require immunoglobulin replacement therapy do you believe will ultimately be better served by subcutaneous immunoglobulin?
    • • 
      > 75%
    • • 
      50–75%
    • • 
      25–50%
    • • 
      5–25%
    • • 
      < 5%
  • 17
    How much risk do current reimbursement standards for IG pose to the health of PID patients?
    • • 
      Extreme risk
    • • 
      Serious risk
    • • 
      Moderate risk
    • • 
      Slight risk
    • • 
      No real risk
  • 18
    Approximately what proportion of your patients with mild to moderate PID would you say are satisfied with the management of their disease? Would you say0ellip;
    • • 
      All (91–100%)
    • • 
      Most (51–90%)
    • • 
      Some (11–50%)
    • • 
      Few (1–10%)
    • • 
      None (0%)
  • 19
    On average, how often do you recommend that PID patients in otherwise good health be seen by a specialist immunologist (for adults or children)?
    • • 
      Every 3 months
    • • 
      Every 6 months
    • • 
      Every 12 months
    • • 
      Every 2 years
    • • 
      Only if levels or symptoms change
  • 20
    Do you use prophylactic antibiotic therapy for some of your patients with PID to prevent infection (excluding Pneumocystis prophylaxis)?
    • • 
      Yes
    • • 
      No – go to question 26
  • 21
    In which primary immunodeficiency diseases do you feel that prophylactic antibiotic therapy can be mildly, moderately or extremely clinically useful in preventing infection (excluding Pneumocystis prophylaxis)?
    • Extremely useful (A)

    • Moderately useful (B)

    • Mildly useful (C)

    • Not useful at all (D)

    • Agammaglobulinaemia XLA

    • Ataxia telangiectasia

    • Chronic granulomatous disease

    • Chronic mucocutanous candidiasis

    • CVIDs

    • Complement deficiency

    • DiGeorge syndrome

    • Hyper-IgM syndromes

    • Hyper-IgE syndrome

    • IgG subclass deficiencies

    • Selective IgA deficiency

    • SCID

    • Severe congenital neutropenia

    • Specific antibody deficiency

    • IFN-γ/IL-12 cytokine axis defect

    • Wiskott–Aldrich syndrome

    • XLP

  • 22
    What is the prophylactic antibiotic you use most commonly to prevent infection in children with antibody deficiencies?
    • ____________________________

    • at a dose of ________mg/kg every ______• hours • days

  • 23
    What is the prophylactic antibiotic you use most commonly to prevent infection adults with antibody deficiencies?
    • ____________________________

    • at a dose of ________mg every ______• hours and for • days

  • 24
    Do you rotate the antibiotic you use for prophylaxis in your patients with antibody deficiencies?
    • • 
      No, I do not rotate prophylactic antibiotics
    • • 
      Yes, I typically rotate antibiotics monthly
    • • 
      Yes, I typically rotate antibiotics biannually
    • • 
      Yes, I typically rotate antibiotics annually
    • • 
      Yes, I typically rotate prophylactic antibiotics but using some other regimen
  • 25
    Do you use prophylactic antibiotic therapy as an adjunct to IG therapy in order to prevent infection in patients with PID?
    • • 
      In all patients (91–100%)
    • • 
      In most patient (51–90%)
    • • 
      In some patients (11–50%)
    • • 
      In a few patients (1–10%)
    • • 
      I never use antibiotics this way (0%)
  • 26
    Do you believe there is a greater than placebo effect benefit to any of the following alternative therapies for enhancing immunity, or preventing infection in patients with PID?
    • MARK AS MANY AS APPLY

    • • 
      Massage therapy
    • • 
      Acupuncture
    • • 
      Additional vitamins (rather than therapeutic)
    • • 
      Nutritional supplements
    • • 
      Herbal formulations
    • • 
      Probiotics
    • • 
      Biofeedback
    • • 
      Hypnotherapy
    • • 
      Meditation
    • • 
      Yoga
    • • 
      Aerobic exercise
  • 27
    Do you believe that any of the following hygiene-related interventions offer a greater benefit than cost for patients with PID?
    • MARK AS MANY AS APPLY

    • • 
      Alcohol-based hand gels for patient
    • • 
      Alcohol-based hand gels for family
    • • 
      Alcohol-based hand gels for classroom
    • • 
      Regular soap and water hand washing
    • • 
      Use of anti-bacterial soaps
    • • 
      Avoidance of daycare
    • • 
      Home schooling
    • • 
      HEPA filter-based air purifiers in the home
    • • 
      Dehumidification systems in the home
    • • 
      Exclusion of furred pets from the home
    • • 
      Exclusion of feathered pets from the home
    • • 
      Use of disinfectant cleaners in the home
    • • 
      Use of water filtration systems in the home
  • 28
    Do you use licensed vaccines as a treatment for PID patients (not including allergy vaccines, influenza vaccination or the required paediatric immunization schedule)?
    • • 
      In all patients (91–100%)
    • • 
      In most patients (51–90%)
    • • 
      In some patients (11–50%)
    • • 
      In a few patients (1–10%)
    • • 
      I never use vaccines this way (0%)
  • 29
    For which PID patients do you recommend avoidance of live viral vaccination?
    • MARK AS MANY AS APPLY

    • • 
      Agammaglobulinaemia XLA
    • • 
      Ataxia telangiectasia
    • • 
      Chronic granulomatous disease
    • • 
      Chronic mucocutanous candidiasis
    • • 
      Common variable immunodeficiencies (CVIDs)
    • • 
      Complement deficiencies
    • • 
      DiGeorge syndrome
    • • 
      Hyper-IgM syndromes
    • • 
      Hyper-IgE syndrome
    • • 
      IgG subclass deficiencies
    • • 
      Selective IgA deficiency
    • • 
      Severe combined immunodeficiencies (SCID)
    • • 
      Severe congenital neutropenia
    • • 
      Specific antibody deficiency
    • • 
      IFN-γ/IL-12 cytokine axis defect
    • • 
      Wiskott–Aldrich syndrome
    • • 
      X-linked lymphoproliferative syndrome (XLP)
  • 30a.
    Are you aware of any professional guidelines for the diagnosis and management of primary immunodeficiency diseases?
    • • 
      Yes
    • • 
      No SKIP TO Q31
  • 30b.
    Who publishes those guidelines?
    • _____________________________

  • 31
    Do you know that physicians in your community who may not receive this survey are caring for PID patients?
    • • 
      Yes ANSWER Q32
    • • 
      No SKIP TO Q33
  • 32
    What are their specialities? (check all that apply)
    • • 
      Immunology
    • • 
      Paediatric rheumatology
    • • 
      Adult rheumatology
    • • 
      Paediatric infectious diseases
    • • 
      Adult infectious diseases
    • • 
      Haematology oncology
    • • 
      Other________________________
  • 33
    In what year did you graduate from medical school?
    • _____ YEAR

  • Please try to answer all questions to the best of your ability based upon your average approach to the ‘typical’ patient with PID. If you have specific additional concerns or comments regarding a particular question you may list them below (or separately).

  • Question concern

    • ____________________________

    • ____________________________

    • ____________________________

    • ____________________________

Appendix B

Geographic distribution of ESID respondents

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