To the Editor
Allergic rhinitis affects approximately 15-30% of the United States (US) population, and accounts for over 22 million healthcare visits annually.1,2 Allergic rhinitis treatments were estimated to cost $11.2 billion in 2005, which was a near doubling over a five-year period.1 Additionally, this condition accounts for significant indirect costs with approximately 6 million lost work days each year.3
Subcutaneously administered allergen immunotherapy (AIT) is a cost-effective and disease-modifying treatment that has been used for the past century to successfully treat allergic rhinitis, allergic conjunctivitis, asthma, and Hymenoptera venom allergy.4 AIT is administered to 2.6 million people in the US each year, resulting in approximately 16 million annual injections.5
AIT is thought to be a safe treatment, with large local reactions (0.7%-4% of injections) and systemic allergic reactions (0.2% of injections) being the most common adverse sequelae.4 Data on the risk of infection from AIT are scant. There are no identifiable reports of infection resulting from AIT in the literature, and a single study evaluated this issue and demonstrated no risk of local infection after AIT injection.6
Proposed US Pharmacopeia (USP) guideline changes currently under consideration would result in a drastic restriction in the availability of AIT. For this reason, we sought to further explore the safety of current AIT practices. Our objective was to examine the historical risk of infection from AIT in a large patient population in an integrated healthcare system with electronic health record (EHR) data.
We analyzed data from the Partners Research Patient Database Repository (RPDR), a repository of all EHR data within a health system that includes Massachusetts General Hospital (MGH) and Brigham and Women's Hospital (BWH). We identified all AIT injections administered using Current Procedure Terminology (CPT) codes 95115 and 95117 over a 10-year period from November 1, 2005 through October 31, 2015. We included patients who received AIT at one of two main allergy practices at MGH or BWH. Patient demographic information, such as age, sex, and self-reported race/ethnicity, were also obtained from RPDR.
The primary outcome of this analysis was skin and soft tissue infection (SSTI) or systemic infection within 5 days after AIT injection. We identified infections using previously validated codes from the International Classification of Diseases, Ninth Edition (ICD-9) (Online Repository Table E1).7,8 We included codes billed from either an inpatient or outpatient location at any hospital or clinic affiliated with MGH or BWH. Each identified infection was followed by a comprehensive electronic chart review by at least one board-certified allergist/immunologist (D.S. B., A.B., A.A.L) to determine if the injection could be reasonably deemed to have caused the identified infectious process. Criteria for association of infection with AIT administration were presence of an infectious process in the skin or soft tissue contiguous to the site of AIT injection, or a bloodstream infection which did not have an obvious origin elsewhere. Ethical clearance for this study was provided by the Partners Human Research Committee.
Among 3,242 patients, we identified 136,322 episodes of AIT injection during the 10-year study period (Table I). The median number of injections per patient was 30 [interquartile range (IQR) 13-54]. The median patient age at first injection was 38 years (IQR 28-50). Most patients were female (60%) and white (75%).
Table I. Baseline characteristics of the cohort (136,322 injections among 3,242 patients).
| Characteristic | n (%) |
|---|---|
| Median age at first injection, years (IQR) | 38 (28-50) |
| Male | 1,285 (40) |
| Race/ethnicity | |
| White | 2442 (75) |
| Black | 169 (5) |
| Hispanic | 246 (8) |
| Other | 385 (12) |
| Median number of injections per patient (IQR) | 30 (13-54) |
Abbreviations: IQR, interquartile range
Within this data set, 66 patients had 86 episodes of billing for infections occurring within 5 days of receiving an AIT injection. Thirty-seven infections (43%) were classified as SSTIs, and 49 infections (57%) were classified as systemic infections. After review of the original medical record, all of the SSTIs were found to be at sites remote from the AIT administration and unrelated. Likewise, none of the systemic infections was attributed to AIT (details are provided in Table II).
Table II. Infections identified in the cohort within 5 days after AIT injection (86 infections among 66 patients).
| Type of Infection (ICD-9 code) | n (%)173 |
|---|---|
| Viral pneumonia, unspecified (480.9) | 1 (1) |
| Bacterial pneumonia, unspecified (482.9) | 6 (7) |
| Bronchopneumonia, organism unspecified (485) | 2 (2) |
| Pneumonia, organism unspecified (486) | 38 (44) |
| Influenza with pneumonia (487.0) | 1 (1) |
| Cellulitis and abscess of finger (681.00) | 1 (1) |
| Cellulitis and abscess of toe (681.1) | 1 (1) |
| Impetigo (684) | 6 (7) |
| Folliculitis (704.8) | 25 (29) |
| Hydradenitis (705.83) | 4 (5) |
| Bacteremia (790.7) | 1 (1) |
In this large retrospective cohort study of 136,322 AIT injections over a 10-year period at two large academic medical centers, we identify no findings of SSTI or systemic infection attributable to AIT injection. These data come from two of the largest Allergy/Immunology practices in Massachusetts, with MGH having 20 allergists on staff, and BWH having 29 allergists on staff.
Within each of these institutions, allergen extracts are mixed separately using aseptic technique based on current USP chapter <797> guidelines, but not consistent with proposed USP changes. Most commercial extracts are 50% glycerinated, and dilutions are made using sterile saline containing phenol. Studies of the sterility of allergen extracts have demonstrated that bacterial contamination is extremely rare (1 in 2085).9 There have been no case reports in the published literature of infection resulting from AIT injections. To our knowledge, only one prior study, Lay et al,6 examined infectious risk and AIT. This retrospective study examined 26,795 injections administered to 272 patients over a six-year period, and found that no patients experienced fever or SSTI at the site of injection. Additionally, they found that no patients required antibiotics or other medical treatment for infection. Our study examined a significantly larger population of patients across two large allergy practices.
Strengths of this study include the large sample size (>130,000 AIT injections in >3000 patients), the 10-year study period, and use of high-quality EHR data, which reduces the possibility of misclassification. Although we do not have a closed health system, our methods would have identified infections that may have been diagnosed in other practices within our healthcare system (e.g. urgent care clinics or primary care office).
A potential limitation is that minor localized infections may have gone unreported and would not be captured in this analysis; however any major complications would have been captured. Another limitation is that these data were collected retrospectively from the EHR using ICD-9 codes. While ICD-9 codes have been validated to identify SSTIs,8 identification of systemic infections using ICD-9 codes are less clear. However, we used a broad array of ICD-9 codes, and adapted codes used from a prior study (Stevenson et al7) to identify post-operative systemic infections. Ultimately, we reviewed all suspected cases with a formal chart review. A final limitation is that racial/ethnic minorities may have been underrepresented in our cohort.
In conclusion, in this large retrospective cohort study of risk of infection with AIT, we did not find any cases of SSTI or systemic bacterial infections from AIT injections. These findings suggest that the sterility and safety practices in place during the study period are adequate to prevent adverse infectious outcomes related to the preparation and administration of AIT.
Supplementary Material
Acknowledgments
Funding: This work was supported by the National Institutes of Health (grant T32 HL116275 to D.S.B.).
Abbreviations
- AIT
Allergen Immunotherapy
- BWH
Brigham and Women's Hospital
- EHR
Electronic Health Record
- ICD-9
International Classification of Diseases, Ninth Edition
- MGH
Massachusetts General Hospital
- RPDR
Partners Research Patient Database Repository
- SSTI
Skin and soft tissue infection
- US
United States
- USP
United States Pharmacopeia
Footnotes
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