DO NOT COPY. Nearly 300 primary immunodeficiency diseases

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1 Pulmonologist perspectives regarding diagnosis and management of primary immunodeficiency diseases Jordan S. Orange, M.D., Ph.D., 1 Javeed Akhter, M.D., 2 Filiz O. Seeborg, M.D., M.P.H., 1 Marcia Boyle, M.S., 3 Christopher Scalchunes, M.P.A., 3 and Vivian Hernandez-Trujillo, M.D. 4 ABSTRACT Background: The time from symptom onset to diagnosis for patients with primary immunodeficiency diseases (PIDD) is an average of 12 years, but prompt diagnosis and treatment can promote best outcomes. Objective: Because the manifestations of PIDD are often sinopulmonary in nature, patients with undiagnosed PIDD are frequently referred to pulmonologists. This study sought to identify opportunities among these specialists to improve diagnosis and clinical management of patients with PIDD. Methods: A survey was sent to American Medical Association and American Osteopathic Association members whose specialty was pulmonology. Responses were compared with those from a historical survey of 71 subspecialist immunologists (American Academy of Allergy, Asthma & Immunology members who devoted 10% of their practice to patients with PIDD). Results: The surveys were returned by 485 pulmonologists, 49% of whom had diagnosed at least one patient with PIDD. In comparison with subspecialist immunologists, fewer pulmonologists were aware of the professional PIDD diagnosis and management guidelines and fewer followed up patients with various PIDDs. Pulmonologists and subspecialist immunologists also differed in the practice of prescribing prophylactic antibiotics and immunoglobulin replacement and in avoiding live viral vaccines. Conclusion: Differences in the diagnosis and treatment of patients with PIDD between these two groups of specialists revealed areas in which PIDD-focused educational initiatives may be helpful for pulmonologists. (Allergy Asthma Proc 37:e162 e168, 2016; doi: /aap ) Nearly 300 primary immunodeficiency diseases (PIDD), a heterogenous group of disorders that arise from developmental or genetic defects in the immune system, have been identified to date. 1 Sinopulmonary manifestations and their complications are extremely common in patients with PIDD and may be the From the 1 Department of Pediatrics, Section of Immunology, Allergy and Rheumatology, Texas Children s Hospital and Baylor College of Medicine, Houston, Texas, 2 Pediatric Pulmonology, Advocate Children s Hospital, Oak Lawn, Illinois, 3 Immune Deficiency Foundation, Towson, Maryland, and 4 Division of Allergy & Immunology, Nicklaus Children s Hospital, Miami, Florida The Immune Deficiency Foundation sponsored the mail survey of pulmonologist members of the American Medical Association and American Osteopathic Association. Support for the survey on which this article is based was provided by Baxalta US Inc., now part of Shire, through an unrestricted educational grant provided to the Immune Deficiency Foundation Writing, editorial, and graphics support, provided by BlueMomentum, an Ashfield Company, part of UDG Healthcare PLC, was made possible through funding provided by Baxalta US Inc. Baxalta US Inc. was not involved in the writing of this manuscript J.S. Orange received grants from CSL Behring and Baxalta; received personal consulting fees from CSL Behring, Baxalta, ASD, Walgreens, ADMA, and Atlantic Research; serves on the medical advisory council to the Immune Deficiency Foundation. F.O. Seeborg received grants from Baxalta. V. Hernandez-Trujillo is a speaker for CSL Behring, Baxalta, and Meda; spokesperson for Sanofi and Merck; an advisory board member for Baxalta, Sanofi, and Merck; attendee at the Immunoglobulin Conference; medical advisory board member for the Immune Deficiency Foundation. The remaining authors have no conflicts of interest pertaining to this article Supplemental data available at Address correspondence to Jordan S. Orange, M.D., Section of Immunology, Allergy and Rheumatology, Texas Children s Hospital, 1102 Bates St, Ste 330, Houston, TX address: orange@bcm.edu Copyright 2016, OceanSide Publications, Inc., U.S.A. presenting symptom. These are, in large part, due to deficient immune responses, with resulting overt or subclinical infections. 2,3 As many as 60% of patients with antibody deficiency diseases experience at least some pulmonary complications, 4 which have the potential to be both severe and treatable. 5 Approximately 90% of patients with common variable immunodeficiency (CVID) experience vulnerability to bacterial pathogens within the upper and lower airways. 6 Pulmonary complications often require management by a pulmonary specialist, and specific treatments may be warranted to minimize and ameliorate long-term damage. 5 Owing to these pulmonary complications and opportunities for intervention, pulmonologists are often the first specialists who these patients visit, often before seeing an immunologist. Concurrently, when a patient is diagnosed with PIDD by another specialist, the pulmonologist is often the first specialist to whom they are referred. Early diagnosis and initiation of appropriate treatment strategies are important to minimize long-term damage and reduce the occurrence of symptoms, but many patients with PIDD go undiagnosed or experience a significant delay in time from symptom onset to diagnosis During that time, 44% of patients experience some form of permanent functional impairment; the most commonly reported decline was in lung function (54%) (Immune Deficiency Foundation, unpublished data, 2012). Through an ongoing collaborative effort, the American Academy of Allergy, Asthma & Immunology (AAAAI) e162 November December 2016, Vol. 37, No. 6

2 Primary Immunodeficiency Committee and the Immune Deficiency Foundation conducted a number of physician surveys to assess diagnosis and management of patients with PIDD Because of the prevalence of pulmonary manifestations and complications in patients with PIDD, as well as the therapeutic opportunity to prevent and improve lung disease in these patients, pulmonologists have an important role in the clinical management of pediatric and adult patients with PIDD. A needs assessment is an important first step toward creating materials that can best educate physicians. The primary goal of this survey was to appreciate the practice of pulmonologists and identify knowledge gaps and areas for focus regarding the diagnosis and treatment of patients with PIDD in pulmonary practice. METHODS Survey Subjects We conducted a survey of members of the American Medical Association and the American Osteopathic Association who identified their specialty as related to pulmonology, including critical and intensive care. A four-page questionnaire was mailed to eligible pulmonologists in direct patient care in the United States. Survey Design and Administration The survey questionnaire was developed by the AAAAI Primary Immunodeficiency Committee and the Immune Deficiency Foundation and was designed to evaluate PIDD practice. Here, the survey specifically assessed the recognition, diagnosis, and management of patients with PIDD by physicians who specialize in pulmonology (Supplemental Appendix 1). The questionnaire was self-administered and anonymous, and the collected information included a number of issues related to the diagnosis and management of patients with PIDD in the areas of patient care setting; general awareness of PIDD; number of PIDD diagnoses of patients who were followed up; and utilization of specific diagnostic and treatment strategies, including use of immunoglobulin replacement therapy, vaccination recommendations, and prophylactic antibiotics. The first mailing occurred in March 2011, and the second mailing was in May Data collection was completed in June A $25 incentive was offered to physicians who completed the survey. Data Analysis A descriptive analysis was carried out for all the responses. For some response sets, pulmonologist responses were compared with responses of 71 subspecialist immunologists in a historical survey. 12 Subspecialist immunologists were defined as AAAAI members who devoted 10% of their practice to PIDD management. Analysis was conducted by using SPSS Statistics 18 (SPSS Inc., Chicago, IL). The 2 and Fisher exact tests were used in the comparisons; 95% confidence intervals were calculated and reported for the responses. A p value of 0.05 was considered significant. RESULTS Survey Response Of 5000 surveys that were mailed to pulmonologists actively practicing in the United States, 501 were returned. Of those, only the 485 from pulmonologists actively seeing patients were evaluated. Although the response rate may be low, it was similar to response rates of the survey of PIDD management among subspecialist immunologist members of AAAAI, which provided the comparative population for the current analysis. 12 Some questions were left unanswered and had a smaller number of respondents. Demographics of Survey Respondents Thirty-nine percent of respondents reported a specialty of adult pulmonology (Table 1), and 16% (n 77) were primary treatment providers for at least one patient with PIDD. Significantly fewer pulmonologists than subspecialist immunologists (11% versus 79%, respectively; p 0.001) were aware of published professional guidelines regarding management of PIDD. 14,15 Fifty-two percent of the pulmonologists reported that they expected fewer than three new patients with PIDD per year. Clinical Experience with Patients with PIDD Nearly half (49%) of the pulmonologists diagnosed at least one patient with PIDD. When they suspected that a patient might have an underlying PIDD, 37% reported that they ordered diagnostic tests, 32% ordered diagnostic tests and referred the patient to an immunologist, and 20% referred the patient to an immunologist only. Of the pulmonologists who ordered diagnostic tests, the most commonly ordered tests were quantitative serum immunoglobulins (96%), immunoglobulin G (IgG) subclasses (83%), and a complete blood cell count with manual differential (66%) (Fig. 1). Comparative data were not available in the subspecialist immunology survey; however, PIDD practice guidelines recommend as first-line intervention a complete blood cell count with differential and an overall measurement of immune status and function by testing for serum immunoglobulin levels, leukocyte and lymphocyte subpopulations, and specific immune responses. 14 The most commonly followed-up PIDD diagnoses among pulmonologists were CVID, IgG subclass deficiency, and immunoglobulin A (IgA) deficiency, with at least one patient having been followed up by 57%, 51%, and 42% of pulmonologists, respectively. In comparison, a significantly greater proportion of subspecialist immunologists reported following up patients Allergy and Asthma Proceedings e163

3 Table 1 Demographics and professional characteristics of survey respondents Characteristic Pulmonologist Respondents, no. (%) (N 485) Subspecialist Immunologists, no. (%) (N 71) Specialty Pulmonology, general 76 (16) NA Pulmonology, pediatric 47 (10) NA Pulmonology, adult 260 (54) NA Critical care and/or intensive care 18 (4) NA Fellow 74 (15) NA Other 10 (2) NA Year of medical school graduation (12) 0 (0) (48) 18 (25) (320) 28 (39) (7) 19 (27) Missing or invalid 12 (3) 6 (9) How comprehensively was PIDD covered in medical school? Very well 13 (3) NA Adequately 112 (23) NA Only a little 329 (68) NA Not at all 30 (6) NA Missing or no response 1 ( 1) NA How comprehensively was PIDD covered in postmedical training? Very well 8 (2) NA Adequately 86 (18) NA Only a little 336 (69) NA Not at all 52 (11) NA Missing/no response 3 (1) NA No. patients seen in 1 week (39) 17 (24) (27) 16 (23) (13) 14 (20) (13) 9 (13) (7) 12 (17) No. patients expected to see in the next 12 months (29) NA (22) NA (13) NA (7) NA (12) NA (17) NA Missing or invalid 5 (1) NA NA Not applicable; PIDD primary immunodeficiency disease. with the same diagnoses (CVID, 99%; IgG subclass deficiency, 96%; and IgA deficiency, 89%; p 0.001) (Fig. 2). Diagnosis and Management A number of survey questions focused on the treatment and management of patients diagnosed with PIDD. One of the more common interventions recommended for consideration in diagnostic and treatment algorithms for PIDD is the use of prophylactic antibiotics. 14 Although prophylactic antibiotic use, either in a continuous, intermittent, or rotational regimen, is considered a common treatment approach for some subtypes of PIDD, 12,16 only 35% (n 111) of the 314 e164 November December 2016, Vol. 37, No. 6

4 Figure 1. The percentage of pulmonologists (N 333) who ordered specific tests for the diagnosis of PIDD. The majority of pulmonologists surveyed ordered quantitative serum immunoglobulins (95.8%) and IgG subclasses (82.9%) when they suspected PIDD; both tests are recommended in diagnostic algorithms in PIDD practice guidelines (from Ref. 14). Ab Antibody; CBC automated complete blood count with automated differential; CBC manual CBC with manual differential; CH50 hemolytic complement; CT computed tomography; DTH delayed-type hypersensitivity; Igs immunoglobulins; IgG immunoglobulin G; lymph lymphocyte; PIDD primary immunodeficiency disease. pulmonologists who treated or followed up at least one patient with PIDD, compared with 88% of the subspecialist immunologists, used antibiotic prophylaxis for the prevention of infections (p ). Of those pulmonologists who reported using antibiotic prophylaxis, fewer pulmonologists than subspecialist immunologists reported that prophylactic antibiotics were extremely useful in patients with chronic granulomatous disease, severe congenital neutropenia, and hyper-ige syndrome (Fig. 3), all of which were described as having substantive pulmonary manifestations. 16,17 Furthermore, 62% of pulmonologists rotated antibiotic use compared with 55% of subspecialist immunologists. A cornerstone treatment for patients with an antibody deficiency component of their disease, which is a major category of PIDD, is polyclonal immunoglobulin Figure 2. The percentage of pulmonologists who had ever followed up patients with the following PIDDs. *p AT Ataxia telangiectasia; CGD chronic granulomatous disease; CMC chronic mucocutaneous candidiasis; CVID common variable immunodeficiency; DiGeorge DiGeorge syndrome; Hyper-IgM hyperimmunoglobulin M syndrome; IgA, immunoglobulin A deficiency; IgG Sub immunoglobulin G subclass deficiency; PIDD primary immunodeficiency disease; SCID severe combined immunodeficiency; SpAb specific antibody defect; WAS Wiskott-Aldrich syndrome; XLA X-linked agammaglobulinemia. used as immunoglobulin replacement therapy. When pulmonologists were asked about the effectiveness of immunoglobulin replacement therapy, 25% (122/485) reported that they believed that immunoglobulin replacement therapy overall was very effective in the treatment of antibody deficiency disorders. Although intravenous immunoglobulin replacement therapy has been available for decades, U.S. Food and Drug Administration approved subcutaneous immunoglobulin (SCIG) preparations have more recently been licensed for use in PIDD. 18 Of the 48 pulmonologists who treated or followed up at least one patient with PIDD and managed his or her immunoglobulin treatment, only a minority reported being very familiar (10% [n 5]) or somewhat familiar (56% [n 27]) with the use of SCIG, whereas 31% (n 15) reported they were not too familiar with SCIG. Analogous data were not Allergy and Asthma Proceedings e165

5 collected in the survey of subspecialist immunologists; however, in our opinion, likely, the majority (but not all) of subspecialist immunologists are familiar with SCIG. Overall, the most frequent use of immunoglobulin replacement therapy among respondents was in patients diagnosed with X-linked agammaglobulinemia (XLA) (90%) compared with 100% of subspecialist immunologists (p 0.001) (Fig. 3). Significantly fewer pulmonologists than subspecialist immunologists recommended immunoglobulin therapy for patients diagnosed with CVID (70% versus 98%; p ), which was surprising, given that CVID is the most prevalent serious PIDD and that these patients represent the largest application of immunoglobulin therapy within PIDD. 6,14 Statistically significant differences in the use of immunoglobulin were also noted among numerous other diagnoses (Fig. 4). The use of immunoglobulin Figure 3. The percentage of pulmonologists and subspecialist immunologists who believed that prophylactic antibiotics are extremely useful in the following PIDDs. *p AT Ataxia telangiectasia; CGD chronic granulomatous disease; CMC chronic mucocutaneous candidiasis; CVID common variable immunodeficiency; CytoDef type-1 cytokine axis defect; DiGeorge DiGeorge syndrome; Hyper IgE hyperimmunoglobulin E syndrome; Hyper IgM hyperimmunoglobulin M syndrome; IgA immunoglobulin A deficiency; IgE immunoglobulin E; IgG Sub immunoglobulin G subclass deficiency; PIDD primary immunodeficiency disease; SCID severe combined immunodeficiency; SCN severe congenital neutropenia; SpAb specific antibody defect; WAS Wiskott-Aldrich syndrome; XLA X-linked agammaglobulinemia. was also notable because the most common starting dose recommended was 400 mg/kg, similar to recommendations of specialist immunologists. 12 However, a higher percentage of pulmonologists were likely to use lower rather than higher doses, unlike the specialist immunologists. The use of live viral vaccines is discouraged in patients with certain PIDDs. 19 Thus, a key issue in PIDD management is the determination of which patients with PIDD would benefit from receiving live vaccines versus those who are at greater risk for harm. At least half of all surveyed pulmonologists recommended avoiding live viral vaccination in patients with severe combined immunodeficiency (SCID) (62%), XLA (59%), and CVID (51%) (Fig. 5) compared with 85%, 55%, and 45% of subspecialist immunologists, respectively. Significant differences in live viral vac- Figure 4. The percentage of pulmonologists who recommended IVIG therapy for patients with a specific PIDD diagnosis (in all or most patients within the listed diagnosis). *p 0.001; **p 0.015; ***p CGD Chronic granulomatous disease; CVID common variable immunodeficiency; DiGeorge DiGeorge syndrome; Hyper-IgM hyperimmunoglobulin M syndrome; IgA immunoglobulin A deficiency; IgG Sub immunoglobulin G subclass; IVIG intravenously administered immunoglobulin; PIDD primary immunodeficiency disease; SCID severe combined immunodeficiency; XLA X-linked agammaglobulinemia. e166 November December 2016, Vol. 37, No. 6

6 Figure 5. The percentage of pulmonologists who avoided live vaccines for patients with a specific PIDD. *p 0.041; **p 0.012; ***p CGD Chronic granulomatous disease; CVID common variable immunodeficiency; DiGeorge DiGeorge syndrome; Hyper-IgM hyperimmunoglobulin M syndrome; IgA immunoglobulin A deficiency; IgG Sub immunoglobulin G subclass deficiency; PIDD primary immunodeficiency disease; SCID severe combined immunodeficiency; SpAb specific antibody defect; WAS Wiskott-Aldrich syndrome; XLA X-linked agammaglobulinemia. cine avoidance were observed between the pulmonologists and subspecialist immunologists for patients diagnosed with the DiGeorge syndrome, hyper-igm syndrome, SCID, and IgG subclass deficiency (p 0.001), IgA deficiency (p 0.012), and specific antibody deficiency (p 0.041) (Fig. 5). DISCUSSION The current study showed that the pulmonologists in our survey frequently encountered patients with PIDD, noting significant differences between types of diagnostic tests ordered and current PIDD guidelines, and a more frequent recommendation for lower immunoglobulin treatment compared with immunologists. The latter was especially relevant in light of a metaanalysis of intravenous immunoglobulin studies that demonstrated a dose relationship with the incidence of pneumonia. 20 Because the pulmonologists are likely to experience pneumonia or some other lung-related complication in patients with PIDD as a reason for referral, optimal dosing with therapeutic immunoglobulin is likely to be more relevant to patients with PIDD of pulmonologists. A key goal is to diagnose PIDD before the onset of clinical symptoms to help prevent complications of untreated disease because an early diagnosis is associated with better prognosis and quality of life. 3 The recommendation by the Secretary s Advisory Committee for Heritable Disorders in Newborns and Children to add SCID to the uniform screening panel for newborns, for example, exemplifies this sentiment. 21 Early detection and proper management of PIDDs with immunoglobulin replacement and antibiotic treatment, however, may lower the frequency and severity of infections that impact quality of life and prognosis. Therefore, to decrease the delay in the diagnosis of PIDD, survey studies have been conducted to assess awareness of PIDD, 22 and recommendations have been tailored to physicians of various specialties likely to encounter patients with PIDD-related symptoms Some specific recommendations target pulmonologists because of the prevalence of respiratory and pulmonary symptoms among patients with PIDD 2,23,26 Notably, one of the 10 warning signs of PIDD issued by the Jeffrey Model Foundation and the American Red Cross to raise awareness is two or more episodes of pneumonia in a year. 2 Immunoglobulin treatment has the potential to improve lung function in patients with PIDD who also have chronic lung disease. 3,5 Pulmonologists surveyed here reported that they used immunoglobulin replacement for the treatment of all or most of their patients with XLA and SCID. It, therefore, was surprising that fewer than one-third used this treatment in patients with CVID because it is the most prevalent PIDD that can routinely benefit from immunoglobulin treatment 4,6,14 Pulmonologists who suspect a PIDD may then refer their patient to an immunologist for further assessment and definitive diagnosis, including the utility of immunoglobulin replacement and a subsequent treatment plan. Our study included some relevant limitations, including that the cross-sectional nature of this survey may not have reflected causal relationships and that surveys are always subject to bias. However, minimal amounts of response bias have been shown in physician surveys 27,28 and maintaining anonymity in the current survey attempted to minimize bias. CONCLUSION Given the high frequency of respiratory and pulmonary complications associated with PIDD and, there- Allergy and Asthma Proceedings e167

7 fore, the likelihood of referral to pulmonologists, increased educational and training initiatives aimed at improving recognition and awareness of PIDD in this subset of physicians has the potential to be high yield. REFERENCES 1. Picard C, Al-Herz W, Bousfiha A, et al. Primary immunodeficiency diseases: An update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency J Clin Immunol 35: , Roxo Júnior P. Primary immunodeficiency diseases: Relevant aspects for pulmonologists. J Bras Pneumol 35: , Jesenak M, Banovcin P, Jesenakova B, and Babusikova E. Pulmonary manifestations of primary immunodeficiency disorders in children. Front Pediatr 2:77, Bierry G, Boileau J, Barnig C, et al. Thoracic manifestations of primary humoral immunodeficiency: A comprehensive review. Radiographics 29: , de Gracia J, Vendrell M, Alvarez A, et al. 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