What email address or phone number would you like to use to sign in to Docs.com?
If you already have an account that you use with Office or other Microsoft services, enter it here.
Or sign in with:
Signing in allows you to download and like content, and it provides the authors analytical data about your interactions with their content.
Embed code for: Diagnostic Delay_Primary Inmunodeficiencies
Select a size
123 Journal of Clinical Immunology ISSN 0271-9142 J Clin Immunol DOI 10.1007/s10875-017-0398-2 Diagnostic Delay of Primary Immunodeficiencies at a Tertiary Care Hospital in Peru- Brief Report Liz E. Veramendi-Espinoza, Jessica H. Zafra-Tanaka, Gabriela A. Pérez- Casquino & Wilmer O. Córdova- Calderón 123 Your article is protected by copyright and all rights are held exclusively by Springer Science +Business Media New York. This e-offprint is for personal use only and shall not be self- archived in electronic repositories. If you wish to self-archive your article, please use the accepted manuscript version for posting on your own website. You may further deposit the accepted manuscript version in any repository, provided it is only made publicly available 12 months after official publication or later and provided acknowledgement is given to the original source of publication and a link is inserted to the published article on Springer's website. The link must be accompanied by the following text: "The final publication is available at link.springer.com”. ORIGINAL ARTICLE Diagnostic Delay of Primary Immunodeficiencies at a Tertiary Care Hospital in Peru- Brief Report Liz E. Veramendi-Espinoza1 & Jessica H. Zafra-Tanaka1 & Gabriela A. Pérez-Casquino1 & Wilmer O. Córdova-Calderón1,2 Received: 4 February 2017 /Accepted: 24 April 2017 # Springer Science+Business Media New York 2017 Abstract Objective The aim of the study was to assess the diagnostic delay in pediatric patients with primary immunodeficiencies (PID) at a tertiary care hospital in Peru. Methods Adescriptive study wascarried outinwhich patients from a third-level referral center in Peru were included. Those without a specific diagnosis of PID were excluded. Data was collected by reviewing the medical records and interviewing patients’ family members. Results A total of 45 patients with a mean of 7.4 years (SD = 4.3) were studied. The most frequent diagnosis was predominant antibody defects (35.5%), and the diagnostic de- lay had a median of 12.17 months (IQR 5.1–30.3). Conclusions The most frequently diagnosed group of PID was predominant antibody deficiency. The overall median di- agnostic delays for PID and predominant antibody deficiency were 12 and 14 months, respectively. Even though early de- tection of PIDs is crucial for effective treatment, current avail- able laboratory tests required for PID diagnosis are both com- plex and expensive. Early detection and management of these pathologies cannot be achieved without training non- specialist health professionals in the diagnosis of PID, as well as integrating multidisciplinary and multi-center cooperation at both national and international levels. Keywords Immunologic deficiencysyndromes .immune systemdiseases . pediatrics .delayeddiagnosis(MeSH) Introduction Primary immunodeficiencies (PID) are diseases caused by genetic defects of the immune system at a cellular or molecu- lar level. These defects generate complications such as severe and recurrent infections that can lead to organ failure and death, as well as autoimmunity, atopy, and malignancy [1, 2]. PIDs represent a public health problem, not only because they are not asrareascommonly believed, since cumulatively, they have a global incidence of 10.3 per 100,000 person-years [3–6], but also because of the high cost they represent for the health system. In Peru, it is estimated that there are 2800 people living with PID , of which only 108 patients are registered at the Latin American Society for Immunodeficiencies (LASID) ; thus, only 3.8% of people with PID in Peru have been diag- nosed and reported. This problem is shared by several coun- tries in Latin America, where the only 0.97% of the estimated number of people living with PID are officially registered . In an effort to register these diseases, LASID published the first registry of PID patients in 1998 . Currently, there are 6664patientsregistered. Argentina reports the highest number of patients, with 2368 individuals registered (35.53% of all registered in Latin America), while Peru, despite being the seventh country that reports PIDs, has 105 (1.58% of total registered) registered individuals. These patients were identi- fied at one of the three referral centers in the country . Electronic supplementary material The online version of this article (doi:10.1007/s10875-017-0398-2) contains supplementary material, which is available to authorized users. * Liz E. Veramendi-Espinoza email@example.com 1 Universidad Nacional Mayor de San Marcos, Facultad de Medicina Humana San Fernando, Lima, Peru 2 Centro de Referencia Nacional de Asma Alergia Inmunología (CERNAAI), Instituto Nacional de Salud del Niño, Breña, Peru J Clin Immunol DOI 10.1007/s10875-017-0398-2 Author's personal copy Delay in diagnosis of PID from the onset of symptoms contributes to delayed administration of specific treatments, increased morbidity (recurrent infections such as pneumonia or sinusitis), poor quality of life, and mortality [1, 3, 9]. Delay in diagnosis varies depending on the clinical setting (from general hospitals with no specialists, to tertiary care hospitals specialized in the management of these diseases), fluctuating between 1 and 4 years for PID [1, 10, 11]. In Peru, the average time in diagnostic delay is 6.7 years (ranging between 1 and 36 years) . Increasing our current knowledge of PIDs and their diag- nostic delay is important for evaluating the true prevalence of PIDs, as well as guiding strategies aimed at improving their management. However, to our knowledge, despite the conse- quences and the high cost of delayed diagnosis, there are no recent studies on this problem in Peru. Thus, the objective of this study was to determine the diagnostic delay of patients with PID in a third level pediatric institution in Peru. Methods A descriptive study was carried out at the National Referral Center for Asthma, Allergy, Immunology (CERNAAI for its acronym in Spanish), which operates within the National Child Institute ofHealth (INSN). INSNisa tertiaryhealthcare facility that serves pediatric patients with public insurance who present with diseases of complex management through- out the country. Patients registered in this center between 2013 and 2015 were included in the present study. Patients referred to the CERNAAI without a definite PID diagnosis at the time of the study were excluded. Patients in CERNAAI were referred by consultations within the INSN or by referrals from other healthcare facilities nationwide. Data was collected by reviewing clinical records and interviewing patients’ family members. Patients were coded numerically to ensure confidentiality. The data collected were age (in months), gender, specific diagnosis, major diagnostic group, date of onset of symptoms, and date of primary immu- nodeficiency diagnosis. The different diseases were classified by the nine major groups of PID according to the International Union of Immunological Societies (IUIS) expert committee:  immu- nodeficiencies affecting cellular and humoral immunity , combined immunodeficiencies with associated or syndromic features , predominantly antibody deficiencies , diseases of immune dysregulation , congenital defects of phagocyte number, function, or both , defects in intrinsic and innate immunity , autoinflammatory disorders , complement deficiencies, and  phenocopies of PID . Diagnostic delay was defined as the time between the onset of symptoms and the actual diagnosis of the disease. The time of onset of symptoms was recorded in the medical history by an immunologist. The date of diagnosis of the disease was defined as the date of diagnosis of any of the nine major groups of PID. Data Analysis For the analysis of data quality, the existence of inconsistent data was verified. In the descriptive analysis, absolute and rel- ative frequencies were used for categorical variables. For the continuous variables, mean and standard deviation were calcu- lated if they followed a normal distribution; in the case of non- normal distributions, the median and interquartile range were used. Stata v12 statistical software was used for data analysis. Ethics Informedconsent wasobtainedfromparents ofall participants included in the study. Patients were coded numerically to en- sure confidentiality. Results There were 58 children being studied or treated at CERNAAI, of which 13 were excluded because they did not have a spe- cific diagnosis of PID. Thus, 45 children with PID (77.6% of the total records) were included in our analyses. The mean age was 7.4 ± 4.3 years and 58% were male. The most frequent major group of PID was predominantly antibody deficiencies (35.6%), followed by congenital defects ofphagocyte (22.2%),defectsinintrinsic and innateimmunity (17.8%), combined immunodeficiencies with associated or syndromic features (15.6%), diseases of immune dysregula- tion (6.7%), and immunodeficiencies affecting cellular and humoral immunity (2.2%). (See Table 1) The onset of symptoms presented a median of 10.4 months (IQR 2.00–25.6) and the diagnostic delay had a median of 12.2 months (IQR 5.1–30.3). The PID group with the shortest time to onset of symptoms (Median 2 months; IQR 0.03–2.9) and lowest diagnostic delay (Median 10.3 months; IQR 4.0– 17.9) was congenital defects of phagocyte, followed by de- fects in intrinsic and innate immunity, onset of symptoms of 6.8 months (IQR 2.1–17.4) and a diagnostic delay of 9.9 months (IQR 6.7–45.9). (See Table 2) Discussion Predominantly antibody deficiencies represented 35.6% of the PID. This percentage is lower than that found by the European Society of Immunology (ESID) and LASID, where predomi- nantly antibody deficiencies represented 55 and 52%, J Clin Immunol Author's personal copy respectively. In Latin America, the frequency of this group of diseases varies widely. For example, predominantly antibody deficiencies represented 29.8% of cases of PID in Mexico , 56.5% in Colombia , 61% in Brazil  and 42.7% inChile.Thismay bebecause indevelopingcoun- tries,there are nohomogeneous guidelinesfor thediagnosis of patients with PID. Among the patients studied, none presented autoinflammatory disorders or complement deficiencies. The low prevalence of these conditions worldwide could explain these results, as its frequency in the ESID registry was 2% . They may have not been reported in our registry because high diagnostic suspicion and affordable laboratory tests are required. Table 1 Distribution frequency of primary immunodeficiency diseases according to the IUIS classification in the National Reference Center for Asthma Allergy Immunology National Child Institute of Health (INSN) PID specific diagnosis n = 45 Percent Immunodeficiencies affecting cellular and humoral immunity 1 2.2 Severe combined immunodeficiency 1 2.2 Combined immunodeficiencies with associated or syndromic features 7 15.6 Wiskott-Aldrich syndrome 3 6.7 Hyper IgE Syndrome 2 4.4 Ataxia telangiectasia 2 4.4 Predominantly antibody deficiencies 16 35.6 Primary agammaglobulinemia 12 26.7 Other predominantly antibody deficiencies 1 2.2 Transient hypogammaglobulinemia of infancy 1 2.2 Hyper IgM 1 2.2 Common variable immunodeficiency disorders 1 2.2 Diseases of immune dysregulation 3 6.7 Familial hemophagocytic lymphohistiocytosis 1 2.2 Autoimmune lymphoproliferative syndrome 1 2.2 Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) 1 2.2 Congenital defects of phagocyte number, function, or both 10 22.2 Congenital neutropenias 5 11.1 Leukocyte adhesion deficiency 1 2.2 X-linked chronic granulomatous disease 4 8.9 Defects in intrinsic and innate immunity 8 17.8 Mucocutaneous candidiasis 4 8.9 Mendelian susceptibility to mycobacteria 4 8.9 Autoinflammatory disorders 0 0 Complement deficiencies 0 0 Phenocopies of PID 0 0 Table 2 Onsetofsymptomsanddiagnostic delay ofprimary immunodeficiency diseases accordingtothe IUIS classificationinthe National Reference Center for Asthma Allergy Immunology National Child Institute of Health (INSN) PID specific diagnosis Onset of symptoms (months) n = 36 Diagnostic delay (months) n = 29 Immunodeficiencies affecting cellular and humoral immunity 23.4 (23.4–23.4) 18.1 (18.1–18.1) Combined immunodeficiencies with associated or syndromic features 6.7 (1.5–23.9) 20.2 (8.5–39.4) Predominantly antibody deficiencies 18.7 (11.1–61.6) 13.8 (3.9–29.0) Diseases of immune dysregulation 61.3 (1.0–121.5) 51.8 (0.6–103.1) Congenital defects of phagocyte number, function, or both 1.7 (0.0–2.9) 10.3 (4.0–17.9) Defects in intrinsic and innate immunity 6.8 (2.1–17.4) 9.9 (6.7–45.9) Total 10.4 (2.0–25.6) 12.2 (5.1–30.3) Median and interquartile range of time are shown from the onset of symptoms and the diagnostic delay in months J Clin Immunol Author's personal copy The diagnostic delay for PID varies according to the clinical setting. For example, a cohort followed for 31 years (1976 to 2006) in the USA had a median overall diagnostic delay of 4.7 years; however, this diagnostic delay was low- er in the last 10 years at 2.7 years . According to the report by the German National Registry for PID, the diag- nostic delay varied according to the type of PID, with an average of 4 years for the variable common immunodefi- ciency (CVID), 1 to 2 years for chronic granulomatous disease (CGD), and 1 year for agammaglobulinemia . The United Kingdom registry found a diagnostic delay of 5 years for CVID and 1 year for both CGD and agamma- globulinemia between 2008 and 2012 . In a study in Saudi Arabia, an overall diagnostic delay of 21.6 months (between less than 1 month and 38 years) was found, and diagnostic delay was 13.5 months for combined immuno- deficiency and 46 months for predominantly antibody de- ficiencies . The difference between the different coun- tries may be due to the organization of their health systems for the management of PID (number of establishments, human and financial resources) along with the health care provider’s experience in diagnosing PID. In recent years, countries with multiple centers and a large registry system show a lower diagnostic delay. In a Peruvian study of 15 patients with PID in a hospital funded by the social security system (1997 to 2008), the diag- nostic delay was 6 years and 7 months (range 1 to 36 years) .Inour report, the diagnosticdelay had a medianof1 year. This could be explained by the recent implementation of re- ferral centers specialized in PID. However, this is not enough to diagnose and treat all patients with PID. Another possible explanation for the shorter diagnostic delay time than that found in the literature is the accessi- bility of diagnostic tools for the most frequent diagnosis: agammaglobulinemia. This is supported by the fact that autoinflammatory disorders, which are pathologies harder to diagnose because of the resources needed, were not di- agnosed . For example, a tertiary care hospital in Mexico, which served patients from all over the country, had a diagnostic delay of 22 months. In this study, the group of PID that presented the greatest diagnostic delay was complement defects, which was not diagnosed among our patients . The less common PIDs, which are more difficult to detect, are not being diagnosed, which may help explain the level of underreporting and biased estimates of the overall diagnostic delay in Peru. The lack of appropriate equipment in laboratories, the high costs involved, and the lack of specific laboratory tests could influence the diagnostic delay. A study con- ducted by physicians in Brazil revealed that only 34.1% of the doctors tested patients with recurrent infections for PID. The main barriers cited were lack of access to an appropriately equipped laboratory and the cost of testing . A study conducted in Canada found that pediatricians recommended specialized tests such as IgG subtypes or neutrophil oxidative capacity as screening tests in 77 and 66% of the cases, respectively . Therefore, we recom- mend the implementation of immunological tests in the laboratories and the development of guidelines for ade- quate and rapid diagnosis when PID is suspected. In addi- tion, information should be provided to general practi- tioners and specialists about initial screening tests such as complete blood count, lymphocyte subpopulations, and se- rum immunoglobulins, which are available in all health care settings [9, 20, 21]. Limitations The main limitation of the study was access to only one of the three-referral centers that manage PIDs in Peru. Moreover, this facility only provides care pediatric populations. It is im- portant to consider that around 69.4% of people living with PID are over 15 years of age . Since the results found in this study cannot be applied to the entire national PID population, studies in adults are recommended. Physicians treating PID patients for upper respiratory tract infections do not suspect of immunodeficiencies as these in- fections have high incidence in Peru during the childhood. Parents believe that these recurrent infections are common during childhood. Therefore, it is difficult to assess the exact date of the onset of symptoms and diagnosis for physicians as they collect information from the parents. For this study, we could not calculate the onset of symptoms or delay of diagno- sis for all participants included in the analysis for the reasons mentioned above. Conclusions The most frequent major group of PID was predominantly antibody deficiencies (35.6%) followed by congenital defects of phagocytes (22.2%). The median of the overall diagnostic delay was 12.2 months. For predominantly antibody deficien- cies, it was 14 months. PIDs are frequent but poorly diagnosed diseases. Early detection and treatment of PIDs cannot be achieved in isola- tion—training of non-specialist health personnel is required, as well as interdisciplinary and multicenter cooperation at the national and international levels. These measures would re- duce diagnostic delay and provide timely treatment to ensure better quality of life for patients. Compliance with Ethical Standards Conflicts of Interest The authors declare that they have no conflict of interest. J Clin Immunol Author's personal copy References 1. Condino-Neto A, Sorensen RU, Gómez-Raccio AC, King A, Espinosa-Rosales FJ. Current state and future perspectives of the Latin American Society for Immunodeficiencies (LASID).Allergol Immunopathol. 2015;43(5):493–7. 2. Raje N, Dinakar C. Overview of immunodeficiency disorders. Immunol Allergy Clin N Am. 2015;35(4):599–623. 3. Joshi AY, Iyer VN, Hagan JB, St JL. Sauver, Boyce TG. Incidence and temporal trends of primary immunodeficiency: a population- based cohort study. Mayo Clin Proc. 2009;84(1):16–22. 4. Bousfiha AA, Jeddane L, Ailal F, Benhsaien I, Mahlaoui N, Casanova J-L, et al. Primary immunodeficiency diseases world- wide: more common than generally thought. J Clin Immunol. 2013;33:1–7. 5. Modell V, Knaus M, Modell F. An analysis and decision tool to measure cost benefit of newborn screening for severe combined immunodeficiency (SCID) and related T-cell lymphopenia. Immunol Res. 2014;60(1):145–52. 6. Reust CE. Evaluation of primaryimmunodeficiency disease in chil- dren. Am Fam Physician. 2013;87(11):773–8. 7. Errante PR, Franco JL, Espinosa-Rosales FJ,SorensenR, Condino- Neto A. Advances in primary immunodeficiency diseases in Latin America: epidemiology, research, and perspectives. Ann N YAcad Sci. 2012;1250:62–72. 8. Sociedad Latinoamericana de Immundeficiencias. Estadísticas - RegistrodeIDP2016[updatedSetiembredel2016.Availablefrom: https://registrolasid.org/docs/Estatisticas_LASID-2016_Set.pdf. 9. Ed V. European Society for Immunodeficiencies (ESID) members. Patient-centred screening for primary immunodeficiency, a multi- stage diagnostic protocol designed for non-immunologists: 2011 update. Clin Exp Immunol. 2011;167:108–19. 10. Gathmann B, Goldacker S, Klima M, Belohradsky BH, Notheis G, Ehl S, et al. The German national registry for primary immunode- ficiencies (PID). Clin Exp Immunol. 2013;173(2):372–80. 11. Edgar JD, Buckland M, Guzman D, Conlon NP, Knerr V, Bangs C, et al. The United Kingdom primary immune deficiency (UKPID) registry: report of the first 4 years’ activity 2008–2012. Clin Exp Immunol. 2014;175(1):68–78. 12. Córdova-Calderón WO. Características clínicas y epidemiológicas de las inmunodeficiencias primarias en el Hospital Guillermo Almenara Irigoyen entre los años 2000 y 2010. [Tesis de postgrado]. Lima: Universidad Nacional Mayor de San Marcos (UNMSM); 2012. 13. Picard C, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Conley ME, et al. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for primary immunodeficiency 2015. J Clin Immunol. 2015;35(8):696–726. 14. Lugo-Reyes SO, Ramirez-Vazquez G, Hernández AC, Medina- Torres EA, Ramirez-Lopez AB, España-Cabrera C, et al. Clinical features, non-infectious manifestations and survival analysis of 161 children with primary immunodeficiency in Mexico: a single center experience over two decades. J Clin Immunol. 2014;36(1):56–65. 15. Ramírez-Roa JL, Vargas-Rumilla MI. Caracterización de inmunodeficiencias primarias en pacientes pediátricos que acudieron al Hospital Universitario Clínica San Rafael entre 2010 y 2014 [Tesis de postgrado]. Bogotá: Universidad Militar Nueva Granada; 2016. 16. Carneiro-Sampaio M, Morales-Vasconcelos D, Kokron CM, Jacob CMA, Toledo-Barros M, Dorna MB, et al. Primary immunodefi- ciencydiseasesindifferentage groups: a reporton1,008 cases from a single Brazilian reference center. J Clin Immunol. 2013;33(4): 716–24. 17. Poli C, Hoyos-Bachiloglu R, Borzutzky A. Primary immunodefi- ciencies in Chile evaluated through ICD-10 coded hospital admis- sions. Allergol Immunopathol (Madr). 2017;45(1):33–39 18. Al-Saud B, Al-Mousa H, Gazlan SA, Al-Ghonaium A, Arnaout R, Al-Seraihy A, et al. Primary immunodeficiency diseases in Saudi Arabia: a tertiary care hospital experience over a period of three years (2010–2013). J Clin Immunol. 2015;35(7):651–60. 19. de Oliveira DE, Aranda CS, Nobre FA, Fahl K, JTL M, Felix E, et al. Medical awareness concerning primary immunodeficiency diseases in the city of São Paulo, Brazil. Einstein (São Paulo, Brazil). 2013;11(4):479–85. 20. Al-Hammadi S, Al-Reyami E, Al-Remeithi S, Al-Zaabi K, Al-Zir R, Al-Sagban H, et al. Attentiveness of pediatricians to primary immunodeficiency disorders. BMC Res Notes. 2012;5:393. doi: 10.1186/1756-0500-5-393. 21. Eley B, Esser M. Investigation and management of primary immu- nodeficiency in South African children. S Afr Med J 2014;104(11): 793–96. J Clin Immunol Author's personal copy of primary immunodeficiency: a population- based cohort study. Mayo Clin Proc. 2009;84(1):16–22. 4. Bousfiha AA, Jeddane L, Ailal F, Benhsaien I, Mahlaoui N, Casanova J-L, et al. Primary immunodeficiency diseases world- wide: more common than generally thought. J Clin Immunol. 2013;33:1–7. 5. Modell V, Knaus M, Modell F. An analysis and decision tool to measure cost benefit of newborn screening for severe combined immunodeficiency (SCID) and related T-cell lymphopenia. Immunol Res. 2014;60(1):145–52. 6. Reust CE. Evaluation of primaryimmunodeficiency disease in chil- dren. Am Fam Physician. 2013;87(11):773–8. 7. Errante PR, Franco JL, Espinosa-Rosales FJ,SorensenR, Condino- Neto A. Advances in primary immunodeficiency diseases in Latin America: epidemiology, research, and perspectives. Ann N YAcad Sci. 2012;1250:62–72. 8. Sociedad Latinoamericana de Immundeficiencias. Estadísticas - RegistrodeIDP2016[updatedSetiembredel2016.Availablefrom: https://registrolasid.org/docs/Estatisticas_LASID-2016_Set.pdf. 9. Ed V. European Society for Immunodeficiencies (ESID) members. Patient-centred screening for primary immunodeficiency, a multi- stage diagnostic protocol designed for non-immunologists: 2011 update. Clin Exp Immunol. 2011;167:108–19. 10. Gathmann B, Goldacker S, Klima M, Belohradsky BH, Notheis G, Ehl S, et al. The German national registry for primary immunode- ficiencies (PID). Clin Exp Immunol. 2013;173(2):372–80. 11. Edgar JD, Buckland M, Guzman D, Conlon NP, Knerr V, Bangs C, et al. The United Kingdom primary immune deficiency (UKPID) registry: report of the first 4 years’ activity 2008–2012. Clin Exp Immunol. 2014;175(1):68–78. 12. Córdova-Calderón