Common variable immunodeficiency: experience in Puerto Rico.
La inmunodeficiencia comun variable es una de las inmunodeficiencias primarias mas comunes. El proposito de este estudio ha sido el analizar las caracteristicas clinicas y la respuesta a la terapia con inmunoglobulina intravenosa de un grupo de pacientes a los que se hizo el diagnostico de inmunodeficiencia comun variable en el Hospital Universitario del Centro Medico de Puerto Rico. Los datos obtenidos se compararon con varias series de pacientes informados en otros lugares. No tenemos conocimiento de que este tema haya sido presentado ni informado en la literatura medica de nuestro pais anteriormente. En el grupo de pacientes estudiados, se observaron diversas presentaciones clinicas entre las que se incluyen: desordenes alergicos, fenomenos de autoinmunidad y procesos infecciosos. En general, los pacientes estudiados mostraron caracteristicas clinicas similares a las observadas en otras series informadas en la literatura medica revisada, a excepcion de una mayor incidencia de alergias y la presencia de autoanticuerpos. Estos hallazgos ameritan ser corroborados mediante el examen futuro de una muestra de pacientes mas signiticativa.
Common variable immunodeficiency (CVI) is a primary immunodeficiency characterized by hypogammaglobulinemia and an increased susceptibility to infections. The degree and the type of deficiency of serum immunoglobulins, as well as, the clinical course vary from patient to patient, hence the term "variable". The aim of this report is to describe the clinical characteristics and the response to gammaglobulin therapy of a group of patients with CVI followed at the University Hospital of the Puerto Rico Medical Center. To our knowledge, no data on primary immunodeficiencies in Puerto Rico has been reported in the literature. The study group exhibits specific characteristics as compared to other reported series.
Key words: Common variable immunodeficiency; Hypogammaglobulinemia, Immunoglobulin therapy.
The primary immunodeficiency diseases are a diverse group of disorders, mostly of genetic origin, in which one of several components of the immune system ate altered (1). The net result is failure to mount an appropriate and effective immune response against pathogens, thus leading to infections. Approximately one hundred different types of these conditions have been described, and the overall prevalence of all types in Europe is estimated to be as high as 1:500, while the other 1:500 remain undiagnosed (2,3).
Common variable immunodeficiency (CVI) accounts for over 50% of the primary immunodeficiencies cases encountered clinically. The term variable denotes the fact that the immunoglobulin levels are not uniformly decreased and that the clinical manifestations are diverse. Its onset may occur at any age, but frequently it is diagnosed after puberty.
Besides infections (usually in the sinuses and the respiratory tract), CVI is associated with several autoimmune conditions, such as rheumatoid arthritis, idiopathic thrombocytopenia, hemolytic anemia, neutropenia and pernicious anemia. Gastrointestinal manifestations include a myriad of conditions, mostly malabsorption syndromes and infectious diarrhea. The mechanism(s) explaining this type of immunodeficiency remains unknown. Defects in transcriptional activation of switch regions, excessive CD8 T cells interferon gamma production, suboptimal T-B cell interactions through the CD40 ligand and transcription factor deficiencies have been suggested, among other etiologies (4).
The aim of this report is to describe the clinical characteristics and the response to therapy with intravenous gammaglobulin of a group of patients with CVI followed at the University Hospital at the Puerto Rico Medical Center.
The study group comprised patients referred by primary physicians and subspecialists for evaluation of suspected immunological compromise to the Immunology Clinic of the University Hospital. Of the total population of patients with CVI identified at the clinic, a group of twenty patients was entered in the study and followed over a three-year period. Those patients under 2 years of age and with an underlying cause for hypogammaglobulinemia were excluded.
All patients underwent a complete history and physical examination using a standard format at the initial visit. Baseline laboratory tests were performed through a uniform protocol, including complete blood count, liver and renal function tests. In addition, patients had an immunological evaluation consisting of: quantitative immunoglobulin levels (two separate samples), lymphocyte profile (T,
B, CD4, CD8 and natural killer cells), CH50, PCR-HIV and HCV, ANA and antibody profiles, as indicated.
Protocol. After the screening for CVI, informed consent was obtained for data gathering and prior to initiation of IV gammaglobulin therapy. Participating patients received IV gammaglobulin therapy every four weeks using 400mg/ kg, as the standard dose. Pre-infusion immunoglobulin levels were taken at 3, 6, 12, 18, 24, 30 and 36 months of treatment.
Gammagard (Baxter) Solvent/Detergent Treated Human gammaglobulin preparation was administered to all patients, except in one case in which the same preparation was used but was not solvent/detergent treated. All patients received pre-medication with steroids.
Statistical analysis. Continuous variables that were normally distributed were expressed as mean standard deviations ([+ or -] SD). The one sample T test was used to determine differences between the normal values of immunological parameters and the values of the patient group. The repeated measures analysis of variance was applied to express the differences in improvement in the trough IgG level within the measured intervals.
As shown in Figures 1 and 2, the majority of the patients were females (60%) and most of the patients were diagnosed between the age ranges of 15 to 25 years. A family history of immunodeficiencies was present in only five cases.
Table 1 describes the major presenting symptoms. As seen, infections were the most common manifestation of the disease. Allergies and bronchial asthma were common, followed by autoimmune conditions. Only one patient in the study group had IgA deficiency prior to the diagnosis of CVI.
As shown in Table 2, sinusitis was the most frequent infectious presentation. Within the study period of three years, various clinical conditions were identified in the patient group, including autoimmune entities and H. pylori infestation.
One interesting aspect of the population studied was the prevalence of antibodies directed against different cells and tissues, with the predominance of anti-platelet antibodies (Table 4). All of the three major immunoglobulins: IgG, IgA and IgM were decreased in these patients to a variable degree. As illustrated in Figure 3, the baseline IgG levels were significantly low, not exceeding a mean value of 64.7 mg./dL
[FIGURE 3 OMITTED]
[FIGURE 4 OMITTED]
Table 5 describes the results of the lymphocyte analysis in the study group. All patients had T, B, CD4, CD8 and NK cells within the normal ranges for the given parameter. The IgG pre-infusion levels at the intervals measured did not show statistically significant variations within the time frame of the study (baseline to three years), as presented in Figure 4. After one year of IV gammaglobulin therapy, there was a significant reduction in episodes of pneumonia, as compared to baseline. Patients tolerated the therapeutic regimen reasonably well, as there were no major complications reported. Table 6 describes the minor side effects seen, headache being the most frequent.
In the patient identified with chronic active hepatitis by HCV, this condition was related to the IV gammaglobulin recall that occurred in 1994, and was the only one who received the non-solvent/detergent treated product.
The group of patients presented in this study shows particular characteristics, as compared to other published series. A predominance of female to male patients was observed in contrast to the series reported by Cunningham-Rundles, which had an equal gender representation (5). As reported in other series, infection was the most frequent presentation in the study group. However, the predominance of respiratory conditions, allergies and bronchial asthma observed in the study group has not been consistently reported in other patient groups. This factor may be related to the overall high prevalence of asthma in Puerto Rico (6).
Another peculiar aspect of the group studied was the significantly high frequency of autoimmune manifestations (47%), as compared to a reported frequency of 26% in other reported series (7). It is interesting to note that autoimmune phenomena in patients with CVI have been associated to granuloma formation in other reported series, yet that relationship was not seen in the patients studied by us (8). Immune thrombocytopenic purpura was the most common autoimmune manifestation observed in the group of patients studied, whereas autoimmune hemolytic anemia has been the most frequently reported one by other authors. Gastrointestinal tract involvement was found in 51% of the studied patients, compared to 17% in other reported groups (9).
Although the just mentioned differences might indicate peculiarities of CVI in Puerto Rico, it must be remembered that our study group was small. No attempt was made in this study to identify subsets of CVI patients in terms of defective T cell function, as no proliferative in vitro studies, cytokine analysis or apoptosis indexes were assessed. However, none of our patients had lymphopenia.
It has been previously described in the medical literature that more than half of CVI patients present abnormalities of T cell activation and a deficient secretion of interferon gamma and interleukins 2, 4, 5 and 10 (10,11). All our patients had B cell positive agammaglobulinemia and absence of underlying conditions to explain the low antibody production, so the diagnosis of CVI was uniformly established.
Further study of T cell function is advisable in this group of patients to determine if it is related in anyway to the high frequency of autoimmune conditions observed. An extension of the study population is in order to assess if the tendencies observed in the group of patients studied holds. An ongoing surveillance study is in effect as lower serum IgG levels at the time of diagnosis have been associated to an earlier mortality.
(1.) Sneller, M., Strober, W. et al. New insights into common variable immunodeficiency. Ann Intern Med 1993;118:720-730.
(2.) The First Baxter Expertise Report on Primary Immune Deficiency Diseases in Europe. European Parliament Event, Strasbourg, October 23, 2002.
(3.) Bonilla, F A, Geha, R S. Primary immunodeficiency diseases. J Allergy Clin Immunol 2003;111:S-571.
(4.) Piqueras, B, Lavenu-Bombled, C et al. Common variable immunodeficiency patient classification based on impaired B cell memory differentiation correlates with clinical aspects. J Clin Immunol 2003;23:385-400.
(5.) Cunningham-Rundles, C, Bodian, C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol 1999;92: 34-48.
(6.) Perez Perdomo, R, Perez Cardona, C et al. Estado de Salud de la Poblacion Adulta de Puerto Rico Basado en Caracteristicas Seleccionadas del Sistema de Vigilancia de Factores de Riesgo Asociados a la Conducta: 1996-2000. Universidad de Puerto Rico, Recinto de Ciencias Medicas, Escuela Graduada de Salud Publica, 2004.
(7.) Michel, M, Chanet, V et al. Autoimmune thrombocytopenic purpura and common variable immunodeficiency: analysis of 21 cases and review of the literature. Medicine 2004;83:254-263.
(8.) Mechanic, L J Dikman, Set al. Granulomatous disease in common variable immunodeficiency. Ann Intern Med 1997; 127:613-617.
(9.) Kalha, 1, Sellin, J H. Common variable immunodeficiency and the gastrointestinal tract. Curr Gastroenterol Rep 2004;6:377-383.
(10.) Holm, A M, Aukrusto P et al. Impaired secretion of IL-10 by T cells from patients with common variable immunodeficiency-involvement of protein kinase A type 1 2003;170:5772-5773.
(11.) Di Renzo, M, Zhou, Z et al. Enbanced apoptosis of T cells in common variable immunodeficiency: role of defective CD28 co-stimulation. Clin Exp Immunol. 2000;120:503-510.
(12.). White, W B, Ballow, M. Modulation of suppressor cell activity by cimetidine in patients with common variable hypogammaglobulinemia. N Engl J Med 1985;312:198-202.
(13.) Cunningham-Rundles, C, Kazbay, K et al. Enhanced humoral immunity in common variable immunodeficiency after long-term treatment with polyethylene glycol-conjugated interleukin-2. N Engl J Med 1994;331:918-921.
MARIA L. SANTAELLA, MD, FACP, FAAAAI *; IVONNE FONT, MD *; ORVILLE DISDIER, MS ([dagger])
Form the * Department of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico and ([dagger]) the Diabetes Center at the Puerto Rico Medical Center.
Table 1. Presenting Symptoms of Patients with CVI Symptoms--Diagnoses # of cases Infections 20 Allergies 13 Bronchial asthma 10 Malabsorption syndromes 9 ITP 5 Aseptic arthritis 3 Hypothyroidism 2 Bronchiectasis 2 Rheumatoid arthritis 2 Crohn's disease 1 IgA deficiency 1 Table 2. Infections in CVI Patients Type of infection # of cases Sinusitis 20 Otitis 15 Bronchopneumonia 14 Infectious diarrhea 9 Table 3. Medical Conditions Identified in CVI Patients Throughout Study Period Condition # of cases ITP 2 Alopecia totalis 1 Autoimmune hemolytic anemia 1 Pernicious anemia 1 Neutropenia 1 H. pylori 4 Table 4. Autoantibody Profile in CVI Patients Antibod # cases ANA 5 Antiplatelet 7 Anti-parietal cell 1 Anti-thyroid 2 Anti-intrinsic factor 1 Table 5. Baseline Immunologic Parameters in Patients Studied Item Baseline value % Normal P value (mean [+ or -] SD) ranges (%) T cells 70.8 60-80 n. s. CD4 43.7 34-58 n. s. CD8 29.1 20-36 n. s. B lymphocyte 11.3 6-19 n. s. Natural killer 10.7 7-31 n. s Table 6. Side Effects Reported by Patients After IV Ig Therapy Finding # of Patients Headache 18 Body aches 15 Nausea--vomiting 7 Fever 4 Chronic active hepatitis (HCV) 1 Figure 1. Gender distribution of patients in the study Male 40% Female 60% Note: Table made from pie chart. Figure 2. Age distribution (in years) of patients in the study 5-9 5% 15-25 65% 10-14 20% 26-30 10% Note: Table made from pie chart.
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|Author:||Santaella, Maria L.; Font, Ivonne; Disdier, Orville|
|Publication:||Puerto Rico Health Sciences Journal|
|Date:||Mar 1, 2005|
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