This study presents the first national registry of primary immunodeficiencies in adult patients in a Central American country. The PID records in Latin America are not systematic, therefore their frequencies are estimated to be higher than those reported . In adults, PID should be considered in presence of recurrent or persistent infections of unusual severity or rapid progression, affecting multiple sites or being caused by opportunistic or unusual pathogens, leukopenia, history of parental consanguinity and positive family anamnesis . However, other findings that should guide the diagnosis are more than one pneumonic episode or one or more serious infections in the past, frequent use of antibiotics and suboptimal response to treatment, non-surgical absence of adenoids, recurrent skin, soft tissue and deep organs abscesses, recurrent oral and genital ulcers, recurrent eczema, diffuse presence of warts or molluscum contagiosum, non-infectious granulomas, idiopathic bronchiectasis, persistent lymphopenia or neutropenia, idiopathic hypereosinophilia, IgE higher than 2000 IU/mL, autoimmune or allergic diseases, chronic diarrhea, characteristic facies, skeletal abnormalities, neurological symptoms and hearing loss [14, 15]12.
In this study, PID diagnostics were made under the criterion of clinical immunologists, based on the phenotypic analysis of each case, the laboratory tests available in public hospitals, and genetic studies in some cases. Similar to many Latin American countries, Costa Rica has limitations in PID diagnosis, as no genomic studies can be provided to confirm all suspected cases, nor functional immunological tests are available always at the public health system.
The largest number of patients diagnosed with PID came from the central urban region, which is expected as the majority of the Costa Rican population is concentrated in this area. A statistical analysis of the frequency of PID according to the urban and rural areas was not possible as a clear differentiation between these populational zones is not well defined in Costa Rica. The distribution by province of origin to establish whether there is any genetic pattern justifying variation in prevalence remains unclear. The high heterogeneity in PID distribution per province might be related to the presence of specialized clinics only in urban areas.
In relation to the aimed national prevalence estimation of this study, there were two distributions modeled with a Poisson pattern, given the condition of a rare disease under study. A parameter p, representing the proportion of people that has been diagnosed with PID in Costa Rica, is denoted as our estimation of interest. One of these models is based only in verified diagnosed cases, whereas the other model describes a scenario including hidden cases related to underdiagnosed PID patients considering a possible underestimation. This model considers patients that may not have been diagnosed due to different possible reasons, as for example living too far from specialized clinics or lack of expertise diagnosing PID in physicians not sufficiently trained in immunology.
Female patients showed a higher prevalence of PID in this study. PID registries in Latin America are limited and distribution data for these pathologies according to sex and geographic area are in general controversial. US registries show higher prevalence of any kind of PID female sex  In contrary, German records report higher prevalence in men, similar as in Iran and the United Kingdom  The Swiss register shows an equitable prevalence between the two sexes  It should be noted that, although a higher PID trend is documented in the male sex, many of the registries are intertwined with pediatric populations, where X-linked conditions are common. In records involving only adult populations, the PID prevalence tends to be similar in both sexes .
The most common PID in this registry was idiopathic neutropenia due to the cohort of Hospital Dr. Calderón Guardia patients, while in the cohort of Hospital México the most frequently diagnosed PID was CVID. All neutropenic patients had histological bone marrow study and cytogenetic analysis to exclude hematological malignancies and aplastic syndromes.
Unlike to globally published data, in which the most common PID is SIgAD [9, 20], our study shows that this disorder does not seem to prevail in Costa Rica. However, excluding idiopathic neutropenia, the most prevalent diagnoses were humoral PID, that complies with the epidemiology described in other countries [3, 21].
In this study, PID patients frequently associated atopic manifestations, mainly of the antibody disorders subgroup. Previously, a close relationship between PID and atopic syndrome has been well documented, possibly mediated through non-IgE related Th1 and Th2 responses [22, 23].
The most common comorbidity detected in this cohort was dyslipidemia, accompanied by hepatic steatosis in some cases. It is unclear whether metabolic diseases could be another consequence of immune incompetence, treatment or an independent factor. No clinical studies provide information about incidence of metabolic and cardiovascular disease in the adult PID population up to now. Efforts in this regard need to be made, as metabolic syndrome may add comorbidity to immunodeficient patients, exacerbating the accompanying inflammatory state.
Autoimmune diseases were common in this registry, related in the first place to antibody deficiencies, which has been documented by previous studies  Patients with primary complement disorders also show autoimmune disorders. Deficiency of early components in the classic complement pathway favors the development of systemic autoimmune diseases, principally systemic lupus erythematosus . In this study, 12 cases with primary complement defects and concomitant systemic lupus erythematosus (SLE) were documented in this study. These patients remained asymptomatic but showed persistent hypocomplementemia despite an adequate disease management and absence of disease activity indicators over years. It should be mentioned that some of these patients maintained high double strand DNA levels despite SLE remission. As well, in some of these patients a diminution of more than one complement fraction was observed. These findings raise the doubt if, instead being consequence of PID, these conditions were related to a secondary complement deficit caused by persistence of autoantibodies directed against complement. Ideally, factor C2 should be quantified in these cases, given its prominent role in apoptotic debris removal . Nevertheless, in Costa Rica no further complement fractions other than C1q, C3 and C4 are quantified in public hospitals.
Among patients with idiopathic neutropenia, a major association with autoimmune diseases was described anteriorly. Autoimmunity associated neutropenia occurs secondary to concomitant autoimmune disease, due to anti-polymorphonuclear antibodies. In several countries such as in Costa Rica, an important limitation for an accurate idiopathic neutropenia diagnosis is the unavailability of tests to determine anti-neutrophil antibodies, which are critical to differentiate between autoimmune neutropenia as a single entity or as a manifestation of other autoimmune diseases. The presence of anti-polymorphonuclear antibodies excludes the diagnosis of idiopathic neutropenia, caused by various genetic alterations resulting in a decreased neutrophil count .
Regarding the pathogens isolated during infections, PID patients showed similarities with other case series published worldwide. In general, the organic complications mostly documented were respiratory ones. The relationship between IgG deficiency and pulmonary complications in PID is well known. Despite adequate replacement with IVIG, patients with PID continue to experience recurrent respiratory infections, triggering progressive lung function deterioration . This clinical outcome was observed in patients of this study as well.
Unlike other countries in which subcutaneous immunoglobulin is routinely used for substitutive therapy, in Costa Rica only IVIG is available in the public health system so far. Unfortunately, this affects the adherence of our PID patients to treatment, increasing the negative impact of these conditions and worsening their prognosis.
Studies conducted over the past decade have corrected the underestimation about prevalence of PID in adults, evidencing that their occurrence is not lower than in children. Although most of these diseases are usually diagnosed in childhood, most PID patients are actually adults . In any case, the management of PID differs significantly between children and adults, which requires an adequate, complex diagnostic approach, follow-up strategies and diverse therapeutic approaches . The PID manifestations in adults can be multisystemic, therefore these disorders need an early suspicion and timely reference to a clinical immunologist specialized in adult patients, to prevent complications and sequelae. Similarly, the general population must be sensitized to suspect PID, so that patients show up early to the health system.
Possibly, many adult carriers of PID remain undiagnosed worldwide, which limits truthful epidemiological knowledge about these entities in the general population. The promptness of the PID diagnosis is a crucial factor that can minimize the organic damage and therefore influence the prognosis directly. Likewise, early diagnosis of PID in adults is of high importance in terms of genetic counseling.