Many systemic inflammatory diseases seen in rheumatological practice occur in the young and can be from birth, such as the autoinflammatory diseases detailed in the chapter on autoinflammatory syndromes. Many have been shown to be due to genetic malfunction affecting the innate or adaptive immune system. PIDs are a group of diseases with clinical symptoms usually from birth due to gene mutations affecting the immune system. Therefore it is not surprising that some of the clinical symptoms resemble recognizable rheumatological clinical syndromes seen by rheumatologists.

The spectrum of recognized PIDs classically affects the intracellular transmission of signals from outside the cell, affecting the differentiation of lymphocytes and other immune cells or the production of antibodies and other molecules that orchestrate the inflammatory or immune responses. All of these functions are crucial in body defense as well as the regulation of the immune and inflammatory response. Sometimes there are cases of combined immunodeficiencies such as in Wiskott-Aldrich syndrome (WAS) and Aicardi-Goutieres syndrome (AGS). The genetic mutations causing AGS have only been recently described [10] and have typical clinical features of small- and medium-size vasculitis, arthritis, and cerebral calcification. The manifestation of rheumatic clinical features in PID can also help the researcher and clinician to consider the “right place to look” for a cause of the rheumatologic disease.

Early diagnosis has a significant impact on the prognosis of PIDs and has lifesaving implications. Timely treatment prevents organ damage and improves chance of cure by hematopoietic stem cell transplant in diseases amenable to such treatments. While definitive diagnosis of PIDs may require sophisticated functional and molecular studies, a significant proportion of PIDs can be picked up by simple tests such as full blood count and serum immunoglobulin levels. Absolute lymphocyte count (ALC) should be interpreted according to age-matched reference range. The fact that ALC < 2.5 × 10⁹/L is abnormal in infants is often under-recognized. Lymphopenia is common in some rheumatological disorders such as systemic lupus erythematosus (SLE) especially after commencement of immunosuppressive treatment, but if accompanied by recurrent or unusual infections and autoimmunity, lymphocyte subset should be performed to exclude T-cell immunodeficiency. Genetic defects in cytokine and T-cell receptor signaling, V(D)J recombination, and basic cellular processes such as purine and pyrimidine metabolism classically cause severe combined immunodeficiencies (SCID) which usually present in infancy with limited survival. However, it is increasingly recognized that patients with “leaky” SCID can present later in life with recurrent infections and autoimmune manifestations [11].

Boys with recurrent sinopulmonary infections who have absence of tonsils and lymph nodes on examination and low immunoglobulin levels may have congenital agammaglobulinemia, most often XLA. Male infants with eczema, recurrent infections, thrombocytopenia, and small platelet size on blood film likely have a diagnosis of Wiskott-Aldrich syndrome (WAS). Patients suffering from granulomatous inflammation, chronic diarrhea mimicking inflammatory bowel disease, and soft tissue and deep organ abscesses with normal blood counts and immunoglobulin levels should be tested for phagocytic functions to exclude chronic granulomatous disease (CGD) by nitroblue tetrazolium test (NBT) or dihydrorhodamine reduction (DHR) test. The reader can refer to excellent guidelines on multistage diagnostic protocols for screening and investigations of PIDs [12, 13].

The population of Asia comprises more than 4.2 billion people (60 % of the world population) living in 46 different countries and states. Like the rest of the world, health service provision closely parallels economic wealth, which differs widely between, and within, states. Socioeconomic development is a major determinant of the under-five mortality [14]. According to the WHO analysis of global causes of child mortality in 2010, infections account for 64.6 % of deaths in children aged 1–59 months in Southeast Asia, compared with 26.9–45.7 % in the Western Pacific, Europe, and Americas. Pneumonia and diarrhea together accounted for 25 % of such deaths in Southeast Asia and 18 % in the Western Pacific, compared with 12 % in the Americas and 13 % in Europe. In Southeast Asia, vaccine-preventable diseases such as pertussis and measles accounted for 4 % of child mortality, but not in Americas and Europe [15].

Practically, the recognition of PID only comes when infection-related childhood mortality is brought below a certain threshold, so that children suffering from infections occurring at exceptional frequencies, of extraordinary severity, or caused by unusual organisms will survive long enough to receive sufficient attention from healthcare professionals. In Asia, organized medical service for patients with PID is available in Japan, Taiwan, Hong Kong, Mainland China, Singapore, Thailand, and South Korea, while there are only occasional reports of PID from Vietnam, the Philippines, and Sri Lanka [16].

Advances in the diagnosis and management of PID have taken place in India during the past 10–15 years. According to a recent review by Sudhir Gupta et al. [17], a total of 820 cases were evaluated for suspected PID from 2007 to 2010 in the Institute of Immunohaematology, Mumbai. Of these 820 cases, 122 cases were diagnosed with PID. In the Postgraduate Institute of Medical Education and Research, Chandigarh, a total of 153 cases were diagnosed with PID from 1992 to 2010. Majority of the PID patients in Chandigarh (41.9 %) had predominantly antibody deficiency diseases, which included XLA, X-HIM, AR-HIM, common variable immunodeficiency (CVID), selective IgA deficiency with or without IgG2 subclass deficiency, isolated IgG2 subclass deficiency, and prolonged transient hypogammaglobulinemia. In Mumbai, 15.5 % of patients were reported to have predominantly antibody deficiency diseases. Interestingly, around 30 % of PID patients in Mumbai had diseases of immune dysregulation, including perforin deficiency, Munc 13–4/Syntax 11 deficiency, Griscelli syndrome II, Chédiak-Higashi syndrome, Hermansky-Pudlak syndrome II, and autoimmune lymphoproliferative syndrome (ALPS) [18]. Only one patient with autoinflammatory disorder (TRAPS-TNFR-associated periodic fever) was reported in Chandigarh, but none from Mumbai. The incidence of various PIDs in the two centers differs significantly. This may reflect differences in patterns and number of referrals to each center, as well as diagnostic tools and expertise available at each of these institutions. Furthermore, a possibility of racial and ethnic differences cannot be excluded. It is possible that different PIDs may be clustered in these regions, for example, WAS in Northern India (Chandigarh) and immunodeficiency with hypopigmentation in Western India (Mumbai).

Genetic defects causing abnormal development and maintenance of T- and B-cells may result in predisposition to autoimmunity in patients with PID. Mechanisms include impaired immune tolerance, defects in regulation of cellular growth and proliferation, defects in immune-mediated clearance, and aberrations in innate cellular mechanisms [19].