We present here the largest study of children with elevated serum levels of IgG. To our knowledge, this is the first attempt to compile an inclusive differential diagnosis for hypergammaglobulinemia in the pediatric population. The vast majority (almost 95%) of patients in our study had identifiable disorders that could explain their hypergammaglobulinemia, and these conditions could be subdivided into clinically relevant categories. Of these, autoimmune/autoinflammatory disorders were by far the most common.
Hypergammaglobulinemia is well-recognized as a key feature of SLE and lupus-related conditions . The diffuse B cell activation and autoantibody production that is characteristic of SLE is also central to disease pathogenesis. Both MCTD and Sjogren’s syndrome are thought to have related pathogenic mechanisms. SLE and MCTD were the most common diseases observed in this study, representing 17% of the children with hypergammaglobulinemia. While other rheumatologic conditions, such as forms of juvenile arthritis, were also diagnosed relatively frequently, the number with SLE and MCTD was disproportionate to the overall prevalence of these disorders in the pediatric population (approximately 3–12 per 100,000, less than 1/4 of the prevalence of juvenile arthritis [8, 9]). Autoimmune conditions of the gastrointestinal tract were also common, in particular inflammatory bowel disease and autoimmune hepatitis.
The infectious conditions associated with high IgG levels also fell into distinct categories. Chronic respiratory infections, such as those seen in patients with CF, were the most common infection associated with high IgG levels. Hypergammaglobulinemia was first noted in CF patients almost 40 years ago , and IgG levels correlate with disease progression [11, 12]. Streptococcal-associated conditions were also common in our cohort, particularly non-suppurative complications of streptococcal infection (rheumatic fever, post-streptococcal glomerulonephritis, and post-streptococcal arthritis). Hypergammaglobulinemia has long been noted in patients with acute rheumatic fever, and was described at almost the same time that IgG was first characterized . While IgG levels do not seem to correlate with severity of disease, hypergammaglobulinemia may help distinguish active rheumatic fever from inactive rheumatic heart disease . The reason for the uniquely potent serologic response to streptococcal infections is unclear, though streptococcus has a propensity for causing a wide variety of post-infectious sequelae. Among these, Henoch-Schonlein purpura and polyarteritis nodosum were identified only rarely in the present cohort.
Gammopathy, both monoclonal and polyclonal, has been described in adults with a variety of chronic liver conditions [15–17]. In our pediatric cohort, liver disease was a relatively rare association with hypergammaglobulinemia, even when including patients with autoimmune and infectious hepatitis. High IgG levels in the context of autoimmune and infectious liver conditions may reflect chronic immune activation, but the mechanism by which primary liver dysfunction leads to gammopathy in the absence of systemic inflammation is not known. Other factors related to the aging process, or accumulated exposures over time, may explain the discrepancy in the incidence of liver disease among adults and children with hypergammaglobulinemia.
There were only a few patients with malignant conditions in our cohort; all had lymphoproliferative disorders. Two of these had presented to rheumatologists prior to their oncologic diagnosis. The first, a 14 year old girl, had initially been diagnosed with viral arthritis. Additional clinical findings one year later led to the diagnosis of Hodgkin’s lymphoma. The second patient was a 17 year old with multiple physical examination and laboratory criteria consistent with MCTD. However, he was also found to have extensive lymphadenopathy and hepatomegaly. Further evaluation ultimately revealed Burkitt lymphoma. Due to the small number of proliferative disorders in our cohort, we are unable to speculate whether lymphocyte dysregulation led to both hypergammaglobulinemia and development of the malignancy, nor can we identify risk factors for distinguishing autoimmune from malignant conditions. In general, however, malignancy appears to be a rare cause of hypergammaglobulinemia in children.
Given the prevalence of autoimmune conditions in our pediatric cohort with hypergammaglobulinemia, we developed a predictive algorithm for identifying patients who are at increased risk for autoimmunity. We anticipate that this algorithm may be useful in the evaluation of children with unexplained systemic inflammation, since children with hypergammaglobulinemia are most likely to be incidentally identified on the basis of an elevated ESR. While elevated fibrinogen levels cause a high ESR in children with actual inflammation , high immunoglobulin levels can also contribute to elevation of the ESR in those with HIV, SLE, and other conditions identified among our study subjects. In such patients, the presence of a low white blood cell count, low hemoglobin, low CRP and female gender should increase concern for a possible autoimmune disease.
Hypergammaglobulinemia in patients with autoimmune/autoinflammatory disorders is multifactorial in etiology. Polyclonal B cell activation is well known to play a prominent role in SLE and other conditions characterized by autoantibodies . Multiple cytokines influence this B cell activation. For example, B cell activating factor (BAFF) and IL-6 are elevated in SLE and other autoimmune diseases . Interestingly, IL-6 has pleiotropic pro-inflammatory effects that also play a role in the pathogenesis of autoinflammatory conditions [21, 22]. It is not clear how B cells influence autoinflammatory disorders such as NOMID and Crohn disease; one possibility may be that B cell activation and antibody production in these conditions are bystander effects of IL-6 activity.
A significant limitation of this study is the potential bias among children in whom a decision was made to measure immunoglobulin levels. Rheumatologists and immunologists are more likely to check immunoglobulin levels than other specialists, and thus patients with rheumatologic and immunologic disorders are probably overrepresented in our cohort. On the other hand, studies of hypergammaglobulinemia in adults, and previous case series in children, do not suggest that large numbers of children who have other illnesses or who are entirely well are likely to have IgG levels above 2000 mg/dL. Nonetheless, as our predictive algorithm was developed from this potentially skewed population, it will require prospective testing before its general applicability can be confirmed.