Abstract
Background
Patients with a low IgG level alone or with low IgA or IgM levels have been reported to be susceptible to respiratory tract infections and recurrent sinusitis. Patients diagnosed with common variable immunodeficiency have a higher prevalence of autoimmune diseases and lymphoid malignancies. Mastocytosis is a myeloproliferative disease that is not typically associated with autoimmune disease or frequent infections.
Objective
We sought to determine the distribution of immunoglobulin levels in children and adults with mastocytosis, as well as to evaluate the impact of low immunoglobulin levels on the clinical management of patients with mastocytosis.
Methods
We performed a 10-year retrospective analysis on 320 adult and pediatric patients with mastocytosis for immunoglobulin levels by using an electronic medical query. We identified 25 adults and 9 children with 1 or more low immunoglobulin levels. Patient records were examined for a history of infections and autoimmune disorders.
Results
Serum immunoglobulin levels in children and adults with mastocytosis fell within a normal range. Of the patients with low IgG levels alone or with low IgM and/or IgA levels, 20% had a history of infections and 20% of adults had autoimmune disorders. The most common infection was recurrent otitis media.
Conclusion
Patients with mastocytosis typically have normal immunoglobulin levels. With few exceptions, those with low immunoglobulin levels did not have frequent infections or autoimmune diseases. These data support the conclusion that routine determination of immunoglobulin levels in patients with mastocytosis is not required and should be reserved for patients with clinical conditions that might be related to an immunoglobulin deficiency.
Key words: Mastocytosis, immunoglobulin, pediatrics, adults, infection, autoimmune
Introduction
Mastocytosis is a disease with abnormal growth and accumulation of mast cells (MCs), which in many patients is accompanied by MC mediator–related symptoms.1 The broad classification is divided into cutaneous mastocytosis, in which the major accumulation of MCs occurs in the skin, and systemic mastocytosis (SM), with abnormal accumulation of MC in extracutaneous organ systems.2 On the basis of clinical information, a histologic and immunohistochemical examination of the bone marrow and cytologic and laboratory findings (including measurement of serum tryptase levels), and molecular studies (such as for the KIT D816V gain-of-function mutation), the diagnosis of SM is then refined by using the World Health Organization criteria to distinguish more advanced forms of SM (an MC sarcoma) from reactive MC hyperplasia.2,3
Common variable immunodeficiency (CVID) is a collection of hypogammaglobulinemia syndromes diagnosed in patients older than 2 years. The criteria for the diagnosis are a marked reduction in serum IgG level with concurrent reductions in IgA and/or IgM levels, insufficient antibody responses to infections or immunizations, and absence of additional primary or secondary immune defect.4,5 The hallmark of the disease is recurrent infections (primarily sinopulmonary). From 30% to 50% of patients will also develop noninfectious manifestations, including autoimmune disease, granulomas, interstitial lung diseases, enteropathies, lymphoid hyperplasia, and malignancies.4,6
Assessment of the immunoglobulin profiles of patients with a diagnosis of mastocytosis is not routine. Here, we demonstrate that low immunoglobulin levels are not typical, and when present, they were limited especially to IgG, with only 3 patients (8.8%) experiencing frequent sinopulmonary infections. When those with low IgG levels associated with low IgA and/or IgM were assessed, 1 patient who experienced frequent episodes of otitis media (3.8%) was identified. Patients with a low IgA level alone constituted 4% of all patients, which was lower than percentage among the general population (7%). Thus, patients with mastocytosis generally have immunoglobulin levels within a normal range. Those with low immunoglobulin levels are at low risk for clinically relevant infections. The investigation of immunoglobulin levels in patients with mastocytosis may thus be limited to individuals who manifest a clinical profile consistent with immune suppression.
Results and discussion
The immunoglobulin data for all patients are shown in Fig 1, A for adults and Fig 1, B for children. Most immunoglobulin levels fall within the normal range, with the exception of IgE levels, which tend to be lower in patients with mastocytosis.7 Data from adult and pediatric patients with low immunoglobulin levels are shown in Fig 2. Although the median values appear significantly different, the range of values in adults (IgG level, 414-677 mg/dL; IgM level, 19-39 mg/dL; and IgA level, <5-87 mg/dL) are not so disparate from the pediatric ranges for IgG and IgM levels (IgG level, 333-674 mg/dL; IgM level, 26-30 mg/dL; and IgA level, 11-19 mg/dL). In both groups, the majority of the low values were between the 50th and 75th quartile.
Fig 1.
Individual immunoglobulin levels in adult patients with mastocytosis. A, Adults with mastocytosis immunoglobulin levels span the normal range of values (normal values: IgG < 700 mg/dL; IgM < 40 mg/dL; and IgA < 91 mg/dL), with some patients in the low range for IgG, IgM, and IgA levels. Patients with mastocytosis tend to have lower IgE values, as demonstrated. B, Pediatric patients (aged 13 months-14 years) with mastocytosis span a wider range of values owing to the age-related normal values for IgG, IgM, and IgA levels. IgE levels are also lower (normal level < 90 mg/dL). Dotted lines represent cutoffs for the normal range. Blue lines represent the median and interquartile range.
Fig 2.
Patients with low immunoglobulin levels. A, Only 25 adult patients had low immunoglobulin levels, with the majority shown in the IgG and IgA classes, respectively. B, In all, 9 pediatric patients had low immunoglobulin levels, with a majority seen in the IgG class. Patients with a combination of low IgG level with IgA or IgM level are colored similarly in all graphs. Dotted lines represent cutoffs for the normal range. Blue lines represent the median and interquartile range.
A total of 34 patient records (10.6% [including records for 25 adults and 9 children]) were then analyzed on the basis of criteria set for low immunoglobulin levels. In all, 15 patients had low IgA or IgM levels alone and were not included in the analysis of infections and autoimmune diseases because only 1 adult with IgA deficiency had any finding (a tonsillectomy for recurrent pharyngitis). The average age for adult patients with mastocytosis and low immunoglobulin levels was 60 years (range 36-78 years), whereas the average age for the pediatric patients diagnosed with mastocytosis with low immunoglobulin levels was 7 years (range 1-14 years). As shown in Table I, the pediatric patients had lower immunoglobulin levels, as was expected on the basis of age-appropriate values.8 In all of the patients, low IgG level was the most common finding (n = 14 [41%]), followed by low IgA level (n = 13 [38%]) and a combination of low IgG level with low IgA or low IgM level and low IgM level alone (n = 5 and 2, respectively).
Table I.
Demographics of patient groups with mastocytosis categorized by immunoglobulin levels
| Patients | Total | Sex, M/F |
Disease variant | Average age (range), y | Median serum tryptase level (range), ng/mL | Median IgG level, mg/dL | Median IgM level, mg/dL | Median IgA, mg/dL |
|---|---|---|---|---|---|---|---|---|
| All variants with the exception of aggressive SM | 286 | 105/181 | All variants | 40 (1-79) | 26.2 (1.5-1607) | 987 | 107 | 173 |
| Adult patients with low immunoglobulin levels | 25 | 7/18 | MIS, ISM, SSM | 53 (30-68) | 25.7 (4.9-291) | 552 | 35 | 62.5 |
| Pediatric patients with low immunoglobulin levels | 9 | 8/1 | MCPM, DCM, MTOMA, ISM | 7 (1-14) | 14 (2.7-192) | 350 | 28 | 16.5 |
Normal adult immunoglobulin levels are as follows: IgG, less than 700 mg/dL; IgM, less than 40 mg/dL; and IgA, less than 91 mg/dL. Pediatric values are age-based.8
DCM, Diffuse cutaneous mastocytosis; F, female; ISM, indolent systemic mastocytosis; M, male; MCPM, maculopapular cutaneous mastocytosis; MIS, mastocytosis in the skin; MTOMA, mastocytoma; SSM, smoldering systemic mastocytosis.
In the pediatric population, only 1 patient met the criteria for CVID (patient 1) and had a history of respiratory syncytial virus as an infant but was only 4 years old when evaluated. Two additional patients (patient 2 and patient 5) experienced more infections than would be predicted for their age, and both had low IgG levels. One was treated with replacement therapy for recurrent otitis and mastoiditis (Table II). No pediatric patient had an autoimmune disorder, but this may have been related more to age in this population (average age 7 years).
Table II.
Infectious and autoimmune disease history in pediatric patients with low immunoglobulin levels
| Immunoglobulin | Infection | Autoimmune disease |
|---|---|---|
| IgG only | ||
| Pediatric patient 2 | Mastoiditis, frequent OM | |
| Pediatric patient 4 | None | |
| Pediatric patient 5 | Sinus infections (× 3); cellulitis (× 2) | |
| Pediatric patient 6 (resolved) | ||
| IgG and IgA | ||
| Pediatric patient 1 | Respiratory syncytial virus | |
| IgG and IgM | ||
| Pediatric patient 3 | Frequent OM, molluscum contagiosum |
No autoimmune diseases; 16% with a family member with CVID. Patients with IgA or IgM level only are not included (n = 3).
Regarding the adult population, only 1 patient had a history of chronic sinusitis, but that patient did not meet the the criteria for CVID, and 1 patient also experienced frequent OM (Table III). The adult patients were more frequently diagnosed with an autoimmune disorder (20%); however, this prevalence was lower than that reported in the patients with CVID. In adult patients, tryptase levels correlated with immunoglobulin levels when all were factored in (P = .036), but no single immunoglobulin correlated with tryptase level (see Fig E1, A in the Online Repository at www.jaci-global.org). There were no correlations between tryptase and immunoglobulin levels in the pediatric data set (see Fig E1, B). Thus, as suspected, tryptase level did not affect immunoglobulin levels.
Table III.
Infectious and autoimmune disease history in adult patients with low immunoglobulin levels
| Immunoglobulin | Infection | Autoimmune disease |
|---|---|---|
| IgG only | ||
| Adult patient 2 | Chronic sinusitis | |
| Adult patient 4 | ||
| Adult patient 5 | Frequent OM with hearing loss | |
| Adult patient 6 | ||
| Adult patient 7 | Hypothyroidism | |
| Adult patient 8 | Frequent folliculitis (and MRSA) | |
| Adult patient 9 | ||
| Adult patient 10 | Thyroiditis | |
| Adult patient 11 | Chronic spontaneous urticaria | |
| Adult patient 13 | Protein C deficiency | |
| IgG and IgA | ||
| Adult patient 1 | Lyme disease, pneumonia/meningitis at age 16 y | |
| Adult patient 12 | None | Raynaud syndrome |
| IgG and IgM | ||
| Adult patient 3 (resolved) | None | None |
Patients with IgA or IgM level only are not included (n = 12 ) (see the text).
MRSA, Methicillin-resistant Staphylococcus aureus.
To our knowledge, this is the first study to systematically evaluate low immunoglobulin levels in adult and pediatric patients with mastocytosis. It has been reported that patients with low IgG levels alone or in combination with low IgA or IgM levels may have more respiratory infections and autoimmune diseases without meeting the criteria for CVID.5,9,10 In this retrospective analysis, we report that the occurrence of low immunoglobulin levels in those with mastocytosis is unusual (8%), and when present, such levels are not typically associated with chronic or recurrent infections. In patients with CVID, the most common manifestation is sinopulmonary, and in our patient cohort, sinopulmonary infections were confined to the upper respiratory tract; moreover, all of them were treated in an outpatient setting. Although we did not document antibody titers, most patients did not experience infections consistent with a poor response to routine immunizations. The 1 patient who was treated with replacement therapy for mastoiditis had normal antibody titers and normal lymphocyte phenotyping (data not shown). Two patients with low IgG values at ages 13 and 25 months and correction by 60 and 42 months, respectively, could have met the criteria for transient hypogammaglobulinemia of infancy; however, these patients did not experience frequent bacterial infections during the period of low values.
Autoimmune diseases were not seen this pediatric cohort. However, 20% of the adults in this cohort with low immunoglobulin levels reported an autoimmune disorder, compared with rates of 30% to 50% in patients with CVID. The prevalence of CVID in the general population is approximately 1 in 25,000 to 75,000 subjects.11 An international survey of physicians from a network of specialized centers reported the prevalence of CVID in the United States as being 15.8%.12 In all, 5 patients demonstrated a combination of low IgG level with low IgA and/or IgM level (1.47%); however, only 1 patient had a family member in whom CVID had been diagnosed (a diagnostic criterion), but without manifestations of frequent infections. In addition, as reported in the literature, there was a predominance in adult females with low immunoglobulin levels (80%).
This study highlights the importance of managing mastocytosis and other possible disease entities such as sinusitis or inflammatory bowel disease as separate disease processes. Mastocytosis has a major effect as a myeloproliferative disease on symptomatology due to an increased MC burden, and their constitutive activation with mediator release, which impacts multiple organ systems, along with IgE expression and allergic inflammation. In this population of patients with mastocytosis, low immunoglobulin levels did not appear to alter the immunoregulatory functions controlling infections or autoimmunity. Thus, a more extensive evaluation of immunoglobulin levels and immune function should be reserved for patients with mastocytosis with characteristic signs of immune dysregulation.
For details on the study methods, please see the Methods section of the Online Repository (at www.jaci-global.org).
Clinical implications.
This cohort study demonstrates that there is a low prevalence of infectious and autoimmune disorders in patients with mastocytosis with low IgG levels alone or in combination with low IgM and/or IgA levels.
Footnotes
Supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH). The content is solely the responsibility of the authors and does not represent the official views of the NIH.
Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.
Supplementary data
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