Researchers characterize malignancy risk with IgE deficiencies

Key takeaways:

• 23.5% of patients with an IgE deficiency had a malignancy diagnosis.
• Nonatopic patients were more likely to have a malignancy than atopic patients.
• Skin testing may help assess malignancy risk.

Patients with diagnoses of various IgE deficiencies do not share equal odds for developing malignancies, according to a study published in The Journal of Allergy and Clinical Immunology: In Practice.

Skin tests and immunological measurements may help physicians assess risks for malignancies among these patients, Ariela M. Agress, MD, assistant professor in the division of pediatric allergy-immunology at Children’s Hospital at Montefiore in New York, and colleagues wrote.

“Most allergists focus on evaluating high IgE levels in patients with allergies and do not spend much time contemplating those with low or absent IgE levels,” Agress told Healio. “However, a number of studies have shown that IgE-deficient patients have a higher risk for developing a malignancy compared to non-IgE-deficient patients.”

Previously, Agress and colleagues uncovered a relationship between IgE deficiency and increased malignancy rates, specifically in patients with negative allergy skin testing.

“This brought to light the concept that perhaps not all IgE-deficient patients are the same and that there may be other associated immunological characteristics related to the increase in malignancy risk,” she said. “Thus, we sought to evaluate the different immune characteristics in our IgE-deficient cohort and their associations with malignancy risk.”

Study design, results

The researchers reviewed the records of 408 adults (mean age at diagnosis, 53.37 years; 75% women) with an IgE deficiency, defined as a total serum level of less than 2.5 kU/L, seen at their facility between 2005 and 2020. Also, 54.1% of the patients had rhinitis, and 33.9% had asthma.

Among the 127 patients (63.5%) who had environmental skin testing, 44 (35%) were atopic, defined as having at least one positive skin test.

In total, 23.5% of the cohort had any type of malignancy.

Researchers found that malignancy appeared significantly more common among nonatopic vs. atopic patients (20.5% vs. 9.1%; OR = 4.36; 95% CI, 1.11-17.13). The most common malignancies among the nonatopic patients included hematological cancers (n = 8; 47%) and breast cancer (n = 6; 35%). The four malignancies in the atopic patients included breast, endometrial and rectal cancer and an unknown malignancy.

Next, researchers classified patients with available data into three categories. First, patients with selective IgE deficiency had normal levels of other immunoglobulin isotypes, including IgA, IgM and IgG (n = 134). Immune abnormalities in this group included CD4 lymphopenia (11.9%), mannose-binding lectin deficiency (21.9%) and abnormal lymphocyte mitogen response (45.5%).

The second group included patients with a documented diagnosis of common variable immunodeficiency (CVID; n = 48). In the third category, non-CVID humoral abnormalities, patients had an IgE deficiency with at least one other low immunoglobulin isotype but none of the criteria for a CVID diagnosis (n = 75).

Researchers noted that the non-CVID humoral abnormalities group was older (mean age, 57 years vs. 52 years; P = .01) and had a smaller proportion of women (60% vs. 81.3%; P = .006) than the selective IgE deficiency group. Also, the selective IgE deficiency group had significantly lower proportions of IgG1, IgG2, IgG3 and IgG4 subclass deficiencies than the patients with CVID, but there were no differences in these parameters between the selective IgE deficiency group and the non-CVID humoral abnormality group.

The non-CVID humoral abnormality group appeared at significantly greater risk for a malignancy diagnosis than the selective IgE deficiency group (42.7% vs. 20.1%; OR = 2.99; 95% CI, 1.41-6.31).

The CVID group had higher rates of a malignancy diagnosis than the selective IgE deficiency group as well, at 31.3%, but the odds ratio did not reach statistical significance (OR = 0.65; 95% CI, 0.27-1.56).

Patients with selective IgE deficiency (OR = 2.18; 95% CI, 1.07-4.46), CVID (OR = 3.31; 95% CI, 1.23-8.83) and non-CVID humoral abnormality (OR = 6.56; 95% CI, 2.91-14.7) all had higher odds for a malignancy diagnosis than an age- and sex-matched cohort of patients with normal IgE levels, which had a malignancy rate of 12.7%.

Characteristics associated with a diagnosis of malignancy among patients with an IgE deficiency included older age (OR = 1.03; 95% CI, 1.01-1.05), having a non-CVID humoral abnormality (OR = 2.79; 95% CI, 1.37-5.68), IgM deficiency (OR = 2.46; 95% CI, 1.13-5.36), IgG2 deficiency (OR = 10.14; 95% CI, 1.9-54.1) and CD4 lymphopenia (OR = 7.81; 95% CI, 2.21-27.63).

Conclusions, next steps

Although prior studies had found higher rates of and risks for malignancies among patients with an IgE deficiency, Agress and colleagues called this study the first to demonstrate an association between specific immunologic characteristics of these patients and higher odds for a diagnosis of malignancy. The researchers also called reactivity to environmental skin tests useful in characterizing these associations among patients with IgE deficiencies and symptoms resembling allergic rhinitis.

“First, we validated our prior finding that IgE-deficient patients with allergic-like symptoms may have either positive or negative allergy skin testing and that those with negative skin testing are specifically at risk for malignancy,” Agress said.

“Second, we found that there are indeed other specific immune changes in some IgE-deficient patients that significantly increase the risk of malignancy,” she continued. “For example, those IgE-deficient patients with low levels of other immunological parameters (low IgG, IgA, IgM, IgG2 or CD4) had higher odds of having a malignancy diagnosis.”

But the researchers also cautioned that whether underlying but unapparent malignancies could be responsible for the IgE deficiency or if an underlying immune abnormality could cause the deficiency and the malignancy remains unknown, prompting a need for additional studies measuring other components of the immune system to better measure malignancy risk among these patients.

“Our findings suggest that patients with IgE deficiency may benefit from additional monitoring over time to evaluate if they eventually develop an overt immunodeficiency,” Agress said. “Additionally, close monitoring for cancer occurrence may be indicated, specifically in nonatopic IgE-deficient patients and in those with some other associated abnormalities of the immune system.”

Denisa E. Ferastraoaru, MD, associate professor of allergy-immunology, Albert Einstein College of Medicine/Montefiore Medical Center, also contributed to this article.

For more information:

Ariela M. Agress, MD, can be reached at aagress@montefiore.org.