Neurologic Conditions and Symptoms Reported Among Common Variable Immunodeficiency Patients in the USIDNET

To the Editor:

Common variable immunodeficiency (CVID) is increasingly recognized as a group of distinct and varied clinical phenotypes associated with a range of inflammatory, autoimmune, and malignant disorders [1]. Neurologic complications in CVID are rare but can be associated with significant morbidity and mortality [2]. Current knowledge regarding neurologic complications in CVID patients is limited to case reports and small case series [2].

To improve our understanding of neurologic complications that occur in CVID, we queried the United States Immunodeficiency Network (USIDNET), a registry of primary immunodeficiency patients, for neurologic conditions and symptoms reported in CVID patient records. We also queried the cohort for age at symptom onset and diagnosis, year of birth, race, sex, immunoglobulin replacement therapy (age at initiation of therapy, route, dose), genetic diagnosis, and laboratory data. If multiple immunoglobulin levels were reported, the average was used for analysis. Statistical analyses were performed using Stata/IC 16.0 (StataCorp, College Station, TX). Fischer’s exact test was used for comparisons of proportions, and the Wilcoxon rank-sum test was used to compare medians between two groups.

The query returned 1227 CVID patient records. Patients with non-CVID diagnoses were excluded (two with autoimmune lymphoproliferative syndrome; one with BTK mutation), resulting in a cohort of 1224 patients. There were 1315 neurologic conditions and symptoms reported in 49.1% (601/1224) of the USIDNET CVID cohort. Among these 601 patients, the median age of diagnosis was 29.6 years (range 0–73), 65.9% (396/601) were female, and 96.3% (579/601) were on immunoglobulin replacement therapy (IgG-RT). Specific gene mutations reported were TACI (n = 25), CD19 (n = 2), ICOS (n = 1), and NFKB2 (n = 4).

The distribution of reported neurologic conditions and symptoms among the 601 patients were neuropsychiatric (53.7%, 323/601), headache (35.6%, 214/601), developmental delay (12.5%, 75/601), neuropathy (10.8%, 65/601), infection (10.7%, 64/601), seizures (10.7%, 64/601), endocrine disorder (6.0%, 36/601), vertigo (5.0%, 30/601), cerebrovascular disease (4.7%, 28/601), changes in sensory acuity or function (4.5%, 27/601), sleep disorder (4.2%, 25/601), movement disorder (3.7%, 22/601), autoimmune disease (2.8%, 17/601), cognitive impairment (2.8%, 17/601), neoplasms (2.7%, 16/601), balance disorder (2.5%, 15/601), congenital malformations (2.2%, 13/601), traumatic brain injury (1.3%, 8/601), altered mental status (0.5%, 3/601), and other (3.3%, 20/601).

The majority of infections (n = 72) were meningitis (66.7%, 48/72) and encephalitis (20.8%, 15/72). There were four cases of brain abscesses, two of meningoencephalitis and a single case each of HTLV-1 associated paraparesis, poliomyelitis, and progressive multifocal leukoencephalopathy. Although data regarding the causative pathogen were limited, bacterial, viral, and fungal pathogens were all represented (Supplemental Table I).

There were 36 patients (2.9%, 36/1224) diagnosed with 42 endocrine conditions. The majority of these were adrenal cortical hypofunction (n = 25) and growth hormone deficiency (n = 11). The remaining conditions were adrenocorticotropic hormone deficiency (n = 3), hypopituitarism (n = 2), and empty sella syndrome (n = 1).

There were 17 patients (1.4%, 17/1224) with neurologic autoimmune diagnoses (n = 19): cerebral vasculitis (n = 5) and demyelinating disease (n = 5), two cases of brain granuloma, and a single case each of autoimmune sensorineural hearing loss, autoimmune encephalitis, leukoencephalopathy, myasthenia gravis, neuritis, neuromyelitis optica, and chronic lymphocytic inflammation. When comparing CVID patients with and without neurologic autoimmune conditions, patients with neurologic autoimmune conditions had a significantly higher rate of other, non-neurologic autoimmune diseases (35.3% [6/17] versus 10.5% [126/1207], p < 0.006). Specific non-neurologic autoimmune conditions reported are shown in Supplemental Table II. Median age at symptom onset and at diagnosis and reported IgG, IgA, and IgM levels were lower in CVID patients with neurologic autoimmune conditions compared with those without (Table 1). Although these differences were not statistically significant, this was not unexpected as the sample sizes were not adequately powered. The following immunosuppressive agents were reportedly used for the treatment of neurologic autoimmune conditions: corticosteroids (n = 12), azathioprine (n = 2), abatacept (n = 1), hydroxychloroquine (n = 1), methotrexate (n = 1), mycophenolate mofetil (n = 1), and sirolimus (n = 1).

Table 1.

Clinical and laboratory characteristics of CVID patients with and without neurologic autoimmune manifestations

	n		Mean [SD]		Median [IQR]
	With	Without	With	Without	With	Without
Age of onset (years)	12	695	11.9 [14.5]	19.1 [18.4]	7.5 [1.5–14.5]	13.8 [3.0–30.0]
Age of diagnosis (years)	14	937	25.5 [20.7]	30.0 [20.2]	17.0 [10.0–46.0]	29.0 [11.5–47.0]
IgG	17	1090	661.5 [572.8]	723.0 [405.9]	587.0 [238.0–865.0]	699.0 [433.0–986.0]
IgA	15	977	30.9 [42.8]	64.8 [182.8]	19.0 [7.0–39.0]	24.0 [7.0–73.0]
IgM	15	976	38.6 [36.8]	67.3 [196.9]	27.0 [12.0–49.0]	34.0 [14.8–72.0]

Neurologic neoplasms were reported in 16 patients: brain lesions (n = 6), pituitary adenoma (n = 3), meningioma (n = 2), benign neoplasm of the brain (n = 2), acoustic neuroma (n = 1), cerebral cyst (n = 1), and pituitary gland neoplasm (n = 1).

In addition to somatic neurologic conditions, CVID patients also had psychiatric diagnoses including depression (n = 233), anxiety (n = 83), ADHD (n = 61), PTSD (n = 6), adjustment disorder (n = 1), bipolar disorder (n = 1), borderline personality disorder (n = 1), eating disorders (n = 1), OCD (n = 1), and panic disorder (n = 1). This highlights the importance of attention to mental health and quality of life for this patient population.

Discussion

To our knowledge, this is the first cross-sectional survey of neurologic conditions and symptoms reported in the USIDNET CVID cohort. Findings suggest that neurologic complications are more common in CVID patients than previously recognized, as at least one neurologic condition or symptom was reported in 49.1% (601/1224) of the cohort. Neurologic infectious, endocrine, and autoimmune conditions previously reported in the literature accounted for only 10.1% (133/1315) of the neurologic complications reported, highlighting the importance of reviewing national cohort data from registries such as the USIDNET to improve our understanding of clinical outcomes in CVID.

The high number of patients with neuropathy and seizures could represent a lost opportunity for diagnosis as it is unclear how many of these patients were evaluated for neurologic infections, autoimmune disease, or nutritional deficiencies that could have been causing these symptoms. Indeed, vitamin E and B12 deficiencies due to CVID-associated autoimmune inflammatory bowel disease and enteropathy have been reported to cause neurologic symptoms in CVID [3, 4].

Review of USIDNET data identified characteristics that could potentially help identify CVID patients with neurologic symptoms due to neurologic autoimmune conditions sooner to prevent diagnostic delay. CVID patients with neurologic autoimmune conditions in the USIDNET cohort had a significantly higher incidence of non-neurologic autoimmune conditions and lower, albeit not significantly, age at symptom onset and immunoglobulin levels. This is of importance as prior reports have emphasized the challenge of distinguishing between neurologic infections and neurologic autoimmune disease and identifying differentiating characteristics would greatly improve care by allowing for earlier diagnosis and treatment [2].

Treatment of neurologic autoimmune disease in the USIDNET CVID cohort consisted of a wider range of immunosuppressive therapy than the corticosteroids and TNFα inhibitors previously reported to provide stabilization or resolution of symptoms, highlighting the need for collaborative investigations to identify optimal treatment strategies for CVID patients with neurologic autoimmune disease [2]. Interestingly, in line with two previously reported CVID cases where IgG-RT prevented recurrences of myelitis [5], we found that IgG levels were lower, albeit not significantly, in CVID patients with neurologic autoimmune conditions despite receiving similar IgG-RT doses, perhaps reflecting a need for higher doses in these patients. Further study is needed to address this question. It also remains to be seen whether increasing doses of IgG-RT would provide protection against neurologic autoimmune manifestations.

This report is subject to limitations as the cohort is limited to patients reported in the USIDNET and data are dependent on physician reporting. Furthermore, few conclusions can be directly drawn from the registry data regarding the prevalence of conditions such as chronic neurologic disorders, headaches, and mood disorders in CVID patients, as these conditions have a high community prevalence in the USA (20%, 14%, and 20%, respectively) [6]. However, reviewing data from national cohorts still provides insight that otherwise could not be obtained for rare primary immunodeficiency conditions.

In summary, neurologic conditions and symptoms in CVID patients occur more commonly than previously recognized. Neurologic symptoms should raise attention to the possibility of underlying autoimmune, infectious, or nutritional causes. The presence of non-neurologic autoimmune diagnoses raises the suspicion for neurologic autoimmune disease. Further investigation is needed to improve the identification and management of neurologic diagnoses in CVID.

Abbreviations

CVID

Common variable immunodeficiency

USIDNET

United States Immunodeficiency Network

IgG-RT

Immunoglobulin replacement therapy