Complications of untreated hypogammaglobulinemia in a patient with common variable immunodeficiency – A case report

Abstract

Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder characterized by decreased or undetectable serum levels of immunoglobulin G (IgG), decreased levels of IgA isotypes, and poor specific antibody production in response to vaccines and pathogens. Owing to hypogammaglobulinemia, patients have increased susceptibility to infections and a higher risk of malignancies. Here we present a case study of patient with a diagnosis of CVID, who refused immunoglobulin replacement therapy despite plenty of complications. Patient suffered from recurrent respiratory and digestive tract infections, diarrhea, malnutrition, infection of the central nervous system, and autoimmune complications. The complications of untreated hypogammaglobulinemia eventually led to the death of the patient at the age of 63 years. Patients with CVID have an increased susceptibility to chronic infections and subsequent complications; hence, proper treatment with immunoglobulin replacement therapy should be administered. Owing to the increased risk of autoimmunity and malignancy, regular surveillance should be conducted in patients with CVID. Understanding the natural history of untreated hypogammaglobulinemia emphasizes the need for early diagnosis, appropriate treatment, and vigilant follow-up in patients with CVID.

Introduction

Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder caused by the impairment of B cell differentiation, ¹ which results in decreased or undetectable serum levels of immunoglobulin G, decreased levels of at least one IgA, ² and poor specific antibody production in response to vaccines and pathogens. ³ Patients with hypogammaglobulinemia suffer from recurrent bacterial and viral infections, mainly with sino-pulmonary and gastrointestinal involvement and persistent diarrhea with malnutrition. ⁴ Furthermore, immune dysregulation leads to multiple noninfectious complications, including autoimmunity, ⁵ chronic lung disease, gastrointestinal and liver diseases, and malignancies. With a prevalence of approximately 1:25 000–1:50 000, CVID is the most frequent symptomatic primary immunodeficiency disorder in adults. ⁶ However, CVID is an inherited disease, and its onset may occur at any age, most commonly from 20 to 40 years of age. ⁷

Case report

In this case study, we present a 63-year-old patient with CVID and pernicious anemia who developed multiple immunodeficiency complications. Notably, hypogammaglobulinemia was initially identified at the age of 29 (in 1981), but subsequent immunological surveillance was declined by the patient. Over time, patient experienced recurrent respiratory infections accompanied by diarrhea, as well as infections with Herpes zoster and Giardia lamblia, all managed symptomatically. In 2009, the patient began regular monitoring at the immunology outpatient clinic, leading to the diagnosis of CVID. Laboratory tests conducted over the time are summarized in Tables 1–3. Within lymphocyte subpopulations assessed over the period 2009–2015, a deficiency of helper T lymphocytes (T CD3+CD4+) stands out. However, their count was higher than the exclusion criteria for CVID established by ESID (European Society for Immunodeficiencies) for registry purposes. ⁸ Cytotoxic T lymphocytes (CD3+CD8+) were consistently elevated. We also observed a deficiency in NK (natural killer) cells and B lymphocytes. The B lymphocyte count was insufficient to determine the B lymphocyte subpopulation.

Table 1.

Laboratory analysis of the patient.

	2009	2012	2015	Normal range (unit)
RBC	4.3	5.13	4.35	4.7–6.1 (1012/L)
HBC	14.1	14.2	11.6	14–18 (g/dL)
MCV	100	86	79.8	80–94 (fL)
WBC	4.35	3.83	2.27	4.5–11 (109/L)
Neutrophils	2.4	2.13	0.77	1.9–8 (109/L)
Lypmphocytes	1.32	1.23	1.22	0.9–5 (109/L)
Eosinophils	0.15	0.06	0.04	0.1–0.5 (109/L)
PLT	115	93	52	130–400 (109/L)
Creatinine	0.71	–	0.54	0.7–1.3 (mg/dL)
AST	23	30	44	5–34 (U/L)
ALT	23	34	37	0–55 (U/L)
GGTP	27	65	66	16–64 (U/L)
ALP	82	115	139	40–150 (U/L)
Bilirubin	0.6	0.7	0.51	0.2–1.2 (mg/dL)
Albumin	45	–	27	35–50 (g/L)
TP	55	–	51	64–83 (g/L)
β2mg	–	3.52	3.15	0.97–2.64 (mg/L)
Fe	–	53	33	65–175 (ug/dL)
Ferritin	–	23.96	33.56	21.81–274.66 (ng/mL)
Vitamin B12	161	614	1141	179–1162 (pg/mL)
Ca	–	8.47	8.6	8.9–10 (mg/dL)

RBC, Red Blood Cell Count; HBC, Hemoglobin; MCV, Mean Corpuscular Volume; WBC, White Blood Cell Count; PLT, Platelets; AST, Aspartate transaminase; ALT, Alanine transaminase; GGTP, gamma-glutamyl transferase; ALP, Alkaline phosphatase; TP, total protein; β2mg; beta-2-microglobulin; Fe, ferrum; Ca, Calcium; g, gram; mg, milligram; ug, microgram; ng, nanogram; pg, picogram; L, liter; fL, femtoliter; mL, milliliter; dL, deciliter; U, units. Abnormalities in blood results are bolded. “Abnormalities in blood results are bolded (acording to laboratory range)”.

Table 2.

Serum levels of immunoglobulin of the patient.

	2009	2012	2015	Normal range (g/L)
IgA	<0.03	<0.05	<0.03	0.63–4.84
IgG	<0.21	<1.081	9.68	5.40–20.34
IgM	<0.02	<0.025	<0.05	0.22–2.40

Ig, Immunoglobulin; g, gram; L, liter.

Table 3.

Lymphocyte phenotype of the patient.

	2009		2012		2015
	109/L (normal range)	Percentage % (normal range)	109/L (normal range)	Percentage % (normal range)	109/L (normal range)	Percentage % (normal range)
Lymphocyte (total)	1.64 (0.9–5.0)	-	1.69 (0.9–5.0)	-	1.22 (0.9–5.0)	-
Lymphocyte T CD3+ CD4+	0.25 (0.6–0.98)	15 (43–54)	0.22 (0.43–1.51)	13 (32–67)	0.20 (0.43–1.51)	16 (32–67)
Lymphocyte T CD3+ CD8+	1.30 (0.42–0.66)	79 (28–37)	1.39 (0.10–0.84)	82 (8–40)	0.98 (0.10–0.84)	80 (8–40)
Lymphocyte T CD3+	1.54 (1.0–1.54)	94 (71–79)	1.62 (0.61–2.25)	96 (49–87)	1.17 (0.61–2.25)	96 (49–87)
Lymphocyte B CD19+	0.07 (0.16–0.27)	4 (11–16)	0.03 (0.03–0.41)	2 (6–35)	0.02 (0.03–0.41)	1 (6–35)
Lymphocyte NK CD3–CD56+	0.03 (0.13–0.25)	2 (8–15)	0.03 (0.11–0.65)	2 (6–35)	0.01 (0.11–0.65)	1 (6–35)

L, liter.

Since July 2015, patient exhibited new neurological symptoms, including dysphagia, dysarthria, muscle weakness in the right limbs, balance disturbances, and delusions. Family members reported aggressive and unusual behaviors. Due to general health deterioration, patient eventually agreed to receive intravenous immunoglobulin (IVIG) replacement therapy and to conduct neurological diagnostics. No abnormalities in the cerebrospinal fluid were found; however, hypogammaglobulinemia assessment of oligoclonal bands was unreliable. Magnetic resonance imaging (MRI) of the central nervous system (CNS) revealed subcortical equivocal diffuse infiltrations in both cerebral hemispheres, corresponding to lymphoma (Figure 1(a)–(c)). Spinal cord involvement was also observed at the C7 level (Figure 1(d)). Computed tomography (CT) of the CNS indicated areas of reduced density in the frontal and parietal lobes, potentially related to cerebral microcirculation insufficiency. “Myasthenia gravis” was excluded. During the same month, the patient was admitted to the psychiatric ward due to worsening aggressive behaviors.

Figure 1.

Magnetic resonance imaging (MRI) in August 2015. Diffuse subcortical lesions showed on axial T2 turbo inversion recovery magnitude (TIRM) Dark Fluid MRI scans (A–C). Spinal cord lesion at the level of C7 visible on a sagittal TIRM MRI scan.

In October 2015, the patient was admitted to the Department of Immunology for organ assessment. At that time, the only treatment he was receiving was vitamin B12 injections once a month, without any other medications. The initial physical examination revealed cachexia, hepatomegaly, lung crepitations, and skin scars resulting from a herpes zoster infection. Blood tests (Table 1) and immunological analyses (Tables 2–3) identified several abnormalities. The IgG levels were within the normal range due to immunoglobulin replacement therapy. A chest and abdomen CT scan revealed lung fibrosis, bronchiectasis without intestinal changes. Mediastinal lymph nodes were not enlarged. Additionally, hepato-splenomegaly was observed. Subsequently, the patient was discharged to the Neurosurgical Department to perform a stereotactic biopsy. The histopathological examination of the brain revealed an infection without lymphatic infiltration or neoplastic cells. Subsequently, for further neurological evaluation, the patient was admitted to the Department of Neurology. A CNS MRI showed multifocal abnormalities in the white matter, with no progression compared to the previous MRI, suggesting a viral infection rather than lymphoma. In the differential diagnosis, progressive multifocal leukoencephalitis, Human Immunodeficiency Virus (HIV), and Cytomegalovirus (CMV) infection were considered. Although the serum level of CMV IgG antibodies was elevated, IgM levels remained normal. Both the polyoma JC virus DNA test and HIV screening test were negative results. Unfortunately, before a definitive diagnosis could be established, the patient developed severe pneumonia, leading to acute respiratory failure and eventual death at the age of 63. Remarkably, despite experiencing symptoms for over 30 years, the patient had received only five infusions of intravenous immunoglobulin in replacement therapy.

Discussion

Recurrent infections are the most common symptoms, affecting more than 70% of the patients with CVID. ⁹ Bagheri et.al. analyzed the demographics, health-related parameters, and mortality rate of patients with CVID who were followed up for over 20 years. Patients received regular immunoglobulin replacement therapy at doses of 400–600 mg/kg every 3–4 weeks. Notably, respiratory tract infections emerged as the primary complications and the leading cause of mortality in this group. Although immunoglobulin replacement cannot fully control infectious complications, ¹⁰ current data indicate that it effectively reduces infection risk. ¹¹ Salehzadeh et al. found that IVIG administration led to a decrease in lower respiratory tract infections compared to the pre-IVIG period. ¹²

Patients with CVID face an increased risk of malignancies, primarily lymphomas ⁹ and gastric cancer. ¹ In a study conducted in Italy involving 455 CVID patients, 25% developed malignancies, with lymphoma being the most frequently diagnosed, mainly of B-cell origin. Interestingly, while lymphoma is more common, gastric cancer has a higher mortality rate. ¹³ Another study by Bruns et al. found that among 219 patients, 12.3% were diagnosed with at least one type of cancer, with gastric cancer, non-melanoma, and non-Hodgkin lymphoma being the most frequent types. Immune dysregulation is associated with cancer development in CVID patients. ¹⁴ In Australian cohort, the presence of noninfectious complications was linked to significantly reduced survival. ¹⁵

Previous researches highlights the impact of diagnostic delay in primary immunodeficiencies (PIDs) on mortality risk. ¹⁶ In Polish patients, the median delay before 2000 was 15 years (ranging from 0 to 57), while after 1999, it decreased to 3 years (ranging from 0 to 19). ¹⁷ Longitudinal observations of 72 Iranian patients with CVID revealed that irregular surveillance and improper IVIG administration were associated with higher mortality rates compared to proper management. ¹⁸ Although immunoglobulin replacement therapy effectively prevents recurrent infections, ¹⁹ it does not appear to prevent non-infectious complications. ²⁰ Therefore, further attempts are being made to create protocols for proper patient monitoring. ⁶

Conclusions

Patients with CVID may experience extended symptom-free periods despite their underlying illness. However, complications may arise due to insufficient treatment and lack of proper monitoring. Research from various countries consistently demonstrates that lack of surveillance and improper treatment significantly increases the mortality rate among CVID patients. Therefore, early disease diagnosis and implementation of appropriate treatment are essential.