Common Variable Immunodeficiency: Symptoms, Types, Causes and Treatment

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency in adults, yet it remains underdiagnosed and misunderstood due to its heterogeneity and complexity. People living with CVID experience a range of symptoms, which can affect not only their immune system’s ability to fight infections but also other organ systems through autoimmune and inflammatory processes. In this article, we’ll break down the core aspects of CVID—exploring its symptoms, the recognized types, underlying causes, and available treatments. Whether you’re a patient, caregiver, or healthcare professional, this comprehensive guide will help you navigate the landscape of CVID with clarity and depth.

Symptoms of Common Variable Immunodeficiency

CVID doesn’t present the same way in everyone; its symptoms can be subtle or severe, intermittent or chronic. Understanding the various manifestations is crucial for early diagnosis and effective management.

Symptom	Description	Frequency/Impact	Source(s)
Infections	Recurrent respiratory (sinusitis, pneumonia), GI infections	Most common, significant morbidity	1 2 12
Autoimmunity	Thrombocytopenia, hemolytic anemia, others	10–33% of patients	4 5 8 15
GI Symptoms	Diarrhea, bloating, “celiac-like” disease	26–46% of patients	3 8 12
Lymphoproliferation	Enlarged lymph nodes, splenomegaly	20–48% of patients	8 9 12
Chronic Lung Disease	Bronchiectasis, interstitial lung disease	14–30% of patients	1 8 12
Granulomas	Sarcoid-like lesions in organs	5–10% of patients	5 8
Malignancy	Lymphoma, other cancers	6–16% of patients	5 8 12

Table 1: Key Symptoms

Infections: The Hallmark of CVID

Infections, especially of the upper and lower respiratory tract (sinusitis, bronchitis, pneumonia), are the most frequent initial and ongoing problem for people with CVID. Patients may also experience recurrent or chronic gastrointestinal infections, presenting as diarrhea, bloating, or abdominal pain. Infections are often caused by common bacteria like Streptococcus pneumoniae and Haemophilus influenzae, but persistent or unusual infections can also occur 1 2 12.

Autoimmune and Hematologic Manifestations

A paradox of CVID is the frequent development of autoimmune diseases, despite an overall weakened immune response. The most common are immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA), but patients might also develop rheumatoid arthritis or other autoimmune conditions 4 5 8 15. These can precede, coincide with, or follow the diagnosis of CVID.

Gastrointestinal and Hepatic Symptoms

Gastrointestinal symptoms, such as chronic diarrhea, abdominal discomfort, and malabsorption, are very common. Many patients show “celiac-like” histopathology with increased intraepithelial lymphocytes, but without classic celiac disease markers 3 8. Liver involvement may occur as granulomas or nodular regenerative hyperplasia 8.

Lymphoproliferation, Lung Disease, and Granulomas

Enlarged lymph nodes (lymphadenopathy), spleen (splenomegaly), and chronic lung conditions like bronchiectasis or interstitial lung disease are frequent non-infectious complications 8 12. Additionally, 5–10% of patients develop granulomatous lesions—sarcoid-like masses that can affect the lungs, liver, skin, or other organs 5 8.

Malignancy Risk

CVID is associated with an increased risk of lymphoma (especially B-cell types) and other cancers, affecting up to 16% of patients in some cohorts 5 8 12. Vigilant screening is important, as these complications can significantly impact prognosis.

Types of Common Variable Immunodeficiency

CVID is not a single disease but a spectrum of disorders with varying clinical and immunological features. Recognizing the subtypes helps tailor management and anticipate complications.

Type/Group	Defining Features	Clinical Relevance	Source(s)
Infection-only	Recurrent infections, few/no other complications	Best prognosis	2 12 14
Autoimmune	Presence of autoimmune diseases	Increased morbidity	4 8 12 15
Lymphoproliferative	Enlarged nodes, spleen, non-malignant growths	Linked to organ damage	8 9 12
Granulomatous	Granuloma formation in organs	May mimic sarcoidosis	5 8 12
Malignant	Development of lymphoma/cancers	Worse survival	8 12
Immunological Subtypes	Defects in memory B cells, switched B cells	Guides prognosis & therapy	2 7 14

Table 2: CVID Types

Clinical Phenotypes

Cohort studies have shown that patients can be grouped based on their dominant complications:

• Infection-only phenotype: These patients experience mostly recurrent infections without major immune dysregulation. They tend to have the best outcomes 2 12 14.
• Autoimmune/Inflammatory phenotype: Marked by the presence of autoimmune diseases, chronic lung or GI inflammation, often with increased morbidity 4 8 15.
• Lymphoproliferative phenotype: Characterized by persistent lymphadenopathy or splenomegaly, sometimes progressing to malignancy 8 9 12.
• Granulomatous phenotype: A subset develops granulomas in organs, which can be mistaken for sarcoidosis and may require complex management 5 8 12.
• Malignant phenotype: Development of lymphoma or other cancers, associated with the highest risk of mortality 8 12.

Immunological Classification

CVID can also be classified by laboratory findings, particularly B-cell subpopulations:

• Switched memory B cell deficiency is a hallmark in many patients and correlates with more severe disease, persistent infections, and risk of autoimmunity 2 7 14.
• Other immunophenotypic variants involve abnormalities in T cells, antigen-presenting cells, or unique molecular markers 2 9 14.

Why Classification Matters

Identifying the type of CVID in a patient guides prognostication, surveillance, and therapeutic choices. For example, those with autoimmune or granulomatous disease often need immunosuppression in addition to immunoglobulin replacement 4 5 8.

Causes of Common Variable Immunodeficiency

CVID’s roots are complex, involving both genetic and environmental factors, and in most cases, a definitive cause remains elusive.

Cause Type	Details/Genes Involved	Prevalence/Significance	Source(s)
Genetic (Monogenic)	Mutations in NFKB1, TNFRSF13B, CTLA4, LRBA, others	2–30% of cases, variable by cohort	6 9 10 11
Complex/Polygenic	Multiple genetic variants, gene-environment	Likely majority, variable penetrance	6 10
Immunological Defect	Impaired B-cell differentiation, antibody production	Universal in CVID	2 7 9
Unknown/Idiopathic	No identifiable cause	Most cases	2 7

Table 3: Causes of CVID

Genetic Causes

While CVID is sometimes considered a monogenic disorder, only about 2–30% of cases (depending on the cohort and depth of genetic testing) have identifiable single-gene mutations. The most common genes implicated include:

• NFKB1: The most frequent monogenic cause, leading to defects in B-cell differentiation 9 11.
• TNFRSF13B (TACI), CTLA4, LRBA, PIK3R1, and others: Each causes a unique subset of CVID-like disease, often with specific clinical features 6 9 10.

Complex and Oligogenic Inheritance

Most CVID cases arise from more complex inheritance patterns, possibly involving multiple genes, intermediate penetrance, or environmental triggers 6 10. Family studies have shown variable expression even among individuals carrying the same mutation.

Immunological Mechanisms

The central defect in CVID is a failure of B lymphocytes to mature into antibody-producing plasma cells, resulting in low levels of immunoglobulins (IgG, often IgA and/or IgM) and poor vaccine responses. T cell and antigen-presenting cell dysfunction are also commonly observed, which explains the wide range of symptoms and complications 2 7 9.

Environmental and Idiopathic Factors

In many patients, no clear genetic or environmental cause is found. Diagnosis is made by exclusion—ruling out other causes of low immunoglobulins and recurrent infection 2 7.

Treatment of Common Variable Immunodeficiency

Management of CVID is multifaceted and tailored to each patient’s clinical presentation, aiming to prevent infections, control autoimmune complications, and monitor for malignancy.

Treatment	Purpose/Approach	Common Use Cases	Source(s)
Immunoglobulin Replacement	Restores antibody levels, prevents infections	Universal, life-long therapy	13 14 16
Antibiotics	Treat/prevent acute and chronic infections	Frequent infections, exacerbations	1 2 16
Immunosuppressants	Control autoimmunity, granulomatous disease	Autoimmune or inflammatory complications	4 5 8 16
Hematopoietic Stem Cell Transplant	Experimental/rare; for severe or refractory cases	Select patients with severe disease	16
Surveillance	Early detection of complications/cancers	All patients	8 12 16

Table 4: CVID Treatments

Immunoglobulin Replacement Therapy

The cornerstone of CVID treatment is regular immunoglobulin (Ig) replacement, administered intravenously or subcutaneously. This therapy reduces the frequency and severity of infections, improves quality of life, and may decrease the risk of some complications 13 14 16. Optimal dosing is individualized based on infection control rather than targeting a specific IgG level 13.

Antibiotics

Patients often require prompt antibiotics for acute infections. In some cases, long-term prophylactic antibiotics are used for those with frequent infections or structural lung damage 1 2 16.

Managing Non-infectious Complications

• Autoimmune diseases may require corticosteroids, immunosuppressants, or other biologics. Intravenous immunoglobulin can help prevent some hematologic autoimmunity, but additional therapies are often needed 4 5 8 15 16.
• Granulomatous disease may be managed with corticosteroids or other immunomodulators, balancing infection risk 5 8 16.
• Malignancy surveillance is essential due to increased lymphoma risk 8 12 16.

Advanced and Supportive Therapies

In rare, severe, or refractory cases, hematopoietic stem cell transplantation (HSCT) has been attempted, but with variable outcomes and significant risks 16. Supportive care—including vaccinations (non-live), pulmonary rehabilitation, and nutritional support—is also important.

Monitoring and Individualization

Given the variability of CVID, regular monitoring for infections, autoimmunity, organ involvement, and malignancy is crucial 8 12 16. Treatment plans should adapt over time to the patient’s evolving clinical picture.

Conclusion

Common variable immunodeficiency is a complex, multifaceted disorder that can present in myriad ways and affect nearly every organ system. Early recognition and individualized management are essential to improving outcomes. Here’s a recap of the core points:

• CVID manifests with recurrent infections, autoimmune complications, GI/lung involvement, lymphoproliferation, granulomas, and increased cancer risk 1 2 5 8 12.
• It is not a single disease, but a collection of clinical and immunological phenotypes, each with unique challenges and prognoses 2 8 12.
• While some monogenic causes are known (notably NFKB1 and others), most cases are due to complex, sometimes polygenic, and often still unknown mechanisms 6 9 10.
• Treatment revolves around immunoglobulin replacement, prompt infection control, immunosuppression for non-infectious complications, and vigilant monitoring for malignancy 13 14 16.
• Individualized care, lifelong surveillance, and patient education are vital for optimizing health and quality of life.

CVID remains a diagnostic and therapeutic challenge, but ongoing research is illuminating its mechanisms and paving the way for better-targeted therapies. Whether you are living with CVID or involved in its management, staying informed and proactive makes all the difference.