Primary Immunodeficiency

A group of rare genetic disorders causing increased susceptibility to infections due to immune system defects

Table of Contents

Overview

Primary immunodeficiency diseases (PIDs) are a group of more than 450 rare, chronic disorders in which part of the body's immune system is missing or functions improperly. Also known as inborn errors of immunity, these conditions are typically caused by genetic defects that affect the development or function of immune cells. PIDs affect an estimated 1 in 1,200 people worldwide, though many cases remain undiagnosed.

Unlike secondary immunodeficiencies caused by external factors such as medications, infections, or environmental conditions, primary immunodeficiencies are present from birth due to genetic mutations. These disorders can affect various components of the immune system, including B cells (which produce antibodies), T cells (which coordinate immune responses), natural killer cells, phagocytes, and the complement system.

The severity of primary immunodeficiency varies widely, from mild conditions that may not be diagnosed until adulthood to severe combined immunodeficiency (SCID) that can be life-threatening in infancy without treatment. Early recognition and appropriate management can significantly improve outcomes and quality of life for patients with PIDs. Advances in genetic testing, immunoglobulin replacement therapy, and stem cell transplantation have revolutionized treatment options for these conditions.

Symptoms

The symptoms of primary immunodeficiency vary depending on which part of the immune system is affected and the severity of the deficiency. The hallmark of PIDs is increased susceptibility to infections, but symptoms can be subtle and may develop gradually over time.

Primary Symptoms

  • Cough - persistent or recurrent, often due to respiratory infections
  • Fatigue - chronic tiredness due to frequent infections and immune system stress
  • Decreased appetite - often associated with chronic illness and infections
  • Frontal headache - may result from sinus infections or intracranial complications
  • Arm stiffness or tightness - can occur with certain autoimmune manifestations

Infection-Related Symptoms

  • Recurrent bacterial, viral, fungal, or parasitic infections
  • Pneumonia or bronchitis occurring multiple times per year
  • Chronic sinus or ear infections
  • Severe or unusual infections that don't respond to standard treatment
  • Infections with opportunistic organisms
  • Slow healing of cuts and wounds

Autoimmune and Inflammatory Symptoms

  • Autoimmune diseases (rheumatoid arthritis, lupus, inflammatory bowel disease)
  • Chronic diarrhea or malabsorption
  • Skin rashes or eczema
  • Joint pain and swelling
  • Enlarged lymph nodes, spleen, or liver
  • Blood disorders (anemia, thrombocytopenia)

Growth and Development Issues

  • Failure to thrive in children
  • Delayed growth and development
  • Chronic weight loss
  • Developmental delays
  • Poor response to vaccines

Warning Signs: The Jeffrey Modell Foundation has identified 10 warning signs of primary immunodeficiency, including eight or more new ear infections within one year, two or more serious sinus infections within one year, and failure of an infant to gain weight or grow normally.

Causes

Primary immunodeficiency diseases are caused by genetic defects that affect the development, function, or regulation of immune system components. These genetic mutations can be inherited or occur spontaneously during development.

Genetic Basis

More than 450 different genes have been identified as causes of primary immunodeficiency. These genes encode proteins essential for immune cell development, signaling, activation, or function. Defects in these genes lead to various types of immune dysfunction.

Major Categories of PIDs

  • Antibody deficiencies (Humoral): Affect B cell function and antibody production (Common Variable Immunodeficiency, X-linked Agammaglobulinemia)
  • T cell deficiencies (Cellular): Impair T cell development or function (Severe Combined Immunodeficiency, DiGeorge syndrome)
  • Combined immunodeficiencies: Affect both B and T cells (SCID, Wiskott-Aldrich syndrome)
  • Phagocyte disorders: Impair neutrophil or macrophage function (Chronic Granulomatous Disease)
  • Complement deficiencies: Affect complement system proteins
  • Innate immunity defects: Affect pattern recognition or interferon pathways

Inheritance Patterns

X-linked Recessive

Primarily affects males (X-linked Agammaglobulinemia, X-linked SCID). Females are typically carriers but may have mild symptoms.

Autosomal Recessive

Requires mutations from both parents (Adenosine Deaminase deficiency SCID). Parents are usually carriers without symptoms.

Autosomal Dominant

One mutated gene from either parent can cause disease (some forms of CVID). Variable penetrance and expression are common.

De Novo Mutations

New mutations not inherited from parents (some cases of SCID). These account for about 25% of all PID cases.

Risk Factors

The primary risk factor for developing a primary immunodeficiency is having a genetic predisposition. However, several factors can influence the likelihood of diagnosis and disease severity.

Genetic Risk Factors

  • Family history of primary immunodeficiency
  • Family history of recurrent infections
  • Parental consanguinity (increased risk of recessive disorders)
  • Male gender (for X-linked disorders)
  • Ethnic background (certain populations have higher prevalence of specific PIDs)
  • Previous affected siblings

Clinical Indicators

  • Recurrent infections in infancy or childhood
  • Failure to thrive despite adequate nutrition
  • Unusual or severe infections with common pathogens
  • Poor response to standard antimicrobial treatments
  • Autoimmune diseases at a young age
  • Adverse reactions to live vaccines

Newborn Screening

Many states now include SCID in newborn screening programs, allowing for early detection before symptoms develop. This has dramatically improved outcomes for affected infants.

Diagnosis

Diagnosing primary immunodeficiency requires a high index of suspicion, detailed clinical history, and comprehensive immunologic evaluation. Early diagnosis is crucial for optimal outcomes and genetic counseling.

Initial Assessment

Clinical History

  • Detailed infection history (frequency, severity, pathogens)
  • Family history of immunodeficiency or recurrent infections
  • Growth and development patterns
  • Autoimmune manifestations
  • Response to vaccines and treatments

Physical Examination

  • Growth parameters and failure to thrive
  • Lymph node, spleen, and liver examination
  • Skin findings (rashes, infections, warts)
  • Evidence of chronic infections
  • Developmental abnormalities

Laboratory Testing

Initial Screening Tests

  • Complete blood count with differential
  • Immunoglobulin levels (IgG, IgA, IgM, IgE)
  • Specific antibody responses to vaccines
  • Complement levels (CH50, AH50)
  • T, B, and NK cell enumeration by flow cytometry

Advanced Testing

  • T cell proliferation assays
  • Neutrophil function tests (oxidative burst)
  • Genetic testing and whole exome sequencing
  • Enzyme activity assays (ADA, PNP)
  • Protein expression studies

Newborn Screening

SCID Screening: T cell receptor excision circles (TRECs) are measured in dried blood spots to identify severe combined immunodeficiency before symptoms develop.

Treatment Options

Treatment of primary immunodeficiency focuses on replacing missing immune components, preventing infections, and managing complications. The approach varies significantly based on the specific type and severity of the immunodeficiency.

Immunoglobulin Replacement Therapy

Intravenous Immunoglobulin (IVIG)

Regular infusions of pooled antibodies from healthy donors to replace missing antibodies in patients with humoral immunodeficiencies.

  • Typical dose: 400-600 mg/kg every 3-4 weeks
  • Administered in hospital or infusion centers
  • Significantly reduces infection frequency and severity
  • Requires IV access and several hours per infusion

Subcutaneous Immunoglobulin (SCIG)

Self-administered injections under the skin, providing more steady antibody levels and greater convenience.

  • Weekly doses of 100-150 mg/kg
  • Can be administered at home
  • Fewer systemic side effects
  • Better quality of life for many patients

Antimicrobial Prophylaxis

Bacterial Prophylaxis

  • Trimethoprim-sulfamethoxazole for Pneumocystis prevention
  • Azithromycin for respiratory bacterial infections
  • Targeted antibiotics based on specific deficiencies

Antifungal Prophylaxis

  • Fluconazole or itraconazole for systemic fungal infections
  • Particularly important in T cell deficiencies
  • Regular monitoring for drug interactions

Antiviral Prophylaxis

  • Acyclovir for herpes virus prevention
  • Immunoglobulin preparations with specific antibodies
  • Avoid live viral vaccines

Definitive Treatments

Hematopoietic Stem Cell Transplantation (HSCT)

Potentially curative treatment for severe forms of PID, particularly SCID and certain combined immunodeficiencies.

  • Best outcomes when performed early, before infections develop
  • Matched sibling donors preferred, but unrelated donors increasingly used
  • Success rates >90% for SCID when performed in first 3.5 months of life
  • Requires pre-transplant conditioning in some cases

Gene Therapy

Emerging treatment that introduces functional genes into patient's cells to correct the underlying defect.

  • Approved for ADA-SCID and X-linked SCID
  • Uses patient's own stem cells modified with viral vectors
  • Avoids need for chemotherapy conditioning
  • Long-term follow-up ongoing to assess safety and efficacy

Supportive Care

  • Nutritional support and management of malabsorption
  • Physical therapy for growth and development
  • Pulmonary care and chest physiotherapy
  • Management of autoimmune complications
  • Psychological support for patients and families
  • Regular monitoring for complications and treatment response

Prevention

While primary immunodeficiencies cannot be prevented as they are genetic conditions, early detection through screening and genetic counseling can help families make informed decisions and ensure prompt treatment.

Genetic Counseling and Testing

Families with a history of primary immunodeficiency should seek genetic counseling to:

  • Understand inheritance patterns and recurrence risks
  • Discuss carrier testing for family members
  • Learn about prenatal and preimplantation genetic testing options
  • Make informed family planning decisions
  • Understand implications for other family members

Infection Prevention Strategies

  • Maintain excellent hygiene practices
  • Avoid crowds during cold and flu seasons
  • Practice food safety to prevent foodborne illnesses
  • Avoid contact with individuals with active infections
  • Stay up to date with recommended (non-live) vaccines
  • Consider prophylactic antimicrobials as prescribed
  • Regular hand washing and use of alcohol-based sanitizers

Early Detection Programs

Newborn Screening

SCID screening using TREC analysis is now available in many regions, allowing for early detection and treatment before life-threatening infections occur.

Family Screening

Siblings and other family members of diagnosed patients should be evaluated for subclinical disease or carrier status.

When to See a Doctor

Early recognition of primary immunodeficiency is crucial for optimal outcomes. Parents and healthcare providers should be alert to patterns of recurrent or severe infections that may indicate an underlying immune defect.

Jeffrey Modell Foundation Warning Signs:

  • Eight or more new ear infections within one year
  • Two or more serious sinus infections within one year
  • Two or more months on antibiotics with little effect
  • Two or more pneumonias within one year
  • Failure of an infant to gain weight or grow normally
  • Recurrent, deep skin or organ abscesses
  • Persistent thrush in mouth or fungal infection on skin
  • Need for intravenous antibiotics to clear infections
  • Two or more deep-seated infections including septicemia
  • A family history of primary immunodeficiency

Emergency Situations

Seek immediate medical attention for:

  • Signs of severe infection (high fever, difficulty breathing, altered mental status)
  • Severe diarrhea with dehydration
  • Unusual or opportunistic infections
  • Failure to respond to standard antimicrobial treatments
  • Signs of graft-versus-host disease in transplant patients

When to See an Immunologist

Referral to a clinical immunologist should be considered when patients meet warning signs criteria or have:

  • Recurrent infections with unusual organisms
  • Poor response to standard treatments
  • Family history of immunodeficiency
  • Autoimmune diseases at a young age
  • Adverse reactions to live vaccines

Frequently Asked Questions

Are primary immunodeficiencies contagious?

No, primary immunodeficiencies are genetic conditions and cannot be transmitted from person to person. However, people with PIDs are more susceptible to catching infections from others.

Can people with primary immunodeficiency receive vaccines?

Most vaccines are safe, but live vaccines (such as MMR, varicella, rotavirus) are generally contraindicated. Inactivated vaccines are recommended and may require additional doses or boosters.

What is the prognosis for primary immunodeficiency?

Prognosis varies widely depending on the specific type and severity. With early diagnosis and appropriate treatment, many people with PIDs can live relatively normal lives. Some severe forms may be curable with stem cell transplantation.

How is primary immunodeficiency different from allergies?

Allergies involve an overactive immune response to harmless substances, while primary immunodeficiencies involve an underactive or absent immune response. Some PIDs can be associated with allergic symptoms, but the underlying mechanisms are different.

Can adults develop primary immunodeficiency?

While PIDs are present from birth, many are not diagnosed until adulthood due to mild symptoms or late onset of manifestations. Common variable immunodeficiency, for example, often isn't diagnosed until the 20s or 30s.

Is genetic testing always necessary?

While genetic testing can provide definitive diagnosis and guide treatment decisions, not all patients require it immediately. Clinical diagnosis based on immunologic testing may be sufficient for treatment decisions in some cases.

References

  1. Tangye SG, et al. Human inborn errors of immunity: 2022 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2022;42(7):1473-1507.
  2. Picard C, et al. International Union of Immunological Societies: 2017 Primary Immunodeficiencies Committee Report on Inborn Errors of Immunity. J Clin Immunol. 2018;38(1):96-128.
  3. Bonilla FA, et al. International Consensus Document (ICON): Common Variable Immunodeficiency Disorders. J Allergy Clin Immunol Pract. 2016;4(1):38-59.
  4. Jeffrey Modell Foundation. 10 Warning Signs of Primary Immunodeficiency. 2023.
  5. Buckley RH. Transplantation of hematopoietic stem cells in human severe combined immunodeficiency: longterm outcomes. Immunol Res. 2011;49(1-3):25-43.
  6. European Society for Primary Immunodeficiencies. Diagnostic and Clinical Care Guidelines. 2023.