What are the clinical features of immunodeficiencies?

Clinical Features of Immunodeficiencies

The principal clinical manifestation of immunodeficiency is increased susceptibility to infections that are repetitive, severe, refractory to therapy, and caused by organisms of low virulence, with the specific pattern of infections varying by the type of immune defect. 1

Primary Infectious Manifestations

Recurrent infections are the hallmark presentation, occurring with unusual severity, frequency, and duration compared to immunocompetent individuals. 1 These infections respond poorly to standard antimicrobial therapy and may involve opportunistic pathogens rarely seen in healthy hosts. 1

Infection Patterns by Immunodeficiency Type

Antibody deficiencies (comprising ~50% of all primary immunodeficiencies) present with: 1

• Recurrent sinopulmonary infections with encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae) 1
• Recurrent viral respiratory tract infections 1
• Recurrent gastrointestinal infections 1
• Up to 26% of children >2 years with invasive pneumococcal disease have an identifiable primary immunodeficiency 1

Severe Combined Immunodeficiency (SCID) presents with: 1

• Failure to thrive 1
• Chronic diarrhea 1
• Severe/disseminated infections 1
• Opportunistic infections (Pneumocystis jirovecii pneumonia) 1
• Persistent rash 1
• Abnormal newborn screening results 1

Phagocytic cell defects manifest as: 1

• Chronic Granulomatous Disease (CGD): Deep-seated infections, abscesses with granuloma formation 1
• Leukocyte Adhesion Deficiency (LAD): Recurrent serious bacterial infections, delayed umbilical cord separation, poor wound healing, lack of pus formation 1
• Hyper-IgE Syndrome (HIES): Chronic dermatitis, recurrent lung infections with pneumatoceles, skin infections, bone fragility, failure to shed primary teeth 1

Innate immune defects present with: 1

• NEMO deficiency: Severe bacterial and opportunistic infections, anhidrotic ectodermal dysplasia 1
• IRAK-4 defect: Severe gram-positive bacterial infections in early childhood 1
• Chronic mucocutaneous candidiasis (CMCC): Chronic skin and mucous membrane fungal infections 1
• Herpes simplex encephalitis (HSE): Isolated herpes simplex encephalitis 1

Complement deficiencies cause: 1

• Recurrent bacterial infections with encapsulated organisms 1
• Neisseria species infections (meningococcal, gonococcal) 1

Non-Infectious Manifestations

Autoimmune diseases occur with increased frequency across many immunodeficiencies, arising from the same immunologic defect or dysregulation that predisposes to infection. 1 Common manifestations include: 1

• Autoimmune cytopenias (thrombocytopenia, hemolytic anemia, neutropenia) 1
• Inflammatory arthropathies 1
• Vasculitides 1
• Autoimmunity may be the initial presenting feature before infectious complications become apparent 2

Malignancies develop at higher rates, predominantly: 1

• Hematologic malignancies (lymphoma and leukemia) 1
• Gastric carcinoma (particularly in CVID) 3

Immune dysregulation syndromes present with: 1

• Autoimmunity 1
• Lymphoproliferation 1
• Hemophagocytic lymphohistiocytosis (HLH) 1

Syndrome-Specific Features

Wiskott-Aldrich Syndrome: Thrombocytopenia with bleeding/bruising, eczema, recurrent infections with encapsulated organisms, autoimmunity 1, 4

Ataxia-Telangiectasia: Chronic sinopulmonary disease, cerebellar ataxia, oculocutaneous telangiectasia, malignancy, IgA deficiency 1, 4

DiGeorge Syndrome: Hypocalcemic seizures from hypoparathyroidism, cardiac disease, abnormal facies, infections, abnormal newborn screening 1, 4

Common Variable Immunodeficiency (CVID): Variable reduction in ≥2 major immunoglobulin classes with impaired specific antibody responses, often presenting in adults with diagnostic delay 4, 3, 5

Selective IgA Deficiency: Most common primary immunodeficiency (1:300-700 in white Americans), with >50% remaining asymptomatic; symptomatic patients have recurrent sinopulmonary infections, atopic disease (18-19%), and increased risk of autoimmunity 4, 6

Critical Clinical Pitfalls

Do not dismiss immunodeficiency based on normal appearance between infections - a single severe infection in infancy warrants evaluation, not waiting for recurrence. 7

Document infection details meticulously: Identify specific pathogens, anatomic sites, and treatment responses to distinguish true bacterial infections from viral illnesses or allergic conditions. 1

Exclude secondary causes: Rule out immunosuppression from medications (antiepileptics, gold, penicillamine, hydroxychloroquine, NSAIDs), HIV infection, malnutrition, protein-losing disorders, and anatomic abnormalities before diagnosing primary immunodeficiency. 1, 4

Consider non-immunologic mimics: Allergic inflammation, adenoid hypertrophy, cystic fibrosis, ciliary dyskinesia, and environmental factors (daycare, smoke exposure) can cause recurrent infections without immunodeficiency. 1

Recognize transfusion risks: Patients with very low or absent IgA may develop anti-IgA antibodies, creating anaphylactic risk with blood products. 4

Monitor for progression: 20-25% of patients with partial IgA deficiency progress to complete selective IgA deficiency or evolve into CVID, particularly with family history. 4

Atypical presentations are common: Autoimmune disease, severe atopy, lymphoproliferation, or malignancy may be the initial manifestation before infectious complications, and the presence of ≥2 autoimmune disorders should prompt immunodeficiency evaluation. 8, 2