What are the symptoms and signs of immune deficiency in individuals of all ages, including those with a history of recurrent infections, autoimmune disorders, or immunosuppressive therapy, such as prednisone (corticosteroid) or azathioprine (immunosuppressant)?

Symptoms and Signs of Immune Deficiency

Suspect immune deficiency when patients present with recurrent sinopulmonary infections (≥8 ear infections, ≥2 serious sinus infections, or ≥2 pneumonias per year), severe bacterial infections requiring IV antibiotics, infections with opportunistic organisms, failure to thrive, or associated autoimmune/lymphoproliferative complications. 1

Infectious Manifestations

The pattern of infections provides critical clues to the specific type of immune defect:

Recurrent Sinopulmonary Infections

• Recurrent bacterial infections of the sinuses, ears, and lungs are the hallmark of antibody deficiency disorders 2
• Patients experience chronic sinusitis, otitis media, and pneumonia that respond poorly to standard antibiotic therapy 2, 3
• The majority of immunodeficient patients with recurrent sinusitis have defects in humoral immunity, particularly selective IgA deficiency and common variable immunodeficiency 2
• Infections typically involve encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae 2, 4

Severe and Life-Threatening Infections

• Deep-seated abscesses, meningitis, osteomyelitis, or sepsis requiring IV antibiotics indicate possible phagocytic defects or combined immunodeficiency 1
• Infections with organisms of low pathogenicity should alert physicians to probable congenital immune deficiency 2
• Opportunistic infections (Pneumocystis jirovecii, disseminated fungal infections) suggest severe combined immunodeficiency (SCID) or AIDS 2

Pathogen-Specific Patterns by Immune Defect Type

• Antibody deficiencies: Gram-positive bacterial infections, particularly encapsulated organisms 2, 4
• Cellular immune deficiencies: Mycobacterial, protozoal, fungal, viral, and opportunistic bacterial infections 2, 4
• Phagocytic disorders: Staphylococcal, fungal, and gram-negative organisms; deep-seated infections with abscess and granuloma formation 2, 4
• Complement deficiencies: Neisserial infections (recurrent meningococcal meningitis) 2, 4

Non-Infectious Clinical Manifestations

Gastrointestinal Symptoms

• Chronic diarrhea and failure to thrive are prominent features, especially in SCID 5
• Malabsorption and chronic diarrhea may result from giardiasis, which is common in common variable immunodeficiency 3
• Persistent gastrointestinal infections with organisms like Giardia lamblia or Cryptosporidium 4, 3

Dermatologic Findings

• Eczema, particularly in Wiskott-Aldrich syndrome 2
• Persistent thrush (oral candidiasis) or chronic mucocutaneous candidiasis 2, 6
• Skin abscesses, particularly with staphylococcal infections 2, 6
• Unexplained skin rash 6
• Petechiae and purpura (seen in Wiskott-Aldrich syndrome with thrombocytopenia) 2

Autoimmune and Lymphoproliferative Manifestations

• The presence of 2 or more autoimmune disorders should prompt evaluation for primary immunodeficiency 7
• Autoimmune cytopenias (hemolytic anemia, thrombocytopenia, neutropenia) 2
• Inflammatory arthropathies and vasculitides 2
• Lymphadenopathy and hepatosplenomegaly, suggesting immune dysregulation syndromes 2
• Autoimmune manifestations may be the initial clinical presentation before infectious complications become apparent 7

Physical Examination Findings

• Clubbing of digits 2
• Rales and rhonchi on pulmonary examination 2
• Mucous membrane infections 2
• Oculocutaneous telangiectasia (ataxia-telangiectasia) 2
• Abnormal facies and cardiac disease (DiGeorge syndrome) 2
• Delayed separation of umbilical cord and poor wound healing (leukocyte adhesion deficiency) 2

Age-Specific Considerations

Infants and Young Children

• In infants less than 2 years of age with recurrent and life-threatening infections, pursue immunodeficiency evaluation expeditiously 2
• Failure to thrive with chronic diarrhea 5, 6
• Disseminated infections following live vaccine administration 5, 4
• Hypocalcemic seizures (DiGeorge syndrome) 2
• Many states now screen newborns for SCID, which may detect severe immunodeficiencies early 2

Adults

• Recurrent sinopulmonary infections despite aggressive medical management 2
• Late-onset presentations of common variable immunodeficiency 8, 3
• Development of bronchiectasis from chronic respiratory infections 8

Warning Signs Requiring Immediate Evaluation

"Red flags" that mandate immunodeficiency workup include: 6, 9

• Recurrent invasive infections
• Infections with atypical pathogens
• Partial response to antibiotic treatment with frequent antibiotic use
• Failure to thrive
• Chronic diarrhea and persistent fungal infections
• Family history of immunodeficiency or unexplained early childhood deaths 2, 6

Secondary Immunodeficiency Considerations

Physicians must distinguish primary from secondary immunodeficiency by evaluating: 2

• Immunosuppressive medications (corticosteroids like prednisone suppress immune function and increase infection risk with all pathogens) 10
• Azathioprine causes immunosuppression through suppression of cell-mediated immunity and antibody production 11
• HIV infection or AIDS 2
• Malnutrition, protein-losing disorders 2
• Malignancies, particularly hematologic 2

Critical Pitfalls to Avoid

• Do not dismiss recurrent infections as "normal childhood illnesses" when frequency and severity exceed expected patterns 1, 6
• Do not delay evaluation in therapy-refractory sinusitis; 10% may have common variable immunodeficiency and 6% may have IgA deficiency 2
• Do not overlook autoimmune manifestations as potential presenting features of immunodeficiency 7
• In suspected SCID, do not wait for genetic confirmation before initiating protective measures and referral for hematopoietic stem cell transplantation 5