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Primary Immune Deficiency (PID)

About PID

PID is a class of inherited disorders of the immune system that predispose individuals to an increased rate and severity of infection, immune dysregulation with autoimmune disease and malignancy. A high rate of comorbidities can occur with PID, including pulmonary diseases, rheumatological diseases, congestive heart failure, renal failure and autoimmune disease.

Infections can occur in any part of the body, including the skin, sinuses, throat, ears, lungs, brain or spinal cord, urinary or intestinal tracts.

Infections may be characterized as repetitious, difficult to solve or unusually severe.

There are more than 400 primary immunodeficiencies recognized by the International Union of Immunological Societies, and according to the NIH there are approximately 500,000 people affected in the United States.

What are the symptoms of PID?

Individuals with PID are predisposed to severe and frequent infections

  • Typical infections include those of the sinuses, ears, and lungs
  • Infections can lead to lung damage and shorten lifespan

PID, particularly CVID, is also associated with: 

  • Immune dysregulation and autoimmune disease
    • Autoimmune complications contribute to morbidity/mortality
    • Autoimmune hematologic complications often present as  Immune Thrombocytopenia Purpura (ITP) and Autoimmune Hemolytic Anemia (AIHA)
  • Malignancy

PIDs may present as routine infections and go undetected in the primary care setting

  • PID is underdiagnosed and associated with long diagnostic delays
    • The time to diagnosis following symptom onset is on average on average 12.4 years
How is PID Treated?
According to AAAAI Working Group Update on the use of immunoglobulins in human disease:
  • Ig therapy (IV or SC) is required for patients with PID characterized by impaired antibody production, usually accompanied by recurrent or unusually severe infection
  • Mandatory for patients with severe PIDs that directly impact B-cell function and antibody production
  • Increasingly seen as important in other PIDs in which antibody or B-cell dysfunction is implicated but may not be as apparent in conventional testing
According to AAAAI, ACAAI and JCAAI: Practice Parameters (2015):
  • Ig therapy is indicated for all PID disorders with significantly impaired antibody production
  • Patients receiving Ig therapy should have regular monitoring of IgG trough levels, blood cell counts, and serum chemistry
Physicians should consider evaluating for PID in patients who exhibit two or more of these warning signs.
Pediatric Patients

  1. Four or more new ear infections within 1 year
  2. Two or more serious sinus infections within 1 year
  3. Two or more months on antibiotics with little effect
  4. Two or more episodes of pneumonia within 1 year
  5. Failure of an infant to gain weight or grow normally
  6. Recurrent deep skin or recurrent organ abscesses
  7. Persistent thrush in mouth or fungal infection on skin
  8. Need for IV antibiotics to clear infections
  9. Two or more deep-seated infections including septicemia
  10. Family history of PID
Adult Patients

  1. Two or more new ear infections within 1 year
  2. Two or more serious sinus infections within 1 year, in the absence of allergy
  3. One episode of pneumonia per year for more than 1 year
  4. Chronic diarrhea with weight loss
  5. Recurrent viral infections (colds, herpes, warts, condyloma)
  6. Recurrent need for IV antibiotics to clear infections
  7. Recurrent deep skin or recurrent organ abscesses
  8. Persistent thrush or fungal infection of the skin or anywhere
  9. Infection with normally harmless tuberculosis-like bacteria
  10. Family history of PID
Guiding Principle Issue Guiding Principle Rationale
Indication IVIg therapy is indicated as replacement therapy for patients with PID characterized by absent or deficient antibody production. This is an FDA-approved indication for IVIg, for which all currently available products are licensed. 
Diagnosis There are a large number of PID diagnoses for which IVIg is indicated and recommended. Many have low total levels of IgG, but some have a normal level with documented specific antibody deficiency.;
Frequency of IVIg treatment IVIg is indicated as continuous replacement therapy for primary immunodeficiency. Treatment should not be interrupted once a definitive diagnosis has been established. 
Dose IVIg is indicated for patients with primary immunodeficiency at a starting dose of 400-600 mg/kg every 3-4 weeks. Less frequent treatment, or use of lower doses, is not substantiated by clinical data.
IgG trough levels IgG trough levels can be useful in some diagnoses to guide care but are NOT useful in many and should NOT be a consideration in access to IVIg therapy
Site of Care The decision to infuse IVIg in a hospital, hospital outpatient, community office, or home based setting must be based upon clinical characteristics of the patient. 
Route Route of immunoglobulin administration must be based upon patient characteristics. The majority of patients are appropriate for intravenous and a subset for subcutaneous therapy.
Product IVIg is not a generic drug and IVIg products are not interchangeable. A specific IVIg product needs to be matched to patient characteristics to protect patient safety. A change of IVIg product should occur only with the active participation of the prescribing physician.

Table adapted from the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma & Immunology


1. Bonilla FA, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. 2005;94:S1-S63. 2. Immune Deficiency Foundation Accessed March 13, 2021. 3. Boyle JM, et al. Population Prevalence of Diagnosed Primary Immunodeficiency Diseases in the United States. J Clin Immunol. 2007;27:497-502. 4. Modell V. The impact of physician education and public awareness on early diagnosis of primary immunodeficiencies.. Immunol Res. 2007;38:43–47. 5. Immune Deficiency Foundation. Primary Immunodeficiency Diseases in America: 2007. The third national survey of patients. Published May 1, 2009 6. Cunningham-Rundles C, et al. J Allergy Clin Immunol. 2004;113(4):747-55. 7. Bousfiha A, et al. J Clin Immunol. 2020;40:66-81. 8. McCusker C et al. Primary Immunodeficiency. Allergy, Asthma Clin Immunol. 2011;7(Suppl 1):S11. 9. Kobrynski  L. Subcutaneous immunoglobulin therapy: a new option for patients with primary immunodeficiency diseases.. Biologics. 2012;6:277–287. 10. Agarwal S et al. Ann Allergy Asthma Immunol. 2019;123(5):454-460. 11. Shapiro RS. Am J Hematol. 2011;86:49–55. 12. Warning Signs of Primary Immunodeficiency for Adults. presented by the Jeffrey Modell Foundation. Warning Signs of PI in adults.pdf. Accessed March 16 2021 13. Perez EE, et al. J Allergy Clin Immunol. 2017;139(3s):S1-S46. 14 .Bonilla FA, et al. J Allergy Clin Immunol. 2015;136(5):1186-205.e1-78.

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