Disease States: Primary Immune Deficiency Diseases (PIDDs)
By Jean McCaslin, RN IgCN - September 9, 2022

In general, nurses see and treat infectious processes with great frequency. It is ironic though that so many of us are unaware of the existence of Primary Immunodeficiency Disorders. Most hospital exposure is in the treatment of patients with Secondary Immune Deficits. Patients might become immune-compromised from chemotherapy, chronic steroid treatment, treatment with B-cell depleting therapies (e.g., RITUXAN^®, OCREVUS^®, KESIMPTA^®, and others) malnutrition, trauma, or perhaps due to HIV or leukemia to name a few.

There are greater than 400 forms of Primary Immune Deficiency Diseases (PIDDs) recognized by the International Union of Immunological Societies.¹ These rare genetic diseases are chronic, at times debilitating, and often costly per the National Institute of Health (NIH).¹ PIDDs are also known as Inborn Errors of Immunity (IEI). These can affect anyone regardless of gender, age, or ethnicity. They share a common thread; part of the immune system is missing or not functioning properly. This leads to the hallmark of increased susceptibility to infection; it could involve the sinuses, lungs, skin, ears, throat, spinal cord, brain, urinary tract or intestinal tracts. Physical exam may also identify signs of a PIDD including enlargement of lymph nodes, the liver or spleen. For some, inflammatory bowel disease, autoimmune symptoms or blood vessel inflammation could indicate a PIDD.

Initial Presentation Statistics: In an April 2022 publication of the Journal of Allergy and Clinical Immunology, these statistics were noted upon analysis of 16,486 patients:

• 68% presented with infection only, 9% with immune dysregulation only and 9% with a combination of both.
• 12% presented with syndromic features, 4% had lab abnormalities only, 1.5% were diagnosed due to family history only and 0.8% presented with malignancy.

Age and Gender: In the same study, these age-related observations were made:

• 2/3 of patients with IEI presented before age 6 and 1/4 developed initial symptoms as adults.
• When immune dysregulation was the first reported manifestation, the average age reported was between ages 6 and 25. In this category, up until age 10, there was a male predominance; then it reversed to female predominance after the age of 40.
• When infection was the first reported manifestation, the average age noted was greater than 30 years of age.
• The most known types of PIDD involve B-cell/antibody deficiencies affecting humoral immunity. These make up approximately 65% of all PIDDs.

PIDD Mechanisms by Prevalence: Per JMF 2017 survey:

• Antibody Deficiencies (59.6%): The quantity or quality of antibodies produced are involved. e.g., Agammaglobulinemia, Common Variable Immune Deficiency, IgG Subclass Deficiency, Selective IgA Deficiency.
• Cellular or Combined Immunodeficiencies (24.9%): The T-cells or T and B-cells are both involved. e.g., Severe Combined Immune Deficiency (SCID), Wiskott-Aldrich Syndrome (WAS), Hyper IgM Syndrome.
• Innate Immune Disorders (6.5%): Innate components are involved. e.g., Chronic Granulomatous Disease (CGD), Hyper IgE Syndrome, Complement Deficiencies, Innate Immune Defects, Phagocytic Cell Disorders.
• Immune Dysregulation (2.2%): The regulation of the immune response is involved. e.g., Enteropathy, X-linked syndrome, Polyendocrinopathy.
• Other (6.8%)

Work-up for PIDDs

Dependent on the segment of the immune cascade affected and based on symptoms, testing is variable and can be quite confusing; it is uniquely specialized. The complexity of the immune system can make the identification and treatment of immune disorders very difficult. Patients frequently are treated by various generalists and specialists before these disorders are diagnosed as complete immunological testing may not have been deemed necessary.

When a PIDD is suspected, a CBC with diff, total serum IgG and IgG-subclasses is ordered. Some physicians will investigate pneumococcal titers and titers from early childhood vaccines.

Clinical History: The hallmark of PIDDs is recurrent infection. Some infections may present as unusual, recurrent, severe, persistent, or familial. They may be bacterial, viral, or fungal infections of the:

• Eye: Conjunctivitis
• Ear: Otitis Media
• Sinuses: Rhinitis, Acute sinusitis
• Throat: Pharyngitis, Tonsillitis, Adenitis
• Lungs: Croup, Acute Bronchitis, Pneumonia; Fungal in CGD
• Skin: as in CGD
• Brain: Meningitis
• Bone: CGD
• GI Tract: Severe diarrhea
• Surgical Sites: Poor healing, purulent drainage

In babies and toddlers, many symptoms of PIDD may be dismissed as common to their age group or due to repetitive exposure at childcare facilities. Oftentimes in children, the diagnosis of PIDDs is delayed or misidentified as another disorder. Signs of concern include:

• Failure to thrive
• Prolonged diarrhea, frequent regurgitation
• Baby formula intolerance
• Acute or chronic dehydration
• Frequent low-grade or high-grade fevers
• Recurrent Otitis Media with hearing loss
• Recurrent urinary tract infections
• Prolonged cough

Family History and Genetic Testing: Some PIDDs are X-linked; others may be more elusive to detect a genetic link. Sometimes disorders are identified by family history, which triggers laboratory investigation of multiple family members with similar manifestations.

Laboratory Testing: Most commonly, serum electrophoresis is used to measure IgG levels and Ig subclasses. Protective titers of past vaccines are assessed as well as pneumococcal titers. Newborns are now screened for SCIDs in all 50 states.

Vaccine Challenge: When pneumococcal titers show poor protection, a vaccine may be trialed to see if the patient can produce increased protective levels. Oftentimes diphtheria and tetanus vaccine challenges are also done; in some cases, Haemophilus influenzae type b (Hib) challenge as well.

For this blog post, a partial overview of some PIDDs involving Antibody Deficiency and Cellular or Combined Immunodeficiencies is provided. Many of these disorders are treated with IgG replacement. These disorders are quite complex; for full information, it is best to research a particular disorder of interest more fully.

Types of PIDDs

Antibody Deficiency Disorders

IgG subclass Deficiency: IgG is made up of 4 types of IgG subclasses denoted by number. The expected quantity of these different subclasses is variable throughout life. IgG1 (60-70%), IgG2 (20-30%), IgG3 (5-8%), IgG4 (1-3%).² When one or more IgG subclasses are low in number in the presence of a normal serum IgG level, an IgG subclass deficiency is present. Most commonly IgG2 or IgG3 are low in IgG subclass deficiency. In IgG1 deficiencies, a low total serum IgG is present; the diagnosis would likely be CVID rather than IgG subclass deficiency. Children under age 10 normally have low IgG4 levels.

The presence of an IgG-subclass deficiency alone does not always result in frequent infections; for this reason, many go undiagnosed. The decision to consider IgG replacement requires further investigation through vaccine challenges, additional lab work (pneumococcal titers), and infection monitoring. Oftentimes a pneumococcal vaccine can facilitate protection against common infective agents. When a vaccine response fails and serious infections arise, IgG infusion may be prescribed. Many patients diagnosed initially with an IgG-subclass disorder will eventually have a decrease in their total IgG level; these patients convert to the diagnosis of CVID.

Specific Antibody Deficiency (SAD): These patients lack the ability to form antibodies specifically to polysaccharide antigens. In children, if a vaccine challenge with polysaccharide vaccine is done, SAD children would have less than a 50% response; an adult would have less than a 70% response. They have normal serum immunoglobulins and IgG subclass concentrations. They produce normal/protective antibody response to protein antigens. Some patients with SAD initially might have a moderate polysaccharide vaccine response, but it would wane within months.

SAD patients suffer frequent, recurrent lung, bronchi, ears or sinus infections. In children, prophylactic antibiotic regimens are common to combat polysaccharide infective organisms.

Common Variable Immune Deficiency (CVID): The specific cause of CVID is unknown. This PIDD as the name suggests is the most prevalent. Both males and females may be affected by CVID. Twenty percent are diagnosed in childhood typically after age 4. Most patients are diagnosed after age 30. Typical presenting features are infections of the nasal sinuses, ears, lungs, and bronchi. Repetitive infections can cause scarring, leading to impaired respiratory function (sinuses, lungs, bronchi) or permanent hearing loss when the ears are involved. Patients with CVID have depressed antibody responses, low serum IgG levels, and low IgA and/or low IgM. Many patients have weak, partial vaccine responses and require additional boosters to achieve adequate protection.

Patients may have enlarged lymph nodes and spleen. The GI tract may be affected by collections of lymphocytes along the intestine causing malabsorption, diarrhea, nausea, and/or weight loss. Granulomas may develop in lymph nodes, lungs, liver, skin, or other organs. CVID may be suspected when abnormalities are seen in a routine CBC. Some patients develop a low platelet count or are found to be anemic.

Cellular or Combined Immunodeficiencies

Hyper-IgM Syndrome: These individuals present with normal or elevated IgM and low or absent other immunoglobulins. Initial symptoms are usually noted by adolescence. When not identified and treated, life-threatening infections may be experienced. Clinical findings can vary from person to person depending on the type and severity. Hyper-IgM Syndrome has several types including X-linked, Type 2, Type 3, Type 4, and Type 5. Each type is differentiated by the organs affected, laboratory findings, propensity for and location of viral and bacterial organisms, individual sequelae, and genetic testing.

These disorders are serious and can cause a variety of multi-system complications which may include pneumocystis carinii infections, including pneumonia. Pyogenic infections can occur in the sinuses, lungs, eyelids, skin, and other areas. Mild infections can become rapidly systemic. Chronic diarrhea may occur by 6 months of age and could cause malabsorption with associated nutritional deficiencies. Failure to thrive diagnoses are not unusual. Infants and children may also develop skin disorders such as warts, papules, macules on the skin, scalp, and the skin covering the joints. The lymphatic system and bones may also be affected.

Autoimmune disorders involving the blood, joints, thyroid, bowels, and kidneys may occur as well as neurological disorders due to infections of the brain or spine. Certain types of cancers are more prevalent as well. Deficiencies of certain enzymes are associated with certain subtypes.

Severe Combined Immune Deficiency (SCID): When the presenting symptoms of one X-linked genetic disorder are missed, the results may be fatal to newborns. In SCID, both T-lymphocytes and B-lymphocytes are absent or do not function. There are 13 genetic defects that can potentially cause SCID. Hallmark symptoms include recurrent, severe, unusual infections, failure to thrive, persistent diarrhea, and persistent low-grade or mid-grade fevers. Typically, a SCID diagnosis takes 6 months. When missed and left untreated, the results are fatal. All 50 U.S. states now perform newborn screening for T-cell receptor excision circle assay (TREC). It can identify SCIDs and other disorders associated with low T-lymphocyte production.

Wiskott-Aldrich Syndrome (WAS): A genetically inherited, X-linked recessive (males exhibit; females carry) immune deficiency with the hallmark characteristics of frequent ear infections, low platelet count/thrombocytopenia, bloody diarrhea, and skin rash/eczema.

Treatment for PIDDs

Education: When anyone is being tested or recently diagnosed with a PIDD it can be extremely anxiety-producing. Knowledge is power for parents, patients, family members, clinicians and teachers involved in a PIDD person’s life. Adequate understanding of the modifications needed, specific to the PIDD identified is important to provide adequate support, surveillance, reporting, care, and advocacy.

Infection Prevention: Thorough hand washing and home cleanliness/hygiene are vital. Avoid people who are visibly sick and wear a mask when prudent. For patients with recurrent infections, a regimen of prophylactic antibiotics may be prescribed. For severe PIDDs and bone marrow transplant (BMT) patients, reverse isolation may be implemented.

Surveillance: In PIDDs it is important to identify emerging infections as quickly as possible. Reporting early evidence of infection to the physician can be helpful in preventing or limiting the scarring effects seen with more serious infections. Signs could include fever, increased heart rate, flushed face, sweating, hoarse or raspy voice, cough, irritability, ear-tugging, or drainage of malodorous or yellow/green secretions.

Thoughtful Communication: Oftentimes, treatment for infective episodes is received from multiple disciplines (ENT, GP, urgent care centers, etc.). It is important to always notify the immunologist or other specialist treating the PIDD when an infection occurs, even if the infection has resolved. Changes to the treatment regimen made be warranted if frequent breakthrough infections are occurring.

In addition to clinical communication with medical professionals, it may be helpful to inform daycare staff, teachers, school nurses, coworkers, or close friends involved in the lives of PIDD patients. Enlarging the circle of support for some people can have a very calming effect and assist in the acceptance of a PIDD by the patient or family member(s).

Support groups can be helpful for newly diagnosed patients and parents if only to understand that they are not alone, despite the rarity of their disorder.

IgG Replacement/Augmentation: Immune globulin infusion is a life-saving therapy for many individuals with PIDDs. The infusion of donor antibodies via the intravenous (IVIG) or subcutaneous (SCIG) route of administration provides protection from infection that is missing, ineffective, or insufficient in one’s own body.

Allogeneic Hematopoietic Stem Cell Transplant/Bone Marrow Transplant (BMT): The only curative treatment for Hyper-IgM Syndrome, SCIDS and WAS. In SCIDs, if a transplant is done by 3 months of age, anti-rejection drugs are not needed, and rejection is unlikely, as these babies’ immature immune systems have not developed antibodies capable of attacking the transplanted cells.

Genetic Counseling: When gene-sequencing has identified a specific genetic anomaly, it is prudent to follow up with a geneticist to inform personal and family decisions.

Gene Therapy: This option is currently being studied in Hyper-IgM Syndrome, SCIDS, and WAS. It involves the replacement of a faulty gene with a healthy gene to cure genetically linked illnesses.

Treatment of Affiliated Symptoms: Antibody deficiencies are relatively easily managed (IgG infusion, an occasional antibiotic course, and infection and laboratory monitoring). The more severe cellular or combined immunodeficiencies often require significant support from a team of specialists. These could include physicians and nurses from pediatrics, infectious disease, immunology, hematology, hepatology, nephrology, dermatology, transplant medicine, critical care medicine and gastroenterology.

It is an exciting time to be involved in the care of PIDD patients. As immune globulin infusion nurses, we are in the cat-bird seat. We are privileged to treat these patients with such rare disorders. As new treatments evolve, we could be privy to learning about novel research and treatment options being investigated currently. At a time when genetic testing is a reality and gene therapy is a possibility. As the number of identified PIDDs continues to grow and new treatments become available, it is important that we stay informed.

References

1. Thalhammer J, Kindle G, Nieters A, et al. Initial Presenting Manifestations in 16,486 Patients with Inborn Errors of Immunity Include Infections and Noninfectious Manifestations. The Journal of Allergy and Clinical Immunology, vol. 148, no. 5, November 2021, pp. 1332-1341. Accessed at www.jacionline.org/article/S0091-6749(21)00654-0/fulltext.
2. Immune Deficiency Foundation. IgG Subclass Deficiency. Accessed at www.primaryimmune.org/about-primary-immunodeficiencies/specific-disease-types/igg-subclass-deficiency.