Primary immunodeficiency: When recurrent infections signal something more

Stuart L Abramson, MD, PhD, FAAP

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Table 5

When children present with recurrent infections, treatment of the specific infection is typically paramount in the clinician’s mind. While obviously necessary, such focus on resolving the infection may distract from considering an underlying condition, such as allergies or immunodeficiencies, that may be occasioning the recurrent infections.

“Some immunodeficiency disorders are not picked up as early as they might be because pediatricians are so focused on treating, for example, an ear infection from crisis to crisis with antibiotics that they may not get at the real cause, which might be an immunodeficiency,” says Stuart L Abramson, MD, PhD, FAAP, director, Allergy/Immunology Services, Shannon Medical Center/Shannon Clinic, San Angelo, Texas.

It is estimated that primary immunodeficiencies (PIs) occur in about 1:2000 live births.¹ Unlike secondary immunodeficiencies that occur in connection with other conditions (for example, viral infections, malignancies, or malnutrition), PIs are inherited disorders affecting the functioning of the immune system. Children and adults with PIs are predisposed to infection, autoimmune disease and aberrant inflammatory response, and malignancy.

A key presenting feature of all immunodeficiency disorders is an increased susceptibility to infection. Therefore, children who present with frequent infections should be on the clinician’s radar as potentially having immunodeficiency disorders. This is the first step in recognizing and managing what could be a life-altering condition if not caught and treated early. Early diagnosis and treatment are critical to preventing or reducing the significant morbidity and mortality that can result if PIs are left undiagnosed and untreated.²

“’Chance favors the prepared mind,’” says Abramson, quoting the French scientist Louis Pasteur. “If you don’t think about it, you aren’t going to make the diagnosis and help these patients. So just thinking about the problem, being alert to the early warning signs, and getting the proper testing and referral can make all the difference.”

In a presentation at the 2017 American Academy of Pediatrics (AAP) meeting in Chicago, Illinois, titled “Recurrent infections: Is it immunodeficiency?” Abramson discussed the warning signs suggestive of a PI, a stepwise approach to making the diagnosis, and management issues in the care of children with PI disorders.³

Warning signs

Abramson opened his talk with a description of the different types of immunodeficiency disorders, focusing specifically on PI disorders. All PIs stem from the failure of one or more of the body’s defensive mechanisms to properly function. The type of PI depends on the specific defect of the immune system-whether it is characterized by a humoral (antibody) deficiency, cellular deficiency, or a combination of both humoral and cellular deficiencies.¹

Fifty percent of PIs are primary B-cell disorders: both more-common PIs (eg, selective immunoglobulin A [IgA] deficiency disorders) and uncommon PIs (eg, X-linked agammaglobulinemia). Other types of PIs are categorized as combined B-cell and T-cell immunodeficiencies (20%), phagocyte immunodeficiencies (18%), T-cell immunodeficiencies (10%), and complement immunodeficiencies (2%).¹ Abramson provided a brief description of several common and uncommon PIs and their clinical presentations (Table 1).

To help clinicians recognize when a child may have a PI, Abramson referred to a quick checklist of 10 warning signs developed by the Jeffrey Modell Foundation.² As noted in Table 2, a child who presents with 2 or more of these warning signs should undergo further assessment to make the differential diagnosis. Some of these symptoms also may indicate an underlying undiagnosed and untreated allergy, so making the correct diagnosis is crucial.

Abramson emphasized the importance of pediatricians knowing these 10 warning signs because “they are often the first line of defense in terms of picking up these patients and getting them to the proper specialists.”

Early diagnosis, treatment critical

Diagnosis of a PI disorder is based on stepwise approach involving 4 stages. Table 3 lists the stepwise approach to diagnosis recommended by the Jeffrey Modell Centers Network. Abramson said that most PIs (about 75%) can be diagnosed by obtaining a complete blood count (CBC) and quantitative immunoglobulin levels (stage 1).

If either test is abnormal, he emphasized, it is important to repeat the test to ensure that the first reading was not a lab error and that the positive test truly reflects a persistent problem.

“Unless you get a follow-up test, for example, of an initial test that showed either a low or high white blood cell count, you don’t know whether the blood cell count has normalized,” Abramson said. “In the case of a very low lymphocyte count that remains low, that could be indicative of a cellular immunodeficiency and not just a viral infection.”

“Viral infections can lower the white blood count, but if it doesn’t go away, it may be a persistent cellular deficiency,” he reiterated.

If a positive test persists after repeat testing, further diagnosis is indicated. For any diagnosis required after stage 1, Abramson suggests pediatricians consider referral to an allergist or immunologist for further workup. In addition to a potential diagnosis of a PI, some of these children with recurrent infections (eg, recurrent otitis) may have an underlying allergy that needs to be diagnosed or ruled out to make the correct differential diagnosis.

Following this stepwise diagnostic approach and referring children to specialists when warranted are critical to ensuring an accurate and early diagnosis.

“Early diagnosis is very important for some of these disorders because if the patient goes for a long period of time with recurrent infections, this can sometimes cause more chronic problems,” said Abramson, citing the potential for, among other conditions, the development of bronchiectasis if the underlying PI goes undetected and untreated.

In addition, Abramson said that early detection is critical for children who have a severe PI because they can be candidates for bone marrow transplantation. These children typically have an immunodeficiency that poses serious, life-threatening outcomes if immune reconstitution is not achieved. “If you wait too long and the infection becomes too difficult to treat or becomes chronic, it’s much riskier to do a bone marrow transplant because you have to immunosuppress the patient as you don’t want them to develop a graft-versus-host reaction,” he said. Characteristics for transplantation for PI disorder are listed in Table 4.

Currently, most children diagnosed with PI disorders are treated with immunoglobulin therapies that can be delivered either intravenously in the clinic or subcutaneously at home.⁴ Table 5 describes a standard intravenous immunoglobulin therapy. For some children, subcutaneous therapy at home may be a better option. When compared with intravenous therapy, the benefits of subcutaneous therapy include improved quality of life, lower costs, and lower systemic adverse effects. However, disadvantages may include the need for more frequent treatments and local reactions at infusion sites.

Summary

Children presenting with recurrent infections may have underlying immunodeficiency disorders. Pediatricians should be alert to the warning signs indicating the potential for a PI disorder. Diagnosis includes a stepwise approach that begins with analysis of a CBC and quantitative immunoglobulin levels. If the results are positive after repeat testing, children should be referred to a specialist for further workup.

For most children diagnosed with a PI disorder, intravenous or subcutaneous immunoglobulin therapy is the standard treatment if specific antibody production is deficient.^4,5 Bone marrow transplantation is indicated for children with severe PI disorders. For all patients, early detection and treatment are critical to avoid long-term adverse effects of an untreated PI disorder.

References:

1. Bonilla FA, Khan DA, Ballas ZK, et al; Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma, and Immunology; American College of Allergy, Asthma, and Immunology; and Joint Council of Allergy, Asthma, and Immunology. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015;136(5):1186-1205.

2. Modell V, Gee B, Lewis DB et al. Global study of primary immunodeficiency diseases (PI)-diagnosis, treatment, and economic impact: an updated report from the Jeffrey Modell Foundation. Immunol Res. 2011;51(1):61-70.

3. Abramson SL. Recurrent infections: Is it immunodeficiency? F1120. Presented at: American Academy of Pediatrics National Conference and Exhibition; September 16-19, 2017; Chicago, IL.

4. Yong PL, Boyle J, Ballow M, et al. Use of intravenous immunoglobulin and adjunctive therapies in the treatment of primary immunodeficiencies: a working group report of and study by the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma, and Immunology. Clin Immunol. 2010;135(2):255–263.

5. Orange JS, Ballow M, Stiehm ER, et al. Use and interpretation of diagnostic vaccination in primary immunodeficiency: a working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma, and Immunology. J Allergy Clin Immunol. 2012;130(3 suppl):S1-S24.