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Clinician Education: How to Identify and Treat PI

June 8, 2021

Physicians seeking in-depth information on how to identify and treat patients with primary immunodeficiencies can watch two recent IDF clinician education programs presented by experts in the field of PI.

The clinician education presentations, available online, include:

  • “Finding a Zebra in Your Practice” by Dr. Sarah Henrickson, attending physician with the division of Allergy and Immunology at Children’s Hospital of Philadelphia and instructor of pediatrics at Pearlman School of Medicine at the University of Pennsylvania
  • “Found a Zebra: Now What?” by Dr. Karin Chen, attending physician at Seattle Children’s Hospital, and Professor, Division of Immunology, Department of Pediatrics at the University of Washington School of Medicine, and Dr. Jack Routes, attending physician at Children’s Hospital in Milwaukee, Professor of Pediatrics, Medicine, and Microbiology and Immunology, Section Chief, Allergy and Clinical Immunology at the Medical College of Wisconsin, and member of IDF Physician Advisory Committees

In “Finding a Zebra in Your Practice,” Dr. Henrickson described the immune system components – including the innate and adaptive immune systems, the lymphatic system, and T and B cells – and how cells work in general to fight off infections.

“Think about what best a cell is able to do, what pathogen it is best able to fight, and what happens when it’s absent and look for those patterns in our patients,” she said.

The pace of discovery of monogenic primary immune deficiency is remarkable, said Dr. Henrickson, with more than 430 identified so far.

“Monogenic inborn errors of immunity are an increasingly important component of primary care medicine. There are many reasons for this. One is that we are finding new genes that cause disease all the time, and the immune system is definitely an important part in that growth of our understanding,” she said.

New facets about PI are discovered every day through research, including the following:

  • While pathogens cause a broad range of infections, patients also have a susceptibility to a narrow group of pathogens.
  • Other phenotypes of PI now include hyper-inflammatory responses and autoimmunity.
  • While PI causes problems in cells from the bone marrow, PI also causes defects directly in end organs.
  • A diagnosis is not one gene, as previously thought, but rather one gene can have many phenotypes dysregulated, and many genes can cause the same phenotype.

“I think it’s important to remain humble as our genomic knowledge increases to what we think we know to what we actually understand about the immune system because we have so much to learn,” she said.

Patients with PI often go undetected for many years prior to diagnosis. When evaluating recurrent infections, physicians should review medical and family history, and focus on the infection history including the types, severity, frequency, duration, treatments, and hospitalizations.

Physicians should also take into consideration:

  • Common infections being more frequent or occurring at ages outside of the normal timeframe (for example, infections like thrush experienced beyond infancy)
  • History of severe infections, even once
  • Unusual organisms as causes for the infection
  • Multiple bacterial infections
  • Abnormally high numbers of pediatric infections beyond the normal pattern

Once the physician has ruled out other causes for recurrent infections, such as defects in host barriers and secondary immunodeficiencies not related to genetics, then he or she should consider inborn errors of immunity. Furthermore, if there is a combination of autoimmunity, infections, and/or malignancy, think immune dysregulation.

“All of these scenarios are worthy of deeper thought from an immune perspective and consideration of partnering with a clinical immunologist,” said Dr. Henrickson.

Dr. Henrickson also provided an overview of several PIs, describing their clinical characteristics, and relevant testing. Those PIs included: combined immunodeficiencies; severe combined immunodeficiency; predominantly antibody deficiencies; X-linked agammaglobulinemia; common variable immunodeficiency disorder; and phagocytic cell disorders.

Concerning symptoms and test results that warrant further investigation should prompt physicians to refer the patient to a clinical immunologist for additional work-up and consider genetic testing in conjunction with the clinical immunologist and/or geneticist. Why is it important to know the gene?

“If you have a patient and you’re worried about immune function, especially if you’re also worried about the presence of autoimmunity or malignancy, it is so important to refer and have them be fully diagnosed to the point of a mechanism, if possible because there are targeted therapies for some of these disorders that can dramatically improve patient quality of life and lifespan,” said Dr. Henrickson.

Dr. Henrickson also referred physicians to the Clinical Immunology Society’s to learn more about PI, and to the IDF and CIS to locate partner immunologists.

During “Found a Zebra: Now What?” Dr. Chen covered the following topics:

  • Antibody deficiencies
  • IVIG and subcutaneous immune globulin replacement
  • Antibiotics for treatment and prophylaxis
  • Immunizations – when and when not to immunize

“We decided to focus on the topic of antibody deficiencies because they are one of the most common groups of immune deficiency disorders that providers will encounter in their practices,” said Dr. Chen.

Chen listed the classic PIs including neutrophil defects like CGD, complement deficiency, cellular immunodeficiency like SCID, rare genetic diagnoses like Wiskott-Aldrich syndrome, antibody immunodeficiencies (the largest group of immune issues) including CVID, X-linked agammaglobulinemia, and specific antibody deficiency.

Physicians should work closely with immunologists to care for patients with PI and, in general, the following are treatments for patients with these disorders:

  • Replacement
    • Immunoglobulins
    • Enzyme replacement – recombinant adenosine deaminase (just for SCID)
  • Preventive
    • Antibiotics, antifungals, antivirals
    • Immunizations – what to avoid and receive
  • Restorative
    • Bone marrow transplant
    • Gene therapy

The most commonly treated PI is CVID, which causes defects in B cell maturation and can lead to global immune dysfunction. Diagnostic criteria include:

  • Low IgG and low IgA or IgM levels with recurrent infection
  • Failure to produce specific antibodies to vaccines
  • Exclusion of other causes of hypogammaglobulinemia

Dr. Chen detailed intravenous and subcutaneous immune globulin treatment, providing details on the products, who should receive it, how to administer it, dosage, and side effects. She also discussed antibiotics, antifungals, and antivirals as a preventative therapy, as well as how physicians should provide vaccines only after ensuring they are appropriate for the diagnosis.

Dr. Routes focused primarily on CVID and said that he sees between 200 and 300 patients with a CVID diagnosis.

“For the practicing physicians out there, CVID will be the predominant disorder that they will follow with their patients and the local clinical immunologists. It accounts for the vast majority of PI in both kids and adults,” said Dr. Routes.

Dr. Routes shared the following facts about the condition:

  • Most common, life-threatening PI
  • Onset at almost any age, clinical course variable, delay in diagnosis common
  • Infections – Respiratory Tract Infections/GI Common
  • Invasive infections markedly decrease with replacement gammaglobulins
  • Non-infectious complications the most important cause of morbidity and mortality
  • Pulmonary disease: interstitial lung disease
  • Cancer (B cell lymphomas, gastric carcinoma)
  • Liver disease (nodular regenerative hyperplasia)
  • GI disease (enteropathy, inflammatory bowel disease)
  • Autoimmune cytopenias

Dr. Routes pointed to a study by Dr. Charlotte Cunningham-Rundles and colleagues of 473 CVID patients which showed that 68 percent had non-infectious complications, and the risk of death was eleven-fold higher for those patients. B cell lymphoma, hepatitis, functional or structural lung impairment, and GI disease including enteropathy cause increased mortality rates.

All patients with CVID, as well as XLA, should have a CT of the chest in order to determine the extent of how the condition is affecting the lungs. The most common lung abnormality in CVID patients is bronchiectasis, and these patients require a higher dose of gammaglobulin to prevent infection. In patients with severe bronchiectasis, the treatment may be similar to that used in cystic fibrosis.

Another common condition developed by those with CVID is granulomatous and lymphocytic interstitial lung disease (GLILD). GLILD, because of the presence of non-caseating granuloma, is frequently confused with sarcoidosis. However, GLILD is a distinct clinical entity. Patients with GLILD have an increased incidence of other non-infectious complications including autoimmune cytopenias, enteropathy, liver disease, and B cell lymphomas.

The optimal treatment of GLILD is controversial. However, recent studies from Dr. Routes and colleagues indicate that GLILD can be treated with a combination of rituximab and antimetabolite medications. This combination of immunosuppressive therapy appears to induce remissions regardless of the presence or absence of pathogenic mutation leading to a CVID-like immunodeficiency.

To listen to “Finding a Zebra in Your Practice,” click here.
To listen to “Found a Zebra? Now What?” click here.
To link to the IDF Healthcare Professionals Resource page, click here.


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