Medscape recently sat with Dr Paul J. Maglione, Assistant Professor of Medicine in the Section of Pulmonary, Allergy, Sleep, and Critical Care Medicine at Chobanian and Avedisian School of Medicine.

Medscape: Welcome, Dr Maglione. Thank you for joining us to shed some light on primary immunodeficiency diseases and how we can improve patient care.

Dr Maglione: My pleasure.

In Your Own Words, What Are Primary Immunodeficiency Diseases?

Primary immunodeficiency diseases (PIDDs) are caused by genetically mediated dysregulation of the innate or adaptive immune system. Unlike with secondary immunodeficiency, individuals are born with these deficiencies rather than acquiring them because of medication or some other chronic disease.^[1] The potential manifestations of PIDDs are highly variable and can range from asymptomatic to severe; patients may suffer from repeated infection, autoimmunity, immune dysregulation, inflammation, end-stage organ damage, and malignancy.^[1-3] In some cases, PIDDs manifest primarily as autoimmune conditions, confounding diagnosis of diseases regarded by many as solely an increased susceptibility to pathogenic infections.^[4]

Over 400 monogenic disorders and their associated morbidities fall under the umbrella of PIDD.^[5] Although each individual PIDD is rare, as a group, these diseases affect roughly 500,000 people in the United States.^[6] Among these, immunoglobulin A (IgA) deficiency is the most common, affecting about 1 in every 500 people; however, most of these cases are asymptomatic.^[7] Researchers believe that PIDDs are far more common than current statistics suggest due to the cryptic nature of diagnosis.^[8]

Who Can Be Affected by PIDD?

Anyone of any age group or ethnicity can be affected by a PIDD. Although many PIDDs are more commonly diagnosed in infants and children, who tend to have more severe disease presentation, there is a second peak of diagnosis in early adulthood made predominantly of antibody deficiencies.^[1,9] Some studies of pediatric newborn cohorts suggest that PIDDs appear roughly equally among racial groups.^[10,11]

In adult cohorts in the United States, PIDD is most frequently diagnosed in White patients, while Latino and Black patients tend to be underrepresented in studies of diagnosis and treatment relative to their proportion in the population. This disparity may result from underdiagnosis of PIDD in these populations rather than a true difference in prevalence.^[12]

Demographically, studies of PIDD frequently subdivide data into sex or age classes, but few look specifically at the racial or ethnic breakdown of known PIDD cases.^[13] Ideally, data are analyzed with attention to race and ethnicity to identify populations at higher risk for certain genetic disorders.^[13]

How Is PIDD Diagnosed?

Pediatric populations. Universal severe combined immunodeficiency (SCID) disease screening was first implemented for all newborns in 2008 in a hospital in Wisconsin^[14]; by 2018, newborn screening had become a routine procedure in almost every state.^[11]

Many pediatric patients are overlooked and must be diagnosed based on clinical presentation (Table 1). Although standards may vary depending on the patient and the specific immunodeficiency, some authors have suggested specific warning signs to help aid in diagnosis.^[7] In the future, we might expect to see a demographic shift in PIDD diagnosis in adult populations or older pediatric cohorts as a result of universal, equitable early diagnosis in infancy, but those data aren't yet available.

Adult populations. Like pediatric patients, adults with PIDD are typically diagnosed following recurrent or unusual infections (Table 1).^[7] Adult PIDD can be complex to diagnose and challenging to treat depending on the involved genetic disorder.^[7]

Table 1. Ten Warning Signs of Primary Immunodeficiency^[7]

PI, primary immunodeficiency.

What Is the Current State of the PIDD Treatment Landscape?

As one might imagine, there are numerous PIDD treatment options available that vary depending on the aspect of the immune system implicated in active disease.^[15,16] Newborns and infants diagnosed with immune disorders can be treated with bone marrow transplant or hematopoietic stem cell transplant.^[11] However, these types of transplants become more complex as patients age and may be impossible in adulthood, making screening and treatment in infancy especially important.^[17]

Without prompt diagnosis and treatment, many infants will have several severe and potentially fatal infections within the first year of life. Infants diagnosed and treated with a bone marrow transplant before 3.5 months of age have a 90% chance of long-term survival (> 20 years), although that figure drops to 50% in infants diagnosed and treated after 3.5 months.^[18]

In adult patients with deficiencies of the adaptive immune system -- most commonly primary antibody deficiency (PAD) -- intravenously or subcutaneously delivered immunoglobulin therapy is the standard of care.^[19] Intravenous and subcutaneous delivery are equally efficacious for the majority of patients and can be selected based on patient preferences, ability to adhere to treatment, and lifestyle factors.^[15] Depending on a patient's needs, a variety of other disease-specific treatments are available^[16]: these may include immunosuppressants for those with autoimmune and chronic inflammatory diseases, nutritional supplementation for those with severe gastrointestinal disease, and pulmonary rehabilitation or supplemental oxygen in those with severe respiratory disease. For patients with less severe immunodeficiencies, prophylactic antibiotics or short courses of steroids may be appropriate.^[16]

What Are Some of the Main Challenges That Impact PIDD Management?

The first major hurdle is simply recognition of a primary immunodeficiency. Existing projections estimate that up to 70% to 90% of patients with PIDD remain undiagnosed.^[19] Newborn screening is designed to detect T-cell deficiencies and may miss other disorders.^[20] In adults, diagnosis is complex -- lack of routine screening and varying clinical presentations lead to frequent misdiagnoses.^[21]

Signs of PIDD in adults may not always be recognized by primary care clinicians, and there can be hesitancy to refer patients to immunologists for further testing.^[21] These clinicians may want to avoid unnecessary cost to the patient or avoid overburdening specialists with a case that might not have an immunodeficiency. Many patients referred to our immunology practice don't end up having an immunodeficiency. I'm happy to see patients and conduct additional testing, giving patients without immunodeficiency some peace of mind in the process of finding cases who do need additional support. It is well worth the effort.

How Do Health Inequities Impact PIDD Management?

Less research has been conducted on health disparities for PIDD than on other types of immunological diseases, but there is evidence of worse outcomes for certain groups, such as Black and Hispanic people.^[13]

Healthcare access. Systemic inequities result in similar diagnosis and treatment delays. Racial minorities are more likely to live in medically underserved areas that have longer wait times and issues such as limited access to subspecialty care.^[13] Primary care clinicians, whether they are physicians, nurse practitioners, or physician assistants, can and do provide many of the immunology referrals for these populations. Overburdened primary care clinics are less likely to have the time to explore a complex diagnosis with variable presentation. As a result, even patients who have a regular primary care clinician may need to do a fair amount of self-advocacy and visit a variety of specialists to find a diagnosis -- something that uninsured or underinsured families might not have the time or resources to do.

Diagnosis. Minority groups are less likely to be diagnosed with PIDD and tend to have worse PIDD outcomes.^[12] This disparity could stem from a variety of factors, including lack of resources to pursue diagnosis, challenges with working hour rigidity or transportation needs, and lack of proximity to specialty care. More severe economic challenges can also confound diagnosis.

Anecdotally, I have treated patients who have complex needs, such as those experiencing homelessness, who experienced diagnosis and treatment delays due to their housing situation. It may be more difficult to identify potential immunodeficiency if someone is living outside or in suboptimal housing. It can be easy to point to other causes of repeat infections, such as lack of access to washing facilities or clean sleeping spaces.

Treatment. Racial diversity is low among hematopoietic stem cell donors, which can slow unrelated donor transplant efforts for pediatric patients, leaving them vulnerable to infection.^[13] Inequitable access to treatment can also be a major problem, due to either cost or logistics; therapies such as immunoglobulin are not available to all individuals.^[22] At Boston Medical Center (BMC), we have a more ethnically diverse patient population than the average clinic. BMC is also a safety net hospital, meaning that all patients are treated regardless of their ability to pay. Even so, a retrospective analysis of PAD cases from 2012 to 2019 showed that patients who identified as Black were significantly less likely to receive IgG-replacement therapy despite higher prevalence in our patient population.^[23] Black patients were also more likely to present with bronchiectasis or other chronic infection-related sequalae.^[23]

What Can Clinicians Do to Improve Health-Related Quality of Life (HRQoL) and Reduce Health Disparities in Patients With PIDD?

Overall, many of the necessary changes will need to happen at the institutional level. Individual clinicians can make a difference by pushing for systemic change and hiring diverse faculty and staff.^[13] Education on the importance of cord blood donation as well as diversification of the bone marrow donor pool can improve equity by speeding the unrelated matching process for patients requiring transplants.^[13]

Clinicians can also advocate for individual patients in their care. There are many hurdles for underserved patients, such as those in rural areas or individuals who are uninsured or underinsured. For patients from rural areas without specialty care close by, I have found that telehealth and remote collaboration with the on-site care team can help with treatment access once I have seen a patient in-office.

Patient-guided care also has enormous potential to improve HRQoL in PIDD patients overall. In my experience, we have better treatment success with patients who have an opportunity to tell us what they want and what best suits their everyday life. Certain common therapies, such as immunoglobulin, can be given intravenously or subcutaneously.^[15] Several studies have been conducted on patient preferences and quality of life (QoL) impacts of PIDD treatments.^[24,25] Both adult and pediatric patients experienced improved QoL with intravenous immunoglobulin infusions, and at-home immunoglobulin infusions may further improve QoL because of improved convenience and ability to engage in other activities.^[26,27]

For patients in rural areas or individuals with limited mobility, subcutaneous delivery might be the most convenient way to receive the treatment. In contrast, patients with adherence challenges or who have trouble with tasks requiring fine-motor coordination might benefit from routine visits to clinics for infusions.^[15] The most important thing is listening to the patient and allowing them to have some control over their care.

Is There Anything Else Clinicians Need to Know About PIDDs?

I would just remind clinicians to lean on each other -- the pharmacists and nurses that work at infusion centers are extremely knowledgeable, and I’ve definitely benefitted at least as much from their expertise as they have from mine.

The nice thing about immunology is that because we're such a science-heavy specialty, a lot of us are physician-scientists. I'm not seeing patients 5 days a week, which frees up some of my time for advocacy and problem solving. PIDD is more common than one might think. Our patients will benefit from caring clinicians remaining alert to the warning signs and providing referrals to immunology for suspected cases. Even if a patient ends up not having a PIDD or other immunological issue, we’re happy to see them.

This transcript has been edited for style and clarity.