Recognizing and managing secondary immunodeficiency in allergy clinics

Secondary immunodeficiency is an acquired reduction in immune function caused by treatments such as chemotherapy, biologics, or long-term steroids, as well as by certain systemic diseases. It often develops in adults being treated across multiple specialties. Respiratory teams may be the first to notice warning signs; recurrent infections, unusual pathogens, or poor responses to standard care, especially in patients with asthma or COPD.

As part of our Respirology Reflections series, we interviewed Dr S Shahzad Mustafa (Rochester Regional Health & University of Rochester School of Medicine and Dentistry, Rochester, NY, USA) to explore key clinical clues, investigations, and management strategies for secondary immunodeficiency, particularly in the context of allergy and asthma. This Q&A covers high-risk medications, infection patterns that should raise suspicion, how to differentiate secondary from primary immunodeficiency, recommended screening tests, approaches to reducing infectious complications, and the importance of coordinated, multidisciplinary follow-up.

Q. Which infection patterns or clinical features should raise suspicion of secondary immunodeficiency rather than uncontrolled allergy or asthma?

There are red flags for immunodeficiency. Patients who are experiencing recurrent infections should at least raise the suspicion of possible secondary immunodeficiency, and certainly patients who are experiencing significant or life-threatening infections. Our patients with allergic rhinitis, asthma and sinusitis certainly have sinopulmonary infections that lead to infections, but it’s uncommon for patients with asthma to have a lobar pneumonia, a bacteraemia, or even 3 or 4 episodes of bacterial sinusitis. If you are seeing a patient with repeated or certainly more life-threatening infections, invasive infections, bacterial infections, consider whether the patient has predisposing risk factors for immunodeficiency and whether they need further evaluation.

Q. How can secondary immunodeficiency be distinguished from primary immunodeficiency in adult allergy patients?

We talk about primary immunodeficiency a lot, but it’s far less common than secondary immunodeficiency. Primary immunodeficiency tends to present in younger ages: ages 4–6, teenage years and in the 20s, whereas secondary immunodeficiency tends to present later in life. There’s nuance to the differentiation, but I would implore clinicians to think about the possibility of underlying immunodeficiency and to initiate an evaluation. Then if there are concerns for primary or secondary immunodeficiency, that can be investigated by a board-certified clinical immunologist.

Q. What initial investigations are appropriate when secondary immunodeficiency is suspected, and which results should prompt referral?

If there is a concern for recurrent infections, severe infections, or unusual infections, initiate an evaluation for immunodeficiency. The simplest way to do this would be to check serum immunoglobulin (Ig). For most clinicians, I would encourage ordering 3 immunoglobulin classes, IgG, IgM, and IgA, and for screening, add in a complete blood count (CBC).

If the pre-test probability is relatively low or moderate and the labs are normal, that is very reassuring, but not perfect. If your pre-test probability for immunodeficiency is incredibly high, then I would encourage referral to a clinical immunologist for further, more advanced diagnostics.

If immunoglobulin levels are high (hypergammaglobulinemia), think about myeloproliferative processes, such as multiple myeloma. Here, a serum protein electrophoresis (SPEP) would be appropriate. If levels are low, that can generate a referral for an immunologist. Finally, if levels are normal, there is a potential to rule out immunodeficiency, although this is not conclusive.

Q. What risk mitigation strategies can be used in allergy patients with suspected or confirmed secondary immunodeficiency to reduce infectious complications while maintaining disease control?

It is very important to identify secondary immunodeficiency, and we have management strategies to decrease infectious complications and improve morbidity and mortality. Often it starts with the ability to vaccinate a patient, if they are able to mount an adequate response. Vaccination can increase the patient’s IgG levels for the antigen and decrease infectious complications.

Commonly used strategies, particularly in hematologic malignancies (e.g., chronic lymphocytic leukaemia), include low-dose antibiotic prophylaxis, and in individuals with more severe secondary immunodeficiency, immunoglobulin replacement is considered. When treating secondary immunodeficiency, it is also important to treat the underlying condition and minimize any immunosuppression. In individuals with hematologic malignancy, treatment of the condition may lead to immune reconstitution and minimize the need for immunosuppressive medications.

Q. How and when should patients with secondary immunodeficiency be reassessed, and how should care be coordinated with other specialties when management needs to change?

Secondary immunodeficiency can be due to a host of reasons, including medication use or an underlying condition. I would encourage taking a multidisciplinary approach to care, working with the treating specialists managing the condition, such as an oncologist, rheumatologist or neurologist, and involving immunology colleagues for a thorough diagnostic evaluation and then for choosing an appropriate therapy. In primary immunodeficiency, treatment is often indefinite (e.g., immunoglobulin replacement), but in secondary immunodeficiency, you may consider risk mitigation strategies that are more temporizing, potentially while the patient is on therapy. Again, a multidisciplinary approach is key.

Respirology Reflections is our new, expert-led, practice pearls series delivering concise, actionable insights from leading experts in respiratory and pulmonary medicine. Designed to help healthcare professionals stay current, it highlights real-world challenges, emerging evidence, and actionable strategies to enhance clinical practice, strengthen decision-making, and build confidence in an increasingly complex and fast-evolving field.