The Iatrogenic Paradox: How Advanced Therapies Are Sparking an Immune Crisis

MAASTRICHT, Netherlands – October 14, 2026 – We are living in a golden age of targeted medical therapies. From chimeric antigen receptor (CAR)-T cell treatments that reprogram the body to hunt leukemia, to monoclonal antibodies that halt multiple sclerosis in its tracks, the frontiers of human health are expanding at a staggering pace. Yet, as we celebrate these technological marvels, a parallel crisis is quietly unfolding in the shadows of our success. The very treatments designed to save lives are inadvertently dismantling the biological defenses of the patients who receive them.

At the 2026 meeting of the European Society for Immunodeficiencies (ESID), this systemic blind spot has taken center stage. Healthcare experts, patient advocates, and biopharmaceutical leaders have issued an urgent call to address the escalating rate of Secondary Immunodeficiencies (SIDs). Driven predominantly by the expanding clinical use of immunosuppressive and biologic therapies, this acquired immune dysfunction represents a profound iatrogenic paradox: in curing or managing one devastating disease, we are frequently engineering another.

The Biological Cost of Precision Medicine

To understand the mechanics of this crisis, one must look at the biological cost of modern targeted therapies. Anti-CD20 agents, such as rituximab and ocrelizumab, have revolutionized the treatment of hematological malignancies and severe autoimmune diseases. However, these drugs operate by systematically depleting CD20-positive B cells. Because these cells are the precursors to antibody-producing plasma cells, their destruction inherently cripples the patient's ability to produce vital immunoglobulins (IgG, IgM, IgA).

The clinical literature paints a stark picture of this collateral damage. Secondary antibody deficiency develops in an estimated 25 to 40 percent of patients receiving long-term rituximab-based regimens. The numbers are even more pronounced in the realm of CAR-T cell therapy. Because these engineered cells feature an "on-target, off-tumor" effect—destroying healthy B cells right alongside malignant ones—approximately 91 percent of post-CAR-T patients experience hypogammaglobulinemia, a condition that can persist for years.

A forthcoming 2025 paper in Frontiers in Immunology by Elkhalifa et al. underscores this emerging trend, noting that secondary antibody deficiencies have become vastly more prevalent than their primary, genetic counterparts. Yet, despite the predictability of these immune failures, healthcare systems remain structurally ill-equipped to catch them before severe complications arise.

The Diagnostic Clock and Irreversible Harm

The human cost of this clinical oversight is measured in delayed recognition, recurrent severe infections, and preventable hospitalizations. Data presented at ESID 2026 by Kedrion Biopharma and the Italian Association for Primary Immunodeficiencies (AIP APS) sheds new light on the severity of these diagnostic delays.

The organizations unveiled preliminary findings from the expansion of the MAPPA (Measurement of Patient-Perceived Burden and Assessment of care) survey, which recently broadened its scope from Italy to Portugal, Spain, and Turkey. The data reveals a troubling reality: more than half of the respondents did not receive a diagnosis until after the age of 18. Even more alarmingly, 28 percent of patients reported having already suffered permanent organ or tissue damage by the time their immunodeficiency was finally identified.

"Giving patients a voice means recognizing the value of their real-life experiences as an essential source of knowledge," said Alessandro Segato, President of AIP APS. "By turning these experiences into evidence, we can identify shared needs and challenges that may otherwise remain unseen. These insights can help strengthen awareness and contribute to improving diagnosis, care and support for people living with Primary Immunodeficiencies at a European level."

Complicating the diagnostic landscape is the revelation that many presumed secondary cases mask deeper genetic anomalies. Johan Prevot, Executive Director of the International Patient Organization for Primary Immunodeficiencies (IPOPI), noted that while SIDs are receiving more attention, a significant subset of these patients actually harbor an underlying, previously undiagnosed Primary Immunodeficiency (PID). For these individuals, the administration of a biologic drug acts as a catalyst, unmasking a genetic vulnerability that had previously remained dormant.

Bridging the Specialty Divide

The root of this diagnostic failure lies in the highly siloed nature of modern medicine. Oncologists and rheumatologists are understandably laser-focused on eradicating tumors or halting autoimmune attacks. In the high-stakes environment of treating a primary disease, the secondary failure of the immune system is often missed, its symptoms misattributed to the general malaise of cancer treatment or disease progression.

Currently, there is a distinct lack of universally accepted, routine screening protocols mandated by major oncology or hematology organizations for hypogammaglobulinemia in patients receiving these therapies. While monitoring IgG levels is generally suggested, it is rarely systematically enforced.

"Awareness of Secondary Immunodeficiencies has improved in recent years, but significant gaps remain," stated Dr. Silvia Sánchez-Ramón, Head of the Immunology Department at La Paz University Hospital in Madrid. "Earlier recognition, stronger collaboration among specialties and wider adoption of evidence-based practices are essential to ensure patients are diagnosed earlier and receive appropriate care."

Bridging this gap requires a fundamental shift in clinical workflows. Immunologists must be integrated into the care continuum of oncology and rheumatology patients from the moment a B-cell depleting therapy is prescribed, ensuring that baseline immunoglobulin levels are recorded and routinely monitored.

Reshaping the Global Plasma Economy

Beyond the clinical and human imperatives, the surge in SIDs is sending massive shockwaves through the global biopharmaceutical market. As the population of patients with acquired immune dysfunction swells, so too does the demand for Immunoglobulin Replacement Therapy (IgRT). Administered intravenously (IVIG) or subcutaneously (SCIG), these plasma-derived therapies are the primary lifeline for patients who can no longer produce their own antibodies.

The global plasma fractionation market, valued at roughly $33.7 billion in 2023, is projected to nearly double to $64.9 billion by 2032. This explosive growth is heavily predicated on the rising incidence of drug-induced immunodeficiencies. For companies like Kedrion Biopharma, which operates in over 100 countries and ranks as the world's fifth-largest player in plasma-derived products, this represents both a massive commercial opportunity and a daunting supply chain challenge.

Human blood plasma is a finite resource, entirely dependent on human donors. The accelerating demand for immunoglobulins threatens to outpace collection capabilities unless systemic changes are made to diagnostic and treatment pipelines. Kedrion's active presence at ESID 2026—presenting safety data on immunoglobulin therapies and backing the MAPPA initiative—highlights a strategic pivot. Biopharma companies are no longer just manufacturing treatments; they are actively investing in the clinical advocacy required to build sustainable diagnostic networks.

"Progress in clinical management of Secondary Immunodeficiencies depends on strong multi-disciplinary collaborations as well as connections between science, clinical practice and patient experience," explained Gorana Dasic, Vice President and Global Medical Affairs Head at Kedrion Biopharma. "Through research collaborations, patient-focused projects and contributions in clinical and scientific advancements shared at scientific meetings, Kedrion is committed to helping build the networks and knowledge that can improve earlier diagnosis and more informed care."

As targeted therapies continue to advance, the medical community is being forced to reckon with the biological debt those treatments incur. The rise of Secondary Immunodeficiencies is not a failure of modern medicine, but a complex byproduct of its success. Addressing it will require breaking down the walls between medical specialties, rethinking global plasma supply chains, and acknowledging that curing a disease is only half the battle if the patient is left defenseless in its wake.