Personalized Management of Chronic Rhinosinusitis in the Context of Immune Deficiency.

Introduction

Chronic rhinosinusitis (CRS) and recurrent acute rhinosinusitis (RARS) are important sources of patient morbidity, particularly in those individuals with underlying immunodeficiency states. 1 As the condition implies, CRS is defined as persistent sinonasal inflammation lasting at least 12 weeks and is characterized by a cascade of hallmark symptoms including nasal obstruction, mucopurulent nasal drainage, facial pain or pressure, and varying degrees of olfactory loss. The diagnosis is further supported with either endoscopic or radiographic evidence of disease. 2 , 3 The histopathology of CRS, often seen secondary to sustained mucosal inflammation, results in cellular infiltrates, epithelial barrier disruption, and thickening and remodeling of the sinonasal mucosa. 4 In contrast, RARS describes acute bacterial infections which can often be severe, recurrent, or unresponsive to appropriate courses of antimicrobial therapy. 5 , 6 While most immunocompetent patients clear bacterial sinus infections efficiently, recurrent or refractory presentations ought to raise increased suspicion for an underlying state of immunodeficiency. 1 , 6–9

Immunodeficiency represents an important predisposing factor in both phenotypes of rhinosinusitis. Primary immunodeficiencies, such as common variable immunodeficiency, selective IgA deficiency, and specific antibody deficiency, are frequently associated with recurrent sinopulmonary infections. 1 , 7–9 Similarly, secondary immunodeficiencies, including those related to hematologic malignancy, immunosuppressive therapy, or systemic diseases, confer increased susceptibility to infectious processes of the sinonasal tract and upper airway. 1 , 8 , 10–12 Impaired humoral immunity is particularly relevant, as effective clearance of encapsulated pathogens such as Streptococcus pneumoniae and Haemophilus influenzae requires intact antibody production and opsonization. 8 , 10 , 13 Deficiencies in innate immune pathways, in contrast, can lead to impaired mucociliary clearance and epithelial barrier function which may further promote bacterial persistence, biofilm formation, and chronic mucosal inflammation characteristic of CRS. 14–16

Distinguishing CRS from recurrent or recalcitrant bacterial rhinosinusitis in immunodeficient hosts can be challenging for physicians, as both conditions may present with overlapping symptoms and poor response to standard medical therapy. 1 , 6 , 9 High-resolution computed tomography (CT) and nasal endoscopy remain essential diagnostic modalities; 2 , 3 however, comprehensive immunologic evaluation is critical in patients with frequent or refractory infections. 6 , 8 , 9 Measurement of quantitative immunoglobulins, IgG subclasses, and functional antibody responses to polysaccharide and protein antigens provides valuable information regarding humoral competence. 1 , 8 Furthermore, the identification of immune dysfunction has important therapeutic implications as management may extend beyond conventional antibiotics and corticosteroids to include long-term antimicrobial prophylaxis, surgical intervention, selective vaccination and immunoglobulin replacement therapy in select conditions. 1 , 6–9

This review will discuss the work-up and diagnosis of primary and secondary immunodeficiency disorders in patients with CRS. It will also expand on the current treatment options for this patient population.

Classification and Prevalence of Immunodeficiency in Patients with CRS

Primary Immunodeficiency

Primary Antibody Deficiency

Primary immunodeficiencies (PIDs) represent a diverse group of inherited or intrinsic disorders characterized by impaired immune function, with primary antibody deficiencies (PAD) constituting the most prevalent and clinically significant subtype. 1 These include selective immunoglobulin A (IgA) deficiency, common variable immunodeficiency (CVID), and specific antibody deficiency (SAD); each defined by defects in immunoglobulin quantity or function. 1 Selective IgA deficiency, the most common PAD in Western populations with approximately 1 in 200 to 1000 prevalence, is often asymptomatic, but predisposes to recurrent mucosal infections such as RARS. 1 , 9 CVID, though rarer – approximately 0.5 to 10% of patients with CRS – is associated with varying morbidity, including respiratory infections, autoimmunity, and lymphoproliferative disorders. 1 , 6 , 9 SAD, marked by poor responses to polysaccharide antigens despite normal immunoglobulin levels, is also increasingly recognized across age groups. 1

While the general prevalence of humoral immune defects is low, upwards of 20% of adults with recalcitrant CRS may harbor an underlying antibody deficiency representing a subset with significantly higher prevalence than baseline population rates. 6 , 9 This stronger association underscores the importance of immunologic evaluation in CRS patients with recurrent bacterial exacerbations, poor response to medical therapy, or persistent disease despite appropriate surgery. 1

Timely recognition of antibody deficiency in CRS patients is critical for guiding targeted interventions. Immunoglobulin replacement therapy has demonstrated efficacy in reducing infection frequency, improving sinonasal outcomes, and preventing progression to lower respiratory tract complications such as bronchiectasis; 17 , 18 however, persistent local disease may occur despite adequate systemic immunoglobulin levels, necessitating a multidisciplinary approach that integrates medical management, endoscopic sinus surgery (ESS), and ongoing immunologic monitoring. 6 , 8 , 9 , 18 Current guidelines advocate for immunologic screening in patients with refractory or atypical CRS. 6 , 9 , 18 Ultimately, identifying and treating antibody deficiencies in this population offers a precision-based strategy.

Secondary Immunodeficiency

Immunodeficiency in Cancer

Secondary immunodeficiency (SID) is a common complication in cancer patients, arising either from the malignancy itself or as a consequence of its treatment. In contrast to primary immunodeficiencies, SIDs are acquired and may be underrecognized despite the significant risk of susceptibility to infection and impaired quality of life.

In hematologic malignancies such as chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), SID is primarily driven by impaired B-cell function and hypogammaglobulinemia, leading to reduced antibody production and poor mucosal immunity. 19 Solid tumors may also contribute to SID through malnutrition, tumor burden, and immunosuppressive therapies. 20 Chemotherapy, radiation, and targeted agents such as anti-CD20 monoclonal antibodies (eg, rituximab) further compromise immune defenses by depleting lymphocytes and disrupting mucosal barriers. 19 , 21 Other well established mechanisms include suppression or elimination of T-cells, or suppression of pro-inflammatory transcription factors. 22

CRS in immunocompromised patients often presents with atypical features including refractory symptoms, frequent exacerbations, and colonization by opportunistic pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus . 1 , 10 Studies have shown that patients with SID exhibit recurrent or chronic rhinosinusitis, and CRS may be the first clinical manifestation of an underlying immune defect. 22 In cancer patients, this overlap is especially concerning as untreated CRS can serve as a nidus for systemic infections and further compromise immune recovery. 22 Diagnosis of SID in the context of malignancy requires a high index of suspicion as a number of treatments can deplete key immune regulators of the body, such as B-cells, cytokines, and neutrophils, which may predispose to the need for more extensive treatment or surgery. 22 Nasal endoscopy and sinus CT imaging are essential for evaluating the extent of mucosal disease and guiding treatment.

Management of severe or refractory CRS within this population includes culture-directed antibiotics, but often relies heavily on ESS to assist with pathogen clearance, allow for reduced inflammatory load, and improve the chance of recovery. 18 , 23 Moreover, immunoglobulin replacement therapy has been shown to reduce infection rates and improve CRS outcomes in selected patients with hypogammaglobulinemia. 22 , 24 , 25

Immunodeficiency in Transplant Patients

CRS is an important clinical problem in patients with secondary immunodeficiency following solid organ transplantation, arising from the interplay between immunosuppressive therapy, impaired mucosal defenses, and altered host–pathogen interactions. To prevent graft rejection, transplant recipients typically require long-term immunosuppressive regimens incorporating calcineurin inhibitors, antiproliferative agents, corticosteroids, and in some cases monoclonal antibodies or mTOR inhibitors. 26 These agents impair adaptive immunity through suppression of T-lymphocyte activation, inhibition of B-cell proliferation and antibody production, and attenuation of cytokine signaling. 26 Concurrently, innate immunity is disrupted, with reduced neutrophil chemotaxis, diminished macrophage activity, and compromised epithelial barrier integrity. 26 The cumulative effect is a profound impairment in mucosal immune surveillance and pathogen clearance within the sinonasal tract. 27

Vulnerability contributes to both increased susceptibility to acute sinonasal infections and the development of CRS. The sinonasal mucosa, normally reliant on coordinated ciliary function and local IgA secretion for pathogen defense, becomes unable to effectively clear microbial biofilms and environmental antigens. 15 Persistent bacterial or fungal colonization, together with impaired epithelial repair mechanisms, drives chronic inflammation and mucosal remodeling. 14 , 15 Unlike CRS in immunocompetent individuals which often involves dysregulated type 2 inflammation, 2 , 3 CRS in transplant recipients is more strongly linked to defective immune defense and opportunistic infection, including fungal pathogens and multidrug-resistant organisms. 28

CRS in this population is frequently refractory to conventional medical therapy. 28 Topical and systemic antibiotics may be less effective due to resistant organisms, and corticosteroids are limited by potential interactions with systemic immunosuppressants. Endoscopic sinus surgery can provide mechanical clearance and enhance topical drug delivery, yet perioperative care requires careful modulation of immunosuppression to balance infection risk with graft protection. 23 , 28

Immunomodulators and Immunodeficiency

CRS in the setting of immunomodulatory therapy represents a growing clinical concern as the use of targeted biologics and small-molecule agents expands across autoimmune, oncologic, and inflammatory conditions. Unlike the global immunosuppression induced by organ transplantation regimens, immunomodulators exert selective effects on discrete components of the immune system, thereby reshaping mucosal defense and susceptibility to sinonasal disease. Agents such as tumor necrosis factor (TNF) inhibitors, Janus kinase (JAK) inhibitors, integrin blockers, and B-cell depleting therapies alter innate and adaptive immune responses in ways that impair host capacity to control infection and regulate inflammation within the sinonasal tract. 29–32

The pathophysiology of CRS in this population reflects both diminished antimicrobial defense and aberrant inflammatory signaling. TNF inhibitors, for example, blunt macrophage activation and granuloma formation, predisposing to persistent bacterial and fungal colonization. 29 JAK inhibitors interfere with interferon and interleukin signaling critical to mucosal immunity, 33 while B-cell targeted therapies, such as rituximab, reduce antibody production thus limiting IgA-mediated protection in the sinonasal epithelium. 34 These alterations can compromise mucociliary clearance, epithelial barrier repair, and microbial surveillance, facilitating chronic microbial biofilm persistence and promoting sinonasal inflammation. 30 CRS under immunomodulatory therapy is frequently infection-driven, refractory to standard therapies, and complicated by opportunistic organisms. 30 Additionally, prolonged or recurrent sinonasal infection may exacerbate underlying systemic disease, complicating immunomodulator dosing and necessitating close interdisciplinary coordination. 29 , 30

Immunodeficiency Secondary to Autoimmunity

Unlike classical primary immunodeficiency, autoimmune immunodeficiency arises when immune dysregulation not only drives autoantibody production and self-reactivity, but also paradoxically impairs protective host defense. 35 This phenomenon is most evident in disorders such as CVID with autoimmune features, autoimmune lymphoproliferative syndrome, and antibody deficiency secondary to variations of autoimmune cytopenia. 36 The resulting hypogammaglobulinemia, impaired class-switch recombination, or dysfunctional lymphocyte activity directly compromise mucosal immunity in the upper airways. 36

The pathophysiology linking autoimmune immunodeficiency and CRS is multifaceted; reduced production of immunoglobulins – particularly IgA and IgG – impairs opsonization, neutralization of pathogens and mucosal defense against bacteria and viruses in the sinonasal epithelium. 1 , 35 , 36 Defective T- and B-cell regulation, which is common in these conditions, diminishes adaptive immune surveillance, 37 , 38 while chronic systemic inflammation can further weaken epithelial barrier integrity. 4 At the same time, autoimmune-mediated tissue injury within mucosal surfaces may contribute to epithelial disruption and persistent microbial colonization. 4 Together, these abnormalities foster an environment prone to recurrent infections, biofilm persistence, and persistent sinonasal inflammation, all of which are commonly seen in CRS. 4

CRS in this context often has a bacterial or mixed bacterial-fungal basis, reflecting impaired clearance rather than eosinophilic or type 2–driven inflammation typical of some immunocompetent CRS phenotypes. 2 , 4 , 14

Treatment

Several treatment options are considered for patients with CRS and immunodeficiency. These include clinical response to the Pneumovax-23 vaccination, prophylaxis antibiotics, immunoglobulin (Ig) replacement therapy, and surgical treatment. Table 1 provides a summary of some of the clinical studies that looked at the outcome of treatment in this patient population.

Vaccination

Since infections by encapsulated bacteria such as S. pneumoniae are pivotal in the pathogenesis of CRS, it stands to reason that vaccination offers both insight into immune competence and a potential therapeutic benefit.

In a meta-analysis by Bose et al, humoral immunodeficiencies such as IgG, IgA, and IgM deficiencies were found in approximately 13% of patients with recurrent CRS and 23% of those with difficult-to-treat disease; 49 moreover, as a prognostic tool, impaired response to pneumococcal polysaccharide vaccines despite normal immunoglobulin levels is identified in up to 23% of patients with refractory CRS. 49 , 50 A retrospective study of 129 refractory CRS patients revealed 72% had low baseline pneumococcal antibody titers. Among those, 11.6% met criteria for SAD based on inadequate vaccine response. 50 Further to this point, another study demonstrated that 67% of refractory CRS patients failed to mount a >4-fold increase in more than 7 of 14 antibody serotypes after Pneumovax 23 (PPSV23), reflecting high prevalence of functional antibody deficiency. 51

Conjugate pneumococcal vaccines (eg, PPSV23) may elicit adequate responses in adult patients who fail to respond to polysaccharide vaccines; such responses are associated with fewer sinus infections requiring antibiotics. A study by Bareiss et al, showed that administering PPSV23 to patients with nonprotective titers has been shown to produce protective responses in approximately 89% of CRS and 90% of recurrent ABRS patients. Post-vaccination, these patients experienced significant reductions in CRS/RARS diagnoses, antibiotic use, and corticosteroid prescriptions. 39

Antibiotics

Antibiotics remain integral to the management of CRS in immunodeficient patients, with roles spanning acute therapy, prophylaxis, and complication management. While prophylactic regimens can reduce infection frequency in some patients, their benefits are inconsistent, and risks of resistance are significant. Antibiotics are commonly prescribed for acute bacterial exacerbations of CRS. While randomized controlled trials (RCTs) in the general CRS population show modest symptomatic benefit, 52 the risk of progression to severe or systemic infection in the immunodeficient patients warrants a lower treatment threshold. In the non-type 2 endotype of CRS, low-dose, long-term macrolides (eg, azithromycin, clarithromycin) provide both antimicrobial and immunomodulatory effects. Meta-analyses suggest potential improvements in endoscopic scores and infection frequency; 41 however, data specific to immunodeficient patients are limited, and concerns regarding antimicrobial resistance and cardiac toxicity restrict their use.

In cases of orbital, intracranial, or osseous complications, immunodeficient patients typically require aggressive IV antibiotic regimens combined with surgical drainage. 53 Outcomes are generally favorable with early multidisciplinary management, though complication rates remain higher compared to immunocompetent CRS patients.

Lastly, as it relates to prophylactic dosing and treatment, antibiotics are frequently employed in antibody deficiencies to prevent recurrent sinopulmonary infections. Observational studies report reductions in infection frequency, 54 though high-quality RCTs in CRS cohorts, especially patients with immunodeficiency, are lacking. Comparative analyses suggest that while prophylaxis can reduce episodes, other treatments such as immunoglobulin replacement therapy often provides more durable infection control in patients with significant antibody defects. 1

Immunoglobulin Replacement Therapy (IRT)

IRT supplies exogenous IgG, compensating for absent or dysfunctional antibody production; this prevents recurrent infections by various means including neutralizing bacterial toxins and opsonizing pathogens, enhancing complement activation and phagocytosis, and maintaining protective serum antibody levels against encapsulated organisms. 1 , 8 , 10 , 13 It should be noted that while IRT addresses infection susceptibility, it does not directly modulate the chronic inflammatory pathways (eg, type 2 inflammation, tissue remodeling) central to CRS, explaining the persistence of symptoms in some patients. 1

Cohort studies and meta-analyses consistently show that IRT reduces the frequency and severity of sinopulmonary infections in antibody deficiency disorders and leads to improved patient outcomes. 42–44 , 55 In a 2016 study by Walsh et al, a retrospective review of adults with either CVID or SAD and CRS were evaluated. After initiation of IRT, the authors found improvements in patient Lund-Mackay scores, lower rates of sinusitis and respiratory infections, and discontinuation of prophylactic antibiotics in over 50% of the patient population. 42 Later, Makary et al, retrospectively evaluated adults with primary immunodeficiency on IRT. The population included a mix of CVID, hypogammaglobulinemia, and SAD. Of the 58 patients included in the study, there was a significant reduction in the need for revision sinus surgery and a marked reduction in the rates of recurrent acute bacterial sinusitis or exacerbations of CRS. 43 Lastly, a 2023 study by Garvey et al who specifically examined patients with CRS and immunodeficiency determined that initiation of IRT reduced the need for antibiotics and steroids, and led to improvements in SNOT-22 scores. 44

Endoscopic Sinus Surgery

Endoscopic sinus surgery (ESS) is a cornerstone intervention for patients with medically recalcitrant CRS. While robust evidence supports its efficacy in the general population, outcomes in patients with underlying immunodeficiency remain less well defined due to limited and heterogeneous data. 2 , 3 , 45–48

A 2010 study by Khalid et al, who reviewed 22 adult patients with CRS matched 1:1 with immunocompetent patients with CRS who underwent ESS, showed similar improvements in post-operative endoscopy scores quality of life; however, immunocompetent patients reported significantly worse baseline Rhinosinusitis Disability Index (RDS) compared to their immunocompromised counterparts. 45

Later work performed by Dao et al 46 and Samargandy et al 47 further showed that surgical treatments (ie, ESS) for immunocompromised patients leads to improved outcomes; Dao et al retrospectively reviewed a total of 132 patients with varying types of chronic and acute rhinosinusitis with multiple comorbidities denoting an immunocompromised state and determined that treatment plans which incorporate surgical treatment lead to improved patient outcomes and reduced morbidity. 46 In contrast, Samargandy et al specifically evaluated 13 patients with immunoglobulin deficiencies and CRS who underwent ESS; 47 while not statistically significant, their study suggested that patients with immunoglobulin deficiency undergo higher rates of revision surgery for their CRS (31% versus 12%), though both patient population experience meaningful improvement in SNOT-22 scores post-operatively. 47 Their conclusions were in support of their earlier work which suggested patients with immunodeficiency benefit from ESS. 23

Most recently, a 2025 study by Gao et al retrospectively reviewed a mixed cohort of patients with immunodeficiency conditions including PID, autoimmune disease, and those on immunomodulating medications. 48 Overall, their work found that following ESS, patients with immunodeficiencies are at higher odds of complications including meningitis and CSF leak, are more likely to develop acute rhinosinusitis, show higher use of steroids and antibiotics in the acute post-operative period, and are more likely to need revision surgery. 48

Strength and Limitations of Review

Despite the abundance of literature on immunodeficiency, chronic rhinosinusitis, and associated management strategies, connecting basic science to clinical application remains a great challenge; as such, this review aims to serve as a roadmap for clinicians while working with these patients.

The strengths of this review are born out of the volume of recent and high-yield literature incorporated into both the review and recommendations. Utilizing basic science as a foundation and closely weaving it into clinical studies, the authors utilize the most up-to-date research on the topics of concern with the goal of improving both patient care and outcomes.

All works are not without their weaknesses, and this review is not immune to that. Reviews and the clinical recommendations they make are heavily reliant on the available literature. Due to the nuances of this clinical population, while there is a great deal of basic science to reference, there are fewer clinical studies – particularly those that focus on patient outcomes – to reference when discussing treatment and outcomes; moreover, because of the multi-disciplinary nature of treatment, there are even fewer groups of clinicians who work closely with this population of patients. This makes robust clinical management even more challenging. Nevertheless, this area continues to be an evolving field and in need of much further multi-disciplinary research.

Summary and Conclusion

The intersection of CRS, RARS, and immunodeficiency underscores the central role of host defense mechanisms in sinonasal homeostasis. Recognition of underlying immune defects is essential for accurate diagnosis, rational treatment selection, and reduction of disease burden in this high-risk population. Treatment for all patients spans vaccination strategies, culture-directed antibiotics, immunoglobulin replacement therapy and appropriate reversal of secondary causes, and ESS. While primary immunodeficiency patients may benefit from IRT, this is not the case for patients with secondary immunodeficiency, particularly those with immunodeficiency secondary to malignancy, transplant, or autoimmunity. IRT consistently reduces sinopulmonary infections and improves sinonasal outcomes and should be initiated in the care of all patients found to have primary immunodeficiency, particularly in those with a history of multiple recurrent sinopulmonary infections or who have required multiple courses of intravenous antibiotics to clear infections. ESS remains important for medically refractory disease, improving symptoms and access for topical therapy, though recent data suggest higher revision rates in immunodeficient cohorts, warranting multidisciplinary, personalized care ( Table 2 ). ESS should therefore be utilized to aid in allowing for improve sinus cavity drainage by maintaining mucociliary clearance. Further to this point, one ought to consider ESS in both primary and secondary immunodeficiency patients with either recurrent or complicated sinonasal infections with the goals of improving access for specimen culture and to allow for better topical medication delivery to aid in eradication of bacterial and their biofilm byproducts. Overall, identifying immune deficiency disorders enables precision management that blends medical therapy, IRT, and judicious surgery to reduce infections and improve quality of life.

Funding Statement

This article was completed without any financial support of any kind.

Data Sharing Statement

No data was generated through artificial intelligence or any other means. Any data from previously published works has been cited appropriately throughout the article.

Author Contributions

Christopher Bell: conceptualization, resources, writing - original draft, review & editing

Amber Luong: conceptualization, resources and writing - review & editing

Chadi Makary: conceptualization, formal analysis, resources and writing, review & editing

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

AL is a consultant for Lyra Therapeutics, Medtronic, Neurent Medical, Sanofi, Sound Health Systems and Stryker; received fees from Amgen/AstraZeneca, GlaxoSmithKline, Regeneron, Sanofi, and Maxwell Biosciences; owns stock in Aerin Medical; and obtained research funding from Eli Lily, Insmed, Lyra Therapeutics, and Sanofi.

The other authors have no competing interests to disclose.

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Associated Data

Data Availability Statement

No data was generated through artificial intelligence or any other means. Any data from previously published works has been cited appropriately throughout the article.