ENTs Urged to Look Beyond Refractory Sinus Disease for Underlying Immune Deficiency

For many patients with chronic rhinosinusitis (CRS), repeated rounds of antibiotics, corticosteroids, and endoscopic sinus surgery eventually bring symptoms under control. But in those whose disease remains stubbornly refractory, the real diagnosis may lie outside the sinonasal cavity.

The culprit in up to a quarter of these resistant cases is primary immunodeficiency (PID), a condition that ENT physicians are uniquely positioned to detect and manage (Int Forum Allergy Rhinol. doi:10.1002/alr.23090). But that work requires bringing both curiosity and self-awareness to your CRS evaluations, noted Jay Shah, MD, FAAP, FACS, the medical director of the pediatric aerodigestive program at University Hospitals of Cleveland Medical Center/Rainbow Babies and Children’s Hospital and associate professor of otolaryngology–head and neck surgery at Case Western Reserve University School of Medicine, both in Cleveland, Ohio.

In the case of failed endoscopic sinus surgery, for example, “sometimes we have to be humble and ask, why did it fail? Was it surgical or was there something else?” Dr. Shah said.

In the past few years, he said, “I have come to realize that in many of my refractory CRS patients, the lack of response is not because the surgery went wrong; it’s because there’s something that is not allowing their innate immunity to fight the problem that led to the surgery.”

Dr. Shah presented an overview of PID as a possible cause of CRS at the Immunoglobulin National Society’s most recent National Conference, in Arlington, Texas. One of the practical strategies he offered was a list of red flags to look for, including:

• Patients experiencing more than eight new sinus infections within one year, with two or more considered serious;
• Two months of failed antibiotics, followed by the need for IV antibiotics to clear the sinus infection; and
• Failure of an infant to gain weight or grow normally.

Chronic or recurrent pneumonia, otitis media, bronchiectasis, and obstructive pulmonary disease are other PID warning signs to heed, he noted. An increased frequency of chest infections, meningitis and/or sepsis, as well as gastrointestinal and cutaneous infections, should also raise suspicion that an underlying immune dysfunction may be at work.

If enough of these signals are present, it’s time to determine whether the cause truly is PID “or whether a patient is simply under-immunized,” Dr. Shah said. To make that determination, one effective strategy is to give the patient Pneumovax 23 (PPSV23), a pneumococcal vaccine that protects against 23 strains of Streptococcus pneumoniae bacteria, a common cause of recurrent sinus and otologic disease. “If they get this Pneumovax booster, which is a polysaccharide vaccine that tests the immune system’s ability to produce immunoglobulins, and you check their antibody titers and their titers go roughly from 0.1 to 7.20, then you know their response to earlier vaccinations, typically with pneumococcal conjugate vaccine [PCV], waned,” he said. In such cases, “they just needed that PPSV23 booster to rebuild their immunity and break the cycle of recurrent infections.”

If their antibody titers remain low, on the other hand, “that is a huge red flag that they have PID, and your next step will likely need to be a consultation with an immunologist.”

A 2023 study by Bonaventure et al. confirmed that the PPSV booster can be a highly effective indicator for a CRS patient’s immune function. The study included 242 patients (ages 0 to 21 years) who were diagnosed primarily with recurrent acute otitis media, chronic rhinitis, and chronic otitis media with effusion and who had received the four-dose PCV schedule. Initial testing revealed that only 27% of the patients had titers conferring immunity from their prior PCV vaccinations. Approximately 85 of the patients were then revaccinated with PPSV, and antibody responses conferring immunity reached 91.8% (Ann Otol Rhinol Laryngol. doi:10.1177/00034894231182745). “That 10% of remaining nonresponders are the ones you have to worry about,” Dr. Shah said. “Those are the patients who may benefit from immunologic evaluation and targeted immunotherapy rather than repeated courses of antibiotics or additional sinus surgery.”

For ENT physicians who practice in a tertiary care center such as Children’s Hospital, where patients often are referred after multiple failed surgeries and antibiotics and repeated bouts of illness, that 10% figure can be misleadingly low.

“Almost every week, I have a parent come with this typical but incredibly frustrating story of failed interventions,” Dr. Shah said. “I get their child over to immunology, and working together, we get a panel of tests done, we determine they have PID, they get their Ig therapy injections, and within a short period of time, they show major improvements, and we’ve broken the cycle of failed surgical and antibiotic interventions.”

Where to Start with Testing

But not all community ENT physicians have ready access to an immunologist for consultation, noted Chadi A. Makary, MD, MSc, FARS, FACS, the chief of rhinology and endoscopic skull base surgery at West Virginia University (WVU), in Morgantown, W.Va. Fortunately, there are some initial immunologic workups an ENT physician can order. “If we do the initial panel and interpretation, we may not need to send everyone to an immunologist,” he said. “That’s a big plus if you’re not practicing in a large academic medical or tertiary care setting,” said Dr. Makary, who co-authored two recent evidence-based reviews of how to manage CRS patients with PID in children (Int Forum Allergy Rhinol. doi:10.1002/alr.23468) and adults (Int Forum Allergy Rhinol.  doi.org/10.1002/alr.23206).

As for which tests to order, “I typically recommend CBC [complete blood count] with differential; quantitative serum immunoglobulin levels (IgG, IgA, and IgM); and assessment of functional antibody responses, particularly pneumococcal vaccine titers, which we outlined in our evidence-based reviews,” he said. “Depending on the clinical scenario, additional testing such as tetanus antibody titers, lymphocyte subsets, or complement studies may be appropriate, but these are often best guided by an immunologist.”

Indeed, knowing when to reach out to an immunologist is critical, Dr. Makary stressed. “The goal isn’t simply to identify an abnormal laboratory value; it’s to determine whether the patient has a clinically significant immune deficiency that warrants treatment,” he said. To that end, “immunologists can perform more comprehensive immune testing, interpret complex results, assess vaccine responses, and determine whether therapies such as immunoglobulin replacement are indicated.”

If Ig therapy is deemed an option, the next question is, are there data to support its efficacy? That was a major focus of Dr. Makary and his colleagues when authoring their evidence-based reviews, and their basic conclusion, after scouring PubMed, EMBASE, and Cochrane literature databases, was that the evidence is mixed.

On the positive side, Dr. Makary noted, one of his own studies included in the literature looked at 58 patients with CRS and primary antibody deficiency (PAD)—a more general term than PID that includes any inherited disorder affecting the immune system (PID typically involves impaired B-cell function and antibody production). The study found that 58.6% of the patients given Ig replacement therapy had no acute infections during 4.2 years of follow-up (Laryngoscope. doi:10.1002/lary.29694).

A study of 22 patients with immunoglobulin deficiency and resistant CRS by May et al., in contrast, found that all patients failed intravenous immunoglobulin therapy and subsequently required surgery (Eur Arch Otorhinolaryngol. doi:10.1007/s004050050186). And a Quinti et al. study of 224 patients with common variable immunodeficiency (CVID)—one of the few trials in the evidence-based review to include a large number of patients—yielded mixed results. While IVIG significantly reduced the incidence of acute infections such as pneumonia and otitis, the investigators reported a progressive increase in the number of patients who developed chronic rhinosinusitis and lung disease. Those latter findings in the patients with CVID (a subvariant of PAD) were observed in all age groups, including the pediatric population (J Clin Immunol. doi:10.1007/s10875-007-9075-1).

Still, taken together, the efficacy and safety data for Ig therapy in the evidence-based review were deemed compelling enough to warrant a “preponderance of benefit over harm” assessment by Dr. Makary and his co-authors, along with a statement that Ig treatments should be deemed “an option” in patients with CRS and immune dysfunction.

The Toll of a Missed PID Diagnosis

Dr. Makary stressed that such evidence-based deliberations are useful in assessing the likely benefits of Ig therapy, but they only go so far. “You also have to consider the striking cost of missing PID in these patients or not managing it effectively, whether it be with Ig replacement or some other immunomodulatory therapy,” he stressed. CRS patients, he explained, “may spend years cycling through repeated antibiotic courses, corticosteroids, imaging studies, office visits, and multiple surgical procedures while the underlying immune defect goes untreated.”

During that time, ongoing inflammation can lead to irreversible mucosal remodeling and progressive upper and lower airway damage (Laryngoscope. doi:10.1002/lary.22374). And while surgery can improve symptoms and facilitate topical therapy, “it cannot correct the immune deficiency itself,” Dr. Makary said. “Disease recurrence remains common if the immunologic disorder is left untreated.”

What’s more, the cumulative healthcare burden of CRS “can be substantial,” he stressed. In addition to the aforementioned repeated antibiotic exposures and imaging, there are also costly emergency department visits, hospitalizations, and multiple operations (Laryngoscope. doi:10.1002/lary.24630).

Given those high stakes, asked whether there is one key improvement ENT physicians can make when managing these refractory patients, Dr. Makary replied, “test more for immune deficiency.” The baseline assays he recommended “are relatively simple, quick lab tests,” he said. “And you will be surprised how many times you will find abnormalities that, when properly identified and managed, can make a huge difference in these patients’ lives.”

Another Call for Testing

Aaron N. Pearlman, MD, FACS, an associate professor of clinical otorhinolaryngology at Weill Cornell Medical College, in New York, agreed that ENT physicians are “perfectly capable” of ordering and interpreting these initial tests of immune function in CRS patients. He also agreed that obtaining PPSV23 titers “is a great place to start.” If the titers are high, “great,” Dr. Pearlman said. “If they’re low, and you give them a booster and they respond, that means they were just under-immunized, which can happen in patients who are years out from their last vaccination.”

For patients who fail to respond to the PPSV23 booster, “that’s when I start suspecting immune dysfunction and order follow-up tests.” Typically, he noted, “I’ll start with quantitative immunoglobulins (IgG, IgA, IgM) and see what unfolds.”

Dr. Pearlman said it’s also important to measure a CRS patient’s response to the Haemophilus influenzae type b (HiB) vaccine, because the organism it protects against is one of the more common causes of recurrent sinus infections and related disease. Specific to the HiB vaccine, “the problem is that most adult primary care physicians don’t have this vaccine to boost, since it’s usually done in a pediatric setting,” he said.

Why is that a potential problem? “Because patients can be lost to follow-up and it may never get done,” he said. “So, I have workflow processes in place that allow me to check with them to ensure they got the booster and, six to eight weeks later, have their titer retested.” As ENT physicians, “this is our responsibility,” he stressed. “It can’t all be on the patient. Because if the testing process breaks down, all of your initial interventions and workups have gone for naught.”

That testing process can also break down if the panel is not clearly focused on assays that yield “the best bang for the buck,” stressed Dr. Pearlman, who has a research interest in the immunologic basis of sinus disease. In a 2020 study he co-authored, his team looked at the prevalence of abnormal immunologic test results in 27 pediatric patients with CRS or recurrent acute rhinosinusitis (Am J Rhinol Allergy. doi.org/10.1177/1945892419875088). The investigators found that IgM deficiencies were the most commonly detected (13%), followed by IgA (11.1)%. Additionally, four (23.5%) of the 17 patients had significantly elevated IgE levels, “which pointed to an allergic etiology,” Dr. Pearlman said. “We also found an increased incidence of insufficient protective titers to polysaccharide vaccines and HiB titers, which were not protective in 55% and 30% of the patients, respectively.”

Bottom line? “We concluded that high-yield testing in children with recurrent sinus disease should include titers to polysaccharide antigens—specifically, Strep pneumo and H. influenzae—but that at least during initial testing, you can probably forego thyroid studies and tests for tetanus and diphtheria antibodies,” Dr. Pearlman said.

Don’t Hesitate to Ask for Help

In doing the above study, “I came to realize that when I did my rhinology fellowship all those years ago, I really should have done an immunology fellowship, because our understanding of chronic sinusitis has changed from seeing it as an infection to now thinking about it as an inflammatory condition that can be spurred by immune dysfunction,” Dr. Pearlman said. In some patients, the picture may be simple enough for an ENT physician to navigate, as in those whose testing reveals they simply are under-immunized—“that person doesn’t need an immunologist consult or evaluation,” he said. “But for those nonresponders, the immunologic picture can quickly get super-complicated, so be ready and willing to call for an immunologist consult.”

He cautioned, however, that not all patients with documented immune dysfunction will respond to treatments such as Ig therapy, because there is not a 100% causal relationship between CRS and those immune deficits. Having said that, he added, “I can tell you that in my own practice, I have seen major improvements after identifying and treating an immunodeficiency.” Instead of a patient getting upwards of eight to 10 sinus infections a year, “maybe now they are getting one or two,” Dr. Pearlman said. “But that won’t occur in every case where you intervene. So be prepared for that.”

As for other important concepts to keep in mind when managing CRS patients with suspected immune dysfunction, Dr. Pearlman reaffirmed the need to not be a “one-and-done” type of ENT practitioner with these patients. Whether it is following up to ensure the right immune function tests have been ordered and the results analyzed by key care team members, or seeking out an immunologist consult, “don’t be lulled into inattention because these nonresponders represent a small part of your patient base,” he said. “They need as much—or arguably more—of your attention to break that cycle of repeated sinus disease and failed treatments as your more responsive patients.”    

David Bronstein is a freelance medical writer based in New Jersey.