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Figure 1.
Interferon γ (IFN-γ) and interleukin (IL) 12p40 production in a patient with treatment-resistant chronic rhinosinusitis (CRS) and a suspected defect in IL-12 production compared with that in control children (n = 23). The results shown were obtained when peripheral blood mononuclear cells (106 cells/mL) were cultured with phytohemagglutinin (PHA) (10 µg/mL) and biologically active IL-12p70 (0.2 pg/mL) for 4 days. Production of IFN-γ is normalized in response to exogenous IL-12p70 use, but IL-12p40 production is markedly low with use of PHA and IL-12p70.

Interferon γ (IFN-γ) and interleukin (IL) 12p40 production in a patient with treatment-resistant chronic rhinosinusitis (CRS) and a suspected defect in IL-12 production compared with that in control children (n = 23). The results shown were obtained when peripheral blood mononuclear cells (106 cells/mL) were cultured with phytohemagglutinin (PHA) (10 µg/mL) and biologically active IL-12p70 (0.2 pg/mL) for 4 days. Production of IFN-γ is normalized in response to exogenous IL-12p70 use, but IL-12p40 production is markedly low with use of PHA and IL-12p70.

Figure 2.
Interferon γ (IFN-γ) (A) and interleukin (IL) 12p40 (B) levels produced by peripheral blood mononuclear cells (106 cells/mL) from patients with treatment-resistant chronic rhinosinusitis (CRS) using stimuli of phytohemagglutinin (PHA) (10 µg/mL), biologically active IL-12p70 (0.2 pg/mL), and IL-18 (1 ng/mL). Owing to low IFN-γ production with these stimuli but elevated IL-12p40 production with PHA and IL-12p70, these patients were suspected of having an IL-12 receptor–mediated signaling defect.

Interferon γ (IFN-γ) (A) and interleukin (IL) 12p40 (B) levels produced by peripheral blood mononuclear cells (106 cells/mL) from patients with treatment-resistant chronic rhinosinusitis (CRS) using stimuli of phytohemagglutinin (PHA) (10 µg/mL), biologically active IL-12p70 (0.2 pg/mL), and IL-18 (1 ng/mL). Owing to low IFN-γ production with these stimuli but elevated IL-12p40 production with PHA and IL-12p70, these patients were suspected of having an IL-12 receptor–mediated signaling defect.

Figure 3.
Interferon γ (IFN-γ) and interleukin (IL) 12p40 levels produced by peripheral blood mononuclear cells (106 cells/mL) from patients with treatment-resistant chronic rhinosinusitis (CRS) using stimuli of phytohemagglutinin (PHA) (10 µg/mL), biologically active IL-12p70 (0.2 pg/mL), or IL-18 (1 ng/mL). In contrast to patients with CRS in Figure 2, these patients produced excessive IFN-γ and IL-12p40 in response to IL-12p70 use, indicating a defect in biological functions of intrinsic IL-12.

Interferon γ (IFN-γ) and interleukin (IL) 12p40 levels produced by peripheral blood mononuclear cells (106 cells/mL) from patients with treatment-resistant chronic rhinosinusitis (CRS) using stimuli of phytohemagglutinin (PHA) (10 µg/mL), biologically active IL-12p70 (0.2 pg/mL), or IL-18 (1 ng/mL). In contrast to patients with CRS in Figure 2, these patients produced excessive IFN-γ and IL-12p40 in response to IL-12p70 use, indicating a defect in biological functions of intrinsic IL-12.

Figure 4.
Interferon γ (IFN-γ) levels produced by peripheral blood mononuclear cells (106 cells/mL) in a patient with treatment-resistant chronic rhinosinusitis (CRS) using stimuli of phytohemagglutinin (PHA) (10 µg/mL), biologically active IL-12p70 (0.2 pg/mL), and IL-18 (1 ng/mL). Peripheral blood mononuclear cells produced little IFN-γ, irrespective of the stimuli used, indicating a defect in intrinsic IFN-γ production.

Interferon γ (IFN-γ) levels produced by peripheral blood mononuclear cells (106 cells/mL) in a patient with treatment-resistant chronic rhinosinusitis (CRS) using stimuli of phytohemagglutinin (PHA) (10 µg/mL), biologically active IL-12p70 (0.2 pg/mL), and IL-18 (1 ng/mL). Peripheral blood mononuclear cells produced little IFN-γ, irrespective of the stimuli used, indicating a defect in intrinsic IFN-γ production.

Table 1. 
Clinical Features of Patients With Chronic Rhinosinusitis Treated With Exogenous Interferon Gamma
Clinical Features of Patients With Chronic Rhinosinusitis Treated With Exogenous Interferon Gamma
Table 2. 
Results of Sinus Lavage Cultures
Results of Sinus Lavage Cultures
Table 3. 
Clinical Outcomes After Supplemental Exogenous Interferon Gamma Use
Clinical Outcomes After Supplemental Exogenous Interferon Gamma Use
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Original Article
May 2003

Effects of Exogenous Interferon Gamma on Patients With Treatment-Resistant Chronic Rhinosinusitis and Dysregulated Interferon γ ProductionA Pilot Study

Author Affiliations

From the Departments of Pediatrics (Drs Jyonouchi, Sun, and Kelly) and Otolaryngology (Dr Rimell), School of Medicine, University of Minnesota, Minneapolis. Dr Jyonouchi is now with the Department of Pediatrics, University of Medicine and Dentistry of New Jersey, Newark. The authors have no relevant financial interest in this article.

Arch Otolaryngol Head Neck Surg. 2003;129(5):563-569. doi:10.1001/archotol.129.5.563
Abstract

Objective  To evaluate the effects of exogenous interferon gamma treatment in patients with chronic rhinosinusitis and evidence of aberrant production of interferon γ (IFN-γ) and its regulatory cytokines.

Methods  Ten patients with treatment-resistant chronic rhinosinusitis (4 males and 6 females) treated with exogenous interferon gamma (50 µg/m2) were retrospectively evaluated by assessing clinical outcomes compared with clinical and laboratory findings before interferon gamma treatment.

Results  Dysregulated IFN-γ production was suspected to be characterized by (1) decreased interleukin 12 production (n = 1), (2) defects in interleukin 12 receptor signaling (n = 4), (3) intrinsic defects in interleukin 12 (n = 4), and (4) decreased IFN-γ production. Eight patients had a history of chronic otitis media with positive bacterial cultures of sinus lavage samples. Adverse skin reactions to various antibiotics were reported in 7 patients. Asthma was reported in 4 patients. Along with sinusitis symptoms, these conditions were better controlled in all 9 patients who received exogenous interferon gamma for longer than 3 months. In 1 patient, interferon gamma treatment was discontinued after 3 weeks secondary to "presumed" tremor that was later diagnosed as a tic. Repeated surgical procedures and hospitalizations were reported in 2 patients after interferon gamma treatment secondary to recurrent chronic otitis media/mastoiditis/catheter infection and G-tube leakage. Interferon gamma treatment was discontinued in 1 of these patients because of a concern about neutropenia that occurred after catheter infection. Adverse effects of using exogenous interferon gamma were generally limited to local skin reactions.

Conclusion  Exogenous interferon gamma may be a therapeutic option in a subset of patients with treatment-resistant chronic rhinosinusitis and evidence of dysregulated IFN-γ production.

CHRONIC rhinosinusitis (CRS) unresponsive to conventional treatment imposes a clinical challenge and consumes a great deal of medical resources.1 We2 did not detect demonstrable abnormalities using the conventional immune workup available to clinical allergists and immunologists in most patients with treatment-resistant CRS treated in the Pediatric Otolaryngology/Allergy/Immunology Clinic at Fairview University Medical Center (Minneapolis, Minn). Nevertheless, these patients continued to experience sinus inflammation requiring repeated surgical procedures, prolonged courses of oral and intravenous antibiosis, and various anti-inflammatory medications (corticosteroid nasal inhalers, leukotriene receptor antagonists, etc). We2 frequently found evidence of dysregulated production of interferon γ (IFN-γ) and its regulatory cytokines by sinus lavage (SL) and peripheral blood mononuclear cells (PBMCs) in patients with treatment-resistant CRS. These patients tended to initially have chronic otitis media (COM) resistant to conventional treatment (intravenous or oral antibiosis and pressure equalization tube placement). In 2 such patients with treatment-resistant CRS who did not respond to intravenous immunoglobulin therapy, we tried administering exogenous interferon gamma-1b (Actimmune; Genentech Inc, South San Francisco, Calif) to control CRS. They responded well to interferon gamma treatment, with marked improvement in daily activity. Both patients had normal chemiluminescence and chemotaxis, indicating that they do not have chronic granulomatous disease.

Immune responses to invading microbes are regulated by an intricate network of innate and adaptive immunity. Innate immunity mounts rapid initial immune responses by recognizing common microbial or tissue necrosis structures through pattern recognition receptors expressed by phagocytes and natural killer cells.3,4 Innate immunity also regulates subsequent adaptive immune responses by modulating expression of costimulatory and adhesion molecules on antigen-presenting cells, antigen processing, and production of proinflammatory and regulatory cytokines.3,4 Antigen-presenting cells present antigen to resting naive and memory T cells, which are then activated into the effecter-stage T-cell subsets characterized by their distinguished cytokine production patterns: type 1 and type 2 (T1 and T2) T cells.5,6 The T1 responses are dominated by phagocytic cell-mediated immune responses, with a marked increase in production of T1 cytokines (IFN-γ, interleukin [IL] 2, and tumor necrosis factor β) and production of antibodies that augment opsonization.5,6 The T2 responses are characterized by eosinophil-mediated inflammatory responses with production of T2 cytokines (IL-4, IL-5, and IL-13) and IgG4 and IgE antibodies.57 Dysregulated T1 and T2 responses have been implicated as the cause of the various disorders.6,7 Our8 previous results revealed T1-dominant inflammatory responses in the sinus in patients with nonatopic CRS and apparent excessive IFN-γ production by SL cells. On the other hand, Gollob et al9 found that patients with immunodeficiency involving regulatory mechanisms of IFN-γ production may present with treatment-resistant CRS or COM; in these patients, exogenous interferon gamma may be a therapeutic option.

Given the favorable results in 2 index patients, we retrospectively accessed the clinical outcomes of an interferon gamma trial of 10 patients with treatment-resistant CRS in whom we found evidence of dysregulated production of IFN-γ by PBMCs. These patients were administered interferon gamma after the failure of all other conventional medical approaches.

METHODS
STUDY POPULATION

In the past 4 years, we treated 10 patients with treatment-resistant CRS (6 females and 4 males aged 3-43 years) who underwent sinus surgery or placement of a pressure equalization tube plus sinus tap. All patients had numerous bouts of rhinosinusitis lasting longer than 3 months and positive findings on imaging studies, underwent multiple courses of intravenous antibiosis (>14 days), and had repeated sinus surgeries. All the participants had undergone adenoidectomy before the sinus surgery or at the time of the first sinus surgery. However, sinusitis did not resolve or recurred within 3 months of surgery in all the patients. The clinical features are summarized in Table 1. Antibiotic treatment was discontinued 1 week before surgery. The study protocol was approved by the institutional review committee at the University of Minnesota, and a signed written consent form was obtained before surgery and before SL and peripheral blood samples were drawn. The presence of asthma and allergic rhinitis was evaluated by history, physical examination, skin prick test reactivity or IgE antibody levels against common aeroallergens (dust mites, grass/tree/ragweed pollens, cats, and molds, including Alternaria, Cladosporium, Aspergillus fumigatus, Epicoccum, and Penicillium), and pulmonary function tests, including responses to β2-agonist or methacholine challenge (for patients >12 years old).10 Except for patient 1 (IgA deficiency) and patient 10 (common variable immunodeficiency [CVID]), none of the patients revealed any immune abnormalities by conventional immune workup (serum immunoglobulin levels, IgG subclass levels, T and B cell numbers, mitogen responses, and chemiluminescence). Control peripheral blood samples were obtained from 23 healthy children without a history of asthma, allergic rhinitis, or CRS.

PROTOCOL FOR EXOGENOUS INTERFERON GAMMA TREATMENT

For patients with treatment-resistant CRS, administration of exogenous interferon gamma was tried after sinus surgery and analysis of the peripheral blood and SL samples. We tested the peripheral blood samples at least once before starting interferon gamma treatment to confirm the initial results (no SL cells were taken). The dose given was 50 µg/m2 subcutaneously every Monday, Wednesday, and Friday. This dose is equivalent to that used for patients with chronic granulomatous disease and was selected because it was shown to be effective in patients with a partial defect in IFN-γ production secondary to defective IL-12 receptor (IL-12R) signaling.9 Exogenous interferon gamma treatment was tried for at least 3 months as long as no adverse reactions were observed.

SAMPLE COLLECTION AND CULTURE

Sinus lavage samples were obtained by flushing the maxillary sinus through an 18-gauge spinal needle attached to a collection trap via a 2-way stop as reported previously.8 Sample collection was performed after the induction of general anesthesia. In 9 of 10 patients, SL samples were sent to the clinical microbiology laboratory for bacterial and fungal cultures.

ASSESSMENT OF PRODUCTION OF IFN-γ AND ITS REGULATORY CYTOKINES

Sinus lavage cells were filtered through coarse gauze to remove mucins and tissue debris, spun down briefly, and washed once with phosphate-buffered saline solution. Peripheral blood mononuclear cells were obtained by centrifuging cells with Ficoll-Hypaque density gradient at 1500 rpm for 30 minutes at room temperature. Sinus lavage cells (2 × 105 cells/mL) and PBMCs (106 cells/mL) were cultured in RPMI 1640 supplemented with additives as reported previously8 for 4 days in a 5% carbon dioxide incubator. Stimulants used include mitogens (phytohemagglutinin [PHA] [2 mg/L] and concanavalin A [1 mg/L]) (Sigma-Aldrich Corp, St Louis, Mo), dust mite extract as recall antigen (a mixture of Dermatophagoides farinae and Dermatophagoides pteronyssinus [5 mg/L of each]) (Greer, Lenoir, NC), and regulatory cytokines that stimulate IFN-γ production (IL-12p70 [BD Pharmingen, San Diego, Calif] and IL-18 [R&D Systems, Minneapolis]).11 Dust mite antigen was selected as a recall antigen because most patients demonstrate responses to dust mite antigen in assays of cytokine production by PBMCs without seasonal variation (unpublished observations).12 Levels of IFN-γ and IL-5 were measured as representative T1 and T2 cytokines. Levels of IL-10, IL-12p40, and IL-18 were also measured as representative regulatory cytokines for IFN-γ production; IL-12 and IL-18 augment IFN-γ production, whereas IL-10 suppresses it.11,13,14 Levels of IL-4 were not measured because we detected little in the cultures of PBMCs and SL cells in previous studies.2,8 Interleukin 12p70, a biologically functional IL-12, was not measured because it is rapidly degraded into IL-12p40 and IL-12p35 and is difficult to detect when PBMCs and SL cells are cultured with these stimuli (unpublished observation).13,14 Cytokines (IFN-γ, IL-4, IL-5, IL-10, IL-12p40, and IL-18) added to the culture medium without cells are stable, and we recovered more than 90% of the cytokines after 4 days' incubation.

Levels of all the cytokines except IL-18 were measured using enzyme-linked immunosorbent assay sets (OptEIA; BD Pharmingen). Levels of IL-18 were measured by using standards and antibodies (R&D Systems). Briefly, appropriately diluted duplicate samples with the culture medium or standards were added to an enzyme-linked immunosorbent assay plate (NUNC Inc, Naperville, Ill) precoated with the first antibody and blocked with assay diluents. Then the plate was incubated at room temperature for 2 hours, washed well, and incubated with biotinylated second antibody and streptavidin–horseradish peroxidase conjugate (100 µL/well) at room temperature for 1 hour. After washing, the color was developed by adding substrate solution (tetramethylbenzidine, 100 µL/well) (DAKO, Carpinteria, Calif), and optical density at 450 nm was read using optic density at 650 nm as a reference value. Intravariation and intervariation of cytokine levels were less than 5%.

STATISTICAL ANALYSIS

The equality of 2 sets of data values was evaluated using the Mann-Whitney test (2 sets of independent samples) or the Wilcoxon weighed ranks test (2 sets of related samples). Comparison of multiple values was performed using the Kruskal-Wallis test. Correlation of 2 variables was assessed using the Kendall τ-b test. Differences with P<.05 were significant.

RESULTS
CYTOKINE PRODUCTION BY PBMCs AND SL CELLS

Initially we selected 10 patients with findings indicating dysregulated IFN-γ and IL-12 production by PBMCs. Defects in IL-12p70 production were indicated when PBMCs produced low normal IFN-γ levels with PHA (<500 pg/mL), normal IFN-γ levels with IL-12p70, and low IL-12p40 levels with PHA and IL-12p70 (<1 SD − mean values of control children) (Figure 1). This patient also produced low IFN-γ (<500 pg/mL) with concanavalin A and recall antigens (tetanus and dust mite). Defects in IL-12R signaling were indicated when PBMCs produced low IFN-γ levels with PHA (<1000 pg/mL), IL-12p70 (<500 pg/mL), and IL-18 (<50 pg/mL) (Figure 2A) and excessive IL-12p40 production with PHA, IL-12p70, or IL-18 (>2 SD + control mean) (Figure 2B). Two of these children (siblings) were confirmed to have defects in IL-12R signaling by Western blot analysis.9 Intrinsic defects of IL-12 were indicated with PBMCs producing excessive IFN-γ with IL-12p70 but low normal IFN-γ levels with PHA and other stimuli along with excessive IL-12p40 production with IL-12p70 and IL-18 (>2 SD + control mean) (Figure 3). In these patients we also observed elevated spontaneous IL-18 production by SL cells (>400 pg/105 SL cells). Defects in IFN-γ production were suspected with low IFN-γ production by PBMCs (<200 pg/mL) with any of these stimuli (Figure 4). In these 10 patients, before starting interferon gamma treatment, we repeated the assays at least once using PBMCs to confirm the results. Both treatment-resistant CRS and control PBMCs produced equivalent amounts of IL-10 with PHA, IL-12p70, and IL-18.

Sinus lavage cells from none of the patients produced little IFN-γ without stimuli. Sinus lavage cells from patients with possible IL-18 defects produced IFN-γ levels greater than 500 pg/mL with PHA (3 patients) and IL-12p70 (1 patient) and also produced IL-12p40 (>300 pg/mL) without stimuli (Figure 3). Production of IL-10 by SL cells was variable with these stimuli. There was no correlation between the levels of IFN-γ, IL-10, and IL-12p40 produced by CRS SL cells and PBMCs (P>.05).

CULTURE RESULTS

No fungus was detected in any of the 7 SL samples tested. In 9 of 9 patients, bacterial cultures were positive (Table 2). Also, 8 of 10 patients had a history of COM, and 1 of these patients had recurrent mastoiditis growing Staphylococcus aureus and coagulase-negative Staphylococcus species from middle ear lavage samples (patient 2).

CLINICAL OUTCOMES

The clinical outcomes are summarized in Table 3. Clinical improvement, including reduction in the frequency of intravenous and oral antibiosis, fewer school days missed, and better daily activity, occurred in 9 of 10 patients. However, 1 patient was lost to follow-up after subsequent sinus surgery 8 months after starting interferon gamma treatment. In 5 of 10 patients, quality of life improved from 1 to 2 to 9 to 10 on a scale from 1 to 10. One adult patient with severe combined immunodeficiency did not require any antibiosis for sinusitis after starting exogenous interferon gamma supplementation. Chronic otitis media has been reported in 8 of 10 patient, and 7 of these patients had COM better controlled with use of exogenous interferon gamma. Patient 2 continued to have mastoiditis and COM after interferon gamma treatment; this patient did not respond to intravenous immunoglobulin administration previously. Seven of 10 patients with suspected defects in IL-12 and IL-18 circuits also had a history of adverse reactions to antibiotic drug therapy, mainly skin reactions such as urticaria and erythematous rash. Such skin reactions were better controlled in 6 of 7 patients after starting exogenous interferon gamma treatment. Four of 10 patients were diagnosed as having asthma, and their asthma condition has been better managed with use of exogenous interferon gamma, but 1 patient was lost to follow-up after 8 months of interferon gamma treatment (patient 4). Two patients required repeated hospitalizations after starting interferon gamma treatment mainly because of repeated central catheter infection. In 1 of these 2 patients, exogenous interferon gamma use was discontinued owing to neutropenia after central catheter infection. In patient 7, exogenous interferon gamma use was discontinued after 3 weeks because of tremor. Later, neurologic evaluation revealed that this patient most likely has tics with no electroencephalographic or neurologic abnormalities. There were no substantial local reactions in any patients treated with exogenous interferon gamma except for transient local pains at the site of injection.

COMMENT

We2 previously showed that aberrant production of IFN-γ and its regulatory cytokines by PBMCs can be found in a subset of patients with treatment-resistant CRS. These patients may have primary lacuna immunodeficiency that is not yet defined at molecular levels, and they may benefit from exogenous interferon gamma administration. This pilot study evaluated the effects of exogenous interferon gamma use in 10 patients with treatment-resistant CRS and aberrant production of IFN-γ and IL-12 by PBMCs. Our results indicate that exogenous interferon gamma may be an additional treatment option for these patients.

Chronic rhinosinusitis is heterogeneous in its etiology, and patients with CRS who are unresponsive to conventional treatment impose a clinical challenge. We8 previously reported that elevated IFN-γ production by SL cells is likely to be associated with positive microbial cultures and the absence of atopy. We2 also found elevated IFN-γ production by SL cells with concurrent elevated spontaneous production of IL-12 or IL-18 in 12 of 19 patients with treatment-resistant CRS. These findings indicate that in patients with treatment-resistant CRS, SL cells may be activated to produce IL-12 and IL-18 through microbial products, leading to elevated IFN-γ production by SL cells; IL-12 and IL-18 synergistically augment IFN-γ production.11,13,14 However, 4 of 19 patients with CRS revealed little IFN-γ production by SL cells despite elevated IL-12p40 and IL-18 production.2 Interleukin 10 and transforming growth factor β counterregulate the actions of IL-12 and IL-18 on IFN-γ production.15,16 However, there was no evidence of excessive production of IL-10 and transforming growth factor β by SL cells in these patients. Thus, inhibitory effects of IL-10 or transforming growth factor β were unlikely to be associated with decreased IFN-γ production by SL cells in these patients.2 Instead, we suspected intrinsic defects of IL-12 actions on IFN-γ production. In 2 siblings (patients 8 and 9), we found evidence of a defect in IL-12R–mediated signal transduction.9 They responded well to exogenous interferon gamma treatment. In 2 other unrelated patients with treatment-resistant CRS whose PBMCs revealed low IFN-γ production, we also observed good clinical responses with administration of exogenous interferon gamma. This study retrospectively evaluated the therapeutic effects of administering exogenous interferon gamma in 10 patients with treatment-resistant CRS to whom exogenous interferon gamma was given secondary to suspected defects in IFN-γ and IL-12 circuits, as detailed in the "Results" section.

All our patients began taking exogenous interferon gamma after failed responses to multiple sinus surgeries, numerous courses of intravenous or oral antibiosis, and various anti-inflammatory medications. The defects suspected in these patients are as follows. One patient was suspected of having defects in IL-12p70 production as evidenced by low IL-12p40 and IFN-γ production with various stimuli but normal IFN-γ production with exogenous IL-12p70. In 4 patients, defects of IL-12R signaling were indicated secondary to low IFN-γ production but elevated IL-12p40 production with IFN-γ–inducing cytokines (IL-12 and IL-18). As reported previously,2 we found evidence of IL-12R–mediated intracellular signaling defects in 2 of these patients. In another 4 patients, we observed elevated IL-12p40 production with IFN-γ–inducing cytokines. However, PBMCs from these patients also produced excessive IFN-γ with exogenous IL-12p70. Nevertheless, PBMCs from these patients produced low IFN-γ levels (<700 pg/mL) with other stimuli, indicating an intrinsic defect in IL-12. Last, 1 patient with CVID revealed low IFN-γ production (<200 pg/mL) irrespective of the stimuli, indicating a defect in IFN-γ production. It is unlikely that any of these patients had a variant form of chronic granulomatous disease because all the patients revealed normal chemiluminescence and none had a history of recurrent staphylococcal skin infection or abscess formation in the other organs.

All of these patients clinically responded well to administration of exogenous interferon gamma except for 1 patient in whom treatment was discontinued after 3 weeks secondary to tremorlike symptoms. Clinically, these patients are characterized by a history of COM (8 of 10 patients) before the development of CRS and positive microbial cultures of SL samples (9 of 9 patients). Immune defects involving regulatory cytokines for IFN-γ production are reported to reveal normal results in antibody responses, lymphocyte phenotypes, proliferative responses to mitogens and recall antigen, and production of reactive oxygen species. Still, they are susceptible to certain organisms, including mycobacterium and salmonella, but not to fungal or viral infection.17,18 Our results also indicate that normal IFN-γ production may be important in the clearance of intracellular microbes in the sinus and middle ear. On the other hand, exogenous interferon gamma administration may help clear sinus inflammation by simply augmenting intracellular killing or other mechanisms in patients with CRS and normal results in our assay systems. It will be best to further dissect the mechanisms of dysregulated IFN-γ production at molecular levels to develop better screening measures to identify patients with CRS who are responsive to exogenous interferon gamma treatment.

In patients 2 and 3, we found slightly elevated serum IgE levels (237 and 371 IU/mL) and a history of asthma. However, these patients were reported to be nonreactive to routine skin prick allergy testing. In both patients, S aureus grew from SL samples; however, they did not have any other features of Job syndrome. In patients with atopic dermatitis, skin colonization of S aureus–producing superantigen has been implicated with elevated serum IgE levels secondary to polyclonal activation of T and B cells in the skin.19,20 Elevated serum IgE levels observed in these 2 patients might have been associated with persistent growth of S aureus in the sinus.

One notable clinical feature in our patients was frequent adverse reactions to oral and intravenous antibiotic drug treatment involving mainly the skin (observed in 7 of 10 patients). Most skin reactions occurred after the patients took several doses of antibiotics. Thus, these skin reactions are unlikely to be IgE mediated. Moreover, 5 of these 7 patients tolerated antibiotics that they reacted to earlier after starting interferon gamma treatment. Patient 9, who was shown to have signal transduction defects through IL-12R, developed 30 × 30 erythema with intradermal injection of purified protein derivative when she had lymphadenitis with Mycobacterium avium; usually a purified protein derivative reaction with atypical mycobacterium infection does not cause erythema greater than 10 × 10.9 It is possible that dysregulated IFN-γ production may be associated with non–IgE-mediated adverse reactions to multiple medications in these patients, although their mechanisms need to be further explored.

Exogenous interferon gamma was also administered to 1 adult patient with CVID and treatment-resistant CRS because CRS persisted despite appropriate intravenous immunoglobulin supplementation (0.6 g/kg every 3 weeks) and extensive antibiosis for more than 6 months. This patient's PBMCs produced low IFN-γ (<200 pg/mL) in response to mitogens and IL-12 or IL-18. Within 4 weeks of starting interferon gamma treatment, her sinus symptoms (sinus headache, purulent nasal discharge, facial fullness, sinus tenderness, earaches, etc) almost completely resolved. Although her symptoms recur whenever she starts smoking because of stress, so far she has been free of CRS (confirmed by using imaging studies). The cause of CVID is heterogeneous, and various T-cell abnormalities have been reported in patients with CVID.21 One of the major clinical features of CVID includes CRS that may not resolve with use of supplemental intravenous immunoglobulin and aggressive antibiosis. In patients with CVID (eg, patient 10), exogenous interferon gamma may also be an additional treatment option.

The dose of exogenous interferon gamma used in this study is that used for patients with chronic granulomatous disease, since the safety of exogenous interferon gamma with this low dose has been well proved.22 However, 1 patient did not tolerate administration of exogenous interferon gamma secondary to suspected tremors. This was later diagnosed as tics; it might be associated with the fact that exogenous interferon gamma needs to be administered as a subcutaneous injection. Other possible complications with exogenous interferon gamma treatment include induction of TH1-dominant autoimmune disorders. In patients with CVID, it is reported that autoimmune conditions may occur more frequently than in the general population.21 We did not find any evidence of autoimmune phenomena in our patients. However, dysregulated IFN-γ production could predispose individuals to autoimmune phenomena apart from interferon gamma treatment, and it will be best to monitor autoimmune phenomena in these patients as recommended in patients with CVID.

In conclusion, patients with treatment-resistant CRS whose PBMCs reveal evidence of dysregulated IFN-γ production may frequently respond to exogenous interferon gamma treatment, greatly reducing the frequency of sinus surgery, hospitalization, and intravenous and oral antibiosis (for treating CRS). These patients tend to have a history of COM, positive bacterial cultures of SL samples, and frequent adverse reactions to administration of multiple antibiotics. Further analysis of the dysregulated mechanisms of IFN-γ production at molecular levels may reveal better biomarkers for the efficacy of using exogenous interferon gamma for treatment-resistant CRS.

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Corresponding author and reprints: Harumi Jyonouchi, MD, Division of Allergy/Immunology/Infectious Disease/Pulmonology, Department of Pediatrics, University of Medicine and Dentistry of New Jersey, 185 S Orange Ave, Newark, NJ 07103-2714 (e-mail: jyanouha@umdnj.edu).

Accepted for publication September 24, 2002.

This study was supported in part by grants from Lion's Multiple 5M Hearing Foundation and the Minnesota Medical Foundation, Minneapolis.

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