Refractory chronic rhinosinusitis: pathophysiology and management of chronic rhinosinusitis persisting after endoscopic sinus surgery

Refractory chronic rhinosinusitis (RCRS) is defined as persistence of signs and symptoms of chronic rhinosinusitis, despite technically adequate endoscopic sinus surgery. Rather than a simple, prolonged bout of acute sinusitis, it instead appears to be secondary to an interaction of a susceptible host with the outside environment. Inflammatory responses to colonizing bacteria appear to be responsible for a significant portion of the pathophysiology. Reduction of bacterial load and inflammation of the mucosa play an important role in controlling the disease. Novel treatment strategies, with an emphasis on topical therapies, seem to offer optimal management. In this review, current concepts on the pathophysiology and current therapies available for RCRS are outlined. A practical management strategy based on the author’s personal experience draws upon these concepts, and is detailed in this review of an unusual topic.     

The role of infection in chronic rhinosinusitis

Chronic rhinosinusitis is a common condition, yet little is understood about its pathogenesis. Chronic infection traditionally has been considered a significant factor in the etiology and manifestations of chronic rhinosinusitis. Bacteria can be recovered in most cases of chronic rhinosinusitis, most commonly consisting of Staphylococcus species, anaerobes, and in some cases, gram-negative bacteria. Increasing trends toward bacterial resistance have been identified in chronic rhinosinusitis. Recently, a potential role for fungal infection has emerged. A knowledge of the microbiology of chronic rhinosinusitis will help guide treatment, but more research is required to understand further the exact role of infection in the pathophysiology of chronic rhinosinusitis.     

The role of ubiquitous airborne fungi in chronic rhinosinusitis

Chronic rhinosinusitis (CRS) is a confusing disease for both allergists and otorhinolaryngologists, partially due to its poorly understood pathophysiology and partially due to its limited treatment options. Several recent reports now provide evidence for a better understanding of the etiology and the relationship of CRS to airborne fungi, especially to Alternaria. First, the development of novel methods enables detection of certain fungi in mucus from the nasal and paranasal sinus cavities. Second, a non-immunoglobulin E-mediated immunologic mechanism for reactivity of CRS patients to certain common fungi has been described. Third, these fungi are surrounded by eosinophils in vivo, suggesting that they are targeted by eosinophils. Fourth, the preliminary results of studies using antifungal agents to treat patients with CRS are promising. Overall, these recent discoveries provide a logical mechanism for the pathophysiology of CRS, and they also suggest promising avenues for treatment of CRS with antifungal agents.     

The role of innate immunity in the pathogenesis of chronic rhinosinusitis

Chronic rhinosinusitis (CRS) is a heterogeneous inflammatory condition with a multifactorial basis. Infectious triggers of CRS have been proposed, but demonstration remains elusive. Evolving research suggests that abnormal host mucosal immune responses, rather than specific pathogens themselves, may underlie the chronic inflammatory state. Despite constant contact with airborne particulates and microorganisms, the sinonasal epithelium maintains mucosal homeostasis through innate and adaptive immune mechanisms that eliminate potential threats. Innate immunity encompasses a broad collection of constitutive and inducible processes that can be nonspecific or pathogen directed. Some innate immune pathways are closely intertwined with tissue growth and repair. The persistent inflammation observed in CRS may result from a pathologic imbalance in innate immune interactions between the host and the environment. Impairment of critical innate immune protection renders the sinonasal mucosal surface susceptible to colonization and potential injury, stimulating the prominent adaptive immune response that characterizes CRS.     

The role of iron in the pathophysiology and treatment of chronic hepatitis C

Increased hepatic iron content may be observed in patients with chronic hepatitis C infection, and may contribute to disease severity. The presence of hemochromatosis gene mutations is associated with increased hepatic iron accumulation and may lead to accelerated disease progression. Hepatic iron depletion has been postulated to decrease the risk of hepatocellular carcinoma in patients with cirrhosis due to chronic hepatitis C. It is possible that iron depletion stabilizes or improves liver histology and slows disease progression in these individuals. The present article reviews the prevalence and risk factors for hepatic iron overload in chronic hepatitis C, with emphasis on the available data regarding the efficacy of iron depletion in the treatment of this common liver disease.     

Serum IgG4 as a biomarker reflecting pathophysiology and post-operative recurrence in chronic rhinosinusitis

BackgroundType 2 chronic rhinosinusitis (CRS), especially eosinophilic CRS (ECRS), is an intractable upper airway inflammatory disease. Establishment of serum biomarkers reflecting the pathophysiology of CRS is desirable in a clinical setting. As IgG4 production is regulated by type 2 cytokines, we sought to determine whether serum IgG4 levels can be used as a biomarker for CRS.MethodsAssociation between the serum IgG4 levels and clinicopathological factors was analyzed in 336 CRS patients. Receiver operating characteristics (ROC) analysis was performed to determine the cut-off value of serum IgG4 levels that can be used to predict the post-operative recurrence.ResultsSerum IgG4 levels were significantly higher in patients with moderate to severe ECRS versus those with non to mild ECRS. The levels were also significantly higher in asthmatic patients and patients exhibiting recurrence after surgery compared to controls. ROC analysis determined that the best cut-off value for the serum IgG4 level to predict the post-operative recurrence was 95 mg/dL. The corresponding sensitivity and specificity were 39.7% and 80.5%, respectively. When we combined the two cut-off values for the serum IgG4 and periostin, patients with high serum levels of either IgG4 or periostin exhibited a high post-operative recurrence (OR: 3.95) as compared to patients having low serum levels of both IgG4 and periostin.ConclusionsThe present results demonstrate that the serum IgG4 level is associated with disease severity and post-operative course in CRS. In particular, the combination of serum IgG4 and periostin could be a novel biomarker that predicts post-operative recurrence.     

The effect of medical treatments on the bacterial microbiome in patients with chronic rhinosinusitis: a pilot study

Background

Antibiotics and corticosteroids are prescribed to patients with chronic rhinosinusitis (CRS) to reduce bacterial burden and mucosal inflammation. Unfortunately, clinical improvement is often short‐lived and symptoms frequently recur following cessation of treatment. The impact of these systemic therapies on bacterial communities is not well understood. Improved knowledge of how medical therapies influence the intranasal ecosystem may allow for more effective prescribing and the development of more targeted treatments.

Methods

Twenty patients with CRS were randomized to receive either doxycycline 100 mg twice daily or prednisone 30 mg once daily for 7 days. A further 6 patients with CRS were recruited as untreated controls. Swabs were taken immediately before and after the study period. Symptom scores (22‐item Sino‐Nasal Outcome Test [SNOT‐22]) were recorded. Bacterial communities were characterized using 16S ribosomal RNA (rRNA) gene‐targeted amplicon sequencing. Bacterial abundance was estimated using quantitative polymerase chain reaction (PCR) of 16S rRNA gene copies.

Results

Bacterial profiles were dominated by members of the genera Corynebacterium and Staphylococcus. Patients treated with either doxycycline or prednisone had variable and unpredictable changes in communities. The average relative abundance of Propionibacterium increased after treatment in the doxycycline treatment group, and Corynebacterium reduced in the prednisone group. Significant differences in clinical scores, bacterial community richness, diversity, and bacterial abundance were not seen after treatment.

Conclusion

The short‐term response of bacterial communities to antibiotic or corticosteroid therapy is unpredictable. This study suggests that the use of systemic therapy in patients with stable CRS should be rationalized to minimize antibiotic‐associated morbidity and bacterial dysbiosis.

     

The new histologic classification of chronic rhinosinusitis

Two histologic patterns of disease are found in chronic rhinosinusitis. The first is dominated by eosinophilia and polypoid changes. Glandular hyperplasia and hypertrophy characterize the second. We present the evidence supporting the existence of these two patterns of disease and link these histologic patterns to the larger pathophysiologic processes that drive them. This histologic classification should be acknowledged both in the clinical setting and in laboratory research of chronic rhinosinusitis.     

The price of pain in chronic rhinosinusitis

Background

Chronic rhinosinusitis (CRS) is associated with productivity losses exceeding US$13 billion annually. Although pain is well known to significantly affect patient productivity in other diseases, its economic impact on CRS‐related lost productivity has not been examined. The objective of this study was to determine whether CRS‐related facial pain correlates with lost productivity in patients with CRS.

Methods

Seventy patients with CRS were enrolled in a cross‐sectional investigation. Patients with a history of systemic inflammatory disease, ciliary dysfunction, chronic pain syndromes, migraines, and fibromyalgia were excluded. Pain was measured using the Brief Pain Inventory Short Form (BPI‐SF) and the Short‐Form McGill Pain Questionnaire (SF‐MPQ). Presenteeism, absenteeism and lost work, and household and overall productivity were assessed. Regression analysis was performed to assess potential confounders, including depression.

Results

Pain as measured with BPI‐SF and SF‐MPQ total scores correlated with all domains of productivity losses. Overall, lost productivity was significantly correlated with pain (R range, 0.354‐0.485; p < 0.001). Presenteeism (reduced work efficiency) had the highest correlation with all of the overall pain scores (R range, ?0.366 to ?0.515; p < 0.001). Lost household productivity time was the least affected by pain (R range, 0.267‐0.389; p < 0.05). These correlations remained statistically significant after regression analysis, which accounted for depression (p < 0.05).

Conclusion

A significant correlation exists between CRS‐related facial pain and productivity losses in patients with CRS that is independent of depression. Facial pain has the strongest correlation with presenteeism, which is the main driver of productivity losses and indirect costs associated with CRS.