Mucociliary Clearance Differs in Mild Asthma by Levels of Type 2 Inflammation.

BACKGROUND: Although mucus plugging is a well-reported feature of asthma, whether asthma and type 2 inflammation affect mucociliary clearance (MCC) is unknown. RESEARCH QUESTION: Does type 2 inflammation influence mucus clearance rates in patients with mild asthma who are not receiving corticosteroids? STUDY DESIGN AND METHODS: The clearance rates of inhaled radiolabeled particles were compared between patients with mild asthma with low (n = 17) and high (n = 18) levels of T2 inflammation. Fraction exhaled nitric oxide (Feno) was used to prospectively segregate subjects into T2 Lo (Feno < 25 ppb) and T2 Hi (Feno > 35 ppb) cohorts. Bronchial brush samples were collected with fiber-optic bronchoscopy, and quantitative polymerase chain reaction was performed to measure expression of genes associated with T2 asthma. MCC rate comparisons were also made with a historical group of healthy control subjects (HCs, n = 12). RESULTS: The T2 Lo cohort demonstrated increased MCC when compared with both T2 Hi and historic HCs. MCC within the T2 Hi group varied significantly, with some subjects having low or zero clearance. MCC decreased with increasing expression of several markers of T2 airway inflammation (CCL26, NOS2, and POSTN) and with Feno. MUC5AC and FOXJ1 expression was similar between the T2Lo and T2Hi cohorts. INTERPRETATION: Increasing T2 inflammation was associated with decreasing MCC. High rates of MCC in T2 Lo subjects may indicate a compensatory mechanism present in mild disease but lost with high levels of inflammation. Future studies are required to better understand mechanisms and whether impairments in MCC in more severe asthma drive worse clinical outcomes.

Chemosensory Cell-Derived Acetylcholine Drives Tracheal Mucociliary Clearance in Response to Virulence-Associated Formyl Peptides.

Mucociliary clearance through coordinated ciliary beating is a major innate defense removing pathogens from the lower airways, but the pathogen sensing and downstream signaling mechanisms remain unclear. We identified virulence-associated formylated bacterial peptides that potently stimulated ciliary-driven transport in the mouse trachea. This innate response was independent of formyl peptide and taste receptors but depended on key taste transduction genes. Tracheal cholinergic chemosensory cells expressed these genes, and genetic ablation of these cells abrogated peptide-driven stimulation of mucociliary clearance. Trpm5-deficient mice were more susceptible to infection with a natural pathogen, and formylated bacterial peptides were detected in patients with chronic obstructive pulmonary disease. Optogenetics and peptide stimulation revealed that ciliary beating was driven by paracrine cholinergic signaling from chemosensory to ciliated cells operating through muscarinic M3 receptors independently of nerves. We provide a cellular and molecular framework that defines how tracheal chemosensory cells integrate chemosensation with innate defense.

Relationship between nasal mucociliary clearance and disease severity in children with allergic rhinitis: A comparative cross-sectional study

OBJECTIVES: Mucociliary clearance (MCC) is impaired due to chronic inflammation in allergic rhinitis. Our aim was to evaluate MCC in children with allergic rhinitis, to determine its relationship with disease severity and evaluate MCC change after nasal irrigation. MATERIALS AND METHODS: Saccharin test was performed in 51 patients with allergic rhinitis and in 50 controls. Nasal irrigation was performed to the patients and saccharin test was repeated at the 10th minute. Total nasal symptom score (TNSS) and visual analogue scale (VAS) results were recorded. Patients were divided into mild/moderate-severe groups according to TNSS, VAS, and ARIA guidelines. Nasal MCC time (NMCCT) of the patients and the controls and NMCCT before and after nasal irrigation of the patients were compared. Correlations between NMCCT and TNSS/VAS were evaluated. NMCCTs of the mild and moderate-severe groups were compared. The cut-off values were calculated to discriminate the patient group. RESULTS: The mean NMCCT of the patient group was higher than the controls. Mean NMCCTs were different between before and after irrigation. NMCCT was higher in uncontrolled/moderate-severe groups than in controlled/mild groups. NMCCT correlated positively with VAS and TNSS. The sensitivity and specificity of NMCCT > 535 s were found to be 86.27% and 94%, respectively. CONCLUSIONS: In children with allergic rhinitis, the prolongation of MCC may be identified with the easily applicable saccharin test, the deterioration in MCC increases as disease severity increases. Nasal irrigation is important in children with allergic rhinitis to improve MCC

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Immunopathology of Airway Surface Liquid Dehydration Disease.

The primary purpose of pulmonary ventilation is to supply oxygen (O2) for sustained aerobic respiration in multicellular organisms. However, a plethora of abiotic insults and airborne pathogens present in the environment are occasionally introduced into the airspaces during inhalation, which could be detrimental to the structural integrity and functioning of the respiratory system. Multiple layers of host defense act in concert to eliminate unwanted constituents from the airspaces. In particular, the mucociliary escalator provides an effective mechanism for the continuous removal of inhaled insults including pathogens. Defects in the functioning of the mucociliary escalator compromise the mucociliary clearance (MCC) of inhaled pathogens, which favors microbial lung infection. Defective MCC is often associated with airway mucoobstruction, increased occurrence of respiratory infections, and progressive decrease in lung function in mucoobstructive lung diseases including cystic fibrosis (CF). In this disease, a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene results in dehydration of the airway surface liquid (ASL) layer. Several mice models of Cftr mutation have been developed; however, none of these models recapitulate human CF-like mucoobstructive lung disease. As an alternative, the Scnn1b transgenic (Scnn1b-Tg+) mouse model overexpressing a transgene encoding sodium channel nonvoltage-gated 1, beta subunit (Scnn1b) in airway club cells is available. The Scnn1b-Tg+ mouse model exhibits airway surface liquid (ASL) dehydration, impaired MCC, increased mucus production, and early spontaneous pulmonary bacterial infections. High morbidity and mortality among mucoobstructive disease patients, high economic and health burden, and lack of scientific understanding of the progression of mucoobstruction warrants in-depth investigation of the cause of mucoobstruction in mucoobstructive disease models. In this review, we will summarize published literature on the Scnn1b-Tg+ mouse and analyze various unanswered questions on the initiation and progression of mucobstruction and bacterial infections.

Tranexamic Acid Influences the Immune Response, but not Bacterial Clearance in a Model of Post-Traumatic Brain Injury Pneumonia.

The antifibrinolytic agent, tranexamic acid (TXA), an inhibitor of plasmin formation, currently is evaluated to reduce bleeding in various conditions, including traumatic brain injury (TBI). Because plasmin is implicated in inflammation and immunity, we investigated the effects of plasmin inhibition on the immune response after TBI in the presence or absence of induced pneumonia. Wild-type mice treated with vehicle or TXA or mice deficient in plasminogen (plg-/-) underwent TBI using the controlled cortical impact model. Mice were then subjected to Staphylococcus aureus induced pneumonia and the degree of immune competence determined. Significant baseline changes in the innate immune cell profile were seen in plg-/- mice with increases in spleen weight and white blood cell counts, and elevation in plasma interleukin-6 levels. The plg-/- mice subjected to TBI displayed no additional changes in these parameters at the 72 h or one week time point post-TBI. The plg-/- mice subjected to TBI did not exhibit any further increase in susceptibility to endogenous infection. Pneumonia was induced by intratracheal instillation of S. aureus. The TBI did not worsen pneumonia symptoms or delay recovery in plg-/- mice. Similarly, in wild type mice, treatment with TXA did not impact on the ability of mice to counteract pneumonia after TBI. Administration of TXA after TBI and subsequent pneumonia, however, altered the number and surface marker expression of several myeloid and lymphoid cell populations, consistent with enhanced immune activation at the 72 h time point. This investigation confirms the immune-modulatory properties of TXA, thereby highlighting its effects unrelated to inhibition of fibrinolysis.

Lavage lipidomics signatures in children with cystic fibrosis and protracted bacterial bronchitis.

BACKGROUND: Balanced composition of a well-functioning pulmonary surfactant is crucial and essential for normal breathing. Here, we explored whether the composition of lipids recovered by broncho-alveolar lavage (BAL) in children with cystic fibrosis (CF) differ from children with protracted bacterial bronchitis (PBB) and controls. We wanted to differentiate, if alterations are primarily caused by the disease process or secondary due to an increased amount of cell-membrane lipids derived from inflammatory cells. METHODS: Comprehensive lipidomics profiles of BAL fluid from children diagnosed with CF, PBB and controls were generated by electrospray ionization tandem mass spectrometry analysis. BAL cell differential and numbers were examined. RESULTS: 55 children (37 patients with CF, 8 children with PBB and 10 controls) were included in this study. Results showed comparable total quantities of lipids in all groups. Phospholipids were the major lipid fraction and similar in all groups, whereas the fractions of cholesteryl esters were less and of free cholesterol were increased in children with CF. Among the phospholipids, patients with CF had higher proportion of the non-surfactant membrane-lipids in the classes phosphatidylethanolamine based plasmalogens (PE P), phosphatidylethanolmine (PE) and phosphatidylserine (PS), but a lower proportion of phosphatidylcholine (PC) compared to healthy controls. No such changes were identified in the BAL fluid of children diagnosed with PBB. No differences were observed for the surfactant lipids dipalmitoyl-phosphatidylcholin (PC 32:0) and phosphatidylglycerol (PG). CONCLUSIONS: In CF patients with neutrophilic airway inflammation the lipid composition for surfactant phospholipid components were unchanged, whereas alteration in lipid profile were characteristic for those found in membranes of inflammatory cells. We suspect that the changes in CF were caused by the prolonged inflammation in contrast to a relatively short standing process in PBB.

Emerging therapies in adult and paediatric bronchiectasis.

Bronchiectasis is a chronic respiratory disorder characterized by persistent productive cough and recurrent chest infections secondary to permanent structural airway damage. The current treatment strategies for this debilitating disorder are limited to prompt antibiotic treatment of infective exacerbations and regular airway clearance techniques. Despite its high morbidity and associated mortality across all age groups, it has been a neglected area of research in respiratory medicine and there remain no licensed disease-modifying therapies. In this review, we have explored the numerous potential therapeutic targets to break the vicious cycle of infection and inflammation seen in these patients and the novel therapeutic agents that have been developed to target them. We have reviewed the role of novel anti-inflammatory agents designed to target the persistent neutrophilic inflammatory infiltrate seen in bronchiectatic airways, including neutrophil elastase inhibitors, CXCR2 (CXC chemokine receptor 2) antagonists, DPP-1 (dipeptidyl peptidase 1) inhibitors, PDE4 (phosphodiesterase 4) inhibitors and statins. Furthermore, we have explored novel targets to improve mucociliary clearance, namely ENaC (epithelial sodium channel) inhibitors, and discussed the potential of alternative antimicrobial strategies such as inhaled phages. Our review highlights the importance of a multi-faceted approach to bronchiectasis management, which aims not only to eradicate or suppress bronchial infection but also to break the cycle of persistent airway inflammation that results in progressive lung damage in these patients.

[New opportunities for inhaled therapy for inflammatory diseases of the respiratory system]. / Novye vozmozhnosti ingaliatsionnoi terapii pri vospalitel'nykh zabolevaniiakh respiratornoi sistemy.

The paper considers current approaches to mucoregulatory therapy for various inflammatory diseases of the respiratory system. It gives the advantages and disadvantages of common drugs used in their treatment. Emphasis is laid on the use of inhaled hypertonic saline of NaCl in combination with hyaluronic acid (Hyaneb). Clinical examples of its use in chronic obstructive pulmonary disease, acute and chronic bronchitis, and severe asthma are considered.

Effects of Pseudomonas aeruginosa on CFTR chloride secretion and the host immune response.

In the healthy lung the opportunistic pathogen, Pseudomonas aeruginosa, is rapidly eliminated by mucociliary clearance, a process that is dependent on the activity of the CFTR anion channel that, in concert with a number of other transport proteins, regulates the volume and composition of the periciliary surface liquid. This fluid layer is essential to enable cilia to clear pathogens from the lungs. However, in cystic fibrosis (CF), mutations in the CFTR gene reduce Cl- and [Formula: see text] secretion, thereby decreasing periciliary surface liquid volume and mucociliary clearance of bacteria. In CF this leads to persistent infection with the opportunistic pathogen, P. aeruginosa, which is the cause of reduced lung function and death in ~95% of CF patients. Others and we have conducted studies to elucidate the effects of P. aeruginosa on wild-type and Phe508del-CFTR Cl- secretion as well as on the host immune response. These studies have demonstrated that Cif (CFTR inhibitory factor), a virulence factor secreted by P. aeruginosa, is associated with reduced lung function in CF and induces the ubiquitination and degradation of wt-CFTR as well as TAP1, which plays a key role in viral and bacterial antigen presentation. Cif also enhances the degradation of Phe508del-CFTR that has been rescued by ORKAMBI, a drug approved for CF patients homozygous for the Phe508del-CFTR mutation, thereby reducing drug efficacy. This review is based on the Hans Ussing Distinguished Lecture at the 2016 Experimental Biology Meeting given by the author.

HIV Infects Bronchial Epithelium and Suppresses Components of the Mucociliary Clearance Apparatus.

Recurrent lung infections and pneumonia are emerging as significant comorbidities in the HIV-infected population in the era of combination antiretroviral therapy (cART). HIV infection has been reported to suppress nasal mucociliary clearance (MCC). Since the primary components driving nasal MCC and bronchial MCC are identical, it is possible that bronchial MCC is affected as well. Effective MCC requires optimal ciliary beating which depends on the maintenance of the airway surface liquid (ASL), a function of cystic fibrosis transmembrane conductance regulator (CFTR) activity and the integrity of the signaling mechanism that regulates ciliary beating and fluid secretion. Impairment of either component of the MCC apparatus can compromise its efficacy and promote microbial colonization. We demonstrate that primary bronchial epithelium expresses HIV receptor CD4 and co-receptors CCR5 and CXCR4 and can be infected by both R5 and X4 tropic strains of HIV. We show that HIV Tat suppresses CFTR biogenesis and function in primary bronchial epithelial cells by a pathway involving TGF-ß signaling. HIV infection also interferes with bronchial epithelial cell differentiation and suppresses ciliogenesis. These findings suggest that HIV infection suppresses tracheobronchial mucociliary clearance and this may predispose HIV-infected patients to recurrent lung infections, pneumonia and chronic bronchitis.

Safety and benefits of inhaled hypertonic saline following airway challenges with endotoxin and allergen in asthmatics.

OBJECTIVE: To determine whether induced sputum (IS) with hypertonic saline inhalation is safe to use in asthmatics within 24 hours of two commonly used airway challenges, namely endotoxin and dust mite allergen, and to assess whether IS can enhance mucociliary clearance (MCC) rates in asthmatics. METHODS: IS (three 7-minute inhalation periods of 3%, 4%, and 5% hypertonic saline) was employed before (N = 29) and within 24 hours of inhaled challenges with endotoxin (N = 13) and dust mite allergen (N = 12) in a cohort of mild to moderate asthmatics. Safety was assessed by lung function (Forced Expiratory Volume in 1 second; FEV1) and MCC was measured using a radiolabeled gamma scintigraphy method (Tcm99 sulfur colloid). IS was performed pre and post MCC. RESULTS: No significant lung function decrement was observed before or after inhaled challenges with endotoxin or dust mite allergen. IS significantly enhanced MCC rates before and after inhaled endotoxin challenge. CONCLUSION: Based on a small cohort, IS is safe to use in mild to moderate asthmatics before and within 24 hours of inhaled challenges with endotoxin and dust mite allergen. Furthermore, IS has beneficial effects on host defense function in asthmatics by enhancing MCC rates.

Innate and Adaptive Immunity in Cystic Fibrosis.

Cystic fibrosis (CF) lung disease is characterized by persistent and unresolved inflammation, with elevated proinflammatory and decreased anti-inflammatory cytokines, and greater numbers of immune cells. Hyperinflammation is recognized as a leading cause of lung tissue destruction in CF. Hyper-inflammation is not solely observed in the lungs of CF patients, since it may contribute to destruction of exocrine pancreas and, likely, to defects in gastrointestinal tract tissue integrity. Paradoxically, despite the robust inflammatory response, and elevated number of immune cells (such as neutrophils and macrophages), CF lungs fail to clear bacteria and are more susceptible to infections. Here, we have summarized the current understanding of immune dysregulation in CF, which may drive hyperinflammation and impaired host defense.

The innate immune function of airway epithelial cells in inflammatory lung disease.

The airway epithelium is now considered to be central to the orchestration of pulmonary inflammatory and immune responses, and is also key to tissue remodelling. It acts as the first barrier in the defence against a wide range of inhaled challenges, and is critically involved in the regulation of both innate and adaptive immune responses to these challenges. Recent progress in our understanding of the developmental regulation of this tissue, the differentiation pathways, recognition of pathogens and antimicrobial responses is now exploited to help understand how epithelial cell function and dysfunction contributes to the pathogenesis of a variety of inflammatory lung diseases. Herein, advances in our knowledge of the biology of airway epithelium, as well as its role and (dys)function in asthma, chronic obstructive pulmonary fibrosis and cystic fibrosis will be discussed.

[Up-to-date findings in the host defence mechanism to cryptococcus infection].

Cryptococcus neoformans is a medically important opportunistic fungal pathogen with a polysaccharide capsule surrounding the yeast-like cells. In hosts with impaired cell-mediated immunity such as AIDS, uncontrolled infection causes life-threatening meningoencephalitis. In immunocompetent individuals, the host immune response usually limits the growth of the fungal pathogen at the primary infected site, where it may persist, without completely eradicated, in a latent state because of its ability to escape from killing by macrophages. Th1 response in adaptive immunity is essential for the host defense to cryptococcal infection, in which interferon (IFN)-γ polarizes innate macrophages into fungicidal M1 macrophages. Recently, we found that caspase recruitment domain family member (CARD9), an adaptor protein in a signal transduction triggered by C-type lectin receptors, plays a key role in the early production of IFN-γ at the site of infection by recruiting NK cells and CD4(+) and CD8(+) memory-phenotype T cells. We also found that IL-4 produced by Th2 cells stimulates broncoepithelial cells to secrete mucin, which may lead to promotion in the mucociliary clearance of C. neoformans. Here, we summarize the up-to-date findings in the host defense mechanism to this infection with focusing on our recent data.

Effect of secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1) on airway epithelial cells.

Acetylcholine (ACh) exerts various anti-inflammatory effects through α7 nicotinic ACh receptors (nAChRs). We have previously shown that secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1), a positive allosteric modulator of α7 nAChR signaling, is down-regulated both in an animal model of asthma and in human epithelial cells treated with an inflammatory cytokine related to asthma. Our aim of this study was to explore the effect of SLURP-1, signal through α7 nAChR, in the pathophysiology of airway inflammation. Cytokine production was examined using human epithelial cells. Ciliary beat frequency of murine trachea was measured using a high speed camera. The IL-6 and TNF-α production by human epithelial cells was augmented by siRNA of SLURP-1 and α7 nicotinic ACh receptor. The cytokine production was also dose-dependently suppressed by human recombinant SLURP-1 (rSLURP-1). The ciliary beat frequency and amplitude of murine epithelial cells were augmented by PNU282987, a selective α7 nAChR agonist. Those findings suggested that SLURP-1 and stimulus through α7 nicotinic ACh receptors actively controlled asthmatic condition by stimulating ciliary beating and also by suppressing airway inflammation.

Mucociliary clearance defects in a murine in vitro model of pneumococcal airway infection.

Mucociliary airway clearance is an innate defense mechanism that protects the lung from harmful effects of inhaled pathogens. In order to escape mechanical clearance, airway pathogens including Streptococcus pneumoniae (pneumococcus) are thought to inactivate mucociliary clearance by mechanisms such as slowing of ciliary beating and lytic damage of epithelial cells. Pore-forming toxins like pneumolysin, may be instrumental in these processes. In a murine in vitro airway infection model using tracheal epithelial cells grown in air-liquid interface cultures, we investigated the functional consequences on the ciliated respiratory epithelium when the first contact with pneumococci is established. High-speed video microscopy and live-cell imaging showed that the apical infection with both wildtype and pneumolysin-deficient pneumococci caused insufficient fluid flow along the epithelial surface and loss of efficient clearance, whereas ciliary beat frequency remained within the normal range. Three-dimensional confocal microscopy demonstrated that pneumococci caused specific morphologic aberrations of two key elements in the F-actin cytoskeleton: the junctional F-actin at the apical cortex of the lateral cell borders and the apical F-actin, localized within the planes of the apical cell sides at the ciliary bases. The lesions affected the columnar shape of the polarized respiratory epithelial cells. In addition, the planar architecture of the entire ciliated respiratory epithelium was irregularly distorted. Our observations indicate that the mechanical supports essential for both effective cilia strokes and stability of the epithelial barrier were weakened. We provide a new model, where--in pneumococcal infection--persistent ciliary beating generates turbulent fluid flow at non-planar distorted epithelial surface areas, which enables pneumococci to resist mechanical cilia-mediated clearance.

Pneumococcal pneumonia: mechanisms of infection and resolution.

Vaccination and antimicrobial therapy remain the cornerstones of the management of pneumococcal pneumonia. Despite significant successes, the capacity of the pneumococcus to evolve in the face of the selective pressure of anticapsular immunity challenges immunization programs. Treatment focuses on antimicrobial therapy but ignores the central role of the dysregulated inflammatory response during pneumonia. Future therapeutic approaches need to build on the considerable recent advances in our understanding of the pathogenesis of pneumococcal pneumonia, including those from models of pneumonia. Enhancement of the essential components of the host response that prevents most colonized individuals from developing pneumonia and strategies to limit inappropriate inflammatory responses to lower respiratory tract infection are approaches that could be exploited to improve disease outcome. This review highlights recent discoveries relating to the microbial and host determinants of microbial clearance and regulation of the inflammatory response, which provide clues as to how this could be achieved in the future.

Airway epithelial NF-κB activation promotes Mycoplasma pneumoniae clearance in mice.

BACKGROUND/OBJECTIVE: Respiratory infections including atypical bacteria Mycoplasma pneumoniae (Mp) contribute to the pathobiology of asthma and chronic obstructive pulmonary disease (COPD). Mp infection mainly targets airway epithelium and activates various signaling pathways such as nuclear factor κB (NF-κB). We have shown that short palate, lung, and nasal epithelium clone 1 (SPLUNC1) serves as a novel host defense protein and is up-regulated upon Mp infection through NF-κB activation in cultured human and mouse primary airway epithelial cells. However, the in vivo role of airway epithelial NF-κB activation in host defense against Mp infection has not been investigated. In the current study, we investigated the effects of in vivo airway epithelial NF-κB activation on lung Mp clearance and its association with airway epithelial SPLUNC1 expression. METHODOLOGY/MAIN RESULTS: Non-antimicrobial tetracycline analog 9-t-butyl doxycycline (9-TB) was initially optimized in mouse primary tracheal epithelial cell culture, and then utilized to induce in vivo airway epithelial specific NF-κB activation in conditional NF-κB transgenic mice (CC10-(CA)IKKß) with or without Mp infection. Lung Mp load and inflammation were evaluated, and airway epithelial SPLUNC1 protein was examined by immunohistochemistry. We found that 9-TB treatment in NF-κB transgene positive (Tg+), but not transgene negative (Tg-) mice significantly reduced lung Mp load. Moreover, 9-TB increased airway epithelial SPLUNC1 protein expression in NF-κB Tg+ mice. CONCLUSION: By using the non-antimicrobial 9-TB, our study demonstrates that in vivo airway epithelial NF-κB activation promotes lung bacterial clearance, which is accompanied by increased epithelial SPLUNC1 expression.

Managing upper respiratory tract complications of primary ciliary dyskinesia in children.

PURPOSE OF REVIEW: Primary ciliary dyskinesia (PCD) is a rare and heterogeneous disease that is often misdiagnosed or diagnosed late with more advanced sequelae. PCD primarily effects the respiratory tract, yet most research focuses on the lower respiratory tract manifestations, most of which is derived from research on cystic fibrosis. Little is known about the management of the upper respiratory tract sequelae of PCD. This review summarizes the available evidence for the management of otologic and sinonasal manifestations of PCD. RECENT FINDINGS: The natural history of otitis media with effusion and hearing loss in PCD appears to fluctuate into adulthood and does not resolve by the age of 9 years, regardless of treatment, as previously assumed. Ventilation tube insertion improves hearing in PCD, but may lead to a higher rate of otorrhoea when compared with the general population. Sinonasal disease in PCD is poorly studied; however, it appears that patients with chronic rhinosinusitis (CRS) may benefit from long-term macrolide therapy and endoscopic sinus surgery (ESS) in recalcitrant disease. Therapies targeted at improving mucociliary clearance have not been tested specifically in PCD. Pharmacogenetic therapy is currently under investigation to target the primary defect in PCD. SUMMARY: Otologic sequeale in PCD should undergo lifelong evaluation and monitoring and ventilation tube insertion should be considered to avoid complications of chronic hearing loss. Sinonasal disease benefits from macrolide therapy and ESS. Randomized controlled trials of treatment efficacy of the upper respiratory tract manifestations of PCD are lacking.