CFAP300 mutation causing primary ciliary dyskinesia in Finland.

Primary ciliary dyskinesia (PCD) is a rare genetic condition characterized by chronic respiratory tract infections and in some cases laterality defects and infertility. The symptoms of PCD are caused by malfunction of motile cilia, hair-like organelles protruding out of the cell that are responsible for removal of mucus from the airways and organizing internal organ positioning during embryonic development. PCD is caused by mutations in genes coding for structural or assembly proteins in motile cilia. Thus far mutations in over 50 genes have been identified and these variants explain around 70% of all known cases. Population specific genetics underlying PCD has been reported, thus highlighting the importance of characterizing gene variants in different populations for development of gene-based diagnostics. In this study, we identified a recurrent loss-of-function mutation c.198_200delinsCC in CFAP300 causing lack of the protein product. PCD patients homozygous for the identified CFAP300 mutation have immotile airway epithelial cilia associated with missing dynein arms in their ciliary axonemes. Furthermore, using super resolution microscopy we demonstrate that CFAP300 is transported along cilia in normal human airway epithelial cells suggesting a role for CFAP300 in dynein complex transport in addition to preassembly in the cytoplasm. Our results highlight the importance of CFAP300 in dynein arm assembly and improve diagnostics of PCD in Finland.

Assessment of inhaled corticosteroid treatment response in asthma using hypertonic histamine challenge-induced cough.

BACKGROUND AND AIMS: Bronchial provocation tests may be utilised to monitor the efficacy of the corticosteroid treatment. Unfortunately, these measurements necessitate good patient cooperation during the spirometry. Coughing during such tests is related to the degree of the bronchoconstriction and occurs involuntarily, i.e. independent of patient cooperation. This study aimed to evaluate the utility of a hypertonic histamine challenge-induced cough in assessing the efficacy of inhaled corticosteroid treatment. METHODS: A total of 16 steroid-naïve asthmatics and 10 non-asthmatic, symptomatic controls received 800-microg beclomethasone (Beclomet Easyhaler(R), Orion Ltd., Orion Pharma, Helsinki, Finland) via powder inhaler per day for 8 weeks. Videoed inhalation challenge with hypertonic histamine solution was performed before and after the treatment. Symptom questionnaire was completed before both challenges. The airway responsiveness to hypertonic histamine was expressed as the cumulative number of coughs divided by the final histamine concentration administered [coughs/concentration ratio (CCR)] and as the provocative concentration of histamine to induce a 20% fall in FEV(1)(PC(20)). RESULTS: CCR [geometric mean; 95% confidence interval (CI)] of the asthmatic subjects decreased from 494 (209-1168) to 73.6 (29.8-182) coughs per mg/mL (P = 0.002). Their PC(20) levels were 1.31 (1.07-1.60) and 1.91 (1.33-2.74) mg/mL over the treatment period (P = 0.01). The symptom frequency also decreased significantly in the asthmatics (P = 0.039). There were no significant changes in PC(20) level, in CCR level or in symptom frequency in non-asthmatic subjects during the treatment. CONCLUSIONS: Hypertonic histamine challenge-induced cough and PC(20) are sensitive measures in assessing the treatment effect in asthma. The cough response may be especially useful in subjects who cannot perform spirometry reliably.

Utility of cough response during hypertonic histamine challenge in diagnosing asthma.

Airway responses to bronchial provocation tests are traditionally assessed with spirometry which necessitates considerable patient co-operation. It has been shown that coughing during bronchial provocation tests is related to the degree of bronchoconstriction which, in turn, is independent of patient co-operation. The aim of the present study was to evaluate the utility of coughing induced by the hypertonic histamine challenge in the differential diagnosis of asthma in a clinically relevant patient population. The study population consisted of 25 healthy volunteers, 30 asthmatics, and 82 non-asthmatic subjects with respiratory symptoms due to other diseases. Hypertonic histamine solution was administered with ultrasonic nebuliser with the challenges being videotaped. The cough response was expressed as the cumulative number of coughs divided by the final histamine concentration administered (CCR). The geometric mean (95% CI) of CCR for asthmatics was 302 (166-562) coughs per mg/ml, for the symptomatic controls 29.5 (20.0-43.7) coughs per mg/ml (p<0.001) and for the healthy controls 6.61 (3.02-14.5) (p<0.001) coughs per mg/ml. According to the ROC curve, the optimal cut-off point for logCCR was 2.22, with the specificity and sensitivity to detect asthma among symptomatic subjects being 86% and 70%. Cough response to hyperosmolar challenge may be useful in the differential diagnosis of airway diseases.

Lactase-induced occupational protein contact dermatitis and allergic rhinoconjunctivitis.

Enzymes are high-molecular-weight proteins and highly sensitizing occupational allergens used widely in industrial processes. Lactase has been described to cause work-related respiratory and conjunctival immunoglobulin (Ig)-E-mediated sensitizations in workers in the pharmaceutical industry. In these previous reports, allergic rhinoconjunctivitis or asthma was confirmed with prick tests but not by challenge tests. Lactase previously has not been described as a cause of immediate or delayed contact skin reaction. Furthermore, there are no previous reports of lactase-specific IgE. We report a case of protein contact dermatitis and allergic rhinoconjunctivitis from occupational exposure to lactase in a pharmaceutical worker. The patient exhibited strong positive responses to lactase in prick tests. In an open application test, lactase elicited whealing, and in patch testing, lactase elicited an eczematous reaction. Serum lactase-specific IgE antibodies were demonstrated in immunospot and radioallergosorbent test assays, and lactase-IgE-binding fractions and their specificities were examined in immunoblot and immunoblot inhibition assays. The chamber challenge test was performed to detect the association between lactase sensitization and rhinoconjunctival symptoms. Our results have confirmed the previous observations that lactase can induce occupational IgE-mediated respiratory and conjunctival sensitizations, but they show that contact skin reactions caused by lactase may also occur.

Utility of hypertonic histamine challenge in distinguishing difficult-to-diagnose asthma.

INTRODUCTION: Although classical asthma is associated with airway hyperresponsiveness (AHR), this condition is also present in many cardiopulmonary disorders undermining the rational basis of its measurement in the differential diagnosis of asthma. We have recently introduced a new method to investigate AHR, the hypertonic histamine challenge (HHC). OBJECTIVE: The aim of this study was to evaluate the differential diagnostic power of HHC in a clinically representative sample of 138 patients. METHODS: Fifty-seven patients from the outpatient clinic of the authors' hospital with symptoms indicative of asthma were consecutively recruited. Asthma was confirmed in 31 subjects. The remaining 26 subjects formed the control group, in conjunction with seven patients with COPD, 15 patients with interstitial lung disease, 21 patients with rhinitis, 13 patients with heart failure and 25 healthy controls. Hypertonic histamine solution was administered with an ultrasonic nebuliser. RESULTS: Only the PC(20) values of asthmatic subjects differed statistically significantly from those of the healthy group (P < 0.0001). The receiver operator characteristic curve indicated that a PC(20) value of 0.83 mg/mL would be the optimal cut-off point of HHC to separate the asthmatics from the symptomatic controls with a sensitivity of 81% and specificity of 70%. With the PC(20) values of 0.1 and 4.0 mg/mL, the sensitivities were 42% and 100%, and the specificities were 96% and 40%, respectively. In these limits, HHC either confirmed or excluded asthma in 64 out of 138 patients (46%). CONCLUSION: The authors' attempt to improve the accuracy of the airway challenge test by combining direct and indirect challenges did not overcome the diagnostic limitations of previously utilised airway challenges.

Occupational sensitization to storage mites in the personnel of a water-damaged grocery store.

OBJECTIVES: To investigate the occupational exposure and sensitization to storage mites (SM) in sales staff working in a moisture-damaged and three healthy reference buildings. METHODS: The study population consisted of the entire personnel (n=12) in the moisture-damaged grocery store. They all suffered from persistent upper respiratory tract symptoms. Twelve (in results 11) symptom-free controls working in three healthy reference groceries were matched with age, sex and occupation. Dust samples from each building were examined for mites. The clinical study consisted of otorhinolaryngological examination and determination of IgE reactivity. Specific serum IgE antibodies were measured against three SMs and two house dust mites (HDM). Skin prick tests (SPT) were made to the same five mites and to five common aeroallergens. If sensitization to any of the SMs was detected, a nasal provocation test (NPT) was performed. RESULTS: SMs were found in all buildings. In all, seven cases and four control subjects showed IgE-mediated reactivity. Sensitization to mites was detected in six cases and in three controls and in 2/12 and 3/11 this was the only IgE antibody response observed. In addition, one case and one control subject were sensitized to common aeroallergens. NPT with SMs was positive in four cases and in one control. CONCLUSIONS: In grocery stores, the personnel are exposed to SMs. The risk of sensitization to mites is obvious and an IgE response can occur without any reactivity to common aeroallergens. SM allergy may in some cases explain the chronic rhinitis related to moisture-damaged buildings.