Ciprofloxacin-induced immune-mediated thrombocytopenia: No cross-reactivity with gemifloxacin.

WHAT IS KNOWN AND OBJECTIVE: Fluoroquinolone-induced immune-mediated thrombocytopenia is uncommon, and no reports of cross-reactivity among fluoroquinolones exist. Here, we describe a case of ciprofloxacin-induced immune thrombocytopenia with no cross-reactivity with gemifloxacin. CASE DESCRIPTION: A 77-year-old woman showed profound thrombocytopenia immediately after two ciprofloxacin injections for pneumonia. Platelet counts recovered rapidly after ciprofloxacin discontinuation. She had experienced thrombocytopenia after ciprofloxacin administration 4 years earlier, which was assumed to be ciprofloxacin-induced immune-related. Interestingly, no thrombocytopenia occurred following the subsequent exposure to another fluoroquinolone, gemifloxacin. WHAT IS NEW AND CONCLUSION: No cross-reactivity occurred between ciprofloxacin and gemifloxacin in this fluoroquinolone-induced immune thrombocytopenia case.

Natural killer T cells are dispensable in the development of allergen-induced airway hyperresponsiveness, inflammation and remodelling in a mouse model of chronic asthma.

Natural killer T (NK T) cells have been shown to play an essential role in the development of allergen-induced airway hyperresponsiveness (AHR) and/or airway inflammation in mouse models of acute asthma. Recently, NK T cells have been reported to be required for the development of AHR in a virus induced chronic asthma model. We investigated whether NK T cells were required for the development of allergen-induced AHR, airway inflammation and airway remodelling in a mouse model of chronic asthma. CD1d-/- mice that lack NK T cells were used for the experiments. In the chronic model, AHR, eosinophilic inflammation, remodelling characteristics including mucus metaplasia, subepithelial fibrosis and increased mass of the airway smooth muscle, T helper type 2 (Th2) immune response and immunoglobulin (Ig)E production were equally increased in both CD1d-/- mice and wild-type mice. However, in the acute model, AHR, eosinophilic inflammation, Th2 immune response and IgE production were significantly decreased in the CD1d-/- mice compared to wild-type. CD1d-dependent NK T cells may not be required for the development of allergen-induced AHR, eosinophilic airway inflammation and airway remodelling in chronic asthma model, although they play a role in the development of AHR and eosinophilic inflammation in acute asthma model.

A case of famotidine-induced anaphylaxis.

Famotidine is considered to be safe, causing very few adverse events. We describe a case of famotidine-induced anaphylaxis in a 23-year-old man who presented with dyspnea, seizure-like activity, and comatose mental state immediately after an intravenous injection of cefazedone and famotidine for the preoperative preparation of left varicocele. He completely recovered with epinephrine, fluid replacement, and corticosteroids. Skin tests with cefazedone and other beta-lactam antibiotics were all negative but skin tests with famotidine showed a clear positive immediate reaction. Interestingly, we also observed clear positive skin reactions to other H2-receptor antagonists such as nizatidine and ranitidine, which have similar side chains to the ring structures. Our case suggests that famotidine may induce immunoglobulin E-mediated anaphylaxis and have cross-reactivity with nizatidine and ranitidine. Clinicians should therefore be aware of possible life-threatening adverse reactions to commonly used H2-receptor antagonists such as famotidine.

Blood eosinophil counts for the prediction of the severity of exercise-induced bronchospasm in asthma.

It has been suggested that airway eosinophilic inflammation is associated with the severity of exercise-induced bronchospasm (EIB). Blood eosinophils are known to be an indirect marker of airway inflammation in asthma. The aim of this study is to investigate that a simple and easy blood test for blood eosinphil counts may predict the severity of EIB in asthma. Seventy-seven men with perennial asthma (age range 18-23 years) were included. Lung function test, skin prick test, and blood tests for eosinophils counts and total IgE levels were performed. Methacholine bronchial provocation test and, 24 h later, free running test were carried out. EIB was defined as a 15% reduction or more in post-exercise FEV1 compared with pre-exercise FEV1 value. Atopy score was defined as a sum of mean wheal diameters to allergens. EIB was observed in 60 (78%) of 77 subjects. Asthmatics with EIB showed significantly increased percentages of eosinophils (P<0.01), log eosinophil counts (P<0.001), and atopy scores (P<0.05) and decreased log PC20 values (P < 0.05) compared with asthmatics without EIB. Asthmatics with eosinophils of > 700 microl(-1) (36.9 +/- 12.7%) had significantly greater maximal % fall in FEV1 after exercise than asthmatics with eosinophils of < 350 microl(-1) (24.7 +/- 16.6%, P <0.05). Blood eosinophil counts > 350 microl(-1) yielded the specificity of 88% and positive predictive value of 93% for the presence of EIB. When a multiple regression analysis of maximal % fall in FEV1 according to log eosinophil counts, log PC20, log IgE and atopy score was performed, only blood eosinophil counts were significant factor contributing to the maximal % fall in FEV1 after exercise. These findings not only suggest that a simple blood test for eosinophils may be useful in the prediction of the severity of EIB, but also reinforce the view that airway eosinophilic inflammation may play a major role in EIB in asthma.

Airway responsiveness as a direct factor contributing to the dyspnoea perception in asthma.

It is not clear whether airway responsiveness is directly related to the perception of bronchoconstriction in asthma. The purpose of this study is to directly compare the perception of induced bronchoconstriction among the groups classified according to the degree of airway responsiveness. Two hundred and twenty-seven patients with the definitive or suspected asthma underwent a methacholine provocation test. During the test, the degree of dyspnoea was assessed by a modified Borg scale. The perception of induced bronchoconstriction was indicated by the slope in the linear regression analysis between changes in Borg score and the reduction in forced expiratory volume in 1 sec (FEV1) as a percentage of baseline value. The provocative concentration of methacholine resulting in 20% fall in FEV1 (PC20) was calculated. The degree of airway responsiveness to methacholine was categorized as moderate to severe airway hyper-responsiveness (AHR) if PC20 was < 1 mgml(-1), mild AHR if PC20 was > or =1 but < or =4 mgml(-1), borderline AHR if PC20 was >4 but < or =16 mgml(-1), and normal airway responsiveness (negative AHR) if PC20 was > 16 mgml(-1). Positive AHR was defined as PC20< or =4 mgml(-1). Another index of bronchial responsiveness (BR index) was calculated as the log [(% decline in FEV1/log final methacholine concentration as mg dl(-1)+10]. We found that the geometric mean of the slope was lower in subjects with positive AHR (0.12, n=115) than in subjects with negative AHR (0.17, n=72; P<0.01). The geometric mean of the slope in subjects with borderline AHR (0.14, n=40) was between the two groups. Furthermore, the slope was decreased in asthmatics with moderate to severe AHR compared with mild AHR (P <0.05), although the baseline FEV1 did not differ between the two groups. In multiple regression analysis, airway responsiveness expressed as BR index had a significant effect on the perception of bronchoconstriction. We conclude that the perception of bronchoconstriction is diminished in patients with AHR and the degree of airway responsiveness may be directly related to the perception of bronchoconstriction in asthmatic subjects.

Effects of BCG revaccination on asthma.

In a study conducted 1 year ago, we found that Th1 immune enhancement following Bacille Calmette-Guérin (BCG) vaccination effectively suppressed human asthma. To investigate whether revaccination would further improve lung function, BCG vaccine was given again. Current lung function tended to improve in the Repeated BCG group (n = 9), but not in the Single BCG group (previously the placebo group) (n = 11), compared with that 1 year ago. The BCG vaccination improved lung function in both groups, and the Repeated BCG group showed a significant increase in the peripheral blood interferon gamma/interleukin 4 ratio. These findings suggest that repeated BCG vaccinations might be effective in asthma therapy.

BCG infection in allergen-presensitized rats suppresses Th2 immune response and prevents the development of allergic asthmatic reaction.

Recent investigations demonstrate that bacille Calmette-Guerin (BCG), a potent inducer of Th1 response, infection prior to allergen sensitization inhibits Th2 immune responses to the allergen. However, it is not clear whether BCG infection in allergen-presensitized rats switches off Th2 response and prevents allergic asthmatic reaction to the subsequent allergen exposure. In this study we investigate whether BCG infection in ovalbumin (OVA)-presensitized Sprague-Dawley rats suppresses airway hyperresponsiveness and eosinophilic inflammation induced by OVA and Th2 cytokine production. BCG infection in OVA-presensitized rats significantly inhibited not only the sensitivity of airway smooth muscle to electrical field stimulation and acetylcholine but also absolute eosinophil counts in bronchoalveolar lavage fluid. As a correlate, interleukin-4 (IL-4) production significantly decreased and interferon-gamma (IFN-gamma) slightly increased, resulting in a markedly decreased ratio of IL-4-IFN-gamma in OVA-presensitized rats with BCG infection. These results indicate that BCG infection in pre-sensitized rats suppresses allergic asthmatic reaction and Th2 immune response. It is possible from these findings that BCG vaccine may be used as an immunomodulating agent for the sensitized host with preestablished Th2 memory.

Relationship between changes in interferon-gamma production by peripheral blood T cells and changes in peak expiratory flow rate in patients with chronic stable asthma.

BACKGROUND: Cytokines production by T helper lymphocytes (Th cells), which orchestrate the interplay of the different cells involved in airway inflammation of asthma, may be reflected in peripheral blood. Some studies have suggested that the Th cell cytokines by peripheral blood T cells correlate with asthma severity. OBJECTIVE: To investigate the relationship between changes in IFN-gamma production by peripheral blood T cells and changes in lung function in chronic stable asthmatics. METHODS: Sixteen patients with chronic stable moderate asthma aged 35-65 years (nine women) were recruited. Morning and evening peak expiratory flow rates (PEFR) monitoring and blood sampling for peripheral blood T cell culture, total IgE and blood eosinophils were performed at baseline and week 12. Levels of IFN-gamma, IL-4 and IL-5 in culture supernatants of peripheral blood T cell were determined by using enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: Patients with increased IFN-gamma changes from baseline showed significantly increased changes in morning (P = 0.02) and evening (P < 0.05) PEFR compared with those with decreased IFN-gamma changes. The changes in IFN-gamma production and IFN-gamma: IL-4 ratio significantly correlated with the changes in morning PEFR (Rs = 0.59, P < 0.02; Rs = 0.63, P < 0.01, respectively) and tended to correlate with the changes in evening PEFR (Rs = 0.45, P = 0.08; Rs = 0.5, P = 0.05, respectively). The changes in IL-4 and IL-5 did not correlate with the changes in IgE and blood eosinophils, respectively. CONCLUSIONS: These findings suggest that IFN-gamma may be associated with the alteration of lung function in asthmatics and play a role in the pathophysiology of chronic stable asthma.

Atopy may be related to exercise-induced bronchospasm in asthma.

BACKGROUND: Recent studies suggest that atopy may be associated with exercise-induced bronchospasm (EIB) in asthma. However, it is not clear whether atopy is related to EIB, regardless of airway hyper-responsiveness (AHR) to methacholine, because asthmatic subjects often show AHR to exercise and methacholine simultaneously. OBJECTIVE: To investigate whether atopy is related to EIB in asthmatic subjects, independently of AHR to methacholine. METHODS: Fifty-eight male asthmatic subjects were studied. Initial spirometry was performed. Skin prick test was carried out, using 53 common allergens including mites dust antigen. Atopy score was defined as a sum of mean weal diameters to all allergens tested. Methacholine bronchial provocation testing was performed. Twenty-four hours later, free running test was performed. Positive EIB was defined as a 15% reduction or more in FEV1 from baseline after exercise. RESULTS: All subjects had AHR to methacholine. The degree of AHR to methacholine in asthmatics with EIB was similar to that in asthmatics without EIB. However, atopy score and skin reaction to Dermatophagoides pteronyssinus significantly increased in asthmatics with EIB compared with those without EIB (P < 0.05, respectively). Furthermore, the degree of EIB significantly correlated with atopy score in all subjects (r = 0.35, P < 0.01). This relationship was maintained even after the exclusion of EIB-negative asthmatic subjects. CONCLUSION: Atopy defined as skin test reactivity may contribute to the development of EIB in asthma, independently of AHR to methacholine.

Effects of BCG infection on Schultz-Dale reaction, allergen-specific IgE levels, and Th2 immune response in sensitized rats.

BACKGROUND: BCG, a potent inducer of Th1 immune response, has been suggested to suppress Th2 response which is known to mediate IgE-mediated allergic disorders, in particular allergic asthma. Schultz-Dale reaction is known to be a model of IgE-mediated hypersensitivity. This study was done to investigate whether BCG infection suppresses the Schultz-Dale reaction by inhibiting Th2 response and allergen-specific IgE production. METHODS: Twenty-four Sprague-Dawley rats were sensitized and provoked with ovalbumin (OVA). A pretreatment of 6 x 10(4) colony forming units of BCG or saline was done 7 days before sensitization. The Schultz-Dale reaction was represented as tracheal smooth muscle contractions to 50 micrograms/mL OVA challenge in vitro. Serum OVA-specific IgE levels and IFN-gamma and IL-4 concentrations in bronchoalveolar lavage fluid (BALF) were measured. RESULTS: The Schultz-Dale reaction and serum OVA-specific IgE levels were significantly decreased in BCG infected and OVA sensitized rats compared with only sensitized rats (p < 0.01 and p < 0.05, respectively). As compared with only sensitized rats, IL-4 concentration and a ratio of IFN-gamma:IL-4 in BCG infected and OVA sensitized rats were significantly decreased (p < 0.001) and increased (p < 0.05), respectively. The Schultz-Dale reaction was correlated with OVA-specific IgE levels (r = 0.50, p < 0.05), IL-4 concentration (r = 0.69, p < 0.001), and ratio of IFN-:IL-4 (r = -0.44, p < 0.05). OVA-specific IgE levels were correlated with IL-4 concentration (r = 0.61, p < 0.01) and ratio of IFN-gamma:IL-4 (r = -0.48, p < 0.05). CONCLUSION: These findings suggest that BCG infection prior to allergen sensitization may inhibit Schultz-Dale reaction developed in the sensitized rat tracheal smooth muscle via the suppressive effects of Th2 immune response and allergen-specific IgE production.

BCG infection during pre-sensitization or even post-sensitization inhibits airway sensitivity in an animal model of allergic asthma.

The objective of this study is to investigate whether BCG infection before, during or after sensitization suppresses allergen-induced airway hyperresponsiveness and eosinophilic inflammation in allergic asthma rats, and to determine the required dose of BCG to induce such an inhibition. Eighty-seven Sprague-Dawley (SD) rats were sensitized and provoked with ovalbumin (OA). A pretreatment of 6 x 10(4) or 6 x 10(5) colony forming units (CFUs) of BCG or saline was done at four different times: 3 days before sensitization, at sensitization, 3 days before provocation, or at provocation. The assessment of tracheal smooth muscle (TSM) responsiveness to electrical field stimulation or acetylcholine (ACh) and bronchoalveolar lavage (BAL) were performed 1 day after OA provocation. Doses of 6 x 10(4) CFUs inhibited TSM sensitivity of rats infected 3 days before sensitization or at sensitization, but not 3 days before provocation or at provocation. However, doses of 6 x 10(5) CFUs significantly inhibited not only the airway eosinophilia of rats infected 3 days before sensitization or at sensitization, but also the TSM sensitivity of rats infected 3 days before provocation or at provocation. In conclusion, BCG infection suppresses the development of sensitivity of airway smooth muscle and airway eosinophilic inflammation in allergic asthma rats. Furthermore, a relatively high dose of BCG infection inhibits airway sensitivity, even after allergen sensitization.

Desensitization to urine-derived gonadotropins in a woman with secondary infertility.

BACKGROUND: Urine-derived gonadotropins have been used to treat infertility but may cause allergic reactions. IgE-mediated hypersensitivity reactions can be treated with desensitization, especially when new therapies such as recombinant human gonadotropins are unavailable. OBJECTIVE: This case is described to highlight a successful intervention with desensitization in a woman with a complicated history of secondary infertility. She had been treated with ovulation-induction regimens, such as IVF-M (in vitro fertilization-human menopausal gonadotropin [hMG]) and IVF-C (human chorionic gonadotropin [hCG]), for intrauterine insemination. During treatment, however, she experienced reactions to IVF-M and IVF-C. Because she strongly wanted a baby and no alternative preparation was available, desensitization was attempted. METHODS: Intradermal tests with IVF-M and IVF-C using both negative and positive controls were performed on the patient and four normal control subjects. Immediate wheal-and-flare reactions occurred only in the patient. ELISA and ELISA inhibition tests showed positive responses to IVF-M and IVF-C, but not to highly purified hMG, hCG, or D-mannitol, a preservative in IVF-M and IVF-C. Desensitization to IVF-M and IVF-C was done with a protocol used for parenteral desensitization to penicillin. RESULTS: During the IVF-M desensitization, the intramuscular injections were well tolerated. For the next 2 days, daily administration of IVF-M was uneventful. Thirty-six hours later, desensitization to IVF-C was performed successfully. The patient had two intrauterine inseminations and became pregnant. CONCLUSIONS: Nongonadotropin proteins in urine-derived gonadotropins cause IgE-mediated hypersensitivity reactions. Acute desensitization to urine-derived gonadotropins can be performed effectively, as shown in our current case.

Increase in airway hyperresponsiveness among workers exposed to methylene diphenyldiisocyanate compared to workers exposed to toluene diisocyanate at a petrochemical plant in Korea.

BACKGROUND: The purpose of this study was to investigate the prevalence of airway hyperresponsiveness induced by methylene diphenyldiisocyanate (MDI) and toluene diisocyanate (TDI) at a petrochemical industry complex in Korea. METHODS: Questionnaires, allergic skin test, and nonspecific airway hyperresponsiveness (AHR) were studied in 64 exposed workers and 27 control subjects. Questionnaires included questions about symptoms of cough, wheezing, chest tightness, dyspnea, rhinorrhea, sneezing, itching, stuffiness, tearing, urticaria, sore throat, and exacerbating time. Methacholine challenge tests were done. Bronchial responsiveness (BRindex) defined as log (% fall in FEV(1))/log (last concentration of methacholine +10). RESULTS: Prevalence of AHR (PC20 FEV(1) < 16.0 mg/mL of methacholine) was higher in MDI-exposed workers than in TDI-exposed workers [4/20 (20%) vs. 2/42 (4.7%), P<0.05]. Twenty-three workers (36%) of all subjects had respiratory symptoms. MDI-exposed workers, in comparison with control subjects, had higher BRindex (0.73+/-0.04 vs. 0.62+/-0.02, P<0.05). Workers exposed to TDI or MDI who had respiratory symptoms (n = 23), in comparison to workers exposed to TDI or MDI without respiratory symptoms (n = 41), had significantly higher BRindex (0.82+/-0.06 vs. 0.60+/-0.02, P<0.05). FEV(1) was significantly negatively correlated with BRindex (r = -0.253, P<0.05). BRindex was not correlated with atopy, smoking status, and exposure duration. CONCLUSIONS: These findings suggest that workers exposed to MDI are at a higher risk of asthma in comparison with TDI-exposed workers and control subjects at a petrochemical plant in Korea.

The relationship between alveolar epithelial proliferation and airway obstruction after ozone exposure.

BACKGROUND: Proliferating cell nuclear antigen (PCNA) is a component of multiprotein complexes that are expressed during cell proliferation. Ozone induces cell necrosis and a consequent increase in cell proliferation. METHODS: To investigate the effects of acute ozone inhalation on cell proliferation and airway obstruction in BALB/C mice, we examined enhanced pause (Penh) as an index of airway obstruction and PCNA expression by immunohistochemical staining. RESULTS: Compared with controls that received filtered air, the ozone-exposed groups had increased PCNA expression in the alveolar epithelial cells. In rank order, the highest PCNA index was found following 2.0 p.p.m. ozone exposure. In the 2.0 p.p.m. ozone group, there was a PCNA index of 16.83 +/- 0.57% (mean +/- SEM; P< 0.01), compared with 4.25 +/- 0.5% at 0.12 p.p.m., 6.83 +/- 0.60 at 0.5 p.p.m and 12.16 +/- 0.48% at 1 p.p.m. Following ozone exposure, Penh was increased in a dose-dependent manner. There was a significant correlation between the PCNA index in alveoli and Penh (r = 0.63, P< 0.01). CONCLUSIONS: These data suggest that ozone can induce alveolar epithelial cell proliferation in a dose-dependent manner, and that alveolar epithelial cell proliferation is correlated with airway obstruction.

Outdoor air pollutants derived from industrial processes may be causally related to the development of asthma in children.

BACKGROUND: There is no consistent evidence that outdoor air pollutants are involved in the development of asthma. OBJECTIVE: The aim of this study was to determine whether outdoor air pollutants derived from industrial processes were related to the prevalence of asthma, bronchial hyperresponsiveness, and atopy in exposed children. METHODS: A total of 7,511 children from 7 to 12 years of age were recruited in the study. Eight hundred eighty-eight of 1,009 (88%) of the subjects living around industrial factories and 5,998 of 6,502 (92%) living in a less polluted neighboring area responded to the ISAAC questionnaire. A total of 1,492 subjects 8 to 9 years old underwent skin prick tests for 11 common aeroallergens. A total of 732 of the subjects from 8 to 9 years of age underwent bronchial provocation tests with hypertonic saline (BPT-HS). RESULTS: The prevalence of ever experiencing wheezing and wheeze during the last 12 months was 25.6%, and 18.8% among the children living in the more polluted area. This was significantly higher than for those living in the less polluted area (14.2% and 9.0%, respectively). The positive rate of BPT-HS (the provocative dose of hypertonic saline causing 20% fall of FEV, < or = 23 mL) was higher among those in the more polluted area than in children living in the less polluted area (12.2% vs 7.5%). However, the rate of atopy based on the skin tests was the same in the two groups (28.3% vs 30.6%). CONCLUSIONS: The prevalence of asthma and bronchial hyperresponsiveness was higher among children living around the heavily industrial area compared with those living in the less polluted area, despite similar atopic sensitization.

Effects of prednisolone on eosinophils, IL-5, eosinophil cationic protein, EG2+ eosinophils, and nitric oxide metabolites in the sputum of patients with exacerbated asthma.

Corticosteroids are considered to be one of the most effective medicine for asthma by suppressing airway inflammation. This study was carried out to investigate the effects of prednisolone in the sputum of exacerbated asthmatics. Clinical severity, cell differentials, levels of interleukin (IL)-5, eosinophil cationic protein (ECP), EG2+ eosinophils, and nitric oxide (NO) metabolites were measured. Sputum was examined 2 weeks apart in 13 exacerbated asthmatics before and after prednisolone treatment, and once in 12 stable asthmatics. We used a sandwich ELISA for IL-5, fluoroimmunoassay for ECP, immunohistochemical staining for EG2+ eosinophils, a NO metabolites assay using modified Griess reaction. Exacerbated asthmatics, in comparison with stable asthmatics, had significantly higher proportion of eosinophils, higher level of ECP, higher percentage of EG2+ eosinophils, and NO metabolites. Exacerbated asthmatics after treatment with prednisolone had reduced the proportions of eosinophils, reduced level of IL-5, ECP and percentage of EG2+ eosinophils. FEV1 was correlated with the proportion of eosinophils, ECP, and IL-5 respectively. These findings suggest that prednisolone is considered to be effective medicine for asthma by suppressing eosinophil activation through IL-5.