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1. International prevalence and risk factors evaluation for drug-resistant Streptococcus pneumoniae pneumonia

Author

Aliberti, S, Cook, GS, Babu, BL, Reyes, LF, Rodriguez, AH, Sanz, F, Soni, NJ, Anzueto, A, Faverio, P, Sadud, RF, Muhammad, I, Prat, C, Vendrell, E, Neves, J, Kaimakamis, E, Feneley, A, Swarnakar, R, Franzetti, F, Carugati, M, Morosi, M, Monge, E, Restrepo, MI, Aruj, PK, Attorri, S, Barimboim, E, Caeiro, JP, Garzon, MI, Cambursano, VH, Ceccato, A, Chertcoff, J, Lascar, F, Di Tulio, F, Diaz, AC, de Vedia, L, Ganaha, MC, Lambert, S, Lopardo, G, Lopez, V, Luna, CM, Malberti, AG, Morcillo, N, Tartara, S, Pensotti, C, Pereyra, B, Scapellato, PG, Stagnaro, JP, Shah, S, Lotsch, F, Thalhammer, F, Anseeuw, K, Francois, CA, Van Braeckel, E, Vincent, JL, Djimon, MZ, Bashi, J, Dodo, R, Nouer, SA, Chipev, P, Encheva, M, Miteva, D, Petkova, D, Balkissou, AD, Yone, EWP, Ngahane, BHM, Shen, N, Xu, JF, Rico, CAB, Buitrago, R, Paternina, FJP, Ntumba, JMK, Carevic, VV, Jakopovic, M, Jankovic, M, Matkovic, Z, Mitrecic, I, Jacobsson, MLB, Christensen, AB, Bodtger, UCH, Meyer, CN, Jensen, AV, Baunbaek-knudsen, G, Petersen, PT, Andersen, S, Abd El-Wahhab, IES, Morsy, NE, Shafiek, H, Sobh, E, Abdulsemed, KA, Bertrand, F, Brun-Buisson, C, de Montmollin, E, Fartoukh, M, Messika, J, Tattevin, P, Khoury, A, Ebruke, B, Dreher, M, Kolditz, M, Meisinger, M, Pletz, MW, Hagel, S, Rupp, J, Schaberg, T, Spielmanns, M, Creutz, P, Suttorp, N, Siaw-Lartey, B, Dimakou, K, Papapetrou, D, Tsigou, E, Ampazis, D, Bhatia, M, Dhar, R, D'Souza, G, Garg, R, Koul, PA, Mahesh, PA, Jayaraj, BS, Narayan, KV, Udnur, HB, Krishnamurthy, SB, Kant, S, Limaye, S, Salvi, S, Golshani, K, Keatings, VM, Martin-Loeches, I, Maor, Y, Strahilevitz, J, Battaglia, S, Carrabba, M, Ceriana, P, Confalonieri, M, Monforte, AD, Del Prato, B, De Rosa, M, Fantini, R, Fiorentino, G, Gammino, MA, Menzella, F, Milani, G, Nava, S, Palmiero, G, Petrino, R, Gabrielli, B, Rossi, P, Sorino, C, Steinhilber, G, Zanforlin, A, Carone, M, Patella, V, Scarlata, S, Comel, A, Kurahashi, K, Bacha, ZA, Ugalde, DB, Zuniga, OC, Villegas, JF, Medenica, M, van de Garde, EMW, Mihsra, DR, Shrestha, P, Ridgeon, E, Awokola, BI, Nwankwo, ONO, Olufunlola, AB, Olumide, S, Ukwaja, KN, Irfan, M, Minarowski, L, Szymon, S, Froes, F, Leuschner, P, Meireles, M, Ferrao, C, Ravara, SB, Brocovschii, V, Ion, C, Rusu, D, Toma, C, Chirita, D, Dorobat, CM, Birkun, A, Kaluzhenina, A, Almotairi, A, Bukhary, ZAA, Edathodu, J, Fathy, A, Enani, AMA, Mohamed, NE, Memon, JU, Bella, A, Bogdanovic, N, Milenkovic, B, Pesut, D, Borderias, L, Garcia, NMB, Alarcon, HC, Cilloniz, C, Torres, A, Diaz-Brito, V, Casas, X, Gonzalez, AE, Fernandez-Almira, ML, Gallego, M, Gaspar-Garcia, I, del Castillo, JG, Victoria, PJ, Martinez, EL, de Molina, RM, Marcos, PJ, Menendez, R, Pando-Sandoval, A, Aymerich, CP, de la Torre, AL, Garcia-Olive, I, Rello, J, Moyano, S, Sibila, O, Rodrigo-Troyano, A, Sole-Violan, J, Uranga, A, van Boven, JFM, Torra, EV, Pujol, JA, Feldman, C, Yum, HK, Fiogbe, AA, Yangui, F, Bilaceroglu, S, Dalar, L, Yilmaz, U, Bogomolov, A, Elahi, N, Dhasmana, DJ, Ions, R, Skeemer, J, Woltmann, G, Hancock, C, Hill, AT, Rudran, B, Ruiz-Buitrago, S, Campbell, M, Whitaker, P, Youzguin, A, Singanayagam, A, Allen, KS, Brito, V, Dietz, J, Dysart, CE, Kellie, SM, Franco-Sadud, RA, Meier, G, Gaga, M, Holland, TL, Bergin, SP, Kheir, F, Landmeier, M, Lois, M, Nair, GB, Patel, H, Reyes, K, Rodriguez-Cintron, W, Saito, S, Noda, J, Hinojosa, CI, Levine, SM, Angel, LF, Whitlow, KS, Hipskind, J, Sukhija, K, Totten, V, Wunderink, RG, Shah, RD, Mateyo, KJ, Noriega, L, Alvarado, E, Aman, M, Labra, L, Aliberti, S, Cook, G, Babu, B, Reyes, L, H. Rodriguez, A, Sanz, F, Soni, N, Anzueto, A, Faverio, P, Sadud, R, Muhammad, I, Prat, C, Vendrell, E, Neves, J, Kaimakamis, E, Feneley, A, Swarnakar, R, Franzetti, F, Carugati, M, Morosi, M, Monge, E, Restrepo, M, Aliberti, S., Cook, G. S., Babu, B. L., Reyes, L. F., Rodriguez, A. H., Sanz, F., Soni, N. J., Anzueto, A., Faverio, P., Sadud, R. F., Muhammad, I., Prat, C., Vendrell, E., Neves, J., Kaimakamis, E., Feneley, A., Swarnakar, R., Franzetti, F., Carugati, M., Morosi, M., Monge, E., Restrepo, M. I., Aruj, P. K., Attorri, S., Barimboim, E., Caeiro, J. P., Garzon, M. I., Cambursano, V. H., Ceccato, A., Chertcoff, J., Lascar, F., Di Tulio, F., Diaz, A. C., de Vedia, L., Ganaha, M. C., Lambert, S., Lopardo, G., Luna, C. M., Malberti, A. G., Morcillo, N., Tartara, S., Pensotti, C., Pereyra, B., Scapellato, P. G., Stagnaro, J. P., Shah, S., Lotsch, F., Thalhammer, F., Anseeuw, K., Francois, C. A., Van Braeckel, E., Vincent, J. L., Djimon, M. Z., Bashi, J., Dodo, R., Nouer, S. A., Chipev, P., Encheva, M., Miteva, D., Petkova, D., Balkissou, A. D., Yone, E. W. P., Ngahane, B. H. M., Shen, N., Xu, J. -F., Rico, C. A. B., Buitrago, R., Paternina, F. J. P., Ntumba, J. -M. K., Carevic, V. V., Jakopovic, M., Jankovic, M., Matkovic, Z., Mitrecic, I., Jacobsson, M. -L. B., Christensen, A. B., Bodtger, U. C. H., Meyer, C. N., Jensen, A. V., Baunbaek-Knudsen, G., Petersen, P. T., Andersen, S., El-Wahhab, I. E. -S. A., Morsy, N. E., Shafiek, H., Sobh, E., Abdulsemed, K. A., Bertrand, F., Brun-Buisson, C., de Montmollin, E., Fartoukh, M., Messika, J., Tattevin, P., Khoury, A., Ebruke, B., Dreher, M., Kolditz, M., Meisinger, M., Pletz, M. W., Hagel, S., Rupp, J., Schaberg, T., Spielmanns, M., Creutz, P., Suttorp, N., Siaw-Lartey, B., Dimakou, K., Papapetrou, D., Tsigou, E., Ampazis, D., Bhatia, M., Dhar, R., D'Souza, G., Garg, R., Koul, P. A., Mahesh, P. A., Jayaraj, B. S., Narayan, K. V., Udnur, H. B., Krishnamurthy, S. B., Kant, S., Limaye, S., Salvi, S., Golshani, K., Keatings, V. M., Martin-Loeches, I., Maor, Y., Strahilevitz, J., Battaglia, S., Carrabba, M., Ceriana, P., Confalonieri, M., D'Arminio Monforte, A., Del Prato, B., De Rosa, M., Fantini, R., Fiorentino, G., Gammino, M. A., Menzella, F., Milani, G., Nava, S., Palmiero, G., Petrino, R., Gabrielli, B., Rossi, P., Sorino, C., Steinhilber, G., Zanforlin, A., Carone, M., Patella, V., Scarlata, S., Comel, A., Kurahashi, K., Bacha, Z. A., Ugalde, D. B., Zuniga, O. C., Villegas, J. F., Medenica, M., van de Garde, E. M. W., Mihsra, D. R., Shrestha, P., Ridgeon, E., Awokola, B. I., Nwankwo, O. N. O., Olufunlola, A. B., Olumide, S., Ukwaja, K. N., Irfan, M., Minarowski, L., Szymon, S., Froes, F., Leuschner, P., Meireles, M., Ferrao, C., Ravara, S. B., Brocovschii, V., Ion, C., Rusu, D., Toma, C., Chirita, D., Dorobat, C. M., Birkun, A., Kaluzhenina, A., Almotairi, A., Bukhary, Z. A. A., Edathodu, J., Fathy, A., Enani, A. M. A., Mohamed, N. E., Memon, J. U., Bella, A., Bogdanovic, N., Milenkovic, B., Pesut, D., Borderias, L., Garcia, N. M. B., Alarcon, H. C., Cilloniz, C., Torres, A., Diaz-Brito, V., Casas, X., Gonzalez, A. E., Fernandez-Almira, M. L., Gallego, M., Gaspar-Garcia, I., Del Castillo, J. G., Victoria, P. J., Martinez, E. L., de Molina, R. M., Marcos, P. J., Menendez, R., Pando-Sandoval, A., Aymerich, C. P., de la Torre, A. L., Garcia-Olive, I., Rello, J., Moyano, S., Sibila, O., Rodrigo-Troyano, A., Sole-Violan, J., Uranga, A., van Boven, J. F. M., Torra, E. V., Pujol, J. A., Feldman, C., Yum, H. K., Fiogbe, A. A., Yangui, F., Bilaceroglu, S., Dalar, L., Yilmaz, U., Bogomolov, A., Elahi, N., Dhasmana, D. J., Ions, R., Skeemer, J., Woltmann, G., Hancock, C., Hill, A. T., Rudran, B., Ruiz-Buitrago, S., Campbell, M., Whitaker, P., Youzguin, A., Singanayagam, A., Allen, K. S., Brito, V., Dietz, J., Dysart, C. E., Kellie, S. M., Franco-Sadud, R. A., Meier, G., Gaga, M., Holland, T. L., Bergin, S. P., Kheir, F., Landmeier, M., Lois, M., Nair, G. B., Patel, H., Reyes, K., Rodriguez-Cintron, W., Saito, S., Noda, J., Hinojosa, C. I., Levine, S. M., Angel, L. F., Whitlow, K. S., Hipskind, J., Sukhija, K., Totten, V., Wunderink, R. G., Shah, R. D., Mateyo, K. J., Noriega, L., Alvarado, E., Aman, M., Labra, L., Aliberti S., Cook G.S., Babu B.L., Reyes L.F., Rodriguez A.H., Sanz F., Soni N.J., Anzueto A., Faverio P., Sadud R.F., Muhammad I., Prat C., Vendrell E., Neves J., Kaimakamis E., Feneley A., Swarnakar R., Franzetti F., Carugati M., Morosi M., Monge E., Restrepo M.I., Aruj P.K., Attorri S., Barimboim E., Caeiro J.P., Garzon M.I., Cambursano V.H., Ceccato A., Chertcoff J., Lascar F., Di Tulio F., Diaz A.C., de Vedia L., Ganaha M.C., Lambert S., Lopardo G., Luna C.M., Malberti A.G., Morcillo N., Tartara S., Pensotti C., Pereyra B., Scapellato P.G., Stagnaro J.P., Shah S., Lotsch F., Thalhammer F., Anseeuw K., Francois C.A., Van Braeckel E., Vincent J.L., Djimon M.Z., Bashi J., Dodo R., Nouer S.A., Chipev P., Encheva M., Miteva D., Petkova D., Balkissou A.D., Yone E.W.P., Ngahane B.H.M., Shen N., Xu J.-F., Rico C.A.B., Buitrago R., Paternina F.J.P., Ntumba J.-M.K., Carevic V.V., Jakopovic M., Jankovic M., Matkovic Z., Mitrecic I., Jacobsson M.-L.B., Christensen A.B., Bodtger U.C.H., Meyer C.N., Jensen A.V., Baunbaek-Knudsen G., Petersen P.T., Andersen S., El-Wahhab I.E.-S.A., Morsy N.E., Shafiek H., Sobh E., Abdulsemed K.A., Bertrand F., Brun-Buisson C., de Montmollin E., Fartoukh M., Messika J., Tattevin P., Khoury A., Ebruke B., Dreher M., Kolditz M., Meisinger M., Pletz M.W., Hagel S., Rupp J., Schaberg T., Spielmanns M., Creutz P., Suttorp N., Siaw-Lartey B., Dimakou K., Papapetrou D., Tsigou E., Ampazis D., Bhatia M., Dhar R., D'souza G., Garg R., Koul P.A., Mahesh P.A., Jayaraj B.S., Narayan K.V., Udnur H.B., Krishnamurthy S.B., Kant S., Limaye S., Salvi S., Golshani K., Keatings V.M., Martin-Loeches I., Maor Y., Strahilevitz J., Battaglia S., Carrabba M., Ceriana P., Confalonieri M., D'Arminio Monforte A., Del Prato B., De Rosa M., Fantini R., Fiorentino G., Gammino M.A., Menzella F., Milani G., Nava S., Palmiero G., Petrino R., Gabrielli B., Rossi P., Sorino C., Steinhilber G., Zanforlin A., Carone M., Patella V., Scarlata S., Comel A., Kurahashi K., Bacha Z.A., Ugalde D.B., Zuniga O.C., Villegas J.F., Medenica M., van de Garde E.M.W., Mihsra D.R., Shrestha P., Ridgeon E., Awokola B.I., Nwankwo O.N.O., Olufunlola A.B., Olumide S., Ukwaja K.N., Irfan M., Minarowski L., Szymon S., Froes F., Leuschner P., Meireles M., Ferrao C., Ravara S.B., Brocovschii V., Ion C., Rusu D., Toma C., Chirita D., Dorobat C.M., Birkun A., Kaluzhenina A., Almotairi A., Bukhary Z.A.A., Edathodu J., Fathy A., Enani A.M.A., Mohamed N.E., Memon J.U., Bella A., Bogdanovic N., Milenkovic B., Pesut D., Borderias L., Garcia N.M.B., Alarcon H.C., Cilloniz C., Torres A., Diaz-Brito V., Casas X., Gonzalez A.E., Fernandez-Almira M.L., Gallego M., Gaspar-Garcia I., Del Castillo J.G., Victoria P.J., Martinez E.L., de Molina R.M., Marcos P.J., Menendez R., Pando-Sandoval A., Aymerich C.P., de la Torre A.L., Garcia-Olive I., Rello J., Moyano S., Sibila O., Rodrigo-Troyano A., Sole-Violan J., Uranga A., van Boven J.F.M., Torra E.V., Pujol J.A., Feldman C., Yum H.K., Fiogbe A.A., Yangui F., Bilaceroglu S., Dalar L., Yilmaz U., Bogomolov A., Elahi N., Dhasmana D.J., Ions R., Skeemer J., Woltmann G., Hancock C., Hill A.T., Rudran B., Ruiz-Buitrago S., Campbell M., Whitaker P., Youzguin A., Singanayagam A., Allen K.S., Brito V., Dietz J., Dysart C.E., Kellie S.M., Franco-Sadud R.A., Meier G., Gaga M., Holland T.L., Bergin S.P., Kheir F., Landmeier M., Lois M., Nair G.B., Patel H., Reyes K., Rodriguez-Cintron W., Saito S., Noda J., Hinojosa C.I., Levine S.M., Angel L.F., Whitlow K.S., Hipskind J., Sukhija K., Totten V., Wunderink R.G., Shah R.D., Mateyo K.J., Noriega L., Alvarado E., Aman M., and Labra L.

Subjects
0301 basic medicine, Male, Streptococcus pneumonia, antibiotic resistance, Internationality, sputum examination, bronchiectasis, very elderly, Antibiotics, Prevalence, Drug resistance, medicine.disease_cause, Logistic regression, Global Health, Community-Acquired Infections/epidemiology, lung lavage, 0302 clinical medicine, Community-acquired pneumonia, Cost of Illness, Risk Factors, drug resistant Streptococcus pneumoniae pneumonia, 030212 general & internal medicine, Microbial drug resistant, Aged, 80 and over, adult, international cooperation, drug effect, Middle Aged, influenza vaccination, Anti-Bacterial Agents, antiinfective agent, Europe, Community-Acquired Infections, Hospitalization, Global burden of disease, Streptococcus pneumoniae, Infectious Diseases, risk factor, bacterium identification, Female, community acquired infection, influenza, liver disease, pneumococcal vaccination, Pneumococcal infection, hospitalization, medicine.drug, Microbiology (medical), medicine.medical_specialty, Asia, medicine.drug_class, 030106 microbiology, Settore MED/10 - Malattie Dell'Apparato Respiratorio, Article, Anti-Bacterial Agents/pharmacology, 03 medical and health sciences, Internal medicine, Drug Resistance, Bacterial, Pneumonia, Pneumococcal/epidemiology, medicine, Humans, controlled study, human, tetracycline, Hospitalization/statistics & numerical data, Aged, levofloxacin, nonhuman, business.industry, disease association, microbiology, community acquired pneumonia, macrolide, Pneumonia, asthma, South America, Pneumonia, Pneumococcal, vaccination, medicine.disease, major clinical study, antibiotic sensitivity, penicillin derivative, Penicillin, Streptococcus pneumoniae/drug effects, blood examination, Africa, North America, microbiological examination, business
Abstract

Objective: Streptococcus pneumoniae is the most frequent bacterial pathogen isolated in subjects with Community-acquired pneumonia (CAP) worldwide. Limited data are available regarding the current global burden and risk factors associated with drug-resistant Streptococcus pneumoniae (DRSP) in CAP subjects. We assessed the multinational prevalence and risk factors for DRSP-CAP in a multinational point-prevalence study. Design: The prevalence of DRSP-CAP was assessed by identification of DRSP in blood or respiratory samples among adults hospitalized with CAP in 54 countries. Prevalence and risk factors were compared among subjects that had microbiological testing and antibiotic susceptibility data. Multivariate logistic regressions were used to identify risk factors independently associated with DRSP-CAP. Results: 3,193 subjects were included in the study. The global prevalence of DRSP-CAP was 1.3% and continental prevalence rates were 7.0% in Africa, 1.2% in Asia, and 1.0% in South America, Europe, and North America, respectively. Macrolide resistance was most frequently identified in subjects with DRSP-CAP (0.6%) followed by penicillin resistance (0.5%). Subjects in Africa were more likely to have DRSP-CAP (OR: 7.6; 95% CI: 3.34-15.35, p < 0.001) when compared to centres representing other continents. Conclusions: This multinational point-prevalence study found a low global prevalence of DRSP-CAP that may impact guideline development and antimicrobial policies. Published by Elsevier Ltd on behalf of The British Infection Association.

Published
2019
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2. Induced Sputum: Whole Sample

Author

Keatings Vm and Nightingale Ja

Subjects
medicine.medical_specialty, COPD, medicine.diagnostic_test, business.industry, Respiratory disease, respiratory system, medicine.disease, respiratory tract diseases, Bronchoscopies, Bronchoscopy, Biopsy, medicine, Intensive care medicine, business, Volunteer, Invasive Procedure, Asthma
Abstract

With the introduction of fiberoptic bronchoscopy and the ability to carry out bronchoscopic biopsy and broncho-alveolar lavage (BAL) in patients and control subjects, characterisation of inflammation in airways diseases such as asthma and chronic obstructive respiratory disease (COPD) has been possible. This has allowed emphasis to be placed on the role of inflammation in diseases such as asthma (1) and COPD (2). Bronchoscopy, being an invasive procedure, carries an associated morbidity (3,4). Although bronchoscopy is carried out in patients with moderate or even severe airflow limitation for clinical indications, it is not ethically justified to carry out research bronchoscopies on such patients, as it is essential to pursue research procedures carrying the minimum risk to volunteer subjects. Thus BAL, for the purposes of research in airways diseases, is limited to patients with mild airflow obstruction, thus requiring extrapolation of findings to a more heterogeneous group of patients. As a consequence of its invasive nature, the number of times the procedure can be repeated is limited so that it may be difficult to study the kinetics of the inflammatory response. In addition, it may be difficult to recruit volunteers for studies that necessitate bronchoscopy.

Published
2003
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3. Prediction of low pulse oxygen saturation in COVID-19 using remote monitoring post hospital discharge.

Author

Doheny EP, Flood M, Ryan S, McCarthy C, O'Carroll O, O'Seaghdha C, Mallon PW, Feeney ER, Keatings VM, Wilson M, Kennedy N, Gannon A, Edwards C, and Lowery MM

Subjects
Humans, Heart Rate, Oxygen Saturation, Pandemics, Retrospective Studies, Hospitals, Clinical Deterioration, COVID-19 diagnosis
Abstract

Background: Monitoring systems have been developed during the COVID-19 pandemic enabling clinicians to remotely monitor physiological measures including pulse oxygen saturation (SpO 2 ), heart rate (HR), and breathlessness in patients after discharge from hospital. These data may be leveraged to understand how symptoms vary over time in COVID-19 patients. There is also potential to use remote monitoring systems to predict clinical deterioration allowing early identification of patients in need of intervention., Methods: A remote monitoring system was used to monitor 209 patients diagnosed with COVID-19 in the period following hospital discharge. This system consisted of a patient-facing app paired with a Bluetooth-enabled pulse oximeter (measuring SpO 2 and HR) linked to a secure portal where data were available for clinical review. Breathlessness score was entered manually to the app. Clinical teams were alerted automatically when SpO 2  < 94 %. In this study, data recorded during the initial ten days of monitoring were retrospectively examined, and a random forest model was developed to predict SpO 2  < 94 % on a given day using SpO 2 and HR data from the two previous days and day of discharge., Results: Over the 10-day monitoring period, mean SpO 2 and HR increased significantly, while breathlessness decreased. The coefficient of variation in SpO 2 , HR and breathlessness also decreased over the monitoring period. The model predicted SpO 2 alerts (SpO 2  < 94 %) with a mean cross-validated. sensitivity of 66 ± 18.57 %, specificity of 88.31 ± 10.97 % and area under the receiver operating characteristic of 0.80 ± 0.11. Patient age and sex were not significantly associated with the occurrence of asymptomatic SpO 2 alerts., Conclusion: Results indicate that SpO 2 alerts (SpO 2  < 94 %) on a given day can be predicted using SpO 2 and heart rate data captured on the two preceding days via remote monitoring. The methods presented may help early identification of patients with COVID-19 at risk of clinical deterioration using remote monitoring., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Published
2023
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4. Glucocorticoid treatment reduces exhaled nitric oxide in cystic fibrosis patients.

Author

Linnane SJ, Thin AG, Keatings VM, Moynihan JB, McLoughlin P, and FitzGerald MX

Subjects
Adult, Cross-Over Studies, Double-Blind Method, Female, Humans, Lung Volume Measurements, Male, Spirometry, Breath Tests, Cystic Fibrosis drug therapy, Nitric Oxide analysis, Prednisolone therapeutic use
Abstract

In cystic fibrosis (CF), low concentrations of exhaled nitric oxide (NO) and reduced expression of inducible nitric oxide synthase (iNOS) in airway epithelium have been reported. However, abundant iNOS expression has been found in the subepithelial tissues and elevated concentrations of NO metabolites in breath condensate and sputum. These conflicting results may be explained by increased scavenging of NO by superoxide radicals, resulting in rapid conversion to peroxynitrite, so that only a small proportion of the NO produced in the lung tissue reaches the airway lumen. If iNOS were active in the CF lung, exhaled NO would be further reduced by glucocorticoid treatment. CF patients (n = 13) were recruited to a double-blind, placebo-controlled study with crossover. Treatment comprised prednisolone or placebo for 5 days with a 9 day washout. After each treatment, exhaled NO was measured, spirometry performed and blood collected for measurement of serum nitrogen dioxide/nitrous oxide (NO2/NO3). Ten patients (8 male) completed the study. Following prednisolone treatment (mean +/- SD) exhaled NO concentration (3.1 +/- 1.6 parts per billion (ppb)) was significantly reduced versus placebo treatment (4.9 +/- 4.2 ppb; p<0.05, Wilcoxon signed-rank test). Spirometric indices and serum NO2/NO3 concentration were unchanged. These findings support the hypothesis that glucocorticoids suppress nitric oxide production in cystic fibrosis airways by reducing inducible nitric oxide synthase expression or by inhibiting recruitment of neutrophils, cells which express inducible nitric oxide synthase.

Published
2001
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5. A polymorphism in the tumor necrosis factor-alpha gene promoter region may predispose to a poor prognosis in COPD.

Author

Keatings VM, Cave SJ, Henry MJ, Morgan K, O'Connor CM, FitzGerald MX, and Kalsheker N

Subjects
Aged, Alleles, Cross-Sectional Studies, Female, Gene Frequency, Genotype, Humans, Lung Diseases, Obstructive metabolism, Lung Diseases, Obstructive mortality, Male, Middle Aged, Polymerase Chain Reaction, Prognosis, Prospective Studies, Survival Rate, DNA, Neoplasm genetics, Genetic Predisposition to Disease genetics, Lung Diseases, Obstructive genetics, Polymorphism, Genetic, Promoter Regions, Genetic genetics, Tumor Necrosis Factor-alpha genetics
Abstract

Study Objectives: To determine whether the adenine (A)-guanine (G) substitution polymorphism at position - 308 on the tumor necrosis factor-alpha gene confers susceptibility to COPD or to the development of a more severe form of disease., Design: A cross-sectional study was undertaken to compare the frequency of the A allele in a group of 106 patients with COPD with that in a control population (n = 99). Patients were followed up prospectively for a period of 2 years., Participants and Setting: Participants included 106 COPD patients recruited from a respiratory outpatient clinic and 99 control subjects recruited from patients admitted for cardiac catheterization., Measurements and Results: DNA was extracted from venous blood, and each subject was genotyped for the polymorphism by polymerase chain reaction amplification and restriction digestion using Nco1. There was no increased frequency of the A allele in patients compared to control subjects. AA homozygous patients had less reversible airflow obstruction (p<0.05) and a significantly greater mortality (both all-cause and respiratory deaths) on follow-up (p<0.001), despite a shorter cigarette smoking history., Conclusions: This study suggests that homozygosity for this A allele predisposes to more severe airflow obstruction and a worse prognosis in COPD.

Published
2000
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6. Total sputum nitrate plus nitrite is raised during acute pulmonary infection in cystic fibrosis.

Author

Linnane SJ, Keatings VM, Costello CM, Moynihan JB, O'Connor CM, Fitzgerald MX, and McLoughlin P

Subjects
Acute Disease, Adult, Breath Tests, Cystic Fibrosis metabolism, Disease Progression, Female, Humans, Male, Nitrates analysis, Nitrites analysis, Respiratory Function Tests, Cystic Fibrosis physiopathology, Nitric Oxide metabolism, Respiration, Sputum chemistry
Abstract

Nitric oxide (NO) can be detected in exhaled gas in human subjects. It is produced by nitric oxide synthase (NOS) and is rapidly metabolized to nitrite and nitrate (NO2/NO3). Exhaled NO is reported to be elevated in patients with asthma, bronchiectasis, or upper respiratory tract infection. Recent reports have shown no increase of exhaled NO in stable cystic fibrosis (CF). We hypothesized that NOS activity is increased in patients with acute pulmonary exacerbation of CF. We therefore measured exhaled NO and sputum NO2/NO3 in three subject categories: patients with acute pulmonary exacerbation of CF, patients with stable CF, and healthy control subjects. Mean +/- SD exhaled NO was significantly higher in control subjects (8.8 +/- 4.9 ppb) than in both acute (3.8 +/- 3.9 ppb) and stable (5.0 +/- 2.5 ppb) patients. Sputum NO2/NO3 was significantly higher in acute patients (774 +/- 307 micromol/L) when compared with both stable patients (387 +/- 203 micromol/L) and control (421 +/- 261 micromol/L) subjects. Sputum NO2/NO3 did not return to normal in a subgroup of patients assessed after 2 wk of intensive antibiotic and glucocorticoid treatment. These results confirm that exhaled NO is not a useful measure of airway inflammation in CF. Elevated levels of sputum NO2/NO3 suggest that NOS is activated during acute pulmonary exacerbations of CF.

Published
1998
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7. Exhaled nitric oxide and bronchoalveolar lavage nitrite/nitrate in active pulmonary sarcoidosis.

Author

O'Donnell DM, Moynihan J, Finlay GA, Keatings VM, O'Connor CM, McLoughlin P, and Fitzgerald MX

Subjects
Adult, Breath Tests, Bronchoalveolar Lavage Fluid cytology, Cell Count, Female, Humans, Luminescent Measurements, Male, Middle Aged, Sarcoidosis, Pulmonary pathology, Bronchoalveolar Lavage Fluid chemistry, Nitrates analysis, Nitric Oxide metabolism, Nitrites analysis, Sarcoidosis, Pulmonary metabolism
Abstract

Increased exhaled nitric oxide (NO) may reflect respiratory tract inflammation in untreated asthmatics. We compared exhaled NO and bronchoalveolar lavage (BAL) nitrate/nitrite (NO3-/NO2-) in 10 patients who had untreated, active pulmonary sarcoidosis with those of normal control subjects. Exhaled NO concentrations, determined by chemiluminescence, were similar in patients and control subjects (peak NO concentration of patients [mean +/- SD]: 13.6 +/- 5.9 parts per billion [ppb], peak NO concentration of control subjects: 11.2 +/- 5.7 ppb, p = 0.32; mean alveolar NO concentration of patients: 7.8 +/- 4.4 ppb, mean alveolar NO concentration of control subjects: 7.1 +/- 4.2 ppb, p = 0.70; end-tidal NO concentration of patients: 6.9 +/- 4.5 ppb, end-tidal NO concentration of control subjects: 6.6 +/- 4.0 ppb, p = 0.60). BAL NO2- was assayed using a modified Griess reaction after reduction of NO3- to NO2-. There was no significant difference in mean BAL NO2- concentrations, expressed as nanomoles per milliliter of epithelial lining fluid (patients: 544 nmol/ml, control subjects: 579 nmol/ml, p = 0.81) or as nanomoles per milliliter of BAL fluid (patients: 6.7 nmol/ml, control subjects: 5.7 nmol/ml, p = 0.41). These data suggest that excess NO generation does not accompany the respiratory tract inflammation of pulmonary sarcoidosis.

Published
1997
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8. Late response to allergen is associated with increased concentrations of tumor necrosis factor-alpha and IL-5 in induced sputum.

Author

Keatings VM, O'Connor BJ, Wright LG, Huston DP, Corrigan CJ, and Barnes PJ

Subjects
Adolescent, Adult, Blood Proteins analysis, Bronchial Provocation Tests, Carrier Proteins analysis, Eosinophil Granule Proteins, Eosinophils cytology, Granulocyte-Macrophage Colony-Stimulating Factor analysis, Humans, Leukocyte Count, Lipocalin-2, Lipocalins, Peroxidase analysis, Proto-Oncogene Proteins, Sputum chemistry, Sputum cytology, Acute-Phase Proteins, Allergens immunology, Asthma immunology, Hypersensitivity, Immediate immunology, Interleukin-5 analysis, Oncogene Proteins, Ribonucleases, Tumor Necrosis Factor-alpha analysis
Abstract

Bronchial antigen challenge of sensitized atopic patients with asthma results in an early fall in FEV1, followed in a proportion of patients by a late (4 to 24 hours) fall. The late response is accompanied by an increase in bronchial reactivity, which is widely believed to reflect local influx and degranulation of inflammatory cells, particularly eosinophils, in association with elevated local secretion of cytokines. We hypothesized that the development of a late-phase bronchoconstrictor response and airway eosinophilia after allergen challenge of sensitized atopic patients with asthma is associated with elevated induced sputum concentrations of the eosinophil-active cytokines IL-5 and granulocyte-macrophage colony-stimulating factor and the proinflammatory cytokine tumor necrosis factor-alpha. We counted inflammatory leukocytes and measured cytokine concentrations in induced sputum at baseline and 24 hours after inhalational allergen challenge of 15 atopic patients with asthma who had previously demonstrated a late response. We observed significant increases in the numbers of eosinophils and the concentrations of their granule products, eosinophil cationic protein and eosinophil peroxidase. In contrast, the numbers of neutrophils and concentrations of two of their products, myeloperoxidase and human neutrophil lipocalin, did not significantly change. The numbers of sputum eosinophils correlated with the maximal late-phase fall in FEV1. Concentrations of IL-5 and tumor necrosis factor-alpha, but not granulocyte-macrophage colony-stimulating factor, were significantly elevated after allergen challenge. We conclude that the relatively noninvasive technique of induced sputum production can be used to monitor the effect of bronchial provocation on cytokine concentrations in asthma.

Published
1997
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9. Cellular profiles in asthmatic airways: a comparison of induced sputum, bronchial washings, and bronchoalveolar lavage fluid.

Author

Keatings VM, Evans DJ, O'Connor BJ, and Barnes PJ

Subjects
Adult, Bronchi pathology, Bronchoscopy, Eosinophils, Female, Humans, Male, Neutrophils, Asthma pathology, Bronchoalveolar Lavage Fluid cytology, Sputum cytology
Abstract

Background: Analysis of bronchoalveolar lavage fluid has improved our understanding of the pathogenesis of asthma. Safety issues and access to expert resources limit this techniques as a research tool. Induced sputum is a non-invasive method of collecting airway fluid which is applicable to subjects with a range of severity of airflow obstruction. The method of sputum collection and processing differs between groups. A study was undertaken to compare induced sputum with bronchoscopically collected fluid., Methods: Sixteen patients with mild stable asthma underwent both sputum induction and bronchoscopic examination with bronchial washings and bronchoalveolar lavage (BAL) in random order, with each procedure being separated by an interval of 12 days. Airway fluid was processed and stained for differential cell counting., Results: Induced sputum was relatively rich in neutrophils and eosinophils compared with bronchial washings and BAL fluid (mean (SE) 1.3 (0.4)%, 5.0 (2.7)%, and 36.4 (3.7)% neutrophils and 0.6 (0.1)%, 1.6 (0.6)%, and 3.3 (1.1)% eosinophils in BAL fluid, bronchial washings, and induced sputum, respectively). The proportions of cells obtained at sputum induction correlated with those in bronchial washings but not BAL fluid (r = 0.6 and 0.7 for neutrophils and eosinophils, respectively, p < 0.05). By contrast, induced sputum had a lower proportion of lymphocytes and macrophages than bronchial washings or BAL fluid, without any correlation., Conclusion: Induced sputum is rich in neutrophils and eosinophils and poor in lymphocytes, suggesting an origin in the larger airways. Induced sputum adequately reflects the findings in fluid collected by direct bronchoscopy.

Published
1997
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10. Granulocyte activation markers in induced sputum: comparison between chronic obstructive pulmonary disease, asthma, and normal subjects.

Author

Keatings VM and Barnes PJ

Subjects
Adult, Aged, Asthma blood, Eosinophil Granule Proteins, Humans, Leukocyte Count, Lung Diseases, Obstructive blood, Middle Aged, Sputum chemistry, Asthma metabolism, Blood Proteins analysis, Granulocytes metabolism, Inflammation Mediators analysis, Lung Diseases, Obstructive metabolism, Ribonucleases
Abstract

Airway inflammation is present in asthma and is thought to play a significant part in the development of airflow obstruction. In chronic obstructive pulmonary disease (COPD), neutrophilic inflammation is present in the airway lumen, whereas the submucosa displays a lymphocytic infiltrate. Less is known about the nature and mechanisms of inflammation in COPD than in asthma. Induced sputum allows noninvasive sampling of respiratory tract secretions from patients and control subjects, allowing characterization of cells and measurement of soluble markers. We exploited this technique in order to compare the presence and quantify specific markers of eosinophil and neutrophil activation in subjects with asthma or COPD, and control subjects. Differential cell counts showed significantly higher neutrophil percentages in the patients with COPD compared with other groups, while patients with asthma had higher numbers of eosinophils. The neutrophil markers myeloperoxidase (MPO), from primary granules in neutrophils, and human neutrophil lipocalin (HNL), released from secondary granules, were elevated in patients with asthma and COPD compared with control subjects but markedly more so in COPD. The difference between COPD and asthma was more marked for HNL than for MPO suggesting that HNL may be a better marker for discriminating between these conditions. Concentrations of the eosinophil granule protein, eosinophil cationic protein (ECP), and the eosinophil granule-derived enzyme, eosinophil peroxidase (EPO) were raised in the patients with asthma and those with COPD.

Published
1997
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11. Effects of inhaled and oral glucocorticoids on inflammatory indices in asthma and COPD.

Author

Keatings VM, Jatakanon A, Worsdell YM, and Barnes PJ

Subjects
Administration, Inhalation, Administration, Oral, Administration, Topical, Aged, Asthma metabolism, Budesonide, Female, Humans, Inflammation drug therapy, Inflammation metabolism, Lung Diseases, Obstructive metabolism, Male, Middle Aged, Respiratory Function Tests, Sputum chemistry, Anti-Inflammatory Agents administration & dosage, Anti-Inflammatory Agents therapeutic use, Asthma drug therapy, Cytokines metabolism, Glucocorticoids administration & dosage, Glucocorticoids therapeutic use, Lung Diseases, Obstructive drug therapy, Prednisolone administration & dosage, Prednisolone therapeutic use, Pregnenediones administration & dosage, Pregnenediones therapeutic use
Abstract

The role of glucocorticoids in the treatment of chronic obstructive pulmonary disease (COPD) is controversial. We have previously described high numbers of neutrophils and high concentrations of the inflammatory cytokines interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha), and of the cell activation markers eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), myeloperoxidase (MPO), and human neutrophil lipocalin (HNL) in COPD patients as compared with controls, and have postulated that the cytokines TNF-alpha and IL-8 play a role in propagating the inflammatory response in COPD. We have now studied the effects of inhaled and oral glucocorticoids on these inflammatory indices in induced sputum. Initially, we studied the effect of a 2-wk course of inhaled budesonide (800 mg twice daily for 2 wk) in 13 patients with severe COPD (mean FDV1: 35% predicted). There was no clinical benefit in either lung function or symptom scores, and no significant change in the inflammatory indices as measured by total and differential cell counts and concentrations of TNF-alpha eosinophil activation markers ECP and EPO, and neutrophil activation markers MPO and HNL. Because the lack of anti-inflammatory effect might have been due to poor drug delivery as a result of severe airflow limitation, we undertook a study examining the antiinflammatory effect of oral prednisolone (30 mg daily for 2 wk) in patients with COPD and undertook the same measurements in 10 patients with atopic asthma. Sputum eosinophil numbers, ECP, and EPO were significantly reduced in the asthmatic patients but were not modified in COPD. This confirms the clinical impression that inhaled steroids have little antiinflammatory effect, at least in the short term in this group of patients, and suggests that the inflammatory process in COPD is resistant to the antiinflammatory effect of glucocorticoids.

Published
1997
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12. Differences in interleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma.

Author

Keatings VM, Collins PD, Scott DM, and Barnes PJ

Subjects
Adult, Aged, Asthma pathology, Bronchoalveolar Lavage Fluid cytology, Eosinophils, Female, Humans, Inflammation, Leukocyte Count, Lung Diseases, Obstructive pathology, Male, Middle Aged, Neutrophils, Reproducibility of Results, Smoking metabolism, Smoking pathology, Sputum cytology, Asthma metabolism, Interleukin-8 analysis, Lung Diseases, Obstructive metabolism, Sputum chemistry, Tumor Necrosis Factor-alpha analysis
Abstract

Asthma and chronic obstructive pulmonary disease are characterized by chronic airway inflammation. Studies using bronchoalveolar lavage (BAL) have shown an increased proportion of eosinophils in the BAL fluid from asthmatics compared with that from normal subjects, whereas studies of chronic obstructive pulmonary disease (COPD) have shown increased numbers of neutrophils. Induced sputum allows sampling of respiratory tract secretions from patients and control subjects, providing a noninvasive method of studying airway secretions and allowing characterization of cells and measurement of soluble markers. We investigated whether induced sputum was a useful method of studying airway fluid from patients with moderate to severe COPD and whether it could be used to compare inflammation in this condition with that in asthma. An initial reproducibility study was undertaken. Sputum was induced twice in 13 patients with severe COPD at a 14-d interval. Total and differential cell counts were carried out and were found to be reproducible over this period. Sputum was then induced in 14 patients with COPD, 23 patients with asthma, 12 healthy cigarette smokers, and 16 normal nonsmoking control subjects. We found a significant increase in neutrophils and increased concentrations of tumor necrosis factor-alpha (TNF alpha) and interleukin-8 (IL-8) in the patients with COPD compared with the smoking and nonsmoking control subjects. Interleukin-8, but not TNF alpha, was significantly higher in the COPD group than in the asthmatic group. We conclude that the cytokines TNF alpha and IL-8 may be involved in the inflammation in COPD.

Published
1996
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