INT J TUBERC LUNG DIS 19(2):205–209 Q 2015 The Union http://dx.doi.org/10.5588/ijtld.14.0470
Survey of French physician practices in treatment and control of transmission of smear-positive tuberculosis ´ F. Mecha¨ ı,* J. Figoni,* B. Wyplosz,† O. Aoun,‡ O. Bouchaud,* J. Robert§¶# ˆ ˆ *Service des Maladies Infectieuses et Tropicales, Assistance Publique-Hopitaux de Paris (APHP), Hopital Avicenne, ˆ ˆ Universite´ Paris 13, Bobigny, †Service des Maladies Infectieuses et Tropicales, APHP, Hopital Bicetre, Le Kremlin ‡ ˆ ´ ´ ´ erence ´ Bicetre, Centre Medical des Armees de Colmar, Colmar, Haut-Rhin, §Centre National de Ref des ´ ´ ´ ˆ ´ Mycobacteries et de la Resistance des Mycobacteries aux Antituberculeux, APHP, Hopitaux Universitaires Pitieˆ ere, ` Salpetri Paris, ¶Unite´ 1135, Centre d’Immunologie et des Maladies Infectieuses, Universite´ Paris 06, Universite´ ´ Paris, #Unite´ 1135, Centre d’Immunologie et des Maladies Infectieuses, Pierre et Marie Curie, Sorbonne Universites, ´ Institut National de la Sante´ et de la Recherche Medicale, Paris, France SUMMARY OBJECTIVES:
To evaluate isolation practices and management of sputum smear-positive tuberculosis (TB) in France. M E T H O D S : A survey was conducted using a questionnaire e-mailed in 2011 and 2012 to physicians of the French Society of Infectious Diseases, the French Respiratory Society and the French National Society of Internal Medicine. R E S U LT S : Of 311 responders, a quarter stated they treated more than 25 TB cases per year. A total of 87.8% declared they routinely used a four-drug regimen in the initial intensive phase. Of the 311 physicians who responded, 31.9% removed isolation precautions after three negative acid-fast bacilli (AFB) sputum results, 19.0% after 15 days of treatment and 34.1% only in
case of clinical improvement. According to 71% of the responders, discharge from hospital despite positive AFB sputum smear results was ‘possible’. A routine AFB sputum smear was performed after 2 months of treatment by only 21% of the responders. C O N C L U S I O N : Despite recent national guidelines, the management of isolation precautions for sputum smearpositive TB remains heterogeneous, and a significant proportion of physicians use a three-drug regimen. Further efforts should be made to implement TB guidelines, mainly by raising awareness through national scientific institutions, but also by obtaining better evidence. K E Y W O R D S : smear-positive tuberculosis; isolation precautions; treatment
TUBERCULOSIS (TB) remains a major public health concern worldwide. The World Health Organization (WHO) estimated that 8.6 million people were newly infected in 2012, of whom 1.3 million died.1 In France, 4975 cases of TB disease were reported in 2012 to the French Institute for Public Health Surveillance (Institut de Veille Sanitaire, Saint Maurice, France).2 Of these, 74% had pulmonary TB, of whom approximately 50% were smear-positive. There are many international3–7 and national8–10 guidelines on the management of pulmonary TB. Most of these guidelines agree that all patients should be treated with the standardised four-drug regimen, i.e., isoniazid, rifampicin, ethambutol and pyrazinamide. However, airborne isolation precautions may vary with different countries on duration and discontinuation criteria. The first 1994 Centers for Disease Control and Prevention (CDC) guidelines recommended discontinuing airborne isolation after
clinical improvement with effective treatment and three smear-negative sputum samples.4 In 2000, the Infectious Diseases Society of America (IDSA) added to the CDC criteria the criterion that a smear-positive patient could be discharged if he/she lived with persons already exposed to TB or with persons who were not immunosuppressed or young children.6 The IDSA and CDC guidelines were updated in 2005 in collaboration with the American Thoracic Society (ATS).7 This updated version mainly combined both older versions regarding the discontinuation of airborne precautions. According to the 2011 UK guidelines, airborne isolation could be discontinued after 2 weeks of a standard regimen unless the patient was hospitalised in the same ward as immunosuppressed patients.5 In France, the most recent guidelines, issued in 2010, recommend airborne isolation until three smear-negative sputum samples are obtained.10
Correspondence to: Fr´ed´eric M´echa¨ı, Service des Maladies Infectieuses et Tropicales, Hopital Avicenne, Bobigny, France. ˆ Tel: (þ33) 1 48 95 54 21. Fax: (þ33) 1 48 95 54 28. e-mail: [email protected] Article submitted 30 June 2014. Final version accepted 30 September 2014.
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The International Journal of Tuberculosis and Lung Disease
Table 1 Characteristics of the 311 physicians who responded to the questionnaire Characteristic
n (%)
Medical specialisation Respiratory medicine Infectious diseases Internal medicine Others Type of health care facility Teaching or large referral hospital General hospital Private practice Others
177 64 61 9
(56.9) (20.6) (19.6) (2.9)
140 123 38 10
(45.0) (39.6) (12.2) (3.2)
Number of tuberculosis cases managed yearly ,25 25–50 .50
236 (75.9) 69 (22.2) 6 (1.9)
Total
311 (100)
However, other conditions, such as favourable clinical course and effective treatment regimen, also need to be met.7 The 2010 French guidelines recommend a significantly longer duration of isolation than the 2004 guidelines, which proposed discontinuing airborne isolation after 15 days of treatment in case of a favourable clinical course.9,10 The French Expert Committee estimated that available data did not allow lack of infectiousness to be estimated based on a single criterion of 2 weeks of effective treatment. These conservative recommendations also apply to smear-negative patients with pulmonary cavities, who should be isolated during the first 2 weeks of an effective treatment regimen.10 The aim of our survey was to collect data on current practices among physicians regarding isolation precautions and treatment of pulmonary TB in France in 2011–2012, and to compare the results with recent guidelines. We used a standardised questionnaire e-mailed to physicians and specialists likely to manage patients with respiratory TB.
METHODS A standardised questionnaire was e-mailed to all physicians who were members of the French Infectious Diseases Society (Soci´et´e de Pathologie Infectieuse de Langue Fran¸caise [SPILF], Paris, France), the French Respiratory Society (Soci´et´e de Pneumologie de Langue Fran¸caise [SPLF], Paris, France), and the French National Society of Internal Medicine (Soci´et´e Nationale de M´edecine Interne [SNFMI], Rouen, France). The 12-item questionnaire assessed current practices in their hospital department. Questions were related to the implementation of isolation precautions (negative-pressure room, duration) and criteria for discontinuing precautions and for discharge. The systematic use of sputum smear testing at months 2 and 6 of treatment was recorded. A final three questions were related to anti-tuberculosis
treatment, including systematic use of the standard four-drug regimen, the role of fluoroquinolones as a first-line drug and of plasma anti-tuberculosis drug dosages. The questionnaire was sent out twice to improve the response rate, in November 2011 and February 2012. Answers were analysed using Epi Infoe version 3.5 (CDC, Atlanta, GA, USA).
RESULTS Participant characteristics Among the 311 (10%) responders, 177 (56.9%) were respiratory specialists, 64 (20.6%) were infectious disease specialists, 61 (19.6%) were physicians in internal medicine and 9 (2.9%) were working in other departments (Table 1). One hundred and forty (45%) worked in a teaching hospital or a large referral hospital, 123 (39.6%) in a general hospital and 38 (12.2%) in private practice, either in primary care or in private hospitals. More than three quarters (n ¼ 236, 75.9%) of the responders reported that they treated fewer than 25 new TB cases per year (Table 1). Of the remaining 75 (24.1%) physicians who reported treating at least 25 TB cases a year, 64% were respiratory physicians and 60% worked in a teaching hospital. Anti-tuberculosis treatment regimens A total of 273 (87.8%) physicians stated that they routinely used a four-drug regimen in the initial intensive phase of treatment among newly diagnosed TB patients (Table 2). Although this proportion was slightly higher among infectious disease physicians (92.2%) than among respiratory (89.8%) and internal medicine physicians (80.3%), the differences were not statistically significant. It is of note that the fourdrug standard regimen was applied by 93% of those physicians who treated at least 25 TB cases a year. A total of 84 (27%) physicians considered using fluoroquinolones as a first-line drug in cases who were intolerant to rifampicin (RMP) or isoniazid (INH), or in cases with risk factors for multidrugresistant TB (MDR-TB) (poor adherence during previous anti-tuberculosis treatment, patient from a country with high MDR-TB prevalence) (Table 2). The remaining 227 (73%) physicians stated that they had never used fluoroquinolones to treat standard TB. Concentrations of anti-tuberculosis drugs in plasma were routinely measured by 30 (9.6%) physicians. In addition, 110 (35.4%) responders reported measuring plasma drug concentrations in specific situations such as co-administration of antiretroviral drugs, clinical and/or biological intolerance, suspicion of non-adherence and extremes of weight. The remaining 171 (55%) physicians reported that they did not measure plasma drug concentrations (Table 2).
Management of smear-positive TB
Table 2
207
Management of a new tuberculosis case by the 311 responders
Characteristic
n (%)
Standard intensive phase regimen Four-drug regimen Three-drug regimen (no ethambutol) Use of fluoroquinolones as first-line drug Never Risk factor for resistance Allergy/side effect related to another drug Osteoarticular tuberculosis Other
273 (87.8) 38 (12.2) 227 43 19 2 20
(73.0) (13.8) (6.1) (0.7) (6.4)
Measurement of anti-tuberculosis drug plasma concentrations Never Routine Risk of drug-drug interaction or presence of comorbidities* Other (side effects, poor outcome, poor adherence, etc.)
171 30 82 28
(55.0) (9.6) (26.4) (9.0)
Reasons for discontinuation of airborne isolation precautions 715 days of effective drug treatment with favourable clinical course Automatically after 15 days of effective drug treatment Smear-negative sputum Culture-negative sputum Significant decrease in AFB in sputum Cough resolution Other Not stated
106 59 99 2 2 3 15 25
(34.1) (19.0) (31.9) (0.6) (0.6) (1.0) (4.8) (8.0)
Total
311 (100)
* HIV co-infection with antiretroviral drugs, renal or hepatic failure, other comorbidities. AFB ¼ acid-fast bacilli; HIV ¼ human immunodeficiency virus.
Airborne isolation precautions Airborne isolation was discontinued on day 15 by 165 (53.1%) physicians if the TB clinical course was favourable (34.1%), or routinely, regardless of the clinical course (19%). Airborne isolation was discontinued only in cases of smear-negative or culturenegative sputum by respectively 99 (31.9%) and 2 (0.6%) physicians. For the remaining 20 (6.4%) responders, airborne isolation was discontinued when specific criteria were met, such as a decrease in the number of acid-fast bacilli (AFB) in the sputum or resolution of cough. The proportion of physicians following the latest French recommendations10 regarding airborne isolation was not significantly different between physicians treating at least 25 TB cases a year (30.9%) and those treating fewer than 25 a year (34.7%). Only 48 (15.4%) physicians reported having negative-pressure isolation rooms in their facility. A total of 221 (71.1%) physicians said they would authorise hospital-to-home discharge despite persistent smear-positive sputum after 15 days of active treatment. However, among the latter, 156 (70.6%) would authorise discharge only if neither children nor immunosuppressed individuals were at home. The majority of the responders (n ¼ 227, 73%) would discontinue airborne isolation earlier than day 15 if the patient became smear-negative, and 250 (80.4%) would even allow early hospital-to-home discharge if evidence of absence of increased risk of transmission among contacts compared to contacts of patients with initial smear-negative sputum was available.
Finally, respectively 20.8% (n ¼ 64) and 8.1% (n ¼ 25) of the responders reported performing microbiological follow-up after 2 and 6 months of treatment (direct examination and sputum smear or gastric lavage culture).
DISCUSSION This survey on the hospital management of smearpositive TB is the first to be performed in France on a large scale. It shows wide variations in practice and some discrepancies with either the French or the international recommendations for TB management. The optimal initial drug regimen is well established for smear-positive TB cases: both national and international guidelines recommend routine use of a four-drug combination. However, 12% of responders stated that they systematically started with a threedrug regimen, i.e., a regimen that did not include ethambutol (EMB). The lack of adherence to antituberculosis treatment guidelines has already been reported in France, but mainly regarding excessive length of treatment.11,12 The use of a three-drug regimen increases the risk of multidrug resistance in case of initial resistance to INH, which is the most frequent resistance pattern observed in industrialised countries. A three-drug combination regimen should be reserved for precisely defined cases, for example where initial drug resistance is very unlikely or following drug susceptibility testing (DST) results.13 The advent of newer rapid molecular tools for the detection of INH and RMP resistance may be of
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The International Journal of Tuberculosis and Lung Disease
interest when choosing between a three- or four-drug regimen, although difficulties remain regarding the sensitivity of these new tests in the detection of INH resistance.14 The detection of AFB in sputum smears at the end of the 2-month intensive phase and at treatment completion (6 months) is advised by the WHO.15 Our results show that the implementation of WHO guidelines is very poor in France (respectively 21% and 8% of responders systematically performed sputum smear controls at 2 and 6 months); it is therefore generally impossible to differentiate between cure and treatment completion according to international definitions. However, the relevance of sputum smear monitoring has, to our knowledge, not yet been established in countries with reliable medical health care systems that are able to provide sputum cultures with routine DST, efficient imaging and satisfactory clinical improvement during follow-up. We did not record planned treatment duration in our survey, as this had recently been studied by Tattevin et al., who reported that a standardised 6-month regimen was applied by 91% of infectious disease physicians for pulmonary TB, in particular among human immunodeficiency virus negative patients.12 Regarding discontinuation of airborne precautions, the results of our survey showed that less than one third of French physicians complied with the 2010 French guidelines, i.e., discontinuation was based solely on AFB sputum smear results. Consequently, two thirds of responders did not comply with French guidelines or with any of the guidelines issued by United States institutions.6,7,10 Overall, 19% declared removing the requirement for isolation after 2 weeks of treatment, regardless of sputum smear results, in line with the latest UK recommendations and the 2004 French recommendations.5,9 Finally, 34% of the physicians based discontinuation criteria on clinical improvement combined with effective treatment, a strategy not mentioned in any of the cited guidelines.4–10 Approximately half of French physicians treating infectious TB patients do not comply with any local or international guidelines for discontinuation of airborne isolation precautions. Reasons for the lack of adherence to guidelines are numerous and have been extensively reported elsewhere.16 From our study, it is likely that the existence of many different recommendations does not favour adherence to any one of these. This lack of consensus may be taken as poor quality evidence, and consequently a lack of agreement. The fact that some physicians comply with the oldest and not the latest guidelines may reflect a lack of awareness. However, the survey respondents were members of scientific societies, suggesting that they were likely to be kept informed of any changes. Our study had some weaknesses. As it covered only 10% of physicians registered with the participating
societies, we cannot claim that our findings are representative of French practice in general. The fact that 75% of the respondents declared treating fewer than 25 cases a year suggests that the respondents did not have extensive experience in TB management, and that they may have been looking for new information and continuing medical education through different means, including this survey. This may also explain the poor knowledge about the national guidelines. However, all respondents were members of scientific societies, which meant that they were qualified in the management of infectious TB patients. Of note, data from the National Reference Centre for Mycobacteria show that among the 270 French hospitals and private practice laboratories performing mycobacterial research, 83% reported fewer than 25 culture-positive cases a year (personal data). Our sample therefore does not over-represent less active practitioners. Finally, our survey was based on subjective responses from participants and may not reflect observed practices. The study nevertheless showed that French practice regarding isolation precautions and treatment practice for sputum smear-positive TB patients were heterogeneous and did not comply with national or international guidelines. Acknowledgements The authors would like to express their sincere gratitude to the responding physicians, who made this survey possible. We also thank the Syndicat National des M´edecins Infectiologues, the Soci´et´e de Pathologie Infectieuse de Langue Fran¸caise and the Soci´et´e de Pneumologie de Langue Fran¸caise for distributing the questionnaire by e-mail. Conflicts of interest: none declared.
References 1 World Health Organization. Global tuberculosis report, 2013. WHO/HTM/TB/2013.11. Geneva, Switzerland: WHO, 2013. 2 Antoine D, Belghiti F, Guthman J P, Campese C, L´evy-Bruhl D, Che D. Cases of tuberculosis notified in France in 2012. Bull Epid´emiol Hebdo 2014; 20: 352–359. 3 American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America. Treatment of tuberculosis. Am J Respir Crit Care Med 2003; 167: 603– 662. 4 Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care facilities, 1994. Centers for Disease Control and Prevention. MMWR Recomm Rep 1994; 43 (RR13): 1–132. 5 National Collaborating Centre for Chronic Conditions, Centre for Clinical Practice at National Institute for Health and Care Excellence. Tuberculosis: clinical diagnosis and management of tuberculosis, and measures for its prevention and control. London, UK: NICE, 2011. 6 Horburgh Jr. C R, Feldman S, Ridzon R. Practice guidelines for the treatment of tuberculosis. Clin Infect Dis 2000; 31: 603– 609. 7 American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America. Controlling tuberculosis in the United States. Am J Respir Crit Care Med 2005; 172: 1169–1227.
Management of smear-positive TB
8 Recommandations de la soci´et´e de pneumologie de langue fran¸caise sur la prise en charge de la tuberculose en France. Rev Mal Respir 2004; 21: 414–420. 9 Groupe de Travail du Conseil Sup´erieur d’Hygi`ene Publique. Preventing the transmission of tuberculosis in healthcare institutions. Med Mal Infect 2004; 34: 404–410. [French] 10 Minist`ere de la Sant´e et des Sports, Haut Conseil de la Sant´e Publique. Surveiller et pr´evenir les infections associ´ees aux soins. Paris, France: Minist`ere de la Sant´e et des Sport, 2010. [French] 11 Valin N, Hejblum G, Borget I, et al. Factors associated with excessively lengthy treatment of tuberculosis in the eastern Paris region of France in 2004. BMC Public Health 2010; 10: 495. 12 Tattevin P, Chapplain J M, Lesprit P, et al. Tuberculosis
13 14
15
16
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treatment duration in France: from guidelines to daily practice. Eur J Inter Med 2006; 17: 427–429. Mitchison D A. Role of individual drugs in the chemotherapy of tuberculosis. Int J Tuberc Lung Dis 2000; 4: 796–806. Brossier F, Veziris N, Truffot-Pernot C, Jarlier V, Sougakoff W. Performance of the GenoType MTBDR line-probe assay for detection of resistance to rifampin and isoniazid in strains of Mycobacterium tuberculosis with low- and high-level resistance. J Clin Microbiol 2006; 44: 3659–3664. World Health Organization. Treatment of tuberculosis: guidelines. 4 th ed. WHO/HTM/TB/2009.420. Geneva, Switzerland: WHO, 2010. Cabana M D, Rand C S, Powe N R, et al. Why don’t physicians follow clinical practice guidelines? A framework for improvement. JAMA 1999; 282: 1458–1465.
Management of smear-positive TB
i
RESUME
´ valuer les pratiques d’isolement et la OBJECTIFS : E prise en charge des tuberculoses bacillif`eres en France. M E´ T H O D E S : Une enquˆete en ligne a e´ t´e men´ee en 2011 et 2012 a` l’intention des m´edecins des soci´et´es fran¸caises de pathologies infectieuses, de pneumologie et de m´edecine interne. R E´ S U LT A T S : Parmi les 311 m´edecins ayant r´epondu, un quart affirme prendre en charge plus de 25 cas de tuberculose (TB) par an. Parmi l’ensemble des personnes interroge´ es, 87,8% ont d e´ clar e´ prescrire une quadrith´erapie a` la phase initiale d’attaque. Parmi ces praticiens, les mesures d’isolement e´ taient lev´ees par 31,9% d’entre eux apr`es trois examens microscopiques des crachats n e´ gatifs, 19% levaient l’isolement syst´ematiquement apre` s 15 jours de traitement et 34,1% seulement en cas d’am´elioration clinique. Le
retour a` domicile malgr´e un examen microscopique des crachats toujours positif e´ tait « envisageable » pour 71% des r´epondants. Un controle ˆ de l’examen des crachats pour la recherche des bacilles acido-alcoolo-r´esistants e´ tait r´ealis´e par seulement 21% des participants a` 2 mois de traitement. C O N C L U S I O N : Malgr e´ des recommandations nationales r e´ centes, l’application des mesures d’isolement pour la TB bacillif`ere reste h´et´erog`ene, et une proportion significative de cliniciens pr´escrivent une trith´erapie antituberculeuse. Des efforts suppl´ementaires doivent eˆ tre faits pour mieux diffuser ces recommandations, principalement par une meilleure information au sein des soci e´ t e´ s savantes, mais e´ galement par le biais de donn´ees scientifiques plus solides. RESUMEN
Evaluar las pra´cticas de aislamiento y el tratamiento de los casos de tuberculosis (TB) con baciloscopia positiva en Francia. M E´ T O D O S: Se realiz o ´ una encuesta mediante un cuestionario distribuido por v´ıa electronica ´ en el 2011 y el 2012 a los m´edicos de la Sociedad Francesa de Enfermedades Infecciosas, la Sociedad Respiratoria Francesa y la Sociedad Nacional Francesa de Medicina Interna. R E S U LT A D O S: Una cuarta parte de los 311 m´edicos que respondieron afirmo´ tratar ma´s de 25 casos de TB cada ano. ˜ Un total de 87,8% declaro´ el uso corriente de un r´egimen con cuatro medicamentos en la fase intensiva, al comienzo del tratamiento. Las precauciones de aislamiento fueron aplicadas por los profesionales como sigue: el 31,9% las suspend´ıa despu´es de haber obtenido tres resultados negativos de la baciloscopia de esputo, el 19,0% sistema´ticamente despu´es de 15 d´ıas de O B J E T I V O S:
tratamiento y el 34,1% de los m´edicos interrump´ıa las precauciones solo cuando observaban una mejor´ıa cl´ınica. Segun ´ el 71% de quienes respondieron, el alta hospitalaria hacia el hogar era ‘posible’ pese a los resultados positivos de la baciloscopia de esputo. Despu´es de 2 meses de tratamiento, solo 21% de los me´ dicos practicaba de manera sistema´tica una baciloscopia de esputo. ´ N: Pese a las directrices nacionales CONCLUSIO recientes, la aplicaci on ´ de las precauciones de aislamiento de los pacientes tuberculosos con baciloscopia positiva sigue siendo heterog´enea y una alta proporcion ´ de profesionales utiliza reg´ımenes con tres medicamentos. Se precisan nuevas iniciativas que fomenten el cumplimiento de las directrices sobre el tratamiento de la TB, especialmente por intermedio de las sociedades cient´ıficas nacionales y aumentando adema´s el acopio de datos fidedignos.
Survey of French physician practices in treatment and control of transmission of smear-positive tuberculosis ´ F. Mecha¨ ı,* J. Figoni,* B. Wyplosz,† O. Aoun,‡ O. Bouchaud,* J. Robert§¶# ˆ ˆ *Service des Maladies Infectieuses et Tropicales, Assistance Publique-Hopitaux de Paris (APHP), Hopital Avicenne, ˆ ˆ Universite´ Paris 13, Bobigny, †Service des Maladies Infectieuses et Tropicales, APHP, Hopital Bicetre, Le Kremlin ‡ ˆ ´ ´ ´ erence ´ Bicetre, Centre Medical des Armees de Colmar, Colmar, Haut-Rhin, §Centre National de Ref des ´ ´ ´ ˆ ´ Mycobacteries et de la Resistance des Mycobacteries aux Antituberculeux, APHP, Hopitaux Universitaires Pitieˆ ere, ` Salpetri Paris, ¶Unite´ 1135, Centre d’Immunologie et des Maladies Infectieuses, Universite´ Paris 06, Universite´ ´ Paris, #Unite´ 1135, Centre d’Immunologie et des Maladies Infectieuses, Pierre et Marie Curie, Sorbonne Universites, ´ Institut National de la Sante´ et de la Recherche Medicale, Paris, France SUMMARY OBJECTIVES:
To evaluate isolation practices and management of sputum smear-positive tuberculosis (TB) in France. M E T H O D S : A survey was conducted using a questionnaire e-mailed in 2011 and 2012 to physicians of the French Society of Infectious Diseases, the French Respiratory Society and the French National Society of Internal Medicine. R E S U LT S : Of 311 responders, a quarter stated they treated more than 25 TB cases per year. A total of 87.8% declared they routinely used a four-drug regimen in the initial intensive phase. Of the 311 physicians who responded, 31.9% removed isolation precautions after three negative acid-fast bacilli (AFB) sputum results, 19.0% after 15 days of treatment and 34.1% only in
case of clinical improvement. According to 71% of the responders, discharge from hospital despite positive AFB sputum smear results was ‘possible’. A routine AFB sputum smear was performed after 2 months of treatment by only 21% of the responders. C O N C L U S I O N : Despite recent national guidelines, the management of isolation precautions for sputum smearpositive TB remains heterogeneous, and a significant proportion of physicians use a three-drug regimen. Further efforts should be made to implement TB guidelines, mainly by raising awareness through national scientific institutions, but also by obtaining better evidence. K E Y W O R D S : smear-positive tuberculosis; isolation precautions; treatment
TUBERCULOSIS (TB) remains a major public health concern worldwide. The World Health Organization (WHO) estimated that 8.6 million people were newly infected in 2012, of whom 1.3 million died.1 In France, 4975 cases of TB disease were reported in 2012 to the French Institute for Public Health Surveillance (Institut de Veille Sanitaire, Saint Maurice, France).2 Of these, 74% had pulmonary TB, of whom approximately 50% were smear-positive. There are many international3–7 and national8–10 guidelines on the management of pulmonary TB. Most of these guidelines agree that all patients should be treated with the standardised four-drug regimen, i.e., isoniazid, rifampicin, ethambutol and pyrazinamide. However, airborne isolation precautions may vary with different countries on duration and discontinuation criteria. The first 1994 Centers for Disease Control and Prevention (CDC) guidelines recommended discontinuing airborne isolation after
clinical improvement with effective treatment and three smear-negative sputum samples.4 In 2000, the Infectious Diseases Society of America (IDSA) added to the CDC criteria the criterion that a smear-positive patient could be discharged if he/she lived with persons already exposed to TB or with persons who were not immunosuppressed or young children.6 The IDSA and CDC guidelines were updated in 2005 in collaboration with the American Thoracic Society (ATS).7 This updated version mainly combined both older versions regarding the discontinuation of airborne precautions. According to the 2011 UK guidelines, airborne isolation could be discontinued after 2 weeks of a standard regimen unless the patient was hospitalised in the same ward as immunosuppressed patients.5 In France, the most recent guidelines, issued in 2010, recommend airborne isolation until three smear-negative sputum samples are obtained.10
Correspondence to: Fr´ed´eric M´echa¨ı, Service des Maladies Infectieuses et Tropicales, Hopital Avicenne, Bobigny, France. ˆ Tel: (þ33) 1 48 95 54 21. Fax: (þ33) 1 48 95 54 28. e-mail: [email protected] Article submitted 30 June 2014. Final version accepted 30 September 2014.
206
The International Journal of Tuberculosis and Lung Disease
Table 1 Characteristics of the 311 physicians who responded to the questionnaire Characteristic
n (%)
Medical specialisation Respiratory medicine Infectious diseases Internal medicine Others Type of health care facility Teaching or large referral hospital General hospital Private practice Others
177 64 61 9
(56.9) (20.6) (19.6) (2.9)
140 123 38 10
(45.0) (39.6) (12.2) (3.2)
Number of tuberculosis cases managed yearly ,25 25–50 .50
236 (75.9) 69 (22.2) 6 (1.9)
Total
311 (100)
However, other conditions, such as favourable clinical course and effective treatment regimen, also need to be met.7 The 2010 French guidelines recommend a significantly longer duration of isolation than the 2004 guidelines, which proposed discontinuing airborne isolation after 15 days of treatment in case of a favourable clinical course.9,10 The French Expert Committee estimated that available data did not allow lack of infectiousness to be estimated based on a single criterion of 2 weeks of effective treatment. These conservative recommendations also apply to smear-negative patients with pulmonary cavities, who should be isolated during the first 2 weeks of an effective treatment regimen.10 The aim of our survey was to collect data on current practices among physicians regarding isolation precautions and treatment of pulmonary TB in France in 2011–2012, and to compare the results with recent guidelines. We used a standardised questionnaire e-mailed to physicians and specialists likely to manage patients with respiratory TB.
METHODS A standardised questionnaire was e-mailed to all physicians who were members of the French Infectious Diseases Society (Soci´et´e de Pathologie Infectieuse de Langue Fran¸caise [SPILF], Paris, France), the French Respiratory Society (Soci´et´e de Pneumologie de Langue Fran¸caise [SPLF], Paris, France), and the French National Society of Internal Medicine (Soci´et´e Nationale de M´edecine Interne [SNFMI], Rouen, France). The 12-item questionnaire assessed current practices in their hospital department. Questions were related to the implementation of isolation precautions (negative-pressure room, duration) and criteria for discontinuing precautions and for discharge. The systematic use of sputum smear testing at months 2 and 6 of treatment was recorded. A final three questions were related to anti-tuberculosis
treatment, including systematic use of the standard four-drug regimen, the role of fluoroquinolones as a first-line drug and of plasma anti-tuberculosis drug dosages. The questionnaire was sent out twice to improve the response rate, in November 2011 and February 2012. Answers were analysed using Epi Infoe version 3.5 (CDC, Atlanta, GA, USA).
RESULTS Participant characteristics Among the 311 (10%) responders, 177 (56.9%) were respiratory specialists, 64 (20.6%) were infectious disease specialists, 61 (19.6%) were physicians in internal medicine and 9 (2.9%) were working in other departments (Table 1). One hundred and forty (45%) worked in a teaching hospital or a large referral hospital, 123 (39.6%) in a general hospital and 38 (12.2%) in private practice, either in primary care or in private hospitals. More than three quarters (n ¼ 236, 75.9%) of the responders reported that they treated fewer than 25 new TB cases per year (Table 1). Of the remaining 75 (24.1%) physicians who reported treating at least 25 TB cases a year, 64% were respiratory physicians and 60% worked in a teaching hospital. Anti-tuberculosis treatment regimens A total of 273 (87.8%) physicians stated that they routinely used a four-drug regimen in the initial intensive phase of treatment among newly diagnosed TB patients (Table 2). Although this proportion was slightly higher among infectious disease physicians (92.2%) than among respiratory (89.8%) and internal medicine physicians (80.3%), the differences were not statistically significant. It is of note that the fourdrug standard regimen was applied by 93% of those physicians who treated at least 25 TB cases a year. A total of 84 (27%) physicians considered using fluoroquinolones as a first-line drug in cases who were intolerant to rifampicin (RMP) or isoniazid (INH), or in cases with risk factors for multidrugresistant TB (MDR-TB) (poor adherence during previous anti-tuberculosis treatment, patient from a country with high MDR-TB prevalence) (Table 2). The remaining 227 (73%) physicians stated that they had never used fluoroquinolones to treat standard TB. Concentrations of anti-tuberculosis drugs in plasma were routinely measured by 30 (9.6%) physicians. In addition, 110 (35.4%) responders reported measuring plasma drug concentrations in specific situations such as co-administration of antiretroviral drugs, clinical and/or biological intolerance, suspicion of non-adherence and extremes of weight. The remaining 171 (55%) physicians reported that they did not measure plasma drug concentrations (Table 2).
Management of smear-positive TB
Table 2
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Management of a new tuberculosis case by the 311 responders
Characteristic
n (%)
Standard intensive phase regimen Four-drug regimen Three-drug regimen (no ethambutol) Use of fluoroquinolones as first-line drug Never Risk factor for resistance Allergy/side effect related to another drug Osteoarticular tuberculosis Other
273 (87.8) 38 (12.2) 227 43 19 2 20
(73.0) (13.8) (6.1) (0.7) (6.4)
Measurement of anti-tuberculosis drug plasma concentrations Never Routine Risk of drug-drug interaction or presence of comorbidities* Other (side effects, poor outcome, poor adherence, etc.)
171 30 82 28
(55.0) (9.6) (26.4) (9.0)
Reasons for discontinuation of airborne isolation precautions 715 days of effective drug treatment with favourable clinical course Automatically after 15 days of effective drug treatment Smear-negative sputum Culture-negative sputum Significant decrease in AFB in sputum Cough resolution Other Not stated
106 59 99 2 2 3 15 25
(34.1) (19.0) (31.9) (0.6) (0.6) (1.0) (4.8) (8.0)
Total
311 (100)
* HIV co-infection with antiretroviral drugs, renal or hepatic failure, other comorbidities. AFB ¼ acid-fast bacilli; HIV ¼ human immunodeficiency virus.
Airborne isolation precautions Airborne isolation was discontinued on day 15 by 165 (53.1%) physicians if the TB clinical course was favourable (34.1%), or routinely, regardless of the clinical course (19%). Airborne isolation was discontinued only in cases of smear-negative or culturenegative sputum by respectively 99 (31.9%) and 2 (0.6%) physicians. For the remaining 20 (6.4%) responders, airborne isolation was discontinued when specific criteria were met, such as a decrease in the number of acid-fast bacilli (AFB) in the sputum or resolution of cough. The proportion of physicians following the latest French recommendations10 regarding airborne isolation was not significantly different between physicians treating at least 25 TB cases a year (30.9%) and those treating fewer than 25 a year (34.7%). Only 48 (15.4%) physicians reported having negative-pressure isolation rooms in their facility. A total of 221 (71.1%) physicians said they would authorise hospital-to-home discharge despite persistent smear-positive sputum after 15 days of active treatment. However, among the latter, 156 (70.6%) would authorise discharge only if neither children nor immunosuppressed individuals were at home. The majority of the responders (n ¼ 227, 73%) would discontinue airborne isolation earlier than day 15 if the patient became smear-negative, and 250 (80.4%) would even allow early hospital-to-home discharge if evidence of absence of increased risk of transmission among contacts compared to contacts of patients with initial smear-negative sputum was available.
Finally, respectively 20.8% (n ¼ 64) and 8.1% (n ¼ 25) of the responders reported performing microbiological follow-up after 2 and 6 months of treatment (direct examination and sputum smear or gastric lavage culture).
DISCUSSION This survey on the hospital management of smearpositive TB is the first to be performed in France on a large scale. It shows wide variations in practice and some discrepancies with either the French or the international recommendations for TB management. The optimal initial drug regimen is well established for smear-positive TB cases: both national and international guidelines recommend routine use of a four-drug combination. However, 12% of responders stated that they systematically started with a threedrug regimen, i.e., a regimen that did not include ethambutol (EMB). The lack of adherence to antituberculosis treatment guidelines has already been reported in France, but mainly regarding excessive length of treatment.11,12 The use of a three-drug regimen increases the risk of multidrug resistance in case of initial resistance to INH, which is the most frequent resistance pattern observed in industrialised countries. A three-drug combination regimen should be reserved for precisely defined cases, for example where initial drug resistance is very unlikely or following drug susceptibility testing (DST) results.13 The advent of newer rapid molecular tools for the detection of INH and RMP resistance may be of
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The International Journal of Tuberculosis and Lung Disease
interest when choosing between a three- or four-drug regimen, although difficulties remain regarding the sensitivity of these new tests in the detection of INH resistance.14 The detection of AFB in sputum smears at the end of the 2-month intensive phase and at treatment completion (6 months) is advised by the WHO.15 Our results show that the implementation of WHO guidelines is very poor in France (respectively 21% and 8% of responders systematically performed sputum smear controls at 2 and 6 months); it is therefore generally impossible to differentiate between cure and treatment completion according to international definitions. However, the relevance of sputum smear monitoring has, to our knowledge, not yet been established in countries with reliable medical health care systems that are able to provide sputum cultures with routine DST, efficient imaging and satisfactory clinical improvement during follow-up. We did not record planned treatment duration in our survey, as this had recently been studied by Tattevin et al., who reported that a standardised 6-month regimen was applied by 91% of infectious disease physicians for pulmonary TB, in particular among human immunodeficiency virus negative patients.12 Regarding discontinuation of airborne precautions, the results of our survey showed that less than one third of French physicians complied with the 2010 French guidelines, i.e., discontinuation was based solely on AFB sputum smear results. Consequently, two thirds of responders did not comply with French guidelines or with any of the guidelines issued by United States institutions.6,7,10 Overall, 19% declared removing the requirement for isolation after 2 weeks of treatment, regardless of sputum smear results, in line with the latest UK recommendations and the 2004 French recommendations.5,9 Finally, 34% of the physicians based discontinuation criteria on clinical improvement combined with effective treatment, a strategy not mentioned in any of the cited guidelines.4–10 Approximately half of French physicians treating infectious TB patients do not comply with any local or international guidelines for discontinuation of airborne isolation precautions. Reasons for the lack of adherence to guidelines are numerous and have been extensively reported elsewhere.16 From our study, it is likely that the existence of many different recommendations does not favour adherence to any one of these. This lack of consensus may be taken as poor quality evidence, and consequently a lack of agreement. The fact that some physicians comply with the oldest and not the latest guidelines may reflect a lack of awareness. However, the survey respondents were members of scientific societies, suggesting that they were likely to be kept informed of any changes. Our study had some weaknesses. As it covered only 10% of physicians registered with the participating
societies, we cannot claim that our findings are representative of French practice in general. The fact that 75% of the respondents declared treating fewer than 25 cases a year suggests that the respondents did not have extensive experience in TB management, and that they may have been looking for new information and continuing medical education through different means, including this survey. This may also explain the poor knowledge about the national guidelines. However, all respondents were members of scientific societies, which meant that they were qualified in the management of infectious TB patients. Of note, data from the National Reference Centre for Mycobacteria show that among the 270 French hospitals and private practice laboratories performing mycobacterial research, 83% reported fewer than 25 culture-positive cases a year (personal data). Our sample therefore does not over-represent less active practitioners. Finally, our survey was based on subjective responses from participants and may not reflect observed practices. The study nevertheless showed that French practice regarding isolation precautions and treatment practice for sputum smear-positive TB patients were heterogeneous and did not comply with national or international guidelines. Acknowledgements The authors would like to express their sincere gratitude to the responding physicians, who made this survey possible. We also thank the Syndicat National des M´edecins Infectiologues, the Soci´et´e de Pathologie Infectieuse de Langue Fran¸caise and the Soci´et´e de Pneumologie de Langue Fran¸caise for distributing the questionnaire by e-mail. Conflicts of interest: none declared.
References 1 World Health Organization. Global tuberculosis report, 2013. WHO/HTM/TB/2013.11. Geneva, Switzerland: WHO, 2013. 2 Antoine D, Belghiti F, Guthman J P, Campese C, L´evy-Bruhl D, Che D. Cases of tuberculosis notified in France in 2012. Bull Epid´emiol Hebdo 2014; 20: 352–359. 3 American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America. Treatment of tuberculosis. Am J Respir Crit Care Med 2003; 167: 603– 662. 4 Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care facilities, 1994. Centers for Disease Control and Prevention. MMWR Recomm Rep 1994; 43 (RR13): 1–132. 5 National Collaborating Centre for Chronic Conditions, Centre for Clinical Practice at National Institute for Health and Care Excellence. Tuberculosis: clinical diagnosis and management of tuberculosis, and measures for its prevention and control. London, UK: NICE, 2011. 6 Horburgh Jr. C R, Feldman S, Ridzon R. Practice guidelines for the treatment of tuberculosis. Clin Infect Dis 2000; 31: 603– 609. 7 American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America. Controlling tuberculosis in the United States. Am J Respir Crit Care Med 2005; 172: 1169–1227.
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8 Recommandations de la soci´et´e de pneumologie de langue fran¸caise sur la prise en charge de la tuberculose en France. Rev Mal Respir 2004; 21: 414–420. 9 Groupe de Travail du Conseil Sup´erieur d’Hygi`ene Publique. Preventing the transmission of tuberculosis in healthcare institutions. Med Mal Infect 2004; 34: 404–410. [French] 10 Minist`ere de la Sant´e et des Sports, Haut Conseil de la Sant´e Publique. Surveiller et pr´evenir les infections associ´ees aux soins. Paris, France: Minist`ere de la Sant´e et des Sport, 2010. [French] 11 Valin N, Hejblum G, Borget I, et al. Factors associated with excessively lengthy treatment of tuberculosis in the eastern Paris region of France in 2004. BMC Public Health 2010; 10: 495. 12 Tattevin P, Chapplain J M, Lesprit P, et al. Tuberculosis
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treatment duration in France: from guidelines to daily practice. Eur J Inter Med 2006; 17: 427–429. Mitchison D A. Role of individual drugs in the chemotherapy of tuberculosis. Int J Tuberc Lung Dis 2000; 4: 796–806. Brossier F, Veziris N, Truffot-Pernot C, Jarlier V, Sougakoff W. Performance of the GenoType MTBDR line-probe assay for detection of resistance to rifampin and isoniazid in strains of Mycobacterium tuberculosis with low- and high-level resistance. J Clin Microbiol 2006; 44: 3659–3664. World Health Organization. Treatment of tuberculosis: guidelines. 4 th ed. WHO/HTM/TB/2009.420. Geneva, Switzerland: WHO, 2010. Cabana M D, Rand C S, Powe N R, et al. Why don’t physicians follow clinical practice guidelines? A framework for improvement. JAMA 1999; 282: 1458–1465.
Management of smear-positive TB
i
RESUME
´ valuer les pratiques d’isolement et la OBJECTIFS : E prise en charge des tuberculoses bacillif`eres en France. M E´ T H O D E S : Une enquˆete en ligne a e´ t´e men´ee en 2011 et 2012 a` l’intention des m´edecins des soci´et´es fran¸caises de pathologies infectieuses, de pneumologie et de m´edecine interne. R E´ S U LT A T S : Parmi les 311 m´edecins ayant r´epondu, un quart affirme prendre en charge plus de 25 cas de tuberculose (TB) par an. Parmi l’ensemble des personnes interroge´ es, 87,8% ont d e´ clar e´ prescrire une quadrith´erapie a` la phase initiale d’attaque. Parmi ces praticiens, les mesures d’isolement e´ taient lev´ees par 31,9% d’entre eux apr`es trois examens microscopiques des crachats n e´ gatifs, 19% levaient l’isolement syst´ematiquement apre` s 15 jours de traitement et 34,1% seulement en cas d’am´elioration clinique. Le
retour a` domicile malgr´e un examen microscopique des crachats toujours positif e´ tait « envisageable » pour 71% des r´epondants. Un controle ˆ de l’examen des crachats pour la recherche des bacilles acido-alcoolo-r´esistants e´ tait r´ealis´e par seulement 21% des participants a` 2 mois de traitement. C O N C L U S I O N : Malgr e´ des recommandations nationales r e´ centes, l’application des mesures d’isolement pour la TB bacillif`ere reste h´et´erog`ene, et une proportion significative de cliniciens pr´escrivent une trith´erapie antituberculeuse. Des efforts suppl´ementaires doivent eˆ tre faits pour mieux diffuser ces recommandations, principalement par une meilleure information au sein des soci e´ t e´ s savantes, mais e´ galement par le biais de donn´ees scientifiques plus solides. RESUMEN
Evaluar las pra´cticas de aislamiento y el tratamiento de los casos de tuberculosis (TB) con baciloscopia positiva en Francia. M E´ T O D O S: Se realiz o ´ una encuesta mediante un cuestionario distribuido por v´ıa electronica ´ en el 2011 y el 2012 a los m´edicos de la Sociedad Francesa de Enfermedades Infecciosas, la Sociedad Respiratoria Francesa y la Sociedad Nacional Francesa de Medicina Interna. R E S U LT A D O S: Una cuarta parte de los 311 m´edicos que respondieron afirmo´ tratar ma´s de 25 casos de TB cada ano. ˜ Un total de 87,8% declaro´ el uso corriente de un r´egimen con cuatro medicamentos en la fase intensiva, al comienzo del tratamiento. Las precauciones de aislamiento fueron aplicadas por los profesionales como sigue: el 31,9% las suspend´ıa despu´es de haber obtenido tres resultados negativos de la baciloscopia de esputo, el 19,0% sistema´ticamente despu´es de 15 d´ıas de O B J E T I V O S:
tratamiento y el 34,1% de los m´edicos interrump´ıa las precauciones solo cuando observaban una mejor´ıa cl´ınica. Segun ´ el 71% de quienes respondieron, el alta hospitalaria hacia el hogar era ‘posible’ pese a los resultados positivos de la baciloscopia de esputo. Despu´es de 2 meses de tratamiento, solo 21% de los me´ dicos practicaba de manera sistema´tica una baciloscopia de esputo. ´ N: Pese a las directrices nacionales CONCLUSIO recientes, la aplicaci on ´ de las precauciones de aislamiento de los pacientes tuberculosos con baciloscopia positiva sigue siendo heterog´enea y una alta proporcion ´ de profesionales utiliza reg´ımenes con tres medicamentos. Se precisan nuevas iniciativas que fomenten el cumplimiento de las directrices sobre el tratamiento de la TB, especialmente por intermedio de las sociedades cient´ıficas nacionales y aumentando adema´s el acopio de datos fidedignos.
