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HCDCP NEWSLETTER MINISTRY OF HEALTH & SOCIAL SOLIDARITY

Hellenic Center for Disease Control and Prevention Agrafon 3- 5, Maroussi, 15123, Tel: +30 210 5212000, info@keelpno.gr, http://www.keelpno.gr

October 2011

Vol. 08/ Year 1st

ISSN 1792-9016

HCDCP HELLENIC CENTER FOR DISEASE CONTROL & PREVENTION

Contents Editorial: Tuberculosis in Greece and the world 2-5 Surveillance Data 6-8 Invited article 9-26 HCDCP Departments Activities 27-28 Recent publications 29 Interesting activities 30-35 Future conferences and meetings 36 Quiz of the month 36 Outbreaks around the world 37 Myths and truths 38-39 News from HCDCP Administration 40

Tuberculosis in Greece and the world Tuberculosis (TB) is one of the most serious infectious diseases, with incalculable financial impact on health systems all over the world. Even though, since 2004, globally the incidence of the disease has been reduced, the total number of deaths from tuberculosis continues to increase, mainly because of the emergence of multi-drug-resistant tuberculosis (MDR-TB), with primary rifampicin and isoniazid resistance, and extremely drugresistant tuberculosis (XDR-TB), with additional resistance to quinolones and one of the three injectable second-line drugs (amikacin, kapreomycin and kanamycin). According to the European Center for Disease Control and Prevention (ECDC) and the World Health Organization (WHO), in 2009 the incidence of tuberculosis in Greece was 5.2 cases per 100,000 population, although only half of the cases were laboratory-confirmed. The TB surveillance system has significant malfunctions, and according to a recent study conducted by the Office for Respiratory Diseases of the Hellenic Center for Disease Control and Prevention (HCDCP) an important underreporting of the disease has been found. Additionally, TB cases have increased in certain population groups, such as immigrants, human immunodeficiency virus (HIV)-positive people, prisoners and homeless people. Co-operation among all stakeholders in the diagnosis, treatment, prevention and epidemiological surveillance of the disease, through implementation of national TB control programs, seems to be the only way to control the disease, both in Greece and internationally. Particularly for Greece, it is imperative that the recently (2008) prepared TB control program is implemented immediately by adapting it to the current financial situation.

Evaggelos Vogiatzakis

Chief Editor:

Highlights

Ch. Hadjichristodoulou Scientific Board: Ν. Vakalis Ε. Vogiatzakis P. Gargalianos- Kakoliris Μ. Daimonakou- Vatopoulou Ι. Lekakis C. Lionis Α. Pantazopoulou V. Papaevagelou G. Saroglou Α. Tsakris Editorial Board: M. Angelopoulou R. Vorou Ph. Koukouritakis Κ. Mellou S. Parissis Τ. Patoucheas V. Roumelioti V. Smeti V. Tsatsareli Ch. Tsiara Μ. Fotinea Ε. Hadjipashali

The Mandatory Notification System of the Hellenic Centre for Diseases Control and Prevention (HCDCP) records an overall decline in the number of declared tuberculosis (TB) cases and a parallel increase of TB cases in immigrants. More in page 2

The Ministry of Health and Social Solidarity in cooperation with the Hellenic Centre for Diseases Control and Prevention (HCDCP) developed a national action plan for the prevention of communicable diseases in which TB control program is included. Defining the rules on legislative initiatives and coordination among the bodies of TB control programs are necessary to improve the epidemiological surveillance of tuberculosis. More in page 24

The Hellenic Centre for Diseases Control and Prevention (HCDCP) in cooperation with the European Legionnaires’ Disease Surveillance Network (ELDSNet) and the Health Protection Agency (HPA) is investigating clusters of legionnaires’ disease cases among tourists who accommodated in Corfu. An expert team sent by the Central Public Health Laboratory and the Regional Public Health Laboratory of Thessaly in coordination with the local health authoroties performed risk assessment on accommodation and collected samples. More in page 29 Multidrug-resistant tuberculosis (MDRTB) is a continually increasing global problem of public health. In our country, MDR-TB is diagnosed in 2.5% of Greek patients while the rates are twofold higher among immigrants. More in page 20


Editorial Epidemiological data on tuberculosis in Greece, 2004-2010 Tuberculosis (TB) is one of the most common infectious diseases worldwide and continues to be a major public health problem despite the fact that there is effective treatment for it.

Finally, regarding the recording of cases based on prior anti-tuberculosis treatment, the highest rate (60.2 -83.2%) occurred in new cases that were not previously diagnosed with tuberculosis (Figure 7). Figure 1: Reported cases of tuberculosis, Greece 2004-2010

It causes annually over one million deaths mainly in the developing countries and approximately 140 new cases per 100000 population, worldwide. In Greece the notification of TB is mandatory according to the following: 1. The Royal Decree/ Gazette of the Government of Greece 262Α/1950 “on measures against epidemics and mandatory declaration of these”. 2. The Law 3204/2003- Gazette of the Government of Greece 296Α/24-12-2003, Artcile 44, Paragraph 1: “At the Center for Infectious Disease Control in Greece each infectious disease is archived and any public or private provider offering healthcare services or an individual practitioner, within legitimate operation, is required to report to the Center for Infectious Disease Control in Greece cases of infectious disease that is aware of”. Under current law, the Department of Epidemiological Surveillance and Intervention of the Hellenic Center for Disease Control and Prevention (HCCDP, former Center for Infectious Disease Control in Greece) is authorized by the Data Protection Authority to keep a relevant filing system for public health reasons. The notification is made via a special bulletin, «INFECTIOUS DISEASE STATEMENT - TUBERCULOSIS». This record is comprised of all necessary data, so as to enable the epidemiological recording of the disease through data analysis and implement public health measures for the TB cases’ immediate environment. Additionally, the systematic surveillance of the disease is necessary to monitor the indicators set by the World Health Organization (WHO) and European Centre for Disease Control (ECDC), in order to control TB on a European and international level. Based on these goals by 2015 the prevalence and deaths due to tuberculosis should be reduced to 50% in comparison to 1990 data and by 2050 the disease should not be a public health problem anymore. An analysis of data collected annually through the mandatory notification system for the period 2004 - 2010 shows that in our country an average of 600 cases is reported each year. Also there is a gradual reduction of notified cases, specifically from 761 in 2004 to 490 in 2010. With regard to the reported cases in Greeks and the percentage of all reported cases, a decrease trend is observed. On the contrary, in reported cases of migrants the trend is increasing (Figure 1 and Figure 2). It should be noted though that studies that have calculated the number of new TB cases through the consumption of anti-TB drugs, have shown significant underreporting of the disease.

Figure 2: Frequency distribution of TB reported cases by nationality, Greece 2004-2010

Also, we do not actually know the exact rate of TB increase in the number of persons with foreign nationality, from 2004 to 2010. Hence we are unable to determine exactly how much of the decrease trend of cases is due to underreporting and in what extend the increased trend in migrants is due to a recent possible increase in their population.

Most Greek TB cases occurred in persons aged 65 and older, while most TB cases in foreigners occurred in those aged 25 to 34 years (Figure 4). The difference between Greeks and foreigners in the age distribution is consistent with the fact that the majority of migrants in our country are people of working age. The average incidence rate per 100000 population by geographic region (NUTS-I, Nomenclature of Territorial Units for Statistics) was higher in Central Greece and Attica, while the lower incidence rate was recorded in the area of the Aegean Islands and Crete (Figure 5). Regarding the type of the disease, the largest proportion (66.4%-74.9%) of cases was pulmonary, whereas the rate of the extra pulmonary location and forms was low. Also in 20.4% of the reported Greek cases as well as in 16.2% of cases occurring in foreign-born persons their chest x-rays showed cavities (Figure 6). The presence of cavities is important in the epidemiology of the disease because these cases are more contagious.

2

Editorial

Editorial

Overall, during the period 2004-2010 the 64.1% of the total number of reported cases were Greeks, 34% were of foreign nationality, while in 1.9% of cases the nationality is not determined (Figure 3).

3


Figure 3: Frequency distribution of TB reported cases by nationality, Greece 2004-2010

Figure 6: Frequency distribution of reported cases of pulmonary tuberculosis based on the presence of cave by nationality, Greece 2004 – 2010

Figure 4: Age distribution of the TB reported cases by nationality, Greece 2004-2010

Figure 7: Frequency distribution of TB recorded cases based on prior anti-tuberculosis treatment, Greece 2004-2010

Figure 5: Average TB reported incidence rate by geographic region (NUTS-I), Greece 2004-2010

Editorial

Editorial

Office for respiratory diseases

4

5


Surveillance Data

Table 1: Number of notified cases in September 2011, median number and range of notified cases in September for the years 2004−2010, Mandatory Notification System, Greece

Table 2: Number of notified cases by place of residence (region)*, August 2011, Mandatory Notification System, Greece

Disease

Disease

Number of notified cases

Region

0-0

Pertussis

0

1

0-5

Legionellosis

2

3

1-5

Leishmaniasis

4

4

2-6

Leptospirosis

2

2

1-4

Listeriosis

1

0

0-3

*Place of residence is defined as the home address of the patient.

EHEC infection

0

0

0-0

Rabies

0

0

0-0

Table 3: Number of notified cases by age group and gender*, August 2011, Mandatory Notification System, Greece

Melioidosis/glanders

0

0

0-0

20

40

27-85

Meningitis (bacterial, aseptic)

0-1 0-2 0-1 6-16 0-0 0-0 2-13 0-0 0-0 0-3 2-38

1

3

1-7

Plague

0

0

0-0

Mumps

0

2

0-5

Poliomyelitis

0

0

0-0

Q Fever

0

0

0-0

59

122

45-243

Shigellosis

8

4

1-13

Severe acute respiratory syndrome

0

0

0-0

Congenital rubella

0

0

0-0

Congenital syphilis

0

0

0-0

Congenital toxoplasmosis

0

0

0-0

Cluster of foodborne/waterborne disease cases

1

0

0-0

Τetanus/neonatal tetanus

0

1

0-3

Tularaemia

0

0

0-0

Trichinosis

0

0

0-0

Typhoid fever/paratyphoid

1

1

1-4

23

50

45-80

0

0

0-0

Tuberculosis Cholera

6

0 0 0 0 0

0 1 1 0 1

0 0 0 0 0

0 1 0 0 0

0 3 0 0 0

0 0 0 0 0

0 0 0 0 0

0 1 1 0 1

1 1 7 1 1

0 3 20 0 0

0 0 0 0 0

0 0 0 0 0

0 0 0 1 0

0 0 1 0 0

1

0

0

0

0

0

0

0

0

0

0

0

0

1

0 0 0 0 2 0 15 0

0 0 0 0 3 0 3 0

0 0 0 0 0 0 1 0

0 0 0 0 2 0 3 0

0 0 0 0 1 0 6 2

0 0 0 0 0 0 0 0

0 1 1 0 4 0 1 0

0 1 0 0 1 0 2 2

0 1 1 1 6 1 19 4

0 0 0 0 0 0 1 0

0 0 0 0 0 0 4 0

0 0 0 0 0 0 0 0

0 1 0 0 1 0 4 0

2 0 0 0 0 0 0 0

Cluster of foodborne/waterborne disease cases

0

0

0

0

0

0

0

0

1

0

0

0

0

0

Typhoid fever/paratyphoid Tuberculosis

0 3

0 2

0 1

0 0

0 1

0 0

0 4

0 3

1 8

0 1

0 0

0 0

0 0

0 0

Range

Meningococcal disease

Salmonellosis (non-typhoid/paratyphoid)

Unknown

0

Crete

0

Southern Aegean

Haemorrhagic fever

Northern Aegean

0-0

Peloponnese

0

Attica

0

Sterea Greece

0-5

Western Greece

3

Ionian islands

2

Thessalia

2-19

Epirus

5

Western Macedonia

0

Hepatitis B, acute & HBsAg(+) in infants <12 months Hepatitis C, acute & confirmed anti-HCV positive (1st diagnosis) Measles

Central Macedonia

Median number September 2004−2010 0 0 0 12 0 0 3 0 0 1 10

Eastern Macedonia and Thrace

September 2011 0 0 1 10 0 0 30 0 0 2 3

Botulism Chickenpox with complications Anthrax Brucellosis Diphtheria Arbo-viral infections Malaria Rubella Smallpox Echinococcosis Hepatitis Α

Surveillance Data

Number of notified cases

Anthrax Brucellosis Malaria Echinococcosis Hepatitis A Hepatitis C, acute & confirmed anti-HCV positive (1st diagnosis) Legionellosis Leishmaniasis Leptospirosis Listeriosis Meningitis (bacterial, aseptic) Meningococcal disease Salmonellosis (non-typhoid/paratyphoid) Shigellosis

Disease

Anthrax Echinococcosis Hepatitis A Hepatitis C, acute & confirmed antiHCV positive (1st diagnosis) Legionellosis Leishmaniasis Leptospirosis Listeriosis Meningitis (bacterial, aseptic) Meningococcal disease Salmonellosis (non-typhoid/ paratyphoid) Shigellosis Typhoid fever/ paratyphoid Tuberculosis

F 0 0 0

Number of notified 1−4 5−14 15−24 M F M F M F 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0

cases by 25−34 M F 0 0 1 0 0 1

age group (years) and gender 35−44 45−54 55−64 65+ M F M F M F M 0 0 0 0 0 0 1 0 0 0 1 0 0 0 0 0 1 0 0 0 0

F 0 0 0

Un. M 0 0 0

F 0 0 0

0

0

0

0

0

0

0

0

0

1

1

0

0

0

0

0

0

0

0

0

0 0 0 0

0 0 0 0

0 1 0 0

0 1 0 0

0 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0

1 0 0 0

0 0 0 0

0 0 1 1

0 1 0 0

1 0 1 0

0 1 0 0

0 0 0 0

0 0 0 0

3

0

1

0

0

1

0

0

2

0

0

0

0

0

0

1

2

0

5

5

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1

0

4

4

7

8

9

3

1

4

2

1

0

1

1

0

0

3

6

5

0

0

1

0

1

2

0

2

0

0

1

0

0

0

0

0

0

0

1

0

0

0

0

0

0

0

0

0

1

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1

0

0

3

0

1

0

2

3

3

2

1

0

6

1

0

0

<1 M 0 0 0

*M, male; F, female. 7

Surveillance Data

Surveillance Data


The data presented are derived from the Mandatory Notification System (MNS) of the Hellenic Center for Disease Control and Prevention (HCDCP). Forty-five infectious diseases are included in the list of the mandatory notifiable diseases in Greece. Notification forms and case definitions can be found on HCDCP’s website (www.keelpno.gr). It should be noted that the data for September 2011 are provisional and may be slightly modified/corrected in the future. Data interpretation should be made with caution, because there are indications of under-reporting to the system. Department of epidemiological surveillance and intervention

Invited article Laboratory diagnosis of tuberculosis The microbiological diagnosis of tuberculosis (TB) is an important tool for disease control. It consists of both conventional methods (acid-fast microscopy, culture, biochemical identification, anti-tuberculosis drug-susceptibility testing; DST) and modern molecular techniques. The targets of microbiological testing include the detection and isolation of mycobacteria, species identification, detection of drug resistance, monitoring patient responses to therapy and epidemiological typing of Mycobacterium strains. There are three levels of laboratory for diagnosis. The first-level laboratories carry out sample collection, preparation, staining, microscopy and referral to second-level laboratories. Second-level laboratories have adequate equipment and experience to cultivate and identify the mycobacteria. These laboratories send isolates for confirmation of identification and DST at third-level laboratories. Third-level laboratories comprise reference laboratories for TB diagnosis, where full first- and secondline DST, strain typing and epidemiological investigations take place. In Greece, much of the primary laboratory diagnosis and sensitivity control, and almost all the DST, takes place at the Microbiology Laboratory, National Reference Laboratory for Mycobacterium (NRLM), ‘Sotiria’ Chest Diseases Hospital, Athens (Figures 1, 2, 3, 4 and Table 1). Conventional methods for laboratory diagnosis Clinical specimens should be representative of the lesion, and not be contaminated. Specimens should originate mainly from the respiratory system. The clinician must contact the laboratory on how best to obtain and transport clinical material. After sample preparation, for example liquidation, homogenization, decontamination and neutralization, staining and microscopy take place. Either acid-fast (Ziehl-Neelsen, Kinyon) or fluorescent (auramine, rodamine) staining is implemented [1]. At least 103-104 bacilli/ml should be present in a sample for a positive result. This probability increases when the bacilli number is higher. For biological fluids, the sensitivity decreases compared with sputum (35-70%). A positive result confirms a clinical diagnosis, but a negative result does not exclude the disease. Microscopy is non-specific and M. tuberculosis cannot be differentiated from atypical mycobacteria; however, microscopy is the cheapest and fastest method of detection and provides information on a patient’s clinical response to treatment.

Surveillance Data

DST should be applied to all new cases of tuberculosis, when microscopy [and culture for multi-drug-resistant (MDR)-TB] remains positive 3 months after therapy and when there is no satisfactory clinical response to treatment. DST is performed using different methods. The proportional method remains the gold standard and the only method for evaluating patient responses to treatment. Control of resistance to PZA (pyrazinamide) requires an acidic pH, so it is only performed in automated systems and in proper liquid media. Depending on the media used, the Clinical and Laboratory Standards Institute (CLSI) and World Health Organization (WHO) have proposed different concentrations of anti-TB drugs. The USA Center for Disease Control and Prevention (CDC) suggests that DST should be performed using automated 8

9

Invited article

A culture is performed on either solid media, for example Lowenstein-Jensen (L-J) or Middlebrook 7H10/11 (Petrof method, modified Petrof, NAOH 2% Ν-acetyl-cystein), or liquid media. Sensitivity ranges between 80% and 93% and specificity is more than 98%. A positive result is expected during the fifth and sixth weeks, but in week 1 cultures should be checked daily for potential development of rapidly growing mycobacteria (RGM). The evaluation of a positive result is based on the number of colonies developed. Liquid media cultures include Bactec 460 and the automated Bactec MGIT 960 [2]. The first utilizes vials containing liquid medium Middlebrook 7Η12, with a substrate for mycobacteria growth labeled with 14C. The substrate metabolism by the bacilli releases 14CO2, which is then measured. Advantages are a shorter time to arrive at a positive culture (<7 days for atypical, 9-14 days for M. tuberculosis) and increased sensitivity. Disadvantages are an increased risk of contamination, no colony formation, the use of radioactive substances and high costs. The Bactec MGIT 960 requires liquid medium Middlebrook 7Η9 incorporating a silicon substrate, which fluoresces under conditions that lack Ο2, which is consumed by the micro-organisms. The advantages compared with Bactec 460 is that no radioactive substances are used and DST is feasible.


systems, which provide faster results, even if the results should be confirmed by conventional culture in L-J. DST for first-line drugs has been standardized; however, for second-line drugs no method has yet received international acceptance. With the increasing isolation of MDR-TB and extremely drug-resistant (XDR)-TB strains, there is an urgent need for standardization of these methods as well. Molecular methods for laboratory diagnosis Because of the slow growth rate of the M. tuberculosis complex (MTBC) bacilli, molecular techniques have become the cornerstone for rapid detection of TB. Developed from in-house techniques to fully automated assays, the nucleic-acid amplification tests (NAAT) may provide results in a couple of days or even hours upon receipt of the specimen by the laboratory. Furthermore, the need for the rapid detection of resistance in MTBC has led to the development and implementation of genotyping assays that are able to identify resistance-associated mutations directly from clinical samples. Resistance to the most common anti-tuberculosis drugs, and particularly to rifampicin, is particularly amenable to rapid molecular detection because the vast majority of resistant strains contain mutations in restricted regions of specific genes. Currently there are two commercially available line-probe assays endorsed by WHO, detecting mutations associated with rifampicin and rifampicin and isoniazid resistance (the INNO-LiPA Rif. TB kit and GenoType MTBDRplus, respectively), Recently, an assay (Xpert MTB/ RIF) has been developed, and endorsed by WHO for world-wide application, that permits the simultaneous detection of MTBC presence and rifampicin resistance, which may serve as a surrogate marker for MDR-TB. Thousands of articles have been published regarding the diagnostic accuracy of NAAT for TB. Commercial tests have been shown to give more consistent results than in-house assays. Metaanalyzes have found high specificity but lower and highly variable estimates of sensitivity. In the most recent study [3], the pooled sensitivity was estimated to be 0.85 (range 0.36-1.00) and the pooled specificity 0.97 (range 0.54-1.00). In general, NAAT performance is lower in extrapulmonary and microscopically negative pulmonary samples. Thus NAAT alone cannot be recommended as a replacement for conventional tests for diagnosing TB. Line-probe assays perform excellently regarding rifampicin resistance in culture isolates. However, for isoniazid the sensitivity is lower, because additional genetic mutations, not detected by the assay, have been shown to confer drug resistance. Regarding their use directly in clinical specimens, the assays retain their high performance, particularly in microscopically positive specimens [4]. Finally, for the recently introduced assay that combines MTBC detection and rifampicin resistance, the accumulating literature indicates very promising results, including paucibacillary disease, for example extrapulmonary, human immunodeficiency virus (HIV) convection and pediatric TB [5]. In conclusion, NAAT have sped up the diagnosis of both TB and its resistance to the major anti-TB drugs, and the growing scientific and technological momentum could revolutionize the field in the near future.

of latent tuberculosis infection (LTBI). IGRA are blood-based tests that essentially measure the presence of specific M. tuberculosis-reactive T cells sensitized by a previous infection with M. tuberculosis. Two commercial IGRA are available, the QuantiFERON-TB Gold In-Tube assay (QFT-GIT) (Cellestis Ltd, Australia) and the T-SPOT-TB (Oxford Immunotec, UK). They were developed to support the diagnosis of LTBI but research is also ongoing for expanding its use to the diagnosis of active tuberculosis. Uncertainty remains regarding the effectiveness of IGRA. Compared with the TST (tuberculin skin test), IGRA are not confounded by prior bacille Calmette-Guérin (BCG) vaccination and are less likely to be influenced by previous exposure to most non-tuberculous mycobacteria (NTM), because of the target antigens selected to stimulate cellular immune responses. IGRA should not replace the existing standard diagnostic methods for the diagnosis of active TB. Α negative IGRA result does not exclude active TB disease. Regarding the diagnosis of LTBI, IGRA may be used in conjunction with an overall risk assessment in order to identify individuals for whom preventive treatment should be considered (e.g. immunocompromised people, children, close contacts and recently exposed individuals). References: 1. Steingart KR, Henry M, Ng V, et al. Fluorescence versus conventional sputum smear microscopy for tuberculosis: a systematic review. Lancet Infect Dis 2006;6:570-581. 2. Cruciani M, Scarparo C, Malena M, et al. Meta-analysis of BACTEC MGIT 960 and BACTEC 460 TB, with or without solid media, for detection of mycobacteria. J Clin Microbiol 2004;42(5):2321-2325. 3. Ling DI, Flores LL, Riley LW, Pai M. Commercial nucleic-acid amplification tests for diagnosis of pulmonary tuberculosis in respiratory specimens: meta-analysis and meta-regression. PLoS One 2008;3(2):e1536. 4. Ling DI, Zwerling AA, Pai M. Rapid diagnosis of drug-resistant TB using line probe assays: from evidence to policy. Expert Rev Respir Med 2008;2:583-588. 5. Lawn SD, Nicol MP. Xpert(®) MTB/RIF assay: development, evaluation and implementation of a new rapid molecular diagnostic for tuberculosis and rifampicin resistance. Future Microbiol 2011;6:1067-1082. 6. Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diaseases. Am J Respir Crit Care Med 2007;175:367-416. 7. European Center for Disease Prevention and Control. Use of Interferon-Gamma Release Assays in Support of TB Diagnosis. Stockholm: ECDC, 2011.

Infections caused by non-tuberculosis mycobacteria (NTM) are diagnosed with increasing frequency world-wide. For the laboratory diagnosis of NTM, as much clinical material as possible should be provided for culture. Cultures should include both liquid and solid media. Quantitation of the number of colonies should be performed to aid clinical diagnosis. Supplemented culture media and special culture conditions (lower incubation temperatures; 30°C) should be used for material cultured from skin lesions, joints and bone. The time (in days) to detection of mycobacterial growth should be stated on the laboratory report. Clinically significant NTM isolates should be identified routinely to the species level. Differentiation between M. avium and M. intracellulare is not yet clinically significant. RGM (especially M. chelonae, M. abscessus and M. fortuitum) should be identified to the species level. Susceptibility of RGM for eight agents (amikacin, cefoxitin, clarithromycin, ciprofloxacin, doxycycline, linezolid, sulfamethoxazole and tobramycin) can also be used to facilitate identification of M. abscessus, M. chelonae and M. fortuitum. Communication between the clinician and the laboratory technician is essential for proper diagnosis.

Invited article

Invited article

Laboratory diagnosis of non-tuberculosis mycobacteria [6]

Interferon-gamma release assays (IGRA) [7] Interferon-gamma release assays (IGRA) are relatively new tools introduced for the diagnosis 10

11


Figure 1: New cases of TB per year, NRLM, Athens (1995-2010)

Figure 2: MDR-TB, NRLM, Athens (1995-2010)

Invited article

Year Phenotype

1995 (n=320)

1996 (n=336)

1997 (n=344)

1998 (n=410)

1999 (n=545)

2000 (n=650)

2001 (n=628)

2002 (n=520)

2003 (n=540)

2004 (n=460)

2005 (n=497)

2006 (n=466)

2007 (n=454)

2008 (n=431)

2009 (n=441)

2010 (n=461)

TOTAL (n=7503)

SM INH SM+INH SM+INH+EMB+RIF INH+RIF SM+EMB+INH RIF INH+SM+RIF EMB PZA+SM+INH+EMB+RIF INH+EMB INH+EMB+RIF SM+PZA+INH+RIF PZA+INH+EMB+RIF SM+EMB SM+EMB+RIF SM+RIF PZA SM+PZA+INH PZA+INH+EMB SM+PZA+INH+EMB EMB+RIF SM+PZA PZA+INH PZA+EMB SM+PZA+EMB PZA+INH+RIF SM+PZA+EMB+RIF PZA+RIF SM+PZA+RIF

26 7 5 3   1 3 1 2   2     1 1       1       2 1            

9 9 6 2   3 1 1 9     2     1         1                    

18 13 8 11 1 4   1 2 2 1 1 1               2                  

15 10 10 2 2   3 2   3 3 2 1 1 1 2 1   1                      

15 6 6 8 4 3 1 5 3 10 1   3 1   1   5   1 1       1          

16 8 9 2 7     1   1   1 3   2   1       1           1 1    

18 17 15 4 3 2 1 2 1 4     1 1         1                      

12 11 7 6 9   4 4 3     1               3                    

14 16 24 9 7 4 6 4 1   2         1                            

10 26 10 7 2 3 3 3 1   1 2         1         1                

23 8 6 6 1 6 5 2 1     2     2 3 1         1                

22 1 5 6 3 3 3 4 5                         2                

23 5 9 12   6 2 1             1 1 2                          

11 6 10 2 3 5         1   1 4     1   2   1                  

13 5 6 4   1 1 2   6       2                       1        

20 2 5 2 1 4 1 3 1   1   1                                  

265 150 141 86 43 45 34 36 29 26 12 11 11 10 8 8 7 5 5 5 5 4 2 1 1 1 1 1 0 0

Total

56

44

65

59

75

54

70

60

88

70

67

54

62

47

41

41

953

SM, streptomycin; INH, isoniazid; RIF, rifampicin; EMB, ethambutol; PZA, pyrazinamide 12

13

Invited article

Table 1: Phenotypes of resistance to the first anti-TB drugs, NRLM, Athens (1995-2010)


Tuberculosis diagnosis update

Figure 3.

The new gene Xpert MTB/RIF assay Improved and timely diagnosis of tuberculosis (TB), especially in smear-negative paucibacillary and in multi-drug-resistant tuberculosis (MDR-TB), is a global priority. Conventional diagnosis relies on bacterial culture and drug-susceptibility testing (DST), a slow and labor-intensive process. Until the results are available, patients are not given appropriate treatments, MTB (m.tuberculosis) strains are spread, and resistance to drugs is amplified. Alarming increases in MDR-TB (2.7% MDR-TB among new cases in Greece in 2008), the global emergence of extremely drug-resistant TB (XDR-TB) and high mortality in drug-resistant TB/human immunodeficiency virus (HIV) co-infection have highlighted the urgency for rapid diagnostic tests [1,2].

Papaventsis D, Nikolaou S, Karabela S, et al. Tuberculosis in Greece: bacteriologically confirmed cases and anti-tuberculosis drug resistance, 1995-2009. Euro Surveill 2010;15(28):pii=19614. Available at http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19614 Figure 4.

In December 2010, the World Health Organization (WHO) endorsed the new Gene Xpert MTB/ RIF assay and recommended its use within the context of national plans for the appropriate management of TB, MDR-TB and HIV-associated TB. The broad consensus achieved, regarding agreement on interim diagnostic algorithms, the positioning of Xpert MTB/RIF in risk groups, and implementation, was summarized in a Rapid Implementation of Xpert MTB/RIF document [3], aimed at guiding a systematic roll-out of Xpert MTB/RIF in varying epidemiological and resource settings, with a view to large-scale implementation. The Xpert MTB/RIF is a real-time fully automated diagnostic molecular test that has the potential to revolutionize and transform TB care and control [4]. It was developed by the Foundation for Innovative New Diagnostics (FIND), Cepheid and the University of Medicine and Dentistry of New Jersey, with funding from the National Institute of Health (NIH) and the Bill and Melinda Gates Foundation. The test: simultaneously detects TB and rifampicin drug resistance, which is a reliable indicator for MDR-TB • provides accurate results in less than 2 h so that patients can be offered proper treatment on the same day • has minimal bio-safety and training requirements, and can be housed in non-conventional laboratories. WHO policy recommendation •

The WHO Global Consultation confirmed a solid evidence base to support widespread use of Xpert MTB/RIF for the detection of TB and rifampicin resistance, and resulted in the following main recommendations [5]. 1. Xpert MTB/RIF should be used as the initial diagnostic test in individuals suspected of having MDR-TB or HIV-associated TB. (Strong recommendation) 2. Xpert MTB/RIF may be considered as a follow-on test after microscopy in settings where MDR-TB or HIV is of lesser concern, especially in further testing of smear-negative specimens. (Conditional recommendation acknowledging major resource implications)

Invited article

Simona Karabela, Medical Biopathologist, PhD, Consultant Panayotis Ioannidis, Molecular Biologist, PhD Dimitrios Papaventsis, Medical Biopathologist, PhD, Consultant Vogiatzakis Evangelos, Medical Biopathologist, Clinical Microbiologist, PhD, Co-ordinator Director Microbiology Laboratory – National Reference Laboratory for Mycobacteria, ‘Sotiria’ Chest Diseases Hospital

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The Xpert MTB/RIF assay does not, however, eliminate the need for conventional tests, which are required to monitor treatment success and detect resistance to drugs other than rifampicin. In settings or patient groups where rifampicin resistance is rare, Xpert MTB/RIF results indicating rifampicin resistance should be confirmed by conventional DST or line-probe assays (LPA) (Table 1). In addition, several operational conditions need to be met for successful implementation of the assay [5]. Greece, with a rifampicin resistance rate of 4%, fulfills all prerequisites for implementation of the Gene Xpert MTB/RIF assay at a country level [2]. In an evaluation study conducted in the Microbiology Laboratory - National Reference Laboratory for Mycobacteria (NRLM), ‘Sotiria’ Chest Diseases Hospital, Athens, the GeneXpert MTB/RIF was highly effective for TB diagnosis and identification of rifampicin-resistant strains even in smear-negative or extrapulmonary samples [6]. In January 2011, FIND negotiated a 75% price reduction for the public sector of 116 lowincome countries. Subsequently, NRLM negotiated with FIND and the Stop TB Partnership for a preferential price of the Xpert MTB/RIF assay for Greece. Given its geographical position as a major entry point of refugees into the European Union (EU) (mostly from high TB-endemic countries, including MDR-TB), WHO and FIND agreed to an alternative special pricing relationship 15

Invited article

Papaventsis D, Nikolaou S, Karabela S, et al. Tuberculosis in Greece: bacteriologically confirmed cases and anti-tuberculosis drug resistance, 1995-2009. Euro Surveill 2010;15(28):pii=19614. Available at http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19614


with Cepheid as a special case, solely for purchase orders originating from the Greek Ministry of Health. The price discount exceeds 60%. Direct activation of this agreement may result in significant benefits for the treatment of tuberculosis in our country. Table 1: Key prerequisites before country-wide implementation of the Xpert MTB/RIF assay [5]

1. Allow decision making on prioritizing placement of the technology and optimizing use of Xpert MTB/RIF in highrisk patient groups from the prevalence data of MDR-TB and HIV-associated TB

Diagnostic policy reform

2. Plan to modify existing diagnostic algorithms as part of the NTP (National Toxicology Program) strategy to introduce Xpert MTB/RIF testing

Laboratory network

3. Existing capacity and referral network to provide qualityassured laboratory services with: a) culture and DST, to determine resistance to first- and second-line drugs at a central level (at least), quality-assured through an established link with a supranational reference laboratory; b) sputum smear microscopy, for TB testing and treatmentresponse monitoring; c) culturing, to monitor responses to MDR-TB treatment

Laboratory workload

Infrastructure

1. WHO. Multidrug and Extensively Drug-Resistant TB (M/XDR-TB): 2010 Global Report on Surveillance and Response. Geneva: WHO, 2010. WHO/HTM/TB/2010.3. Available at http://whqlibdoc.who.int/ publications/2010/9789241599191_eng.pdf. 2. Papaventsis D, Nikolaou S, Karabela S, et al. Tuberculosis in Greece: bacteriologically confirmed cases and anti-tuberculosis drug resistance, 1995-2009. Euro Surveill 2010;15(28):pii=19614.

Prerequisite Epidemiological data

References:

3. WHO. Rapid Implementation of Xpert MTB/RIF. Geneva: WHO, 2011. WHO/HTM/TB/2011.2. Available at http://whqlibdoc.who.int/publications/2011/9789241501569_eng.pdf. 4. WHO. Fact Sheet: Xpert MTB/RIF Test. Geneva: WHO, 2011. Available at http://www.who.int/tb/ features_archive/factsheet_xpert_may2011update.pdf [accessed May 2011]. 5. WHO. Policy Statement: Automated Real-Time Nucleic Acid Amplification Technology for Rapid and Simultaneous Detection of Tuberculosis and Rifampicin Resistance: Xpert MTB/RIF system. Geneva: WHO, 2011. WHO/HTM/TB/2011.4. Available at http://whqlibdoc.who.int/ publications/2011/9789241501545_eng.pdf. 6. Ioannidis P, Papaventsis D, Karabela S, et al. Cepheid GeneXpert MTB/RIF assay for Mycobacterium tuberculosis detection and rifampin resistance identification in patients with substantial clinical indications of tuberculosis and smear-negative microscopy results. J Clin Microbiol 2011;49(8):3068-3070. Dimitrios Papaventsis, Panayotis Ioannidis, Vogiatzakis Evangelos, Microbiology Laboratory – National Reference Laboratory for Mycobacteria, ‘Sotiria’ Chest Diseases Hospital

4. The potential number of samples from high-risk groups for Xpert MTB/RIF testing in the facility where implementation is intended should range from 10 to 20 a day or 2000 to 4000 annually, in order to ensure optimal efficiency (4-module Gene Xpert module) 5. Stable electricity supply in the facilities where implementation is intended, or sufficient measures to ensure uninterrupted supply (generator, solar panels, battery/UPS backup, etc.) 6. Secure premises for the equipment to prevent theft of the Gene Xpert unit and the computer/laptop 7. Adequate storage of cartridges within the recommended temperature range (2-28°C)

Bio-safety

9. Bio-safety microscopy

Personnel

10. 1-2 staff per site with basic computer literacy and knowledge of laboratory registers who can be trained to perform the testing and maintain the equipment

Treatment capacity

11. Sufficient capacity for treatment of identified TB and MDR-TB patients, available and in line with international recommendations

Financing

12. Secure funding from national budget or donors/partners

Procurement

13. Country importation procedures allowing the procurement of both equipment and consumables (regulatory registration or waiver) and exchange of modules for annual calibration

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requirements

similar

to

sputum

smear

Invited article

Invited article

8. Appropriate measures to prevent the ambient temperature exceeding 30°C in the room where the equipment will be installed (e.g. ventilation and air conditioning)

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The European Reference Laboratory Network for Tuberculosis (ERLN-TB) ’Timely and accurate laboratory diagnosis of TB is a central component of any TB control program’ In January 2010, the European Center for Disease Control (ECDC) launched the European Reference Laboratory Network for Tuberculosis (ERLN-TB). This was in response to a situational analysis of tuberculosis (TB) reference laboratory services by Drobniewski et al. [1], which demonstrated the added value of a European Union (EU) network of reference laboratories for TB. All EU/European Economic Area member states and EU candidate countries officially nominated one or two laboratories with reference functions for participation in the network. From Greece, the Microbiology Laboratory - National Reference Laboratory for Mycobacteria, ‘Sotiria’ Chest Diseases Hospital, Athens, was nominated by the Hellenic Center for Disease Control and Prevention (HCDCP) to participate.

such as short latency period, intrinsic resistance and higher transmission ability [4]. The epidemiological situation of TB in Greece [5] and our experience from participation in ERLN-TB activities highlights the need for KEELPNO to undertake an initiative in order to finance and support the development of the Greek laboratory network for TB laboratory diagnosis in the near future. Figure 1: European Reference Laboratory Network for TB (ERLN-TB): organizational structure

The three main goals of the network are to: 1. support methods harmonization within the EU/EEA 2. develop external quality assurance (EQA) schemes 3. provide training activities within the network to ensure EU-wide capacity building. A consortium of TB laboratory experts, led by the Health Protection Agency (HPA) National Mycobacterium Reference Laboratory, London, United Kingdom, has been assembled to support the network. ERLN-TB has been awarded a financial grant for 4 years by the ECDC. The organizational structure of ERLN-TB is depicted in Figure 1. Within the first year, the network completed the first version of a handbook on TB laboratory diagnostic methods. This is a compilation of the most reliable methods and highlights key considerations regarding biosafety and quality assurance [2]. In addition, ERLN-TB has participated in the production of a guidance document on the use of interferon-gamma release assays (IGRA) [3], contributed towards the compilation of a mycobacteria reference strain collection, promoted twinning arrangements between network laboratories and developed a web platform containing training materials and other relevant documents (http://erlntb.eu/).

References: 1. Drobniewski FA, Nikolayevskyy V, Hoffner S, et al. The added value of a European Union tuberculosis reference laboratory network – analysis of the national reference laboratory activities. Euro Surveill 2008;13(12)pii:8076. 2. European Center for Disease Prevention and Control. Mastering the Basics of TB Control: Development of a Handbook on TB Diagnostic Methods. Stockholm: ECDC, 2011. Available at http://ecdc.europa.eu/ en/publications/Publications/1105_TER_Basics_TB_control.pdf) (accessed 6 May 2011).

The network has identified the need and added value of a training program for TB laboratory support experts. During the first 2 years, five workshops addressing issues such as laboratory diagnosis of TB, epidemiology, contact tracing, funding and management, were held in London and Milan. The first cohort of eight support experts graduated in summer 2011. A second group will be selected in late 2011. The laboratory support experts form a valuable resource from the ECDC for support in country visits and TB laboratory-related issues.

3. European Center for Disease Prevention and Control. Use of Interferon-Gamma Release Assays in Support of TB Diagnosis. Stockholm: ECDC, 2011. Available at http://ecdc.europa.eu/en/ publications/Publications/1103_GUI_IGRA.pdf) (accessed 18 March 2011).

In 2011, a working group for the development of an EU-adapted guidance on the use of molecular methods for the rapid detection of M. tuberculosis and drug resistance was established. The network is also liaising closely with the ECDC funded Molecular Surveillance of MDR-TB in the EU project. In total 30 countries, represented mainly by their reference laboratories, are participating in this project, co-ordinated by the RIVM institute (the Netherlands) and the ECDC. The aim of the project is to trace the international transmission of multi-drug-resistant (MDR)/ extremely drug-resistant (XDR)-TB in the EU and neighboring countries by applying 24-loci VNTR (Variable Number Tandem Repeat) typing. More than 1800 strains isolated in 22 countries have been analyzed and 46% of them have been identified as belonging to 68 clusters, presumably indicating the transmission of MDR/XDR-TB. In many EU countries systematic contact tracing has confirmed the epidemiological and genotypic results. VNTR typing has shown the ongoing extension of one extremely large cluster of the Beijing genotype that comprises 449 strains from 15 countries, including one from Greece. Of the 54 MDR/XDR-TB strains isolated in our laboratory since 2007, 31 have been genotyped. It is noteworthy that 13 (42%) of these belong to the Beijing family, which is considered to harbor strains with more aggressive characteristics,

5. Papaventsis D, Nikolaou S, Karabela S, et al. Tuberculosis in Greece: bacteriologically confirmed cases and anti-tuberculosis drug resistance, 1995-2009. Euro Surveill 2010;15(28):pii=19614. Available online http://www.eurosurveillance.org/ViewArticle. aspx?ArticleId=19614

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4. Molecular surveillance of multidrug resistant tuberculosis in the European Union 3rd meeting on the ECDC/RIVM project, 27-28 September 2011, Chania, Crete, Greece

Dimitrios Papaventsis, Medical Microbiologist, PhD, Panayotis Ioannidis, Molecular Biologist, PhD Vogiatzakis Evangelos, Medical Biopathologist, Clinical Microbiologist, PhD, Co-ordinator Director Microbiology Laboratory – National Reference Laboratory for Mycobacteria, ‘Sotiria’ Chest Diseases Hospital Invited article

Invited article

A comprehensive EQA system for microscopy, culture, identification and drug-susceptibility testing of Mycobacterium tuberculosis has also been implemented (two rounds in 2010, one round in 2011). INSTAND e.V., a World Health Organization (WHO) collaborating center for quality assurance and standardization, was selected as the main provider co-ordinated by the National Reference Center, Borstel, Germany. Following the success of the first year, the development and implementation of EQA schemes for molecular-based methods has been added to the 2011 EQA.

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Μulti-drug-resistant and extremely drug-resistant tuberculosis Introduction The fight against tuberculosis (TB) world-wide is today facing a huge challenge. The increasing resilience and multiple resistance of Mycobacterium tuberculosis to anti-TB drugs makes all control efforts more complex and demanding in order to protect public health. Resistance terminology Primary resistance: this resistance occurs in patients who have not had prior treatment with anti-TB drugs. Acquired resistance: this resistance occurs in patients who have had prior treatment with anti-TB drugs. Monoresistance: resistance to one of the four primary anti-TB drugs and streptomycin (isoniazid, rifampicin, ethambutol, pyrazinamide and streptomycin) Polyresistance: resistance to two or more anti-TB drugs, other than both isoniazid and rifampicin. Multi-drug resistance (MDR): TB that is resistant to at least isoniazid and rifampicin, the two most powerful first-line anti-TB drugs. Isolates that are multiply resistant to any other combination of anti-TB drugs but not to isoniazid and rifampicin are not classified as MDR-TB. Extreme drug-resistance (ΧDR): TB that has developed resistance to at least rifampicin and isoniazid, as well as to at least one of the following second-line anti-TB injectable drugs, amikacin, kanamycin and capreomycin. Figure 1: XDR-TB is a subtype of MDR-TB [1]

According to data from the National Reference Center for Mycobacteria, which are almost identical to those of the anti-TB department and MDR-TB unit of the ‘Sotiria’ Chest Diseases Hospital, for the last 15 years (1995-2010) in all new TB cases in Greece an average rate of MDR-TB 2.5% has been found. In addition, the average MDR-TB rate for immigrants was double that (5%). With regard to XDR-TB in the last 5 years, in the anti-TB registry department the number of cases among Greeks is similar to the number of cases among immigrants. This can be explained by the massive entry and granting of Greek citizenship to expatriates from the former Soviet Union countries in the last decade. Prevention and treatment of MDR-TB and XDR-TB The pathogenetic mechanisms of resistance to M. tuberculosis are briefly as follows. In isolated mycobacteria, drug-resistance is the result of genetic mutation. Although the rate of individual mutations is relatively small, patients with active TB have a significantly larger number of bacteria. Therefore, there can be thousands of mutations in a drug. If there has been prior exposure to a single drug, the mycobacteria subpopulation that is resistant to this particular drug will multiply and dominate. Thus at least two drugs to which the mycobacterium is sensitive must be included in TB treatment. If the patient fails to take the medication as prescribed by the physician, or if the therapist does not provide the appropriate treatment, drug resistance may occur. In developing countries this is the result of a lack of medication or discontinuation of the medication required, as well as the low quality of medication [5]. Resistant and MDR forms of TB, epidemic forms and TB in certain population groups should be monitored to enable immediate intervention and limit the spread of mycobacteria. The treatment of multi-drug forms must take place in special units staffed by appropriate nursing and medical personnel specialized in MDR-TB treatment. It is well known that excessive use of secondary anti-TB drugs (able only to address drug-resistant TB) from non-specialized health centers in eastern Europe and developing countries has created a huge problem, with highly resistant and incurable forms of TB emerging [6]. In our country, almost all patients (more than 98%) with MDR-TB and XDR-TB are treated by the anti-TB department of the ‘Sotiria’ Chest Diseases Hospital. The anti-TB department consists of the Multi-Resistant TB Unit, which is the only one in Greece, and outpatient offices divided into two sections, 1) health centers in which patients receive TB treatment and 2) health centers for TB prevention. For the proper treatment of MDR-TB and XDR-TB in Greece, our country should be committed to the immediate implementation of the DOTS (directly observed treatment, short-course) program (which requires diagnosis, drugs and patient adherence to the treatment regimen), as defined by WHO. Otherwise, with the current economic crisis even the minimum level of health care for TB monitoring and treatment will collapse. The money needed for TB health care is not prohibitive, even under the current circumstances. Therapeutic failure

Invited article

It is estimated that 1,900,000,000 people have been infected with M. tuberculosis (latent infection) world-wide (according to World Health Organization data in 2009). New TB cases have totaled 940,000 (WHO, 2009) [11]. In 2008, 440,000 new MDR-TB cases were reported, which corresponds with an average rate of 3.6% for all TB cases world-wide and 3.3% of new TB cases. Each year around 150,000 deaths from MDR-TB are reported. The prevalence of resistance is clearly high in the former Soviet Union and China. In contrast, countries with the lowest MDR-TB prevalence are America, western and central Europe and Africa. These data seem to be proportionally related to the implementation of a national TB control program in each country [2, 3]. The 27 countries with more than 10% of MDR-TB new cases are: Ethiopia, Azerbaijan, Armenia, Vietnam, Bulgaria, Georgia, Estonia, Bangladesh, India, Indonesia, Kazakhstan, China, Congo, Kyrgyzstan, Latvia, Belarus, Lithuania, Miamar, Moldova, Nigeria, South Africa, Ukraine, Uzbekistan, Pakistan, Russian Federation, Tajikistan and Philippines [4]. MDR-TB and XDR-TB are serious problems in our country, growing since 1990 after the massive entry of economic migrants and political refugees from eastern Europe, Asia and Africa 20

The term therapeutic failure is used to describe the presence of positive cultures after completing 4 months of anti-TB treatment. The etiology is multi-factorial and is often the result of a combination of circumstances. In summary, the reasons for therapeutic failure may be the result of: 1) noncompliance of the patient, 2) inappropriate regimen, 3) primary resistance of M. tuberculosis to anti-TB drugs, 4) malabsorption of drugs, and 5) reinfection with a new strain. The majority of TB patients belong to special social groups, who are often alcoholics, human immunodeficiency virus (HIV) seropositive, homeless, drug users and elderly people who live alone or have mental and cognitive disorders, and thus the implementation of anti-TB treatment can be troublesome. Furthermore, the patient may not follow all the medical advice to receive the medication properly, with the exact dosage at the right time. This usually happens after an initial period of full treatment, when the patient feels quite well and decides arbitrarily to discontinue the medication entirely or a part of it. Sometimes the patient takes the initiative to reduce or discontinue entirely the anti-TB treatment because of the treatment’s side-effects [7]. Treatment It must be stressed that the fight against MDR-TB and XDR-TB should be undertaken in specialized medical units with experienced medical and nursing staff, as well as with an appropriate building 21

Invited article

Epidemiology


infrastructure. Therapeutic operations of drug-resistant TB are based on test results that control the in vitro susceptibility of isolated mycobacteria with specific anti-TB drugs. The choice of treatment is determined by the drug resistance, the nature of drugs used in the past, whether the patient is under medical supervision and the possible side-effects. It is also well known that the results of susceptibility testing can be significantly delayed (from a few weeks to 2 months), although recently the susceptibility testing for isoniazid and rifampicin using molecular techniques can give reliable results within just a few hours. In some circumstances, when the chance of resistance is high, it is necessary to start treatment for resistant TB before completion of sensitivity tests. Such circumstances are related to patients for whom the standard anti-TB treatment fails (positive cultures after 4 months of treatment), who have received anti-TB treatments in the past, reported contact with resistant-TB patients or were born in countries with a high TB prevalence. The treatment can be modified once the susceptibility test results are available [8]. Patients with MDR-TB should be provided with at least four or more drugs to which the isolated strain is sensitive. We start with the available first-line anti-TB drugs and then add a fluoroquinolone or an injectable drug. Additionally, other second-line drugs must be administered orally so that four to six are given in total.

Response. Geneva: WΗΟ, 2010. 5. assal M, et al. Extensively drug-resistant tuberculosis. Lancet Infect Dis 2009;9:19-30. 6. National TB Control Program. National Action Plan for the Prevention of Communicable Diseases p. 116 Paragraph 6.2.2 Monitoring of Specific Forms of TB 2008-2012. Athens: Ministry of Health & Social Solidarity, 2008. Available at www.ygeianet.gov.gr. 7. Polyzogopoulos D, Polychronopoulos V. Clinical Pulmonary. Second Edition, Volume II. Paschalides Publications, 2005; pp. 1798-1804. 8. Chan E, et al. Multidrug-resistant and extensively drug-resistant tuberculosis: a review. Curr Opin Infect Dis 2008;21:587-595. 9. Curry F. Drug-Resistant Tuberculosis. State of California: National Tuberculosis Center, 2008. 10. Orenstein E. et al. Treatment outcomes among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis. Lancet Infect Dis. 2009;9:153-161. Dr Κ. Kostandinou Pneumonoloist-TB Specialist, Director of Anti-TB Department ‘Sotiria’ Chest Diseases Hospital

In brief, our therapeutic strategy is as follows: 1. remove from our arsenal all drugs with known TB resistance 2. take nothing for granted until the results of the susceptibility tests are received 3. use the injectable capreomycin or amikacin as the cornerstone of treatment 4. look for primary drugs with a sensitive strain (if any at all) 5. if not administered, fluoroquinolone (moxifloxacin or levofloxacin) is necessary 6. of the other second-line drugs, we mostly prefer ethionamid, cycloserine and p-aminosalicylic acid (PAS) 7. alternatively, and in desperate situations, we can administer linezolid, clofazimine, imipenem, thioridazine and amoxicillin in combination with clavulanic acid, isoniazid, rifabutin, PA–824 (nitroimidazopyran) and TMC207 (diarylquinoline) 8. all patients receive pyridoxine at a daily dose of 150 mg 9. the drugs are administered at the maximum allowable doses and are not saved for later use 10. patients are treated in negative pressure rooms, where the air comes from an HEPA (High Efficiency Particulate Arresting) filter, while in public places ultraviolet radiation should be used 11. health care workers should wear appropriate protective masks (3M 1873V) 12. treatment must be maintained for at least 18 months after a negative culture. As mentioned earlier, XDR-TB is defined as resistance to at least isoniazid and rifampicin, plus resistance to a fluoroquinolone and at least one of the three injectable second-line drugs amikacin, kanamycin and capreomycin. The planning of the therapeutic response of XDR-TB is equivalent to that described for MDR-TB. We begin with any in vitro-active first-line TB drug, followed by second-line drugs and finally third-line drugs. Furthermore, patients with XDR-TB should take into account the potential benefits of surgery. To maximize the benefits of surgery, the disease should be localized, so that after a lobectomy or pneumonectomy the remaining lung tissue is disease-free. Also, surgery should be performed by an experienced surgeon and only after several months of treatment. Even after a successful surgical procedure a full anti-TB treatment should be administered [7, 9, 10]. References: Invited article

Invited article

1. LoBue P. Extensively drug-resistant tuberculosis. Curr Opin Infect Dis 2009;22:167-173. 2. Konstandinou K. MDR-TB. In Dimopoulos G, Infections of the Respiratory System. Parisian Publications, 2010; pp. 513-518. 3. Wright A, et al. Epidemiology of antituberculosis drug resistance 2002-07: an update analysis of the Global Project on Anti-Tuberculosis Drug Resistance Surveillance. Lancet. 2009;373:1861-1873. 4. WΗΟ. Multidrug and Extensively Drug-Resistant TB (M/XDR-TB): Global Report on Surveillance and 22

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TB control program

Tuberculosis treatment up-date

The serious problem of tuberculosis (TB) in eastern Europe, and particularly the specter of possibly incurable TB (extremely drug-resistant tuberculosis; XDR-TB), has stimulated the European continent, resulting in a proposition to increase the funding to fight against TB in order to achieve the objectives of the Global Plan to Stop TB 2006-2015 (56 billion dollars over the next 3 years).

Recent data concerning tuberculosis (TB) treatment accentuate three major changes. 1) National health systems and health workers are fully responsible for successful TB treatment and cure [1]. This strategy helps to improve treatment success and to diminish the rates of treatment failure, relapse and drug resistance development. 2) Intermittent regimens are more acceptable with the precondition of direct therapy observation (DOT). The above two changes are fulfilled by DOT implementation. 3) In certain cases prolonged therapy is indicated in order to decrease treatment failure and relapse.

Three major problems were identified: the lack of a legislative framework; different aims and disorganization; and the lack of synchronization of the anti-TB institutes and confused objectives. The following suggestions were submitted. 1. Regarding the lack of a legislative framework, it is proposed that: a) there should be compulsory hospitalization/isolation of TB patients, b) health care services should be established, c) deportation of TB patients should be suspended, d) administration of medicines should be cost-free, e) the legal system should be revised according to present needs and f) pension plans and allowance policies should be modernized. 2. The TB Committee’s work has shown that in Greece almost 1/3 of TB-treated cases are reported, and it seems that this has not changed. Thus WHO does not accept the official documents reported by the health authorities in Greece (seven new cases/100,000/year) and estimates that 19/100,000 is the real number [2]. The Committee proposes a ‘double safety net’, which means: a) hospitals should not allow a patient to be discharged without an accompanying statement, b) before fulfilling the prescription, the pharmacist should complete a form or certify that there is one, c) prescriptions of anti-TB drugs should be controlled. 3. The disorder and vagueness of objectives, in addition to confusion among the bodies that fight TB, were considered to be the main problem. It is striking that while there has been legislation and an adequate infrastructure since 1960, they have never been fully implemented. The following were suggested. a) Completing the map of staffed anti-TB health centers in all (former) prefectures of the country, their access to respiratory clinics, their modernization with up-to-date electronic means and generous enhancement of paramedical staff (e.g. health visitors). Once organized, the anti-TB clinics will provide a means of permanent collaboration with the public health directorate of each (former) prefecture. b) Enhancing the clinic specializing in MDR-TB in Athens and launching one in Thessaloniki. These two specialized clinics will be the principal bodies for treatment of MDR-TB.

Invited article

c) Classifying microbiological coverage into three levels based on the accreditation of all laboratories: i) essential [(former) prefectural general hospitals], for simple tests and cultures, ii) full (clinics specializing in MDR-TB and university hospitals), and iii) the National Reference Center for Mycobacteria (clinics specializing in MDR-TB in Athens and Thessaloniki). All these comments and suggestions were incorporated into the National Action Plan, and according to a feasibility study the amount of 4,059,566 euros is indicated for 2008-2012. It is therefore clear that the failure of TB control is a direct result of broad disparities in wealth and health care services across countries and also within each country. TB control is after all a matter of justice and human rights. It is a universal priority and should attract generous technical and financial support from the international community. WHO, Weekly Epidemiological Record, 23 January 2004, No 4, 2004, 79, 25-40 For further information please visit: 1) http://ygeianet.gov.gr, 2) http://who.int/wer

S. Kostandopoulos, Professor of Pulmonary Medicine, University of Ioannina

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The scientific rationale of short-course chemotherapy is based on certain biological characteristics of Mycobacterium tuberculosis (MTB). It is a slow-growing bacterium (approximately 24 h). The prolonged period of growing partly explains the drug efficacy of the one dose per day. It develops drug-resistant mutations spontaneously. A resistant mutation to one anti-TB drug occurs in approximately one in 10 [7] organisms [2]. Improper prescription of drugs and noncompliant patients leads to the dominance of drug-resistant MTB. Several in vitro and in vivo studies indicate that four hypothetical populations of organisms may exist in a patient with TB [3]: 1) actively growing organisms, usually present extracellularly and especially within aerated cavities; 2) slow, intermittently growing organisms in an unstable part of the lesion; 3) organisms surviving under microaerobic conditions in a low environmental pH, either in inflammatory lesions or within phagolysosomes of macrophages; and 4) completely dormant organisms surviving under anaerobic conditions. The first population is of about 10 [8] organisms and the following second and third populations approximately 10 [5] organisms. Isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E) are included in the first category (line) of oral agents. Streptomycin (S) used to be a first-line drug but now is included in the third (injectable) category of drugs [1]. The anti-TB drugs mentioned above have three major actions: 1) a bactericidal action, defined as their ability to kill actively growing bacilli rapidly, e.g. isoniazid and, to a lesser extent, rifampicin and streptomycin; 2) a sterilizing action, defined as their capacity to kill semi-dormant organisms, e.g. rifampicin and pyrazinamide; 3) prevention of emergence of bacillary resistance to drugs, e.g. isoniazid and rifampicin, and less so for streptomycin, ethambutol and pyrazinamide [4]. TB therapy has two phases, an initial intensive phase and a continuation phase. The initial intensive phase aims to kill the actively growing bacilli (population A) rapidly. Treatment failure is the consequence of an unsuccessful initial phase. The continuation phase aims to sterilize by destroying all the bacilli, especially the intracellular ones (populations B and C). Relapse is the result of an unsuccessful continuation phase of treatment. The modern treatment regimens for new cases of sputum-positive pulmonary TB are based on the results of many relevant clinical studies performed previously. The standard regimen today, as recommended by the World Health Organization (WHO) and International Union against Tuberculosis and Lung Disease (IUATLD), comprises a combination of HRZE for 2 months, followed by HR for a further 4 months [1, 5]. Streptomycin is not generally recommended as a fourth drug in the intensive phase, because of its higher resistance rate than that of ethambutol and its requirement for a parenteral route of administration. In the past, the 8-month regimen consisting of 2 months of HRZE, followed by 6 months of HE, has been shown to be effective. A recent randomized study revealed that the 8-month regimen of 2HRZE/6HE was significantly inferior to the 6-month regimen of 2HRZE/4HR [6]. Thus WHO currently recommends phasing out the 8-month regimen [1]. A regimen without pyrazinamide in the initial intensive phase must be given for >6 months. Such regimens are 2HRE/7HR and 2HRE/9HR, given to pan-susceptible TB with a limited bacillary load. Such regimens are not recommended for patients in countries with high rates of isoniazidresistant TB [7]. Greece is included in those countries. The administration of pyrazinamide beyond 2 months has not been shown to offer any advantage to the estimated treatment outcome. Furthermore, the prolonged administration of pyrazinamide increases the risk of hepatotoxicity [9]. For individual cases with extensive disease and slow sputum bacteriological conversion, administration of Z beyond 2 months may seem acceptable. This prolongation of the intensive phase is not currently supported by WHO.

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Invited article

To achieve the objectives of the Global Plan to Stop TB 2006-2015, all European countries were requested to submit a National Tuberculosis Control Program. The Tuberculosis Committee of the Hellenic Center for Disease Control and Prevention (HCDCP) had already started working on this program, which has been completed, and since 2007 it has been part of the National Action Plan to Prevent Communicable Diseases, 2008-2012. HCDCP’s Tuberculosis Committee estimated the current situation in Greece and the ways by which the World Health Organization (WHO) objectives can be fulfilled.


Regimens comprising four drugs in the intensive phase given on a daily base, followed by two drugs in the continuation phase given three times per week, have been proven to be highly efficacious (e.g. 2HRZS/4H3R3) [11, 12]. Concern has been raised regarding their efficacy in cases with cavitation and positive sputum cultures after 2 months of treatment. It has to be mentioned that intermittent regimens are recommended with a precondition of DOT. As is known, DOT is not implemented in Greece. WHO recommends intermittent regimens given three times per week, but not twice-weekly regimens because of high rates of treatment failure and relapse. For the same reasons intermittent regimens are not recommended for human immunodeficiency virus (HIV)-positive patients with TB and all TB patients living in HIVprevalent settings [1].

Tuberculosis and air travel International travel has become increasingly easy and readily available. Reported episodes of potential transmission of tuberculosis (TB) infection on board aircraft, and the increasing incidence of multi-drug-resistant (MDR)-TB and emergence of extremely drug-resistant (XDR)TB, have raised considerable anxiety among travelers, health authorities, airline companies and the media. There is evidence that transmission of mycobacteria of the Mycobacterium tuberculosis complex may occur during long flights (>8 h) from an infectious source (a passenger or crew member with infectious pulmonary or laryngeal TB) to other passengers and crew. However, no case of clinical or bacteriologically confirmed TB disease associated with exposure during air travel has been identified [1].

References:

A detailed systematic review of the literature has identified a limited number of incidents with evidence for TB transmission during air travel. Additionally, there was insufficient evidence of the effectiveness of contact tracing [2].

1. WHO. Treatment of Tuberculosis. Guidelines, 4th edn. WHO/HTM/TB/2009.420. Geneva: WHO, 2010.

Before the flight [3]

2. Mitchison DΑ. Basic mechanisms of chemotherapy. Chest 1979;76(Suppl):771–781. 3. David HL. Probability distribution of drug-resistant mutants in unselected populations of Mycobacterium tuberculosis. Appl Microbiol 1970;20:810–814. 4. Mitchison DA. The diagnosis and therapy of tuberculosis during the past 100 years. Am J Respir Crit Care Med 2005;171:699–706. 5. Κωνσταντίνου Κ και Παπαβασιλείου Α. Θεραπεία φυματίωσης. Κατευθυντήριες οδηγίες για τη διάγνωση και εμπειρική θεραπεία λοιμώξεων. ΚΕΕΛΠΝΟ, υπό έκδοση. 6. Jindani A, Nunn AJ, Enarson DA. Two 8-month regimens of chemotherapy for treatment of newly diagnosed pulmonary tuberculosis: international multicentre randomized trial. Lancet 2004;364:1244–1251. 7. Combs DL, O’Brien RJ, Geiter L. USPHS tuberculosis short-course chemotherapy trial 21: effectiveness, toxicity and acceptability: the report of final results. Ann Intern Med 112:397–406. 8. Hong Kong Chest Service/British Medical Research Council. Controlled trial of 2, 4 and 6 months of pyrazinamide in 6-month three-times-weekly regimens for smear-positive pulmonary tuberculosis, including an assessment of a combined preparation of isoniazid, rifampin and pyrazinamide. Results at 30 months. Am Rev Respir Dis 1991;143:700–706. 9. Chang KC, Leung CC, Yew WW, et al. Hepatotoxicity of pyrazinamide: cohort and case–control analyses. Am J Respir Crit Care Med 2008;177:1391–1396. 10. Blumberg HM, Burman WJ, Chaisson RE, et al. 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. 11. China Tuberculosis Control Collaboration. Results of directly observed short-course chemotherapy in 112,842 Chinese patients with smear-positive tuberculosis. Lancet 1996;347:358–362. 12. Snider DE Jr, Graczyk J, Bek E, et al. Supervised 6-month treatment of newly diagnosed pulmonary tuberculosis using isoniazid, rifampin, and pyrazinamide with and without streptomycin. Am Rev Respir Dis 1984;130:1091–1094. Invited article

HCDCP Departments Activities

M. Toumbis, Pneumonologist, Director, 6th Respiratory Department, ‘Sotiria’ General Hospital

Patients with confirmed infectious pulmonary TB should avoid air travel. If a patient with confirmed infectious pulmonary TB requires unavoidable air travel, the patient should postpone travel until after a 2-week treatment has been completed. If it is not possible to delay travelling for 2 weeks, then a travel protocol should be agreed between the patient, the local public health authority (public health team) and the airline in question. The patient should cover his or her nose and mouth while coughing, to reduce exposure, be isolated for the duration of travel and use a face mask. The risk of infection of passengers with MDR-TB and XDR-TB should be assessed using national guidelines. During the flight [3] If a passenger is suspected of having TB, he or she should be relocated to an isolated seat separate from other travelers (if possible) and be provided with a surgical face mask and a sufficient amount of disposable tissues. Flight attendants should follow IATA (International Air Transport Association) guidelines for infection control and, if possible, collect locator cards from travelers to facilitate contact tracing, if needed. Contact tracing Contact tracing should be considered if the index case is confirmed as having infectious pulmonary TB, AND there is evidence of transmission to other contacts AND the duration of the flight is longer than 8 h AND the time elapsed between the flight and diagnosis of the case is not longer than 3 months [3]. Contact tracing is recommended for passengers sitting in the same row, two rows ahead and two rows behind the index case [1]. The exposure of the cabin crew is generally less intensive and should be assessed by the airline’s medical service. There is no evidence that patients with MDR-TB or XDR-TB are more infectious than patients with sensitive TB [3]. References: 1. WHO. Tuberculosis and Air Travel: Guidelines for Prevention and Control, 3rd edn. Geneva: WHO, 2008. Available at http://www.who.int/tb/publications/2008/978924154 7505/en/ [accessed 18/10/2011]. 2. Abubakar I. Tuberculosis and air travel: a systematic review and analysis of policy. Lancet Infect Dis 2010;10:176-183. 3. ECDC. Risk Assessment Guidelines for Diseases Transmitted on Aircraft (RAGIDA). Part 2: Operational Guidelines, 2nd edn. ECDC, 2010. Available at http://www.ecdc. europa.eu/en/ publications/Publications/Forms/ [accessed 18/10/2011] Paraskevi Smeti, Andriana Pavli, Helena Maltezou , travel medicine office department for interventions in health care facilities

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HCDCP Departments Activities

Cases with initial cavitation and positive sputum cultures after 2 months of treatment have been found to be associated with an increased risk of failure and relapse. In those cases it is possibly justified to prolong the continuation phase of anti-TB therapy to give a total duration of 9 months [10].


The Hellenic Center for Disease Control and Prevention (HCDCP) was informed through the: European Legionnaires’ Disease Surveillance Network (ELDSNet) UK Health Protection Agency (HPA) Mandatory Declaration System in our country of a total of 15 confirmed cases of Legionnaires’ disease, mostly in British tourists, who traveled to Corfu from 18/07/2011 to 12/10/2011 and stayed in nine different accommodations in various areas from 05/10/2011 to 18/10/2011. Specifically, these nine men and six women (14 British and one Greek), aged from 39 to 79 years, had symptoms from 08/02/2011 to 10/10/2011.

• • •

So far the following have been isolated from clinical specimens: Legionella pneumophila Sgp1 subgroup ‘Allentown/France’ from five patients (ST23 in four of them) and και Legionella pneumophila subgroup Philadelphia ST1 from one patient. HCDCP, joint with the Central Public Health Laboratory (CPHL) and the Regional Public Health Laboratory (RPHL) of Thessaly, formed an investigation team that went to Corfu from 12/10/2011 to 15/10/2011 and took the following actions. 1. A briefing with the Regional Director and the Vice-Regional Director of Corfu, the Mayor of Corfu, the Directorate of Public Health and the Regional Unit of Corfu. 2. A meeting with the President, the Infectious Disease Nurse of the Committee on Nosocomial Infections and the President of the Scientific Board of the General Hospital of Corfu. The medical personnel of the health centers of Aghios Athanasios, Aghios Markos, Lefkimi and the General Hospital of Corfu were also informed. An active search for other cases of Legionnaires’ disease was also conducted. A British male patient (3-day azithromycin) was identified at the General Hospital of Corfu and a clinical specimen was received for culture in the Central Public Health Laboratory (CPHL). 3. A risk assessment for Legionella transmission was carried out and environmental samples were taken from all possible sources of contamination, in co-operation with the supervisors of the Department of Health Control of the Directorate of Public Health/Regional Unit of Corfu. In particular, 110 water samples were taken from the reported accommodations and five samples from other possible sources of exposure in the town of Corfu (fountains, airport, etc.), and they have already been examined in the two laboratories, CPHL and RPHL, of Thessaly. The isolated strains will be standardized at the CPHL-RPHL network and the HPA. 4. Instructions for the control and prevention of disease (immediate and long-term) were given by the local health authorities and HCDCP to the hotel managers, accommodation owners and tourist operators. 5. A second meeting was held with the Regional Director of the Ionian Islands, the ViceRegional Director of Corfu, the Mayor of Corfu, the Health Directorate, the President of the Hoteliers’ Association, accommodation owners and tourist operators.

HCDCP Departments Activities

6. Following the field visit conducted by the investigation team, a detailed account was reported and all questions were answered. 7. Remedial actions will be sent based on the risk assessment of the hotels and the laboratory results. Hotels that continue to operate will be required to take immediate corrective action and repeat sampling. Hotels that are closed for winter will take corrective actions and repeat sampling before the summer season opening. HCDCP is in constant communication with HPA, the European Center for Disease Control (ECDC) and the local health bodies in order to exchange information. In this context, a teleconference was held with ECDC and HPA in order to take co-ordinating actions. Additionally, HCDCP plans to take further samples from hotels and tourist accommodations in Corfu, in co-operation with the health authorities and before the summer season. Office for respiratory diseases

News from the international literature Dominant TNF-α+ Mycobacterium tuberculosis–specific CD4+ T-cell responses discriminate between latent infection and active disease A. Harari, V. Rozot, F. Bellutti Enders, M. Perreau, J. Mazza Stalder, L. P. Nicod, M. Cavassini, T. Calandra, C. Lazor Blanchet, K. Jaton, M. Faouzi, C. L. Day, W. A. Hanekom, P.-A. Bart and G. Pantaleo Nature Med 2011;17(3) Rapid diagnosis of active Mycobacterium tuberculosis (Mtb) infection remains a clinical and laboratory challenge. The authors in this study have analyzed the cytokine profile [interferonγ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2)] of Mtb-specific T cells by polychromatic flow cytometry. They studied Mtb-specific CD4+ T-cell responses in subjects with latent Mtb infection and active tuberculosis (TB) disease. The results showed a substantial increase in the proportion of single-positive TNF-α Mtb-specific CD4+ T cells in subjects with active disease, and this parameter was the strongest predictor of diagnosis of active disease versus latent infection. They validated the use of this parameter in a cohort of 101 subjects with TB diagnosis unknown to the investigator. The sensitivity and specificity of the flow cytometry– based assay were 67% and 92%, respectively; the positive predictive value was 80% and the negative predictive value was 92.4%. Therefore, they conclude that the proportion of singlepositive TNF-α Mtb-specific CD4+ T cells is a new tool for the rapid diagnosis of active TB disease.

Matrix metalloproteinases in tuberculosis P. T. Elkington, C. A. Ugarte-Gil and J. S. Friedland Eur Respir J 2011;38:456–464 Tuberculosis (TB) remains a global health pandemic. Infection is spread by the aerosol route and Mycobacterium tuberculosis must cause lung destruction to be transmitted to new hosts. Such inflammatory tissue damage is responsible for the morbidity and mortality in patients. The underlying mechanisms of matrix destruction in TB remain poorly understood but consideration of the lung extracellular matrix predicts that matrix metalloproteinases (MMP) will play a central role, because of their unique ability to degrade fibrillar collagens and other matrix components. Since the proposed concept of a matrix-degrading phenotype in TB a decade ago, diverse data implicating MMP as key mediators in TB pathology have accumulated. In this paper the authors review the lines of investigation that have indicated a critical role for MMP in TB pathogenesis, consider regulatory pathways driving MMP and propose that inhibition of MMP activity is a realistic goal as an adjunctive therapy to limit immunopathology in TB.

Usefulness of serum procalcitonin levels in pulmonary tuberculosis M. Ugajin, S. Miwa, M. Shirai, H. Ohba, T. Eifuku, H. Nakamura, T. Suda, H. Hayakawa and K. Chida Eur Respir J 2011;37:371–375 There are very few data on serum procalcitonin (PCT) levels in pulmonary tuberculosis (PTB) patients who are negative for human immunodeficiency virus (HIV). In this study the authors’ aim was to assess serum PCT in consecutive patients diagnosed with pulmonary tuberculosis or community-acquired pneumonia (CAP) on admission, to discriminate between PTB and CAP, and to examine the value of prognostic factors in PTB. One-hundred and two PTB patients, 62 CAP patients and 34 healthy volunteers were enrolled. Serum PCT in PTB patients was significantly lower than in CAP patients (mean  ±  SD 0.21  ±  0.49 versus 4.10  ±  8.68 ng/ mL; P<0.0001). Using a receiver-operating characteristic curve analysis, serum PCT was an appropriate discrimination marker for PTB and CAP (area under the curve 0.866). PTB patients with ≥0.5 ng/mL (normal cut-off) had a significantly shorter survival period than those with ≤0.5 ng/mL (P<0.0001). The authors conclude that serum PCT is not habitually elevated in HIV-negative PTB patients and is a useful bio-marker for discriminating between PTB and CAP; however, when serum PCT is outside the normal range, it is a poor prognostic marker. Stavros Anevlavis MD, PhD, Demosthenes Bouros MD, PhD Medical School, Democritus University of Thrace, Department of Pneumonology, University of Alexandroupolis

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Recent Publications

Investigation of Legionnaires’ disease clusters in British travelers to Corfu


Interesting Activities 1st meeting of the Public Health Laboratory Network The effect of the Kallikratis plan (focusing mainly on the restructuring of the decentralized administration) in public health services and the need to adapt these services to the new decentralized administration, the importance of the role of public health supervisors, and the need to improve co-ordination among all partners involved in the hygiene control program, were some of the issues discussed during the first conference of the Public Health Laboratory Network, held at the Central Laboratory of Public Health (KEDY) in Vari. The President of the Hellenic Center for Disease Control and Prevention (HCDCP), Professor Jenny Kourea-Kremastinou, and the General Director of Public Health of the Ministry of Health and Social Solidarity, Ms Pantazopoulou, welcomed everyone. The meeting began with a presentation of the Public Health Laboratory Network by the Deputy Director of HCDCP, Mrs E. Hatzipaschali, followed by Mrs V. Karaouli, Head of the Division of Sanitary Engineering & Environmental Hygiene of the Ministry of Health and Social Solidarity, who spoke on water quality law. Dr K. Barberis, Head of the Testing Laboratory Directorate of the Hellenic Food Authority (EFET), also elaborated on the same topic. Afterwards, Mrs M. Pasiotou, Head of the National Reference Laboratory for Salmonellosis and Antimicrobial Resistance of the Ministry of Rural Development and Food, presented the most common salmonella serotypes in domestic food of animal origin. Dr E. Velonakis, Technical Head of KEDY, referred to the role of the laboratory in hygiene control. The first part of the conference ended with a speech by Mr Pasvouri, President of the Panhellenic Association of Public Health Supervisors, on the Kallikratis plan, followed by discussions of the preceding presentations. There is a very strong need for further co-ordination between all the authorities involved in order to improve and update the sampling methods, which is perhaps at 50% of the proper procedure for the course of sampling. During the second and last part of the conference, the Public Health Laboratory Network (Central and Regional Thessaly, Crete and East Macedonia and Thrace), demonstrated the importance of the protection of public health, legionella control in water systems in hospitals and dental offices, the study of human zoonoses and the role of water in the development of nosocomial infections. The conference was a great success, with massive participation by scientists representing all the authorities involved, including regions, municipalities and hospitals, as well as the Ministry of Health and Social Solidarity. At the end of the meeting everyone expressed the desire for another session, which highlights the need for continuous updating, training and development regarding public health.

Interesting Activities

Interesting Activities

Personnel affairs office and secretariat administration, central laboratory of public health

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ECDC-BRICK capacity-building workshop, 13-14 October 2011, Central Public Health Laboratory, Vari

A 2-day training course took place in the Central Public Health Laboratory on 13-14 October 2011, organized by the European Center for Disease Prevention and Control (ECDC)-BRICK project group as a follow-up to the output of a meeting held at the European Bio-safety Association in Estoril Portugal, Laboratory Networks and Biosafety Communities: How to make Bio-safety pan-European?, on April 2011. The objectives of this capacity-building event, which was launched as a pilot program, were training in bio-safety and further training needs assessment of the host country and the international participants.

European Antibiotic Awareness Day 18 November 2011

Overconsumption of antibiotics, mainly broad spectrum, leads to the continuously rising public health problem of antibiotic resistance. According to the most recent data presented by the European Surveillance of Antimicrobial Consumption (ESAC), of the total outpatient antibiotic use in European Union (EU) member states for the year 2008, for Greece this level rose to 45 defined daily doses (DDD), almost double the average recorded in other European countries (Figure 1). Figure 1:

Total outpatient antibiotic use in EU member states for 2008.

In order to assess these objectives, the first day of the program included a series of high-level presentations on decisive points of bio-risk, and a practical component with scenario-based activities, followed by a practical and educational emergency spill exercise on the second day. The participants were asked for their feedback about this training course and especially about its effectiveness and usefulness. A list of the trainers and the participants is provided below. Expert

Institute/Organization

Allan Bennett

Health Protection Agency (HPA), UK

Heather Sheeley

HPA, UK

Gary Burns

Astra Zeneca, UK

Kathrin Summermatter

Institute of Virology and Immunoprophylaxis, Switzerland

Evelien Kampert

Rijksinstituut voor Volksgezondheid en Milieu (RIVM), the Netherlands

Juergen Mertsching

Hannover Medical School, Germany

National Reference Vector-borne Infections and Leptospirosis Laboratory, National Center of Infectious and Parasitic Diseases Head of Hungarian Bio-safety Laboratory, National Center for Epidemiology, Hungary

*Total use, i.e. including inpatients (CY, GR, LT). **Reimbursement data, i.e. not including over-the-counter sales without a prescription (ES).

Sergejs Nikisins

Infection Center of Latvia

***Data from 2007 (MT).

Kyriaki Tryfinopoulou

Central Public Health Laboratory

Angeliki Chaldoupi

Central Public Health Laboratory

Dimitra Katsarou Angeliki Papagiannopoulou Fotini Tsalikoglou

Hellenic Center for Disease Control and Prevention

Christina Panagiotidi

Ministry of Health and Social Solidarity

Ivanova Vladislava

Interesting Activities

Zoltan Kis

Joseph Papaparaskevas Kate Themeli-Digalaki Joanna Marinou Simona Karabela Fanourios Kontos

Ministry of Health and Social Solidarity Ministry of Health and Social Solidarity Department of Microbiology, Athens Medical School Director of Clinical Microbiology Laboratory, General Hospital of Piraeus ‘Tzanion’ General Hospital ‘Sotiria’ General Hospital ‘Sotiria’ National Reference Laboratory for Mycobacteria ‘Attikon’ University Hospital

Kyriaki Tryfinopoulou, laboratory for hospital infections and antimicrobial resistance, central public health laboratory 32

Since 2008 in all European countries, after the European Centre for Disease Prevention and Control (ECDC) initiative with the launch of 18 November as Antibiotic Awareness Day, concerted efforts have been carried out in the form of campaigns, aimed mainly at appropriate use and reducing overconsumption of antimicrobial agents. Two main groups are the target audiences of the concept. The first group is the general public, in order to make adults, mainly parents regarding their children, aware that the prescription of antibiotics for the management of viral infections is not only contraindicated, but could possibly be harmful to human health (through colonization by multi-resistant pathogens). The second, and primary, target group comprises the health care professionals, both primary and hospital prescribers. In detail, the central objective is to promote the prudent use of antimicrobial agents through the following guidelines: (i) antibiotic prescriptions in the community, as well as in hospitals, should be based on evidence-based medicine and international recommendations and guidelines (the most recently published, which are easily accessible via the Internet) regarding proper agent and dose selection and duration of therapy; (ii) encouraging physicians to follow the most recently published guidelines for chemoprophylaxis (not only regarding proper selection, but also on the timely interruption of the prophylaxis given after the recommended schedule); and (iii) performing de-escalation of the initially empirical therapy, as soon as the results of cultures obtained before the administration of therapy are available. Office of nosocomial infections, microbial resistance and rational use of antibiotics, department for interventions in health care facilities 33

Interesting Activities

Participants


Cross-border co-operation workshop: Turkey, Bulgaria and Greece, 3-4 October 2011, Istanbul, Turkey A cross-border co-operation workshop between Turkey, Bulgaria and Greece was held in Istanbul on 3-4 October 2011 and hosted by the International Organization for Migration (IOM) and the corresponding office of the Ministry of Interior of Turkey. The workshop was attended by local and central-level representatives of the three countries for border surveillance, customs control, passport control and public health. Dr Botsi attended the workshop as a representative for the Hellenic Center for Disease Control and Prevention (HCDCP). The European Union (EU) and the embassy of England in Turkey were also represented The following topics were covered. 1. Border control surveillance: the legal and institutional situation as well as developments in the area of border control. Best practices regarding common border gates. Suggestions were made for the improvement of co-operation at the borders of the three countries. 2. The legal framework and practice related to irregular migration, asylum seekers and refugees. The possibilities for co-operation among the three countries for irregular migration and trafficking in human beings were also discussed. 3. Customs control: to facilitate legal trade between neighboring countries, collecting prearrival information, risk analysis and joint training. 4. The legal framework and co-operation mechanisms with respect to plant and veterinary inspections at the borders between the three countries. 5. Detection regarding public health: • institutional structures against public health risks and the importance of border control • international health regulations and the steps to be taken • areas of co-operation against public health risks between the three countries, information exchange and co-ordinated controls on the borders. The Greek proposals on public health issues were included in the common statement of the three countries. C. Botsi, HCDCP scientific associate

Train the trainer workshop: WHO bio-risk management advanced trainer program, 1222 September 2011, Prague, Czech Republic In response to an invitation from the World Health Organization (WHO), I participated in the WHO bio-risk management advanced trainer program, which took place in the hotel Movenpick in Prague from 12 to 22 September 2011. The working language of the course was English. In total there were 10 participants, from Albania, Bosnia-Herzegovina, Bulgaria, Greece, Estonia, Latvia, Lithuania, Romania and Czech Republic. Our facilitators were Dr Stefan Wagener, Dr Magdi Saad and Dr Pamela Lupton-Bowers. This is an advanced training course for trainers in bio-risk management. The course introduces a new concept in bio-risk management that combines risk assessment, risk mitigation and a performance-based approach. In addition, the course includes a cutting-edge training component based on the latest science and theory behind accelerated and adult training. This seminar helps professionals enter bio-safety and bio-security training and builds the knowledge and skills of individuals who train, as well as educate in, bio-risk management. The seminar was very well organized and the facilitators were experts in bio-safety and bio-security training. The methods used for training were group work, case studies and scenarios, short presentations, demonstrations, hands-on activities, and questions and answers. The organizers provided us with all the training material in order to practice and deliver this material in two workshops, which each of the participants has to conduct within the following 6 months in their own country. The objectives of the workshop were for participants to understand: bio-risk has bio-safety and bio-security components bio-risk management includes risk assessment, risk mitigation and a performance management-AMP model • the key principles of risk assessment and benefits of a robust risk assessment methodology • a new tool for risk assessment, the BioRAM model, which is in the final validation stage and will be available shortly through WHO • the key principles of risk mitigation, the four categories of mitigation control measures and the value of elimination or substitution before the implementation of mitigation control measures • performance systems and components and the role of performance in bio-risk management • laboratory bio-risk management standard CWA 15793:2008 as a performance and PDCA (plan-do-check-act)-based management system • the principles and theories of adult-learning techniques. During the second week and after 1 day of coaching all the participants, we had to practice and lead a session in one of the subjects of the seminar, and we received professional reviews and feedback from our facilitators in order to learn and improve our training skills. • •

Interesting Activities

Interesting Activities

Kyriaki Tryfinopoulou, laboratory for hospital infections and anti-microbial resistance, central public health laboratory

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Outbreak news, October 2011

Future conferences and meetings November 2011

Avian influenza [1]

2-5 November 2011

Future Conferences and Meetings

Title: 12th IUSTI-World Congress of Sexually Transmitted Infections & AIDS City: New Delhi Country: India Venue: Vigyan Bhavan, Maulana Azad Road, New Delhi 110 001 Phone: +91 11 6569 8950 / 2453 1364 Website: http://www.iusti2011.org 25-27 November 2011 Title: 23rd Panhellenic Congress of AIDS City: Athens Country: Greece Venue: Divani Caravel Hotel Phone: +30 210 72 23 046 Website: http://www.aids2011.gr/

As of 26 October 2011, the Ministry of Health of Indonesia has announced three cases of human infection with avian influenza A (H5N1) virus. Of the 181 cases confirmed to date in Indonesia, 149 have been fatal. Measles [2] In 2011, several measles outbreaks have been reported from European and African countries, with several reported outbreaks in the Americas linked to Europe or Africa. Europe As of 20 September 2011, 40 countries have reported 26,025 confirmed measles cases for the period Januaryâ&#x20AC;&#x201C;July 2011. The highest number of cases was reported from France, with 14,025 cases for the first 6 months of the year. In addition, 11 of all cases were lethal (six in France, one in Germany, one in Kyrgyzstan, one in Romania, one in the Former Yugoslav Republic of Macedonia and one in the United Kingdom). The most recent outbreak (12 cases) was reported from Israel in September. Africa Î&#x2018;s of September 2011, measles outbreaks are being reported by the Democratic Republic of the Congo (more than 103,000 cases, 1,100 deaths), Nigeria (17,428 cases), Zambia (5,397 cases) and Ethiopia (2,902 cases). Americas

25-27 November 2011 Title: 2nd Panhellenic Congress of Public Health & Social Medicine City: Larissa Country: Greece Venue: Larissa Imperial Hotel Phone: +30 210 68 27 405 Website: http://www.tmg.gr/innet/UsersFiles/sa/Documents/Congresses/ Congress_2011/2oDYKI_A_ANAKOINOSI_FINAL.pdf International relations office, HCDCP

The last case of endemic measles was reported from the region in 2002. In 2011 the region has received reports of several outbreaks linked with the arrival of measles virus from other regions. The largest, in Quebec, Canada, involves 742 reported cases. Other outbreaks have been reported from the United States (213 cases), Ecuador (41 cases), Brazil (18 cases), Columbia (seven cases), Mexico (three cases) and Chile (six cases). Most of these outbreaks are linked to arrivals from Europe, except for outbreaks in the United States and Chile, which are linked to cases from Malaysia, and the outbreak in Ecuador, linked to Kenya. References: 1. World Health Organization (WHO). Available at: http://www.who.int/influenza/human _animal_ interface/ [accessed 27 October 2011] 2. World Health Organization (WHO). Available at: http://www.who.int/csr/don/ [accessed 27 October 2011]

Quiz of the month

Travel medicine office, department for interventions in health care facilities

Which famous British actress, who had twice won a Best Actress Academy Award, died of chronic tuberculosis in 1967 that had first been diagnosed in 1944?

Outbreaks around the world

What is the name of the first and youngest professor in the medical school of the University of Athens, who died of tuberculosis when he was just 29 years old? Send your answer to the following e-mail: Quiz of the month

info-quiz@keelpno.gr The September quiz answer: Lewis Carroll For more information: http://www.who.int/mediacentre/factsheets/smallpox/en/index.html Four people answered correctly. 36

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Myths and truths •

A Bacille–Calmette Guerin (BCG)- The BCG vaccine is protective for only a short period vaccinated person cannot get TB of time. It does not offer life-long protection. It may help protect babies and younger children from developing serious forms of TB (e.g. meningitis). The BCG vaccine has limited efficacy in adults and usually causes false-positive tuberculin skin test reactions

BCG false-positive TST can be BCG vaccination may produce a TST reaction that distinguished from true TB infection cannot be distinguished from a true TB infection. To distinguish BCG from true TB infection, IGRA (Interferon-Gamma Release Assays) such as QuantiFERON–TB Gold IT are highly specific

My TST test result was negative, so I This is not correct. More than 20% of people who do not have TB are infected with TB do not have a positive reaction to the test

Commercial serodiagnostics are WHO recently endorsed a negative recommendation strongly recommended for childhood policy that current commercial TB serodiagnostic TB tests should not be used in individuals with suspected active pulmonary or extrapulmonary TB, irrespective of their HIV status. This recommendation also applies to childhood TB

Only patients with active TB need Additional tests to determine whether a TSTanti-TB medication positive person has developed TB are needed: a chest X-ray and, if abnormal, serial sputum testing. Even if these tests are negative, the doctor may prescribe a course of preventive medication for 6-12 months. This strategy greatly lowers the risk of a later TB development

About tuberculosis

Myths and truths

Truths

Tuberculosis (TB) is a hereditary Genetics plays no role in the transmission and disease acquisition of TB. TB is not a hereditary disease; however, members of the same family may be infected. The infection is transmitted from person to person through air TB is caused by excessive smoking

Smokers are predisposed to developing respiratory diseases. However, TB is caused by the bacterium Mycobacterium tuberculosis

TB is a disease of the past. There is TB continues to be a major problem world-wide. The no TB in Greece now World Health Organization (WHO) estimates that there were 9.4 million new TB cases and 1.7 million deaths from TB in 2009, equal to 4,700 deaths a day. TB is still present in Greece. Although the prevalence of the disease is low, and the number of new TB cases decreasing, the number of new TB cases among immigrants has increased six-fold during the past 15 years. Resistance to first- and second-line anti-TB drugs remains higher in Greece than in most other countries in western Europe TB is a disease of the lower socio- TB is an airborne disease and can be easily economic classes contracted by anyone, rich or poor. However, overcrowding, lack of ventilation, poor access to health care, malnutrition, etc., predispose poorer people to TB. Certain populations, e.g. immigrants, human immunodeficiency virus (HIV)-positive and immunocompromised patients, elderly people and homeless people, are at a greater risk. Individuals in contact with these people are also at risk

TB infection is always followed by Only about 10% of infected people will develop TB at disease some point in their lives. A person can be infected with TB for years without developing the disease

A positive tuberculin skin test (TST) The tuberculin skin test only indicates whether the indicates active TB patient has been infected with a Mycobacterium strain. The test confirms only exposure to the disease, not the presence of disease. A person has the disease only when:

For more information please visit http://www.thetruthabouttb.org/ Dimitrios Papaventsis, Evangelos Vogiatzakis, microbiology laboratory– national reference laboratory for mycobacteria, ‘Sotiria’ chest diseases hospital

Myths and truths

Myths

the tuberculin skin test is positive the disease is symptomatic and the infection is contagious

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News from the Hellenic Center for Disease Control and Prevention administration 3rd meeting of the scientific officers’ Public Health Laboratory Network On 6 October 2011, the 3rd scientific meeting of experts from the Public Health Laboratory Network took place in the Central Public Health Laboratory, in the presence of all technical officers and laboratory staff. Issues relating to the expansion of the network as a whole and individually for each laboratory, as well as operational and technical issues, were discussed. The first edition of an electronic platform in sampling was presented and results are being prepared for an online use. Furthermore, the Technical Director of Accreditation informed the attendees on relevant topics and the objectives of the Public Health Laboratory Network.

Implementation of an action plan for health education regarding West Nile virus The Hellenic Center for Disease Control and Prevention (HCDCP) office in Thessaloniki completed the implementation of a health education action plan for West Nile Virus (WNV) and protection against mosquitoes. The aims of the health education action plan are as follows. 1. Information/education of the regional educational staff of Central Macedonia and Thessaly, in order to create a core team (health education managers and teachers) that has a multiplier effect in the dissemination of knowledge regarding precautions to protect teachers, students and parents. A total of 1,037 teachers were informed in 11 counties. 2. Continuing information/education of health personnel in the health centers of the 3rd, 4th and 5th health regions in Greece on West Nile virus issues, protection against mosquitoes and communication methods to increase public awareness. In total, health personnel from 34 health centers were informed.

News from the HCDCP Administration

ECDC/WHO joint mission in Lakonia A joint mission by both World Health Organization (WHO) and European Center for Disease Control (ECDC) experts was sent to Lakonia, Greece, in response to outbreaks of malaria occurring in the area, in order to assess the status of the epidemic. From 26 to 30 September 2011, the first visit was held by a team of ECDC experts, while a joint ECDC/WHO mission was held from 10 to 14 October 2011. The expert team made a field visit to the areas with confirmed malaria cases and met with representatives from the Reference Laboratory for Influenza of the National School of Public Health (ESDY) as well as with HCDCP experts and local authorities, and they discussed how they were informed about the course of the epidemic and the fight against it. The ECDC/WHO joint mission report on the risk of malaria mentioned that the risk is relatively low and is observed in agricultural areas from May to October.

ÊÅÍÔÑÏ ÅËÅÃ×ÏÕ & ÐÑÏËÇØÇÓ ÍÏÓÇÌÁÔÙÍ (ÊÅ.ÅË.Ð.ÍÏ.)

Editors: HCDCP HELLENIC CENTER FOR DISEASE CONTROL & PREVENTION

Τ. Kourea- Kremastinou HCDCP President T. Papadimitriou HCDCP Director

Graphic Design: Ε. Lazana


HCDCP Newsletter October