Home About us Editorial board Ahead of print Current issue Archives Submit article Guidelines Contacts Login 
ISSN: Print -2349-0977, Online - 2349-4387


 
 Table of Contents  
THE EVOLUTION - CURRENT CONCEPTS IN TUBERCULOSIS
Year : 2017  |  Volume : 4  |  Issue : 1  |  Page : 27-33

Unveiling the new definitions, diagnostic basis, and therapeutic approaches


Department of Pulmonary Medicine, TNMC and BYL Nair Hospital, Mumbai, Maharashtra, India

Date of Web Publication6-Nov-2017

Correspondence Address:
Jyotsna Joshi
Department of Pulmonary Medicine, TNMC and BYL Nair Hospital, Mumbai, Maharashtra
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/astrocyte.astrocyte_61_17

Rights and Permissions
  Abstract 


Tuberculosis (TB) is a notifiable infectious disease. Globally, 20% patients of TB are contributed by India. The World Health Organization (WHO) and the Revised National Tuberculosis Control Program (RNTCP) formulates guidelines for management of TB. There have been advances in various aspects of TB. This review enumerates the progress aiming the therapeutic aspects for TB. The WHO revised definitions in TB in 2013. With the availability of rapid diagnostics and WHO goal of universal access to the same; the diagnostic approach was modified. The RNTCP shifted therapy administration for drug sensitive TB (DS-TB) from thrice weekly to daily regimen in 2017. The WHO updated the drug resistant TB (DR-TB) guidelines in 2016. Bedaquiline and delamanid got enlisted as add-on drugs in the revised classification. In the end, we discuss various pipelines in development of TB.

Keywords: Bedaquiline, delamanid, revised national tuberculosis control program, shorter regimen, vaccines, world health organization


How to cite this article:
Desai U, Joshi J. Unveiling the new definitions, diagnostic basis, and therapeutic approaches. Astrocyte 2017;4:27-33

How to cite this URL:
Desai U, Joshi J. Unveiling the new definitions, diagnostic basis, and therapeutic approaches. Astrocyte [serial online] 2017 [cited 2017 Nov 22];4:27-33. Available from: http://www.astrocyte.in/text.asp?2017/4/1/27/217658




  Introduction Top


India is a high burden country for tuberculosis (TB). One fourth of the global TB cases occur in the Indian population. The incidence rate of TB notified to the World Health Organization (WHO) in 2015 was 217 per lakh population with estimated 79000 to be of multi-drug resistant/rifampicin resistant tuberculosis (MDR/RR-TB).[1] Though only 28876 laboratory-confirmed cases of MDR/RR-TB and 3048 laboratory-confirmed cases of extensively drug resistant tuberculosis (XDR-TB) were reported then. The estimated percentage of MDR/RR-TB in new and previously treated cases is 2.5% and 16% respectively.[1] While, the cure rate of first-line therapy is well-documented in literature, MDR-TB management is based on guidelines formulated with less robust evidence globally. The WHO MDR-TB factsheet, 2016 update states, “Only 52% of the MDR/RR-TB patients who started treatment in 2013 were successfully treated, while 17% of patients died and in 9% of patients their treatment failed (22% were lost to follow-up or not evaluated). The treatment success rate in XDR-TB patients was only 26%”.[2] The diagnostics and management of TB have undergone a sea change. This review aims to address the advances in the nomenclature, diagnostic approach, management principles, and guidelines with an emphasis on the 2016 updates in TB.


  The Nomenclature Top


First and foremost, the diagnosis of TB has shifted from empirical basis to being backed with microbiological evidence, even in extrapulmonary cases. The WHO revised definition and reporting framework for TB in 2013. TB suspect terminology has been renamed as presumptive TB referring to a patient who presents with symptoms or signs suggestive of TB. TB cases have been classified into bacteriologically confirmed and clinically diagnosed. A bacteriologically confirmed TB case is one from whom a biological specimen is positive by acid fast bacilli (AFB) smear microscopy, culture or WHO-approved rapid diagnostics (WRD) such as GeneXpert. A clinically diagnosed TB case does not fulfil the criteria for bacteriological confirmation but has been diagnosed with active TB by a clinician or other medical practitioner who has decided to give the patient a full course of TB treatment. This definition includes cases diagnosed on the basis of chest X-ray abnormalities or suggestive histology and extrapulmonary cases without laboratory confirmation. Other definitions of new, previously treated, relapse, treatment after failure, and other previously treated cases remained same. Previously known as treatment after default patients have been renamed as treatment after loss to follow-up patients.[3]

TB cases are classified into categories based on drug susceptibility testing (DST) of clinical isolates confirmed to be Mycobacterium tuberculosis (MTB): 1) Monoresistance, 2) Polydrug resistance (PDR), 3) MDR, 4) XDR, 5) RR [Table 1]. These categories are not all mutually exclusive. The last includes any resistance to rifampicin, whether monoresistance, MDR, polydrug resistance, or XDR. While it has been the practice until now to limit the definitions of monoresistance and PDR to first-line drugs only, future drug regimens may make it important to classify patients by their strain resistance patterns to fluoroquinolones, second-line injectable agents, and any other anti-TB drug for which reliable DST becomes available.[3] The terminology of pre-XDR-TB, which indicates RR-TB/MDR-TB with resistance to any one of the fluoroquinolone's or second-line injectable agents but not both, discussed widely in publications was first described in 2008.[4],[5] Although, it is not recognized by the WHO or CDC as a definition. Subsequently, researchers described totally drug resistant (DR) TB.[6],[7],[8] The terminology was not recommended by the WHO in view of technical difficulties with DST of many anti-TB drugs, the lack of standardized DST methods for several anti-TB drugs (including new investigational drugs) and insufficient evidence to link such DST results to treatment outcomes of patients.[9] The terminology of extremely drug resistant TB (XXDR-TB) defined as cases of XDR-TB failing on therapy with second-line anti-tuberculosis therapy (ATT) was then recommended to be used interchangeably.[10]
Table 1: Definitions in Tuberculosis

Click here to view



  The Revised Diagnostic Approach Top


The advancements in diagnostics are mandatory for newer aspects of management of TB research to be implemented. The universal access to TB diagnostics and DST is a WHO goal.[11] The use of newer tests for improving the sensitivity of AFB smear like fluorescence microscopy (FM) and light-emitting diode (LED) FM was suggested by the WHO in 2009–10.[12] The use of rapid tests like the WHO-approved rapid diagnostics (WRD), i.e., GeneXpert and Line probe assay was advocated. In view of the higher yield, GeneXpert has been recommended to be used at diagnosis in TB suspects in both pulmonary and extrapulmonary cases. The conventional Revised National Tuberculosis Control Program (RNTCP) diagnostic approach for pulmonary and extrapulmonary TB was modified in the 2016 with the availability of the WHO-approved rapid diagnostics (WRD) [Figure 1] and [Figure 2].[13] Clinically treatment failures and DR-TB contacts are the most important patient groups wherein DR-TB should be suspected. With the global up-scaling of TB diagnostics and the availability of WRD; the WHO recommends UNIVERSAL ACCESS TO DST to diagnose RR-TB.[11]
Figure 1: Diagnostic algorithm for pulmonary tuberculosis under the revised national tuberculosis control program (RNTCP).

Click here to view
Figure 2: Diagnostic algorithm for extrapulmonary tuberculosis under the revised national tuberculosis control program (RNTCP).

Click here to view


The RNTCP planned a phased wise implementation of this WHO goal as per its logistics. Hence, it created the MDR suspect criteria [Table 2].[14] As the regional laboratories got upgraded and accredited for DST; more and more patients would be evaluated with DST at baseline. However, till date the RNTCP criteria do not include DST testing of new pulmonary sputum positive cases that are non HIV-TB, and non DR-TB contacts at baseline. Rest all patient subgroups including extrapulmonary cases are assessed with baseline DST to rifampicin. For cases of RR-TB, the WHO 2014 companion handbook for programmatic management of DR-TB has laid recommendations for second-line DST. These state “DST methods for the SLI drugs (capreomycin, kanamycin, and amikacin) and fluoroquinolones are accurate and reproducible. It should not be performed unless the required laboratory quality and biosafety standards, infrastructure, capacity, rigorous quality assurance is in place, and sustainable high proficiency has been demonstrated for isoniazid and rifampicin testing. The use of line probe assays for second-line has been encouraged in management of DR-TB. Routine DST for other second-line drugs like ethionamide, cycloserine, PAS, bedaquiline, delamanide, clofazimine, amoxycillin-clavulinic acid, linezolid is not recommended as accuracy and reproducibility of laboratory testing cannot be guaranteed. The reliability of InhA mutation and cross resistance with ethionamide in laboratory reports is not recommended.”[15]
Table 2: Revised National Tuberculosis Control Program multi-drug resistant tuberculosis suspect criteria

Click here to view



  Management Principles Top


The principles of therapy for DS and DR-TB remain the same. However, application of these basic principles differs with advances. Counseling about the disease and informing about whether pulmonary/extrapulmonary disease, the basis of diagnosis, infectious status that it is a curable disease and briefly discussing the adverse drug reactions is very important before prescribing ATT. TB therapy is a two phased chemotherapy. DS-TB therapy is an evidence based treatment. In DS-TB therapy; the initial intensive phase (IP) consists of four drugs to achieve a “quick kill” and prevent drug resistance. In the continuation phase (CP), two or three drugs are given to kill the “persisters”. This therapy is also called the short course chemotherapy consisting of isoniazid (H), rifampicin (R), pyrazinamide (Z), and ethambutol (E) for 2 months followed by H, R, and E for 4 months. Thus the total duration of therapy is 6 months. The therapy should always be given directly observed/under supervision (DOT). Frequent modifications to the therapy are to be avoided. Adding a single drug in potential failure cases also known as addition syndrome is a strict NO. The use of second-line ATT empirically should be avoided. The management principles for DR-TB are discussed by the WHO [15] and RNTCP [14] in the programmatic management of drug-resistant tuberculosis (PMDT) guidelines, although the level of evidence is of inferior quality as compared to DS-TB. The diagnosis of DR-TB mandates a DST backup. No empirical therapy is considered. Again, DOT is a corner stone for successful management. Four or more new drugs to which the patient has never been exposed to are used in the regimen. The patients are referred to a DR-TB center for pretreatment evaluation and referral for second-line DST. The duration for DR-TB therapy is 24–27 months consisting of 6–9 months of intensive phase and 18 months of continuation phase.[16]


  Therapeutic Advances in Ds-Tb Top


The RNTCP practiced thrice weekly regimen for treatment of DS-TB. The program gradually planned shifting to daily regimen phasing out the intermittent regimen in the entire country. In 2016, HIV cases co-infected with TB were covered. Followed by in February 2017, 107 districts implemented the daily regimen. The daily regimen administers daily fixed dose combinations (FDC) of first-line ATT as per weight bands. A FDC is a combination of two or more active drugs in a fixed dose. The new cases would be treated with 8 weeks of IP of H, R, Z, and E administered in form of four drug FDC given daily as per weight bands. Followed by 16 weeks of CP of H, R, and E administered in form of three drug FDC given daily as per weight band. The retreatment cases would receive IP of 8 weeks of injectable streptomycin (S), with four drug FDC and 4 weeks of four drug FDC daily as per weight bands. The CP consists of 20 weeks of three drug FDC. Twenty-eight days medications would be dispensed to the patient at each visit. The supervision of therapy is ensured with the help of a DOT provider or family member. A novel free call feedback system has been introduced to further ensure compliance. The FDC are wrapped in envelopes which are printed with hidden numbers behind the pills. When patients dispense a dose, they reveal a hidden TOLL FREE number on which they give a free call. This call information is updated in the system online and information about missed doses/calls is sent promptly to the health visitor. The FDC weight bands are enumerated in [Table 3]. Introduction of kid-friendly DS-TB medications is planned in future under RNTCP.
Table 3: Fixed dose combination (FDC) weight bands for daily regimen of drug sensitive Tuberculosis

Click here to view


These will consist FDC in WHO-recommended dosage with no requirement for squashing or slicing, rapidly dispersible and with fruit flavors.[17]

DR-TB-WHO 2016 Updates

With the availability of results of DR-TB patients initiated on second-line therapy under programmatic conditions globally, it was realized that only 50% had a successful outcome.[2] While failures were a meagre 10%; the deaths and loss to follow-up posed a formidable problem considering the long duration of therapy and the side effects. Hence, the WHO updated DR-TB management guidelines in 2016 based on reviews of aggregated and individual patient data from published and unpublished studies. The WHO formulated these guidelines aiming at its “End TB strategy” in spite of a weak level of evidence in absence of robust high quality studies considering the heterogeneous nature of the disease and challenges in management. To begin with, the guidelines recommended a DST backed correct diagnosis and strict DOT.[18]

The grouping of medicines used for the treatment of MDR/RR-TB and XDR-TB was revised on the basis of the updated evidence reviews for effectiveness and safety [Table 4]. The medicines, i.e., the “core” second-line components of DR-TB regimen were classified in four groups (A, B, C, and D). Group D is divided into three subgroups, i.e., D1, D2, and D3. Clofazimine and linezolid are now considered more important, while p-aminosalicylic acid has been reclassified with agents used only as a last option. Clarithromycin and other macrolides are not recommended for use in DR-TB. WHO considered only the medicines in these four groups as relevant for DR-TB therapy under programmatic conditions. In DR-TB therapy, a conventional regimen should consist of at least five effective TB medicines during the intensive phase, including pyrazinamide and four second-line TB medicines: one chosen from Group A, one from Group B, and at least two from Group C. If a five-drug regimen cannot be composed as given above, an agent from Group D2 (if available) and other agents from Group D3 may be added. Group D1 drugs are to be used only if likely to be sensitive.
Table 4: Reclassification of drugs recommended for treatment of drug resistant Tuberculosis

Click here to view


The shorter regimens of 9–12 months have been recommended conditionally instead of longer regimens in a selected group of patients with MDR/RR-TB who were not previously treated with second-line drugs after excluding resistance to fluoroquinolones and second-line injectable agents. This was based on analysis of observational studies in 10 countries which gave a shorter DR-TB regimen of 9–12 months with good treatment success of 84% and rare relapses in previously untreated patients.[19]

FDA-approved newer drugs: Bedaquiline and delamanid

In 2012, Bedaquiline received accelerated approval from the US Food and Drug Administration (FDA) on basis of phase IIb study [20] for treating pulmonary MDR-TB patients with no other effective treatment options. It is an ATP synthase inhibitor, depletes mycobacteria of their energy stores and can potentially remain active against TB, which often becomes resistant to older, bacteriostatic drugs. Bedaquiline is available with conditional access under the RNTCP in India.[21] It is given in presence of an optimized background regimen consisting of three to four drugs in a dose of 400 mg twice daily for 2 weeks followed by 200 mg once a day thrice weekly for 22 weeks for a maximum duration of 6 months. The adverse effects were nausea, arthralgia, headache, hyperuricemia, vomiting, dizziness, increased transaminases, myalgia, diarrhea, and QTc prolongation on electrocardiogram. Delamanid was granted conditional approval by the European Medicine Agency in April 2014 on basis of Phase IIb trial [22] and studies for safety and efficacy. Delamanid (OPC-67683), a nitro-dihydro-imidazooxazole derivative, inhibits mycolic acid synthesis and has shown potent in vitro and in vivo activity against DR-TB strains. The drug is not available in India unless in a trial setup.


  The Future Top


The advances in TB have laid way to future research which is also worded as “pipelines”. In the diagnostic pipeline, the lateral flow urine lipoarabinomannan assay (LF-LAM) which detects mycobacterial LAM has emerged as a potential point-of-care test for TB. The TrueNAT, an Indian GeneXpert competitor is undergoing accreditation and offers promise. At the laboratory research level are projects like gene expression signatures, oral swab for TB DNA, and immune activation markers. The prevention pipeline is focusing on predictors of disease progression through gene-based signatures of risk and studying bacterial individuality with persistence.[23] The vaccines in development include the M. vaccae in phase III, M72/ASO in phase IIb and VPM1002 in phase IIa of clinical research. While latent TB infection (LTBI) is known of from decades, the WHO has only recently published guidelines for management of the same.[24] Numerous new tests and drugs are in research for LTBI. But till date, the diagnosis of LTBI by tuberculin skin test (TST)/interferon-gamma release assay (IGRA) and treatment with isoniazid monotherapy for 6 months remains validated. While isoniazid preventive therapy is advised in contacts of sputum positive DS-TB, there is no consensus on prophylaxis for contacts of sputum positive DR-TB.[23]

The TB treatment pipeline has seen the most activity though “no answers” yet. There are just five drugs from four classes in development including bedaquiline and delamanid, which already have conditional marketing approval in some countries. Bedaquiline and delamanid phase III studies have been started but results will be available by 2018. Other three study drugs are pretomanid, sutezolid, and Q203. The STAND trial which evaluated pretomanid, moxifloxacin, and pyrazinamide has been put on hold in view of unexpected fatalities. The Nix-TB trial for XDR-TB; however, is ongoing wherein therapy consists of pretomanid, bedaquiline, and linezolid. Sutezolid, an oxazolidinone, has entered phase IIb studies. The STREAM-II study, is testing bedaquiline in a 9-month injectable-free regimen, as well as a 6-month combination, started enrolling in March 2016. Since 2012, Perchlozone and SQ109 are used in the Russian market in spite of the Russian health regulating authority being criticized globally for no peer-reviewed clinical trial data in English to support the efficacy of these drugs. Many trials are testing the combinations of drugs already on the market, called repurposed drugs namely moxifloxacin, clofazimine, and linezolid.


  Conclusions Top


India is a high TB burden country. Advances in the nomenclature, diagnostic approach, management principles, and guidelines have reformatted the outlook towards the disease. With the invention of the WHO approved rapid diagnostics, i.e., GeneXpert and Line probe assay; a stern emphasis is laid on the microbiological confirmation of the disease.

The correct diagnosis, counselling, and direct supervision of therapy remain the pillars of a successful therapy. The RNTCP 2016 recommendations adopted daily therapy with FDC for the treatment of DS-TB from previous thrice weekly regimen. The WHO 2016 recommendations for DR-TB reclassified drugs, included new drugs bedaquiline and delamanid and postulated possible future shorter regimens. The TB pipeline holds promise on various newer unventured aspects.

The newer developments are indeed enterprising. Though one must remember; the basics of diagnosis with microbiology, adherence to therapy guidelines, ensuring supervision of therapy, and programmatic support are the cornerstones of the END TB strategy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
2.
WHO. Multi-drug resistant tuberculosis(MDR-TB) 2016 update. http://www.who.int/tb/challenges/mdr/mdr_tb_factsheet.pdf?ua=1. [Accessed on 2017 Apr 07].  Back to cited text no. 2
    
3.
WHO. Definitions and reporting framework for tuberculosis-2013 revision (updated December 2014). http://apps.who.int/iris/bitstream/10665/79199/1/9789241505345_eng.pdf. [Accessed on 2017 Apr 07].  Back to cited text no. 3
    
4.
Banerjee R, Allen J, Westenhouse J, Oh P, Elms W, Desmond E, et al. Extensively drug resistant tuberculosis in California, 1993-2006. Clin Infect Dis 2008;47:450-7.  Back to cited text no. 4
    
5.
Mlambo CK, Warren RM, Poswa X, Victor TC, Duse AG, Marais E. Genotypic diversity of extensively drug resistant tuberculosis in South Africa. Int J Tuberc lung Dis 2008;12:99-104.  Back to cited text no. 5
    
6.
Migliori GB, De Iaco G, Besozzi G, Centis R, Cirillo DM. First tuberculosis cases in Italy resistant to all tested drugs. Euro Surveill 2007;12:E070517.1  Back to cited text no. 6
    
7.
Velayati AA, Masjedi MR, Farnia P, Tabarsi P, Ghanavi J, Ziazarifi AH, et al. Emergence of new forms of totally drug-resistant tuberculosis bacilli: Super extensively drug-resistant tuberculosis or totally drug-resistant strains in iran. Chest 2009;136:420-5.  Back to cited text no. 7
    
8.
Udwadia ZF, Amale RA, Ajbani KK, Rodrigues C. Totally drug-resistant tuberculosis in India. Clin Infect Dis 2012;54:579-81.  Back to cited text no. 8
    
9.
WHO. “Totally Drug-Resistant TB”: A WHO consultation on the diagnostic definition and treatment options Dates: 21-22 March 2012 WHO/HQ Geneva, Switzerland. http://www.who.int/tb/challenges/xdr/Report_Meeting_totallydrugresistantTB_032012.pdf. [Accessed on 2017 Apr 07].  Back to cited text no. 9
    
10.
Karkhanis VS, Joshi JM. Is XDR-TB asub-group of MDR-TB? Need to reorganize alphabets again! Indian J Tuberc 2012;59:187-9.  Back to cited text no. 10
    
11.
WHO. Towards universal access to diagnosis and treatment of multidrug-resistant and extensively drug-resistant tuberculosis by 2015-WHO progress report 2011. http://apps.who.int/iris/bitstream/10665/44557/1/9789241501330_eng.pdf. [Accessed on 2017 Apr 07].  Back to cited text no. 11
    
12.
WHO. Approaches to improve sputum smear microscopy for tuberculosis diagnosis. Expert Group meeting report. Geneva 31 October 2009. http://www.who.int/tb/laboratory/egmreport_microscopymethods_nov09.pdf. [Accessed on 2017 Apr 17].  Back to cited text no. 12
    
13.
RNTCP. Technical and operational guidelines for tuberculosis control in India 2016, chapter 3- Case findings and diagnosis strategy. http://tbcindia.nic.in/showfile.php?lid=3216. [Accessed on 2017 Apr 27].  Back to cited text no. 13
    
14.
RNTCP. Guidelines on programmatic management of drug resistant tuberculosis (PMDT) in India May2012. http://tbcindia.nic.in/showfile.php?lid=3155. [Accessed on 2017 Apr 17].  Back to cited text no. 14
    
15.
WHO. Companion handbook to the WHO guidelines for programmatic management of drug resistant tuberculosis 2014. http://apps.who.int/iris/bitstream/10665/130918/1/9789241548809_eng.pdf?ua=1&ua=1. [Accessed on 2017 Apr 17].  Back to cited text no. 15
    
16.
Joshi JM. TB chemotherapy in 21st century: Back to basics. Lung India 2011;28:193-200.  Back to cited text no. 16
[PUBMED]  [Full text]  
17.
RNTCP. Technical and operational guidelines for tuberculosis control in India 2016. http://tbcindia.nic.in/showfile.php?lid=3219. [Accessed on 2017 Apr 17].  Back to cited text no. 17
    
18.
Falzon D, Schünemann HJ, Harausz E, Angulo LG, Leinhardt C, Jaramillo E, et al. World Health Organization treatment guidelines for drug-resistant tuberculosis, 2016 update. Eur Respir J 2017;49:1602308.  Back to cited text no. 18
    
19.
WHO. WHO treatment guidelines for drug-resistant tuberculosis, 2016 update (WHO/HTM/TB/2016.04) Online Annexes 4, 5, 6. 2016. http://apps.who.int/iris/bitstream/10665/250125/5/9789241549639-webannexes-eng.pdf. [Accessed on 2017 Apr 07].  Back to cited text no. 19
    
20.
Diacon AH, Pym AP, Grobusch M, Patientia R, Rustomjee R, Page-Shipp L, et al. The diarylquinoline TMC207 for multidrugresistant tuberculosis. N Engl J Med 2009;360:2397-405.  Back to cited text no. 20
    
21.
RNTCP. Guidelines for use of Bedaquiline in RNTCP PMDT in India. http://www.tbcindia.nic.in/showfile.php?lid=3246. [Accessed on 2017 Apr 07].  Back to cited text no. 21
    
22.
Gler MT, Skripconoka V, Garavito ES, Xiao H, Cabrera-Rivero JL, Vargas-Vasquez DE, et al. Delamanid for multidrug-resistant pulmonary tuberculosis. N Engl J Med 2012;366:2151-60.  Back to cited text no. 22
    
23.
Frick M, Lessem E, McKenna L. 2016 pipeline report tuberculosis edition- Diagnostics, treatment, prevention and vaccines in development.http://www.pipelinereport.org/sites/default/files/2016%20Pipeline%20TB%20Edition_0.pdf. [Accessed on 2017 Apr 17].  Back to cited text no. 23
    
24.
WHO. Guidelines on management of latent tuberculosis infection. http://apps.who.int/iris/bitstream/10665/136471/1/9789241548908_eng.pdf?ua=1&ua=1. [Accessed on 2017 Apr 17].  Back to cited text no. 24
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
The Nomenclature
The Revised Diag...
Management Princ...
Therapeutic Adva...
The Future
Conclusions
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed68    
    Printed2    
    Emailed0    
    PDF Downloaded22    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]