Annals of sbv 2015 4(2) by Dept of Medical Informatics

ISSN 2395 - 1982

SRI BALAJI VIDYAPEETH ACADEMY OF HEALTH PROFESSIONS EDUCATION AND ACADEMIC DEVELOPMENT

ANNALS OF SBV Volume 4 - Issue 2 JULY - DEC 2015

Theme

Tuberculosis in the past, present and in future

A Publication of

SRI BALAJI VIDYAPEETH

Annals of SBV Editorial Advisors Rajaram Pagadala K R. Sethuraman Editor-in-Chief N. Ananthakrishnan Core Committee M. Ravishankar Seetesh Ghose R. Pajanivel

V.N. Mahalakshmi Karthiga Jayakumar K.A. Narayan R. Jagan Mohan

Issue Editor J. Mohanasundaram Associate Editor Manuscript Editors A. Sundaramurthy M.I. Glad Mohesh A.N. Uma

Editorial Assistant Saurabh Shrivastava

Statistical Consultant G. Ezhumalai Editorial, Technical and Production Consultant A.N. Uma Published, Produced and Distributed by

Sri Balaji Vidyapeeth

Editorial correspondence to Editorial, Technical and Production Consultant

Annals of SBV Sri Balaji Vidyapeeth

(Deemed University, Accredited by NAAC with 'A' Grade) Mahatma Gandhi Medical College & Research Institute Campus Pillaiyarkupam, Puduchery - 605 403 INDIA E.mail:annals@sbvu.ac.in | Phone : +91 413 2615449 to 58 | Fax : +91 413 2615457 Visit Annals of SBV Online at http://www.annals.sbvu.ac.in

INDEX From the editor's desk - Mohanasundaram J

14. Images in Abdominal Tuberculosis - Gokul D Yatheendranathan

15. Potpouri - Saurabh RamBihariLal Shrivastava

Where does the world stand in the fight against the tuberculosis? 2015 update.

2. Tuberculosis Today & Tomorrow - Srividhya G

Effective implementation of contact tracing in tuberculosis: Pros and Cons

3. Tuberculosis in Pregnancy - Sathyakala Rajendiran, Suthanthiradevi

How many of us are practically aware about directly observed treatment in tuberculosis?

4. Childhood Tuberculosis - Prema R

5. Cutaneous Tuberculosis - Srinivasan G., Jeyakumari Jeevan

6. Postmortem Hazard of Mycobacterium Tuberculosis - Swayam Jothi S

1. Role of Herbs in Tuberculosis: A Compilation. - Mohanasundaram J

7. A Review of Current Status of Tamil Nadu under Revised National Tuberculosis Control Program. - Uma Devi V

8. Danio Rerio (Zebrafish): A Cost Effective Animal Model for Anti-Tuberculosis Drug Research. - Glad Mohesh M.I.

9. Tuberculosis: Implications for Anaesthesia - Vishwanath R Hiremath, Pranjali Kurhekar, Dilip Kumar, Krishna Prasad

Unusual Presentations of Tuberclulosis 10. Acute fulminant Myocarditis – A rare complication of Tuberculosis - Sridhar R V, Senthil Kumar S, Srividhya G

11. Tuberculosis of Breast - Shantha Mohanasundaram, Deepa N, Dr. Hemanathan G

12. Tuberculosis and Dentistry - Surya V., Manikandan G

13. Imaging in Tuberculosis - Subramanian V

Interventions to strengthen airborne infection control in healthcare establishments

Role of infrastructure in the management of drug resistant tuberculosis in India Moving forward to accomplish tuberculosis related Millennium Development Goal-6 Declaring tuberculosis as a notifiable disease in India: A landmark development in the prevention and control.

Enhancing the contribution of private health sector in tuberculosis control activities in India

Incorporating tuberculosis in undergraduate medical curriculum

Striving hard to achieve universal access to tuberculosis care: Indian perspective

Annals of SBV

From the Editor’s Desk

“Tuberculosis in the past, present and in future” Annals of SBVU is a prestigious biennial scientific journal published by Sri Balaji Vidyapeeth, Deemed to be University, Puducherry, each issue with a specific theme. The responsibility of bringing out the current issue has been assigned by SBVU to the constituent off campus institution Shri Sathya Sai Medical College & Research Institute which is situated near Tiruporur in Kanchipuram District, Tamilnadu. As the Head of SSSMCRI, I am privileged to be the Issue Editor for the July-Dec 2015 issue. As a consensus opinion in view of the endemicity of disease Tuberculosis in Kanchipuram district, with large number of different varieties of Tuberculosis cases coming in to our Hospital it has been decided to dedicate this issue with the theme “Tuberculosis in the past, present and in future” . This title is more apt as the famous Tambaram TB sanatorium started during 1928 is in Kanchipuram district and an important WHO/ICMR clinical trial on the efficacy of BCG vaccine was carried out in Chengalpattu of Kanchipuram district during 1968. Dr.A.Sundaramurthy, a sincere and dedicated specialist in Pulmonology who is the HOD, TB& CD has been the Associate Editor for this issue to review the articles for the scientific validity of the contents. Mr.Glad Mohesh MI, Asst. Professor of Physiology and Dr. Saurabh R. Shrivastava Assistant Professor of Community Medicine rendered the manuscript edition and editorial assistance respectively for this issue. Dr. AN Uma, Asst. Professot in Medical Genetics, Dept. of Anatomy, MGMCRI also rendered support in the edition of this issue. Hope all readers will be exposed to all varieties of Tuberculosis in a scientific way and enrich their knowledge on this very old and still a dreaded disease due to multidrug resistance and its co-existence with other dreaded companions like HIV.

Role of Herbs in Tuberculosis: A Compilation Dr. J Mohanasundaram, Dean & Professor of Pharmacology Shri Sathya Sai Medical College and Research Institute, Sri Balaji Vidyapeeth , Nellikuppam, Kancheepuram Dist., Tamil Nadu – 603 108, India.

Abstract 

I n this article the role of herbs in Tuberculosis have been compiled based on their availability as commonly used household remedies such as spices, condiments, fruits, vegetables, flowers etc and other herbs based on their effectiveness in inhibiting Mycobacterium. tuberculosis both normal or multidrug resistant strains or their ability to prevent anti tuberculous drug induced adverse effects such as hepatotoxicity. The herbs or formulations which have relevance to tuberculosis andscientifically evaluated invitro or invivo in animal models or in clinical studies and found to have positive effects have been included in this compilation.

Key Words: Anti-tuberculous herbs,Multi drug resistant Tuberculosis, Anti tuberculous drug induced Toxicity

Dr. J. Mohanasundaram, Dean, SSSMCRI.

Introduction The disease Tuberculosis is in existence since time immemorial(1). The specific Chemotherapy with effective agents were available only from mid-20th century. Complementary and alternative medicine including herbs & nutritional agents are in use with adjunct role(2). After the introduction of Specific Chemotherapeutic agents the role of herbs have turned in to different dimensions such as: a. Amelioration of toxicity induced by anti tubercular drugs like Rifampicin, INH, Ethambutol etc. b. Adjuvant role in overcoming Multi Drug Resistance.

Discussion In this article the herbs which have some scientific evidence on their effect in vitro or invivo or in clinical studies with reference to Tuberculosis have been enumerated. Agents that are being used as general health restorers and immune boosters including Common house hold remedies like

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Ann. SBV, July-Dec 2015;4(2)

vegetables, fruits, spices, condiments are enlisted below with their role against Tuberculosis are: Green Tea – (Theasinensis)is rich in ant-oxidants and a general immune-booster which will help in fighting tuberculosis. green tea extract administration for one weekreverted back the oxidative stress parameters induced by MT infection in miceto near normal levels as evidenced by a fall in catalase, glutathione peroxidase, total thiol and extent of lipid peroxidation with concomitant increase in the levels of SOD and reduced glutathione in infected animals(3) Garlic – (Allium sativum) hasanti bacterial property against Tubercle bacilli as it contains sulphur. Garlic also contains allicin and ajoene which helps to inhibit the bacterial growth.Rao and coworkers demonstrated, as early as in 1946, the in vitro inhibitory effect of allicin on the growth of M.tuberculosis(4).Liu et al has shown that garlicin can inhibit MTB protein synthesis and also inhibit bacterial rotamase, thus preventing DNA replication and degradation resulting in MTB death.(5)

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Onion – (Allium cepa) is reported for the first time to possess inhibitory activity against isolates of MT by Gupta et al(13)

Herbs effective against (drug sensitive and Multidrug resistant) Tuberculosis:

Black pepper (Piper nigrum) – Pepper has anti inflammatory properties which will help to reduce the inflammation. An active principle of pepper Piperineby reducing the required dose of expensive toxic Rifampicin by 60 percent,there by reducing the cost and side effects of Rifampicin and also effective against Tuberculosis.(6)

Acalyphaindica, Adhatodavasica, Allium cepa, Allium sativum and Aloe vera (Aqueous extracts of leaves of) – exhibited inhibitory activity of 95, 32, 37, 72, 32 per cent, respectively against MDR isolate DKU-156 and 68, 86, 79, 72, 85 per cent, respectively for another MDR isolate JAL-1236,, of M. tuberculosis. in L-J medium.(13)

Cinnamomum – A study conducted in India showed that extracts of Cinnamomumzeylanicum (CZ) had activity against M. tuberculosiswith an MIC of 100 μg/ml for water extract and MIC-200 μg/ml for ethanolic extract(7) and a study conducted inTurkey showed that M. tuberculosisstrains H37Rv and H37Ra had MIC of 1024μg/ml and 512μg/ml respectively and MBC was >2048 μg/ml of CZ for both strains.(8)

Andrographispaniculata – Themethanolic extract of A. paniculata showed maximum antimycobacterial activity at 250μg/ml against all the tested strains of M. tuberculosis (H37Rv, MDR, and drug sensitive). Based on bioassay guided fractionation, andrographolide was identified as the potent molecule.(14)

Mint (Menthapiperita) – has anti bacterial property and helps in the healing of the tissues affected by tuberculosis. The in vitro antibacterial activities of ethanolic extracts showed 0.39 mg/ ml consistency of M. spicata and 100mg/ ml consistency of M. piperita as the least concentrations which inhibit growth of Mycobacterium. bovis in comparison with isoniazid.(9) Annonasquamosa – Administration of methanolic extracts of Annonasquamosa prevented isoniazid-rifampicin-induced elevation in the levels of serum diagnostic liver marker enzymes in experimental groups of rats.Flavanoids were thought to be the main bioconstituent responsible for the hepatoprotective activity against anti tubercular drug induced toxicity(10) Drumstick leaves (Moringaoleifera) – have antibacterial and anti- inflammatory properties which will help to eliminate the bacteria from the lungs. The leaf ethyl acetate extract of M. oleifera showed the highest activity against Mycobacterium madagascariense with minimum inhibition concentration (MIC) value of 0.37381 mg/ml while the seeds ethyl acetate extracts had MIC value of 0.37381 mg/ ml against both M. madagascariense and M.indicuspranii.(11) Zingiberofficinalis – [10]-gingerol isolated from ginger rhizome, has been reported as active inhibitor of M. avium and M. tuberculosis in vitro(12) Apart from the above common ingredients other agents like Banana, Custard apple, gooseberry, orange, pineapple, walnut are also supposed to have beneficial effects in Tuberculosis by virtue of theirnutitional value vitamin contents and general immune boosting effects.

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Artemisia afra – Tuber. A study showed that A. afra has in vitro anti-mycobacterial activity, modulates pulmonary inflammation in early mycobacterial infection, and suggest that the mouse experimental tuberculosis model may serve as a useful assay for evaluating the utility of phytotherapy.(15) Azadirachtaindica – The neem extract suppressed MTBinfected monocytes in a dose-dependent manner (P<0.001) in the expressions of secreted TNF-a, iNOS and MTB Ag85 respectively in 24 hr culture supernatants of MTB-infected monocytes.(16) Berberis vulgaris – Barberry or is highly effective in relieving TB symptoms and is used to complement conventional treatment. The active ingredient in barberry is berberine which has bacterial properties and aids in killing the tuberculosis. Berberine can inhibit MTB in vitro, and the activities are concentration dependent.(17,18) Calendula officinalis – In a study the Minimum Inhibitory Concentration of aquous (aq) and ethanolic(E) extracts of C.officinalisagainst M. tuberculosisstrains C: ATCC 35808 and H37RV ATCC 25618 and clinical isolates of M. tuberculosis were 125 µg/ml(Aq) , 3.9 µg/ml (E) respectively and the Minimum Bactericidal Concentration were 250 µg/ml (Aq) , 7.8 µg/ml (E).The ethanolic extract can be tried as antibacterial agents against MDR-TB.(19) Carica papaya – Theethanolic extract of leaves and seeds of Carica papayashowed anti-tb activity against clinical strains of sensitive and drug resistant M. tuberculosis (pyrazinamide, streptomycin, ciprofloxacin) in an in-vitro bioassay.(20) Catharanthusroseus – C.roseus and Piperine were evaluated against Ofloxacin resistant M. tuberculosis which showed

Ann. SBV, July-Dec 2015;4(2)

that both act as efflux pump inhibitor and synergistically more active and the percentage of relative inhibitiory zone of C.roseus was 133 % and piperine was 111 %.(21) Chenopodiumambrosioides – n acetone extract of C. ambrosioides was effective against a resistant H37Rv strain of M. tuberculosis at 0,1 g/mL(22) Cola nitida and C. milleni – Methanol extract of root bark of both C. nitida and milleniwere found to be potent against both M. bovis and strains of M. vaccae.(23) Croton pseudopulchellus, Ekebergiacapensis, Eucleanatalensis, Nidorellaanomala and Polygala myrtifolia – A study on the South African medicinal plants used to treat pulmonary diseases for activity against drug-resistant and drug-sensitive strains ofM. tuberculosisrevealed that the minimal inhibitory concentration of Croton pseudopulchellus, Ekebergiacapensis, Eucleanatalensis, Nidorellaanomala and Polygala myrtifolia was 0.1 mg/ml against the H37Rv strain and the. Extracts of Chenopodiumambrosioides, Ekebergiacapensis, Eucleanatalensis, Helichrysummelanacme, Nidorellaanomala and Polygala myrtifolia were active against the resistant strain at 0.1 mg/ml.(24) Curcuma pseudomonata (Hill Turmeric) – Hexane, chloroform, ethyl acetate and methanol extracts of rhizome of Curcuma pseudomontana showed activity against M.tuberculosisstrain H37 RV at 100 and 50mg/ml.(25) Eucleanatalensis – A binaphthoquinoid, diospyrin, was isolated from Eucleanatalensis showed activity against drugsensitive and drug-resistant strains of M. tuberculosiswith an MIC of 100 microg/ml for all.(26) Morindacitrifolia – A crude ethanol extract and hexane fraction from Morindacitrifolia Linn. (Rubiaceae) show antitubercular activity. E-Phytol, a mixture of the two ketosteroids, and the epidioxysterol derived from campesta5,7,22-trien-3beta-ol all show pronounced antitubercular activity.(27) Peristrophebicalyculata – A yellow-brown essential oil can be extracted by distillation, shows in vitro activity against the growth of various strains of MT.(28) Salvia hypargeia – A new abietanediterpenoidHypargenin F isolated from the root extracts of Salvia hypargeia was active against MT.(29) Solanumtorvum – Methyl caffeate isolated from Solanumtorvum showed moderate antimicrobial and prominent antimycobacterial activities with minimum inhibitory conAnn. SBV, July-Dec 2015;4(2)

centration (MIC) of 8 μg/ml against M. tuberculosis H(37) Rv and Rif(R) strains.(30) Withaniasomnifera – a herb known as Aswagandha and used in Ayurvedic medicine which contains many useful medicinal chemicals, including withanolides (steroidal lactones), alkaloids, which was shown to enhance absorption of Antituberculous drugs isoniazid and pyrazinamide and hastened the AFB sputum conversion in to negativity and reduction in ESR hence useful as an Adjunct therapy with Anti tubercular drugs.(31) Zizyphusmauritiana Mauritine M & nummularines H – isolated from MeOH extract obtained from the root of the Ziziphusmauritiana demonstrated antimycobacterial activity against M.tuberculosiswith the MIC of 72.8 and 4.5 μM, respectively.(32)

Herbs which alleviate Anti Tuberculous Therapy inducedhepato toxicity: Boerhaaviadiffusa – A study showed that flavanoids and tannins also B-sitsterol have both antioxidant and antihypercholesterol properties and may be responsible for the protective activity of Boerhaaviadiffusa against antitubercular drugs.(33) Bombaxcieba – Flavanoids and sequiterpenoids which scavenge free radicals were thought to be reason for effectiveness of B. cieba plant against anti-tubercular drug toxicity.(34) Cassia fistula – Anti-tubercular protective action of C. fistula is due to presence of flavanoids present in it..(35) Cnidoscoluschayamansa – C. chayamansa significantly prevented Rifampicin-Isoniazid-induced elevation in the levels of serum diagnostic liver marker enzymes aspartate amino transferase , alanine amino transferase and alkaline phosphatase level in experimental groups of rats.(36) Curcuma longa and Tinosporacordifolia – combination prevented anti-tuberculosis treatment (ATT) induced hepatotoxicity and the incidence and severity of hepatotoxicity was significantly lower in trial group.(37) Cuscutareflexa – A study of methanol extract of aerial parts of Cuscutareflexa revealed protective effect on hepatotoxicity induced by antitubercular drugs in rats.(38) Garciniaindica – Aq. Extract of Garciniaindicaattenuated the antitubercular drug (ATD)-induced elevated levels of aspartate aminotransferase, alanine transaminase, alkaline phosphatase, bilirubin, and malondialdehyde and restored Page 9

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the ATD-depleted levels of glutathione (GSH), superoxide dismutase, catalase, GSH peroxidase, and GSH reductase.(39) Ginkobiloba – Two major mechanisms that may be responsible for hepatoprotective activity of G.biloba are flavanoids which may be responsible for scavenging activity of reactive oxygen species that were produced due to toxicity caused by anti TB drugs.(40) Jasminumgrandiflorum – JG leaves extract treatment in rats revealed hepatoprotective activity in isoniazid induced liver damage.(41) Ocimumsanctum – Co-administration of OS leaf extract along with the anti – tubercular drugs significantly prevented all the biochemical and histological alterations caused by the antitubercular drugs and significantly reversed all the histopathological scores.(42) Picorhizakurroa – By its counter acting effects of free radicals by the presence of electrophillic constituent, picroside II and kurkoside or to an activated conjugation of anti TB drugs with GSH in liver P. kurroa ameliorated hepatotoxic effect induced by Rifampicin in rats.(43) Phyllanthusfraternus – (Bhumyamalaki) showedhepatoprotective effect in a 12 weeks clinical study on patients receiving Anti tuberculartreatment.(44) Pulsatillachinensis – has been shown to inhibit MTB in vitro. It can also reduce the hepatotoxicity jnduced by rifampicin and isoniazid hence has a protective action against liver damage and combining this in antitubercular therapy can reduce the side effects.(45) Rhodomyrtustomentosa – It was found thatphenolic compounds were responsible for the protective activity of this plant against antitubercular drugs induced hepatic damage.(46)

to 10 patients with Tuberculosis in a Clinical study for 12 weeks from initiation of Anti Tubercular Treatment. Liver functions were periodically monitored which revealed the hepatoprotective efficiency of this formulation over the placebo at the end of the study.(44) A Chinese medicinal formulation for treating tuberculosis of intestine CN 102847027 A – A patent related to the invention of a Chinese medicinal formulation for treating tuberculosis of intestine, comprising Poriacocos, Poria, Semen ArmeniacaeAmarum, Coixlacryma-jobi seed, Dioscoreaopposita, Radix Adenophorae and/or Radix Glehniae, stir-baked Radix Stemonae, CrinisCarbonisatus, Limonitum, RhizomaCynanchiStauntonii, Atractylodesmacrocephala, Terminaliachebula, HerbaPlantaginis, Ecliptaprostrata, Aster tataricus, Citrus reticulata peel, parched RhizomaAtractylodis, and Radix Glycyrrhizae as raw materials. The invention can effectively treat tuberculosis of intestine with notable curative effect and no adverse side effect.(49) Cervical lymph node tuberculosis treatment traditional Chinese medicine CN 103845422 A – The invention belongs to a traditional Chinese medicine, specifically to a cervical lymph node tuberculosis treatment traditional Chinese medicine, which is characterized by comprising, by weight, 20-40 g of white paeony root, 10-20 g of bupleurumchinense, and 10-20 g of tuckahoe, wherein the selected white paeony root, the selected bupleurumchinense and the selected tuckahoe are washed, are subjected to air-drying, and are grinded into fine powder with a particle size of 100 mesh, and the one part of the obtained drug powder is directly and orally taken twice a day. According to the present invention, based on the Chinese medical science syndrome differentiation theory, characteristics of simple formula, easily available materials, low cost, high treatment effect, no toxic-side effect and effective cervical lymph node tuberculosis treatment are provided.(50)

Spirulina maxima – protects liver from Isoniazid and Rifampicin drug induced toxicity.(48)

Chinese Formulations – Compound preparations. It has been proved that Feitai Capsule, ShenlingBaizhu Powder, Compound Astragalus Capsule, anti-phthisis capsule and other Chinese patent poly herbal drugs used in conjunction with chemotherapeutic drugs can promote the sputum negative conversion rate, cavity closure rate, and lesion absorption rate; meanwhile, they can also alleviate the toxic effects of anti-TB drugs, rapidly improve TB symptoms, and thereby increase the efficacy.(51)

Herbal Formulations:

Turkish herbal Formulation

Liv-600- Herbal formulation – Liv-600 an Ayurvedic formulation containing hydroalcoholic extract of Daruharidra (Berberisaristata) roots, Kakmachi (Solanumnigrum) whole plant, Ghritakumari (Aloe vera) ariel parts was administered

Ankaferd Blood Stopper® (ABS) – a Turkish formulation which is a mixture of plant extracts prepared from Alpiniaofficinarum, Glycyrrhizaglabra, Thymus vulgaris, Urticadioica and Vitisvinifera, has homeostatic and anti-

Sophoraflavescens – has a monomeric alkaloid matrine, which can improve the body’s immune system, resist inflammation, inhibits bacteria, and protects the liver hence useful in Tuberculosis.(47)

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Ann. SBV, July-Dec 2015;4(2)

bacterial effects. ABS MIC values for various sensitive and resistant strains ranged between between <1.37-21.88 µg/ ml. It was shown that 16 fold diluted concentration of the topically used ABS solution was found to be active against tuberculosis bacilli in vitro. Thus ABS might be used as a supportive agent together with anti-tuberculous drugs during debridement of multiple drug-resistant M.tuberculosis caused osteomyelitis and lymphadenitis lesions.(52) UkrineImmunomodulator – Immunoxel (Dzherelo™) is an oral, herbal immunomodulator formulation containing water-alcohol extract of 27 medicinal plants used in Ukraine for adjunct therapy for Tuberculosis showed that immunotherapeutic intervention increased bodyweight and decreased the incidence of new opportunistic infections and caused Enhancement of efficacy of tuberculosis drugs in HIV-infected patients with active pulmonary tuberculosis.(53) A study on the sublingualImmunoxelpreparation.along with standard Anti tuebrculous therapy showed that 1% of TB patients became sputum-negative and the conversion rate was independent of whether the subject was having multidrug-resistant TB or TB with HIV coinfection.(54)

Conclusion It can be seen from this compilation that there is a wealthof herbs which have potential role in tuberculosis. It may be a surprise that many commonly used household remedies like condiments, spices vegetables and fruits have scientifically documented anti tubercular property . These can be consumed freely with out much restriction as they are also nutritional supplements. Usage of other herbs on routine basis has the following restrictions. They can be used as adjunct/supportive therapy only to enhance the activity of routine anti tuberculous drugsespecially in multi drug resistant tuberculosis and to prevent the adverse effects of drugs like INH, Rifampicin etc. and not as a sole therapy for Tuberculosis. More over many of the herbs enumerated here need further clinical validation for their safety and efficacy before their routine use in TB except the ones which have already are use in alternate systems of medicine such as Ayurveda, Siddha etc. in which case only under the supervision of experts in both allopathy and the respective alternate system of medicine. This is essential as there may be drug interaction between the herb and routine drugs and there may be also adverse effects per se for the herbs apart from documented adverse effects for the antituberculous drugs. Judicious use Ann. SBV, July-Dec 2015;4(2)

of combination of herbal drugs with routine antitubercular drugs may be of importance in managing toxicity of drugs and multidrug resistant strains in future.

References 1. Masson M, Molnár E, Donoghue HD, Besra GS, Minnikin DE, et al. Osteological and Biomolecular Evidence of a 7000-Year Old Case of Hypertrophic Pulmonary Osteopathy Secondary to Tuberculosis from Neolithic Hungary. PLoS ONE 8(10): e78252 (2013). 2. http://umm.edu/Health/Medical-Reference-Guide/Complementary-andAlternative-Medicine-Guide/Condition/Tuberculosis. 3. Guleria RS1, Jain A, Tiwari V, Misra MK.Protective effect of green tea extract against the erythrocytic oxidative stress injury during M.tuberculosis infection in mice. Mol Cell Biochem. 2002 Jul;236(1-2):173-81. 4. Rao RR, Rao SS, Natarajan S, Venkataraman PR. Inhibition of M.tuberculosis by garlic extract. Nature 1946;157. 5. Liu YL, Liu ZP. Observing the Effect of Alltride Enteric-Coated Soft Capsules Combined With Anti-tuberculosis Medicine on Pulmonary Tuberculosis. Zhong Guo Yi Liao Qian Yan 2008,;3:23-5. 6. Zutshi RK, Singh R, Zutshi U, Johri RK, Atal CK. Influence of piperine on rifampicin blood levels in patients of pulmonary tuberculosis. The Journal of the Association of Physicians of India 1985, 33(3):223-224. 7. Sivakumar A, Jayaraman G. Anti-tuberculosis activity of commonly used medicinal plants of south India. J Med Plants Res. 2011;5:6881–6884. 8. Tekwu EM, Askun T, Kuete V, Nkengfack AE, Nyasse B, Etoa FX, Beng VP. Antibacterial activity of selected cameroonian dietary spices ethno-medically used against strains of M.tuberculosis. J Ethnopharmacol.2012;142:374–382. doi: 10.1016/j.jep.2012.05.003. 9. Said Maham, FatemehFallah, Gita Eslami, Sepideh Shamsafar, Rahele Radmanesh , BitaPourkaveh. The antimycobacterium activity of menthapiperita and menthe spicataethanolic extract against mycobacterium Bovis in comparison with isoniazid. Iran J Clin Infect Dis 2011 Vol 6 No. 2. 10. Mohamed Saleem TS, Christina AJM , Chidambaranathan N , Ravi V , Gauthaman K. Hepatoprotective activity of Annonasquamosa Linn. on experimental animal model. International Journal of Applied Research in Natural Products Vol. 1(3), pp. 1-7, Sep/Oct 2008. 11. John Wilson Nkya, Paul Erasto, Musa Chacha. Antimycobacterial and cytotoxicity activities of Moringaoleifera Lam extracts. American Journal of Research Communication, 2014, 2(9): 108-120. 12. Miri P, Bae J and Lee DS. Antibacterial activity of [10]-gingerol and [12]-gingerol isolated from ginger rhizome against periodontal bacteria. Phytotherapy Res. 2008; 22:1446-1449. 13. Renu Gupta, Bandana Thakur, Pushpendra Singh , H.B. Singh , V.D. Sharma , V.M. Katoch, & S.V.S. Chauhan Anti-tuberculosis activity of selected medicinal plants against multidrug resistant M.tuberculosis isolates. Indian J Med Res. 2010;131:809-13. 14. Prabu A, Hassan S, Prabuseenivasan, Shainaba AS, Hanna LE2, Kumar V.Andrographolide: A potent antituberculosis compound that targets Aminoglycoside 2’-N-acetyltransferase in M.tuberculosis. J Mol Graph Model. 2015 Sep; 61:133-40. 15. Ntutela S1, Smith P, Matika L, Mukinda J, Arendse H, Allie N, Estes DM, Mabusela W, Folb P, Steyn L, Johnson Q, Folk WR, Syce J, Jacobs M. Efficacy of Artemisia afraphytotherapy in experimental tuberculosis. Tuberculosis (Edinb). 2009 Dec;89 Suppl 1:S33-40. 16. Jawed Iqbal, Ajay Kumar & Najmul Islam. Azadirachtaindica induced suppression of M.tuberculosis secreted proteins in human monocyte 17. IJSRM June 2015 Vol.:1, Issue:2 Importance of Herbal Remedies in the Treatment of HIV & TB Infection Priyanka M. Mandhare, Bhagwat H. Garje , Amitkumar A. Khade. 18. Kuang TJ, Dong M, Song P, et al. In vitro antibacterial effects of berberine on M.tuberculosis. ZhongGuoZhong Yao ZaZhi 2001;26:867-8, 19. BehanmRafiee ; SepidehGhani ; DavoudSadeghi ; ShojaatDashti Pour ; Nader Mosavari The Antibacterial Effects of Plantago Minor, Calendula Officinalis and

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Annals of SBV Eucalyptus Polycarpa Extracts AgaintsM.tuberculosisInvitro . http://eprints. arums.ac.ir/5177/1/Minor.pdf. 20. Naga Swathi SreeKavuri, SravaniYangalasetti, VenkataRaoVutla. Anti-tubercular Activity of Leaf and Seed Extract of Carica papaya. InRaventipid: PlantaActiva, 2016(1): 1-3, 2015. 21. Raja A AbdulKapur M Fijju M and Mohamed Salique S. In vitro studies on Efflux pump Inhibition of Catharanthusroseus and piperine against ofloxacin resistant M.tuberculosis. International Journal of Pharmaceutical Science Invention. 22. http://www.mmh-mms.com/downloads/mp07chenopodiumambrosioides.pdf 23. Adeniyi BA, Groves MJ, Gangadharam PR. In vitro anti-mycobacterial activities of three species of Cola plant extracts (Sterculiaceae). Phytother Res. 2004 May;18(5):414-8. 24. Lall N, Meyer JJ. In vitro inhibition of drug-resistant and drug-sensitive strains of M.tuberculosis by ethnobotanically selected South African plants. J Ethnopharmacol 66: 347-54 6 (1999). 25. J. Graham Gurusiddesh B Hiremath, Basappa B Kaliwal.Antitubercular activity of the rhizome of Curcuma pseudomontana. International Journal of Pharmaceuticals and Health care Research 12/2013; 01(04):178-183. 26. Lall N1, Meyer JJ Inhibition of drug-sensitive and drug-resistant strains of M.tuberculosis by diospyrin, isolated from Eucleanatalensis. J Ethnopharmacol. 2001 Dec;78(2-3):213-6. 27. Saludes JP1, Garson MJ, Franzblau SG, Aguinaldo AM Antitubercular constituents from the hexane fraction of Morindacitrifolia Linn.(Rubiaceae). Phytother Res. 2002 Nov;16(7):683-5. 28. A-D.Burkill, H.M. The useful plants of West Tropical Africa families. Royal Gardens kew. (1985) 320 pp. 29. Ulubelen A1, Evren N, Tuzlaci E, Johansson C. Diterpenoids from the roots of Salvia hypargeia. J Nat Prod. 1988 Nov-Dec; 51(6):1178-83. 30. Balachandran C1, Duraipandiyan V, Al-Dhabi NA, Balakrishna K, Kalia NP, Rajput VS, Khan IA, Ignacimuthu S. Antimicrobial and Antimycobacterial Activities of Methyl Caffeate Isolated from Solanumtorvum Swartz. Fruit. Indian J Microbiol. 2012 Dec; 52(4):676-81. 31. P. K. Debnath, JaydebChattopadhyay, AchintyaMitra, AnjanAdhikari, MirzaSamsurAlam, S. K. Bandopadhyay, JayramHazra. Adjunct therapy of Ayurvedic medicine with anti tubercular drugs on the therapeutic management of pulmonary tuberculosis. J Ayurveda Integr Med. 2012 Jul-Sep; 3(3): 141–149. 32. PanomwanPanseeta a, KanlayaLomchoey a, SamranPrabpaib, PalangponKongsaeree b, c, ApichartSuksamrarn d , SomsakRuchirawat e, SunitSuksamrarn. Antiplasmodial and antimycobacterialcyclopeptide alkaloids from the root of Ziziphusmauritiana. Phytochemistry, 72 (2011), 909–915. 33. Muthulingam, M. Antihepatotoxic Effects of Boerhaaviadiffusa L. on Antituberculosis Drug, Rifampicin Induced Liver Injury in Rats. Journal of Pharmacology and Toxicology, 3(2), 75-83. (2008). 34. Ravi, V., Patel, S. S., Verma, N. K., Datta, D., &Saleem, T. M. Hepatoprotective activity of Bombaxceiba Linn against isoniazid and rifampicin-induced toxicity in experimental rats. International Journal of Applied Research in Natural Products, 3(3), 19-26 (2010). 35. Jehangir, A., Nagi, A. H., Shahzad, M., & Azam, Z. Thehepato-protective effect of Cassia fistula (amaltas) leaves in isoniazid and rifampicin induced hepatotoxicity in rodents. Biomedica, 26(2), (2010). 36. Soni, R. K., Dixit, V., Irchhaiya, R., &Alok, Spotential herbal hepatoprotective plants: an overviews. International Journal of Pharmaceutical Sciences and Research, 5(3), 774, (2014). 37. Meghna R Adhvaryu, Narsimha M Reddy, and Bhasker C Vakharia. Prevention of hepatotoxicity due to anti tuberculosis treatment: A novel integrative approach. World J Gastroenterol. 2008 Aug 14; 14(30): 4753–4762.

38. Balakrishnan, B. R., Sangameswaran, B., &Bhaskar, V. H. Effect of methanol extract of Cuscutareflexa aerial parts on hepatotoxicity induced by antitubercular drugs in rats. International Journal of Applied Research in Natural Products, 3(1), 18-22. (2010). 39. Panda, V. S., Ashar, H. D., &Sharan, A.Antioxidant and hepatoprotective effects of Garciniaindica fruit rind in antitubercular drug-induced liver injury in rats. Botanics: Targets & Therapy, 3. (2013). 40. Karunamoorthi, K., Jegajeevanram, K., Vijayalakshmi, J., & Mengistie, E. Traditional Medicinal Plants A Source of Phytotherapeutic Modality in ResourceConstrained Health Care Settings. Journal of Evidence-Based Complementary & Alternative Medicine, 18(1), 67-74. (2013). 41. Dhamal, N., Patel, M., &Pawar, S. Evaluation of Jasminumgrandiflorum for hepatoprotective activity in isoniazid induced liver damage. Internat J Pharm Sci Res, 3, 2568-2573. (2012). 42. Razvi Syed Ubaid, Kothekar Mudgal Anantrao, Jaju J. B. and Md. Mateenuddin. Effect of Ocimum sanctum (os) leaf extract on hepatotoxicity induced by antitubercular drugs in rats. Indian J PhysiolPharmacol 2003; 47(4) 465–470. 43. Jeyakumar, R., Rajesh, R., Meena, B., Rajaprabhu, D., Ganesan, B., Buddhan, S., &Anandan, R . Antihepatotoxic effect of Picrorhizakurroa on mitochondrial defense system in antitubercular drugs (isoniazid and rifampicin)-induced hepatitis in rats. Journal of Medicinal Plants Research, 2(1), 17-19 (2008). 44. Y K Sharma, Harbans Singh and B L Mehra. Hepatoprotective effect of few Ayurvedic herbs in patients receiving antituberculus treatment. Indian Journal of Traditional Knowledge Vol. 3(4), October 2004, pp. 391-396. 45. Wang SY, Wang XL, Liu MM. Experimental study of effects of Chinese bulbul extracts againstingM.tuberculosis in vitro. Shi Zhen Guo Yi Guo Yao 2011;22:2965-6. 46. Geetha, K. M., Patil, V., &Murugan, V. Hepatoprotective activity of aqueous alcoholic (70%) extract of Rhodomyrtustomentosa (Aiton) Hassk against antitubercular drugs induced hepatic damage. International Journal of Green Pharmacy, 6(4), 295. (2012). 47. Chen CS, Liang Y.Analysis of the potency of matrine in the inhibition of mycobacteritum tuberculosis. Shou Du Yi Yao 2006;13:44. 48. Jatav, S. K., Kulshrestha, A., Zacharia, A., Singh, N., Tejovathi, G., Bisen, P. S., & Prasad, G. B. K. S. Spirulina maxima protects liver from Isoniazid and Rifampicin drug toxicity. Journal of evidence-based complementary & alternative medicine, 19(3),189-194.(2014). 50. http://www.google.com/patents/CN103845422A?cl=en. 51. Xia Zhang, Jing Guo. Advances in the treatment of pulmonary tuberculosis. J Thorac Dis 2012;4(6):617-623. 52. Deveci A1, Coban AY, TanrıverdiÇaycı Y, Acicbe O, TaşdelenFışgın N, Akgüneş A, Ozatlı D, UzunM,Durupınar B. [In Vitro Effect of Ankaferd Blood Stopper®, a Plant Extract Against Mycobacterium tuberculosis Isolates].[Article in Turkish]. Mikrobiyol Bul. 2013 Jan;47(1):71-8. 53. Arjanova OV1, Prihoda ND, Yurchenko LV, Sokolenko NI, Vihrova LA, Pylypchuk VS, Frolov VM, Kutsyna GA. Enhancement of efficacy of tuberculosis drugs with Immunoxel (Dzherelo) in HIV-infected patients with active pulmonary tuberculosis. Immunotherapy. 2009 Jul;1(4):549-56. doi: 10.2217/imt. 09.25. 54. Efremenko YV1, Arjanova OV, Prihoda ND, Yurchenko LV, Sokolenko NI, Mospan IV, Pylypchuk VS, Rowe J,Jirathitikal V, Bourinbaiar AS, Kutsyna GA. Clinical validation of sublingual formulations of Immunoxel (Dzherelo) as an adjuvant immunotherapy in treatment of TB patients. Immunotherapy. 2012 Mar; 4(3):273-82.

Tuberculosis Today & Tomorrow Dr. G. Srividhya, Associate Professor Department of Pulmonary Medicine, Shri Sathya Sai Medical College and Research Institute, Sri Balaji Vidyapeeth, Nellikuppam, Kancheepuram Dist., Tamil Nadu – 603 108, India.

Epidemiology: Tuberculosis (TB) is second only to HIV/AIDS as the greatest killer disease worldwide due to a single infectious agent. In 2014, 9.6 million people were diagnosed with TB, of which 1.2 million people were diagnosed with HIV(1). 5.4 million men were diagnosed with the disease. An estimated 1 million children were struck with TB. The largest number of new TB cases occurred in the SouthEast Asia and Western Pacific Regions, accounting for 58% of new cases globally in 2014. The 6 countries that contribute to largest number of incident cases in 2014 were India, Indonesia, Nigeria, Pakistan, People’s Republic of China and South Africa. Death due to TB in 2014.

TOTAL DEATHS DUE TO TB

1.5 MILLION

DEATH DUE TO TB IN HIV

0.5 MILLION

DEATH DUE TO TB IN WOMEN

4,800,000

DEATH DUE TO TB IN WOMEN WITH HIV

1,40,000

DEATH DUE TO TB IN MEN

8,90,000

DEATH DUE TO TB IN CHILDREN

1,40,000

Drug-Resistant TB: Globally in 2014, an estimated 480 000 people developed MultiDrug-Resistant TB (MDR TB) and there were an estimated 190 000 deaths from MDR TB. 123 000 people were diagnosed with MDR TB in 2014, about a quarter of the total 480 000 new cases of MDR-TB that occurred in 2014. Globally, data show an average cure rate of only 50% for treated MDR-TB patients.

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Ann. SBV, July-Dec 2015;4(2)

Extensively drug-resistant tuberculosis, or XDR-TB, is a strain of tuberculosis, that is resistant to four commonly used anti-TB drugs ( INH,RIF,one injectable second line drug & quinolones). XDR-TB has been reported by 105 countries by 2015. An estimated 9.7% of people with MDR-TB have XDR-TB. There are an estimated 40,000 people infected with XDR-TB today. XDR-TB is emerging as an extremely deadly global threat. There is no regulatory-approved regimen for curing XDR-TB. Treatment of XDR-TB is difficult because of longer duration of treatment with drugs that have serious toxicity & cost of treatment is also very high.

Recent Advances in diagnosis of Drug Resistant TB: The use of the rapid test Xpert MTB/RIF has been in use since 2010. By 2015, 69% of countries recommended using Xpert MTB/RIF as the initial diagnostic test for people at risk of drug-resistant TB, and 60% recommended it as the initial diagnostic test for people living with HIV. The Xpert MTB/RIF assay, detects Mycobacterium tuberculosis with a limit of detection (LOD) of 130 CFU/ml sputum, and detects mutations in the MTB rpoB gene which cause rifampicin resistance (RIF-R).

Disadvantages of Xpert MTB/RIF: 1. Limited sensitivity (60 – 80%) in smear-negative TB. 2. False RIF resistance have been reported which is attributed to abnormal real-time PCR curves or missidentification of RIF-susceptible (RIF-S) synonymous rpoB mutants as RIF-R. An upfront in diagnostic test for MDRTB called the GeneXpert Omni is in development. GeneXpert Omni by the virtue of its portability caters to molecular diagnostic testing into disseminated locations. Page 13

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Advantages of GeneXpert Omni • Small and Portable • Proven Cartridge Technology • Durable • Low Power Consumption • Automatic Connectivity • Solid State • Integrated Battery A next-generation cartridge called GeneXpert Ultra is also in development. This could potentially replace conventional culture as the primary TB diagnostic tool. The Xpert MTB/ RIF Ultra is a cartridge-based nested PCR amplification capable to amplify patient DNA sample more accurately. The current Xpert MTB/RIF test has a limit of detection (LOD) of 130 CFU/ml. A larger DNA reaction chamber in the cartridge will enable Xpert MTB/RIF Ultra to bring the LOD down ten-fold, to approximately 10 CFU/ml (across all strains) — a level similar to or potentially better than liquid culture. The new Ultra assay is much more sensitive than Xpert & the specificity of Ultra RIF-R is likely to be higher. The Ultra assay is expected to increase TB detection in smear-negative patients and provide more reliable RIF-R detection.

Recent Advances in Treatment of Tuberculosis:

From the above line diagram it is quite evident that there has been no discovery in the anti tubercular treatment over the past 45 years. Short falls of current TB regimens: • Long duration of treatment ( 6-9 months duration ) • High relapse rate in some subgroups (15%) • Interactions with HIV treatment • Inadequate drugs to treat XDR strains. Why do we need new drugs to treat TB? • Shorten overall treatment duration • Lower relapse rates • Development of regimens with fewer adverse effects, particularly less hepatotoxicity • Novel drugs that can be given easily and safely in combination with Anti Retroviral Therapy • Regimens that are effective in treating MDR-TB/ XDR-TB & shorten the duration of treatment.

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Novel drugs in clinical trials are: NEWER DRUG

PHASE OF CLINICAL TRIAL

DELAMANID

PHASE 2

PA 824

PHASE 2

SQ109

PHASE 2

LL 3858

PHASE 2

SUTEZOLID

PHASE 2

AZD -5847

PHASE 1

Repurposed drugs include members of the fluoroquinolone, oxazolidinone, riminophenazine and rifamycin families. Bedaquiline is a diarylquinoline which inhibits Mycobacterial ATP Synthase & approved by the FDA in December 2012, & it was the first new medicine formulated against TB after forty years. Considerable controversy exists regarding approval of the drug, as the FDA’s ruling was based on a treatment outcome Vs patient deaths. In the clinical trials, death rates among patients taking Bedaquiline were more (a rate of death of 11.4% in the treatment group, compared to 2.5% in the control group)(5), even though they had resolution of TB based on sputum cultures. It is for this reason that the label comes with a caution of “INCREASED MORTALITY; QT PROLONGATION” & it is used only when an effective alternative treatment regimen is not available. Delamanid (OPC67683), a dihydro-nitroimidazooxazole derivative is an experimental drug for the treatment of MDR TB .It is a pro-drug that is activated by the enzyme deazaflavin dependent nitroreductase (Rv3547). A reactive intermediate metabolite, formed between delamanid and desnitro-imidazooxazole derivative, is known to inhibit mycolic acid production. It inhibits the synthesis of mycobacterial cell wall components, namely the methoxy mycolic acid and ketomycolic acid . Delamanid also causes QT prolongation(6). Delamanid was associated with an increase in sputumculture conversion at 2 months among patients with MDR TB. Delamanid remains a promising drug in treating MDRTB, XDR-TB, and TB in HIV because of its better efficacy, minimal toxicity, and absence of interaction with ART. Pretomanid (PA 824) is a bicyclic nitroimidazole-like molecule with a very complex mechanism of action. It is active against both replicating and hypoxic, non-replicating Mycobacterium tuberculosis. The aerobic bactericidal mechanism of this drug appears to involve inhibition of cell wall mycolic acid synthesis. The respiratory poisoning through NO release seems to be important for its anaerobic activity . Ann. SBV, July-Dec 2015;4(2)

The combination of Moxifloxacin, Pretomanid, and Pyrazinamide (MPaZ regimen)(4) with the aim of shortening the duration of treatment is under trial . In phase 2 trial it was a safe, well tolerated regimen with better bactericidal activity in drug-susceptible tuberculosis during 8 weeks of treatment. Results are consistent with both drug-susceptible and MDR tuberculosis. This regimen is ready for phase 3 trials in patients with drug-susceptible tuberculosis and MDR-tuberculosis. Nix-TB tests a 3 drug regimen consisting of Bedaquiline, a drug with conditional regulatory approval; Pretomanid, which is under trial; and linezolid, an oxazolidinone antibiotic that has been used off-label to treat TB. This trial may be effective in people with XDR-TB who have no other treatment options. It includes patients as young as 14 and those who are co-infected with HIV with a CD4 count of 50 or higher. Nix-TB is an open-label trial that enables patients to be assessed at regular intervals with the aim of being cured in six to nine months. Participants are also monitored for two years after completing treatment to ensure they do not relapse.

Newer Vaccines The only vaccine against M. TB, Bacille Calmette-Guérin (BCG), discovered in 1921, has variable protective efficacy. WHO recommends vaccinating HIV-uninfected infants with BCG as it provides protection against severe extrapulmonary forms of paediatric TB. However its efficacy in protecting against pulmonary TB is variable . A safe, effective and cheap vaccine against TB will contribute to a great advance in the control of Tuberculosis. 16 TB vaccine candidates are in Phase IIb studies in the field at present. 5 of which are based on whole cell mycobacteria, and the rest are sub-unit vaccines in which MTB antigens are expressed as recombinant proteins that are formulated with adjuvants or presented in recombinant viral vectors. “Modified Vaccinia Ankara”, MVA- a pox virus vectored vaccine expressing the Mycobacterium tuberculosis antigen 85A, is under phase IIb “Proof-of-concept” (PoC) trial in South Africa. Current TB vaccine candidates are designed to be either • A prime vaccine that prevents TB infection as well as disease in infants who have not been infected with MTB.

Ann. SBV, July-Dec 2015;4(2)

• A booster vaccine, which when administered during adolescence would prevent reinfection or arrest progression to active disease for those who are latently infected, as BCG immunity wanes. • Immunotherapeutic vaccine as an adjuvant with ATT for TB patients, to shorten the duration of treatment and/or reducing relapse rates.

Auxotrophic Vaccine To overcome the adverse affects of BCG vaccines in immunodeficient patients , auxotrophic strains of BCG are under study to assess their safety profile and efficacy against tuberculosis in people at risk for HIV.

DNA Vaccine A novel tuberculosis (TB) vaccine; a combination of the DNA vaccines expressing mycobacterial heat shock protein 65 (HSP65) and interleukin 12 (IL-12) delivered by the hemagglutinating virus of Japan (HVJ)-liposome orenvelope (HSP65 + IL-12/HVJ) is under development. The addition of IL-12 was found to augment Th1 response in a dose-dependent manner and offered a protective immune response against a virulent challenge.

Subunit Vaccine By using the techniques of recombinant DNA, several antigens like heat shock protein (hsp) 60, hsp70, Ag85, ESAT-6 and CFP10 etc have been identified as new candidate vaccines against TB.(7) The ESAT-6 antigen from Mycobacterium tuberculosis is a dominant target for cell-mediated immunity in the early phase of tuberculosis (TB) in TB patients as well as in various animal models. Vaccination with ESAT-6 delivered in a combination of monophosphoryl lipid A(MPL) an immunomodulator and dimethyl dioctadecyl ammoniumbromide (DDA) provoked a strong ESAT-6specific T-cell response and protective immunity comparable to that achieved with Mycobacterium bovis BCG has been showed in various studies.

Adjuvants There is a marked difference in the immune responses induced by the different adjuvants and both IFA (incomplete Freund’s

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Annals of SBV

adjuvant), (DDA) are identified as potential adjuvants for a TB subunit vaccine. DDA coadjuvanted with either the Th1-stimulating polymer poly (I-C) or other cytokines like IFN gamma, interleukin 2 (IL-2), and IL-12 are under trial(8).

References: 1. WHO Global Tuberculosis Report 2015. 2. Multidrug-resistant tuberculosis (MDR-TB) 2015 update. 3. Xpert MTB/RIF Ultra: A New Near-Patient TB Test With Sensitivity Equal to Culture David Alland, Rutgers New Jersey Medical School, Newark, NJ, United States.

4. Expert Opin Investig Drugs. 2013 Jul;22(7):927-32. doi: 10.1517 /13543784.2013.801958. Epub 2013 May 21. PA-824, moxifloxacin and pyrazinamide combination therapy for tuberculosis. 5. Dawson R, Diacon A. Mahajan, R. (2013). Bedaquiline: First FDA-approved tuberculosis drug in 40 years”. International Journal of Applied and Basic Medical Research 3(1): 1–2. 6. Gler, M. T et al .Delamanid for Multidrug-Resistant Pulmonary Tuberculosis. New England Journal of Medicine 2012; 366 (23): 2151–2160. 7. Current Pharmaceutical Biotechnology, Volume 2, Number 2. 8. Biotechnology in the Development of New Vaccines and Diagnostic Reagents Against Tuberculosis.

Tuberculosis In Pregnancy Dr. Sathiyakala Rajendiran, Associate Professor Dr. Suthanthiradevi, Professor & Head Department of Obstetrics & Gynecology, Shri Sathya Sai Medical College and Research Institute, Sri Balaji Vidyapeeth, Nellikuppam, Kancheepuram Dist., Tamil Nadu – 603 108, India.

Introduction

Screening tests

Tuberculosis is a common air-borne infection which affects one-third of world’s population. There are 8 million new cases and 2 million deaths every year due to tuberculosis as per estimates.(1)

Tuberculin skin test and interferon gamma release assays are the two screening tests for detecting tuberculosis, available at present.

India accounts for 30% of the burden of all tuberculous cases in the world.2 90% of the infected patients remain dormant and only 10% of the infected patients exhibit active tuberculosis.

Tuberculosis and pregnancy As tuberculosis in India is more prevalent in the general population, it is not uncommon to find pregnant women being infected by tuberculosis .Incidence and mode of transmission of tuberculosis are not altered by pregnancy. Pregnancy doesn’t alter the clinical course of tuberculosis. Dormant infection during pregnancy doesn’t cause any major maternal or fetal adverse outcomes. Active infection results in preterm delivery, low birth weight, intrauterine growth restriction and increase in perinatal mortality. The outcome of pregnancy depends on the site of infection and timing of diagnosis in relation to delivery. Extra pulmonary tuberculosis accounts for 20% of the tuberculosis infection.(3) During pregnancy, extra pulmonary site infections such as renal ,intestinal, skeletal and meningeal tuberculosis has been reported.(4) Congenital tuberculosis is a rare complication of in-utero tuberculous infection due to maternal hematogenous spread. Only 300 cases have been reported in literature.(5) Page 16

Ann. SBV, July-Dec 2015;4(2)

Tuberculin skin test: In this test, purified protein derivative (PPD) of intermediate strength -5 tuberculin units, is used. If intracutaneous administration of PPD results in induration of ≥5mm, it is considered positive and further evaluation with chest radiograph (with lead shielding of abdomen) is needed. If the induration is ≥10mm, no further evaluation is needed and treatment should be initiated. HIV testing should be offered to all tuberculin skin test positive patients. In India, as the prevalence of tuberculosis is high, more than 50% of the Indian population show tuberculin skin test positive. Hence, tuberculin skin test is of limited value for screening in India.(6) Pregnancy doesn’t affect the response to tuberculin skin test.(7) But in immunocompromised patients such as HIV infected patients, induration of ≥5mm should be considered an indication for treatment without further evaluation. Interferon Gamma Release Assays (IGRAs): IGRA is a blood test which measures interferon gamma release in response to antigens present in mycobacterium tuberculosis but not Bacille-Calmette Gue’rin(BCG).The two IGRAs available are QuantiFERON –TB Gold and T –SPOT. IGRAs are highly reliable in diagnosing tuberculosis especially during pregnancy.(8)

Diagnosis The symptoms of active tuberculosis in pregnancy include low grade fever, cough with minimal sputum, hemoptysis and weight loss. Chest radiograph shows infiltrative patterns, Page 17

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Annals of SBV

cavitation or mediastinal lymphadenopathy. Stained smears of sputum shows acid fast bacilli. Sputum AFB culture can also be done to confirm the diagnosis. Nucleic acid amplification assay and drug sensitivity testing can also be done.

Isoniazid (INH) prophylaxis The indications for giving INH prophylaxis during pregnancy include tuberculin skin test positive, HIV positive or recent tuberculosis exposure. Pyridoxine in the dosage of 25 to 50 mg/day, should be given along with INH, to prevent neuropathy.

Safety profile of antitubercular drugs(9) Though Isoniazid (H), Rifampicin(R) and Ethambutol (E) cross the placenta, they do not cause teratogenicity in fetus. Isoniazid and Ethambutol belong to pregnancy category A drugs. Rifampicin belongs to pregnancy category C drugs. Pyrazinamide (Z) is pregnancy category B2 drug. Pyrazinamide is gaining popularity for use during pregnancy and is recommended by WHO and International Union Against Tuberculosis and Lung disease. Hence, all the four drugs (HRZE) can be safely used during pregnancy. Drugs which are proved to be teratogenic, and hence contraindicated during pregnancy include Streptomycin, Kanamycin, Amikacin, Capreomycin and Fluoroquinolones.

Treatment during pregnancy In active tuberculosis cases, the four drug regimen (HRZE +pyridoxine )is recommended. In the first two months, the bactericidal phase, HRZE is given. In the next four months, the continuation phase, HR is given.(8) Liver function test is done every month to rule out hepatic dysfunction due to anti tubercular treatment. There are no specific recommendations for labour and delivery except infection precautions for active disease.

Treatment in postpartum period There is increased risk for hepatic dysfunction in the postpartum period if the mother is on anti tubercular treatment. Hence strict surveillance of liver function test is recommended. Isolation of baby from the mother is not needed but contact should be limited. The mother should wear a surgical mask until she becomes smear negative. Breast feeding is not contraindicated. The prognosis is bad

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if tuberculosis is diagnosed at late stage of the disease in the postpartum period. If there is no clinical suspicion of congenital tuberculosis, after obtaining gastric aspirate from the infant, INH prophylaxis (10mg/kg/day) with pyridoxine (5mg daily) should be commenced and continued for three months. If the tuberculin skin test is negative at three months, BCG vaccine should be given .In case of positive tuberculin test in the baby, INH prophylaxis is given for six months after ruling out active tuberculosis.Even though antitubercular drugs are secreted in breast milk, the concentration is so low that neither therapeutic nor toxic level is reached in the baby. Hence, appropriate anti tubercular treatment must be given for baby with active disease.

References 1. Dye C, Scheele S, Dolin P, et al.Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project. JAMA Aug 1999; 282(7):677-86. 2. World Health Organisation; Research for Action :understanding and controlling tuberculosis in India; 2000:12. 3. Wilson E. Thelin T, Dilts P. Tuberculosis complicated by pregnancy. Am J Obstet Gynaecol 1972; 115:526-31. 4. Jana N, Vasishta K, Saha SC, Ghosh K.Obstetrical outcomes among women with extrapulmonary tuberculosis.N Engl J Med. Aug 1999; 341(9):645-9. 5. Armstrong L, Garay SM. Tuberculosis and pregnancy and tuberculous mastitis. In: Rom WN, Garay SM eds Tuberculosis. Boston. Little Brown and Company; 96:89-98. 6. Bhide A, Arulkumaran S, Damania KR, Daftary SN. Arias’ Practical Guide to High Risk Pregnancy and Delivery. A South Asian perspective. 4th edition. 328-330.

7. Present P, Comstock GW. Tuberculin sensitivity in pregnancy. Am Rev Respir Dis 1975; 112 : 413-16. 8. Cunningham, Leveno, Bloom et al. Williams obstetrics. 24th edition.1019-1021. 9. Guideline -Treatment of tuberculosis in pregnant women and newborn infants. version 3. Department of health-Queensland. 10. Török ME, Yen NT, Chau TT et al.Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV) associated tuberculous meningitis. Clin Infect Dis. 2011 Jun; 52(11):1374-83. 11. Blanc FX, Sok T, Laureillard D et al. CAMELIA Study Team. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med. 2011 Oct 20; 365(16):1471-81. 12. Havlir DV, Kendall MA, Ive P, Kumwenda J et al. AIDS Clinical Trials Group Study A5221. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med. 2011 Oct 20; 365(16):1482-91. 13. Karim A, Naidoo K, Grobler A et al. Integration of Antiretroviral Therapy with Tuberculosis Treatment. N Engl J Med. 2011 Oct 20; 365(16):1492–1501.

Multi drug resistant tuberculosis (MDR-TB) Though it’s rare, the morbidity due to MDR-TB is high. There are no existing guidelines for the treatment of MDR-TB and hence, elective abortion should be considered. (8) If the patient wants to continue the pregnancy, counseling should be given regarding the risks of exposing the fetus to the known and unknown side effects of second line drugs. Breast feeding is contraindicated. Isolation of baby from mother should be done until she is smear negative.

Concurrent HIV and tuberculosis infection The prognosis is poor for both mother and baby if there is concurrent HIV and tuberculosis infection. The risk of transmission of both infection to the infant is increased. Treatment of these women is really a challenging one. Beginning concomitant therapy with anti-retroviral and anti-tubercular drugs can cause immune reconstitution inflammatory syndrome (IRIS) with toxic drug effects.10 Recent studies support earlier administration of highly active anti-retroviral therapy(HAART) -within 2 to 4 weeks- after starting antituberculous drugs.(11,12,13)

Prevention BCG vaccination in childhood, isolation of open TB cases and their prompt treatment and screening of all close contacts of tuberculosis-affected patients can prevent the morbidity and mortality associated with tuberculosis in pregnancy. These strategies can also reduce the overall tuberculous disease burden in the world.

Ann. SBV, July-Dec 2015;4(2)

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Childhood Tuberculosis

• Exclusion of co-infection with HIV also has important implications because it often makes the clinical diagnosis.

Treatment

Childhood Tuberculosis Prof. Prema. R, Professor Department Of Paediatrics, Shri Sathya Sai Medical College & Research Institute, Sri Balaji Vidyapeeth, Nellikuppam, Kancheepuram Dist., Tamil Nadu – 603 108, India.

March 24th 1982 was the first ever World T.B Day celebrated!!! “If the number of victims that a disease claims is the measure of its significance, then all diseases, particularly the most dreaded infections such as bubonic plague, asiatic cholera etc must rank far behind tuberculosis” – ROBERT KOCH

Recommendations as per WHO (Sep, 2013) (1) • isoniazid (H) 10 mg/kg (range 7–15 mg/kg); maximum dose 300 mg/ day • rifampicin (R) 15 mg/kg (range 10–20 mg/kg); maximum dose 600 mg/ day • pyrazinamide (Z) 35 mg/kg (range 30–40 mg/kg) • ethambutol (E) 20 mg/kg (range 15–25 mg/kg) • Pharmacokinetic studies show that the revised dosages – Benefits • result in higher blood levels in young children, including those under 2 years of age. • an excellent safety profile • No increased risk of toxicity (drug induced hepatotoxicity due to isoniazid & pyrazinamide, optic neuritis due to ethambutol),

New Strategies Introduction

Diagnosis of Childhood T.B

Tuberculosis (TB) is one of the most frequent infectious causes of death globally. It is the largest killer disease often associated with HIV infection.

• Diagnosis of T.B in children presents as a greater challenge than that in any other groups, due to the varied presentations, difficulties in collecting appropriate samples for testing etc. • There have been many methods of diagnosis and new methods are fast emerging

Of the total population: • 8 million new cases occur every year, with • 2.3 million deaths each year of which 2,50,000 are children India bears nearly 1/4th of the global burden • 3.5 million children in India have T.B • There is 40% chance of infection in children less than 6 years • It increases by 80% by 16 years • From infancy till 10 years of age the risk of infection is inversely proportional to the age. • Still few percentages go undetected. • Children are more likely to develop extra pulmonary TB than adults. • Various predisposing factors are whooping cough, measles, PEM, HIV infection, contact with household T.B and children not immunized with BCG vaccine.(1)

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Methods in recent use

• •

Indian National Strategic Plan 2012-2017, – Aim-early case detection – Achievement of almost 90% cure rate. At present there is no easy way to diagnose latent infection (LTBI), in a highly prevalence setting like our Nation, India.

Further Challenges (2)

• • • •

combating resistance Breaking the HIV and TB partnership Screening the Child laborers Physician patient contact is essential to ensure compliance and assess – toxicity – efficacy of treatment

Prevention

• • • •

Enhanced nutrition, better housing & sanitation Personal hygiene Antenatal screening and management of HIV and AIDS • Health education to children and adults

Conclusion • Challenges and the preventive strategies will reduce the burden of adult TB, reducing childhood TB is an indicator of recent transmission (adult) and thus serves a sentinel event. • Both physician and patient share the responsibility of successful treatment and to reduce the burden of TB TODAY in our nation.

REFERENCE 1. w w w. l i b d o c . w h o . i n t / p u b l i c a t i o n s / 2 0 1 3 / 9 7 8 9 2 4 1 5 0 3 7 0 9 _ eng.pdf. 2. Carlos M. Perez-Velez, Ben J. Marais. Tuberculosis in Children. N Engl J Med 2012; 367:348-361.

• proper diagnosis • Early detection of cases,

• Most recent is the Xpert MTB/RIF assay, which has been developed recently for detection of extrapulmonary TB. • Cochrane database review suggested that there was an overall sensitivity of 88% and a pooled specificity of 98% as compared to culture. • USES OF IGRA: Interferon Gamma Release Assay’s (IGRA) measure the in vitro response to specific M. tuberculosis antigens. While these assays are more specific than TST (tuberculosis skin test) (BCG does not cause a false-positive result), they have not been found to perform better than TST.A positive IGRA indicates infection but does not confirm the disease. • HIV testing is a very important “point-of-care” test that is already widely available.

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Cutaneous Tuberculosis

The incidence is 10-15%, 2-3 times more seen in females and may present as single or few lesions. well demarcated, annular or accurate plaques which slowly spread centrifugally. The periphery shows erythematous to brownish, deep seated nodules which on diascopy may stand out as apple jelly nodules. Centre becomes atrophic in course of time, depigmented and scarred. characteristically, new nodules appear within area of scarring.

Cutaneous Tuberculosis

3. Tuberculosis Verucosa Cutis:

Dr.Jeyakumari Jeevan, Professor. Dr.Srinivasan G, Professor & Head, Department of Dermatology, Shri Sathya Sai Medical College & Research Institute,

Fig 6: Tuberculosis Verucosa Cutis of the foot

Sri Balaji Vidyapeeth, Nellikuppam, Kancheepuram Dist., Tamil Nadu â&#x20AC;&#x201C; 603 108, India.

Introduction Cutaneous tuberculosis has been part of human history since pre-historic period and it has been a global health problem. Due to the HIV epidemic the emergence of resistance strains of M.tuberculosis, the rise in immunosuppressive therapy, the ease of migration of people, decline in TB control efforts, super-imposed on the pre-existing factors of poverty and malnutrition there was rise in the incidence of mycobacterial infection in developing countries. Better living standard and improved treatment methods have led to a decline in the incidence of mycobacterial infections in developed countries.(1) The discovery of M-tuberculosis by Robert Koch in 1882 and advance in descriptive pathology during 19th century helped to establish cutaneous tuberculosis as a part of this infectious diseases.

Classification2

Fig 3: Lupus Vulgaris of the buttocks Sites of predilection: Buttocks, upper extremities and face Complications: Ulcerations, Hypertrophic lesions and squamous cell carcinoma, It needs to be differentiated from Discoid Lupus Erythematous. Fig 1: Spectrum Of Cutaneous Tuberculosis

Fig 7: Tuberculosis Verucosa Cutis of the finger

4. Orificial TB

Clinical variants dependent on the hostâ&#x20AC;&#x2122;s immunity and route of entry. The common presentations of cutaneous TB are lupus vulgaris, scrofulderma, TB verrucosa cutis and tuberculides

1 Lupus Vulgaris: (TB Luposa)

Exogenous sources: Tb chancre, warty Tb and lupus vulgaris.

Fig 4: Scrofuloderma of the foot Figure 5 shows cutaneous TB due to direct extension of the infection from an underlying TB present either in a lymph node (cervical less often, axillary and inguinal), and also seen in bone or a joint.It manifest as chronic sinuses with hyper pigmented undermined edges. Tuberculin test will be positive.

Endogenous sources: contiguous spread-scrofuloderma, Auto inoculation-orificial Tb and haematogenous consisting of miliary Tb, lupus vulgaris and Tb gumma Tuberculides: micro popular, lichen scrofulosorum, popular, Papulo Necrotic Tuberculide and Nodular and Erythema nodosum consisting of Erythema induratum (BAZIN)

2. Scrofuloderma: (TB cutis colliquativa)

Clinical Features3

Fig 2: Lupus Vulgaris of the face

Ann. SBV, July-Dec 2015;4(2)

Fig 8 : Orificial TB Orificial TB is a rare type. Auto inoculation of mucosa or skin adjacent to a natural orifice draining an active internal Tb infection.

5. Acute Millary TB: (TB Cutis Disseminata, TB Cutis Acuta Generalisata) Fig 5: Cutaneous TB of the lymph node

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Tuberculosis Verucosa Cutis is a common form of cutaneous TB, inoculated from outside into a skin of a individual with a high degree of immunity due to previous exposure. It is seen as a single indolent verrucous wart nodule with a serpiginous edge and an erythematous areola with indurate base centre may shows scarring. Often seen on trauma prone sites like hands and feet. Can be easily differentiated from verruca vulgaris

Ann. SBV, July-Dec 2015;4(2)

A rare, hematogenous dissemination from primary lung focus in patients with low immunity Page 23

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6. TB Gumma: (Metastatic TB Ulcer)

Investigations 4

TB Gumma is seen in children with low socio economic status and immune suppressive hosts. It is transmitted by acute heamtogenous dissemination from primary focus,

To confirm Diagnosis of TB we need to do Biopsy. ISOLATION OF M.TUBERCULOSIS: AFB in pus and culture of TB may be possible, but only from some lesions<10%.We can also do PCR test

Postmortem Hazard of Mycobacterium Tuberculosis Dr. Swayam Jothi S , Professor & Head,

Treatment 5

Department of Anatomy, Shri Sathya Sai Medical College & Research Institute,

S.NO

PHASE

DURATION

DRUG

DOSAGE

Intensive Phase (to achieve rapid bacterial killing)

2 months

Isoniazid Rifampicin Ethambutol Pyrazinamide

5mg/kg 10mg/kg 15mg/kg 30mg/kg

Maintenance Phase ( kill persistent bacteria)

4 months

Isoniazid Rifampicin

5mg/kg 10mg/kg

REFERENCES

1. 2. 3. 4. 5.

Bravo FG, Gotuzzo E. Cutaneous tuberculosis. Clin Dermatol. 2007;25(2):173–180. Fariña MC, Gegundez MI, Piqué E, et al. Cutaneous tuberculosis: a clinical, histopathologic, and bacteriologic study. J Am Acad Dermatol. 1995;33(3):433–440. MacGregor RR. Cutaneous tuberculosis. Clin Dermatol. 1995;13(3):245–255. Barbagallo J, Tager P, Ingleton R, et al. Cutaneous tuberculosis: diagnosis and treatment. Am J Clin Dermatol. 2002;3(5):319–328. Dinnes J, Deeks J, Kunst H, et al. A systematic review of rapid diagnostic tests for the detection of tuberculosis infection. Health Technol Assess. 2007;11(3):1–196.

Sri Balaji Vidyapeeth, Nellikuppam, Kancheepuram Dist., Tamil Nadu – 603 108, India.

Tubercular decay has been found in the spines of Egyptian mummies in the British Museum. Tuberculosis has been present in humans since antiquity. The earliest unambiguous detection of M. tuberculosis involves evidence of the disease in the remains of bison in Wyoming dated to around 17,000 years ago. Cadavers are the main studying material of Anatomists.1 Mycobacterium tuberculosis, hepatitis B and C, the AIDS virus HIV and prions are the infectious pathogens of risk for those who handle the dead bodies during embalming procedures and dissection of cadavers. Tuberculosis affects not only lungs but many of the organs of the body.The organism is an acid fast bacillus.The risk of acquiring tuberculosis varies according to occupation and Anatomy department workers are at particular risk of contracting tuberculosis carried by cadavers2-4.Embalming cases known to be infectious with M .tuberculosis, hepatitis B and C. HIV and prions should be avoided. Every cadaver should be regarded as an infectious material. But if the bodies are to be embalmed for a short duration or for transportation, the task is undertaken. When the cause of death is not known, people involved are at risk for the following reasons. First, in suspension tests,the cell-free infectious agent is tested,whereas in humans,some infective agents can localize within cells. Second, the concentration of the embalming fluid components decreases as they diffuse throughout the human body.Third, several classes of products, including formalin,alcohols and phenolic agents are partially inactivated by the presence of protein. This sensitivity to organic load suggests that the efficiency of the disinfectants will be much lower in cadavers than in vitro tests.5 Fourth, although a certain fixatives at certain levels may be cidal to a single agent or even a group or class of

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Ann. SBV, July-Dec 2015;4(2)

infectious agents, other agents that co exist may survive as mentioned above thus complete disinfection may not be accomplished. This being the situation an attempt was made by taking up a small project work on 28 cadavers with 84 samples of body fluids from them for Gram’s and AFB staining techniques. All were negative.6However,the following precautions have to be followed. Universal precaution while embalming. Vaccination is must for all who handle cadavers against Hepatitis B and M. tuberculosis7 One must update their knowledge in this field to help ensure the safety of all educators,researchers, and students under their charge.

References: 1. Aziz MA, Mckenzie JC, Wilson JS ,Cowie RJ,Ayeni SA, Dunn BK. 2002. The human cadaver in the age of biomedical informatics. Anat Rec (New Anat) 269:20-32. 2. Smith GS. 1953 Tuberculosis as a necropsy room hazard. J Clin Pathol 6 :132-134. 3. Sterling TR, Brehm WT, Moore RD, Chaisson RE.1999. Tuberculosis vaccination versus isoniazid preventive therapy: A decision analysis to determine the preferred strategy of tuberculosis prevention in HIV-infected adults in the developing world. Int J Tuberc Lung Dis 3:248-254. 4. Kappel TJ, Reinartz JJ, Schmid JL, Holter JJ Azar MM. 1996. The Viability of Mycobacterium tuberculosis in formalin fixed autopsy tissue; Review of literature and brief report. Hum Pathol 27:1361-1364. 5. De Craemer D. 1994, Postmortem viability of human immunodeficiency virus implications for teaching of anatomy. N Eng J Med 331:1315. 6. Karthika Jayakumar, Swayam Jothi: 2012. Safety in Handling of cadavers International journal of Medical and Clinical Research Vol: 3,Issue 3,2012,pp140-142. 7. Sterling TR.Pope DS, Bishai WR, Harrington S, Gershon RR, Chaissson RE. 2000.Transmission of Mycobacterium tuberculosis from a cadaver to an embalmer. N Engl J Med 342:246-248.

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A Review of Current Status of Tamil Nadu under Revised National Tuberculosis Control Program

In 2014, TamilNadu has an incidence of 108 TB cases / 1lakh population. The Pediatric cases out of total new cases are 3385 (5%). the registration and the start of treatment are satisfactory as 83% of smear positive cases are started on treatment within 7 days of diagnosis. As the Intensive Phase is given in most parts in PHCs, initial follow up and end of treatment follow up are good. 82% of cases are tested for follow up sputum at the end of the treatment within 7 days of last dose.

A Review of Current Status of Tamil Nadu under Revised National Tuberculosis Control Program Dr.V.Uma Devi, Professor& Head, Department of General Medicine, Shri Sathya Sai Medical College & Research Institute, Sri Balaji Vidyapeeth, Nellikuppam, Kancheepuram Dist., Tamil Nadu – 603 108, India.

Introduction Tuberculosis remains worldwide public health problem despite the fact the causative organism was discovered more than 100 years ago and highly effective drugs are available. Tuberculosis is a top infectious disease killer in the world. It occurs in every part of the world. The largest number of TB cases occurred in South East Asian and Western Pacific Region. About 80% of total reported cases occurred in 22 countries in 2014 with Africa topping the list with a prevalence of 281/ 1 lakh. (Compared to world average 133/1lakh). Tuberculosis is one of the leading causes of mortality in India- killing -2 persons every three minute, nearly 1,000 every day. Currently India has a TB prevalence of 197/1 lakh. Around 2200 new cases of tuberculosis are reported in India in 2014(ranging from 2000 – 2300 in various regions of India). Around 220 people have died in 2014 in India due to Tuberculosis alone. TB affects all ages and both sexes. It is a social disease with medical aspects and is a measure of social welfare.1

Nationwide Control Measures TB control was started in way back in 1962 with National Tuberculosis Control Programme. Domiciliary treatment was recommended under NTCP with a standard drug

treatment for 12-18 months. Priority was given to newly detected patients than re-treatment cases and drugs supplied free of cost. Chemotherapy of TB underwent revolutionary changes in the seventies owing to the availability of two well-tolerated and highly effective drugs – Rifampicin and Pyrazinamide. These drugs allowed short course chemotherapy (SCC) and made it possible to simplify treatment and reduce its duration. By 1992 under revised national tuberculosis control programme the short course chemotherapy under direct observation was made the corner stone of the control programme. The strategy of Directly Observed Treatment, Short-course (DOTS) is based largely on research done in India in the field of TB over the past 35 years and is adopted in >180 countries.

Revised National Tuberculosis Control Program (RNTCP)

Fig 1: TB suspects examined/1lakh population One of the major policy decision taken by RNTCP in the year 2010 is to change the focus of the NSP case detection objective of at least 70 % to the concept of universal access to good quality care for TB patients. There is now global consensus that the twin objectives of 70/85 alone is not enough to achieve adequate reduction of TB transmission and reduction in disease burden at the pace with which epidemiological impact is expected (Fig 1). With the aim of improving the collection of patient care information, in May 2012 India declared TB to be a notifiable disease (Fig 2). This means that in future all private doctors, caregivers and clinics treating a TB patient must report every case of TB to the government. for this purpose the government uses a portal NIKSHAY. By 2014, 1845 TB patients are notified by the private sector.

In Tamil Nadu, Revised National Tuberculosis Control Program(RNTCP) is implemented since 2001.Today RNTCP covers 33 districts in Tamil Nadu with a total population of 754.72 lakhs. In the year 2013 about 6, 59,389 presumptive TB cases were screened and 80,407 patients were registered for TB. There are 220 TB units and 784 Designated Microscopy Centres across the state to carry on the diagnosis and treatment of TB. The total TB case notification in Tamil Nadu was 109 cases per lakh per year for the year 2013.

Ann. SBV, July-Dec 2015;4(2)

Among the smear positive cases, 84% cure rate is achieved in Tamil Nadu. 5% of the smear positive patients died. 2% failure and 4% defaulters were reported. 64% cure rate is achieved in retreatment cases with 2% going for DOTS plus treatment The pitfalls in RNTCP are that (1) The Programme mostly emphasis on identifying the case and registering for the treatment and does not emphasize on health education for continued treatment and follow up. (2)

Continuous and adequate supply of all drugs is of paramount importance in the success of DOTS. as complete treatment with DOTS reduces the emergence of resistance thereby promoting the individual’s as well as the country’s economy as the treatment with DOTS plus is highly costly and tiresome . (3)

In case of category I failure instead of adding one other drug it would be better to treat as per drug sensitivity. Also the current 2nd line drugs used in regimen are available in the market and most commonly used for various other illnesses which may be a cause for resistance. (4)

Fig 2: Incidence of TB cases notified /1lakh population in India Page 26

The current upsurge of tuberculosis in previously controlled western countries is due to HIV infection. TB is the most common opportunistic infection in HIV and both disease virtually co-exist that in the RNTCP all patients receiving ATT are counseled for HIV testing and treated according to HIV status. In 2014, 110 cases of TB with HIV positive are reported in India (8.3/1lakh) ranging from 96 to120 in different regions. in Tamilnadu, 92% of the TB patients know the HIV status and 6% are HIV positive. Number of HIV infected TB patients who are put on ART are 79% and those put on cotrimoxazole prevention treatment is 90%.2

Ann. SBV, July-Dec 2015;4(2)

Training of doctors in diagnostic skills is necessary to correctly exclude other mimicking conditions like silicosis and finding out the probable cases as a considerable prevalence and spread are attributable to non-diagnosis.

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The uncertainty of sputum smear negative cases may continue to spread infection in the community, if their x –rays are found inconclusive.(5) Enabling public–private partnership to prevent dropouts and emergence of resistance the social stigma associated with TB should be curbed with appropriate IEC and political commitment for TB has to be increased. Community participation and the role of NGOs

should be increased further for the sustained implementation and success of DOTS.

REFERENCEs 1. Annual report of RNTCP-2014. 2. Global burden of Tuberculosis-2015 by WHO.

Danio rerio (Zebrafish): A Cost Effective Animal Model For Anti-Tuberculosis Drug Research Glad Mohesh M I, Assistant Professor Narasimha Rao B, Professor & Head Department of Physiology, Shri Sathya Sai Medical College & Research Institute, Sri Balaji Vidyapeeth, Nellikuppam, Kancheepuram Dist., Tamil Nadu – 603 108, India. e-mail: gladmohesh@gmail.com

Abstract 

Animal models help us to understand and explore disease mechanisms. Every disease causing organism has its own evolving genome and interacting ways with the environment, which demands new animal models for studying them. Versatile and cost effective disease models are always in demand for drug discovery. Laboratory mouse and rat animal models, though well appreciated in the fields of drug discovery and basic science research is getting replaced with the disease models of Zebrafish as they are easy to breed, hold and discard. Cost effectiveness and the less implied Animal ethics regulations have made researchers in the West to shift to this model. Although Zebrafish models on various diseases are available, tuberculosis disease model is discussed here for the benefit of researchers interested or involved in anti-tuberculosis drug discovery.

Key Words: Antituberculosis, Drug discovery, Zebrafish, Animal model.

Introduction Robert Koch, the celebrated German physician and microbiologist discovered the causative agent of tuberculosis, Mycobacterium tuberculosis in the year 1882.1 Since then, there is a severe competition among the drug discoverers in developing a drug that could hunt down this menace. The race is still on with the emergence of more complex and virulent MDR and XDR strains of the tubercle bacilli. Annual Tuberculosis report (2015) of WHO reports TB as one of the major health problem in the South East Asian region of the World with an estimated incidence of 3.4 million new cases of TB occurring each year. 2 India stands first among the 22 high TB burden countries in the World with 24% of the estimated global incidence and 20% of global TB related deaths. In this existing critical situation and with our research institutes joining the race in the field of Page 28

Ann. SBV, July-Dec 2015;4(2)

drug discovery against this microbe, it becomes necessary to introduce to the early career researchers interested in antituberculosis research with this easy to set-up, cost effective and feasible research unit in their respective work place. The disease model to be discussed, Mycobacterium marinum is not the direct tuberculosis animal model but a surrogate model that’s genomically so close to that of the original.

Zebrafish- An introduction Dania rerio (Zebrafish) is a tropical fresh water fish native to India, Bangladesh, Nepal and Burma. It belongs to the family Ciprinidae. Adult fishes grow to a size of 4cm in length with a lifespan of 4 years. They become fertile by 4-5 months after the hatch. They bear the name of zebra for the blue stripes they have on the side of the body. Sexual dimorphism exists and is easy to identify. They grow well with the commonly available aquarium food flakes and breed Page 29

Danio rerio (Zebrafish): A Cost Effective Animal Model For Anti-Tuberculosis Drug Research

Annals of SBV

easy in captivity. Thereby raising the fries and to convert the available lab space into a small animal breeding and holding unit is possible with the purchase of a few small aquarium tanks.

Danio rerio (Zebrafish)

standardized methodologies available for both transgenesis and gene knockdown techniques, they serve best animal models.4 There are well established Zebrafish disease models for diseases like Parkinson’s disease 5-7 Kidney function,8 Porphyria, Ocular disorders, Cardiomyopathy, Muscular dystrophy, Ear defects, Alzheimer’s disease, Melanoma, Pancreatic carcinoma and other Intestinal cancers.9 Although the common mouse model has occupied a strong position in the scientific labs due to its mammalian physiology, experimental limitations are there to use them in large scale studies which requires space, manpower and money. Zebrafish has its own advantages with its small size, easy to breed and hold. Also the entire development of the embryo takes place outside the body and is highly transparent to visualize, intervene and document the changes or results. At least 70% of human protein coding genes including disease causing genes have ortholog in Zebrafish which suggests its importance for disease modeling.10 With our understanding on the genetic basis of human diseases and with our expertise in deep sequencing strategies, there is a rise in the number of Zebrafish cancer disease models. Thus Zebrafish disease models are becoming an authentic alternative for mouse or rat models.

Tuberculosis disease model in Zebrafish

AFB stain shows positive for M.marinum

Zebrafish as a disease model Dr. George Streisinger, in the early 1970’s from the University of Oregon established Zebrafish as an animal model for genetic studies.3 Later, his colleagues developed the embryonic developmental map for the same. Zebrafish, as a vertebrate has similarities to mammals at both the genetic & tissue levels thereby with the available

Page 30

As discussed earlier, Tuberculosis is a deadly disease and the hunt for better drugs is happening across the globe. Tuberculosis disease burden in India is huge and devastating with the emergent of drug resistant tubercle bacilli. A surrogate model for tuberculosis on Zebrafish will serve the purpose for the preliminary screening of synthetic or herbal anti-tuberculosis drug formulations. In 1926, Mycobacterium marinum that causes fish tuberculosis was first isolated. M. marinum being a genetically close associate to Mycobacterium tuberculosis infects Zebrafish easily. Exposure to infected fish or to the aquarium water causes cutaneoous infections in humans.11 This bacteria does not grow in temperature of more than 370C 12 and it has a relatively short generation time. Though M.marinum is associated to M.tuberculosis, it does not have the potency to affect humans, except in immunocompromised individuals causing a serious threat. However M.marinum can be handled safely in a lab using BSL – II precautions.13 The parameters for the effect of the new drug given orally in a disease model for drug discovery can be assessed by estimating change in the bacterial count and body weight. Methodology is validated with anti tuberculosis drugs such as rifampicin, isoniazid, and moxifloxacin.14

Ann. SBV, July-Dec 2015;4(2)

M.marinum infected fish homogenates were cultured in the lab with added antibiotics to avoid contamination with other normal flora 15 µl of bacteria is inoculated intraperitoneally using 29 gauge insulin syringe to make the fish infected with M.marinum. 0.75million bacteria/fish is a standardized quantity(14) Standard drugs like rifampicin or Isoniazid or Ethambutol or even combinations can administered orally & compared with the chosen new drug(5µl/fish)

Group I (n=10) control infected

Group II(n=10) Amoxicillin negative control

Group III (n=10) Rifampicin or equivalent

Group IV (n=10) new drug(X)

Two week study

I. Infection stage (0 - 7th day) - disease confirmed by, 1) the appearance of tuberculous lesions 2) >40% reduction in body weight 3) 500% increase in the MPN assay

II. Treatment stage (8th -14th day) (5µL/fish) drug dosage differs with each drug(to be standardized)

III. Effect of the new drug evaluated by, 1) Recovery in the body weight 2) Reduction in the bacterial load (MPN assay)

Multiple trials with different dosages of the same drug or with combinations of more than one drug can be experimented any number of times as the time period of the entire study is two weeks with <50 small fishes and more importantly within a less budget. Data collection and statistical analysis follows the same as for any other animal studies.

Further Implications Every department can initiate research with this new animal model not only in terms of anti-tuberculosis drug research but also with other basic science research areas like behavioral, hematological, motor and sensory physiology. Institutions can have a well equipped single Zebrafish animal facility that can inbreed fishes and supply to the needy individual researcher. Literature review from Indian subcontinent showed much of the embryonic toxicological research in Zebrafish model than in any other available disease models. It is high time that medical colleges can adopt this model

Ann. SBV, July-Dec 2015;4(2)

as a replacement for the Animal house facility due its cost effectiveness and less or no regulatory issues.

Conclusion Zebrafish infected with Mycobacterium marinum is found to be a validated surrogate model for anti tuberculosis drug research. This cost effective model is gaining much importance and popular among researchers worldwide. It is high time that we need to use this model to discover a drug that could wipe out the tuberculosis menace well before it fails the mankind.

Acknowledgements We thank our Management and Dean for giving us permission to initiate one such Zebrafish animal facility in our department at Shri Sathya Sai Medical College & Research Institute.

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Annals of SBV

*We thank Dr.Karthika Jayakumar, Professor & Head, Department of Microbiology for supporting us to utilize her lab facility and also by giving us the report/photograph of the findings.

References 1. http://www.nobelprize.org/nobel_prizes/medicine/laureates/1905/koch-bio. html. 2. Tuberculosis control in the South-East Region. Annual TB report 2015.WHO. pgs 5-99. 3. http://zfin.org/zf_info/zfbook/zfbk.html. 4. Thomas A Rando. Of fish and men. Nature chemical biology.2014; 10: 91-92. 5. Donglai Shenget al. Deletion of the WD40 Domain of LRRK2 in Zebrafish Causes Parkinsonism -Like Loss of Neurons and Locomotive Defect. PLoS Genetics, 2010; 6 (4): e1000914 DOI: 10.1371/journal.pgen.1000914. 6. Zebrafish as a new model organism for Parkinson’s disease. Rob Willem sen, Wiebren Hasselaar, Herma van der Linde, Vincenzo Bonifati. Proceedings of Measuring Behavior. 2008; 50-51.

7. Panula, P., et al. (2006) Modulatory Neurotransmitter Systems and Behavior: Towards Zebra fish Models of Neurodegenerative Diseases. Zebrafish 2006; 3(2): 235-47. 8. Y. Ito, A. Kato, T. Hirata, S. Hirose, M. F. Romero. Na /H and Na /NH4 -exchange activities of Zebrafish NHE3b expressed in Xenopus oocytes. AJP: Regulatory, Integrative and Comparative Physiology, 2014; DOI: 10.1152/ ajpregu.00363.2013. 9. Julien Ablain1 and Leonard I. Zon. Of fish and men: using Zebrafish to fight human diseases. Trends in Cell Biology December 2013;23(12):584-586. 10. Howe, K. et al. The Zebrafish reference genome sequence and its relationship to the human genome. Nature 2013; 496, 498–503. 11. Bruno, D.W., J. Griffiths, C.G. Mitchell, B.P. Wood, Z.J. Fletcher, F.A. Drobniewski, T.S. Hastings. “Pathology attributed to Mycobacterium chelonae infection among farmed and laboratory-infected Atlantic salmon Salmo salar”. Diseases of Aquatic Organisms. 1998;33: 101-109. 12. Stamm, Luisa M et al. “Mycobacterium marinum escapes from phagosomes and is propelled by actin-based motility”. JEM. 2003; 198: 1361-1368. 13. L. Ramakrishnan, Images in clinical medicine. Mycobacterium marinum infection of the hand, N. Engl. J. Med. 1997; 337:612. 14. Jonnalagadda Padma Sridevi, Hasitha Shilpa Anantaraju, Pushkar Kulkarni, Perumal Y, Dharmarajan Sriram. Optimization and validation of Mycobacterium marinum-induced adult Zebrafish model for evaluation of oral anti-tuberculosis drugs. International Journal of Mycobacteriology. 2014;3:259-267.

Tuberculosis: Implications for Anaesthesia Dr. Prof Vishwanath R Hiremath, Dr. Pranjali Kurhekar, Dr.Dilip Kumar, Dr.Krishna Prasad. T Department of Anaesthesiology and Critical care, Shri Sathya Sai Medical College and Research Institute, Sri Balaji Vidyapeeth, Nellikuppam, Kancheepuram Dist., Tamil Nadu – 603 108, India.

Abstract 

uberculosis (TB) remains one of the major occupational risk hazards for anaesthesiologist and T health care workers in operation rooms in some of the developing countries. Anaesthesiologists do come across providing anaesthesia for patients with active tuberculosis or problems unrelated to tuberculosis like trauma and for various surgeries.As per the World Health Organization (WHO) reporting in 2013, 9 million new cases are supposed to be suffering from TB; among this 2-3% cases are found to be drug resistant. It is true that effective infection control measures and the availability of effective antibiotics for mycobacterium tuberculosis have decreased the risk of nosocomial infection. However, anaesthesiologist and the health workers in the developing countries are still at the risk of tuberculosis transmission from the patients when compared to their counterparts in the developed countries; due to the lack of adequate resources to prevent nosocomial transmission of tuberculosis. Hence, the special precautions need to be under taken by the anaesthesiologist while providing anaesthesia to these patients. From the patient point of view various drug interactions, side effects of anti-tuberculosis drugs needs to be considered preoperatively along with necessary investigations. Immune compromised patients with co infected HIV have a higher risk of developing tuberculosis.

Key Words: Tuberculosis, Anaesthesia, Nosocomial Infection, Transmission, Drug resistant

Introduction Tuberculosis still remains as one of the world’s commonest communicable diseases. As per the World Health Organization (WHO) reporting in 2013, 9 million new cases are supposed to be suffering from TB; among this 2-3% cases are found to be multi drug resistant(MDR)1,2. India has high incidence and prevalence of disease with high rate of transmission. Prevalence of all forms of TB in India is estimated to be 5.05 per thousand people. Increasing prevalence of TB in the society definitely has significant impact on anaesthetic management. Anaesthesiologist has Page 32

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to face a number of challenges while providing anaesthesia to TB patient. Patient may present with pulmonary or constitutional symptoms which may affect the fitness for surgery and course of anaesthetic management.MDR requires prolonged treatment with 4 to 5 drugs resulting in the increased cost with added risk of side effects. There has been a marked increase in the number of tuberculosis cases, which has paralleled the emergence of HIV3, 4. Anaesthesiologists are commonly involved in providing anaesthesia for TB patients with active disease or problems unrelated to TB like trauma and various other procedures. Risk of nosocomial infection to the anaesthetist and other health care providers in operation room environment5 appears particularly high when there Page 33

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Annals of SBV

is increased exposure combined with inadequate infection control measures. A thorough preoperative evaluation and investigation is essential along with consideration for various drug interactions and adverse effects of anti TB drugs while planning anaesthesia technique.

Patho Physiology Tuberculosis is a communicable disease by Mycobacterium tuberculosis via the airborne small droplets (0.5-5μm). Usually, infection occurs between household contacts with prolonged contact. However, exposure to only a few bacteria is needed to establish infection. Because of its high oxygen tension, the primary site of infection is the upper lobe of the lung, forming the Ghon’s focus. Bacteria invade and replicate within macrophages. This is followed by a T cellmediated response, which walls off the infected cells to form a granuloma. Bacteria within the granuloma can become dormant, resulting in latent infection. At this stage, the patient will be asymptomatic, but may show a positive response to a tuberculin skin test6. Factors that increase the likelihood of progression to active disease include time of exposure (most common in the first year), age of the patient (younger than five years old), and the competency of the immune system7. Infected patient can aerosolize large number of bacteria and efficiently transmit them to the anaesthesia machine when intubated. The pathogens reside in the machine for prolonged periods of time; particularly Y-piece, mask, breathing circuit hoses will become readily contaminated with patient’s secretions.

Diagnosis Traditionally, diagnosis is made by visualizing acid-fast bacilli in the sputum. Newer technology, such as the Xpert®M.tuberculosis/resistance to rifampicin or GeneXpert®, makeuse of real-time polymerase chain reaction to detect specific DNA sequences. They can provide much quicker results (within two hours), as well as information on rifampicin resistance7. Obtaining a sputum sample can be difficult in children, and the diagnosis is usually made on the basis of signs and symptoms of tuberculosis, positive contact and a positive tuberculin skin test (Monteux)8. Gastric aspirates can be used, but have a pick-up rate of less than 40%9. T cell interferon-g (IFN-g) release assays, which measure the number of IFN-g-secreting T cells, have been developed as an alternative immune-based approach to the tuberculin skin test to detect infection10. Page 34

Treatment The cornerstone of treatment is directly observed treatment (DOT) for at least six months. First-line treatment includes rifampicin, isoniazid (INH), ethambutol and pyrazinamide, given according to guidelines for new cases, retreatment, and children younger than eight years of age11. Tuberculosis treatment has the potential for serious sideeffects, some of which may impact on the anaesthetist. Rifampicin can cause thrombocytopaenia when given in high doses. INH may cause sensory neuropathy, which should be ascertained clinically before performing regional nerve blocks. This complication can be prevented by adding pyridoxine (vitamin B6) in high-risk cases. Ethambutol has the potential to cause optic neuritis. Hence, it is not routinely given to children. Drug-induced hepatitis is a worrying complication. When tuberculosis treatment is combined with concomitant antiretroviral therapy, a mild elevation in liver enzymes is common. However, symptomatic hepatitis has a mortality of almost 5%11-13, and requires immediate halting of tuberculosis drugs, with careful re-introduction under specialist care. Wherever possible, surgery should be avoided during this period.

Anaesthetic Management The patient of TB may require anaesthesia for diagnostic procedures (Lymphnode biopsies, Brochoscopies), complications of tuberculosis (Hydrocephalus, intestinal obstruction) and other emergency surgeries. Three major concerns for the anaesthesiologist include: general state of the patient’s health (nutrition and aneamia ), impact of the disease on organ function, and potential drug interactions between antitubercular agents and anaesthetic agents. Further, nosocomal infection transmission to the staff, anaesthetist and other patients is the threat of active disease.

Pre Operative Assessment of Patient The preoperative care of these patients involves a thorough assessment involving accurate medical history, physical examination and evaluation of required necessary investigations. Depending on the clinical evaluation, investigations like sputum culture, chest x-ray, PFT, LFT, ABGmay be considered. These patients should preferably undergo evaluation in negative pressure ventilated room or isolated room to prevent the spread of aerosol infection. In a known case of TB, sputum smear examination for negative AFB has its own importance. For patients under Ann. SBV, July-Dec 2015;4(2)

treatment, sputum smear for AFB taken on three different days need to be negative. It is preferable to postpone the elective procedures until patient is no longer infective. The nutritional status of the patient, aneamia, temperature needs to be evaluated and documented. The treatment history includes the details of antitubercular drugs and their effects on various organs like liver (rifampicin), nervous system (INH and streptomycin),hematology (thrombocytopenia) and kidney (ethambutol). Drug induced hepatitis is a serious complication in patients with TB associated with HIV. Symptomatic hepatitis is generally responsible for 5% mortality hence TB drug therapy needs to be stopped immediately; if possible surgery should be avoided during this period. Subsequently under strict supervision by specialist, drugs can be restarted. However, during routine anaesthetic management the patient on medication should continue the drugs even on the day of operation with sips of water.

Anaesthetic Technique Choice of anaesthetic technique depends on the patient, the procedure and the severity of the disease. Regional anaesthesia is often preferred in patients with chronic lung disease to avoid problems due to disease as such and potential drug interactions. Local anaesthetic agents exert their action primarily at the site of injection, and help to avoid many of the drug interactions. Increased metabolism may result in a decreased risk of local anaesthetic toxicity.However, this may not be possible in some procedures and patient may require Drug

general anaesthesia. When general anaesthesia is planned drugs should be tailored and planned to limit the expected drug interaction. Hepatotoxic drugs must be avoided. Recovery from the effect of intravenous induction agents is primarily due to redistribution. Anti TB agents lead to enzyme induction (P-450) which may result in enhanced metabolism of anaesthetic drugs there by accumulation of toxic metabolic products11.This increased metabolism may have potential for awareness during total intravenous anaesthesia.Inhalational agent, halothane having a potential for hepatotoxicity should be avoided. Action of depolarizing muscle relaxants (MR) will not be affected until pseudocholine esterase levels are markedly reduced due to severe hepatic dysfunction. Non depolarizing MR atracurium, cis-atracurium (alternate metabolism) and pancuronium (renal excretion) are minimally affected by TB therapy12. Streptomycin may potentiate the effects of non depolarizing MR hence, NMR have to be titrated as per response with frequent evaluation by nerve stimulator. The anti TB drug, Rifampicin is known to enhance effect of UDP glucoronyl transferase involved in metabolism of morphine, thereby reducing efficacy of oral morphine13. Fentanyl and alfentanil are both extensively metabolized by CYP450 3A4, therefore, also show the potential for a shortened duration of action. Tramadol and brufen can be safely used as their effects are unchanged11,12.

Effect of TB treatment

Recommendation Beware of risk of awareness with total intravenous anaesthesia

Induction agents

Unchanged

Volatile agents

An increased risk of halothane Newer agents are preferable hepatitis

Local anaestheticagents

Unchanged

Muscle relaxants

Increased metabolismof Titrate/ monitor response using nerve rocuronium/vecuronium stimulator

Opiates

Increased metabolism, often Titrate to effect. The use of regional more frequent dosing technique and patient controlled analgesia is recommended

Useful to avoid general anaesthetia and opioids

Fig 1: Effects of Tuberculosis Treatment on Various Anaesthetic Agents

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Spread of Tuberculosis The spread of tuberculosis to other patientsespecially immunocompromised, anaesthesiologist and theatre staff is an area of concern. Because of the close proximity of the patient’s airway during intubation, mechanical ventilation,suctioning and brochoscopic procedures anaesthetists are at particular risk14,16. In 2005, the American Society of Anesthesiologists (ASA) has come up with guidelines relating to the perioperative management of patients with active tuberculosis19. Elective surgery should be delayed until the patient is no longer infectious. The ASA defines this as having been on treatment for 2-3 weeks, clinically getting better, and having had three negative sputum smears on different days. Elective cases should be taken up as the last case of the day followed by fumigation to allow the decontamination of theatre following the operation. The patient should always be transferred to operation room wearing well fitting surgical mask or a N95®mask. (Fig 2) brought straight to theatre, rather than waiting in holding area to avoid exposure to other patients.Surgery should be performed with as few personnel as possible to reduce the number of potential contact with the index patient. To prevent contamination of the anaesthesia machine and circuit high efficiency particulate air(HEPA) filter should be placed between the Y connector and the mask, LMA, or endotracheal tube. Bacterial filters placed on expiratory limb of ventilator or anaesthesia machines may help to reduce discharge of TB bacilli into the ambient air. Sterilization of instruments should follow standard protocols.

than one hour between cases, M. tuberculosis has been shown to pass through the anaesthetic machine18. Post operative care should, if possible, take place in a room with negative pressure or ante room that provides some isolation from outside hallways. However, because most post anaesthesia care units are not so designed, immediate post operative care should be maintained in OR until the patient can be safely transferred to a suitable isolation room. Patients who require intensive care should be placed in private room with the ventilations techniques that need AFB isolation precautions. The N95® mask should be placed back on as soon as active airway management is no longer required. However, these masks increase airway flow resistance by approximately 120%.19A large venture-type face mask can be placed over the N95® mask to provide supplemental oxygenation. The N95® should not be worn by the patient if he or she is hypoxic or in respiratory distress; if hypoxia or respiratory distress occurs the maskshould be removed.

6. Knechel NA. Tuberculosis: pathophysiology, clinical features, and diagnosis. Crit Care Nurse. 2009;29(2):34-43. 7. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J RespirCrit Care Med. 2000;161(4 Pt 2): 221-242. 8. Moore DP, Schaaf HS, Nuttall J, Marais BJ. Childhood tuberculosis guidelines of the Southern African Society for Paediatric Infectious Diseases. South Afr J Epidemiol Infect. 2009;24(3):57-68. 9. Small PM, Maddhykar P. Tuberculosis diagnosis: time for a game change. ClinPharmacolTher. 2010;363(11):1070-1071. 10. Menon PR. A prospective assessment of the role of bronchoscpoly and bronchoalveolar lavage in evaluation of children with pulmonary tuberculosis. J Trop Pediatr. 2011;57(5):363-367. 11. Lalvani A, Pareek M. A 100-year update on diagnosis of tuberculosis infection. Br Med Bull. 2010;93:69-84. 12. Swart A, Harris V. Drug interactions with tuberculosis therapy. The South African Journal of Continuing Medical Education. 2005; 23(2):56-60. 13. Sweeney P, Bromilow J. Liver enzyme induction and inhibition: implications for anaesthesia. Anaesthesia. 2006;61(2):159-177. 14. Fromm MF, Eckhardt K, Schanzle G, et al. Loss of analgesic effect of morphine due to coadministration of rifampicin. Pain. 1997;7291):261-267.

15. Backman B, Olkkola KT, Neuvonen PJ. Rifampin drastically reduces plasma concentrations and effects of oral midazolam. ClinPharmacolTher. 1996; 59(1):7-13. 16. Tait AR. Occupational transmission of tuberculosis: implications for the anesthesiologist. AnesthAnalg. 1997;85(2):444-451. 17. Jensen PA, Lambert LA, Iademarco MF, Ridzon R. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings. Centers for Disease Control and Prevention. 2005. c2012. Available from: http://www. cdc.gov/mmwr/preview/mmwrhtml/ rr5417a1.htm. 18. Langevin PB, Rand RH, Layon AJ. The potential for dissemination of Mycobacterium tuberculosis through the anesthesia breathing circuit. Chest. 1999;115(4):1107-1114. 19. Lee HP, Wang de Y. Objective assessment if increase in breathing resisrance of N95 respirators on human subjects. Ann OccupHyg. 2011;55(8):917-921. 20. National Institute for Clinical Excellence.Tuberculosis: clinical diagnosis and management of tuberculosis, and measures for its prevention and control. NICE [homepage on the Internet]. 2011. c2012. Available from: www.nice. org.uk/nicemedia/live/13422/53642/53642.pdf. 21. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J RespirCrit Care Med. 2000;161(4 Pt 2):221-224.

Skin testing program for at-risk staff have been advocated by ASA, as well as in the most recent National Institute for Clinical Excellence guidelines.20 Staff members who receive a positive tuberculin skin test are prescribed INH for 6-9 months. This has been shown to prevent progression to active disease20.

Conclusion Given the increase in prevalence of HIV and multi drug resistance , tuberculosis will continue to be an important occupational risk for anaesthetists and operation theatre staff. By the virtue of their involvement in procedures that will induce aerosolization of the tubercular bacillus anaesthesiologists are potentially at risk. Hence, it is imperative that anaesthesia personnel should have appropriate training and education regarding the implementation of personal protective practices as well as tuberculin testing. Risk of patient to patient transmission through anaesthesia circuit is low if efficient bacterial and viral filters are used.

REFERENCES

Figure 2: Example of an N95® mask Theatre staff also must wear N95® masks, especially true for high-risk procedures, such as intubation and bronchoscopy. The anaesthetist should ensure adequate anaesthesia and muscle relaxation. Unless gas flows are stopped for more Page 36

1. National strategic plan for HIV and AIDS ,STIS and TB,2012-2016. 2. Floyd K, Baddeley A, Dias HM, et al. The sixteenth global report of tuberculosis. World Health Organization [homepage on the Internet]. 2011. c2012. Available from: http://whqlibdoc.who.int/ publications/2011/9789241564380_eng.pdf. 3. Akolo C, Adetifa I, Shepperd S, Volmink J. Treatment of latent tuberculosis infection in HIV infected persons. [Cochrane review] In: The Cochrane Library, Issue 1; 2010. 4. Chandra A, BarsavalikarJN, Bhatnagar A. Tuberculosis and Anaesthesia.Journal of Indian Medical Asso 2013;111(3):178-180. 5. Teo DJ, Lim JW.Transmission of tuberculosis from patient to healthcare workersin anaesthesia context. Ann Acad Med Singapore 2004;33(1)95-9.

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Acute fulminant Myocarditis – A rare complication of Tuberculosis

Acute fulminant Myocarditis – A rare complication of Tuberculosis Dr. R V Sridhar, Dr. S Senthil Kumar, Department of Cardiology Dr. G Srividhya2, Department of Chest medicine Shri Sathya Sai Medical College & Research Institute, Sri Balaji Vidyapeeth, Nellikuppam, Kancheepuram Dist., Tamil Nadu – 603 108, India.

Introduction uberculosis is generally thought to spare organs like T Myocardium, thyroid, pancreas and skeletal muscle. Tuberculous involvement of the heart usually presents as pericarditis.Myocarditis as initial presentation is quite rare, prevalence of which in various series is about 0.2%1.Herein we present a patient who happens to be a Pulmonary tuberculosis treatment defaulter presenting with Acute fulminant myocarditis. It is important to consider this remote but a real entity, particularly in areas of high prevalence, in view of its favourable prognosis with prompt recognition and timely Anti-tuberculous treatment.

Case Report A 30 year old male presented to the emergency room with history of high grade fever, cough and dyspnea for a week with worsening orthopnea and paroxysmal nocturnal dyspneafor two days. Clinically he was febrile, in severe congestive cardiac failure, pitting bilateral pedal edema, intense diaphoresis, Pulse rate 120/min and B.P 90/70 mm hg, intense respiratory distress, RR 40/min, SPO2 48% in room air and 88% with 10 liters of O2. Cardiovascular examination showed raised JVP, cardiac apex in 6th intercostal space lateral to mid clavicular line, a prominent S3 gallop, soft mitral regurgitation murmur, bilateral extensive crepitation’s and rhonchi. No pericardial rub or knock was present. Other systems were unremarkable except for tender congestive hepatomegaly. His past medical history was noteworthy for smear positive pulmonary tuberculosis two months ago and was put on Anti tuberculous therapy in TB Sanatorium which he subsequently stopped after a few weeks on his own due to malaise, fatigue and dyspepsia. There was no history of Diabetes mellitus, Autoimmune Page 38

disorder, drug addiction, Sexually transmitted disease’s or alcoholism.

Echocardiogram revealed Dilated Left atrium and Left ventricle, prolonged EPSS, Moderate Mitral regurgitation, severe LV dysfunction, Global hypokinesia with 20% Ejection fraction and mild pericardial effusion. There was no evidence of constriction, pulmonary hypertension, mass, vegetation’s or shunts. Fig (5, 6, 7 and 8)

Clinical differentials considered were Acute fulminant myocarditis which could be commonly Idiopathic, Viral, rarely Drug induced, Giant cell myocarditis and remotely Tuberculous Myocarditis. Tuberculous constrictive pericarditis which is more common is clinically unlikely in our patient as it is chronic in presentation, may have aprominent pericardial knock and usually does not have extensive crepitation’s in the chest. Following are the results of investigations. Hb 15.5 gm/dl, Total leukocyte count 16,500 with 76% neutrophils,15% lymphocytes, No eosinophils or monocytes, platelet count 2.6 lakhs and ESR was elevated to120mm/hr.Total CK and CK-MB were raised. HIV serology was negative. ABG revealed type 1 respiratory failure. Chest X-ray showed cardiomegaly with severe pulmonary edema (Fig 1) and chest X raydone outside two months ago showed bilateral extensive pulmonary tuberculosis (Fig 2). ECG on presentation (Fig 3) showed normal sinus rhythm with sinus tachycardia and nonspecific st-t changes and subsequently showed anteriort wave inversion indicating ongoing myocarditis (Fig 4)

Patient was shifted to coronary care unit and was started on Inotropes, Vasodilators, Diuretics, Vasopressors, Digoxin, Enalapril, prophylactic LMWH and was restarted on Antituberculous therapy. After 24 hours, his clinical condition stabilized andwas less breathless with stable vitals, Respiratory rate 18/min and SPO2 97% in room air. The following differentials for Acute fulminant myocarditis were considered and elaborated in the subsequent discussion. Tuberculous myocarditis, although rare it is a definite entity and clinically considered in our patient due to presence of active parenchymal tuberculosis, presenting with myocarditis and with no other obvious predisposition to it. Drugs like INH, Pyrazinamide and Rifampicin2 are well known to have caused myocarditis albeit very rare. Idiopathic giant cell myocarditis is rare, aggressive and often diagnosed post mortem3. Subsequently after few days the patient was referred out to confirm our diagnosis with myocardial biopsy, serum viral titers, cardiac MRI, the results of which are awaited.Anti-

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Tuberculosis of Breast

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tuberculous therapy was started in view of active pulmonary tuberculosis ,strong clinical suspicion of TB Myocarditis, its association with sudden cardiac death and very low likelihood of ATT altering the investigation results.

Discussion Tuberculous myocarditis was first repoted in 1664 by Maurocordat and the second case after 97 years in 1761 by Morgagni4. As such cases of tuberculous myocarditis reported in literature are few and far between with maximum reported live cases of about four.Tuberculosis commonly affects pericardium and usually has a favorable course with treatment. Myocardial involvement is extremely rare and can present even as sudden cardiac death5. Presentation with fulminant myocarditis as in our patient has been reported in about four cases6 .Tuberculous infection of the myocardium usually occurs through hematogenous, retrograde lymphatic or spread from endobronchial tuberculosis. Horn and Saphir7 described three histological types of myocardial tuberculosis. Nodular tubercles (granulomas), miliary tubercles of the myocardium and Diffuse infiltrative types. Myocardial tuberculosis can manifests as Acute fulminant myocarditis, supraventricular arrhythmias, ventricular tachycardia, varying degrees of conduction block, sudden cardiac death, ventricular aneurysms, pseudo aneurysms, aortic insufficiency, coronary arteritis. Myocardial tuberculosis almost always shows evidence of tuberculosis at other sites as in our patient8. Even though myocardial involvement by tuberculosis is rare it should be suspected as a cause of congestive cardiac failure in any patient with features of tuberculosis. Prognosis of tuberculous myocarditis is generally favorable4. Antituberculous drugs INH, rifampicin and pyrazinamide can cause eosinophilic myocarditis. Presenting characteristics may include a rash, peripheral eosinophilia and multiorgan dysfunction. Myocardial involvement varies but usually does not result in fulminant heart failure as in our patient. Corticosteroids and drug withdrawal usually resolve this syndrome9. Idiopathic giant cell myocarditis represents a rare but distinct entity of unknown origin with unfavorable

prognosis. Typical IGCM affects young adults and histology shows myocyte damage, eosinophils, foci of lymphocytic infiltrates, and multinucleated giant cells. Although the age and severity of cardiac symptoms in our patient makes IGCM a likely diagnosis, presence of active parenchymal tuberculosis, quick response to standard cardiac care, absence of other extra cardiac autoimmune manifestations in the patient makes it difficult to be certain without Endomyocardial biopsy and myocardial gene expression profiling. However Endomyocardial biopsy is not without pitfalls like availability, poor sensitivity and intra-observer variability and should not be the sole criteria for diagnosis10. These factors and clinical scenario of active parenchymal pulmonary tuberculosis led us to prudentially manage this patient empirically as Tuberculous Myocarditis with AntiTuberculous therapy with which he stabilized and improved. In summary here we present a patient with extensive bilateral active pulmonary tuberculosis who presented with clinical, electrocardiographic and echocardiographic features of Acute fulminant myocarditis likely Tuberculous and is recovering on standard cardiac care and Anti-tuberculous therapy.

Tuberculosis of Breast Dr. Shantha Mohanasundaram, Dr. Hemanathan G, Department of Pathology Dr. Deepa N, Department of General Surgery Shri Sathya Sai Medical College & Research Institute, Sri Balaji Vidyapeeth, Nellikuppam, Kancheepuram Dist., Tamil Nadu – 603 108, India.

Abstract 

uberculosis of breast is rare in the west.It is rare even in developing countries where the T incidence of Extra Pulmonary Tuberculosis is high. Kancheepuram District in Tamilnadu is known for its endemicity in Tuberculosis. Tuberculosis of breast occurring in young female which is a rare site for Extra Pulmonary Tuberculosis is presented here.

Key Words: Breast tuberculosis, Epitheloid granuloma, Langhan’s giant cells

REFERENCES 1. Alan G Rose. Cardiac tuberculosis. Archives of Pathology Laboratory Medicine. 1987; l l:422. 2. Li, et al. A case report of eosinophilic myocarditis and a review of the relevant literature. BMC Cardiovascular Disorders. 2015;15:15. 3. Rina K, et al. Diagnosis, treatment and outcome of Giant cell myocarditis in the era of combined immunosuppression. Circulation. 2013;6:15-22. 4. Agarwal MP. Avasthi R. Miliary tuberculosis presenting as myocarditis. IndJ of Tuber. 1994;41:171. 5. Wallis PJW, Branfoot AC, Emerson PA. Sudden death due to myocardial tuberculosis. Thorax. 1984;39:155.  6. Wilbur I’ll. Myocardial tuberculosis; A case of congestive heart failure. Am Rev Tuberc. 1938;38:769. 7. Horn H, Saphir O. The involvement of the myocardium in tuberculosis: a review of the literature and report of three cases. Am Rev Tuberc. 1935;32:492. 8. Bali HK, Wahi S, Sharma BK, Anand IS, Datta BN, Wahi PL. Myocardial Tuberculosis. Am Heart J. 1990;120:703-6. 9. Jared WM, William DG. Myocarditis “Current Trends in Diagnosis and Treatment. Circulation. 2006;113:876-90. 10. Krasniqi N, Eriksson. Gene expression profiling: time to file diagnostic uncertainty in inflammatory heart diseases. European Heart Journal. 2014;35:2138-9.

Introduction Tuberculosis is broadly classified into pulmonary and extra pulmonary tuberculosis based on the site of occurrence. Extra pulmonary tuberculosis is seen in brain,bones,jo ints,kidneys,testes,ovary, spleen, thyroid and breast.The occurrence of tuberculosis in breast is rare1 among the extra pulmonary lesions. It is also rare even in developing countries like India,where the incidence is high2.This could be due to the hostile environment of the breast,which resists the proliferation of Tubercle bacilli –Mycobacterium tuberculosis.Tuberculosis breast was first reported in the west in 1829 by Sir Astley Cooper3.In India the first case was reported by Choudary in 19574.The incidence in India is between 0.64 to 3.59%5, 6.Tuberculosis of breast in western countries is less than 0.1% of breast lesions.Tuberculosis of the breast presenting as a lump is difficult in differentiating it from carcinoma breast7.

Case History A 28year old female came to the surgical outpatient Department of Shri Sathya Sai Medical College and Research Institute, with complaints of swelling in the left breast of Page 40

Ann. SBV, July-Dec 2015;4(2)

one month duration. She had no history of pain or fever. Her last child birth was two years ago on examination a lump 6x 3 cms was made out in the upper outer quadrant. No ulceration over the swelling. No nipple discharge. The central axillary lymph nodes was enlarged .The following investigation were done. Haemoglobin -10.5g /dl ESR-12 minutes 1hour Xray chest- with in normal limits FNAC breast and Lymphnode –Nonspecfic inflammatory lesion. The clinical diagnosis was considered as 1. Carcinoma of breast.2. Pyogenic abscess. Later the patient underwent lumpectomy. Lump was sent for histopathological examination.

Pathological Findings Gross examination of specimen showed skin covered yellowish soft tissue mass 10x8.5x5 cm. Cut surface of the mass was yellowish 6x3x3 cm,and firm in consistency [Fig 1]. Page 41

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TB Breast is classified as Nodular Tuberculosis mastitis Disseminated Tuberculosis

treated with anti Tuberculosis drugs. Residual lump can be removed by surgery.If correct diagnosis is made mutilating surgery like radical mastectomy done for breast carcinoma can be avoided.

Breast abscess. 1. Nodular Tuberculosis Mastitis Common variety,well circumscribed and painless.It is difficult in the later stages to differentiate from breast carcinoma10. 2. Disseminated Tuberculosis It is a rare type. Multiple foci are seen in the breast.Lesion is painfull, ulceration is seen in the skin.Multiple sinuses are seen in the skin.The draining nodes are enlarged and matted.

Fig.1: Cut surface of the breast showing fat (yellow) and whitish area – TB lesion

3. Breast Abscess Sometimes TB breast present as breast abscess with pus formation.

Microscopic examination showed breast tissue with multiple epitheloid granuloma with central caseous necrosis surrounded by Langhans giant cells and lymphocytes [Fig 2a & 2 b].Based on these findings a diagnosis of Tuberculosis breast was made.

Conclusion Fig 2 b) Epitheloid granuloma with Langhan’s Giant cells and surrounding lymphocytes (H and E X 40

Tuberculosis of Breast is rare.It is uncommon even in places where the incidence of Tuberculosis is high. Tuberculosis of breast is often misdiagnosed as carcinoma of breast.It can be

REFERENCES 1. Kakkar S, Kapila K, Singh MK, Verma K. Tuberculosis of the breast: A cytomorphologic study. ActaCytol. 2000;44:292–6. 2. Rangabashyam N, Gnanaprakasan D, Krishnaraj B, Manohar V, Vijayalakshmi SR. Spectrum of benign breast lesions in Madras. J R CollSurgEdinb 1983;28:369-73. 3. Cooper A. Illustration of the diseases of the breast. Part I.London: Longman, Rees, Orme, Brown and Green; 1829. p. 73. 4. Chaudhary M. Tuberculosis of the breast. Br J Dis Chest 1957; 23 : 195-9. 5. Dharkar RS, Kanhere MH, Vaishya ND, Baisarya AK. Tuberculosis of the breast. J Indian Med Assoc 1968; 50 : 207-9 6. Mukerjee P, George M, Maheshwari HB, Rao CP. Tuberculosis of the breast. J Indian Med Assoc.1974;62:410–2. 7. Shinde SR, Chandawarkar RY, Deshmukh SP. Tuberculosis of the breast masquerading as carcinoma: A study of 100 patients. World J Surg. 1995;19:379–81. 8. Banerjee SN, Ananthakrishnan N, Mehta RB, Prakash S. Tuberculosis mastitis: A continuing problem. World J surg 1987; 11:105-9. 9. Shukla HS, Kumar S. Benign breast disorders in nonwestern populations: Part II - Benign breast disorders in India. World J Surg. 1989;13:746–9. 10. Graunsman RI, Goldman ML. Tuberculosis of the breast-report of nine cases including two cases of co-existing carcinoma and tuberculosis. Am J Surg. 1945;67:48.

The patient was put on anti tuberculosis drugs.

Discussion Tuberculosis is rare in breast tissue. If at all seen, it is observed in young lactating women. It is uncommon in puerperal girls and older women. It is rare in males. The more susceptible ones are pregnant and lactating women. Lactating breast is easily affected due to increase vascularity and dilated ducts with predisposition to trauma 8,which aid in the spread of infection. The routes of spread are blood, lymphatics and extension from adjacent tissue. Now it is accepted the majority of TB breast is secondary .The primary focus could be elsewhere in the body 8.The lesion is usually seen in the upper outer quadrant 9 due to spread from axillary node lesion. In our case all the above findings were present.

Fig.2 a) Multiple epitheloid granuloma in breast tissue (H and E X10)

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However at times the lump may be hard, and fixed to the underlying skin and muscle simulating malignancy. Sometimesit can also discharge pus through sinuses simulating pyogenic abscess.

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Tuberculosis and Dentistry

Tuberculosis and Dentistry Dr.Manikandan G., Dr.Surya V., Department of Dentistry Shri Sathya Sai Medical College & Research Institute, Sri Balaji Vidyapeeth, Nellikuppam, Kancheepuram Dist., Tamil Nadu – 603 108, India.

Introduction Tuberculosis is an Infectious disease caused by mycobacterium tuberculosis, which primarily affects the lungs but also capable of involving almost any site in the body including the oral cavity.

Transmission:

• Aerosolized droplets 5µm in diameter. • Estimated 5-200 orgs required for infection. • Spreads through the air when a person: • Sneezes • Coughs • Speaks

Diagnosis: • Chest x-ray -> air appears black in lungs. • Tuberculin skin test (TST or PPD).

Relationship of TB with dentistry: • In dentistry, the incidence of exposure to an active TB patient is quite low. • This does not mean the dental health care worker should not concern themselves with good diagnosis and preventive measures and realization that patients may be infected with TB. • Most common oral manifestation include typical lesion in indurate chronic, non-healing ulcer that is usually painful. • Bony involvement of maxilla and mandible may result in tuberculosis osteomyelitis. Page 44

• In fact it may involve submandibular and cervical lymph nodes leading to tuberculosis lymphadenitis. • Tongue is the most common site affected followed by palate, lips, buccal mucosa and superficial deep painful ulcers. • This does not mean the dental health care worker should not concern themselves with good diagnostic and preventive measures and realization that patients may be infected with TB. • Most common oral manifestation include typical lesion in indurated chromic, non-healing ulcer that is usually painful. • Bony involvement of maxilla and mandible may results in tuberculosis osteomyelitis. • In face it may involve submandibular and cervical lymph nodes leading to tuberculosis lymphadenitis. • Tongue is the most common site affected followed by palate, lips, buccal mucosa & superficial deep painful ulcers. Chronic sinus infection/ use of decongestants leads to dry mouth. • Aspiration of oral cavity secretions containing oral bacteria into respiratory tract cause pneumonia. • Inflammatory products from gingival tissue & pathogenic bacteria can aspirated in lower airway promotes lung infection. • Medications such as corticosteroids used over a period of time causes candidiasis. • Exposure to dental materials such as meth acrylate and natural rubber latex increases the risk for allergic respiratory hypersensitivity.

Safety measures by dentist: • Clinical dental practice has a potential for transmission of various infections from patient to dentist, patient

Ann. SBV, July-Dec 2015;4(2)

to patient as well as dentist to patient due to close proximity to the nasal and oral cavities of the patient. • Barrier should be created to prevent the transmission of the infections and to make the clinical procedures safe from the threat of cross infection. • For known active tuberculosis patients, TB isolation rooms which are appropriately equipped room with effective evacuation

Risk for infectiousness: • Coughing • Undergoing cough-inducing or aerosol-generating procedure • Failing to cover cough • Having cavitation on chest radiograph • Risk for transmission • Exposure in small, enclosed spaces • Inadequate ventilation • Recirculating air containing infectious droplets • Inadequate cleaning and disinfection of equipment • Improper specimen-handling procedures

Sterilization • Proper sterilization of all the instruments should be done before and after the treatment of that patient. • The dentist should also disinfect his/her hand after treatment.

Treatment: Treatment of oral tuberculosis lesion is the same as the systemic tuberculosis. The most effective regimens require a combination of four drugs namely Isoniazid, rifampicin, pyrazinamide and ethambutol, administered daily for the first two months and followed by an additional four months with only two drugs[isoniazid and rifampicin]

Case Report : 1 A 40 year old man presented to the department of dental and oral surgery complaining of an ulcer in the mouth which had been present for the last two months and was gradually increasing in size. He did not have any systemic complaints, was not on any medications and had no history of any allergy. He was a chronic smoker and was unable to give up the habit. Physical examination did not reveal any extra oral abnormality. His left submandibular lymph nodes were enlarged, mobile and non-tender to palpation. Intraorally, his oral hygiene was graded as poor with generalized mobility of all teeth and moderate deposits of Ann. SBV, July-Dec 2015;4(2)

stains present throughout the dentition. Almost all of his teeth had some degree of attrition and some of his teeth were clinically missing. Soft tissue examination revealed a single discrete ulcer of less than 1 cm in diameter present on the left buccal mucosa. The ulcer was bordered by well-defined margins around which were several small nodular swellings. On palpation, the ulcer was tender with indurated margins. The other mucosal surfaces in the mouth were normal. Panoramic radiographs did not reveal any abnormality in the maxillofacial region. A complete general examination revealed no other contributory abnormalities. Correlating these features of a chronic ulcer of two months duration with an associated history of smoking and involvement of the sub mandibular lymph nodes, a differential diagnosis of malignant neoplasm, tuberculosis and mycoticulcer was arrived at. The diagnostic workup included serum analysis for human immunodeficiency virus which turned out to be non-reactive. Cultures for acid fast bacilli and fungi were negative. An incisional biopsy of the oral ulcer was done and the specimen was sent for histopathological examination. The histopathology showed multiple confluent and discrete granulomas composed of epithelioid histiocytes and Langhans giant cells with central caseous necrosis confirming the diagnosis of tuberculosis. Following the biopsy report, a chest radiograph and a routine medical consultation were requested both of which turned out negative results. AFB tissue culture and smear were positive for M. tuberculosis. The patient was then referred to the Department of Internal Medicine where he was started on anti-tuberculosis therapy. Six months later at follow up, the oral ulcer had healed.

Case Report : 2 A 7 year old girl was referred to the Department of Dental and Oral Surgery for evaluation of a chronic painful ulcer in the mouth. History obtained from the parent revealed that the oral ulcer was present in the left lower gingiva since the last one month. The child had difficulty in eating and brushing her teeth. Her family history disclosed that one of her maternal aunts had been diagnosed with pulmonary tuberculosis and was on treatment. On extra oral examination, multiple cervical lymph nodes and the left submandibula group of lymph nodes were enlarged and tender. Intra orally, her oral hygiene was fair and she was in the mixed dentition stage. A large irregular ulcer was present in the lower left gingiva involving the labial and the lingual aspects in relation to 31,72 and 73. The ulcer had extended to the labial vestibule, had a granular surface and was tender. The margins were well defined. Page 45

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There was no other abnormality elsewhere within the oral cavity. Intra oral radiographs revealed unerupted 32 and 33. There was no radiographic evidence of involvement of the underlying bone. A complete general examination did not yield any significant findings. The differential diagnosis included tuberculosis and autoimmune disorder. Laboratory investigations which included evaluation of immunoglobulins were found to be within normal limits. Sero analysis for HIV was negative. The ESR was 92mm at 1 hr. A chest radiograph showed increased vascular markings with no infiltrates or mediastinal adenopathy. An incisional biopsy of the ulcer was then done under general anaesthesia along with excision of the left submandibular lymph node and the specimens were sent for histopathological analysis. Tissue samples were also sent for AFB culture and smear and returned positive for M.tuberculosis.The histopathology of the oral mucosal biopsy showed epithelioid granulomas . Biopsy of the submandibular lymph node showed multiple confluent and discrete necrotizing granulomas . The reports were confirmatory for tuberculosis. The child was then referred back to the Department of Child Health where she was started on anti-tuberculosis therapy.

Discussion Although tuberculosis has a definite affinity for the lungs, it can affect any part of the body including the mouth. Oral manifestations of tuberculosis are usually seen secondary to infection in some other part of the body (1). Studies of Farber et al (2) indicated that less than 0.1% of tuberculosis patients whom they examined exhibited oral lesions. According to Tiecke (3), the prevalence of oral manifestations in patients with pulmonary tuberculosis ranges from 0.8% 3.5%. Occasionally the recognition of an oral tuberculous lesion precedes the detection of pulmonary tuberculosis (4). Compared with tuberculous involvement of other parts of the body, the primary occurrence of this disease in the oral cavity and jaw bones is relatively rare. Oral lesions of tuberculosis are nonspecific in their clinical presentation and are often overlooked by the clinician (1). Although the pathogenesis of oral involvement is not definitely established, it appears most likely that the organisms gain entry into the mucosal tissue through a break in the surface (5) The probable importance of an intact mucosal epithelium in providing protection against the infection has support from the observation of Abbot et al (6) who were able to isolate the tubercle bacilli from mouth washings of 44.9 % of the patients with active pulmonary lesions. When the primary lesions of tuberculosis occur in the

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mouth, the most frequent sites of involvement are gingiva, tooth extraction sockets and the buccal folds (1). The systemic factors that favor the chances of oral infection in tuberculosis includes lowered host resistance (7) and increased virulence of the organisms. The local predisposing factors may be poor oral hygiene (8), local trauma (9), and the presence of existing lesions like leucoplakia (10), periapical granulomas (11), dental cysts (12), dental abscess (13), jaw fractures (14) and periodontitis (15). The common manifestation of oral tuberculosis is an ulcerative lesion of the mucosa. The lesion may be preceded by an opalescent vesicle or nodule which may break down as a result of caseation necrosis to form an ulcer. The typical tuberculous ulcer is an irregular lesion with ragged undermined edges, minimal induration and often with a yellowish granular base (1) . Tiny single or multiple nodules called ‘sentinel tubercles’ may also be seen surrounding the ulcer (8). On the tongue, the common sites for atuberculous ulcer are the lateral border, tip, anterior dorsum and the ventral surface (2) . The tongue lesions are usually painful, greyishyellow, firm and well demarcated. The palatal lesions of tuberculosis may be seen as granulomas (16) or ulcerations (17) and are usually more common in the hard palate than in the soft palate. The gingival lesions may present as exuberant and granulating or as mucosal erosions. Sometimes these lesions may be seen simultaneously with marginal periodontitis (18). Involvement of the maxilla and mandible usually results in tuberculous osteomyelitis. Tuberculosis of the jaw bones may be secondary or primary (19) and occurs as a result of either deep extension of the gingival lesion, from an infected postextraction socket or through hematogenous spread of the infection. The mandible shows a greater predisposition to the infection than the maxilla In a study conducted by Chapotel(20), fifty cases of tuberculous osteomyelitis involved the lower jaw bone.

Conclusion Tuberculous lesions of the oral cavity can assume a nonspecific clinical appearance. If the mucosais involved, the lesions may present as ulcerations, nodules, fissures, plaques, granulomas and vemicous proliferations. When the jaw bones are involved, the disease presents features of chronic osteomyelitis. Primary lesions of tuberculosis manifest in the oral cavity as non-healing chronic ulcers. When diagnosing such lesions with non-healing tendency, tuberculosis should be considered in the differential diagnosis. In this assessment, a complete physical examination should also be included, with diagnostic tests such as chest radiographs, biopsy specimens for histological studies and culture of the organism. An early diagnosis with prompt treatment will usually result in a complete cure.

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Case Report : 3 A 17-year-old female patient reported to the Department of Oral Medicine and Radiology, complaining of a painful swelling in her right submandibular region that had been present for two months and was originally noticed on June 13th 2009. The swelling was initially the size of a peanut and had been gradually increasing until it reached the present size.(Fig1) On general examination the patient was thin and malnourished. There was no fever, cough, or weight loss symptoms present. Past medical history and family history was not significant. On extraoral examination, inspection showed a single diffuse swelling with illdefined borders of approximately 4 × 3 cm in the right submandibular region. The overlying skin was the same as surrounding skin. On palpation a mass was felt in the right submandibular region, which was firm in consistency, tender, nonfluctuant, noncompressible, mobile, and showed signs of matting. On intraoral examination, odontogenic involvement due to the swelling was not present. Other lymph nodes were not palpable.(Fig 2)A clinical diagnosis of right submandibular tuberculous lymphadenitis was considered. Differential diagnosis of right submandibular sialadenitis, right submandibular gland calcification was considered.A panoramic radiograph was carried out and it did not reveal odontogenic origin in relation to the swelling (Fig 3). A Mantoux test was positive. No abnormality was detected in chest radiographs (Fig 4). A complete hemogram showed a hemoglobin level to be 8.8 gm%, the red blood cell reading was 3.3 million/cu mm, and the total white blood cell count was 8,200 cells/cu mm. By comparison, normal range hemoglobin is 12%–16 gm%, red blood cells 4–5 million/cu mm, and total white blood cells 4000–11000 cells/cu mm. Erythrocyte sedimentation rate (ESR) was raised 1st hour 75 mm, 2nd hour 105 mm.

Fig 1: Swelling in right submandibular region.

Ann. SBV, July-Dec 2015;4(2)

Fig 2: Swelling with ill-defined borders.

Fig 3: Panoramicradiograph showing no odontogenic orgin in relation to the swelling

Fig 4: Chest radiograph showing no abnormality

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Fig 5: Ultrasound scan showing right submandibular tuberculosis lymphadenopathy An ultrasound scan of the patient’s neck revealed multiple hypoechoic nodular lesions of varying sizes in the right submandibular region, abutting and displacing the right submandibular salivary gland. The largest of the lesions measured 3.4*2.9 cm and matting was apparent (Fig 5). There were a number of other similar smaller lesions along the right jugular vein, which is suggestive of lymphadenopathy. The ultrasound report was consistent with that of right submandibular and jugular tuberculous lymphadenopathy. Ultrasound-guided fine-needle aspiration biopsy (FNAB) revealed a cellular aspirate showing plenty of small and large lymphocytes. Necrotic debris was seen in focal areas, and few epithelioid cells or giant cells seen.(Fig 6 & 7)

Fig 6: Fine needle aspiration biopsy showing epithelioid cells.

Fig 7: Fine needle aspiration biopsy showing giant cell and necrotic debris. Page 48

The ultrasound-guided FNAB report was compatible with that of tuberculous lymphadenitis. Regarding the clinical presentation of the case and the investigation reports a final diagnosis of right submandibular tuberculous lymphadenitis was arrived at. The patient was referred to the TB hospital for further treatment. Treatment consisted of anti-TB drugs for a period of 6 months. No complications occurred, and no further surgery was required.

Histopathological examination of the biopsy specimens or material collected by fine needle aspiration of the cervical swellings was an important aid in the diagnosis of the disease because the finding of granulomatous lesions with epithelioid cells was highly suggestive of TB. The microbiological detection of mycobacteria was negative in almost 50% of the cultures and smears performed.24 The difficulties in detection of mycobacteria in orofacial TB, either by staining or by culture, are clearly reported in the literature.27

Discussion

Conclusion

In the case three report, the patient had a swelling of about 4 × 3 cm in the right submandibular region. Intraoral examination revealed no obvious odontogenic involvement, which could be the cause of the swelling. A panoramic radiograph of the affected area was taken to check for any underlying source of odontogenic involvement with respect to the swelling; it did not reveal any odontogenic origin in relation to the swelling and thus it was determined that the swelling was nonodontogenic in origin.

Primary TB of the orofacial region is more commonly found in children and adolescents than in adults.3,4 In the present case, adolescent age, poor socioeconomic and nutritional status of the patient, the clinical presentation of the case, and the investigation reports were taken into consideration for a final diagnosis of right submandibular primary tuberculous lymphadenitis.

The presence of matting in the mass of the swelling and nonodontogenic nature of the swelling was taken into consideration for a clinical diagnosis of right submandibular tuberculous lympadinitis.

TB affecting primarily cervical lymph nodes is uncommon. In absence of systemic signs and symptoms, as in our case, it can be difficult to diagnose TB. Awareness by the clinician of such a presentation would make diagnosis of TB easier. Diagnosis of the disease in the initial stages would be beneficial not only to the patient to allow them to receive early treatment, but also in preventing the spread of the disease to others. Thus, oral clinicians can contribute to the diagnosis of TB with awareness of the presentation of the disease and extra care in their regular practice.

The target organ of MTB is the bronchopulmonary apparatus and the head and neck are usually secondary.16–22 The patient underwent a Mantoux test and complete hemogram. The Mantoux test was positive and the complete hemogram showed raised ESR 75 mm at 1st hour, 105 mm at 2nd hour. The positive Mantoux test and the raised ESR further strengthened our clinical diagnosis of right submandibular tuberculous lymphadenitis. There is no single diagnostic test for TB23 although positivity for the tuberculin skin test was found in 84% of TB patients.24 A chest radiograph of the patient was taken and no abnormality was observed in the chest radiograph. If a tubercular lesion is suspected, a chest X-ray is indicated to investigate the possibility of pulmonary involvement.25 To evaluate the swelling further, an ultrasound scan of the patient was taken. The ultrasound scan report was consistent with that of right submandibular tuberculous lymphadenopathy.

Overall Summary

Acknowledgement:

The authors would like to thank Dr. Don K. Abraham for his technical expertise.

REFERENCES 1. Crompton GK, Haslett C, Chilvers ER. Diseases of the respiratory system. Davidson’s principles and practice of medicine. 18th ed. London, UK: Churchill Livingstone; 1999;347–353. 2. Lee KC, Schecter G. Tuberculous infection in the head and neck. EarNose Throat J. 1995;74:395–399.

3. Popowich L, Heydt S. Tuberculous cervical lymphadenitis. J OralMaxillofac Surg. 1982;40:522–524. 4. Ishikawa H, Hyo Y. Tuberculous submandibular lymphadenitis. J OralMaxillofac Surg. 1982;40:302–305. 5. Iype EM, Ramdas K, Pandey M, et al. Primary tuberculosis of the tongue: report of three cases. J Oral Maxillofaic Surg. 2001;39:402–403. 6. O’Conell JE, George MK, Speculand B, Pahor AL. Mycobacterial infection of the parotid gland: an unusual cause of parotid swelling. J Laryngol Ootal. 1993;107:561–564. 7. Hock-Liew E, Shin-Yu L, Chuang-Hwa Y, Wei-Jen C. Oral Tuberculosis.Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;81:415–420. 8. Phelan JA, Jimenez V, Tompkins DC. Tuberculosis: infectious diseases and dentistry. Dent Clin North Am. 1996;40:327–340. 9. Reichmand LB. The U shaped curve of concern. Am Rev Respir Dis.1991;144:741–742. 10. Ito FA, de Andrade CR, Vargas PA, Jorge J, Lopes MA. Primary tuberculosis of the oral cavity. Oral Dis. 2005;11:50–53. 11. Rinaggio J. Tuberculosis. Dent Clin North Am. 2003;47:449–465. 12. Yepes JF, Sullivan J, Pento A. Tuberculosis: medical management update. Oral Surg Oral Med Oral Pathol Oral Radiol Endod.2004;98:267–273. 13. Aziz MA, Wright A, Laszlo A, DeMuynck A, Portaels F, VanDeun A.Epidemiology of ant tuberculosis drug resistance (The global project on ant tuberculosis drug resistance surveillance): an updated analysis. Lancet. 2006;368:2142–2154. 14. Prabhu SR, Sengupta SK. Bacterial infections due to mycobacteria.Oral Diseases in the Tropics. 1st ed. Oxford University Press; Delhi, India: 1993;195–202. 15. Ajay GN, Laxmikanth C, Prashanth SK. Tuberculous ulcer of tongue with oral complications of oral antituberculosis therapy. Ind J Dent Res. 2006;17:87–90. 16. Hashimoto Y, Tanioka H. Primary tuberculosis of the tongue: report of a case. J Oral Maxillofac Surg. 1989;47:744–746. 17. Rauch MD, Friedman E. Systemic tuberculosis initially seen as an oral ulceration: report of case. J Oral Surg. 1978;36:387–389. 18. Prabhu SR, Daftary DK, Pholakia HM. Tuberculosis ulcer of the tongue:report of case. J Oral Surg. 1978;36:384–386. 19. Worsae N, Reibel J, Rechnitzer C. Tuberculous osteomyelitis of the mandible. Br J Oral Maxillofac Surg. 1984;22:93–98. 20. Haddad NM, Zaytoun GM, Hadi U.Tuberculosis of the soft palate and unusual presentation of OFT. Otolarynol Head Neck Surg. 1987;97:91–99. 21. Pande T.K, Hiran S, Rao VVB. Primary Lingual Tuberculosis caused by M. Bovis infection. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1995;80:172–274. 22. Kolokotronis A, Antoniadis D, Trigonids G. Oral tuberculosis. OralDis. 1996;2:242–243. 23. Barga M, Blum JH, Graeme-Cook FM. A 57-year old man with fever and jaundice after intravesical installation of bacilli calmette-guerin for bladder cancer. Weekly clinicopathological exercises. N Engl J Med.1998;339:831–837. 24. Mignogna MD, Muzio LLO, Favia G, et al. Oral tuberculosis: a clinical evaluation of 42 cases. Oral Dis. 2000;6:25–30. 25. MacFarlane TW, Samaranayake LP. Clinical oral microbiology.Butterworth; London; 1989;112–115. 26. Chao SS, Loh KS, Tan KK, Chong SM. Tuberculous and non-tuberculouscervic allymphadenitis:Aclinicalreview.Otolaryngol Head Neck Surg. 2002;126:176– 179. 27. Hocking TL, Choi C. Tuberculosis: a strategy to detect and treat new and reactivated infections. Geriatrics. 1997;52:52–64.

With the results of all the above investigations pointing towards a diagnosis of TB lymphadenitis, an ultrasoundguided FNAB was carried out for the histopathological examination. The ultrasound-guided FNAB revealed clusters of epithelioid cells and few giant cells, which was compatible with that of tuberculous lymphadenitis. Fine needle aspiration is the most frequent and useful diagnostic technique available to diagnose lymph node TB.26 Ann. SBV, July-Dec 2015;4(2)

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Imaging IN tuberculosis

CT CHEST – Coronal Reconstruction Mass within the cavity in right upper lobe

Imaging IN tuberculosis Prof. V. Subramanian, Professor & Head

Ultrasound Neck with enlarged cervical nodes

Department of Radiology, Shri Sathya Sai Medical College & Research Institute, Sri Balaji Vidyapeeth, Nellikuppam, Kancheepuram Dist., Tamil Nadu – 603 108, India.

CECT BRAIN Multiple Tuberculomata

MRI BRAIN WITH CONTRAST Multiple ring enhancing lesions in Brain

CT CHEST - Intra-cavity fungal ball - Air crescent sign LYMPH NODE Diagram showing the location of the lymph node

Supine

CT BRAIN Right sided lesion with perilesional edema, compressing the ventricles

Same patient CXR showing Miliary TB

CHEST X-RAY Parenchymal lesion in right upper lobe

Prone

Tracheal and mediastinal shift to left due to fibrosis

CHEST X RAY - Blunting of left cardio and costo phrenic angles silhouetting the left dome of diaphragm and left lower cardiac border

CHEST X RAY-TB with parenchymal Calcification Page 50

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ULTRASOUND Right pleural effusion Page 51

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CHEST X RAY - Left side pleural calcification

CHEST X RAY-Primary pulmonary infiltrate with right hilar node enlargement

ELBOW JOINT Destruction with soft tissue changes

BARIUM MEAL Barium study showing ileo-cecal junction lesion.

CHEST X RAY - Miliary TB EXTRA PULMONARY TB - C T SCAN TB spine with bilateral Psoas abscess L > R

X RAY PELVIS Tuberculosis affecting the right hip

BARIUM MEAL Terminal ileum thickening due to tuberculosis

X RAY CALCANEUM Tuberculosis of calcaneum CHEST X RAY - Cavity in right upper lobe

TUBERCULOSIS SPINE – MRI Wedge compression with retrolisthesis of L4 vertebra

BARIUM ENEMA Narrowing of the transverse colon HRCT CHEST - Left upper lobe Bronchiectasis

Tuberculosis of Genito Urinary System IVU- Papillary necrosis

TUBERCULOSIS SPINE – MRI Wedging with cord compression

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CT SCAN Right renal parenchymal calcification

HYSTERO SALPINGOGRAM (HSG) Both fallopian tubes appear rigid with small terminal sacculations.

IMAGES IN Abdominal Tuberculosis Dr. Gokul D. Yatheendranathan, Assistant Professor Department of General Surgery , Shri Sathya Sai Medical College & Research Institute, Sri Balaji Vidyapeeth, Nellikuppam, Kancheepuram Dist., Tamil Nadu â&#x20AC;&#x201C; 603 108, India.

X RAY Right adrenal calcification

NON CONTRAST CT Bilateral adrenal calcification

Tuberculosis can involve any part of the gastrointestinal tract and is the sixth most frequent site of extra-pulmonary involvement after lymphatic, genitourinary, bone and joint, miliary and meningeal TB. Both the incidence and severity of abdominal tuberculosis is expected to increase with the increasing incidence of HIV infection. Tuberculosis bacteria reach the gastrointestinal tract via haematogenous spread, ingestion of infected sputum, or direct spread from infected contiguous lymph nodes and fallopian tubes.The gross pathology is characterized by transverse ulcers, fibrosis, thickening and strictures of the bowel wall, enlarged and matted mesenteric lymph nodes, omental thickening, and peritoneal tubercles.Peritoneal tuberculosis occurs in three forms: wet type with ascites, dry type with adhesions, and fibrotic type with omental thickening and loculated ascites.

The most common site of involvement of the gastrointestinal tuberculosis is the ileocaecal region. Ileocaecal and small bowel tuberculosis presents with a palpable mass in the right lower quadrant and/or complications of obstruction, perforation or malabsorption especially in the presence of stricture.

Fig 2: Illeal Stricture with proximal illeal perforation

Source : Department of Radiology, SSSMCRI.

Fig 1: Tuberculous Intestinal cocoon Page 54

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Rare clinical presentations include dysphagia, odynophagia and a mid-oesophageal ulcer due to oesophageal tuberculosis, dyspepsia and gastric outlet obstruction due to gastroduodenal tuberculosis, lower abdominal pain and haematochezia due to colonic tuberculosis, and annular rectal stricture and multiple perianal fistulae due to rectal and anal involvement. Chest X-rays show evidence of concomitant pulmonary lesions in less than 25 per cent of cases. Useful modalities for investigating a suspected case include small bowel barium meal, barium enema, ultrasonography, computed tomographic scan and colonoscopy. Ascitic fluid examination reveals straw coloured fluid with high protein, serum ascitic albumin gradient less than 1.1 g/dl, predominantly lymphocytic cells, and Adenosine Deaminase levels above 36 U/l. Laparoscopy is a very useful investigation in doubtful cases. Management Page 55

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is with conventional anti-tubercular therapy for at least 6 months. The recommended surgical procedures today are conservative and the period of preoperative drug therapy is controversial.

Take home points 1. Abdominal TB denotes involvement of GIT, peritoneum and/or draining lymph nodes. 2. Tubercular process can involve any organ in the abdominal cavity. 3. There is absence of extra abdominal lesions in the majority of patients. 4. A high index of clinical suspicion is necessary in any patient presenting with vague abdominal symptoms. 5. Radiological findings may be equivocal or merely contributory. 6. Most common site of involvement is ileo-caecal region. 7. A Histopathological confirmation is essential before making a firm diagnosis of tubercular abdomen 8. Diagnostic laparotomy or laparoscopy necessary for histological/microbiological diagnosis in peritoneal/ lymph node TB 9. Anti-tuberclous therapy forms the first line of management for patients with abdominal tuberculosis. 10. Therapeutic surgery essential for complications like Int. obstruction, perforation, peritonitis.

Fig 3: Peritoneal cavity & small bowel studded with

POTPOURI Dr. Saurabh RamBihariLal Shrivastava, Assistant Professor Department of Community Medicine , Shri Sathya Sai Medical College & Research Institute, Sri Balaji Vidyapeeth, Nellikuppam, Kancheepuram Dist., Tamil Nadu â&#x20AC;&#x201C; 603 108, India.

Where does the world stand in the fight against the tuberculosis? 2015 update Globally, in the fight against tuberculosis (TB), the year 2015 marks as an important milestone, with the world, achieving the Millennium Development Goal (MDG) - 6 pertaining to TB (halting and reversing the trend of the disease), shifting from MDGs to the next era of Sustainable Development Goals (SDGs), and from the Stop TB Strategy to the End TB Strategy.1 The estimates released under the Global TB control 2015 report revealed that close to 9.6 million people were diagnosed with TB, of which 12% were HIV-positive.1Since the year 1990, a remarkable reduction in TB associated mortality of close to 50% has been achieved, accounting for more than 40 million lives saved worldwide.1,2 Further, the 2015 targets pertaining to the reduction in the incidence, prevalence and mortality have been met in nine of the high-burden nations.2 In addition, the global TB incidence has reduced by more than 18% since the beginning of the 20th century.1 However, despite of all the achievements and the availability of an effective diagnostic / therapeutic option through which nearly all cases can be cured, TB still remains as one of the biggest public health threat globally.1-3

tubercles

Nevertheless, 1.5 million individuals died from TB, including 0.4 million deaths among the TB-HIV coinfected in 2014, which is unacceptable as most of these deaths could have been easily prevented.2,4 The health sector is falling significantly short in closing the detection gap as only 62.5% of the patients suffering from TB were notified to the health agencies.1 Further, only 25.6% of the estimated multidrug-resistant TB patients were detected and reported which raises a serious question mark on the quality of care and the surveillance mechanism.2 Even in the incidence aspect, almost 9.6 million new TB cases have Page 56

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been diagnosed, which is much more than the estimates of the year 2013, when 9 million cases were diagnosed.1 In addition, significant gaps have been identified in the funding aspect to ensure sound implementation of the existing prevention & control interventions.2 Even though, a definitive improvement in the treatment initiation of multi drug resistant TB patients has been reported, nevertheless the global cure rate has been only 50%, which is a serious issue of public health concern.1 However, if the international stakeholders really want to accomplish the proposed targets under SDGs (viz. minimize the TB deaths by 90% in comparison with the 2015 estimates, decrease incidence by 80% and to ensure that no household is burdened with enormous expenditure because of TB), a lot needs to be done.1,2 There is an enormous need to bridge the gap on both diagnostic and treatment initiation fronts.4 At the same time, quality research to facilitate the development of new diagnostics / drugs / vaccines, will also bring rich dividends to the TB prevention & control activities.2,5 Most of the above gaps can be addressed, if there is a continuous monetary support towards the current strategies, so that primary health care can be strengthened.1,2 To conclude, even though the battle against tuberculosis is paying off in terms of reduction in incidence, prevalence and mortality, if the policy makers really want to end the epidemic of TB, an up scaling of the existing services and financial investment in the research arena is the need of the hour.

References 1. World Health Organization. Global tuberculosis report. Geneva: WHO press; 2015. 2. World Health Organization. Tuberculosis mortality nearly halved since 1990; 2015. Available from: http://who.int/mediacentre/news/releases/2015/ tuberculosis-mortality/en/ Last accessed on 2015 Dec 5. 3. Gulland A. Tuberculosis killed 1.5 million people in 2014. BMJ. 2015;351:h5798. 4. World Health Organization. Global tuberculosis report. Geneva: WHO press; 2014. 5. Sharma SK, Kohli M, Yadav RN, Chaubey J, Bhasin D, Sreenivas V, et al. Evaluating the Diagnostic Accuracy of Xpert MTB/RIF Assay in Pulmonary Tuberculosis. PLoS One. 2015;10(10):e0141011.

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Interventions to strengthen airborne infection control in healthcare establishmentse For decades together, owing to the exposure to different airborne pathogens, a wide range of outbreaks, epidemics, and pandemics of respiratory illnesses have been reported across the globe.1 The majority of the respiratory infections are predominantly transmitted from one person to another through the airborne route via droplets exposing multiple susceptible individuals to the infection.2 The public health concern of airborne infections rises enormously in healthcare settings, especially due to the overburdened hospital, poor ventilation, and the presence of immune-suppressed patients in the premises of hospitals.1,2 The World Health Organization and other international agencies have together released guidelines regarding airborne infection control in different settings. 3 The suggested measures include three broad categories, namely administrative, environmental and personal protective measures.3,4 The administrative control comprises of education & training of staff (viz. importance of infection control, educating about the precise work of healthcare staff); outpatient settings (like awareness activities for promoting cough etiquette by the patients, screening respiratory symptomatic & reducing their duration of stay in the hospital, modifications in the seating arrangement of doctor and patients based on the location of door & windows); and inpatient settings (such as minimizing hospitalization of patients, measures to reduce incidence of nosocomial infections, sensitizing patients and attendants about cough hygiene, segregating respiratory symptomatic to separate areas, maintain spacing by ward decompression, safe sputum collection, etc.).3,4 However, the environmental control measures mainly comprise of indoor patient segregation, bed spacing as per norms, maintaining adequate ventilation, and ensuring extra precaution in high risk wards of the hospital.4,5 At the same time, by encouraging the use of personal protective equipments among the patients and healthcare staff, the subsequent risk of transmission can be significantly minimized.4 To conclude, implementation of standard airborne infection control measures in health care establishments requires a comprehensive package of interventions to minimize the incidence of airborne nosocomial infections.

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References 1. Martin PMV, Martin-Granel E. 2,500-year evolution of the term epidemic. Emerg Infect Dis. 2006;12(6):976-80. 2. Subhash SS, Baracco G, Fennelly KP, Hodgson M, Radonovich LJ Jr. Isolation anterooms: important components of airborne infection control. Am J Infect Control. 2013;41(5):452-5. 3. Writing Committee (CDC, WHO, IUATLD). Tuberculosis infection control in the era of expanding HIV care and treatment: An addendum to WHO guidelines for the prevention of tuberculosis in heath care facilities in resource limited settings. Geneva: WHO Press; 1999. Available from: http://whqlibdoc.who.int/hq/1999/ WHO_TB_99.269_ADD_eng.pdf [Last accessed on 2016 Jan 13]. 4. Ministry of Health and Family Welfare. Guidelines on airborne infection control in healthcare and other settings. New Delhi, 2010. Available from: http://www.tbcindia.nic.in/pdfs/Guidelines_on_Airborne_Infection_Control_ April2010Provisional.pdf [Last accessed on 2016 Jan 8]. 5. Escombe AR, Moore DAJ, Friedland JS, Evans CA, Gilman RH. Natural ventilation for prevention of airborne contagion. PLoS Med. 2007;4:e68.

Effective implementation of contact tracing in tuberculosis: Pros and Cons In the modern era, tuberculosis (TB) has been acknowledged as one of the leading causes of morbidity and mortality resulting from an infectious disease.1 In-fact, the global estimates revealed that almost 9.6 million new cases of TB and 0.48 million cases of multi-drug resistant TB have been reported across the world in the year 2014.1 Globally, early establishment of the diagnosis and prompt treatment initiation has been recommended as the one of the key strategies in TB related control activities.1,2 At the same time, especially in high prevalence settings, the “Directly Observed Treatment and short-course chemotherapy” approach has not paid rich dividends.3 Thus, the strategy of “contact tracing” has been advocated to supplement the existing measures to reduce the burden of TB.4 Even though, passive case finding has been adopted in heterogeneous settings for case detection owing to the resource constraints, contact tracing is a key intervention to ensure early detection of TB cases.3,5 Contact tracing has shown its effectiveness in augmenting case detection rates of pulmonary, extra-pulmonary & multidrug resistant TB cases, initiation of prompt treatment, and in preventing reactivation of the latent cases.3,5 However, some pre-requisites should be satisfied before implementation of contact tracing in a specific setting, namely its necessity based on the caseload in the area, identification of contacts & other attributes (like proximity to the index case, duration of exposure, extent of tracing, etc.), and tools/technique which will be adopted for its execution in the community.3,6

Further, its universal application is restricted owing to the time-consuming process; execution by the overburdened health care professionals; and inefficiencies in data collection, storage, and retrieval as it is conducted either by interviewing or using paper forms.6,7 In an attempt to neutralize the existing hurdles, measures like conducting home and workplace visits rather than conduction of interview;8 and adoption of mobile health applications to promote digitalization & easy retrieval of data;6 can be implemented. To conclude, owing to the enormous scope of contact tracing in reducing the magnitude of tuberculosis, the health staffs should be regularly motivated to ensure its implementation in the community.

References 1. World Health Organization. Global Tuberculosis Report 2015. Geneva: WHO press; 2015. 2. Shrivastava SR, Shrivastava PS, Ramasamy J. Fostering directly observed treatment in tuberculosis: A program manager’s perspective. Int J Health Policy Manag. 2014;2(1):51-2. 3. Begun M, Newall AT, Marks GB, Wood JG. Contact tracing of tuberculosis: a systematic review of transmission modelling studies. PLoS One. 2013;8(9):e72470. 4. Kasaie P, Andrews JR, Kelton WD, Dowdy DW. Timing of tuberculosis transmission and the impact of household contact tracing. An agent-based simulation model. Am J Respir Crit Care Med. 2014;189(7):845-52. 5. Jurcev Savicevic A. Five “W” in tuberculosis contact tracing: why, when, who, where, and what? Lijec Vjesn. 2011;133(1-2):65-8. 6. Ha YP, Littman-Quinn R, Antwi C, Seropola G, Green RS, Tesfalul MA, et al. A mobile health approach to tuberculosis contact tracing in resource-limited settings. Stud Health Technol Inform. 2013;192:1188. 7. Tian Y, Osgood ND, Al-Azem A, Hoeppner VH. Evaluating the effectiveness of contact tracing on tuberculosis outcomes in Saskatchewan using individualbased modeling. Health Educ Behav. 2013;40(1 Suppl):S98-110. 8. Duarte R, Neto M, Carvalho A, Barros H. Improving tuberculosis contact tracing: the role of evaluations in the home and workplace. Int J Tuberc Lung Dis. 2012;16(1):55-9.

How many of us are practically aware about directly observed treatment in tuberculosis? The tuberculosis related prevention and control activities are planned and executed as per the guidelines released by the Revised National TB Control Program (RNTCP) in India.1 Directly Observed Treatment (DOT) has been identified as one of the crucial pillars necessary for ensuring higher cure rates.1 Under the DOT strategy, a DOT provider is a trained person other than the family member, who ensures and supports the patient in consuming their anti-TB drugs.1 Owing to the longer duration of anti-TB treatment, it becomes really imperative to ensure that patients should

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continue to take medications, even if the disease symptoms have subsided.1 In-fact, a rapid surge in the number of drug resistant forms of TB has been observed, as the majority of the initially diagnosed TB patients is not completing their entire course of treatment.2 As it is totally unpredictable to identify the patients who will default from their therapy, DOT has emerged as an effective approach to reduce non-adherence.1 In-fact, the findings of epidemiological studies have revealed a significant decline in the incidence of microbiological failure, default, acquired drug resistance, case fatality; early detection of adverse drug reactions; and improvement in the quality of life.3-5 Further, it is very important to understand that DOT does not refer to consumption of anti-TB drugs in front of a DOT provider.1 It is much more than that, and in ideal circumstances, whenever a patient comes to the DOT center, it is the duty of the DOT provider to ask the patient first to sit down and relax, inquire about any complaints / issue, trace the patient-wise box based on his TB identification number, take out one strip / blister, remove the drugs from the blister and give into the hands of the patient, offer a glass of drinking water, ask the patient to consume the drugs, ensure that the patient has swollen the drugs by using a tongue depressor (if possible); and finally, even motivate the patient to continue their treatment for the complete duration.6 However, a wide range of shortcomings have been identified in the smooth implementation of the DOT strategy in the community settings like rigid timings of the government health centers, disease associated stigma, lack of accessibility to the health centers, shortage of health professionals, poor awareness among the general population (pertaining to disease, its treatment, prevalent social norms), no awareness activities for the target population, and limited involvement of the private sector, especially in remote areas.4,6 Most of the above mentioned shortcomings can be addressed through the Treatment adherence scheme (public-private partnership scheme) in which any community DOT provider who ensures the compliance to therapy will be given an honorarium on treatment completion.7 Further, measures like preparing a streetwise DOT directory, roping in different private sector agencies, motivating private practitioners to adhere to the RNTCP guidelines; conducting periodic awareness campaigns, encouraging community volunteers to become DOT providers; ensuring proper counseling (viz. regarding the nature / duration of treatment, need of adherence) of the patient, facilitating prompt release of honorarium, and adopting innovative tools like videophone to encourage administration of DOT.2,6,7 Page 59

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To conclude, directly observed treatment possesses enormous potential and is a key strategy to ensure completion of the treatment and thereby significantly minimize the risk of drug resistant TB.

References 1. TBC India. Managing the RNTCP in your area - A training course (Modules 1-4). Available from: http://tbcindia.nic.in/documents.html [Last accessed on 2015 Dec 24]. 2. TBC India. Guidelines for PMDT in India; 2012. Available from: http://tbcindia. nic.in/documents.html [Last accessed on 2015 Dec 19]. 3. Pasipanodya JG, Gumbo T. A meta-analysis of self-administered vs directly observed therapy effect on microbiologic failure, relapse, and acquired drug resistance in tuberculosis patients. Clin Infect Dis. 2013;57(1):21-31. 4. Seaworth BJ, Armitige LY, Griffith DE. First do no harm--adverse events, drug intolerance, and hepatotoxicity: how can we not justify directly observed therapy for treating tuberculosis? Clin Infect Dis. 2013;57(1):1063-4. 5. Chung WS, Li CR. Can DOTS improve quality of life among patients with pulmonary tuberculosis? Int J Tuberc Lung Dis. 2013;17(3):425-6. 6. Shrivastava SR. Directly observed treatment short course (DOTS) strategy. In: Shrivastava SR, editor. Tuberculosis Control – An Indian perspective. USA: SM Open Access eBook; 2014. 7. TBC India. Managing the RNTCP in your area - A training course (Modules 5-9). Available from: http://tbcindia.nic.in/documents.html [Last accessed on 2015 Dec 22].

Role of infrastructure in the management of drug resistant tuberculosis in India The evidences for antimicrobial resistance have been reported worldwide, leading to a reduction in the effectiveness of treatment for many infectious diseases.1 In-fact, resistance has been observed for all first line drugs used to treat tuberculosis (TB), and has emerged as a serious challenge for the health sector worldwide.2 Further, the most recent estimates for multi-drug resistant (MDR) TB, suggest that in the year 2014, almost 0.48 million new cases were reported, of which India, China and Russia accounted for more than fifty percentage of the cases.3 However, by no means these estimates reflect the accurate picture as a large number of cases are never notified to the health authorities.3 Although, many reasons contribute to high case load of drug-resistant TB, nevertheless factors like weaknesses in the health system, poor infrastructure support, and scarcity of resources definitely enhances the magnitude of the problem.4 In India, services for MDR-TB are delivered under the programmatic management of drug resistant TB

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(PMDT) initiative since its launch in 2007, and there is a definitive plan to upscale the services in a phase-wise manner to extend the services to all.1 However, owing to the resource constraints prevalent in the Indian settings, the MDR-TB diagnostic services cannot be offered to all, and thus MDRTB suspects (or high risk) have been identified.2-4 This highrisk group of patients can be screened for MDR-TB through culture and drug sensitivity testing (C&DST).2 Further, under PMDT, three MDR suspect criteria – A, B, and C were proposed to ensure gradual expansion of the PMDT services in the whole nation in tandem with the expansion of the laboratory services, so that existing certified laboratories are not overburdened.2,5 Thus, Criteria-A was implemented initially in most of the parts of the nation, and based on the caseload of MDR-TB patients, plan was formulated to implement Criteria-B and C (Table 1). The ultimate set target is to implement Criteria-C by the end of 2015 in all districts of the nation.2 In addition, to improve upon the diagnostic services, the process of certification of different laboratories and establishment of more national reference laboratories has been given due attention.2,6 Further, the national government has also collaborated with Foundation for innovative new diagnostics (FIND) agency to consolidate the infrastructure.7

Table 1: MDR-TB suspect criteria MDR-TB suspect criteria A

Limitation - Despite the knowledge that 2-3% of the newly diagnosed TB patients and 15% of retreatment TB cases Cat II smear positive at 4th are resistant to first line drugs, even before initiation of month; treatment, they are still managed with ineffective drugs and thus, patients lose significant amount of crucial time. All pulmonary TB cases who are contacts of known MDR- These patients continue to remain a potential source of TB cases transmission of MDR-TB infection in the absence of effective treatment. Cat I failure at 5th month;

Patients who are on Cat-I treatment, three months are saved, while in retreatment cases, all are considered as MDR-TB All smear positive retreatment suspect immediately upon diagnosis. pulmonary TB cases at diagnosis; & Free services are offered to even those patients who were accessing private sector earlier. Any smear positive follow-up of new cases at the end of intensive Limitation - No provisions for smear negative retreatment phase / later or retreatment cases patients

In addition to Criteria-B

1. World Health Organization. Antimicrobial resistance - Fact sheet N°194; 2015. Available from: http://who.int/mediacentre/factsheets/fs194/en/ [Last accessed on 2016 Jan 11]. 2. TBC India. Guidelines for PMDT in India; 2012. Available from: http://tbcindia. nic.in/documents.html [Last accessed on 2016 Jan 13]. 3. World Health Organization. Global Tuberculosis Report 2015. Geneva: WHO press; 2015. 4. Verma R, Khanna P, Mehta B. Revised national tuberculosis control program in India: the need to strengthen. Int J Prev Med. 2013;4(1):1-5. 5. John TJ, Vashishtha VM, John SM, Sudarshanam TD. Tuberculosis control must be scientifically defined and soundly designed. Indian J Med Res. 2010;132:4-8. 6. Ministry of Health & Family Welfare. National PMDT scale-up plan – India 2011-12; 2011. Available from: http://www.tbcindia.nic.in/ [Last accessed on 2016 Jan 17]. 7. Foundation for Innovative New Diagnostics. India’s contribution in rolling out newer and rapid diagnostics towards PMDT scale-up; 2012. Available from: http://www.finddiagnostics.org/export/sites/default/resource-centre/ presentations/find_fifth_symposium_iuatld2012/08_Balasangameshwara_ RolloutOfNewDxInIndia.pdf.

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Limitations / Comments

Patients, who have availed treatment from the government sector, are only eligible for free MDR-TB diagnostic / treatment facilities.

In conclusion, timely strengthening of the infrastructure under the national program can significantly assist the policy makers to accomplish the universal TB care for all.

References

Eligibility

In addition to Criteria-A

No provisions for persons detected with pulmonary TB for the first time.

All smear negative retreatment pulmonary TB cases at the time of diagnosis; and HIV-TB co-infected cases

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Moving forward to accomplish tuberculosis related Millennium Development Goal-6 Over the last couple of decades, tuberculosis (TB) has remained a major public health threat, not only because of its magnitude, but even due to its universal distribution, associated mortality, the burden posed to the health system, increased financial expenses, and massive impact on the quality of life of the patient, their family members, and even the society.1,2 Acknowledging the same, tuberculosis was included as one of the goals in the Millennium Development Goals (MDG-6) and the target was set to halt and reverse the trend of the disease by 2015.1,2 However, as the magnitude of the disease has remained persistently high, the World Health Organization (WHO) has identified five key priority areas to fast track the progress and eventually achieve MDG6, namely 1. Reaching the missed cases: Owing to the shortcomings in the surveillance system and because of the stigma associated with the disease, a large number of cases go unreported.1,2 In-fact, in the year 2014 itself, out of the estimated 9.6 million people who were estimated to suffer from the disease, only 6 million were actually notified to the health authorities.1 Similarly, only 0.12 million cases of MDR-TB were diagnosed & reported, in comparison to the estimated 0.48 million cases. This clearly indicates that millions of cases are either undiagnosed or unreported and is a major set-back for the public health authorities.1 At the same time, there is an immense need to make tuberculosis as a notifiable disease, and strengthen contact tracing, so that each and every case diagnosed by any means can be offered appropriate treatment.2,3 2. Addressing MDR-TB: The incidence of MDR-TB has increased at an unprecedented rate across the globe and thus there is a need to strengthen the health system response to cope up with the challenge.4 There is an immense need to improve upon the diagnostic services (so that results can be obtained at the earliest), ensure easy geographical access to the diagnostic services, sensitization of the health professionals to adhere to the diagnostic & therapeutic algorithm, create awareness about the serious nature of the disease among the general population / TB patients, about the need to complete the course of treatment, involvement of all the stakeholders, including private sector, and to make the health services more people-friendly (like psychosocial support, counseling, etc.).1,4

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3. Augmenting the response to TB/HIV: TB-HIV co-infection goes hand in hand and thus should be dealt together. Even though, the number of HIV-positive TB patients who were initiated with antiretroviral therapy (ART) in the year 2014 was 0.39 million, but this was unacceptable as it was expected that ART should be initiated for all 1.2 million TB-HIV co-infected people.1 The need of the hour is to streamline the entire strategy of coordination between TB & HIV related activities at different levels of the program, so that both diagnosis of opportunistic infection & treatment of the same can be offered at the earliest.1,2 4. Augmenting financial support: The recent global estimates suggest that a funding gap of US$ 1.4 billion was identified to ensure smooth implementation of the existing prevention & control activities for the year 2015.1 It will be extremely wrong to expect favorable results in the absence of sustained financial assistance from the stakeholders, as most of the families have to make a catastrophic expenditure on the illness and simultaneously monetary support is always required to expand the range of services, especially in remote settings.1,2,4 5. Timely adoption of innovations in the program: This is a crucial aspect and the national program managers should be always open to adopt recent innovations in the program to ensure benefit to the community.1,3 The innovations can be like the extension of TB-Diabetes Mellitus collaborative activities, newer strategies for creating awareness about the disease, building partnership with different stakeholders, the adoption of newer diagnostic / therapeutic modalities, and adoption of online reporting.3,5 To conclude, although on a global scale we might achieve the target set for MDG-6, nevertheless wide gaps have been identified in the high burden nations. Thus, it is the need of the hour to focus on priority areas and work in collaboration to reduce the overall burden of the disease.

References 1. World Health Organization. Global Tuberculosis Report 2015. Geneva: WHO press; 2015. 2. TBC India. Managing the RNTCP in your area - A training course (Modules 1-4). Available from: http://tbcindia.nic.in/documents.html. 3. Shrivastava SR, Shrivastava PS, Ramasamy J. Modifications in the Revised National Tuberculosis Control Program to achieve universal access to tuberculosis care. CHRISMED J Health Res. 2014;1(1):45-7. 4. TBC India. Guidelines for PMDT in India; 2012. Available from: http://tbcindia. nic.in/documents.html. 5. TBC India. NIKSHAY. Available from: http://www.tbcindia.nic.in/.

Declaring tuberculosis as a notifiable disease in India: A landmark development in the prevention and control The recently adopted Sustainable Development Goals pertaining to tuberculosis aims to minimize the TB associated death rates by 90% (in comparison with 2015 estimates), reduce incidence by 80% and ensure that no household financial status is compromised with catastrophic costs due to TB, by the year 2030.1 However, the primary cause of public health concern is that almost 40% & 75% of new TB and MDR-TB cases went undiagnosed or unreported in the year 2014.1 This is a big challenge for the policy makers as most of these unreported patients take some or no treatment and not only later on present as drug resistant TB cases, but even transmit the disease to numerous susceptible contacts.1 From the Indian perspective, the nation has been identified as one of the leading contributors of TB cases, accounting for almost 25% of all global cases.1 Further, most of the cases often are not reported, predominantly because of the limitations inherent to the public health system, and private sector being the preferred choice of first contact for almost 70% of the general population.2,3 To counter this challenge in India, since 2012, TB has been regarded as a notifiable disease (viz. all TB cases diagnosed by any means should be reported to the health authorities).4 This will help the program managers to quantify the precise magnitude of the disease, so that up-scaling of the TB control activities can be planned and implemented in an evidence-based manner.4 However, the program managers have to be proactive and target all the stakeholders to ensure that the process of notification is smooth and complete.4,5 In-fact, different strategies can be tried to involve private practitioners (like sensitization sessions about different basic aspects of TB, collection of notification report by the health workers, encouraging the practice of nil-reporting, regular sessions to address stakeholdersâ&#x20AC;&#x2122; concern, etc.) and other professional bodies, hospitals, medical colleges, laboratories, etc.4,5 In addition, the general population can be sensitized about the need and importance of notification through different mass media techniques.4 Finally, the option of online reporting, offering some form of incentive to private practitioners as a source of encouragement, and periodic monitoring by the designated officers should be explored to enhance effectiveness of notification.4,5 To conclude, the declaration of TB as a notifiable disease was needed for a very long period of time. However, it is just the start, and it has opened numerous potential areas in

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which a lot of efforts have to be put in to eventually benefit the general population in years to come.

References 1. World Health Organization. Global Tuberculosis Report 2015. Geneva: WHO press; 2015. 2. Managing the RNTCP in your area - A training course (Modules 1-4). Available from: http://tbcindia.nic.in/documents.html [Last accessed on 2016 Jan 13]. 3. Ministry of Health and Family Welfare. National family health survey (NFHS-3); 2005-06. Available from: http://www.measuredhs.com/pubs/pdf/SR128/SR128. pdf [Last accessed on 2016 Jan 17]. 4. Ministry of Health and Family Welfare. Guidance for TB Notification in India; 2012. Available from: http://tbcindia.nic.in/pdfs/Guidance%20tool%20for%20 TB%20notification%20in%20India%20-%20FINAL.pdf [Last accessed on 2016 Jan 19]. 5. Lo HY, Yang SL, Chou P, Chuang JH, Chiang CY. Completeness and timeliness of tuberculosis notification in Taiwan. BMC Public Health. 2011;11:915.

Enhancing the contribution of private health sector in tuberculosis control activities in India Time and again, it has been reiterated that the battle against TB cannot be won unless each stakeholder from the private health sector is involved, and the entire health sector fight together as a team.1 In India, owing to the limitations associated with public health sector and a preference for the private sector among the majority of the population, involvement of the private sector is a must.2 The Revised National TB Control Program (RNTCP) has initiated ten different schemes for TB related services, namely 1. Advocacy Communication and Social Mobilization scheme: The aim is to increase the level of awareness about the different aspects of the disease and the services offered. 2. Sputum collection center scheme: The rationale is to negate the problem of no easy accessibility to the designated microscopy centers (DMCs). 3. Sputum pick-up and transport service scheme: This scheme ensures that collected sputum samples are picked-up and then transported to the DMC for examination. 4. Designated microscopy-cum-treatment center scheme: This scheme creates a provision for a private laboratory to assist the government health authorities in reaching the diagnosis (and offering treatment through a community volunteer). 5. Laboratory technician scheme: It can be used if there is a shortage of laboratory technicians in the health sector. 6. Culture and drug sensitivity testing scheme: The aim is to reduce the burden on the existing laboratories Page 63

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and at the same time speed-up the process of obtaining the results through the involvement of a private certified laboratory. 7. Treatment adherence scheme: To encourage community DOT providers so that the compulsion of the patients to come to the directly observed treatment (DOT) center can be neutralized. 8. Slum scheme: It is applicable in urban slums where people the residents have minimal accessibility to the public health system. 9. Tuberculosis unit scheme: Its option can be explored in those areas where the government health system is extremely poor and thus routine implementation of RNTCP prevention & control activities cannot be ensured. 10. TB-HIV scheme: This scheme can be implemented among high risk groups of people to meet with the special needs of the vulnerable section of society.3-5 or all these schemes, both logistic and financial support will be offered to the private service provider to ensure that all the services are delivered in a quality assurance manner.3 However, there is a great need to sensitize the private sector about the existence of these schemes under RNTCP, so that they can also play a significant role in the fight against TB.3 In conclusion, the private health sector possesses an immense potential and it is the responsibility of the public health sector to bridge the existing gaps and enhance their contribution in the prevention and control of the disease.

References 1. World Health Organization. Global Tuberculosis Report 2015. Geneva: WHO press; 2015. 2. Ministry of Health and Family Welfare. National family health survey (NFHS-3); 2005-06. Available from: http://www.measuredhs.com/pubs/pdf/SR128/SR128.pdf 3. TBC India. Managing the RNTCP in your area - A training course (Modules 5-9). Available from: http://tbcindia.nic.in/documents.html [Last accessed on 2016 Jan 25]. 4. Shrivastava SR, Shrivastava PS, Ramasamy J. Implementation of public health practices in tribal populations of India – Challenges & Remedies. Healthc Lowresource Settings. 2013;1:e3. 5. TBC India. Guidelines for PMDT in India; 2012. Available from: http://tbcindia. nic.in/documents.html [Last accessed on 2016 Jan 26].

Annals of SBV

periodic modification in the existing guidelines.1 However, another major role of the medical college is that they provide the platform for grooming future doctors and thus it is our responsibility to train them effectively in the different aspects of the tuberculosis disease in a systematic manner.1,2 Although, in the currently recommended curriculum, tuberculosis is taught to the aspiring doctors in their under-graduation, a wide range of deficiencies has been identified, namely poor sensitization of students about TB while entering into medical college, limited correlation between first year subjects (like anatomy / physiology) and their clinical association; dearth of integrated sessions on tuberculosis; low awareness about the recent development in the diagnosis and treatment of TB among both faculty and students, non-scientific examination format, no mandatory requirement for faculties to be trained in teaching to become teachers, and existence of a wide gap between the medical education and the public health department.3-5 Most of the existing shortcomings can be easily addressed, provided there is a mutual participation between policy makers, stakeholders from medical colleges and Medical Council of India.5 These stakeholders can plan together all corrective measures like mandatory training of all doctors who want to be teachers, the introduction of a foundation course at the time of entry into under-graduation, ensure early clinical exposure from the first year itself, organizing integrated teaching sessions on TB regularly, inclusion of TB related practical questions in exams, encouraging non-formal modes or community-based teaching like role plays, planning visit of students to designated microscopy center / directly observed treatment center, motivating students to conduct short-term research work, and ensure implementation of the above measures through the medical college core committee.1,3-5 To conclude, as medical students are the future health care providers and tuberculosis is a major public health concern in India, there is a great need to train them well enough to ensure that they are ready to play their part effectively in reducing the burden of the disease once they come out of their under-graduation.

Incorporating tuberculosis in undergraduate medical curriculum Medical colleges, being a tertiary care health institute, plays a significant role in the diagnosis and management of the sputum negative and extra-pulmonary TB patients, management of adverse drug reactions, other program administrative activities, facilitation of research work, and

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1. Shrivastava SR, Shrivastava PS, Ramasamy J. Knowledge and practices about Revised National Tuberculosis Control Program among clinicians of a medical college in India: A cross-sectional study. Prog Health Sci. 2013;3(1):94-103. 2. Zhao Y, Ehiri J, Li D, Luo X, Li Y. A survey of TB knowledge among medical students in Southwest China: is the information reaching the target? BMJ Open. 2013;3:e003454. 3. Medical Council of India. Vision 2015 - Medical council of India; 2011. Available from: http://www.mciindia.org/tools/announcement/MCI_booklet.pdf [Last accessed on 2016 Jan 13].

Striving hard to achieve universal access to tuberculosis care: Indian perspective In India, since the introduction of the Revised National TB Control Program (RNTCP) in 1992, the program has been geographically scaled-up and considerably improved upon various aspects to respond to the challenges of drug resistant TB, logistic constraints, administrative issues, poor infrastructure, shortage of human resources, and even lack of financial support.1,2 Further, different avenues pertaining to the diagnostic set-up, treatment options, the involvement of different stakeholders (like private provider, medical colleges, international agencies, etc.), and even operational modifications in the outreach implementation of the program have been strengthened, not only to expand the reach of services, but eventually accomplish universal access to TB care.1,2

Diagnostic services: • Sputum microscopy has been acknowledged as the gold standard tool for diagnosis of pulmonary TB, as it is easy to conduct, high specificity-reliabilityreproducibility of results, cheap, provides information about infectiousness or progress of patient put on treatment, and its feasibility in low resource settings. • Prohibiting the use of serological tests and interferon gamma release assay. • Project LIGHT: A project LIGHT (LED Fluorescent Microscopy in Gaining TB Cases in High workload Teaching Hospitals) has been piloted in 200 medical colleges, which have a caseload of more than 25 slides per day. This method can provide prompt results and significantly reduces the workload on laboratory technicians. • Drug-resistant TB: In order to negate the limitations of solid & liquid culture, especially in terms of time required to get the result, RNTCP has adopted line probe assay (result obtained within 1-2 days), and Xpert TB test (results within 2 hours) in various districts of the nation. • Development of standardized guidelines for the training of the laboratory technicians and other stakeholders.

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• To start additional national reference laboratories in capital cities of Madhya Pradesh & Odisha.3-7

Treatment of Adult and Paediatric TB • Withdrawing category-III treatment regimen. • A commitment to ensure uninterrupted supply of drugs through proper inventory control. • Plan to introduce six weight bands for paediatric TB, in contrast to the existing four categories. • Change in the dosage of isoniazid chemoprophylaxis from 5 to 10 mg/kg body weight. • Plan to supply MDR-TB drugs in five weight bands (existing - three weight categories). • Release of specific guidelines for storage of second line anti-TB drugs.1,8

Other developments in the program • Formulation of standards for TB care in India. • Declaration of TB as a notifiable disease. • Introduction of NIKSHAY software – To encourage online reporting & monitoring of patients. • Stringent implementation of the airborne infection measures in health establishments. • Up-scaling of TB-DM coordination activities in hundred districts each year. • Strengthening of the existing TB-HIV strategies. • Emphasis on organization of periodic sensitization sessions for all stakeholders. • Development of a strategic document for assisting program managers in their supervision activities. • Measures to prevent the sale of anti-TB drugs without prescription. • Periodic revision in the financial norms: The monetary allocations have been revised for ACSM activities, conduction of operational research / thesis, grants for thesis, organized conferences, etc.1,7,9-12 Altogether, the program managers are showing lots of commitment in exercising their duties, and now it is the responsibility of the entire team of health professionals to work together in collaboration with the community to ensure that universal access to TB care is achieved.

References 1. TBC India. Managing the RNTCP in your area - A training course (Modules 1-4). Available from: http://tbcindia.nic.in/documents.html [Last accessed on 2015 Dec 24]. 2. TBC India. Managing the RNTCP in your area - A training course (Modules 5-9). Available from: http://tbcindia.nic.in/documents.html [Last accessed on 2016 Jan 8].

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Annals of SBV 3. World Health Organization. Commercial serodiagnostic tests for diagnosis of tuberculosis, 2011. Geneva: WHO press; 2011. 4. International Union against Tuberculosis and Lung Disease. Project LIGHT increases the number of TB cases diagnosed at test sites. Available from: http:// www.theunion.org/index.php/en/newsroom/news/item/2350-project-lightincreases-the-number-of-tb-cases-diagnosed-at-test-sites [Last accessed on 2016 Jan 11]. 5. Albert H, Bwanga F, Mukkada S, Nyesiga B, Ademun JP, Lukyamuzi G, et al. Rapid screening of MDR-TB using molecular Line Probe Assay is feasible in Uganda. BMC Infect Dis. 2010;10:41. 6. RNTCP-FIND-WHO CBNAAT Project. Available from: http://www.finddiagnostics. org/export/sites/default/media/events/2012/pdf/Flyer_CBNAAT_India.pdf [Last accessed on 2016 Jan 13]. 7. Shrivastava SR, Shrivastava PS, Ramasamy J. Standards of tuberculosis care: An Indian perspective. Prog Health Sci. 2014;4(1):280-282.

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8. TBC India. Guidelines for PMDT in India; 2012. Available from: http://tbcindia. nic.in/documents.html [Last accessed on 2016 Jan 14]. 9. Shrivastava SR, Shrivastava PS, Ramasamy J. Notification of tuberculosis cases in India: Moving ahead in Revised National Tuberculosis Control Program. Infect Ecol Epidemiol. 2013;3:23006. 10. TBC India. NIKSHAY. Available from: http://www.tbcindia.nic.in/ [Last accessed on 2016 Jan 24]. 11. TBC India. Guidelines â&#x20AC;&#x201C; Technical specifications. Available from: http://www. tbcindia.nic.in/documents.html [Last accessed on 2016 Jan 26]. 12. NPCDCS. Operational guidelines - National programme for prevention and control of cancer, diabetes, cardiovascular diseases and stroke (NPCDCS); 2012. Available from: http://health.bih.nic.in/Docs/Guidelines/Guidelines-NPCDCS.pdf [Last accessed on 2016 Jan 26].

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Annals of SBV

Annals of SBV Sri Balaji Vidyapeeth

(Deemed University, Accredited by NAAC with 'A' Grade)

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Ann. SBV, July-Dec 2015;4(2)