Child and Chest Health Care Delhi NCR

Tuberculosis is very very old disease of human .

There has been many research in the field of diagnosis and treatment of tuberculosis.

Inspite of all the efforts worldwide,it is still the killer disease due to various reasons responsible for the emergence of drug resistant TB (Tuberculosis).

Chief responsible factors for the increased incidence of tuberculosis are poverty leading to undernutrition, and HIV infection.

Main causes of emergence of drug resistance is not completing the prescribed regimen of treatment and high burden of tuberculosis.

TERMINOLOGIES BEING USED:

Monoresistant tuberculosis-Resistance of tuberculosis to any first line drug-Rifampicin,Isoniazid,pyrazinamide,ethambutol

Polyresistant tuberculosis: Resistance of tuberculosis to more than one drug but not to both Rifampicin and Isoniazid

Multi drug resistant(MDR) tuberculosis: Resistance to both Rifampicin and Isoniazid with or without resistance to other drugs

Pre-extensively drug resistant(PRE-XDR) tuberculosis:Resistance to both Rifampicin and isoniazid with resistance to either fluoroquinilones or second line injectables but not to both fluoroquinolones and second line injectables(SLI)

Extensively drug resistant tuberculosis(XDR):Resistance to Rifampicin,Isoniazid,fluoroquinolones and second line injectables(SLI)

RR-TB:Resistance to Rifampicin with or without resistance to other antituberculous drugs

SECOND LINE INJECTABLES(SLI):Amikacin,Kanamycin and capreomycin

PRIMARY RESISTANCE:When a child or adult becomes infected with drug resistant strain of Mycobacterium tuberculosis

SECONDARY/ACQUIRED RESISTANCE:This is more common.The individual is infected with drug sensitive strain of Mycobacterium tuberculosis but it becomes drug resistant during treatment due to selection of resistant mutant strain.The cause of such resistance is incopmlete or suboptimal treatmen

TERMS USED IN DIAGNOSTIC PROCESSES

C-Tb skin test;This is a new test for the detection of tuberculosis infection.In this test ESAT6/CFP10 antigens are used.It is done in the same way as Tuberculin skin test(TST).Antigen is injected intradermally on the forearm and reaction is read after 48-72 hours with the ball pen-scale method.An induration of 5mm is taken as positive irrespective of age,BCG status and whether with HIV or non HIV.The sensitivity is comparable to TST(MANTOUX TEST) and IGRA(QUANTIFERON GOLD)

IGRA(QUANTIFERON TB GOLD IN TUBE TEST;QFT-GIT: AND T-SPOT TB TEST:T-SPOT):This test is based on the principle of white blood cells of individuals infected with mycobacterium release interferon gamma when mixed with antigens derived from Mycobacterium.In this test whole blood is taken from individual and then mixed to ESAT6/CFP10 antigens and result is available within 24 hours.It does not differentiate between active and latent Tb.This test is not affected by BCG vaccination and is specific for Mycobacterium tuberculosis but not reliable below 5 years of age.

TESTS TO DETECT MYCOBACTERIUM:

LAMP;Loop mediated isothermal amplification test is 15% more sensitive than Zeil Neilson microscopy(smear microscopy) which is most widely used traditional test to detect Mycobacterium in smear preparation of sample in the form of sputum or gastric aspirate. It is temperature independent test ,done manually for amplification of DNA and can be read by naked eye with ultraviolate light.The report is available within one hour.WHO has recommended it as an alternative to ZN microscopy as it can be used in periphery

LED-FM:Light emitting diode fluorescent microscopy is 10 % more sensitive than ZN microscopy.With proper training it can be used in periphery although its specificity is less.WHO has recommended it as an alternative to ZN microscopy.According to WHO policy paper its sensitivity is 86.3%

CBNAAT :Cartridge based nucleic acid amplification test is based on polymerase chain reaction for the ampilification of DNA.Report is available within 2 hours.It can detect live as well as dead tuberculous bacilli ,so it can not be a replacement for smear microscopy and culture based drug sensitivity test for folllow up.It is also known as GenXpert /Rif test.It also detects Rifampicin resistance.Its sensitivity is 89% and specificity is 99%

GenXpert ultra(CBNAAT ULTRA):It is an advance version of GenXpert which is ultrasensitive with main difference from GenXpert is ,it can detect Mycobacterium from sputum even if the number of bacilli per ml is as low as 16,whereas in GenXpert ,the number of bacilli should be 131/ml for detection

TRUENAT;It has been developed in India by Molbio Diagnostics Pvt.Ltd.Goa.Its sensitivity and specificity to detect Mycobacteria and Rifampicin resistance is similar to CBNAAT/GenXpert test.But it requires 0.5 ml of sample as compared to CBNAAT which requires 1 ml.It is battery operated and not fully automated so it does not require continuous power supply and can be used in periphery

LPA-Line probe assay is based on polymerase chain reaction with reverse hybridization technique.First line assay detects resistance to isoniazid while second line LPA detects resistance to Fluoroqinolones and SLI.Report is available within 24-48 hours.According to recent RNTCP guideline,if Rifampicin resitance is detected on CBNAAT,second sample is sent to detect isoniazid resistance by LPA.If isoniazid resistance is detected,second line LPA is done for Fluoroquinolones and SLI.If Rifampicin sensitivity is detected on CBNAAT,sample is sent for LPA to detect isoniazid resistance.

According to WHO,END TB Programme,all patients should be subjected to DST(Drug sensitivity test) and the reference standard for this test is either liquid or solid culture.The report becomes available in 12 weeks.

To meet the requirement of universal DST as recommended by WHO,rapid tests are being developed as-NEXT GENERATION SEQUENCING(NGS).It is a rapid molecular test to detect mutations responsible for drug resistance.These are of 3 types

Targeted NGS-it sequences the specific point on gene of Mycobacterium tuberculosis

Whole genome sequencing(WGS)It sequences the whole genome ,so it is better than TNGS.

Pyrosequencing-it is method of sequencing by synthesis.

DRUGS TO TREAT RESISTANT TUBERCULOSIS:

GROUP-A-Levofloxacin or Moxifloxacin,Bedaquiline,Linezolid

GROUP-B-Clofazimine,Cycloserine or Teridizone

GROUP-C-Ethambutol,Delamanid,Pyrazinamide,Imipenam-cilastin or Meropenam,Amikacin or Streptomycin,Ethionamide or Prothionamide,Para-Aminosalicylic acid(PAS)

There are TWO regimens for the treatment of drug resistant tuberculosis,Long course and Short course

Long course is for 18-20 months-According to WHO 2019 guideline, 2 drugs from Group A except Bedaquiline in children,1-2 drug from Group B along with Delamanid must be chosen and the list of at least 5 drugs is completed from Group C.After 6 months of continuation phase,Delamanid is withdrawn and at least 4 drugs should be continued for the rest of the period of treatment..

DELAMANID CAN BE GIVEN TO CHILDREN ABOVE 3 YEARS OF AGE

SHORT COURSE REGIMEN:It is given for a period of 9-12 months.Usually the intensive phase is of 4-6 months consisting of Moxifloxacin,high dose isoniazid,ethambutol,,pyrazinamide,clofazimine,ethionamide or prothionamid,Kanamycin or Amikacin(7 drugs) followed by a fixed period of 5 months of Moxifloxacin,clofazimine,pyrazinamide and ethambutol(4 drugs)

Drug resistance to Fluoroquinolones and second line injectables should be ruled out before initiating short course treatment.

Now a days it is being emphasised and WHO in June 2020 has recommended ,all oral drug regimen where injectables shuold be replaced by Bedaquiline.FDA has approved Bedaquiline above 12 years of age but in India it has been approved above 18 years in accordance to RNTCP guideline.

NOTE:High dose isoniazid- dose is 15-20 mg/kg/day-it can cause optic and peripheral neuritis,ANA positivity,agranulocytosis,vasculitis and thrombocytopenia.

Linezolid-Dose 15 mg /kg od for wt<15 kg and 10-12 mg/kg od,for >15kg.It causes Myelosuppression,peripheral and optic neuritis and lactic acidosis.It penetrates CNS well

Ethionamide/Prothionamide causes hypothyroidism

EPTB and CNS Tb should be treated with longer regimen

REFERENCES:

TB facts.GenXpert Test-TB diagnosis,TB resistance testing,CBNAAT.2018.Available at:http://www.tbfacts.org/genexpert/Accessed

2019

World Health Organisation(WHO).The use of next generation sequencing technologies for The detection of mutations Associated with drug resistance in Mycobacterium toberculosis Complex;Technical guide.Available at http://apps.who.int/iris/handle/10665/27443.Accessesd2019.

World Health Organisation.WHO consolidated guideline on Drug Resistasnt tuberculosis treatment 2019?Available at :https:apps.who.int/iris/bitstream/handle/10665/311389/9789241550529-eng.pdf.Accessed 2019

Pediatric tuberculosis is a burden to society and nation .

It is prevalent in every society and every nation.

It spreads by aerosols which comes in air after coughing by a diseased person and then inhaled by healthy person .

In children ,it is mostly contracted by a diseased adult suffering from pulmonary tuberculosis .

Lifetime risk for an infected child to become diseased is 10%.

CBNAAT-cartridge based nucleic acid amplification test, also known as GeneXpert test is now investigation of choice to detect Mycobacterium tuberculosis in children suspected to be suffering from tuberculosis .

The sensitivity of this test in sputum smear positive case is 98% and specificity is 99% but in smear negative and culture positive  cases its sensitivity is only 72% but specificity is 99%

In GA(gastric aspirate sample ) the sensitivity is only 68% in culture positive sample  and specificity is 99%.

Presently it is done on sputum, gastric aspirate ,CSF ,pleural fluid ,lymph done aspirate ,ascitic fluid,synovial fluid but  not on blood .

In lymph node aspirate,the positivity is 35%.

In some children,in which induced sputum and gastric aspirate are negative ,BALf,bronchoalveolar lavage fluid obtained by bronchoscopy has been found to be positive.

The sensitivity is  low in  Synovial fluid,pericardial fluid,ascitic fluid and very low in pleural fluid.

SO ,NEGATIVE TEST RESULT OF CBNAAT/GeneXpert TEST DOES NOT RULE OUT TUBERCULOSIS

Only one sample is needed and if unable to send the sample to lab immediately, it can be stored safely in refrigerator for 7 days but should not be freezed .

It is a real time PCR test and gives result in 2 hours.

It detects Mycobacterium tuberculosis as well as its resistance to Rifampicin.

If resistance to Rifampicin is detected and there is no suspicion of resistant tuberculosis clinically,then a fresh second sample is sent.

In second sample, if there is sensitivity to Rifampicin, it is labelled as Drug sensitive TB.

In GeneXpert Ultra test,second sample is not required.

The yeild is high in this test if there is chest X-ray findings suggestive of tuberculosis.

In case of only clinical suspicion with no radiological findings,the sensitivity is approximately 10%

SO,FOR THE HIGH YIELD,THIS TEST SHOULD BE SENT WHEN THERE IS SUSPICIOUS LESION ON CHEST X-RAY

In case of pleural effusion,the highest yield is from the examination of pleural biopsy which is positive in 80% cases.

The culture of pleural fluid is positive in only 10% of cases.

Other recommended tests are LPA-Line probe assay and LAMP-Loop mediated isothermal amplification.

These tests (CBNAAT,LPA annd LAMP)are called WRDT-WHO recommended rapid detection test.

The Gold standard diagnostic test is now, liquid culture in the form of MGIT-Mycobacterium growth indicator tube culture which gives result in 3 weeks.Previously it was solid culture.

Culture is positive in 1/3 to 1/2 cases of Tuberculosis.

FUTURE PROSPECT: CBNAAT has been used to detect Mycobacterium tuberculosis in stool sample  in children.Its sensitivity in one study in children and persons with HIV has been found to be over 80% and specificity over 95% when compared to respiratory sample.

After multicentre study,it may become the preferred sample for children in which respiratory sample is difficult to obtain.

TREATMENT:

Category II (CAT II) Treatment comprising of 2HRZES+1HRZE+5HRE has been completely withdrawn now.

There is  only one category now, for all patiens ,comprising of 2HRZE+4HRE,FIRST LINE ATT

For newly diagnosed cases,whether smear positive or smear negative this treatment should be completed for 6 months.

All patients,who have not taken ATT previously or have taken it for less than 4 weeks are labelled as New Case

In cases of neurotuberculosis or spinal tuberculosis,the continuation phase comprising of HRE should be extended for 8 months.

In cases of relapse,defaulters, retreatment,treatment after failure, and any contact with resistance tuberculosis,the sample should be sent for DST-Drug sensitivity test,  while the treatment started as 2HRZE+4HRE.

If the result comes as sensitive to first line medications,the treatment should be completed with this regimen only

If resistance comes to any drug, then the second line drugs should be started according to the sensitivity pattern.

Second line drugs are less potent and should be given for prolonged time.

Two highly potent drugs Dalaminid and Bedaquilline are now recommended for treatment of children with resistant tuberculosis.

Bedaquilline is recommended for children 6 years and above.

Dalaminid is recommended for children 3 years and above.

These two drugs are available at selected centres in India

In cases of LTBI -Latent tuberculosis bacillus infections,in which only Tuberculin sensitivity test or IGRA is positive but there is no clinical symptom and sign or any lesion in any organ suggestive of tuberculosis,no treatment is given in India.

In Western countries,the current recommendation is to treat LTBI with 12 Doses of HP-3HP-(3 months of HP)

Previously it was recommended for adults,but now it is recommended in children also

In such cases(LTBI),weekly doses of Rifapentine and isoniazid is given for 12 weeks.

Currently,it is not recommended for children below 2 years of age.

All children receiving isoniazid should be given daily dose of 10 mg of pyridoxine.

Definite indications of steroid along with ATT are TBM,Pericarditis,Addisons disease,Miliary TB with alveolocapillary block and TB uveitis.

Steroid can be given in endobronchial tuberculosis,pleurisy with severe distress,bronchial compression,mediatinal compression syndrome,laryngeal TB,and TB-IRIS(Immune reconstitution inflammatory sundrome).

Evidence is not sufficient for tuberculoma.

Prednisolone 1-2 mg/kg/day or dexamethasone 0.6mg/kg/day or any steroid in equivalent doses ,should be given for 4 weeks then tapered over next 4 weeks.

REFERENCES:

RNTCP Updated Pediatric TB Guidelines 2019 developed by Revised National TuberculosisControl Programme and Indian Academy of Pediatrics.

Guidance document draft as on 04.02.2019,Central TB division,Ministry of Health and Family Welfare,New Delhi India

CDC:Treatment Regimen for Latent TB infection

CDC:The 12 dose Regimen forLatent Tb infecvtion Treatment:Fact Sheet for clinicians

Eur Respir J 2019 53:1801832; published ahead of print 2018,
doi:10.1183/13993003.01832-2018

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

;