TUBERCULOSIS

 Definition: Tuberculosis  is a chronic bacterial infection caused by a group of

bacteria, Mycobacterium tuberculosis complex, the most common of which

is Mycobacterium tuberculosis. Less frequently, it can be caused by

Mycobacterium bovis and Mycobacterium africanum.

• Tuberculosis usually affects the lungs in which case it is called pulmonary TB.

• In addition to the lungs, any part of the body can be affected with this

bacterium and in this case, it is called extra-pulmonary TB.

• Common extra-pulmonary sites affected include the lymph nodes,

pleura, spine, urinary tract, the brain, joints, bone and abdomen.

• HIV infection is one of the most important risk factors for the development of active tuberculosis.

CLINICAL FEATURES

• The clinical features of tuberculosis depend on the specific organ affected.

• The clinical features can be grouped: general (non-specific) and organ specific

#The general symptoms of TB (pulmonary or extra-pulmonary):

o Weight loss, fever, night sweats, loss of appetite, fatigue, malaise

o Malnourished and chronically sick appearance

#Organ specific 

* Pulmonary tuberculosis 

− Cough that lasts for more than 2 weeks with or without sputum production

− Chest pain,Hemoptysis,Shortness of breat

* Tuberculous lymphadenitis 

− Slowly growing painless lymph node enlargement

− Initially firm and discrete, later become matted and fluctuant.

− Formation of abscesses and discharging sinuses, which heal with scarring.

* Tuberculous pleurisy

− Pleuritic chest pain (pain while breathing/coughing/sneezing)

− Intermittent cough,Shortness of breath

− Signs of pleural effusion (dullness, decreased/absent air entry and decreased tactile fremitus)

* TB of bones and/or joints 

− Localized pain and/or swelling +/- discharge, stiffness of joints

− Spine (TB spondylitis): localized swelling over the back(gibbus),

back pain paralysis (weakness of the lower extremities)* Abdominal TB

− Chronic non-specific abdominal pain with diarrhea or constipation,

− Fluid in the abdominal cavity (ascites).

− Mass (inflammatory mass) in the abdomen

* Tuberculous meningitis

− Headache, fever, vomiting: insidious onset

− Neck stiffness, impaired level of consciousness.

* Tuberculous pericarditis

− Chest pain (pleuritic),Shortness of breath,and Pericardial friction rub or distant heart sounds

INVESTIGATIONS AND DIAGNOSIS 

Microbiologic tests to identify the bacilli

* Sputum direct microscopy: Ziehl Nielsen (acid fast bacilli) (AFB) staining

− Three sputum specimens (SPOT-EARLY MORNING-SPOT) need to be collected and examined in two consecutive days

− Result must be available on the second day.

* Gene Xpert MTB/RIF

− A fully automated DNA/molecular diagnostic test to detect TB and Rifampicin resistance simultaneously.

− It is recommended as the initial diagnostic test for all persons being evaluated for TB

* Sputum culture and drug susceptibility

− Culture is the gold standard , It takes weeks to get the results.

− If sputum AFB and/or Gene Xpert are negative and there is a strong suspicion, sputum culture can be sent to a referral

laboratory. However, treatment for an alternative diagnosis or “clinical TB” should not be delayed.

* Line Probe Assay (LPA)

− A test to identify the presence of specific mutations on the genes

of TB bacilli which are responsible for Isoniazid and Rifampicin resistance.

− It is a rapid and accurate test to identify cases with MDR-TB.

− The test may be available in referral laboratory for patients

suspected of MDR-TB.

• Body fluid analysis and identification of pathogen

* Pleural fluid, ascitic fluid, CSF

-Cell count with differential

− Protein, glucose,LDH,Gene Xpert ,Cytology (cytopathology)

Chest X-ray

TREATMENT OF DRUG SUSCEPTIBLE TB

Non pharmacologic

• Counseling: adherence, the nature of treatment, contact screening

• Good nutrition, Adequate restAdmission for severely ill patients e.g., Tb meningitis, pericarditis Pharmacologic

• Standardized combination treatment: all patients in a defined group receive the same treatment regimen.

• A combination of 4 or more anti-TB medicines.

• Directly observed treatment (DOT)First line anti-TB Medicines

• The first line anti-TB medicines available for TB treatment in Ethiopia are:

o Rifampicin (R): the most bactericidal and potent sterilizing agent

o Isoniazid (H): highly bactericidal especially in the first few days

o Pyrazinamide (Z): only active in acidic environment and bacilli inside macrophages

o Ethambutol (E): bacteriostatic and effective to prevent drug

resistance when administered with other potent drugs

*Standardized first line treatment regimen for new drug

susceptible (presumed to be drug susceptible) tuberculosis

o New pulmonary TB (PTB) patients presumed or known to have drugsusceptible TB

New extrapulmonary TB (EPTB) patients

− Standardized regimen: 6 months total (2 months intensive and 4

months continuation phase) 2RHZE/4RH

− Intensive phase: 2 months Rifampicin, Isoniazid, Pyrazinamide & Ethambutol (2RHZE)

− Continuation: 4 months Rifampicin and Isoniazid (4RH)Extended continuation phase

 The following extrapulmonary forms of Tb require prolonged

continuation phase

− CNS (TB meningitis or Tuberculoma)

− Bone or joint TB (Vertebral (TB spondylitis), joint and

osteomyelitis), which require prolongation of the continuation phase for

o Regimen (a total of 12 months: 2months intensive phase and 10 months

continuation phase); 2RHZE/10RH

• Adjuvant corticosteroid therapy

 Adjuvant corticosteroid therapy, dexamethasone or prednisolone

tapered over 6-8weeks should be used for patients with the following

two extrapulmonary forms

− TB meningitis ,and TB pericarditis

Corticosteroid for TB meningitis

o Dexamethasone 12 mg/day OR Prednisolone 60mg/day for 3 weeks

and then decreased gradually during the subsequent 3 weeks.

MONITORING OF PATIENTS ON TREATMENT

• Clinical monitoring: during scheduled visit, a patient receiving anti-TB

treatment should be checked for the following

* Persistence or reappearance of clinical feature of TB

* Weight monitoring: weight is a useful indicator of clinical improvement

especially in children and should be monitored monthly.

* Occurrence of Adverse drug reaction ,Development of TB complications.

* Adherence: by reviewing the “treatment supporter card” or UNIT TB register

* Risk for drug resistance, and need for drug susceptibility testing screening

− Unsatisfactory response to treatment beyond two months of

treatment should alarm the possibility of drug resistance or alternative diagnoses

Management of adverse reaction to First line Anti-TB drugs

o Health workers should regularly monitor for occurrence of side effects

to the Anti-TB drugs administered to the patient.

Isoniazid (H)Adverse reaction

Isoniazid (H) Skin rash, Sleepiness and lethargy, Peripheral neuropathy

(paresthesia, numbness and limb pain), Hepatitis.

Rare: Convulsions, pellagra, arthralgia, anemia, lupoidreactions

Drug interactions

Al(OH)3 decreases its absorptionINH inhibits metabolism of

phenytoin, diazepam carbamazepine and warfarin hence increases the serum concentrations

Rifampicin(R) Adverse reaction

 

 

Gastrointestinal reactions (abdominal pain, nausea, vomiting), Hepatitis, Generalized

cutaneous reactions, Thrombocytopenic purpura.

Rare: Osteomalacia, pseudomembranous colitis, acute renal failure, shock, hemolytic anemia

Drug interactions

Increase metabolism of warfarin, corticosteroids,

antifungal agents, protease inhibitors, non- nucleoside reverse transcriptase inhibitors,

oral hypoglycemic agents, oral contraceptives hence reduces serum levelsof these medicine

Ethambotol (E):-Adverse reaction

Retrobulbar/Optic neuritis, (impairment of vision, red–green blindness, blurring)

Rare: Generalized cutaneous ,reactions, arthralgia, peripheral neuropathy

Pyrazinamide (Z):-Adverse reaction

Arthralgia, Hepatitis; Rare: Gastrointestinal reactions,utaneous reactions,

csideroblastic anaemia

Treatment of patients with renal failure:

* In patients with estimated GFR <30ml/min or those on dialysis the

dose of Ethambutol and Pyrazinamide need to be reduced from daily to three times per week.

* Rifampicin and Isoniazid do not need adjustment in patients with renal failure.

* To reduce Ethambutol and Pyrazinamide without reducing Rifampicin

and Isoniazide make using the available fixed drug combinations, use the following regimen.

− Intensive phase: RHZE three days per week and RH the remaining four days( for 2 months)

− Continuation phase: RH daily

• Treatment of patients with (previously known) liver disorder

(e.g. hepatitis, cirrhosis):

* Most anti-TB medicines can cause liver damage. ,* Do not give Pyrazinamide.

* Isoniazid & Rifampicin plus one or two non- hepatotoxic medicines

(Ethambutol and/or Streptomycin) can be used, for a total duration of eight months: 2SERH/6RH

* If the patient has severe liver damage or jaundiced: Streptomycin plus

Isoniazid plus Ethambutol in the initial phase followed by Isoniazid &

Ethambutol a total duration of 12 months: 2 SHE /10 HE

Treatment during pregnancy and breast-feeding

Pregnant women living with HIV are at higher risk for TB during pregnancy and postpartum, twhich

can have severe consequences for both the mother and the infant. Pregnancy should no disqualify

women living with HIV or HIV-negative pregnant women who are eligible for receiving TPT since

isoniazid and rifampicin, the medicines commonly used in preventive treatment, are considered safe

for use in pregnancy (classified as Pregnancy Category C by U.S. Food and Drug Administration).

Therefore, TPT should be started during the antenatal and postnatal periods along with due care.

Routine LFT is not indicated when TPT is given during pregnancy unless there are other hazards.

Vitamin B6 supplementation should be given routinely to all pregnant and breastfeeding women on TPT.

 Rifampicin is generally considered safe for use during pregnancy, and no dose adjustment is

needed although no safety or efficacy data are available specifically for pregnant and postpartumwomen

. There are limited data on the efficacy and safety of rifapentine in pregnancy and therefore

1HP and 3HP should not be used in pregnancy until more safety data are available. Until such data

become available, IPT may be used for TPT among pregnant and postpartum women with HIV with due supportive care and monitoring.

Preventive treatment using isoniazid and or rifampicin can be safely given to breastfeeding

Supplemental pyridoxine (vitamin B6) should be given to the infant who is taking isoniazid or whose  breastfeeding mother is taking isoniazid

Women receiving oral or hormonal contraceptives

Rifampicin and rifapentine interact with oral and hormonal contraceptive medications with a

potential risk of decreased contraceptive efficacy. Women receiving oral contraceptives while on

rifampicin or rifapentine should either:

§ change the oral contraceptive pill and use an alternative (such as depot

medroxyprogesterone acetate (DMPA) every eighth week or higher dose oestrogen (50μ)) in

consultation with a clinician; or

§ use another form of contraception, a barrier contraceptive or intrauterine device.

In women having hormonal contraceptive implants, the interval for replacing the implants may need

to be shortened from 12 weeks to eight weeks (ACTG study A5338)

TB preventive treatment in New born

Once a pregnant woman with TB has been on treatment for TB for several weeks before delivery,

is less likely that the baby will become infected. The risk is highest if a mother is diagnosed at the

time of delivery or shortly thereafter. If a pregnant woman is found to have pulmonary TB shortly

before delivery, then the baby, and if possible, the placenta, should be investigated for evidence  

congenital TB infection. If the result is positive, the new born should be treated accordingly.asymptomatic, the new born should receive TB preventive treatment followed by BCG immunization. Breastfeeding can be safely continued during this period.

Management of babies born to mothers with TB disease:

§ Assess the newborn. If the newborn is not well, refer to a specialist/paediatrician. It is

important to ensure that the mother receives effective TB treatment so that she is no longer

infectious. Also, ensure that infection control measures are in place in the nursery, especially

if the baby is in an inpatient facility for care when preterm or small at birth.

§ If the newborn is well (absence of any signs or symptoms presumptive of TB), provide TPT

and delay bacille Calmette-Guérin (BCG) vaccination until TPT is complete. Administer

pyridoxine at 5–10 mg/day.

§ If the infant is HIV-exposed (mother is HIV infected) and on nevirapine, IPT should be started.

TPT with RH and HP cannot be given along with nevirapine prophylaxis since rifamycins

decrease nevirapine levels and may result in increased mother-to-child transmission of HIV.

§ At the end of TPT, perform TST or IGRA. If test for TB infection is negative or not available,

give BCG (unless the baby is HIV-positive).

§ If the mother is taking anti-TB drugs, she can safely continue to breastfeed. Mother and baby

should stay together, and the baby may be breastfed while on TPT.

§ Infant breastfeeding from a mother on either TB treatment or TPT should receive pyridoxine

for the duration of the mother’s treatmen

Treatment of patients also infected with HIV

o All patients with HIV and active TB who are not on ART should be

started on ART as described below:

− CD4 <50 cells/mm3: Initiate ART within 2 weeks of starting TB treatment

− CD4 counts ≥50 cells/mm: Initiate ART within 8 weeks of starting TB treatment.

− During pregnancy, regardless of CD4 count: Initiate ART as early

as feasible, for to prevent HIV transmission to the infant (AIII).

− With tuberculous meningitis: Initiate ART after 8 weeks of TB treatment.

o Rifampicin can interact certain ARVS, particularly, some protease

inhibitors; hence, drug interaction should be checked.

 DRUG RESISTANT TB

• TB is considered drug-resistant (DR) when the causative agent

(mycobacterium tuberculosis) is not killed by one or more of the available

anti-TB medicines.

• Medicine- resistant TB can be primary or secondary (acquired).

• Primary resistance is medicine resistance among new cases i.e. persons

who have never been previously treated for TB.

• Secondary resistance is medicine resistance among previously treated individuals.

• There are five different types of medicine resistance:

o Mono-resistance: Resistance to one anti-tuberculosis medicine.

o Poly-resistance: Resistance to more than one anti-tuberculosis

medicine, other than Isoniazid and Rifampicin.

o Multidrug-resistance (MDR)-TB: Resistance to at least isoniazid and

rifampicin, two most important first-line drugs.

o Extensive drug-resistance (XDR-TB): Resistance to any of the

fluoroquinolones, and at least one of the injectable Second Line

Medicines (capreomycin, kanamycin and Amikacin), in addition to resistance to INH and rifampicin. o Total drug-resistance (TDR-TB): resistance to all anti TB medicines.

The clinical features of medicine susceptible and medicine resistant TB are the same.

INVESTIGATION AND DIAGNOSIS

• Direct smear microscopy,Gene Xpert MTB/RIF test

• Line Probe Assay (LPA) directly from the sputum specimen or

cultured sampleulture and Drug Susceptibility Test (DST)

• The definitive diagnosis of medicine-resistant TB depends on laboratory

diagnosis through Medicine Susceptibility testing (DST); it requires that

M.tuberculosis is isolated and medicine susceptibility test is completed.

• Other investigations: Chest X-ray, HIV test, CBC, urinalysis, FBS, LFT, RFT,

Serum electrolyte, TSH, HCG, Audiometric test.TREATMENT OF MDR-TB • Cure the TB patient and restore quality of life and productivity

• Prevent death from active TB or its late effects and • Prevent TB relapse

• Prevent the development and transmission of extensive medicine resistance

• Decrease transmission

Non pharmacologic

• Surgery (see the adjunct therapies section below) and Adherence counseling

• Psychosocial and emotional support, Nutritional support

Pharmacologic

• Treatment of isoniazid monoresistant TB

o Rifampicin, Ethambutol, Pyrazinamide and Levofloxacin for duration of 6 months.

• Monitoring patient response to MDR-TB treatment using culture

o Treatment response should be monitored clinically, radiographically,and bacteriologically

o Sputum smear microscopy and culture monthly.

o When cultures remain positive after 3 months of treatment, do drug susceptibility tests

• Care and support for patients with MDR/RR-TB

o Health education and counselling on the disease and treatment adherence.

o One or more of the following treatment adherence interventions

(complementary and not mutually exclusive) may be offered to patients

− Tracers and/or digital medication monitor;

− Material support to the patient

− Psychological support to the patient, Staff education

• Treatment of Contacts Exposed to MDR-TB

o For close contacts with presumed MDR TB latent infection, give 6 to 12

months treatment with a fluoroquinolone alone or with a second drug,

on the basis of source-case isolate DST.

o Pyrazinamide should not be used as the second drug.