MANAGEMENT OF TB-HIV CO-INFECTION BY THE RESPIRATORY/INFECTIOUS DISEASE UNIT,UCTH, CALABAR.

MANAGEMENT OFTB-HIV CO-INFECTION

BY THE RESPIRATORY/INFECTIOUS

DISEASE UNIT,UCTH, CALABAR

TUBERCULOSIS IN CHILDREN• It is commonly asked why young children with tb are not infectious.– They generally have a closed infection– They do not have significant cough. – They lack tussive force necessary to suspend infectious particles in

the air.– When cough is present children rarely produce sputum– When sputum is produced, organisms are sparse because they are

in low concentration in the endobronchial secretions of children.

Diagnosis of TB in children- The Traditional Diagnostic prerequisites

Combination of Combination of :: Contact with infectious adult caseContact with infectious adult case Symptoms and signsSymptoms and signs Positive tuberculin skin test (TST)Positive tuberculin skin test (TST) Suspicious CXRSuspicious CXR Bacteriological confirmationBacteriological confirmation SerologySerology

List of symptoms that may suggest TB in children:• Fever (Low or high grade), not responding to anti-

malaria treatment

• Weight loss, Static weight or failure to gain weight

• Failure to thrive

• Recent febrile illness with rash & desquamation (measles, persistent/continuous cough with vomiting (pertussis)

List of Suggestive Symptoms,continued• Loss of appetite

• Lymph node swellings

• Angle deformity of the spine (back swelling) • Joint or bone swellings

• Neck stiffness, vomiting, convulsions, impaired conscious (TB meningitis)

List of possible Physical signs • Chronically or s’tmes acutely ill looking +/- pallor• Small weight for the age (underweight), or features

of PEM • Discrete, or matted, frequently non-tender cervical

lymphadenopathy• Features of co-existing HIV or immunocompromised

status• Hypersensitivity parameters, eg Phlycternular

conjuctivitis, Erythema Nodosum• Manifestations of Primary Pulmonary Disease

(primary complex, bronchial)• Chest signs, or features of Extra-pulmonary TB.

TB Diagnosis in children & “value” of score charts

• In some countries, score charts are used for the diagnosis of TB in children but have rarely been evaluated or validated against a “gold standard” Marais BJ. Arch Dis child 2005;90:1166-70

• Score charts also perform poorly in PTB and HIV infected children!

Key features suggestive of TB• The presence of 3 or more of the following should strongly suggest

a diagnosis of TB: - Chronic symptoms suggestive of TB - Physical signs highly suggestive of TB - Positive TST - CXR suggestive of TB

Manifestations of TB in children

• >70% of children who develop TB disease have pulmonary manifestations, but ~25 – 35% may have an extrapulmonary presentation

• The most common extrapulmonary form is lymph

node TB accounting for about 2/3 of cases of extrapulmonary TB

• 2nd most common form is meningeal disease occurring in 13% of patients

TB-HIV COINFECTION

• Manifestations of co-existent HIV-infection:

– Persistent generalized lymphadenopathy, respiratory illnesses like pharyngotonsilitis, otitis media, mastoiditis, pneumonias, painless parotid enlargement.

– Gastrointestinal conditions like oropharyngeal candidiasis, diarrhoea, vomiting

Other HIV-related Conditions

• Pneumocystis pneumonia• Oesophageal candidiasis• Extrapulmonary cryptococcosis• Invasive salmonella infection• Lymphoid interstitial pneumonitis• Herpes Zoster (shingles) • Kaposi’s Sarcoma• Lymphoma

Other pointers of HIV infection:

– Oral: Herpes simplex, oral thrush, oral hairy leucoplakia

– Cutaneous: Chickenpox, molluscum contangiosum

- Delayed developmental milestones– Severe progressive encephalopathy

History - Evaluation• Careful history (including carefully extracting a

history of TB contact)

• Symptoms: commonest: - Chronic cough > 21 days - Fever T > 38oC for 14 days after excluding common causes, such as malaria or pneumonia

- Wt loss or FTT • Some children with TB infection may not develop

any signs or symptoms at any time

Phlycternular conjunctivitis

Phlyctenular conjunctivitis

Erythema nodosum

A child with TBM and opisthotonus

Tuberculous adenitis

TB Spine with Gibbus (Thoraco-lumbar)

Clinical features of HIV infection and associated conditions

Clinical features of HIV infection and associated conditions

National Paediatric ART Training Slides Unit 4 13 National Paediatric ART Training Slides Unit 4 13

Severe wasting Non-specific dermatitis

Dermatomal Herpes zoster

Clinical features of HIV infection and associated conditions cont….



Oral candidiasis




Tuberculin Skin Testing (TST)

• TST is the method used for detecting whether an individual has come in contact with the TB bacilli.

• The TST used is the Mantoux test, containing 5 tuberculin units administered intradermally.

• The test is read as mm of induration at 48 to 72 hours.

Mantoux Test

• A positive test occurs when a person is infected with M. tb but does not necessarily indicate disease

• Interpretation:- 0 – 4mm = negative- 5 – 9mm = borderline- ≥ 10mm = positive in all other children irrespective of the BCG vaccination- ≥ 5mm = positive in HIV infected children and severely malnourished children (marasmus, kwashiorkor)

• Useful in screening household contacts with TB

• Fewer HIV infected children will have a positive TST

• TST may be negative initially but positive after 2-3 mo of treatment

Chest Radiograph as a diagnostic tool of TB

• Spectrum of radiolographic changes depends on the stage of the disease & the nature of the intrathoracic complications

• There are no pathognomonic radiological signs of tuberculosis; other lung lesions (viral, bacterial & fungal LIP & IPH) can mimic those of pulmonary TB.

• Additional radiographs like cervical, spinal/vertebral & abdominal may also be required

Chest Radiograph as a diagnostic tool of TB - 2

• Certain radiological lesions may however suggest PTB:- Miliary mottling- Hilar or paratracheal lymphadenopathy - ± parenchymal involvement

- Collapse consolidation- Pleural effusion

• Cavitatory lesions are rare, but should nevertheless be looked for,

• Rarely chest X-ray may be normal

HILAR/PERIHILAR OPACITIES

Perihilar adenopathy

14/06/12

Radiological Picture of LIP

• Diffuse bilateral reticulonodular infiltrates may appear similar to miliary TB

• Bilateral hilar or mediastinal lymph node enlargement

LIP vs Miliary TB

LIP Miliary TB

LIP

Is this Miliary TB? No, it’s varicella pneumonia!

Bacteriological diagnosis in children• Isolation of TB bacilli from

clinical specimens remains the gold standard for diagnosis

• Isolation in children is more difficult than in adults, as they have paucibacillary disease

• The yield of the organism is low even in the best centres (<50%).

Specimen collection 1. Sputum :

- 10 years or older who can expectorate an on the spot specimen, an early morning specimen and another on the spot specimen

2. Gastric aspiration (fasting, early morning)

- Aspiration of gastric contents should be performed fasting, ideally while still recumbent after overnight sleep. - Therefore usually performed in hospitalized patients. - Strict adherence to the recommended collection techniques improves the yield of the procedure, as does the collection of specimens on three consecutive days.

Specimen collection-13. Induced sputum • The use of nebulized hypertonic saline to induce coughing

allows the production of respiratory specimens in children who cannot expectorate voluntarily

• Yield from 1 induced sputum specimen = 3 daily gastric

aspirates, and is ↑ further by repeated procedures • 149 children hospitalized pneumonia, Zar 2000

• median age 9 (3-30) months• IS in 142 (95%)• Induced Sputum positive in 15(10.6%) vs 9 Gastric Lavage (6.3%),

p=0.08

Specimen collection -2

4. Broncho-alveolar lavage 5. Fine needle aspiration (FNA): of enlarged glands for

AFB and cytology – has a high bacteriological yield

6. Biopsy

Other diagnostic parameters

• FBC and ESR- may be normal but commonly leucocytosis with a relative lymphocytosis and a high ESR

• BCG test– Normal BCG evolution– Accelerated BCG reaction

• Novel/Recent Advances in

TB Diagnosis

Lipoarabinomannan (LAM) assay

• Antigen capture ELISA assays for the detection of lipoarabinomannan (LAM) in sputum and urine samples has shown promise in suspected TB adults (Boehme C et al, Trans Roy Soc Trop Med Hyg 2005;99:893-900)

• LAM is a cell wall lipopolysaccharide antigen specific for M. tuberculosis

• Released from metabolically active or degrading cells

• Secreted intact in urine

• Results are rapid, typically within 2-3 hours • 76.5% sensitive in smear negative cases, 80.3% sensitive overall, 99% specific

• Performs well in the HIV-infected subgroup

Interferon Gamma Release assays (IGRA)

• New in-vitro test which measures interferon production by T-cells

• Principle: sensitised T cells produce interferon when mycobacterial Ags are encountered

• M. tuberculosis-specific Ags• Available IGRA-based Tests: 1. Quantiferon-TB - IFN production (pg/ml) 2. T SPOT-TB

- Detects number T cells producing IFN

TST vs IFN assays: traditional vs novel

TST IFN Sensitivity 75-90%* 80-95%*Specificity 75-90% 95-100%Cross react BCG Yes NoCross react NTM Yes NoBoosting Yes NoCost Low ModeratePatient visits 2 1Lab no yes

* Less in the immunocompromised(Nahid, Proc Am Thorac Soc, 2006)

Concerns with IFN assays• Cannot distinguish latent from active disease

• Few studies in children

• ? efficacy in very young/ HIV/ high incidence TB countries

• Discordance with TST results – Pai Lancet Infect Dis 2004, Mahomed IJTLD 2006

• ? impact of TB treatment

• Need for laboratory

• Cost

• Promising and more sensitive than TST

Other Newer M. tuberculosis detection methods

• BACTEC offer slightly superior sensitivity and reduced turn around times compared with conventional Loweinstein –Jensen medium (LJ-medium)

• MODS( microscopic observation drug susceptibility assay) 8 days to culture positivity – limited utility in children

• PCR: limited utility in children and low sensitivity in paucibacillary TB

• NAAT (nucleic acid amplification test) rapid test (WHO endorsed): 100mins

• TB fluorescence microscopy • Gene expert tb test

TB/HIV co-infection in children

• Should HIV testing be done in all children suspected of having TB (Yes)

• Should all HIV+ve children be screened for TB? (Yes)

• How do you differentiate HIV associated lung disease from TB disease?

• Can children with HIV lung disease also have TB disease? (Yes)

TREATMENT OF TB IN CHILDREN

Anti-TB treatment: 2 phases

• Intensive phase- to rapidly eliminate majority of bacilli

- to prevent emergence of drug resistance

• Continuation phase- to eradicate dormant organisms

• Either phase can be given daily or 3-times weekly.

Main objectives in TB Rx

• To rapidly kill most bacilli in order to:- stop disease progression- prevent transmission of infection

• To effect cure and prevent relapse (eliminate dormant bacilli)

• To do the above with minimal adverse reaction

• To prevent development of drug-resistant organisms

Desirable Characteristics of Drugs

• Bactericidal

• Good sterilizing activity

• Prevent of drug-resistance

• Low toxicity

1st Line Anti-TB (Essential Drugs WHO)

1. Rifampicin

2. Pyrazinamide

3. Isoniazid

4. Ethambutol

5. Streptomycin

Doses first-line anti-TB drugs

Drug (Abbrev) Recommended daily dose in mg/kg BW (range)

Current New

Isoniazid (H) 5 (4-6) 10 (5-15)

Rifampicin (R) 10 (8-12) 15 (10-20)

Pyrazinamide (Z) 25 (20-3) 35 (30-40)

Ethambutol (E) 20 (15-25) 20 (15-25)

Streptomycin (S) 15 (12-18) 15 (12-18)?

Codes for TB Rx regimens

• 2SHRZ/4H3R3

• Number in front of each phase = duration in

months

• Letters = abbreviated drugs

• Subscript numbers following a letter = number of

doses per week of that drug.

• If no subscript = drug is daily

Treatment: WHO category I

New smear positive PTB

New smear negative PTB with extensive parenchymal involvement

Severe forms of extraPTB

Severe concomitant HIV disease

Treatment

- 2HRZE, 4HR or 6HE

TB Meningitis

- 2HRZS, 4HR

Treatment: WHO category II

Previously treated smear positive PTB

- Relapse

- Treatment interruption-RAD

- Treatment failure

Treatment

- 2HRZES/1HRZE 5HRE

Other Basic Principles

• Combination therapy - always• Use fixed dose combination drugs if possible• DOTS – directly observed therapy, short course• Uninterrupted drug supply

Children with severe forms of TB (meningitis,

disseminated, TB spine, and TB pericarditis) should have

streptomycin added during the intensive phase

Pharmacological challenges

Rifampicin • Decreases the plasma level of Nevirapine (37%), efavirenz

(25%), not enough info on dosage adjustment in children.

RMP can be used with EFV in children over 3years

• Decreases plasma level of all PIs Lopinavir(75%)

ritonavir(35%) (LPV/r, Kaletra, Aluvia),

• Decreases plasma level of Zidovudine, abacavir

First line anti-TB drugs: Adverse effects

Drugs Adverse eventsIsoniazid Skin rash, hepatotoxic, peripheral

neuritis,psychosis

Rifampicin Hepatoxic, red urine, anorexia, nausea, abdominal pain, thrombocytopenia, druginteractions

Pyrazinamide Hepatotoxic, arthralgia

Ethambutol Optic neuritis

Streptomycin Rash, anaphylaxis, oto- and nephrotoxic

Drug-resistant Tb; Definitions

• Mono-drug resistance: Resistance to single drug

• Poly-drug resistance: Resistance to 2 or more drugs, but not to both INH and RMP

• MDR TB: Resistance to INH & RMP +/- other drugs

• XDR TB: MDR & 2nd-line injectable & quinolone

• Primary resistance: No previous anti-TB Rx or less than 1 month

• Acquired resistance: Previous anti-TB Rx >1 month

Drugs resistant TB… (contd)

• WHO estimated that 511 000 new cases of MDR-TB

occurred in 2007, 4.9% of all TB cases

• Contribution of Nigeria largely unknown

• Lately, Rifampicin mono-resistance seems on the

increase in especially HIV-infected adults

Causes of Drug Resistant TB

• Poor management of drug-susceptible or mono-resistant TB cases

e.g. incorrect regimens, interrupting treatment (drug supplies, poor bio-availibility), poor adherence by patients

• Poor management of MDR-TB cases leads to transmission of MDR-TB strains

e.g. late diagnosis, not doing DST in relapse/retreatment cases, poor infection control measures especially in high prevalence HIV settings

MDR-TB in children

• Disease (>90%) in children usually develops within 12 months of infection

• This has to be confirmed with DST and DNA-fingerprinting

• Contact tracing and follow-up of children exposed to MDR/XDR-TB should receive high priority

2nd-line drugs - WHO Reserve Drugs

• Ethionamide/prothionamide

• Ofloxacin/levofloxacin/moxifloxacin

• Cycloserine/terizidone

• Kanamycin/amikacin

• Capreomycin

• Para-amino salicylic acid

REFERENCES

• Proceedings from the Technical Consultation Workshop on Improving Management of Tuberculosis in children-June, 2010

• NTBLCP 2010 guidelines• Paediatric ART guidelines 2010

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