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

2. 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.

3. Diagnosis of TB in children- The Traditional Diagnostic prerequisites
Combination of :
Contact with infectious adult case
Symptoms and signs
Positive tuberculin skin test (TST)
Suspicious CXR
Bacteriological confirmation
Serology

4. 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)

5. 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)

6. 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.

7. 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:
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

9. 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

10. 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

11. Other HIV-related Conditions
Pneumocystis pneumonia
Oesophageal candidiasis
Extrapulmonary cryptococcosis
Invasive salmonella infection
Lymphoid interstitial pneumonitis
Herpes Zoster (shingles)
Kaposi’s Sarcoma
Lymphoma

12. Other pointers of HIV infection:
Oral: Herpes simplex, oral thrush, oral hairy leucoplakia
Cutaneous: Chickenpox, molluscum contangiosum
- Delayed developmental milestones
Severe progressive encephalopathy

13. History - Evaluation - Chronic cough > 21 days
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

14. Phlycternular conjunctivitis

15. Phlyctenular conjunctivitis

16. Erythema nodosum

18. A child with TBM and opisthotonus

19. Tuberculous adenitis

20. TB Spine with Gibbus (Thoraco-lumbar)

21. Clinical features of HIV infection and associated conditions
Severe wasting
Non-specific dermatitis
National Paediatric ART Training Slides Unit

22. Clinical features of HIV infection and associated conditions cont….
Dermatomal Herpes zoster
National Paediatric ART Training Slides Unit

23. Clinical features of HIV infection and associated conditions cont….
Oral candidiasis
National Paediatric ART Training Slides Unit

24. 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.

25. 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

26. 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

27. 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

28. HILAR/PERIHILAR OPACITIES

29. Perihilar adenopathy

30. 14/06/12-Homogenous opacity on the right lung field sparing the right perihilar region with loss of cardiac and diaphragmatic silhouettes and mediastinal shift to the left(pleural effusion). Patchy opacities are noted on the left lung field with blunting of the left costophrenic angle. Cardiac size cannot be assessed. Bony thorax appears normal.
Radiological Conclusion: Atypical pneumonia with bilateral pleural effusion RT>>Lt.?PTB
14/06/12

31. 22/06/12

32. 29/06/12-Bilateral widespread diffuse patchy opacities with background groundglass haziness obscuring the right cardiac border and hemidiaphragm including the ipsilateral costophrenic angle. Wideninmg of the superior mediastinum noted. ?Reactive thymic hyperplasia ? Adenopathy. A loculated homogenous opacity in the right upper lung zone with a lamellar component along the distal right coastal margin suggestive of loculated effusion with pleural adhgesions.
Radiological conclusion:Atypical pneumonia ? Tuberculosis

33. Previosly generalised patchy opacities with bilateral pleural effusion Rt>>Lt with mediastinal shift to the left ( see 14/06/12). Progressively there has been some reduction in the quantity of pleural fluid on the right but no significant change in parenchymal consolidative changes. Near homogenous opacities obliterating the cardiac and diaphragmatic silhouettes. Recently (see 10/07/12), the effusion on the left is worsening. Cardiac size cannot be fully assessed.
Impression:Tuberculous pneumonia with effusion in a background of HIV

34. 02/07/12

35. Radiological Picture of LIP
Diffuse bilateral reticulonodular infiltrates may appear similar to miliary TB
Bilateral hilar or mediastinal lymph node enlargement

36. LIP vs Miliary TB
LIP
Miliary TB

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

38. 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%).

39. Specimen collection 2. Gastric aspiration (fasting, early morning)
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.

40. Specimen collection-1 3. 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

41. Specimen collection -2 Broncho-alveolar lavage
Fine needle aspiration (FNA): of enlarged glands for AFB and cytology – has a high bacteriological yield
6. Biopsy

42. 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

43. Novel/Recent Advancesin
TB Diagnosis

44. 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: )
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

45. 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

46. TST vs IFN assays: traditional vs novel
TST IFN
Sensitivity %* %*
Specificity % %
Cross react BCG Yes No
Cross react NTM Yes No
Boosting Yes No
Cost Low Moderate
Patient visits
Lab no yes
* Less in the immunocompromised
(Nahid, Proc Am Thorac Soc, 2006)

47. 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

48. 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

50. 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)

51. TREATMENT OF TB IN CHILDREN

52. 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.

53. 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

54. Desirable Characteristics of Drugs
Bactericidal
Good sterilizing activity
Prevent of drug-resistance
Low toxicity

55. 1st Line Anti-TB (Essential Drugs WHO)
1. Rifampicin
2. Pyrazinamide
3. Isoniazid
4. Ethambutol
5. Streptomycin

56. Doses first-line anti-TB drugs
Drug (Abbrev) Recommended daily dose in mg/kg BW (range)
Current New
Isoniazid (H) 5 (4-6) (5-15)
Rifampicin (R) 10 (8-12) (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)?

57. 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

58. 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

59. Treatment: WHO category II
Previously treated smear positive PTB
- Relapse
- Treatment interruption-RAD
- Treatment failure
Treatment
- 2HRZES/1HRZE 5HRE

60. 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

61. 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

62. First line anti-TB drugs: Adverse effects
Drugs Adverse events
Isoniazid Skin rash, hepatotoxic, peripheral neuritis,psychosis
Rifampicin Hepatoxic, red urine, anorexia, nausea, abdominal pain, thrombocytopenia, drug interactions
Pyrazinamide Hepatotoxic, arthralgia
Ethambutol Optic neuritis
Streptomycin Rash, anaphylaxis, oto- and nephrotoxic

63. 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

64. 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

65. 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

66. 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

67. 2nd-line drugs - WHO Reserve Drugs
Ethionamide/prothionamide
Ofloxacin/levofloxacin/moxifloxacin
Cycloserine/terizidone
Kanamycin/amikacin
Capreomycin
Para-amino salicylic acid

68. REFERENCES
Proceedings from the Technical Consultation Workshop on Improving Management of Tuberculosis in children-June, 2010
NTBLCP 2010 guidelines
Paediatric ART guidelines 2010

69. THANK
YOU
FOR
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