TB in Pediatric HIV

1
TB in Pediatric HIV

• Ana M. Alvarez, M.D.
• Division of Pediatric Infectious Diseases and
  Immunology
• University of Florida Health Science
  Center/Jacksonville

2
Disclosure of Financial Relationships

• This speaker has no significant financial
  relationships with commercial entities to
  disclose.
• This slide set has been peer-reviewed to ensure
  that there are no conflicts of interest
  represented in the presentation.

3
Children are NOT small adults!
4
Objectives

• Review the epidemiology of TB, and its close
  relation with the epidemiology of HIV
• Review the clinical presentation and diagnosis of
  TB in children, including the differences in the
  HIV-infected individuals
• Briefly discuss the management of TB in
  HIV-infected children

5
Tuberculosis Epidemiology
6
(No Transcript)
7
TB Case Rates, United States, 2004
D.C.
lt 3.5 (year 2000 target)
3.64.9
gt 4.9 (national average)
Cases per 100,000.
8
Reported TB Cases United States, 19822004
No. of Cases
1982
1987
1991
1995
1999
2004
Year
All case counts and rates for 19932003 have been
revised based on updates received by CDC as of
April 1, 2005.
9
Reported TB Cases by Age Group United States, 2004
lt15 yrs (7)
gt65 yrs (19)
1524 yrs (11)
2544 yrs (34)
4564 yrs (29)
10
TB Case Rates by Race/Ethnicity United States,
19932004
Cases per 100,000
All races are non-Hispanic. Since 2003,
Asian/Pacific Islander category includes either
1) persons who reported race as Asian only or 2)
Native Hawaiian or Other Pacific Islander only.
All case counts and rates for 19932003 have been
revised based on updates received by CDC as of
April 1, 2005.
11
Trends in TB Cases in Foreign-born Persons,
United States, 19862004
No. of Cases
Percentage
All case counts and rates for 19932003 have been
revised based on updates received by CDC as of
April 1, 2005.
12
Countries of Birth for Foreign-born Persons
Reported with TB United States, 2004
Mexico (25)
Other Countries (38)
Philippines (11)
S. Korea (3)
Viet Nam (8)
Haiti (3)
China (5)
India (7)
13
Estimated HIV Coinfection in Persons Reported
with TB, United States,19932003
Coinfection
Note Minimum estimates based on reported
HIV-positive status among all TB cases in the
age group.
All case counts and rates for 19932002 have been
revised based on updates received by CDC as of
April 1, 2005.
14
TB Definitions

• Exposed person recent contact with a person with
  suspected or confirmed, contagious TB, negative
  TST, PE and CXR.
• Latent tuberculosis infection (LTBI) positive
  TST, no physical findings of disease, negative
  CXR or calcifications
• Tuberculosis disease signs/symptoms and/or
  radiographic manifestations
• Pulmonary
• Extrapulmonary
• Both

15
Populations with High Prevalence of TB infection

• Close contacts of an infectious TB case
• Foreign-born persons from high-prevalence
  countries
• Residents of long-term facilities (correctional
  facilities, nursing homes)
• HIV-infected, users of illicit drugs, homeless
• Migrant farm workers
• The elderly

16
Conditions That Increase the Risk of TB Disease

• HIV infection
• Substance abuse (especially drug injection)
• Recent infection with M. tuberculosis
• CXR findings suggestive of previous TB and
  history of inadequate treatment
• Certain medical conditions malignancies,
  immunosuppressive therapy, diabetes mellitus,
  chronic renal failure/hemodialysis, silicosis,
  malnutrition.

17
TB and HIV Co-infection

• TB and HIV infection each result in a host immune
  response, which in turn influences the natural
  progression of the other pathogen
• Persons co-infected with HIV and M. tuberculosis
  are at very high risk of developing TB disease
• 10/year vs. 10 over lifetime (HIV-)

18
TB and HIV Co-infection

• Immune response to TB enhances HIV viral
  replication
• In vitro studies (activated macrophages)
• TB treatment alone leads to reductions in viral
  load.
• Active TB accelerates the natural course of HIV
• Mortality rate for patients with TB
• HIV is 4 times higher than HIV-
• After the initial period, deaths are related to
  HIV, not TB

19
Diagnosis of Tuberculosis

• Medical history
• Physical examination
• Tuberculin skin test
• Chest radiograph
• Bacteriologic or histologic exam

20
Diagnosis of Tuberculosis

• Medical history
• Symptoms of disease
• History of exposure, infection, or disease
• Past TB treatment
• Demographic risk factors
• Medical conditions that increase risk for TB
  disease

21
Pediatric TuberculosisClinical Presentations

• Pulmonary TB
• 75-80 of presentations in children
• Symptoms depend on the age
• Infants fever, persistent cough, decreased
  appetite, wheezing
• School-aged children can be asymptomatic
• Adolescents productive, prolonged cough
  (gt3weeks), with systemic symptoms (fever, chills,
  night sweats, loss appetite, weight loss)

22
Pediatric TuberculosisClinical Presentations

• Primary pulmonary TB
• Typical primary focus with hilar adenopathy with
  or without focal infiltrates, usually mild to
  moderate symptoms (could be asymptomatic)
• Progressive primary progression of primary focus
  to produce extensive pulmonary infiltrates and
  cavitation, severe symptoms resembling pyogenic
  pneumonia (rare)

23
Pediatric TuberculosisClinical Presentations

• Chronic pulmonary TB (Adult-type)
• Results from reactivation producing cavitation
• Usually presents with classic symptoms.
• Rare in young children, but can occur in
  adolescents.

24
Chest Radiograph in Children with TB

• Enlarged mediastinal or hilar lymph nodes with or
  without parenchymal lesions
• Persistent chest pathology not responding to
  routine antibiotics

25
(No Transcript)
26
(No Transcript)
27
(No Transcript)
28
Chest Radiograph in Children with TB

• Enlarged mediastinal or hilar lymph nodes with or
  without parenchymal lesions
• Persistent chest pathology not responding to
  routine antibiotics
• Rapid and unexplained appearance of a nodular
  reticular pattern

29
(No Transcript)
30
Chest Radiograph in Children with TB

• Enlarged mediastinal or hilar lymph nodes with or
  without parenchymal lesions
• Persistent chest pathology not responding to
  routine antibiotics
• Rapid and unexplained appearance of a nodular
  reticular pattern
• Pleural effusion

31
(No Transcript)
32
Chest Radiograph in Children with TB

• Enlarged mediastinal or hilar lymph nodes with or
  without parenchymal lesions
• Persistent chest pathology not responding to
  routine antibiotics
• Rapid and unexplained appearance of a nodular
  reticular pattern
• Pleural effusion
• Cavitary lesions

33
(No Transcript)
34
Diagnosis of TuberculosisClinical Presentations

• Extrapulmonary
• More common in HIV children than HIV-
• Symptoms depend on the site affected
• Swollen LN (TB Lymphadenopathy)
• Mental status changes (TB meningitis)
• Back pain (TB of the spine)
• Chronic otorrhea (TB mastoiditis)

35
(No Transcript)
36
(No Transcript)
37
Diagnosis of TuberculosisClinical Presentations

• TB Meningitis
• Classic TB symptoms
• Fever, chronic cough, and wt loss
• Neurologic signs/symptoms
• Headache/irritability, vomiting
• Altered mental status, seizures
• Cranial nerve palsy
• Hemiplegia, quadriplegia

38
Diagnosis of TuberculosisClinical Presentations

• TB Meningitis
• CSF findings Mononuclear pleocytosis, elevated
  protein, low glucose
• AFB smear and culture yield of is low
• PCR variable sensitivity and specificity
• Negative does not rule it out!

39
Diagnosis of TuberculosisClinical Presentations

• TB Meningitis
• Radiologic findings
• CXR with classic findings
• Head CT
• Meningovascular enhancement, tuberculoma
  formation, obstructive hydrocephalus STRONGLY
  SUGGESTIVE
• Brain MRI
• Superior in defining lesions of basal ganglia,
  midbrain and brain stem

40
(No Transcript)
41
Comparison of Diagnostic Criteria of TB
Meningitis in HIV-infected and uninfected
Children

• 34 HIV and 56 HIV- children (South Africa)
• Neurologic presentation and CSF findings were
  similar
• Significant differences
• Classic Head CT findings less prominent in HIV
• Evidence of pulmonary TB was more frequent in
  HIV
• Conclusion diagnosis requires high index of
  suspicion!!!
• PIDJ 20062565-69

42
Diagnosis of TuberculosisClinical Presentations

• Miliary TB
• Results from hematogenous spread, affecting 2 or
  more organs
• Signs symptoms fever, malaise, weight loss,
  night sweats, lymphadenopathy, hepatosplenomegaly,
  etc.
• 30 may develop meningitis
• TST may be nonreactive
• CXR has a characteristic pattern

43
(No Transcript)
44
(No Transcript)
45
Clinical manifestations of active TB in early vs.
late HIV infection in adults
46
AAP Recommendations for Tuberculin Skin Testing
(TST)Red Book 2003

• Annual TST is indicated
• Children infected with HIV
• Incarcerated adolescents

47
Administering the Tuberculin Skin Test (TST)

• Use intradermal Mantoux test with
  0.1 ml of 5 TU PPD tuberculin
• Creation of a visible wheal is crucial to
  accurate testing
• Read reaction 48 - 72 hours after injection
• Parents are NOT to read the skin test.
• Measure only induration (transversely to the long
  axis of the forearm)
• Record results in millimeters

48
Administering the Tuberculin Skin Test (TST)

• A reaction that develops after 72 hours should be
  read and considered the result
• TST can be administered during the same visit
  that immunizations, including live-virus vaccines
• If TST cannot be administered at the same time,
  it should be deferred for 4-6 weeks post
  vaccination (only for live-virus vaccines)
• BCG vaccination is not a contraindication to TST

49
Anergy

• Do not rule out diagnosis of TB on the basis of a
  negative tuberculin skin test result
• Consider anergy in persons with no reaction,
  especially persons with HIV infection,
  immunosuppressive therapy, severe or febrile
  illness or overwhelming TB disease
• Test of anergy by administering at least two
  other delayed-type hypersensitivity antigens in
  conjunction with tuberculin skin testing is NO
  longer recommended.

50
BCG Vaccination and Tuberculin Skin Testing

• BCG may cause positive reaction to tuberculin
  skin test
• Recent BCG vaccination (lt5 years)
• Multiple BCG vaccinations
• Evaluate all BCG-vaccinated persons who have a
  positive skin test result for preventive therapy

51
Classifying the Tuberculin Reaction

• ?? 5 mm is positive in
• HIV-positive persons
• Recent contacts of an active TB case
• Patients with organ transplants and other
  immunosuppressed patients
• Children suspected to have tuberculosis disease
• Chest X-rays or clinical presentation
• Red Book 2003

52
Classifying the Tuberculin Reaction

• ??5 mm is positive in
• Children suspected to have tuberculosis disease
• Chest roentgenogram consistent with active or
  previously active tuberculosis
• Clinical evidence of tuberculosis
• Red Book 2003

53

• HIV-infected individuals, infants and children
  lt4 y/o and postpubertal adolescents are at
  increased risk of progression to disease and
  should be evaluated and treated as soon as TB is
  suspected.

54
Specimen collectionWhich is the best sample in
children?

• Traditionally (AAP Red Book 2003)
• Gastric aspirates for young children or older
  children without a productive cough.
• Obtain with NG tube upon awakening the child and
  before ambulation or feeding
• Submit three specimens
• For older children and adolescents with
  productive cough
• Obtain three spontaneous sputum specimens
• Culture pleural fluid, CSF, other body fluids and
  biopsy specimens for AFB.

55
Specimen collectionRole of Induced Sputum in
Children

• Recent study (Lancet 2005 365 130)
• Compared the yield of induced sputum (IS) with
  gastric aspirates in young children (mean age 13
  mo, range 1mo-5 years)
• Results
• 1 IS 3 gastric aspirates (64-66)
• 3 IS much better 87
• Minor side effects increased coughing,
  epistaxis, vomiting, wheezing.

56
Specimen collectionWhich is the best sample in
children?

• Problems with gastric aspirates
• Need for overnight stay
• One study suggested it can be done as outpatient,
  but results not duplicated
• Time consuming and unpleasant
• Problems with induced sputum
• Risk of bronchospasm/need to give bronchodilators
• Limited experience in very young children
• Most centers are not familiar or comfortable with
  the procedure in children

57
Specimen collectionWhich is the best sample in
children?

• New Suggestions
• For young children (less than 5 y?)
• Gastric aspirates
• For older children without a productive cough
• Induced sputum
• For older children and adolescents with
  productive cough
• Spontaneous sputum
• Culture pleural fluid, CSF, urine, other body
  fluids and biopsy specimens

58
Bacteriologic Evaluation

• Cultures should be obtained in young children
  when
• Source case isolate is not available
• Known or suspected MDR TB
• The child is immunocompromised (ALL HIV)
• Cases of extrapulmonary TB

59
Smear Examination and Culture

• Strongly consider TB in patients with smears
  containing acid-fast bacilli (AFB)
• Use culture to confirm diagnosis of TB
• Culture all specimens, even if smear is negative
• Use follow-up smear
  examinations to assess patients infectiousness
  and response to tx

60
Management of Tuberculosis
61
Recommendations for Treatment of TBATS/CDC/IDSA
2003 Whats New?

• The responsibility is assigned to the public
  health program/provider, NOT the patient.
• Patient-centered case management and DOT are
  strongly recommended.
• Emphasis on the importance of obtaining sputum
  cultures at completion of initial phase of Tx.
  (risk of relapse).
• Extended Tx is recommended for patients with
  cavitation, whose cultures remain after 2
  months of Tx
• Treatment completion is defined by number of
  doses ingested, as well as duration of Tx.

62
Directly Observed Therapy (DOT)

• In DOT, a health care worker watches the patient
  swallow each dose of medication
• Consider DOT for all patients it is the best way
  to ensure adherence
• DOT should be used with all intermittent regimens
• DOT can lead to significant reductions in relapse
  and acquired drug resistance

63
Treatment of TB in HIV-infected patients

• Treatment principles are the same as for
  HIV-negative patients.
• Important differences in management
• Drug interactions
• Paradoxical reactions
• Potential for acquiring resistance to rifamycins
  with highly intermittent regimen

64
HIV Co-infection and Drug interaction issues with
rifamycins

• Rifamycins induce hepatic enzymes causing
  significant drug interactions with ARV.
• Without rifamycin in the regimen, a delay in
  response and a poorer outcome may occur.
• A rifamycin should NOT be excluded from the
  anti-TB regimen.

65
HIV Co-infection and Drug interaction issues with
rifamycins

• Rifabutin has fewer interactions than Rifampin,
  but may require adjustments for its dose and the
  dose of certain ARV agents
• Rifampin can be used with certain ARV
  combinations (efavirenz, ritonavir-saquinavir,
  triple NRTI)
• CONSULT AN EXPERT!!!

66
HIV Co-Infection and the Paradoxical Reaction

• Temporary exacerbation of symptoms, signs,
  radiological findings after beginning of anti-TB
  meds
• Presumed to be the result of immune
  reconstitution
• Can happen in HIV-negative patients, but happens
  more often in HIV on ARV
• 36 HIV on ARV
• 7 HIV no ARV
• lt1 HIV-

67
HIV Co-Infection and the Paradoxical Reaction

• Signs may include high fevers, increase in size
  and inflammation of LN, expanding CNS lesions,
  worsening pulmonary infiltrates, enlarging
  pleural effusion
• Must rule out other causes, including TB
  treatment failure
• Steroids have been used to treat severe reactions
  

68
Recommended Treatment Regimens for
Drug-susceptible TB

• HIV co-infection
• Identical recommendations to those for
  HIV-uninfected persons, with 2 exceptions
• Patients with advanced HIV (CD4lt100) should be
  treated with daily or 3x week (NOT 2xweek) in the
  continuation phase
• INH-rifapentine 1x week (continuation phase)
  should not be used in any HIV-infected patient

69
Recommended Treatment Regimens for
Drug-susceptible TB

• Latent TB infection
• Isoniazid-susceptible 9 mo of INH daily
  (OPTIMAL)
• Isoniazid-resistant 4 mo of Rif daily (Adults)
• or intolerant 6 mo of Rif daily (Children)
• INH-Rif resistant Consult Specialist
• If daily therapy is not possible, DOT twice a
  week may be used
• for 9 mo.

70
Recommended Treatment Regimens for
Drug-susceptible TB in Infants, Children and
AdolescentsRed Book 2003

• Infection or Disease
• Category Regimen___________________
• Pulmonary 2 mo INH, R and PZA daily,
• (children) followed by 4 mo of INH
  and R
• Meds can be administered 2-3 /week by DOT after
  the first 2 weeks to 2 months.

71
Recommended Treatment Regimens for
Drug-susceptible TB in Infants, Children and
AdolescentsRed Book 2003

• If drug resistance is a concern, another drug
  (ethambutol or AG) is added until drug
  susceptibilities are determined.
• For hilar adenopathy only, 6 mo of INH and R are
  suficient.
• The optimal treatment of pulmonary TB in children
  and adolescents with HIV infection has not been
  established.
• AAP recommends at least 9 months, although there
  are no data to support this recommendation.

72
Recommended Treatment Regimens for
Drug-susceptible TB in Infants, Children and
AdolescentsRed Book 2003

• Extrapulmonary (except meningitis)
• Same as Pulmonary
• Meningitis
• 2 mo of INH, R, PZA, and AG or
  ethionamide daily, followed by 7-10
  mo of INH and R, daily or 2/week (9-12
  mo total)

73
Recurrent TB in Pediatric HIV

• May be due to
• Relapse (same strain)
• Reinfection (different strain)
• Factors adherence, resistance, duration of tx.
  course, severe immunodeficiency
• Reinfection is more common in areas of high TB
  incidence
• More common in HIV than HIV- children
• 16 vs. less than 5
• PIDJ 2005 24 685-691

74
Recurrent TB in Pediatric HIV

• South African study
• Relapse was more common than reinfection
• Poor adherence was reported in only 10 and there
  was no resistance
• 55 of children with recurrences had
  bronchiectasis, cavitation or fibrotic changes on
  CXR at end of tx (1st episode)
• Possible role in predisposing to recurrences
• Raises questions about adequate duration of tx.
• PIDJ 2005 24 685-691

75
Initial Evaluation

• HIV testing is recommended for all active cases.
• Consider it for LTBI cases.
• Assess risk factors for Hep B and C
• Send serologies accordingly
• Known HIV
• Chem LFTs, renal function
• CBC with platelets
• Testing of visual acuity and color vision
  (ethambutol)

76
Evaluation and Monitoring of Therapy

• Monthly clinical evaluations
• Assess clinical response
• Assess drug adherence
• Monitor for paradoxical reaction
• Monitor for signs/symptoms of hepatitis or other
  toxic effects
• Visual acuity and color discrimination when using
  ethambutol.

77
Summary

• TB case rates have been declining since 1993
• BUT
• HIV case rates continue to rise
• TB cases continue to be reported in every state
• Estimated 10-15 million persons in the U.S. are
  infected with M. Tuberculosis
• Without intervention, about 10 will develop TB
  disease at some point
• Estimated 900,000 people in the U.S. are living
  with HIV
• People co-infected with HIV and TB have a 100
  times greater risk of developing TB disease.

78
All children infected with HIV should be tested
for TB annuallyandif infected, should complete
therapy as soon as possible.
79
Thank you!