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					            Advanced Course on AFB Microscopy
                  17 – 28 November 2003
                       Nairobi, Kenya


           Epidemiology of Tuberculosis




Dr. John. R. Mansoer, MD, MPH
Technical Advisor TB/Leprosy Control
CDC/NLTP Kenya
                     A Model for the Epidemiology of Tuberculosis



 Risk                   Risk                    Risk                         Risk
factors                factors                 factors                      factors

                                                           Infectious
                                                          tuberculosis
                                 Subclinical
          Exposure                infection                                              Death

                                                         Non-infectious
                                                          tuberculosis



                                                                   Rieder HL. Infection 1995;23:1-4
Exposure to tubercle bacilli
     Risk factors for exposure to
           M. tuberculosis
o   Incidence of infectious tuberculosis
o   Duration of infectiousness
o   Number of cases/contacts interactions per unit
    of time of infectiousness

    -population density
    -family size
    -climatic conditions
    -age of sources of infection
    -gender
        Infection with tubercle bacilli

• Transmitted by airborne route

• (M.Bovis: contaminated milk)
Risk of Infection Given Exposure:
   Largely Exogenous Factors


      Particles    x     Exposure time
      Volume

 Particles:       Production of infectious droplet nuclei
 Volume:          Volume of air and ventilation
 Exposure time:   Time of inhaling air with droplet nuclei
                             Number of Droplets produced by Different
                                 Aerosol Producing Maneuvers
                     50000


                     40000
Number of droplets




                     30000


                     20000


                     10000


                         0
                                 Coughing         Talking         Singing

                             Loudon RG, et al. Am Rev Respir Dis 1968;98:297-300
Infection with tubercle bacilli
  Characteristics of an infectious patient

• 5,000 bacilli/1mL: positive smear
• 10,000 bacilli/1mL: 95% probability positive

• Sputum smear positive patients are the major source
  of infection in the community

• Sputum smear negative patients are responsible for
  15-20% of transmission
                         Tuberculous Infection Among Close Contacts (Children <15 yr)
                                    by Bacteriologic Status of Index Case
                    70       s+/c+


                    60
                                     s-/c+
                    50
Per cent infected




                    40                       s-/c-

                                                         s+/c+
                    30
                                                                                    s+/c+
                    20
                                                                         s-/c-
                                                                                            s-/c+   s-/c-
                    10                                           s-/c+

                     0
                              Bedfordshire                   Rotterdam                Saskatchewan
                              1948 - 1952                   1967 - 1969                1966 - 1971
                                                            Shaw JB, et al. Am Rev Respir Dis 1954;69:724-32
                                                     van Geuns HA, et al. Bull Int Union Tuberc 1975;50:107-21
                                                      Grzybowski S, et al. Bull Int Union Tuberc 1975;50:90-106
 Clearance of Air

o Dispersion of bacilli
o Survival of bacilli
                      Killing of BCG by Sunlight and in Open Sky Without
                            Direct Exposure to Direct Rays of the Sun
                      7
                     10

                      6
                     10
Number of colonies




                      5
                     10
   (log scale)




                      4
                     10
                      3
                     10
                                                                                 Skyshine
                      2
                     10                     Sunlight
                      1
                     10

                           05 15 30    60                                              240
                                            Exposure time (minutes)
                                      Edwards LB, et al. Bull World Hlth Organ 1952;5:333-6
Extent of Contact

o Proximity
o Length of contact
                         Tuberculous Infection Among Children by Type of
                          Contact and Bacteriologic Status of Index Case,
                         British Columbia and Saskatchewan, 1966 - 1971
                    40        Close
                    35
                    30
Per cent infected




                    25
                    20
                    15                 Casual                Close
                    10
                                                                      Casual
                     5
                     0
                                 Smear +                       Smear -
                              Grzybowski S, et al. Bull Int Union Tuberc 1975;50:90-106
   Incidence and prevalence of infection

• Tuberculin survey: imperfect measuring tool?

• Low-income countries: 50% or more of productive
  population infected
• Industrialized countries: 10% or less of productive
  population infected
• Globally: approximately 30% of population infected
        Estimate Disease Burden from Risk of Infection?


It has been stated:
1% risk of infection                 <=>   50 incident sputum smear-
                                           positive cases / 100,000


Underlying assumptions:
o 10 transmissions / case / year
o 2 years of infectiousness / case


Thus:
100 cases / 100,000                       2,000 transmissions / 100,000
 50 cases / 100,000                       1% risk of infection
              Tuberculosis Disease
Major risk factors:
• Time since infection
• HIV infection
• Untreated/poorly treated previous TB
• Other factors:
      -age
      -gender
      -malnutrition
      -diabetes
      -silicosis
      -genetic factors
                                         Reported Tuberculosis Cases, Western Europe, 1974 - 1990
Notifications per 100,000 (log scale)


                                        30




                                        20




                                        15




                                                   1975             1980            1985            1990
                                                                  Year of notification
                                                   Raviglione MC, et al. Bull World Health Organ 1993;71:297-306
                                        Notification Rates of Sputum Smear-Positive
                                        Tuberculosis in Three Sub-Saharan Countries
                            80
Notifications per 100,000



                                                              Senegal
                            60

                                            Tanzania
                            40


                            20            Malawi



                            0
                                 1982    1984   1986   1988     1990    1992   1994   1996   1998   2000
                                                         Year of notification
                                 Reports of National Tuberculosis Programs, 1982-1999
                                    KNCV. Mission Report No.6 Tanzania, March 2000
          KNCV / Norwegian Health Association. Mission Report No. 32 Malawi, Jan 2000
                                     IUATLD Mission Report No. 28 Senegal, Aug 2000
                           NLTP Kenya, TB Casefinding: 1987 - 2002

          85,000
                                                                                                               82114
          80,000
                                       Sm+ PTB
          75,000
                                       Sm- PTB
          70,000
                                       EPTB
          65,000
                                       Relapses
          60,000
                                       All TB
          55,000

          50,000
Numbers




          45,000

          40,000

          35,000                                                                                               34337
                                                                                                               31765
          30,000

          25,000

          20,000

          15,000
                                                                                                               11578
          10,000

           5,000                                                                                               4434

              0
                   '87   '88   '89   '90   '91   '92   '93   '94   '95   '96   '97   '98   '99   '00   '01   '02
                                                              Year
                                         NLTP Kenya, TB Case Notification Rates
                                              (n/100,000 pop.): 1989 - 2002


                       300



                                          Sm+ PTB
                       250

                                          All TB


                       200
N/100,000 population




                       150




                       100




                       50




                        0
                             '89   '90    '91   '92   '93   '94   '95   '96   '97   '98   '99   '00   '01   '02
                                                                   Year
                                   NLTP Kenya, Case Notification Rates Smear Positive PTB and All Types of TB cases: 2002

                       700
                                   650


                       600                                                                                      PTB+   All TB


                       500
N/100,000 population




                       400
                                                 341
                                                             314
                             275
                       300                                                263
                                                                                      242
                                                                                                     217
                                                                                                                 203        191
                       200                                                                                                             182
                                           149         139                                                                                        140
                                                                   110
                                                                                100             88
                       100                                                                                 75          82         74
                                                                                                                                             53


                        0
                               NBIP         COP         NYP              KEN      EAP               NEP    RVPN         RVPS       CEP        WEP

                                                                                        Provinces
                      WHO Forecasts for Tuberculosis Incidence, 1990 - 2005
                3.0
                                                                            Africa
Million cases




                2.0




                1.0

                                                                            Industrialized
                                                                                countries
                0.0
                             1990       1995           2000          2005
                                      Dolin PJ, et al. WHO Document 1993;WHO/TB/93.173
           Public Health Importance of a Risk Factor

 There are two elements that make a risk factor to be important for public
health: the prevalence of the factor in the population and the strength of
the factor

  It is a bit of a judgment call, but we consider recent infection to be the
most important on this list. Everywhere in the world, whenever a new case
of infectious tuberculosis emerges, the diagnosis and commencement of
treatment are usually only made after that case has already infected one or
more other persons.

HIV infection is certainly the most important risk factor in many countries of
sub-Saharan Africa, but it is not (yet) the case in India and China which
account together for about one third of the world population.
  HIV infection and tuberculosis disease

• TB infected/HIV-: 5-10% life time risk to progress to
  TB disease

• TB infected/HIV+: 5% annual risk to progress to TB
  disease
Determinants for the Frequency of HIV-Associated Tuberculosis in a Community



              Total population

                                                     Prevalence and incidence of
                                                     infection with M. tuberculosis
                    Infected with
                                                     Prevalence and incidence
                    M. tuberculosis
                                                     of HIV infection

                                                     Overlap of the two respective
                                                     population segments



                                 Infected with HIV
 Impact of HIV on the Epidemiology of Tuberculosis

Direct:   o   Reactivation of tuberculous infection acquired before
              HIV infection

          o   Progression of tuberculous infection acquired after
              HIV infection

Indirect: o   Transmission to the population not infected with HIV

                              Sutherland I. Br Comm Dis Rep 1990:10
                                 Correlation Between Extent of HIV-Induced Immuno-
                                Suppression and Clinical Manifestation of Tuberculosis
                              500                    Pulmonary tuberculosis
Median CD4 cell count / mm3



                              400
                                                 Lymphatic, serous tuberculosis


                              300                             Tuberculous meningitis


                              200                                          Disseminated tuberculosis



                              100



                                0
                                                Duration of HIV infection

                                                De Cock KM, et al. J Am Med Assoc 1992;268:1581-7
                                 Impact of HIV Infection on Tuberculosis Notifications
                                        in Chiang Rai, Thailand, 1985 - 1994
                           500
No. of cases (log scale)




                                                                                    All cases

                           400



                           300

                                                                                    HIV-neg cases


                           200


                                  85                     90                        95
                                                   Year of notification
                                                               Yanai H, et al. AIDS 1996;10:527-31
                             TB Incidence HIV prevalence in Kenya
                            TB incidence andand HIV Prevalence
                           900                             0.16

                           800                             0.14
TB Incidence per 100,000




                           700
                                                           0.12




                                                                  HIV Prevalence
                           600                                                     TB Incidence
                                                           0.1
                           500                                                     TB Data
                                                           0.08
                           400                                                     HIV Prevalence
                                                           0.06
                           300                                                     HIV Data
                           200                             0.04

                           100                             0.02

                            0                              0
                            1980   1990   2000   2010   2020

                                          Year
                        800                                                                                                                                                        850
                                                                                                800
                                                                                                                                                                                   800        Mombassa
                                            Kisumu
                        700                                                                                           Nairobi                                                      750
                                                                                                700
                                                                                                                                                                                   700
                        600                                                                                                                                                        650
                                                                                                600
                                                                                                                                                                                   600
Incidence per 100,000




                                                                                                                                                           Incidence per 100,000
                                                                        Incidence per 100,000
                                                                                                                                                                                   550
                        500
                                                                                                500                                                                                500
                                                                                                                                                                                   450
                        400                                                                                                                                                                           1994
                                                                                                400                                                                                400
                                                                                                                                                                                   350
                        300                                                                     300                                                                                300
                                                                                                                                                                                   250
                        200                                                                     200                                                                                200
                                                                                                                                                                                   150
                        100                                                                     100                                                                                100
                                                                                                                                Omit first point
                                                                                                                                                                                   50
                         0                                                                       0                                                                                  0
                          1980   1985    1990    1995    2000    2005                             1980       1985    1990   1995        2000        2005                             1980   1985   1990       1995   2000   2005


                        30
                                                                                                  30                                                                                30
                        25              Kisumu                                                                                                                                                     Mombassa
                                                                                                  25                  Nairobi                                                       25                       1994
                        20                                                                        20                                                                                20
                        15                                                                        15
                                                                                                                                                                                    15
                        10                                                                        10
                                                                                                                                                                                    10
                                                                                                   5
                         5                                                                         0                                                                                 5
                         0                                                                            1980    1985   1990   1995       2000        2005                              0
                         1980    1985    1990    1995   2000    2005                                                                                                                 1980   1985    1990      1995   2000   2005
Risk Factors for Death from
       Tuberculosis
o   Site and form of tuberculosis

o   Patient’s and doctor’s delay
                            Tuberculosis Cases by Form and Site and
                          Expected Case Fatality from Untreated Disease
                    100
                                         Other
                                     Osteoarticular            Other
                    80
Per cent of cases




                                      Lymphatic

                    60                Pulmonary,
                                      smear-neg
                                                            Pulmonary,
                    40                                      smear-pos
                                      Pulmonary,
                    20                smear-pos


                     0
                                        Cases                 Fatal
                                                              cases
                                Data on cases: Rieder HL. Tubercle 1985;66:179-186
                                                    Data on fatality: Various sources
                      Sources

• Epidemiologic basis of tuberculosis control –
  Hans Rieder/IUATLD (1-st Edition 1999)
• NLTP Kenya: Annual Reports
• NLTP Kenya/WHO: research data (not yet published)

				
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