There are nearly 100 viruses of the herpes group that infect many different animal species. Official name of herpesviruses that commonly infect human is Humans herpesvirus (HHV) herpes simplex virus types 1 (HHV 1) Herpes simplex virus type 2 (HHV 2) Varicella-zoster virus (HHV 3) Epstein-Barr virus, (HHV 4) Cytomegalovirus (HHV 5) Human herpesvirus 6 (HHV 6) Human herpesvirus 7 (HHV 7) Human herpesvirus 8 (HHV 8) (Kaposi's sarcoma-associated herpesvirus). Herpes B virus of monkeys can also infect humans hELMINTHS#corona virus#Aspergillosis#BUGANDO#CUHAS#CUHAS#CUHAS

1. TUBERCULOSIS
DR.HAMISI MKINDI,MD.
TO DOWNLOAD CONTACT:
hermyc@live.com

2.  A 46 years old male pt who was admitted from home
with history of coughing blood on two different
occasions in the past two weeks associated with fever,
profuse nocturnal sweating, loss of appetite,
significance weight loss of 8 kg in less than a month and
easy fatiguability. POSITIVE hx of IV drug use.
 On Physical examination, He was Ill looking, cachexic,
febrile T- 39.6, PR- 110 Bpm, RS- 20 bpm, BP- 130/76,
SPO2- 98%
 RR; Unilateral right side crepitation, more on the upper
lobes
 Initial chest x-ray; infiltration on the right upper lobe
with a sign of Cavitation.

4.  Provisional diagnosis.?? Ddx??
 Other investigation that we can order?
 Mostly likely organism?
 Pathogenesis/Immunology of the disease?
 Is the patient high risk or low risk patient?
 Most likely co- infection?
 Initial treatment?
 Prevention and prophylaxis measures

5. Tuberculosis
Presenter : SAIMON MAGANGA
ILLUMINATA KAFUMU
Supervisor: Prof. STEPHEN MSHANA

6. Presentation outline
 Introduction
 Structural differences between Tb and other bacteria
 Transmission
 Pathogenesis / Immunology
 Clinical presentation of different forms of Tb.
 Diagnostic tools/methods and challenges
 Treatment and resistance challenges
 MDR/XDR
 MDR Treatment
 Tb vaccination
 Prevention and Prophylaxis
 Discussion

7. INTRODUCTION
 Tuberculosis. Describes as a chronic infectious
disease with broad range of clinical illness caused
by Mycobacterium tuberculosis complex.
 In humans the commonest cause is Mycobacterium
tuberculosis.
 other mycobacterium spp such as;
• Mycobacterium bovis,
• Mycobacterium avium complex (MAC),
• Mycobacterium canetti and
• Mycobacterium Africanum may rarely cause TB,

8. Introduction
 Tuberculosis is primarily the disease of the lungs
however it can affect other organs e.g. meninges,
lymph nodes, brain, kidney, GIT, bones and joints etc
 Humans are the only known
reservoir for Mycobacterium
tuberculosis

9. epidemiology
 Over 30% of people in the world are
infected with TB
 Majority of TB patients (80%) are in
22 high burden countries
 Tanzania has an incidence of (253/100,000) is ranked 14th
out of 30 (Source: WHO report 2020)

10. TB Prevalence in Tanzania
 In year 2018, a total of 75,845 cases of all forms were
notified, which is an increase of 6,205 cases or 9%
compared to the year 2017. New and relapse TB cases
notified were 74,692 among them, 48% were
bacteriological confirmed TB cases, 79% were pulmonary
TB cases (NTLP 2018)

12. CELL WALL STRUCTURE

14. Microbiology of TB
 Mycobacterium tuberculosis was discovered by Robert
Koch in 1882.
 They are Obligate aerobic, non spore forming acid fast
bacilli
 Called acid fast bacillus because the resist
decolourisation with acid or alcohol after being stained
by carbofuschin dye.
 They have cell wall made of mycolic acid which
contributes to pathogenicity also have waxy layer which
help to survive in adverse conditions

15. Microbiology cont
 M. Tuberculosis can be differentiated
from other mycobacteria:-
Grow slowly and lack pigment
Produce niacin
Reduce nitrates
Produce heat sensitive catalase (
inactivated by heating to 68C at pH of
7.0)
Other mycobacteria produce large
amount of heat stable catalase

16. Transmission
 Transmission is from human with active disease through
aerosal droplets.
 Transmission occurs significantly while coughing,
sneezing, singing, talking or spiting
At this time, they expel infectious aerosol droplets 0.5 to 5
µm in diameter.
 Avoid prolonged, frequent and intense contact with
active Tb patients especially for immunocompromised
non Tb infected people.

17. Pathogenesis
 About 90% of those infected with M.tuberculosis have
asymptomatic, latent TB infection.
 With only a 10% lifetime chance that a latent infection
will progress to TB disease.
 TB infection begins when the mycobacteria reach the
pulmonary alveoli, where they invade and replicate
within the endosomes of alveolar macrophages.

18. Pathogenesis cont
 In the few weeks (4-6wks) the body has
almost no immune defense against
infection with M. tuberculosis.
 Bacterial multiplication proceeds for
weeks both in the initial focus and
lymphohematogenous metastatic foci
until the development of
hypersensitivity and cellular immunity
 Lymphocytes, mostly CD4+ cells bearing
the alpha form of the T cell receptor
are capable of recognizing mycobacteria
that have been processed and presented
by macrophage

20. Mycobacteria Evasion
mechanism

21. Pathogenesis cont
 When lymphocytes encounter antigen in
association with MHC class II molecule on
the macrophage surface it is activated
and proliferates producing a clone of
reactive lymphocytes
 T cells produce many lymphokines which
attract, retain and activate macrophage
at the site of antigen
 Activated macrophage accumulate high
concentrations of lytic enzymes and
reactive metabolites that
mycobactericidal

22. Pathogenesis cont
 Alveolar macrophage secrete a number
of cytokines
 Interleukin I contribute to fever
 IL -6 contributes to hyperglobulinemia
 Tumor necrotic factor alpha (TNF-
alpha)contributes :
• Killing of mycobacteria
• Formation of granulomas
• Systemic symptoms such as fever and
weight loss

23. Pathogenesis cont
 Qualitative and quantitative defect of CD4+ T
cells explain inability of HIV +ve pt to contain
mycobacteria proliferation
 When the population of activated
lymphocytes reach a certain size, cutaneous
delayed reactivity to tuberculin becomes
manifest
 The pathological features of tuberculosis are
the result of the degree of hypersensitivity
and the local concentration of antigen

24. Pathogenesis cont
 Necrosis in tuberculosis tend to be
incomplete resulting in solid or semisolid
acellular and amorphous material known
as caseous necrosis
 The chemical environment and low
oxygen tension inhibit microbial
multiplication
 The primary site of infection in the lungs
is called the Ghon focus, and is generally
located in either the upper part of the
lower lobe, or the lower part of the upper
lobe.(commonly at the subpleural)

25. Granuloma

26. Granuloma

27. Caseous NECROSIS

29. Pathogenesis cont
 Macrophages, T lymphocytes, B lymphocytes and
fibroblasts are among the cells that aggregate to form a
granuloma, with lymphocytes surrounding the infected
macrophages.

30. Pathogenesis cont
 The granuloma functions not only to prevent
dissemination of the mycobacteria, but also
provides a local environment for communication
of cells of the immune system.
 Within the granuloma, T lymphocytes secrete
cytokines such as interferon gamma, which
activates macrophages to destroy the bacteria
with which they are infected.
 Cytotoxic T cells can also directly kill infected
cells, by secreting perforin and granulysin.
 Mycobacteria are not always eliminated within the
granuloma, but can become dormant, resulting in
a latent infection.

31. Pathogenesis cont
 Another feature of the granulomas of human
tuberculosis is the development of cell death,
also called necrosis, in the center of
tubercles
 To the naked eye this has the texture of soft
white cheese and was termed caseous
necrosis.
 If TB bacteria gain entry to the bloodstream
from an area of damaged tissue they spread
through the body and set up many foci of
infection, all appearing as tiny white
tubercles in the tissues.

33. Pathogenesis cont
 This severe form of TB disease is most common in
infants and the immunocompromised pts, elderly and is
called miliary tuberculosis.
 Patients with this disseminated TB have a fatality rate
of approximately 20%, even with intensive treatment.
 Tissue destruction and necrosis are balanced by healing
and fibrosis.
 Affected tissue is replaced by scarring and cavities
filled with cheese-like white necrotic material.
 During active disease, some of these cavities are joined
to the air passages bronchi and this material can be
coughed up.

34. Natural history
 After 5 years 50% of pulmonary disease will die of the
disease.
 25% will be self cured(health)
 Another 25% will be ill with chronic infectious disease

35. Types of tuberculosis
I. Pulmonary tuberculosis
II. Extra- Pulmonary tuberculosis
 Pulmonary tuberculosis
Clinical features
 Typical symptoms of pulmonary TB include a
productive cough, fever, and weight loss.
Occasionally, patients may present with
hemoptysis or chest pain.
 Other systemic symptoms include anorexia,
fatigue, or night sweats.

36. Extrapulmonary tuberculosis
Tuberculous meningitis
 Patients may present with a
headache that is either intermittent
or persistent for 2-3 weeks.
 Subtle mental status changes may
progress to coma over a period of
days to weeks.
 Fever may be low-grade or absent.

37. Extrapulmonary cont
Skeletal TB
 The most common site of involvement is the
spine (Pott disease).
 Symptoms include back pain or stiffness.
 Lower extremity paralysis occurs in as many as
half the patients with undiagnosed Pott’s
disease.
 Tuberculous arthritis usually involves only 1
joint.
 Although any joint may be involved, the hip or
the knee is affected most commonly, followed
by the ankle, elbow, wrist, and shoulder.
 Pain may precede radiographic changes by
weeks to months.

38. Extrapulmonary cont
Tuberculous lymphadenitis
 The most common site is in the
neck along the sternocleidomastoid
muscle.
 It usually is unilateral, with little or
no pain.
 Advanced disease may suppurate
and form a draining sinus.

39. Gastrointestinal TB
 Any site along the gastrointestinal tract may become infected.
 Symptoms are referable to the site infected, including the following:
 Non healing ulcers of the mouth or anus
 Difficulty swallowing with esophageal
disease
 Abdominal pain mimicking peptic ulcer
disease with stomach or duodenal infection
 Malabsorption with infection of the small
intestine
 Pain, diarrhea, or hematochezia with
infection of the colon.

40. Genital urinary TB
 Reported symptoms include flank pain,
dysuria, or frequency.
 In men, genital TB may manifest as
epididymitis or a scrotal mass.
 In women, genital TB may mimic pelvic
inflammatory disease.
 TB causes approximately 10% of sterility
in women worldwide and approximately
1% in industrialized countries.

41. Cutaneous TB
 Direct inoculation may result in an
ulcer or wartlike lesion.
 Contiguous spread from an infected
lymph node typically results in a
draining sinus.
 Hematogenous spread may result in
a reddish brown plaque on the face
or extremities (lupus vulgaris) or
tender nodules or abscesses.

42. Other forms of
extrapulmonary TB
 TB of the pleura
 TB peritonitis
 TB pericarditis

43. Diagnosis of TB
 The diagnosis of TB starts with proper history and physical examination.
 Laboratory examinations
 AFB microscopy for sputum and aspirates
 Culture - sputum, aspirates for EPT
 Histological examination - Biopsy tissue
 Gene Xpert (NAA test, RIF/MTB, LPA)
 Interferon Gamma Release Assay
 Radiological test, although alone NOT reliable
 Chest X ray or CT scan
 For patients unable to produce any sputum
(eg, children), early morning gastric aspirate
may produce a good specimen.

44. Sputum smear
 It is the gold standard investigation for PTB
 Standard 2: All patients (adults,
adolescents, and children who are
capable of producing sputum)
suspected of having pulmonary TB
should have at least two, and
preferably three, sputum specimens
obtained for microscopic examination.
When possible, at least one early
morning specimen should be obtained.

45. Sputum smear cont
 Direct smears of unconcentrated sputum are common
worldwide
 They are fast simple and cheap
 Ziehl Neelsen stain with Carbofuschin dye is more
common

46. Ziehl-Neelsen Stain

47. Chest X ray
 People with chest X ray suggestive of PTB should submit their sputum for
microscopy

48. Culture
 Available culture methods use either solid or liquid media
 A sample of sputum or tissue require initial liquefication
and decontamination
 Mostly used is N-acetyl –L-cysteine as a mucolytic in 1% NaCl
 This kills other organisms, M.tb are protected by their fatty
acid rich cell wall
 The sample is then neutralized, centrifuged and the
sediment is inoculated in the media
 Uncontaminated fluid or normally sterile tissues should not
be contaminated as some loss mycobacterial viability

49. Culture cont
 Solid culture media are of two general types:
 Agar bases e.g Middlebrook 7H11
 Egg based e.g Lowenstein Jensen
 The BACTEC radiometric system for culturing
mycobacteria
 It is a liquid system which uses radioactive
palmitate as a sole carbon source
 Inclusion of p-nitro-alpha-acetylamino- -
hydroxypropiophenone in the incubation media
inhibit the growth of M.Tb complex (including M.
bovis and M. africunum
 But does not inhibit mycobacteria other than
tuberculosis

50.  Pleural, cerebrospinal, peritoneal, and pericardial fluids
should be analyzed for protein and glucose (compared
with simultaneous blood glucose).
 Cell and differential counts should be obtained.
 A high protein (> 50% of the serum protein
concentration), lymphocytosis, and a low glucose are
usually found in tuberculous infections, but neither
their presence nor their absence is diagnostic.
 For pleural tuberculosis the diagnostic yield can be
increased by obtaining pleural tissue for histologic study
and culture by needle biopsy at the time of diagnostic
thoracentesis.
 Peritoneal biopsies are best obtained via laparoscopy.

51. Mantoux tuberculine skin test
 Used for screening especially for children
 Can also be used for high risk individuals
 A purified protein derivative is injected intradermal in
the forearm (0.1ml)
 The induration is read after 48 to 72 hrs
 Induration > 10mm in children less than 4 yrs a/c risk of
disemminated disease
 Induration >15mm in children more than 4 yrs is also
significant

52. False positive TST
 Prior infections/exposures to non tuberculous
mycobacterium
 Recent BCG vaccination

53. TB AND HIV
 TB is the third highest cause of
morbidity and mortality in Tanzania
after HIV/AIDS and malaria
 Immune compromised people are
very prone to develop TB, including
PLHIV
 TB is the leading cause of death for
PLHIV
 HIV frequently co-exists with TB

54. TB AND HIV
 14 million people are co-infected world wide
 9% of TB cases are attributable to HIV world wide
 Infection after exposure10-20% vs
5,10%
 Progressive primary disease after
infection 30% vs 5 -10%
 Reactivation of latent infection 5-
10% annual vs 5-10% lifetime

55. TB in HIV Infection
 In pre HIV era 80-85% of TB infection presented as PTB.
 Up to 15% as EPTB
 5% mixture of PTB and EPTB
 While in HIV era 60-70% PTB,while EPTB 50-60%
 PTB presentation depends on HIV progression
 In low CD4 PTB presents with high fever,dyspnoea and
wt loss
 In low CD4 sputum smear often –ve,no typical chest x
ray findings of PTB(cavitation or infiltates in lung apex)

57. Treatment of tuberculosis
 It is important with the aim of curing the patient and
preventing the spread of the disease to the community.
 Case definition in TB treatment
 New case: a patient who has never had treatment for
TB before or has been on treatment for not more than 4
weeks
 Relapse: a patient declared cured or treatment
completed who reports back to health services and is
found to be AFB positive
 Failure: a patient who, while on treatment, is AFB
positive at 5-months or later during the course of
treatment

58. Case definition cont
 Return after default: a patient who returns to
treatment bacteriological positive, after having
interrupted treatment for 2-months or more and who
had been on RX for more than 4 weeks
 Transfer-in: a registered TB patient on Rx received
from another region
 Other: any TB patient who does not fit in one of the
above definitions

59. TB treatment regimen
 There are two TB treatment phases: initial phase
(intensive) and continuation phase
 During initial phase:
 There is rapid killing of the TB bacilli
 Initial phase takes 2months with 4 drugs
 Patients mostly become non-infectious after about 2
weeks
 During continuation phase:
 Drugs kill the persisters
 Prevent relapse after completion of treatment
 Continuous phase takes 2 drugs for 4 or 6 months

60. Treatment regimen cont
 1st line drugs-
isoniazid,rifampicin,rifapentine,rifabutin,ethambutol
and pyrazinamide
 2nd line drugs –
cycloserine,ethionamide,levofloxacine,moxifloxacin,gat
ifloxacine,P aminosalicylic
acid,streptomycin,amikacin/kanamycin,capreomycin

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TB IN CHILDREN, DR MERCY 61

62. Reasons for combination
therapy
 the biological different populations of
the bacteria needs specific metabolic
acting drugs.
 combination therapy reduces resistance.
In each population there are spontaneous
mutations of resistant bacteria which
would be selected under inadequate
therapy.
 combination therapy reduces the toxicity
of the different substances.

63. Side effects of first line ant
tuberculosis drugs
 Isoniazid:-mild LFT elevation or hepatitis-
peripheral neuritis-hypersensitivity
 Rifampin:-orange colored secretions-
hepatitis or thrombocytopenia-OCP may
be ineffective
 Pyrazinamide-hepatotoxicity-
hyperuricemia
 Ethambutol-optic neuritis (usually
reversible)-decreased red-green color
discrimination-GI tract disturbances-
hypersensitivity

64. Treatment of extrapulmonary
TB
 Most of extrapulmonary TB can be treated for 6
months,except TB of bone and joints can be treated for
6 to 9 months,Tb meningitis for 9 to 12 months.

65. Drug Resistant TB
This is a form of TB in which first-line anti-TB drugs have little or
no effect against M. tuberculosis. The diagnosis is confirmed
through molecular tests and culture and DST of M.
tuberculosis strains.
Four different categories of drug resistance have been identified:
• Mono resistant TB: Resistance to any single first-line anti-TB
drug.
• MDR TB: Resistance to at least both isoniazid and rifampicin.
• XDR TB: This is multidrug resistance, with additional resistance
to any fluoroquinolones (ofloxacin, levofloxacin, moxifloxacin)
and at least one of the three injectable drugs (amikacin,
kanamycin, capreomycin).

66. TB drug resistance
 Multidrug resistance(MDR-TB)-resistance to at least
Isoniazid and Rifampicin.
 It is a man made phenomenon due to inadequate
treatment regimen or poor adherence to treatment
 It common to people with HIV and Tb coinfection
 It causes pts to use 2nd line drugs with longer treatment
duration,more toxicity and expensive

67. Former MDR TB REGIMENS TANZANIA
Group Drugs
Group A – Fluoroquinolones Levofloxacin (Lfx), Moxifloxacin (Mfx),
Group B – Injectable agents Kanamycin (Km), Amikacin (Am) ; Capreomycin (Cm)
Group C – Other core second-line
agents
Ethionamide (Eto), Protionamide (Pto), Cycloserine (Cs), Linezolid (Lzd),
Clofazimine (Cfz)
Group D - Add-on agents
(not part of the core MDR-
TB regimen)
D1 Pyrazinamide (Z), Ethambutol (E),
High-dose isoniazid (Hh)
D2 Bedaquiline (Bdq), Delamanid (Dlm)
D3 p-aminosalicylic acid (PAS)
Amoxicillin-clavulanate (Amx-Cl)
Grouping of anti-TB agents used to treat DR-TB

68. Former MDR TB REGIMENS TANZANIA (phasing out)
Standardised short regimen
4-6 Km, Mfx, Pto, Cfz, E, Z, H(h)
5 Mfx Cfz E Z
Individualized Long MDR TB Regimen;
MDR TB
8 Km/Cm, Cs, Lfx, Eto, Z,
12 Cs, Eto, Z, Lfx
Individualized Long MDR TB Regimen;
XDR TB
12Cm Lfx, Bdq, Dlm6 , Lzd, Cfz, PAS.
12 Lfx, Lzd, Cfz, PAS
❑DR-TB is generally treatable, however,
extensive treatment - 9 months up to
24 months
❑Using eligibility criteria patients can be
started on;
• Standardized shorter regimen (9-11
months)
• Individuslized Long regimen (20
months) - MDR-TB patients
• Individualised Long regimen (24
months) - XDR-TB patients

69. SECOND LINE ANTI TB MEDICINES STOCKS
Currently existing stock of recommended second line drugs and MOS
Group A SOH MOS Group B SOH MOS Group C SOH MOS
Lfx 500mg 65,800 7 Cfz 100mg 50,000 4 E 400mg 100,800 8
Bdq 100mg 22,550 12 Cs 250mg 0 - Dlm 50mg 2,016
Lzd 600mg 23,050 12 Z 500mg 443,520 11
PASER 1,2600 7
ETO 250mg 28,400 2
PTO 184,400 5

70. Proposed regimens - Tanzania
1. Long regimen adults (routine)
 6 Lfx - Bdq - Lzd - Cfz – Cs / 12 Lfx - Cfz - Cs
 Substitute; E, Eto, PAS, Z, Dlm
2. Short regimen adults (Operational Research);
 6 Bdq – Lzd – Lfx – Cfz – Cs – Z / 3-5 Lfx – Cfz – Cs – Z
 6 Bdq – Dlm– Lfx – Cfz – Cs – Z / 3-5 Lfx – Cfz – Cs – Z
3. Short Regimen children (routine)
 6 Lfx – Bdq – Lzd – Cs / 3 Lfx – Lzd – Cs
 Substitute; PAS, Dlm, E, Eto, Z, Mfx
 BQD not used for children <6yrs, Delanamid <3yrs
 Treatment prolonged (12-15 mths)in selected cases ; meningitis, TB bone, Spine

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TB IN CHILDREN, DR MERCY 71

72. Extensive drug resistance TB
 It is MDR plus resistance to floroquinolones and one of
the 3 second line
injectables.kanamycin,amikacin,capreomycin
 South Africa has reported the number of XDR-TB
 It is common in HIV pts
 98% dies with an avarage of 25 days since admission

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TB IN CHILDREN, DR MERCY 73

74. Anti-TB resistance
 Primary drug-resistance: “New Cases”
Drug resistance in a patient who has never
been treated for tuberculosis or received
less than one month of therapy
 Secondary (acquired) drug-resistance:
“Previously Treated Cases”
Drug resistance in a patient who has
received at least one month of anti-TB
therapy

75. Prophylaxis and vaccination
 All infant born to smear +ve mother are
given INH 5mg/kg for six months.
 Isoniazid Preventive Therapy (IPT)
 Can be given to people with HIV who have a high TB risk and
have been screened to exclude active TB
 Adults: 300 mg daily for 6 to 9 months

76. vaccination
 Many countries use Bacillus Calmette-Guérin (BCG)
vaccine as part of their TB control programs, especially
for infants.
 The protective efficacy of BCG for preventing serious
forms of TB (e.g. meningitis) in children is greater than
80%

77. references
 Principles and practice of infectious diseaes 4th ed by
Mandell L et al.
 Medical microbiology 19th ed by Jawetz et al.
 Harrison’s Principles of Internal medicine 16th ed by
Kasper et al.
 National guideline for management of HIV and TB latest
edition.