Tuberculosis 140515184439 Phpapp01

7/26/2019 Tuberculosis 140515184439 Phpapp01

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PATHOGENESIS OF TUBERCULOSIS

Assistant Prof. of Infectious DiseasesAssistant Prof. of Infectious Diseases

20142014

Dr. Mohamed Zakaria Sayed-AhmedDr. Mohamed Zakaria Sayed-Ahmed


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Is the most prevalent communicable infectious disease

on earth and remains out of control in many

developing nations

It is a chronic specific inflammatory infectious disease

caused by Mycobacterium tuberculosis in humans

Usually attacks the lungs but it can also affect any parts

of the body

TUBERCULOSIS (TB)

Pathogenesis of Tuberculosis

Introduction Etiology Epidemiology Pathophysiology Clinical features Diagnosis Treatment


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Coinfection with HIV

o Accelerates the progression of both diseases

o e!uiring rapid diagnosis and treatment of both diseases

Tuberculosis can produce atypical signs and symptoms in

infants" the elderly" and immunocompromised hosts

and it can progress rapidly in these patients

TUBERCULOSIS (TB)




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Myco!cte"i#$ t#e"c#%o&i&

It presents either as latent T# infection $%T#I& or as progressive

active disease'

The latter typically causes progressive destruction of the lungs" leading

to death in most patients (ho do not receive treatment

Common cause other than tuberculosis includes)o M' avium intracellulare" M' scrofulaceumo M' ulcerans" M' fortuitum" etc'

ETIOLOG'




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oughly one of every three people on earth is infected by

M' tuberculosis (HO *++,)

The distribution is very uneven" (ith the highest incidences

found in southern Asia and sub*+aharan Africa

In the Unite- St!te&" about ,- million people have %T#I"

evidenced by a positive skin test .puri/ed protein derivative

$PPD&0 but no signs or symptoms of disease

EPI.EMIOLOG'




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Every year appro1imately ,'2 million people develop T#

Tuberculosis $T#& kills about 3 million people each year

4ith the spread of AID+" tuberculosis continues to lay (aste to

large populations

The emergence of drug resistant organism threatens to make this

disease once again incurable

EPI.EMIOLOG'




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%o( socioeconomic status

Cro(ded living conditions

Diseases that (eakens immune system like 5I6

Person on immunosuppresants like steroid 5ealth care (orkers

Migration from a country (ith a high number of cases

Alcoholism

ecent Tubercular infection $(ithin last 3 years&

I+7 8ACT9+ 98 TU#ECU%9+I+




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5I6 is the most important risk factor for active T#" because

the immune de/cit prevents patients from containing the initial

infection

oughly ,:; of U+ T# patients are coinfected (ith 5I6" !n-

roughly 3:; of T# patients ages 3< to == years are coinfected

(ith 5I6

COINFECTION ITH HUMANIMMUNO.EFICIENC' VIRUS (HIV)




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P#%$on!"y TB (>


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od shaped"

:'3*:'< in D" 3*= in %

Mycolic acid present in its cell

(all" makes it acid fast

It resists decolouriation (ith

acid alcohol

Aerobic and non motile

It multiplies slo(ly" can remain dormant for decades

C5AECTEI+TIC+ 98 M' TU#ECU%9+I+




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Pe"&on0to01e"&onthrough the

air by a person (ith active T#

disease of the lungs

%ess fre!uently transmitted by)

Ingestion of M4 o5i&

found in unpasteuried milk

Inoc#%!tion$in skin tuberculosis&

T"!n&1%!cent!% "o#te $rare route&

5o( is T# TransmittedF


Droplet nuclei

containig tubercle

baccilli

Tubercle bacilli

multiply in the alveoli



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P"i$!"y Infection

The progression to clinical disease in a previously une1posed"

immunocompetent person depends on th"ee f!cto"&6

$,& The number of M' tuberculosis organisms inhaled

$3& Infecting dose and the virulence of these organisms

(7) The -e5e%o1$ent of !nti0$yco!cte"i!% ce%%0$e-i!te-

i$$#nity

Immunity to M' tuberculosis is primarily mediated by TH8 cells"

(hich stimulate macrophages to kill the bacteria

PIMAG TU#ECU%9+I+




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.i&e!&e th!t -e5e%o1& in ! 1"e5io#&%y

#ne/1o&e- 1e"&on' Almost al(ays begins in

lungs Inhaled bacilli implant in the distal airspaces

of lo(er part of upper lobe or upper part of

lo(er lobe

,*,'< cm area of grey (hite inflammation

(ith consoldation develops" called as

@hon focus(hich often caseates

PIMAG TU#ECU%9+I+

@honHs comple1) +ubpleural granuloma at right along(ith @ranuloma in the hilar lymph node


Parenchymal lung lesion %nns involvement J @honHs comple1



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.i&e!&e th!t -e5e%o1& in ! 1"e5io#&%y

#ne/1o&e- 1e"&on' Almost al(ays begins in

lungs Inhaled bacilli implant in the distal airspaces

of lo(er part of upper lobe or upper part of

lo(er lobe

,*,'< cm area of grey (hite inflammation

(ith consoldation develops" called as

@hon focus(hich often caseates

PIMAG TU#ECU%9+I+

@honHs comple1) +ubpleural granuloma at right along(ith @ranuloma in the hilar lymph node


Parenchymal lung lesion %nns involvement J @honHs comple1

http://www.google.com.sa/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=mhhwhoSE5K-LtM&tbnid=5hQhYX9xj302eM:&ved=&url=http%3A%2F%2Fmedical-dictionary.thefreedictionary.com%2Fpulmonary%2Btuberculosis&ei=MnITU-71CqyT0AX8l4GoCQ&psig=AFQjCNHEJzfEPsTnk5PCbwhgngkmMT0Vog&ust=1393869450303508http://www.google.com.sa/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=mhhwhoSE5K-LtM&tbnid=5hQhYX9xj302eM:&ved=&url=http%3A%2F%2Fmedical-dictionary.thefreedictionary.com%2Fpulmonary%2Btuberculosis&ei=MnITU-71CqyT0AX8l4GoCQ&psig=AFQjCNHEJzfEPsTnk5PCbwhgngkmMT0Vog&ust=1393869450303508http://www.google.com.sa/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=mhhwhoSE5K-LtM&tbnid=5hQhYX9xj302eM:&ved=&url=http%3A%2F%2Fmedical-dictionary.thefreedictionary.com%2Fpulmonary%2Btuberculosis&ei=MnITU-71CqyT0AX8l4GoCQ&psig=AFQjCNHEJzfEPsTnk5PCbwhgngkmMT0Vog&ust=1393869450303508


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1. M. tuberculosisenters macrophages by endocytosis mediated by several macrophage receptors)mannose receptors bind lipoarabinomannan" a glycolipid in the bacterial cell (all

3' Inside the macrophage" M. tuberculosisreplicates (ithin the phagosome by blocking phaglysosome formation

? Inhibition of Ca3signals

and blocking recruitment? Assembly of the proteins

(hich mediate

phagosome*lysosomefusion



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,' About - (eeks after infection" a T5, response against M. tuberculosisis mounted that activatesmacrophages to become bactericidal'

3' Differentiation of T5, cells depends on the presence of I%*,3" (hich is produced by antigen presenting cells

-' Mature T5, cells" both in

lymph nodes and lung" produce

I8*K' IFN- is the critical

mediator which drives

macrophages to becomecompetent to contain the M.

tuberculosis infection.



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Hi&to1!tho%o3ic!% ch!n3e&

@ranulomatous inflammation forms both caseating

and non caseating tubercles

Tuberculous granuloma has the follo(ing criteria),' ounded outlines

3' Central caseous necrosis

-' Transformed macrophages called epithelioid cells

=' %ymphocytes" plasma cells" and fibroblasts

PIMAG TU#ECU%9+I+


Tubercle bacilli



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PIMAG TU#ECU%9+I+

4ell*defined granulomas ' They have rounded outlines' The center contains

several %anghans giant cells' @ranulomas are composed of transformed

macrophages called epithelioid cells along (ith lymphocytes" plasma cells" and

fibroblasts' The localied" small appearance of these granulomas suggests that

the immune response is fairly good


Collar of

lymphocytes"

plasma cells

Centralcaseated

necrosis

@iant multinucleated

cells $langhans type

Agrregation

of epithliod

cells


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PIMAG TU#ECU%9+I+

Occ!&ion!%%y even in immunocompetent

individuals" tubercular granulomas might

not sho( central caseation

In i$$#no"e&&e- in-i5i-#!%& tuberculosis may

not elicit a granulomatous response $Lnonreactive

tuberculosisL& instead" sheets of foamy histiocytes are

seen" packed (ith mycobacteria that are demonstrable

(ith acid*fast stains



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No 1"o3"e&&ion

5ealing by fibrosis and calcification

Ghon& co$1%e/ after undergoing progressive

fibrosis produces radiologically detectable

calcification called as R!n9e co$1%e/

P"o3"e&&i5e 1"i$!"y t#e"c#%o&i&

Primary miliary tuberculosis

Dissemination to organs like liver" spleen" kidney" ''etc'

8ATE 98 PIMAG TU#ECU%9+I+


Tubercle bacilli escape

and multiply



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+EC9DAG PU%M9AG TU#ECU%9+I+

The #11e" 1!"t& of oth %#n3& Showe-6

? @ray*(hite areas of caseation

? Multiple areas of softening and cavitation




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The lesion may heal (ith fibrous scarring and calcification

The lesions may coalesce together to form large area of

tuberculous pneumonia and produce progressive secondary

pulmonary tuberculosis producing pulmonary e1tra pulmonary

lesions)

Tuberculous caseous pneumonia

8ibrocaseous tuberculosis

Miliary tuberculosis

8ATE 98 +EC' PU%M9AG TU#ECU%9+I+




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E1tensive infection via hematogenous spread

In %#n36 lesions are either microscopic or small" visible foci $3mm& of

yello( (hite consolidation scattered through out lung parenchyma

Mi%i!"y 1#%$on!"y -i&e!&e can cause pleural effusion" tuberculous

empyema or obliterative fibrous pleuritis'

E/t"! 1#%$on!"y $i%i!"y t#e"c#%o&i& is most prominent in the

liver" spleen" bone marro(" adrenals" meninges" kidneys" fallopian

tubes and epididymis but can involve any organ

MI%IAG TU#ECU%9+I+




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MI%IAG TU#ECU%9+I+

Mi%i!"y t#e"c#%o&i& of the &1%een

The cut surface sho(s numerous gray*(hite granulomas




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In tissues or organs seeded he$!to3eno#&%y

Commonly involved organs include)

Intestinal tuberculosis $Primary" +econdary and hyperplastic&

Meninges $Tuberculous meningitis&

7idneys $enal tuberculosis&

Adrenals $Addison disease&

#ones $9steomyelitis&

6ertebrae $Pott disease&

8allopian tubes $+alpingitis&

ENTA PU%M9AG TU#ECU%9+I+



P th i f T b l i


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5I6 infection is the most important risk factor for active T#'

As CD= lymphocytes multiply in response to the

mycobacterial infection" 5I6 multiplies (ithin these cells and

selectively destroys them" gradually eliminating the T#*/ghting

lymphocytes

5I6*infected patients infected (ith T# are at a substantially higher

risk of early mortality compared (ith 5I6*negative T# patients

Most clinicians elect to begin T# treatment /rst' A reasonable time to

begin 5I6 treatment is after 3 months of T# treatment

In:#ence of HIV Infection on P!tho3ene&i&



P th i f T b l i


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C%IICA% 8indings



P th i f T b l i


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Si3n& !n- Sy$1to$&

Patients typically present (ith (eight loss" fatigue" a productive

cough" fever" and night s(eats

Phy&ic!% E/!$in!tion

Dullness to chest percussion" rales

Auscultation revealed vocal fremitus sound

L!o"!to"y Te&t&

Moderate elevations in the (hite blood cell $4#C& count

(ith a lymphocyte predominance

C%IICA% PE+ETATI9 98 TU#ECU%9+I+



P th i f T b l i


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Che&t R!-io3"!1h6

Patchy or nodular infiltrates in the apical areas of the upper lobe

or the superior segment of the lo(er lobes

Cavitation that may sho( air*fluid levels as the

infection progresses

C%IICA% PE+ETATI9 98 TU#ECU%9+I+



CT &c!n6 To diagnose T# that has spread throughout the body

$miliary T#& and to detect lung cavities caused by T#

MRI6 This test looks for T# in the brain or the spine



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Chest radiographs in pulmonary tuberculosis



A' Infiltrates in left lung

#' @honHs comple1 $Primary tuberculosis&

C' #ilateral advanced pulmonary tuberculosis and cavitation in apical area of right lung

A BC

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egative T+TO or

I@AOO result

People E1posed to M' tuberculosis

Infected

(ith M'

tuberculosi

s

'e&No

o developed

%T#I or T#

o Infection

Positive T+T or

I@A result

o symptoms

ormal chest

radiograph

5as %T#I

Develop symptoms later

o active infection

symptoms

abnormal chest

radiograph

Positive culture

May be infectious

5as T# Disease


O T+T $Tuberculin skin test&O I@A $Interferon*@amma

elease Assays&

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Infection (ith M' tuberculosis typically leads to the development

of delayed hypersensitivity to M' tuberculosis antigens" (hich can

be detected by the tuberculin $M!nto#/& test

About 3 to = (eeks after infection" intracutaneous inection of

purified protein derivative of M' tuberculosis (PP.) induces a

visible and palpable induration that peaks in => to 23 hours

.IAGNOSIS

S2IN TESTING


Pathogenesisof Tuberculosis

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A positive tuberculin test result signifies cell*mediated

hypersensitivity to tubercular antigens' It does not differentiate

bet(een infection and disease

8alse*negative reactions may be produced by certain viral infections"

sarcoidosis" malnutrition" immunosuppression

8alse*positive reactions may also result from infection by atypical

mycobacteria

.IAGNOSIS





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S1#t#$ e/!$in!tion

Are essential to confirm T# #est collected in morning before any meal

+putum e1amination on - days" increase chances of detection

+putum can be collected from laryngeal s(ab or bronchial (ashing In

&$!%% chi%-"en" gastric lavage can be e1amined'

+mear should be prepared from thick dirty part of sputum stained

(ith Qiehl*eelson techni!ue

'

.IAGNOSIS





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Al(ays treat (ith multiple drugs' ever add a single drug to a

failing regimen'

Treatment course depends on the categories of the patient

Usually R months" sometimes S months

8our drugs for t(o monthsIsoniaid ifampicin Ethambutol *

Pyrainamide

T(o drugs for four or seven monthsIsoniaid * ifampicin

.OTS$Directly 9bserved Treatment +hort*course & is given

TREATING TB .ISEASE (GENERAL PRINCIPLES)





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I&oni!;i-is the preferred drug for treating latent T# infection

@enerally" isoniaid alone is given for S months for latent

T# infection $%T#I& reduces a personHs lifetime risk of active T#

TREATING LATENT INFECTION





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REFERENCES

Introduction Etiology Epidemiology Pathophysiology Clinical features Diagnosis eferences


,' Charles A' Pelo!uin' Tuberculosis' In) Ph!"$!cothe"!1y6 A P!tho1hy&io%o3ic A11"o!ch" 2th ed' Dipiro BT"

Talbert %" Gee @C" et al'" eds' e( Gork) Mc@ra(*5ill 3::>),>-S,>'

R'Pathology and therapeutics for pharmacist) A # for clinical pharmacy practice*@reen and 5arris"

Chapman and hall publication'
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5417a1.htm?s_cid=rr5417a1_ehttp://www.cdc.gov/mmwr/preview/mmwrhtml/rr5417a1.htm?s_cid=rr5417a1_e


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Thank you for your attention


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BACK-UP SLIDES

Tuberculosis


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The caseous material from a case of secondary tuberculosis in an

individual (ith high degree of hypersensitivity" may spread to rest of

the lung producing caseous pneumonia'

TU#ECU%9U+ CA+E9U+ PEUM9IA

Tuberculosis

8I#9CA+E9U+ TU#ECU%9+I+

The original area of Tuberculous pneumonia undergoes massive central

caseation necrosis (hich may*#reak in to a bronchus forming a cavity

called as Cavitary or 9pen 8ibrocaseous T#

and become the source of spread of infection to others $opentuberculosis&'It can lead to endobronchial and endotracheal T#'emain as a soft caseous lesion (ithout drainage in to a bronchus or

bronchiole to produce a non cavitary lesion called as Chronic 8ibrocaseous

T#'


Tuberculosis


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PAT59@EE+I+ 98 TU#ECU%9+I+

Introduction Etiology Epidemiology Pathogenesis

M'Tuberculosis Aersols"

Ingestion%ocal %ns

$Primary comple1&

#lood generalied

T#

$miliary T#&

MacrophagekilledsomeT#,st(

eek

Aggregation of

macrophage

$Tubercle form&

8ibrouscapsule

andcaseated

center

4ith or (ithout

calcification and

li!uification

Contagious

e1tension via blood

vessels to bronchi

and viscera

T*lymphocyte

mediated reaction

$Tissue damage&

Tuberculosis


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9ccurs in three forms

,' Primary intestinal tuberculosis ) Used to occur by ingestion of

unpasteurised co(Hs milk infected (ith Mycobacterium bovis' #ut no( a

days most cases are due to M' tuberculosis'

Most commonly ileocaecal region is involved'

+ubse!uently" mesentric lymph nodes are affected (hich sho( typical

tuberculous granulomatous inflammatory reaction (ith caseation

necrosis

ITE+TIA% TU#ECU%9+I+

Introduction Etiology Epidemiology Pathophysiology

Tuberculosis


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3' +econdary intestinal tuberculosis)

+(allo(ing of sputum in patients (ith active pulmonary tuberculosis

may cause secondary intestinal tuberculosis'

Most commonly in the terminal ileum and rarely in the colon'

5istologically) tubercles (ill be present'

Mucosa and submocosa sho( ulceration and the muscularis may be

replaced by variable degree of tuberculosis'

-' 5yperplastic intestinal tuberculosis ) The caecum and ascending

colon are thick (alled (ith mucosal ulceration' 5istologically) caseating

tubercles (ill be present'



Tuberculosis


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3' +econdary intestinal tuberculosis)

+(allo(ing of sputum in patients (ith active pulmonary tuberculosis

may cause secondary intestinal tuberculosis'

Most commonly in the terminal ileum and rarely in the colon'

5istologically) tubercles (ill be present'

Mucosa and submocosa sho( ulceration and the muscularis may be

replaced by variable degree of tuberculosis'

-' 5yperplastic intestinal tuberculosis ) The caecum and ascending

colon are thick (alled (ith mucosal ulceration' 5istologically) caseating

tubercles (ill be present'



Tuberculosis


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Cutaneous tuberculosis has various clinical and morphological forms

depending on the mode of entry and (hether it is primary or

secondary infection'

%UPU+ 6U%@AI+ ) It is reactivation type of tuberculosis' @enerally

involves the face and the lesions are formed of red patches in (hich

small" firm nodules reside' Microscopically" non necrotic and less commonly necrotic

granulomas are found in the dermis'

CUTAE9U+ TU#ECU%9+I+

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.OTS (-i"ect%y o&e"5e- t"e!t$ent &ho"t0co#"&e) is the

name givento the tuberculosiscontrol strategy recommended by

the 4orld 5ealth 9rganiation'.,0According to 459" WThe most

cost*effective (ay to stop the spread of T# in communities (ith ahigh incidence is by curing it' The best curative method for T# is

kno(n as D9T+'X.30D9T+ has five main components)

@overnment commitment $including political (ill at all levels" and

establishment of a centralied and prioritied system of T#monitoring" recording and training&'

Case detection by sputum smear microscopy'

+tandardied treatment regimen directly of si1 to eight months

observed by a healthcare (orker or community health (orker for

at least the first t(o months'

A regular" uninterrupted drug supply'

A standardied recording and reporting system that allo(s

assessment of treatment results'
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