infectious diseases 12

Infectious Diseases Infectious Diseases (1&2)(1&2)

INTRODUCTION TUBERCULOSIS

Spread & Dissemination of Spread & Dissemination of MicrobesMicrobes

The bloodblood is a hostilehostile environment to most microorganisms, those entering the blood are destroyeddestroyed rapidly

BACTEREMIA:BACTEREMIA: Is the presence of Is the presence of small numbersmall number of of low virulencelow virulence bacteria in the bacteria in the blood of normal individuals blood of normal individuals without multiplicationwithout multiplication Usually associated with severe localized infectionlocalized infection such as penumococcal pneumonia, after tooth extractinThe bacteria detected by blood cultureculture &disappeardisappear from it when the local infection subsides


SEPTICEMIA:SEPTICEMIA:

Means the Means the presence & multiplicationpresence & multiplication of of highly pathogenichighly pathogenic bacteria in the blood such as pyogenic cocci .bacteria in the blood such as pyogenic cocci .

The condition indicates a seriousserious infection with profound toxemia & failure of the host defenses

Small hemorrhages due to capillarycapillary endothelial damage occur, high counts of neutophilsneutophils, enlarged spleenenlarged spleen

It is rapidly fatalfatal with rapid disseminationdissemination of the infection to various sites in the body


PYAEMIA:PYAEMIA: Means Means puspus in the blood in the blood

Associated with pyogenicpyogenic infection

Septic thrombusSeptic thrombus (infected by bacteria and infiltrated by neutrophils) are fragmentedfragmented and carried off in the blood as small micro-emboli where they occlude smaller vesselsocclude smaller vessels, causing local injurylocal injury by the obstruction and by the release of toxins from the bacteria

Results in either pyaemic abscessespyaemic abscesses or septic infarction


TOXEMIA:TOXEMIA:

Is the presence of circulating bacterial toxins in the Is the presence of circulating bacterial toxins in the bloodblood

Infection ≠ DiseaseInfection ≠ Disease

Infection:Infection: Seeding of a focus with organisms, which may or may not cause clinically significant tissue damage “i.e. disease”

Only a small fraction of those who contract an Only a small fraction of those who contract an infection develop active disease:infection develop active disease: Generally, 3-4% of previously unexposed individuals

acquire active disease during the 1st year after infection & no more than 15% do so thereafter

TuberculosisTuberculosis

Is a communicable chronic granulomatous disease caused by Mycobacterium tuberculosisMycobacterium tuberculosis It usually involves the lungs but may affect any organ or tissue in the body Typically results in caseating granulomas

Tuberculosis – Tuberculosis – EpidemiologyEpidemiology

~ 1.7 billion individuals are infected worldwide “~ 1/3 of the world’s population”

3 million deaths / year A leading cause of death globally Accounts for ~ 6% of deaths worldwide Is the most common cause of death

resulting from a single infectious agent

Tuberculosis – Tuberculosis – EpidemiologyEpidemiology

Until the mid 1980smid 1980s, in the USA & Western countries there was a declinedecline in TB infection

The incidence in Western population increased in HIV-infected persons & in immigrants from high prevalence areas

The lunglung is the most common important clinical site of infection

Tuberculosis – Routes of Tuberculosis – Routes of infectioninfection

1.1. Respiratory tract:Respiratory tract: Most cases are acquired by direct person to person

transmission of airborneairborne droplets with organisms from an active caseactive case to a susceptible host

2.2. Intestinal tractIntestinal tract

3. Skin by inoculation

4. Congenital by transplacental spread

Tuberculosis – Tuberculosis – MicroorganismMicroorganism

MM. . tuberculosis hoministuberculosis hominis Transmitted by inhalation of infective droplets, coughed or

sneezed into the air from patients with active “open” PTB “airborne” or by exposure to contaminated secretions

MM. . bovisbovis Transmitted by milk from diseased cows intestinal &

oropharyngeal TB Rare

MM. . avium-intracellulareavium-intracellulare Very low virulence rarely cause disease in normal hosts Cause disseminated infection in 10-30% of AIDS pts

Tuberculosis – Tuberculosis – Predisposing FactorsPredisposing Factors

A number of factors predispose to the development of TB :

1.1. AccessAccess of organism: close contact with open cases of disease, e.g. increased in crowded & unhygienic working and living conditions

2.2. SusceptibilitySusceptibility of individual: the old, very young, black & Asian populations have and increased susceptibility

Tuberculosis – Tuberculosis – Predisposing FactorsPredisposing Factors

3.3. NutritionNutrition: a disease of the undernourished & under privileged “poor”

4.4. OccupationOccupation: increased incidence of TB in some types of pneumoconiosis (silicosis & in health workers)

5.5. Other DiseasesOther Diseases: such as; pre-existing chronic lung disease, chronic renal failure, Hodgkin diseases, diabetes mellitus, alcoholism, corticosteroid, immunosuppressive & cytotoxic drug therapy, immunodeficiencies; AIDS

Tuberculosis - Characters Tuberculosis - Characters of the Organismsof the Organisms

AerobicAerobic, acid-fast bacilliacid-fast bacilli Has no known exotoxins, endotoxinsno known exotoxins, endotoxins Has waxy coat “high contents of complex lipids” that causes them to retain the red dye when treated with acid in acid-fast stainacid-fast stain & resist decolorization

Tuberculosis - Tuberculosis - PathogenesisPathogenesis

MacrophagesMacrophages are the primary cells infected by M. tuberculosis.

EarlyEarly in infection, tuberculosis bacilli replicate essentially unchecked, while laterlater in infection, the T-helper response stimulates macrophages to contain the proliferation of the bacteria.


M. tuberculosis entersenters macrophages by endocytosisendocytosis mediated by several macrophage receptors: Macrophages mannose receptorsMacrophages mannose receptors Complement receptorsComplement receptors

Once inside the macrophage, M. tuberculosis replicates within the phagosomereplicates within the phagosome by blocking blocking fusionfusion of the phagosome & lysosome


The earliest stage of primary tuberculosisprimary tuberculosis (<3 weeks)(<3 weeks) in the nonsensitized individual is characterized by unchecked proliferation of bacteria in the pulmonary alveolar macrophages & airspaces, with resulting bacteremiabacteremia & seeding of multiple sites

Despite the bacteremia, most patients at this stage are asymptomaticasymptomatic or have a mild flulike illness


The genetic make-upgenetic make-up of the host may influence the course of the disease

In some people with polymorphisms in the NRAMP1 genepolymorphisms in the NRAMP1 gene, the disease may progress from this point without development of an effective immune response “↓microbicidal function”

NRAMP1 proteinNRAMP1 protein is a transmembrane proteintransmembrane protein found in endosomes and lysosomes & may have role in generation of generation of anti-microbial oxygen radicalsanti-microbial oxygen radicals

About 3 weeksAbout 3 weeks after infection, a Ta THH1 response1 response against M. tuberculosis is mounted that activates macrophages to become bactericidalbactericidal


TTHH0 cells are stimulated by0 cells are stimulated by mycobacterial antigens

drained to the lymph node, which are presented with class II major histocompatibility proteins by antigen presenting cells “macrophages”

Differentiation of TH1 cells depends on the presence

of IL-12IL-12, which is produced by antigen presenting produced by antigen presenting cellscells that have encountered the mycobacteria

Mature TH1 cells, both in lymph nodes and in the

lung, produce IFN-γIFN-γ


IFN-γIFN-γ is the critical mediator which activates macrophages to activates macrophages to become competentbecome competent to contain the M. tuberculosis infection

IFN-γ stimulates formation of the phagolysosomesstimulates formation of the phagolysosomes in infected macrophages, exposing the bacteria to an inhospitable acidic environment

IFN-γ also stimulates inducible nitric oxide synthasealso stimulates inducible nitric oxide synthase (iNOS),(iNOS), which produces nitric oxide (NO) produces nitric oxide (NO)

NONO generates reactive nitrogen intermediatesnitrogen intermediates and other free free radicalsradicals capable of oxidative destructionoxidative destruction of several mycobacterial constituents, from cell wall to DNA.


In addition to stimulating macrophages to kill mycobacteria, the TTHH1 response1 response orchestrates the formation of granulomas formation of granulomas & caseous necrosis & caseous necrosis

Activated macrophagesActivated macrophages, stimulated by IFN-γ, produce TNFTNF, which recruits monocytesrecruits monocytes

These monocytes differentiate into the "epithelioiddifferentiate into the "epithelioid histiocytes"histiocytes" that characterize the granulomatous response

CD4+ TCD4+ THH1 cells 1 cells also facilitates development of CD8+ T also facilitates development of CD8+ T cellscells,, which can kill the TB-infected macrophages

DefectsDefects in any of steps of TTHH1 response1 response result in poorly formed granulomas, absence of resistance, & disease progression


In many peopleIn many people, this response contains the bacteria and doesn't cause significant tissue destruction or doesn't cause significant tissue destruction or illnessillness

In other peopleIn other people, the infection progresses and the ongoing immune response results in tissue results in tissue destructiondestruction due to caseation &cavitation

Tuberculosis – Type IV Tuberculosis – Type IV Hypersensitivity ReactionHypersensitivity Reaction

It can be detected by tuberculin “Mantoux” testtuberculin “Mantoux” test: ~2-4 wks after infection, intracutaneous injection of

0.1 mL of PPD induces a visible & palpable induration “at least 5 mm in diameter” that peaks in 48-72 hrs

Positive testPositive test indicates cell-mediated hypersensitivity & doesn’t differentiate between infection & disease

False-negative testFalse-negative test may be produced by certain viral infections, sarcoidosis, malnutrition, Hodgkin disease, immunosuppression & overwhelming active TB

False-positive testFalse-positive test may result from infection by atypical mycobacteria

Tuberculosis – Natural Tuberculosis – Natural History & SpectrumHistory & Spectrum

MajorityMajority

Primary TuberculosisPrimary Tuberculosis

Occurs in previously unexposedpreviously unexposed & therefore unsensitizedunsensitized persons

In non immunized childrennon immunized children Elderly & profoundly immunosuppressedElderly & profoundly immunosuppressed

persons may lose their sensitivity to M. tuberculosis & develop primary tuberculosis

Source of infection: exogenousexogenous Only 5% will develop significant disease

Primary Tuberculosis – Primary Tuberculosis – Gross MorphologyGross Morphology

Typically; inhaled bacilli implant in the distal airspaces of the lower part of the upper lobelower part of the upper lobe or upper part of the upper part of the lower lobelower lobe, usually close to the pleuraclose to the pleura

As sensitization develops; 1-1.5 cm area of gray-white inflammatory consolidation forms “Ghon focus”“Ghon focus”

In most cases the center of the focus develops caseous necrosis

Tubercle bacilli either free or within macrophage drain into regional lymph nodelymph node caseating granulomacaseating granuloma


Ghon’s complexGhon’s complex = Parenchymal lesion + Hilar lymph node involvement

• This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis. The node has a cheesy tan to white appearance. Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation



• In most persons (95%), cell-mediated immunity controls infection & the granulomatous disease will not progress. Over time, the granulomas decrease in size, fibrose, and can calcify, leaving a focal calcified spot on a chest radiograph that suggests remote granulomatous disease “Ranke complex”“Ranke complex”

Primary tuberculosis is the pattern seen with initial infection with tuberculosis, most often in children. Reactivation or reinfection to produce secondary

tuberculosis is more typically seen in adult


Primary Tuberculosis – Primary Tuberculosis – Microscopic MorphologyMicroscopic Morphology

The site of active involvement shows granulomatous inflammation with or without caseation & with multinucleated giant cells, that are surrounded by lymphocytes & fibroblastic rim

Well-defined non-caseating granulomas . Granulomas are composed of transformed macrophages called epithelioid cells along with lymphocytes, occasional PMN's, plasma cells, and fibroblasts.


Caseous necrosis is characterized by acellular pink areas of necrosis that is surrounded by a granulomatous

inflammatory process


At high magnification, the granuloma demonstrates epithelioid macrophages that are elongated with long, pale nuclei and pink cytoplasm. The

macrophages fuse to form giant cells. The typical giant cell for infectious granulomas is called a Langhans giant cell and has the nuclei lined up along

one edge of the cell.


This is the acid fast stain of Mycobacterium tuberculosis (MTB). Note the red rods


Primary Tuberculosis – FatePrimary Tuberculosis – Fate

1. Fibrosis & calcification “healing”“healing” ( 95%95% of cases). Only 5% of the newly infected persons are symptomatic

• Scar may harbor viable bacilliviable bacilli for years and perhaps for life: Act as a nidus for reactivationreactivation at a later time when host defenses are compromised

2 . 2 . ““PProgressive primary tuberculosisrogressive primary tuberculosis””::• Occurs in immunosuppressed patients, malnourished children &

elderly• The primary focus enlarge:

A.A. Acute pneumonia-like picture:Acute pneumonia-like picture: • Lower & middle lobe consolidation, pleural involvement

with effusion or empyema, hilar lymph node enlargement, cavitation is rare


B.B. Direct spreadDirect spread:: • Erosion into bronchial tree produces:

• Foci of infection in other parts of the lung• Laryngeal tuberculosis from coughed infected sputum• Intestinal tuberculosis from swallowing infected sputum


C.C. Haematogenous spread into blood vesselsHaematogenous spread into blood vessels: : • Will produce:

• Isolated - organ tuberculosis “in kidney, bone, meninges, adrenal gland & fallopian tubes”: The organisms are destroyed in all the organs but persist only in one organ

• Systemic generlized miliary tuberculosis: When the infective foci seed the pulmonary venous return to the heart dissemination through systemic circulation to different organs especially liver, bone marrow, spleen, adrenals, meninges, kidneys, fallopiantubes and epididymis

Morphology:Morphology: Microscopic or small, visible (2mm) foci of yellow- white consolidation scattered throughout the affected organs

Secondary “Reactivation or Secondary “Reactivation or Post Primary” TuberculosisPost Primary” Tuberculosis

Tuberculosis that develops in a previously sensitized host

Causes:Causes:1.1. ReactivationReactivation of dormant primary lesions when host

resistance is weakened “most common” – main method in low prevalence areas

2.2. Exogenous reinfectionExogenous reinfection due to: “main in high prevalence areas” Waning of the protection offered by the primary disease OR Large inoculum of virulent bacilli

Only <5% with primary tuberculosis develop secondary TB

Secondary “Reactivation or Secondary “Reactivation or Post Primary” TuberculosisPost Primary” Tuberculosis

- Morphology- Morphology

Classic locationClassic location: the apex of one or both upper lobes The initial lesion is usually a small focus of small focus of

consolidationconsolidation, less than 2 cm in diameter in the apexapex Because of preexistent hypersensitivitypreexistent hypersensitivity, a rapid and rapid and

marked tissue responsemarked tissue response will start & will try to wall offwall off this focus

Regional LNs are less prominently involved Cavitation allow spread of infection via airways & is

an important source of infectivity Microscopically:Microscopically: Sharply circumscribed, firm, gray-

white to yellow areas with central caseation & peripheral fibrosis

Secondary “Reactivation or Secondary “Reactivation or Post Primary” Tuberculosis Post Primary” Tuberculosis – Fate & Course– Fate & Course

1.1. Healing:Healing:• In favorable cases, having good immune response or after

Rx• Progressive fibrous encapsulation and calcification

fibrocalcific scarfibrocalcific scar • Usually impossible to find tubercle bacilli within these

lesions


2.2. Progressive pulmonary tuberculosis:Progressive pulmonary tuberculosis:• Apical lesion enlarges with expansion of the area of

caseation (progressive cavitating pulmonary tuberculosis)• Erosion into a bronchus evacuation of the caseous center

“open lesion” ragged, irregular cavity lined by caseous material that is poorly walled off by fibrous tissue

• Erosion of blood vessels haemoptysis• Involvement of the pleural cavity serous pleural

effusion, tuberculous empyema or obliterative fibrous pleuritis


With adequate treatmentWith adequate treatment the process may be arrested, healing by fibrosis which might distort the pulmonary architecture

If treatment is inadequate or with impaired If treatment is inadequate or with impaired host defenses:host defenses: Spread of infection

Secondary “Reactivation or Secondary “Reactivation or Post Primary” Tuberculosis Post Primary” Tuberculosis – Spread – Spread

Direct expansion Dissemination through the bronchial tree establish new foci of infection in the lung and produce tuberculous broncopneumomia Endobronchial, endotracheal and laryngeal tuberculosis:

When infected material spreads either through lymphatic channels or from expectorated infectious material The mucosal lining studded with many minute grnulomatous lesions

Dissemination through lymphatics or vascular system miliary tuberculosis

This is an example of granulomatous disease of the lung. The pattern of smaller nodules which have a propensity for upper lobe involvement suggests a granulomatous process rather than metastatic disease

Secondary Tuberculosis – Secondary Tuberculosis – Gross MorphologyGross Morphology

On closer inspection, the granulomas have areas of caseous necrosis. This is very extensive granulomatous disease. This pattern of multiple caseating granulomas primarily in the upper lobes is most characteristic of secondary (reactivation) tuberculosis. However, fungal granulomas (histoplasmosis, cryptococcosis, coccidioidomycosis) can mimic this pattern as well


When there is extensive caseation and the granulomas involve a larger bronchus, it is possible for much of the soft, necrotic center to drain out and leave behind a cavity. Cavitation is typical for large granulomas with tuberculosis. Cavitation is more common in the upper lobes


This is more extensive caseous necrosis, with confluent cheesy tan granulomas in the upper portion of this lung in a patient with tuberculosis. The tissue destruction is so extensive that there are areas of cavitation (cystic spaces) being formed as the necrotic (mainly liquefied) debris drains out via the bronchi


Intestinal TuberculosisIntestinal Tuberculosis

Due to drinking contaminated milkcontaminated milk It was common, now is less frequent Today in developed countries it is often a complication of advanced secondary T.B & is due to swallowing of coughed swallowing of coughed upup infective material It is accompanied by involvement of the oro-pharyngeal lymphoid tissue and involvement of neck lymph nodes The organisms are trapped in mucosal lymphoid aggregates of small and large bowel inflammatory enlargement & ulceration of the overlying mucosa, particularly in ileum Ulcers are rounded or oval, have undermined ragged edges and soft yellow caseous floor

Hematogenous Spread:Hematogenous Spread:Isolated-Organ Isolated-Organ TuberculosisTuberculosis

Appear in any organ or tissue seeded via blood

Can be the presenting manifestation of T.B

The favored sites are:

Bone: Tuberculous osteomyelitis

Vertebral involvement results in “Pott’s disease”

Lymph nodes, spleen, adrenals, kidneys, meninges,

fallopian tubes, epidydymis,…

Hematogenous Spread:Hematogenous Spread:Systemic Miliary Systemic Miliary TuberculosisTuberculosis

• Via pulmonary venous return:Via pulmonary venous return:

The infective material return to the heart disseminate the organisms into the systemic arterial system

Most prominently involved organs are spleen, liver, bone marrow, adrenals, kidneys, fallopian tubes, epididymis, and meninges

NOTE:NOTE: Tissues resistant to TB infection are: Heart, striated muscle, Thyroid and pancreas

Hematogenous Spread:Hematogenous Spread:Miliary Pulmonary Miliary Pulmonary TuberculosisTuberculosis

• Via lymphatics into lymphatic ducts:Via lymphatics into lymphatic ducts:

Empty into the venous return to right side of the heart pulmonary arteries diffuse miliary T.B. of the lung

When the immune response is poor or is overwhelmed by an extensive infection, then it is possible to see the gross pattern of granulomatous disease seen here. This is a "miliary" pattern of granulomas because there are a multitude of small tan granulomas, about 2 to 4 mm in size, scattered throughout the lung parenchyma. The miliary pattern gets its name from the resemblence of the granulomas to millet seeds

Miliary Tuberculosis – Miliary Tuberculosis – Gross MorphologyGross Morphology

This is a caseating granuloma of tuberculosis in the adrenal gland. Tuberculosis used to be the most

common cause of chronic adrenal insufficiency. Now, idiopathic (presumably autoimmune) Addison's disease

is much more often the cause for chronic adrenal insufficiency

Adrenal Gland TuberculosisAdrenal Gland Tuberculosis

This spleen shows a miliary pattern of granulomatous inflammation, with numerous small tan granulomas. This suggests a

poor immune response. This patient had AIDS. The infection turned out to be Mycobacterium avium-intracellulare (MAI), also

known as Mycobacterium avium-complex (MAC)

Miliary Tuberculosis in Miliary Tuberculosis in SpleenSpleen

Tuberculosis – Clinical Tuberculosis – Clinical FeaturesFeatures

Localized type may be asymptomatic Low grade remittent fever, night sweats, malaise, anorexia, weight loss Sputum at first mucoid and later purulent Haemoptysis in half of the patients Pleuretic pain

Tuberculosis – DiagnosisTuberculosis – Diagnosis

History, physical examination, radiological findings “consolidation & cavitation”“consolidation & cavitation”

Identification of the acid-fast bacilli in smears and culture of sputum “10 weeks”

PCR amplification of M. tuberculosis DNA

Tuberculosis – PrognosisTuberculosis – Prognosis

Depends on: The extent of the disease and the patient immune

status

Secondary amyloidosis may occur in persistent cases

Tuberculosis – Chronic Tuberculosis – Chronic ConsequencesConsequences

1.1. Pulmonary fibrosisPulmonary fibrosis The lung lesions may heal with fibrosis at any stage, particularly with

treatment This ranges from minor apical scarring to extensive and severe

widespread fibrosis producing localized to widespread honey-comb appearance of the lung tissue. It is particularly seen in relapsing and progressive untreated disease

This is complicated by respiratory failure & cor pulmonale 2.2. Pleural fibrosisPleural fibrosis Fibrosis commonly obliterate the pleural space

3.3. BronchiectasisBronchiectasis Damage to the bronchial walls and scarring can cause distal pulmonary

collapse, secondary infection and bronchiectasis

Infection in Infection in Immunocompromised Immunocompromised IndividualsIndividuals

Mycobacterial infection of all types are increased in immunocompromised individuals and is in most cases due to reactivation of latent infectionreactivation of latent infection

Features are similar to infection in immunocompetent individuals but disease usually progresses more rapidlyprogresses more rapidly due to decreased host response

Atypical Mycobacterial Atypical Mycobacterial InfectionInfection

These infections are caused by a group of non-tuberculous mycobacteria of which the most important types are M. M. avium- intracellulareavium- intracellulare and M. kanasiiM. kanasii The organisms are widely distributed in soil, water & soil, water & domestic animalsdomestic animals Infection is acquired directly from the environmentacquired directly from the environment and not by case to case contact Infection by these organisms is seen in immunocompromised patients particularly AIDS It can be seen also in immunocompetent individuals with chronic pulmonary disease

The lymph nodes in this mesentery, best seen at the left, are enlarged and have cut surfaces that appear yellow-tan. These nodes are filled with sheets of Mycobacterium avium-complex (MAC) organisms, and the immune response is so poor in this AIDS patient that there is no focal granuloma formationno focal granuloma formation

Atypical Mycobacterial Atypical Mycobacterial Infection – Gross Infection – Gross MorphologyMorphology

Microscopically, Mycobacterium avium-intracellulare infection is marked by numerous acid fast organisms growing within numerous acid fast organisms growing within macrophagesmacrophages. Lots of bright red rods are seen, particularly in macrophages, in this acid fast stain of lymph node

Atypical Mycobacterial Atypical Mycobacterial Infection – Microscopic Infection – Microscopic MorphologyMorphology

infectious diseases 12

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