Infectious Diseases  12
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Infectious Diseases  12 Infectious Diseases 12 Presentation Transcript

  • Infectious Diseases (1&2)
  • Spread & Dissemination of Microbes
    • The blood is a hostile environment to most microorganisms, those entering the blood are destroyed rapidly
    • Is the presence of small number of low virulence bacteria in the blood of normal individuals without multiplication
    • Usually associated with severe localized infection such as penumococcal pneumonia, after tooth extractin
    • The bacteria detected by blood culture & disappear from it when the local infection subsides
  • Spread & Dissemination of Microbes
    • Means the presence & multiplication of highly pathogenic bacteria in the blood such as pyogenic cocci .
    • The condition indicates a serious infection with profound toxemia & failure of the host defenses
    • Small hemorrhages due to capillary endothelial damage occur, high counts of neutophils , enlarged spleen
    • It is rapidly fatal with rapid dissemination of the infection to various sites in the body
  • Spread & Dissemination of Microbes
    • PYAEMIA:
    • Means pus in the blood
    • Associated with pyogenic infection
    • Septic thrombus (infected by bacteria and infiltrated by neutrophils) are fragmented and carried off in the blood as small micro-emboli where they occlude smaller vessels , causing local injury by the obstruction and by the release of toxins from the bacteria
    • Results in either pyaemic abscesses or septic infarction
  • Spread & Dissemination of Microbes
    • TOXEMIA:
    • Is the presence of circulating bacterial toxins in the blood
  • Infection ≠ Disease
    • 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 infection develop active disease:
      • Generally, 3-4% of previously unexposed individuals acquire active disease during the 1 st year after infection & no more than 15% do so thereafter
  • Tuberculosis
    • Is a communicable chronic granulomatous disease caused by Mycobacterium tuberculosis
    • It usually involves the lungs but may affect any organ or tissue in the body
    • Typically results in caseating granulomas
  • Tuberculosis – Epidemiology
    • ~ 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 – Epidemiology
    • Until the mid 1980s , in the USA & Western countries there was a decline in TB infection
    • The incidence in Western population increased in HIV-infected persons & in immigrants from high prevalence areas
    • The lung is the most common important clinical site of infection
  • Tuberculosis – Routes of infection
    • Respiratory tract:
      • Most cases are acquired by direct person to person transmission of airborne droplets with organisms from an active case to a susceptible host
    • Intestinal tract
    • Skin by inoculation
    • Congenital by transplacental spread
  • Tuberculosis – Microorganism
    • M . tuberculosis 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
    • M . bovis
      • Transmitted by milk from diseased cows  intestinal & oropharyngeal TB
      • Rare
    • M . avium-intracellulare
      • Very low virulence  rarely cause disease in normal hosts
      • Cause disseminated infection in 10-30% of AIDS pts
  • Tuberculosis – Predisposing Factors
    • A number of factors predispose to the development of TB :
      • Access of organism : close contact with open cases of disease, e.g. increased in c ro wded & unhygienic working and living conditions
      • Susceptibility of individual : the old, very young, black & Asian populations have and increased susceptibility
  • Tuberculosis – Predisposing Factors
      • Nutrition : a disease of the undernourished & under privileged “poor”
      • Occupation : increased incidence of TB in some types of pneumoconiosis ( silicosis & in health workers )
      • Other 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 of the Organisms
    • Aerobic , acid-fast bacilli
    • Has no 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 stain & resist decolorization
  • Tuberculosis - Pathogenesis
    • Macrophages are the primary cells infected by M. tuberculosis .
    • Early in infection, tuberculosis bacilli replicate essentially unchecked, while later in infection, the T-helper response stimulates macrophages to contain the proliferation of the bacteria.
  • Tuberculosis - Pathogenesis
    • M. tuberculosis enters macrophages by endocytosis mediated by several macrophage receptors:
      • Macrophages mannose receptors
      • Complement receptors
    • Once inside the macrophage, M. tuberculosis replicates within the phagosome by blocking fusion of the phagosome & lysosome
  • Tuberculosis - Pathogenesis
    • The earliest stage of primary tuberculosis (<3 weeks) in the nonsensitized individual is characterized by unchecked proliferation of bacteria in the pulmonary alveolar macrophages & airspaces, with resulting bacteremia & seeding of multiple sites
    • Despite the bacteremia, most patients at this stage are asymptomatic or have a mild flulike illness
  • Tuberculosis - Pathogenesis
    • The genetic make-up of the host may influence the course of the disease
    • In some people with polymorphisms in the NRAMP1 gene , the disease may progress from this point without development of an effective immune response “↓microbicidal function”
    • NRAMP1 protein is a transmembrane protein found in endosomes and lysosomes & may have role in generation of anti-microbial oxygen radicals
    • About 3 weeks after infection, a T H 1 response against M. tuberculosis is mounted that activates macrophages to become bactericidal
  • Tuberculosis - Pathogenesis
    • T H 0 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 T H 1 cells depends on the presence of IL-12 , which is produced by antigen presenting cells that have encountered the mycobacteria
    • Mature T H 1 cells, both in lymph nodes and in the lung, produce IFN-γ
  • Tuberculosis - Pathogenesis
    • IFN-γ is the critical mediator which activates macrophages to become competent to contain the M. tuberculosis infection
    • IFN-γ stimulates formation of the phagolysosomes in infected macrophages, exposing the bacteria to an inhospitable acidic environment
    • IFN-γ also stimulates inducible nitric oxide synthase (iNOS), which produces nitric oxide (NO)
    • NO generates reactive nitrogen intermediates and other free radicals capable of oxidative destruction of several mycobacterial constituents, from cell wall to DNA .
  • Tuberculosis - Pathogenesis
    • In addition to stimulating macrophages to kill mycobacteria, the T H 1 response orchestrates the formation of granulomas & caseous necrosis
    • Activated macrophages , stimulated by IFN-γ, produce TNF , which recruits monocytes
    • These monocytes differentiate into the &quot;epithelioid histiocytes&quot; that characterize the granulomatous response
    • CD4+ T H 1 cells also facilitates development of CD8+ T cells , which can kill the TB-infected macrophages
    • Defects in any of steps of T H 1 response result in poorly formed granulomas, absence of resistance, & disease progression
  • Tuberculosis - Pathogenesis
    • In many people , this response contains the bacteria and doesn't cause significant tissue destruction or illness
    • In other people , the infection progresses and the ongoing immune response results in tissue destruction due to caseation &cavitation
  • Tuberculosis - Pathogenesis
  • Tuberculosis - Pathogenesis
  • Tuberculosis - Pathogenesis
    • In summary , immunity to M. tuberculosis is primarily mediated by T H 1 cells , which stimulate macrophages to kill the bacteria
    • This immune response, while largely effective, comes at the cost of hypersensitivity and the accompanying tissue destruction
    • Reactivation of the infection or re-exposure to the bacilli in a previously sensitized host results in rapid mobilization of a defensive reaction but also increased tissue necrosis
  • Tuberculosis – Type IV Hypersensitivity Reaction
    • It can be detected by tuberculin “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 test indicates cell-mediated hypersensitivity & doesn’t differentiate between infection & disease
      • False-negative test may be produced by certain viral infections, sarcoidosis, malnutrition, Hodgkin disease, immunosuppression & overwhelming active TB
      • False-positive test may result from infection by atypical mycobacteria
  • Tuberculosis – Natural History & Spectrum Majority
  • Primary Tuberculosis
    • Occurs in previously unexposed & therefore unsensitized persons
    • In non immunized children
    • Elderly & profoundly immunosuppressed persons may lose their sensitivity to M. tuberculosis & develop primary tuberculosis
    • Source of infection: exogenous
    • Only 5% will develop significant disease
  • Primary Tuberculosis – Gross Morphology
    • Typically; inhaled bacilli implant in the distal airspaces of the lower part of the upper lobe or upper part of the lower lobe , usually close to the pleura
    • As sensitization develops; 1-1.5 cm area of gray - white inflammatory consolidation forms “Ghon focus”
    • In most cases the center of the focus develops caseous necrosis
    • Tubercle bacilli either free or within macrophage drain into regional lymph node  caseating granuloma
  • Primary Tuberculosis – Gross Morphology
    • Ghon’s complex = Parenchymal lesion + Hilar lymph node involvement
  • Primary Tuberculosis – Gross Morphology
    • 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
  • Primary Tuberculosis – Gross Morphology
    • 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”
  • Primary Tuberculosis – Gross Morphology                                                                              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 – Microscopic Morphology
    • The site of active involvement shows granulomatous inflammation with or without caseation & with multinucleated giant cells, that are surrounded by lymphocytes & fibroblastic rim
  • Primary Tuberculosis – Microscopic Morphology Well-defined non-caseating granulomas . Granulomas are composed of transformed macrophages called epithelioid cells along with lymphocytes, occasional PMN's, plasma cells, and fibroblasts.
  • Primary Tuberculosis – Microscopic Morphology
  • Primary Tuberculosis – Microscopic Morphology Caseous necrosis is characterized by acellular pink areas of necrosis that is surrounded by a granulomatous inflammatory process
  • Primary Tuberculosis – Microscopic Morphology 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.
  • Primary Tuberculosis – Microscopic Morphology This is the acid fast stain of Mycobacterium tuberculosis (MTB). Note the red rods
  • Primary Tuberculosis – Fate
    • F ibrosis & calcification “healing” ( 95% of cases ).
    • O nly 5% of the newly infected persons are symptomatic
      • Scar may harb o r viable bacilli for years and perhaps for life : A ct as a nidus for reactivation at a later time when host defenses are compromised
    • 2 . “ P rogressive primary tuberculosis ” :
      • Occurs i n i mmunosuppressed patients, malnourished children & elderly
      • The primary focus enlarg e:
        • Acute pneumonia-like picture:
        • Lower & middle lobe consolidation, p l e ural involvement with effusion or empyema, hilar lymph node enlarge ment , cavitation is rare
  • Primary Tuberculosis – Fate
    • Direct 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
  • Primary Tuberculosis – Fate
    • Haematogenous spread into blood vessels :
    • Will produce:
      • Isolate d - 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 m iliary tuberculosis : When the infective foci seed the pulmonary venous return to the heart  dissemination t hrough systemic circulation to different organs e specially liver, bone marrow, spleen, adrenals, meninges, kidneys, fallopiantubes and epididymis
    • Morphology: Microscopic or small, visible (2mm) foci of yellow- white consolidation scattered throughout the affected organs
  • Secondary “Reactivation or Post Primary” Tuberculosis
    • Tuberculosis that develops in a previously sensitized host
    • Causes:
    • Reactivation of dormant primary lesions when host resistance is weakened “most common” – main method in low prevalence areas
    • Exogenous 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 Post Primary” Tuberculosis - Morphology
    • Classic location : the apex of one or both upper lobes
    • The initial lesion is usually a small focus of consolidation , less than 2 cm in diameter in the apex
    • Because of preexistent hypersensitivity , a rapid and marked tissue response will start & will try to wall off this focus
    • Regional LNs are less prominently involved
    • Cavitation  allow spread of infection via airways & is an important source of infectivity
    • Microscopically: Sharply circumscribed , firm, gray-white to yellow areas with central caseation & peripheral fibrosis
  • Secondary “Reactivation or Post Primary” Tuberculosis – Fate & Course
    • Healing:
    • In favorable cases , having good immune response or after Rx
    • Progressive fibrous encapsulation and calcification  fibrocalcific scar
    • Usually impossible to find tubercle bacilli within these lesions
  • Secondary “Reactivation or Post Primary” Tuberculosis – Fate & Course
    • 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
  • Secondary “Reactivation or Post Primary” Tuberculosis – Fate & Course
    • With adequate treatment the process may be arrested, healing by fibrosis  which might distort the pulmonary architecture
    • If treatment is inadequate or with impaired host defenses: Spread of infection
  • Secondary “Reactivation or Post Primary” Tuberculosis – Spread
    • Direct expansion
    • Dissemination t hrough the bronchial tree establish new foci of infection in the lun g and produce tuberculous broncopneumomia
    • Endobronchial, endotracheal and laryngeal tuberculosis:
      • When infected material spreads either through lym phatic channels or from expectorated infectious material
      • The mucosal lining studded with many minute grnulomatous lesions
    • Dissemination through lymphatics or vascular system  miliary tuberculosis
  • Secondary Tuberculosis – Gross Morphology 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 – Gross 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
  • Secondary Tuberculosis – Gross Morphology 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
  • Secondary Tuberculosis – Gross Morphology 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 Tuberculosis
    • Due to drinking contaminated 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 up infective material
    • It is accompanied by involvement of the oro-pharyngeal lymphoid t issue 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: Isolated-Organ Tuberculosis
    • 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: Systemic Miliary Tuberculosis
    • 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:
      • Tissues resistant to TB infection are: Heart, striated muscle, Thyroid and pancreas
  • Hematogenous Spread: Miliary Pulmonary Tuberculosis
    • 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
  • Miliary Tuberculosis – Gross Morphology            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 &quot;miliary&quot; 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
  • Adrenal Gland Tuberculosis 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
  • Miliary Tuberculosis in Spleen 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)
  • Tuberculosis – Clinical Features
    •   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 – Diagnosis
    • History, physical examination, radiological findings “consolidation & cavitation”
    • Identification of the acid-fast bacilli in smears and culture of sputum “10 weeks”
    • PCR amplification of M. tuberculosis DNA
  • Tuberculosis – Prognosis
    • Depends on:
      • The extent of the disease and the patient immune status
    • Secondary amyloidosis may occur in persistent cases
  • Tuberculosis – Chronic Consequences
    • Pulmonary 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
    • Pleural fibrosis
    • Fibrosis commonly obliterate the pleural space
    • Bronchiectasis
    • Damage to the bronchial walls and scarring can cause distal pulmonary collapse, secondary infection and bronchiectasis
  • Infection in Immunocompromised Individuals
    • Mycobacterial infection of all types are increased in immunocompromised individuals and is in most cases due to reactivation of latent infection
    • Features are similar to infection in immunocompetent individuals but disease usually progresses more rapidly due to decreased host response
  • Atypical Mycobacterial Infection
    • These infections are caused by a group of non-tuberculous mycobacteria of which the most important types are M. avium- intracellulare and M. kanasii
    • The organisms are widely distributed in soil, water & domestic animals
    • Infection is acquired 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
  • Atypical Mycobacterial Infection – Gross Morphology 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 formation
  • Atypical Mycobacterial Infection – Microscopic Morphology Microscopically, Mycobacterium avium-intracellulare infection is marked by numerous acid fast organisms growing within macrophages . Lots of bright red rods are seen, particularly in macrophages, in this acid fast stain of lymph node
  • PRIMARY   SECONDARY   Affect: * Previously unexposed, unsensitized persons * Non immune children * Elderly & immuncomprised * Very young Source: * Exogenous * 5% develop significant disease Morphology & Site: * Primary T.B. mostly in lung rarely in intestine, pharynx, larynx & skin * Involve lower part of upper lobe or upper part of lower lobe close to pleura * Ghon-focus A 1-1.5 cm gray white inflammatory consolidation with involvement of hilar lymph node * In 95% of cases the development of cell- mediated immunity control the infection & no lesion develops     Affect: * Previously sensitized persons   Sources: * Develop from: - Reactivation of dormant lesion - Primary lesion if immunity of host is lowered “exogenous reinfection” - 5% of primary T.B. develop secondary T.B   Morphology & Site: * Localized at the apex of both or one upper lobes because of better 0 2 tension * Less lymph node involvement than the primary * Cavitation is more common with dissemination along air ways - Cavitation is a source of infection by sputum * Typically consolidating lesion 1-2 cm, firm gray-yellow at apical pleura with central caseation & peripheral fibrosis
  •   Histology: * Typically granulomatous inflammation, both caseating and non-caseating   Outcome: * Hypersensitivity & increased resistance * Healing & scarring of Ghon-focus but may be still a focus for reactivation * May progress to progressive primary T.B. or disseminated T.B. especially in AIDS, malnourished, very old, very young & Eskimos Progressive primary T.B .: 1. Progressive enlargement of the primary focus with lung destruction & cavitation 2. Extension to the pleura  pleural effusion or empyema 3. Enlarged lymph nodes  obstruct bronchi  bronchiectasis    
    • Histology:
    • * Same
    • Outcome:  
    • * The apical lesion may heal spontaneously
    • Or with treatment and become a fibrocalcific
    • Scar
    • * Depress and pucker the pleural surface and can cause pleural adhesion
    • Progressive pulmonary tuberculosis:
    • Apical lesion enlarge with expansion of
    • caseation.(cavitary fibrocaseous TB)
    • Erosion into bronchus with evacuation
    • forming irregular cavity poorly
    • delineated by fibrosis  open lung lesion
    • Erosion into blood vessels  hemoptysis
    • Invasion of pleural space  pleural
    • effusion, tuberculous empyema or
    • obliteraytive fibrous pleuritis
  •   Dissemination: * Erosion into bronchi with spread of the Infection  - Foci of infection in other parts of the lung - Tuberculous pneumonia - Laryngeal T.B. from coughed sputum - Intestinal T.B. from swallowing of infected material   * Erosion of vessels  - Lymphatics  foci of infection in the lung  lung miliary T.B. - Blood vessels  systemic miliary T.B. - Single-organ T.B. in bone, kidney, joint, brain…    
    • Fate:
    • * With adequate treatment:
    • - The process is arrested by healing with
    • fibrosis & destruction of the lung architecture
    • If treatment is inadequate and host defence is impaired:
    • - Spread of infection occurs
    • Spread:
    • * Dissemination via airways, lymphatics & BV
    • Miliary pulnmonary disease when bacilli drain
    • via lymphatics in lymphatic duct to the right
    • heart back to the lung and give miliary T.B.
    • Miliary systemic T.B. when infective foci seed
    • the pulmonary venous return to the heart to the
    • systemic circulation (liver, bone, spleen,
    • adrenals, fallopian tubes)
    • Endobronchial, endotracheal laryngeal miliary
    • granuloma
    • Isolated organ T.B.
    • Intestinal T.B.