TUBERCULOSIS
Etiology. Tuberculosis is a classical chronic specific granulomatous inflammation caused by Mycobacterium tuberculosis or Koch’s bacillus. R. Koch discovered this basillus in 1882. The organism has 5 distinct pathogenic strains: hominis, bovis, avium, murine, and cold-blooded vertebrate strain. The first two strains (hominis and bovis) are definitely infective to people. There are 4 groups of atypical mycobacteria: photochromogens, scotochromogens, non-chromogens and rapid growers. M. tuberculosis hominis is a slender rod-like bacillus, 4 1m in length, and can be demonstrated by the following methods:
Acid fast staining, fluorescent dye methods, culture of the organism in Lowenstein-Jensen medium for 6 weeks, Guinea pig inoculation method by subcutaneous injection of the organisms.
In spite of great advances in chemotherapy and immunology, tuberculosis still continues to be worldwide in distribution, more common in developing countries of Africa, Latin America and Asia.
Epidemiology. Human beings acquire infection with tubercle bacilli by one of the following routes: • inhalation of organisms present in fresh cough droplets or in dried sputum from an open case of pulmonary tuberculosis;
• ingestion of the organisms leads to development to tonsillar or intestinal tuberculosis. This mode of infection of human tubercie bacilli is from self- swallowing of infected sputum of an open case of pulmonary tuberculosis, or ingestion of bovine tubercle bacilli from milk of diseased cows;
• inoculation of the organisms into the skin may rarely occur from infected postmortem tissue;
• transplacental route results in development of congenital tuberculosis in ferns from infected mother and is a rare mode of transmission.
FORMS AND FEATURES OF PULMONARY TUBERCULOSIS*
|
Stage |
Immune Reactivity |
Clinicopathologic Features |
|
Stage 1 (primary) |
|
|
|
a. Initial infection |
No immunity |
Clinically inapparent nonspecific alveolitis |
|
b. Initial infection |
Developing immunity |
Ghon’s primary affection: isolated granulomatous reaction, most commonly in right upper lobe |
|
Primary lymphatic spread |
Developing immunity |
Lymphatic spread of infection to regional lymph nodes with respective granulomas: Ranke primary complex |
|
Stage II (early postprimary generalization) |
|
|
|
a. Lymphatic spread |
Good |
Isolated subpleural caseous granuloma, upper segments of right upper lobe |
|
b. Bronchogenic spread |
Intermediate |
Acinar-nodular pulmonary tuberculosis with progressive caseous granulomas |
|
Poor |
Progressive caseous pneumonia without prominent granulomatous reaction |
|
|
Hematogenous spread |
Intermediate |
Systemic hematogenous caseous granulomas of different sizes (ie, different ages) |
|
(late postprimary generalization) |
|
|
|
d. Hematogenous spread |
Nonimmune —> reactive |
Miliary tuberculosis with systemic granulomas of uniform size (and age) |
|
e. Hematogenous spread (also in early postprimary spread) |
A-reactive |
Miliary systemic necroses, tuberculosepsis acutissima, typhobacillosis Landouzy |
|
Stage III (isolated organ tuberculosis) |
High |
Limited spread in isolated organs: cavernous pulmonary of renal tuberculosis, isolated tuberculomas (granulomas) in brain, spine, and other organs |
|
Late generalization |
High —> low |
Local or systemic spread of isolated organ tuberculosis (lymphatic, bronchogenic, or hematogenous) |
*The degree of immune reactivity (not resistance to disease) can be monitored by tuberculin skin testing; toxicity of tubercle bacteria is partly determined ird t.K tor.”
The disease spreads in the body by various routes:
1. Local spread. This takes place by macrophages carrying the bacilli into the surrounding tissues.
2. Lymphatic spread. Tuberculosis is primarily an infection of lymphoid tissues. The bacilli may pass into lymphoid follicles ofpharynx, bronchi, intestines or regional lymph nodes resulting in regional tuberculous lymphadenitis which is typical of childhood infections. Primary complex is primary focus with lymphangitis and lymphadenitis.
3. Hematogenous spread. This occurs either as a result of tuberculous bacillemia because of the drainage of lymphatics into the venous system or due to caseous material escaping through ulcerated wall of a vein. This produces millet seed-sized lesions in
different organs of the body like lungs, liver, kidneys, bones and other tissues and is known as miliary tuberculosis.
Classification of tuberculosis. Tuberculosis is classified according to the clinical course into: tuberculosis of children and teenagers, tuberculosis of the lungs, tuberculosis of the other organs and systems.
There are 3 clinico-morphological types of tuberculosis:
1. Primary tuberculosis.
2. Secondary tuberculosis.
3. Hematogenic tuberculosis.
The most common pattern of human tuberculosis (TB) is pulmonary. The tuberculosis organism is inhaled into the alveolar spaces of the lung, but other tissues are also affected.
The main morphological characteristic of rnberculous is granuloma (rnbercle) formation in the affected areas. Each tubercle has an area of caseous tissue necrosis at its center. This is characterized by its homogeneity, and no ghost pattern of the original tissue structure remains. Viable mycobacteria are present within the necrotic debris.
Macroscopically, this necrotic tissue resembles cream cheese, hence its descriptive name caseous necrosis. The reason for the necrosis at the center of tubercles is uncertain, as it is not seen in the center of granulomas caused by other agents. A rnbercle is composed of activated macrophages with surrounding lymphoid cells and fibroblasts. The structure of a typical tuberculous granuloma is as follows: around the central area of caseous necrosis lies a collection of large, activated macrophages.
Histologically, this functional activation is manifest by the presence of bulky pale-staining granular cytoplasm, which is rich in endoplasmic reticulum. Because of a minimal resemblance to some epithelial cells, the term epithelioid cells was originally coined for these macrophages. Some of the activated macrophages cells fuse to form large multinucleate cells with many nuclei arranged around the periphery, and a large central cytoplasmic mass. In TB these giant macrophages are called Langhans’ cells. Around the zone of macrophages bordering the central caseous necrosis lies a collar of lymphocytes, reflecting the immunological response to the presence of mycobacteria.
As the tubercle persists, some fibroblasts appear within the lymphocyte collar and outside it. These are recruited by secretion of cytokines from the activated macrophages.
The outcome of tubercie formation depends on the balance between two conflicting sets of factors: those predisposing to extension of infection (ingestion of large numbers of highly virulent organisms, poor immune response) and those predisposing to containment, or healing and eradication of infection (ingestion of small numbers of poorly virulent organisms, good immune response, administration of appropriate antibiotics).
The outcomes of a granuloma may be:
1. The caseous material may undergo liquefaction and extend into surrounding soft tissues, discharging the contents on the surface. This is called cold abscess although there are no pus cells in it.
3. The adjacent granulomas may coalesce together enlarging the lesion which is surrounded by progressive fibrosis.
Primary tuberculosis. The infection of an individual who has not been previously infected or immunized is called primary tuberculosis or Ohon’s complex, or childhood tuberculosis.
Primary complex is the lesion produced at the site of entry with foci in main draining lymphatic vessels and lymph nodes. The most commonly involved tissues for primary complex are lungs and hilar lymph nodes. The other tissues which may show primary complex are tonsils and cervical lymph nodes, and in the case of ingested bacilli the lesions may be found in small intestine and mesenteric lymph nodes.
Primary complex in lungs consists of 3 components ponents: Secondary pulmonary tuberculosis. The lesions in secondary pulmonary tuberculosis are usually located at the subapical region of one or both the lungs, probably due to spread of infection from Simon’s focus. Simon’s focus is hematogenous spread of infection from primary complex to the apex of the affected lung where the oxygen tension is high and favorable for growth of aerobic tubercle bacilli.
The secondary pulmonary tuberculous lesion is located in the apex of one or both lungs. It begins as a small focus of consolidation, usually less than
Histologically similar to the Ghon’s focus, it has a central area of caseous necrosis that is surrounded by a granulomatous inflammatory response. In most cases, destruction of lung leads to cavitation. There is little involvement of lymph nodes, as spread of organisms to regional nodes is prevented by a vigorous tissue-based hypersensitivity response.
There are several clinico-morphological forms (stages) of secondary pulmonary tuberculosis:
1. Acute focal tuberculosis.
2. Fibrofocal tuberculosis.
3. Infiltrative tuberculosis.
4. Tuberculoma.
5. Tuberculous caseous pneumonia.
6. Acute cavernous tuberculosis.
7. Fibrocavei-nous tuberculosis.
8. Cirrhotic tuberculosis.
Tuberculoina is typically a firm, lobulated mass of granulomatous inflammation with central caseous necrosis, up to several centimeters in diameter, and walled off by fibrous tissue. Lesions occur within the pulmonary parenchyma.
Fibrocavernous tuberculosis. The original area of tuberculous pneumonia undergoes massive central caseatioecrosis which may: either break into a bronchus from a cavity (cavitary or open fibrocaseous tuberculosis), or remain as a soft caseous lesion without drainage into a bronchus or bronchiole to produce a non-cavitary lesion (chronic fibrocaseous tuberculosis). The cavity provides favorable environment for proliferation of tubercle bacilli due to high oxygen tension. The cavity may communicate with bronchial tree and become the source of spread of infection (<<open tuberculosis>>). The open case of secondary tuberculosis may implant tuberculous lesion on the mucosal lining of air passages producing endobronchial and endotracheal tuberculosis. Ingestion of sputum containing tubercle bacilli from endogenous pulmonary lesions may produce laryngeal and intestinal tuberculosis.
Macroscopically, the tuberculous cavity is spherical with thick fibrous wall, lined by yellow, caseous necrotic tissue and the lumen is traversed by thrombosed blood vessels. There are foci of connective tissue growth around the wall of the cavity. Tuberculous caseous pneumonia. In a highly susceptible, highly sensitized individual, tuberculous infection may spread rapidly throughout large areas of lung parenchyma and produce a diffuse bronchopneumonia, or lobar exudative consolidation, at one time descriptively referred to as <<galloping consumption>>. Sometimes, with such overwhelming disease, well-developed tubercles do not form, and it may be difficult to establish on histologic grounds the tuberculous nature of the pneumonic process. However, numerous bacilli are usually present in such exudates. Microscopically, the lesions show exudative reaction with edema, fibrin, polymorphs and monocytes but numerous tubercle bacilli can be demonstrated in the exudates.
Haematogenic tuberculosis. This is hematogenous spread of tuberculous infection from primary focus or later stages of tuberculosis. The spread is either by entry of infection into pulmonary vein producing disseminated or isolated organ lesion in different extra-pulmonary sites (e.g. liver, spleen, kidney, brain and bone marrow) or into pulmonary artery restricting the development of miliary lesions within the lung.
Tuberculosis oe the Urinary Tract
Tuberculosis of the urinary tract develops as a consequence of hematogenous dissemination of the tubercle bacilli (usually Mycobacterium tuberculosis). Urinary tract involvement has a peak incidence between the ages of 30 and 50 years and occurs more frequently in males. Bilateral involvement, particularly of the upper poles of the kidneys, is common. After the initial involvement of the kidneys, spread may occur to other components of the urinary tract. In countries where the dairy industry is closely regulated, the infecting organism is usually the human strain, but infection by the bovine strain is prevalent in other parts of the world. The lesions are those of a caseating granulomatous process with predisposition to cavitation and calcification. The kidneys are a common site of involvement in miliary tuberculosis in children.
Sometimes, only small numbers of tubercle bacilli escape into the blood and, if host defenses are effective, most of the organisms die. However, for reasons that are not yet certain, some bacilli settle in specific organs and may remain dormant for many years, only
proliferating and producing overt disease at a later date, often after the initial lung and lymph node lesions have healed. Known as metastatic tuberculosis or isolated organ tuberculosis, those organs particularly involved in this pattern of disease include: adrenal glands, kidney, fallopian tube, epididymis, brain and meninges and bones and joints.
The main hematogenic form of tuberculosis is miliary tuberculosis of the lungs.
Miliary tuberculosis of the lungs. The miliary lesions are millet seed-sized (
Microscopically, the lesions show the structure of tubercies with minute areas of caseatioecrosis.
The commoon-pulmonary tuberculosis are tuberculosis of brain, kidney, bones and cartilages.
Tuberculosis of the brain. Infection of the nervous system with TB may cause meningitis or abscess. Infection of the CNS by Mycobacterium tuberculosis is by blood spread from a site of primary infection, most commonly the lung. There are two main types of infection.
Meningitis is characterized by numerous granulomas in the leptomeninges, with features of chronic meningitis. Infection is most marked around the base of the brain and, even when infection is treated, there is often development of meningeal fibrosis to cause hydrocephalus.
Tuberculous abscess (tuberculoma) forms with infection of the brain parenchyma. A tuberculoma is typically a firm, lobulated mass of granulomatous inflammation with central caseous necrosis, up to several centimeters in diameter, and walled off by fibrous tissue. Lesions occur within the cerebral hemispheres, but are most common in the cerebellum. Treatment with antibiotics is usually ineffective and surgical excision is required.
In tuberculosis of bones and cartilages tuberculous osteomyelitis — especially spondylitis, coxitis (hip joint disease), gonitis develop.
Complications of tuberculosis are variable and depend on clinico-morphological types of the disease.
In primary tuberculosis, tuberculous meningitis, pleurisy, pericarditis, peritonitis may occur.
In secondary tuberculosis, hemorrhages, pneumothorax, empyema of the pleura, amyloidosis develop.
Causes of death are cardiopulmonary insufficiency, pulmonary hemorrhage, sepsis due to disseminated miliary tuberculous, amyloidosis.
MILIARY TUBERCULOSIS
Miliary tuberculosis defines the presence of innumerable, tiny, discrete tuberculous lesions in the lungs and other organs owing to the seeding of these tissues by blood-borne tubercle bacilli.
The word “miliary” was used originally by John Jacob Manget in 1700′ to denote the small size of such lesions, generally less than
PATHOGENESIS
Miliary tuberculosis results from a massive hematogenous spread of tubercle bacilli, which may occur either at the time of primary infection or at a time remote from the primary infection. The quantity of the tuberculous bacillemia and the immunologic competence of the host are important factors that determine the outcome of such dissemination.
A caseous focus more easily may erode into a blood vessel, leading to widespread dissemination of the tubercle bacilli
PATHOLOGY
The pathologic features of miliary tuberculosis are similar but with certain specific characteristics. Grossly, the lungs or other organs have small, punctate, rounded lesions of more or less uniform size. Their color varies from gray to reddish-brown, depending on the organ examined and their stage of development.
Miliary foci lead to the classic changes de scribed as tubercles. Lymphocytes and macro-phages are intermixed with epithelioid cells ar ranged in roughly spherical dimensions. Caseatioecrosis affects the central core of some lesions, whereas others are entirely free of caseation. With appropriate staining, acidfast bacilli may be found within macrophages or epithelioid cells or in the central caseum
The pathology also varies with the mechanism of dissemination. In persons in whom a caseous lesion can be demonstrated to involve a large blood vessel, it is hypothesized that massive tuberculous bacillemia took place. These organisms disseminate in accord with the blood flow, and lesions can be demonstrated in the spleen, liver, lungs, bone marrow, kidneys, adrenals, and eyes. Less commonly, they seed the thyroid, breast, pancreas, heart, prostate, testes, and pituitary. The frequency of organ involvement is shown in Table 1.
TABLE 1. Organ Involvement in Miliary Tuberculosis at Necropsy
|
Organ (% involved): |
|
|
Spleen |
86% |
|
Liver |
91 |
|
Lungs |
100 |
|
Bone marrow |
24 |
|
Kidneys |
62 |
|
Adrenals |
14 |
|
Eye |
— |
|
Thyroid |
19 |
Miliary lesions in HIV-positive cases may present the same pathologic features as in HlV-negative subjects. In general, however, the lesions demonstrate more necrosis and less cellular reaction. Acid-fast bacilli are usually more numerous than in lesions from HIV-negative cases. Granulomas tend to be poorly formed and giant cells infrequent. In advanced AIDS cases, miliary lesions may consist of foci of necrosis teeming with tubercle bacilli but with little or no surrounding cellular reaction. Hill and associates described lesions in some patients with AIDS at autopsy who had foci of acute tuberculous pneumonia in the airspaces rather than in the interstitium. The lesions consisted of necrotic alveolar septa surrounded by a few monocytes and neutrophils.
MILIARY TUBERCULOSIS IN HIV-INFECTED PERSONS
The presence of HIV infection has had a major influence on the epidemiology, pathology, clinical, laboratory, and radiologic manifestations of tuberculosis. HIV infection, whether inapparent or presenting with AIDS, has altered the characteristics of miliary tuberculosis as well.
At present, hospitals serving endemic areas of HIV infection find that a majority of adults admitted with miliary or focal extrapulmonary tuberculosis have co-existing HIV infection. The incidence of miliary dissemination has greatly increased among HIV-infected subjects as compared with noninfected subjects. Hill and associates suggested that miliary dissemination is clinically recognizable in at least 10% of patients with AIDS-related tuberculosis. Entry into the bloodstream in such persons appears to occur principally from heavily infected necrotic lymph nodes in the hilum, in the mediastinum, or from extrathoracic sites. It has been suggested that a more severe T-helper-cell immunosuppression predisposes to mycobacteremia.
The histocytologic changes of miliary foci in HIV-positive subjects depend on the degree of impairment of the cellular response to the presence of the tubercle bacilli. Patients without profound immunosuppression and with normal or moderately suppressed levels of CD4 lymphocytes may have classic, well-organized tubercles. Those with marked lymphopenia or with AIDS usually have atypical foci with few inflammatory cells and poorly formed granulomas. These are usually necrotic and contain large concentrations of organisms. Some lesions appear as microabscesses consisting of polymorphonuclear leukocytes and are teeming with tubercle bacilli. At autopsy, a case may demonstrate a spectrum of histopathologic changes in different organs ranging from typical tubercles to microabscesses.
The symptoms and signs in HIV-infected patients with miliary tuberculosis are similar to those in persons who are not HIV-infected. However, the former may have evidence of other clinical signs of immunosuppression such as oral thrush, Candida esophagitis, generalized lymphadenopathy, and skin lesions of Kaposi’s sarcoma. Except for more profound lymphopenia, especially of CD4 cells, the laboratory manifestations are similar to those in subjects who are not HIV-infected.
The chest radiograph of HIV-infected patients with miliary tuberculosis demonstrates a typical pattern of the disease. Most of these patients also have hilar and mediastinal lymphadenopathy as well as diffuse small parenchymal nodules. A significant portion, however, may not have typical lesions and may have either a normal-appearing chest film or only hilar or mediastinal lymphadenopathy. At times, HRCT may demonstrate very small lesions that are undetectable by conventional chest radiograph.
Subacute disseminated tuberculosis
This form of the tuberculosis develops during decreased resistance of the organism, in senile age, during immunodepression therapy.
Pathologic anatomy. Subacute disseminated tuberculosis appears during affection of intralobular veins and intralobular branches of pulmonary artery.
It results formulation of great simetric focuses (5-
Chronic disseminated tuberculosis of lungs
Appears not entirely effective therapy of the subacute disseminated tuberculosis, his observed more frequently as independent form. Characterized by presence of temporary remission of a disease and acute condition, which is caused by bacteriemia, dissemination and infiltrating changes in lungs.
Pathologic anatomy. Process has apica-caudal dissemination. Calculated focuses are situated in upper segments of lungs, but fresh focuses there are lower. Symetric cavities formulate in upper segments, emphysema prevails in lower segments
Clinical picture. Disseminated tuberculosis as independent disease begins under mask of grippe or othe respiratory disease. High temperature continues for 7-10 days, then fever is observed. Onset is possible as fever and innoticable for patients and pathologic process is found out during prophylactic roentgenography.
Sometimes chronic disseminated tuberculosis manifests itself some years after exudative pleuritis or tuberculous affection of other organs – bones, urogenital system
So, onset of chronic disseminated tuberculosis can be different, but its origin is chronic course with acute periods and temporary remissions of disease.
During remission patients feel well, complaints are absent. During acute period dissemination focuses, infiltrative or destructive changes appear in lungs, increases temperature, hyperhydrosis appears, general weakness, productive couph.
During long course pneumosclerosis and emphysema formulate, patient’s condition becomes worse, manifests itself pulmo-cardial insufficiency. In theese cases patients complain about dyspnea, productive couph.
During progressive process the development of massive fibrosis changes is observed. In superior lung segments there are wooden sound, warsh breasing, moist fine bubbling rales. Emphysema couses slow respiration and dull sound during percussion.
Focal ( Nidus) lung tuberculosis (FLT)
Infiltrative lung tuberculosis (ILT)
Caseous pneumonia
Focal ( Nidus) lung tuberculosis (FLT)
In this form of tuberculosis, foci of specific inflammation are formed in the lungs with a size up to 1cm, single or multiple, 1-side or 2-side, localized in 1-2 segment.
Pathogenesis and pathanatomy. FLT belongs to secondary tuberculosis, meaning that it develops in long-time infected organisms the with presence of some infectious immunity and has features of limited organ injury(
Theories of secondary tuberculosis development:
– exogenic super infection;
– endogenic reactivation of remining foci of infection.
According to exogenic theory, secondary tuberculosis is a result of repeatedly getting virulent tubercular infection into the lungs – super infection Development of such fresh exogenic foci starts with endobronchitis of subsegmentary bronchus that transforms into panbronchitis, sometimes caseous. Around it there is formed focus of specific pneumonia firstly exudative, then productive character.
By endogenic theory, for development of secondary tuberculosis new infection is not obligatory. It may occur as a result of reactivation of tuberculosis infection in residual tubercular changes after primary tuberculosis that might take place without considerable clinical symptoms. In such old changes mycobacteria may stay living for a long time. Under the influence of different endogenic and exogenic factors which influence negatively on immunity; they are able to revert into virulent and reproductive..
Third way of formation of focal tuberculosis is involution of other forms – infiltrative, disseminated and even cavernous.
Thus, focal tuberculosis includes very different processes: fresh foci formed as a result of exogenic superinfection or endogenic reactivation by lymphogenic, hematogenic or bronchogenic ways and old foci formed in process of back development of other tuberculosis forms. So, it may be at the start of lung tuberculosis or its finish.
But focal tuberculosis includes only processes with active, not finished specific inflammation. FLT is divided into soft focal (acute) with fresh foci of exudative or productive character and fibrouse focal (chronic) at which foci are surrounded with a connective tissue capsule, sometimes with elements of calcination
Focal tuberculosis is localized on apical parts or under clavicles. It is connected with limited mobility of apices, their insufficient aeration, weak vascularisation, slow lymph circulation, hypersenssensivity. There is also possible of MBT coming from tonsils of cervical lymph nodes
Infiltrative lung tuberculosis (ILT)
ILT is a zone of specific inflammation mostly of exudative character, with size more than
Pathogenesis and pathanatomy.. Infiltrate develops as a result of perifocal inflammation around fresh foci that appeared due to exogenic superreinfection or endogenic reactivation. Thus it may be continuation of soft-focal tuberculosis. Often the stage of development in the lungs of fresh foci stays not revealed, and sickness is revealed with formed infiltrate
Tuberculosis infiltrate may be a result of perifocal, inflammation around severed old foci formed at involution of lung tuberculosis. Fast development of infiltrate is a result of hyperergic reaction of lung tissue to a high quantity of virulent MBT that quickly reproduces. At ILT there are injured several pulmonary lobules, segments, subsegment or whole lobe in zone of perifocal pneumonia around fresh or old severed foci. Areas of caseous are usually formed in the center of infiltrate. Under the action of proteolysis enzymes caseous is dissolved, excreted through draining bronchus and cavity of destruction is formed.
Caseous masses may be partly aspirated into other (usually inferior) parts of lungs; they become basis for formation of fresh foci of broinchogenic dissemination..
Caseous pneumonia is a clinical form of tuberculosos with massive caseous changes in lungs and severe, progressive clinical course.
Pathogenesis and pathanatomy. This process appears as a secondary one in patients with decreased immune reactivity as a result after superreinfection by massive doses of highly virulent, sometimes resistant mycobactreria of tuberculosis or as a result after endogenic reactivation of old process with immunodepressive therapy. It is thought that some role for malignant course of disease plays secondary non-specific infection. Lobar caseous pneumonia develops on a background of cloud-like infiltrate or lobitis, when during expressed hyperergic tissue reaction becomes an almost total caseous necrosis of tubercular infiltrate, which dominates under the perifocal inflammation. Colicvation causes multiple cavities of disintegration of gigantic caverna, which occupies whole lobe of lung. Then infection in lungs can enlarge through bronchi
Thus they’re the following variants of caseous pnemonia:
1. Lobar is a total caseous necrosis of cloudlike infiltrate or lobitis.
2. Lobuluar:
– As a result of aspirative pnemonia after bleeding;
– Malignant course of subacute disseminative tuberculosis of
lung;
– Complications of terminal stages of chronic form of
tuberculosis;
– Spreading of caseous masses in bronchi and lungs through the
fistula with lymphatic nodes.
