Primary tuberculosis

1. Primary tuberculosis LECTURE doc. KravchenkoN.S.

2. Tuberculosis which develops in primary infected people is called primary tuberculosis. It is diagnosed often in children and teenagers. More rarely in young people. Topical sings of primary tuberculosis are: a) The intensity tuberculin test reaction; b) lesion of lymphatic system (especially lymphatic nodes); c) tendency to lymphogenous and hematogenous dissemination; d) state of hypersensibilization of organism to pathogenic agent; e) possibility of spontaneous recovery. Tuberculin intensifier is the appearance of first positive tuberculin reaction after a negative one within a year or its increase in persons vaccinated. Primary tuberculosis usually displays in three main forms: - tuberculous intoxication in children and teenagers (tuberculosis without established localization); - primary tuberculous complex; - tuberculosis of intrathoracic lymphatic nodes.

3. The clinical expression of disease caused by Mycobacterium tuberculosisis greatly different in infants, children, and adolescents than in adults. Whereas most adult pulmonary tuberculosis is caused by a reactivation of dormant organisms that are lodged in the apices of the lungs during hematogenous dissemination at the time of infec­tion, pediatric tuberculosis is usually a complica­tion of the pathophysiologic events surrounding the initial infection. The interval between infection and disease is usually long - years to decades - in adults but is often only weeks to months in small children. Children are more prone to extrapulmonary tuberculosis but rarely experience infectious pulmonary disease. As a result of the basic differ­ence in pathophysiology of tuberculosis between adults and children, the approach to diagnosis, treatment, and prevention of infection and disease in children is very different.

4. TERMINOLOGY The terminology used to describe various stages and presentations of pediatric tuberculosis often has been a source of confusion for physicians. It follows the pathophysiology, but the stages are often less distinct in children. Exposure means that the child has had signifi­cant contact with an adult or adolescent with in­fectious pulmonary tuberculosis. The contact investigation examining those persons close to a suspected case of tuberculosis with a tuberculin skin test, chest radiograph, and physical exam­ination is the most important activity in a com­munity to prevent tuberculosis in children. The most frequent setting for exposure of a child is the household, but it can occur in a school, day care center, or other closed setting. In this stage, the tuberculin skin test result is negative, the chest radiograph appears normal, and the child lacks signs or symptoms of disease. Some exposed chil­dren may have inhaled droplet nuclei infected with M. tuberculosis and have early infection, but the clinician cannot know it because it takes up to 3 months for delayed hypersensitivity to tuber­culin a positive skin test result to develop.

5. Infection occurs when a person inhales droplet nuclei containing M. tuberculosis, which becomes established intracellularly within the lung and as­sociated lymphoid tissue. The hallmark of tubercu­losis infection is a reactive tuberculin skin test. In this stage, the child has no signs or symptoms and the chest radiograph either appears normal or reveals only granuloma or calcifications in the lung parenchyma, regional lymph nodes, or both. In many countries, all children with tuberculosis infection should receive treatment, usually with isoniazid (INH), to prevent the devel­opment of disease in the near or distant future. Disease occurs when signs or symptoms or radiographic manifestations caused by M. tuberculo­sis become apparent. The word tuberculosis refers to disease. Not all infected patients have the same risk of developing disease. An immunocompetent adult with untreated tuberculosis infection has ap­proximately a 5% to 10% lifetime risk of experi­encing disease; one half of the risk occurs in the first 2 to 3 years after infection. Historical studies have shown that up to 40% of immunocompetent infants with untreated tuberculous infection de­velop disease often serious, life threatening forms within 1 to 2 years.

6. EPIDEMIOLOGY Disease and Infection Because most children with tuberculous infection and disease acquired the organism from an adult in their environment, the epidemiology of childhood tuberculosis tends to follow that in adults. The risk of a child acquiring tuberculous infection is environmental, determined by the likelihood that he or she will be in contact with an adult with contagious tuberculosis. In contrast, the risk of a child developing tuberculous disease depends more on host immunologic and genetic factors. It is estimated that the worldwide annual burden of tuberculosis on children is 1.5 million cases and 500,000 deaths. Adult tuberculosis case numbers have increased over the past decade in every re­gion of the world except Western Europe. There are no comparable data, but it is likely that child­hood tuberculosis has grown in numbers as well. Most children are infected with M. tuberculosisin the home, but outbreaks of childhood tuberculo­sis centered in elementary and high schools, nurs­ery schools, family day-care homes, churches, school buses, and stores still occur. In most cases, a high-risk adult working in the area has been the source of the outbreak.

7. The recent epidemic of human immunodefi­ciency virus (HIV) infection has had a profound effect on the epidemiology of tuberculosis among children as a result of two major mechanisms: (1) HIV-infected adults with tuberculosis may trans­mit M. tuberculosis to children, some of whom will develop tuberculosis disease (2) chil­dren with HIV infection may be at increased risk of progressing from tuberculosis infection to dis­ease. Several studies of childhood tuberculosis have demonstrated that increased case rates have been associated with a simultaneous increase among HIV-infected adults in the community. In developing countries, tuberculosis infection rates among the young population average 20% to 50%. In most children in the United States, the risk is less than 1%, but in some urban populations the risk is much higher.

8. Transmission Children usually are infected by an adult or ado­lescent in the immediate household, most often a parent, grandparent, or household employee. Casual extrafamilial contact is the source of infection much less often, but babysitters, schoolteachers, music teachers, school-bus drivers, parishioners, nurses, garden­ers, have been implicated in individual cases and in hundreds of mini-epi­demics within limited population groups. Within the household of an infectious adult, the infants and toddlers almost always are infected. Also at high risk are the older children and teenag­ers who help the ailing adult. Adults with pulmonary disease who are re­ceiving regular, appropriate chemotherapy proba­bly rarely infect children; much more dangerous are those with chronic tuberculous disease that is unrecognized, inadequately treated, or in relapse because of development of resistance. Children with tuber­culosis rarely, if ever, infect other children. Many children with the disease have tuberculin-negative parents.

9. When transmission of M. tuberculosis has been documented in children's hospitals, it almost invariably has come from an adult with undiagnosed pulmonary tuberculosis. In tuber­culous children, M. tuberculosis in endobronchial secretions are relatively sparse, and productive cough is not at all characteristic of endothoracic tuberculosis or of miliary disease. When young children cough, they lack the tussive force of adults. Adolescents with typical reactivation-type pulmonary tuberculosis may be as infectious as adults. Children nevertheless play an extremely important role in the transmission of tuberculosis, not so much because they are likely to contami­nate their immediate environment but because they harbor a partially healed infection that lies dormant, only to reactivate as infectious pulmo­nary tuberculosis many years later under the so­cial, emotional, and physiologic stresses arising during adolescence, adulthood, or old age. Thus, children infected with M. tuberculosis constitute a long-lasting reservoir of tuberculosis in the popu­lation.

10. PATHOGENESIS IN CHILDREN Primary tuberculosis is always result of exogenous infection. The infection penetrates into organism by: - aerogenic (the most often way of penetration) - alimentary; - contact way. 1. The primary complex of tuberculosis consists of local disease at the portal of entry and the regional lymph nodes that drain the area of the primary focus. In more than 95% of cases the portal of entry is the lung. M. tuberculosis within particles larger than 10 (xm usually are caught by the mucociliary mechanisms of the bronchial tree and are expelled. Small particles are inhaled beyond these clearance mechanisms. However, primary infec­tion may occur anywhere in the body. 2. Ingestion of milk infected with bovine tuberculosis can lead to a gastrointestinal primary lesion. 3. Infection of the skin or mucous membrane can occur through an abrasion, cut, or insect bite.

11. The number of M. tuberculosis required to establish infection in children is unknown, but only several organisms are probably necessary. The incubation period in children between the time the M. tuberculosis enter the body and the development of cutaneous hypersensitivity is usu­ally 2 to 12 weeks, most often 4 to 8 weeks. The onset of hypersensitivity may be accompanied by a febrile reaction that lasts from 1 to 3 weeks. During this phase of intensified tissue reaction, the primary complex may become visible on chest radiograph. During this time, the primary focus grows larger but does not yet become encapsu­lated. As hypersensitivity develops, the inflamma­tory response becomes more intense and the re­gional lymph nodes often enlarge. The paren-chymal portion of the primary complex often heals completely by fibrosis or calcification after under­going caseous necrosis and encapsulation. Occasionally, the parenchymal lesion may continue to enlarge, resulting in focal pneumonitis and thickening of the overlying pleura. If caseation is intense, the center of the lesion may liq­uefy, empty into the associated bronchus, and leave a residual primary tuberculous cavity.

12. During the development of the parenchymal lesion and the accelerated caseation brought on by the development of hypersensitivity, M. tuberculosis from the primary complex spread via the bloodstream and lymphatics to many parts of the body. The areas most commonly seeded are the apices of the lungs, liver, spleen, meninges, perito­neum, lymph nodes, pleura, and bone. This dis­semination can involve either large numbers of bacilli, which leads to disseminated tuberculous disease, or small numbers of bacilli that leave microscopic tuberculous foci scattered in various tissues. Initially, these metastatic foci are usually clinically inapparent, but they are the origin of both extrapulmonary tuberculosis and reactivation pulmonary tuberculosis in some children. The tubercle foci in the regional lymph nodes develop some fibrosis and encapsulation, but heal­ing is usually less complete than in the parenchymal lesions. Viable M. tuberculosis may persist for decades after calcification of the nodes. In most cases of primary tuberculosis infection, the lymph nodes remain normal in size. However, because of their location, hilar and paratracheal lymph nodes that become enlarged by the host inflammatory reaction may encroach upon the re­gional bronchus. Partial obstruction caused by ex­ternal compression may lead at first to hyperinfla­tion in the distal lung segment. Such compression occasionally causes complete obstruction of the bronchus, resulting in atelectasis of the lung segment.

13. More often, inflamed caseous nodes attach to the bronchial wall and erode through it, leading to endobronchial tuberculosis or a fistulous tract. The extrusion of infected caseous ma­terial into the bronchus can transmit infection to the lung parenchyma and cause bronchial obstruc­tion and atelectasis. The resultant lesion is a combination of pneumonia and atelectasis. The radiographic findings of this process have been called epituberculosis, collapse-consolidation, and segmental tuberculosis. Rarely, tuberculous intrathoracic lymph nodes invade other adjacent struc­tures such as the pericardium or esophagus. Massive lympho-hematogenous dissemination leading to meningitis or miliary or disseminated disease occurs in 0.5% to 2% of infected children, usually no later than 3 to 6 months after infection. Clinically significant lymph node or endobronchial tuberculosis usually appears within 3 to 9 months. Lesions of the bones and joints usually take at least a year to develop; renal lesions may be evident 5 to 25 years after infection. In general, complications of the pri­mary infection occur within the first year.

14. How Children with Tuberculosis Are Discovered In the developing world, the only way children with tuberculosis disease are discovered is when they present with a profound illness that is consis­tent with tuberculosis. Having an ill adult contact is an obvious clue to the correct diagnosis. The only available laboratory test usually is an acid-fast smear of sputum, which the child rarely pro­duces. In many regions, chest radiography is not available. To aid in diagnosis, a variety of scoring systems have been devised that are based on avail­able tests, clinical signs and symptoms, and known exposures. However, the sensitivity and specificity of these systems can be very low, lead­ing to both over- and under-diagnosis of tuber­culosis.

15. In industrial countries, children with tuberculosis usually are discovered in one of two ways. 1) One way is consideration of tuberculo­sis as the cause of a symptomatic pulmonary or extrapulmonary illness. Discovering an adult con­tact with infectious tuberculosis is an invaluable aid to diagnosis; the yield from a contact investi­gation usually is higher than that from cultures from the child. 2)The second way is discovery of a child with pulmonary tuberculosis during the con­tact investigation of an adult with tuberculosis. Typically, the affected child has few or no symp­toms, but investigation reveals a positive tubercu­lin skin test result and an abnormal chest radio­graph appearance. In some areas of the United States, up to 50% of children with pulmonary tuberculosis are discovered in this manner, before significant symptoms have begun.

16. Tuberculous intoxication in children and teenagers is a clinical form of primary tuberculosis, which is characterized by complex of symptoms of functional derangement without local manifestation of disease. Morfological substrat of tuberculous intoxication are minimal specific (tuberculous granuloma with areas of microcaseose) and paraspecific changes, usually in lymphatic system.

17. Clinical manifestations. Complaints on aggravation of appetite, sweating, not constant subfebrile body temperature, emotional instability, decreasing of memory. Objectively: paleness, decreasing of skin turgor, micropoliadenitis (increasing of quantity and sizes of periferal lymphatic nodes more than five groups). During percussion changes over the lungs are absant. Auscultation: sometimes dry rales. Laboratory and other methods of investigation. In hemogram can be slight leukocytosis with an insignificant shift to the left, lymphopenia, eosinophilia, monocytosis, ESR is normal or increased. Roengenological examination. In reviewable roentgenogram and tomogram of lungs there are no changes usually. Sometimes it can be strengthen of lungs picture.

18. Differential diagnosis. It is necessery to exclude diseases accompanied by intoxication: chronical sourses of infection of oral cavity and epipharynx: chronical tonsillitis, pielonephritis, rheumatism, hepatocholecystitis, helminthic invasions. Main diagnostic criterions of tuberculous intoxication are: - tuberculin intensifier - symptoms of intoxication - absence of roentgenological changes - excluding of intoxication with different ethiology Treatment. Isoniazidum 10mg/kg of weight + rifampicinum10 mg/kg or etambutol 20mg/kg for 4-6 months, vitamins B1, B6, C.

19. Primary tuberculous complex Primary tuberculous complex is characterized by development of specific general changes in lungs (primary effect), lesion of intrathoracic lymphatic nodes and lymphangitis. Patological anatomy: zone of tuberculous granulations and caseous necrosis is forming in lungs. Zone of perifocal toxic edema and serofibrinous inflammation is forming around zone of specific inflammation. These changes form primary affect. Infection extence in lymphatic vessels from primary affect to the root of lungs (lymphangitis) and injury of root lymphatic nodes is taking place (lymphadenitis). fig. 1

20. Clinical manifestations. Asymptomatic course of disease can be present under little specific changes in lungs. Complaints: subfebrile temperature, decrease of body weight, bad appetite, quick tiredness. Coughing happens seldom. Inspection: paleness, decrease of skin turgor, paraspecific changes, micropolyadenitis. These changes can be absent. Percussion: dullness over lung component with a big size. Weakend breathing with streached exhale. Hemogram: Leucocytosis 10-13 T/l, insignificant shift to the left, lymphopenia, monocytosis, SSE 20-25 mm/h. Tuberculin test - intensivity of tuberculin reaction, hyperergic reaction. MBT are rarely to be found. X-ray diagnostics: Phases: 1) infiltrative or pneumonic; 2) resorbtion (suction,bipolarities); 3) scarring 4) calcification. fig. 2

21. Complications are connected with lung component: - decomposition of primary affect with primary cavern forming Complications connected with regional lymphadenitis: - hematogenic dessimination - lymphogenic dessimination - pleuritis - extencing of specific process from lymphatic node to It’s results: a) formation of fistula b) dispersion of caseous masses, bronchogenic dessemination c) disorder of bronchial permeability fig. 3

22. The differential diagnostics is performed with : 1) Pneumonia; 2) Eosinofilic infiltration; 3) Peripheral or central cancer. Unspecific pneumonia usually beging sharply after catching cold, respiratory infection with the high body temperature, general weakness, pespiration, considerable shortness of breath. Auscultatorily is defned many dry and moist rales. Blood examination: high leucocitosis and high ESR.

23. Tuberculosis of intrathoracic lymphatic nodesis specific injury of lymphatic nodes of lungs’ root and mediastinum. Pathomorphological forms: a) hyperplastic b) caseous form fig. 4 The clinic of uncomplicated tuberculosis of intrathoracic lymphatic nodes is similar to that of primary tuberculous complex. Clinical-radiological forms of tuberculosis of intrathoracic nodes: 1) Small form – deformation and strengthening of pulmonary picture near lung root, decreasing of root structure. 2) Infiltrative – root shadow is widened with not clear contour (ouyline). 3) Tumorshaped – widening of mediastinum or lung root with polycicle clear contour

24. Differntial diagnosis is conduction with: Lymphogranulomatosis, lymphosarcoma, lymphoid leukemia, unspecific adenopathy, mediastinal cancer, sarcoidosis. For this the following procedures are performed: 1) X-ray examination in right and lateral projections; 2) Tomography on bifurcation level ( middle microscopic section); 3) Tuberculin tests, bronchoscopy as well as punctured or operative biopsy. Treatment of local forms of: Stationary : 2 months-Isoniazidum 10 mg/kg of body weight +Rifampicinum 10 mg/kg of body weight +Pyrazinamidum 25 mg/kg of body weight. Under extend process, complications prescribe: + streptomycinum 15-20 mg/kg of body weight. Next 4 months - Isoniazidum + rifampicinum or ethambutolum. General course of treatment lasts for 6-9 mounths. Vitamins B1, B6, C, desensibilizinig preparations are also prescribed.