CHAPTER 2

TUBERCULOSIS

Tuberculosis is a global public health concern. In 1993 it was declared by the World Health Organisation (WHO) to be a global emergency. Although the principles of management of tuberculosis (TB) were established 30 to 40 years ago, and the efficacity of short-course chemotherapy has been known for some 20 years, TB is still not diagnosed and treated properly in many parts of the world. Thus it is now vital to emprove the knowledge about TB in order to provide proper diagnosis and treatment of the disease in an individual patient and in the community.

2.1. HISTORY OF TUBERCULOSIS

Tuberculosis — a disease also known as consumption, wasting disease, and the white plague — has affected humans for centuries. This contagious, potentially fatal infection is most commonly caused by the airborne bacterium Mycobacterium tuberculosis and occasionally caused by M. bovis, or M. africanum. Genetic evidence (the strong degree of DNA homology) and the immunological properties suggest that M. tuberculosis evolved through genetic mutations from M. Bovis in humans after cattle domestication. Although other mycobacteria cause diseases that mimic tuberculosis, those infections are not contagious, and most respond poorly to drugs that are very effective against tuberculosis.

People have been contracting tuberculosis since ancient times. The bony difformities found in skeletons, drawings and sculptures in Egypt, Peru and other countries are very suggestive of Pott`s disease. Evidence of human tuberculosis, most convincingly as spinal gibbus, has been unearthed in petrified bones that date to 8000 B.C.; a study of a remarkably preserved Incan child of A.D. 700 demonstrated microscopic acid-fast bacilli in a psoas abscess; Pott`s disease has been found in Egyptian mummies.

Tuberculosis was accurately described (“lung fever” with emaciation, cough and expectoration of blood) in the earliest writings and classical texts of Chinese, Greek and Roman physicians. It was also known as “wasting disease”, phthisis, consumption and scrofula (lymph node tuberculosis).

During the 1600-s there was a dramatic increase of the consumption cases in the overcrowded cities in Britain and throughout the western Europe. A remarkable work which anticipates the germ theory for the etiology of tuberculosis is Benjamin Martin`s book entitled “A New Theory of Consumption, More Especially of Phthisis or Consumption of the Lungs”. He believed that tuberculosis was

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contagious and infection was induced by very small living creatures; his ideas will be confirmed more than 100 years later by Villeman and Koch.

Tuberculosis became a major scourge in Europe during the Industrial Revolution, when overcrowding in cities was common, accounting for more than 30 percent of all deaths. For many people, a diagnosis of TB was a slow death sentence.At the end of the 18-th century, the cause of tuberculosis was still unknown, the early attempts at control had failed and the treatments were ineffective. In 1799, one of four deaths was attributed to tuberculosis.

Until the mid-1800s, people thought that tuberculosis, or TB, was hereditary. They did not realize that it could be spread from person to person through the air.

In the early 1800’s Auenbrugger descovered the method of percussion and Laennec invented the stethoscope; the nomenclature and vocabulary that Laennec created for auscultation remain in use today. Auscultation and percussion remained the only methods of examination of the chest until Roentgen discovered the x-rays investigation. A special mention should be made for Laennec`s pathological description of the different stages in tuberculosis evolution in different organs, claiming for the first time the unity of the disease. Unfortunately, after years of study of the disease, Laennec died of tuberculosis at the age 45.

In 1839, the generic designation “tuberculosis” was suggested by Schonlein for all manifestations of phthisis, recognizing the tubercle as the fundamental anatomical lesion. Ghon studied the characteristic changes produced by the primary infection in children and supported the theory that most tuberculosis is acquired by inhalation. In 1865 a French surgeon, Jean-Antoine Villeman, demonstrated that TB is a specific infection due to an inoculable agent. He inoculated products of the disease, such as sputum, from human lung to lower animals and from animal to animal and proved that disease developed in inoculated animals.

The etiology of tuberculosis was elucidated in 1882 by the great German scientist Robert Koch. He discovered the bacteria that causes the disease (the tubercle bacillus), and developed a method of cultivation for the bacilli, which permitted separation of colonies and made possible isolation of individual strains. He also demonstrated the different reactions following secondary and primary infection (the Koch phenomenon) and produced the extract of dead tubercle bacilli called “tuberculin”.

Veterinarians were the first to recognize and demonstrate the potential diagnostic use of tuberculin, because tuberculosis was common in cattle. Systematic tuberculin testing in cattle was instituted to control the spread of disease among animals and to humans. Pasturization of milk assured further protection for humans. The best method used to identify the infected humans remained the intradermal inoculation of tuberculin introduced by Charles Mantoux in 1908.

In 1896 Roentgen discovered diagnostic radiology in tuberculosis, but the method was received with caution by the clinicians. X-ray examination of the chest

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became routine only in the 1930-s and around 1950-s, mass x-ray screening became a major thrust in the control of tuberculosis.

Concerning the modes of transmission, several theories were developed: dust, soiled hands, contaminated surfaces and moist droplets produced by cough were incriminated in the pathogenesis of tuberculosis. Only after 1950, Wells demonstrated the current mechanism of transmission by “droplet nuclei”(the moist particles eliminated by cough dry rapidly in atmosphere; they carry a single bacillus or a small clump of bacilli and float freely in the air for considerable periods of time). Wells` work was capital for the modern strategies of tuberculosis control. Preventing infected droplet nuclei to spread in the environment can be achieved by adequate air exchanges, maintaining negative pressure in the contaminated areas, using devices to filter the air leaving the contaminated room, etc.

Yet half a century passed between Koch`s isolation of the tubercle bacillus and discovery of drugs that cure TB. Prolonged hospitalization, bed rest in sanatorium, artificial pneumothorax and thoracoplasty (rib resection to diminish the volume of the thoracic cavity and collapse a part of the lung in order to heal a subsequent TB cavity) were the main therapeutic issues in the pre-antibiotic era. Many people with TB were sent to sanatoriums, special rest homes where they followed a prescribed routine every day. No one knows whether sanatoriums really helped people with TB; even so, many people with TB could not afford to go to a sanatorium, and they died at home.

The BCG vaccination (an attenuated strain of Mycobacterium bovis obtained by Calmette and Guerin) was first used in 1921 in Paris, particularly for children at high risk. The variable effectiveness of the BCG vaccine (ranging from 0 to 80%), the possible reasons for these differences and the maintainance of residual virulence of the BCG strain are still subjects of interdisciplinar debates.

The history of collapse therapy began in 1894 when Carlo Forlanini first induced pneumothorax successfully through the chest wall, in order to collapse and “rest” the sic part of the lung and promote healing. Artificial pneumothorax was effective in about one third of cases, especially in patients with unilateral disease.

In 1911, Hans Christian Jacobeus invented the thoracoscope and performed cauterisation of pleural adhesions, enhancing the usefulness of therapeutic pneumothorax. After 1880 thoracic surgery for tuberculosis developed the technique of thoracoplasty: ribs were removed to bring the chest wall down to the lung. Several variations on the procedure were developed, and collapse of the lung was sometimes achieved by introduction of oil, paraffin or plastic spheres into an extraperiosteal pocket (plombage thoracoplasty), attempting to minimize deformity and lung function impairment. Even if effective in about 80% of selected patients, such therapy sometimes led to longer sanatorium stays, chronic impairment of respiratory function and increased mortality. Only in 1934 the techniques of pulmonary resection (lobectomy, pneumonectomy) were accomplished successfully for tuberculosis. In absence of specific drug therapy, lung resections

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were commonly followed by complications like spread of tuberculosis, fistula formation and empyema; therefore, postoperative mortality was about 20-40%.

Until the 1940s and 1950s, there was no real cure for TB; a breakthrough came in 1943 when an American scientist, Selman Waksman (Nobel Prize in 1944) discovered streptomycine, a drug that could kill TB bacteria. With the development of the antibiotics - streptomycin in the 1940s, isoniazid in the 1950s, ethambutol in the 1960s, and rifampin in the 1970s - the battle against tuberculosis seemed to be won; many people with TB were cured, and the death rate for TB dropped dramatically. Drug therapy revolutionized the treatment of tuberculosis around the world. Sanatoriums were almost abandoned, ambulatory therapy developed and surgery was used only in very selected cases.

However, in the mid-1980s, the number of cases began to rise again. AIDS, combined with overcrowding and unsanitary conditions in many urban areas, homeless shelters, and prisons, has again made tuberculosis a serious public health problem. It remains a major disease of mankind on a worldwide basis. The problem is especially worrisome because some strains of tuberculosis bacteria have become resistant to the antibiotics used to treat the disease.

2.2. EPIDEMIOLOGY OF TUBERCULOSIS

Tuberculosis is present worldwide, with a very high prevalence in Asian countries, where 60-80% of children below the age of 14 years are infected. The prevalence of TB increases with poor social conditions, inadequate nutrition and overcrowding. The World Health Organisation (WHO) estimates that:

- about one third of the world`s population is infected by Mycobacterium tuberculosis;

- world-wide in 1996 there were about 8 million new cases of TB with 3 million deaths;

- TB is the leading cause of death due to a single infectious agent;- 95% of the TB cases and 98% of TB deaths are in developing countries.Death from tuberculosis represents 25% of all avoidable deaths in the

developing world.- 75% of TB cases in developing countries are in the age group 20 - 50 years,

which represents men and women in their most productive years.In the future it is expected that tuberculosis will remain one of the 10 leading

causes of mortality and morbidity in the world. Although the rates of TB will decrease in many countries, the total number of TB patients will increase to ten million new cases in 2020. The main reasons for the increasing global TB burden are:

- poverty in various populations, not only in developing countries but also in inner city populations in developed countries;

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- changing demographics, with increasing world population and changing age structure;

- insufficient and inadequate health coverage of the population, especially in poor countries and of the vulnerable groups of the population in all countries;

- impact of HIV epidemics;- neglect and underfunding of the TB control programmes, with inadequate

case detection, inadequate case management and poor cure rates.Case rate = the number of cases that occur during a certain time period,

divided by the size of the population during that time period; the case rate is often expressed in terms of a population size of 100 000 persons.

PEOPLE AT HIGHER RISK FOR TB EXPOSURE OR INFECTION

1. Close contacts are at high risk of being infected with M. tuberculosis.Close contacts, or people who spend time with someone who has infectious TB disease, are at high risk of being infected with M. tuberculosis. Close contacts may include family members, coworkers, or friends.

2. TB infection and disease occur often among people born and/or living in areas of the world where TB is common, such as Asia, Africa, and Latin America. In most cases, these persons become exposed to and infected with M. tuberculosis in their country of birth.

3. Age: the risk of acquiring infection increases with age, during the period from infancy to early adult life, probably because of increasingly numerous contacts with other persons. In developed countries, TB is more common among the elderly. Many elderly people were exposed to and infected with M. tuberculosis when they were younger and TB was more common than it is today. Because a larger proportion of elderly people have TB infection, this group is at higher risk for TB disease. Of all TB cases reported in 1997 in USA, 24% were in people 65 years of age and older, even though this age group made up only 13% of the population. Elderly people living in nursing homes are at an even higher risk for TB.

4. Sex: in nearly all populations, males are more likely to be infected than females, probably because their varied contacts in most societies.

5. The average rate of TB infection is higher in areas with low household income than in areas with the high household income. The reasons for this are not entirely clear, but some possible reasons are crowding, inadequate living conditions, malnutrition, and poor access to health care.

6. TB infection and disease are also more common among homeless people. In addition, according to studies published in 1986, from 18% to 51% of homeless people have TB infection. Homeless people may be at higher risk of developing TB disease once infected because of malnutrition and poor access to health care. Moreover, in some areas they may be more likely than the general population to be infected with HIV.

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7. People who inject illicit drugs are more likely to be exposed to or infected with M. tuberculosis. This may be because a large proportion of people in this risk group have other risk factors for exposure to TB, such as being low-income and having poor access to health care. People who inject illicit drugs are also at high risk of developing TB disease once infected, perhaps because they are more likely to be HIV infected. Also, it is possible that injecting illicit drugs weakens the immune system. The risk of being exposed to TB is higher in certain settings because many people in these facilities are at risk for TB.

8. Special settings: In 1984 and 1985, people living in nursing homes and correctional facilities were four times as likely to have TB disease as those who were not in this situation, because the risk of being exposed to TB is higher than in other places. The risk of exposure to TB is even higher if the facility is crowded.

For example, TB is a problem in nursing homes. In a 29-state survey conducted in 1984 and 1985, in USA the rate of TB disease was twice as high for elderly people living in nursing homes as for elderly people not living in nursing homes.

TB is also a problem in correctional facilities. A CDC study conducted in 1984 and 1985 showed that there were four times as many TB cases in people living in correctional facilities as there were in people of the same age who did not live in correctional facilities. There are several reasons why rates of TB disease are higher in correctional facilities. First, many inmates already have TB infection and therefore are at higher risk of developing TB disease. Second, an increasing number of inmates are infected with HIV, which means that they are more likely to develop TB disease if they become infected with M. tuberculosis. Finally, some correctional facilities are crowded, which promotes the spread of TB.

Other settings where people at risk for TB are grouped together are homeless shelters and drug treatment centers. People who live or work in these settings are at higher risk of being exposed to TB.

9. People who work in health care facilities, such as clinics and hospitals, may be exposed to TB on the job. The risk of exposure depends on the number of TB patients in the facility, the employee's duties, and the effectiveness of the infection control procedures in the facility.

HIGH-RISK GROUPS FOR DEVELOPING TB FOLLOWING INFECTION

The following high-risk groups and individuals have been identified:1. Age:

the age group 20 –50 years, especially males, are at risk; the elderly also; tuberculin reactors passing through adolescence and young adulthood

(especially females), and children in the first 5 years of life (especially infants)(children between the ages of 6 and 12 years are largely protected from morbidity and mortality);

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2. Contacts: especially important are recent, close contacts of cases of active TB;

3. Immigrants, refugees, and temporary migrant workers: these people often come from countries of relatively higher prevalence

than the host country; the incidence rate among immigrants is highest in the first few years after

arrival, but a relatively higher rate persists for decades after entry, and is largely determined by the prevalence of infection in the country of origin;

4. Socioeconomic circumstances: the homeless, the poor, the uneducated and the unemployed carry an

increased risk of TB; these unfavorable characteristics are exaggerated by substance abuse,

most notably of alcohol and intravenous drugs;5. Persons with inactive TB:

those with fibrotic apical lung lesions presumed to represent healed TB who have not been treated or have been inadequately treated;

6. Recent tuberculin conversion: within 1 to 2 years of a negative or insignificant tuberculin reaction there

is a high risk of tuberculous disease.7. Diseases, disorders and drugs that predispose infection to progress to disease:

HIV infection measles silicosis malignant neoplasms (carcinoma of head and neck, stomach, and lung;

Hodgkin's disease, non-Hodkin's lymphoma; acute lymphocitic and myelogenous leukemia);

other immune deficiency disorders primarily affecting cell-mediated immunity (congenital and acquired);

immunosuppressive therapy (chemotherapy, or radiotherapy) and corticosteroids (in chronic high doses);

diabetes mellitus (particularly where severe and unstable); hemodialysis, chronic end-stage renal deficiency with uremia; gastrectomy, jejunoileal bypass; conditions associated with nutritional deficiency, substantial weight loss;

that-thin persons; heroin addiction, intravenous drug abuse and heavy smoking; organ transplantation (with emphasis on renal transplant combined with

renal failure and immunosupressive therapy).

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2.3. BACTERIOLOGY OF TUBERCULOSIS

TB is caused by organisms called Mycobacterium tuberculosis, tubercle bacilli or Koch bacilli (table 4).

M. tuberculosis is a type of mycobacteria. Some mycobacteria are called tuberculous mycobacteria because they cause TB or similar diseases: M. tuberculosis, M. bovis, and M. africanum. Other mycobacteria are called nontuberculous mycobacteria because they do not cause TB. One common type of nontuberculous mycobacteria is M. avium complex. Nontuberculous mycobacteria are NOT usually spread from person to person.

Table 4 - Mycobacterium species and the disease they produce:

SPECIES DISEASE PRODUCEDM. tuberculosis Most cases of human TBM.bovis Cattle and rarely human TBRare forms: M. avium-intracellulare Fowl and human TB M. kansasii Human TB M. xenopi Human TB M. scrofulaceum Lymph node infection

GENERAL CHARACTERISTICS OF M. TUBERCULOSIS

M. tuberculosis is a thin rod, with round extremities, 2–5 um long and 0,2– 0,3 um thick. It is nonmotile, without capsule and spore.

The mycobacterial wall structure has many common elements with the genera Corynebacterium and Nocardia. One main structural element is the presence of mycolic acids (fatty acids with about 70 carbon atoms) which play a major role in acid fastness of mycobacteria. These are esterified to arabinogalactan, another principal element of the cell wall structure, with major role in the immunology of tuberculosis. The “cord factor”, initially thought to be characteristic of virulent strains, has been demonstrated in all mycobacterial species.

The high content of lipid in the cell wall is responsible not only for the extreme hydrophobicity of mycobacterial cells, but also for the resistance of mycobacteria to chemical injury like decontamination procedures using sulfuric acid, sodium hydroxide and/or detergents. It also explains the susceptibility of M. tuberculosis to heat, x- and UV rays and alcohol. The tubercle bacilli keep their viability for weeks at +4oC and for years at –70oC.

Stained with the Ziehl–Neelsen method, M. tuberculosis resists decolorization with strong mineral acids and alcohol, hence the term “acid-alcohol fast”, and appears at microscope examination as curved or straight small red or pink rods. The property of acid-fastness is used to detect mycobacteria.

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Fluorescent staining with auramine O is the preferred staining method because it is faster and more sensitive than the traditional Ziehl-Neelsen method. Smear examination is an easy and qiuck procedure; results should be available within 24 hours of specimen collection. However, smear examination permits only the presumptive diagnosis of TB because the acid-fast bacilli on a smear may be other mycobacteria than M. tuberculosis. Furthermore, many TB patients have negative acid-fast smears.

M. tuberculosis has two main growth characteristics: it does not grow on ordinary culture media but only on enriched ones and it multiplies slowly (every 17-18 hours). The first appearance of grossly visible colonies takes 3-4 weeks. A positive culture for M. tuberculosis confirms a diagnosis of TB. Culture examinations should be done on all specimens, regardless of acid-fast bacilli (AFB) smear results.

The M. tuberculosis culture media presently available are simply classified into solid and liquid media. The most commonly used solid media are egg or agar based. When a solid medium, usually Lowenstein-Jensen, and conventional biochemical tests are used, the isolation of the organism can take 6 to 12 weeks. If a liquid medium is inoculated for growth (using the BACTEC radiometric system) and rapid methods are used for species identification, culture results should be available within 10 to 14 days of specimen collection. The BACTEC TB system is a rapid method of detection of mycobacterial growth, based on the measurements of 14CO2 produced by the growth of tubercle bacilli in a liquid medium containing 14-labeled palmitic acid. A major advantage of the BACTEC TB system is the rapid testing for antimicrobial susceptibility of M. tuberculosis to isoniazid, rifampin, ethambutol and streptomycin.

M. tuberculosis is a strict aerobe organism, equipped with catalase, peroxidase and superoxid-dismutase; its growth rate is highly dependent on the oxygen tension. When the oxygen supply is high, as in the TB cavity of the lung, M. tuberculosis multiplies freely; when it is low, as in the solid caseous foci of the lung, M. tuberculosis multiplies slowly or not at all.

Like all bacterial genomes, the mycobacterial genome is subject to a wide range of mutations which affect sensitivity to antituberculous agents. Mutants resistant to streptomycin, isoniazid, rifampin, pyrazinamide and ethambutol have been selected in the test tube and during the course of TB chemotherapy. Three factors appear to be important for the selection of drug-resistant mutants:

- the first is the proportion of resistant mutants in normally susceptible strains of tubercle bacilli, which ranges from 1 per 105 to 1 per 108;

- the second is the size of the bacillary population from which drug-resistant mutants are intended to be selected (the larger the bacillary population, the higher the chance it contains resistant mutants);

- the third factor is the antimicrobial quality of the drug used (the more bactericidal the drug, the easier the selection of mutants, of course on condition that the drug is used alone).

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The genes responsible for drug resistance in tubercle bacilli have not yet been identified, but a classic feature of a mutant resistant to a given drug is to remain susceptible to other drugs. Clinicians take advantage of that feature in always treating patients with a combination of drugs, each of them being active against the mutants resistant to other drugs.

Nucleic acid probes specific for the genus Mycobacterium, the M. tuberculosis complex, M. avium and M. intracellulare provide a rapid method of species identification. Once the mycobacteria have been grown in culture, nucleic acid probes can identify species in 2 to 8 hours. High-performance liquid chromatography (HPLC), which detects differences in the spectrum of mycolic acids in the cell wall, is equally rapid.

Polymerise chain reaction (PCR) techniques are being developed that could be performed directly on sputum or other clinical specimens to diagnose TB more quickly. However, PCR is not available for the routine diagnosis of TB.

2.4. PATHOLOGY OF TUBERCULOSIS

Primary pulmonary tuberculosis – The initial focus of primary infection is the Ghon complex, which consists of a parenchymal subpleural lesion and enlarged caseous lymph nodes draining the parenchymal focus. The evolution of the initial infection is variable, but in most cases patients are asymptomatic and the lesions undergo fibrosis and calcification. Rarely, in children and immunodeficient adults, progressive spread with cavitation, tuberculous pneumonia or miliary tuberculosis may follow a primary infection.

Secondary pulmonary tuberculosis – Most cases of secondary TB represent reactivation of an old, subclinical infection. During primary infection bacilli may disseminate without producing symptoms and establish themselves in sites with high oxygen tension, particularly the lung apices. Reactivation in such sites occurs in no more than 5-10% of cases of primary infection (figure 25).

The secondary pulmonary TB lesion is located in the apex of one or both lungs. It begins as a small focus of consolidation, usually less than 3 cm in diameter. Less commonly, initial lesions may be located in other regions of the lung, particularly about the hilum. In most cases of secondary TB, the regional lymph nodes develop foci of similar tuberculous activity. In the favorable case, the initial parenchymal focus develops a small area of caseous necrosis that does not cavitate, because it fails to communicate with a bronchus. The usual course is of progressive fibrous encapsulation, leaving only fibrocalcic scars.

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Figure 25 - Diagrammatic representation of the many patterns of secondary tuberculosis, ranging from initial apical loalization to miliary dissemination

(Cotran, 1994).

Histologically, coalescent granulomas are present, composed of epithelioid cells surrounded by a zone of fibroblasts and lymphocytes that usually contains Langhans` giant cells. Some necrosis (caseation) is usually present in the centers of these tubercles, depending on the sensitization of the patient and the virulence of the organisms. As the lesion progresses, more tubercles coalesce to create a confluent area of consolidation. The subsequent evolution of the secondary lesions is variable: they either may heal spontaneously or with therapy, resulting in a fibrocalcic nodule, or may progress to cavitary TB, miliary TB and tuberculous bronchopneumonia

Cavitary fibrocaseous tuberculosis – Secondary active lesions continue to progress over a period of months or years, causing further pulmonary and distant

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organ involvement. At the site of the lung TB lesion, the caseous focus drains into a bronchiole and transforms into a cavity. Growth and multiplication of the tubercle bacilli are favored by the increased oxygen tension.

In most cases, the cavity remains localized to the apex (apical cavitary fibrocaseous TB). The cavity is lined by a yellow-gray caseous material and is separated from the normal lung tissue by fibrous tissue. When cavitation occurs, the pathways for further dissemination of the TB are prepared. The infective material may now dissemniate through the airways to other sites in the lung or upper respiratory tract. Cavitary fibrocaseous TB may affect one, many or all lobes of both lungs in the form of isolated tubercles, confluent caseous foci or large areas of caseation necrosis.

In the progress of the disease, the pleura is inevitably involved and serous pleural effusions, tuberculous empyema, or massive obliterative fibrous pleuritis may be found. Accompatying the endobronchial TB, laringeal and intestinal TB may occur.

Miliary tuberculosis – Lymphohematogenous dissemination may give rise to miliary TB, confined only to the lungs or involving other organs also. The distribution of miliary lesions depends on the pathway of dissemination. The main targets for miliary seeding are the bone marrow, liver, spleen and retina, providing sites for biopsy or direct visualization of disease (retinal choroid tubercles). In the miliary type of distribution, individual lesions vary from one to several millimeters in diameter and are distinct, yellow-white, firm areas of consolidation that usually do not have visible central caseation necrosis or cavitation at the time of examination. Histologically, however, they present the pattern of single or multiple confluent tubercles with microscopic central caseation.

Tuberculous bronchopneumonia - In the highly sensitized individual, the tuberculous infection may spread rapidly throughout large areas of lung parenchyma and produce a diffuse bronchopneumonia or lobar exudative consolidation. Sometimes, with such overwhelming disease, well-developed tubercles do not form, and it may be difficult to establish the TB nature of the pneumonic process. However, numerous bacilli are usually present in such exudates.

The clinical course of pulmonary TB depends entirely on the activity, extent and pattern of distribution of the tuberculous pulmonary infection.

2.5. IMMUNOLOGY OF TUBERCULOSIS

In 1964, Mackaness demonstrated that TB immunity depended on the activation of macrophages, the central cells of granulomas and on immunologically specific T lymphocytes.

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Immunologically competent cells of the human host recognize M. tuberculosis by its antigens; when compared with other pathogens, mycobacteria have a very large panoply of antigens. The heat shock protein antigen is produced by mycobacteria under stressful conditions and has a role in maintaining bacterial integrity. Studies with monoclonal antibodies have demonstrated that this protein has multiple epitopes many of which appear to be shared with epitopes of human proteins that might be related to human autoimmune diseases.

The mycobacterial cell wall is a complex structure with many elements of immunologic importance: mycolic acid lipid, arabinogalactan (the principal structural element of the cell wall), cord factor (lipid associated with vrulence), etc.

The central phenomenon of the TB immunology is the formation of tubercles (hypersensitivity granulomas), recognized as the main histopathological lesions of tuberculosis. These lesions are chiefly composed of macrophages activated in response to mycobacterial antigenes. Monocytes, the circulating form of tissue macrophages, enter tissues at the site of tuberculous infection in response to chemotactic cytokines. Once agregated in granulomas, monocytes become the palisading histiocytes or epithelial cells characteristic of granulomas, and some of these cells fuse to form Langhans giant cells. The most important mediator of these events is tumor necrosis factor. It was demonstrated that granuloma formation is antigen-specific and it is dependent on thymic but not bursal lymphocytes.

The main host immune defenses against tuberculosis are: cell-mediated immunity, defined as a process that activates macrophages so

that they can kill and digest the bacilli they ingested; delayed-type hypersensitivity, defined as a process that destroys the

unactivated macrophages within which tubercle bacilli are multiplying.The T lymphocyte is the most important cell for protective cell-mediated

immunity and for delayed-type hypersensitivity. The CD4 T lymphocyte has the central role in protective immunity against M. tuberculosis (figure 26).

In the majority of TB infected persons, the natural defence mechanisms – macrophages, natural killer cells, neutrophils – are not completely effective against mycobacteria. In most cases, the acquired immune response is responsible for control of TB infection. At the site of infection, unactivated macrophages destroy by phagocytosis a great part of the tubercle bacilli. Then, macrophages present on their surface antigens obtained from phagocytosed bacilli to the T cells (antigen-recognition units). After exposure to mycobacteria, macrophages produce cytokines such as interleukines (IL-10, IL-12, IL-1, IL-6) and tumour necrosis factor (TNF-) with immunoregulatory properties.

CD4+ T cells recognise peptide antigen fragments presented by class II major histocompatibility molecules (MHC) on antigen-presenting cells. Antigen-activated T cells then secrete cytokines such as interpheron-, which in turn stimulate (activate) macrophages to become more effective in destroying mycobacteria and controlling their growth. A strong immune response leads to successful containment of the primary infection and is characterized by a positive tuberculin

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skin reaction, mediated primarily by CD4+ T cells. These memory CD4+ T cells are responsible for controlling quiescent foci of infection and also provide protection against exogenous reinfection with the tubercle bacillus. Although CD4+ T cells have the dominant role in TB cell-mediated immunity, other T cell subsets, such as and CD8+ T cells have complementary roles; all three subsets are sources of interpheron- and competent cytotoxic effector cells.

Figure 26 - Stimuli of macrophage activation:lymphokines (interferon gamma) from immune–activated T cells and

nonimmunologic stimuli such as endotoxin; Ag = antigen (Cotran, 1994)

Cell-mediated immunity and delayed-type hypersensitivity are successive stages of the same immune response to bacillary invasion. Both processes can stop the multiplication of tubercle bacilli, because no bacillary growth occurs in dead macrophages, which are the major component of solid caseous necrotic tissue. With both responses, specific antigens locally stimulate T lymphocytes to produce lymphokines that attract and activate macrophages. Various inflammatory mediators are involved, such as cytokines, arachidonic acid metabolites, hydrolytic enzymes and reactive oxygen and nitrogen intermediates.

The main difference between cell-mediated immunity and delayed hypersensitivity is that the first kills bacilli by amplifying the macrophages` power to destroy intracellularly the germs they ingest (without destruction of the lung tissue), while the second works by killing bacilli-laden unactivated macrophages,

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often resulting in damage of the host lung tissue. The pulmonary damage in clinical tuberculosis appears to be due almost entirely to delayed hypersensitivity.

2.6 PATHOGENESIS OF TUBERCULOSIS

In 1991, Dannenberg described four stages in the pathogenesis of tuberculosis: onset, symbiosis, immune control and liquefaction.

Stage 1 (first week): onset or invasionInhalation is by far the most important mode of transmission of TB. The 1-2

m droplet nuclei that are inhaled and reach the alveoli contain no more than 2 or 3 tubercle bacilli. A single droplet nucleus can cause infection if it contains fully virulent mycobacteria and is implanted in a site where local innate resistance is low. The first defense against infection at the alveolar level is the alveolar macrophage. Derived from circulating monocytes, alveolar macrophages ingest bacteria and other inhaled particulates, becoming nonspecifically activated in the process. Depending on host genetic factors and the degree of nonspecific activation, alveolar macrophages ingesting mycobacteria have variable, innate microbicidal capacity.

Mycobacterial virulence mechanisms are effective against nonactivated macrophages but not against fully activated ones. Thus, both the virulence of inhaled tubercle bacilli and the innate resistance of the ingesting alveolar macrophages determine whether the initial inoculum is destroyed, or whether bacilli replicate, ultimately leading to destruction of the macrophage.

The dose of droplet nuclei required to cause infection will be high in persons whose macrophages have great innate microbicidal capacity, and bacilli are at low virulence. In persons whose macrophages have relatively low innate microbicidal capacity and bacilli are fully virulent, the infecting dose will be low, probably a single droplet nucleus.

Stage 2 (weeks 2 and 3): symbiosisWhen innate macrophage microbicidal capacity is inadequate to destroy the

initial few tubercle bacilli of the droplet nucleus, the bacilli multiply intracellularly and are released when these macrophages die. Monocytes derived from the circulation are attracted to the focus by various chemotactic factors, initiating granuloma formation. Early lesions consist mostly of concentric layers of immature macrophages containing mycobacteria. Although immature monocytes ingest the released tubercle bacilli, they have no capacity to destroy or inhibit their growth, which proceeds exponentially. Like alveolar macrophages, blood-derived monocytes acquire bactericidal activity only upon specific activation by the T lymphocytes, as cell-mediated immunity develops. This stage of the infection is referred to as symbiotic, since the bacilli are multiplying and the macrophages are accumulating, and neither is destroyed by the other.

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In the stage of uncontrolled bacillary multiplication, some mycobacteria are transported to the draining lymph nodes where the pathological process is repeated. Bacilli can also spread to distant sites via the bloodstream.

Stage 3 (after week 3): immunologic controlAt 3 weeks, when both cellular immunity and delayed hypersensitivity

develop, there are skeins of tubercle bacilli growing in unactivated macrophages. In many, the bacilli are too numerous to be killed by the cellular immunity process. Cell-mediated immunity results in the accumulation of large numbers of activated, microbicidal macrophages around solid caseous tuberculous foci.

Delayed hypersensitivity can stop the logarithmic growth by killing the nonactivated immature macrophages that permit intracellular multiplication of tubercle bacilli. Such killing results in formation of the caseous centre of the tubercle. Bacilli are unable to multiply in solid caseous (necrotic) tissue because of anoxia, low pH and toxic fatty acids. In such caseous tissue, some bacilli may remain “dormant” for many years or even a lifetime.

After control is established, mature macrophages accumulate around the periphery of the caseous lesion (epithelioid cells), preventing further extension. In normal host, the bacillary population is stable during the third stage of pathogenesis, as growth is counterbalanced by bacillary destruction and inhibition.

Stages 1–3 comprise the pathogenesis of primary TB in the immunologically normal host. Primary TB is most often a subclinical, self-limited illness. In high-prevalence populations, primary infection is early in life, often the result of household exposure to parents or grandparents with infectious, cavitary tuberculosis. Under low-prevalence conditions, the majority of the population reaching adulthood have not been infected. Although human primary TB is usually self-limited, the infection can progress locally or systemically when host defenses are inadequate. An apical or subapical primary site, undernutrition, concomitant illnesses, immunosuppressive therapy and, most important, HIV coinfection are factors predisposing to progressive primary tuberculosis.

Stage 4: liquefaction and lung cavity formationWhen cell-mediated immunity is weak, bacilli released from the caseous center

are ingested by partially activated macrophages. Therefore delayed hypersensitivity continues to stop intracellular bacillary multiplication by killing macrophages. The caseous center enlarges and local lung tissue is destroyed. The bacilli are spread by lymphatic and hematogenous routes to other sites, where tissue destruction continues.

Delayed hypersensitivity is associated with liquefaction of the solid caseous center of the TB granuloma. In liquefied caseous material, the bacilli find again a favourable environment and they multiply profusely, for the first time extracellularly. When a liquefied caseous lesion discharges its contents into a nearby bronchus, a cavity is formed within the lung. Bacilli spread via the

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bronchial tree to other parts of the lung, extending the disease and sometimes causing caseous bronchopneumonia and death. Through the same bronchial route, the bacilli reach the external environment and may infect other persons.

Whereas primary lesions occur throughout the lungs, with a predominance in the lower lobes due to the distribution of the ventilation, postprimary disease is an upper lung phenomenon. Bacilli reach the upper lung either through lymphohematogenous dissemination occuring during primary infection or through the airways in instances of exogenous reinfection.

The antibacillary drugs affect the course of tuberculosis: first, they kill or inhibit bacilli growing extracellularly in the liquefied caseous material of cavities and render the patient noninfectious. Second, they kill or inhibit bacilli multiplying in unactivated macrophages and are therefore effective in infants and immunosuppressed patients. Antimicrobial therapy frequently does not kill all the bacilli, because dormant M. tuberculosis can survive for years, probably in nonliquefied caseous material. These persisting bacilli may reactivate the disease after therapy is discontinued.

The pathogenic mechanism of cavitary tuberculosis in adults can be either exogenous reinfection (in high-prevalence countries) or endogenous reactivation of an old infection (in low-prevalence countries).

Usually, in infected persons, cell-mediated immunity maintains the “dormant” mycobacteria from the sites of primary lesions in a stady state level. Continuous release of small amounts of bacillary antigens maintains tuberculin reactivity and protective immunity. When this equilibrium is disturbed by some event like stress, malnutrition, HIV infection, immunosuppressive therapy, alcohol, etc., liquefaction of the caseous centre of the granuloma allows extracellular growth and multiplication of tubercle bacilli. Thus, the TB infection progresses to contagious postprimary tuberculosis.

TRANSMISSION OF TUBERCULOSISTB is spread from person to person through the air. When a person with

infectious TB disease (TB that can be spread) coughs or sneezes, tiny particles containing M. tuberculosis may be expelled into the air. These particles, called droplet nuclei, are about 1 to 5 microns in diameter (less than 1/5000 of an inch) (figure 27). Droplet nuclei can remain suspended in the air for several hours, depending on the environment. Transmission is the spread of an organism, such as M. tuberculosis, from one person to another. If another person inhales air that contains these droplet nuclei, transmission may occur. Not everyone who is exposed to an infectious TB patient becomes infected with M. tuberculosis. Effective chemotherapy is the single most important factor in reducing the infectiousness of a TB contagious person at any stage of the disease.

The probability that TB will be transmitted depends on three factors: how contagious is the TB patient; in what kind of environment did the exposure occur;

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how long did the exposure last.

Figure 27 - Transmission of TB.TB is spread from person to person through the air. The dots in the air represent

droplet nuclei containing tubercle bacilli.

Fluid lining the respiratory tract and any microorganisms contained in it may become aerosolised by high-velocity airflow during coughing, sneezing and other forced expiratory maneuvers. Transmission occurs most efficiently in enclosed environments where the source, infectious droplet nuclei, and potential hosts are concentrated.

Infection begins when droplet nuclei (dried residue of respiratory droplets) reach the alveoli. When a person inhales air that contains droplets, most of the larger droplets (greater than 5 m in diameter) become lodged in the upper respiratory tract (the nose and throat), where infection is unlikely to develop. However, the droplet nuclei may reach the alveoli where infection begins in the alveolar macrophage, and this requirement defines the size of infectious droplet nuclei as approximately 1-3 m in diameter. If organisms are destroyed before they replicate to 10-15 generations, infection is aborted without an immunological record (tuberculin skin test negative).

At first, the tubercle bacilli multiply in the alveoli and a small number enter the bloodstream and spread throughout the body. Bacilli may reach any part of the body, including areas where TB disease is more likely to develop . These areas include the upper portions of the lungs, as well as the kidneys, the brain, and bone (figure 28). Within 2 to 10 weeks, however, the body's immune system usually intervenes, halting multiplication and preventing further spread.

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Figure 28 - Spread of M. tuberculosis throughout the bodyTB INFECTIONTB infection means that tubercle bacilli are in the body but the body's immune

system is keeping the bacilli under control. The immune system does this by producing special immune cells called macrophages that surround the tubercle bacilli. The cells form a hard shell that keeps the bacilli contained and under control. TB infection is detected by the tuberculin skin test. Most people with TB infection have a positive reaction to the tuberculin skin test. People who have TB infection but not TB disease are NOT infectious — in other words, they cannot spread the infection to other people. These people usually have a normal chest X-ray. It is important to remember that TB infection is not considered a case of TB.

The purpose of diagnosing TB infection is to identify (1) people with TB infection who may be given treatment to prevent them from developing TB disease and (2) people who may have TB disease and who need treatment to be cured. In most cases, TB disease is diagnosed with certain laboratory tests (bacteriologic examination, chest x-ray). It is important to evaluate people who have symptoms of TB disease; if they are found to have TB disease, they need treatment to be cured and to avoid spreading TB to others. For this reason, the diagnosis of TB disease is crucial to controlling the spread of TB in homes and communities.

Diagnosis of TB infection: the tuberculin skin test (Mantoux test)

The tuberculin skin test is used to determine whether a person has TB infection. In this test, a substance called tuberculin is injected into the skin. Tuberculin is a protein derived from tubercle bacilli that have been killed by heating. In most people who have TB infection, the immune system will recognize the tuberculin because it is similar to the tubercle bacilli that caused infection. This will cause a cell-mediated immune reaction to the tuberculin. Tuberculin is used for diagnosing TB infection; it is not a vaccine.

Tuberculin testing is indicated in the following situations:

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examining a person who is not sick but who may have TB infection, such as a person who has been exposed to someone who has TB. In fact, the tuberculin skin test is the only way to diagnose TB infection before the infection has progressed to TB disease;

screening groups of people for TB infection; examining a person who has symptoms of TB disease; screening groups of children and teenagers for BCG vaccination.Different types of tuberculin tests are available, such as the Mantoux tuberculin

skin test and the multiple-puncture test. The Mantoux tuberculin skin test is the preferred type because it is the most accurate.

The Mantoux skin test is given by using a needle and syringe to inject 0.1 ml of 5 tuberculin units of liquid tuberculin between the layers of the skin (intradermally), usually on the forearm. A tuberculin unit is a standard strength of tuberculin. The tuberculin used in the Mantoux skin test is also known as purified protein derivative, or PPD. For this reason, the tuberculin skin test is sometimes called a PPD skin test.

With the Mantoux skin test, the patient's arm is examined 48 to 72 hours after the tuberculin is injected. Most people with TB infection have a positive reaction to the tuberculin. The reaction is an area of induration (swelling that can be felt) around the site of the injection. The diameter of the indurated area is measured across the forearm; erythema (redness) around the indurated area is not measured, because the presence of erythema does not indicate that a person has TB infection.

Whether a reaction to the Mantoux tuberculin skin test is classified as positive depends on the size of the induration and the person's risk factors for TB (table 5). a) In most cases, people who have a very small reaction or no reaction probably do not have TB infection. b) An induration of 5 or more millimetres is considered a positive reaction for the following people:

people with HIV infection; close contacts of people with infectious TB; people with chest x-ray findings suggestive of previous TB disease; people who inject illicit drugs and whose HIV status is unknown.

c) An induration of 10 or more millimetres is considered a positive reaction for the following people:

people born in areas of the world where TB is common; people who inject illicit drugs but who are known to be HIV negative; low-income groups with poor access to health care; people who live in residential facilities (for example, nursing homes or

correctional facilities); people with medical conditions that appear to increase the risk for TB (not

including HIV infection), such as diabetes; children younger than 4 years old;

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people in other groups likely to be exposed to TB, as identified by local public health officials.

Table 5 - Classifying the tuberculins skin test reaction

5 or more millimeters 10 or more millimeters 15 or more millimeters

An induration of 5 or more millimeters is considered positive for

People with HIV infection

Close contacts

People who have had TB disease before

People who inject illicit drugs and whose HIV status is unknown

An induration of 10 or more millimeters is considered positive for

Foreign-born persons

HIV-negative persons who inject illicit drugs

Low-income groups

People who live in residential facilities

People with certain medical conditions

Children younger than 4 years old

People in other groups as identified by local public health officials

An induration of 15 or more millimeters is considered positive for

People with no risk factors for TB

d) An induration of 15 or more millimeters is considered a positive reaction for people with no risk factors for TB.

For people who may be exposed to TB on the job (such as health care workers and staff of nursing homes or correctional facilities), the classification of the skin test reaction as positive or negative depends on

the size of the induration; the employee's individual risk factors for TB; the risk of exposure to TB in the person's job.

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Therefore, in facilities where the risk of exposure to TB is very low, 15 or more millimeters of induration may be considered a positive reaction for employees with no other risk factors for TB. In facilities where TB patients receive care, 10 or more millimetres of induration may be considered a positive reaction for employees with no other risk factors for TB.

Usually, in areas with high incidence of TB infection and disease, the tuberculin skin test is classified as positive (in HIV negative persons) when the horizontal diameter of induration is greater than 10 mm .

Most people who have a positive skin test reaction will have a positive reaction if they are skin tested later in their lives, regardless of whether they receive treatment. This is because the tuberculin skin test detects the immune response to tuberculin, not the presence of tubercle bacilli in the body.

False-positive PPD reactions:the skin test is a valuable tool, but it is not perfect. Sometimes people who are

not infected with M. tuberculosis can still have a positive reaction to the PPD tuberculin skin test; this is called a false-positive reaction. The two most common reasons for false positive PPD reactions are infection with nontuberculous mycobacteria (mycobacteria other than M. tuberculosis) and vaccination with BCG (bacillus Calmette-Guérin). BCG is a vaccine for TB disease that is used in many countries. People who are infected with nontuberculous mycobacteria or who have been vaccinated with BCG may have a positive reaction to the tuberculin skin test even if they do not have TB infection.

People who have a positive PPD reaction should be further evaluated for TB disease, regardless of whether they were vaccinated with BCG. There is no reliable way to distinguish between a positive PPD reaction caused by true TB infection and a reaction caused by other mycobacteria or by vaccination with BCG. However, the reaction is more likely to be truly caused by TB infection if any of the following are true:

the reaction is large; the person was BCG-vaccinated a long time ago; the person comes from an area of the world where TB is common; the person has been exposed to someone with infectious TB disease; the person's family has a history of TB disease.

False-negative reactions:some people have a negative reaction to the tuberculin skin test even though

they have TB infection; these are called false-negative reactions and may be caused by:

anergy, the inability to react to skin tests because of a weakened immune system. Many conditions, such as HIV infection, cancer, or severe TB

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disease itself, can weaken the immune system and cause anergy. HIV infection is a main cause of anergy. Because of their risk for anergy and their risk for TB, in selected situations HIV-infected people may be tested for anergy if they have a negative reaction to the tuberculin skin test. However, anergy testing is not recommended as a routine component of TB screening among HIV-infected persons.

recent TB infection (within the past 10 weeks). It takes 2 to 10 weeks after TB infection for the body's immune system to be able to react to tuberculin and detect TB infection. For this reason, close contacts of someone with infectious TB disease who did not react to the PPD tuberculin skin test should be retested 10 weeks after the last time they were in contact with the person who has TB disease.

very young age (younger than 6 months old). Because their immune systems are not yet fully developed, children younger than 6 months old may have a false-negative reaction to the tuberculin skin test.

a false-positive reaction or a false-negative reaction may occur when the tuberculin skin test is given incorrectly or the results are not measured properly.

TB screening programs and two-step testingMany residential facilities, health care facilities, and other settings have TB

screening programs. This means that employees and residents are periodically given tuberculin skin tests. The purposes of the screening program are to:

identify people who have TB infection and possibly TB disease, so that they can be given treatment as needed;

determine whether TB is being transmitted in the facility. In a TB screening program, employees or residents are skin tested when they

start their job or enter the facility. This is called the baseline skin test. If they have a negative skin test reaction, they may be retested at regular intervals thereafter (for most employees, repeat testing should be done at least once a year.)

Employees or residents whose skin test reaction converts from negative to positive between screening intervals have probably become infected with M. tuberculosis. These skin test conversions may indicate that TB is being transmitted in the facility. People with skin test conversions are at high risk of developing TB disease because they were infected with M. tuberculosis relatively recently (within the past 2 years). In order to detect TB transmission and identify people who have skin test conversions, accurate information must be obtained for every employee's baseline skin test, as well as for additional skin tests.

One factor that can affect the accuracy of the baseline skin test is the booster phenomenon. The booster phenomenon happens because in some people who have TB infection, the ability to react to tuberculin lessens over time. When these people are skin tested many years after they became infected with M. tuberculosis, they

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may have a negative reaction. However, if they are tested again within a year of the first test, they may have a positive reaction. This is because the first skin test "jogged the memory" of the immune system, boosting its ability to react to tuberculin. It may appear that these people were infected between the first and second skin tests (recent TB infection). Actually, the second, positive reaction is a boosted reaction (due to TB infection that occurred a long time ago). The booster phenomenon occurs mainly among older adults. It can present a problem in TB screening programs. This is because a negative reaction to the baseline skin test, followed by a positive reaction to a subsequent skin test that is given up to a year later, may be caused by either:

recent TB infection in a person who was NOT infected at the time of the baseline skin test, or

a boosted reaction in a person who WAS infected at the time of the baseline skin test.

To avoid misinterpretation, a strategy has been developed for telling the difference between boosted reactions and reactions caused by recent infection. This strategy, called two-step testing, means that if a person has a negative reaction to an initial skin test, he or she is given a second test 1 to 3 weeks later. If the reaction to the second test is positive, it probably is a boosted reaction (due to TB infection that occurred a long time ago). If the reaction to the second test is negative, the person is considered uninfected. In this person, a positive reaction to a skin test given later on will probably be due to recent infection.

Thus, because it provides accurate information about each employee's baseline skin test reaction, two-step testing is used in many TB screening programs for skin testing employees when they start their job. In particular, two-step testing is often used in hospitals and nursing homes.

TB DISEASESome people with TB infection develop TB disease. TB disease develops when

the immune system cannot keep the tubercle bacilli under control and the bacilli begin to multiply rapidly. The risk that TB disease will develop is higher for some people than for others. TB disease can develop very soon after infection or many years after infection. About 5% of the people who have recently been infected with M. tuberculosis will develop TB disease in the first year or two after infection. Another 5% will develop disease later in their lives. In other words, about 10% of all people who have TB infection will develop disease at some point. The remaining 90% will stay infected, but free of disease, for the rest of their lives.

Briefly, we may conclude that: people who are exposed to TB may or may not develop TB infection; people with TB infection may or may not develop TB disease; the risk of developing TB disease is highest in the first 2 years after

infection (figure 29).

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Figure 29 - Progression of TB.

For people with TB infection and no risk factors , the risk of developing TB disease is about 5% in the first two years after infection and about 10% over a lifetime. Because about half the risk of developing TB disease is concentrated in the first 2 years after infection, it is important to detect new infection early. People with TB infection can be given treatment to prevent them from getting TB disease. Thus, detecting new infection early helps prevent new cases of TB. 

The presence of certain risk factors raises dramatically the probability of developing TB disease (table 6).

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Table 6 - Risk factors for developing TB disease after infection.

RISK FACTORHOW MANY TIMES HIGHER IS THE

RISK OF TB DISEASE1

AIDS 170HIV infection 113

Recent TB infection (within past 2 years)

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Certain medical conditions2 23-1611Compared to the risk for people with no known risk factors 2For example, diabetes, certain types of cancer, or immunosuppressive therapy

Major similarities and differences between TB infection and TB disease are shown in table 7.

Table 7 - TB infection versus TB disease

TB Infection TB Disease (in the lungs)

Tuberculin skin test usually positive Tuberculin skin test usually positiveChest X-ray usually normal Chest X-ray usually abnormal

Sputum smears and cultures negative Sputum smears and cultures positiveNo symptoms Symptoms such as cough, fever, weight

lossNot infectious Often infectious before treatment

Not a case of TB A case of TB

2.7. TUBERCULOSIS CLASSIFICATION SYSTEM

Many systems have been used to classify people who have TB. The current classification system is based on the pathogenesis of TB. In particular, doctors should be aware that any patient with a classification of 3 or 5 should be receiving treatment for TB, and the case or suspected case should be reported.

Class 0:No exposure to TBNot infectedNo history of exposure, negative reaction to the tuberculin skin test.

Class 1: Exposure to TBNo evidence of infectionHistory of exposure, negative reaction to a tuberculin skin test given at least 10 weeks after exposure.

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Class 2:TB infectionNo TB diseasePositive reaction to the tuberculin skin test, negative smears and cultures, no clinical or x-ray evidence of TB disease

Class 3:Current TB diseasePositive culture for M. tuberculosis, or a positive reaction to the tuberculin skin test and clinical or x-ray evidence of current TB disease.

Class 4:Previous TB disease (not current)Medical history of TB disease, or abnormal but stable x-ray findings for a person who has a positive reaction to the tuberculin skin test, negative smears and cultures, and no clinical or x-ray evidence of current TB disease.

Class 5:TB suspectedSigns and symptoms of TB disease, but evaluation not complete.

Definitions

1. Infection with M. tuberculosis: is defined as infection with M. tuberculosis, manifested by a significant tuberculin skin test reaction without any sign of clinically and/ or radiologically active disease.

2. Tuberculosis refers to clinically and/ or bacteriologically and/or histologically and/or radiologically active disease

3. A definite case of TB is a case with culture confirmed disease due to M. tuberculosis complex (a patient with two consecutive sputum smear examinations positive for acid- fast bacilli or one sputum examination and radiological signs and clinician’s decision to treat is also considered a “definite case”). “Other than definite” cases are those meeting both of the following conditions: 1) a clinician’s judgement that the patient’s clinical and/or radiological signs and/or symptoms are compatible with TB, and 2) a clinician’s decision to treat the patient with a full courses of chemotherapy .

4. A new case is a patient who has never had drug treatment for TB or who has taken anti-TB drugs for less than 4 weeks.

5. A relapse is a patient who has been declared cured of any form of TB in the past by a physician, after one or more full course of chemotherapy and has developed sputum smear positive or culture positive disease.

6. A treatment failure is a patient who, while on treatment, remains or reverts to being smear positive and/or culture positive 5 months or later after commencing treatment, or a patient who was initially smear negative before starting treatment and becomes smear and/or culture positive after the second month of treatment.

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7. A treatment after interruption is a patient who interrupted treatment for 2 months or more, and returned to the health service with smear positive and/or culture positive sputum (also a smear-negative patient, but still with active TB as judged on clinical and radiological assessment).

8. A chronic case is a patient who remains or again becomes smear and/or culture positive after completing a fully supervised standard re- treatment regimen. In particular, a patient is declared “cured” if he/she has completed a full course of treatment and a) if the diagnosis was confirmed by culture and there is a documented conversion (culture negative) on at least one occasion during the continuation phase or b) if the diagnosis was based on microscopy and there is documented evidence of 2 negative sputum smears during the continuation phase. When the bacteriological evidence is not available, the result of treatment is defined “treatment completed”. The sum of cases cured and completing treatment represents cases “treated successfully”. “Treatment failure” is a patient who failed to achieve bacteriological conversion within 5 months from the start of treatment, or, who after previous conversion, becomes sputum smear or culture positive again, and in whom the first line treatment is replaced by second line treatment.

9. High risk groups are population segments with an incidence clearly in excess of that in the general population, defined as having an incidence of > 100 cases per 100 000 population.

10. Preventive chemotherapy is defined as the treatment of infection with M. tuberculosis to prevent progression to active TB.

11. Chemoprophylaxis is defined as the treatment of individuals at risk of acquiring TB who are not infected.

12. Recent infection is defined as a positive tuberculin skin test reaction after documentation of a negative tuberculin skin test within the preceding 2 years.

13. Fibrotic lesions are defined as well-delineated radiographic lesions compatible with healed TB.

14. Low incidence countries are those countries where the incidence of all forms of notified TB is below 20 cases per 100 000 population.

15. DOTS is defined as Directly Observed Treatment, Short Course (direct observation of the patient swallowing the pills) and is the World Health Organization -recommended strategy of TB control. It includes several technical elements:

case detection among symptomatic patients who self- report to health services and are diagnosed by sputum smear microscopy;

standardised short course chemotherapy to, at least, all confirmed sputum smear positive cases;

regular drug supply; the establishment and maintenance of a standardised recording and

reporting system, which enables assessment of treatment results.

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2.8. PRIMARY TUBERCULOSIS; TUBERCULOSIS IN CHILDREN

2.8.1. PRIMARY TUBERCULOSIS IN CHILDREN: PATHOGENESIS

Like in adults, in children the most common portal of entry for TB bacilli is the lung (95% of cases). However, primary infection may occur in any part of the body. The time between the entrance of bacilli in the lung and the development of skin hypersensitivity to tuberculin is usually 2-12 weeks. During this period the primary complex can become visible on a chest X-ray.

The primary complex in the lung includes a parenchimal focus (small round opacity of 3-10 mm diameter, with subpleural location in 70% of cases) and regional lymphadenitis (hilar and paratracheal lymph node enlargement). The primary focus often undergoes caseous necrosis and encapsulation and heals by fibrosis and calcification.

Sometimes, in children with low immune defense and poor nutrition, the primary focus continue to enlarge, resulting in focal pneumonitis and thickening of the overlying pleura. If caseous necrosis is intense, the center of the primary focus liquefies, caseum is eliminated in a bronchus and leaves a residual cavity.

Also, the parenchimal focus situated just below the surface of the lung may rupture, allowing caseous material and bacilli to leak in the pleural space. The fluid is usually absorbed without difficulty, but in rare cases it may become purulent and tuberculous empyema results.

From the primary focus, bacilli reach the regional lymph nodes which become larger. Enlarged lymph nodes situated in proximity of bronchi can compress the airway and narrow it, resulting in collapse of one segment or lobe. A soft lymph node with caseous center can break through the wall of a bronchus. The caseous content of the node can leak into the airway, resulting in several major complications:

- blocking of the main bronchus with caseous material; collapse of one entire lung and risk of suffocation. Bronchoscopy has to be done immediately to remove the caseous content of the main bronchus.

- spread of the disease – via airways- everywhere in the lungs.Lymph nodes which are in close contact with the posterior part of the

pericardium may excavate and rupture in pericardium, resulting in TB pericarditis. From both the focus and the nodes bacilli can escape in the bloodstream (eroding a blood vessel or through lymphatics) and disseminate the disease to the liver, spleen, bones, brain, kidneys, etc.

There are several ways of TB transmission in children. From coughing adults : the danger is greater when the cougher does not take

any care. The infectious mother is a danger for her child, and so is an infectious teacher, doctor, nurse working with children. Almost always when children are

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infected, TB bacilli come from a member of the family or a near neighbor. The epidemiology of childhood TB follows that in adults.

In 1990s, about 15 000 000 new cases of TB and 5 000 000 deaths occured among children under 15 years of age. Childhood TB has little influence on the epidemiology of the disease in the community because children are rarely a source of infection to contacts. Children with primary tuberculosis rarely, if ever, infect other children or adults. If children cough, they rarely produce sputum and they lack the tussive force of adults. The mortality rates for children from newborn to 4 years are twice that for children ages 5–15, mostly because of the higher incidence of TB meningitis and disseminated disease in very young population.

TB is probably underdiagnosed in children with HIV infection because the similarity of its clinical aspect to other opportunistic infections and the difficulty of confirming TB in children with positive cultures.

From milk or food: this unusual way of contamination concerns mainly the transmission of Mycobacterium bovis. The source of infection is represented by sic cattle (with tuberculosis of the udder) which eliminate in their milk M. bovis. Children are infected after ingestion of unboiled milk; therefore infection can begin in the mouth, tonsils or intestine.

Through the damaged skin: TB bacilli from an infectious patient can induce a primary infection of the exposed skin, especially if there is a cut or break.

2.8.2. CLINICAL FORMS OF TB IN CHILDRENIntrathoracic tuberculosis

Pulmonary TB – in the lung parenchyma a small primary focus (< 10 mm), located subpleural can be visible. Hilar and/or mediastinal lymph node enlargement is always present. Sometimes lymph nodes are too small to be identified and computed tomography is necessary to reveal them. This stage of the infection can remain non-symptomatic and the immune system can stop the progression to TB disease. In very young children, in HIV-infected or malnourished, infection can progress rapidly to local and spread disease (figure 30).

There is a left hilar enlargement due to tuberculous hilar adenopathy. Progressive pulmonary TB – is a very severe complication induced by the

enlargement and cavitation of the primary focus. The resulting disease is a TB pneumonia or bronchopneumonia with fatal evolution in 50% of cases without treatment.

Pleural effusion – 3-6 months after infection, the primary focus may enlarge and rupture in the pleural space, resulting in unilateral or bilateral (rarely) pleural effusion. The fluid is a citrine exudate with >80% lymphocytes. Diagnosis is difficult because acid-fast stain of the pleural fluid is negative and the culture is positive only in 50% of cases. Pleural biopsy can establish the diagnosis on the basis of histology (granuloma with caseous necrosis).

Pericardial effusion – only in 4% of pediatric TB; the fluid is serofibrinous

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or hemorrhagic, exudate with lymphocytes. Clinical signs include a pericardial friction rub, distant heart sounds and paradoxical pulse. Healing with fibrosis of the pericardial sac leads to constrictive pericarditis. Cultures from the fluid are positive in 30-70% of cases. Partial or complete pericardiectomy may be necessary if constrictive pericarditis develops.

Figure 30 - Primary tuberculosis

Miliary TB – is an early complication of the primary infection (3-6 months after) induced by the blood spread of TB bacilli, resulting in disease of several organs: lungs, liver, spleen, brain. Rarely the onset is dramatic; more often it is insidious, the child developing progressively anorexia, low-grade fever, weight loss, hepatosplenomegaly and generalized lymphadenopathy. In 90% of cases, the chest x-ray shows after 3 weeks a miliary TB aspect: small opacities, 1-3 mm diameter, spread throughout both lungs. Respiratory distress may develop, meningitis can occur in 20-30% of cases and also choroid tubercles. Sputum smears and gastric washings are often negative in microscopy and the diagnosis is confirmed by cultures only in 33% of cases. The suspicion of tuberculosis can be

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established by finding a link to a recently diagnosed case of infectious pulmonary TB in an adult. If properly treated with antituberculous drugs, miliary TB has a very good prognosis. Severe respiratory distress may require temporary corticosteriod treatment.

Extrathoracic tuberculosis

TB meningitis – results from formation of caseous lesions in the meninges and cerebral cortex during the lymphohematogenous spread of the primary infection. A thick exudate infiltrates the meningeal blood vessels; the brainstem is often involved, leading to disfunction of cranial nerves III, VI and VII. Usually, the clinical evolution of TB meningitis is gradual, following 3 stages. During the first 1-2 weeks, nonspecific symptoms develop (fever, headache, sleepiness), without focal neurologic signs. Then, abruptly, convulsions, vomiting, nuchal rigidity, lethargy and hypertonia appear, concomitant with the development of hydrocephalus and increased intracranial pressure. Without treatment, the third and final stage follows with coma, disfunctions in the vital functions (respiration, pulse) and paraplegia.

The cerebrospinal fluid is clear, with a leukocyte count of 10-500/mm3, and lymphocyte predominance. Glucose level in the cerebrospinal fluid is low (20-40 mg/dl) and protein level is high (>400 mg/dl). The chest x-ray is normal in 50% of cases and the tuberculin skin test is positive in 60% of cases. The hystory of a recent contact with an infectious TB patient leads to the suspicion of TB meningitis, which is confirmed by microscopic examination and mycobacterial culture of the cerebrospinal fluid .

Abdominal TB – can develop from ingestion of unboiled milk of tuberculous cows, from aliments contamined with human bacilli eliminated by a careless coughing adult or from blood spread to peritoneum from a lung primary focus. The primary focus may be in the intestine. The mesenteric lymph nodes enlarge, soften and may spread their caseous content in the peritoneal cavity, resulting in TB peritonitis. Sometimes enlarged lymph nodes stick together the coils of the intestines, leading to partial or complete intestinal obstruction. In girls, involvement of the fallopian tubes and ovaries can be a cause of infertility.

TB of the lymph nodes – involves more often the cervical nodes that drain a primary focus from the lungs via mediastinal nodes. The nodes enlarge slowly and are painless; initially a large, firm lymph node is surrounded by several smaller ones. Later on, the nodes stick together, become soft and fluctuent, the skin is fixed over them and “cold abcess” appears; draining the abcess and systemic antituberculous treatment are necessary for healing lymph nodes TB.

When lymph nodes TB is associated with AIDS, generalised enlargement of the lymph nodes occur.

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2.8.3. DIAGNOSIS OF TUBERCULOSIS IN CHILDREN

TB diagnosis in children has some special aspects: isolation of M. tuberculosis in respiratory secretions is difficult because

children don`t eliminate sputum by cough; cultures are done from gastric washings or bronchial aspiration through endoscope;

the diagnosis is based on finding a positive tuberculin skin test, an abnormal chest radiograph and the history of TB contact.

previous BCG vaccination can pose problems with the interpretation of a tuberculin skin test.

nucleic acid amplification techniques (PCR) have a limited role for the TB diagnosis in children but PCR is useful in diagnosing pulmonary and extrapulmonary TB in children with AIDS.

2.8.4. DIFFERENTIAL DIAGNOSIS OF PRIMARY TB

Primary tuberculosis involves mainly children and teenagers and has a roentgenographic aspect of a parenchymal focus (Gohn focus) accompanied by the regional lymphadenitis. Therefore, in young patients with respiratory symptoms and hilar enlargement on a chest x-ray, we must review all the possible etiologies and indicate the appropriate investigations. Several anatomic elements of the hilum can produce an x-ray aspect of hilar enlargement: bronchi, vessels and lymph nodes.

CAUSES OF HILAR ENLARGEMENT

Vascular causes - ectatic vessels,- left heart failure,- pulmonary hypertension,- left to right shunt,- pulmonary aneurysm.

Lymph node enlargement - tuberculosis,- lymphoma, leukemia,- sarcoidosis,- hilar metestasis,- bacterial or viral adenitis,- mononucleosis,- silicosis,- fungal adenitis.

Neoplasms - central bronchogenic carcinoma,- mediastinal tumors.

Superposition of structures - aortic aneurysm,- pneumonia of the

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- perihilar region,- anterior segment of upper lobe,- superior segment of lower lobe.

- vertebral deformity,- chest wall process.

Because all the mentioned diseases can have a chest x-ray aspect of hilar and mediastinal enlargement, a complete investigation is necessary for a correct diagnosis

INVESTIGATION OF HILAR LYMPH NODE ENLARGEMENT

postero-anterior and lateral roentgenograms, tomograms, CT scan, bacteriologic investigation of sputum, cytologic investigation of sputum, tuberculin skin test.If these non-invasive investigations are not conclusive for diagnosis, more

invasive procedures are indicated: fiber-bronchoscopy with - bronchial biopsy,

- transbronchial punction in a lymph node,- bronchiolo-alveolar lavage with bacteriologic,cytologic and immunologic investigation of the lavage fluid,

arteriography of pulmonary vessels, open lung biopsy, mediastinoscopy.

DIFFERENTIAL DIAGNOSIS OF HILAR AND MEDIASTINAL ADENITISINFECTIOUS DISEASES

Bacteria - Mycobacterium tuberculosis: unilateral adenopathy in 80% of cases; in 40% cases paratracheal adenopathy; parenchymal disease usually present on X-ray.- Pasteurella tularensis: unilateral hilar adenopathy; nodules in parechyma; pleural effusion.- Bacillus anthracis: bilateral hilar and mediastinal adenopathy; non-segmental lung opacities (pulmonary hemorrage).

Mycoplasma pneumoniae: hilar adenopathy and segmental pneumonia. Viruses - Rubeola: bilateral hilar adenopathy and diffuse interstitial

pattern in parenchyma.

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- Varicella zoster,- Echo-virus,- infectious mononucleosis,- AIDS.

Chlamydia psittaci. Parasites - Tropical eosinophilia: bilateral hilar adenopathy and

micronodular pattern in the lungs. Fungi - Histoplasma capsulatum: involves all thoracic lymph nodes;

usually associated with parenchymal disease.

NEOPLASTIC DISEASES

Bronchogenic carcinoma: unilateral hilar adenopathy (bilateral and mediastinal in late stages); atelectasis of lung parenchyma.

Hodgkin or non-Hodgkin lymphoma: bilateral, asymmetrical hilar adenopathy; paratracheal and retrosternal lymph node enlargement.

Lymphosarcoma: bilateral, asymmetrical adenopathy with parenchymal consolidation.

Leukemia: hilar and mediastinal, symmetrical adenopathy, pleural effusion and parenchymal involvement.

Metastatic lymphangitic carcinoma: unilateral or bilateral hilar and mediastinal adenopathy, with diffuse reticular and nodular pattern,basal in distribution (figure 31).

OCCUPATIONAL DISEASES

Silicosis: hilar, symmetrical adenopathy, with eggshell; diffuse reticulo-nodular pattern in parenchyma.

Farmer`s lung: bilateral, symmetrical hilar adenopathy, with diffuse micronodular pattern in the lung parenchyma.

Berylliosis: same aspect Smallpox handler`s lung: bilateral, symmetrical adenopathy and round

opacities (5-15 mm diameter) in parenchyma.

IDIOPATHIC DISEASES

Sarciodosis: bilateral, symmetrical hilar and mediastinal adenopathy, in 50% of cases parenchimal fibrosis is associated; extrathoracic disease is frequent.

Hamman-Rich interstitial fibrosis: hilar symmerical adenopathy, with fine reticular pattern in the lung parenchyma.

Histiocytosis-x: hilar and mediastinal bilateral adenopathy; diffuse micronodular pattern of the lung parenchima; x-bodies visible by electron microscopy in the Langerhans cells.

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Idiopathic pulmonary hemosiderosis: bilateral hilar adenopathy associated with alveolar and interstitial diffuse disease.

Figure 31- Lymphangitis carcinomatosaExtensive shadowing, predominant linear is seen in both lungs. Prominent septal

lines and a few nodules are present adjacent to the hilar zones

2.8.5.TREATMENT OF TB IN CHILDREN

As in adults, short-course chemotherapy (6 months) is successful. Therapy implies association of four TB drugs in the initial phase (first 2 months) and two drugs in the continuation phase (4 months). There are some special treatment aspects in children that need to be mentioned:

drug resistance is rare in children; most cases of resistance in children are 73

primary resistance, resulted from initial infection with an already resistant bacillus);

because children often develop extrapulmonary forms of TB, drugs used in the specific treatment must penetrate different tissues (the meninges) and fluids;

children tolerate larger doses/kg than adults and have fewer adverse reactions than adults;

because of its visual effects which are difficult to monitor in children, ethambutol is contraindicated under 6 years of age.

The doses of TB drugs used in children will be detailed in the TB treatment chapter.

2.8.6. PREVENTION OF TUBERCULOSIS IN CHILDREN

Isoniazid (INH) preventive therapy - There is a large amount of data to sustain the effectiveness of INH in preventing the progression of tuberculous infection to tuberculous disease. Presumably, INH decreases the number of tubercle bacilli in inapparent foci formed at the time of the primary infection.

Studies of preventive therapy conducted by the US Public Health Service during a 10-year period of observation showed that INH preventive therapy resulted in a 61% reduction in tuberculosis cases.

The indications for the use of INH preventive therapy include: - children under 6 years of age which are in contact with an contagious TB

patient;- TB contacts over 6 years of age, with positive tuberculin skin test; difference

must be made between artificial immunization (BCG vacination) and natural TB infection;

- HIV infected children with a tuberculin skin test > 5mm.- HIV infected children which are in contact with a TB patient.For children, the dose is 10 mg per kilogram of body weight, up to a dose of

300 mg per day. The recommended duration of INH administration is 6 months. Current tuberculosis must be excluded before preventive therapy is started.

Hepatitis is the major toxic effect of INH and must be balanced against the benefit of preventive therapy. The risk of INH-associated hepatitis increases with age: it is rare among persons under 20 years of age. Asymptomatic increases in serum transaminase levels are much more frequent than symptomatic hepatitis and occur in nearly 10% of all persons taking INH.

Children receiving INH preventive therapy should be monitored at monthly intervals to detect symptoms that may be caused by drug-related hepatitis. These symptoms are nonspecific in nature and include anorexia, gastrointestinal complaints, fever, and myalgia. Complaints more specifically related to the liver, such as jaundice, dark urine, and abdominal discomfort in the right upper quadrant are relatively uncommon. Children having symptoms suggestive of hepatitis should

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have tests of liver function performed and if they are abnormal, the drug should be discontinued.

Preventive therapy in children who have been exposed to INH-resistant organisms is a problem of increasing concern. When the risk of INH-resistant organisms transmission is great, rifampin is the prophilactic agent of choice. If the contact case is also resistant to rifampin, multidrug preventive therapy should be strongly considered.

Immunization The BCG vaccine was derived from a strain of M. bovis and attenuated

through serial passage in culture. Artificial infection with the organism stimulates the immunologic response that occurrs with natural tuberculous infection. The effect of this nonspecific response is to improve the ability of a person who has recently been infected with M. tuberculosis to contain the infection and prevent early dissemination of mycobacteria. No protection is provided for persons who are already infected when BCG is given. The reported effectiveness of BCG vaccination varies widely, probably because of variations in the potency of different strains of the organism and differing conditions and methods of administration of the vaccine. Indications for the use of BCG in developed countries are limited. Vaccination also may be considered for selected groups of population that demonstrate an excessive rate of new infections (usually more than 1% per year) and in which the usual approaches to tuberculosis control have failed.

2.9. POSTPRIMARY (SECONDARY) PULMONARY TUBERCULOSIS

2.9.1. DIAGNOSISBefore clinicians can diagnose TB disease in a patient, they must think of the

possibility of TB when they see a patient with symptoms of TB or abnormal chest x-ray findings. Because TB is not as common as it was many years ago, many clinicians do not consider the possibility of TB when making diagnoses for patients who have symptoms of TB. When this happens, the diagnosis of TB may be delayed or even overlooked, and the patient will remain ill and possibly infectious. Anyone with symptoms of TB and/or a positive skin test reaction should be evaluated for TB disease.

There are four steps in diagnosing TB disease.

I. The medical history - A medical history is the part of a patient's life history that is important for diagnosing and treating the patient's medical condition. It includes social, family, medical, and occupational information about the patient. To obtain a medical history, the clinician should ask whether the patient has:

a. been exposed to a person who has infectious TB, b. symptoms of TB disease,

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c. had TB infection or TB disease before, d. risk factors for developing TB disease.Clinicians should suspect TB disease in patients with any of these factors.

II. The tuberculin skin test - Patients with symptoms of TB disease are often given a tuberculin skin test. However, they should always be evaluated for TB disease, regardless of their skin test results. Furthermore, clinicians should not wait for tuberculin skin test results when evaluating patients who have symptoms of TB disease. Instead, they should give the patient a tuberculin skin test at the same time as they start the other steps in the diagnosis of TB disease.

III. The chest x-ray - If the patient has TB disease in the lungs, the chest x-ray usually shows signs of TB disease.

IV. The bacteriologic examination - concerns the smear (microscopy) and the culture (growth) of clinical specimens (for example, sputum or urine) in the laboratory. The bacteriologic examination has four parts:

a. obtaining a specimen, b. examining the specimen under a microscope, c. culturing the specimen, d. doing drug susceptibility testing on positive cultures.

 I. The medical history

a. Exposure to TB. One important part of the medical history is asking the patient about his or her

exposure to TB. Patients should be asked whether they have spent time with someone who has infectious TB. Some people may have been exposed to TB in the distant past, when they were children. Others may have been exposed more recently. Anyone who has been exposed to TB may have TB infection. Some people become infected with M. tuberculosis without knowing that they were exposed to it. The risk of being exposed to TB is higher in some areas of the world, for some occupations (for example, some health care workers) and in some residential facilities (for example, nursing homes or correctional facilities).

b. Symptoms of TB disease. Another important part of the medical history is checking for symptoms of TB

disease. People with TB disease may or may not have symptoms. However, most patients with TB disease have one or more symptoms that led them to seek medical care. Occasionally, TB is discovered during a medical examination for an unrelated condition (for example, when a patient is given a chest x-ray before undergoing surgery). Usually, when patients do have symptoms, the symptoms have developed gradually, and they have been present for weeks or even months. Pulmonary TB disease usually causes one or more of the following symptoms:

cough (lasting more than 3 weeks);76

pain in the chest when breathing or coughing; coughing up sputum or blood (hemoptysis); dispnea (associated with miliary tuberculosis). The general symptoms of TB disease (pulmonary or extrapulmonary) include: weight loss, fatigue, malaise, low-grade fever, night sweats, anorexia. The symptoms of extrapulmonary TB disease depend on the part of the body

that is affected by the disease. For example, TB of the spine may cause pain in the back; TB of the kidney may cause blood in the urine. All of these symptoms may be also caused by other diseases, but they should prompt the clinician to suspect TB disease.

A physical examination is an essential part of the evaluation of any patient. It cannot confirm or rule out TB disease, but it can provide valuable information about the patient's overall condition and other factors that may affect how TB disease is treated if it is diagnosed.

c. Previous TB infection or TB disease. During the medical history, the clinician should ask the patient whether he or

she has ever been diagnosed with or treated for TB infection or disease. Patients known to have a positive skin test reaction probably have TB infection. If they were infected within the past 2 years, they are at high risk for TB disease. Patients who have had TB disease before should be asked when they had the disease and how the disease was treated. If the regimen prescribed was inadequate or if the patient did not follow the recommended treatment, TB may recur, and it may be resistant to one or more of the drugs used.

d. Risk factors for developing TB disease. A fourth part of the medical history is checking for risk factors for developing

TB disease (infection with HIV, alcohol abuse and drug injection, recent TB infection, chest x-ray findings suggestive of previous TB, diabetes mellitus, silicosis, prolonged therapy with corticosteroids, immunosuppressive therapy, leukemia, Hodgkin's disease, cancer of the head and neck, severe kidney disease, certain intestinal conditions, low body weight). Clinicians should determine whether patients have any of these conditions. In particular, HIV infection greatly increases the risk that TB infection will progress to TB disease.

II. The tuberculin skin test

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Patients with symptoms of TB disease are often given a tuberculin skin test to detect exposure to and infection with TB. However, as many as 20% of patients found to have TB disease have a negative tuberculin skin test reaction. For this reason, patients with symptoms of TB disease should always be evaluated for TB disease, regardless of their skin test results. Furthermore, for patients with symptoms of TB disease, clinicians should not wait for tuberculin skin test results (72 hours) before starting other diagnostic tests. A tuberculin skin test is not necessary for patients known to have had a previous positive tuberculin skin test reaction.

III. The chest x-ray

The chest x-ray is useful for diagnosing TB disease because about 85% of TB patients have pulmonary involvement. It may show infiltrates, cavities, pleural effusions, miliary nodules, hilar or mediastinal lymphadenopaties. The purposes of the chest x-ray are to:

help rule out the possibility of pulmonary TB disease in a person who has a positive reaction to the tuberculin skin test;

check for lung abnormalities in people who have symptoms of TB disease. However, the results of a chest x-ray cannot confirm that a person has TB

disease. A variety of illnesses may produce abnormalities whose appearance on a chest x-ray resembles TB. Although an abnormality on a chest x-ray may lead a clinician to suspect TB, only a bacteriologic positive culture and a positive sputum smear for acid-fast bacilli (M. tuberculosis) proves that a patient has tuberculosis. Moreover, a chest x-ray cannot detect TB infection.

In patients who are infected with HIV, pulmonary TB disease may have an unusual appearance on the chest x-ray or even the x-ray may even appear entirely normal (10% of cases).

Postprimary tuberculosis is localized usually in the apical and posterior segments of the upper lobes. It is believed that the majority of TB locations in these areas is caused by reactivation of viable but dormant bacilli transmitted hematogenously to these sites during the primary infection. The right lung is involved more often than the left. The lower lobes are involved in 7% or less of patients with active tuberculosis. Lesions of the basal pulmonary segments predominate in women (particularly during pregnancy) and in diabetic patients.

Several roentgenographic patterns can be identified in postprimary tuberculosis:

local exudative lesions; cavitation; bronchogenic spread and acute tuberculous pneumonia or

bronchopneumonia; miliary; tuberculoma.

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a) Local exudative tuberculosis: airspace consolidation, patchy or confluent (figure 32), situated in the apical and posterior segments of the upper lobes or the superior segment of a lower lobe (Fowler segment). Cavitation may be present. Hilar or mediastinal lymph node enlargement is uncommon (5% of cases).

Figure 32 - Infiltrative tuberculosisThere is patchy shadowing in the right upper lobe

b) Cavitation: lysis of semisolid caseous material and elimination from the center of the lesion into the bronchial tree leeds to cavity formation. The wall of untreated TB cavity may be thin or thick, smooth or internally nodular. Sometimes, a fluid level can be identified in the cavity, suggesting a secondary infection, probably with anaerobic germs. Under specific therapy, the cavity may diminish and finally disappear; in some treated patients, the cavity wall becomes very thin and regular, like an air-filled cystic space (figure 33).

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Figure 33 - Cavitary tuberculosisPatchy consolidation – with multiple cavitation areas – is present, predominantly in

the right upper and left middle zones. Sputum was positive for acid-fast bacilli.

c) Acute TB pneumonia, bronchopneumonia : when liquefied caseous material expels in the bronchial tree, TB can disseminate and generate new foci of infection in the same lobe or in other lobes of either lung. Extension of TB through surrounding airspaces generates a pneumonic consolidation, very difficult to differentiate from that caused by Streptococcus pneumoniae. Finding a cavity in the same lung or the other one suggests the TB etiology of pneumonia (figure 34).

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Figure 34 - Tuberculous bronchopneumoniaThere are widespread poorly-defined opacities, confluent in both

upper lobes and a cavity in the right apex.

d) Miliary tuberculosis: tiny, discrete (1-3mm) opacities, widely and uniformly distributed throughout both lungs. It may take 6 weeks or even more between the hematogenous dissemination of TB in the lungs and the moment when small opacities become visible on the chest x-ray. When first visible, opacities measure 1mm in diameter and they may enlarge without adequate therapy. Under correct TB treatment, clearing is very rapid and complete. Without treatment, the major cause of death is respiratory failure (figure 35).

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Figure 35 - Miliary tuberculosisWidespread small nodules, 2-3 mm in diameter, are present in both lungs

(hematogenous dissemination)

e) TB bronchiectasis and bronchostenosis: in postprimary tuberculosis, bronchiectasis can develop by two mechanisms. Most commonly, destruction and fibrosis of the lung parenchyma results in retraction and irreversible bronchial dilatation. Also, tuberculous bronchitis associated with granulation tissue may heal with fibrosis and cicatricial bronchostenosis.

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f) Tuberculoma : is a round or oval opacity situated usually in an upper lobe. The diameter measures between 0,5 and 4 cm and the contour is smooth and sharply defined. In 80% of cases, discrete opacities (“satellite lesions”) can be identified near the main lesion. Most of tuberculomas remain stable for a long time and may calcify. Those exceeding 3 cm should be resected (figure 36).

Figure 36 - TuberculomaThere is a well-defined nodular opacity in the upper left lobe,

following treated postprimary tuberculosis.

IV. The bacteriologic examination

The next step in diagnosing TB disease is the bacteriologic examination. This is done in a laboratory that specifically deals with M. tuberculosis and other mycobacteria (a mycobacteriology laboratory). There are four parts to a bacteriologic examination:

a. Obtaining a specimen.

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Specimens that will be sent to the laboratory can be obtained in several ways. Usually, patients who are suspected of having pulmonary TB disease simply cough up sputum (phlegm from deep in the lungs) into a sterile container for processing and examination. This is the cheapest and easiest procedure.

If a patient cannot cough up sputum on his or her own, other techniques can be used to obtain a specimen. An induced sputum sample can be obtained by having the patient inhale a saline (salt water) mist, which causes the patient to cough deeply. This procedure is easily done, and it should be used to help patients cough up sputum if they cannot do so on their own. Induced specimens are often clear and watery, so they should be labeled "induced specimen" so that they will not be confused with saliva.

Another procedure, bronchoscopy, can be used to obtain pulmonary secretions or lung tissue. In this procedure, an instrument called the bronchoscope is passed through the mouth directly into the diseased portion of the lung, and some sputum or lung tissue is removed. Bronchoscopy should be used only when patients cannot cough up sputum on their own and an induced specimen cannot be obtained.

A fourth procedure, gastric washing, involves inserting a tube through the patient's nose and passing it into the stomach. The idea is to get a sample of sputum that has been coughed into the throat and then swallowed. Gastric washings are done in the morning because patients usually swallow sputum during the night. This procedure is usually used only when patients cannot cough up sputum on their own, an induced specimen cannot be obtained, and bronchoscopy cannot be done. However, gastric washings are often used for obtaining sputum from children. Most children produce little or no sputum when they cough.

It is very important for health care workers to use precautions to control the spread of tubercle bacilli during these procedures and any other procedures that may cause persons who have pulmonary TB disease to cough.

In patients who have extrapulmonary TB disease, specimens other than sputum are obtained. The specimen obtained from these patients depends on the part of the body that is affected. For example, urine samples are obtained from patients suspected of having TB disease of the kidney, and cerebro-spinal fluid samples are obtained from the area around the spine in patients suspected of having TB meningitis.

b. Examining the specimen under a microscope. Before the specimen is examined under a microscope, it is smeared onto a

glass slide and stained Ziehl-Nielsen or with auramine O. Then laboratory personnel use the microscope to look for acid-fast bacilli (AFB) on the smear. AFB are mycobacteria that stay stained even after they have been washed in an acid solution. When AFB are seen in a smear they are counted and classified according to the number of AFB seen. There is a system for reporting the number of AFB that are seen at a certain magnification. According to the number of AFB seen, the smears are classified as 4+, 3+, 2+, or 1+. In smears classified as 4+, 10 times as

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many AFB were seen as in smears classified as 3+; in 3+ smears, 10 times as many as in 2+ smears; and in 2+ smears, 10 times as many as in 1+ smears.

Smears that are classified as 4+ and 3+ are considered strongly positive; 2+ and 1+ smears are considered moderately positive (table 8). If very few AFB are seen, the smear is classified by the actual number of AFB seen (no plus sign). For example, if only 4 AFB were seen in the entire smear, the smear is classified as "4 AFB seen." Smears classified in this way are considered weakly positive. Finally, if no AFB are seen, the smear is called negative. But a negative smear does not rule out the possibility of TB because there can be AFB in the smear that were not seen.

It takes only a few hours to prepare and examine a smear. Therefore, the results of the smear examination should be available to the clinician within 1 day. The results of the smear examination can be used to help determine the infectiousness (contagiousness) of the patient. However, because AFB are not always tubercle bacilli, patients who have positive smears do not necessarily have TB. Only the positive mycobacterium cultures can confirm the diagnosis. Furthermore, as mentioned previously, patients who have negative smears may have TB.

Table 8 - Smear classifications and results

RESULT OF SMEAR EXAMINATION CLASSIFICATION INFECTIOUSNESS

OF THE PATIENT4+ Strongly positive Very infectious3+ Strongly positive Very infectious2+ Moderately positive Infectious1+ Moderately positive Infectious

Number of AFB seen(no plus sign) Weakly positive Infectious

No AFB seen Negative May not be infectious

c. Culturing the specimenCulturing the specimen means growing the mycobacteria on media, substances

that contain nutrients, in the laboratory. When the mycobacteria have formed colonies (groups), they can be identified. All specimens should be cultured, regardless of whether the smear is positive or negative. Culturing the specimen is necessary to determine whether the specimen contains M. tuberculosis and to confirm a diagnosis of TB disease. (However, in some cases, patients are diagnosed with TB disease on the basis of their signs and symptoms, even if their specimen does not contain M. tuberculosis).

The first procedure in culturing the specimen is to detect the growth of the mycobacteria. Mycobacteria grow very slowly. When solid media are used to culture the specimen, it can take as long as 2 to 8 weeks for the growth of the

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mycobacteria to be detected. However, rapid culturing methods that involve liquid media can decrease this time to 4 to 8 days.

The second procedure is to identify the organism that has grown. All types of mycobacteria will grow in solid or liquid media. For this reason, laboratory tests must be done to determine whether the organism is M. tuberculosis or one of the nontuberculous mycobacteria. Traditional tests require an additional 3 to 6 weeks from the time the cultures have grown. However, other tests have been developed to shorten the time it takes to identify the type of mycobacteria present in clinical specimens. When M. tuberculosis is identified in a patient's culture, the patient is said to have a positive culture for M. tuberculosis. A positive culture for M. tuberculosis, also called an M. tuberculosis isolate, confirms the diagnosis of TB disease.

When M. tuberculosis is NOT identified in a patient's culture, the patient is said to have a negative culture for M. tuberculosis. A negative culture does not necessarily rule out the diagnosis of TB disease; as mentioned earlier, some patients with negative cultures are diagnosed with TB disease on the basis of their signs and symptoms.

d. Drug susceptibility testingDrug susceptibility tests, the final part of the bacteriologic examination, are

done to determine which drugs will kill the tubercle bacilli that are causing disease in a particular patient. Tubercle bacilli that are killed by a particular drug are said to be susceptible to that drug, whereas those that can grow even in the presence of a particular drug are said to be resistant to that drug. The drug susceptibility pattern of a strain of tubercle bacilli is the list of drugs to which the strain is susceptible and to which it is resistant. The results of drug susceptibility tests can help clinicians choose the appropriate drugs for each patient. This is very important. Patients with TB disease who are treated with drugs to which their strain of TB is resistant may not be cured. In fact, their strain of TB may become resistant to additional drugs.

Drug susceptibility tests should be done when a patient is first found to have a positive culture for M. tuberculosis (that is, the first isolate of M. tuberculosis). In addition, drug susceptibility tests should be repeated if a patient has a positive culture for M. tuberculosis after 2 months of treatment or if a patient does not seem to be getting better. That way, the clinician can find out whether the patient's strain of TB has become resistant to certain drugs; if necessary, the clinician may change the drugs used for treating the patient.

In the laboratory, drug susceptibility testing can be done using solid media. Organisms that grow in media containing a specific drug are considered resistant to that drug. This technique is slow, taking as long as 8 to 12 weeks. Rapid methods for drug susceptibility testing can shorten this time to 3 weeks.

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2.9.2. DIFFERENTIAL DIAGNOSIS OF POSTPRIMARY (SECONDARY) PULMONARY TUBERCULOSIS

Because tuberculosis can manifest similar symptoms and signs as many other pulmonary diseases, until the diagnosis is confirmed (by positive bacteriology of sputum or histology of tissue samples) we must make a correct differential diagnosis of TB

The most common roentgenographic aspects of postprimary TB are: pulmonary nodules cavities milliary dissemination pleural effusion.

DIFFERENTIAL DIAGNOSIS OF PULMONARY SOLITARY ROUND OPACITIES

CONGENITALLUNG

DISEASE

Bronchogenic cyst: lower lobes predilection, has a round shape and is well delimited;

Pulmonary sequestration: lower lobe location, above the diaphragm;

Pulmonary arterio-venous fistula: round opacity that needs arteriography for diagnosis;

Hammartoma: benign peripheral tumor, frequent in men at age 60 and more; clinically silent.

INFECTIOUS Bacteria- M. tuberculosis: tuberculoma is a round opacity situated

inthe upper lobes, well delimited, often with calcifications and in 80% of cases with “satellite” lesions.

Fungi - Histoplasma capsulatum: situated in the lower lobes,

they often have central calcification.- Aspergillus fumigatus: the fungal opacity is called

aspergiloma; it has upper lobe predilection, in pre-existant lung cavities (TB, aeric cysts, bronchiectasis); frequently causes hemoptysis (figure 37).

Parasites Hydatid cyst: round, well delimited opacity, common in

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endemic areas.

NEOPLASTIC Adenocarcinoma: peripheral round opacity, less than 4 cm diameter; for diagnosis, bronchoscopy and even open lung biopsy are necessary.

Hematogenous metastasis (figure 38) usually located in the lower lobes; well delimited; primary tumor has to be diagnosed for histology.

Multiple myeloma (plasmocytoma): round opacity of the lung, bone involvement and typical haematologic aspect.

Figure 37 - AspergilomaThere is a round nodular opacity in the right apex. Close inspection shows a thin-

lined cavity surrounding the mycetoma.

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Figure 38 - Solitary metastatic noduleIn the lower part of the right hilum there is a round opacity, well-delimited, which

is a unique metastasis from an ovarian carcinoma.

DIFFERENTIAL DIAGNOSIS OF CAVITARY LUNG DISEASE

CONGENITAL intralobar pulmonary sequestration: 2/3 of cases are located in theleft lower

lobe and 1/3 in the right lower lobe; the opacity is contiguous to the diaphragm and when excavated it has an air-fluid level and can be multiloculated.

bronchogenic cyst (excavated) : located in the lower lobes, has a thin wall and in 75% of cases has an air-fluid level.

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INFECTIOUS

Bacteria - Staphylococcus aureus: one or several small abcesses; empyema can be

present.- Klebsiella pneumoniae: upper lobe abcess aspect and pleural effusion.- M. tuberculosis (TB cavity): apical and posterior location, regular

contour, “satellite lesions”, AFB positive sputum and cultures.- Pseudomonas aeruginosa: cavity with lower lobe location; abcess and

empyema can be the result of dissemination an extrathoracic site; most of cases are immuno hosts.

- Streptococcus pneumoniae: usually upper lobe abcess, containing necrotic material.

- Anaerobic germs: complicates aspiration pneumonia in immunodepressed patients.

Fungi - Actinomyces israelii: involves lower lobes; thick walled abcess associated

with empyema.- Cryptococcus neoformans: same aspect.- Histoplasma capsulatum: multiple cavities in upper lobes.- Aspergillus fumigatus: thin-walled cavity with mycetoma inside; can

complicate previous lung cavities. Parasites

- Entamoeba histolytica (amebiasis): cavity in the right lobe, thick-walled, accompanied by pleural effusion.

- ruptured Hydatid cyst: when cyst ruptures in a bronchus, the cavity has the “water-lily” aspect.

NEOPLASTIC

Bronchogenic carcinoma – can evoluate with necrosis and cavitation; Metastasis - the cavity has a thick, irregular wall; Hodgkin`s disease- bronchoscopy is necessary for diagnosis.

PULMONARY THROMBOEMBOLISM - with infarction, necrosis and cavitation can be infected and have the aspect of a lung abcess. The patient has hemoptysis, cardiac arrythmia, deep phlebitis, hematic pleural effusion. Lung scintigram is necessary for diagnosis.

IMMUNE DISEASES

Wegener`s granulomatosis: multiple, thick-walled cavities; lesions in the kidneys and nose.

Rheumatoid disease: multiple masses with cavitation and pleural effusion or pneumothorax; positive rheumatoid serology.

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AIRWAY DISEASES

Blebs and aeric cysts: thin-walled cavities with upper lobes predilection; when infected, they have an air-fluid level.

Cystic bronchiectasis: predilection for lower lobes; multiple thin-walled cavities, usually suprainfected; CT for diagnosis.

PSEUDOCAVITIES AND PSEUDOCYSTS can mimic a cavitary image in the lung parenchyma Rib anomalies and calcified cartilage Ring-shaped pleural scars Loculated pneumothorax Hernias of the diaphragm Superopsition of vascular structures

DIFFERENTIAL DIAGNOSIS OF MILIARY TUBERCULOSIS

INFLAMMATORY DISEASES Miliary viral pneumonia Sarciodosis (in the second and third stage) Extrinsec alergic alveolitis Collagen vascular diseases - panarteritis nodosa

- rheumatoid arthritis Histoplasmosis

NEOPLASMS

Miliary carcinomatosis (figure 39) Lymphangitic carcinomatosis: lower lobes predilection Broncho-alveolar carcinoma Malignant lymphoma

MISCELLANEOUS Pneumoconiosis: professional exposure to inhaled particles , Hemosiderosis Histiocytosis X Amyloidosis Multiple microaneurysms

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Figure 39 - Miliary carcnomatosisWidespread nodules, 3-5 mm in diameter are present in both lungs. Nodules are

confluenting in the upper right lobe.

2.9.3. TREATMENT OF TUBERCULOSIS

Treating pulmonary tuberculosis benefits both the patient and the community, because it prevents the further transmission of TB. Tuberculosis must be treated for at least 6 months; in some cases, treatment lasts even longer. Most of the acid-fast bacilli (AFB) are killed during the first 2 months (the initial phase) of treatment, but a few germs can remain dormant for a long time. The drugs used in the TB treatment are not as effective against dormant bacilli as they are against active, multiplying ones. Hence, treatment must last for another several months (the

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continuation phase) to kill these few remaining bacilli. If treatment is not continued for a long enough time, the surviving bacilli may cause a relapse of tuberculosis at a later time.

BASIC PRINCIPLES OF THE TB TREATMENT

1. Provide safest, effective therapy in shortest time.2. Directly observed therapy (DOT).3. Use multiple drugs to which organisms are susceptible.4. Never add a single drug to a failing regimen.5. Ensure adherence to therapy.6. Treatment regimens have 2 phases:

Initial phase: 4 or 3 drugs daily; in areas where less than 4% of cases are resistant to isoniazid, 3 drugs (H, R and Z) may be adequate for the initial regimen

Continuation phase: 2 drugs, 3 days per week.7. TB drugs are administered only once a-day, in the morning (before

breakfast).8. Treatment side effects will be monitored.9. Protection of rifampicin (rifampicine should not be used for the treatment

of other diseases, in order to avoid selection of resistant germs).10. All cases of tuberculosis will be registered.11. TB treatment is free of charges.12. In special situations treatment lasts longer than 6 months:

9 months, if pyrazinamide or rifampicine are not used; 12 months, in AIDS patients and in extrapulmonary TB; 18-24 months, in multidrug-resistant tuberculosis.

DRUGS USED IN TB CHEMOTHERAPY

The drugs commonly used in the treatment of new cases of tuberculosis and in retreatments of TB with sensitive germs are:

Isoniazid (H) Rifampicin (R) Pyrazinamide (Z) Streptomycin (S) Ethambutol (E).

Isoniazid Isoniazid is very powerful, bactericidal drug; it has few adverse effects and is

very cheap. Because it is very effective against the tubercle bacilli, the dose is small. Usually it is given by mouth, but in special circumstances it can be given intravenously. High effective concentrations of the drug are obtained in all tissues and the CSF. There is no cross-resistance with other drugs.

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Dose - daily: 5 mg/kg/day, maximum 300 mg, in a single dose- 3 days/week: 10 mg/kg/day, maximum 750 mg/day- chemoprophylaxis (preventive therapy): 5 mg/kg/day.

The drug is supplied as tablets of isoniazid alone, 100 mg or 300 mg/tablet, or combined with other TB drugs: - isoniazid + rifampicin + pyrazinamide = rifater

- isoniazid + rifampicin = RIFINAHSide effects: Hepatitis is the main toxic effect, directly correlated with age

(incidence rate 0.5% - 1%, higher in females). Alcohol consumption and the co-existence of acute or chronic hepatitis are other important risk factors. Transient elevations of hepatic enzymes may be observed in the first period of therapy but do not usually give rise to hepatitis. Elevation of hepatic enzymes to 4 times the normal value requires discontinuation of isoniazid treatment.

In alcoholics and neurologic patients, isoniazid may induce neuropathy that can be treated with Pyridoxine 100-200 mg/day and prevented supplementing Pyridoxine (10 mg/ day). In case neuropathy appears, the drug should be promptly stopped. Attention must be payed when H and phenytoin or carbamazepine are simultaneously given because their serum levels can increase: a dose adjustment may be needed.

Rare side effects of isoniazid are gastric pain, nausea, drowsiness, lupus erythematosus syndrome. The main contraindications to isoniazid use are known hypersensitivity.

RifampicinRifampicin is supplied as capsules containing 150 mg or 300 mg each (syrup

is also available) and should be taken half an hour before breakfast, in a single dose. It can be combined with other TB drugs in the same tablet. Effective concentrations are obtained in all tissues and moderate levels in the CSF. Patients should be warned that rifampicine colours urine, sweat and tears pink.

Dose - daily: 10 mg/kg/day, maximum 600mg/day; under 50 kg body weight: maximum 450 mg/day

- 3 days/week: 10 mg/kg/day, maximum 600 mg/daySide effects are more common with intermittent than with daily rifampicin-

containing regimens. Although liver transaminases can rise transiently at the beginning of treatment, accompanied by jaundice, a true hepatitis is a rare event. Gastrointestinal upset, pruritus and skin eruptions are known rifampicin-induced side effects. A "flu-like" syndrome (fever, chills, headache) can occur. Thrombocytopenic purpura, haemolysis, severe renal failure and shock, more frequently with intermittent administration of the drug (particularly if the daily dosage of rifampicin is above 600 mg/ day or is > 10 mg/ kg body weight/day) can also occur. These severe side effects are due to immuno-alergic reactions and occur at the beginning of retreatments. In these cases, rifampicin should be stopped, replaced by another first line drug and not used again in that patient.

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As rifampicin is an important inducer of hepatic enzymes, the activity of other drugs metabolised in the liver may be reduced. These drugs include oral coumarin anticoagulants, oral diabetic drugs, digoxin, methadone, morphine, phenobarbital and dapsone. Remember to reduce the dose when the patient ceases to take rifampicin. In particular, women using the contraceptive pill should be advised of the potential risk related to the reduced effectiveness of the method. The interaction with methadone may be important in drug addicts under treatment.

When used simultaneously, isoniazid and rifampicin can produce hepatitis (hepatocellular damage, seldom associated with cholestasis) in 3-4% of patients. These abnormalities usually appear during the first 2 weeks of treatment. A very low risk of hepatitis is described among children treated with isoniazid alone, while its combination with rifampicin increases the risk significantly (up to 6,9%). The main contraindications to rifampicin use are known hypersensitivity to rifamycins.

PyrazinamidePyrazinamide is a highly bactericidal drug, very effective in killing

intracellular TB bacilli. It is supplied as tablets of 500 mg.Dose - daily: 25-30 mg/kg/day, maximum 2g/day, in a single dose; under 50

kg body weight, maximum 1,5g/day; - 3 days/week: 40mg/kg/day, maximum 3g/day.

Side effects: hepatitis (rising of liver transaminases), rash, abdominal distress and hyperuricemia (with or without arthralgia) are the commonest side effects of pyrazinamide. The facial flushing or erythematous rash with pruritus appearing in the first days of treatment are usually self-limiting. Hyperuricemia, caused by the inhibition of renal tubular secretion is rarely symptomatic. Patients with diabetes should be carefully monitored since blood glucose concentrations may become labile. Arthralgia, particularly of the shoulders, commonly occurs and is responsive to simple analgesics. They do not seem to correlate with the level of uric acid and not respond to allopurinol. Both hyperuricemia and arthralgia may be reduced by intermittent administraton of pyrazinamide. The main contraindications to pyrazinamide use are known hypersensitivity and severe hepatic impairment.

EthambutolEthambutol is a bacteriostatic drug, given orally, and is used mainly to prevent

selection of resistant strains of acid-fast bacilli to the main first-line TB drugs. Dose - daily: 15-25 mg/kg/day, in capsules of 250 mg or tablets of 400 mg.

15 mg/kg/day after the 8-th week of treatment (to avoid dose-related side effects)- 3 days/week: 30mg/kg/day, maximum 1,5 g/day.

Side effects: The main and most severe adverse effect of ethambutol is retrobulbar neuritis which is usually dose-related. Although it is very rare at a dosage of 15 mg/kg body weight/day and normal renal function, its frequency increases to nearly 3% when doses of 25 mg/kg body weight/ day are administered

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and/or in the presence of impaired renal function. Patients complain of blurred vision, red-green blindness (early symptoms) and, later, central scotomata. Visual acuity monitoring is strongly advised before administering ethambutol, and later if the patient reports visual symptoms. The drug should be stopped immediately when visual symptoms appear. As optic atrophy is usually reversible, proper clinical monitoring prevents irreparable ocular damages. Renal failure (determining higher blood levels of ethambutol) increases the probability that ocular side effects might occur. Due to difficulties of monitoring visual acuity in children, the drug should be used with caution and only after the age of 6 years. Signs of peripheral neuritis in the legs, rashes or abdominal distress may occasionally develop. Contraindications to ethambutol use include known hypersensitivity, pre-existing optic neuritis from any cause, inability to report symptomatic visual disturbances, and a creatinine clearance of less than 50 ml/ minute.

StreptomycinStreptomycin is a bactericidal drug providing effective concentrations in most

body tissues. Because it is not absorbed from the intestine, it is administered by intramuscular injection. It crosses the placenta and can induce deafness to the newborn; therefore streptomycin is never used in pregnant women. As it is excreted almost entirely through kidney, the drug should be avoided or the dosage should be lowered in patients with diminished renal function. Streptomycin sulphate is supplied as a powder in vials of 1g and is used for intramuscular injection by adding distilled water. Injections should be given once a-day, in a different site, because injections in the same site are very painful. Sterile syringes and needles must be provided for each injection, in order to avoid spreading of HIV and B-hepatitis. If there is no reliable sterilisation of syringes and needles, streptomycin will be substituted with ethambutol (for oral administration).

Doses - daily: 15 mg/kg/day, maximum 1g/day, in a single dose; less than 50 kg body weight, maximum 0,750 g/day;- 3 days/week: 15 mg/kg/day, maximum 1 g/day.

Side effects: Ototoxicity, due to irreversible damage of the vestibular branch of eighth cranial nerve, is the main side effect. Vertigo, ataxia, nystagmus and sometimes hearing loss are the commonest symptoms. Damage to the vestibular nerve is shown by giddiness, vomiting and unsteadiness that can predominate in darkness; treatment should be stopped immediately.

Nephrotoxicity, especially in those patients with preexisting renal insufficiency, is described. The association of isoniazid and other ototoxic/ nephrotoxic drugs (other aminoglycoside antibiotics, amphotericin B, cefalosporins, ethacrynic acid, cyclosporin, cisplatin, furosemide and vancomycin) might increase both the frequency and severity of symptoms. Dosage should be reduced if headache, vomiting, vertigo and tinnitus occur. Minor side effects are fever, skin rashes and eosinophilia. Dosage should be reduced by 50% if urinary output falls, albuminuria occurs or tubular casts are detected in the urine.

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Streptomycin should be avoided, when possible, in children (the injections are painful and irreversible auditory nerve damage may occur), and their dosage reduced in the elderly and in presence of renal impairment. In patients with renal impairment, renal function monitoring is mandatory and, where possible, serum levels of the drug should be monitored periodically to ensure plasma concentrations (measured when the next dose is due) do not exceed 4 mg/ml. Streptomycin may potentiate the effect of neuromuscular blocking agents administered during anesthesia. Contraindications to streptomycin use are represented by known hypersensitivity (anaphylactic reactions may occur after injection of streptomycin), auditory nerve impairment and myasthenia gravis.

The treatment of tuberculosis is similar for children and adults. Generally, the use of ethambutol is avoided in children (especially less 6 years old) because they are too young to be monitored for changes in their vision. Streptomycin should be used instead, if necessary. Infants and children with milliary TB and/or extrapulmonary involvement (bone and joint, meningitis, etc) should receive a longer treatment, lasting 12 months. In children diagnosed with tuberculosis, treatment will be started immediately, because they are susceptible to develop very severe forms of TB soon after infection (table 9).

Table 9 - Main drugs and doses (mg/kg/day); maximum dosage/day in parentheses

DRUG DAILY DAILY 3 TIMES /WEEK

3 TIMES /WEEK

CHILDREN ADULTS CHILDREN ADULTSISONIAZID

(H)10-20

(300 mg)5

(300 mg)20-40

(750 mg)10

(750 mg)RIFAMPICIN

(R)10-20

(600 mg)10

(600 mg)10-20

(600 mg)10

(600 mg)PYRAZINAMID

E(Z)

15-30(2 g)

30(2 g)

50(3 g)

50(3 g)

ETHAMBUTOL(E)

15-25(1,5 g)

15-25(1,5 g)

30(1,5 g)

30(1,5 g)

STREPTOMYCIN

(S)

20(1 g)

15(1 g)

30(1,5 g)

30(1,5 g)

SECOND LINE DRUGS USED IN TB TREATMENT

Quinolones – ofloxacin and ciprofloxacin - have been demonstrated to be moderately effective against M. tuberculosis and MAC (Mycobacterium avium complex) and are used as second-line drugs in case of resistance or intolerance to

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first-line drugs. The side effects are rare (3 to 7%) and usually mild and transient, including abdominal pain, nausea, vomiting, dizziness, headache and increased liver enzymes. As they may impair growth and produce injury to growing cartilage, the permission for their use in growing children differs among European countries.

Aminoglycosides (kanamycin, amikacin) and polypeptides (capreomycin)As for streptomycin, the major side effects are nephrotoxicity, ototoxicity, and

neuromuscolar blockade. Their dosage should be reduced in patients with renal impairment.

Ethionamide-ProthionamideGastrointestinal intolerance (abdominal pain, nausea, vomiting) is the most

frequent side effect. The drugs are hepatotoxic and may cause hyperglycemia in diabetics. They can increase cycloserine side effects on the central nervous system. Daily doses of 0,5-1 g (subdivided in 2-3 times a day) usually limit the gastrointestinal upset.

Rifamycins (rifabutin, rifapentine)Rifabutin and rifapentine have similar adverse effects and spectrum of activity

with rifampicin, although rifabutin is also active against M. avium. Basically, the indication for both drugs in the treatment of TB is the same as rifampicin, but they are actually used only for multidrug-resistant tuberculosis.

Rifabutin: due to partial cross-resistance, one third of rifampicin-resistant strains are susceptible to rifabutin.

Rifapentine: having a rather long half-life (>14 hours), might allow once-weekly administration.

Cycloserine - The most serious adverse effects, which are dose-related, are those affecting the central nervous system: psychosis, depression, headache, seizures and vertigo. Alcoholics and those patients receiving dosages > 500 mg/ day are at major risk of developing side effects. Sedatives and anticonvulsivant drugs are effective in controlling the symptoms. The monitoring of blood levels (to keep levels < 30 g/ml) has been suggested, especially in patients with impaired renal clearence.

Para-aminiosalicylic acid - Gastrointestinal upset, rash, bloating, diarrhoea and nausea are the more frequently observed side effects. Intravenous administration partially limits the gastrointestinal reactions.

Other drugs (claritromycine, augmentin) - Recently, some antibiotics used in the treatment of non-specific infections of the low respiratory tract proved their effectiveness against non-tuberculous mycobacteria. They were also successfully used, in combination with other 4-5 drugs, for the treatment of multidrug-resistant (MDR) tuberculosis.

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CATEGORIES OF STANDARD TB TREATMENT

New casesTreatment regimens comprise an initial (intensive) phase of 2 months and a

continuation phase usually lasting 4 months. During the intensive phase, when 4 drugs are given, there is a rapid killing of tubercle bacilli. During this phase adequately treated patients become rapidly non-infectious (in the presence of susceptible strains) and symptoms improve. The vast majority of sputum smear positive patients, when correctly treated, achieve sputum conversion (a negative sputum smear examination) within 2 months. In the continuation phase, fewer drugs are necessary, but for a longer duration. The sterilising effect of the drugs eliminates the remaining bacilli and prevents subsequent relapse.

In sputum smear positive patients there is a risk of selecting resistant strains, as these patients harbour and excrete a large number of metabolically active bacilli. Short- course regimens consisting of 4 drugs during the intensive phase (Isoniazid (H) + Rifampicin (R) + Pyrazinamide (Z) + Ethambutol (E) or Streptomycin (S) and 2 drugs during the continuation phase (H+R) significantly reduce this risk. These regimens are as effective in patients with organisms initially resistant to one of the drugs (excluding R) as in those with sensitive organisms. In pulmonary sputum smear negative and extrapulmonary patients the risk of selecting resistant mutants is significantly lower, as these patients harbour fewer bacilli. Properly designed controlled clinical trials have proved the efficacy of chemotherapy regimens consisting of 3 drugs during the intensive phase (HRZ) and 2 drugs during the continuation phase (HR).

Retreatment casesAs previously treated patients are more likely to have acquired drug resistance

to at least isoniazid, the standard WHO recommended re-treatment regimen includes:

a) 5 drugs for 2 months followed by 4 drugs for 1 month during the intensive phase (which is administered for 3 months);

b) 3 drugs in the continuation phase (which is administered for 5 months).This approach allows the patient to receive at least 3 active drugs during the

initial phase, reducing the risk of selecting further resistant bacilli. The treatment regimens recommended by WHO are summarised in the

following table. Patients are classified into 4 treatment categories: I: new sputum smear positive and other severe cases; II: retreatment cases; III: multidrug-resistant TB.The use of four drugs in the intensive phase in communities in which there is

even a small risk (> 2%) of single drug resistance has been recommended. In specific areas at higher risk of multidrug resistance, at least 5 drugs may be needed

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during the intensive phase in new cases and at least four (but possibly as many as six or seven drugs) in retreatment cases.

Simultaneous use of DOT and/or fixed dose combination (FDC) tablets may prevent the spread of drug resistance (table 10).

Table 10 - Categories of TB standard treatment

TB treatment category

TB patients

WHO recommended TB treatment regimens

Initial phase (daily)

Continuation phase

(3/week)

I

New smear positive pulmonary TB;new smear negative pulmonary TB with extensive parenchymal involvement;new cases of severe forms of extra-pulmonary TB.

2 months HRZE or

HRZS4 months HR

II

Sputum smear positive relapse;treatment failure;treatment after interruption.

2 months HRZES ++ 1 month

HRZE

5 months HRE

III

Drug-resistant TB (MDR, XDR) Individualized treatment regimens

18-24 and more

ADHERENCE TO DIRECTLY OBSERVED TREATMENT (DOTS)

Obviously, the treatment of tuberculosis lasts longer than for other infectious diseases and requires more drugs. Ensuring that patients follow the recommended course of treatment (adhere to treatment) may be difficult because many patients are reluctant to take several different medications for many months. The most effective strategy to encourage patients` adherence to treatment is directly observed therapy short course (DOTS). This means that the patient swallows each dose of the prescribed drugs under the supervision of a health care worker or another designated person.

A major way to help patients to adhere to treatment is to educate them about tuberculosis: its spread, its diagnosis and treatment, how to avoid contamination of other persons by treating the contagious cases.

Another way to improve patient adherence is to offer them small rewards called incentives and enablers. For example, patients may receive food, restaurant

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coupons, clothing as an incentive. These rewards should be chosen according to the patients` needs and they are usually offered along with the directly observed treatment.

Patients who are not receiving directly observed therapy, more often in the continuation phase when treatment is administered 3 times/week, must be monitored for their adherence to treatment. There are several ways to verify if the treatment is taken correctly:

assess the clinical response to treatment; check if the patient is reporting to the clinic according to the schedule; at each patients` visit to the clinic, count the number of remaining pills to

determine how many were taken; use urine tests to detect the presence of TB medication in urine.

Monitoring for adverse reactionsAll patients receiving treatment for tuberculosis must be educated about the

symptoms caused by adverse reactions to the TB drugs. Some of the symptoms may be insignificant, like the orange coloration of urine from rifampicin, while others, such as vomiting, abdominal pain, jaundice, visual troubles, etc, indicate real intolerance to one or several drugs. Patients should know that medical examination and treatment reevaluation is necessary as soon as serious drugs side effects appear. Clinical evaluation for adverse reactions should be performed at least monthly.

Patient monitoring for treatment response

The patient undergoing anti-TB chemotherapy should be monitored to evaluate response to treatment and to promptly identify and manage drug-induced toxicity and to evaluate the performance of the programme. Clinicians use three methods to determine whether a patient is responding to treatment.

a) Clinical evaluation: in all patients under TB treatment symptoms should gradually improve and eventually go away. Patients whose symptoms do not improve during the first 2 months of treatment, or whose symptoms worsen after improving initially, should be reevaluated.

b) Bacteriological monitoring is possible only among “definite cases”. If a patient is smear and culture positive, the minimum requirement is to carry out a smear examination after the initial phase of treatment. Sputum specimens should be examined at least every month until the culture results have converted from positive to negative. For more than 85% of patients who are treated with isoniazid and rifampicin, cultures will convert to negative after the patient has received two months of treatment. If sputum smear conversion is achieved, a negative culture result during the continuation phase (end of 4th month) is sufficient to declare the patient cured if the full course of treatment is completed. Bacteriological monitoring at the end of treatment is strictly recommended in definite cases in

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order to assess precisely that the patient had been cured. In patients unable to produce sputum (because they do not cough) induction of sputum with hypertonic saline may be a non-invasive way of obtaining an adequate sample.

c) Radiologic evaluation: although repeated x-rays are not as important as monthly bacteriologic and clinical evaluations, patients should have an x-ray of the chest at the end of the initial phase and at the end of treatment. X-rays are also useful for patients who have negative culture results before the treatment or who have certain types of extrapulmonary TB, such as bone and joint TB. Radiological and clinical monitoring represent the only possible means of monitoring pulmonary smear/ culture negative and extrapulmonary cases.

Tuberculin skin test cannot be used to determine whether a patient is responding to treatment or not because most people with a positive skin test will remain positive when retested later in their lives, with or without TB treatment.

Patients who do not respond or who relapse should be reevaluated if: symptoms do not improve during the first 2 months of therapy; symptoms worsen after improving initially; culture results have not become negative after 2 months of treatment; culture results become positive after being negative.Reevaluation means checking for drug resistance by repeating the drug

susceptibility tests and assessing whether the patient has been taking medication as prescribed. A new regimen may be required and treatment may last longer.

TREATMENT IN SPECIAL SITUATIONS

Several health conditions can affect TB treatment (chronic renal failure, liver disease, silicosis, etc.) and special situations(pregnancy, lactation, paediatric age, etc.) require modifications of the standard regimens.

a) Chronic renal failureIsoniazid, rifampicin, and pyrazinamide are predominantly metabolised by the

liver and may be given in renal failure. Streptomycin and other aminoglycosides are excreted exclusively by the kidneys and should be used with caution in renal failure. Renal function should be measured before treatment is started. Streptomycin levels should be measured in renal failure and not exceed 4 mg/l to avoid toxicity. If the patient is being dialysed, streptomycin should be given 4-6 hours before dialysis. Ethambutol dosage should be reduced in renal impairment. In patients with creatinine clearance of 50-100 ml/min, 25 mg/Kg body weight three times weekly should be used. If the clearance is 30-50, the same dose should be given twice weekly. If clearance is 10-30, a dose of 15 mg/Kg three times weekly has been suggested. Patients on dialysis should be given 25 mg/kg 4-6 hours before dialysis. Serum levels may be monitored.

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b) Management of TB treatment in the presence of liver failureLiver function tests should be measured before treatment is started. If these are

normal, the patient should be advised about possible symptoms arising from liver function disturbance such as malaise, nausea or jaundice. The patient should be advised not to drink alcohol during treatment. Should the patient complain of symptoms attributable to liver function abnormality while on treatment, liver function should be measured. If the results are abnormal, treatment with possible hepatitic drugs (isoniazid, rifampicin and pyrazinamide) should be stopped until liver function returns to normal. The same procedure should be carried out if the patient becomes icteric on treatment. Once liver function returns to normal, drugs may be restarted in full dosage. If liver disturbance occurs for a second time, hepatitic causing drugs should again be stopped and added one at a time in the presence of two non-hepatitic causing drugs (streptomycin and ethambutol).

The presence of abnormal liver function tests before treatment is not necessarily a contraindication to treatment with hepatitic causing drugs. In this situation, a rise in bilirubin should lead to a discontinuation of these drugs. They may be retried, provided the liver function returns to its pre-treatment levels.

Some authorities advocate routine liver function testing during treatment and discontinuing hepatitic drugs if enzyme levels exceed five times the upper limit of normal. There are no general data to support this practice. It should be born in mind that serious untreated TB at most sites may be fatal.

c) SilicosisThere is evidence that standard 6-months short course chemotherapy may be

inadequate in silico-TB. A treatment longer than the standardised one is recommended (up to 8 months) because of the difficulties in penetration of the drugs into fibrotic lung and impairment of macrophage function. If pyrazinamide is not included during the initial intensive phase, it is recommended that the treatment be continued up to 12 months. TB in other pneumoconioses (coal workers’ pneumoconiosis) can be treated with standard regimens.

d) Diabetes mellitusDiabetic patients are at major risk of TB. Standard regimens are adequate. It

should be remembered that rifampicin reduces the serum levels of some oral hypoglycaemic drugs such as the sulphonyl-ureas.

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e) Human immunodeficiency virus (HIV)Patients with HIV-associated TB also present with extra-pulmonary disease.

When the disease is pulmonary, the classical upper zone infiltration with cavitation may be absent on chest radiography and uncharacteristic patterns may be detected (hilar adenopathy, middle and lower-zone non cavitating infiltrates). Those with very low CD4+ cell counts may present with disseminated disease. Mortality is higher than in HIV negative disease.

As adherence to the prescribed regimen is the most important determinant of success, the same regimens recommended for HIV negative individuals are effective for HIV positive patients. Though continuation of treatment beyond the standard length has been recommended, there is little scientific data to support this. Adverse effects of medication are more frequent in HIV positive patients. Thiacetazone, a drug not usually used in Europe, should be avoided. Where sterility of needles cannot be guaranteed, streptomycin should not be used to avoid potential HIV transmission. Several nosocomial outbreaks of drug resistant TB in HIV positive patients had been recently described in Europe. Where drug resistance is suspected, regimens for drug resistant TB should be used.

f) Immunosuppression (other than HIV)Immunosuppression, induced iatrogenically through immunosuppressive drugs

or related reticuloendothelial neoplasms can act as risk factors of TB. There is evidence that standard regimens are adequate for these patients, although the underlying disease is responsible for an excess mortality.

g) Comatose patientStandard treatment should be prescribed, avoiding the administration of

ethambutol as visual acuity cannot be monitored. Different routes of administration need to be used: isoniazid and rifampicin can be given both by syrup, isoniazid, rifampicin and streptomycin by i.v. infusion, isoniazid and streptomycin by i.m. injection and pyrazinamid crushed through a nasogastric tube. I.v. drugs should be available in units admitting comatose patients.

h) Pregnancy and lactationIn pregnancy, standard short course chemotherapy can be given. According to

WHO recommendations, all the first line drugs can be safely administered except streptomycin, because it may cause (as other aminoglycosides) foetal ototoxicity. The effect of both the combined oral contraceptive and progesterone-only pill is reduced by regimens containing rifampicin. The occurrence of pregnancy in women with TB taking rifampicin is not an indication for termination of pregnancy. Most anti-TB drugs are present in small concentrations in breast milk. However, these levels are well tolerated by infants, although they do not provide adequate therapy or preventive therapy. Breast feeding is not contraindicated , except in cases where the mother is highly infectious (sputum smear positive).

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Although isolation until sputum smear conversion has been suggested, evidence exists that isoniazid can protect the newborn from postnatal infection even when infants are not isolated from their mother.

i) Paediatric ageThe basic principles of treatment of TB in children are essentially the same as

for adults: as TB in children is usually an immediate complication of primary infection,

they typically have closed caseous lesions with relatively few mycobacteria. As the probability of acquiring drug resistance is proportional to the size of the bacillary population, children are considered to be at lower risk of developing acquired drug resistance during treatment.

the risk of developing extrapulmonary TB, especially disseminated disease and meningitis (requiring prompt and effective treatment), is higher than in adults.

normally, due to pharmacokinetics, children tolerate larger doses of drugs per kg of body weight and are less likely to develop side effects than adults. However, children with disseminated TB or meningitis or who are malnourished may develop hepatotoxicity, especially when the daily dosage of isoniazid exceeds 10 mg/kg body weight.

due to the lack of specific drug formulations, the administration of drugs in pediatrics may sometimes need crushing pills or making up unstandardised suspensions. If this problems are not considered in advance, they may cause delays and interruptions of treatment and/ or administration of inappropriate doses. The regimen for pulmonary TB is a 6 month regimen including isoniazid,

rifampicin and pyrazinamide during the intensive phase (first 2 months) and isoniazid + rifampicine during the continuation phase (4 months). The same regimen is recommended both for disseminated disease and lymphnode TB. Some authors recommend a longer duration for meningitis and TB of the bones (9-12 months) and the use of a fourth drug when drug resistance is likely or suspected.

This standard regimen is generally well tolerated. The supplementation with pyridoxine supplement is recommended in malnourished children. Although transiently elevated liver transaminase levels are described in 3%-10% of children taking isoniazid, the risk of developing hepatotoxicity is very low. Rifampicin is well tolerated and adverse reactions such as leukopenia, thrombocytopenia and flu-like syndrome are rare. Pyrazinamide, extensively used in children over the past 10 years has proved to be well tolerated in a daily dose of 30-40 mg/kg body weight. Streptomycin, less frequently prescribed than in the past, is also well tolerated. Ethambutol, not recommended for general use in children because of the difficulties in monitoring optic toxicity, should be limited to schoolchildren and adolescents and when drug resistant TB is suspected. Several second-line drugs, including ethionamide, polypeptides (capreomycin) and aminoglycosides (kanamycin, amikacin) are well tolerated. It is recommended that liver function be

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tested before the commencement of therapy and, in case of disseminated TB, meningitis or other risk factors, every two weeks for the first two months. Liver function monitoring is mandatory when clinical signs and symptoms (fever, malaise, vomiting, jaundice, weight loss) appear.

j) Treatment of newbornPrevention of infection and disease in the newborn is strictly related to the

control of TB in the mother. When TB disease is suspected or diagnosed in the newborn, a standard short course chemotherapy has to be given.

k) Treatment and drug interactions in geriatricsThe elderly with TB should receive standard short-course chemotherapy.

However, as decreased renal and hepatic clearance is described in elderly patients, they are more susceptible to adverse effects from drug treatment. Furthermore, the drug half-life and organ response to a given antiTB drug may be altered, and the elderly patient may have multiple illnesses requiring different drugs. A few issues deserve special attention. As rifampicin induces liver enzymes, the clearance of several drugs often used

in the elderly may be accelerated (warfarin, steroids, hypoglycemic agents, digoxin, theophylline, beta- blockers). Proper monitoring and adjustment of the dosages may be needed.

Pyrazinamide can cause hyperuricemia, although gout attacks are very rare. Uric acid measurement is not generally recommended, except in the case of a previously documented hyperuricemia. In case of symptoms, appropriate treatment (Allopurinol) should be prescribed.

As the risks of acquiring streptomycin-induced nephrotoxicity and ototoxicity are increased in the elderly, the recommended daily dose of streptomycin (10 mg/Kg/day) should not exceed 750 mg/day.

2.9.4 TREATMENT OF LATENT TB INFECTION (PREVENTIVE THERAPY)

Preventive therapy is the medication given to persons who have TB infection, to prevent them from developing TB disease. Isoniazid given for 6 to 12 months is effective in decreasing the risk of future tuberculosis in adults and children with TB infection demonstrated by a positive tuberculin skin test. For adults and children with HIV infection, close contacts of infectious cases and those with fibrotic lesions on chest radiograph, a reaction greater than 5mm is considered positive. For other at-risk adults and children, including infants and children younger than 4 years of age, a reaction greater than 10 mm is positive. For persons who are not likely to be infected with M. tuberculosis, a reaction greater than 15 mm is positive.

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Risk Group Tuberculin reaction size Treatment duration

HIV infected persons 5 mm1 12 monthsClose contacts TB patients 5 mm2 6 months Fibrotic lesions at chest-x ray 5 mm 12 monthsRecently infected persons 10 mm 6 monthsHigh-risk medical conditions3 10 mm 6-12 monthsHigh risk group, < 35 yrs4 10 mm 6 monthsNo high-risk, < 35 yrs 15 mm 6 months

1Anergic, HIV-infected person with an estimated risk of M. tuberculosis infection of 10% may also be considered for isoniazid preventive chemotherapy.

2Tuberculin negative contacts, especially children, should be given chemoprophylaxis for 2-3 months after contact is ended and then retested with PPD-tuberculin. Those remaining negative should stop preventive therapy.

3Includes diabetes mellitus, prolonged therapy with systemic corticosteroids, other immunosuppressive therapy, some hematological and reticuloendotelial diseases, HIV-seronegative injecting drug users, end-stage renal disease, and clinical situations associated with rapid weight loss.

4Includes persons born in high prevalence countries, medically underserved low-income populations, and residents of long-term care facilities.

Persons with a positive skin test and any of the following risk factors should be considered for preventive therapy regardless of age:

persons with HIV infection; persons at risk for HIV infection with unknown status; close contacts of sputum-positive persons; newly infected persons (recent skin converters); persons with medical conditions that increase the risk of tuberculosis

(diabetes mellitus, corticosteroid treatment, other immunosuppressive therapy, intravenous drug users, hematologic and reticuloendotelial malignancies, end-stage renal disease and clinical conditions associated with rapid weight loss or chronic denutrition).

In some circumstances, persons with negative skin tests should also be considered for preventive therapy: children who are in close contact of infectious cases and anergic HIV-infected adults at increased risk for TB. Children younger than 6 months old who have been exposed to infectious TB should take preventive therapy because they are at risk of rapidly developing TB disease and they may have a false-negative tuberculin skin test. The children should be retested when they are 6 months old. If they have a negative skin test and 10 weeks have passed since they were last exposed to TB, the preventive therapy may be stopped.

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Because HIV-infected contacts are managed in a different way comparing to those who are HIV-negative, HIV testing is recommended if there are risk factors for acquisition of HIV infection.

In the absence of any of the above risk factors, persons younger than 35 years of age with a positive skin test in the following high incidence groups should also be considered for preventive therapy:

foreign-born persons from high-prevalence countries; medically undeserved low-income persons from high-prevalence

populations; residents of facilities for long-term care.

The duration of the preventive therapy is of: 12 months for adults and children with HIV infection and other conditions

associated with immunosuppression; 6 months for adult TB contacts without HIV; 9 months for children.In persons with positive tuberculin skin test and silicosis or fibrotic lesions on

the chest x-ray (without evidence of active TB), preventive therapy consists of: 4 months of isoniazid + rifampin or 12 months of isoniazid.Routine monitoring for adverse side effects of isoniazid consist of: in persons younger than 35, monthly symptom review; in persons older than 35, hepatic enzymes should be measured prior to

starting isoniazid and monitored monthly, in addition to symptom review; increased risk of hepatitis is associated with daily use of alcohol, chronic liver disease, drug abuse and certain concurrent medications.

People who may be exposed to TB at their job (health care workers and staff of nursing homes or correctional facilities) should be evaluated for preventive therapy if they have a positive skin test.

Evaluation for preventive therapyAll people being considered for preventive therapy should receive a medical

evaluation: to exclude the possibility of active TB (clinical and x-ray); treating TB

disease with a single drug can lead to drug resistance; to determine whether the patient has ever been treated for TB infection or

disease; if they were adequately treated, they should not be treated again; to find out if the patient has any medical problems that may complicate

therapy or require more careful monitoring (liver diseases, alcoholism).

Alternative regimens for preventive therapyPersons who are presumed to be infected with isoniazid-resistant germs should

be treated with rifampicin for 6 months, rather than with isoniazid.

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Persons at high risk of developing tuberculosis (immunodepressed) who are likely to be infected with multidrug-resistant organisms may receive a preventive therapy with 2 drugs to which the infecting organism is known to be susceptible. Two suggested regimens are ethambutol + pyrazinamide or pyrazinamide + a quinolone (ofloxacin, ciprofloxacin).

2.10. TUBERCULOSIS AND AIDS

2.10.1. EPIDEMIOLOGY

In 1995, worldwide there were 17 million persons with HIV infection. About one third of them were simultaneously infected with tuberculosis and HIV:

- 70% in Africa,- 20% in Asia,- 8% in Latin America.

In some African countries, 20-70% of the TB patients are HIV+, frequently infected with the HIV-2 type. The development of TB is often the first clinical sign of AIDS. In sub-saharian Africa and Asia

- heterosexual spread of AIDS is the commonest, - tB incidence is high and - M. tuberculosis complicates HIV infection in both sexes.

In North America - TB incidence is low, - AIDS patients often develop opportunistic (atypical)

mycobacteriosis or tuberculosis with resistant germs.The risk of HIV infected persons for developing tuberculosis is generally 10

times greater than in non infected ones. when TB infection occurs first and then the person becomes HIV+, the risk of

developing TB is 5-10% per year and 50% for a lifetime; when HIV infection occurs first, 50% of cases develop TB after the primary

infection with M. tuberculosis (within a few months). Once an HIV+ patient becomes also infected with TB, the infection can progress very rapidly and cause clinical disease. TB tends to occur relatively early in the course of HIV infection.The risk factors that influence the occurrence of TB in HIV+ patients are:

the prevalence of latent infection with TB in population, the exposure of HIV+ persons to infectious TB, the degree of immunosuppression, the use of TB preventive therapy.

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2.10.2. DIAGNOSIS OF TB IN HIV+ PATIENTS

The tuberculin skin test in the early stages of HIV infection, the reactivity is maintained; in HIV+

persons, the skin test is interpreted as positive when the transversal diameter of the induration is over 5 mm.

in the late stages of HIV infection, the tuberculin skin test is negative.The skin reactivity to tuberculin, mumps antigen, candida antigen, etc. depends

on the CD4 count in the peripheral blood. To check if a patient with negative Mantoux test is really non-infected with tuberculosis or has a false-negative reaction (is infected but not able to react because of the very low CD4 number), we have to check also for mumps and candida antigens. If a person has a positive reaction to mumps and/or candidin antigens and a negative Mantoux test, we can consider she is not infected with TB. If a person does not react to any of the mentioned antigens, the Mantoux test can be false-negative and we have to be cautious in infirming the diagnosis of TB.

The sputum examination : smears may be negative despite important changes in the chest x-ray. Sputum induction and bronchoscopy (with bronchial aspiration and broncho-alveolar lavage) may be necessary to obtain deep-lung specimens of respiratory secretions for bacteriologic examination.

Clinical features: - fever and weight loss are very common in people with AIDS and TB;- cough and hemoptysis are less common in TB with AIDS;- extrapulmonary TB is common;- miliary TB is more common in HIV+ patients; M. tuberculosis can be

found in blood cultures more often than in HIV negative TB patients;- unusual sites of TB are more often in AIDS patients: tuberculomas of the

brain, TB of the chest wall, etc. In a TB patient we suspect HIV infection if he has the following clinical signs:- general lymph node enlargement (in late HIV stages, nodes are painful

and tender);- candida infection;- chronic diarrhoea;- herpes zoster;- Kaposi`s sarcoma (red vascular nodules on the skin, particularly on the

palate);- generalized itchy dermatitis;- chronic or generalized herpes simplex;- neuropathy (burning feeling in the feet);- persistent genital painful ulceration.

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Chest x-ray (table 11) in the early stage of HIV infection, TB has its usual roentgenographic

appearances: upper lobes location, usual cavitation, rarely mediastinal lymph node enlargement, miliary and pleural or pericardial effusion

in the late stage of AIDS - large mediastinal lymph nodes;- atypical locations: lower lobes;- cavitation is rare;- miliary is frequent;- pleural/pericardial effusion is common.

Table 11 - Chest x-ray aspect in HIV patients

FEATURE EARLY HIV STAGE LATE HIV STAGE

Skin test Positive NegativeAdenopathy

(hilar/mediastinal) Unusual Common

Lung distribution Upper lobes Lower-middle lobesCavitation Present Absent

Extrapulmonary TB 10-15% > 50%The influence of tuberculosis on the course of HIV infection- tuberculosis accelerates the course of HIV infection;- preventive therapy with isoniazid in tuberculin-positive patients delays

the onset of HIV-associated opportunistic infections. Also, survival seems to be prolonged the mechanism of HIV acceleration by M. tuberculosis is increased viral replication stimulated by the immune activation of TB. TB treatment decreases the levels of circulating HIV.

2.10.3. TREATMENT OF TUBERCULOSIS IN AIDS PATIENTS

Because in AIDS patients M. tuberculosis can be more often resistant to one or several TB drugs, all isolated strains should be tested for drug susceptibility. If the TB bacilli are sensitive to the usual first line drugs, a four drug treatment should be started in new cases (category 1) and a five drug combination is indicated for retreatments (category 2) (table 12).

Special features of TB treatment in HIV+ patients

high rate of drug resistance, especially to rifampin, associated with- gastrointestinal symptoms (low absorbtion),- noncompliance to treatment,- low CD4 cell count.

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Table 12 - Treatment of tuberculosis in AIDS patients

TREATMENT CAEGORY INITIAL PHASE CONTINUATION PHASE

New TB cases(category 1)

2 months, daily ISONIAZID (H) 300 mg RIFAMPIN ® 600 mg PYRAZINAMIDE (Z) 2 g ETHAMBUTOL (E) 1250 mg

4 months, 3 times/week ISONIAZID (H) 600 mg RIFAMPIN ® 600 mg

Retreatments (category 2)

2 months, daily ISONIAZID (H) 300 mg RIFAMPIN ® 600 mg PYRAZINAMIDE (Z) 2 g ETHAMBUTOL (E) 1250 mg STREPTOMYCIN (S) 1 g

1month, daily, only the first four drugs (without streptomycin)

5 months, 3 times/week ISONIAZID (H) 600 mg RIFAMPIN ® 600 mg ETHAMBUTOL (15mg/kg/day)

Multidrug-resistant TB(category 3)

18 months from the date when sputum cultures become negative for AFB (a total treatment of 2 years).The first and second line TB drugs are used according to the drug sensitivity tests for the TB bacillus. Treatment must be started with an association of 5-6 drugs.

side effects of the TB drugs are more frequent in HIV+ patients; drug interactions: rifampin interacts with the protease inhibitor class and the

non-nucleoside reverse transcriptase inhibitors (antiretroviral agents). Rifampin accelerates the antiretroviral agents` metabolism resulting in sub-therapeutic concentrations of these drugs. Also, protease inhibitors raise serum concentrations of rifampin, resulting in increased drug toxicity. There are two possibilities of TB treatment in such situations:- a 6 months treatment, starting with 4 drugs, before initiating protease inhibitors therapy, or- a 9 months treatment, starting with 4 drugs, replacing rifampin with rifabutin (150 mg/day only) associated with protease inhibitors (indinavir, nelfinavir).

occurrence of paradoxical worsening of signs and symptoms in patients receiving a combination of TB and antiretroviral therapy: 3-6 weeks after the onset of protease inhibitor therapy, fever occurs associated with lymphadenopathy, new infiltrates and effusions.

2.10.4 PREVENTION OF TUBERCULOSIS IN HIV+ PERSONS

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All persons with HIV infection should have a baseline tuberculin skin test. Annual skin testing should be considered in patients at risk of exposure to TB. A positive tuberculin skin test is defined as larger than 5 mm diameter. Indications of preventive therapy:

- tuberculin-positive individuals, only after active TB has been ruled out,- history of tuberculin positivity without prior prophylaxis,- exposure to infectious TB, regardless of the tuberculin test.

Preventive therapy regimens for HIV+ persons are:- ISONIAZID 300 mg daily for 12 months;- ISONIAZID 10 mg/kg three times/week, 12 months;- RIFAMPIN 600mg/day + PYRAZINAMIDE 20 mg/kg/day, 2 months;- ISONIAZID 300 mg + RIFAMPIN 600 mg daily, 3 months.

2.10.5. PULMONARY COMPLICATIONS OF HIV INFECTION

INFECTIOUS COMPLICATIONS

Viruses - Cytomegalovirus- Varicella zoster- Epstein Barr

Bacteria a) community-acquired: Pneumococcus Haemophylus influenzae Group B streptococci Branhamella catarrhalis Staphylococcus aureus b) hospital-acquired: Staphylococci Aerobic gram-negative rods c) mycobacteriosis: M. tuberculosis

Non - tuberculous mycobacteria (M. avium, M. kansasi, M. xenopi, etc)

Fungi - Candida - Cryptococcus neoformans - Histoplasma capsulatum - Coccidioides immitis - Aspergillus fumigatus Parasites - Pneumocystis carinii - Toxoplasma gondii Malignancies - Kaposi`s sarcoma

- Non-Hodgkin`s lymphoma Interstitial pneumonitis - lymphocytic interstitial pneumonitis

- non-specific interstitial pneumonitisThe main causes of death among persons with HIV infection are:

tuberculosis – 32% septicemia – 11%

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cerebral toxoplasmosis – 10% pneumonia – 8% meningitis – 5% other infections – 10% malignancies – 6%

Pneumocystis carinii pneumonia

P. carinii pneumonia is the most frequent respiratory complication associated with HIV infection. Despite the therapy and prevention with trimethoprim-sulfamethoxazole and pentamidine, the mortality can attend 26% of the cases.

The parasite has an airborne transmission from an unknown reservoir. Pneumonia results from the reactivation of a latent infection acquired early in childhood. The infection involves the alveolar spaces which contain an acellular, eosinophilic material with pneumocystis-adults and trophozoites.

The consequences on the respiratory function include a serious impairment of gas exchange and the reduction in lung volumes (vital capacity, total lung capacity).

Clinical symptoms of the disease occur generally when the CD4 lymphocites count is less than 200/mm3. The disease has a slowly progressive (1 month) evolution with fever, dry cough, dyspnea on exertion. In 80% of cases, LDH is elevated following the severity of infection.

The typical x-ray aspect consists in diffuse alveolo-interstitial pattern, predominant in lung bases. However, P.carinii pneumonia can have an atypical roentgenographic aspect, with focal infiltrates, nodules, cavities or even pneumothorax due to rupture of pneumatoceles (effects of AZT treatment for AIDS).

The diagnosis is established by the microscopic examination of sputum, other pulmonary secretions or lung biopsy.

In the treatment of pneumocystosis, TRIMETHOPRIM-SULFAMETHOXAZOLE is considered the drug of choice; it has the added advantage that its antimicrobial spectrum provides coverage against many bacteria that may cause pneumonia in the same patients. The dose is 20 mg/kg/day, for 3 weeks. The drug is usually administered intravenously during the first few days of treatment and then orally in 4 doses (every 6 hours). Trimethoprim-sulfamethoxazole has important side-effects consisting of fever, rash, neutropenia, thrombocytopenia, leukopenia, hepatitis.

Another option in the treatment of P. carinii pneumonia is PENTAMIDINE. The rate of clinical response is similar with trimethoprim-sulfametoxazole (60-80%) and so is the rate of adverse reactions. Common toxic manifestations include hypotension, tachycardia, azotemia, elevated serum potassium, hepatitis, neutropenia, pancreatitis, hypocalcemia. The dose is 4 mg/kg/day, intravenously, for 21 days.

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The combination DAPSONE-TRIMETHOPRIM appears to be as effective as the options mentioned above for the treatment of mild-moderate P. carinii pneumonia and may be less toxic.

Prophylaxis of recurrence of P. carinii pneumonia after successful initial therapy can be achieved either with trimethoprim-sulfamethoxazole (in lower doses) or with aerosolized pentamidine.

Kaposi`s sarcoma

Kaposi`s sarcoma is the most common HIV-associated malignancy, involving the lung parenchyma, airways, pleura, the hilar or mediastinal lymph nodes and also other extrathoracic organs. A high incidence of the disease was noticed in HIV-positive homosexual men.

The intrathoracic manifestations follow in 95% of cases the muco-cutaneous lesions. Over 60% of patients (2/3 of them) have a coexisting opportunistic infection. The usual respiratory symptoms of Kaposi`s sarcoma are dyspnea, dry cough, fever, chest pain and hemoptysis.

Radiographic abnormalities include four main patterns: interstitial pattern, nodular lesions, pleural effusions on one or both sides of the thorax, hilar and/or mediastinal adenopathy.

The diagnosis of Kaposi`s sarcoma of the lung must be worked up using invasive procedures: bronchoscopy (red or violacious flat or slightly raised lesions) with bronchial

biopsy, thoracentesis and pleural biopsy, percutaneous computed tomographic-directed lung biopsy.

Treatment: in patients with a CD4 cell count greater than 200/mm3, INTERFERON-ALPHA in conjunction with ZIDOVUDINE (AZT) may cause remission. If the CD4 cell count is under 200/mm3, chemotherapy with several agents and radiotherapy are recommended.

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2.11. DISSEMINATED TUBERCULOSIS

2.11.1. CLINICAL FINDINGS

Disseminated (miliary) tuberculosis is a multisystem process, producing a complex of nonspecific symptoms including fever, anorexia, weight loss, weakness and fatigue. In children and immunosuppressed patients, disseminated tuberculosis is a direct result of progressive primary infection. In older persons, however, the pathogenesis is that of bloodstream seeding during recrudescence of previously dormant foci, usually within the lungs.

Physical findings are nonspecific: fever in 75% of cases, with pulmonary findings, hepatomegaly, lymphadenopathy and splenomegaly. Neurologic findings and meningism may dominate when there is meningeal involvement, and there may be detectable ascites when peritonitis is present. The only specific physical finding consists of tubercles in the choroidal coat of the retina, which are visible through an ophthalmoscope. The choroidal tubercles are usually multiple, about one fourth the diameter of the disk, gray-white or yellow in color.

2.11.2 DIAGNOSIS

Because of the nonspecific nature of presenting manifestations, disseminated tuberculosis often poses a difficult diagnostic problem. The typical chest x-ray abnormality consists of uniformly distributed small nodular densities (miliary TB).

Presumably because of more severe systemic effects of the disease, the tuberculin skin test is less frequently positive in miliary tuberculosis than in other forms of the disease. Most studies report only 50% of patients with an initial positive reaction to 5 units of PPD. Because the miliary lesions in the lungs are predominantly interstitial in location, sputum smears and cultures are less likely to demonstrate tubercle bacilli than in usual pulmonary tuberculosis. Acid-fast stains show organisms in 25% to 30% of patients and M. tuberculosis is isolated in 50% to 70%. The definitive diagnosis of disseminated tuberculosis depends on isolation of the organism and/or histology of tissue samples. Bronchoscopy with transbronchial biopsy has a high yield and in most instances should be the next step. In addition, joint, pleural, or peritoneal fluid should be aspirated and subsequent biopsies are indicated; lumbar puncture should be performed if there are neurologic signs or symptoms. Biopsy of liver or bone marrow, with histologic examinations and culture, each has a 40% positive yield.

Disseminated tuberculosis has been associated with a wide range of hematologic abnormalities. Anemia has been noted in 50% of patients with disseminated tuberculosis but is severe (hematocrit less than 30%) only in about 15%. The pattern is usually that of an anemia of chronic disease but may resemble aplastic anemia or myelofibrosis with pancytopenia. Abnormalities of the white blood cells also are encountered, and leukemoid reactions, agranulocytosis and leukopenia are reported. In recent years, there have been several reports of

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disseminated intrav11ascular coagulation, often accompanied by the adult respiratory distress syndrome, occurring in association with disseminated tuberculosis.

With chemotherapy following the same principles as in active pulmonary TB, mortality rates are very low unless meningitis is present. Six to nine - month regimens are effective. Thus, the same regimens recommended for initial treatment of pulmonary tuberculosis can be recommended for extrapulmonary forms. In contrast to pulmonary tuberculosis, however, corticosteroid treatment and surgical interventions may play an important role.

The frequency of extrapulmonary tuberculosis was increasing prior to the HIV epidemic but has gone up considerably in association with HIV. In patients with advanced HIV infection and tuberculosis approximately 60% have extrapulmonary involvement with or without pulmonary disease. Extrapulmonary tuberculosis presents several important problems that differ from those presented by pulmonary disease: it is more difficult to diagnose than pulmonary TB, bacteriologic confirmation usually requires an invasive procedure and it may be life-threatening and if cured, may leave significant residual effects (disseminated, meningitis, pericarditis). Compared with pulmonary tuberculosis, extrapulmonary disease is more common among younger persons; however, there is a progressive increase in case rates with increasing age.

2.11.3. LYMPH NODE TUBERCULOSIS

The presenting manifestations of lymph node tuberculosis depend, in part, on the location of the involved nodes. By far the most frequent site of involvement is the neck, and mediastinal involvement is second; however, any lymph node in the body may be affected.

Typically, the process is first noted as a painless enlargement of one or more of a group of nodes. Although initially discrete and firm, they tend to become inflamed and fluctuant and subsequently drain spontaneously if they are not treated. Mediastinal nodes may compress airways, causing cough, whereas abdominal adenitis may be associated with abdominal pain. Systemic symptoms are generally absent unless there is other involvement.

The differential diagnosis can be extensive, ranging from cat-scratch disease to lymphoma. However, in a young, otherwise healthy patient with a positive tuberculin test, the diagnosis is usually apparent. When there is doubt, excisional biopsy or aspiration may be necessary. Cultures are positive in only 50% to 60% of cases thought to be tuberculous. In children, because of the greater frequency of adenitis caused by nontuberculous mycobacteria, culture of the organism is essential.

Chemotherapy is nearly always successful. However, resolution of the clinical findings is slow, and nodal enlargement and inflammation persist for many months. During the initial months of chemotherapy, the response is considered adequate if

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the condition does not worsen. Surgery rarely is needed, except to provide diagnostic material. If a fluctuant node appears to be ready to erode through the skin, however, drainage is indicated.

2.11.4 GENITOURINARY TUBERCULOSIS

The symptoms produced by genitourinary tuberculosis depend, in large part, on the specific site of involvement. Typically, urinary symptoms predominate over systemic symptoms and dysuria, urinary frequency, hematuria and, occasionally, flank pain are the most frequent complaints. In males with lower urinary tract involvement, epididymitis, orchitis, or prostatitis may be the causes of the initial manifestations.

In women, infertility, pelvic pain, and menstrual irregularity may be presenting complaints. In women, involvement of the reproductive organs without concomitant renal tuberculosis is more common than in men. Constitutional symptoms also may occur but are more common when there is extragenitourinary involvement.

The urinalysis shows abnormalities in the majority of patients. The combination of pyuria in an acid urine without detection of pyogenic bacteria in culture is highly suggestive of tuberculosis. When genitourinary tuberculosis is suspected, at least three morning urine specimens should be obtained for direct examination and cultures. In some patients with tuberculosis in other sites, especially the lung, urine cultures may grow M. tuberculosis in the absence of evidence of urinary involvement.

Renal tuberculosis originates in the cortex of the kidney. Parenchymal destruction may occur, causing spread into the medulla and associated papillary necrosis or cavitation. The inflammation and scarring also may involve the collecting system and ureters, with subsequent stricture formation and hydronephrosis. Involvement of the bladder can cause scarring and contraction.

Chemotherapy is highly successful in the genitourinary type. Rarely, nephrectomy may be indicated because of intractable pain, chronic pyogenic infection in a nonfunctioning kidney, hematuria, or persistent tuberculous disease caused by multidrugresistant mycobacteria.

2.11.5 BONE AND JOINT TUBERCULOSIS

Skeletal tuberculosis most frequently involves the spine (50% to 70%), but any bone or joint in the body may be affected. Multiple lesions also may occur and may be difficult to distinguish from metastatic neoplasm. Pain is the usual presenting complaint, although the process is usually more indolent than is septic arthritis or osteomyelitis. Soft tissue swelling may also occur but usually fits the pattern of a "cold abscess" without apparent erythema or tenderness. In most instances, bone involvement occurs together with joint space invasion; thus, arthritic symptoms

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may predominate. Spinal tuberculosis also may be associated with abscess formation in the paraspinous tissues and within the confines of the spinal canal. The latter occurrence can cause nerve root or spinal cord compression, sometimes with severe neurologic sequelae, including paraplegia.

Radiographically, skeletal tuberculosis cannot be distinguished with certainty from other chronic infectious processes and, as was noted earlier, it may occasionally mimic metastatic neoplastic lesions. Typically, the radiographic picture is one of concurrent lysis and sclerosis of bone, with articular cartilage destruction indicated by narrowing of the joint space. In the spine, this is most commonly seen in the lower thoracic or upper lumbar vertebrae in adults, and in the thoracic vertebrae in children. With progressive bone destruction, the anterior portions of adjacent vertebrae collapse, producing a gibbous deformity. Computed tomographic scanning of the spine is a more sensitive means of detecting both bone lesions and paraspinous abscesses than is conventional radiographic examination.

Although a strong presumptive diagnosis of skeletal tuberculosis may be made on the basis of radiographic findings, final diagnosis usually requires a positive tuberculin skin test, evident tuberculosis elsewhere, or biopsy confirmation. Aspiration of joint fluid and needle or open biopsy of bone lesions or synovium usually provides histologic and bacteriologic confirmation of the diagnosis.

The basic principles of chemotherapy for pulmonary tuberculosis apply to skeletal disease. Surgical intervention is usually unnecessary. Surgical decompression and debridement, sometimes accompanied by vertebral fusion, may be essential in spinal tuberculosis that is causing progressive neurologic abnormalities. Other involved joints should be immobilized and prevented from bearing weight.

2.11.6 CENTRAL NERVOUS SYSTEM TUBERCULOSIS

In spite of the effectiveness of specific chemotherapy, tuberculous meningitis remains a lethal condition with mortality rates of 25% and even more. The poor prognosis is caused in part by the long duration of the process before therapy is started. The symptoms usually evolve over a period of several weeks to months and include fever, malaise and anorexia; these progress to headaches, behavioral changes, stiff neck, photophobia and, finally, seizures and coma. Physical findings may consist of fever, nuchal rigidity, papilledema, choroidal tubercles and focal neurologic signs. Cranial nerve palsies are common. Focal neurologic signs also may be present in patients with isolated tuberculomas without meningitis. Tuberculomas may also involve any area of the spinal cord, producing symptoms relating to the site of the lesion. More than 50% of patients with tuberculous meningitis have evidence of tuberculosis elsewhere, whereas those with tuberculomas usually have no other evident sites of disease.

Lumbar puncture in patients with meningitis typically shows an increase in cerebrospinal fluid pressure. The fluid itself contains 10 to 1000 white blood cells

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per mm3 that are predominantly mononuclear leukocytes, an increased protein concentration, and a decreased glucose concentration. Protein concentrations may be extremely high, depending on the intensity and duration of the illness. Acid-fast staining of cerebrospinal fluid smears shows organisms in only a small number of patients, and the organism is isolated in cultures in 30% - 50% of cases.

There are no specific radiographic findings associated with tuberculosis of the central nervous system. In children, however, there may be radiologic evidence of intracranial hypertension. Computed tomographic examination of the head is a sensitive means of detecting tuberculomas.

Treatment should be started promptly in all patients in whom central nervous system tuberculosis is proved or strongly suspected. Isoniazid and rifampin, and to a lesser extent streptomycin, ethambutol and pyrazinamide penetrate inflamed meninges sufficiently to provide adequate cerebrospinal fluid concentrations. Corticosteroids are especially beneficial in patients with more severe neurologic impairment, especially those with cerebral edema or high CSF protein concentration.

A poor prognosis in tuberculous meningitis correlates with increasing age, with the presence of coma or confusion at the time of diagnosis and with increasing protein concentrations in the cerebrospinal fluid. The effects of these factors are reflected in both death rates and frequency of neurologic residua.

2.11.7 .GASTROINTESTINAL TUBERCULOSIS

Tuberculosis of the gastrointestinal tract, abdominal organs and peritoneum are rare TB locations that often are diagnosed during invasive investigation for abdominal diseases of unknown etiology. Any portion of the digestive tract from mouth to anus may be involved, although lesions proximal to the terminal ileum are extremely unusual. The sites of most common occurrence are the terminal ileum, cecum and rectum. In the ileum and cecum, presenting manifestations are usually pain and/or intestinal obstruction, whereas rectal lesions may be manifested as fistulas, fissures or abscesses. Radiographically, the lesion may be impossible to distinguish from neoplasm or inflammatory bowel disease and in most patients, the diagnosis is made during surgery.

Tuberculous involvement of the peritoneum is manifested most frequently with abdominal pain, often accompanied by abdominal swelling. Fever, weight loss, and anorexia are also common. Combination of these symptoms is usually present several months before the diagnosis is made. Radiographic evidence of pulmonary tuberculosis (current or old), when present, can sustain the diagnostic suspicion.

Ascitic fluid from patients with tuberculous peritonitis typically is exudative. It should be kept in mind, however, that when hypoalbuminemia is present, the protein content of the fluid may be less than 3.5 g per deciliter and yet be an exudate. White blood cells are predominantly lymphocytes. Acid-fast organisms

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are seen rarely on stained smears of ascitic fluid and the frequency of positive cultures varies between 30% and 50%. Histologic examination and culture of peritoneal tissue provide the best diagnostic yield. Laparoscopy or limited laparotomy is the preferred technique and allows directed biopsies. Because of abdominal pain or mass, laparotomy often is performed for diagnostic purposes. When findings compatible with tuberculosis are encountered during laparotomy, specimens should be obtained for both histologic and bacteriologic evaluations.

Antituberculosis chemotherapy is quite successful in treating any form of gastrointestinal tuberculosis, but the frequency of bowel obstruction because of fibrotic residua is not established. Corticosteroids are recommended for prevention of severe fibrosis.

2.11.8. PERICARDIAL TUBERCULOSIS

Tuberculous involvement of the pericardium is an uncommon - but potentially lethal - form of extrapulmonary tuberculosis. The symptoms, physical findings, and laboratory abnormalities associated with tuberculous pericarditis may be the result of the infectious process itself or of the pericardial inflammation causing pain, effusion, and hemodynamic effects. The systemic symptoms produced by the infection are nonspecific: fever, weight loss and night sweats are common. Symptoms of cardiopulmonary origin tend to occur later and include cough, dyspnea, orthopnea, ankle swelling and chest pain; often pain is affected by position and worsens on inspiration.

Apart from fever, the most common physical findings are those caused by the pericardial fluid (cardiac tamponade) and/or fibrosis (constriction). Definitive diagnosis of tuberculous pericarditis requires identification of the tubercle bacillus in pericardial fluid or tissue. Although not absolutely conclusive, demonstration of caseating granulomas in the pericardium in the presence of consistent clinical circumstances provides evidence of a tuberculous etiology. Less conclusive evidence is the finding of another form of tuberculosis in a patient with pericarditis of undetermined etiology. We can also suspect TB in the case of a patient with a positive tuberculin skin test and pericarditis of unproved etiology.

Tubercle bacilli are identified in pericardial fluid in less than 30% (smear and culture combined). Biopsy of the pericardium with both histologic and bacteriologic evaluation is more likely to provide a diagnosis. Approximately 25% of patients with tuberculous pericarditis have evidence of other organ involvement when the pericarditis is diagnosed. Because of the potentially life-threatening nature of pericardial tuberculosis, treatment with antituberculosis agents should be instituted as soon as the diagnosis is made or strongly suggested. The probability of cardiac constriction is greater in patients who have had symptoms longer. Therefore, early therapy may reduce the incidence of this complication. Corticosteroids are valuable in treating patients with tuberculous pericarditis - those with effusion as well as those with constrictive pericarditis. The doses are in

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the range of 60 to 80 mg of prednisone given daily for the first 4 weeks with a gradually decreasing dose during the next 6 to 8 weeks.

If hemodynamic compromise occurs, pericardiectomy may be necessary. Although pericardiocentesis generally improves the circulatory status, the improvement is usually temporary. The longer the effusion persists, the thicker and more adherent is the pericardium, and the more difficult the pericardiectomy. In general, if venous hypertension persists beyond 6 months because of pericardial disease, pericardiectomy is indicated. With proper therapy, mortality from TB pericarditis is probably in the range of 20% and constriction occurs in about 15%.

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CHAPTER 3

PLEURAL DISEASES

3.1. PLEURA: STRUCTURE AND FUNCTION

The pleura is a thin membrane lining the interior surface of the chest wall, the superior surface of the diaphragm, the lateral aspect of the mediastinum (parietal pleura) and enveloping the lungs (visceral pleura); the interlobar fissures are also lined by visceral pleura. The visceral and parietal pleurae become continuous at the hila, creating two anatomically distinct potential spaces in each side of the thorax. In conclusion,

the serous membrane covering the lung parenchima is called the visceral pleura;

the serous membrane covering the chest wall, the diaphragm and the mediastinum is called the parietal pleura.

The pleural space lies between the lung and the chest wall and normally contains a thin layer of fluid that serves as a coupling system between lungs and the rib cage. Fluid is removed from the pleural cavity via the lymphatics situated in the parietal pleura. In healthy individuals this fluid is probably less than 10 ml in each pleural space; the fluid contains 1.5 to 2g of protein/dl and about 4500 cells/ml (predominantly mesothelial cells, monocytes, lymphocytes and a few granulocytes).

The lymphatics have the capacity to absorb 20 times more fluid than is normally formed. Even though 600 to 800 ml is formed per day in healthy individuals, the pleural space is kept relatively free of fluid.

3.2. CLASSIFICATION OF PLEURAL DISEASES

There are four main types of pleural diseases: pleural effusions: the presence of fluid in the pleural space; pleuritis: acute pleural inflamation with no significant effusion; fibrothorax: thickening of the pleura; pneumothorax: the presence of air in the pleural space.

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3.3. PLEURAL EFFUSIONS

3.3.1 PATHOPHYSIOLOGY

Pleural fluid accumulates when pleural fluid formation exceeds absorbtion. Normally, fluid enters the pleural space from:

the capillaries in the parietal pleura, the interstitial space of the lung via the visceral pleura, the peritoneal cavity via small holes in the diaphragm.A pleural effusion may develop when the balance of formation and absorption

is upset to favor fluid formation. Excess fluid or pleural effusion is formed in the following situations:

when excessive hydrostatic pressure in the visceral pleura exists (cardiac failure),

when reduced osmotic pressure decreases reabsorption of fluid (nephritic syndrome),

when the lymphatics draining the visceral pleura are obstructed (central carcinoma),

when the permeability of the visceral or parietal pleura is disrupted (inflammation, carcinomatous involvement).

The first two situations characteristically produce a transudate, but the latter two produce an exudate.

3.3.2 THE PLEURAL SYNDROME Symptoms: small pleural effusions can be asymptomatic. The predominant

clinical manifestation of pleural disease is pleuritic pain, which is characteristically "sharp" or "cutting" and associated with respiration. The pain increases on inspiration and decreases on expiration. Deep breathing, coughing and sneezing are particularly painful, but pain may also be exacerbated by body movement. The pain is generally well localized to the adjacent area of disease, but pleuritic pain may also be referred to the abdomen or to the shoulder. The combination of low chest pain and ipsilateral shoulder pain is highly suggestive of diaphragmatic pleural disease. When pleuritic pain presents with its classic characteristics, it is generally not difficult to determine its origin, but it may be mistaken for extrathoracic, particularly subdiaphragmatic, pathology.

Other symptoms frequently associated with pleural disease are dyspnea, cough, and fever. Dyspnea may be the presenting symptom, since pleuritic pain may have been transient or not present at all in patients with chronic effusions. Dyspnea is often more severe if the effusion has collected rapidly or if a large effusion exists, because compression of the lung results in a restrictive ventilatory defect. Dispnea is worse when the patient lies on the healthy side.

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Dyspnea and cough are often manifestations of "mediastinal shift," when the mediastinal contents are shifted to the unaffected side. Cough, when present, produces little or no sputum unless concomitant parenchymal disease is present. Fever often accompanies infection but may also be a manifestation of pulmonary infarction, neoplastic or collagen vascular disease.

Physical examination: Examination of the chest should be accompanied by a general examination,

including the recording of lymphadenopathy, finger clubbing, skin lesions, signs of cardiac failure, or abdominal features that would help determine the cause of pleural involvement.

- inspection – a massive pleural effusion may cause bulging of the intercostal spaces; movements of the chest wall are reduced or absent;

- palpation – decrease in tactile fremitus;- percussion –"dullness" or "flatness" over the fluid;- auscultation – breath sounds are decreased or absent over the effusion;

decreased vocal fremitus and resonance; pleural friction rub occurs in pleuritis and at the onset or the end of a pleural effusion.

Physical signs are absent if less than 200-300 ml of pleural fluid is present.

3.3.3. DIAGNOSTIC TESTS

The chest x-ray is the first approach in evaluating pleural disease but can be aided by ultrasound or computed tomographic (CT) scans in confusing situations. On postero-anterior films, at least 300 ml of fluid must be present before the costophrenic angle becomes blunted, although a lateral film may reveal an opacification of the posterior costophrenic angle before any abnormality is seen on the postero-anterior chest radiograph. By the time the typical appearance of a small effusion develops in the erect adult, at least 1 L of fluid is present.

Radiologically, this appearance includes the loss of the contour of the diaphragm, which is now replaced by a concave opacity; in large effusions, half the hemithorax or more may be opacified and the consequent increased pressure may result in displacement of the mediastinum to the contralateral side. Fluid may be confirmed by a lateral decubitus film with the patient lying on the affected side. In this position, effusions of 100 ml or less may be detected.

Atypical appearances of effusions occur when there are pleural adhesions, when the fluid loculates, or when air and fluid are within the pleural cavity (hydropneumothorax). Occasionally, fluid is present in the interlobar fissures and may form a pseudotumor, which disappears when the fluid is reabsorbed.

Pleural ultrasound - is a particularly useful technique for determining the location of fluid in the presence of loculated effusions, to help in draining either pus or blood from the pleural space.

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Computed tomography - is particularly useful in evaluating pleural disease in areas not well visualized on conventional radiographs. The extent of pleural effusions can be well defined, and mass lesions frequently can be distinguished from fluid to guide needle biopsy or drainage of fluid.

Thoracentesis - should be performed when the cause of the pleural effusion is not apparent, if empyema (accumulation of pus in the pleural space) is suspected, or if the effusion is producing dyspnea. The gross appearance of the fluid is important, particularly in determining if the fluid is uniformly blood stained. Empyema or chylous effusions may be recognized at the time of the procedure. The importance of the initial thoracentesis is to differentiate between a transudate, which does not require further investigation, and an exudate, which indicates inflammation or malignancy.

Laboratory tests of pleural fluid should include total and differential white blood cell count, protein, glucose and LDH. A high percentage of lymphocytes in pleural fluid suggests tuberculosis (as does the absence of mesothelial cells) or cancer. Low levels of glucose in pleural fluid point toward cancer, empyema, tuberculosis, esophageal rupture, or connective tissue disease (rheumatoid pleuritis or systemic lupus erythematosus pleuritis). Elevated levels of amylase in pleural fluid suggest one of four diagnoses: pancreatitis, pancreatic pseudocyst, pancreatic cancer, or esophageal rupture.

Pleural biopsy - If the cause of an exudate is not determined by initial examination of the fluid, pleural biopsy using Abrams or Cope needle should be undertaken to provide more material for histology and culture. Contraindications include bleeding diathesis, poor respiratory reserve, empyema and absence of pleural fluid. The yield of the procedure approximates 55% in pleural malignancy and over 75% in pleural tuberculosis if the tissue fragments are submitted for culture as well as histology.

Thoracoscopy - with a flexible or rigid instrument provides direct visualization of the visceral and parietal pleura on the lateral and the diaphragmatic areas - is used to evaluate effusions of undetermined etiology and increase the diagnostic yield.

Thoracotomy is sometimes needed to acquire large specimens for analysis and establish the diagnosis of pleural malignancy. It is especially indicated for the diagnosis of malignant pleural mesothelioma. Despite investigation, 5% to 15% of pleural effusions remain undiagnosed.

3.3.4.CLASSIFICATION OF PLEURAL EFFUSIONS

According to their etiology, pleural effusions can be: primary pleural diseases (very rare) or secondary pleural involvement in other diseases.The predominant causes of pleural effusions are congestive heart failure,

neoplastic disease and infections.

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According to the type of fluid, a pleural effusion can be: transudate - Mechanisms leading to formation of transudates include increase

in hydrostatic pressure (congestive heart failure), decreased oncotic pressure (hypoalbuminemia) and greater negative intrapleural pressure (acute atelectasis).

exudate - form as a result of disease of the pleura itself in association with increased capillary permeability (pneumonia) or reduced lymphatic drainage (carcinoma obstructing lymphatic drainage).

empyema - is an exudative pleural effusion caused by direct infection of the pleural space, causing the pleural fluid to appear purulent or turbid.

hemorrhagic (hemothorax) – Hemotorax is the presence of gross blood in the pleural space, usually a result of chest trauma. If the hematocrit of pleural fluid is more than 50% of the hematocrit of peripheral blood, hemothorax is present. Hemorrhagic pleural effusion is a mixture of blood and pleural fluid.

chylous or chyliform effusion - Pleural fluid milky in appearance should be centrifuged. Clearing of the milky appearance from the supernatant suggests empyema, whereas persistent cloudy or turbid supernatant signifies chylous pleural effusion.

Pleural effusions are classified as transudates or exudates to help in differential diagnosis and to allow appropriate therapy.

An exudate is a pleural fluid having one or more of the following features: pleural fluid protein > 30g/L; pleural fluid protein to serum protein ratio > 0.5; pleural fluid LDH to serum LDH ratio > 0.6; pleural fluid LDH greater than two-thirds the upper limit of normal serum

LDH.Transudates lack the distinguishing protein and LDH findings described

above and often have other typical characteristics (white blood cell count < 1000/uL, predominance of mononuclear cells in the differential, glucose level in pleural fluid equal to that of serum and normal pH). Main causes of transudates and exudates are listed in table 13.

3.3.5 TRANSUDATIVE PLEURAL EFFUSIONS

Transudates suggest the absence of local pleural disease; more than 90% are due to congestive heart failure. Effusions resulting from congestive heart failure are frequently bilateral, but if unilateral, the right side is more frequently affected. If the signs of cardiac failure are florid, thoracentesis is not necessary unless another cause is suspected. Effusions secondary to cardiac failure usually decrease with successful treatment of the underlying disease.

Constrictive pericarditis and superior vena caval obstruction may be associated with either transudate or exudate.

Table 13 - Clasification of pleural effusions

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TransudatesA. Increased hydrostatic pressure

1. Congestive heart failure2. Constrictive pericarditis3. Superior vena caval obstruction

B. Decreased oncotic pressure1. Hypoalbuminemia

a. Nephrotic syndromeb. Cirrhosis

2. Intra-abdominal diseaseCirrhosis with ascites

ExudatesA. Infections

1. Parapneumonic empyema or effusion2. Tuberculosis3. Fungi4. Parasites5. Viral

B. Neoplasms1. Bronchogenic carcinoma2. Metastatic carcinoma3. Lymphoma and leukaemia4. Mesothelioma

C. Pulmonary emboli and infarctionD. Intra-abdominal disease

1. Subdiaphragmatic abscess2. Pancreatitis3. Meigs' syndrome

E. Connective tissue and hypersensitivity disease1. Rheumatoid arthritis2. Lupus erythematosus3. Dressler's syndrome4. Drug reaction

F. Miscellaneous1. Esophageal rupture2. Lymphedema3. Myxedema4. Atelectasis5. Uremia

G. IdiopathicHemothoraxLipidic

A. Chylous

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Transudates caused by a reduced oncotic pressure (hypoalbuminemia) are seen in nephrotic syndrome or cirrhosis. Ascites is usually present. Patients with nephrotic syndrome usually have bilateral effusions that reaccumulate after thoracentesis unless the underlying cause is treated. The effusion associated with ascites resulting from cirrhosis is right sided in two thirds of patients, left sided in one sixth, and bilateral in another sixth. Occasionally, thoracentesis is necessary, but the effusions usually respond to diuretic therapy or when the liver disease improves. The fluid is transported through the diaphragm, so paracentesis may be helpful in relieving the pleural effusion.

Small pleural effusions may develop in patients undergoing peritoneal dialysis. The fluid is similar to the dialysate and is reabsorbed when dialysis is terminated.

3.3.6. EXUDATIVE PLEURAL EFFUSIONS

Parapneumonic effusions They frequently occur with bacterial pneumonias and may also accompany

lung abscess or bronchiectasis. These effusions may be sterile or may contain infectious organisms. The common organisms responsible for empyema reported in recent series are anaerobes (often more than one organism), Staphylococcus aureus, Pseudomonas species, and Escherichia coli. Streptococcus pneumoniae is less often identified as a causative organism since the advent of effective antibiotics, although parapneumonic effusions are seen in 40% to 60% of patients with pneumococcal pneumonia. It is important to examine a parapneumonic effusion early to determine whether it is likely to resolve with appropriate antibiotic therapy or whether tube drainage is required; sterile effusions can usually be managed with thoracentesis alone. A white cell count greater than 15 000/mm3 or a pH less than 7.3 suggests that tube drainage will decrease the morbidity produced by the effusion. Once empyema has developed, drainage of the pleural space is almost always necessary to effect a bacteriologic cure and preserve pulmonary function. Empyema may also be a complication of thoracic surgery, trauma, or ruptured esophagus. Recognition of the underlying condition and drainage of the pleural space are important in the successful management of these patients.

Parapneumonic effusion usually responds to systemic antibiotic therapy. A common management decision is whether to drain a parapneumonic effusion via tube thoracostomy. The therapeutic intent of drainage is to avoid progression of the effusion from the exudative to subsequent (fibrinopurulent and organized) stages. The goal is to avoid pleural thickening that may trap the lung and cause permanent loss of lung function. Uncomplicated parapneumonic effusion (no pleural infection is present) is likely to resolve spontaneously, and chest tube drainage is not required.

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In complicated parapneumonic effusion, pleural fluid is either frank pus or has the potential to organize into a fibrous "peel." Tube thoracostomy is required for parapneumonic effusion if any of the following is present:

- the fluid resembles frank pus or bacteria are seen on Gram stain, - pleural fluid glucose is < 50 mg/dL, - pleural fluid pH is < 7.2 and the LDH is > 1000 units/L. Serial thoracentesis

is not an effective strategy for treatment of complicated parapneumonic effusions.A parapneumonic effusion that does not respond to drainage within 24 hours

may have become loculated. In such cases, ultrasound examination is required to guide placement of an additional chest tube in the proper location. Open surgical drainage may be necessary if these measures are ineffective.

Tuberculous pleural effusion Bacillary pleural effusion may be either a serous exudative pleurisy or a

frank tuberculous empyema. The former is associated with a small inoculation of tubercle bacilli into the pleural space when a subpleural, caseous focus ruptures, with a subsequent hypersensitivity response to the tuberculoprotein of the organisms; usually the pulmonary parenchyma appears normal on chest radiograph.

Serous exudative effusion occurs within 3 to 6 months of the primary infection, and most patients are reactive to tuberculin, although a negative skin test does not exclude the diagnosis. Clinically the presentation may be acute, with fever and chest pain of a few days' duration, or subacute, with symptoms of up to a month's duration; less frequently the symptoms may have persisted for longer. As pleural fluid increases, the pain tends to decrease, and, in the majority of cases, the process resolves spontaneously. In the vast majority of patients the effusion is small to moderate in size and unilateral (figure 40).

Tuberculous pleurisy is still a frequent finding in the developing world. It is also an important diagnosis to make because, although the natural history of tuberculous pleurisy results in resolution in the early phase, 45% to 65% of patients will proceed to active pulmonary tuberculosis if untreated.

Analysis of the fluid usually shows a very high protein content (more than 5 g/dl) and a lymphocyte predominance (>80%) in the white cells. Occasionally a polymorphonuclear predominance is seen early in the disease. Glucose and lactate dehydrogenase (LDH) levels are not helpful in distinguishing tuberculous from malignant effusions. Only rarely are acid-fast bacilli seen on smears of pleural fluid. Cultures of the fluid yield the organism in approximately 40% to 50% of specimens. Needle biopsy of the pleura, with culture of the biopsy specimen in addition to histologic examination, provides the diagnosis in 75% to 80% of cases. In spite of the relatively low yield of the standard bacteriologic procedures, the diagnosis can be established presumptively in the presence of compatible pleural fluid findings and a positive tuberculin test result. In this situation, even in the absence of bacteriologic confirmation, the patient should be treated for tuberculous pleuritis. Corticosteroids may cause more rapid resolution of the effusion and less

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residual pleural scarring, but such scarring only rarely presents a problem in any event.

Figure 40 - Tuberculous right pleural effusionThere is a homogenous opacity, well delimited, in the right costophrenic angle and

the lower part of the right pleural cavity.

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Tuberculous empyema is a much less common form of pleural involvement. This is a more chronic, indolent process that is usually associated with active pulmonary parenchymal tuberculosis and is the result of a bronchopleural fistula. The fluid is occasionally green in color and is less viscid than frank pus, or it may appear to be indistinguishable from empyema caused by other organisms. The bacteria are usually seen on direct acid-fast smear; cultures are positive. Tube drainage is necessary and may need to be prolonged. If not drained, the empyema may erode directly through the chest wall (empyema necessitatis).

Tuberculous pleural effusion needs specific chemotherapy with an association of three or four drugs during six months.

Pyopneumothorax is seen as a complication of suppurative lung disease, tuberculosis, or ruptured esophagus. Large-tube thoracostomy drainage is required to prevent the development of fibrothorax. Hemopneumothorax may occur after trauma to the chest, and chest tube drainage is required, as for hemothorax

Pulmonary infections caused by Actinomyces israelii and Nocardia asteroides are frequently associated with an empyema that may penetrate through the chest wall to present as a subcutaneous swelling or a draining sinus. Both are subacute or chronic diseases; N. asteroides is more common in immunosuppressed patients. The diagnosis of A. israelii is suggested by the presence of sulfur granules in the pleural fluid or draining sinuses, and confirmation is obtained by culture. Nocardiosis may be associated with hematogenous dissemination and a less favorable outcome. Patients with actinomycosis are best treated with high-dose penicillin but also respond to prolonged tetracyline or lincomycin therapy. Those with nocardiosis are treated with sulfonamides.

Viral diseases and Mycoplasma pneumonias may be infrequently accompanied by effusions that are usually small and resolve without specific therapy. Rarely, Mycoplasma pneumonia is associated with a larger effusion, and thoracentesis is required to exclude the development of empyema. Coxsackievirus B infection producing pleurodynia may be associated with a small pleural effusion for which no specific therapy is required.

Parasitic infections that may produce pleural exudates include amebiasis when the right-sided effusion is the result of either sympathetic effusion or rupture of a liver abscess through the diaphragm to produce an empyema. The diagnosis may be suspected in endemic areas and confirmed by demonstrating a liver abscess in the presence of hemagglutination tests. Treatment is usually satisfactory with antiamebic drugs, but occasionally surgical drainage is required. Hydatid disease of the lungs or liver, caused by Echinococcus granulosus, may sometimes be complicated by pleural involvement.

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Malignant pleural effusion is the most common cause of exudative effusion, particularly in older patients and when the effusion is moderate to massive in extent. The leading cause of malignant effusion is lung cancer, followed by breast carcinoma and then lymphoma; ovarian and other carcinomas, sarcomas, and pleural tumors are less frequent causes. If bilateral effusions are present, the cause is more likely metastatic carcinoma than bronchogenic carcinoma. The mechanisms responsible for malignant effusion are increased permeability caused by pleural metastases involving visceral or parietal pleura and lymphatic obstruction resulting in impaired pleural lymphatic drainage. Most malignant effusions are symptomatic, the most common symptoms being cough, chest pain, and dyspnea, anorexia, weight loss and general malaise.

The diagnosis of malignant pleural involvement may be confirmed by cytologic examination of the fluid or by pleural biopsy (figure 41). Repeat aspiration and biopsy result in a diagnostic yield of up to 80%. Bronchoscopy and diagnostic thoracoscopy has increased the yield to more than 90% in some centers. It is important to establish if malignant cells are present in the effusion because this indicates that curative surgery is not feasible. Management of patients with malignant effusion caused by lung cancer depends on the identification of the primary tumor. If the primary is likely to be responsive to chemotherapy, this treatment may provide cure or long-term palliation. If the primary tumor is not chemosensitive and the effusion is causing symptoms, drainage of the pleural space and pleurodesis may be helpful. If the lung re-expands well with thoracentesis, chemical pleurodesis is worth attempting in selected patients. Various chemical irritants have been tried: tetracycline, bleomycin, doxycycline and more recently, insufflation of talc at thoracoscopy is very effective in producing pleurodesis in patients whose effusions can be drained with good expansion of the underlying lung.

The management of patients with metastatic carcinomas and lymphomas producing pleural effusion depends on the treatment of the primary tumor. Chemical pleurodesis or radiation therapy may be useful in controlling symptoms. Small effusions that do not produce significant symptoms do not need specific therapy.

Malignant mesothelioma is a rare tumor, associated with asbestos exposure. It occurs most frequently in asbestos workers, particularly in the manufacturing industries. The interval between first exposure and presentation with the tumor is usually 25 to 45 years. Initially, discrete plaques and nodules of firm tumor occur in the pleura; these progress to produce adherent parietal and visceral pleura, which encases and constricts the lung. Invasion of the chest wall or pericardium may occur. The diagnosis may only be confirmed by open biopsy. Special stains and electron microscopy may be necessary to differentiate the tumor from adenocarcinoma.

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Figure 41 - Neoplastic pleural effusionLarge, homogenous, opacity in the inferior part of the left peural cavity. Pleural

shadow in the right costophrenic angle.

Clinical presentation usually occurs in patients over age 40 years, with insidious onset of dyspnea and chest pain. Weight loss and a dry cough develop with progression of the disease. Clinically and radiologically, a pleural effusion usually is found. After drainage, irregular pleural thickening may be seen in association with loss of volume of the underlying lung. This may be better visualized on a chest CT scan, when any pericardial or mediastinal involvement can also be appreciated. The pleural fluid is yellow or serosanguineous. It is seldom possible to confirm the diagnosis on cytologic examination alone. The prognosis is poor because these tumors are relatively unresponsive to chemotherapy or irradiation. Occasionally, excision of the pleura is successful in prolonging survival, and this modality should be considered if an open biopsy is undertaken.

Benign mesotheliomas remain localized and produce large, well-circumscribed globular masses, and only 10% are associated with pleural effusions. About 50% of these tumors are asymptomatic, but 20% are associated with hypertrophic

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osteoarthropathy. Diagnosis is made at thoracotomy, when the treatment is surgical excision.

Pulmonary infarction occurs in 30% to 50% of patients with pulmonary embolism and is often accompanied by a pleural effusion. Pleuritic chest pain, usually of abrupt onset and associated with dyspnea and hemoptysis, is present in about 80% of cases. Radiologically the effusion may be associated with a parenchymal infiltrate and bilateral effusions may be seen. The fluid usually has the characteristics of an exudate and is blood stained in 50% of patients.

Intra-abdominal diseases - Diseases of the gastrointestinal tract sometimes produce exudative pleural effusion. Pancreatic disease is frequently complicated by effusion; acute pancreatitis is associated with pleural effusion in nearly 20% of patients. The effusion is most often on the left side. The mechanism may be:

- transdiaphragmatic transfer of fluid arising from the pancreatic inflammation, - or a sinus tract formation between the pancreatic bed and the pleura. The fluid, which is often serosanguineous, frequently has very high amylase

levels. Persistence of the effusion after the pancreatitis has resolved suggests the possibility of pancreatic abscess or pseudocyst. In these patients the effusion may be resolved only by a surgical approach to the pancreatic disease.

Subphrenic abscess is a complication of gastrointestinal surgery, splenectomy, and exploratory laparotomy for trauma. Approximately 50% of subphrenic abscesses are associated with a pleural effusion, which usually has a high white cell count and is sterile. CT scan or ultrasound may be helpful in demonstrating the subphrenic fluid collection. If a right-sided effusion is present, the possibility of intrahepatic abscess, either pyogenic or amebic, should be considered.

Meigs' syndrome is the association of a pelvic neoplasm with ascites and pleural effusion. It was originally described with benign fibromas of the ovary but has been associated with other benign pelvic tumors. The exudative effusion is characteristically right sided but may be bilateral. The ascites is not always detected clinically unless the pelvic tumor is large. The syndrome resolves after removal of the tumor.

Connective tissue disease - About 5% of patients with rheumatoid arthritis develop pleural effusions; this finding is more common in males and in older patients with a long history of arthritis and subcutaneous nodules. The effusion characteristically produces symptoms of pleuritic pain and usually is small to moderate in size and unilateral. One third of patients have associated intrapulmonary manifestations of rheumatoid arthritis. The fluid generally is yellow and may be turbid; lymphocytes predominate. Characteristically the fluid glucose level is very low (usually <20 mg/dl), the pH is low (< 7.20) and LDH and rheumatoid factor titers are high. Another interesting feature is the fluid tends to contain cholesterol crystals or high levels of cholesterol. Rheumatoid effusions

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tend to resolve slowly and respond poorly to therapy; occasionally, decortication is required.

Systemic lupus eritematosus may affect the pleura, producing an effusion in 16% to 40% of patients. The effusions tend to be small and recurrent; they are frequently bilateral. The fluid is a yellow exudate in which either polymorphs or lymphocytes may predominate. Unlike rheumatoid pleuritis, glucose level and pH tend to be near serum levels, and antinuclear antibodies may be demonstrated. Also, in contrast to those with rheumatoid effusion, patients with pleural disease of lupus erythematosus respond to corticosteroid therapy.

Dressler's syndrome is characterized by pericarditis, pleuritis and pneumonitis occurring after pericardial injury caused by trauma, surgery or myocardial infarction. Pleural effusion may develop, with yellow or sanguineous fluid. The patient's symptoms usually respond to nonsteroidal anti-inflammatory drugs.

Miscellaneous disorders - Asbestos exposure has been associated with benign exudative pleural effusions that are sometimes persistent or recurrent and may lead to pleural fibrosis; occasionally, these effusions are followed by the development of mesothelioma.

Esophageal rupture, although infrequent, should always be considered in the differential diagnosis of pleural effusion because the mortality is very high if the condition is not treated rapidly. The diagnosis should be suggested if the fluid examination reveals a high amylase (salivary) level, a low pH, squamous epithelial cells, and occasionally, food particles.

3.3.7. HEMOTHORAX

Hemothorax occurs when a significant amount of blood is present in the pleural space, as opposed to a serosanguineous effusion. The hematocrit is usually more than 50% of the blood level. The most common cause of hemothorax is trauma, either penetrating or nonpenetrating and is often associated with a pneumothorax. Occasionally, spontaneous pneumothorax is complicated by a small hemothorax (figure 42). Iatrogenic hemothorax is being reported more frequently with placement of central venous catheters, thoracentesis or pleural biopsy.

Nontraumatic hemothorax occurs infrequently but is seen in metastatic pleural disease and as a complication of anticoagulant therapy. Hemothorax is generally managed by the immediate insertion of one or more large chest tubes in order to control bleeding by causing apposition of pleural surfaces; chest tubes help the physician determine the amount of bleeding and decrease the risk of complications such as empyema and eventual fibrothorax. As much blood as possible should be drained before the chest tube is removed. Thoracotomy is occasionally required to control bleeding, remove large volumes of blood clots, and treat coexisting complications of trauma such as bronchopleural fistula. A very small hemothorax

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that is stable or improving on chest radiograph can be managed without tube drainage.

Figure 42 - HemopneumothoraxSpontaneous partial right pneumothorax complicated by a small hemothorax.

3.3.8. LIPID EFFUSIONS

Lipid effusions occur in two situations: a chylothorax forms when the thoracic duct is disrupted and chyle enters the pleural space; and in longstanding effusions, large amounts of cholesterol accumulate to produce a chyliform effusion, and the

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patient is said to have a pseudochylothorax. It is important to distinguish between these two conditions because the etiology and management are completely different.

Chylothorax occurs acutely as a result of disruption of the thoracic duct. The most common cause of chylothorax is tumor, predominantly lymphoma. The second most frequent cause is trauma, generally in a postoperative situation after cardiovascular surgery. In about 15% of patients, the cause is said to be idiopathic, including congenital. Chyle is bacteriostatic, so infection occurs infrequently. The fluid is milky white and odorless and the constituents can be confirmed by staining with Sudan III and analyzing the triglyceride content, which is usually greater than 150mg/dl. The demonstration of chylomicrons in the fluid establishes the diagnosis. The pleural surfaces are normal. Treatment is directed to the cause. Repeated aspiration is not advisable because the patient may become nutritionally depleted. Treatment of patients with progressive chylous effusions includes thoracic duct ligation, if conservative measures fail.

Pseudochylothorax occurs as a result of accumulation of cholesterol complexes in a chronically thickened pleural space, a phenomenon sometimes seen in cases of trapped lung, tuberculous pleuritis, or rheumatoid pleural effusion. The pathogenesis of pseudochylothorax is not known, but most patients with chyliform effusion have longstanding effusion with thickened, occasionally calcified pleura. The fluid is negative when stained with Sudan III dye and has a high-cholesterol content, sometimes greater than 1000 mg/dl. These effusions may result from rheumatoid arthritis or tuberculosis but are often idiopathic. Treatment is directed toward the underlying condition, and occasionally, decortication is indicated.

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