**5. Diagnosis of tuberculosis**

6 Global View of HIV Infection

who may have been exposed to TB, this person are screened for TB infection and disease 8, 26-

In order to the decrease in the number of TB cases reported annually is very important to

 To improve prevention and TB control programs in state and local health department. To Increase attention to ensuring that patients complete drug therapy through directly

In the control of TB disease is also important to know the Groups at High Risk for TB 29, 30:

Low-income groups with poor access to health care, including homeless people.

People who live or work in residential facilities (Example: nursing correctional

Infection with HIV makes people susceptible to rapidly progressive tuberculosis; over 10

The occurrence of TB infection and disease in children provide important information about the spread of TB in homes and communities. When a child has TB infection or disease is

Other adults and children in the household or community have probably been exposed

Drug-resistant TB is transmitted in the same way as drug-susceptible TB. The earlier outbreaks of multidrugs-resistant (MDR) TB support the findings that drug-resistant TB is no less infectious than drug-susceptible TB, although prolonged periods of infectiousness that often occur in the patients with drug-resistant TB may facililate transmission. Drug resistance was divided in two types; primary resistance and secondary or acquired resistance. Primary resistance develops in persons who are initially infected, with resistant organisms. Second resistance, or acquired resistance develops during TB therapy, either because the patient was treated with an inadequate regimen or because the patient did not take the prescribed regimen appropriately 27, 29, 32. The MDR-TB are resistant to rifampicin and isoniazid drugs. Recently drug-resistant tuberculosis (XDR-TB) is defined as tuberculosis caused by a *Mycobacterium* 

To increase federal resources for TB control and other public health efforts.

28.

comply three factors 29:

Elderly people.

facilities).

TB in Children:

important to learn if 29-31 : Recent TB transmition.

**4.1 Drug-resistant tuberculosis** 

observed therapy (DOT).

People who inject illicit drugs.

People at Higher Risk for TB disease:

 People who inject illicit drugs. People with HIV infection.

People at Higher Risk for Exposure or Infection:

 Close contacts of people with infectious TB disease. People born in areas of the world where TB is common.

Other people who may be exposed to TB on the job.

 People recently infected with *Mycobacterium tuberculosis*. People with chest x-ray suggestive of previous TB disease.

People in other groups as identified by local public health officials.

People with other medical conditions that can increase the risk for TB.

millions peoples are infected with both HIV and *Mycobacterium tuberculosis* <sup>8</sup>*.* 

to TB; if they are infected, they may develop TB disease in the future.

The systemic symptom of Tuberculosis include fever, chills, night sweats, appetite loss, weigh loss, and easy fatigability, the symptoms of pulmonary TB are productive and prolonged cough (>14-21 week) , chest pain and in some case the patient present hemoptysis. It is important to ask persons suspected of having tuberculosis about their history of TB exposure, infection, or disease. The clinicians may also contact the local health department for information about whether a patient has received tuberculosis treatment in the past, if the drug regimen was inadequate or if the patient may did not adhere to therapy, this disease may recur and may be drug resistant. Also is important to consider demographic factors; country of origin, age, ethnic or racial group and occupation, this factors may increase the patient's risk for exposure to TB or drug-resistant TB disease. Clinicians should determinate whether the patient has medical conditions, especially HIV infection, because this infection increases the risk for TB disease. All patients who do not know their current HIV status should be referred for HIV counseling and testing 26, 27.

The tuberculin skin test and the chest radiography, are two probes that help in the diagnostic for TB disease. Tuberculin skin testing useful for 29:


A negative reaction to the tuberculin skin test does not exclude the diagnosis of TB, especially for patients with severe TB illness or infection with HIV. Some persons may not react to the tuberculin skin test if they are tested too soon after being exposed to the infection. Generally it takes 2-10 week after infection for a person to develop an immune response to tuberculin. In children younger than 6 months of age may not react to the tuberculin skin test because their immune systems are not yet fully developed 32.

#### **5.1 Chest radiography**

The chest radiography is for:


In HIV-infected persons, pulmonary TB may appear in the chets radiograph. For example; TB disease may cause infiltrates without cavities in any lung zone, or it may cause

Infection for *Mycobacterium tuberculosis* and

were more better 44-46.

solutions 47-51.

they often are diluted by the large fluid volume 16-19, 37-39.

Nontuberculous Mycobacteria in the HIV/AIDS Patients 9

receive a variety of extrapulmonary specimens: aseptically collected body fluids, surgically excised tissue, aspirated or draining pus, and urine. Others ascetically collected specimens are the body fluids as spinal, pleural, pericardial, synovial, ascetic, blood, pus, and bone marrow are aseptically collected by the physician using aspiration techniques or surgical procedure. Acid-fast bacilli may be difficult to isolate from some of these specimens because

The identification of TB can be done by traditional culture materials include egg-based solid media, such as Löwenstein-Jensen medium, and synthetic solid media as Middlebrook 7H10 and 7H11 agars. The identification depends on the visualization of mycobacterial colonies and is limited by the slow growth rate of these organisms. A major advance in laboratory diagnosis of TB has been the development of systems based on detecting growth in liquid media with the use of radiometric methods as Bactec System. In this, the medium contains palmitic acid labeled with carbon-14. The metabolism of this fatty acid by growing mycobacteria liberates radioactive carbon dioxide, periodic sampling of the gasses in the

Species identification was accomplished with biochemical test that often involved additional diagnostic delays. Others techniques, currently being evaluated in a number of clinical settings include identification based on chromatography techniques for the studies of some specific lipids present in the wall of *Mycobacterium* 42, 43. Also genetic probes are now availed for the identification of *Mycobacterium tuberculosis* and several other common mycobacterial species. These probes recognize species-specific sequences of ribosomal RNA. Theoretically, genetic probe as polymerase chain reaction (PCR), may permit diagnosis directly form patients specimens, eliminating the need for culture of organism. In practice, the utility of PCR has been limited by problems with the sensitivity and particularly, the specificity of results. In some laboratories, the sensitivity and specificity have been reported to exceed 85%. However, in several laboratories, false-positive rates ranged from 3% to 20%, and in one, 77% of positive results were false. In the last time the Genotype Mycobacteria Direct Assay (GTMD), a novel commercial assay based on nucleic acid sequence-based amplification technology, was evaluated for detection of *Mycobacterium tuberculosis* complex and some atypical mycobacterial species from clinical samples, and your sensitivity, specificity, positive predictive, and negative predictive were evaluated and these results

Environmental opportunistic mycobacteria are those that are recovered form natural and human influenced environments and can infect and cause disease in humans, animals, and birds. Other names for these mycobacteria are nontuberculous, however, they cause tuberculous lesions, also other name is atypical mycobacterial, it distinguish from ¨typical¨ *Mycobacterium tuberculosis*, and them nontuberculous mycobacteria (NTM). The environmental opportunistic mycobacteria are normal inhabitants of natural waters, drinking water, and soils. They can be isolated from biofilms, aerosol, and dusts. The distribution of NTM and the incidence of disease caused by them is perhaps are not fully understood in most parts of the world. NTM are widely distributed in nature and have been isolated from natural water, rap water, tap water, and water used in showers and surgical

culture-containing flask permits rapid detection of mycobacterial growth 40-41.

**6. Nontuberculous mycobacteria in the environment** 

mediastinal or hiliar lymphadenophaty with or without accompanying infiltrates and/or cavities. In HIV-positive persons, almost any abnormality on a chest radiographic may indicate TB. In fact, the radiograph of an HIV-positive person with TB disease may even appear entirely normal. Abnormalities on chest radiographs may be suggestive of, but are never diagnostic of TB. However, chest radiographic may be used to rule out the possibility of pulmonary TB in a person who has a positive reaction to the tuberculin skin test and no symptoms of disease 29, 31, 32, 34.

Summarizing the possibility of TB should be considered in persons who have these symptoms, person suspected of having this disease should be referred for a medical evaluation, which should include a medical history, a physical examination, a Mantoux tuberculin skin test or tuberculosis purified protein derivate (PPD) skin test, a chest radiograph. Also, it is very important any appropriate bacteriologic or histological examinations in this patients, principally in all inmmunosuppressed patients, of course including the HIV patients 29.

Person with symptoms of TB pulmonary disease should have at least three sputum specimens examined by smear and culture. The bets way would be to get serial specimens collected early in the morning on 3 consecutive days. A health care worked should be prepared and directly supervise at least during the first time sputum collection. This personal should give properly instructed in how to produce a good specimen, the patients should be informed that sputum is the material brought up form the lungs and that mucus from the nose or throat and saliva are not good specimens 35, 36.

Recommends for Specimen Collection:


#### **5.2 Laboratory examination**

Detection of acid-fast bacilli (AFB) in stained smears examined microscopically may provide the first bacteriologic of TB. The traditional method for to detect AFB is the Zielh-Neelsen coloration, it is a method more economic. There are other methods that increased sensitivity as fluorescent methods. Smear examination is an easy and quick procedure, because the results should be available within 24 hours of specimen collection. However, smear examination permits only the presumptive diagnosis of TB because many TB patients have negative AFB smears. The sensitivity of smear examination may be reduced if the directed inflammatory response and relative absence of cavitary lesions results in fewer organisms expectorated in sputum. There has been concern that the utility of sputum acid-fast smears may be reduced in HIV-infected populations 36, 37.

#### **5.3 Extrapulmonary TB disease**

This disease is not taking in account as causative agent of an extrapulmonary disease because the chest radiography is normal or tuberculin skin test is negative, or both. Mycobacteria may infect almost any organ in the body, the laboratory should expect to

mediastinal or hiliar lymphadenophaty with or without accompanying infiltrates and/or cavities. In HIV-positive persons, almost any abnormality on a chest radiographic may indicate TB. In fact, the radiograph of an HIV-positive person with TB disease may even appear entirely normal. Abnormalities on chest radiographs may be suggestive of, but are never diagnostic of TB. However, chest radiographic may be used to rule out the possibility of pulmonary TB in a person who has a positive reaction to the tuberculin skin

Summarizing the possibility of TB should be considered in persons who have these symptoms, person suspected of having this disease should be referred for a medical evaluation, which should include a medical history, a physical examination, a Mantoux tuberculin skin test or tuberculosis purified protein derivate (PPD) skin test, a chest radiograph. Also, it is very important any appropriate bacteriologic or histological examinations in this patients, principally in all inmmunosuppressed patients, of course

Person with symptoms of TB pulmonary disease should have at least three sputum specimens examined by smear and culture. The bets way would be to get serial specimens collected early in the morning on 3 consecutive days. A health care worked should be prepared and directly supervise at least during the first time sputum collection. This personal should give properly instructed in how to produce a good specimen, the patients should be informed that sputum is the material brought up form the lungs and that mucus

In persons unable to cough up sputum, induce sputum, bronchoscopy or gastric

To use clean, sterile, one-use, plastic, disposable containers that have been washed with

Detection of acid-fast bacilli (AFB) in stained smears examined microscopically may provide the first bacteriologic of TB. The traditional method for to detect AFB is the Zielh-Neelsen coloration, it is a method more economic. There are other methods that increased sensitivity as fluorescent methods. Smear examination is an easy and quick procedure, because the results should be available within 24 hours of specimen collection. However, smear examination permits only the presumptive diagnosis of TB because many TB patients have negative AFB smears. The sensitivity of smear examination may be reduced if the directed inflammatory response and relative absence of cavitary lesions results in fewer organisms expectorated in sputum. There has been concern that the utility of sputum acid-fast smears

This disease is not taking in account as causative agent of an extrapulmonary disease because the chest radiography is normal or tuberculin skin test is negative, or both. Mycobacteria may infect almost any organ in the body, the laboratory should expect to

from the nose or throat and saliva are not good specimens 35, 36.

Get 3 sputum specimens for smear examination and culture.

To transport specimens to the laboratory as soon as possible.

Before chemotherapy and drug therapy is started.

dichromate sulfuric acid and sterilized.

may be reduced in HIV-infected populations 36, 37.

test and no symptoms of disease 29, 31, 32, 34.

including the HIV patients 29.

aspiration.

**5.2 Laboratory examination** 

**5.3 Extrapulmonary TB disease** 

Recommends for Specimen Collection:

receive a variety of extrapulmonary specimens: aseptically collected body fluids, surgically excised tissue, aspirated or draining pus, and urine. Others ascetically collected specimens are the body fluids as spinal, pleural, pericardial, synovial, ascetic, blood, pus, and bone marrow are aseptically collected by the physician using aspiration techniques or surgical procedure. Acid-fast bacilli may be difficult to isolate from some of these specimens because they often are diluted by the large fluid volume 16-19, 37-39.

The identification of TB can be done by traditional culture materials include egg-based solid media, such as Löwenstein-Jensen medium, and synthetic solid media as Middlebrook 7H10 and 7H11 agars. The identification depends on the visualization of mycobacterial colonies and is limited by the slow growth rate of these organisms. A major advance in laboratory diagnosis of TB has been the development of systems based on detecting growth in liquid media with the use of radiometric methods as Bactec System. In this, the medium contains palmitic acid labeled with carbon-14. The metabolism of this fatty acid by growing mycobacteria liberates radioactive carbon dioxide, periodic sampling of the gasses in the culture-containing flask permits rapid detection of mycobacterial growth 40-41.

Species identification was accomplished with biochemical test that often involved additional diagnostic delays. Others techniques, currently being evaluated in a number of clinical settings include identification based on chromatography techniques for the studies of some specific lipids present in the wall of *Mycobacterium* 42, 43. Also genetic probes are now availed for the identification of *Mycobacterium tuberculosis* and several other common mycobacterial species. These probes recognize species-specific sequences of ribosomal RNA. Theoretically, genetic probe as polymerase chain reaction (PCR), may permit diagnosis directly form patients specimens, eliminating the need for culture of organism. In practice, the utility of PCR has been limited by problems with the sensitivity and particularly, the specificity of results. In some laboratories, the sensitivity and specificity have been reported to exceed 85%. However, in several laboratories, false-positive rates ranged from 3% to 20%, and in one, 77% of positive results were false. In the last time the Genotype Mycobacteria Direct Assay (GTMD), a novel commercial assay based on nucleic acid sequence-based amplification technology, was evaluated for detection of *Mycobacterium tuberculosis* complex and some atypical mycobacterial species from clinical samples, and your sensitivity, specificity, positive predictive, and negative predictive were evaluated and these results were more better 44-46.

## **6. Nontuberculous mycobacteria in the environment**

Environmental opportunistic mycobacteria are those that are recovered form natural and human influenced environments and can infect and cause disease in humans, animals, and birds. Other names for these mycobacteria are nontuberculous, however, they cause tuberculous lesions, also other name is atypical mycobacterial, it distinguish from ¨typical¨ *Mycobacterium tuberculosis*, and them nontuberculous mycobacteria (NTM). The environmental opportunistic mycobacteria are normal inhabitants of natural waters, drinking water, and soils. They can be isolated from biofilms, aerosol, and dusts. The distribution of NTM and the incidence of disease caused by them is perhaps are not fully understood in most parts of the world. NTM are widely distributed in nature and have been isolated from natural water, rap water, tap water, and water used in showers and surgical solutions 47-51.

Infection for *Mycobacterium tuberculosis* and

**7.1 Clinical manifestations** 

mycobacteria is quite broad 8, 51.

**7.2 Pulmonary infections** 

**7.3 Cutaneous infection** 

Nontuberculous Mycobacteria in the HIV/AIDS Patients 11

age. Many investigations have observed decreasing rates of TB concomitant with the increases in NTM. Finally, an interaction between the host and pathogen could involve a

Environmental opportunist or nontuberculous mycobacteria (NMT) include both slowly and rapidly growing. The range of infections caused by environmental opportunist

*Mycobacterium avium-intracellulare* complex (MAC) strains have been a major cause of pulmonary and other infections, principally in the HIV patients. MAC infections were commonly seen in chronic obstructive airway disease and in the in the geriatric patients too. *Mycobacterium kansasii and Mycobacterium scrofulaceum* have been considered an important cause of pulmonary infections. *Mycobacterium xenopi*, an unusual specie has been encountered as a pathogen in patients with other underlying lung diseases. Others species of slow grown as *Mycobacterium simiae* (*Mycobacterium ´habana´*)*, Mycobacterium szulgai, Mycobacterium malmoense* and *Mycobacterium fortuitum* of rapid grown are other pathogens

*Mycobacterium szulgai, Mycobacterium marinum, Mycobacterium ulcerans* and *Mycobacterium vaccae* have been reported to be a cause of skin infectious. *Mycobacterium marinum*, specie has been recognized as a causative organism of swimming pool granuloma or fish tank granuloma. It causes papular lesions in the extremities and may be confused with sporotricosis. *Mycobacterium ulcerans* is established cause of buruli ulcer, *Mycobacterium* 

*Mycobacterium fortuitum* causes pyogenic lesions in the soft tissue, joints, bursae and injection abscesses, while *Mycobacterium chelonae abscessus* is a well known cause of wound infections, a new related species *Mycobacterum immunogenum* has been recently been recognized as a cause of sepsis. *Mycobacterium marinum* also causes infections of bones, joints, tendon sheaths especially in AIDS patients. *Mycobacterium smegmatis,* and more recently *Mycobacterium wolinskyi* and *Mycobacterium thermoresistible* have been reported to cause wound infection and also bacteraemia. *Mycobacterium terrae* complex *(Mycobacterium terrae, Mycobacterium nonchromogenicum* and *Mycobacterium triviale*) may be associated with mycobacterial disease. Also occasionally *Mycobacterium nonchromogenicum* and *Mycobacterium chelonae* have been identified as causes of acupuncture induced infections. *Mycobacterium septicum* a new rapidly growing species has been reported to be associated

Infection of the submaxillar, cervical, inguinal or preauricular lymph nodes is the most common presentation of NTM lymphadenitis. The involved lymph nodes are generally unilateral (95%) and not tender 54-57. The nodes may enlarge rapidly, and even rupture, with

major increase in pathogen exposure or potential inoculum size 63-67.

reported to be associated with pulmonary infections 51, 65-68.

*vaccae* has also been reported to be a cause of skin infections 51-56.

**7.4 Wound infection bone, joints and bursae and sepsis** 

with catheter related bacteremia 49, 51, 57,58.

**7.5 Lymphadenitis** 

It is common observation that environmental mycobacteria cause disease in individuals who offer some opportunity due to altered local or systemic immunity. Chronic obstructive pulmonary diseases, emphysema, pneumoconiosis, bronchiectasis, cystic fibrosis, thoracic scoliosis, aspiration due to esophageal disease, previous gastrectomy and chronic alcoholism are some of conditions which have been linked to disease due to NTM. While the reasons may be less clear in conditions like adenitis in children, such factors may be quite obvious in other conditions like bronchiectasis, surgical procedures, injections, break in skin surface due to wounds and generalized immune deficiency states like AIDS, use of immunosuppressive agents as used in transplant patients, etc 50, 51.

#### **6.1 Pathogenesis**

The mechanisms of pathogenesis of NTM are not very clear and have not been adequately investigated. Very low CD4 counts and defective cytokine response have been linked to severe infections in AIDS patients 50.

Nontuberculous mycobacteria have been reported to cause localized or disseminated disease depending on local predisposition and/or degree of immune deficit. In non-HIV patients, different NTM may cause localized pulmonary disease, adenitis, soft tissue infections, infections of joints and bones, bursae, skin ulcers and generalized disease in individuals like leukemia, transplant patients, etc. In AIDS patients the manifestations may range from localized to disseminated disease. Clinical features will include local organ specific signs and symptoms to persistent high grade fever, night sweats, anemia and weight loss in addition to nonspecific symptoms of malaise, anorexia, diarrhea, myalgia and occasional painful adenopathy 52-57.

#### **7. Epidemiology of human infection with nontuberculous mycobacteria**

The frequency of NTM pulmonary disease has been reported to be increasing on several continents. Changing patient populations, most notably from infection with HIV, have greatly increased the numbers of people at risk 57-60. Studies addressing the epidemiology of NTM infection may be broadly divided into three types: cutaneous delayed-type hypersensitivity to NTM antigens has been used to study large samples of people in many countries. These studies have the strength of providing information regarding simple infection in large groups of people but suffer from the lack of information regarding the prevalence of disease. Another drawback of this study type reflects the relatively poor specificity of the skin test, as well as overlap in reactivity among various Mycobacterial species. The second useful type of epidemiologic study of NMT infection includes investigations reviewing consecutive isolates from a mycobacterial laboratory. In the presence of adequate laboratory protocols to avoid contamination with environmental organisms, these studies provide unequivocal evidence of infection but have the obvious shortcoming of a lack of clinical data, preventing the assessment regarding the presence or absence of disease. The final and most useful study type combines information from the mycobacterial laboratory and the clinician's assessment 55-62.

A true increase in rates of infection and disease could be related to the host, the pathogen, or some interaction between the two. Host changes leading to increased numbers of susceptibility could play an important role, with increased numbers of patients with inadequate defenses from diseases such as HIV infection, malignancy, or simply advanced age. Many investigations have observed decreasing rates of TB concomitant with the increases in NTM. Finally, an interaction between the host and pathogen could involve a major increase in pathogen exposure or potential inoculum size 63-67.

#### **7.1 Clinical manifestations**

10 Global View of HIV Infection

It is common observation that environmental mycobacteria cause disease in individuals who offer some opportunity due to altered local or systemic immunity. Chronic obstructive pulmonary diseases, emphysema, pneumoconiosis, bronchiectasis, cystic fibrosis, thoracic scoliosis, aspiration due to esophageal disease, previous gastrectomy and chronic alcoholism are some of conditions which have been linked to disease due to NTM. While the reasons may be less clear in conditions like adenitis in children, such factors may be quite obvious in other conditions like bronchiectasis, surgical procedures, injections, break in skin surface due to wounds and generalized immune deficiency states like AIDS, use of

The mechanisms of pathogenesis of NTM are not very clear and have not been adequately investigated. Very low CD4 counts and defective cytokine response have been linked to

Nontuberculous mycobacteria have been reported to cause localized or disseminated disease depending on local predisposition and/or degree of immune deficit. In non-HIV patients, different NTM may cause localized pulmonary disease, adenitis, soft tissue infections, infections of joints and bones, bursae, skin ulcers and generalized disease in individuals like leukemia, transplant patients, etc. In AIDS patients the manifestations may range from localized to disseminated disease. Clinical features will include local organ specific signs and symptoms to persistent high grade fever, night sweats, anemia and weight loss in addition to nonspecific symptoms of malaise, anorexia, diarrhea, myalgia and

**7. Epidemiology of human infection with nontuberculous mycobacteria** 

mycobacterial laboratory and the clinician's assessment 55-62.

The frequency of NTM pulmonary disease has been reported to be increasing on several continents. Changing patient populations, most notably from infection with HIV, have greatly increased the numbers of people at risk 57-60. Studies addressing the epidemiology of NTM infection may be broadly divided into three types: cutaneous delayed-type hypersensitivity to NTM antigens has been used to study large samples of people in many countries. These studies have the strength of providing information regarding simple infection in large groups of people but suffer from the lack of information regarding the prevalence of disease. Another drawback of this study type reflects the relatively poor specificity of the skin test, as well as overlap in reactivity among various Mycobacterial species. The second useful type of epidemiologic study of NMT infection includes investigations reviewing consecutive isolates from a mycobacterial laboratory. In the presence of adequate laboratory protocols to avoid contamination with environmental organisms, these studies provide unequivocal evidence of infection but have the obvious shortcoming of a lack of clinical data, preventing the assessment regarding the presence or absence of disease. The final and most useful study type combines information from the

A true increase in rates of infection and disease could be related to the host, the pathogen, or some interaction between the two. Host changes leading to increased numbers of susceptibility could play an important role, with increased numbers of patients with inadequate defenses from diseases such as HIV infection, malignancy, or simply advanced

immunosuppressive agents as used in transplant patients, etc 50, 51.

**6.1 Pathogenesis** 

severe infections in AIDS patients 50.

occasional painful adenopathy 52-57.

Environmental opportunist or nontuberculous mycobacteria (NMT) include both slowly and rapidly growing. The range of infections caused by environmental opportunist mycobacteria is quite broad 8, 51.

#### **7.2 Pulmonary infections**

*Mycobacterium avium-intracellulare* complex (MAC) strains have been a major cause of pulmonary and other infections, principally in the HIV patients. MAC infections were commonly seen in chronic obstructive airway disease and in the in the geriatric patients too. *Mycobacterium kansasii and Mycobacterium scrofulaceum* have been considered an important cause of pulmonary infections. *Mycobacterium xenopi*, an unusual specie has been encountered as a pathogen in patients with other underlying lung diseases. Others species of slow grown as *Mycobacterium simiae* (*Mycobacterium ´habana´*)*, Mycobacterium szulgai, Mycobacterium malmoense* and *Mycobacterium fortuitum* of rapid grown are other pathogens reported to be associated with pulmonary infections 51, 65-68.

#### **7.3 Cutaneous infection**

*Mycobacterium szulgai, Mycobacterium marinum, Mycobacterium ulcerans* and *Mycobacterium vaccae* have been reported to be a cause of skin infectious. *Mycobacterium marinum*, specie has been recognized as a causative organism of swimming pool granuloma or fish tank granuloma. It causes papular lesions in the extremities and may be confused with sporotricosis. *Mycobacterium ulcerans* is established cause of buruli ulcer, *Mycobacterium vaccae* has also been reported to be a cause of skin infections 51-56.

#### **7.4 Wound infection bone, joints and bursae and sepsis**

*Mycobacterium fortuitum* causes pyogenic lesions in the soft tissue, joints, bursae and injection abscesses, while *Mycobacterium chelonae abscessus* is a well known cause of wound infections, a new related species *Mycobacterum immunogenum* has been recently been recognized as a cause of sepsis. *Mycobacterium marinum* also causes infections of bones, joints, tendon sheaths especially in AIDS patients. *Mycobacterium smegmatis,* and more recently *Mycobacterium wolinskyi* and *Mycobacterium thermoresistible* have been reported to cause wound infection and also bacteraemia. *Mycobacterium terrae* complex *(Mycobacterium terrae, Mycobacterium nonchromogenicum* and *Mycobacterium triviale*) may be associated with mycobacterial disease. Also occasionally *Mycobacterium nonchromogenicum* and *Mycobacterium chelonae* have been identified as causes of acupuncture induced infections. *Mycobacterium septicum* a new rapidly growing species has been reported to be associated with catheter related bacteremia 49, 51, 57,58.

#### **7.5 Lymphadenitis**

Infection of the submaxillar, cervical, inguinal or preauricular lymph nodes is the most common presentation of NTM lymphadenitis. The involved lymph nodes are generally unilateral (95%) and not tender 54-57. The nodes may enlarge rapidly, and even rupture, with

Infection for *Mycobacterium tuberculosis* and

40, 43,44,48, 83, 84

**in the HIV/AIDS patients** 

infected with HIV 53,85,86.

effusions 24,30,67,69,89.

Nontuberculous Mycobacteria in the HIV/AIDS Patients 13

qualitative and quantitative, grown on MaConkey agar, sodium chloride tolerance, etc, are adequate to identify majority of clinically relevant mycobacteria. This strategy is very necessary and important for the diagnostic of NTM, however, some time consuming and is not conclusive for many isolates with variable characters. For this reason others alternative diagnostic techniques are recommended, for example, the analysis of the mycolic acids of mycobacteria by thin layer chromatography (TLC) and high performance liquid chromatography (HPLC), and more recently the identification and characterization of NTM by molecular methods, based on new knowledge about the gene sequences of mycobacteria many gene probes for the identification of isolates as well as amplification of specific gene fragments from the lesions and mycobacterial culture isolates have been developed; gene probes, polymerase chain reaction (PCR) techniques, DNA fingerprinting techniques, etc, 35-

**9.** *Mycobacterium tuberculosis* **and nontuberculous mycobacteria diseases** 

After years of worldwide decline of tuberculosis (TB), this disease has returned as a big problem in the Public Health. The resurgence of TB in the past decades is closely linked to acquired immunodeficiency syndrome (AIDS) pandemic. The high susceptibility of patients infected with the human immunodeficiency virus (HIV) to TB and others mycobacterial infections is unique, creating a lot of diagnostic and therapeutic challenges for clinicians 12,32,24. Pulmonary tuberculosis is the most common manifestation of tuberculosis in adults

HIV/TB co-infection occurs in various stages of HIV infection, with the clinical pattern correlating with the patient's immune status. In the early stages of HIV infection, when immunity is only partially compromised, the features are more typical of tuberculosis, commonly with upper lobe cavitations, and the disease resembles that seen in the pre-HIV era. HIV-infected patients present with atypical pulmonary disease due to immune deficiency advances, resembling primary tuberculosis or extra pulmonary and disseminated

The clinical symptoms are severally similar in HIV-infected and HIV-negative patients. However, cough is reported less frequently by HIV-infected patients, probably because there is less cavitations, inflammation and endobronchial irritation as a result of a reduction in cell-mediated immunity. Similarly, haemoptysis, which results from caseous necrosis of

In general, the traits that characterize HIV-TB co-infection include the potential for rapid progression from primary infection to disseminated disease, atypical radiographic features of pulmonary disease, increased frequency of extrapulmonary disease and involvement of unusual sites of infection. All of these atypical features seem to occur more commonly with more advance stages of immunosuppression and the paradigm that emerges is one of typical TB early in the course of HIV infection and atypical manifestation with advanced HIV disease, in this case the atypical features included lower lobe alveolar opacities, multifocal alveolar opacities, interstitial infiltrates, mediastinal adenopathy and pleural

disease, commonly with hilar adenopathy and lower lobe infection 87.

the bronchial arteries, is less common in HIV-infected patients 87.88.

**9.1 Clinical symptoms in pulmonary tuberculosis** 

formation of sinus tracts that result in prolonged local drainage. Other nodal groups outside of the head and neck may be involved occasionally. Distinguishing tuberculous from nontuberculous lymphadenitis is key because the former requires drug therapy and public health tracking, whereas the latter does not. A definitive diagnosis of NTM lymphadenitis is made by recovery of the causative organism form lymph node cultures. A simple diagnostic biopsy or incision and drainage of the involved lymph nodes should be avoided, since most of these procedures will be followed by fistulae formation with chronic drainage. However, even with excised nodes with compatible histopathology, only about 50% will yield positive cultures, because in some case these smear-positive, culture-negative cases may be due to fastidious species such as *Mycobacterium haemophilum* or *Mycobacterium genavence*. Approximately 80% of culture-proven cases of NTM lymphadenitis are due to *MAC*. It´s predominance is due to a change approximately from 20-30 years ago, when most geographic areas reported *Mycobacterium scrofulaceum* as the most common etiologic agent, only about 10% of the culture-proved mycobacterial cervical lymphadenitis in children is due to *Mycobacterium avium* complex and *Mycobacterium scrofulaceum*. Also *Mycobacterium haemophilum, Mycobacterium malmoense, Mycobacterium fortuitum* and others have been isolated from cases of lymphadenitis including HIV patients. In contrast, in adults more than 90% of the culture-proven mycobacterial lymphadenitis is due to *Mycobacterium tuberculosis* 8, 67, 70-76*.*

#### **7.6 Disseminated disease in immunocompromized individuals**

Disseminated disease due to NTM in AIDS patients usually occurs only in those with very advanced immunosuppressant, because these patients frequently have other complications, the diagnosis of mycobacterial infection may be confused or delayed. The diagnosis is exceedingly rare in person with >100 CD4 cells, and it should usually be suspected only in persons with <50 CD4 cells 53. *MAC* have been found to be more commonly isolated from HIV-positive and HIV-negative patients, in their the portal of entry mainly through the gut 31 67,69. Persistent high grade fever, night sweats, anemia and weight loss in addition to nonspecific symptoms of malaise, anorexia, diarrhoea, myalgia and occasional painfuladenopathy are common signs and symptoms associated with MAC disease in AIDS cases. Others pulmonary and extrapulmonary mycobacterial infections in AIDS patients are for *Mycobacterium kansasii* , *Mycobacterium scrofulaceum*, *Mycobacterium xenopi*, *Mycobacterium simiae*, *Mycobacterium fortuitum*-*Mycobacterium chelonei* complex, *Mycobacterium malmoense, Mycobacterium szulgai*, and more recently *Mycobacterium genavense*, *Mycobacterium haemophilum* and *Mycobacterium celatum* 74-82.

#### **8. Identification of nontuberculous mycobacteria**

Traditional identification of NTM, as well as *Mycobacterium tuberculosis*, has relied upon statistical probabilities of presenting a characteristic reaction pattern in battery biochemical test. The niacin test was the most useful for separating NTM and *Mycobacterium tuberculosis* because the former is usually negative, whereas isolates of *Mycobacterium tuberculosis* are positive. Runyon devised the first good scheme for grouping NTM based on growth rates and colony pigmentation. For the diagnostic of NTM is very important to know the growth rates and colony pigmentation, and biochemical test such as, niacin production, nitrate reduction, tween-80 hydrolysis, arylsulphatase, urease, tellurite reduction, catalase

formation of sinus tracts that result in prolonged local drainage. Other nodal groups outside of the head and neck may be involved occasionally. Distinguishing tuberculous from nontuberculous lymphadenitis is key because the former requires drug therapy and public health tracking, whereas the latter does not. A definitive diagnosis of NTM lymphadenitis is made by recovery of the causative organism form lymph node cultures. A simple diagnostic biopsy or incision and drainage of the involved lymph nodes should be avoided, since most of these procedures will be followed by fistulae formation with chronic drainage. However, even with excised nodes with compatible histopathology, only about 50% will yield positive cultures, because in some case these smear-positive, culture-negative cases may be due to fastidious species such as *Mycobacterium haemophilum* or *Mycobacterium genavence*. Approximately 80% of culture-proven cases of NTM lymphadenitis are due to *MAC*. It´s predominance is due to a change approximately from 20-30 years ago, when most geographic areas reported *Mycobacterium scrofulaceum* as the most common etiologic agent, only about 10% of the culture-proved mycobacterial cervical lymphadenitis in children is due to *Mycobacterium avium* complex and *Mycobacterium scrofulaceum*. Also *Mycobacterium haemophilum, Mycobacterium malmoense, Mycobacterium fortuitum* and others have been isolated from cases of lymphadenitis including HIV patients. In contrast, in adults more than 90% of the culture-proven mycobacterial lymphadenitis is due to *Mycobacterium* 

Disseminated disease due to NTM in AIDS patients usually occurs only in those with very advanced immunosuppressant, because these patients frequently have other complications, the diagnosis of mycobacterial infection may be confused or delayed. The diagnosis is exceedingly rare in person with >100 CD4 cells, and it should usually be suspected only in persons with <50 CD4 cells 53. *MAC* have been found to be more commonly isolated from HIV-positive and HIV-negative patients, in their the portal of entry mainly through the gut 31 67,69. Persistent high grade fever, night sweats, anemia and weight loss in addition to nonspecific symptoms of malaise, anorexia, diarrhoea, myalgia and occasional painfuladenopathy are common signs and symptoms associated with MAC disease in AIDS cases. Others pulmonary and extrapulmonary mycobacterial infections in AIDS patients are for *Mycobacterium kansasii* , *Mycobacterium scrofulaceum*, *Mycobacterium xenopi*, *Mycobacterium simiae*, *Mycobacterium fortuitum*-*Mycobacterium chelonei* complex, *Mycobacterium malmoense, Mycobacterium szulgai*, and more recently *Mycobacterium genavense*, *Mycobacterium* 

Traditional identification of NTM, as well as *Mycobacterium tuberculosis*, has relied upon statistical probabilities of presenting a characteristic reaction pattern in battery biochemical test. The niacin test was the most useful for separating NTM and *Mycobacterium tuberculosis* because the former is usually negative, whereas isolates of *Mycobacterium tuberculosis* are positive. Runyon devised the first good scheme for grouping NTM based on growth rates and colony pigmentation. For the diagnostic of NTM is very important to know the growth rates and colony pigmentation, and biochemical test such as, niacin production, nitrate reduction, tween-80 hydrolysis, arylsulphatase, urease, tellurite reduction, catalase

**7.6 Disseminated disease in immunocompromized individuals** 

*haemophilum* and *Mycobacterium celatum* 74-82.

**8. Identification of nontuberculous mycobacteria** 

*tuberculosis* 8, 67, 70-76*.*

qualitative and quantitative, grown on MaConkey agar, sodium chloride tolerance, etc, are adequate to identify majority of clinically relevant mycobacteria. This strategy is very necessary and important for the diagnostic of NTM, however, some time consuming and is not conclusive for many isolates with variable characters. For this reason others alternative diagnostic techniques are recommended, for example, the analysis of the mycolic acids of mycobacteria by thin layer chromatography (TLC) and high performance liquid chromatography (HPLC), and more recently the identification and characterization of NTM by molecular methods, based on new knowledge about the gene sequences of mycobacteria many gene probes for the identification of isolates as well as amplification of specific gene fragments from the lesions and mycobacterial culture isolates have been developed; gene probes, polymerase chain reaction (PCR) techniques, DNA fingerprinting techniques, etc, 35- 40, 43,44,48, 83, 84

#### **9.** *Mycobacterium tuberculosis* **and nontuberculous mycobacteria diseases in the HIV/AIDS patients**

After years of worldwide decline of tuberculosis (TB), this disease has returned as a big problem in the Public Health. The resurgence of TB in the past decades is closely linked to acquired immunodeficiency syndrome (AIDS) pandemic. The high susceptibility of patients infected with the human immunodeficiency virus (HIV) to TB and others mycobacterial infections is unique, creating a lot of diagnostic and therapeutic challenges for clinicians 12,32,24. Pulmonary tuberculosis is the most common manifestation of tuberculosis in adults infected with HIV 53,85,86.

HIV/TB co-infection occurs in various stages of HIV infection, with the clinical pattern correlating with the patient's immune status. In the early stages of HIV infection, when immunity is only partially compromised, the features are more typical of tuberculosis, commonly with upper lobe cavitations, and the disease resembles that seen in the pre-HIV era. HIV-infected patients present with atypical pulmonary disease due to immune deficiency advances, resembling primary tuberculosis or extra pulmonary and disseminated disease, commonly with hilar adenopathy and lower lobe infection 87.

#### **9.1 Clinical symptoms in pulmonary tuberculosis**

The clinical symptoms are severally similar in HIV-infected and HIV-negative patients. However, cough is reported less frequently by HIV-infected patients, probably because there is less cavitations, inflammation and endobronchial irritation as a result of a reduction in cell-mediated immunity. Similarly, haemoptysis, which results from caseous necrosis of the bronchial arteries, is less common in HIV-infected patients 87.88.

In general, the traits that characterize HIV-TB co-infection include the potential for rapid progression from primary infection to disseminated disease, atypical radiographic features of pulmonary disease, increased frequency of extrapulmonary disease and involvement of unusual sites of infection. All of these atypical features seem to occur more commonly with more advance stages of immunosuppression and the paradigm that emerges is one of typical TB early in the course of HIV infection and atypical manifestation with advanced HIV disease, in this case the atypical features included lower lobe alveolar opacities, multifocal alveolar opacities, interstitial infiltrates, mediastinal adenopathy and pleural effusions 24,30,67,69,89.

Infection for *Mycobacterium tuberculosis* and

**3B***)* and *Mycobacterium fortuitum* (**Figure 3C**)

Care Med1994;149:1359-1374.

**10. References** 

Nontuberculous Mycobacteria in the HIV/AIDS Patients 15

Fig. 2. Biopsy of liver pedicle lymph nodes for *Mycobacterium tuberculosis* in AIDS patients.

A B C

Fig. 3. AIDS patients with skin lesions from *Mycobacterium avium complex* (**Figure 3A, Figure** 

A B C

[1] Center for Disease Control and Prevention. A strategic plan for the elimination of tuberculosis from the United States. MMWR 1989;38 (Suppl No. S-3). [2] American Thoracic Society and Center for Disease Control and Prevention. Treatment of

tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit

Fig. 4. Lymphadenitis cervical from *Mycobacterium tuberculosis* **(Figure 4A)**, inguinal-testes lesions from *Mycobacterium avium complex* in lymphatic system (**Figure 4B, Figure 4C)**.

#### **9.2 Clinical symptoms in extrapulmonary tuberculosis**

The main manifestation of extrapulmonary tuberculosis in AIDS patients are lymphadenopathy, pleural effusion, meningitis, pericardial effusion and miliary tuberculosis. This diagnostic is often difficult because the patients with HIV are prone to all of the usual bacterial and viral infection that affect a non-HIV infected patients, so, the presentation of extrapulmonary tuberculosis in HIV-infected patients is generally no different 8, 69.

#### **9.3 Nontuberculous mycobacterial infection in HIV/AIDS patients**

The clinical relevant of NMT infection in HIV/AIDS patients are very frequent, this infection can be pulmonary and extrapulmonary and their symptoms are the same that *Mycobacterium tuberculosis* 51-54, 69. Recently, the nontuberculous mycobacterial are also denominated as environmental opportunist mycobacterial. Normally, they live as environmental saprophytes and they cause opportunist disease in human. Many cases of NTM are associated with some form of immune deficiency in special HIV/AIDS patients. In this group of patients is frequently to find this mycobacterial species as etiological agent for this reason is very important their microbiology diagnostic which is different to *Mycobacterium tuberculosis* 90, 91.

Disseminate *Mycobacterium avium complex* (MAC) diseases was one of the first opportunist infections recognized in the syndrome of AIDS since 20 years ago. The interest of the diagnostic of disseminated MAC and others species of nontuberculous mycobacteria infection have been increased as a result of the HIV pandemic. The prevention and treatment in nontuberculous mycobacteria are life long because cure of them were not achievable in AIDS patients with profound immune suppression. The precise immune defect predisposing HIV/AIDS patients to disseminated diseases is unknown 92 .

The main manifestation of pulmonary and extrapulmonary infections for *Mycobacterium tuberculosis* and nontuberculous mycobacterial are the same affecting lung, pleura, skin, lymphatic system and producing dissemination infection (**Figure 1, Figure 2), (Figure 3A-3B-3C, Figure 4A-4B**) 8, 63,69. For this reason is very important the highly active antiretroviral therapy (HAART) for treatment of AIDS patients that has been associated with a market reduction in the incidence of most opportunistic infection 82,89,92.

So, is very important that the mycobacteriology laboratory should give a definitive diagnostic, because in immunosuppressed patients is important to find resistant alcohol acid bacillus in order to detect the co-infection with *Mycobacterium tuberculosis* which is the most frequently agent found. Nevertheless, others species of mycobacteria may be causing infection and should be search for.

Fig. 1. Messenteric lymph nodes for *Mycobacterium tuberculosis* in AIDS patients.

The main manifestation of extrapulmonary tuberculosis in AIDS patients are lymphadenopathy, pleural effusion, meningitis, pericardial effusion and miliary tuberculosis. This diagnostic is often difficult because the patients with HIV are prone to all of the usual bacterial and viral infection that affect a non-HIV infected patients, so, the presentation of extrapulmonary tuberculosis in HIV-infected patients is generally no

The clinical relevant of NMT infection in HIV/AIDS patients are very frequent, this infection can be pulmonary and extrapulmonary and their symptoms are the same that *Mycobacterium tuberculosis* 51-54, 69. Recently, the nontuberculous mycobacterial are also denominated as environmental opportunist mycobacterial. Normally, they live as environmental saprophytes and they cause opportunist disease in human. Many cases of NTM are associated with some form of immune deficiency in special HIV/AIDS patients. In this group of patients is frequently to find this mycobacterial species as etiological agent for this reason is very important their microbiology diagnostic which is different to

Disseminate *Mycobacterium avium complex* (MAC) diseases was one of the first opportunist infections recognized in the syndrome of AIDS since 20 years ago. The interest of the diagnostic of disseminated MAC and others species of nontuberculous mycobacteria infection have been increased as a result of the HIV pandemic. The prevention and treatment in nontuberculous mycobacteria are life long because cure of them were not achievable in AIDS patients with profound immune suppression. The precise immune

The main manifestation of pulmonary and extrapulmonary infections for *Mycobacterium tuberculosis* and nontuberculous mycobacterial are the same affecting lung, pleura, skin, lymphatic system and producing dissemination infection (**Figure 1, Figure 2), (Figure 3A-3B-3C, Figure 4A-4B**) 8, 63,69. For this reason is very important the highly active antiretroviral therapy (HAART) for treatment of AIDS patients that has been associated with a market

So, is very important that the mycobacteriology laboratory should give a definitive diagnostic, because in immunosuppressed patients is important to find resistant alcohol acid bacillus in order to detect the co-infection with *Mycobacterium tuberculosis* which is the most frequently agent found. Nevertheless, others species of mycobacteria may be causing

defect predisposing HIV/AIDS patients to disseminated diseases is unknown 92 .

Fig. 1. Messenteric lymph nodes for *Mycobacterium tuberculosis* in AIDS patients.

reduction in the incidence of most opportunistic infection 82,89,92.

**9.2 Clinical symptoms in extrapulmonary tuberculosis** 

**9.3 Nontuberculous mycobacterial infection in HIV/AIDS patients** 

different 8, 69.

*Mycobacterium tuberculosis* 90, 91.

infection and should be search for.

Fig. 2. Biopsy of liver pedicle lymph nodes for *Mycobacterium tuberculosis* in AIDS patients.

Fig. 3. AIDS patients with skin lesions from *Mycobacterium avium complex* (**Figure 3A, Figure 3B***)* and *Mycobacterium fortuitum* (**Figure 3C**)

Fig. 4. Lymphadenitis cervical from *Mycobacterium tuberculosis* **(Figure 4A)**, inguinal-testes lesions from *Mycobacterium avium complex* in lymphatic system (**Figure 4B, Figure 4C)**.

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**2** 

*1Norway 2,4Uganda 3USA 5Ethiopia* 

**A Problem or Not?** 

*Medicine, Makerere University* 

**Non-Tuberculous Mycobacteria in Uganda:** 

*1Department of Food Safety and Infection Biology, Norwegian School of Veterinary Science 2Department of Veterinary Public Health and Preventive Medicine, Faculty of Veterinary* 

*3Department of Epidemiology and Biostatistics/ Population Health, college of Public health,* 

HIV/AIDS scourge has been and still is a devastating disease since its advent in the late 70's, claiming up to 25 million lives globally (WHO, 2010). The United Nations program on AIDS (UNAIDS) estimated that 39.5 million people were living with HIV/AIDS by the end of 2006, 63% of these were in Sub Saharan Africa. Furthermore, 4.3 million people were reported to be newly infected with HIV while 2.9 million had lost their lives to AIDS in 2006 alone (UNAIDS, 2010). It is also reported that young people of age 15 and above account for 40% of new infections (CWYF, 2007). Epidemiological models predict a growing trend of the disease most notably the alarming incidence of new infections in sub-Saharan Africa,

In many regards, Uganda is considered a global role model in awareness, prevention and control of HIV/AIDS (Aidsmap, 2006*;* Kaiser family foundation, 2005). The first cases of AIDS in Uganda were identified in Rakai district off the shores of Lake Victoria in 1982 (Serwadda et al 1985; MOH, 2006). AIDS was clinically characterized by wasting, this is why it is popularly known as 'slim disease' (Serwadda et al., 1985). Just as before, this disease is still characterized by opportunistic infections, notable are *Mycobacterium avium* complex infections which are usually the causes of fatality in victims (Serwadda et al., 1985; MOH, 2006). In the late 1980's a famous Ugandan Musician Philly Bongole Lutaaya paved the way

**1. Introduction 1.1 HIV/AIDS** 

Western Europe and Asia (UNAIDS, 2010).

**1.2 HIV/AIDS in Uganda: Past and current situation** 

Adrian Muwonge1, Ashemeire Patience4, Clovice Kankya2,

Demelash Biffa5, Eystein Skjerve1 and James Oloya3

*132 Coverdell centre, University of Georgia Athens, 4Faculty of Community Psychology, Makerere University, 5Schools of Veterinary Medicine, Hawassa University,* 

