Introduction In 2005 the Centers for Disease Control and Prevention (CDC) published new guidelines for preventing the transmission of Mycobacterium tuberculosis (MBT) in healthcare facilities.1 These guidelines replace all previous CDC guidelines for tuberculosis (TB) infection-control in healthcare settings and apply to all settings in which healthcare workers (HCWs) might either share air space with persons with infectious TB disease or have contact with clinical specimens containing MBT. The magnitude of the risk varies by setting, occupational group, prevalence of TB in the community, patient population served in the setting, procedures performed, and effectiveness of TB infection-control measures. However, every setting in which services are provided to persons who have suspected or confirmed TB disease should have a TB infection-control plan. The 2005 guidelines explicitly identify oral healthcare facilities as outpatient settings in which patients with suspected or confirmed infectious TB disease are expected to be encountered
Etiology and Epidemiology Robert Koch first described MBT, the causative organism for tuberculosis, in 1882.2 MBT is carried in airborne particles called droplet nuclei that are generated when persons with infectious TB disease cough, sneeze, shout, sing, or talk (Figure 1).3,4 
| Figure 1. MBT is carried in airborne particles called droplet nuclei that are generated when persons with infectious TB disease coughs, sneezes, shouts, sings, or talks. |
These droplet nuclei are between 1-5 microns in size, which can remain suspended in air for hours and can be carried in normal air currents throughout a room or building.5 The probability of a person exposed to MBT becoming infected depends on the concentration of infectious droplet nuclei in the air and the duration of the exposure to a person with infectious TB disease.1 Environmental factors such as exposure in confined spaces, inadequate ventilation, and recirculation of air containing infectious droplet nuclei further increase the likelihood of transmission.6 The persons at highest risk for exposure to an infection with MBT are close contacts of persons who share air space in a household or other enclosed environment with a person with pulmonary tuberculosis (Table 1).6 Table 1. Persons at highest risk for exposure to an infection with MBT.6 Population | Examples | Foreign-born persons from countries with a high incidence of TB disease who arrived in the U.S. within the past five years | Africa, Asia, Eastern Europe, Latin America, and Russia | Persons who frequently travel to countries with a high incidence of TB disease | Residents and employees of settings that are high risk | Correctional facilities, long-term care facilities, and homeless shelters | Populations at high risk who are defined locally as having an increased incidence of TB disease | - Foreign-born persons
- Hispanics
- Blacks
- Asians
- Patients untreated for latent TB infection
- HIV-infected patients
- Patients receiving immunosuppressive therapy
| Populations at high risk who are defined locally as medically underserved and who have low income | Infants, children, and adolescents exposed to adults in high-risk categories | HCWs who serve patients who are at high risk | HCWs with unprotected exposure to a patient with TB disease |
When susceptible hosts inhale droplet nuclei, the bacilli travel through the mouth or nasal passages, the upper respiratory tract, and bronchi to the alveoli where a local infection is established.7 The immune response to such infections is predominantly cell-mediated, involving both CD4+ and CD8+ T-cells.8 Pulmonary macrophages process the antigens and present them to both major-histocompatibility-complex (MHC) class II molecules, which activate CD4+ cells; and to MHC class I molecules, which activate CD8+ T cells. Within two to ten weeks following exposure the immune response will limit further multiplication of MBT. However, if the quantity or virulence of the TB bacilli is such that they overwhelm the immune response, the bacilli may disseminate throughout the body by lymphatic and hematogenous spread.9,10 TB is recognized worldwide as the leading cause of death from an infectious disease, responsible for approximately two million deaths annually.11 In the United States, a total of 14,097 TB cases were reported to the CDC in 2005, which represented a 2.9% decrease from 2004 and the TB case rate of 4.8 per 100,000 in 2005 represented a 3.8% decline compared with 2004.12 The decrease in the annual case rate slowed, from an annual average of 5.6% for 1993 through 2002 to an average of 3.1% for 2003 through 2005.12 The rate of TB in foreign-born persons was 8.7 times that of those born in the United States. In addition, Hispanics, Blacks, and Asians had TB rates 7.3, 8.3, and 19.6 times higher than whites, respectively. Moreover, the number of multidrug-resistant (MDR) cases of TB increased by 13.3% compared to 2003 (the most recent year for which complete drug-susceptibility data are available). The slower deceleration of TB rate nationally, the disparity of TB rates between whites and racial/ethnic minorities, and the increased incidence of MDR cases all threaten progress toward the goal of eliminating TB in the United States.
Clinical ManifestationsLatent TB infection (LTBI)The immune response to MBT culminates in the formation of tuberculous granulomas at foci of infection. Consequently, not all bacilli are eliminated from the body and those incarcerated in granulomas can remain viable for many years.13,14 At this stage, the person infected is said to have LTBI. Although immunological test results for MBT are positive, these patients have no symptoms, no radiographic abnormalities compatible with tuberculosis, and all bacteriologic studies are negative. Patients with LTBI are not contagious. Tuberculosis (TB disease)Approximately 5-10% of the people who become infected with MBT and who are not treated for LTBI will develop TB disease during their lifetime (Table 2).1,15,16 Table 2. Diseases and conditions that increase the risk of progression from LTBI to TB Disease1,15,16 - HIV infection
- History of infection with MBT within the past two years
- History of untreated or inadequately treated TB disease
- Infants and children aged <4 years
- Diabetes mellitus
| - Chronic renal failure
- Immunosuppressive therapy
- Silicosis
- Malignancies (carcinoma of the head, neck, lung; leukemia; lymphoma)
- Intestinal bypass or gastrectomy
- Body weight ≥10% below ideal weight
|
The lung is the most common site for TB disease. Classic symptoms include chronic ill health, coughing with hemoptysis, low-grade fever, weight loss, and night sweats. About 15% of patients with TB disease present with an extrapulmonary site of infection. This is especially common in patients who have both TB and an HIV infection. Expectoration of the infected sputum may cause tuberculous tracheitis, laryngitis (hoarseness, coughing, and pain), and tuberculous ulcers on the tonsils (dysphagia) and nasal cavity (obstruction, perforation, nasal discharge).17,18 When the cervical lymph nodes are involved, they may caseate forming tuberculous abscesses or undergo fibrosis and calcification.17,18 Swallowing of the infected sputum may result in tuberculous ulceration of the ileum. In a few instances, there is rapid pathologic progression and the tubercle bacilli spread via the bloodstream to many organs giving rise to miliary tuberculosis.19 Oral Manifestations of TBThe estimated prevalence of oral tuberculous lesions ranges from 0.05 to 5%.20,21,22 Oral lesions are usually secondary, reflecting oral inoculation with infected sputum or as a result of hematogenous spread.20,23,24 Rare cases of primary tuberculous involvement of oral structures have been reported.20,25-28 In a recent study evaluating patients with TB and a co-infection with HIV, the prevalence of oral tuberculous lesions was found to be 1.33%.24 Oral tuberculous lesions are nonspecific in their clinical presentation, and their consideration in the differential diagnosis requires a high degree of awareness.24,29-34 While all oral tissues may be affected, in the cohort of patients with both TB disease and HIV-infection, the palate and dorsum of the tongue (Figure 2) were the most frequent sites of oral involvement.20,24,28 These data are in agreement with those reported by other investigators in patients with TB disease without an HIV-infection.35,36,20,24,28 Pain and cervical lymphadenopathy are common but not universal findings.24 A rare case of tuberculous osteomyelitis of the mandible and several cases of tuberculous parotitis have been documented.37-40 
| Figure 2. Oral tuberculous lesion of the dorsum of the tongue in a patient with both TB disease and HIV infection |
Diagnosis Early diagnosis of infection with MBT is important because of the nature of the disease. The tuberculin skin test or a blood assay for Mycobacterium tuberculosis are useful for screening groups of people for LTBI with exposure rates that substantially exceed those of the general population (Table 1).1
Latent TB InfectionThe tuberculin skin test (TST), which is the Mantoux intradermal test, using 5 tuberculin units of tween-stabilized purified protein derivative (PPD)-tuberculin is the traditional method of diagnosing LTBI.1 The antigen is injected intracutaneously into either the volar or dorsal surface of the forearm. In patients with LTBI, the TST evokes a delayed hypersensitivity reaction to the tuberculin mediated by T-lymphocytes producing an area of redness and swelling. The test is read at 48 to 72 hours. Erythema is disregarded, and the diameter of the induration is measured (Table 3). Table 3. Interpreting the tuberculin skin test reaction.1 Induration of ≥5 mm | Induration of ≥10 mm | Induration of ≥15 mm | People with HIV infection | Foreign-born persons | People with no risk factors for TB | Close contacts of people with TB | HIV-negative persons who use illicit drugs People with no risk factors for TB | People who have had TB disease before | People in residential facilities | Illicit drug users | Children ≤4 years of age |
While the relative specificity of the TST skin test is high, both false positive and false negative reactions have been reported.41 False-positive reactions may be due to previous sensitization with mycobacterial antigens, as may be seen following vaccination with Bacille Calmette-Guerin (BCG).42 False-negative reactions to the TST have been reported in immunocompromized patients, in patients with recent exposure to MBT, and in very young children.41-42 The CDC recommends persons with a positive TST undergo further evaluation.43 In recent years a number of in vitro diagnostic tests in the form of blood assays for Mycobacterium tuberculosis (BAMT) have been developed. One of these tests approved by the Food and Drug Administration (FDA) for the detection of latent TB infection is the QuantiFERON®-TB Gold (QFT-G) test.44 This test detects the release of interferon-gamma in fresh heparinized blood from sensitized persons when it is incubated with mixtures of synthetic peptides representing two proteins present in MBT. The sensitivity of QFT-G is statistically similar to that of TST for detecting TB infection. However, the QFT-G measures cell-mediated response to peptides from two MBT proteins not present in any BCG vaccine strains and absent from the majority of mycobacteria other than MBT. Hence, the QFT-G has greater selectivity. TB DiseaseAlthough the history, physical examination, TST and/or QFT-G data, and other studies such as chest radiographs are helpful and at times may strongly suggest TB disease, definitive diagnosis usually requires the demonstration of MBT in the patient's tissues or secretions.1 Bacteriologic examination, which includes obtaining a specimen of sputum, detection of acid-fast bacilli (AFB) in stained (Ziehl-Neelsen method) smears examined microscopically, may provide the first bacteriologic clue to TB disease. However, not all AFB are tubercle bacilli, therefore, a positive bacteriologic culture for MBT is essential to confirm the diagnosis. DNA probes specific for the genus Mycobacterium now are used routinely to identify specific mycobacterium. When the presence of MBT has been confirmed, it is then necessary to perform drug susceptibility testing on positive cultures.
Principles of Medical ManagementPreventionImmunization with viable Mycobacterium bovis BCG is the most widely used preventive measure to control tuberculosis worldwide. Administered to newborns in a single dose, it prevents severe disease and reduces mortality among children from miliary and meningeal disease.45,46 However, BCG does not protect against pulmonary tuberculosis in children or adults.45,46 As mentioned earlier, optimal immune response to MBT infection appears to involve both CD4+ and CD8+ T-cells.8 BCG activates CD4+ T-cells by being taken up by macrophages and residing within phagosomes which are membrane-enclosed vacuoles. These antigens, once processed in the phagosomes, then readily interact with MHC class II molecules. However, the ability of the bacillus to block acidification of the phagosomes precludes its release into the cytoplasm and for an antigen to bind to MHC class I molecules it must be processed in the cytoplasm of the infected cells. Consequently, BCG fails to elicit a CD8+ T-cell response. A recently developed recombinant bacillus with an impaired ability to counter the acidification of phagosomes will soon enter phase 1 clinical trials.47 This new vaccine is likely to be more effective because it targets both CD4+ and CD8+ T-cells. Treatment of Infection with MBTThe goal of antibacterial chemotherapy is to induce selective toxicity. Selectivity can be realized by attacking targets: - Unique to the pathogen
- In the pathogen that are similar to but not identical to those of the host
- In the pathogen that are shared by the host but that vary in importance between pathogen and host
One target is the bacterial cell wall, a structure that is both unique and essential for the survival of most pathogenic bacteria.48 The bacterial cell wall is a three-dimensional meshwork of peptide-crosslinked sugar polymer (peptidoglycan or murein) surrounding the cell just outside its cytoplasmic membrane. Bacteria may be conveniently divided into two groups, Gram-positive and Gram-negative, based on the relative abilities of bacteria to retain purple Gram-stain after being washed with an organic solvent such as acetone. Gram-positive bacteria retain the stain and appear purple, whereas Gram-negative bacteria lose the stain and appear pink. The ability to retain stain results from two distinguishing characteristics of cell wall architecture. In Gram-positive bacteria, the cell wall is composed of a thick layer of murein (Figure 3A). The murein layer in Gram-negative bacteria is thinner but it is surrounded by a second, outer lipid bilayer membrane (Figure 3B). The cell wall of mycobacteria, which include the causative agent of tuberculosis, is similar to that of Gram-negative bacteria (Figure 3C).  | Figure 3A. In Gram-positive bacteria, the cell wall is composed of a thick layer of murein. |  | Figure 3B. The murein layer in Gram-negative bacteria is thinner but it is surrounded by a second, outer lipid bilayer membrane. |  | Figure 3C. The cell wall of mycobacteria, which includes the causative agent of tuberculosis, is similar to that of Gram-negative bacteria. The main difference being mycobacteria has a thick outer membrane composed of two leaflets that are asymmetrical in size and composition. |
Both are enclosed by an inner cytoplasmic membrane, a thin murein layer, and an outer membrane. The main difference is that, in mycobacteria, the outer membrane is thick, composed of two leaflets that are asymmetrical in size and composition.49 The inner leaflet is composed of arabinogalactan and mycolic acid, and the outer leaflet is composed of extractable phospholipids. Cell wall biosynthesis takes place in the following three major steps: - Synthesis of murein monomers from amino acids and sugar building blocks (N-acetylglucosamine [NAG] and N-acetylmuramic acid [NAM]).
- Polymerization of the monomers into linear peptidoglycans.
- Crosslinking of the polymers into a three-dimensional meshwork.
In mycobacteria the NAM residues of the cell wall are modified by the addition of a long chain consisting of a NAG-arabinogalactan linker topped with mycolic acid. The addition of arabinose units is catalyzed by the enzyme arabinosyl transferase. The synthesis of mycolic acid includes the formation of saturated hydrocarbon chains catalyzed by the enzyme fatty acid synthetase 1 (FAS1), which are then linked by the enzyme fatty acid synthetase 2 (FAS2). The linked products undergo further enzymatic transformations to become mycolic acid. Standard antimycobacterial treatment regimens include antibiotics that target unique targets such as the synthesis of NAG-arabinogalactan and the early steps in mycolic acid synthesis (Table 4). Table 4. Antimycobacterial agents.1,51 First-line Drugs | Drug | Mechanism of Action | Adverse Drug Effects | Ethambutol | Inhibits arabinosyl tranferase | Optic neuritis
Loss of visual acuity | Pyrazinamide | Inhibits fatty acid synthetase1 | Morbilliform rash
Arthralgias
Hyperuricemia | Isoniazid | Inhibits fatty acid synthetase2 | Hepatitis
Peripheral neuropathy
Inhibits CYP450 enzymes | Rifamycins:
Rifampin
Rifabutin
Rifapentin | Bind to RNA polymerase and inhibit transcription | Hepatitis
Flu-like symptoms
Morbilliform rash
GI disturbances
Induce CYP450 enzymes | Second-line Drugs | Cycloserine | Inhibits monomer synthesis | Psychosis
Seizures
Peripheral neuropathy | Ethionamine | Inhibits fatty acid synthetase2 | Hepatitis
Hypothyroidism | Aminoglycosides:
Streptomycin
Capreomycin
Kanamycin
Amikacin | Bind to the 30S ribosomal subunit and inhibit translation | Ototoxicity
Nephrotoxicity
Neuromuscular blockade | Fluoroquinolones:
Ciprofloxacin
Ofloxacin
Gatifloxacin
Levofloxacin
Moxifloxacin | Inhibit topoisomerase II (DNA gyrase), thereby releasing DNA with staggered double-stranded breaks | Nausea
Abdominal pain
Restlessness
Confusion | Aminosalicylic acid | Competitive para-aminobenzoic acid antagonist | GI disturbances | Combination Drugs | Rifamate | isoniazid + rifampin | Rifater | isoniazid + rifampin + pyrazinamide |
Antimycobacterial agents are almost always used in combination. The frequency of resistance mutations and the number of bacteria present in a clinical infection dictate this therapeutic strategy.50 Each tuberculous lesion in an infected lung can contain 108 bacteria. The frequency of mutant resistance to any single antimycobacterial drug is about one in 106 bacteria. This means in each tuberculous lesion an average of about 100 bacteria are resistant to an antimycobacterial drug even before that drug is administered. Combination therapy with two drugs reduces the likelihood of encountering pre-existing resistance to about one bacterium in 1012. Treatment with four drugs further lowers this possibility to one in 1024. Resistance to antimycobacterial agents is primarily chromosomal. The treatment of infections with MBT can be divided into treatment of LTBI and treatment of TB disease. Guidelines with detailed management recommendations are published and updated regularly.1,51 Treatment of Latent TB infectionThe risk for progression from LTBI to TB disease is highest during the first two years after infection and is often predicated on concomitant medical conditions that alter the ability of the immune system to maintain the isolation of MBT (Table 2).52-53 HIV infection is the most important risk factor.55-59 It has been estimated persons infected with MBT and co-infected with HIV have a 6-10% risk per year of developing TB disease, while an immunocompetent person infected with MBT has a 10% life-time risk for TB disease.60 Isoniazid, given for nine months in a single daily dose, is the drug of choice for the treatment of LTBI.6 Patients who become TST positive following exposure to patients with MBT resistant to isoniazid and those patients with intolerance to isoniazid may be treated with rifampin for four months.61 For patients with known exposure to MDR TB disease, a regimen with two drugs to which MBT is susceptible is recommended for nine to 12 months.62,63 The Treatment of LTBI in Pregnant PatientsA TST or BAMT should be administered to all women who are at risk for MBT infection, and those who have LTBI should be treated to prevent maternal and congenital TB disease.6,64 It is postulated an MBT infection in utero is either the result of (1) hematogenous infection through the umbilical vein or (2) prenatal aspiration of infected amniotic fluid.65,66 Congenital TB is rare but fatal if untreated and it is difficult to diagnose in time to treat successfully without knowledge of a maternal history of TB. 66,67 Isoniazid is considered safe for the treatment of LTBI in pregnancy.68 |
رد: TUBERCULOSIS- INFECTION CONTROL / EXPOSURE