Tuberculosis

TUBERCULOSIS

TB is a major cause of morbidity and mortality all over the world but the greatest burden is borne by developing countries. TB is caused mainly by the bacterium Mycobacterium tuberculosis (M. tuberculosis)
TB is a chronic infection. The great majority of infections are caused by M. tuberculosis. TB can also be caused by M. bovis, which is acquired by drinking unpasteurised milk from infected cows
TB is an ancient disease which remains a worldwide problem. The importance of TB is evident in the following facts:
1. About 1 in 3 of the world’s population are infected with tubercle bacilli and someone is newly infected every second
2. Although most infected people remain asymptomatic, TB causes illness in about 8 million people every year
3. About 2 million people die from TB every year - more deaths than for any other infectious disease.
Where does TB occur?
About 95% of the world’s cases of TB occur in the developing countries of South East Asia, Sub-Saharan Africa and the Western Pacific. The largest number of cases occur in South East Asia and this region accounts for 33% of incident cases globally. The highest mortality from TB also occurs in this region. It is estimated that 1-2% of the Indian population are infected with tubercle bacilli.
The global incidence of TB has increased in the last two decades. This has been attributed to a number of factors, including:
the HIV pandemic
emergence of drug-resistant strains of M. tuberculosis
poor national TB control programmes
worsening socio-economic conditions in many countries
GLOBAL BURDEN
More than 2 billion people (about one-third of the world population) are estimated to be infected with Mycobacterium tuberculosis . The global incidence of tuberculosis (TB) peaked around 2003 and appears to be declining slowly. In 2007 there were an estimated 13.7 million chronic active cases, and in 2010, 8.8 million new cases, and 1.45 million deaths, mostly in developing countries. The absolute number of tuberculosis cases has been decreasing since 2005 and new cases since 2002.
China has achieved particularly dramatic progress, with an 80 percent decline in its TB mortality rate. The distribution of tuberculosis is not uniform across the globe; about 80% of the population in many Asian and African countries test positive in tuberculin tests, while only 5–10% of the U.S. population test positive.
The incidence of TB varies with age. In Africa, TB primarily affects adolescents and young adults. However, in countries where TB has gone from high to low incidence, such as the United States, TB is mainly a disease of older people, or of the immunocompromised.
Microbiology:
M. tuberculosis is a non-motile, rod-shaped bacterium. It is an obligate aerobe, which explains why it tends to be found in the well-aerated, upper lobes of the lungs.
It is a slow growing organism (dividing only every 16-20 hours) that lives within tissue macrophages. Humans are the only reservoir of M. tuberculosis. Both cows and humans serve as reservoirs for M. bovis.
The organism does not have the characteristics of either Gram positive or negative bacteria.
The Ziehl-Neelsen stain is used to demonstrate the presence of the bacilli in a smear. They appear as bright red rods against a contrasting background.
The cell wall is a major factor in the virulence of the organism. It resists destruction by many antibiotics, acids, alkalis, osmotic lysis and oxidation and enables the organism to survive inside macrophages.


How is TB transmitted?
Nearly all TB infection is acquired by inhalation of respiratory droplets from an infectious contact. Air droplets 3-5 μm diameter coughed, sneezed or spat out by an “open” case of TB. The droplets are inhaled by a close contact. This may lead to a lung infection which then may go on to develop into disease – in the lungs and/or in other organs.
Abdominal TB can also result from drinking unpasteurised cow’s milk infected with M. bovis.
Between 70-90% of individuals exposed toTB will not develop any symptoms or signs of infection.
The reasons for this are unclear but, in view of the known risk factors for infection, they may include inhalation of an insufficient number of organisms to cause infection or adequate immunity to prevent an infection becoming established.

Following inhalation, TB bacilli settle in the alveoli. This results in a small focus of local inflammation in the lung parenchyma. This primary focus usually occurs in the upper lobes in adults but may occur in any of the lung lobes in children. More than one focus may occur in the same patient.
The organisms then spread via the local lymphatics to the nearest hilar lymph nodes, which may then enlarge.
The primary focus and the enlarged regional lymph nodes form the primary complex or “Ghon complex”.
What happens next depends on the size of the infecting dose and the resistance of the host. Most commonly, the primary focus is “walled-off” by the immune system and lies dormant for years. The infection may be reactivated years later if the immune system of the host becomes weakened.
The primary focus is not contained and lung disease may develop in several ways:
*The primary focus enlarges and undergoes central necrosis to form a cavity
*The infection can spread locally and result in tuberculous bronchopneumonia
*Marked swelling of the mediastinal lymph nodes may compress large bronchi and result in lobar collapse
*The enlarged lymph node may act like a one-way valve causing hyperinflation of a lung or lobe
*The adjacent pleura can become infiltrated by M. tuberculosis resulting in a hypersensitivity reaction characterised by granulomas composed mainly of lymphocytes
*Pleural infiltration may result in a pleural effusion which is rich in lymphocytes – a useful pointer to the diagnosis when pleural fluid is aspirated and analysed
Long term complications of the damage to lung tissue include emphysema and bronchiectasis
Haematogenous dissemination of M. tuberculosis leads to granuloma formation in many organs. Examples include:
Diffuse infection of the lungs: “miliary” TB
Brain: TB brain abscess
Meninges: TB meningitis
Bones: TB osteomyelitis – commonly affects the spine and is then called “Potts’ disease”
Pericardium; TB pericarditis and pericardial effusion
Disseminated disease is most likely to occur in the immunocompromised patient (e.g. HIV/AIDS, malnutrition) and at extremes of age.


Natural history following TB exposure
What are the likely outcomes following exposure to open TB?
Dormant TB (90%) well no TB disease not infectious to others Active TB (10%) ill likely to die if untreated infectiousInfection(10-30%)No infection(70-90%)Exposure to TBActivation of infection results in disease

What are the symptoms and signs of TB?

1. Primary infection with no spread of the disease
Individuals with primary infection do not usually have any symptoms or signs of ill health although some people develop a minor flu-like illness.
The response of the immune system to the infection may result in clinical signs of hypersensitivity to M. tuberculosis in a minority of people, for example:
erythema nodosum
phlyctenular keratoconjunctivitis
They will also have a positive Mantoux test
2. Active infection: symptoms
Symptoms of TB can be divided into general symptoms and those specific to the organ infected.
TB can result in a myriad of symptoms depending on which organs are involved and how their function is affected.
The lung is the predominant organ affected, being involved in over 75% of cases.
Commonly affected organs following haematogenous spread from the lung are the abdomen, lymph nodes, spine, meninges, kidneys, bone and reproductive organs.
TB lymphadenitis presents as painless enlargement of the superficial lymph nodes. The neck is the commonest site involving the cervical, submandibular, pre and post- auricular lymph nodes. The lymph nodes are non-tender, matted together and rubbery in consistency. It is common for enlarged lymph nodes to ulcerate and discharge.
3. Pulmonary and abdominal TB
Pulmonary TB (PTB)
The apical region is the most commonly affected in adults. Pulmonary lesions may involve any part of the lung in infancy and childhood.
Examination of the respiratory system may be completely normal even in active disease. Abnormalities which may be detected clinically include signs of consolidation, collapse, pleural effusion and fibrosis
Abdominal TB
Pathology affects the mesenteric and the retroperitoneal glands, the omentum and the gastrointestinal tract. Patients may present with weight loss, diarrhoea or constipation, abdominal distension (from ascites) or chronic intestinal obstruction. Enlarged mesenteric lymph nodes may be palpable as multiple intra-abdominal masses.
Tuberculosis of the spine – “Pott’s disease”
TB commonly affects the spine, especially in young children, and usually presents as a swelling on the back.
The lower thoracic and the upper lumbar vertebrae are the usual sites, however any vertebra can be affected.
Diagnosis:
Diagnosis of TB is based on –
Typical history of chronic cough with the general symptoms of fever, malaise and weight loss
Presence of general and specific clinical signs
Positive findings on relevant investigations – usually CXR and sputum smear stained for acid-fast bacilli
It is important to note that specific symptoms and signs may be absent…
TB should be suspected in any chronically-ill person!
Sputum examination
Useful in adults with productive cough
Sputum microscopy: Smear stained with the Ziehl-Nielsen stain to demonstrate the presence of the acid and alcohol fast bacilli (AFB). When positive, patient is referred to as “smear-positive” or “open TB” and risk of transmission of infection to others is very high. However, the test often negative in patients with TB. Yield is higher in patients with lung cavities.
Sputum culture: Takes about 6-8 weeks and so is of limited use in clinical diagnosis.
Gastric washings examined for AFB: Carried out in children as they swallow rather than cough-up sputum. The test aims to recover the swallowed AFB from the stomach. Test positive in only about one third of children with TB.
Other investigations
Other investigations are indicated depending on the organs/ systems affected by the disease
Spinal radiographs in Pott’s disease
Lymph node aspirate (microscopy, culture and cytology) or biopsy (histology and culture) in TB lymphadenitis
Lumbar puncture for cerebrospinal fluid analysis in TB meningitis (microscopy, biochemical analysis and culture)
Treatment
Administration of a single antibiotic in the treatment of TB has been shown to lead to the development of mycobacteria resistant to that drug
Combination chemotherapy is the treatment of choice; effective regimens for the treatment of TB must contain multiple drugs to which the organisms are sensitive
Using drug combinations minimises the development of drug-resistant strains
Treatment: DOTS
DOTS means Directly Observed Therapy Short Course.
It involves the administration of a combination of antituberculous drugs to a TB patient under the supervision of a healthcare personnel. DOTS helps to ensure compliance, reduce transmission by shortening the period of infectivity, improve the cure rate and reduce the risk of drug resistance
There are many regimens for treating TB, but commonly used drugs include:
Intramuscular streptomycin
Oral rifampicin
Oral isoniazid (INH)
Oral pyrazinamide
Oral ethambutol may be substituted for IM streptomycin in patients that are above the age of 6 years
Treatment lasts for 6 months (but IM streptomycin / oral ethambutol and oral pyrazinamide are usually given during the first 60 days of treatment only.
Prevention and Control
The World Health Organisation has declared TB a global health emergency
Several other organisations are involved in TB control, including the International Union Against TB and Lung Disease, the Center for Disease Control (USA) and the Global Plan to Stop TB (GPSTB).
TB control remains a worldwide challenge. There is a need to improve DOTS coverage and meet the emerging challenges of TB occurring in people with HIV/AIDS and multidrug resistant TB.
TB Control Strategies include –
Case finding: aims to identify TB cases promptly and treat them with effective drugs.
Contact tracing: Close contacts of TB cases are screened for evidence of infection. Mantoux positive cases are treated with oral isoniazid for 6-9 months to prevent them from developing the disease.
BCG vaccination: Although the efficacy of BCG vaccination in protecting against TB is controversial, it is generally accepted that BCG is more effective in preventing disseminated disease and death, than pulmonary TB.
Medication resistance
Primary resistance occurs in persons infected with a resistant strain of TB. A person with fully susceptible TB develops secondary resistance (acquired resistance) during TB therapy because of inadequate treatment, not taking the prescribed regimen appropriately, or using low-quality medication. Drug-resistant TB is a public health issue in many developing countries, as treatment is longer and requires more expensive drugs.
Multi-drug-resistant tuberculosis (MDR-TB) is defined as resistance to the two most effective first-line TB drugs:rifampicin and isoniazid.
Extensively drug-resistant TB (XDR-TB) is also resistant to three or more of the six classes of second-line drugs.
Totally drug-resistant TB (TDR-TB), which was first observed in 2003 in Italy, but not widely reported until 2012, is resistant to all currently-used drugs.


BCG Vaccine
Recommendations
Children. BCG vaccination should only be considered for children who have a negative tuberculin skin test and who are continually exposed, and cannot be separated from, adults who:
1. Are untreated or ineffectively treated for TB disease (if the child cannot be given long-term treatment for infection); or
2. Have TB caused by strains resistant to isoniazid and rifampcin.
Health Care Workers. BCG vaccination of health care workers should be considered on an individual basis in settings in which
A high percentage of TB patients are infected with M. tuberculosis strains resistant to both isoniazid and rifampcin;
There is ongoing transmission of such drug-resistant M. tuberculosis strains to health care workers and subsequent infection is likely; or
Comprehensive TB infection-control precautions have been implemented, but have not been successful.
Health care workers considered for BCG vaccination should be counseled regarding the risks and benefits associated with both BCG vaccination and treatment of Latent TB Infection (LTBI).
Contraindications
Immunosuppression. BCG vaccination should not be given to persons who are immunosuppressed (e.g., persons who are HIV infected) or who are likely to become immunocompromised (e.g., persons who are candidates for organ transplant).
Pregnancy. BCG vaccination should not be given during pregnancy. Even though no harmful effects of BCG vaccination on the fetus have been observed, further studies are needed to prove its safety.
Iraq is one of the countries in WHO Eastern Mediterranean Region (WHO-EMRO) with the highest tuberculosis (TB) burden. The estimated incidence of TB is about 130 new cases / 100.000 population / year [WHO / MOH 2003], with about 30.000 new cases per year among which 12600 new smear positive pulmonary Tuberculosis (PTB).
Control of TB is a top priority for Iraqi Ministry of Health (MOH) and a most challenging task. the Directed Observed Therapy – Short Course (DOTS) has been adopted in