By Norman Ward,2014-06-26 21:39
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Tuberculosis ...


    1 Summary

    ? Tuberculosis: a very important and very common mycobacterial disease ? Influence of the AIDS epidemic

    ? Airborne transmission is the most common

    ? Involving the lungs or extrapulmonary

    ? Primary infection, reinfection or reactivation due to immunosuppression ? Diagnosis preferably by Ziehl staining (fast) and sometimes via culture (delayed result) ? Treatment with drug combinations: INH, RMP, EMB, STM, PZA ? Increasing problem with multiresistant bacteria (= resistant to at least INH+RMP)

2 General

    Tuberculosis is a very old problem for humanity. In 1994 tuberculosis bacilli were found in a

    1000-year-old mummy, disinterred in Chiribaya Alta, Peru. This mummy dated from before

    the time of Colombus and the later conquistadors. This negated the opinion that Europeans

    had introduced tuberculosis to that continent. In 1997, DNA of Mycobacterium tuberculosis

    was also found in an Egyptian mummy from Thebes (3000 years old). It is possible that the

    bacterium originates from the one causing bovine tuberculosis. Some people claim that

    tuberculosis started to spread among humans after the domestication of cattle. The

    bacterium has approximately 4000 genes, including an unusually large number which are

    connected with lipogenesis and lipolysis. M. tuberculosis has 250 enzymes for lipid

    metabolism, compared to some 50 in Escherichia coli. The complete genome was mapped in


3 Present situation

    Tuberculosis was and is a serious problem for the individual patient and for public health.

    Globally there are 8 million new cases per year with 2 to 3 million deaths. It is therefore,

    together with AIDS and malaria, among the most important infectious diseases. One hundred

    years ago, one Belgian in 12 died of tuberculosis. In 1943 this was one in 23, in 1990 one in

    1000. From 1953 until 1984 the number of cases in the Western world fell every year by 6%.

    Since 1985 this trend has been reversed (partly due to the AIDS epidemic). For example in

    the USA there were 18% more cases of tuberculosis in 1991 than in 1985. The problem is

    much more pronounced in developing countries. The importance of tuberculosis has greatly

    increased in recent years, not only in view of the increasing number of cases, but also

because of the appearance of multiresistant mycobacteria. Many tuberculosis patients are

    infected with HIV and many HIV patients are infected with tuberculosis. As the number of 3, the risk of active tuberculosis increases 10 to 30-fold. CD4 cells falls below 500 to 250/mm

4 Koch’s bacillus

    In 1882 the German physician Robert Koch discovered the pathogen: Mycobacterium

    tuberculosis or Koch’s bacillus. He received the Nobel prize for this in 1905. A closely related

    pathogen, Mycobacterium bovis, infects a large number of animal species (chiefly cattle

    [Bovidae] and deer [Cervidae]). Bison, camel, llama, giraffe, kudu, pigs and badgers can all

    be infected. This bacterium also occasionally infects humans, but this kind of zoonotic

    transmission is rare today. Tuberculosis should not be regarded as a zoonosis. Vice versa,

    from time to time some animals (dogs, parakeets, elephants, guinea pigs, etc.) may become

    infected with Mycobacterium tuberculosis. Mycobacterium avium causes avian tuberculosis. Infection with M. avium may occur in dogs, cats, cattle, sheep and pigs. Human infections

    also occur and are difficult to treat. Mycobacterium paratuberculosis causes intestinal illness in cattle, sheep and goats (Johne’s disease). Mycobacterium paratuberculosis should not be confused with Corynebacterium pseudotuberculosis, a bacterium which causes "pigeon fever" in horses or with Yersinia pseudotuberculosis. [The name "pigeon fever" refers to a painful swelling in the

    horse's pectoral muscles that resembles a puffed-out pigeon breast.]

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    Note: classification of mycobacteria

    At present there are more than 70 recognised species of mycobacteria. Usually the non-

    tubercular are divided into two large groups: the fast-growing and the slow-growing. This

    name refers to the speed of formation of visible colonies on solid culture bases. Fast growers

    produce colonies within 7 days, slow growers in more than 7 days. The slow growing bacteria

    are divided further into 3 groups depending on pigmentation. Runyon group I contains the

    photochromogens, group II contains the scotochromogens and group III the non-chromogens.

    Group IV of the non-tuberculous mycobacteria contains the fast growers. Scotochromogen

    species produce yellow-orange pigment (carotinoids) in the dark. Photochromogen species

    produce their pigment after exposure to light. These divisions have no fixed taxonomic worth,

    but are important to practical identification schemes. Some bacteria are very closely related

    to each other: e.g. Mycobacterium tuberculosis, M. bovis, M. africanum and M. microti (the M.

    tuberculosis complex); Mycobacterium avium and M. intracellulare (MAC). Some mycobacteria cannot as yet be cultured in vitro (M. leprae). Some species cause infection in humans very

    rarely, but the course of these infections can be severe (e.g. Mycobacterium asiaticum).

5 Transmission

    When someone with open pulmonary tuberculosis coughs, the expectorated air contains

    countless droplets with many bacteria. The same occurs when talking, laughing or sneezing.

    Large droplets quickly fall, but small droplets (aerosol) can stay airborne for a long time. The

    water in such droplets evaporates and the residual bacteria continue to float in the air. They

    may then be breathed in by someone else (airborne transmission). The mycobacteria are

    swiftly killed by ultraviolet rays (daylight). Transmission is therefore usually indoors, and this

    explains the familial clustering of cases, and also the clusters in various areas such as the

    classroom, the workplace, cafés, aeroplanes. Tuberculosis bacteria present on sheets, chairs,

    etc., are normally not dispersed as aerosol and do not present a direct risk for the

    environment. Traditionally it was assumed that only patients with open pulmonary

    tuberculosis (smear-positive persons) were important in transmission. The detection limit for

    bacilli, however, is 5000-10,000 bacilli/ml measured by light microscopy. The infectious dose

    is less than 10 bacilli. This means that also smear-negative (culture positive) people may be

    sources of transmission. The proportion of transmissions caused by them is assumed to be

    approximately 17%. Infection with M. bovis is much rarer than infection with M. tuberculosis.

    Transmission of Mycobacterium bovis may occur due to drinking non-pasteurised infected

    milk. The transmission of bovine tuberculosis may also be airborne (infection from coughing


6 Course of infection

    Once the micro-organisms have arrived in the lungs, they undergo intracellular multiplication

    in macrophages. This produces a small pneumonic consolidation focus (Ghon focus)

    accompanied by swelling of the lymph nodes in the hilum of the lung (also called the primary



    There are then several possibilities:

    ? Most bacteria are destroyed by cellular defence and the few survivors are neutralized

    (they can no longer multiply). In the macrophages, as the result of phagocytosis,

    mycobacterial constituents are released which are presented to the T-lymphocytes as

    antigen. This cell-mediated immune response reaches full development in the course of 3

    to 8 weeks. If an extract of tuberculosis bacteria (PPD: purified protein derivative) is

    then injected into the skin, the defence cells of the patient react to this: there is a

    positive skin test (Mantoux test). The patient is not ill, however. Often the only residual

    lesion that can be observed on a chest X-ray of an infected, asymptomatic person is

    calcification of the hilar lymph nodes.

    ? If the cellular defence of the patient is later reduced (e.g. by AIDS), the small number of

    dormant bacteria may be activated and give rise to evolutive tuberculosis (reactivation or

    post-primary tuberculosis). The latter chiefly involves the apices of the lung, i.e. the

    upper lobes or the apical segments of the lower lobes. A sizable percentage of the

    tuberculosis which occurs in immunodeficient persons will be due to reinfection, as

    opposed to reactivation.

    ? Alternatively, if the initial cellular defence fails to control multiplication, bacteria continue

    to invade the pulmonary tissue. This may heal spontaneously or evolve further into

    active pulmonary tuberculosis (primary pulmonary tuberculosis). The latter is typically

    accompanied by enlarged hilar lymph nodes. There is progressive destruction of

    pulmonary tissue with possibly formation of cavities in the lung. The patient will

    expectorate bacteria (open pulmonary tuberculosis) and thus threaten his or her


    ? If bacteria are carried to other organs through the blood, there will be miliary

    tuberculosis (L. miliarius = millet seed). This is a very serious illness. It results in a

    characteristic chest X-ray picture of bilateral finely disseminated grains of not more than

    1-2 (max 5 mm) diameter.

    ? Late flare-ups of disseminated tuberculosis lead to organ tuberculosis, e.g. tuberculous

    pericarditis with or without constriction, involvement of the kidneys, hip, etc. ? There is much discussion regarding the site of re-infection and re-activation. At present

    it is known for certain that re-infection can occur and is responsible for some of the

    clinical disease. People who have had tuberculosis must not be regarded as immune. By

    means of various molecular techniques (DNA fingerprinting) attempts are being made to

    determine the role re-infection plays in the tuberculosis problem. This will vary

    depending on the frequency of open pulmonary tuberculosis in the population. ? A few years ago a more virulent clone of Mycobacterium tuberculosis, called the “Beijing

    strain”, was isolated. This strain exhibited a typical pattern upon DNA analysis

    (spoligotyping). Contrary to usual expectations, this is a bacterium which apparently has

    increased fitness (most mutations decrease fitness when compared with the wild type).

    Only time will tell what role this strain will play in the problem of tuberculosis.


Note: TB reactivation

    AIDS is not the only way in which tuberculosis may be activated. Recently it has been

    observed that patients with Crohn’s disease or rheumatoid arthritis who are treated with

    infliximab (Remicade?), a monoclonal antibody against tumour necrosis factor alpha, exhibit

an unusually high incidence of activation. People with vitamin D deficiency are at higher risk

    of active pulmonary tuberculosis. For example, the vegetarian Gujarati in London, away from

    their sunny Indian homeland and suffering vitamin D deficiency due to their special diet, are

    at a 10 percent higher risk than other population groups in London.

7 Clinical aspects

    7.1 Clinical aspects, general

    Tuberculosis may affect any organ in the body. Extrapulmonary locations (involvement

    outside the lung) are common in AIDS. Chronic fever is often present. Night sweats are a

    common symptom. Loss of weight is also frequent. In some countries (e.g. Cambodia) misuse

    of cortisone is common. Such practices will of course exacerbate the course of the disease.

There is substantial evidence that host genetic factors are important in determining

    susceptibility to mycobacteria. The major histocompatibility complex and vitamin-D receptor

    genes may be involved in determining human susceptibility to mycobacteria.

7.2 Clinical aspects, pulmonary tuberculosis

    CD_1092_035c.jpg cd_1026_079c.jpg Pulmonary tuberculosis is the most common (70 %). Initially there are few symptoms. The patient may be tired and listless. There is loss of weight, anorexia, mild fever and night

    sweats. There is a chronic, productive cough, sometimes with bloody phlegm. In children

    there are rarely cavities and the sputum contains few acid-fast rods. Sometimes gastric

    aspiration will be necessary for the diagnosis. The Mantoux test is positive in HIV-negative

    children. All in all, the diagnosis is often difficult. Pulmonary tuberculosis may be particularly

    disastrous in combination with pneumoconiosis.


    Diff. diagnosis of lung cavity: In case of Ziehl-negative pulmonary cavities, consideration should also be given to inactive healed tuberculous residual lesions, paragonimiasis and

    fungal infection (e.g. histoplasmosis of the lung), melioidosis, a necrotising tumour or

    pulmonary abscess. The latter may be the result of staphylococcal infection or Klebsiella

    pneumonia. A pulmonary abscess often follows aspiration. Situations where this is common

    include coma, post-anaesthesia, epilepsy, drunkenness, swallowing disorders and

    oesophageal problems such as achalasia or mega-oesophagus in Chagas’ disease. An

    intrabronchial foreign object is another aetiological possibility for pulmonary abscess. It is

important to check whether there is clubbing. An Echinococcus granulosus cyst in the lung is

    generally thin-walled and sharply delineated, unlike a tuberculous cavity or a pulmonary

    abscess. Congenital or acquired bronchial stenosis are rare causes.


    Aspergilloma can locate within a lung cavity. This may persist for many years without

    symptoms. Haemopthysis is the most common clinical complication. At radiography, a mobile

    rounded mass surrounded by a crescentic air shadow (air-crescent sign) is noted inside a

    lung cavity. Such a fungal ball is usually mobile. Thickening of the wall of the tuberculous

    cavity is an early radiological sign.


    A tuberculous pulmonary artery mycotic aneurysm is also known as a Rasmussen aneurysm.

    It results from the weakening and external erosion of the pulmonary arteryl wall, followed by

    dilation of a branch of a pulmonary artery in a tuberculous cavity. It may lead to rupture and



    Bronchopleural fistula and bronchiectasis can result as complications of pulmonary

    tuberculosis. Tracheobronchial stenosis can result from external compression or inflammation

    and scarring of the tracheobronchial wall. Complete destruction of a whole lung is not

    uncommon in late pulmonary tuberculosis. Broncholithiasis is an uncommon complication.


    Bronchogenic carcinoma and pulmonary tuberculosis can coexist, creating a difficult

    diagnostic problem. Tuberculosis may promote lung cancer ("scar cancer") and carcinoma

    may lead to reactivation of tuberculosis by eroding into an encapsulated focus and by

    decreasing the patient's resistance.

7.3 Clinical aspects, pleura

    Involvement of the pleura (7% of patients) is accompanied by an effusion of pleural fluid.

    This is an exudate and the fluid is thus rich in protein (> 3g%). It is often difficult to detect

    acid-fast rods in this fluid. There is more chance of finding the bacteria in a pleural biopsy.

    For this a special needle is needed (Abrams needle, also possible with a Vim-Silverman). DD:

    Pleural exudate may also occur in pneumonia, pulmonary embolism, neoplasia and certain

    auto-immune diseases such as SLE [systemic lupus erythematosus] and RA [rheumatoid



    Chronic pleural tuberculosis can lead to a chyliform or pseudochylous pleural effusion. In

    these cases, it is thought that there is slow and steady accumulation of cholesterol from

    degenerated red and white blood cells. On a CT-scan, a fat-fluid or even fat-calcium level can

    be seen sometimes.

    7.4 Clinical aspects, pericardium Cd_1038_034c.jpg Cd_1026_093c.jpg

    Initially there may be exudative pericarditis. At a later stage the chronic granulomatous inflammatory process provokes thickening of the pericardium, which can lead to constrictive pericarditis with calcifications. The thickened pericardium encloses the heart and makes diastolic expansion difficult, especially when the effusion is sudden. The cardiac output falls considerably as a result. The radiological image of pericardial effusion may be similar to cardiomegaly in myocarditis or dilated cardiomyopathy, but a “water flask”-shaped heart

    shadow is suggestive for pericardial effusion. The jugular distension may increase upon deep inhalation (Kussmaul’s sign). At the same time the blood pressure falls by more than 10 mm Hg (paradoxical pulse). Paradoxal pulse is an exaggeration of the normal variation in the pulse volume with respiration, becoming weaker with inspiration and stronger with expiration. These changes are independent of changes in pulse rate. A pericardial friction rub is usually present, unless large effusions exist. The ECG shows low voltage complexes with PR-depression, concave ST-segments in all leads, flat or inverted T-waves, with or without atrial fibrillation. Echocardiography is very helpful in this disease, but is not available in many hospitals in third world countries. By means of an abdominal ultrasound, however, (more commonly available) it is also possible to detect pericardial fluid via the subxyphoidal route (when one uses an abdominal probe).

Note: pericardial effusion

    Both layers of the normal pericardium are 1-2 mm thick. They enclose a space which normally contains 15-35 mL pericardial fluid. More than 250 mL fluid is needed to enlarge the cardiac outline on chest X-ray. Lesser amounts can be detected by echography.

    7.5 Clinical aspects, miliary tuberculosis Cd_1026_096c.jpg

    If there is dissemination throughout the body with further multiplication of the bacteria, the term miliary tuberculosis is used (2 to 3% of patients). The patient loses weight, is febrile and the general condition deteriorates progressively. If untreated, the patient dies. The chest X-ray shows a characteristic picture (disseminated round "millet seeds"). A Ziehl stain of the sputum is often negative. The white blood cell count is normal in 60-90% of patients. There are a few other disorders which may cause a similar radiological picture, such as pulmonary haemosiderosis (e.g. in long-term mitral stenosis), deep fungal infections (e.g.

    histoplasmosis), pneumonia from varicella virus (chickenpox) and alveolar microlithiasis, also rarely in pneumoconiosis (in mine workers), sarcoidosis, histiocytosis X and diffuse metastases (thyroid, melanoma).

    7.6 Clinical aspects, meninges Tuberculous meningitis often begins very slowly, although subacute development of symptoms also occurs frequently. There may be one or more cerebral/meningeal granulomas (tuberculomata are best visible on MRI). There is quite often headache, also subfebrility. The patient may develop abnormal behaviour, evolving to sleepiness, confusion, psychotic behaviour, stupor and coma. Disturbed gait and ataxia may be present. Sometimes there is involvement of the cranial nerves, epilepsy, and vomiting. Sixth nerve palsy associated with increased intracranial pressure is a well-known false localizing sign. Neck stiffness is not always present. Upon lumbar puncture the cerebrospinal fluid is clear. It will contain both neutrophils and lymphocytes (generally more lymphocytes than neutrophils). The protein content is elevated and the glucose level lowered. The bacteria can only rarely be detected using Ziehl on the cerebrospinal fluid. In 50% of patients the chest X-ray is normal, and more often than not, there are no signs of tuberculosis in other organs. Differentiation from cryptococcal meningitis is important. Other less common disorders which may be included in a differential diagnosis are Lyme disease, brucellosis, Q fever, neurosyphilis, trypanosomiasis, listeriosis, sarcoidosis, lymphoma and leukaemic meningitis.

    7.7 Clinical aspects, kidney Cd_1024_063c.jpg CD_1092_043c.jpg CD_1092_051c.jpg

    Haematuria, proteinuria and sterile pyuria (pus cells in urine without the usual bacteria of urinary tract infections). Late-onset tuberculous cystitis is possible. Note that in approximately 15% of patients there is secondary pyogenic infection of the bladder. Often there are asymptomatic or vague, general symptoms. Renal calcification may occur (visible on plain X-ray of abdomen). Destruction of the renal calices can be seen on IVP [intravenous pyelogram] with ulceration, obliteration or dilation. Ureteral strictures may occur, with secondary dilation, atrophic kidney and compensatory hypertrophy of the other kidney. These lesions must be differentiated from schistosomiasis, chronic pyelonephritis and nephrocalcinosis. Tuberculosis of the adrenal gland may lead to Addison’s disease. The primary site will often not be discovered.

7.8 Clinical aspects, bone

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    Involvement of the spinal column or Pott’s disease (Percivall Pott, English physician 1713-

    1788) often results in back pain with stiffness, hunch back (kyphosis) with local swelling with or without a fistula to the skin. The lesion is generally localised at the thoracic or upper lumbar vertebrae, although the cervical vertebrae are sometimes affected. A very severe complication is compression of the spinal cord with paraparesis or paraplegia. Immobilisation during the first weeks or months of treatment may avoid significant complications. If pus from a lumbar vertebral abscess passes along the fascia of the psoas muscle, it may collect in the groin to form a cold abscess. The patient may keep the hip bent (antalgic posture) if there is psoas irritation. Involvement of the joints, e.g. the hip or knee, is not infrequent. Tuberculous coxitis should be differentiated from Calvé-Legg-Perthes disease (osteochondritis of the upper end of the femur resulting from aseptic necrosis of the epiphysis), hip infarct in sickle cell anaemia, Gaucher’s disease (lysosomal storage disorder) or steroid use, septic arthritis and trauma. Another, rare disease entity in tuberculosis is reactive sterile polyarthritis (Poncet’s syndrome) which can be quite serious.

    7.9 Clinical aspects, peritoneum Cd_1080_029c.jpg

    Tuberculous peritonitis results in chronic exudative ascites with chronic fever. The peritoneum contains countless disseminated small nodules (granulomatous lesions), which can be observed by laparoscopy. Acid-fast bacteria can be detected in the ascites fluid in a minority of cases. A biopsy of the nodular lesions will show granulomatous inflammation with acid-fast rods.

    7.10 Clinical aspects, intestines People with pulmonary tuberculosis may swallow expectorated bacteria. This may lead to involvement of the intestines (e.g. the ileocaecal region). Intestinal involvement may also occur due to drinking milk infected with bovine tuberculosis (Mycobacterium bovis). Either an

    ulcerative or a hypertrophic form may result. The ulcerative form of the disease may be very similar to Crohn’s disease.

7.11 Clinical aspects, lymph nodes

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    Mycobacterial infection of the cervical lymph nodes results in scrofula. This occurs in 3% of

    patients, leading to enlarged nodes, which are slightly painful, firmly attached to the skin and

    sometimes with chronic fistulisation. On a biopsy thick, cheese-like (caseous) pus in the node

    can be seen. This pus does not smell. If there is tuberculous involvement of the inguinal

    nodes, elephantiasis may result. Differentiation from actinomycosis must be made

    (microscopy: sulphur granules). A genital infection with Chlamydia trachomatis

    (lymphogranuloma venereum) or with Calymmatobacterium granulomatis (donovanosis) may

    lead to similar lesions as inguinal tuberculosis.

7.12 Clinical aspects, skin

    The symptoms vary greatly: chronic ulcers, infiltrates (lupus vulgaris; the name "lupus"

    comes from "wolf" in the sense of "voracious"), wart-like lesions (tuberculosis verrucosa

    cutis). If the lesions are very destructive the term “lupus vorax” is sometimes used.

    Sometimes another mycobacterium such as Mycobacterium ulcerans may cause serious skin

    lesions (see "Buruli ulcer"). These can often be found quite quickly on a smear, but for

    correct identification which is important for therapy, a culture is essential.

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    Differentiation from sarcoidosis, leishmaniasis, syphilis, yaws, sickle cell anaemia, tropical

    ulcer, subcutaneous/deep mycosis and skin cancer is also important. Erythema nodosum on

    the lower legs may be secondary in tuberculosis. Tuberculids are a form of allergic reaction to

    the mycobacteria, but these skin lesions are rare. Tuberculosis may also cause

    granulomatous vasculitis, with a predilection for the lower legs. Strong antigenic stimulation

    plays a part in this disorder, which is known clinically as Bazin’s erythema induratum.

8 Diagnosis

    8.1 Diagnosis, general

    The diagnosis of tuberculosis is best made by detecting the bacteria, Mycobacterium

    tuberculosis, which is not always possible. The disease may be suspected from the case

    history. The contribution made by physical examination is tends to be limited for the

    pulmonary form, but more important for the extrapulmonary forms.

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