Recognise tuberculosis in a pot, on a slide, and in a set of results.
Explain why the disease looks different in a patient with advanced HIV.
Explain the clinical features of tuberculosis, and what each test adds to the diagnosis.
Why this disease is important
Nigeria carries the heaviest tuberculosis burden in Africa and ranks sixth in the world.
Children are about one in ten notified cases, and undernutrition is a major driver.
You will meet tuberculosis again and again, as a student and as a doctor. Several specialties see this one disease from different angles, so this module gives you five lenses on one condition.
Consider this case
A 34-year-old man presents with a ten-week history of cough, drenching night sweats and progressive weight loss. He has a firm swelling in the right side of his neck. He was diagnosed with HIV four years ago, stopped attending the clinic eighteen months back, and restarted antiretroviral therapy six weeks ago.
On examination he is febrile and visibly wasted. There is bronchial breathing at the right apex and a group of matted, non-tender cervical nodes.
Investigations: haemoglobin 9.2 g/dL with normocytic normochromic RBCs, raised ESR, monocytosis, CD4 count 92 cells/microlitre. Sodium 126 mmol/L. Corrected calcium 2.78 mmol/L with a suppressed parathyroid hormone. Chest radiograph shows a right apical cavity. Two sputum smears are negative for acid-fast bacilli; rapid molecular testing on sputum detects the M. tuberculosis complex with no rifampicin resistance. An excised cervical node shows granulomas with central caseous necrosis, and Ziehl-Neelsen on the section is negative. He starts 2(RHZE)/4(RH).
How did the cavity form, and why is it at the apex?
Recognise how tuberculosis appears in tissue, and why.
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Morbid Anatomy
By the end of this lens you can
Describe a gross specimen.
Identify the parts of a granuloma, and the features of a tuberculous granuloma.
Distinguish a Ghon focus, a Ghon complex and a Ranke complex.
Describe the course of a tuberculous lesion in the lung.
Distinguish latent infection from active disease, and recognise extrapulmonary tuberculosis.
Distinguish tuberculosis from lymphoma on a lymph node biopsy.
DDefinition
Tuberculosis is a chronic infection caused by Mycobacterium tuberculosis. walls the organism off inside : with and around a dead centre of .
Self checkA lymph node biopsy from a patient with tuberculosis shows a necrotising granuloma. What would you expect to find at its centre?
: dead tissue that has lost its structure. On gross examination, caseous necrosis is soft and cheese-like, and down the microscope it has no nuclei or visible architecture.
IIdentification
At a viva bench you meet tuberculosis as a pot and a slide. How will you approach the case?
How do you know this is a lung specimen? Notice the defining anatomy, including the shape, lobar organisation, and the hilar structure. On low power microscopy, notice the thin walled alveoli with prominent air spaces.
You are at a viva bench in the morbid anatomy department. In front of you are a pot holding a slice of lung and a slide taken from the same patient. The examiner says: tell me about this case.
What do you examine first?
CorrectThe right order. Say where the lesion sits, what colour it is, whether it is solid or open to an airway, and whether the rest of the lung is spared. The gross appearance tells you what to expect on the slide.
Not this oneYou can get there, but you have skipped the gross appearance and arrive at the slide with nothing to test. The examiner asked about the case, and the pot comes first.
Not this oneAt this bench the station tests what the specimen shows. Describe, then interpret, then ask for the history.
Not this oneA stain does not help at this point. Bacilli are easiest to find early, while the lesion is exudative and caseous, and once it has fibrosed and calcified you usually cannot find them. Describe the specimen first.
MMorphology: gross
Here, you can focus on the visible abnormalities on the lung specimen.
Open a marker
1The cavity
Erosion of an apical caseous focus into a bronchus empties the necrotic centre, leaving a ragged, irregular cavity lined by caseous material. The sputum now carries bacilli, so a patient with a cavity is highly infectious.
2The cavity wall
Ragged, firm and poorly walled off by fibrous tissue. Erosion of blood vessels in this wall produces haemoptysis.
3Multiple areas of softening
The upper zones are riddled with grey-white caseation and several separate areas of softening and cavitation, rather than one clean defect. This is coalescence of nodules over months.
4The lower zones
Congested but not cavitated. Secondary disease localises to the apex of one or both upper lobes. This may relate to the high oxygen tension there, since the organism is an obligate aerobe.
Figure 1Cavitary tuberculosis. Necrotic material has emptied into a bronchus, leaving a cavity open to the airway.Yale Rosen, Atlas of Pulmonary Pathology · CC BY-SA 2.0 · reproduced unmodified
Figure 2Miliary tuberculosis involving the spleen. Innumerable nodules, all of similar size, which is the discriminating feature.Yale Rosen, Atlas of Pulmonary Pathology · CC BY-SA 2.0 · reproduced unmodified
MMorphology: histology
Down the microscope, tuberculosis is a , built in layers from a dead centre outwards.
Open a marker
1Central caseation
Structureless and granular, with no nuclei and no preserved architecture. To the naked eye it looks like soft cheese, hence the word ‘caseous’. Bacilli, when demonstrable, will be seen here.
2Epithelioid macrophages
Activated macrophages with abundant cytoplasm and elongated nuclei, palisaded around the necrotic centre.
3Langhans giant cell
Epithelioid macrophages fused into one large cell. Its nuclei sit in a horseshoe around the edge, leaving the centre of the cell clear.
4Lymphocyte rim
Sensitised T lymphocytes at the periphery. They are the source of the signal that activates the macrophages in the wall, so the structure depends on their continued presence.
5Fibroblasts and collagen
Spindled cells and collagen deposited at the margin. Granulomas heal by fibrosis and calcification, and this zone is what later becomes the calcified nodule found incidentally at autopsy.
Figure 3Necrotising granuloma in pulmonary tuberculosis. Central caseous necrosis, a palisade of epithelioid histiocytes around it, and a lymphocyte cuff at the periphery.Yale Rosen, Atlas of Pulmonary Pathology · CC BY-SA 2.0 · reproduced unmodified
Caseous necrosis
Structureless and granular. No nuclei, no cell outlines. This is where the bacilli are, when a stain finds any.
Epithelioid macrophages
Activated macrophages with abundant cytoplasm, packed shoulder to shoulder. Their presence makes the lesion a granuloma.
Langhans giant cells
Epithelioid macrophages fused together, nuclei pushed to the edge in a horseshoe. Present in granulomas of many causes.
Lymphocyte rim
The sensitised T cells that keep the macrophages activated. The wall stands only while they are there.
Fibroblasts and collagen
The outer margin, closing the lesion off. This is the zone that later fibroses and calcifies.
Diagram of a granuloma in concentric zones. Structureless caseous necrosis at the centre, a palisade of epithelioid macrophages around it, Langhans giant cells within that palisade, a rim of lymphocytes outside, and fibroblasts laying collagen at the edge.
Figure 5Langhans giant cell. The nuclei sit in a ring around the periphery of the cell, leaving the central cytoplasm free. A foreign body giant cell has its nuclei scattered at random instead.Ed Uthman, Houston, Texas · CC BY 2.0
DDifferentials
Tuberculosis is not the only disease that forms granulomas or enlarges a lymph node. These can look like it, and this is what separates them.
Figure 6Sarcoidosis. Non-necrotising granulomas with many multinucleate giant cells, and no caseation.Yale Rosen, Atlas of Pulmonary Pathology · CC BY-SA 2.0 · reproduced unmodified
What looks the same
Granulomas without caseation. It also raises calcium through vitamin D, just as tuberculous granulomas do.
What separates it
Not the slide alone, because tuberculous granulomas can lack caseation too. Stain for acid-fast bacilli whenever you see granulomas.
Figure 7Hodgkin lymphoma, nodular sclerosis type. Large atypical Reed-Sternberg-type cells among small lymphocytes, eosinophils and bands of collagen. No granulomas and no caseation.Yale Rosen, Atlas of Pulmonary Pathology · CC BY-SA 2.0 · reproduced unmodified
What looks the same
An enlarged lymph node. On a peripheral node biopsy in Nigeria, tuberculosis and the lymphomas are the two leading diagnoses.
What separates it
Caseation points to tuberculosis. Reed-Sternberg cells point to lymphoma. The gross specimen cannot decide it.
Figure 8Foreign body granuloma: a granulomatous reaction to keratin, with foreign body giant cells and chronic inflammatory cells.Department of Pathology, Calicut Medical College · CC BY-SA 4.0 · reproduced unmodified
What looks the same
Multinucleate giant cells.
What separates it
In a foreign body giant cell the nuclei are scattered at random through the cytoplasm. In a Langhans giant cell they sit in a horseshoe at the edge.
EEtiology
Tuberculosis is caused by Mycobacterium tuberculosis, an acid-fast bacillus. This section covers the risk factors: what turns exposure into infection, and infection into disease.
Self checkA 9-year-old girl has had a firm, matted swelling in the neck for three months. She has no cough. The family keeps cattle and drinks unpasteurised milk. Which of the following is true of the route of transmission?
Not this oneAge changes how children present, with failure to thrive, a persistent cough or lymphadenopathy. The route of entry determines the site, and her history points to it.
CorrectThe milk history points to ingestion, and she has no cough to suggest a lung focus. Tuberculosis from contaminated milk was once a common primary infection.
Not this oneHaematogenous spread seeds many organs at once. A single group of enlarged nodes and a milk history point to ingestion.
Not this oneInhaled infection begins in the lung and drains to the hilar nodes.
PPathogenesis
How an inhaled organism survives, sets off the immune response, and leaves a lesion behind. Use the arrows to move through each step, and watch the chart light up as you go.
Droplet nuclei reach the alveolus
Phagocytosed by alveolar macrophage
Phagosome-lysosome fusion inhibited
Spread to regional lymph nodes
T cells sensitised
Macrophages activated, epithelioid change
Fusion into Langhans giant cells
Caseous necrosis at the centre
Ghon focus, then Ghon complex
Contained
Fibrosis and calcification, Ranke complex
Containment fails
Erosion into a bronchus, cavity
Bacilli in sputum
Flow chart of pathogenesis. Droplet nuclei reach an alveolus, a macrophage phagocytoses the organism, phagosome-lysosome fusion is inhibited, organisms spread to regional lymph nodes, T cells are sensitised, macrophages are activated and become epithelioid, some fuse into Langhans giant cells, the centre caseates, forming the Ghon focus and then the Ghon complex. From there the lesion either fibroses and calcifies into a Ranke complex, or erodes into a bronchus leaving a cavity and bacilli in the sputum.
Inhalation and phagocytosis
Droplet nuclei are small enough to slip past the mucus of the upper airway and reach an alveolus, each carrying only a few bacilli. They land at the bottom of the upper lobe or the top of the lower lobe, usually close to the pleura. An alveolar macrophage phagocytoses them.
The organism survives phagocytosis
Sulfatides in the wall inhibit the phagosome from fusing with the lysosome that carries the bactericidal enzymes. Phagocytosed bacteria are not destroyed. They multiply within the macrophage, which then carries them through lymphatics and blood to distant sites.
Sensitisation in the draining node
Bacilli, free or within phagocytes, travel via lymphatics to the regional nodes, which also often caseate. Macrophages present antigen to T helper cells, and sensitised T cells multiply and enter the circulation in search of the organism.
Activated macrophages destroy tissue as well as bacteria
Sensitised T cells returning to the lesion activate the macrophages, which acquire epithelioid morphology and attack the bacteria. The attack destroys lung tissue at the same time. The necrotic centre is granular and cheese-like: . Some epithelioid cells fuse into Langhans giant cells.
Ghon focus, Ghon complex, Ranke complex
The parenchymal lesion is the Ghon focus, a grey-white area of consolidation one to one and a half centimetres across. Combined with the caseating node that drains it, it is the Ghon complex. Cell-mediated immunity controls the infection in most people, the complex fibroses and calcifies, and the healed pair is the Ranke complex.
Or dissemination
Where containment fails, the apical caseous focus expands and erodes into a bronchus, evacuating its centre and leaving a cavity. Affected patients now produce sputum containing bacilli, and disease disseminates along the airways.
Ghon focus
A single subpleural lesion, low in the upper lobe. Caseous at the centre.
Ghon complex
The focus plus the hilar node that drains it, joined by lymphatics. This pairing is primary tuberculosis.
Ranke complex
The same pair after it has healed. Both fibrose and calcify, and turn up years later as an incidental finding.
Three-stage diagram. First a single subpleural Ghon focus in the lung. Then the same focus joined by lymphatics to a caseating hilar node, together the Ghon complex. Then both shrunken and calcified, the Ranke complex.
Figure 12Sub-pleural primary focus, the Ghon focus, in gross lung.Yale Rosen, Atlas of Pulmonary Pathology · CC BY-SA 2.0 · reproduced unmodified
Open a marker
1The parenchymal focus
The Ghon focus: a subpleural area of consolidation in the lower part of the upper lobe or the upper part of the lower lobe.
2The draining hilar node
Bacilli travel along lymphatics to the regional nodes, which caseate in turn. Parenchymal lesion plus nodal lesion is the Ghon complex, and the pairing is the signature of primary disease.
3The lymphatic route
Nothing is visible along this line. The link is lymphatic drainage: the involved node is the node that drains the focus.
Figure 13Chest radiograph showing a Ghon complex in active tuberculosis: the parenchymal focus together with the involved hilar node.Basem Abbas Al Ubaidi · CC BY
Figure 14Ranke complex: the Ghon complex after fibrosis and calcification. The arrow marks the healed subpleural focus at the edge of the lung. The dotted circle marks the calcified hilar node that drained it.Yale Rosen, Atlas of Pulmonary Pathology · CC BY-SA 2.0 · reproduced unmodified
Self checkAt autopsy you find a calcified subpleural nodule and a calcified hilar node in someone who was never diagnosed with tuberculosis. What happened to this person?
They were infected, but their cell-mediated immunity contained it. That is what happens in the majority of people. The parenchymal focus and the node that drained it both fibrosed and calcified, leaving the Ranke complex. Organisms may still have been alive inside it. Had their resistance failed at any point, the lesion would have reactivated.
SClinical presentation
Tuberculosis may have varying signs and symptoms depending on the patient’s age and immune status.
Symptoms
Malaise, anorexia, weight loss and night sweats. A cough with increasing purulent sputum, and haemoptysis in a substantial proportion.
Signs
Low-grade fever that rises late each afternoon. Weight loss.
Why
Cytokines from activated macrophages drive the fever, sweats and weight loss. The sputum comes from a cavity open to an airway, at the apex of one or both upper lobes, and the haemoptysis from vessels eroded in its wall.
Symptoms
A persistent cough, or none at all. Most primary infections cause no symptoms.
Signs
Failure to thrive on the growth chart. Lymphadenopathy.
Why
Primary disease in a child enlarges lymph nodes rather than destroying lung, so there is often no cavity. Undernutrition is both cause and consequence, and a major driver in Nigeria.
Symptoms
Often no cough. Symptoms follow the organs involved outside the lung.
Signs
Signs of extrapulmonary or disseminated disease rather than a simple lobar illness.
Why
A granuloma needs a strong cell-mediated response. Below a CD4 count of 200 the lung shows lower and middle lobe consolidation, hilar nodes and no cavity, and disease outside the lung rises steeply. Pulmonary tuberculosis defines WHO clinical stage 3; extrapulmonary disease defines stage 4.
Self checkA 3-year-old boy is brought to the hospital by his mother because he has not gained weight for six months. His mother describes a constant cough. He has no night sweats and no fever today. His older brother was treated for tuberculosis last year. Which of the following is most accurate?
Not this onePrimary infection causes no symptoms, or only a mild illness, in most people. No fever and no sweats is typical of childhood disease.
Not this oneA negative smear is expected at this age and tells you little. A child of three swallows sputum rather than coughing it up.
CorrectFailure to thrive, a constant cough and a household contact are how tuberculosis presents at this age.
Not this oneA cavity needs a strong immune response and many organisms. Small children usually have neither.
IInvestigations
The routine workup for tuberculosis spans multiple specialties: the morbid anatomist makes the tissue diagnosis, the microbiologist looks for the organism, the haematologist reads the blood picture, and the chemical pathologist reads the fluids.
Self checkA lymph node biopsy from a 30-year-old man with a four-month history of cough, neck swelling and unintentional weight loss shows granulomas with epithelioid macrophages and giant cells, and no caseation anywhere. Does that exclude tuberculosis?
No. Tuberculous granulomas may lack caseation even in immunocompetent patients. Stain for acid-fast bacilli whenever you see granulomas, caseating or not.
Self checkA 28-year-old woman has a cervical node biopsied. It shows granulomas with central caseous necrosis and several Langhans giant cells. Ziehl-Neelsen on the same block shows no acid-fast bacilli. Which of the following is most accurate?
Not this oneDropping the diagnosis because of a negative stain is the commonest mistake here. The stain confirms well and excludes poorly.
CorrectA positive stain confirms your diagnosis, but a negative stain does not exclude it.
Not this oneA negative stain is the usual result in a tuberculous node, so repeating it will most likely give the same answer. Molecular testing on the tissue is more useful.
Not this oneLanghans giant cells appear in granulomatous disease of several causes. They are not unique to tuberculosis.
CCourse
Most tuberculous infections are contained by an intact immune system. In immunocompromised patients, the disease behaves very differently.
None. Primary infection is asymptomatic in most people, or produces no more than a mild flu-like illness.
Transmission
No. There are no bacilli in sputum, so nothing is aerosolised.
What the tests show
Tuberculin testing or an interferon gamma release assay is positive, indicating exposure. Sputum studies are negative.
The tissue
Bacteria walled off within a granuloma, dormant but viable. The lesion fibroses and calcifies.
Symptoms
Insidious onset of malaise, anorexia, weight loss and low-grade remittent fever appearing late in the afternoon, with night sweats. Sputum becomes purulent, and haemoptysis occurs in a substantial proportion.
Transmission
Yes, where the lung is involved and a lesion has cavitated, because the sputum then contains bacilli.
What the tests show
Sputum acid-fast stain, culture or molecular testing may be positive. The immunological tests remain positive.
The tissue
Granulomas with central caseation, progressive tissue destruction, and in the lung a cavity where the caseous centre has evacuated.
Self checkA 40-year-old man has a positive tuberculin test after his coworker was diagnosed. He has no cough, no fever and no weight loss, and his chest radiograph is normal. His wife asks whether he can pass the infection to their children. Which of the following is most accurate?
Not this oneCell-mediated immunity contains rather than eradicates M. tuberculosis. Bacteria walled off in a granuloma remain dormant but viable, which is why reactivation is possible decades later.
CorrectTransmission requires bacilli in sputum, which requires a lesion communicating with an airway. Containment prevents that.
Not this oneNothing in the history suggests a false positive. A true positive in a well man with a normal radiograph is latent infection, which does not spread.
Not this onePrimary infection almost always begins in the lung and drains to the regional nodes, so latent infection is not limited to the nodes.
Not this oneTransmission needs bacilli in sputum, and latent infection puts none there. Close contact with him carries no risk while the infection stays contained.
CComplications
When containment fails, the lesion keeps destroying tissue in and around the lung.
CExtrapulmonary tuberculosis
Tuberculosis can reach almost any organ. Everywhere the process is the same: a granuloma forms, the centre caseates, tissue is destroyed, and fibrosis replaces it.
Outline of a human body. Each extrapulmonary site of tuberculosis lights up when you choose it: the meninges in the head, the cervical lymph nodes in the neck, the pleura and pericardium in the chest, the adrenal glands and kidneys, the ileum in the abdomen, the fallopian tubes in the pelvis, the spine, and the whole body for miliary disease.
Ward
A 14-year-old girl has had back pain for five months and now walks with difficulty. She has lost weight and has night sweats. Her uncle, who lives with the family, was treated for pulmonary tuberculosis last year. There is a sharp angular prominence in the mid thoracic spine. Imaging shows two adjacent vertebral bodies destroyed, the intervertebral disc between them lost, and a soft tissue collection lying in front of the spine.
What is this condition called?
Tuberculosis of the vertebrae, known as Pott disease. The angular deformity is a gibbus and follows anterior collapse of adjacent bodies.
What is the paraspinal collection?
A cold abscess. It may extend along tissue planes and present at a distance from the spine, as an abdominal or pelvic mass.
What is the most feared acute complication?
Cord compression. Collapsed bodies and the anterior collection can compress the cord, which is the likely cause of her difficulty walking.
Figure 16Gibbus deformity from tuberculosis of the spine.National Museum of Health and Medicine (US Department of Defense) · No known copyright restrictions
Ward
A 31-year-old man has had headache and fever for three weeks, and for the past four days he has been confused. On examination, when asked to look to his left, his left eye does not move outward past the midline. Lumbar puncture gives clear fluid with a high protein, a low glucose and a lymphocytosis.
Where is the disease, and how do you know?
In the meninges. A dense grey exudate collects in the basal leptomeninges, around the optic chiasm and the vessels at the base of the brain. The cranial nerves leaving the brainstem pass through this exudate, which is why they fail.
What does the fluid tell you?
Clear cerebrospinal fluid (CSF), lymphocytosis, raised CSF protein and low glucose fits tuberculous meningitis, but there are other differentials. Send it for microbiology and consider adenosine deaminase once bacterial meningitis and cryptococcosis are ruled out.
The lesion is granulomatous, and granulomatous inflammation develops over weeks. A history of hours to days should prompt you to reconsider the diagnosis.
He later develops a stroke. How could that happen?
The exudate wraps around the vessels of the circle of Willis as they pass through it. Those vessels become inflamed, narrow and thrombose, cutting off blood supply and causing a stroke.
Figure 17Tuberculous meningitis. Thick grey gelatinous exudate fills the basal cisterns and encases the vessels and cranial nerves at the base of the brain.Yale Rosen, Atlas of Pulmonary Pathology · CC BY-SA 2.0 · reproduced unmodified
Check yourself
Why is a patient with latent infection not infectious?
Transmission requires bacilli in sputum, which requires a lesion open to an airway. Walled-off organisms reach no airway.
What makes the miliary pattern recognisable?
Innumerable foci of about two millimetres, all of the same size, resembling millet seeds.
What converts a caseous focus into a cavity?
Erosion into a bronchus, which evacuates the caseous centre and leaves a ragged cavity poorly walled off by fibrous tissue.
Name the commonest form of extrapulmonary tuberculosis and its usual site.
Lymphadenitis, usually cervical, called scrofula.
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Microbiology and Parasitology
By the end of this lens you can
Explain why M. tuberculosis is called acid fast.
Name the virulence factors in the cell wall, and say what each one does.
Describe how tuberculosis spreads, and how often infection becomes disease.
Describe how you would test a patient with suspected tuberculosis.
Interpret a negative smear, and say what it does not rule out.
Describe how drug resistance develops and how it spreads.
The organism
Mycobacterium tuberculosis is a rod-shaped bacterium, or bacillus, that causes tuberculosis. It is acid-fast, it is an obligate aerobe (meaning it needs oxygen to survive), and it grows very slowly.
M. tuberculosis is one of the mycobacteria: a group of rod-shaped bacteria with walls full of special lipids that contribute to their virulence and give them unique staining properties.
Organism
Key point
Mycobacterium tuberculosis
Tuberculosis.
Mycobacterium leprae
Leprosy.
Non-tuberculous mycobacteria
Over 100 other species, grouped together.
Nocardia
The other major acid-fast organism, outside the mycobacteria.
The lipid wall resists ordinary stains, so the laboratory uses the acid-fast stain, as follows:
Red stain, with heat
The smear is covered with the red dye carbol fuchsin and heated, so the dye gets into the waxy wall.
Acid alcohol
Acid alcohol is poured over the smear. It removes the red dye from most bacteria. The lipids in the mycobacterial wall do not dissolve, so these rods keep their red colour.
Blue counterstain
Methylene blue is added. Everything that lost the red dye now takes up the blue.
Reading the smear
Acid-fast bacilli are red rods on a blue background. They hold fast to the red stain, which is where their name comes from.
A finished sputum smear.
Open a marker
1Acid-fast bacilli
Slender red rods. Carbol fuchsin is driven into the wall with heat, then acid alcohol is poured over the smear. The wall lipids do not dissolve, so the rods stay red.
2Methylene blue counterstain
Everything that lost the red stain takes up the blue counterstain. The blue makes the red rods easier to see.
Figure 18Ziehl-Neelsen stain of sputum sample. Acid-fast bacilli appear as red rods against a methylene blue background.Ajay Kumar Chaurasiya · CC BY-SA 4.0 · reproduced unmodified
The lipid wall shapes how the organism grows, both in the body and in the laboratory.
The cell wall and virulence factors
Several of the wall lipids protect the organism from the host.
Each lipid is built from mycolic acid, and in the table below, each row is built from the ones above it.
Component
What it is
Mycolic acid
A large fatty acid in the wall. It makes the organism acid-fast.
Mycoside
A mycolic acid bound to a sugar, forming a glycolipid. Only acid-fast organisms have mycosides.
Cord factor
A mycoside made of two mycolic acids joined to the sugar trehalose.
Sulfatides
Mycosides like cord factor, with sulfate groups on the sugar.
Wax D
A complex mycoside that boosts the immune response to other antigens.
Three of them act directly on the host.
Cord factor lines the bacilli up side by side in culture.
Open a marker
1Cord formation
Bacilli lie parallel to each other in cords. Cord factor causes this. It is two mycolic acids joined to the sugar trehalose, and only virulent strains have it.
2Individual bacilli at the margin
At the edge of the cord, single rods can be seen.
Figure 19Classic serpentine cording of the Mycobacterium tuberculosis complex, Ziehl-Neelsen stain from a positive MGIT culture.Ajay Kumar Chaurasiya · CC0
Self checkA researcher removes one lipid from the wall of M. tuberculosis. The organism can now no longer survive inside macrophages, because its phagosomes fuse with lysosomes. Which of the following was removed?
Not this oneCord factor stops neutrophils moving and damages mitochondria. It does not act on phagosome fusion.
CorrectSulfatides stop the phagosome from fusing with the lysosome, so the organism survives inside the macrophage.
Not this oneWax D boosts the immune response as an adjuvant. It does not protect the organism inside the macrophage.
Not this oneMycolic acid makes the wall acid-fast. The block on phagosome fusion comes from the sulfatides.
Transmission and risk
Tuberculosis spreads through the air, but most people who breathe it in never become ill.
An adult with pulmonary tuberculosis sends droplet nuclei into the air when coughing, singing, laughing or talking. Each is about 5 micrometres across and carries about 5 bacilli.
Infection
A close contact, such as someone in the same household, has about a 30% chance of being infected.
Disease soon after
About 5% of infected people develop tuberculosis in the next 1 to 2 years.
Disease later
Another 5% develop it later in life, when dormant organisms reactivate. That makes a 10% lifetime risk for anyone infected.
With HIV
In a person with HIV the risk of reactivation is far higher: about 10% every year.
Self checkA 28-year-old woman shares a room with her brother, who has smear-positive pulmonary tuberculosis. She is HIV negative and well. Which of the following is most accurate about her risk?
Not this oneMost infected people never become ill. Her lifetime risk, if infected, is about 10%.
Not this oneHIV raises the risk sharply. But an HIV-negative person who is infected still has about a 10% lifetime risk of disease.
CorrectAbout 5% of infected people develop tuberculosis within 1 to 2 years, and another 5% later in life.
Not this oneOnly about 5% of infected people develop disease in the first 1 to 2 years.
Laboratory tests
The microbiology laboratory works through microscopy, culture and sensitivity: it looks for the organism under the microscope, grows it, then tests it against the drugs. For tuberculosis it also uses molecular tests and tests of the immune response.
Whether acid-fast bacilli are present, and roughly how many.
What it cannot tell you
The species or drug resistance. It cannot tell M. tuberculosis from the non-tuberculous mycobacteria, and it is often negative when there are few bacilli.
Time to result
Same day.
Figure 21Auramine O fluorescence microscopy. Acid-fast bacilli fluoresce as bright yellow-green rods because auramine binds the mycolic acids of the cell wall.Siduduziwe Nxumalo · CC BY-SA 4.0 · cropped
What you see
Fluorescent yellow-green rods on a dark background.
What it tells you
Whether acid-fast bacilli are present, and roughly how many. Fluorescent rods are quicker to find than rods stained with Ziehl-Neelsen.
What it cannot tell you
The species or drug resistance, and it is often negative when there are few bacilli.
Time to result
Same day.
Figure 22The rapid molecular test: a sputum cartridge goes into a bench-top analyser.patandfam · AI-generated
What you see
A printed result: M. tuberculosis detected or not, and rifampicin resistance detected or not.
What it tells you
Whether M. tuberculosis DNA is in the sample, and whether the organism is resistant to rifampicin.
What it cannot tell you
Whether the organisms are viable, or resistance to drugs other than rifampicin.
Time to result
Within hours.
Figure 23Mycobacterium tuberculosis on Loewenstein-Jensen medium. Composite plate showing whole slopes, colony detail at increasing magnification, and a Ziehl-Neelsen smear.Erika C. and Martina Drackova, Jevicko microbiology laboratory · CC BY-SA 4.0 · reproduced unmodified
What you see
Rough, dry, buff (cream-coloured) colonies that clump together on Loewenstein-Jensen medium. A Ziehl-Neelsen smear of the colonies confirms them.
What it tells you
The species, and susceptibility to each drug.
What it cannot tell you
A quick answer.
Time to result
Up to six weeks for visible growth.
Figure 24Purified protein derivative is injected just under the skin of the forearm.patandfam · AI-generatedFigure 25The swelling is measured across, as induration, days later.patandfam · AI-generated
What you see
Induration (a firm swelling) where purified protein derivative was injected, measured across in millimetres. Erythema does not count.
What it tells you
Whether the person has been infected at some time.
What it cannot tell you
Whether disease is active now. BCG can make it positive. It can be negative in up to one in three people with active lung disease, and in anergy: steroid use, malnutrition, sarcoidosis, Hodgkin lymphoma and AIDS.
Time to result
Read at 48 to 72 hours, at a second visit.
Figure 26The interferon gamma release assay uses a blood sample and an incubator.patandfam · AI-generated
What you see
A blood result: how much interferon gamma the patient's lymphocytes release when they meet tuberculosis antigens.
What it tells you
Whether the person has been infected at some time. BCG and most non-tuberculous mycobacteria do not make it positive, and it needs only one visit.
What it cannot tell you
Whether disease is active now.
Time to result
A day or two.
Figure 3Necrotising granuloma in pulmonary tuberculosis. Central caseous necrosis, a palisade of epithelioid histiocytes around it, and a lymphocyte cuff at the periphery.Yale Rosen, Atlas of Pulmonary Pathology · CC BY-SA 2.0 · reproduced unmodified
What you see
A with and on a tissue section.
What it tells you
Tissue changes typical of tuberculosis, from a biopsy or an excised node.
What it cannot tell you
The species or drug resistance.
Time to result
Days.
Reading the tuberculin test
Tuberculin reactions have no single cut-off. Each risk group has its own.
Who is tested
Positive from
People with HIV, or on immunosuppression
5 mm
People from a high-incidence country, which includes every sub-Saharan African country, healthcare workers, former prisoners, and people with diabetes or renal failure
10 mm
Everyone else
15 mm
Drug resistance
Resistance starts in one patient's lesion and then spreads to other people.
Any large population of M. tuberculosis holds a few organisms that are naturally resistant to any one drug. They are present before any drug is given.
Monotherapy selects them
Under inadequate treatment, especially a single drug, the resistant organisms become the dominant population. This was first seen in patients given streptomycin alone.
The resistant population regrows
The survivors multiply back to the original number, and the whole population is now resistant. Clinically this looks like relapse.
Resistant organisms spread
The next person inhales resistant organisms and has resistant disease from the start, without taking any drug. Failure to treat the first episode properly is the commonest cause of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis.
Self checkA rapid molecular test on sputum reports M. tuberculosis detected and rifampicin resistance detected. It gives no result for the other first-line drugs. Which of the following is true of the rifampicin result?
Not this oneHow common it is does not matter here. Rifampicin resistance raises concern for resistance to isoniazid as well.
CorrectRifampicin resistance is half of the definition of MDR tuberculosis, which is resistance to both isoniazid and rifampicin. This test reports rifampicin only, so isoniazid susceptibility is still needed to confirm MDR.
Not this oneResistance to each of these drugs arises by mutation. Resistant organisms exist in the population before any drug is given.
Not this oneThe assay reads nucleic acid, and resistance does not change how the organism looks.
Check yourself
Why do mycobacteria stay red after acid alcohol?
The lipids in the wall do not dissolve in acid alcohol, so the red carbol fuchsin stays in the rods.
What does a positive tuberculin reaction show?
Infection with the organism at some time in the past. It does not show that disease is active now.
What advantages does the interferon gamma release assay have over the skin test?
Prior BCG vaccination does not make it positive, and it needs one visit instead of two. It shares every other limitation.
Why is culture not the first investigation?
Growth takes up to six weeks, too slow for a first answer. Culture is still sent, because it gives the species and full drug susceptibility once the organism grows.
How can someone who has never taken a tuberculosis drug have resistant disease?
Inadequate treatment selects resistant organisms in one patient. That patient then passes them to the next person by the usual route.
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Haematology and Immunology
By the end of this lens you can
Describe the immune response to tuberculosis, from phagocytosis to granuloma.
Explain why the lung damage is a type IV hypersensitivity reaction.
Interpret the blood count and the film in chronic tuberculosis.
Predict what the biopsy shows as the CD4 count falls.
The immune response
In tuberculosis, contains the bacillus. Macrophages phagocytose it but cannot kill it until sensitised T cells activate them.
Phagocytosed, survives inside
Antigen presented to T helper cells
T cells sensitised
Sensitised cells reach the lesion
Macrophages activated
Bacteria destroyed, tissue destroyed
Caseous necrosis
Giant cells, fibroblasts, collagen
Bacteria walled off in the granuloma
Healing by fibrosis and calcification
Flow chart of the immune response. The organism is phagocytosed but not killed, antigen is presented to T helper cells, T cells are sensitised, sensitised cells reach the lesion, macrophages are activated, bacteria and lung tissue are destroyed together, the centre becomes caseous, giant cells and fibroblasts and collagen form the wall, the organisms are walled off, and the lesion heals by fibrosis and calcification.
Survival inside the macrophage
On first exposure the host has no specific immunity. Inhaled bacteria bring in neutrophils and macrophages and are phagocytosed, but they are not destroyed. They multiply inside the macrophages, which carry them through lymphatics and blood to distant sites.
Antigen presentation
Some macrophages manage to break up the organism and present its protein antigens to T helper cells. This starts the cell-mediated response.
Macrophage activation
Sensitised T cells multiply, enter the circulation to find the organism, and on meeting their antigen activate the macrophages waiting at the lesion.
Tissue destruction
Activated macrophages can now destroy the bacteria, and their attack also destroys the lung tissue around them. The dead centre is granular and cheese-like: . This tissue damage is a type IV delayed hypersensitivity reaction.
Granuloma formation
, , fibroblasts and collagen surround the caseous centre, with lymphocytes at the edge. The lymphocytes keep the macrophages activated, so the wall holds only while they are present. Inside this the bacteria are held back but stay alive.
Healing
Granulomas heal by fibrosis, calcification and scarring, and the organisms in them often become too few to find on staining. If host resistance later falls, the bacteria may grow again.
Tuberculin and interferon gamma tests
The T cell sensitisation behind this response can be measured using the tuberculin skin test and the interferon gamma release assay.
Self checkWhy can a positive tuberculin skin test not establish active disease?
In a tuberculin skin test, purified protein derivative (PPD) is injected into the skin. In a person who has been infected, a firm swelling (induration) appears at 48 to 72 hours. This is a type IV delayed hypersensitivity reaction. The induration shows sensitisation. But, latent infection and active disease are both sensitised, so the reaction is the same in both.
Self checkA 30-year-old nurse has a BCG scar and a positive tuberculin skin test at staff screening. She has no symptoms and a normal chest radiograph. An interferon gamma release assay is also positive. Which of the following is true of the second test?
Not this oneBoth tests report only that the immune system has met the antigen. Sensitisation looks the same in latent infection and in active disease.
CorrectThe assay measures interferon gamma released in response to antigens specific to M. tuberculosis, so BCG does not make it positive. But it cannot separate latent infection from active disease, because sensitisation looks the same in both.
Not this oneThe two tests agree. Both detect sensitisation, by different means, and both are positive.
Not this oneBCG can make a skin test positive, but it does not make the assay positive. A positive assay alongside the skin test points to real sensitisation.
The blood picture
The immune tests show only that the body has met the organism. The full blood count and film show the effect of chronic inflammation on the blood and, in disseminated disease, on the marrow.
Tuberculosis can cause either, so the direction does not exclude it.
Pancytopenia
Marrow infiltration. Lymphoma, myeloma and metastatic tumour do the same.
Neutropenia and marrow fibrosis
Seen in miliary disease.
Leuco-erythroblastic film
Miliary disease in the marrow pushes erythroblasts and immature granulocytes into the blood.
Leukaemoid reaction
Can occur in disseminated disease.
Self checkA 45-year-old woman has had pulmonary tuberculosis for several months. Her haemoglobin is well below the reference range, and her white cell and platelet counts are normal. The red cells are normocytic and normochromic. Serum iron is low and ferritin is normal. Which of the following is the most likely cause of her anaemia?
Not this oneA low serum iron does not prove iron deficiency. Chronic inflammation holds iron in the stores, so the ferritin stays normal. The ferritin separates the two.
CorrectNormocytic normochromic cells, a low serum iron and a normal ferritin is the pattern of anaemia of chronic disease. Iron is kept in the stores.
Not this oneTuberculosis can deplete folate through excess use, but folate deficiency makes the red cells macrocytic. These cells are normocytic.
Not this oneMarrow infiltration lowers all three cell lines and gives a pancytopenia. Her white cells and platelets are normal.
Self checkYour patient's full blood count is entirely normal. How much does that lower the probability of tuberculosis?
Very little. None of the blood findings in tuberculosis is specific, and none is always present, so a normal count does not exclude tuberculosis.
Tuberculosis in immune deficiency
The granuloma holds only while cell-mediated immunity works. As that immunity falls, as in advanced HIV, the granuloma loses its structure, the bacilli multiply and the disease spreads beyond the lung.
IntactImmunocompetent host
The typical tubercle: central granular caseation surrounded by epithelioid macrophages and multinucleate giant cells. This is the usual response in someone with cell-mediated immunity to the organism, and it contains the infection in most people.
Caseating granuloma with giant cellsOrganisms contained but viableLesion fibroses and calcifiesBacilli hard to find on staining
Mildly reducedCD4 above about 300
The usual pattern of secondary tuberculosis: apical disease with cavitation. The response is still strong enough to wall off the focus. It carves out a cavity, and the patient coughs bacilli out of it.
!Warning: Apical disease with cavitationGranulomas still forming!Warning: Sputum contains bacilliExtrapulmonary disease uncommon
Substantially reducedCD4 below 200
The disease looks like progressive primary tuberculosis: lower and middle lobe consolidation, enlarged hilar lymph nodes and no cavity. Progressive primary tuberculosis is particularly common at this level.
!Warning: Lower and middle lobe consolidation!Warning: Enlarged hilar lymph nodes!Warning: Non-cavitary, so smear often negative!Warning: Extrapulmonary involvement rising
AbsentSevere immune deficiency
Immunosuppression blunts the CD4 response, and the typical granulomatous reaction is absent. Lesions are sheets of macrophages containing numerous bacilli. Nothing contains the organism, and extrapulmonary disease predominates.
!Warning: Granulomas absent!Warning: Sheets of bacilli-laden macrophages!Warning: Extrapulmonary disease predominates!Warning: Extrapulmonary disease defines WHO clinical stage 4
Diagram of a granuloma that loses its structure as cell-mediated immunity falls. At full immunity a caseating granuloma with giant cells and an intact rim. As the CD4 count falls the wall becomes disorganised, the cavity disappears, and at the lowest setting there is no granuloma at all, only sheets of macrophages filled with bacilli.
Self checkWhy does the same disease produce a cavity in one patient and none at all in another?
The patient's own response makes the cavity. It takes a strong local response to wall off a caseous focus and then destroy the tissue around it. With a CD4 count above about 300, that response is intact and the disease is apical and cavitary. Below 200, the disease shows as lower and middle lobe consolidation with enlarged hilar lymph nodes and no cavity. With severe deficiency no granuloma forms at all.
Check yourself
Why is the tuberculin skin test read at 48 to 72 hours, and not straight away?
The induration is a type IV delayed hypersensitivity reaction, and a cell-mediated response takes that long to mount.
What does an interferon gamma release assay measure?
Interferon gamma released by the patient's lymphocytes in response to antigens specific to M. tuberculosis, which reports sensitisation.
Which anaemia does chronic tuberculosis produce, and what is the iron profile?
Anaemia of chronic disease. Normocytic and normochromic, with a low serum iron and a preserved ferritin.
What does a biopsy show when the CD4 response is absent?
No granulomas. Sheets of macrophages containing numerous bacilli.
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Chemical Pathology
Tuberculosis and its treatment change the chemistry of the body fluids and the blood. For example, inflamed meninges and pleura change the cerebrospinal and pleural fluid, hyponatraemia and hypercalcaemia develop, and antituberculosis drugs raise the transaminases and uric acid.
By the end of this lens you can
Interpret the cerebrospinal fluid in tuberculous meningitis.
Identify a pleural exudate, and name the test that suggests tuberculosis.
Distinguish the causes of hyponatraemia in tuberculosis.
Explain hypercalcaemia with a suppressed parathyroid hormone.
Interpret the liver function tests and uric acid during treatment.
Self checkA 31-year-old man has had headache and fever for three weeks and is now confused. When asked to look to one side, one eye does not move outward past the midline. Lumbar puncture gives clear fluid with a raised protein, a low glucose against a paired plasma sample, and mostly lymphocytes. Which of the following best explains these findings?
Not this oneA low glucose does occur in pyogenic meningitis. But that illness is acute, and its fluid is cloudy with neutrophils. Three weeks of headache, clear fluid and lymphocytes do not fit.
CorrectTuberculous meningitis lies at the base of the brain, where it traps the cranial nerves, most often the sixth and then the third. An eye that will not move outward is a sixth nerve palsy. Three weeks of illness, clear fluid, lymphocytes and a low glucose all fit.
Not this oneClear fluid with lymphocytes fits a viral meningitis, but viral meningitis does not lower the glucose.
Not this oneThe raised protein and the low glucose show disease of the meninges.
Pleural fluid
Tuberculosis also inflames the pleura, and the fluid that collects is an exudate.
Self checkA 29-year-old woman has a pleural effusion. The pleural fluid protein is well above 30 grams per litre, the lactate dehydrogenase is raised, and cytology shows no malignant cells. Cultures are negative after several days. Which of the following is most accurate?
Not this oneA protein above 30 grams per litre makes this an exudate. A transudate is low in protein, and comes from a change in the pressures across a healthy pleura.
CorrectThe protein makes it an exudate, and tuberculosis is an infective cause. The organism is hard to culture, so a raised adenosine deaminase in the fluid would support tuberculosis.
Not this oneA raised lactate dehydrogenase fits malignancy or inflammation but cannot tell them apart. Cytology found no malignant cells.
Not this oneThe organism is hard to culture, so negative cultures do not exclude tuberculosis. This is why adenosine deaminase is measured.
Hyponatraemia
Tuberculosis causes hyponatraemia in two main ways: by destroying both adrenal glands, which is Addison's disease, or through the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in pulmonary disease or meningitis. Volume, potassium and pigmentation tell them apart.
Depleted. Aldosterone is lost, so sodium and water are lost.
Raised, because aldosterone is lost.
Pigmentation, from the high adrenocorticotrophic hormone (ACTH).
SIADH
Normal. The kidney holds water, which dilutes the sodium.
Normal.
A concentrated urine.
Cerebral salt wasting
Depleted.
Normal.
Seen in tuberculous meningitis. The blood results match SIADH.
Pituitary disease (rare)
Normal. Without cortisol the kidney cannot excrete water.
Normal, because aldosterone is kept.
No pigmentation, because ACTH is low.
Self checkA 38-year-old man with disseminated tuberculosis has hyponatraemia. He is pigmented, his potassium is raised, and he is clinically volume depleted. Which of the following best explains his results?
Not this onePituitary disease lowers ACTH. A dilutional hyponatraemia develops, but the skin is not pigmented, and the potassium stays normal because aldosterone is kept. This man is pigmented and has hyperkalaemia.
CorrectDestruction of all zones of both adrenal cortices is Addison's disease. Losing aldosterone as well as cortisol gives the sodium and water loss and the hyperkalaemia. The raised ACTH gives the pigmentation.
Not this oneA raised globulin can interfere with some assays. It does not cause pigmentation, hyperkalaemia or volume depletion.
Not this oneSIADH causes a dilutional hyponatraemia, with a concentrated urine. It does not cause hyperkalaemia or pigmentation, and the patient is not volume depleted.
Hypercalcaemia
Granulomas can cause hypercalcaemia. Their activated macrophages make active vitamin D outside the kidney's control, and the parathyroid glands respond correctly by suppressing parathyroid hormone.
Flow chart: activated macrophages in the granuloma make active vitamin D outside the kidney's control, more calcium is absorbed from the gut, hypercalcaemia results, and parathyroid hormone is suppressed.
A 44-year-old man with active pulmonary tuberculosis has hypercalcaemia on routine blood tests, using the albumin-adjusted calcium. His parathyroid hormone is suppressed. He has no bone pain, imaging shows no skeletal disease, he takes no thiazide and he is well hydrated.
Which of the following best explains both results?
Not this oneThis gives a raised parathyroid hormone, or one that is inappropriately normal for the calcium. His is suppressed, so his glands are responding correctly to hypercalcaemia. Something else has raised it.
CorrectGranulomas cause hypercalcaemia through vitamin D, in tuberculosis as in sarcoidosis. Their activated macrophages increase vitamin D activity outside the kidney's normal control, and the parathyroid glands stop releasing parathyroid hormone.
Not this oneMalignancy is a major cause of severe hypercalcaemia, through bony metastases or parathyroid hormone related peptide made by the tumour. But imaging shows no skeletal disease.
Not this oneThiazides are one of the commonest causes of mild hypercalcaemia, because they reduce renal calcium excretion. But he takes no thiazide.
Liver function tests and uric acid
Isoniazid, rifampicin and pyrazinamide are hepatotoxic, so the transaminases (alanine aminotransferase, ALT, and aspartate aminotransferase, AST) are measured during treatment. A rise above five times the upper limit of normal, or above three times with symptoms such as jaundice, nausea or abdominal pain, marks drug-induced liver injury. Ethambutol spares the liver.
Pyrazinamide reduces the renal excretion of uric acid, and ethambutol does too. Hyperuricaemia is common, but it rarely brings on an attack of gout.
Self checkA 40-year-old man is six weeks into treatment for pulmonary tuberculosis. He has no symptoms. His ALT is six times the upper limit of normal and his serum uric acid is raised. Which of the following is most accurate?
CorrectA rise above five times the upper limit of normal marks drug-induced liver injury even without symptoms. Isoniazid, rifampicin and pyrazinamide can all cause it.
Not this oneSymptoms lower the threshold to three times the upper limit of normal. Without symptoms the threshold is five times, and his ALT is above it.
Not this oneEthambutol decreases uric acid excretion, but it spares the liver. The raised ALT points to isoniazid, rifampicin or pyrazinamide.
Not this oneHyperuricaemia is common on pyrazinamide, but it rarely brings on gout. Gout is a clinical diagnosis, made from an inflamed joint.
Check yourself
What does a suppressed parathyroid hormone with hypercalcaemia tell you?
The parathyroid glands are responding correctly to the hypercalcaemia, so something outside the glands is raising it.
What protein concentration suggests a pleural exudate?
Above 30 grams per litre is a rough guide. Light's criteria are more accurate, because they compare the fluid protein and lactate dehydrogenase with the serum.
A patient with tuberculous meningitis has hyponatraemia. How do you tell SIADH from cerebral salt wasting?
By the volume status. The blood results are the same, but in SIADH the volume is normal, and in cerebral salt wasting the patient is volume depleted.
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Pharmacology
By the end of this lens you can
Describe how each of the four first-line drugs works.
Name the main adverse effect of each drug.
Explain why treatment uses four drugs for two months, then two for four.
Predict how rifampicin affects the other drugs a patient is taking.
Definition and notation
First-line treatment for tuberculosis uses four drugs together: rifampicin (R), isoniazid (H), pyrazinamide (Z) and ethambutol (E). The regimen is written 2(RHZE)/4(RH): all four for two months, the intensive phase, then rifampicin and isoniazid for four months, the continuation phase.
Self checkA woman's treatment card reads 2(RHZE)/4(RH). She is in week ten of treatment. Which of the following is most accurate?
Not this onePyrazinamide is in the first bracket only, so it stopped at two months. Most of its benefit comes early, and longer use adds to its hepatotoxicity.
CorrectWeek ten falls in the continuation phase, the second bracket: rifampicin and isoniazid for four months. They are the two main drugs, and they clear the organisms that persist after the intensive phase.
Not this oneThe notation gives the drugs and the months, not the doses. After two months only the drugs in the second bracket continue.
Not this oneThe numbers add: two months, then four. Treatment ends at month six.
Self checkWhy is tuberculosis treated for months when most bacterial infections are treated for days?
The organism grows slowly: mycobacteria divide only every eighteen to twenty-four hours in the laboratory. The patient improves within a few weeks, but treatment runs for months to clear the organisms that persist and to stop relapse.
The four drugs
Each drug has its own target in the organism. Isoniazid and ethambutol stop the cell wall being built, rifampicin stops RNA being made, and the target of pyrazinamide is still unclear.
A prodrug switched on by a mycobacterial enzyme, KatG. It then blocks the enzymes that build mycolic acid, so the organism cannot make its wall. Resistance comes from mutation or loss of KatG, or from a change in the target enzyme. Cross-resistance with ethionamide can occur.
What it acts on
Rapidly growing bacilli and organisms inside cells. It reaches all body fluids, cells and .
Adverse effects and interactions
Hepatitis, the most serious effect; risk rises with age, with rifampicin and with daily alcohol. Peripheral neuropathy from relative pyridoxine deficiency, prevented by pyridoxine. Convulsions in those prone to seizures. Inhibits the metabolism of phenytoin and carbamazepine, so their adverse effects grow stronger.
How it works
Bactericidal (it kills the organism). It blocks RNA transcription by binding the beta subunit of mycobacterial DNA-dependent RNA polymerase. Resistance comes from mutations that lower the polymerase's affinity for the drug, and resistant strains emerge rapidly when it is used alone.
What it acts on
Organisms inside and outside cells.
Adverse effects and interactions
Induces hepatic cytochrome P450 enzymes, so many other drugs are cleared faster. Nausea, vomiting and rash. Orange-red urine, tears and secretions; tears can permanently stain soft contact lenses. A flu-like illness with intermittent higher doses.
How it works
Mechanism unclear. Bacterial pyrazinamidase converts it to pyrazinoic acid, the active form. Some resistant strains lack this enzyme, so the drug is never converted.
What it acts on
Bacilli in acidic lesions and inside macrophages.
Adverse effects and interactions
May contribute to hepatotoxicity. Hyperuricaemia is common, but it rarely brings on gout.
How it works
Bacteriostatic (it stops growth without killing). It inhibits arabinosyl transferase, an enzyme that helps build the mycobacterial cell wall.
What it acts on
Mycobacteria only.
Adverse effects and interactions
Optic neuritis: falling visual acuity and loss of red-green discrimination. Risk rises at higher doses and in renal impairment. Decreases uric acid excretion.
Self checkA first-line antituberculosis drug is a prodrug. A mycobacterial enzyme switches it on, and it then blocks synthesis of the molecule that makes the organism acid-fast. Which of the following drugs is described?
Not this oneRifampicin is not a prodrug. It blocks RNA polymerase.
CorrectKatG switches isoniazid on, and it then blocks the enzymes that build mycolic acid. Mycolic acid makes the wall lipophilic and acid-fast.
Not this onePyrazinamide is also a prodrug, switched on by pyrazinamidase. Its exact target is unclear, and it is not described as acting on mycolic acid.
Not this oneEthambutol inhibits arabinosyl transferase, a different enzyme of the cell wall.
The two phases
The bacilli in one patient are not all alike: some grow fast, some live inside macrophages or in acidic lesions, and some persist long after the patient feels better. Each antituberculosis drug only targets some of them, so each has its place in the two phases.
Day oneIntensive phase, RHZE
The bacillary load is at its highest. Within it are small numbers of organisms naturally resistant to any one drug. Four drugs start together because several drugs suppress those organisms.
!Warning: Resistant organisms already presentIsoniazid acts on rapidly growing bacilliPyrazinamide reaches acidic lesionsEthambutol until susceptibility is known
Week twoIntensive phase, RHZE
The patient can feel better within the first few weeks, but the infection has not gone.
Pyrazinamide stops: most of its benefit comes early, and longer use adds to its hepatotoxicity. Ethambutol is not part of the continuation phase. Rifampicin and isoniazid go on.
Pyrazinamide and ethambutol stopRifampicin and isoniazid continue!Warning: Persistent organisms remain
Month fourContinuation phase, RH
Isoniazid and rifampicin, the two main drugs, go on alone. They clear organisms that persist after the intensive phase.
Rifampicin kills inside and outside cellsIsoniazid acts on growing bacilli!Warning: Stopping now risks relapse
Month sixCourse complete
Treatment for drug-susceptible tuberculosis lasts at least six months.
Persistent organisms clearedLowest risk of relapse
Timeline of the six-month regimen. Four drugs run across the first two months, then pyrazinamide and ethambutol stop and rifampicin and isoniazid continue alone for the remaining four months.
Each drug's place in the course
Drug
Phase
Reason
Isoniazid
Both phases
One of the two main drugs; acts on rapidly growing bacilli
Rifampicin
Both phases
One of the two main drugs; kills inside and outside cells
Pyrazinamide
Intensive phase only
Most benefit comes early; longer use adds to hepatotoxicity
Ethambutol
Intensive phase only
Included until susceptibility results are known
Combination therapy and resistance
The intensive phase starts four drugs at once because of resistance.
Any large population of M. tuberculosis holds a few organisms naturally resistant to any one drug. They are there before treatment begins.
Selection by a single drug
Under pressure from inadequate treatment, and especially from a single drug, these resistant organisms become the dominant population.
Streptomycin alone
Resistance developed rapidly in patients given only streptomycin, and the share of resistant strains rose over time. For the same reason rifampicin is never given alone in active disease.
Combination therapy
An organism resistant to one drug is killed by the others.
Self checkFirst-line treatment for tuberculosis starts four drugs together. Which of the following best explains this?
Not this oneSpeed of killing is not the reason. Treatment runs long after the patient improves, whatever the number of drugs.
CorrectA large population already holds a few organisms resistant to any one drug. One drug alone lets them take over. Several drugs together suppress them.
Not this oneBoosting is not the reason for the combination. Each drug has its own mechanism and its own site of action.
Not this oneIsoniazid and rifampicin both kill bacilli. Ethambutol is bacteriostatic, but that does not explain the combination.
Adverse effects
An adverse effect shows up as a symptom or a test result. Some findings point to one drug; others are shared by several.
Findings that point to a drug
Self checkA 52-year-old man is six weeks into treatment for pulmonary tuberculosis. He says colours look washed out, and he can no longer tell the red wire from the green one at work. His visual acuity has fallen since treatment began. Which of the following drugs is the most likely cause?
Not this oneRifampicin colours tears orange-red and can stain contact lenses. It does not damage the optic nerve.
Not this oneIsoniazid lowers pyridoxine and causes a peripheral neuropathy. It rarely affects the optic nerve; the classic cause is ethambutol.
Not this onePyrazinamide causes hyperuricaemia and may contribute to hepatotoxicity. It does not affect vision.
CorrectLoss of red-green discrimination with falling visual acuity is optic neuritis, the main adverse effect of ethambutol.
Shared toxicity and drug interactions
Three of the four drugs can cause jaundice. Rifampicin also speeds the clearance of other drugs, including those taken for HIV.
Self checkA woman is four weeks into treatment with 2(RHZE)/4(RH). She becomes jaundiced, with transaminases several times the upper limit of normal. She takes no other medicine and does not drink alcohol. Which of the following is most likely responsible?
Not this oneHepatitis is the most serious adverse effect of isoniazid. But rifampicin and pyrazinamide started on the same day and are also hepatotoxic, so isoniazid cannot be singled out.
Not this oneHepatitis from rifampicin alone is rare. Liver dysfunction rises when it is given with isoniazid and pyrazinamide.
Not this oneThe main adverse effect of ethambutol is optic neuritis. It is not one of the drugs that damage the liver.
CorrectIsoniazid, rifampicin and pyrazinamide are all hepatotoxic, and all three started on the same day. The timing cannot show which one caused it.
Not this oneThree of the four drugs are hepatotoxic. Tuberculosis can also involve the liver, but the drugs remain the likely cause.
Self checkA man on antiretroviral therapy with a protease inhibitor starts treatment for pulmonary tuberculosis. Over the next few weeks the plasma levels of his antiretroviral drugs fall. He has missed no doses. Which of the following best explains the fall?
Not this oneInhibition would raise levels, so the direction is wrong. Isoniazid does inhibit the metabolism of phenytoin and carbamazepine, which is a different interaction.
CorrectRifampicin induces the hepatic cytochrome P450 enzymes that clear other drugs, so their levels fall. Rifabutin is a much weaker inducer.
Not this onePyrazinamide acts on the liver and on uric acid. It does not change how other drugs are absorbed or cleared.
Not this oneEthambutol acts on the eye and on uric acid excretion. It does not change how other drugs are cleared.
Check yourself
Why is rifampicin never given alone for active disease?
Resistant strains emerge rapidly when it is used alone.
Why is pyrazinamide stopped after the intensive phase?
Most of its benefit comes early in treatment, and longer use adds to its hepatotoxicity.
Which three first-line drugs can damage the liver?
Isoniazid, rifampicin and pyrazinamide.
What does rifampicin do to urine and tears?
Turns them orange-red, along with faeces and other secretions. Tears may permanently stain soft contact lenses.
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Assessment
Multiple choice questions
24 questions
1. A 32-year-old man has coughed for two months and lost weight. A lung biopsy shows several rounded lesions composed of epithelioid macrophages and multinucleate giant cells with a peripheral rim of lymphocytes. None of the lesions shows central necrosis.
Which of the following is the most appropriate next step?
Not this oneAbsence of caseation does not exclude the diagnosis, so the stain is indicated regardless.
CorrectTuberculous granulomas may not show central caseation even in immunocompetent patients. So special stains for acid-fast organisms are indicated whenever granulomas are present, whether or not caseous necrosis is present.
Not this oneEpithelioid macrophages with multinucleate giant cells define a granuloma of any cause. They show the pattern but do not identify the cause.
Not this oneThe specimen is adequate: it has yielded diagnostic granulomas. Nothing here indicates a sampling failure.
Not this oneNon-caseating granulomas occur in sarcoidosis and in tuberculosis, so the finding does not choose between them.
2. An 81-year-old woman dies of heart failure. At autopsy there is a small calcified nodule just beneath the pleura in the lower part of the upper lobe, and a calcified hilar lymph node on the same side. Neither lung shows active inflammation.
Which of the following best describes these findings?
Not this oneThe Ghon focus is the parenchymal lesion alone. A hilar node is involved here, so the term is incomplete.
Not this oneThe Ghon complex is the parenchymal and nodal lesion together, but describes the primary complex rather than the healed and calcified remnant.
CorrectIn most people cell-mediated immunity controls the primary infection. The Ghon complex then fibroses and calcifies, and the healed, calcified pair is called the Ranke complex.
Not this oneA tuberculoma is a discrete mass of granulomatous tissue, not a calcified parenchymal lesion paired with its node.
Not this oneMiliary disease is innumerable foci of about two millimetres scattered through the organ, not two calcified lesions.
3. A 46-year-old man has been ill for four months. At autopsy the upper parts of both lungs contain many grey-white areas of caseation, with softening and cavities. The lower zones are congested but have no cavities.
Which of the following best explains this distribution?
CorrectSecondary tuberculosis usually sits at the apex of one or both upper lobes. The reason is not settled, but it may relate to the high oxygen tension there, since the organism is an obligate aerobe.
Not this oneLymphatic drainage does not explain apical disease, and the primary focus lower down drains readily to its hilar node.
Not this oneGravity would favour the bases. Primary disease does sit lower in the lung, where inhaled droplets land.
Not this oneMacrophage numbers do not explain apical disease, and fewer macrophages would not favour an aerobe.
Not this oneTemperature does not explain apical disease. Oxygen tension may.
4. A 27-year-old woman dies after a short febrile illness. At autopsy the spleen, liver and both lungs contain innumerable grey-white foci, each about two millimetres across, and all of them of similar size.
Which feature of the foci best identifies the pattern?
Not this onePale foci occur in many processes, including tumour deposits and other granulomatous infections.
CorrectSystemic miliary tuberculosis follows haematogenous dissemination, so every focus is seeded in the same event and all are therefore of comparable size. The lesions are named for their resemblance to millet seeds, and the pattern is most prominent in liver, bone marrow, spleen, adrenals, meninges, kidneys and fallopian tubes.
Not this oneSplenic involvement is expected in disseminated disease but is not what identifies the pattern.
Not this oneNumber alone is insufficient. Metastatic deposits may also be numerous and characteristically vary in size.
Not this oneConsistency does not separate this from other nodular processes.
5. A 40-year-old man is screened after his brother is diagnosed with pulmonary tuberculosis. He is entirely well, with no cough and no weight loss, and his chest radiograph is normal. His tuberculin skin test is strongly positive.
Which of the following best describes his condition?
Not this oneContainment is not eradication. Organisms remain viable within the granuloma, so reactivation can follow a later fall in host resistance.
CorrectIn latent tuberculosis the bacteria are walled off in a granuloma and remain dormant but viable, with no further complications in an immunocompetent host. Transmission requires bacilli in sputum, which requires a lesion communicating with an airway.
Not this oneNothing in the history suggests active disease. He is asymptomatic, and primary infection is asymptomatic in the great majority of cases.
Not this oneA strongly positive reaction in a household contact of a confirmed case is most simply explained by infection with the same organism.
Not this oneThere is no clinical evidence of nodal disease, and assuming an occult active site is unsupported.
6. A 14-year-old girl has had back pain for five months and now walks with difficulty. She has lost weight and has night sweats. Her uncle, who lives with the family, was treated for pulmonary tuberculosis last year. There is a sharp angular prominence in the mid thoracic spine. Imaging shows the intervertebral disc destroyed with the two adjacent vertebral bodies, and a soft tissue collection anterior to the spine tracking towards the pelvis.
What is the anterior collection called?
CorrectVertebral tuberculosis is Pott disease, and paraspinal cold abscesses may extend along tissue planes to present as an abdominal or pelvic mass. Skeletal disease characteristically destroys the intervertebral disc together with the two adjacent vertebral bodies.
Not this oneA Ghon focus is the primary parenchymal lesion in the lung and has no application beside the spine.
Not this oneA tuberculoma is a discrete solid mass of granulomatous tissue, not a collection tracking along tissue planes.
Not this oneA sequestrum is a fragment of dead bone separated from living bone, not a soft tissue collection.
Not this oneA Ranke complex is a healed, calcified primary parenchymal lesion with its draining node.
7. A 28-year-old woman has a cervical lymph node removed. Histology shows granulomas with central caseous necrosis and scattered Langhans giant cells. A Ziehl-Neelsen stain on the same tissue block shows no acid-fast bacilli.
Which of the following is the best interpretation of the negative stain?
Not this oneDropping the diagnosis because of a negative stain is the commonest mistake here. The stain confirms well and excludes poorly.
CorrectMost tuberculous lymph nodes confirmed on histology show no acid-fast bacilli on Ziehl-Neelsen staining. The stain needs many bacilli, and they become harder to find as the lesion fibroses and calcifies.
Not this oneAcid-fastness depends on the lipid content of the wall, not on whether the organism is alive, and that is not why this section is negative. The organisms are too few to find.
Not this oneThe specimen yielded diagnostic caseating granulomas, so it was adequate.
Not this oneNon-tuberculous mycobacteria are also acid-fast, so they would not explain a negative stain.
8. A 34-year-old man attends a general outpatient clinic with a cough of six weeks, weight loss and night sweats. The hospital laboratory offers GeneXpert, smear microscopy and culture.
Which investigation should be requested first?
CorrectThe Nigerian national guideline makes GeneXpert MTB/RIF the first test for all presumptive tuberculosis. It detects the organism and reports rifampicin resistance in one run.
Not this oneSmear microscopy is the right fallback where molecular testing is not accessible. Here it is accessible, and a negative smear does not exclude disease.
Not this oneCulture does give species and full susceptibility, but it takes up to six weeks for visible growth, so it cannot be the first answer.
Not this oneA positive reaction indicates exposure and infection at some time in the past, not disease now.
Not this oneThe assay cannot separate active from latent infection, the same limitation as the skin test. Its single advantage is that BCG does not make it positive.
9. A 30-year-old nurse has a visible BCG scar. At staff screening her tuberculin skin test is positive. She is asymptomatic with a normal chest radiograph. An interferon gamma release assay is then sent and is also positive.
Which limitation do the two tests share?
Not this oneThis is true of the tuberculin test and is the one limitation the interferon gamma assay does not share, because it uses antigens specific to M. tuberculosis.
Not this oneThe tuberculin test requires a return visit at 48 to 72 hours for the induration to be measured. The blood assay does not.
CorrectBoth show only that the immune system has met the antigen. Neither can separate active from latent tuberculosis.
Not this oneNeither waits for advanced disease. Both turn positive once sensitisation has occurred.
Not this oneA normal radiograph has no bearing on either test, and extrapulmonary disease would not appear on a chest film.
10. A 22-year-old woman has newly diagnosed pulmonary tuberculosis. She has never been diagnosed with tuberculosis before and has taken no medication for it. A rapid molecular test on her sputum reports the organism present with rifampicin resistance detected.
Which of the following best explains her resistance?
CorrectPopulations of M. tuberculosis contain small numbers of naturally resistant organisms. Inadequate treatment in one patient allows them to become dominant, and the resistant organism is then transmitted by the ordinary airborne route. Failure to treat the initial episode appropriately is the commonest cause of both multidrug-resistant and extensively drug-resistant disease.
Not this oneResistance to a drug is selected by that drug. An immune response does not select for resistance to an agent that was never present.
Not this oneResistance in an untreated patient is expected, because resistant organisms spread from person to person.
Not this oneThe assay identified the M. tuberculosis complex, so this is not a non-tuberculous mycobacterium.
Not this oneRifampicin resistance follows mutation in the polymerase gene of this organism, and is not conferred by unrelated antibiotics.
11. A 36-year-old man with advanced HIV and a CD4 count of 40 cells per microlitre has fever and weight loss. A transbronchial biopsy shows sheets of macrophages with no palisading, no giant cells and no organised architecture. An acid-fast stain on the same section shows numerous bacilli in every field.
Which immunological deficit best explains this appearance?
CorrectImmunosuppression blunts the ability to mount a CD4 mediated response, and as a result the characteristic granulomatous reaction to tuberculosis is absent. Lesions in such patients lack granulomas and consist instead of sheets of macrophages containing numerous bacilli.
Not this oneCD8 cells contribute to the response, but the deficit that abolishes the granuloma in advanced HIV is loss of CD4 mediated immunity.
Not this oneContainment rests on cell-mediated immunity. Antibody neither builds nor maintains a granuloma.
Not this oneMacrophages take up the organism readily and then fail to kill it. The failure is the missing cell-mediated response that should activate them.
Not this oneComplement is not the mechanism of granuloma formation and its deficiency does not produce this picture.
12. A 44-year-old man with disseminated tuberculosis has a haemoglobin, white cell count and platelet count all below the reference range. The blood film shows nucleated red cells together with myelocytes and metamyelocytes.
Which process best explains both the film and the counts?
Not this oneAnaemia of chronic disease explains a normocytic anaemia and not a pancytopenia with immature cells in the blood.
CorrectMiliary tuberculosis can infiltrate the marrow. Marrow infiltration lowers all three counts and gives a leuco-erythroblastic film, with nucleated red cells and immature white cells in the blood.
Not this oneHypersplenism can depress counts, but it does not release erythroblasts and granulocyte precursors into the blood the way marrow infiltration does.
Not this oneIron deficiency lowers the haemoglobin, but it does not lower the white cells and platelets or put immature cells into the blood.
Not this oneTuberculosis can deplete folate through excess utilisation, but that gives a megaloblastic picture rather than this one.
13. A 24-year-old woman has had a firm, painless swelling in the neck for three months. The node is excised. Its cut surface shows pale, soft, crumbly material replacing most of the node. The main differential is tuberculosis or lymphoma.
Which histological feature most reliably points to tuberculosis?
CorrectCaseous necrosis within granulomas points to tuberculosis, and Reed-Sternberg cells point to Hodgkin lymphoma. In Nigeria these are the two leading diagnoses on a peripheral node biopsy.
Not this oneMatting is macroscopic and both processes can produce firm, adherent nodes.
Not this oneMitotic activity does not reliably separate a granulomatous process from a lymphoma.
Not this oneA peripheral lymphocyte rim is part of the granuloma itself and appears in granulomatous disease of any cause.
Not this oneCervical nodes are the commonest site for both, so site does not choose between them.
14. A 45-year-old woman has had pulmonary tuberculosis for several months. Her haemoglobin is well below the reference range. The red cells are normocytic and normochromic. White cell and platelet counts are normal. Serum iron is low and ferritin is normal.
Which process best explains her anaemia?
Not this oneA low serum iron does not establish deficiency. True deficiency depletes the stores, so the ferritin would be low.
CorrectThis is anaemia of chronic disease, and tuberculosis is a recognised cause. Iron is held in the stores instead of reaching the marrow, so the cells stay normocytic, the ferritin is preserved and the serum iron falls.
Not this oneTuberculosis can deplete folate through excess utilisation, but folate depletion produces macrocytosis and these cells are normocytic.
Not this oneMarrow infiltration lowers all three counts and puts immature cells into the blood. Here the white cells and platelets are normal.
Not this oneHaemolysis would alter the indices and leave biochemical evidence of red cell destruction.
15. A 44-year-old man with active pulmonary tuberculosis has hypercalcaemia on an albumin-adjusted calcium. His parathyroid hormone is suppressed. He has no bone pain, imaging shows no skeletal disease, he takes no thiazide and he is well hydrated.
Which mechanism best explains both results?
Not this oneInappropriate secretion means release that negative feedback does not properly inhibit, which gives a raised or inappropriately normal value. A suppressed value is the opposite.
CorrectGranulomas cause hypercalcaemia through vitamin D, in tuberculosis as in sarcoidosis. The cause lies outside the parathyroid glands, so they correctly stop releasing parathyroid hormone.
Not this oneMalignancy accounts for much severe hypercalcaemia, most of it from bony metastases, but this patient has no skeletal disease on imaging.
Not this oneThiazides are among the commonest causes of mild hypercalcaemia, and he is not taking one.
Not this oneEctopic parathyroid hormone related peptide accounts for most of the remaining malignant hypercalcaemia, and it would not fit a man with granulomatous lung disease and no tumour.
16. A 38-year-old man with disseminated tuberculosis has hyponatraemia and hyperkalaemia. He is hyperpigmented and clinically volume depleted.
Which lesion best explains this combination?
CorrectAddison's disease is bilateral destruction of all zones of the adrenal cortex, and tuberculosis of the adrenal glands causes it in countries where the disease is common. Loss of aldosterone as well as cortisol gives sodium and water depletion with hyperkalaemia, and the raised ACTH causes the pigmentation.
Not this oneTuberculosis is a listed infectious cause of hypopituitarism, but in ACTH deficiency there is no hyperpigmentation because ACTH is not raised, and no hyperkalaemia because aldosterone is controlled by angiotensin. The hyponatraemia there is dilutional.
Not this oneRaised globulins can interfere with some assays, but they do not produce pigmentation, hyperkalaemia or volume depletion.
Not this oneTerminal ileal disease impairs bile salt and vitamin B12 absorption and does not produce this electrolyte picture.
Not this oneGranulomatous vitamin D excess causes hypercalcaemia. It does not cause hyperkalaemia or pigmentation.
17. A 52-year-old man is six weeks into treatment for pulmonary tuberculosis. He reports that colours look washed out and that he can no longer distinguish a red wire from a green one at work. Formal testing shows reduced visual acuity compared with the start of treatment.
Which drug is most likely responsible?
Not this oneRifampicin turns tears and other secretions orange-red and may permanently stain soft contact lenses. It does not damage the optic nerve.
Not this oneIsoniazid produces a peripheral neuropathy through relative pyridoxine deficiency, presenting as paraesthesia of the hands and feet.
Not this onePyrazinamide causes hyperuricaemia and may contribute to hepatotoxicity.
CorrectThe main adverse effect of ethambutol is optic neuritis, which reduces visual acuity and red-green discrimination. The risk rises at higher doses and in renal impairment.
Not this oneStreptomycin's toxicities are ototoxicity and nephrotoxicity.
18. A 29-year-old woman taking treatment for pulmonary tuberculosis develops paraesthesia of the hands and feet which has progressed slowly over several weeks. Examination confirms a symmetrical sensory neuropathy.
Which of the following best explains this?
CorrectIsoniazid causes a relative pyridoxine deficiency, which leads to a peripheral neuropathy with paraesthesia of the hands and feet. Pyridoxine prevents it. The same mechanism causes isoniazid's sideroblastic anaemia.
Not this oneEnzyme induction by rifampicin affects the metabolism of coadministered drugs and does not produce a peripheral neuropathy.
Not this onePyrazinamide does cause hyperuricaemia, which rarely brings on gout. It does not cause a sensory neuropathy.
Not this oneEthambutol's target, arabinogalactan, is a mycobacterial cell wall component. Human nerves do not contain it, so the mechanism cannot operate.
Not this oneStreptomycin toxicity is ototoxic and nephrotoxic. A symmetrical sensory neuropathy is not its pattern.
19. A 41-year-old man is established on antiretroviral therapy including a protease inhibitor, with a suppressed viral load. He is diagnosed with pulmonary tuberculosis and starts the standard four-drug regimen. Over the following weeks the plasma concentrations of his antiretroviral drugs fall, and he has missed no doses.
Which of the following best explains the fall?
Not this oneInhibition would raise concentrations rather than lower them. Isoniazid does inhibit the metabolism of carbamazepine and phenytoin, which is a different interaction.
CorrectRifampicin induces the hepatic cytochrome P450 enzymes that clear other drugs, so those drugs are removed faster. Rifabutin is a much weaker inducer.
Not this oneNo such binding is described, and an absorption problem would not follow the time course of enzyme induction.
Not this oneEthambutol is mainly excreted in urine, but it is not the agent behind this interaction.
Not this oneProtein binding displacement is not the mechanism, and streptomycin is not part of the standard regimen.
20. A first-line antituberculosis drug is a prodrug. A bacterial enzyme converts it to its active form, and some resistant strains lack that enzyme. Its exact target is unclear.
Which drug is this, and where is it most active?
Not this oneIsoniazid is most effective against rapidly growing bacilli and is also active inside cells. It is a prodrug, but it is activated by the mycobacterial catalase-peroxidase KatG, not by pyrazinamidase.
Not this oneRifampicin is not a prodrug. It blocks RNA transcription by binding the beta subunit of the mycobacterial RNA polymerase.
CorrectPyrazinamide must be enzymatically hydrolysed by pyrazinamidase to pyrazinoic acid, which is the active form, and some resistant strains lack the enzyme. It is active against tuberculosis bacilli in acidic lesions and in macrophages. Most of its clinical benefit occurs early, so it is stopped after the intensive phase.
Not this oneEthambutol inhibits arabinosyl transferase directly and is not described as requiring bacterial activation.
Not this oneStreptomycin is an aminoglycoside whose action appears greater against extracellular organisms, and it is not a prodrug.
21. A 33-year-old woman is four weeks into treatment for pulmonary tuberculosis with rifampicin, isoniazid, pyrazinamide and ethambutol. She has developed jaundice and nausea. Her ALT is four times the upper limit of normal. She takes no other medication and does not drink alcohol.
Which of the following is most accurate?
Not this oneFive times the upper limit is the threshold without symptoms. She has jaundice and nausea, so three times is enough.
CorrectWith symptoms such as jaundice and nausea, an ALT above three times the upper limit of normal marks drug-induced liver injury. Isoniazid, rifampicin and pyrazinamide can all cause it, and all three started on the same day, so the timing cannot single one out.
Not this oneEthambutol spares the liver. Its main adverse effect is optic neuritis.
Not this oneDrug-induced liver injury commonly appears within the first weeks of treatment, as here.
Not this oneHepatitis from rifampicin alone is rare. Isoniazid, rifampicin and pyrazinamide share the risk, and all three started together.
22. A 45-year-old man has had a cough for three months. His sputum smear is reported as showing acid-fast bacilli on Ziehl-Neelsen staining. A Gram stain of the same sample shows no organisms.
Which component of the cell wall explains these staining results?
Not this oneArabinogalactan is a wall component and the target of ethambutol, but it does not explain the staining.
CorrectMycolic acid, a long-chain fatty acid, makes the wall waxy and lipophilic. The Gram stain cannot get in. Once carbol fuchsin is driven into the wall with heat, acid alcohol cannot wash it out, so the bacilli stay red. Isoniazid works by blocking the synthesis of mycolic acid.
Not this oneCord factor is built from two mycolic acids and trehalose. It lines the bacilli up in cords and adds to virulence, but the staining comes from mycolic acid in the wall.
Not this onePeptidoglycan is what the Gram stain colours in other bacteria, so it cannot explain why this organism does not stain.
Not this onePyrazinoic acid is the active form of pyrazinamide. It is not part of the wall.
23. A man with active pulmonary tuberculosis has hypercalcaemia with a suppressed parathyroid hormone. His lung biopsy shows granulomas with sheets of large pale cells with plenty of cytoplasm around an area of granular necrosis.
Which cell is the source of his hypercalcaemia?
CorrectThe large pale cells are epithelioid macrophages, the activated macrophages that form the wall of the granuloma. They increase vitamin D activity outside the kidney's control, which raises the calcium and suppresses parathyroid hormone.
Not this oneSensitised T cells in the peripheral rim activate the macrophages, so they act upstream. They are not the cell in question.
Not this oneFibroblasts deposit collagen at the margin during healing and have no part in the calcium result.
Not this oneNeutrophils appear in the early local infiltrate but do not define this lesion or generate the abnormality.
Not this oneThe renal tubular cell performs the regulated conversion in health. Here the granuloma is the unregulated source.
24. A 39-year-old man with advanced HIV has tuberculous lymphadenitis. The node shows numerous acid-fast bacilli with no granuloma formation. He is established on antiretroviral therapy including a protease inhibitor, and rifampicin-based treatment is being started.
Which of the following is true for this patient?
CorrectAdvanced HIV blunts the CD4 response, so no granuloma forms and the node shows sheets of macrophages full of bacilli. Rifampicin induces cytochrome P450 enzymes, so his protease inhibitor will be cleared faster and its levels will fall.
Not this oneThe deficit in advanced HIV is in CD4 mediated immunity, and rifampicin induces rather than inhibits, so both halves are wrong.
Not this oneAbundant bacilli indicate failed containment, which is the opposite of a vigorous response, and the interaction is well recognised.
Not this oneThe absent granuloma is a consequence of the immunodeficiency, not of its treatment.
Not this oneB cells do not build granulomas, and isoniazid is not the agent responsible for the fall in antiretroviral concentrations.
Practical stations
13 stations
Pot stationYale Rosen, Atlas of Pulmonary Pathology · CC BY-SA 2.0 · reproduced unmodifiedDescribe this specimen.
A slice of lung in which the upper parts are riddled with grey-white areas of caseation and multiple areas of softening and cavitation. The lower zones are comparatively spared. This is secondary pulmonary tuberculosis.
What process produced the cavity?
In progressive pulmonary tuberculosis the apical lesion and its area of caseation expand. Erosion into a bronchus evacuates the caseous centre, creating a ragged, irregular cavity lined by caseous material and poorly walled off by fibrous tissue.
Why is the disease apical rather than basal?
Secondary tuberculosis is classically localised to the apex of one or both upper lobes. The reason is obscure but may relate to the high oxygen tension there, the organism being an obligate aerobe.
What would you expect on a slide from this specimen?
Coalescent nodules with central caseation, surrounded by epithelioid macrophages and multinucleate giant cells with a peripheral rim of lymphocytes. Bacilli can be demonstrated in early exudative and caseous phases but are usually impossible to find in late fibrocalcific lesions.
What risk does this patient pose to the people around them?
Cavitation and erosion into the airways make the patient a source of infection, because affected patients produce sputum containing the bacilli.
Pot stationYale Rosen, Atlas of Pulmonary Pathology · CC BY-SA 2.0 · reproduced unmodifiedDescribe what you see.
A cut surface of lung containing a single well defined subpleural lesion filled with pale caseous material, with surrounding parenchyma otherwise unremarkable.
Name the lesion and account for its position.
The Ghon focus. Inhaled bacilli implant in the distal air spaces of the lower part of the upper lobe or the upper part of the lower lobe, typically close to the pleura, producing an area of grey-white consolidation one to one and a half centimetres across whose centre undergoes caseous necrosis.
What completes the Ghon complex?
The regional lymph node. Bacilli, free or within phagocytes, travel by lymphatics to the draining nodes, which also often caseate. The combination of parenchymal and nodal lesions is the Ghon complex.
What becomes of this lesion if the patient remains well?
Cell-mediated immunity controls the infection in the great majority of cases, so the complex undergoes progressive fibrosis and calcification often follows, detectable as a Ranke complex.
Pot stationYale Rosen, Atlas of Pulmonary Pathology · CC BY-SA 2.0 · reproduced unmodifiedWhat is this specimen and what is abnormal?
Lymph node, cut across, with pale soft friable material replacing most of the node and only a thin rim of residual nodal tissue at the periphery.
Name the process and the clinical term for this site.
Caseating granulomatous lymphadenitis. Lymphadenitis is the most frequent form of extrapulmonary tuberculosis, usually occurring in the cervical region, where it is called scrofula.
In Nigeria, which two diagnoses would you hold in mind, and what separates them?
Tuberculosis and the lymphomas, which together account for most peripheral node biopsies. Caseous necrosis within granulomas indicates tuberculosis; Reed-Sternberg cells indicate Hodgkin lymphoma.
The Ziehl-Neelsen stain on this tissue is negative. What follows?
Very little. Most histologically confirmed tuberculous nodes in this setting do not stain positive. Presumptive extrapulmonary tuberculosis is confirmed by molecular test, smear, culture or histology, so molecular testing on the tissue adds more than repeating the stain.
How would the pattern differ in a patient with HIV?
Nodal disease tends to be unifocal in the immunocompetent, with most patients having no concurrent extranodal disease. Patients who are HIV positive almost always have multifocal disease, systemic symptoms and either pulmonary or other organ involvement.
Pot stationWellcome Collection · CC BY-SA 4.0 · reproduced unmodifiedWhat organ is this and what do you see?
Spleen, cut across, with numerous grey-white granulomas distributed evenly through the cut surface.
Which feature identifies the pattern, and what is it called?
That the foci are small, about two millimetres, and all of similar size. This is systemic miliary tuberculosis, named for the resemblance of the foci to millet seeds.
How did the organisms arrive here?
Systemic miliary tuberculosis follows haematogenous dissemination throughout the body, so every focus is seeded in the same event, so they are all of comparable size.
Which other organs would you expect to be involved?
It is most prominent in the liver, bone marrow, spleen, adrenal glands, meninges, kidneys, fallopian tubes and epididymis.
What would the blood film show if the marrow were involved?
Miliary tuberculosis produces a leuco-erythroblastic film, and marrow infiltration causes pancytopenia. Disseminated disease can also produce a leukaemoid reaction.
Pot station
Yale Rosen, Atlas of Pulmonary Pathology · CC BY-SA 2.0 · reproduced unmodifiedIdentify the two abnormalities.
A small pale calcified subpleural nodule, indicated by the arrow, and a calcified lymph node at the hilum of the same lung.
Name the combination.
A Ranke complex: a Ghon complex that has undergone progressive fibrosis with subsequent calcification.
Does this mean the patient was cured?
Not necessarily. Bacteria walled off within a granuloma remain dormant but viable. At some point in the future, perhaps through a depression in host resistance, they may grow again, which is the basis of reactivation disease.
Pot stationYale Rosen, Atlas of Pulmonary Pathology · CC BY-SA 2.0 · reproduced unmodifiedWhat are you looking at, and which surface?
The inferior surface of the brain. A thick grey gelatinous exudate covers the base, around the brainstem and the interpeduncular region, while the surfaces further out are clear.
Name the condition and say why the exudate sits where it does.
Tuberculous meningitis, the commonest form of tuberculosis in the nervous system. The exudate is densest at the base, around the optic chiasm and the vessels of the circle of Willis.
Which structures are running through that exudate, and what does the patient notice?
The cranial nerves, so the patient presents with a squint or a facial weakness. The basal cisterns pass through it too, and blocking them causes hydrocephalus.
Now the exception. This patient had a stroke. How does a meningitis do that?
The same exudate surrounds the vessels of the circle of Willis. They narrow and thrombose, and the territory they supply infarcts. A meningitis causes a stroke because the inflammation is sitting on the arteries.
Slide stationYale Rosen, Atlas of Pulmonary Pathology · CC BY-SA 2.0 · reproduced unmodifiedDescribe this field from the centre outwards.
A central zone of granular structureless necrosis, surrounded by large pale cells with abundant cytoplasm and elongated nuclei, then a rim of small dark lymphocytes, with spindled cells and collagen at the margin.
Name each component.
Central caseous necrosis, a palisade of epithelioid macrophages, a peripheral lymphocyte rim, and fibroblasts with collagen deposition at the edge. Multinucleate giant cells may be present within the palisade.
What produced the necrosis?
The host. Sensitised T cells activate the macrophages, which destroy the bacteria, and during that stage the macrophage attack also destroys the surrounding lung tissue. The tissue damage is a type IV delayed hypersensitivity reaction.
Now the exception. Would the absence of caseation have changed your interpretation?
It should not stop you looking. Tuberculous granulomas may not show central caseation even in immunocompetent patients, so acid-fast stains are indicated whenever granulomas are present, irrespective of caseation.
Slide stationEd Uthman, Houston, Texas · CC BY 2.0Identify the large cell at the centre.
A multinucleate giant cell with its nuclei arranged peripherally in a horseshoe. This is a Langhans giant cell, formed by fusion of infiltrated macrophages.
How is it distinguished from a foreign body giant cell?
By the arrangement of the nuclei: peripheral in a Langhans cell, randomly scattered through the cytoplasm in a foreign body giant cell.
Does this cell establish tuberculosis?
No, and this granuloma is non-caseating. Epithelioid macrophages and multinucleate giant cells define granulomatous inflammation of any cause. The cell names itself, not the disease.
What would you need before calling it tuberculosis?
Acid-fast stains, which are indicated whenever granulomas are present, together with the clinical setting. Definitive identification rests on demonstrating the organism or its nucleic acid, and culture remains the standard because it also allows susceptibility testing.
Slide stationAjay Kumar Chaurasiya · CC BY-SA 4.0 · reproduced unmodifiedWhat stain is this, and what are you looking for?
A Ziehl-Neelsen stain of sputum. You are looking for red bacilli against a blue background.
Explain why the organisms are red and everything else is blue.
A smear is covered with carbol fuchsin and heated to aid dye penetration. Acid alcohol is then poured over it and a counterstain of methylene blue applied. The wall lipids of the mycobacterium do not dissolve in acid alcohol, so the red stain does not wash off. Bacteria that are not acid-fast lose the red stain and take on the blue.
The report reads scanty acid-fast bacilli seen. What does that establish, and what does it not?
That acid-fast bacilli are present and roughly how many. It does not identify the species, and it says nothing about drug susceptibility.
Now the exception. A second patient's smear shows nothing. Can you exclude tuberculosis?
No. The smear requires a high bacillary load, so it confirms well and excludes poorly. In nodal disease most histologically confirmed cases are smear negative, and the tuberculin test is also negative in a substantial minority of people with active pulmonary disease.
Slide stationYale Rosen, Atlas of Pulmonary Pathology · CC BY-SA 2.0 · reproduced unmodifiedWhat does this section show?
An acid-fast stain of tissue containing numerous bacilli, among inflammatory cells and debris, with no organised granuloma anywhere in the field.
What is missing, and what should have been present?
The granulomatous architecture. In a host with cell-mediated immunity the expected response is a tubercle with central caseation surrounded by epithelioid macrophages and multinucleate giant cells.
What kind of patient does this come from?
One who is overtly immunocompromised. Immunosuppression blunts the ability to mount a CD4 mediated response, so the characteristic granulomatous reaction is absent, and lesions consist of sheets of macrophages containing numerous bacilli.
Now the exception. What would the same stain show in a patient whose immunity is intact?
Very little, often nothing. Bacilli are demonstrable in early exudative and caseous phases but are usually impossible to find later, and in nodal disease only about one in six confirmed cases stains positive. The abundance here is a measure of failed containment rather than of a heavier infection.
Viva stationTell me what you know about the granuloma in tuberculosis.
A focus of caseous necrosis surrounded by epithelioid macrophages and multinucleate giant cells, with fibroblasts, collagen and a peripheral rim of lymphocytes. Its presence with caseation defines the tubercle.
Why does the host build one instead of killing the organism?
Because phagocytosed bacteria are not destroyed. Sulfatides inhibit fusion of the phagosome with the lysosome containing the bactericidal enzymes, so the organism multiplies within the macrophage. Killing needs sensitised T cells to activate those macrophages, and the activated attack destroys lung tissue as well. That produces the caseous centre.
A patient has tuberculosis and no granuloma at all. How?
Immunosuppression blunts the CD4 mediated response, and the characteristic granulomatous reaction is then absent. Lesions consist of sheets of macrophages packed with bacilli. Progressive primary disease of this kind is particularly common below a CD4 count of 200 cells per microlitre.
Viva stationTell me what you know about acid-fastness.
Once stained, the organism is not decolourised by acidified organic solvents. The wall is highly lipophilic and rich in mycolic acid, so the lipids do not dissolve in acid alcohol and the stain is retained.
A patient's smear is negative. What have you learned?
Almost nothing about whether this patient has tuberculosis. The smear requires a high bacillary load, so it confirms well and excludes poorly.
Where does a negative stain mislead most, and what would you send instead?
Nodal disease. In a Nigerian review of histologically confirmed tuberculous lymphadenitis, only about one in six stained positive, so the stain is negative in most true cases. Send tissue for histology, where the caseating granuloma carries the diagnosis, and an aspirate for molecular testing, which also reports rifampicin susceptibility.
Viva stationTell me what you know about the standard regimen.
2(RHZE)/4(RH). Isoniazid, rifampicin, ethambutol and pyrazinamide for two months, the intensive phase, then isoniazid and rifampicin for four months, the continuation phase.
Why do two drugs stop at two months?
Neither stops at random. Most of the clinical benefit from pyrazinamide comes early in treatment, and longer use adds to its hepatotoxicity, so it stops after two months. Ethambutol is included until culture and susceptibility results are known, and may be stopped once the isolate is known to be susceptible to the other three.
Why use four drugs at all, when one good drug would be simpler?
Because populations of M. tuberculosis contain small numbers of organisms naturally resistant to a particular drug. Under selective pressure from monotherapy those organisms emerge as the dominant population, which was demonstrated in patients given streptomycin alone. Multidrug therapy suppresses them, and rifampicin is never given as a single agent for this reason.
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Morbid Anatomy
Tell me what you know about caseous necrosis.
Necrosis in which dead tissue loses all structure and becomes soft, granular and cheese-like. Down the microscope it is structureless, with no nuclei and no preserved architecture.
Where in the tuberculous granuloma does caseous necrosis sit?
At the centre, ringed by epithelioid macrophages and giant cells, with lymphocytes outside them.
Why does the centre of the granuloma die?
Activated macrophages attack the bacteria and destroy the surrounding tissue at the same time.
Where in the granuloma would you look for bacilli?
In the caseous centre, when they can be found at all.
Tell me what you know about the Ghon complex.
The Ghon focus is the parenchymal lesion alone, one to one and a half centimetres, subpleural. The Ghon complex is that focus together with the caseating node that drains it.
What happens to the Ghon complex in most people?
It fibroses and calcifies. The healed pair is the Ranke complex, and organisms may still be alive inside it.
Where in the lung does secondary tuberculosis usually occur?
At the apex of one or both upper lobes.
Why does secondary tuberculosis favour the apex?
The reason is not settled, but it may relate to the high oxygen tension there, since the organism is an obligate aerobe.
Tell me what you know about the Langhans giant cell.
A multinucleate cell formed when epithelioid macrophages fuse, with its nuclei in a horseshoe around the edge.
Does a Langhans giant cell mean the patient has tuberculosis?
No. It marks an immune granuloma of any cause. In a foreign body giant cell the nuclei are scattered instead.
A granuloma has giant cells but no caseation. What would you do next?
Request acid-fast stains anyway. Tuberculous granulomas may lack caseation even in immunocompetent patients, so stains are indicated whenever granulomas are present.
Tell me what you know about the differential diagnosis of granulomatous inflammation.
Tuberculosis is not the only cause. Sarcoidosis and foreign body reactions also form granulomas, and Hodgkin lymphoma also enlarges lymph nodes. Caseation and acid-fast stains help separate them.
How does sarcoidosis differ from tuberculosis on the slide?
Its granulomas lack caseation. But tuberculous granulomas can lack caseation too, so stain for acid-fast bacilli whenever you see granulomas.
How do you tell a foreign body giant cell from a Langhans giant cell?
In a foreign body giant cell the nuclei are scattered through the cytoplasm. In a Langhans giant cell they sit in a horseshoe at the edge.
On a lymph node biopsy, how do you separate tuberculosis from Hodgkin lymphoma?
Caseation points to tuberculosis, and Reed-Sternberg cells point to Hodgkin lymphoma. The gross specimen cannot decide it.
Tell me what you know about extrapulmonary tuberculosis.
Tuberculosis can reach almost any organ. The process is the same everywhere: a granuloma forms, the centre caseates, tissue is destroyed and fibrosis replaces it. The lymph nodes are the commonest site.
What is Pott disease?
Tuberculosis of the spine. Two adjacent vertebrae and the disc between them are destroyed, with a cold abscess. Anterior collapse gives an angular deformity, a gibbus.
What is the most feared complication of Pott disease?
Cord compression from the collapsed vertebral bodies and the abscess in front of the cord.
What does renal tuberculosis show in the urine?
Sterile pyuria: pus cells in the urine, but no organism on Gram stain or routine culture.
Which organs does miliary tuberculosis affect most?
The liver, bone marrow, spleen, adrenals, meninges, kidneys, fallopian tubes and epididymis.
Microbiology and Parasitology
Tell me what you know about the cell wall of Mycobacterium tuberculosis.
It is highly lipophilic and rich in mycolic acid, a long-chain fatty acid. It also carries cord factor and sulfatides.
Why does Mycobacterium tuberculosis not take up the Gram stain?
The wall is highly lipophilic, rich in mycolic acid, so it stains poorly with Gram stain.
How is Mycobacterium tuberculosis stained?
With the Ziehl-Neelsen stain. Carbol fuchsin is applied with heat to drive it into the wall, acid alcohol is poured over the smear, and methylene blue counterstains the background.
What does acid-fast mean?
The wall lipids do not dissolve in acid alcohol, so the organism keeps the red stain when everything else loses it.
What is cord factor?
A mycoside formed from two mycolic acids and trehalose, found only in virulent strains. It lines the bacteria up in cords.
What does cord factor do to the host?
It inhibits neutrophil migration, damages mitochondria and releases tumour necrosis factor.
What do sulfatides do?
They stop the phagosome from fusing with the lysosome, so the organism survives inside the macrophage.
What does Wax D do?
A complex mycoside that acts as an adjuvant. It may switch on the protective cell-mediated response.
Tell me what you know about the diagnosis of pulmonary tuberculosis.
In Nigeria the GeneXpert MTB/RIF assay is the first test for all presumptive tuberculosis. Smear microscopy is the fallback where it is not available. Culture gives the species and full susceptibility later.
Why is the GeneXpert MTB/RIF test done first?
It detects the organism and reports rifampicin susceptibility in one run.
Why is culture not the first test?
Growth takes up to six weeks.
A sputum smear is negative. Can you exclude tuberculosis?
No. The smear needs a high bacillary load, so it confirms well and excludes poorly.
In tuberculous lymphadenitis, is the smear usually positive?
No. Most confirmed cases are smear negative.
Tell me what you know about the transmission of tuberculosis.
It spreads through the air in droplet nuclei, which an adult with lung disease releases by coughing, singing, laughing or talking.
How likely is a household contact to become infected?
About 30%.
Once a person is infected, how often does disease develop?
About 5% within 1 to 2 years and another 5% later in life, so a 10% lifetime risk.
How does HIV change that risk?
The risk of reactivation is about 10% every year.
Tell me what you know about drug-resistant tuberculosis.
Any large population of M. tuberculosis holds a few organisms naturally resistant to any one drug. Under inadequate treatment, especially a single drug, they become the dominant population.
What is MDR tuberculosis?
Multidrug-resistant tuberculosis: resistance to both isoniazid and rifampicin.
What is XDR tuberculosis?
Extensively drug-resistant tuberculosis: MDR tuberculosis with added resistance to a fluoroquinolone and to bedaquiline or linezolid. With fluoroquinolone resistance alone it is called pre-XDR.
How can someone who has never taken a tuberculosis drug have resistant disease?
They inhale resistant organisms from another person. Failure to treat the first episode properly is the commonest cause of MDR and XDR tuberculosis.
The GeneXpert MTB/RIF test reports rifampicin resistance. What does that suggest?
Concern for MDR tuberculosis. Rifampicin resistance is half of the definition, so isoniazid susceptibility is still needed to confirm it.
Haematology and Immunology
Tell me what you know about the immune response to tuberculosis.
Alveolar macrophages phagocytose the bacillus but do not kill it. Macrophages present antigen to T helper cells, and sensitised T cells return to activate the macrophages at the lesion. The activated attack destroys the bacteria and the lung tissue together, and the granuloma walls off what survives.
How does the bacillus survive inside the macrophage?
Phagocytosed bacteria are not destroyed. Sulfatides inhibit fusion of the phagosome with the lysosome, so the organism multiplies and survives within the macrophage.
What type of hypersensitivity causes the tissue damage?
Type IV delayed hypersensitivity.
Where else in tuberculosis do you see a type IV reaction?
In the induration of the tuberculin skin test.
Tell me what you know about the full blood count and blood film in tuberculosis.
Nothing in it is specific. It shows chronic inflammation with a marrow response.
Give me three abnormalities you might find.
Anaemia of chronic disease, monocytosis, and pancytopenia from marrow infiltration.
What does miliary tuberculosis add to the blood film?
Marrow fibrosis and a leuco-erythroblastic film.
What do the iron studies show in the anaemia of chronic disease?
The serum iron is low and the ferritin is preserved, because iron is held in the stores. The cells are normocytic and normochromic.
Tell me what you know about tuberculosis in advanced HIV.
Immunosuppression blunts the CD4 response, and the granulomatous reaction to the organism is weak or absent.
What would a tissue biopsy show in advanced HIV?
Often no granulomas at all, only sheets of macrophages containing numerous bacilli.
How does the chest X-ray change when the CD4 count falls below 200?
Below a CD4 count of 200 it looks like progressive primary disease: lower and middle lobe consolidation, hilar nodes and no cavity.
Tell me what you know about the tuberculin skin test.
Purified protein derivative is injected into the skin. In a person who has been infected, a firm induration appears at 48 to 72 hours. It is a type IV delayed hypersensitivity reaction, and it shows sensitisation.
Can a positive tuberculin skin test confirm active disease?
No. Latent infection and active disease are both sensitised, so the reaction is the same in both. In a high-burden country many healthy adults test positive.
How does the interferon gamma release assay differ from the skin test?
It is a blood test. It measures interferon gamma released in response to antigens specific to M. tuberculosis, so BCG does not make it positive. Like the skin test, it cannot separate latent infection from active disease.
A nurse with a BCG scar has a positive skin test. What does a positive interferon gamma release assay add?
BCG can make the skin test positive, but not the assay. A positive assay points to real sensitisation to M. tuberculosis.
Chemical Pathology
Tell me what you know about hypercalcaemia in tuberculosis.
Granulomas cause hypercalcaemia through vitamin D, in tuberculosis as in sarcoidosis. The parathyroid glands respond correctly, so parathyroid hormone is suppressed.
In a patient with hypercalcaemia, what does a suppressed parathyroid hormone tell you?
The parathyroid glands are responding correctly to the hypercalcaemia, so something outside the glands is raising it.
Where does the extra vitamin D come from?
Activated macrophages in the granulomas. They increase vitamin D activity outside the kidney's normal control.
Can blood tests separate tuberculosis from sarcoidosis?
No. The granulomas of sarcoidosis cause hypercalcaemia through vitamin D in the same way.
Tell me what you know about hyponatraemia in tuberculosis.
It comes by three routes: destruction of both adrenal glands, which is Addison's disease; the syndrome of inappropriate antidiuretic hormone secretion (SIADH); or, rarely, ACTH deficiency from tuberculous hypopituitarism.
What is Addison's disease?
Bilateral destruction of all zones of the adrenal cortex. Usually autoimmune, but tuberculosis causes it in countries where tuberculosis is common.
Why does Addison's disease cause hyponatraemia?
Aldosterone is lost as well as cortisol, so sodium and water are depleted, with hyperkalaemia.
How does SIADH cause hyponatraemia?
The kidney holds water, so a dilutional hyponatraemia develops and the urine is concentrated. Severe pulmonary tuberculosis or tuberculous meningitis can cause it.
How does ACTH deficiency from pituitary disease cause hyponatraemia?
Aldosterone is preserved. The hyponatraemia is dilutional, from loss of the cortisol needed for free water excretion.
How do you tell Addison's disease from pituitary disease?
By the potassium and the pigmentation. Addison's gives hyperkalaemia, and pigmentation from the raised ACTH. ACTH deficiency gives neither.
Tell me what you know about pleural fluid in tuberculosis.
It is an exudate, with a protein above 30 grams per litre and mostly lymphocytes. Culture is often negative, so a negative culture does not exclude tuberculosis.
How do you confirm that pleural fluid is an exudate?
By Light's criteria. Any one of three marks an exudate: a fluid to serum protein ratio above 0.5, a fluid to serum lactate dehydrogenase ratio above 0.6, or a fluid lactate dehydrogenase above two thirds of the upper limit of normal for serum.
Which test in the pleural fluid suggests tuberculosis when culture is negative?
Adenosine deaminase, released mainly by activated macrophages. A level above 40 units per litre suggests tuberculosis where the disease is common.
Tell me what you know about the cerebrospinal fluid in tuberculous meningitis.
It is clear or only slightly cloudy, with mostly lymphocytes, a raised protein, and a low glucose compared with a paired plasma sample.
How does the cerebrospinal fluid differ in pyogenic meningitis?
Pyogenic meningitis is acute, and its fluid is cloudy with neutrophils.
Why is a plasma glucose taken at the same time as the lumbar puncture?
The cerebrospinal fluid glucose is read as a ratio against a plasma glucose taken at the same time.
In tuberculous meningitis, where does the exudate sit?
At the base of the brain, around the optic chiasm and the vessels of the circle of Willis.
What does the basal exudate cause?
Cranial nerves passing through it fail, blocked basal cisterns cause hydrocephalus, and narrowed, thrombosed vessels cause strokes.
Which enzyme in the cerebrospinal fluid suggests tuberculosis?
Adenosine deaminase, which comes mainly from activated macrophages. A raised level suggests tuberculosis when the organism cannot be found.
Tell me what you know about liver function tests during treatment for tuberculosis.
Isoniazid, rifampicin and pyrazinamide can all raise the transaminases. A rise above five times the upper limit of normal, or above three times with symptoms, marks drug-induced liver injury. Ethambutol spares the liver.
Which other blood result rises with pyrazinamide?
The uric acid, because pyrazinamide reduces its renal excretion. Hyperuricaemia is common, but it rarely brings on gout.
Pharmacology
Tell me what you know about the standard first-line treatment for tuberculosis.
2(RHZE)/4(RH). Isoniazid, rifampicin, pyrazinamide and ethambutol for two months, the intensive phase. Then isoniazid and rifampicin for four months, the continuation phase.
Why are four drugs started together?
Populations of M. tuberculosis contain small numbers of organisms naturally resistant to any one drug. One drug alone lets them become the dominant population. Several drugs together suppress them.
Why do only rifampicin and isoniazid continue after two months?
They are the two main drugs, and they clear the organisms that persist after the intensive phase. Most of the benefit from pyrazinamide comes early, and longer use adds to its hepatotoxicity.
How long is treatment for tuberculous meningitis?
2(RHZE)/10(RH). The continuation phase runs for ten months.
Tell me what you know about isoniazid.
A hydrazide, active against rapidly growing bacilli and organisms within cells. Hepatitis is its most serious adverse effect.
How does isoniazid work?
It is a prodrug switched on by a mycobacterial enzyme, KatG. It then blocks the enzymes that build mycolic acid, so the wall cannot be made.
How does resistance to isoniazid arise?
Mutation or deletion of KatG, so the prodrug is never switched on, or a change in the target enzyme itself.
A patient on isoniazid has tingling in the hands and feet. Why?
The drug causes a relative pyridoxine deficiency, which leads to a peripheral neuropathy. Pyridoxine prevents it.
Tell me what you know about ethambutol.
It inhibits arabinosyl transferase, an enzyme that helps build the mycobacterial cell wall. It is bacteriostatic and specific for mycobacteria.
What is the main adverse effect of ethambutol?
Optic neuritis, with reduced visual acuity and loss of red-green discrimination.
Which patients are at greater risk of optic neuritis?
Patients on higher doses, and patients with renal impairment.
Tell me what you know about rifampicin.
It blocks RNA transcription by binding the beta subunit of mycobacterial DNA-dependent RNA polymerase. It is bactericidal for organisms inside and outside cells.
A patient on a protease inhibitor for HIV starts rifampicin. What happens to the protease inhibitor?
Rifampicin induces cytochrome P450 enzymes, so the protease inhibitor is cleared faster and its level falls.
How does resistance to rifampicin arise?
Mutations lower the affinity of the bacterial RNA polymerase for the drug. Resistant strains emerge rapidly when it is used alone.
Tell me what you know about pyrazinamide.
A prodrug that bacterial pyrazinamidase converts to pyrazinoic acid, the active form. It acts on bacilli in acidic lesions and inside macrophages. Its exact target is unclear.
Why is pyrazinamide given only in the intensive phase?
Most of its benefit comes early, and longer use adds to its hepatotoxicity.
What are the main adverse effects of pyrazinamide?
Hepatotoxicity, and hyperuricaemia, which is common but rarely brings on gout.
How does resistance to pyrazinamide arise?
Some resistant strains lack pyrazinamidase, so the drug is never converted to its active form.
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Mycolic acid
Microbiology and Parasitology
A long-chain fatty acid in the outer wall. Heat drives carbol fuchsin into the wall. Acid alcohol cannot dissolve those wall lipids, so the organism keeps the red stain. Everything else loses it and takes the blue counterstain. That is acid-fastness. The same lipid excludes Gram stain.
The lipid wall is part of why the macrophage cannot kill what it has phagocytosed. So containment needs cell-mediated immunity, not a single cell, and the tissue damage that follows is a type IV reaction.
Isoniazid is switched on by a mycobacterial enzyme and then blocks the enzymes that build mycolic acid. The molecule that makes the organism hard to stain and hard to kill is the target of the drug with the strongest early activity.
Central caseous necrosis surrounded by epithelioid macrophages and multinucleate giant cells, with fibroblasts and collagen at the rim. Caseation is granular and cheese-like to the naked eye.
Sensitised T cells activate macrophages, which destroy the bacteria and, in doing so, destroy lung tissue. The necrosis is a consequence of the immune response, not of the organism directly. This is type IV delayed hypersensitivity.
Granulomas cause hypercalcaemia through vitamin D, in tuberculosis and sarcoidosis alike. The lesion itself generates the abnormality, so the calcium follows the disease activity.
A negative Ziehl-Neelsen does not exclude tuberculosis. In a Nigerian review of histologically confirmed tuberculous lymphadenitis, roughly one in six stained positive. The tuberculin test is also negative in a substantial minority of people with active pulmonary disease.
Granulomas may lack central caseation even in immunocompetent patients, so acid-fast stains are indicated whenever granulomas are present, whether caseation is there or not. Architecture and stain are read together, and neither alone settles it.
The tuberculin reaction and the interferon gamma release assay both report that the immune system has met the antigen. Neither separates latent infection from active disease.
Immunosuppression blunts the CD4 mediated response, and the characteristic granulomatous reaction is absent. Lesions consist of sheets of macrophages containing numerous bacilli.
Above a CD4 count of about 300 the picture is usual apical cavitary disease. Below 200 it resembles progressive primary disease, with lower and middle lobe consolidation, hilar lymphadenopathy and no cavity. Extrapulmonary involvement rises with the depth of immunodeficiency.
Rifampicin induces cytochrome P450 enzymes and shortens the half-life of coadministered drugs. Rifabutin is a weaker inducer and is preferred in patients taking protease inhibitors or certain non-nucleoside reverse transcriptase inhibitors.
Lymphadenitis is the most frequent form of extrapulmonary tuberculosis, usually cervical and known as scrofula. Disease tends to be unifocal, and most patients have no other organ involved. In HIV it is almost always multifocal.
Presumptive extrapulmonary tuberculosis is confirmed by molecular test, smear, culture or histology. Sampling the site gives all four routes from one procedure.
Sulfatides, mycosides resembling cord factor, inhibit the phagosome from fusing with the lysosome that carries the bactericidal enzymes. Phagocytosed bacteria are not destroyed; they multiply and survive inside the macrophage.
Pyrazinamide is a prodrug hydrolysed to pyrazinoic acid and is active against bacilli in acidic lesions and within macrophages. Most of its benefit comes early and longer use adds to its hepatotoxicity, so it is withdrawn after the intensive phase.
Necrosis in which dead tissue loses all structure and becomes soft, granular and cheese-like. Down the microscope it has no nuclei and no preserved architecture.
Cell-mediated immunity
Defence carried out by T cells. Sensitised T cells activate macrophages so that they can kill the organisms they have phagocytosed.
Epithelioid macrophage
An activated macrophage with abundant cytoplasm and an elongated nucleus. These cells form the wall of the granuloma.
Granuloma
A compact collection of epithelioid macrophages, often with multinucleate giant cells, ringed by lymphocytes.
Langhans giant cell
A multinucleate cell formed when macrophages fuse. Its nuclei sit in a horseshoe around the edge of the cell.
Necrotising granuloma
A granuloma whose centre has died. In tuberculosis the dead centre is caseous.
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