TUBERCULOSIS CASE STUDY
Patient
The patient was a 46 year old male who was diagnosed following admission to hospital with active respiratory tuberculosis (TB).
History of presenting complaint
In the 6 week period prior to admission, the patient had experienced a worsening dry cough which was unrelieved by over-the-counter (OTC) cough medicines. He presented to A&E when his cough became productive and purulent, and he had experienced two episodes of haemoptysis. He had also been experiencing night sweats, and was aware of having lost some weight, although he was unsure of how much.
Past medical history
The patient reported no previous illnesses or medical treatment.
Social history
The patient was born in China, and had arrived in the country approximately 6 months prior to his admission to hospital. He was staying with a friend and was working on a casual basis in a factory. He had just begun to apply for the right to remain in the UK. He did not smoke or drink alcohol. He was unaware of any family medical history.
Drug history
The patient’s drug history was confirmed by speaking to him (with the assistance of an interpreter). He was not registered with a GP in the UK, and took no regular medicines. He had bought some OTC cough medicines in the last few weeks; he could not remember their names and, as they had not been effective, he had stopped taking them over a week previously.
Examination details
Chest examination: Trachea central; expansion right = left. Dull to percussion on both right and left apices. Slight expiratory wheeze.
Chest X-ray: Shadowing in upper lobe of both lungs
Sputum samples: Smear positive for acid-fast bacillus. Culture: mycobacterium tuberculosis
In addition, blood tests including full blood count, urea and electrolytes and liver function tests were completed. Blood borne virus testing was completed with the informed consent of the patient. The patient’s weight was checked, and his temperature was regularly monitored and documented.
Diagnosis
The results of the investigations above, together with a thorough clinical assessment of the patient, led to a diagnosis of active respiratory tuberculosis.
Clinical progress
Day 1: The patient was admitted via A&E, where his presenting symptoms led to his case being discussed quickly with an infectious disease specialist. As it was suspected that he might have active respiratory TB, and would therefore be considered an infection risk, arrangements were made for rapid transfer to a ward with a negative pressure isolator room. On arrival, he was commenced on empirical TB treatment, his admission bloods having shown no renal or hepatic impairment, and satisfactory visual field testing having been completed. The clinical pharmacist confirmed his medication history and documented it in his notes, and counselled him on the medication he was to receive. The patient was also prescribed paracetamol for pyrexia. Two induced sputum samples were obtained and sent for culture.
Day 2: A further induced sputum sample, obtained in the early morning, was sent for culture. The patient met the TB liaison nurse for the first time.
Day 4: The patient was tolerating his TB medication well, and reported no adverse effects, although he had noticed that his urine was red. His liver enzymes were slightly elevated, although still within laboratory reference range. His other blood results were also within laboratory reference range. He was still occasionally pyrexial. He reported that his appetite had improved a little. All blood borne virus tests had returned negative.
Day 8: Culture results confirmed the initial diagnosis of active respiratory TB. No other organism was grown in the cultures. The patient continued to feel better and was no longer pyrexial. All blood tests remained within laboratory reference range, and his liver enzymes had returned to close to pre-treatment levels.
Day 15: The patient’s weight was checked, and was found to have increased to 66.3kg (from 63.6kg at admission). His medication was reviewed and amended to take account of this.
Day 17: The patient’s blood tests (urea and electrolytes, liver function tests) confirmed no adverse effect of amending his medication two days previously.
Day 18: Preliminary discharge planning was commenced: as Directly Observed Therapy (DOT) was being considered, the clinical pharmacist was asked to calculate a 3 times weekly dose regimen for the patient. This was documented in the patient’s notes.
Day 20: Having completed over two weeks of treatment, the patient’s health had improved sufficiently for him to be considered well enough to go home. Plans had been made for a more permanent residence for him. Following a discussion with the patient, medical staff, the TB liaison nurse and the clinical pharmacist, it was decided that he did not require DOT, but would instead remain on daily medication which would be supplied in a weekly blister pack (prepared by the hospital pharmacy), and would be supported in the community by the TB liaison nurse. He was counselled on all of his medicines and on the use of the blister pack by the clinical pharmacist, with the assistance of an interpreter. He was to be followed up at clinic in one month’s time.
Discussion
Tuberculosis (TB) is an infectious disease caused by the mycobacterium tuberculosis complex. It is a notifiable disease. Although it continues to be a leading cause of mortality in low and middle income countries, public perception in the UK has until recently assumed that TB is no longer an issue here, due to the mass screening campaign in the first part of the 20th century, and the availability of the Bacillus Calmette-Guérin (BCG) vaccine.
However, the number of cases reported in the UK has risen steadily in the first decade of the 21st century, with 8963 cases reported in 2011. The majority of patients were born outside the UK, with coming from south Asia and sub-Saharan Africa. (1)
Of particular concern is the emergence of multi-drug resistant TB (MDRTB) – where there is resistance to at least rifampicin and isoniazid, two of the mainstays of standard TB therapy. If these cannot be used, second-line treatment can involve the use of medications for which there is less evidence of benefit and which may have more harmful side effects. There may also be implications for cost, given that some of the medications used, (for example, amikacin), can only be given by the intravenous route, necessitating hospitalisation. Patients in low income countries may not have access to either the facilities or the funds to obtain adequate treatment. It is of vital importance to quickly identify everyone who is infected, and to ensure that they are treated effectively with the correct medicines, at the correct dosage, for the correct length of time. (2)
TB is usually spread by the inhalation of airborne droplets which are expelled by infectious people whilst sneezing or coughing. Once inhaled, the body’s immune system is activated, and in approximately 80% of people, the bacteria are killed. In the remainder, the bacteria may remain dormant within granulomas formed during the immune response; the patient is said to have latent TB. About 5-10% of patients with latent TB will go on to develop active TB later in life.
Where the body’s immune system fails to destroy or to control the bacteria, they will begin to divide and spread; the patient is then said to have active TB. As the main route of infection is via the lungs, it is unsurprising that the most commonly recognised form is respiratory TB. Characteristic symptoms include cough (initially dry, becoming productive and purulent), night sweats, weight loss and fatigue. Other recognised variants include:
- Central Nervous System (CNS) TB – patient presents with non-specific symptoms such as anorexia, malaise, headache and vomiting, and then develops meningeal inflammation and focal neurological symptoms.
- Bone and joint TB – associated with, amongst other symptoms, back pain and kyphosis.
- Lymph node TB – most commonly seen in the cervical lymph nodes, which become enlarged but which may become asymmetrical.
- Disseminated TB – bacilli spread throughout the bloodstream, causing malaise, fever, anorexia and weight loss.
- Pericardial TB – may be associated with pericardial effusion.
Treatment for all forms except CNS TB usually lasts for six months; CNS TB is normally treated for at least nine months. (3, 4)
Positive diagnosis is made in a number of ways depending on the variant involved.
- Active non-respiratory TB – A biopsy is taken from the affected site and is sent for culture.
- Active respiratory TB – Shadowing on the patient’s chest X-ray may suggest TB – this is normally apical in TB, as opposed to basal in pneumonia. Sputum smear microscopy is then used, where the sputum sample is checked for the presence of acid-fast bacilli. However, this does not discriminate between Mycobacterium tuberculosis and other mycobacteria, so it is necessary to send sputum samples for culture to confirm the diagnosis. This technique has the added advantage of allowing for drug resistance testing to be carried out at the same time.
- Latent TB – The tuberculin skin test (Mantoux test) is commonly used – a small amount of PPD tuberculin is injected into the forearm. If a reaction is seen when the test is “read” 48 – 72 hours later, this is a sign that the patient has either latent TB or has received the BCG vaccine, or has been exposed to non-tuberculous bacteria. A positive result therefore warrants further investigation. It should also be noted that false-negative results can be seen in patients who are immunosuppressed.
IMMEDIATE MANAGEMENT
As the patient was suspected to have active respiratory TB, the priority was to ensure prompt, appropriate and effective treatment for the patient. It was also necessary to trace all of his close contacts, so that they could be screened for TB, and could be treated if necessary.
Patients who are diagnosed with active TB which is not drug-resistant, and who are not clinically unwell do not necessarily need to be admitted to hospital for initiation of treatment. However, if there are concerns about the patient’s condition or extenuating socio-economic circumstances, the patient should be admitted to a single room in hospital – this should be a negative-pressure room if the ward concerned also cares for immunosuppressed patients (e.g. those with HIV). The patient should remain in this room until discharge, or until at least two weeks’ treatment has been completed. The patient should wear a mask if there is a need to leave the room during this period. (3, 4)
In this case, the patient’s eligibility to remain in the UK was being examined by the authorities. There was concern that if he did not receive appropriate treatment immediately, the patient might default from attending for treatment, and would present a public health risk if he remained untreated. For this reason, he was admitted to a ward with a negative pressure room, where he remained for almost three weeks. During this time, his legal status was clarified, and he was discharged into a much more stable environment.
Empirical treatment
The standard treatment for TB for adults and children consists of four drugs.
Rifampicin
Rifampicin is a bactericidal agent which acts by inhibiting RNA polymerase. It is effective at killing organisms with slow metabolic activity. It can cause transient elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin, which does not generally require disruption to treatment; however, more serious hepatic toxicity can occur, and patients should be told how to recognise signs of liver disorder, such as persistent nausea, vomiting, malaise or jaundice. (Vomiting is usually the initial sign). Treatment should be stopped and immediate medical advice should be sought. Rifampicin also causes body secretions such as urine and tears to become orange-red; this may have consequences for patients who wear soft contact lenses. Rifampicin also induces hepatic enzymes, which can accelerate the metabolism of several drugs, including oestrogens, corticosteroids, phenytoin, sulfonylureas and anticoagulants. Adjustments to a patient’s usual medication regimen may be necessary when TB treatment is both started and stopped. Mild cutaneous reactions may also occur.
Rifampicin is taken for six months, and dose is decided by body weight (Adult dose: <50kg, 450mg daily; 50kg and above, 600mg daily). (5)
Isoniazid
Isoniazid is a bactericidal agent, which acts by inhibiting mycolic acid synthesis, thus disrupting cell wall synthesis. It is also associated with liver toxicity. Its main side effect is peripheral neuropathy, and may also rarely cause psychosis. TB patients who receive isoniazid and who have pre-existing risk factors for peripheral neuropathy (e.g. malnutrition, HIV, diabetes mellitus, alcohol dependence, pregnancy, chronic renal failure) should therefore be prescribed prophylactic pyridoxine as part of their treatment. The pyridoxine dose used is normally 10mg daily; however this strength is difficult to obtain, so 25mg daily or 50mg on alternate days may also be used. Isoniazid is taken for six months, and the adult dose is 300mg daily. (5)
Pyrazinamide
Pyrazinamide is a bactericidal agent, particularly in acidic environments. It is thought to inhibit cell membrane transport function and/or to disrupt energy metabolism, and is only active against intracellular dividing forms of M. tuberculosis. It is also associated with liver toxicity and with gout. Pyrazinamide is taken for the two month “initial” phase only, and dose is decided by body weight (Adult dose: <50kg, 1.5g daily; 50kg and over, 2g daily). (5)
Ethambutol
Ethambutol is a bacteriostatic agent. It prevents cell wall synthesis by inhibiting arabinosyl transferase, which is responsible for producing arabinogalactan in the cell wall. It is associated with visual disturbances (loss of acuity, colour blindness and restriction of visual fields): all patients should undergo visual acuity testing by Snellen chart prior to treatment, and should be counselled to report any visual changes during treatment. Ethambutol is taken for the two month “initial” phase only, and dose is decided by body weight (Adult dose: 15mg/kg daily). (5) If the patient does not have isoniazid resistance, ethambutol treatment can be stopped as treatment with three drugs is sufficient.
In order to aid patient adherence to treatment, fixed-dose combinations of the standard treatments are available. As well as reducing the tablet burden for the patient, these also have the advantage of containing most or all of the drugs in one tablet – the patient cannot, therefore, be selective in which drug he takes. (6)
Available products include:
Rifater – Each tablet contains rifampicin 120mg, isoniazid 50mg and pyrazinamide 300mg. Dose is by body weight: adult <40kg, 3 tablets daily; 40-49kg, 4 tablets daily; 50-64kg, 5 tablets daily; 65kg and over, 6 tablets daily. Used for the “initial” two month phase. (7)
Rifinah – Available as two strengths: 300/150 – rifampicin 300mg + isoniazid 150mg – for adult patients 50kg and over, 2 tablets daily; 150/100 – rifampicin 150mg + isoniazid 100mg – for adult patients under 50kg, 3 tablets daily. Used for the “continuation” phase following “initial” two month phase. (8)
Voractiv – Each tablet contains rifampicin 150mg, isoniazid 75mg, pyrazinamide 400mg and ethambutol 275mg. Dose is by body weight: Adult 30-39kg, 2 tablets daily; 40-54kg, 3 tablets daily; 55-70kg, 4 tablets daily. Not recommended for use in patients weighing over 70kg. Used for the “initial” phase of treatment. (9) (Note this product was not available at the time that this patient was treated; it is also (at the time of writing) not accepted for use within Scotland by the Scottish Medicines Consortium). (10)
COUNSELLING
It is vitally important that TB medication is taken correctly for maximum benefit. Patients should be counselled to take all of their tablets at the same time, (preferably before breakfast), either at least 30 minutes before food or at least 2 hours after food. Patients who are prescribed regimens containing isoniazid should be advised to avoid foods which contain histamine (such as skipjack tuna) and tyramine (such as red wine and cheese). Patients should be advised to check with a pharmacist that any other medication prescribed does not interact with their TB treatment, and should be reminded of the possible signs of hepatotoxicity. They should also be advised to report any loss of visual acuity, or tingling of the hands or feet, and should be reminded that their bodily secretions may be stained red.
At the beginning of treatment, the patient weighed 63.6kg. He was commenced on Rifater (five tablets daily) and ethambutol 1000mg daily. His weight was monitored during his admission; after 15 days of treatment, his weight was recorded as 66.3kg. His Rifater dose was increased to six tablets daily, whilst his ethambutol dose remained unchanged. This regimen remained unaltered on discharge, and the patient was to be reviewed at clinic four weeks later. He was counselled (via an interpreter) both on commencement of treatment and on discharge, on how to take his medication, on the main potential side effects of treatment, and on the need to report potential signs of hepatotoxicity and visual disturbances promptly. He showed good understanding of the information given.
The patient was prescribed pyridoxine 25mg daily. On discharge, he received his medication in a dosette box, so there was no need to counsel him on the need to halve tablets. He was aware of having received the halved tablet as part of his daily treatment, and the reason for which it was prescribed.
MULTI-DRUG RESISTANT TB (MDR-TB)
TB is said to be multi-drug resistant where resistance to at least rifampicin and isoniazid is demonstrated. Treatment is necessarily more complex, involving the use of a greater number of drugs over a much longer period of time. Fortunately, in this case, the patient demonstrated no drug resistance, and was able to be treated with the standard TB regimen.
DIRECTLY-OBSERVED THERAPY
The importance of good adherence to treatment cannot be over-stated, and all patients should therefore be assessed at the commencement of treatment as to whether they will be able to comply unaided. Where there is concern, various measures may be instigated, one of which is Directly-Observed Therapy (DOT). Here, the patient is observed to swallow his TB medication by a healthcare worker, either in his home or at a clinic or hospital. For reasons of practicality, the regimen is usually tailored to three times a week dosing. This type of regimen is useful for patients who are street-dwellers or who have demonstrated poor adherence in the past; medication can be kept at the clinic or by the nurse so that it is not mislaid. DOT should be used for patients who are stable and clinically well. (3, 4)
The patient was initially considered for DOT as his housing situation was unclear. When this was clarified, it was decided that it would be more appropriate for him to remain on a daily regimen and to manage his own medication with the aid of a dosette box, with regular support from the TB liaison nurse. As he did not have a GP at the time of discharge, his TB medication continued to be supplied from the hospital pharmacy. This situation was to be reviewed at his next clinic appointment.
Contact tracing
Once a patient has been diagnosed with active TB, it is important to perform contact tracing, and to screen all household members and close contacts. Whilst it is important to identify further active cases, it is also important to identify latent cases and to determine the extent of transmission which has occurred. Testing is by Mantoux test, with interferon-gamma testing used in those who have positive skin tests or who have received the BCG vaccine. (11) If detected, latent TB can be treated with regimens including rifampicin and/or isoniazid – the exact regimen used depends on the age of the patient and whether they have HIV.
Further information
This patient was not a native of the UK and had only a few words of English. It was extremely important that the patient understood the serious nature of his illness and the need for strict adherence to his treatment. For this reason, an interpreter was booked for the period of the ward round twice a week, so that the multidisciplinary team could communicate with him clearly and could ensure good understanding. As clinical pharmacist, I was able to counsel the patient on his medication during this period, and was satisfied with his understanding.