Обратная связьThis section focuses on monitoring the progress of treatment and identifying any problems that may arise during treatment of DS-TB. Examples of such problems are adverse drug reactions or delayed response to treatment, which might require additional investigations to decide whether to continue the therapy or change the treatment strategy.
All patients should be monitored to assess their response to therapy. Regular monitoring of patients also facilitates adherence to treatment and completion of treatment.
Although people with DS-TB are much less likely than those with MDR-TB to fail treatment, it is important to outline the principles of effective monitoring where drug resistance and possible failure are suspected. Regular clinical examination (with monitoring of body weight), CXR and laboratory monitoring make it easier to determine whether something is wrong and thus take rapid action.
All patients, their treatment supporters and health workers should ideally be instructed to report the persistence or reappearance of symptoms of TB (including weight loss), slow clinical improvement, symptoms of adverse drug reactions or treatment interruptions. Patient weight should be monitored each month, and dosages should be adjusted if weight changes. When possible, radiological monitoring may also be useful. Regular clinical examinations should be performed by the treating physician.
A written record of all medications given, bacteriological response and AEs should be maintained for every TB patient on the TB treatment card.
9.1 Clinical examination
The classic symptoms of TB – cough, sputum production, fever and weight loss – generally improve within the first few weeks of treatment. Cough and sputum production can persist after sputum conversion in patients with extensive lung damage (often due to late diagnosis), but even in those with extensive lung damage, improvement is usually seen within 1–2 months of effective treatment. Persistent fever, weight loss or recurrence of any of the classic symptoms of TB should prompt investigation for possible treatment failure, undetected resistance to one or more drugs in the current treatment regimen or untreated comorbidities. The recurrence of TB symptoms after sputum conversion may be the first sign of treatment failure. For children, height and weight should be measured monthly to ensure that they are growing normally. Normal growth rate usually resumes after a few months of successful treatment. For adults, weight should also be recorded monthly (height is only recorded at the start of treatment, to calculate BMI).
The frequency of clinical visits depends on the patient’s clinical condition and evolution. On average, for an outpatient with no specific problems, clinical examination is usually done every week during the first month and once per month thereafter if the patient is stable. More frequent clinical examinations may be necessary, depending on the clinical condition of the patient.
At every visit, the patient should be asked about the occurrence of AEs; also, any potential difficulties in treatment adherence should be discussed with the patient and their treatment supporter.
Clinical visits should coincide with bacteriological and clinical laboratory examination schedules, to limit time and transportation constraints for the patient.
In extrapulmonary DS-TB, it is essential to monitor the clinical evolution to assess the treatment response because, in general, bacteriological monitoring is difficult.
9.2 Chest radiography
In the first few months of treatment, the patient’s chest radiograph may appear unchanged or show only slight improvement. Although there are no formal recommendations on this, it is prudent to undertake CXR at baseline, at the end of the second month of treatment and at the end of treatment, to document progress and to use for comparison if the patient’s clinical condition changes at any time after the achievement of treatment success (92). A chest radiograph at the end of treatment is also useful to optimally manage TB pulmonary sequelae after treatment (92).
For extrapulmonary TB (in particular TB of the bone or joint), both radiographic examination and computed tomography (CT) can provide information on the evolution of the disease. However, some changes detected by CXR may never return to baseline; hence, the response often needs to be evaluated based on both clinical and radiographic findings. In contrast with pulmonary TB treatment, it is difficult to define what constitutes a cure in extrapulmonary TB.
9.3 Sputum smear and culture
Response to treatment in pulmonary TB patients is also monitored by bacteriological sputum smear examination and culture. For pulmonary DS-TB, the most important evidence of improvement is conversion of the sputum culture to negative. For extrapulmonary TB, sputum smears and cultures are only performed during the monitoring period if the patient develops pulmonary signs, or in the rare situation when materials valid for microbiological examinations are collected from the extrapulmonary site.
For people with DS-TB, sputum smear microscopy may be performed at the end of the second month of treatment. Sputum specimens should also be collected for smear examination at each follow-up sputum check. Specimen collection should not interrupt treatment, and specimens should be transported to the laboratory promptly; if a delay in transport is unavoidable, specimens should be refrigerated or kept as cool as possible.
A positive sputum smear at the end of the second month may indicate any of the following:
- even though the treatment response was good, non-viable bacteria remain present and are visible by microscopy;
- resolution is slow because the patient had extensive cavitation and a heavy initial bacillary load (this often occurs in cases of late diagnosis);
- a poor treatment response occurred for one of the following reasons:
- the initial phase of therapy was poorly supervised and patient adherence was poor;
- anti-TB drugs were of suboptimal quality;
- doses of anti-TB drugs are below the recommended range;
- the patient has comorbid conditions that interfere with either adherence or treatment response (e.g. diabetes or cancer);
- the patient may have undetected DR-TB that is not responding to first-line treatment; or
- although this is rare, the patient either does not absorb, or has suboptimal absorption of, one or more anti-TB drugs (74).
Sputum culture can be used for treatment monitoring. Although monthly culture is recommended for MDR/RR-TB cases (17, 74, 93, 94), this can also be useful for DS-TB, particularly at the end of the second month of treatment and at the end of treatment if the patient does not improve clinically, or at any other time if failure is suspected because of possible drug resistance. Where drug resistance is suspected, DST needs to be performed – the core of which is to test for resistance to isoniazid, rifampicin and moxifloxacin (if used) – and, if possible, to undertake DST using rapid tests for second-line drugs (92).
The reasons behind a positive culture during treatment monitoring are the same as those mentioned above for sputum smear; however, a difference is that a positive culture indicates that viable bacilli are present.
Molecular tests such as Xpert MTB/RIF are not used to monitor response to treatment.
Although sputum smear is useful because of its much shorter turnaround time, sputum culture is much more sensitive for detection of ongoing active disease or treatment failure. Therefore, culture is useful to monitor the progress of treatment. Sputum smear and culture examinations depend on the quality of the sputum produced, so care should be taken to obtain adequate specimens and transport them to the laboratory according to standard procedures, to maintain the viability of the bacilli and thus obtain a valid culture result. A tracking system should be in place for all specimens sent for culture until results are obtained by the referring facility or clinician.
Where sputum smears and cultures are persistently positive for acid-fast bacilli, it is necessary to undertake assessment for non-TB mycobacteria (NTM), because colonization or infection with NTM secondary to TB in a damaged lung is not uncommon. In such cases, even where TB is adequately treated, treatment may need to be directed towards the NTM as well. Additional imaging and possibly bronchoscopy should be considered, to confirm the diagnosis of NTM infection leading to disease (95).
Culture conversion is not equivalent to cure. Some patients may initially convert and later revert to positive sputum culture, usually when undetected drug resistance is present. In rare cases, malabsorption can be the cause.
DST should be repeated for patients who remain smear and culture positive, or for whom treatment failure is suspected. In such cases, it is usually not necessary to repeat DST within 2–3 months of the previous DST. Table 1.9.1 summarizes the activities involved in and the frequency of monitoring.
Table 1.9.1. Summary of activities for monitoring treatment response
AE: adverse event; BMI: body mass index; DR-TB: drug-resistant TB; DST: drug susceptibility testing; TB: tuberculosis; VST: video-supported treatment.
9.4 Assessment of patients when treatment failure is suspected
Any patient not clinically responding to therapy after several weeks should be considered as being at risk for failure. In particular, patients should be considered as being at high risk for treatment failure if they had at least 3 months of full adherence to what was deemed to be an effective treatment regimen with quality-assured drugs, but show evidence of active disease – either clinical, radiographic or bacteriological (DST or culture) – or reappearance of disease. The following steps are recommended in such a situation.
Confirm treatment
The treatment card should be reviewed to confirm that the patient has fully adhered to treatment.
Look for undetected comorbidities
Some undetected comorbidities mimic treatment failure through clinical and chest radiographic deterioration that occurs simultaneously with repeated culture-negative and smear-negative results. These comorbidities (e.g. NTMs, fungal infections, lung infections or a pulmonary malignancy) should be diagnosed and treated appropriately. Illnesses that may decrease absorption of medicines (e.g. chronic diarrhoea) or may result in immune suppression (e.g. HIV infection) should also be excluded.
Review the bacteriological data
A single positive culture in the presence of an otherwise good clinical response can be caused by a laboratory contaminant or error. In such cases, subsequent cultures that are negative help to prove that the apparently positive result did not reflect treatment failure. Positive smears with negative cultures may be caused by the presence of dead bacilli and thus do not necessarily indicate treatment failure.
Review the DST
If there is evidence of acquired resistance to any drug, treatment failure is likely and a new regimen for DR-TB may need to be started promptly.
Review CXR
If comparison of CXR at baseline and at the current time shows no improvement or deterioration of the CXR image, this may indicate failure of TB treatment.
Review treatment regimen
The treatment regimen should be reviewed in relation to medical history, contacts and all DST reports. If any resistance appears that was not present or evident previously, the patients should be managed as DR-TB or MDR-TB with a new regimen, and rapid action should be taken to ensure that adequate infection control measures are implemented.
Consider malabsorption
In rare cases, genetic reasons mean that one or more drugs are not well absorbed, leading to suboptimal blood levels, suboptimal effect of the drug and potential development of drug resistance. Therapeutic drug monitoring, based on collection of a dried drop of blood (which can be easily sent by normal mail to one of the laboratories performing the test), makes it possible to evaluate the drug level in the blood and, eventually, to adjust the dose. Although not yet recommended by WHO, other clinical guidelines do recommend this test in specific cases (44).
Absorption of drugs is reduced in severely ill patients admitted to the critical care department with conditions such as central nervous system TB or acute respiratory distress syndrome. In such cases, intravenous anti-TB treatment should be considered until the situation improves and a nasogastric tube can be used.