The Patient Experience Across the Cascade of TB Care
In LMICs, someone with a TB symptom, such as a persistent cough, typically seeks care at a PHC facility. There, if their responses to a screening questionnaire suggest TB, they provide a sputum sample. The sample is typically sent outside the PHC facility for diagnosis by microscopy or by molecular tests where they are available. If the patient cannot provide sputum (such as children and patients living with HIV), they are referred out for a diagnostic chest X-ray. Transfer of samples or referral of patients outside the PHC facility delays diagnosis and causes loss to follow-up in the cascade of care. If TB is confirmed, the patient returns for TB treatment. Missed diagnosis is currently the most critical gap to fill to stop the spread of TB and drug resistance.
WHO Guidelines
WHO TB guidelines provide recommended standards for comprehensive TB prevention and care, without specifying at what level of health facilities these services should be provided.
Screening/Prevention
Most people with TB enter the health system at the PHC level. There, they are assessed for TB symptoms using a questionnaire. The WHO four-symptom screen asks about cough, fever, weight loss, and night sweats. This screen is prompted by the patient having one of the following: a relevant symptom; exposure to someone with active TB; high-risk factors such as living with HIV; or findings from a higher-level health facility, such as an abnormal chest X-ray or blood test result. TB symptom screening is also used by community health workers in active case-finding programs.WHO guidelines for systematic screening for pulmonary TB encompass multiple tools: assessment of symptoms, chest X-rays, computer-aided detection software (for automated interpretation of digital chest X-ray images), molecular WHO-approved rapid diagnostic tests (nucleic acid and non-nucleic acid tests with different trade-offs for their applicability), and C-reactive protein (for people living with HIV).
Challenges
Symptom screening does not require infrastructure, but it is a subjective tool whose quality and consistency vary depending on the patient’s understanding and willingness to share symptoms and the care provider’s interpretation of them. Chest X-ray screening is recommended, especially for children, but it is not commonly available at the PHC level as is the case for recommended molecular diagnostic testing, which results in delayed diagnosis and missed opportunities for TB care.
Diagnosis
Sample CollectionWhen a person is deemed highly likely to have TB based on screening results, they provide biological samples for diagnosis. Typically, screening and sample collection for diagnosis are done at the PHC level. Patients self-collect 3-5 ml of their sputum in a plastic cup, which is then sealed and sent to a higher-level facility or central laboratory for diagnostic testing by microscopy or molecular tests.
Sample Preparation
To diagnose TB in countries where it is common, patient sputum is usually analyzed by microscopy, although molecular testing is becoming more common. Sputum is smeared on a microscope slide, and after Ziehl-Neelsen staining, mycobacteria are directly detected. Sputum processing for molecular testing incorporates devices for lysing the thick mycobacterial cell wall.
Testing
TB diagnosis in high-burden countries is done through microscopy, molecular testing, or chest X-ray. Some PHC facilities perform microscopy-based TB testing, but most send out samples for diagnostic testing at high-level facilities or central laboratories.
A WHO standard for universal access to rapid tuberculosis molecular diagnostics includes benchmarks to ensure that results are provided in a timely manner so as to be useful for patient management. WHO guidelines for TB diagnostics encompass a set of molecular rapid diagnostic tests. When such molecular tests have been used in screening to identify a person with presumptive TB, the guidelines recommend additional clinical evaluation and further tests, such as chest X-ray or repeat molecular tests with additional sputum samples, for definitive diagnosis of TB.
Challenges
Patients typically make multiple visits to health care providers before a formal TB diagnosis, with it taking days to receive initial test results and about an additional week for diagnosis and confirmation. This delays diagnosis and causes loss to follow-up. Producing sputum can be unpleasant for patients, and children and people living with HIV may be unable to produce it. The self-collection process for sputum leads to variable sample quality. Trained personnel are required for the subsequent sample handling and sputum smear microscopy, adding to the challenges for routine use of the method at the PHC level. Advantages of molecular testing for diagnosis over the more commonly used microscopy is that nucleic acid amplification tests (NAATs) have much higher sensitivity and specificity, and they can incorporate detection of specific types of drug-resistance in Mycobacterium tuberculosis strains. Only a small subset of molecular tests is available at the point of care, with more tests available at central testing facilities for which sample transfer can introduce delays in diagnosis. Challenges with NAATs at the point of care, however, include cost, servicing and supplies, and sample processing that itself can require multiple devices. Diagnostic immunoassay tests based on detection of the lipoarabinomannan (LAM) mycobacterial antigen in urine samples have advantages based on sample accessibility, their ease of use, and cost, but these tests are less sensitive than NAATs.
Treatment
Once a patient is diagnosed with TB, treatment typically takes 6 months to complete, or longer if there is drug resistance. Patients need to take multiple antibiotic pills, and PHC facilities are responsible for delivering treatment and supporting patients in adhering to treatment until completion. Cases of drug-resistant TB may require more specialized treatment outside the PHC level.Treatment monitoring to support adherence is done through direct pill counting and directly observed therapy (DOT). A WHO handbook also recommends digital systems to support patients taking medication as prescribed: short message service (SMS), medication event monitoring systems (MEMS), and video-supported treatment (VOT). Post-treatment, the outcome is typically monitored at the community level in follow-up home visits and at PHC-level health facilities. Updated WHO guidelines for treatment include new shorter drug regimens and considerations for special patient populations.
Challenges
Poor medication adherence can lead to treatment failure, disease relapse, and drug resistance. Adherence is influenced by factors including social stigma, lack of social support, lack of nutrition, adverse effects of medications, forgetfulness, and challenges from health care infrastructure, including sufficient access to the drugs.
Missed Diagnosis is the Biggest Gap in TB Care
TB is preventable and treatable. Missed diagnosis is currently the most critical gap to fill to stop the spread of TB and drug resistance. Across 30 countries with a high incidence of TB, the biggest drop-off in the cascade of care is people with presumptive TB not getting diagnosed (Figure 1). Seven critical transitions could close the TB diagnostic gap (Figure 2). From the same perspective, the WHO Standard on universal access to rapid tuberculosis diagnostics delineates a series of benchmarks to be achieved.
The TB Cascade of Care
Closing the TB Diagnostic Gap
Legend: Figure 2. Seven transitions that can transform how TB is diagnosed and close the diagnostic gap (DOI: https://www.nature.com/articles/s41564-023-01365-3)