Diagnosis.

International guidelines and national policies provide little to no guidance on diagnosing PTLD. Spirometry is the most commonly used diagnostic tool for assessing respiratory impairment after treatment of tuberculosis. While spirometry is useful for identifying obstructive and restrictive respiratory disease, it does not capture the full spectrum of PTLD. There are limited data on the use of other diagnostics such as non-spirometric pulmonary function tests (e.g. lung volumes or diffusion capacity), echocardiography, symptom-based scoring (e.g. the modified Medical Research Council scale [17] or the Health-related Quality of Life scale [18]), oxygen saturation, and 6 minute walk tests. These important measures are mostly confined to smaller studies [19–21].

Relying on spirometry to diagnose PTLD also misses other important associated morbidity, such as pulmonary hypertension. Pulmonary hypertension is suspected to be a significant source of post-TB morbidity, such as in the case of Matlosa presented above, but the burden of disease is unknown as it is rarely formally assessed [22]. Pulmonary hypertension from respiratory causes has a high mortality rate with a mean survival of 4.1 years [23]. While the gold standard diagnosis of right-heart catheterization is unlikely to be practical in many settings, diagnosis based on echocardiography provides reasonable test characteristics with a sensitivity and specificity of 83% and 72%, respectively [24].

The role of imaging in the assessment of PTLD is also an important consideration. Chest x-ray (CXR) and computer tomography (CT) of the lungs are the most commonly used imaging modalities in assessing tuberculosis and its sequelae. Abnormal imaging findings on CXR and CT after treatment of tuberculosis include cavitation, bronchiectasis, and fibrosis. The prevalence of these findings in PTLD patients is highly variable, [25] and the relationship between imaging findings and spirometric or functional impairment has not been well studied.

Linkage to care.

Once PTLD is diagnosed, there is no standard guidance on how to link patients to follow-up care within the health system. After a diagnosis of PTLD is established, patients need to be linked to an outpatient system (such as a non-communicable disease [NCD] clinic) that can help them manage their illness and any associated comorbidities.

Treatment.

International guidelines and national policies provide little guidance on treatment of PTLD. Current clinical standards provide recommendations for pulmonary rehabilitation [4] and limited recommendations on pharmacologic therapy [3]. Recommendations on treating chronic hypoxemia and pulmonary hypertension are lacking. Frontline physicians need the assistance of national policies and clinical guidelines to help them create a patient-centered treatment plan for each patient’s unique physiology.

Funding.

Specific funding for the screening, diagnosis, and management of PTLD is limited, as is funding for research on PTLD. An online search of funding databases identified only one PTLD specific grant [26]. Major funders, such as the Global Fund and the United States Government provide support for specific diseases such as TB, HIV, and Malaria as well as non-specific funding for health systems strengthening, but fitting PTLD into those existing funding streams is a challenge.

Guidelines and policies.

Global and national guidelines and strategies, starting with the WHO consolidated guidelines on tuberculosis, should be updated to include PTLD. As a starting point, we propose consideration of the following objectives for incorporation into international guidelines and NSPs:

1) Every patient who completes therapy for TB should be screened for PTLD

Initial screening should take place at the conclusion of TB therapy and should include, at a minimum, spirometry, chest x-ray, clinical history, and a standardized symptomatic tool (e.g. mMRC or HRQOL). Additional diagnostic testing such as echocardiography, 6-minute walk test, and computed tomography can be considered based on individual clinical assessment. Screening for PTLD has the added benefit of improving a health system’s ability to diagnose other chronic respiratory diseases–as has been accomplished with the implementation of silicosis screening in Rwanda [27].

2) Linkage to chronic care should be provided for all patients identified with PTLD

Once patients are diagnosed with PTLD, they need to be linked to an outpatient system that can support the management of their chronic respiratory disease and any other comorbidities. TB treatment is sometimes provided under the auspices of national TB programs that operate specific TB clinics or “corners” within a health center, rather than a general outpatient department. Thus, after treatment for TB, patients need to be connected to another program, such as an NCD clinic that can continue their management. Improving PTLD care within an NCD program is an opportunity to strengthen NCD programs and NCD management more generally.

3) Patients with PTLD should be provided pulmonary rehabilitation if indicated

Pulmonary rehabilitation is an important cornerstone in the treatment of chronic respiratory disease, and thus it should be provided for PTLD patients who are likely to benefit, such as those who can tolerate some degree of exercise but whose health-related quality of life is affected by their respiratory impairment.

4) Patients with PTLD should be considered for pharmacologic therapy tailored to individual clinical phenotypes

The standard of care for PTLD should include an initial assessment of pulmonary function tests upon completion of tuberculosis treatment, followed by individualized therapy based on symptoms and pathophysiology. For example, patients with evidence of COPD would be treated according to standardized COPD guidelines [28], including inhalers such as bronchodilators and corticosteroids. However, the benefit of inhaled corticosteroids should be weighed against concerns about associated increased risk of reactivation of tuberculosis [29]. Inhaled trepostinil, although not currently widely available, has demonstrated improved exercise capacity in patients with pulmonary hypertension due to interstitial lung disease [30] and could be considered in PTLD patients with WHO Group III pulmonary hypertension.

5) All patients with chronic hypoxemia should be provided with home oxygen

In PTLD patients with chronic hypoxemia, treatment with long-term oxygen therapy should be provided. Limited evidence exists for benefit specifically in PTLD patients [31], but oxygen is the mainstay of treatment for hypoxemia and home oxygen has long been known to improve survival in a variety of conditions, including COPD [32].

Patients with PTLD and chronic hypoxemia must have access to home oxygen. The 76th World Health Assembly adopted a resolution calling for increasing access to medical oxygen [33]. However, the resolution focuses primarily on oxygen in health facilities, and it does not address access to home oxygen. Patients like Matlosa who are chronically dependent on oxygen must not be condemned to living in a healthcare facility indefinitely because of chronic hypoxemia. Clinicians must be equipped with the knowledge and resources to send patients home from the hospital with oxygen, if indicated.

National Oxygen Roadmaps supported by influential organizations, including the Global Oxygen Alliance (GO2AL), should include home oxygen for chronic hypoxemia as a key priority and advocate for its availability.

6) PTLD-related outcomes should be included as essential endpoints in TB clinical trials

Traditionally, clinical trials of new TB drug regimens have utilized microbiologic cure as the primary clinical endpoint. However, with the increasing recognition of the prevalence of chronic respiratory impairment after curative TB treatment, there has been a push to include post-TB endpoints in clinical trials [34]. New regimens should be evaluated not only by their success in obtaining microbiologic cure but also by their ability to prevent post-TB complications.

Funder leadership and prioritization.

Major funders, like The Global Fund and the United Sates government, should leverage their considerable influence to establish PTLD as a priority. However, PTLD cannot be completely siloed within tuberculosis programming. As a chronic disease, addressing PTLD requires robust health systems that can provide long-term follow-up, ideally through linkage to established non-communicable disease (NCD) programs. Of course, it has increasingly been recognized that even vertical programs targeting diseases like TB also require strengthening healthcare systems more broadly in more of a “diagonal” approach [35] in order to effectively and sustainably treat the target diseases. In the most recent Global Fund strategy [16], there is an increased emphasis on providing funding for “resilient and sustainable systems for health” (RSSH), and The Global Fund now provides flexibility for countries to revise the funding split between disease programs and programs that provide RSSH. The Global Fund should specifically fund interventions for PTLD screening and treatment. For now, funding for these interventions should be provided under both the TB and RSSH funding streams. However, we need to combine our advocacy for the increasing recognition of the importance of PTLD with an acknowledgement of the shortcomings in international NCD funding and advocacy for improved NCD funding streams.

There will be an argument that the focus of policy dollars should be on the eradication of TB, and that eradication of TB will prevent all future cases of PTLD. Proponents of this view may claim that the research on PTLD is “immature” and highlight uncertainties about the best approaches to screening and treatment. This argument is misguided, and reminiscent of the old arguments that all HIV funding should be on prevention and not treatment. It is possible to tackle both active TB and PTLD at the same time. In fact, the substantial burden of disease posed by PTLD should make it imperative. The evangelists of “cost-effectiveness” would argue that it does not make sense to provide long-term oxygen support to patients like Matlosa. We posit that the patients experiencing these conditions would have opposing value judgements.