Introduction and Background of the Project

1. Introduction

The diagnosis of tuberculosis (TB) relies primarily on sputum-based testing, but many people needing diagnostic testing are unable to independently generate a sputum specimen of sufficient quantity or quality for a good result. An inexpensive, point-of-care tool that could be used to assist people to increase sputum volume and bacillary load has the potential to be game-changing to increase the access to and the performance of current and future sensitive TB diagnostics.

Positive expiratory pressure (PEP) devices create sound waves that, when blown, loosen phlegm in the lungs and enable individuals to increase the quantity and quality of sputum they can produce. The Lung Flute (Medical Acoustics, Buffalo, NY, USA) is a PEP device invented in 2002 that consists of a simple plastic flute with a vibrating reed for facilitating sputum expectoration. The Lung Flute has lower risk of adverse events than isotonic saline-based sputum induction devices, does not require an electrical supply, and is simple to use, making it particularly well suited for primary care and community-based screening. The Lung Flute ECO is a more recently developed paper-based version of the Lung Flute that is inexpensive enough to be used as a disposable, point-of-care tool to aid in sputum production in low-resource settings.

In this study, we aim to evaluate the performance of the Lung Flute and Lung Flute ECO to improve sputum-based TB diagnosis, primarily in vulnerable groups, in a TB endemic setting.

2. Project objective

The primary objective is to evaluate the proportion of presumptive TB clients who test positive for TB after using the Lung Flute ECO or the Lung Flute^® HR, as compared to the standard of care with no device to aid in sputum production.

The secondary objectives are:

1. To compare the proportion of presumptive TB clients who are able to submit sputum samples for testing after using Lung Flute ECO prototype, Lung Flute^® HR and the standard of care

2. To compare average quality and quantity of sputum samples submitted using Lung Flute ECO prototype, Lung Flute^®, and the standard of care

3. To assess the feasibility, safety, user satisfaction, and cost effectiveness of the Lung Flute ECO prototype and the Lung Flute^® HR as compared to the standard of care

3. Project design

We will evaluate performance of the Lung Flute ECO and the Lung Flute^® HR across multiple sites in Cameroon. The study focuses on evaluating test access and accuracy in patient groups with documented challenges to produce sputum on demand, including children 6-14 years of age, women, the elderly, people living with HIV, people admitted to hospital, and asymptomatic persons screening positive for TB by digital chest x-ray.

How can your partnership (project) address global health challenges?

The impact of the Lung Flute upon the TB diagnostic yield will be catalytic, meaning that it is expected to increase the access to and the efficiency of both new and established screening and diagnostic tools for TB and MDR-TB. Sputum is a particularly information-rich specimen type, which, in addition to its diagnostic uses for an array of infectious pathogens in addition to TB, also can be used to assess disease susceptibility, severity, progression, and the effectiveness of the immunological response.

What sort of innovation are you bringing in your project?

The Lung Flute and Lung Flute ECO have not previously been evaluated at a large scale in a TB endemic setting, where their impact is expected to be greatest. The ability of the Lung Flute to aid in the production of sputum samples of superior quality and quantity at low-cost and point of care has the potential to improve the usefulness all sputum-based TB diagnostic tests. Determining the feasibility and cost effectiveness are also key to understanding the potential impact of this tool.

Role and Responsibility of Each Partner

Research Institute of Tuberculosis (RIT) will serve as the Designated Development Partner, managing timelines, benchmarks, metrics and methods for evaluation of sputum quality, quantity, and yield according to global laboratory standards. RIT will support laboratory capacity-building and quality assurance.

Institute of Tropical Medicine (ITM)’s role will be to align the trial with global TB strategic needs and best practices, assess equipoise, fidelity, saturation, leading statistical evaluation, and cost-effectiveness analyses.

Center for Health Promotion and Research (CHPR) also known as the TB Reference Laboratory Bamenda (TRLB) in Cameroon is an expertise center for TB diagnostics. CHPR will implement the product evaluation in the field, collecting data using their existing digital laboratory network platform.

Acoustic Innovations (AI) will contribute expertise in sound engineering, product development, acoustic evaluation, design optimization, manufacturing, licensing, marketing, packaging, and shipping.

Others (including references if necessary)

References

1. Doumit M, Jaffé A. Use of the lung flute for sputum induction in children with cystic fibrosis: A pilot study. Pediatr Pulmonol [Internet]. 2015;50(4):340–3.

2. von Braun A, Sekaggya C, Henning L, Nakijoba R, Kambugu A, Fehr J, et al. ‘If at first you don’t succeed, try again’. Looking beyond the initial results of a failed tuberculosis diagnosis. Public Heal Action. 2015;5(3):170–2.

3. Sakashita K, Fujita A, Takamori M, Nagai T, Matsumoto T, Saito T, et al. Efficiency of the Lung Flute for sputum induction in patients with presumed pulmonary tuberculosis. Clin Respir J. 2018;12(4):1503–9.

4. Su J, Anjuman N, Guarnera MA, Zhang H, Stass SA. Analysis of Lung Flute – collected Sputum for Lung Cancer Diagnosis. Biomark Insights. 2015;10:55–61.

Final Report

1. Project objectives

We aim to trial and test a simple and inexpensive paper version of the Lung Flute to enable sputum sample expectoration for tuberculosis (TB) testing. The Lung Flute ECO, which is made from paper, has been re-designed to address WHO concerns. Initial testing showed similar performance with lower cost and environmental impact. We will evaluate Lung Flute ECO performance vs. the spontaneous sputum expectoration with standard of care (SoC) in target groups in Cameroon to determine its potential contribution to volume of molecular testing, diagnostic yield, as well as safety, acceptability, and cost effectiveness.

2. Project design

We conduct acoustic analytical evaluation and operational evaluation with two comparators, standard of care (SoC) and Lung Flute ECO, including cost effectiveness. We include 14 high throughput laboratory testing hubs with molecular test capacity (i.e. GeneXpert Ultra) serving a minimum of 1,000 presumptive TB clients at each site during the study period. To mitigate bias due to clinical and laboratory staff behavioral differences and/or regional differences in expectoration attitudes or behavior, we use a randomized cross-over design.

3. Results, lessons learned

The product development and analytical evaluation of the Lung Flute ECO (LF ECO) (Milestones 1 and 2) were completed as planned. A total of 12,820 LF ECO were shipped by Acoustic Innovations to Cameroon in four batches. 

In Phase 1, participants were enrolled from March to May 2022; 1,271 people were randomly assigned, 1,172 completed both interventions, and 1,097 had data available for inclusion in the primary analysis. A sputum volume of >1mL was obtained from a greater proportion of the participants after use of the Lung Flute ECO versus after video instruction only (117/1,097 (10.7%) vs 46/1,097 (4.2%)); OR 2.6, 95% CI 1.9-3.7, p<0.001)). All adverse events and symptoms aggravation reported after use of the Lung Flute ECO were mild; all new events were grade 1 and all symptom aggravation events were due to an increase from grade 1 to 2. All adverse events resolved on their own within 30 minutes. Participants were generally satisfied with use of the Lung Flute ECO.

Recruitment for Phase 2 of the study was mostly completed in May 2023, with 9,250 participants enrolled; inclusion of people screened for TB using chest X-ray continued until September 15th to enroll more people from this entry point. Overall, 991 people (approximately 10%) were diagnosed with TB. Data collection for the follow-up of participants at two months post-enrollment continued until August 2023. In an interim analysis of 4,670 participants in Feb 2023, 481 (10.3%) had TB detected on the Xpert MTB/RIF Ultra. Among these, TB was detected in a greater proportion of the participants after use of the Lung Flute ECO versus after video instruction only (82/4,670 (1.8%) vs 54/4,670 (1.2%)). Analysis of the complete data set for Phase 2 is ongoing and is planned to be completed in Q4 2023.

Overall, use of the Lung Flute ECO was well tolerated and assisted people to be evaluated for TB to produce an adequate volume of sputum for TB diagnostic testing. These initial results support further investigation of the performance of the Lung Flute ECO to assist in sputum collection and TB detection in different and larger populations.