Experts have found that more than 80% of people in Asia and Africa who have culture-confirmed pulmonary tuberculosis (TB) don’t have persistent coughs – one of the symptoms most commonly associated with the disease – while more than 60% have no cough at all.
The international study, which aimed to explore the prevalence of subclinical pulmonary TB, also found that not only did most TB patients in 12 high-burden countries did not have a cough, more than a quarter had no other symptoms associated with the disease.
The lack of a persistent cough is significant because it’s one of the primary symptoms that triggers the diagnostic process for TB in HIV-negative patients, reports CIDRAP.
That means patients not reporting a persistent cough could face delays in diagnosis and treatment of a disease that killed 1.3m people in 2022. TB is the second-leading cause of death from a single infectious agent, after Covid-19.
The findings could help explain why there’s such a significant gap each year between the number of new TB cases reported globally (7.5m in 2022) and the estimated number of people who develop the disease (10.6m, also in 2022).
“A persistent cough is often the entry point for a diagnosis, but if 80% of those with TB don’t have one, then it means a diagnosis will happen later, possibly after the infection has already been transmitted to many others, or not at all,” said corresponding study author Frank Cobelens, MD, PhD, a professor of global health at Amsterdam University Medical Centre.
Subclinical TB – major source of transmission?
To estimate the prevalence of subclinical pulmonary TB, a term introduced to capture people with TB pathology who do not report clinically recognisable symptoms, Cobelens and colleagues from the scTB Meta Investigator Group analysed national TB prevalence surveys conducted in 12 countries (eight in Africa and four in Asia) with the WHO between 2007 and 2019.
The prevalence of TB was based on chest X-ray and symptom screening in participants aged 15 and older, and TB was defined by positive Mycobacterium tuberculosis sputum culture.
The researchers used three case definitions for subclinical pulmonary TB: no persistent cough (two weeks or more), no cough at all, and no symptoms (such as cough, chest pain, fever, night sweats and weight loss).
Individual participant data were available for 602 863 participants, of whom 1 944 had culture-confirmed TB. After adjusting for incomplete sensitivity of x-ray screenings and missed or contaminated cultures, the proportions of subclinical TB were 82.8% (95% confidence interval [CI], 78.6% to 86.6%) for no persistent cough and 62.5% (95% CI, 56.6% to 68.7%) for no cough at all.
In a subset of four surveys that contained information on symptoms other than cough, the adjusted proportion of TB patients with no symptoms was 27.7% (95% CI, 21.0% to 36.4%).
Higher average proportions of TB with no persistent cough or no cough at all were found among women, younger participants, and urban residents.
Among smear-positive TB patients, who are more contagious than those with smear-negative results, 29.1% (95% CI, 25.2% to 33.3%) had no persistent cough, and 23.1% (95% CI, 18.8% to 27.4%) had no cough at all.
New approach needed
Cobelens said the findings indicate a need to rethink TB-identification strategies and scale up enhanced case-finding approaches like chest X-ray screening.
“It’s clear that current practice, especially in the most resource-poor settings, will miss large numbers of patients with TB,” he said.
“We should instead focus on X-ray screening and developing inexpensive and easy-to-use tests.”
In a commentary accompanying the study – which was published in The Lancet Infecious Diseases – TB experts Xiaolin Wei of the University of Toronto and Wenhong Zhang of Fudan University in Shanghai said the findings call for revisiting the definition of TB-suggestive symptoms that warrant clinical investigation.
They suggest, for example, that persistent cough could be replaced by any cough, fever, weight loss, night sweats, or chest pain.
Innovative technologies like mobile vans, computer-aided radiology, and rapid molecular tests could also bolster active case-finding initiatives and help identify more subclinical TB patients, they said.
“Subclinical TB hides a higher prevalence … and poses an imminent challenge to WHO’s target of ending tuberculosis by 2035,” they wrote. “Subclinical TB therefore requires further studies in microbiology, public health, and clinical care to optimise policies in its diagnosis, treatment, and management.”
Study details
Prevalence of subclinical pulmonary tuberculosis in adults in community settings: an individual participant data meta-analysis
Logan Stuck, Eveline Klinkenberg, Frank Cobelens et al.
Published in The Lancet Infectious Diseases on 12 March 2024
Summary
Background
Subclinical pulmonary tuberculosis, which presents without recognisable symptoms, is frequently detected in community screening. However, the disease category is poorly clinically defined. We explored the prevalence of subclinical pulmonary tuberculosis according to different case definitions.
Methods
We did a one-stage individual participant data meta-analysis of nationally representative surveys that were conducted in countries with high incidence of tuberculosis between 2007 and 2020, that reported the prevalence of pulmonary tuberculosis based on chest x-ray and symptom screening in participants aged 15 years and older. Screening and diagnostic criteria were standardised across the surveys, and tuberculosis was defined by positive Mycobacterium tuberculosis sputum culture. We estimated proportions of subclinical tuberculosis for three case definitions: no persistent cough (ie, duration ≥2 weeks), no cough at all, and no symptoms (ie, absence of cough, fever, chest pain, night sweats, and weight loss), both unadjusted and adjusted for false-negative chest x-rays and uninterpretable culture results.
Findings
We identified 34 surveys, of which 31 were eligible. Individual participant data were obtained and included for 12 surveys (620 682 participants) across eight countries in Africa and four in Asia. Data on 602 863 participants were analysed, of whom 1944 had tuberculosis. The unadjusted proportion of subclinical tuberculosis was 59·1% (n=1149/1944; 95% CI 55·8–62·3) for no persistent cough and 39·8% (773/1944; 36·6–43·0) for no cough of any duration. The adjusted proportions were 82·8% (95% CI 78·6–86·6) for no persistent cough and 62·5% (56·6–68·7) for no cough at all. In a subset of four surveys, the proportion of participants with tuberculosis but without any symptoms was 20·3% (n=111/547; 95% CI 15·5–25·1) before adjustment and 27·7% (95% CI 21·0–36·4) after adjustment. Tuberculosis without cough, irrespective of its duration, was more frequent among women (no persistent cough: adjusted odds ratio 0·79, 95% CI 0·63–0·97; no cough: adjusted odds ratio 0·76, 95% CI 0·62–0·93). Among participants with tuberculosis, 29·1% (95% CI 25·2–33·3) of those without persistent cough and 23·1% (18·8–27·4) of those without any cough had positive smear examinations.
Interpretation
The majority of people in the community who have pulmonary tuberculosis do not report cough, a quarter report no tuberculosis-suggestive symptoms at all, and a quarter of those not reporting any cough have positive sputum smears, suggesting infectiousness. In high-incidence settings, subclinical tuberculosis could contribute considerably to the tuberculosis burden and to Mycobacterium tuberculosis transmission.
The Lancet editorial – The hidden threat of subclinical tuberculosis (Open access)
CIDRAP article – More than 80% of TB patients lack persistent cough, study finds (Open access)
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