Calling a step by step holistic integrative medical diagnosis roadmap for tuberculosis in China

Dear editor,

Since Mycobacterium tuberculosis was discovered in 1882, tuberculosis (TB) is one of the major respiratory infections diseases worldwide. [1] Great efforts have been made to eliminate the public health hazards caused by TB, but there are still about 25 000 people dying from TB every week, and approximately 40% of those infected patients remain undiagnosed. [2] TB still remains a significant global health problem, especially in low-income and middle-income countries and regions. In 2015, the World Health Organization (WHO) proposed a strategy aiming to reduce deaths due to TB by 95% and cut TB incidence by 90% between 2015 and 2035, while also seeking to have zero TB-affected households experiencing catastrophic financial costs due to the disease by 2035. [3] However, WHO Global Tuberculosis Report of 2022 reports that there were still approximately 10.60 million newly diagnosed TB patients all over the world; the estimated number of new TB cases in China was still about 780,000 in 2021. [1]

TB is a curable disease and many diagnostic methods for TB have been established during past several dozen years, including TB smear, sputum culture, TB immunological technique, chest imaging, and modern molecular biology tests. These diagnostic techniques above have promoted our clinical practice of TB in the era of evidence-based medicine (EBM) in China, because the doctor’s clinical procedures have become more precise. However, these approaches alone are lacking of sufficient sensitivity and specificity for effective diagnosis of active TB cases. Due to the imbalance of medical resources in China, it was necessary to conceive a step by step integrated diagnostic roadmap for TB to improve the logical thinking ability of TB specialists in China.

Holistic integrative medicine (HIM), which has been for the first time proposed by Prof. Daiming Fan, a patient should be considered a holistic system composed of multiple organs that are well integrative and is being greatly affected by the people around him or her and the society where he or she is living. [4] As for TB, understanding and application of HIM concept should be very critical to address such a complex issue. We should use the concept of HIM to integrate existing diagnostic technologies and methods, in order to improve the etiological accuracy of TB patients, so as to achieve the WHO’s goal of ending the TB epidemic by 2035 in China. Specifically, clinically diagnosed TB should consider step by step his or her epidemiological, clinical symptoms, signs, imaging features, and relative specific laboratory tests such as pure protein derivative of tuberculin (PPD) tests, smear test, sputum culture, interferon-gamma release assay (IGRAs), serological markers, and modern molecular biological detection test.

Here, we recommend a step by step HIM diagnosis roadmap of TB to end the epidemic of tuberculosis by 2035 in China, to help to promote the healthy coverage in China.

① The first step, if a person with immunocompetent presents TB related symptoms, signs, or imaging features, further identification of the pathogen is required, and the patient needs to be considered for suspected TB unless a clear pathogen is confirmed (Orange arrow and frame).

② The second step, anti-TB treatment is required if routine etiological testing, including TB sputum smear and culture, is positive, followed by Mycobacterium tuberculosis strain identification and resistance testing (Red arrow and frame).

③ The third step, immunological testing, including but not limited to PPD tests and IGRAs, is required if routine etiological tests are negative. A clinical diagnosed case of TB and diagnostic anti-TB therapy should be considered if typical symptoms, signs, and imaging features of TB are present coupled with positive PPD and IGRAs (Green arrow and frame).

④ The fourth step, some high-level hospitals can also perform modern molecular biological tests, including TB deoxyribonucleic acid (TB-DNA), Gene X-pert^® test (X-Pert), next generation sequencing (NGS) tests, to assist in the etiological diagnosis of confirmed TB (Blue arrow and frame).

⑤ The fifth step, under all the etiological negative cases, some common serological tests, including erythrocyte sedimentation rate (ESR), TB antibody (TB-Ab), interleukin 2 (IL-2), IFN-γ-inducible protein 10 (IP-10), etc., should be further examined in order to assist in the diagnosis of suspected TB. In some patients with pleural effusion, a comprehensive assessment of cancer antigen 125 (Ca-125) and adenosine deaminase (ADA) levels are also required (Purple arrow and frame).

⑥ The sixth step, histopathological examination plays an extremely important role in both confirmed and suspected cases of TB if tissue is available (Black arrow and frame).

TB is an ancient and modern disease. To eliminate TB, we need to integrate the existing resources of the whole society and the wisdom of all mankind to improve the diagnosis rate and the cure rate of TB, so as to achieve the WHO’s proposal to end the TB epidemic by 2030. The specific step by step HIM diagnosis roadmap for TB diagnostic roadmap proposed by us are shown in Fig. 1.

Fig. 1

A step by step holistic integrative medical diagnosis roadmap for TB in China. Ab: antibody; ADA: Adenosine deaminase; Ca-125: cancer antigen 125; DNA: deoxyribonucleic acid; ESR: erythrocyte sedimentation rate; IGRA: interferon gamma release assay; IL-2: interleukin 2; IP-10: IFN-γ-inducible protein 10; NGS: next generation sequencing; PPD: tuberculin test of pure protein derivative; TB: tuberculosis; X-Pert: Gene X-pert® test; +: positive; −: negative