Does “Latent Tuberculosis Infection (LTBI)” Really Exist? Genealogy of a Medical Nosology ()
1. Introduction
Latent tuberculosis infection (LTBI) was defined in 2015 by the WHO “as a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens without evidence of clinically manifested active TB” [1]. Thus, LTBI diagnosis relies on secular means: normal chest radiography and positive tuberculin skin test (TST). However, the nosology of “LTBI” is recent. In front of that recent enthusiasm, this paper reports a historical perspective of LTBI concept, to study the forces of production and dissemination of that medical nosology.
2. Method
We used a bibliometric analysis and literature review, referenced in the PubMed/MEDLINE and OldMEDLINE databases between 1879 and 2020, using the terms “latent tuberculosis infection (LTBI)”, “primary tuberculosis”, “tuberculin skin test”, “tuberculosis”, and from reference books on tuberculosis and phthysiology. Particular attention was given to the writings of George Canetti (1911- 1971), physician and microbiologist, who was interested in the study of “prehistory of consumption”, and a pioneer in tuberculosis prophylactic treatment [2] [3].
3. Results
If “the prehistory of consumption” [2], a period that separated primary tuberculosis infection from the emergence of the disease in adults, has always interested researchers, the name “latent tuberculosis infection (LTBI)” was promoted recently. The interest for this nosology is shown in a bibliometric analysis based on the term “latent tuberculosis infection” (Graph 1). A total of 7787 publications were found, of which 6389 (95%) in the period 2000-2020. The limited use in the scientific literature of the 20th century of “LTBI” is not due to a lack of interest in this issue, according to the abundance of occurrences for “tuberculin skin
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Graph 1. Bibliometrics for “LTBI”, “primary tuberculosis infection”, and “tuberculin skin test” using the PubMed database, 1901-2020.
test” (TST) or “tuberculosis primary infection” since the 1950s. A historical perspective is required to explain the change in nomenclature (Table 1).
At the beginning of the 20th century, the nosological outlines of TB and tuberculosis latency were imprecise, following the diagnostic progress of chest X- rays (1895, Röntgen) and TST (1906, Von Pirquet). The term LTBI came first to cover the subclinical stages of TB, while the physiological latency was called “abortive tuberculosis infection” [4], “nascent or undeveloped case” [5], “tuberculosis allergy” [3]. Published in 1916, the theory of Ranke, describing the tuberculosis in 3 stages, was a dominant paradigm in phthisiology [2]. Nonetheless, although the term “primary complex” (or Gohn-Ranke complex) and “tuberculosis primary infection” are still used, the classification of Ranke is nowadays no longer taught and its author unknown. In the 1950s, TST standardization [6] brought a huge interest for diagnosis of “tuberculosis primary infection”. Starting in the 1960s, random therapeutic trials examined the benefit of isoniazid in anti-tuberculosis chemoprophylaxis [7] [8] [9] [10]. These original articles are nowadays cited in the current guidelines for the treatment of LTBI; however, they never used the terminology “LTBI treatment”, but “chemoprophylaxis of tuberculosis” [8], or “tuberculosis preventative therapy” [11]. From the 1990s, the terminology of LTBI appears in the scientific recommendations of the American thoracic Society (ATS) [11], to denominate a positive TST, but is not often used in comparison with “primary tuberculosis” or “tuberculin skin test” (Graph 1). In 2000, the American Thoracic Society in association with the Centers for Disease Control and Prevention (CDC) proposed to “change terminology”, and to use “treatment of LTBI”, rather than “preventative treatment” or “chemoprophylaxis” [12]. The author argued that nosological change by promotion of tuberculosis antibiotic prophylaxis. It must be noted that this terminology has resonated strongly in scientific publications and public health policies by being immediately adopted by the WHO and the American, Canadian, British, Australian, and French public health agencies. Between 2005 and 2018, several meta-analyses regarding the treatment of LTBI were published [13]. In 2015, the WHO published “Guidelines for the treatment of LTBI” [1] and gives a consensus definition for LTBI, making of a biological phenomenon (immunodiagnosis positivity) the definition of LTBI. This recommendation also aims to make the treatment of LTBI in certain groups at risk one of the pillars of the new fight against tuberculosis, called the “End TB Strategy” [14].
4. Discussion
The nomenclature change for LTBI in the 21th century is not related to usual diagnostic tools (X-Ray and TST). We hypothesize that the success of that terminology is also determined by epidemiological, social, and economic factors.
1) The prevalence of the disease
In the first half of the 20th century, a positive TST was considered to be the norm, and not a pathological condition. Because the risk to develop a TB with a positive TST is very low [15] [16], and depends on many other factors (date from the infection, immunodepression) [17], it was not relevant to characterize an ordinary event without therapeutic impact. In the second half of the 20th century, the decrease of the incidence of TB, and the prediction of eradication of TB by the end of the 2nd millennium [18] made LTBI meaningless. However, a new world epidemic has provided it with new relevance: the occurrence of Human Immunodeficiency Syndrome (HIV). Coinfection by an old pathogen (Koch’s Bacillus) and a new one (HIV) was responsible for a heightened risk of the disease [19], and an increase in the number of cases and deaths in the world. AIDS elicited a heightened interest regarding immunity in TB, and the search for means of prevention. Identification and preventative treatment for persons living with HIV infected by M. tuberculosis became an issue.
2) A public health choice
It was a major change perspective that has displaced the optimism of the previous decades: as of 1993, the WHO has declared tuberculosis to be a “global emergency” [20] and wished to “revisit the elimination of tuberculosis”. A statistical projection estimated that one third of the world’s population was “infected with M. tuberculosis”, and WHO used this argument to strengthen preventive action against tuberculosis. LTBI treatment became in certain groups at risk one of the pillars of the new fight against tuberculosis, called the “End TB Strategy”. LTBI definition became hegemonic all over the world, even if it is meaningless in high TB prevalence countries: the need of preventive treatment in front of a positive immunodiagnosis varies according the population studied (risk factors, date of infection) [17] [21], and mainly concerns low TB incidence countries for which recommendations have been written [22].
3) The economic need of a new denomination
Another element influencing the terminology of LTBI was economic, with the emergence of diagnostic tests that revealed the synthesis of gamma interferon (IFN-γ) by T lymphocytes specific for tuberculosis antigens (IGRA tests for “Interferon-γ Release Assays”). These tests were developed in veterinary medicine in the 1990s, with the notion of replacing IDR by a fast test for cattle farms in Australia [23]. As of 2001, two tests have been commercialized: QuantiFERON- TB® and T-SPOT.TB®. In 2001, IGRA tests were approved by the Food and Drug Administration for the diagnosis of LTBI [24] and have been commercialized, that occurred at the same time as greater use of the term “LTBI”. Compared to the TST, IGRA tests offer simplicity and better traceability. Nonetheless, IGRA tests, like the TST, do not determinate i) whether the bacillus has been eradicated or whether live bacilli persist, ii) whether the LTBI has progressed toward TB disease and when [25]. The prognosis value of these tests is, therefore, very low [15] [16]. Since then, the commercialisation of IGRA tests influenced nosological evolution, in the sense that it is crucial for the development of a diagnostic test to be able to denominate what relates to its positivity.
5. Conclusion
In the recent years, convergent forces like health public policies, combined with epidemiologic and economic factors, strengthened the use of LTBI terminology as a dominant paradigm. In fact, LTBI nomenclature was driven by the promotion of a new strategy for tuberculosis control. Nevertheless, several acceptances are superimposed under the terminology “LTBI”, depending on the point of view of the pathophysiologist (infra-clinical infectious state), public health (positive immunodiagnosis as a risk factor for TB) or patients. Because of diagnostic difficulties, confusion and paradoxes within the same medical category, criticisms have been formulated. The current pathophysiology of tuberculosis infections recognizes a spectrum of subclinical pathological conditions, putting in question the binary categorization of LTBI/tuberculosis [26] [27] [28]. Lee and Al highlight that LTBI nosology could mask certain realities [29], and even stymie fundamental research [30]. The use of a diagnosis for identifying disease processes is crucial in the field of medicine and for therapeutic issues, but it remains essential that the diagnostic noun represent real processes.