Think tuberculosis—but is thinking enough?
Authors: Peter M Keller, Hansjakob Furrer
Journal: The Lancet Infectious Diseases (2020)

In The Lancet Infectious Diseases, David Barr and colleagues1Barr DA Lewis JM Feasey N et al.Mycobacterium tuberculosis bloodstream infection prevalence, diagnosis, and mortality risk in seriously ill adults with HIV: a systematic review and meta-analysis of individual patient data.Lancet Infect Dis. 2020; (published online March 13.)https://doi.org/10.1016/S1473-3099(19)30695-4Summary Full Text Full Text PDF PubMed Scopus (22) Google Scholar report on Mycobacterium tuberculosis bloodstream infection (BSI) in seriously ill HIV-infected adults. In a systematic review and meta-analysis of individual patient data from 20 published and three unpublished studies and datasets, Barr and colleagues found a higher prevalence of M tuberculosis-positive blood cultures in critically ill HIV-infected patients with tuberculosis than previously reported in a review in a less selected population2Pavlinac PB Lokken EM Walson JL Richardson BA Crump JA John-Stewart GC Mycobacterium tuberculosis bacteremia in adults and children: a systematic review and meta-analysis.Int J Tuberc Lung Dis. 2016; 20: 895-902Crossref PubMed Scopus (13) Google Scholar (45% vs 15·5%) and a higher risk of mortality within 30 days in those with M tuberculosis BSI than in those without (adjusted hazard ratio 2·48, 95% CI 2·05–3·08). Furthermore, they found that delaying tuberculosis treatment for more than 4 days in critically ill patients with M tuberculosis BSI was associated with increased early mortality compared with no delay (odds ratio 3·2, 95% CI 1·2–8·8). The conclusions of the study seem straightforward: as with any bacterial BSI we should not delay antimicrobial treatment for HIV-infected patients with M tuberculosis BSI. However, how do we identify these patients? Even in settings where blood cultures for tuberculosis can be done, the results will only be available after more than 10 days, too late to define early treatment strategies based on microbiology results. A tuberculosis-positive blood culture is a marker of disseminated tuberculosis but by no means a perfect one. As with bacterial blood cultures, the likelihood of finding positive results depends on the amount of blood that is cultured, and with one or even two negative cultures we cannot exclude disseminated tuberculosis.3Barr DA Kerkhoff AD Schutz C et al.HIV-associated Mycobacterium tuberculosis bloodstream infection is underdiagnosed by single blood culture.J Clin Microbiol. 2018; 56: e01914-e01917Crossref PubMed Scopus (9) Google Scholar Disseminated tuberculosis is associated with HIV-induced immunosuppression, especially in patients on antiretroviral therapy and with low CD4 cell counts.4Havlir DV Barnes PF Tuberculosis in patients with human immunodeficiency virus infection.N Engl J Med. 1999; 340: 367-373Crossref PubMed Scopus (410) Google Scholar Although tuberculosis usually progresses slowly because of the long generation time of the bacterium, disseminated tuberculosis might also present rapidly, akin to sepsis (so-called Landouzy sepsis, named after the French physician Louis Théophile Josef Landouzy, 1845–1917). This manifestation is more often encountered in regions with high HIV and tuberculosis prevalence. Since HIV-infected patients with disseminated tuberculosis rarely have cavitary lung disease with high mycobacterial load in sputum, rapid sputum-based diagnostic tests, such as microscopy or PCR-based Xpert MTB/RIF, might be negative, as was the case for 28% of the patients with M tuberculosis BSI in the analysis (appendix p 14). By contrast, tests for urinary lipoarabinomannan (LAM) are more likely to be positive in disseminated tuberculosis than in pulmonary tuberculosis, and the diagnostic yield of urine LAM for patients with M tuberculosis BSI in the study was 52% (95% CI 35–69). The authors estimate that the combined diagnostic yield of rapid sputum diagnostics and urinary LAM for prediction of M tuberculosis BSI is 82% (71–90%; appendix p 14). Therefore, in about one in six (100/18) patients with tuberculosis BSI we would have no positive rapid laboratory test pointing towards tuberculosis. Coming back to the clinical situation, we are confronted with a seriously ill HIV-infected patient with danger signs, such as increased respiration rate, high temperature, elevated heart rate, or inability to walk. According to WHO guidance,5WHOImproving the diagnosis and treatment of smear-negative pulmonary and extrapulmonary tuberculosis among adults and adolescents. Recommendations for HIV-prevalent and resource-constrained settings. World Health Organization, Geneva2006Google Scholar we would start with empirical antibacterial therapy and look for tuberculosis by Xpert MTB/RIF. If Xpert is negative and the patient shows no clinical improvement after 3–5 days of parenteral antibiotics, WHO recommends starting tuberculosis therapy. However, taking the data from Barr and colleagues' study1Barr DA Lewis JM Feasey N et al.Mycobacterium tuberculosis bloodstream infection prevalence, diagnosis, and mortality risk in seriously ill adults with HIV: a systematic review and meta-analysis of individual patient data.Lancet Infect Dis. 2020; (published online March 13.)https://doi.org/10.1016/S1473-3099(19)30695-4Summary Full Text Full Text PDF PubMed Scopus (22) Google Scholar into account, is delaying tuberculosis treatment the right thing to do? In patients at risk of disseminated tuberculosis with danger signs, we would, on the basis of Barr and colleagues' findings, add a urinary LAM test to Xpert and start tuberculosis treatment if one of these tests is positive. However, even with these two rapid tests we would probably miss about 18% of patients with disseminated tuberculosis and put them at higher mortality risk if we defer tuberculosis treatment for 4 days or more. Does that mean we should treat every patient with anti-tuberculosis therapy, in addition to empirical antibiotics, irrespective of tuberculosis test results, from the beginning? This decision depends on the prevalence of tuberculosis in the population we care for. If the risk of tuberculosis is near to zero (eg, in regions with low tuberculosis prevalence), the negative aspects of treating all patients for tuberculosis, including costs, side-effects, and drug interactions, outweigh the potential benefits. However, in settings where tuberculosis prevalence is high (eg, in sub-Saharan Africa and south and southeast Asia), not delaying tuberculosis treatment might be recommended even in patients with negative rapid tuberculosis test results. Although such an approach is feasible in regions with low prevalence of multidrug-resistant (MDR) tuberculosis, how would we start tuberculosis treatment in settings where prevalence of MDR tuberculosis is high. In case of a positive Xpert MTB/RIF, we have decision guidelines6WHOWHO consolidated guidelines on drug-resistant tuberculosis treatment. World Health Organization, Geneva2019Google Scholar to start tuberculosis treatment according to the result of the rifampicin test. But what would we do in the case of positive urinary LAM or negative rapid tests but a high pre-test likelihood of tuberculosis? Would we start an MDR tuberculosis treatment regimen with even more side-effects and costs, or would we start conventional tuberculosis treatment? Finally, should we give a full course of tuberculosis treatment to all critically ill patients in settings of high tuberculosis prevalence with negative rapid tuberculosis tests, thus confirming a diagnosis of tuberculosis if the patient's health improves in a few days? These questions must be answered before we can design algorithms for diagnosis and treatment of suspected M tuberculosis BSI for integration into public health strategies. Therefore, let us think, discuss, and design implementation trials for the sake of our patients' survival. HF reports grants to his institution from ViiV, Abbott, Gilead, Pfizer, Merck Sharp & Dohme, and Sandoz, outside the submitted work. PMK declares no competing interests. Mycobacterium tuberculosis bloodstream infection prevalence, diagnosis, and mortality risk in seriously ill adults with HIV: a systematic review and meta-analysis of individual patient dataIn critically ill adults with HIV-tuberculosis, M tuberculosis BSI is a frequent manifestation of tuberculosis and predicts mortality within 30 days. Improved diagnostic yield in patients with M tuberculosis BSI could be achieved through combined use of sputum Xpert and urine LAM. Anti-tuberculosis treatment delay might increase the risk of mortality in these patients. Full-Text PDF Open Access