Unmasking the hidden tuberculosis mortality burden in a large post mortem study in Maputo Central Hospital, Mozambique

Discussion

This study, which is part of one of the largest autopsy studies conducted in sub-Saharan Africa, demonstrates the enormous burden of TB among children and adults, including maternal deaths, dying in a reference hospital in Mozambique. An even higher burden was found among HIV-positive adults and maternal cases, in whom the proportion of TB findings rose up to 51% and 39%, respectively. Importantly, it also shows alarming proportions of TB disease missed by clinicians and highlights the limitations of clinical diagnosis for ascertaining TB in resource-constrained settings. In addition, the use of molecular assays (this is the first time Xpert Ultra has been used in a post mortem study) allowed M. tuberculosis to be detected in 8% (18 out of 223) of patients in whom no histological changes were identified, possibly reflecting early forms of TB. This indicates that the total burden of TB at death might be even higher than what has been reported in clinical and epidemiological and even in many autopsy studies.

A high burden of TB has also been found in some autopsy studies in the countries neighbouring Mozambique, within the context of high HIV and TB burden. In Zambia, 65% of deaths in hospitalised patients aged >16 years (81% HIV-positive) were due to TB, and in Kwazulu Natal, South Africa, 50% of adult inpatient deaths aged 20–45 years had culture-confirmed TB (96% HIV-positive) [10, 26]. A meta-analysis of autopsy studies showed that the prevalence of TB among HIV-positive adult deaths in sub-Saharan Africa was 43.2% (95% CI 38.0–48.3%) [2]. We found a slightly lower percentage of cases in which TB was the CoD, perhaps because of different HIV treatment status, or because in some cases TB findings were not deemed as the most likely CoD. In fact, in their meta-analysis Gupta et al. [2] reported that in 91.4% (95% CI 85.8–97.0%) of cases in which TB was present at death it was also the primary CoD. Interestingly, we found that TB was the CoD in 50% of cases in which TB disease was present at death. This considerable proportion of TB disease not causing death can largely be explained by the additional cases with concomitant TB that were captured by a detailed pathological evaluation and the use of TB-PCR and Xpert Ultra in the diagnostic algorithm, and which might have been missed in other studies using traditional diagnostic tools.

Additionally, in 18 cases with no histological evidence of TB, M. tuberculosis DNA was detected by two different molecular methods. These findings make the classification of this form of TB especially difficult, since the post mortem diagnosis of TB is not based on the diagnostic criteria used in living patients (sputum sample, presence of symptoms or chest radiography). It is unlikely that these findings correspond to contamination in the autopsy room, since disposable materials are used in each autopsy and the time that the tissue samples are exposed to potential airborne contamination is limited. Neither is it likely that these are false-positive cases, since DNA was detected by two different assays with different molecular targets. These findings may represent cases of incipient TB in which small histological lesions might be present but missed, since not all the tissue from all the organs was sampled for histological analysis [27]. However, these M. tuberculosis DNA findings may also represent the increasingly controversial concept of latent TB infection. Although it has been postulated that TB infection cannot be detected through direct diagnostic methods [28], it has been suggested that it might be detected through detailed molecular studies in cases without histological evidence [29]. It has also been suggested that there could be periods in the so-called latency or unstable infection period during which M. tuberculosis replicates at a higher rate, but this replication remains self-controlled [14]. The present study suggests and supports the idea of the existence of a spectrum of TB disease, ranging from early forms of TB in which few bacilli are present (that might not necessarily develop into TB disease) to the traditional patent TB lesions (figure 3).

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FIGURE 3

Natural history of the tuberculosis (TB) model depending on bacillary burden and the likelihood of having immunological, microbiological, histological or radiological evidence at the time of death. Adapted from a model described by Esmail et al. [14].

Clinical misclassification of TB was very frequent. In >80% of TB identified as the CoD in CDA, the clinicians failed to identify TB as the event leading to death, and overall 67% of cases with TB disease at death were missed by the clinicians. Conversely, in 45% of the cases clinicians incorrectly established TB as the main cause of death or the presence of TB disease at death. The clinicopathological discrepancies of TB disease at death have been reported previously and have implications for patient management as well as for estimating TB mortality burden [9, 10]. Clinical diagnosis is not a good proxy of mortality by TB, and contrarily to what it was expected, it was poor in both HIV-positive and HIV-negative cases with TB disease. Thus, it is likely that the results of verbal autopsies are similarly bad or even worse as a tool to quantify TB mortality [12, 13, 30]. Nonetheless, more studies comparing verbal autopsies with CDA are needed in order to demonstrate their usefulness as a tool for assessing TB mortality burden. It was of note that out of the 36 cases with TB findings in whom clinicians specified TB as a clinical diagnosis, only 18 were started on anti-TB treatment (prior to or during admission). Possible reasons for this may be that when the patient died, clinicians might have reconsidered the potential diagnoses of the patient and then added TB, or that patients might have been too ill or died very early during admission, thus anti-TB treatment was not initiated. Poor reporting of anti-TB treatment initiation cannot be discarded.

Our study has several limitations. First, our conclusions can only be generalised to hospitalised patients of settings with similar epidemiological characteristics and do not necessarily represent the contribution of TB to all population-based mortality in Maputo or Mozambique. The likelihood of being hospitalised depends on access to healthcare, health infrastructure, severity of disease determined by healthcare workers and severity perceived by patients and relatives, among other sociological and behavioural factors. Likewise, diagnostic discrepancies might occur less frequently in larger hospitals, thus, those found in this study (carried out at the main reference hospital of the country) might underestimate the number of clinicopathological discrepancies in general Mozambican health facilities. Second, as mentioned previously, all the organ samples were analysed histologically, but not all in their entirety, thus some cases of concomitant TB might have been missed. Third, TB culture was not contemplated in the study design, and this method could have helped to better characterise the microbiological findings. Likewise, the use of Xpert Ultra as a screening tool in all cases could have determined a higher number of confirmed cases and allowed estimation of the added yield of the use of this highly sensitive technology. Last, the quality of the clinical information may have been suboptimal in some cases of hospitalised patients with severe disease status, and their degree of consciousness might have caused information bias in some of the results. Thus, despite comprehensive evaluation of all the clinical records available, some relevant information about the medical history might have been missed by patients or relatives.

In conclusion, we found a high burden of TB disease at death (as CoD and as concomitant disease) in all groups studied. The use of highly sensitive molecular tests in CDA helped to identify cases of TB disease at death that would have otherwise been missed. Indeed, the results demonstrate that in our setting, clinical diagnoses miss most of the TB disease which is detected in CDA. In addition, Xpert Ultra may have the potential to identify earlier forms of TB, before histological lesions are evident, or potentially, unstable latent TB infection.