While lungs are the organs primarily affected in TB, accounting for nearly 70% of TB cases, infection can also affect other organs through lymphohematogenous spread.1,2 Typical extrapulmonary disease locations include lymph nodes, pleura, genitourinary tract, bones and joints, meninges, peritoneum and pericardium.2,3 Disseminated TB (dTB) has been increasingly observed in immunocompromised hosts,4,5 especially in developing countries, where dTB is a major cause of morbidity and mortality due to higher rates of TB-human immunodeficiency virus (HIV) co-infection.1 It is often difficult to establish diagnosis, and the clinical presentation of dTB is commonly non-specific, with symptoms varying according to the affected organs.2,4,5 Retinal choroidal tubercles are a pathognomonic finding of dTB, they are identified in only about 5–20% of the cases.6 Similarly, the classic chest X-ray features of miliary TB may help in the diagnosis, although less than a third of dTB patients may present them.7 One study revealed that 33–80% of dTB cases were only diagnosed post-mortem, during autopsies.8 Thus, diagnostic delay is probably one of the main reasons why dTB is associated with higher mortality rates than pulmonary TB (pTB).1,2,4

Therefore, it is essential to recognize the most important risk factors for dTB, because a strong clinical suspicion may be the key towards early diagnosis and consequent beginning of effective treatment. Our research aims to contribute to the study of clinical predictors associated with dTB, which may be helpful for more effective prevention and intervention strategies.

Risk factors for dTB may be empirically known, but have not been systematically modelled in a cohort of patients. In turn, this may contribute to a delay in the diagnosis of dTB, which further aggravates the disease.1 Disseminated TB remains a public health concern in sub-Saharan countries,1 mostly driven by the syndemic of HIV.18 In Portugal, disseminated disease is a rare presentation, accounting for only 1.3% of all TB cases notified in the national report of 2014.9 Contrasting with this figure, we describe a high frequency of dTB (19.5%) in the present cohort, which, to the best of our knowledge, supports the largest analysis of its kind in a European population. Although this represents a much higher proportion compared to the general population, previous studies have also shown higher prevalence of dTB in hospitalized patients.7 This might be explained by the more aggressive diagnostic workup that is usually performed in hospitals,5 thus improving detection rates of disseminated disease. On the other hand, the hospital where the study was based serves a large urban area and is a reference centre for treatment of several comorbid conditions related to/with higher risk for dTB, particularly HIV, increasing the proportion of co-infected patients compared to that reported in the regional monitoring system.19 Nevertheless, 10.2% subjects were not tested for HIV in our sample. Although mandatory after TB diagnosis, we believe that the frequency of non-tested cases was influenced by clinician's personal judgement, comprising essentially older patients without any known risk factors for HIV co-infection.

Both HIV infection and pharmacological immunosuppression, including transplant recipients, were main risk factors for dTB in the present study. The importance of cell-mediated immunity was further illustrated by the inverse correlation found between the CD4+ T cells count in HIV patients and the frequency of cases of dTB. Previous studies have highlighted the prognostic value of T cells count in this context1,20 and have shown that blood culture may be a valuable tool for diagnosing dTB in HIV co-infected patients and that mycobacteremia is often a sign of bad prognosis.1 Thus, early recognition and treatment are likely to be important measures and, given the longer time for culture conversion observed, future randomized controlled trials are needed to determine the optimal duration of treatment in these particular cases. Retrospective reviews have previously shown higher relapse rates in HIV-1 infected patients treated for 6 months compared to those treated for longer21 and that ≥8 months of rifamycin-containing treatment might be required for optimal treatment outcomes.22

Additionally, the existing studies reveal that dTB prevalence is also higher in diabetics, alcohol abusers, patients with chronic liver disease, cases of malnutrition and those undergoing hemodialysis.5,24 Remarkably, in this study patients with diabetes and advanced chronic kidney disease did not show increased risk for dTB. However, we report a significant association with chronic liver failure/cirrhosis, either caused by alcohol abuse or HCV infection. The liver seems to have a central role in the clearance of bacteria from the bloodstream, through the hepatic reticuloendothelial system, mainly by Kupffer cells.25,26 Furthermore, laboratory evidence highlights a reduction of T cell function and chemotaxis in patients with liver cirrhosis.27 These data may thus explain why dTB is a common complication in patients with advanced liver disease.28

The time between the onset of symptoms and the diagnosis was higher in the dTB group, highlighting the problem of diagnostic delay due to unspecific clinical presentation.24 This might have led to more advanced disease, with dTB patients reporting higher rates of constitutional symptoms, namely fever, night sweats and weight loss. Studies that took place in low resource regions and with poor access to healthcare described symptoms lasting for up to 52 weeks.29,30 Like a previous report,31 our data suggest that the delay in TB treatment might also increase the likelihood of M. tuberculosis dissemination, although this hypothesis should be further explored in future controlled studies. In fact, dTB patients had more frequently bilateral lung involvement, which means that local disease progression may precede systemic progression. However, our study did not show that the delay in diagnosis had an impact on mortality. Longer evolution of the disease in the dTB group may be also associated to a decline in haemoglobin level, which is often a marker of iron deficit.32 Iron deficiency itself has been associated with impaired cellular immunity and reduced ability to control infection.32,33

Chronic respiratory disease, which is a known risk factor for pTB,34,35 was less frequent in patients with disseminated disease, as were a few classic features of respiratory involvement (dyspnoea, haemoptysis, presence of cavitation and pleural effusion). However, 40% of dTB in our sample had a miliary lung involvement. A review study revealed that radiographic aspects of miliary TB are present in about 29% of the cases of dTB,7 but frequency may reach 70% with HIV co-infection.4

Due to the retrospective design of the study, the selection and analysis of certain variables were limited by lack of information. Still, our results highlight relevant data. For instance, alcohol intake was sometimes reported in a qualitative manner, as regular consumption, or abuse, which may be affected by the personal perspective of the clinician. But, importantly, this variable allowed us to etiologically classify the chronic liver failure. Another limitation inherent to this study lies in the fact that this was a hospital sample, which might not be representative of the outpatient patients or accurately reflect the TB national panorama. Finally, the inclusion of miliary TB criteria in the definition of dTB may have affected the sampling, due to the low sensitivity and specificity of pulmonary radiological presentation.7,36 This limitation was waived by independent review of chest X-rays by two clinicians.

The non-specificity of the signs and symptoms may limit a timely diagnosis of dTB and contribute to this globally growing problem. The results observed in this study revealed predictors that may aid the diagnosis of disseminated disease, enhancing the early onset of treatment and consequently improving the clinical outcome. Patients who are immunocompromised, have chronic liver failure or cirrhosis, and longer duration of symptoms, specially fever, night sweats and weight loss, are at higher risk of developing dTB. A more systematic approach should be offered to these patients, particularly to HIV patients with under 50 CD4+ cells/mm3, for whom performing blood cultures and bone marrow or liver biopsy sampling may enhance diagnostic yield of disseminated forms of disease. Future studies will be required to determine if these cases would benefit of longer treatment regimens.

The author has no conflicts of interest to declare