Etiological spectrum of persistent fever in the tropics and predictors of ubiquitous infections: a prospective four-country study with pooled analysis

Abstract

Background Persistent fever, defined as fever lasting for 7 days or more at first medical evaluation, has been hardly investigated as a separate clinical entity in the tropics. This study aimed at exploring the frequencies and diagnostic predictors of the ubiquitous priority (i.e., severe and treatable) infections causing persistent fever in the tropics. Methods In six different health settings across four countries in Africa and Asia (Sudan, Democratic Republic of Congo [DRC], Nepal, and Cambodia), consecutive patients aged 5 years or older with persistent fever were prospectively recruited from January 2013 to October 2014. Participants underwent a reference diagnostic workup targeting a pre-established list of 12 epidemiologically relevant priority infections (i.e., malaria, tuberculosis, HIV, enteric fever, leptospirosis, rickettsiosis, brucellosis, melioidosis, relapsing fever, visceral leishmaniasis, human African trypanosomiasis, amebic liver abscess). The likelihood ratios (LRs) of clinical and basic laboratory features were determined by pooling all cases of each identified ubiquitous infection (i.e., found in all countries). In addition, we assessed the diagnostic accuracy of five antibody-based rapid diagnostic tests (RDTs): Typhidot Rapid IgM, Test-itTM Typhoid IgM Lateral Flow Assay, and SD Bioline Salmonella typhi IgG/IgM for Salmonella Typhi infection, and Test-itTM Leptospira IgM Lateral Flow Assay and SD Bioline Leptospira IgG/IgM for leptospirosis. Results A total of 1922 patients (median age: 35 years; female: 51%) were enrolled (Sudan, n = 667; DRC, n = 300; Nepal, n = 577; Cambodia, n = 378). Ubiquitous priority infections were diagnosed in 452 (23.5%) participants and included malaria 8.0% (n = 154), tuberculosis 6.7% (n = 129), leptospirosis 4.0% (n = 77), rickettsiosis 2.3% (n = 44), enteric fever 1.8% (n = 34), and new HIV diagnosis 0.7% (n = 14). The other priority infections were limited to one or two countries. The only features with a positive LR ≥ 3 were diarrhea for enteric fever and elevated alanine aminotransferase level for enteric fever and rickettsiosis. Sensitivities ranged from 29 to 67% for the three RDTs targeting S. Typhi and were 9% and 16% for the two RDTs targeting leptospirosis. Specificities ranged from 86 to 99% for S. Typhi detecting RDTs and were 96% and 97% for leptospirosis RDTs. Conclusions Leptospirosis, rickettsiosis, and enteric fever accounted each for a substantial proportion of the persistent fever caseload across all tropical areas, in addition to malaria, tuberculosis, and HIV. Very few discriminative features were however identified, and RDTs for leptospirosis and Salmonella Typhi infection performed poorly. Improved field diagnostics are urgently needed for these challenging infections. Trial registration NCT01766830 at ClinicalTrials.gov.

Accuracy of C-reactive Protein and Procalcitonin for Diagnosing Bacterial Infections Among Subjects With Persistent Fever in the Tropics

“…Few data inform the approach to persistent fever in tropical settings, and few clinical and basic laboratory features have some discriminative value in this clinical scenario [19]. Diagnostic uncertainty often leads to antibiotic escalation, which was also reflected in this study, as almost 70% of participants were given antibiotics at initial evaluation.…”

“…In this study, we managed to evaluate the diagnostic accuracy of CRP and PCT in large prospective cohorts in different tropical settings, and the extensive workup using disease-specific reference tests allowed us to study their diagnostic performance for identifying the preselected priority conditions. However, there were several methodological limitations, some of which were related to the source NIDIAG study itself; these have been discussed in detail previously [19]. Most importantly, the diagnostic tools focused mainly on the target priority conditions, leaving some diagnostic uncertainty for other diseases, sometimes applying merely clinical criteria.…”

“…Detailed methodology, setting, and main findings of the NIDIAG persistent fever study are described elsewhere [18,19]. Concisely, between January 2013 and October 2014, patients presenting with fever of ≥7 days' duration were enrolled from 6 study sites in 4 countries: Cambodia, the Democratic Republic of Congo (DRC), Nepal, and Sudan.…”

“…Baseline clinical and demographic characteristics have been described in detail previously. Around 20% of subjects were aged <18 years [19]. Serum samples were available for a total of 1919 subjects in the source study.…”

“…nidiag.eu) consortium published the results of a large prospective study aimed at identifying the causes of persistent fever in 4 tropical countries, focusing on a set of priority (ie, severe and treatable) diseases [18]. The study showed that no clinical or basic laboratory features reliably distinguish between specific bacterial diseases [19].…”