Published May 2, 2022 | Version v1
Journal article Open

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

  • 1. Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium
  • 2. Infectious Diseases Operative Unit, Santa Maria delle Croci Hospital, AUSL Romagna, Ravenna, Italy
  • 3. Faculty of Medicine, University of Khartoum, Khartoum, Sudan
  • 4. B. P. Koirala Institute of Health Sciences, Dharan, Nepal
  • 5. Sihanouk Hospital Center of HOPE, Phnom Penh, Cambodia
  • 6. Institut National de Recherche Biomédicale, Kinshasa, Democratic Republic of Congo
  • 7. IHU-Méditerranée Infection & Aix-Marseille University, Marseille, France
  • 8. JD MacLean Centre for Tropical Diseases, McGill University Health Centre, Montreal, Canada
  • 9. Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium
  • 10. Division of Tropical and Humanitarian Medicine, Geneva University Hospitals and University of Geneva, Geneva, Switzerland

Description

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.

Files

12916_2022_Article_2347.pdf

Files (964.9 kB)

Name Size Download all
md5:23d7cc3bfe7ba084d5d46710942fc7fa
47.2 kB Download
md5:1525f2461bf82baa63880cad5fc2215c
896.4 kB Preview Download
md5:c2452589b841923ee4e9f29ba0e7c943
21.2 kB Download

Additional details

Funding

NIDIAG – Syndromic approach to Neglected Infectious Diseases (NID) at primary health care level: an international collaboration on integrated diagnostic-treatment platforms 260260
European Commission