Disease-specific plasma protein profiles in patients with fever after traveling to tropical areas
Authors: Sundling Christopher , Yman Victor , Mousavian Zaynab , Angenendt Sina , Foroogh Fariba , von Horn Ellen , Lautenbach Maximilian Julius , Grunewald Johan , Färnert Anna , Sondén Klara 
Published: March 2023

Objectives

Fever is common among individuals seeking healthcare after traveling to tropical regions. Despite the association with potentially severe disease, the etiology is often not determined. Cytokines are soluble mediators dynamically regulated in the response to infection. Measuring cytokines in the blood can therefore be informative to understanding the host-response to infection and can potentially indicate the type of pathogen that causes the disease.

Method

In this study, we measured 49 host-response proteins in the plasma of 124 patients with fever after travel to tropical or subtropical regions. The patients had confirmed diagnosis of either malaria, dengue fever, influenza, bacterial respiratory tract infection, or bacterial gastroenteritis, representing the most common disease etiologies. We used multivariate and machine learning methods to assess host-response protein profiles between the different disease groups and healthy control subjects with the aim of identifying disease-associated protein signatures.

Results

The host-response varied between disease groups and different combinations of proteins contributed to distinguishing infected patients from healthy controls, and from each other. Malaria displayed the most unique protein signature, indicating a strong immunoregulatory response with high levels of IL10, sTNFRI and II, and sCD25 but low levels of sCD40L. In contrast, bacterial gastroenteritis had high levels of sCD40L, APRIL, and IFN-γ, while dengue was the only infection with elevated IFNα2.

Conclusions

These results suggest that characterization of the inflammatory profile of individuals with fever can help to identify disease-specific host responses, which in turn can be used to guide future research on diagnostic strategies and adjuvant treatment.

Author summary

Upon infection with a pathogen, the host’s immune system will sense the infection and initiate an immune response. Depending on the type of pathogen and the cells that sense it, the resulting immune response will be different. Fever is a common symptom of infection and it is often difficult to identify the specific pathogen responsible for the disease. In this study, we aimed to characterise and compare circulating inflammation-associated proteins elicited in response to the most common pathogens leading to fever after travel to tropical or subtropical areas. The pathogens included viruses, bacteria, and parasites. Based on the protein signatures, we could observe both disease-general patterns (upregulated in all disease groups) and disease-specific patterns (associated with specific diseases). Malaria displayed the most unique signature and was associated with the upregulation of several immunoregulatory proteins. Possibly in response to a pro-inflammatory response. Dengue fever was also associated with a mix of pro- and anti-inflammatory proteins, while bacterial gastroenteritis had a mainly pro-inflammatory profile. Comparing the protein profiles between diseases indicated unique patterns that could potentially be further developed for clinical use.