Typhomalaria co-infection: Revisiting two tropical diseases from immunological perspective

 Corresponding author: Felly Moelyadi Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution License 4.0. Typhomalaria co-infection: Revisiting two tropical diseases from immunological perspective Felly Moelyadi 1, *, Ketut Suryana 1, Gde Giri Prathiwindya 1 and Jefferson Caesario 2 1 Department of Internal Medicine, Wangaya Regional General Hospital, Denpasar, Bali, Indonesia, 2 Department of Nanotechnology Engineering, Faculty of Advanced Technology and Multidicipline, Airlangga University, Surabaya, East Java, Indonesia. World Journal of Biology Pharmacy and Health Sciences, 2025, 23(03), 239–246 Publication history: Received on 29 July 2025; revised on 14 September 2025; accepted on 15 September 2025 Article DOI: https://doi.org/10.30574/wjbphs.2025.23.3.0818 Abstract Objective: This review explores the immunological interplay between Plasmodium spp. and Salmonella spp. Material and methods: The review was conducted through searches of PubMed, Scopus, Web of Science, and Google Scholar using keywords related to typhomalaria co-infection. Articles discussing epidemiology, clinical features, immunological mechanisms, and diagnostic approaches were included, with no language restrictions. Relevant findings were synthesized qualitatively due to heterogeneity in study designs and outcomes. Results: Reported co-infection rates vary widely across settings (e.g., 30.3% in Cameroon). This variation was influenced by socioeconomic, demographic, and environmental factors. Immunologically, Plasmodium-induced hemolysis, complement depletion, and impaired macrophage function increase susceptibility to Salmonella infection, while dual infection augments pro-inflammatory cytokine release, Toll-like receptor activation, and oxidative stress. These mechanisms contribute to heightened disease severity, including hepatosplenomegaly, anemia, and septicemia. Conclusion: Typhomalaria co-infection exacerbates clinical outcomes via synergistic immunopathological mechanisms. Clinicians in endemic regions should maintain a high index of suspicion and employ comprehensive diagnostic strategies. Keywords: Malaria; Typhoid Fever; Co-Infection; Salmonella Enterica; Plasmodium; Immunology 1. Introduction The World Malaria Report 2023 revealed that around 249 million malaria cases occurred worldwide with an estimated 608,000 fatalities in 2022 [1]. Meanwhile, the expected number of global typhoid fever cases was 13.5 million in 2010 [2]. The high prevalence of these diseases increases the likelihood of co-infection. Various studies have investigated the incidence of typhomalaria co-infection and found varied results across settings. For example, one study reported a 30.3% co-infection rate in Cameroon [3]. The geographical distribution of Plasmodium spp. (malarial parasites) and typhoidal/non-typhoidal Salmonella (NTS) the pathogens responsible for typhoid fever – facilitates co-infection, particularly in tropical regions where malaria is endemic. Malaria and typhoid often present with overlapping febrile symptoms, which can potentially cause misdiagnosis in endemic regions, such as Indonesia [2]. Moreover, typhomalaria co-infection can lead to serious complications, including maternal and childhood anemia, fever, miscarriage, stillbirth, and mortality [4]. Therefore, World Journal of Biology Pharmacy and Health Sciences, 2025, 23(03), 239–246 240 understanding the immunological interplay between Plasmodium spp. and Salmonella spp. is essential to improving diagnostic accuracy and guiding better intervention. 2. Material and Methods This review was conducted to explore the immunological interactions between Plasmodium spp. and Salmonella spp. Relevant literature was identified through searches of PubMed, Scopus, Web of Science, and Google Scholar. The search combined keywords including “typhomalaria,” “malaria and typhoid co-infection,” “Plasmodium,” “Salmonella enterica,” and “immunology.” No restrictions on language or publication year were applied. Articles were considered eligible if they addressed malaria–typhoid co-infection in humans, with a focus on epidemiology, clinical features, immunological mechanisms, or diagnostic approaches. Animal studies without clear translational relevance, conference abstracts, and reports focusing solely on one disease without co-infection data were excluded. Titles and abstracts were screened for relevance, and potentially eligible articles were reviewed in full text. Additional studies were identified by screening the reference lists of included papers. Findings were synthesized qualitatively, and results were organized thematically into epidemiology, clinical manifestations, and immunological interactions. 3. Result and Discussion 3.1. Typhomalaria Co-infection Articles reviewed in this study showed that typhoid and malaria share social determinants (e.g., poverty, sanitation) and immunological responses that contribute to their propagation [5]. Consequently, individuals living in endemic regions are more susceptible to co-infection, either occurring concurrently or through acute infection exacerbating a chronic condition. Accurate diagnosis requires a high index of suspicion, as clinicians may mistakenly diagnose symptoms as a single illness [6]. The concept of "typhomalaria" was initially documented by Army physician J. J. Woodward in 1862 during the American Civil War, describing febrile illnesses with typhoid-like intestinal lesions and intermittent fever patterns [7]. However, subsequent laboratory advancements in the late 19th century demonstrated that these illnesses were either single infections or, rarely, co-infections with both S. typhi and Plasmodium sp [8]. The shared social factors of the malaria-typhoid co-infection have been evidenced by earlier studies. For example, one study reported a 30.3% co-infection rate in Cameroon, with significant correlations between education level, occupation, and co-infection [3]. This finding suggests a link between socioeconomic factors and disease susceptibility, indicating individuals with low socioeconomic levels are more vulnerable to this co-infection. Other studies have reported different results regarding gender and age prevalence [9], [10]. Studies revealed a significant prevalence of coinfection among males and rural residents. The prevalence might be attributed to their greater exposure to occupational, domestic, and leisure activities compared to female and urban residents [11]. Teenagers and young adults also exhibited a higher rate of co-infection [12]. Reviewed articles also investigated clinical features of this co-infection. They demonstrated that malaria-typhoid coinfections are significantly associated with fever and chills symptoms, which may assist doctors in the differential diagnosis during the physical examination [13], [14]. However, a contrasting result was reported in Northwest Ethiopia, demonstrating no significant associations between clinical, sociodemographic, or behavioral factors and the coinfection [15]. In sub-Saharan Africa, hepatosplenomegaly might result from chronic parasitic infection, including malaria and schistosomiasis, with a strong association with increased levels of pro-inflammatory cytokines and regulatory mediators to induce tissue repair [16]. In addition, more severe complications, such as hepatic failure, have been described, which result from the rupture of schizonts in infected hepatocytes [17], [18]. These findings highlight the limitations of clinical features alone in guiding diagnosis. Although malaria and typhoid fever share sociodemographic domains, evidence suggests that Salmonella infection seems more preventable through better hygiene and sanitation [19], [20]. Thus, the incidence of Salmonella infection is elevated in lowand middle-income countries, exceeding 100 cases per 100,000 individuals annually, while developed nations exhibit a significantly lower incidence [21], [22], [23]. Typhoid fever significantly contributes to global morbidity and mortality, with estimates of 16–33 million cases and 500,000 to 600,000 deaths each year [24]. Increased awareness and adherence to preventative measures, such as hand hygiene and sanitation, may contribute to a lower incidence of these diseases [25], [26]. The immunological interplay between Plasmodium spp. and Salmonella spp. was frequently discussed as a critical factor in disease progression. In this review, a cross-sectional observational study in Cameroon demonstrated a significant World Journal of Biology Pharmacy and Health Sciences, 2025, 23(03), 239–246 241 increase in serum IL-6 and cortisol concentration in patients with typho-malaria compared to controls. Meanwhile, a reduction in serum IL-10 was observed compared to Plasmodium mono-infection. Moreover, patients with typhomalaria also exhibited a positive correlation between IL-2, IFN-γ, and IL-6 and stress scores [27]. The immunological mechanisms underlying these associations remain complex and require further investigation. Specifically, it has been proposed that complement deficits and hemolysis during malaria infection can lead to hepatic iron accumulation, increasing susceptibility to Salmonella sp. Infection [10]. Immunology plays a central role in the pathogenesis of both typhoid infection and malaria. Understanding immune responses separately (typhoid, malaria) is important before examining their interaction. This section reviews key immunological mechanisms implicated in each infection and their co-infection. 3.2. Immunology of Typhoid Infection Relative bradycardia, known as Faget’s sign, is a clinical paradoxical phenomenon in which the heart rate is lower than expected for a given elevation in body temperature, typically applied when the temperature exceeds 38.9°C (102°F) and the pulse fails to rise by 8–10 beats per minute per Celsius degree [28]. This pulse-temperature dissociation has been reported in several infectious diseases, including Salmonella enterica serovar Typhi (typhoid fever), malaria, dengue, Legionnaire’s disease, Q fever, and leptospirosis [29]. In typhoid fever, relative bradycardia is observed in up to 48% of adult patients. Although its exact pathogenesis remains unclear, proposed mechanisms include increased vagal tone, cytokine-mediated cardiac modulation, and direct pathogen effects on the myocardium [30]. Some of these proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6, increase vagal tone, therefore, decreasing heart rate [31]. Furthermore, leukopenia is commonly observed in typhoid infection. Leukopenia is a decrease in the number of white blood cells in peripheral blood, which is generally caused by a decrease in neutrophils (neutropenia) [32]. Lipopolysaccharide endotoxin in S. typhi can cause leukopenia; thus, in laboratory results of patients with typhoid fever, leukopenia and neutropenia may be found in approximately 25% of cases. However, severe leukopenia (less than 2,000 cells per microliter) is rare [33]. In this case, the complete blood count revealed normal hemoglobin and platelet levels, with a relative leukopenia (12.4%) but no absolute leukopenia (WBC 6600/μL). This finding aligns with the typical hematological profile seen in typhoid fever, where leukopenia and neutropenia occur in approximately 25% of cases due to bone marrow suppression by S. typhi lipopolysaccharide endotoxin, although severe leukopenia (<2000/μL) is rare [34]. 3.3. Immunology of Plasmodium infection Table 1 shows the complexity of Plasmodium cycles in host organisms, both cell-mediated and humoral immunity, in defense mechanisms against malaria. These mechanisms primarily depend on early cell-mediated innate responses and the activation of antigen-specific T cells [35]. Table 1 Immune System Classification.[36] Humoral Immunity Cellular Immunity Innate Immunity Complement system Macrophage, Mast cell, dendritic cell, NK cell, granulocytes (basophil, eosinophil, neutrophil) Adaptive Immunity B-Lymphocyte, Plasma cell, Antibodies T-helper lymphocyte (CD4+) and T-cytotoxic lymphocyte (CD8+) Legends: Classification of the immune system showing the main components and their cellular or humoral elements involved in innate and adaptive immunity. Abbreviations and notes: NK = Natural Killer; MHC = Major Histocompatibility Complex; Ig = Immunoglobulin; CD = Cluster of Differentiation. During the pre-hepatic stage, antibodies play important roles by recognizing parasite antigens, including Thrombospondin-related adhesive protein (TRAP), circumsporozoite protein (CSP), and Liver Stage Antigen 1 (LSA1). These antibodies inhibit sporozoite invasion of hepatocytes and reduce the risk of clinical malaria [37]. In the subsequent hepatic stage, cellular immunity, comprising both CD8+ and CD4+ T cells, recognizes parasite-derived peptides on the surface of infected hepatocytes. This liver stage of infection presents an opportunity for adaptive immunity intervention [38]. However, cytotoxic CD8+ T cells provide primary protection by binding to major histocompatibility complex (MHC) class I [39], [40]. Interferon-gamma (IFN-γ) produced by CD8+ T cells exerts a potent inhibitory effect on malaria parasite development during the liver stage [41]. Moreover, NK cells expressing Fas and perforin/granzyme pathways serve an intermediary role in cell-mediated immunity [42]. World Journal of Biology Pharmacy and Health Sciences, 2025, 23(03), 239–246 242 In the erythrocytic stage, immune responses vary according to Plasmodium species and the characteristics of infected cells. P. vivax and P. ovale preferentially infect reticulocytes (young erythrocytes) [43] retaining nuclei and express MHC class I molecules. This activates circulating CD8+ T cells that express granzyme B, perforin, and granulysin [44]. On the other hand, mature erythrocytes infected by P. falciparum lack MHC class I expression, resulting in reduced direct cytotoxicity mediated by CD8+ T cells [45]. The role of CD8+ T cells during the blood stage of P. falciparum infection remains incompletely understood. Still, it is significantly associated with higher febrile responses, anaemia, and complications such as cerebral malaria [46], [47]. Other immune cells, including NK cells and γδ T-cells, trigger cytotoxicity against blood-stage P. falciparum by producing IFN-γ and tumor necrosis factor-alpha (TNF-α) [35], [48], [49]. Finally, the sexual stages of Plasmodium development begin within erythrocytes as the parasites mature and export numerous proteins [50]. Antibodies play crucial roles in neutralizing and opsonizing parasites, as well as activating antibody-dependent cellular inhibition through several isotypes (IgM, IgG, and IgE) [35]. A subset of CD4+ T cells, known as T follicular helper cells, correlates with B cell activation within germinal centers, generating high-affinity antibodies and memory B cell (MBC) responses [51], [52]. These memory B cells constitute the primary source of protection upon reinfection [35]. 3.4. Immunology of Typhomalaria Co-Infection Several studies in this review have reported that malaria-associated bacteraemia constitutes up to one-third of deaths from severe malaria. Non-typhoidal Salmonella (NTS), in particular, has been reported as a major incidence that demonstrates higher mortality rates than malaria alone [53], [54]. The interaction between Plasmodium and Salmonella involves multiple immunological pathways. In severe malaria with massive haemolysis, the released hemeoxygenase-1 enzyme demobilizes granulocytes, impairs leucocytes, and suppresses macrophage function. It causes multiplication of invasive bacteria and, ultimately, septicaemia [55], [56], [57]. Moreover, the sequestration of parasitized red blood cells in the intestine reduce blood flow within the mucosal gut barrier, thereby heightening the intestinal vulnerability to bacterial infection (Figure1) [58]. The alteration of immunological reactivity due to Plasmodium infection may increase the risk of bacterial superinfection [59], [60]. Figure 1 Pathophysiological Interactions Between Typhomalaria Co-infection World Journal of Biology Pharmacy and Health Sciences, 2025, 23(03), 239–246 243 The dual infection induces more expression of TLR-2 and TLR-4 triggering more intensive inflammatory response (NFκB, Th1/Th2 cytokines) and subsequently critical liver damage, oxidative stress, and hemeoxygenase-1 [61]. The complements (C3, C4, and C1q) which are normally central to humoral defence against both Salmonella and Plasmodium, decrease with severe malaria [10]. The significant reduction of C1q and C3 deposition in P. falciparum infection, impairs humoral and cellular immunity to S. Typhimurium in children, explaining the increase of susceptibility to typhoid infection [62]. Moreover, adaptive immune impairment compounds vulnerability. Reduced B and T cell activation were observed in vivo, consequently increased intestinal translocation and dissemination of NTS to the liver [54]. These findings suggest that malaria-related immune changes can increase the risk of invasive Salmonella infection. Although some cited studies were retrospective and potentially subject to recall bias, they contribute crucial insights into the epidemiological trends and immunological mechanisms of typhoidal and malarial co-infections. The inherent variability in study designs and populations across the literature, while posing challenges for direct comparison, underscores the need for continued research in diverse settings. Importantly, this review highlights the importance of maintaining a high index of suspicion for co-infection in endemic areas, particularly in patients presenting with atypical or overlapping clinical features and to guide optimal management strategies. 4. Conclusion This study concludes that typhomalarial co-infection should be considered in patients with overlapping febrile illnesses in endemic areas. Immunological interactions between the two pathogens can exacerbate disease severity. Therefore, clinicians should maintain a high index of suspicion and apply comprehensive diagnostic strategies for timely management. Compliance with ethical standards Disclosure of conflict of interest The authors declare no competing conflicts of interest. References [1] H.-I. 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