Typhoid Fever in a Non-Endemic Country: Diagnostic and Therapeutic Challenges in a Returning Traveler

Abstract

Background: Typhoid fever (TF) is a systemic infection caused by Salmonella enterica serovar Typhi, typically associated with regions where sanitation and access to clean water are inadequate. Although rare in non-endemic countries, TF remains a diagnostic consideration in travelers returning from endemic areas with febrile illness. Case report: We present the case of an 18-year-old female who developed TF following recent travel to Nigeria. The initial clinical presentation, including fever, dysuria, and abdominal pain, led to a misdiagnosis of acute pyelonephritis. Malaria, arboviral infections, acute viral hepatitis, and parasitic diseases were systematically ruled out through clinical evaluation, serological testing, and parasitological analysis. The clinical course was marked by fever, abdominal pain, somnolence, and hematological and hepatic abnormalities. Blood cultures confirmed the diagnosis, with the isolate verified and serotyped by the National Center of Infectious and Parasitic Diseases. Targeted antimicrobial treatment with ceftriaxone and levofloxacin resulted in full recovery, with no evidence of relapse or chronic carriage over a three-month follow-up period. Conclusions: This case highlights the critical importance of a structured differential diagnostic approach and microbiological confirmation in febrile patients with relevant travel history. In non-endemic settings, where TF may be underrecognized, early recognition, pathogen identification, and appropriate antimicrobial therapy remain essential to favorable outcomes and public health safety.

1. Background

TF is an acute systemic infection caused by Salmonella enterica serovar Typhi, a Gram-negative, facultative anaerobic bacterium from the family Enterobacteriaceae, with humans as the only reservoir. It remains a significant health concern in regions with limited access to safe drinking water and inadequate sanitation infrastructure, such as South Asia, Sub-Saharan Africa, and parts of South America [1,2]. Despite the availability of preventive and therapeutic measures, TF continues to pose a public health challenge due to the moderate efficacy of existing vaccines (~55%) and the growing prevalence of multidrug-resistant (MDR) strains [3]. In non-endemic regions like Bulgaria, TF is encountered primarily among travelers returning from endemic areas and migrants, which necessitates increased diagnostic vigilance among clinicians [1,2]. Typical symptoms include fever, malaise, abdominal pain, constipation, enlargement of liver and spleen, and a characteristic typhoid state manifested by delirium or obtundation. In some cases, rose-colored spots may appear on the chest and abdomen [4]. Diagnosis can be challenging due to its nonspecific clinical manifestation, often leading to misdiagnosis. This case report outlines the diagnostic course and clinical management of a young female patient whose early presentation mimicked a urinary tract infection, resulting in a delayed diagnosis of typhoid fever following her return from West Africa, where she had visited family. The aim is to emphasize the critical role of epidemiological history, differential diagnosis, and microbiological confirmation when evaluating febrile patients in non-endemic settings.

2. Case Presentation

An 18-year-old female was admitted to the Department of Internal Medicine at University Hospital “St. Marina”–Varna, Bulgaria, with an initial working diagnosis of acute pyelonephritis. One week prior to admission, she had developed a fever of up to 39 °C, diffuse abdominal pain, dysuria, myalgia, arthralgia, and anorexia, with no clinical improvement despite treatment with cefpodoxime.

The patient had returned from Nigeria approximately one month prior, where she had stayed with relatives for four weeks. As a medical student, she traveled during the summer academic break. She had received the yellow fever vaccination, as required for travel to endemic regions, and did not seek additional medical consultation prior to departure.

Upon admission, the patient was in moderately impaired general condition, febrile up to 39 °C, somnolent, but responsive. Physical examination revealed a dry, coated tongue; absence of rash or lymphadenopathy; and soft, non-tender abdomen without hepatosplenomegaly. There were no signs of respiratory or neurological involvement. Laboratory tests indicated anemia, thrombocytopenia, and leukopenia with marked neutrophilia, elevated liver enzymes, hypoalbuminemia, and hypoproteinemia. Inflammatory markers (CRP, ferritin) were significantly elevated. Electrolyte disturbances included hyponatremia and hypokalemia (

Table 1. Laboratory findings during hospitalization (day 1 and day 12).

Test	Day 1 (14.11)	Day 12 (26.11)	Reference Range
Hb (g/L)	100.0	116.0	120–160
RBC (×1012/L)	3.94	4.25	3.8–5.2
WBC (×109/L)	3.68	5.74	4.0–10.0
Neutrophils (%)	70.7	55.7	40–75
Basophils (%)	0.4	0.8	0–1
Monocytes (%)	3.6	4.4	2–8
Eosinophils (%)	0.0	0.1	0–5
Lymphocytes (%)	25.3	35.8	20–45
Plt (×109/L)	58	163	150–400
Urea (mmol/L)	13.3	8.2	2.5–8.3
Creatinine (µmol/L)	99	89	44–97
Total protein (g/L)	51.0	69.5	64–83
Albumin (g/L)	25.0	34.0	35–52
ALT (U/L)	680.0	108.0	<40
AST (U/L)	2586.0	85.0	<40
GGT (U/L)	140.0	41.0	<38
CRP (mg/L)	174.0	16.09	<5
Na (mmol/L)	129.0	135.0	135–145
K (mmol/L)	3.3	3.7	3.5–5.1
Cl (mmol/L)	95.0	101.0	98–107

Abbreviations: Hb, hemoglobin; RBC, red blood cell count; WBC, white blood cell count; Plt, platelets; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyltransferase; CRP, C-reactive protein. Day 1: admission; Day 12: discharge.

). Urinalysis showed proteinuria, leukocyturia, and erythrocyturia, suggesting possible renal involvement. Imaging studies (abdominal ultrasound and chest X-ray) revealed no abnormalities.

During the first three days of hospitalization in the Department of Internal Medicine, the patient remained febrile, with body temperature gradually rising to 39–39.5 °C and persisting at this level in a continuous pattern, consistent with the typical fever curve of typhoid fever [1]. The fever was accompanied by malaise, diffuse abdominal discomfort, and profound weakness.

Comprehensive microbiological and serological investigations were performed. Serological tests for acute viral hepatitis, Epstein–Barr virus (EBV), cytomegalovirus (CMV), influenza virus, and vector-borne diseases were negative. Thick and thin blood smears (three samples) were negative for Plasmodium spp. Urine and stool cultures yielded no pathogenic microorganisms, whereas blood cultures were positive for Salmonella enterica serovar Typhi. Blood cultures were processed using the automated BACTEC 9050 system (BD, Franklin Lakes, NJ, USA), with an incubation period of up to 5 days. Upon indication of microbial growth, the isolate was identified by MALDI-TOF MS (Bruker Daltonics, Bremen, Germany and confirmed by VITEK 2 Compact (bioMérieux, Marcy-l’Étoile, France). Antimicrobial susceptibility testing was performed using the Kirby–Bauer disk diffusion method and interpreted according to EUCAST 2025 criteria. The isolate was confirmed and serotyped by the National Center of Infectious and Parasitic Diseases (NCIPD) and demonstrated susceptibility to amoxicillin/clavulanic acid, ampicillin, aztreonam, cefotaxime, ceftazidime, ceftriaxone, levofloxacin, meropenem, and piperacillin/tazobactam.

Following consultation with an infectious diseases specialist, the patient was transferred to the Infectious Diseases Clinic for further diagnostic evaluation and management. Upon admission, she presented with persistent fever, accompanied by abdominal pain, loss of appetite, pronounced weakness, and a generally reduced level of activity and interaction, consistent with a developing typhoid state. No signs of peritoneal irritation were noted, and surgical pathology was ruled out. Etiological treatment was initiated according to the antibiotic susceptibility profile of the isolated pathogen, consisting of Ceftriaxone (2 × 2.0 g/day IV) and Levofloxacin (1 × 500 mg/day IV) for a total duration of 10 days. Pathogenetic and symptomatic management included glucose-saline infusions, plasma transfusion, dexamethasone, H₂-receptor antagonists for stress ulcer prophylaxis, hepatoprotective agents, antipyretics, and a mild laxative. Within four days of targeted therapy, the patient’s temperature began to decline, and defervescence was achieved by day six of treatment, accompanied by a progressive improvement in overall condition, appetite restoration, and normalization of mental status. Laboratory follow-up demonstrated a steady regression of inflammatory activity and hepatic involvement. By day 12, serum AST levels had decreased from 2586 U/L to 85 U/L, ALT from 680 U/L to 108 U/L, and CRP from 174.0 mg/L to 16.09 mg/L, with normalization of hematologic indices and electrolytes (Table 1).

This comprehensive therapeutic approach led to rapid infection control and complete clinical recovery. The patient was discharged in good condition after obtaining negative blood, urine, and stool cultures. Follow-up stool cultures performed at one and three months after discharge yielded no growth of Salmonella enterica serovar Typhi, consistent with the absence of a chronic carrier state. At both follow-up visits, she remained in good general health, with no clinical or laboratory evidence of relapse.

In compliance with national public health regulations, the case was promptly notified to the Regional Health Inspectorate. An epidemiological investigation was initiated, including tracing and microbiological testing of close contacts. No Salmonella Typhi was isolated among the examined individuals, and no secondary cases were detected. As the patient was a medical student, temporary restriction from clinical training was recommended until negative follow-up cultures confirmed clearance.

Formal ethical approval was not required for this case report, as it describes the clinical management of a single, fully anonymized patient. Generative AI (ChatGPT, OpenAI, GPT-4, 2025) was used exclusively for language editing and formatting support. No scientific content was generated using AI tools. The authors confirm that the final manuscript is original and free of plagiarism, including in figures and text.

3. Discussion

Travel to developing regions is associated with an increased risk of acquiring infectious diseases, with travelers visiting friends and relatives (VFRs) representing a particularly vulnerable subgroup. They often face extended stays, greater exposure to local conditions, and lower rates of pre-travel medical advice, making them more likely to underestimate infectious risks [5,6]. Recent data from the European Centre for Disease Prevention and Control (ECDC) indicate that VFR travelers account for over one-third of imported typhoid cases in Europe, with the majority originating from sub-Saharan Africa and South Asia [7]. This highlights the need for more effective pre-travel screening and risk communication, as most of these infections are preventable through vaccination and adherence to food and water precautions. In this case, the patient, who traveled to Nigeria to visit relatives, had not received typhoid vaccination and did not undergo pre-travel counseling, placing her within the high-risk VFR category typically associated with limited adherence to preventive measures. Although precise details of her movements within Nigeria were unavailable, the epidemiological investigation confirmed that she had stayed with relatives for approximately four weeks. The lack of a detailed travel itinerary represents a minor limitation in reconstructing potential exposure sources.

Typhoid vaccination remains a cornerstone of pre-travel prevention strategies for individuals visiting endemic regions. Current recommendations advise immunization for all travelers aged two years and older to areas with ongoing transmission of Salmonella Typhi. Two vaccines are available: the injectable Vi capsular polysaccharide (ViCPS) vaccine and the live oral Ty21a formulation, both providing moderate protection (50–80%) and requiring periodic boosters. More recently, Vi conjugate vaccines (TCVs) have demonstrated higher efficacy and longer-lasting immunity and have been integrated into national immunization programs in several endemic countries, including Nigeria, although they are not yet available in many non-endemic regions³. The absence of typhoid vaccination in this case illustrates a persisting gap in preventive measures among VFR travelers and underlines the importance of structured pre-travel consultation to mitigate the risk of imported enteric fever.

This case also highlights the importance of pre-travel counseling and education for individuals traveling to endemic regions. Strengthening awareness of region-specific infectious risks, ensuring timely vaccination, and promoting preventive measures such as safe food and water consumption are essential strategies to reduce the incidence of imported infections. Educational initiatives targeting VFR travelers are particularly valuable, as this group often underestimates the risk of acquiring endemic diseases and is less likely to seek pre-travel medical advice.

In returning travelers, fever persisting for more than five days necessitates a systematic diagnostic approach, with epidemiological history serving as a key component. In the present case, the patient—a VFR traveler—was initially misdiagnosed with acute pyelonephritis based on the presence of fever, abdominal pain, and anorexia; however, the absence of supporting features such as lumbar pain or positive urine cultures necessitated diagnostic reconsideration. Although renal involvement in typhoid fever is uncommon, similar cases presenting with clinical manifestations resembling acute pyelonephritis or glomerulonephritis have been described in the literature, underscoring the diagnostic challenges in distinguishing typhoid fever from primary renal diseases. Typhoid-associated renal dysfunction is usually secondary to endotoxemia, hypovolemia, or immune complex deposition rather than direct bacterial invasion, which explains the transient proteinuria and microscopic hematuria sometimes observed during the acute phase [8]. In our patient, the absence of lumbar pain, negative urine cultures, and normal renal imaging effectively excluded primary renal pathology, supporting the interpretation that the urinary findings represented transient inflammatory changes associated with typhoid fever rather than a separate urinary tract infection. This emphasizes the importance of maintaining a broad differential diagnosis and considering enteric fever in febrile patients returning from endemic regions, even when initial findings suggest an alternative focus of infection.

Malaria remains a major concern in travelers returning from endemic regions [9]; however, in the present case, repeated negative blood smears effectively ruled out this diagnosis. According to CDC guidelines, when malaria is excluded in patients returning from sub-Saharan Africa, the differential diagnosis should include arthropod-borne viral infections (e.g., dengue, yellow fever), invasive meningococcal disease, salmonellosis (including typhoid and paratyphoid fever), and parasitic diseases such as schistosomiasis and trypanosomiasis [10]. The stepwise exclusion of these infections through serological and parasitological testing exemplifies a structured diagnostic algorithm that should be standard in the management of febrile travelers. The availability of multiplex molecular assays in reference laboratories could further improve early pathogen identification and optimize therapy. Based on these considerations, the diagnostic work-up was extended to include arboviral and parasitic infections. Dengue, schistosomiasis, and amebiasis, as well as EBV, CMV, and hepatotropic viruses, were all excluded based on clinical presentation and laboratory findings. The patient’s persistent fever, typhoid state with obnubilation, abdominal pain, and abnormal hematological and hepatic profiles, combined with positive blood cultures for Salmonella enterica serovar Typhi, led to the final diagnosis of TF.

In recent years, the diagnostic approach to TF has undergone significant advancements, driven by both the increasing antimicrobial resistance of circulating strains and the need for rapid and accurate pathogen verification. Blood culture remains the gold standard for the diagnosis of TF, with a sensitivity ranging from 40% to 80%, depending on the volume of the sample and any prior antimicrobial therapy. In cases of negative blood cultures, bone marrow cultures may offer significantly higher diagnostic sensitivity. However, due to the invasive nature of the procedure, their routine application is limited. Stool cultures are positive in approximately 30% of patients with TF, and their diagnostic value increases as the disease progresses. This likely explains the negative stool culture result in our patient, in whom microbiological investigations were performed during the early phase of clinical manifestation. Rapid molecular methods, such as RT-PCR, which allow for the detection of S. enterica serovar Typhi-specific genes directly from blood or feces, are gaining prominence. These techniques exhibit high sensitivity and specificity but remain limited in routine clinical practice due to the need for specialized equipment and high costs. Serological tests, such as the classical Widal test, are being used with decreasing frequency because of their low specificity and the risk of false-positive results in cases of previous exposure or vaccination. Confirmation of TF should be achieved through culture-based verification, as serotyping of the isolated strain is important for both accurate clinical management and epidemiological control, including cluster tracking and the identification of potential local outbreaks. In the Bulgarian context, NCIPD plays a key role in the reference verification of invasive salmonellosis, through the implementation of serotyping, molecular analysis, and monitoring of antimicrobial resistance. In the present case, the S. enterica serovar Typhi isolate was confirmed by NCIPD, with an antibiogram issued and susceptibility established to a broad range of antimicrobial agents, which enabled targeted and effective therapy¹.

Antimicrobial therapy should be guided by local patterns of antimicrobial resistance. In this case, the patient was treated with ceftriaxone and levofloxacin, as confirmed by the susceptibility profile of the isolated strain. The increasing prevalence of MDR and extensively drug-resistant (XDR) Salmonella typhi strains represents a significant global health concern, particularly in regions such as South Asia and sub-Saharan Africa. As of 2023, more than 120 cases of XDR Salmonella typhi have been reported in the United States, including cases in patients without recent international travel history, underscoring the need for continued epidemiological vigilance even in non-endemic settings [11]. Initial antimicrobial therapy should be guided by regional resistance patterns, with carbapenems and azithromycin recommended as first-line agents in areas with high prevalence of XDR Salmonella typhi. Early initiation of therapy is critical to prevent complications and reduce mortality [12]. Before hospital admission, the patient had received oral cefpodoxime, a third-generation cephalosporin, without clinical improvement. Although cefpodoxime exhibits in vitro activity against Salmonella enterica serovar Typhi and has been used successfully in uncomplicated pediatric cases in endemic regions, oral third-generation cephalosporins generally provide suboptimal exposure in systemic infections. Their limited bioavailability and poor intracellular penetration render them less effective against intracellular pathogens such as S. typhi. In contrast, parenteral ceftriaxone achieves higher and more sustained serum and tissue concentrations, making it the preferred first-line therapy in typhoid fever. The absence of clinical improvement in our patient following pre-admission oral cefpodoxime therapy was therefore likely due to pharmacokinetic limitations rather than antimicrobial resistance [13]. Empirical dual therapy with ceftriaxone and levofloxacin was initiated in view of the patient’s severe clinical presentation, hepatic involvement, and the need for rapid bactericidal action before antimicrobial susceptibility results were available. Although the isolate was subsequently confirmed as fully susceptible, combination therapy was maintained to ensure early infection control and prevent delayed response. As highlighted by Crump et al. [14] combinations of fluoroquinolones, cephalosporins, and azithromycin are frequently employed in patients who fail to respond promptly to monotherapy. The potential benefits of such combinations include broadening antimicrobial coverage, exploiting possible drug synergy, and reducing the likelihood of resistance emergence during treatment. This therapeutic approach in our patient was therefore clinically justified and consistent with current expert recommendations for severe or complicated typhoid fever [14].

The patient received pathogenetic and supportive therapy including plasma transfusion and a short course of dexamethasone. Plasma administration was indicated due to pronounced hypoproteinemia (total protein 51 g/L) and hypoalbuminemia (25 g/L) observed at admission, consistent with significant protein loss and hepatic dysfunction. The correction of oncotic imbalance in such cases is important to restore plasma volume, improve microcirculatory perfusion, and support hepatic recovery. Adjunctive corticosteroid therapy in typhoid fever remains controversial and is generally reserved for severe forms of the disease. In our patient, the presence of somnolence and features of a developing typhoid state justified a short adjunctive course of dexamethasone to modulate systemic inflammation and prevent further neurological deterioration. According to current evidence, high-dose dexamethasone may be lifesaving in patients presenting with delirium, obtundation, stupor, coma, or shock, particularly in younger adults who tend to manifest greater neuropsychiatric morbidity during typhoid fever. Early initiation of corticosteroids before decompensation is associated with reduced mortality and relapse risk [15].

Despite the absence of complications or relapse during follow-up, the potential for chronic carriage remains an important consideration. Studies suggest that relapse occurs in up to 10% of cases, while 1–4% of patients may develop chronic carrier states. According to the British Infection Association guidelines [16], individuals at high risk of transmission should undergo culture of three stool samples taken 48 h apart, beginning one week after completion of antimicrobial therapy, as intermittent shedding of S. Typhi or S. Paratyphi may occur [16]. In Bulgaria, post-treatment follow-up follows a similar principle: two stool cultures are obtained at one and three months after discharge, each consisting of samples collected 48 h apart. This approach aims to detect possible intermittent excretion of the pathogen and to ensure microbiological clearance. In the present case, both post-treatment stool cultures were negative for Salmonella enterica serovar Typhi, confirming the absence of a carrier state.

This case highlights the importance of a structured diagnostic approach, microbiological confirmation, and tailored therapy in the management of travelers returning with febrile illness. The role of national reference laboratories in serotyping, molecular analysis, and antimicrobial resistance monitoring is indispensable for accurate diagnosis, appropriate treatment, and epidemiological control. Beyond individual case management, imported typhoid fever illustrates the broader challenges of globalization in infectious disease control and the continuing need for cross-border collaboration, data sharing, and preparedness even in non-endemic countries.

4. Conclusions

Our clinical case highlights the diagnostic and therapeutic challenges of managing TF in non-endemic countries. Its clinical significance remains underestimated, often resulting in delayed diagnosis and a higher risk of complications. A thorough epidemiological history, particularly recent travel to endemic regions, is crucial in guiding diagnostic decisions. Travelers to such areas are at higher risk of infectious diseases, necessitating enhanced clinician awareness and familiarity with region-specific pathologies.