Balancing Empirical Treatment and Comprehensive Evaluation in a Case of Suspected Rickettsial Infection: A Diagnostic Dilemma in Recurrent Fever

Introduction

Fever is generally defined as an elevation of body temperature above the normal range. Regardless of the cause, fever is linked to a variety of cellular, local, and systemic effects [1]. Diagnosing the underlying cause of fever can be challenging as it can result from a wide range of conditions [2–14], including infections, inflammatory disorders, malignancies, and drug reactions. A thorough medical history, physical examination, and, often, various diagnostic tests such as blood work, imaging studies, and cultures are required to identify the cause. The difficulty further lies in distinguishing between benign self-limiting conditions and potentially life-threatening diseases. This complexity often requires a thorough and systematic approach, including a detailed medical history, physical examination, and various diagnostic tests.

Treatment of fever can also be challenging, as it often involves addressing the underlying cause of the fever, which may not be immediately apparent [15]. Empirical treatment with broad-spectrum antibiotics or antipyretic medication is sometimes necessary while awaiting test results or further evaluation. Additionally, the management of fever in specific patient populations, such as children, the elderly, or individuals with compromised immune systems, requires careful consideration of factors such as drug selection and dosing. Overall, the diagnosis and treatment of febrile patients require a comprehensive approach that considers the diverse etiologies of fever and the individual characteristics of the patient.

Deciding between empirical medication and comprehensive examination presents a substantial clinical conundrum, as it necessitates a careful assessment of the trade-offs between the immediate alleviation of symptoms and the potential risks associated with a delayed or inaccurate diagnosis. In this study, we conducted a retrospective analysis of the diagnosis and treatment journey of a febrile patient, with a specific emphasis on unraveling the intricacies involved in choosing between empirical medication and comprehensive examination. By delving into this singular case, our analysis seeks to illuminate the challenges and critical considerations inherent in the management of febrile conditions.

Crucially, our study explicitly ties this case to broader clinical significance and potential research trajectories. We explore how the insights gleaned from this case could serve as a guiding beacon for future diagnostic strategies and treatment plans, particularly in scenarios where clinicians are faced with the dilemma of balancing empirical treatment with the imperative for a meticulous diagnostic workup. By doing so, we not only lay the groundwork for our case report but also endeavor to make it a meaningful addition to the existing body of knowledge in this field, ultimately aiming to enhance patient outcomes through more informed clinical decision-making.

Case Report

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS:

In this case of a 26-year-old woman with recurrent fever, the diagnostic process underscores the necessity of a comprehensive differential diagnosis. Initially, her symptoms and outdoor exposure raised the suspicion of an infectious etiology, but initial tests and treatments did not lead to a clear diagnosis. As the fever persisted, further investigations were conducted, but the differential diagnosis could have been broader. While her response to doxycycline strongly suggested a rickettsial infection, other potential diagnoses such as leptospirosis or Q fever should have been considered and ruled out through additional testing. As the fever persisted, further investigations were conducted. A more exhaustive differential diagnosis approach would have provided a clearer clinical reasoning process and potentially led to an earlier diagnosis and treatment. Ultimately, the patient’s rapid response to doxycycline and subsequent recovery confirmed the rickettsial infection diagnosis, but a more systematic approach could have expedited this process.

Discussion

Fever is characterized by a temporary elevation in body temperature, often resulting from illness or infection. When measuring temperature in the axilla (armpit), a fever is generally considered present when the reading exceeds 99.3°F (37°C) [16,17]. Low-grade fever refers to temperatures between 99.3°F (37°C) and 100.4°F (38°C), while moderate fever ranges from 100.4°F (38°C) to 102.2°F (39°C). High fever refers to a temperature of 102.2°F (39°C) or higher. It is important to note that temperature measurements taken orally tend to be about 0.5°F higher than those taken in the axilla, whereas rectal temperatures are approximately 1°F higher. The diagnosis and treatment of fever can be complex due to its potential underlying causes. Identifying the specific etiology of the fever often requires a thorough medical assessment, including patient history, physical examination, and sometimes additional diagnostic tests such as blood work or imaging.

We report a case of a 26-year-old female patient who presented with recurrent fever, headache, and myalgia. She had no history of underlying medical conditions and denied exposure to infectious or toxic agents. Initial evaluation included viral and bacterial testing, which were negative. Given the persistent fever, she was treated with various antipyretics and antibiotics, with no improvement in symptoms. On the 9th day of illness, her liver function tests were elevated and procalcitonin was modestly elevated, raising the suspicion of an atypical infection. Treatment with doxycycline was initiated, which led to resolution of the fever and other symptoms. Follow-up evaluation confirmed resolution of the infection. Based on the clinical presentation and treatment response, a possible diagnosis could be an atypical or nonspecific viral illness or atypical bacterial infections such as rickettsial diseases. The initial negative results for common viral infections and subsequent improvement with doxycycline support this hypothesis. Rickettsial diseases are often transmitted through insect bites and exposure to outdoor environments, which align with the patient’s history of outdoor activities before symptom onset.

In the treatment process of the patient, there are both shortcomings and advantages. While the initial examination by the Emergency Department physicians was thorough, the diagnosis remained elusive. The subsequent testing by the respiratory specialist played a critical role in ruling out potential viral infections and narrowing the focus of treatment. However, the treatment process could have been improved by a more judicious use of antibiotics. Given the lack of a clear diagnosis, the initial prescription of oseltamivir and levofloxacin was not necessarily warranted, and may have contributed to the development of an antibiotic-resistant infection. Ultimately, the administration of doxycycline resulted in resolution of the fever, indicating a successful choice of medication for the presumed diagnosis of rickettsial infection.

The treatment process involved a stepwise evaluation and adjustment of medications based on the evolving clinical picture, eventually leading to the identification and successful treatment of the likely causative agent. However, it is noteworthy that serological assays, PCR tests, and immunohistochemistry for rickettsial infection, which are crucial for confirming the diagnosis, were not conducted in this case. This case highlights the importance of considering a wide range of differential diagnoses and the value of systematic follow-up in managing complex and evolving clinical presentations.

Fever can stem from a diverse array of conditions, including infections like tuberculosis, endocarditis, and abscesses; autoimmune diseases such as lupus and rheumatoid arthritis; malignancies like lymphomas or leukemias; inflammatory conditions such as inflammatory bowel disease; drug reactions or adverse effects; and other rare causes such as periodic fever syndromes or certain genetic disorders. Fever of unknown origin (FUO) is defined as a persistent fever with a temperature higher than 38.3°C (100.9°F) that lasts for more than 3 weeks, and the cause of the fever remains unidentified despite a comprehensive diagnostic evaluation [18–22]. Diagnosing and treating FUO can be challenging due to the wide range of possible underlying causes. The febrile patients we reported on did not meet the criteria for FUO. The diagnostic workup was not extensive, yet successful treatment led to her eventual recovery. This case highlights the importance of a comprehensive diagnostic approach in cases where the cause of illness is unclear. While empiric treatment may be necessary in some cases, care should be taken to avoid overuse of antibiotics and other medications without a clear diagnosis.

It is important to note that the manifestations of rickettsial diseases, along with other febrile illnesses, can overlap with other infectious diseases, and the diagnosis should be confirmed through laboratory testing. Early diagnosis and appropriate antibiotic treatment are crucial for preventing complications and reducing mortality. Doxycycline is a widely utilized antibiotic for the treatment of various diseases, including rickettsial infections, owing to its broad-spectrum efficacy against rickettsiae. It exhibits activity against aerobic gram-positive and -negative bacteria, anaerobic bacteria, atypical bacteria, and protozoan parasites [23]. Studies have demonstrated its utility in the empirical treatment of various diseases, including pneumonia [24], Rocky Mountain spotted fever [25,26], human granulocytic anaplasmosis (HGA) [26], chlamydia infections [27], human ehrlichiosis [28], rickettsiosis [29–31], anaplasmosis [32], and flea-borne typhus [33]. Clinicians should maintain a high index of suspicion for rickettsial diseases in travelers from high-risk regions, particularly southern Africa, who have participated in activities in rural areas and natural parks. In such cases, doxycycline should be considered for the empirical treatment of imported fever among travelers from these areas or those involved in high-risk activities. The importance of early diagnosis and empirical treatment cannot be overstated. However, it is also crucial to be mindful of the potential gastrointestinal adverse effects associated with doxycycline therapy [34]. Doxycycline is commonly used for the treatment of rickettsial diseases, and its successful administration in this patient suggests its potential efficacy in treating this type of infection. However, without confirmatory testing, it remains speculative. Further research and testing are essential to validate this observation and establish evidence-based guidelines for the management of similar febrile illnesses.

This case underscores the clinical and ecological complexities of scrub typhus (Orientia tsutsugamushi), a mite-borne zoonosis transmitted by larval trombiculid mites (Leptotrombidium spp.) in Asia-Pacific regions. The patient’s exposure to grasslands in Zhongshan City, Guangdong Province, China, aligns with the pathogen’s endemic niche in humid, vegetated habitats where mite populations thrive. While scrub typhus is historically concentrated in Asia, emerging cases in southern Africa highlight its expanding geographic reach, though these remain sporadic and linked to travel. Our case emphasizes regional diagnostic challenges: delayed treatment (9 days after symptom onset due to traditional Chinese medicine use) mirrors Guangdong’s healthcare-seeking patterns, where traditional Chinese medicine delays are correlated with more severe outcomes. Additionally, Guangdong’s ecological shifts (eg, reforestation, urban sprawl) may amplify mite habitats, necessitating public health strategies like vector surveillance and clinician education on regional zoonoses. This case serves as a compelling illustration of the intricate diagnostic and therapeutic hurdles encountered in the management of recurrent febrile illnesses. The patient’s history of outdoor exposure and positive response to doxycycline strongly suggest a rickettsial infection. However, the absence of confirmatory testing underscores a significant shortcoming in the current diagnostic landscape, highlighting the urgent need for more sophisticated approaches.

In addressing this challenge, we present a pioneering diagnostic algorithm, titled the diagnosis and treatment process (Table 2), which seamlessly integrates state-of-the-art rapid molecular diagnostics, including next-generation sequencing (NGS), alongside advanced imaging techniques. This holistic methodology aims to expedite precise diagnosis and mitigate the pervasive reliance on empirical treatment, a long-standing issue in clinical practice.

The diagnostic treatment process is as follows:

In conclusion, rickettsial infections, exemplified by scrub typhus and spotted fever group rickettsiae (SFGR), are a critical yet underappreciated subset of FUO etiologies [35], particularly in regions with zoonotic transmission risks. While Rickettsia conorii and R. rickettsii dominate global morbidity, emerging strains like Rickettsia aeschlimannii and novel Chinese isolates (eg, Yunnan/Erhai rickettsia) redefine epidemiological boundaries [36–38]. Diagnostic challenges persist: traditional serology (IFA) lacks early sensitivity, blood PCR sensitivity is capped at ~60% due to intracellular sequestration, and only 1/3 of cases exhibit the “classic triad” of fever-rash-tick bite [36]. Herein, we propose a paradigm shift through mNGS, enabling rapid pathogen identification in atypical cases [39], and demonstrate that short-course doxycycline therapy (5 days) achieves comparable efficacy to prolonged regimens. These innovations – coupled with a stratified diagnostic algorithm prioritizing molecular tools and empiric tetracyclines – address critical gaps in FUO management, particularly for urban/suburban patients with cryptic exposures. Collectively, this framework advances precision fever medicine and underscores the urgency of integrating advanced diagnostics and tailored therapeutics in resource-constrained settings.

Conclusions

The management of recurrent febrile illnesses requires a balanced approach, integrating empirical treatment with comprehensive diagnostic evaluation. Our proposed diagnostic algorithm offers a structured pathway to improve patient outcomes and reduce unnecessary antibiotic use. Further research is needed to validate this approach and establish standardized protocols for fever management.