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

Abstract

Patient: Female, 26-year-old

Final Diagnosis: Rickettsial infection

Symptoms: Recurrent fever

Clinical Procedure: —

Specialty: Infectious Diseases

Objective: Unknown etiology

Background

Fever, defined as an elevation in body temperature beyond the normal range, presents a diagnostic and therapeutic challenge due to its multifactorial etiology. The purpose of publishing this case report is to highlight the diagnostic challenges posed by recurrent fever and emphasize the importance of a systematic and comprehensive approach, while also proposing a novel diagnostic algorithm to improve management and minimize unnecessary antibiotic use.

Case Report

We report a case of a 26-year-old woman with recurrent fever, headache, and myalgia, unresponsive to initial antiviral and antibiotic therapies. Despite negative viral and bacterial tests, various medications failed to produce significant clinical improvement. Elevated liver function tests and procalcitonin levels suggested an atypical infection. Administration of doxycycline led to symptom alleviation; however, the diagnosis remains unconfirmed without definitive testing. This case underscores the importance of adopting a systematic and comprehensive diagnostic approach for unclear illnesses. While empirical treatment may be necessitated, caution is urged to avoid unjustified use of antibiotics and medications without a clear diagnosis. Balancing empirical therapy with thorough evaluation is crucial for effective fever management, minimizing the risks of misdiagnosis or inappropriate treatment. We propose a novel diagnostic algorithm integrating rapid molecular diagnostics and advanced imaging to minimize unnecessary antibiotic use and improve patient outcomes.

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 essential to validate this approach and establish standardized protocols for fever management.

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

A 26-year-old woman presented with recurrent fever for 3 days. She had experienced recurrent fever (axillary temperature ranging from 38.5°C to 39.2°C) without any apparent triggers, accompanied by headache and muscle soreness. There were no associated symptoms of dyspnea or respiratory distress, cough, sputum production, nausea, vomiting, abdominal pain, or diarrhea. Self-administration of ibuprofen resulted in temporary normalization of body temperature, lasting for 6–8 hours before fever recurred. Since the onset of symptoms, she reported poor mental state and decreased appetite, with normal urinary and bowel habits and no significant changes in body weight. Two days prior to the onset of symptoms, she had visited a grassland (Zhongshan City, Guangdong Province, China) and an outdoor hot spring. She had no significant medical history, denied exposure to infested water or endemic areas, denied any specific unhealthy habits, denied family members with history of infectious or genetic diseases, had no food or drug allergies, and had no known genetic disorders.

The initial physical examination at her first visit revealed no cardiovascular, respiratory, or abdominal abnormalities. She had skin intact without abrasions or scabs, and no palpable superficial lymphadenopathy. She had a negative result for COVID-19 nucleic acid (2019-nCoV), routine blood tests showed a low white blood cell count, with normal percentages of neutrophils and lymphocytes but decreased absolute values. The attending emergency physician suspected viral infection and advised her to drink plenty of water, use loxoprofen sodium for fever reduction, and prescribed traditional Chinese medicine for treatment. On the 5^th day of onset, as her fever symptoms did not improve, she sought consultation from the Respiratory Medicine Department. Tests for COVID-19 nucleic acid (2019-nCoV), influenza A virus (FluAV), influenza B virus (FluBV), respiratory syncytial virus (RSV), respiratory adenovirus (Radv), human rhinovirus (HRV), and Mycoplasma pneumoniae (MP) were all negative. A routine blood test showed a return to normal white blood cell count, with normal percentages and absolute values of neutrophils and lymphocytes. Infectious diseases (viral or bacterial) were considered, and she was prescribed oseltamivir (75 mg PO twice daily) and levofloxacin (0.5 PO once daily) in addition to loxoprofen sodium for fever reduction. After taking the medication for 2 days, the fever did not improve. On the 7^th day of onset, she visited the Emergency Department and was treated with azithromycin (0.5 PO once daily) and ibuprofen for fever reduction. On the 9^th day of onset, as the fever symptoms persisted, she returned to the Emergency Department. Despite a detailed physical examination, no abnormalities were found. Liver function tests showed alanine aminotransferase (ALT) at 275 U/L and aspartate aminotransferase (AST) at 98 U/L; blood routine testing indicated normal white blood cell count with a slightly elevated percentage of neutrophils; procalcitonin (PCT) was elevated at 0.29 ng/ml, and a chest X-ray revealed no abnormalities in the heart and lungs. The emergency physician suspected infection with Rickettsia and prescribed doxycycline hydrochloride tablets (0.1 PO every 12 hours) for treatment. After taking doxycycline hydrochloride for 1 day (on the 10^th day of onset), the fever disappeared and she continued the medication for a total of 7 days. After 16 fever-free days, a follow-up liver function test showed no abnormalities, confirming recovery (Table 1).

Table 1.

Detailed process of treatment and abbreviations for tests and examinations.

Onset time (days)	Symptoms	Laboratory tests	Imaging findings	Treatment regimen
Day 3	Recurrent fever (38.5–39.2°C), headache, myalgia	WBC: 2.85×109/L (↓3.69–9.16) NEUT%: 67.0% LYMPH%: 25.3% (↓20.0–40.0) EO%: 0% (↓0.5–5.0)	N/A	Hydration, loxoprofen sodium, traditional Chinese medicine
Day 5	Recurrent fever (38.5–39.0°C), headache, myalgia	Influenza A/B, RSV, HRV, MP: All negative WBC: 4.63×109/L LYMPH%: 26.13% (↓20.0–40.0)	N/A	Oseltamivir (75 mg PO BID) + levofloxacin (0.5 g PO QD) + ibuprofen
Day 7	Recurrent fever (38.3–39.2°C), headache, myalgia	–	N/A	Azithromycin (0.5 g PO QD) + ibuprofen
Day 9	Recurrent fever (38.5–39.2°C), headache, myalgia	ALT: 275 U/L (↑7–40) AST: 98 U/L (↑13–35) PCT: 0.29 ng/mL (↑0.00–0.05) WBC: 5.35×109/L	X-ray: Normal	Doxycycline hyclate (0.1 g PO q12 h)
Day 10	Afebrile, no abnormal physical examination findings	–	N/A	Continued doxycycline hyclate
Post-fever (Day 16)	Resolution of symptoms	ALT: 28 U/L AST: 20 U/L Alb: 43.3 g/L TBIL: 12.6 μmol/L	N/A	Discontinued antibiotics

WBC – white blood cell count; NEUT% – neutrophil percentage; LYMPH – lymphocyte percentage; MONO% – monocyte percentage; EO% – eosinophil percentage; BASO% – basophil percentage; NEUT# – neutrophil absolute value; LYMPH# – lymphocyte absolute value; MONO# – monocyte absolute value; BASO# – eosinophil absolute value, basophil absolute value; 2019-nCoV – COVID-19 nucleic acid; FluAV – influenza A virus; FluBV – influenza B virus; RSV – respiratory syncytial virus; Radv – respiratory adenovirus; HRV – human rhinovirus; MP – Mycoplasma pneumonia; ALT – alanine aminotransferase; AST – aspartate aminotransferasel Alb – albumin Glb – globulin; TBIL – total bilirubin; DBIL – direct bilirubin; IBIL – indirect bilirubin; PCT – procalcitonin

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 9^th 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.

Table 2.

Diagnosis and treatment process of FUO.

Step	Specific actions	Key notes (rickettsial focus)
1. Initial assessment	– Epidemiological history Tick bite exposure Recent travel to grassland/hot springs Contact with pets/rodents – Physical exam Rash morphology (maculopapular/eschar) Lymphadenopathy (axillary/groin) Arthralgia/myalgia	Case relevance: Grassland exposure and fever pattern support rickettsial etiology
2._Laboratory screening	– Rickettsial-specific tests IgM/IgG serology (indirect immunofluorescence) PCR for Rickettsia spp. (ompA/ompB genes) Weil-Felix test (OX19 agglutination) – Differential diagnostics Leptospira (microscopic agglutination) Q fever (complement fixation test)	Limitation: Delayed antibody rise → repeat serology if early negative
3. Imaging	– Targeted imaging Skin ultrasound (eschar localization) Chest CT (if interstitial pneumonia suspected)	Case note: Normal CXR despite systemic inflammation; consider CT if progression
4. Empirical therapy	– First-line treatment Doxycycline 100 mg twice daily orally (loading dose) Avoid fluoroquinolones in children/pregnancy – Adjunctive measures Monitor LFTs (ALT/AST elevation common)	Case outcome: Fever resolved within 72 h of doxycycline, confirming empiric therapy efficacy
5._Confirmatory diagnosis	– Histopathology Skin biopsy with immunohistochemical staining for Rickettsia antigens – Serum paired titers 4-fold rise in IgG titers confirms acute infection	Case gap: Biopsy not performed but clinical response supports diagnosis
6. Follow-up	– Cure criteria Afebrile ≥72h Normalized transaminases (ALT/AST) Negative PCR post-treatment	Long-term monitoring: Screen for chronic complications (e.g., endocarditis) if relapse suspected

The diagnostic treatment process is as follows:

• Initial Assessment: By meticulously gathering a comprehensive medical history, conducting a thorough physical examination, and performing fundamental laboratory tests, we can formulate preliminary hypotheses regarding the potential causes of fever. This step is pivotal in narrowing the differential diagnosis and directing subsequent investigative efforts.

• Infectious Disease Screening: With due consideration of the patient’s epidemiological background, the priority lies in ruling out both common and uncommon infectious agents. This targeted strategy ensures efficient resource allocation and prompt initiation of appropriate therapy if an infectious etiology is suspected.

• Non-Infectious Disease Screening: Once infectious diseases have been reasonably excluded, the focus shifts to screening for autoimmune disorders, neoplasms, and other inflammatory conditions. A meticulous evaluation of these non-infectious factors is indispensable for achieving a definitive diagnosis.

• Further Diagnosis: In instances where the diagnosis remains elusive, we employ advanced molecular diagnostic techniques or tissue biopsy to uncover the underlying cause. These invasive or non-invasive methods can provide crucial insights that may necessitate a change in the treatment trajectory.

• Empirical Treatment: In the absence of a definitive diagnosis, the selection of targeted anti-infective or anti-inflammatory treatment should be approached with caution. Decisions should be grounded in clinical suspicion while avoiding the indiscriminate use of broad-spectrum antibiotics. This approach helps maintain antibiotic efficacy and minimizes the risk of adverse events.

• Follow-Up and Evaluation: Regularly assess the treatment response, make necessary adjustments to the treatment plan, and devise a long-term management strategy. This ongoing monitoring ensures optimal management of the patient’s condition and prompt addressal of any emerging complications.

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.