- Diagnostic Challenge: Overlapping endemic febrile illnesses necessitate comprehensive clinical-epidemiological correlation, as multiple positive serologies alone are insufficient for definitive diagnosis in resource-limited settings.
- Laboratory Interpretation: Multiple positive serological tests for endemic febrile illnesses require cautious interpretation due to potential cross-reactivity or prior exposure, preventing premature diagnostic closure or overtreatment.
- Clinical Strategy: In endemic regions, integrate treatment response as a vital diagnostic tool when initial broad-spectrum therapy fails, guiding pathogen-specific escalation amidst ambiguous serologies.
Introduction
Fever during the post-monsoon season in South Asia can be deceptively complex. In areas where typhoid fever, scrub typhus, brucellosis, dengue, malaria, and other febrile illnesses overlap, a single patient may present with symptoms that fit several conditions at once. This creates a major diagnostic challenge for clinicians, especially when laboratory resources are limited and serological tests may cross-react.
Our latest published case report, “Acute Febrile Illness With Triple Co‐Infection: A Case Report on the Diagnostic Challenges of Overlapping Febrile Illnesses,” describes a 35-year-old female from Jhapa, Nepal, whose illness initially appeared to be a routine acute febrile syndrome but ultimately revealed evidence of multiple overlapping infections.
Why this case matters
Acute febrile illness is one of the most common presentations in emergency and outpatient care across tropical and subtropical regions. The challenge is not just identifying a fever — it is determining which pathogen is responsible, whether multiple pathogens are involved, and whether test results reflect true infection or cross-reactivity.
This case is important because it demonstrates three practical lessons:
- Endemic infections can overlap clinically. Fever, fatigue, myalgia, hepatosplenomegaly, cytopenias, and elevated liver enzymes are shared by many tropical infections.
- Serology must be interpreted cautiously. Positive tests for multiple infections do not always mean each organism is causing active disease, but they cannot be ignored without clinical correlation.
- Treatment response remains a critical clue. The patient did not improve on initial therapy but became afebrile after rifampicin was added for suspected brucellosis.
Case overview
A 35-year-old female presented with five days of fever, fatigue, and myalgia during the post-monsoon season. On examination, she had high-grade fever, tachycardia, and crackles in the right lower lung field.
Laboratory evaluation showed:
- Anemia
- Leukopenia
- Elevated inflammatory markers
- Elevated liver enzymes
- Hepatosplenomegaly on abdominal ultrasound
Serological testing was positive for Salmonella typhi IgG/IgM, scrub typhus IgM, and Brucella abortus antigens. Blood and urine cultures were negative.
The patient was initially treated with ceftriaxone and doxycycline, but there was no clinical improvement. After serological evidence suggested brucellosis, rifampicin was added. She became afebrile within three days and was discharged on doxycycline and rifampicin. At three-month follow-up, she had recovered completely.
The diagnostic dilemma
The central problem in this case was not simply “which infection was present?” but rather:
How should clinicians interpret multiple positive serological tests in a patient from an endemic region?
In resource-limited settings, serology is often used because culture, PCR, and confirmatory testing may not be readily available. However, serological assays may cross-react, remain positive from previous exposure, or produce false positives. This can lead to overtreatment, undertreatment, or delayed treatment.
The case reinforces that diagnosis should not depend on a laboratory result alone. Instead, clinicians must combine:
- Epidemiological context
- Seasonality
- Exposure history
- Clinical findings
- Laboratory patterns
- Imaging
- Treatment response
- Follow-up outcomes
Key clinical takeaways
1. Do not anchor too early
When a patient in an endemic region tests positive for one febrile illness, it can be tempting to stop looking. This case shows why premature diagnostic closure can be risky.
2. Multiple positive serologies need clinical interpretation
A “positive” result should be treated as part of the puzzle, not the final answer. The more overlapping the regional disease burden, the more cautious the interpretation must be.
3. Treatment response can refine the diagnosis
The patient’s improvement after adding rifampicin supported the clinical relevance of brucellosis in this presentation.
4. Follow-up confirms the outcome
Three-month recovery without relapse supported the adequacy of the final treatment approach.
Broader implications
This case has implications beyond a single patient. It highlights the need for better diagnostic algorithms for acute febrile illness in Nepal and similar settings. Clinicians need practical pathways that account for local epidemiology, test limitations, and treatment availability.
It also emphasizes the importance of case reporting. Rare or complex presentations may not change guidelines immediately, but they help clinicians recognize diagnostic patterns, avoid common pitfalls, and improve patient care in real-world settings.
Conclusion
Overlapping febrile illnesses remain a major clinical challenge in endemic regions. This case reminds us that laboratory tests must be interpreted in context, especially when multiple serologies are positive. Careful clinical judgment, awareness of local disease patterns, and close monitoring of treatment response are essential to avoid missed or delayed diagnoses.
References
- Basyal S, Parajuli R, et al. Acute Febrile Illness With Triple Co‐Infection: A Case Report on the Diagnostic Challenges of Overlapping Febrile Illnesses. Clinical Case Reports. DOI: 10.1002/ccr3.73376.
- Basnyat B, et al. Scrub typhus should be considered in the differential diagnosis of acute febrile illness in Nepal and other endemic settings, particularly during the post-monsoon season.
- Devkota S, et al. Seroprevalence and clinical features of scrub typhus among febrile patients attending a referral hospital in Kathmandu, Nepal. This study highlights the diagnostic limitations of serology, including potential cross-reactivity between typhoid, typhus, and leptospirosis tests in endemic regions.
- Centers for Disease Control and Prevention. Clinical Overview of Brucellosis. CDC; 2026. This reference supports the clinical relevance of brucellosis as a prolonged febrile illness and summarizes diagnostic and treatment considerations.
- Johns Hopkins Center for Infectious Diseases in India. Acute Febrile Illness and Sepsis. This overview emphasizes that acute febrile illness has broad, nonspecific presentations and remains difficult to diagnose in low- and middle-income settings because of limited diagnostic capacity.