CASE STUDY
Pandemic Preparedness & Fever in a Returning Traveler
A 44-year-old woman presents to your primary care clinic with severe headache, fever, chills, nausea, vomiting, diarrhea, and a diffuse rash. She just traveled back from Uganda, where she went on a safari.
This case will guide you through a clinical encounter to understand the patient's health challenges – and how to respond.
LEARNING OBJECTIVES
Understand how globalization, travel, and changes to human-animal interface create opportunities for pandemics
Identify sentinel cases of diseases with pandemic potential to safeguard human, animal, and planetary health
CLINICAL COMPETENCIES
Know how to perform a comprehensive history, exam, and diagnostic testing for fever in a returning traveler
Understand how to diagnose emerging zoonoses and high-consequence pathogens
Apply measures to ensure healthcare and laboratory worker safety
Communicate and coordinate with public health outbreak response
A Continuing Medical Education activity presented by the Stanford Center for Innovation in Global Health and the University of Washington. View CE information and claim credit HERE.
Clinical Approach
Consider the following questions as you work through this case:
Understand how geography, activities, and host risk factors contribute to infection.
Build a differential diagnosis based on geographic exposures as well as activities.
Expand your differential diagnosis based on immune status.
Learn to recognize important symptoms.
Fever and altered mental status in a returning traveler signals an emergency.
A complete physical exam and laboratory diagnostics can help narrow your differential diagnosis.
Be prepared to coordinate with public health officials.
If the suspected pathogen has outbreak or pandemic potential, notify and coordinate with local-, state-, and national-level public health officials immediately.
History
Taking a clinical history of your patient yields the following information:
Chief complaint
- Severe headache, fever, chills, nausea, vomiting, and diarrhea
History of present illness
- Patient went on a safari to Uganda for two weeks, where her activities were camping, white water rafting, and viewing wildlife.
- She viewed wildlife from a four-wheel drive vehicle. She entered a cave to see pythons and bats. She did not consume unpasteurized cheese or milk.
- She fell out of the raft while whitewater rafting.
- When she did develop diarrhea and fever, she took two doses of ciprofloxacin but came to the emergency room when symptoms did not abate.
- No reported mosquito or tick bites.
Past medical history
- No significant existing medical issues
Medications
- Faithfully took atovaquone-proguanil as malaria prophylaxis, had typhoid and yellow fever vaccines, as well as age-appropriate vaccinations
- Took 2 doses of ciprofloxacin for “travelers’ diarrhea”
Allergies
- No known allergies
Family history
- N/A
Social & enviromental history ("Social-E")
- States that five days ago she returned from a two-week safari in Uganda
- Went camping and white-water rafting, visited villages, and viewed wildlife on the savannah and in a cave
- She is a business executive and is married; she travelled with her husband who is not having symptoms
- Occasional wine: 3-4 glasses/week
Review of systems
- Denies headache, joint pain, cough, bloody emesis, or bloody diarrhea
Discussion
What would you ask next?
What would you examine, and which lab tests would you order?
Key History Follow-Up Questions
Asking your patient the following questions gives you more information:
How many days has it been since your trip?
- A cut-off of 21 days can help distinguish the incubation periods for pathogens.
- Less than 21 days for most pathogens (e.g., arboviruses, hemorrhagic fever viruses, respiratory viruses, Rickettsiae). Greater than 21 days for other infections (TB, malaria, protozoal).
- It has been five days since the patient returned from the trip.
Where did you travel?
- Depending on the answer to this question, you may consider different pathogens or diseases/conditions, such as (but not limited to):
- Sub-Saharan Africa: malaria, arboviral diseases, acute HIV, Rickettsiae, hemorrhagic viruses
- North Africa/Middle East/Mediterranean: Brucellosis, Q fever, Middle East Respiratory Syndrome (MERS)
- Southeast Asia: Typhoid fever, scrub-typhus, arboviral diseases (including dengue and Chikungunya), melioidosis, malaria, Nipah virus
- Latin America: malaria, arboviral diseases (including Zika, dengue, and Chikungunya), leishmaniasis
- Everywhere: HIV, tuberculosis (TB), leptospirosis (if rodent or freshwater exposure)
- The patient went to Uganda.
Are you immunocompromised in any way?
- Immunocompromised individuals are more susceptible to TB and opportunistic infections. Asplenic patients are more susceptible to encapsulated bacterial organisms (such as infection from Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae), Capnocytophaga after a dog bite, and babesiosis. Infants, elderly, pregnant, and immunocompromised persons at increased risk for zoonotic disease.
- The patient does not believe she is immunocompromised. Her spleen is intact.
- You can also ask the patient if they have any history of recurrent infections in childhood or thereafter to futher assess if she is immunocompromised.
Did you come into contact with anyone with TB or other respiratory diseases? Did you have sex while you were abroad?
- If yes to sexual activity, think about HIV and sexually transmitted infections.
- The patient did not come into contact with anyone sick.
Did you come into contact with untreated freshwater? Unpasteurized dairy or raw food? Soil?
- Exposure to freshwater may lead to leptospirosis or schistosomiasis.
- Eating unpasteurized dairy may result in Brucellosis or Q fever.
- Contaminated foods may lead to enteric fever (typhoid).
- Skin contact with soil may indicate helminths.
- The patient went whitewater rafting and fell into the water.
Were you directly involved in animal birthing or butchering?
- If so, think about brucellosis, Q fever, and Rift Valley fever.
- The patient was not directly involved in animal birthing or butchering but did view wildlife in caves.
Were you bitten by an insect or other animal while abroad?
- Animal bites may lead to bartonellosis, rabies, or rat bite fever.
- For arthropods... Mosquitoes: West Nile fever, Zika, chikungunya, dengue, filariasis
- Ticks: Lyme disease, anaplasmosis, babesiosis, tick-borne relapsing fever, many Rickettsia
- Fleas: plague, endemic/murine typhus (R. typhi)
- Lice: bartonellosis, epidemic typhus (R. prowazekii)
- Sandflies: leishmaniasis
- Flies: onchocerciasis (black fly), trypanosomiasis (tsetse fly)
- Triatoma bugs: Chagas disease
- The patient was not bitten.
Were you in a healthcare setting, such as a hospital or local clinic, on your trip?
- If the patient answers yes, then start to think about COVID-19, MERS, SARS, influenza, and TB.
- The patient was not in a healthcare setting while abroad.
Was there any flooding or extreme weather events?
- If yes, you could more closely consider cholera, typhoid, schistosomiasis, and leptospirosis.
- There were no extreme weather events while the patient was on her trip.
Were you, or anyone who you were traveling with, sick on the trip back home? And since coming home, have you had any exposure to sick people or animals or ticks and mosquitoes?
- No recent exposure
Physical Exam
When you examine your patient, you learn the following:
General
- Drowsy, appears ill
- Temperature 37°C, pulse 100, BP 110/70
HEENT
- Pupils equal and reactive
- Clear sclerae and conjunctivae
- Throat benign
Neck
- Supple. No masses.
Chest & lungs
- Clear chest
Heart & cardiovascular
- Regular rate and rhythm. No murmur.
Abdomen
- Decreased bowel sounds. Some diffuse tenderness but no rebound.
Genitourinary
- No costovertebral angle tenderness
Skin
- Diffuse maculopapular rash on trunk – not on face or extremities. * No petechiae or purpura
Musculoskeletal
- Unremarkable
Neurological
- Seems confused as to where she is. Difficulty following commands
- Negative Kernig’s, Brudzinski signs
- Movements symmetric
- Deep tendon reflexes 2+ symmetric
Key Points for Physical Exam
CONsider the following as you conduct a physical exam:
Current or recent fever combined with altered mental status indicate an emergency.
For vitals, a pulse rate slow for the degree of fever may suggest typhoid fever or rickettsial disease.
On the skin, maculopapular rashes are very common in many types of infections.
Petechiae or hemorrhagic lesions suggest dengue fever, meningococcemia, or viral hemorrhagic fevers. Rose spots, small red spots on abdomen and chest may suggest typhoid fever.
Localized lymphadenopathy may indicate certain bacterial and parasitic infections; generalized may suggest viral and fungal infections or noninfectious causes.
Hepatosplenomegaly is associated with malaria, visceral leishmaniasis, typhoid, brucellosis, Q fever, and malignancy.
Red sclerae/conjunctivae suggests leptospirosis.
Diagnostics
YOU OBTAIN THE FOLLOWING INFORMATION:
Bloodwork: WBC 900/uL (ref. range: 4,500-10,500 uL), AST 9,660 U/dL (ref. 15-41) and ALT 4,823 U/dL (ref 14-54), Cr 2.3 mg/dL
Key Points in Lab Diagnostics
CONsider the following as you evaluate your patient’s results:
CBC w/ diff: looking for eosinophilia, lymphocytopenia, and thrombocytopenia.
Eosinophilia: parasitic infection, fungal infection, tuberculosis, drug reaction
Lymphocytopenia: viral infection (e.g., HIV, dengue), typhoid, COVID-19
Thrombocytopenia: malaria, dengue, HIV, typhoid, Rickettsia spp., sepsis/disseminated intravascular coagulation (DIC)
CMP: pay attention to elevated LFTs, which may signal hepatitis.
If you suspect brucellosis: take two sets of blood cultures before starting antibiotics; alert the lab.
If you suspect malaria: thick and thin blood smear every 12-24 hours for a total of three sets AND rapid diagnostic tests (RDTs).
If you suspect leptospirosis: look for proteinuria and hematuria using a urine analysis (UA) with urine culture and send leptospirosis serology and PCR (urine and serum).
Consider offering HIV testing to patients.
In a case of severe unexplained infection you should also consider performing PCR, multiplex PCR, or next generation sequencing (NGS).
Nested RT-PCR has been developed to improve sensitivity but can be subject to contamination.
Next generation sequencing is becoming more available for molecular epidemiology.
Serological tests such as ELISA antibody testing can be considered but often lack specificity due to cross-reactivity and there can be a lag before antibodies are detectable. Therefore serology may not be as useful during the acute phase.
Saving both early and convalescent phase samples can be helpful for future testing.
Virus isolation may only be available in certain reference labs (ie CDC). It is considered the gold standard but is quickly giving way to PCR.
If hemorrhagic virus is suspected isolate patient in negative pressure room with personal protection use and ante-room (see CDC guidelines).
If patient presents with an unknown pneumonia-syndrome, they should be placed in airborne isolation until a diagnosis is clear.
Relocate the patient to a bio-containment facility if your hospital cannot provide isolation at this level.
Alert the laboratory if suspected case of viral hemorrhagic fevers (VHFs).
If ANY Biosafety (BSL) level 3 agents are suspected, follow infection control guidelines and alert the lab immediately (examples: hemorrhagic fever viruses, brucella.
Our patient is admitted to a local hospital for acute hepatitis, confusion, nausea, and vomiting. At the hospital, she is given IV fluids and started on doxycycline for possible leptospirosis. While diagnostics are pending, she is noted to have pancytopenia, coagulopathy, myositis, pancreatitis, and encephalopathy.
Testing was negative for leptospirosis, HIV, viral hepatitis, malaria, arboviral infection, acute schistosomiasis, and rickettsial infection. Early convalescent serum (10 days after illness onset) was submitted to CDC for testing and demonstrated no evidence of VHFs via serology or virus isolation.
Differential diagnoses for fever and altered mental status:
Bacterial infection: Meningitis, typhoid fever, meningococcemia
Viral infection: Yellow fever, rabies, viral hemorrhagic fevers (VHFs) – Ebola, Marburg, Lassa, Rift Valley fever, arboviruses, Nipah virus
Parasitic infection: African trypanosomiasis, Plasmodium falciparum (malaria)
Differential diagnoses for our patient’s exposure history in Uganda:
White-water rafting: Leptospirosis, acute schistosomiasis
Visiting rural villages: Malaria, Lassa fever, hepatitis viruses, arboviruses (dengue, Chikungunya, Rift Valley fever, Crimean-Congo hemorrhagic fever), HIV, viral hepatitis
Wildlife viewing in caves: Rabies, Marburg virus, Ebola virus
Other things to consider in differential diagnosis:
Toxic exposure: Pesticide poisoning, heavy metals
Drugs: Cocaine, etc.
Metabolic: Hyperglycemia, hyper or hypernatremia, etc.
Differential Diagnosis
working towards a conclusion:
Ultimately, the patient was discharged with unknown diagnosis and had a prolonged recovery with persistent abdominal pain, fatigue, and "mental fog.”
However, 6 months later, another tourist from the Netherlands visited the same cave as the previous patient in Uganda and died of Marburg virus (MARV) infection.
The Colorado patient requested repeat testing. She was found to have anti-MARV IgG by ELISA. This prompted additional testing of the archived day 10 serum, which was positive for MARV by nested RT-PCR.
Final Diagnosis
the case continues to unfold:
Discussion
What would have been your public health response to this diagnosis?
Marburg virus disease has a high case fatality rate (24-90%)
The disease presents in 3 phases: generalized phase (flu-like), early organ phase (neurological symptoms, vascular permeability), and late organ phase (DIC, shock, multiorgan failure).
Therefore early supportive hospital care is critical. This includes replacing fluids and electrolytes, giving blood products, and managing multi-organ failure.
There is no approved treatment for this virus, so supportive measures are key to management. There are experimental therapies including monoclonal antibodies and antivirals.
You should implement appropriate infection control measures. For VHFs this includes patient isolation in a negative pressure room, appropriate PPE, and relocating the patient to a bio-containment facility if possible.
Beyond the various steps you can take as an individual provider, here’s what your role as a clinician in public health looks like:
Pathogens with pandemic potential, such as hemorrhagic fever viruses, should be reported to the local public health department, state health department, CDC’s Special Pathogens Branch, and WHO. These organizations can conduct a more thorough public health investigation to determine additional exposures and contact tracing.
For viruses that are transmitted primarily via contact with bodily fluids, such as Marburg virus, keep in mind that close contacts, healthcare workers, and lab workers are at high-risk of exposure.
Management & Treatment
You can help your patient in the following ways:
Reducing host vulnerability / susceptibility (host factors):
See a travel clinic before travel to be adequately vaccinated and advised
Visit websites that provide up-to-date information on health risks (e.g., CDC travel website, Passport Health)
Reducing exposures / improving environments (environmental factors):
Counsel cave precautions in VHF areas of the world
Limit freshwater exposures, and wash off afterwards
Be careful with eating (only boiled, peeled, or cooked foods) in countries with sanitation challenges
Avoid close contact with wildlife – including opportunities to touch or feed wild animals that have been habituated, including as tourist attractions; be wary of entering bat caves
Prevention
ways to reduce vulnerability and exposures:
Beyond the Clinic
Your patient's health depends on larger factors:
Marburg virus is a single-stranded RNA virus in the family of filoviruses, which includes Ebola virus. Although the origins of some recent Marburg virus disease outbreaks are unknown, prior index cases of Marburg virus infection have been associated with exposures to mining or caves. The Egyptian fruit bat is a reservoir host, and humans have been infected via contact or inhalation of contaminated bat guano. Marburg virus has an average incubation period is 5-9 days. Human-to-human transmission occurs likely through contact with bodily fluids and fomites, with possible sexual transmission. Reducing transmission can include steps like avoiding cave or mine exposure, personal protective equipment (PPE), hand washing, and safer sex practices.
Increasing globalization, travel, and contact with wildlife poses risk for future epidemics of VHFs and zoonotic diseases. In fact, 5 of the 6 Public Health Emergencies of International Concern have been emerging zoonoses. SARS-CoV-2 is just one noticeable example of this ongoing trend.
Increasing urbanization, intensive animal agriculture, and deforestation, as well as shifting climate patterns, are causing humans and wildlife to come into contact more frequently. The more encounters there are, the more likely a new, pandemic-capable pathogen will jump between species (“spillover”). A pathogen is capable of causing a pandemic if it is highly transmissible, especially those that transmit by airborne or waterborne routes in turn allowing one individual to infect many, or those which can transmit effectively even from deceased hosts.
It has been estimated that three-quarters of all emerging pathogens in humans come from animals. While it is unknown what the next pandemic pathogen will be, it will most likely be zoonotic in origin.
There have been multiple recent outbreaks of Marburg virus disease as well as other VHFs in Africa. Clinicians must be aware of ongoing outbreaks and exposure risks, so that they can quickly identify, isolate, and treat patients with VHFs to prevent outbreaks from spreading.
Clinicians must also be aware how climate change and alterations to the human-animal interface contribute to outbreaks. For example, changes to bat roosting patterns as well as human activities may cause more bat-borne virus spillover events.
The CDC notified the WHO and Uganda Ministry of Health about the case. The cave visited by both patients was closed to visitors. A contact tracing protocol was implemented, identifying approximately 260 contacts (220 healthcare workers, 30 lab workers, and 10 social contacts). No severe febrile illness was identified.
*Note: this is based on a real story.
Case Follow Up
what happens next:
Call to Action
Clinicians can take action to advance planetary health:
At the clinic:
Alert clinicians are key to detecting sentinel cases of zoonotic outbreaks, since you are the “first line” that encounters a wide range of patients every day.
VHFs are highly contagious with a high case fatality rate, so patients must be isolated carefully and quickly. That’s what makes high clinical suspicion and a detailed exposure history so important for diagnosis and contact tracing.
In your community:
If you’re part of an institution that has a department dedicated to working on climate and health, an easy initial step would be to get into touch with them and have a first meeting.
Otherwise, you can act as a trusted voice in your community regarding future pandemics. Write op-eds, be interviewed by local news agencies, and/or attend local meetings (eg. at town hall) to make your knowledge more visible on this issue.
At the societal level:
You have the opportunity to collaborate with public health researchers and officials and climate science communities to plan a response to new pathogens. This can take the form of new research partnerships, increased communication with public health agencies, or joint articles in publications aimed at a general audience.
Advocate for less deforestation and destruction of wildlife habitat and for improved biosafety with animal agriculture.
Summary and
Key Learning Points
also available for download here:
Overall:
Recent travel to a foreign country, fever, and altered mental status may signal a life-threatening pathogen. Send the patient to hospital and determine what type of pathogen it is (and if you will need to inform public health officials).
Knowing incubation periods and geographic endemicity is crucial for diagnosis –consider web-based reference tools for endemicity and syndromic presentations.
A thorough physical exam, history of travel (and associated activities during time abroad), and blood tests are also crucial to diagnosis.
RT-PCR has become a fast method for diagnosing RNA viruses, although next-gen sequencing is progressing rapidly. Working with local, state, and national laboratories for diagnostic testing is crucial for detecting uncommon pathogens.
Diagnosis:
Determine the type of testing needed by symptoms, and activities that took place during travel.
Additional testing may be needed to ascertain various diseases (eg. 3 thick films/rapid diagnostic tests for malaria).
Save 2 red tops for future serologic testing
Management, treatment, and public health:
For viral hemorrhagic fevers (VHFs), patient isolation in a negative pressure room and appropriate PPE are crucial.
Treatment depends on the type of pathogen (eg. antibiotics for bacteria, etc.).
Most importantly, for pathogens with pandemic potential, such as VHFs, alert local, state, and national public health offices.
Additional Resources
Traveler safety:
Datasets on infectious diseases (EIDs):
MicrobeNet (CDC’s online tool that helps clinicians identify pathogens)
Maps of the spread of infectious diseases:
ArboNET Disease Maps (CDC map of arboviruses in the US)
Map Gallery (WHO maps based on specific diseases)
HealthMap (worldwide map of infectious disease alerts)
Interactive maps | Infectious Diseases Data Observatory (many maps, mostly related to malaria and visceral leishmaniasis/VL)
Disease Maps | U.S. Climate Resilience Toolkit (US-wide maps of 7 vector-borne diseases)
Articles on VHFs:
Clinical Management of Viral Hemorrhagic Fevers (from the journal Viral Infections)
Information for Healthcare Workers | Viral Hemorrhagic Fevers (VHFs) | CDC
More information on clinicians’ role in preventing and detecting the next pandemic:
Reporting pathogen to CDC: How NNDSS Conducts Case Surveillance | CDC
References
Eby, P., Peel, A.J., Hoegh, A. et al. Pathogen spillover driven by rapid changes in bat ecology. Nature 613, 340–344 (2023). https://doi.org/10.1038/s41586-022-05506-2
Fujita, N., et al. Imported case of Marburg hemorrhagic fever-Colorado, 2008. Morbidity and Mortality Weekly Report 58.49 (2009): 1377-1381.
Judson SD, Rabinowitz PM. Zoonoses and global epidemics. Curr Opin Infect Dis. 2021 Oct 1;34(5):385-392. doi: 10.1097/QCO.0000000000000749. PMID: 34310453.
Lo Re V 3rd, Gluckman SJ. Fever in the returned traveler. Am Fam Physician. 2003 Oct 1;68(7):1343-50. PMID: 14567489.
Marburg (Marburg Virus Disease) Treatment. Centers for Disease Control and Prevention (CDC). Published August 13, 2021. https://www.cdc.gov/vhf/marburg/treatment/index.html
Marburg virus disease. World Health Organization. Published August 7, 2021. https://www.who.int/news-room/fact-sheets/detail/marburg-virus-disease
Marks M, Johnston V, Brown M. Fever in the Returned Traveler. Hunter's Tropical Medicine and Emerging Infectious Diseases. 2020;1077-1086. doi:10.1016/B978-0-323-55512-8.00150-2
McMichael AJ. Extreme weather events and infectious disease outbreaks. Virulence. 2015;6(6):543-547. doi:10.4161/21505594.2014.975022
Mehedi M, Groseth A, Feldmann H, Ebihara H. Clinical aspects of Marburg hemorrhagic fever. Future Virol. 2011;6(9):1091-1106. doi:10.2217/fvl.11.79
Thwaites, Guy E., and Nicholas PJ Day. Approach to fever in the returning traveler. New England Journal of Medicine 376.6 (2017): 548-560.
Wilder-Smith A, Osman S. Public health emergencies of international concern: a historic overview. J Travel Med. 2020 Dec 23;27(8):taaa227. doi: 10.1093/jtm/taaa227. PMID: 33284964; PMCID: PMC7798963.
WHO to identify pathogens that could cause future outbreaks and pandemics. World Health Organization 2023. https://www.who.int/news/item/21-11-2022-who-to-identify-pathogens-that-could-cause-future-outbreaks-and-pandemics
Woolhouse ME, Gowtage-Sequeria S. Host range and emerging and reemerging pathogens. Emerg Infect Dis. 2005 Dec;11(12):1842-7. doi: 10.3201/eid1112.050997. PMID: 16485468; PMCID: PMC3367654.
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