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Fever patient
Fever in the newly returned traveler is both a broad and fascinating diagnostic challenge. This area is particularly relevant to work in the emergency department (ED), especially in densely populated cities and regions with large immigrant populations.

Fever in the Newly Returned Traveler

January 1, 2026

By Evan R. Miller, DO, and Matthew D. Oram, MD

Contacts: [email protected]; [email protected]

Editor’s Note

Fever in the newly returned traveler is both a broad and fascinating diagnostic challenge. This area is particularly relevant to work in the emergency department (ED), especially in densely populated cities and regions with large immigrant populations.

As international travel becomes increasingly common, this underscores the importance of systematically screening returning travelers in the United States to ensure early identification and prompt management.

EDs across the United States play a vital role in promoting safe travel through diligent screening and acute interventions. These evaluations can be complex, with overlapping symptoms and conditions that may be encountered infrequently depending on the regional epidemiology within the United States where one practices.

Definition of the Problem

Fever in a recently returned traveler represents a potentially serious clinical presentation that requires urgent evaluation. The range of possible underlying illnesses is broad, and failure to recognize critical conditions early can result in significant morbidity and mortality. Therefore, clinicians must adopt a comprehensive and systematic approach to avoid missing life-threatening diagnoses.

At the time of initial presentation, it is essential to identify patients who may pose a risk of highly transmissible infections and place them in appropriate isolation when indicated. Early laboratory testing and imaging should be considered in patients with concerning features. A thorough travel history remains the cornerstone of evaluation, with particular emphasis on the continent, countries, high-risk activities, timing of symptom onset relative to travel, and any prophylactic measures taken, including vaccines and malaria chemoprophylaxis.3

Relevance to the Adult Population

Many initial workups for infectious diseases can begin in the ED; however, the immediate priority must remain the stabilization and management of critically ill patients. In many cases, further diagnostic evaluation is most appropriately pursued in the inpatient setting under the guidance of infectious disease or tropical medicine specialists.

Among returned travelers, conditions such as malaria, dengue fever, typhoid fever, and severe diarrheal illnesses are common causes of critical illness necessitating hospital admission and, in some cases, intensive care management. A structured approach is essential, incorporating a detailed assessment of travel destinations, potential exposures (including food, water, environmental factors, and contact with livestock), as well as recognition of key clinical features. This systematic evaluation increases diagnostic accuracy and ensures that serious and time-sensitive conditions are identified and treated promptly.4

Epidemiology

It is essential to maintain a high index of suspicion for exotic diseases and infections in patients with fever and recent travel. These patients should be approached with caution because of the potential need for isolation and contact precautions; however, a thorough evaluation is essential for accurate diagnosis and effective treatment. This article will discuss returning travelers to the United States specifically, but a similar approach could be applied around the world.

Between 43% and 79% of travelers who frequently visited developing regions such as Asia and Africa reported becoming ill, with diarrhea the most commonly cited symptom.5 One systematic review found that tropical infections accounted for approximately 33% of diagnoses among febrile returned travelers, with malaria responsible for about one-fifth of cases (22%), dengue for 5%, and enteric fever for 2%. Non-tropical infections represented 36% of cases, with gastroenteritis at 14% and upper respiratory tract infections at 13%. Considerable variability across data sources exists, so further research in this area would be beneficial.6

Older travelers are at particular risk because of comorbid conditions and relatively weaker immune systems. They would benefit from appropriate pre-travel vaccinations. Ensuring use of repellents and mosquito nets and prophylactic medications is additionally important in prevention and should be emphasized in pre-travel screening exams whenever possible.7

Immunocompromised individuals are at significantly elevated risk for infection even at baseline. One study from the United States and Canada actually showed that about 36% of solid organ transplant recipients may travel abroad to more resource-limited settings within their first post-transplant year. They also reported not only traveling to areas specifically affected by dengue and malaria, but poor adherence to interventions such as hepatitis vaccinations and mosquito prevention.8 Although data are limited, emerging evidence suggests that malaria may be associated with more severe outcomes in immunocompromised populations especially. There have been reports of malaria transmission via organ donation, even if the patient in question did not have a recent travel history. The possibility of cerebral malaria with parasitemia has been reported and must be considered during evaluation. Studies also have shown a predisposition to severe cases of dengue, tuberculosis, and fungal infections.9

Pediatric patients also represent a high-risk group for significant illness severity and mortality. One large multicenter study emphasizes the importance of recognizing age-specific susceptibility and noted that children often can present disproportionately early, typically within the first week after returning from visiting relatives abroad. Although no fatalities were reported in this study, it is important to recognize that this population can present earlier and with symptoms such as diarrhea, dermatologic manifestations, and systemic fever, which occurred in approximately one quarter of the cases reported. The authors also mentioned concerns about the potential for respiratory compromise in this population. Overall mortality risk among travelers presenting with fever is approximately 0.5%.13 In the pediatric population, the mortality rate is lower, but the rate of hospitalization is higher. It is important to maintain a high index of clinical suspicion for infectious disease and pay close attention to possible early manifestations of illness in pediatric patients, such as those mentioned earlier.10

Pregnant and breastfeeding groups also are at elevated risk of severe complications and disease course, with one study showing about 25% of pregnant women traveling to areas at higher risk of yellow fever specifically. The study showed how the travel patterns of populations like pediatric patients, pregnant women, and older adult individuals were similar overall to those of the general adult population.11 It cited how the lack of data and guidelines makes recommendations for these at-risk groups particularly challenging. Special care should be taken in the ED for significantly increased mortality risk, with diseases like hepatitis E leading to maternal death in up to 25% of cases. Pregnancy increases risks for contracting genitourinary and respiratory infections.44

Etiology

The two most common causes of fever in the returned traveler are repeatedly shown to be malaria, followed by dengue. Coupled with enteric fevers, leptospirosis, and scrub typhus, this encompasses around 90% of the serious causes of tropical infections that are seen.2 In travelers coming from sub-Saharan Africa with febrile illness, malaria is predominant, with dengue being more common in travelers from the rest of the world, such as South America, the Caribbean, and Asia. As previously stated, overall mortality risk in a febrile returned traveler is around 0.5%, with about 4% of ill travelers overall having a serious illness.13,45

The most important part of workups in history is determining where exactly the patient traveled.

Specific Illnesses

Malaria

Pathophysiology

Malaria remains endemic throughout most tropical regions, spanning approximately 90 countries worldwide.49 Transmission continues to pose a major global health challenge. As of 2023, the Centers for Disease Control and Prevention (CDC) has reported local malaria transmission occurring in three southern states and one eastern state in the United States. A large majority of malaria cases occur in Africa, which accounts for most of the estimated 247 million cases worldwide each year. In contrast, the United States reports approximately 2,000 cases annually, primarily among travelers returning from endemic areas.49 The global mortality rate is approximately 0.26%, and in the United States specifically it is 0.3%.14

Five Plasmodium species are known to infect humans: P. falciparum, P. vivax, P. malariae, P. ovale, and P. knowlesi. Among these, P. falciparum is responsible for the most severe disease and the highest mortality worldwide.13 This also represents the most common life-threatening infection in febrile returned travelers. Transmission occurs through the bite of an infected Anopheles mosquito, which typically feeds between dusk and dawn. After inoculation, Plasmodium parasites migrate to the liver, where they undergo asexual reproduction before entering the bloodstream and infecting erythrocytes. The dormant hepatic stage — known as the hypnozoite form — occurs in P. vivax and P. ovale, leading to potential relapses weeks to months after initial infection. Fever and rigors in returning travelers often coincide with the erythrocytic phase of the parasite’s life cycle, when merozoites are released from infected red blood cells into the circulation.14

History

Obtaining a detailed history is essential, especially to include any prior malaria infection, specific recent travel destinations, and possible hospitalizations abroad. The clinician should ask patients if they had recent contact with people known or suspected to be sick with malaria, and whether the patient was taking any malaria prophylaxis. Ask about common presenting symptoms, such as intermittent fevers and chills, headaches, myalgias, and malaise. Gastrointestinal symptoms, such as nausea, vomiting, and diarrhea, also commonly can be seen.

Physical Exam

Look for conjunctival pallor and hepatomegaly and/or splenomegaly. Splenomegaly in a returned traveler with fever has a positive likelihood ratio for malaria of 5.1-13.6.6 Altered mental status may be seen in severe cases or cerebral malaria. Thrombocytopenia has a positive likelihood ratio of 2.9-11 in returned travelers with fever and may be evidenced by petechial rash or mucosal bleeding.6

Severe Malaria

Severe malaria typically occurs from delayed treatment of uncomplicated malaria and is marked by clinical or laboratory evidence of organ dysfunction. Cerebral malaria, pulmonary edema, renal failure, shock, and bleeding all are possibly severe complications of malaria. Unstable vitals, such as hypotension or bleeding, would warrant admission and possible transfusion. Additional signs of jaundice may be seen. Pay attention for signs of respiratory distress and hypoglycemia.

Laboratory Tests

Obtain complete blood count (CBC), complete metabolic panel (CMP), coagulation tests, lactate, and blood cultures. Thrombocytopenia on CBC is highly predictive of malaria and carries a likelihood ratio (LR) of 5.6. Hyperbilirubinemia has an LR of 7.3.50 This shows that having thrombocytopenia and hyperbilirubinemia can significantly increase the likelihood of malaria, but these laboratory tests alone cannot definitively diagnose malaria. Thick and thin blood smears are the gold standard for diagnosis, with P. falciparum having the highest sensitivity and specificity (99.7% sensitive, 94.2% specific).14

Imaging

Consider a chest radiograph for any respiratory symptoms and abdominal computed tomogoraphy (CT) for any hepatic/splenomegaly found on a physical exam.

Specialized Tests

Thick and thin blood smear is most important and is the gold standard for diagnosis. It requires lower numbers of parasites for detection at five to 10 parasites per microliter. This can be repeated on admission if it is negative and high suspicion remains. There are additional rapid tests available with 99.7% sensitivity and 94.2% specificity at levels of at least 5,000 parasites per microliter.14 However, these tests cannot distinguish reliably between, or diagnose as reliably, non-falciparum strains of malaria.

Management

Initiate specific antibiotic treatment based on malaria strain and admit the patient to hospital for further management with consultation to the infectious disease physician. Treat with supportive care with IV fluids and symptomatic management for fevers, AKI, hypoglycemia, etc. Blood smears can be repeated every 12-24 hours if needed. For treatment, known P. falciparum or an unknown strain should receive artemether-lumefantrine or alternative treatments like atovaquone-proguanil. Artesunate should be administered for severe cases.14

Disposition

Admission for these patients is recommended for continued management and observation.15,40

Tuberculosis

Pathophysiology

Tuberculosis (TB) is transmitted by airborne droplets. These bacilli reach to the base of the lungs and the alveoli where they are killed by macrophages. Most commonly people will have latent infections, which are not transmissible, but up to 15% will go on to develop active disease.16 If active, this is contagious and can lead to significantly higher morbidity and mortality and tissue destruction in the host. This continues to be a leading cause of death worldwide. It was the top cause of death in 2023, with an estimated 13 million deaths reported to the World Health Organization.17 Tuberculosis is most commonly seen in the lungs, but extrapulmonary TB actually can be found in any other organ system of the body. Although extrapulmonary tuberculosis is rarely contagious, it can cause significantly higher mortality, and immunocompromised patients also are more susceptible to these disseminated disease presentations. As much as 20% of new TB cases diagnosed in the United States are extrapulmonary.46

History

A concerning history in the newly returned traveler and red flag symptoms in general, are chronic cough, weight loss, night sweats, and fever, in addition to hemoptysis and fatigue. Additional concerns are patients at extremes of age, such as children or older adults, and immunocompromised patients, who have an elevated risk in general and especially for extrapulmonary tuberculosis. In addition to international travel in general, high-risk settings are long-term residence in endemic areas, comorbid HIV infections, and incarceration.

Physical Exam

The physical exam often can be nonspecific, but with TB mostly affecting the lungs, the exam may show crackles or paucity of lung sounds in certain regions with evidence of consolidation. Extrapulmonary TB also can be variable depending on the specific organ involvement and can demonstrate lymphadenopathy, neck rigidity, and others. If the patient has four or more symptoms of cough, night sweats, chest pain, fever, hemoptysis, or weight loss, they are more likely to have TB, with a sensitivity of 69% and specificity of 81%.58

Red Flag Symptoms/Features

Cough, night sweats and weight loss, fatigue, fever, hemoptysis, immunocompromise, incarceration, and homelessness are red-flag symptoms and features.

Laboratory Tests

In addition to obtaining basic lab work such as complete blood count (CBC), basic metabolic panel (BMP), lactate, consideration of D-dimer in cases of hemoptysis, blood cultures in septic-appearing patients for concern for co-infection, several specialized tests are available. Nucleic acid amplification tests (NAATs) of respiratory sputum are first-line for concern of active tuberculosis. NAATs show sensitivity of 85% overall and specificity as high as 98% for diagnosis.17 Classic tests like the interferon gamma release assay (IGRA) of the blood or tuberculin skin test are only for latent TB and are not recommended for active disease considerations because they demonstrate prior sensitization and not necessarily acute illness. Sputum smear should be obtained and repeated twice for a total of three specimens. Mycobacterial culture is the gold standard for diagnosis but often can take much longer than NAATs and smears. An approach using smears, cultures, and NAATs is most important, and NAATs and smears often can give the quickest initial clinical decision-making information.

Imaging

The ED clinician should obtain chest X-ray early in individuals with presentations concerning for tuberculosis. A normal chest X-ray can exclude tuberculosis in most patients unless they are immunocompromised. Consider CT scanning for extrapulmonary evaluation, extensive involvement, or atypical presentations.

Specialized Tests

NAATs that now are recommended as first-line tests for diagnosis of TB with respiratory sputum samples. Mycobacterial culture and AFB smears commonly are used and can take longer for diagnosis, as discussed earlier.

Management

Respiratory isolation with airborne precautions should be initiated as soon as possible. Contact the local public health office and infectious disease specialist for positive results and/or concerning exams. Most cases of tuberculosis do not need to be started on treatment on an emergent basis, and discussion should be initiated with the infectious disease specialist for guidance on this decision. Of note, symptoms can overlap with pneumonia, and fluoroquinolones should be avoided if at all possible for partial treatment of tuberculosis and increasing resistance of TB to fluoroquinolones. Standard therapy focuses on a four-drug regimen for two months and two drugs for four months, for a total of six months of treatments. Medication therapy focuses on rifampin, isoniazid, pyrazinamide, and ethambutol. Latent tuberculosis is not infectious, and treatment can be pursued in an outpatient setting with close follow-up with an infectious disease provider. Isoniazid typically is used as monotherapy for six to nine months. Unless explicitly instructed by public health or infectious disease experts, TB medications are not usually required in the emergency department setting and should be discussed with the infectious disease provider. Prompt treatment of co-infections, especially with antibiotics for sepsis, is warranted. There is a significant risk of co-infection with HIV, with approximately 4% of tuberculosis patients also having HIV infection, and significantly increasing risk of mortality, with about 12% of TB-related deaths associated with HIV as well.47

Disposition

It is recommended to adhere to advice from consulted infectious disease providers, especially regarding starting medications on admission for treatment of TB. Tend toward hospitalization in these patients to ensure full evaluation and beginning of treatment. Special considerations are hospitalization for severe disease and respiratory compromise or inability to secure follow-up or treatment adherence.16,48

Dengue

Pathophysiology

Dengue is caused by several different types of the dengue virus and is transmitted specifically by the Aedes mosquito. The virus replicates in lymph nodes following infection and cycle of dependable three stages of illness, including fevers, more critical infection, and return to recovery. An elevated risk of secondary infection and patients with prior infection with dengue are at higher risk, showing increasing severity the second time they are infected.19

History

Dengue is one of the most common causes of fever in the newly returned traveler, especially in regions such as central South America, the Caribbean, Asia. Patients can report fever, severe retro-orbital headache, diffuse myalgias, rash, nausea or vomiting, and symptoms of bleeding.13,18

Physical Exam

Fever, petechial rash, subjective myalgias and arthralgias, and mucosal bleeding may be evident on physical exam. Patients can present with petechial rash over abdomen and feet, typically described as “white islands in a sea of red.” Studies have shown the combination of joint, muscle, or bone pain along with rash, dyspnea, and rhinorrhea can carry as high as 78% sensitivity and 63% specificity.59

Red-Flag Symptoms/Features

Severe abdominal pain, nausea, vomiting, mucosal bleeding, altered mentation, thrombocytopenia, and petechial rash are red-flag symptoms.

Laboratory Tests

It is recommended to obtain basic laboratory tests, such as complete blood count, BMP, hepatic function panel, lipase, and prothrombin time/partial thromboplastin time/international normalized ratio (PT/PTT/INR). Lab work can show thrombocytopenia and elevated transaminases.

Imaging

Imaging is not routinely indicated unless there is clinical suspicion for pleural effusion in more severe disease.

Specialized Tests

In resource-limited settings, an inexpensive test sometimes used to evaluate for dengue is a tourniquet test in which a tourniquet is placed for a five minutes over the arm and let down for two minutes. The development of a high amount of petechiae (10 or more in 1 square inch) in that area can be used as a diagnostic tool pointing toward dengue. This test actually approaches 100% specificity but is limited by low sensitivity.60 Specialized laboratory tests include DENV NAAT and IgM serology. It is recommended to use the DENV NAAT (RT-PCR) if within seven days of the start of symptoms. NAAT can detect up to 82% of cases within the first few days of illness.51 Use DENV IgM serology after five days of illness. These can be repeated if negative results are present but symptoms persist.18

Management

Dengue fever has no specific targeted therapy, notably no antiviral treatments and no recommendation for steroids. Treatment is focused on supportive care, encouraging hydration and antipyretics and treatment of pain. With more severe symptoms, hospital admission is recommended for continued IV fluid resuscitation and monitoring of laboratory tests and vital signs. Notably, platelet transfusion is not routinely indicated, and nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin should be avoided. Report all suspected cases to public health authorities.19

Disposition

Mild cases of dengue can be discharged home, with severe cases admitted to hospital for monitoring. Consider ICU level care for any signs of severe shock.

Chikungunya

Pathophysiology

Chingungunya is a virus transmitted through the Aedes mosquito and can be difficult to distinguish from dengue. It is known for high fever and polyarthralgias, and it can progress to more significant systemic symptoms like myocarditis, Guillain-Barre, ocular disease, and sometimes acute kidney injury. The disease course typically lasts a week or 10 days, but chronic arthralgias can persist for up to years.

History

Key elements of the history that are concerning for chikungunya are recent travel to areas like Central and South America, the Caribbean, Africa, and Asia. Symptoms usually start within one to 12 days. Patients may mention recent mosquito exposure or bites. They may describe symptoms like fever, myalgias or arthralgias, nonspecific rash, or conjunctivitis.13

Physical Exam

One can classically see high temperature, subjective pain in large joints, and maculopapular rash that can be seen in the extremities to involve the palms and soles, abdomen, and even face. More severe or critical cases may show neurologic deficits. The combination of fevers and polyarthralgia carries a positive likelihood ratio (LR) of 7.6 for chikungunya.61

Red-Flag Symptoms/Features

Especially concerning symptoms are signs of shock, encephalopathy or meningitis, Guillain-Barre, and bullous skin lesions.

Laboratory Tests

The clinician should begin by obtaining basic lab work with CBC, BMP, hepatic function panel, and lipase. CBC could show thrombocytopenia, although alternative diagnoses like dengue are more likely if severe thrombocytopenia is present. BMP and HFP could show transaminitis and AKI. Consider an escalated sepsis workup if symptoms are more severe. It is recommended to obtain co-testing for malaria and dengue because of significant overlap in symptomatology.13,21

Imaging

Imaging is not routinely indicated in evaluation.

Specialized Tests

In the first week of illness, RT-PCR is preferred for diagnosis. Specificity of this test is nearly 100%, while sensitivity is at least 75%.52 After seven days, serology with IgM/IgG Elisa can be used, and PRNT can be used in difficult cases. It is recommended to discuss with the infectious disease consultant and with the institution’s lab to confirm availability.22

Management

Treatment is focused on supportive care, with no antiviral medication or vaccination. Report confirmed cases to the local public health authority.20

Disposition

The ED clinician can consider admission or discharge based on the severity of symptoms and ability to follow up. If a patient has severe disease, a high-risk history, or is unlikely to be able to follow up, lean toward admission.20

Zika

Pathophysiology

The pathophysiology of Zika virus involves transmission by the Aedes mosquitoes in the Flavivirus genus, transmitted primarily by mosquitoes, but with additional sexual, vertical, and sometimes transfusion methods. Most people are asymptomatic or exhibit mild symptoms, but the main risk arises with congenital Zika infection, which can result in microcephaly, and neurologic complications like Guillain-Barre and encephalitis. Most infections occur in South America and, more recently, southern U.S. states. Treatment is focused on primarily symptomatic management and supportive care.23

History

As with any other infectious disease presentation, the key history in the emergency department focuses on specific areas of recent travel and any high-risk behavior. Symptoms usually begin in the next two weeks after exposure. Patients may describe fevers, rashes, arthralgias, and conjunctivitis. Special care must be taken in pregnant patients for consideration of transmission of virus from mother to child and possible risks to the developing fetus.

Physical Exam

Since most cases are mild, the physical exam may be unremarkable. Some of the most common physical exam findings are maculopapular rash, fever, and conjunctivitis. Encephalitis is rare but may cause altered mental status, seizures, or coma. Pruritic rash and conjunctivitis carry a sensitivity of 87% and specificity of 78% for Zika diagnosis.62

Red-Flag Symptoms/Features

Most concerning symptoms are neurologic deficits or symptoms, such as altered mental status and weakness, which can suggest Guillain-Barre or encephalitis. Regarding concerns for vertical transmission in the newborn, symptoms can be hypotonia and microcephaly. As such, special care should be taken with pregnant patients. Severe thrombocytopenia shown on lab tests is possible and would be highly concerning as well.23

Laboratory Tests

Basic laboratory tests do not provide specific diagnostic benefits, but they may be helpful in recognizing Zika complications such as thrombocytopenia. Broaden to a more expanded workup if severe symptoms or signs of sepsis or respiratory compromise are suspected. For special testing, nucleic acid amplification testing, which is NAAT or RT-PCR of serum and urine within two weeks of symptoms, can be considered. Sensitivity is 96.1% and has a specificity of 100%.53 This also can be obtained from cerebrospinal fluid (CSF) if necessary. IgM serology also can be considered after seven days, but cross-reactivity is higher, and so consideration needs to be given to alternative infections or co-infection with pathologies such as dengue. For pregnant patients, the same NAAT of serum and urine can be obtained up to 12 weeks after the onset of symptoms. It is recommended to consider testing for dengue and chikungunya for overlapping symptomatic presentations.13,23

Imaging

Imaging is not routinely recommended for uncomplicated cases. However, it is recommended to obtain fetal ultrasonography if Zika exposure is suspected to assess for fetal malformation.

Management

Treatment will focus on supportive care, especially in mild symptoms. Focus on hydration and controlling fever with acetaminophen. It is recommended that NSAIDs be avoided until dengue is excluded. There are no current recommendations for antiviral therapy or availability of vaccinations. All suspected cases should be reported to public health authorities, and pregnant patients will require a multidisciplinary approach. Prompt consultation to OB-GYN is recommended for fetal monitoring.24

Disposition

Especially in mild cases, most patients can be discharged with outpatient follow-up. As with any other disease course with severe, and especially neurologic symptoms, patients should be admitted. Pregnant patients or neonates with abnormal congenital findings should warrant admission and specialist consultation to Infectious Disease and OB-GYN.24

Typhoid Fever

Pathophysiology

Typhoid fever, also sometimes called enteric fever, is caused by salmonella infection. Salmonella, with the serotype typhi, is acquired by the fecal-oral route and ingestion of contaminated food or water. After being ingested, the bacteria invade the intestinal mucosa and can cause systemic symptoms through hematogenous dissemination. Symptoms can onset in as little as one to two weeks, but they can take up to four weeks to present. Patients are at elevated risk if they present following travel to high-risk areas.25

History

The most important part of the history is recent travel (including travel to high-risk regions like South Asia, Africa, Latin America, and the Middle East), consumption of certain foods, exposure to known carriers, fever, subjective headache, abdominal pain, general malaise, anorexia, or diarrhea. Specific food consumption that would put the patient at elevated risk includes raw fruits and vegetables with consideration of contaminated water, unpasteurized dairy and shellfish harvested with contaminated water, and consumption of foods and drinks from street vendors. Vaccines are available but are not completely protective. Injectable vaccines and an oral vaccine are available. Of note, fever unresponsive to antimalarials can indicate this is a possible diagnosis.

Typhoid fever can present in stages. It classically presents with progression through several stages over three to four weeks if untreated. The first week begins with rising fever and malaise, and gastrointestinal (GI) symptoms may develop. The second week indicates a more established disease, and fever can continue to rise, such as to between 39 and 40 degrees Celsius. Patients can show bradycardia, hepatosplenomegaly, and abdominal distension, sometimes demonstrating mental confusion. Rashes can present with rose spots and erythematous maculopapular lesions and can be seen on the trunk in approximately 10% of cases. Severe cases may involve delirium and signs of gastrointestinal perforation. The third week, if untreated, can show more severe complications, including GI bleeding with intestinal perforation and a toxic-appearing patient with encephalopathy. In the fourth week, the virus can show resolution of symptoms, but fatigue may persist for weeks. Patients may become chronic carriers in about 5% of cases with GI colonization.26

Physical Exam

Patients commonly present with fever and abdominal tenderness with hepatosplenomegaly. Sometimes the classic rose-colored maculopapular rash is evident. Children may present more often with diarrhea and adults may present with constipation. More severe disease courses can involve GI bleeding, peritonitis, and encephalopathy with confusion. Physical exam findings are nonspecific, and they alone cannot reliably distinguish typhoid from other similar pathology. Studies have attempted to delineate clinically significant symptoms and concluded that three or more days of fever with either fever at presentation, absent cough, or a few days of being unable to conduct usual activity yielded only a sensitivity of 95% and specificity of 14%.63

Red-Flag Symptoms/Features

Red-flag symptoms are signs of GI hemorrhage and bleeding, signs of intestinal perforation with an acute abdomen with peritonitis, encephalopathy with altered mental status, systemic signs of severe dehydration or shock with persistent vomiting, or more generalized signs of sepsis or end-organ dysfunction. As with any other severe disease course, admission to critical care with an infectious disease consultation would be recommended.

Laboratory Tests

Begin with basic laboratory work such as CBC, CMP, and lipase. Consider fecal occult blood testing and coagulation tests for signs of bleeding. More severe disease or signs of developing typhoid fever should prompt blood cultures, which are the preferred diagnostic tests. The clinician could consider bone marrow culture, which shows the highest sensitivity but is rarely performed in the ED setting. Reasoning is discussed later in specialized tests. Stool and urine cultures are an option but are less sensitive. Consider alternative diagnoses of malaria with rapid testing or blood smears to exclude co-infection. Classically, CBC would show thrombocytopenia and lymphopenia. Transaminitis may be seen on liver function testing, and elevated lactate and C-reactive protein (CRP) may be seen in severe disease as well.

Imaging

CT imaging may be warranted if there is clinical concern for peritonitis.

Specialized Tests

Blood cultures are positive in up to 80% of patients with typhoid and are standard for diagnosis. Sensitivity varies from approximately 40% to 80%. Bone marrow culture is more sensitive and can be positive in more than 90% of patients with typhoid.25 Blood culture sensitivity is higher in the first week and is reduced with antibiotic usage. Bone marrow culture can be positive even in patients taking antibiotics for several days. Stool cultures can be considered, but they depend on the amount of feces obtained. The detection rate can vary widely and could be positive in chronic carriers as well. A specialized Widal's test is a consideration, but it is more controversial because of its variability among different geographic areas. As such, this is helpful when used in combination with locally determined parameters and not routinely recommended in the ED setting. Additional more specific serologic and PCR tests are being developed, but they are not routinely recommended at this time.27

Management

Consideration of travel history and specific resistance patterns are key for antibiotic management. Research has shown fluoroquinolones are the most effective medication for this disease, are rapidly effective, and are safe in all age groups. Of note, there is concern for developing resistance to this class of drugs. For most U.S. cases, and especially in travelers to South Asia, the preferred antibiotic regimen involves azithromycin and ceftriaxone. For suspected or drug-resistant cases, especially among patients with travel to the Middle East (specifically Pakistan and Iraq), carbapenem can be considered for a complicated illness. For severe disease courses, patients should be administered IV fluoroquinolones and steroids with dexamethasone. Pregnant patients should receive beta-lactam antibiotics like ceftriaxone. As with any other severe illness, it is recommended to administer adjuvant-supportive care with IV fluids and antipyretics, pay close attention to nutrition status, and pursue admission to the hospital or ICU with consultation to infectious disease. All cases should be reported to the local public health authority.25,26

Disposition

In international areas with endemic typhoid, up to 90% of cases are managed at home with bed rest, oral rehydration, and antibiotics.26 As such, outpatient management can be considered in well-appearing patients with no significant comorbidities. Admission is recommended for patients with severe disease and inability to tolerate oral therapy, equivocal diagnosis, or unreliable outpatient follow-up. Pursue hospitalist admission for patients with clinical dehydration and laboratory abnormalities. For cases with severe laboratory abnormalities or significantly altered mental status, pursue ICU admission with infectious disease consultation.26

Rickettsial Infections

Background and Pathophysiology

Rickettsial infections are a group of zoonotic diseases caused by obligate intracellular bacteria of the order Ricketsialles In this group are Rocky Mountain spotted fever, Mediterranean spotted fever, and tick-bite fever. They are placed under the primarily tick- or mite-borne group. The next group to consider is the typhus group, which are louse-borne and can be transmitted by fleas. Next is a scrub typhus group caused by chigger mites. Additional considerations are ehrlichiosis and anaplasmosis, which are transmitted by ticks. Q-Fever, also known as Coxiella burnetti, historically was under the same group but now is considered distinct. These are increasingly recognized in the United States emergency department with domestic travel causing illnesses like Rocky Mountain spotted fever, ehrlichiosis, and anaplasmosis. International travelers can present with such illnesses as African tick-bite fever, Mediterranean spotted fever, and scrub typhus. Travelers from Africa, especially Sub-Saharan Africa, can show African tick-bite fever, while travelers from the Asia-Pacific region are at risk for scrub typhus. Rickettsial organisms are passed by skin bites from predominantly mites and ticks and through disseminated infection can lead to multisystem involvement. Disease severity can vary widely by specific etiology and cause. For example, scrub typhus can be life-threatening and more severe, while African tick-bite fever typically can show a milder disease course.28

History

These diseases classically present with fever and nausea, as well as subjective headaches and myalgias. Physical exam findings of rash can be indicative of and help differentiate specific diseases. Rashes are described more specifically later, but can involve maculopapular distributions, petechiae, and eschars. The typical incubation time is five to 10 days.

Physical Exam

The type, distribution, and timing of rash can help differentiate between many etiologies. Classically, the rash of Rocky Mountain spotted fever starts five days after the onset of fever with a maculopapular appearance. It typically begins as a maculopapular eruption about the wrist and ankles and can spread centrifugally. The rash can progress in more severe cases to petechiae but may be absent.

Mediterranean and African tick-bite fever can show maculopapular or papulovescicular rash and frequently is accompanied by eschars. There may be multiple eschars and can be present in up to 100% of patients with this disease, but the literature shows a wide range (53% to 100%).64 Marine typhus can show maculopapular rash in the trunk, with eschars not being typical, but only about half of patients affected show rash in general. Scrub typhus most often is shown to have a single eschar at the site of the bite from a chigger, and the rash is more variable. Sometimes it can show vesicular or maculopapular rash. Anaplasmosis and ehrlichiosis more commonly can present with rash in children, but in general rarely present with rash and usually are nonspecific. (13)

Red-Flag Symptoms/Features

Physical exam findings of widespread maculopapular or petechial rash are indicative of a severe disease course. Lymphadenopathy and signs of end-organ dysfunction or encephalopathy are especially concerning. Additional signs of shock and evidence of end-organ dysfunction necessitate admission to the hospital for further management.

Laboratory Tests

Obtaining basic laboratory tests with CBC and CMP is recommended. It is recommended to obtain additional coagulation tests, creatine kinase, and blood cultures for differentiation from other similar disease pathologies. An escalated workup to include inflammatory markers and lactate is warranted in signs of severe illness, sepsis, or organ dysfunction. Testing can reveal leukopenia or leukocytosis, thrombocytopenia, and transaminitis. These tests usually show mild abnormalities and can be absent, especially early in the disease course, and cannot necessarily guide treatment decisions or make a formal diagnosis. PCR testing or serology is useful for more specific diagnostic evaluation, with eschar swabs and skin biopsy the most helpful. For ehrlichiosis and anaplasmosis, NAAT is preferred.29

Imaging

Imaging is not routinely recommended.

Specialized Tests

Antibody titers frequently are negative in the first week to 10 days of illness, so initial serology may be nonconfirmatory. Cross-reactivity is common in this group. PCR testing with NAAT is the preferred method for early detection, especially in cases of ehrlichiosis and anaplasmosis. Rickettsial infections in general carry a sensitivity of up to 95% and specificity of up to 96% on PCR testing.54 Skin biopsy, especially for Rocky Mountain spotted fever, would be expected to provide a identification. Serologic testing remains the preferred method for early detection, especially in cases of ehrlichiosis/anaplasmosis. While serologic testing remains the standard, there is high cross-reactivity amongst diseases in this group, and this is mostly for retrospective confirmation.18

Management

Regardless of the specific etiology, this class of diseases warrants empiric doxycycline treatment. Regardless of age or pregnancy status, delays can result in increased morbidity and mortality. Treatment should not be withheld for confirmatory laboratory testing. Report confirmed cases to the local public health authority.28

Disposition

Admission is warranted for a more severe disease course, evidence of organ dysfunction, or inability to secure follow-up.

Hemorrhagic Fevers

Pathophysiology

Viral hemorrhagic fevers are a group of highly transmissible viral infections caused by viruses from five different families, the most well-known of which are hantavirus, Ebola, dengue hemorrhagic fever, and yellow fever. Transmission is mostly between humans and animals, but human-to-human transmission also is possible. These viruses induce endothelial damage, multi-organ failure, and impair coagulation leading to coagulopathy that can result in shock and hemorrhage if not controlled. Vaccines are available for some of these viruses.

History

As with any other fever in a returned traveler, a detailed history is important, with highest risk regions in this group being Africa and parts of Asia, known outbreaks or known sick contacts, and incubation period being up to three weeks. It is important to ask about possible vaccinations, such as hepatitis and yellow fever, and malaria prophylaxis for consideration of comorbid conditions. Patients can present initially with nonspecific, flu-like illness, such as headaches and dizziness, fevers, myalgias and arthralgias, rash, diarrhea, nausea, and vomiting. Severe illness can present with significant bleeding, such as bloody diarrhea, hematemesis, or darkening of stools and melena. Petechiae, bruising, and mucosal bleeding also may be seen. This can progress to involve hypovolemic shock, multi-organ failure, sepsis, and disseminated intravascular coagulation (DIC).13

Physical Exam

Patients may have several subjective findings, such as headache and myalgias, but the physical exam can show petechial or ecchymotic rash and GI symptoms like vomiting or diarrhea, some of which can be bloody as well. Severe cases can show fevers and unstable vital signs, indicating shock, pulmonary edema, or organ failure. Some viruses can have specific features, such as renal failure in hantavirus. No single physical exam finding has an especially high likelihood ratio. Symptoms of fever (87%) and fatigue (76%) were most common, and the symptom with the highest odds ratio (OR) was diarrhea (pOR 2.99; 95% confidence interval [CI] 2.00-4.48).31

Ebola virus and Marburg virus can demonstrate pin-sized papular erythematous rash appearing in less than a week, which can be followed by a desquamation of the rash. Patients typically show mucosal bleeding and oozing from puncture sites. Lassa fever can involve significant facial and periorbital edema with less frequently seen petechial hemorrhage. More commonly, one can see pharyngitis and hearing loss. Hantavirus can show petechial eruption on the neck and sunburn-like reddening of the skin on the head and upper torso, and the patient can have facial edema and flank pain. Yellow fever classically involves jaundice, as well as bradycardia in the setting of high fever, bruising and epistaxis, possible hematuria, and retinopathy in rare cases. Jaundice is the most distinguishing feature of yellow fever.

Red-Flag Symptoms/Features

GI bleeding, including signs of hematemesis or frankly bloody or melanotic stools, is significantly concerning. Signs of severe shock, altered mental status, or organ failure warrant emergency stabilization and monitoring in the ICU.

Laboratory Tests

Coagulation studies are warranted in addition to basic laboratory tests. Hemorrhagic shock is a feared complication of these illnesses. Obtaining a type and screen early would be prudent. Because of overlapping symptoms and geographic distributions, consider testing for malaria. Patients with hemorrhagic fever may demonstrate leukopenia, thrombocytopenia, anemia, transaminitis, and consumptive coagulopathy.

Imaging

There is no specific recommendation for empiric imaging.

Specialized Tests

The gold standard for evaluation with special testing for viral hemorrhagic fevers includes NAAT such as RT-PCR. Antigen detection assays like ELISA are more useful in point-of-care or low-resource settings and can help differentiate from other causes of fever. Sensitivity and specificity of RT-PCR are both close to 100% for Ebola.55 Serologic testing is used to detect virus-specific antibodies but is less useful in early disease processes because of potential cross-reactivity between infections.30

Management

Initial isolation and control of potentially infected people is essential. Prompt use of personal protective equipment (PPE), isolation, and droplet and contact precautions are recommended. Use supportive care strategies with aggressive fluid rehydration and avoid NSAIDs because of bleeding risk, as with malaria and dengue for example. For Ebola specifically, monoclonal antibodies are available, and empiric antimalarial medications should be strongly considered if malaria has not yet been excluded. Analgesics can be given for pain and fever control, with avoidance of NSAIDs and consideration of blood product administration in severe hemorrhage, anemia, or thrombocytopenias. Promptly alert local public health authorities and consult infectious disease specialist.

Disposition

Admission with consultation by an infectious disease specialist is warranted for risk of transmission. After notifying public health authorities, coordinated care with infectious disease often is pursued.31

Acute Human Immunodeficiency Virus

Pathophysiology

A high index of suspicion is required for the diagnosis of acute human immunodeficiency virus (HIV), and it should be suspected in recent travelers with high-risk exposures or behaviors. Acute HIV is highly infectious and difficult to distinguish. It can present within weeks of transmission and is characterized by rapid replication and viremia. This virus can be transmitted sexually, parenterally, or vertically by birth, and is most common in adults between 20 and 30 years of age. The virus attacks the body’s macrophages and CD4 cells and presents in three stages: acute, latency, and acquired immunodeficiency syndrome (AIDS). This article will focus on the acute stage, which will present with flu-like symptoms within two to four weeks; however, diagnosis is complicated by the fact that many patients also can be asymptomatic.42

History

The clinician should obtain a detailed history of travel and high-risk behavior, such as unprotected sex, needle sharing, and contact with bodily fluids. Early in the disease course, patients could be asymptomatic or present with nonspecific flu-like symptoms.42

Physical Exam

Physical exam often is nonspecific and can include fever and lymphadenopathy, pharyngitis, oral ulcerations, and subjective myalgias and arthralgias. Lymphadenopathy is the most useful sign and has a positive likelihood ratio of 3.1 (95%, CI: 1-5.2).56

Red-Flag Symptoms/Features

Acute presentations with altered mental status, sepsis or severe leukopenia, concerning opportunistic infection, or end organ dysfunction all warrant augmented workup and admission.

Laboratory Tests

Basic laboratory work is recommended to start, and then escalation to include viral panel and hepatic function panel (HFP) and lipase depending on the presence of abdominal complaints. Obtain lactate and blood cultures if patients are acutely ill-appearing. If there is a generally concerning story for sexually transmitted infection (STI) transmission, consider testing with urinalysis (UA), gonorrhea, chlamydia, trichomonas, and potentially syphilis depending on the region. Concern for transmission via needle sharing should warrant hepatitis B and C testing. Specific testing for HIV is described later in the section on specialized tests.

If acute HIV is diagnosed, it is recommended to obtain a viral load and CD4 count in addition to kidney and liver function testing. Order lipid panel and blood glucose, and ensure screening for additional STIs and consideration of cryptococcal antigen testing if the CD4 count is below 100.

Imaging

Imaging is not indicated unless specific concerns on the history or physical exam warrant it.

Specialized Tests

It is recommended to obtain specialized testing for HIV in the emergency department with acute concerns, which starts with an HIV-1/2 antigen/antibody immunoassay. If this is reactive, an additional HIV-1/HIV-2 antibody differentiation immunoassay is necessary. If this is negative and there still is high clinical suspicion, obtaining an additional NAAT for HIV ribonucleic acid (RNA) can be considered. HIV RNA is the most sensitive and specific method for diagnosis at 97.6% and 100%, respectively.38,57

Management

In cases of postexposure prophylaxis (PEP), PEP should be initiated as soon as possible, ideally within 72 hours. The Infectious Diseases Society of America recommends starting antiretroviral therapy within seven days of diagnosis. Contraindications include patient objection or clinical concerns for superinfection with cryptococcal meningitis, for example. The recommended PEP is a three-drug regimen with tenofovir fumarate plus emtricitabine plus dolutegravir or raltegravir for 28 days. Individuals with confirmed HIV infection should be started on a three-drug regimen as soon as possible. It is recommended to use bictegravir plus tenofovir alafenamide plus emtricitabine. Contraindications and special consideration are given to pregnant patients and patients with liver and kidney impairment. Counsel these patients on avoidance of high-risk behaviors and avoidance of transmission and provide close follow-up. Positive HIV tests warrant reporting to the local public health authority.

Patients with unstable vitals or signs of severe illness or organ dysfunction should receive a broadened workup to include additional laboratory tests and cultures for sepsis, fluids, antibiotics, and admission.39

Disposition

Patients usually can be discharged with close follow-up, but unstable or acutely ill patients, or those with signs of sepsis or end-organ dysfunction, should be admitted.

General Approach

History

It is important to rapidly assess for signs of acute illness such as shock, respiratory compromise, or altered mentation, and act quickly if patients are acutely ill. If possible, obtaining a detailed history of where the patient recently traveled, including possible exposures to sick individuals, new food or water sources, and the timeline of the illness is recommended. Ask about any specific activities while travelling, such as camping, swimming, etc. Any sort of vaccinations or prophylaxis is important to know. As with any other patient, ask about associated symptoms, such as fevers, cough and whether it is productive, vomiting or diarrhea, and underlying medical conditions. Ask if the patient had traveled to this region before and if they have had an illness like this before or any type of exotic/tropical illness in the past. General timing of symptoms as well as the course of fevers, such as whether it comes and goes and how long it has been present, can help to differentiate the underlying etiology.

Physical Exam

Approach the physical exam initially as with any other patient. Assess cardiopulmonary function, and check for equal pulses and any evidence of altered mentation. Any difficulty with respiration or coarse breath sounds could suggest pulmonary pathology. Skin findings, such as jaundice, rash, or possible cellulitis, are important clues to note. Examine the throat and neck for evidence of lymphadenopathy, paying close attention to any swelling or purulence in the back of the throat. Perform a careful examination of the abdomen, paying close attention to any organomegaly, especially swelling of liver or spleen. Consider genital or rectal examination if the patient has complaints of melanotic or bloody stool.

Laboratory Tests and Imaging

Have a low bar to obtain basic laboratory work in any febrile or ill-appearing patient with recent travel. Suggested laboratory tests include CBC, BMP, hepatic function panel, PT/PTT/INR, lactate, ESR/CRP, viral testing, and consideration of blood/urine cultures and serologies. Obtain a chest X-ray and consider escalation to computed tomography of the abdomen, especially with abdominal tenderness or hepatosplenomegaly. For travelers to countries with high prevalence of malaria, obtain rapid malaria testing and blood smears. Consider stool testing for ova/parasites for concerns of diarrhea and/or bloody stools. For any endorsed high-risk sexual practices, obtain testing for gonorrhea, chlamydia, syphilis, and HIV.

Work-up and Management

The most important first step is to establish a timeline of patient symptoms and where exactly they traveled and any high-risk activities or exposures. Review the Centers for Disease Control and Prevention website for information on high-risk infectious diseases in that area and correlate with the patient presentation based on history and physical exam. Use basic laboratory tests and any imaging to narrow the differentials. Obtain additional laboratory work and disease-specific diagnostic tests as indicated and described earlier, such as Lyme serology, yellow fever, malaria, etc. Escalate evaluation with blood cultures, inflammatory markers, and additional testing based on the patient's history and exposures, such as serologic testing for zoonotic tick-borne illnesses, possible hepatitis etiologies, and following imaging results accordingly.

If there is concern for transmissible diseases, promptly isolate patients as quickly as possible. If the patient has recently visited endemic areas for dengue or malaria, obtain thick and thin blood smears, and consider ACT or artusinate for severe malaria. Consider empiric antibiotics in ill-appearing patients with fever to cover for rickettsial infections, for which you can use doxycycline or azithromycin. If a rash is present, consider etiologies such as dengue, Zika, HIV, measles, and rickettsia. With a fever of more than seven days duration, consider enteric fever and treatment with ceftriaxone. If jaundice is present, obtain acute viral serologies, and evaluate for possible biliary pathology. If there is clinical concern for enteric fever, blood cultures and stool microscopy are indicated.

Common benign causes of fever or diarrhea include simple traveler's diarrhea, giardia, and shigella, and usually are self-limiting. In cases of patient presentation with bloody diarrhea and anemia, obtain type and screen, consider transfusion, and obtain a stool culture. Provide rehydration with IV fluids, and administer additional antibiotic treatment with fluoroquinolones or macrolides.

For well-appearing and low-risk patients, outpatient management may be appropriate. Admit ill-appearing patients, those with significant laboratory abnormalities, patients with concerns for poor follow-up, those who require expedited evaluation by an infectious disease specialist or respiratory isolation. For critical patients with altered mentation and unstable vitals, consider ICU admission. Report confirmed cases of infectious diseases to the local public health department and adhere to any advice and recommendations given by the institution’s infectious disease expert. Use the quick Sequential Organ Failure Assessment (qSOFA) scoring to help guide disposition decisions, with qSOFA score of 2 or greater warranting ICU-level care.13

Disposition

For well-appearing patients with no significant risk factors, consider discharge with outpatient follow-up and possible antibiotic management. For patients with poor follow-up, or concerning findings on labs, vitals, or those that would benefit from expedited follow-up with infectious disease for undifferentiated disease and/or needing respiratory isolation, tend towards admission. For critical-appearing patients, unstable vitals, or significantly depressed GCS, tend towards critical care admission.41

Summary

Using a systematic approach and workup for the development of new fever and illness in the returned traveler in the emergency department can lead to better outcomes for patients and communities. Start with a strong foundation in a focused history and physical exam and compare where the patient traveled and their symptoms to the CDC's recommendations for workup and most common diseases. Have a low threshold to obtain basic laboratory testing, basic serologies for infections such as malaria and dengue, and consider consultation with the local public health authority and infectious disease specialist. Any patient who needs a more expeditious workup or close follow-up, or is in critical condition should have a broadened workup, and the clinician should tend toward inpatient admission. Through a systematic approach, ED clinicians can improve workups for patients and improve health outcomes. Patients also can follow up with an infectious disease specialist prior to any exotic travel for prophylactic vaccinations, immunizations, and red-flag symptoms.13,15

Evan R. Miller, DO, Wright-Patterson AFB/Wright State University Emergency Medicine Resident - PGY2, Dayton, OH

Matthew D. Oram, MD, Clinical Assistant Professor, Emergency Medicine, Boonshoft School of Medicine, Wright State University, Dayton, OH

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