Mosquito-Borne Diseases in the 21st Century
May 1, 2024 42 minutes read
There is no doubt that the 21st century has ushered in unexpected challenges, from the COVID-19 pandemic that isolated most of us, to readily available options for global travel that can expose individuals to different places, cultures, and health risks. Migration and population displacement also contribute to the changing demographic and epidemiologic landscape of the United States. Mosquito-borne pathogens are of specific concern, causing millions of illnesses and hundreds of thousands of deaths across the globe each year. Climate change has altered and expanded the geographical distribution for key vectors of travel-related and mosquito-borne illnesses, making some of these diseases endemic to areas where they were absent in the recent past. Therefore, it is imperative that practitioners become familiar with travel-related and global illnesses, their geographical prevalence, current epidemiologic trends, clinical presentations, and management. Many of these diseases have reporting requirements, so clinicians must have knowledge of their reporting responsibilities and local processes for such reporting.
Introduction
Hundreds of millions of people across the globe are affected by mosquito-borne diseases each year, and travelers who do not exercise caution and take preventive measures, such as using protective clothing, using mosquito nets, and applying insect repellent, are at especially high risk. Mosquito-borne diseases are found mostly in tropical and subtropical destinations, ranging from America to Africa and Asia. However, urbanization, global travel, climate change, and human population growth have increased the potential for mosquitoes to proliferate, expand their geographic range, and cause disease on a much wider scale. Chikungunya virus, dengue, filariasis, Japanese encephalitis virus, malaria, West Nile virus, yellow fever, and Zika virus are particular sources of concern for travelers venturing into regions where these vectors abound. This article will focus on these mosquito-borne illnesses, especially the flaviviruses. The last section provides a table with other relevant travel-related infections.
Evolving Geographic Distributions and Demographics Due to Weather and Climate Changes
Climate change has emerged as a critical factor shaping the landscape of health challenges. The climate plays a vital role in the seasonal pattern and temporal distribution of diseases transmitted through arthropod vectors. As our planet experiences changes in precipitation and temperature, the habitats, behavior, reproduction, and distribution of disease-carrying mosquitoes are evolving as well.1
Rising global temperatures and extreme weather events could expand the range of disease-causing mosquitoes and lead to an increased incidence of diseases such as dengue, chikungunya, malaria, Zika, and yellow fever. As mosquito ranges evolve, these tropical and subtropical diseases could spread toward the poles and affect large swathes of Europe, America, Africa, and Asia.
Some diseases, such as malaria, already had their geographic ranges expand in the last century. Locally acquired malaria cases were diagnosed in the United States. The Centers for Disease Control and Prevention (CDC) issued a Health Alert Network Health Update in the summer of 2023 after locally acquired malaria cases were identified in Florida (seven cases, Plasmodium vivax), Texas (one case, Plasmodium vivax), and Maryland (one case, Plasmodium falciparum). Before these cases, local transmission of malaria was not documented in the United States since 2003. While the overall risk for malaria transmission in the United States is exceedingly low, Anopheles mosquitoes are widespread in the United States and are capable of transmitting malaria. Furthermore, the CDC reports that locally acquired dengue cases were documented in Florida and California in 2023. Local, non-travel-related cases of dengue infection are rare and sporadic in the United States.
However, local transmission of dengue has been documented in Florida, Hawaii, Texas, California, and Arizona since 2000, and the Aedes mosquitoes that transmit dengue are found throughout the United States. This highlights the importance of early diagnosis and treatment of travel-related infections, both to prevent severe disease and to reduce the risk of local transmission.
Unfortunately, unless something is done on a global scale, studies estimate that mosquito-borne diseases such as Zika could threaten an additional 1.3 billion people by 2050, and that dengue fever will affect more than 60% of the world’s population by 2080.2,3 There is a major concern that expansion of mosquito habitats to higher altitudes and latitudes could make these tropical diseases commonplace in what are now thought of as temperate climates.
Given the rising global temperatures and the ever-expanding threat of mosquito-borne diseases, it is imperative that clinicians stay up to date with the diagnosis, management, and prevention of these critical travel-related illnesses. Clinicians should have a high index of suspicion for mosquito-borne pathogens when evaluating patients with travel history to endemic areas, especially when patients have unexplained fever, rash, or arthralgia.
Epidemiology
Travel-related illness is a common occurrence in today’s society. Health issues are self-reported in as many as 43% to 79% of travelers to low- and middle-income countries.4 However, most of these health problems are not exotic and are instead mild, self-limited, and cosmopolitan in nature. Still, up to 8% of travelers to the developing world (more than 4 million people) seek medical care during or after travel.5
These illnesses encompass a wide spectrum of diseases and health conditions that can affect travelers during or after their trips. Exposure to infectious agents, environmental factors, or even preexisting medical conditions can be exacerbated by travel. The epidemiology of travel-related illnesses is influenced by various factors, including the destination, traveler demographics, travel duration and type, vaccination history, chemoprophylaxis (and its compliance), and the time of year.
Infections associated with travel are transmitted most frequently via enteral, respiratory, vector-borne, and/or sexual exposures.5 These travel-related infections can be caused by viruses, bacteria, and various parasites. Patients with travel-associated infections most commonly present with gastrointestinal complaints, fever, and dermatologic complaints.6 However, more serious infections can result in encephalitis, hemorrhagic complications, respiratory complaints, and death.
The geographic region of travel, specific travel activities (camping, sexual activity, new tattoos), exposures (insect bites, animal encounters, food/water ingestion), and living situation (sleeping arrangements, mosquito nets, air conditioning, water purification, etc.) all are important factors to consider when assessing risk for travel-related illness.4 Clinicians must be especially cognizant of potentially severe, transmissible infections (e.g., Ebola and Middle East respiratory syndrome [MERS]) that require enhanced infection-control measures and high levels of care.
Mosquito-borne diseases are an exceptionally important subgroup of travel-related illnesses. These diseases are spread by the bite of an infected mosquito and are responsible for significant morbidity and mortality.
Initial Evaluation
When evaluating a returning traveler with a potential travel-related illness, a systematic approach is crucial. A thorough history should be conducted to gather information about the patient’s trip, including the destination, duration of stay, and activities undertaken. Specific attention should be paid to potential exposures, such as consuming local foods and beverages, insect bites, sexual encounters, and animal contact.4
Risk factors for travel-related illnesses vary depending on the destination and the traveler’s individual characteristics. Immunization status, underlying medical conditions, and prescription medications all can affect susceptibility to specific diseases. Age, pregnancy, and immune status also should be considered when assessing risk for illness and transmission.
Most travel-related infections have short incubation periods, and the majority of returning travelers seek medical care for their symptoms within one month of travel. However, some travel-related diseases, such as leishmaniasis, malaria, schistosomiasis, tuberculosis, and human immunodeficiency virus (HIV), may manifest weeks to months after a traveler returns.7
After obtaining a complete history, paying particular attention to the risk factors discussed earlier, a thorough physical examination should be performed. Clinicians initially should assess the patient for hemodynamic instability, respiratory distress, hemorrhagic manifestations, and any abnormal neurologic findings.
During the exam, physicians should inspect for hepatosplenomegaly, genital lesions, lymphadenopathy, rashes, and any ocular changes. Clinicians also should pay particular attention to the skin examination, evaluating for rashes, jaundice, and the presence of any insect/tick bites.
Diagnostic Workup
The diagnostic workup for travel-related illnesses may involve a range of laboratory tests, imaging studies, and consultations with infectious disease specialists. It is essential to maintain a high index of suspicion for tropical diseases, especially in patients presenting with fever, gastrointestinal symptoms, or skin lesions after recent travel to endemic areas. However, it is important to remember that most travel-related illnesses are cosmopolitan and common in nature, rather than rare and exotic diseases.7
In general, the diagnostic workup is guided by a thorough history and physical examination. The geographic region, risk factors, and potential diseases endemic to the region visited are especially important in narrowing the differential diagnosis.
Common diagnostic tests for travel-related illnesses are listed in Table 1.7
Table 1. Common Diagnostic Tests for Travel-Related Illnesses7 |
Laboratory Tests
Imaging Studies
Other
PCR: polymerase chain reaction; MRI: magnetic resonance imaging; EEG: electroencephalogram |
Consultation with specialists in infectious disease and in tropical medicine, when available, can be especially helpful when confronted with patients with signs and symptoms concerning for travel-related illness. These physicians have advanced training and expertise in travel-related diseases. They can help confirm the diagnosis, assist with management, and provide guidance on reporting and infection control measures for transmissible diseases. Critical care specialists and neurologists can be consulted as needed.
In the United States, the CDC has hotlines available for diagnostic or management assistance for select diseases (https://wwwnc.cdc.gov/travel/page/contact).
Specific Mosquito-Borne Diseases
Mosquito-borne diseases are a significant global concern with a profound impact on public health and socioeconomic development. These diseases are transmitted to humans through the bite of infected mosquitoes, which serve as vectors for a wide range of pathogens. Mosquito-borne illnesses manifest with varying degrees of severity, from mild flu-like symptoms like fever, rash, and arthralgia, to life-threatening conditions such as hemorrhage, renal failure, liver failure, neurologic dysfunction, and shock.7 Locally, effective vector-control programs and preventive measures have been essential in managing and mitigating the impact of these diseases. However, the ever-evolving nature of both mosquitoes and pathogens, along with factors like climate change and globalization, threaten to expand the normal distribution of these diseases and cause morbidity and mortality on a much wider scale.
This article will discuss a few of the more notorious diseases transmitted by mosquitoes in more detail. Specifically, this article will review chikungunya virus, dengue, filariasis, malaria, West Nile virus, yellow fever, and Zika virus. These are relatively common illnesses, and it is crucial that clinicians consider these diseases when they encounter symptomatic patients who traveled to endemic areas.
Chikungunya Virus
Epidemiology
Chikungunya virus (CHIKV) emerged in the Americas in 2013 with the first outbreak in the Caribbean. Prior to this, it occurred primarily in Africa, Southeast Asia, Indian and Pacific Islands, and southern Europe. CHIKV now has been identified in more than 110 countries.8
CHIKV is a single-stranded ribonucleic acid (ssRNA) alphavirus of the family Togaviridae that is transmitted to humans by the mosquito vectors Aedes aegypti and Aedes albopictus. Both are widely distributed, adapted to urban environments, and active in the daytime.4 Vertical transmission from mother to fetus also has been described, which can result in neonatal chikungunya. This risk is highest when mothers are symptomatic at the time of delivery.1 While overall case fatality rates of chikungunya are low, a significant proportion of patients develop chronic manifestations, which contribute to its morbidity.9
Pathophysiology
CHIKV travels to the lymph nodes after inoculation. Viremia occurs with circulation in blood and lymphatics, with infected monocyte-derived macrophages transporting CHIKV into target organs. These include the muscles, joints, liver, and brain. While acute disease arises from CD8+, CD4+ T-cells, and cytokine response, infected monocytes may persist in the joints, leading to all the chronic manifestations of the disease.10
Clinical Features
Asymptomatic infection occurs in approximately 3% to 28% of cases. An incubation period of three to seven days is typical before disease onset. The most common symptoms include the sudden onset of high fever and severe arthralgias. Headache, nausea, vomiting, myalgias, conjunctivitis, and occasionally anterior uveitis also may occur.
Patients also can develop a maculopapular rash, which may involve the trunk and extremities, but occasionally also includes the palms, soles, and face. Myocarditis, hepatitis, and acute renal disease are rare but severe.11 CHIKV also can (less commonly) cause neuro-invasive disease, resulting in encephalitis, myelitis, and Guillain-Barré syndrome.12 Neonatal infections carry an increased risk of severe complications and high risk of poor neurologic outcomes.11
Diagnostic Studies
Diagnosis in the acute phase (within five days from symptom onset) is best achieved by detecting viral RNA with reverse transcriptase polymerase chain reaction (RT-PCR). Serology (enzyme-linked immunoassay [ELISA] or indirect fluorescent antibody test [IFA]) may detect anti-CHIKV immunoglobulin M (IgM) and may be used up to several weeks post infection. Immunoglobulin G (IgG) may be detected after several weeks, up to years, following infection.
Because of the similarities in presentation, identical vector, and risks of exposure with dengue and Zika viruses, concomitant testing is warranted in all suspected cases.10
Management/Prevention
Mainstays of prevention include mosquito avoidance. In November 2023, the U.S. Food and Drug Administration (FDA) approved the first-ever vaccine against CHIKV, Ixchiq (Valneva), under its accelerated approval pathway. Although reportedly effective in inducing neutralizing antibodies in trial patients, currently there are no direct data on human clinical effectiveness.13
There is no directed treatment for chikungunya. Rest and hydration are recommended. Symptomatic therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) can be used; however, dengue infection should be ruled out prior to their use because of the potential risk of hemorrhage. Acetaminophen is an alternative for fever and arthralgias. Chronically, NSAIDs, corticosteroids, and physical therapy may assist with chronic/relapsing joint pain, which can be quite debilitating.11
Complications/Controversies
Most patients with typical symptoms recover within seven to 10 days from acute disease. Significant morbidity arises from relapsing rheumatologic complications, including polyarthritis, tenosynovitis, fatigue, retinitis, optic neuritis, and other ocular inflammation syndromes, which can occur for months following the acute infection. These can be chronic, debilitating, and difficult to treat.10
Disposition
Most patients with chikungunya can be managed as outpatients. Admission may be warranted in special populations, including infants, the elderly, the immunocompromised, and patients with comorbidities (such as hypertension, diabetes, and cardiovascular disease), or in patients with severe, organ-threatening manifestations.
Dengue Virus
Epidemiology
Dengue viruses were first isolated in the 1940s and have since been found widespread in tropical and subtropical regions around the world.14 Dengue is the world’s most common human vector-borne viral disease. The World Health Organization (WHO) estimates around 400 million infections occur annually, with 100 million annual cases of symptomatic dengue. Globally, the incidence has increased from around 500,000 to more than 5 million cases reported to WHO from 2000 to 2019.1 Imported cases have been seen in all states and are most concentrated in population centers like New York, New Jersey, Florida, California, and Texas.15
There are four serotypes of the dengue virus (DENV 1-4). They are flaviviruses, which are transmitted by the mosquito vector sp. Aedes aegypti (and A. albopictus). The vector is present in urban and residential contexts, placing an estimated half of the world’s population at risk.16,17 Transmission to humans occurs during a blood meal of the infected female mosquito. Subsequently, viremic humans perpetuate the cycle when fed upon by a mosquito. Vertical transmission from mother to fetus also can occur.17
Pathophysiology
Although not clearly defined, several cell types, including Langerhans cells, dendritic cells, mast cells, and fibroblasts, have been proposed as early targets for infection. The dissemination of infection is not fully understood but is thought to occur via lymph nodes, then through peripheral leukocytes to lymphoid tissues, and ultimately to multiple organs.18 Recovery from dengue infection confers long-lasting serotype-specific immunity.
The phenomenon of antibody-dependent enhancement (ADE) appears to contribute to an elevated risk of severe dengue in secondary infections, particularly with different viral serotypes. With ADE, non-neutralizing antibodies complex with virions of a subsequent serotype to enhance uptake and infection of monocytes and macrophages causes increases in cytokine production and manifestation of severe disease.19
Clinical Features
While most infections are asymptomatic, typical symptoms of the initial febrile phase last two to seven days and include high fever, severe headache, retro-ocular pain, nausea, vomiting, adenopathy, and rash. Severe pain of the bones, muscles, and joints may be present, and is responsible for the “breakbone fever” characteristic description of dengue. The critical phase begins after defervescence and lasts for 24-48 hours. Patients either begin to recover or progress to severe dengue. Increased vascular permeability during this phase can cause significant plasma leakage, resulting in peripheral edema, ascites, or pleural effusion. A rising hematocrit signals intravascular hemoconcentration. Patients may progress to refractory shock, despite resuscitative efforts, with thrombocytopenia, leukopenia, transaminitis, and hyponatremia.
Patients can develop hemorrhage and multi-organ dysfunction. Myocarditis also has been reported in up to 15% of cases of dengue.20 The convalescent phase begins as plasma leakage subsides, blood counts recover, and third-spaced fluids are reabsorbed.21
The 2009 WHO classification can be used to gauge severity of disease. Dengue Without Warning Signs is defined as the presence of at least two of the following: nausea, vomiting, headache/retro-orbital pain, myalgia/arthralgia, petechiae (positive tourniquet test), and leukopenia. Dengue With Warning Signs includes abdominal pain, persistent vomiting, clinical fluid accumulation, mucosal bleeding, lethargy/restlessness, postural hypotension, hepatomegaly, and rapidly falling platelets or rising hematocrit. Severe Dengue includes: 1) shock or respiratory distress due to severe plasma leakage; 2) severe bleeding (hemorrhagic fever); or 3) severe organ involvement, including liver, central nervous system (CNS), cardiac, or other system.21 According to CDC data, approximately 2% of dengue cases reported in the United States and its territories from 2010-2020 were classified as “severe.”
Diagnostic Studies
Dengue patients will have leukopenia and low platelet counts. Additional testing should include complete blood count (CBC), serum electrolyte, bicarbonate, lactic acid, glucose, renal function, and liver function testing at the time of presentation to establish baseline and identify warning signs or severe cases.
Chest radiography, electrocardiography, and cardiac enzymes can help identify cardiomyopathy and pulmonary edema.22 Point-of-care ultrasound also may be used to help predict progression to severe disease. Pleural effusions, significant pulmonary B-lines, ascites, and pericardial effusion may suggest plasma leakage.23 Gallbladder wall thickening has been shown to be an early predictor of progression to severe disease.24
Nucleic acid amplification tests (NAATs) are preferred to confirm the diagnosis of dengue in serum or cerebrospinal fluid (CSF) specimens collected seven days or less from the onset of symptoms. Immunoassays to detect viral nonstructural protein 1 (NS1) also are available. IgM ELISA testing is most useful for diagnosis more than one week from onset. IgG ELISA is not useful for acute diagnosis.22 Rapid antigen tests for dengue NS1 are used in some contexts but have not been approved by the FDA for use in the United States.
Management/Prevention
Mosquito avoidance and vector control remain key to preventing infection and the spread of dengue. Currently, one vaccine, Dengvaxia or CYD-TDV, has been approved by the FDA. It is indicated for children ages 9-16 years living in dengue-endemic areas of the United States (including U.S. territories) and who have serologically proven prior primary dengue immunity.
This is unlike other vaccines as this one requires the patient to have a prior infection with some existing immunity. It is not approved for travelers, since it can increase the risk of severe dengue in persons without prior dengue infection.21
There are no specific treatments for dengue. Cornerstones include hydration, rest, and acetaminophen for fever and pain. Potentially anticoagulating drugs, such as aspirin or NSAIDs, should be avoided.21 Patients with severe dengue and shock are managed with intravenous (IV) fluid resuscitation using isotonic crystalloids or colloids for refractory shock. Blood transfusion is indicated in cases of life-threatening hemorrhage. However, transfusion of platelets is reserved only for those with active hemorrhage and severe thrombocytopenia.25 All these severe cases should receive management in consultation with infectious disease specialists, when available.26
Complications/Controversies
In 2016, a massive vaccination program with Dengvaxia was initiated in the Philippines. An estimated 800,000 children received the vaccine. Up to 10% (80,000) of these children who never had prior infection with dengue thus were placed at increased risk of severe dengue. Multiple subsequent deaths were attributed to exposure to Dengvaxia, leading to a backlash in the form of vaccine hesitancy and public mistrust.27 Subsequent approvals of Dengvaxia by the FDA and in other nations specify its indication only for those with proven prior dengue infection.
Disposition
Patients with dengue who lack relevant coexisting conditions can be managed as outpatients in the absence of WHO-defined warning signs. These conditions include pregnancy, age extremes, diabetes, renal failure, obesity, hemolytic disease, or any concerning social situation. Prior to discharge, patients should tolerate oral fluids, urinate within six hours, and have normal or near normal blood counts and liver function tests. Discharged patients should have a clear plan for close follow-up. The WHO recommends daily evaluations by a healthcare provider during the critical phase. The evaluation includes assessment for development of warning signs, including measurements of hematocrit, platelets, and white blood cell counts. All other patients, or any patient with evidence of warning signs or severe dengue, should be hospitalized, with severe cases often requiring intensive care.26
Malaria
Epidemiology
According to the WHO, there were an estimated 247 million global cases of malaria in 2021, and an estimated 619,000 deaths. As of 2022, the WHO lists 84 malaria-endemic countries, with sub-Saharan Africa bearing the overwhelming burden of disease and death.28
Etiology/Pathophysiology
Malarial disease is caused by blood parasites of the genus Plasmodium. There are four species that primarily infect humans: P. falciparum, P. vivax, P. ovale, and P. malariae. A key differentiating feature of the P. vivax and P. ovale life cycle is the formation of the dormant hypnozoite stage, which can persist in liver tissue, with the ability to cause relapses in bloodstream disease long after the initial infection.29 A fifth species, P. knowlesi, primarily is a simian parasite in macaque monkeys found across Southeast Asia, which also can infect and has the potential to cause life-threatening disease in humans.
Infected female Anopheles mosquitoes transmit sporozoites of the Plasmodium parasite to a human host during a blood meal. These circulate to the liver, where they invade hepatocytes and develop into schizonts, containing a mass of merozoites. Upon rupture, these enter the bloodstream where they infect erythrocytes. In this erythrocytic phase, the parasite then forms the trophozoite phase, where it initially undergoes asexual multiplication forming erythrocytic schizonts. The erythrocyte is ultimately lysed and releases a mass of new merozoites, which go on to re-infect more blood cells.29
The lysis of infected erythrocytes releases antigens and provokes a response from host macrophages and cytokines. This corresponds to the febrile response that is characteristic of malaria. Erythrocyte lysis also results in hemolytic anemia. In P. falciparum infections, changes to the structure of infected erythrocytes can lead to sequestration of infected cells in venules and capillary beds. This obstructs microcirculation, resulting in end organ damage. This is the major cause of malaria’s most severe clinical manifestations, including cerebral malaria. Immunologic phenomena can cause further systemic complications, such as glomerulonephritis and thrombocytopenia.
Clinical Features
Malaria can be broadly differentiated into uncomplicated vs. severe disease. The initial presentation of malaria is nonspecific and includes malaise, headache, myalgia, and fever with chills. Tachycardia, tachypnea, cough, nausea, vomiting, diarrhea, abdominal pain, and diaphoresis also are common. As the disease progresses, recurrent febrile paroxysms occur, which are characterized by chills and fever with fatigue lasting several hours, then abating. These can develop periodicity of approximately 48-hour cycles in P. falciparum, P. vivax, and P. ovale infections, and 72-hour periods with P. malariae. This cycle corresponds to synchronization of schizont rupture and merozoite release from erythrocytes. Patients have uncomplicated malaria when presenting with signs and symptoms of malaria and a positive parasitological test (microscopy or rapid diagnostic test), but without any features of severe malaria.30 (See Table 2.)
Severe malaria is defined as presenting with one or more severe features (see Table 2) in the presence of P. falciparum (or P. vivax or P. knowlesi) and without an alternative cause.30 Severe malaria is considered a medical emergency. It is associated with increased mortality, although the magnitude of the increase is variable, depending on specifics of the infection (e.g., parasite load), host factors (e.g., age, comorbidities, pregnancy, immunity), context (e.g., access to referral, high-level intensive care unit [ICU]), and the treatment (e.g., timing and availability of effective drugs).31
Table 2. Severe Malaria — WHO Guidelines — October 2023 |
|
Clinical Manifestation |
Definition |
Impaired level of consciousness |
Glasgow Coma Scale score < 11 (adult); Blantyre coma score < 5 (pediatric); inability to swallow |
Prostration |
Generalized weakness so that the person is unable to sit, stand, or walk without assistance |
Multiple convulsions |
More than two episodes within 24 hours |
Acidosis |
Base deficit of > 8 mEq/L or, if not available, plasma bicarbonate level of < 15 mmol/L or venous plasma lactate ≥ 5 mmol/L. Severe acidosis manifests clinically as respiratory distress (rapid, deep, labored breathing). |
Hypoglycemia |
Blood or plasma glucose < 40 mg/dL (< 2.2 mmol/L) for children ≥ 5 years and adults; glucose < 54 mg/dL (< 3 mmol/L) for children < 5 years |
Severe malarial anemia |
Hemoglobin ≤ 5 g/dL or hematocrit ≤ 15% in children < 12 years (< 7 g/dL and < 20%, respectively, in adults) with parasite count of > 10,000 parasites/µL. |
Renal impairment |
Plasma or serum creatinine > 3 mg/dL (265 µmol/L) or blood urea > 20 mmol/L |
Jaundice |
Plasma or serum bilirubin > 50 µmol/L (3 mg/dL) plus one of the following:
|
Pulmonary edema |
Radiographically confirmed or oxygen saturation < 92% on room air, with respiratory rate > 30/min, often with chest indrawing or crepitation on auscultation |
Significant bleeding |
Including recurrent or prolonged bleeding (from nose, gums, or venipuncture sites), hematemesis, or melena |
Shock |
Compensated shock, defined as capillary refill ≥ 3 seconds or temperature gradient (mid to proximal limb), but no hypotension. Decompensated shock, defined as systolic blood pressure < 70 mmHg in children or < 80 mmHg in adults with evidence of impaired perfusion (cool peripheries) or prolonged capillary refill |
Hyperparasitemia |
P. falciparum:
P. knowlesi:
P. vivax:
|
Adapted from: World Health Organization. WHO Guidelines for malaria. Oct. 16, 2023. https://www.who.int/publications/i/item/guidelines-for-malaria |
|
Diagnostic Studies
Parasitological diagnosis of malaria is important to avoid overtreatment, given the nonspecific signs and symptoms.30 Malaria should be suspected in any patient with an acute febrile illness and relevant exposure to an endemic region.32 The WHO recommends that in all settings, suspected malaria should be confirmed with a parasitological test, if possible. However, in patients with suspected severe malaria or other high-risk groups (such as HIV/acquired immunodeficiency syndrome [AIDS]), lack of or delay in testing should not delay antimalarial treatment.30
Light microscopy of thick and thin blood smears is considered the field standard, although in practice its accuracy is dependent on the skill of the microscopist. It is relatively resource- and infrastructure-intensive to maintain highly skilled technicians, as well as the materials and equipment required for microscopy diagnosis. In addition to diagnosing malaria, microscopy has the advantages of allowing for quantification of parasite density and speciation. Rapid diagnostic tests (RDTs) use immuno-chromatography for the detection of parasite-specific antigens. They have the key advantages of ease of use with limited training and limited infrastructure required.30 However, the sensitivity and specificity of RDTs are somewhat less than those of microscopy.33
Additional testing helps define severity in malaria. CBCs, plasma glucose, liver function (bilirubin and transaminases), and renal function (creatinine and blood urea nitrogen) are recommended. Acidosis may be gauged by serum bicarbonate, blood gas, and lactic acid levels. Thrombocytopenia is another important finding, particularly in P. vivax infections.30
Management/Prevention
Travelers from non-malaria-endemic regions should employ protective measures to avoid infection. Mosquito bite prevention is cornerstone, involving avoiding exposure outdoors between dusk and dawn, covering exposed skin, sleeping with bed netting treated with insecticide (such as permethrin), and sleeping in screened or air-conditioned rooms. Use of an approved insect repellent also is effective, and products containing N,N-diethyl-3-methylbenzamide (DEET) are considered the gold standard.34
The CDC “Yellow Book” is an excellent publication, available online, compiling country and region-specific guidelines. It should be reviewed in advance of travel to provide updated guidance. Chemoprophylaxis regimens vary by patient, exposure, and itinerary. Most common choices include either atovaquone-proguanil, doxycycline, or mefloquine.35 Tafenoquine is another option but requires testing for glucose-6-phosphate dehydrogenase (G6PD) deficiency prior to use.36 Chloroquine should be used only in regions without documented resistance.35
In 2021, the WHO approved the use of a P. falciparum malaria vaccine, RTS,S/AS01 (Mosquirix), for children in sub-Saharan Africa in areas of high transmission.37 A primary series with booster was found to be 39% effective against clinical malaria and 29% effective against severe malaria in follow-up phase. Long-term follow-up has shown decreasing efficacy with time.38 More recently, in October 2023, a second vaccine against P. falciparum malaria, R21/Matrix-M, was approved by the WHO.39 A Phase IIb trial suggested efficacy against clinical malaria in the treatment groups of > 70% at one-year follow-up.40
First-line therapies for uncomplicated P. falciparum malaria, or with species not identified, include oral artemisinin-containing combination therapies (ACT), typically for a three-day course. In the United States, artemether-lumefantrine (Coartem, four tablets PO at 0 and 8 hours) is the drug of choice. Atovaquone-proguanil (Malarone, four tablets PO qd) is an alternative but should not be used if the patient had prior exposure to the drug as chemoprophylaxis. Both of the previously mentioned medications are available at fixed-dose weight-based regimens for adult and pediatric patients. Pregnant women are at increased risk for severe disease in the mother and with fetal complications. In pregnancy, uncomplicated P. falciparum malaria should be treated with ACT (artemether-lumefantrine), mefloquine, or quinine sulfate plus clindamycin. Additional treatment regimens for both adult and pediatric patients are available on the CDC website and can be used in consultation with an infectious disease specialist.41
All patients with severe malaria (see Table 2) should be treated rapidly with parenteral antimalarials, regardless of species of parasite. IV artesunate (2.4 mg/kg at 0, 12, and 24 hours) is the drug of choice for adults and pediatric patients. Serial thin blood smears should be obtained at 24 hours. Additional doses depend on the patient’s clinical condition and on the parasite’s density found on the thin smear.41
Disposition
If parasite speciation by microscopy is not readily available, consider the possibility of P. falciparum malaria in any patient with possible exposure. Patients with confirmed or suspected P. falciparum or P. knowlesi, or any patient in whom the Plasmodium species has not yet been identified, should be admitted to the hospital, since severe disease can develop quickly, even after the initiation of therapy. Those with uncomplicated malaria due to P. vivax, P. malariae, or P. ovale who tolerate oral medications may be managed as outpatients if they have close follow-up and the ability to access additional care as needed. All patients with severe malaria (see Table 2) should be admitted, preferably to an intensive care unit.41
West Nile Virus
Epidemiology
West Nile virus (WNV) holds the crown as the “most widely distributed arbovirus in the world.”42 It was first isolated in the West Nile district of Uganda in 1937 and since has caused multiple outbreaks globally. The initial epidemics were in the Middle East and Mediterranean during the 1950s and 1960s.42,43
WNV reached the United States in 1999, with New York as the site of the first case. Since then, the virus has circulated throughout the Americas. The disease has been reported throughout the mainland United States. WNV is seen primarily in the summer and early autumn; however, cases have been documented year-round. In the United States, the Mountain, West Central, and Central Plains states experience the highest incidence of cases.42,43
Pathophysiology
Originating from the Flavivirus genus, WNV is transmitted to humans by the Culex species of mosquitoes. Mosquitoes and birds serve as vectors and hosts, respectively, in an enzootic cycle. Human transmission occurs when a mosquito vector exits the cycle and infects humans and other vertebrates.42,44 The virus is transmitted through saliva. After transmission, the virus uses multiple phases to infect the host. Keratinocytes and dermal dendritic cells provide the environment for viral replication initially. This is followed by the visceral-organ dissemination phase, in which the viral replication occurs in lymph nodes and ultimately spreads to various organs. The most severe complication of WNV is due to neuro-invasive disease. There are several hypotheses as to how the virus crosses the blood-brain barrier, including traversing disrupted cells directly, transporting across the blood-brain barrier via infected macrophages, and axonal retrograde transport.45,46
Clinical Features
The majority of humans infected by WNV do not develop any symptoms. There is a spectrum of clinical manifestations in the approximately 20% of people who exhibit symptoms. The most common symptoms include fever, headache, myalgias, and nausea and vomiting. Individuals also may develop a morbilliform, non-pruritic rash over the torso and extremities.47 Severe illness and poorer outcomes are more common in the elderly and in immunocompromised populations.47
The most severe consequence of WNV is the spread to the CNS, which occurs in less than 1% of infected people. This neuro-invasive form is characterized by meningitis, encephalitis, and a polio-like syndrome. Meningitis, most seen in the younger population, is characterized by the classic symptoms of severe headache and nuchal rigidity. This generally is associated with full recovery. WNV encephalitis generally affects adults older than the age of 55 years and immunocompromised individuals. Patients can exhibit upper extremity tremors and cerebellar ataxia. On magnetic resonance imaging (MRI), there are foci of hyperintense signal at the brainstem and thalamus.48 Extrapyramidal symptoms also can be present. Polio-like paralysis develops within the first one to three days of symptom onset and can first present as an asymmetric paralysis.47
Diagnostic Studies
Standard workup may include a CBC, liver enzyme testing, and an electrolyte panel in patients with nonspecific symptoms. If CNS findings are present, neuroimaging with computed tomography (CT, if available) and a lumbar puncture should be performed. Definitive diagnosis is made through detection of serum and/or CSF antibodies. IgG antibody sero-conversion, IgM antibody ELISA testing, and viral RT-PCR tests are commercially available.43,49
Management/Prevention
While vaccines against WNV exist for animals, there are none available for humans. Thus, heightened awareness during high transmission months and mosquito bite prevention remain the mainstays. Mosquito netting, mosquito repellent, avoiding still, low-lying areas of water, and wearing light-colored clothing can help. On a community level, vector control measures are advised.43
Since there is no specific treatment for WNV, supportive care remains the mainstay treatment for patients with WNV. Many patients will require only symptomatic control and may not require admission to the hospital. Admission should be considered for high-risk individuals at risk for worsening symptoms. Individuals with CNS involvement (neuro-invasive disease) should be admitted to the hospital for ongoing care and observation for the development of bulbar symptoms and respiratory failure. Studies of long-term outcomes of patients exhibiting signs of a post-polio-type syndrome from WNV also are pending.
Disposition
Disposition depends on the patient’s clinical status. Those with easily reversible electrolyte derangements from dehydration and non-intractable headaches can be safely discharged home with strict return precautions. Any patients exhibiting signs of neuro-invasive disease need admission and monitoring for signs of clinical worsening (such as flaccid paralysis, ventilatory failure, coma, etc.).
Yellow Fever
Epidemiology
A viral hemorrhagic fever, yellow fever (YF) is yet another mosquito-borne illness that is endemic to sub-Saharan Africa and tropical areas of South America.50 Worldwide, it results in 200,000 infected patients and 30,000 deaths. Several species of mosquitoes (A. hemagogus) are responsible for transmission to humans. Like WNV, the YF virus also is of the genus Flavivirus and is maintained in an enzootic cycle among monkeys. While the last documented case in the United States was at the beginning of the 20th century, physicians should maintain a high index of suspicion for the disease in returning travelers. In the Western Hemisphere in 2023, there have been five cases of yellow fever reported: two in Bolivia and three in Brazil.
Virus transmission is seasonal, with peak incidence during the rainy season (January to May) in South America, and at the end of the rainy season (July to October) in East and West Africa. The CDC notes the estimated risk of contracting the illness for an unvaccinated traveler in West Africa is 50 in 100,000 and five in 100,000 in South America.50
Pathophysiology
The YF virus replicates in the lymph nodes nearest the site of the blood meal. After the virus reaches the bloodstream, it is transported to various organs. YF has a proclivity for the liver, and the resulting jaundice gives it the name “yellow fever.” Cell death and subsequent cytokine release and storm is purported to be the mechanism of viral action.51,52
Clinical Features
More than 50% of infected patients will not develop symptoms of YF.53 For those individuals showing symptoms, the initial presentation consists of constitutional symptoms, such as myalgias, fatigue, headache, nausea and vomiting, back pain, and fever.50 Patients may improve after the first few days of symptoms. For the approximately 12% of patients who progress to severe disease, systemic symptoms will recur within 48 hours of the initial “recovery.” These symptoms include oliguria, multi-organ failure, hepatitis, hemorrhage, disseminated intravascular coagulation, circulatory shock, and, in some cases, death.50
Diagnostic Studies
A few different options are available for diagnosis. RT-PCR tests can help identify YF in the early phases of RNA replication. Serology testing using ELISA to detect IgM antibodies can reveal a preliminary diagnosis. However, it is important to note that other flaviviruses may lead to false positives. A plaque reduction neutralization test can provide a confirmatory diagnosis but requires specialized equipment. Virus isolation by inoculation of cell cultures also can yield results, although it is important to note that viral RNA may not be detectable in the later stages of illness, and therefore cannot definitively rule out YF. Lastly, a liver biopsy can be performed; however, it is only for use in a postmortem exam, since biopsy during active illness is contraindicated due to the high risk of bleeding.50,54-56
Management/Prevention
There is no specific treatment for YF. Supportive care remains the mainstay for this illness. Care must be taken to avoid any medications or procedures that may increase the risk of bleeding.
The YF vaccine (YF-VAX) is an inexpensive and safe preventive measure. The vaccine, which has been available in the United States for more than 80 years, is recommended for all persons traveling into or through endemic areas. The YF vaccine is a live, attenuated vaccine and, therefore, is not recommended for immunocompromised patients or infants younger than 6 months of age. Of course, personal measures to avoid exposure to mosquitoes are always recommended.50
Disposition
If suspecting YF in a returning traveler, contact your hospital infection control and report the case to the local department of health. The patient should be admitted to the hospital and monitored closely for signs of worsening circulatory compromise and coagulopathy.
Zika Virus
Epidemiology
Zika virus (ZV) is a Flaviviridae first isolated from a rhesus monkey in Uganda in 1947. It was not until 2007 that ZV appeared outside of Africa and Asia. Today, it has been reported on every continent other than Antarctica.57,58 Since 2018, the CDC has not had any reported cases of ZV acquired locally within the United States.
Pathophysiology
The disease is transmitted from the Aedes mosquito to humans. The virus infects the epidermal keratinocytes, skin fibroblasts, and the Langerhans cells. The virus travels to further replicate in the lymph nodes, and subsequently is transported via the bloodstream to other organ systems.
Clinical Features
Much like with the other Flaviviridae, it is estimated that about 80% of individuals infected with ZV remain asymptomatic. Of those persons who are symptomatic, initial symptoms are nonspecific and include a low-grade fever, myalgias, and headache. A few differentiating features of ZV include a diffuse, erythematous rash that spreads from a cranial to caudal fashion. It often is accompanied by joint pain and edema.57
Progression to severe illness is quite rare, and most illnesses resolve over the course of several days to weeks.
Diagnostic Studies
Virus isolation remains the gold-standard diagnosis. However, like YF, the results are dependent on the phase of RNA replication and viremia. NAATs also can be performed on blood, urine, and semen samples.
Management/Prevention
The management is largely supportive, since most patients will recover from the acute illness. One of the differentiating features of ZV is its ability to be sexually transmitted. If an individual is planning a pregnancy or is pregnant, they should avoid traveling to areas where Zika transmission is occurring, if at all possible.59 In those with partners who have been diagnosed with ZV, it is recommended that they either use condoms or abstain from sexual intercourse for the duration of the pregnancy.
To date, there are no vaccines or specific antivirals for ZV. Therefore, preventive measures that focus on reductions to mosquito exposure should be taken.
Complications/Controversies
Congenital ZV is perhaps the most feared complication of the virus. ZV is one of the TORCH (toxoplasmosis/Toxoplasma gondii, other infections, rubella virus, cytomegalovirus, herpes simplex virus-2 or neonatal herpes simplex virus) infections; that is, the infections that cross the placenta and cause fetal loss or life-long morbidity in the neonates. Congenital ZV, also termed congenital Zika syndrome, has been diagnosed in up to 6.7% of children born to women with confirmed ZV infection.60 The syndrome is characterized by abnormal fetal neurological development, microcephaly, cerebral calcifications, ventriculomegaly, hypoplasia of the cerebellum and brainstem, and lissencephaly. Up to 70% of patients have ocular findings, such as chorioretinal and optic nerve abnormalities.61
Disposition
Most patients with ZV can be safely discharged home. Women of childbearing age who are planning on getting pregnant or are pregnant should be referred to OB/GYN for counseling. If they are caring for a patient with Zika, they should avoid coming into contact with any body fluids.
Filariasis
Etiology and Epidemiology
Filariasis is a group of diseases caused by microscopic thread-like round worms transmitted by biting insects, typically mosquitoes or flies. Residents of the United States are unfamiliar with human infestations, although many are familiar with canine infections caused by Dirofilaria immitis, the dog heartworm.62 Worldwide, filariasis exists in southern Asia, sub-Saharan Africa, the South Pacific, and in the tropical climes of South America.63 It is estimated that 60 million people worldwide are infected and 1 billion people live in areas with risk of transmission.64
Pathophysiology
The disease is spread from person to person by mosquito bites or bites from flies. An infected patient provides a blood meal, and the respective insect transmits the infection to another person. Typically, multiple bites are required over several months to develop lymphatic filariasis. The microscopic worms passed into the skin travel to the lymph vessels, where they grow into adults. It takes about six months for the adult worms to develop after a bite. The adult worms live in their host for five to seven years and mate, producing millions of microscopic worms, called microfilariae, which then are released into the bloodstream. Adult worms usually are found in lymphatic vessels or lymph nodes. The most common Filaria infection worldwide is caused by Wuchereria bancrofti.
Other pathogens include Brugia malayi and Brugia timori.63 Onchocerciasis is a filarial eye infection (loiasis) from Loa loa and causes loss of vision, known as “river blindness.” The infection does not involve the lymphatic system.65 Onchocerciasis will not be discussed here.
Clinical Features
Infection usually is silent, and most people will never develop clinical symptoms. If the lymphatic system is overwhelmed with filaria, it results in disfiguring and disabling disease with severe lymphedema. The lymphatic vessels become dysfunctional, resulting in limb swelling (elephantiasis) and, occasionally, swollen genitalia (hydrocele). The swollen limbs exhibit thick and pitted skin and can develop secondary infections.
Early stages may be accompanied by lymphangitis, lymphadenopathy, and eosinophilia. Chronic infections can cause a syndrome of pulmonary eosinophilia with eosinophilic pulmonary infiltrates, wheezing, dyspnea, chest pain, bloody sputum, and peripheral eosinophilia.63
Diagnostic Studies
The diagnosis is confirmed by finding the microfilaria in a peripheral blood smear stained with Giemsa or H&E. The worms have a nocturnal periodicity, and the best specimens for diagnosis are obtained at night.
The diagnosis also is made by identifying the filaria in lymphatic tissue when a lymph node biopsy is performed due to lymphadenopathy. Antigen detection using an immunoassay exists and is useful in the field, but it is not available in the United States. The best imaging modality is ultrasound, since it is possible to detect moving adult worms in lymphatic vessels, known as the “filarial dance sign.”64,66
Management/Prevention
Prevention requires reduced exposure to biting mosquitoes and flies. Once infected, elephantiasis can be managed with good skin hygiene and elevation to reduce secondary infections. However, there is no cure.
Diethylcarbamazine (DEC) at 6 mg/kg/day for one or 12 days kills microfilariae and some of the adult worms and can be obtained through the CDC, since it is not FDA-approved in the United States. However, if there is concern of infection with Loa loa, DEC can result in death, and ivermectin becomes the drug of choice for lymphatic filariasis and onchocerciasis.63 In some studies, monotherapy doxycycline at 200 mg per day for four to six weeks has been shown to kill adult worms.
Eventual eradication of the disease will require treatment of all infected human carriers, since they are the source for subsequent human infections.63
Complications/Controversies
Globally, lymphatic filariasis is considered a neglected tropical disease because of the lack of research and funding dedicated to the diseases in this category.67
Disposition
If the diagnosis is made in the ED, infectious disease physicians should be consulted for medication recommendations. Patients with elephantiasis should be referred to a specialist who can manage lymphedema and continue to educate the patient about good skin hygiene and early treatment of any secondary infection.63 Disfigurement can cause social isolation and loss of employment requiring social service involvement.
Other Viral and Tick-Borne Encephalitides
Infectious encephalitis is an acute inflammation of the brain parenchyma due to an infection from a virus, bacteria, parasite, or fungi. Infectious encephalitides are caused by viruses in 60% of cases.68 They result in rapid development of encephalopathy. Clinically, the condition is defined by altered mental status for more than 24 hours and at least two of the following: a fever (38 degrees or greater), new-onset seizures, new-onset focal neurologic findings, CSF pleocytosis, and electroencephalogram or neuroimaging consistent with encephalitis.68 Exotic viral encephalitides have a high morbidity and mortality and, therefore, should be diagnosed rapidly. Typically, these patients require ICU admission, where the management is supportive and targeted at the specific symptoms.
Given the long list of infectious encephalatides, and the fact that certain pathogens, although not transmitted by mosquitoes, hold clinical signficance, each pathogen is briefly addressed in Table 3. Of note, the majority of these are nationally notifiable conditions and have mandatory reporting requirements. The CDC has updated information on specific testing for each of these conditions.
Table 3. Infectious Encephalitides |
|||
Name |
Vector |
Geographic Distribution |
Special Features |
Japanese encephalitis70 |
Culex species of mosquito |
|
|
Western, Eastern, and Venezuelan equine encephalitis (WEE, EEE, and VEE) |
Mosquito (Aedes, Coquillettidia, and Culex genera) bite via avian amplifying hosts |
|
|
St. Louis encephalitis |
Culex species of mosquito via avian amplifying hosts |
|
|
La Crosse encephalitis71 |
Aedes triseriatus mosquito |
|
|
Tick-borne encephalitis72 |
|
|
|
Murray valley encephalitis73 |
Culex mosquito |
|
|
Powassan virus74 |
Ixodes tick |
|
|
Henipa viruses:75
|
Exposure to bats and pigs |
|
|
Jamestown Canyon76 |
Mosquitoes (Culiseta, Aedes, Anopheles) |
|
|
Usutu virus76 |
Culex, Aedes, and Anopheles mosquitoes via avian amplifying hosts |
|
|
Cache Valley virus76 |
|
|
|
Other Considerations in a Returning Traveler
When encountering a returning traveler with an acute febrile illness, always consider the timing of the travel, the type and length of travel (along with the potential for exposure to mosquitoes and other vectors), and current disease prevalence in the areas visited. Although exotic diseases always need to be in the differential diagnosis, many returning travelers will only have common diseases. With more prevalent traveling, special populations, such as pregnant women, immunomodulated patients, and those at the extremes of the age spectrum, can be exposed and return home with these diseases.
This article focused on mosquito-borne diseases, but there are many other global health diseases, including HIV, tuberculosis, Ebola/Marburg, typhoid and paratyphoid fever, schistosomiasis, Chagas disease, scrub typhus, and helminthic infections. Clinicians must always remain familiar with these disease presentations, their basic management, and their diagnosis. The CDC and WHO both have very up-to-date websites that are useful resources. Finally, understand that many of the diseases discussed in this article have mandatory reporting.
Conclusion
International travel and global interdependence are a staple of the modern world, and the planet seems to be getting smaller every day. Mosquito-borne illnesses, such as chikungunya virus, dengue, filariasis, Japanese encephalitis virus, malaria, West Nile virus, yellow fever, and Zika virus, in particular, pose a grave threat to travelers and have the potential to affect a significant portion of the global community due to climate change and urbanization.
To provide optimal care for returning travelers, it is essential to stay informed about the evolving epidemiology of travel-related diseases. Clinicians also must consider changing geographic distributions of these diseases due to climate change. A thorough evaluation includes a comprehensive history, including type of travel (leisure, adventure) and use of prophylaxis, coupled with current knowledge of epidemiologic trends in the areas visited (https://wwwnc.cdc.gov/travel/notices). The physical examination might give clues to the inciting agent or show complications from the infection. A detailed yet focused diagnostic workup is crucial for identifying and managing travel-related illnesses promptly, ensuring the best possible outcomes for patients, reducing the risk of local transmission, and improving the quality of care for our interconnected global community.
Acknowledgments: Infectious Disease Consultant – Dr. Louis M. Katz
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Hundreds of millions of people across the globe are affected by mosquito-borne diseases each year, and travelers who do not exercise caution and take preventive measures are at especially high risk. Mosquito-borne diseases are found mostly in tropical and subtropical destinations, ranging from America to Africa and Asia. Chikungunya virus, dengue, filariasis, Japanese encephalitis virus, malaria, West Nile virus, yellow fever, and Zika virus are particular sources of concern for travelers venturing into regions where these vectors abound. This article will focus on these mosquito-borne illnesses, especially the flaviviruses.
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