Emerging Infections of International Public Health Importance

Objectives:

Identify 3 emerging infectious diseases that are a particular risk for international travelers
Discuss the transmission factors involved in travelers exposure to the emerging infectious diseases
Discuss recommendations that should be given to international travelers to prevent exposure to emerging infectious diseases

The most important things to consider in thinking about Travel and Emerging infections are not the details related to diagnosis and treatment of each disease, but what the risks are to travelers, why travelers constitute a special population contributing to global spread of emerging infectious diseases, and what can we do about this?

The definition of an emerging infectious disease is discussed in the first lecture and can be found in the Institute of Medicine, Emerging Infections: Microbial Threats to Health in the United States publication from 1992.

Travel encompasses several forms of human geographic relocations, such as the migration of workers and refugees within countries (rural/urban) and between countries, as well as travel for tourism, relief work, or business. Global journeys have been made easier and faster through commercial jet airplane travel. Rapid transit enables persons infected in one region of the world where a given disease is prevalent to be transported within a day or two to another region of the world where that disease is exotic and rarely seen, before developing symptoms of illness.

This slide shows that there were 26 unexpected outbreaks of infectious diseases worldwide within the past 2 years. On this list includes ebola, hantavirus, influenza A H9N2, Japanese encephalitis and others.

As mentioned earlier, persons from endemic areas migrating or immigrating to non-endemic areas can inadvertently contribute to the spread of infectious diseases.

This slide shows the number in thousands of persons arriving into the United States either as immigrants or refugees for the years 1987-1997.

This slide shows that the United States is one of the countries that accept a large number of immigrants and refugees.

Immigrant populations can bring diseases with them and these vary according to the region of the world they come from. Diseases that have been associated with these populations include tuberculosis, malaria, parasitic diseases, blood borne pathogens, viral diseases, and vaccine preventable diseases.

International travelers also can bring non-endemic illnesses back with them. A study by Steffen et al looked at the incidence of illness per month of stay in a developing country. He found that travelers’ diarrhea occurred in 30%, malaria in 2%, acute febrile respiratory tract illness in 1% and smaller numbers of hepatitis A, gonorrhea, and animal bites. There have also been outbreaks of specific diseases associated with international travel such as the leptospirosis outbreak among the eco-tourism competition in Borneo, and most recently, the new influenza-like illness, Severe Acute Respiratory Syndrome (SARS) in travelers to Asia.

Fever in the returned traveler may signal a serious, and possibly life-threatening condition. Surveillance for fever in the returning traveler should be an important public health tool. This is currently being accomplished by networks of emergency rooms and travel clinics throughout the world looking for illnesses that present with fever. These are then further characterized as fever with rash, fever without rash, fever with jaundice, fever with respiratory features, fever with bleeding etc. Then specific diagnostic tests can be performed. The linking of these networks should allow for faster communication among countries to notify of specific illnesses and take proper public health measures.

The challenge of evaluating international travelers is that they can be exposed to an exotic disease in an endemic area and return home to a non-endemic region before the incubation period of any given infection is completed. The medical approach to fever is to consider whether the illness is due to an exotic tropical disease or a cosmopolitan disease. Based on the examination are there many other defining features.

Febrile illnesses associated with travel can be broken down by the usual incubation periods: short, medium or long.

Specific diagnostic factors are necessary to determine potential cause of fever in the returned traveler. Where did they go, what were the geographic exposures they encountered? What types of activities were they involved with such as ingestion of unusual foods, swimming in local waters, contact with locals and/or, commercial sex workers, rural travel, camping, insect bites, and any contact with animals including scratches or bites. It is also important to know the traveler’s immunization status, adherence to malaria prophylactic medication, and underlying diseases.

Malaria is a leading cause of morbidity and mortality worldwide with 300-500 million new infections and 3 million deaths annually. In developing countries approximately 3000 children die every day from malaria, which is 10 times more than those killed in wars. Approximately 30,000 European and North American travelers are infected with malaria annually.

The resurgence of malaria is due to several factors: Inadequate public health infrastructure in endemic areas results in inadequate mosquito control measures, inadequate personal protection measures and inadequate methods of diagnosis and treatment of infected persons. Global population growth has forced new human development of areas that were previously vector habitats and has resulted in more human exposure in these areas. Global migration has also contributed by bringing infected persons into uninfected areas where the vector exists and creating a new cycle of transmission. The emergence of drug resistant strains has also contributed to the resurgence because existing drugs have become inadequate to prevent and treat malaria infections, and there is limited access to newer antimalarial drugs in some areas where the need for them is greatest.

This map shows distribution of chloroquine-sensitive and chloroquine-resistant malaria.

This table shows us from which countries the imported malaria cases have come from. We can see that the majority of the cases are from Africa and Asia. This includes those who were born in the US and those who were foreign born. Many of the foreign born US residents return to their country of origin to visit family. They also tend not to seek out pre-travel medical advice. These are also the areas that have the highest incidence of chloroquine resistant malaria.

This slide breaks down the malaria cases into their specific species. It is important to note the date of onset from when a traveler returns to the United States. There are still cases being detected up to one year after returning. Remember, fever in a returned traveler even up to one year can be malaria and should be evaluated.

The malaria lifecycle is important to understand when we talk about chemoprophylaxis and treatment. The female anopheline mosquito injects infective malaria sporozoites into the circulation when biting humans for a blood meal. These sporozoites go to the liver where invade the hepatocytes, and mature into primary schizonts or become hypnozoites (which can remain dormant for months to years). After incubation, the primary schizonts are released from ruptured liver cells, and invade circulating red blood cells (RBCs). In the RBCs, the parasite develops through trophozoite stages, then into secondary schizonts which are released by rupture of the infected RBCs, and invade other RBCs in the circulation. The high fever spikes associated with malaria infections correspond to the rupture of the infected red cells. Characteristic trophozoite stages in RBCs can be identified by Giemsa stain of peripheral blood smears. In each infection, some of the trophozoites develop into male and female gametocytes and can be picked up by a feeding mosquito to begin the process again. Some species of malaria, P. vivax and P. ovale, have a propensity to form hypnozoites in the liver, and can reactivate months to even years later, develop into primary schizonts, and then follow the same pathway as described earlier. This is one way that a malaria infection can evade chemoprophylaxis, since many of the antimalarial drugs work on the red blood cell parasite stages, and not the latent stages in the liver.

This slide lists the current medications that are used for malaria prevention. None of these medications is 100% effective however. The effectiveness of the medication is dependent on several factors. One: is the traveler actually taking the medication as recommended? Two: is there drug resistance in the area of travel and therefore failure of the medication even if taken? Three: do the drug side effects make travelers discontinue the medication before the recommended time? Four: the medications may not have been stored properly and kept their potency.

This slide emphasizes the fact that while several drugs that have been commonly used to prevent malaria, there is a wide range of protective efficacy. In addition to medication, protection from mosquito bites is a very effective and important prevention strategy. Personal protective measures against mosquito bites include insect control measures, use of bed nets, protective clothing and insect repellant. Diagnosis and treatment of active infections also contribute to interruption of the transmission cycle in malaria-endemic areas. A malaria vaccine is currently not available but there is a lot of research being done in this area.

Dengue is also a mosquito borne infection, and it is one of the vector borne viral infections.

Dengue is spread by either the Aedes aegypti or Aedes albopictus mosquitoes. Its predominant distribution is in the tropics and subtropics between 30 degrees north and 30 degrees south latitudes. There are currently 50-100 million cases of dengue reported per year worldwide. However, there are less than 100 cases reported in the United States. Since symptoms can be mild, many cases may be missed or not send a patient to the doctor for evaluation. Dengue can present as either dengue fever which has milder symptoms and a very low case fatality rate or as dengue hemorrhagic fever which can have a high case fatality rate. Out of 500,000 cases of dengue hemorrhagic fever, there have been 25,000 deaths.

Dengue has a relatively short incubation period ranging from 3-15 days and usually presents with fever, headache and back pain. The entire illness usually lasts 7-21 days but can cause chronic fatigue up to 1 year. There are 4 serotypes of dengue, DEN-1, DEN-2, DEN-3, and DEN-4. All can cause primary infection with dengue. A second infection usually with DEN-2 has a much higher likelihood of causing severe dengue fever and dengue hemorrhagic fever. There does appear to be immunity to each of the dengue types.

The emergence of dengue has come about for several reasons. Migrating human populations with increased urbanization and crowded poor living conditions provide ideal conditions for transmission. The Aedes mosquito vectors are typically urban mosquitoes and can breed in small collections of stagnant water, such as accumulate in discarded cans, bottles, and tires. In addition, the reduction or absence of environmental vector control programs has allowed a resurgence of mosquito populations in endemic areas. Finally, expansion of dengue transmission areas occurs when the mosquito vectors inhabiting trash, such as discarded tires, are transported to new areas for dumping.

This map shows the global distribution of the dengue vector (Aedes aegypti) in gray and endemic areas for dengue infections in black. The possibility for endemic dengue does exist in the United States, especially in the south where the Aedes aegypti mosquito exists. If immigration of persons from an endemic area with dengue in the viremic stage of infection moved into this region, transmission of dengue infections could occur among the local populace without their leaving the country. Like malaria, dengue infections can be prevented by personal precautions against mosquito bites. Unlike malaria, there is no effective chemoprophylaxis for dengue. The added environmental measure is to reduce the Aedes breeding sites by covering water sources or eliminating open stagnant water near human habitation.

Leptospirosis etiologic agent is Leptospira interrogans. L. interrogans has over 20 serogroups and over 200 serovars. It has global distribution except for the Polar Regions. It is most commonly spread from from bodies of freshwater (rivers, streams, lakes), moist soil or other environments contaminated with urine of infected animals such as dogs, rodents, and cattle. The majority, 90-95% of cases, have a mild self-limiting disease. Five to 10% of cases can be severe and associated with icterus, fever, and organomegaly.

The incubation period for leptospirosis is 7-14 days. The initial presentation is high fever with acute onset, headache, myalgia, conjunctival suffusion, abdominal pain, rashes, cough and hepatosplenomegaly. Early detection means early treatment and improvement in outcome. The second stage coincides with the appearance of circulating IgM antibodies. The fever may be low grade or absent. Meningitis is the hallmark of this stage. Uveitis can occur but may be delayed and can occur after weeks or months.

Prevention of leptospirosis includes rodent control measures, personal protective equipment for occupational exposures; avoid contact with contaminated water, wetlands, mud and other environments. Chemoprophylaxis with weekly doxycycline may be used for individuals likely to have high risk exposures through occupational or recreational activities.

Dengue hemorrhagic fever and yellow fever are the two most common hemorrhagic infections that affect travelers. A few other viral hemorrhagic fevers that are less common in travelers will be mentioned here because they have been newsworthy and scare people.

The other hemorrhagic fever viruses include Ebola, Marburg, Rift Valley, Crimean-Congo and Lassa fever. I will briefly cover a few points on each of these viruses.

This slide shows us where each of these specific hemorrhagic viruses tend to occur.

Yellow fever is an arbovirus of the flavivirus genus. It is spread by the arthropod vector Aedes aegypti. Its geographic distribution is in tropical South America and sub-Saharan Africa. The incubation period is approximately 3-6 days and has a clinical triad of hepatitis, proteinuria, and hemorrhagic diathesis. The case fatality rate for yellow fever is 25-50% of those affected. The good news for yellow fever is there is a vaccine available which is very effective for prevention of disease. Unfortunately, the majority of people who live in yellow fever endemic areas have not received this vaccine mainly due to lack of resources. The other people who succumb to this disease are travelers who do not receive appropriate travel advice and pre-travel vaccinations.

Rift Valley fever is a phlebovirus which was first recognized in 1930 in Kenya and is endemic to East Africa. This is a zoonotic disease transmitted to humans by mosquito bites or by direct handling of infected animals and their products. There have also been laboratory acquired infections by direct contact and aerosolization. It has an incubation period of 2-6 days and present as a flu-like illness. It has low mortality however 5% of persons can have permanent neurologic impairment or blindness. In 1997-1998 there was a huge outbreak of Rift Valley fever associated with a livestock outbreak and there were 89,000 human cases. In 2000, this infection spread beyond Africa to affect animals and humans in Saudi Arabia and Yemen. This is an emerging problem in the Middle East.

Crimean-Congo hemorrhagic fever is a reemerging infection in certain areas and is endemic in Eastern Europe, the Mediterranean region, Western Asia, and Africa. The vector for this disease is the tick. Most persons become infected by encroaching on areas where the tick is endemic and this exposure will likely increase as populations expand and travel to more rural areas continues. The incubation period is 2-9 days and has a case fatality rate of 25-33%.

Lassa fever is from the Arenaviridae family and the predominant vector is the rodent. It does have the capacity to transmit from human to human in households, hospitals, and other situations of close personal contact. Lassa fever has an insidious presentation of fever, weakness, malaise with severed headache and painful sore throat. The incubation period is 7-18 days. The characteristic pathology shows hepatocyte necrosis with focal necrosis of adrenal glands and the spleen. Clinical findings include fever in 33%, bleeding in 15-20%, pleural or pericardial signs in 20% and thrombocytopenia with depressed platelet function. Diagnosis is made by serum indirect fluorescent antibody, virus isolation from serum or by RT-PCR. Early treatment (within 6 days) with ribavirin has been reported to reduce the case fatality rate from 15-20% down to 5-9%.

Ebola and Marburg viruses are members of the family Filoviridae. They have a rapid incubation period of 4-6 days and cause severe hemorrhages with a high case fatality rate. Nonhuman primates appear to be the source of infections in some outbreaks but this can also spread from person to person by inappropriate barrier techniques and contamination in hospitals. Transmission is usually by direct contact with infected blood and secretions and can be prevented by good public health measures and blood/secretion precautions. Diagnosis is made by a reverse transcript based PCR but no treatment outside of supportive care is available.

General preventive measures for the viral hemorrhagic diseases include controlling animal-to-human contact; control leisure pursuits in rural venues in high risk areas; increase awareness among travelers to remote areas; and taking occupational health measures with use of protective gear and vaccination if available.

In summary, international travelers are at risk of exposure to emerging infectious diseases because of travel to endemic areas and the activities undertaken at their destinations. Strategies for prevention include seeking appropriate pre-travel advice and vaccinations, being counseled on risky practices and activities, taking appropriate chemoprophylaxis if available, using personal protective measures while traveling; and avoiding high risk areas if possible.

Study Questions:

Name a travel-related emerging infection that has person-to-person transmission.
What advice should a health care worker volunteering in an Ebola outbreak receive to protect themselves?
What are the transmission factors involved in travelers exposure to emerging infectious diseases?