By John C. Christenson, MD, and Philip R. Fischer, MD, DTM&H
Dr. Christenson is an infectious disease specialist and Clinical Professor of Pediatrics at Indiana University School of Medicine in Indianapolis. Dr. Fischer is Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN.
Dr. Christenson and Dr. Fischer report no financial relationships relevant to this field of study.
The International Society of Travel Medicine met in Washington, DC, from June 5-9. Overall, there were 1,250 participants in the conference. The 107 podium speakers came from 21 countries on five continents. Many of the sessions were relevant to readers of Infectious Disease Alert, and some key information is highlighted here.
Artesunate has proven effectiveness in treating severe malaria. However, there have been cases of delayed-onset hemolysis following artesunate use. Thomas Zoller from Germany reviewed data suggesting that following treatment, previously infected red blood cells can have “pitting” with altered red cell membranes that put them at risk of future hemolysis (with shorter red cell life spans). Patients with higher levels of parasitemia and patients with higher hemoglobin levels at the time of infection were at greater risk of post-treatment hemolysis. African patients seem to have less risk of delayed post-artesunate hemolysis than do patients not of African ethnic origin, but the reasons for this difference are not clear. Limited studies suggest that autoimmunity is not responsible for the delayed post-treatment hemolysis. Patients with severe malaria should be evaluated at least at 8-10 days and 14-18 days after the beginning of treatment with artesunate to rule out hemolysis.
Tafenoquine is newly available in the United States for the prevention and treatment of malaria. Katherine Tan from the Centers for Disease Control and Prevention reviewed current uses of tafenoquine. Typically, Plasmodium falciparum causes severe malaria and death. However, reviews of U.S. cases of severe and fatal malaria show that 5% of severe malaria is due to P. vivax and that those with severe malaria have similar risks of death regardless of the species that has infected them. P. vivax and P. ovale can lie dormant in the liver in hypnozoite forms that are not killed by standard antimalarials and can emerge to cause malaria many months after the initial infection (and treatment). (Atovaquone-proguanil kills liver schizonts but not hypnozoites.) Primaquine is effective against hypnozoites, but it requires a longer daily treatment course (since it has a half-life of six hours). Tafenoquine has a longer half-life (15 hours) and is effective with less frequent dosing. Studies suggest that prophylactic tafenoquine is about 86% effective with daily doses for three days followed by weekly doses in semi-immune adults. In malaria-naïve individuals, prophylactic tafenoquine was about 95% effective. A final dose may be given one week after completion of travel. Tafenoquine can be given to adults who are not pregnant or breastfeeding and who have no history of psychiatric illness (because of possible increased risks of side effects) as long as they are known to have normal glucose-6-phosphate dehydrogenase activity.
Susan Hills from Atlanta, Lin Chen from Boston, and Fabrice Simon from France reviewed current epidemiology, clinical courses, and long-term management of mosquito-transmitted, alphavirus-induced arthritides. Besides chikungunya, other less common viruses that can cause arthritis include Ross River, Mayaro, O’nyong’nyong, Sindbis, and Barmah Forest viruses.
First recognized in Tanzania in the 1950s, chikungunya virus has spread during the past 15 years to infect people in many tropical and even subtropical areas of the world. U.S. travelers were most affected in 2014 and 2015, but cases continue to present in the United States, mostly in travelers to Asia now. Ross River virus is limited mostly to northeast Australia, with about 5,000 cases per year, but the virus also is endemic in Papua New Guinea and Irian Jaya, Indonesia. It is sometimes seen in travelers to Fiji and it might be seen on other Pacific islands. Mayaro virus was first isolated in Trinidad in 1954 and is seen sometimes in forested areas of Central and South America and the Caribbean. O’nyong’nyong virus was first isolated in Uganda in 1959 and now occurs across Central Africa; a couple of travelers have been infected. Sindbis virus was first identified in Egypt in 1952 and has been seen in Europe, Asia, Africa, and Oceania, but most virus activity is in northern Europe and South Africa. There are just about 1,000 cases of Barmah Forest virus infection in Australia each year, and many cases are asymptomatic.
In addition to alphaviruses, arthritis also can be caused by parvovirus B19, Epstein-Barr virus, hepatitis viruses, and retroviruses. Nonetheless, arthritis is most common and most severe with chikungunya virus infection. As Aedes mosquitoes expand their range, Mayaro virus might emerge as a more common cause of illness in coming years.
Unlike the situation with some other viruses, less than 20% of chikungunya-infected individuals remain asymptomatic. Fever is nearly uniform. Various uncommon but severe complications have been reported, especially in newborns and the elderly. Up to half of infected patients go on to develop chronic arthritis. Arthritis is more common in patients older than 45 years of age, in those with pre-existing osteoarthritis, and in those who had severe joint pain at the time of their initial presentation.
Most chronic post-chikungunya joint pain is mechanical and might relate to inflamed tendons rather than to actual joint inflammation; nonetheless, about 2% with chronic pain do have inflammatory synovitis. Chronic post-chikungunya pain is associated with fatigue, deconditioning, weight gain, and depression, with significant reduction in the quality of life. Multifaceted treatment can help with the various associated comorbidities.
Data to guide the management of joint pain are extremely limited. So far, there is no evidence to support the use of antiviral agents or monoclonal antibodies for treatment. Pain management is important. Short-term steroids often are advised, but supportive data are limited. For the couple percent of patients with inflammatory arthritis, methotrexate is advised, but treatment failures are more common if methotrexate is started after the first year of symptoms. Biologic agents are not advised because of some infection risk coupled with minimal to no known benefit. What is needed for treatment? Physical therapy is critically important, and one study suggests that Pilates is helpful. Most patients improve significantly with pain control, physical therapy, and functional restoration.
Rabies prevention is challenging, partly when choosing who needs pre-exposure vaccination and partly because of the cost of vaccines. In April 2018, the World Health Organization released new guidelines.1 Since the 13-dose rabies vaccine of Pasteur in 1885, there has been significant progress. Pre-exposure prevention is suggested for travelers at higher risk of an animal bite (animal workers, children, joggers, long-distance cyclists), especially when post-exposure vaccination might not be readily available. The pre-exposure vaccine may be provided with two doses separated by a week, either with a total of two intramuscular vaccine doses or with two intradermal doses at different sites on each of the two vaccine administration days; a third dose would be given to immunocompromised patients. As discussed by an expert panel, the current standard in the United States now is for four doses of post-exposure intramuscular vaccine in patients who did not receive pre-exposure vaccination (days 0, 3, 7, and 14-21, but not given in the gluteal region, with immune globulin as soon as possible after the exposure but certainly within a week of the beginning of vaccination — intramuscularly and especially around the wounds). Smaller volumes of dosing may be used, and the total doses can be dropped to three (with cost savings) if the vaccine is given intradermally, based on reasonable effectiveness data. Two doses of post-exposure vaccine (without immune globulin) are effective to boost protection in travelers who received pre-exposure vaccine.
Resistance to common antimicrobials is common in many parts of the world. David Tribble from Uniformed Services University of the Health Sciences in Bethesda, MD, reviewed bacterial resistance to antimicrobials in south and southeast Asia and the relevance of antimicrobial resistance to travelers. Multi-resistant Enterobacteriaceae, Staphylococcus aureus (even to vancomycin), and Salmonella Typhi are common, with risk of travelers developing resistant urinary tract infection and difficult-to-treat systemic infections. Traveler’s diarrhea is increasingly resistant to ciprofloxacin in Asia, with about 20% of cases resistant now; some resistance to azithromycin is reported. Even asymptomatic travelers can transmit resistant germs to relatives and colleagues after returning from their travel.
Laura Nellums from London reviewed the impact of antimicrobial resistance in migrants after reminding her large audience that Alexander Fleming predicted antibiotic overuse and resistance in his Nobel Prize lecture 75 years ago. In Europe, 73% of multi-drug-resistant tuberculosis occurs in individuals born outside of Europe. About 10% of migrants to Europe have methicillin-resistant Staphylococcus aureus, and about 27% harbor multi-resistant Enterobacteriaceae; carriage persists long after arrival in Europe.
Worldwide, according to Regina LaRocque from Harvard, 35 billion daily doses of antibiotics are used each year, and antibiotics are essential to the practice of modern medicine. Antibiotics are used widely, and 35% of rivers in Africa carry water with dangerously high levels of antibiotics. However, antibiotic resistance accounts for as many deaths as influenza, HIV, and tuberculosis combined. Multi-resistant gram-negative organisms are especially prevalent in Asia. Even in the United States, it is the first (not repeated) use of an antibiotic that increases the risk of developing resistance. Thus, prevention of antimicrobial resistance can focus on avoiding unnecessary initial prescription of antibiotics. Key risk factors for harboring resistant organisms are traveling (especially to Asia), having traveler’s diarrhea, and using antibiotics during travel. At least some travelers regain their pre-trip microbiome pattern and lose resistant germs over the three months following travel. Within a large network of travel clinics during recent years, the prescription of antibiotics for stand-by use for traveler’s diarrhea has dropped from about 93% to 69%.
Get a Travel History!
With concern for Zika and other travel-related illnesses, Lin Chen and colleagues at a hospital in Cambridge, MA, retrospectively reviewed pre-visit screening for a history of travel outside the United States within the 30 days of the medical visit. Overall, 5,642 patients had traveled, mostly to Latin America; 989 were of reproductive age and had been to a Zika-endemic area. Of the 161 patients who had traveled and were hospitalized, 41 had symptoms compatible with Zika (such as fever, arthralgia, or rash); two of them were confirmed Zika-positive. Attention to pre-visit screening and Zika testing might have identified many other patients either with acute Zika infection or at risk of future consequences of Zika infection.
A research group from an experienced Swiss travel clinic randomized patients with gastrointestinal symptoms and blastocystis-positive stool tests to receive metronidazole or placebo. There was no difference in outcomes between the two groups. As with previous studies, these new data suggest that blastocystis is unlikely pathogenic in human intestines.
Obviously, the impact of travel extends far beyond infections. Admitting that air travel accounts for a significant carbon dioxide load in the environment, the conference theme centered on “Travel Medicine in a Changing Climate.” The opening ceremony and initial plenary session were dedicated to the discussion of health effects of climate change. Clearly, changing climates are associated with changing risks of infection. Participants thought about wise stewardship of environmental resources in tangible ways. There were no printed programs for the meeting, reducing paper consumption. Each participant received a commemorative mug at the beginning of the conference, and no cups were provided during meals and breaks. One day of the conference featured only plant-based snacks and meals. Conference participants were tangibly reminded that travel offers positive value and that behavioral choices can mitigate some of the negative environmental consequences of travel.