Travel-associated zoonotic bacterial diseases Eyal Leshema,b,, Eyal Meltzera,b, and Eli Schwartza,b a
Center for Geographic Medicine and Internal Medicine C, Chaim Sheba Medical Center, Tel Hashomer and bSackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Correspondence to Professor Eli Schwartz, Center for Geographic Medicine, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel Tel: +972 3 5305000; fax: +972 3 5302011; e-mail:
[email protected]
Eyal Leshem and Eyal Meltzer contributed equally to the writing of the article.
Current Opinion in Infectious Diseases 2011, 24:457–463
Purpose of review Bacterial zoonoses are increasingly described in association with travel. Some bacterial zoonoses constitute important causes of post-travel illness. We focus on leptospirosis and rickettsiosis – the most common travel-associated bacterial zoonoses. Recent findings Leptospirosis is regarded to be the most common zoonotic disease worldwide. In industrialized countries recreational exposures, both domestic and overseas, are increasingly becoming a major source of infection. Asymptomatic infection is rare among travelers. Rickettsial diseases account for approximately 1.5–3.5% of febrile travelers. In several series of travel-related rickettsioses, the most common travel-related rickettsial disease is Rickettsia africae. Other rickettsioses including Q fever, scrub typhus and murine typhus are considered rare among travelers. Whereas timely diagnosis of both diseases is still based on exposure history, antigen detection tools to aid the diagnosis during the acute illness are under research and far from being available. Due to these constrains, currently, the true incidence of both diseases is probably underestimated. Summary Both leptospirosis and spotted fever may be rapidly fatal. Empiric doxycycline in severely ill febrile travelers should be considered. There is an urgent need for widely available antigen detection diagnostic tools to improve the detection of leptospirosis and rickettsial infections during the acute illness. Keywords bacteria, leptospira, rickettsia, travel, zoonoses Curr Opin Infect Dis 24:457–463 ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins 0951-7375
Introduction
Leptospirosis
Bacterial zoonoses are relatively rare causes of travelassociated diseases, especially compared with parasitic and viral diseases [1,2]. However, several bacterial zoonoses have been described in association with travel and constitute important causes of posttravel illness (Table 1) [3,4,5,6–8,9,10,11–17]. The diagnosis of bacterial zoonoses may prove challenging because of the nonspecific nature of presentation in some, and the rarity of others. Confirmation may also prove difficult because of the fastidious nature of many of these bacteria, and the lack of rapid widely available tools for laboratory diagnosis during the acute phase of the disease. Therefore, a thorough history, including detailed travel history and possible exposures, along with a high index of suspicion may allow rapid diagnosis and treatment.
Leptospirosis is considered the most common zoonosis worldwide. Leptospira infect a variety of wild and domestic animals. Infected animals chronically secrete Leptospira in their urine and contaminate the environment. Leptospira may survive for extended periods in fresh water, damp soil, and vegetation. Human infection occurs by direct contact with infected animal urine or tissues, or indirectly by contact with contaminated water or soil. Spirochetes may enter through broken or even intact skin, mucous membranes or conjunctiva.
Our review is focused on the two most common travel-associated bacterial zoonoses: leptospirosis and rickettsiosis. 0951-7375 ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
The genus Leptospira was traditionally divided into two groups: Leptospira biflexa (nonpathogenic) and Leptospira interrogans (pathogenic). There are over 250 Leptospira serovars divided into 24 serogroups based on antigenic relatedness. Modern classification based on genetic relatedness divides Leptospira into 20 species, of which 14 are considered pathogenic or intermediately pathogenic [18]. DOI:10.1097/QCO.0b013e32834a1bd2
458 Tropical and travel-associated diseases
Epidemiology in travelers
Due to its ubiquitous distribution, leptospirosis is said to be found wherever it is sought. Disease incidence is higher in tropical and developing countries compared with industrialized countries. This is explained by several factors including higher temperature and humid environments, allowing longer survival of Leptospira in the environment, heavy rainfall and flooding bringing bacteria in closer contact with humans, traditional agricultural and irrigation methods, increased exposure to animals, and poor water disposal infrastructure. The disease burden is expected to increase in areas with multiple risk factors combining climate changes, increased waterfall, urbanization, poverty and crowding in urban slums [19], for example in northern India disease incidence increased from 11% in 2004 to 20% in 2008 [20]. In industrialized countries, the incidence of leptospirosis has dramatically declined over the past decades. This decrease is attributed to mechanization of agricultural methods and therefore decreased environmental and animal exposure [4,21,22,23]. Despite the overall decline in disease incidence, recreational exposures are becoming more common as a source of infection. Indeed, a recent Australian study revealed a shift from occupational to recreational exposures [23]. This is strengthened by recent studies from industrialized countries highlighting the fact that although incidence is declining, domestic water exposures lead to disease resurgence and
Key points Leptospirosis and rickettsiosis are the most common travel-associated bacterial zoonoses. In industrialized countries recreational exposures, both domestic and overseas, are increasingly becoming a major source of infection with Leptospira. The most common travel-related rickettsial disease is African tick bite fever caused by Rickettsia africae. Both leptospirosis and spotted fever may be rapidly fatal and empiric doxycycline in severely ill febrile travelers should be considered. There is an urgent need for widely available antigen detection diagnostic tools to improve the detection of leptospirosis and rickettsial infections during the acute illness. outbreaks (Table 2) [24–29]. Reported outbreaks followed recreational exposure, agricultural exposure (taro farming, strawberry harvest) and military activities involving fresh water submergence. Thus, although leptospirosis incidence is declining in industrialized countries, it continues to colonize both animal reservoirs and the environment, thereby infecting exposed individuals. In recent years, travel-related leptospirosis becomes a significant source of the disease in industrialized countries. In Germany, 16% of cases between 1997 and 2000 were acquired abroad [21]. In Australia, 19%
Table 1 Bacterial zoonotic diseases (selected references) Disease
Bacterial cause
Zoonoses described in relation to travel Brucellosis [3] Brucella spp. Leptospira spp. Leptospirosis [4,5,6] Lyme disease [7] Borrelia burgdorferi Murine typhus [8,9] Q fever [9,10,11]
Rickettsia typhi Coxiella burnetii
Scrub typhus [9,12] Spotted fever [9,13–15]
Orientia tsutsugamushi Rickettsia conorii Rickettsia africae Tick borne relapsing fever [16] Borrelia spp. Travelers diarrhea [17] Campylobacter spp. Salmonella spp. Other zoonoses rarely/never described in relation to travel Anthrax Bacillus anthracis Cat scratch disease Erysipeloid Fish tank granuloma Glanders Listeriosis Pasteurellosis Plague Psittacosis Rat bite fever Tularemia
Bartonella henselae Erysipelothrix rhusiopathiae Mycobacterium marinum Burkholderia mallei Listeria monocytogenes Pasteurella multicida Yersinia pestis Chlamydophila psittaci Streptobacillus moniliformis Francisella tularensis
Main reservoirs
Transmission mode to humans
Cattle, goats, sheep, pigs Rodents, dogs, cattle, ruminants Ticks, rodents, sheep, deer, small mammals Rats Cattle, cats, goats, sheep
Dairy products, milk Infected urine, water Tick bite
Rodents, birds, monkeys Dogs Cattle Rodents, pigs, birds Poultry, farm animals Poultry, cattle, sheep, pigs Livestock, wild animals, environment Cats Fish, environmental exposure Fish Horse, donkey, mule Cattle, sheep, soil Dogs, cats, many mammals Rats and their fleas Birds, poultry, ducks Rats Rabbits, wild animals, environment, ticks
Rat fleas Aerosol, direct contact, milk, fomites Trombiculid mites (chiggers) Tick bite Tick bite Raw meat, milk Foodborne Direct contact, ingestion Bite, scratch Direct contact Direct contact, water Direct contact Dairy produce, meat products Bite/scratch, direct contact Flea bite Aerosol, direct contact Bite/scratch, milk, water Direct contact, aerosol, ticks, inoculation
1/7 (14%) 0 0/27 (0) 5/6 (83%) 0 NA
11/24 (45%) 0 7/23 (30%) (MAT >1 : 100) 4/17 (23%) (MAT >1 : 800)a
Strawberry harvest Triathlon: swimming
Adventure race: swimming, canoeing, portaging the canoe 3/44 (7%) 0 NA Military combat skills training Canoeing
Travel-related outbreaks of leptospirosis were reported following water-related sports events, rafting or military drills (Table 3). There are scarce data regarding the epidemiology of sporadic leptospirosis in travelers (Table 4). Although these data may represent only a minority of travel-related cases, several conclusions can be drawn: (1) Most patients acquired the infection in South-east Asia (most Israeli travelers were exposed in the Mekong river in Laos). (2) The majority of patients were male. (3) There were no reports of deaths in either outbreak reports or sporadic travel-related cases. NA, data not available. a Study population included strawberry harvesters from eastern Europe with possible repeated exposure.
Hospitalization Deaths Asymptomatic seroconversion
21/52 (40%) 0 4/197 (2%)
Military jungle training and pond swimming 72/72 (100%) 0 NA Triathlon: swimming
6/65 (9%) 72/193 (37%) 52/474 (11%)
Number of patients/ total participants Type of exposure
of cases in 2008 were acquired overseas [23]. A recent review from the UK reported that over half of leptospirosis cases were acquired abroad, predominantly in tropical and subtropical countries [2]. We have recently shown that in Israel the proportion of travel-related cases rose from 1.7% of all cases between 1985 and 1999 to 83% in 2008 [4]. The estimated incidence of travel-related leptospirosis was 1.78/100 000 travelers per year reflecting risk ratio of 29 for travel-related compared with locally acquired leptospirosis [4].
3/5 (60%) 0 1/142 (1%)
24/153 (16%) 5/142 (4%) 44/192 (96%) 7/27 (26%)
Germany, 2007 [29] Germany, 2006 [28] USA, Florida 2005 [27] Israel, 2002 [26] Ireland, 2001 [24] Peru, 1999 [25] USA, Illinois 1998 [24] Country and year of the event
Table 2 Outbreaks of leptospirosis associated with domestic fresh water exposure (water sports and recreational events, military training, agriculture)
Travel-associated zoonotic bacterial diseases Leshem et al. 459
Clinical features
Leptospirosis incubation is 1–32 days (median 9 days) and median duration is 14 days [27,30]. Most symptomatic patients develop a mild illness consisting of fever, chills, headache and myalgia. Severe forms of the disease may manifest in acute renal failure, hepatitis, jaundice, myocarditis and meningoencephalitis. In recent years there are multiple studies of severe pulmonary hemorrhagic leptospirosis resulting in high morbidity and mortality. Pulmonary leptospirosis was recently also described in travelers [4,5,31]. We found that 55% of travel-related cases in Israel were defined as severe leptospirosis [4]. Despite the high proportion of severe cases, mortality due to leptospirosis in travelers seems to be rare (Tables 3 and 4). The clinical presentation and severity of leptospirosis depend on both host and pathogen-related factors. The correlation between disease severity and infecting serovar is a matter of ongoing debate. In Israeli travelers, severe manifestations and longer hospitalizations were significantly more common among those infected with icterohaemorrhagiae serogroup compared with nonicterohaemorrhagiae serogroup infections [4]. A recent study of severe leptospirosis in Guadeloupe demonstrated infection with serovar icterohaemorrhagiae was an independently associated risk factor for severe disease [32]. Other prognostic factors for severe disease identified in this study included late initiation of antibiotics, hypertension and alcoholism [32].
460 Tropical and travel-associated diseases Table 3 Travel associated outbreaks of leptospirosis (recreational events, military training)
Number of patients/total participants Exposure Hospitalization Deaths Asymptomatic seroconversion
Panama, 1961
Okinawa, Japan, 1987
Costa Rica, 1996
Malaysian Borneo, 2000
9/365 (2%)
22/97 (22%)
9/26 (34%)
80/189 (42%)
Military exercise: overnight jungle walk 9/9 (100%) 0 8/167 (4%)
Military combat skills training (7/15, 47%) and recreational swimming (15/82,18%) 9/9 (100%) 0 2/86 (2%)
White- water rafting
Multisport endurance event: swimming, kayaking, caving, mountain biking 29/80 (36%) 0 NA
2/9 (22%) 0 NA
NA, data not available. Data from [24].
Asymptomatic seroconversion appears to be rare in travelers (as demonstrated in outbreak investigations; Tables 2 and 3). Recently it was reported that healthy individuals living in a highly endemic area shed Leptospira in their urine despite lack of clinical or serologic evidence of a recent infection [33]. This may reflect persistent asymptomatic renal colonization in humans. Diagnosis
Most current diagnostic methods for leptospirosis provide retrospective diagnosis. Thus, during the acute illness, diagnosis must be based on a high index of suspicion combined with a history of recent travel, recreational or occupational water exposure. Nonspecific clues include elevated creatinine, elevated bilirubin (in the presence of mildly elevated or normal aminotransferases), leukocytosis with left shift, and thrombocytopenia [24]. Efforts to develop molecular tools for diagnosing leptospirosis during the acute stage are ongoing. Real-time PCR was recently shown to allow rapid early detection of Leptospira in about half of the patients. Interestingly, diagnosis was made at presentation in four of five fatal cases in this study [34]. Pulsed-field gel electrophoresis shows promise as an alternative to serological tests (which are available only in reference laboratories) for serovar identification [18].
Prevention and treatment
Traveler education regarding the risks of fresh water exposure in endemic areas is highly important. Whereas doxycycline use is widely regarded as protective [35], a recent review concluded that regular use of weekly oral doxycycline 200 mg increases the odds for nausea and vomiting with unclear benefits in reducing seroconversion or clinical consequences of leptospirosis [36]. Doxycycline chemoprophylaxis remains an attractive option for participants of water-related activities in malaria endemic areas. There are no widely approved human vaccines for leptospirosis at the present time. However, there are ongoing efforts to develop better vaccines for animal and human use [37]. Treatment of leptospirosis consists of penicillin G or ampicillin for severe cases and doxycycline for mild or moderate disease. Ceftriaxone and azithromycin are regarded to be good alternatives. Recent studies show conflicting evidence regarding the use of immune-suppressive regimens in cases of severe leptospirosis. One study showed that adding methylprednisolone to antibiotics may reduce mortality in patients with severe leptospirosis [38]. A second study demonstratd the efficacy of combined plasma exchange therapy and cyclophosphamide in severe pulmonary hemorrhagic leptospirosis [39]. Another study showed no benefit from
Table 4 Demographic and epidemiologic characteristics of sporadic cases of leptospoirosis among international travelers
Number Nationality Acquired in South-east Asia Latin America and the Caribbean Africa Oceania East Europe Male sex Mean age Water-related activity Hospitalized Mortality
Leshem et al. [4]
van Crevel et al. [6]
Hoffmeister et al. [5]
Total
20 Israeli
32 Dutch
24 German and Austrian
76
15 (75%) 1 (5%) 2 (10%) 2 (10%) 0 18 (90%) 28 16/18 (89%) 20 (100%) 0/20
28 (87%) 3 (9%) 0 0 0 26 (81%) 31 31 (96%) 25 (78%) 0/32
9 (38%) 12 (50%) 0 0 3 (13%) 20 (83%) 40 20/23 (87%) 24 (100%) 0/24
The features of travelers were reported in three series (N ¼ 76).
52 16 2 2 3 64
(69%) (21%) (3%) (3%) (4%) (84%) 33 67/73 (91%) 69 (90%) 0/76
Travel-associated zoonotic bacterial diseases Leshem et al. 461
adding desmopressin and dexamethasone to therapy of severe leptospirosis patients with pulmonary involvement [40].
Rickettsial diseases Rickettsiae are a family of Gram-negative, obligate intracellular bacteria. The number, geographic extent and clinical manifestations of rickettsial diseases form a rapidly evolving field. Molecular diagnostics have dramatically influenced this field, enabling new associations of specific rickettsial species with specific symptom-complexes. Most Rickettsiae depend on arthropod vectors for their transmission. Some rickettsial species are globally distributed, whereas others are more geographically restricted. Travelers, by entering the arthropod vectors’ habitat, may become infected with Rickettsiae. The likelihood of rickettsial infection is also highly dependent on the ‘voraciousness’ of the arthropod vector. Therefore, the distribution of travel-related rickettsial diseases creates a complex map, highly dependent on specific exposures in specific locales. Recent data on travel-related rickettsial diseases
The best epidemiological data to date on travel-related rickettsial diseases have come from a recent summary of the GeoSentinel data [9]. GeoSentinel is a global system of clinics reporting on travel-related illness. Overall, rickettsial diseases comprised 0.6% of all diagnoses over 12 years and 1.5% of diagnoses made among febrile patients. In a previous study from the same group, the incidence of rickettsial disease was on par with mononucleosis and enteric fever, whereas among travelers to sub-Saharan Africa Rickettsiae were the second identifiable cause of fever after malaria [41].
place of R. africae. In a summary of the EuroTravNet registry, among febrile travelers, 50 cases (3.5%) of rickettsial diseases were reported. Rickettsial diseases were the third identifiable cause of fever (after malaria and dengue), with R. africae the most frequent pathogen [15]. Similar data were reported in series from Germany [42] and Sweden [43]. Rickettsial diseases other than R. africae can be considered as rare among travelers. Orientia tsustsugamushi – the agent of scrub typhus reported in 5.7% of GeoSentinel Rickettsia cases – was mostly acquired in South-east Asia. Scrub typhus was the cause of the only fatal rickettsial infection in the GeoSentinel series. However, two Israeli men have developed multiorgan failure probably due to R. conorii acquired in India [9]. Typhus group Rickettsiae are the third frequent infection in the GeoSentinel study [9]. Here, however, definite diagnoses are hampered by the nonspecific character of most rickettsial serological assays, since other species, notably the globally distributed R. felis (cat flee spotted fever) may cross-react with murine typhus [8]. Thus, in only one GeoSentinel case was R. typhi proven by PCR. On the contrary, murine typhus may easily be missed since it not infrequently presents as a ‘spotless’, ‘escharless’ febrile illness [14]. Thus, the true burden of typhus group Rickettsiae among travelers is undetermined. The constellation of fever, rash and eschar should alert a clinician to the possibility of a rickettsial disease. However, a ‘spotless’ spotted fever is not rare. Mediterranean spotted fever, a main killer rickettsial disease among travelers, is no exception, and a therapeutic delay was seen in all recent fatalities and near fatalities [13,44,45]. Doxycycline should be considered early in the course of a severe sepsis syndrome in a traveler returning from the Mediterranean, Africa or Asia.
The leading condition was by far Rickettsia africae infection, which accounted for 75% of all cases. African tick bite fever (ATBF) classically manifests as a combination of fever, vesicular rash and an inoculation eschar(s), although neither fever nor rash is universal. The tick vector of ATBF, Amblyomma hebraeum, is notable for aggressive questing behavior, accounting for the oftenseen case clusters, and multiple inoculation eschars. The dominance of safari travel-related ATBF has caused the whole rickettsial disease cohort to differ significantly from destination-matched controls: rickettsial disease patients were older, had traveled preponderantly to Southern and Eastern Africa, and were more likely to have traveled during the late Antipodean summer – the time of higher vector activity [9].
Travel-related Coxiella infections
Additional registries from Europe show similar findings to the GeoSentinel registry, confirming the predominant
Coxiella burnetti has been classified in the past among the Rickettsiae, but is in fact a gamma-proteobacteria, more closely related to Legionella. Because of its historic
Additional under-recognized rickettsial syndromes include subacute meningitis (R. helvetica) and TIBOLA (tick-borne lymphadenopathy). The latter comprises fever with regional lymphadenopathy (often cervical/ occipital) eschar – a syndrome caused by R. slovaca (and probably by R. mongolotimonae and other spotted fever Rickettsiae as well). Although TIBOLA is mostly recognized as an autochthonous European disease, a few cases were seen in travelers [46].
462 Tropical and travel-associated diseases
association, it is included here. Coxiella is a highly infectious global mammalian zoonotic disease. It is easily spread by aerosol, and does not require an arthropod vector. Most cases manifest as pneumonia or a nonspecific febrile illness, but severe complications including endocarditis and granulomatous hepatitis are also seen. Q fever may be acquired both as a rural zoonosis from exposure to livestock and as an urban zoonosis, in which the main culprit is probably exposure to parturient cats or kittens. Recent data on travel-related Coxiella infections
As the diagnosis relies on late seroconversion and symptoms are often nonspecific and self-limited, the actual burden of travel-related Q fever is difficult to gauge. The best recent source of data on travel-related Q fever is again the GeoSentinel database. Travel-related Q fever appears to be rare with just 11 reported cases among 99 355 travelers, and largely associated with travel to Africa, presumably through exposure to rural environments and game during Safari travel [9]. In a smaller retrospective study from Madrid, Q fever accounted for only 0.7% of febrile returning travelers; 60% were acquired during travel to Africa [11]. In recent years, Q fever has been increasingly reported in American servicemen returning from Iraq [10]. As many as 10% of army personnel seroconverted to Q fever and presented clinically mostly as a nonspecific febrile illness [10]. Whether this risk can be generalized to civilians traveling to this region is unknown. Another ongoing outbreak of interest is a large-scale epidemic of Q fever in the Brabant-Limburg region in southern Netherlands. To date, about 3700 human cases have been recorded; however, cases among travelers to the Netherlands are lacking. The European Centers for Diseases Control has recently estimated the risk (in the context of the safety of accepting blood donation) associated with travel to the affected areas at about three of 100 000 travelers per day [47]. It is probably safe to recommend that travelers at high risk for complications of Q fever (e.g. pregnant women or patients with prosthetic heart valves) avoid agrotourism or exposure to rural settings in the affected region.
diagnostic delays. Empiric doxycycline in severely ill febrile travelers should be considered, since serological confirmation of both conditions may depend on convalescent sera. There is an urgent need for widely available antigen detection diagnostic tools to improve the detection of leptospirosis and rickettsial infections during the acute illness.
Acknowledgements Conflicts of interest There are no conflicts of interest.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 511). 1
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4 Leshem E, Segal G, Barnea A, et al. Travel-related leptospirosis in Israel: a nationwide study. Am J Trop Med Hyg 2010; 82:459–463. A nationwide study of leptospirosis in Israel describing the increasing incidence of travel-related cases. Severe disease with multiorgan failure was common especially among travelers infected with icterohaemorrhagiae serogroup. Hoffmeister B, Peyerl-Hoffmann G, Pischke S, et al. Differences in clinical manifestations of imported versus autochthonous leptospirosis in Austria and Germany. Am J Trop Med Hyg 2010; 83:326–335. One of few studies describing the epidemiologic and clinical features of travelrelated leptospirosis. In this multicenter study from Germany and Austria, travelrelated cases are compared with locally acquired cases.
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9
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Conclusion Bacterial zoonoses form a large, heterogeneous group of diseases; however, among travelers leptospirosis and rickettsial infections are of major importance, whereas other pathogens are infrequently seen. Both leptospirosis and spotted fever may rapidly develop into life-threatening conditions, especially if the diagnosis is delayed. A careful history regarding fresh water and arthropod exposure and a thorough search for eschars and rash may decrease
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