Behrens, Ron H.

Gushulak, Brian D.

Hatz, Christoph H.

MacPherson, Douglas W.

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CORRESPONDENCE • CID 2007:44 (1 March) • 761impetus to definitely conclude that anincrease and subsequent decrease of GMafter administration of caspofungin rep-resents treatment failure. In our patient,this was not the case. An increase and de-crease in GM during therapy does not nec-essarily presage the outcome in one wayor another. Our point was that one shouldexercise caution in interpreting the GMserum ratio in patients who receive cas-pofungin—or any other antifungal, forthat matter.AcknowledgmentsPotential conflicts of interest. P.E.V. has beena consultant for Merck & Company, Gilead Sci-ences, Schering-Plough, Pfizer, and Vicuron.R.R.K. and J.P.D.: no conflicts.Rocus R. Klont,1,3 J. Peter Donnelly,2,3and Paul E. Verweij1,3Departments of 1Medical Microbiologyand 2Hematology, Radboud University NijmegenMedical Center, and 3Nijmegen University Centerfor Infectious Diseases, Nijmegen, The NetherlandsReferences1. Miceli MH, Anaissie EJ. When a paradoxicalincrease in serum galactomannan antigen dur-ing caspofungin therapy is not paradoxical afterall. Clin Infect Dis 2007; 44:757–60.2. Klont RR, Mennink-Kersten MA, RuegebrinkD, et al. Paradoxical increase in circulating As-pergillus antigen during treatment with cas-pofungin in a patient with pulmonary asper-gillosis. Clin Infect Dis 2006; 43:e23–5.3. Maertens J, Glasmacher A, Selleslag D, et al.Evaluation of serum sandwich enzyme-linkedimmunosorbent assay for circulating galacto-mannan during caspofungin therapy: resultsfrom the caspofungin invasive aspergillosisstudy. Clin Infect Dis 2005; 41:e9–14.4. Petraitis V, Petraitiene R, Sarafandi AA, et al.Combination therapy in treatment of experi-mental pulmonary aspergillosis: synergistic in-teraction between an antifungal triazole and anechinocandin. J Infect Dis 2003; 187:1834–43.5. Verweij PE, Weemaes CM, Curfs JH, BretagneS, Meis JF. Failure to detect circulating Asper-gillus markers in a patient with chronic gran-ulomatous disease and invasive aspergillosis. JClin Microbiol 2000; 38:3900–1.6. van Vianen W, de Marie S, ten Kate MT, MathotRA, Bakker-Woudenberg IA. Caspofungin: an-tifungal activity in vitro, pharmacokinetics, andeffects on fungal load and animal survival inneutropenic rats with invasive pulmonary as-pergillosis. J Antimicrob Chemother 2006; 57:732–40.7. Wiederhold NP, Kontoyiannis DP, Jingduan C,et al. Pharmacodynamics of caspofungin in amurine model of invasive pulmonary aspergil-losis: evidence of concentration-dependent ac-tivity. J Infect Dis 2004; 190:1464–71.8. Scotter JM, Chambers ST. Comparison of gal-actomannan detection, PCR-enzyme-linkedimmunosorbent assay, and real-time PCR fordiagnosis of invasive aspergillosis in a neutro-penic rat model and effect of caspofungin ac-etate. Clin Diagn Lab Immunol 2005; 12:1322–7.Reprints or correspondence: Dr. Rocus R. Klont, Dept. of Med-ical Microbiology, Radboud University Nijmegen Medical Cen-ter, Nijmegen University Center for Infectious Diseases, P.O.Box 9101, 6500 HB Nijmegen, The Netherlands (r.klont@mmb.umcn.nl).Clinical Infectious Diseases 2007; 44:760–1 2007 by the Infectious Diseases Society of America. Allrights reserved. 1058-4838/2007/4405-0024$15.00Illness in Travelers VisitingFriends and Relatives: WhatCan Be Concluded?To the Editor—We were interested toread the GeoSentinel report by Leder etal. [1] that focused on an important groupof international travelers who, to date,have not been clearly defined in terms ofdemographic characteristics and travel-related morbidity. We suggest that thereare significant issues related to the design,analysis, interpretation, and conclusionsof the study that require comment. Al-though Leder and colleagues acknowledgeseveral limitations in their report, practi-tioners who are not familiar with the na-ture of the GeoSentinel program and/orwho do not work with migrant travelersmay not fully appreciate the significanceof these limitations.First, although the classification of trav-elers into 3 groups looks appealing, theclassifications have been applied retroac-tively to the data, and the consequencesof this are significant. The retrospectivecohort nature of the study design limitsthe interpretation of outcomes to a cohortassociation and diminishes the generaliz-ability of the conclusions to wider practiceoutside of the participating GeoSentinelcenters.Second, there is no design evidence thatthe recategorization of travelers into “im-migrant visiting friends and relatives,”“traveler visiting friends and relatives,”and “tourist,” as defined within the report,is either robust or reliably discriminatingfor travel-related risk or for health out-comes.Third, the data recruitment allows forthe introduction of both patient referraland selection bias. This may create epi-demiological associations that may not berepresentative of travelers outside of thestudy group. GeoSentinel sites are oftenacademic or tertiary care centers, and arepredominantly based in America; thus,they may be biased towards recruitingtourists rather than travelers visitingfriends and relatives. Patterns of access tomedical service by migrants may differfrom those of the host population [2]. Al-lowable health insurance coverage and is-sues of willingness to pay for services inthe visited nation [3] may influence pre-travel and posttravel service use by trav-elers visiting friends and relatives. Insur-ance coverage may be linked to the study’sobservations of early clinical presentationby tourist travelers, compared with thetravelers visiting friends and relatives (whohave limited insurance) .Other design considerations include theacquisition of diseases, such as malaria,which are primarily related to the desti-nation rather than the reason for travel.Analysis of travel to regions of West Africaand East and southern Africa would havebeen more reflective of actual risk thanreasons for travel. There is evidence thattravelers visiting friends and relatives areoverrepresented as travelers [4] to bothAsia and sub-Saharan Africa, and the rel-ative high proportion of disease prevalencein the group may be a reflection of greaterexposure to and not increased likelihoodof disease. The differing pattern of mor-bidity among the groups of travelers andimmigrants visiting friends and relativesmay relate to their economic status, accessto and use of services, and medical care–seeking behavior, rather than to travel-associated risk.All of these factors combined are designissues that we believe makes studies likethe Leder et al. [1] study difficult to extend762 • CID 2007:44 (1 March) • CORRESPONDENCEbeyond the participating GeoSentinel clin-ics. Nonetheless, the report by Leder andcolleagues and similar studies highlight theimportance of defining and determiningpopulation-based risk factors in cohortsof travelers. Existing limitations of currentdata at this time do not allow the asso-ciations of outcomes that are demon-strated in the report to be extended to alltravelers and immigrants visiting friendsand relatives or migrant travelers.AcknowledgmentsPotential conflicts of interest. R.H.B. andC.H.H. contribute to TropNetEurop. B.D.G. andD.W.M.: no conflicts.Ron H. Behrens,1 Christoph H. Hatz,2Brian D. Gushulak,3 andDouglas W. MacPherson41Hospital for Tropical Diseases, London School ofHygiene and Tropical Medicine, United Kingdom;2Swiss Tropical Institute, Basel, Switzerland;3Migration Health Consultants, Vienna, Austria; and4Migration Health Consultants, McMasterUniversity, Hamilton, Ontario, CanadaReferences1. Leder K, Tong S, Weld L, et al. Illness in travelersvisiting friends and relatives: a review of theGeoSentinel Surveillance Network. Clin InfectDis 2006; 43:1185–93.2. Rao D. Choice of medicine and hierarchy ofresort to different health alternatives amongAsian Indian migrants in a metropolitan cityin the USA. Ethn Health 2006; 11:153–67.3. Ku L, Matani S. Left out: immigrants’ accessto health care and insurance. Health Aff (Mill-wood) 2001; 20:247–56.4. Angell SY, Behrens RH. Risk assessment anddisease prevention in travelers visiting friendsand relatives. Infect Dis Clin North Am2005; 19:49–65.Reprints or correspondence: Dr. Ron Behrens, Dept. of Infec-tious and Tropical Diseases, London School of Hygiene andTropical Medicine, Keppel St., Rm. 286C, London, WC1E 7HT,UK (Ron.Behrens@lshtm.ac.uk).Clinical Infectious Diseases 2007; 44:761–2 2007 by the Infectious Diseases Society of America. Allrights reserved. 1058-4838/2007/4405-0025$15.00DOI: 10.1086/511687Reply to Behrens et al.To the Editor—We appreciate the op-portunity to discuss several points ad-dressed by Behrens et al. [1], some ofwhich were already addressed in our orig-inal article [2]. GeoSentinel is a networkof 33 globally dispersed clinics, mostly atacademic or tertiary care centers. We haveacknowledged the possibility of referral orselection biases that may limit generaliz-ability of our findings beyond specializedtravel and/or tropical medicine clinics.GeoSentinel data are not predomi-nantly from the US population. Of the60,000 patients in the entire database, 42%were seen at clinic sites in Asia, 26% inEurope, 20% in the United States, 9% inCanada, and 3% in Australia and NewZealand. For our study [2], 44% of theimmigrants visiting friends and relativeswere seen at clinic sites in Europe, 30%in Canada, 21% in the United States, and5% in Australia and New Zealand.GeoSentinel clinics serve diverse patientpopulations; some clinics see greater pro-portions of immigrants, and others seemore travelers. At the average US Geo-Sentinel site, 25% of the patients are im-migrants visiting friends and relatives.Eleven percent of patients at Europeansites and 23% of patients at Canadian sitesare immigrants visiting friends andrelatives.The categorization of travelers as “vis-iting friends and relatives” in itself impliesa number of differences, including pre-vious exposure, genetic predisposition,types of exposure during travel, and med-ical care–seeking patterns. We agree withBehrens et al. [1] that, in most countries,access to and use of medical services maydiffer between groups of travelers visitingfriends and relatives and other travelers.The different patterns of morbidity amongthe groups of travelers visiting friends andrelatives may relate not only to their travel-associated risk, but also to behavioral, cul-tural, and economic factors.As noted by Behrens et al. [1], certaindiagnoses primarily relate to the regionvisited, and travelers visiting friends andrelatives are overrepresented as travelers tosome regions. To correct for this, we pre-sented results by region (tables 2–4), withlogistic regressions to adjust for destina-tion and other possible confounders (fig-ure 1) [2]. Insufficient data precluded sep-aration of West from East and southernAfrica. As stated in the article, our resultsdo not indicate the rate of incidence ofdisease or absolute risk of disease, butrather reflect relative morbidity.Because travelers visiting friends andrelatives generally do not seek medical careprior to travel [3], prospective studies donot exist. In our study [2], patient datawere collected in a standardized way, withpredesignated data fields; thus, the retro-active classification into 3 groups is irrel-evant. As stated, some misclassification ofimmigrants visiting friends and relativesand travelers visiting friends and relativesmay have occurred. However, by catego-rizing travelers and immigrants visitingfriends and relatives into subgroups, wehave shown significant differences be-tween groups in the relative morbidity fora number of travel related diseases. As withany original approach to an issue, we havenot claimed that the groups are robust;our results require validation to determinewhether they can be replicated.A recent exhaustive literature reviewconcluded that “there are no publishedrecommendations and little data on pro-viding care to this population of travelers”[4, p. 2857]. Other recent authoritative re-views have found few primary studies ofthis population [5, 6]. Our results repre-sent, to our knowledge, the first data fo-cused solely on populations of travelersand immigrants visiting friends and rela-tives from a global surveillance networkand clearly highlight significant issues ofmorbidity among this population, com-pared with tourist travelers. Our findingssuggest important considerations for ad-ditional understanding of migrant pop-ulations.AcknowledgmentsPotential conflicts of interest. All authors: noconflicts.

Illness in Travelers Visiting Friends and Relatives: What Can Be Concluded?

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