Health Risks of Travelers With Medical Conditions—A Retrospective Analysis

Rosanne W. Wieten MD, Tjalling Leenstra MD, PhD, Abraham Goorhuis MD, PhD, Michèle van Vugt MD, PhD, Martin P. Grobusch MD, PhD
DOI: http://dx.doi.org/10.1111/j.1708-8305.2011.00594.x 104-110 First published online: 1 March 2012

Abstract

Background Traveling the world may result in infection with tropical or other travel‐associated diseases. This applies increasingly also to people with immune‐compromising and other medical conditions, as well as to elderly individuals. To reduce exposure and susceptibility to health risks, there is a need for appropriate pre‐travel advice for these particular groups of travelers.

Methods In this observational study, we analyzed the overall risk of health problems among travelers with underlying medical conditions who attended the University of Amsterdam's Academic Medical Center's (AMC) travel clinic from January to October 2010. Telephone questionnaires were administered to 345 travelers with underlying conditions and 100 healthy travelers.

Results The most common underlying medical conditions studied included: (1) diabetes mellitus; (2) impaired immunity due to use of immune‐suppressing medication; (3) reduced gastric barrier; and (4) HIV infection. The overall incidence of travel‐related diseases (TRDs) was higher among those patients with underlying medical conditions compared to healthy travelers [incidence rate ratio (IRR) 2.26, 95% CI (1.29–3.98)]. Of all diseases reported, gastrointestinal disease, fever, and respiratory problems were reported most frequently. Travel to Central America, South Central Asia, Northeast Asia, and North Africa was associated with increased risk of contracting TRD. Hepatitis B protection was absent or unknown in 75% of these travelers.

Conclusions Travelers with medical conditions had a higher risk of obtaining TRD, predominantly gastrointestinal in nature.

People travel the world extensively, and increasingly so. Between 20 and 70% of the 50 million people from the industrialized world visiting the developing world report illness associated with their travel. Although most illnesses are mild, 1 to 5% of returned travelers become ill enough to seek medical attention, and 1 in 100, 000 succumbs to travel‐related disease (TRD).1

Among patients with underlying medical conditions, diseases acquired during travel may lead to more severe consequences compared to healthy travelers.2–5 Also, depending on the underlying condition there may be diminished immunogenicity and clinical efficacy of vaccinations. Live attenuated vaccines, such as that for yellow fever, may elicit disease.

As the overall mobility of this group of travelers increases, so does their motivation to travel to destinations outside Europe and Northern America. Tailor‐made pre‐travel advice relates to the type and severity of the immune disorder.

The immune‐deficiencies that influence travel can be divided in several groups:

  1. humoral immune‐deficiency with primary or secondary hypo‐ or agammaglobulinaemia, eg, due to the use of rituximab, chronic lymphatic leukemia, multiple myeloma, or nephrotic syndrome;

  2. cellular immune‐deficiency, eg, due to HIV infection or immune‐suppressive therapy;

  3. nonspecific immune disturbance due to defective barriers such as skin or mucosal disorders, or a reduced gastrointestinal acid barrier;

  4. other conditions that cause a higher risk of infection such as diabetes, malignancies, pregnancy, functional asplenia/splenectomy, hematologic stem cell transplantations, complement disorders, cardiovascular prostheses, and older age (>60 years).

Because the different components of the immune system are intertwined, immune‐deficiency is often of a combined type.6

Literature and many recommendations exist on the HIV‐infected traveler in whom the degree of immune‐compromise can be quantified by measuring CD4+ lymphocytes.4,7,8 Little evidence and fewer recommendations are available with respect to transplant patients, and even less with respect to other forms of immune‐suppression. In addition, no well‐validated laboratory measures are available that quantify the degree of immune‐suppression in these patients.

This analysis focuses on travel‐related health risks for different groups of travelers with underlying medical conditions who visited the Academic Medical Center travel clinic in Amsterdam. In the Netherlands, national guidelines for pre‐travel advice have been issued by the LCR (Landelijk Coördinatiecentrum Reizigersadvisering).9 These serve as guidance for all travelers, including immune‐compromised travelers. By assessing which groups of travelers with medical conditions have high risks of relevant TRD compared to healthy travelers, we aim at identifying areas in which future research might contribute to optimizing those guidelines.

Methods

From January through October 2010, we collected the following data from persons visiting the AMC Travel Clinic: (1) demographic details; (2) details on travels; (3) pre‐travel advice/vaccinations given; (4) clinical details; and (5) self‐reported illness during travel.

Study Sample

Travelers were eligible for inclusion as traveler with a medical condition if they had one of the following conditions: HIV positivity, congenital immune‐deficiencies, malignancy, asplenia or splenic dysfunction, defective skin‐, mucosal or gastrointestinal barriers, diabetes, pregnancy, renal failure, cardiopulmonary diseases, blood and complement disorders, neurological/psychiatric diseases, allergies, or if they used immune‐suppressive medication.

Study subjects were contacted for oral consent and follow‐up by telephone. Those who did not answer the telephone questionnaire were excluded from statistical analysis.

The healthy group of travelers was randomly selected and frequency‐matched by age group (0–20, 20–60, 60+ years), gender, and travel destination. Recruitment was stopped after 100 healthy travelers had completed the telephone questionnaire. Travelers were excluded if there was insufficient information about their medical history or travel details.

Data Sources

Data were collected from two different electronic databases. The first was Orion Globe 7.4.1 (WKM Business Software BV, Assen, The Netherlands), which is routinely used to register vaccination and chemoprophylaxis prescription at the pre‐travel clinic. The second was Norma EMD/EPD (MI Consultancy, Katwijk, The Netherlands), which is used as the electronic patient record for daily clinical care at the AMC and includes medical details of patients.

Orion Globe 7.4.1 was used to collect information on travel and demographic details (age, gender, country of destination, travel period and duration, pre‐travel vaccinations, and antibiotics prescribed). Norma EMD/EPD was used to collect information on clinical specifics such as patient history, medication, and relevant laboratory parameters: eg, CD4+ count in HIV positive patients.

Through telephone questionnaires, we obtained details on the occurrence of health problems during or after travel: type of illness, timing, self‐medication, contact with local medical facilities (including hospital admission), and disease outcome.

Additionally, we questioned participants about the nature of their travel (whether visiting friends or relatives, vacation, internship, or business).

Definitions

Travel destinations: We reported a maximum of three countries of destination. If patients visited more than three countries, we specified the region as described by Freedman and colleagues.10 If a patient had visited three continents or more, we defined the journey as a world trip. In our statistical analysis, we defined the region where exposure most likely happened, deduced from timing of TRD, as the travel destination.

Medication: We documented both name and dosage of immune‐suppressive agents used. Additionally, we documented use of other medication (only the drug, not the dosage).

A minimum of 10 mg prednisolone per day or an equivalent was noted, based on the LCR statement that this is the minimum dose to exert a relevant effect on the immune system.9 For chemotherapy among cancer patients, we only included patients who had their last course <3 months prior to inclusion, as no significant effect on the immune system is expected after this period.6,9

Reported health problems: Health problems were divided in syndrome categories as described by Freedman and colleagues.10 If available, we documented a diagnosis.

Relevant TRD: We defined relevant TRD as self‐reported fever (measured temperature above 38°C); self‐reported diarrhea with or without blood (acute: frequent loose stools lasting >1 d; persistent to chronic: frequent loose stools lasting >14 d), infectious dermatological disorders, respiratory problems, and fatigue/overall malaise lasting over 7 days resulting in a physician's consultation. We excluded health problems that did not potentially have an infectious cause from the definition of TRD (eg, traumatic injuries). If more than one health problem was reported in the same time period (<3 d between the onset of the two symptoms), we recorded the predominant symptom. TRD occurred during travel and if after travel, onset was within the known incubation period of the disease.

Ethical Issues

For this noninterventional study in our patient cohort, a votum of the AMC ethics committee was not required.

Data Analysis

The main outcome measure was the incidence rate ratio (IRR) of TRD. Incidence rates (IRs) were calculated by dividing the number of TRDs by traveled time in weeks. IRRs were calculated as the IR of specific groups of travelers (eg, travelers with underlying conditions) divided by the IR of a reference group (eg, healthy travelers). Confidence intervals for IRRs were calculated using episheet.

We compared duration of TRD in days in those treated with pre‐travel and during travel prescribed antibiotics and duration of travel in days for persons with and without TRD using an independent samples t‐test. Statistical analysis was performed using PASWstatistics18 (IBM, Chicago, IL, USA).

Results

Study Population

The study population included 420 patients who were found eligible. Baseline characteristics of the study population are presented in Table 1. The telephone questionnaire was answered by 345 of 420 (82.1%) patients and 100 of 123 (81.3%) healthy travelers.

View this table:
Table 1

Baseline characteristics of 420 patients and 123 healthy travelers visiting the AMC travel clinic from January to October 2010

Age > 60Immune‐suppressivesGastric barrier reduced (antacids)Diabetes mellitusHIV positiveTotal*Healthy group
Questionnaire answered/ all travelers contacted 90/10788/10566/7754/6532/51345/420100/123
Age (y)
 Median66445853454743
 Interquartile range62–7034–5647.5–6442.3–6139.3–50.831–6031.5–60.0
Male sex (%)52 (57.8)30 (34.1)27 (40.9)23 (42.6)16 (50.0)139 (40.3)44.0 (44)
Duration of travel (d)
Median2020.51821282121
Interquartile range14–2114–2814–2413.3–2814–30.814–2814–28
Visiting friends and relatives (%)13 (14.4)13 (14.8)17 (25.8)10 (18.5)10 (31.3)62 (14.8)25
Travel destination
 Caribbean0423080
 Central America2120070
 Middle East12104532411
 North Africa9111081373
 Northeast Asia3121160
 South America181111555519
 South Central Asia746100237
 Southeast Asia1826131178323
 Sub‐Saharan Africa17141111138532
Prescribed emergency self‐treatment antibiotics (%)§ 22 (24.4)51 (58.0)29 (43.9)25 (46.3)10 (31.3)107 (32.6)0 (0)
Reported disease 353831181614413
TRD (%)22 (24.4)29 (33.0)20 (30.3)13 (23.3)12 (37.5)99 (28.7)13
Antibiotic treatment (%)4 (4.4)6 (6.8)3 (4.5)3 (5.4)5 (15.6)25 (7.2)1
Hospitalized (%)3 (3.3)3 (3.4)1 (1.5)2 (3.6)1 (3.1)9 (2.6)0
  • * Some travelers had multiple potentially immunocompromising conditions, or were >60 years of age and had a medical condition.

  • Percentages and numbers apply to the answered questionnaires.

  • Other travel destinations were Western Europe, Northeast Asia and Eastern Europe, or to multiple regions, for which ascertainment of exposure was impossible.

  • § In the Netherlands, antibiotic prescription is recommended for travelers with insulin‐dependent diabetes, HIV infection with CD4 counts <500/µL, immune‐suppressive medication, and an impaired humoral immunity or an impaired gastric or mucosal barrier.

  • All health problems reported by travelers.

  • Relevant travel‐related disease.

Preexisting Medical Conditions

Main groups consisted of travelers with HIV, a reduced gastric barrier, diabetes mellitus, and immune‐suppressants, as shown in Table 2.

View this table:
Table 2

Differences in travel‐related disease (TRD) occurrence among travelers with pre‐existing conditions, compared to healthy travelers

NTRDTraveled weeksIRR*
Total underlying medical conditions 345991148.142.16 (1.21–3.86)
Immune suppressants8829291.712.49 (1.29–4.79)
 1. Prednisolone156473.20 (1.21–8.42)
 2. Antimetabolites18651.432.95 (1.12–7.76)
 3. Transplant‐related drugs18954.574.10 (1.75–9.60)
 4. Chemotherapeutic agents31686.431.75 (0.67–4.60)
 5. Tumor necrosis factor‐alpha blockers24683.431.81 (0.69–4.77)
Gastric barrier reduced 6620188.572.65 (1.32–5.33)
Diabetes mellitus5413158.862.05 (0.95–4.42)
 IDDM3810107.292.34 (1.03–5.34)
 NIDDM16351.571.45 (0.41–5.08)
HIV3212133.862.24 (1.16–4.92)
 CD4 <500/µL19858.863.40 (1.40–8.20)
 CD4 >500/µL134751.33 (0.43–4.10)
Healthy travelers10013326.14Reference group
  • Patients with various pre‐existing conditions compared to those with no pre‐existing conditions.

  • IRR = incidence rate ratio; IDDM = insulin‐dependent diabetes mellitus; NIDDM = noninsulin‐dependent diabetes mellitus.

  • * IRRs with 95% confidence intervals.

  • Some travelers had several medical conditions.

  • Out of 66 patients with an impaired gastric barrier, 65 were due to a medical and 1 due to a surgical intervention.

Of 345 patients, 90 were aged over 60. Many of these 60+ travelers had a cardiac disorder (37/90, 41%), a reduced gastric barrier (32/90, 35.6%), or diabetes mellitus (15/90, 16.7%).

At least one health problem was reported in 144 (39.7%) patients. We excluded 45 noninfectious health problems, resulting in 99 (27.8%) relevant health problems.

Compared to healthy travelers, all pre‐existing conditions had a high risk of TRD (Table 2). The highest IRRs were found for travelers using immune‐suppressants, specifically transplant‐related drugs, prednisolone, and antimetabolites.

HIV positives with CD4 counts <500/µL and those with reduced gastric barriers also had high IRRs. No difference was found between age >60 and <60 within the group with underlying conditions [IRR 1.03, 95% CI (0.64–1.65)].

Hepatitis B Serology

Protective hepatitis B serology was observed among 78 of 420 (18.6%) travelers with a medical history. In 71 (91.0%) travelers, serologic protection (anti‐HBs GMT > 10UI/L) was recorded. In 7 (9.0%) travelers, serology showed an active hepatitis B infection. In addition, 27 (6.4%) travelers of the same group were vaccinated against the virus but protection was not verified serologically. Among the other 315 (75%) travelers with a medical history, all serologic markers were either negative (8.1%) or unknown (66.9%) (data not shown).

Travel Destinations

Popular destinations were Africa (36.4%), Asia (31.9%), and Central/South America (19.6%) (Figure 1). Countries visited most frequently were Indonesia (61 visits), Surinam (55 visits), Ghana (39 visits), and Thailand (35 visits).

Figure 1

Rates of visits per country. Rates of visits to each country of the group with underlying medical conditions. Popular destinations were Africa (36.4%), Asia (31.9%), and Central/South America (19.6%). The most frequently visited countries were Indonesia (61 visits), Surinam (55 visits), Ghana (39 visits), and Thailand (35 visits).

Table 3 shows the effect of travel destinations compared to Southeast Asia on TRD. The highest IRRs were observed for travelers to Central America [IRR 2.78, 95% CI (0.95–8.10)] encompassing Mexico, Guatemala, Honduras, Nicaragua, Costa Rica, Panama, Belize, and El Salvador; Northeast Asia [2.20, (0.65–7.36)] encompassing China, Japan, and Mongolia; South Central Asia [1.96, (0.95–4.07)] encompassing Myanmar, Thailand, Cambodia, Laos, Vietnam, Indonesia, Malaysia, Singapore, and the Philippines; and North Africa [1.92, (0.94–3.90)] encompassing Morocco, Western Sahara, Algeria, Tunisia, Libya, Egypt, Sudan, and South Sudan. No increased risk was found for those visiting friends and relatives [0.53, (0.32–0.88)].

View this table:
Table 3

Relevant travel‐related disease (TRD) in 345 travelers with underlying medical conditions visiting various travel destinations with Southeast Asia as a reference group

NTRD*Traveled weeksIRsIRR
Caribbean83230.131.81 (0.54–6.08)
Central America7419.570.202.78 (0.95–8.10)
Middle East24545.860.111.51 (0.57–4.01)
North Africa371286.570.141.92 (0.94–3.90)
Northeast Asia6318.710.162.20 (0.65–7.36)
South America559230.710.040.54 (0.25–1.18)
South Central Asia231178.430.141.96 (0.95–4.07)
Southeast Asia8321292.430.07Reference group
Sub‐Saharan Africa8526291.710.091.24 (0.70–2.20)
Europe10115.570.060.87 (0.12–6.46)
  • IRR = incidence rate ratio.

  • * TRD for various travel destinations with Southeast Asia as a reference group, compared by a chi‐square test.

  • IRRs with 95% confidence intervals. Seven patients went on a world trip, these data are not included in the table.

Travel Duration

The average travel duration for those with TRD was 27.3 days and for those without TRD 21.9 days [p = 0.03, mean difference 5.39; 95% CI (1.53–9.25)].

Travel‐Related Health Problems

In Table 4, various types of reported travel‐related health problems are presented. Acute gastrointestinal disorders were reported most frequently. There were no reports of vaccine preventable diseases or malaria.

View this table:
Table 4

Specific travel‐related diseases (TRDs) in various groups of travelers with underlying medical conditions and healthy travelers

Immune‐suppressantsAge > 60Gastric barrier reducedDiabetes mellitusHIVOverall underlying conditionsHealthy
N2922201312* 99* 13
GI : acute diarrhea18 (62.1)11 (50.0)10 (50.0)6 (46.2)7 (58.3)54 (54.5)6 (46.2)
GI : chronic diarrhea3 (10.3)2 (9.1)3 (15.0)1 (7.7)1 (8.3)10 (10.1)1 (7.7)
GI : other0 (0.0)0 (0.0)0 (0.0)0 (0.0)0 (0.0)2 (2.0)0 (0)
Fever4 (13.7)2 (9.1)1 (5.0)2 (15.4)1 (8.3)13 (13.1)0 (0)
Dermatological1 (3.4)2 (9.1)3 (15.0)1 (7.7)1 (8.3)6 (6.1)3 (23.1)
Respiratory2 (6.9)4 (18.2)2 (10.0)2 (15.4)2 (16.6)9 (9.1)0 (0)
Other0 (0.0)1 (4.5)1 (5.0)1 (7.7)0 (0.0)5 (5.1)3 (23.1)
  • * In one of the HIV patients, two episodes of TRD were reported. In the overall group with underlying conditions, three persons had two episodes of TRD.

  • GI = gastrointestinal tract disease.

Twenty‐five patients were treated with antibiotics [15 (60.0%) for diarrhea, 5 (30.0%) for respiratory disease, and 5 (30.0%) for other disease]. In 8 (32%) cases, the antibiotics used were those prescribed pre‐travel. The mean duration of disease was 11.63 days in this group versus 12.94 days in the groups in which they were not prescribed as (emergency) self‐treatment [p = 0.82, mean difference 1.31; 95% CI (−10.39 to 13.00)].

Conclusions

We presented an overview of various groups of travelers with underlying medical conditions, their travel destinations, and risk of obtaining TRD. Although results are based on small numbers of individuals, interesting observations on specific health problems were made.

We found that (1) travelers with underlying conditions are at increased risk for health problems, specifically those using immune‐suppressive medication, HIV positives with CD4 counts <500/µL, and those with a reduced gastric barrier; (2) traveling to Central America, South Central Asia, Northeast Asia, and North Africa was associated with an increased risk of TRD; (3) gastrointestinal symptoms were reported most frequently; (4) we found a low protection rate against hepatitis B in travelers with underlying conditions.

The fact that we found most groups of travelers with underlying medical conditions to be at increased risk for health problems is an important finding. However, as not all recent studies point to the same conclusion, 11 further prospective research on this topic is definitely useful.

An impaired cellular response among patients using immune‐suppressive medication probably accounts for the high rate of TRDs.3 Risk of infection for HIV positive patients depends on CD4 counts. With higher and stable CD4 counts, travel risks are considerably lower.2,9,12 This is illustrated by the difference in IRR we found among those with CD4 counts >500/µL [IRR 1.33, 95% CI (0.43–4.10)] and <500/µL [3.40, (1.40–8.20)]. Reduced mucosal and gastric barriers are known causes of increased risk of contracting gastroenteritis.12,13

In the group with underlying conditions, travelers aged >60 were not found to have an increased risk of contracting TRD compared to travelers aged <60. This is in accordance with previous studies 14,15 and despite waning immunity, as described elsewhere.5,16

For diabetics, an increased risk for TRD was found, specifically for those with insulin‐dependent diabetes mellitus (IDDM). Although it is widely accepted that hyperglycemia causes a higher propensity for infections 17,18 and that metabolic dysregulation in IDDM patients is a frequent problem, 19 there is controversy about the susceptibility to infections in diabetics. A study by Baaten and colleagues, for example, showed that diabetic travelers have a low risk of infection compared to healthy controls.20

The types of health problems (gastrointestinal problems, fever, dermatological, and respiratory complaints) were similar to those described previously in healthy populations.10

Gastrointestinal complaints were most frequently reported (66.7% of all TRDs, 19.1% overall attack rate). Previously, travelers' diarrhea has been described with attack rates ranging from 34.4% 21 to 52% 12 in general populations. An explanation for our lower percentage might be our more narrow definition of travelers' diarrhea.

In a study by Freedman and colleagues, 33.5% of 17,353 ill‐returned travelers reported gastrointestinal disease.10 We can therefore conclude that our overall attack rate is low (18.5%), but the relative percentage of gastrointestinal disease (66.7%) is high compared to other studies. This high percentage could be explained by our exclusion of noninfectious diseases.

Only 18.6% of the population with a medical history had a known protective hepatitis B titer. Importantly, in this population, 2.6% were admitted in a foreign health‐care facility. The WHO has advised all countries to integrate universal hepatitis B vaccination into their national immunization programs by 1997.22 Until recently, such a program was not implemented in the Netherlands, because there is a low carrier rate of hepatitis B in the Dutch population.23 In developing countries, however, prevalence is high compared to Europe and North America 24 and unsafe needle practices are still common.25 Moreover, the disease may follow a more severe course in patients with an impaired immune system.26 Possibly, vaccination against this virus could more often be considered in this group of travelers.

This study has several strengths, as well as weaknesses. Regarding strengths, due to the broad inclusion criteria, all groups that visited the travel clinic and all frequently visited destinations could be described. Additionally, specific groups could be assessed in detail and an indication of the risks for various regions could be assessed.

However, because of the retrospective nature of this study, details on the timing and exact symptoms of health problems may not be reliable. Also, not much detail on the etiology of reported diseases could be acquired. Because our control group was relatively small, low statistical power could have obscured and influential observations (eg, on travel habits) could have exaggerated observed associations.

In conclusion, we found that travelers with underlying conditions were at increased risk for TRD compared to healthy travelers. Prospective studies are needed to assess whether broader indications for (emergency) self‐treatment antibiotics and hepatitis B vaccination might reduce morbidity. Also, prospective research should assess the pathogenic causes of travel‐related health risks of at least the largest groups of travelers with underlying medical conditions.

Declaration of Interests

The authors state that they have no conflicts of interest.

Acknowledgments

We thank all staff of the Center of Tropical Medicine and Tropical Medicine at the Academic Medical Center, University of Amsterdam for their support and Gerard Cohen Tervaert for critically reading the manuscript. Part of this paper has been prepared by R. W. as final‐medical‐studies research project.

References

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