Abstract

Despite the worldwide distribution of Coxiella burnetii, Q fever is not a frequent infection in travelers. This disease should be considered in recent travelers from the tropics with unknown fever, headache, raised liver enzymes, and low platelets. Five cases in western travelers to the tropics returning with fever are presented.

Q fever is a zoonotic disease caused by Coxiella burnetii, a gram‐negative, obligate, intracellular bacterium in eukaryotic cells that share characteristics with Rickettsia, Legionella, and Francisella. It has the capability to survive permanently inside the macrophages, causing a chronic disease after an acute episode. Another characteristic is its antigenic variation, called phase variation. The bacteria can enter in a sporulation‐like process, conferring resistance to some adverse environmental conditions, facilitating its dissemination. It is acquired by spore inhalation or by ingestion of raw milk or food from contaminated animals. Domestic animals, above all ungulates and occasionally pets (cats, rabbits, and dogs), are known reservoirs of these bacteria, and persons at risk include those exposed to farm animal and products, typically farmers, veterinarians, and abattoir workers. The clinical presentation is usually benign, polymorphic, and nonspecific, varying from asymptomatic cases, acute Q fever (isolated fever, atypical pneumonia, and hepatitis) to chronic Q fever (endocarditis and vascular infections).1–3

Despite the fact that it is a frequent disease and distributed worldwide, surprisingly it is rarely described in travelers.4–13 Five cases of Q fever in western febrile travelers from the tropics are presented.

Patients and methods

This is a retrospective study of patients in whom Q fever was diagnosed at the Tropical Medicine and Clinical Parasitology Unit, Infectious Diseases Department, Ramón y Cajal Hospital, Madrid, from January 1996 through December 2006. The Q fever screening test was carried out for every returned traveler (outpatients and inpatients), taking into consideration the patient’s clinical features: fever, pneumonia, hepatitis, headache, etc., as well as to perform other tests. An unexplained fever may be suspected to have other infections in returning travelers such as Epstein–Barr virus, cytomegalovirus, dengue, Mediterranean spotted fever, enteric fever, viral hepatitis, brucellosis, malaria, or legionellosis. Diagnosis of Q fever was confirmed by immunofluorescence (IF) (indirect IF; BioMérieux S.A., Marcy l’Etoile, France). Indirect IF is the reference method for serological diagnosis of C burnetii infection with a high level of sensitivity and specificity, whereas complement fixation tests take longer time to become positive and are less specific and sensitive. In our microbiology laboratory to diagnose an acute Q fever infection, we perform a semiquantitative IF assay [unique dilution of serum, 1 in 80 for immunoglobulin (Ig) G and 1 in 20 for IgM], in which outcomes are informed by symbols and the titers level these correspond to are: (−), approximately equal to <80 negative values; (+), approximately equal to 80 to 200 weak positive; (++), approximately equal to 200 to 800 medium positive; and (+++), approximately equal to >800 high positive.

The definitive diagnosis of acute Q fever is based on the detection of antibodies IgM and/or seroconversion of antibodies IgG in pairs of serum separated by 2 to 4 weeks. In infections with prolonged course, there are high titer levels maintained of IgG without IgM. The diagnosis of acute Q fever is characterized by elevated antibodies against phase II antigens by IF (IgG ≥ 200 and IgM ≥ 50), while chronic Q fever is diagnosed by antibodies against phase I antigens (IgG ≥ 800). To avoid misleading results, we consider that IgG antibodies to phase I antigens should not be performed in every patient unless there is any clinical suspicion of chronic disease. None of our five patients present clinical evidence of chronic infection.

Results

Among 1,990 returned travelers, 708 febrile travelers (35.8%) were evaluated and five cases of Q fever identified among those with fever (frequency 0.7%). A description of the clinical and epidemiological features of the patients is shown in Table 1.

Table 1

Clinical and epidemiological features of five travelers with Q fever*

Patient Age/gender Type of travel/country/duration of stay Suspected epidemiological exposure/time elapsed in between arrival and onset of symptoms Clinical presentation Laboratory and image test IgM‐II Q fever serology IgG‐II Q fever serology Treatment Outcome 
32/male Business/Mozambique/5 d Indirect contact with animals (shed)/18 d Fever, severe headache, arthralgia, myalgia, splenomegaly P: 90,000; SGOT: 100; SGPT: 92; normal and sterile CSF; normal CxR Acute: −; convalescent: +++ Acute: −; convalescent: +++ Doxycycline Symptoms during 15 d; no complications 
22/female Tourism/Philippines/60 d Rural areas/10 d before arrival Fever, headache, myalgia, splenomegaly P: 13,000; SGOT: 71; SGPT: 51; CxR not performed Acute: +++; convalescent: − Acute: +++; convalescent: +++ Doxycycline Symptoms during 120 d; no complications 
32/male Tourism/Kenya/12 d Rural areas/10 d Fever, headache, malaise, constipation, hepatosplenomegaly P: 98,000; SGOT: 1,160; SGPT: 1,106; normal CxR Acute: −; convalescent: +++ Acute: −; convalescent: +++ Ciprofloxacine Symptoms during 7 d; no complications 
28/male Tourism/Venezuela and Dominican Republic/15 d Rural areas, contact with animals (horses)/2 d Fever, headache, arthralgia, myalgia, ocular pain, constipation, nonproductive cough, hepatosplenomegaly P: 61,000; SGOT: 115; SGPT: 112; normal CxR Acute: +++; convalescent: +++ Acute: −; convalescent: +++ Doxycycline Symptoms during 30 d; no complications 
33/male Tourism/Ivory Coast and Burkina Faso/30 d Rural areas/13 d Fever, hepatomegaly, tachyarrhythmia P: 56,000; SGOT: 62; SGPT: 91; normal CxR; normal TTE Acute: ++; convalescent: − Acute: ++; convalescent: +++ Doxycycline Symptoms during 40 d; no complications 
Patient Age/gender Type of travel/country/duration of stay Suspected epidemiological exposure/time elapsed in between arrival and onset of symptoms Clinical presentation Laboratory and image test IgM‐II Q fever serology IgG‐II Q fever serology Treatment Outcome 
32/male Business/Mozambique/5 d Indirect contact with animals (shed)/18 d Fever, severe headache, arthralgia, myalgia, splenomegaly P: 90,000; SGOT: 100; SGPT: 92; normal and sterile CSF; normal CxR Acute: −; convalescent: +++ Acute: −; convalescent: +++ Doxycycline Symptoms during 15 d; no complications 
22/female Tourism/Philippines/60 d Rural areas/10 d before arrival Fever, headache, myalgia, splenomegaly P: 13,000; SGOT: 71; SGPT: 51; CxR not performed Acute: +++; convalescent: − Acute: +++; convalescent: +++ Doxycycline Symptoms during 120 d; no complications 
32/male Tourism/Kenya/12 d Rural areas/10 d Fever, headache, malaise, constipation, hepatosplenomegaly P: 98,000; SGOT: 1,160; SGPT: 1,106; normal CxR Acute: −; convalescent: +++ Acute: −; convalescent: +++ Ciprofloxacine Symptoms during 7 d; no complications 
28/male Tourism/Venezuela and Dominican Republic/15 d Rural areas, contact with animals (horses)/2 d Fever, headache, arthralgia, myalgia, ocular pain, constipation, nonproductive cough, hepatosplenomegaly P: 61,000; SGOT: 115; SGPT: 112; normal CxR Acute: +++; convalescent: +++ Acute: −; convalescent: +++ Doxycycline Symptoms during 30 d; no complications 
33/male Tourism/Ivory Coast and Burkina Faso/30 d Rural areas/13 d Fever, hepatomegaly, tachyarrhythmia P: 56,000; SGOT: 62; SGPT: 91; normal CxR; normal TTE Acute: ++; convalescent: − Acute: ++; convalescent: +++ Doxycycline Symptoms during 40 d; no complications 

(−) = approximately equal to <80 negative values; (++) = approximately equal to 200 to 800 medium positive; (+++) = approximately equal to >800 high positive; CSF = cerebrospinal fluid; CxR = chest x‐ray; Ig = immunoglobulin; IgG‐II Q fever serology = antiphase II IgG antibodies against Coxiella burnetii detected by indirect immunofluorescence test; IgM‐II Q fever serology = antiphase II IgM antibodies against C burnetii detected by indirect immunofluorescence test; P = platelets (cells/μL); SGOT = aspartate aminotransferase (IU/L); SGPT = alanine aminotransferase (IU/L); TTE = transthoracic echocardiogram.

*

Convalescent serum taken 2 to 4 weeks after the acute phase.

All five patients were healthy, young, immunocompetent Caucasians, with no history of disease, neither surgical procedure nor drug allergy. None of them had previous heart valvular damage disease.

Of the cases of Q fever, there were four men and one woman with a mean age of 29 years (range 22–33 y), and all were short‐term travelers to the tropics (range 5–60 d, mean 24 d). Three patients had traveled to sub‐Saharan Africa, one to Latin America, and one to Asia. Four were tourism trips and one was business related.

History of direct exposure to animals was present in two patients. The other three patients had not been directly exposed to animals but had been staying in rural areas.

Of the five cases of Q fever diagnosed, only one of them (patient 2) had symptoms that started out before returning to Spain, and in the rest of the patients, the average time having passed was 10.75 days (range 2–18 d). The symptoms’ median duration was 42.4 days (range 7–120 d).

All five patients presented with fever, three had arthralgia and myalgia, four had headache, three showed gastrointestinal symptoms, one had ocular pain, one with dry cough, one with conjunctival jaundice, and one with malaise. None had shortness of breath or other clinical severity criteria. On physical examination, two patients had hepatosplenomegaly, two had splenomegaly, and one had hepatomegaly. Chest radiography was normal in all patients.

The patient who traveled to Mozambique presented with meningitis‐like symptoms, but analysis of cerebrospinal fluid yielded normal results. Another patient’s clinical presentation at onset was tachyarrhythmia, which resolved after treatment with digitalics.

Laboratory findings at admission showed normal white blood cell counts, thrombocytopenia (range 13,000–98,000; mean 63,600 cells/μL), and abnormal liver function test (range: aspartate aminotransferase 62–1,160 and alanine aminotransferase 51–1,106) in all five patients.

Two patients presented initially a negative serology but seroconverted in the second serum, 4 weeks later.

The treatment proposed to patients, either doxycycline 100 mg twice a day for 14 days or ciprofloxacine 750 mg twice a day for 14 days, is part of a standardized empirical treatment against some infections, which includes Q fever, leptospirosis, rickettsiosis, and typhoid fever.

Patient 4 received both doxycycline and ciprofloxacin because of a previous misinterpretation of Salmonella typhi serology. Patient 5 was initially treated with both doxycycline and rifampin, but when endocarditis was ruled out, treatment with rifampin was interrupted. No complications were observed and nobody developed a chronic Q fever stage.

Discussion

Despite the worldwide distribution of C burnetii, Q fever is not a frequently reported disease in travelers, with less than 50 cases described in the literature during the past three decades in international travelers.4–13 Furthermore, a recent review of data from GeoSentinel found only six cases of Q fever among 3,842 travelers presenting a systemic febrile illness (frequency 0.15%): five were travelers and one was a migrant traveler (D. O. Freedman, personal communication 2006 ). Outbreaks in groups of travelers remain anecdotal.5

In most published series in nontravelers, the infection varies widely from asymptomatic cases (which represent about 50% of cases) and self‐limited flulike syndromes to prolonged fever forms with different grades of hepatic or pulmonary involvement and prolonged fevers of unknown origin. Frank hepatitis is rare, but hepatomegaly and raised liver enzymes are common.2 There is one case of fatal hepatitis in an Icelandic traveler 8 and another with acute hepatitis returning from the Canary Islands.10

In countries like Spain, where Q fever is endemic, differentiation between autochthonous and imported Q fever could be problematic, especially because the incubation period can be as long as 40 days. However, none of the present cases had recently visited endemic areas in Spain, and all developed symptoms shortly after return from abroad. Also, the serological pattern was compatible with acute disease in all of them, making more likely the possibility of imported rather than autochthonous Q fever.

White cell count is usually normal in acute disease, and thrombocytopenia is present in 25% of cases.1–3 All our patients presented typical clinical signs of acute flulike disease, with symptoms starting soon after return. Symptoms and signs may vary and are nonspecific; therefore, diagnosis can eventually be missed if Q fever is not considered. In previous descriptions of Q fever in travelers, some asymptomatic patients were diagnosed from a retrospective survey prompted by an index case.5,9 Moreover, the development of fever of unknown origin, accompanied by headache, abnormal liver function tests, and thrombocytopenia could also suggests other more common diagnoses in a returned traveler from the tropics, particularly malaria, dengue, and enteric fever.

In our series, only two of five patients (40%) reported direct contact with animals. The absence of history of direct exposure does not rule out the possibility of Q fever as contact may be indirect.

The treatment of choice for acute Q fever is doxycycline twice a day during 2 weeks. Fluorquinolones, macrolides, and cotrimoxazole are second‐choice drugs. Antibiotics can shorten the duration of fever if administered promptly but might not have any impact on outcomes during the acute phase if administered after the third day of fever.2 Mortality rate in acute illness is 2.4%, and administration of antibiotic treatment is possibly preventing development of chronic Q fever.

Though Q fever is endemic in many countries, it is uncommon in travelers. This is probably due to insufficient practitioner awareness and underdiagnosis. It should be considered in recent travelers from the tropical and subtropical countries with fever of unknown origin, headache, raised liver enzymes, and low platelets. Absence of direct animal contact does not rule out this infection. Clinical features of Q fever in travelers do not differ from those observed in nontravelers.

Declaration of interests

The authors state that they have no conflicts of interest.

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