Fever, dyspnea, and hepatitis in an Iraq veteran

A healthy 42-year-old US Army reservist returned home to Oregon in early April after a 12-month deployment in Iraq. About 6 weeks later, he developed a mild nonproductive cough; then, over the next 2 weeks, his symptoms progressed to myalgia, mild headache, fever, chills, drenching night sweats, and dyspnea on exertion.

About 2 weeks after the onset of his symptoms, he saw his primary care provider. The results of laboratory tests at that time were normal except for the following:

• Platelet count 110 × 10⁹/L (reference range 150–400)
• Alkaline phosphatase 354 IU/L (40–100)
• Alanine aminotransferase 99 IU/L (5–36)
• Aspartate aminotransferase 220 IU/L (7–33).

Chest radiography was negative. He was told he had a viral infection and was sent home with no treatment.

1. Which of the following is the most likely diagnosis in this patient?

• Influenza
• Ehrlichiosis
• Q fever
• Visceral leishmaniasis
• Malaria

Military operations in Iraq and Afghanistan have involved large numbers of US Army Reserve and National Guard personnel: by 2007, more than 500,000 Reserve and National Guard personnel had served in these combat operations.¹ Although these personnel are generally healthy and receive mandatory travel screenings, prophylactic drug treatment, and vaccinations, their close, long-term exposure to local populations and environments puts them at risk of many infections.²

Often, these veterans develop symptoms after returning home, and they seek medical care from providers outside the military medical system.^3,4 Civilian health care providers are thus increasingly called on to recognize clinical syndromes associated with military operations.

FEVER IN RETURNED SOLDIERS

The presentation of this 42-year-old veteran has an extensive differential diagnosis. His symptoms arose more than a month after his return from Iraq, meaning he could have acquired an infection in Iraq, on his trip home, or even after arriving home.

A number of common viral and atypical respiratory pathogens could be involved, and although circulating influenza was not common at the time of year he happened to return (spring), it remains a possibility. However, the duration of his illness, with symptoms that gradually worsened over 12 days, argues against influenza and community-acquired respiratory and other viral illnesses.

Aronson et al⁵ have reviewed the infectious risks in deployed military personnel.⁵ Infectious syndromes that have manifested in military personnel a month or more after returning from Iraq or Afghanistan include malaria, Q fever, brucellosis, typhoid fever, and leishmaniasis.⁵

Malaria

Malaria should be considered in all travelers from endemic areas presenting with fever, especially if they have thrombocytopenia and anemia. Plasmodium vivax is present in Iraq, but transmission is rare and isolated. Defense Medical Surveillance System data show that most of the recent malaria cases in US military personnel were acquired in Afghanistan or Korea. Many of these cases were caused by P vivax and manifested weeks to months after exposure, and diagnosis was significantly delayed because the provider did not consider malaria in the differential diagnosis.^4,6,7

Testing for malaria with serial thick and thin blood smears and the BinaxNOW (Iverness Medical, Princeton, NJ) rapid test, when available, should be done in all those who have served in malaria-endemic regions and who present with unexplained fever or consistent symptoms. Testing should be done even if prophylaxis was taken or the potential exposure was weeks to months before presentation.

Brucellosis

Brucellosis, a zoonosis typically acquired by ingesting unpasteurized dairy products, has a high prevalence in Eurasia. A nonspecific, multisystem illness with fever, hepatitis, and arthritis (classically sacroiliitis) is commonly described.

Brucellosis is less likely in our patient, given that he denied consumption of local dairy products while deployed. Also, he had prominent respiratory symptoms, which would not be typical of brucellosis.

Leishmaniasis

Leishmaniasis, a parasitic disease transmitted by sand flies, manifests in one of three ways, ie, as a cutaneous, a mucosal, or a visceral disease. Most infections recently reported in US military personnel have been cutaneous and were acquired in Iraq, where Leishmania major is the primary species.⁸ Visceral disease mimics lymphoma (fever, hepatosplenomegaly, and cytopenia), but only a handful of cases have been reported from Iraq and Afghanistan.⁹ The incubation period of visceral leishmaniasis is prolonged, and civilian providers should consider it even if the patient’s period of deployment was relatively long ago.

Q fever in military personnel

Q fever is caused by the intracellular bacterium Coxiella burnetii.

Q fever has been reported in more than 150 US military personnel deployed to Iraq and Afghanistan.^10–12 However, it may be more common than that. In one report, 10% of patients admitted to a combat support hospital in Iraq with International Classification of Diseases, Ninth Revision codes potentially consistent with Q fever tested positive for it.¹³ And in several cases that manifested after deployment, Q fever was not considered initially by the health care provider.^11,14 In response, the US Centers for Disease Control and Prevention (CDC) released a health advisory in May 2010 alerting providers about Q fever in travelers returning from Iraq and the Netherlands.¹⁵

Q fever is a zoonosis associated with a wide range of animal reservoirs, primarily agricultural livestock such as cattle, goats, and sheep, but also a variety of other animals. There are multiple routes of transmission, including direct animal contact, ingestion of unpasteurized dairy products, and, most commonly, inhalation of aerosolized particles contaminated by animal droppings or secretions.¹⁶ Tick-borne and sexual transmission have been reported in rare instances.^17,18 Importantly, in many cases from Iraq and from an outbreak in the Netherlands there was no obvious exposure.¹⁹

Q fever is a potential agent of bioterrorism; therefore, a large-scale, single-point outbreak should raise concern about a possible intentional release of the organism.²⁰

Q fever has myriad presentations

About 60% of cases of Q fever infection are asymptomatic.²¹ In the United States, the estimated seroprevalence is 3%. Such a high seroprevalence, despite the relatively small number of reported cases, suggests that this infection is often subclinical.²²

After 2 to 3 weeks of incubation, Q fever infection can produce a wide range of presentations involving almost any organ system (Table 1).¹⁶ An influenza-like illness with fever, pneumonia, and hepatitis is classic. Often, headache is severe enough to warrant lumbar puncture. Atypical and often severe presentations include gastrointestinal or neurologic manifestations.^23–25 Rates of hospitalization and in-hospital death are low in acute disease: hospitalization occurs in roughly 2% of cases, and death in about 1% of those hospitalized.^26,27

The presentation may mimic that of conditions caused by common community pathogens such as Legionella, Rickettsia, cytomegalovirus, Ebola virus, influenza, Mycoplasma, and human immunodeficiency virus (primary infection). Heightened suspicion is needed to prevent delays in diagnosis and treatment.

This patient’s symptoms and his recent deployment made Q fever very likely.