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Managing your differential diagnosis list: considering bias and recognizing unexpected infectious agents.

Many recent veterinary school graduates will recall 2 pieces of advice; "when you hear hoof beats, think horses, not zebras," and "the simplest explanation is usually the correct one." In any medical field, these "tidbits" are crucial to keeping providers' differential diagnosis list concise and making sure it is prioritized correctly. When teaching new veterinary or medical students, it is logical that one should not spend as much time on diseases that they are less likely to see in practice. For example, veterinary students outside of the Pacific Northwest may only learn about Salmon Poisoning Disease (SPD) in the theoretical sense as they may never see a case during their studies, let alone treat a patient while in school. SPD is a disease caused by the bacterium Neorickettsia helmintheoca which is carried by the fluke, Nanophyetus salminocola. The fluke is found most classically in salmon, which is why the disease is so common in the Pacific Northwest. Thus, veterinary students in that area will be far more likely to see and treat the disease while in school than their colleagues in other locations. It causes a sudden onset of vomiting, diarrhea, decreased appetite and lethargy, and is often fatal without appropriate treatment. (1) The importance of this geographic bias is illustrated by the experiences of a recent Veterinary Corps officer (VCO) at Joint Base Lewis-McChord (JBLM) who saw a 3-year-old female spayed Labrador presenting for vomiting, diarrhea, and decreased appetite of about 5 days duration. The VCO considered the typical differentials; foreign body, gastroenteritis, infectious causes, nongastrointestinal signs, but did not consider SPD as she went to school in another area and was thus unfamiliar with the disease. Luckily a senior clinician at the clinic brought SPD to the VCO's attention. The diagnosis was confirmed and the dog was treated successfully. This example serves as a reminder to clinicians that geographical bias can preclude the correct diagnosis.

Army VCOs must ensure they account for their regional biases when seeing patients. Due to the international and mobile nature of the Department of Defense and its members, these geographic "zebras" are even more likely to walk into our exam rooms. Recognizing and addressing these biases is important, not only for treating the individual patient but also for general public health. Many of the diseases discussed below are communicable and potentially zoonotic. When we are asking questions about a pet's history and performing our physical exam, we must recognize our own biases and remind ourselves to use a problem-oriented approach to our patients. In doing so, we can remind ourselves that while those biases might be valid in certain situations, they may hinder an accurate diagnosis in another. Furthermore, we must consider diseases that are endemic in the patient's previous geographic location or areas to which the pet may have traveled. Remembering our biases and considering travel will help practitioners manage their differential diagnosis list.

RECOGNIZING BIAS AND UNCOVERING "ZEBRAS"

As explained above, certain diseases are not discussed in detail at veterinary schools in different geographical locations because they are absent or have a very low prevalence which may lead to a basic geographical bias preventing us from considering different causative agents. Veterinary clinicians may leave certain diseases off of their differential diagnosis list because they have not considered travel (whether international or within the United States). This travel may be by the presenting animal, disease vectors, owners, or other domestic and wild animals with which the patient had contact. Failure to account for this geographic bias may result in numerous diseases not considered, although those diseases could be the cause of the patient's clinical signs.

One source of bias is failure to account for the international movement of humans and animals from areas with different endemic diseases. For example, rabies has been around for thousands of years and has great public health significance, but it is often not included on differential diagnoses lists for neurologic canine patients within the United States. International travel allows rabies to enter new geographic regions, and should make it mandatory to include on the differential diagnosis list for any animal with neurologic symptoms. The canine rabies virus variant, associated with dog-to-dog transmission, is most often responsible for the estimated 55,000 human rabies virus deaths worldwide each year. (2) By contrast, there were 5,000 rabid dogs reported in the United States in 1950. That number was down to 79 in 2006, when the canine rabies virus variant was declared eradicated in the United States. (3) Today, rabies is well controlled in the United States due to effective and readily available vaccines along with stray animal control. Consequently, when presented with a neurologic case in the United States, many clinicians may not initially consider rabies as a possible differential. However, recent events have served as reminder to the military importance of rabies. This disease is enzootic in the Middle East where many of our Soldiers deploy. Unfortunately, Soldiers may not understand why they are not allowed to keep stray dogs as pets; the stray dog may remind them of home, and they are often very resentful when these "pets" are removed. In fact, there are several organizations who are dedicated to bringing these stray dogs from the Middle East to the United States, and other countries, to be reunited with the Soldiers. This action has directly resulted in at least one case of a rabid dog being imported into the United States, and the exposure of numerous American citizens to the deadly rabies virus. (4) The act of keeping pets while deployed, although against policy, has also resulted in the unfortunate and unnecessary death of a Soldier from rabies and countless others receiving postexposure prophylaxis; a treatment which can be both painful and expensive. (5) It is so important for Veterinary Corps officers and other medical providers to understand the prevalence of rabies and other endemic diseases where our Soldiers deploy, when considering differential diagnoses. This is also a concern for civilian veterinarians as they are even less likely to include foreign diseases such as rabies on a differential list, but it is possible for them to see a dog adopted from an area where those diseases are endemic. Rabies is a real possibility, even in the United States, when you consider the mobility of our population and the possibility of international travel.

But there are also other "zebras" to consider which are far more likely within the United States, but are still often overlooked due to "localized" geographical location. Lyme disease, for example, is caused by Borrelia burgdoferi, a bacterium carried by the Ixodes tick, the most common in the United States being I scapularis and Ipacificus. Previously, Lyme disease has had a few endemic areas of the United States, most commonly in the northeast (by far the most common location), while also being reported with some frequency in Wisconsin, Minnesota, California, and Oregon. (6) Recent surveillance data indicates that Lyme disease is increasing in terms of reported cases, as shown in the Table. (7) A review of Centers for Disease Control and Prevention data clearly shows an expansion (illustrated in the Figure) of Lyme from those previously endemic areas to many cases in previously unaffected states as it is now present in all of the lower 48 states. Over the last few decades, Lyme disease has spread for a variety of reasons including temperature, moisture, forest cover, and population density. All of these factors were used by the Companion Animal Parasite Council to predict the spread of Lyme disease occurrence within the United States. (8) Lyme disease can present with numerous signs including fever, lameness, anorexia, lethargy, and lymphadenopathy, and may or may not present with swollen joints. (1) These general signs can make the disease somewhat challenging to diagnose. But, there are risk factors to help clinicians determine likelihood of infection. One study evaluated the potential predictive value of canine seroprevalence as it relates to human cases of Lyme disease in a given county. The study found that there was correlation between canine seroprevalence and human incidence. Specifically, the presence of Lyme in more than 5% of dogs was associated with human Lyme incidences that were above average--the median number of human cases increased by more than 20 individuals (compared to a canine seroprevalence of 1.1% to 5%). (9) However, a much earlier study (1991) (10) was not able to prove the same association between canine and human cases. (It is important to note that the studies were performed 10 years apart and on different continents, so it is possible that the predictive value of canine Lyme cases is very location-dependent.) However, the earlier study still concluded that canines are good sentinels for human cases, given that they are much more likely to come in contact with the tick vector. They are, therefore, more likely to be infected early after the vector enters their geographic location.

Chagas' disease is another example of a diagnosis that can be missed due to geographical bias, and, according to the World Health Organization, its distribution is expanding due to the movement of people from Latin American to other locations around the world. (11) It is a parasitic disease caused by Trypanosoma cruzi that initially presents with fever, lymphadenopathy, and hepatosplenomegaly, along with other general symptoms. (7) The protozoa are spread by the Reduviidae or triatomine (kissing bug). Among humans, Chagas' disease is the most common cause of congestive heart failure in the world. (12) Within endemic areas, the disease has moved from the more rural areas into cities via human migration. (13) The infection has also been shown to spread into many southern states in the United States from Georgia to California because of the high population of animals involved in the protozoa's life cycle: raccoons, opossums and canines. It is also important to remember that eleven different species of the triatomine bug are present in the United States. Bern et al. noted that "there are more than 130 triatomine species in the Americas, many of which can be infected by and transmit T cruzi." (14) This is particularly concerning given the risk of long-term carriers with Chagas' disease. Studies have proven that a chronic phase of infection is possible in humans and they can serve as reservoirs for subsequent T cruzi infections. (15) It is theorized that chronically infected canines may also serve as potential reservoirs for canine and human disease transmission. (16) The US Department of Defense trains all of its military working dogs (MWDs) at Lackland Air Force Base (AFB) in San Antonio, Texas, where the disease is endemic. These MWDs are potentially exposed to Chagas' disease during training, and could serve as potential reservoirs for disease transmission at their new duty site, particularly if the MWDs are asymptomatic prior to their permanent change of station move. Multiple dogs previously located at Lackland AFB have tested positive for Chagas' antibody, and at least one MWD has died of the myocardial effects of the disease (unpublished data, Department of Defense Military Working Dog Hospital, 2014). Thus, VCOs in all areas of the United States must consider Chagas' as a diagnosis.

New or emerging diseases in certain areas of the world are also concerning given human animal and human travel. Leishmaniasis is endemic in several regions throughout the world including locations where US military personnel and animals are stationed (eg, Middle East, southern Europe). (15) A case of canine leishmaniasis was recently diagnosed at the Joint Base LewisMcChord Veterinary Center in Washington state. The patient was a 2-year-old male mixed-breed dog who initially presented to a civilian veterinarian for inability to gain weight, lethargy, and decreased appetite. A thorough history revealed that the dog was adopted from Afghanistan. Unfortunately, no records were available as to whether the dog received a health examination by an accredited veterinarian prior to travel or whether he was healthy and free of disease at that time, though the adoption agency stated that animals are free of clinical signs prior to entry into the United States. He was started on antibiotics, but because he showed no improvement, the clients brought him to the Joint Base Lewis-McChord clinic for a second opinion. At the second presentation, he had persistent weight loss in addition to 2 mm to 5 mm white nodules around his eyes and on his muzzle. These nodules were aspirated and contents examined under microscopy where it was revealed that they contained the protozoon that causes leishmaniasis, which is an obligate intracellular parasite. The patient was started on oral medications based on case reports using the medications available. Later, the client opted to move to a civilian clinic and at last follow-up was doing very well, gaining weight, increased energy, and owner-perceived less pain.

As previously mentioned, leishmaniasis is a disease of military importance; more than 600 soldiers have been diagnosed with the cutaneous form of the disease after deployments to Iraq, Kuwait, and Afghanistan. (17) Clearly, human and animal travel is playing a role in the expanding distribution of leishmaniasis cases at diagnosis. Leishmaniasis is a disease caused by the protozoa, Leishmania spp and it is spread by the sand fly. (1) Numerous different species of the protozoa have been known to cause infection including L major and L tropica which tend to cause the cutaneous form, and L infantum and L donovani which cause the visceral form. (15) This has typically only been found in areas where the sand fly is established. But there is the possibility of spread without the sand-fly vector. One meta-analysis explained that dogs can spread the disease sexually or transplacentally. (18) Additionally, while direct zoonotic transmission is believed to be a rare occurrence, (19) there are phlebotomine sand files (genus Lutzomyia) within the United States. (20) While a competent vector has not been identified, vector-borne transmission is nonetheless theoretically possible. All of these issues mean that leishmaniasis has potential to become an issue for both veterinary and human medicine in the United States, which could pose challenges for clinicians in diagnosis and successful treatment, especially considering that medications for treatment are not readily available in the United States. Late diagnosis could therefore be catastrophic for a patient in that treatment could be delayed and insufficient.

MANAGEMENT OF DIFFERENTIAL LISTS

How does the clinician manage a differential diagnosis list when theoretical possibilities are almost endless? The most important management tool is a thorough history. It is crucial that the clinician determines any travel history, human or animal, since all diseases discussed here are a concern for both human and animal health, and most are zoonotic. Another possibility is to recommend preventive measures for disease even when not in an area considered endemic. For example, should military veterinarians recommend a Lyme disease vaccine to all patients, even in those areas where Lyme is not considered endemic? In addition, clinicians must consider diagnostics, such as the bloodwork, imaging, or cytology that may help to diagnose a disease that may not even be on their differential list. This means considering tests that give enough information to direct later diagnostics and remembering to use the problem-oriented approach. Even basic tests such as in-house cytology can be crucial in identifying certain infectious diseases, including parasites or fungus. Finally, VCOs as well as other clinicians must maintain an open line of communication, meaning that we need to discuss cases, write case-reports, and otherwise keep our colleagues informed of new diseases within a geographic location. This will help our colleagues keep these "zebras" in mind.

IN SUMMARY

Every day, providers must manage cases based on the most likely explanation for the information presented. But, it is the responsibility of the provider to ensure that all of the needed information is attained. We are constantly biased by various factors as clinicians, including geographic location (as the examples above illustrate). Providers must ensure that these "zebras," and others like them, are always kept on our differential diagnosis list. It is also crucial to ensure that the historical information is complete and the physical exam is thorough. In truth, rabies virus must also be on the differential for a dog with unknown vaccination history with neurologic symptoms, and SPD should be on the list for any dog that is vomiting. How far up we rank them on the list of differential diagnoses depends on how thoroughly we conduct our patient histories and account for potential geographic biases. Only by doing so can we endeavor to reach the correct diagnoses in time to implement appropriate treatment.

REFERENCES

(1.) Kahn CM, Line S, eds. The Merck Veterinary Manual. 9th ed. New York: John Wiley & Sons, Inc; 2005.

(2.) WHO Expert Consultation on Rabies: First Report. Geneva, Switzerland: World Health Organization; 2005. WHO Technical Report Series 931. Available at: http://www.who.int/rabies/trs931_%2006_05. pdf. Accessed December 3, 2014.

(3.) Blanton JD, Hanlon CA, Rupprecht CE. Rabies surveillance in United States during 2006. J Am Vet Med Assoc. 2007; 231(14):540-556.

(4.) Centers for Disease Control and Prevention. Rabies in a dog imported from Iraq--New Jersey, June 2008. MMWR Morb Mortal Wkly Rep. 2008; 57(39):1076-1078.

(5.) Centers for Disease Control and Prevention. Imported human rabies in a US Army Soldier New York, 2011. MMWR Morb Mortal Wkly Rep. 2012; 61(17):302-305.

(6.) Heymann DL, ed. Control of Communicable Diseases Manual. 18th ed. Washington, DC: American Public Health Association; 2004.

(7.) Centers for Disease Control and Prevention. Lyme Disease [internet]. Available at: http://www.cdc. gov/lyme/stats/maps/interactiveMaps.html. Accessed October 20, 2014.

(8.) Little SE, Lund C, DeBess E. Lyme disease is expanding its range westward in 2014 [internet]. Companion Animal Parasite Council Web site; 2014. Available at: http://www.capcvet.org/expertarticles/lyme-disease-is-expanding-its-range-west ward-in-2014/. Accessed December 3, 2014.

(9.) Mead P, Goel R, Kugeler K. Canine serology as adjunct to human Lyme disease surveillance. Emerg Infect Dis. 2011; 17(9):1710-1712.

(10.) Lindenmayer JM, Marshall D, Onderdonk AB. Dogs as sentinels for Lyme disease in Massachusetts. Am J Public Health. 1991; 81(11):1448-1455.

(11.) WHO Fact Sheet No. 340: Chagas' disease (American trypanosomiasis) [internet]. World Health Organization Web site; 2014. Available at: http://www. who.int/mediacentre/factsheets/fs340/en/. Accessed December 3, 2014.

(12.) Barr S. Canine Chagas' disease (American trypanosomiasis) in North America. Vet Clin North Am Small Anim Pract. 2009; 39(6):1055-1064.

(13.) Bern C, Kjos S, Yabsley MJ, Montgomery SP. Trypanosoma cruzi and Chagas' Disease in the United States. Clin. Microbiol. Rev. 2011; 24(4):655-681.

(14.) Sarkar S, Strutz SE, Frank SM, Rivaldi CL, Sissel B, Sanchez-Cordero V. Chagas disease risk in Texas. PLos Negl Trop Dis. 2010; 4(10):e836.

(15.) Shanks GD, Karwacki JJ, Kanesa-thasan N, et al. Diseases transmitted primarily by arthropod vectors. In: Kelley PW, ed. Military Preventive Medicine: Mobilization and Deployment. Vol 2. Fort Sam Houston, TX: The Borden Institute; 2005:803-936.

(16.) Crisante G, Rojas A, Teixeira MM, Anez N. Infected dogs as a risk factor in the transmission of human Trypanosoma cruzi infection in western Venezuela. Acta Trop. 2006; 98(3):247-254.

(17.) Weina PJ, Neafie RC, Wortmann G, Polhemus M, Aronson NE. Old world leishmaniasis: an emerging infection among deployed US military and civilian workers. Clin Infect Dis. 2004; 39(11):1674-1680.

(18.) Quinnell RJ, Courtenay O. Transmission, reservoir hosts and control of zoonotic visceral leishmaniasis. Parasitology. 2009; 136(14):1915-1934.

(19.) Ferrer L. Canine leishmaniais: overview. Clinician's Brief [serial online]. April 2013. Available at: http://www.cliniciansbrief.com/article/canineleishmaniasis-overview. Accessed December 3, 2014.

(20.) Mann RS, Kaufman PE, Bulter JF. Feature Creatures: sand fly [internet]. University of Florida Web site; 2013. Available at http://entnemdept.ufl. edu/creatures/misc/flies/Lutzomyia_shannoni.htm. Accessed October 29, 2014.

AUTHORS

CPT Seal is Veterinary Officer-in-Charge of the Veterinary Section, Naval Submarine Base Kings Bay, Georgia.

CPT Hunter is Chief of Veterinary Services Fort Bliss Branch, Texas.

Cases of Lyme disease reported in the United States for each of the
years 2001 through 2013.Data from Centers for Disease Control and
Prevention (http://www.cdc.gov/lyme/stats/index.html).

Year                    2001     2002     2003     2004     2005

Total Reported Cases   17,029   23,763   21,273   19,804   23,305

Year                    2006     2007     2008     2009     2010

Total Reported Cases   19,931   27,444   28,921   29,959   22,561

Year                    2011     2012     2013

Total Reported Cases   24,364   22,014   27,203
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Author:Seal, Lauren; Hunter, Aimee
Publication:U.S. Army Medical Department Journal
Article Type:Report
Geographic Code:1USA
Date:Jan 1, 2015
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