For pet lovers, outdoors enthusiasts, and in general, anyone who spends a lot of time in areas where rodents and other such wildlife are prevalent, tick-borne illnesses should be a part of the differential diagnosis when the symptoms include fever, rash, arthralgias, myalgias, neuralgias, and fatigue.  The information contained in this discussion comes from the latest data posted on the CDC’s web-site.  The tick seen on this screen is Amblyomma americanum, also known as the Lone Star Tick, and the vector for many tick-bite related illnesses (for example, Southern Tick-Associated Rash Illness, Human Ehrlichiosis, and Lyme Disease).

 

 

Since 1992, tick-borne illnesses such as Lyme disease have been on the rise, and since 1998, there have been 15,000 or more reported cases each year of Lyme disease alone.  The CDC has not posted their data for the year 2005 to date.  Lyme disease is not the only tick bite related illness that is on the rise.

 

 

Rock Mountain Spotted Fever is also on the rise with 1100 plus cases reported in 2002, and an estimated 1200 or more projected new cases per year.  With this rise in incidence of these diseases, it is important for the laboratorian and other health care providers to be aware of these illnesses and include them in the differential diagnosis of a patient where appropriate.  I have chosen to look at these diseases by order of CDC reported prevalence of disease.

 

 

Lyme disease is caused by the bacterium, Borrelia burgdorferi, and is transmitted to humans by the bite of infected blacklegged ticks.  The most common vectors being Ixodes scapularis (the common deer tick) or Ixodes pacificus; it has also been carried by the Lone Star tick, Amblyomma americanum.  It is most commonly found in the Northeastern and North Central United States.  Lyme disease cases are generally more numerous in the early spring and summer when the tick nymphs are at their greatest activity level.  Typical symptoms include fever, headache, fatigue, and a characteristic skin rash called erythema migrans.  The patient on this screen has multiple erythema migrans.  If the disease is left untreated, infection can spread to the heart, the joints and the nervous system. Symptoms generally present within 3 to 30 days of exposure.  However, because these symptoms can also be seen with a number of other illnesses, these symptoms are often overlooked until the disease is in a more progressed state.  At which point, features such as Bell’s palsy (loss of muscle tone on one or both sides of the face), severe headaches, and neck stiffness or other autoimmune disease like symptoms begin to present themselves.  In these latter stages of the disease, meningitis, autoimmune diseases, stroke, paraneoplastic syndromes, and other such medical conditions become part of the differential diagnosis.  Lyme disease is often diagnosed  based on the patient’s remembering the characteristic rash and an exposure to infected ticks, which is uncovered when discussing the patient’s symptom history.  Laboratory testing is usually helpful and quite necessary to make the diagnosis in the later, more advanced stages of the disease.  Borrelia burgdorferi is often diagnosed using an enzyme linked immunosorbent assay with Western blot confirmation; these are the methods preferred by the CDC for reporting.  Very rarely are cultures of this organism performed and some laboratories will use even more questionable methods such as urinary antigen detection, immunofluorescent antibody testing, and immunohisto-chemical staining, and lymphocyte transformation studies.  Most patients are treated successfully using drugs such as Doxycycline, Amoxicillin, or Cefuroxime.  Lyme disease is usually worse symptomatically for the elderly and the immunosuppressed; these individuals may require a longer treatment cycle, but generally recover with no serious complications.   As of 2004, it is estimated that there will be approximately 20,000 new cases per year.

 

 

Rocky Mountain Spotted Fever is the most severe and most frequently reported rickettsial illness in the US.  It also occurs in Mexico, Central, and South America.  The disease is caused by Rickettsia rickettsii and is often transmitted by ticks such as Dermacentor variabilis (known as the American dog tick), Dermacentor andersoni (known as the Rocky Mountain Wood tick), Amblyomma cajennense, and Rhipicephalus sanguineus.  It was first discovered in the Snake River Valley of Idaho in 1896 and was often called “black measles” because of the characteristic rash.  It was a dreaded and frequently fatal disease that affected hundreds of people in this area.  In response to the severity of this problem the Rocky Mountain Laboratory was established in Hamilton, Montana.  Howard T. Ricketts first established the identity of the organism causing the disease, which now bears his name.  The disease took on the name of Rocky Mountain Spotted fever due to the geographic region in which it was first recognized; however, it is prevalent throughout North, Central, and South America.  Disease onset is usually 5 to 10 days post exposure.  The patient generally presents with one or more of the following symptoms:  the characteristic measle-looking rash (as seen here, but in a much more subtle form), fever, nausea, vomiting, severe headache, muscle pain, loss of apetite, abdominal pain, arthralgias, and diarrhea.  Again, this tick-borne illness is very non-specific at the onset and could appear and be misdiagnosed as any other infectious or non-infectious disease even by the most experienced physician.  However, as the disease progresses, patients may become thrombocytopenic, hyponatremic, experience elevated liver enzymes and more pronounced symptoms.  It is not uncommon for severe cases to involve the respiratory system, central nervous system, gastrointestinal system or the renal system.  This disease is worst for elderly patients, males, African-Americans, alcoholics, and patients with G6PD deficiency.  Rocky Mountain Spotted Fever is often diagnosed using an indirect immunofluorescence assay, which is considered the reference standard by the CDC; however, ELISA and PCR techniques are rapidly challenging the CDC’s standard in reliability and usefulness in monitoring a patient’s response and recovery from the illness.  Chloramphenicol, Tetracycline, and Doxycycline are the most common antibiotics used in treating Rocky Mountain Spotted Fever.  It is estimated that approximately 1200 or more new cases will present on a yearly basis.

 

 

Human ehrlichiosis is caused by several bacterial species in the genus Ehrlichia.  What began as a common veterinary pathogen was first recognized as a human pathogen in 1953 in Japan.  Initially called Sennetsu fever and caused by the bacterium now known as Ehrlichia sennetsu; this variation is characterized by high fever and lymphadenopathy.  Ehrlichia sennetsu is very rare outside the Far East and Southeast Asia with the majority of cases centering in western Japan.  In the US, however, four members of the Ehrlichia genus have been known to cause disease in humans.  The common names for these variants comes from the hematologic cell line most generally affected by the organism.  For instance, human granulocytic Ehrlichiosis is commonly caused by the species Ehrlichia equii and Ehrlichia phagocytophila; human monocytic Ehrlichiosis is caused by Ehrlichia chaafeensis (and is the most common form of the disease); human granulo-eosinophilic Ehrlichiosis is usually caused by Ehrlichia ewingii.  Amblyomma americanum, the Lone Star tick is the vector for Ehrlichia chaafeensis and Ehrlichia ewingii.  Ixodes scapularis and pacificus tend to be the carriers for the organisms, Ehrlichia equii and Ehrlichia phagocytophila. Helminths are the most likely vector for Ehrlichia sennetsu.  In each of these cases symptoms begin to present within 5 to 10 days of the exposure.  The symptoms include fever, headache, malaise, myalgias, nausea, vomiting, diarrhea, cough, arthralgias, confusion, and an occasional rash (which is a more common pediatric finding).  The disease in any variant is worst for the elderly, the immunosuppressed, and splenectomized individuals, with Ehrlichia ewingii being a more commonly seen organism in the immunosuppressed.  Human Granulocytic Ehrlichiosis is commonly seen in Northeastern, South Central, Southeastern, and the West Coast of the US, while Human Monocytic Ehrlichiosis is commonly seen in the Southeastern and Midwestern US, and Ehrlichia ewingii has been reported primarily in the South Central and Southeastern US.  Ehrlichia’s morulae can be seen as mulberry-looking inclusions in the affected cell line. Ehrlichia patients will usually have laboratory findings such as a low WBC count, low platelet count, elevated liver enzymes, and morulae present in the morphologic features described in the WBC differential.  Confirmatory diagnosis is usually performed by an indirect immunofluorescence assay in which antibodies in the serum bind to the organisms on the slide and are detected by a fluorescien-labeled conjugate; this is considered the principle tool of choice for the diagnosis of Ehrlichiosis.  PCR methods are rapidly rising in popularity because of their sensitivity, specificity, and the potential for using them to monitor therapy.  Rarely is direct isolation of the organism performed; however, this difficult, time-consuming approach is considered the gold standard for laboratory diagnosis.  DH82 or HL-60 cells are incubated with EDTA treated patient blood (taken from the patient prior to antibiotic therapy); the organisms can be viewed within 7 to 12 days from the point incubation was initiated.  Other methods are presently being developed to broaden the arsenal of diagnostic tools available.  Human monocytic ehrlichiosis will occur in approximately 31 out of 100,000 persons per year; human granulocytic ehrlichiosis will occur in approximately 16 out of 100,000 persons per year, and due to the recent discovery of Ehrlichia erwingii it is too early to have valid statistics on its incidence of disease.  Ehrlichiosis is treated using Doxycycline, Tetracycline, and Rifampin.  Approximately half of those presenting with Ehrlichiosis will require hospitalization, but recovery is quite marked after the initiation of treatment with the minimum course of antibiotic therapy requiring 5 to 7 days.

 

 

Babesiosis is caused by a hemoprotozoan parasite of the genus Babesia.  Babesia microti and Babesia divergens have been identified in the majority of human cases, but variants of Babesia microti have been identified.  These variants have many wondering if they are not separate species.  Little is known about the incidence and prevalence of Babesiosis because it is commonly found in malaria-endemic areas and is often misdiagnosed as a result.  The vectors for this parasite are Ixodes dammini and Ixodes scapularis.  Disease symptoms begin to present within 1 to 4 weeks from the initial infective moment.  The symptoms are much like that of malaria – fever, chills, sweating, myalgias, fatigue, hepatosplenomegaly, and hemolytic anemia.  Plasmodium species (malaria responsible organisms) should always be included in the differential diagnosis of this disease.  Babesiosis is usually worst for the elderly, the immunosuppressed and the splenectomized patient.  Diagnosis of the disease can be made using Wright’s Giemsa stained thick and thin blood films (just like malaria), IFA, ELISA, PCR, and FISH.  Babesia microti is considered the more common agent and IFA is the method of choice for diagnosis.  Babesia divergens is usually responsible for the most severe cases of Babesiosis and laboratories testing for this organism use a combination of IFA, FISH and PCR methods.  Babesia microti is commonly found in the Northeastern and Midwestern US.  The MO1 variant of Babesia microti is usually found in the Northeastern US and the WA-1 variant is generally associated with the West Coast.  The WA-1 variant is found to give false negative results in some clinical laboratory tests, which is why it is believed WA-1 may not actually be Babesia microti.  Babesia divergens is more common in European countries.  Patients usually respond well to treatment with Clindamycin, Quinine, Atovaquone, and Azithromycin; all drugs of choice used to treat malaria patients.

 

 

This slide demonstrates how easy it is to misdiagnose babesia.  Both plasmodium and babesia organisms can have multiple chromatin dots in the classic ring form.  There can be multiple ring forms per cell.  The Babesia prep (seen here) is a thick film which has been Wright’s Giemsa stained and the Plasmodium prep is a Wright’s Giemsa stained thin film.

 

 

Which brings us to the most recently described tick borne illness - Southern Tick-Associated Rash Illness; STARI is a new comer to Tick-borne illnesses.  It is so new that the causative agent is still being determined.  At the present time, it is thought to be Borrelia lonestari.  Amblyomma americanum is being touted as the vector for this disease.  Incubation period is estimated to be approximately 7 days.  It generally demonstrates with the characteristic rash (seen here), accompanied by fatigue, fever, headache, muscle, and joint pains.  Lyme disease is part of the differential diagnosis; however, unlike Lyme disease, STARI has not been linked to any arthritic, neurological, or other chronic symptoms.  It has presently been cited as occurring in the South Central and Southeastern US.  The CDC and NIH are currently searching for patients and infected ticks to develop diagnostic testing methods.  Symptoms appear to rapidly resolve themselves after treatment with Doxycycline, Amoxicillin, or Cefuroxime.  Expect to hear more about this illness as the investigation progresses.

 

 

All of the information in this discussion and more was found at the web-site listed here.  In the handout, you have the web-site browser page from which I launched my investigation and a chart summary of this discussion.  You will find many instances in this continuing education unit, in which I used the very wording, graphs, and pictures on the CDC web-site.  I do apologize for not putting a footnote or citation at each one.

 

Organism	Disease	Vector	Incubation Period	Signs & Symptoms	Differential Diagnosis	Lab Techniques	Treatment	Prognosis	Geographic Region	Incidence
Babesia microti -WA-1 variant -MO1 variant	Common Agent for Babesiosis	Deer Tick (aka Ixodes dammini or Ixodes scapularis)	1 to 4 weeks	Fever, chills, sweating, myalgias, fatigue, hepatosplenomegaly, hemolytic anemia	Plasmodium falciparum	Thick and Thin Blood Films IFA ELISA PCR FISH	Clindamycin Quinine Atovaquone Azithromycin	Worst for elderly, immunosuppressed, and splenectomized patients	Northeastern and Midwestern US	Prevalence of this disease is sketchy due to misidentification in malaria endemic areas
Babesia divergens	Less common agent for Babesiosis, (generally responsible for more severe cases)	Deer Tick (aka Ixodes dammini or Ixodes scapularis)	1 to 4 weeks	Fever, chills, sweating, myalgias, fatigue, hepatosplenomegaly, hemolytic anemia	Plasmodium falciparum	Thick and Thin Blood Films IFA ELISA PCR FISH	Clindamycin Quinine Atovaquone Azithromycin	Worst for elderly, immunosuppressed, and splenectomized patients	More common in Europe & splenectomized patients	Prevalence of this disease is sketchy due to misidentification in malaria endemic areas
Borrelia burgdorferi	Lyme Disease	Deer Tick (aka Ixodes scapularis) or Blacklegged Tick (aka Ixodes pacificus)	3 to 30 days	Fever, headache, fatigue, skin rash (erythema migrans), arthralgias, lymphadenopathy, facial (Bell’s) palsy, cardiac problems, and nervous system impairments	Other illnesses with similar signs and symptoms	ELISA IFA Western Blot Urine antigen Immunofluorescent staining, lymphocyte transformation	Doxycycline Amoxicillin Cefuroxime	Worst for elderly and immunosuppressed individuals, but is generally treatable with no serious complications	Northeastern and North Central US	Approximately 20,000 cases per year as of 2004 CDC statistics
Ehrlichia chaffeensis	Human Ehrlichiosis (monocytic variant)	Lone Star Tick (aka Amblyomma americanum)	5 to 10 days	Fever, headache, malaise, myalgias, nausea, vomiting, diarrhea, cough, arthralgias, confusion, occasional rash (more common pediatric symptom)	Other illnesses with similar signs and symptoms	IFA PCR Direct Isolation EIA	Doxycycline Tetracyclines Rifampin	Worst for elderly, immunosuppressed, and splenectomized patients	Southeastern and Mid- Western US	Approximately 31 cases per 100,000 persons
Ehrlichia equii	Human Ehrlichiosis (granulocytic variant)	Deer Tick (aka Ixodes scapularis) or Blacklegged Tick (aka Ixodes pacificus)	5 to 10 days	Fever, headache, malaise, myalgias, nausea, vomiting, diarrhea, cough, arthralgias, confusion, occasional rash (more common pediatric symptom)	Other illnesses with similar signs and symptoms	IFA PCR Direct Isolation EIA	Doxycycline Tetracyclines Rifampin	Worst for elderly, immunosuppressed, and splenectomized patients	Northeastern South Central, South Eastern, and West Coast of US	Approximately 16 cases per 100,000 persons
Ehrlichia phagocytophila	Human Ehrlichiosis (granulocytic variant)	Deer Tick (aka Ixodes scapularis) or Blacklegged Tick (aka Ixodes pacificus)	5 to 10 days	Fever, headache, malaise, myalgias, nausea, vomiting, diarrhea, cough, arthralgias, confusion, occasional rash (more common pediatric symptom)	Other illnesses with similar signs and symptoms	IFA PCR Direct Isolation EIA	Doxycycline Tetracyclines Rifampin	Worst for elderly, immunosuppressed, and splenectomized patients	Northeastern South Central, South Eastern, and West Coast of US	Approximately 16 cases per 100,000 persons
Ehrlichia ewingii	Human Ehrlichiosis (granuloeosinophilic variant)	Lone Star Tick (aka Amblyomma americanum)	5 to 10 days	Fever, headache, malaise, myalgias, nausea, vomiting, diarrhea, cough, arthralgias, confusion, occasional rash (more common pediatric symptom)	Other illnesses with similar signs and symptoms	IFA PCR Direct Isolation EIA	Doxycycline Tetracyclines Rifampin	Most commonly seen in immunosuppressed patients (i.e., HIV, transplant)	South Central and South Eastern US	Recently discovered to cause Human Ehrlichiosis -  no definite statistics
Ehrlichia sennetsu	Sennetsu fever or glandular fever	Probably helminths in fish	5 to 10 days	Fever, headache, malaise, myalgias, nausea, vomiting, diarrhea, cough, arthralgias, confusion, occasional rash (more common pediatric symptom)	Other illnesses with similar signs and symptoms	IFA PCR Direct Isolation EIA	Doxycycline Tetracyclines Rifampin	Worst for elderly, immunosuppressed, and splenectomized patients	Japan, Malaysia	Unknown
Rickettsia rickettsii	Rocky Mountain Spotted Fever (aka Black Measles)	American Dog Tick (Dermacentor variabilis) Rocky Mountain Wood Tick (Dermacentor andersoni) Amblyomma cajennense and Rhipicephalus sanguineus	5 to 10 days	Characteristic measles-looking rash, fever, nausea, vomiting, severe headache, muscle pain, loss of appetite, abdominal pain, arthralgias, diarrhea	Other illnesses with similar signs and symptoms	Abnormal CBC Hyponatremia Elevated LFT’s IFA ELISA Latex Agglutination Dot Immunoassays PCR IHC	Chloramphenicol, Tetracyclines, Doxycycline	Worst for elderly, males, African-Americans, alcoholics, and patients with G6PD deficiency	North, Central, and South American Continents	Approximately 1200 or more new cases per year
Unknown agent ?Borrelia lonestari	Southern Tick-Associated Rash Illness (STARI)	Lone Star Tick (aka Amblyomma americanum)	Within 7 days	Lyme disease-like rash, fever, fatigue, headache, muscle and joint pain	Lyme disease and other similar illnesses	CDC and NIH searching for patients and ticks to develop methods	Doxycycline Amoxicillin Cefuroxime	Unknown	South Central and South Eastern US	Disease to new to have definite statistics