Ehrlichiosis: Rare Diseases Caused by Ticks

History

The ehrlichia bacteria was discovered in Africa in 1925 by Cowdry, an American scientist. The first species to be identified — Ehrlichia ruminantium — was found to be the cause of heartwater disease, a fatal illness in ruminants like cattle, sheep, goats, and deer [4]. 

In 1935, another species of Ehrlichia, Ehrlichia canis, was identified in Algerian dogs with ticks with fever and anemia [5]. Both E. canis and E. ruminantium were initially identified as species belonging to the genus Rickettsia. But, in 1945, they were re-classified into a new genus Ehrlichia, named after the Nobel Prize-winning German bacteriologist Paul Ehrlich [6].

E. canis was responsible for a huge outbreak in Vietnam in the 1960s. Several US military dogs stationed in the country during that time died from complications due to hemorrhagic illness [1,2].

Ehrlichiosis was considered a veterinary disease until the first case of human ehrlichiosis was identified in the US in the late 1980s [2]. The type of Ehrlichia bacteria responsible for the illness was E. chaffeensis [1,2]. Ever since its discovery, the number of cases of E. chaffeensis infection has increased steadily [7].

Over time, several other species that cause ehrlichiosis in humans were discovered. These include Anaplasma phagocytophilum, E. ewingii, and E. muris eauclairensis. [5]. 

Epidemiology

The group of ehrlichoisis diseases in humans include:

Human Monocytic Ehrlichiosis (HME)

HME is caused by E. chaffeensis, a bacteria whose primary reservoir is deer [1,8]. HME can be sometimes life-threatening, especially in immunocompromised people. Most of the human ehrlichiosis cases reported in the US have been caused by E. chaffeensis [7]. HME is usually reported in the south-eastern and south-central regions of the country where there is a high density of lone star ticks [1]. These include Arkansas, Maryland, Mississippi, Oklahoma, and Tennessee [8]. 

HME was first described in 1986 and since then the cases kept gradually increasing [8]. For instance, in 2000, only 200 cases of HME were reported. By 2019, the number of cases reported was 2,093. Though the number of cases increased, the mortality rate declined over the course of time to about 1% in recent years [7]. The median age of people diagnosed with HME was 53 years. 

Human Granulocytic Anaplasmosis (HGA)

HGA was formerly known as Human Granulocytic Ehrlichiosis or HGE. HGA is caused by Anaplasma phagocytophilum (formerly referred to as Ehrlichia phagocytophila), primarily spread by mice, rats, and voles (small rodents that live near rivers or in fields) [1]. HGA has a fatality rate of less than 1% [9]. Together, HME and HGA are responsible for the majority of ehrlichiosis infections in humans so far [8].

HGA was first identified in 1990 [10]. Between 1994 and 2005, around 2,900 HGA cases in the US were reported to the CDC. The annual incidence of HGA cases during that time was around 1.6 cases per million [8]. The highest number of cases were reported in 2017 (5,762 cases) and the second-highest number of cases were reported in 2019 (5,655 cases) [9].

The disease is prevalent in the US, Europe, and Australia. In the Asian continent, HGA is found in China, Korea, Russia, and Siberia [1]. In the US, the states of Connecticut, Wisconsin, and New York had the highest incidence rates. HGA cases peak during the summer season, as black-legged ticks are usually active during this season. The median age of people diagnosed with HGA is 51 years [8]. 

Human Ewingii Ehrlichiosis (HEE)

E. ewingii is the species of bacteria that causes Human Ewingii Ehrlichiosis. E.ewingii’s primary reservoirs are dogs and deers [1,8]. It was first discovered in 1992 but it was only in 1998 that it was recognized as one of the causes of human ehrlichiosis [1]. 

In the United States, HEE cases are mostly reported from the south-eastern, south-central, and mid-Atlantic regions [1]. They include the states of Tennessee, Missouri, and Oklahoma. According to the CDC, the number of HEE cases reported from 2008 to 2019 was 261. None of them were found to be fatal [7]. A majority of people infected with HEE are either HIV patients or those who had an organ transplant (immunosuppressed individuals) [8]. 

Other types of Human Ehrlichiosis

Other species that cause ehrlichiosis in humans include E. canis, E. muris eauclairensis, E. Wisconsin-Minnesota, and N. sennetsu. 

• E.canis causes severe illness in dogs and can be fatal [5]. Though dogs are its primary reservoir, human E.canis infections have been reported in South America, Mexico, and Venezuela. Individuals affected by this infection can experience a wide range of illnesses – from asymptomatic to severe [5, 8]. 
• E. muris eauclairensis is a relatively new species of Ehrlichia [7]. It was identified in patients in the upper mid-western regions of the United States (mainly Wisconsin and Minnesota) in 2009 [5,7]. As of today, over 115 cases of human ehrlichiosis caused by E. muris eauclairensis were reported with no fatalities [7]. 
• Human Sennetsu Ehrlichiosis (HSE) or Sennetsu Fever is a rare disease with no fatalities reported so far [1]. It was first discovered in Japan in 1953. HSE is mainly reported in southeast Asia in countries like Japan, Laos, Thailand, the Philippines, and Malaysia. These are countries where eating raw fish is common — one of the ways in which an HSE infection spreads to humans [11,12]. 

How is it Spread?

Ehrlichiosis can be transmitted to humans through:

Tick bites: People get infected when they are bitten by ticks that carry the bacteria. The lone star tick is the primary vector that transmits different types of ehrlichiosis, including HME, HSE, and HEE. Other types of ehrlichiosis, namely, HGA and HWME, are transmitted by black-legged or deer ticks [1,7]. The American dog tick is another vector that spreads ehrlichiosis infections [13].

Blood transfusion or organ transplant: Ehrlichiosis can also be transmitted through blood transfusion or organ transplant [14].

Eating Raw fish: In some cases, eating an infected raw fish can cause Human Sennetsu Ehrlichiosis or Sennetsu Fever [12].

Biology of the Disease

The bacteria that cause ehrlichiosis in humans infect white blood cells (leukocytes). The type of white blood cells targeted depends on the species of ehrlichiosis. For instance, E. chaffeensis mainly affects monocytes and, in severe cases, the granulocytes. A. phagocytophilum and E. ewingii, however, primarily infect granulocytes (neutrophils and occasionally eosinophils).

When ehrlichiosis pathogens enter the human body, they make their way into white blood cells through a cellular process called endocytosis. Once inside, they start to multiply and then rupture the cell walls or host cell membranes to get released into the bloodstream. Now, the larger numbers of bacteria can infect more white blood cells. This vicious cycle continues to repeat, which increases the severity of the infection [2].

Diagnosis

Diagnostic methods include:

PCR: Polymerase Chain Reaction (PCR) is the most sensitive method to diagnose ehrlichiosis during the first week of the infection. Apart from detecting the presence of E. chaffeensis and A. phagocytophilum DNA, the PCR method is very effective in tracing out the DNA of E. ewingii. This is because they are quite indistinguishable during the initial stages of the infection.

Giemsa staining of blood smears: This is one of the fastest and most inexpensive diagnostic methods to detect the presence of bacteria in white blood cells. The test must be performed before starting the antibiotic regimen. This is because test sensitivity decreases once treatment begins, making it difficult to detect the pathogens. The best time to perform this test is a week after the onset of the disease.

Blood culture: Blood culture is a standard diagnostic tool to diagnose ehrlichiosis but it has its shortcomings. The test can be time-consuming as it might take anywhere between two to 36 days. It may not be practical for clinicians to wait a long time before treating infected individuals. Another challenge with this method is that it is not possible to do a blood culture to detect the E. ewingii species.

Serology: Serology can be used if the ehrlichiosis diagnosis has to be done two to four weeks after the onset of the disease because test sensitivity will be high during this time. Note: this method is not very effective in detecting the presence of E. ewingii but it is effective in confirming A. phagocytophilum or E. chaffeensis infections [1].

Symptoms

The incubation period (time taken for symptoms to appear) for ehrlichiosis is one to two weeks following the bite of an infected tick. A challenge with ehrlichiosis is that the tick bites are usually painless. This makes it challenging for an individual to remember exactly when he or she was bitten by the tick. Instead, an ehrlichiosis diagnosis can be considered a possibility if an infected individual happened to have recently visited tick-friendly places that are grassy, brushy, or wooded. 

Any delay in treatment can increase the severity of the disease. Especially those who are very young, too old, or those with a weak immune system are at a greater risk [15]. Infected people usually have the following symptoms during the first five days of the illness:

• Fever
• Chills
• Cough
• Headache
• Malaise
• Muscle pain
• Joint pain
• Stiff neck
• Nausea
• Vomiting
• Diarrhea
• Loss of appetite
• Confusion
• Rashes (In case of HME and is more common in children)

The later stage of the illness is marked by the following clinical manifestations:

• Inflammation of the brain and surrounding tissue
• Respiratory failure
• Uncontrolled bleeding
• Organ failure
• Death [1,15].

Treatment

The recovery time for human ehrlichiosis is generally short if antibiotic treatment is started during the early phase of the disease. Fever usually comes down within one to three days after starting the treatment. Antibiotics such as doxycycline or tetracycline are commonly prescribed as their clinical response has been found to be fast and effective. 

The white blood cell and platelet count generally come back to normal levels a week after treatment. However, individuals may experience malaise for a few weeks or months more, depending on their general health [1,2]. The antibiotics medical regimen for ehrlichiosis is:

• Adults: 100 mg of doxycycline is administered either orally or intravenously twice a day. Alternatively, 500 mg of tetracycline is administered orally every six hours.
• Children (8+ years): 2.2 mg per kg of doxycycline is administered either orally or intravenously twice a day (maximum 100 mg/dose). Alternatively, 25 to 50 mg per kg of tetracycline is administered orally every six hours (maximum 500 mg/dose).
• Children (less than 8 years): 10 mg per kg of rifampin, orally twice a day (maximum 300 mg/dose).
• Pregnant women: 300 mg of rifampin orally twice a day [1].

Prevention

There is currently no vaccine available to prevent ehrlichiosis. Here are a few preventive measures to protect yourself, your loved ones, and your pets (especially dogs) from the infection:

• Avoid visiting places filled with thick grass and brushy or wooded areas because ticks tend to favor these types of places.
• Regularly trim the grass in your garden.
• If possible, avoid visiting endemic regions during the warmer months as ticks are very active during this time.
• If spending time outdoors or visiting places where ticks may be present, cover your body completely with clothes. 
• You may use tick repellents that can be sprayed on clothes and apply tick repellents containing DEET on the exposed parts of your body for extra protection.
• Make it a practice to examine your body after spending time outdoors and remove any ticks attached to the body. Checking and removing ticks early can prevent you from being infected as ticks must be attached to the body for at least 24 hours in order to infect the host. Do the same for your pet.
• Shower once you are back from outdoor activities. Taking a shower within two hours of coming indoors reduces the risk of getting Lyme Disease (LD).
• Sometimes, ticks might cling to your clothes and come in contact with your body when used again. So, it is better to tumble-dry clothes in a high-heat setting once you are back from outdoor activity [2,16].