OVERVIEW: What every practitioner needs to know

Are you sure your patient has ehrlichiosis? What are the typical findings for this disease?

Ehrlichioses are zoonotic acute undifferentiated febrile illnesses caused by rickettsia-like bacteria and transmitted to humans by ticks. While most infections are mild, children can have severe, even fatal outcomes.

The term “ehrlichiosis” encompasses infections in children caused by at least three distinct species in the family Anaplasmataceae; therefore, clinical manifestations may differ, although few studies in children, other than for human monocytic ehrlichiosis (HME), have been published.

Key symptoms and signs of HME (causative agent Ehrlichia chaffeensis) and human granulocytic anaplasmosis (HGA; causative agent Anaplasma phagocytophilum) follow (few pediatric cases of Ehrlichia ewingii ehrlichiosis have been reported):

The most common symptoms for HME in children include the following:

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Fever (100%), headache (77%), myalgia (77%), any rash (57%), abdominal pain (62%), and nausea or vomiting (57%); altered mental status or other symptoms/signs suggestive of central nervous system (CNS) involvement (36%).

Less frequently encountered symptoms and signs include the following:

Lymphadenopathy (50%), diarrhea (36%), altered mental status (36%), and conjunctivitis (14%)

Symptoms among children with HGA include the following:

Fever (93%), headache and myalgia (both 73%), and rigors (60%) are common

Less frequently encountered symptoms and signs include the following:

Nausea (33%), vomiting and abdominal pain (both 27%), arthralgias (27%), anorexia (30%), and cough (20%) occur less frequently; rash is documented in only 13%, and all were erythema migrans related to concurrent Lyme disease. Signs and symptoms suggestive of CNS involvement are rare with HGA.

Chronic or persistent disease with a low fever or no fever is unlikely to be either HME, HGA, or E. ewingii ehrlichiosis.

Physical findings:

Physical examination is most often unrevealing. Hepatomegaly or splenomegaly occurs in as many as 50% of cases. Edema of the face and hands can occur in children.

Clues in the routine laboratory examination:

Routine laboratory studies are sometimes helpful, especially the presence of thrombocytopenia, leukopenia, and elevated activity of serum hepatic transaminases.

Thrombocytopenia: 93% HME; 38% HGA

Leukopenia: 57% HME; 80% HGA

Elevated serum aspartate aminotransferase and alanine aminotransferase activity: 85%-92% for HME; 40%-50% for HGA

What other disease/condition shares some of these symptoms?

Other rickettsial infections, such as Rocky Mountain spotted fever, and murine typhus are part of the differential diagnosis.

Rash and septic-like presentations can also occur with meningococcemia.

Viral infections, including enteroviruses, Colorado tick fever (Orbivirus), tick-borne encephalitis (flaviviruses), and some bunyaviruses are mimics.

Other mimics include typhoid fever, secondary syphilis, Lyme disease, leptospirosis, toxic shock syndrome, scarlet fever and rheumatic fever, rubella, parvovirus infection, Kawasaki disease, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, Henoch-Schönlein purpura and hemolytic uremic syndrome, among others.

What caused this disease to develop at this time?

HME and HGA virtually only occur after tick bites; thus, a history of tick bite or exposure to tick habitats is an important feature, especially within the previous 10 days, since the incubation period is about 7-10 days.

Rare examples of perinatal, transfusion-related, and nosocomial transmission have been reported.

Most exposures occur during spring and summer when the weather is warm and outdoor activity frequent.

Exposure to rural and suburban environments and outdoor pets such as dogs increase the risk for tick bites.

The triad of fever, rash, and tick bite or fever, rash, and headache at any time during the illness are present in only 43%-54% of children.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Early diagnosis and treatment of HME and HGA should not depend on any specific laboratory diagnostic test; it depends on clinical, historical, and limited laboratory findings.

The white blood cell count is usually low or within normal limits, although leukocytosis (23%) can also be observed.

Platelet counts are often low or normal.

CSF pleocytosis:

HME: about 25% of children will have mononuclear pleocytosis; glucose levels are usually normal, but protein levels are elevated.

HGA: pleocytosis in children has not been reported and is rare in any patient with HGA.

Examination of Wright- or Giemsa-stained blood smears for intracellular inclusions in monocytes for HME (~2% sensitive) and neutrophils for HGA (~25%-75% sensitive) can rapidly suggest the diagnosis.

Polymerase chain reaction methods for amplification of E. chaffeensis,
A. phagocytophilum, or E. ewingii DNA from blood are sensitive and specific for early diagnosis, but not widely available.

Serologic studies are the diagnostic gold standard, although acute-phase serologic analysis alone is very unlikely to provide useful diagnostic information. However, it should be obtained to demonstrate seroconversion or fourfold increase in antibody titers over several weeks.

Would imaging studies be helpful? If so, which ones?

Imaging studies are rarely helpful.

Confirming the diagnosis

No clinical decision algorithms are available for suspecting/confirming the diagnosis of HME or HGA.

If you are able to confirm that the patient has ehrlichiosis, what treatment should be initiated?

If clinical suspicion warrants consideration of HME, HGA, or another form of ehrlichiosis, treatment should be instituted promptly, as it could be lifesaving. The American Academy of Pediatrics recommends the use of doxycycline as the drug of choice for treatment of HME and HGA in children of any age. Early treatment, before day 5 of illness, is advocated for the likelihood of a good outcome.

Doxycycline treatment should be continued for at least 3 days after fever resolves and clinical improvement is observed, for a total minimum course of 7 days. Typically, treatment duration is 7-10 days, although severe or complicated disease could require longer treatment courses.

For children weighing less than 45 kg, doxycycline is given at 4.4 mg/kg/d intravenously or orally in two divided doses, not to exceed a total of 100 mg/dose.

For children weighing more than 45 kg, doxycycline is given as 100 mg twice daily intravenously or orally.

Chloramphenicol is not considered an effective alternative; both E. chaffeensis and A. phagocytophilum are resistant in vitro.

Fluoroquinolones should not be used for HME, and little evidence supports effectiveness in HGA.

Limited anecdotal reports suggest that rifampin could be useful in children with HGA.

What are the adverse effects associated with each treatment option?

Doxycycline can be associated with tooth staining in children; however, this adverse effect is related to total dosage during childhood years and doxycycline is now used sparingly. Gastrointestinal disturbances and photosensitivity can also occur.

What are the possible outcomes of ehrlichiosis?

Most children with HME and HGA do well after treatment, especially if treated within the first 5 days after onset. With doxycyline treatment, defervescence will occur in most within 2 days.

Infection is severe enough that between 40% and 93% of children with HME and 42% of children 5-9 years of age with HGA require hospitalization. Intensive care unit admission and deaths are reported for children with both HME and HGA; the case fatality rate for HME is 3.7% among children 5-9 years of age and 0.6% overall for HGA.

Long-term sequelae have not been reported nor are well-studied for children after HME or HGA; corroborated chronic or persistent infection has not been observed.

One epidemiologic study that included some children documented recurrent or persistent fevers, shaking chills, sweating, and fatigue more frequently in the year after HGA was diagnosed than in an age-matched uninfected cohort.

Owing to the high case fatality rate (0.6%-3.6%) with HME and HGA, treatment with doxycycline can be lifesaving. Compared with the risks of tooth staining, gastrointestinal disturbances, or photosensitivity, the benefits of treatment far outweigh any risks.

What causes this disease and how frequent is it?

HME and HGA are caused by infection with the obligate intracellular bacteria Ehrlichia chaffeensis and Anaplasma phagocytophilum, respectively. These bacteria live in cycles between ticks and their normal mammalian hosts such as field mice and deer.

When an infected tick bites a human and transmits the organism, it infects leukocytes that can spread through the blood to all tissues and organs. These bacteria can alter the function of the infected leukocytes to promote inflammation, which is beneficial to the bacterium because of the recruitment of new leukocytes that can be hosts for the expanding infection; however, the proinflammatory response can lead to inflammatory tissue injury, including increased vascular permeability. The clinical impact can be the appearance of a “vasculitis” syndrome without true histopathologic vasculitis.

HME Epidemiologic Features

Incidence, seasonal variation, age distribution: Infection occurs only where tick infection and endemic cycles exist. For HME, this includes predominantly the southcentral, southeastern, mid-Atlantic, and increasingly, northeastern parts of the United States where the major tick vector, Amblyomma americanum, is abundant.

The majority of HME cases reported to the Centers for Disease Control (CDC) in the United States occur in late spring through summer (May-August) when tick activity is at a peak, but cases also occur in fall and infrequently in winter.

In the United States, a minority of HME (10%) is reported in individuals 19 years of age and younger.

Infection is acquired by the bites of infected ticks, usually adult (large) ticks:
A. americanum ticks are the major and only proven vector species for E. chaffeensis. There is currently no evidence that early tick removal after attachment will reduce the risk for transmission of the bacterium from an infected tick.

Predisposing Exposures

Exposure to tick-infested environments is the primary risk factor for transmission of
E. chaffeensis and the development of HME.

Activity outdoors during warm months when ticks are active, especially in areas where Rocky Mountain spotted fever has occurred, increase risk.

Domestic pets, such as dogs, are potential vehicles for exposure to infected ticks and pose an especially high risk for children.

A higher risk for A. americanum tick exposure and E. chaffeensis infection exists where white-tailed deer (Odocoileus virginianus) are found in abundance.

HGA Epidemiologic Features

Incidence, seasonal variation, age distribution: Infection occurs only where tick infection and endemic cycles exist. For HGA, this includes predominantly the northeastern, Mid-Atlantic, and upper midwestern parts of the United States where the primary vector in North America,
Ixodes scapularis (black-legged or deer tick) is abundant.

HGA also occurs in Central Europe and eastern parts of Asia (China, Korea, Siberia).

The majority (64%) of HGA cases reported to the CDC in the United States occur in June through August, when the nymphal stage of the tick vector is active, in part explaining an association with “small ticks.” Less than 3% of cases occur in the winter months.

In the United States, a minority of HME (10%) is reported in individuals 19 years of age and younger.

Infection is acquired through the bites of infected ticks, usually small nymphal ticks that are most active during the summer months in North America.

I. scapularis ticks are the major vector species for A. phagocytophilum in eastern North America, whereas Ixodes pacificus
, Ixodes ricinus, and Ixodes persulcatus are competent vectors in California, Europe, and Asia, respectively.

In animal models, transmission from an infected tick can take as little as 4 hours, diminishing the opportunity to interrupt transmission by removal of attached ticks. Thus prevention relies mostly on avoiding tick-infested areas and tick bites.

Predisposing exposures

Exposure to tick-infested environments is the primary risk factor for transmission of
A. phagocytophilum and development of HGA, although transmission through blood transfusion, transplacental transmission during pregnancy, and, rarely, nosocomial transmission by exposure to infected blood are reported.

Activity outdoors during warm months when ticks are active, especially in areas where HGA occurs, increases risk.

A higher risk for infection exists where Lyme disease and babesiosis are also prevalent owing to the shared tick vector; coinfections with more than one Ixodes-transmitted pathogen are reported.

Increased severity and complications are known to occur with HME and HGA in patients with underlying immunocompromising conditions, such as HIV infection, chemotherapy for cancer, corticosteroid or use of other immune suppressive drugs, organ transplantation, and with preexisting illnesses such as diabetes mellitus.

Relative risk (RR) for hospitalization (RR,1.8-1.9), life-threatening complications (RR, 2.5-2.8), or death (RR, 3.7-3.9) is higher for those who are immunocompromised and have
E. chaffeensis or A. phagocytophilum infection compared with those who are infected but immunocompetent.

How do these pathogens/genes/exposures cause the disease?

E. chaffeensis, A. phagocytophilum, and related species enter the bloodstream after tick bite.

The bacteria attach to and enter either monocytes (E. chaffeensis) or neutrophils (A. phagocytophilum) at the site of tick bite, and then disseminate through blood or lymphatic vessels to tissues and organs.

E. chaffeensis and A. phagocytophilum grow in leukocytes and alter normal function, increasing inflammatory response and diminishing antimicrobial response. The activated, infected cells promote inflammation and recruitment of new leukocytes that will sustain bacterial replication, but lead to focal and even systemic inflammation, increases in vascular permeability, organ and tissue injury, ischemia, hypotension, and in severe cases, respiratory distress or multiorgan failure.

Severity in HGA, and likely in HME, relates to induction of an inflammatory or immunopathogenetic state, including macrophage activation or hemophagocytic-like syndromes.

Other clinical manifestations that might help with diagnosis and management

HME and HGA occasionally present with signs or symptoms referable to a single organ system, such as acute abdomen, leading to misdiagnosis and unnecessary surgery for appendicitis, cholecystitis, or small bowel obstruction.

What complications might you expect from the disease or treatment of the disease?

Most infections resolve rapidly after doxycycline treatment; lack of response within 3 days of treatment should prompt search for alternative diagnoses.

Complications are infrequent in children but include hypotension that mimics a septic or toxic shock-like syndrome, acute respiratory distress, meningoencephalitis (HME only) with rare persistent neurologic deficits (global encephalopathy, short-term memory loss, and requirement for speech, physical, and occupational therapy), and macrophage activation and hemophagocytic syndromes.

Complications reported in adults, but not yet in children, include brachial plexopathy, demyelinating polyneuropathy, cranial nerve neuropathy, myocarditis, rhabdomyolysis, coagulopathy and hemorrhage, renal failure, and opportunistic infections.

Are additional laboratory studies available; even some that are not widely available?

Culture of E. chaffeensis and A. phagocytophilum is an alternative that provides unequivocal evidence of infection; however, this is not offered in clinical, commercial, or reference laboratories to any extent, and may take 1 week to 1 month or more to provide a result.

Testing of ticks after tick bite for the presence of E. chaffeensis,
A. phagocytophlum, and other species in the Anaplasmataceae family has no role in therapeutic or prophylaxis decisions.

How can ehrlichiosis be prevented?

There is no evidence that prophylactic doxycycline for tick bites provides any benefit for preventing HME, HGA, or other forms of ehrlichiosis in humans.

No effective vaccines are available.

Key preventive measures include the following:

Avoiding tick-infested environments

Performing frequent “tick checks” with prompt removal of any attached ticks

Wearing light-colored clothing, including long pants and long sleeved shirts and tick-repellants (although these often inactivate sunscreens)

Using insecticide/acaricide-treated clothes

What is the evidence?

Schutze, GE, Buckingham, SC, Marshall, GS. “Human monocytic ehrlichiosis in children”. Pediatr Infect Dis J. vol. 26. 2007. pp. 475-9. (Review of human monocytic ehrlichiosis among children from the "tick belt" states across the southeastern and southern central United States.)

Wormser, GP, Dattwyler, RJ, Shapiro, ED. “The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America”. Clin infect Dis. vol. 43. 2006. pp. 1089-134. (Comprehensive IDSA clinical guidelines that includes information about human granulocytic anaplasmosis.)

Krause, PJ, Corrow, CL, Bakken, JS. “Successful treatment of human granulocytic ehrlichiosis in children using rifampin”. Pediatrics. vol. 112. 2003. pp. e252-3. (Description of several cases of pediatric human granulocytic anaplasmosis for which rifampin was used for treatment.)

Maurin, M, Bakken, JS, Dumler, JS. “Antibioic susceptibilities of Anaplasma (Ehrlichia) phagocytophilum strains from various geographic areas in the United States”. Antimicrob Agents Chemother. vol. 47. 2003. pp. 413-5. (In vitro susceptibilities for several North American strains of Anaplasma phagocytophilum.)

Dumler, JS, Dey, C, Meier, F, Lewis, LL. “Human monocytic ehrlichiosis: a potentially severe disease in children”. Arch Pediatr Adolesc Med. vol. 154. 2000. pp. 847-9. (Case report and review of severe human monocytic ehrlichiosis in children.)

Dahlgren, FS, Mandel, EJ, Krebs, JW. “Increasing incidence of Ehrlichia chaffeensis and Anaplasma phagocytophilum in the United States, 2000-2007”. Am J Trop Med Hyg. vol. 85. 2001. pp. 124-31. (Epidemiological summary of ehrlichiosis in the United States from 2000-2007, including information relevant to childhood infection.)

Hanson, D, Walter, AW, Powell, J. “Ehrlichia-induced hemophagocytic lymphohistiocytosis in two children”. Pediatr Blood Cancer. vol. 56. 2011. pp. 661-3. (Case descriptions of severe pediatric human monocytic ehrlichiosis and hemophagocytic syndrome.)

Burns, S, Saylors, R, Miain, A. “Hemophagocytic lymphohistiocytosis secondadry to Ehrlichia chaffeensis infection: a case report”. J Pediatr Hematol Oncol. vol. 32. 2010. pp. e142-3. (Case report of hemophagocytic syndrome in a child with human monocytic ehrlichiosis.)

Esbenshade, A, Esbenshade, J, Domm, J. “Severe ehrlichia infection in pediatric oncology and stem cell transplant patients”. Pediatr Blood Cancer. vol. 54. 2010. pp. 776-8. (Severe ehrlichiosis in children with immune compromise after organ transplantation.)

Dhand, A, Nadelman, RB, Aquero-Rosenfeld, M. “Human granulocytic anaplasmosis during pregnancy: case series and literature review”. Clin Infect Dis. vol. 45. 2007. pp. 589-93. (Case series and review of human granulocytic anaplasmosis during pregnancy, with descriptions of fetal outcome.)

Moss, WJ, Dumler, JS. “Simultaneous infection with Borrelia burgdorferi and human granulocytic ehrlichiosis”. Pediatr Infect Dis J. vol. 22. 2003. pp. 91-2. (Case report documenting co-infection with simultaneous human granulocytic anaplasmosis and Lyme borreliosis.)

Ongoing controversies regarding etiology, diagnosis, treatment

Both HME and HGA are widely presumed to be persistent infections that could require long-term therapy to manage or suppress, especially in the context of suspected Lyme disease or babesiosis. The data supporting this contention are nearly nonexistent and are based largely on antibody titers that persist long after effective doxycycline treatment and recovery and on uncontrolled studies or anecdotal reports of clinical response to long-term antimicrobial therapy. Seroreversion could take as long as 4 years in some individuals without any evidence of persistent or recurrent clinical disease.

One epidemiologic study demonstrated significantly higher reporting of recurrent or continuous fevers, chills, fatigue, and sweating for up to 1 year after a diagnosis of HGA compared with a similar population without HGA.

At least two new species in the Anaplasmataceae family have been recognized to cause human infection in the last several years (Ehrlichia muris–like agent and
Neoehrlichia mikurensis); no pediatric infections have been reported for these infections.