Human Granulocytic Anaplasmosis

Synopsis

Human granulocytic anaplasmosis (HGA), a deer tick transmitted rickettsial infection caused by Anaplasma phagocytophilum, is a common cause of undifferentiated fever in the Northeast and Upper Midwest U.S. Patients are often initially diagnosed with a mild viral infection, and illness readily resolves in most cases. However, as many as 3% may develop life threatening complications and nearly 1% die from the infection. A history of tick bite and a high degree of clinical suspicion thus warrant consideration for doxycycline treatment in both adults and children, even in the absence of known tick bite, a negative blood film examination, or pending results of specific A. phagocytophilum diagnostic tests such as paired serology or PCR on acute phase blood. Antibody tests and titers should not be used to monitor active infection as detectable antibodies can remain present for years. Moreover, persistent infection has never been reported. While co-infections with Borrelia burgdorferi and Babesia microti occur, there is little evidence to suggest synergism of disease or a role for A. phagocytophilum in chronic illness. Preventive measures include avoiding tick-infested areas, use of tick repellents, and careful searches of skin to remove attached ticks; no vaccine is available.

INTRODUCTION

Tick-borne infections have been recognized in the United States for more than a century. Following the description of the agent of Rocky Mountain spotted fever (RMSF) in 1906,¹ several clinically important tick-associated human infectious syndromes have since been characterized.^2-10 One tick-borne infection, human granulocytic anaplasmosis (HGA) caused by the rickettsia Anaplasma phagocytophilum, is transmitted by Ixodes scapularis ticks in the U.S. and can be sometimes confused with or complicates Lyme disease. A compilation of data published by the CDC and in Morbidity and Mortality Weekly Reports since HGA became nationally reportable includes at least 15,952 cases since 1995 (Figure 1). In fact, the incidence of HGA increased 12-fold between 2001 and 2011, and the disease can cause severe illness and occasionally death in otherwise healthy individuals. While many patients with competent immune systems resolve their illnesses spontaneously even without antibiotic treatment, most symptomatic patients benefit from specific antibiotic therapy. As with most rickettsial infections, poor outcomes can occur without early identification and specific treatment, usually with doxycycline. The major difficulty with HGA is that the early symptoms and signs are nonspecific, often mimicking a viral illness, and rapid sensitive tests for diagnosis early in infection are not widely available. Thus, it is difficult to arrive at a specific diagnosis early in the course of the illness when antibiotic therapy is most likely to be successful. This chapter will focus on current practice for the diagnosis and management of HGA.^11,12

Figure 1.

Reported cases of tick-borne rickettsial infections in the U.S., 1987-2013. The cumulative area plots demonstrate the overall burden of infection during this time interval. HGA – human granulocytic anaplasmosis; HME – human monocytic ehrlichiosis; spotted fever – spotted fever group rickettsioses, including Rocky Mountain spotted fever; nos – not otherwise specified. Data extracted from Morbidity and Mortality Weekly Reports, 1987-2014.

PATIENT HISTORY

Most cases of HGA develop in individuals exposed to or bitten by Ixodes ticks.^13-16 Thus, a history of a tick bite or well established exposure to ticks is an important historical clue. Ticks in the Ixodes persulcatus-complex serve as competent vectors for multiple pathogens that can infect humans including A. phagocytophilum,¹¹ Borrelia burgdorferi (the agent of Lyme borreliosis),¹⁷ Babesia microti (the agent of babesiosis),¹⁸ Ehrlichia muris-like agent,¹⁹ Borrelia miyamotoi,³ and Powassan virus ²⁰Vector ticks in North American endemic habitats include Ixodes scapularis in the northeastern and upper Midwest regions of the USA, and I. pacificus along the northern Pacific coast. Despite its wide distribution, the majority of HGA cases are reported from the upper Midwest and northeastern United States, overlapping the endemic regions for Ixodes scapularis (the black-legged deer tick).²¹ Recent epidemiologic studies of tick habitats demonstrate that the endemic areas have expanded, and as such it is anticipated that so will the range where HGA will be found in humans.^22-24 However, at least 25% of patients with proven HGA do not report exposure to ticks and thus, it should not be used as an absolute criterion for diagnosis or clinical suspicion.

Seroprevalence and incidence vary directly with age, suggesting that the principal risk factor for contracting HGA is duration of residence in endemic areas.^25,26 Ixodes scapularis ticks, while widespread, transmit infections to human in a rather limited geographic range. Therefore, understanding the ranges of endemic risk is also a critical component for patient evaluation. Serosurveys among individuals bitten by ticks in the USA demonstrate A. phagocytophilum seroprevalence rates ranging between 8.9 and 36%.²⁵ Bakken et al. reported a seroprevalence of 14.9% among healthy residents from northwestern Wisconsin who had no history of a recent tick bite.²⁶ The highest annual US average HGA incidence rates between 2000 and 2007 were reported in Rhode Island (32.1 per million), Minnesota (30.2 per million), Connecticut (13.1 per million), Wisconsin (8.2 per million), New York State (7.7 per million) and Massachusetts (6.5 per million).²¹ However, HGA incidence rates exceeding 650 cases per million are also reported in some northwestern Wisconsin counties.^14,21,27 HGA also occurs at a much lower incidence in Europe and Scandinavia and it is increasingly described in eastern parts of Asia, especially China, South Korea, and Japan.

Despite the strong association with tick bite, HGA can be acquired through alternate exposures to A. phagocytophilum. Horowitz described HGA in a woman during pregnancy.²⁸ The infant developed HGA eight days after being borne, and the authors argued that transplacental transmission A. phagocytophilum occurred. Several butchers from northwestern Wisconsin acquired HGA after butchering large quantities of white tail deer carcasses during hunting season[36].²⁹ None of the butchers had noted a preceding tick-bite, raising the query as to whether they acquired HGA by direct exposure to infected deer blood through skin cuts, through inhalation of aerosolized blood, or through infected blood splashed directly on mucous membranes. A cluster of HGA cases associated with a severely hemorrhagic febrile illness occurred after nosocomial exposure in a Chinese hospital, ostensibly associated with exposure to the index patient’s blood or respiratory secretions.³⁰ A. phagocytophilum remains viable and infectious in refrigerated, stored blood for as long as 18 days.³¹ A seroprevalence study of 992 blood-donors from Connecticut and Wisconsin demonstrated that 0.4 to 0.9% of the blood donors have A. phagocytophilum antibodies.³² There is no U.S. mandate to screen blood products for A. phagocytophilum infection, and at least 8 cases of HGA acquired via transfusions of infected leuko-reduced blood products have been reported since 2007.³³

Beyond A. phagocytophilum, Ixodes ticks are often coinfected with other human pathogens.^34,35 Coinfections also occur frequently in the white-footed mouse (Peromyscus leucopus),^36,37 and serological investigations and prospective studies of humans who had Lyme borreliosis demonstrate that between 1 and 9 % of individuals living in Wisconsin,³⁸ or western Sweden³⁹ have serologic evidence of prior A. phagocytophilum infection. In a subsequent surveillance study of HGA in Wisconsin, 7 of 142 patients (5%) had erythema migrans and serologic evidence of recent B. burgdorferi infection,²⁷ and both pathogens have been recovered in culture from coinfected individuals on several occasions.⁴⁰ Thus, sequential or simultaneous infections caused by multiple human pathogens could occur after one or multiple tick-bites, and physicians who diagnose and treat patients with HGA must always consider the possibility of co-infection with other tick-borne agents.

Presentations and Complications

Patients with HGA frequently present with a nonspecific febrile illness. The clinical range of HGA spans from asymptomatic infection to fatal disease and there is a direct correlation between patient age and/or comorbid illnesses and the severity.⁴¹ Most symptomatic patients report exposure to ticks one to two weeks before the onset of illness and often complain of fever/sweating/rigors, headache, myalgia, and arthralgia (Table 1), although the physical examination is often otherwise unrevealing. HGA can be severe with 36% of patients requiring hospitalization and 3% with life-threatening complications;²¹ in one report, up to 17% of hospitalized patients required admission to an intensive care unit.¹⁴ Even though many patients present with severe headache or stiff neck prompting lumbar puncture, spinal fluid analysis is usually unremarkable.⁴² Only a single patient with defined meningitis had A. phagocytophilum documented in the CSF.,⁴³ Among 2,040 cases reported to the CDC between 2000-2007, five (0.2%) had reports of meningitis or encephalitis.²¹

Table 1.

Published signs, symptoms, and key laboratory abnormalities (%) reported among laboratory-confirmed human granulocytotropic anaplasmosis (HGA) in the USA, Europe, and in Asia (N = 68 to 794 across features).

Frequency of complaint	Symptom, Sign, or Laboratory Abnormality (number patients evaluated)	Median % (IQR)
Common	Fever (794)	100 (90-100)
	Malaise (391)	97 (90-98)
	Headache (648)	82 (64-93)
	Myalgia (789)	76 (67-87)
	Arthralgia (661)	56 (27-69)
	Elevated serum ALT or AST (397)	83 (63-98)
	Thrombocytopenia (566)	75 (61-91)
	Leukopenia (566)	55 (47-71)
Less common	Stiff neck (64)	45 (34-48)
	Nausea (521)	39 (35-49)
	Cough (523)	29 (20-30)
	Elevated serum creatinine (199)	49 (25-71)
	Anemia (198)	28 (6-44)
Uncommon	Diarrhea (317)	21 (13-28)
	Vomiting (312)	20 (19-29)
	Confusion (470)	17 (17-18)
	Rash* (489)	6 (3-10)

^*Erythema migrans where described

Serious opportunistic infections can occur in immunocompromised patients during the course of HGA, and fatal cases of herpes simplex esophagitis, Candida albicans pneumonitis/esophagitis, and invasive pulmonary aspergillosis are described.^14,44,45 Even though the case fatality rate is ≤1%, significant complications can occur, including septic or toxic shock-like syndrome, acute respiratory distress syndrome, invasive opportunistic infections with both viral and fungal agents, rhabdomyolysis, pancarditis, acute renal failure, hemorrhage, and neurologic diseases such as brachial plexopathy, demyelinating polyneuropathy, and acute transient sensorineural hearing loss.^21,45-48

Most patients present with nonspecific changes in routine hematological and chemistry blood tests. Permutations of leukopenia, a left shift (sometimes reaching 50% or even higher), thrombocytopenia, and mild to moderate elevation of hepatic transaminase activities are present in the majority of patients and provide suggestive clues to the diagnosis.^41,49 Although both leukopenia and thrombocytopenia are present in many patients at the initial presentation, these abnormalities usually normalize by the end of the second week. Thus, normal WBC and platelet concentrations should not dissuade medical providers from including HGA in the differential diagnosis if the patient reports illness for more than 1 week. In contrast, patients who present with nonspecific fever of less than 7 days duration and either leukocytosis or thrombocytosis have a low probability of having HGA.⁴⁹

Diagnostic Testing and Imaging

HGA can be laboratory-confirmed at the point of care by examination of a Wright- or Giemsa-stained peripheral blood smear during the early stage of infection.^41,49,50 At least 20%, and in some studies up to 100% of patients present with morulae in the cytoplasm of peripheral blood neutrophils in the first week of illness.^15,50,51 PCR amplification of A. phagocytophilum–specific DNA from acute phase blood^14,15,52 or isolation of A. phagocytophilum in HL-60 promyelocytic leukemia cell cultures inoculated with acute phase blood^13,41,53 can also confirm the diagnosis during the early stage of infection, but these test modalities are available in only a limited number of public health and commercial reference laboratories. Acute and convalescent serologic testing using an indirect fluorescent antibody method for A. phagocytophilum IgG with demonstration of four-fold change or seroconversion is the most sensitive confirmatory laboratory test, and has been used most commonly to confirm HGA.^25,38,54-56 Specific IgM tests are only reactive during the first 40 days after infection, and are less sensitive than those that detect IgG antibodies, even during this early interval.⁵⁷ Once a patient becomes seroreactive, antibodies can persist for months or years in the absence of any clinical or laboratory-based evidence for ongoing infection; thus, reductions in antibody titers cannot be used as monitors of effective treatment.^25,55 Patients infected by A. phagocytophilum will often develop antibodies that concurrently react with Ehrlichia chaffeensis, the causative agent of human monocytic ehrlichiosis. In some regions, the ticks that transmit these bacteria are both abundant. Thus, the definitive diagnosis must include antibody titers for both pathogens.

The minimal presumptive diagnostic criteria for HGA are unexplained fever and non-specific symptoms such as headache, generalized myalgias, and rigors accompanied by suggestive changes in routine laboratory tests.^{11,12,14,41,56} Probable and laboratory-confirmed HGA require a nonspecific febrile illness and laboratory confirmation by PCR, culture of blood, and/or detection of specific A. phagocytophilum antibodies in serum (Table 2). Patients who present with an acute clinical illness compatible with HGA should always be considered for specific antibiotic treatment.^12,14,41,56 HGA is a reportable illness and all confirmed cases must be reported to the CDC or to the local state health department in the state where the diagnosis was made. The tabular list of International Classification of Diseases (ICD-9) has categorized HGA under the subheading tick-borne rickettsioses/other ehrlichiosis with the numerical code 082.49 (ICD-10 code A77.49).⁵⁸ It is important to remember that bites by infected Ixodes ticks may lead to simultaneous infections caused by multiple pathogens. The reported frequency of Lyme disease and HGA coinfection varies between 2 to 11.7%,⁵⁹ and patients who have a positive blood culture for A. phagocytophilum and-or a four-fold rise in antibody titer to at least 640 have significantly more symptoms in total than patients with early Lyme disease defined by the presence of erythema migrans only.⁶⁰

Table 2.

Modified case definitions^* for human granulocytic anaplasmosis (HGA). ⁸²

Case definition	Laboratory test result
Supportive HGA	Morulae present in peripheral blood smear neutrophilsa or
	Single serum A. phagocytophilum IgG titer by IFAb ≥ 640
Confirmed HGA	A. phagocytophilum IFA IgG seroconversion d or
	Positive A. phagocytophilum PCRc of blood or
	Isolation of A. phagocytophilum from bloode or
	A. phagocytophilum antigen present in tissue sample by immunohistochemistry

^*Definitions are dependent upon a presentation with manifestations clinically-consistent with HGA.

^aLight microscopy of Wright stained peripheral acute phase blood;

^bIndirect immunofluorescent antibody test with A. phagocytophilum antigen;

^cPolymerase chain reaction with specific A. phagocytophilum primers;

^dFourfold or greater change in serum antibody titer;

^eIsolation of A. phagocytophilum from blood incubated in HL-60 human promyelocytic cell line.

Imaging studies play little additional roles in the specific diagnosis of HGA but can be very useful for evaluation of the extent of disease and specific organ/tissue involvement.

DIFFERENTIAL DIAGNOSIS

Owing to the undifferentiated presentation of HGA, the differential diagnosis can be vast. With the common manifestations of fever, headache, myalgia and malaise, viral syndromes such as enterovirus infection, Epstein-Barr virus infection, human herpes virus-6 infection, human parvovirus B19 infection, viral hepatitis, West Nile fever and Chickungunya fever should be included on the list of differential diagnoses. Other tick-borne infections including Lyme disease, Borrelia miyamotoi infection, babesiosis, Ehrlichia muris-like agent infection, Powassan virus infection, and B. hermsii relapsing fever must also be kept in mind. Acute bacterial infections to consider include disseminated gonococcal infection, endocarditis, meningococcemia, Mycoplasma pneumoniae infection, group A streptococcal post-infectious syndrome, secondary syphilis, septic shock syndromes, and typhoid fever (Table 3). Inflammatory illnesses of a possible infectious or non-infectious origin include allergic drug reactions, idiopathic thrombocytopenic purpura, immune complex-mediated illnesses, Kawasaki disease, thrombotic thrombocytopenic purpura, and hemophagocytic and macrophage activation syndromes.

Table 3.

Differential Diagnosis of Human Granulocytic Anaplasmosis.

Exposure type	Viral syndromes	Bacterial agents/syndromes	Parasitic agents/syndromes	Non-infectious syndromes
History of vector exposure	Powassan virus disease/tick-borne encephalitis	Lyme disease	Babesiosis
	West Nile virus disease	B. miyamotoi infection	Malaria
	Dengue virus fever	B. hermsii infection
	Colorado tick fever	E. chaffeensis infection
	Heartland virus fever	E. ewingii infection
	Severe fever with thrombocytopenia virus infection	E. muris-like agent infection
	Chickungunya virus disease	Rocky Mountain spotted fever
		Murine typhus
		African tick-bite fever
		Scrub typhus
		Bartonellosis
		Tularemia
		Leptospirosis
No vector exposure	EBV infection	Acute bacterial endocarditis		Kawasaki syndrome
	Human herpes virus-6 infection	Secondary syphilis		ITP
	Parvovirus B19 infection	N. gonorrhea sepsis		TTP
	Viral hepatitis A, B, C	N. meningitidis sepsis		Hemophagocytic syndrome
	Enterovirus infection	Group A Streptococcal infection		Immune-complex illness
	Hantaan virus infection	Leptospirosis		Allergic drug reaction
		Typhoid fever		Acute leukemia
				Lymphoma

Typically, patients with HGA present during the warm seasons when ticks are known to be active, and up to 75% will report tick bite or exposure to ticks in known tick-infested regions. Other vector-borne zoonoses should be considered for the patient who has had recent documented insect or arthropod-bites, including babesiosis,, Colorado tick fever, human monocytic ehrlichiosis, leptospirosis, Lyme disease, murine typhus, Q fever, rat-bite fever, Rocky Mountain spotted fever and tularemia. In travelers, the list could be expanded to include dengue fever, malaria, leptospirosis, and tick-borne encephalitis. Occasionally the major manifestation will be reflected in hematologic laboratory abnormalities when the differential diagnosis should also include malignancies such as leukemia and lymphoma, especially when intracytoplasmic structures such as Auer rods may be identified and confused with morulae.

TREATMENT

In vitro investigations indicate that A. phagocytophilum is uniformly susceptible to the tetracycline antibiotics.^61-64 Doxycycline hyclate has traditionally been the agent of choice because of its good patient tolerance and favorable pharmacokinetic properties compared with other tetracycline derivatives. For the most part, HGA is a mild illness, but there is a known direct relationship between serious infection, including cases with a fatal outcome, and patient variables such as advanced age, ongoing immunosuppressive therapy, predisposing chronic inflammatory illnesses or underlying malignant diseases.^42,51 Because of the potential for serious or even fatal infection it is therefore recommended that all patients with suspected or documented HGA should undergo treatment with oral or intravenous doxycycline hyclate in the absence of specific contraindications to tetracycline drugs (Table 4).

Table 4.

Recommended antibiotic treatment for human granulocytic anaplasmosis.^11,12,65,66

Antibiotic drug	Patient age (years)	Antibiotic dose	Duration (days)
Doxycycline hyclate	≤ 8	2.2 mg/kg 2 times daily IVa or POb	4 - 5c
	> 8	100 mg 2 times daily IV or PO	10 - 14d
Tetracycline HCl	> 8	500 mg 4 times daily PO	10 - 14
Rifampin	Pediatrice	20 mg/kg/d (max. 600 mg) in 2 divided doses PO	5 - 7f
	Adultg	300 mg 2 times daily PO	5 - 7

^aIntravenous administration;

^bOral administration,

^cUntil fever has resolved and three additional days;

^d14 days recommended if suspected co-incubating B. burgdorferi infection;

^eIndividuals aged 16 years or less;

^fShort duration since therapy not directed towards co-incubating B. burgdorferi infection;

^gIndividuals aged 18 years or older.

The recommended therapy for adults is doxycycline 100 mg given orally at 12 hour intervals.^42,65 Children older than 8 years should also be treated with doxycycline given in divided doses with dosage adjusted to the patient’s weight (4.4 mg/kg/24 hours, maximum dose 100 mg).^65,66 Doxycycline is also the drug of choice for children who are seriously ill regardless of age.⁶⁶ Doxycycline therapy typically leads to clinical improvement in 24-48 hours.^14,41,65,66 Thus, patients who fail to respond to treatment within this time frame should be re-evaluated for alternative diagnoses and treatment.

The optimal duration of doxycycline therapy has not been established. Patients who have been treated for 7 to 10 days resolve their infection completely, and relapse or chronic infection has never been reported, even for those patients who were never treated with an active antibiotic. However, adult patients who are considered at risk for co-infection with B. burgdorferi should continue doxycycline therapy for a full 14 days. A shorter course of doxycycline (5 to 7 days) has been advocated for pediatric age-group patients because of the potential risk for adverse effects (dental staining) seen occasionally in young children.^65-67

Rifamycins also have excellent in vitro activity against A. phagocytophilum.^61-63 A few pregnant women and pediatric patients have been treated successfully with rifampin.^68-70 Thus, patients who have HGA and who are unsuited for tetracycline treatment due to a history of drug allergy or pregnancy, and children younger than 8 years of age who are not seriously ill should be considered for rifampin therapy. Studies with levofloxacin demonstrate some activity in vitro.^61-63 However, at least one patient with HGA who received a 13 day course of levofloxacin initially had a clinical response only to relapse when the regimen was discontinued suggesting that fluoroquinolones should not be used.⁷¹

PROGNOSIS AND LONG TERM OUTCOME

More than 15,952 patients were diagnosed with HGA and reported to state and federal health-agencies since 1994. Only 8 patients are known from published literature to have died during the active phase of HGA, although a CDC review of national surveillance systems between 2000 and 2007 identified 11 fatalities.^14,21,44,45 While the case fatality rate for HGA has been estimated at 1.2% among those 20-39 years of age, the overall case fatality rate is likely between 0.2% and 1.2%.²¹ Published case-report series indicate that HGA most often is a mild, self-limited illness that resolves even without antibiotic treatment.^{14,15,55,72-74}

Patients who are treated with doxycycline or rifampin typically resolve fever and most of their physical complaints within 24 to 48 hours. A small number of patients who are diagnosed with HGA do not receive any antibiotic therapy or they receive ineffective antibiotic therapy, but nearly all these patients make a complete recovery within 60 days.¹⁴ PCR analysis of serial blood samples collected from untreated patients during convalescence indicates that bacteremia can persist for up to 30 days.^29,75-77 There are no published reports of patients with active clinical illness persisting beyond two months, although a single longitudinal study in Wisconsin reported significantly more recurrent or continuous fevers, chills, fatigue and sweats within 1 year after infection.⁷³ Thus, the long term prognosis appears to be favorable and patients are expected to make a complete recovery. There is currently no published clinical evidence to suggest that untreated HGA evolves into a chronic illness in humans, as persistently elevated antibody titers should be interpreted as evidence of past infection rather than proof of an ongoing unresolved infectious process.

IMMUNITY AND REINFECTION

Most patients acquire HGA in the geographical region where they live, work or recreate.^{14-16,21,72,73} It is therefore reasonable to assume that those individuals remain at risk for future bites by infected Ixodes ticks and potential HGA reinfection. Nevertheless, conclusive evidence of A. phagocytophilum infection occurring more than once is exceedingly rare.⁷⁸ Passive administration of A. phagocytophilum antibodies partially protects laboratory animals in murine models of HGA against infection; thus, it is likely that patients who develop high antibody titers to A. phagocytophilum are equally protected against reinfection after subsequent tick-bites. Serum A. phagocytophilum antibody titers remain elevated for a median of 12-18 months after HGA has resolved.³⁸ However, some infected human patients maintain elevated A. phagocytophilum antibody titers for as long as 3 years after infection.^16,25,55 Whether previous infections of humans leads to immunologic memory and a subsequent anamnestic protective immune response upon re-challenge with A. phagocytophilum is unknown.

Horses that are convalescent from A. phagocytophilum infection develop immunity and resistance to experimental challenge 8 weeks after infection.⁷⁹ However, laboratory mice that were actively immunized with lysates of purified A. phagocytophilum were only partially protected against challenges with A. phagocytophilum.⁸⁰ The incomplete protection by both immunization with heat-inactivated bacteria and passive antibody administration suggests that protective immunity requires more than the presence of antibodies.

PREVENTION

Avoidance of tick bites and prompt removal of attached ticks remain the best disease prevention strategy. Individuals who are exposed in tick habitats should wear protective clothing, including long-sleeved shirts, long-legged pants, socks wrapped outside the pant legs and close-toed shoes to make it harder for ticks to reach bare skin and attach (bite). Light-colored pants could make it easier to see and remove crawling ticks. Tick repellents such as DEET (N,N-diethyl-m-toluamide) are available for application to exposed skin and clothing, and alternative repellents such as picaridin are becoming more readily available. These agents should be considered for use by individuals whose occupation or recreation exposes to tick habitats where the risk of being bitten is high. Permethrin cannot be applied directly to skin, but can be applied to clothing before the clothing is worn and is considered an excellent choice for significant exposure risks. No vaccines that prevent human or veterinary granulocytic anaplasmosis are currently available.

Persons who spend time in tick-endemic areas should inspect themselves frequently for ticks. All attached ticks should be removed by gently grasping the tick with tweezers or forceps close to the skin and slowly pulling straight out with constant traction. Routine disinfection of the bite wound with isopropyl alcohol or tincture of iodine reduces the risk of contamination of the bite site with skin bacteria. Studies have shown that a period of 4 to 24 hours or more may be necessary before A. phagocytophilum becomes biologically “activated” and successful transmission of infective organisms from the tick to the host takes place.⁸¹ Thus, the longer an infected tick is permitted to feed, the more likely the bite will result in infection. Therefore, prompt and complete removal of attached ticks is indicated to minimize the risk of infection. The potential value of prophylactic doxycycline administration has never been tested in prospective, randomized trials.

SUMMARY

Patients who present with non-specific fever after exposure to ticks should be evaluated by clinical examination and routine laboratory testing to determine if the illness is potentially a tick-borne infection. Laboratory abnormalities such as leukopenia with relative granulocytosis and a left shift, thrombocytopenia, and mild increases in serum hepatic transaminase activities warrant consideration for treatment with doxycycline. These patients should also undergo specific laboratory testing to confirm the diagnosis of HGA.

Sensitive and specific laboratory tests that provide rapid diagnostic confirmation are generally not available in the acute care setting.^11,41 Thus, patients with suspected HGA should begin empiric antibiotic treatment as soon as blood samples have been collected for confirmatory laboratory testing. Acute phase serum samples should be paired with convalescent serum to detect seroconversion in those instances, especially when blood-smear microscopy, PCR, or cell culture testing are either unavailable or inconclusive.

Figure 2.

Anaplasma phagocytophilum-infected band neutrophil in human peripheral blood (Wright stain, original magnification × 260). The top left inset shows the same band neutrophil and demonstrates several morulae with a stippled basophilic appearance corresponding to individual bacteria (magnification × 520). The bottom right insert shows A. phagocytophilum cultivated in vitro in the human promyelocytic leukemia cell line HL-60. Here, the individual basophilic bacteria are easily visualized within vacuoles of the infected cell (LeukoStat stain; magnification × 520).

Key Points.

• The clinical presentation of human granulocytic anaplasmosis is an acute febrile nonspecific viral-like illness. Leukopenia, thrombocytopenia and elevated hepatic transaminases are commonly seen early in disease.

• A history of a tick bite or exposure is important, but its absence and lack of a diagnostic test result should not mitigate clinical consideration.

• Early treatment with doxycycline for adults and children (including those younger than 8 years of age) should be instituted on clinical suspicion alone.

• Although hospitalization occurs in 36%, and life threatening disease occurs in 3% of cases; the case fatality rate is low (0.6%) and most patients resolve infections without complications.

• Persistent infection has not been demonstrated, and evidence to support a role in chronic illness is lacking. Acute coinfections with other tick-transmitted pathogens can occur.