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"The Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America"
Published: 01 November 2006
Выдержки:
HGA
Primary management options considered. The management options that were considered included oral or parenteral antimicrobial therapy for patients diagnosed with symptomatic HGA.
Outcomes evaluated. The panel weighed both the risks and consequences of developing acute and late complications of HGA and the economic costs and possible adverse effects of antimicrobial therapy. The desired outcome is to resolve the symptoms and signs of HGA while minimizing the adverse effects of antimicrobial therapy.
Background and diagnosis of HGA. HGA is a rickettsial infection of neutrophils [338, 339]. The infectious agent,
A. phagocytophilum, is transmitted by the bite of infected
Ixodes ticks, and human infection occurs in areas in the United States and Europe where Lyme disease is endemic [340–343]. In contrast to Lyme disease, however, HGA is infrequently diagnosed in children.
Clinical manifestations are nonspecific and may include fever, chills, headache, and myalgias [94, 95, 341–344]. The incubation period is 5–21 days [344]. Laboratory features may include leukopenia, lymphopenia, thrombocytopenia, and mild elevation of liver enzyme levels. In most cases, HGA is a mild, self-limited illness, and all clinical signs and symptoms resolve in most patients within 30 days, even without antibiotic therapy [340]. However, serious manifestations of infection, including a fatal outcome, have been reported in patients with factors known to suppress the immunologic response to infection, such as advanced age, immunosuppressive therapy, chronic inflammatory illnesses, or underlying malignant diseases [340, 345, 346]. Chronic infection due to
A. phagocytophilum has not been described in humans.
Prior to initiation of antibiotic therapy,
A. phagocytophilum can be detected in blood samples by smear examination, PCR, or culture using HL60 cells [94, 345, 347–349]. Identification of the characteristic intragranulocytic inclusions on blood smear is the most rapid diagnostic method, but such inclusions are often scant in number or sometimes absent; in addition, other types of inclusions unrelated to HGA, or overlying platelets, can be misinterpreted by inexperienced observers [349]. The most sensitive diagnostic method is acute-phase
and convalescent-phase serologic testing using an indirect fluorescent antibody assay (acute-phase testing alone is not sufficiently sensitive) [348–350]. Serologic testing is often the only way to diagnose a patient who has already begun to receive antibiotic treatment. Immunostaining of
A. phagocytophilum antigen in a tissue sample is an uncommonly used diagnostic modality [344]. Doxycycline therapy leads to clinical improvement in 24–48 h [340, 345, 346, 351]. Thus, patients who do not respond to treatment within this time frame should be reevaluated for alternative diagnoses and treatment, including coinfection with
B. microti in certain geographic areas (see Babesiosis below).
Evidence to support treatment recommendations. There are no controlled clinical trials on the use of antibiotics for treatment of HGA. Doxycycline and rifampin are both highly active against
A. phagocytophilum in vitro [352–354], and recommendations for therapy have been based on published reports of the clinical response to these drugs. It is generally accepted that all symptomatic patients should be treated with an appropriate antimicrobial agent, because it may be very difficult to distinguish patients who will have a self-limited illness from those who will develop a complicated or fatal course of HGA [351].
Most of the clinical experience in treatment of adults has been with doxycycline at a dosage of 100 mg twice per day given orally [340, 345, 351]. There is only limited experience in the use of doxycycline for treatment of HGA in children [355–360] or pregnant women [357]. Doxycycline was used successfully to treat a pregnant woman who developed symptomatic HGA during parturition [357]. Her newborn child was subsequently diagnosed with HGA and was also treated successfully with doxycycline. In addition, a 5-year-old boy, who had simultaneous HGA and Lyme disease, was treated successfully with doxycycline [359]. Recently a 38-year-old woman was diagnosed with HGA 10 days after she had delivered a healthy baby [355]. She was treated with doxycycline for 2 weeks while breast-feeding, and both mother and baby were well at a later follow-up examination. Although the American Academy of Pediatrics has recommended doxycycline as the preferred antibiotic for treatment of children diagnosed with clinically apparent HGA [361], a small number of pediatric-age patients and pregnant women have also been treated successfully with rifampin [358, 362, 363].
The optimal duration of antimicrobial therapy for HGA has not been established. At first, patients were treated empirically with doxycycline for 10–14 days, and the recommendations for duration of treatment followed the guidelines for treatment of Lyme disease. Clinical experience, however, has shown that adult patients who have been treated for 7–10 days experienced complete resolution of their infections, and relapse or chronic infection has not been demonstrated [27, 94, 95, 341, 343]. A shorter course of doxycycline (4–7 days) has been advocated for patients <8 years of age because of the potential risk for adverse effects from this drug (dental staining) in young children [340, 351, 364, 365].
There is no published clinical experience on the use of clarithromycin or azithromycin for treatment of HGA. Certain fluoroquinolones, such as levofloxacin, are active against
A. phagocytophilum in vitro [352–354], but a single case report and a small study of immunodeficient mice (severe combined immune deficient [SCID]) have suggested that this class of drugs may not be curative of infection [366]. Chloramphenicol is inactive against
A. phagocytophilum in vitro [352–354] and has been ineffective for treatment of horses infected with
A. phagocytophilum [367].
Recommendations
1. All symptomatic patients suspected to have HGA should be treated with antimicrobial therapy because of the risk of complications (A-III). Suspicion for HGA is based on the acute onset of unexplained fever, chills, and headache, often in association with thrombocytopenia, leukopenia, and/or increased liver enzyme levels in patients with exposure to
I. scapularis or
I. pacificus ticks within the prior 3 weeks. Confirmation of the diagnosis is based on laboratory testing (see above), but antibiotic therapy should not be delayed in a patient with a suggestive clinical presentation pending the results.
2. Doxycycline is recommended as the treatment of choice for patients who are suspected to have symptomatic HGA (A-II). The dosage regimen for adults is 100 mg given twice per day by mouth (or intravenously for those patients unable to take an oral medication) for 10 days. This treatment regimen should be adequate therapy for patients with HGA alone and for patients who are coinfected with
B. burgdorferi.
Although a 10-day treatment course of doxycycline may be offered to all children as well (C-III), the panel preferred a modified approach in which severity of illness, age of the child, and the presence or absence of coinfection with
B. burgdorferi were each considered to minimize an already low risk of drug toxicity [365]. The suggested dosage of doxycycline for children with HGA is 4 mg/kg per day in 2 divided doses (maximum, 100 mg per dose) given orally (or intravenously for children unable to take an oral medication). Children at least 8 years of age may be treated with a 10-day course of doxycycline. For severely ill children <8 years of age without concomitant Lyme disease, the panel recommended an abbreviated treatment course of 4–5 days (i.e., for ∼3 days after resolution of fever) (B-III). Children treated with an abbreviated course of therapy should be closely observed to ensure resolution of clinical and laboratory abnormalities. If the child has concomitant Lyme disease, then amoxicillin (50 mg/kg per day in 3 divided doses; maximum, 500 mg per dose) or cefuroxime axetil (30 mg/kg per day in 2 divided doses; maximum, 500 mg per dose) should be initiated at the conclusion of the course of doxycycline to complete a 14-day total course of antibiotic therapy (B-III). Recommended management of less-severely ill children with HGA is discussed below.
3. Patients with mild illness due to HGA who are not optimally suited for doxycycline treatment due to a history of drug allergy, pregnancy, or age <8 years, may be treated with rifampin for 7–10 days using a dosage regimen of 300 mg twice per day by mouth for adults and 10 mg/kg twice per day for children (maximum, 300 mg per dose) (B-III). Rifampin-treated patients should be closely observed to ensure resolution of clinical and laboratory abnormalities. Because rifampin is not effective therapy for Lyme disease, coinfected patients should also be treated with amoxicillin or cefuroxime axetil as used for the treatment of erythema migrans (see tables 2 and 3) (A-I). No other antimicrobial can be recommended for the treatment of HGA (E-III).
4. Persistence of fever for >48 h after initiation of doxycycline suggests that the diagnosis of HGA is incorrect or, more remotely, that the patient is coinfected with
B. microti.
5. Treatment is not recommended for asymptomatic individuals who are seropositive for antibodies to
A. phagocytophilum (E-III).