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Infection with Ehrlichia in childhood
CURRENT LITERATURE AND CLINICAL ISSUES
Infection with Ehrlichia in childhood In April 1986 a life-threatening multisystem disease associated with leukopenia, thrombocytopenia, and abnormal liver function tests developed in a man who had incurred numerous tick bites approximately 2 weeks previously.~ The illness was initially thought to be Rocky Mountain spotted f6ver, but results of serologic tests were negative. Intraleukocytic inclusions resembling Ehrlichia species and an antibody response to Ehrliehia canis suggested the etiologic diagnosis.2 Numerous reports of children and adult~ with human ehrlichiosis have since appeared. We wilt summarize these reports and present newer data Of relevance to the pe-: diatrician. ETIOLOGY
EhrHchia organisms are nomnotile, gram-negative intracellular bacteria that replicate in a manner analagous to chlamydiae.3 After leukocytic phagocytosis, the elementary body divides into initial bodies and matures into a morula, the contents of which are released with cell lysis. Alternatively, the cell can divide, retaining a morula in each new cell. Until recently, six species of Ehrlichia were thought to producedisease in animals and human beings. A new species of EhrIichia, E. chaffeensis sp. nov., has recently been identified as the cause of human erhlichiosis.3a E. eanis infection was initially reported in Algerian dogs in 1935. 4 In the United States, serologic evidence of infection with this rickettsial organism has been found in 57% of dogs in 21 states) Rhipieephalus sanguineus, the brown dog tick, is the vector of canine ehrlichiosis.6 The vector of human ehrlichiosis has not been identified. EPIDEMIOLOGY Since the initial report, 257 cases of human ehrlichiosis have been diagnosed by or reported to the Centers for Disease Control from 21 states in the United States (Centers for Disease Control: unpublished data). Cases have been recognized primarily along the Atlantic coast and in south central areas, but a few cases have been reported from the Rocky Mountain states and as far west as Washington State. 711 The first case from outside the United States was recently reported from Portugal. 12 Approximately 75% of human patients with ehrlichiosis have a history of tick bite) Most of the remaining patients
9/34/36201
998
report having been in a tick-infested area. Predictably, a majority of the patients develop illness from March to October, when ticks are most prevalent.8 The median age of patients with ehrlichiosis is 42 years, compared with 31 years for patients with RMSF. s However, numerous patients as young as 2 to 4 years of age have been reported. 1316 From 1986 to 1988, a total of 10 cases of ehrlichiosis were diagnosed in patients from 2 to 11 years of age in Oklahoma. 17 PATHOGENESIS The diseases caused by Ehrlichia species appear to be both dose and host dependent,4 Ehrlichia infections are characterized by a lack of severe inflammatory response, pyogenic reaction, and tissue necrosis. However, a response RMSF
RockyMountain spotted fever
[
by the lymph0reticular system is seen in infections with Ehrliehia species, including infections with the human Ehrlichia agent and Ehrlichia sennetsu, the etiologic agent of an infectious mononucleosis-like syndrome occurring in Japanese and Malaysians.3' 4 The agent of human ehrlichiosis appears to be tropic for hematopoietic tissue. Abnormalities in bone marrow aspirates have ranged from hypoplasia is to erythrophagocytosis. 14An immune-mediated response may also play a role in the often-observed thrombocytopenia, as it does in canine ehrlichiosis.4 The complete elucidation of the pathogenesis of human ehrlichiosis awaits the propagation of the human ehrlichiosis agent in an experimental animal model. CLINICAL MANIFESTATIONS Human ehrlichiosis has a wide clinical spectrum, from inapparent infection, to a mild viral-like illness, to severe life-threatening disease. 19, 20 The incubation period for human infection ranges from 1 to 21 days. 7 Eighteen children with human ehrlichiosis have been reported. 13-Iv,19,2i The clinical and laboratorY features of these children are shown in the Table. The patients ranged in age from 2 to 11 years; 12 (66%) were male. As in adults with human ehrlichiosis, fever was common. Gastrointestinal symptoms, including anorexia, nausea, and vomiting, were slightly more common in children. Abdominal pain and tenderness have also been reported in both children and adults. 3, 14, 15, I9 More than
Volume 120 Number 6
60% of children were reported to have a rash, in comparison with 44% of adults. 3, 22 The rashes reported in children were erythematous, macular, papular, vesicular, petechial, scarlatiniform, or vasculitic. Arthralgia and conjunctival injection have also been reported. TM 15 Three children had meningitis, whereas pulmonary manifestations (including pleural effusion and noncardiogenic pulmonary edema) and pharyngitis each was a feature in four children. LABORATORY FEATURES The most common laboratory features of human ehrliehiosis in both adults and children involve the hematopoietic tissue and include leukopenia, lymphopenia, and thrombocytopenia (Table). Anemia was noted in about a third of the reported cases of human ehrlichiosis in children. Elevation of liver enzyme activities, particularly aspartate aminotransferase, have been seen early in illness both in adults and children. 3, 15, 23 Hyponatremia is an uncommon finding in human ehrlichiosis. Renal abnormalities, including elevated blood urea nitrogen and serum creatinine concentrations, proteinuria, and hematuria may be present, although renal failure has not been reported as a feature of ehrlichiosis in children. 14, 19 Children usually have an excellent prognosis; the blood, liver, and kidney abnormalities resolve 1 to 2 weeks after treatment. Three fatalities caused by human ehrlichiosis have been reported in adults and none in children; two of these cases were diagnosed serologically and the third by observing pathognomonic intraleukocytic morulae of Ehrlichia before death. 8, 24 DIAGNOSIS
Tissue examination. Morulae have only rarely been observed before death in mononuclear and polymorphonuclear cells from peripheral blood or bone marrow of infected patients.i, 14 An immunohistologic technique for the specific identification of Ehrlichia organisms from a fatal case of human ehrlichiosis has recently been developedY This avidinbiotin immunoperoxidase method revealed that morulae were most frequently seen in macrophages and uncommonly in lymphocytes. The splenic red pulp and periarteriolar lymphoid sheath harbored most organisms, followed by liver, lymph node, and other tissues. Pathologic examination of three fatal cases revealed gastrointestinal hemorrhage; mild interstitial pneumonitis; perivascular lymphohistiocytic infiltrates in the lungs, liver, kidneys, and heart; and bone marrow hyperplasia. 26 Focal hepatocyte necrosis, hepatocyte dropout, Kupffer cell hyperplasia, and erythrophagocytosis were present. Isolation and polymerase chain reaction amplification. The isolation of Ehrlichia organisms from a 21-year-old
Ehrlichia infection in childhood
999
T a b l e . Clinical and laboratory findings in children with ehrlichiosis Children with findings Findings
Clinical Fever Gastrointestinal symptoms Rash Myalgia Headache Laboratory Leukopenia Lymphopenia Thrombocytopenia Anemia Elevated liver enzyme activities Hyponatremia
No.
%
18 (18)* 13 (18) 11 (18) 08 (13) 10 (10)
100 72 61 62 100
11 (16) 12 (16) 10 (13) 06 (16) 08 (10) 03 (09)
69 75 77 38 80 33
Data from references 13-17, 19, 21. *Numberin parenthesesrepresentstotal numberof childrenfor whomspecific informationregardingeach findingis known.
man with clinical signs and symptoms compatible with the diagnosis of human ehrlichiosis was recently reported) a, 27 Electron micrograph examination of the infected cells revealed that inclusion bodies were surrounded by a distinct cytoplasmic membrane, as previously described for the Ehrlichieae. The 16S ribosomal ribonucleic acid sequencing indicated that the new isolate was similar, but not identical, to E. canis. The polymerase chain reaction amplification technique has also been successfully utilized to detect the human agent of ehrlichiosis in blood samples from five seropositive patients. 28 This technique may presumptively identify and differentiate RMSF and human ehrlichiosis. Serodiagnosis. The case definition for human ehrlichiosis, before the isolation of the human agent, required a fourfold or greater rise or fall in the indirect immunofluorescent antibody titer to E. canis, with a minimum titer of 64. 3 The Centers for Disease Control now uses the human Ehrtichia agent as the antigen in the immunofluorescentantibody test and follows the same serologic case definition. DIFFERENTIAL
DIAGNOSIS
The differential diagnosis of ehrlichiosis has most often included RMSF. Rash and hyponatremia have occurred with greater frequency in RMSF; leukopenia at initial presentation has more commonly been noted in ehrlichiosis. Other diagnostic considerations have included infectious mononucleosis, leptospirosis, Kawasaki syndrome, meniningococcemia, collagen vascular disease, leukemia, enteroviral and cytomegaloviral infections, babesiosis, tularemia, and Lyme disease. Concurrent infection with two tick-borne
1000
Barton, Rathore, a n d Dawson
pathogens has been documented2l a n d therefore must, in rare instances, be given consideration.
THERAPY
The Journal o f Pediatrics June 1992
6.
7.
Tetracycline appears to be the drug of choice for canine ehrlichiosis.4,.29 Studies in animals a n d clinical experience accrued in man suggest t h a t tetracycline and its analogs are also probably the drugs of choice in h u m a n ehrlichiosis, although this is not universally accepted. 3~ 31 Limited experience with chloramphenicol suggests t h a t it m a y be a suitable t h e r a p e u t i c alternative. 15'17 N o data are available collaparing the efficacy of chloramphenicol with tetracycline. Initiation of therapy with either agent has been associated with defervescence, clinical improvement, and hematologic response. 15' 23 However, recovery has also l~een reported in individuals who did not receive a n y antibiotic treatment.17, 23 In vitro cultivation of the Ehrlichia species pathogenic for h u m a n beings will provide the basis for the determination of antimicrobial efficacy and future therapeutic recommendations. Leslie L. Barton, MD Department o f Pediatrics University o f Arizona Health Sciences Center Tucson, A Z 85724 Mobeen H. Rathore, MD Department o f Pediatrics University o f Florida Health Science Center Jacksonville, FL 32209 Jacqueline E. Dawson, M S Department o f Pediatrics Viral and Rickettsia Zoonoses Branch Division of Viral and Rickettsial Diseases Centers for Disease Control Atlanta, GA 30333
8.
9.
10.
11.
12.
13.
14. 15. 16. 17. 18.
19. 20.
21. REFERENCES
1. Maeda K, Markowitz N, Hawley, RC, Ristic M, Cox D, McDade JE. Human infection with Ehrlichia canis, a leukocytic rickettsia. N Engl J Med 1987;316:853-6. 2. McDade JE. Ehrlichiosis: a disease of animals and humans. J Infect Dis 1990;161:609-17. 3. Fishbein DB, Dawson JE. Ehrlichiae. In: Balows A, Hausler WJ Jr, Herrmann KL, Isenberg HD, Shadomy H J, eds. Manual of clinical microbiology. 5th ed. Washington, D.C.: American Society for Microbiology, 1991. 3a. Dawson JE, Anderson BE, Fishbein DB, et al. Isolation and characterization of an Ehrlichia sp. from a patient diagnosed with human ehrlichiosis. J Clin Microbiol 1991;29:2741-5. 4. Rikihisa Y. The tribe Ehrlichieae and ehrlichial diseases. Clin Microbiol Rev 1991;4:286-308. 5. Keefe T J, Holland C J, Salyer PE, Ristic M. Distribution of Ehrlichia canis among military working dogs in the world and
22.
23.
24.
25.
26.
selected civilian dogs in the United States. J Am Vet Med Assoc 1982;181:236-8. Groves MG, Dennis GL, Amyx HL, Huxsoll DL. Transmission of Ehrlichia canis to dogs by ticks (Rhipicephalus sanguineus). Am J Vet Res 1975;36:937-40. Fishbein DB, Kemp A, Dawson JE, Greene NR, Redus MA, Fields DH. Human ehrlichiosis: prospective active surveillance in febrile hospitalized patients. J Infect Dis 1989;160:803-9. Eng TR, Harkess JR, Fishbein DB, et al. Epidemiologic, clinical, and laboratory findings of human ehrlichiosis in the United States, 1988. JAMA 1990;264:2251-7. Harkess JR, Ewing SA, Crutcher JM, Kudlac J, McKee G, Istre GR. Human ehrlichiosis in Oklahoma. J Infect Dis 1989;159:576-9. Rohrbach BW, Harkess JR, Ewing SA, Kudlac J, McKee GL, Istre GR. Epidemiologic and clinical chracteristics of persons with serologic evidence of E. eanis infection. Am J Public Health 1990;80:442-5. Taylor JP, Betz TG, Fishbein DB, Roberts MA, Dawson J, Ristic M. Serological evidence of possible human infection with Ehrlichia in Texas. J Infect Dis 1988;158:217-20. Morals JD, Dawson JE, Greene C, Filipe AR, Galhardas LC, Bacellar F. First European case of ehrlichiosis. Lancet 1991;338:633-4. Edwards MS, Jones JE, Leass DL, Whitmore JW, Dawson JE, Fishbein DB. Childhood infection caused by Ehrlichia canis or a closely related organism. Pediatr Infect Dis J 1988;7:651-4. Doran TI, Parmley RT, Logas PC, Chamblin S. Infection with Ehrlichia canis in a child. J PEDIATR 1989;114:809-12. Barton LL, Foy TM. Ehrlichia canis infection in a child. Pediatrics 1989;4:580-1. Golden SE. Aseptic meningitis associated with Ehrlichia canis infection. Pediatr Infect Dis J 1989;8:335-6. Harkess JR, Ewing SA, Brumit T, Mettry CR. Ehrlichiosis in children. Pediatrics 1991 ;87:199-203. Pearce C J, Conrad ME, Nolan PE, Fishbein DB, Dawson JE. Ehrlichiosis: a cause of bone marrow hypoplasia in humans. Am J Hematol 1988;28:53-5. Rathore MH. Ehrlichia canis infection in children. South Med J (in press). Petersen LR, Sawyer LA, Fishbein, et al. An outbreak of ehrlichiosis in members of an army reserve unit exposed to ticks. J Infect Dis 1989;159:562-7. Barton LL, Dawson JE, Letson GW, Luisiri A, Scalzo AL Simultaneous ehrlichiosis and Lyme disease. Pediatr Infect Dis J 1990;9:127-9. Edwards MS. Human ehrlichiosis. In: Aronoff SC, Hughes WT, Kohl S, Speck WT, Wald ER, eds. Advances in pediatric infectious diseases. St. Louis: Mosby-Year Book 199 l ;6:16378. Fishbein DB, Sawyer LA, Holland C J, et al. Unexplained febrile illnesses after exposure to ticks: infection with an Ehrlichia? JAMA 1987;257:3100-4. Walker DH, Taylor JP, Buie JS, Dearden C. Fatal human ehrlichiosis [Abstract D-76]. Abstracts of the Annual Meeting of the American Society for Microbiology May 14-18, 1989, New Orleans, Louisiana. Dumler JS, Brouqui P, Aronson J, Taylor JP, Walker DH. Identification of Ehrlichia in human tissue. N Engl J Med 1991;325:1109-10. Dumler JS, Aronson JF, Walker DH. Human ehrlichiosis: pathologic findings in three fatal cases [Abstract 510]. Ab-
Volume 120 Number 6
stracts of the Annual Meeting of the United States and Canadian Academy of Pathology, March 17-22, 1991, Chicago, Illinois. 27. Dawson J, Anderson B, Fishbein D, et al. Cultivation of an Ehrlichia from a patient with human ehrlichiosis [Abstract 11]. Abstracts of the Ninth Sesqui-annual Meeting of the American Society for Rickettsiology and Rickettsial Diseases, May 1-5, 1991, Galveston, Texas. 28. Anderson B, Dawson J, Tzianabos T. PCR amplification of ehrlichial DNA from blood of human ehrlichiosis patients [Abstract 1]. Abstracts of the Ninth Sesqui-annual Meeting of
Ehrtichia infection in childhood
1 O0 1
the American Society for Rickettsiology and Rickettsial Diseases, May 1-5, 1991, Galveston, Texas. 29. Buhles WC Jr, Huxsoll DL, Ristic M. Tropical canine pancytopenia: clinical, hematologic, and serologic response of dogs to Ehrlichia canis infection, tetracycline therapy, and challenge inoculation. J Infect Dis 1974;130:357-67. 30. Brouqui P, Raoult D. In vitro susceptibility of Ehrlichia sennetsu to antibiotics. Antimicrob Agents Chemother 1990; 34:1593-6. 31. Barton LL. Therapy of human ehrlichiosis reconsidered. Antimicrob Agents Chemother 1991;35:398.
Infection with Ehrlichia in childhood In April 1986 a life-threatening multisystem disease associated with leukopenia, thrombocytopenia, and abnormal liver function tests developed in a man who had incurred numerous tick bites approximately 2 weeks previously.~ The illness was initially thought to be Rocky Mountain spotted f6ver, but results of serologic tests were negative. Intraleukocytic inclusions resembling Ehrlichia species and an antibody response to Ehrliehia canis suggested the etiologic diagnosis.2 Numerous reports of children and adult~ with human ehrlichiosis have since appeared. We wilt summarize these reports and present newer data Of relevance to the pe-: diatrician. ETIOLOGY
EhrHchia organisms are nomnotile, gram-negative intracellular bacteria that replicate in a manner analagous to chlamydiae.3 After leukocytic phagocytosis, the elementary body divides into initial bodies and matures into a morula, the contents of which are released with cell lysis. Alternatively, the cell can divide, retaining a morula in each new cell. Until recently, six species of Ehrlichia were thought to producedisease in animals and human beings. A new species of EhrIichia, E. chaffeensis sp. nov., has recently been identified as the cause of human erhlichiosis.3a E. eanis infection was initially reported in Algerian dogs in 1935. 4 In the United States, serologic evidence of infection with this rickettsial organism has been found in 57% of dogs in 21 states) Rhipieephalus sanguineus, the brown dog tick, is the vector of canine ehrlichiosis.6 The vector of human ehrlichiosis has not been identified. EPIDEMIOLOGY Since the initial report, 257 cases of human ehrlichiosis have been diagnosed by or reported to the Centers for Disease Control from 21 states in the United States (Centers for Disease Control: unpublished data). Cases have been recognized primarily along the Atlantic coast and in south central areas, but a few cases have been reported from the Rocky Mountain states and as far west as Washington State. 711 The first case from outside the United States was recently reported from Portugal. 12 Approximately 75% of human patients with ehrlichiosis have a history of tick bite) Most of the remaining patients
9/34/36201
998
report having been in a tick-infested area. Predictably, a majority of the patients develop illness from March to October, when ticks are most prevalent.8 The median age of patients with ehrlichiosis is 42 years, compared with 31 years for patients with RMSF. s However, numerous patients as young as 2 to 4 years of age have been reported. 1316 From 1986 to 1988, a total of 10 cases of ehrlichiosis were diagnosed in patients from 2 to 11 years of age in Oklahoma. 17 PATHOGENESIS The diseases caused by Ehrlichia species appear to be both dose and host dependent,4 Ehrlichia infections are characterized by a lack of severe inflammatory response, pyogenic reaction, and tissue necrosis. However, a response RMSF
RockyMountain spotted fever
[
by the lymph0reticular system is seen in infections with Ehrliehia species, including infections with the human Ehrlichia agent and Ehrlichia sennetsu, the etiologic agent of an infectious mononucleosis-like syndrome occurring in Japanese and Malaysians.3' 4 The agent of human ehrlichiosis appears to be tropic for hematopoietic tissue. Abnormalities in bone marrow aspirates have ranged from hypoplasia is to erythrophagocytosis. 14An immune-mediated response may also play a role in the often-observed thrombocytopenia, as it does in canine ehrlichiosis.4 The complete elucidation of the pathogenesis of human ehrlichiosis awaits the propagation of the human ehrlichiosis agent in an experimental animal model. CLINICAL MANIFESTATIONS Human ehrlichiosis has a wide clinical spectrum, from inapparent infection, to a mild viral-like illness, to severe life-threatening disease. 19, 20 The incubation period for human infection ranges from 1 to 21 days. 7 Eighteen children with human ehrlichiosis have been reported. 13-Iv,19,2i The clinical and laboratorY features of these children are shown in the Table. The patients ranged in age from 2 to 11 years; 12 (66%) were male. As in adults with human ehrlichiosis, fever was common. Gastrointestinal symptoms, including anorexia, nausea, and vomiting, were slightly more common in children. Abdominal pain and tenderness have also been reported in both children and adults. 3, 14, 15, I9 More than
Volume 120 Number 6
60% of children were reported to have a rash, in comparison with 44% of adults. 3, 22 The rashes reported in children were erythematous, macular, papular, vesicular, petechial, scarlatiniform, or vasculitic. Arthralgia and conjunctival injection have also been reported. TM 15 Three children had meningitis, whereas pulmonary manifestations (including pleural effusion and noncardiogenic pulmonary edema) and pharyngitis each was a feature in four children. LABORATORY FEATURES The most common laboratory features of human ehrliehiosis in both adults and children involve the hematopoietic tissue and include leukopenia, lymphopenia, and thrombocytopenia (Table). Anemia was noted in about a third of the reported cases of human ehrlichiosis in children. Elevation of liver enzyme activities, particularly aspartate aminotransferase, have been seen early in illness both in adults and children. 3, 15, 23 Hyponatremia is an uncommon finding in human ehrlichiosis. Renal abnormalities, including elevated blood urea nitrogen and serum creatinine concentrations, proteinuria, and hematuria may be present, although renal failure has not been reported as a feature of ehrlichiosis in children. 14, 19 Children usually have an excellent prognosis; the blood, liver, and kidney abnormalities resolve 1 to 2 weeks after treatment. Three fatalities caused by human ehrlichiosis have been reported in adults and none in children; two of these cases were diagnosed serologically and the third by observing pathognomonic intraleukocytic morulae of Ehrlichia before death. 8, 24 DIAGNOSIS
Tissue examination. Morulae have only rarely been observed before death in mononuclear and polymorphonuclear cells from peripheral blood or bone marrow of infected patients.i, 14 An immunohistologic technique for the specific identification of Ehrlichia organisms from a fatal case of human ehrlichiosis has recently been developedY This avidinbiotin immunoperoxidase method revealed that morulae were most frequently seen in macrophages and uncommonly in lymphocytes. The splenic red pulp and periarteriolar lymphoid sheath harbored most organisms, followed by liver, lymph node, and other tissues. Pathologic examination of three fatal cases revealed gastrointestinal hemorrhage; mild interstitial pneumonitis; perivascular lymphohistiocytic infiltrates in the lungs, liver, kidneys, and heart; and bone marrow hyperplasia. 26 Focal hepatocyte necrosis, hepatocyte dropout, Kupffer cell hyperplasia, and erythrophagocytosis were present. Isolation and polymerase chain reaction amplification. The isolation of Ehrlichia organisms from a 21-year-old
Ehrlichia infection in childhood
999
T a b l e . Clinical and laboratory findings in children with ehrlichiosis Children with findings Findings
Clinical Fever Gastrointestinal symptoms Rash Myalgia Headache Laboratory Leukopenia Lymphopenia Thrombocytopenia Anemia Elevated liver enzyme activities Hyponatremia
No.
%
18 (18)* 13 (18) 11 (18) 08 (13) 10 (10)
100 72 61 62 100
11 (16) 12 (16) 10 (13) 06 (16) 08 (10) 03 (09)
69 75 77 38 80 33
Data from references 13-17, 19, 21. *Numberin parenthesesrepresentstotal numberof childrenfor whomspecific informationregardingeach findingis known.
man with clinical signs and symptoms compatible with the diagnosis of human ehrlichiosis was recently reported) a, 27 Electron micrograph examination of the infected cells revealed that inclusion bodies were surrounded by a distinct cytoplasmic membrane, as previously described for the Ehrlichieae. The 16S ribosomal ribonucleic acid sequencing indicated that the new isolate was similar, but not identical, to E. canis. The polymerase chain reaction amplification technique has also been successfully utilized to detect the human agent of ehrlichiosis in blood samples from five seropositive patients. 28 This technique may presumptively identify and differentiate RMSF and human ehrlichiosis. Serodiagnosis. The case definition for human ehrlichiosis, before the isolation of the human agent, required a fourfold or greater rise or fall in the indirect immunofluorescent antibody titer to E. canis, with a minimum titer of 64. 3 The Centers for Disease Control now uses the human Ehrtichia agent as the antigen in the immunofluorescentantibody test and follows the same serologic case definition. DIFFERENTIAL
DIAGNOSIS
The differential diagnosis of ehrlichiosis has most often included RMSF. Rash and hyponatremia have occurred with greater frequency in RMSF; leukopenia at initial presentation has more commonly been noted in ehrlichiosis. Other diagnostic considerations have included infectious mononucleosis, leptospirosis, Kawasaki syndrome, meniningococcemia, collagen vascular disease, leukemia, enteroviral and cytomegaloviral infections, babesiosis, tularemia, and Lyme disease. Concurrent infection with two tick-borne
1000
Barton, Rathore, a n d Dawson
pathogens has been documented2l a n d therefore must, in rare instances, be given consideration.
THERAPY
The Journal o f Pediatrics June 1992
6.
7.
Tetracycline appears to be the drug of choice for canine ehrlichiosis.4,.29 Studies in animals a n d clinical experience accrued in man suggest t h a t tetracycline and its analogs are also probably the drugs of choice in h u m a n ehrlichiosis, although this is not universally accepted. 3~ 31 Limited experience with chloramphenicol suggests t h a t it m a y be a suitable t h e r a p e u t i c alternative. 15'17 N o data are available collaparing the efficacy of chloramphenicol with tetracycline. Initiation of therapy with either agent has been associated with defervescence, clinical improvement, and hematologic response. 15' 23 However, recovery has also l~een reported in individuals who did not receive a n y antibiotic treatment.17, 23 In vitro cultivation of the Ehrlichia species pathogenic for h u m a n beings will provide the basis for the determination of antimicrobial efficacy and future therapeutic recommendations. Leslie L. Barton, MD Department o f Pediatrics University o f Arizona Health Sciences Center Tucson, A Z 85724 Mobeen H. Rathore, MD Department o f Pediatrics University o f Florida Health Science Center Jacksonville, FL 32209 Jacqueline E. Dawson, M S Department o f Pediatrics Viral and Rickettsia Zoonoses Branch Division of Viral and Rickettsial Diseases Centers for Disease Control Atlanta, GA 30333
8.
9.
10.
11.
12.
13.
14. 15. 16. 17. 18.
19. 20.
21. REFERENCES
1. Maeda K, Markowitz N, Hawley, RC, Ristic M, Cox D, McDade JE. Human infection with Ehrlichia canis, a leukocytic rickettsia. N Engl J Med 1987;316:853-6. 2. McDade JE. Ehrlichiosis: a disease of animals and humans. J Infect Dis 1990;161:609-17. 3. Fishbein DB, Dawson JE. Ehrlichiae. In: Balows A, Hausler WJ Jr, Herrmann KL, Isenberg HD, Shadomy H J, eds. Manual of clinical microbiology. 5th ed. Washington, D.C.: American Society for Microbiology, 1991. 3a. Dawson JE, Anderson BE, Fishbein DB, et al. Isolation and characterization of an Ehrlichia sp. from a patient diagnosed with human ehrlichiosis. J Clin Microbiol 1991;29:2741-5. 4. Rikihisa Y. The tribe Ehrlichieae and ehrlichial diseases. Clin Microbiol Rev 1991;4:286-308. 5. Keefe T J, Holland C J, Salyer PE, Ristic M. Distribution of Ehrlichia canis among military working dogs in the world and
22.
23.
24.
25.
26.
selected civilian dogs in the United States. J Am Vet Med Assoc 1982;181:236-8. Groves MG, Dennis GL, Amyx HL, Huxsoll DL. Transmission of Ehrlichia canis to dogs by ticks (Rhipicephalus sanguineus). Am J Vet Res 1975;36:937-40. Fishbein DB, Kemp A, Dawson JE, Greene NR, Redus MA, Fields DH. Human ehrlichiosis: prospective active surveillance in febrile hospitalized patients. J Infect Dis 1989;160:803-9. Eng TR, Harkess JR, Fishbein DB, et al. Epidemiologic, clinical, and laboratory findings of human ehrlichiosis in the United States, 1988. JAMA 1990;264:2251-7. Harkess JR, Ewing SA, Crutcher JM, Kudlac J, McKee G, Istre GR. Human ehrlichiosis in Oklahoma. J Infect Dis 1989;159:576-9. Rohrbach BW, Harkess JR, Ewing SA, Kudlac J, McKee GL, Istre GR. Epidemiologic and clinical chracteristics of persons with serologic evidence of E. eanis infection. Am J Public Health 1990;80:442-5. Taylor JP, Betz TG, Fishbein DB, Roberts MA, Dawson J, Ristic M. Serological evidence of possible human infection with Ehrlichia in Texas. J Infect Dis 1988;158:217-20. Morals JD, Dawson JE, Greene C, Filipe AR, Galhardas LC, Bacellar F. First European case of ehrlichiosis. Lancet 1991;338:633-4. Edwards MS, Jones JE, Leass DL, Whitmore JW, Dawson JE, Fishbein DB. Childhood infection caused by Ehrlichia canis or a closely related organism. Pediatr Infect Dis J 1988;7:651-4. Doran TI, Parmley RT, Logas PC, Chamblin S. Infection with Ehrlichia canis in a child. J PEDIATR 1989;114:809-12. Barton LL, Foy TM. Ehrlichia canis infection in a child. Pediatrics 1989;4:580-1. Golden SE. Aseptic meningitis associated with Ehrlichia canis infection. Pediatr Infect Dis J 1989;8:335-6. Harkess JR, Ewing SA, Brumit T, Mettry CR. Ehrlichiosis in children. Pediatrics 1991 ;87:199-203. Pearce C J, Conrad ME, Nolan PE, Fishbein DB, Dawson JE. Ehrlichiosis: a cause of bone marrow hypoplasia in humans. Am J Hematol 1988;28:53-5. Rathore MH. Ehrlichia canis infection in children. South Med J (in press). Petersen LR, Sawyer LA, Fishbein, et al. An outbreak of ehrlichiosis in members of an army reserve unit exposed to ticks. J Infect Dis 1989;159:562-7. Barton LL, Dawson JE, Letson GW, Luisiri A, Scalzo AL Simultaneous ehrlichiosis and Lyme disease. Pediatr Infect Dis J 1990;9:127-9. Edwards MS. Human ehrlichiosis. In: Aronoff SC, Hughes WT, Kohl S, Speck WT, Wald ER, eds. Advances in pediatric infectious diseases. St. Louis: Mosby-Year Book 199 l ;6:16378. Fishbein DB, Sawyer LA, Holland C J, et al. Unexplained febrile illnesses after exposure to ticks: infection with an Ehrlichia? JAMA 1987;257:3100-4. Walker DH, Taylor JP, Buie JS, Dearden C. Fatal human ehrlichiosis [Abstract D-76]. Abstracts of the Annual Meeting of the American Society for Microbiology May 14-18, 1989, New Orleans, Louisiana. Dumler JS, Brouqui P, Aronson J, Taylor JP, Walker DH. Identification of Ehrlichia in human tissue. N Engl J Med 1991;325:1109-10. Dumler JS, Aronson JF, Walker DH. Human ehrlichiosis: pathologic findings in three fatal cases [Abstract 510]. Ab-
Volume 120 Number 6
stracts of the Annual Meeting of the United States and Canadian Academy of Pathology, March 17-22, 1991, Chicago, Illinois. 27. Dawson J, Anderson B, Fishbein D, et al. Cultivation of an Ehrlichia from a patient with human ehrlichiosis [Abstract 11]. Abstracts of the Ninth Sesqui-annual Meeting of the American Society for Rickettsiology and Rickettsial Diseases, May 1-5, 1991, Galveston, Texas. 28. Anderson B, Dawson J, Tzianabos T. PCR amplification of ehrlichial DNA from blood of human ehrlichiosis patients [Abstract 1]. Abstracts of the Ninth Sesqui-annual Meeting of
Ehrtichia infection in childhood
1 O0 1
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