Supported by an unrestricted educational grant from Wyeth-Ayerst Laboratories
Volume III, Issue 1 - May 1999
Supported by an unrestricted educational grant from Wyeth-Ayerst Laboratories
Tularemia is a zoonosis caused by Francisella tularensis. Human infection is incidental and usually results from interaction with biting or blood-sucking insects. Ticks are the source for most of the human cases in the endemic areas of the southeastern US. Tularemia is common in Arkansas, Oklahoma, and Missouri, where more than 50% of the cases in the US occur.
The 2 main biovariants of F. tularensis-tularensis (type A) and palearctica (type B)--are both found in the US. Type A produces more serious disease in humans. Without treatment, the associated fatality rate is approximately 5%. Type B produces a milder, often subclinical infection. In the southeastern US, the disease can be carried by Dermacentor andersoni (Rocky Mountain wood tick), Dermacentor variabilis (American dog tick), and Amblyomma americanum (Lone Star tick). F. tularensis is transmitted frequently during blood meals taken by embedded ticks following hours of attachment. After inoculation into the skin, the organism multiplies locally. Within 2 to 5 days (range 1 to 10 days), it produces an erythematous, tender, or pruritic papule. The bacteria spread to regional lymph nodes, producing lymphadenopathy and, with bacteremia, may spread to distant organs.
Tularemia often starts with a sudden onset of fever, chills, headache, and generalized myalgias and arthralgias (Figure 1). Most patients with tularemia (75% to 85%) acquire the infection by inoculation of the skin. In adults, the most common localized form is inguinal and femoral lymphadenopathy; in children, cervical lymphadenopathy is most common. The clinical manifestations of tularemia have been divided into various syndromes, which are listed in Figure 1.
Ulceroglandular and glandular tularemia account for approximately 75% to 85% of cases. The ulcer is nonhealing with a punched-out appearance that lasts from 1 to 3 weeks and gradually develops a black base. Simultaneously, the regional lymph nodes become tender and severely enlarged. The affected lymph nodes may become fluctuant and drain spontaneously, but usually the condition resolves with effective treatment. Late suppuration of lymph nodes has been described in up to 25% of patients but material from these nodes usually reveals sterile necrotic tissue. In 5% to 10% of patients, a skin lesion may be inapparent, with lymphadenopathy plus systemic signs and symptoms being the only physical findings (glandular tularemia).
Tularemia must be considered in the differential diagnosis of atypical pneumonia which is unresponsive to ß-lactam antibiotics and in a patient with a history of travel to an endemic area. As many as 10% to 15% of children with clinical manifestations of tularemia have parenchymal infiltrates. Patients with pneumonia usually have a nonproductive cough and may have dyspnea or pleuritic chest pain. X-ray films of the chest usually reveal bilateral patchy infiltrates, lobar parenchymal infiltrates, and cavitary lesions. Pleural effusions may have a predominance of mononuclear leukocytes or granular leukocytes and sometimes red blood cells.
Suspect patients should be treated presumptively with confirmatory diagnostic testing. However, up to 40% of patients with tularemia have no known history of epidemiologic contact. The diagnosis of tularemia most frequently is confirmed by serologic testing. In the standard tube agglutination test, a single titer of >=1:160 is interpreted as a presumptive positive result. A 4-fold increase in titer between paired serum samples collected 2 to 3 weeks apart is considered diagnostic. False-negative serologic responses are obtained early in infection. Up to 30% of patients infected for 3 weeks have negative serology. A microagglutination test that may be as much as 100-fold more sensitive has been described and is currently being used in many clinical laboratories.
A wide variety of antibiotics, including the newer cephalosporins, are ineffective for treatment. Recent studies indicated that extended spectrum cephalosporins were active against F. tularensis in vitro but clinical case reports suggested a nearly universal failure rate of ceftriaxone in pediatric patients with tularemia. Fluoroquinolones have shown promise because of their relatively low toxicity and potential for oral administration. Streptomycin, given intramuscularly at a dose of 7.5 to 10 mg/kg every 12 h, is considered the drug of choice for adults. Streptomycin also is considered the drug of choice for children with the appropriate dosage 30 to 40 mg/kg daily in 2 divided doses administered intramuscularly. In children, after a clinical response is demonstrated at 3 to 5 days, the dosage can be reduced to 10 to 15 mg/kg/d in 2 divided doses. Therapy typically is continued for 7 to 10 days. Gentamicin, at a dosage of 1.7 mg/kg given intravenously or intramuscularly every 8 h, is also effective. In a recent pediatric study symptoms such as tender lymphadenitis and pharyngitis also responded within 24 to 72 hours of the start of gentamicin therapy. In successfully treated patients defervescence usually occurs within 2 days but skin lesions and lymph nodes may take 1 to 2 weeks to heal. When therapy is not initiated within the first several days of illness, defervescence may be delayed. Relapses are uncommon with streptomycin or gentamicin therapy.
The distribution of HME closely overlaps the endemic area of the presumed tick vector with infections occurring predominantly in patients from the south and southeastern US. By the end of 1995, 20 states had reported cases of E. chaffeensis, with most patients residing in Texas, Oklahoma, Arkansas, Missouri, and Georgia. HME is predominantly rural (66%), seasonal (68% of cases occur from May to July), and shows a male predominance (75%). Infection has been described in 37 children with an average age of 6.7 years (range 7 months to 13.7 years). There has been a slightly greater number of boys (57%) and most have resided in a rural area. E. chaffeensis has been detected in 2 tick species, A. americanum (the Lone Star tick) and Dermacentor variabilis (the American dog tick). White-tailed deer (Odocoileus virginianus) in 15 southern to southeastern states have been found to have antibodies reactive with E. chaffeensis.
Fever, rash, headache, and hepatosplenomegaly are the most common abnormalities encountered on physical examination in patients with HME (Figure 2). The rash associated with HME is noted more commonly in children (66%) than in adults (36% to 47%). The rash usually is distributed on the trunk or extremities and may be macular, maculopapular, petechial, or a combination of components may coexist. Other reported abnormalities have included nuchal rigidity, cervical or inguinal adenopathy, photophobia or conjunctivitis, conjunctival hemorrhage, arthralgias, and edema of the hands and feet or face.
Life-threatening disease has been described in children. In one series, 25% of all patients with HME required intensive care therapy. The mortality rate for HME is <2% in adults and approximately 16% have serious manifestations or clinical complications. In these adult patients, renal dysfunction or failure, laboratory evidence of intravascular coagulopathy, cardiomegaly, seizures, and coma were the most commonly encountered complications. Recently, long-term neurologic sequelae have been recognized in 2 children.
Evaluation of the laboratory findings for 37 children with HME demonstrated a characteristic profile among those for whom data are available (Figure 3). Elevated serum aminotransferase levels, thrombocytopenia, and an absolute lymphopenia are the most common abnormalities noted. The thrombocytopenia, lymphopenia, and leukopenia are usually transient and are most pronounced at 5 to 7 days of illness. Anemia, when present, usually is not severe. Hyponatremia can be significant; renal abnormalities also have been described. In a recent review of central nervous system manifestations of human ehrlichiosis, the most common cerebrospinal fluid abnormalities noted were lymphocytic pleocytosis (73%), elevated protein values (76%), and borderline low glucose concentrations (24%).
The Centers for Disease Control and Prevention case definition for HME requires a clinically compatible history with a minimum antibody titer to E. chaffeensis of >1:64 or a 4-fold or greater change in antibody titers from acute and convalescent sera using indirect fluorescent antibody testing. The use of an E. chaffeensis specific polymerase chain reaction (PCR) to detect the 16S ribosomal ribonucleic acid genes in the blood of patients with acute infections appears to be more promising. The sensitivity of the test approaches 90%; the specificity remains undetermined.
When initially recognized, the treatment approach to human ehrlichiosis was similar to that of RMSF. Children older than 9 years received doxycycline and those younger than 9 years received chloramphenicol. The interpretation of these anecdotal reports and small series' of patients is difficult, however, because the natural history of untreated HME is not known. Of the 37 children described to date, 21 have been treated with tetracyclines, 15 have received chloramphenicol, and 1 received no therapy. The only patient who died was treated with chloramphenicol. The issue of the proper medication for HME in children younger than 9 years is not resolved. We have chosen to use doxycycline (4 mg/kg/d twice daily with a maximum daily dose of 100 mg twice daily for 7 to 10 days) to treat any patient, regardless of age, with symptomatic HME. The choice of doxycycline is based on recent data demonstrating that patients with RMSF treated with chloramphenicol were more likely to die than patients treated with doxycycline, questions concerning the efficacy of chloramphenicol in treatment of HME, the lack of a liquid chloramphenicol product in the US, and knowledge that staining of the teeth by tetracyclines seems to be dosage related.
RMSF is a potentially fatal multisystem illness caused by Rickettsia rickettsii, a Gram-negative, obligate intracellular coccobacillus. A feeding tick inoculates rickettsia into the dermis from which the rickettsia disseminate hematogenously. The seasonal occurrence (April to October) of RMSF is associated with feeding activity of the vectors-the wood tick (Dermacentor andersoni) and the dog tick (Dermacentor variabilis) The incidence is highest in children ages 5 to 9 years. For all ages, risk factors include exposure to dogs, residence in wooded areas, and male gender.
Clinical signs and symptoms of RMSF emerge after an average incubation of 1 week, which may range from 2 to 14 days, depending on the inoculum size. Patients present with fever, severe frontal headache, and myalgias. Additional complaints may include photophobia, nausea, vomiting, abdominal pain, dry cough, malaise, and confusion. The rash usually appears on days 3 to 5 of the illness, initially as small, erythematous macules on the wrists and ankles that then spread to the palms, soles, and trunk. Macules initially blanch, then progress to petechiae or purpura. However, up to 15% of patients develop either no rash or an atypical rash.
Disseminated infection presents with signs of increased vascular permeability, including conjunctivitis, edema, hypotension, prerenal azotemia, consumption coagulopathy, encephalopathy, and pneumonitis. Central nervous system involvement can manifest as meningismus, paralysis, ataxia, deafness, aphasia, and blindness. Progression to adult respiratory distress syndrome, renal failure, coma, or seizures strongly correlates with a fatal outcome. The mortality rate is 2% to 4%, but increases to 25% in patients in whom diagnosis and treatment are delayed after day 5 of illness.
Early treatment dramatically reduces the mortality associated with RMSF and should be initiated on clinical and epidemiologic grounds. Prompt clinical diagnosis requires a high index of suspicion because, at presentation, the triad of fever, rash, and exposure to ticks is found in only 60% to 70% of cases. Indirect fluorescent antibody testing is standard but does not become positive until days 6 to 10 of illness. The PCR method has proven specific but of variable sensitivity. Laboratory abnormalities also are not helpful in prompt diagnosis because they are nonspecific and occur later in illness. Patients often demonstrate a normal or low leukocyte count with left shift, anemia, thrombocytopenia, hyponatremia, and elevated levels of serum transaminases. Cerebrospinal fluid pleocytosis and increased protein levels may be present in about one third of cases.
Doxycycline is the treatment of choice in all patients, regardless of age, and should be continued until 72 hours after defervescence (approximately 7 days) to reduce the risk of relapse. Because of the concern over increased mortality with chloramphenicol, experts now advocate using doxycycline in children younger than 9 years of age. Long-term sequelae in patients who have severe illness may include neurologic deficits and limb amputation following development of gangrene.
Richard F. Jacobs, M.D.
Horace C. Cabe Professor of Pediatrics
Chief, Pediatric Infectious Diseases
University of Arkansas for Medical Sciences
Arkansas Childrenžs Hospital
Little Rock, Arkansas
Ehrilchia
Rocky Mountain Spotted Fever
