150 DiPHTHEriA
Image 42.1
Pharyngeal diphtheria with membranes covering the tonsils and uvula in a 15-year-old girl. Tonsillar and pharyngeal diphtheria may need to be differ- entiated from group A streptococcal pharyngitis, infectious mononucleosis, vincent angina, acute toxoplasmosis, thrush, and leuke mia, as well as other, less common entities, including tularemia and acute cytomegalovirus infection.
Image 42.2
Bull neck appearance of diphtheritic cervical lymphadenopathy in a 13-year-old boy.
isolates should be sent through the state health department to the Centers for Disease Control and Prevention.
Treatment
• Antitoxin. Because the condition of patients with diphtheria can deteriorate rapidly, a single dose of equine antitoxin should be administered on the basis of clinical diagno- sis, even before culture results are available.
Antitoxin and its indications for use and instructions for administration are available through the Centers for Disease Control and Prevention. To neutralize toxin from the organism as rapidly as possible, intravenous administration of the antitoxin is preferred.
Before intravenous administration of anti- toxin, tests for sensitivity to horse serum should be performed, initially with a scratch test. Allergic reactions of variable severity to horse serum can be expected in 5% to 20%
of patients. The dose of antitoxin depends on the site and size of the diphtheria mem- brane, duration of illness, and degree of toxic effects; presence of soft, diffuse cervical lymphadenitis suggests moderate to severe toxin absorption. Antitoxin is probably of no value for cutaneous disease.
• Antimicrobial therapy. Erythromycin administered orally or parenterally for 14 days, aqueous penicillin G administered intravenously for 14 days, or penicillin G procaine administered intramuscularly for 14 days constitutes acceptable therapy. Anti- microbial therapy is required to stop toxin production, to eradicate the C diphtheriae organism, and to prevent transmission, but it is not a substitute for antitoxin, which is the primary therapy. Elimination of the organism should be documented 24 hours after completion of treatment by 2 consecu- tive negative cultures from specimens taken 24 hours apart.
• Immunization. Active immunization against diphtheria should be undertaken during convalescence from diphtheria; dis- ease does not necessarily confer immunity.
• Cutaneous diphtheria. Thorough cleansing of the lesion with soap and water and administration of an appropriate antimicro- bial agent for 10 days are recommended.
DiPHTHEriA 151
Image 42.4
Chest radiograph of a 2-year-old boy with laryngotracheal diphtheria. Diphtheritic pneumonia was obscured by hyperaeration on chest radiograph at time of admission to hospital due to laryngotracheal membranous obstruction.
Courtesy of Edgar O. Ledbetter, mD, FAAP.
Image 42.3
A 5-year-old Latin American boy with nasal diphtheria. Courtesy of Paul Wehrle, mD.
Image 42.5
Diphtheritic pneumonia 3 days after the admission radiograph in image 42.4 following a tracheostomy complicated by early pneumo- thorax. unfortunately, the tracheal membrane was not visualized at the time of tracheostomy and diphtheria antitoxin therapy was not prescribed. Courtesy of Edgar O. Ledbetter, mD, FAAP.
Image 42.6
Diphtheria pneumonia (hemorrhagic) with bronchiolar membranes (hematoxylin-eosin stain). From the patient in images 42.4 and 42.5.
Courtesy of Edgar O. Ledbetter, mD, FAAP.
Image 42.7
This is a close-up of a diphtheria skin lesion caused by the organism Corynebacterium diphtheriae. Courtesy of Centers for Disease Control and Prevention/Dr Brodsky.
152 DiPHTHEriA
Image 42.8
A diphtheria skin lesion on the leg. Corynebacterium diphtheriae can not only affect the respiratory, cardiovascular, renal, and neurologic systems, but the cutaneous system as well, where it sometimes manifests as an open, isolated wound. Courtesy of Centers for Disease Control and Prevention.
Image 42.9
Nasal membrane of diphtheria in a preschool-aged white boy. Courtesy of George Nankervis, mD.
DiPHTHEriA 153
Image 42.10
Number of reported cases, by year—united States, 1982–2012. Courtesy of Morbidity and Mortality Weekly Report.
Image 42.11
Baby graves dating from the 1890s in a central mississippi family cemetery. Diphtheria was a common cause of these infant deaths prior to the introduction of a toxoid vaccine around 1921.
in the preantibiotic era, treatment was limited to comfort care or tracheotomy. vaccination of children and adults has reduced the number of diphtheria cases in the united States. However, reluctance to immunize children sets the stage for another generation of rows of tiny memories. Courtesy of Will Sorey, mD.
154 EHRLICHIA, ANAPLASMA, AND rELATED iNFECTiONS
complications in some children after severe disease, and more commonly with Ehrlichia infections. Fatal infections have been reported more commonly for Ehrlichia chaffeensis infec- tions (approximately 1%–3%) than for anaplas- mosis (<1%). Typically, E chaffeensis presents with more severe disease than does Anaplasma phagocytophilum. People with underlying immunosuppression are at greater risk of severe disease.
Ehrlichia and Anaplasma species do not cause vasculitis or endothelial cell damage character- istic of some other rickettsial diseases. How- ever, because of the nonspecific presenting symptoms, Rocky Mountain spotted fever should be considered. The recently discovered, tick-borne Heartland virus can also present similarly.
Etiology
In the United States, human ehrlichiosis and anaplasmosis are caused by at least 4 different species of obligate intracellular bacteria:
E chaffeensis, Ehrlichia ewingii, Ehrlichia muris–like agent, and A phagocytophilum (Table 43.1). Ehrlichia and Anaplasma species are gram-negative cocci with tropisms for different white blood cell types. E muris is suspected to cause disease in Russia and Japan. Neorickettsia sennetsu may cause illness in Asia, while the organism designated as Neoehrlichia mikurensis has been found in various European and Asian countries.
Epidemiology
The reported incidences of E chaffeensis and A phagocytophilum infections during 2012 were 3.8 and 8.0 cases per million population, respectively. These diseases are under- recognized, and selected active surveillance programs have shown the incidence to be sub- stantially higher in some areas with endemic infection. Most cases of E chaffeensis and E ewingii infection are reported from the south central and southeastern United States, as well as East Coast states. Ehrlichiosis caused by E chaffeensis and E ewingii are associated with the bite of the lone star tick (Amblyomma americanum). To date, cases attributable to the new E muris–like agent have been reported
43
Ehrlichia, Anaplasma, and Related Infections
(Human Ehrlichiosis, Anaplasmosis, and Related Infections)
Clinical Manifestations
Infections by members of the bacterial family Anaplasmataceae (genera Anaplasma, Ehrlichia, Neorickettsia, and the proposed genus Neoehrlichia) cause human illness with similar signs, symptoms, and clinical courses.
All are acute, systemic, febrile illnesses, with common systemic manifestations, including fever, headache, chills, malaise, myalgia, and nausea. More variable symptoms include arthralgia, vomiting, diarrhea, cough, and confusion. Rash is more common in Ehrlichia infections than Anaplasma infections and is more common in children (up to 60% of cases).
More severe manifestations of these diseases can include acute respiratory distress syn- drome, encephalopathy, meningitis, dissemi- nated intravascular coagulation, spontaneous hemorrhage, and renal failure. Significant labo- ratory findings in Anaplasma and Ehrlichia infections may include leukopenia, lymphope- nia, thrombocytopenia, hyponatremia, and elevated serum hepatic transaminase concen- trations. Cerebrospinal fluid abnormalities (ie, pleocytosis with a predominance of lym- phocytes and increased total protein con- centration) are common. Neorickettsiosis is characterized by lymphadenopathy, a sign that is not commonly seen with infections by other members of this bacterial family. As with ehrlichiosis and anaplasmosis, patients with neoehrlichiosis often have had leukocytosis and elevated C-reactive protein concentrations, but liver transaminase levels are usually within normal ranges. Most cases of neoehrlichiosis have been in people with underlying immuno- suppressive conditions.
Without treatment, symptoms typically last 1 to 2 weeks, but prompt antimicrobial therapy will shorten the duration and reduce the risk of serious manifestations and sequelae. Following infection, fatigue may last several weeks; some reports suggest the occurrence of neurologic
EHRLICHIA, ANAPLASMA, AND rELATED iNFECTiONS 155
only from Minnesota and Wisconsin. Most cases of human anaplasmosis have been reported from the upper Midwest and north- east United States (eg, Wisconsin, Minnesota, Connecticut, New York) and northern Califor- nia. In most of the United States, A phagocyto
philum is transmitted by the black-legged tick (Ixodes scapularis), which is also the vector for Lyme disease (Borrelia burgdorferi) and babe- siosis (Babesia microti). This tick is also sus- pected to be a vector for the E muris–like agent.
In the western United States, the western black- legged tick (Ixodes pacificus) is the main vector for A phagocytophilum. Various mammalian wildlife reservoirs for the agents of human ehrlichiosis and anaplasmosis have been identi- fied, including white-tailed deer and wild rodents. In other parts of the world, other bacterial species of this family are transmitted by the endemic tick vectors for that area. An exception is N sennetsu, which occurs in Asia and is transmitted through ingestion of infected trematodes residing in fish.
Reported cases of symptomatic ehrlichiosis and anaplasmosis are characteristically in older people, with age-specific incidences greatest in people older than 40 years. How- ever, seroprevalence data indicate that expo- sure to E chaffeensis may be common in children. In the United States, most human infections occur between April and September, and the peak occurrence is from May through July. Coinfections of anaplasmosis with other tick-borne diseases, including babesiosis and Lyme disease, may cause illnesses that are more severe or of longer duration than a sin- gle infection.
Incubation Period
E chaffeensis, 5 to 14 days; A phagocytophilum, 5 to 21 days.
Diagnostic Tests
Detection of specific DNA in a clinical speci- men by polymerase chain reaction assay is a sensitive and specific means for early diagno- sis. Whole blood anticoagulated with ethylene- diaminetetraacetic acid should be collected at
the first presentation before antibiotic therapy has been initiated. Polymerase chain reaction assays for anaplasmosis and ehrlichiosis are available commercially. Sequence confirmation of the amplified product provides specific iden- tification and is often necessary to identify infection with certain species (eg, E ewingii;
E muris–like agent in the United States).
Identification of stained peripheral blood smears to look for classic clusters of organism known as morulae may occasionally indicate infection with Anaplasmataceae, but this method is generally insensitive and is not rec- ommended as a first-line diagnostic tool. In many patients, serologic testing can be used to demonstrate evidence of a 4-fold change in immunoglobulin (Ig) G–specific antibody titer by indirect immunofluorescence antibody assay between paired serum specimens. Cross- reactivity between species can make it difficult to interpret the causative agent in areas where geographic distributions overlap. Detection of IgG antibodies in acute and convalescent sera is recommended when assessing acutely infected patients. E ewingii and E muris–like agent infections are best confirmed by molecu- lar detection methods.
Treatment
Doxycycline is the drug of choice for treat- ment of human ehrlichiosis and anaplasmosis, regardless of patient age, and has also been shown to be effective for the other Anaplasma- taceae infections. Ehrlichiosis and anaplasmo- sis can be severe or fatal in untreated patients or patients with predisposing conditions; ini- tiation of therapy early in the course of disease helps minimize complications of illness. Most patients begin to respond within 48 hours of initiating doxycycline treatment. Treatment with trimethoprim-sulfamethoxazole has been linked to more severe outcome and is contrain- dicated. Treatment should continue for at least 3 days after defervescence; the standard course of treatment is 5 to 10 days. Unequivocal evi- dence of clinical improvement is generally within 7 days, although some symptoms (eg, headache, malaise) can persist for weeks.
156EHRLICHIA,ANAPLASMA, AND rELATED iNFECTiONS
Table 43.1