EPSTEiN-BArr viruS iNFECTiONS 165
45
EpsteinBarr Virus
166 EPSTEiN-BArr viruS iNFECTiONS
is commonly contracted early in life, particu- larly among members of lower socioeconomic groups, in which intrafamilial spread is com- mon. Endemic infectious mononucleosis is common in group settings of adolescents, such as in educational institutions. No seasonal pat- tern has been documented. Intermittent excre- tion in saliva may occur throughout life after acute infection.
Incubation Period 30 to 50 days.
Diagnostic Tests
Routine diagnosis depends on serologic testing.
Nonspecific tests for heterophile antibody, including the Paul-Bunnell test and slide agglutination reaction test, are available most commonly. The heterophile antibody response is primarily immunoglobulin (Ig) M, which appears during the first 2 weeks of illness and gradually disappears over a 6-month period.
The results of heterophile antibody tests are often negative in children younger than 4 years, but heterophile antibody tests identify approxi- mately 85% of cases of classic infectious mono- nucleosis in older children and adults. An absolute increase in atypical lymphocytes dur- ing the second week of illness with infectious mononucleosis is a characteristic but nonspe- cific finding. However, the finding of greater than 10% atypical lymphocytes together with a positive heterophile antibody test result in the classical illness pattern is considered diagnos- tic of acute infection.
Multiple specific serologic antibody tests for EBV infection are available. The most com- monly performed test is for antibody against the viral capsid antigen (VCA). IgG antibodies against VCA occur in high titer early in infec- tion and persist for life. Testing for presence of IgM anti-VCA antibody and the absence of antibodies to Epstein-Barr nuclear antigen (EBNA) identifies active and recent infections.
Because serum antibody against EBNA is not present until several weeks to months after onset of infection, a positive anti-EBNA result excludes an active primary infection. Testing for antibodies against early antigen is not routinely performed. In selected cases, early antigen testing is useful. Epstein-Barr virus
serologic tests are based on quantitative immu- nofluorescent antibody assays performed dur- ing various stages of mononucleosis and its resolution, although detection of antibodies by enzyme immunoassays is usually performed by clinical laboratories. Serologic testing for EBV is useful, particularly for evaluating patients who have heterophile-negative infec- tious mononucleosis and for cases in which the infectious mononucleosis syndrome is not completely present.
Isolation of EBV from oropharyngeal secre- tions by culture in cord blood cells is possible, but techniques for performing this procedure usually are not available in routine diagnostic laboratories, and viral isolation does not neces- sarily indicate acute infection. Polymerase chain reaction (PCR) assay for detection of EBV DNA in serum, plasma, and tissue and reverse transcriptase-polymerase chain reac- tion assay for detection of EBV RNA in lym- phoid cells, tissue, or body fluids are available commercially and may be useful in evaluation of immunocompromised patients and in com- plex clinical problems.
Treatment
Patients suspected to have infectious mono- nucleosis should not be given ampicillin or amoxicillin, which cause nonallergic morbilli- form rashes in a high proportion of patients.
Although therapy with short-course cortico- steroids may have a beneficial effect on acute symptoms, because of potential adverse effects, their use should be considered only for patients with marked tonsillar inflammation with impending airway obstruction, massive spleno- megaly, myocarditis, hemolytic anemia, or hemophagocytic lymphohistiocytosis. Decreas- ing immunosuppressive therapy is beneficial for patients with EBV-induced posttransplant lymphoproliferative disorders.
Contact and collision sports should be avoided until the patient is recovered fully from infec- tious mononucleosis and the spleen is no lon- ger palpable. In the setting of acute infectious mononucleosis, participation in strenuous and contact situations can result in splenic rupture.
After 21 days, limited noncontact aerobic activ- ity can be allowed if there are no symptoms
EPSTEiN-BArr viruS iNFECTiONS 167 and no overt splenomegaly. Clearance to par-
ticipate in contact or collision sports is appro- priate after 4 weeks after onset of symptoms if
the athlete is asymptomatic and has no overt splenomegaly. Repeat monospot or EBV sero- logic testing is not recommended.
Image 45.1
Atypical lymphocyte in a peripheral blood smear of a patient with infectious mononucleosis. This lymphocyte is larger than normal lymphocytes, with a higher ratio of cytoplasm to nucleus. The cytoplasm is vacuolated and basophilic. This may also be present in cytomegalovirus infections.
Image 45.2
Bilateral cervical lymphadenopathy in an 8-year- old boy with Epstein-Barr virus disease who remained relatively asymptomatic. Courtesy of Edgar O. Ledbetter, mD, FAAP.
Image 45.3
Cervical lymphadenopathy in a 7-year-old girl with infectious mononucleosis.
Image 45.4
This morbilliform rash arose in a patient with infectious mononucleosis after amoxicillin was prescribed.
This is a nonallergic cutaneous eruption. Courtesy of Centers for Disease Control and Prevention/Dr Thomas F. Sellers, Emory university.
168 EPSTEiN-BArr viruS iNFECTiONS
Image 45.5
Epstein-Barr virus encephalitis. Axial fluid atten- uated inversion recovery magnetic resonance image shows basal ganglia hyperintensity (arrows).
Image 45.6
A preadolescent child with infectious mono- nucleosis with petechiae on the soft palate and uvula without exudation.
Image 45.7
A conjunctival hemorrhage of the right eye of a patient with infectious mononucleosis. At times, noninfectious conjunctivitis, as well as other corneal abnormalities, may manifest itself due to the body’s systemic response to viral infections, such as infectious mononucleosis. Courtesy of Centers for Disease Control and Prevention/Dr Thomas F. Sellers, Emory university.
Image 45.8
Schematic representation of the evolution of antibodies to various Epstein-Barr virus antigens in patients with infectious mononucleosis. reproduced with permission from American Society for microbiology. Epstein-Barr virus. in: rose Nr, de macario EC, Folds JD, eds. Manual of Clinical Laboratory Immunology. 5th ed. Washington, DC: American Society for microbiology; 1997:634–643.
ESCHERICHIA COLI AND OTHEr GrAm-NEGATivE BACiLLi 169
46
Escherichia coli and Other GramNegative Bacilli
(Septicemia and Meningitis in Neonates) Clinical Manifestations
Neonatal septicemia or meningitis caused by Escherichia coli and other gram-negative bacilli cannot be differentiated clinically from septi- cemia or meningitis caused by other organ- isms. The early signs of sepsis can be subtle and similar to signs observed in noninfectious processes. Signs of septicemia include fever, temperature instability, heart rate abnormali- ties, grunting respirations, apnea, cyanosis, lethargy, irritability, anorexia, vomiting, jaun- dice, abdominal distention, cellulitis, and diar- rhea. Meningitis, especially early in the course, can occur without overt signs suggesting cen- tral nervous system involvement. Some gram- negative bacilli, such as Citrobacter koseri, Cronobacter (formerly Enterobacter) sakazakii, Serratia marcescens, and Salmonella species, are associated with brain abscesses in neonates with meningitis caused by these organisms.
Etiology
E coli strains, often those with the K1 capsular polysaccharide antigen, are the most common cause of septicemia and meningitis in neo- nates. Other important gram-negative bacilli causing neonatal septicemia include Klebsiella species, Enterobacter species, Proteus species, Citrobacter species, Salmonella species, Pseu
domonas species, Acinetobacter species, and Serratia species. Nonencapsulated strains of Haemophilus influenzae and anaerobic gram- negative bacilli are rare causes.
Epidemiology
The source of E coli and other gram-negative bacterial pathogens in neonatal infections during the first few days of life typically is the maternal genital tract. Reservoirs for gram- negative bacilli can also be present within the health care environment. Acquisition of gram- negative organisms can occur through person- to-person transmission from hospital nursery personnel and from nursery environmental sites, such as sinks, countertops, powdered
infant formula, and respiratory therapy equip- ment, especially among very preterm neonates who require prolonged neonatal intensive care management. Predisposing factors in neonatal gram-negative bacterial infections include maternal intrapartum infection, gesta- tion less than 37 weeks, low birth weight, and prolonged rupture of membranes. Metabolic abnormalities (eg, galactosemia), fetal hypoxia, and acidosis have been implicated as predis- posing factors. Neonates with defects in the integrity of skin or mucosa (eg, myelomenin- gocele) or abnormalities of gastrointestinal or genitourinary tracts are at increased risk of gram- negative bacterial infections. In neonatal intensive care units, systems for respiratory and metabolic support, invasive or surgical procedures, indwelling vascular access cath- eters, and frequent use of broad-spectrum antimicrobial agents enable selection and proliferation of strains of gram-negative bacilli that are resistant to multiple anti- microbial agents.
Multiple mechanisms of resistance in gram- negative bacilli can be present simultaneously.
Resistance resulting from production of chromosomally encoded or plasmid-derived AmpC β-lactamases or from plasmid-mediated extended-spectrum β-lactamases (ESBLs), occurring primarily in E coli, Klebsiella spe- cies, and Enterobacter species but reported in many other gram-negative species, has been associated with nursery outbreaks, especially in very low birth weight neonates. Organisms that produce ESBLs are typically resistant to penicillins, cephalosporins, and monobactams and can be resistant to aminoglycosides.
Carbapenems-resistant strains have emerged among Enterobacteriaceae, especially Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter species. Extended-spectrum β-lactamase– and carbapenemase-producing bacteria often carry additional genes confer- ring resistance to aminoglycosides and sulfon- amides, as well as fluoroquinolones.
Incubation Period
Variable, ranging from birth to several weeks after birth or longer in very low birth weight, preterm neonates with prolonged hospitalizations.
170 ESCHERICHIA COLI AND OTHEr GrAm-NEGATivE BACiLLi
Diagnostic Tests
Diagnosis is established by growth of E coli or other gram-negative bacilli from blood, cere- brospinal fluid (CSF), or other, usually sterile sites. Special screening and confirmatory labo- ratory procedures are required to detect some multidrug-resistant gram-negative organisms.
Molecular diagnostics are increasingly being used for identification of pathogens; specimens should be saved for resistance testing.
Treatment
Initial empiric treatment for suspected early- onset gram-negative septicemia in neonates is ampicillin and an aminoglycoside. An alter- native regimen of ampicillin and an extended- spectrum cephalosporin (eg, cefotaxime) can be used, but rapid emergence of cephalosporin- resistant organisms, especially Enterobacter species, Klebsiella species, and Serratia species, and increased risk of colonization or infection with ESBL-producing Enterobacteriaceae can occur when use is routine in a neonatal unit.
Hence, routine use of an extended-spectrum cephalosporin is not recommended unless gram-negative bacterial meningitis is sus- pected. The proportion of E coli bloodstream infections with onset within 72 hours of life that are resistant to ampicillin is high among very low birth weight neonates. These E coli infections are almost invariably susceptible to gentamicin, although monotherapy with an aminoglycoside is not recommended.
Once the causative agent and in vitro anti- microbial susceptibility pattern are known, nonmeningeal infections should be treated with ampicillin, an appropriate aminoglyco- side, or an extended-spectrum cephalosporin (eg, cefotaxime). Many experts would treat nonmeningeal infections caused by Entero
bacter species, Serratia species, or Pseudo
monas species and some other, less commonly occurring gram-negative bacilli with a β-lactam antimicrobial agent and an amino- glycoside. For ampicillin-susceptible CSF isolates of E coli, meningitis can be treated
with ampicillin or cefotaxime; meningitis caused by an ampicillin-resistant isolate is treated with cefotaxime with or without an aminoglycoside. Combination therapy with cefotaxime and an aminoglycoside antimicro- bial agent is used for empirical therapy and until CSF is sterile. Some experts continue combination therapy for a longer duration.
Expert advice from an infectious disease specialist can be helpful for management of meningitis.
The drug of choice for treatment of infections caused by ESBL-producing organisms is meropenem, which is active against gram- negative aerobic organisms with chromo- somally mediated AmpC β-lactamases or ESBL-producing strains, except carbapenemase- producing strains, especially some K pneu
moniae isolates. Of the aminoglycosides, amikacin retains the most activity against ESBL-producing strains. An amino glycoside or cefepime can be used if the organism is susceptible. Expert advice from an infectious disease specialist can help in management of ESBL-producing gram-negative infections in neonates. The treatment of infections caused by carbapenemase-producing gram-negative organisms is guided by expert advice from an infectious disease specialist.
All neonates with gram-negative meningitis should undergo repeat lumbar puncture to ensure sterility of the CSF after 24 to 48 hours of therapy. If CSF remains culture positive, choice and doses of antimicrobial agents should be evaluated, and another lumbar puncture should be performed after another 48 to 72 hours. Duration of therapy is based on clinical and bacteriologic response of the patient and the site(s) of infection; the usual duration of therapy for uncomplicated bac- teremia is 10 to 14 days, and for meningitis, minimum duration is 21 days. All neonates with gram-negative meningitis should undergo careful follow-up examinations, including testing for hearing loss, neurologic abnormali- ties, and developmental delay.
ESCHERICHIA COLI AND OTHEr GrAm-NEGATivE BACiLLi 171
Image 46.1
Computed tomography scan of the head of a neonate 3 weeks after therapy for Escherichia coli meningitis demonstrating widespread destruction of cerebral cortex secondary to vascular thrombosis.
Neonate was blind, deaf, and globally intellec tually disabled and had diabetes insipidus. Courtesy of Carol J. Baker, mD, FAAP.
Image 46.2
icteric premature neonate with septicemia and perineal and abdominal wall cellulitis due to Escherichia coli.
Image 46.3
infant with Escherichia coli septicemia and perineal cellulitis, scrotal necrosis, and abdominal wall abscesses below the navel that required surgical drainage and antibiotics.
Image 46.4
Sepsis and pneumonia with empyema due to Escherichia coli. This newborn died at 12 hours of age.
Image 46.5
Pneumonia due to Klebsiella pneumoniae with prebronchoscopy lung abscess. Courtesy of Edgar O. Ledbetter, mD, FAAP.
172 ESCHERICHIA COLI AND OTHEr GrAm-NEGATivE BACiLLi
Image 46.10
Skin lesions due to Pseudomonas aeruginosa in child with neutropenia and septicemia.
Image 46.6
Pneumonia due to Klebsiella pneumoniae with lung abscess. Cavitation with air-fluid level shown postbronchoscopy drainage. repeat broncho- scopy was required for further drainage.
Courtesy of Edgar O. Ledbetter, mD, FAAP.
Image 46.7
Klebsiella pneumoniae pneumonia in a 4-month- old with spontaneous tension pneumothorax.
Courtesy of Edgar O. Ledbetter, mD, FAAP.
Image 46.8
A 5-week-old girl with Klebsiella pneumoniae sepsis and meningitis with bilateral saphenous vein thrombophlebitis (illness began with diarrhea). Copyright martin G. myers, mD.
Image 46.9
Bullous, necrotic, umbilicated lesions in infant with septicemia due to Pseudomonas aeruginosa.
ESCHERICHIA COLI AND OTHEr GrAm-NEGATivE BACiLLi 173
Image 46.11
Sepsis due to Pseudomonas aeruginosa with early ecthyma gangrenosum.
Image 46.12
Sepsis due to Pseudomonas aeruginosa with rapidly progressing ecthyma gangrenosum.
Image 46.13
Gram stain of Escherichia coli in the cerebro- spinal fluid of a neonate with meningitis.
Image 46.14
Escherichia coli on sheep blood agar. Courtesy of Julia rosebush, DO; robert Jerris, PhD; and Theresa Stanley, m(ASCP).
174 ESCHERICHIA COLI DiArrHEA
47
Escherichia coli Diarrhea
(Including Hemolytic Uremic Syndrome) Clinical Manifestations
At least 5 pathotypes of diarrhea-producing Escherichia coli strains have been identified.
Clinical features of disease caused by each pathotype are summarized in Table 47.1.
• Shiga toxin-producing E coli (STEC) organisms are associated with diarrhea, hemorrhagic colitis, and hemolytic uremic syndrome (HUS). Shiga toxin-producing E coli O157:H7 is the serotype most often implicated in outbreaks and is consistently a virulent STEC serotype, but other sero- types can also cause illness. Shiga toxin- producing E coli illness typically begins with nonbloody diarrhea. Stools usually become bloody after 2 or 3 days, representing the onset of hemorrhagic colitis. Severe abdominal pain is typically short lived, and low-grade fever is present in approximately one-third of cases. In people with presump- tive diagnoses of intussusception, appendici- tis, inflammatory bowel disease, or ischemic colitis, disease caused by E coli O157:H7 and other STEC should be considered.
Table 47.1