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  • 1. © 2002 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 20 VIRAL INFECTION — 1 20 VIR AL INFECTION Jennifer W Janelle, M.D., and Richard J. Howard, M.D., Ph.D. . Approach to Viral Exposure Compared with primary care physicians, such as internists, fami- patients are known to be infected with HIV or HBV. The CDC has ly physicians, and pediatricians, surgeons are seldom called on to taken the position that blood and body fluid precautions should be treat viral infections.Viral infections nonetheless deserve the atten- used consistently for all patients because medical history and phys- tion of surgeons because these infections can cause illness in ical examination cannot reliably identify all patients infected with patients after operation, albeit infrequently, and can spread to the HIV or other blood-borne pathogens and because in emergencies hospital staff. Some viral infections (e.g., infections with the there may be no time for serologic testing. If these universal precau- hepatitis viruses, HIV, and cytomegalovirus [CMV]) can result tions are implemented, as the CDC recommends,1-5 no additional from administration of blood or blood products or can be trans- precautions should be necessary for patients known to be infected mitted to hospital personnel through needle-stick injury. Viral with HIV. infections can also result from organ transplantation or trauma The CDC does not recommend routine HIV serologic testing for (e.g., rabies, which is transmitted by the bite of an infected ani- all patients.1-5 HIV serologic testing of patients is recommended for mal). Some viruses, especially the herpesviruses, frequently infect management of health care workers who sustain parenteral or mu- immunosuppressed patients, in whom the viruses can cause cous membrane exposure to blood or other body fluids, for patient severe illness and even death. In many surgical practices, there are diagnosis and treatment, and for counseling associated with efforts increasing numbers of immunosuppressed patients, including to prevent and control HIV transmission in the community.1-5 organ transplant recipients; patients with cancer; patients receiv- Nevertheless, some hospitals and physicians are likely to per- ing cancer chemotherapy, steroids, and other immunosuppressive form serologic testing of patients if it is possible that health care drugs; the elderly; and the malnourished. Some viral infections workers will be exposed to the patients’ blood or other body flu- can cause neoplastic disease for which operation may become ids, as would be the case with patients undergoing major opera- necessary. Examples are hepatitis B virus (HBV) and hepatitis C tive procedures or receiving treatment in intensive care units. virus (HCV), which are implicated in the etiology of hepatocellu- Those who favor routine preoperative testing of patients undergo- lar carcinoma; Epstein-Barr virus (EBV), which can cause a lethal ing invasive procedures maintain that precautions are more likely lymphoproliferative disorder in immunosuppressed patients; and to be followed and additional steps taken to lower the likelihood human T cell lymphotropic virus type I (HTLV-I), which can of virus transmission from patients to health care workers when it induce a T cell leukemia. Viral infections very likely can cause is known which patients are HIV positive.6,7 If such policies are other neoplasms as well. adopted, the CDC advocates certain principles: (1) obtain con- sent for testing, (2) inform patients of results and provide coun- seling to seropositive patients, (3) ensure confidentiality, (4) en- Prevention of Transmission of HIV, Hepatitis B Virus, sure that seropositive patients will not receive compromised care, and Hepatitis C Virus and (5) prospectively evaluate the efficacy of the program in re- ducing the incidence of exposure of health care workers to blood TRANSMISSION FROM PATIENTS TO HEALTH CARE WORKERS or body fluids of patients who are infected with HIV. The Centers for Disease Control and Prevention (CDC) has Although possible acquisition of HIV infection is the major con- published extensive recommendations for preventing transmission cern for any health care worker who is exposed to blood products in of HIV, the etiologic agent of AIDS.1-5 Applicable to clinical and the workplace, acquisition of viral hepatitis is actually much more laboratory staffs,3,4 to workers in health care settings [see Table 1]1 likely. From a single needle-stick exposure, the estimated average and in other occupational settings,1 and to health care workers risk of HIV transmission is 0.3%, whereas that of HCV transmis- performing invasive procedures,1-5 these precautions are appropri- sion ranges from 0% to 10%.8 The risk that HBV will be transmit- ate for preventing transmission not only of HIV but also of other ted from a single needle-stick exposure varies according to the he- blood-borne viruses, including HBV and HCV. The recommen- patitis B e antigen (HBeAg) status of the source patient, ranging dations share the objective of minimizing exposure of personnel to from 1% to 6% for HBeAg-negative patients to 22% to 40% for blood and body secretions from infected patients, whether through HBeAg-positive patients.9-11 That health care workers are at in- needle-stick injury or through contamination of mucous mem- creased risk for hepatitis B is indicated by the seroprevalence of branes or open cuts. HBV in this population, which is two to four times that in the gen- Despite the apparently low risk of such exposure, the CDC rec- eral United States population (6% to 15% versus < 5%).9,12 This ommends enforcement of these as well as other standard infection seroprevalence is expected to decrease with the availability of the control precautions, regardless of whether health care workers or hepatitis B vaccine and the mandate from the Occupational Safety
  • 2. © 2002 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 20 VIRAL INFECTION — 2 Table 1 Precautions to Prevent Transmission of HIV1 Universal Precautions suscitation bags, or other ventilation devices should be available for use in areas in which the need for resuscitation is predictable. 1. All health care workers should use appropriate barrier precautions routine- ly to prevent skin and mucous membrane exposure when contact with 5. Health care workers who have exudative lesions or weeping dermatitis blood or other body fluids of any patient is anticipated. Gloves should be should refrain from all direct patient care and from handling patient care worn for touching blood and body fluids, mucous membranes, or nonintact equipment until the condition resolves. skin of all patients; for handling items or surfaces soiled with blood or body fluids; and for performing venipuncture and other vascular-access proce- 6. Pregnant health care workers are not known to be at greater risk for con- dures. Gloves should be changed after contact with each patient. During tracting HIV infection than health care workers who are not pregnant; how- procedures that are likely to generate aerosolized droplets of blood or other ever, if a health care worker acquires HIV infection during pregnancy, the in- body fluids, masks and protective eyewear or face shields should be worn fant is at risk for infection resulting from perinatal transmission. Because of to prevent exposure of mucous membranes of the mouth, nose, and eyes. this risk, pregnant health care workers should be especially familiar with Gowns or aprons should be worn during procedures that are likely to gen- and strictly adhere to precautions to minimize the risk of HIV transmission. erate splashes of blood or other body fluids. Additional Precautions for Invasive Procedures 2. Hands and other skin surfaces should be washed immediately and thor- 1. All health care workers who participate in invasive procedures must use ap- oughly if contaminated with blood or other body fluids. Hands should be propriate barrier precautions routinely to prevent skin and mucous mem- washed immediately after gloves are removed. brane contact with blood and other body fluids of all patients. Gloves and surgical masks must be worn for all invasive procedures. Protective eye- 3. All health care workers should take precautions to prevent injuries caused wear or face shields should be worn for procedures that commonly result by needles, scalpels, and other sharp instruments or devices during proce- in the generation of aerosolized droplets, splashing of blood or other body dures; when cleaning used instruments; during disposal of used needles; fluids, or the generation of bone chips. Gowns or aprons made of materi- and when handling sharp instruments after procedures. To prevent nee- als that provide an effective barrier should be worn during invasive proce- dle-stick injuries, needles should not be recapped, purposely bent or bro- dures that are likely to result in the splashing of blood or other body fluids. ken by hand, removed from disposable syringes, or otherwise manipulat- All health care workers who perform or assist in vaginal or cesarean deliv- ed by hand. After they are used, disposable syringes and needles, scalpel eries should wear gloves and gowns when handling the placenta or the blades, and other sharp items should be placed in puncture-resistant con- infant until blood and amniotic fluid have been removed from the infant’s tainers for disposal; the puncture-resistant containers should be located as skin and should wear gloves during postdelivery care of the umbilical cord. close as practical to the area of use. Large-bore reusable needles should be placed in a puncture-resistant container for transport to the reproces- 2. If a glove is torn or a needle-stick or other injury occurs, the glove should sing area. be removed and a new glove used as promptly as patient safety permits; the needle or instrument involved in the incident should also be removed 4. Although saliva has not been implicated in HIV transmission, to minimize from the sterile field. In the event of an injury, postexposure evaluation the need for emergency mouth-to-mouth resuscitation, mouthpieces, re- should be sought as soon as possible. & Health Administration (OSHA) directing that all health care No additional precautions are necessary for these individuals workers potentially exposed to blood or other potentially infectious because their risk of acquiring HIV, HCV, or HBV is so low; in material either be offered hepatitis B vaccine free of charge, demon- fact, transmission to them has not been documented. However, strate immunity to hepatitis B, or formally decline vaccination.13 staff should be educated about appropriate procedures. Workers That vaccination has been effective in decreasing the incidence of should wear gloves when handling blood and body fluids of all hepatitis B in health care workers is shown by the decrease in infec- patients and should wear masks in areas where blood may spatter tion rates from 174/100,000 in 1982 to 17/100,000 in 1995.14 (e.g., the dialysis unit or the obstetrics unit). Most series have not found the seroprevalence of HCV to be higher TRANSMISSION FROM HEALTH CARE WORKERS TO PATIENTS in health care worker groups at risk than in the general popula- tion.14 That hepatitis B and hepatitis C are much more common To date, there have been only two reports of HIV transmis- than HIV in health care workers is a strong argument for using uni- sion from infected health care workers to patients. In one versal precautions in all patients. report, DNA sequence analysis linked a Florida dentist with One reason why hepatitis B is so much more transmissible than AIDS to HIV infection in six of his patients.18 In the other, an HIV is the greater number of virus particles in the blood of hepati- orthopedic surgeon in France may have transmitted HIV to tis B carriers. These persons have blood concentrations of 108 to one of his patients in the course of an operation.19 Despite 109 virus particles/ml, compared with 102 to 104/ml for persons extensive investigation, no break in infection control precau- with HIV infection and 106/ml for persons with HCV infection. tions was documented in either case, nor was any clear-cut The extensive guidelines that have been established by the means of transmission identified. CDC for the care of patients with HBV infection4,15-17 also apply HBV transmission from health care workers to patients is to patients with HIV infection. Patients known to have hepatitis B, known to occur. Nineteen case reports have documented physi- hepatitis C, or AIDS need not be put in a private room unless they cian-to-patient transmission.20-32 Eighteen of the 19 physicians are fecally incontinent or are shedding virus in body fluids. Health were surgeons; seven of the surgeons were gynecologists, three care workers should wear gloves and gowns when they have con- were cardiac surgeons, and one was an orthopedic surgeon. All tact with or may have contact with a patient’s blood, feces, or other of the physicians were positive for HBeAg. Three of the gyne- body fluids. Needles used for drawing blood should be disposed cologists made a practice of handling needle tips. Of the 135 of with special care: they must not be reused, recapped, or patients studied, 121 had clinical hepatitis B, and 14 had only removed from the syringe. Hands must be washed before and serologic evidence of infection. Forty-one of the 135 patients after direct contact with the patient or with items that have been were accounted for by the only nonsurgeon, a family practition- in contact with the patient’s blood, feces, or body fluids. er from rural Switzerland. There are many additional cases of Published recommendations also provide guidelines for health HBV having been transmitted by dentists and oral surgeons. In care workers who are not directly involved in patient care (e.g., addition, three patients’ relatives, two members of a surgeon’s housekeeping personnel, kitchen staff, and laundry workers).1-7 family, and one laboratory technician became infected.
  • 3. © 2002 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 20 VIRAL INFECTION — 3 Human immunodeficiency virus (HIV) Health care worker is exposed to any patient's blood or body secretions by a needle stick or by a splash in the eye or mouth The health care worker should be counseled about the risk of HIV infection and should follow U.S. Public Health Service recommendations for preventing HIV transmission. Patient is judged on clinical and epidemiologic grounds to be a likely source of HIV infection Ask the patient to consent to serologic testing for HIV. Patient refuses to Patient is seropositive Patient is seronegative Patient is seronegative be tested and has no other evidence of but has engaged in Evaluate the health care worker HIV infection high-risk behavoirs Follow state and local for clinical or serologic evidence laws regarding testing No further follow-up of the Perform baseline HIV of HIV infection as soon as for a nonconsenting health care worker is necessary. testing of the health care possible after the exposure. patient's HIV source worker. Repeat test 3 Consider prophylaxis: status. months and 6 months Low to moderate risk: AZT plus 3TC. after exposure. High risk: AZT plus 3TC plus indinavir. Health care worker is seronegative Repeat serologic testing 6 wk and 3, 6, 12 mo after exposure. Rabies All bites and wounds should be immediately and thoroughly cleansed with soap and water. Bite of domestic animal (dog or cat) Bite of wild Bite of another animal (skunk, animal (e.g., bat, fox, coyote, livestock) raccoon, bobcat, or other Consult with carnivore) public health officials to Animal is healthy Animal shows Animal escapes determine need at time of attack signs of rabies Regard as rabid unless proved for treatment. Consult with public Observe the animal negative by health officials to for 10 days. If the animal laboratory tests. determine need shows signs of rabies, for treatment. proceed with treatment. Give the exposed person RIG (20 IU/kg). If anatomically feasible, infiltrate the full dose around the wounds. Infiltrate any remaining RIG I.M. at a site distant from that of vaccine administration. Also, administer 1.0 ml of HDCV into the deltoid muscle or, in children, the upper thigh on days 0, 3, 7, 14, and 28. If the animal is available, kill it and immediately examine its brain tissue for the presence of rabies by using fluorescent antibody tests. If the tests are negative, discontinue HDCV.
  • 4. © 2002 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 20 VIRAL INFECTION — 4 Hepatitis B Chronic exposure Acute exposure Health care workers and other groups at risk for exposure to hepatitis B should receive the HB vaccine series before Source of exposure is Source of exposure is HBsAg status of source of exposure. HBsAg-positive HBsAg-negative exposure is unknown No treatment is needed If source is known to be at unless the exposed person high risk, act as if source has never received the HB is HBsAg-positive. vaccine series, in which case it should be initiated. Exposed person has Exposed person previously never been vaccinated vaccinated with HB vaccine Give a single dose of HBIG. Known responder: Test for anti-HBs. If Initiate the HB vaccine series. adequate, no treatment is needed. If inadequate, give one booster dose. Known nonresponder: Give two doses of HBIG, or give one dose of HBIG and initiate revaccination. Responder unknown: Test for anti-HBs. If adequate, no treatment is needed. If inadequate, give one dose of HBIG plus an HB vaccine booster dose. Exposed person previously received HB Exposed person has never vaccine series been vaccinated Known responder: No treatment is needed. Initiate the HB vaccine series. Known nonresponder: If the source is at high risk for HB virus infection, consider proceeding as if source had been proved positive for HBsAg. Responder unknown: Test for anti-HBs. If adequate, no treatment is needed. If inadequate, give one dose of HBIG plus an HB vaccine booster dose. Approach to Viral Exposure Hepatitis C Perform serologic testing for ALT and HCV antibody at time of exposure and again at 6 months. If anti-HCV is detected, confirmatory testing with recombinant immunoblot is indicated. HCV immunoglobulin is no longer recommended.
  • 5. © 2002 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 20 VIRAL INFECTION — 5 In five studies, patients of 16 health care workers (including be informed of the incident and, if consent is obtained, tested for two surgeons) who were positive for hepatitis B surface antigen serologic evidence of HIV infection. If consent cannot be (HBsAg) were prospectively followed for evidence of hepatitis.33-37 obtained, procedures for testing the patient should be followed in A total of 784 patients were followed and were compared with accordance with state and local laws. Testing of needles or other 656 patients cared for by health care workers who were HBsAg sharp instruments associated with exposure to HIV is not recom- negative. None of the patients acquired overt hepatitis or became mended, because it is unclear whether the test results would be seropositive for HBsAg. Eight (1.02%) of the 784 patients cared reliable and how they should be interpreted.41 for by HBsAg-positive health care workers developed antibody to Health care workers exposed to HIV should be evaluated for HBsAg (anti-HBs), but so did six (0.91%) of the 656 patients cared susceptibility to blood-borne infection with baseline testing, for by health care workers who were negative for HBsAg. These including testing for HIV antibody. If the patient who is the source reports suggest that the likelihood of infected surgeons’ or other of exposure is seronegative and exhibits no clinical evidence of health care workers’ transmitting HIV or HBV to their patients is AIDS or symptoms of HIV infection, further follow-up of the extremely low. Chronic carriers of HBsAg who are seronegative health care worker is usually unnecessary.41 If the source patient is for HBeAg are much less likely to transmit HBV than persons seropositive or is seronegative but has engaged in high-risk behav- who are HBeAg positive. iors, baseline and follow-up HIV-antibody testing of the health Before the cases of transmission of HIV from the dentist to six care worker at 6 weeks, 3 months, and 6 months after exposure of his patients were reported, the CDC had not taken a position should be considered.41 Seroconversion usually occurs within 6 to on whether HBV- or HIV-infected surgeons should be allowed 12 weeks of exposure; infrequently, it occurs considerably later. to continue practicing medicine. After these cases were report- Three cases of delayed HIV seroconversion among health care ed, the CDC held meetings of health care professionals and workers have been reported.42-44 In all three patients, an HIV anti- other interested parties and published its recommendations on body test yielded negative results at 6 months but positive results July 12, 1991.38 These recommendations called for physicians at some point during the following 1 to 7 months. In two cases, not to perform “exposure-prone invasive procedures” unless coinfection with HCV had occurred and took an unusually severe they sought counsel from an expert review panel and were course. At present, it is unclear whether coinfection with these two advised under what circumstances, if any, they might be allowed viruses directly influences the timing or severity of either infection, to continue to perform these procedures. Physicians would have but most experts recommend close monitoring for up to 1 year for to notify prospective patients of their seropositivity. These rec- health care workers exposed to both viruses in whom serologic ommendations were strongly resisted by the medical communi- evidence of HCV infection develops. ty because at that time, only one health care worker, the dentist, Treatment of the exposed health care worker should begin had been implicated in transmitting HIV to his patients, no with careful washing of the exposure site with soap and water. mechanism of transmission had been elucidated, no other Mucous membranes should be flushed with water. There is no patients had HIV transmitted by a health care worker, and inva- evidence that either expressing fluid by squeezing the wound sive procedures that were “exposure prone” (exposing the or applying antiseptics is beneficial, though antiseptics are not patient to blood of the health care worker) were impossible to contraindicated. The use of caustic agents (e.g., bleach) is not define. After subsequent meetings, the CDC abandoned its recommended. attempts to define exposure-prone procedures but did not alter Any health care worker concerned about exposure to HIV its recommendations. Rather, it left it up to the states to define should receive follow-up counseling regarding the risk of HIV exposure-prone procedures. Subsequently, the President’s transmission, postexposure testing, and medical evaluation, Commission on AIDS recommended that HIV-infected health regardless of whether postexposure prophylaxis is given. HIV care workers should not have to curtail their practices or inform antibody testing should be performed at specified intervals for their patients of their infection. at least 6 months after the exposure (e.g., at 6 weeks, 3 Transmission of HCV from health care workers to patients has months, and 6 months). The risk of HIV transmission is been reported. In one such case, a cardiac surgeon transmitted believed to depend on several factors: how much blood is HCV to at least five patients during valve replacement surgery.39 involved in the exposure, whether the blood came from a In another, an anesthesiologist in Spain may have infected source patient with terminal AIDS (thought to be attributable more than 217 patients by first injecting himself with nar- to the presence of large quantities of HIV), whether any host cotics, then giving the remainder of the drugs to his patients.40 factors are present that might affect transmissibility (e.g., At present, no recommendations exist for restricting the pro- abnormal CD4 receptors for HIV), and whether the source fessional activities of health care workers with HCV infection. patient carries any aggressive HIV viral mutants (e.g., syncytia- inducing strains). Factors indicating exposure to a large quan- tity of the source patient’s blood (and thus a high risk of HIV Management of Viral transmission) include a device visibly contaminated with the Exposure patient’s blood, a procedure that involved a needle placed directly in a vein or artery, and a deep injury.45 HIV During the follow-up period, especially the first 6 to 12 weeks, The CDC has issued rec- exposed health care workers should follow the U.S. Public Health ommendations for the Service recommendations for preventing further transmission of management of potential HIV.1-4 These recommendations include refraining from blood, semen, exposure of health care or organ donation and either abstaining from sexual intercourse or workers to HIV.1,4,41 If a using measures to prevent HIV transmission during intercourse.46 health care worker is exposed by a needle stick or by a splash in The circumstances of the exposure should be recorded in the eye or mouth to any patient’s blood or other body fluids, and the worker’s confidential medical record and should include the HIV serostatus of the patient is unknown, the patient should the following:
  • 6. © 2002 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 20 VIRAL INFECTION — 6 Table 2 Recommendations for Hepatitis B Prophylaxis after Percutaneous or Permucosal Exposure15 HBsAg Status of Source of Exposure Hepatitis B Vaccination Status of Exposed Person HBsAg-Positive HBsAg-Negative Untested or Unknown Unvaccinated Give single dose of HBIG Initiate HB vaccine series Initiate HB vaccine series Initiate HB vaccine series Previously vaccinated Test exposed person for anti-HBs If anti-HBs levels are adequate,* no treatment is needed; if they are No treatment is needed No treatment is needed Known responder inadequate, give an HB vaccine booster dose No response to three-dose vaccine series: give two doses of HBIG or one dose of HBIG plus revaccination If source is at high risk for hepatitis B Known nonresponder No response to three-dose vaccine No treatment is needed infection, consider proceeding as if series plus revaccination: give one source had been demonstrated to be dose of HBIG as soon as possible HBsAg-positive and a second dose 1 mo later Test exposed person for anti-HBs Test exposed person for anti-HBs Response unknown If anti-HBs levels are adequate,* no If anti-HBS levels are adequate,* no treatment treatment is needed; if they are No treatment is needed is needed; if they are inadequate, initiate inadequate, give one dose of HBIG revaccination plus an HB vaccine booster dose *An adequate anti-HBs level is ≥ 10 mlU/ml, which is approximately equivalent to 10 sample ratio units (SRU) on radioimmunoassay or a positive result on enzyme immunoassay. 1. The date and time of the exposure. been associated with side effects, include GI (e.g., nausea or diar- 2. Details of the exposure, including (a) where and how the expo- rhea), hematologic, endocrine (e.g., diabetes), and urologic effects sure occurred, (b) the type and amount of fluid or other mate- (e.g., nephrolithiasis with indinavir). According to some early data, rial involved, and (c) the severity of the exposure (for a percu- 50% to 90% of health care workers receiving combination regi- taneous exposure, this would include the depth of injury and mens for postexposure prophylaxis (e.g., zidovudine plus 3TC, whether fluid was injected; for a skin or mucous membrane with or without a protease inhibitor) reported one or more subjec- exposure, it would include the extent and duration of contact tive side effects that were substantial enough to cause 24% to 36% and the condition of the skin—chapped, abraded, or intact). of the workers to discontinue postexposure prophylaxis.47-49 3. A description of the source of the exposure, including (if Whether antiretroviral agents should be chosen for postexpo- known) whether the source material contained HIV or other sure prophylaxis on the basis of the resistance patterns of the blood-borne pathogens, whether the source was HIV positive, source patient’s HIV remains unclear. Transmission of resistant the stages of any diseases present, whether the patient had pre- strains has been reported50-52; however, in the perinatal clinical viously received antiretroviral therapy, and the viral load. trial that studied vertical transmission of HIV, zidovudine pre- vented perinatal transmission despite genotypic resistance of HIV 4. Details about counseling, postexposure management, and to zidovudine in the mother.53 Further study of the significance of follow-up.41 genotypic resistance is necessary before definitive recommenda- The data currently available on primary HIV infection indicate tions can be made. that systemic infection does not occur immediately.There may be HEPATITIS B a brief window of opportunity during which postexposure anti- retroviral therapy may modify viral replication. Findings from ani- Both passive immuniza- mal and human studies provide indirect evidence of the efficacy of tion with hepatitis B im- antiretroviral drugs in postexposure prophylaxis. The majority of mune globulin (HBIG) these studies included zidovudine (AZT); consequently, all post- and active immunization exposure prophylaxis regimens now in use include AZT. with hepatitis B vaccine Combination treatment regimens using nucleoside reverse tran- (HB vaccine) are currently scriptase inhibitors and protease inhibitors have proved effective. available for prophylaxis Accordingly, most experts now recommend dual therapy with two against hepatitis B [see nucleosides (zidovudine and lamivudine) for low- to moderate- Table 2]. risk exposures. For high-risk exposures, most experts would add a protease inhibitor (usually either indinavir or nelfinavir) to the two Passive Immunoprophylaxis nucleoside reverse transcriptase inhibitors. These medications HBIG is prepared by Cohn ethanol fractionation from plasma should be started as soon as possible after the exposure (within selected to contain a high titer of anti-HBs; this process inacti- hours rather than days) and should be continued for 4 weeks. vates and eliminates HIV from the final product. In the United An important component of postexposure care is encouraging States, HBIG has an anti-HBs titer of at least 1:100,000 by and facilitating compliance with the lengthy course of medication. radioimmunoassay.54 HBIG provides temporary, passive Therefore, careful consideration must be given to the toxicity pro- protection. It is indicated after low-volume percutaneous or files of the antiretroviral agents chosen. All of these agents have mucous membrane exposure to HBV; it is not effective for high-
  • 7. © 2002 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 20 VIRAL INFECTION — 7 Table 3—Candidates for Hepatitis B Vaccine15 older than 19 years and 5 µg (0.5 ml) for persons 11 to 18 years of age. For immunologically impaired patients, including hemodialy- Persons with occupational risk (e.g., health care sis patients, the dose is 40 µg for all three vaccines. For postexpo- workers, public safety workers) sure prophylaxis with Engerix-B, a regimen of four doses given Clients and staffs of institutions for the develep- soon after exposure and 1, 2, and 12 months afterward has been mentally disabled approved. Hemodialysis patients HB vaccine is more than 90% effective at preventing infection Sexually active homosexual men or clinical hepatitis in susceptible persons. Protection is virtually Users of illicit injectable drugs complete in persons who develop adequate antibody. Routine testing Recipients of certain blood products (e.g., for immunity after vaccination is not recommended, but testing patients with clotting disorders who receive should be considered for persons at occupational risk who require clotting factor concentrates) postexposure prophylaxis for needle-stick exposure. Household and sexual contacts of HBV carriers Between 30% and 50% of persons who have been vaccinated Adoptees from countries of high HBV endemicity will cease to have detectable antibody levels within 7 years, but pro- Other contacts of HBV carriers (vaccination is tection against infection and clinical disease appears to persist.54,55 Preexposure usually not required unless there are special vaccination The need for booster doses has not been established. Revaccination circumstances, such as biting or scratching, or medical conditions, such as severe skin dis- of individuals who do not respond to the primary series will produce ease, that facilitate transmission) adequate antibody in 15% to 25% of cases after one additional Populations with high endemicity of HBV infec- dose and in 30% to 50% after three additional doses.56 tion (e.g., Alaskan natives, Pacific islanders, Although effective HB vaccines have been available since 1982, and refugees from HBV-endemic areas) the incidence of hepatitis B in the United States continued to in- Inmates of long-term correctional facilities crease in the first decade of HB vaccine use. In 1991, the Advisory Sexually active heterosexual persons with multi- ple sexual partners Committee for Immunization Practices (ACIP), citing the safety of the vaccine and the evidence of continuing spread of HBV, rec- International travelers who spend more than 6 mo in HBV-endemic areas and have close ommended universal vaccination of all infants born in the Unit- contact with the local population ed States.57 All infants born in the United States Adolescents 11 to 12 years old who have not Recommendations for Exposure to Blood That Contains previously been vaccinated (or May Contain) HBsAg Perinatal exposure (infants born to HBsAg-posi- Acute exposure The U.S. Public Health Service has provid- tive mothers) ed recommendations for hepatitis B prophylaxis after accidental Acute exposure to blood that contains (or might percutaneous, mucous membrane, or ocular exposure to blood contain) HBsAg Postexposure that contains (or may contain) HBsAg [see Table 2].43 These reco- vaccination Sexual partners of persons with acute HBV infections mmendations are based on consideration of several factors: (1) Household contacts of persons with acute whether the source of the blood is available, (2) the HBsAg sta- HBV infections (infants and older persons who tus of the source, and (3) the hepatitis B vaccination and vacci- have had identifiable blood exposure to the nation-response status of the exposed person. After exposure, a index patient) blood sample should be obtained from the person who was the source of the exposure and should be tested for HBsAg. The hepatitis B vaccination status and the anti-HBs response status volume exposure (e.g., blood transfusion). The recommended (if known) of the exposed person should be reviewed. Because dose of HBIG for adults is 0.06 ml/kg I.M. Passive prophylaxis passive administration of antibody with HBIG does not inhibit with HBIG should begin as soon as possible after exposure— the active antibody response to HB vaccine, the two can be given ideally, within 24 hours.54 simultaneously Active Immunoprophylaxis Chronic exposure The U.S. Public Health Service rec- Two types of HB vaccine are currently licensed in the United ommends that persons who are at risk for exposure to HBV States, plasma-derived vaccine (Heptavax-B) and recombinant receive the HB vaccine series [see Table 3].54 Health care workers vaccine (Recombivax HB and Engerix-B). Heptavax-B contains who are at increased risk for acquiring hepatitis B include all alum-adsorbed 22 nm HBsAg particles purified from human plas- physicians (especially surgeons), dentists, and laboratory and sup- ma and processed to inactivate the infectivity of HBV and other port personnel, such as nurses and technicians who work in the viruses. Plasma-derived vaccine is no longer being produced in the operating room or who have contact with infected patients, blood United States, but similar vaccines are produced and used in China or blood products, or excreta. Because of their frequent exposure and other countries. In the United States, use of Heptavax-B is lim- to blood and their high risk of hepatitis B, all surgeons should ited to persons allergic to yeast. Recombivax HB and Engerix-B are receive HB vaccine. As of 1994, however, only 50% of surgeons prepared by recombinant DNA technology in common baker’s (or had been vaccinated, despite the proven efficacy and safety of the brewer’s) yeast, Saccharomyces cerevisiae. vaccine and surgeons’ increased risk of exposure.58 Hospital per- For primary vaccination, three I.M. injections (into the deltoid sonnel who do not have frequent contact with blood or blood muscle in adults and children and into the anterolateral thigh mus- products (e.g., the janitorial, laundry, and kitchen staffs) need not cle in infants and neonates) are given, with the second and third be vaccinated. doses 1 and 6 months after the first dose.54 The dose for Heptavax-B Screening of personnel and patients for anti-HBs before vacci- and Engerix-B is 20 µg (volume, 1.0 ml) for persons older than 11 nation is indicated only for individuals in high-risk groups; it has years, and that for Recombivax HB is 10 µg (1.0 ml) for persons not been found to be cost-effective outside these groups.
  • 8. © 2002 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 20 VIRAL INFECTION — 8 HEPATITIS C RABIES The only tests currently The CDC has made approved by the U.S. Food recommendations for the and Drug Administration prevention of rabies in for diagnosis of hepatitis C people bitten by animals are those that measure anti- [see Table 4].63 Bite wounds body to HCV. These tests should always be thorough- detect anti-HCV in at least ly scrubbed with soap and 97% of infected patients, water. Postexposure anti- but they cannot distinguish between acute, chronic, and resolved rabies treatment includes both rabies immune globulin (RIG) infection.59 The positive predictive value of enzyme immunoassay and human diploid cell (rabies) vaccine (HDCV). The decision (EIA) for anti-HCV varies depending on the prevalence of the to administer such treatment should be based on the following infection in the population. Therefore, supplemental testing of a considerations. specimen with a positive EIA result with a more specific assay (e.g., the recombinant immunoblot assay [RIBA]) may detect Species and Availability of Biting Animal false positives, especially when asymptomatic persons are being In the United States, rabies is most commonly transmitted by tested. Qualitative polymerase chain reaction (PCR) testing for skunks, raccoons, foxes, and bats. Livestock occasionally transmit HCV RNA can also be used to identify HCV.This test can detect the virus, but rodents and lagomorphs (i.e., rabbits and hares) are HCV at concentrations as low as 100 to 1,000 viral genome rarely infected.64 In different parts of the country, different animals copies/ml, and it can detect HCV RNA in serum or plasma with- predominate in the transmission of the virus. The likelihood that in 1 to 2 weeks after viral exposure and weeks before alanine domestic cats or dogs in the United States will be infected varies aminotransferase (ALT) levels rise or anti-HCV appears.59 Un- from region to region. The chances of rabies transmission by a der optimal conditions, the reverse transcriptase PCR assay for domestic animal that has been properly immunized are minimal. HCV can identify 75% to 85% of persons who are anti- Whether an animal is available for observation after biting some- HCV–positive and more than 95% of persons with acute or one also influences the need for antirabies prophylaxis. In certain chronic hepatitis C.59 Quantitative assays for measuring HCV cases, an animal that bites a person must be killed and tissue from RNA are also available but are less sensitive and should not be its brain checked for the presence of rabies by fluorescent antibody used as primary tests for confirming or excluding the diagnosis of tests as soon as possible [see Table 4]. HCV infection or monitoring the end point of treatment. 59 The data currently available on prevention of HCV infection with Type of Exposure immune globulin (IG) indicate that this approach is not effective Infected animals transmit rabies primarily by biting, although as postexposure prophylaxis for HCV infection.59 Interferon may licking may introduce the virus into open cuts in skin or mucous have a role in the treatment of acute hepatitis C: several studies membranes.Transmission occasionally occurs as a result of aerosol have shown that interferon may delay or prevent the onset of exposure: the virus may be excreted in the urine and feces of infect- chronic hepatitis C in patients treated early in the course of acute ed bats, aerosolized during urination and defecation, and then HCV infection.60-62 inhaled, for example, by spelunkers exploring caves. Table 4 Rabies Postexposure Prophylaxis63 Animal Species Condition of Animal at Time of Attack Treatment of Exposed Person* Healthy and available for 10 days of observation None, unless animal develops rabies† ‡ Rabid or suspected rabid RIG (20 IU/kg) and HDCV§ (five 1.0 ml doses Domestic Dog, cat intramuscularly, on days 0, 3, 7, 14, and 28) Unknown (escaped) Consult public health officials. If treatment is ‡ indicated, give RIG and HDCV ‡ Skunk, bat, fox, coyote, bobcat, Regard as rabid unless proved negative by RIG (20 IU/kg) and HDCV (five 1.0 ml doses Wild raccoon, other carnivores laboratory testsI I intramuscularly, on days 0, 3, 7, 14, and 28) Livestock, rodents, lagomorphs Consider individually. Local and state public health officials should be consulted on questions about Other (rabbits and hares) the need for rabies prophylaxis. Bites of squirrels, hamsters, guinea pigs, chipmunks, gerbils, rats, mice, other rodents, and lagomorphs almost never call for antirabies prophylaxis. *All bites and wounds should immediately be thoroughly cleansed with soap and water. If antirabies treatment is indicated, both rabies immune globulin (RIG) and human diploid cell rabies vaccine (HDCV) should be given as soon as possible, regardless of the interval from exposure. (The administration of RIG is the more urgent procedure. If HDCV is not immediately available, start RIG and give HDCV as soon as it is obtained.) Local reactions to vaccines are common and do not contraindicate continuing treatment. Discontinue vaccine if fluorescent antibody tests of the animal are negative. † During the usual holding period of 10 days, begin treatment with RIG and HDCV at first sign of rabies in a dog or cat that has bitten someone. The symptomatic animal should be killed immediately and tested. ‡ The full dose should be infiltrated around the wounds; any remaining RIG should be given I.M. at a site distant from that of vaccine administration. If RIG is not available, use antirabies serum, equine (ARS). Do not use more than the recommended dosage of RIG or ARS. § HDCV should be administered into the deltoid (not the gluteus) muscle in adults and adolescents. In children, it may be administered into the upper thigh. II The animal should be killed and tested as soon as possible. Holding for observation is not recommended.
  • 9. © 2002 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 20 VIRAL INFECTION — 9 Circumstances of the Bite ratory workers and field personnel, and persons planning to stay An unprovoked attack is more indicative of a rabid animal for more than 1 month in areas where canine rabies is highly preva- than is a provoked attack. lent and access to appropriate medical care is limited.The recom- If the animal shows signs of rabies or the patient has been bit- mended preexposure regimen is 0.1 ml of HDCV on days 0, 7, and ten by a wild animal that is not captured, the patient should be 21 or 28.67 Testing for adequate antibody response is not necessary treated as soon as possible with both RIG and HDCV. The rec- for persons at low risk for exposure, but administration of booster ommended dose of RIG for postexposure prophylaxis is 20 doses every 2 to 3 years is recommended for those at high risk for IU/kg.63 If anatomically feasible, the entire dose of RIG should be exposure. Postexposure treatment for persons who have received infiltrated into the area around the wound.65,66 Postexposure preexposure immunization consists of 1 ml HDCV on days 0 and HDCV should be given I.M. in five 1.0 ml doses on days 0, 3, 7, 3 only, without RIG.68 14, and 28.63 Those with adequate preexposure immunization Although only a few cases of clinical rabies occur each year should receive two 1.0 ml doses of HDCV I.M. on days 0 and 3 in the United States, approximately 30,000 persons a year but should receive no RIG. For adults, the vaccine should be are given postexposure prophylaxis. In 1992, 49 states, the administered in the deltoid area. For children, the anterolateral District of Columbia, and Puerto Rico collectively reported aspect of the thigh is also acceptable.The gluteal area should never 8,644 cases of animal rabies and one case of human rabies to be used for HDCV injections, because administration in this area the CDC.69 The total expense associated with one rabid dog results in lower neutralizing antibody titers.63 HDCV must not be in California was $105,790, even though no human contract- given in the same region as RIG. ed rabies.70 This amount represents the costs of human The CDC recommends that preexposure immunization be con- antirabies treatment, vaccination of other animals, and animal- sidered for high-risk groups, such as animal handlers, certain labo- containment programs. Discussion Size and Structure of Viruses structural characteristics determined from electron microscopy Viruses are among the smallest and simplest of microorgan- (e.g., dimensions and site of assembly).Viruses are categorized into isms. Human viruses can be as small as 18 to 26 nm in diameter two broad groups depending on whether their nucleic acid is RNA (parvoviruses) or as long as 300 nm (vaccinia virus), slightly or DNA. These two groups can be subdivided first according to longer than Chlamydia (a bacterium). Viruses do not have the whether the nucleic acid is single stranded or double stranded and complex enzyme systems required for synthesis of nucleic acid then according to the presence or absence of an envelope. Single- precursors, they lack ribosomes for protein synthesis, and they stranded RNA viruses that replicate by means of a DNA step (i.e., have no energy-generating mechanism. Consequently, they can- retroviruses) are grouped separately from those that do not. not replicate outside cells. The core of a virus is made of either RNA or DNA, but never both. The nucleic acid can be either single stranded or double Identification of Viruses stranded.This nucleic acid core is surrounded by the capsid, which Viruses can be identified by means of (1) serologic tests, (2) iso- is a protein coat made up of capsomers, repetitive subunits con- lation of virus, (3) histologic examination, (4) detection of viral sisting of one protein or at most a few. Because the viral nucleic antigens, (5) detection of viral nucleic acid, and (6) electron mi- acid must code for coat proteins, a limitation in the number of cap- croscopy. One or more of these techniques may be applicable to a sid proteins conserves viral nucleic acid. The capsid protects the given viral infection. nucleic acid from nucleases in the environment, serves as its vehi- Specimens must be handled properly to maximize the likelihood cle of transmission from one host to another, and plays a role in the of identifying the virus. If isolation of the virus is desired, blood and attachment of the virus to the receptor sites on susceptible cells. tissue samples should be taken promptly to the virology laboratory The complete nucleic acid–protein coat complex is termed the and inoculated onto the appropriate cell line. Samples obtained at nucleocapsid. For many viruses, the nucleocapsid is the complete night or on weekends can be placed in a balanced salt solution or virus particle, the virion. Other viruses, such as herpesviruses, may tissue culture medium and kept in a refrigerator until taken to the acquire an envelope, an additional lipid-containing membrane coat laboratory. If microscopic identification of the virus is planned, around the nucleocapsid, by budding through a membrane of the specimens must be preserved appropriately. Routine preservation host cell [see Figure 1]. Some viruses may also have an enzyme in formalin, for example, permits visualization of viral inclusions by associated with their core that replicates the nucleic acid. Examples routine staining and light microscopy. For identification of viral are the DNA polymerase of the HBV and the reverse transcriptase antigens by immunofluorescence techniques, the tissue specimen of retroviruses. should be immediately frozen, preferably in liquid nitrogen. Spec- imens to be examined by electron microscopy must be placed in glutaraldehyde or another appropriate fixative. Classification of Viruses Viruses, like other organisms, are classified into families, gen- SEROLOGIC TESTS era, and species, but most viral species do not have formal names The antibody response to viral antigens can be detected in and in practice are referred to by common names (e.g., cytomegalo- the serum of patients with viral infections. An IgM response virus, coxsackievirus, Norwalk virus, and varicella-zoster virus). usually indicates recent exposure to the virus, whereas the Viruses can also be classified by chemical characteristics and by presence of IgG reflects past exposure.
  • 10. © 2002 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 20 VIRAL INFECTION — 10 Envelope Icosahedral Capsid Core DNA 50 nm Figure 1 The capsomers and the irregularly shaped surrounding envelope of a cytomegalovirus are highlighted by negative staining with uranyl acetate (above). A typical herpesvirus (right) consists of a central core containing DNA; an icosahedral capsid, a sur- rounding layer of protein made up of 162 individual capsomers; and an envelope, a membrane coat acquired when the virus buds from the nuclear membrane of the host cell. For most acute primary infections, serum obtained during late detected because they inhibit the cytopathic effects of a second test recovery or after recovery (convalescent serum) has an increased virus. This phenomenon is called viral interference. Other viruses antibody titer, compared with serum obtained early in the course (e.g., myxoviruses) cause changes in the cell membrane so that red of the disease (acute serum). Most tests are performed on an ini- blood cells adhere to the cell surface (hemadsorption).The identi- tial serum dilution of 1:2 or 1:10 and on serial twofold dilutions ty of isolated viruses can be confirmed by use of specific antisera thereafter. A fourfold increase in titer (indicated by reactivity of a that are known to inhibit viral growth. two-tube dilution) usually represents a significant increase in anti- Tissue suspected of containing an encephalitis or other neu- body response and is considered to constitute seroconversion. An rotropic virus can be minced and the extract injected intracere- immunocompromised host may occasionally fail to mount an brally into an infant mouse. If the mouse dies and bacteria can- antibody response. not be cultured from the brain, the injected material presumably Some viruses are so common that patients may already have contained such a virus. If antiserum of known specificity neu- antibody titers when the disease is first suspected. Herpesviruses tralizes the virus, the specificity of the antiserum indicates the are ubiquitous and are present in many healthy people in latent specific identity of the virus. The criterion for neutralization is form. At the onset of herpesvirus infections, patients may already that inoculation of neutralized virus will not kill the mouse. have the corresponding antibody. Nevertheless, their antibody titer will almost always increase significantly after recovery. A variety of serologic tests are available in the clinical labora- tory: complement fixation, radioimmunoassay, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, immune precipitation, immune blotting, latex agglutination, virus neu- tralization, indirect hemagglutination, immune adherence hem- agglutination, and hemagglutination inhibition. None of these serologic tests is appropriate for identification of all viruses. ISOLATION OF VIRUS The isolation of virus requires appropriate specimen collection and inoculation into animals or onto appropriate cell lines. Blood sent for virus isolation should be unclotted because some viruses, such as herpesviruses, are found primarily in lymphocytes. If cell- associated viruses are suspected, lymphocytes should be inoculat- ed directly onto target cells. Several types of cells are available for growing viruses, and no single cell line is appropriate for all of them.Therefore, it is helpful to the laboratory to know which virus the clinician suspects. Viruses that grow in cell monolayers in tissue culture have cyto- pathic effects that can be recognized under the microscope (e.g., Figure 2 Cells infected with cytomegalovirus become large and rounding, transformation, or death) [see Figure 2]. Some viruses, round (arrows). Note the uniform appearance of adjacent uninfect- such as rubella, produce no direct cytopathic effects but can be ed cells.
  • 11. © 2002 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 20 VIRAL INFECTION — 11 can be detected in this way in EBV-related cancers and lympho- proliferative disorders. ELECTRON MICROSCOPY Although seldom used routinely, electron microscopy allows rapid identification (in a matter of hours) of viruses in body flu- ids, tissues, and tissue extracts. Identification of viruses in body fluids and tissue extracts by this method is easier if the samples are first concentrated by ultracentrifugation, evaporation, or ul- trafiltration. HBV has been observed in specimens from hepatitis patients only after ultracentrifugation. Epidemiology of Viral Infections of Interest to Surgeons Viral infections are spread to humans via several patterns of transmission: (1) direct transmission from humans with sympto- matic infection (e.g., HBV, HCV herpesviruses, and HIV), (2) transmission from asymptomatic human carriers (e.g., HBV, HCV, HIV, and varicella-zoster virus), (3) transmission from arthropods (e.g., encephalitis and dengue viruses), and (4) transmission from other animals (e.g., rabies virus). Figure 3 Kidney biopsy shows cytomegalovirus-infected tubular Viral infections are common in immunosuppressed patients in epithelial cells (arrows). In such cells, a dark intranuclear inclusion general and especially in recipients of organ transplants, who must is surrounded by a clear halo. Inclusions usually indicate sites of take immunosuppressive drugs to prevent rejection. The over- previous or current viral replication. whelming majority of these infections are caused by members of the herpesvirus family (e.g., CMV, herpes simplex viruses, vari- HISTOLOGIC EXAMINATION cella-zoster virus, and EBV); infections with HBV and with papo- Histologic examination of biopsy and autopsy tissues may vaviruses (e.g., human papillomavirus, which causes warts, and demonstrate changes that are typical of certain viruses. Members BK virus) are also frequent. of the herpesvirus group can be characterized by intranuclear Because surgical patients are frequently given transfusions of inclusions surrounded by a clear halo [see Figure 3]. RNA viruses blood or blood products and because hospital staff often incur usually produce inclusions in the cytoplasm; for instance, dark- accidental needle-stick injury, viruses that can be transmitted by staining intracytoplasmic inclusions in the brain tissue of ani- these routes are of prime interest to surgeons and their patients. mals or patients are diagnostic of rabies infection and are called Examples of such viruses are HBV, hepatitis D, HCV, HIV, HTLV- Negri bodies. Inclusion bodies are either masses of closely packed I, and the herpesviruses, including EBV and CMV. These viruses virus particles or remnants of prior virus replication. can also be transmitted by organ transplantation either from the cells of the organ itself (e.g., HBV in liver cells or CMV in kidney DETECTION OF VIRAL ANTIGENS cells) or from blood that has not been completely removed from Viral antigens can be detected in tissues by techniques employing the organ. Changes in donor acceptance and screening policies their corresponding antibodies. If virus is present, these antigens over time have increased the safety of the blood supply and should may be visible microscopically under ultraviolet light either by direct continue to do so in the future [see Table 5].71 immunofluorescence (i.e., in tissue sections stained with fluorescein- labeled antiviral antibody) or by indirect immunofluorescence (i.e., in tissue sections exposed first to antiviral antibody and then to fluo- HIV rescein-labeled anti−γ-globulin antibody). Fluorescence microscopy Two serotypes of HIV, HIV-1 and HIV-2, have been identified. requires specimens that are fresh frozen (preferably in liquid nitro- Both can cause AIDS. HIV-1 accounts for virtually all cases of gen). Immunofluorescence staining of cells in tissue culture can de- AIDS in the United States and equatorial Africa. HIV-2 is found tect viral antigens before cytopathic effects are evident.Viral antigens almost exclusively in West Africa; only a few cases of HIV-2 infec- in formalin-fixed tissue can be identified by immunohistochemical tion have occurred in the United States. microscopy (e.g., using peroxidase-labeled antibodies). Because AIDS patients are immunodepressed, they are sus- ceptible to opportunistic infections and neoplasms, especially non- DETECTION OF VIRAL NUCLEIC ACID Hodgkin lymphoma, Pneumocystis carinii pneumonia, and Kaposi Viral nucleic acids can be detected in body fluids and tissues at sarcoma. AIDS is most prevalent in the United States among male virus concentrations too low to be detected by other means. The homosexuals, abusers of I.V. drugs, and hemophiliacs. Since the PCR permits amplification of even a small number of copies of implementation of testing for blood-borne HIV and the near-elim- viral nucleic acid. In theory, even a single copy of a specific DNA ination of HIV from blood products, the incidence of HIV infection can be detected by PCR. Before PCR is performed, DNA can be in the hemophiliac population has diminished markedly; however, synthesized from viral RNA by means of reverse transcriptase. in recent years, the incidence in the heterosexual population has The PCR product can be detected by gel electrophoresis and been increasing rapidly. compared with known viral DNA.This test is currently being used HIV can be transmitted by transfusion of whole blood, packed to diagnose CMV infection and is more sensitive than current red cells, plasma, factor VIII concentrates, factor IX concentrates, serologic testing for HCV. Nucleic acid hybridization can detect and platelets. The likelihood that a person will become infected viral nucleic acid in tissue specimens. Epstein-Barr virus genomes with HIV after receiving a single-donor blood product that tests
  • 12. © 2002 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 20 VIRAL INFECTION — 12 Table 5 Changes in Donor Acceptance transmission from blood, tissue, or other body fluids can occur in and Screening Policies Instituted to Reduce the health care setting as a result of percutaneous injury (e.g., from needles or other sharp objects), contamination of mucous mem- the Risk of Transmitting Infectious Diseases71 branes or nonintact skin (e.g., skin that is chapped, abraded, or affected by dermatitis), prolonged contact with intact skin, or con- Policy Implementation Date tamination involving an extensive area.79 HIV infection may be Screening for HBsAg July 1972 contracted through a variety of sources including blood, semen, vaginal secretions, visibly bloody fluids, and a number of other flu- Voluntary exclusion of persons at high risk for March 1983 ids for which the precise risk of transmission is undetermined AIDS (e.g., cerebrospinal, synovial, pleural, peritoneal, pericardial, and Redefinition of high-risk behavior to include men amniotic fluid). Infection may also be contracted from concen- who have had sex with more than one man December 1984 trated HIV used in research settings.79 The results of multiple since 1979 prospective studies quantifying transmission risk associated with a Testing for antibody to HIV-1 Spring 1985 discrete occupational HIV exposure indicate that the average risk of HIV transmission associated with needle punctures or similar Redefinition of high-risk behavior to include any man who has had sex with another man since September 1985 percutaneous injuries is approximately 0.3%. The estimated risk 1977 of transmission from mucocutaneous exposure to HIV-contami- nated material is 0.03%. As of December 1999, the CDC had Implementation of a mechanism to allow donors to indicate confidentially that their donations October 1986 received reports of 56 U.S. health care workers in whom docu- should not be used for transfusion mented HIV seroconversion was temporally related to occupa- tional HIV exposure. Of these 56, 48 had percutaneous expo- Testing for alanine aminotransferase (ALT, former- Winter 1986–1987 sures, five mucocutaneous exposures, two both percutaneous and ly SGPT) mucous membrane exposures, and one an unknown route of ex- Testing for anti-HBc Spring 1987 posure.80 Another 138 possible cases of occupational HIV trans- Testing for antibody to HTLV-1 January 1990 mission—six involving surgeons—have been reported in persons with no risk factors for HIV transmission other than workplace Testing for antibody to HCV May 1990 exposure; however, seroconversion after a specific exposure was Testing for antibody to HIV-2 April 1992 not documented. There may be other health care workers who also have acquired HIV infection from needle-stick or mucous Testing for HIV-1 antigen March 1996 membrane exposure but have not been reported, either because they and their patients have not been tested or because they have other risk factors for HIV infection positive for HIV approaches 100%.72-73 Before the advent of sero- The concentration of virus in the blood or serum of antigen-pos- logic testing for HIV in 1985, 0.04% of 1,200,000 blood dona- itive individuals is several orders of magnitude less for HIV than for tions in the United States were estimated to be HIV positive.74 HBV.The number of needle-stick exposures to HIV that have actu- AIDS has developed in more than 8,500 recipients of blood trans- ally led to a positive test result for HIV has been extremely small, fusions, blood components, or transplanted organs or tissue. whereas hepatitis B occurs in as many as 40% of health care work- Federal regulations now require that all prospective blood and ers exposed to the virus by needle-stick injury. Despite this relative- plasma donors be screened for antibody to HIV by ELISA. Be- ly low infectiousness, AIDS is much more feared than hepatitis B cause this test yields a low rate of false positive results, assay by the because AIDS is often fatal. Although hepatitis B is usually not fatal more sensitive Western blot electrophoresis is always used to con- and is often of short duration, several health care workers die of firm positive ELISA results. Routine testing of blood donors has hospital-acquired hepatitis B and hepatitis C each year. greatly reduced HIV transmission via blood transfusions, but infec- tion can still occur if the donor has been infected with HIV but has not yet developed antibody.75 The risk of HIV transmission via Hepatitis transfusion of screened blood that is negative for HIV is estimated Several viruses can cause hepatitis. Hepatitis A virus (HAV) and to be one in 200,000 to one in 2,000,000 per unit transfused in the HBV cause what were formerly known as infectious hepatitis and United States.76 Antibody to HIV usually develops within 4 weeks serum hepatitis, respectively. HCV is the major cause of parenter- to 6 months of HIV infection.77 From the time of infection until the ally transmitted non-A, non-B hepatitis. Hepatitis E virus is a com- appearance of antibody, infected individuals will test negative by mon cause of epidemic non-A, non-B hepatitis, which is chiefly ELISA or Western blot, and their blood might still be used for found in developing countries in Africa and Asia. Hepatitis D virus transfusion. (HDV, formerly called the delta agent) is defective or incomplete HIV and AIDS can also be transmitted by organ transplanta- and is pathogenic only in the presence of HBV.The hepatitis virus- tion.78 So far, only a small number of patients have been found to es are the most common infectious agents to which hospital per- be infected in this way, but more will undoubtedly be reported. sonnel may be exposed. Herpesviruses can also cause serious and These patients received transplants before HIV testing of potential sometimes fatal hepatitis, especially in severely immunocompro- donors became possible. All prospective organ and tissue donors mised patients, such as recipients of organ or bone marrow trans- now should be tested for HIV infection and other blood-borne plants and patients receiving intensive chemotherapy for cancer. viral infections. HEPATITIS A HIV infection is also a potential problem in health care work- ers, who are exposed to a large and growing population of AIDS HAV is a small (27 nm), single-stranded RNA virus belonging patients. In the United States, an estimated 1.0 to 1.5 million peo- to the enterovirus subgroup of picornaviruses. Its almost exclusive ple are infected with HIV but as yet have no symptoms. HIV transmission by the fecal-oral route is enhanced by poor personal
  • 13. © 2002 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 20 VIRAL INFECTION — 13 hygiene, poor sanitary conditions, and crowding. Transmission findings that are indicative of chronic HBV infection. There are, can be contained by careful hand washing and the isolation of however, several clinical syndromes linked to HBV infection that excretions. Unlike other types of viral hepatitis, hepatitis A is rarely may provide a clue to the presence of chronic HBV infection. transmitted by blood, blood products, or needle sticks and is rare- These syndromes include polyarteritis nodosa, membranous or ly transmitted among hemodialysis patients, health care workers, membranoproliferative glomerulonephritis, leukocytoclastic vas- and I.V. drug abusers. The infrequent parenteral transmission of culitis, erythema nodosum, arthritis, and serum sickness. HAV is attributed in part to its lack of an asymptomatic carrier state. Hepatitis A can be transmitted percutaneously only during Antigens a brief period of viremia before the onset of symptoms and jaun- HBV has a diameter of 42 nm and contains circular, double- dice.The chance that an infected person will donate blood during stranded DNA. The protein coat on its outer surface is termed this short period is small; also, patients are usually outside the hos- hepatitis B surface antigen. HBsAg is made in quantities greatly pital during this period. exceeding the amount required to coat the nucleic acid. The excess surface antigen appears in the serum as spheres 22 nm in HEPATITIS B diameter or tubules of the same diameter and of varying length. HBV is a member of the Hepadnaviridae family of DNA virus- These spheres and tubules contain no nucleic acid and hence are es. It is most prevalent in the Far East, the Middle East, Africa, not infectious. They may persist in the serum for prolonged peri- and parts of South America, where as many as 15% of the gener- ods, even for life, and in great quantities, up to 1012 to 1014 sur- al population are chronic carriers. Worldwide, the most common face antigen particles (500 µg protein) per milliliter.82 mode of transmission is from mother to child during the perina- The hepatitis B virus also has a nucleocapsid core, the outside tal period. In the United States, however, sexual or parenteral of which contains the hepatitis B core antigen (HBcAg). HBcAg transmission has been implicated in most infections.The high-risk is not detected in hepatitis B during acute infection, because its groups for chronic HBV infection in the United States include I.V. antigenic determinants are hidden by the outer surface antigen of drug users, men who have sex with men, other individuals with the intact virion. multiple sexual partners, household contacts and sexual partners Inside the hepatitis B nucleocapsid is a DNA-dependent DNA of HBV carriers, health care workers, patients on long-term polymerase and the hepatitis B e antigen, which is thought to be hemodialysis, and organ transplant recipients.81 either an internal component or a degradation product of the core antigen. HBeAg is found only in the serum of individuals whose Clinical Course serum also contains HBsAg, and it appears in the serum of virtu- The clinical course of hepatitis B is extremely variable: infection ally all patients early in the course of HBV infection.The presence ranges from the completely asymptomatic to the rapidly fatal.The of HBeAg in serum is indicative of the presence of large numbers incubation period averages 75 days but can last from 40 to 180 of circulating intact virions: serum containing HBeAg is estimat- days. Exposure to HBV has five potential outcomes: (1) no infec- ed to be one million times more infectious than serum containing tion occurs; (2) acute hepatitis develops, followed by clearance of HBsAg but not HBeAg. infection; (3) acute fulminant infection develops, leading to hepat- ic necrosis and death; (4) acute hepatitis develops without clear- Serology ance of infection, and a chronic carrier state ensues; and (5) no HBsAg can be detected in the serum within a few weeks of viral acute illness develops, but a chronic carrier state ensues. exposure [see Figure 5]. It usually persists throughout the sympto- Approximately 55% of adults infected with HBV have no symp- matic period and does not disappear until after recovery. Anti- toms despite serologic documentation of infection (see below), HBs appears shortly after the disappearance of HBsAg [see Table which explains why blood donors who seem to be in good health 6]. During this window period, neither HBsAg nor anti-HBs is de- are capable of transmitting the virus. Other individuals infected tectable [see Table 7]. Anti-HBs persists for years and is associated with HBV may have such mild symptoms (e.g., slight malaise, with immunity to reinfection. HBV can be differentiated into eight fatigability, and loss of appetite) that they do not seek medical serotypes on the basis of determinants of the surface antigen. attention. Hepatitis B core antigen (HBcAg) is not found free in the Approximately 45% of people infected with HBV experience serum, but antibody to HBcAg (anti-HBc) becomes detectable at typical acute, icteric hepatitis, which is characterized by fatigue, an early stage in the course of acute infections, 1 to 2 weeks after anorexia, nausea, vomiting, and hepatomegaly. In approximately the appearance of HBsAg. Titers of anti-HBc fall after the disap- 1% of adults infected with HBV, acute fulminant hepatitis devel- pearance of HBsAg but persist for life. In patients with chronic ops. This condition is characterized by progressive hepatocellular hepatitis B, HBsAg remains detectable indefinitely, and titers of destruction, encephalopathy, and deepening coma. Fulminant anti-HBc remain high.Years after infection, titers of anti-HBs may hepatitis causes death in approximately 80% of affected adults have fallen to undetectable levels, and anti-HBc may be the only and 30% of affected children. marker of previous infection. HBeAg is detectable immediately after In approximately 5% to 10% of hepatitis B cases, the infection the appearance of HBsAg. Antibody to HBeAg (anti-HBe) appears becomes chronic. Patients with chronic hepatitis may be asymptom- just after HBeAg becomes undetectable (usually before the disap- atic or may have clinical and histologic evidence of the disease, as pearance of HBsAg) and persists for 1 to 2 years [see Figure 5]. well as persistently elevated levels of serum aminotransferases [see HEPATITIS D Figure 4].With time, many patients pass to an asymptomatic carri- er state, and serum aminotransferase levels fall.The duration of the HDV is a defective, 35 to 37 nm RNA virus that can infect only asymptomatic carrier state appears to be indefinite. Chronic HBV persons who are also infected with HBV, because it uses HBsAg infection can result in hepatocellular carcinoma, which is especially for its structural protein shell. HDV is found worldwide and is common in China, Southeast Asia, and sub-Saharan Africa. especially prevalent in the Amazon basin, central Africa, southern Because most patients remain asymptomatic until the devel- Italy, and the Middle East.83 HDV infection is less common in the opment of end-stage liver disease, there are no specific clinical United States and Western Europe, where it is generally associat-
  • 14. © 2002 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 20 VIRAL INFECTION — 14 Incubation Symptoms or Persistent Disease Period Subclinical Hepatitis Anti-HBc Alanine Aminotransferase Serum Concentration HBsAg DNA Polymerase Anti-HBe HBeAg 0 1 2 3 4 5 6 7 8 2 4 6 8 10 Months after Infection Years after Infection Figure 4 Schematic shows virologic, clinical, and serologic events of a hepatitis B infection that becomes persistent. ed with parenteral blood exposure, typically in the setting of I.V. clinical features are similar to those of other types of hepatitis. Hep- drug abuse or multiple transfusions. atitis E virus (HEV) is prevalent in the developing world, where it Clinically, hepatitis D is found only in association with acute or is spread by the fecal-oral route and has been associated with large chronic hepatitis B, and it cannot last longer than hepatitis B does. outbreaks as well as sporadic cases. Outbreaks have been linked to Depending on the state of the HBV infection, HDV infection contaminated water supplies. No cases of HEV infection acquired appears either as a coinfection or a superinfection. Coinfection in the United States have been reported to date, but HEV acquisi- occurs when acute HDV infection and acute HBV infection are tion has been reported in international travelers. present simultaneously; superinfection occurs when acute HDV Hepatitis C is the most common cause of nonalcoholic liver dis- infection is superimposed on chronic HBV infection. Coinfection ease in the United States. HCV is an RNA virus of the flavivirus with HDV is associated with fulminant hepatitis and a mortality of family. It can be transmitted through parenteral exposure (usually in 2% to 20%.84 Fewer than 5% of cases of coinfection progress to the setting of I.V. drug abuse), sexual contact, or the sharing of a chronic hepatitis D. In contrast, superinfection with HDV results household with an HCV-infected person; however, some persons in chronic HDV hepatitis, often with cirrhosis, in more than 70% with HCV infection have none of these risk factors, and there may of cases. The clinical and biochemical features of HDV infection be other means of transmission that have yet to be elucidated. Before resemble those of HBV infection alone. Chronic active hepatitis B the advent of antibody testing, HCV infection accounted for the ma- progresses faster when hepatitis D is also present. Chronic HDV jority (75% to 95%) of cases of posttransfusion hepatitis.83 Since the infection is more likely to result in severe morbidity and mortality spring of 1990, when a serologic test for HCV became available, all than chronic HBV or HCV infection alone. transfused blood has been screened for HCV, and the incidence of Diagnosis of acute HDV infection may be difficult: HDAg ap- transfusion-associated hepatitis C has fallen precipitously. At pre- pears in the circulation only briefly and often goes undetected. Anti- sent, however, I.V. drug use still accounts for a large proportion body to HDAg (anti-HD) of the IgM class subsequently appears in (60%) of HCV transmission in the United States.59 serum in low titers. Because no anti-HD IgG response occurs, no The presence of anti-HCV IgG appears not to be protective: serologic marker of previous HDV infection may remain after recov- blood donors with anti-HCV antibody can transmit hepatitis.62 Sur- ery. Chronic HDV infection is easier to diagnose: high titers of anti- veys of HCV seropositivity indicate that 0.2% to 0.6% of volunteer HD in the serum indicate ongoing HDV infection, and HDV anti- blood donors carry anti-HCV IgG,83 and the prevalence may be gen is detectable in the liver by means of immunohistochemical much higher among high-risk populations (e.g., residents of large in- techniques. Moreover, IgM anti-HD remains detectable in serum.83 ner-city communities). The prevalence of anti-HCV IgG is high among I.V. drug users, hemodialysis patients, and hemophiliacs. NON-A, NON-B HEPATITIS: HEPATITIS E AND HEPATITIS C Non-A, non-B hepatitis is divided into two varieties, an epi- Clinical Manifestations demic form (hepatitis E) and a parenterally transmitted form The incubation period of hepatitis C averages 7 to 8 weeks in (hepatitis C).85 Hepatitis E is an acute, self-limited disease whose length but may be as short as 2 weeks or as long as 15. The clini-
  • 15. © 2002 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 20 VIRAL INFECTION — 15 Incubation Period Acute Hepatitis Convalescence Anti-HBc Alanine Aminotransferase Serum Concentration HBsAg Anti-HBs DNA Polymerase HBeAg Anti-HBe 0 1 2 3 4 5 6 7 8 2 4 6 8 10 Months after Infection Years after Infection Figure 5 Schematic shows virologic, clinical, and serologic events during acute hepatitis B infection. cal manifestations and biochemical alterations associated with chronic HCV infection, with mixed results: frequently, there is lit- acute hepatitis C are similar to but milder than those associated tle response to treatment, or viremia returns after treatment. The with hepatitis B. Serum aminotransferase levels can fluctuate combination of interferon with ribavirin has shown promise, how- widely; the peak levels are lower than those seen in hepatitis B (10 ever. Interferon treatment is generally reserved for patients who to 20 times normal as opposed to 20 to 50 times normal). Only have chronic HCV infection and show evidence of active necroin- about 25% of cases of acute HCV infection are icteric, and the flammatory liver disease with persistent ALT elevations. mortality for acute infection is about 1%. Most patients have no HEPATITIS IN HOSPITAL PERSONNEL acute illness suggestive of HCV infection. Antibody is not always present early in infection, and there are no clinically available Patients with hepatitis can infect hospital personnel with the assays for detecting IgM antibody to HCV. Thanks to improve- ments in the immunodetection of HCV, however, the interval before anti-HCV can be detected has decreased from the 6 to 12 Table 6 Serologic Markers of Hepatitis B Infection months required with the first-generation tests to 8 to 12 weeks with the second-generation assays.83 Present in acute and chronic infection The most striking feature of HCV infection is its tendency to HBsAg Indicator that person is infectious become chronic in as many as 50% to 75% of cases. One study found that even among the 1% to 10% of individuals with HCV Appears 2 to 16 wk after HBsAg disappears from the serum whose bloodstreams had been cleared of HCV according to RT- Anti-HBs Persists for years PCR assay, as many as 90% still had HCV in the liver.86 It is esti- Confers immunity mated that in the United States, nearly four million people are Not present in the serum seropositive for HCV, and more than 30% of liver transplantations HBcAg Found in the hepatocyte are performed to treat end-stage liver disease related to chronic HCV infection. The presence of anti-HCV IgG does not distin- Appears in serum with or shortly after HBsAg guish acute from chronic hepatitis.Within 10 years, cirrhosis may Anti-HBc Persists for years develop in as many as 20% to 25% of patients with active hepati- May be only indicator of hepatitis B infection tis87; accordingly, these patients must be followed up carefully. Appears in the early acute phase Chronic active hepatitis is characterized by elevated serum Indicates serum is highly infectious HBeAg aminotransferase levels; however, other test results remain nor- Persistence beyond 10 wk suggests progression to chronic mal, and the patient is usually asymptomatic until end-stage liver carrier state disease develops. Liver biopsy shows inflammation around the Anti-HBe Good prognosis for resolution of infection portal triads. Recombinant interferons have been used to treat
  • 16. © 2002 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 20 VIRAL INFECTION — 16 virus via needle-stick injuries and other forms of accidental expo- Table 7 Serologic Patterns of Hepatitis B Infection sure. Conversely, physicians who are chronic carriers of HBV or HCV can infect their patients. According to a nationwide seroepi- HBsAg Anti-HBs Anti-HBe Interpretation demiologic survey reported in 1978, approximately 19% of physi- cians have anti-HBs, compared with 3.5% of healthy volunteer + – – Early acute hepatitis B blood donors [see Table 8].88 Anti-HBs was found in 28% of sur- + – + Late acute hepatitis B geons, the highest prevalence in any medical specialty. For physi- cians, the likelihood of being positive for anti-HBs correlates with Window period between disappearance age and the number of years in practice. The risk of hepatitis is of HBsAg and appearance of anti-HBs or greatest among medical staff members in renal dialysis units, – – + Chronic carrier with low HBsAg level or oncology units, and the clinical laboratory. Since 1978, when these Infection in the remote past data were reported, HBV vaccination has made it impossible to perform similar, more recent studies, because vaccination rather – + + Past hepatitis B infection than previous infection would be responsible for the presence of antibodies. Infection in the remote past or Physicians and other staff members who care for hemodialysis – + – Immunization with hepatitis B vaccine or patients with end-stage renal disease are at greater risk for acquir- HBIG received within the past 1 to 2 mo ing HBV because of the high prevalence of hepatitis in such + = detectable—– = not detectable patients [see Table 9].89,90 Transmission of HBV decreases in dialy- sis centers when close attention is paid to hygienic technique. Isolation of patients who are carriers of HBsAg also reduces the tion appears to increase the risk of hepatocellular carcinoma in incidence of HBV in hemodialysis patients and staff.91 HCV-infected persons.A widespread program of vaccination against From 0.28% to 9.3% of health care workers have antibody to HBV could greatly decrease the incidence of hepatocellular carci- HCV.92-94 In one study from Connecticut, five (12.5%) of 40 sur- noma. Epidemiology, molecular biology, and comparative patholo- geons had antibody to HCV.92 In another study, from New York gy provide strong circumstantial evidence that hepatitis B is a sig- City, eight (1.75%) of 456 dentists had anti-HCV antibody.93 The nificant factor in the etiology of hepatocellular carcinoma.The risk highest prevalence among dentists was found to occur in oral sur- of primary hepatocellular carcinoma is more than 250 times geons (9.3%). As use of vaccines for HBV becomes more wide- greater in carriers of HBV than in noncarriers. HBV markers can spread [see Management of Viral Exposure, Hepatitis B, above], be found in 80% to 90% of patients with hepatocellular carcino- HCV may come to predominate over HBV as the cause of the rare ma. Perhaps the best epidemiologic data indicating that hepatitis B cases of hepatitis transmitted from hospital personnel to patients. precedes hepatocellular carcinoma were obtained in Taiwan from male civil servants between 40 and 60 years of age.98 Approximately EPIDEMIOLOGY OF POSTTRANSFUSION HEPATITIS 3,500 HBsAg carriers were matched by age and place of birth Both HBV and HCV can be transmitted by percutaneous (either mainland China or Taiwan) to 3,000 HBsAg-negative men, and other routes.89 Rare cases of hepatitis have been attributed who served as control subjects. An additional group of 16,000 to the infusion of immune globulin, although its preparation by HBsAg-negative men between 40 and 60 years of age served as ethanol fractionization normally destroys hepatitis virus (as well unmatched control subjects. After subjects were followed for 2 to 4 as HIV). Albumin is pasteurized by heating at 60° C for 10 years, 50 cases of hepatocellular carcinoma were found, all but one hours, which destroys hepatitis virus. of which occurred in chronic HBsAg carriers. Because of the current criteria for acceptable blood donors, eli- HCV is also associated with chronic infection in a high per- mination of payment for blood donation, and serologic testing for centage (approximately 50%) of cases. In many countries, chron- HBV and HCV, the risk of contracting hepatitis B from a blood ic HBV infection remains the leading factor in the development of transfusion is now much lower than it once was. In the United hepatocellular carcinoma, whereas in Japan, Korea, and southern States, it is now rare for either HBV or HCV to be transmitted via Europe, 50% to 75% of cases of hepatocellular carcinoma are blood transfusion. According to the latest estimates available, the risk of HCV transmission via this route is approximately 1/103,000 (95% CI, 28,000 to 288,000), and that of HBV transmission is Table 8 Frequency of Antibody to Hepatitis B 1/63,000 (95% CI, 31,000 to 147,000).95 Surface Antigen (Anti-HBs) by Physician Specialty88 HDV can also be passed by transfusion. In a study of 262 patients who had posttransfusion hepatitis and whose serum Number of Positive Specialty was positive for HBsAg, anti-HD was found in nine patients.96 Patients Tested Results (%) HDV can be detected in 24% of HBsAg-positive drug abusers and in approximately 50% of HBsAg-positive hemophiliacs. Surgery 176 50 (28) Pathology 37 10 (27) LONG-TERM EFFECTS OF CHRONIC HEPATITIS Pediatrics 63 13 (21) Chronic hepatitis can lead to problems requiring surgical inter- Internal medicine 259 46 (18) vention. It can cause cirrhosis, which in turn can cause portal hy- Anesthesiology 59 10 (17) pertension and bleeding varices that necessitate portal systemic Obstetrics-gynecology 63 10 (16) shunting. In addition, HBV and HCV predispose to hepatocellular Family practice 341 54 (16) carcinoma, the most prevalent visceral cancer in the world. The Nonpatient care 25 1 (4) condition is especially prevalent in China, Southeast Asia, and sub- All others combined 169 26 (15) Saharan Africa. It is estimated that 25% of chronically infected per- Total 1,192 220 (18.5) sons die of cirrhosis or hepatocellular carcinoma.97 HBV coinfec-
  • 17. © 2002 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 20 VIRAL INFECTION — 17 Table 9 Prevalence of Hepatitis B Virus (HBV) Serologic Markers in Various Populations90 Prevalence of Serologic Markers of HBV Infection (%) Population HBsAg All Markers Immigrants or refugees from areas 13 70 –85 where HBV is highly endemic Clients in institutions for the 10 –20 35 –80 mentally retarded High risk Users of illicit parenteral drugs 7 60 –80 Homosexually active men 6 35 –80 Household contacts of HBV carriers 3 –6 30 –60 Hemodialysis patients 3 –10 20 –80 Health care workers with frequent 1–2 15 –30 blood contact Intermediate Prisoners (male) 1–8 10 –80 risk Staffs of institutions for the mentally 1 10 –25 retarded Health care workers with no or 0.3 3 –10 infrequent blood contact Low risk Healthy adults (first-time volunteer 0.3 3 –5 blood donors) associated with chronic HCV infection.99 In Japan, mortality from cal posttransfusion syndrome and from the urine of half of these hepatocellular carcinoma increased approximately twofold in the patients.89 The condition is nonfatal and self-limited, but it may re- 1980s, a change that may be attributable to a higher incidence of sult in prolonged hospitalization and a long, expensive search for the HCV-associated liver cancer.100 source of fever. Although uncommon in adults 30 years of age and older, the syndrome can occur in as many as 10% of susceptible chil- dren and adults younger than 30 years. Herpesviruses This syndrome can also occur in patients who receive trans- fusions but who do not undergo open-heart operation. Occasional CYTOMEGALOVIRUS cases that develop postoperatively in patients who did not receive CMV is a member of the Β herpesvirus family and is the largest transfusions are thought to be the result of reactivation of latent in- virus known to infect humans. In some U.S. cities, the seropreva- fection. EBV can sometimes cause the syndrome. lence of CMV is 60% to 70%. Like other members of the her- The incidence of posttransfusion CMV infection is related to the pesvirus family, CMV is capable of remaining within its host in a kind of blood or blood product transfused. CMV is highly cell latent state, probably by down-regulating cell surface markers (e.g., associated and is transmitted with leukocytes, which may be pre- HLA-1) and thus avoiding immune destruction. Latent CMV has sent in transfusions of packed red blood cells, platelets, or white been found in circulating mononuclear cells, polymorphonuclear blood cells; transmission from transfusion of fresh frozen plasma or cells, vascular endothelium, renal epithelial tissue, and pulmonary cryoprecipitate has not been documented.14 Therefore, efforts to secretions. The virus may become reactivated in the setting of decrease the number of white blood cells in the transfused blood immunodeficiency, such as may arise with HIV infection, trans- would be expected to decrease the rate of transfusion-associated plantation, or significant stress from operations or injuries. In non- CMV infection. Approximately 50% of patients who receive whole immunocompromised patients, CMV typically causes a self-limit- blood seroconvert to CMV, whereas only 10% of those who receive ed mononucleosis-like syndrome characterized by fever and mild washed packed red blood cells seroconvert.The risk of seroconver- hepatic transaminase abnormalities. In immunocompromised pa- sion to CMV is between 12% and 100% when whole blood, either tients, however, CMV infection can be much more severe and even fresh or stored, is transfused.101 In one study, transfusion of frozen potentially life threatening, causing myelosuppression, pneumoni- deglycerolized red blood cells resulted in seroconversion in only tis, colitis, and retinopathy. 3% of patients,89 whereas in another, seroconversion occurred in 58% of 36 leukemic patients transfused with lymphocytes.102 Posttransfusion Cytomegalovirus Infection (Posttransfusion The risk of posttransfusion CMV infection is also related to the or Postperfusion Syndrome) volume of blood received. In one study, 7% of patients receiving a The transmission of CMV by extracorporeal perfusion is respon- single unit of whole blood seroconverted, whereas anti-CMV sible for the occasional development of a syndrome similar to mono- antibody titers rose in 21% of patients receiving more than one unit.103 nucleosis in patients who have undergone open-heart operation.The The risk of infection per unit of blood transfused is estimated to syndrome characteristically appears 3 to 5 weeks after operation; its range between 2.7% and 12%.104 features are splenomegaly, fever, atypical lymphocytosis, and, occa- Preexisting antibody to CMV does not protect transfusion sionally, hepatomegaly, erythematous rash, and eosinophilia.89 CMV recipients against reinfection. After transfusion of whole blood, can be isolated from the blood of virtually all patients with the typi- titers of antibody to CMV will increase in 10% of recipients (an
  • 18. © 2002 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 20 VIRAL INFECTION — 18 indication of reinfection) and in 19% of patients who did not have Several systematic studies have demonstrated that CMV caus- antibody to CMV before transfusion (an indication of infection). es clinical illness in renal transplant recipients. In four studies, Whereas a seronegative recipient of CMV-positive blood has a clinical illness developed in 83% of 76 patients with primary infec- 21% chance of seroconversion, the risk of seroconversion from the tion, compared with 44% of 268 patients with reactivation of a receipt of one unit of CMV-negative blood is only 2%.89 However, previous infection.89,109,110 the sensitivity of the serologic test for CMV is such that even when Recipients of renal transplants in whom CMV causes clinical ill- blood that tests seronegative is used, there is still a residual 0% to ness most commonly present with fever. Fever occurs in 95% of pa- 6% risk of CMV transmission.105 tients with CMV infection and may be prolonged. Patients with CMV Because so many patients receive blood transfusions during infection also frequently present with anorexia, arthralgias, and leuko- operation, it is understandable that evidence of posttransfusion penia. Other clinical features of the disease are diffuse pulmonary in- CMV infection has been found in many patients postoperatively filtrates, pancreatitis, transplant malfunction, and systemic bacterial (e.g., after gynecologic surgery, cholecystectomy, appendectomy, and fungal superinfections. Invasion of the GI tract by CMV may lumbosacral fusion, splenectomy, and transplantation). It has also cause gastritis and ulcers in both the duodenum and the colon, which been found in surgical patients who are victims of trauma or burns. in turn may lead to hemorrhage and perforation. Biopsies demon- However, it is surprising that infection with CMV, a ubiquitous strate CMV inclusions at the base of the ulcers.The virus appears to virus, does not occur more frequently after transfusion. Between 30% invade the vascular endothelium, and bleeding is possibly a result of and 54% of the adult population in the United States have antibody vascular occlusion and ischemic necrosis of the overlying tissue. to CMV, an indication of previous infection.89 Because infection with Lethal CMV disease is characterized by the presence of most of the virus is probably lifelong, a significant proportion of blood donors the features listed above. Liver dysfunction is found in 100% of harbor the virus.The prevalence of antibody to CMV is 25% in units patients with lethal disease but in only 50% to 75% of patients with of blood from donors between 18 and 23 years of age and increases mild or moderate infection, and CMV viremia occurs in 46% to to 89% in blood from donors older than 60 years.The overall preva- 48% of patients with severe CMV infection but in only 26% to lence of seropositive blood donors is between 30% and 70%. 28% of patients with mild to moderate infection. Leukopenia and the presence of atypical leukocytes also correlate with the severity Cytomegalovirus in Transplant Recipients of the disease. CMV infection after renal transplantation is also CMV infection occurs not only in patients who have received associated with pneumonia, hepatitis, encephalitis, and retinitis. blood transfusions but also in those who have suffered trauma, those Whether or not CMV infection causes or leads to graft rejec- receiving immunosuppressive therapy, and those with neoplastic dis- tion is uncertain. Both the highest incidence of CMV infection ease.The groups at highest risk for CMV infection are probably re- (> 80%)89,109,110 and the highest incidence of graft rejection occur cipients of organ transplants and of bone marrow transplants.106-108 within the first 3 months after transplantation. In several studies, Numerous studies have documented the high incidence of CMV in- young patients and recipients of second kidney transplants were at fection after organ transplantation: the rates range from 26% to higher risk for graft loss if they had CMV than if they did not.89,109,110 100%.89,109,110 Primary CMV infection occurs in patients who do not In most studies, however, it is extremely difficult to demonstrate a have antibody to CMV before receiving transplants. Infections are relation between CMV infection and graft rejection. considered to be reactivated if they occur in patients who did have an- Of the multiple factors affecting the risk of CMV infection in tibody to CMV before receiving transplants. Rates of infection in pa- transplant recipients, the most important are (1) the familial relation tients receiving cardiac or bone marrow transplants are similar to and HLA matching between the kidney donor and the recipient those in patients receiving kidney transplants. and (2) the CMV serology of both the donor and the recipient.The The high incidence of CMV infections after transplantation was presence of antibody in transplant recipients before transplantation recognized in the early days of such procedures. At autopsy of pa- seems to offer a small amount of protection against fever caused by tients who died after renal transplantation, the intranuclear inclu- CMV but does not protect against more serious consequences of sions typical of CMV were found in tissue from the lungs, the parotid the infection, such as leukopenia, graft failure, and death. glands, the lymph nodes, the liver, the pancreas, the parathyroid, and CMV infection is also a major problem in liver, heart, and bone the brain. CMV has been cultured repeatedly from the urine of marrow transplant recipients.106,108 In liver transplant recipients, transplant recipients, and the frequency of seroconversion among CMV is a cause of hepatitis and liver dysfunction that can be con- them has been high. fused with rejection or other causes of liver malfunction,106 and it Likely sources of the virus are blood, because fresh blood can can lead to lethal infection. CMV pneumonitis in bone marrow transmit CMV, and the organ transplant itself, because CMV can transplant recipients is the most common life-threatening infectious grow in renal tubular epithelial cells and can be transmitted as a la- complication after transplantation.The severity of infection in bone tent virus. In several studies, recipients of kidney transplants had a marrow transplant recipients may be attributable to the higher inci- much higher incidence of CMV infection when the donors had anti- dence of host versus graft disease in patients with CMV pneumoni- body to CMV than when the donors did not. In one study, 57% of tis (82%) than in those without CMV pneumonitis (27%).112 recipients of kidneys from seropositive donors acquired CMV infec- tion after transplantation, compared with 8% of recipients of kidneys Prevention and Treatment of Cytomegalovirus Infection from seronegative donors.111 Even patients who have antibody to Several methods have been proposed to reduce the incidence of CMV can acquire new CMV infections as a result of transfusion or CMV infection after transfusion or transplantation. One method transplantation because there is more than one antigenic variety of is to eliminate as many white blood cells as possible from trans- the virus. Also, CMV that is latent in many patients who have anti- fused blood because CMV is almost certainly transmitted solely body before transplantation may be reactivated after transplantation through these cells. From 90% to 100% of viable leukocytes in by host versus graft reactions, corticosteroids, or other immunosup- blood have been removed from frozen deglycerolized erythro- pressive drugs. Hospital personnel, family members, and the envi- cytes. In one study, transfusion of 24 hemodialyzed patients with ronment play very small roles in transmission of CMV to transplant leukocyte-free red blood cells from frozen deglycerolized blood recipients. prevented subsequent CMV infection.104
  • 19. © 2002 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 20 VIRAL INFECTION — 19 Another approach is to transfuse blood only from CMV-nega- 2 weeks after transfusion.These elevations indicate either reinfection tive donors. Because the majority of posttransfusion CMV infec- or reactivation of a latent infection.89 Because EBV is associated with tions are asymptomatic, however, the increased cost of performing cells and does not exist free in serum to any great extent, antibody to serologic tests on all donated units might be difficult to justify. EBV in either donors or recipients is unlikely to provide substantial Storage of blood to reduce infectiousness of CMV is another protection against infection resulting from blood transfusions or or- approach, but storage from 48 to 72 hours does not significantly gan transplants. Among transfused patients who do not have preex- reduce transmission of CMV infection. Irradiating the blood to isting antibody to EBV, the prevalence of EBV infection can reach render the CMV noninfectious is unacceptable because it causes 33% to 46%. In these patients, the absence of preexisting antibody cell transformation in vitro. Furthermore, in one study, adminis- presumably rules out reactivation of latent EBV infection as the tration of leukocytes previously exposed to 1,500 cGy (1,500 source of infection. rads) of gamma radiation resulted in an increased incidence of EBV occurs worldwide. In the United States, nearly all adults CMV infection among recipients of these cells.102 and as many as 65% of persons of all ages have antibody to EBV. Because the incidence of CMV infection is higher in patients Infection is thought to occur in infancy, and as many as 17% of who receive kidney transplants from seropositive donors, some infants have antibody to EBV. By 5 years of age, 72% of children centers do not transplant kidneys from seropositive donors into have antibody to EBV, and the prevalence in adults is similar.122 seronegative recipients. However, no published reports indicate Thus, the majority of blood donors in the United States have been that this practice leads to a significant alteration in the outcome of previously infected with EBV and probably have latent virus in renal transplantation with respect to graft rejection. Moreover, their leukocytes. Although it is clear that EBV can be transmitted excluding kidneys from seropositive donors makes it more diffi- by blood when the transfusion occurs within 3 days of donation, cult to find kidneys for seronegative recipients. it is not known whether blood stored for longer periods can trans- Many attempts have been made to develop a CMV vaccine for mit the virus. Because EBV is predominantly intracellular, plasma administration before viral exposure by multiple passages of the and its derivatives do not transmit the virus. virus in tissue culture.Two such vaccines have been used in clini- The diagnosis of EBV infection is made serologically.Tests both cal trials, one prepared from the AD169 strain and the other from for IgM antibody to capsid antigens and for IgG antibody to the the Towne 125 strain of the virus. Immunization with these vac- early antigens of EBV or tests of serial samples for IgG antibody to cines can elicit both serum antibody and cell-mediated immunity. capsid antigens must be used. The heterophil antibody test (the In one trial, the vaccine prepared from the Towne 125 strain low- Paul-Bunnell test) and a rapid slide test that is equivalent (the ered the incidence of clinical disease but not of infection, and the monospot test) are also used in most clinical studies to screen for disease tended to be less severe in vaccinated patients than in con- EBV infection before more specific diagnostic tests are performed. trol subjects who received placebo.113 In cases of posttransfusion infection, IgG antibody to EBV can Human IG has been administered after transfusion or trans- be detected at least 10 days before the onset of symptoms, and EBV plantation in attempts to prevent associated CMV infection. In can be cultured from circulating lymphocytes 11 days before the on- one study, it reduced life-threatening infection to a less severe set of symptoms. In patients with acute infection, EBV is found in form in most patients, but in other studies, not surprisingly, it pro- approximately three of every 104 peripheral blood lymphocytes.123 vided no consistent benefit.114-117 In patients who are already In contrast, all recovered persons with antibodies to EBV are thought seropositive, the virus is latent inside their cells, where it is proba- to have the virus in one of every 107 circulating lymphocytes. bly not accessible to serum antibody. Patients with primary infec- EBV is strongly implicated in the etiology of a posttransplanta- tions may not benefit from antibody treatment, because her- tion lymphoproliferative disorder (PTLD).89,124,125 EBV has been pesviruses seem to transfer from cell to cell without ever existing isolated from the tissues of most cases of PTLD, but not all.126,127 free in serum. Even CMV hyperimmune globulin has no clear Non–EBV-related cases of PTLD typically occur later after trans- benefit in patients with clinical CMV infection.118 It may, howev- plantation, and their etiology has not been elucidated. er, help control severe infections, such as those seen in bone mar- PTLD comprises three general clinical presentations: (1) a mono- row transplant recipients. nucleosis-like syndrome involving the tonsils and the peripheral Several antiviral agents have been used in attempts to reduce the lymph nodes, (2) a diffuse polymorphous B-cell infiltration in many incidence or lessen the effect of CMV infection. Among these visceral organs, and (3) localized extranodal tumors in the GI tract, agents are interferon, transfer factor, immune globulin, and nucle- the neck, the thorax, or other parts of the body. Patients whose dis- oside derivatives, such as cytarabine, vidarabine, and acyclovir (see ease is limited to a single organ or to lymph nodes often respond to below). Immune globulins, acyclovir, and ganciclovir are effective a reduction in immunosuppression or antiviral therapy; however, at preventing CMV infection in transplant recipients.109,110,114,119,120 once the infection becomes widespread, the disease progresses rap- Ganciclovir and foscarnet are active against CMV in vitro. Ganci- idly and is fatal in more than 75% of cases.128 In solid organ trans- clovir is currently being used to treat CMV and is the most effec- plant recipients, PTLD may be limited to the allograft. There is tive agent in organ transplant recipients (see below).109,110,119-121 some evidence to suggest that PTLD may have organ-specific fea- tures that promote lymphoproliferation: allograft involvement has EPSTEIN-BARR VIRUS been reported in 17% of renal transplant recipients, 8.6% of liver EBV is the herpesvirus responsible for infectious mononucleosis. transplant recipients, and as many as 60% to 80% of lung or intesti- It can be found in B cells in peripheral blood of infected patients and nal transplant recipients.128 in tumor cells of patients with Burkitt lymphoma and nasopharyn- The persons at highest risk for PTLD are EBV-seronegative per- geal carcinoma. It remains in a latent form in an infected host for sons receiving EBV-positive organs or bone marrow. Most infec- years, probably for life. Most posttransfusion EBV infections are tions occur within the first 4 months after transplantation.129 Several asymptomatic. Seroconversion to EBV will develop in approximate- specific risk factors for the development of PTLD have been identi- ly 8% of recipients transfused with between two and 14 units of fied: a seropositive graft in a seronegative recipient, certain types of blood. In as many as 5% of patients with preexisting antibody to organ allografts (with intestinal transplants carrying the highest EBV, significant elevations of antibody titers may develop, beginning risk), any type of immunosuppression that blunts cellular immuni-
  • 20. © 2002 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 20 VIRAL INFECTION — 20 ty to EBV (with risk increasing as immunosuppression becomes been identified and specifically targeted for chemotherapeutic at- more pronounced), and the presence of other infections (CMV in tack, very few agents have been effective against human viruses. particular). Among these is amantadine, which is used for both prophylaxis The optimal treatment of lymphoproliferative disorders remains and treatment of influenza A. Agents that were found to be effec- unclear. Some early EBV-associated lymphoproliferative disorders tive for prophylaxis against smallpox, such as methisazone, now in solid organ transplant recipients have regressed completely after have no use, because the disease has been eradicated. reduction of immunosuppression.130,131 Early PTLD may respond There are few effective chemotherapeutic agents for hepati- to antiviral therapy with acyclovir or ganciclovir, which may pre- tis or most of the other major viral diseases that concern surgeons, vent infection of resting B cells, but such therapy is less likely to be but several agents have been used for the treatment of herpes- effective in the face of high concentrations of latently infected cir- virus infections, especially in immunosuppressed patients [see culating or tissue-invasive B cells. Some investigators also report Table 10]. These agents, derivatives of purines and pyrimidines, resolution of PTLD after treatment with interferon alfa.132,133 interfere with viral nucleic acid synthesis. Transmission of EBV can occur simultaneously with transmis- sion of CMV or hepatitis virus. Although hepatitis accompanies Acyclovir and Valacyclovir EBV infections in sporadic cases, EBV alone has not been docu- Acyclovir (acycloguanosine) is a nucleoside derivative that is mented as a cause of posttransfusion hepatitis. used to treat herpesvirus infections, especially herpes simplex and varicella-zoster infections in immunocompromised hosts. HERPES SIMPLEX VIRUS Valacyclovir is the L-valyl ester prodrug of acyclovir. In cases of Infection or reactivation of infection with herpes simplex virus mucocutaneous herpes simplex and herpes zoster, acyclovir can type 1 (HSV-1) follows renal transplantation in 50% to 75% of shorten the period of virus shedding, decrease pain, and promote patients, most often within 30 days after transplantation. Reacti- more rapid scabbing and healing of lesions. Acyclovir is also the vation of infection is more common than primary infection: only drug of choice for encephalitis caused by herpes simplex, but it 14% of patients who are seronegative before transplantation is not effective in patients with established neurologic damage become infected, but infection is reactivated in 64% of patients resulting from herpes simplex or varicella-zoster infections or who were already seropositive before transplantation. in patients infected with CMV. Acyclovir inhibits the replication Most cases of HSV-1 infection after transplantation are clinical- of EBV in actively replicating cells but does not affect latent or ly inapparent and are indicated only by a significant rise in titer of persistent infection. antibody to the virus.The most prevalent clinical manifestation is The total daily dose of acyclovir is 10 to 25 mg/kg, given by I.V. herpes labialis, that is, fever blisters affecting not only the lips but infusion lasting 60 minutes. The recommended length of par- also the mucous membranes of the oral cavity and the skin of the enteral acyclovir therapy ranges from 5 to 10 days, depending on head and neck. Although these lesions are painful and may make the indication. A major side effect of such therapy is phlebitis at eating, drinking, and taking oral medications difficult, they are usu- the injection site; rash, leukopenia, and neurotoxicity may also ally self-limited and heal without treatment or reduction of immu- occur. Acyclovir applied topically as a 5% ointment is effective in nosuppression. However, HSV-1 infection can take a much more immunocompromised patients for the treatment of limited cuta- malignant course, disseminating to cause pneumonitis, fulminant neous herpes infections and in patients with normal immunity for hepatitis, upper GI hemorrhage, encephalitis, aseptic meningitis, the treatment of initial episodes (but not recurrent episodes) of and death. genital herpes simplex infection. Oral acyclovir seems to be effec- tive as prophylaxis against reactivated herpes simplex infection in VARICELLA-ZOSTER VIRUS recipients of bone marrow transplants and in patients immuno- Varicella-zoster virus (VZV), another herpesvirus, is the etio- suppressed as a result of HIV infection. logic agent of herpes zoster and chicken pox.This virus resides in the dorsal root ganglia of adults who had primary varicella infec- Penciclovir and Famciclovir tion in childhood. Herpes zoster is more common in organ trans- Penciclovir is a nucleoside analogue that is similar to acyclovir plant recipients, in patients with cancer (especially those who have with respect to spectrum of activity and potency against herpes- leukemia or lymphomas), in burn patients, and in patients receiv- viruses. Famciclovir is the diacetyl ester of penciclovir. Penciclovir ing immunosuppressive drugs. Serologic evidence of VZV infec- requires thymidine kinase (TK) for phosphorylation and thus is tion occurs in 8% to 16% of renal transplant recipients. The le- inactive against thymidine kinase–deficient strains of HSV or VZV; sions of herpes zoster become evident 12 to 511 days after organ however, it may be active against some TK-altered or polymerase transplantation. mutants that are resistant to acyclovir as well as against some fos- In children or adults who have not already had chicken pox and carnet-resistant HSV isolates. In experimental settings, topical, pa- occasionally even in children who have, VZV can cause dissemi- renteral, and oral penciclovir and oral famciclovir have been effec- nated chicken pox in many organs, which may be fatal. tive against HSV infection. AGENTS EFFECTIVE AGAINST HERPESVIRUSES Vidarabine Because the essential synthetic activities of viruses depend on Vidarabine (ara-A) is effective against herpes simplex and vari- the metabolic machinery of their host, it has been difficult to cella-zoster viruses as well as poxviruses, oncornaviruses, and devise specific antiviral agents that interfere with viral replication rhabdoviruses. It is used mostly to combat herpesvirus infections but are not harmful to host cells.134,135 Many antiviral agents are in immunosuppressed patients. In these patients, vidarabine accel- too toxic to be used clinically. In contrast, antibacterial agents that erates healing of cutaneous herpes zoster, decreases its rates of are both toxic to bacteria and safe for human cells are easier to cutaneous dissemination and of visceral complications, and short- design because the structure and metabolic machinery of bacteria ens the duration of postherpetic neuralgia. For systemic use, a are distinct from those of host cells. daily dose of 10 to 15 mg/kg of vidarabine is administered I.V. over Although intracellular processes unique to viral replication have a period of 12 hours. The duration of therapy for herpes zoster is
  • 21. © 2002 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 20 VIRAL INFECTION — 21 Table 10 Antiviral Therapy of Clinical Benefit Virus Condition Regimen Keratitis 3% Acyclovir ointment or 1% Trifluridine solution or 3% Vidarabine ointment or 0.5% IDU ointment or 0.1% IDU drops Treatment usually not indicated; may use 1% penciclovir cream Herpes labialis or topical acyclovir q. 2 hr while patient is awake for 4 days Genital herpes Primary Acyclovir, 200 mg p.o. 5 times daily or 400 mg p.o., t.i.d., for 10 days, or Valacyclovir, 500 mg–1 g p.o., b.i.d., for 10 –14 days, or Famciclovir, 250 mg p.o., t.i.d., for 10 days* Herpes simplex Recurrent Acyclovir, 200 mg p.o. 5 times daily or 400 mg p.o., t.i.d., for virus 5 days, or Valacyclovir, 500 mg p.o., b.i.d., for 5 days, or Famciclovir, 125 mg p.o., b.i.d., for 5 days Prophylaxis Acyclovir, 400 mg p.o., b.i.d., or Valacyclovir, 500 mg–1 g p.o., q.d., or Famciclovir, 250 mg p.o., b.i.d. Encephalitis Acyclovir,10 mg/kg t.i.d. I.V. for 14–21 days Acyclovir, 10 mg/kg I.V. q. 8 hr for 10–21 days (20 mg/kg Neonatal HSV I.V. q. 8 hr if neonate is premature) Immunocompromised host Acyclovir, 5 mg/kg I.V. q. 8 hr for 7 days or 400 mg p.o. 5 times daily for 14–21 days, or Famciclovir, 500 mg p.o., b.i.d., for 7 days,* or Valacyclovir, 1 g p.o., t.i.d., for 7 days* Immunocompetent host Eye infections 3% Acyclovir ointment Shingles Acyclovir, 800 mg p.o. 5 times daily for 7–10 days, or Varicella-zoster virus Valacyclovir, 1 g p.o., t.i.d., for 7–10 days, or Famciclovir, 500 mg p.o., t.i.d., for 7–10 days Immunocompromised host Acyclovir, 10–12 mg/kg I.V. q. 8 hr for 7 days (500 mg/m2 ) Immunocompromised host Retinitis Ganciclovir, 5 mg/kg I.V. q. 12 hr for 14–21 days,† or Cytomegalovirus Foscarnet, 90 mg/kg (adjusted for renal function) I.V. q. 12 hr for 14–21 days, or Cidofovir, 5 mg/kg I.V. weekly for 2 weeks, then every other week CMV pneumonia Ganciclovir, 2.5 mg/kg I.V. q.d. for 20 days * Not approved by the FDA for this indication. † An intraocular insert is also available. Ganciclovir 5 days. Side effects include anorexia, weight loss, nausea, vomit- ing, weakness, anemia, leukopenia, thrombocytopenia, tremors, Ganciclovir (DHPG, 2′-NDG, or BIOLF-62) is an acyclic and thrombophlebitis at the site of administration. nucleoside structurally related to acyclovir but with greater activity against CMV in vitro and in vivo. It is effective in treating CMV Idoxuridine disease in transplant recipients and AIDS patients.The usual total Idoxuridine (5-iodo-2′-deoxyuridine) (IUdR, IDU) was the first daily dose of ganciclovir is 7.5 to 10 mg/kg, given in two or three clinically effective antiviral nucleoside. It is a halogenated pyrimi- divided doses. The dosage should be adjusted if the patient has dine that resembles thymidine in structure. Topical application of decreased renal function. Myelosuppression is the principal dose- either a 0.1% solution or a 0.5% ointment of idoxuridine is effec- limiting toxic side effect. tive treatment of herpes simplex keratitis but not of recurrent her- pes labialis or localized zoster. In the United States, IDU is approved Foscarnet only for topical treatment of HSV keratitis. When combined with Foscarnet (trisodium phosphonoformate) is a pyrophosphate de- dimethyl sulfoxide (DMSO), IDU is active against herpes zoster rivative that inhibits herpesvirus DNA polymerases and retroviral re- and recurrent or primary genital HSV infection. In Europe, IDU verse transcriptases.134-136 In the United States, it has been used for is available in combination with DMSO for the treatment of her- the prevention and treatment of CMV retinitis in patients with AIDS. pes labialis, herpes genitalis, and herpes zoster. For patients who have received renal or bone marrow transplants,
  • 22. © 2002 WebMD Inc. All rights reserved. ACS Surgery: Principles and Practice 8 CRITICAL CARE 20 VIRAL INFECTION — 22 foscarnet is given in a bolus injection of 9 mg/kg followed by infusion wild animals.69 Before 1950, more than 8,000 cases of rabies in of 0.015 to 0.090 mg/kg/min I.V. for 7 days. Foscarnet is also used to dogs were reported each year in the United States; the number is treat acyclovir-resistant HSV infection.The major toxicity associated now fewer than 150 a year. with foscarnet is nephrotoxicity; CNS side effects (e.g., headache, Rabies proceeds from a prodrome of fever, malaise, and head- tremor, irritability, and seizures) can also occur. ache, to hyperactivity and diffuse cerebral dysfunction, and then to coma and death. From 5% to 20% of patients may also show pro- gressive paralysis. Occasionally, there is no history of an animal bite. Viral Infections from Animal and Human Bites Diagnosis can be confirmed by culture of saliva, cerebrospinal flu- Surgeons are frequently called on to treat patients who have id, or brain tissue; demonstration of rabies antigen in the cornea or been bitten by either an animal or another person. Such bites can skin; or measurement of serum antibody to rabies virus. At post- transmit several viruses and other infections. Certainly, rabies is mortem examination, typical intracytoplasmic inclusions (Negri the most feared viral infection transmitted in this way. Viruses bodies) can be seen in the brain cells. that are found in saliva, such as HBV, herpesviruses, and possibly Although the number of cases of human rabies is small, the HIV, can be transmitted by a human bite, although such cases disease is an important problem because of the large number of are most likely rare. animal bites that occur each year. Surgeons may have to consider From zero to five cases of human rabies occur each year in the rabies prophylaxis in patients whom they treat for bite injuries United States. Animal rabies is widespread and is found in every [see Management of Viral Exposure, Rabies, above, and 1:7 Acute state except Hawaii. In 1992, more than 8,600 cases of animal Wound Care]. Also, two fatal cases of rabies have occurred in re- rabies were reported to the CDC by 49 states, the District of Co- cipients of corneal transplants from a patient whose cause of lumbia, and Puerto Rico. The great majority of cases occur in death was later found to be rabies.137 References 1. Recommendations for prevention of HIV transmis- tions transmitted by blood and blood products. Prin- lated to previous operations and dental treatment. Br sion in health-care settings. MMWR Morb Mortal ciples and Practice of Infectious Disease, 5th ed. J Med 293:33, 1986 Wkly Rep 36(suppl 2):1S, 1987 Mandell GL, Bennet JE, Dolin R, Eds. 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