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“The only thing necessary for these diseases to the triumph is for good people and governments to do nothing.”


   


 

20 Viral Infections

Jennifer W. Janelle, M.D.

Clinical Professor of Medicine, Division of Infectious Diseases, Department of Medicine
University of Florida College of Medicine

Richard J. Howard, M.D., Ph.D., F.A.C.S.

Robert H. and Kathleen M. Axline Professor of Surgery, Division of General Surgery and Transplantation, Department of Surgery
University of Florida College of Medicine


Approach to Viral Exposure

Compared with primary care physicians, such as internists, family physicians, and pediatricians, surgeons are seldom called on to treat viral infections. Viral infections nonetheless deserve the attention of surgeons because these infections can cause illness in patients after operation, albeit infrequently, and can spread to the hospital staff. Some viral infections (e.g., infections with the hepatitis viruses, HIV, and cytomegalovirus [CMV]) can result from administration of blood or blood products or can be transmitted to hospital personnel through needle-stick injury. Viral infections can also result from organ transplantation or trauma (e.g., rabies, which is transmitted by the bite of an infected animal). Some viruses, especially the herpesviruses, frequently infect immunosuppressed patients, in whom the viruses can cause severe illness and even death. In many surgical practices, there are increasing numbers of immunosuppressed patients, including organ transplant recipients; patients with cancer; patients receiving cancer chemotherapy, steroids, and other immunosuppressive drugs; the elderly; and the malnourished. Some viral infections can cause neoplastic disease for which operation may become necessary. Examples are hepatitis B virus (HBV) and hepatitis C virus (HCV), which are implicated in the etiology of hepatocellular carcinoma; Epstein-Barr virus (EBV), which can cause a lethal lymphoproliferative disorder in immunosuppressed patients; and human T cell lymphotropic virus type I (HTLV-I), which can induce a T cell leukemia. Viral infections very likely can cause other neoplasms as well.

Prevention of Transmission of HIV, Hepatitis B Virus, and Hepatitis C Virus

 

Transmission from Patients to Health Care Workers

The Centers for Disease Control and Prevention (CDC) has published extensive recommendations for preventing transmission of HIV, the etiologic agent of AIDS.1–5 Applicable to clinical and laboratory staffs,3,4 to workers in health care settings [see Table 1]1

Table 1 - Precautions to Prevent Transmission of HIV1

Universal Precautions

1.       All health care workers should use appropriate barrier precautions routinely to prevent skin and mucous membrane exposure when contact with blood or other body fluids of any patient is anticipated. Gloves should be worn for touching blood and body fluids, mucous membranes, or nonintact skin of all patients; for handling items or surfaces soiled with blood or body fluids; and for performing venipuncture and other vascular-access procedures. Gloves should be changed after contact with each patient. During procedures that are likely to generate aerosolized droplets of blood or other body fluids, masks and protective eyewear or face shields should be worn to prevent exposure of mucous membranes of the mouth, nose, and eyes. Gowns or aprons should be worn during procedures that are likely to generate splashes of blood or other body fluids.

2.       Hands and other skin surfaces should be washed immediately and thoroughly if contaminated with blood or other body fluids. Hands should be washed immediately after gloves are removed.

3.       All health care workers should take precautions to prevent injuries caused by needles, scalpels, and other sharp instruments or devices during procedures; when cleaning used instruments; during disposal of used needles; and when handling sharp instruments after procedures. To prevent needle-stick injuries, needles should not be recapped, purposely bent or broken by hand, removed from disposable syringes, or otherwise manipulated by hand. After they are used, disposable syringes and needles, scalpel blades, and other sharp items should be placed in puncture-resistant containers for disposal; the puncture-resistant containers should be located as close as practical to the area of use. Large-bore reusable needles should be placed in a puncture-resistant container for transport to the reprocessing area.

4.       Although saliva has not been implicated in HIV transmission, to minimize the need for emergency mouth-to-mouth resuscitation, mouthpieces, resuscitation bags, or other ventilation devices should be available for use in areas in which the need for resuscitation is predictable.

5.       Health care workers who have exudative lesions or weeping dermatitis should refrain from all direct patient care and from handling patient care equipment until the condition resolves.

6.       Pregnant health care workers are not known to be at greater risk for contracting HIV infection than health care workers who are not pregnant; however, if a health care worker acquires HIV infection during pregnancy, the infant is at risk for infection resulting from perinatal transmission. Because of this risk, pregnant health care workers should be especially familiar with and strictly adhere to precautions to minimize the risk of HIV transmission.

Additional Precautions for Invasive Procedures

1.       All health care workers who participate in invasive procedures must use appropriate barrier precautions routinely to prevent skin and mucous membrane contact with blood and other body fluids of all patients. Gloves and surgical masks must be worn for all invasive procedures. Protective eye-wear or face shields should be worn for procedures that commonly result in the generation of aerosolized droplets, splashing of blood or other body fluids, or the generation of bone chips. Gowns or aprons made of materials that provide an effective barrier should be worn during invasive procedures that are likely to result in the splashing of blood or other body fluids. All health care workers who perform or assist in vaginal or cesarean deliveries should wear gloves and gowns when handling the placenta or the infant until blood and amniotic fluid have been removed from the infant's skin and should wear gloves during postdelivery care of the umbilical cord.

2.       If a glove is torn or a needle-stick or other injury occurs, the glove should 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 from the sterile field. In the event of an injury, postexposure evaluation should be sought as soon as possible.

 

 and in other occupational settings,1 and to health care workers performing invasive procedures,1–5 these precautions are appropriate for preventing transmission not only of HIV but also of other blood-borne viruses, including HBV and HCV. The recommendations share the objective of minimizing exposure of personnel to blood and body secretions from infected patients, whether through needle-stick injury or through contamination of mucous membranes or open cuts.

Despite the apparently low risk of such exposure, the CDC recommends enforcement of these as well as other standard infection control precautions, regardless of whether health care workers or patients are known to be infected with HIV or HBV. The CDC has taken the position that blood and body fluid precautions should be used consistently for all patients because medical history and physical examination cannot reliably identify all patients infected with HIV or other blood-borne pathogens and because in emergencies there may be no time for serologic testing. If these universal precautions are implemented, as the CDC recommends,1–5 no additional precautions should be necessary for patients known to be infected with HIV.

The CDC does not recommend routine HIV serologic testing for all patients.1–5 HIV serologic testing of patients is recommended for management of health care workers who sustain parenteral or mucous membrane exposure to blood or other body fluids, for patient diagnosis and treatment, and for counseling associated with efforts to prevent and control HIV transmission in the community.1–5

Nevertheless, some hospitals and physicians are likely to perform serologic testing of patients if it is possible that health care workers will be exposed to the patients' blood or other body fluids, as would be the case with patients undergoing major operative procedures or receiving treatment in intensive care units. Those who favor routine preoperative testing of patients undergoing invasive procedures maintain that precautions are more likely to be followed and additional steps taken to lower the likelihood of virus transmission from patients to health care workers when it is known which patients are HIV positive.6,7 If such policies are adopted, the CDC advocates certain principles: (1) obtain consent for testing, (2) inform patients of results and provide counseling to seropositive patients, (3) ensure confidentiality, (4) ensure that seropositive patients will not receive compromised care, and (5) prospectively evaluate the efficacy of the program in reducing the incidence of exposure of health care workers to blood or body fluids of patients who are infected with HIV.

Although possible acquisition of HIV infection is the major concern for any health care worker who is exposed to blood products in the workplace, acquisition of viral hepatitis is actually much more likely. From a single needle-stick exposure, the estimated average risk of HIV transmission is 0.3%, whereas that of HCV transmission ranges from 0% to 10%.8 The risk that HBV will be transmitted from a single needle-stick exposure varies according to the hepatitis B e antigen (HBeAg) status of the source patient, ranging from 1% to 6% for HBeAg-negative patients to 22% to 40% for HBeAg-positive patients.9–11 That health care workers are at increased risk for hepatitis B is indicated by the seroprevalence of HBV in this population, which is two to four times that in the general United States population (6% to 15% versus < 5%).9,12 This seroprevalence is expected to decrease with the availability of the hepatitis B vaccine and the mandate from the Occupational Safety & Health Administration (OSHA) directing that all health care workers potentially exposed to blood or other potentially infectious material either be offered hepatitis B vaccine free of charge, demonstrate immunity to hepatitis B, or formally decline vaccination.13 That vaccination has been effective in decreasing the incidence of hepatitis B in health care workers is shown by the decrease in infection rates from 174/100,000 in 1982 to 17/100,000 in 1995.14 Most series have not found the seroprevalence of HCV to be higher in health care worker groups at risk than in the general population.14 That hepatitis B and hepatitis C are much more common than HIV in health care workers is a strong argument for using universal precautions in all patients.

One reason why hepatitis B is so much more transmissible than HIV is the greater number of virus particles in the blood of hepatitis B carriers. These persons have blood concentrations of 108 to 109 virus particles/ml, compared with 102 to 104/ml for persons with HIV infection and 106/ml for persons with HCV infection.

The extensive guidelines that have been established by the CDC for the care of patients with HBV infection4,15–17 also apply to patients with HIV infection. Patients known to have hepatitis B, hepatitis C, or AIDS need not be put in a private room unless they are fecally incontinent or are shedding virus in body fluids. Health care workers should wear gloves and gowns when they have contact with or may have contact with a patient's blood, feces, or other body fluids. Needles used for drawing blood should be disposed of with special care: they must not be reused, recapped, or removed from the syringe. Hands must be washed before and after direct contact with the patient or with items that have been in contact with the patient's blood, feces, or body fluids.

Published recommendations also provide guidelines for health care workers who are not directly involved in patient care (e.g., housekeeping personnel, kitchen staff, and laundry workers).1–7 No additional precautions are necessary for these individuals because their risk of acquiring HIV, HCV, or HBV is so low; in fact, transmission to them has not been documented. However, staff should be educated about appropriate procedures. Workers should wear gloves when handling blood and body fluids of all patients and should wear masks in areas where blood may spatter (e.g., the dialysis unit or the obstetrics unit).

Transmission from Health Care Workers to Patients

To date, there have been only two reports of HIV transmission from infected health care workers to patients. In one report, DNA sequence analysis linked a Florida dentist with AIDS to HIV infection in six of his patients.18 In the other, an orthopedic surgeon in France may have transmitted HIV to one of his patients in the course of an operation.19 Despite extensive investigation, no break in infection control precautions was documented in either case, nor was any clear-cut means of transmission identified.

HBV transmission from health care workers to patients is known to occur. Nineteen case reports have documented physician-to-patient transmission.20–32 Eighteen of the 19 physicians were surgeons; seven of the surgeons were gynecologists, three were cardiac surgeons, and one was an orthopedic surgeon. All of the physicians were positive for HBeAg. Three of the gynecologists made a practice of handling needle tips. Of the 135 patients studied, 121 had clinical hepatitis B, and 14 had only serologic evidence of infection. Forty-one of the 135 patients were accounted for by the only nonsurgeon, a family practitioner from rural Switzerland. There are many additional cases of HBV having been transmitted by dentists and oral surgeons. In addition, three patients' relatives, two members of a surgeon's family, and one laboratory technician became infected.

In five studies, patients of 16 health care workers (including two surgeons) who were positive for hepatitis B surface antigen (HBsAg) were prospectively followed for evidence of hepatitis.33–37 A total of 784 patients were followed and were compared with 656 patients cared for by health care workers who were HBsAg negative. None of the patients acquired overt hepatitis or became seropositive for HBsAg. Eight (1.02%) of the 784 patients cared for by HBsAg-positive health care workers developed antibody to HBsAg (anti-HBs), but so did six (0.91%) of the 656 patients cared for by health care workers who were negative for HBsAg. These reports suggest that the likelihood of infected surgeons' or other health care workers' transmitting HIV or HBV to their patients is extremely low. Chronic carriers of HBsAg who are seronegative for HBeAg are much less likely to transmit HBV than persons who are HBeAg positive.

  


 

Before the cases of transmission of HIV from the dentist to six of his patients were reported, the CDC had not taken a position on whether HBV- or HIV-infected surgeons should be allowed to continue practicing medicine. After these cases were reported, the CDC held meetings of health care professionals and other interested parties and published its recommendations on July 12, 1991.38 These recommendations called for physicians not to perform 'exposure-prone invasive procedures' unless they sought counsel from an expert review panel and were advised under what circumstances, if any, they might be allowed to continue to perform these procedures. Physicians would have to notify prospective patients of their seropositivity. These recommendations were strongly resisted by the medical community because at that time, only one health care worker, the dentist, had been implicated in transmitting HIV to his patients, no mechanism of transmission had been elucidated, no other patients had HIV transmitted by a health care worker, and invasive procedures that were 'exposure prone' (exposing the patient to blood of the health care worker) were impossible to define. After subsequent meetings, the CDC abandoned its attempts to define exposure-prone procedures but did not alter its recommendations. Rather, it left it up to the states to define exposure-prone procedures. Subsequently, the President's Commission on AIDS recommended that HIV-infected health care workers should not have to curtail their practices or inform their patients of their infection.

Transmission of HCV from health care workers to patients has been reported. In one such case, a cardiac surgeon transmitted HCV to at least five patients during valve replacement surgery.39 In another, an anesthesiologist in Spain may have infected more than 217 patients by first injecting himself with narcotics, then giving the remainder of the drugs to his patients.40 At present, no recommendations exist for restricting the professional activities of health care workers with HCV infection.

Management of Viral Exposure

HIV

The CDC has issued recommendations for the management of potential exposure of health care workers to HIV.1,4,41 If a health care worker is exposed by a needle stick or by a splash in the eye or mouth to any patient's blood or other body fluids, and the HIV serostatus of the patient is unknown, the patient should be informed of the incident and, if consent is obtained, tested for serologic evidence of HIV infection. If consent cannot be obtained, procedures for testing the patient should be followed in accordance with state and local laws. Testing of needles or other sharp instruments associated with exposure to HIV is not recommended, because it is unclear whether the test results would be reliable and how they should be interpreted.41

Health care workers exposed to HIV should be evaluated for susceptibility to blood-borne infection with baseline testing, including testing for HIV antibody. If the patient who is the source of exposure is seronegative and exhibits no clinical evidence of AIDS or symptoms of HIV infection, further follow-up of the health care worker is usually unnecessary.41 If the source patient is seropositive or is seronegative but has engaged in high-risk behaviors, baseline and follow-up HIV-antibody testing of the health care worker at 6 weeks, 3 months, and 6 months after exposure should be considered.41 Seroconversion usually occurs within 6 to 12 weeks of exposure; infrequently, it occurs considerably later. Three cases of delayed HIV seroconversion among health care workers have been reported.42–44 In all three patients, an HIV antibody test yielded negative results at 6 months but positive results at some point during the following 1 to 7 months. In two cases, coinfection with HCV had occurred and took an unusually severe course. At present, it is unclear whether coinfection with these two viruses directly influences the timing or severity of either infection, but most experts recommend close monitoring for up to 1 year for health care workers exposed to both viruses in whom serologic evidence of HCV infection develops.

Treatment of the exposed health care worker should begin with careful washing of the exposure site with soap and water. Mucous membranes should be flushed with water. There is no evidence that either expressing fluid by squeezing the wound or applying antiseptics is beneficial, though antiseptics are not contraindicated. The use of caustic agents (e.g., bleach) is not recommended.

Any health care worker concerned about exposure to HIV should receive follow-up counseling regarding the risk of HIV transmission, postexposure testing, and medical evaluation, regardless of whether postexposure prophylaxis is given. HIV antibody testing should be performed at specified intervals for at least 6 months after the exposure (e.g., at 6 weeks, 3 months, and 6 months). The risk of HIV transmission is believed to depend on several factors: how much blood is involved in the exposure, whether the blood came from a source patient with terminal AIDS (thought to be attributable to the presence of large quantities of HIV), whether any host factors are present that might affect transmissibility (e.g., abnormal CD4 receptors for HIV), and whether the source patient carries any aggressive HIV viral mutants (e.g., syncytia-inducing strains). Factors indicating exposure to a large quantity of the source patient's blood (and thus a high risk of HIV transmission) include a device visibly contaminated with the patient's blood, a procedure that involved a needle placed directly in a vein or artery, and a deep injury.45

During the follow-up period, especially the first 6 to 12 weeks, exposed health care workers should follow the U.S. Public Health Service recommendations for preventing further transmission of HIV.1–4 These recommendations include refraining from blood, semen, or organ donation and either abstaining from sexual intercourse or using measures to prevent HIV transmission during intercourse.46

The circumstances of the exposure should be recorded in the worker's confidential medical record and should include the following:

1.       The date and time of the exposure.

2.       Details of the exposure, including (a) where and how the exposure occurred, (b) the type and amount of fluid or other material involved, and (c) the severity of the exposure (for a percutaneous exposure, this would include the depth of injury and whether fluid was injected; for a skin or mucous membrane exposure, it would include the extent and duration of contact and the condition of the skin-chapped, abraded, or intact).

3.       A description of the source of the exposure, including (if known) whether the source material contained HIV or other blood-borne pathogens, whether the source was HIV positive, the stages of any diseases present, whether the patient had previously received antiretroviral therapy, and the viral load.

4.       Details about counseling, postexposure management, and follow-up.41

The data currently available on primary HIV infection indicate that systemic infection does not occur immediately. There may be a brief window of opportunity during which postexposure antiretroviral therapy may modify viral replication. Findings from animal and human studies provide indirect evidence of the efficacy of antiretroviral drugs in postexposure prophylaxis. The majority of these studies included zidovudine (AZT); consequently, all postexposure prophylaxis regimens now in use include AZT. Combination treatment regimens using nucleoside reverse transcriptase inhibitors and protease inhibitors have proved effective. Accordingly, most experts now recommend dual therapy with two nucleosides (zidovudine and lamivudine) for low- to moderate-risk exposures. For high-risk exposures, most experts would add a protease inhibitor (usually either indinavir or nelfinavir) to the two nucleoside reverse transcriptase inhibitors. These medications should be started as soon as possible after the exposure (within hours rather than days) and should be continued for 4 weeks.

An important component of postexposure care is encouraging and facilitating compliance with the lengthy course of medication. Therefore, careful consideration must be given to the toxicity profiles of the antiretroviral agents chosen. All of these agents have been associated with side effects, include GI (e.g., nausea or diarrhea), hematologic, endocrine (e.g., diabetes), and urologic effects (e.g., nephrolithiasis with indinavir). According to some early data, 50% to 90% of health care workers receiving combination regimens for postexposure prophylaxis (e.g., zidovudine plus 3TC, with or without a protease inhibitor) reported one or more subjective side effects that were substantial enough to cause 24% to 36% of the workers to discontinue postexposure prophylaxis.47–49

Whether antiretroviral agents should be chosen for postexposure prophylaxis on the basis of the resistance patterns of the source patient's HIV remains unclear. Transmission of resistant strains has been reported50–52; however, in the perinatal clinical trial that studied vertical transmission of HIV, zidovudine prevented perinatal transmission despite genotypic resistance of HIV to zidovudine in the mother.53 Further study of the significance of genotypic resistance is necessary before definitive recommendations can be made.

Hepatitis B

Both passive immunization with hepatitis B immune globulin (HBIG) and active immunization with hepatitis B vaccine (HB vaccine) are currently available for prophylaxis against hepatitis B [see Table 2].

Table 2 - Recommendations for Hepatitis B Prophylaxis after Percutaneous or Permucosal Exposure15

Hepatitis B Vaccination Status of Exposed Person

HBsAg Status of Source of Exposure

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

Known responder

If anti-HBs levels are adequate,* no treatment is needed; if they are inadequate, give an HB vaccine booster dose

No treatment is needed

No treatment is needed

Known nonresponder

No response to three-dose vaccine series: give two doses of HIBG or one dose of HBIG plus revaccination

If source is at high risk for hepatitis B infection, consider proceeding as if source had been demonstrated to be HBsAg-positive

No response to three-dose vaccine series plus revaccination: give one dose of HBIG as soon as possible and a second dose 1 mo later

No treatment is needed

Test exposed person for anti-HBs

Test exposed person for anti-HBs

Response unknown

If anti-HBs levels are adequate,* no treatment is needed; if they are inadequate, give one dose of HBIG plus an HB vaccine booster dose

No treatment is needed

If anti-HBs levels are adequate,* no treatment is needed; if they are inadequate, initiate revaccination

* An adequate anti-HBs level is ³ 10 mlU/ml, which is approximately equivalent to 10 sample ratio units (SRU) on radioimmunoassay or a positive result on enzyme immunoassay.

 

 

Passive Immunoprophylaxis

HBIG is prepared by Cohn ethanol fractionation from plasma selected to contain a high titer of anti-HBs; this process inactivates and eliminates HIV from the final product. In the United States, HBIG has an anti-HBs titer of at least 1:100,000 by radioimmunoassay.54 HBIG provides temporary, passive protection. It is indicated after low-volume percutaneous or mucous membrane exposure to HBV; it is not effective for high-volume exposure (e.g., blood transfusion). The recommended dose of HBIG for adults is 0.06 ml/kg I.M. Passive prophylaxis with HBIG should begin as soon as possible after exposure-ideally, within 24 hours.54

Active Immunoprophylaxis

Two types of HB vaccine are currently licensed in the United States, plasma-derived vaccine (Heptavax-B) and recombinant vaccine (Recombivax HB and Engerix-B). Heptavax-B contains alum-adsorbed 22 nm HBsAg particles purified from human plasma and processed to inactivate the infectivity of HBV and other viruses. Plasma-derived vaccine is no longer being produced in the United States, but similar vaccines are produced and used in China and other countries. In the United States, use of Heptavax-B is limited to persons allergic to yeast. Recombivax HB and Engerix-B are prepared by recombinant DNA technology in common baker's (or brewer's) yeast, Saccharomyces cerevisiae.

For primary vaccination, three I.M. injections (into the deltoid muscle in adults and children and into the anterolateral thigh muscle in infants and neonates) are given, with the second and third doses 1 and 6 months after the first dose.54 The dose for Heptavax-B and Engerix-B is 20 µg (volume, 1.0 ml) for persons older than 11 years, and that for Recombivax HB is 10 µg (1.0 ml) for persons older than 19 years and 5 µg (0.5 ml) for persons 11 to 18 years of age. For immunologically impaired patients, including hemodialysis patients, the dose is 40 µg for all three vaccines. For postexposure prophylaxis with Engerix-B, a regimen of four doses given soon after exposure and 1, 2, and 12 months afterward has been approved.

HB vaccine is more than 90% effective at preventing infection or clinical hepatitis in susceptible persons. Protection is virtually complete in persons who develop adequate antibody. Routine testing for immunity after vaccination is not recommended, but testing should be considered for persons at occupational risk who require postexposure prophylaxis for needle-stick exposure.

Between 30% and 50% of persons who have been vaccinated will cease to have detectable antibody levels within 7 years, but protection against infection and clinical disease appears to persist.54,55 The need for booster doses has not been established. Revaccination of individuals who do not respond to the primary series will produce adequate antibody in 15% to 25% of cases after one additional dose and in 30% to 50% after three additional doses.56

Although effective HB vaccines have been available since 1982, the incidence of hepatitis B in the United States continued to increase in the first decade of HB vaccine use. In 1991, the Advisory Committee for Immunization Practices (ACIP), citing the safety of the vaccine and the evidence of continuing spread of HBV, recommended universal vaccination of all infants born in the United States.57

Recommendations for Exposure to Blood That Contains (or May Contain) HBsAg

Acute exposure The U.S. Public Health Service has provided recommendations for hepatitis B prophylaxis after accidental percutaneous, mucous membrane, or ocular exposure to blood that contains (or may contain) HBsAg [see Table 2].43 These recommendations are based on consideration of several factors: (1) whether the source of the blood is available, (2) the HBsAg status of the source, and (3) the hepatitis B vaccination and vaccination-response status of the exposed person. After exposure, a 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 (if known) of the exposed person should be reviewed. Because passive administration of antibody with HBIG does not inhibit the active antibody response to HB vaccine, the two can be given simultaneously

Chronic exposure The U.S. Public Health Service recommends that persons who are at risk for exposure to HBV receive the HB vaccine series [see Table 3].54 Health care workers who are at increased risk for acquiring hepatitis B include all physicians (especially surgeons), dentists, and laboratory and support personnel, such as nurses and technicians who work in the operating room or who have contact with infected patients, blood or blood products, or excreta. Because of their frequent exposure to blood and their high risk of hepatitis B, all surgeons should receive HB vaccine. As of 1994, however, only 50% of surgeons had been vaccinated, despite the proven efficacy and safety of the vaccine and surgeons' increased risk of exposure.58 Hospital personnel who do not have frequent contact with blood or blood products (e.g., the janitorial, laundry, and kitchen staffs) need not be vaccinated.

Screening of personnel and patients for anti-HBs before vaccination is indicated only for individuals in high-risk groups; it has not been found to be cost-effective outside these groups.

Hepatitis C

The only tests currently approved by the U.S. Food and Drug Administration for diagnosis of hepatitis C are those that measure antibody to HCV. These tests detect anti-HCV in at least 97% of infected patients, but they cannot distinguish between acute, chronic, and resolved infection.59 The positive predictive value of enzyme immunoassay (EIA) for anti-HCV varies depending on the prevalence of the infection in the population. Therefore, supplemental testing of a specimen with a positive EIA result with a more specific assay (e.g., the recombinant immunoblot assay [RIBA]) may detect false positives, especially when asymptomatic persons are being tested. Qualitative polymerase chain reaction (PCR) testing for HCV RNA can also be used to identify HCV. This test can detect HCV at concentrations as low as 100 to 1,000 viral genome copies/ml, and it can detect HCV RNA in serum or plasma within 1 to 2 weeks after viral exposure and weeks before alanine aminotransferase (ALT) levels rise or anti-HCV appears.59 Under optimal conditions, the reverse transcriptase PCR assay for HCV can identify 75% to 85% of persons who are anti-HCV-positive and more than 95% of persons with acute or chronic hepatitis C.59 Quantitative assays for measuring HCV RNA are also available but are less sensitive and should not be used as primary tests for confirming or excluding the diagnosis of HCV infection or monitoring the end point of treatment. 59 The data currently available on prevention of HCV infection with immune globulin (IG) indicate that this approach is not effective as postexposure prophylaxis for HCV infection.59 Interferon may have a role in the treatment of acute hepatitis C: several studies have shown that interferon may delay or prevent the onset of chronic hepatitis C in patients treated early in the course of acute HCV infection.60–62

Rabies

The CDC has made recommendations for the prevention of rabies in people bitten by animals [see Table 4].63 Bite wounds should always be thoroughly scrubbed with soap and water. Postexposure antirabies treatment includes both rabies immune globulin (RIG) and human diploid cell (rabies) vaccine (HDCV). The decision to administer such treatment should be based on the following considerations.

Species and Availability of Biting Animal

In the United States, rabies is most commonly transmitted by skunks, raccoons, foxes, and bats. Livestock occasionally transmit the virus, but rodents and lagomorphs (i.e., rabbits and hares) are rarely infected.64 In different parts of the country, different animals predominate in the transmission of the virus. The likelihood that domestic cats or dogs in the United States will be infected varies from region to region. The chances of rabies transmission by a domestic animal that has been properly immunized are minimal.

Whether an animal is available for observation after biting someone also influences the need for antirabies prophylaxis. In certain cases, an animal that bites a person must be killed and tissue from its brain checked for the presence of rabies by fluorescent antibody tests as soon as possible [see Table 4].

Table 4

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

Domestic

Dog, cat

Rabid or suspected rabid

RIG (20 IU/kg) and HDCV§ (five 1.0 ml doses intramuscularly, on days 0, 3, 7, 14, and 28)

Unknown (escaped)

Consult public health officials. If treatment is indicated, give RIG and HDCV

Wild

Skunk, bat, fox, coyote, bobcat, raccoon, other carnivores

Regard as rabid unless proved negative by laboratory tests||

RIG (20 IU/kg) and HDCV (five 1.0 ml doses intramuscularly, on days 0, 3, 7, 14, and 28)

Other

Livestock, rodents, lagomorphs (rabbits and hares)

Consider individually. Local and state public health officials should be consulted on questions about 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.

||The animal should be killed and tested as soon as possible. Holding for observation is not recommended.

 

 

Type of Exposure

Infected animals transmit rabies primarily by biting, although licking may introduce the virus into open cuts in skin or mucous membranes. Transmission occasionally occurs as a result of aerosol exposure: the virus may be excreted in the urine and feces of infected bats, aerosolized during urination and defecation, and then inhaled, for example, by spelunkers exploring caves.

Circumstances of the Bite

An unprovoked attack is more indicative of a rabid animal than is a provoked attack.

If the animal shows signs of rabies or the patient has been bitten by a wild animal that is not captured, the patient should be treated as soon as possible with both RIG and HDCV. The recommended dose of RIG for postexposure prophylaxis is 20 IU/kg.63 If anatomically feasible, the entire dose of RIG should be infiltrated into the area around the wound.65,66 Postexposure HDCV should be given I.M. in five 1.0 ml doses on days 0, 3, 7, 14, and 28.63 Those with adequate preexposure immunization should receive two 1.0 ml doses of HDCV I.M. on days 0 and 3 but should receive no RIG. For adults, the vaccine should be administered in the deltoid area. For children, the anterolateral aspect of the thigh is also acceptable. The gluteal area should never be used for HDCV injections, because administration in this area results in lower neutralizing antibody titers.63 HDCV must not be given in the same region as RIG.

The CDC recommends that preexposure immunization be considered for high-risk groups, such as animal handlers, certain laboratory workers and field personnel, and persons planning to stay for more than 1 month in areas where canine rabies is highly prevalent and access to appropriate medical care is limited. The recommended preexposure regimen is 0.1 ml of HDCV on days 0, 7, and 21 or 28.67 Testing for adequate antibody response is not necessary for persons at low risk for exposure, but administration of booster doses every 2 to 3 years is recommended for those at high risk for exposure. Postexposure treatment for persons who have received preexposure immunization consists of 1 ml HDCV on days 0 and 3 only, without RIG.68

Although only a few cases of clinical rabies occur each year in the United States, approximately 30,000 persons a year are given postexposure prophylaxis. In 1992, 49 states, the District of Columbia, and Puerto Rico collectively reported 8,644 cases of animal rabies and one case of human rabies to the CDC.69 The total expense associated with one rabid dog in California was $105,790, even though no human contracted rabies.70 This amount represents the costs of human antirabies treatment, vaccination of other animals, and animal-containment programs.

Discussion

 

Size and Structure of Viruses

 

Viruses are among the smallest and simplest of microorganisms. Human viruses can be as small as 18 to 26 nm in diameter (parvoviruses) or as long as 300 nm (vaccinia virus), slightly longer than Chlamydia (a bacterium). Viruses do not have the complex enzyme systems required for synthesis of nucleic acid precursors, they lack ribosomes for protein synthesis, and they have no energy-generating mechanism. Consequently, they cannot replicate outside cells.

Figure 1a - Cytomegalovirus

 

 

Figure 1b - Typical Herpesvirus

 

A typical herpesvirus consists of a central core containing DNA; an icosahedral capsid, a surrounding 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.

 

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 stranded. This nucleic acid core is surrounded by the capsid, which is a protein coat made up of capsomers, repetitive subunits consisting of one protein or at most a few. Because the viral nucleic acid must code for coat proteins, a limitation in the number of capsid proteins conserves viral nucleic acid. The capsid protects the nucleic acid from nucleases in the environment, serves as its vehicle of transmission from one host to another, and plays a role in the attachment of the virus to the receptor sites on susceptible cells. The complete nucleic acid-protein coat complex is termed the nucleocapsid. For many viruses, the nucleocapsid is the complete virus particle, the virion. Other viruses, such as herpesviruses, may acquire an envelope, an additional lipid-containing membrane coat around the nucleocapsid, by budding through a membrane of the host cell [see Figures 1a and 1b]. Some viruses may also have an enzyme associated with their core that replicates the nucleic acid. Examples are the DNA polymerase of the HBV and the reverse transcriptase of retroviruses.

Classification of Viruses

 

Viruses, like other organisms, are classified into families, genera, and species, but most viral species do not have formal names and in practice are referred to by common names (e.g., cytomegalovirus, coxsackievirus, Norwalk virus, and varicella-zoster virus). Viruses can also be classified by chemical characteristics and by structural characteristics determined from electron microscopy (e.g., dimensions and site of assembly). Viruses are categorized into two broad groups depending on whether their nucleic acid is RNA or DNA. These two groups can be subdivided first according to whether the nucleic acid is single stranded or double stranded and then according to the presence or absence of an envelope. Single-stranded RNA viruses that replicate by means of a DNA step (i.e., retroviruses) are grouped separately from those that do not.

Identification of Viruses

 

Viruses can be identified by means of (1) serologic tests, (2) isolation of virus, (3) histologic examination, (4) detection of viral antigens, (5) detection of viral nucleic acid, and (6) electron microscopy. One or more of these techniques may be applicable to a given viral infection.

Specimens must be handled properly to maximize the likelihood of identifying the virus. If isolation of the virus is desired, blood and tissue samples should be taken promptly to the virology laboratory and inoculated onto the appropriate cell line. Samples obtained at night or on weekends can be placed in a balanced salt solution or tissue culture medium and kept in a refrigerator until taken to the laboratory. If microscopic identification of the virus is planned, specimens must be preserved appropriately. Routine preservation in formalin, for example, permits visualization of viral inclusions by routine staining and light microscopy. For identification of viral antigens by immunofluorescence techniques, the tissue specimen should be immediately frozen, preferably in liquid nitrogen. Specimens to be examined by electron microscopy must be placed in glutaraldehyde or another appropriate fixative.

Serologic Tests

The antibody response to viral antigens can be detected in the serum of patients with viral infections. An IgM response usually indicates recent exposure to the virus, whereas the presence of IgG reflects past exposure.

For most acute primary infections, serum obtained during late recovery or after recovery (convalescent serum) has an increased antibody titer, compared with serum obtained early in the course of the disease (acute serum). Most tests are performed on an initial serum dilution of 1:2 or 1:10 and on serial twofold dilutions thereafter. A fourfold increase in titer (indicated by reactivity of a two-tube dilution) usually represents a significant increase in antibody response and is considered to constitute seroconversion. An immunocompromised host may occasionally fail to mount an antibody response.

Some viruses are so common that patients may already have antibody titers when the disease is first suspected. Herpesviruses are ubiquitous and are present in many healthy people in latent form. At the onset of herpesvirus infections, patients may already 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 laboratory: complement fixation, radioimmunoassay, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, immune precipitation, immune blotting, latex agglutination, virus neutralization, indirect hemagglutination, immune adherence hemagglutination, 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 inoculated 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.

Figure 2 - Cells Infected with Cytomegalovirus

 

Cells infected with cytomegalovirus become large and round (arrows). Note the uniform appearance of adjacent uninfected cells.

 

Viruses that grow in cell monolayers in tissue culture have cytopathic effects that can be recognized under the microscope (e.g., rounding, transformation, or death) [see Figure 2]. Some viruses, such as rubella, produce no direct cytopathic effects but can be detected because they inhibit the cytopathic effects of a second test virus. This phenomenon is called viral interference. Other viruses (e.g., myxoviruses) cause changes in the cell membrane so that red blood cells adhere to the cell surface (hemadsorption). The identity of isolated viruses can be confirmed by use of specific antisera that are known to inhibit viral growth.

Tissue suspected of containing an encephalitis or other neurotropic virus can be minced and the extract injected intracerebrally into an infant mouse. If the mouse dies and bacteria cannot be cultured from the brain, the injected material presumably contained such a virus. If antiserum of known specificity neutralizes the virus, the specificity of the antiserum indicates the specific identity of the virus. The criterion for neutralization is that inoculation of neutralized virus will not kill the mouse.

Histologic Examination

Figure 3 - Kidney Biopsy inCytomegalovirus Infection

 

Kidney biopsy shows cytomegalovirus-infected tubular epithelial cells (arrows). In such cells, a dark intranuclear inclusion is surrounded by a clear halo. Inclusions usually indicate sites of previous or current viral replication.

Histologic examination of biopsy and autopsy tissues may demonstrate changes that are typical of certain viruses. Members of the herpesvirus group can be characterized by intranuclear inclusions surrounded by a clear halo [see Figure 3]. RNA viruses usually produce inclusions in the cytoplasm; for instance, dark-staining intracytoplasmic inclusions in the brain tissue of animals or patients are diagnostic of rabies infection and are called Negri bodies. Inclusion bodies are either masses of closely packed virus particles or remnants of prior virus replication.

Detection of Viral Antigens

Viral antigens can be detected in tissues by techniques employing their corresponding antibodies. If virus is present, these antigens may be visible microscopically under ultraviolet light either by direct 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 fluorescein-labeled anti-g-globulin antibody). Fluorescence microscopy requires specimens that are fresh frozen (preferably in liquid nitrogen). Immunofluorescence staining of cells in tissue culture can detect viral antigens before cytopathic effects are evident. Viral antigens in formalin-fixed tissue can be identified by immunohistochemical microscopy (e.g., using peroxidase-labeled antibodies).

Detection of Viral Nucleic Acid

Viral nucleic acids can be detected in body fluids and tissues at virus concentrations too low to be detected by other means. The PCR permits amplification of even a small number of copies of viral nucleic acid. In theory, even a single copy of a specific DNA can be detected by PCR. Before PCR is performed, DNA can be synthesized from viral RNA by means of reverse transcriptase. The PCR product can be detected by gel electrophoresis and compared with known viral DNA. This test is currently being used to diagnose CMV infection and is more sensitive than current serologic testing for HCV. Nucleic acid hybridization can detect viral nucleic acid in tissue specimens. Epstein-Barr virus genomes can be detected in this way in EBV-related cancers and lymphoproliferative disorders.

Electron Microscopy

Although seldom used routinely, electron microscopy allows rapid identification (in a matter of hours) of viruses in body fluids, 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 ultrafiltration. 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 symptomatic 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).

Viral infections are common in immunosuppressed patients in general and especially in recipients of organ transplants, who must take immunosuppressive drugs to prevent rejection. The overwhelming majority of these infections are caused by members of the herpesvirus family (e.g., CMV, herpes simplex viruses, varicella-zoster virus, and EBV); infections with HBV and with papovaviruses (e.g., human papillomavirus, which causes warts, and BK virus) are also frequent.

Because surgical patients are frequently given transfusions of blood or blood products and because hospital staff often incur accidental needle-stick injury, viruses that can be transmitted by these routes are of prime interest to surgeons and their patients. Examples of such viruses are HBV, hepatitis D, HCV, HIV, HTLV-I, and the herpesviruses, including EBV and CMV. These viruses 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 cells) or from blood that has not been completely removed from the organ. Changes in donor acceptance and screening policies over time have increased the safety of the blood supply and should continue to do so in the future [see Table 5].71

HIV

 

Two serotypes of HIV, HIV-1 and HIV-2, have been identified. Both can cause AIDS. HIV-1 accounts for virtually all cases of AIDS in the United States and equatorial Africa. HIV-2 is found almost exclusively in West Africa; only a few cases of HIV-2 infection have occurred in the United States.

Because AIDS patients are immunodepressed, they are sus-ceptible to opportunistic infections and neoplasms, especially non-Hodgkin lymphoma, Pneumocystis carinii pneumonia, and Kaposi sarcoma. AIDS is most prevalent in the United States among male homosexuals, abusers of I.V. drugs, and hemophiliacs. Since the implementation of testing for blood-borne HIV and the near-elimination of HIV from blood products, the incidence of HIV infection in the hemophiliac population has diminished markedly; however, in recent years, the incidence in the heterosexual population has been increasing rapidly.

HIV can be transmitted by transfusion of whole blood, packed red cells, plasma, factor VIII concentrates, factor IX concentrates, and platelets. The likelihood that a person will become infected with HIV after receiving a single-donor blood product that tests positive for HIV approaches 100%.72–73 Before the advent of serologic testing for HIV in 1985, 0.04% of 1,200,000 blood donations in the United States were estimated to be HIV positive.74 AIDS has developed in more than 8,500 recipients of blood transfusions, blood components, or transplanted organs or tissue.

Federal regulations now require that all prospective blood and plasma donors be screened for antibody to HIV by ELISA. Because this test yields a low rate of false positive results, assay by the more sensitive Western blot electrophoresis is always used to confirm positive ELISA results. Routine testing of blood donors has greatly reduced HIV transmission via blood transfusions, but infection can still occur if the donor has been infected with HIV but has not yet developed antibody.75 The risk of HIV transmission via transfusion of screened blood that is negative for HIV is estimated to be one in 200,000 to one in 2,000,000 per unit transfused in the United States.76 Antibody to HIV usually develops within 4 weeks to 6 months of HIV infection.77 From the time of infection until the appearance of antibody, infected individuals will test negative by ELISA or Western blot, and their blood might still be used for transfusion.

HIV and AIDS can also be transmitted by organ transplantation.78 So far, only a small number of patients have been found to be infected in this way, but more will undoubtedly be reported. These patients received transplants before HIV testing of potential donors became possible. All prospective organ and tissue donors now should be tested for HIV infection and other blood-borne viral infections.

HIV infection is also a potential problem in health care workers, who are exposed to a large and growing population of AIDS patients. In the United States, an estimated 1.0 to 1.5 million people are infected with HIV but as yet have no symptoms. HIV transmission from blood, tissue, or other body fluids can occur in the health care setting as a result of percutaneous injury (e.g., from needles or other sharp objects), contamination of mucous membranes or nonintact skin (e.g., skin that is chapped, abraded, or affected by dermatitis), prolonged contact with intact skin, or contamination involving an extensive area.79 HIV infection may be contracted through a variety of sources including blood, semen, vaginal secretions, visibly bloody fluids, and a number of other fluids for which the precise risk of transmission is undetermined (e.g., cerebrospinal, synovial, pleural, peritoneal, pericardial, and amniotic fluid). Infection may also be contracted from concentrated HIV used in research settings.79 The results of multiple prospective studies quantifying transmission risk associated with a discrete occupational HIV exposure indicate that the average risk of HIV transmission associated with needle punctures or similar percutaneous injuries is approximately 0.3%. The estimated risk of transmission from mucocutaneous exposure to HIV-contaminated material is 0.03%. As of December 1999, the CDC had received reports of 56 U.S. health care workers in whom documented HIV seroconversion was temporally related to occupational HIV exposure. Of these 56, 48 had percutaneous exposures, five mucocutaneous exposures, two both percutaneous and mucous membrane exposures, and one an unknown route of exposure.80 Another 138 possible cases of occupational HIV transmission-six involving surgeons-have been reported in persons with no risk factors for HIV transmission other than workplace exposure; however, seroconversion after a specific exposure was not documented. There may be other health care workers who also have acquired HIV infection from needle-stick or mucous 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

The concentration of virus in the blood or serum of antigen-positive individuals is several orders of magnitude less for HIV than for HBV. The number of needle-stick exposures to HIV that have actually led to a positive test result for HIV has been extremely small, whereas hepatitis B occurs in as many as 40% of health care workers exposed to the virus by needle-stick injury. Despite this relatively low infectiousness, AIDS is much more feared than hepatitis B because AIDS is often fatal. Although hepatitis B is usually not fatal and is often of short duration, several health care workers die of hospital-acquired hepatitis B and hepatitis C each year.

  


 

Hepatitis

 

Several viruses can cause hepatitis. Hepatitis A virus (HAV) and HBV cause what were formerly known as infectious hepatitis and serum hepatitis, respectively. HCV is the major cause of parenterally transmitted non-A, non-B hepatitis. Hepatitis E virus is a common cause of epidemic non-A, non-B hepatitis, which is chiefly found in developing countries in Africa and Asia. Hepatitis D virus (HDV, formerly called the delta agent) is defective or incomplete and is pathogenic only in the presence of HBV. The hepatitis viruses are the most common infectious agents to which hospital personnel may be exposed. Herpesviruses can also cause serious and sometimes fatal hepatitis, especially in severely immunocompromised patients, such as recipients of organ or bone marrow transplants and patients receiving intensive chemotherapy for cancer.

Hepatitis A

HAV is a small (27 nm), single-stranded RNA virus belonging to the enterovirus subgroup of picornaviruses. Its almost exclusive transmission by the fecal-oral route is enhanced by poor personal hygiene, poor sanitary conditions, and crowding. Transmission can be contained by careful hand washing and the isolation of excretions. Unlike other types of viral hepatitis, hepatitis A is rarely transmitted by blood, blood products, or needle sticks and is rarely transmitted among hemodialysis patients, health care workers, and I.V. drug abusers. The infrequent parenteral transmission of HAV is attributed in part to its lack of an asymptomatic carrier state. Hepatitis A can be transmitted percutaneously only during a brief period of viremia before the onset of symptoms and jaundice. The chance that an infected person will donate blood during this short period is small; also, patients are usually outside the hospital during this period.

Hepatitis B

HBV is a member of the Hepadnaviridae family of DNA viruses. It is most prevalent in the Far East, the Middle East, Africa, and parts of South America, where as many as 15% of the general population are chronic carriers. Worldwide, the most common mode of transmission is from mother to child during the perinatal period. In the United States, however, sexual or parenteral transmission has been implicated in most infections. The high-risk groups for chronic HBV infection in the United States include I.V. drug users, men who have sex with men, other individuals with multiple sexual partners, household contacts and sexual partners of HBV carriers, health care workers, patients on long-term hemodialysis, and organ transplant recipients.81

Clinical Course

The clinical course of hepatitis B is extremely variable: infection ranges from the completely asymptomatic to the rapidly fatal. The incubation period averages 75 days but can last from 40 to 180 days. Exposure to HBV has five potential outcomes: (1) no infection occurs; (2) acute hepatitis develops, followed by clearance of infection; (3) acute fulminant infection develops, leading to hepatic necrosis and death; (4) acute hepatitis develops without clearance of infection, and a chronic carrier state ensues; and (5) no acute illness develops, but a chronic carrier state ensues.

Approximately 55% of adults infected with HBV have no symptoms despite serologic documentation of infection (see below), which explains why blood donors who seem to be in good health are capable of transmitting the virus. Other individuals infected with HBV may have such mild symptoms (e.g., slight malaise, fatigability, and loss of appetite) that they do not seek medical attention.

Approximately 45% of people infected with HBV experience typical acute, icteric hepatitis, which is characterized by fatigue, anorexia, nausea, vomiting, and hepatomegaly. In approximately 1% of adults infected with HBV, acute fulminant hepatitis develops. This condition is characterized by progressive hepatocellular destruction, encephalopathy, and deepening coma. Fulminant hepatitis causes death in approximately 80% of affected adults and 30% of affected children.

Figure 4 - Events of Persistent Hepatitis B Infection

 

Schematic shows virologic, clinical, and serologic events of a hepatitis B infection that becomes persistent.

 

In approximately 5% to 10% of hepatitis B cases, the infection becomes chronic. Patients with chronic hepatitis may be asymptomatic or may have clinical and histologic evidence of the disease, as well as persistently elevated levels of serum aminotransferases [see Figure 4]. With time, many patients pass to an asymptomatic carrier state, and serum aminotransferase levels fall. The duration of the asymptomatic carrier state appears to be indefinite. Chronic HBV infection can result in hepatocellular carcinoma, which is especially common in China, Southeast Asia, and sub-Saharan Africa.

Because most patients remain asymptomatic until the development of end-stage liver disease, there are no specific clinical findings that are indicative of chronic HBV infection. There are, however, several clinical syndromes linked to HBV infection that may provide a clue to the presence of chronic HBV infection. These syndromes include polyarteritis nodosa, membranous or membranoproliferative glomerulonephritis, leukocytoclastic vasculitis, erythema nodosum, arthritis, and serum sickness.

Antigens

HBV has a diameter of 42 nm and contains circular, double-stranded DNA. The protein coat on its outer surface is termed hepatitis B surface antigen. HBsAg is made in quantities greatly exceeding the amount required to coat the nucleic acid. The excess surface antigen appears in the serum as spheres 22 nm in diameter or tubules of the same diameter and of varying length. These spheres and tubules contain no nucleic acid and hence are not infectious. They may persist in the serum for prolonged periods, even for life, and in great quantities, up to 1012 to 1014 surface antigen particles (500 µg protein) per milliliter.82

The hepatitis B virus also has a nucleocapsid core, the outside of which contains the hepatitis B core antigen (HBcAg). HBcAg is not detected in hepatitis B during acute infection, because its antigenic determinants are hidden by the outer surface antigen of the intact virion.

Inside the hepatitis B nucleocapsid is a DNA-dependent DNA polymerase and the hepatitis B e antigen, which is thought to be either an internal component or a degradation product of the core antigen. HBeAg is found only in the serum of individuals whose serum also contains HBsAg, and it appears in the serum of virtually all patients early in the course of HBV infection. The presence of HBeAg in serum is indicative of the presence of large numbers of circulating intact virions: serum containing HBeAg is estimated to be one million times more infectious than serum containing HBsAg but not HBeAg.

Serology

Figure 5 - Events of Acute Hepatitis B Infection

 

Schematic shows virologic, clinical, and serologic events during acute hepatitis B infection.

 

HBsAg can be detected in the serum within a few weeks of viral exposure [see Figure 5]. It usually persists throughout the symptomatic period and does not disappear until after recovery. Anti-HBs appears shortly after the disappearance of HBsAg [see Table 6]. During this window period, neither HBsAg nor anti-HBs is detectable [see Table 7]. Anti-HBs persists for years and is associated with immunity to reinfection. HBV can be differentiated into eight serotypes on the basis of determinants of the surface antigen.

Hepatitis B core antigen (HBcAg) is not found free in the serum, but antibody to HBcAg (anti-HBc) becomes detectable at an early stage in the course of acute infections, 1 to 2 weeks after the appearance of HBsAg. Titers of anti-HBc fall after the disappearance of HBsAg but persist for life. In patients with chronic hepatitis B, HBsAg remains detectable indefinitely, and titers of anti-HBc remain high. Years after infection, titers of anti-HBs may have fallen to undetectable levels, and anti-HBc may be the only marker of previous infection. HBeAg is detectable immediately after the appearance of HBsAg. Antibody to HBeAg (anti-HBe) appears just after HBeAg becomes undetectable (usually before the disappearance of HBsAg) and persists for 1 to 2 years [see Figure 5].

Hepatitis D

HDV is a defective, 35 to 37 nm RNA virus that can infect only persons who are also infected with HBV, because it uses HBsAg for its structural protein shell. HDV is found worldwide and is especially prevalent in the Amazon basin, central Africa, southern Italy, and the Middle East.83 HDV infection is less common in the United States and Western Europe, where it is generally associated with parenteral blood exposure, typically in the setting of I.V. drug abuse or multiple transfusions.

Clinically, hepatitis D is found only in association with acute or chronic hepatitis B, and it cannot last longer than hepatitis B does. Depending on the state of the HBV infection, HDV infection appears either as a coinfection or a superinfection. Coinfection occurs when acute HDV infection and acute HBV infection are present simultaneously; superinfection occurs when acute HDV infection is superimposed on chronic HBV infection. Coinfection with HDV is associated with fulminant hepatitis and a mortality of 2% to 20%.84 Fewer than 5% of cases of coinfection progress to chronic hepatitis D. In contrast, superinfection with HDV results in chronic HDV hepatitis, often with cirrhosis, in more than 70% of cases. The clinical and biochemical features of HDV infection resemble those of HBV infection alone. Chronic active hepatitis B progresses faster when hepatitis D is also present. Chronic HDV infection is more likely to result in severe morbidity and mortality than chronic HBV or HCV infection alone.

Diagnosis of acute HDV infection may be difficult: HDAg appears in the circulation only briefly and often goes undetected. Antibody to HDAg (anti-HD) of the IgM class subsequently appears in serum in low titers. Because no anti-HD IgG response occurs, no serologic marker of previous HDV infection may remain after recovery. Chronic HDV infection is easier to diagnose: high titers of anti-HD in the serum indicate ongoing HDV infection, and HDV antigen is detectable in the liver by means of immunohistochemical techniques. Moreover, IgM anti-HD remains detectable in serum.83

Non-A, Non-B Hepatitis: Hepatitis E and Hepatitis C

Non-A, non-B hepatitis is divided into two varieties, an epidemic form (hepatitis E) and a parenterally transmitted form (hepatitis C).85 Hepatitis E is an acute, self-limited disease whose clinical features are similar to those of other types of hepatitis. Hepatitis E virus (HEV) is prevalent in the developing world, where it is spread by the fecal-oral route and has been associated with large outbreaks as well as sporadic cases. Outbreaks have been linked to contaminated water supplies. No cases of HEV infection acquired in the United States have been reported to date, but HEV acquisition has been reported in international travelers.

Hepatitis C is the most common cause of nonalcoholic liver disease in the United States. HCV is an RNA virus of the flavivirus family. It can be transmitted through parenteral exposure (usually in the setting of I.V. drug abuse), sexual contact, or the sharing of a household with an HCV-infected person; however, some persons with HCV infection have none of these risk factors, and there may be other means of transmission that have yet to be elucidated. Before the advent of antibody testing, HCV infection accounted for the majority (75% to 95%) of cases of posttransfusion hepatitis.83 Since the spring of 1990, when a serologic test for HCV became available, all transfused blood has been screened for HCV, and the incidence of transfusion-associated hepatitis C has fallen precipitously. At present, however, I.V. drug use still accounts for a large proportion (60%) of HCV transmission in the United States.59

The presence of anti-HCV IgG appears not to be protective: blood donors with anti-HCV antibody can transmit hepatitis.62 Surveys of HCV seropositivity indicate that 0.2% to 0.6% of volunteer blood donors carry anti-HCV IgG,83 and the prevalence may be much higher among high-risk populations (e.g., residents of large inner-city communities). The prevalence of anti-HCV IgG is high among I.V. drug users, hemodialysis patients, and hemophiliacs.

Clinical Manifestations

The incubation period of hepatitis C averages 7 to 8 weeks in length but may be as short as 2 weeks or as long as 15. The clinical manifestations and biochemical alterations associated with acute hepatitis C are similar to but milder than those associated with hepatitis B. Serum aminotransferase levels can fluctuate widely; the peak levels are lower than those seen in hepatitis B (10 to 20 times normal as opposed to 20 to 50 times normal). Only about 25% of cases of acute HCV infection are icteric, and the mortality for acute infection is about 1%. Most patients have no acute illness suggestive of HCV infection. Antibody is not always present early in infection, and there are no clinically available assays for detecting IgM antibody to HCV. Thanks to improvements in the immunodetection of HCV, however, the interval before anti-HCV can be detected has decreased from the 6 to 12 months required with the first-generation tests to 8 to 12 weeks with the second-generation assays.83

The most striking feature of HCV infection is its tendency to 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 whose bloodstreams had been cleared of HCV according to RT-PCR assay, as many as 90% still had HCV in the liver.86 It is estimated that in the United States, nearly four million people are seropositive for HCV, and more than 30% of liver transplantations are performed to treat end-stage liver disease related to chronic HCV infection. The presence of anti-HCV IgG does not distinguish acute from chronic hepatitis. Within 10 years, cirrhosis may develop in as many as 20% to 25% of patients with active hepatitis87; accordingly, these patients must be followed up carefully.

Chronic active hepatitis is characterized by elevated serum aminotransferase levels; however, other test results remain normal, and the patient is usually asymptomatic until end-stage liver disease develops. Liver biopsy shows inflammation around the portal triads. Recombinant interferons have been used to treat chronic HCV infection, with mixed results: frequently, there is little response to treatment, or viremia returns after treatment. The combination of interferon with ribavirin has shown promise, however. Interferon treatment is generally reserved for patients who have chronic HCV infection and show evidence of active necroinflammatory liver disease with persistent ALT elevations.

Hepatitis in Hospital Personnel

Patients with hepatitis can infect hospital personnel with the virus via needle-stick injuries and other forms of accidental exposure. Conversely, physicians who are chronic carriers of HBV or HCV can infect their patients. According to a nationwide seroepidemiologic survey reported in 1978, approximately 19% of physicians have anti-HBs, compared with 3.5% of healthy volunteer blood donors [see Table 8]

Table 9 - Prevalence of Hepatitis B Virus (HBV) Serologic Markers in Various Populations90

Population

Prevalence of Serologic Markers of HBV Infection (%)

HBsAg

All Markers

Immigrants or refugees from areas where HBV is highly endemic

13

70–85

High risk

Clients in institutions for the mentally retarded

10–20

35–80

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

Intermediate risk

Health care workers with frequent blood contact

1–2

15–30

Prisoners (male)

1–8

10–80

Staffs of institutions for the mentally retarded

1

10–25

Low risk

Health care workers with no or infrequent blood contact

0.3

3–10

Healthy adults (first-time volunteer blood donors)

0.3

3–5

 

 

.88 Anti-HBs was found in 28% of surgeons, the highest prevalence in any medical specialty. For physicians, the likelihood of being positive for anti-HBs correlates with age and the number of years in practice. The risk of hepatitis is greatest among medical staff members in renal dialysis units, oncology units, and the clinical laboratory. Since 1978, when these data were reported, HBV vaccination has made it impossible to perform similar, more recent studies, because vaccination rather than previous infection would be responsible for the presence of antibodies.

Physicians and other staff members who care for hemodialysis patients with end-stage renal disease are at greater risk for acquiring HBV because of the high prevalence of hepatitis in such patients [see Table 9].89,90 Transmission of HBV decreases in dialysis centers when close attention is paid to hygienic technique. Isolation of patients who are carriers of HBsAg also reduces the incidence of HBV in hemodialysis patients and staff.91

From 0.28% to 9.3% of health care workers have antibody to HCV.92–94 In one study from Connecticut, five (12.5%) of 40 surgeons had antibody to HCV.92 In another study, from New York City, eight (1.75%) of 456 dentists had anti-HCV antibody.93 The highest prevalence among dentists was found to occur in oral surgeons (9.3%). As use of vaccines for HBV becomes more widespread [see Management of Viral Exposure, Hepatitis B, above], HCV may come to predominate over HBV as the cause of the rare cases of hepatitis transmitted from hospital personnel to patients.

Epidemiology of Posttransfusion Hepatitis

Both HBV and HCV can be transmitted by percutaneous and other routes.89 Rare cases of hepatitis have been attributed to the infusion of immune globulin, although its preparation by ethanol fractionization normally destroys hepatitis virus (as well as HIV). Albumin is pasteurized by heating at 60° C for 10 hours, which destroys hepatitis virus.

Because of the current criteria for acceptable blood donors, elimination of payment for blood donation, and serologic testing for HBV and HCV, the risk of contracting hepatitis B from a blood transfusion is now much lower than it once was. In the United States, it is now rare for either HBV or HCV to be transmitted via 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 1/63,000 (95% CI, 31,000 to 147,000).95

HDV can also be passed by transfusion. In a study of 262 patients who had posttransfusion hepatitis and whose serum was positive for HBsAg, anti-HD was found in nine patients.96 HDV can be detected in 24% of HBsAg-positive drug abusers and in approximately 50% of HBsAg-positive hemophiliacs.

Long-term Effects of Chronic Hepatitis

Chronic hepatitis can lead to problems requiring surgical intervention. It can cause cirrhosis, which in turn can cause portal hypertension and bleeding varices that necessitate portal systemic shunting. In addition, HBV and HCV predispose to hepatocellular carcinoma, the most prevalent visceral cancer in the world. The condition is especially prevalent in China, Southeast Asia, and sub-Saharan Africa. It is estimated that 25% of chronically infected persons die of cirrhosis or hepatocellular carcinoma.97 HBV coinfection appears to increase the risk of hepatocellular carcinoma in HCV-infected persons. A widespread program of vaccination against HBV could greatly decrease the incidence of hepatocellular carcinoma. Epidemiology, molecular biology, and comparative pathology provide strong circumstantial evidence that hepatitis B is a significant factor in the etiology of hepatocellular carcinoma. The risk of primary hepatocellular carcinoma is more than 250 times greater in carriers of HBV than in noncarriers. HBV markers can be found in 80% to 90% of patients with hepatocellular carcinoma. Perhaps the best epidemiologic data indicating that hepatitis B precedes hepatocellular carcinoma were obtained in Taiwan from male civil servants between 40 and 60 years of age.98 Approximately 3,500 HBsAg carriers were matched by age and place of birth (either mainland China or Taiwan) to 3,000 HBsAg-negative men, who served as control subjects. An additional group of 16,000 HBsAg-negative men between 40 and 60 years of age served as unmatched control subjects. After subjects were followed for 2 to 4 years, 50 cases of hepatocellular carcinoma were found, all but one of which occurred in chronic HBsAg carriers.

HCV is also associated with chronic infection in a high percentage (approximately 50%) of cases. In many countries, chronic HBV infection remains the leading factor in the development of hepatocellular carcinoma, whereas in Japan, Korea, and southern Europe, 50% to 75% of cases of hepatocellular carcinoma are associated with chronic HCV infection.99 In Japan, mortality from hepatocellular carcinoma increased approximately twofold in the 1980s, a change that may be attributable to a higher incidence of HCV-associated liver cancer.100

Herpesviruses

 

Cytomegalovirus

CMV is a member of the B herpesvirus family and is the largest virus known to infect humans. In some U.S. cities, the seroprevalence of CMV is 60% to 70%. Like other members of the herpesvirus family, CMV is capable of remaining within its host in a latent state, probably by down-regulating cell surface markers (e.g., HLA-1) and thus avoiding immune destruction. Latent CMV has been found in circulating mononuclear cells, polymorphonuclear cells, vascular endothelium, renal epithelial tissue, and pulmonary secretions. The virus may become reactivated in the setting of immunodeficiency, such as may arise with HIV infection, transplantation, or significant stress from operations or injuries. In nonimmunocompromised patients, CMV typically causes a self-limited mononucleosis-like syndrome characterized by fever and mild hepatic transaminase abnormalities. In immunocompromised patients, however, CMV infection can be much more severe and even potentially life threatening, causing myelosuppression, pneumonitis, colitis, and retinopathy.

Posttransfusion Cytomegalovirus Infection (Posttransfusion or Postperfusion Syndrome)

The transmission of CMV by extracorporeal perfusion is responsible for the occasional development of a syndrome similar to mononucleosis in patients who have undergone open-heart operation. The syndrome characteristically appears 3 to 5 weeks after operation; its features are splenomegaly, fever, atypical lymphocytosis, and, occasionally, hepatomegaly, erythematous rash, and eosinophilia.89 CMV can be isolated from the blood of virtually all patients with the typical posttransfusion syndrome and from the urine of half of these patients.89 The condition is nonfatal and self-limited, but it may result in prolonged hospitalization and a long, expensive search for the source of fever. Although uncommon in adults 30 years of age and older, the syndrome can occur in as many as 10% of susceptible children and adults younger than 30 years.

This syndrome can also occur in patients who receive transfusions but who do not undergo open-heart operation. Occasional cases that develop postoperatively in patients who did not receive transfusions are thought to be the result of reactivation of latent infection. EBV can sometimes cause the syndrome.

The incidence of posttransfusion CMV infection is related to the kind of blood or blood product transfused. CMV is highly cell associated and is transmitted with leukocytes, which may be present in transfusions of packed red blood cells, platelets, or white blood cells; transmission from transfusion of fresh frozen plasma or cryoprecipitate has not been documented.14 Therefore, efforts to decrease the number of white blood cells in the transfused blood would be expected to decrease the rate of transfusion-associated CMV infection. Approximately 50% of patients who receive whole blood seroconvert to CMV, whereas only 10% of those who receive washed packed red blood cells seroconvert. The risk of seroconversion to CMV is between 12% and 100% when whole blood, either fresh or stored, is transfused.101 In one study, transfusion of frozen deglycerolized red blood cells resulted in seroconversion in only 3% of patients,89 whereas in another, seroconversion occurred in 58% of 36 leukemic patients transfused with lymphocytes.102

The risk of posttransfusion CMV infection is also related to the volume of blood received. In one study, 7% of patients receiving a single unit of whole blood seroconverted, whereas anti-CMV antibody titers rose in 21% of patients receiving more than one unit.103 The risk of infection per unit of blood transfused is estimated to range between 2.7% and 12%.104

Preexisting antibody to CMV does not protect transfusion recipients against reinfection. After transfusion of whole blood, titers of antibody to CMV will increase in 10% of recipients (an indication of reinfection) and in 19% of patients who did not have antibody to CMV before transfusion (an indication of infection). Whereas a seronegative recipient of CMV-positive blood has a 21% chance of seroconversion, the risk of seroconversion from the receipt of one unit of CMV-negative blood is only 2%.89 However, the sensitivity of the serologic test for CMV is such that even when blood that tests seronegative is used, there is still a residual 0% to 6% risk of CMV transmission.105

Because so many patients receive blood transfusions during operation, it is understandable that evidence of posttransfusion CMV infection has been found in many patients postoperatively (e.g., after gynecologic surgery, cholecystectomy, appendectomy, lumbosacral fusion, splenectomy, and transplantation). It has also been found in surgical patients who are victims of trauma or burns.

However, it is surprising that infection with CMV, a ubiquitous virus, does not occur more frequently after transfusion. Between 30% and 54% of the adult population in the United States have antibody to CMV, an indication of previous infection.89 Because infection with the virus is probably lifelong, a significant proportion of blood donors harbor the virus. The prevalence of antibody to CMV is 25% in units of blood from donors between 18 and 23 years of age and increases to 89% in blood from donors older than 60 years. The overall prevalence of seropositive blood donors is between 30% and 70%.

Cytomegalovirus in Transplant Recipients

CMV infection occurs not only in patients who have received blood transfusions but also in those who have suffered trauma, those receiving immunosuppressive therapy, and those with neoplastic disease. The groups at highest risk for CMV infection are probably recipients of organ transplants and of bone marrow transplants.106–108 Numerous studies have documented the high incidence of CMV infection after organ transplantation: the rates range from 26% to 100%.89,109,110 Primary CMV infection occurs in patients who do not have antibody to CMV before receiving transplants. Infections are considered to be reactivated if they occur in patients who did have antibody to CMV before receiving transplants. Rates of infection in patients receiving cardiac or bone marrow transplants are similar to those in patients receiving kidney transplants.

The high incidence of CMV infections after transplantation was recognized in the early days of such procedures. At autopsy of patients who died after renal transplantation, the intranuclear inclusions typical of CMV were found in tissue from the lungs, the parotid glands, the lymph nodes, the liver, the pancreas, the parathyroid, and the brain. CMV has been cultured repeatedly from the urine of transplant recipients, and the frequency of seroconversion among them has been high.

Likely sources of the virus are blood, because fresh blood can transmit CMV, and the organ transplant itself, because CMV can grow in renal tubular epithelial cells and can be transmitted as a latent virus. In several studies, recipients of kidney transplants had a much higher incidence of CMV infection when the donors had antibody to CMV than when the donors did not. In one study, 57% of recipients of kidneys from seropositive donors acquired CMV infection after transplantation, compared with 8% of recipients of kidneys from seronegative donors.111 Even patients who have antibody to CMV can acquire new CMV infections as a result of transfusion or transplantation because there is more than one antigenic variety of the virus. Also, CMV that is latent in many patients who have antibody before transplantation may be reactivated after transplantation by host versus graft reactions, corticosteroids, or other immunosuppressive drugs. Hospital personnel, family members, and the environment play very small roles in transmission of CMV to transplant recipients.

Several systematic studies have demonstrated that CMV causes clinical illness in renal transplant recipients. In four studies, clinical illness developed in 83% of 76 patients with primary infection, compared with 44% of 268 patients with reactivation of a previous infection.89,109,110

Recipients of renal transplants in whom CMV causes clinical illness most commonly present with fever. Fever occurs in 95% of patients with CMV infection and may be prolonged. Patients with CMV infection also frequently present with anorexia, arthralgias, and leukopenia. Other clinical features of the disease are diffuse pulmonary infiltrates, pancreatitis, transplant malfunction, and systemic bacterial and fungal superinfections. Invasion of the GI tract by CMV may cause gastritis and ulcers in both the duodenum and the colon, which in turn may lead to hemorrhage and perforation. Biopsies demonstrate CMV inclusions at the base of the ulcers. The virus appears to invade the vascular endothelium, and bleeding is possibly a result of vascular occlusion and ischemic necrosis of the overlying tissue.

Lethal CMV disease is characterized by the presence of most of the features listed above. Liver dysfunction is found in 100% of patients with lethal disease but in only 50% to 75% of patients with mild or moderate infection, and CMV viremia occurs in 46% to 48% of patients with severe CMV infection but in only 26% to 28% of patients with mild to moderate infection. Leukopenia and the presence of atypical leukocytes also correlate with the severity of the disease. CMV infection after renal transplantation is also associated with pneumonia, hepatitis, encephalitis, and retinitis.

Whether or not CMV infection causes or leads to graft rejection is uncertain. Both the highest incidence of CMV infection (> 80%)89,109,110 and the highest incidence of graft rejection occur within the first 3 months after transplantation. In several studies, young patients and recipients of second kidney transplants were at higher risk for graft loss if they had CMV than if they did not.89,109,110 In most studies, however, it is extremely difficult to demonstrate a relation between CMV infection and graft rejection.

Of the multiple factors affecting the risk of CMV infection in transplant recipients, the most important are (1) the familial relation and HLA matching between the kidney donor and the recipient and (2) the CMV serology of both the donor and the recipient. The presence of antibody in transplant recipients before transplantation seems to offer a small amount of protection against fever caused by CMV but does not protect against more serious consequences of the infection, such as leukopenia, graft failure, and death.

CMV infection is also a major problem in liver, heart, and bone marrow transplant recipients.106,108 In liver transplant recipients, CMV is a cause of hepatitis and liver dysfunction that can be confused with rejection or other causes of liver malfunction,106 and it can lead to lethal infection. CMV pneumonitis in bone marrow transplant recipients is the most common life-threatening infectious complication after transplantation. The severity of infection in bone marrow transplant recipients may be attributable to the higher incidence of host versus graft disease in patients with CMV pneumonitis (82%) than in those without CMV pneumonitis (27%).112

Prevention and Treatment of Cytomegalovirus Infection

Several methods have been proposed to reduce the incidence of CMV infection after transfusion or transplantation. One method is to eliminate as many white blood cells as possible from transfused blood because CMV is almost certainly transmitted solely through these cells. From 90% to 100% of viable leukocytes in blood have been removed from frozen deglycerolized erythrocytes. In one study, transfusion of 24 hemodialyzed patients with leukocyte-free red blood cells from frozen deglycerolized blood prevented subsequent CMV infection.104

Another approach is to transfuse blood only from CMV-negative donors. Because the majority of posttransfusion CMV infections are asymptomatic, however, the increased cost of performing serologic tests on all donated units might be difficult to justify.

Storage of blood to reduce infectiousness of CMV is another approach, but storage from 48 to 72 hours does not significantly reduce transmission of CMV infection. Irradiating the blood to render the CMV noninfectious is unacceptable because it causes cell transformation in vitro. Furthermore, in one study, administration of leukocytes previously exposed to 1,500 cGy (1,500 rads) of gamma radiation resulted in an increased incidence of CMV infection among recipients of these cells.102

Because the incidence of CMV infection is higher in patients who receive kidney transplants from seropositive donors, some centers do not transplant kidneys from seropositive donors into seronegative recipients. However, no published reports indicate that this practice leads to a significant alteration in the outcome of renal transplantation with respect to graft rejection. Moreover, excluding kidneys from seropositive donors makes it more difficult to find kidneys for seronegative recipients.

Many attempts have been made to develop a CMV vaccine for administration before viral exposure by multiple passages of the virus in tissue culture. Two such vaccines have been used in clinical trials, one prepared from the AD169 strain and the other from the Towne 125 strain of the virus. Immunization with these vaccines can elicit both serum antibody and cell-mediated immunity. In one trial, the vaccine prepared from the Towne 125 strain lowered the incidence of clinical disease but not of infection, and the disease tended to be less severe in vaccinated patients than in control subjects who received placebo.113

Human IG has been administered after transfusion or transplantation in attempts to prevent associated CMV infection. In one study, it reduced life-threatening infection to a less severe form in most patients, but in other studies, not surprisingly, it provided no consistent benefit.114–117 In patients who are already seropositive, the virus is latent inside their cells, where it is probably not accessible to serum antibody. Patients with primary infections may not benefit from antibody treatment, because herpesviruses seem to transfer from cell to cell without ever existing free in serum. Even CMV hyperimmune globulin has no clear benefit in patients with clinical CMV infection.118 It may, however, help control severe infections, such as those seen in bone marrow transplant recipients.

Several antiviral agents have been used in attempts to reduce the incidence or lessen the effect of CMV infection. Among these agents are interferon, transfer factor, immune globulin, and nucleoside derivatives, such as cytarabine, vidarabine, and acyclovir (see below). Immune globulins, acyclovir, and ganciclovir are effective at preventing CMV infection in transplant recipients.109,110114,119,120 Ganciclovir and foscarnet are active against CMV in vitro. Ganciclovir is currently being used to treat CMV and is the most effective agent in organ transplant recipients (see below).109,110119–121

Epstein-Barr Virus

EBV is the herpesvirus responsible for infectious mononucleosis. It can be found in B cells in peripheral blood of infected patients and in tumor cells of patients with Burkitt lymphoma and nasopharyngeal carcinoma. It remains in a latent form in an infected host for years, probably for life. Most posttransfusion EBV infections are asymptomatic. Seroconversion to EBV will develop in approximately 8% of recipients transfused with between two and 14 units of blood. In as many as 5% of patients with preexisting antibody to EBV, significant elevations of antibody titers may develop, beginning 2 weeks after transfusion. These elevations indicate either reinfection or reactivation of a latent infection.89 Because EBV is associated with cells and does not exist free in serum to any great extent, antibody to EBV in either donors or recipients is unlikely to provide substantial protection against infection resulting from blood transfusions or organ transplants. Among transfused patients who do not have preexisting antibody to EBV, the prevalence of EBV infection can reach 33% to 46%. In these patients, the absence of preexisting antibody presumably rules out reactivation of latent EBV infection as the source of infection.

EBV occurs worldwide. In the United States, nearly all adults and as many as 65% of persons of all ages have antibody to EBV. Infection is thought to occur in infancy, and as many as 17% of infants have antibody to EBV. By 5 years of age, 72% of children have antibody to EBV, and the prevalence in adults is similar.122 Thus, the majority of blood donors in the United States have been previously infected with EBV and probably have latent virus in their leukocytes. Although it is clear that EBV can be transmitted by blood when the transfusion occurs within 3 days of donation, it is not known whether blood stored for longer periods can transmit the virus. Because EBV is predominantly intracellular, plasma and its derivatives do not transmit the virus.

The diagnosis of EBV infection is made serologically. Tests both for IgM antibody to capsid antigens and for IgG antibody to the early antigens of EBV or tests of serial samples for IgG antibody to capsid antigens must be used. The heterophil antibody test (the Paul-Bunnell test) and a rapid slide test that is equivalent (the monospot test) are also used in most clinical studies to screen for EBV infection before more specific diagnostic tests are performed.

In cases of posttransfusion infection, IgG antibody to EBV can be detected at least 10 days before the onset of symptoms, and EBV can be cultured from circulating lymphocytes 11 days before the onset of symptoms. In patients with acute infection, EBV is found in approximately three of every 104 peripheral blood lymphocytes.123 In contrast, all recovered persons with antibodies to EBV are thought to have the virus in one of every 107 circulating lymphocytes.

EBV is strongly implicated in the etiology of a posttransplantation lymphoproliferative disorder (PTLD).89,124,125 EBV has been isolated from the tissues of most cases of PTLD, but not all.126,127 Non-EBV-related cases of PTLD typically occur later after transplantation, and their etiology has not been elucidated.

PTLD comprises three general clinical presentations: (1) a mononucleosis-like syndrome involving the tonsils and the peripheral lymph nodes, (2) a diffuse polymorphous B-cell infiltration in many visceral organs, and (3) localized extranodal tumors in the GI tract, the neck, the thorax, or other parts of the body. Patients whose disease is limited to a single organ or to lymph nodes often respond to a reduction in immunosuppression or antiviral therapy; however, once the infection becomes widespread, the disease progresses rapidly and is fatal in more than 75% of cases.128 In solid organ transplant recipients, PTLD may be limited to the allograft. There is some evidence to suggest that PTLD may have organ-specific features that promote lymphoproliferation: allograft involvement has been reported in 17% of renal transplant recipients, 8.6% of liver transplant recipients, and as many as 60% to 80% of lung or intestinal transplant recipients.128

The persons at highest risk for PTLD are EBV-seronegative persons receiving EBV-positive organs or bone marrow. Most infections occur within the first 4 months after transplantation.129 Several specific risk factors for the development of PTLD have been identified: a seropositive graft in a seronegative recipient, certain types of organ allografts (with intestinal transplants carrying the highest risk), any type of immunosuppression that blunts cellular immunity to EBV (with risk increasing as immunosuppression becomes more pronounced), and the presence of other infections (CMV in particular).

The optimal treatment of lymphoproliferative disorders remains unclear. Some early EBV-associated lymphoproliferative disorders in solid organ transplant recipients have regressed completely after reduction of immunosuppression.130,131 Early PTLD may respond to antiviral therapy with acyclovir or ganciclovir, which may prevent infection of resting B cells, but such therapy is less likely to be effective in the face of high concentrations of latently infected circulating or tissue-invasive B cells. Some investigators also report resolution of PTLD after treatment with interferon alfa.132,133

Transmission of EBV can occur simultaneously with transmission of CMV or hepatitis virus. Although hepatitis accompanies EBV infections in sporadic cases, EBV alone has not been documented as a cause of posttransfusion hepatitis.

Herpes Simplex Virus

Infection or reactivation of infection with herpes simplex virus type 1 (HSV-1) follows renal transplantation in 50% to 75% of patients, most often within 30 days after transplantation. Reactivation of infection is more common than primary infection: only 14% of patients who are seronegative before transplantation become infected, but infection is reactivated in 64% of patients who were already seropositive before transplantation.

Most cases of HSV-1 infection after transplantation are clinically inapparent and are indicated only by a significant rise in titer of antibody to the virus. The most prevalent clinical manifestation is herpes labialis, that is, fever blisters affecting not only the lips but also the mucous membranes of the oral cavity and the skin of the head and neck. Although these lesions are painful and may make eating, drinking, and taking oral medications difficult, they are usually self-limited and heal without treatment or reduction of immunosuppression. However, HSV-1 infection can take a much more malignant course, disseminating to cause pneumonitis, fulminant hepatitis, upper GI hemorrhage, encephalitis, aseptic meningitis, and death.

Varicella-Zoster Virus

Varicella-zoster virus (VZV), another herpesvirus, is the etiologic agent of herpes zoster and chicken pox. This virus resides in the dorsal root ganglia of adults who had primary varicella infection in childhood. Herpes zoster is more common in organ transplant recipients, in patients with cancer (especially those who have leukemia or lymphomas), in burn patients, and in patients receiving immunosuppressive drugs. Serologic evidence of VZV infection occurs in 8% to 16% of renal transplant recipients. The lesions of herpes zoster become evident 12 to 511 days after organ transplantation.

In children or adults who have not already had chicken pox and occasionally even in children who have, VZV can cause disseminated chicken pox in many organs, which may be fatal.

Agents Effective Against Herpesviruses

Because the essential synthetic activities of viruses depend on the metabolic machinery of their host, it has been difficult to devise specific antiviral agents that interfere with viral replication but are not harmful to host cells.134,135 Many antiviral agents are too toxic to be used clinically. In contrast, antibacterial agents that are both toxic to bacteria and safe for human cells are easier to design because the structure and metabolic machinery of bacteria are distinct from those of host cells.

Although intracellular processes unique to viral replication have been identified and specifically targeted for chemotherapeutic attack, very few agents have been effective against human viruses. Among these is amantadine, which is used for both prophylaxis and treatment of influenza A. Agents that were found to be effective for prophylaxis against smallpox, such as methisazone, now have no use, because the disease has been eradicated.

There are few effective chemotherapeutic agents for hepatitis or most of the other major viral diseases that concern surgeons, but several agents have been used for the treatment of herpesvirus infections, especially in immunosuppressed patients [see Table 10].

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

Herpes labialis

Treatment usually not indicated; may use 1% penciclovir cream 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 virus

Recurrent

Acyclovir, 200 mg p.o. 5 times daily or 400 mg p.o., t.i.d., for 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

Neonatal HSV

Acyclovir, 10 mg/kg I.V. q. 8 hr for 10–21 days (20 mg/kg 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

Varicella-zoster virus

  Shingles

Acyclovir, 800 mg p.o. 5 times daily for 7–10 days, or

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.

 

 These agents, derivatives of purines and pyrimidines, interfere with viral nucleic acid synthesis.

Acyclovir and Valacyclovir

Acyclovir (acycloguanosine) is a nucleoside derivative that is used to treat herpesvirus infections, especially herpes simplex and varicella-zoster infections in immunocompromised hosts. Valacyclovir is the L-valyl ester prodrug of acyclovir. In cases of mucocutaneous herpes simplex and herpes zoster, acyclovir can shorten the period of virus shedding, decrease pain, and promote more rapid scabbing and healing of lesions. Acyclovir is also the drug of choice for encephalitis caused by herpes simplex, but it is not effective in patients with established neurologic damage resulting from herpes simplex or varicella-zoster infections or in patients infected with CMV. Acyclovir inhibits the replication of EBV in actively replicating cells but does not affect latent or persistent infection.

The total daily dose of acyclovir is 10 to 25 mg/kg, given by I.V. infusion lasting 60 minutes. The recommended length of parenteral acyclovir therapy ranges from 5 to 10 days, depending on the indication. A major side effect of such therapy is phlebitis at the injection site; rash, leukopenia, and neurotoxicity may also occur. Acyclovir applied topically as a 5% ointment is effective in immunocompromised patients for the treatment of limited cutaneous herpes infections and in patients with normal immunity for the treatment of initial episodes (but not recurrent episodes) of genital herpes simplex infection. Oral acyclovir seems to be effective as prophylaxis against reactivated herpes simplex infection in recipients of bone marrow transplants and in patients immunosuppressed as a result of HIV infection.

Penciclovir and Famciclovir

Penciclovir is a nucleoside analogue that is similar to acyclovir with respect to spectrum of activity and potency against herpesviruses. Famciclovir is the diacetyl ester of penciclovir. Penciclovir requires thymidine kinase (TK) for phosphorylation and thus is inactive against thymidine kinase-deficient strains of HSV or VZV; however, it may be active against some TK-altered or polymerase mutants that are resistant to acyclovir as well as against some foscarnet-resistant HSV isolates. In experimental settings, topical, parenteral, and oral penciclovir and oral famciclovir have been effective against HSV infection.

Vidarabine

Vidarabine (ara-A) is effective against herpes simplex and varicella-zoster viruses as well as poxviruses, oncornaviruses, and rhabdoviruses. It is used mostly to combat herpesvirus infections in immunosuppressed patients. In these patients, vidarabine accelerates healing of cutaneous herpes zoster, decreases its rates of cutaneous dissemination and of visceral complications, and shortens the duration of postherpetic neuralgia. For systemic use, a daily dose of 10 to 15 mg/kg of vidarabine is administered I.V. over a period of 12 hours. The duration of therapy for herpes zoster is 5 days. Side effects include anorexia, weight loss, nausea, vomiting, weakness, anemia, leukopenia, thrombocytopenia, tremors, and thrombophlebitis at the site of administration.

Idoxuridine

Idoxuridine (5-iodo-2Á-deoxyuridine) (IUdR, IDU) was the first clinically effective antiviral nucleoside. It is a halogenated pyrimidine that resembles thymidine in structure. Topical application of either a 0.1% solution or a 0.5% ointment of idoxuridine is effective treatment of herpes simplex keratitis but not of recurrent herpes labialis or localized zoster. In the United States, IDU is approved only for topical treatment of HSV keratitis. When combined with dimethyl sulfoxide (DMSO), IDU is active against herpes zoster and recurrent or primary genital HSV infection. In Europe, IDU is available in combination with DMSO for the treatment of herpes labialis, herpes genitalis, and herpes zoster.

Ganciclovir

Ganciclovir (DHPG, 2Á-NDG, or BIOLF-62) is an acyclic nucleoside structurally related to acyclovir but with greater activity against CMV in vitro and in vivo. It is effective in treating CMV disease in transplant recipients and AIDS patients. The usual total daily dose of ganciclovir is 7.5 to 10 mg/kg, given in two or three divided doses. The dosage should be adjusted if the patient has decreased renal function. Myelosuppression is the principal dose-limiting toxic side effect.

Foscarnet

Foscarnet (trisodium phosphonoformate) is a pyrophosphate derivative that inhibits herpesvirus DNA polymerases and retroviral reverse transcriptases.134–136 In the United States, it has been used for the prevention and treatment of CMV retinitis in patients with AIDS. For patients who have received renal or bone marrow transplants, foscarnet is given in a bolus injection of 9 mg/kg followed by infusion of 0.015 to 0.090 mg/kg/min I.V. for 7 days. Foscarnet is also used to treat acyclovir-resistant HSV infection. The major toxicity associated with foscarnet is nephrotoxicity; CNS side effects (e.g., headache, tremor, irritability, and seizures) can also occur.

Viral Infections from Animal and Human Bites

 

Surgeons are frequently called on to treat patients who have been bitten by either an animal or another person. Such bites can transmit several viruses and other infections. Certainly, rabies is the most feared viral infection transmitted in this way. Viruses that are found in saliva, such as HBV, herpesviruses, and possibly HIV, can be transmitted by a human bite, although such cases are most likely rare.

From zero to five cases of human rabies occur each year in the United States. Animal rabies is widespread and is found in every state except Hawaii. In 1992, more than 8,600 cases of animal rabies were reported to the CDC by 49 states, the District of Columbia, and Puerto Rico. The great majority of cases occur in wild animals.69 Before 1950, more than 8,000 cases of rabies in dogs were reported each year in the United States; the number is now fewer than 150 a year.

Rabies proceeds from a prodrome of fever, malaise, and headache, to hyperactivity and diffuse cerebral dysfunction, and then to coma and death. From 5% to 20% of patients may also show progressive paralysis. Occasionally, there is no history of an animal bite. Diagnosis can be confirmed by culture of saliva, cerebrospinal fluid, or brain tissue; demonstration of rabies antigen in the cornea or skin; or measurement of serum antibody to rabies virus. At postmortem examination, typical intracytoplasmic inclusions (Negri bodies) can be seen in the brain cells.

Although the number of cases of human rabies is small, the disease is an important problem because of the large number of animal bites that occur each year. Surgeons may have to consider rabies prophylaxis in patients whom they treat for bite injuries [see Management of Viral Exposure, Rabies, above, andsee 1:7 Acute Wound Care]. Also, two fatal cases of rabies have occurred in recipients of corneal transplants from a patient whose cause of death was later found to be rabies.137

Acknowledgments

 

Figure 1 Micrograph courtesy of F. K. Lee, A. J. Nahmias, and S. Stagno, Emory University. Drawing by George V. Kelvin.

Figures 4 and 5 Albert Miller.

References

 

1. Recommendations for prevention of HIV transmission in health-care settings. MMWR Morb Mortal Wkly Rep 36(suppl 2):1S, 1987 [PMID 10843503]

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