Bartlett HIV/AIDS Review, October 15, 2004
Bartlett HIV/AIDS Review, October 15, 2004
Giblin TB, Sinkowitz-Cochran RL, Harris PL, et al. Clinicians' perceptions of the problem of antimicrobial resistance in health care facilities. Arch Intern Med. 2004;164:1662-1668. The US Centers for Disease Control and Prevention (CDC) has waged a national campaign to deal with antimicrobial resistance in healthcare settings with their so-called "12-step program." This study is an analysis of clinicians' perceptions of antibiotic resistance and the potential effectiveness of this campaign. The data were collected from replies to a questionnaire completed by 117 clinicians and focus groups with 28 participants, all done in Pittsburgh, Pennsylvania. According to the analysis, there was a perception that resistance was a problem nationally, but less of a problem locally. The components of the 12-step program that were regarded as most important were vaccination, restrained use of antibiotics, and the removal of catheters. The most important precautions to keep in mind are stopping therapy when the infection is cured, treating the infection rather than colonization, and practicing antibiotic control. Data for each of the 12 steps are summarized in Table 1 .
The study authors conclude that antibiotic resistance is a complex national problem. Clinicians believe that this issue is more of a national than a local concern, but a review of sensitivity patterns at the institutions included in the survey showed that this belief was unfounded.
Comment: Although the results of the survey are not surprising, the best methods for dealing with the problem are not clear. Suggestions include (1) simple, preventive messages; (2) presentations and professional society and other meetings; (3) computer-tracking systems, electronic physician order entry, clinical pathways, and local antibiograms; and (4) presentations that specify job relevance to this issue.
Lopman BA, Reacher MH, Vipond IB, Sarangi J, Brown DW. Clinical manifestation of norovirus gastroenteritis in health care settings. Clin Infect Dis. 2004;39:318-324. This is a report of a prospective analysis of outbreaks of gastroenteritis in healthcare facilities in Avon, England, including 4 major hospitals, 11 community hospitals, and 135 nursing homes. Cases were defined as (1) at least 2 episodes of vomiting, (2) at least 3 episodes of diarrhea, or (3) both, each during a 24-hour period. An outbreak was defined as more than 2 cases in a given location within 7 days. Norovirus was tested by reverse-transcriptase polymerase chain reaction (RT-PCR). Results showed 271 events that fell within the definition of outbreak, including 33 in nursing homes and 238 in hospitals. Norovirus was detected in 50% of hospital outbreaks and 74% of nursing home outbreaks. The study authors note that outbreaks not due to norovirus were caused by rotavirus and Clostridium difficile and were not markedly different. Of those due to norovirus, vomiting was reported by 67%; the median duration was 2 days, except in hospital patients in whom the mean duration was 3.7 days. The study authors conclude that norovirus is a common cause of outbreak diarrhea and vomiting within healthcare facilities involving staff and patients; it is mild and brief, but is more prolonged and severe in hospitalized patients as compared with hospital staff.
Schrag SJ, McGee L, Whitney CG, et al. Emergence of Streptococcus pneumoniae with very-high-level resistance to penicillin. Antimicrob Agents Chemother. 2004;48:3016-3023. The analysis is based on results from the CDC's Active Bacterial Core surveillance of the Emerging Infections Program Network, which has tested the antibiotic susceptibility of Streptococcus pneumoniae from invasive pneumococcal infections defined by recovery from a normally sterile site, primarily from bacteremia. During the period from 1995 to 2001, there were 23,996 pneumococcal isolates tested, and 22,025 (1%) had a minimum inhibitory concentration (MIC) of ≥ 8 mcg/mL to penicillin. The following observations apply to the 226 strains in this highly resistant category:
The study authors conclude that the high-level resistance by S pneumoniae to penicillin that is emerging is associated with multiple drug resistance and requires monitoring.
Comment: This report may predict an ominous future for use of beta-lactams, which are currently considered the drug of choice for serious pneumococcal infections. Nevertheless, the increase in annual prevalence of pneumoccocal infection over the 6 years of study was relatively slow. Also, as the study authors point out, the dominant serotypes are 23F and 14, which are included in the protein-conjugated vaccine that appears to be highly effective in children. This vaccine seems to prevent these infections in children and their parents. Of interest, the fluoroquinolones, doxycycline, and clindamycin had relatively good efficacy against the strains that were highly resistant to beta-lactams.
Centers for Disease Control and Prevention (CDC). Update: investigation of rabies infections in organ donor and transplant recipients -- Alabama, Arkansas, Oklahoma, and Texas, 2004. MMWR Morb Mortal Wkly Rep. 2004;53:615-616. The CDC previously reported on 3 organ transplant recipients at Baylor University Medical Center, Dallas, Texas, who developed rabies from an organ donor. This study includes an additional patient who received a liver transplant at Baylor and subsequently died of encephalopathy. The donor in this case showed no evidence of rabies virus, but the donor of organs from the previously reported cases was the source of a segment of an iliac artery that was used in this recipient. Thus, the total toll from this donor with previously unsuspected rabies is 4 organ transplants with lethal outcomes ascribed to rabies encephalitis. It is also noted that the donor, on further investigation, reported being bitten by a bat.
Comment: This important but isolated case is now tightly constructed. The donor from Arkansas apparently had a bat bite, the most common method of rabies transmission in the United States. He subsequently had an enigmatic neurologic syndrome that proved fatal, and he was the source of transplanted tissue to 5 patients, including 4 who subsequently died with rabies encephalitis and 1 who died postoperatively.
Warrell MJ, Warrell DA. Rabies and other lyssavirus diseases. Lancet. 2004;363:959-969. This review of rabies and related viruses contains the following highlights.
European bat lyssavirus: A lethal case of rabies attributed to this virus was reported in Scotland in 2002, indicating that this disease was again present in England after a century of no cases. Bat rabies has been documented in Europe for about 50 years, but there are only 4 human infections known.
The United States: Thirty-five indigenous human rabies cases have been reported from 1958 to 2000. Thirty-two were caused by bat strains, of which 26 had no history of a bat bite. Twelve, however, had had physical contact with a bat.
Pathogenesis: The virus, which is inoculated with saliva through the skin, travels retrograde along the peripheral nerves to the central nervous system (CNS) at a rate of 50-100 mm/day and produces massive replication when reaching the CNS. Virus replication occurs intraneuronally. Infected patients have profound symptoms of encephalitis, but minimal histopathologic changes.
Clinical presentation: Paresthesia, usually with itching, at the site of the bite is the only prodromal symptom. The classic clinical expressions are hydrophobia and aerophobia. A neuropsychiatric illness with history of travel to a rabies-endemic area during the previous months or even years suggests this diagnosis. In the United States, contact with a bat may be trivial.
Diagnosis: Diagnostic tests are summarized in Table 3 .
Survivors: Since 1970, there have been reports of 5 patients who have survived rabies encephalitis. All received the rabies vaccine before the onset of symptoms but none received rabies immune globulin (RIG). In each case, the diagnosis was established by high antibody concentrations in the cerebrospinal fluid. Some were given nervous tissue vaccines that may cause postvaccinal encephalitis and consequently are questioned. Three of the patients had profound persisting neurologic defects.
Treatment: There is no effective treatment.
Prevention: The best method is to eliminate animal vectors, especially domestic dog sources, which account for 90% of human cases worldwide. With reference to bat rabies, there is no way to eliminate the source; therefore, avoidance of contact and prompt postexposure prophylaxis are advocated. The most successful prevention is preexposure vaccination; this has been universally effective with 3doses of tissue culture vaccine given on days 0, 7, and 28 with a booster after 1 year. With preexposure vaccination, postexposure treatment consists of 2 doses of vaccine on days 0 and 3. For postexposure treatment in the usual setting of a suspected or established exposure, there are 3 components: First, thorough washing of the wound site with soap and water reduces transmission by 50%. Virucidal agents with iodine or alcohol may be preferred. Second, a standard vaccine (HDCV; Imuvax Rabies, Aventis Pasteur or PCECV; Rabipur, Rab Avert Chiron) is given by intramuscular injection on days 0, 3, 7, 14, and 28. These tissue culture rabies vaccines are rarely associated with neurologic complications. Third, RIG passive immunization with a single dose should be infiltrated to the bite wound as soon as possible. It should be noted that RIG is expensive, scarce, and recommended only for severe injuries.
Jarvis WR. Controlling antimicrobial-resistant pathogens. Infect Control Hosp Epidemiol. 2004;25:369-372. The study author provides summary and editorial comments on several articles in this issue of Infection Control and Hospital Epidemiology, with emphasis on methicillin-resistant Staphylococcus aureus infection (MRSA), which now accounts for 50% to 70% of nosocomial S aureus strains worldwide, and vancomycin-resistant enterococci (VRE), which has increased from 0% to 25% for nosocomial enterococcal infections in the United States. Highlights of the review are:
The study authors conclude that SHEA has recently recommended a comprehensive program to control MRSA, VRE, and other resistant pathogens, including the following elements: (1) surveillance cultures, (2) barrier precautions for those colonized and infected, (3) hand hygiene, and (4) judicious use of antibiotics.
It is noted that the 2004 SHEA Annual Meeting included at least 10 presentations documenting the benefit of these recommendations for reducing or eliminating the transmission of MRSA or VRE and improving patient outcomes.
Baddour LM, Yu VL, Klugman KP, et al. Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia. Am J Respir Crit Care Med. 2004;170:440-444. The International Pneumococcal Study Group previously reported the results of a prospective study of pneumococcal pneumonia with bacteremia from 21 hospitals in 10 countries on 6 continents from 1998 through 2001. In that study, the mortality rate was 139 of 844 (16.5%) by day 14. Analysis of this experience showed that patients who were seriously ill (defined as having a Pitt bacteremia score of 4 or more) were 8-fold more likely to die than those with lower scores (54.6% vs. 7.3%). This study failed to show that penicillin resistance conferred a mortality risk and that discordant therapy (defined as use of an antibiotic that lacked in vitro activity) had an observable effect. This study concerns an analysis of the 14-day mortality rate for those who received monotherapy vs combination treatment. Monotherapy was defined as a single antibiotic within 2 days of a positive blood culture; combination therapy was 2 antibiotics within the first 2 days of a positive blood culture. Patients who did not receive antibiotics, who had treatment delayed for more than 24 hours, or who had an "inconsistent regimen" were eliminated, leaving 592 patients in the analysis population. Analysis showed no difference between those receiving monotherapy vs those receiving combination therapy (11.5% vs 10.4%, respectively, P = NS). However, a subset analysis of those who were seriously ill had a substantially lower mortality rate with combination therapy (55.3% vs 23.4% for monotherapy vs combination treatment, respectively; P = .002). Lower mortality rates were noted when one of the 2 antibiotics was a beta-lactam, vancomycin, or a macrolide; there were no adequate numbers to analyze fluoroquinolones or clindamycin. The most common regimen was a beta-lactam, and a separate analysis of this group showed a significant decrease in patients who received a beta-lactam combination as compared with those who received monotherapy with a beta-lactam. These results are summarized in Table 4 .
The study authors conclude that combination antibiotic therapy for seriously ill patients with bacteremic pneumococcal pneumonia confers a benefit on the basis of 14-day mortality results.
Comment: This report augments 3 prior retrospective analyses that all show better outcome with pneumococcal bacteremia from combination antibiotic therapy. These studies used diverse regimens, and it has not been possible to clarify the specific ingredients of combination therapy, and the mechanism of this benefit is also unclear. Current guidelines from the Infectious Diseases Society of America (IDSA) recommend combination therapy for routine use in patients who are seriously ill with pneumonia (Mandell LA. Clin Infect Dis. 2003;31:383), but the rationale is for optimal coverage of Legionella as well as S pneumoniae. It has been noted by Austriam and Gold that antibiotic therapy for pneumococcal bacteremia has an extraordinary impact on mortality, but this has not affected mortality in the first 3 days. It was noted in the previous study by Yu and colleagues that the full analysis of data from 844 patients showed that two thirds of deaths occurred in the first 3 days, again suggesting that this early component of therapy is particularly important and challenging. This study by Baddour and associates presented Kaplan-Meier survival graphs indicating that the major benefit of combination therapy was in the first 3 days. Data from Medicare also show that rapid institution of antibiotic treatment favorably affects outcome, although this applies to pneumonia in general without subset analysis of those with pneumococcal bacteremia. Thus, a possible conclusion is that both rapid therapy and combination therapy are important components of treating seriously ill patients with community-acquired pneumonia.
Widdowson MA, Cramer EH, Hadley L, et al. Outbreaks of acute gastroenteritis on cruise ships and on land: identification of a predominant circulating strain of norovirus -- United States, 2002.J Infect Dis. 2004;190:27-36. The Vessel Sanitation Program of the CDC requires reports of gastroenteritis on cruise ships that enter US waters from foreign countries if the attack rate exceeds 2% for passengers and/or crew. Gastroenteritis is defined as at least 3 episodes of diarrhea within 24 hours or vomiting with 1-2 episodes of loose stools, abdominal cramps, headache, myalgia, or fever. During 2002, there were 21 outbreaks reported compared with 7 in 2001. This report concerns an investigation from 14 outbreaks on 12 cruise ships for which the CDC received stool samples. Of these, 12 (86%) were due to human calicivirus infections, including 11 due to noroviruses and 1 to sapovirus. Of the 11 norovirus outbreaks, 8 (73%) were attributed to GII norovirus, including 7 involving the "Farmington Hills strain" (GII/4). During 2002, the CDC also confirmed 33 land-based outbreaks attributed to noroviruses, including 10 (30%) associated with the Farmington Hills strain. Table 5 summarizes the experience with the 7 outbreaks on cruise ships, including 5 with 2 or more contiguous cruises and 1 that continued 42 days with 4 continuous cruises (Ship F). The table also includes the 10 land-based outbreaks involving the Farmington Hills strain. The table provides the source of the outbreak, the attack rate for passengers, and the major mechanism of transmission.
The study authors conclude that there needs to be better outbreak surveillance to monitor norovirus strains and to identify common sources to permit better epidemiologic control.
Comment: This study calls attention to the important role of norovirus as the major cause of outbreaks of viral gastroenteritis. Control of these infections is confounded by the fact that normal volunteer studies suggest that over 30% of norovirus infections are asymptomatic and shedding may occur for up to 14 days after the onset of disease. This experience also shows the diversity of the sources of outbreak, which is primarily person-to-person, but also may be foodborne, waterborne, or environmental. The study authors call attention to the importance of full genetic characterization of the emergent strains, such as the Farmington Hills strain, because this information may prove helpful in epidemiologic investigations and vaccine development.
Centers for Disease Control and Prevention (CDC). Update: influenza activity -- United States and worldwide, 2003-04 season, and composition of the 2004-05 influenza vaccine. MMWR Morb Mortal Wkly Rep. 2004;53:547-552. Table 6 summarizes the World Health Organization (WHO) and the CDC experiences with influenza for 2003-2004.
According to these data, the predominant strain by far globally was influenza A (H3N2). The same holds true for the United States, but antigenic analysis showed that 89% were the drift-variant A/Fujian/411/2002. In the United States, the influenza season peaked during the week ending December 27, 2003 (week 52), which is substantially earlier than in the 4 prior seasons.
Of particular interest during the past season was the experience with avian influenza, primarily influenza A (H5N1), which caused 34 cases and 23 deaths (68%) primarily in persons aged 5-24 years in Vietnam and Thailand. This highly pathogenic strain affected domestic poultry, live-bird markets, and backyard farms in 8 Asian countries. Attempts at control included the killing of over 100 million domestic poultry. The global experience with avian influenza is summarized in Table 7 .
The vaccine strain for 2004-2005 will contain A/New Caledonia/20/99-like (H1N1), A/Fujian/411/2002-like (H3N2), and B Shanghai/361/2002-like viruses. As noted above, the Fujian strain became the predominant circulating strain in the 2003-2004 influenza season. A previous study suggested that the vaccine for 2003-2004 was not effective, but subsequently there have been 3 additional unpublished studies that all demonstrated vaccine effectiveness. It is anticipated that vaccine manufacturers will produce 90-100 million doses of this vaccine for the United States next season.
Piccirillo JF. Clinical practice. Acute bacterial sinusitis. N Engl J Med. 2004;351:902-910. This Clinical Practice review on acute bacterial sinusitis was written by Jay Piccirillo, an ear, nose, and throat (ENT) surgeon from Washington University in St. Louis, Missouri. Here are some highlights of the review.
Frequency of bacterial infection in patients with viral rhinosinusitis: .5% to 2% of all cases, up to 50% in patients who are seen in a medical clinic, and up to 80% in patients seen in ENT services.
Distinction between bacterial and viral infection: Most rhinoviral infections improve in 7-10 days. The recommendation is to make this distinction on the basis of persistence of symptoms for more than 10 days or the worsening of symptoms after 5-7 days.
Imaging: X-ray criteria are sinus opacity, a fluid level, or a marked mucosal thickening, but these do not distinguish bacterial from viral infections. Computed tomographic (CT) scans do not distinguish bacterial vs viral infection either and are frequently misleading.
Symptomatic therapy: Available evidence indicates minimal benefit.
Antibiotic therapy: The literature is extensive and confusing. Here are some highlights:
Complications: Patients with periorbital swelling, erythema, and face pain with or without mental status changes should have CT scanning and treatment with azithromycin, fluoroquinolone, ceftriaxone, or amoxicillin-clavulanate.
Allergic rhinitis: Loratadine proved successful in a placebo-controlled trial. Intranasal steroids, such as flunisolide spray, appear effective. Intranasal steroids also shortened the duration of symptoms in patients with exacerbations of chronic rhinitis.
Guidelines: Recommendations of the American College of Physicians include the following:
Sobel JD, Wiesenfeld HC, Martens M, et al. Maintenance fluconazole therapy for recurrent vulvovaginal candidiasis. N Engl J Med. 2004;351:876-883. This is a prospective, multicenter, randomized trial of weekly fluconazole compared with placebo in women with recurrent vulvovaginal candidiasis. Eligibility required a positive potassium hydroxide preparation of vaginal secretions and at least 4 documented episodes of Candida vaginitis within the previous 12 months. Women with HIV infection were excluded. The treatment was fluconazole, 150 mg weekly for 6 months. Patients were seen monthly for a detailed clinical history, pelvic exam, and vaginal fungal culture. Baseline cultures showed that Candida albicans accounted for 401 of 427 (94%) of cases. Results at the end of therapy (6 months) showed a dramatic difference in outcome with clinical remissions in 91% of fluconazole recipients as compared with 36% in the placebo group and negative fungal cultures in 81% in the fluconazole group as compared with 28% in the placebo group. Fungal cultures obtained during the course of therapy showed no fluconazole-resistant strains of C albicans defined at a MIC threshold of 64 mcg/mL and no change in the MIC90 for fluconazole in either group. An additional 6 months of observation after therapy showed that the clinical benefit was still significantly greater in the fluconazole group, but the difference was less striking at 43% vs 22%. These results are summarized in Table 9 .
The study authors conclude that long-term weekly treatment with fluconazole can significantly reduce the rate of recurrence of symptomatic vaginal candidiasis, but long-term cure is elusive.
Comment: Chronic, recurrent vaginal candidiasis is said to occur in 5% to 8% of women. Treatment may be topical with intravaginal azoles given once or twice weekly, but this is less popular than oral treatment. The clinical benefit achieved with weekly fluconazole might be expected. The particularly important components of this study are the inclusion of a placebo-control group to substantiate the benefit and especially the laboratory studies showing the lack of evolution of fluconazole resistance. Of particular concern in this study are the facts that some patients had persistent symptoms and most had a recurrence of chronic symptoms by 6 months after discontinuing weekly treatment. The cause of these persistent and recurrent infections is not known.
Polk RE, Johnson CK, McClish D, Wenzel RP, Edmond MB. Predicting hospital rates of fluoroquinolone-resistant Pseudomonas aeruginosa from fluoroquinolone use in US hospitals and their surrounding communities Clin Infect Dis. 2004;39:497-503. The study authors examined the correlation between fluoroquinolone use and increased resistance by Pseudomonas aeruginosa. Hospital use of fluoroquinolones was based on data from 24 hospitals during the period from 1999 through 2001 and expressed as defined daily doses/1000 patient-days. Data for community use were based on information obtained from IMS Health (www.imshealth.com) with zip codes for participating hospitals within a 10-mile radius. The results showed a correlation between increasing use of fluoroquinolones and decreasing sensitivity of P aeruginosa to these agents. Both community and hospital use of fluoroquinolones predicted resistance; levofloxacin was associated with resistance, but ciprofloxacin was not. These results are summarized in Table 10 .
The study authors conclude that fluoroquinolone use contributes to resistance, including multiply resistant P aeruginosa, which is sensitive only to colistin; that both hospital and community use contribute to this trend; and there appears to be a difference in the fluoroquinolone implicated because the association was found with levofloxacin and not with ciprofloxacin.
Comment: The association between fluoroquinolone use and resistance by P aeruginosa is not surprising. However, the data suggesting that this difference is primarily due to levofloxacin and not ciprofloxacin are surprising. The study authors conclude that their observations suggest either restraint in the use of fluoroquinolones or preferential use of ciprofloxacin.
Huang DB, Awasthi M, Le BM, et al. The role of diet in the treatment of travelers' diarrhea: a pilot study. Clin Infect Dis. 2004;39:468-471. The study authors report their experience with 105 US college students aged 18-26 years attending summer sessions in Guadalajara who participated in various antimicrobial studies. Patients with acute diarrhea on restricted diets were instructed to take clear liquids to match diarrheal losses and limit solid foods to salted crackers, tortillas, and bread or toast; when symptoms improved, they could add bananas, rice, potatoes, baked chicken, or fish. Foods to avoid until symptoms had cleared were red meat, cheese, milk, butter, ice cream, vegetables, fried foods, coffee, alcohol, and fruit other than bananas. Those on unrestricted diets were told to replenish diarrheal losses with fluids but to eat and drink whatever they wished. There were 48 subjects randomized to the restricted diet and 57 to the unrestricted diet. An analysis of trial diaries indicated that only 5 subjects did not adhere to their assignments. The analysis showed no difference in outcome. Specifically, the duration of diarrhea defined as the "time to last unformed stool" was a mean of 37 hours in the restricted diet group and 33 hours in those with no restrictions. The study authors conclude that the study showed no obvious benefit of a restricted diet in the treatment of acute travelers' diarrhea in patients who were receiving an antimicrobial agent. Specifically, they recommend that patients who are hungry should eat.
Dodek P, Keenan S, Cook D, et al. Evidence-based clinical practice guideline for the prevention of ventilator-associated pneumonia. Ann Intern Med. 2004;141:305-313. The following represents the summary opinion of the Joint Planning Group of the Canadian Critical Care Society and Canadian Critical Care Trials Group on ventilator-associated pneumonia (VAP) on the basis of a systematic search of controlled trials before April 2003, with 3 bibliographic databases: MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews ( Table 11 ).
Hopkin M. Fears grow as blood stocks pass on prions undetected. Nature. 2004;430:712. The "News" section of Nature reviews issues relating to 2 patients who acquired variant Creutzfeldt-Jakob disease (vCJD) from transfusions. To date, there have been 142 deaths in Britain due to this disease, and the assumption has been that these were acquired by consuming beef. All of these patients have been homozygotes at codon 129 of the prion protein (PrP) gene, but the second case of transfusion-associated infection was a patient who was heterozygous at this loci. This is a patient who received a transfusion in 1999, died of an aneurysm, and had the PrP of vCJD identified in the spleen and lymph nodes. This observation suggests that there may be many more asymptomatic carriers and that blood donations may become an important potential mechanism of transmission.
Zou S, Dodd RY, Stramer SL, Strong DM; Tissue Safety Study Group. Probability of viremia with HBV, HCV, HIV, and HTLV among tissue donors in the United States. N Engl J Med. 2004;351:751-759. The study authors examine the issue of transmitting "bloodborne pathogens" by tissue donations. The current method for screening is a retrospective review of the donor's medical history and testing of blood for hepatitis B surface antigen (HBsAg) and antibody to HIV, hepatitis C virus (HCV), and human T-cell lymphotrophic virus (HTLV). Information from blood donors was analyzed to define the possibility of viremia in the "window period" and the potential value of nucleic acid-amplification (NAA) screening to detect these viruses. The results are summarized in Table 12 , which provides the estimated frequency of viremia that would not be detected with standardized screening. Also included is the upper bounds by confidence intervals and the change that would be achieved with NAA screening.
The study authors conclude that NAA testing of tissue donors would significantly reduce the probability of these infections with transplantation. Further, they estimate the cost of such screening at less than $5 per product.
Stramer SL, Glynn SA, Kleinman SH, et al. Detection of HIV-1 and HCV infections among antibody-negative blood donors by nucleic acid-amplification testing. N Engl J Med. 2004;351:760-768. This is a report from the National Heart, Lung, and Blood Institute Nucleic Acid Test Study Group reviewing the experience in the United States in screening blood donations for HIV-1 and HCV from 1999, when the screening began, through April 2002. During this time, over 98% of blood samples for donation had NAA screening of antibody negative blood; the number positive for HIV-1 RNA was 12 of 37,164,054 U, approximately 1 of 3.1 million donations. For HCV RNA, it was 170 of 39,721,404 U or about 1 of 230,000 donations. The study authors estimate that this screening has prevented the transmission of 5 HIV infections and 56 HCV infections each year, and has reduced the individual risk of transmission-associated HIV and HCV to 1 of 2,000,000 U.
Comment: Transmission of infectious agents by blood and tissue has been the subject of substantial recent comment with attention focused on the recent experience with rabies, prion disease, and West Nile virus acquired from blood and/or tissue. These 2 studies in The New England Journal of Medicine deal with the more conventional bloodborne pathogens that are somewhat different, although the mechanism of screening to detect donors in the window period is being applied with West Nile virus in donors from high-prevalence areas. The cost of this testing is an issue. The report by Zou and associates makes a reasonable-sounding estimate of less than $5 per specimen for tissue. The editorial by Jesse Goodman from the US Food and Drug Administration (FDA) analyzes the finances with a somewhat different method: The prevention of 5 HIV infections and 56 HCV infections/year costs over $100 million or about $2 million/infection prevented. The issue is confounded by the importance of consumer confidence, liability, and the possibility of other pathogens.
Giblin TB, Sinkowitz-Cochran RL, Harris PL, et al. Clinicians' perceptions of the problem of antimicrobial resistance in health care facilities. Arch Intern Med. 2004;164:1662-1668. The US Centers for Disease Control and Prevention (CDC) has waged a national campaign to deal with antimicrobial resistance in healthcare settings with their so-called "12-step program." This study is an analysis of clinicians' perceptions of antibiotic resistance and the potential effectiveness of this campaign. The data were collected from replies to a questionnaire completed by 117 clinicians and focus groups with 28 participants, all done in Pittsburgh, Pennsylvania. According to the analysis, there was a perception that resistance was a problem nationally, but less of a problem locally. The components of the 12-step program that were regarded as most important were vaccination, restrained use of antibiotics, and the removal of catheters. The most important precautions to keep in mind are stopping therapy when the infection is cured, treating the infection rather than colonization, and practicing antibiotic control. Data for each of the 12 steps are summarized in Table 1 .
The study authors conclude that antibiotic resistance is a complex national problem. Clinicians believe that this issue is more of a national than a local concern, but a review of sensitivity patterns at the institutions included in the survey showed that this belief was unfounded.
Comment: Although the results of the survey are not surprising, the best methods for dealing with the problem are not clear. Suggestions include (1) simple, preventive messages; (2) presentations and professional society and other meetings; (3) computer-tracking systems, electronic physician order entry, clinical pathways, and local antibiograms; and (4) presentations that specify job relevance to this issue.
Lopman BA, Reacher MH, Vipond IB, Sarangi J, Brown DW. Clinical manifestation of norovirus gastroenteritis in health care settings. Clin Infect Dis. 2004;39:318-324. This is a report of a prospective analysis of outbreaks of gastroenteritis in healthcare facilities in Avon, England, including 4 major hospitals, 11 community hospitals, and 135 nursing homes. Cases were defined as (1) at least 2 episodes of vomiting, (2) at least 3 episodes of diarrhea, or (3) both, each during a 24-hour period. An outbreak was defined as more than 2 cases in a given location within 7 days. Norovirus was tested by reverse-transcriptase polymerase chain reaction (RT-PCR). Results showed 271 events that fell within the definition of outbreak, including 33 in nursing homes and 238 in hospitals. Norovirus was detected in 50% of hospital outbreaks and 74% of nursing home outbreaks. The study authors note that outbreaks not due to norovirus were caused by rotavirus and Clostridium difficile and were not markedly different. Of those due to norovirus, vomiting was reported by 67%; the median duration was 2 days, except in hospital patients in whom the mean duration was 3.7 days. The study authors conclude that norovirus is a common cause of outbreak diarrhea and vomiting within healthcare facilities involving staff and patients; it is mild and brief, but is more prolonged and severe in hospitalized patients as compared with hospital staff.
Schrag SJ, McGee L, Whitney CG, et al. Emergence of Streptococcus pneumoniae with very-high-level resistance to penicillin. Antimicrob Agents Chemother. 2004;48:3016-3023. The analysis is based on results from the CDC's Active Bacterial Core surveillance of the Emerging Infections Program Network, which has tested the antibiotic susceptibility of Streptococcus pneumoniae from invasive pneumococcal infections defined by recovery from a normally sterile site, primarily from bacteremia. During the period from 1995 to 2001, there were 23,996 pneumococcal isolates tested, and 22,025 (1%) had a minimum inhibitory concentration (MIC) of ≥ 8 mcg/mL to penicillin. The following observations apply to the 226 strains in this highly resistant category:
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The study authors conclude that the high-level resistance by S pneumoniae to penicillin that is emerging is associated with multiple drug resistance and requires monitoring.
Comment: This report may predict an ominous future for use of beta-lactams, which are currently considered the drug of choice for serious pneumococcal infections. Nevertheless, the increase in annual prevalence of pneumoccocal infection over the 6 years of study was relatively slow. Also, as the study authors point out, the dominant serotypes are 23F and 14, which are included in the protein-conjugated vaccine that appears to be highly effective in children. This vaccine seems to prevent these infections in children and their parents. Of interest, the fluoroquinolones, doxycycline, and clindamycin had relatively good efficacy against the strains that were highly resistant to beta-lactams.
Centers for Disease Control and Prevention (CDC). Update: investigation of rabies infections in organ donor and transplant recipients -- Alabama, Arkansas, Oklahoma, and Texas, 2004. MMWR Morb Mortal Wkly Rep. 2004;53:615-616. The CDC previously reported on 3 organ transplant recipients at Baylor University Medical Center, Dallas, Texas, who developed rabies from an organ donor. This study includes an additional patient who received a liver transplant at Baylor and subsequently died of encephalopathy. The donor in this case showed no evidence of rabies virus, but the donor of organs from the previously reported cases was the source of a segment of an iliac artery that was used in this recipient. Thus, the total toll from this donor with previously unsuspected rabies is 4 organ transplants with lethal outcomes ascribed to rabies encephalitis. It is also noted that the donor, on further investigation, reported being bitten by a bat.
Comment: This important but isolated case is now tightly constructed. The donor from Arkansas apparently had a bat bite, the most common method of rabies transmission in the United States. He subsequently had an enigmatic neurologic syndrome that proved fatal, and he was the source of transplanted tissue to 5 patients, including 4 who subsequently died with rabies encephalitis and 1 who died postoperatively.
Warrell MJ, Warrell DA. Rabies and other lyssavirus diseases. Lancet. 2004;363:959-969. This review of rabies and related viruses contains the following highlights.
European bat lyssavirus: A lethal case of rabies attributed to this virus was reported in Scotland in 2002, indicating that this disease was again present in England after a century of no cases. Bat rabies has been documented in Europe for about 50 years, but there are only 4 human infections known.
The United States: Thirty-five indigenous human rabies cases have been reported from 1958 to 2000. Thirty-two were caused by bat strains, of which 26 had no history of a bat bite. Twelve, however, had had physical contact with a bat.
Pathogenesis: The virus, which is inoculated with saliva through the skin, travels retrograde along the peripheral nerves to the central nervous system (CNS) at a rate of 50-100 mm/day and produces massive replication when reaching the CNS. Virus replication occurs intraneuronally. Infected patients have profound symptoms of encephalitis, but minimal histopathologic changes.
Clinical presentation: Paresthesia, usually with itching, at the site of the bite is the only prodromal symptom. The classic clinical expressions are hydrophobia and aerophobia. A neuropsychiatric illness with history of travel to a rabies-endemic area during the previous months or even years suggests this diagnosis. In the United States, contact with a bat may be trivial.
Diagnosis: Diagnostic tests are summarized in Table 3 .
Survivors: Since 1970, there have been reports of 5 patients who have survived rabies encephalitis. All received the rabies vaccine before the onset of symptoms but none received rabies immune globulin (RIG). In each case, the diagnosis was established by high antibody concentrations in the cerebrospinal fluid. Some were given nervous tissue vaccines that may cause postvaccinal encephalitis and consequently are questioned. Three of the patients had profound persisting neurologic defects.
Treatment: There is no effective treatment.
Prevention: The best method is to eliminate animal vectors, especially domestic dog sources, which account for 90% of human cases worldwide. With reference to bat rabies, there is no way to eliminate the source; therefore, avoidance of contact and prompt postexposure prophylaxis are advocated. The most successful prevention is preexposure vaccination; this has been universally effective with 3doses of tissue culture vaccine given on days 0, 7, and 28 with a booster after 1 year. With preexposure vaccination, postexposure treatment consists of 2 doses of vaccine on days 0 and 3. For postexposure treatment in the usual setting of a suspected or established exposure, there are 3 components: First, thorough washing of the wound site with soap and water reduces transmission by 50%. Virucidal agents with iodine or alcohol may be preferred. Second, a standard vaccine (HDCV; Imuvax Rabies, Aventis Pasteur or PCECV; Rabipur, Rab Avert Chiron) is given by intramuscular injection on days 0, 3, 7, 14, and 28. These tissue culture rabies vaccines are rarely associated with neurologic complications. Third, RIG passive immunization with a single dose should be infiltrated to the bite wound as soon as possible. It should be noted that RIG is expensive, scarce, and recommended only for severe injuries.
Jarvis WR. Controlling antimicrobial-resistant pathogens. Infect Control Hosp Epidemiol. 2004;25:369-372. The study author provides summary and editorial comments on several articles in this issue of Infection Control and Hospital Epidemiology, with emphasis on methicillin-resistant Staphylococcus aureus infection (MRSA), which now accounts for 50% to 70% of nosocomial S aureus strains worldwide, and vancomycin-resistant enterococci (VRE), which has increased from 0% to 25% for nosocomial enterococcal infections in the United States. Highlights of the review are:
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The study authors conclude that SHEA has recently recommended a comprehensive program to control MRSA, VRE, and other resistant pathogens, including the following elements: (1) surveillance cultures, (2) barrier precautions for those colonized and infected, (3) hand hygiene, and (4) judicious use of antibiotics.
It is noted that the 2004 SHEA Annual Meeting included at least 10 presentations documenting the benefit of these recommendations for reducing or eliminating the transmission of MRSA or VRE and improving patient outcomes.
Baddour LM, Yu VL, Klugman KP, et al. Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia. Am J Respir Crit Care Med. 2004;170:440-444. The International Pneumococcal Study Group previously reported the results of a prospective study of pneumococcal pneumonia with bacteremia from 21 hospitals in 10 countries on 6 continents from 1998 through 2001. In that study, the mortality rate was 139 of 844 (16.5%) by day 14. Analysis of this experience showed that patients who were seriously ill (defined as having a Pitt bacteremia score of 4 or more) were 8-fold more likely to die than those with lower scores (54.6% vs. 7.3%). This study failed to show that penicillin resistance conferred a mortality risk and that discordant therapy (defined as use of an antibiotic that lacked in vitro activity) had an observable effect. This study concerns an analysis of the 14-day mortality rate for those who received monotherapy vs combination treatment. Monotherapy was defined as a single antibiotic within 2 days of a positive blood culture; combination therapy was 2 antibiotics within the first 2 days of a positive blood culture. Patients who did not receive antibiotics, who had treatment delayed for more than 24 hours, or who had an "inconsistent regimen" were eliminated, leaving 592 patients in the analysis population. Analysis showed no difference between those receiving monotherapy vs those receiving combination therapy (11.5% vs 10.4%, respectively, P = NS). However, a subset analysis of those who were seriously ill had a substantially lower mortality rate with combination therapy (55.3% vs 23.4% for monotherapy vs combination treatment, respectively; P = .002). Lower mortality rates were noted when one of the 2 antibiotics was a beta-lactam, vancomycin, or a macrolide; there were no adequate numbers to analyze fluoroquinolones or clindamycin. The most common regimen was a beta-lactam, and a separate analysis of this group showed a significant decrease in patients who received a beta-lactam combination as compared with those who received monotherapy with a beta-lactam. These results are summarized in Table 4 .
The study authors conclude that combination antibiotic therapy for seriously ill patients with bacteremic pneumococcal pneumonia confers a benefit on the basis of 14-day mortality results.
Comment: This report augments 3 prior retrospective analyses that all show better outcome with pneumococcal bacteremia from combination antibiotic therapy. These studies used diverse regimens, and it has not been possible to clarify the specific ingredients of combination therapy, and the mechanism of this benefit is also unclear. Current guidelines from the Infectious Diseases Society of America (IDSA) recommend combination therapy for routine use in patients who are seriously ill with pneumonia (Mandell LA. Clin Infect Dis. 2003;31:383), but the rationale is for optimal coverage of Legionella as well as S pneumoniae. It has been noted by Austriam and Gold that antibiotic therapy for pneumococcal bacteremia has an extraordinary impact on mortality, but this has not affected mortality in the first 3 days. It was noted in the previous study by Yu and colleagues that the full analysis of data from 844 patients showed that two thirds of deaths occurred in the first 3 days, again suggesting that this early component of therapy is particularly important and challenging. This study by Baddour and associates presented Kaplan-Meier survival graphs indicating that the major benefit of combination therapy was in the first 3 days. Data from Medicare also show that rapid institution of antibiotic treatment favorably affects outcome, although this applies to pneumonia in general without subset analysis of those with pneumococcal bacteremia. Thus, a possible conclusion is that both rapid therapy and combination therapy are important components of treating seriously ill patients with community-acquired pneumonia.
Widdowson MA, Cramer EH, Hadley L, et al. Outbreaks of acute gastroenteritis on cruise ships and on land: identification of a predominant circulating strain of norovirus -- United States, 2002.J Infect Dis. 2004;190:27-36. The Vessel Sanitation Program of the CDC requires reports of gastroenteritis on cruise ships that enter US waters from foreign countries if the attack rate exceeds 2% for passengers and/or crew. Gastroenteritis is defined as at least 3 episodes of diarrhea within 24 hours or vomiting with 1-2 episodes of loose stools, abdominal cramps, headache, myalgia, or fever. During 2002, there were 21 outbreaks reported compared with 7 in 2001. This report concerns an investigation from 14 outbreaks on 12 cruise ships for which the CDC received stool samples. Of these, 12 (86%) were due to human calicivirus infections, including 11 due to noroviruses and 1 to sapovirus. Of the 11 norovirus outbreaks, 8 (73%) were attributed to GII norovirus, including 7 involving the "Farmington Hills strain" (GII/4). During 2002, the CDC also confirmed 33 land-based outbreaks attributed to noroviruses, including 10 (30%) associated with the Farmington Hills strain. Table 5 summarizes the experience with the 7 outbreaks on cruise ships, including 5 with 2 or more contiguous cruises and 1 that continued 42 days with 4 continuous cruises (Ship F). The table also includes the 10 land-based outbreaks involving the Farmington Hills strain. The table provides the source of the outbreak, the attack rate for passengers, and the major mechanism of transmission.
The study authors conclude that there needs to be better outbreak surveillance to monitor norovirus strains and to identify common sources to permit better epidemiologic control.
Comment: This study calls attention to the important role of norovirus as the major cause of outbreaks of viral gastroenteritis. Control of these infections is confounded by the fact that normal volunteer studies suggest that over 30% of norovirus infections are asymptomatic and shedding may occur for up to 14 days after the onset of disease. This experience also shows the diversity of the sources of outbreak, which is primarily person-to-person, but also may be foodborne, waterborne, or environmental. The study authors call attention to the importance of full genetic characterization of the emergent strains, such as the Farmington Hills strain, because this information may prove helpful in epidemiologic investigations and vaccine development.
Centers for Disease Control and Prevention (CDC). Update: influenza activity -- United States and worldwide, 2003-04 season, and composition of the 2004-05 influenza vaccine. MMWR Morb Mortal Wkly Rep. 2004;53:547-552. Table 6 summarizes the World Health Organization (WHO) and the CDC experiences with influenza for 2003-2004.
According to these data, the predominant strain by far globally was influenza A (H3N2). The same holds true for the United States, but antigenic analysis showed that 89% were the drift-variant A/Fujian/411/2002. In the United States, the influenza season peaked during the week ending December 27, 2003 (week 52), which is substantially earlier than in the 4 prior seasons.
Of particular interest during the past season was the experience with avian influenza, primarily influenza A (H5N1), which caused 34 cases and 23 deaths (68%) primarily in persons aged 5-24 years in Vietnam and Thailand. This highly pathogenic strain affected domestic poultry, live-bird markets, and backyard farms in 8 Asian countries. Attempts at control included the killing of over 100 million domestic poultry. The global experience with avian influenza is summarized in Table 7 .
The vaccine strain for 2004-2005 will contain A/New Caledonia/20/99-like (H1N1), A/Fujian/411/2002-like (H3N2), and B Shanghai/361/2002-like viruses. As noted above, the Fujian strain became the predominant circulating strain in the 2003-2004 influenza season. A previous study suggested that the vaccine for 2003-2004 was not effective, but subsequently there have been 3 additional unpublished studies that all demonstrated vaccine effectiveness. It is anticipated that vaccine manufacturers will produce 90-100 million doses of this vaccine for the United States next season.
Piccirillo JF. Clinical practice. Acute bacterial sinusitis. N Engl J Med. 2004;351:902-910. This Clinical Practice review on acute bacterial sinusitis was written by Jay Piccirillo, an ear, nose, and throat (ENT) surgeon from Washington University in St. Louis, Missouri. Here are some highlights of the review.
Frequency of bacterial infection in patients with viral rhinosinusitis: .5% to 2% of all cases, up to 50% in patients who are seen in a medical clinic, and up to 80% in patients seen in ENT services.
Distinction between bacterial and viral infection: Most rhinoviral infections improve in 7-10 days. The recommendation is to make this distinction on the basis of persistence of symptoms for more than 10 days or the worsening of symptoms after 5-7 days.
Imaging: X-ray criteria are sinus opacity, a fluid level, or a marked mucosal thickening, but these do not distinguish bacterial from viral infections. Computed tomographic (CT) scans do not distinguish bacterial vs viral infection either and are frequently misleading.
Symptomatic therapy: Available evidence indicates minimal benefit.
Antibiotic therapy: The literature is extensive and confusing. Here are some highlights:
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Complications: Patients with periorbital swelling, erythema, and face pain with or without mental status changes should have CT scanning and treatment with azithromycin, fluoroquinolone, ceftriaxone, or amoxicillin-clavulanate.
Allergic rhinitis: Loratadine proved successful in a placebo-controlled trial. Intranasal steroids, such as flunisolide spray, appear effective. Intranasal steroids also shortened the duration of symptoms in patients with exacerbations of chronic rhinitis.
Guidelines: Recommendations of the American College of Physicians include the following:
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Sobel JD, Wiesenfeld HC, Martens M, et al. Maintenance fluconazole therapy for recurrent vulvovaginal candidiasis. N Engl J Med. 2004;351:876-883. This is a prospective, multicenter, randomized trial of weekly fluconazole compared with placebo in women with recurrent vulvovaginal candidiasis. Eligibility required a positive potassium hydroxide preparation of vaginal secretions and at least 4 documented episodes of Candida vaginitis within the previous 12 months. Women with HIV infection were excluded. The treatment was fluconazole, 150 mg weekly for 6 months. Patients were seen monthly for a detailed clinical history, pelvic exam, and vaginal fungal culture. Baseline cultures showed that Candida albicans accounted for 401 of 427 (94%) of cases. Results at the end of therapy (6 months) showed a dramatic difference in outcome with clinical remissions in 91% of fluconazole recipients as compared with 36% in the placebo group and negative fungal cultures in 81% in the fluconazole group as compared with 28% in the placebo group. Fungal cultures obtained during the course of therapy showed no fluconazole-resistant strains of C albicans defined at a MIC threshold of 64 mcg/mL and no change in the MIC90 for fluconazole in either group. An additional 6 months of observation after therapy showed that the clinical benefit was still significantly greater in the fluconazole group, but the difference was less striking at 43% vs 22%. These results are summarized in Table 9 .
The study authors conclude that long-term weekly treatment with fluconazole can significantly reduce the rate of recurrence of symptomatic vaginal candidiasis, but long-term cure is elusive.
Comment: Chronic, recurrent vaginal candidiasis is said to occur in 5% to 8% of women. Treatment may be topical with intravaginal azoles given once or twice weekly, but this is less popular than oral treatment. The clinical benefit achieved with weekly fluconazole might be expected. The particularly important components of this study are the inclusion of a placebo-control group to substantiate the benefit and especially the laboratory studies showing the lack of evolution of fluconazole resistance. Of particular concern in this study are the facts that some patients had persistent symptoms and most had a recurrence of chronic symptoms by 6 months after discontinuing weekly treatment. The cause of these persistent and recurrent infections is not known.
Polk RE, Johnson CK, McClish D, Wenzel RP, Edmond MB. Predicting hospital rates of fluoroquinolone-resistant Pseudomonas aeruginosa from fluoroquinolone use in US hospitals and their surrounding communities Clin Infect Dis. 2004;39:497-503. The study authors examined the correlation between fluoroquinolone use and increased resistance by Pseudomonas aeruginosa. Hospital use of fluoroquinolones was based on data from 24 hospitals during the period from 1999 through 2001 and expressed as defined daily doses/1000 patient-days. Data for community use were based on information obtained from IMS Health (www.imshealth.com) with zip codes for participating hospitals within a 10-mile radius. The results showed a correlation between increasing use of fluoroquinolones and decreasing sensitivity of P aeruginosa to these agents. Both community and hospital use of fluoroquinolones predicted resistance; levofloxacin was associated with resistance, but ciprofloxacin was not. These results are summarized in Table 10 .
The study authors conclude that fluoroquinolone use contributes to resistance, including multiply resistant P aeruginosa, which is sensitive only to colistin; that both hospital and community use contribute to this trend; and there appears to be a difference in the fluoroquinolone implicated because the association was found with levofloxacin and not with ciprofloxacin.
Comment: The association between fluoroquinolone use and resistance by P aeruginosa is not surprising. However, the data suggesting that this difference is primarily due to levofloxacin and not ciprofloxacin are surprising. The study authors conclude that their observations suggest either restraint in the use of fluoroquinolones or preferential use of ciprofloxacin.
Huang DB, Awasthi M, Le BM, et al. The role of diet in the treatment of travelers' diarrhea: a pilot study. Clin Infect Dis. 2004;39:468-471. The study authors report their experience with 105 US college students aged 18-26 years attending summer sessions in Guadalajara who participated in various antimicrobial studies. Patients with acute diarrhea on restricted diets were instructed to take clear liquids to match diarrheal losses and limit solid foods to salted crackers, tortillas, and bread or toast; when symptoms improved, they could add bananas, rice, potatoes, baked chicken, or fish. Foods to avoid until symptoms had cleared were red meat, cheese, milk, butter, ice cream, vegetables, fried foods, coffee, alcohol, and fruit other than bananas. Those on unrestricted diets were told to replenish diarrheal losses with fluids but to eat and drink whatever they wished. There were 48 subjects randomized to the restricted diet and 57 to the unrestricted diet. An analysis of trial diaries indicated that only 5 subjects did not adhere to their assignments. The analysis showed no difference in outcome. Specifically, the duration of diarrhea defined as the "time to last unformed stool" was a mean of 37 hours in the restricted diet group and 33 hours in those with no restrictions. The study authors conclude that the study showed no obvious benefit of a restricted diet in the treatment of acute travelers' diarrhea in patients who were receiving an antimicrobial agent. Specifically, they recommend that patients who are hungry should eat.
Dodek P, Keenan S, Cook D, et al. Evidence-based clinical practice guideline for the prevention of ventilator-associated pneumonia. Ann Intern Med. 2004;141:305-313. The following represents the summary opinion of the Joint Planning Group of the Canadian Critical Care Society and Canadian Critical Care Trials Group on ventilator-associated pneumonia (VAP) on the basis of a systematic search of controlled trials before April 2003, with 3 bibliographic databases: MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews ( Table 11 ).
Hopkin M. Fears grow as blood stocks pass on prions undetected. Nature. 2004;430:712. The "News" section of Nature reviews issues relating to 2 patients who acquired variant Creutzfeldt-Jakob disease (vCJD) from transfusions. To date, there have been 142 deaths in Britain due to this disease, and the assumption has been that these were acquired by consuming beef. All of these patients have been homozygotes at codon 129 of the prion protein (PrP) gene, but the second case of transfusion-associated infection was a patient who was heterozygous at this loci. This is a patient who received a transfusion in 1999, died of an aneurysm, and had the PrP of vCJD identified in the spleen and lymph nodes. This observation suggests that there may be many more asymptomatic carriers and that blood donations may become an important potential mechanism of transmission.
Zou S, Dodd RY, Stramer SL, Strong DM; Tissue Safety Study Group. Probability of viremia with HBV, HCV, HIV, and HTLV among tissue donors in the United States. N Engl J Med. 2004;351:751-759. The study authors examine the issue of transmitting "bloodborne pathogens" by tissue donations. The current method for screening is a retrospective review of the donor's medical history and testing of blood for hepatitis B surface antigen (HBsAg) and antibody to HIV, hepatitis C virus (HCV), and human T-cell lymphotrophic virus (HTLV). Information from blood donors was analyzed to define the possibility of viremia in the "window period" and the potential value of nucleic acid-amplification (NAA) screening to detect these viruses. The results are summarized in Table 12 , which provides the estimated frequency of viremia that would not be detected with standardized screening. Also included is the upper bounds by confidence intervals and the change that would be achieved with NAA screening.
The study authors conclude that NAA testing of tissue donors would significantly reduce the probability of these infections with transplantation. Further, they estimate the cost of such screening at less than $5 per product.
Stramer SL, Glynn SA, Kleinman SH, et al. Detection of HIV-1 and HCV infections among antibody-negative blood donors by nucleic acid-amplification testing. N Engl J Med. 2004;351:760-768. This is a report from the National Heart, Lung, and Blood Institute Nucleic Acid Test Study Group reviewing the experience in the United States in screening blood donations for HIV-1 and HCV from 1999, when the screening began, through April 2002. During this time, over 98% of blood samples for donation had NAA screening of antibody negative blood; the number positive for HIV-1 RNA was 12 of 37,164,054 U, approximately 1 of 3.1 million donations. For HCV RNA, it was 170 of 39,721,404 U or about 1 of 230,000 donations. The study authors estimate that this screening has prevented the transmission of 5 HIV infections and 56 HCV infections each year, and has reduced the individual risk of transmission-associated HIV and HCV to 1 of 2,000,000 U.
Comment: Transmission of infectious agents by blood and tissue has been the subject of substantial recent comment with attention focused on the recent experience with rabies, prion disease, and West Nile virus acquired from blood and/or tissue. These 2 studies in The New England Journal of Medicine deal with the more conventional bloodborne pathogens that are somewhat different, although the mechanism of screening to detect donors in the window period is being applied with West Nile virus in donors from high-prevalence areas. The cost of this testing is an issue. The report by Zou and associates makes a reasonable-sounding estimate of less than $5 per specimen for tissue. The editorial by Jesse Goodman from the US Food and Drug Administration (FDA) analyzes the finances with a somewhat different method: The prevention of 5 HIV infections and 56 HCV infections/year costs over $100 million or about $2 million/infection prevented. The issue is confounded by the importance of consumer confidence, liability, and the possibility of other pathogens.
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