From the publishers of

The New England Journal of Medicine

November 2008

Vol. 11 No. 11

Persistence of Humoral Immunity for 90 Years!

nderstanding the duration of the immune response is very important both for the design of new vaccines and for the development of immunization strategies. Recent research has shown that the half-life of the antibody response to some antigens exceeds 50 years ( JW Infect Dis Dec 2007, p. 95, and N Engl J Med 2007; 357:1903). Now, investigators have used recombinant hemagglutinin (HA) that has been produced based on the sequence of the 1918 pandemic H1N1 influenza virus to study the residual immune response of pandemic survivors. The investigators identified 32 individuals, aged 91 to 101, many of whom recalled illness in the household during the 1918 pandemic. All were found to have serum-neutralizing activity against the 1918 H1N1 virus; 94% showed serologic reactivity to the 1918 HA (i.e., hemagglutination inhibition assay titres 1:40), versus only 10% of 30 individuals born between 1926 and 1955. Peripheral blood mononuclear cells were isolated from eight of the survivors, and seven of the samples had circulating B cells that produced antibodies to the 1918 HA. Five monoclonal antibodies against the 1918 HA were developed from B cells isolated from three survivors. These monoclonal antibodies showed cross-reactivity with a genetically related 1930 swine influenza strain but not with human H1N1 isolates from 1943, 1947, or 1999. One of the five antibodies showed slight cross-reactivity with a human H1N1 isolate from 1977. Each of the five protected mice against lethal infection with the reconstructed 1918 virus.

virus suggests that the pandemic survivors humoral immunity was not the result of immunologic boosting from infection by related viruses, but rather that humoral immunity can persist for at least 9 decades after exposure. Richard T. Ellison III, MD
Yu X et al. Neutralizing antibodies derived from the B cells of 1918 influenza pandemic survivors. Nature 2008 Sep 25; 455:532.

Bacterial Pneumonia as Pandemic Flu Killer

he 19181919 influenza pandemic caused an estimated 675,000 excess deaths in the U.S. As we prepare for the next pandemic, we need to understand whether these deaths were caused by primary viral infection or secondary bacterial infection. To investigate this issue, researchers from the NIH reexamined postmortem samples from 58 people who died of influenza during the 19181919 pandemic and reviewed pathologic and bacteriologic information, from 109 published autopsy series, on 8398 persons who died during the pandemic.

Microscopic examination of recut lung tissue sections from pandemic victims revealed evidence of severe acute bacterial pneumonia in almost all cases. The autopsy literature from the time of the pandemic demonstrated a consensus that most deaths resulted not from direct effects of the (as-yet-unidentified) causative agent of influenza, but rather from severe secondary pneumonia caused by well-known bacterial pathogens most often pneumococci, streptococci, and staphylococci. Notable findings from the autopsy series include extensive bacterial invasion, with phenomenal numbers of organisms and dense neutrophil infiltration. Review of 96 autopsy series totaling 5266 pandemic victims revealed bacterial growth in >95% of cases, with Streptococcus pneumoniae predominating (isolated from 23.5% of victims).

Comment:
This study is an important reminder that secondary bacterial infection was the major killer during the greatest influenza pandemic in modern history. If, during a future influenza pandemic, secondary bacterial infection occurs as commonly as it did in 19181919, the availability of

TA B L E O F C O N T E N T S
Persistence of Humoral Immunity for 90 Years! ........................................ 81 Bacterial Pneumonia as Pandemic Flu Killer ............................. 81 Maraviroc: Phase III Studies Published ............................................. 82 Clinical Practice Guideline Watch: Hepatitis B: Identification and Management ................................. 83 When Did HIV Emerge? .......................... 83 Prolonged Shedding of Norwalk Virus in Feces ...................................... 84 Baby Steps Toward Polio Eradication ...... 84 Kawasaki Disease: Predicting Treatment Nonresponse........................................ 84 Oral Probiotics to Prevent Necrotizing Enterocolitis .................... 85 New Formulation of Combination Antimalarial Drug for Children ........... 85 Bronchoscopy for Diagnosing TB in Children ..................................... 85 Procalcitonin to Guide Antibiotic Use in Primary Care ........... 86 A Herd Effect of PCV-7 or Quinolones on S. pneumoniae ? ......... 86 Doxycycline or Tetracycline for Primary Syphilis .................................. 87 Levofloxacin and E. coli Resistance ........ 87 Aspergillosis in Stem-Cell Transplantation ................................... 87 Transplant-Associated LCMV Infection ................................... 88

Comment:
That the monoclonal antibodies generated in this work were specific to the 1918

Journal Watch (and its design) is a registered trademark of the Massachusetts Medical Society.
An editorially independent literature-surveillance newsletter summarizing articles from major medical journals. 2008 Massachusetts Medical Society. All rights reserved. Disclosure information about our authors can be found at http://infectious-diseases.jwatch.org/misc/board_disclosures.dtl

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JOURNAL WATCH INFECTIOUS DISEASES bacterial vaccines and antibiotics will be at least as important as that of influenza vaccines and antivirals. As the authors and an editorialist point out, pandemic planning should incorporate strategies to prevent and treat bacterial pneumonia. Daniel J. Diekema, MD, MS
Morens DM et al. Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: Implications for pandemic influenza preparedness. J Infect Dis 2008 Oct 1; 198:962. McCullers JA. Planning for an influenza pandemic: Thinking beyond the virus. J Infect Dis 2008 Oct 1; 198:945.

Volume 11

Number 11

EDITOR-IN-CHIEF

Larry M. Baddour, MD
Professor of Medicine, Division of Infectious Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota
DEPUT Y EDITOR

Richard T. Ellison III, MD

Professor of Medicine, Molecular Genetics and Microbiology, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester
FOUNDING EDITOR

undetectable VLs when given maraviroc twice daily than when given maraviroc once daily, with no evidence of increased toxicity.) Although the proportion of patients with hepatitis C or B virus coinfection was low, maraviroc appeared to be safe in this population. Among patients who experienced virologic failure on maraviroc and underwent repeat tropism testing, 57% were found to have dual-mixed or X4-tropic HIV.

Neil R. Blacklow, MD
Professor and Chairman Emeritus, Department of Medicine, University of Massachusetts Medical School, Worcester, and Lecturer on Medicine, Harvard Medical School, Boston
EXECUTIVE EDITOR

Comment:
Unlike other antiretroviral medications, maraviroc binds to a host protein rather than to a viral target. To date, the drug appears to be safe and well tolerated, and it does not appear to have excess rates of hepatotoxicity or malignancy, which had been concerns with other CCR5 antagonists; nevertheless, longterm monitoring for unexpected adverse events is warranted. As anticipated, the rate of virologic suppression was highest when maraviroc was combined with other active agents; results should be even better than those seen in the MOTIVATE trials when maraviroc is given with active drugs, such as darunavir, etravirine, and raltegravir, that were not available during the study period. Maraviroc should be restricted to patients who are infected with R5-tropic HIV only, which somewhat limits its use. For example, in studies of treatmentexperienced patients, 38% to 50% were found to have nonR5-tropic HIV. The proportion may be even higher with use of a new, enhanced tropism assay that can detect minority viral populations better than did the first-generation assay employed in the MOTIVATE studies. Although testing with this new assay might exclude more patients from using maraviroc, treatment results may be even better among those who qualify, because in some cases virologic failure probably arises from selection of preexisting nonR5-tropic HIV that was missed by the original test. Rajesh T. Gandhi, MD
Gulick RM et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med 2008 Oct 2; 359:1429. Ftkenheuer G et al. Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection. N Engl J Med 2008 Oct 2; 359:1442. Dolin R. A new class of anti-HIV therapy and new challenges. N Engl J Med 2008 Oct 2; 359:1509.

Elizabeth B. Schmidt
Massachusetts Medical Society
A S S O C I AT E E D I T O R S

Neil M. Ampel, MD
Professor of Medicine and Public Health, University of Arizona College of Medicine; Staff Physician, Southern Arizona VA Health Care System, Tucson

Maraviroc: Phase III Studies Published

IV enters cells by binding to the CD4 molecule and a coreceptor. One of the main viral coreceptors is CCR5. Maraviroc, the first CCR5 antagonist to be approved, underwent phase III testing in two large, industryfunded, multinational studies called MOTIVATE 1 and 2; the results of these two pivotal trials have just been published. A total of 1049 adults with R5-tropic HIV only and resistance to or previous treatment with drugs from three antiretroviral classes were randomized to receive once- or twice-daily maraviroc or placebo along with optimized background therapy. Agents that were investigational when the study was launched including the now-approved drugs darunavir, raltegravir, and etravirine were not permitted. At week 48, 46% of the twice-daily maraviroc group and 43% of the oncedaily maraviroc group had viral loads (VLs) <50 copies/mL, compared with 17% of the placebo group. CD4-count increases were also greater with maraviroc than with placebo (mean, 124 cells/mm3 in the twice-daily maraviroc group vs. 61 cells/mm3 in the placebo group). The rate of drug discontinuation because of treatment-related adverse events was low (3%) in all three groups. In subgroup analyses, maraviroc was superior to placebo in patients who had CD4 counts <50 cells/mm3 at baseline or VLs 100,000 copies/mL at screening. (In fact, the approved dosing is based, in part, on 24-week findings that more participants in these hard-totreat groups and in the group with HIV resistant to all other agents achieved

Robert S. Baltimore, MD
Professor of Pediatrics and Epidemiology, Yale University School of Medicine; Associate Hospital Epidemiologist for Pediatrics, YaleNew Haven Hospital

Stephen G. Baum, MD
Senior Associate Dean for Students and Professor of Medicine, Albert Einstein College of Medicine, Bronx, New York

Daniel J. Diekema, MD, MS

Clinical Professor, Departments of Internal Medicine and Pathology, University of Iowa Carver College of Medicine; Hospital Epidemiologist, VA Medical Center, Iowa City

Lynn L. Estes, PharmD

Assistant Professor of Medicine, Mayo Clinic College of Medicine, and Infectious Disease Pharmacy Specialist, Mayo Clinic, Rochester, Minnesota

Rajesh T. Gandhi, MD
Associate Professor of Medicine, Harvard Medical School; Director, HIV Clinical Services and Education, Massachusetts General Hospital, Boston

Thomas Glck, MD
Professor of Medicine, University of Regensburg; Chief, Department of Medicine, District Hospital Trostberg, and Chief, Infectious Diseases Consulting Service, District Hospitals Traunstein and Trostberg, Bavaria, Germany

Mary E. Wilson, MD
Associate Clinical Professor of Medicine, Harvard Medical School; Associate Professor, Department of Global Health and Population, Harvard School of Public Health, Boston
M A S S AC H U S E T T S M E D I C A L S O C I E T Y

Ronald J. Elliott, Philip J. LoPiccolo, Catherine Tomeo Ryan, Staff Editors Terri Autieri, Copy Editor; Gina DeDominici, Layout Christopher R. Lynch, Vice President for Publishing Alberta L. Fitzpatrick, Publisher Matthew ORourke, Director, Editorial Operations and Development Art Wilschek, Christine Miller, Lew Wetzel, Advertising Sales William Paige, Publishing Services Bette Clancy, Customer Service
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November 2008

JOURNAL WATCH INFECTIOUS DISEASES

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CLINIC AL PR AC TICE GUIDELINE WATCH

Hepatitis B: Identification and Management

Target Group: Public health officials, organizations, and healthcare professionals involved in the development, delivery, and evaluation of prevention and clinical services Sponsoring Organization: U.S. Centers for Disease Control and Prevention Type: Consensus of experts in the fields of prevention, care, and treatment of chronic hepatitis B virus (HBV) infection Key Points: In the U.S., the number of new HBV infections has declined substantially during the last 2 decades as a result of vaccination programs. Worldwide, however, about 350 million people have chronic HBV infection, and >600,000 people die each year from HBV-related liver disease. Many individuals with HBV infection remain asymptomatic for years; therefore, their contacts are unlikely to receive vaccination or HBV-directed care. For these reasons, and because we have effective treatment modalities that may prevent cirrhosis and cancer, optimization of screening tactics is important. The guidelines describe the serologic markers that are present during the various phases of chronic HBV infection and provide an expanded list of populations for whom screening is recommended. These high-risk groups now include household contacts and sex partners of persons with chronic HBV infection, men who have sex with men, injection-drug users, HIV-infected or otherwise immunocompromised patients, persons with liver disease of unknown etiology, and individuals born in areas where the prevalence of chronic HBV is 2% (lowered from 8%). The recommendation for wider screening is consistent with existing public health policy, which focuses on protecting contacts, including healthcare workers, as well as treating HBV-infected persons. The primary screening tool recommended is a serologic assay for hepatitis B surface antigen (HBsAg). A confirmed positive HBsAg result indicates active infection, either chronic or acute. Chronic infection is determined by the absence of IgM antibody to hepatitis B core antigen or the persistence of HBsAG or HBV DNA in the blood for 6 months. Programs for implementing screening procedures are described. The document also includes discussion of vaccination strategies for screened individuals and their contacts and provides details of contact management, patient education, and the development of surveillance registries of persons with chronic HBV infection. A section on medical management of chronic HBV infection notes rapid changes in the therapy for this condition; seven therapies two alfainterferon preparations and five antiviral agents with activity against HBV have now received FDA approval.

Comment:
These recommendations are timely, if not overdue, given the developments in prevention, recognition, and treatment of hepatitis B. Stephen G. Baum, MD
Centers for Disease Control and Prevention (CDC). Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. MMWR Recomm Rep 2008 Sep 19; 57:1.

When Did HIV Emerge?

he first AIDS cases in the U.S. were reported in 1981. Soon thereafter, HIV was identified as the underlying pathogen. A viral sequence from 1959 (ZR59) represents the earliest known HIV infection; however, the lack of other viral sequences from before 1976 has hindered efforts to estimate when HIV entered the human population. Now, investigators have shed light on this issue by analyzing the sequence from a newly discovered HIV isolate from 1960. Bouins-fixed, paraffin-embedded histopathologic blocks were found in the 19581962 archives of the Department of Anatomy and Pathology at the University of Kinshasa in the Democratic Republic of Congo. One lymph node specimen, obtained from an adult female in 1960, contained HIV RNA. Comparison of the sequence from this sample (DRC60) with ZR59 and three reference sequences from samples collected between 1981 and 1997 suggests that

the most recent common ancestor virus was circulating near the beginning of the twentieth century; a Bayesian skyline plot yielded an estimate sometime between 1884 and 1924. The genetic distance between ZR59 and DRC60 indicates that the virus diversified in Africa long before the recognition of AIDS.

that the rise of cities may have facilitated the establishment and early spread of HIV in Africa. Rajesh T. Gandhi, MD
Worobey M et al. Direct evidence of extensive diversity of HIV-1 in Kinshasa by 1960. Nature 2008 Oct 2; 455:661.

Comment:
HIV probably entered the human population by cross-species transmission of an ancestral virus found in wild chimpanzees in central Africa. Based on the present analysis, this event may have occurred around the beginning of the twentieth century. What factors contributed to the subsequent spread of the virus? The investigators note that no sites with more than 10,000 people existed in central Africa until after 1910. The emergence of HIV at about the same time as the development of urban agglomerations and its subsequent diversification as human population increased later in the century suggests

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JOURNAL WATCH INFECTIOUS DISEASES

Atmar RL et al. Norwalk virus shedding after experimental human infection. Emerg Infect Dis 2008 Oct; 14:1553.

Volume 11

Number 11

Prolonged Shedding of Norwalk Virus in Feces

oroviruses, the most common cause of viral gastroenteritis in the U.S., are responsible for an estimated 23 million cases per year. To better understand fecal excretion of Norwalk virus, researchers in Texas challenged healthy adults aged 18 to 50 with oral doses of Norwalk virus ranging from 4.8 to 4800 reverse-transcriptase (RT)-PCR units. After challenge, participants were observed for 96 hours in a research center. Thereafter, fecal samples were collected daily for 21 days and then weekly for 5 additional weeks. Eleven of 16 participants who met the criteria for Norwalk virus infection had gastroenteritis, as defined by the research protocol. Median duration of symptoms and signs was 23 hours (range, 1061 hours). Viral shedding as measured by immunomagnetic capture (IMC) RT-PCR was first detected a median of 36 hours after challenge (range, 18110 hours); in seven participants, virus was detected in fecal specimens 3 to 14 hours before signs or symptoms developed. Viral shedding as measured by antigen ELISA was first detected approximately 33 hours after inoculation. Shedding peaked a median of 4 days after challenge. Virus concentration dropped over time, but in 11 of 16 participants, feces remained positive by IMC RT-PCR for 4 weeks after inoculation; 2 participants still tested positive on day 56.

Comment:
The findings from these two studies and from other investigations ( JW Infect Dis Jun 2007, p. 45, and Lancet 2007; 369:1356 and 1363) provide strong evidence that the WHO will achieve its goal of global poliovirus eradication. Although much more work is needed, the progress to date engenders optimism. Larry M. Baddour, MD
El-Sayed N et al. Monovalent type 1 oral poliovirus vaccine in newborns. N Engl J Med 2008 Oct 16; 359:1655. Jenkins HE et al. Effectiveness of immunization against paralytic poliomyelitis in Nigeria. N Engl J Med 2008 Oct 16; 359:1666. Ehrenfeld E and Chumakov K. Monovalent oral poliovirus vaccines A good tool but not a total solution. N Engl J Med 2008 Oct 16; 359:1726.

Baby Steps Toward Polio Eradication

wenty years ago, the WHO pledged to eradicate poliomyelitis. The number of cases decreased by >99% between 1988 and 2005, and wild poliovirus type 2 was eliminated, but eradication has remained elusive. In response to calls for a more immunogenic product, researchers quickly developed a new monovalent type 1 oral poliovirus vaccine. In two recent studies, investigators examined the efficacy of this vaccine in children. El-Sayed and colleagues conducted a randomized trial involving 421 newborns at three clinics in Egypt. They compared humoral antibody responses after a single dose of monovalent type 1 or trivalent oral poliovirus vaccine administered at birth and quantified mucosal immunity after a challenge dose of monovalent vaccine administered 30 days after birth. They also determined adverse events following vaccination. Thirty days after vaccine administration, the rate of seroconversion to type 1 virus was higher in the monovalentvaccine group than in the trivalentvaccine group (55% vs. 32%; P <0.001). Mucosal immunity also differed between groups: 7 days after monovalent type 1 vaccine challenge, the proportion of participants who were excreting type 1 virus in stool was lower in the monovalent-vaccine group than in the trivalent-vaccine group (26% vs. 42%; P =0.001). Both vaccines were well tolerated; no serious adverse events were attributed to either one. Using a national surveillance database, Jenkins and colleagues identified cases of virologically confirmed poliomyelitis reported between 2001 and 2007 in Nigerian children aged <15 years. This database also contained information on the types of vaccines and the number of doses administered. The efficacy of monovalent type 1 oral poliovirus vaccine against paralysis from type 1 poliomyelitis was four times that of the trivalent oral vaccine (67% [95% confidence interval, 3982] vs. 16% [95% CI, 1021]).

Kawasaki Disease: Predicting Treatment Nonresponse

or most children with Kawasaki disease (KD), treatment with intravenous immunoglobulin (IVIG) reduces the duration of fever and other symptoms and decreases the risk for developing coronary artery aneurysms. For some children, however, a single treatment with IVIG does not produce symptom abatement, and the risk for developing coronary artery aneurysms increases. Researchers at a large childrens hospital in California reviewed the medical records of KD patients discharged from 2002 through 2006 to determine the risk factors for nonresponse to IVIG treatment. At this hospital, diagnosis of KD followed American Heart Association guidelines, and details of KD management (including the treatment doses of IVIG and aspirin, as well as follow-up protocol) were standardized through the use of a clinical pathway. Of 196 children with KD, 40 (20%) did not respond to initial therapy i.e., they had persistent fever, or recurrence of fever >48 hours after completing IVIG infusion. Multivariate analysis revealed that the risk factors for nonresponse were an albumin level 3 mg/dL, a band count >10% on peripheral blood smear, and an abnormal initial echocardiographic examination. Responders and nonresponders were similar in other laboratory results and in age, ethnicity,

Comment:
Knowledge of the timing and intensity of viral shedding is relevant in considering transmission risk. The start of shedding before symptom onset and the occurrence of peak shedding after symptom resolution could contribute to rapid spread of infection in a population. The sensitive techniques used in this study suggested persistence of virus up to 8 weeks after inoculation, although, as the authors acknowledge, the assay could not determine whether virus was still infectious at that time. Another limitation stems from the fact that participants were not tested for Norwalk virus before inoculation, although they were screened for history of recent gastroenteritis and had negative studies for enteric pathogens and ova and parasites. Mary E. Wilson, MD

November 2008

JOURNAL WATCH INFECTIOUS DISEASES A composite of death or NEC of stage 2 also occurred less frequently in the treatment group (4 of 217 vs. 20 of 217; P =0.002). The probiotic agents caused no infections or other adverse effects.

Page 85

duration of fever at time of diagnosis, and peak temperature.

Comment:
Previous studies have shown these and other laboratory findings to be associated with poorer treatment outcome in KD. The 20% nonresponse rate seen here is somewhat higher than the 10% to 15% reported earlier, however. This difference may be explained, at least in part, by the fact that 11 patients re-treated with IVIG before the standard 48-hour waiting period were categorized as nonresponders. These risk factors can help to identify children who may need more-aggressive treatment and closer follow-up. The information provided is also useful in advising families about the prognosis for their children who are diagnosed with KD. Robert S. Baltimore, MD
Ashouri N et al. Risk factors for nonresponse to therapy in Kawasaki disease. J Pediatr 2008 Sep; 153:365.

Comment:
One flaw in this study was a significantly lower birth weight in the treatment group than in the controls (mean, 1029 g vs. 1077 g), which required statistical adjustment. The reduction of neonatal sepsis that has been reported in previous studies was not shown here. Nonetheless, the present findings do add to accumulating evidence favoring the use of probiotics in VLBW infants. Robert S. Baltimore, MD
Lin H-C et al. Oral probiotics prevent necrotizing enterocolitis in very low birth weight preterm infants: A multicenter, randomized, controlled trial. Pediatrics 2008 Oct; 122:693.

group vs. 98.5% for the crushed-tablet group). Drug concentrations and the proportion of patients with late parasitological failure (11.4% vs. 13.4%) were also similar between groups. Adverse reactions were similar in frequency and type between formulations, with vomiting being the most common drug-related adverse event (7.4% vs. 9.3%).

Comment:
The new formulation had safety and efficacy profiles similar to those of the conventional one. Will more infants and children be able to achieve therapeutic drug levels (and have better survival) with a sweet, cherry-flavored drug? In this study population that was treated in a controlled setting, both drugs were delivered effectively. In a nonstudy setting, the new drug might perform better, but that remains to be seen. Editorialists note that crushing the conventional tablets at home may lead to loss of active ingredients and thus to underdosing. Mary E. Wilson, MD
Abdulla S et al. Efficacy and safety of artemether-lumefantrine dispersible tablets compared with crushed commercial tablets in African infants and children with uncomplicated malaria: A randomised, single-blind, multicentre trial. Lancet 2008 Oct 15; [e-pub ahead of print]. (http://dx .doi.org/10.1016/S0140-6736(08)61492-0) Teklehaimanot A and Teklehaimanot HD. Alternative form of artemetherlumefantrine for infants. Lancet 2008 Oct 15; [e-pub ahead of print]. (http://dx .doi.org/10.1016/S0140-6736(08)61493-2)

Oral Probiotics to Prevent Necrotizing Enterocolitis

ecrotizing enterocolitis (NEC) is a devastating intestinal condition primarily affecting very-low-birth-weight (VLBW) premature newborns. Some studies have linked it to feeding practices. Evidence from two clinical trials suggests that orally administered probiotics reduce the incidence of NEC in VLBW infants, but the optimal strains, dosage, duration, and timing of treatment have not been determined. Now, in a prospective, blinded study conducted from April 2005 through May 2007 at seven neonatal ICUs in Taiwan, researchers have explored this issue further. A total of 443 VLBW premature infants (gestational age, <34 weeks; birth weight, <1500 g) without other preexisting conditions who had no major anomalies and survived to start enteral feeding were randomized to receive a mixture of Lactobacillus acidophilus and Bifidobacterium bifidum (Infloran; available from commercial sources; 125 mg/kg/ dose twice daily with feeds), or regular feeds without probiotics, for 6 weeks. Feeding practices were standardized, as were diagnosis and classification of NEC. Among the 434 infants who completed the study, NEC of stage 2 developed less frequently in treated infants than in controls (4 of 217 vs. 14 of 217; P =0.02).

New Formulation of Combination Antimalarial Drug for Children

orldwide, most deaths from malaria occur in infants and young children. One hurdle in treating pediatric patients is delivering antimalarial drugs in a form that achieves therapeutic blood levels. Artemisinincontaining combination therapy is now recommended for most areas and is being used in many countries. In a single-blind study partly supported by industry, investigators compared the efficacy and safety of artemetherlumefantrine in two forms: newly developed dispersible cherry-flavored tablets and crushed conventional tablets. The study was conducted in five malariaendemic African countries. Infants and children aged 12 years with acute uncomplicated falciparum malaria were admitted to a hospital and randomized to receive conventional or dispersible tablets, suspended in water, at weightappropriate doses twice daily for 3 days. Among the 899 patients who were randomized, 70% were aged 1 to 5 years; 782 patients completed the 42-day follow-up. Day-28 PCR-corrected cure rates in the intent-to-treat population, which included patients who took one or more full doses of medication and had at least one follow-up visit, were similar between groups (97.8% for the dispersible-tablet

Bronchoscopy for Diagnosing TB in Children

B is difficult to diagnose in children because of problems in obtaining good-quality sputum samples. Endobronchial TB (ETB) tuberculous infection of the tracheobronchial tree is particularly difficult to diagnose because it is not evident on radiographic imaging. Now, researchers in Turkey describe their experience with flexible bronchoscopy (FB) as an adjunct to other tests for diagnosis of complicated and persistent TB in children. The study involved 70 children with suspected TB (respiratory symptoms and radiographic findings suggestive of TB; positive contact history) or an inadequate response to 8 weeks of antiTB treatment. All underwent FB with bronchoalveolar lavage.

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JOURNAL WATCH INFECTIOUS DISEASES care among adult outpatients who had acute RTIs. All participants were believed consistent with evidence-based guidelines to require antibiotic treatment. When PCT-arm patients had PCT levels >0.25 g/L, a bacterial infection was considered likely, and antibiotic prescription was recommended; for lower levels, antibiotic prescription was discouraged. When antibiotics were withheld, a second PCT level was obtained within 6 to 24 hours. If the level was then >0.25 g/L or had increased by >50% with no clinical improvement, antibiotics were recommended. In addition, all patients prescribed antibiotics based on PCT levels were reassessed after 3 days, and antibiotics were discontinued if the level was 0.25 g/L. The primary outcome measure was the number of days in the first 2 weeks during which daily activities were restricted by an RTI. Of 458 patients randomized, 455 were evaluated at 2 weeks. The antibioticprescription rate was significantly lower in the PCT arm than in the standard-care arm (25% vs. 97%). The number of RTIrestricted days and the rate of ongoing or relapsing infection at 28 days were similar between arms.

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Number 11

ETB was diagnosed by FB in 12 of the 26 children (46%) with inadequate treatment response and in 21 of the 44 children (48%) with suspected TB. The remaining children all had normal bronchoscopic findings. Forty-two percent of those with ETB had external bronchial compression. The only complication of FB was transient hypoxia (in 3 children).

A Herd Effect of PCV-7 or Quinolones on S. pneumoniae?

treptococcus pneumoniae is a leading cause of meningitis and respiratory tract infections. In an industrysponsored study, researchers in Spain examined whether changes in S. pneumoniae nonsusceptibility in adults and children correlated with licensure of 7-valent pneumococcal conjugate vaccine (PCV-7) for immunization of children and of respiratory quinolones for treatment in adults. All invasive S. pneumoniae isolates received at the Spanish National Reference Pneumococcal Laboratory from January 2000 through August 2007 (n=12,957) were serotyped, and their susceptibility to penicillin, erythromycin, and levofloxacin was determined. Data on PCV-7 distribution during that period were obtained from the manufacturer; figures for antibiotic consumption were obtained from Intercontinental Marketing Services Health, Inc. During the study period, respiratory quinolone consumption increased and was correlated with rising levels of levofloxacin nonsusceptibility in adults. (Even with the increase, the nonsusceptibility rate for levofloxacin in 2007 1.6% was low compared with the >20% rates for penicillin and erythromycin.) No levofloxacin nonsusceptibility was seen in children, however, suggesting that adults use of quinolones had no herd effect on nonsusceptibility in children. In contrast, PCV-7 use increased and was correlated with decreased prevalence of PCV-7 serotypes and decreased penicillin nonsusceptibility in both children and adults. A herd effect is likely because use of PCV-7 in children affected serotype prevalence and susceptibility in adults.

Comment:
These findings demonstrate that FB can be helpful in evaluating equivocal, complicated, or persistent TB cases; they also reveal a high incidence of ETB in the study cohort, which was carefully selected and in a country with a moderate incidence of TB. Overall incidence of the condition remains unknown, however, because the procedure is not routinely performed in TB patients. In the present study, a benefit of FB was that 20 of the 33 children with ETB were diagnosed with lesions for which adjunctive corticosteroid treatment was used. Some infection-control measures should be borne in mind with respect to FB. Bronchoscopy in patients with suspected or proven TB should be performed in an appropriate procedure room under negative pressure. Because of concerns about infectious aerosols, all participants should be wearing N95 or equivalent OSHA-approved respirators. Robert S. Baltimore, MD
Cakir E et al. Flexible bronchoscopy for diagnosis and follow up of childhood endobronchial tuberculosis. Pediatr Infect Dis J 2008 Sep; 27:783.

Comment:
Using PCT level to guide antibiotic therapy for outpatients with RTIs dramatically reduced antibiotic use without increasing the risk for adverse outcomes. These results are even more striking considering that the study enrolled only patients who were believed to need antibiotics by physicians in a country where antibioticprescription rates are much lower than in the U.S. As an editorialist notes, wide adoption of this approach requires development of a rapid, accurate, and inexpensive office-based PCT test. Daniel J. Diekema, MD, MS
Briel M et al. Procalcitonin-guided antibiotic use vs a standard approach for acute respiratory tract infections in primary care. Arch Intern Med 2008 Oct 13; 168:2000. Schwartz DN. [Invited commentary] Arch Intern Med 2008 Oct 13; 168:2007.

Procalcitonin to Guide Antibiotic Use in Primary Care

espiratory tract infections (RTIs) are among the most common reasons for antibiotic prescription in primary care. A test that can differentiate between bacterial and viral RTIs could help to reduce antibiotic use. Procalcitonin (PCT) levels have been used as a marker for bacterial infection in hospitalized patients but have not been evaluated in the primary care setting. In a recent randomized trial, investigators in Switzerland (1 of whom received research support from the maker of the PCT assay used in the study) compared a PCT-guided approach with standard

Comment:
PCV-7 clearly has had a positive effect in decreasing the incidence of invasive S. pneumoniae infections in children, and a herd effect is suggested in adults. However, rates of invasive S. pneumoniae infections caused by nonvaccine serotypes have risen, and increasing antimicrobial nonsusceptibility in these strains has been reported. Continued surveillance of serotypes and susceptibility patterns is needed. Lynn L. Estes, PharmD

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November 2008

JOURNAL WATCH INFECTIOUS DISEASES

Wong T et al. Primary syphilis: Serological treatment response to doxycycline/ tetracycline versus benzathine penicillin. Am J Med 2008 Oct; 121:903.

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Fenoll A et al. Has the licensing of respiratory quinolones for adults and the 7-valent pneumococcal conjugate vaccine (PCV-7) for children had herd effects with respect to antimicrobial non-susceptibility in invasive Streptococcus pneumoniae? J Antimicrob Chemother 2008 Sep 26; [e-pub ahead of print]. (http://dx.doi.org/ 10.1093/jac/dkn413)

Levofloxacin and E. coli Resistance

rinary tract infections (UTIs) are among the most common reasons for outpatient antibiotic prescriptions. At Denver Community Health Services, which manages >400,000 outpatient visits each year, levofloxacin was substituted as the preferred antibiotic for outpatient UTI therapy in 1999, when the trimethoprim-sulfamethoxazole (TMP-SMX) resistance rate reached 24%. Subsequently, a rise in the levofloxacin resistance rate was observed. The investigators used institutional pharmacy and microbiology laboratory databases to assess the changes in outpatient antibiotic use and resistance between 1998 and 2005. During the study period, levofloxacin prescriptions per 1000 outpatient visits increased from 3.1 to 12.7 (P <0.01). Meanwhile, the percentage of Escherichia coli isolates resistant to levofloxacin increased from 1% in 1999 to 9% in 2005. Of the 81 levofloxacin-resistant isolates identified from among outpatient specimens submitted in 2005, all but 1 were from urinary sources. Although the number of outpatient prescriptions for sulfonamides decreased by 49% during the study period, the resistance rate of E. coli to TMP-SMX increased slightly, from 26% in 1999 to 30% by the end of 2005. The investigators also performed a case-control study comparing 41 patients with levofloxacin-resistant E. coli UTIs in 2005 to 82 matched patients with levofloxacin-susceptible E. coli infections. In multivariate analysis, two factors were significantly associated with levofloxacin resistance: previous hospitalization and levofloxacin use during the preceding year. Levofloxacin-resistant E. coli isolates were more likely than levofloxacin-susceptible ones to be resistant to other antibiotics used to treat UTIs (P <0.0001).

Doxycycline or Tetracycline for Primary Syphilis

enzathine penicillin is the treatment of choice for primary syphilis. However, it has some disadvantages, including cost, injection-site pain, and contraindication in penicillin-allergic patients. Little research has been done on the use of alternative agents, such as doxycycline and tetracycline. Now, in a retrospective cohort study conducted in Alberta, Canada, researchers have compared serologic response rates between patients treated with a single injection of benzathine penicillin and those treated with 14 days of either doxycycline (100 mg twice daily) or tetracycline (500 mg 4 times daily). Participants had a first-time diagnosis of primary syphilis between 1980 and 2001. Criteria for exclusion included HIV positivity, a nonreactive nontreponemal rapid plasma reagin (RPR) test at baseline, and inadequate follow-up. Serologic treatment success was defined as a decline in baseline RPR test antibody titer by 4-fold within 6 months, by 8-fold within 12 months, or by 16-fold within 24 months. Among the 445 participants, 420 (94%) received penicillin, and 25 (6%) received either doxycycline or tetracycline. Serologic success occurred in 97% of the penicillin recipients compared with 100% of the doxycycline/tetracycline recipients. The estimated median time to treatment success was 72 days for penicillin and 43 days for doxycycline/ tetracycline (P =0.16).

increased use of levofloxacin for treating UTIs and development of resistance. Unfortunately, no concomitant decrease was seen in resistance to TMP-SMX. In fact, levofloxacin-resistant isolates showed an increased likelihood of resistance to other classes of antibiotics that are used to treat UTIs. Neil M. Ampel, MD
Johnson L et al. Emergence of fluoroquinolone resistance in outpatient urinary Escherichia coli isolates. Am J Med 2008 Oct; 121:876.

Aspergillosis in Stem-Cell Transplantation

nvasive aspergillosis is a major cause of death in allogeneic stemcell transplant recipients. Knowing that Aspergillus species can affect immunecell activation by interacting with specific toll-like receptors (TLRs) and that mutations in TLR genes have been associated with increased risk for various infections, investigators in Seattle examined whether single nucleotide polymorphisms in four TLR genes in donor cells influence the risk for invasive aspergillosis in unrelated stem-cell transplant recipients. The studys first (discovery) phase involved 336 patients who had undergone allogeneic hematopoietic-cell transplantation from an unrelated donor. Thirty-three of them developed either proven or probable invasive aspergillosis during follow-up (median follow-up duration among survivors, 84 months). On multivariable analysis, independent risk factors for the development of invasive aspergillosis were donor single nucleotide polymorphism (1363T) of TLR4 haplotype S4; cytomegalovirus seropositivity in the patient, the donor, or both; and acute graft-versus-host disease. The second (validation) phase of the study featured a matched casecontrol design and involved recipients of transplants from either unrelated or related donors. Donor haplotype S4 was identified as a risk factor for invasive aspergillosis among patients who received transplants from unrelated donors (odds ratio, 5.00; 95% confidence interval, 1.0424.01) but not among those who received transplants from related donors (OR, 2.29; 95% CI, 0.935.68).

Comment:
This study has several limitations for example, it was retrospective and record-based, and very few participants were treated with doxycycline or tetracycline. Despite these flaws, the results suggest that treatment with doxycycline or tetracycline for 14 days leads to good outcomes in patients with primary syphilis. Neil M. Ampel, MD

Comment:
A strength of this study is the completeness of the data, because records were computerized. The findings demonstrate a nearly linear association between

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JOURNAL WATCH INFECTIOUS DISEASES manifests as a flulike syndrome, although aseptic meningitis or fatal hemorrhagic feverlike disease can develop. In April 2008, an organ-procurement organization reported to the CDC that two recipients of kidneys from a common 49-year-old donor who had aseptic meningitis at the time of organ harvest had become ill; one had died. The donors antemortem cerebrospinal fluid (CSF) contained 478 white blood cells (96% lymphocytes) per mm3 and had an elevated protein level. Tests for bacteria and herpesvirus were negative, but one blood culture grew out methicillinresistant Staphylococcus aureus. Standard donor screening tests for viral pathogens and syphilis were negative; however, archived serum, collected 1 day before death but not tested until about 6 weeks later, revealed IgM and IgG antibodies to LCMV. Recipient A, a 70-year-old woman with end-stage renal disease (ESRD), was readmitted to the hospital 3 weeks posttransplant and died 1 week later with hepatic insufficiency, multisystem organ failure, and shock. Recipient B, a 57-year-old man with ESRD, was re-

Volume 11

Number 11

Comment:
This work provides additional evidence of how our genes or transplant donors genes affect health. The findings support the possibility that genetic screening could be used to identify individuals at increased risk for certain maladies, and that such knowledge could enable us to optimize interventions, including strategies to prevent infection in allogeneic stem-cell transplant recipients. Larry M. Baddour, MD
Bochud P-Y et al. Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. N Engl J Med 2008 Oct 23; 359:1766.

admitted 2 weeks posttransplant with a similar clinical presentation. He died 8 weeks later, despite discontinuation of immunosuppressive drugs and treatment with ribavirin and immunoglobulin. PCR and immunohistochemical staining revealed evidence of LCMV in organ and blood specimens from both recipients.

Comment:
This report describes the fourth cluster of fatal LCMV disease in organ-transplant recipients. The donor had the very high CSF white-cell count and the lymphocyte predominance that are typical of LCMV meningitis. Although the incidence of this infection is probably too low to warrant routine screening, potential donors with LCM-compatible syndromes (including aseptic meningitis) should not have their organs transplanted. Stephen G. Baum, MD
Centers for Disease Control and Prevention (CDC). Brief report: Lymphocytic choriomeningitis virus transmitted through solid organ transplantation Massachusetts, 2008. MMWR Morb Mortal Wkly Rep 2008 Jul 25; 57:799.

Transplant-Associated LCMV Infection

he house mouse is the natural reservoir for lymphocytic choriomeningitis virus (LCMV), but other small rodents such as hamsters, guinea pigs, and rats can also be infected. Humans acquire the virus through exposure to rodent excreta. LCMV infection in humans is rarely (<1%) fatal and often