Intussusception, infection, and immunization: summary of a workshop on rotavirus.

This article summarizes the proceedings of a workshop sponsored by the National Institutes of Health and the National Vaccine Program Office, and held in Bethesda, Maryland, on January 21, 2000. The objective of the meeting was to focus research toward an understanding of the basis for the possible association between intussusception and the reassortant rhesus-human rotavirus vaccine tetravalent (RRV-TV). After numerous reports of intussusception after administration of RRV-TV, the manufacturers of this vaccine voluntarily withdrew it from the United States market. The American Academy of Pediatrics, the Advisory Committee on Immunization Practices, and the American Academy of Family Physicians also withdrew their original recommendations for administration of RRV-TV to children at 2, 4, and 6 months of age. These actions will have global implications for the prevention of morbidity and mortality attributable to rotavirus infection. Benefit-cost ratios for the use of RRV-TV will be substantially different in developing countries compared with developed countries. Therefore, extensive research is needed in both of these settings, to further our understanding of the epidemiology, pathogenesis, and pathology of both rotavirus disease and intussusception to enable optimal prevention. The workshop reviewed the current understanding of the possible association between RRV-TV and intussusception, as well as the possible association between a variety of viral infections and intussusception. The workshop also identified critical areas of research regarding this possible association. This research will be essential not only for the development of safe and effective rotavirus vaccines, but for the development of other oral vaccines as well.

New approaches to the treatment of group A streptococcal pharyngitis.

An orally administered antimicrobial regimen for the treatment of pharyngitis caused by group A beta-hemolytic streptococci that could be given once daily and for less than 10 days would be convenient and might improve compliance, decrease cost, and result in fewer side effects compared with a regimen given multiple times daily for 10 days. Previous attempts to administer oral penicillin once daily or for less than 10 days were not successful. Several cephalosporins and azithromycin have been reported to be effective when administered once daily or for less than 10 days. However, large, comprehensive studies have not been performed. In addition, the spectra of these cephalosporins and azithromycin are much broader than that of penicillin, and, even when they are administered for short courses, they are more expensive. Therefore, these novel regimens cannot be endorsed and should not supplant penicillin as the agent of choice. In contrast, once-daily amoxicillin therapy appears to be effective, is inexpensive, and has a narrower spectrum of antimicrobial activity; if these findings are confirmed by additional investigations, it could become an alternative regimen for the treatment of pharyngitis caused by group A beta-hemolytic streptococci.

Lyme disease.

Lyme disease, which is caused by Borrelia burgdorferi and transmitted in the United States primarily by Ixodes scapularis (the deer tick), is the most common vector borne disease in the United States. Its most frequent manifestation, a characteristic, expanding annular rash (erythema migrans), sometimes accompanied by myalgia, arthralgia, and malaise, occurs in nearly 90% of persons with symptomatic infection. Other manifestations of Lyme disease include seventh cranial nerve palsy, aseptic meningitis, and arthritis. Extensive coverage in the press about the serious effects of Lyme disease has led to widespread anxiety about this illness that is far out of proportion to the actual morbidity that it causes. This problem is exacerbated by the frequent use of serological tests to eliminate the possible diagnosis of Lyme disease in persons with only nonspecific symptoms (such as arthralgia or fatigue) who have a very low probability that Lyme disease is the cause of their symptoms. Consequently, misdiagnosis is frequent and is the most common cause of failure of treatment. The prognosis for most persons with Lyme disease is excellent.

HCV RNA levels in hepatocellular carcinomas and adjacent non-tumorous livers.

To determine the antiviral effects of drugs targeted to hepatitis C virus (HCV) in chronic hepatitis patients, an accurate quantitative method with high sensitivity is needed. Reverse transcription nested polymerase chain reaction (RT-PCR) is the most sensitive method for the detection of HCV sequences in clinical specimens. However, this method is not quantitative. For this purpose, a quantitative competitive assay was developed that combines RT and PCR followed by image analysis to quantify HCV RNA. This assay targets the highly conserved 5' non-coding region of HCV and is based on the co-amplification of wild type HCV RNA with known amounts of mutant synthetic RNA. The mutant internal control used in these experiments differs from the wild type RNA by two nucleotide substitutions, which introduces an internal restriction enzyme site. In this report, this method was used to determine the levels of positive strand RNA in 11 HCV positive hepatocellular carcinomas (HCC) and compared these with adjacent non-tumorous liver tissue. To confirm that the difference in viral titers is not related to variations in the amount of RNA used in the assay, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA was also assessed by competitive RT-PCR in all tissue extracts. Using this competitive assay it was determined that HCV RNA levels in the liver and tumor samples ranged from 10(3) to 10(6) molecules per microg of total RNA which is similar to previous reports. Interestingly, the amount of HCV in all the non-tumorous liver specimens were found to be significantly higher (P<0.05) than the surrounding tumors, while the GAPDH mRNA levels were found to be similar in both liver and tumor. Competitive RT-PCR is a sensitive, accurate and reliable method to determine HCV titers in clinical specimens. Using this method it was determined that malignant tumor cells harbor less HCV as compared with the surrounding non-tumorous liver cells.

Long-term outcomes of persons with Lyme disease.

CONTEXT: Few data exist about the long-term outcomes of patients with Lyme disease. OBJECTIVE: To assess the long-term outcomes of patients with Lyme disease. DESIGN: Two-part project including a community-based longitudinal cohort study and a matched cohort study. SETTING AND PARTICIPANTS: Six hundred seventy-eight patients identified from a random sample of all reports of Connecticut residents with suspected Lyme disease submitted to the Connecticut Department of Public Health from 1984-1991 were evaluated in the longitudinal study; for a random subsample of 212 patients from the larger study, 212 age-matched controls without Lyme disease also were enrolled. MAIN OUTCOME MEASURES: Self-reports or parents' reports of symptoms and ability to perform certain daily activities since diagnosis of Lyme disease; scores on the 36-Item Short-Form Health Survey and the Center for Epidemiologic Studies-Depression scale, for adults, by case-definition status and between patients and controls. RESULTS: Of the 678 patients, 51.6% were female, 34.4% were children, and 64.3% met the national surveillance case definition for Lyme disease. Most patients (85.6%) were treated with antimicrobial agents. Interviews were conducted a median of 51 months after diagnosis (range, 15-135 months). An increased frequency of symptoms (eg, pain, fatigue) or of difficulty with daily activities (eg, performing housework, exercising) was reported by 69% of the patients, although few (19%) of these problems were attributed to Lyme disease. Whenever there was a statistically significant difference in the frequencies of either increased symptoms or increased difficulties with typical activities between those who did or did not meet the surveillance case definition, in all instances the greater frequency of problems was in the group that did not meet the case definition. The frequencies of reports of both increased symptoms and increased difficulties with typical activities among patients who had been diagnosed as having Lyme disease were similar to those among age-matched controls without Lyme disease. CONCLUSIONS: In this cohort, although many patients reported increases in symptoms and/or increased difficulties with typical daily activities between 1 and 11 years after diagnosis of Lyme disease, the frequencies of these reports were similar to the frequencies of such reports among age-matched controls without Lyme disease.

Detection of hepatitis C virus RNA sequences in cholangiocarcinomas in Chinese and American patients.

OBJECTIVE: To investigate the role of hepatitis C virus (HCV) in the malignant transformation of bile duct cells. Tissues from 6 Chinese patients and 6 American patients with cholangiocarcinoma were studied. METHODS: RNA was extracted from the selected tumor areas of formalin-fixed, paraffin embedded sections, followed by reverse transcription double polymerase chain reaction (RT-PCR) and Southern blotting. RESULTS: Positive and negative strand HCV RNA sequences were detected in seven out of twelve patients with cholangiocarcinoma. A high positive rate was found in Chinese patients (83%) as compared to US patients (33%). CONCLUSION: Our finding suggests HCV may play a role in the malignant transformation of bile duct cells.

Potential mechanisms for failure to eradicate group A streptococci from the pharynx.

OBJECTIVE: To investigate the relative efficacy of orally administered cefadroxil and penicillin V in the treatment of group A streptococcal (GABHS) pharyngitis and the mechanism(s) responsible for failure of antimicrobial therapy to eradicate GABHS from the pharynx. STUDY DESIGN: A prospective, randomized clinical trial was conducted in four pediatric offices in which 462 patients with acute pharyngitis and positive culture for GABHS were randomly assigned to receive cefadroxil (n = 232) or penicillin V (n = 230). RESULTS: Bacteriologic treatment success rates for patients in cefadroxil and penicillin groups were 94% and 86%, respectively. However, among patients classified clinically as likely to have bona fide GABHS pharyngitis, there was no difference in bacteriologic treatment success rates in cefadroxil and penicillin groups (95% and 94%, respectively). Among patients classified clinically as likely to be streptococcal carriers, bacteriologic treatment success rates in cefadroxil and penicillin groups were 92% and 73%, respectively. The presence of beta-lactamase and/or bacteriocin-producing pharyngeal flora had no consistent effect on bacteriologic eradication rates among patients in either penicillin or cefadroxil treatment groups or among patients classified as having either GABHS pharyngitis or streptococcal carriage. CONCLUSIONS: Neither beta-lactamase nor bacteriocin produced by normal pharyngeal flora are related to bacteriologic treatment failures in GABHS pharyngitis. Cefadroxil seems to be more effective than penicillin V in eradicating GABHS from patients classified as more likely to be streptococcal carriers. However, among patients we classified as more likely to have bona fide GABHS pharyngitis, the effectiveness of cefadroxil and penicillin V seems to be comparable.

Effect of schistosomiasis and hepatitis on liver disease.

Infection with hepatitis C virus (HCV) has become the most important public health problem in Egypt. In Egypt, viral hepatitis along with infection with Schistosoma mansoni is the major cause of chronic liver disease and liver cirrhosis. Although HCV infection is highly prevalent in Egypt, very little information is available on the distribution of the different genotypes of HCV. Our aims in this study were first to determine the prevalence of viral and parasite infections in patients with chronic liver disease and then to assess the distribution of HCV genotypes in these patients. In the present study, 151 individuals (50 with chronic liver disease, 51 with chronic diseases of organs other than the liver, and 50 apparently healthy persons) were investigated. The last 2 groups served as control groups. These individuals were subjected to routine liver function tests and detection of serum antibodies to bilharziasis, hepatitis B surface antigen (HBsAg), and HCV. Furthermore, the presence of hepatitis G virus (HGV) and HCV in the serum samples were tested for by a reverse transcription polymerase chain reaction (RT-PCR). Prevalence of different genotypes of HCV in patients positive for HCV were determined by RT-PCR using type-specific primers. Results of the study revealed that 84, 74, 12, and 20% of patients with chronic liver disease were positive for Schistosoma mansoni, HCV, HBsAg, and HGV, respectively, as compared to 51, 43.1, 2, and 4% of patients with other chronic diseases and 22, 6, 0, and 0% of apparently healthy individuals. One hundred percent of patients with chronic liver disease, 72.5% of those with other diseases, and 26% of normal controls were shown to have at least one of the studied infectious agents. Two or more of the agents were highly coincident in patients with chronic liver disease. In Egypt, HCV genotype 4a is highly prevalent, where it contributed 85% of the tested samples in comparison to 10, 2.5, and 2.5% for subtypes 1b, 2a, and 3a, respectively. In conclusion, these results suggest that in Egypt, HCV along with schistosomal parasite infection is the major risk factor for chronic liver disease. In most Egyptian patients, HCV genotype 4 is highly prevalent.

Once-daily therapy for streptococcal pharyngitis with amoxicillin.

OBJECTIVE: An orally administered antimicrobial regimen for the treatment of group A beta-hemolytic streptococcal (GABHS) pharyngitis given once rather than multiple times each day would be more convenient and might result in improved patient compliance. The purpose of this study was to evaluate the effectiveness of once-daily amoxicillin in the treatment of GABHS pharyngitis. PATIENTS: Children presenting to a private pediatric office with GABHS pharyngitis. DESIGN: Patients were randomly assigned to receive orally either amoxicillin (750 mg once daily) or penicillin V (250 mg three times a day) for 10 days. Compliance was monitored by urine antimicrobial activity. OUTCOMES: Outcomes were measured by impact on the clinical course, eradication of GABHS within 18 to 24 hours, and bacteriologic treatment failure rate as determined by follow-up throat cultures 4 to 6 and 14 to 21 days after completing therapy. GABHS isolates were serotyped to distinguish bacteriologic treatment failures (same serotype as initial throat culture) from new acquisitions (different serotypes). RESULTS: During the 16 months of this study, 152 children between 4 and 18 years of age (mean, 9.9 years) were enrolled; 79 children were randomly assigned to receive once-daily amoxicillin and 73 were assigned to receive penicillin V three times a day. The children in the two treatment groups were comparable with respect to age, duration of illness before initiation of therapy, compliance, and signs and symptoms at presentation. There was no significant difference in the clinical or bacteriologic responses of the patients in the two treatment groups at the 18- to 24-hour follow-up visit. Bacteriologic treatment failures occurred in 4 (5%) of the 79 patients in the amoxicillin group and in 8 (11%) of the 73 patients in the penicillin V group. CONCLUSIONS: These data demonstrate that once-daily amoxicillin therapy is as effective as penicillin V therapy given three times a day for the treatment of GABHS pharyngitis, and if confirmed by additional investigations, once-daily amoxicillin therapy could become an alternative regimen for the treatment of this disease.

Intractable diarrhea from cytomegalovirus enterocolitis in an immunocompetent infant.

Infection with cytomegalovirus (CMV) in infants can be congenital or perinatal. Infected infants may be asymptomatic or present with pneumonia, rash, hepatosplenomegaly, or encephalitis.1 In the presence of an immunodeficiency, severe and sometimes fatal disease may occur. To our knowledge, CMV has not been identified previously as a cause of intractable diarrhea of infancy. We report the case of a 5-week-old immunocompetent infant with intractable diarrhea attributable to CMV-induced enterocolitis. Recognition of this infection and initiation of ganciclovir therapy was associated with a rapid improvement and resolution of the diarrhea.

Clinical outcome of a protocol to produce immunosuppression in rhesus monkeys (Macaca mulatta): application to infectious disease and gene therapy studies.

Induced immunosuppression is required for a number of studies using rhesus monkeys (Macaca mulatta). This report describes the clinical outcome and safety of a dose-finding experiment that determined doses of cyclophosphamide and prednisone that could be used to induce a state of immunosuppression in rhesus monkeys. After determining the optimum dose of immunosuppressive agents, the protocol was then used on animals participating in infectious disease and gene therapy studies. Splenectomy was performed in some animals to increase the severity of immunosuppression. The onset, duration, and severity of lymphopenia and leukopenia were consistent in all animals. In most animals, physical examination findings and clinical serum chemistry profiles demonstrated only transient abnormalities. With proper clinical monitoring, combination treatment with cyclophosphamide and prednisone is an effective and safe method for inducing immunosuppression in rhesus monkeys.

Lyme arthritis in children: clinical epidemiology and long-term outcomes.

OBJECTIVE: Although Lyme disease has become a relatively common cause of arthritis among children in areas of the country in which the disease is endemic, little information is available about the clinical epidemiology and long-term outcomes of children with Lyme arthritis. We conducted a long-term follow-up study to determine the clinical epidemiology of Lyme arthritis in children as well as their long-term outcomes. PATIENTS AND METHODS: All children seen between 1982 and 1991 at the Pediatric Rheumatology Clinic at Newington Children's Hospital (Newington, CT) with an initial diagnosis of Lyme disease were identified. Medical records were reviewed and structured telephone interviews were conducted to obtain demographic, clinical, and follow-up data. RESULTS: A total of 90 children (63% boys) with a mean age of 8.3 years (range, 1.8-16 years) at the time of diagnosis of Lyme arthritis were evaluated. Lyme arthritis was preceded by early Lyme disease in 23 (26%) of the children; however, only 8 (35%) of these children had been treated with appropriate antimicrobial therapy at that early stage. Ninety percent of the children had arthritis of at least one knee, while small joints were rarely involved. For the 31 children who underwent arthrocentesis, the mean white blood cell count in the synovial fluid was 38 000 cells/mm3 (range, 7000-99 000 cells/mm3) with predominantly neutrophils. For the 79 children for whom an erythrocyte sedimentation rate was determined, the highest level for 61 (77%) was >20 mm/h and for 36 (46%) was >50 mm/h. Antimicrobial therapy was initiated 2 days to 5.5 years (median, 2 months) after the onset of symptoms. However, 5 of the children were never treated with antimicrobials. Fifty-one percent of the patients had a single episode of arthritis, while 49% reported recurrent episodes of arthritis over a period of 1 week to 8 years (median, 6 months). Two children (2%) developed chronic arthritis and underwent arthroscopic synovectomy. At the time of the telephone follow-up evaluation, performed 2 to 12 years (median, 7 years) after the onset of the Lyme arthritis, 4 children had ongoing musculoskeletal complaints that resulted in mild to moderate impairment of school or sports activities, but none of the children had evidence of active arthritis. CONCLUSION: The results of this investigation suggest that the prognosis for children with Lyme arthritis who are treated with appropriate antimicrobial therapy is excellent.