Vaccination against influenza in rheumatoid arthritis: the effect of disease modifying drugs, including TNF alpha blockers.

OBJECTIVE: To assess the efficacy and safety of vaccination against influenza virus in patients with rheumatoid arthritis, with special emphasis on the effect of disease modifying antirheumatic drugs (DMARDs), including tumour necrosis factor alpha (TNFalpha) blockers. METHODS: 82 rheumatoid patients and 30 healthy controls were vaccinated with a split-virion inactivated vaccine containing 15 mug haemagglutinin (HA) per dose of each of B/Hong Kong/330/2001 (HK), A/Panama/2007/99 (PAN), and A/New Caledonian/20/99 (NC). Disease activity was assessed by tender and swollen joint count, morning stiffness, evaluation of pain, Health Assessment Questionnaire, ESR, and C reactive protein on the day of vaccination and six weeks later. Haemagglutination inhibiting (HI) antibodies were tested by a standard WHO procedure. Response was defined as a fourfold or more rise in HI antibodies six weeks after vaccination, or seroconversion in patients with a non-protective baseline level of antibodies (<1/40). Geometric mean titres (GMT) were calculated to assess the immunity of the whole group. RESULTS: Six weeks after vaccination, a significant increase in GMT for each antigen was observed in both groups, this being higher in the healthy group for HK (p=0.004). The percentage of responders was lower in rheumatoid patients than healthy controls (significant for HK). The percentage of responders was not affected by prednisone or any DMARD, including methotrexate, infliximab, and etanercept. Indices of disease activity remained unchanged. CONCLUSIONS: Influenza virus vaccine generated a good humoral response in rheumatoid patients, although lower than in healthy controls. The response was not affected by the use of prednisone or DMARDs.

Emergence of influenza A H1N2 reassortant viruses in the human population during 2001.

Influenza A H1N2 viruses, which emerged during 2001, are genetic reassortants between H1N1 and H3N2 subtype viruses which have cocirculated in the human population since 1977. They possess a H1 hemagglutinin antigenically and genetically similar to contemporary A/New Caledonia/20/99 (H1N1)-like viruses and seven genes closely related to those of recent A/Moscow/10/99 (H3N2)-like viruses. The viruses have spread to many regions of the world and have predominated over H1N1 viruses in several countries. Since half of the amino acid changes which accumulated in the HAs of H1N1 viruses since 1995 are in residues implicated in receptor binding, functional changes in the H1 HA may have facilitated its replacement of the H3 HA and may contribute to the future epidemiologic significance of these H1N2 viruses.

Influenza surveillance during winter 1997-1998 in Israel.

BACKGROUND: Each winter influenza activity is a major cause of morbidity and mortality both in Israel and worldwide. OBJECTIVES: To identify the influenza viruses active in Israel during the winter season and to assess the extent of influenza morbidity. METHODS: Information was collected on a population of 18,684 individuals enrolled in two community clinics in central Israel. It included the total number of visits for acute respiratory infection--including influenza and influenza-like illness (ARI/flu-like)--during a 20 week surveillance period (23 November 1997 to 27 March 1998) and the percent of influenza virus isolates in nasopharyngeal specimens from a sample of patients with ARI/flu-like collected on a weekly basis during the same period. RESULTS: A total of 5,947 visits for ARI/flu-like were recorded among 18,684 enrolled patients in two community clinics (18.1%). The progressive increase in the number of visits for ARI/flu-like reached a peak on week 2/98 with 597 visits and a rate of 31.95 visits per 1,000 population. After this, a decrease to the initial values was evident by week 12/98. Most affected patients were in the age groups 5-14 and 65 years and over, with a rate of 733.5 and 605.3 visits per 1,000 population, respectively. Influenza virus was isolated from 92 of the 426 nasopharyngeal specimens (21.6%). The most commonly detected strain was A/Sydney/5/97 (H3N2) like (77.2%). The peak rate of isolates was recorded at the beginning of January (01/98). CONCLUSIONS: A/Sydney/5/97 (H3N2) like-strain was the dominant influenza virus. Its presence did not prevent the simultaneous activity of influenza A/H1N1 virus. The dynamic of the clinical disease as expressed by the weekly visit rate for ARI/flu-like was similar to the temporal pattern of the virological findings. The extent of morbidity suggests moderate epidemic activity.

Influenza vaccine efficacy in young, healthy adults.

Findings concerning influenza vaccine efficacy in young, healthy adults are inconsistent. A high incidence of influenza in the winter of 1995 provided an opportunity to study the efficacy of influenza vaccine among young, healthy military personnel. Influenza activity was confirmed by isolation of influenza A and B viruses from nasopharyngeal swab specimens from hospitalized soldiers. Self-administered questionnaires concerning vaccination status and disease symptoms were used in two study groups: recruits and veteran soldiers serving in different camps. Six hundred eighty-four individuals had received influenza vaccine and 652 had not. Vaccine efficacy was found to be 38.1% (P = .002) for preventing febrile illness with or without symptoms and slightly higher (41.6%; P < .001) for preventing fever together with upper respiratory tract symptoms. The current influenza vaccine significantly reduced febrile illness among healthy military personnel.

Molecular epidemiology of adenovirus type 7 in Israel: identification of two new genome types, Ad7k and Ad7d2.

The molecular epidemiology of Adenovirus type 7 in Israel was investigated. Fifty-seven adenovirus isolates identified as serotypes 7 or 7a which were recovered from patients in Israel between 1968 and 1995 were analyzed by restriction enzymes digestion using BamHI for primary discrimination and identification of genome types and by six additional enzymes: BstEII, HpaI, BglI, BglII, BclI, and XbaI for confirmation and determination of genomic subtypes. Four digestion patterns were identified with BamHI; one of them was new. Using BstEII, two patterns were obtained, one of them new. Digestion with the other five enzymes yielded known patterns. The analysis revealed four different genomic types and subtypes, which circulated in Israel in different years: subtype 7a1; type 7b, a type with a new BamHI pattern which was designated type 7K, and a subtype with a new BstEII pattern which differed from type 7d by one restriction site and was designated type 7d2. Twenty-two isolates from 1968 through 1975 and from 1984 were Ad7a1. Three isolates from 1973-1974 were Ad7b. Five isolates from 1968 through 1973 were Ad7K and 27 isolates from 1992 through 1995 were Ad7d2. This demonstrates the temporal change in the circulating genome types with up to three genome types cocirculating in 1 year (1973). The two new types, Ad7k and Ad7d2 could have evolved in Israel or could have been imported by travellers and immigrants from neighboring or distant countries.

Identification of a new strain of fastidious enterovirus 70 as the causative agent of an outbreak of hemorrhagic conjunctivitis.

A 1994 outbreak of acute hemorrhagic conjunctivitis in Israel was caused by an enterovirus 70 strain that was distinct from previously reported strains. Characterization was by electron microscopy (eye washes), reverse transcription-PCR (RT-PCR; eyewash, specimens, eye swabs, and tears), and sequence analysis of RT-PCR-amplified fragments from the 5' noncoding region and VP1.

Detection of adeno-associated virus type 2 sequences in the human genital tract.

Adeno-associated virus (AAV) is a defective parvovirus with unknown pathogenicity. It requires helper functions for its normal replication in human tissue and therefore is not readily isolated from clinical specimens. We have used the PCR method to examine the following clinical samples for the presence of AAV sequences: (i) 15 nasopharyngeal aspirates from symptomatic patients, (ii) 7 swab or fluid specimens from vesicles of patients suspected of having varicella-zoster virus infections, (iii) 21 human papilloma virus-positive genital biopsy specimens, (iv) 61 genital swab specimens from women suspected of having herpes simplex virus (HSV) infection examined either directly or following propagation in tissue culture, (v) 62 samples of first-trimester aborted material, including 38 samples from spontaneous abortions and 24 samples from induced abortions, (vi) 11 samples of chorionic villi taken from women undergoing genetic prenatal diagnosis, and (vii) three lots of cultured human embryonic cells. AAV sequences were detected only in samples taken from the genital tracts of women suspected of having HSV infection and not in any of the other types of samples. Samples from 11 patients were positive for AAV: for 4 patients the original swab sample was positive, for 4 patients the cultured swab sample was positive, and for 3 patients both the original swab samples and the cultures were positive. Five of the 11 patients were infected with HSV. Our study demonstrates the presence of AAV in the female genital tract. However, in contrast to a previous report (E. Tobiasch, M. Rabreau, K. Geletneky, S. Larue-Charlus, F. Severin, N. Becker, and J. R. Schlehofer, J. Med. Virol. 44:215-222, 1994), we did not find solid evidence of its replication in maternal or embryonal tissues from the first trimester of pregnancy. The questions of a potential pathogenic etiology of AAV and the interaction with HSV remain open.

Measles immunity and response to revaccination of a young adult population in Israel.

In order to evaluate the true immune status and the effect of revaccination on a young adult population, we collected serum samples from 289 military recruits who were vaccinated during an outbreak in 1991. Most vaccinees, age 18-25 years, had apparently been immunized once before as infants. Sera collected just prior to the vaccination and 14 and 28 days afterwards were tested for measles antibodies by hemagglutination inhibition (HI) and enzyme-linked immunosorbent assay (ELISA)-IgM. Before vaccination, 46 (15.9%) of the subjects had no HI antibodies, (< 1:4) and 48 (16.6%) had borderline (1:4) HI titer. Following vaccination, only ten (3.5%) remained negative and 19 (6.6%) had borderline titer. The increase in HI antibody titer was inversely proportional to the prevaccination titer, and 159 subjects (55.0%) showed no increase at all. The geometric mean titer (GMT) rose from 9.14 to 21.47. Among the prevaccination-negative subjects (HI < 1:4) 28 (60.9%) reached a postvaccination titer of > or = 1:8, and eight (17.4%) reached a titer of 1:4. Twelve (26.1%) of the negative subjects seroconverted and developed IgM, 16 (35%) seroconverted without IgM, and 18 (39%) remained negative and did not develop IgM. A group of eight vaccinees with prevaccination titer of > or = 1:4 developed IgM. Some were probably infected by the circulating wild-type virus prior to the vaccination. Thus, a total number of 20 of the 289 subjects studied (6.9%) had true negative preimmune status as judged by the IgM test. However, the vaccination campaign prevented further measles cases, apparently by increasing the population's immunity, particularly in individuals with very low titers or without measles antibodies.

Determination of immunity to measles virus in young adults: comparative evaluation of a commercial enzyme immunoassay and the hemagglutination inhibition techniques.

BACKGROUND: Determination of the immune status against measles in young adults requires careful evaluation of the laboratory methods because of waning immunity. The hemagglutination inhibition (HI) test and enzyme-linked immunosorbent assay (ELISA) may lack the sensitivity required to detect very low levels of antibodies. In addition, the correlation between ELISA-IgG assays and the degree of protection from measles is not well defined. OBJECTIVES: (a) Evaluation of a commonly used measles ELISA-IgG test kit in comparison with the hemagglutination inhibition (HI) test which corresponds strongly to virus neutralization; (b) determination of false negative rates of the ELISA-IgG and the HI tests; (c) evaluation of the ELISA-IgG test kit as a quantitative assay. STUDY DESIGN: One hundred and eighty serum samples collected from 60 vaccinated young adults immediately before vaccination and 14 and 28 days postvaccination, were tested comparatively by HI and by a commercial ELISA-IgG kit. For evaluation of false negative rates, postvaccination sera of a cohort of 48 vaccinees with negative HI or ELISA-IgG prevaccination sera were tested for IgM. Sixty-three of the samples were also titrated by the ELISA-IgG kit using serial dilutions, for comparison with HI titers. RESULTS: Using the HI test as a reference method, the ELISA-IgG kit was found to have overall accuracy of 81%, sensitivity of 80% and specificity of 84%. The false negative and the false positive rates were 20% and 16%, respectively. In contrast, when we used postvaccination IgM test to distinguish between true and false prevaccination negatives in both the HI and ELISA-IgG tests, we found that the false negative rates were 75.6% by ELISA and 72.5% by HI, and false positive rates were 2.4% and 0%, respectively. Serum titers determined by the ELISA-IgG test were generally 5-10-fold higher than the corresponding HI titers, but without a consistent correlation. CONCLUSIONS: Both the ELISA-IgG and the HI tests frequently failed to detect residual immunity. The two tests also did not correlate well with each other suggesting that different antigenic determinants of the virus are involved in each assay and therefore the HI test should not be used as a reference method for evaluation of the sensitivity of ELISA IgG kits.

Serological evidence for hepatitis E virus infection in Israel.

Israel is suspected to be endemic for hepatitis E virus (HEV) because of its geographic location and the large-scale immigration from endemic countries. Although no cases of local HEV infection have been diagnosed, a serological survey would provide indirect evidence for such infection. We examined sera from 1,416 healthy subjects, including 1,139 Jews from various regions of Israel and 277 Arabs, most of whom reside in the West Bank of the Jordan River. In addition, we tested 13 non-A, non-B, and non-C viral hepatitis patients. Sera were screened for antibody to hepatitis E virus (anti-HEV) by a newly developed enzyme immunoassay (EIA) and by immunoblots for both IgG and IgM anti-HEV activity. Positive samples were confirmed by neutralization. The seroprevalence found by EIA was 2.81% and 1.81% in the Jewish and Arab populations, respectively. More than a 2-fold higher prevalence in males compared to females and an increase with age were found in both populations. However, these differences were nonsignificant. The geographical distribution was even throughout the country, except for two clusters of 3 and 4 seropositive individuals possibly reflecting past foci of infection. Eight of 37 EIA-positive sera were positive for IgG, and 3 were positive for IgM by the immunoblot assay. Among hepatitis patients (9 acute and 4 chronic), one patient with chronic hepatitis was positive for both IgG and IgM. Our study provides indirect evidence that Israel is endemic for HEV.(ABSTRACT TRUNCATED AT 250 WORDS)

Application of ELISA for IgM, IgA and antigen detection for rapid diagnosis of respiratory syncytial virus infections: a comparative study.

BACKGROUND: Infection with Respiratory Syncytial Virus (RSV) can be rapidly diagnosed by detection of viral antigen in nasopharyngeal secretions (NPS) or serologically by detecting IgM and IgA antibodies. OBJECTIVES: To evaluate the above methods for reliability and rapidity, and compare them with the complement fixation (CF) test and virus isolation. STUDY DESIGN: Viral antigen was tested in 145 NPS samples by ELISA in parallel with tissue culture isolation. The geometric mean titer (GMT) of complement fixing antibodies in various age groups was determined from 92 individual serum samples by CF test. The diagnostic methods, CF test, ELISA-IgM and ELISA-IgA, were evaluated using 21 pairs of acute and convalescent sera. Appearance of IgM and IgA in serum samples with low or negative CF titers was studied in two age groups: 0-10 months (n = 82), and 11 months-9 years (n = 47). RESULTS: From the 145 NPS samples, 20 samples were positive by both ELISA and virus isolation, 9 were positive only by ELISA and 5 were positive only by virus isolation. The GMT by age group for 92 sera evaluated by CF test were 40 (0-10 months), 195 (11-24 months), 269 (2-4 years), 173 (5-12 years) and 132 (adults). Among the 21 paired sera examined, CF test detected 13 RSV infections by antibody rise or seroconversion while the ELISA-IgM/IgA tests identified all 21 infections, 7 of them in the first sample. The presence of IgM alone or IgM and IgA antibodies was demonstrated in both age groups examined; however, IgA alone was found only in the age group 11 months and older. CONCLUSIONS: ELISA for antigen detection is better than virus isolation because it is faster (6-20 h vs. 3-20 days, respectively) and more sensitive (29/34 vs. 25/34 positives, respectively). ELISA-IgM and ELISA-IgA was more sensitive and reliable than the CF test, particularly for the 0-10 month age group. Thus, when necessary, serological diagnosis of RSV infection can be based on the presence of IgM and/or IgA antibodies in serum samples obtained early after onset of symptoms.

Inhibition of several strains of influenza virus in vitro and reduction of symptoms by an elderberry extract (Sambucus nigra L.) during an outbreak of influenza B Panama.

A standardized elderberry extract, Sambucol (SAM), reduced hemagglutination and inhibited replication of human influenza viruses type A/Shangdong 9/93 (H3N2), A/Beijing 32/92 (H3N2), A/Texas 36/91 (H1N1), A/Singapore 6/86 (H1N1), type B/Panama 45/90, B/Yamagata 16/88, B/Ann Arbor 1/86, and of animal strains from Northern European swine and turkeys, A/Sw/Ger 2/81, A/Tur/Ger 3/91, and A/Sw/Ger 8533/91 in Madin-Darby canine kidney cells. A placebo-controlled, double blind study was carried out on a group of individuals living in an agricultural community (kibbutz) during an outbreak of influenza B/Panama in 1993. Fever, feeling of improvement, and complete cure were recorded during 6 days. Sera obtained in the acute and convalescent phases were tested for the presence of antibodies to influenza A, B, respiratory syncytial, and adenoviruses. Convalescent phase serologies showed higher mean and mean geometric hemagglutination inhibition (HI) titers to influenza B in the group treated with SAM than in the control group. A significant improvement of the symptoms, including fever, was seen in 93.3% of the cases in the SAM-treated group within 2 days, whereas in the control group 91.7% of the patients showed an improvement within 6 days (p < 0.001). A complete cure was achieved within 2 to 3 days in nearly 90% of the SAM-treated group and within at least 6 days in the placebo group (p < 0.001). No satisfactory medication to cure influenza type A and B is available. Considering the efficacy of the extract in vitro on all strains of influenza virus tested, the clinical results, its low cost, and absence of side-effects, this preparation could offer a possibility for safe treatment for influenza A and B.

Sex differences in the humoral antibody response to live measles vaccine in young adults.

BACKGROUND: Following vaccination of children using high-titre live measles vaccine, excess non-specific mortality was reported, particularly among females. Since vaccination with live measles virus results in a temporary depression of the immune response to other antigens, the female predominance in subsequent non-measles mortality may be due to sex differences in response to live measles vaccines. METHODS: In this study, the immunogenicity of standard titre live Schwarz strain measles vaccine was examined 2 and 4 weeks post-vaccination in 223 males and 66 female aged 18-20 years in Israel in 1991. RESULTS: Females had higher post-vaccination geometric mean titre (GMT) at all levels of pre-vaccination titres at both 2 and 4 weeks. Furthermore, after controlling for differences in pre-vaccination titres, overall the post-vaccination GMT for females was about 50% higher than for males (P < 0.001). CONCLUSIONS: These findings indicate that females exhibit a stronger humoral immune response to measles vaccine. Possible sex differences in immunosuppression following measles vaccination should be explored.

Adenovirus type 8 conjunctivitis outbreak in a neonatal intensive care unit.

An outbreak of adenovirus type 8 conjunctivitis occurred in seven premature infants who had undergone ophthalmological examination four to seven days previously. Three of the affected infants, treated with steroids because of bronchopulmonary dysplasia, showed systemic manifestations and deterioration of their respiratory disease. Second and third waves affected nine staff and 12 family members.

West Nile fever encephalitis.

Three cases of meningoencephalitis caused by the West Nile virus in young people are described. All patients had high fever, severe headaches, and meningeal irritation. One patient had papillitis and a maculopapular rash. Lymphadenopathy, which is a common finding in West Nile fever, was not found in any of our patients. Duration of the disease was one to two weeks, and recovery was complete. Cerebrospinal fluid examination revealed an increase in protein and pleocytosis (predominantly polymorphonuclears). We believe that West Nile encephalitis is not rare in Israel.

Stimulation of antibodies to Epstein-Barr virus (EBV) in acute viral infections.

Acute and convalescent sera from 77 patients with serologically confirmed influenza, measles and adenovirus infections and from 36 healthy controls were tested for the level of antibodies to Epstein-Barr (EB) virus. In the three groups of patients significantly higher titers of antibodies to EB viral capsid antigen (VCA) were found as compared to the controls. In 19 patients twofold or higher rise in antibody titers between the first and second blood sample was demonstrated. It is suggested that in patients with influenza, measles or adenovirus infections, involvement of lymphocytes leads to reactivation of EB virus and antibody formation is stimulated.

Latent viruses and Bell's palsy in children.

4 children with unilateral facial palsy--Bell's palsy (BP)--had serological evidence of primary infection with Epstein-Barr virus (EBV). Concomitant infection with cytomegalovirus (CMV) was demonstrated in 1 child while in all 4 children a rise in antibody titers to an additional one or two viruses was demonstrated. The viruses involved were herpes simplex, CMV and adenovirus which are latent in humans. Immunosuppression induced by EBV and steroid treatment may cause reactivation of these viruses resulting in rise in antibody titers. The need for prolonged serological follow-up for possible reactivation of latent viruses in BP is emphasized.