Helen L. Regnery

Common Emergence of Amantadine- and Rimantadine-Resistant Influenza A Viruses in Symptomatic Immunocompromised Adults

The importance and significance of amantadine- or rimantadine-resistant influenza viruses in immunocompromised patients was studied in a population of adult bone marrow transplant (BMT) recipients and patients with leukemia prospectively cultured for respiratory viruses. Influenza A viruses were isolated from 29 patients with acute respiratory illness (14 BMT recipients and 15 patients with leukemia). Fifteen patients (52%) received amantadine (n = 4) or rimantadine (n = 11) therapy. All influenza isolates recovered from six patients shedding virus for > or = 3 days were screened for antiviral susceptibility; resistant isolates were further genetically characterized. Initial influenza isolates were susceptible to amantadine or rimantadine, but subsequent isolates from five of six patients were resistant. Influenza-associated mortality was similar among patients with and without documented antiviral resistance (2 of 5 vs. 5 of 24). We conclude that development of antiviral resistance in immunocompromised individuals should be considered when they have been treated with antivirals and have shed influenza virus for a prolonged period. Isolation procedures should be instituted for all immunocompromised patients with influenza, both during and after therapy with amantadine or rimantadine.

Influenza A among Patients with Human Immunodeficiency Virus: An Outbreak of Infection at a Residential Facility in New York City

Although annual influenza vaccination is recommended for persons who are infected with human immunodeficiency virus (HIV), data are limited regarding the epidemiology of influenza or the effectiveness of influenza vaccination in this population. We investigated a 1996 outbreak of infection with influenza A at a residential facility for persons with AIDS. We interviewed 118 residents and employees, reviewed 65 resident medical records, and collected serum samples for measurement of influenza antibody titers. After controlling for history of smoking, influenza vaccination, and resident or employee status, in a multivariate model, HIV infection was not statistically associated with influenza-like illness (ILI). Symptoms and duration of ILI were similar for most HIV-infected and HIV-uninfected persons. However, 8 (21.1%) of 38 HIV-infected persons with ILI (vs. none of 15 HIV-uninfected persons) were either hospitalized, evaluated in an emergency room, or had ILI lasting > or = 14 days (P=.06). Vaccination effectiveness (VE) was similar for HIV-infected and HIV-uninfected persons. Vaccination was most effective among HIV-infected persons with CD4 cell counts of >100 cells/microL (VE, 65%; 95% CI, 36%--81%) or HIV type 1 virus load of <30,000 copies/mL (VE, 52%; 95% CI, 11%--75%). Providers should continue to offer influenza vaccination to HIV-infected persons.

Antigenic and genetic characterization of the haemagglutinins of recent cocirculating strains of influenza B virus

The antigenic and genetic characteristics of the haemagglutinins of influenza type B viruses isolated since 1988 during periods of both widespread activity (1990/1991) and sporadic activity (1989/1990) were examined using microneutralization tests and direct RNA sequencing. During 1989/1990, influenza B viruses representative of two distinct lineages antigenically and genetically related to either B/Victoria/2/87 or B/Yamagata/16/88 were isolated, and a minor drift variant of B/Yamagata/16/88, B/Hong Kong/22/89, was identified. In 1990/1991, B/Hong Kong/22/89- or B/Yamagata/16/88-like viruses accounted for the majority of the influenza virus isolates in most countries. Sequence analysis of the HA1 domains of representative viruses confirmed the continued existence of two main lineages among recent strains of influenza B virus and identified unique amino acid changes that could account for the altered antigenic reactivity of some variants. Sequence analysis of the HA2 domains of some of the recent influenza B viruses allowed for a comparison of the evolutionary rates and patterns between the HA1 and HA2 domains.

Low Incidence of Rimantadine Resistance in Field Isolates of Influenza A Viruses

The spread of drug-resistant influenza viruses type A to close contacts in families, schools, and nursing homes has been well documented. To investigate whether drug-resistant influenza viruses circulate in the general population, 2017 isolates collected in 43 countries and territories during a 4-year period were tested for drug susceptibility in a bioassay. Drug resistance was confirmed by detection of specific mutations on the M2 gene that have been shown to confer resistance to amantadine or rimantadine. Sixteen viruses (0.8%) were found to be drug-resistant. Only 2 of these resistant viruses were isolated from individuals who received amantadine or rimantadine treatment at the time the specimens were collected. For 12 individuals use of amantadine or rimantadine could be excluded, and from the remaining 2 patients information about medication was unavailable. These results indicate that the circulation of drug-resistant influenza viruses is a rare event, but surveillance for drug resistance should be continued.

Comparison of 10 influenza A (H1N1 and H3N2) haemagglutinin sequences obtained directly from clinical specimens to those of MDCK cell- and egg-grown viruses

PCR was used to amplify and sequence the complete HA1 region of the haemagglutinin (HA)-encoding genes of 10 clinical isolates of influenza virus of the H1N1 or H3N2 subtypes. These sequences were compared to those obtained from viruses isolated from the same specimens after passage in eggs and MDCK cells. Amino acid substitutions in the egg-derived HA sequences were found in nine out of the 10 specimens analysed, whereas seven out of eight of the MDCK-derived HA sequences were identical to those in the corresponding original specimens. Changes in the H1 HA occurred at residues 77a, 196 (also found in the corresponding HA from the MDCK isolate), 225, 226 and 227; changes in the H3 HA occurred at residues 137, 156, 186, 248 and 276. In addition, we have shown that an amino acid change at residue 145 in the HA of the H3 subtype that was previously demonstrated to be egg-selected is now present in circulating strains.

Influenza: Global surveillance for epidemic and pandemic variants

Influenza viruses, unlike other viruses for which vaccines have been developed, undergo rapid and unpredictable antigenic variation in the hemagglutinin (HA), the surface glycoprotein primarily responsible for eliciting neutralizing antibodies during infection. Because of this antigenic variability and its consequences, the World Health Organization (WHO) in 1947 established an international network of collaborating laboratories to monitor the emergence and spread of new epidemic and pandemic strains of influenza. This network now includes three international WHO collaborating centers and over 100 WHO national collaborating laboratories. The primary purpose of this network is to detect, through laboratory surveillance, the emergence and spread of antigenic variants of influenza that may signal a need to update the formulation of the influenza vaccine. This laboratory surveillance network has provided the strains needed to update the vaccine as well as a repository of influenza viruses useful for studying the antigenic and genetic evolution of this virus. Knowledge gained from molecular studies on the evolution of drift variants and on the emergence of pandemic strains has made influenza a useful model for understanding the potential threat of other emerging or reemerging microbial diseases.

Kinetics of humoral response in children with acute lymphoblastic leukemia immunized with influenza vaccine in 1993 in Poland.

A total of 49 children with acute lymphoblastic leukemia were immunized with a purified subvirion trivalent influenza vaccine (Wyeth-USA) and monitored for hemagglutination inhibition (HI) and neuraminidase inhibition (NI) antibodies before vaccination, and then three weeks and six months after vaccination. Results for HI antibodies were evaluated as geometric mean titre (GMT), mean fold antibody increase (MFI), protection and response rates and those for NI antibodies as geometric mean titre (GMT) and mean fold antibody increase (MFI). Six months after vaccination GMT for hemagglutinin 1 (H1) was much higher than previous values. GMT for hemagglutinin 3 (H3) and hemagglutinin B (HB) was lower than three weeks after vaccination, but much higher than the original values. In the control group GMT for H1 was on a low level all the time and for H3 and HB it was lower when compared with the original values. The proportion of vaccines to antibodies > or = 40 ranged between 45% and 88%. Six months after vaccination GMT for neuraminidase 1 (N1) increased when compared with the second sampling; for neuraminidase 2 (N2) and neuraminidase B (NB) it was slightly lower. In the control group GMT for all antigens was on a low level all the time. The results point to a significant seroconversion for both components after vaccination when compared with the control group.

Decreased antibody response among nursing home residents who received recalled influenza vaccine and results of revaccination, 1996-97

In November 1996, 11 lots of one U.S. manufacturers 1996-97 trivalent influenza vaccine were voluntarily recalled because of decreasing potency of the A/Nanchang/933/95 (H3N2) component. Because the elderly are at high risk of developing influenza-related complications, we assessed the postvaccination antibody titers of nursing home residents who received recalled vaccine and assessed the antibody response to revaccination. Blood samples were collected 3 weeks after vaccination from 86 residents at three nursing homes who received recalled vaccine and 86 residents at three other nursing homes who received a different manufacturers vaccine. Medical records were reviewed. Residents of one nursing home were later revaccinated. Blood samples were collected on the day of revaccination and again in 3 weeks. Serum was tested by hemagglutination inhibition for antibody to all three components of the 1996-97 influenza vaccine. The geometric mean antibody titer (GMT) (33 vs 55; p=0.01) and the percentage of residents with an antibody titer > or = 1:40 (52 vs 67%; p=0.04) to the A/Nanchang/933/95 component were lower among residents who received recalled vaccine compared to those who received non-recalled vaccine, but had similar GMTs against the other two vaccine components. After revaccination, the GMT to A/Nanchang/933/95 increased from 24 on the day of revaccination to 39 (p=0.01) in residents from one nursing home. Therefore, vaccination with the recalled vaccine was associated with lower postvaccination antibody titers to A/Nanchang/933/95, but not against the other two vaccine components. Revaccination was moderately effective in increasing antibody titers. With annual changes in influenza vaccine strains, routine post-release stability testing of influenza vaccine should continue.