In November 1996, 11 lots of one U.S. manufacturer’s 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 manufacturer’s 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 ≥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.

OBJECTIVES: To prospectively detect amantadine-resistant influenza when amantadine was used for influenza A outbreak control.DESIGN: Prospective clinical surveillance and viral culture of all new respiratory illnesses during the course of amantadine prophylaxis.SETTING: A 721-bed, 14-ward nursing home for veterans and spouses during an influenza A outbreak (1993-94).PARTICIPANTS: Residents of a veterans hospital and their spouses.MEASUREMENTS: Nasopharyngeal and throat viral culture. All residents with positive cultures who developed new respiratory symptoms while receiving or residing on a unit receiving amantadine prophylaxis had antiviral-resistance testing and polymerase chain reaction restriction analyses performed.RESULTS: Amantadine prophylaxis was administered sequentially on nine of 14 wards to all well residents for 14 to 31 days/ward to control influenza outbreaks between December 9, 1993, and January 28, 1994. Amantadine treatment was simultaneously provided to 29 ill residents. Between December 3, 1993, and January 22, 1994, 68 culture-positive cases of influenza A were detected. Twenty subjects were receiving or residing on units receiving amantadine prophylaxis. Amantadine sensitivity testing could be performed on 16 residents; 12 residents had amantadine resistant strains. Four of the 12 had not received any antiviral treatment. Illness onset ranged from 1 to 22 days after amantadine prophylaxis was begun on the individual's unit. Two ribonucleic acid (RNA) mutations in the gene coding the M2 protein transmembrane region were observed that were clustered in time and space. Isolates from two roommates, one receiving amantadine for 18 days and one on no antiviral, had identical RNA sequences.CONCLUSION: Antiviral resistance may be responsible for failure of prophylaxis in nursing home outbreaks. Strategies that use different classes of antivirals for prophylaxis and treatment may limit emergence and transmission of resistant virus.

An outbreak of severe pneumococcal pneumonia among children occurred in Iowa from November 1995 through January 1996. An associated outbreak of influenza disease was predominantly caused by influenza A (H1N1) for the first time since 1989. We conducted a case-control study to determine whether preceding influenza infection was directly associated with pneumococcal illness. We identified 13 children with severe pneumococcal pneumonia. Patients were more likely than control subjects to report experiencing an influenza-like illness in the 7-28 days preceding admission (matched odds ratio [OR], 12.4; 95% confidence interval [CI], 1.7-306). Likewise, family members of patients were more likely than those of control subjects to report experiencing an influenza-like illness in the 28 days preceding their admission date (OR, 2.6; 95% CI, 1.0-6.3). Patients were more likely than control subjects to have a positive influenza A (H1N1) convalescent serology (matched OR, 3.7; 95% CI, 1.0-18.1). This study provides direct and indirect evidence that influenza infection led to severe pneumococcal pneumonia among these children. Prevention of pneumococcal disease should be included among the potential benefits of influenza vaccination.

PROBLEM/CONDITIONInfluenza epidemics occur nearly every year during the winter months and are responsible for substantial morbidity and mortality in the United States, including an average of approximately 114,000 hospitalizations and 20,000 deaths per year.REPORTING PERIODThis report summarizes U.S. influenza surveillance data from October 1994 through May 1997, from both active and passive surveillance systems.DESCRIPTION OF SYSTEMDuring the period covered, CDC received weekly reports from October through May from a) state and territorial epidemiologists on estimates of local influenza activity, b) approximately 140 sentinel physicians on their total number of patient visits and the number of cases of influenza-like illness (ILI), and c) approximately 70 World Health Organization (WHO) collaborating laboratories in the United States on weekly influenza virus isolations. WHO collaborating laboratories also submitted influenza isolates to CDC for antigenic analysis. Throughout the year, vital statistics offices in 121 cities reported deaths related to pneumonia and influenza (P&I) weekly, providing a measure of the impact of influenza on mortality.RESULTSDuring the 1994-95 influenza season, 25 state epidemiologists reported regional or widespread activity at the peak of the season. Cases of ILI reported by sentinel physicians exceeded baseline levels for 4 weeks, peaking at 5%. Influenza A(H3N2) was the most frequently isolated influenza virus type/subtype. The longest period of sustained excess mortality was 5 consecutive weeks, when the percentage of deaths attributed to P&I exceeded the epidemic threshold, peaking at 7.6%. During the 1995-96 season, 33 state epidemiologists reported regional or widespread activity at the peak of the season. ILI cases exceeded baseline levels for 5 weeks, peaking at 7%. Influenza A(H1N1) viruses predominated, although influenza A(H3N2) and influenza B viruses also were identified throughout the United States. P&I mortality exceeded the epidemic threshold for 6 consecutive weeks, peaking at 8.2%. The 1996-97 season was the most severe of the three seasons summarized in this report. Thirty-nine state epidemiologists reported regional or widespread activity at the peak of the season. ILI reports exceeded baseline levels for 5 consecutive weeks, peaking at 7%. The proportion of respiratory specimens positive for influenza peaked at 34%, with influenza A(H3N2) viruses predominating. Influenza B viruses were identified throughout the United States, but only one influenza A(H1N1) virus isolate was reported overall. The proportion of deaths attributed to P&I exceeded the epidemic threshold for 10 consecutive weeks, peaking at 9.1%.INTERPRETATIONInfluenza A(H1N1), A(H3N2), and B viruses circulated during 1994-1997. Local surveillance data are important because of geographic and temporal differences in the circulation of influenza types/subtypes.PUBLIC HEALTH ACTIONSCDC conducts active national surveillance annually from October through May for influenza to detect the emergence and spread of influenza virus variants and monitor the impact of influenza-related morbidity and mortality. Surveillance data are provided weekly throughout the influenza season to public health officials, WHO, and health-care providers and can be used to guide prevention and control activities, vaccine strain selection, and patient care.

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.

References 1. Berlin OGW, Novak SM, Porschen RK, Long EG, Stelma GN, Schaeffer FW. Recovery of Cyclospora organisms from patients with prolonged diarrhea. Clin Infect Dis 1994;18:606-9. 2. Ash LR, Orihel TC. Collection and preservation of feces. Parasites: a guide to laboratory procedures and identification. Chicago: ASCP Press; 1991. p. 3-53. 3. Weber R, Bryan RT, Owen RL, Wilcox CM, Gorelkin L, Visvesvara GS. Improved light microscopical detection of microsporidia spores in stool and duodenal samples. N Engl J Med 1992;326:161-6. 4. Berlin OGW. Mycobacteria. In: Baron EJ, Finegold SM, editors. Diagnostic microbiology. 8th ed. St. Louis: C.V. Mosby; 1990. p. 597-640. 5. Ash LR, Orihel TC. Atlas of human parasitology. 4th ed. Chicago: ASCP Press; 1997. 6. Centers for Disease Control and Prevention. Update: outbreaks of cyclosporiasis—United States, 1997. MMWR Morb Mortal Wkly Rep 1997;46:451-2. 7. Centers for Disease Control and Prevention. Update: outbreaks of cyclosporiasis—United States and Canada, 1997. MMWR Morb Mortal Wkly Rep 1997;46:521-3. 8. Colley DG. Widespread food-borne cyclosporiasis outbreaks present major challenges. Emerg Infect Dis 1996;2:354-6. 9. Eberhard ML, Pienazek NJ, Arrowood MJ. Laboratory diagnosis of Cyclospora infections. Arch Pathol Lab Med 1997;121:792-7.

The purpose of this workshop was to review the status of regions so that if a pandemic strain arises in these vast areas, it may be detected. Various models may be adopted for this pursurveillance activities and to recommend new approaches necessary to detect and control pandemics. The specific questions pose; one that has proven successful would be to create ‘‘twinning’’ or sister laboratories. The developed country laboratory that the panel addressed were as follows: • Is the current global surveillance network equipped to rapwould adopt the facility in the less-developed country and provide advice for and assistance in improving capabilities. These efforts idly detect a new pandemic strain of influenza, to monitor the impact as the virus spreads, and to disseminate surveillance are not without costs in time, travel, and equipment. The World Health Organization (WHO), through its collaboinformation in a timely manner? • How can surveillance data be used to control a pandemic? rating centers in London, Atlanta, and now Melbourne, has taken the lead in working with a network of national labora• What are the ways by which increased research efforts can improve virologic and disease surveillance? tories. Alan Hampson described the history of WHO and the development of the concept of the networks of National InfluThe panel agreed that adequate surveillance is critical for the prompt detection of influenza variants, including strains of enza Centres. However, at present, only C60 countries have national centers, and these function at various levels of activity. pandemic potential. Both the detection of the viruses and the diseases they cause are components of this effort, which, by While surveillance activity has increased in some countries, in particular China, it is important to realize that similar condiits very nature, must be international in scope. Surveillance questions were examined formally by the group, which intions for transmission exist in many areas of South and Southeast Asia and that it is impossible to obtain either specimens cluded participants from France, Norway, Australia, Japan, Hong Kong, and the United States. or data from these areas. Another issue that needs to be considered in improving the collection of potential pandemic viruses is the substrate to be Current Global Surveillance Networks used. If eggs are not available, is there a cell line that can be used? Also, is that cell line going to be acceptable if the virus Claude Hannoun, chair of the session, reported on two issues: the methods used over many years in France and now in other isolate turns out to be one that should be a candidate for the new vaccine and there is insufficient time available to isolate countries in Western Europe for surveillance and the absence of laboratories in certain parts of the world. In Europe, a system another representative virus in a suitable substrate? These issues need to be considered as laboratories with capabilities to of sentinel physicians collects samples for virus isolation from practices covering large geographic areas. Specimens are transcollect and process specimens and to identify and characterize new isolates are recruited. ported to central laboratories, and recovery of viruses has been good. As a result, it has been possible to recognize quickly the China remains a focus both in terms of dense population, which in the past had little sampling of influenza viruses, and occurrence of influenza outbreaks and to let physicians and the public know about the timing and virus strains involved in the the well-known likelihood that new pandemic strains arise from this region. Helen Regnery reviewed the existing virologic suroutbreaks. Studies are underway, sponsored by the European Scientific Working Group on Influenza, to better define the veillance program in China, which has been organized and supported by the WHO collaborating center at the Centers for impact of influenza in the European region. Hanspeter Zimmerman reported on the Swiss system of sentinel physician surveilDisease Control and Prevention (CDC) in Atlanta since 1989. Currently, eight surveillance sites have been established in diflance, which was developed so that attack rates could be generated for various regions of the country. ferent geographic locations. Each site collects specimens from persons with acute respiratory disease and performs the initial Other parts of the world are less well covered by laboratories, and in some extensive regions, especially in Africa, laboratories isolation. After isolation, influenza viruses are transported to the Institute of Virology in Beijing, where samples are lyophiwith the capability of identifying viruses simply do not exist. Contacts have been made to help develop laboratories in these lized and forwarded to the CDC for further characterization. Information provided with submitted specimens includes collection date, the patient’s age and geographic location, and the extent of influenza activity in the area at the time of specimen Chair: Claude Hannoun; rapporteur: Nancy H. Arden; participants: Lars collection. Haaheim, Alan W. Hampson, Arnold S. Monto, Kuniaki Nerome, Helen Regnery, Frederick L. Ruben, Kennedy F. Shortridge, and Hanspeter Zimmerman. Held at: Pandemic Influenza: Confronting a Re-emergent Threat, Bethesda, Use of Surveillance Data to Control Pandemics Maryland, 11–13 December 1995.

PROBLEM/CONDITION:CDC conducts active surveillance annually from October through May on the emergence and spread of influenza virus variants and the impact of influenza-related morbidity and mortality. Influenza activity is also monitored throughout the year by passive surveillance.REPORTING PERIOD COVERED:This report summarizes U.S. influenza surveillance from October 1992 through May 1994.DESCRIPTION OF SYSTEM:Influenza surveillance comprises four components, three of which provide weekly data from October through May: a) state and territorial epidemiologists provide estimates of local influenza activity; b) approximately 140 sentinel physicians report their total number of patient visits and the number of cases of influenza-like illness; and c) approximately 70 collaborating laboratories of the World Health Organization (WHO) report weekly influenza virus isolations and submit selected influenza isolates to CDC for antigenic analysis. Throughout the year, vital statistics offices of 121 cities report deaths related to pneumonia and influenza (P&I), providing an index of the impact of influenza on mortality.RESULTS:Influenza B viruses predominated during the 1992-93 influenza season, but influenza A(H3N2) isolates increased and were associated with outbreaks in nursing homes at the end of the season. The increase in influenza A(H3N2) activity was associated with a rise in P&I-related mortality. Preseason outbreaks of influenza A(H3N2) virus were reported during August and September 1993 in Louisiana. In the past, preseason outbreaks of influenza have been associated with earlier than usual epidemic-level activity. During the 1993-94 influenza season, activity rose during November and December and peaked earlier than usual, during the last week of December and the first week of January; influenza A(H3N2) viruses predominated.INTERPRETATION:The change in predominance from influenza B to influenza A in the spring of 1993 emphasizes the importance of annual influenza surveillance. Although influenza vaccine is effective against both influenza A and B, the antiviral drugs amantadine and rimantadine are effective only against influenza A. Outbreaks during the summer of 1993 emphasize that influenza should be considered a possible cause of respiratory infections during summer and early autumn.ACTIONS TAKEN:Surveillance data were provided weekly throughout the influenza season to public health officials, WHO, and health-care providers.

Influenza virus is one of the most ubiquitous organisms on the planet, causing illness in much of the population each year. The dynamic nature of the influenza virus requires similarly dynamic surveillance and prevention initiatives. The efforts of national surveillance programs, overseen by the World Health Organization and administered by institutions such as the U.S. Centers for Disease Control and Prevention, the U.S. armed forces, and 60 to 70 collaborating laboratories, annually culminate in the development of effective influenza vaccines. The U.S. Air Force's contribution is via Project Gargle, through which bases in various locations worldwide conduct active surveillance and submit throat swab specimens for virus isolation and characterization; the results of these laboratory analyses help determine the composition of the following year's influenza vaccine. These collaborative efforts have resulted in an identical or close antigenic match between vaccine and epidemic strains in 8 of the last 9 influenza seasons.

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.

In July 1991, an influenza A virus, designated A/Maryland/12/91 (A/MD), was isolated from the bronchial secretions of a 27-year-old animal caretaker. He had been admitted to the hospital with bilateral pneumonia and died of acute respiratory distress syndrome 13 days later. Antigenic analyses with postinfection ferret antisera and monoclonal antibodies to recent H1 swine hemagglutinins indicated that the hemagglutinin of this virus was antigenically related to, but distinguishable from, those of other influenza A (H1N1) viruses currently circulating in swine. Oligonucleotide mapping of total viral RNAs revealed differences between A/MD and other contemporary swine viruses. However, partial sequencing of each RNA segment of A/MD demonstrated that all segments were related to those of currently circulating swine viruses. Sequence analysis of the entire hemagglutinin, nucleoprotein, and matrix genes of A/MD revealed a high level of identity with other contemporary swine viruses. Our studies on A/MD emphasize that H1N1 viruses in pigs obviously continue to cross species barriers and infect humans.

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.

During the 1991-92 influenza season, sustained regional influenza activity began to be reported by state and territorial epidemiologists in the United States in mid-October 1991. Sustained reporting of widespread influenza activity began in early November 1991, 5-10 weeks earlier than in any of the previous nine influenza seasons. Influenza caused substantial morbidity among school-age children and excess mortality among the elderly. Regional outbreaks of influenza ended 2-6 weeks earlier than in the previous nine influenza seasons, based on the last sustained state and territorial epidemiologists' reports. Nationally, > 99% of isolates were influenza A. Influenza A(H3N2) predominated in all regions of the country, but isolation of influenza A(H1N1) increased proportionally as the season progressed. Isolation of influenza B (< 1% of total isolates) clustered after February. The majority of isolates characterized were antigenically similar to components in the 1991-92 influenza vaccine. However, an influenza A(H1N1) strain that had undergone antigenic drift was detected in many regions of the country; this strain will be included in the 1992-93 influenza vaccine.

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.