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Drinka PJ, Gravenstein S, Schilling M, Krause P, Miller BA, Shult P. Duration of Antiviral Prophylaxis During Nursing Home Outbreaks of Influenza A: A Comparison of 2 Protocols. Arch Intern Med. 1998;158(19):2155–2159. doi:10.1001/archinte.158.19.2155
We performed a randomized trial of 2 protocols guiding the duration of antiviral chemoprophylaxis during outbreaks of influenza A in a rural, 700-bed nursing home for veterans and their spouses with 14 nursing units in 4 buildings.
Half of all residents volunteered to participate. Nursing units were randomized, and the effectiveness of short-term (minimum, 14 days and 7 days without the onset of a case in the building) vs long-term (minimum, 21 days and 7 days without the onset of a case in the 4-building facility) prophylaxis was compared using amantadine hydrochloride in the influenza seasons of 1991-1992 and 1993-1994 and rimantadine hydrochloride in the influenza season of 1994-1995. A "case" is defined as an incident of a respiratory tract illness and the isolation of an influenza virus organism. We compared the number of cases after the discontinuation of short vs long-term chemoprophylaxis. Prospective surveillance identified residents with new respiratory tract symptoms, and specimens for viral cultures were obtained even in the absence of temperature elevation.
We documented influenza A virus activity during 3 seasons (32, 68, and 12 patients, respectively). During the 1991-1992, 1993-1994, and 1994-1995 influenza seasons, the patients on 11 floors were assigned to receive short-term chemoprophylaxis and those on 10 floors were assigned to long-term chemoprophylaxis. Only in 1993-1994 did chemoprophylaxis extend beyond 14 or 21 days when new cases continued beyond 14 days. Amantadine-resistant strains were circulating at that time. None of the participants in the prospective, controlled study had influenza develop after the termination of short- or long-term chemoprophylaxis.
Antiviral chemoprophylaxis can be administered for the longer duration of 14 days or, in the absence of new culture-confirmed illness in the nursing building, for 7 days.
RECOMMENDATIONS to limit influenza outbreaks in nursing homes include vaccination, measures to limit exposure to infectious secretions, and the administration of antiviral agents. In 1990, when this study was initiated, the Center for Disease Control (now the Centers for Disease Control and Prevention [CDC]) recommended that "to be fully effective as prophylaxis, the antiviral drug must be taken each day for the duration of influenza activity in the community."1 A conscientious clinician might continue chemoprophylaxis for the duration of activity in the most localized reporting area, which might be as large as an entire state. "Community" public health agencies have not had the responsibility to expeditiously inform nursing home practitioners when "activity" is over, and they cannot reliably predict it. Recommendations for effectively administering antiviral chemoprophylaxis that include limiting the duration, possible toxicity, expense, and the emergence of antiviral resistance need to be clarified.2-4 The goal of this study was to investigate the optimal duration of antiviral chemoprophylaxis using 2 protocols of differing durations. This work includes prospective surveillance with viral culture of all consenting symptomatic nursing home residents and is not directly comparable with most previously reported outbreaks that were identified retrospectively after dramatic, widespread clinical illness.
More recently, the CDC recommended that chemoprophylaxis in nursing homes "should be continued for at least 2 weeks or until approximately 1 week after the end of the outbreak."5 Our experience supports this recommendation.
The Wisconsin Veterans Home, King, is a skilled nursing facility for veterans and their spouses. It has 4 nursing buildings and a separate activity building for all residents. The 4 nursing buildings contained 13 nursing floors during the 1991-1992 influenza season. The facility subsequently operated 14 floors following the construction of a new building and the closure of a building. The average daily census was 680 in 1991-1992, 690 in 1993-1994, and 718 in 1994-1995 (Table 1). During the 1991-1992, 1993-1994, and 1994-1995 influenza seasons, 86%, 89%, and 86% of all residents and 34%, 46%, and 41% of nursing staff, respectively, were vaccinated with the commercially available trivalent influenza virus vaccine (Fluzone, Connaught Laboratories Inc, Swiftwater, Pa).
A prospective influenza surveillance and culturing program was maintained as part of a study sponsored by the National Institutes of Health that was designed to compare the effectiveness of 2 protocols for administering amantadine hydrochloride or rimantadine hydrochloride chemoprophylaxis in nursing homes. Participants were clinically assessed twice each week by study nurses. Surveillance nurses visited 259 study participants in 1991-1992, 396 participants in 1993-1994, and 400 participants in 1994-1995 to identify new respiratory tract symptoms. Nursing staff who provided routine care also alerted surveillance nurses to new respiratory tract symptoms in all residents, including those not in the study. Using polyester (Dacron) fiber swabs, nasopharyngeal and throat specimens were obtained from all consenting symptomatic residents. A resident with a new respiratory illness was not required to have a temperature elevation for specimens to be taken. Swabs were placed in individual tubes containing virus transport media (veal broth with gentamicin sulfate, penicillin G sodium, streptomycin sulfate, and amphotericin B) and cooled to 4°C within 1 hour. Specimens were sent to the Wisconsin State Laboratory of Hygiene, Madison, and cultures started within 30 hours of acquiring the specimen. A "case" is defined as an incident of a respiratory tract illness in which the pathogen was culture-confirmed to be influenza A virus.
On culture confirmation of influenza A from a person working or living in the facility, we recommended that physicians treat any resident with respiratory tract symptoms identified within 48 hours of the onset with amantadine or rimantadine for 5 days. Antiviral therapy was discouraged if a resident had a new respiratory tract illness for longer than 48 hours.
Nursing units were stratified according to the average level of nursing care (skilled nursing facility vs intermediate care facility 1). The surveillance nurses were unaware of the randomization of a nursing unit until an outbreak was declared on that unit. A nursing unit included residents residing on a given floor of a building within the facility. The criterion for an influenza outbreak on a floor was met when 10% of the residents were documented to have the onset of a respiratory tract symptom within 7 days after influenza A virus had been cultured in a resident of the building.6 Often, these newly symptomatic residents were afebrile. With the declaration of an outbreak, the study participants living on that floor were randomly assigned as a group to long- or short-term chemoprophylaxis. The short-term group received chemoprophylaxis for a minimum of 14 days and, until there was no new onset of culture-confirmed illness in the building, for 7 days. The long-term group received chemoprophylaxis for a minimum of 21 days and, until there was no new onset of culture-confirmed illness in the entire 4-building facility, for 7 days. The standard of care for this facility was to treat the residents not enrolled in the study for nearly the same duration as the short-term group in 1991-1992 (average, 15 days), exactly the same duration in 1993-1994, and for a shorter duration (average, 13 days) in 1994-1995. Data from residents not enrolled in the formal study are also included in this report. The institution and termination of chemoprophylactic treatment were managed for study participants by the authors according to the protocols.
Amantadine was administered in 1991-1992 and 1993-1994; rimantadine was administered in 1994-1995. All residents received an initial amantadine hydrochloride dose of 100 mg. The dose was subsequently reduced for elevated serum creatinine levels, as calculated by the Cockroft and Gault formula, and was given in the morning as 100 mg/d (estimated creatinine clearance, >0.50 mL/s [>30 mL/min]), every other day (estimated creatinine clearance, 0.27-0.50 mL/s [16-30 mL/min]), or every fourth day (estimated creatinine clearance, <0.25 mL/s [<15 mL/min]). In 1994-1995, rimantadine hydrochloride was administered at a daily dose of 100 mg.
Amantadine chemoprophylaxis was withheld from residents who had a previous respiratory tract infection since the date of onset of the first culture-proven viral illness within the building (possibly influenza A virus); residents who refused; those who were receiving ongoing amantadine treatment of a neurologic condition; and residents who had significant agitation, seizure disorder, or an unsteady gait. Rimantadine chemoprophylaxis was withheld because of the first 3 contraindications. The staff registered nurse had the discretion to discontinue chemoprophylaxis if new adverse clinical events were suspected to be drug effects.
During an outbreak, measures were taken to limit transmission. Residents with a new respiratory illness ate their meals in the hallway adjacent to the entrance of their room and were asked to remain in their rooms and wear a mask if they left their room. The last 2 recommendations were encouraged but could not be mandated. Staff caring for symptomatic residents were encouraged to wear masks and wash their hands frequently. Notices were placed at all building entrances requesting that community members with respiratory symptoms postpone their visit.
Influenza was proved to circulate in the facility during all study years. Thirty-two cases were identified during 28 days in 1991-1992, 68 cases were identified during 51 days in 1993-1994, and 12 cases were identified during 33 days in 1994-1995 (Table 1). This report does not include the 1992-1993 outbreak in which only influenza B virus was isolated, and antiviral agents were not administered.
During the 1991-1992 season, 7 floors met the "outbreak" criterion during 7 days; the residents of 4 floors were randomly assigned to receive short-term chemoprophylaxis and the residents of 3 floors were to receive long-term chemoprophylaxis. In the entire facility, 339 residents were considered for amantadine chemoprophylaxis, 218 received chemoprophylaxis, and a total of 42 on all floors received amantadine treatment of influenzalike illness. In 1993-1994, 9 floors met the "outbreak" criterion during 27 days; the residents of 5 floors were randomly assigned to receive short-term and the residents of 4 floors were to receive long-term chemoprophylaxis. A total of 454 residents were considered for amantadine chemoprophylaxis, 283 received chemoprophylaxis, and 29 residents on all floors received amantadine treatment. In 1993-1994 only, chemoprophylaxis was administered beyond the minimum of 14 or 21 days because of continued case finding. The total duration of chemoprophylaxis ranged from 14 to 45 days. In 1994-1995, 5 floors met the "outbreak" criterion during 34 days; the residents of 3 floors were randomly assigned to receive short-term and those of 2 floors were to receive long-term rimantadine chemoprophylaxis. A total of 204 residents were considered for chemoprophylaxis, 199 received it, and 51 residents on all floors received rimantadine treatment.
In the 1991-1992 season, 22 of the residents receiving chemoprophylaxis had the drug discontinued, and 3 had a reduction in their dosage. In the 1993-1994 season, 76 residents had chemoprophylaxis discontinued, 6 of them because of the identification of illnesses yielding influenza A viral organisms. (Amantadine-resistant strains were identified in 1993-1994 from persons who were receiving amantadine or who were residing on wards where chemoprophylaxis had been instituted [Helen Regnery, PhD, oral communication, October 11, 1995]). In 1994-1995, 27 residents had rimantadine chemoprophylaxis discontinued. The reasons for discontinuation were mental status changes, agitation, unsteady gait, falls, or gastrointestinal tract symptoms, including anorexia.
During the study, 171 study participants were randomly assigned to the long-term protocol, and 210 study participants were randomly assigned to the short-term protocol. An additional 338 residents not enrolled in the formal study were treated nearly the same as the short-term group (see the "Patients and Methods" section). No case of influenza was documented among study participants after the discontinuation of short-term antiviral chemoprophylaxis. A patient who was not enrolled in the formal study became ill 3 days after the end of a 14-day period of chemoprophylaxis during the largest outbreak in 1993-1994 (68 cases). Following the report of this illness, amantadine prophylaxis was restarted. Intensive surveillance continued each year for 44 to 64 days following the onset of illness in the last patient. The following number of cultures failing to grow the organism were obtained after the last case: 64 in 1991-1992, 57 in 1993-1994, and 44 in 1994-1995.
Influenza activity within each building was variable. The first cases occurred within the facility 18 to 26 days after the first organisms were confirmed by culture from a regional laboratory and 18 to 38 days following the first culture confirmation of organisms in Wisconsin. Because outbreaks were declared 1 nursing unit at a time, there was a period during which outbreaks were declared within the facility; the first to the last outbreaks were declared over 7 to 34 days. Influenza activity was consistently of a shorter duration in the facility than in the community. The last organisms were culture confirmed from the facility at 6 to 62 days before the regional laboratory's last confirmed viral organism was isolated and 31 to 62 days before that in the state.
Amantadine or rimantadine chemoprophylaxis may be limited to 14 days and, until there is no new onset of culture-confirmed influenza, for 7 days within a nursing building. A longer course of chemoprophylaxis was not demonstrated to be more effective. As stated in the introduction, the CDC recommendation was that to be fully effective, antiviral prophylaxis must be taken for the duration of influenza A activity in the community. Our 3-year experience supports defining "community" as tightly as a single nursing building if chemoprophylaxis is guided by careful surveillance. Influenza activity within a nursing building was more focal than the regional or 4-building facility as a whole. Timely and accurate information regarding influenza activity within the building, not surprisingly, could allow a more focused duration of prophylaxis. Our overall conclusions regarding the duration of chemoprophylaxis are strengthened because 338 residents not enrolled in the study were treated in nearly the same manner as the short-duration group.
Much has been written about the administration of unnecessary drugs in nursing homes and in geriatric practice. Cost and adverse drug reactions motivate clinicians to limit therapy to the shortest effective duration. Because of the focal, sometimes short-lived, nature of influenza activity within a single nursing building, the potential emergence of antiviral resistance, and the expense and toxicity of antiviral chemoprophylaxis, we advocate surveillance with influenza cultures to verify both the onset of an outbreak and its end so that antiviral chemoprophylaxis can be administered for the shortest effective duration.
THE IMPORTANCE of cultures at the Wisconsin Veterans Home was underscored in December 1995 after the completion of this study when 285 cases of influenza A were culture confirmed in Wisconsin, and outbreaks of respiratory tract illness were encountered in 2 of our buildings. However, 18 organisms of parainfluenza virus 1 were cultured, with no influenza A virus. Based on statewide data, a conscientious clinician should have suspected an influenza outbreak. If cultures had not been obtained, antiviral chemoprophylaxis could have been started unnecessarily. In December 1992, we identified a large outbreak of respiratory tract illness, but current antiviral agents would have been ineffective because it was caused by influenza B virus. Both of these observations underscore that if chemoprophylaxis is initiated in the face of a "suspected" outbreak, continued antiviral chemoprophylaxis should be confirmed by culture.7 Our experiences described here are similar to those of Nicholson et al,8 who performed prospective surveillance of 515 residents of English homes for the elderly. Persons with a new onset of respiratory tract symptoms were identified, and viral cultures and serologic studies were performed. These investigators report that "respiratory symptoms in the study population evidently were caused mostly by pathogens other than influenza virus during the influenza period documented nationally."8
The importance of obtaining cultures at the end of the anticipated period of influenza prophylaxis was suggested in 1991-1992 when the authors of this report identified respiratory syncytial virus overlapping the end of influenza A virus activity.9 Prophylaxis could have unnecessarily been continued based on the continued occurrence of respiratory tract illnesses if surveillance culturing had not been in place. Thus, once chemoprophylaxis has been initiated, viral cultures of any new illnesses are helpful in guiding its cessation. Finally, the isolation of influenza A virus from a resident whose respiratory tract illness began in the second week of chemoprophylaxis would suggest a resistant strain and might prompt a switch to another prophylactic medication as new antiviral agents become available.10
In 1993-1994, chemoprophylaxis was extended beyond 14 days in the face of continued viral isolation, including amantadine-resistant strains. Amantadine resistance has previously been encountered during nursing home outbreaks.11-13 In 1 report,13 a resistant organism was cultured before the use of amantadine. No treatment of index cases in households, 3- to 5-day treatment, or isolation of residents being treated for active infection has been recommended to limit the emergence and transmission of resistant strains.5,12,14,15 Further study will be required to determine how to administer antiviral drugs when resistant strains are suspected. The onset of influenza A illness in residents days after achieving effective levels of amantadine or rimantidine, as occurred in 1993-1994, should suggest the presence of resistant strains. In this study, antiviral medication use did not deviate from the stated protocol.
In 1997, reviewers16 noted that the cost of administering generic amantadine for 7 days (100 mg/d) was $2.37, but a similar dose and duration of rimantadine therapy were $10.49. In the same article, it was stated that rimantadine had "gastrointestinal adverse effects similar to those of amantadine, but a lower risk of [central nervous system] adverse effects."16 The cost of administering rimantadine for 7 days to 200 residents is about $2100. Our current cost for an influenza culture is about $50. One week of rimantadine therapy, therefore, has a cost similar to 40 viral cultures. Even with intense prospective surveillance that sometimes began before the first influenza A viral organism was isolated in Wisconsin, we averaged 80 cultures per 200 residents per season (Table 1). Our system of intensive surveillance with cultures is unlikely to become the standard of care. Greater economy in standard practice might include surveillance cultures restricted to febrile respiratory tract illness after influenza A virus had been cultured by a regional laboratory. If influenza A virus was cultured as the predominant organism within a facility, cultures could be suspended until the clinical criteria for an outbreak were met or being approached. At that time, specimens could be obtained from all residents with respiratory tract illness of a recent onset for culture and antiviral prophylaxis initiated pending the results of the cultures. Cultures of any new respiratory tract illnesses could be suspended, to begin again before the anticipated discontinuation of prophylaxis (14 days). We suspect that future research will demonstrate that it is cost-effective to perform clinical surveillance for a new onset of respiratory tract symptoms followed by viral cultures to confirm an outbreak's beginning and end to limit chemoprophylaxis to the shortest effective duration. We are unable to confidently recommend a specific protocol.
Our results showing no additional viral organisms among study participants after the planned discontinuation of the short-term protocol must be placed within the context of the specific methods used in both arms of the study. These methods include the recommendations for antiviral treatment of symptomatic residents, outbreak criterion, the size of the outbreak unit, and the means of withholding or discontinuing chemoprophylaxis in individual residents. In addition, influenza may show significant annual variation in contagiousness and virulence. Nonetheless, our conclusion that amantadine or rimantadine chemoprophylaxis can be limited to 14 days and 7 days, respectively, after the last onset of a culture-confirmed illness within a nursing building is based on 3 separate years of study and supports the current CDC recommendations for the use of chemoprophylaxis in a nursing home.5 We present the only controlled data in existence regarding the duration of antiviral chemoprophylaxis in a nursing home.
Since the manuscript was accepted for publication, we recently passed through the 1997-1998 influenza season and experienced an outbreak of influenza A with the largest number of positive cultures documented from a nursing home. A total of 154 (21.4%) of 720 residents of the 4-building Wisconsin Veterans Home had influenza type A isolated from respiratory tract secretions between January 14 and May 14, 1998. Antiviral prophylaxis was administered to residents on 13 nursing units for 14 days. In the face of prolonged influenza activity (121 days), the short-term protocol used for administering antiviral prohylaxis presented in the ARCHIVES would have lead to discontinuation of prophylaxis before disease onset in 61 of 154 cases (3 residents died). These cases occurred on 10 separate nursing units with the first new cases 2, 5, 8, 13, 19, 23, 23, 61, 61, and 78 days following an initial period of prophylaxis administered according to our published short-term protocol. Prophylaxis was restarted for residents in some of the units. We believe that these later cases represented reintroduction of influenza to the nursing unit. It is uncertain whether a longer period of initial prophylaxis with rimantadine would have been optimal given potential toxicity, expense, and emergence of resistant strains. The late deaths are of concern. This recent experience does not change our recommendation for an initial duration of prophylaxis with rimantadine of 2 weeks, and 7 days beyond the onset of the last case in a nursing building. Influenza type A activity shows substantial year to year variability in attack rates, duration, and excess mortality. Any protocol must be adapted to the variability. Our protocol can serve as a starting point for practitioners and other researchers. Surveillance for new respiratory tract illness must continue if influenza remains prevalent in the surrounding community to identify reintroduction of influenza.
Accepted for publication March 5, 1998.
This study was supported by grants AG 09632 and AG 00548 from the National Institutes of Health, Bethesda, Md (Dr Gravenstein).
Amantadine was provided by DuPont Pharma, Wilmington, Del, and rimantadine was provided by Forest Pharmaceuticals Inc, St Louis, Mo.
Reprints: Stefan Gravenstein, MD, Department of Internal Medicine–Geriatrics, Glennan Center for Geriatrics and Gerontology, Eastern Virginia Medical School, 825 Fairfax Ave, Suite 201, Norfolk, VA 23507-1912.