LEVETIRACETAM IN PLASMA BY UV – CODE Z04310 INTRODUCTION Treatment of the epileptic patients requires a multidisciplinary medical knowledge, regarding i.e. pharmacology, psychology and social science. In this contest the various antiepileptic drugs (AEDs) are used to decrease the frequency and/or severity of seizures in people with epilepsy. Monitoring of plasmatic con
Inside cover.fmTimothy M. Uyeki,* Yu-Hoi Chong,† Jacqueline M. Katz,* Wilina Lim,† Yuk-Yin Ho,†
Sophia S. Wang,* Thomas H.F. Tsang,* Winnie Wan-Yee Au,† Shuk-Chi Chan,† Thomas
Rowe,* Jean Hu-Primmer,* Jensa C. Bell,* William W. Thompson,* Carolyn Buxton
Bridges,* Nancy J. Cox,* Kwok-Hang Mak,† and Keiji Fukuda*
In April 1999, isolation of avian influenza A (H9N2) viruses from humans was confirmed for the first time.
H9N2 viruses were isolated from nasopharyngeal aspirate specimens collected from two children whowere hospitalized with uncomplicated, febrile, upper respiratory tract illnesses in Hong Kong during March1999. Novel influenza viruses have the potential to initiate global pandemics if they are sufficiently trans-missible among humans. We conducted four retrospective cohort studies of persons exposed to these twoH9N2 patients to assess whether human-to-human transmission of avian H9N2 viruses had occurred. Noserologic evidence of H9N2 infection was found in family members or health-care workers who had closecontact with the H9N2-infected children, suggesting that these H9N2 viruses were not easily transmittedfrom person to person. n April 1999, two World Health Organization reference Hong Kong are not highly pathogenic in chickens (8), whereas I laboratories independently confirmed the isolation of avian antigenic analysis of the H9N2 viruses isolated from humans
influenza A (H9N2) viruses for the first time in humans (1).
in southern China suggested that they were more closely H9N2 viruses were isolated from nasopharyngeal aspirate related to the G9-like viruses (9). However, the G1-like viruses specimens collected from two young children who were hospi- contain internal genes that are highly homologous to those of talized in Hong Kong during March 1999 (2). The children highly pathogenic influenza A (H5N1) viruses isolated from were not related, were hospitalized at different facilities, did chickens and humans in Hong Kong in 1997 (7).
not have any known contact with or link to each other, and had The first and only documented human outbreak of highly not traveled outside Hong Kong (2). Both children had uncom- pathogenic avian influenza A (H5N1) virus infections resulted plicated, febrile, upper respiratory tract illnesses and fully in 18 hospitalizations and six deaths among Hong Kong resi- recovered (Table 1) (2). Evidence for five additional human dents during 1997 (10-12). A case-control study identified illnesses attributed to H9N2 in Guangdong Province, China, recent exposure to live poultry as an important risk factor for during 1998 has been reported (3). Detection of antibody to H5N1 infection (13), and cohort studies suggested that human- H9N2 has been reported from persons in northern and south- to-human transmission of H5N1 virus was limited (14,15).
ern China (3,4) and poultry workers in Hong Kong (5), sug- The poor transmissibility of these H5N1 viruses among gesting that additional unrecognized human H9N2 infections humans and the elimination of approximately 1.5 million chickens appear to have been key factors that stopped this out- H9N2 viruses have been prevalent in domestic poultry (chickens, ducks, geese, quail, and pigeons) throughout Asia Avian populations, including domestic poultry and water- since the early 1990s and were also isolated from swine in fowl, are the natural reservoir for all 15 known Influenza A Hong Kong in 1998 (6). H9N2 viruses circulating in Asia have virus (FLUAV) hemagglutinin (HA) subtypes, including H5 been classified into three antigenically and phylogenetically and H9 viruses (16). Viruses with novel HA can emerge when distinct sublineages (7). Two of these Asian H9N2 virus sub- animal and human FLUAV genes undergo reassortment in the lineages, influenza A/Quail/Hong Kong/G1/97 (G1-like lin- same host or when viruses from an animal host, such as swine eage) and influenza A/Chicken/Hong Kong/G9/97 (G9-like or poultry, directly infect susceptible persons who lack protec- lineage), were isolated from poultry in Hong Kong (6). The tive immunity against the novel HA (17,18). In addition to two Hong Kong children were infected by G1-like viruses, ability to infect humans, the transmissibility of a novel Influ- influenza A/Hong Kong/1073/99 and A/Hong Kong/1074/99 enzavirus is a key factor influencing whether the novel virus (8). The H9N2 viruses that have been isolated from poultry in can cause an influenza pandemic (19). The emergence of novel *Centers for Disease Control and Prevention, Atlanta, Georgia, USA; 1Presented in part at the International Conference on Emerging Infec- and †Department of Health, Hong Kong Special Administrative Region tious Diseases 2000, Atlanta, Georgia, July 2000 (Poster #55), Session Emerging Infectious Diseases • Vol. 8, No. 2, February 2002 Table 1. Clinical characteristics of two children infected with influenza A (H9N2) viruses, Hong Kong, 1999a aSource: Epidemiologic investigation by the Hong Kong Department of Health and review of medical records.
bCRP = C-reactive protein; WBC = leukocytes; AST = aspartate aminotransferase; CXR = chest X-ray; U/A = urinalysis; NP = nasopharyngeal; EIA = enzyme immunoassay influenza A (H1N1), A (H2N2), and A (H3N2) viruses led to patients. During face-to-face interviews conducted in either three influenza pandemics during the 20th century (19). English or Cantonese, staff from the Hong Kong Department The identification of two children who had acute infection of Health administered a detailed questionnaire to a group of with novel H9N2 virus strains provided the first opportunity to household members, family members, and relatives of each investigate their transmissibility and pandemic potential H9N2-infected child. The questionnaire assessed the level of among humans. We report the results of four retrospective exposure and contact with the H9N2-infected patient during cohort studies designed to detect serologic evidence of H9N2 the infectious period, along with other suspected risk factors virus infection among family members and health-care work- for H9N2 infection, such as recent contact with poultry and ers (HCWs) exposed to the two H9N2 patients, as well as swine. A similar questionnaire administered to HCWs asked about contact with each H9N2-infected patient during thepatient’s hospitalizations (patient 1: March 1-8, 1999; patient 2: March 5-7, 1999), and recent exposure to poultry and swine.
The target populations included HCWs at the two hospitals All participants provided written, signed informed consent.
where the H9N2-infected patients received care, as well as Approximately 10 cc of blood was provided by each partici- family and household members of the patients. The infectious pant approximately 5 to 6 weeks (except where indicated) after period for an H9N2 patient was defined as a 15-day period the onset of the H9N2 patients’ illnesses to test for antibody to beginning from the day before illness onset to the 14th day after illness onset (patient 1: February 27 to March 13, 1999;patient 2: March 3 to 17, 1999). The infectious period was Serologic Testing
defined conservatively to reflect the potential for prolonged Serum samples from all study participants and the two viral shedding, especially since children can shed influenza H9N2 patients were tested for antibody to FLUAV H9N2 by a viruses for longer periods than adults. Close contact was microneutralization assay at both the Centers for Disease Con- defined as coming within 3 m of an H9N2-infected patient.
trol and Prevention (CDC), Atlanta, and the Hong Kong Participants were defined as exposed if they had close contact Department of Health Government Virus Unit Laboratory, as with an H9N2 patient during the infectious period. An unex- described (20), except that A/Hong Kong/1073/99 (HK/1073; posed person was defined as having had no contact with the H9N2) virus, isolated from patient 1, was used in the assay.
H9N2 patients during the infectious periods. Unexposed sub- Specimens from H9N2 patients were single serum samples jects included family members and relatives who did not live collected 35 days (patient 2) and 39 days (patient 1) after ill- in the same household as and had no contact with an H9N2 ness onset. The virus isolated from patient 2 (A/Hong Kong/ patient, and HCWs who worked on hospital units different 1074/99) was antigenically indistinguishable from HK/1073.
from those where the H9N2 patients were located and who Sera were considered positive by microneutralization if anti- denied exposure to the H9N2 patients.
H9 titers >80 were obtained in at least two independent assays. At CDC, a Western blot assay with bromelain-purified or Study Design
baculovirus-expressed recombinant hemagglutinin (rHA; Pro- We conducted four retrospective cohort studies of either tein Sciences, Inc., Meriden, CT) from HK/1073 virus was HCWs or family and household members of the H9N2 used to confirm each positive microneutralization result, as Emerging Infectious Diseases • Vol. 8, No. 2, February 2002 described (14). Microneutralization-positive sera were Study Participants
adsorbed with FLUAV H3N2 viruses to remove antibodies The demographic characteristics of the study participants that were cross-reactive among FLUAV subtypes before are shown in Table 3. For H9N2 patient 1, exposed and unex- retesting by microneutralization assay. Serum (50 µL) mixed posed family members or HCWs did not differ significantly by with 100 µg of purified virus was incubated 45 min at 20°C age or sex. For H9N2 patient 2, exposed and unexposed and then 2 h at 4°C. Virus was pelleted by ultracentrifugation HCWs did not differ by age or sex. For family members of (30 min at 45,000 rpm and 4°C). To remove residual virus, H9N2 patient 2, the unexposed participant was older than the serum was further adsorbed twice with 10% v/v turkey red exposed participants, but the number of study participants was blood cells (RBC) (30 min at 4°C) and then centrifuged to very small. In the HCW cohorts of both H9N2 patients, more At the Government Virus Unit in Hong Kong, microneu- tralization-positive sera were confirmed by a single radial Family Member Cohort Studies
hemolysis assay for H9N2 antibodies, based on a modified, Fourteen of 15 eligible persons were enrolled in the family previously described protocol (21). HK/1073 virus-turkey cohort study (3 exposed immediate family members and 11 RBC complexes, cross-linked by chromium, and complement unexposed relatives) of H9N2 patient 1. One exposed partici- were suspended in an agarose matrix. Sera were added to 2- pant reported respiratory symptoms within the 2 weeks after mm diameter agarose wells. After overnight incubation at onset of illness in the patient. This participant’s serum was 35°C, a zone of hemolysis around the wells indicated the pres- obtained 3 weeks after H9N2 patient 1’s illness onset and was ence of anti-H9N2 antibodies. Sera producing hemolysis were seronegative for H9N2 antibodies. No other participant absorbed with HK/1073 virus concentrate by mixing 15 µL of reported respiratory illness. All 14 study participants tested sera with 5 µL of virus concentrate, followed by a 1-h incuba- seronegative for H9N2 antibodies (Table 3).
tion at room temperature. The mixture was then retested as All seven family and household members eligible for the described. The absence of hemolysis confirmed the presence family cohort study of H9N2 patient 2 were enrolled (six of H9N2 antibody. Absorption with A/Sydney/05/97 (H3N2)- exposed and one unexposed family and household members).
like and A/Beijing/262/95 (H1N1)-like viruses was done to Two exposed participants reported respiratory symptoms remove the nonspecific zones so only H9N2 antibody reacted within 2 weeks after onset of illness in H9N2 patient 2. The on the single radial hemolysis plates. Sera were considered unexposed participant reported no respiratory illness. All positive for H9N2 antibodies if the microneutralization assay seven study participants tested seronegative for H9N2 antibod- and all confirmatory tests were positive in both laboratories.
Sera from the two H9N2-infected children were also tested by enzyme-linked immunosorbent assay (ELISA) to detect HCW Cohort Studies
immunoglobulin (Ig) G and IgM antibodies to H9 as described The HCW study population for H9N2 patient 1 consisted (14), except that HK/1073 rHA (1 µg/mL) was used as the of 30 exposed HCWs from 4 hospital units and 75 unexposed antigen. ELISA titers were calculated as the reciprocal of the HCWs from 14 hospital units. Three exposed and three unex- highest dilution of sera that gave an A490 value greater than the posed HCWs reported respiratory symptoms (cough, sore mean A490 plus 3 standard deviations of six to seven negative throat, or rhinorrhea) during H9N2 patient 1’s hospitalization age-matched controls at an equivalent dilution of sera. A titer or within 5 days of the date of hospital discharge. All 30 exposed study participants were seronegative for H9N2 anti-bodies. One of the 75 unexposed HCWs was seropositive Statistical Analysis
(Table 3). The HCW who tested seropositive for antibodies to Univariate analysis of associations between exposure vari- H9N2 had no known exposure to a confirmed H9N2-infected ables and antibodies to H9N2 virus results were done by SAS patient and reported no contact with poultry or swine. 6.12 (SAS Institute Inc., Cary, NC).
The HCW study population for H9N2 patient 2 was 15 exposed and 23 unexposed HCWs from four hospital units.
One exposed HCW declined to participate. Four exposedHCWs reported respiratory symptoms beginning 2 to 5 weeks Serologic Response to H9N2 Virus Infection
after contact with the patient. All 38 study participants tested Patient 1 was positive for antibodies to H9 by all serologic seronegative for H9N2 antibodies (Table 3). assays and had substantial titers of H9 HA-specific IgG andIgM antibodies (Table 2). Low titers of H9 HA-specific IgG Discussion
and IgM antibodies were detected by ELISA in serum from These cohort studies suggest that influenza A (H9N2) patient 2, but no neutralizing antibody response was detected.
viruses were not transmitted from the two H9N2-infected chil-dren to family and household members or HCWs who were Emerging Infectious Diseases • Vol. 8, No. 2, February 2002 Table 2. Serologic responses of two patients from Hong Kong infected with influenza A (H9N2) virus aTiters expressed as the geometric mean of four replicate titers; titers >80 were considered positive for anti-H9 antibodies.
bWestern blots were performed by using a purified baculovirus-expressed recombinant HK/1073 HA as antigen.
cEnzyme-linked immunosorbent assay (ELISA) immunoglobulin (Ig) G and IgM antibodies were detected on plates coated with purified baculovirus-expressed recombinant HK/1073 HA (1 µg/mL). Titers are expressed as the geometric mean of duplicate endpoint titers estimated as described in Methods. A titer >1,600 was considered positive for anti-H9 antibodies.
exposed to the H9N2 patients during their acute illness infec- H5N1 viruses among humans have several possible explana- tious periods. As described for the avian influenza A (H5N1) tions (14,15). The genomes of the H9N2 and H5N1 strains that viruses (15,20), a combination of serologic assays was effec- were isolated from humans were derived entirely from avian tive in detecting H9 virus-specific antibodies in two pediatric influenza viruses; no reassortment with circulating human cases of H9N2 infection. However, the same serologic assays influenza A viruses had occurred. It is possible that the avian did not detect H9 antibodies in family members or HCWs virus genome limits viral spread among humans. The molecu- exposed to the H9N2 patients. Only two known exposed per- lar basis of influenza virus transmission among humans and sons, an HCW and a family member of one H9N2 patient, other species remains poorly understood. However, following declined to participate in the studies. The HCW who tested the introduction of an avian virus into humans, alterations in seropositive for antibodies to H9N2 had no known exposure to receptor-binding specificity of the HA are likely necessary for a patient with confirmed H9N2 infection or contact with poul- effective human-to-human transmission (22). Alternatively, try or swine. The timing of H9N2 infection in this HCW could the children may not have shed H9N2 virus in titers sufficient to facilitate transmission to other persons. Neither H9N2-infected Evidence for influenza A (H9N2) infection as the cause of child had coughing or sneezing that would have enhanced trans- acute illness in the two patients includes the direct isolation of mission to persons who had close contact with them. H9N2 viruses from nasopharyngeal aspirate specimens during To improve specificity for detecting antibody for H9N2 the acute phase of illness (1) and the detection of H9-specific over that of the hemagglutination-inhibition antibody assays IgM antibodies, suggesting recent infection with an H9 virus.
used previously (3), we used a combination of confirmatory No other bacterial or viral pathogens were identified except for tests and an adsorption step to reduce cross-reactivity with isolation of adenovirus type 3 from patient 1. The significance antibodies to other influenza viruses. Sera testing positive by of the latter finding is unknown since this patient did not have neutralization test were then tested by Western blot assay. Sera typical signs of adenovirus type 3 infection, such as conjunc- positive for both these assays were further tested by neutraliza- tivitis. Isolation of adenovirus in this patient could represent tion assay following adsorption of sera with influenza A acute atypical infection, acute subclinical infection, or persis- (H3N2) viruses. Sera that were negative for antibodies to tent viral shedding from previous adenovirus infection. H9N2 by neutralization assay were not tested by Western blot The apparent lack of human-to-human transmission of because of resource limitations. However, all sera from chil- avian H9N2 viruses and the low transmissibility of avian dren who were contacts of the H9N2 patients, as well as the Table 3. H9N2 serologic results of cohort studies involving family members and health-care workers, Hong Kong, 1999 Emerging Infectious Diseases • Vol. 8, No. 2, February 2002 patients themselves, were also tested by an H9-specific markets reopened in June 2001. No human illnesses attributed ELISA. Both patients but none of the exposed children tested to avian influenza viruses have been identified since the two H9N2 cases in 1999. However, these recent events have Because of insufficient sera, the H9N2 patients were not heightened the need to understand the public health risk of tested for antibodies to neuraminidase (NA). The N2 NA of H5N1, H9N2, and other avian influenza viruses. the H9N2 viruses isolated from patients is antigenically dis- These limited studies suggest that avian influenza A tinct from that of recent H3N2 human viruses, although some (H9N2) viruses were not transmitted from the two infected cross-reactivity with human H2N2 and early H3N2 viruses has children to exposed household members, relatives, or HCWs been reported (8). However, additional studies from our labo- in Hong Kong. However, H9N2 viruses are widely distributed ratory indicate that the apparent cross-reactive antibodies that in avian populations, can infect humans, and could evolve or could be removed from some human sera by adsorption with undergo genetic reassortment with potential for increased H3N2 viruses was not due to cross-reactivity between the N2 pathogenicity and transmissibility in humans. The recent NAs, since these sera also reacted with a reassortment H9N7 emergence of human infections with avian influenza A (H9N2) and (H5N1) viruses highlights the need to improve Because only two H9N2 cases were identified, we did not surveillance for influenza viruses in poultry, swine, and conduct a case-control study to identify risk factors for H9N2 humans, especially in Asia. Further studies to assess the health infection. Thus, the sources and modes of acquisition of H9N2 risks posed by H9N2 and other avian influenza viruses are for the two infected children are unknown. The Hong Kong Department of Health found that one H9N2 patient had verybrief exposure to live chickens 11 days before onset of illness Acknowledgments
but did not directly touch the birds. No other contacts with live We thank Ericka Sinclair for assistance with data entry and analy- poultry, swine, or other animals for either H9N2 patient were sis, and Alexander Klimov, Henrietta Hall, Feda Masseoud, and found. There was no known contact or common exposure Anglia Eick for laboratory support. We greatly appreciate the contri- butions and support of the following persons and groups in Hong During the 1997 FLUAV (H5N1) outbreak in Hong Kong, Kong: Margaret Chan, Paul Saw, and staff of the Hong Kong Depart- a case-control study found that visiting a poultry stall or mar- ment of Health, Hospital Authority, St. Paul’s Hospital, United Chris- ket with live poultry during the week preceding illness was the tian Hospital, Hong Kong University, Chinese University of Hong main risk factor for H5N1 infection (12). During that outbreak, Kong, Department of Agriculture and Fisheries, and the Special the Hong Kong Department of Health enhanced its active sur- Investigation Group on Avian Influenza. We also thank colleagues veillance for influenzalike illness and influenza viruses in hos- from St. Jude Children’s Research Hospital, Memphis, Tennessee; pitals, general outpatient clinics, and physicians’ offices. This World Health Organization (WHO) Collaborating Centre for Refer- enhanced surveillance system detected the two novel H9N2 ence and Research on Influenza, National Medical Institute for Medi- cal Research, London, England; WHO Headquarters, Geneva, We were able to obtain only one convalescent-phase blood Switzerland; and Southeast Poultry Laboratories, Athens, Georgia. specimen from study participants, which limited our ability to Dr. Uyeki is a pediatrician and medical epidemiologist in the document seroconversion. However, none of the exposed per- Influenza Branch, Centers for Disease Control and Prevention. His sons were seropositive for H9N2. Currently, there are no sero- interests include the epidemiology of influenza and other infectious prevalence data on rates of H9N2 infection in children or the general population. One study of a cohort of poultry workersin Hong Kong found that approximately 30% were seroposi- References
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Kong markets (24). After chicken deaths were observed in Seroprevalence of antibody to H9N2 viruses in poultry workers of HongKong. Poster #52, Session 7, July 16, 2000. International Conference on some markets, the Hong Kong government temporarily closed Emerging Infectious Diseases 2000, July 16-19, 2000, Atlanta, GA.
all wholesale and retail live poultry markets for cleaning, 6. Guo YJ, Krausse S, Senne DA, Mo IP, Lo KS, Xiong XP, et al. Character- stopped importing poultry from China, and slaughtered ization of the pathogenicity of members of the newly established H9N2 approximately 1.3 million birds during May 2001. The poultry influenza virus lineages in Asia. Virology 2000;267:279-88.
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21. Schild GC, Henry-Aymard M, Pereira HG. A quantitative, single-radial- MMWR Morb Mortal Wkly Rep 1998;46:1245-7. diffusion test for immunological studies with influenza virus. J Gen Virol 11. Claas ECJ, Osterhaus ADME, van Beek R, de Jong JC, Rimmelzwaan GF, Senne DA, et al. Human influenza A H5N1 virus related to a highly 22. Matrosovich M, Zhou N, Kawaoka Y, Webster R. The surface glycopro- pathogenic avian influenza virus. Lancet 1998;351:472-7.
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15. Katz JM, Lim W, Bridges CB, Rowe T, Hu-Primmer J, Lu X, et al. Anti- Address for correspondence: Tim Uyeki, Influenza Branch, Division of Viral body response in individuals infected with avian influenza A (H5N1) and Rickettsial Diseases, National Center for Infectious Diseases, Centers for viruses and detection of anti-H5 antibody among household and social Disease Control and Prevention, Mailstop A32, 1600 Clifton Road, NE, contacts. J Infect Dis 1999;180:1763-70.
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Emerging Infectious Diseases • Vol. 8, No. 2, February 2002
INTRODUCTION The consumption of alcohol in contemporary society is predominantly seen in a positive manner. It is difficult to recognize and determine the pattern of consumption that could be recognized as a disease and at the same time mobilize professional in the public health sector to reduce the problems resulting from the abuse of alcohol. A double standard exists in modern society: drin