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Peer-Reviewed Journal Tracking and Analyzing Disease Trends

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Journal Tracking and Analyzing Disease Trends pages 1–146 EDITOR-IN-CHIEF D. Peter Drotman Managing Senior Editor

EDITOR-IN-CHIEF D. Peter Drotman

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Emerging Infectious Diseases

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Ban Mishu-Allos, Nashville, Tennessee, USA Philip P. Mortimer, London, United Kingdom Fred A. Murphy, Galveston, Texas, USA Barbara E. Murray, Houston, Texas, USA

P. Keith Murray, Geelong, Australia

Stephen M. Ostroff, Harrisburg, Pennsylvania, USA David H. Persing, Seattle, Washington, USA Richard Platt, Boston, Massachusetts, USA Gabriel Rabinovich, Buenos Aires, Argentina Mario Raviglione, Geneva, Switzerland Leslie Real, Atlanta, Georgia, USA David Relman, Palo Alto, California, USA Connie Schmaljohn, Frederick, Maryland, USA Tom Schwan, Hamilton, Montana, USA Ira Schwartz, Valhalla, New York, USA Tom Shinnick, Atlanta, Georgia, USA Bonnie Smoak, Bethesda, Maryland, USA Dixie E. Snider, Atlanta, Georgia, USA Rosemary Soave, New York, New York, USA Frank Sorvillo, Los Angeles, California, USA P. Frederick Sparling, Chapel Hill, North Carolina, USA Robert Swanepoel, Johannesburg, South Africa Phillip Tarr, St. Louis, Missouri, USA Timothy Tucker, Cape Town, South Africa Elaine Tuomanen, Memphis, Tennessee, USA John Ward, Atlanta, Georgia, USA Mary E. Wilson, Cambridge, Massachusetts, USA

Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 15, No. 1, January 2009

January 2009 On the Cover Cameron Hayes (b. 1969) The Russians knew perfectly well that

January 2009

January 2009 On the Cover Cameron Hayes (b. 1969) The Russians knew perfectly well that the
January 2009 On the Cover Cameron Hayes (b. 1969) The Russians knew perfectly well that the

On the Cover

Cameron Hayes (b. 1969) The Russians knew perfectly well that the happiness of the African animals was that they had such low expectationsbefore the pets were introduced (detail) (2008) Oil on linen (203.2 cm × 254 cm) Copyright Cameron Hayes Courtesy Ronald Feldman Fine Arts, New York

About the Cover p. 140


Past, Present, and Future of Japanese Encephalitis T.E. Erlanger et al.

JE is increasing in some areas (due to population growth and intensi ed rice irrigation) but declining in others.


Threat of Dengue to Blood Safety in Dengue-Endemic Countries A. Wilder-Smith et al.

Modeling the risk for transmission of this disease by blood transfusions is quanti ed.




Sphingomonas paucimobilis Bloodstream Infections Associated with Contaminated Intravenous Fentanyl L.L. Maragakis et al.

Compounding pharmacies should be required to follow good manufacturing practices, including end- product sterility testing.


Human Infection with Highly Pathogenic Avian Inuenza Virus (H5N1) in Northern Vietnam,



N.D. Hien et al.

Treatment with oseltamivir or methylprednisolone was not effective, and 7 of 29 patients died.

was not effective, and 7 of 29 patients died. p. 54 p. 40 Enhanced Hygiene Measures

p. 54

p. 40

was not effective, and 7 of 29 patients died. p. 54 p. 40 Enhanced Hygiene Measures

Enhanced Hygiene Measures and Norovirus Transmission Potential during an Outbreak J.C.M. Heijne et al.

Improved hygiene measures can reduce norovirus transmission potential by 85%.


Selection Tool for Foodborne Norovirus Outbreaks L.P.B. Verhoef et al.

Surveillance data provided a practical tool that prospectively selects potential food-related norovirus outbreaks and assists health workers in narrowing the number of outbreaks requiring follow-up.

Historical Reviews


Venetian Rule and Control of Plague Epidemics on the Ionian Islands during 17th and 18th Centuries K. Konstantinidou et al.


Measures taken by the Venetian administration to combat plague were successful.

Parapneumonic Empyema Deaths during Past Century, Utah J.M. Bender et al.


Vaccine strategies and antimicrobial stockpiling to control empyema will be important in preparing for the next in uenza pandemic.



Microsporidiosis and Malnutrition in Children with Persistent Diarrhea, Uganda S.M. Mor et al.


Invasive Disease Caused by Nontuberculous Mycobacteria, Tanzania J.A. Crump et al.


Experimental Infection of Dogs with Avian-Origin Canine Inuenza Virus (H3N2) D. Song et al.

Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 15, No. 1, January 2009

January 2009 Another Dimension 139 It Can’t Happen Here M. Natiello Letters 115 Falciparum Malaria

January 2009

Another Dimension

139 It Can’t Happen Here M. Natiello



Falciparum Malaria in Patient 9 Years after Leaving Malaria-Endemic Area


Linezolid-Resistant Staphylococcus cohnii, Greece


Buruli Ulcer in Long-Term Traveler to Senegal


Maternal-Fetal Transmission of Parachlamydia acanthamoebae


Emerging Mycobacteria spp. in Cooling Towers


Clostridium difcile–related Hospitalizations in US Adults, 2006


Pulmonary Tuberculosis and Mycobacterium bovis, Uganda


Vertical Transmission of Pneumocystis jirovecii in Humans


Avian Inuenza Virus (H5N1) in Human, Laos


Fatal HIV Encephalitis in HIV- Seronegative Patients


Classical ctxB in Vibrio cholerae O1, Kolkata, India


Sphingomonas mucosissima Bacteremia in Patient with Sickle Cell Disease


WU Polyomavirus in Fecal Specimens of Children with Acute Gastroenteritis


SCCmec Typing in MRSA Strains of Animal Origin (response)


School Closure to Reduce Inuenza Transmission (response)

Books and Media

139 Legionella: Molecular Microbiology

News and Notes

About the Cover

: Molecular Microbiology News and Notes About the Cover 59 Personal Protective Equipment and Risk for


Personal Protective Equipment and Risk for Avian Inuenza (H7N3)


Morgan et al.


Imported Case of Poliomyelitis, Melbourne, Australia, 2007 A.J. Stewardson et al.


Isolation of Candidatus Bartonella melophagi from Human Blood R.G. Maggi et al.


Botulism from Drinking Pruno D.J. Vugia et al.


Bordetella avium and Novel Bordetella Strain from Patients with Respiratory Disease A.T. Harrington et al.


Clonal Multidrug-Resistant

Corynebacterium striatum Strains, Italy


Campanile et al.


Enterovirus 71 Outbreak, Brunei


AbuBakar et al.


Novel Human Rotavirus Genotype G5P[7] from Child with Diarrhea, Cameroon M.D. Esona et al.


Serotype G12 Rotaviruses, Lilongwe, Malawi N.A. Cunliffe et al.


G2 Strain of Rotavirus among Infants and Children, Bangladesh S.K. Dey et al.


Rotavirus Genotype Distribution after Vaccine Introduction, Brazil F.A. Carvalho-Castro et al.


Rickettsia helvetica in Dermacentor reticulatus Ticks


Dobec et al.


Antimicrobial Resistance in Salmonella enterica Serovar Typhimurium E.M. Nielsen et al.


Predicting High Risk for Human Hantavirus Infections, Sweden G.E. Olsson et al.


Polyomaviruses KI and WU in

Immunocompromised Patients with Respiratory Disease


Mourez et al.


Hepatitis E Virus Genotype 3 Diversity, France

110 Hepatitis E Virus Genotype 3 Diversity, France p. 57 p. 68 F. Legrand-Abravanel et al.

p. 57

p. 68

Hepatitis E Virus Genotype 3 Diversity, France p. 57 p. 68 F. Legrand-Abravanel et al. 140

F. Legrand-Abravanel et al.

140 Traveling Light and the Tyranny of Higher Expectations

Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 15, No. 1, January 2009

Past, Present, and Future of Japanese Encephalitis

Tobias E. Erlanger, Svenja Weiss, Jennifer Keiser, Jürg Utzinger, and Karin Wiedenmayer

Japanese encephalitis (JE), a vector-borne viral dis- ease, is endemic to large parts of Asia and the Paci c. An estimated 3 billion people are at risk, and JE has recently spread to new territories. Vaccination programs, increased living standards, and mechanization of agriculture are key factors in the decline in the incidence of this disease in Ja- pan and South Korea. However, transmission of JE is likely to increase in Bangladesh, Cambodia, Indonesia, Laos, Myanmar, North Korea, and Pakistan because of popula- tion growth, intensi ed rice farming, pig rearing, and the lack of vaccination programs and surveillance. On a global scale, however, the incidence of JE may decline as a result of large-scale vaccination programs implemented in China and India.

J apanese encephalitis (JE) is a vector-borne viral disease that occurs in South Asia, Southeast Asia, East Asia,

and the Pacic (1). An estimated 3 billion persons live in countries where the JE virus is endemic (2), and the annual incidence of the disease is 30,000–50,000 cases (1). The disease can cause irreversible neurologic damage. The JE virus (JEV) is mainly transmitted by the mosquito Culex tritaeniorrhynchus, which prefers to breed in irrigated rice paddies. This mosquito species and members of the Cx. gelidus complex are zoophilic. Wading ardeid water birds (e.g., herons and egrets) serve as virus reservoirs, but the virus regularly spills over into pigs, members of the fam- ily of equidae (e.g., horses and donkeys), and humans. The annual number of human deaths is 10,000–15,000, and the estimated global impact from JE in 2002 was 709,000 dis- ability-adjusted life years (DALYs) (1,3). However, these statistics should be interpreted with care because the trans- mission of JE is highly dynamic; hence, the disease usually occurs in epidemics, and there is considerable uctuation in estimates of its global impact. In 1999, JE caused 1,046,000

Author af liation: Swiss Tropical Institute, Basel, Switzerland

DOI: 10.3201/eid1501.080311

DALYs; in the 2 subsequent years, it caused 426,000, and 767,000 DALYs, respectively (3). Underlying factors that might explain these uctuations are contextual determi- nants (mainly environmental factors) and spillover effects into the human population, which trigger epidemics. Reporting of JE cases depends on the quality of health information systems and the ability to clinically and sero- logically diagnose the disease. JE is often confused with other forms of encephalitis. Differential diagnosis should therefore include other encephalitides (e.g., conditions caused by other arboviruses and herpesviruses) and infec- tions that involve the central nervous system (e.g., bacterial meningitis, tuberculosis, and cerebral malaria) (4). Figure 1 shows the transmission of JE and highlights contextual determinants. Because infected pigs act as am- plifying hosts, domestic pig rearing is an important risk fac- tor in the transmission to humans (1). Two distinct epide- miologic patterns of JE have been described. In temperate zones, such as the northern part of the Korean peninsula, Japan, China, Nepal, and northern India, large epidemics occur in the summer months; in tropical areas of south- ern Vietnam, southern Thailand, Indonesia, Malaysia, the Philippines, and Sri Lanka, cases occur more sporadically and peaks are usually observed during the rainy season (5). Thus far, the reasons for the spread of JE are not fully understood. Bird migration might play a role in dispers- ing JEV (6). Accidental transportation of vectors, human migration, and international travel seem to be of little im- portance because viremia in humans is usually low and of short duration and because humans are dead-end hosts (1). JE was likely introduced into northern Australia by wind- blown mosquitoes from Papua New Guinea (7) (Figure 1). The main pillar of JE control is the use of a live at- tenuated vaccine for humans, which was developed some 40 years ago (8). Currently available JE vaccines are rela- tively safe and effective, but a drawback is that multiple doses are required (1,9). Effective delivery of the vaccines




Climate: rainfall, temperature, and wind

Ecosystem: plants, predators, and water bodies

Agriculture: irrigation and pig farming


Proximity to irrigated agriculture and pig farming, exposure and behavior, health system, population movement, and housing



Virus: pathogenicity and proliferation

Vector: population densitiy, longevity, infectiousness, and susceptibility

Human host: age and immunity

Animal hosts: immunity, exposure, and bird migration

INSTITUTIONAL DETERMINANTS Environmental management Vaccination, reduction of exposure Poverty alleviation
reduction of
Vaccination of
pigs, separating
pigs from humans
Culex tritaeniorhynchus transmits the virus by taking blood meals from endotherms
Culex tritaeniorhynchus
transmits the virus by
taking blood meals
from endotherms
transmits the virus by taking blood meals from endotherms irrigation Intermittent Amplification Pigs, herons, and


the virus by taking blood meals from endotherms irrigation Intermittent Amplification Pigs, herons, and egrets act
the virus by taking blood meals from endotherms irrigation Intermittent Amplification Pigs, herons, and egrets act
the virus by taking blood meals from endotherms irrigation Intermittent Amplification Pigs, herons, and egrets act



Pigs, herons, and egrets act as reservoir and amplifying hosts

Figure 1. Contextual determinants and transmission of Japanese encephalitis.

to poor, rural communities therefore remains a formidable challenge, and compliance and delivery costs have to be considered (10). Two vaccine candidates are in late-stage clinical development. The rst one is a second-generation, live inactivated, single-dose vaccine grown in Vero cells. It is the yellow fever virus–based chimeric vaccine and will soon enter the market (1). The second candidate is an atten- uated SA 14–14–2 virus strain, adjuvanted with aluminum hydroxide and also grown in Vero cells (9,11). The vaccination of pigs represents another potential strategy to control JE, but it is not widely used for 2 main reasons. First, the high turnover in pig populations would require annual vaccination of newborn pigs, which would be costly. Second, the effectiveness of live attenuated vac- cines is decreased in young pigs because of maternal anti- bodies (12). Environmental management for vector control, such as alternative wetting and drying of rice elds (also known as intermittent irrigation), can substantially reduce vector breeding while saving water, increasing rice yields, and reducing methane emission (13). However, an effective irrigation requires well-organized educational programs, suf cient water at specic times during the rice-growing cycle, and an adequate infrastructure. In addition, because vectors are largely dispersed, intermittent irrigation should be applied to all rice elds over large areas and during the entire cropping season, which is often not feasible (14). En- vironmental management measures are most viable if they are readily integrated into a broader approach of pest man- agement and vector management (15). Chemical control of vector populations with insecti- cides such as pyrethroids, organophosphates, and carbam- ates plays a marginal role in JE control. In some circum- stances (for example, when an outbreak of JE occurs in a densely populated area), space spraying can break the trans- mission cycle in the short term. However, rising levels of

insecticide resistance have compromised the effectiveness of this emergency measure. Indeed, JE vectors that prefer manmade habitats, such as irrigated rice elds, are often heavily exposed to pesticide selection pressure. Although JE vectors are prone to develop insecticide resistance, usu- ally this issue arises with insecticides that are not directly targeted to JE control, but rather are targeted to control of other pests (16). We provide a historic account of the origin of JE and disease epidemics, describe the current situation, and dis- cuss several factors that might explain the rise of JE inci- dence in some countries and its decline in others. Finally, we speculate about possible future trends.

Historic Account Genetic studies suggest that JEV originated from an ancestral virus in the area of the Malay Archipelago. The virus evolved, probably several thousand years ago, into different genotypes (I–IV) and spread across Asia (17). The history of the clinical recognition and recording of JE dates to the 19th century. JE appeared as recurring en- cephalitis outbreaks in the summer season. The rst clinical case of JE was recorded in 1871 in Japan. Half a century later, also in Japan, a large JE outbreak involving >6,000 cases was documented. Subsequent outbreaks occurred in 1927, 1934, and 1935. In 1924 an agent from human brain tissue was isolated; 10 years later, it was proven to be JEV by transfection into monkey brains. The role of Cx. tritaenio- rhynchus as a vector and the involvement of wading ardeids and pigs as reservoir hosts were demonstrated in 1938 (18). Table 1 shows when the rst JE cases were described in countries currently considered JE-endemic. On the Ko- rean Peninsula, the rst JE cases were recorded in 1933. On the Chinese Mainland, the rst JE cases were documented in 1940. In the Philippines, rst reports of JE cases occurred in the early 1950s (19). Eventually, the JE epidemic reached Pakistan (1983) as the furthest extension in the West, and Papua New Guinea (1995) and northern Australia (Torres Straight) as the furthest south. In parts of southeastern Russia (Primorje Promorsij), a few JE cases have been reported oc- casionally (e.g., 2 cases from 1986 to 1990) (18). JE is poten- tially endemic to Afghanistan, Bhutan, Brunei Darussalam, and the Maldives, but to our knowledge, no cases have been reported in these countries in the past 30 years. According to the World Health Organization (WHO), JE is endemic to the Western Pacic Islands, but cases are rare (20). The en- zootic cycle on those Pacic Islands might not sustain viral transmission; hence, epidemics occur only after introduction of virus from JE-endemic areas. Subtle changes in the spa- tiotemporal distribution of JEV are difcult to track; thus, the year when a rst case of JE in a country is reported does not necessarily correspond with the actual rst occurrence of JE in that country (Table 1) (21–35).

Japanese Encephalitis

Table 1. First reported case and current situation of Japanese encephalitis in the main disease-endemic countries



Total population in rural JE-endemic areas (% of total)*





DALYs in

Trend of JE incidence§























106,385,000 (75)











11,293,000 (80)









422,532,000 (32)







18 )



597,542,000 (54)







24 )



116,114,000 (52)







25 )



43,969,000 (34)







26 )

North Korea


8,606,000 (38)







27 )

South Korea


9,194,000 (19)






(27 )




4,643,000 (78)







28 )



8,854,000 (35)







29 )



35,077,000 (69)







18 )



4,567,000 (20)






(30 )


Papua New


5,109,000 (87)







21 )




18,536,000 (12)







27 )

The Philippines


31,081,000 (37)







19 )












Sri Lanka


16,381,000 (79)










43,364,000 (68)







18,27 )



61,729,000 (73)







27,33 )

*Japanese encephalitis (JE)–-endemic areas drawn from map provided in (34 ); rural population estimates derived from United Nations Urbanization Revisions (2 ). †Information retrieved from questionnaires answered by employees from Ministry of Health and World Health Organization country offices. ‡Estimates for 2002 from World Health Organization (20). DALYs, disability-adjusted life years. §<1% of the country is JE-endemic (Torres Straight islands, Cape York Peninsula). NA, not available. ¶Two deaths since 1995 ( 35). #Virus isolated from mosquito (29). **JE cases are very rare; highest risk is on Okinawa, Miyako, and Ishigaki islands. Between 1995 and 2005, 3 cases were reported (all in 2002) (26). ††First isolated from humans. During World War II, an outbreak that was probably due to JE occurred (31).

Present Situation Nearly half of the human population currently lives in countries where JEV occurs. As shown in Figure 2, JE is concentrated in China, India, and the Southeast Asian peninsula. Current epidemiologic data on JE are summarized in Table 1. These data were gathered from a diversity of sources, including peer-reviewed literature, specialized text books, and reports from national health departments and international organizations, such as WHO and the Food and Agriculture Organization. We also contacted national health ministries and WHO country of ces for up-to-date information regarding country-speci c JE sta- tistics. This was accomplished by administering a stan- dardized questionnaire. There are 2 distinct trends in JE incidence. In countries such as Bangladesh, Cambodia, India, and Laos, where no specic diagnostic centers, vaccination programs, and sur- veillance systems are in place, the incidence of JE appears to have increased in recent years. On the contrary, in China, Japan, Nepal, South Korea, Sri Lanka, and Thailand, where vaccination programs are being implemented and regular surveillance is pursued, the incidence of JE is stable or declining. Despite the availability of WHO estimates, the

situation in North Korea, Myanmar, Pakistan, and Papua New Guinea remains largely unknown. However, underreporting is substantial in most JE- endemic countries; hence, it is conceivable that annual JE incidence is considerably higher than heretofore reported. For example, an estimate that used a representative inci- dence of 25/10,000 (not immunized), and a 1994 popula- tion estimate of 700 million children <15 years of age who live in JE-endemic areas suggested 175,000 cases annually with 43,750 deaths, and 78,750 cases with lasting seque- lae. Adjusted for vaccine coverage, the estimate is 125,000 cases per year (36).

Emerging JE The emergence of JE can probably be explained by 2 factors. First, JE-endemic countries experienced an un- precedented population growth in recent decades. For ex- ample, in Eastern Asia, South-Central Asia, and Southeast Asia, the population more than doubled, from 1.7 billion in the mid-1950s to 3.5 billion 50 years later (2). Second, pig rearing has grown exponentially and rice-production systems, particularly irrigated rice farming, have increased both in cropping area and cropping intensity. In China, for example, pork production doubled from 1990 to 2005.


PERSPECTIVES Figure 2. Disability-adjusted life years (DALYs) per 100,000 persons in Japanese encephalitis–endemic

Figure 2. Disability-adjusted life years (DALYs) per 100,000 persons in Japanese encephalitis–endemic countries. Numbers in parentheses indicate estimated number of deaths in 2002 according to the World Health Organization ( 20 ). NA, not available.

Today, the total rice-harvested area of all JE-endemic countries (excluding the Russian Federation and Australia) is 1,345,000 km 2 , an increase of 22% in the past 40 years. Over the same time span, the total rice production in these countries has risen from 226 million tons to 529 million tons (+134%) (37). Table 2 presents information on 3 key environmen- tal contextual determinants of JE transmission, strati ed by country. The following issues are offered for consid- eration. First, the number of people living in close prox- imity to irrigated areas re ects the fraction of the popu- lation that potentially is at an elevated risk of acquiring JE. Methods for calculating those numbers have been described elsewhere (13). Second, the absolute and rela- tive change of irrigated rice area and, third, the relative change in pork production can be used as proxies for al- terations in the risk of acquiring JE. In absolute numbers (116.6 million) and in relative terms, most people living in close proximity to irrigated areas are from Bangladesh (82%); the second largest population lives in India (107.8 million), followed by China (22.0 million). The largest irrigated rice area in 2005 was found in India (41.9 mil- lion ha), followed by China (29.0 million ha), Bangladesh (10.5 million ha), and Thailand (10.0 million ha). Highest increases in irrigated rice areas in the past 15 years were estimated for Myanmar (+47%) and Cambodia (+30%). Highest increases in pork production occurred in Myan- mar (+381%), Vietnam (+147%), and China (+87%). On the other hand, pork production declined in Malaysia

(–47%), North Korea (–35%), and Japan (–23%). Despite the fact that irrigated rice production and pig rearing are key factors in the transmission of JE, crude numbers fail to completely explain the complex interplay of various contextual determinants of the disease. Clearly, where rice production and pig rearing overlap, the impact on JE transmission is stronger than in areas where both ac- tivities are physically separated. This is the case, for ex- ample, in Malaysia, where the Malays mainly grow rice in 1 area and the Chinese rear pigs in another area. Here, the social determinant of religion (most Malays are Muslim) plays a decisive factor (Table 2).

Conclusion and Outlook Discovered 125 years ago, JE has spread widely in the 20th century. Almost half of the human population now lives in countries where the disease is endemic. JE is a vector-borne epidemic with several features that are typi- cal of an emerging infectious disease. The failure to halt the spread of JE in Asia and the Pacic region, despite the availability of an effective and inexpensive vaccine for 40 years, is of considerable public health concern. A similar conclusion has been drawn for yellow fever, a disease that can also be prevented by vaccination yet is rampant (38). Similar to schistosomiasis, malaria, food-borne tremato- diasis, lymphatic lariasis, and dengue, one of the main reasons for the proliferation of JE is the ecologic transfor- mation caused by water resources development and man- agement that create suitable breeding sites for vectors and intermediate hosts, which in turn inuence the frequency and transmission dynamics of these diseases (39). High-quality data on transmission and incidence of JE are lacking in various countries. Although clinical and serologic methods to diagnose and monitor JE are avail- able, health systems in many developing countries are un- able to differentiate encephalitis diagnoses. Information regarding the distribution and public health importance of JE in Bangladesh, Cambodia, Indonesia, North Korea, Laos, Myanmar, Papua New Guinea, and Pakistan is in- adequate. Such epidemiologic information, however, is mandatory for advocacy and allocation of resources for the control of JE. Examples of countries with successful JE control programs are Japan and South Korea. Before the 1950s, these countries experienced JE outbreaks, but incidence rates have remained stable for >2 decades. The following key control strategies and developments might explain the successful decline of JE in these countries:

1) large-scale immunization programs for humans, 2) pig immunization and the separation of pig rearing from hu- man settlements, 3) changes in agricultural practices (e.g., enhanced mechanization and decrease of irrigated land), and 4) improved living standards (e.g., better housing and urbanization).

Japanese Encephalitis

Table 2. Rice irrigation and pork production by Japanese encephalitis–endemic country, 1990 and 2005*


Persons in close proximity to rice irrigation†

Rice paddy area,

Rice paddy

% Change in paddy area

% Change in pork production†



area, 2005†

Australia Bangladesh Cambodia China India Indonesia Japan North Korea South Korea Laos Malaysia Myanmar Nepal Papua New Guinea Pakistan The Philippines Singapore Sri Lanka Thailand Vietnam





































































































*NA, not available. †Sources of data and method of calculation are described by Keiser et al. (13). ‡Source: Food and Agriculture Organization (37).

We speculate that JE incidence is increasing mainly in low-income countries. However, because reliable gures about JE emergence are lacking due to the absence of rigor- ous monitoring systems, more research is needed to support or refute this claim. In any event, lack of political will and nancial resources are 2 important reasons why JE is often given low priority. These factors might explain the paucity of JE immunization programs for children in low-income countries where the disease is endemic. Nevertheless, Sri Lanka and Nepal, 2 countries with limited health budgets, and Thailand and Vietnam have managed to successfully control JE. The national situations with respect to JE in the near future could develop as follows. We hypothesize that in Cambodia, Laos, and Myanmar, severe JE outbreaks could occur in the near future, partially explained by increases in irrigated rice farming and enhanced pig rearing. The JE situation in North Korea is not well understood, but on the basis of the population’s general health status, we predict that JE will likely remain a substantial public health issue in the years to come. Bangladesh and Pakistan are among the worst affected and most populous countries in which JE is endemic, and yet effective surveillance is missing. Outbreaks are likely to occur but will remain largely un- detected. Muslim countries such as Bangladesh and Paki- stan have traditionally been JE free. JEV transmission ends in Pakistan, even though the JE vector is abundant further to the West. The recent rise in JE in those countries has yet to be fully investigated and shows the complexity of transmission of this disease. In Indonesia, Malaysia, the

Philippines, and Singapore, JE incidence has usually been low, and transmission will remain stable at a relatively low level. Given the paucity of data in Indonesia, a monitor- ing system should be established to document changes over time. Occasional small JE outbreaks might also occur in Papua New Guinea with spillover to Australia. Awareness of the disease and vaccination coverage rates are high in Australia, particularly in the region of the Torres Strait; hence, it seems unlikely that larger epidemics will occur anytime soon. The overall trend of JE has been declining over the past 3 decades, and we anticipate that this trend will continue in the long term. Indeed, China and India inuence JE gures on a global scale because most people living in JE-endemic areas are concentrated in these 2 countries. The incidence of JE in China has declined since 1971, coincident with economic growth and development. Meanwhile, the na- tional JE vaccination program has been integrated into the Expanded Program on Immunization, and, at present, >110 million doses of a live, attenuated vaccine (SA14–14–2 strain) are produced annually. However, social, economic, and health policy changes in the face of privatization and a more market-based economy have led to reduced funding for immunization programs and somewhat reduced salaries for public health workers, particularly in the poorest prov- inces. As a consequence, these changes have contributed to increasing disparities in immunization coverage rates between the wealthy coastal and the less developed rural provinces and thus to the recently observed differences in levels of JE incidence between those regions (40).


The incidence of JE in India is still increasing, and the case-fatality rate of reported cases is high, i.e., 10%–30% (online Technical Appendix, supplementary reference 41; available from www.cdc.gov/EID/content/15/1/1-Techapp. pdf). India currently has no national vaccination program, but the Ministry of Health has recently drawn up a plan in which children 1–12 years of age will be immunized. In Tamil Nadu and Uttar Pradesh, immunization programs are already running; thus, JE incidence might stabilize in those regions. However, overall trends for India are difcult to predict because JE endemicity is heterogeneous and be- cause socioeconomic conditions for control differ substan- tially from 1 state to another (online Technical Appendix, supplementary reference 42). Coverage of immunization programs and changes in agricultural practices will further inuence JE transmis- sion. In Taiwan, for example, the average age for the onset of conrmed JE cases shifted from children <10 years to- ward adulthood, explained by a high coverage of vaccinated children (online Technical Appendix, supplementary refer- ence 43). Interestingly, the peak JE transmission, which occurred in August in the 1960s, shifted to June beginning in the 1980s. Improvements in pig-feeding technologies, which resulted in shorter periods from birth to pregnancy of female pigs, has been proposed as an important reason explaining the shift in transmission (online Technical Ap- pendix, supplementary reference 44). Climate change has been implicated in the increase of transmission of several vector-borne diseases (online Technical Appendix, supplementary reference 45). For example, a potential effect of climate change has been shown empirically for dengue virus, which is closely re- lated to that of JE (online Technical Appendix, supple- mentary reference 46). Although JE vector proliferation might be in uenced in a similar way than that predicted for dengue vectors, the potential impact of climate change on JE remains to be investigated. Indeed, climate change could not only directly increase JE vector proliferation and longevity but could also indirectly increase disease because of changing patterns of agricultural practices such as irrigation (online Technical Appendix, supplementary references 47,48). Areas with irrigated rice-production systems may become more arid in the future, and the impact of ooding will be more dramatic, which in turn might result in JE outbreaks. Generally, extreme rainfall after a period of drought can trigger outbreaks in situa- tions in which vector populations rapidly proliferate and blood feeding is spilling over to humans. Climate change may also in uence migration patterns of birds, which may result in JEVs being introduced into new areas. However, little is known about reservoir bird migration patterns; hence, this issue remains to be investigated (6).

The culicines that transmit JE are usually highly zoo- philic, and human outbreaks are therefore the result of a spill- over of the virus from the animal reservoir into the human population. Studies in Sri Lanka showed that spillovers hap- pen when there is rapid and dramatic buildup of Culex spp. populations to the extent that the number of human blood meals passes a threshold after which virus transmission be- gins (online Technical Appendix, supplementary reference 49). Such rapid buildups are a result of extreme weather conditions or of rice elds in semi-arid areas being ooded before rice is transplanted. Information on vector population dynamics would be very useful in early warning systems and could also help improve targeting of control programs. In conclusion, JE can be controlled, with effective sur- veillance systems and vaccines playing key roles. Although currently available vaccines are effective, the need for 3–4 injections compromises compliance and increases delivery costs (10). The advent of second-generation, cell-culture– derived vaccines will continuously replace mouse-brain and hamster kidney cell–derived vaccines. Such develop- ments will hopefully boost current vaccination programs and deliver safer, more efcacious, and cheaper vaccines that comply with regulatory norms. Political will and com- mitment, nancial resources, intersectoral collaboration (between the Ministries of Health and Agriculture and oth- er stakeholders to set up vaccination programs for young children), as well as changing agricultural practices, pig vaccination, rigorous monitoring, and surveillance will go a long way in controlling JE.

Acknowledgments We thank those employees of national Ministry of Health and regional WHO ofces who answered our questionnaire. Spe- cial thanks to Barbara Matthys for her expert help in drawing Figure 2.

This investigation received nancial support from Novartis Vaccines. J.K. (project no. PPOOA-114941) and J.U. (project no. PPOOB–102883 and PPOOB–119129) are grateful to the Swiss National Science Foundation for personal career development grants.

Dr Erlanger is an afliate of the Swiss Tropical Institute in its Department of Public Health and Epidemiology. His main re- search interests pertain to environmental epidemiology of vector- borne diseases and health impact assessment.


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Address for correspondence: Tobias E. Erlanger, Department of Public Health and Epidemiology, Swiss Tropical Institute, PO Box CH-4002, Basel, Switzerland; email: tobias@erlanger.ch

Use of trade names is for identication only and does not imply endorsement by the Public Health Service or by the U.S. Department of Health and Human Services.


Threat of Dengue to Blood Safety in Dengue-Endemic Countries

Annelies Wilder-Smith, Lin H. Chen, Eduardo Massad, and Mary E. Wilson

Dengue, the most common arbovirus infection glob- ally, is transmitted by mosquito vectors. Healthcare-related transmission, including transmission by blood products, has been documented, although the frequency of these occur- rences is unknown. Dengue is endemic to Singapore, a city- state in Asia. Using mathematical modeling, we estimated the risk for dengue-infected blood transfusions in Singapore

in 2005 to be 1.625–6/10,000 blood transfusions, assuming

a ratio of asymptomatic to symptomatic infections of 2:1 to

10:1. However, the level of viremia required to cause clinical

dengue cases is person-dependent and unknown. Further studies are needed to establish the magnitude of the threat that dengue poses to blood safety in countries where it is endemic. It will then be possible to assess whether screen- ing is feasible and to identify approaches that are most cost- effective on the basis of characteristics of local populations and seasonality of dengue.

E merging infectious diseases pose threats to the gen- eral human population, including recipients of blood

transfusions. Dengue is an expanding problem in tropical and subtropical regions and is now the most frequent ar- boviral disease in the world, with an estimated annual 100 million cases of dengue fever, 250,000 cases of dengue hemorrhagic fever, and 25,000 deaths per year (1). Den- gue virus infections have been reported in >100 countries; 2.5 billion people live in areas where dengue is endemic (1). It is also increasingly reported to occur in interna- tional travelers (2). Dengue is of major international pub- lic health concern because of the expanding geographic

Author af liations: National University Singapore, Singapore (A. Wilder-Smith); Harvard Medical School, Boston, Massachusetts, USA (L.H. Chen, M.E. Wilson); Harvard School of Public Health, Boston (M.E. Wilson); Mount Auburn Hospital, Cambridge, Mas- sachusetts, USA (L.H. Chen, M.E. Wilson); and University of São Paulo, São Paulo, Brazil (E. Massad)

DOI: 10.3201/eid1501.071097

distribution of the virus and competent mosquito vectors, increased frequency of epidemics, cocirculation of mul- tiple virus serotypes, and emergence of dengue hemor- rhagic fever in new areas. Dengue virus belongs to the family Flaviviridae and is transmitted by mosquitoes of the genus Aedes (1). Flavivi- ruses are small, lipid-enveloped, positive-stranded RNA vi- ruses (1). Dengue infection has a viremic phase that lasts 4–8 days (3), and most infections remain subclinical (4). Viremia can precede the onset of symptoms in persons with clinical disease. Plasma viral RNA levels range from 10 5.5 to 10 9.3 copies/mL, and blood collected during this phase may be in- fective when transfused into susceptible hosts (5). A literature search conducted in March 2008 on blood transfusion and dengue did not identify any published re- ports of blood transfusion–associated dengue in dengue- endemic countries. Healthcare-associated transmission is difcult to ascertain in dengue-endemic countries, although there is 1 report of possible transmission of dengue in a healthcare setting in Hong Kong, Special Administrative Region, People’s Republic of China, attributed to a viremic resident of Hong Kong (6). In contrast, healthcare-acquired dengue infections in countries in which dengue is not en- demic can be determined. Several reports have described travelers who returned from dengue-endemic countries to those not endemic for dengue and transmitted dengue in- fection to healthcare workers by needlestick injury or mu- cocutaneous exposure to blood (7,8). Healthcare-associated transmission of viruses among humans has been recently reviewed for dengue and other aviviruses such as West Nile virus (WNV) and yellow fever virus (9). Routes of transmission include percutane- ous, mucous membrane, bone marrow transplant, organ transplant, hemodialysis, and transfusion of blood products (68,1025) (Table) However, despite good evidence for its transmission in healthcare settings, dengue is currently not considered a risk to blood safety.

We draw parallels from recent experiences with West Nile fever and encephalitis in the United States. WNV rst appeared in the United States in 1999 and has since spread throughout the country, resulting in thousands of cases of disease (26). Approximately 80% of WNV infections are asymptomatic (27). By 2002, 23 patients in the United States were conrmed to have acquired WNV through transfused

blood and blood products (erythrocytes, platelets, and fresh- frozen plasma) (23). The estimated risk for virus transmis- sion through transfusion during the 1999 WNV epidemic in New York was 1.8/10,000–2.7/10,000 donations, and 2.0 viremic donations/10,000 donors in the borough of Queens (28). Of the 2.5 million blood donations screened for WNV from June through December 2003, 0.05% were positive

at the rst screening and 0.02% were conrmed (29). In

response to these ndings, by 2003, essentially all blood donations in the United States were being tested for WNV.

In contrast, no screening of blood products is conducted for

dengue, although dengue virus is estimated to affect >100

million persons annually in tropical and subtropical regions.

A recent study in Puerto Rico reported nucleic acid testing

for dengue virus in the blood supply and found the viral RNA prevalence to be 7.3/10,000 U of blood donations, which approximates the prevalence of WNV in the United States during the transmission season (30). In addition, screening of donors in Honduras and Brazil has identied dengue virus RNA (0.37% and 0.06% of blood donations or 37/10,000 and 6/10,000 blood donations, respectively) by using a transcription-mediated amplication assay (31). We postulate that dengue virus poses a greater threat worldwide to blood safety than WNV but that this hypoth-

Dengue and Blood Safety

esis has been neglected because dengue occurs predomi- nantly in developing countries. We used mathematical modeling to estimate the risk for dengue in Singapore. Sin- gapore is an industrialized Asian city-state in which dengue is endemic. This city-state has the capacity to implement blood screening for dengue. The dengue seroprevalence rate in the adult population in Singapore, which has a popu- lation of 4 million persons, is 45% (32). In 2005, 14,209 cases of symptomatic dengue infections were reported in Singapore, a large proportion (80%) of which were in adolescents or adults (33). We calculated the force of in- fection in this population. The force of infection is dened as follows: per capita new cases in a nite period = rate of contacts by potentially infective persons × (no. viremic persons in a population in a nite period/total population in a nite period). If one assumes that there were 11,367 reported adult cases in Singapore in 2005 (80% of 14,209) and a ratio of asymptomatic to symptomatic cases of 2:1, a total of 34,101 viremic adults in 2005 would have viremia that lasts <1 week. This nding indicates there would be 656 infective persons per week, which translates to 0.00016 viremic per- sons in a nite period per total population in a nite period. If one considers that there are 80,000 blood transfusions in Singapore per year, there would be 1,538 transfusions per week. Therefore, the force of infection for 2005 in Sin- gapore was 13 infective blood donations. However, if we assume a ratio of asymptomatic to symptomatic cases of 10:1, we then have 125,037 viremic persons, or 2,405 infective persons per week. This nding indicates that the number of viremic persons in the popu-

Table. Reported healthcare-associated transmission of flaviviruses


Route of transmission





Several healthcare workers were infected after needlestick injuries during care of returned travelers who had diagnoses of dengue. A healthcare worker became infected with dengue 3 virus after being splashed in the face by blood from a febrile traveler who had a diagnosis of dengue. A 17-year-old man from Hong Kong, Special Administrative Region, People’s Republic of China, donated blood in July 2002, from which erythrocytes were transfused to a 72-year-old woman, in whom febrile illness consistent with dengue fever developed 3 d later. A 6-year-old child from Puerto Rico became infected with dengue 4 virus from a bone marrow transplant and died. Dengue hemorrhagic fever developed after a living donor renal transplant.

(8,10–13 )


(7,14 )

Blood transfusion

(15 )

Bone marrow transplant

(16 )

Renal transplant

( 17 )

Yellow fever


A laboratory technician acquired yellow fever after obtaining blood and performing a blood count on a yellow fever patient; he died subsequently. Yellow fever was transmitted to at least 30 other scientists and laboratory workers after contact with mouse or monkey blood or tissues or handling infected animals.

(18–20 )

West Nile


Virus was transmitted to 2 microbiologists by laceration or needlestick injuries in laboratory. Virus was transmitted to numerous recipients of blood products. Virus was transmitted to transplant recipients from kidneys, liver, and heart of an infected donor. Virus infection in a cluster of 3 hemodialysis patients suggested transmission through a common dialysis machine.

(21 )


( 22,23 ) (24 )

Organ transplant


(25 )


lation in a nite period/total population in a nite period is 0.00060115. We would then end up with a force of in- fection for 2005 of 48 infective donations. Depending on the ratio of asymptomatic to symptomatic infections, there were 13–48 dengue infected blood donations in Singa- pore in 2005. With 80,000 blood transfusions annually in Singapore, the proportion of infected blood transfusions would be 1.625–6/10,000 transfusions, which is consis- tent with reported dengue RNA prevalence in blood dona- tions in Puerto Rico, Brazil, and Honduras (30,31). This proportion is similar or even higher than the estimated risk for WNV transmission by transfusion during the 1999 epi- demic in New York, which was reported to be 1.8/10,000– 2.7/10,000 donations (28). A total of 1.625–6/10,000 blood transfusions would translate to 3.25–12 potentially infec- tive blood transfusions/1 million persons in Singapore, if one assumes a ratio of asymptomatic to symptomatic case between 2:1 and 10:1. Further, a recent report provides well-documented evidence of a cluster of blood transfu- sion–associated dengue infections in Singapore (34). Why has transfusion-associated dengue not yet been widely recognized as a problem in dengue-endemic coun- tries? Lack of recognition is likely due to lack of aware- ness that dengue is transmitted not only by vectors but also by blood products. Because of the effects of infection and recurring epidemics in dengue-endemic countries, isolated cases of healthcare-acquired infections will go unnoticed. In many healthcare facilities, patients are not protected from mosquitoes, and it is therefore difcult to ascertain whether infections were related to blood transfusions or exposure to vectors. Further, risk for transmission by transfusion may depend on the level of viremia, which has been shown to correlate with severity of disease (35). It is likely, although not proven, that viremia is lower and shorter in duration in asymptomatic persons than in symptomatic persons. The risk for transfusion-associated dengue will vary greatly from 1 country to another, depending on the epidemiologic pattern of dengue and the immunity level in the population. In countries where dengue is mainly a childhood disease, risk for blood transfusion–transmitted dengue will be lower because of lack of overlap of infected and blood-donating populations. However, risk for nosocomial transmission from needlesticks and other blood exposures would exist in all areas with dengue. Blood transfusion–related dengue will likely repre- sent only a small proportion of all dengue cases in dengue- endemic countries. Screening blood for dengue antigens in dengue-endemic countries would be costly and should therefore be recommended only after careful assessment of risk for infection and cost per blood product–associat- ed dengue infection averted. Therefore, the rst step is to quantify this risk in a systematic study. Risk will vary by

geographic region and season and may change over time. We suggest targeted nucleic acid amplication testing of individual donations in high-prevalence regions, a strategy that was implemented successfully for screening of WNV in the United States in 2004 (36); nucleic acid amplica- tion tests of minipools of several samples of donated blood have also been proposed (36). A prototype nucleic acid test, which is suitable for high-throughput screening, has been developed for detection of dengue virus RNA in blood donations (31). The initial study should be conducted dur- ing the dengue transmission season to identify maximum incidence of viremic donations. This testing would pro- vide a baseline estimate of risk for transmission of infec- tive blood. If the risk is found to be substantial, healthcare providers would need to decide at what threshold screen- ing should be instituted. Policies will also be inuenced by economic resources available and healthcare priorities of a country or region.

Dr Wilder-Smith is director of the Travellers’ Screening and Vaccination Clinic at the National University Hospital of Singa- pore and associate professor at the National University of Singa- pore. Her research interests are dengue, meningococcal disease, and travel health.


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24. Iwamoto M, Jernigan DB, Guasch A, Trepka MJ, Blackmore CG, Hellinger WC, et al. Transmission of West Nile virus from an organ donor to four transplant recipients. N Engl J Med. 2003;348:2196– 203. DOI: 10.1056/NEJMoa022987

25. Centers for Disease Control and Prevention. Possible dialysis-re- lated West Nile virus transmission—Georgia, 2003. MMWR Morb Mortal Wkly Rep. 2004;53:738–9.

26. Komar N. West Nile virus: epidemiology and ecology in North America. Adv Virus Res. 2003;61:185–234. DOI: 10.1016/S0065-


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results of a household-based seroepidemiological survey. Lancet. 2001;358:261–4. DOI: 10.1016/S0140-6736(01)05480-0

28. Biggerstaff BJ, Petersen LR. Estimated risk of West Nile virus trans- mission through blood transfusion during an epidemic in Queens, New York City. Transfusion. 2002;42:1019–26. DOI: 10.1046/


29. Ludlam CA, Powderly WG, Bozzette S, Diamond S, Koerper MA, Kulkarni R, et al. Clinical perspectives of emerging pathogens in bleeding disorders. Lancet. 2006;367:252–61. DOI: 10.1016/S0140-


30. Hamish M, Stramer S, Tomashek K, Muñoz J. Linnen, J, Petersen L. Prevalence of dengue virus nucleic acid in blood products donated in Puerto Rico. 56th Annual Meeting of the American Society of Tropi- cal Medicine and Hygiene; 2007 Nov 4–8: Philadelphia. Abstract


31. Linnen JB, Collins A, Cary C, Kolk JDP. Detection of dengue virus RNA in blood donors from Honduras and Brazil with a prototype transcription-mediated amplication assay. Annual Meeting of the American Association of Blood Banks; 2006 Oct 21–24: Miami. Ab- stracts. p. 11.

32. Wilder-Smith A, Foo W, Earnest A, Sremulanathan S, Paton NI. Seroepidemiology of dengue in the adult population of Singapore. Trop Med Int Health. 2004;9:305–8. DOI: 10.1046/j.1365-3156


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Address for correspondence: Annelies Wilder-Smith, Department of Medicine, National University Singapore, 119407 Singapore; email:


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Sphingomonas paucimobilis

Bloodstream Infections Associated with Contaminated Intravenous Fentanyl 1

Lisa L. Maragakis, Romanee Chaiwarith, Arjun Srinivasan, Francesca J. Torriani, Edina Avdic, Andrew Lee, Tracy R. Ross, Karen C. Carroll, 2 and Trish M. Perl 2


Medscape, LLC is pleased to provide online continuing medical education (CME) for this journal article, allowing clinicians the opportunity to earn CME credit. Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide CME for physicians. Medscape, LLC designates this educational activity for a maximum of 0.5 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certi- cate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation at http://www.medscape.com/cme/eid; (4) view/print certicate.

Learning Objectives Upon completion of this activity, participants will be able to:

Describe the types of bacterial contamination associated with different compounding pharmacy medications.

Describe the features of Sphingomonas paucimobilis bacteria.

Identify the types of exposure associated with transmission of S. paucimobilis infection with contaminated fentanyl.

Describe a strategy that would limit the occurrence of compounding pharmacy product contamination.

Editor Lynne Stockton, Copy Editor, Emerging Infectious Diseases. Disclosure: Lynne Stockton has disclosed no relevant nancial relationships.

CME Author Désirée Lie, MD, MSEd, Clinical Professor, Family Medicine, University of California, Orange; Director, Division of Faculty Development, UCI Medical Center, Orange, California. Disclosure: Désirée Lie, MD, MSEd, has disclosed no relevant nancial relationships.

Authors Disclosures: Lisa L. Maragakis, MD, MPH; Romanee Chaiwarith, MD, MHS; Arjun Srinivasan, MD; Francesca J. Torriani, MD, FIDSA; Edina Avdic, PharmD; Andrew Lee, BS, MPH; and Tracy R. Ross, BS, have disclosed no relevant nancial relationships. Karen C. Carroll, MD, has disclosed that she has received grants for clinical support from BD GeneOhm, Prodesse, MicroPhage, and has served as an advisor or consultant to Boehringer Ingelheim and OpGen. Trish M. Perl, MD, MSc, has disclosed that she has received grants for clinical research from 3M and Sage and has served as an advisor or consultant to 3M, TheraDoc, and GlaxoSmithKline. Dr. Perl has also disclosed that she has served on the data monitoring board for Cadence.

Nationally distributed medications from compounding pharmacies, which typically adhere to less stringent quality- control standards than pharmaceutical manufacturers, can lead to multistate outbreaks. We investigated a cluster of 6 patients in a Maryland hospital who had Sphingomonas paucimobilis bloodstream infections in November 2007. Of the 6 case-patients, 5 (83%) had received intravenous fen-

Author af liations: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA (L.L. Maragakis, A. Lee, K.C. Carroll, T.M. Perl); Johns Hopkins University Bloomberg School of Public Health, Baltimore (R. Chaiwarith); Centers for Disease Control and Prevention, Atlanta, Georgia, USA (A. Srinivasan); University of California, San Diego, California, USA (F.J. Torriani); and The Johns Hopkins Hospital, Baltimore (E. Avdic, T.R. Ross)

DOI: 10.3201/eid1501.081054

tanyl within 48 hours before bacteremia developed. Cultures of unopened samples of fentanyl grew S. paucimobilis; the pulsed- eld gel electrophoresis pattern was indistinguish- able from that of the isolates of 5 case-patients. The con- taminated fentanyl lot had been prepared at a compound- ing pharmacy and distributed to 4 states. Subsequently, in California, S. paucimobilis bacteremia was diagnosed for 2 patients who had received intravenous fentanyl from the same compounding pharmacy. These pharmacies should adopt more stringent quality-control measures, including prerelease product testing, when compounding and distrib- uting large quantities of sterile preparations.

1 Data presented in part at the 18th Annual Meeting of the Society for Healthcare Epidemiology of America; Orlando, Florida; April 6, 2008 (abstract 478).

2 These authors contributed equally to this article.

C ompounding pharmacies are licensed or registered by state pharmacy boards to combine “reasonable

quantities” of ingredients to ll a valid prescription from a licensed practitioner for an individual patient (1). Some pharmacies, however, have moved beyond this role and, in anticipation of receiving routine orders, prepare larger quantities of compounded preparations for national dis- tribution to healthcare facilities (2,3). Nationally distrib- uted medications from compounding pharmacies, which typically adhere to less stringent quality-control standards than pharmaceutical manufacturers, can lead to multi- state outbreaks that may be dif cult to detect. Sunenshine et al. recently reported a 5-state outbreak of Serratia marcescens bloodstream infections associated with con- taminated intravenous magnesium sulfate from a com- pounding pharmacy (3). Other reported outbreaks caused by contaminated medications from compounding phar- macies include the following: S. marcescens infections

associated with betamethasone injection, Pseudomonas putida septicemia caused by use of contaminated ush solutions in a special-care nursery, Burkholderia cepacia infections caused by contaminated intravenous ush so- lutions, Pseudomonas uorescens bloodstream infections associated with a heparin/saline ush, and Exophiala der- matitidis infections caused by injection of contaminated steroids (4–10; Table 1). Sphingomonas paucimobilis is an aerobic bacterium found in soil and water; it is a rare cause of healthcare- associated infections (11,12). S. paucimobilis has been re- ported to cause outbreaks of bacteremia among immuno- compromised patients in hematology and oncology units; these outbreaks are possibly related to bacterial coloniza- tion of hospital water systems (13,14). An S. paucimobilis outbreak in mechanically ventilated neonates was linked to contaminated temperature probes (15). In November 2007, The Johns Hopkins Hospital Department of Hospital

Sphingomonas paucimobilis Bloodstream Infections

Epidemiology and Infection Control initiated an outbreak investigation after being notied by the hospital’s microbi- ology laboratory of the growth of S. paucimobilis in several patients’ blood cultures over a 2-week period.

Methods The Johns Hopkins Hospital is a 926-bed, tertiary- care, academic hospital in Baltimore, Maryland, USA. For this investigation, we de ned a case-patient as any patient in our hospital whose cultures of blood or of other normally sterile body sites grew S. paucimobilis in No- vember 2007. S. paucimobilis isolates were characterized as gram-negative rods that are yellow-pigmented, glucose nonfermenting, and weakly oxidase positive; they were preliminarily identi ed by the BD Phoenix Automated Microbiology System (BD Diagnostics, Inc. Sparks, MD, USA). All S. paucimobilis isolates were con rmed by cell wall fatty acid analysis using gas liquid chromatography (Sherlock Microbial Identi cation System version 4.5, li- brary 5.0; MIDI, Inc. Newark, DE, USA). Microbiology records from January 2006 through November 2007 were examined to identify case-patients and to establish the baseline rate of S. paucimobilis bacteremia. We identi ed common exposures for case-patients and focused on in- travenous infusions, medications, and contrast agents and on case-patients’ clinical signs, treatments, and outcomes. Because most of the blood cultures growing S. paucimo- bilis were collected in BacT/Alert FA bottles containing activated charcoal (bioMérieux, Durham, NC, USA), we cultured noninoculated bottles from clinical units by plac- ing them directly into the blood culture instrument to as- sess for intrinsic contamination. On the basis of informa- tion from the medical record review, samples for bacterial culture were taken from 4 implicated lots of intravenous fentanyl mixed in 0.9% sodium chloride solution. All 4 lots came from an out-of-state compounding pharmacy,

Table 1. Recently published reports of infectious outbreaks associated with contaminated medications prepared at compounding pharmacies, United States, 2002–2007



Infection (no. patients)

Mode of transmission

Location of outbreak


Serratia marcescens

Bloodstream infections (18)

Intravenous magnesium sulfate

California, New Jersey, North Carolina, New York, Massachusetts California


S. marcescens

Meningitis, epidural abscess, or joint infection (11)* Bloodstream infections and sepsis (2 pediatric patients) Acute hepatitis C (16)

Epidural or intra-articular injection of betamethasone Intravenous antibiotic-lock flush solution Injected radiopharmaceutical for myocardial perfusion study Heparin/saline intravenous flush


Burkholderia cepacia




Hepatitis C virus


clinics in Maryland



Bloodstream infections (64)

Missouri, New York, Texas, Michigan, South Dakota



Exophiala dermatitidis

Meningitis (5)†

Epidural injection of methylprednisolone‡


pain management


clinics in North Carolina

*3 case-patients died. †1 case-patient died. ‡Prepared by a compounding pharmacy in South Carolina and supplied to hospitals and clinics in 5 states.


hereafter called pharmacy A. All S. paucimobilis iso- lates were strain typed by pulsed- eld gel electrophoresis (PFGE) after digestion with XbaI using standard methods and interpreted according to criteria established by Ten- over et al. (16). We investigated the possibility that fentanyl had been tampered with or diverted by tracing the narcotic chain of custody, reviewing controlled substance procedures, visu- ally inspecting fentanyl bags for signs of tampering, test- ing fentanyl concentrations, and analyzing personnel ac- cess records from the automated medication management system (Pyxis, Cardinal Health; www.cardinal.com/us/ en/providers/products/pyxis/index.asp). The investigation was coordinated with public health authorities, including the Centers for Disease Control and Prevention (CDC) and the Baltimore City Health Department. CDC performed a multistate case-nding investigation by working with the compounding pharmacy to trace the distribution of impli- cated lots of intravenous fentanyl and by asking recipient healthcare institutions whether they had identied cases of S. paucimobilis bacteremia. We notied the US Food and Drug Administration (FDA) of our ndings, and the FDA investigated compounding practices at pharmacy A. The Johns Hopkins University Institutional Review Board ap- proved this study and waived informed consent.

Results S. paucimobilis was isolated from the blood cultures of 6 patients; the samples were collected from November 11 through November 23, 2007. The organism was not isolated from cultures of any other body site. Case-patients had var- ious underlying medical conditions and had been admitted to different hospital units: neurologic intensive care unit (3 patients), medical intensive care unit (1 patient), oncology center (1 patient), and medicine unit (1 patient) (Table 2). S. paucimobilis grew in multiple sets of blood cultures (5 patients) and from blood cultures collected on >1 date (3 patients). In the preceding 22 months, S. paucimobilis had been isolated from blood cultures of 4 patients (Figure 1). As a result of S. paucimobilis bloodstream infections, 5 of the case-patients reported here received antimicrobial drug treatment and had central intravenous catheters or implant- ed medication ports removed and replaced. One of these patients had an adverse reaction (rash and renal insufcien- cy) to antimicrobial drug treatment. All 5 patients treated with antimicrobial agents became free of S. paucimobilis bloodstream infection and survived. One patient (patient 5, Table 2) died of group A streptococcal sepsis before blood culture results for S. paucimobilis were available. No breaches of infection control procedures or inap- propriate blood culture practices were identied. Blood for culture was collected by staff in each unit rather than by

Table 2. Demographic and clinical characteristics of patients with Sphingomonas paucimobilis bloodstream infection, United States,


Patient no./

Hospital unit

Date(s) of fentanyl administration†

Date(s) of


age, y/gender

(US state)

Clinical diagnosis







Osteomyelitis; MRSA


Nov 14

ADT, central line removed and replaced ADT, central line removed and replaced




wound infection





Oct 29–31,

Nov 14,





Nov 2–3,

Nov 18


Nov 11–22




Nov 10–11

Nov 11

ADT, central line removed and replaced





Nov 16–18

Nov 17


Nov 19



Subarachnoid hemorrhage Group A streptococcal sepsis Head and neck tumor

Nov 18

Nov 18

ADT, central line removed and replaced ADT§





Nov 16

Nov 16





Nov 20,

Nov 20,

ADT, implanted medication port removed and replaced




Nov 26

Nov 23




Temporal lobe

Oct 29

Oct 29









Nov 8

Nov 8




fistula; aorto-

bifemoral bypass


*All infections (except in patient 1) developed after administration of intravenous fentanyl compounded at an out-of-state pharmacy; MD, Maryland; CA, California; NCCU, neurologic critical care unit; MICU, medical intensive care unit; SICU, surgical intensive care unit; NA, not applicable; ADT, antimicrobial drug therapy; MRSA, methicillin-resistant Staphylococcus aureus; PFGE, pulsed-field gel electrophoresis. †Intravenous fentanyl in 0.9% sodium chloride solution from a 250-mL (10 g/mL) bag prepared at compounding pharmacy A. ‡Strain A is the outbreak strain that was indistinguishable by PFGE from the fentanyl isolates. §The patient died of Group A streptococcal sepsis before the blood culture results for S. paucimobilis became available. ¶Isolates from patients 7 and 8 in the California hospital were not available for strain typing.

Sphingomonas paucimobilis Bloodstream Infections

7 Other strain 6 Outbreak strain Unknown strain 5 4 3 2 1 0 No.
Other strain
Outbreak strain
Unknown strain
No. patients

Jan Feb Mar Apr May Jun

Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun

Jul Aug Sep Oct Nov Dec Jan Feb Mar




Figure 1. Epidemiologic curve showing the number of patients with Sphingomonas paucimobilis bacteremia at The Johns Hopkins Hospital, Baltimore, Maryland, USA, January 2006 through March 2008.


central vascular access team. No growth occurred from

of fentanyl administered to patients were not available at

cultures of 50 noninoculated activated charcoal blood cul-

either hospital. The 2 other hospitals that had received the


bottles; this nding was therefore not consistent with

implicated fentanyl lot did not detect any case-patients.

pseudo-outbreak or intrinsic contamination of the bottles. Pharmacy records showed that 5 (83%) of 6 case-patients


The outbreak ended after the implicated fentanyl lot was removed from clinical areas. All bags of the implicated lot


received at least 1 intravenous dose of fentanyl (10 μg/

that could be located were tested for sterility at The Johns


in 250 mL 0.9% sodium chloride) within the 48 hours

Hopkins Hospital and CDC before being discarded. The

before S. paucimobilis bacteremia developed. No other common exposure was identied. We found that our hos- pital had outsourced preparation of 250-mL fentanyl bags to pharmacy A, which shipped several lots to the hospital every 2 weeks. Cultures of unopened samples from 1 implicated fen- tanyl lot grew S. paucimobilis that had a PFGE pattern in-

rest of the lot had either been used or was expired and de- stroyed. No product was recalled by pharmacy A. Investigation found no evidence of tampering with or diversion of fentanyl within the Maryland hospital. We found stringent procedures in place to document and se- cure the narcotic chain of custody. No signs of tampering were visible on implicated bags of fentanyl that later grew

distinguishable from that of the isolates of the 5 patients who had received intravenous fentanyl (Figure 2). A sixth case-patient (patient 1; Table 2), who did not receive intra- venous fentanyl, had S. paucimobilis with a unique PFGE pattern. Of 26 unopened bags from the implicated lot of fentanyl that were cultured, 16 (62%) grew S. paucimobilis. Cultures of 9 samples from 3 other fentanyl lots in use dur-

S. paucimobilis, and the bags contained the expected con- centration of fentanyl. We found that it was possible, al- though difcult, to remove and replace safety seals on the bags, which potentially could allow diversion of fentanyl without visible signs of tampering. Analysis of personnel access records from the automated medication and supply management system (Pyxis, Cardinal Health) did not iden-


the outbreak period produced no growth.

tify any 1 person who had accessed >1 of the machines

CDC’s multistate case-nding investigation deter- mined that pharmacy A had distributed the contaminated fentanyl lot to 4 hospitals in different states. A California hospital that had received the implicated lot subsequently

where the fentanyl was stored in the 4 hospital units with case-patients. These 250-mL bags of intravenous fentanyl in 0.9% sodium chloride solution (10 μg/mL) are currently avail-

identied 2 additional case-patients who had S. paucimobi- lis bacteremia after administration of intravenous fentanyl from pharmacy A (Table 2). After diagnosis of bacteremia, these 2 case-patients received treatment with appropriate antimicrobial drugs without removal of existing central lines and were subsequently discharged from the hospital without complications from the bacteremia. At the Califor-

able only from pharmacy A and 1 other out-of-state com- pounding pharmacy. This preparation is the most fre- quently used at our institution and is not available from any pharmaceutical manufacturer. Because commercially available opioid alternatives at the desired concentration are not available, and to avoid disruption of patient care, our hospital continued to purchase the compounded prepa-


hospital, no unopened bags of the implicated fentanyl

ration from pharmacy A. For 3 months after the outbreak,

lot were available for culture, and the bloodstream isolates were not available for PFGE analysis. Specic lot numbers

our microbiology laboratory performed sterility testing by culturing samples from each fentanyl lot received. None of


RESEARCH Figure 2. Results of pulsed- fi eld gel electrophoresis (PFGE) of Sphingomonas paucimobilis isolates

Figure 2. Results of pulsed- eld gel electrophoresis (PFGE) of Sphingomonas paucimobilis isolates obtained in November 2007. Lanes 1 and 10, molecular weight marker; lanes 2–7, bloodstream isolates from patients 1–6, respectively; lane 8, isolate from contaminated fentanyl; lane 9, unrelated control isolate. Patients 2 through 6 received intravenous fentanyl within 48 hours before S. paucimobilis bacteremia developed and had isolates with a PFGE pattern indistinguishable from that of fentanyl isolates. Patient 1 did not receive intravenous fentanyl and had S. paucimobilis bacteremia with a distinct PFGE pattern.

these samples grew any bacterial or fungal pathogens. We do not have access to the results of FDA’s investigation into compounding practices at pharmacy A.

Discussion We describe a multistate outbreak of S. paucimobilis bacteremia that was associated with contaminated intra- venous fentanyl prepared at an out-of-state compounding pharmacy. Astute observation by microbiology laboratory staff, good communication, and swift implementation of an epidemiologic investigation led to expeditious charac- terization of the source of the infections and termination of the outbreak. Pharmacy A prepares large quantities of compounded pharmaceutical preparations and distributes them to many states in anticipation of orders. In contrast to pharmaceutical manufacturers, traditional compounding pharmacies are not routinely inspected by FDA to ensure that they have the capacity to consistently produce high- quality drugs. In response to other infectious outbreak inci- dents, the FDA has warned compounding pharmacies that the high-volume production of pharmaceutical prepara- tions in response to bulk orders constitutes manufacturing and is inconsistent with traditional pharmacy compounding (17,18). Current good manufacturing practice regulations, as dened by FDA, require end-product sterility testing, among other stringent controls, when sterile pharmaceuti- cal products are manufactured (19). Although traditional

pharmacy compounding lls a commercial void when FDA-approved, commercially available drugs cannot meet patients’ medical needs, the lack of end-product sterility testing and other standards of good manufacturing practice is a serious potential threat to patient safety when com- pounding pharmacies produce and distribute large quan- tities of sterile pharmaceutical preparations. Multistate distribution of compounded preparations makes outbreaks and clusters of infections even more difcult to detect and manage. In 2001, as a result of a dispute over advertising re- strictions, the Supreme Court ruled that the compounding provisions of the FDA Modernization Act of 1997 were unconstitutional (2022). In 2002, the FDA issued guid- ance to clarify the FDA’s position on pharmaceutical compounding; the guidance identi ed factors that are con- sidered in deciding whether to initiate enforcement action with respect to compounding (1). FDA historically has not taken enforcement actions against pharmacies engaged in traditional pharmacy compounding, but it has directed its enforcement against establishments whose activities are normally associated with a drug manufacturer. However, much of the investigation, regulation, and enforcement of compounding falls to state licensing boards (2,18). The American Society of Health-System Pharmacists (ASHP), the United States Pharmacopeia (USP), and the National Association of Boards of Pharmacy have issued practice and quality assurance guidelines for sterile compound- ing of pharmaceutical preparations (23,24). In 2004, USP chapter 797 put forth a set of enforceable standards for the compounding of sterile preparations (25); recently re- vised standards took effect on June 1, 2008 (24). These standards do not require end-product sterility testing for most compounded preparations (24). Some states require compounding pharmacies to comply with USP 797 and ASHP standards; however, a national survey found that many pharmacies are not fully compliant with ASHP qual- ity assurance guidelines (26), and a 2006 survey docu- mented incomplete awareness and implementation of USP 797 standards (27). From 1990 through 2002, the FDA received reports of >55 quality problems associated with compounded preparations (28); Table 1 shows reports of 6 such incidents published since 2002. An FDA survey in 2001 found 34% of tested preparations from compound- ing pharmacies failed to meet analytic testing standards, although none failed sterility tests (28). Our investigation had limitations. Neither hospital could trace the lot numbers administered to each patient, so we could neither conrm which patients received contami- nated lots of fentanyl nor assess an attack rate for receipt of the contaminated lots. We did not conduct a case–control study to calculate an odds ratio for administration of fen- tanyl being the primary risk factor for infection. Isolates

from California case-patients were not available for strain typing. Finally, we do not have access to FDA’s investiga- tional ndings regarding pharmacy A, which might indicate the source of the contamination. Despite these limitations, the available evidence strongly suggests that contaminated fentanyl from pharmacy A was the source of this multistate outbreak of S. paucimobilis bloodstream infections. FDA continues to face many serious and complex chal- lenges (29,30). Our investigation, along with other similar published reports, indicates that the issue of large-scale pharmaceutical production and distribution by compound- ing pharmacies is also an urgent concern that requires at- tention. Pharmacies that compound and distribute large quantities of sterile pharmaceutical preparations without prescriptions for individual patients should be considered manufacturers and should be required to follow good manu- facturing practices, including end-product sterility testing. Until stricter regulations are imposed and enforced, hospital pharmacists and administrators must be cautious when outsourcing compounded pharmaceutical prepara- tions and should consider the possibility of contaminated sterile pharmaceutical products when unusual organisms or patterns of disease are detected. Hospital personnel may be unaware that preparation of pharmaceutical products has been outsourced to a compounding pharmacy (3) and may not recognize the different regulatory requirements and po- tential implications of this decision. Healthcare facilities should strongly consider recording lot numbers of com- pounded medications administered to individual patients because this would aid investigations. Increased outsourc- ing of compounded pharmaceutical preparations makes surveillance for unexpected untoward events increasingly important. Compounding pharmacies should adhere to the standards set forth in USP 797 and should adopt more strin- gent quality control measures, including prerelease product testing, when preparing and distributing large quantities of sterile preparations.

Acknowledgments We thank Beryl Rosenstein, Margaret Garrett, Jeff Natter- man, Alex Shangraw, Ernest Feroli, Teresa Wakeeld, Kimberly Eskey, Mark Romagnoli, and members of the Microbiology Lab- oratory, Risk Management, Facilities, Pharmacy, and Security Departments of The Johns Hopkins Hospital; we also thank Laura Herrera, Mary Grace Munoz, and David Blythe.

L.L.M. was supported by grants 1 K01 CI000300 and 1 R01 CI000530 from the Centers for Disease Control and Prevention.

Dr Maragakis is an assistant professor of medicine in the Division of Infectious Diseases at the Johns Hopkins University School of Medicine. She is also an associate hospital epidemi- ologist at The Johns Hopkins Hospital. Her research interest is healthcare-associated gram-negative infections.

Sphingomonas paucimobilis Bloodstream Infections


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15. Lemaitre D, Elaichouni A, Hundhausen M, Claeys G, Vanhaeseb- rouck P, Vaneechoutte M, et al. Tracheal colonization with Sphin- gomonas paucimobilis in mechanically ventilated neonates due to contaminated ventilator temperature probes. J Hosp Infect. 1996;32:199–206. DOI: 10.1016/S0195-6701(96)90146-2


16. Tenover FC, Arbeit RD, Goering RV. How to select and interpret molecular strain typing methods for epidemiological studies of bac- terial infections: a review for healthcare epidemiologists. Molecular Typing Working Group of the Society for Healthcare Epidemiology of America. Infect Control Hosp Epidemiol. 1997;18:426–39.

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18. Galson SK. Statement before the Senate committee on health, edu- cation, labor and pensions hearing on “federal and state role in phar- macy compounding and reconstitution: exploring the right mix to protect patients”; 2003 [cited 2008 Mar 28]. Available from http://


19. US Food and Drug Administration. Guidance for industry; sterile drug products produced by aseptic processing—current good manu- facturing practice; 2004 [cited 2008 Apr 2]. Available from http://


20. Western States Medical Center v. Shalala, 238 F.3d 1090 (9th Cir.


21. Thompson v. Western States Medical Center, 535 U.S. 357 (2002).

22. Harteker LR. Federal court strikes down compounding regulations. Am J Health Syst Pharm. 2001;58:638,640,643.

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Available from http://www.usp.org/ products/797Guidebook 25. Kastango ES, Bradshaw BD. United States Pharmocopeia

25. Kastango ES, Bradshaw BD. United States Pharmocopeia chapter 797: establishing a practice standard for compounding sterile prepa- rations in pharmacy. Am J Health Syst Pharm. 2004;61:1928–38.

26. Morris AM, Schneider PJ, Pedersen CA, Mirtallo JM. National sur- vey of quality assurance activities for pharmacy-compounded sterile preparations. Am J Health Syst Pharm. 2003;60:2567–76.

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Address for correspondence: Lisa L. Maragakis, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Department of Hospital Epidemiology and Infection Control, 600 N Wolfe St, Osler 425, Baltimore, MD 21287, USA; email: lmaraga1@jhmi.edu

Use of trade names is for identication only and does not imply endorsement by the Public Health Service or by the U.S. Department of Health and Human Services.

or by the U.S. Department of Health and Human Services. 18 Emerging Infectious Diseases • www.cdc.gov/eid

Human Infection with Highly Pathogenic Avian In uenza Virus (H5N1) in Northern Vietnam,


Nguyen Duc Hien, Nguyen Hong Ha, Nguyen Tuong Van, Nguyen Thi Minh Ha, Trinh Thi Minh Lien, Nguyen Quoc Thai, Van Dinh Trang, Takuro Shimbo, Yoshimitsu Takahashi, Yasuyuki Kato, Akihiko Kawana, Samu Akita, and Koichiro Kudo

We performed a retrospective case-series study of patients with in uenza A (H5N1) admitted to the National Institute of Infectious and Tropical Diseases in Hanoi, Viet- nam, from January 2004 through July 2005 with symptoms of acute respiratory tract infection, a history of high-risk exposure or chest radiographic ndings such as pneumo- nia, and positive ndings for A/H5 viral RNA by reverse transcription–PCR. We investigated data from 29 patients (mean age 35.1 years) of whom 7 (24.1%) had died. Mor- tality rates were 20% (5/25) and 50% (2/4) among patients treated with or without oseltamivir (p = 0.24), respectively, and were 33.3% (5/15) and 14.2% (2/14) among patients treated with and without methylprednisolone (p = 0.39), re- spectively. After exact logistic regression analysis was ad- justed for variation in severity, no signi cant effectiveness for survival was observed among patients treated with osel- tamivir or methylprednisolone.

H uman infection with the highly pathogenic avian in- uenza A virus (H5N1) was discovered in Hong

Kong Special Administrative Region, People’s Repub- lic of China, in 1997 (1–3). It has since been identied in other countries, primarily in Southeast Asia. Among 100 conrmed infected patients, 46 have died in Vietnam since 2003 (4,5). Severe viral pneumonia accompanied by diffuse alve- olar damage develops in patients infected with inuenza vi-

Author af liations: National Institute of Infectious and Tropical Dis- eases, Hanoi, Vietnam (N.D. Hien, N.H. Ha, N.T. Van, N.T.M. Ha, T.T.M. Lien, N.Q. Thai, V.D. Trang); and International Medical Cen- ter of Japan, Tokyo, Japan (T. Shimbo, Y. Takahashi, Y. Kato, A. Kawana, S. Akita, K. Kudo)

DOI: 10.3201/eid1501.080073

rus (H5N1) (6). High viral load causes intense cytokine re- actions and inammation (7). Clinical factors that might be associated with severity include age, delayed consultation, lower respiratory tract lesions, and leukopenia (4,8–10). However, few cases have reported which factors, including patient management, affect outcomes. Our study reviews the clinical courses of patients treated in Hanoi, Vietnam, and investigates the association between clinical ndings and survival. The effects of oseltamivir and other neuraminidase inhibitors have been demonstrated in experimental mod- els (11–13), but their outcomes in humans have not been veried. Randomized controlled trials would be optimal for investigating the effectiveness of oseltamivir compared with placebo, but they are not an option because of ethical issues. Therefore, this issue can only be addressed through observational studies. Despite limited empirical evidence, the World Health Organization (WHO) reported that oselta- mivir improved survival (14) and recommended treatment with oseltamivir because of high mortality rates associated with inuenza A virus (14,15). Patients from northern Viet- nam are described in detail.

Methods We investigated patients infected with inuenza A vi- rus (H5N1) who were referred to the National Institute of Infectious and Tropical Diseases in Hanoi, Vietnam, from other local hospitals from January 2004 through July 2005. Pediatric patients were admitted to another institution in Hanoi and were excluded from the present study. A WHO inspection team at the National Institute for Hygiene and Epidemiology in Hanoi virologically conrmed H5N1 sub- type infection in the patients by using a reverse transcrip-


tion–PCR (RT-PCR) for inuenza A/H5. We investigated only patients with H5N1 subtype infection determined from symptoms of acute respiratory tract infection, a history of high-risk exposure, or chest radiographic ndings such as pneumonia. All patients were reported to WHO as having conrmed infection with avian inuenza virus (H5N1). We excluded other patients with positive RT-PCR results be- cause of reasons described below. The study was reviewed and approved by the ethics committees at the International Medical Center of Japan and the National Institute of Infec- tious and Tropical Diseases in Vietnam. Data were obtained for general characteristics, history of high-risk exposure, medical history, symptoms, signs, microbiologic and biochemical test results, chest radio- graphic ndings, treatment strategies, and outcomes from medical records from April through October 2006. We investigated associations between clinical ndings and survival by using univariate analysis. Initial laboratory and chest radiographic ndings after hospitalization were recorded in the medical charts and used. The relationship between survival and treatment with oseltamivir or meth- ylprednisolone was investigated by adjusting for factors related to severity in an exact logistic regression analysis, which is appropriate for small amounts or unbalanced bi- nary data (16). Because the study cohort was small, deaths were few and overtting was possible (17,18); only 1 cova- riate could be added for adjustment into the logistic regres- sion model. Therefore, we used leukocyte counts, platelet counts, aspartate aminotransferase (AST) levels, and urea nitrogen levels as an adjustment for severity because these values are associated with reported outcomes (14). Also, many missing observations prevented adjustment using al- bumin levels. Data were analyzed by using the Wilcoxon test, χ 2 test, and Fisher exact test when appropriate and the statistical package SAS version 8.2 (SAS Institute, Cary, NC, USA).

Results Among 41 patients who were hospitalized from January 2004 through July 2005 and had positive RT-PCR results, 12 were excluded from the study (3 patients whose medical records were unavailable; 2 patients related to persons with conrmed H5N1 subtype pneumonia who were asymptom- atic, positive for viral RNA, and treated with prophylactic oseltamivir; and 7 patients who had some illnesses, particu- larly respiratory diseases, which complicated interpretation of the clinical course or chest radiographic ndings). We therefore studied 29 patients with clinically and virologi- cally conrmed inuenza A (H5N1) infection. Table 1 shows the general characteristics of the pa- tients, and the Figure shows the clinical course from on- set of disease to hospitalization and discharge. Patients ranged in age from 14 to 67 years with a mean age of

Table 1. Characteristics of 29 patients infected with highly pathogenic avian influenza virus (H5N1), northern Vietnam,




Age, y, mean ± SD M:F sex (%) High-risk exposure, no. (%)† Poultry Sick poultry Family infected with H5N1 virus subtype Sick poultry or person Hospitalization after disease onset, median, d (IQR) Hospital stay, median, d (IQR) Treated with oseltamivir, no. (%) Began treatment with oseltamivir after disease onset, median, d (IQR) Treated with methylprednisolone, no. (%) Died, no. (%)

35.1 ± 14.4 15:14 (52:48)

19 (65.5)

12 (41.4)

6 (20.7)

15 (51.7)

6 (4–8)

14 (9–17)

25 (86.2)

7 (5–10)

15 (51.7)


*IQR, interquartile range. †Poultry, a history of exposure to sick or healthy poultry; sick poultry or person, a history of exposure to sick poultry or a family infected with avian influenza (H5N1).

35.1 years. A total of 25 patients were given 150 mg/day of oseltamivir, and 15 were treated with methylpredni- solone (initial dose 40–160 mg/day, median dose 80 mg/ day). Seven (24.1%) of the 29 patients died. No signicant associations were found between mortality rates and age (p = 0.57), sex (p = 0.68), history of high-risk exposure

(p = 0.57), sex (p = 0.68), history of high-risk exposure Figure. Clinical course of 29

Figure. Clinical course of 29 patients infected with highly pathogenic avian in uenza virus (H5N1), northern Vietnam, 2004–2005. Zero days on horizontal axis represent days of hospitalization at the National Institute of Infectious and Tropical Diseases. Shaded bars, days between disease onset and hospitalization; open bars, days between hospitalization and discharge; dots, start of oseltamivir treatment. Information on the right shows date of hospitalization, age in years, sex, and leukocyte count per microliter.

(contact with poultry [p = 1.00], contact with sick poul- try [p = 1.00], and contact with sick poultry or persons [p = 1.00]). Three of 6 patients from a family infected with H5N1 subtype died, and 4 of 23 patients without such an association died (p = 0.13). Duration between onset of dis- ease and hospitalization was not associated with higher mortality rates (p = 0.98). Table 2 shows initial laboratory ndings at hospital- ization. Leukopenia (neutropenia), thrombocytopenia, hy- poalbuminemia, and increased AST and urea nitrogen lev- els were associated with increased deaths. Five (20.0%) of the 25 patients treated with oseltamivir died, as did 2 (50.0%) of 4 who were not treated (odds ratio 0.25, 95% condence interval [CI] 0.03–2.24, p = 0.24). To adjust for variation in disease severity among patients, exact logistic regression was performed by using leukocyte counts, platelet counts, AST levels, and urea nitrogen lev- els. Adjusted odds ratios for deaths among patients treated with oseltamivir were 0.15 (95% CI 0.00–2.57, p = 0.19), 0.16 (95% CI 0.00–2.23, p = 0.17), 0.54 (95% CI 0.02– 11.85, p = 1.00), and 0.28 (95% CI 0.01–5.16, p = 0.55), respectively, for the 4 adjustments for disease severity. The time between the onset of symptoms and initia- tion of treatment with oseltamivir varied (Table 1, Figure). The mortality rates were 20% (3/15) and 20% (2/10) when treatment with oseltamivir was started within and after 7 days of disease onset. Methylprednisolone was given to 15 of 29 patients. Five (33.3%) of these 15 patients died, and 2 (14.3%) of 14 patients who were not given this drug died (odds ra- tio 3.0, 95% CI 0.48–18.93, p = 0.39). Exact logistic re- gression after adjustment for severity by using leukocyte counts, platelet counts, AST levels, or urea nitrogen levels showed odds ratios for deaths among patients treated with

Human Infection with Avian In uenza Virus (H5N1)

methylprednisolone of 0.74 (95% CI 0.00–9.57, p = 0.82), 1.82 (95% CI 0.18–25.48, p = 0.89), 1.14 (95% CI 0.07– 18.92, p = 1.00), and 2.43 (95% CI 0.28–31.69, p = 0.61), respectively. Thirteen patients were treated with oseltamivir and methylprednisolone. The regression model that included these 2 drugs and interactions did not show effectiveness of either drug.

Discussion The overall mortality rate of 24.1% in this study was lower than rates in previous studies and WHO reports. Table 3 summarizes the characteristics of patients from previous studies. Patients in the present study were older because pediatric patients were excluded because of treat- ment elsewhere. WHO has reported that the mortality rate of 73% for infection with H5NI subtype is highest in persons 10–19 years of age, and that patients 20–39 years of age ac- count for >60% of the deaths (22). The expected mortality rate would be 51.8% if our case-patients had the same age- specic mortality rate as in a WHO report (14). The lower mortality rate in our study could not be explained by an age difference. The relatively high leukocyte count and factors related to outcomes suggest that a reasonably large num- ber of mildly infected patients might have been included, although chest radiographs showed variable progression in lesions from mild to severe. Persons who died were concentrated in the early pe- riod of the study, especially in 2004. Virus genotype and load data could provide useful information on pathogenesis and outcome. However, these data were not available. Factors affecting outcome were leukocyte and plate- let counts, and albumin, ALT, and urea nitrogen levels. Results were consistent with previous ndings (14) and

Table 2. Initial laboratory and chest radiographic results for 29 patients infected with highly pathogenic avian influenza virus (H5N1), northern Vietnam, 2004–2005*


Survived, median (interquartile range), n = 22

Died, median (interquartile range), n = 7

p value

Leukocytes, × 10 3 / L Neutrophils, ×10 3 / L Hemoglobin, g/L Platelets, × 10 3 / L Albumin, g/L AST, U/L Total bilirubin, mol/L Urea nitrogen, mmol/L

7.8 (7.1–12.0)

3.4 (1.7–5.6)†


6.8 (4.8–9.9)

2.3 (1.1–3.8)†


130 (107–137)

121 (103–138)


214 (181–284)

86 (38–139)†


34.5 (31.2–35.1)

21.7 (10.4–29.4)†


45 (28–69)

327 (77–352)†


10.3 (7.6–16.8)

11.4 (7.0–27.1)


4.5 (3.4–5.5)

9 (3.4–14.3)†


Initial chest radiographic findings‡ No or slight lesion Moderate lesion Severe lesion








*Not all laboratory findings and chest radiographic results were available. Results were derived from the following numbers of patients: complete blood count, 29; albumin 12; AST, 25; total bilirubin, 17; urea nitrogen, 27. AST, aspartate aminotransferase. †p<0.05, by Wilcoxon test or Fisher exact test. ‡No or slight lesion, no lesion or localized (occupying less than one third of unilateral lung fields) in 1 lung; moderate, diffuse in 1 lung or localized but evident in both lungs; severe, diffuse in both lungs.


Table 3. Comparison of studies of influenza A virus (H5N1)–infected patients*

Patient age, y, mean ± SD

Leukocyte count, median, × 10 3 / L (IQR)

Hospitalization after disease onset, d, median (IQR)


Author (reference)


No. alive

No. died

Present study Yuen at al. (8)† Tran et al. (4) Chotpitayasunondh et al. (9) Oner et al. (19) Kandun et al. (20) Buchy et al. (21)


35.1 ± 14.4 17.6 ± 20.4 13.7 ± 6.4 22.0 ± 21.4 10.1 ± 4.0 15.4 ± 14.9 16.0 ± 9.9

7.2 (3.9–11.3)

6 (3.5–8)




5.6 (2.47–10.7)

3 (2–4)




2.1 (1.9–2.8)

6 (5–7)




4.43 (2.75–5.64)





3.8 (1.8–5.75)

6 (4–7)




3.59 (2.605–6.3)

7 (5–7)




4.2 (3.6–4.7)

6 (5–7)



*IQR, interquartile range; NR, not reported. †Outcomes of 2 patients were not reported.

suggested that outcome is related to lesions in several organs. Although the mortality rate was lower among patients treated with oseltamivir, differences were not signicant. Exact logistic regression after adjustments for laboratory results yielded an odds ratio of 0.15–0.54 for death. The small number of patients prevented valid adjustment, and confounding factors might not have been sufciently elimi- nated. A larger patient cohort should be able to adjust for severity of disease. If one considers the possibility of confounding fac- tors, the reason oseltamivir was not prescribed should be investigated. If oseltamivir was withheld from patients with severe infections and administered only to those with milder symptoms, the drug would apparently be more ef- fective. Among 4 patients who were not prescribed oselta- mivir, initial RT-PCR results were negative for 1 patient, who subsequently died. Oseltamivir was unavailable for treatment of another patient who died. The other 2 surviv- ing patients were not prescribed oseltamivir because their chest radiographs showed only minimal lesions. There- fore, withholding oseltamivir was not associated with disease severity. Higher doses of oseltamivir or longer drug adminis- tration have improved outcomes in animal models (23,24). Because all patients in our study were given oseltamivir at a dose of 150 mg/day, we could not investigate the effect of a higher dose. Mortality rates were higher in patients treated with methylprednisolone than in those not treated with this drug. This nding can be explained by disease severity because severely ill patients were more likely to be given methyl- prednisolone. However, even after we adjusted for this con- founding effect, no benecial effect of methylprednisolone was observed. Further, an experimental model has recently raised doubt about the effect of cytokine suppression (25). Our study described patients infected with inuenza A virus (H5N1) in Hanoi, Vietnam. These patients had lower mortality rates than those reported in other studies. The reason for the low mortality rate could not be investigated thoroughly without virologic information. Oseltamivir was prescribed in 25 of 29 patients, and their mortality rate was

apparently decreased, although the patient cohort was too small to generate sufcient statistical power. In addition, since our study was an observational study, these ndings might have been inuenced by confounding factors. Fur- ther detailed observations from a larger number of patients are required.

Acknowledgments We thank the staffs of the National Institute of Infectious and Tropical Diseases, Bach Mai Hospital, and the National Institute of Hygiene and Epidemiology for diagnosing the infections and treating patients; and Nguyen Thi Le Hang, Pham Thi Phuong Thuy, and Toshie Manabe for invaluable help in coordinating this study.

This study was supported by a research grant (Research on Emerging and Re-emerging Infectious Diseases) from the Minis- try of Health, Labour and Welfare, Japan, to K.K.

Dr Hien is the director general at the National Institute of Infectious and Tropical Diseases in Hanoi, Vietnam. His research interests are clinical practice and research of infectious and tropi- cal diseases.


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