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Morbidity and Mortality Weekly Report, Dispatches and Updates

Giuseppe

Emeritus
MMWR Dispatch. Update: Infections With a Swine-Origin Influenza A (H1N1) Virus --- United States and Other Countries, April 28, 2009

Update: Infections With a Swine-Origin Influenza A (H1N1) Virus --- United States and Other Countries, April 28, 2009


Since April 21, 2009, CDC has reported cases of respiratory infection with a swine-origin influenza A (H1N1) virus (S-OIV) transmitted through human-to-human contact (1,2).



This report updates cases identified in U.S. states and highlights certain control measures taken by CDC.

As of April 28, the total number of confirmed cases of S-OIV infection in the United States had increased to 64, with cases in California (10 cases), Kansas (two), New York (45), Ohio (one), and Texas (six).


CDC and state and local health departments are investigating all reported U.S. cases to ascertain the clinical features and epidemiologic characteristics.

On April 27, CDC distributed an updated case definition for infection with S-OIV (Box).

Of the 47 patients reported to CDC with known ages, the median age was 16 years (range: 3--81 years), and 38 (81%) were aged <18 years; 51% of cases were in males.


Of the 25 cases with known dates of illness onset, onset ranged from March 28 to April 25 (Figure). To date, no deaths have been reported among U.S. cases, but five patients are known to have been hospitalized.


Of 14 patients with known travel histories, three had traveled to Mexico; 40 of 47 patients (85%) have not been linked to travel or to another confirmed case.


Information is being compiled regarding vaccination status of infected patients, but is not yet available.

According to the World Health Organization (WHO), as of April 27, a total of 26 confirmed cases of S-OIV infection had been reported by Mexican authorities.

Canada has reported six cases and Spain has reported one case.


*Emergency Use Authorizations

If an emerging public health threat is identified for which no licensed or approved product exists, the Project BioShield Act of 2004 authorizes the Food and Drug Administration (FDA) commissioner to issue an Emergency Use Authorization (EUA) so that promising countermeasures can be disseminated quickly for the protection and safety of the U.S. population (3).

In response to the current public health emergency involving swine-origin influenza, FDA issued four EUAs on April 27 to allow emergency use of

* oseltamivir (Tamiflu) and zanamivir (Relenza) for the treatment and prophylaxis of influenza (two EUAs),

* disposable N95 respirators for use by the general public, and

* the rRT-PCR Swine Flu Panel for diagnosis.



Oseltamivir is FDA-approved for treatment and prevention of influenza in adults and children aged ≥1 year.

Zanamivir is FDA-approved for treatment of influenza in adults and children aged ≥7 years who have been symptomatic for <2 days, and for prevention of influenza in adults and children aged ≥5 years.

The EUA allows the use of oseltamivir for treatment of influenza in children aged <1 year and prevention of influenza in children aged 3 months--1 year.

Additionally, traditional prescribing and dispensing requirements might not be met. Under the scope and conditions of current EUAs, mass dispensing of both antiviral medications will be allowed per state and/or local public health authority.

FDA has authorized use of certain N95 respirators to help reduce wearer exposure to pathogenic biological airborne particulates during a public health emergency involving S-OIV.

On April 27, CDC published guidelines for the use of N95 respirators.

For example, respirators should be considered for use by persons for whom close contact with an infectious person is unavoidable. This can include selected individuals who must care for a sick person (e.g., family member with a respiratory infection) at home. Additional information is available at http://www.cdc.gov/swineflu/masks.htm.

Currently, no FDA-cleared tests specifically for the S-OIV strain exist in the United States or elsewhere. For this purpose and to meet the significant increase in demand for influenza testing throughout the country, CDC has developed the rRT-PCR Swine Flu Panel to expand and maintain the operational capabilities of public health or other qualified laboratories by providing a detection tool for the presumptive presence of S-OIV.


Control Measures at Ports of Entry and Travel Warning for Mexico

CDC, in collaboration with industry and federal partners, is continuing to conduct routine illness detection at ports of entry with heightened awareness for travelers who might be infected with S-OIV.

During April 19--27, 15 cases of illness in travelers entering the United States from Mexico that were clinically consistent with S-OIV infection were detected. Of these 15 cases, two were laboratory confirmed as swine-origin influenza A (H1N1). Nine travelers remain in isolation pending completion of evaluation, and four travelers were released to complete travel after influenza virus infection was ruled out.


WHO has declared a Public Health Emergency of International Concern. As part of its responsibilities under the International Health Regulations, CDC is prepared to implement additional screening measures for international flights, if deemed necessary, to prevent exportation of S-OIV. In addition, CDC in collaboration with the U.S. Department of Homeland Security, is distributing travelers health alert notices to all persons traveling to countries with confirmed cases of S-OIV infection.

CDC has recommended that U.S. travelers avoid nonessential travel to Mexico (http://wwwn.cdc.gov/travel/contentswineflumexico.aspx). However, CDC might revise its travel guidance as the outbreak in Mexico evolves and is characterized more completely. Travelers who cannot delay travel to Mexico should visit http://www.cdc.gov/travel and follow the posted recommendations to reduce their risk for infection.


Nonpharmaceutical Community Mitigation

CDC has issued interim guidance for nonpharmaceutical community mitigation efforts in response to human infections with S-OIV (http://www.cdc.gov/swineflu/mitigation.htm). Current recommendations for isolation of patients with cases of S-OIV, household contacts, school dismissal, and other social distancing interventions also are available at http://www.cdc.gov/swineflu/mitigation.htm and will be updated as the situation evolves.


Reported by:

Strategic Science and Program Unit, Coordinating Center for Infectious Diseases; Div of Global Migration and Quarantine, National Center for Preparedness, Detection, and Control of Infectious Diseases; Influenza Div, National Center for Immunization and Respiratory Diseases, CDC Influenza Emergency Response Team, CDC.


References

1. CDC. Swine influenza A (H1N1) infection in two children---southern California, March--April 2009. MMWR 2009;58:400--2.
2. CDC. Update: swine influenza A (H1N1) infections---California and Texas, April 2009. MMWR;58(In press).
3. Nightingale SL, Prasher JM, Simonson S. Emergency Use Authorization (EUA) to enable use of needed products in civilian and military emergencies, United States. Emerg Infect Dis 2007;13:1046--51.

* Additional information is available at http://www.who.int/en.BOX.

The following case definitions are for the purposes of investigations of suspected, probable, and confirmed cases of swine-origin influenza A (H1N1) infection.


Case Definitions for Infection with Swine-Origin Influenza A (H1N1) Virus

A confirmed case of swine-origin influenza A (H1N1) virus infection is defined as an acute febrile respiratory illness in a person and laboratory-confirmed swine-origin influenza A (H1N1) virus infection at CDC by either of the following tests:

1) real-time reverse transcrition--polymerase chainreaction (rRT-PCR), or

2) viral culture.



A probable case of swine-origin influenza A (H1N1) virus infection is defined as acute febrile respiratory illness in a person who is

? positive for influenza A, but negative for H1 and H3 by influenza rRT-PCR.



A suspected case of swine-origin influenza A (H1N1) virus infection is defined as acute febrile respiratory illness in a person

? with onset within 7 days of close contact with a person who has a confirmed case of swine-origin influenza A (H1N1) virus infection, or
? with onset within 7 days of travel to a community, either within the United States or internationally, which has one or more confirmed swine-origin influenza A (H1N1) cases, or
? who resides in a community in which one or more confirmed swine-origin influenza cases have occurred.




FIGURE. Confirmed human cases of swine-origin influenza A (H1N1) infection with known dates of illness onset

* --- United States, April 27, 2009
The figure shows the number of confirmed human cases of swine-origin influenza A (H1N1) infection with known dates of illness onset in the United States as of April 27, 2009. Onset dates were available for 25 of the 64 confirmed cases.


  • One case each had onset on March 28 and 30, April 4, 5, 6 and 11.
  • Two cases had onset on April 12.
  • One case had onset on April 15, 19, 20, and 21.
  • Five cases had onset on April 22.
  • Four cases had onset on April 23.
  • Three cases had onset on April 24, and one case had onset on April 25.

Use of trade names and commercial sources is for identification only and does not imply endorsement by the U.S. Department of Health and Human Services.

References to non-CDC sites on the Internet are provided as a service to MMWR readers and do not constitute or imply endorsement of these organizations or their programs by CDC or the U.S. Department of Health and Human Services.

CDC is not responsible for the content of pages found at these sites.

URL addresses listed in MMWR were current as of the date of publication.

All MMWR HTML versions of articles are electronic conversions from typeset documents. This conversion might result in character translation or format errors in the HTML version. Users are referred to the electronic PDF version (http://www.cdc.gov/mmwr) and/or the original MMWR paper copy for printable versions of official text, figures, and tables. An original paper copy of this issue can be obtained from the Superintendent of Documents, U.S. Government Printing Office (GPO), Washington, DC 20402-9371; telephone: (202) 512-1800. Contact GPO for current prices.
**Questions or messages regarding errors in formatting should be addressed to mmwrq@cdc.gov.
Date last reviewed: 4/28/2009
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<cite cite="http://www.cdc.gov/mmwr/preview/mmwrhtml/mm58d0428a2.htm">Update: Infections With a Swine-Origin Influenza A (H1N1) Virus --- United States and Other Countries, April 28, 2009</cite>
 
Re: Morbidity and Mortality Weekly Report, Dispatches and Updates

MMWR Dispatch. Update: Drug Susceptibility of Swine-Origin Influenza A (H1N1) Viruses, April 2009

Update: Drug Susceptibility of Swine-Origin Influenza A (H1N1) Viruses, April 2009


Since April 21, 2009, CDC has reported cases of respiratory infection with a swine-origin influenza A (H1N1) virus (S-OIV) that is being spread via human-to-human transmission (1). As of April 28, the total number of confirmed S-OIV cases in the United States was 64; these cases occurred in California (10 cases), Kansas (two), New York (45), Ohio (one), and Texas (six).

The viruses contain a unique combination of gene segments that had not been reported previously among swine or human influenza viruses in the United States or elsewhere (1).

Viruses from 13 (20%) of 64 patients have been tested for resistance to antiviral medications.


To date, all tested viruses are resistant to amantadine and rimantadine but are susceptible to oseltamivir and zanamivir.


The purpose of this report is to provide detailed information on the drug susceptibility of the newly detected S-OIVs, which will aid in making recommendations for treatment and prophylaxis for swine influenza A (H1N1) infection.

These data also will contribute to antiviral-resistance monitoring and diagnostic test development.

Adamantane susceptibility was assessed by conventional sequencing or pyrosequencing assay (2) with modifications (3), using viral RNA extracted from original clinical specimens and/or virus isolates.

Susceptibility of virus isolates to the neuraminidase inhibitors (NAIs), including oseltamivir and zanamivir and two investigative NAIs (peramivir and A-315675), was assessed by chemiluminescent neuraminidase inhibition assay using the NAStar Kit (Applied Biosystems, Foster City, California) (4).

The generated IC50 values (i.e., drug concentration needed to inhibit 50% of neuraminidase enzyme activity) of test viruses were compared with those of sensitive seasonal control viruses.

In addition, because H274Y is the most commonly detected mutation in oseltamivir-resistant viruses (4,5), a set of new primers for pyrosequencing of the N1 gene was designed to monitor a residue of the neuraminidase protein at 274 (275 in N1 numbering) in viruses of swine origin (6,7) (Table 1).

All 13 specimens tested contained the S31N mutation in the M2 protein, which confers cross-resistance to the adamantane class of anti-influenza drugs (Table 2).


In addition, a partial sequence deduced from the M2 pyrograms revealed changes characteristic for the M gene of S-OIVs. Existing primers used for the detection of adamantane resistance in seasonal viruses do not work with all tested S-OIVs. Optimized primers have been designed and are currently being validated.

All 13 tested virus isolates exhibited IC50 values characteristic of oseltamivir- and zanamivir-sensitive influenza viruses.


A/Georgia/17/2006 (H1N1), which is a seasonal virus, was used as a control (Table 2).

The IC50 for oseltamivir ranged from 0.28 nM to 1.41 nM, whereas those for zanamivir ranged from 0.30 nM to 1.34 nM.


All tested viruses also were susceptible to peramivir and A-315675.


A subset of viruses (n = 2) tested in the fluorescent neuraminidase inhibition assay showed IC50 for oseltamivir and zanamivir ranging from 1.50 nM to 2.40 nM, similar to the sensitive control.

Among the 36 specimens tested to date with pyrosequencing for the H274Y mutation in N1, none had mutations at residue 274.




Reported by:

L Gubareva, PhD, M Okomo-Adhiambo, PhD, V Deyde, PhD, AM Fry, MD, TG Sheu, R Garten, PhD, C Smith, J Barnes, A Myrick, M Hillman, M Shaw, PhD, C Bridges, MD, A Klimov, PhD, N Cox, PhD, Influenza Div, National Center for Infectious and Respiratory Diseases, Coordinating Center for Infectious Diseases, CDC.


Editorial Note:

In the United States, two classes of antiviral drugs are approved by the Food and Drug Administration (FDA) for use in treating or preventing influenza virus infections: M2 ion channel blockers and NAIs. The M2 blockers (adamantanes) are effective against influenza A viruses, but not influenza B viruses, which lack the M2 protein (8). However, use of the M2 blockers has been associated with the rapid emergence of drug-resistance mutations of the M2 protein among human influenza A viruses of H3N2 subtype, and in H1N1 subtype viruses circulating in certain geographic areas (2,3,9). Adamantane resistance also has been detected in A (H5N1) viruses in Southeast Asia (10,11). In addition, adamantane resistance has been reported for swine viruses in Eurasia (12--14) but not in North America. This rapid increase in resistance has reduced the usefulness of this class of drugs for the management of influenza A infections, and since 2005, CDC has not recommended their use (15), although the emergence of resistance to oseltamivir in seasonal influenza viruses circulating during the 2008--09 season led to changes in CDC recommendations.

*Two NAIs, oseltamivir (Tamiflu [Hoffman-La Roche, Ltd, Basel, Switzerland]) and zanamivir (Relenza [GlaxoSmithKline, Stevenage, United Kingdom]) are FDA-approved drugs for use against type A and type B influenza infections (16). The two drugs differ structurally, resulting in oseltamivir being orally bioavailable, whereas zanamivir is not and must be inhaled (17,18). A third NAI, peramivir (BioCryst, Inc., Birmingham, Alabama), is formulated for intravenous administration and is undergoing clinical trials, and a fourth, called A-315675 (Abbott Laboratories, Abbott Park, Illinois) has only been investigated in preclinical studies.

Compared with M2 blockers, NAIs previously exhibited lower frequency of antiviral resistance during therapeutic use (16,19). However, during the 2007--08 influenza season, emergence and transmission of oseltamivir-resistant A (H1N1) viruses, with a H274Y mutation in the neuraminidase protein, was simultaneously detected in several countries in the Northern Hemisphere (4,20--22) and spread globally (7,9,23). As of April 2009, similar trends have been observed in the 2008--09 influenza season, with many countries reporting up to 100% oseltamivir resistance in A (H1N1) viruses. As a result, the World Health Organization Global Influenza Surveillance Network (GISN) and CDC have emphasized the urgent need for close monitoring of resistance to NAIs.

Current interim antiviral recommendations for treatment and chemoprophylaxis of swine influenza A (H1N1) viruses include the use of either zanamivir or oseltamivir and are available at http://www.cdc.gov/swineflu/recommendations.htm.


References

1. CDC. Swine influenza A (H1N1) infection in two children---southern California, March--April 2009. MMWR 2009;58:400--2.
2. Bright RA, Medina MJ, Xu X, et al. Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern. Lancet 2005;366:1175--81.
3. Deyde VM, Xu X, Bright RA, et al. Surveillance of resistance to adamantanes among influenza A (H3N2) and A (H1N1) viruses isolated worldwide. J Infect Dis 2007;196:249--57.
4. Sheu TG, Deyde VM, Okomo-Adhiambo M, et al. Surveillance for neuraminidase inhibitor resistance among human influenza A and B viruses circulating worldwide in 2004--2008. Antimicrob Agents Chemother 2008;52:3284--92.
5. Lackenby A, Hungnes O, Dudman SG, et al. Emergence of resistance to oseltamivir among influenza A (H1N1) viruses in Europe. Euro Surveill 2008;13(5).
6. Deyde VM, Okomo-Adhiambo M, Sheu TG, et al. Pyrosequencing as a tool to detect molecular markers of resistance to neuraminidase inhibitors in seasonal influenza A viruses. Antiviral Res 2009;81:16--24.
7. Lackenby A, Democratis J, Siqueira MM, Zambon MC. Rapid quantitation of neuraminidase inhibitor drug resistance in influenza virus quasispecies. Antivir Ther 2008;13:809--20.
8. Hayden FG. Adamantadine and rimantadine---clinical aspects. In: DD Richman, ed. Antiviral drug resistance. San Francisco, CA: John Wiley and Sons Ltd.; 1996:59--77.
9. CDC. Influenza activity---United States and worldwide, 2007--08 season. MMWR 2008;57:692--7.
10. He G, Qiao J, Dong C, He C, Zhao L, Tian Y. Amantadine-resistance among H5N1 avian influenza viruses isolated in northern China. Antiviral Res 2008;77:72--6.
11. Cheung CL, Rayner JM, Smith GJ, et al. Distribution of amantadine-resistant H5N1 avian influenza variants in Asia. J Infect Dis 2006;193:1626--9.
12. Krumbholz A, Schmidtke M, Bergmann S, et al. High prevalence of amantadine resistance among circulating European porcine influenza A viruses. J Gen Virol 2009;90(Pt 4):900--8.
13. Schmidtke M, Zell R, Bauer K, et al. Amantadine resistance among porcine H1N1, H1N2, and H3N2 influenza A viruses isolated in Germany between 1981 and 2001. Intervirology 2006;49:286--93.
14. Gregory V, Lim W, Cameron K, et al. Infection of a child in Hong Kong by an influenza A H3N2 virus closely related to viruses circulating in European pigs. J Gen Virol 2001;82(Pt 6):1397--406.
15. Bright RA, Shay DK, Shu B, Cox NJ, Klimov AI. Adamantane resistance among influenza A viruses isolated early during the 2005--2006 influenza season in the United States. JAMA 2006;295:891--4.
16. Moscona A. Neuraminidase inhibitors for influenza. N Engl J Med 2005;353:1363--73.
17. Smith BJ, McKimm-Breshkin JL, McDonald M, Fernley RT, Varghese JN, Colman PM. Structural studies of the resistance of influenza virus neuramindase to inhibitors. J Med Chem 2002;45:2207--12.
18. Colman PM. Zanamivir: an influenza virus neuraminidase inhibitor. Expert Rev Anti Infect Ther 2005;3:191--9.
19. Monto AS, McKimm-Breschkin JL, Macken C, et al. Detection of influenza viruses resistant to neuraminidase inhibitors in global surveillance during the first 3 years of their use. Antimicrob Agents Chemother 2006;50:2395--402.
20. Dharan NJ, Gubareva LV, Meyer JJ, et al. Infections with oseltamivir-resistant influenza A (H1N1) virus in the United States. JAMA 2009;301:1034--41.
21. Hauge SH, Dudman S, Borgen K, Lackenby A, Hungnes O. Oseltamivir-resistant influenza viruses A (H1N1), Norway, 2007--08. Emerg Infect Dis 2009;15:155--62.
22. Meijer A, Lackenby A, Hungnes O, et al. Oseltamivir-resistant influenza virus A (H1N1), Europe, 2007--08 season. Emerg Infect Dis 2009;15:552--60.
23. Besselaar TG, Naidoo D, Buys A, et al. Widespread oseltamivir resistance in influenza A viruses (H1N1), South Africa. Emerg Infect Dis 2008;14:1809--10.
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