EINet Alert ~ Nov 07, 2008

*****A free service of the APEC Emerging Infections Network*****
APEC EINet News Briefs offers the latest news, journal articles, and notifications for emerging infections affecting the APEC member economies. It was created to foster transparency, communication, and collaboration in emerging infectious diseases among health professionals, international business and commerce leaders, and policy makers in the Asia-Pacific region.
In this edition:

1. Influenza News
- Cumulative number of human cases of avian influenza A/(H5N1)
- Global: Encouraging results reported for injectable influenza drug
- Indonesia: Man dies, avian influenza H5N1 suspected
- Laos: Avian influenza H5N1 outbreak in poultry
- Thailand: Avian influenza H5N1 scare in Sukhothai

2. Updates

3. Articles
- WHO Weekly Epidemiological Record Bulletin
- Incubation Period for Human Cases of Avian Influenza A (H5N1) Infection, China
- Vaccination strategies and vaccine formulations for epidemic and pandemic influenza control
- Vaccine Effectiveness Against Laboratory-Confirmed Influenza in Children 6 to 59 Months of Age During the 2003–2004 and 2004–2005 Influenza Seasons
- Highly Pathogenic Avian Influenza Virus (H5N1) Infection in Red Foxes Fed Infected Bird Carcasses
- Influenza Infection in Wild Raccoons
- Neutrophils May Be a Vehicle for Viral Replication and Dissemination in Human H5N1 Avian Influenza
- Safety and Immunogenicity of a Prepandemic Influenza A (H5N1) Vaccine in Children
- Would an Influenza Pandemic Qualify as a Major Disaster Under the Stafford Act?

4. Notifications
- The 7th International Bird Flu Summit
- International Meeting on Emerging Disease and Surveillance (IMED)
- Risky Trade: Infectious Disease in the Era of Global Trade
- Bellagio eHealth Call to Action website launch

1. Influenza News

Cumulative number of human cases of avian influenza A/(H5N1)
Economy / Cases (Deaths)

Bangladesh / 1 (0)
China / 3 (3)
Egypt / 7 (3)
Indonesia / 20 (17)
Viet Nam / 5 (5)
Total / 36 (28)

***For data on human cases of avian influenza prior to 2008, go to: http://depts.washington.edu/einet/humanh5n1.html

Total no. of confirmed human cases of avian influenza A/(H5N1), Dec 2003 to present: 387 (245).
(WHO 9/10/08 http://www.who.int/csr/disease/avian_influenza/en/index.html )

Avian influenza age distribution data from WHO/WPRO: http://www.wpro.who.int/sites/csr/data/data_Graphs.htm (WHO/WPRO 6/19/08)

WHO's maps showing world's areas affected by H5N1 avian influenza (last updated 10/6/08): http://gamapserver.who.int/mapLibrary/

WHO’s timeline of important H5N1-related events (last updated 8/14/08): http://www.who.int/csr/disease/avian_influenza/ai_timeline/en/index.html


Global: Encouraging results reported for injectable influenza drug
BioCryst Pharmaceuticals Inc. reported encouraging results in two phase 2 trials of its injectable antiviral drug, peramivir, a potential new treatment for influenza. Peramivir is a neuraminidase inhibitor, like the licensed antivirals oseltamivir (Tamiflu), which is taken orally, and zanamivir (Relenza), inhaled as a powder.

In one study, a single intravenous (IV) dose of peramivir in outpatients ill with flu reduced the duration of their symptoms by about 22 hours compared with a placebo group, which is a statistically significant difference, according to BioCryst.

In the other trial, hospital patients who were seriously ill with flu were treated for five days with either IV peramivir or oseltamivir, with similar results in both groups, including no deaths and a median of 4.0 days to hospital discharge.

Neither set of results has yet been published in a peer-reviewed journal. The new findings come 13 months after the company reported disappointing results in an earlier phase 2 trial of the drug. In that study, flu patients who received injections of peramivir did better than a placebo group, but the difference was not significant. The company said at the time that the use of shorter needles than were used in an earlier trial probably resulted in inadequate doses.

Outpatient findings
The outpatient study was sponsored and conducted in Japan by Shionogi & Co. Ltd., which in 2007 bought the rights to develop and market peramivir in Japan from BioCryst. The study involved 296 patients who tested positive for influenza within 48 hours after symptom onset. The volunteers were divided into three groups, with 99 receiving 300 milligrams (mg) of peramivir IV, 97 receiving 600 mg of the drug IV, and 100 receiving an IV placebo.

The primary end point was time to alleviation of symptoms, which was 81.8 hours for the placebo group. The respective times for the 300-mg and 600-mg peramivir groups were 59.1 and 59.9 hours, both of which were significant reductions, the company said. In addition, both peramivir groups had significant improvements in a composite symptoms score, starting as early as 24 hours after treatment. The drug was well-tolerated, with adverse-event profiles similar for the treatment and placebo groups.

Hospital study
The inpatient study was designed primarily to assess how long it would take patients with serious or life-threatening flu to become clinically stable with five days of treatment with peramivir or oseltamivir. The study was conducted at centers in the United States, Canada, Hong Kong, Singapore, Australia, New Zealand, and South Africa.

Clinical stability was a composite measure based on temperature, oxygen saturation, respiratory rate, systolic blood pressure, and heart rate. For ethical reasons, the study included no placebo arm. The investigators enrolled 122 patients who had flu confirmed by polymerase chain reaction. Of these, 41 received 75 mg of oseltamivir twice daily, 41 received 200 mg of IV peramivir twice daily, and 40 received 400 mg of IV peramivir twice daily. "The time to clinical stability was 25.3 hours for all groups combined, with no statistically significant differences across treatment groups," Dr. William P. Sheridan, chief medical officer of Biocryst, reported.

Secondary outcomes for all groups included no mortality, no clinical relapse, a median of 4.0 days to hospital discharge, and a median of 10.8 days to resumption of normal activities. Sheridan said no significant differences in any of the efficacy end points were seen, which "was expected given the active control, small sample size, and exploratory phase 2 nature of this study."

In response to questions, he said the study was not designed to show differences between peramivir and oseltamivir. He said peramivir is important because it permits parenteral treatment of flu patients, adding, "At the ICAAC meeting the need for a parenteral drug for influenza has come up several times already. Also there's concern about resistance to existing drugs, including oseltamivir." Sheridan also said that the zero mortality in the study is "an important finding worthy of follow-up," given that a previous epidemiologic study showed a mortality rate of 10% in 219 patients who were not treated with neuraminidase inhibitors.

Dr. Michael Ison of Northwestern University, principal investigator in the study, said, "This landmark study provides us great insight into the course of treatment for patients who are hospitalized for influenza. The results indicate a potential role for antiviral therapy, which is critical as currently there are no antivirals approved for patients hospitalized for acute serious or potentially life-threatening influenza."
(CIDRAP 10/31/08)


Indonesia: Man dies, avian influenza H5N1 suspected
An Indonesian chicken butcher is alleged to have died of bird flu on 3 Nov 2008 after being treated in a hospital for two days. Director of Hasan Sadikin Hospital, Cissy Rachiana Prawira, said that the man suffered from breathing failure due to the pneumonia that had infected his lung. "We have sent a blood test this morning but have yet to receive the result of the test," she said.

Doctor Uun Sunardi said that the man had been declared as a suspect based on a thorax photo indicating his acute pneumonia. "He has [potential] to get infected by the disease [bird flu] as he works as a butcher," he said. The man's father said that his son had suffered from fever since 30 Oct 2008 and that he brought him to the Sartika Asih Hospital on 2 Nov 2008. "After taking a thorax picture, my son was referred to the Hasan Sadikin Hospital [that] night," he said.
(ProMED 11/4/08)


Laos: Avian influenza H5N1 outbreak in poultry
A bird flu outbreak has been confirmed in Donngeun village, Xayaboury district of Xayaboury province of Laos on 4 Nov 2008, by Xayaboury district governor Phompan Souththivohaneas.

The Xayaboury Provincial Avian Influenza Control Committee has declared a red zone, which covers areas within one kilometre radius of the outbreak. This area includes seven villages. All birds in these villages will be slaughtered to prevent the virus from spreading. The movement, consumption, and sale of birds throughout the district has been banned until further notice. This ban also includes products made with the blood of poultry.

A yellow zone will be established to include villages that are outside the red zone, but within 5 km of the outbreak. Villagers in the yellow zone will be advised to destroy birds at the first sign of illness, without waiting to have them tested for the virus.

Phompan said the district public health office was cooperating with the provincial public health department to monitor people's health, particularly those living in the red zone. Checkpoints have also been established throughout the district to prevent the movement of poultry. These checkpoints will remain in place for 45 days after the last case of the virus is identified.
(CIIDRAP 11/4/08, ProMED 11/6/08)


Thailand: Avian influenza H5N1 scare in Sukhothai
Livestock officials in Sukhothai Province reported the discovery of the H5N1 virus in domestic chickens raised in Nong Wong Kwian Village in Swankalok District.

Assistant Village Chief Jamnien Puengwang said that 29 families in the village raised a total of nearly 1000 chickens before a number of them began to die of suspicious causes. She said there were no reports of the deaths of the fowl as some villagers were worried that their fighting birds might be slaughtered due to bird-flu fears. After officials declared the discovery, all chickens in Sawankalok District were destroyed and their owners are to receive 32 baht (approx 0.90 USD) per kg for the killed birds. Sukhothai Governor Yothin Samutkheeree has urged all related agencies to keep a close eye on the probable viral spread, especially in the areas where H5N1 was once found. Locals have been asked to report any suspicious deaths of birds immediately.

During the months of August and September 2008, bird-flu virus was reportedly spreading in Sawankalok District before it was recently detected again in a nearby district.
(ProMED 11/1/08)


2. Updates
- UN: http://www.undp.org/mdtf/influenza/overview.shtml UNDP’s web site for information on fund management and administrative services and includes the website of the Central Fund for Influenza Action. This site also includes a list of useful links.
- WHO: http://www.who.int/csr/disease/avian_influenza/en/index.html The (interim) Influenza Virus Tracking System can be accessed at: www.who.int/fluvirus_tracker.
- UN FAO: http://www.fao.org/avianflu/en/index.html. View the latest avian influenza outbreak maps, upcoming events, and key documents on avian influenza.
- OIE: http://www.oie.int/eng/info_ev/en_AI_avianinfluenza.htm. Link to the Communication Portal gives latest facts, updates, timeline, and more.
- US CDC: Visit "Pandemic Influenza Preparedness Tools for Professionals" at: http://www.cdc.gov/flu/pandemic/preparednesstools.htm. This site contains resources to help hospital administrators and state and local health officials prepare for the next influenza pandemic.
- The US government’s website for pandemic/avian flu: http://www.pandemicflu.gov/. View archived Webcasts on influenza pandemic planning.
- CIDRAP: http://www.cidrap.umn.edu/ Find more than 150 peer-reviewed practices from 25 US states and 37 cities and counties aimed at furthering pandemic preparedness in public health and allied fields.
- PAHO: http://www.paho.org/English/AD/DPC/CD/influenza.htm Link to the Avian Influenza Portal at: http://influenza.bvsalud.org/php/index.php?lang=en. The Virtual Health Library’s Portal is a developing project for the operation of product networks and information services related to avian influenza.
- US National Wildlife Health Center: http://www.nwhc.usgs.gov/disease_information/avian_influenza/index.jsp Read about the latest news on H5N1 in wild birds and poultry.


3. Articles
WHO Weekly Epidemiological Record Bulletin
7 November 2008, vol. 83: 45; 401-412. Available at http://www.who.int/wer. Contents include: WHO external quality assessment project for the detection of subtype influenza A viruses by polymerase chain reaction—summary analysis, 2007 and 2008.


Incubation Period for Human Cases of Avian Influenza A (H5N1) Infection, China
Huai Y, Xiang N, Zhou L, Feng L, Peng Z, Chapman RS, et al. Emerg Infect Dis. November 7, 2008; 14(11). Available from http://www.cdc.gov/EID/content/14/11/1820.htm. (references removed, below)

To the Editor: Since 1997, more than 400 human cases of highly pathogenic influenza A virus (H5N1) infection have been reported worldwide, including 30 from mainland China. Ascertainment of the incubation period for influenza virus (H5N1) is important to define exposure periods for surveillance of patients with suspected influenza virus (H5N1) infection. Limited data on the incubation period suggest that illness onset occurs <7 days after the last exposure to sick or dead poultry. For clusters in which limited human-to-human virus transmission likely occurred, the incubation period appeared to be 3–5 days but was estimated to be 8–9 days in 1 cluster. In China, exposure to sick or dead poultry in rural areas and visiting a live poultry market in urban areas were identified as sources of influenza A virus (H5N1) exposures, but the incubation period after such exposures has not been well described. We conducted a retrospective descriptive study of 24 of 30 influenza virus (H5N1) cases in China to estimate and compare incubation periods for different exposure settings, including case-patients exposed only to sick or dead poultry versus those exposed only to a wet poultry market, where small animals and poultry may be purchased live or slaughtered.


Vaccination strategies and vaccine formulations for epidemic and pandemic influenza control
Joost HM., Kreijtz AD., Osterhaus M, and Rimmelzwaan G. March 2009 (early online release), 5(3). Available at http://www.landesbioscience.com/journals/vaccines/article/6986.

Influenza viruses of the H5N1 subtype cause an ever-increasing number of bird-to-human transmissions and a pandemic outbreak caused by these viruses is imminent. Therefore, the availability of safe and effective vaccines is highly desirable and their development considered a priority. However, using production and use of seasonal influenza vaccine as template for the production of pandemic H5N1 vaccines did not yield effective vaccines. High antigen doses were required to induce appreciable antibody responses. In addition, limited production capacity and long production times are other disadvantages of conventional influenza vaccine preparations. Here, we review recent developments that will contribute to a more rapid availability of sufficient doses of highly efficacious and safe pandemic influenza vaccines. The new developments include the establishment of novel methods to prepare vaccine strains, novel production technologies and the use of novel adjuvants and alternative vaccine formulations.


Vaccine Effectiveness Against Laboratory-Confirmed Influenza in Children 6 to 59 Months of Age During the 2003–2004 and 2004–2005 Influenza Seasons
Eisenberg, Katherine W et al. Pediatrics. November 5, 2008; 122(5): 911-919. Available at http://pediatrics.aappublications.org/cgi/content/abstract/122/5/911.

OBJECTIVE. The goal was to estimate the effectiveness of influenza vaccination against laboratory-confirmed influenza during the 2003–2004 and 2004–2005 influenza seasons in children 6 to 59 months of age. METHODS. We conducted a case-control study with children with medically attended, acute respiratory infections who received care in an inpatient, emergency department, or outpatient clinic setting during 2 consecutive influenza seasons. All children residing in Monroe County, New York, Davidson County, Tennessee, or Hamilton County, Ohio, were enrolled prospectively at the time of acute illness and had nasal/throat swabs tested for influenza with cultures and/or polymerase chain reaction assays. Children with laboratory-confirmed influenza were case subjects and children who tested negative for influenza were control subjects. Child vaccination records from the parent and the child's physician were used to determine and to validate influenza vaccination status. Influenza vaccine effectiveness was calculated as (1 – adjusted odds ratio) x 100. RESULTS. We enrolled 288 case subjects and 744 control subjects during the 2003–2004 season and 197 case subjects and 1305 control subjects during the 2004–2005 season. Six percent and 19% of all study children were fully vaccinated according to immunization guidelines in the respective seasons. Full vaccination was associated with significantly fewer influenza-related inpatient, emergency department, or outpatient clinic visits in 2004–2005 (vaccine effectiveness: 57%) but not in 2003–2004 (vaccine effectiveness: 44%). Partial vaccination was not effective in either season. CONCLUSIONS. Receipt of all recommended doses of influenza vaccine was associated with halving of laboratory-confirmed influenza-related medical visits among children 6 to 59 months of age in 1 of 2 study years, despite suboptimal matches between the vaccine and circulating influenza strains in both years.


Highly Pathogenic Avian Influenza Virus (H5N1) Infection in Red Foxes Fed Infected Bird Carcasses
Reperant LA et al. Emerg Infect Dis. December 2008 (early online release). Available at http://www.cdc.gov/eid/content/14/12/pdfs/08-0470.pdf.

Eating infected wild birds may put wild carnivores at high risk for infection with highly pathogenic avian influenza (HPAI) virus (H5N1). To determine whether red foxes (Vulpes vulpes) are susceptible to infection with HPAI virus (H5N1), we infected 3 foxes intratracheally. They excreted virus pharyngeally for 3–7 days at peak titers of 103.5–105.2 median tissue culture infective dose (TCID50) per mL; they became ill with severe pneumonia, myocarditis, and encephalitis. To determine whether foxes can become infected by the presumed natural route, we fed infected bird carcasses to 3 other red foxes. These foxes excreted virus pharyngeally for 3–5 days at peak titers of 104.2–104.5 TCID50/mL, but only mild or no pneumonia developed. This study demonstrates that red foxes fed bird carcasses infected with HPAI virus (H5N1) can excrete virus while remaining free of severe disease, thereby potentially playing a role in virus dispersal.


Influenza Infection in Wild Raccoons
Hall, Jeffrey S et al. Emerg Inf Dis. December 2008 (early online release). Available at http://www.cdc.gov/eid/content/14/12/pdfs/07-1371.pdf.

Raccoons (Procyon lotor) are common, widely distributed animals that frequently come into contact with wild waterfowl, agricultural operations, and humans. Serosurveys showed that raccoons are exposed to avian influenza virus. We found antibodies to a variety of influenza virus subtypes (H10N7, H4N6, H4N2, H3, and H1) with wide geographic variation in seroprevalence. Experimental infection studies showed that raccoons become infected with avian and human influenza A viruses, shed and transmit virus to virus-free animals, and seroconvert. Analyses of cellular receptors showed that raccoons have avian and human type receptors with a similar distribution as found in human respiratory tracts. The potential exists for co-infection of multiple subtypes of influenza virus with genetic reassortment and creation of novel strains of influenza virus. Experimental and field data indicate that raccoons may play an important role in influenza disease ecology and pose risks to agriculture and human health.


Neutrophils May Be a Vehicle for Viral Replication and Dissemination in Human H5N1 Avian Influenza
Yingying Zhao et al. Clinical Infectious Diseases. November 6, 2008. Available at http://www.journals.uchicago.edu/doi/abs/10.1086/593196.

The mechanism of systemic spread of H5N1 virus in patients with avian influenza is unknown. Here, H5N1 nucleoprotein and hemagglutinin were identified by immunohistochemistry in the nucleus and cytoplasm of neutrophils in the placental blood of a pregnant woman. Viral RNA was detected in neutrophils by in situ hybridization and enhanced real-time polymerase chain reaction. Therefore, neutrophils may serve as a vehicle for viral replication and transportation in avian influenza.


Safety and Immunogenicity of a Prepandemic Influenza A (H5N1) Vaccine in Children
Vajo, Zolton et al. Ped Infec Dis J. October 30, 2008.

Background: The avian influenza A (H5N1) virus is considered to be a potential cause of the next influenza pandemic. Children may be particularly vulnerable to the pandemic virus, and they may react differently than adults to vaccines. We report the results of the first clinical trial of an H5N1 vaccine in children. Methods: Twelve healthy children (mean age +/- SD: 12.73 +/- 2.77 years) received a single dose of 6 [mu]g of the inactivated whole virus vaccine Fluval. Twenty-one days after vaccination, immunogenicity was assessed by hemagglutination inhibition and microneutralization assays. Safety information was collected for 180 days. Results: No side-effects were observed, and the vaccine fulfilled all applicable U.S. and European immunogenicity criteria for licensure. The post/prevaccination geometric mean titer ratio was 16.95, the rate of seroconversion was 75% and the rate of seroprotection was also 75% 21 days after vaccination. Conclusions: We confirmed our earlier findings of the present vaccine in adults showing encouraging safety and immunogenicity properties in children. Studies with the present vaccine in elderly subjects are underway.


Would an Influenza Pandemic Qualify as a Major Disaster Under the Stafford Act?
CRS Report for Congress. October 20, 2008.

This report provides a legal analysis of the eligibility of an influenza pandemic (flu pandemic) to be declared by the President as a major disaster under the Robert T. Stafford Disaster Relief and Emergency Assistance Act. In 1997, the discovery of a virulent H5N1 strain of avian influenza (bird flu) raised the possibility of a flu pandemic occurring in the United States. In such an event, the Stafford Act could provide authority for federal assistance. Although it is widely agreed that emergency assistance under the Stafford Act could be provided by the President in the event of a flu pandemic, questions remain as to whether major disaster assistance would be available. An analysis of the Stafford Act suggests that this issue was not addressed by Congress when it drafted the current definition of a major disaster, and that neither inclusion nor exclusion of flu pandemics from major disaster assistance is explicitly required by the current statutory language. In the 109th Congress, § 210 of S. 3721 would have made any outbreak of infectious disease explicitly eligible for major disaster assistance, but it was not enacted. Complete report available http://www.fas.org/sgp/crs/misc/RL34724.pdf.


4. Notifications
The 7th International Bird Flu Summit
November 13-14, 2008
Monte Carlo Resort
Las Vegas, Nevada, USA

This summit is designed to help you understand the threats of avian flu pandemic in your country, as well as meet your planning requirements -on time, under budget, and with a minimum of disruption to your operations.

Confirmed speakers include:
1 H.E. Dimitris Avramopoulos, Ministry of Health and Social Solidarity of Greece
1 Hon. Dennis Wolff, Secretary, Pennsylvania Department of Agriculture
2 Jonathan Sleeman, VetMB, Dipl. ACZM, MRCVS, RCVS, Wildlife Veterinarian and President
3 Capt. Francis Doris, MSM,MMS,USN, US Homeland Defense Planning and Pandemic
4 Brit Oiulfstad, DVM, MPH, Director of Pandemic Influenza Planning

An updated full agenda and additional information is available on the event website at: http://www.new-fields.com/birdflu7/index.php.


International Meeting on Emerging Disease and Surveillance (IMED)
12-16 February 2009; Vienna, Austria

The abstract deadline for the International Meeting on Emerging Diseases and Surveillance (IMED 2009) is 1 Dec 2008. Accepted abstracts may be presented as posters during two dedicated poster sessions and selected abstracts will be presented in three platform sessions. Topics for abstracts at IMED 2009 include:

• Animal reservoirs for emerging pathogens
• Emerging zoonoses
• Emerging vectorborne diseases in humans and animals
• Models of disease surveillance, detection and reporting
• Outbreak control
• Surveillance using informal sources
• Syndromic surveillance
• Regional disease surveillance
• Laboratory surveillance
• New pathogen discovery
• Avian influenza
• Agents of bioterrorism
• Antibiotic resistance
• Climate change
• Vaccines against emerging diseases

IMED 2009 promises to bring together the public health community, scientists, health care workers, and other leaders in the field of emerging infectious diseases. The meeting will include poster presentations and oral presentations of submitted abstracts. Once again, this meeting will fully embrace "one health" and welcomes the full participation of both the human and veterinary health sectors. The conference will cover a wide range of emerging disease and surveillance issues including outbreak preparedness, prediction maps, climate change, emerging zoonoses, vaccines against emerging pathogens, and vectorborne diseases along with many other topics in an exciting three-day meeting. See the IMED 2009 http://imed.isid.org/ for additional details about the conference and information on submitting an abstract.


Risky Trade: Infectious Disease in the Era of Global Trade
Kimball, Ann Marie. Ashgate Press, Aldershot, UK, 2006.

Book Review
The linkages between facets of globalization and the emergence and recrudescence of infectious disease are a topic of increasing concern for providers of public health, international business concerns, economists, and political elites. Such interdisciplinary inquiry is rare, and sorely needed, at the dawn of the 21st century. Ann Marie Kimball’s book is a welcome addition to those few inquiries that cross the disciplines of epidemiology, economics, and political science. Jargon free, and well written, the book is an excellent analysis of the consequences of globalization upon public health and the consequences of disease for international trade and economic productivity. Full review available in Emerg Inf Dis. October 2008; 14(10). Available http://www.cdc.gov/eid/content/14/10/1678.htm.


Bellagio eHealth Call to Action website launch
Better Health for All Through Integrated, Person-Centered eHealth Systems

As representatives of governments, multilateral agencies, development partners, provider organizations, academic, research and public health institutions, standards development organizations, health care workers, entrepreneurs, information and communication technology experts from the public and private sectors and Global South populations, we assembled at the Making the eHealth Connection: Global Partnerships, Local Solutions conference and collaboratively drived a set of critical actions. We recognize that world citizens now face globalization, dynamic demographic changes, rapid urbanization, rampant spread of chronic and infectious diseases, and failing or limited health care systems. To achieve substantial progress on improving health care quality, access, affordability and efficiency nations must share and work toward a global eHealth vision. Additional information and resources available at the Call to Action http://www.ehealth-connection.org/wiki/index.php?title=Bellagio_eHealth_Call_to_Action.