Will H5N6 Cause the Next Pandemic?

Influenza A(H5N6) is an emerging novel avian influenza that apparently derived from a reassortment of A(H5N1) with A(H6N6). H5N6 was first reported in domestic poultry in early 2014 from Laos, Vietnam, and China. Since then it has continued to be widely reported from domestic flocks in these countries (primarily China).

In April 2014, the first case of a human infected with the H5N6 influenza virus was reported from Sichuan Province in China. Since then, seven additional human cases have been reported, all from China. The most recent case was reported from Jieyang, Guangdong Province a few days ago. Of these eight cases, six have been reported by the World Health Organization (see links below).

Based on onset dates two of these cases occurred in 2014, four in 2015. Onset dates for the two most recent cases have not yet been reported. Among these cases are five males and three females. One of the females was pregnant. Her child was delivered by caesarian section and the woman is apparently still under treatment. Media reports indicate that the child was not infected.  Ages range from 25 to 50 years old. Five the eight have died according to media reports.

Discussion

To date, there is no evidence of human-to-human transmission among these eight cases of H5N6. The fatality rate is high, but there are too few cases to project a fatality rate for a larger population of infected individuals. It is not known if subclinical cases of H5N6 are occurring. No asymptomatic cases have been reported and there are no reports of seroprevelance studies of H5N6 among humans.

As shown in the map below, these eight cases from the past two years are widely scattered over China. The map also depicts the location of reported H5N6 outbreaks in poultry flocks in southern China and northern Laos. Like the distribution of human cases, domestic flocks infected with H5N6 are widely scattered across a large area. The wide-spread geographic distribution of infected poultry along with the dispersed nature of human infections in this area suggests that more human cases are likely to be reported in the future. With such a large animal reservoir this influenza virus could reassort and become more easily transmitted to humans. Were H5N6 to pick up the ability to transit easily among humans, H5N6 could become a deadly pandemic virus. 

Citations for Human Cases of H5N6

H5N6 influenza virus infection, the newest influenza (case 1)

Human infection with a novel, highly pathogenic avian influenza A (H5N6) virus: Virological and clinical findings (case 2 and 3)

Human Infection with a Novel Avian Influenza A(H5N6) Virus (case 4)

WHO Links

http://www.who.int/influenza/human_animal_interface/Influenza_Summary_IRA_HA_interface_October14.pdf (case 1)

http://www.who.int/csr/don/28-december-2014-avian-influenza/en/ (case 2)

http://www.who.int/csr/don/12-february-2015-avian-influenza/en/ (cases 3 and 4)

http://www.who.int/csr/don/14-july-2015-avian-influenza/en/ (case 5)

http://www.who.int/csr/don/4-january-2016-avian-influenza-china/en/ (case 6)
 

Other Selected H5N6 Citations

Reassortant Highly Pathogenic Influenza A(H5N6) Virus in Laos (May 2015)

Two novel reassortants of avian influenza A (H5N6) virus in China (May 2015)

Human H5N6 Influenza Virus Infection: New Disease Outbreak (August 2015)

Observations on H5N1 Bird Flu in 2015

No new human cases of human influenza A(H5N1) infections have been officially reported anywhere in the world since June 2015.[Note] This is a six-month period without reports of any new human cases. Since 2003 when the World Health Organization (WHO) first began reporting human cases of H5N1, the longest interval with no reported H5N1 cases was a span of three months. Three of these 3-month periods of quiescence have occurred, one each in 2004, 2008, and 2012. Is the lack of human H5N1 cases in the last six month a sign that H5N1 is no longer a pandemic threat? Can we breathe a sigh of relief?

Paradoxically, the answer is no. The lack of cases in the past six months should not lull us into a sense of complacency. Between January and June in 2015 there were a total of 143 human cases of H5N1 reported. This is the largest number of reported cases of H5N1 in any one year since the WHO started tracking human infections in 2003. The chart below shows the number of H5N1 cases reported by year since 2003.

1. H5N1 Cases by Year

Of the 143 human cases of H5N1 reported this year, almost all (136) were reported from Egypt. Five additional cases were reported from China and two from Indonesia. The number of cases reported from Egypt this year is ominous. Between 2006 and 2014, Egypt averaged about 3 H5N1 cases per month in January, February, and March. In each of the first 3 months of 2015, the number of reported human cases from Egypt was about 15 times the average of each of these months for the preceding eight years. An epidemic curve for H5N1 cases in Egypt in 2015 is presented below.

2. Egypt Epi Curve 2015

In 2014, Egypt eclipsed Indonesia as the country with the most reported H5N1 cases. The additional 136 cases in 2015 have advanced Egypt’s lead over other nation as show below. The graph depicts the extent of increase reported in 2015. As of 2015, almost 41% of all worldwide cases of H5N1 have been reported from Egypt.

3. H5N1 Case Counts by Country

Age Categories

Almost half of the reported H5N1 cases in 2015 are under 20 years of age. Since 2003, children and adolescents have been disproportionately stricken with H5N1. Pediatric cases (defined here as cases under 20 years of age) represent about 50% of all reported human H5N1 cases. The chart below shows that children from birth to about 6 years old are at greatest risk of contracting an H5N1 infection.

4. H5N1 Pediatric Cases

In 2015, the average age of infection is 23.1 years with a standard deviation of 18.5 years. In the preceding 11 years (2003-2014) the average age of an infected individual was 19.3 years with a standard deviation of 14.7 years. This is a significant difference in the age distribution of H5N1 cases in 2015 compared with earlier years. The chart below shows that a greater-than-average number of H5N1 infections in 2015 occurred in the 30- and 40-year-old age cohorts. The implications of this variability are not clear. Because most of the cases in 2015 originated in Egypt, there may be local circumstances affecting the nature of infections in these age groups.

5. H5N1 Age Cohorts

Gender

Since 2003 females represents about 53% of all H5N1 cases. Among the H5N1 cases in 2015, females again outnumber males at 59% to 41%. Among all the reported pediatric cases (see above), males and females are equally likely to be infected by H5N1.

H5N1 Clusters

It is acknowledged that primary human H5N1 infections result from zoonotic transmission of the virus from primarily domestic poultry. Little information is publicly available on H5N1 clusters in 2015 that could shed light on the potential for human-to-human transmission of the virus. Based on the geographic distribution of cases in 2015 there were a number of geographic clusters and at least two family clusters of H5N1 involving parents and offspring in 2015.

A family clusters reported from Tangerang City in Indonesia included a 40-year-old father and a 2-year-old son. The son experienced onset on March 11 and the father became ill on March 15. Both of these individuals died.

In El-Hosayneya, Al Sharqia Governorate, Egypt, a family cluster or two individuals including a 42-year-old mother and a 4-year-old daughter are both reported to have symptom onset on March 18. The outcome of these two individuals is unknown.

The other suspected geographic clusters in 2015 all occurred in Egypt. A tentative list is provided below.

1. Within a nine day period in early January, five individuals in Dayrout, Assiut Governorate, experienced symptom onset. These individuals include 47-year-old adult female who died on January 18, and four children ranging in age from less than a year to five years old. Two of the children died.

2. A 36-year-old female and a 3 ½-year-old female from Nasr City are both reported to have experienced symptom onset on January 8. The adult died on January 20.

3. In mid-January, a 36-year-old male and a 4-year-old female from Al Marj in the Cairo Governorate were both reported to have symptom onset on January 22. Both individuals apparently recovered.

4. In Helwan, a 42 year-old male experienced symptoms onset on February 3. Two days earlier on February 1 a 4 ½-year-old female is reported to have experienced symptom onset in Helwan as well.

5. Two individuals from Al Matariyyah were reported infected. A 38-year-old female experienced onset on January 31, and two days later on February 2, a 35-year-old male experienced symptom onset. The male died on February 12.

6. In early February, three H5N1 cases were reported from Banha, Al Qalyubiyah; a 3-year-old male, a 3 ½-year-old female, and a 38-year-old male, with onset dates respectively of January 26, February 5, and February 7.

7. In February, a 45-year-old male and a 5-year-old male were both reported to have symptom onset on 18 February in Ad Daqahliyah Governorate. The child recovered but the adult male died on February 23.

8. Two children, a 2 ½-year-old male and a 3-year-old female, were reported H5N1cases from Itsa in Fayyoum Governorate, both with an onset date of June 12.

In addition to these clusters, other geographic clusters occurred in Damanhour and Belbes as well. Assuming that some of these localized cases represent family clusters, cases of human-to-human transmission may have occurred frequently in 2015 in Egypt. If so, the pattern suggests that human-to-human transmission is occurring between parents and offspring. The map below shows the geographic distribution of human H5N1 cases in Egypt in 2015.

6. Geolocations of H5N1 Cases Egypt 2015

H5N1 Fatalities in 2015

For the H5N1 cases reported between 2003 and 2014 the over-all case fatality risk (CFR) is about .58 (based on cases with outcome reported). Information on the outcome of H5N1 infected individuals in 2015 is lacking for almost 50% of the cases. However, for a worst-case scenario the CFR could be .74 for the 2015 cases. Almost all of the cases with unreported outcome were from Egypt.

Discussion

Even though there was a large increase in human H5N1 infections in early 2015 the WHO has not changed it risk outlook stating that “Whenever avian influenza viruses are circulating in poultry, sporadic infections and small clusters of human cases are possible in people exposed to infected poultry or contaminated environments, therefore sporadic human cases would not be unexpected.”

Because primary human infections of H5N1 are almost exclusively linked to zoonotic infection from domestic poultry, poultry outbreak of H5N1 can foreshadow human infections. Although no additional human cases of H5N1 have been reported since June, highly pathogenic avian influenza (HPAI) H5N1 continues to infect domestic poultry flocks around the world. Since June 2015, more than 100 locales have reported HPAI H5N1 infections in domestic poultry flocks (see map below).  Any of these could have resulted in more primary human cases of H5N1, as could future HPAI H5N1 outbreaks. The concern remains that sporadic or small clusters of human cases could give rise to more efficient human-to-human H5N1 transmission leading to an H5N1 epidemic or even a pandemic.

7. HPAI H5N1 Outbreaks Last Half of 2015

Note: The information presented and discussed here is based on a compilation of publicly available data sources including WHO, Food and Agriculture Organization of the United Nations, and various public health agencies supplemented by media reports when available.

updated Dec 21, 2015

Case Details from the Current MERS Outbreak in Riyadh Saudi Arabia, August 2015

The current outbreak in Riyadh started mid-July when a 56-year-old man became infected with Middle East Respiratory Syndrome coronavirus (MERS). This individual had frequent contacts with camels and consumed raw camel milk. This man infected his 52-year-old wife, his 53-year-old brother, and 30-year old son. The index case and his wife are reported to have died.

Almost 120 cases have been confirmed during this MERS outbreak in Riyadh through August 28, 2015.  As in other MERS outbreaks, more males then females are infected, about 61%. The males range in age from 2-109 years old with a median age of 61. The females range in age from 25 to 98 with a median age of 58.

The fatality rate for this outbreak is about 25%, with similar death percentages for both males and females. However the fatality statistics could change because the Saudi Arabia Ministry of Health is reporting that there are at least 50 cases still under treatment.

In this outbreak, most of the infections had been contracted by either visiting or being treated in a hospital with current MERS patients. A few cases are reported to have contact with confirmed MERS patients possibly outside of a healthcare setting. Information on family clusters is not available. It is difficult to assess the extent of family clusters, since that information is not generally available. 

Besides the initial family cluster in this outbreak, one other possible family cluster can be proposed from the data. A 56-year-old female experienced symptom onset on August 7, with her death reported on August 17. The World Health Organization reports that a 28-year-old female had contact with this woman and became symptomatic on August 12. A third individual, a two-year-old boy, also had contact with this woman and became symptomatic on August 12 as well. The boy is reported by the Saudi Arabia Ministry of Health to have recovered. Speculating, this cluster would seem to be a result of a daughter and a grandson interacting with the 56-year-old grandparent.

Healthcare workers represent about 11% of all infected individuals in this current outbreak.  This is similar to the overall percentage of healthcare workers infected with MERS in Riyadh since 2012. About 10% of all of MERS cases reported from Riyadh since 2012 were healthcare workers.

The epidemiological similarities among various MERS outbreaks should begin to provide a framework for understanding and controlling this disease in the future.

The Status of the Current MERS Outbreak in Riyadh, Saudi Arabia

Middle East Respiratory Syndrome (MERS) outbreaks associated with nosocomial infection and human-to-human transmission have been routinely documented since the first cases were first reported in 2012. At least 11 major MERS outbreaks have occurred since then, including the current outbreak in Riyadh, Saudi Arabia.

All the major MERS outbreaks have occurred on the Arabian Peninsula with the exception of a recent outbreak in the Republic of Korea between May and June, 2015 where more than 180 cases could be traced back to a single index case infected on the Arabian Peninsula. With the exception of data from the Republic of Korea outbreak, detailed information is limited on the MERS outbreaks on the Arabian Peninsula.

One or possibly two separate outbreak in the United Arab Emirates included as many as 40 cases between April and May 2014 from Abu Dhabi and Al Ain. All of the remaining major outbreaks from the Arabian Peninsula occurred in Saudi Arabia.

Chronologically, the first major outbreak in Saudi Arabia occurred at Al Hofuf between April and May of 2013 with about 20 cases. Shortly thereafter, another outbreak started in Riyadh in July 2013 and continued for several months. Perhaps as many as 45 individuals were infected in this outbreak. Riyadh again experienced another outbreak with more than 140 cases between February and May of 2014. About this same time, from March through April 2014, more than 200 individuals were reported from a MERS outbreak in Jeddah. Between April and May 2014, separate outbreaks were reported from both Mecca and Madinah with about 30 cases each. Between October and December 2014, Taif experienced a MERS outbreak with at least 25 individuals.

In early 2015 between January and March, an outbreak including at least 60 cases was reported from Riyadh. Between April and June 2015, a MERS outbreak in Al Hofuf resulted in about 40 human infections. Riyadh began experiencing the latest MERS outbreak in July 2015 which is still continuing.

The Riyadh region has experienced the greatest concentration of MERS cases in the world. Since October 2012, there have been 4-5 separate MERS outbreaks among the more than 400 publicly reported cases from Riyadh (see chart). Many of these cases are a result of human-to-human transmission.

These outbreaks are similar in nature. Some infections results from contact with confirmed cases or occurred in a health setting. These outbreaks also included infected healthcare workers.

Based on reports by the Saudi Arabia Ministry of Health and the World Health Organization (WHO), the index case for the current outbreak in Riyadh appears to a 56-year-old male who experienced onset on July 13. He is reported to have frequent contact with camels and consumed raw camel milk. Shortly thereafter, several of his family members, including his wife and son became infected. As this outbreak grew, hospitalized individuals being treated in the same facility as confirmed patients would become infected. Other individuals became infected after seeking treatment for unrelated medical conditions or visiting healthcare facilities where existing MERS cases were being treated. A number of cases trace their infection back to contact with confirmed cases. The distinctive feature of these outbreaks is that they are associated with healthcare facilities where healthcare workers are routinely reported to be infected. Infected healthcare workers are a clear signal of human-to-human transmission during an outbreak.

Through August 28, 2015, more than 110 individuals have been infected with MERS in Riyadh during this outbreak. An epi curve (see below) of the current MERS cases from Riyadh suggests that the outbreak is being contained. The graph compares a 4-day moving average of the number of daily cases reported from Riyadh by the Saudi Arabia Ministry of Health with the 4-day moving average of the distribution of onset dates (posted by WHO) for the reported cases. Because onset dates are not reported by the Saudi Arabia Ministry of health there is a time lag between the initial posting of the cases, and the reporting of onset dates. The declining trend in the number of cases being reported from Riyadh by the Saudi Arabia Ministry of Health suggests this outbreak is being contained and may be over shortly.