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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