Avian Influenza A (H5N1) Age Distribution in Humans

Abstract

To the Editor: A total of 229 confirmed human cases of avian influenza A (H5N1) were reported to the World Health Organization (WHO) from 10 countries of Africa, Asia, and Europe in the 30 months leading up to July 4, 2006 (1). WHO has highlighted the skewed age distribution of these confirmed cases toward children and young adults, with relatively few cases in older age categories (2). An explanation for this age bias is currently lacking, although a range of behavioral, biological, demographic, and data-related factors may account for the observed pattern (2,3).To determine whether the statistical parameters of the case distribution can shed any light on the issue, we reviewed the age profile of patients with confirmed avian influenza A (H5N1) included in WHO’s Situation Updates—Avian Influenza archive (January 13, 2004-May 18, 2006) (4). We supplemented our review with case information from an additional WHO source (5); to allow for the age structure of reporting countries, we accessed age-specific population estimates for 2005 from the Population Division of the United Nations Secretariat (6).For the period under review, age-related information was available for 169 case-patients with WHO-confirmed human avian influenza A (H5N1) in 10 countries. Information for an additional 47 confirmed case-patients, reported to WHO from Vietnam (n = 39) and Turkey (n = 8), could not be ascertained from the published sources. The mean age of the 169 sample case-patients (77 males and 92 females) was 19.8 years (median 18.0; range 0.3-75.0). Age distribution was as follows: 0-9 years, 26.0%; 10-19 years, 29.0%; 20-29 years, 23.1%; 30-39 years, 16.0%; and ≥40 years, 5.9%. Estimated age-specific case rates per million population were 0.15 (0-9 years), 0.15 (10-19 years), 0.13 (20-29 years), 0.08 (30-39 years), and 0.02 (≥40 years).Box-and-whisker plots (7) (Figure) illustrate the skewed nature of the age distribution of cases by sex (A), year of report (B), and patient outcome (C); the third quartiles of the distributions (Q3, defined by the box tops) demarcate an age band (30-35 years) above which proportionally few cases (Age distribution of patients with confirmed cases of avian influenza (H5N1), December 2003-May 2006 (4,5). Box-and-whisker plots show the age distribution of patients by A) sex; B) year of report, C) patient outcome, and D) country. The horizontal line ...Subject to multiple selection biases in the identification and reporting of WHO-confirmed human cases of avian influenza A (H5N1) (2), our analysis yields 3 noteworthy observations: 1) case counts and case rates suggest similar levels of disease activity in the age categories 0-9, 10-19, and 20-29 years; 2) few cases have occurred above the age band of 30-35 years; and 3) the skewed distribution of cases toward children and young adults transcends sex, reporting period, patient outcome, geographic location, and, by implication, local cultural and demographic determinants.Behavioral factors increase the risk for exposure in younger persons and have been proposed as 1 determinant of the age distribution of confirmed human cases of avian influenza A (H5N1) (2). However, the possible role of biologic (immunologic and genetic) and other factors has yet to be determined (3). Such factors may include an age-related bias in case recognition, in which clinical suspicion about the cause of respiratory disease in older persons is lower. Alternatively, we suggest that the 3 observations listed above are consistent with a biological model of geographically widespread immunity to avian influenza A (H5N1) in persons born before 1969, i.e., ≈35 years before the onset of the currently recognized panzootic in domestic poultry. Such a model would account for the similar rates of disease activity in younger age categories, the sudden and pronounced reduction of cases in patients >30-35 years of age, and the age skew that transcends the sociocultural and demographic contexts of countries and continents.The results of broad serologic surveys for antibodies to influenza A (H5N1) virus, suggestive of a cohort effect or otherwise, have yet to be published, although anecdotal reports of completed surveys point to a lack of widespread human infection with the virus (8). Current evidence indicates that pandemic influenza of humans since 1918 has been restricted to 3 influenza A virus subtypes: H1 (1918-57 and 1977-present); H2 (1957-68); and H3 (1968-present) (9,10). If an element of immunity to avian influenza A (H5N1) does exist in older populations, its possible association with geographically widespread (intercontinental) influenza A events before the late 1960s merits further investigation.

Full text

LETTERS
structural protein 4 gene. First-round
primers were AlphaF1 (GenBank
accession no. NC004162, nt
6942–6961, 5′-CSATGATGAARTC
HGGHATG-3′) and AlphaR (nt
7121–7141, 5′-CTATTTAGGACCRC
CGTASAG-3′). Second-round primers
were AlphaF2 (nt 7480–7501) (5′-
TGGNTBAAYATGGAGGTIAAG-
3′) and AlphaR. Sequencing of the
second-round product identified the
virus. A 339-bp fragment (GenBank
accession no. DQ678928) had 97%
identity with the African prototype
strain S27 isolated in Tanzania
(Tanganyika) in 1953 (AF369024) and
100% identity with viral sequences
from Reunion Island in 2006
(DQ443544).
Knowledge of distant epidemics
aids clinical recognition of infections
not commonly seen in Australia.
Websites and electronic bulletins
(e.g., Promed) are a conduit of infor-
mation. On the basis of this case-
patient, those in Australia became
more aware of the chikungunya virus
epidemics affecting the islands of the
southwestern Indian Ocean.
Laboratory diagnosis of chikun-
gunya virus infection is usually sero-
logic. However, alphavirus infections
not endemic to Australia are unlikely
to be diagnosed serologically because
specific assays are generally available
only for those viruses known to circu-
late in Australia. Because viremia of
alphaviruses is brief, success of RT-
PCR depends on early admission and
clinical recognition of infection (6).
Rapid establishment of a defini-
tive diagnosis had substantial benefits
that included management of the
febrile patient, reduced need for fur-
ther investigations, and better progno-
sis. Infection caused by an introduced
arbovirus may have important public
health implications in Australia.
Because immunity in the Australian
population is unlikely, consideration
must be given to the potential for
transmission of the virus to caregivers
and the local community. chikungun-
ya virus is commonly spread by mos-
quitoes of the genera Aedes, including
Aedes aegypti, Ae. furcifer-taylori,
Ae. luteocephalus, Ae. albopictus, and
Ae. dalzieli (7). The Australian Ross
River and Barmah Forest alphaviruses
are spread by many species of Aedes
and Culex (8). Because some local
species could transmit chikungunya
virus, necessary steps should be taken
to ensure containment when a patient
is viremic.
This case highlights the potential
for exotic viruses to be introduced
into Australia by visitors or returning
travelers and the utility of molecular
testing for their rapid detection. The
generic nature of the RT-PCR enabled
detection of an alphavirus with subse-
quent specific identification by
sequencing. Rapid identification and
differentiation in a public health set-
ting minimized the potential for
spread of the virus.
Julian D. Druce,*
Douglas F. Johnson,†
Thomas Tran,*
Michael J. Richards,†
and Christopher J. Birch*
*Victorian Infectious Diseases Reference
Laboratory, North Melbourne, Victoria,
Australia; and †Royal Melbourne Hospital,
Parkville, Melbourne, Victoria, Australia
References
1. Schuffenecker I, Iteman I, Michault A,
Murri S, Frangeul L, Vaney MC, et al.
Genome microevolution of Chikungunya
viruses causing the Indian Ocean outbreak.
PLoS Med. 2006;3:e263.
2. Chikungunya – Indian Ocean update (11):
islands, India. Archive no. 20060330.0961.
2006 Mar 30. [cited 2006 Dec 13].
Available from www.promedmail.org
3. Chikungunya – China (Hong Kong) ex
Mauritius: conf. Archive no. 20060402.
0989. 2006 Apr 2. [cited 2006 Dec 13].
Available from www.promedmail.org
4. Chikungunya – Indian Ocean update (17):
spread to France. Archive no. 20060421.
1166. 2006 Apr 21. [cited 2006 Dec 13].
Available from www.promedmail.org
5. Harnett GB, Bucens MR. Isolation of
Chikungunya virus in Australia. Med J
Aust. 1990;152:328–9.
6. Sellner LN, Coelen RJ, Mackenzie JS.
Detection of Ross River virus in clinical
samples using a nested reverse transcrip-
tion-polymerase chain reaction. Clin Diagn
Virol. 1995;4:257–67.
7. Diallo M, Thonnon J, Traore-Lamizana M,
Fontenille D. Vectors of Chikungunya virus
in Senegal: current data and transmission
cycles. Am J Trop Med Hyg.
1999;60:281–6.
8. Dale PE, Ritchie SA, Territo BM, Morris
CD, Muhar A, Kay BH. An overview of
remote sensing and GIS for surveillance of
mosquito habitats and risk assessment. J
Vector Ecol. 1998;23:54–61.
Address for correspondence: Julian D. Druce,
Victorian Infectious Diseases Reference
Laboratory, 10 Wreckyn St, North Melbourne,
Victoria 3051, Australia, email: julian.druce@
mh.org.au
Avian Influenza A
(H5N1) Age
Distribution in
Humans
To the Editor: A total of 229
confirmed human cases of avian
influenza A (H5N1) were reported to
the World Health Organization
(WHO) from 10 countries of Africa,
Asia, and Europe in the 30 months
leading up to July 4, 2006 (1). WHO
has highlighted the skewed age distri-
bution of these confirmed cases
toward children and young adults,
with relatively few cases in older age
categories (2). An explanation for this
age bias is currently lacking,
although a range of behavioral, bio-
logical, demographic, and data-relat-
ed factors may account for the
observed pattern (2,3).
To determine whether the statisti-
cal parameters of the case distribution
can shed any light on the issue, we
reviewed the age profile of patients
with confirmed avian influenza A
510 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 13, No. 3, March 2007

LETTERS
(H5N1) included in WHO’s Situation
Updates—Avian Influenza archive
(January 13, 2004–May 18, 2006) (4).
We supplemented our review with
case information from an additional
WHO source (5); to allow for the age
structure of reporting countries, we
accessed age-specific population esti-
mates for 2005 from the Population
Division of the United Nations
Secretariat (6).
For the period under review, age-
related information was available for
169 case-patients with WHO-con-
firmed human avian influenza A
(H5N1) in 10 countries. Information
for an additional 47 confirmed case-
patients, reported to WHO from
Vietnam (n = 39) and Turkey (n = 8),
could not be ascertained from the pub-
lished sources. The mean age of the
169 sample case-patients (77 males
and 92 females) was 19.8 years
(median 18.0; range 0.3–75.0). Age
distribution was as follows: 0–9 years,
26.0%; 10–19 years, 29.0%; 20–29
years, 23.1%; 30–39 years, 16.0%;
and ≥40 years, 5.9%. Estimated age-
specific case rates per million popula-
tion were 0.15 (0–9 years), 0.15
(10–19 years), 0.13 (20–29 years),
0.08 (30–39 years), and 0.02 (≥40
years).
Box-and-whisker plots (7)
(Figure) illustrate the skewed nature
of the age distribution of cases by sex
(A), year of report (B), and patient
outcome (C); the third quartiles of the
distributions (Q
3
, defined by the box
tops) demarcate an age band (30–35
years) above which proportionally
few cases (<10%) occurred. The
country-level analysis in plot D
yields similar findings, although
interpretation is limited by the small
numbers of cases (<10) in some
countries (Azerbaijan, Cambodia,
Djibouti, Iraq, and Turkey).
Examination of case-patients in the
30- to 39-year age category showed a
pronounced “front-loading” effect,
with 21 case-patients 30–35 years of
age and only 6 case-patients 36–39
years of age.
Subject to multiple selection
biases in the identification and report-
ing of WHO-confirmed human cases
of avian influenza A (H5N1) (2), our
analysis yields 3 noteworthy observa-
tions: 1) case counts and case rates
suggest similar levels of disease activ-
ity in the age categories 0–9, 10–19,
and 20–29 years; 2) few cases have
occurred above the age band of 30–35
years; and 3) the skewed distribution
of cases toward children and young
adults transcends sex, reporting peri-
od, patient outcome, geographic loca-
tion, and, by implication, local cultur-
al and demographic determinants.
Behavioral factors increase the
risk for exposure in younger persons
and have been proposed as 1 determi-
nant of the age distribution of con-
firmed human cases of avian influen-
za A (H5N1) (2). However, the possi-
ble role of biologic (immunologic and
genetic) and other factors has yet to be
determined (3). Such factors may
include an age-related bias in case
recognition, in which clinical suspi-
cion about the cause of respiratory
disease in older persons is lower.
Alternatively, we suggest that the 3
observations listed above are consis-
tent with a biological model of geo-
graphically widespread immunity to
avian influenza A (H5N1) in persons
born before 1969, i.e., ≈35 years
before the onset of the currently rec-
ognized panzootic in domestic poul-
try. Such a model would account for
the similar rates of disease activity in
younger age categories, the sudden
and pronounced reduction of cases in
patients >30–35 years of age, and the
age skew that transcends the sociocul-
tural and demographic contexts of
countries and continents.
The results of broad serologic
surveys for antibodies to influenza A
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 13, No. 3, March 2007 511
Figure. Age distribution of patients with confirmed cases of avian influenza (H5N1),
December 2003–May 2006 (4,5). Box-and-whisker plots show the age distribution of
patients by A) sex; B) year of report, C) patient outcome, and D) country. The horizontal
line and bullet mark in each box give the median and mean age of cases, respectively.
Variability in age is shown by plotting the first and third quartiles (Q
1
and Q
3
) of the ages
as the outer limits of the shaded box. Whiskers encompass all ages that satisfy the crite-
ria Q
1
– 1.5(Q
3
– Q
1
) (lower limit) and Q
3
+ 1.5(Q
3
– Q
1
) (upper limit). Points beyond the
whiskers denote outliers. Panel C data are based on the recorded status of patients
according to World Health Organization sources, with the category “alive” formed to
include patients who were last reported as hospitalized or discharged. The age band
30–35 years is marked on each graph for reference.

LETTERS
(H5N1) virus, suggestive of a cohort
effect or otherwise, have yet to be
published, although anecdotal reports
of completed surveys point to a lack
of widespread human infection with
the virus (8). Current evidence indi-
cates that pandemic influenza of
humans since 1918 has been restricted
to 3 influenza A virus subtypes: H1
(1918–57 and 1977–present); H2
(1957–68); and H3 (1968–present)
(9,10). If an element of immunity to
avian influenza A (H5N1) does exist
in older populations, its possible asso-
ciation with geographically wide-
spread (intercontinental) influenza A
events before the late 1960s merits
further investigation.
The work described has been under-
taken as part of a program of research
entitled Historical Geography of
Emerging and Re-Emerging Epidemics,
1850–2000, funded by the History of
Medicine Committee of the Wellcome
Trust.
Matthew Smallman-Raynor*
and Andrew D. Cliff†
*University of Nottingham, Nottingham,
England; and †University of Cambridge,
Cambridge, England
References
1. World Health Organization. Cumulative
number of confirmed human cases of avian
influenza A (H5N1) reported to WHO: 4
July 2006. Geneva: The Organization;
2006. Available from http://www.who.
int/csr/disease/avian_influenza/country/en/
index.html
2. World Health Organization. Epidemiology
of WHO-confirmed human cases of avian
influenza A (H5N1) infection. Wkly
Epidemiol Rec. 2006;81:249–57.
3. World Health Organization. Avian influen-
za fact sheet (April 2006). Wkly Epidemiol
Rec. 2006;81:129–36.
4. World Health Organization. Situation
updates–avian influenza. Geneva: The
Organization; 2004–6. Available from
http://www.who.int/csr/disease/avian_influ
enza
5. World Health Organization. Avian influen-
za: assessing the pandemic threat. Geneva:
The Organization; 2005.
6. Population Division of the Department of
Economic and Social Affairs of the United
Nations Secretariat. World population
prospects: the 2004 revision; and world
urbanization prospects: the 2003 revision.
New York: United Nations; 2006. Available
from http://esa.un.org/unpp
7. Tukey JW. Exploratory data analysis.
Reading (MA): Addison-Wesley; 1977.
8. Enserink M. Avian influenza: amid may-
hem in Turkey, experts see new chances for
research. Science. 2006;311:314–5.
9. Dowdle WR. Influenza A virus recycling
revisited. Bull World Health Organ.
1999;77:820–8.
10. Hilleman MR. Realities and enigmas of
human viral influenza: pathogenesis, epi-
demiology and control. Vaccine.
2002;20:3068–87.
Address for correspondence: Matthew
Smallman-Raynor, School of Geography,
University of Nottingham, University Park,
Nottingham, NG7 2RD, England; email:
matthew.smallman-raynor@nottingham.ac.uk
Toxoplasma gondii,
Brazil
To the Editor: Recently, Jones et
al. reported that past pregnancies
increased risk for recent Toxoplasma
gondii infection in Brazil (1). They
did not, however, control for age.
Previous seroepidemiologic studies
have shown that age is a main con-
founding variable in analysis of risk
factors for toxoplasmosis (2). Age can
explain why mothers with more chil-
dren are at higher risk for toxoplasmo-
sis; the longer persons live in areas
with high toxoplasmosis prevalence,
the higher their risk for infection.
Also not explored were drinking
water–related factors. Our recent
study of pregnant women in Quindio,
Colombia, found factors that
explained attributable risk percent for
infection to be eating rare meat
(0.26%) and having contact with a cat
<6 months of age (0.19%) (3).
Drinking bottled water was more sig-
nificantly protective for the group that
did not consume undercooked or raw
meat (odds ratio 0.06, 95% confi-
dence interval 0.006–0.560, p =
0.008). We think that drinking
water–related factors could explain up
to 50% of toxoplasmosis infections in
our region.
Jorge Gomez-Marin*
*Universidad del Quindio, Armenia,
Quindio, Colombia
References
1. Jones JL, Muccioli C, Belfort R Jr,
Holland GN, Roberts JM, Silveira C.
Recently acquired Toxoplasma gondii
infection, Brazil. Emerg Infect Dis.
2006;12:582–6.
2. Juliao O, Corredor A, Moreno GS.
National study of health: toxoplasmosis in
Colombia, Ministry of Health [in
Spanish]. Bogota: National Institute of
Health Press; 1988.
3. Lopez-Castillo CA, Diaz-Ramirez J,
Gomez-Marín JE. Risk factors for
Toxoplasma gondii infection in pregnant
women in Armenia, Colombia [in
Spanish]. Rev Salud Publica (Bogota).
2005;7:180–90.
Address for correspondence: Jorge Gomez-
Marin, Universidad del Quindio, Centro de
Investigaciones Biomedicas, Av Bolivar 12N
Armenia 00, Quindio, Colombia; email:
jegomezmarin@hotmail.com
In response: We thank Dr
Gomez-Marin for his letter regarding
our article on recently acquired
Toxoplasma gondii infection in Brazil
(1). Dr Gomez-Marin states that per-
haps age could account for our finding
that having had children was a risk
factor for recent T. gondii infection
among women. Studies have shown
that age is a risk factor for prevalent T.
gondii infection; i.e., infection preva-
lence increases with age (2).
However, age is not necessarily a risk
factor for recent (incident) infection.
512 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 13, No. 3, March 2007