International Journal of Infectious Diseases 16 (2012) e714–e723

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International Journal of Infectious Diseases

journal homepage: www.elsevier.com/locate/ijid

Review

A review on the clinical spectrum and natural history of human influenza

Warunee Punpanich a,b,*, Tawee Chotpitayasunondh a,c
a
Department of Pediatrics, Queen Sirikit National Institute of Child Health, Bangkok 10400, Thailand
b
College of Medicine, Rangsit University, Bangkok, Thailand
c
Department of Medical Services, Ministry of Public Health, Thailand

A R T I C L E I N F O S U M M A R Y

Article history: Objectives: The objective of this review is to provide updated information on the clinical spectrum and
Received 3 January 2012 natural history of human influenza, including risk factors for severe disease, and to identify the
Accepted 14 May 2012 knowledge gap in this area.
Corresponding Editor: William Cameron, Methods: We searched the MEDLINE database of the recent literature for the period January 2009 to
Ottawa, Canada August 17, 2011 with regard to the abovementioned aspects of human influenza, focusing on
A(H1N1)pdm09 and seasonal influenza.
Keywords: Results: The clinical spectrum and outcomes of cases of A(H1N1)pdm09 influenza have been mild and
Human influenza rather indistinguishable from those of seasonal influenza. Sporadic cases covering a wide range of
Clinical spectrum neurological complications have been reported. Underlying predisposing conditions considered to be
Natural history high-risk for A(H1N1)pdm09 infections are generally similar to those of seasonal influenza, but with two
Risk factors
additional risk groups: pregnant women and the morbidly obese. Co-infections with bacteria and D222/
Prognostic factors
N variants or 225G substitution of the viral genome have also been reported to be significant factors
associated with the severity of disease. The current knowledge gap includes: (1) a lack of clarification
regarding the relatively greater severity of the Mexican A(H1N1)pdm09 influenza outbreak in the early
phase of the pandemic; (2) insufficient data on the clinical impact, risk factors, and outcomes of human
infections caused by resistant strains of influenza; and (3) insufficient data from less developed countries
that would enable them to prioritize strategies for influenza prevention and control.
Conclusions: Clinical features and risk factors of A(H1N1)pdm09 are comparable to those of seasonal
influenza. Emerging risk factors for severe disease with A(H1N1)pdm09 include morbid obesity,
pregnancy, bacterial co-infections, and D222/N variants or 225G substitution of the viral genome.
ß 2012 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

1. Introduction 2. Methods

The pandemic influenza A (H1N1) 2009 virus, or
A(H1N1)pdm09, was first identified in humans in April 2009 in
the southern part of the USA. It was quickly established that the
disease was spreading rapidly from person to person and had been
causing widespread disease in Mexico since early March. On June
11, 2009, the World Health Organization (WHO) declared that a
global pandemic of novel influenza A (H1N1) was underway, as the
transmission had been documented in more than 70 countries.
This review was conducted to focus on the clinical spectrum
and natural history of human disease and the risk factors and
prognostic markers of severe disease for A(H1N1)pdm09 and
seasonal influenza. The relevant literature published from January
2009 to August 17, 2011 (the date of the last keyword search of the
electronic database) is included.
* Corresponding author. Tel./fax: +662 354 8345.
E-mail address: waruneep@gmail.com (W. Punpanich).
We searched the National Library of Medicine through PubMed
for the various aspects of human influenza mentioned above. The
search was limited to human influenza studies published between
January 2009 and August 17, 2011 (the date of the last keyword
search of the electronic database). We focused on A(H1N1)pdm09
and seasonal influenza. We did not include articles that focused
solely on avian influenza. Because we aimed to catalogue and
summarize the existing data rather than perform a meta-analysis
or calculate summary measures, we did not use any specified
methodological quality screens for the study selection. Two
exceptions were: (1) we used ‘research methodology filters’ for
study quality screening by selecting the ‘specific/narrow filter’
option during our search conducted via the ‘clinical queries’ mode
of PubMed when retrieving articles related to influenza risk and
prognostic factors. This approach allowed us to obtain better
quality observational studies, since it focuses on prospective
studies rather than other types of observational studies (see
detailed keywords used below). (2) We excluded studies that

1201-9712/$36.00 – see front matter ß 2012 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ijid.2012.05.1025

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 W. Punpanich, T. Chotpitayasunondh / International Journal of Infectious Diseases 16 (2012) e714–e723
reported associations using only univariate analysis without any
other means to control potential confounding factors.
For risk factors of severe disease or prognostic factors, we
searched via ‘clinical queries using research methodology filters’
with the following search term: {Etiology/Narrow[filter] AND
(‘‘influenza, human’’[MeSH Major Topic] AND (2009[pdat] OR
2010[pdat] OR 2011[pdat]))}, which yielded 332 articles. For
prognostic factors, we used the search term: {Prognosis/Narrow[-
filter] AND (‘‘influenza, human’’[MeSH Major Topic] AND
(2009[pdat] OR 2010[pdat] OR 2011[pdat]))}, which yielded 200
articles.
Regarding aspects of natural history, we used the term: natural
history[tiab] influenza[ti] AND (2009[pdat] OR 2010[pdat] OR
2011[pdat]), which gave us 20 articles.
As each individual study was likely to contain multiple aspects
of our topics of interest, we then imported all of the individual
studies’ citations into a single bibliographic management software
system and discarded duplicate studies. The initial bibliography
contained 668 articles. We reviewed titles and abstracts and
selected studies if we thought they included aspects relevant to our
review. We also searched the references of identified articles for
additional articles that we might have missed using our electronic
search process and, if relevant, added them to the bibliography. We
excluded studies that focused solely on avian influenza, those that
were limited guidelines or generic summaries (except to identify
original data references), those that duplicated results of other
original studies, and those that focused on non-epidemiological
aspects, e.g., risk perception or economic aspects. The final
bibliography contained 662 articles, from which 210 studies were
included in our full report. However, due to the limited space for
this report, we have included only a few of the most relevant
studies.
3. Clinical spectrum and natural history
The incubation period of A(H1N1)pdm09 infection appears to
be approximately 1.4–4 days, which is comparable to that of
seasonal influenza (1–2.4 days).1–9 In some reports, the incubation
period has been shown to be as short as 1 day and may extend to 7
days.4
Viral shedding generally begins approximately 1 day prior to
the onset of symptoms and lasts at least until symptoms resolve.1
The peak viral load tends to occur on the day of symptom onset,
and declines gradually thereafter. In one report, A(H1N1)pdm09
virus was detected in the stool and in the urine in approximately
44% and 7% of cases, respectively.10 The average and/or median
duration of viral shedding from the onset of symptoms has been
reported to range between 4 and 8.5 days.4,11–15 Nevertheless,
children and younger adults may shed for 10 or more days.14,16
Immunosuppressed persons may shed the virus for weeks.17 So far,
no association with the emergence of resistant strains has been
observed among those exhibiting prolonged viral shedding.17,18
Nevertheless, this group may serve as a reservoir for further spread
of the virus.
3.1. Age and gender
Healthy young adults and children are proportionately more
affected than other groups in the population.10,15,19–27 More than
60% of reported cases were among those aged 10–29 years, with
approximately 1% of these being aged 65 years or over.28 A recent
systematic review of 44 published articles from April 1, 2009 to
January 31, 2010 reported that the weighted mean age of
confirmed cases was 18.1 years, with the median age ranging
from 12 to 44 years.28 The relatively low rates among those over
the age of 60 years are consistent with a lack of cross-reactive
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e715
antibody to the novel A(H1N1)pdm09 virus among young adults
and children.26,27,29–33 There is no evidence suggesting significant
differences in symptoms, disease severity, or hospitalization rates
by gender.33–45 The distribution of gender was found to be
comparable among hospitalized cases affected by A(H1N1)pdm09
and seasonal influenza.
4. Clinical spectrum
Studies suggest that about a third of seasonal influenza
infections are asymptomatic.46,47 Although serological studies
and mathematical models have indicated a substantial proportion
of subclinical and mild illness among those with an
A(H1N1)pdm09 infection, the proportion of asymptomatic infec-
tions among A(H1N1)pdm09 infections has not been adequately
characterized. A serological survey from England demonstrated
that a third of children were infected by the pandemic virus during
the first wave of the pandemic in summer 2009. This was 10 times
higher than the estimate from clinical surveillance.29
The spectrum of disease caused by pandemic influenza A
(H1N1) virus infection ranges from a non-febrile, mild upper
respiratory tract illness to severe or fatal pneumonia. In general,
most illnesses due to this virus have been reported to be rather
benign and self-limited, with an abrupt onset of fever and
respiratory symptoms; the illnesses have been found to be
indistinguishable from common viral respiratory illnesses and
seasonal influenza, and do not appear to cause more severe
disease.22,37,48–50 Most patients with mild to moderate influenza A
recover without specific anti-influenza therapy.51 The most
common symptoms are fever and cough. The severity of symptoms
tends to be highest during the first 4 days; systemic symptoms
peak on day 2, and resolve faster than both upper and lower
respiratory symptoms after oseltamivir treatment. Lower respira-
tory symptoms tend to resolve gradually over a 2-week period.52
The proportions of cases displaying particular clinical mani-
festations have varied depending on the study setting. In general,
data from active surveillance are preferable to those obtained from
more specific settings such as cases hospitalized in tertiary
hospitals or intensive care units (ICU). Nonetheless, the results
from surveillance (both active and passive) should be interpreted
with caution. For example, during the early stages of the pandemic,
only those who fulfilled certain clinical and epidemiological
criteria were tested for A(H1N1)pdm09 infection. However,
cumulated evidence suggests that A(H1N1)pdm09 generally
caused a mild illness or asymptomatic infection. Therefore, many
cases with mild illness may have been missed and thus findings in
many reports are likely to represent more severe cases. A recent
systematic review of the clinical features of A(H1N1)pdm09
infection indicated that based on United States Centers for Disease
Control and Prevention (US CDC) influenza-like illness (ILI) criteria,
only cough and fever were the most common clinical features,
documented in more than 80% of confirmed A(H1N1)pdm09
infection cases. In this review, cough (84.9%), fever (84.7%),
headache (66.5%), runny nose (60.1%), and myalgia (58.1%) were
commonly reported among confirmed cases of A(H1N1)pdm09
infection.28 In addition, only 49% of confirmed cases reported
having a ‘sore throat’, which is regarded as a rather insensitive
clinical criterion.28 Although fever has been reported as the most
common manifestation among symptomatic infections, these data
tend to over-represent those with severe illness seeking medical
attention and therefore selectively tested for this virus. A report
from the UK during the first wave of the pandemic found that up to
40% of hospitalized confirmed pediatric cases in Birmingham did
not fulfill the case definition as described by the UK Health
Protection Agency.53
e716 W. Punpanich, T. Chotpitayasunondh / International Journal of Infectious Diseases 16 (2012) e714–e723
A mild illness without fever has been reported in up to 32% of
confirmed cases of A(H1N1)pdm09 infection.8 In approximately a
third of patients, symptoms appeared before the onset of high
fever.1,54 During the first wave of A(H1N1)pdm09 infection in the
USA, the hospitalization rate was approximately 8.2% among all
reported confirmed cases.19 Among hospitalized patients, 3.2–44%
were admitted to the ICU,19,21,43,45,55–69 and 0.5–21.4%
died.19,21,43,45,57,60–64,66–68
Among children, the median duration of fever in
A(H1N1)pdm09 was 3 days,4,51 and this generally resolved
within 8 days in 95% of patients.51 The duration of illness in
cases of A(H1N1)pdm09 infection as determined by active
surveillance appeared to be slightly longer than that of seasonal
influenza, for which acute symptoms, particularly fever, were
reported to last approximately 5 days.33 After the administra-
tion of oseltamivir, 80% of patients became afebrile within 48 h;
48.6% within 24 h.4
Productive cough or expectoration was also commonly
reported, from 20% to 84%.70–73 Acute respiratory symptoms
tended to last longer than other symptoms.1,54 Dyspnea/tachypnea
was found in 31.2% of cases and more commonly among
hospitalized (51.6%) and ICU cases (61.5%).28 Conjunctivitis,
epistaxis, and acute otitis media were also reported frequently.
Systemic and constitutional symptoms are frequent and
include headache, myalgia, arthralgia, and fatigue.28 Of note,
gastrointestinal symptoms, especially diarrhea, appear to be a
more prominent findings in A(H1N1)pdm09 infection compared to
seasonal influenza.43,74 These findings may reflect more extensive
local viral replication or indirect injury of the gastrointestinal
tract.75–79 However, in a systematic review of clinical aspects by
Khandaker et al., the pooled prevalence of diarrhea among
A(H1N1)pdm09 infection cases was 13%,28 which is comparable
to that reported for seasonal influenza (13% and 14% for influenza A
and B, respectively, and 10% for A(H1N1)pdm09 in the same study
by Hawkes et al.51). On the other hand, some reports have shown
the prevalence of diarrhea to be as high as 22–56% of
cases.33,38,74,80–82 Sporadic cases of atypical manifestations include
those with neurological complications such as seizures,33,63,83,84
encephalitis,34,84–93 encephalopathy,65,86,88,90–92,94–99 hemiple-
gia,100 quadriparesis,101,102 acute myelopathy,103 and ataxia.96
Other reported complications include myocarditis,60,65,86,104–106
heart failure,107 hemophagocytic lymphohistiocytosis,108–110 Guil-
lain–Barré syndrome,60 myositis,111 and rhabdomyolysis.111–115
Diffuse viral pneumonitis leading to hypoxemia and acute
respiratory distress syndrome were found to be common clinical
conditions leading to hospitalization and intensive care admission.
This syndrome accounted for approximately 49–72% of ICU
admissions for A(H1N1)pdm09 virus infection.59,116 Shock, renal
failure, encephalopathy, and/or multiorgan dysfunction were
typical features found among fatal cases.
Young children, especially those less than 2 years of age, are at
high risk of influenza complications including severe dehydra-
tion resulting in shock.117 Other complications include invasive
bacterial co-infections118 and neurological complications such as
encephalopathy94,95,98 or encephalitis (sometimes necrotiz-
ing).93 Those with neurological manifestations generally make
a full recovery, but some have reported residual seizures and
significant cognitive deficits especially with necrotizing enceph-
alitis, involvement of the basal ganglia, and significant cerebral
volume loss.96 Other serious complications include myocarditis,
apparent life-threatening episodes, acute abdomen (appendicitis
and intussusception),53 and diabetic ketoacidosis.98 Suspected
transplacental transmission of the A(H1N1)pdm09 virus has
been reported,119,120 and respiratory transmission from a
symptomatic mother to a newborn can occur during the
postpartum period.121
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5. Laboratory findings
A normal or low leukocyte count was reported in the majority of
A(H1N1)pdm09 cases. Although normal or low–normal leukocyte
counts with lymphopenia and elevations in the levels of serum
aminotransferases, lactate dehydrogenase, creatine kinase, and
creatinine have been reported among severe A(H1N1)pdm09
infection cases,122 there is no single laboratory finding indicative of
A(H1N1)pdm09 or seasonal influenza infection. Nevertheless,
lymphopenia, commonly reported in both adults (68.1%)8 and
children (92.3%)8 with A(H1N1)pdm09 infection, typically occurs
on day 2 and resolves by day 7. Further, relative lymphopenia
(<21% of white blood cells) has been reported to be a marker of
A(H1N1)pdm09 virus infection in adults.123 This is consistent with
previous studies reporting the occurrence of lymphopenia in
adults and children with other types of influenza A virus
infections.124,125 Although ‘otherwise unexplained relative lym-
phopenia’ has been regarded as a nonspecific laboratory hallmark
of influenza A infection,126 this finding remains an inconsistent
feature of A(H1N1)pdm09 infection.
Radiographic findings among A(H1N1)pdm09 pneumonia cases
have been rather nonspecific and have commonly included diffuse
mixed interstitial and alveolar or extensive air space infiltrates.
Lobar and multilobar distributions have been reported.48,65,85,127–
133
Chest computed tomography appears to be more sensitive in
detecting pneumonia, especially among immunocompromised
patients,134 and has shown multiple areas of ground-glass
opacities, air bronchograms, nodules, interlobular septal thicken-
ing,135 and alveolar consolidation.81,134,136–141
6. Differentiating influenza infections from other ILI or acute
respiratory infections (ARI)
A few studies have set out to compare clinical data between
A(H1N1)pdm09 and seasonal influenza. Current findings suggest
that the clinical spectrum of A(H1N1)pdm09 infection is relatively
similar to and indistinguishable from that of seasonal influen-
za,49,51,142 although one report suggested that A(H1N1)pdm09
caused more severe infection compared to seasonal influenza
among hematopoietic cell transplant recipients.143 Certain
studies have demonstrated significant differences in terms of
clinical features that may be useful for differentiating influenza
from other respiratory infections or ILI. In general, there is no
single clinical parameter that is useful in distinguishing between
influenza infection and other acute respiratory infections or
between A(H1N1)pdm09 and seasonal influenza. Various studies
have been conducted in different settings, using disparate
combinations of clinical features that are rather study-specific.
Given substantial differences in terms of comparison groups and
variables included in the analysis, a consensus finding for
differentiating clinical features of influenza is unlikely. The lack
of reproducibility and consistency across studies render these
various combinations unpractical in clinical practice. For exam-
ple, a study by Ong et al. found that the combination of WHO ILI
criteria with the absence of leukocytosis had a positive likelihood
ratio of 7.8 for A(H1N1)pdm09 and of 9.2 for seasonal influenza.49
Another prospective study conducted in England compared
clinical features between those with A(H1N1)pdm09 and non-
A(H1N1)pdm09 community-acquired pneumonia (CAP). A mul-
tivariate logistic regression model was generated by assigning one
point for each of five clinical criteria: age 65 years, mental
orientation, temperature 38.8 8C, leukocyte count 12  109/l,
and bilateral radiographic consolidation. The results indicated
that a score of 4 or 5 had a positive likelihood ratio of 9.0 for
predicting A(H1N1)pdm09 influenza-related pneumonia, where-
as a score of 0 or 1 had a positive likelihood ratio of 75.7 for
 W. Punpanich, T. Chotpitayasunondh / International Journal of Infectious Diseases 16 (2012) e714–e723
excluding it.144 Another retrospective multivariate analysis
examining the features of A(H1N1)pdm09 influenza infection
as compared to other CAP indicated that age, the duration of
illness, sputum production, dyspnea, chest pain, and coarse
crackles had a positive association with a diagnosis of CAP. In
contrast, sick contact, sore throat, and rhinorrhea significantly
favored A(H1N1)pdm09 infection.145
A study from Israel comparing clinical features of hospitalized
ILI cases with and without A(H1N1)pdm09 infection showed that
age <65 years and cough were independent predictors of
A(H1N1)pdm09 infection in a multivariate regression analysis.21
At the time of writing, there has only been one study that has taken
into consideration the seasonality of influenza in the analysis – the
study of Michiels et al.146 The results showed that during the
influenza epidemic, ILI contacts, cough, ‘expectoration per illness
day’, nose symptoms, lack of appetite, and body temperature
>37.8 8C were the symptoms most useful for discriminating
influenza from other ILIs.146 During the pre- and post-influenza
epidemic periods, no prediction rule was helpful for confirming
influenza in the age group <5 years and >65 years.146 Outside an
influenza epidemic the absence of cough and fever (>37.8 8C) was
found to make influenza 14 times less likely in ILI patients.146
Among adults, features that may be useful in distinguishing
A(H1N1)pdm09 from seasonal influenza or other ILI include
younger age,74 fewer lower respiratory tract symptoms, obesity,
pregnancy, presence of underlying predisposing co-morbidities,74
and lymphopenia (<0.9  109 cells/l).49
Comparing between A(H1N1)pdm09 and seasonal influenza or
other ILI among pediatric patients, factors associated with
A(H1N1)pdm09 infections were older age,147 black race,147
presence of an underlying condition, presence of wheezing and
underlying asthma,45,148 being less likely to have seizures,148
absence of a neuromuscular disorder,148 having a shorter hospital
stay,45,148 and having a higher incidence of acute respiratory
distress syndrome.45 One retrospective study in Italy among
children with ILI comparing clinical features between confirmed
A(H1N1)pdm09 infection and other uncomplicated flu-like ill-
nesses, found only the white blood cell count, relative and
absolute lymphocyte count, absolute lymphocyte count z-score,
and platelet count to be significantly different. An absolute
lymphocyte count <2556 cells/ml or absolute lymphocyte count
z-score <0.89 appeared to be useful cut-offs to identify children
with A(H1N1)pdm09 infection among those who presented with
an ILI.149
Studies among critically ill children have indicated that
significant factors associated with A(H1N1)pdm09 infections
compared to seasonal influenza are older age,39 a higher likelihood
of having predisposing co-morbidities, especially respiratory
conditions, a lower likelihood of having respiratory failure or
requiring ICU admission, lower morbidity and mortality, and a
shorter hospital stay.39
7. Mortality
Case fatality rates (CFR) reported in the literature vary widely
depending upon the study setting and the mathematical model
used for the estimations. Data from surveillance studies tend to
represent only those fulfilling surveillance criteria, thus mainly
reflect the CFR among symptomatic and more severe cases.
Similarly, several published reports have mainly included
hospitalized and/or critically ill cases. Calculating the CFR is,
thus, highly dependent on estimates of the total number of
symptomatic and/or infected cases.150 A review by Khandaker of
12 studies indicated a 2.9% overall CFR among confirmed
A(H1N1)pdm09 infection cases (cCRF), which reflected an
estimated 0.29% CFR among symptomatic cases (sCFR) and
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e717
0.02% CFR among overall infected cases (iCFR).28,29,151 However,
this value should be interpreted with caution since it combined
data from various study settings with different levels of disease
severity, such as school and/or community outbreaks with those
from hospitalized inpatient settings. In general, the overall
estimated CFR among symptomatic infection cases has been less
than 0.5%, with a wide range of estimates: 0.0004%;25 0.0004–
0.06%;152 0.0054–0.0086%;153 0.026%;154 0.04%;23 0.048%;155
0.3%,156 which are much lower than the initial estimated CFR of
0.4% during the early phase of the epidemic in Mexico.157 This
wide range of estimates reflects uncertainty regarding case
ascertainment, number of infections, other modifiable factors
such as differential efficacy of medical treatment, and clustering
among high-risk populations, as well as the accuracy of model
assumptions used for such estimations. CFRs among hospital-
ized cases (cCFRs) are generally higher than those of symptom-
atic infection (sCFRs), and the CFRs among those requiring
intensive care (iCFRs) have been estimated from 0.16% to
4.48%,151 or approximately 10 times the reported sCFR.29
A model developed by Reed et al. provides an easy-to-
understand and practical approach to the estimation of the CFR
based on epidemiological data. This model takes into consideration
the five parameters of CFR estimation including: (1) proportion of
persons with influenza who seek medical care; (2) proportion of
persons seeking care with a specimen collected; (3) proportion
of specimens collected that are sent for confirmatory testing; (4)
test sensitivity; and (5) proportion of confirmed cases reported.
With this approach, the estimated total number of A(H1N1)pdm09
2009 cases in the USA during the first wave may have been 140
times greater than the reported number of laboratory confirmed
cases.158 A spreadsheet version of the model has been developed
and is available online (http://www.cdc.gov/h1n1flu/tools) for
facilitating the preparedness process and can be adjusted using
local epidemiological data from individual settings and future
outbreaks.
8. Risk factors for A(H1N1)pdm09 infection
Most studies have examined risk factors of severe or
complicated influenza diseases. Only a few studies have examined
risks of A(H1N1)pdm09 infections (including both subclinical and
symptomatic infection). Regarding the risk of A(H1N1)pdm09
seroconversion, one serial serological survey indicated that having
a household contact who had seroconverted was associated with a
higher chance of seroconversion, whereas older age, higher
baseline hemagglutination–inhibition (HI) titers, being in the
military, and being a member of hospital staff (as compared to the
general population) reduced the likelihood of infection.159 Another
prospective, multicenter cohort study during the 2006/2007
influenza season in Berlin also added to the body of evidence
that being a healthcare worker does not increase the risk of
acquiring a seasonal influenza infection. On the other hand, living
with children has a three-time higher risk of seroconversion; the
risk is 14 times higher for those living with three or more
children.47 Immunization with the influenza vaccine was found to
significantly reduce the risk of seroconversion to 50%.47
One meta-analysis examining the relationship between HI
antibody titer and clinical protection against influenza demon-
strated a significant and positive relationship between HI titer and
clinical protection regardless of the viral strain and the vaccination
status of the individuals.160 This relationship highlights the
importance of the level of antibody response and thus challenges
the usual approach of defining protection based on the identifica-
tion of a single threshold. This finding may be useful for comparing
the efficacy of different influenza vaccines in the future.
e718 W. Punpanich, T. Chotpitayasunondh / International Journal of Infectious Diseases 16 (2012) e714–e723

9. Prognostic factors (risk factors for severe disease and
complications)
Underlying predisposing conditions considered high risk for
A(H1N1)pdm09 infections are generally similar to those of
seasonal influenza. Patients with underlying medical conditions
have been over-represented among symptomatic and hospitalized
A(H1N1)pdm09 infection cases in most of the existing studies. The
proportion of patients with predisposing co-morbidities consid-
ered at high risk of influenza infection161 varies according to the
study setting, i.e., public health surveillance, community clinic,
school outbreak, public gathering, or in-patient setting at tertiary
medical centers. Therefore, the overall percentage of those with co-
morbidities among A(H1N1)pdm09 or other influenza infection
cases is not very informative. Those values need to be presented
with their context. For example, data from the adult population
(mainly from hospital-based studies) have shown the reported
proportions to range from 14.2% to 84%.34,57,62,64,65,162–172
Similarly, among the pediatric group, the proportion of
A(H1N1)pdm09 cases with underlying predisposing co-morbid-
ities has been shown to range from 27.5% to 93%.22,61,66,147,173–181
See Table 1 for a summary of the risk factors for severe disease and/
or influenza complications with seasonal and A(H1N1)pdm09
infection.118,150,162,182–200
Data from active surveillance of A(H1N1)pdm09 infections in
the UK have indicated a relatively lower proportion (11%) of those
with predisposing co-morbidities.33 These proportions were
found to be generally higher, ranging from 14% to 92%, among
critically-ill patients requiring ICU admission; however, the
majority of the proportions have been in the range of 70–
76%.92,201–205 In parallel, approximately 49% of pediatric cases
with seasonal influenza have been found to have underlying
predisposing conditions.147 The majority of studies identified that
have reported co-morbid conditions among severe cases of
A(H1N1)pdm09 and/or seasonal influenza have been descriptive
ones, such as surveys or case series. Only the few investigations
using an analytic study design can provide stronger evidence
when determining risk factors for disease severity.
The emerging risk groups for severe A(H1N1)pdm09 infection
in addition to those defined by the Advisory Committee on
Immunization Practices (ACIP) of the US CDC included pregnan-
cy and obesity.74 Two recent systematic reviews have added to
the body of evidence that these two factors are associated with
an increased risk of A(H1N1)pdm09 infection. Pregnant women
are at significantly increased risk of hospitalization, ICU
admission, death, and other serious complications of
A(H1N1)pdm09 infection.182 Further, severely obese patients
(body mass index 40 kg/m2) with A(H1N1)pdm09 infection
were found to be twice as likely to be admitted to the ICU or to
die (p < 0.002) compared to A(H1N1)pdm09 cases who were not
severely obese.183
Regarding the applicability of existing clinical tools in predict-
ing the outcome of A(H1N1)pdm09 pneumonia, most of the
existing pneumonia severity and acute physiology scores, such as
the pneumonia severity index (PSI),55,206–208 the mortality in
emergency department sepsis score,55 CURB-65 CAP severity
index,206,208–210 and CRB-65206 have failed to demonstrate a
predictive ability for in-hospital mortality. One study has shown

Table 1
Risk factors for severe disease and/or influenza complications with seasonal and A(H1N1)pdm09 infectiona

Risk factor Comments

Predisposing co-morbidities
Age <5 years Increased risk especially for children <2 years of age; highest hospitalization rates among children <1 year. However,
the risk of A(H1N1)pdm09 infection is generally lower than seasonal influenza or other acute respiratory illnesses
Pregnancy Risk of hospitalization increased by a factor of 4.3 to 7.2. Risk of ICU admission ranges from 5.8 to 7.4, risk of death
increased by a factor of 10182
Chronic cardiovascular condition Congestive heart failure appears to be over-represented in both A(H1N1)pdm09 and seasonal influenza; hypertension
has not been shown to be an independent risk factor
Chronic lung disorder Asthma, COPD, cystic fibrosis
Metabolic disorder Diabetes mellitus
Neurological condition Neuromuscular, neurocognitive, and developmental disorders have been over-represented, occurring in up to 92% of
fatal cases, especially among children184
Immunosuppression Associated with HIV infection, organ transplantation, malignancy, receipt of chemotherapy or corticosteroids, and
malnutrition. A(H1N1)pdm09 preliminary data do not suggest a substantial, disproportionate impact on HIV-infected
patients185
Morbid obesityb A recent systematic review indicated a two-fold higher risk of ICU admission or influenza death among A(H1N1)pdm09
infection183
Hemoglobinopathy Sickle cell anemia: mainly for seasonal influenza, not yet confirmed as an independent risk factor for A(H1N1)pdm09
severity
Chronic renal disease Renal dialysis or transplantation and acute renal injury have been reported to have a very high fatality rate among
critically ill patients
Chronic hepatic disease Cirrhosis – mainly for seasonal influenza, not yet confirmed as an independent risk factor for A(H1N1)pdm09 severity
Long history of smoking Has been reported to be over-represented among symptomatic A(H1N1)pdm09 infections, but not yet proven to be an
independent risk factor for A(H1N1)pdm09 infection
Long-term aspirin therapy in children Risk of Reye’s syndrome is well documented in seasonal influenza. Little is known regarding this condition and
A(H1N1)pdm09 infection since this complication had not been reported in the published literature at the time of
writing
Age 65 years Highest case fatality rate but lowest rate of infection due to the presence of cross-reactive antibody
Indigenous (disadvantaged population) Associated with higher rates of severe 2009 H1N1 virus infection.162,186–188 Factors that may contribute to this trend
include crowding, an increased prevalence of underlying medical disorders, alcoholism, and smoking, delayed seeking
of or access to care, and possibly unidentified genetic factors162
Others factors
D222/N variants or 225G substitution This mutation has been found to have significant association with severe/complicated A(H1N1)pdm09 infection and/or
viremia189–199
Bacterial co-infection Found in up to 43% of pediatric death. Significant higher prevalence of bacterial co-infection among severe vs. mild cases
of A(H1N1)pdm09 infection118,200

ICU, intensive care unit; COPD, chronic obstructive pulmonary disease.

a
Reprint with permission from Table 1 in reference 150.
b
Morbid obesity is defined as a body mass index (the weight in kilograms divided by the square of the height in meters) of 40 or more.

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 W. Punpanich, T. Chotpitayasunondh / International Journal of Infectious Diseases 16 (2012) e714–e723
the SMART-COP rule as compared to other clinical prediction rules
to yield the best performance in predicting ICU admission in
patients with A(H1N1)pdm09 pneumonia, with 83% accuracy.55 In
addition, one study has indicated that the PSI score is marginally
associated with death among those with A(H1N1)pdm09-associ-
ated pneumonia (adjusted odds ratio = 1.03, 95% confidence
interval 1.01–1.04).69 Nevertheless, the application of these
existing tools in clinical practice remains questionable.
10. Identification of the current knowledge gap
The current knowledge gap includes the following. First, there is
as yet no clarification for the relatively greater severity of the
Mexican A(H1N1)pdm09 influenza outbreak and some of the
A(H1N1)pdm09 cases from other countries. There is no significant
difference in genomic sequence to explain the difference in disease
severity between countries or settings. Second, little is known
about the impact of infections caused by resistant strains of
seasonal and A(H1N1)pdm09 influenza on clinical presentation,
natural history, and treatment outcome. Finally, data from less
developed countries, in particular Sub-Saharan Africa and Asia, are
insufficient to allow these countries to prioritize strategies for
influenza prevention and control. Key data gaps include the role of
common health conditions found in less developed areas, such as
malaria, HIV, and malnutrition, and their interactions with both
seasonal and A(H1N1)pdm09 infections.
Acknowledgements
The World Health Organization Global Influenza Programme
provided financial support for this review. The authors wish to
thank the members of the WHO Working Group of the Public
Health Research Agenda for Influenza, Progress Review, Global
Influenza Program for their participation in the review of the
document.
Disclaimer: The content is solely the responsibility of the
authors and does not necessarily represent the official views or
policies of the World Health Organization.
Conflict of interest: No conflict of interest to declare.
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