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Title A systematic review of the association between obesity andinfluenza A related morbidity and mortality

Author(s) Zhou, Yuyang; 周裕洋

Citation

Issued Date 2014

URL http://hdl.handle.net/10722/206968

Rights Creative Commons: Attribution 3.0 Hong Kong License

Abstract of Project entitled

“A systematic review of the association

between obesity and influenza A related

morbidity and mortality”

Submitted by

ZHOU Yuyang

for the Degree of Master of Public Health

at The University of Hong Kong

in August 2013

Background

Globally, epidemics of obesity and influenza are always two major public health

issues that require immediate actions for human. After the outbreak of pandemic

influenza A (H1N1) in 2009, the relationship between obesity and influenza was

widely recognized due to severe illness and reported death with obesity among

infected cases. We still doubted whether obesity is a risk factor for influenza

infection or not. So I conducted this systemic review to explore the association

between obesity and influenza A morbidity or mortality.

Method

PubMed, Google scholar, and HKU library were searched using a prepared

strategy for all items in English up to 31 July 2014. Search strategy, exclusion and

inclusion criteria, assessment of quality, as well as data analysis were established

for screening all relevant publications.

Findings

Through careful screening, 17 relevant studies were adopted into this review.

There were 9 case control studies of all observational studies. Obesity and

morbid obesity in influenza A infected adults (below 60 years old) could be

regarded as a risk factor for hospitalization and severe sickness. Morbid obesity

would be related with higher risk for mortality and ICU admission.

Conclusion

From my review, there was a strong association between obesity and influenza A

infection had been confirmed. However, we need to carry out further research to

explore the details of impacts. Obese people, as the high-risk population, should

take vaccine during influenza season to protect themselves effectively.

Key words: Influenza A, obesity, body mass index, morbidity, mortality, risk

factors, and severe outcomes.

An abstract of exactly 289 words

III

A systematic review of the association

between obesity and influenza A related

morbidity and mortality

Zhou Yuyang

A Project submitted in partial fulfilment of the requirements for

the Degree of Master of Public Health

at The University of Hong Kong.

August 2013

Declaration

I declare that the Project and the research work thereof represent my own work,

except where due acknowledgement is made, and that it has not been previously

included in a thesis, dissertation or report submitted to this University or to any

other institution for a degree, diploma or other qualifications.

Signed

Zhou Yuyang

Acknowledgements

I would like to express my gratitude to my supervisor Dr. Wu Peng for her

guidance, selfless support and valuable comments. Especially, during the

preparation of proposal, she also discussed with me and helped me with

deciding available topic. I am grateful to Professor. Salvatore and Professor. Jesús

who sent their articles to me.

I would also like to thank all teachers and classmates of MPH program at the

University of Hong Kong.

Contents

Abstract ............................................................................... .................................................I

Declaration ..................................................................... .................................... ..IV

Acknowledgements ......................................................... ............................. ...........V

Illustrations ………......................................................................... ...................................1

Abbreviations and symbols ..........................................................................................3

Chapter 1 Introduction and background

1.1 Influenza A……………………………………………………………..........................................4

1.2 Obesity......................................................... ........................................................... 5

1.3 Hong Kong situation.................................................................................................... 2

1.4 Aims and objectives ......................................................................................................... 3

Chapter 2 Methods

2.1 Search strategy………………………..……………….……………………………...……………7

2.2 Inclusion criteria…………………..………………………….………………………………………8

2.3 Exclusion criteria……………………….……………………………………………….……………8

2.4 Data exaction and analysis……………………………………..…………………………………9

Chapter 3 Results

3.1 Overview………………………………………………………………………………………………...12

3.2 Summary of results……………………………………………………………………………….....12

3.3 Association between obesity and morbidity and mortality……………….………..15

Chapter 4 Discussion

4.1 findings…………………………………………………….…………………………………………….17

4.2 Risk factors.…………………………………………………………………………………………….19

4.3 Implications …………………………………................................................................................21

4.4 limitation and strengths……………………………………………………………………….….22

Chapter 5 Conclusion 23

Appendix……………………………………………………………………………………………………. 24

References……………………………………………………………………..……………………………29

Illustrations

Figures

Figure 1 ---Selection process of literature 13

Figure 2 ---The primary impacts of influenza virus infection on obesity 25

Tables

Table 1 --- BMI classification and formula 4

Table 2 --- Assessment of quality for papers studies 10

Table 3 --- STROBE and CONSORT Statement 26

Appendix

Appendix 1 ---Summary of human model study 23

Appendix 2 ---Checklist for STROBE and CONSORT 26

Abbreviations

WHO World Health Organization

CDC Centers for Disease Control and Prevention

BMI Body Mass Index

Influenza A Influenza A (H1N1) pdm09

ICU Intensive care unit

RCT Randomized controlled trial

IL 6,10 Interleukin 6,10

NB-kB Nuclear factor kappa-light-chain-enhancer of activated B

cells

TNF Tumor Necrosis Factor

OR Odds ratio

RR Risk ratio

CRP C-reactive protein

CVD Cerebrovascular disease

NK Natural killer

DCs Dendritic cells

TIV Trivalent inactivated influenza vaccine

IFN Interferon

mRNA Message Ribonucleic acid

CI Confidence interval

HA Hospital Authority

CHP Center for health protection

HKU The university of Hong Kong

ACIP Advisory Committee on Immunization Practices

Symbols

Kg/m2 Kilogram / square meter

Chapter 1 - Introduction

Influenza A

With frequent recent epidemics and pandemics of influenza, influenza had been

identified as a serious public health problem in recent years.1 These annual

influenza epidemics of worldwide are reported to result in approximately 3 to 5

million cases of severe illness, and roughly 250 to 500 thousand deaths. Annual

cases of known influenza had not be controlled but the future novel pandemics

are likely upcoming. 2 In late April 2009, influenza A (H1N1) virus, a new kind of

the subtype of influenza virus was identified from Mexico and the United States,

could cause the similar common symptoms for instance chills, fever, headache,

muscle pain and cold like respiratory symptoms. The initial outbreak of influenza

A occurred in Mexico, as well as this ongoing epidemic caused a number of

serious cases and death tolls. What is worse, this virus spread rapidly to other

countries, therefore in June the World Health Organization (WHO) declared that

global epidemic and outbreak of Influenza A in 2009 had caused hundreds of

death.3 The definition of influenza mortality is that influenza infection was likely

a contributor to the cause of death, but not necessarily the primary cause of

death. Influenza morbidity means influenza confirmed cases with positive blood

examination.

Obesity is defined as a medical condition with abnormal or excess body fat that

had accumulated over standard extent due to prolonged energy imbalance, and it

presents a risk to health. Although scientists had found that nutrition and the

immune system are closely linked and the function of immune response can be

easily influenced by imbalanced nutritional status such as obesity,4 scientists

seldom focused on obesity and pregnancy patients during severe influenza

epidemics that are prior to the pandemic of H1N1 (2009). Nowadays, morbid

obese which means BMI ≥ 35 kg/m2 with obesity-related health conditions or

BMI ≥40 kg/m2 had been included into the list, which showed some high-risk

groups of population more necessary to receive vaccinated against influenza.

Obese people are more susceptible to get flu-related complications when they get

illness from influenza.5 Age, pregnancy asthma and some chronic disorders had

been seemed as risk factors for seasonal influenza and influenza A. However, only

after the 2009 pandemic H1N1 influenza, the obesity is just considered for the

first time as a novel suspected risk factor for influenza, 6due to higher morbidity

and mortality of influenza in the obese population than general population. The

Centers for Disease Control and Prevention (CDC) reported a high prevalence of

obesity among hospital patients, intensive care unit (ICU) admissions and death

with confirmed pandemic H1N1 influenza infection in 2009.7 8

In 2009 epidemic area of California alone, 62 percent of influenza A patients had

a BMI ≥30 kg ⁄m2, about 30 percent of whom had a BMI ≥40 kg ⁄m2.9

Comparing to the 2009 California Health Interview Survey (CHIS), there were

22.7% of obese adults (based on BMI), including 24.0 % males and 21.5 %

females. 10So I am doubted that what is the association between them. In the

result, since 2009 there were a lot of novel articles have published

demonstrating the impacts of 2009 H1N1 influenza among obese people;

however, most of them exhibited small case reports, case series and animals

model studies which often focus on one point or overlap with other similar

literature. So it is necessary to do a systematic review of currently useful and

available papers to classify all related articles. According to current papers, I can

find that obesity produces a chronic inflammatory state associated with

dysregulated cytokine production, reduced NK cell activity, altered CD4+, CD8+T

cell balance11, and a decreased response to antigen stimulation. These possible

mechanisms could help us to explore the association between obesity and

influenza A.

Obesity

Obesity has become an escalating global epidemic, which is taking over many

parts of the world.12 In 2008, there were more than 1.4 billion that accounts for

35% of all population overweight adults (who are 20 and older), moreover 11%

obese. Yet despite there are some differences among various races and

individuals, we will apply to the most commonly used definitions of obesity and

overweight, which was established by the World Health Organization (WHO).

Body mass index (BMI) would be used in this paper to further assess directly in

terms of fat via the height-weight ratio, which would be shown in Table 1. The

standard is that a BMI greater than or equal to 25 is overweight, anyone of BMI

≥ 30 kg/m2 is obesity, and if BMI≥40 kg/m2 could be deemed as morbid

obesity13. Obesity not only would low quality of life, it but also would increase

the risk of many common comorbidities which can appear metabolic syndrome

such as diabetes mellitus type 2, hypertension, high blood cholesterol, high

triglyceride levels and so on.14 In additional, the immune response of obesity can

be affected directly or indirectly because of changes of individual's metabolic and

endocrine conditions.15 So the obese individuals are more susceptible to viral

and bacterial infections.16

Table 1 BMI formula and classification

Calculation of BMI:

m means weight of people in kilograms and h means height of people in meters

Commonly used WHO classification of BMI:

Classification BMI (kg/m2)

Underweight <18.50

Normal 18.50 - 24.99

Overweight (at risk) 25.00 -29.99

Obese ≥30.00

Obese class I 30.00 - 34.99

Obese class II (severe 35.00 - 39.99

obesity)

Obese class III (morbid

obesity)

≥40.00

Different countries and races have individual standards

Body-mass index (BMI) cut-off points for Hong Kong populations: 17

Classification BMI (kg/m2)

Underweight <18.50

Normal range 18.50 - 22.99

Overweight (at risk) 23.00 -24.99

Moderately Obese 25.00 - 29.99

Severely Obese ≥30.00

Situation in Hong Kong

As of Dec 25, 2009, there were 32,301confirmed cases, the morbidity was 4.5 per

1000 inhabitants 18 and the number of death was 80. This information indicated

that Hong Kong was one of areas with higher incidence of influenza A in 2009.

Obesity as a kind of risk factors for health is also popular in the Hong Kong. The

2012 April statistical survey report illustrates that there were 17.9% overweight

and 18.8% obese respectively based on WHO classification for adult Asians. 19

Even if in August 2010 the WHO declared that the world had entered a

post-pandemic period, this virus was expected to continue to circulate for

following several years in the community as a seasonal influenza strain. In reality,

there were some sporadic individual cases of influenza A (includes other

subtypes) annually in recent years, so it illustrated that the influenza A (H1N1)

virus had turned into one of the seasonal influenza strains in Hong Kong.20 Thus,

it would be a big challenge for aging and densely populated Hong Kong. If

Department of Health wanted to prevent influenza effectively, the key was to

monitor high-risk population and provide vaccine for them.

Aims and objectives

As we found, recommendations of CDC still emphasize standard precautions that

include minimize potential exposures, promote influenza vaccine, monitor

high-risk population and control transmissions.21So I conducted a systematic

review to examine the association between obesity and infection of influenza A

(H1N1) and whether obesity is the high-risk group of influenza. Secondly, it

would be useful to guide policy makers to establish new recommendations of

vaccination in the future epidemic season. Strictly speaking, policy makers

should plan for future analogous seasonal influenza and influenza A, target

vaccination strategies for prevention, guide optimal management, and take more

control measures. Certainly, this review can help people better understand

severe outcomes of obesity on influenza virus (H1N1) infection of 2009.

Chapter 2 - Methods

The systematic review would be conducted with academic thesis submission

guidelines of HKU and according to the PRISMA guidelines.

Search strategy

Relevant published studies and literature were identified from electronic

databases PubMed, Google Scholar and HKU Library. Google Scholar and HKU

library would be considered as supplemented database of the grey literature,

when I could not find full text or e-resource on PubMed. The systematic search of

articles would be conducted using a combined text and the following search

strategies “(Intensive Care Unit admission OR severity OR mortality OR

hospitalization OR morbidity) AND (obesity OR fat OR adiposity) AND (flu OR

influenza A OR H1N1)”. I would apply to Mesh term to minimize the range of my

research. The last PubMed search was performed using the same terms on 31

July 2014 and I set language and human test as filters for the search of electronic

databases. The reference lists of relevant articles that may have been missed

only by the search strategy were also reviewed.

Inclusion Criteria

Only articles with English language were included. Despite most of papers about

influenza A were published from 2009 to now, I would not set date limitation. In

the study design, I would apply to case control study, cross-sectional study and

cohort studies as my screening principle. Only human cases study would be

adopted into this systemic review, in order to meet the aim. Last but not least,

full text is the essential request for including writings.

Exclusion Criteria

First I would exclude articles that were written in English or did not have

original English editions. News, letters, comments or correspondences were not

selected in the review. And literatures only providing association or explaining

risk factors without any statistical analysis or experiments between influenza

and obesity were excluded. If participators of the study were not made up with

obesity groups and infected virus were not influenza A (H1N1) or subspecies, I

could not accept them into the review. If papers only contained key words, they

would be excluded that did not introduce the association and related data.

Data extraction

All enrolled papers were searched through the keywords and foregoing rules

from the database. Then I follow the inclusion and exclusion criteria to screen

articles, but after scanning of the title and abstract, I still doubt whether these

left literatures, which were hard to be rejected by abstract, could correspond to

the needs and scope of this review. Especially there are some case reports and

observational studies that are not only discuss obesity but also research

pregnant women and others chronic diseases conditions. So I applied STROBE

and CONSORT guidelines to weigh individual quality of theses with a three-point

scale22 and identify the strengths and weaknesses of studies (namely A means

good, B means average, and C means unsatisfactory). All assessment subjects

would be shown in Table 2.23 I would evaluate the quality of evidence and study

using corresponding criteria to select a grade for them. These standards and

items would be shown in the Appendix 2.

Data analysis

Firstly, I would classify all findings to compare them in the same level. BMI

would be divided into two parts: obesity means BMI≥30.00 kg/m2 and morbid

obesity means BMI ≥ 40 kg/m2. And age, as a confounder, should be adjusted. So

most of my reviewed papers would be classified as children who were below 20

years old; elders were at least 65 years old, and adults were 20 to 65 years old.

Of course there were other multiple confounders in the models, including gender,

chronic diseases, races, temperature, air pollution receiving public assistance,

education, co-morbidity score, humidity and lifestyles. Especially some chronic

illness for example asthma, cancer, COPD, diabetes, heart diseases and HIV/AIDS

were risk factors for influenza infection. Therefore these infection cases would be

deleted from sample size in studies of my reviewed literatures. Next all Odds

ratio, Risk ratio, confidence interval and p value can be used to illustrate whether

it had statistically significant. Although some conflicts and commons among the

articles could be found, I could depend on the overall results from quality

assessment to evaluate confidences and validities of experiments. Only in this

way could I easily find what are limitations and strengths in their outcomes and

analysis these consequences.

Table 2 Quality assessment of the review

Note that:

A: Good, B: Average and C: Unsatisfactory

Study design: the study is suitable to show the association and impact

Sample size: can the size of population enough to provide evidences

Sample allocation: how to allocated participants into different groups (whether random or other methods)

Participants: can participants represent the obese population or models?

Outcome measurement: Is it the best to indicate the association and its accuracy?

Adjustment: had the confounding factors of results been adjusted?

Overall: based on all former quality indicators.

Quality indictors

Name (author and year) Study design Sample size Sample allocation Participants Outcome Adjustment Overall

Yu, Hongjie, et al.24(2011) B A B A B B A

Ren, Yan-yan, et al. (2013)25 B A B A B B A

Morgan O W, et al. (2010)26 A A B A B A B

Kim C O, et al. (2012)27 B A B B B A B

Viasus D, et al. (2011)28 A A B A A A A

Coleman, Laura A., et al.29 A A B A B A B

Martin, Emily T., et al. (2013) 30 A B B A A A A

Louie J K, et al. (2011)31 A A B A A A A

Yang, Lin, et al. (2013)32 A A A B A B A

Díaz, Emili, et al. (2011)33 A A B A A B A

Louie J K , et al.(2009) 34 A A B B A A A

Barrau M, et al. (2012)35 A A B B A B A

Jain, Seema, et al. (2009)36 A A B A B B B

Hanslik, T, et al. (2010)37 A A B A A B A

Bassetti, M, et al. (2011)38 A C C B B B C

Louie J K, et al. (2009)39 A A B A A A A

Fuhrman, C., et al.(2009) 40

A A B A A A A

Chapter 3 - Results

Overview

The search strategy was run on 31st July 2014 last time and identified 7071

potentially relevant articles with key words in any field. After using filter and

Mesh term 216 unique articles published in English for human models with the

requested articles types. Then I reviewed carefully all titles and abstract, and left

39 papers. The remaining 39 citations after the preliminary screen were then

retrieved by the full texts and evaluated in depth.

10 papers were excluded by no statistical data or no cases in all pages, which is

important for my review. Four articles were deleted as no full text I could receive

on the Internet. Additionally, these four writings do not study on my aim and my

topic that just were mentioned, so they would be failed to comply with inclusion

criteria. Certainly there were five dropping literatures that discussed about other

influenza A subtypes. Finally, left 15 full text papers met all review criteria, which

was built according to my topic. Through reading the reference lists of our 15

included papers, then I added 2 more article. Therefore, there are a total of 17

articles, which years were from 2007 to 2014, would be conducted in this review.

Following figure listed a brief summary of my studies selection process.

Summary of results

All identified published articles would be divided into the following categories:

case control study, case cohort study and cross sectional study. The identified

published evidence fell into the following categories for outcomes:

hospitalizations, ICU admission, severe illness and mortality. Severe sickness did

not have professional explanation, according some relevant papers the definition

of severe diseases was that some serious complications, long-term

hospitalization (at least 24 hours), ICU admission and death cases. And two

major exposures were BMI≥30.00 kg/m2 equal to obesity and BMI≥40.00 kg/m2

seemed as morbid obesity. 14 studies were carried out in western countries and

3 studies were conducted in Asia. All key studies had been summarized in

Appendix 1.

Figure 1 Selection process of literature

216 records screened

7071 records identified from PubMed,

HKU library and Google scholar

6755 records excluded using PubMed

filter and MESH term strategy: not

written in English, article types

according to the include criteria and

human model

39 articles assessed for eligibility

177 records excluded by review

of titles and abstracts

These papers just contained key

words, but they did not study

obesity and influenza

24 articles excluded

10: no statistical data or cases

4: cannot get full-text on the

website

4: study contents is not suitable

my topic

3: pooled analysis

3: other influenza A subtypes

15 articles included in the systematic

review

17 articles included in the systematic review

3: China and Hong Kong

Others are Europe and American

2 articles identified through reading

articles reporting subgroup analysis

results

The association between obesity and influenza A (H1N1)

Association between obesity or morbid obesity as well as hospitalizations

A total of two papers reported on the association between hospitalizations and

obesity. Because hospitalizations had always been regarded as control group to

compare other outcomes. Morgan O W, et al. (2010) 26showed morbidly obese

(BMI ≥40) with or without ACIP recognized chronic conditions would be more

likely to require hospital admission associated with hospitalization (OR = 4.9, 95%

CI 2.4–9.9), (OR = 4.7, 95% CI 1.3–17.2) p value <0.05 respectively. What is more,

the Martin, Emily T., et al. (2013) states obese individuals (BMI ≥30 kg ⁄m2)

were more risk to get hospital admission: [OR = 2.93 (95% CI 1.50, 5.71), P =

0.002] comparing with all non-obese individuals. They had the same

consequence that obesity and morbid obesity were associated with hospital

admission. Obesity was found to be significantly associated with hospitalization,

because Van Kerkhove, Maria D., et al. (2011) 41 showed that the risk of

hospitalization (mean RR hospitalization = 15.0[IQR 9.5-20.4]. Overall I could

find that no matter of obesity or morbid obesity were both high risk for

hospitalization, but morbid obesity adult person has more likely to required

admission of hospital.

Obesity or morbid obesity as a risk factor for ICU admission

A significant number of patients admitted to the intensive care unit (ICU) in

Canada, Ireland, France, USA, Spain and China who had a BMI ≥30 kg ⁄m2.42 And

the global pooled meta-analysis showed that morbid obese BMI ≥40 kg ⁄m2

H1N1 patients were as twice as likely to be admitted to ICU or died (OR: 2.01, 95%

CI: 1.29–3.14, P < 0.002) compared with H1N1 patients who were not morbid

obesity.43 And I found that obesity was a risk factor for ICU admission OR=3.8 CI

[3.0- 4.9] in the Hanslik, T, et al. (2010) as well as when BMI ≥40kg/m2 patients

for OR for ICU admission is 29.35, CI (1.24 – 70.70) p<0.05 Louie J K, et al. (2009).

So in conclusion, obesity and morbid obesity were the higher risk for ICU

admission.

Association between obesity or morbid obesity and death

Morgan O W, et al. (2010) 26had shown that in individuals who aged ≥20 years

death was associated with obesity (OR = 3.1, 95%CI: 1.5–6.6) adjusted chronic

diseases and whit morbid obesity (OR = 7.6, 95%CI 2.1–27.9).

Mortality was associated with all morbid obesity, due to the following data: BMI

40-45kg/m2: 6.5 (95% CI: 5.7–7.3), BMI 45–49.9 kg/m28.9 (95% CI: 7.4–10.4),

50–54.9kg/m29.8 (95% CI: 7.4–12.2), and BMI 55–59.9 kg/m2 13.7 (95% CI:

10.5–16.9).44Louie J K, et al.in 20119 and in 2009 had two studies which all

proved that In multivariate analysis, BMI>40 kg/ m2 OR, 2.8; 95% CI (1.4– 5.9)

were associated with death and the obesity BMI≥30 kg/m2 was significantly

related with death OR= 3.6 CI (1.9-6.2). Consequently, obesity and morbid

obesity were associated with death.

Association between obesity or morbid obesity and severe illness

Many articles of epidemiologic data had illustrated obesity as a risk factor for

admitted to intensive care units and increased mortality from infection with A

(H1N1) pdm09 virus influenza worldwide.45 And severe illness contains these

outcomes. In severe morbidity aspect, there is the study Yu, Hongjie, et al. (2011)

had list different age range to analysis then relationship between obesity and

severe diseases. The results of case control study, which severe illness is the

treatment group and non-severe illness were control group, were that OR=1.40

(1.17–1.69) in 2–17 years of age infected patients, as well as OR=1.99 (1.66–

2.37), p<0.001 in 18–59 years of age, respectively. However, when people > 60

years of age, OR was 0.66 (.38–1.15), p=0.142. Additionally, the Viasus D, et

al.(2011) illustrate that morbid obesity was the independent factors for severe

disease (OR,6.7; 95% CI, 2.25–20.19) p<0.001. Besides Ren, Yan-yan, et al. (2013)

achieved OR of obese was 35.61 (95% CI: 7.96-159.21) (P<0.001). Fuhrman, C.,

et al.(2009) 40also illustrated that obesity was related with severe cases for

influenza infection because of adjusted OR= 9.1 CI(4.4-18.7) P<0.05.

Nevertheless, the Coleman, Laura A., et al. (2013)29 study got the opposite

outcomes neither obesity nor extreme obesity were associated with severe

disorders with all years combined for influenza A, reasons were (OR=1.02 CI

(0.59, 1.78) and OR=1.53 CI (0.76, 3.08) for obesity and extreme obesity

respectively, after adjusting for confounders. These seemed that there are lots

of conflicts among them, but actually we could find commons and the truth.

Because participators of Coleman, Laura A., et al. (2013) 29study did not limited

age ranges, the over sixty years obese elders who could be regarded as a risk

factor for severe influenza patients had been included into their result. At last I

could confirm that obese adult population <60 years of age (BMI ≥ 30 kg/ m2)

was a risk factor among all cases of influenza A for server outcomes. Especially, if

school ages children (7-18 years) have BMI>20.93, they will be the high risk

group for serious illness the OR= 1.95 (1.43–2.66) p<0.01 adjusted age and

gender.

Combined association between obesity or morbid obesity and morbidity or

mortality

In spite of so many papers proof that obesity had become an obvious risk factor

for severe illness, ICU admission and mortality for influenza A patients, and

obesity (age < 60) is related with the hospitalizations for infection. However,

Jain, Seema, et al.(2009)36 and Díaz, Emili, et al. (2011) 33demonstrated the

opposite result the obesity BMI≥30 kg/m2 OR for ICU and death to

hospitalization =0.75 CI (0.40 – 1.43) and The morbid obesity BMI≥40kg/m2

OR for ICU and death to hospitalization=1.53 CI(0.59 – 4.01) p< 0.05 . Thus,

obesity was not significantly associated with ICU and mortality from the

pervious data. Indeed, we could easily find that the control group was

hospitalization, which mean these patients were severe illness. So there were

some little differences among them. In Bassetti, M, et al. study 38, the result was

that there was no statistically significant between obesity and severe disease in

the very small simple size that caused easily systemic error. Hence, these

defected outcomes should be calculated again in bigger sample with the same

condition.

Several reviewed studies demonstrated that obese people, when in contrast to

non-obese group of similar age, or when compared to the general population,

have an increased risk of mortality and morbidity outcomes due to 2009 H1N1

infection. But whether or not obesity could be identified an independent risk for

infection of influenza. According to this review, although I could not find effective

evidences to prove obesity is an independent risk for infection, these results

indicate that obesity especially morbid obesity is a significant novel risk factor

for severe outcomes, hospitalizations, ICU admission and death from A (H1N1)

virus infection.

Chapter 4 - Discussion

Overview

This systematic review had identified the impact of obesity on the influenza

infection. Through these papers I found that obesity (BMI ≥30 kg ⁄m2) was a

novel risk factor for severe illness (age <60) and hospitalizations in influenza

infected cases especially morbid obesity (BMI ≥40 kg ⁄m2). And the risk of

obesity for ICU admission and death among influenza A (H1N1) patients had

been proved in previous literature. 46 47 Of course there would be some

cofounders in this review and including individual article, such as ages, chorionic

diseases, gender and race.

Reviewing the impacting mechanism of obesity on the influenza A infection was a

hard work if I wanted to well evaluate, because most of human studies about this

topic were lacking. So I apply animal models combine results of PBMCs from

influenza A cases to analysis the impact. In mice models the immune response of

influenza infection is clearly associated with obesity.

Impact of obesity on the influenza A infection

In order to evidences of the association between influenza A and obesity, I

searched many related experiments on human or animals model. It is expected

that obesity with influenza infection will alter the immune system and response.

Studies of human cases will include Peripheral blood mononuclear cells (PBMCs)

to explore kinds of immune mediators and numbers changes between lean and

obese cases. Terán-Cabanillas, Elí, et al. (2013)48 illustrates that reduction of

IFN-α and β as well as NF-kB expression will occur in obese-infected patients.

Obesity would decrease quantities of circulating T-cell subsets and T-cell

functionality, especially CD8+ T cell subsets in human model. On the contrary,

obese individuals with white adipose tissue (WAT) would increase expression of

interleukin (IL)-6, tumor necrosis factor (TNF)-a, and C-reactive protein (CRP)

which could result in a low-grade, chronic inflammatory state in Karlsson, Erik

A.,et al.(2012)49. Furthermore, Zhang A J X, et al. (2013)50 found that leptin

reduction by obesity might play an important role in pro-inflammatory cytokine

secretion and result in increasing expressions of IL 6 and TNF-α. The simple

mechanism of process would be shown in appendix 2.

Chronic disorders

Indeed, individuals with a BMI ≥30 kg ⁄m2 increase the risk of lots of physical

and mental diseases. 64% of obese men and 77% women will get diabetes

especially type 2 diabetes, so chronic disorders obesity induced might be the

effect modifiers or confounders for obesity. 51 The OR of ICU admission among

hospitalizations with diabetes was 4.29 (95% CI 1.29–14.3) compared to others

without. 52 Diabetes also could contribute to the increased morbidity and

serious illness risk of A (H1N1) virus influenza infection, which is closely related

with obesity. Cardiovascular disease is also one kind of high risk in complications

of obesity.53 RRs of severe disease were hospitalized people 2.0 CI (1.5–2.2) and

death 9.2 CI (5.4–10.7) respectively. Data on cardiovascular disease in this

population were available to relatively ensure connection between CVD and

serious illness risk of influenza A. Although I need to further studies to

comprehend whether obesity with its commonly related comorbidities

contribute to the impact complexly and together or these comorbidities solely

influence infection, I could discover that obesity would effect the infection of

influenza indirectly or combined with other chronic diseases to impact it.

Additional impacts from obesity

Of course there were some physical effects of obesity on infection. Obesity would

increase airway resistance, impaired gas exchange and alter lung function, which

includes mechanical changes, reducing of lung volumes, and increasing breathing

rates.54

Indeed, several comorbid conditions such as CVD and diabetes which were

associated with obesity had been treated as a risk factor for severe illness of

influenza A.55 In this regard, obesity had indirectly effect or chronic disorders

complexly with obesity influenced on influenza infection need to further studies

to research the relationship.

Implications

According to the above results, we could discuss about the practical prevention

and policy for influenza A.

First the best way to prevent influenza is through use of influenza vaccine.56 So

Centre of health protection and Hospital Authority were able to put obesity into

high-risk population, which needed to receive vaccine during seasonal influenza

epidemics. HA and CHP will set the guideline which introduces vaccine

advantages and basic knowledge of prevention for obese and morbid obese

people. And primary schools should strengthen monitor of obese children and

communities had to strengthen management of the obese elders. During the

influenza season, the government should take vaccine to relevant high-risk

population. In order to prevention of influenza, all persons could check details of

the seasonal flu vaccine from doctors.

Second these results reinforce that the importance of early identification and

treatment were necessary in this high-risk population who suspected influenza.

When obese people infected with influenza A or subtypes, hospitals should

increase monitoring to control severe complications and treatment obese

infected patients optimally, because these group would be more likely getting

worse.

What is more, publicity of good lifestyle was necessary. Therefore, obese people

should usually maintain a balanced diet, regular exercise, adequate rest, and non-

smoke. During influenza season, high-risk population should avoid to public

places and crowded groups. Certainly prevention of obesity and keep healthy

lifestyle would be regarded as one kind of excellent measures for preventing

influenza virus infection.

Further studies about influenza and obesity should not be ignored. RCT had

strong statistical significance and clinical study value that can help us prove that

obesity or morbid obesity was an independent risk factor for influenza infection.

Due to the ethic reason, I could not find any RCTs on the website called clinical

trail Gov. So I held the view that we might need more large sample of community

experiments to explore deeply the association between obesity and influenza

infection.

Hong Kong, as a major city and port, has lots of floating population which will

readily cause influenza epidemics, so preventions should be taken strictly and

management should be improved. Government could set up a special department

to monitor and evaluate all high-risk population.

Limitations and strengths

This literature review had to suffer several identified limitations. First of all, this

review only included English studies, which would be lack of many other regions’

information and cases without English. Secondly, during the search, because

the author alone wrote the review, I might lose some important literatures, which

would cause selection bias for review about topic with using these simple

keywords and combination. Therefore, I should research more times and detail in

more other databases with more similar keywords. Third point, kinds of bias not

only existed in individual papers but also in the review. Studies must suffer

different biases: such as clinical tail, case control study and cases cohort study

would have selection bias, performance bias of various individuals and reporting

bias. Of course, I would do assessment for them in the following part. When

hospitals and department of health collected information about cases, there were

some missing cases and inaccurate information about weight, which was called

information bias. I could not avoid selection bias for instance admission rate bias

and allocation bias in human model. And there were wide differences in

surveillance systems and case management policies of different countries.

Potential confounders had played a significant role in this review, different ages,

gender, chronic diseases, races, temperature, air pollution and lifestyles, which

all would influence the result, could not be adjusted totally in study. And fourthly,

there were not RCTs in results of review. The fifth limitation was that it was

difficult to compare all different outcomes from different studies that applied

various designs and statistical measurements without original epidemical data.

Finally, publications bias could not be avoided, because there were lots of studies,

which might be positive or negative, had not been published. In my review, I

could not conclude all related papers, studies and results into my review to

analysis.

Strengths of this review were the combined search strategy and a large number

of papers reviewed. And I had assessed quality of studies according to the

consort and strobe checklist.

In addition, vaccination should be extended to all health care staff; only in this

way can the spread of infection be minimized. Vaccination is still undoubtedly

one of the most indispensable in the prevention of influenza.

Chapter 5 - Conclusions

Understanding risk factors of influenza A infection is essential in designing

specific interventions to control mortality and morbidity of influenza A (H1N1).

In this review, I have provided several, but not all, pieces of evidence for the

relationship between obesity and morbidity or mortality. Along with the

epidemic of obesity, the prevalence of obesity is increasing at an alarming rate.

Obesity especially morbid obesity, which should be paid more attention, will

increase risk for morbidity, hospitalizations, severe illness and mortality of

influenza A infection. So department of Health should establish a new guideline

to monitor and assist high-risk group for reduction of severe cases and deaths.

And these results can help policy makers and people to cope with the next

influenza A pandemic in preparation. Whether findings can be applied to Hong

Kong populations still needs further clarification, because the BMI classifications

for obese are different. Hence, effective interventions from future studies for

Asians will be taken to reduce prevalence of influenza A infection in Hong Kong

in a long run. Absolutely additional research or epidemiological investigations for

the development of antiviral and anti-obesity therapy are also required.

Appendix

Appendix 1 Summary of human cases and model

Author (Year) Study Design Sample Size Participants Control Main findings

Yu, Hongjie, et al.

(2011)24

Case-control study of

china and do multivariable

logistic regression

9966 confirmed case

patients of the total 31,562

confirmed case patients with

full information from China

CDC

Patients hospitalized with

laboratory-confirmed

2009 H1N1 infection in china

- Age and obesity

1.Some one aged 2–17 years Obese OR=1.34 CI (1.10–1.63) p=0.004

OR of Severe sick to Non-severe illness =1.40 CI (1.17–1.69), P=0.001

OR Non-severe illness to general population =10.45 CI (9.49–11.52), p=0.001

2.Aged 18-59 OR=1.91 CI (1.57–2.31), P<0.001

Severe disorders compare to Non-severe illness 1.99 (1.66–2.37)

Non-severe illness VS general population 1.35 (1.18–1.54) p<0.05

3.Over 60 years old OR=0.68 CI (.37–1.25) p=0.211

Severe illness towards Non-severe diseases for OR= 0.66 (.38–1.15), .142

Non-severe illness vs. general population for OR=1.02 (.69–1.51), .906

Obesity was a risk factor for severe illness when below 60 years old

Ren, Yan-yan, et

al. (2013)

1:1 matched Case–control

study and use

multivariable logistic

regression analysis

343 severe hospitalizations

and 343 randomly selected

mild controls was conducted

of all 3639

Study participants by severity of

manifestations from 2009 H1N1 Influenza,

as reported to the Shandong Center for

disease control and prevention, China,

during the period from May 13, 2009 to

March 31,2010

Patients with mild

manifestations

1.OR of overweight was 3.70 CI (2.04-6.72)

2. Obese OR= 35.61 (95% CI: 7.96-159.21) (P<0.001)

Morgan O W, et

al.

(2010)

A case-control study Remaining 437 patients of all

identified 565 hospitalized

patients with confirmed 2009

pandemic H1N1 infection

during April to July 2009,

304 deaths among persons

with 2009 pandemic

influenza A (H1N1) reported

to CDC in USA

Identified hospitalized patients with

confirmed 2009 pandemic H1N1 infection

which excluded patients who were

pregnant and who were 2 <years old.

Deaths with 2009 pandemic influenza A

(H1N1) from CDC and exclude pregnant

women and children <2 years old.

Patients or death

with recognized

chronic medical

conditions include

cardiovascular

disease,

pulmonary

disease, liver

condition, cancer,

and diabetes.

1. People who over 20 years old, hospitalization was associated with being morbidly obese (BMI ≥40)

with ACIP-recognized chronic conditions (OR = 4.9, 95% CI 2.4–9.9)

2. Obese Individuals without ACIP-recognized chronic conditions (OR = 4.7, 95%CI 1.3–17.2)

3. Individuals aged over 20 years without ACIP-recognized chronic medical conditions death was

associated with obesity (OR = 3.1, 95%CI: 1.5–6.6) and morbid obesity (OR = 7.6, 95%CI 2.1–27.9).

Kim C O, et al.

(2012)

Case control study All 4778 school-aged

children

Participators are school-aged children

from Seodaemun-gu district students (7–

18 years old), Seoul, South Korea

between 18 November and 8 December

2009 who agree with this study and had

not got vaccination.

- 1. Body mass index (BMI) was related with H1N1 infection,

BMI>20.93 OR= 1.95 (1.43–2.66) p<0.01 adjusted age and gender.

2. In addition, WC quartiles were significantly associated with H1N1 infection after adjusting for BMI and

other confounding variables WC > 71.11 OR (95% CI): 2.71 (1.74–4.24),

Viasus D, et al.

（2011）

An observational analysis

of a prospective cohort

study

All 585 patients All adult patients admitted to the hospital

for at least 24 h with confirmed influenza A

(H1N1) virus infection from June 12 to

November 10, 2009,

Patients with

severe disease

1. Independent factors for severe disease were below 50 years old (OR, 2.39; 95% CI, 1.05–5.47),

2. Chronic comorbid conditions (OR, 2.93; 95% CI, 1.41–6.09),

3. Morbid obesity (OR,6.7; 95% CI, 2.25–20.19), concomitant and secondary bacterial co-infection

(OR, 2.78; 95% CI, 1.11–7) and early oseltamivir therapy (OR, 0.32; 95% CI 0.16–0.63).

Coleman, Laura

A., et al.(2013)

Prospective cohort study The 2007–2008 (n = 903),

2008–2009 (n= 869), and

2009 pandemic (n = 851)

season

Adults >20 years with a medical encounter

for acute respiratory illness

Test-negative 1.After adjusting confounders, neither obesity nor extreme obesity were associated with service

outcomes 2009 H1N1 influenza by season or for all years combined (OR=1.02 CI (0.59, 1.78) and

OR=1.53 CI (0.76, 3.08) for obesity and extreme obesity respectively.

2.Obesity was not associated with medically attended influenza among adults in this population.

Martin, Emily T.,

et al.(2013)

A retrospective cohort

study

A total of 161 patients Patients are at least 18 years of age

admitted to the emergency or inpatient

ward of one of the seven hospitals in the

Detroit Medical Center (DMC) system with

a positive clinical laboratory confirmation

of influenza(H1N1) from January 1

through March 31, 2011. All hospitals

were located in the metropolitan Detroit

area.

Underweight (BMI < 18_5), and pregnant

women patients were excluded.

Non-obesity 1. Comparing to non-obese individuals, obese people were more likely to require hospital admission:

[OR = 2.93 (95% CI 1.50, 5.71), P = 0.002].

2.Among hospitalized patients (n = 101), obese people were more likely to require a lengthy hospital

stay (over seven days): [OR: 3.86 (95% CI: 1.03, 14.42), P = 0.045].

Louie J K, et

al.(2011)

Case control study 534 case patients Case patients who were hospitalized with

or died due to 2009 H1N1 infection were

reported in California, who should be older

than 20 years age have enough

information and not pregnant women.

1. At the first 4 months of the pandemic, half of the California residents who were over 20 years

hospitalized with 2009 H1N1 infection were obese.

2. The prevalence of BMI >30 in adults in this case series (51%) was 2.2 times and 1.5 times that

estimated for all adults in California (23.2%) and US (33%), respectively.

3. In multivariate analysis, BMI>40 kg/m2 (OR=2.8; 95% [CI], 1.4– 5.9) and BMI >45 (OR= 4.2; 95%

CI, 1.9–9.4) were associated with mortality.

Díaz, Emili, et al.

(2011),

A prospective,

observational, and

multicenter Cohort study

416 had completed ICU stay

Voluntaries >15 years oldregistry created

after the first reported ICU case. Fever;

respiratory symptoms consistent with

cough, sore throat, myalgia, or

influenza-like illness; and acute respiratory

failure, plus microbiologic confirmation of

A(H1N1).

Non-obesity 1.Obesity was not significantly related with ICU mortality

(Hazard ratio= 1.1; 95% CI(0.69-1.75); P=5 .68).

Yang, Lin, et

al.(2013)

Cohort study Total population of 66820

elders

Aged 65 years and over during July

1998 to December 2010 in Hong Kong,

1. Hazard ratio of influenza-associated mortality was moderate obesity HR 1.018 (0.980, 1.058) and

severe obesity groups HR1.062 (0.972, 1.162) .

2. Obesity was related with higher mortality risks of influenza in old population.

Louie J K , et

al.(2009)

Case – control study 280 obese participants of all

1088 cases

Somebody who was hospitalized at least

24 hours or died with laboratory confirmed

pandemic

2009 influenza A (H1N1) virus infection.

And these cases should be obesity.

Survival obese

infected cases

1. There were no deaths cases aged 0-17 years old.

2. After calculation, others were adults all aged ≥ 18 years old

the obesity BMI≥30 kg/m2 OR for death to hospitalization =1.90 CI (1.07 – 3.38)

The morbid obesity BMI≥40kg/m2 OR for death to hospitalization=1.95 CI (1.07 – 3.56) p< 0.05

3. Statistical significance showed that obesity and morbid obesity were both risk factors for death of

influenza infection in adult hospital patients aged above 18 years old.

Barrau M, et al.

(2012) 57

Observational case control

study

347 hospitalized cases in

total included 331 confirmed

and 16 probable cases

During the 23 July 2009 to 3 March 2010,

347 people infected with influenza A

(H1N1) pdm09 or influenza subtypes who

stayed in hospitalize over 24 hours and

had full data in in the French territories of

the Americas.

Non-severe

patients (survival,

no serious

complications and

without ICU

admissions)

1. Morbid obesity would be related with a higher risk of severe illness: RR = 4.4 95%CI =1.8–10.4)

p<0.01

2. Statistical significance proved that cases of severity were fatter than non-severe.

Jain, Seema, et

al.(2009)

Cross-sectional study 261 hospitalized cases During April to mid-June 2009, somebody

were in hospitals for over 24 hours for

tested positive for the 2009 influenza

H1N1 virus.

Survival

hospitalizations

without ICU

admission

1.the obesity BMI≥30 kg/m2 OR for ICU and death to hospitalization =0.75 CI (0.40 – 1.43)

The morbid obesity BMI≥40kg/m2 OR for ICU and death to hospitalization=1.53 CI(0.59 – 4.01) p< 0.05

2. There is no significant association between obesity and ICU or death.

Hanslik, T, et al.

(2010)

Case control study 1217 hospitalized obese

cases and 267 deaths

Obese cases with the A(H1N1)v influenza

infection during the week 37 of 2009 to

first week of 2010 in France who should

over 1 year old.

General

population in

France

1. Obesity was a risk factor for ICU admission OR=3.8 CI [3.04.9] and obesity was significantly related

with death OR= 3.6 CI [1.96.2].

Bassetti, M, et al.

(2011)

Case control study 81 patients From 1 July to 30 November in

2009,patient with influenza-like symptoms,

and who were hospitalized for more than

24 hours and BMI≥30kg/m2 in Italy

People were not

allowed in to

intensive care unit

(ICU) and survived

1. Using chi-square test get the result (X2, p>0,25).

2. There was no statistically significant between obesity and severe disease

Louie J K, et al.

(2009)

Cross- sectional study 205 cases 205 cases of hospitalization with

confirmed pandemic H1N1 influenza in

Ireland during April to October 2009.

The obesity should BMI≥40kg/m2

Infected people

without ICU

admission

1. Through calculation of BMI ≥40kg/m patients for ICU admission OR=29.35 CI (1.24 – 70.70) p<0.05

2. Morbid obesity was related with ICU admission for hospitalztion.

Fuhrman, C., et

al.(2009)

Cross –sectional study 60 obese cases of 244

severe and non-severe 514

hospitalizations

From July to November 2009 hospitalized

cases of pandemic influenza in France

with obesity.

Hospitalizations

without severe

illness

1. Obesity was associated with severe cases for influenza infection adjusted OR= 9.1 CI(4.4-18.7)

P<0.05

2. Obesity BMI ≥30 Kg/m2 could be regarded as a risk factor

Figure 2 The primary impacts of influenza virus infection on obesity

Obesity

Decrease IFN-α β

and γ, mRNA

expressions

Decrease leptin

and adiponectin

Decrease CD8+

and CD4+ cell

(memory T-cell)

Chronic diseases

(CVD, diabetes, high blood

pressure, high blood

cholesterol)

NK cells and dendritic

cells (DCs) reduce

Genetics

Increase Energy

intake (unhealthy

lifestyle)

Physical and

mental illnesses

Increase expressions

of IL 6 and TNF-α

Influenza infection

Aggravate symptoms of influenza

Influence of infection is not review

in this paper

Increased airway

resistance, impaired gas

exchange and alter lung

mechanics

Appendix 2

Strobe

Consort

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