Author

Study characteristics

Patient characteristics

Definition of favourable clinical course of influenza

Definition of unfavourable clinical course of influenza (includes at least one of the outcomes as defined in the PICO)

Prognostic factors studied and method of measurement (*prognostic factors included in final multivariate model)

Prognostic factors (mentioned in our PICO**) associated with outcomes (unfavourable course of influenza)

Estimates of prognostic effect

adjusted for all variables mentioned in former column

Comments

Bender, 2009

Type of study:

retrospective cohort study

Setting and country: community children hospital / teriary referral center, USA

Period of data collection:July 2001 to June 2004

Funding and conflicts of interest: non-commercial funding.

Inclusion criteria:

Children (<18 years, >6 months) presenting at emergency departments with influenza.

Exclusion criteria: Patients with coinfections of 2 or more respiratory viruses

were excluded. Furthermore, patients who had the first positive

influenza studies longer than 72 hours after admission, suggesting

a nosocomial infection, were excluded

Potential confounders or effect modifiers: not reported

Non-hospitalized (discharged from the ED).

N= 689

Age in months, median (IQR)

11.6 (4.4, 33.3)

Male, n (%)

362 (53%)

Children with

influenza were categorized as hospitalized (admitted to the

paediatric ward, a 24-hour observation unit, or an intensive care

unit)

N= 541

Age in months, median (IQR)

33.3 (3.6, 36)

Male, n (%)

314 (58%)

Demografic, historical, clinical, radiological and lab-variables

Presence/absence of:

High-risk medical condition*, respiratory distress, nasal congestion, current antibiotic use, emesis, cough, fever, poor oral intake, abdominal pain, pharyngitis, diarrhea,

Respiratory distress on examination*, wheeze onexamination, fever at time of examination, cough at time of examination, cough at time of examination, tititis media on time of examination.

Radiographic evidence of pneumonia* (Radiographic data was limited to presumed bacterial pneumonia. Bacterial pneumonia was diagnosed solely based on the reading of a focal infiltrate on chest radiograph by a

board-certified pediatric radiologist. Radiologists were not aware of virologic testing results.)

Laboratory confirmed data:

influenza B infection*, influenza A infection, C-reactive protein, alanine aminotransferase, erythrocyte sedimentation rate, white blood cell count, aspartate aminotransferase

Radiograhpic evidence of pneumonia (related to prognostic factor in PICO: severe respiratory infection**), high risk medical condition, respiratory distress on examination, influenza B infection

Adjusted factor-outcome associations for hospitalization, OR (95%CI):

Radiographic evidence of pneumonia, 7.82 (3.62 to 16.92)

Incremental predictive value¹: not reported

All variables were considered for inclusion for a multivariable

logistic regression model. We used backwards elimination

variable selection.

Variables were dropped either for being nonsignificant (p<0.1) or because of collinearity.

The model

to identify predictors of hospitalization was based on nonmissing

data for all variables (N = 1018). However, in a model where

missing data were imputed using multiple imputation (N =

1230), the same set of predictors was identified.

Viral testing was standard of care for febrile infants

younger than 90 days and in those patients with bronchiolitis.

Dalziel, 2013

Type of study:

Retrospective case-control study

Setting and country: multi-centre, multi country (USA, Canada, New Zealand, Portugal, Israel, Australia, Netherlands)

Period of data collection: between 16 April and 31 December 2009

Funding and conflicts of interest: non-commercial funding, no conflicts of interest

Inclusion criteria:

Children presenting at emergency departments with influenza-like illness.

Exclusion criteria:

We excluded patients as cases if they

were admitted directly into an intensive care unit from a hospital

that was not a study site (because emergency department

documentation and controls were not available), did not fulfil

CDC criteria for influenza-like illness in the emergency

department, or had suspected pH1N1 infection that was not

confirmed by laboratory testing, as defined above.

Mean age ± SD:

Sex: % M / % F

Potential confounders or effect modifiers: not reported

For each case, we identified two controls who

presented with influenza-like illness to the same emergency

department but who did not develop severe outcomes: one

random control and one age matched control.

N=265

Mean (SD) age, years

6.6 (4.7)

Mean (SD) maximum fever at home (°C)

39.0 (0.7)

Cases were children who fulfilled the Centers for

Disease Control and Prevention (CDC) criteria for influenza-like illness at emergency department presentation (fever measured at home or hospital (temperature ≥37.8°C or ≥100°F) and either

cough or sore throat), who subsequently died or were admitted

to an intensive care unit for assisted ventilation,

inotropic/vasopressor support, or both (defined as severe

outcomes) as a result of laboratory confirmed pH1N1 infection.

Age-matched controls n=265:

Mean (SD) age, years

6.4 (4.5)

Mean (SD) maximum fever at home (°C)

39.2 (0.8)

Gender, co-morbidities (asthma, pregnancy, chronic lung disease*, heart disease, diabetes, renal disease, malignancy/immunosuppression, cerebral palsy/developmental delay*), current illness (such as headache, nausea, diarrhoea), physical signs (such as: fever, heart rate, oxygen saturation), laboratory and radiographic investigations (such as radiograph, leukocyte count).

Chronic lung disease**, cerebral palsy / developmental delay**, asthma**, generalised weakness, irritable/drowsy, rhinorrhoea

Adjusted factor-outcome associations for mortality/ICU admission (compared with age-matched controls) OR (95%CI)

Comorbidities:

Chronic lung disease

8.5 (1.6 to 45.1)

Cerebral palsy / developmental delay

65.9 (8.6 to 506)

Incremental predictive value¹: not reported

Variables significant at the P=0.1 level in the

univariable analysis, and with a prevalence among cases and

controls of more than 2%, were included in the initial

multivariable models.

OR for Asthma was not reported, since they only reported significant predictors in the multivariable model

The authors did not include variables from laboratory and radiographic

investigations in the multivariable analysis owing to the low

prevalence of these variables in the control groups.

We choose the age-matched group as the reference standard for the reported OR’s

Imputation was used to account for missing variables in the multiavariable models

Dimitrijev, 2017

Type of study:

Setting and country:

Cohort study,

Serbia

Period of data collection:

2010-2014

Funding and conflicts of interest: none to declare

Inclusion criteria: laboratory confirmed influenza cases reported during the 4 influenza seasons (2010 to 2014) to Institute of Public Health of Serbia

Potential confounders or effect modifiers: not reported

Primary healthcare (n=322);

Sex (female): 157 (48.8%)

Virus:

A: 4 (1.2%)

A (H1) pdm09: 92 (28.9%)

A (H3) 158 (49.1%)

B: 67 (20.8%)

Vaccine history:

11 (3.4%)

Pregnancy in women aged 16 to 45

4 (2.5%)

Hospitalized (H) (n=329)/ ICU patients (ICU) (n=126)

Sex (female)

H: 164 (49.8)

ICU: 54 (42.9)

Virus (H):

A: 14 (4.3%)

A (H1) pdm09: 178 (54.1%)

A (H3) 77 (23.4%)

B: 60 (18.2%)

Virus (ICU):

A: 8 (6.3%)

A (H1) pdm09: 85 (67.5%)

A (H3) 17 (13.4%)

B: 16 (12.7%)

Vaccine history:

H: 8 (2.4%)

ICU: 4 (3.2)

Pregnancy in women aged 16 to 45

H: 11 (6.7)

ICU: 1 (1.9)

Sex,

adults≥65 year*

Type and sub-typed of the virus

Comorbidities*

Age (adults ≥ 65 year)**

Comorbidities** (chronic respiratory diseases, asthma, diabetes mellitus, chronic heart diseases, chronic kidney diseases, immune compromised status)

Type and sub-type of the virus (virus A, A(H1)pdm09, A(H3), B)

More than 3 days from the onset of the symptoms to visiting a physician

Adjusted factor-outcome associations for ICU/hospital admission OR (95%CI):

Hospitalized patients versus. patient treated in public healthcare:

Adults≥65 year: 3.85 (1.57 to 9.45)

Chronic respiratory diseases:

6.68 (2.68 to 16.65

Asthma:

6.82 (1.94 to 23.95

Diabetes Mellitus

4.75 (1.53 to 14.72

Chronic heart diseases

4.29 (2.02 to 9.08)

Chronic kidney diseases:

4.23 (1.35 to. 13.28

Immune compromised status: 4.31 (1.9 to. 9.74

Incremental predictive value¹: not reported

Comorbidities defined as present/absent

All test variables

with statistical significance in the univariate model

(p ≤ 0.10) were included in the multivariate model. Statistical

testing was performed at the level of statistical

significance of 0.05

Garcia, 2015

Type of study:

Retrospective electronic medical record review study

Setting and country:

Single centre, USA

Period of data collection: April 2009 to June 2010

Funding and conflicts of interest: none

Inclusion criteria:

Cases of influenza A(H1N1) pandemic virus (A (H1N1)pdm) were defined as patients aged 0–18

years who presented to TCH between 1 April 2009

and 30 June 2010, and who were diagnosed with

laboratory-confirmed A(HIN1)pdm influenza infection.

Exclusion

criteria: Cases transferred from

other healthcare organizations

Overall, 263 (38%) patients

were hospitalized without being admitted to the

ICU, and 116 (17%) were admitted to the ICU. Males were significantly more likely to be admitted

to the hospital or ICU than females (P = 0·016, OR

1·42, 95% confidence interval (CI) 1·07–1·89).

Compared to non-Hispanic whites, children identified

as minorities were less likely to be admitted to the hospital

or ICU. Black race was associated with 0·54 times lower odds (P = 0·010, 95% CI 0·34–0·87) and

Hispanic with 0·43 times lower odds (P < 0·001, 95%

CI 0·28–0·64). Compared to children with private insurance,

children with Texas Children’s Health Plan

(TCHP)/Medicaid (P = 0·004, odds ratio (OR) 0·63,

95% CI 0·46–0·86) or no insurance (P < 0·001, OR

0·21, 95% CI 0·11–0·35) were less likely to be admitted

to the hospital or ICU. Because of the strength and interaction

of these associations, we adjusted for race

and insurance status in all multivariate models.

N=316

Non-hospitalized cases were

patients who were discharged home directly from the

ED in <24 h

N=379

Hospitalized cases were defined as

those who were admitted for 524 h but were not admitted

to the ICU. ICU cases were defined as patients

admitted to the ICU directly from the ED or during

the course of hospitalization

Co-morbidities:

-cardiovascular condition* -developmental delay* -haemotological disease* -lung condition* -neurocognitive disorder* -neurological disorder* -neuromuscular disorder* -obesity* -premature birth -renal condition* seizure disorder*

Co-morbidities:

-cardiovascular condition** -developmental delay** -haemotological disease** -lung condition** -neurocognitive disorder** -neurological disorder** -neuromuscular disorder** -obesity** -premature birth -renal condition** seizure disorder**

Adjusted factor-outcome associations for (ICU)-admission (Adjusted for race and insurance status)

Developmental delay:

OR: 2.2 (95%CI: 0.99 to 4.87)

Haematological disease

OR: 2.22 (95%CI: 1.22 to 4.05)

Lung condition:

OR: 2.84 (95%CI: 1.55 to 5.21)

Obesity: OR: 3.28 (95%CI: 1.05 to 10.21)

Seizure disorder: OR: 4.71 (95%CI: 2.11 to 10.52)

Incremental predictive value¹: not reported

The following OR’s were not reported for the adjusted multivariate model: -cardiovascular condition

-haemotological disease

-lung condition

-obesity

- seizure disorder

All risk factors on univariate analysis with P≤0·25 were included in multivariate analysis. A backwards step-wise elimination of the highest non-significant value

method was used. Only those factors with P≤0·10

were considered significant in final multivariate

models.

Definitions of specific clinical events are as follows:

Dyspnoea was defined as increased respiratory rate

based on the standard respiratory rate for age, and reported laboured breathing, with or without related

cyanosis, or hypoxaemia (arterial oxygen saturation

below 90%). Cardiovascular diseases included electrical

abnormalities, physical/structural abnormalities

and congenital heart disease. Immunosuppression was defined by receipt of immunosuppressive medications

or chemotherapy. Lung disease was defined by a

collective grouping of chronic lung diseases, including

rare lung disorders. Seizures were defined as clinical

seizures with or without evidence of encephalitis or

meningitis, febrile seizures, and a pre-existing seizure

disorder with increased frequency of seizures.

Author

Study characteristics

Patient characteristics

(ILI/confirmed, influenza type/period, admissiontype)

Definition of favourable clinical course of influenza

Definition of unfavourable clinical course of influenza (includes at least one of the outcomes as defined in the PICO)

Prognostic factors studied and method of measurement (*prognostic factors included in multi-variate model)

Prognostic factors (mentioned in our PICO**) associated with outcomes (unbenificial clinical course of influenza)

Estimates of prognostic effect

Comments

Huang, 2014

Type of study:

Setting and country: databasestudy, Taiwan

Period of data collection: week 26 2009 through week 25 2012

Funding and conflicts of interest:

Hospitalized patients in Taiwan, who had onset of illness from week 26, 2009 through week 25 2012;

A confirmed case is defined as influenza-like

illness and evidence of pneumonia, neurologic symptoms,

myopericarditis or invasive bacterial infections, with a positive

influenza real-time reverse transcription PCR.

Baseline:

Of 4735 patients (413 deaths (8.7%)) who had confirmed hospitalized

influenza with complications, median age was 50 years

(IQR 24–69 years), and median length from illness onset to hospital

discharge or mortality was 8 days (IQR 5–14 days).

Potential confounders or effect modifiers: not reported

Non-fatal (n=4126)

Fatal (399)

Age*, sex*, high-risk medical condition*, vaccinated, oseltamivir treatment withing 48 hours after illness onset*, Influenza PCR result.

Definition high-risk medical condition: Persons who have chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, neurologic, neurodevelopment, hematologic or metabolic (including diabetes mellitus) disorders;

are immunosuppressed (including immunosuppression caused by medications or by HIV);

are pregnant;

are severely obese (body mass index ≥35).

Age**, high-risk medical condition**, age group (over/under 50 years), sex, vaccinated y/n, oseltamivir treatment withing 48 hours after illness onset, influenza PCR result (H1N1/H3N2/B)

Adjusted factor-outcome associations for mortality, OR (95%CI)

Age ≥50 years:

2.05 (p<0.001)

High-risk medical condition:

3,38 (p<0.001)

Incremental predictive value¹: not reported

Variables that differed between the nonfatal and fatal

cases at p,0.05 were evaluated in the multivariate logistic

regression models by using backward elimination procedures,

retaining variables that were associated at p,0.10.

Data in the multi-variate analysis excluded 210 cases (14 deaths) for which low viral loads prevented further subtypings.

LI, 2009

Type of study:

Retrospective cohort

Setting and country:

Two academic medical centers, USA

Period of data collection: 1999 to 2006

Funding and conflicts of interest: None

Inclusion criteria:

Adult patients admitted to ICUs of academic medical centers (consecutive patients).

Laboratory proven

influenza virus infection was defined as follows4: one or more

signs or symptoms of flu-like illness, including abrupt onset of

fever, cough, headache, and myalgia accompanied by the laboratory

evidence of influenza virus infection.

Exclusion criteria:

Not applicable

A total of 111 patients, 54 (48.6%) male, 106 Caucasian (95.4%),

with a mean age of 65.3±18.9 were admitted to the medical ICUs

of two tertiary care hospitals. There was no difference in mortality

between influenza A and influenza B (18.5% versus 25%, P = 0.65). Sixtyfour

patients (57.7%) had pre-existing chronic pulmonary disease

and 19% were immunosuppressed. Only 35 (31%) patients had

received influenza vaccination before hospital admission, although

the vast majorities (106, 95%) were eligible for routine vaccination

based on age and/or chronic disease criteria.

Potential confounders or effect modifiers: not reported

Survivors (n=90)

Non-survivors (n=21)

APACHE III*, ARDS*, history of immunesuprression*

No informationa available on univariate model

APACHE III, ARDS**, history of immunesuppression**

Adjusted factor-outcome associations for mortality, OR (95%CI)

ARDS (acute respiratory distress symptom): 7.7, 2.3–29.

History of

immunosuppression 7.19 (1.9–28).

Incremental predictive value¹: not reported

Immunosuppression was defined as therapy with immunosuppressants,

chemotherapy, radiation or long term/recent high dose of steroids; or active leukemia, lymphoma or AIDS.5 Acute lung injury

(ALI) and ARDS were defined according to the American–European

Consensus Conference.Primary and secondary bacterial infections

were defined according to Center for Disease Control (CDC)

criteria

Tekin, 2019

Type of study:

Cohort study

Setting and country:

Multicentre (11 hospitals); Turkey

Period of data collection: 2015-2016

Funding and conflicts of interest: No funding of any kind was received. The data were generated

as part of routine work. Conflicts of Interest: none to declare.

Inclusion criteria:

Patients who were hospitalized for

an influenza-like illness (ILI) in Istanbul during the 2015–2016

influenza season and who were positive for influenza A by PCR

were included.

Exclusion criteria:

Patients who were diagnosed with influenza B and

influenza A by rapid antigen test (ELISA) were excluded.

The mean age of the 222 patients hospitalized with influenza A

was 39 years (standard deviation (SD) 27 years); 47 patients (21%)

were older than 65 years. One hundred and twenty-six patients (57%) were female. Among the hospitalized patients, 25 (11.2%) died. Thirteen of the 25 fatal cases (54%) had influenza A(H3N2)

and 11 (45%) had influenza A(H1N1); the virus was untyped for one patient (p < 0.001). There were no deaths under age 16 years. The mean age of the patients who died was 65 years; the mean age of

those who survived was 36 years (p < 0.001). The fatality

rate was significantly higher among patients with chronic heart and kidney diseases (p < 0.001), chronic neurological diseases (p = 0.009), and malignancies (p = 0.021)

Potential confounders or effect modifiers: not reported

Survivors (n=197)

Non-suvrivors (n=25)

Age>65 years*

H2N2 versus H1N1*

One day delay for oseltamivir*

Secondary bacterial infection*

Presence of malignancy*

Age>65 years**, H2N2 versus H1N1, one day delay for oseltamivir secondary bacterial infection, presence of malignancy

Adjusted factor-outcome associations for mortality, OR (95%CI)

Age>65 year: OR 6.0 (95%CI: 2.07 to 23.08)

Incremental predictive value¹: not reported

Parameters found to be statistically significant in the

univariate analysis were tested by logistic regression to predict the

risk of fatality.

The independent variables included in the model were age >65 years, detection of influenza A(H3N2) versus influenza A(H1N1), early use of neuraminidase inhibitors, secondary

bacterial infection, and having a malignant disease

Statistical significance was set at

p < 0.05.

Lynfield, 2014

Type of study:

Prospective cohort study

Setting and country:

Period of data collection:

October 2009 and December 2012

Funding and conflicts of interest:

Leidos Prime Contract HHSN261200800001E, NCI/NIAID. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No conflicts of interest.

Inclusion criteria:

A(H1N1)pdm09 virus infection in adults (≥18 years of

age), ranging from outpatients presenting with mild ILI symptoms

(FLU 002) to those with more serious disease requiring hospitalization

(FLU 003), and both studies included follow-up periods.

Initially, sites were not open to enrollment until A(H1N1)pdm09

virus was circulating in their geographic areas.

Laboratory confirmed A(H1N1)pdm09 virus infection

Exclusion criteria: not applicable

Three hundred and seven (78.3%) of

the 392 A(H1N1)pdm09 patients were enrolled from a general

hospital ward and 85 (21.7%) were enrolled from an ICU. The

median age of hospitalized patients with A(H1N1)pdm09 was 48

years;

Fifty-one percent of patients were female;

11% were Asian, 4% were black, and 85% were white/other; the median BMI was 26 kg/m2; 5.3% had a BMI of ≤40 kg/m2; 30%

reported smoking; and 25% of the women aged ≥45 years were

pregnant.

Potential confounders or effect modifiers: not reported

Outpatients n=80;

N=22 with unknown disease status

ICU admission / Hospitalization (FLU003 cohort)

N=290

749 hospitalized patients were enrolled of whom 392 (52%) had laboratory-confirmed A(H1N1)pdm09 virus infection.

Enrolled outpatients with ILI were followed for 14 days for

hospitalization or death. Henceforth for FLU 002 patients, this

composite outcome is referred to as ‘‘disease progression’’.

Enrolled hospitalized patients were followed for 60 days. For general ward patients, outcomes assessed included death, ICU

admission and/or mechanical ventilation, or prolonged hospitalization;

the latter was defined as an inpatient stay exceeding 28

days of the 60-day follow-up period, not necessarily consecutively.

For patients enrolled after ICU admission, death or prolonged

hospitalization for.28 days were the primary outcomes. For FLU003 patients, this composite outcome, stratified according to

whether patients were enrolled from a general ward or ICU, is referred to as ‘‘disease progression’’.

Race (Asian, black, white/other)*; Age, female*; BMI*; onset to enrolment*; season of enrolment*; medical history (smoker, Asthma/COPD, Diabetes, CVD/liver/renal, HIV/other immune)*; enrolment status (general ward; ICU)*

Age**, Co-morbidities** (Asthma/COPD, Diabetes, CVD/liver/renal); HIV/other immune.

Adjusted OR associated with mortality in FLU003 cohort OR (95%CI)

Age: 1.31 (0.95 to 1.8)

Co-morbidities:

Asthma/COPD:

0.49 (0.13 to 1.79)

Diabetes

3.33 (0.97 to 11.4)

CVD/liver/renal: 1.15 (0.37 to 3.61)

Immune-diseases:

3.55 (1.1- 11.5)

Incremental predictive value¹: not reported

enrolled outpatients with ILI were followed up for 14 days for hospitalization or death. Enrolled hospitalized patients were followed for 60 days (outcomes assessed: death, ICU admission, mechanical ventilation, prolonged hospitalization); for patients enrolled after ICU admission: death and prolonged hospitalization were assessed.

Length of hospitalization, resolution of symptoms and resumption of normal activities were assesses at 28 and 60 days after enrolment. Multiple imputation was used for incomplete outcome data

In our analysis we present the FLU 003 cohort since mortality data were available

Among women aged ≤

45 years, pregnancy was associated with an increased risk of

progression in FLU 002 (OR =30.1; p = 0.015) and was not

associated with disease progression in FLU 003 (OR =0.88;

p = 0.89) (p= 0.07 for difference in ORs).

Labeaud, 2013

Type of study:

Retrospective cohort

Setting and country:

Children hospital single centre, USA

Period of data collection: April 2009 to April 2010

Funding and conflicts of interest: not described

Inclusion criteria:

Medical records of all children hospitalized between April

2009 and February 2010, with laboratory-confirmed H1N1

Exclusion criteria:

-

There was no significant difference in H1N1 severity

between age groups or by gender. Race differed among groups,

with those self-reported as “white” more likely to have severe

cases than African Americans or Hispanics (P = 0.02). There was

no difference in average body mass index between groups; obesity

defined as >25.0 kg/m2 was not associated with more severe dis

ease

Potential confounders or effect modifiers: adjusted for age, gender, ethnicity

Hospitalization on general wards (n=90)

paediatric intensive care unit admission, intubation, or death

N=47

Chronic comorbid conditions

Advisory Committee on Immunization

Practices risk factors

Cardiac

Pulmonary

Immunosuppression

Metabolic

Neuromuscular

Hemoglobinopathy

Genetic

Non-Advisory Committee on Immunization

Practices risk factors

Gastrointestinal

Obesity, Prematurity

Age**, sex, race, neuromuscular disorders, O2 requirement, hyponatremia, white blood cell count, platelet count.

Adjusted factor-outcome associations for mortality, ICU-admission or intubation, OR (95%CI)

Age (OR):

0.94 (0.83 to 1.05)

Incremental predictive value¹: not reported

A multivariate logistic regression

model adjusted for age, gender and ethnicity was constructed based

on those factors that approached significance (P < 0.15) to predict

severity of H1N1

Chaves, 2013

Type of study: database study.

Setting and country: surveillance data, USA

Period of data collection: October 2010 through April 2011

Funding and conflicts of interest:

Financial support. The Influenza Hospitalizations Surveillance

Network (FluSurv-NET) is a collaboration of state health departments, academic

institutions, and local partners and is funded by the Centers for

Disease Control and Prevention (CDC). This publication was supported in

part by Cooperative Agreement number CDC-RFA-CK12–1202 and

5U38HM000414 from the CDC. Its contents are solely the responsibility of

the authors and do not necessarily represent the official views of CDC.

Potential conflicts of interest. W. S. is a member of data safety monitoring

boards for Merck and Sanofi-Pasteur and occasionally consults for Pfizer, GlasoSmithKline, and Dynavax.All other authors report no potential

conflicts.

Inclusion criteria:

A person residing in the surveillance area who was admitted to 1

of the surveillance hospitals ≤14 days after or ≤3 days before a

positive influenza test (children / adults)

-October 2010 through April 2011.

Patients treated with antivirals

 Virus type: pH1N1 / B; H3N2 influenza A

Exclusion criteria: hospital acquired

influenza cases (defined as those with onset >3 days

after hospitalization), pregnant women

Demographic characteristics in hospitalized children

were similar by virus type and subtype, although the age distribution

of children with H3N2 was slightly shifted toward children

aged <5 years (P =.02).

Among adults, distribution of cases by virus type and

subtype varied significantly by age (P <.0001). Among those with H3N2, 60.8% of hospitalizations were in those aged ≥65

years, compared with 42.4% and 14.2% among influenza B and pH1N1 respectively. Hospitalizations associated with pH1N1 were highest among those aged 18–49 years (45.7%) and 50–64

years (40.1%). Morbid obesity was more common among patients hospitalized with pH1N1 (18.2%) than among those with H3N2 (9%) or influenza B (9.6%; P <.0001).

Potential confounders or effect modifiers: not reported

Non-severe: admission to hospital. Children: n=689; adults: n=2255

Patient was classified as having severe influenza if admitted to

an ICU or if the patient died during hospitalization.

Children: n=141; adults: n=536

Virustype*, Age*, sex, underlying medical conditions, selected medical conditions (asthma*, chronic lung disease*, chronic vascular disease*, chronic metabolic disease*, neuromuscular disorders*, immunosuppressive status, developmental delay, renal disease, morbid obese), antiviral started <3d from admission, vaccination≥14 days prior to hospitalization.

For adults: morbid obesity and ntiviral started <d from admission were also included in multivariate model, in addition to * (children)

Children:

Virustype, Age**, underlying medical conditions, selected medical conditions (asthma**, chronic lung disease**, chronic vascular disease**, chronic metabolic disease**, neuromuscular disorders**) antiviral started <3d from admission.

For adults:

Virustype, Age**, underlying medical conditions, selected medical conditions (chronic lung disease**, chronic vascular disease**, chronic metabolic disease**, neuromuscular disorders**) antiviral started <3d from admission.

Adjusted factor-outcome associations for mortality or ICU admission, OR (95%CI)

Children:

Age:

<2 years:

1.17 (95%CI: 0.61 to 2.22)

2-4 years:

1.25 (.064 to 2.44)

5-17 years: reference.

Selected underlying medical conditions

Asthma:

1.26 (0.66 to 2.39)

Chronic lung disease:

2.11 (0.97 to 4.57)

Chronic vascular disease:

1.15 (.35 to 3.74)

Chronic metabolic disease: 5.23 (1.74 to 15.69)

Neuromuscular disorder: 4.84 (2.02 to 11.56)

Adults:

Age:

18-49 years:

Reference

50-64 years:

1.2 (95%CI: 0.88 to 1.64)

≥65 years: 0.94 (0.67 to 1.32).

Selected underlying medical conditions

Chronic lung disease:

1.46 (1.12 to 1.89)

Chronic vascular disease:

1.19 (.92 to 1.54)

Chronic metabolic disease: 1.11 (0.87 to 1.42)

Neuromuscular disorder: 1.68 (1.11 to 2.52)

Morbid obesity:

1.17 (0.82 to 1.68)

Incremental predictive value¹: not reported

Loss to follow up:

After excluding 2169 cases with incomplete information on

virus subtype and 494 cases that were either hospital-acquired

cases or cases that occurred in pregnant women, 3621 were further analysed

Variables

known as potential confounders or that were associated

with disease severity in the univariable analysis (P <.10) were

included in the multivariable regression models;

Myles, 2012

Type of study:

Cohort study

Setting and country:

75 hospitals in the UK

Period of data collection: 25 April 2009 to 26 January 2010

Funding and conflicts of interest:

Funding:FLU-CIN was supported by the Department of Health, England (principal

funder), and the Scottish government Chief Medical Officer and Public Health

Directorate in Scotland. Chairmanship of the FLU-CIN Strategy Group that includes

JSN-V-T, WSL, MGS, PJMO, RCR, BLT, SJB, JMcM, JEE and KGN as members was

provided by the Department of Health, England. The report was approved for

publication by the Department of Health, England. All authors had full access to all

data in the study. The FLU-CIN Strategy Group had final responsibility for the

interpretation of findings and decision to submit for publication.

Conflicts of interest: several authors received funding of pharmaceutical companies.

Inclusion criteria:

Patients

with pandemic influenza A/H1N1 2009 infection

(‘pandemic H1N1’) confirmed by real-time reverse transcribed PCR

Exclusion criteria:

Not applicable

N= 1520

The median

length of hospital stay was 3 days (IQR 2e6). One in six (16.5%)

patients needed admission to high dependency (4.1%) or intensive

care (12.4%) units (respectively level 2 and level 3 care) and

the in-hospital case death rate was 5.3% (children 0e15 years:

3.8%; adults 16e64 years: 5.6%; older people >65 years: 10.7%;

first wave: 5.0%; second wave: 5.4%).

Potential confounders or effect modifiers: not mentioned

N= 1252

Controls (admitted patients)

N= 268 ‘Severe outcome’ was

defined as admission to level 2 (high dependency unit) or level 3

(intensive care unit) facilities,ii and/or death

Age*, asthma*, chronic pulmonary conditions*, neurological disorders*, cardiovascular disease*, radiological pneumonia*, C-reative protein*, recorded obsese*, altered consciousness*, dyspnoea*, pre-admission antibiotics, required supplemental oxygen on admission*, intravenous fluid replacement on admission*, delayed admission*, Length of hospital stay, in-hospital antibiotic therapy.

Model I:

Age**, asthma**, chronic pulmonary conditions**, neurological disorders**, cardiovascular disease**, recorded obsesity**,

Model II:

radiological pneumonia**, C-reative protein, altered consciousnes, dyspnoe, pre-admission antibiotics, required supplemental oxygen on admission, intravenous fluid replacement on admission, delayed admission, Length of hospital stay, in-hospital antibiotic therapy.

Adjusted factor-outcome associations for mortality and/or ICU admission and/or high dependency unit, OR (95%CI)

Model 1:

† see below this table

Model 2:

Radiologically confirmed pneumonia: 1.83 (1.27 to 2.64)

Other variables in model 2 (not related to this PICO)

Delayed admission

Presenting symptoms (dyspnoea, altered conscousness, required supplemental oxygen on admission, intravenous fluid replacement on admission, C-reactive protein.

Incremental predictive value¹: not reported

A multivariable regression

analysis was conducted for statistically significant variables

(p≤0.05) identified during univariate analyses; each variable within model 1 or 2 has been adjusted for all other variables in that model.

Two separate

models were constructed to examine potential predictors of

severe outcome: model 1 included patient characteristics

(demographic characteristics and pre-existing comorbidities)

while model 2 included clinical characteristics (symptoms,

findings of clinical examination and investigations). Both models

were then restricted to include only the variables that were

significantly associated with an increased risk

Angelo, 2004

Type of study:

Retrospective chart review

Setting and country:

Single centre, USA

Period of data collection: 1998 - 1999

Funding and conflicts of interest: Not reported

Inclusion criteria:

Adult inpatients whose nasopharyngeal swabs were positive within 48 hours of presentations to the hospital and with charts available (influenza A).

Exclusion criteria:

Influenza B

N= 132

Mean age ± SD:

77 years

Sex: 58% M / 42% F

Smoking history: 14 % current smoker; 30% past smoker, 36% never smoked, 20% not documented.

Average length of stay: 7.4 days;

Race: 92% white; 5% black, 2% Asian, 1% Hispanic.

Potential confounders or effect modifiers: not mentioned

N= 105 usual outcome group: all other patients not included in the poor outcome group.

N= 27 poor outcome group: patients who died, experienced respiratory failure requiring aggressive therapy (intubation, biPAP, nonrebreather or facemask oxygen delivery, or aggressive blood pressure support (vasopressors) during hospitalization

COPD*, coronary artery disease*, congestive heart failure*, stroke or transient ischemic attack*, chronic renal insuffiency, dialysis*, chief complaint of shortness of breath*, mean respiratory rate, mean saturation*, mean creatinine*, CHF/vascular congestion Chest X-ray pattern*, ineterstitial Chest X-ray pattern*

COPD**, coronary artery disease**, congestive heart failure**, stroke** or transient ischemic attack**, chronic renal insuffiency**, dialysis, chief complaint of shortness of breath, mean respiratory rate, mean saturation, mean creatinine, CHF/vascular congestion Chest X-ray pattern, ineterstitial Chest X-ray pattern

Adjusted factor-outcome associations for mortality or respiratory failure, OR (95%CI)

Not reported, no multivariate model was developed because of non-significant factors in univariate analysis

Incremental predictive value¹: not reported

Multivariate analysis using backward stepwise logistic regression was performed on the variables identified as significant by the univariate analysis

Study reference

(first author, year of publication)

Study participation¹

Study sample represents the population of interest on key characteristics?

(high/moderate/low risk of selection bias)

Study Attrition²

Loss to follow-up not associated with key characteristics (i.e., the study data adequately represent the sample)?

(high/moderate/low risk of attrition bias)

Prognostic factor measurement³

Was the PF of interest defined and adequately measured?

(high/moderate/low risk of measurement bias related to PF)

Outcome measurement³

Was the outcome of interest defined and adequately measured?

(high/moderate/low risk of measurement bias related to outcome)

Study confounding⁴

Important potential confounders are appropriately accounted for?

(high/moderate/low risk of bias due to confounding)

Statistical Analysis and Reporting⁵

Statistical analysis appropriate for the design of the study?

(high/moderate/low risk of bias due to statistical analysis)

Bender, 2009

Low

Moderate (not reported)

Moderate (radiographic data without virologic testing results)

Low

Moderate

Low

Dalziel, 2013

Low

Low (imputation for missing data)

Low

Low

Moderate

Low

Dimitrijev, 2017

Low

Moderate (respons rate questionnaire 85%; no info on missing data)

Low

Low

Moderate

Low

Garcia, 2015

Low

Moderate (not reported)

Low

Low

Low (accounted for race and insurance status)

Low

Lynfield, 2014

Low

Low (multiple imputation for missing data)

Low

Low

Moderate

Low

Hong, 2014

Low

Moderate (not reported)

Low

Moderate

Moderate

Low

Huang, 2014

Low

High (214 cases with low viral loads were excluded)

Moderate (compound measure for co-morbidity)

Low

Moderate

Low

LI, 2009

Low

Moderate (not reported)

Moderate

Low

Moderate

Moderate (no info on univariate analysis)

Tekin, 2019

Low

Moderate (not reported)

Low

Low

Moderate

Low

Cvetanosvska, 2016

Not applicable for outcome, no prognostic factors related to our PICO in their multivariate model

Labeaud, 2013

Low

Moderate (not reported)

Low

Low

Moderate

Low

Chaves, 2013

Low

High (many cases excluded)

Low

Low

Moderate

Low

Myles, 2012

Low

Moderate (not reported)

Moderate

Moderate (compound measure)

Moderate

Moderate

Angelo, 2004

Not applicable for outcome, no multivariate model available because of non-significant factors in univariate model