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BMC Infectious Diseases

, 18:637 | Cite as

The role of pneumonia and secondary bacterial infection in fatal and serious outcomes of pandemic influenza a(H1N1)pdm09

  • Chandini Raina MacIntyre
  • Abrar Ahmad Chughtai
  • Michelle Barnes
  • Iman Ridda
  • Holly Seale
  • Renin Toms
  • Anita Heywood
Open Access
Research article
Part of the following topical collections:
  1. Bacterial and fungal diseases

Abstract

Background

The aim of this study was to estimate the prevalence of pneumonia and secondary bacterial infections during the pandemic of influenza A(H1N1)pdm09.

Methods

A systematic review was conducted to identify relevant literature in which clinical outcomes of pandemic influenza A(H1N1)pdm09 infection were described. Published studies (between 01/01/2009 and 05/07/2012) describing cases of fatal or hospitalised A(H1N1)pdm09 and including data on bacterial testing or co-infection.

Results

Seventy five studies met the inclusion criteria. Fatal cases with autopsy specimen testing were reported in 11 studies, in which any co-infection was identified in 23% of cases (Streptococcus pneumoniae 29%). Eleven studies reported bacterial co-infection among hospitalised cases of A(H1N1)2009pdm with confirmed pneumonia, with a mean of 19% positive for bacteria (Streptococcus pneumoniae 54%). Of 16 studies of intensive care unit (ICU) patients, bacterial co-infection identified in a mean of 19% of cases (Streptococcus pneumoniae 26%). The mean prevalence of bacterial co-infection was 12% in studies of hospitalised patients not requiring ICU (Streptococcus pneumoniae 33%) and 16% in studies of paediatric patients hospitalised in general or pediatric intensive care unit (PICU) wards (Streptococcus pneumoniae 16%).

Conclusion

We found that few studies of the 2009 influenza pandemic reported on bacterial complications and testing. Of studies which did report on this, secondary bacterial infection was identified in almost one in four patients, with Streptococcus pneumoniae the most common bacteria identified. Bacterial complications were associated with serious outcomes such as death and admission to intensive care. Prevention and treatment of bacterial secondary infection should be an integral part of pandemic planning, and improved uptake of routine pneumococcal vaccination in adults with an indication may reduce the impact of a pandemic.

Keywords

Influenza A(H1N1)pdm09 Bacterial infection Pneumonia Respiratory infections hospitalization 

Abbreviations

ARDS

Acute respiratory distress syndrome

ARTI

Acute respiratory tract infection

BAL

Bronchoalveolar lavage

BAL

Broncho-alveolar lavage

BC

Blood culture

CT

Computerised tomography

CXR

Chest x-ray

ET

Endotreacheal tube

ICU

Intensive care unit

ILI

Influenza like illness

IV

Invasive ventilation

MeSH

Medical Subject Headings

MV

Mechanical ventilation

NIV

Noninvasive ventilation

NR

Not reported

NS

Not specified

PICU

Pediatric intensive care unit

PRISMA

Preferred Reporting Items for Systematic Reviews

SC

Sputum culture

Background

Influenza pandemics cause morbidity and mortality from both direct viral effects, which tend to present early (within the first few days), and secondary bacterial complications, which tend to present later (after the first week). Evidence of influenza predisposing to bacterial co-infection is seen in seasonal influenza epidemics, past pandemics, pathology studies and animal models [1, 2, 3, 4, 5, 6, 7, 8]. Infection with influenza disrupts the respiratory tract by direct pathogenic effects, which then predisposes to bacterial secondary infection. Conversely, bacterial pathogens in the respiratory tract may also predispose to influenza and other viral infection [9]. During the 1918 pandemic, bacterial pneumonia was a major cause of morbidity and mortality, as shown by studies at the time as well as retrospective study of pathology specimens [10, 11]. At that time, antibiotics were not widely available as they are now, and it is thought that the high observed mortality rate was partially due to the inability to treat secondary bacterial sepsis. The most important bacterial co-infections during an influenza pandemic S. pneumoniae, H. influenzae, S. aureus, and group A Streptococcus (1, 4). However, two early reviews of severe cases of 2009 pandemic influenza A (H1N1) showed no evidence of bacterial pneumonia among 30 hospitalized patients with laboratory-confirmed cases in California (5) and 10 intensive-care patients in Michigan (6). These reports might have led to a perception that bacterial co-infections played a limited role or no role in pandemic influenza deaths in 2009.

The aim of this study was to estimate the prevalence of pneumonia and secondary bacterial infections during the 2009 pandemic of influenza A(H1N1)pdm09.

Methods

Search strategy

A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews (PRISMA) [12].We sought primary studies that presented quantitative data of invasive bacterial co-infection in influenza A(H1N1)pdm09 patients, defined as isolation of a bacterial pathogen from a sterile site. Databases searched included Medline, Pre-Medline, EmBASE and LILACS. The search strategy included a combination of Medical Subject Headings (MeSH) and text words to improve the identification of relevant publications in which bacterial co-infection was not necessarily the primary outcome of interest. The World Health Organisation (WHO) advised on the use of the standardised nomenclature influenza A(H1N1)pdm09 in October 2011 [13]. Prior to this time, various names were used to describe the pandemic virus. As such, a broad search strategy was developed to identify relevant literature in which clinical outcomes of influenza A(H1N1)pdm09 infection were described.

The Medline search included a combination of two searches. The first included the MeSH term influenza A H1N1 subtype OR text words influenza or flu adjacent to H1N1/pandemic/swine AND the MeSH term bacterial infections OR text words bacteria*, streptococcus, pneumococcus or staphylococcus adjacent to pneumonia, secondary, infection or evidence. The second search strategy included the influenza search terms and a combination of severity terms including fatal, severe, death, mortality, morbidity, hospitalisation, critical and admitted. The same search terms were applied to the other databases, after ensuring the MeSH terms of the relevant search terms were consistent across databases. Searches were limited to human studies, published in the English language between 01/01/2009 and 05/07/2012 or accessible online, ahead of print within this timeframe. Hand-searching of the reference lists of included studies and relevant reviews were also undertaken to identify other relevant papers.

Inclusion and exclusion criteria

We included all studies of influenza A(H1N1)pdm09 which report bacterial infections (any sterile site) in influenza A(H1N1)pdm09 cases. Studies including only specific at-risk populations such as transplant or oncology patients or pregnant women were excluded. We included published English language papers of observational studies reporting on ≥10 influenza A(H1N1)pdm09 patients. Case reports and small case series of < 10 patients were also excluded.

Included cases were either fatal or hospitalised cases of confirmed or probable influenza A(H1N1)pdm09 confirmed by PCR or culture. Probable cases (13/75 studies) included those with positive influenza A serology during 2009–2010, but not testing of subtype.

However, studies which included a mixed cohort of influenza A(H1N1)pdm09 and other laboratory-confirmed influenza strains or influenza negative cases were only included if clinical outcomes could be distinguished between influenza A(H1N1)pdm09 and other confirmed strains. We excluded studies which described ambulatory influenza A(H1N1)pdm09 cases, including notifications, clinic visits or Emergency Department visits with no sub-group analysis in which hospital admission or death of patients was described.

For included studies, the definition of co-infection was broad and included any study reporting either pulmonary infection or site unspecified with or without data on bacterial type tested, or specimen tested, including those reporting negative findings. We excluded studies reporting suspected bacterial pneumonia on the basis of clinical findings alone and studies which tested specimens for presence of co-infection with respiratory viruses only. Studies reporting contamination of endotracheal tubes only and those in which patients were recruited on the basis of bacterial infection were excluded if no data on other results were reported. We present the number of cases of reported pneumonia and those requiring mechanical ventilation as per the investigators definition.

Data extraction and assessment

Five reviewers (AH, MB, RT, IR,, HS,) with experience in conducting systematic reviews independently reviewed the titles and abstracts to identify potentially relevant papers. All potentially relevant papers were read by two reviewers (AH, MB) to determine those which met the selection criteria. The results of the search strategy are shown in Fig. 1. An identical data extraction template was used by all reviewers to extract the clinical outcomes, diagnostic data and treatment. Clinical outcomes included the diagnosis of bacterial co-infection, pneumonia, and death. Treatment included mechanical ventilation and use of antibiotics. Diagnostic data included determination of pneumonia and bacterial testing. We also extracted methodological details of the relevant studies including study design, study location and methods of case ascertainment. To ensure consistency in data extraction, each study was independently data extracted by two reviewers. All findings, including discrepancies between reviewers were discussed with an independent senior reviewer (CRM).
Fig. 1

Study diagram

We report bacterial findings separately from pulmonary specimens when available. When site of specimen is not specified or combined, this is reported as such. We report the percentage of tested cases positive for bacteria when available. The variability of the available data precluded the aggregation of results in a quantitative meta-analysis. Results of the studies are summarised and a critically evaluation and interpretation provided. We present results separately for fatal cases, hospitalised cases with confirmed pneumonia, cases admitted to intensive care units (ICU) and hospitalised cases admitted to general wards including criteria for admission if reported. Pneumonia, hospital admission and ICU admission were accepted according to classification in the reviewed papers.

Results

Summary of included studies

A total of 7845 studies were identified on the 2009 pandemic, of which 1444 articles were initially identified from our search of studies potentially about both influenza A(H1N1)pdm09 and bacterial infection. After removal of duplicates, non-human, non-English language, and non-influenza A(H1N1)pdm09 studies, 863 articles remained and abstracts were reviewed. Of those, 350 full papers were reviewed for relevance and 75 studies met the inclusion criteria. The PRISMA diagram of the study selection is shown in Fig. 1.

Reporting of patient clinical outcomes, bacterial testing and bacterial findings varied widely in the included published studies. It was not clear in many studies if pneumonia was community or hospital acquired. The studies also varied in their methodologies and proportion of patients tested, as well as reporting of bacterial testing. Samples and time of sampling were not adequately described in most of the studies.

Eleven studies were on fatal cases, including eight reporting autopsy results and three studies reporting bacterial findings from medical record reviews of notified deaths of confirmed influenza A(H1N1)pdm09. The remaining studies reported bacterial findings from hospitalised cases. Figure 2 shows the average prevalence of bacterial infection in fatal, ICU admitted, general ward admitted and paediatric patients.
Fig. 2

Average prevalence of bacterial infection in fatal, ICU admitted, general ward admitted and paediatric patients

Bacterial co-infection among fatal cases of A(H1N1)2009pdm

Eleven studies reported evidence of bacterial co-infection of fatal confirmed cases of influenza A(H1N1)pdm09 occurring between April 2009 and May 2010 [1, 2, 14, 15, 16, 17, 18, 19, 20, 21, 22]. Eight studies reported autopsy results, including 8 autopsy case series [1, 2, 16, 17, 18, 19, 21, 22] and 3 reporting bacterial findings from medical records reviews only [14, 15, 20]. Five studies were based in the USA [1, 2, 15, 16, 18] while the others were from Mexico [14], Estonia [22], Brazil [17], the United Kingdom [19], Korea [20] and Japan [21].

Influenza A(H1N1)pdm09 infection was confirmed by reverse transcriptase polymerase chain reaction (rtPCR) in either ante-mortem nasopharyngeal swab or post-mortem lung tissue specimens for all cases in all studies. Case definitions for an included fatal case reflected national surveillance reporting and/or autopsy requirements during the pandemic period and enhanced surveillance for the identification of fatal cases included the review of the death certificate registries for influenza as a cause of death.

The study details, bacterial testing and bacterial findings are summarised in Table 1. Where data were available, 44–100% of cases were hospitalised before death, including 55–100% in ICUs, with 35–100% requiring mechanical ventilation support during their hospitalisation and 25–94% of patients with clinical and/or autopsy evidence of pneumonia (viral or bacterial). From chart reviews, positive bacterial growth ranged from 2 to 38% (mean bacterial 23%) [9] of autopsied cases. Of the total coinfection cases, 29% were Streptococcus pneumoniae. The overall rate of bacterial infection was significantly higher in fatal cases compared to nonfatal cases (OR 1.71, 95% CI 1.33 to 2.20). The Korean study of standardised case reports of A(H1N1)pdm09-associated deaths identified during a period of active surveillance estimated ILI case-fatality rate to be 16 per 100,000 cases [20].
Table 1

Bacterial co-infection among the fatal cases of A(H1N1)2009pdm (n = 11)

Author (year)

Study location/ period

Study type

Study population

N (%) autopsied

N (%) hospitalised prior to death

Requirement for

Antiviralsa

n/N (%) any n/N (%) 48 h

Antibioticsb

n/N (%) pre n/N (%) on

n/N (%) during admission

Positive bacterial growth

N (%) bacterial pneumonia

N (%) with S.pneumoniae

Site of isolation

ICU

Mechanical Ventilation

Fajardo-Dolci (2009) [14]

Mexico

16/3/09–16/5/09

Medical record review

N = 100

Consecutive notified hospitalized fatal cases

0/100 (0)

100/100 (100)

NR

84/100 (84.0)

56/100 (56)

NR

94/100 (94)

2/100 (2%)

(Site not mentioned)

77/82 (94.0)

CXR suggestive of pneumonia.

NR

Lee (2010) [1]

USA

4/09–7/09

Enhanced surveillance/confirmed cases in New York City.

N = 47

31/47 (66)

47/47 (100.0)

All 28 cases who died after > 24 in hospital were admitted to ICU

25/47 (80.6)

32/47 (68.0)

NR

NR

NR

13/47 (27.6)

By immunohistochemical analysis or PCR

21/28 with abnormal CXR and multilobar infiltrates.

8/47 (17.0) Lung/airway tissue

By immunohistochemical analysis or PCR

Lucas (2010) [19]

UK

4/09–1/10

Case series.

15% of reported H1N1 deaths

N = 68

Autopsied fatal cases

68/68 (100)

68/68 (100)

NR

NR

NR

NR

20/68 (29.4)

(Culture of lung/ blood)

28/68 (41.2)

- Autopsy findings

- Culture and histopathology

7/68 (10.3)

(6 confirmed and 1 possible through histology) isolation site Lung/ and or blood

Gill (2010) [2]

USA

5/09–7/09

Case series.

Autopsy request New York City (NYC) Office of chief medical examiner (n = 32), family requests (n = 10), deaths outside of NYC (n = 2)

N = 34

Autopsied fatal cases

34/34 (100)

21/34 (61.8)

NR

12/21 (57.1)

NR

NR

10/30 (33.3) Positive bacteria by culture, immunohistochemistry, and/or PCR

18/33 (54.4) have evidence of bacterial co-infection by tissue Gram stain.

6/30 (20) Positive for streptococcus by culture, immunohistochemistry, and/or PCR

16/33 (55) have evidence of bacterial co-infection by tissue Gram stain morphologically compatible with streptococcus.

CDC (2009) [15]

USA

4/09–8/09

Multicenter case series.

100% of reported deaths

N = 36

Pediatric (< 18 yrs).

Hospitalized fatal cases

NR

28/33 (84.8)

24/36 (66.7)

NR

19/30 (63.3)

Status unknown for 6 cases

4/30 (13%)

NR

NR

10/23 (43.5)

Based on culture and pathology results

3/23 (13) from multiple sites in px (BC, lung tissue, pleural fluid, CSF)

Shieh (2010) [18]

USA

5/09–10/09

Notified fatal case series/US CDC

N = 100

Autopsied fatal cases

100/100 (100)

58/87 (66.7)

NR

42/57 (73.7)

44/67 (65.7)

NR

NR

NR

29/100 (29)

Bacterial co-infection positive through PCR and histopathology on lung tissue

38/64 (59) radiological diagnosis of pneumonia

10/100 (10)

Lung tissue through PCR

CDC (2009) [16]

USA

5/09–8/09

Case series (US CDC), multiple (8) states

N = 77

Autopsied fatal cases

77/77 (100)

8/18 (44.0)

NR

7/7 (100.0)

NR

7/9 (77.8)

NR

22/77 (28.6)

Histopathology and positive PCR for bacteria

10/77 (positive through immunohistochemical assays) respiratory tissue

Mauad (2010) [17]

Brazil

7/09–8/09

Case series

N = 21

Autopsied fatal cases

21 (100)

21 (100.0)

16/21 (76.2)

21/21 (100.0)

16/21 (76.2)

NR

13/21 (61.9)

3/9 (33.3)

8/21 (38.1)

6/21 (28.6) diagnosed by culture of bronchial aspirate and/or tissue PCR

Kim (2011) [20]

Korea

8/09–11/09

Active mortality inpatient surveillance

N = 115

Notified hospitalized fatal cases

0/115 (0)

115/115 (100%)

63/115 (54.8)

NR

100/115 (87%)

41/115 (35.6)

NR

34/115 (29.6) positive on blood or sputum culture

34/115 (29.6) positive on blood or sputum culture

97/113 (85.8)

CXR suggestive of pneumonia

3/115 (2.6) bronchoalveolar lavage (BAL)

Streptococcus was also isolated from blood of one case

Nakajima (2012) [21]

Japan

8/09–2/10

Multicenter (15), case series, Tokyo.

N = 20

Autopsied fatal cases

20/20 (100)

11/20 (55.0)

NR

7/20 (35.0)

14/20 (70%)

13/20 (65%)

10/20 (50%)

4/11 (36.4%)

5/20 (25%) Based on histopathological finding (bacteria isolated in 4 of 5)

2/10 (20%)

sputum, blood cultures; lung tissue

Tamme (2012) [22]

Estonia

10/09–5/10

Case series

N = 21

Autopsied fatal cases

19/21 (90)

17/21 (81.0)

15/21(71.4)

NR

3/21 (14.3)

1/21 (4.8%)

16/21 (76.2)

8/21 (38.1)

(Culture performed on 14 samples)

9/21 (42.8)

Culture or Autopsy findings consistent with sepsis or bacterial infection

2/21 (9.5)

Blood and/or lung tissue culture

Antibiotics: time started – “Pre” = started prior admission, “On” = started on admission, “During” = started during admission

Diff Differentiated between bacterial pneumonia, viral pneumonia and ARDS

No diff Did not differentiate between aetiology of abnormal chest imaging

aNumber (percentage) of cases on antivirals; N (%) started within 48 h of symptom onset

bNumber (percentage) of cases on antibiotics commencing pre-admission, on admission or during admission (if reported)

The lowest proportion of co-infection was reported in the first 100 confirmed deaths in Mexico [14] where 94% of patients had multiple foci of pneumonia (based on imaging) and 84% required mechanical ventilation, and only 2 cases had positive bacterial cultures (Staphylococcus epidermidis and Staphylococcus hominis). Of the eight autopsy case series, 3 studies tested lung tissue specimens for evidence of bacterial infection in all included subjects [16, 17, 18] and identified bacterial co-infection diagnosed either before or after death in between 29 and 43% of fatal cases [16, 17, 18]. The highest proportion of culture positive bacterial co-infection from autopsy samples (38%) was reported by Tamme [22].

The reported post-mortem bacteriologic samples included culture, immunohistochemistry and PCR. No studies gave a complete picture of pulmonary bacterial co-infection during the clinical course and corresponding post-mortem findings. Bacterial co-infection identified prior to death was identified from clinically driven testing and no studies had a standardised testing protocol for all included fatal cases. On this basis, bacterial infection complicating A(H1N1)pdm09 ranged from 5 to 14% of fatal cases in the four studies [1, 17, 21, 22] reporting data from clinical testing prior to death (Table 1). Specimens obtained included sputum, bronchial aspirates and bronchoalveolar lavage, but no studies reported details of testing conducted prior to death, including the proportion tested, or the types of bacteria tested for.

Bacterial co-infection among hospitalised cases of A(H1N1)2009pdm with confirmed pneumonia

Eleven studies reported on influenza A(H1N1)pdm09 among hospitalised cases with evidence of pneumonia and are summarised in Table 2. Pneumonia was largely defined based on radiological findings in these studies. Any positive bacterial testing was reported in 9/11 studies and positive bacterial growth was ranged from 0 to 47% (mean 19%). Streptococcus pneumoniae was the most commonly isolated pathogen (54%). In these 9 studies, Acinobacter baumanii was the next most commonly identified bacteria (5–21%), followed by MRSA (3–6%), S. pneumoniae (2–4%) and K. Pneumonia in (1–8%). Of the 11 studies, 2 reported no evidence of bacterial co-infection in their cohort of patients [4, 23], however, neither reported the proportion of patients tested. The study conducted in Mexico early in the pandemic [23] isolated ventilator-associated bacteria in 4 (22%) cases, with Acinetobacter baumannii, Achromobacter xylosoxidans, methicillin-resistant Staphylococcus aureus, and Escherichia coli identified.
Table 2

Bacterial co-infection among hospitalised cases of A(H1N1)2009pdm with confirmed pneumonia (n = 11)

Author and year

Study type

Study population

Case severity

Antivirals*

n/N (%) any

n/N (%) 48 h

Antibiotics†

n/N (%) pre

n/N (%) on

n/N (%) during admission

Any positive bacterial growth

n/N (%) S.pneumoniae

[Site of isolation]

N (%)pneumonia

Method

Diff/no diff

ICU

Mechanical Ventilation

Deaths

Perez-Padilla (2009) [23]

Mexico

3/09–4/09

Single-centre case series (retrospective medical record review) of patients admitted to hospital with pneumonia and A(H1N1)pdm09 (N = 18)

N = 18

12/18 (66.7)

12/18 (66.7)

7/18 (38.9)

14/18 (77.7)

12/18 pre (66.7)

17/18 post (94.4)

0/6 (0) BC

0/2 (0) BA

0/1 (0) pleural fluid

4/18 (22.2) Ventilator Associated pneumonia

0/18 [NR]

NP swab and bronchial aspirates

18 (100)

CXR

No diff

Chien (2010) [3]

Taiwan

07/09–8/09

Nation-wide notified cases (retrospective medical record review)

New pulmonary infiltrates consistent with pneumonia, compatible clinical presentations.

Identification of clinicalyl significant bacteria in respiratory secretion or specimens from sterile compartments was recorded as secondary bacterial infection.

N = 96

35/96 (36.5)

NR

10/96 (10.4)

96/96 (100.0)

- NR

NR

13/96 (13.2) pulmonary NFI (13.5)

2/99 (2) [Respiratory secretions]

13 (13.5)

CXR positive

Champunot (2010) [53]

Thailand

7/09–10/09

Single-centre case series (prospective);

Community acquired, new pulmonary infiltrate (CXR) within 24 h of admission, clinical symptoms

N = 24

13/24 (54.2)

11/24 (45.8)

5/24 (8.3)

24/24 (100%)

- NR

21/24 (87.5)

- Pre = 6

Blood culture 0/24 (0)

Sputum culture 2/24(8.3)

1/24 (4.2) [urine pneumococcal Ag

TOTAL 3/24 (12.5)

1/24 (4.2) [urine pneumococcal Ag]

24 (100.0)

CXR

No diff

Cui (2010) [24]

China

11/09–12/09

Single-centre case series (retrospective medical record review) of patients admitted to a tertiary hospital with pneumonia and H1N1(N = 68)

Blood cultures (BC) - Any patient with high fever > 38.0 °C for ≥3 days or repeated fever.

Sputum cultures (SC) - patients with symptoms of expectoration especially with yellowish/purulent sputum.

N = 68

30/68 (44)

13/68 (19.1)

10/68 (14.7)

68/68 (100.0)

50/68 (74%)

All received antibiotics

65/68 (95.6) received preadmission antibiotics

5/11 (45.5) [BC]

9/29 (31.0) [SC]

Total 11/29 (37.9)

0/11 (0.0) [BC]

0/29 (0.0) [SC]

68/68 (100.0)

CXR

No diff

Cuquemelle [54]

(2011)

France

11/09–4/10

Multicenter (24) case series (retrospective)/ not having received prior antibiotics (N = 103)

Microbiological investigations and biomarker levels were obtained as part of the routine clinical management of patients, at the discretion of the treating physician

N = 103

103/103 (100)

62/103 (60.2)

18/103 (17.5)

NR

0/103 (0)

48/103 (46.6)

Isolation of bacteria

26/103 (25.2) [NS]

Infiltrates on all CXR

Choi [55]

Definition: the presence of an infiltrate on plain chest radiograph.

N = 17

17/17 (100)

All in acute care unit

1/17 (5.9)

1/17 (5.9)

17/17 (100)

17/17 (100)

0/17 (0) BC

0/17 (0) SC

2/17 (11.8) urine Ag test (Legionella)

1/17 (5.9) PCR (TB)

0/17 (100)

Testing for S. pneumo

16/17 (94.1)

CXR

No diff

Viasus [56]

Pneumonia was defined as the presence of a new infiltrate on a chest radiograph plus fever (temperature 38.0-C) and/or respiratory symptoms

N = 234 (210 tested for microbiologic studies)

53/234 (22.6)

42/234 (17.9)

12/234 (5.1)

229/234 (97.9)

50/234 (22.4)

228/234 (97.9)

36/210 (17.1)

Specimens included: culture of blood, normally sterile fluids, or sputum and/or a positive urinary antigen test

26/210 (12.4)

All CXR positive

Piacentini [57]

Compares H1N1 with pneumonia in ICU and community acquired

N = 10

10/10 (100)

5/10 (50)

0/10 (0)

10/10 (100)

10/10 (100)

2/10 (20.0)

Pre-treatment BC, SC, and urinary Ag for S. pneumoniae and Legionella sp.

2/10 (20)

Specimen type NR

CXR positive (multilobar infiltrates) all except 2 (single lobe infiltrates)

Mulrennan [58]

New pulmonary infiltrates on imaging + clinical symptoms

Compared with non-pneumonia H1N1

N = 35

11/35 (31.4)

10/35 (28.6)

2/35 (5.7)

35/35 (100)

NR

5/35 (14.3)

NP, lower resp. tarct

NR

35/35 (100)

CXR

no diff

Ugarte (2010) [25]

Chile

5/09–9/09

Adults

Multicenter (11) case series (retrospective) / adult ICU admissions

Definition: positive culture from a sterile site (e.g. blood) and/or lower respiratory tract specimens, or seroconversion to atypical bacterial pathogens. LRT specimens included expectorated sputum, ET aspirated sputum and BAL

N = 75

75/75 (100.0))

56/75 (74.7)

-

19/75 (25.3)

NR

NR

7/75 (9.3)

Specimens NR

4/75 (5.3) on admission. Site NR

1/5 (20) empyema patients BC

74 (98.7)

CXR

No diff

Busi [4]

 

N = 40

NR

NR

1/40 (2.5)

NR

NR

0/40 (0) Specimen NR

 

40/40 (100) 40 had findings consistent with pneumonia. These 28/40 (70 bilaterial) Non-Diff

Antibiotics: time started – “Pre” = started prior admission, “On” = started on admission, “During” = started during admission

Diff Differentiated between bacterial pneumonia, viral pneumonia and ARDS;

No diff Did not differentiate between aetiology of abnormal chest imaging, NR not reported

Six studies reported use of antibiotics prior to specimen collection in subjects with bacterial co-infection in 21–22% of those tested [23, 24]. One study reported factors associated with acute respiratory distress syndrome (ARDS) or death, with the ARDS-death group more likely to have bacterial co-infections than patients who survived without ARDS or had mild disease [25]. Specimens included sputum, bronchial aspirate, pleural fluid, urine and blood with testing mainly being bacterial culture, but also multiplex PCR assay for respiratory bacterial panels (for detection of Legionella pneumophila, Chlamydophila pneumoniae, and Mycoplasma pneumoniae) and Binax NOW, an in vitro immunochromatographic assay for Streptococcus pneumonia. However, the mPCR assay did not test for S. pneumoniae in one study and the authors could not report the presence of this organism [23].

Bacterial co-infection reported among severe cases of A(H1N1)pdm09 admitted to ICUs

Sixteen studies reported on influenza A(H1N1)pdm09 cases admitted to ICU wards and are summarised in Table 3. Criteria for admission to ICU varied in the included studies, including acute respiratory distress (ARD) [26, 27], acute respiratory failure [28, 29], required mechanical ventilation (MV) [5, 30, 31] or MV or low O2/IV vasoconstrictive drugs [32, 33], MV or ECMO [34] or admitted with no criteria provided [35, 36, 37, 38, 39, 40, 41]. Eleven studies included only PCR confirmed A(H1N1)pdm09 cases, while three included probable cases [31, 39, 40] and another three included both probable and suspected cases [5, 33, 34]. Any positive bacterial testing was reported in 12 studies and bacterial co-infection was identified in 1–43% of cases (mean bacterial 19%, Streptococcus pneumoniae 26%). One study assessed differences in mortality outcomes based on secondary bacterial pneumonia. In a large study involving admissions to 35 ICUs for ILI and ARF requiring mechanical ventilation in Argentina (n = 337), 24% of included patients had bacterial pneumonia on admission, 8% with S. pneumoniae [5]. S.pneumoniae co-infection was associated with higher mortality (OR 2.72 95% CI 1.05–7.06), despite concurrent antibiotic treatment on admission [5]. A Canadian study (N = 168) attributed secondary bacterial infection as a leading cause of death in the 29 (17.3%) fatalities that occurred in this cohort [33].
Table 3

Bacterial co-infection reported among severe cases of A(H1N1)pdm09 admitted in ICUs (n = 16)

Author and year

Study type

Study population

Case severity

Antiviralsa

n/N (%) any

n/N (%) 48 h

Antibiotics†

n/N (%) pre

n/N (%) on

n/N (%) during admission

Any positive bacterial growth

Number (%) patients with S.pneumoniae and site of isolation

Number (%) with bacterial pneumonia

- Method

- Diff/no diff

ICU - ECMO

Mechanical Ventilation

Deaths

Miller (2010) [36]

Utah, USA

5/09–6/09

Adults(16+)

Multicentre (4) case series (+ comparison with local resident population) / Adult (> 15 y) ICU admissions

N = 47

47/47 (100)

- 0

13/47 (27.7)

IV = 11/47 (84.6)

8/47 (14)

47/47 (100.0)

- 45/47 (95.7)

44/47 (93.6)

- NS

6/47 (13)

0/47 (0) BC

0/47 (0) ET aspirate

0/47 (0) SC

0/47 (0) BAL fluid

43/47(91.5)

- CXR

- No diff

Rello [29] (2009)

Spain

6/09–7/09

Adults

Multicentre (20) case series (retrospective) / ICU adult admissions with ARF

N = 32

32/32 (100)

- 0

24/32 (75.0)

- IV = 22/32 (91.7)

- NIV = 2/32 (8.3)

8/32 (25)

32/32 (100.0)

-NS

32/32 (100.0)

1/32 (3.1)

Secondary superinfection with Pseudomonas

aeruginosa were also documented in three patients (9.3).

1/32 (3.1) aspirate

0/32 (0) BC

1/32 (3.1)

respiratory culture

ANZ ECMO [34] (2009)

Australia and New Zealand

6/09–8/09

All ages

Multicentre (15) cohort study (retrospective) / All ages ICU admission with ARDS treated with ECMO

Includes probable casesa

N = 68

68/68 (100)

- 68/68 (100)

68/68 (100)

14/68 (20.6)

64/68 (94.1)

- NS

NR

19/68 (28)

10/68 (14.7) [respiratory secretion/BC]

66/68 (97.1)

CXR/CT

No diff

Estenssoro (2010) [5]

Argentina

6/09–9/09

Adults(15+)

Multicentre (35) inception cohort study (prospective & retrospective) / adult (≥ 15 years) ICU admissions with ILI & ARF requiring MV

Includes probable casesa

N = 337

337/337 (100)

337/337 (100)

NIV = 64/337 (19.0)

156/337 (46.3)

328/336 (98)

- NS

337/337 (100)

- NS

28/337 (8.3)

28 /337 [NS]

8.3

80/337 (23.7)

CXR/CT

Diff

Nin [31] (2011)

Chile, Uruguay

6/09–9/09

Multicenter (10) case series (> 18 yrs) (retrospective and prospective) / Respiratory failure requiring ICU mechanical ventilation **

(confirmed = 77/ 96)

Includes probable casesa

N = 96

96/96 (100)

13/96 (13.5)

96/96 (100)

NIV = 10/96 (10.4)

IV = 86/96 (89.6)

Prone ventilation = 44 /96 (45.8)HFOV = 10/96 (10.4)

48/96 (50)

84/96 (87.5)

- NS

91/96 (94.8)

- NS

8/96 (8)

NR

32/96 (33.3, 8 within first week of admission)

- Purulent sputum, significant growth of pathogen in ET aspirate

- diff

Koegelenberg (2010) [30]

South Africa

8/09–9/09

Adults(18+)

Single-centre case series (prospective)/Adult (> = 18 y) ICU admissions with ARF requiring MV

N = 19

19/19 (100)

- NR

19/19 (100)

- NIV = 2/19 (10.5)

13/19 (68.4)

19/19 (100)

- 14 (73.7)

NR

0/19 (19)

0/19 (0) BC

0/19 (0) ET aspirates

0/19 (0) other NS

0/19 (0)

(10 cases of nosocomial infection (> = 48 h admission)

- CXR

Martin-Loeches [28] (2010)

Spain

1st case - 12/09

Adults (16+)

Multicentre (148) case series (prospective) /Adult (> = 15 y) ICU admissions with ARF

N = 645

645/645 (100)

NR

- IV = 389/645 (60.3)

112/645 (17.4)

620/645 (96.1)

- NS

645/645 (100)

- NS

113/645 (17.5)

62 /645 (9.6)

site NS

Cultures routinely every day

113/645 (17.5)

- CXR + pos culture

- diff

Rice [39] (2012)

US

4/09–4/10

Multicenter (35) case series (retrospective and prospective) / Critically ill cases (> 13 years) admitted to adult ICU’s (Confirmed = 424/683, 62%)

Includes probable casesa

N = 683

683/683 (100)

231/683 (33.8)

- IV = 175/683 (75.8)

- NIV = 56/683 (24.2)

309/683 (45.2)

683/683 (100)

-NS

NR

Total 154/683 (22.5)

Sputum specimen

84/683 (12.3)

Bacteraemia 50 (7.3)

Both 20 (2.9)

10/683 (1.5) BC

207/683 (30.3) clinical coinfection, non-diff

CDC [27]

Patients at a tertiary care hospital in Michigan

N = 10

10/10 (100)

10/10 (100)

3/10 (30%)

10/10 (100)

10/10 (100)

NR

NR

NR

Kim [32]

ICU in 28 Hospitals in SK

245

245/245 (100)

162/245 (100)

99/245 (40.4)

103/245 (42)

243/245 (99.2)

91/245 (37.1)

0/245 (0)

91/245 (37.1)

Malato [35]

ICU in one hosiptal

24

24/24 (100)

6/24 (25)

4/24 (16.7)

20/20 (100)

NR

6/24 (25)

0/24 (0)

6/24 (25)

Kumar [33] (2009)

Canada

4/09–8/09

All ages

Multicentre (38) cohort study (prospective & retrospective) /All age critically ill patients = ICU & requiring MV or IV medication or ≥ 60% inspired O2 fraction

Includes probable casesa

N = 168

168/168 (100)

- 7/168 (4.2)

136/168 (81.0)

- IV = 128/168 (94.1)

- HFOV = 20/168 (14.7)

29/168 (17.3)

NR

NR

 

5/168 (2.9) site NS

54/168 (32.1) possible at presentation; 41/168 (24.4) clinically dx cases following ICU admission

- CXR + culture /clinical opinion

Roch [26]

ARDS cases in ICU

N = 18

18/18 (100)

10/18 (100)

10/10 (100)

NR

NR

0/18 (0)

0/18 (0)

0/18 (0)

Lucker [37]

One hospital ICU, medical charts reviewed

14

14/14 (100)

10/14 (71.4)

2/14 (14.3)

14/14 (100)

13/14 (92.9)

6/14 (42.8)

Of ICU cases

0/14 (0)

6/14 (42.9)

Leen [38]

22 bed ICU in one hospital

N = 31

31/31 (100)

 

3/31 (10)

NR

NR

NR

NR

10/31 (32.2)

Method not mentioned

Torres [40]

Hospital in Chile. Includes probable casesa

N = 11

11/11 (100)

11/11 (100)

0/11 (0)

11/11 (100)

7/11 (63.6)

1/11 (0.9)

Group A Streptococcus

Site NR

0/11 (0)

6/11 (54.5)

Non Diff

Antibiotics: time started – “Pre” = started prior admission, “On” = started on admission, “During” = started during admission

Diff Differentiated between bacterial pneumonia, viral pneumonia and ARDS

No diff Did not differentiate between aetiology of abnormal chest imaging

aH1N1 testing = 53 (77.9) PCR/viral culture, 8 (11.8) serologically diagnosed but flu A not typed [34]; probable cases not defined [31]; Probable: Flu A, not otherwise subtyped [39]

Bacterial co-infection reported among hospitalised cases of influenza A(H1N1)pdm09, not requiring ICU

Twenty two studies reported on hospitalised influenza A(H1N1)pdm09 cases (not requiring ICU) and are summarised in Table 4. Almost all studies include patients admitted to general wards, however some were transferred to ICU during the course of treatment. Most of the studies (19/22) reported bacteria testing and any positive bacterial growth was reported in 1.6–76% cases (mean bacterial 12%, Streptococcus pneumoniae 33%). The number of patients with S.pneumoniae co-infection varied from 1 to 31% depending on site of sample. Palacios et al. conducted a study in Argentina and bacteria was found in 76% of nasopharyngeal samples (152/199), of which Streptococcus pneumoniae was isolated in 31% (62/199) samples [42].
Table 4

Bacterial co-infection reported among hospitalised cases of influenza A(H1N1)pdm09, not requiring ICU (n = 22)

Author and year

Study type

Study population

Case severity n (%)

Antiviral agents

- Number (%) started ≤48 h of symptoms

Antibiotics†

n/N (%) pre

n/N (%) on

n/N (%) during admission

Any positive bacterial growth

Number (%) patients with S.pneumoniae and site of isolation

Number (%) with bacterial pneumonia

- Method

- Diff/no diff

ICU

N

MV

- type

Deaths

CDC (2009) [59]

California, USA

4/09–5/09

State-wide passive surveillance of notified cases / Hospitalized cases for > 24 h

N = 30

6/30 (20)

4/30 (13.3)

0/23 (0)

7 were still hospitalised

15/30 (50)

5/30 (16.7)

0

0/100 (0)

0/100 (0)

15/25 (60)

CXR Non diff

Jain [60] (2009)

USA

4/09–6/09

Notified cases from 24 state health departments to CDC / Hospitalized ≥24 h

N = 272

67/272 (24.6)

42/272 (15.4)

19/272 (7.0)

200/268 (74.6)

78 (29.1)

206/260 (79.2)

- Pre: 30/198

- on: 117/198

3/182 (1.6)

2/182 (1.1) 1 had positive lung tissue culture)

1/n urinary antigen test

1/n BAL fluid

0/n ET aspirate

- CXR 100/249 (40)

(66 patients with bilateral infiltrates)

26 limited to 1 lobe, 6 limited to multiple lobes

- not diff

Louie [61] (2009)

California, USA

4/09–8/09

State-wide enhanced surveillance /Hospitalized or fatal all ages cases

N = 1088

340/1088 (31.3)

193/297 (64.9)

118/1088 (10.8)

701/884 (79.3)

- 357 (40.4)

NR

46/1088 (4.2)

NR

547/833 (65.7)

- CXR/CT + pos bacterial culture(s) 46

- No diff

Dhanoa [62] (2011)

Malaysia

9/09–5/10

Single-centre case series (retrospective)/ Hospitalised patients all ages

N = 50

9/50 (18.0)

6/50 (12.0)

2/50 (4.0)

50/50 (100)

49 (98.0)

- Pre = 8

- On =41

14/45 (31.1)

total 45 culture samples sent

2/45 (4.4) site NR

25/50 (50)

-CXR + clinical opinion

- No diff

To [63] (2010)

China

6/09–10/09

Single-centre case series (retrospective)/ Hospitalized adult patients

N = 69

28/69 (40.6)

26/69 (37.7)

- NS

13/69 (18.8)

69/69 (100)

37/69 (53.6)

- On = 37

0/69 (0)

0/69 (0)

25/69 (36.2)

CXR Non-diff

Viasus [64] (2011)

Spain

6/09–11/09

Multicentre (13) case series (prospective)/ Hospitalized ≥24 h and had a chest radiograph done

N = 585

71/585 (12.1)

52/585 (8.9)

13/585 (2.2)

545/585 (93.3)

416/585 (71.7)

45/585 (7.7)

28/585 (4.8)

234/585 (40)

CXR non diff

Palacios (2009) [42]

Argentina

6/09–7/09

Random sample specimens

N = 199

19/199 (9.5)

NR

20/199 (10)

96/120 (80)

14/120 (11.7)

152/199 (76.3)

62/199 (31.1)

152//199 (76)

Culture pos

Chitnis [6]

Wisconsin, hospital acute care

PCR + cases

N = 252

59/252 (23.4)

34/59 (58)

Of tho9se cases admitted to ICU

11/252 (4.3)

215/250 (86)

204/249 (81.9)

19/241 (7.9)

NR

123/229 (53.7)

CXR non diff

Riera [65]

13 Hospitals in Spain

N = 585

71/585 (12.1)

52/585 (8.9)

13/585 (2.2)

545/585 (93.1)

202/585 (34.5)

316/585 (54)

45/585 (7.7) (Sputum)

2/585 (0.3)

(1 sputum and 1 antigenuria positive

CXR infil 234/585 (40)

Multilobarl infilt 135/585 (23.1)

Semionov [66]

147 cases with CXR results available in Montreal

N = 147

8/147 (5.4)

6/147 (4.1)

4/147 (2.7)

NR

NR

21/42 (50)

(of 42 radiological positive cases)

5/21 (23.8)

(of 21 positive bacterial cases)

42/147 (28.6)

cases positive CXR

Non diff

To [67]

74 cases in Hong Kong

N = 74

28/74 (37.8)

26/74 (35.1)

2/74 (2.7)

69/74 (93.2)

52/74 (70.3)

9/74 (12.2) bacterial positive

8 sputum

1 blood

0/74 (0)

9/74 (12.2) bacterial positive

8 sputum

1 blood

Diff

Masia [68]

Complicated hospital admitted cases in Spain > 18 years, out patients

N = 100

4/100 (4)

NR

0/100 (0)

NR

NR

14/100 (14)

14/100 (14)

Diff

8 urinary antigen pos, 2 isolated from blood and 4 from sputum

14/100 (14)

Diff

Pecavar [69]

Hospitalized cases

N = 66

7/66 (10.6)

NR

NR

62/64 (96.9)

35/61 (57.4)

5/63 (7.9)

2/63 (3.2)

29/57 (50.9)

CXR Non diff

Liu [70]

One hospital in China

N = 46

NR

NR

NR

46/46 (100)

9/46 (19.6)

9/15 (60)

NR

44/46 (95.6)

CXR or CT scan abnormal

Non diff

Nguyen (2010) [71]

UK

4/09–9/09

Multicentre (55) case series (retrospective)/ Hospitalized cases

N = 631

53/631 (8.4)

NR

- IV = 21/631 (3.3)

29/631 (4.6)

474/631 (75.1)

- NS

366/631 (58)

4/102 (3.9%) of cases with radiological pneumonia

1/102 (0.9) sputum culture

0/102 (0) BC

102/349 (29.2)

- CXR

- No diff

Santa-Olalla Peralta [72] (2010)

Spain

4/09–12/09

National surveillance of severe cases (retrospective) / Hospitalized patients all ages (, in Spain

N = 3025

852/3025 (28.2)

438/3.25 (14.5)

200/3025 (6.6)

2521/2779 (90.7)

- 711/2020 (35.2)

NR

292/957 (30.5, bacteria isolated not reported)

NR

NR

Venkata [73] (2010)

USA

5/09–12/09

Single-centre case series (retrospective)/ Electronic medical records of hospitalized adult patients

N = 66

29/66 (43.9)

23/66 (34.8)

- IV = 17 (73.9)

- NIV = 6 (26.1)

5/66 (7.6)

4 more died after discharge from hospital

60/66 (90.9)

- NR

 

14/ 29 (48.2)

Bac culture pos

3/29 (10.3), site NS

14/29 (48.2) confirmed and 10/29 (34.5) probable bacterial pneumonia

- NR

- Diff

Jartti [74]

Cases with severe cases and CXR finding available, I hospital in Finland

N = 135

18/135 (13%)

18/135 (13.3)

3/135 (2.2)

NR

NR

5/135 (3.7)

Site not mentioned

1 /135 (0.7)

Isolated from Plural Fluid

84/135 (62.2)

Rizzo [75]

Sentinel sites, Italy

N = 1278

NR

NR

NR

NR

NR

33/1278 (2.6)

0/1278 (0)

271/1278 (21.2)

Non-diff

Kopel [76]

Til Aviv, cases in ICU and PICU

N = 17

17/17 (100)

NR

7/17 (41.2)

NR

NR

9/17 cases (52.9)

(but likely nosocomial infection, so not included)

0/17 (0)

NR

D’Ortenzio [41]

ReUnion Island, all sites, included 785 reported cases, 282 hospitalized cases included here

N = 282

24/282 (8.5)

15/282 (5.3)

7/282 (2.5)

92/171 (53.8)

39/163 (23.9)

(within 48 h)

NR

NR

NR

24/83 (28.9)

(Confirmed and suspected)

Sample not reported

Dominguez-Cherit [77]

Critically ill, hospitalized in 6 hospital in Maxico

N = 58

58/58 (100)

54/58 (93.1)

24/ 58 (41.4)

57/58 (98.3)

52/58 (89.6)

4/58 (6.9)

0/58 (0)

NR

Antibiotics: time started – “Pre” = started prior admission, “On” = started on admission, “During” = started during admission

Diff Differentiated between bacterial pneumonia, viral pneumonia and ARDS

No diff Did not differentiate between aetiology of abnormal chest imaging

Bacterial co-infection reported among paediatric hospitalised cases (including PICU) of influenza A(H1N1)pdm09

Fifteen studies reported on admitted paediatric influenza A(H1N1)pdm09 cases, including 11 to any hospital ward and 6 restricted to PICU and are summarised in Table 5. The mean prevalence of bacterial co-infection was 16% in studies of paediatric patients hospitalised in general or pediatric intensive care unit (PICU) wards. Rates of bacterial co-infections vary in these studies, ranging from 0 to 87% (mean 5%) in any hospital ward admission to 13–34% (mean 32%) in admission to PICU. The highest rate was reported by Okada [43] who conducted a study in Japan on 46 hospitalised children from July 2009 to January 2010. Bacteria were isolated from nasopharyngeal swabs of 87% admitted cases (40/46)- S. pneumoniae 37.0%; S. pneumoniae and H. influenzae 23.9%, H. influenza, 26.1% and S. aureus 23.9%.
Table 5

Bacterial co-infection reported among paediatric hospitalised cases (including PICU) of influenza A(H1N1)pdm09 (n = 15)

Author and year

Study type

Diagnosis of influenza/ cases

Antiviral agents

- Number (%) started ≤48 h of symptoms

Number (%) patients with S.pneumoniae and site of isolation

Any bacteria positive

Number (%) with bacterial pneumonia

- Method

- Diff/no diff

Antibiotics used (Pre, on, during)

Required

ICU - ECMO

MV

Deaths

Hospitalised

Louie (2010) [7]

California USA

4/09–8/09

State-wide surveillance (California) / Hospitalized or died cases (< 18 years)

PCR/345

221/345 (64.1)

88/ 345 (25.5) with in 48 h

3/345 (0.9)

isolation site NR

15/345 (4.3)

138/229 (60.3)

(F: 4/5; H: 134/224)

163/278 (CT + CXR pos)

- No diff

NR

94/345 (27.4)

35/94 (37) in text

9/345 (2.6)

Libster [78] (2010)

Argentina

5/09–7/09

Multicentre (6) case series (retrospective)/ Hospitalized cases (< 18 years)

PCR/ 251

- 22/ 171(12.9) with in 48 h

(4/34 PICU Px, 18/137 ward px)

2/121 (1.7) BC

1/4 (25.0) empyema

10 /121 (8)

Blood culture

25/251 (10.0) bacterial confirm

- Among 92 CXR, 78% diagnosis was pneumonia

-NonDiff

186/251 (74.1)

- On = 82

47/251 (18.7)

42/251 (16.7)

13/251 (5.2)

Okada [43] 2011

Japan

7/09–1/10

Single-centre case series (retrospective) / Pneumonia, pharyngitis or bronchitis cases (< 15 years) (n = unclear).

PCR/46

44/46 (95.6)

- NR

28/46 (60.9)

NP

40/46 (86.9)

NP positive swab

40/46 (86.9%)

NP swab

Bac pneumonia

21/46 (45.6%) unilateral infiltrates

- CXR

- No diff

32/46 (69.6)

- NS

NR

NR

0/46 (0)

Kumar [79] (2010)

Wisconsin, USA

4/09–8/09

Single-centre case series (retrospective record review)/ Hospitalized (> = 24 h) cases (< 19 years)

PCR/75

74/75 (98.7)

- NR

0 /75 (0)

0/75 (0)

23/75 (34.3)

- CXR

- Diff

60/75 (80.0)

- Pre = 12

- On/during = 48

14/75 (18.7)

4/75 (5.3)

2/75 (2.7)

Miroballi [80] (2010)

New York, USA

05/09–07/09

Multicentre (2) case series (retrospective) / Hospitalized cases (< 18)

PCR (54), EIA, DFA, viral culture/ 115

97/115 (84.3)

- NR

2/115 (1.7) BC

1/115 (0.9) respiratory secretions

4/115 (3.5)

Total NR (11/35 in PICU)

- NR

- Diff NS

89/115 (77.4)

- NS

35/115 (30.4)

11/115 (9.6) in PICU

1/115 (0.9)

O’Riordan [81]

Retrospective case review/hospitalised cases (< 18 yrs)

PCR/ 58

12/58 (20.7)

- NR

1/58 (1.7)

BC

1/58 (1.7)

bacterial culture positive

17/58 (29.3)

- CXR

- No diff

56/58 (96.6)

- NS

12/58 (20.7)

7/58 (12.1)

0/58 (0)

Bettinger [82] (2010)

Canada

5/09–8/09

National active surveillance / hospitalized cases (< 17 years)

PCR/235

107/235 (45.5)

- NR

3/235 (1.3) isolation site NR

8/235 (3.4) culture positive

8/235 (3.4) culture positive

203/235 (86.4)

- NS

39/235 (16.6)

15/235 (6.4)

2/235 (0.9)

Lockman [83] 2010

Retrospective case review (notes)/cases admitted to ICU

PCR/ 13

11/13 (84.6)

- 5 (45.5)

0/13 (0)

0/13 (0)

3/13 (23%)

Nondiff CXR

3/13 (23.1)

- NS

13/13 (100)

6/13 (46.2)

- IV =4 (66.7)

- NIV = 2 (33.3)

0/13 (0)

 Stein [84]

< 18 year, ARI cases, hospitalized in 7 medical centers in Israel

PCR/ 478

413/478 (87.1)

2/478 (0.4)

4/478 (0.8)

172/478 (35.9) CXR non-diff

215/478 (45)

42/478 (8.8)

15/478 (3.1)

3/478 (0.6%)

 Tamma [85]

1 hospital, lab confirm US, <  18 years, retrospective cohot in US

PCR/ 133

106/133 (79.7)

51/133 < 48 h

0/133 (0)

0/133 (0)

28/122 (22.9)

CXR nondiff

61/85 (72%)

27 (20.3)

11/133 (8%)

0

 Parakh [86]

1 hospital, retrospective record review, India PICU and ICU, cases with age < 18 with ILI

PCR/ 25

25/25 (100)

0/25 (0)

0/25 (0)

8/25 (32)

CXR nondiff

NR

7/25 (28)

4/25 (16)

3/25 (12)

PICU

 Farias [87]

Prospective multicentred study/includes nosocomial cases in Argentina(n = 147)

PCR/ 147

135/147 (91.8)

- 116/147 (85.9)

6/147 (4) isolation site NR

50/147 (34)

NR

143/147 (97.3)

147/147 (100)

139/147 (94.6)

- IV = 117 (84.2)

- NIV = 22 (15.8)

57/147 (38.8)

 Randolph (2011) [88]

USA

4/09–4/10

Multicentre (35) case series (retrospective & prospective). Probable 293/838 (35%) cases

PICU cases (< 21 years)

Confirmed- PCR, viral culture

Probable- direct fluorescent antibody, rapid influenza diagnostic test (n = 838)

751/838 (89.6)

- NR (before ICU admission =49)

0/38 (0) BC

15/274 (5.5) respiratory secretions

BC: 0

274/838 (32.7) had pneumonia/other bacterial co-infection

From resp. secretions

274/838 (32.7) had pneumonia/other bacterial co-infection

From resp. secretions

NR

838/838 (100)

- 33 (3.9)

546/838 (67.3)

75/838 (8.9)

 Shin [89]

South Korea, critically ill cases

PCR/30

29/30 (96.7)

0/30 (0)

4/30 (13.3)

Blood c/s positive

22/29 (75.9)

CXR non diff

NR

30/30 (0)

16/30 (53.3)

14//30 (46.7)

 Jouvet [8]

Canada PICUs,

PCR or culture positive /57

44/57 (77.2)

5/27 (18.5)

Lower resp. samples

12/57 (21.1)

Lower resp. samples

12/57 (21.1)

Lower resp. samples

54/57 (94.7)

2/57 (3.5)

39/57 (68.4)

4/57 (7)

Antibiotics: time started – “Pre” = started prior admission, “On” = started on admission, “During” = started during admission

Diff Differentiated between bacterial pneumonia, viral pneumonia and ARDS

No diff Did not differentiate between aetiology of abnormal chest imaging

Discussion

Secondary bacterial infection was an important complication of the 2009 influenza pandemic, with almost 1 in 4 severe or fatal cases having bacterial secondary infections, albeit with varying rates. Bacterial infection appeared to be associated with morbidity and mortality, with higher rates in adults, ICU patients and those with a fatal outcome. Streptococcus pneumoniae was the most common bacteria identified, and in ICU patients, ventilator associated pneumonia with organisms such as Acinetobacter baumannii, Achromobacter xylosoxidans, methicillin-resistant Staphylococcus aureus, and Escherichia coli was common. The prevalence of bacterial co-infection was lower in studies of hospitalized patients not requiring ICU and in studies of paediatric hospitalized patients, although the latter was quite varied.

The overall morbidity and mortality of the 2009 pandemic varied by country, but was cited as being similar to a severe seasonal influenza epidemic [44]. However, two important differences in the epidemiologic pattern of the 2009 pandemic were firstly, a low average age of death in fatal cases (53 years compared to 83 years during seasonal influenza) and high intensive care unit (ICU) occupancy rates [45]. These two features hint at a severe population impact, and a UK study showed a “w” shaped morbidity curve with a peak in young adults [46].

The 1918 pandemic has served as a reference point in pandemic planning, but availability of antibiotics, critical care and extra-corporeal membrane oxygenation (ECMO) have vastly improved survival during a contemporary pandemic, so it would be unlikely that case fatality rates of 1918 would recur in the modern era [45]. The use of ECMO rose sharply in 2009 and is associated with high rates of survival [47].

Further, in understanding the morbidity and mortality impact of a modern pandemic, it is important to quantify the relative contribution of direct viral effects compared to bacterial secondary infections, as treatment and prevention options are also available for bacterial infections.

Testing for bacterial complications during an influenza pandemic is important, but was neglected in most studies which we screened for this review. For optimal response and mitigation of preventable morbidity and mortality, active surveillance during both seasonal and pandemic influenza is necessary, and systems should be in place for rapid assessment of secondary bacterial morbidity and mortality. Diagnosis and treatment of secondary bacterial infections should always be considered during a pandemic [10].

Currently there are limited data on bacterial coinfection during influenza pandemic in 1918. Morens et al. reviewed autopsy data from 58 lung tissue samples collected during the 1918 influenza pandemic and histologic evidence of severe bacterial pneumonia was found in almost all samples [10]. The authors also did a literature search around autopsy case series and examined data of 3074 subjects in 68 high quality autopsy case series. This showed that more than 92% of autopsy lung cultures were positive for at least one bacterium [10]. Another study by Chien et al. reviewed the studies that reported more than 10 sterile-site antemortem cultures from adults with pneumonia during 1918 pandemic [48]. Culture positivity rates among influenza cases without pneumonia was very low (mean < 1%), compare to those with pneumonia (mean, 16%; range, 2 to 50) [48]. Bacterial co-infection rates among hospitalised cases with confirmed pneumonia in this study was 19%, which is comparable to Chien et al.

The rate of bacterial co-infection may be underestimated as many cases are not tested for bacterial infections, and bacterial pneumonia cannot always be differentiated from viral pneumonia on the basis of clinical presentation, radiology and routine blood tests. There is also a need to develop diagnostic algorithms for early identification of bacterial infections in these cases to ensure early detection and treatment of bacterial complications.

The WHO guidelines on vaccines and antivirals for a pandemic, along with many country-specific pandemic plans, do not consider pneumococcal vaccines [49]. The CAPITA trial shows efficacy of conjugate pneumococcal vaccine against pneumonia [50], and the polysaccharide vaccine also has efficacy against invasive pneumococcal disease [51]. We have found evidence that severe and fatal cases of influenza during the 2009 pandemic did comprise secondary bacterial causes, including streptococcus pneumoniae as a contributing factor. Vaccination against streptococcus pneumonia is often neglected in pandemic planning [52], but could have a positive impact on morbidity and mortality. The evidence confirms that prevention of bacterial secondary infection should be an integral part of pandemic planning. Improving uptake of routine pneumococcal vaccination in adults with an indication will cover most patients at risk, and may reduce the impact of a pandemic.

To our knowledge, this is the first systematic review to estimate the prevalence of pneumonia and secondary bacterial infections during pandemic influenza A(H1N1)pdm09. We calculated bacterial co-infection rates separately for fatal cases, hospitalised cases with confirmed pneumonia, hospitalised cases admitted to ICU, hospitalised cases admitted to general wards and paediatric hospitalised cases, showing the highest risk of bacterial infection for fatal and ICU admitted cases.

Conclusion

We found that secondary bacterial infection was an important complication of the 2009 influenza pandemic, with Streptococcus pneumoniae the most common bacteria identified. Bacterial infection appeared to be associated with morbidity and mortality, with higher rates in adults, ICU patients and those with a fatal outcome. Prevention and treatment of bacterial secondary infection should be an integral part of pandemic planning, and improved uptake of routine pneumococcal vaccination in adults with an indication may reduce the impact of a pandemic.

Notes

Acknowledgments

We acknowledge the support of Anthea Katelaris, Anthony Newall and James Wood for some preliminary work on this project.

Funding

No funding was involved in this study.

Availability of data and materials

All data freely available.

Authors’ contributions

CRM: lead investigator, conception and design of the study, drafting and manuscript revision; AH, MB, RT, IR, HS: reviewed the titles and abstracts to identify potentially relevant papers; AH, MB: reviewed all potentially relevant papers to determine those which met the selection criteria and conducted literature review, AAC; reviewed and extracted data from selected paper, prepared first draft of manuscript. All authors approved the final version to be submitted.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

C. Raina MacIntyre has received in-kind support and funding for investigator-driven research from GlaxoSmithKline, Pfizer, Merck, and Seqirus, and has sat on advisory boards for Merck, GlaxoSmithKline and Pfizer. IR: IR has received grant funds for investigator-driven research from GSK, Pfizer and for consultation from Merck. The remaining authors declare that they have no competing interests and have no non-financial interests that may be relevant to the submitted work.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.
    Lee EH, Wu C, Lee EU, et al. Fatalities associated with the 2009 H1N1 influenza A virus in New York city. Clin Infect Dis. 2010;50:1498–504.CrossRefPubMedGoogle Scholar
  2. 2.
    Gill JR, Sheng ZM, Ely SF, et al. Pulmonary pathologic findings of fatal 2009 pandemic influenza A/H1N1 viral infections. Arch Pathol Lab Med. 2010;134:235–43.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Chien YS, Su CP, Tsai HT, et al. Predictors and outcomes of respiratory failure among hospitalized pneumonia patients with 2009 H1N1 influenza in Taiwan. J Inf Secur. 2010;60:168–74.Google Scholar
  4. 4.
    Busi RE, Schinina V, Ferraro F, et al. Radiological findings of pneumonia in patients with swine-origin influenza A virus (H1N1). Radiol Med. 2010;115:507–15.CrossRefGoogle Scholar
  5. 5.
    Estenssoro E, Rios FG, Apezteguia C, et al. Pandemic 2009 influenza A in Argentina: a study of 337 patients on mechanical ventilation. Am J Respir Crit Care Med. 2010;182:41–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Chitnis AS, Truelove SA, Druckenmiller JK, Heffernan RT, Davis JP. Epidemiologic and clinical features among patients hospitalized in Wisconsin with 2009 H1N1 influenza A virus infections, April to August 2009. WMJ. 2010;109:201–8.PubMedGoogle Scholar
  7. 7.
    Louie JK, Gavali S, Acosta M, et al. Children hospitalized with 2009 novel influenza A(H1N1) in California. Arch Pediatr Adolesc Med. 2010;164:1023–31.CrossRefPubMedGoogle Scholar
  8. 8.
    Jouvet P, Hutchison J, Pinto R, et al. Critical illness in children with influenza A/pH1N1 2009 infection in Canada. Pediatr Crit Care Med. 2010;11:603–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Madhi SA, Klugman KP. A role for Streptococcus pneumoniae in virus-associated pneumonia. Nat Med. 2004;10:811–3 Epub 2004/07/13.CrossRefPubMedGoogle Scholar
  10. 10.
    Morens DM, Taubenberger JK, Fauci AS. Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness. J Infect Dis. 2008;198:962–70 Epub 2008/08/20.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Brundage JF, Shanks GD. Deaths from bacterial pneumonia during 1918-19 influenza pandemic. Emerg Infect Dis. 2008;14:1193–9 Epub 2008/08/06.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010;8:336–41.CrossRefGoogle Scholar
  13. 13.
    World Health Organisation (WHO). Standardization of terminology of the pandemic A(H1N1)2009 virus. 2011. Available from: http://www.who.int/influenza/gisrs_laboratory/terminology_ah1n1pdm09/en/. Cited 24 Jan 2013.Google Scholar
  14. 14.
    Fajardo-Dolci G, Gutierrez-Vega R, Arboleya-Casanova H, et al. Clinical characteristics of fatalities due to influenza A (H1N1) virus in Mexico. Thorax. 2010;65:505–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Centers for Disease Control and Prevention. Surveillance for pediatric deaths associated with 2009 pandemic influenza A (H1N1) virus infection - United States, April–August 2009. MMWR Morb Mortal Wkly Rep. 2009;58:941–7.Google Scholar
  16. 16.
    Centers for Disease Control and Prevention. Bacterial coinfections in lung tissue specimens from fatal cases of 2009 pandemic influenza A (H1N1) - United States, May–August 2009. MMWR Morb Mortal Wkly Rep. 2009;58:1071–4.Google Scholar
  17. 17.
    Mauad T, Hajjar LA, Callegari GD, et al. Lung pathology in fatal novel human influenza A (H1N1) infection. Am J Respir Crit Care Med. 2010;181:72–9.CrossRefPubMedGoogle Scholar
  18. 18.
    Shieh W-J, Blau DM, Denison AM, et al. 2009 pandemic influenza A (H1N1): pathology and pathogenesis of 100 fatal cases in the United States. Am J Pathol. 2010;177:166–75.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Lucas S. Predictive clinicopathological features derived from systematic autopsy examination of patients who died with A/H1N1 influenza infection in the UK 2009-10 pandemic. Health Technol Assess. 2010;14:83–114.CrossRefPubMedGoogle Scholar
  20. 20.
    Kim HS, Kim JH, Shin SY, et al. Fatal cases of 2009 pandemic influenza A (H1N1) in Korea. J Korean Med Sci. 2011;26:22–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Nakajima N, Sato Y, Katano H, et al. Histopathological and immunohistochemical findings of 20 autopsy cases with 2009 H1N1 virus infection. Mod Pathol. 2012;25:1–13.CrossRefPubMedGoogle Scholar
  22. 22.
    Tamme K, Minajeva A, Adamson V, et al. Clinical and pathological findings of fatal 2009-2010 pandemic influenza A (H1N1) infection in Estonia. Medicina (Kaunas). 2012;48:48–56.CrossRefGoogle Scholar
  23. 23.
    Perez-Padilla R, De La Rosa-Zamboni D, Ponce De Leon S, et al. Pneumonia and respiratory failure from swine-origin influenza A (H1N1) in Mexico. N Engl J Med. 2009;361:680–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Cui W, Zhao H, Lu X, et al. Factors associated with death in hospitalized pneumonia patients with 2009 H1N1 influenza in Shenyang, China. BMC Infect Dis. 2010;10:145.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Ugarte S, Arancibia F, Soto R. Influenza A pandemics: clinical and organizational aspects: the experience in Chile. Crit Care Med. 2010;38(4 Suppl):e133–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Roch A, Lepaul-Ercole R, Grisoli D, et al. Extracorporeal membrane oxygenation for severe influenza A (H1N1) acute respiratory distress syndrome: a prospective observational comparative study. Intensive Care Med. 2010;36:1899–905.CrossRefPubMedGoogle Scholar
  27. 27.
    Centers for Disease Control and Prevention. Intensive-care patients with severe novel influenza A (H1N1) virus infection - Michigan, June 2009. MMWR Morb Mortal Wkly Rep. 2009;58:749–52.Google Scholar
  28. 28.
    Martin-Loeches I, Sanchez-Corral A, Diaz E, et al. Community-acquired respiratory coinfection in critically ill patients with pandemic 2009 influenza A(H1N1) virus. Chest. 2011;139:555–62.CrossRefPubMedGoogle Scholar
  29. 29.
    Rello J, Rodriguez A, Ibanez P, et al. Intensive care adult patients with severe respiratory failure caused by Influenza A (H1N1)v in Spain. Crit Care. 2009;13:R148.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Koegelenberg CF, Irusen EM, Cooper R, et al. High mortality from respiratory failure secondary to swine-origin influenza A (H1N1) in South Africa. Qjm. 2010;103:319–25.CrossRefPubMedGoogle Scholar
  31. 31.
    Nin N, Soto L, Hurtado J, et al. Clinical characteristics and outcomes of patients with 2009 influenza A(H1N1) virus infection with respiratory failure requiring mechanical ventilation. J Crit Care. 2011;26:186–92.CrossRefPubMedGoogle Scholar
  32. 32.
    Kim S-H, Hong S-B, Yun S-C, et al. Corticosteroid treatment in critically ill patients with pandemic influenza A/H1N1 2009 infection: analytic strategy using propensity scores. Am J Respir Crit Care Med. 2011;183:1207–14.CrossRefPubMedGoogle Scholar
  33. 33.
    Kumar A, Zarychanski R, Pinto R, et al. Critically ill patients with 2009 influenza A(H1N1) infection in Canada. JAMA. 2009;302:1872–9.CrossRefPubMedGoogle Scholar
  34. 34.
    Australia, New Zealand Extracorporeal Membrane Oxygenation Influenza I, Davies A, et al. Extracorporeal Membrane Oxygenation for 2009 Influenza A(H1N1) acute respiratory distress syndrome. JAMA. 2009;302:1888–95.CrossRefGoogle Scholar
  35. 35.
    Malato L, Llavador V, Marmier E, Youssef J, Balick Weber C, Rozé H, Bessede E, Fleury HJ. Pandemic influenza A(H1N1)2009: molecular characterisation and duration of viral shedding in intensive care patients in Bordeaux, south-west France, May 2009 to January 2010. Euro Surveill. 2011;16(4). Available online: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19776.
  36. 36.
    Miller IRR, Markewitz BA, Rolfs RT, et al. Clinical findings and demographic factors associated with ICU admission in Utah due to novel 2009 influenza a(H1N1) infection. Chest. 2010;137:752–8.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Lucker LM, Kherad O, Iten A, et al. Clinical features and outcome of hospitalised adults and children with the 2009 influenza A H1N1 infection at Geneva’s University Hospital. Swiss Med Wkly. 2011;141:w13177.PubMedGoogle Scholar
  38. 38.
    Leen T, Williams TA, Campbell L, et al. Early experience with influenza A H1N109 in an Australian intensive care unit. Intensive Crit Care Nurs. 2010;26:207–14.CrossRefPubMedGoogle Scholar
  39. 39.
    Rice TW, Rubinson L, Uyeki TM, et al. Critical illness from 2009 pandemic influenza A virus and bacterial coinfection in the United States. Crit Care Med. 2012;40:1487–98.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Torres JP, O'Ryan M, Herve B, et al. Impact of the novel influenza A (H1N1) during the 2009 autumn-winter season in a large hospital setting in Santiago, Chile. Clin Infect Dis. 2010;50:860–8.CrossRefPubMedGoogle Scholar
  41. 41.
    D'Ortenzio E, Renault P, Jaffar-Bandjee MC, et al. A review of the dynamics and severity of the pandemic A(H1N1) influenza virus on Reunion island, 2009. Clin Microbiol Infect. 2010;16:309–16.CrossRefPubMedGoogle Scholar
  42. 42.
    Palacios G, Hornig M, Cisterna D, et al. Streptococcus pneumoniae coinfection is correlated with the severity of H1N1 pandemic influenza. PLoS One. 2009;4:1–5.CrossRefGoogle Scholar
  43. 43.
    Okada T, Morozumi M, Matsubara K, et al. Characteristic findings of pediatric inpatients with pandemic (H1N1) 2009 virus infection among severe and nonsevere illnesses. J Infect Chemother. 2011;17:238–45.CrossRefPubMedGoogle Scholar
  44. 44.
    Muscatello DJ, Cretikos MA, Macintyre CR. All-cause mortality during first wave of pandemic (H1N1) 2009, New South Wales, Australia, 2009. Emerg Infect Dis. 2010;16:1396–402 Epub 2010/08/26.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Bishop JF, Murnane MP, Owen R. Australia’s winter with the 2009 pandemic influenza A (H1N1) virus. N Engl J Med. 2009;361:2591–4 Epub 2009/11/27.CrossRefPubMedGoogle Scholar
  46. 46.
    Myles PR, Semple MG, Lim WS, et al. Predictors of clinical outcome in a national hospitalised cohort across both waves of the influenza A/H1N1 pandemic 2009–2010 in the UK. Thorax. 2012;67:709–17.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Bridges B, Rycus P, Fonnesbeck C, Fleming G, Halasa N. Global trends in Extracorporeal membranous Oxygenation use and survival of patients with Influenza-associated illness. Pediatr Crit Care Med. 2016;17:876–83.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Chien Y-W, Klugman KP, Morens DM. Bacterial pathogens and death during the 1918 influenza pandemic. N Engl J Med. 2009;361:2582–3.CrossRefPubMedGoogle Scholar
  49. 49.
    World Health Organisation (WHO). WHO guidelines on the use of vaccines and antivirals during influenza pandemics. 2004.Google Scholar
  50. 50.
    Bonten M, Bolkenbaas M, Huijts S, et al. Community acquired pneumonia immunisation trial in adults (CAPITA). Pneumonia. 2014;3:95.Google Scholar
  51. 51.
    Jackson LA, Neuzil KM, Yu O, et al. Effectiveness of pneumococcal polysaccharide vaccine in older adults. N Engl J Med. 2003;348:1747–55.CrossRefPubMedGoogle Scholar
  52. 52.
    Itzwerth R. Pandemic influenza and critical infrastructure. Sydney: University of New South Wales (UNSW); 2013.Google Scholar
  53. 53.
    Champunot R, Tanjatham S, Kerdsin A, et al. Impact of pandemic influenza (H1N1) virus-associated community-acquired pneumonia among adults in a tertiary hospital in Thailand. Jpn J Infect Dis. 2010;63:251–6.PubMedGoogle Scholar
  54. 54.
    Cuquemelle E, Soulis F, Villers D, et al. Can procalcitonin help identify associated bacterial infection in patients with severe influenza pneumonia? A multicentre study. Intensive Care Med. 2011;37:796–800.CrossRefPubMedGoogle Scholar
  55. 55.
    Choi WJ, Kim WY, Kim SH, et al. Clinical characteristics of pneumonia in hospitalized patients with novel influenza A (H1N1) in Korea. Scand J Infect Dis. 2010;42:311–4.CrossRefPubMedGoogle Scholar
  56. 56.
    Viasus D, Pano-Pardo JR, Pachon J, et al. Pneumonia complicating pandemic (H1N1) 2009: risk factors, clinical features, and outcomes. Medicine (Baltimore). 2011;90:328–36.CrossRefGoogle Scholar
  57. 57.
    Piacentini E, Sanchez B, Arauzo V, et al. Procalcitonin levels are lower in intensive care unit patients with H1N1 influenza A virus pneumonia than in those with community-acquired bacterial pneumonia. A pilot study. J Crit Care. 2011;26:201–5.CrossRefPubMedGoogle Scholar
  58. 58.
    Mulrennan S, Tempone SS, Ling ITW, et al. Pandemic influenza (H1N1) 2009 pneumonia: CURB-65 score for predicting severity and nasopharyngeal sampling for diagnosis are unreliable. PLoS One. 2010;5:e12849.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Centers for Disease Control. Hospitalized patients with novel influenza A (H1N1) virus infection - California, April–May, 2009. MMWR Morb Mortal Wkly Rep. 2009;58:536–41.Google Scholar
  60. 60.
    Jain S, Kamimoto L, Bramley AM, et al. Hospitalized patients with 2009 H1N1 influenza in the United States, April-June 2009. N Engl J Med. 2009;361:1935–44.CrossRefPubMedGoogle Scholar
  61. 61.
    Louie JK, Acosta M, Winter K, et al. Factors associated with death or hospitalization due to pandemic 2009 influenza A(H1N1) infection in California. JAMA. 2009;302:1896–902.CrossRefPubMedGoogle Scholar
  62. 62.
    Dhanoa A, Fang NC, Hassan SS, Kaniappan P, Rajasekaram G. Epidemiology and clinical characteristics of hospitalized patients with pandemic influenza A (H1N1) 2009 infections: the effects of bacterial coinfection. Virol J. 2011;8:501.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    To KKW, Wong SSY, Li IWS, et al. Concurrent comparison of epidemiology, clinical presentation and outcome between adult patients suffering from the pandemic influenza A (H1N1) 2009 virus and the seasonal influenza A virus infection. Postgrad Med J. 2010;86:515–21.CrossRefPubMedGoogle Scholar
  64. 64.
    Viasus D, Pano-Pardo JR, Pachon J, et al. Factors associated with severe disease in hospitalized adults with pandemic (H1N1) 2009 in Spain. Clin Microbiol Infect. 2011;17:738–46.CrossRefPubMedGoogle Scholar
  65. 65.
    Riera M, Payeras A, Marcos MA, et al. Clinical presentation and prognosis of the 2009 H1N1 influenza A infection in HIV-1-infected patients: a Spanish multicenter study. Aids. 2010;24:2461–7.CrossRefPubMedGoogle Scholar
  66. 66.
    Semionov A, Tremblay C, Samson L, et al. Pandemic influenza A (H1N1) 2009: chest radiographic findings from 147 proven cases in the Montreal area. Can Assoc Radiol J. 2010;61:233–40.CrossRefPubMedGoogle Scholar
  67. 67.
    To KKW, Hung IFN, Li IWS, et al. Delayed clearance of viral load and marked cytokine activation in severe cases of pandemic H1N1 2009 influenza virus infection. Clin Infect Dis. 2010;50:850–9.CrossRefPubMedGoogle Scholar
  68. 68.
    Masia M, Padilla S, Antequera P, et al. Predictors of pneumococcal co-infection for patients with pandemic (H1N1) 2009. Emerg Infect Dis. 2011;17:1475–8.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Pecavar B, Nadrah K, Papst L, et al. Clinical characteristics of adult patients with influenza-like illness hospitalized in general ward during Influenza A H1N1 pandemic 2009/2010. Wien Klin Wochenschr. 2011;123:662–7.CrossRefPubMedGoogle Scholar
  70. 70.
    Liu Y, Chen H, Sun Y, Chen F. Antiviral role of toll-like receptors and cytokines against the new 2009 H1N1 virus infection. Mol Biol Rep. 2012;39:1163–72.CrossRefPubMedGoogle Scholar
  71. 71.
    Nguyen-Van-Tam JS, Openshaw PJM, Hashim A, et al. Risk factors for hospitalisation and poor outcome with pandemic A/H1N1 influenza: United Kingdom first wave (May-September 2009). Thorax. 2010;65:645–51.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Santa-Olalla Peralta P, Cortes-Garcia M, Vicente-Herrero M, et al. Risk factors for disease severity among hospitalised patients with 2009 pandemic influenza A (H1N1) in Spain, April - December 2009. Euro Surveill. 2010;15:23.Google Scholar
  73. 73.
    Venkata C, Sampathkumar P, Afessa B. Hospitalized patients with 2009 H1N1 Influenza infection: the Mayo Clinic experience. Mayo Clin Proc. 2010;85:798–805.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Jartti A, Rauvala E, Kauma H, et al. Chest imaging findings in hospitalized patients with H1N1 influenza. Acta Radiol. 2011;52:297–304.CrossRefPubMedGoogle Scholar
  75. 75.
    Rizzo C, Caporali MG, Rota MC. Pandemic influenza and pneumonia due to legionella pneumophila: a frequently underestimated coinfection. Clin Infect Dis. 2010;51:115.CrossRefPubMedGoogle Scholar
  76. 76.
    Kopel E, Amitai Z, Grotto I, Kaliner E, Volovik I. Patients with pandemic (H1N1) 2009 in intensive care units, Israel. Emerg Infect Dis. 2010;16:720–1.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Dominguez-Cherit G, Lapinsky SE, Macias AE, et al. Critically ill patients with 2009 influenza A(H1N1) in Mexico. JAMA. 2009;302:1880–7.CrossRefPubMedGoogle Scholar
  78. 78.
    Libster R, Bugna J, Coviello S, et al. Pediatric hospitalizations associated with 2009 pandemic influenza A (H1N1) in Argentina. N Engl J Med. 2010;362:45–55.CrossRefPubMedGoogle Scholar
  79. 79.
    Kumar S, Havens PL, Chusid MJ, et al. Clinical and epidemiologic characteristics of children hospitalized with 2009 pandemic H1N1 influenza a infection. Pediatr Infect Dis J. 2010;29:591–4.CrossRefPubMedGoogle Scholar
  80. 80.
    Miroballi Y, Baird JS, Zackai S, et al. Novel influenza A(H1N1) in a pediatric health care facility in New York City during the first wave of the 2009 pandemic. Arch Pediatr Adolesc Med. 2010;164:24–30.CrossRefPubMedGoogle Scholar
  81. 81.
    O'Riordan S, Barton M, Yau Y, et al. Risk factors and outcomes among children admitted to hospital with pandemic H1N1 influenza. CMAJ. 2010;182:39–44.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Bettinger JA, Sauve LJ, Scheifele DW, et al. Pandemic influenza in Canadian children: a summary of hospitalized pediatric cases. Vaccine. 2010;28:3180–4.CrossRefPubMedGoogle Scholar
  83. 83.
    Lockman JL, Fischer WA, Perl TM, Valsamakis A, Nichols DG. The critically ill child with novel H1N1 influenza A: a case series. Pediatr Crit Care Med. 2010;11:173–8.CrossRefPubMedGoogle Scholar
  84. 84.
    Stein M, Tasher D, Glikman D, et al. Hospitalization of children with influenza A(H1N1) virus in Israel during the 2009 outbreak in Israel: a multicenter survey. Arch Pediatr Adolesc Med. 2010;164:1015–22.CrossRefPubMedGoogle Scholar
  85. 85.
    Tamma PD, Turnbull AE, Milstone AM, et al. Clinical outcomes of seasonal influenza and pandemic influenza A (H1N1) in pediatric inpatients. BMC Pediatr. 2010;10:72.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Parakh A, Kumar A, Kumar V, Dutta AK, Khare S. Pediatric hospitalizations associated with 2009 pandemic influenza A (H1N1): an experience from a tertiary care center in North India. Indian J Pediatr. 2010;77:981–5.CrossRefPubMedGoogle Scholar
  87. 87.
    Farias JA, Fernandez A, Monteverde E, et al. Critically ill infants and children with influenza A (H1N1) in pediatric intensive care units in Argentina. Intensive Care Med. 2010;36:1015–22.CrossRefPubMedGoogle Scholar
  88. 88.
    Randolph AG, Vaughn F, Sullivan R, et al. Critically ill children during the 2009-2010 influenza pandemic in the United States. Pediatrics. 2011;128:e1450–8.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Shin SY, Kim JH, Kim HS, et al. Clinical characteristics of Korean pediatric patients critically ill with influenza A (H1N1) virus. Pediatr Pulmonol. 2010;45:1014–20.CrossRefPubMedGoogle Scholar

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© The Author(s). 2018

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors and Affiliations

  • Chandini Raina MacIntyre
    • 1
  • Abrar Ahmad Chughtai
    • 2
  • Michelle Barnes
    • 2
  • Iman Ridda
    • 2
  • Holly Seale
    • 2
  • Renin Toms
    • 2
  • Anita Heywood
    • 2
  1. 1.Biosecurity ProgramThe Kirby Institute, UNSW Medicine, University of New South WalesSydneyAustralia
  2. 2.School of Public Health and Community Medicine, Faculty of MedicineUNSW Medicine, the University of New South WalesSydneyAustralia

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