Seasonal influenza epidemiology in sub-Saharan Africa: a systematic review

Review

Seasonal influenza epidemiology in sub-Saharan Africa: a systematic review Bradford D Gessner, Nahoko Shindo, Sylvie Briand

Acute respiratory infection (ARI) is a leading cause of mortality worldwide, of which influenza is an important cause that can be prevented with vaccination. We did a systematic review of research published from 1980 to 2009 on seasonal influenza epidemiology in sub-Saharan Africa to identify data strengths and weaknesses that might affect policy decisions, to assess the state of knowledge on influenza disease burden, and to ascertain unique features of influenza epidemiology in the region. We assessed 1203 papers, reviewed 104, and included 49 articles. 1–25% of outpatient ARI visits were caused by influenza (11 studies; mean 9·5%; median 10%), whereas 0·6–15·6% of children admitted to hospital for ARI had influenza identified (15 studies; mean 6·6%; median 6·3%). Influenza was highly seasonal in southern Africa. Other data were often absent, particularly direct measurement of influenza incidence rates for all ages, within different patient settings (outpatient, inpatient, community), and for all countries. Data from sub-Saharan Africa are insufficient to allow most countries to prioritise strategies for influenza prevention and control. Key data gaps include incidence and case-fatality ratios for all ages, the contribution of influenza towards admission of adults to hospital for ARI, representative seasonality data, economic burden, and the interaction of influenza with prevalent disorders in Africa, such as malaria, HIV, and malnutrition.

Introduction

Methods

Pneumonia is the leading cause of paediatric mortality worldwide1,2 and infections such as Streptococcus pneumoniae, Haemophilus influenzae type b, and respiratory syncytial virus are well recognised contributors to global disease burden.3–7 Recent studies have documented the substantial role of influenza in respiratory infection morbidity and mortality at all ages,8–17 although results from other studies have cast doubt on some of the reports from elderly patients.18,19 Modelling analyses have estimated yearly excess mortality attributable to influenza in the USA to be about 30 000 between 1976 and 2007, depending on the year and underlying assigned cause.16 Other studies have documented the effect of influenza on work11,20 and school absenteeism11,21,22 and on the economic costs of influenza.23–27 Influenza also contributes to acute respiratory infection (ARI) burden by increasing the risk of bacterial pneumonia, particularly that caused by pneumococci.28–31 About 1·1 billion people live in sub-Saharan Africa, an area that has high population growth rates, low life expectancy, and many of the world’s poorest countries.32 Despite the abundance of information from many areas of the world, little is known about influenza epidemiology in sub-Saharan Africa,33 and no systematic review has been published. We aimed to help identify data gaps that might affect policy decisions (such as routine vaccine use and target groups and the need for antiviral drugs), to assess the state of knowledge on seasonal influenza epidemiology in sub-Saharan Africa, and to ascertain unique features of influenza epidemiology in the region. We concentrated on sub-Saharan Africa because epidemiological, socioeconomic, and vaccine policy factors in northern Africa are likely to be substantially different. We focused on seasonal human influenza because data on pandemic or avian and animal influenza are unlikely to greatly inform routine yearly influenza prevention and treatment decisions.

Search strategy and selection criteria

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Lancet Infect Dis 2011; 11: 223–35 Agence de Médecine Préventive, Paris, France (B D Gessner MD); and Global Influenza Programme, WHO, Geneva, Switzerland (N Shindo MD, S Briand MD) Correspondence to: Dr Nahoko Shindo, WHO Global Influenza Programme, Health, Security, and Environment, 20 Avenue Appia, CH-1211, Geneva 27, Switzerland [email protected]

We searched the National Library of Medicine through PubMed for (“influenza” AND “Africa”) OR (“Africa” AND (“pneumonia” OR “acute respiratory infection”)) OR (“influenza” AND each individual sub-Saharan African country); sub-Saharan African countries were defined by the UN Educational, Scientific and Cultural Organization34 with the addition of Reunion. The search was limited to studies of people, studies published in English, French, or Portuguese, and studies published from Jan 1, 1980, to Dec 31, 2009. We selected the starting date of 1980 because of the generally increasing quality of studies in later years, including more consistent and robust testing, the paucity of articles related to seasonal influenza (versus pandemic or historical accounts of influenza), and the increased difficulty in obtaining journal articles from older publications. We searched references of identified articles for additional articles, and we reviewed abstracts and titles and selected studies if we thought they included some aspect of influenza epidemiology. This approach included papers the focus of which was seasonal influenza epidemiology and studies of vaccine, pneumonia in general (in case influenza testing was included), and other viral respiratory illness. We excluded studies that reported results from outside sub-Saharan Africa, that only had data on avian or pandemic influenza, that only had data on unrelated diseases (including animal influenza), that were limited to historical information or generic worldwide summaries (except to identify original data references), that duplicated results in other more comprehensive reports, or that were limited to immunology, drug resistance, or other nonepidemiological factors. We excluded WHO reports of influenza activity published in the Weekly Epidemiologic Report35–41 because data were not consistently published in this format. WHO routinely enters data received through 223

Review

For more on FluNet see http://www.who.int/flunet

the Global Influenza Surveillance Network into the FluNet system, including data published in the Weekly Epidemiologic Reports. We used this system to assess seasonality in the three countries that consistently reported data (Madagascar, Senegal, and South Africa). However, because this system is based on four levels of influenza activity, it could not be used for other purposes. Because we aimed to catalogue and summarise all existing data for this systematic review, we did not use quality screens for studies. The one exception was that we excluded studies that reported seroprevalence data based on a single serological test rather than paired specimens, because this method does not usually provide information on current disease.

Data abstraction and synthesis

See Online for webappendix

BDG abstracted data directly into a structured Excel database. Partly because data-quality screens were not used, we did not validate article selection and data abstraction. We sought data for incidence, proportion of disease caused by different causes, seasonality, underlying illness, concurrent illness, age, outbreak context, and case-fatality ratio. Because of the different methods used in the studies, we did not use summary measures apart from for the proportions associated with influenza among paediatric cases of ARI admitted to hospital and outpatients with ARIs. For these outcomes, summary measures were limited to ranges, means, and medians. Data synthesis mainly consisted of reporting the key findings of individual studies. The main risks of bias in comparison and synthesis of studies were different inclusion criteria and variation in tests used. Another risk of bias was the different times of the year during studies—given the known or potential

1203 articles identified and titles and abstracts screened for eligibility 1187 from database search 16 from other sources

104 potentially relevant articles screened for full review

49 articles included

Figure 1: Flow chart for study selection

224

1099 articles excluded due to lack of relevance for one or more of the following reasons: Influenza not main topic Review or historical article Article focused on avian or animal influenza Article not based in sub-Saharan Africa Article not an epidemiology study Articles on pandemic influenza

55 articles excluded for one or more of the following reasons: Article was worldwide summary from WHO or US CDC Article on pneumonia epidemiology without influenza testing Article not an epidemiology study Review or historical article Article repeated more comprehensive data Article only had a single sample serology

seasonality of influenza, unadjusted analysis might underestimate or overestimate results. To address this issue, when including studies with fewer than 12 months of surveillance in summary calculations of proportions, we assumed that no influenza occurred outside the surveyed months and that the average number of admissions to hospital was the same for surveyed and non-surveyed months. The value for these studies was then calculated as the reported proportion divided by 12 months per year divided by the number of months of surveillance. For studies of at least 12 months, we used reported results. We did subanalyses of studies with durations that were multiples of 12 months, but no conclusions changed. The primary outcomes were incidence of influenza, proportion of individuals treated in hospital or as outpatients for ARI caused by influenza, influenza casefatality ratios in individuals admitted to hospital and during outbreaks, relative frequency of influenza identified in association with ARI compared with that of other viruses, influenza seasonality and risk groups, contribution of influenza outbreaks, the effect of underlying illness on influenza risk, and the association between influenza and other pathogens or disorders. No detailed protocol was written and the review is not registered; instead the authors met and agreed upon the methods and goals as delineated in formal terms of reference.

Results We screened the titles and abstracts of 1203 published articles (figure 1). 49 are included in this report.42–90 Studies varied substantially on the basis of the number of years of assessment, age-groups included, number of influenza isolates obtained, testing methods implemented, and clinical case definitions used (table 1). From 1980 to 2009 there was a modest increase in the number of studies published each year. Although studies originated from 14 countries, only South Africa and Madagascar produced more than five included studies, and seven countries produced only one study each (figure 2, webappendix p 1). Seven countries had data on seasonality reported over at least 12 consecutive months. However, for studies in three countries, data included only nine (Kenya48), 15 (Nigeria62), and 14 (The Gambia86) influenza cases. Additionally, data from the Nigerian paper had inconsistencies between data reported in the abstract and the main results. Data from a second study from The Gambia86 were limited to young children admitted to hospital. For the remaining four countries, data were reported on outpatient influenza over surveillance periods of 2 years to 13 years (figure 3).52,54,55,68,70,73,89 Seasonality was strong in southern Africa (ie, Zambia, Madagascar, and South Africa) and weak in Senegal, which is close to the equator. In addition to these data from peer-reviewed publications, Senegal, Madagascar, and South Africa consistently reported influenza activity www.thelancet.com/infection Vol 11 March 2011

Review

to WHO during 2000–2009 and these same patterns were noted (figure 4; webappendix p 2).91 Eight papers that reported seven different laboratoryconfirmed influenza outbreaks were identified—one in South Africa72 and one in Zambia90 in school-aged children, four in Madagascar (two of which reported the same outbreak),50,53,56,58 one in the Democratic Republic of the Congo,45 and one in Reunion,66 among people of all ages (table 1). The proportion of samples from which influenza was identified ranged from 6% to 95% (mean 41%; median 28%). Three studies reported clinical influenza attack rates that ranged from 34% to 67% (mean 49%; median 47%).45,56,58 In the Democratic Republic of the Congo45 and Madagascar,56,58 attack rates were reported from a few communities known to be experiencing high Tested specimens (n)

rates of disease. For example, in Madagascar, the attack rate was 67% in 750 residents of a small village, but the capital city did not report unusual ARI activity. In the Democratic Republic of the Congo, the attack rate was 47% in 2629 surveyed residents of a single district, which was hypothesised to be a small fraction of the total extent of the outbreak. The residential college outbreak in South Africa involved an attack rate of 34%.72 Case-fatality ratios in people with confirmed influenza were not reported in any of the studies evaluating outbreaks. Two studies reported case-fatality ratios in clinically defined cases. In the Democratic Republic of the Congo,45 case-fatality ratio estimates ranged from 0·8% (six of 792) to 1·4% (18 of 1245) depending on the evaluation design, with higher case-fatality ratios in children younger than 5 years (3·5%) and adults older than 65 years (3·2%).

Months of follow-up; dates With influenza virus (n)

Age range

Clinical setting

Test method

Clinical presentation of tested patients

Outcomes included

Influenza type (n)

Burkina Faso, Bobo-Dioulasso42

NA

NA

7; March 2003–June 2003; February 2006–March 2006

4–29 years

Community

NA

Sore throat, rhinitis

CI

NA

Chad, N’Djamena43

124

0

4; February 1988–May 1988

All ages

Hospital (cases), community (controls)

Culture

Meningitis (cases)

CI

NA

Côte d’Ivoire, Abidjan44

211

30

24; January 2003–December 2004

General population

Outpatient

Culture, ELISA

ILI

OP, A

A (H3), 21 A (H1), 1 B, 8

Democratic Republic of the Congo, Bosobolo District45

6

4

2; November 2002–December 2002 All ages

Outpatient

ELISA, PCR, serology

ILI

O

A (H3N2), 4

Ethiopia, Addis Ababa46

104

7

24; 1987–89

Hospital

Serology

CAP

IA

A, 4 B, 3

Kenya, Nairobi47

600

248

Undefined

Kenya, Nairobi48

822

9

Kenya, Coast Province49

228

Madagascar, Antananarivo50

14–75 years

8; January 2005–August 2005

All ages

Outpatient

IFA

24; November 1981–October 1982

<5 years

Hospital

Culture, IFA Severe ARI

14

27; March 1994–May 1996

≥15 years

Hospital

Serology

Pneumonia, confirmed IA by use of radiography

A, 12 B, 2

211

36

7; January 1978–July 1978

All ages

Outpatient

Culture

NA

O, MM

A, 22 Unknown, 14

Madagascar, Tananarive51

210

12

12; January 1979–December 1979

All ages

Outpatient

Culture

NA

OP, MM

A (H1N1), 12

Madagascar, Tananarive52

259

32

12; January 1981–December 1981

All ages

Outpatient

Culture

ILI

OP, A, S, RDT, MM

A (H3N2), 23 A (H1N1), 4 A (H3), 5

Madagascar, Tananarive53

177

11

1; February 1987

All ages

Outpatient

Culture

ILI

O

A (H1N1), 7 A (H3N2), 4

Madagascar, Tananarive54

264

20

12; January 1989–December 1989

All ages

Outpatient

Culture

Undefined

OP, S, RDT

A (H1N1), 11 B, 8 Unknown, 1

Madagascar, Tananarive55

467

24

12; Januray 1992–December 1992

All ages

Outpatient, hospital

Culture

Undefined

OP, S RDT

A (H3N2), 24

Madagascar, national56

152

27

2; July 2002–August 2002

All ages

Outpatient

Culture, RADT

ARI

O

A (H3N2), 27

6341

427

96; January 1995–December 2002

All ages

Outpatient

Culture

Undefined

OP

A (H3N2), 307 A (H1N1), 18 B, 124

84

24

1; July 2002

All ages

Outpatient

Culture

ARI

O

A (H3N2), 24

Madagascar, Antananarivo57 Madagascar, Fianarantsoa Province58

OP

B, 248

IP, RP, S

A, 4 B, 5

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Review

Tested specimens (n)

Months of follow-up; dates With influenza virus (n)

Age range

Clinical setting

Test method

Clinical presentation of tested patients

Outcomes included

Influenza type (n)

(Continued from previous page) Madagascar, Antananarivo59

80

13

3; May 1983–July 1983

6 days to 10 years

Hospital

Culture

ARI

IP, RP

A, 9 B, 4

Madagascar, Antananarivo60

62

15

3; June 1992–August 1992

<14 years

Hospital

Culture

ARI

IP

A (H3N2), 15

Mali, Koulikoro61

119

NA

7; March 1982–September 1982

<3 years and General 15–19 years population

Serology

Healthy children

RP

Unknown

Nigeria, Ibadan62

44

24

27; May 1985–July 1987

<13 years

Outpatient

Serology

URI

OP, S

A (H3N2), 18 A (H1N1), 4 B, 2

Nigeria, Ibadan63

74

12

16; NA

6 months to Outpatient 12 years

IFA, serology

Asthma

CI

A, 12

Nigeria, Ibadan64

35

7

9; August 1985–April 1986

2–59 months

Hospital

IFA, serology

LRI

IP

A, 5 B, 2

Nigeria, Ibadan65

122

19

30; NA

2–59 months

Hospital

IFA, serology

LRI

IP, RP, CFR-V

A, 16 B, 3

Reunion, national66

NA

79

11; January 1996–November 1996

General population

Outpatient

Culture

ILI

O

A (H3N2), 76 B, 3

Senegal, Dakar67

14

1

25; January 1994–January 1996

All ages

Outpatient

Culture

ILI

OP, SA

B, 1

Senegal, Dakar68

805

48

31; June 1996–December 1998

All ages

Outpatient

Culture

ILI

OP, A, S

Unknown, 48

South Africa, Witwatersrand69

210

61

4; May 1984–August 1984

All ages

Outpatient

Culture

ARI

OP, A

A (H1N1), 23 A (H3N2), 16 B, 22

South Africa, national70

4133

527

120; January 1982–December 1991

All ages

Outpatient

Culture

Respiratory infection

OP, RP, S

A (H3N2), 198 A (H1N1), 193 B, 120 C, 16

South Africa, national71

NA

501

24; January 1997–December 1998

All ages

Outpatient, hospital

Culture

Acute respiratory symptoms (outpatient), severe ARI (inpatient)

SA

A (H3N2), 139 A (H1N1), 10 B, 52 A (H3N2) + B, 4 Unknown, 296

South Africa, Pretoria72

20

19

South Africa, Soweto73

NA

~960

South Africa, Soweto74

817 (flu test) 930 (any viral test)

2; May 2003–June 2003

School age

Outpatient

PCR, IFA

ARI

O

A (H3N2), 19

36; January 1997–December 1999

All ages

Outpatient, hospital

NA

NA

S, MM

Unknown, ~960

70

13; March 1997–March 1998

<5 years

Hospital

IFA, culture LRI

IP, RP, CFR-V, I, UI

A, 50 B, 18 Unknown, 2

14; June 1995–August 1996

<2 years

Hospital

Culture

IP

B, 1

25; March 1997–March 1999

<5 years

Hospital

Culture, IFA Severe pneumonia, severe hypoxia

CFR-I, UI

A, 97 B, 20

12; November 1994–October 1995

<6 years

Hospital

IFA

Severe CAP (ICU)

IP

None identified

South Africa, Cape Town75

162

1

South Africa, Soweto76

NA

117

South Africa, Pretoria Region77

23

0

South Africa, Soweto78

1254

40

7; March 2000–September 2000

<1 year

Hospital

IFA

LRI

IP, RP

Unknown, 40

South Africa, Parow79

137

38

3; June 2002–August 2002

15 days to 13 years

Hospital

IFA, culture LRI

IP, RP

A, 18 B, 20

South Africa, Soweto80

975* 1162

42* 71

NA NA

<2 years

Hospital

IFA

Pneumonia

CI

A, 113

South Africa, Soweto81

1593

73

36; January 2000–December 2002

<2 years

Hospital

IFA

LRI

IP, RP, UI

A, 73

South Africa, Cape Town82

1055

9

24; January 2003–December 2004

13 days to 5 years

Hospital

IFA, culture Respiratory infection

IP, RP

A, 8 B, 1

South Africa, Pretoria83

NA

NA

4; January 2003–August 2004

≥65 years

Community, institutions

ICD-9 codes

Acute respiratory and cardiovascular illness

V

NA

The Gambia, Fajara84,85†

157

5

12; June 1987–May 1988

1–9 years

Hospital

Culture, IFA, serology

LRI/pneumonia

IP, L

A, 1 B, 4

LRI

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Tested specimens (n)

Months of follow-up; dates With influenza virus (n)

Age range

Clinical setting

Test method

Clinical presentation of tested patients

Outcomes included

Influenza type (n)

LRI

IP, RP, S, L

A, 13 B, 1

(Continued from previous page) The Gambia, Basse86

221

14

13; March 1987–March 1988

<5 years

Hospital

Culture, IFA, serology

The Gambia, Banjul87

448

30

36; November 1990–October 1992 <5 years

Hospital

Culture, IFA Pneumonia

IP

A, 21 B, 9

The Gambia88

438

68

13; September 1990–September 1991

<3 months

Hospital

Culture, IFA Multiple; one or more signs of sepsis

CFR-V, S

A, 46 B, 22

3760

144

27; June 1993–September 1995

<5 years

Outpatient

Culture

ARI

OP, S

A (H3N2), 110 B, 34

46

13

1; September 1993

School age

School dormitory

Culture

URI

O

A (H3N2), 13

Zambia, Lusaka89 Zambia, unknown town90

General population refers to all ages. ARI=acute respiratory illness. CAP=community-acquired pneumonia. ICD-9=international classification of diseases 9th revision. ICU=intensive care unit. IFA=immunofluorescent antibody. ILI=influenza-like illness. LRI=lower respiratory infection. URI=upper respiratory infection. A=age distribution. CI=contribution of influenza to other disease. CFR-I=case fatality ratio for confirmed influenza-associated hospitalisation. CFR-V=case-fatality ratio for any viral-associated hospitalisation. I=incidence. IA=inpatient proportion of adult respiratory illness associated with confirmed influenza. IP=inpatient proportion of paediatric respiratory illness associated with confirmed influenza. L=limitations of influenza testing. MM=mortality modelling. NA=not available. O=outbreak. OP=outpatient proportion of respiratory illness associated with confirmed influenza. RADT=rapid antigen detection test. RP=relative proportion of paediatric respiratory illness associated with confirmed influenza. S=seasonality. SA=school absenteeism. UI=underlying illness. V=vaccine trial. *Pneumococcal conjugate vaccine trial; top row is vaccine group, bottom row is placebo group. †References 84 and 85 report results from the same study (with separate papers reporting on separate age-groups) and so are considered together.

Table 1: Characteristics of studies identified

Similarly, during an outbreak in Madagascar,56,58 a casefatality ratio of 2% (27 of 1500) for patients with pneumonia or ARI was reported. In this outbreak, there was an overrepresentation of deaths relative to total cases among those aged 65 years and older who constituted 2·3% of ARI and pneumonia cases, but 26% of deaths. The ratio of deaths to ARI cases did not differ from previous years, indicating that the outbreak involved an increase in the number of people affected rather than severity of ARI cases. Age range was reported in several influenza outbreaks and was highly variable. In one of the Madagascar outbreaks,53 age was known for 11 of 22 patients with influenza virus identified, nine between the ages of 10 years and 39 years. In another of the Madagascar outbreaks,56,58 age distribution of ARI cases was similar to the population age distribution with a modest over-representation of individuals older than 5 years. In the Democratic Republic of the Congo, 57% of 671 patients were younger than 5 years and another 21% were at least 35 years.45 12 studies reported results from outpatient surveillance among individuals of all ages,44,47,51,52,54,55,56,67–70,89 with three reporting results for a surveillance period of less than 12 months;47,69,89 another study, from Nigeria, only reported cases in children younger than 13 years62 (table 1). Of the 12 studies of individuals of all ages, 1–25% of tested patients presenting with ARI had influenza virus identified (mean 9·5%; median 10%). The proportion of clinical samples from which influenza virus was identified was between 5% and 15% for most countries (figure 5), although the proportion was low in Zambia and high in Kenya. 11 of the 12 studies in people of all ages did culture alone, whereas one also included immunofluorescence,47 and one study in children used only serology;62 the proportions of tested samples that were positive for www.thelancet.com/infection Vol 11 March 2011

WHO National Influenza Center in sub-Saharan Africa in 2009* No publications 1–2 publications 3–5 publications 11–15 publications Country not included in the analysis Not applicable

Figure 2: Countries in sub-Saharan Africa literature Data from National Influenza Centers, with peer-reviewed data published between 1980 and 2009. Map produced by the Public Health Information and Geographic Information Systems, WHO. The boundaries shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of WHO about the legal status of any country, territory, city, or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on the map indicate approximate borderlines, for which there might not yet be full agreement. *Ghana was a recognised WHO Influenza Center in 2010, and South Africa has two recognised WHO Influenza Centers.

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45 40 35

Percentage

30 25 20 15 10 5

Senegal68 (n=38; 2 years)

Madagascar52,54,55 (n=76; 3 years)

Zambia89 (n=99; 2 years)

December

October

November

September

July

August

May

June

April

March

January

February

December

October

November

September

July

August

May

June

April

March

January

February

December

October

November

September

July

August

May

June

April

March

January

February

December

October

November

September

July

August

May

June

April

March

January

February

0

South Africa70,73 (n=~1470; 13 years)

Figure 3: Average proportion of total influenza virus identified per month in four sub-Saharan African countries Total influenza virus identified and years of surveillance are reported. South African data are estimated from published graphs. The average yearly proportion was used instead of total proportion across all years to minimise the importance of case counts in a single year. Only complete years of data were included.

2·0

Madagascar Senegal South Africa

1·8 1·6

Activity level

1·4 1·2 1·0 0·8 0·6 0·4 0·2 0 01

3

5

7

9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 Week of year

Figure 4: Average weekly activity levels of influenza virus cases in three sub-Saharan African countries that reported to the WHO FluNet between 2000 and 2009 Data from WHO FluNet; for each week and country, ten data points for the 10 years were averaged (webappendix p 2).91 Individual weekly activity levels were 0 (no activity or no report), 1 (sporadic activity), 2 (local outbreak), 3 (regional outbreak), and 4 (widespread outbreaks).

influenza virus for these two latter studies were the highest documented at 25%47 and 55%,62 respectively. Four studies from four different countries reported agespecific influenza identification (webappendix p 3).44,52,68,69 Of those aged younger than age 15 years or 20 years (depending on the study), influenza virus was identified 228

in 5–28% of specimens (mean 13%; median 10%), whereas results for those aged between 15 or 20 years and 35 or 40 years (depending on the study) varied from 7% to 30% (mean 16%; median 13%), and for those aged 40 years or older (or 35 years in one study), from 4% to 27% (mean 17%; median 24%). 15 studies reported in 16 papers had data on the contribution of influenza to paediatric ARI cases admitted to hospital48,59,60,64,65,74,75,77–79,81,82,84–87 (table 1 and figure 5). Four of these studies59,60,64,79 reported results for fewer than 12 months of surveillance with an emphasis on data collection during the peak of the viral respiratory season; in these cases, the proportion was calculated by assuming that no people during the non-tested months had influenza. For all studies combined, the proportion of children admitted to hospital with ARI from which influenza virus was identified varied from 0% (among 23 children admitted to the intensive care unit) to 15·6% (mean 5·5%; median 6·0%). Age did not affect the number of children with influenza virus identified. Of the 13 studies with an age range reported,48,59,60,64,65,74,75,79,81,82,84–87 nine48,64,65,74,75,81,82,86,87 were in children younger than 5 years, and the percentage with influenza virus identified (adjusted if the study was <12 months) was 0·6–15% (mean 6·6%; median 6·3%), whereas four59,60,79,84,85 included children up to 14 years of age and the adjusted percent ranged from 2·5% to 6·9% (mean 5·1%; median 5·1%). Seven studies48,59,74,75,79,82,87 did immunofluorescence and culture (range 0·6–8·6%; mean 4·1%; median 3·1%), three65,84–86 added serology www.thelancet.com/infection Vol 11 March 2011

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30

25

Proportion (%)

20

Child in hospital 1 Child in hospital 2 Child in hospital 3 Child in hospital 4 Child in hospital 5 Child in hospital 6 Child in hospital 7 All outpatient 1 All outpatient 2 All outpatient 3 All outpatient 4 All outpatient 5

15

10

5

0

South Africa69,70,74,

Madagascar51,52,54,

75,77,78,79,81,82

55,57,59,60

The Gambia84–87

Kenya47,48

Nigeria64,65

Senegal67,68

Zambia89

Côte d’Ivoire44

Figure 5: Proportion of samples with influenza virus identified in sub-Saharan African studies published between 1980 and 2009 Samples are of children admitted to hospital for acute respiratory infection or outpatients with acute respiratory infection in persons of all ages. The proportion of samples with influenza identified for child in hospital 7 was 0%.

(range 2·5–15·6%; mean 8·4%; median 6·3%), two64,78 immunofluorescence alone (range 4·3–15%; mean 9·7%; median 9·7%), and one60 culture alone (6%). Influenza virus can be identified in individuals who do not have ARI symptoms and thus influenza virus identification might not necessarily indicate a causal link to ARI. Three of the 15 studies in children evaluated this issue, all from The Gambia. The first found that 19% (42 of 221) of patients with lower respiratory tract infection had a virus identified versus 15% (14 of 96) of controls.86 No particular virus, including influenza, was identified more often in cases than in controls. The second study identified a virus in 49% (42 of 86) of infants with pneumonia and 19% (8 of 42) of controls; influenza was identified from one infant with pneumonia and from two controls.85 The third study identified a virus in 34% (25 of 74) of tested patients (including three influenza); however, only three patients had identification of a virus alone, with most patients having co-infection with H influenzae or S pneumoniae.84 Two studies focused on establishing the cause of ARI in adults admitted to hospital46,49 by use of serology. In Kenya,49 16 of 281 patients (5·7%) had a virus and 14 (5·0%) had influenza virus identified. In Ethiopia,46 seven of 104 tested patients (6·7%) had a virus, all of whom had influenza virus. 11 hospital-based studies reported results for influenza virus and other viral causes of ARI in www.thelancet.com/infection Vol 11 March 2011

children48,59,65,74,78,79,81,82,86–88 (table 1). There were 1–28% of cases with influenza virus identified (mean 9·6%; median 7·5%), 2–25% for respiratory syncytial virus (mean 13%; median 12%), 2–30% for parainfluenza virus (mean 7·6%; median 4·4%), and 2–23% for adenovirus (mean 7·1%; median 3·7%). Influenza virus was the most commonly identified virus in two studies79,88 and the second-most commonly identified virus in three other studies74,86,87 (figure 6), whereas respiratory syncytial virus was the most commonly identified virus in six studies, adenovirus in two, and parainfluenza virus in one. In four articles that studied human metapneumovirus and influenza, human metapneumovirus was identified in 3–8% of cases (mean 6·0%; median 6·0%).78,79,81,82 25–77% of specimens did not have a virus identified. Two studies reported results in outpatients,70,89 and influenza was the most common virus identified. In South Africa, 13% (527 of 4133) of specimens tested in all agegroups identified influenza virus, with the next most common isolates being adenovirus (3%) and parainfluenza virus (3%). In Zambia, 4% (142 of 3760) of children had influenza virus identified with enterovirus (2%) and adenovirus (1%) the next most common. In a study from Mali,61 community serological analysis was done, thus the data are not comparable to the other studies that assessed ill children. Additionally, this study was done during a known outbreak of respiratory syncytial virus and reported that in children younger than 3 years of age, 229

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Proportion of tested isolates with specific cause (%)

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15

Influenza Respiratory syncytial virus Adenovirus Parainfluenza virus Human metapneumovirus

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0

South Africa79 (n=137; 3 months)

South Africa78 (n=1254; 9 months)

South Africa74 (n=930; 13 months)

South Africa82 (n=1055; 2 years)

South Africa81 (n=1593; 3 years)

Madagascar59 (n=80; 3 months)

The Gambia86 (n=221; 13 months)

The Gambia87 (n=448; 3 years)

The Gambia88 (n=438; 13 months)

Kenya48 (n=822; 2 years)

Nigeria65 (n=122; 30 months)

Figure 6: Proportion of tested samples with identification of respiratory viruses in children admitted to hospital with acute respiratory infection in sub-Saharan Africa, from reviewed studies published between 1980 and 2009

38% (45 of 119) had a four-fold rise in antibody titres to respiratory syncytial virus compared with 18% (21 of 119) for influenza and 3% (3 of 119) for parainfluenza virus. Outside of an outbreak setting, case-fatality ratios for ARI with confirmed influenza have rarely been reported in Africa. The only study identified was in South Africa, for which case-fatality ratios in children younger than 5 years who were admitted to hospital for severe lower respiratory tract infection were 2% in those not infected with HIV and 8% in those with HIV.76 Influenza mortality can be estimated by studying correlations between respiratory disease mortality and influenza seasonality. Few studies from Africa reported this information, possibly because of the few data on seasonality. Three studies from Madagascar documented substantial increases in respiratory disease mortality or overall mortality at the same time that identification of influenza virus peaked.50–52 Another study in South Africa formally modelled trends in mortality by influenza activity and indicated a strong correlation between influenza seasonality and excess hospital mortality in adults, particularly for those aged 65 years and older.73 Vaccine trials often provide insight into disease epidemiology.10,11 The only trial identified that provided data on influenza epidemiology used a case-control design, and reported a decrease of 19% of vaccinated individuals who had the combined outcome of admission to hospital for ARI or cardiovascular disease or death from any cause.83 The authors noted that this effect could be explained by confounding. The only identified study that directly measured influenza incidence was done in South Africa. This study reported an incidence of influenza-associated ARI admission to hospital of 148 per 100 000 per year in children aged 2–23 months who did not have HIV and 1268 per 100 000 per year in children with HIV.74 230

Three papers studied the association between influenza and HIV infection, all from South Africa and all limited to children treated in hospital.74,76,81 Only one74 reported incidence, with children with HIV having an eight times higher risk of admission to hospital from influenzaassociated ARI than did children without HIV. In this study, seasonal patterns of influenza were similar in children with and without HIV, and children with HIV who had influenza were older on average and more likely to have a bacterial co-infection than were children who did not have HIV. The overall ARI case-fatality ratio was 14% (69 of 433) in children with HIV74 versus 2·4% (12 of 497) in children without HIV, but the sample size was too small to evaluate case-fatality ratios by individual viral cause. A second study reported that, in children admitted with lower respiratory tract infection with confirmed influenza, those who had HIV were more likely to be older, have underlying illnesses, have more severe disease, and have indirect evidence of bacterial coinfection than were children without HIV. Although no significant difference in hospital duration or mortality was reported, the mortality rate was 8% in HIV-infected children and 2% in HIV-uninfected children.76 In the third study, in children younger than 2 years who were treated in hospital for lower respiratory tract infection, 4·8% (46 of 951) of those without HIV and 3·6% (22 of 613) of those with HIV had influenza virus identified.81 One study, from The Gambia, reported no association between malnutrition and influenza.87 Among children aged 3 months to 5 years presenting to an outpatient clinic, ten of 158 (6%) malnourished children with pneumonia had influenza identified compared with nine of 119 (8%) malnourished children without pneumonia, nine of 119 (8%) well nourished children with pneumonia, and two of 52 (4%) well nourished children without pneumonia. www.thelancet.com/infection Vol 11 March 2011

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The African meningitis belt extends from Senegal to Ethiopia92 and is characterised by seasonal hyperendemic and epidemic acute bacterial meningitis, mainly meningococcal but also pneumococcal disease. The reasons for this seasonal disease occurrence are unknown, but viral respiratory tract infections (including influenza) might contribute to increased transmission and nasopharyngeal carriage of virulent meningococci and pneumococci.42,43 In South Africa, investigators measured the effect of a seven-valent pneumococcal conjugate vaccine on the occurrence of clinical pneumonia caused by viral pathogens in children younger than 2 years.80 In this study, pneumococcal vaccine effectiveness against pneumonia with confirmed influenza was 41%, with little difference in effectiveness between HIV-infected and HIV-uninfected children. A similar effect was documented against parainfluenza virus, with little effect reported against respiratory syncytial virus and adenovirus. The researchers concluded that pneumococcus has a major role in the development of pneumonia associated with influenza and other viruses. In a study in Nigeria, the occurrence of respiratory viral infection in children admitted for asthma was assessed in 74 children.63 53% (n=39) of individuals had a viral infection, most commonly respiratory syncytial virus (27% of patients; n=20), but also influenza A virus (16%; n=12). During periods of known influenza activity, school absenteeism provides an indicator of influenza burden. In Senegal,67 school absenteeism at two schools in Dakar remained at 2–5% throughout the surveillance period despite peaks in febrile respiratory illness. In South Africa,71 school absenteeism has been monitored since 1987. During 1997, and coincident with a mild influenza season, there was not a substantial rise in school absenteeism versus that during the previous 5 years, whereas absenteeism surged to 8% in 1998 during the peak of an epidemic of influenza A (H3N2). Some studies have reported respiratory disease trends and correlated these with influenza virus identification rates. One study from Madagascar indicated a slight correlation between influenza virus identification and the proportion of outpatient visits for influenza-like illness, and a strong correlation with the proportion of paediatric cases admitted to hospital for ARI.55 Two other studies from Madagascar reported a stronger correlation between the number of individuals in whom the influenza virus was identified, the percentage of tested specimens with influenza virus identified, and the number of outpatient ARI visits.52,54

Discussion As documented in a brief review published in 2002,93 little influenza surveillance infrastructure existed at that time in sub-Saharan Africa. Between 2002 and 2007, of the 46 WHO African Region countries, only South Africa, Senegal, and Madagascar routinely reported influenza activity to WHO, with sporadic reporting from Zambia, Uganda, Mauritius, Reunion, and Kenya.35–41 We found www.thelancet.com/infection Vol 11 March 2011

few published influenza epidemiology data in sub-Saharan Africa, which were concentrated in just a few countries, mainly Madagascar, South Africa, and Senegal and, to a lesser extent, The Gambia, Zambia, and Kenya. In particular, the paucity of robust incidence and mortality data makes assessment of the importance of influenza difficult within sub-Saharan Africa and in comparison to other areas of the world. Several studies commonly identified influenza virus in paediatric ARI cases admitted to hospital, and these data are consistent with recent studies from other areas of the world, for which influenza virus was identified in 3–15% of specimens.94–100 Additionally, the proportion of outpatient illness with influenza virus identified was similar to other areas,100,101 and two influenza outbreaks in Africa documented widespread illness and substantial case-fatality ratios.45,53,56,58 In summary, the influenza burden in Africa seems unlikely to be less than in other areas, and factors such as more restricted access to care in Africa might imply a higher burden. There is a moderate amount of data on influenza seasonality, particularly in southern Africa where winter seasonality is similar to that in North America and Europe. In Zambia, South Africa, and to a large extent, Madagascar, seasonal influenza occurrence corresponded with the drier, cooler winter months of June to August. Of the few countries nearer the equator with published data, influenza seasonality was less pronounced. For example, there was influenza activity during all seasons in Senegal; while average monthly temperatures in Senegal are relatively consistent at 27–32°C, rainfall varies substantially from an average monthly peak of 250 mm between July and September to about 0 mm during November to May. Other studies have reported little influenza seasonality in tropical countries outside Africa,102 despite occasionally strong seasonality for respiratory viruses in general,103 particularly for respiratory syncytial virus.104 If seasonality is minimal or absent in some areas of Africa, identification of influenza burden is difficult, because one method of establishing the overall burden in temperate climates is to model changes in clinical outcomes (such as mortality or admission to hospital for pneumonia) by changes in influenza virus identification rates.16 Additionally, identification of seasonality in the many climatic zones extending across Africa will be essential to planning the timing of public health interventions, such as vaccination. Data on most aspects of influenza epidemiology are scarce. For example, only one study directly estimated influenza incidence. In principle, influenza incidence could be calculated by multiplying reported data for nonspecific ARI incidence and the proportion of outcomes associated with influenza as reported above. However, ARI incidence studies will also need large resources, particularly where access to care is restricted and systematic hospital discharge data are rarely available. For example, Rudan and co-workers3 identified only five studies of paediatric ARI incidence in sub-Saharan Africa,105–109 and estimates varied by a factor of 20, from 0·068 to 1·3 per 231

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Total number of identified studies Influenza incidence

1

Influenza mortality (case-fatality ratios or incidence)

1

Outbreak-associated influenza mortality

0

Seasonality over several years

4

Contribution of influenza to admission of adults to hospital with acute respiratory infection

2

Interaction of influenza with malaria, tuberculosis, and malnutrition

0

Vaccine interventions

1

Contribution of influenza to workplace absenteeism

0

Contribution of influenza to school absenteeism

2

Economic effect of influenza

0

Table 2: Major identified data gaps in the publications on seasonal influenza epidemiology in sub-Saharan Africa

child-year of follow-up. Other non-specific ARI incidences, such as admission of paediatric patients to hospital for pneumonia, were even less common.110 Thus, the only firm conclusion about influenza incidence is that existing data are insufficient to provide meaningful estimates. Other data gaps exist (table 2). Few reports exist on the contribution of influenza to ARI among children aged older than 5 years and adults, particularly in patients admitted to hospital. Data on mortality in confirmed influenza cases were almost entirely absent. Only a few studies reported school absenteeism, and none reported the effect of influenza in the workplace. Although studies in South Africa have reported that HIV infection can increase influenza burden, none evaluated the effect of other disorders prevalent in Africa, such as malaria, tuberculosis, and malnutrition; this omission is a global limitation despite some preliminary work.111–115 No published sub-Saharan African studies have evaluated the effect of influenza virus infection on mortality and admission to hospital in the elderly. Cost data associated with influenza illness were not identified. Finally, few studies used PCR testing, which is the gold standard; the several projects underway in Africa should resolve this deficit. Compared with other tropical or resource-poor settings, data gaps in Africa are severe. For example, several studies in Asia have reported incidence data: Thailand has incidence rates of up to 375 per 100 000 per year for influenza-associated pneumonia,116 Bangladesh has incidences of 2700 per 100 000 per year in children younger than 5 years for influenza-associated pneumonia, and 62 per 100 000 per year in children younger than 5 years for severe lower respiratory tract infection,94 and Vietnam reported an incidence of 870 per 100 000 per year in children younger than 5 years for influenza-associated pneumonia.95 Other studies have reported variability in seasonality, although generally with more disease in the rainy season,101,116–118 have modelled the contribution of influenza to seasonal mortality117 and morbidity,119 and have used vaccines to indicate the effect of influenza on 232

workplace absenteeism.120 Nevertheless, Asia is similar to Africa in that most countries do not use seasonal influenza vaccination,121 and most countries do not have seasonal influenza vaccine policies (webappendix p 2).122 Our systematic review had two major limitations. First, comparison of studies was difficult because of differences in study design that included different case definitions, age-groups, settings of patients, study length, and testing methods. These problems continue to hamper interpretation of data on influenza in Africa and are caused by little agreement among sites within and between countries on common methods and case definitions, restricted budgets and availability of trained people, and uncertainty by decision makers on how to rank influenza among competing health-care priorities. Second, influenza-associated disease varies by time and location in terms of disease burden, risk groups, population susceptibility, and other factors; thus, the identified published data might not be indicative of other locations or of the same locations at different times or among different sub-populations. Lastly, we did not include data from before 1980 or those published in all languages, which might have led to some relevant studies being missed. Africa has made advances to improve data. WHO lends support to National Influenza Centers in several sites (figure 2). The WHO Regional Laboratory Network includes additional sites in Ghana, Nigeria, Gabon, Cameroon, and Zambia. Other surveillance projects are supported by the US Centers for Disease Control and Prevention, Wellcome Trust, International Network of Pasteur Institutes, US Naval Medical Research Unit 3 in Cairo (NAMRU3), US Department of Defense Global Emerging Infections Surveillance and Response System (DoD-GEIS), the European Union, and other groups. In 2009, 14 sub-Saharan African countries within the Global Influenza Surveillance Network reported influenza virus subtypes to WHO, and during 2010, a further ten countries reported data to WHO; the fragility of surveillance is indicated by the failure of three countries to report data during 2010 (through to week 39), despite previously reporting during 2009.91 Despite improvements, without more information, countries in Africa will be unable to assess the relative importance of influenza as a contributor to disease burden and child or adult mortality. This deficiency makes it difficult to justify the importance of influenza vaccine123 or other influenza control measures as a strategy for improving population health and achieving the Millennium Development Goals. To acquire additional information, several measures are needed. First, several countries should establish routine, systematic influenza surveillance that includes laboratory diagnosis, ARI mortality, admission to hospital for ARI, outpatient illness burden, and school and workplace absenteeism. These sites should also strive to establish surveillance in a way that enables the identification of www.thelancet.com/infection Vol 11 March 2011

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disease incidence, and regionalisation of efforts would ensure that the effect on disease outcomes of various socioeconomic, health, and climatic contexts in Africa can be evaluated. Second, centres of excellence could do high-quality studies, such as population-based incidence studies, vaccine effectiveness studies to ensure vaccination programmes work in African populations (with particular emphasis on comorbidities such as HIV, malaria, and malnutrition), or vaccine probe studies to measure the effect of influenza on non-microbiologically confirmed outcomes.5,9 Third, data on cost should be collected and cost-effectiveness evaluations done. Finally, models using these data should be created to assess the usefulness of prevention strategies in different agegroups and for different scenarios. The implementation of these measures will depend on the resources available to countries and country-level prioritisation of health aspects. With a paucity of resources in many sub-Saharan African countries, international support will almost certainly be needed. Nevertheless, African governments have taken steps to identify and focus on gaps in knowledge as indicated by the increasing development of sub-Saharan surveillance networks, the organisation of scientific congresses in the region such as the 2009 African Influenza Scientific Symposium124 and the 2009 African Conference on Pandemic Influenza,125 and high-quality clinical trials designed to establish disease burden such as that ongoing in Senegal.126 Although these efforts have not yet resulted in a great increase in published manuscripts and data, this situation should change within the next few years. Contributors BDG did the literature review and all analyses, and wrote the first version of the manuscript. SB and NS planned the analysis, provided critical review of the manuscript, assisted with identification of appropriate references, and reviewed the final version of the manuscript. Conflicts of interest BDG works for Agence de Médecine Préventive, which receives unrestricted grant support and specific study support from Sanofi Pasteur, a manufacturer of influenza vaccines. Additionally, his organisation receives study support from Pfizer, Merck, and GlaxoSmithKline. He has received honoraria from GlaxoSmithKline but not during the past 3 years. NS and SB declare no conflicts of interest. Acknowledgments The authors are responsible for the views expressed in this publication, which do not necessarily represent the decisions or the stated policy of WHO. References 1 United Nations. Millennium Development Goals Report: 2005. United Nations, New York, NY, 2005. http://unstats.un.org/unsd/ mi/pdf/MDG%20Book.pdf (accessed Nov 24, 2010). 2 United Nations Children’s Fund and The World Health Organization. Pneumonia: the Forgotten Killer of Children. Unicef/WHO, New York, NY, 2006. http://whqlibdoc.who.int/ publications/2006/9280640489_eng.pdf (accessed Nov 24, 2010). 3 Rudan I, Tomaskovic L, Boschi-Pinto C, Campbell H, the WHO Child Health Epidemiology Reference Group. Global estimate of the incidence of clinical pneumonia among children under five years of age. Bull World Health Organ 2004; 82: 895–903. 4 Rudan I, Boschi-Pinto C, Biloglav Z, Mulholland K, Campbell H. Epidemiology and etiology of childhood pneumonia. Bull World Health Organ 2008; 86: 408–16.

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