Management of Group A Streptococcal Sore Throat for the ......management of people with...

Management of Group A

Streptococcal Sore Throat for

the Prevention of Acute

Rheumatic Fever

2011

© Ministry of Health 2011

Published by: New Zealand Guidelines Group (NZGG)

PO Box 10 665, The Terrace, Wellington 6145, New Zealand

ISBN (Electronic): 978-1-877509-60-5

Copyright

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Funding and independence

This work was funded by the Ministry of Health. The work was researched and written by NZGG

employees or contractors. Appraisal of the evidence, formulation of recommendations and

reporting are independent of the Ministry of Health.

Statement of intent

NZGG produces evidence-based best practice guidelines to help health care practitioners, policy-

makers and consumers make decisions about health care in specific clinical circumstances. The

evidence is developed from systematic reviews of international literature and placed within the New

Zealand context.

While NZGG guidelines represent a statement of best practice based on the latest available

evidence (at the time of publishing), they are not intended to replace the health practitioner’s

judgment in each individual case.

Citation: New Zealand Guidelines Group. Management of Group A Streptococcal Sore Throat.

Wellington: New Zealand Guidelines Group; 2011.

Copies of the evidence review are available online at www.nzgg.org.nz.

Contents

Acknowledgments .......................................................................................................... v

About the evidence review ............................................................................................ v

Purpose...................................................................................................................... v

The need for a guidance .............................................................................................. v

Scope of the evidence review....................................................................................... v

Target audience .......................................................................................................... v

Treaty of Waitangi ...................................................................................................... vi

Key point development process................................................................................... vi

Definitions.................................................................................................................. vi

Summary .......................................................................................................................... 1

Key messages ............................................................................................................1

1 Introduction and context ...................................................................................... 2

GAS throat infection ....................................................................................................2

Acute rheumatic fever..................................................................................................2

GAS throat infection in New Zealand ............................................................................3

Acute rheumatic fever in New Zealand..........................................................................3

Ethnic disparities .........................................................................................................9

Signs and symptoms of GAS throat infection............................................................... 13

2 Rapid Antigen Diagnostic Tests ........................................................................ 15

Rapid Antigen Diagnostic Test in people with a current sore throat ............................... 15

Rapid Antigen Diagnostic Test in people with a resolved sore throat ............................. 40

Timing of testing........................................................................................................ 41

3 Antibiotic treatment ............................................................................................ 42

Antibiotic type ........................................................................................................... 42

Antibiotic dose .......................................................................................................... 51

Antibiotic duration...................................................................................................... 60

4 Asymptomatic GAS infection............................................................................. 70

4.1 Prevalence of GAS sore throat ............................................................................. 70

Relationship between prevalence of asymptomatic GAS throat infection and

rheumatic fever................................................................................................ 72

5 Community swabbing ......................................................................................... 75

Rheumatic fever outbreaks ........................................................................................ 75

Swabbing asymptomatic community members and households in areas of

outbreak .......................................................................................................... 77

Appendix 1: Methods.................................................................................................... 84

Contributors .............................................................................................................. 84

Research process ..................................................................................................... 85

Research questions ................................................................................................... 85

Reviewing the literature ............................................................................................. 87

Evidence appraisal .................................................................................................... 89

Appendix 2: Abbreviations and glossary................................................................... 92

Abbreviations ............................................................................................................ 92

Glossary ................................................................................................................... 94

References ..................................................................................................................... 95

Acknowledgments

NZGG would like to thank Dr Richard Milne and his co-authors for granting us

permission to use their analysed data on incidence of acute rheumatic fever in New

Zealand, and Dr Rajesh Khanna, DHB (Paed), MPH; Co-ordinator, National Child

Health Research Centre, National Institute for Health and Family Welfare, Delhi, for

reviewing the analysis of Rapid Antigen Diagnostic Tests.

About the evidence review

Purpose

The purpose of this evidence review is to provide an evidence-based summary of

current New Zealand and overseas evidence to inform best practice in the

management of people with Streptococcal A infection of the throat (pharyngitis)

especially with the aim of preventing one of the more serious sequalae: Acute

rheumatic fever (ARF).

The need for a guidance

Acute rheumatic fever rates in New Zealand have failed to decrease since the 1980s

and remain some of the highest reported in a developed country. 1, 2 In response to this

ongoing problem, the Ministry of Health wished to understand whether there were

specific strategies for managing Group A beta-hemolytic streptococcal throat infection

(GAS) throat infections that could help to lower the rate of ARF and prevent chronic

rheumatic heart disease.

Scope of the evidence review

The evidence review specifically addresses the diagnosis of people with suspected

GAS throat infection using Rapid Antigen Diagnostic tests, and the management of

people with confirmed GAS throat infection using antibiotics. The review also provides

information on asymptomatic GAS throat infection and community swabbing. It should

be noted that the management of GAS throat infection in people with confirmed ARF,

acute or chronic rheumatic heart disease or in people with recurrent GAS throat

infection is beyond the scope of this work and has been excluded.

Target audience

The evidence review and guidance is intended primarily for the providers of care for

New Zealanders with GAS throat infection.

Treaty of Waitangi

The New Zealand Guidelines Group acknowledges the importance of the Treaty of

Waitangi to New Zealand, and considers the Treaty principles of partnership,

participation and protection as central to improving Māori health.

NZGG’s commitment to improving Māori health outcomes means we work as an

organisation to identify and address Māori health issues relevant to each piece of

guidance. In addition, NZGG works to ensure Māori participation is a key part of the

development process. It is important to differentiate between involving Māori in the

guidance development process (the aim of which is to encourage participation and

partnership), and specifically considering Māori health issues pertinent to the topic at

all stages of the development process. While Māori participation in guidance

development aims to ensure the consideration of Māori health issues by the expert

advisory group, this is no guarantee of such an output; the entrenched barriers Māori

may encounter when involved in the health care system (in this case guidance

development) need to be addressed. NZGG attempts to challenge such barriers by

specifically identifying points in the development process where Māori health must be

considered and addressed. In addition, it is expected that Māori health is considered at

all points in the guidance in a less explicit manner.

Key point development process

NZGG convened a multidisciplinary expert advisory group (EAG) comprising members

nominated by a diverse range of stakeholder groups. The research questions

developed by the Ministry of Health and NZGG were discussed with the EAG and were

used to inform the search of the published evidence, from which systematic evidenced-

based statements for best practice were derived. A one-day, face-to-face meeting of

the full EAG was held, plus additional teleconferences, at which evidence was

reviewed and key practice points were developed.

Full methodological details are provided in Appendix 1.

Definitions

Several common terms are currently in use for Group A beta-haemolytic streptococcal

pharyngitis. NZGG has elected to use the term ‘GAS throat infection’ throughout this

document in an attempt to keep the document clear and easy to read.

Management of Streptococcal A Sore Throat 1

Summary

Key messages

Antibiotics should be initiated as soon as possible as there is no evidence to

support current practice of delaying treatment by up to nine days and there is no

evidence to support any other recommendation about the timing of treatment.

Children at high risk of developing rheumatic fever should continue to receive

empiric (immediate) antibiotic treatment and the presence of GAS should continue

to be confirmed by laboratory culture.

To establish asymptomatic carriage rate in the school population, where an

intervention is planned, all consented children should be swabbed before and after

the intervention, regardless of symptoms to allow evaluation of programme

effectiveness.

There is reliable evidence about the efficacy of rapid antigen diagnostic tests, which

give a result much faster than swabbing and testing.

Once daily amoxicillin is the first choice for antibiotic treatment for a GAS throat

infection. Studies comparing amoxicillin with penicillin V report comparable

outcomes. Amoxicillin is likely to achieve better compliance because of its daily

dosing and ability to be taken with food compared with penicillin V’s more frequent

dosing and the requirement to take it on an empty stomach.


1 Introduction and context

GAS throat infection

Streptococcal pharyngitis is caused by a Group A beta-haemolytic streptococcal

infection and can trigger an inflammatory response in pharyngeal cells that causes

many of the signs and symptoms of streptococcal pharyngitis.3 Group A streptococcus

(GAS) is a bacterium often found in the throat and on the skin and can be carried by

people who have no symptoms of illness.4 It affects the pharynx including the tonsils

and possibly the larynx. After an incubation period of 2 to 5 days5, 6 there is an abrupt

onset of illness with sore throat and fever.7 The tonsils and pharynx are inflamed and

tonsillar exudate may be present.3 Throat pain is typically described as severe and is

associated with difficulty in swallowing.3 Symptom severity varies and the presence of

classically associated symptoms such as headache, malaise or gastrointestinal

symptoms may be present in only 35% to 50% of patients.3

GAS sore throat is a communicable disease, spread through close contact with an

infected individual. A definitive diagnosis is made based on the results of a throat

culture. One of the more serious complications is acute rheumatic fever (ARF).

Evidence indicates that antibiotic treatment for GAS throat infection in communities

where the complication is common can reduce progression to ARF by more than two-

thirds.8

Acute rheumatic fever

Acute rheumatic fever is an autoimmune response to infection with GAS bacteria. In

New Zealand this response is primarily thought to be due to GAS throat infections.

Though there has been discussion of the role of GAS skin infections in ARF (skin

sepsis), convincing evidence has yet to be found to support this theory.9

The ensuing generalised inflammatory response to the GAS infection occurs in certain

organs; the heart, joints, central nervous system (ie, brain) and skin. Inflammation of

the heart (carditis) can cause long-term damage to the heart valves requiring heart

valve replacement surgery. The consequence of recurrent exposure to ARF is the

development of rheumatic heart disease (RHD) which may include valvular disease

and cardiac myopathy and sequlae such as heart failure, atrial fibrillation, systemic

embolism, stroke, endocarditis and the requirement for cardiac surgery.10 In the 1990s

RHD was responsible for 120 deaths per year in New Zealand.1


GAS throat infection in New Zealand

While most sore throats are thought to be viral in origin, estimates of the numbers of

sore throats due to GAS vary widely.3 Evidence on rates is slim. A review completed by

the World Health Organization11 investigated the current evidence in relation to the

burden of GAS infections on a worldwide scale and estimated that in children in

developing countries (New Zealand was included in this group given the high rates of

rheumatic fever in specific communities within New Zealand) the number of sore

throats due to GAS could be as high as 40%.11

This estimate was based on the findings from three studies from populations where

ARF is common: New Zealand (primarily in Māori and Pacific communities), Kuwait

and Northern India. As the authors state, a positive GAS finding was not confirmed with

serology and hence the true rate may be lower. New Zealand data is currently being

collected in a school-based sore throat swabbing programme in Opotiki.12 Interim data

shows that between October 2009 and December 2010, 8% of children reporting sore

throats who were swabbed had a GAS infection (211 positive swabs of 2489 taken).

Data collection is ongoing and analysis of trends would currently be premature.12 This

data supports those accepted estimates that between 3% and 36% of sore throats are

due to a GAS infection.3

There is currently no national data collected by ESR (Environmental Science and

Research) for GAS infections in New Zealand independent of the notification of

rheumatic fever.

Acute rheumatic fever in New Zealand

Acute rheumatic fever is reported two ways in New Zealand. The most current data,

available publically in rate form, is that reported by the ESR as part of its annual

surveillance of notifiable diseases. ESR collects this data from the regional public

health units. Local District Heath Boards (DHBs) and treating hospital clinicians are

required to use a specific ARF reporting process to notify regional public health

services of the ARF cases hospitalised within their region; this data is then reported to

ESR by each region (who each have their own database to hold this data). This data

may be reported from the DHBs to the regional public health units late and in bundles

or not at all, given it requires a separate reporting process.

The second source of ARF data in NZ comes from the National Minimum Dataset

(NMDS). This is a centralised dataset, in which all hospital encounters are coded within

the hospitals themselves and entered straight into the database, the direct report

nature does mean the NMDS data is viewed as more reliable and valid. However,

given the large numbers of data involved in the NMDS, rates for ARF are not calculated

on an annual basis.


Case Numbers of acute rheumatic fever

Acute rheumatic fever appears to have been virtually eradicated from most ‘developed’

countries yet rates in New Zealand have failed to decrease since the 1980s and remain

some of the highest reported in a developed country.1, 2

The Ministry of Health’s ESR Annual Surveillance Report of notifiable disease has

reported annually between 100 and 150 cases over the last decade (all ages).13 In

2010, 155 initial cases and 13 recurrent cases of rheumatic fever were notified (for all

ages),14 while analysis of the hospital admissions and ICD discharge data provided in

the NMDS indicated that from 1987 to 2008 there were between 150 and 230 cases

per year (all ages).13

Hospitalisation data indicates that the primary episode of ARF usually occurs in

children aged between 5 to 14 years (Figure 1.1)1, 2 and a recent analysis of the NMDS

hospitalisation data (using data up to 2009) reported 115 index cases of ARF in

children aged 5 to14 years in 2009 (Table 1.1).15 In 2010, approximately 75% (117

cases) of initial attack ARF cases notified were in those aged less than 15 years, with

the highest age-specific rate in the 10 to 14 years age group (25.4 per 100 000

population, 75 cases).14

Figure 1.1 Number of hospitalisations between 2004 and 2010 for acute rheumatic fever

by age

Source: National Minimum Data Set

1, 2


Table 1.1 Annual index cases by year and ethnicity for children 5 to 14 years of age

1993 2009 %change Ratio of 2009 to 1993

Cases Māori 32 62 +98% 2.0 Pacific Islands 17 48 +185% 2.9 European/Other 17 5 -168% 0.3

Total 64 115 +79% 1.8

Source: Milne, R., D. Lennon, et al. (2010). Burden and cost of rheumatic fever and rheumatic heart

disease in New Zealand: focus on school age children. A report to the Ministry of Health. Auckland, New

Zealand, Health Outcomes Associates Limited.

Rates of acute rheumatic fever

It is reported that rates of ARF in New Zealand since 1980 have remained at about 15

cases per 100,000 children aged 5 to 15 years of age.13

An analysis of hospitalisation data between 2000 and 200915 found a mean incidence

rate for New Zealand children (all ethnicities) of 17.2 per 100,000, and distinct

inequalities in the rates between different ethnic groups (Table 1.2).

Table 1.2 ARF incidence rates for New Zealand children 5 to 14 years of age (2000–2009)

Māori Pacific

Non-

Māori/Pacific Total

Rate ratio*

Māori Pacific

Mean 40.2 81.2 2.1 17.2 19.5 39.3

-95%CI 36.8 73.4 1.6 16.1 15.5 31.3

+95%CI 43.8 89.6 2.5 18.2 24.5 49.8

CI = confidence interval

* Compared to non-Māori/Pacific




Of concern is that the inequality between ethnic groups has been widening over time.

In the period studied (1993–2009) incidence rates increased by 79% and 73% for

Māori and Pacific children respectively and declined by 71% for non-Māori/Pacific

categories, with an overall increase of 59%15 (Figure 1.2). Māori and Pacific children 5

to 14 years of age accounted for 92% of new cases of ARF in the period 2000 to 2009

and comprised 30% of children in the 2006 census.15


Figure 1.2 Annual index cases and incidence rates for acute rheumatic fever in 1993–2009 for children 5 to 14 years of age





The notification rates from ESR since 2000 for all ages and ethnicities are displayed in

Figure 1.3 for both initial and recurrent attacks.14

Figure 1.3 Rates of notified rheumatic fever per 100,000 from 2000 to 2010

Source: ESR, 2011

Acute rheumatic fever in New Zealand by region

ESR reports rates for initial ARF attack by DHB, ethnic group, age and sex for the 2010

year. The highest rate of notified cases in 2010 was in Tairawhiti DHB (15.1 per

100,000 population, 7 cases), followed by Counties Manukau (10.6 per 100,000, 52

cases) and Northland (10.2 per 100,000, 16 cases) DHBs.14

However, given the small numbers, rates by DHB are more meaningful if examined

over time. Analysis of the 2000 to 2009 hospitalisation data found that Counties

Manukau DHB had the highest mean annual incidence rate for children (93.9 per

100,000) and contributed 298/700 cases (43%).15 Ninety-nine percent of index cases in

Counties Manukau were in children of Māori or Pacific ethnicity. Table 1.3 displays

incidence for the 2000 to 2009 years by DHB, ethnicity and decile.


Table 1.3 Index ARF cases and incidence rates for deciles 9 and 10 children aged 5 to 14

years, by District Health Board

Index ARF cases in 2000-2009 Mean annual incidence per 100,000

DHBa Māori Pacific

Non-

Māori/

Pacific Total Māori Pacific

Non-

Māori/

Pacific Total

Counties Manukau 111 183 4 298 115.8 121.6 5.6 93.9

Northland 62 1 4 67 99.7 48.3 13.6 71.5

Capital and Coast 9 23 3 35 50.9 102.2 16.1 59.5

Aucklandb 13 49 5 67 58.3 86.8 12.1 55.7

Bay of Plenty 39 3 5 47 63.7 147.1 17.8 51.5

Tairawhiti 19 1 1 21 60.5 85.5 11.7 51.0

Hawke's Bay 27 7 3 37 60.9 107.5 12.2 49.0

Lakes 19 5 1 25 50.5 196.1 6.6 45.2

Waikato 43 3 4 50 60.4 36.6 7.3 37.2

Midcentral 10 2 0 12 43.2 51.7 0.0 22.7

Remaining 11c 20 14 7 41 18.8 29.6 3.9 12.4

Total 372 291 37 700 64.9 96.0 7.5 51.0

Top 10 DHBs 332 278 28 638 75.1 104.1 8.7 61.9

% total casesd 95% 95% 81% 94% Na Na Na Na

% populatione 81% 84% 64% 76% Na Na Na Na

CCDHB=Capital and Coast DHB; CMDHB=Counties Manukau DHB; DHB=District Health

Board; Na=not applicable a Sorted by total incidence rate

b Waitemata patients were also hospitalised at Auckland hospital (ADHB)

c Includes five North Island and all six South Island DHBs

d Percentage of all index cases occurring in the top10 DHBs

e Percentage of NZ population 5–14 years of age


disease in New Zealand: focus on school age children. A report to the Ministry of Health. Auckland,

New Zealand, Health Outcomes Associates Limited.

International rates of acute rheumatic fever

International comparisons for rates of ARF are problematic (due to global data quality

issues) and estimates of the annual number of ARF cases must be considered a very

crude estimate.11, 16 The World Health Organization estimates median incidence of 10

per 100,000 in established market economies; the data was not stratified by initial and

recurrent attack.11 Recent data derived from Aboriginal communities in Australia

indicates an incidence of 374 cases per 100,000,11 which is extremely high. Data on

rates of ARF in Aboriginal communities is probably most usefully compared with data

on the incidence in Māori and Pacific communities, rather than overall New Zealand

incidence.

A systematic review which focused only on prospective population-based studies of

first incidence of ARF (all ages) computed a mean yearly incidence rate of ≤10 cases

per 100,000 in the USA and Western Europe and less than 10 cases per 100,000 in

Eastern Europe, Australia and the Middle East.18 The only study that met the inclusion


criteria for the Australasian area was a New Zealand study from 1984 authored by

Talbot.17 This was assessed by the authors as being of high quality. In that study,

overall incidence in New Zealand was reported as being 22 per 100,000 in a population

of people aged less than 30 years. A subgroup analysis from the Talbot study showed

an incidence of greater than 80 per 100,000 for Māori. Again the authors highlighted

the paucity of high quality population-based prospective studies of ARF around the

world.

Mortality data related to ARF is also problematic.11 Reliable cause-specific mortality

data relating to ARF and RHD are only available from indigenous populations living in

relative poverty in wealthy countries (such as New Zealand). However, the New

Zealand data cited is relatively old (1985–1987); age standardised mortality for RHD

(with or without rheumatic fever) for non-Māori were reported at 2.0 per 100,000 per

year, and 9.6 per 100,000 per year for Māori.11

Ethnic disparities

As has been highlighted in earlier sections, Māori and Pacific children experience a

disproportionally high rate of ARF in New Zealand and rates of disparity are

widening1,15 (Figure 1.2). In the 10 years to 2005, the 5 to 14 year-olds rate for non-

Māori and Other children was reported to be 3.0 per 100,000 (lower than the age

standardised rate for all people of 3.4 per 100,000), while for Māori and Pacific children

rates were 34.1 and 67.1 per 100,000 respectively.1 More recent analysis has found

this disparity to have increased: for the period from 2000 to 2009, Māori children

experienced an initial ARF rate of 40.2 per 100,000 (CI 36.8 to 43.8, p=.05), Pacific

children 81.2 per 100,000 (CI 73.4 to 89.6, p=.05) and non-Māori children 2.1 per

100,000 (CI 1.6 to 2.5, p=.05) (Table 1.2).

From 1996 to 2005, the New Zealand European and Others ARF rate decreased

significantly while Māori and Pacific peoples’ rates increased. Compared with New

Zealand European and Others, rate ratios were 10.0 for Māori and 20.7 for Pacific

peoples.1 These disparities continued to increase after 2005. Incidence rates between

2000 and 2009 for children 5 to 14 years were about 20-fold higher for Māori children

and 40-fold higher for Pacific children in this age group compared with non-

Māori/Pacific categories.15 Rate ratios for Māori children were 19.5 and for Pacific

children were 39.3, when compared with non-Māori children (Table 1.2). During 1993

and 2009 the ethnic disparity for Māori and Pacific children compared with non-

Māori/Pacific children widened both in relative terms (the ratio of incidence rates) and

in absolute terms (the difference in incidence rates) (Table 1.4).


Table 1.4 Changes in ethnic disparity over time for children 5 to 14 years of age during

the period 1993–2009a

Incidence rate ratiob

Incidence rate difference per

100,000 per yearc

1993 2009 1993 2009

Māori 5.8 36.3 21.2 44.5

Pacific 11.7 72.0 47.0 89.7 a Based on linear regression of incidence rates on year

b Incidence rate of Māori or Pacific children divided by that for non-Māori/Pacific children

c Difference in incidence rates between Māori or Pacific compared to non-Māori/Pacific




Deaths associated with chronic RHD have increased from an average of 123 deaths

per annum between 1971 and 1980 to 186 reported deaths in 2006.13 For Māori this

equates to a prevalence rate for mortality of 8.5/100,000 population (95%CI 7.0 to

10.3) and for non-Māori 1.4/100,000 population (95%CI 1.2 to 1.5). Rheumatic heart

disease mortality was over six times greater in Māori than non-Māori (relative risk (RR)

6.27 [95%CI 4.95 to 7.94]).13

Māori experience of rheumatic fever prevention and management

It is important to point out that the susceptibility of both Māori and Pacific children to

rheumatic fever is most likely attributable to economic deprivation (and associated

factors) experienced by Māori and Pacific people in New Zealand (ie, overcrowding,

poor housing conditions, rural locations and decreased access to and utilisation of

health care services)13. However, while a World Health Organization report into global

burden of GAS-related disease states that ‘The burden of GAS diseases and the

association of these diseases with poverty cannot be ignored’,11 the evidence to date

has not been designed to reliably indicate which particular factors contribute to the high

rates of rheumatic fever in New Zealand.

NZGG could not locate any specific data that explored Māori or Pacific people’s

experiences of, or access to, care for rheumatic fever. However, given that the majority

of sore throats are managed in primary care settings, research relating to Māori

experiences of primary care and general practice is relevant.19 In a qualitative

investigation into Māori experience of health care in New Zealand, themes to emerge

from hui with 86 Māori regarding general practice care is encapsulated in the following

statement:

Participants’ experiences of general practice were, in the main, related to how

they had been treated by health staff, and their hesitancy about seeking

treatment. This hesitancy, or ‘wait and see’ attitude, described by many

participants was associated with their financial concerns and their values and

beliefs, as well as with their knowledge of how general practice staff were likely

to treat them based on their previous experiences (Jansen et al). 19


Further surveying of a larger group of Māori (n=651), the majority of whom had either

school- or pre-school aged children (54.2%), revealed, in general, a satisfaction with

health services. However, clustering of the survey results found that that those in the

younger age bracket (aged 39 years or less) reported a greater reluctance to use

health and disability services, and a greater dissatisfaction with the interactions they

had with these services. Of particular concern in relation to the management of sore

throats in primary care is that a significantly-higher proportion of the younger

respondents agreed that:

they had to be quite sick and usually waited until the last minute before going to the

doctor

it was too expensive to go every time they were sick

the doctor was not good value for money

they do not like taking drugs for their illnesses.

Further reporting on the same study, but comparing Māori and non-Māori experiences

of access to primary care,20 found differences in reported access to general practice

care. For example, there were significant differences between Māori and non-Māori

participants in terms of being: seen in the timeframe needed (93% of Māori 96.5% of

non-Māori); given a suitable time (93.8% of Māori 98.3% of non-Māori); given a choice

of times (68.3% of Māori 77.8% of non-Māori); and being seen on time (64.2% of Māori

75.1% of non-Māori).

The authors state that there may be a number of issues that explain the discrepancies,

including non-medical staff attitudes to Māori patients, Māori cultural beliefs (including

the tendency to noho whakaiti – to not cause a ruckus), and self-selection bias into the

study. However, in relation to treatment of sore throat, timely access to a medical

practitioner when required is very important. Once a sore throat is recognised as a

serious issue by individuals and whānau living in high risk communities, a responsive

primary care service upon presentation is no doubt critical to both treatment success

and further developing those individual’s and community’s confidence in an equitable

and responsive healthcare system.20

In terms of use of and access to treatments specifically relevant to the prevention of

rheumatic fever, a study of antibiotic use in Te Tairawhiti between 2005 and 2006,

revealed that Māori are dispensed fewer antibiotics than non-Māori, and the differences

increase for Māori living in rural areas. Forty-eight percent of Māori people and 55% of

non-Māori received one or more antibiotic prescriptions during the study period. Both

Māori and non-Māori living in rural areas received fewer prescriptions for antibiotics,

but the difference was much larger for Māori than for non-Māori. There was very low

prevalence for antibiotic prescriptions for rural Māori children (aged


Messages from research with Māori are clear; their experiences with primary

healthcare services could be improved. For the New Zealand health systems and

individual practitioners within that system it is important to consider how such

experiences may impact upon the effective management of sore throats and the

prevention of ARF.

Indigenous populations’ experience of rheumatic fever care

Given the lack of data identified specific to Māori experiences of ARF prevention and

management, research with indigenous Aboriginal Australians may be useful to

consider in the context of sore throat management approaches with both Māori and

Pacific people, until more specific research is conducted.

Qualitative research on patient’s experiences of rheumatic fever programmes in

Aboriginal communities in the Northern Territories provides useful insight for the

implementation of rheumatic fever prevention programmes.

In a study of Aboriginal people in the Kimberly region of Australia with a diagnosis of

rheumatic fever or rheumatic heart disease there was a varied understanding of either

disease or its management. The findings highlighted the need for culturally-appropriate

access to information about the disease, and the importance of the relationship

between patient and healthcare workers – compliance with medication was closely

linked with positive patient-staff interactions.22 Although the study was mainly about

secondary prophylaxis, the findings may equally apply in the prevention of rheumatic

fever and GAS throat infection prevention.

A second qualitative study exploring the experiences of 15 patients with RHD or a

history of rheumatic fever, 18 relatives and 18 health care workers in a remote

Aboriginal community, found a mix of staff and patient factors influence the success of

the programme in terms of compliance to a secondary prophylaxis regime.23 Staffing

factors that influence compliance included: appropriately trained, socially and culturally

competent staff, staff willingness to treat patients at home, and an active recall system.

Individual and family factors that encouraged uptake of regimes were an enhanced

belief that the disease is chronic and serious, confidence in the health service and a

feeling of holistic care, and family support for the treatment and belief in the efficacy of

the treatment.

The same study found that staff factors that inhibited uptake included: negative

perception of the secondary prophylaxis programme, conflicting priorities for staff, no

effective strategy for dealing with absent patients, staff fatigue and frustration.23

Individual and family factors inhibiting uptake included: conscientious refusal of

treatment, inconvenience to the patient, not ‘belonging’ to the health service, lack of

family support and lack of confidence in the treatment.


Specific issues relating to primary care workforce requirements that have been noted

during rheumatic fever work with aboriginal communities in Australia may also apply to

New Zealand.24 Examples include: a lack of trained health professionals willing to stay

for extended periods of time in remote communities to provide co-ordinated care, and a

high turnover of nursing staff (in remote communities). There is also a scarcity of

appropriately-trained Aboriginal health workers (these people are often considered the

key players of the primary health service in remote settings), who are often pulled in

many directions at the community level. This leads to a high burden of work and

responsibility, with associated high rates of burnout.24

Signs and symptoms of GAS throat infection

Signs and symptoms of GAS throat Infection

Sore throat is one of the common signs and symptoms of streptococcal pharyngitis.6

Four guidelines were identified that summarised data on signs and symptoms of GAS

throat infection;25-28 all agree that the cardinal symptoms suggestive of streptococcal

pharyngitis include:

history of fever

tender anterior cervical adenopathy

exudative tonsillitis

lack of cough.

A systematic review found that the most useful findings for evaluating the likelihood of

streptococcal pharyngitis are the presence of tonsillar exudate, pharyngeal exudate, or

exposure to streptococcal pharyngitis in the previous two weeks (positive likelihood

ratios, 3.4, 2.1, and 1.9 respectively) and the absence of tender anterior cervical nodes,

tonsillar enlargement or exudate (negative likelihood ratios, 0.60, 0.63, and 0.74,

respectively).3

GAS throat infection: timing, length

The Ministry of Health asked the research question below in an attempt to gain a better

understanding of the window of opportunity for throat swabbing in people with

suspected GAS throat infection. NZGG undertook a literature review to answer the

question.

Research question: When do sore throats occur in the natural course of streptococcal

pharyngitis and how long they tend to last?


Body of evidence

Two guidelines from the United States agree that patients are more likely to present

with GAS throat infection in the colder months of winter and spring.25, 26 The New

Zealand Heart Foundation guideline found that evidence was sparse in relation to other

climatic conditions and cite no clear seasonal peak in Auckland over a four-year period.

The natural history is for symptoms to subside within 3 to 5 days unless suppurative

complications intervene.7, 25 Children are most infectious during the acute phase of the

illness;5, 7

however, they may remain infectious for more than two weeks.5 Transmission

is by inhalation of large droplets or direct contact with respiratory secretions.

Summary of findings

No evidence was found to suggest seasonal variation in GAS throat infection in New

Zealand. Evidence from narrative reviews reported the incubation period to be 2 to 5

days and for symptoms to subside within 3 to 5 days from onset. Narrative reviews also

report that children are most infectious during the acute phase of the illness. However,

they may remain infectious for more than two weeks.


2 Rapid Antigen Diagnostic Tests

This chapter addresses diagnostic testing for people with suspected Streptococcal A

infection of the throat, specifically, the accuracy of the Rapid Antigen Diagnostic Test

(RADT). The chapter includes the following topics:

the accuracy of the RADT in people with a current sore throat

the accuracy of the RADT in people with a resolved sore throat

timing of testing.

Rapid Antigen Diagnostic Test in people with a current sore

throat

Research question: In children and adults with sore throats, what is the accuracy of

the Rapid Antigen Diagnostic (RAD) testing compared to culture to confirm GAS?

We did not identify any existing English language systematic reviews investigating

RADT for GAS throat infection. We undertook a systematic review and outline the

specific methodology here, as it differs to the other sections in this report. Methodology

for the remaining chapters can be found in Appendix 1.

Methods

Selection of studies for inclusion

Study design

This review included diagnostic accuracy studies of which there are two basic types,

defined by the Centre for Reviews and Dissemination; single-gate design and two-gate

design. Full details of the designs of these studies is reported elsewhere.29 Single- and

two-gate studies were eligible for inclusion if they compared a RADT/s with culture in a

primary or secondary care setting. Studies were included only if they provided sufficient

data to construct a 2x2 contingency table which displays numbers of true positive

cases, false positive cases, false negative cases, and true negative cases.

Participants

Studies in adults and children who presented to a healthcare facility (primary or

secondary care setting) with symptoms suggestive of streptococcal A throat infection

were eligible for inclusion.

Studies in animals and studies with fewer than 10 participants were excluded. Studies

where RADTs were done to assess outcomes or disease progression after treatment

was started were also excluded.


Index test

Rapid antigen tests for diagnosing Streptococcal A pharyngitis were the index tests

considered in this review. Any rapid antigen test was considered, including:

optical immunoassay

immunochromatographic detection

double sandwich immunoassay

latex particle agglutination

Polymerase chain reaction (PCR) assays.

Reference standard

Culture for diagnosing Streptococcal A pharyngitis was the reference standard

considered in this review. Studies carrying out throat swab culture carried out on blood

agar at the same time as the index RAD test (or with minimal gap) were eligible for

inclusion.

Data extraction and management

For each included study, we used standard evidence tables to extract characteristics of

participants, data about the index tests and reference standard, and aspects of study

methods. We extracted indices of diagnostic performance from data presented in each

primary study by constructing 2x2 contingency tables of true positive cases, false

positive cases, false negative cases, and true negative cases. If these were not

reported, we reconstructed the contingency table using the available information on

relevant parameters (sensitivity, specificity or predictive values). In cases of studies

where only a subgroup of participants met the review inclusion criteria, data was

extracted and presented only for that particular subgroup.

There were some studies where patients had undergone two different index tests with

throat swab culture as the reference standard. In such studies, pooled analysis was

done utilising data from the more common type of index test so as to avoid double

counting.

Assessing study quality

Study quality was assessed using the QUADAS checklist,30 with each item scored as a

yes/no response, or noted as unclear if insufficient information was reported to allow a

judgment to be made; the reasons for the judgment made were documented. Results

of the quality assessment are presented in the text, and in graphs using the Cochrane

Collaboration’s Review Manager 5 software.31 A summary score estimating the overall

quality of an article was not calculated since the interpretation of such summary scores

is problematic and potentially misleading.32, 33

Data analysis and synthesis

Sensitivity, specificity, positive and negative predictive values, and likelihood ratios

(with 95% confidence intervals) were calculated for each test using the methods

described by the Centre for Reviews and Dissemination and are presented in tables.

Efforts were made to identify common threshold points for each test so as to enable


calculation of pooled estimates of sensitivity and specificity. Coupled forest plots and

summary receiver operator curves (sROCs) were generated (with 95% confidence

intervals), giving graphical representations of sensitivity and specificity of a test in each

study and allowing for assessment of diagnostic threshold and the area under the

curve (AUC). Significant heterogeneity was considered where I2 was greater than 50%.

Threshold effect was assessed by visual inspection of the sROC curve and by

computing Spearmans correlation coefficient between the logit of sensitivity and logit of

1-specificity.

In order to explore heterogeneity, we carried out predefined subgroup analysis for

adults and children, and also for the different groups of rapid antigen tests identified in

the literature. Where >10 studies were included in any pooled group, regression

analyses were undertaken to investigate potential sources of observed heterogeneity.

Additionally, we conducted sensitivity analysis excluding two-gate studies. All analyses

were conducted using MetaDiSc software.34

Interpreting the results

Diagnostic threshold

Threshold effects are common in diagnostic studies and occur when the included

studies use different thresholds (explicitly or implicitly) to define positive and negative

test results; this can be the reason for detectable differences in sensitivity and

specificity (heterogeneity). RAD tests utilise specific antibodies to detect the disease

causing organisms and their results come as positive or negative only. However,

threshold variability is expected since the results are based on visual inspection rather

than a standardised measurement. In this analysis, threshold effects have been

investigated in two ways:

a) by visual inspection of the relationship between pairs of accuracy estimates in ROC

curves. If threshold effect is present, the ROC curve will show increasing

sensitivities with decreasing specificities, or vice versa, and is often described as a

‘shoulder-arm’ pattern or a ‘smooth curve’

b) by statistical computation of Spearmans correlation where a strong positive

correlation suggests a threshold effect.

Summary measures

In a ROC curve the true positive rate (sensitivity) is plotted in function of the false

positive rate (100-specificity) for different cut-off points of a parameter. Each point on

the ROC curve represents a sensitivity/specificity pair corresponding to a particular

study. The area under the ROC curve is a measure of how well a parameter can

distinguish between two diagnostic groups (diseased/normal). The value for the area

under the ROC curve can be interpreted as follows: an area of 0.84, for example,

means that a randomly-selected individual from the positive group has a test value

larger than that for a randomly-selected individual from the negative group in 84% of

the time. When the variable under study cannot distinguish between the two groups,

that is, where there is no difference between the two distributions, the area will be

equal to 0.5 (the ROC curve will coincide with the diagonal).


When there is a perfect separation of the values of the two groups, ie, there no

overlapping of the distributions, the area under the ROC curve equals 1 (the ROC

curve will reach the upper left corner of the graph).

The area under the curve was interpreted using the following:

0.9 – 1 = excellent

0.8 – 0.9 = good

0.7 – 0.8 = fair

0.6 – 0.7 = poor

0.5 – 0.6 = very poor.35

Meta-regression

If substantial heterogeneity was identified, the reasons for variability were explored by

meta-regression using the Littenberg and Moses Linear model36 weighted by the

inverse of the variance where there were more than 10 studies in any pooled group.

Estimations of coefficients of the model were performed by least squares method. The

outputs from meta-regression modelling are the coefficients of the model, as well as

the relative diagnostic odds ratio (rdOR) with respective confidence intervals. If a

particular study level co-variate is significantly associated with diagnostic accuracy,

then its coefficient will have a low p-value and the rdOR will give a measure of

magnitude of the association.34

Body of evidence

Thirty-one studies were identified investigating the use of RAD tests in people with

suspected GAS throat infection and are presented in Table 2.1. Studies were

conducted in several countries across the world – 10 studies in the USA, four in

Canada, four in Western Europe (Sweden, Switzerland, Spain and Norway) three each

in the UAE, Brazil and Turkey, three in Asia (Philippines, Hong Kong and Korea), one

in Southern Europe (Cyprus) and one multicentre study spanning Brazil, Croatia, Latvia

and Egypt (see Table 2.1). Except for a single two-gate study (diagnostic case control),

all other studies were single-gate in design. The sample size in the studies ranged from

50 to 2472 patients (mean 587).

Of the 31 included studies, 19 studies reported data in children, nine reported data in

adults, four studies reported data in both children and adults (three reported as a single

data set, one reported as two separate data sets), and in one study age was unclear.


15 commercial brands employing four main types of RAD tests were identified in the

included studies. These were:

nine brands employing chromatographic immunoassay tests: (QuickVue In-Line

Strep A [Quidel Corporation]; Acceava Strep A [Inverness Medical Professional

Diagnostics, Princeton, NJ, USA]; Genzyme OSOM Strep A [Genzyme Diagnostics,

Street, San Diego, CA]; Abbott TestPack Plus Strep A [Abbott Laboratories];

Beckton-Dickinson Link 2 Strep A Rapid Test; Accustrip [Jant Pharmacutical

Corportation, USA]; SD Bioline Strep A RAT [SD, Korea]; Detector strep A direct

[Immunostics] and the Step A Rapid Test Device [SARTD] [Nova Century Scientific

Inc.])

three brands employing sandwich immunoassays Tests: (Diaquick [DIALAB,

Austria]; Kodak SureCell Strep A test [Kodak, USA]; INTEX Strep A Test II [INTEX

Diagnostic Pharmazeutische Produkte, AG])

single brand employing optical immunoassay: (Strep A OIA MAX [Thermo

Biostar/Inverness Medical Professional Diagnostics, Princeton, NJ, USA])

two brands using latex particle agglutination tests: (PathoDx Strep A kit [Inter

Medico]; Reveal color step A test [Murex]).

We did not identify any studies investigating immune-PCR assays.

Twenty-six of the included studies investigated a single index test compared to culture;

five studies used two or more index tests of which only one (the most common) was

included in the pooled results to avoid double counting.

Fourteen of the included studies used sheep blood agar as the reference standard, four

used horse blood agar, one used goat blood agar, ten used blood agar but did not

specify type and two studies did not report the culture medium.


Summary of findings

Table 2.1: Characteristics of included studies

Reference

(study

design)

Country Participants Age Reference

standard Type of RAD test Sens Spec PPV NPV LR+ LR-

Prevalence

Rogo et al

Single-gate37

USA n=228

90% w ere

children

Culture (5%

sheep blood

agar)

Acceava 98.4% 98.8% 96.9% 99.4% 81 (95%CI 20, 320)* 0.02 (0.00, 0.11)* 28.1%

OSOM 98.5% 99.4% 98.5% 99.4% 160 (95%CI 23,

1126)*

0.02 (95%CI 0.00,

0.11)*

28.9%

QuickVue 92.3% 96.3% 90.9% 96.9% 25 (95%CI 11, 55)* 0.08 (0.03, 0.19)* 28.5%

Gurol et al

Single-gate38

Turkey n=453 All age

groups

Culture (5%

sheep blood

agar)

QuickVue 64.6% 96.8% 81.0% 92.8% 81 (95%CI 20, 320)* 0.02 (0.00, 0.11)* 28.1%

0 to 9 years 70% 97.8% 90.3% 91.8% 32 (95%CI 10, 100)* 0.31 (0.19, 0.49)* 22.5%

20+ years 59.4% 96.1% 70.4% 93.8% 15 (95%CI 7.31, 32)* 0.42 (0.28, 0.64)* 13.4%

Sarikaya et

al

Single-gate39

Turkey n=100 Adults aged

18 to 64

Culture (5%

sheep blood

agar)

QuickVue 68.2% 89.7% 65.2% 90.9% 6.65 (95%CI 3.25, 14) 0.02 (0.19, 0.66)

Rimoin et al

Single-gate40

Brazil

Croatia

Egypt

Latvia

n=2472

Children

2 to 12

years

Culture (5%

sheep blood

agar)

OIA MAX 79% 92% 80% 92% 10 (95%CI 8.67, 12) 0.23 (0.20, 0.26)

28.7%

Kim

Single-gate41 Korea n=293

Children

(age not

specif ied)

Culture (no

detail) SD Bioline Strep A 95.9% 91.8% 95.9% 91.8%

11.75 (95%CI 6.04,

22.84)

0.04 (95%CI 0.02,

0.09)

66.5%

Llor et al

Single-gate42 Spain n=222

Adults over

14 years

Culture (5%

blood agar) OSOM 94.5% 91.6% 78.8% 98.1%

11.28 (95%CI 6.8,

18.69)

0.06 (95%CI 0.02,

0.18)

24.7%


Reference

(study

design)



Prevalence

Tanz et al

Single-gate43 USA n= 1848

Children 3 to

18 years

Culture (5%

sheep blood

agar)

QuickVue

71% 97% 91.65% 88.85% 26 (95%CI 19, 36)

0.29 (95%CI 0.26,

0.34)

29.9%

Al-Najjar and

Uduman

Single-gate44

UAE n=425

Children

(80% under

5)

Culture Diaquick 96% 99% 96% 99% 136 (95%CI 44, 419) 0.04 (0.01, 0.13)

14.3%

Camardan et

al

Single-gate45

Turkey n=1248 Children

Overall

Culture (7%

sheep blood

agar)

INTEX Strep A Test

II 89.7% 97.2% 95.1% 93.88% 32 (95%CI 21, 49)

0.11 (95%CI 0.08,

0.14)

38.1%

0 to 6years 89.7% 96.9% 90.8% 96.54% 29 (95%CI 18, 48) 0.11 (95%CI 0.07,

0.17)

25.2%

7 to 12

years 90% 97.5% 97.67% 89.27% 36 (95%CI 16, 80)

0.10 (95%CI 0.07,

0.15)

53.9%

13+ years 87.1% 97.7% 96.43% 91.49% 38 (95%CI 5.5, 261) 0.13 (95%CI 0.05,

0.33)

41.3%

Maltezou et

al

Single-gate46

Cyprus n=451 Children 2 to

14 years

Culture (5%

blood agar)

Beckton-Dickinson

Link 2 Strep A

Rapid Test

83.1% 93.3% 82.4% 93.6% 12 (7.82, 18) 0.18 (0.13, 0.26) 32.4%

Fontes et al

Single-gate47 Brazil n=229

Children 1 to

18 years

Culture (5%

lamb blood

agar)

Latex particle

agglutination 90.7 89.1 72.1 96.9 8.36 (5.42, 13) 0.10 (0.04, 0.24)

23.6%

Wright et al

Single-gate48 USA n=350

Children 0 to

18 years

Culture

(blood agar)

OSOM

85.5% 97% 91% 95% 31 (95%CI 15, 65)

0.15 (95%CI 0.09,

0.25)

24.6%

QuickVue

79.5% 95% 84.6% 93% 17 (95%CI 9.62, 30)

0.21 (95%CI 0.14,

0.33)

24.6%


Reference

(study

design)



Prevalence

Abu Sabbah

and Ghazi

Single-gate49

Saudi

Arabia n=355

Adults and

children

Culture

(horse blood

agar)

Detector Strep A

Direct

88%

91% 70% 97% 10 (95%CI 6.90, 15)

0.13 (95%CI 0.07,

0.25)

18.9%

Children

aged 4 to 14 81% 86% 67% 93% 5.93 (95%CI 3.33, 11)

0.21 (95%CI 0.10,

0.48)

25.2%

Adults aged

>15 93% 93% 73% 98% 14 (95%CI 8.22, 23)

0.08 (95%CI 0.03,

0.24)

16.1%

Araujo Filho

et al

Single-gate50

Brazil n=81 Adults over

18 years

Culture (5%

goat blood

agar)

OIA MAX 93.9% 68.7% 67.4% 94.2% 3.01 (1.96, 4.61)

0.09 (0.02, 0.34)

40.7%

Forw ard et

al

Single-gate51

Canada n=818 overall

Culture (5%

sheep blood

agar)

Step A Rapid Test

Device (SARTD)

71.9% 94.3% 76.9% 92.7% 11 (95%CI 7.92, 14) 0.25 (95%CI 0.19,

0.33)

19.6%

n=328 adults

67.8% 93.8% 77.7% 90.2% 11 (95%CI 7.24, 17)

0.34 (95%CI 0.26,

0.45)

24.1%

n=490 children

Children

w ere 15 years

Culture

(blood agar)

Testpack Plus Strep

A w /OBC[On Board

Controls] II (Abbott

Laboratories)

91.4% 95.3% 92.1% 94.9% 19.3 (95%CI 11, 34) 0.09 (95%CI 0.05,

0.16)

37.6%

Shaheen

and Hamdan

Single-gate53

Amman n=200

Adults

20 to 42

years (mean

28.3 years)

Culture

(blood agar)

Latex particle

agglutination 90.00% 98.22% 90.00% 98.22%

50.70 (95%CI 16.41,

156.61) 0.10 (0.03, 0.30)

15.1%

Atlas et al

Single-gate54

USA n=150 Adults over

18 years Culture Acceava 92.1% 100% 100% 98% Not estimable

0.08 (95%CI 0.03,

0.24)

18.4%


Reference

(study

design)



Prevalence

Ezike et al


Children 5 to

18 years

Culture (5%

sheep blood

agar)

OIA MAX 94.7%

100% 100% 96.2% Not estimable

0.05 (95%CI 0.02-

0.14)* 42.4%

Lindbaek et

al

Single-gate56

Norw ay n=306

Adults and

children

(


Reference

(study

design)



Prevalence

Keahey et al

Single-gate62 Canada n=165

Children age

5 to 16

years

Culture

(Sheep

blood agar)

PathoDx Strep A Kit 86.7% 80.1% 78.3% 87.8% 4.33 (95%CI 2.84,

6.61)

0.17 (95%CI 0.09,

0.30)

45.5%

Gieseker et

al

Single-gate63

USA n=887

Children

(age not

specif ied)

Culture (no

details) OSOM 87.6% 96.2% 87.6% 96.2%

22.81 (95%CI 15.60,

33.37)

0.13 (95%CI 0.09,

0.18)

23.7%

Sheeler et al

Tw o-gate64 USA n=211 cases All ages

Culture (5%

sheep blood

agar)

Testpack Plus 91% 96% 96% 90% 9.92 (95%CI 5.5, 18) 0.04 (95%CI 0.02,

0.11)

50.2%

n=232 controls All ages

Culture (5%

sheep blood

agar)

Testpack Plus 70% 98% 92% 90% 8.88 (95%CI 5.75, 14) 0.09 (95%CI 0.04,

0.24)

20.7%

Wong and

Chung

Single-gate65

Hong

Kong n=1491 All ages

Culture (5%

horse blood

agar)

Accustrip 52.6% 98.2% 52.6% 98.2% 28.9 (95%CI 13, 63) 0.48 (95%CI 0.30,

0.78)

37%

Kurtz et al


Children age

4 to 15

years

Culture (5%

standard)

Testpac Plus

80% 92.7% 83.1% 91.1% 10.89 (6.38, 18.59)

0.22 (95%CI 0.14,

0.34)

31.1%

Alesna et al

Single-gate67

Philip-

pines n=233

All ages

>3 years

Culture (5%

sheep blood

agar) Overall 94.12% 89.45% 60.38% 98.89% 8.92 (95%CI 5.90, 13)

0.07 (95%CI 0.02,

0.25)

14.6%

Testpack Plus 93.3% 94.7% 73.7% 98.9% 18 (95%CI 7.4, 42) 0.07 (95%CI 0.01,

0.47)

13.8%

Kodak SureCell 94.7% 84.8% 52.9% 98.9% 6.22 (95%CI 3.91,

9.88)

0.06 (95%CI 0.01,

0.42)

15.3%

Sens = sensitivity; Spec = specificity; PPV = positive predictive value; NPV = negative predictive value; LR+ = positive likelihood ratio; LR- = negative

likelihood ratio


Quality of included studies

The overall methodological quality is summarised in Figures 2.1 and 2.2.

Most studies reported representative spectrums of patients and explained selection

criteria. Two studies did not recruit a representative spectrum of patients:55, 61 both

studies used a convenience sample based on the availability of the lead investigator.

Two studies did not clearly describe selection criteria.4.9, 53

Almost all the included studies reported avoidance of partial verification and differential

verification, and all reported avoidance of incorporation bias. Only one study did not

adequately describe the details or execution of the RAD test or culture.44 Blinding was

not well reported, approximately 75% of studies reported blinding of the index test, but

less than half of the included studies reported blinding of the reference standard. In one

study it was unclear whether the same clinical information would be available in

practice.64

Withdrawals were not explained in three studies: in one study67 233/269 patients who

completed both RAD test and culture were reported with no reason for withdrawals

given, in another study54 two patients did not receive culture and in the third study45 it

was not clear how many participants were included. Overall, the studies included were

of high quality.


Figure 2.1 Methodological quality of individual studies


Figure 2.2 Summary of methodological quality

Overall results

The forest plots of sensitivities and specificities from all 31 studies are shown in

Figure 2.3. Sensitivities of all tests ranged from 53% to 96%, specificities from 69% to

100%. Of the 31 included studies, 26 reported specificities greater than 90%. Eight of the

31 studies reported sensitivities greater than 80%. The pooled average sensitivity and

specificity were 84.5% (95%CI 83.4 to 85.6) and 94.7% (95%CI 94.2 to 95.1),

respectively, but significant heterogeneity was noted between studies with I2 tests of

89.1% and 89.8%, respectively. Figure 2.4 shows the spread of studies on a ROC plane.


Figure 2.3 Forest plot of overall study results (sensitivity and specificity)

Study

Abu Sabbah 2006

Al Najjar 2008

Alesna 2000

Araujo Filho 2006

Atlas 2005

Camurdan 2008

Chapin 2002

Ezike 2005

Fontes 2007

Forward 2006

Gieseker 2002

Gieseker 2003

Gurol 2010

Humair 2006

Keahey 2002

Kim 2009

Kurtz 2000

Lindbaek 2004

Llor 2009

Maltezou 2008

Nerbrand 2002

Rimoin 2010

Rogo 2011

Rosenberg 2002

Santos 2003

Sarikaya 2010

Shaheen 2006

Sheeler 2002

Tanz 2009

Wong 2002

Wright 2007

TP

59

68

14

31

38

427

173

71

49

123

84

184

51

128

65

187

64

106

52

121

107

561

65

24

11

15

27

165

395

10

71

FP

25

3

5

15

0

22

10

0

19

48

18

26

12

11

18

8

13

27

14

21

19

136

1

1

2

8

3

19

36

9

7

FN

8

3

1

2

3

49

24

4

5

37

3

26

28

12

10

8

16

4

3

25

22

149

1

8

4

7

3

4

158

9

12

TN

263

422

89

33

112

751

313

102

156

610

197

651

362

221

72

90

164

169

153

284

466

1626

161

93

32

70

166

44

1259

486

248

Sensitivity

0.88 [0.78, 0.95]

0.96 [0.88, 0.99]

0.93 [0.68, 1.00]

0.94 [0.80, 0.99]

0.93 [0.80, 0.98]

0.90 [0.87, 0.92]

0.88 [0.82, 0.92]

0.95 [0.87, 0.99]

0.91 [0.80, 0.97]

0.77 [0.70, 0.83]

0.97 [0.90, 0.99]

0.88 [0.82, 0.92]

0.65 [0.53, 0.75]

0.91 [0.86, 0.95]

0.87 [0.77, 0.93]

0.96 [0.92, 0.98]

0.80 [0.70, 0.88]

0.96 [0.91, 0.99]

0.95 [0.85, 0.99]

0.83 [0.76, 0.89]

0.83 [0.75, 0.89]

0.79 [0.76, 0.82]

0.98 [0.92, 1.00]

0.75 [0.57, 0.89]

0.73 [0.45, 0.92]

0.68 [0.45, 0.86]

0.90 [0.73, 0.98]

0.98 [0.94, 0.99]

0.71 [0.67, 0.75]

0.53 [0.29, 0.76]

0.86 [0.76, 0.92]

Specificity

0.91 [0.87, 0.94]

0.99 [0.98, 1.00]

0.95 [0.88, 0.98]

0.69 [0.54, 0.81]

1.00 [0.97, 1.00]

0.97 [0.96, 0.98]

0.97 [0.94, 0.99]

1.00 [0.96, 1.00]

0.89 [0.84, 0.93]

0.93 [0.90, 0.95]

0.92 [0.87, 0.95]

0.96 [0.94, 0.97]

0.97 [0.94, 0.98]

0.95 [0.92, 0.98]

0.80 [0.70, 0.88]

0.92 [0.85, 0.96]

0.93 [0.88, 0.96]

0.86 [0.81, 0.91]

0.92 [0.86, 0.95]

0.93 [0.90, 0.96]

0.96 [0.94, 0.98]

0.92 [0.91, 0.93]

0.99 [0.97, 1.00]

0.99 [0.94, 1.00]

0.94 [0.80, 0.99]

0.90 [0.81, 0.95]

0.98 [0.95, 1.00]

0.70 [0.57, 0.81]

0.97 [0.96, 0.98]

0.98 [0.97, 0.99]

0.97 [0.94, 0.99]

Sensitivity

0 0.2 0.4 0.6 0.8 1

Specificity

0 0.2 0.4 0.6 0.8 1

TP = true positive; TN – true negative; FP = false positive; FN = false negative

Figure 2.4 ROC of RAD tests

Sensitivity analysis excluding the two-gate study design did not significantly alter the

pooled average sensitivity or specificity (84.0% [95%CI 82.8 to 85.1] and 94.8%

[95%CI 94.4 to 95.2], respectively). Post-hoc sensitivity analysis excluding any study

that scored a ‘no’ on the QUADAS checklist did not significantly alter the pooled

average sensitivity or specificity (82.8% [95%CI 81.4% to 84.1%] and 94.5% [95%CI

94.0% to 95.0%], respectively). Significant heterogeneity was noted for all summary

measures.

Chromatographic immunoassay tests

The most commonly-reported rapid antigen tests were chromatographic immunoassay

tests of which nine different types were identified in the included studies. The forest

plots of sensitivities and specificities are shown for 26 comparisons (21 studies) in

Figure 2.5.

Sensitivities of all tests ranged from 53% to 98%, specificities from 70% to 100% with

all but one study reporting specificity of more than 85% (Figure 2.6). The pooled overall

sensitivity and specificity were 83.9% (95%CI 82.3 to 85.4) and 94.4% (95%CI 93.8 to

95.0), respectively. Tests of homogeneity for sensitivity and specificity reported I2 tests

of 90.6% and 89.0%, respectively; indicating significant heterogeneity. Sensitivity

analysis excluding the two-gate study design did not significantly alter the pooled

average sensitivity or specificity (82.5% [95%CI 80.8 to 84.1] and 94.6% [95%CI 94.0

to 95.2], respectively).

Figure 2.5: Forest plot of study results (sensitivity and specificity) for

chromatographic immunoassay tests

QuickVue

Study

Gurol 2010

Nerbrand 2002

Rogo 2011

Sarikaya 2010

Tanz 2009

Wright 2007

TP

51

61

60

15

395

66

FP

12

60

6

8

36

12

FN

28

21

5

7

158

17

TN

362

394

157

70

1259

243

Sensitivity

0.65 [0.53, 0.75]

0.74 [0.64, 0.83]

0.92 [0.83, 0.97]

0.68 [0.45, 0.86]

0.71 [0.67, 0.75]

0.80 [0.69, 0.88]

Specificity

0.97 [0.94, 0.98]

0.87 [0.83, 0.90]

0.96 [0.92, 0.99]

0.90 [0.81, 0.95]

0.97 [0.96, 0.98]

0.95 [0.92, 0.98]

Sensitivity

0 0.2 0.4 0.6 0.8 1

Specificity

0 0.2 0.4 0.6 0.8 1

Acceava

Study

Atlas 2005

Rogo 2011

TP

38

63

FP

0

2

FN

3

1

TN

112

162

Sensitivity

0.93 [0.80, 0.98]

0.98 [0.92, 1.00]

Specificity

1.00 [0.97, 1.00]

0.99 [0.96, 1.00]

Sensitivity

0 0.2 0.4 0.6 0.8 1

Specificity

0 0.2 0.4 0.6 0.8 1

OSOM

Study

Gieseker 2002

Gieseker 2003

Llor 2009

Rogo 2011

Wright 2007

TP

84

184

52

65

71

FP

18

26

14

1

7

FN

3

26

3

1

12

TN

197

651

153

161

248

Sensitivity

0.97 [0.90, 0.99]

0.88 [0.82, 0.92]

0.95 [0.85, 0.99]

0.98 [0.92, 1.00]

0.86 [0.76, 0.92]

Specificity

0.92 [0.87, 0.95]

0.96 [0.94, 0.97]

0.92 [0.86, 0.95]

0.99 [0.97, 1.00]

0.97 [0.94, 0.99]

Sensitivity

0 0.2 0.4 0.6 0.8 1

Specificity

0 0.2 0.4 0.6 0.8 1

Detector Strep A Direct Kit

Study

Abu Sabbah 2006

TP

59

FP

25

FN

8

TN

263

Sensitivity

0.88 [0.78, 0.95]

Specificity

0.91 [0.87, 0.94]

Sensitivity

0 0.2 0.4 0.6 0.8 1

Specificity

0 0.2 0.4 0.6 0.8 1

Abbott Test Pack

Study

Alesna 2000

Humair 2006

Kurtz 2000

Lindbaek 2004

Nerbrand 2002

Rosenberg 2002

Santos 2003

Sheeler 2002

TP

14

128

64

106

107

24

11

165

FP

5

11

13

27

19

1

2

19

FN

1

12

16

4

22

8

4

4

TN

89

221

164

169

466

93

32

44

Sensitivity

0.93 [0.68, 1.00]

0.91 [0.86, 0.95]

0.80 [0.70, 0.88]

0.96 [0.91, 0.99]

0.83 [0.75, 0.89]

0.75 [0.57, 0.89]

0.73 [0.45, 0.92]

0.98 [0.94, 0.99]

Specificity

0.95 [0.88, 0.98]

0.95 [0.92, 0.98]

0.93 [0.88, 0.96]

0.86 [0.81, 0.91]

0.96 [0.94, 0.98]

0.99 [0.94, 1.00]

0.94 [0.80, 0.99]

0.70 [0.57, 0.81]

Sensitivity

0 0.2 0.4 0.6 0.8 1

Specificity

0 0.2 0.4 0.6 0.8 1

Strep A Rapid Test device

Study

Forward 2006

TP

123

FP

48

FN

37

TN

610

Sensitivity

0.77 [0.70, 0.83]

Specificity

0.93 [0.90, 0.95]

Sensitivity

0 0.2 0.4 0.6 0.8 1

Specificity

0 0.2 0.4 0.6 0.8 1

SD Bioline Strep A RAT

Study

Kim 2009

TP

187

FP

8

FN

8

TN

90

Sensitivity

0.96 [0.92, 0.98]

Specificity

0.92 [0.85, 0.96]

Sensitivity

0 0.2 0.4 0.6 0.8 1

Specificity

0 0.2 0.4 0.6 0.8 1

Link 2 Strep A Rapid Test

Study

Maltezou 2008

TP

121

FP

21

FN

25

TN

284

Sensitivity

0.83 [0.76, 0.89]

Specificity

0.93 [0.90, 0.96]

Sensitivity

0 0.2 0.4 0.6 0.8 1

Specificity

0 0.2 0.4 0.6 0.8 1

Accustrip

Study

Wong 2002

TP

10

FP

9

FN

9

TN

486

Sensitivity

0.53 [0.29, 0.76]

Specificity

0.98 [0.97, 0.99]

Sensitivity

0 0.2 0.4 0.6 0.8 1

Specificity

0 0.2 0.4 0.6 0.8 1



The pattern of the points on the summary ROC (sROC) in Figure 2.6 do not show a

threshold effect and the Spearman correlation coefficient was 0.410 (p=0.065)

indicating borderline, but not significant presence of a threshold effect. The area under

the sROC curve was 0.9672. Table 2.2 shows summary measures for chromatographic

immunoassay tests in children and adults; the tests appear to be good at ruling in

streptococcal A sore throat in both groups. The test appears to be better at ruling out

streptococcal A sore throat in adults, however, significant heterogeneity was present in

all summary measures.

Figure 2.6 Summary ROC plot for chromatographic immunoassay tests*

*Red circles indicate children, yellow circles indicate adults, green circles indicate studies that included all

age groups.

Sensitivity sROC Curve

1-specificity 0 0.2 0.4 0.6 0.8 1 0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Symmetric sROC AUC = 0.9672 SE(AUC) = 0.0058 Q* = 0.9153 SE(Q*) = 0.0090


Table 2.2 Summary measures for children and adults

Number of

participants

(number of

studies)

Pooled

sensitivity

(95%CI)

Heterogeneity

(I2)

Pooled

specificity

(95%CI)

Heterogeneity

(I2)

Total

children

n=5444 (11

studies)

81.1 (79.1, 83.0) 91.4% 95.4 (94.7, 96.0) 73.0%

Total

adults

n=1153 (5

studies)

92.1 (88.9, 94.7) 72.4% 92.4 (90.3, 94.1) 86.8%

Total

mixed

population

(adults and

children)

n=1517 (5

studies)

86.4 (82.2, 90.0) 92.1% 92.2 (90.5, 93.6) 95.4%

Total n=8131 (21

studies)

83.9 (82.3, 85.4) 90.6% 94.4 (93.8, 95.0) 89.0%

Pooled results for the most common chromatographic immunoassay tests were similar;

the pooled sensitivity and specificity for the Quickvue test (n=3503, 6 studies), the

OSOM test (n=1977, 5 studies) the Abbott test (n=2065, 8 studies) and the Acceava

test (n=381, 2 studies) were comparable (Table 2.3). Sensitivity analysis excluding the

two-gate study design from the Abbott test did not alter results.

Table 2.3 Summary measures by test brand

Name of test Number of

participants

(number of

studies)

Pooled sensitivity

(95%CI) Heterogeneity

(I2)

Pooled

specificity

(95%CI)

Heterogeneity

(I2)

QuickVue n=3503 (6

studies)

73.3 (70.3, 76.2) 76.4% 94.9 (94.0, 95.7) 92.7%

Acceava n=381 (2

studies)

96.2 (90.5, 99.0) 55% 99.3 (97.4, 99.9) 52.2%

OSOM n=1977 (5

studies)

91.0 (88.2, 93.4) 76.6% 95.5 (94.3, 96.5) 82.2%

Detector

Strep A

Direct

n=355 (1

study)

88 (78–95) - 91 (87, 94) -

Abbott n=2065 (8

studies)

89.7 (87.2, 91.9) 84.3% 92.9 (91.5, 94.2) 88.3%

Strep A

Rapid test

device

n=818 (1

study)

77 (70–83) - 93 (90–95) -

SD Bioline n=293 (1

study)

96 (92, 98) - 92 (85–96) -

Link 2 n=451 (1

study)

83 (76–89) - 93 (90–96) -

Accustrip n=514 (1

study)

53 (29–76) - 98 (97–99) -

Total n=8131 (21

studies)

83.9 (82.3, 85.4) 90.6% 94.4 (93.8, 95.0) 89.0%


Double sandwich immunoassay tests

Three different types of double sandwich immunoassay tests were reported in three

different studies. The forest plots of sensitivities and specificities are shown in Figure

2.7. Tests of homogeneity for sensitivity and specificity reported I2 tests of 45.0% and

94.9%, respectively; indicating no heterogeneity for sensitivity, and significant

heterogeneity for specificity.

Sensitivities ranged from 90% to 96%, specificities from 85% to 99% (Figure 2.8). The

pooled sensitivity and specificity were 90.6% (95%CI 87.9 to 92.9) and 96.9% (95%CI

95.8 to 97.7), respectively. The area under the ROC curve was 0.9802. There are too

few studies of double sandwich immunoassay tests to draw conclusions about their

accuracy.

Figure 2.7 Forest plot of study results (sensitivity and specificity) for double sandwich immunoassay tests

Diaquick

Study

Al Najjar 2008

TP

68

FP

3

FN

3

TN

422

Sensitivity

0.96 [0.88, 0.99]

Specificity

0.99 [0.98, 1.00]

Sensitivity

0 0.2 0.4 0.6 0.8 1

Specificity

0 0.2 0.4 0.6 0.8 1

INTEX Strep A test II

Study

Camurdan 2008

TP

427

FP

22

FN

49

TN

751

Sensitivity

0.90 [0.87, 0.92]

Specificity

0.97 [0.96, 0.98]

Sensitivity

0 0.2 0.4 0.6 0.8 1

Specificity

0 0.2 0.4 0.6 0.8 1

Kodak Surecell

Study

Alesna 2000

TP

18

FP

16

FN

1

TN

89

Sensitivity

0.95 [0.74, 1.00]

Specificity

0.85 [0.76, 0.91]

Sensitivity

0 0.2 0.4 0.6 0.8 1

Specificity

0 0.2 0.4 0.6 0.8 1


The pattern of the points on the summary ROC in Figure 2.8 do not represent a

threshold effect, and the Spearman correlation coefficient was -0.500 (p=0.667)

indicating that a threshold effect is not present.


Figure 2.8 Summary ROC plot for double sandwich immunoassay tests

Pooled results for the double sandwich immunoassay tests were similar; the sensitivity

and specificity for the Diaquick test, the INTEX Strep A test and the Kodak Surecell

were comparable (Table 2.4).

Table 2.4 Study results by test brand

Name of test Number of participants

(number of studies)

Sensitivity (95%CI) Specificity (95%CI)

Diaquick n=496 (1 study in

children)

96 (88, 99) 99 (98, 100)

INTEX Strep

A test II

n=1249 (1 study in

children)

90 (87, 92) 97 (96, 98)

Kodak

Surecell

n=124 (1 study in mixed

population)

95 (74, 100) 85 (76, 91)

Pooled total n=1869 (3 studies) 90.6 (87.9, 92.9) 96.9 (95.8, 97.7)


Optical immunoassay

One optical immunoassay test was reported in five different studies. The forest plots of

sensitivities and specificities are shown in Figure 2.9. Tests of homogeneity for

sensitivity and specificity reported I2 tests of 83.5% and 92.2% respectively, indicating

significant heterogeneity for both sensitivity and specificity.

Sensitivities ranged from 79% to 95%, specificities from 69% to 100% (Figure 2.9). The

pooled sensitivity and specificity were 82.1% (95%CI 79.7 to 84.4) and 93.0% (95%CI

91.9% to 93.9%), respectively.


1-specificity 0 0.2 0.4 0.6 0.8 1 0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1



Figure 2.9 Summary ROC plot for optical immunoassay tests

Study

Araujo Filho 2006

Chapin 2002

Ezike 2005

Gieseker 2002

Rimoin 2010

TP

31

173

71

65

561

FP

15

10

0

12

136

FN

2

24

4

17

149

TN

33

313

102

208

1626

Sensitivity

0.94 [0.80, 0.99]

0.88 [0.82, 0.92]

0.95 [0.87, 0.99]

0.79 [0.69, 0.87]

0.79 [0.76, 0.82]

Specificity

0.69 [0.54, 0.81]

0.97 [0.94, 0.99]

1.00 [0.96, 1.00]

0.95 [0.91, 0.97]

0.92 [0.91, 0.93]

Sensitivity

0 0.2 0.4 0.6 0.8 1

Specificity

0 0.2 0.4 0.6 0.8 1


The pattern of the points on the summary ROC in Figure 12.10 do not represent a

threshold effect, and the Spearman correlation coefficient was -0.400 (p=0.505)

indicating that a threshold effect is not present. The area under the ROC curve was

0.9462.

Figure 2.10 Summary ROC plot for optical immunoassay tests

Table 2.5 shows summary measures for optical immunoassay tests in children and

adults; only one study was conducted in adults with a small number of participants. In

children, optical immunoassay tests appear to be good at both ruling in and ruling out

Streptococcal A sore throat, but are better at ruling in disease. Significant

heterogeneity was present in all summary measures.


1-specificity 0 0.2 0.4 0.6 0.8 1 0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1



Table 2.5 Optical immunoassay tests by adults/children

Number of

participants

(number of

studies)

Pooled

sensitivity

(95%CI)

Heterogeneity

(I2)

Pooled

specificity

(95%CI)

Heterogeneity

(I2)

Total

children

n=3471 (4

studies)

81.8 (79.3, 84.0) 85.1% 93.4 (92.4, 94.4) 88.3%

Total

adults

n=81 (1 study) 94 (90, 99) - 69 (54, 81) -

Total n=3552 (5

studies)

82.1 (79.9, 84.4) 83.5% 93.0 (91.9, 93.9) 92.2%

Regression analysis Possible sources of heterogeneity across the included studies, other than the threshold

effect, were investigated using regression analysis using the co-variates listed below as

predictor variables:

study population (less than, or greater than 200 participants)

prevalence of

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