Management of Group A Streptococcal Sore Throat for the ... · GAS sore throat is a communicable...

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 <6 years) (43%)

compared with that for rural non- Māori (68%) or urban dwellers (80% and 85% for

Māori and non- Māori, respectively). Unfortunately no statistical analysis was

completed to determine if the differences were significant. However, given that in the

Tairawhiti DHB area rates of rheumatic fever in 2010 were the highest in the country at

15.1 per 100 000 population, the report highlights a serious issue that warrants further

exploration and certainly consideration in the context of the prevention of ARF in young

Māori.21


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 <16

years

81.1% 94.9% 75.4% 96.3% 16 (95%CI 9.41, 27) 0.20 (95%CI 0.11,

0.35)

16.2%

Humair et al

Single-gate52

Sw itzer-

land n=372

Patients age

>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

(<10 years)

Culture

(Columbia

agar w ith

horse blood)

TestPack Plus 96% 86% 79.7% 97.7% 7.0 (95%CI 4.92,9.95) 0.04 (95%CI

0.02,0.11)

36%

Santos et al

Single-gate57 Brazil n=50

Children age

1 to 12

years

Culture (5%

blood agar) TestPack 73% 94% 85% 88%

12 (95%CI 3.14,

14.49)

0.28 (95%CI 0.12,

0.66)

34%

Nerbrand et

al

Single-gate58

Sw eden n=536 All ages

Culture (6%

defibrinised

horse blood)

QuickVue

73.9% 86.8% 59.4% 92.7% 5.60 (95%CI 4.28,

7.32)

0.30 (95%CI 0.21,

0.43)

15.3%

n=615 All ages

Culture (6%

defibrinised

horse blood)

TestPack 82.8% 96.1% 92.7% 94.2% 21 (95%CI 14, 33) 0.18 (95%CI 1.02,

0.26)

21.1%

Chapin et al


Children

(age not

specif ied)

Culture (5%

sheep blood

agar).

Thermo Biostar OIA 86.1% 97.1% 93.7% 93.4% 28 (95%CI 15, 52) 0.13 (95%CI 0.09,

0.18)

37.9%

Gieseker et

al

Single-gate60

USA n=302

Children

(age not

specif ied)

Culture OSOM

97% 92% 82% 98% 12 (95%CI 7.4, 18)

0.04 (95%CI 0.01,

0.11)

28.8%

OIA Max

79% 95% 84% 92% 15 (95%CI 8.29, 25)

0.252 (95%CI 0.14,

0.34)

27.2%

Rosenberg

et al

Single-gate61

Canada n=126 All ages

Culture (5%

sheep blood

agar) Testpack 75% 99% 96% 92% 71(95%CI 9.93, 500)

0.25 (95%CI 0.14,

0.46)

25.4%


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 Streptococcal A throat infection (greater or less than 35%)

age (children or adults)

technique of taking swab (described or not described).

Results are shown in Table 2.6, and suggest that none of the variables investigated are

significantly associated with accuracy.

Table 2.6 Results of meta-regression analysis for predicting the presence or absence of streptococcal A throat infection

Meta-Regression (inverse variance weights)

Var Coeff. Std. Err. p - value rdOR [95%CI]

Cte. 5.214 0.4211 0.0000 ---- ----

S -0.073 0.1382 0.6037 ---- ----

<200 -0.981 0.5865 0.1069 0.37 (0.11; 1.25)

prev 0.322 0.4667 0.4965 1.38 (0.53; 3.61)

children -0.212 0.4350 0.6307 0.81 (0.33; 1.98)

swab -0.551 0.4178 0.1994 0.58 (0.24; 1.36)

Var = variance; Coeff. = coefficient; std. err. = standard error; rdOR = relative diagnostic odds

ratio; prev = prevalence

Discussion

Summary of main results

All tests had high diagnostic accuracy. Overall, sensitivities of all tests ranged from

53% to 96%, specificities from 69% to 100% with pooled sensitivity and specificity

outcomes of 84.5% (83.4 to 85.6) and 94.7% (94.2 to 95.1), respectively. The quality of

the included studies was good. Significant heterogeneity was observed overall, and for

most subgroups. The pooled estimates of each test are shown in Table 2.7.


Table 2.7 Pooled estimates of each test

Pooled sens (95%CI) I2 Pooled spec (95%CI) I

2

Chromatographic

immunoassay

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

Double sandwich

immunoassay

90.6% (87.9 to 92.9) 45.0% 96.9% (95.8 to 97.7) 94.9%

Optical

immunoassay

82.1% (95%CI 79.7 to

84.4)

83.5% 93.0% (95%CI 91.9 to

93.9)

92.2%

sens = sensitivity; spec = specificity; I2 = heterogeneity

The most common tests in the included studies were chromatographic immunoassays

and showed good diagnostic performance despite significant heterogeneity. Double

sandwich immunoassays, optical and latex particle agglutination were limited because

of the small number of studies. Although the diagnostic outcomes appear promising,

only three studies investigating double sandwich immunoassays and five studies

investigating optical immunoassays were identified; too few to draw reliable

conclusions about their ability to discriminate between those with and without

streptococcal A throat infection. We included latex particle agglutination in this review,

even though it has most likely been superseded by more modern methods of rapid

antigen testing and requires greater input from the primary care physician than other

methods. Sensitivity analysis excluding the three studies investigating latex particle

agglutination in the overall summary of studies did not alter the results. We did not

report the individual results of latex particle agglutination alone.

Limitations

Significant heterogeneity was present in almost all of the analyses conducted.

Regression analysis revealed that studies with lower numbers (less than 200

participants), studies with a higher prevalence of streptococcal A throat infection

(greater than 35%), subgroups of children and adults, and studies in which the

swabbing method was explicitly described, did not explain the heterogeneity observed.

Potential causes of heterogeneity

The technique used in obtaining swabs is likely an important source of heterogeneity.

Many authors of the included studies claimed to have followed the directions on the

test kit, but there is no way to control the quality of the swab samples. If the swab

comes into contact with other parts of the mouth (for example the tongue or cheek) it

can contaminate the sample. The only thing we were able to do was conduct

regression analysis on the studies providing an explicit description of the swab method

used; however, this does not represent an adequate exploration of swab quality.

Another possible cause of heterogeneity may have been the differences in prevalence.

In children the prevalence ranged from 14.3% to 66.5% (mean 31.2%) and in adults

ranged from 13.4% to 40.7% (mean 25.1%).

Comparison with other reports

We identified one systematic review and meta-analysis published in Spanish, and after

confirming that it had not been published in English we translated the review.68 The

review included 24 studies, some of which we excluded because the authors only

confirmed results of negative rapid antigen tests with culture, and 2x2 contingency


tables could not be constructed. The review concluded that rapid tests offer good

accuracy for use as a diagnostic method; however, the rapid test devices have to be

complemented with culture because of false positive and negative results.

We located a second meta-analysis published in 1999, in abstract form only.69 We

could not locate a full text copy of the published report, nor were we able to contact the

author. The review concluded that variation in test sensitivity is much greater than that

of specificity in reported studies. sROC results indicate that overall test accuracy is

good and that selection of sensitivity thresholds should play a role in determining the

use of the rapid test in the management of sore throat.

The American Heart Association guidelines on acute rheumatic fever and Kawasaki

disease recommends that treatment is indicated for children with acute pharyngitis who

have a positive RAD test, but that a negative test doesn’t necessarily rule out infection

and children with a negative test should have a throat culture.70 The guideline points

out that there are insufficient studies to make recommendations on which rapid antigen

tests perform better than others. For their recommendations in adults, the guideline

suggests that because of the epidemiological features of acute pharyngitis in adults

(eg, low incidence of GAS infections and low risk of acute rheumatic fever), diagnosis

of GAS pharyngitis in most adults on the basis of an RADT alone, without confirmation

of negative RADT results by a negative throat culture, is reasonable and an acceptable

alternative to diagnosis on the basis of throat culture results.

Implications for practice

The key question is whether the number of false positives and false negatives are

acceptable if rapid antigen tests are to be used as a first-line test in detecting

streptococcal A throat infection. Table 2.8 shows the implications of different scenarios;

the sensitivities and specificities represent the pooled estimates derived from the

included studies in this review on a hypothetical population of 100 children and 100

adults with suspected GAS throat infection. The prevalences in Table 2.8 are derived

from the median prevalences in the included studies in this review.

In a hypothetical population of 100 children with suspected streptococcal A throat

infection, three children without the disease would be prescribed antibiotics, potentially

unnecessarily, and five with streptococcal A throat infection would be missed. Rapid

antigen testing would reduce the number of children receiving unnecessary empiric

antibiotics by 71%.


In a hypothetical population of 100 adults with suspected streptococcal A throat

infection, five without streptococcal A throat infection would be prescribed antibiotics,

potentially unnecessarily, and four with streptococcal A throat infection would be

missed. Rapid antigen testing would reduce the number of adults receiving

unnecessary empiric antibiotics by 71%.

The populations included in this review are likely to be inherently different from New

Zealand populations in high risk areas. The included studies spanned a variety of

countries and socioeconomic positions and for most of these regions, the prevalence of

GAS throat infection is unknown. There is very little data on the prevalence of

streptococcal A throat infection in New Zealand. Interim results from a school-based

sore-throat study in Opotiki, an area with a high prevalence of rheumatic fever, showed

a GAS prevalence of 8% in children presenting with sore throats. In a population of 100

children, we would expect to see five children prescribed unnecessary antibiotics and

one child missed using the rapid antigen tests, and we would expect a reduction in

empiric antibiotic use by 88%. Although the populations in the included studies and the

New Zealand high risk populations are likely to be different, the review showed that the

rapid antigen tests performed fairly consistently. It seems reasonable to assume that

the tests would perform similarly in New Zealand as they have in other countries.

Table 2.8 Consequences of pooled diagnostic outcomes on a theoretical sample

Children Adults Children in

Opotiki

Influence on patient

outcome

Prevalence 31% 28% 8% -

Sensitivity 85% 85% 85% -

Specificity 95% 92% 95% -

True positive 26 21 7 Benefit from no delay in

treatment

True negative 66 69 87 Benefit from avoiding

unnecessary antibiotics

False positive 3 6 5 Detriment from

unnecessary antibiotics

False negative 5 4 1 Detriment from delayed

diagnosis

Conclusions

Despite the limitations of this review and the heterogeneity present in many of the

comparisons, rapid antigen tests appear to be a useful tool for basing initial treatment

decisions about streptococcal A throat infection. Specificity was consistently reported at

more than 90% (26 of 31 studies) indicating that rapid antigen tests are useful for

identifying true cases of infection; in cases of a false positive, the detriment to the

patient is an unnecessary course of antibiotics. Sensitivity was consistently reported to

be lower than specificity with a pooled value of 84.5% indicating that rapid antigen tests


are useful for ruling out disease, but are better at ruling in disease. To this end, it

seems reasonable to confirm the results of negative tests with culture.

In the example, if empiric treatment was withheld until culture results were available,

unnecessary antibiotics could be avoided in at least 70% of cases overall.

However, the pooled sensitivity and specificity should be interpreted with caution.

Despite a strict selection of studies based on proper patient recruitment and study

design, heterogeneity was considerable and we could not find adequate causes for the

variability between studies.

Expert advisory group discussion

The group discussed the practicalities of swabbing children’s throats in school-based

clinics and decided that it was too difficult to recommend in the school clinic setting, but

may work better in a general practice setting.

Practicality and cost were considered to be the most important factors in considering

RADTs. Some group members said they would not use them because they did not

have 10 minutes to wait for the test to work and would find using different reagents

fiddly. There was also discussion about whether follow-up culture (for negative results

on RADT) was worthwhile since it would double the cost.

Prevalence was discussed, in that the different prevalence’s in the included studies in

the review were varied; some from school-based populations, some from primary care

etc. The group acknowledged that prevalence is an important issue and makes a

difference to the sensitivity and specificity of a test.

The group did not reach firm conclusions on the usefulness of the RAD tests. Some felt

that empiric antibiotic use would be decreased if an RADT was used in primary care;

some thought that the time it would take to do the test (approximately 10 minutes) was

too difficult in the busy practice environment and they would rather prescribe empiric

antibiotics. There was discussion about whether the RADTs should be recommended

differently in high- and low-risk populations, and whether the addition of risk criteria

could increase diagnostic accuracy.

The group also discussed the issue of swabbing family members and the need for

culture to undertake such swabbing.

Rapid Antigen Diagnostic Test in people with a resolved sore

throat

Research question: In children and adults presenting with a resolved sore throat, what

is the accuracy of the RADT compared to culture to confirm GAS?

Body of evidence

We did not identify any evidence to answer this question.


Timing of testing

Research question: In children and adults presenting with a current sore throat is

immediate RADT and/or Culture more effective than delayed in ensuring diagnostic

accuracy?

Body of evidence

We did not identify any evidence to answer this question.


3 Antibiotic treatment

This chapter addresses antibiotic treatment for people with GAS infection and covers:

antibiotic type

antibiotic dose

antibiotic duration (delayed vs. immediate treatment).

Compliance and adverse events are reported for each comparison.

Antibiotic type

Research question: What is the antibiotic of choice for treatment of children and/or

adults diagnosed with GAS throat infection?

Body of evidence

Systematic reviews

Two systematic reviews were identified that compared different types of antibiotic

therapies for the treatment of GAS throat infection. One review was of good quality71

and the other was of average quality.72 The reviews compared penicillin with other

types of antibiotics (cephalosporins, macrolides and carbacephem).

Primary studies

Four randomised control trials (RCTs) were identified that compared different types of

antibiotic therapies for the treatment of GAS throat infection. All RCTs were of average

quality.73-76 The RCTs either compared oral amoxicillin (either short or long course) with

oral penicillin or penicillin injection or clindamycin with a combination of amoxicillin and

clavulanic acid.

Review findings

Bacteriological success (microbial eradication)/failure

Bacteriological eradication was measured by one average quality systematic review

comparing cephalosporins and penicillin72

in adults and children. Two RCTs were non

inferiority trials in children comparing amoxicillin with penicillin.75, 76 One RCT compared

clindamycin with amoxicillin/clavulanic acid in adolescents and adults,74 and the fourth

RCT was a non inferiority trial comparing amoxicillin with penicillin measured

bacteriological failure of therapy in children.73

Details are provided in Tables 3.1 and

3.2.

Cephalosporins (4 to 5 days or 10 days) versus penicillin (10 days):

ERADICATION: The systematic review stratified results according to whether the trials

were undertaken in the USA or Europe, whether participants were adults or children

and according to duration of cephalosporins (4 to 5 days or 10 days).72 With shortened

doses of cephalosporins (4 to 5 days), bacteriological eradication was significantly

more likely in children, but not in adults (Europe: odds ratio (OR) 1.34 [95%CI 1.04 to


1.72]; USA: OR 2.94 [95%CI 1.99 to 4.33]). Cephalosporin therapy given for 10 days

was significantly more effective in children (no adult trials) (Europe: OR 4.27 [95%CI

3.13 to 5.83]; USA: OR 2.7 [95%CI 2.15 to 3.37]). It was not reported when the

outcome was measured.

Amoxicillin versus penicillin:

ERADICATION: Two non inferiority trials found no difference in the rates of

bacteriological eradication between amoxicillin and penicillin (using a pre-specified

margin of 10% difference) when measured 14 to 45 days after initiation of treatment in

children aged up to 12 years.75, 76 Route of administration varied in the two trials; one

compared oral amoxicillin suspension with a single dose of intramuscular benzathine

penicillin and the other compared amoxicillin sprinkle (sachets of powder for sprinkling

on food) with penicillin VK suspension.

FAILURE: One non inferiority trial found no evidence of a difference in bacteriological

failure rates when measured at various time points (3 to 6 days, 12 to 16 days or 26 to

36 days) between oral amoxicillin and oral penicillin given for 10 days in children aged

5 to 12 years.73 The rates ranged from 6% to 13%. Another non inferiority RCT found

no evidence of a difference in bacteriologic failure with treatments (amoxicillin sprinkle

475 mg to 775 mg for seven days versus penicillin suspension, maximum dose 250 mg

QID for 10 days) on days 14 to 18 or 38 to 45.75 Rates of failure were much higher than

those reported by Lennon; 73 they ranged from 32% to 44%.

Clindamycin versus amoxicillin/clavulanic acid:

ERADICATION: One large multicentre trial found high rates of bacteriological

eradication and no evidence of a difference between oral clindamycin and oral

amoxicillin/clavulanic acid in adults and adolescents (97.9% and 94.4% at day 12, and

99.2% and 99.6% at 3 months).74

Summary: The mixed quality review found substantial benefits for cephalosporin when

compared with penicillin in rates of bacteriological eradication in children, both for

shortened courses of 4 to 5 days and 10 days of cephalosporin versus 10 days of

penicillin in trials conducted both in the USA and Europe. The Cochrane review did not

measure this outcome. Although the benefits were substantial, these findings should be

interpreted with caution, because potential bias arising from lack of blinding,

inadequate follow-up and unexplained heterogeneity cannot be excluded.

Amoxicillin, combined amoxicillin and clavulanic acid, clindamycin and penicillin

appeared to have comparable rates, although the rates varied substantially between

trials.


Table 3.1 Type of antibiotic – Bacteriologic success/eradication

Trial and

setting

Participants Treatment 1 Treatment 2 Results

SYSTEMATIC REVIEWS

Pichichero

and Casey72

Setting not

defined –

studies from

USA and

Europe

Children and

adults –

separate

analyses

Also stratif ied

according to

w hether USA

trials or

European trials

Oral

cephalosporins

(doses not

reported) for:

1. four days

2. f ive days

3. 10 days

Oral penicillin for 10

days

Cephalosporins (10 days) vs. penicillin (10 days):

All w ere analyses of children:

Europe: OR 4.27 (95%CI 3.13 to 5.83)

USA: OR 2.70 (95%CI 2.15 to 3.37)

Cephalosporins (4–5 days) vs. penicillin (10 days):

Children Europe: OR 1.34 (95%CI 1.04 to 1.72)

Children USA: OR 2.94 (95%CI 1.99 to 4.33)

Adults Europe: OR 1.09 (95%CI 0.58 to 2.02) NS

Adults USA: OR 1.65 (95%CI 0.97 to 2.82) NS

RANDOMISED CONTROLLED TRIALS

Pichichero et

al 75

Multicentre

Children <12

years

Oral amoxicillin

sprinkle (475 –

775 mg once

daily for seven

days)

Oral penicillin

suspension (maximum

dose of 250 mg four

times a day for 10

days)

Days 14 to 18:

Amoxicillin: 65.3%

Penicillin: 68%

Rx difference: 95%CI -12 to 6.6%, NS

Days 14 to 18 plus 38 to 45:

Amoxicillin: 55.4%

Penicillin: 56.9%

Rx difference: 95%CI not reported

Rimoin et al76

Low resource

setting in

Croatia and

Egypt

Children 2 – 12

years

Oral amoxicillin

suspension (750

mg once daily)

Penicillin injection

(600,000 to 1.2 million

units, according to

body w eight

ITT analysis:

Croatia: MD 2.5% (95%CI -13.8 to 18.9), NS

Egypt: MD -15.1% (-26.6 to 18.5), NS

PP analysis:

Croatia: MD 1.1% (95%CI -16.2 to 18.5) NS

Egypt: -9.3% (95%CI -26.3 to 7.8) NS

Mahakit et al74

26 centres in

Asia and

three in

Venezuela

Adolescents and

adults, aged 12

to 60 years

Oral clindamycin

(300 mg BID for

10 days)

Oral

amoxicillin/clavulanic

acid 1g (875 mg

amoxicillin/125 mg

clavulanic acid BID for

10 days)

Day 12:

Clindamycin: 97.9%

Amoxicillin/clavulanic acid: 94.4%

NS

3 months:

Clindamycin: 99.2%


NS

OR = odds ratio; CI = confidence interval; NS = not signif icant; ITT = intention to treat; Rx = treatment/therapy; BID =

tw ice daily; MD = mean difference; PP analysis = per protocol analysis


Table 3.2 Type of antibiotic – Bacteriologic failure

Trial and

setting



Pichichero et

al 75

Multicentre

Children <12

years

Oral amoxicillin

sprinkle (475 to

775 mg once

daily for seven

days)

Oral penicillin

suspension (maximum

dose of 250 mg four

times a day for 10

days)

Days 14 to 18:

Amoxicillin: 34.7%

Penicillin: 32.0%

Rx difference not reported

Days 38 to 45:

Amoxicillin: 43.6%

Penicillin: 40.3%


Lennon et al73

Sore throat

clinic at

primary

school in New

Zealand

Children 5 to 12

years

Oral amoxicillin

(750 to 1500 mg

QD for 10 days)

Oral penicillin V (250

to 500 mg BID for 10

days)

Days 3 to 6:

Amoxicillin: 5.8%

Penicillin: 6.2%

Rx difference: 0.3% (upper 95% confidence limit

4.9%)

Days 12 to 16:

Amoxicillin: 12.7%

Penicillin: 11.9%

Rx difference: (upper 95% confidence limit 6.5%)

Days 26 to 36:

Amoxicillin: 10.7%

Penicillin: 11.3%


8.5%)

Rx = treatment/therapy; BID = tw ice daily; QD = once a day

Clinical success (microbial eradication and complete or substantial resolution of

symptoms)/failure

Clinical success (defined in different ways) was measured by five of the six studies.

The Cochrane systematic review compared clinical success in three different

comparisons: cephalosporins versus penicillin, macrolides versus penicillin and

carbacepham versus penicillin, stratified by children and adults.71 The other systematic

review compared cephalosporins with penicillin.72 Two non-inferiority RCTs compared

amoxicillin with penicillin73, 75 and one RCT compared clindamycin with

amoxicillin/clavulanic acid.74 Details are provided in Table 3.3.

Cephalosporins versus penicillin:

The good quality Cochrane systematic review found no evidence of a difference in

symptom resolution in adults and children in intention to treat (ITT) analysis (OR 0.79,

95%CI 0.55 to 1.22) (or in their separate subgroups) but a significant difference was

reported overall in the per protocol analysis.71 The average quality systematic review

comparing 10 days of cephalosporins with 10 days of penicillin found improved clinical

cure in children taking cephalosporins (Europe: OR 2.38, 95%CI 1.68 to 3.35; USA: OR

2.46, 95%CI 2.02 to 2.98) but more variable results with 4 to 5 days of cephalosporins

according to subgroup (Children: Europe: OR 1.75, 95%CI 1.18 to 2.61; US: no

evidence of a difference; Adults: Europe: no evidence of a difference; US: OR 1.78,

95%CI 1.0 to 3.17).72


Macrolides versus penicillin:

The good quality Cochrane systematic review found no evidence of a difference in

symptom resolution between treatments.71

Carbacephem versus pencillin:

The good quality Cochrane systematic review found a significant benefit for

carbacephem in children (OR 0.57, 95%CI 0.33 to 0.99).71


The two non-inferiority trials found no evidence of a difference between amoxicillin and

penicillin between treatments in the resolution of symptoms in children aged up to 12

years.73, 75


Clindamycin was associated with improved clinical cure at day 12 in a mixed group of

adolescents and adults (92.6% vs. 85.2%; p<0.003) but not at three months after the

initiation of treatment (95.4% vs. 95.7%).74

Summary: There appears to be some evidence that cephalosporins and carbacephem

have benefits over penicillin in terms of resolution of symptoms or clinical cure, mostly

in children. However, the Cochrane review found that the findings were inconsistent

across analysis methods (ITT and per protocol) and the numbers needed to treat for

benefit were substantial. The lower quality review confirmed the Cochrane review

findings on clinical cure with cephalosporins but the benefits were more consistent (and

larger) when 10 day courses were compared. The magnitude of the benefit in clinical

cure or resolution of symptoms differed substantially between these two reviews and

may have been caused by differences in quality. The Cochrane systematic review had

strict inclusion criteria and included only double blind trials to minimise the likelihood of

bias in the measurement of outcomes. By contrast, blinding was not a criterion of

inclusion for the average quality review, follow-up time was not reported and many of

the meta-analyses had substantial heterogeneity. Assessment of clinical cure is

subjective and bias as a result of lack of blinding in many of the studies cannot be

excluded.

There was no evidence of a benefit for macrolides when compared with penicillin and

amoxicillin and penicillin appeared to have comparable effects, although clindamycin

was superior to combination treatment with amoxicillin at the completion of treatment in

adults and adolescents.


Table 3.3 Type of antibiotic – Clinical success rates

Trial and

setting


SYSTEMATIC REVIEWS

Van Driel et

al71

Mostly high

resource

countries

Children and

adults –

separate

analyses

Non penicillin

antibiotic class

Penicillin ITT analyses:

(1) Cephalosporins vs. penicillin

Adults and children:

OR 0.79 (95%CI 0.55 to 1.12) NS (subgroups of

adults and children NS)

(2) Macrolides vs. penicillin:


OR 1.11 (95%CI 0.92 to 1.35) NS (subgroups of

adults and children NS)

(3) Carbacephem vs. penicillin:


OR 0.70 (95%CI 0.49 to 0.99)

Children:

OR 0.57 (95%CI 0.33 to 0.99)

Adults:

OR 0.75 (95%CI 0.46 to 1.22)

Pichichero

and Casey 72

Setting not

defined –

studies from

USA and

Europe

Children and

adults –

separate

analyses

Also stratif ied

according to

w hether USA

trials or

European trials

Oral

cephalosporins

(doses not

reported) for:

1. four days

2. f ive days

3. 10 days

Oral penicillin for 10

days

Cephalosporins (10 days) vs. penicillin (10 days):

All w ere analyses of children:

Europe: OR 2.38 (95%CI 1.68 to 3.35)

USA: OR 2.46 (95%CI 2.02 to 2.98)

Cephalosporins (4 to 5 days) vs. penicillin (10

days):

Children Europe: OR 1.75 (95%CI 1.18 to 2.61)

Children USA: OR 0.97 (95%CI 0.60 to 1.57) NS

Adults Europe: OR 1.32 (95%CI 0.67 to 2.63) NS

Adults USA: OR 1.78 (95%CI 1.0 to 3.17)


Lennon et al 73

Sore throat

clinic at

primary

school in NZ

Children 5 to 12

years

Oral amoxicillin

(750 to 1500 mg

QD for 10 days)



days)

Days 3 to 6:

Figures not reported.

Days 12 to 16:

Figures not reported

Days 26 to 36:


Mahakit et al 74

26 centres in

Asia and

three in

Venezuela

Adolescents and

adults, aged 12

to 60 years

Oral clindamycin

(300 mg BID for

10 days)

Oral


acid 1 g (875 mg

amoxicillin/125 mg


10 days)

Day 12:

Clindamycin: 92.6%


P<0.003

3 months:

Clindamycin: 95.4%


NS

Pichichero et

al 75

Multicentre

Children <12

years

Oral amoxicillin

sprinkle (475 to

775 mg once

daily for seven

days)

Oral penicillin

suspension (maximum

dose of 250 mg four

times a day for 10

days)

Days 14 to 18:

Amoxicillin: 86.1%

Penicillin: 91.9%

Rx difference: 95%CI -11.6 to -0.4%

OR = odds ratio; CI = confidence interval; NS = not signif icant; ITT = intention to treat; Rx = treatment/therapy; BID =

tw ice daily; QD = once a day


Bacteriological relapse

Relapse was measured in two studies, one systematic review of good quality71 and one

RCT of mixed quality.73 The Cochrane systematic review measured incidence of

relapse only in evaluable participants as the authors considered that ITT analysis

would seriously overestimate the importance of relapse. Details are provided in Table

3.4.

Cephalosporin versus penicillin:

The systematic review found that cephalosporin was associated with a significant

reduction in the rate of relapse in adults (OR 0.42, 95%CI 0.2 to 0.88; numbers needed

to benefit [NNTB] 33) but not in children.71

Macrolides versus penicillin and carbacephem versus penicillin:

There was no evidence of significant differences in relapse rates between treatments

when macrolides or carbacephem were compared with penicillin.71


Relapse rates were similar between treatments in one non inferiority RCT; they ranged

from 7% to 9% up to 36 days after the initiation of treatment.73

Summary: The incidence of relapse in evaluable adult participants seems to be lower in

those treated with cephalosporins compared with penicillin, but the event rate is low

(approximately 3.5%) and the numbers needed to benefit are quite high (NNTB 33).

There were no differences in the relapse rate between other antibiotics and penicillin.

Table 3.4 Type of antibiotic – Bacteriologic relapse

Trial and

setting


SYSTEMATIC REVIEW

Van Driel et

al71

Mostly high

resource

countries

Children and

adults –

subgroup

analyses

Non penicillin

antibiotic class

Penicillin 1. Cephalosporins vs. penicillin


OR 0.55 (95%CI 0.31 to 0.99), NNTB 50

Children:

OR 0.89 (95%CI 0.33 to 2.43) NS

Adults:

OR 0.42 (95%CI 0.20 to 0.88), NNTB 33

2. Macrolides vs. penicillin:

NS in any analyses

3. Carbacephem vs. penicillin:

NS in any analyses


Lennon et al73

Sore throat

clinic at

primary

school in NZ

Children 5 to 12

years

Oral amoxicillin

(750 to 1500 mg

QD for 10 days)

Oral penicillin V

(250 to 500 mg

BID for 10 days)

Days 12 to 16:

Amoxicillin: 7.6%

Penicillin: 7.6%

Days 26 to 36:

Amoxicillin: 8.8%

Penicillin: 9.4%

Rx difference not reported.

OR = odds ratio; CI = confidence interval; NS = not signif icant; NNTB = number needed to benefit; Rx =

treatment/therapy; BID = tw ice daily; QD = once a day


Compliance

One RCT of average quality, undertaken in two countries with low resource settings,

reported on compliance separately in each country.76 Oral amoxicillin was compared

with a single dose of intramuscular penicillin. Compliance in the amoxicillin group was

84.4% in Croatia but only 30.1% in Egypt (the comparative arm had penicillin injection

so compliance could not be compared), leading the authors to conclude that a single

dose of intramuscular penicillin may be preferable for treatment where compliance is a

major issue. No other studies were identified that compared compliance between

treatments, but a number of studies only analysed participants who had a pre-specified

level of compliance with therapy. Details are provided in Table 3.5.

Summary: There was insufficient evidence to compare rates of compliance between

treatments.

Table 3.5 Type of antibiotic – Compliance

Trial and

setting



Rimoin et al76

Low resource

setting in

Croatia and

Egypt

Children 2 to 12

years

Oral amoxicillin

suspension

(750 mg once

daily)


(600,000 to 1.2 million

units, according to

body w eight

Croatia: 84.4%

Egypt: 30.1%

No comparison made w ith

treatment tw o as compliance w as

100% for this treatment.

Adverse events

Adverse events were measured in one systematic review of good quality71 and two

RCTs of average quality.74, 76 Details are provided in Table 3.6.

Cephalosporins versus pencillin:

There was no evidence of a difference in the rates of adverse events (sore throat, fever

or any adverse event) between treatments in the Cochrane high quality systematic

review.71

Macrolides versus penicillin:

Macrolide therapy caused more adverse events in children in one trial in the Cochrane

systematic review (OR 2.33, 95%CI 1.06 to 5.15; numbers needed to harm [NNTH]

17.2) but there was no evidence of significant differences in these events in adults.71

Carbacephem versus penicillin:

There was no evidence of a difference in the rates of adverse events between

treatments in the Cochrane high quality systematic review.71


In one RCT where oral amoxicillin was compared with intramuscular injection of

penicillin, 67.4% of children receiving penicillin had discomfort at the site of the

injection and 5.3% of children taking oral amoxicillin had rashes and gastrointestinal


symptoms, although no statistical tests were performed.76 No serious adverse events

were reported.


There was no evidence of a difference between treatments in the rate of adverse

events, either overall or by body system; overall rates ranged from 11% to 14% and

were mostly gastrointestinal.74

Summary: There were no clinically important differences in the occurrence of adverse

events between different types of antibiotics, except for an increased rate in children

taking macrolides. These findings are based on a limited number of studies.

Table 3.6 Type of antibiotic – Adverse events

Trial and

setting


SYSTEMATIC REVIEWS

Van Driel et al 71

Mostly high

resource

countries

Children and

adults –

separate

analyses

Non penicillin

antibiotic class

Penicillin 1. Cephalosporins vs. penicillin

NS: rates of sore throat, fever or any adverse

events betw een treatments

2. Macrolides vs. penicillin:

NS: rates of sore throat and fever. Also NS: rates

of any adverse events in adults.

Any adverse events: Children:

OR 2.33 (95%CI 1.06 to 5.15), NNTH 17.2

3. Carbacephem vs. penicillin:

NS: rates of any adverse events


Rimoin et al 76

Low resource

setting in

Croatia and

Egypt

Children 2 to 12

years

Oral amoxicillin

suspension

(750 mg once

daily)


(600,000 to 1.2 million

units, according to

body w eight

Amoxicillin: 5.3% (skin rash, diarrhoea, vomiting,

sw eating, itching, nausea)

IM penicillin: 67.4% (discomfort at the site of

injection)

No statistical comparison made.

Mahakit et al74

26 centres in

Asia and

three in

Venezuela

Adolescents and

adults, aged 12

to 60 years

Oral clindamycin

(300 mg BID for

10 days)

Oral


acid 1 g (875 mg

amoxicillin/125 mg


10 days)

≥1 adverse event:

Clindamycin: 13.8%


NS

Also NS for specif ic adverse events by body

system

OR = odds ratio; CI = confidence interval; NS = not signif icant; NNTH = number needed to harm; BID = tw ice daily

Summary of findings

The evidence base includes primary studies which compared oral amoxicillin (in either

short or long courses) with oral penicillin or pencillin injection, clindamycin with a

combination of amoxicillin and clavulanic acid and systematic reviews which mostly

compared cephalosporins with penicillin, but also included comparisons of macrolides

and carbacephem with penicillin.

In sum, in spite of the marginal benefits found for cephalosporins and carbacephem

(both antibiotics with a wider spectrum) when compared to penicillin, the Cochrane


authors concluded that there is insufficiently convincing evidence to alter current

guideline recommendations for the treatment of patients with GAS throat infection.

Choice of treatment for GAS throat infection needs to take into account prevention of

complications, adverse events, costs and microbial resistance patterns, as well as

efficacy and the evidence for these outcomes is still limited.

The limited number of studies, with non-inferiority designs, comparing amoxicillin with

penicillin reported mostly comparable outcomes.

Antibiotic dose

Research question: What is the efficacy and safety of different doses of antibiotics for

treatment of children and/or adults diagnosed with GAS throat infection?

Body of evidence

Systematic reviews

One systematic review of poor quality was identified.77 It compared azithromycin given

over a period of 3 to 5 days at a dose of 30 mg/kg or 60 mg/kg with a 10 day

comparator antibiotic (mostly penicillin); analyses were stratified for adults and children

and by dose and duration of azithromycin, but not the comparator antibiotic.

Primary studies

Two RCTs of good quality were identified, each of which compared different doses of

the same drug. 78, 79 Jorgensen compared an oral single dose (2 g) of azithromycin with

oral immediate release azithromycin given for 3 days (500 g/day) in adolescents and

adults (≥13 years).79 Clegg et al compared once daily penicillin (750 mg or 1000 mg)

with twice daily amoxicillin (2 doses of 375 mg or 500 mg) for 10 days in children and

adolescents (3 to18 years).78

Three RCTs of average quality were identified which compared doses of different drugs

for treatment of GAS tonsillopharyngitis.73, 75, 76 Pichichero et al compared amoxicillin

sprinkle (475 mg once a day (QD) for ages 6 months to 4 years and 775 mg QD for

ages 5 to 12 years) for seven days with penicillin VK suspension (10 mg/kg of body

weight four times a day (QID), maximum dose 250 mg QID) for 10 days in children

aged six months to 12 years.75 Rimoin et al compared oral amoxicillin suspension (750

mg QD for all weight categories) for 10 days with a single dose of intramuscularly

administered benzathine penicillin G (IM BPG) (600,000 units if body weight <27 kg;

1.2 million units if body weight ≥27 kg).76 Lennon et al compared amoxicillin 1500mg

(or 750 mg for children with body weight ≤30k g) orally QD for 10 days with penicillin V

500mg (or 250 mg for children with body weight ≤20 kg) orally twice a day for 10

days.73


Review findings

Bacteriological success (microbial eradication)/failure

One poor quality systematic review77 and four RCTs, (two of good quality78, 79 and three

of average quality73,75, 76) assessed bacteriological success/eradication or

bacteriological failure. Details are provided in Tables 3.7 and 3.8.

Azithromycin (3 to 5 days) versus comparator antibiotics (10 days):

ERADICATION: Casey and Pichichero77 found that 3 to 5 days of azithromycin

administered at the rate of 30 mg/kg was inferior to the 10 day courses of comparator

antibiotics (mostly penicillin) (OR 0.47, 95%CI 0.24 to 0.91) but was superior to 10 day

courses when administered at the rate of 60 mg/kg (OR 5.27, 95%CI 3.34 to 8.32) in

children. There was no evidence of a difference in the bacteriological cure rates in the

adult studies (which all used doses of 30 mg/kg). In children, five day administration of

azithromycin was superior when compared to 10 day comparator antibiotics (OR 4.37,

95%CI 1.70 to 11.27) but not three day courses (OR 0.62, 95%CI 0.30 to 1.27). In

adults, five day administration of amoxicillin was inferior to 10 day comparator

antibiotics (OR 0.41, 95%CI 0.22 to 0.75).

Azithromycin (single dose of 2 g) versus azithromycin (three day dose of 500 mg/day):

ERADICATION: One non inferiority RCT did not find evidence of a difference between

treatments, at the pre-specified level of 10%, either at the test of cure visit (days 24 to

28) or the long-term follow-up visit (days 38 to 45).79


ERADICATION: One non inferiority RCT found no evidence of a difference in

treatments (amoxicillin suspension 750 mg once daily vs. penicillin injection – 600,000

to 1.2 million units) for bacteriological success in either the intention to treat or

evaluable populations of children, at the pre-specified level of 10% on days 21 to 28.76

Another non inferiority RCT found no evidence of a difference in treatments (amoxicillin

sprinkle 475 mg–775mg for seven days vs. penicillin suspension, maximum dose 250

mg QID for 10 days) in children on days 14 to 18 or 38 to 45.75

FAILURE: One non inferiority RCT found no evidence of a difference in treatments

(oral amoxicillin 750-1500 mg QD for 10 days vs. oral penicillin 250-500 mg twice a day

for 10 days) in children at the pre-specified level of 10% on days three to six, 12 to 16

or 26 to 36.73

Another non inferiority RCT found no evidence of a difference in

treatments (amoxicillin sprinkle 475 mg-775 mg for seven days vs. penicillin

suspension, maximum dose 250 mg QID for 10 days) in the rates of failure on days 14

to 18 or 38 to 45.75

Amoxicillin once daily (750 to 1000 mg) versus amoxicillin twice daily (375 to 500 mg):

FAILURE: One non inferiority RCT found no evidence of a difference in the rates of

bacteriological failure at the pre-specified level of 10% at days 14 to 21.78 Failure rates

ranged from 16% to 20% and included bacteriological persistence (as well as clinical

recurrence). When measured at days 28 to 35, bacteriological failure was significantly

lower (2.8%) in the once daily treatment group when compared with the twice daily

group (7.1%) (mean difference (MD) -4.33, 90%CI -7.7 to -1.0). This statistical

difference was no longer apparent when data from both visits were combined.


Table 3.7 Antibiotic dose – Bacteriological success

Trial and

setting


SYSTEMATIC REVIEWS

Casey and

Pichichero 77

Setting not

specif ied –

trials

undertaken in

the USA and

Europe

Children and

adults –

separate

analyses

Oral

azithromycin (3

to 5 days)

administered at

dosages of

30 mg/kg and

60 mg/kg

Comparator antibiotics

(10 days) – dosage

not specif ied (mostly

penicillin)

Children:

30 mg/kg: OR 0.47 (95%CI 0.24 to 0.91)

60 mg/kg: OR 5.27 (95%CI 3.34 to 8.32)

3 days: OR 0.62 (95%CI 0.30 to 1.27) NS

5 days: OR 4.37 (95%CI 1.70 to 11.27)

Adults:

30 mg/kg: OR 0.86 (95%CI 0.37 to 1.99) NS

3 days: OR 1.87 (95%CI 0.81 to 4.27) NS

5 days: OR 0.41 (95%CI 0.22 to 0.75)


Jorgensen79

Multicentre –

outpatients

Adolescents and

adults

Oral

azithromycin

(single dose 2 g)

extended

release (AZ-ER)

Oral azithromycin

(500 mg/day for

three days) immediate

release (AZ-IR)

Days 24 to 28 follow -up:

AZ-ER: 85.4%

AZ-IR: 81.4%

No difference


AZ-ER: 94.5%

AZ-IR: 92.3%

No difference

Rimoin et al76

Low resource

setting in

Croatia and

Egypt

Children 2 to 12

years

Oral amoxicillin

suspension

(750 mg once

daily)


(600,000 to 1.2 million

units, according to

body w eight

ITT analysis:

Croatia: MD 2.5% (95%CI -13.8 to 18.9), NS

Egypt: MD -15.1% (-26.6 to 18.5), NS

PP analysis:

Croatia: MD 1.1% (95%CI -16.2 to 18.5) NS

Egypt: -9.3% (95%CI -26.3 to 7.8) NS

Pichichero et

al75

Multicentre

Children <12

years

Oral amoxicillin

sprinkle (475 to

775 mg once

daily for seven

days)

Oral penicillin

suspension (maximum

dose of 250 mg four

times a day for 10

days)

Days 14 to 18:

Amoxicillin: 65.3%

Penicillin: 68%

Rx difference: 95%CI -12 to 6.6%, NS


Amoxicillin: 55.4%

Penicillin: 56.9%

Rx difference: 95%CI not reported

OR = odds ratio; CI = confidence interval; NS = not signif icant; ITT = intention to treat; Rx = treatment/therapy; MD =

mean difference; PP analysis = per protocol analysis

Table 3.8 Antibiotic dose - Bacteriological failure

Trial and

setting



Clegg et al78

Single

paediatric

clinic in USA

Children and

adolescents,

aged 3 to 18

years

Oral amoxicillin

(750 to1000 mg,

once daily)

Oral amoxicillin (375

to 500 mg tw ice daily)

Days 14 to 21:

Amoxocillin once daily: 20.1%

Amoxocillin tw ice daily: 15.5%

Rx difference 4.53 (90% CI -0.6 to 9.7) NS

Days 28 to 35:



Rx difference -4.33 (90% CI -7.7 to -1.0)


Trial and

setting


Lennon et al73

Sore throat

clinic at

primary

school in NZ

Children 5 to 12

years

Oral amoxicillin

(750 to 1500 mg

QD for 10 days)



days)

Days 3 to 6:

Amoxicillin: 5.8%

Penicillin: 6.2%


4.9%)

Days 12 to 16:

Amoxicillin: 12.7%

Penicillin: 11.9%

Rx difference: (upper 95% confidence limit 6.5%)

Days 26 to 36:

Amoxicillin: 10.7%

Penicillin: 11.3%


8.5%)

Pichichero et

al 75

Multicentre

Children <12

years

Oral amoxicillin

sprinkle (475 to

775 mg once

daily for seven

days)

Oral penicillin

suspension (maximum

dose of 250 mg four

times a day for 10

days)

Days 14 to 18:

Amoxicillin: 34.7%

Penicillin: 32%

Rx difference not reported.


Amoxicillin: 43.6%

Penicillin: 40.3%


CI = confidence interval; NS = not signif icant; Rx = treatment/therapy; QD = once a day

Summary

The systematic review found that azithromycin administered at a dosage of 60 mg/kg in

children for 3 to 5 days was more effective than other antibiotic regimens (mostly

penicillin) administered for 10 days. In this study, dosages of the comparator regimens

were not reported so it is difficult to make reliable comparisons. Heterogeneity in the

pooled analyses was substantial; when the authors performed a sensitivity analysis

with the inclusion only of trials where the comparative regimen was penicillin, there was

no longer a difference between treatments, although heterogeneity persisted.

Moreover, adverse events and compliance were not measured. The reliability of these

results is not clear and they should be considered tentative.

There was no evidence of statistical differences in bacteriological eradication or failure

in the other dosage comparisons in the studies, except for a lower rate of failure in the

once-daily amoxicillin regimen when compared with twice-daily. All but Jorgensen were

non inferiority trials, with the goals of establishing whether treatments are comparable

in terms of outcomes. Amoxicillin is often given only once a day when compared with

penicillin; since efficacy appears to be at least as good as penicillin, other outcomes

such as compliance, cost and adverse events need to be considered.

Clinical success (microbial eradication and complete or substantial resolution of

symptoms)/failure

One poor quality systematic review77 and three RCTs, were identified which assessed

clinical success (one of good quality79 and two of average quality73, 75). Clinical success


was defined mostly as resolution of or improvement in the presenting signs and

symptoms of GAS infection and the absence of GAS on throat culture). Details are

provided in Table 3.9.

Short-course azithromycin versus long-course comparator antibiotics:

The systematic review77 found that clinical success was significantly increased with

short-course azithromycin when given at a dosage of 60 mg/kg in children (OR 7.51,

95%CI 3.66 to 15.39) but not at a dosage of 30 mg/kg. There was no evidence of a

difference in treatments in adults.

Azithromycin extended release (single dose of 2 g) versus azithromycin immediate

release (500 mg for three days):

There was no evidence of a difference in the rates of clinical success between different

doses of azithromycin, either at days 24 to 28 or days 34 to 45 follow-up.79 Rates

varied at these time points from 92% to 99%.


There was no evidence of a difference in clinical success in two non-inferiority RCTs;

one compared oral amoxicillin (75 to 1500 mg once daily for 10 days) with oral

penicillin (250 to 500 mg twice daily for 10 days)73 and the other compared amoxicillin

sprinkle (475 to 775 mg once daily for seven days) with penicillin suspension

(maximum dose of 250 mg QID for 10 days).75 Where rates were reported, they ranged

from 86% to 92%.

Table 3.9 Antibiotic dose – Clinical success

Trial and

setting


SYSTEMATIC REVIEW

Casey and

Pichichero 77

Setting not

specif ied –

trials

undertaken in

the USA and

Europe

Children and

adults –

separate

analyses

Oral

azithromycin (3

to 5 days)

administered in

children at

dosages of:

a. 30 mg/kg

b. 60 mg/kg

Adults received

only doses of 30

mg/kg

Comparator antibiotics

(10 days) – dosage

not specif ied (mostly

penicillin)

Children:

30 mg/kg: OR 0.92 (95%CI 0.46 to 1.83) NS

60 mg/kg: OR 7.51 (95%CI 3.66 to 15.39)

3 days: OR 1.04 (95%CI 0.51 to 2.13) NS

5 days: OR 6.80 (95%CI 3.30 to 14.01)

Adults:

30 mg/kg: OR 0.86 (95%CI 0.37 to 1.99) NS

3 days: OR 0.56 (95%CI 0.22 to 1.46) NS

5 days: OR 1.53 (95%CI 0.69 to 3.38) NS


Jorgensen79

Multicentre –

outpatients

Adolescents and

adults, aged ≥13

years

Oral

azithromycin

(single dose 2 g)

extended

release (AZ-ER)

Oral azithromycin

(500 mg/day for three

days) immediate

release (AZ-IR)


AZ-ER: 99%

AZ-IR: 96.7%

Rx difference: 95%CI -1.7 to 8.3


AZ-ER: 92.1%

AZ-IR: 95.2%


Level of 10%.


Trial and

setting


Lennon et al73

Sore throat

clinic at

primary

school in NZ

Children 5 to 12

years

Oral amoxicillin

(750 to 1500 mg

QD for 10 days)



days)

Days 3 to 6:


Days 12 to 16:


Days 26 to 36:


Pichichero et

al 75

Multicentre

Children <12

years

Oral amoxicillin

sprinkle (475 to

775 mg once

daily for seven

days)

Oral penicillin

suspension (maximum

dose of 250 mg four

times a day for

10 days)

Days 14 to 18:

Amoxicillin: 86.1%

Penicillin: 91.9%

Rx difference: 95%CI -11.6 to -0.4%

OR = odds ratio; CI = confidence interval; NS = not signif icant; Rx = treatment/therapy; BID = tw ice daily; QD = once a

day

Summary: Clinical success was significantly increased in children, but not adults, with

the use of short-course azithromycin when given at a dosage of 60 mg/kg when

compared with 10 day comparator antibiotics (mostly penicillin). The systematic review

reporting these findings was of poor quality with significant flaws (see above) and the

findings should be regarded with caution. There was no evidence of improved clinical

response with any of the other comparisons made: different doses of azithromycin and

amoxicillin versus penicillin. The amoxicillin versus penicillin trials had a non inferiority

design and clinical success appeared to be comparable.


One good quality RCT78 and one average quality RCT73 were identified that assessed

bacteriological relapse. This outcome was defined as eradication of GAS by culture

after treatment followed by recovery in culture of the same M type of GAS as initially

cultured at baseline. Details are provided in Table 3.10s.

Amoxicillin (750 to 1000 mg once daily vs. 375 to 500 mg twice daily):

Bacteriological relapse was significantly reduced with amoxicillin once daily compared

to amoxicillin twice daily (MD -4.37%, 95%CI -7.4 to -1.3) at days 28 to 35.78

Rates

were 1.9% for amoxicillin once daily and 6.2% for amoxicillin twice daily.


There was no evidence of a difference in the rates of bacteriological relapse between

treatments.73 Bacteriological relapse was 7.6% for both treatments at days 12 to 16

and ranged from 8.8% to 9.4% at days 26 to 36.


Table 3.10 Antibiotic dose – Bacteriological relapse

Trial and

setting



Clegg et al78

Single

paediatric

clinic in USA

Children and

adolescents,

aged 3 to 18

years

Oral amoxicillin

(750 to 1000

mg, once daily)



Visit 3 (28 to 35 days):



Rx difference -4.37 (90% CI -7.4 to -1.3)

Lennon et al73

Sore throat

clinic at

primary

school in NZ

Children 5 to 12

years

Oral amoxicillin

(750 to 1500mg

QD for 10 days)



days)

Days 12 to 16:

Amoxicillin: 7.6%

Penicillin: 7.6%

Days 26 to 36:

Amoxicillin: 8.8%

Penicillin: 9.4%


CI = confidence interval; Rx = treatment/therapy; BID = tw ice daily; QD = once a day

Summary: Bacteriological relapse was less likely with once-daily amoxicillin compared

with twice-daily amoxicillin in one trial. One other trial confirmed that amoxicillin was not

inferior to penicillin in the rates of relapse.

Clinical recurrence

One good quality78 RCT was identified that assessed clinical recurrence. This outcome

was defined as clinical cure followed by recurrence of symptoms and signs of GAS

pharyngitis associated with recovery from throat culture of the same M type of GAS as

initially cultured at baseline. Details are provided in Table 3.11.


There was no evidence of a difference in the rates of clinical recurrence between

treatments at either of two time points. Clinical recurrence ranged from 7.1% to 9.2% at

14 to 21 days and was 0.9% at 28 to 35 days.

Table 3.11 Antibiotic dose – Clinical recurrence

Trial and

setting



Clegg et al78

Single

paediatric

clinic in USA

Children and

adolescents,

aged 3 to 18

years

Oral amoxicillin

(750 to1000 mg,

once daily)

Oral amoxicillin (375–

500 mg tw ice daily)

Visit tw o (14 to 21 days):



Rx difference 2.09 (90% CI -1.6 to 5.8)

Visit three (28 to 35 days):



Rx difference 0.04 (90% CI -1.4 to 1.5)

CI = confidence interval; Rx = treatment/therapy

Summary: Clinical recurrence did not differ significantly with different doses of

amoxicillin and was minimal after 35 days from the start of treatment.


Compliance

Compliance was measured by two good quality RCTs78, 79 and one average quality

RCT.76 Details are provided in Table 3.12.

Azithromycin (single dose 2 g extended release) versus azithromycin (500 mg/day for

three days):

There was no evidence of a difference in the rates of compliance between treatments

in one RCT.79 Compliance was high and ranged from 98% to 100%.


There was no evidence of a difference in the rates of compliance between treatments

in one RCT.78 Compliance was high and ranged from 92% to 93%.


Compliance varied substantially in the two low resource settings in one RCT.76

Compliance was not directly compared with penicillin, which was administered by a

single intramuscular injection (100% compliance). Compliance with the oral dose of

amoxicillin was 84.4% in Croatia and 30.1% in Egypt; low compliance in Egypt was

associated with lower rates of treatment success.

Table 3.12 Antibiotic dose – Compliance

Trial and

setting



Jorgensen79

Multicentre –

outpatients

Adolescents

and adults,

aged ≥13

years

Oral

azithromycin

(single dose 2 g)

extended

release (AZ-ER)

Oral azithromycin

(500 mg/day for

three days)

immediate release

(AZ-IR)


AZ-ER: 100%

AZ-IR: 98%


Clegg et al78

Single

paediatric

clinic in USA

Children and

adolescents,

aged 3 to 18

years

Oral amoxicillin

(750 to 1000

mg, once daily)

Oral amoxicillin

(375 to 500 mg

tw ice daily)

Visit tw o (14 to 21 days):

Amoxocillin once daily: 92%

Amoxocillin tw ice daily: 93%

Rx difference f igures not reported

Rimoin et al76

Low resource

setting in

Croatia and

Egypt

Children 2 to

12 years

Oral amoxicillin

suspension (750

mg once daily)


(600,000 to 1.2

million units,

according to body

w eight

Amoxicillin:

Croatia: 84.4%

Egypt: 30.1%

Compliance w as not statistically

compared w ith penicillin injection as

compliance is 100% w ith this treatment

Rx = treatment/therapy

Summary: There was limited evidence on compliance. Compliance rates varied in the

limited number of trials that assessed this outcome. In one country with a low resource

setting, compliance was very poor with an oral regimen of treatment. It is feasible that

compliance in well-monitored RCTs is likely to be superior to the normal practice

setting and so rates may not be generalisable.


Adverse events

Two RCTs of good quality78, 79 and one RCT of average quality76 were identified that

measured adverse events. Details are provided in Table 3.13.

Azithromycin (single dose 2 g extended release) versus azithromycin (500 mg/day for

three days):

There was no evidence of a difference in the rate of overall adverse events between

treatments in adults and adolescents in one RCT.79 Mild to moderate adverse events,

the majority of which were gastrointestinal, were experienced by 20% of participants in

each treatment group.

Amoxicillin (750 to 1000 mg once daily) versus amoxicillin (375 to 500 mg twice daily):

There was no evidence of a difference in the rate of one of more adverse events

between treatments in children and adolescents in a non-inferiority RCT.78 The rate of

any adverse events ranged from 14% to 17%.

Amoxicillin (750 mg once daily) versus penicillin injection (600,000 to 1.2 million units):

Rates of adverse events were not statistically compared between treatment groups in

children. Of participants having penicillin injections, 67.4% had discomfort at the site of

the injection and 5.3% of participants taking oral amoxicillin had rash or

gastrointestional symptoms.76

Table 3.13 Antibiotic dose – Adverse events

Trial and

setting



Jorgensen79

Multicentre –

outpatients

Adolescents and

adults, aged ≥13

years

Oral

azithromycin

(single dose 2 g)

extended

release (AZ-ER)

Oral azithromycin (500

mg/day for three days)

immediate release

(AZ-IR)

Overall rates days 34 to 45 follow -up:

AZ-ER: 20.3%

AZ-IR: 19.5%


Clegg et al78

Single

paediatric

clinic in USA

Children and

adolescents,

aged 3 to 18

years

Oral amoxicillin

(750 to1000 mg,

once daily)



Any adverse event after day 3:

Amoxocillin once daily: 17%

Amoxocillin tw ice daily: 14%

Rx difference: 2.2% (90% CI -3.0 to 7.3)

Rimoin et al76

Low resource

setting in

Croatia and

Egypt

Children 2 to 12

years

Oral amoxicillin

suspension (750

mg once daily)


(600,000 to 1.2 million

units, according to

body w eight

Amoxicillin: 5.3% (skin rash, diarrhoea, vomiting,

sw eating, itching, nausea)

IM penicillin: 67.4% (discomfort at the site of

injection)

Rx = treatment/therapy; IM = intramuscular

Summary: There was limited evidence on adverse events. There was no evidence of a

difference either in the rates of any adverse events or when specific adverse events

were compared. The majority of these events were gastrointestinal and mild to

moderate in nature.


Summary of findings

The evidence base includes a systematic review which compared short-course

azithromycin (3 to 5 days) with a 10 day course of comparator antibiotics with variable

doses.77 One RCT compared azithromycin given as a single dose as extended release

or over three days as immediate release.79

One RCT compared once-daily with twice-

daily amoxicillin.78 Three other RCTs compared amoxicillin with penicillin, given in

various doses and delivery methods.73, 75, 76

In sum, a poor quality systematic review found benefits for bacteriologic eradication

and clinical success with a 60 mg/kg dose of azithromycin when compared with

comparator antibiotics (with variable doses) over 10 days in children, but not in adults.

Many of the comparator antibiotics were penicillin, but they also included erythromycin,

clarithromycin, amoxicillin-clavulanate, ceflacor and roxithromycin. The outcomes were

reported at variable follow-up times, from three days to 25 days, few studies were

blinded and they were mostly of poor quality. Substantial heterogeneity in the analyses

means that we should treat these findings with caution.

Trials with non-inferiority designs confirmed that different doses of azithromycin in

adults and adolescents and amoxicillin in children and adolescents were comparable.

Outcomes were also comparable in three trials comparing different doses and delivery

methods of amoxicillin when compared with penicillin in children. Where treatments

appear to be comparable, choice of treatment for GAS throat infection should consider

other factors such as cost, potential for resistance, compliance and convenience.

Antibiotic duration

Research question: What is the optimal duration of antibiotic therapy for GAS throat

infection?

Body of evidence

Systematic reviews

Five systematic reviews were identified that had compared different durations of

antibiotic therapies for the treatment of GAS throat infection:

two systematic reviews were identified that were considered to be of good quality80,

81

two systematic reviews were identified that were considered to be of mixed

quality72, 82

one systematic review was considered to be of poor quality.77

Primary studies

Three randomised trials were identified that that had compared different durations of

antibiotic therapies for the treatment of GAS throat infection. All of the identified

randomised trials were considered to be of mixed quality.75, 76, 83


Summary of findings

Bacteriological success/failure (Microbial eradication)

Bacteriological success/failure was reported in five systematic reviews and three

randomised trials.

Short-course oral antibiotic therapy (5 to 7 days) was associated with inferior microbial

eradication rates compared with long course (10 day) oral antibiotic therapy in a meta-

analysis of 11 RCTs.81 The same effect was also observed in six RCTs (n=1258)

involving mainly children or adolescents <18 years. Microbial eradication was

significantly less likely for short-course regimens (OR 0.63, 95%CI 0.40 to 0.98).81

Altamimi et al reported no statistically significant differences between orally

administered short- (3 to 6 days) and long-course (10 day) antibiotic regimens for early

bacteriological failure (within two days after completion of therapy) in a meta-analysis

of 20 RCTs (OR 1.08, 95%CI 0.97 to 1.20).80 The authors concluded that the efficacy

of short- and long-course antibiotics were comparable. However, short-course

regimens may be satisfactory in countries with low rates of rheumatic fever, but in

countries where there is a high prevalence of rheumatic heart disease the results

should be interpreted with caution.80

Pichichero and Casey conducted a meta-analysis comparing four or five days of oral

antibiotics with 10 day oral antibiotic regimens in Europe and the USA.72 There were no

overall pooled data. Nine trials (n=3175) in Europe (OR 1.30, 95%CI 1.03 to 1.64,

p=0.03) favoured the short-course regimen for bacterial success. Three USA trials also

favoured the short-course regimen (OR 2.41, 95%CI 1.76 to 3.30, p<0.00001) of five

days versus 10 days. Bacterial eradication was also found to be more pronounced in

paediatric trials compared to adult trials.72

Casey and Pichichero reported on bacteriological success in a meta-analysis of 14

paediatric and five adult trials administering three to five days of oral antibiotics (short-

course) compared with ten days of oral antibiotics (long-course).77 Overall there was no

statistically significant difference between short-course and long-course groups for

bacterial success rate (OR 0.97, 95%CI 0.44 to 2.14). Sub-group analysis examining

differences between three day versus ten day regimens found no statistical differences

between the regimens (OR 0.62, 95%CI 0.30 to 1.27, p=0.19). For five days versus 10

day regimens the bacterial success rate was significantly higher in the short-course

(five day) regimen (OR 4.37, 95%CI 1.70 to 11.27, p=0.002).77 In the adult trials, there

was no inferiority of short-course (three day) regimens compared with long-course (10

day) regimens (OR 1.87, 95%CI 0.81 to 4.27). Bacterial success rate was significantly

higher in the long-course regimen compared with the five day regimen (OR 0.41,

95%CI 0.22 to 0.78, p=0.006).77 The same authors found no benefit of short-course (4

to 5) oral antibiotic regimens over long-course (10 day regimens) in a meta-analysis of

macrolides and cephalosporin.82

Sakata identified no statistically significant differences between orally administered

short-course (five days) and long-course (10 day) antibiotic regimens in early


bacteriological success as reported at three days after completion of the therapy

(93.8% for short-course and 92.8% for long-course).83

Rimoin et al compared a 10 day oral antibiotic regimen with a single dose intra-

muscular antibiotic therapy in Croatia and Egypt.76 There was no pooled analysis of the

data. Bacteriological treatment success varied between the two countries. In Croatia

there were no differences between the two regimens based on age or gender. In Egypt,

the 10 day oral antibiotic regimen was found to be inferior to intra-muscular antibiotic

therapy after controlling for age and gender (-15.1% difference, 95%CI -26.6 to 3.5).

Eradication of GAS bacteria at 14 to 18 days after treatment was commenced was

65.3% in the short-course (seven days) regimen (n=202) and 68% in the long-course

(10 days) regimen (n=194). There were no statistically significant differences between

the intervention groups.75 At 38 to 45 days follow-up bacterial eradication was still

observed in 55.4% of the short-course regimen (n=195) and 56.9% of the long course

regimen (n=56.9%). There were no statistically significant differences between the

intervention groups.75 Neither intervention met the criteria for ≥85% bacteriological

eradication at test of cure visit.75

Overall, the evidence suggests that short-course antibiotics are at least equivalent to

long-course antibiotic regimens in terms of eradication of GAS bacteria after

completion of therapy. One of the systematic reviews did advise caution in the use of

short-course antibiotic therapy in regions where RHD had a high prevalence.

Clinical success/failure (microbial eradication and complete or substantial

resolution of symptoms)

Clinical success/failure was reported in five systematic reviews and two randomised

trials.

Clinical success was significantly less likely in the short-course (≤7 days) compared

with the long-course (at least two days longer than short-course) regimens (five RCTs,

n=1217; OR 0.49; 95%CI 0.25 to 0.96).81

Early clinical treatment failure (within two weeks of completion of therapy) was

significantly lower in the short-course antibiotic regimens (OR 0.80, 95%CI 0.67 to

0.94; p=0.0078) as reported in a meta-analysis of 19 RCTs.80 There was no

statistically-significant difference between short- and long-course antibiotic regimens

for late clinical recurrence (beyond two weeks from completion of therapy) in a meta-

analysis of 13 RCTs (OR 0.95, 95%CI 0.83 to 1.08).80

Clinical success rates reported by Pichichero and Casey reflected bacteriologic

success rates. There were significant differences favouring shorter regimens in a meta-

analysis of five European paediatric trials (p=0.006) and one USA trial (p=0.05).72

There were no statistically significant differences between short-course (three or five

days) and long-course (10 days) oral antibiotic regimens in adults for clinical success

(3 days, OR 0.56, 95%CI 0.22 to 1.46, p=0.23 vs. five days, OR 1.53, 95%CI 0.69 to


3.38, p=0.29).77 In paediatric trials there were no differences between three day and 10

day regimens (OR 1.04, 95%CI 0.51 to 2.13, p= 0.91). For five days versus 10 day

regimens; the clinical cure rate was found to be significantly higher in the five day

course compared with 10 day oral antibiotic therapy (OR 6.80, 95%CI 3.30 to 14.01,

p<0.0001)77. Casey and Pichichero also reported an inferior result for short duration (4

to 5 days) compared with long duration (10 days) oral penicillin regimens in terms of

clinical success rates.82

Sakata reported 100% clinical success at three days for both five and 10 day courses

of antibiotics.83

Pichichero et al reported clinical success (resolution of signs/symptoms and no new

signs/symptoms) in 86.1% of the short-course (seven day) regimen and 91.9% of the

long-course (10 day) regimen. There were no statistically significant differences

between the intervention groups.75

Overall, the evidence indicates that short-course antibiotics are at least equivalent to

long-course antibiotics for clinical success rates. The exception is for penicillin, for

which a long-course (10 day) regimen would be advised.


Bacterial relapse was reported in one systematic review and one randomised control

trial.

A meta-analysis found no statistically significant differences in this outcome between

short- (≤7 days) or long-course (at least two days longer than short-course) antibiotic

regimens (five RCTs, n=981; OR 1.74; 95%CI 0.88 to 3.46).81 Sakata also reported no

statistically significant differences in relapse after treatment between five day, short-

course (1.3%) and 10 day, long-course (3.45%) antibiotic regimens.83

The evidence indicates that there is no difference in bacteriological relapse between

short- and long-course antibiotic therapy.

Bacteriological recurrence

Bacteriological recurrence was reported in two systematic reviews.

A meta-analysis found bacteriological recurrence was significantly more likely in short-

course (≤7 days) regimens compared with long-course (at least two days longer than

short-course) regimens (three RCTs, n=698; OR 3.02, 95%CI 1.06 to 8.56).81 Altamimi

et al also reported that later bacteriological recurrence (beyond two weeks of

completion of therapy) was significantly worse in short-course regimens (OR 1.31,

95%CI 1.16 to 1.48, p=0.00002, I2 74%), although significant heterogeneity was

observed. Subgroup analysis removing low dose azithromycin (10 mg/kg) resulted in

no statistically significant differences between short-and long-course antibiotic

regimens (OR 1.06, 95%CI 0.92 to 1.22).80


For those studies that had explored long-term outcomes, bacteriological recurrence

was found to be more likely to occur following short-course antibiotic therapy.

Compliance

Compliance was reported in two systematic reviews and two randomised trials.

In a meta-analysis of five RCTs, Altamimi et al reported that compliance was

significantly higher in the orally administered short-course (3 to 6 days) compared with

long-course (10 days) antibiotic regimens (OR 0.21, 95%CI 0.16 to 0.29, p <0.00001,

I2=72%), although significant heterogeneity was observed.80 Casey and Pichichero

reported overall compliance in 16 trials that also favoured short-course regimens (OR

3.10, 95%CI 2.22 to 4.32, p < 0.00001).82

Compliance to a 10 day oral antibiotic regimen varied between the two study sites in a

randomised trial reported by Rimoin et al. In Croatia compliance was 84.4% and in

Egypt compliance was 30.1%. Compliance with a single dose intra-muscular

administration of antibiotics was 100%. The authors concluded that in areas where

compliance may be an issue, a single dose of intra-muscularly administered antibiotic

therapy may be a preferable treatment for GAS throat infection.76

Pichichero et al compared a seven day (short-course) oral antibiotic (in a sprinkle

formulation) with a10 day oral antibiotic regimen (long-course).75 In the intention-to-

treat/safety analysis 100% compliance in the first three days was achieved in 97.2% in

the short-course regimen (n=284) and 83.7% in the long-course regimen (n= 282).

Over the whole study period 80% compliance was achieved by 95.4% in the short-

course regimen and 90.4% in the long-course regimen.75

Overall, the evidence suggests that compliance rates are higher with short-course

regimens and 100% compliance can be achieved through intra-muscular

administration.


The group discussed amoxicillin and penicillin V in terms of first-choice intervention.

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 (see Table 3.14).

There was also discussion around the dosing of amoxicillin and some felt this should

be updated based on reviews and guidelines from the USA. The group also agreed that

IM penicillin was acceptable in situations of poor compliance but would likely not be

good as a standard treatment because children are unlikely to report that they have a

sore throat if the outcome is an injection.


There was discussion about inclusion of a Cochrane review comparing azithromycin

with amoxicillin. This Cochrane review did not meet the inclusion criteria because it

was in patients with lower respiratory tract infection (no mention of GAS) and also

because the majority of included studies were conducted in adults.

There was also discussion of emm typing; some group members felt studies that did

not complete emm typing were flawed as any relapse or recurrence events may be due

to different emm proteins.

The group discussed erythromycin and agreed that is should be reviewed by

PHARMAC and replaced with something that has fewer side effects and improves

compliance (for example, roxithromycin).


Table 3.14 Routine antibiotics

Antibiotic Dose Duration

Amoxycillin Weight <30kg: 750 mg once daily

Weight >30kg: 1500 mg once daily

10 days

Penicillin V Children: 20 mg/kg/day 2–3 times/day (max 500 mg

(250 mg) 3 times/day)

Adults: 500 mg twice daily

On empty stomach

10 days

Benzathine

penicillin G

Children <20 kg: 600,000U

Adults and children >20 kg: 1,200,000U

Single

dose

Erythromycin Children: 40 mg/kg/day in 2 to 4 divided doses

(max 1 g/day)

Adults: 400 mg twice daily

10 days

Delaying antibiotic treatment

Research question: When should antibiotic therapy be administered in children or

adults with GAS to prevent progression to rheumatic fever, reduce likelihood of

antibiotic resistance and ensure compliance?

Body of evidence

Systematic reviews

We identified one Cochrane systematic review of average quality.84

Primary studies

We identified four RCTs85-88 all of which were included in the Cochrane review. None of

these RCTs were appraised as they were assessed for quality and their outcomes

were synthesised in the systematic review.


A cohort study was identified which compared persistence of positive throat culture and

occurrence of rheumatic fever in participants being treated immediately with

sulfadiazine, after nine days with penicillin or no treatment (control). Participants were

young airmen admitted to hospital.89

Review findings

The systematic review compared delayed antibiotic therapy (defined as therapy

initiated more than 48 hours after consultation) with immediate antibiotic therapy

(defined as therapy initiated at the time of consultation) in people with acute respiratory

tract infections (ARTI). Where possible, subgroup analysis was undertaken according

to type of ARTI: sore throat, acute otitis media, cough or common cold. Primary

outcomes were clinical symptoms (relief of GAS symptoms), antibiotic use, patient

satisfaction (as these are all patient-oriented outcomes); secondary outcomes included

adverse effects, complications of disease, re-consultation and use of alternative

therapies.84

The systematic review identified four studies which assessed outcomes in a subgroup

of participants with sore throat. Outcomes were measured on day three and day seven.

Small differences were found in the reduction of GAS symptoms (pain, malaise or

fever) for immediate as compared with delayed antibiotics in some trials but results

were not consistent and no definitive conclusions could be reached. When all trials

were pooled together (all ARTI participants), there was no evidence of differences in

safety outcomes between treatments. When all trials were pooled together (all ARTI

participants), significantly less antibiotic use was found with delayed treatment when

compared with immediate treatment and patient satisfaction was significantly greater

with immediate compared with delayed treatment. Re-consultation rate, recurrence,

relapse and incidence of rheumatic fever and other complications was not measured.

The individual RCTs within the systematic review assessed other outcomes which were

not included in the systematic review. Two double blind RCTs85, 88 and one trial without

blinding86 also assessed rates of recurrence and relapse. Relapse was defined as a

positive throat culture and symptoms suggestive of GAS throat infection at the three

week visit. Early recurrence was defined as any recurrence (signs and symptoms of

GAS throat infection and a positive throat culture) within one month following a three

week follow-up negative culture, and late recurrence was defined as any recurrence

after one month following a three week follow-up negative culture. El Daher et al

(n=306)85 found a reduced relapse rate with delayed treatment compared with

immediate treatment (2% vs. 7%, p=0.04), reduced early recurrence (5% vs. 16%,

p=0.006) and reduced late recurrence (3% vs. 13%, p=0.009). Pichichero et al

(n=142)88 found a reduced late recurrence rate (2% vs. 14%) and reduced combined

early and late recurrence rate (16% vs. 37%) with delayed treatment compared to

immediate treatment, but found no evidence of a difference in relapse or early

recurrence rates. By contrast, Gerber et al86 found no evidence of a difference in

positive follow-up throat cultures, recurrences (14% vs. 12%) or new acquisitions (27%

vs. 24%) between treatments at various time points: 4 days to 2 months, 2 to 4 months,

4 to 5 months. The inconsistency in rates of relapse and/or recurrence could be as a

result of lack of serotyping data on the strains of GAS throat infection isolated. Both El-


Daher et al85 and Pichichero et al88 did not perform serotyping on GAS throat infection

isolates and thus they could not make the distinction between recurrences and new

acquisitions with different strains. Thus, it is not possible to reach definitive conclusions

on rates of relapse and/or recurrence as a result of delaying antibiotic treatment.

The 1954 RCT compared treatment failure (persistence of positive throat culture) and

incidence of rheumatic fever in groups receiving penicillin on days nine, 11 and 13 after

the onset of hospitalisation for tonsillitis or pharyngitis, sulfadiazine at the time of

admission to hospital and placebo (control).89 Treatment failure was measured on day

nine (penicillin: 94%; sulfadiazine 71%; control 95%), day 13 (penicillin: 1%;

sulfadiazine 88%; control 96%), day 21 (penicillin 9%; sulfadiazine 81%; control 85%)

and day 35 (penicillin 9%; sulfadiazine 59%; control 64%). Participants taking penicillin

appeared to have reduced rates of treatment failure after treatment was started

compared to other groups, although no statistical testing was performed. Incidence of

rheumatic fever was measured from onset of pharyngitis to onset of illness. On day

nine, there appeared to be similar rates between groups (penicillin: 1.2%; sulfadiazine:

0.9%; control: 1.4%). Incidence between days nine and days 45 were as follows:

penicillin 0.7%; sulfadiazine 5.2%; control 3.6%. The authors concluded that treatment

of GAS with penicillin nine days after the onset of illness was effective in bacteriologic

eradication and significantly reduced the rate of rheumatic fever.89 However, no direct

comparison was made with patients having immediate antibiotic therapy.

Summary of findings

When comparing immediate with delayed antibiotic therapy for GAS, immediate

therapy appears to be more effective in reducing GAS symptoms when compared to

therapy that has been delayed for at least 48 hours. With regards to preventing relapse

and/or recurrence, the limited evidence is inconsistent and no definitive conclusions

can be reached. There is no direct evidence to determine whether incidence of

rheumatic fever is influenced by the timing of antibiotic therapy and likelihood of

antibiotic resistance and compliance have not been studied.


The group discussed the lack of evidence for delaying antibiotic treatment based on the

studies presented in the review. Discussion focussed on the fact that one study

conducted in 1954, which suggested that patients were effectively treated after nine

days, did not make the correct comparisons to draw this conclusion. The group agreed

that there is no evidence to support a delay in treatment.

Some group members referred to a RCT published by Lennon et al where anecdotal

evidence showed that some children developed ARF at four days. There was

disagreement around the use of the data in this study to support a recommendation

due to the lack of direct comparisons and lack of statistical significance.


There was also discussion of emm typing; some group members felt studies that did

not complete emm typing were flawed as any relapse or recurrence events may be due

to different emm proteins.


4 Asymptomatic GAS infection

This chapter addresses the prevalence of asymptomatic Group A Streptococcus (GAS)

throat infection in the community. It also addresses whether there is any relationship

between the rate of asymptomatic carriage of GAS throat infection and rates of

rheumatic fever. Studies published between 2005 and the present were identified. As

stated in the methodology these questions were not answered using a systematic

review given that the literature in relation to this area of research is primarily

epidemiological and observational in nature.

4.1 Prevalence of GAS sore throat

Research question: At what rate does asymptomatic GAS throat infection occur in the

community?

Body of evidence

Systematic reviews

One meta-analysis was identified that was considered to be of mixed quality.90

Primary studies

Fifteen epidemiological studies addressing the prevalence of asymptomatic GAS in

healthy populations were identified.91-106

These studies were summarised but were not

appraised with a formal appraisal tool due to their study design (see Table 4.1).

Summary of findings

The meta-analysis was of 18 studies of asymptomatic children with no signs or

symptoms of pharyngitis.90 No details were provided on the study designs and there

was significant (p<0.001), unexplained, statistical heterogeneity. The prevalence of

carriage of GAS was lower in pre-school children (<5 years). For all children the

prevalence rate was 12% (95%CI 9 to 14%) in 18 studies of 9662 children, age range

0.5 to 18 years. For children < 5 years the prevalence was 3.8% (95%CI 1 to 7%) in 4

studies of 1036 children.

One study reported on adults97 and one study did not specify the ages of the

population.93 The remaining studies reported on the incidence of asymptomatic GAS

throat infection in children. The ages of the children ranged from >094

to 16 years.103

Almost all of the studies reporting on asymptomatic GAS throat infection in children

recruited the populations from schools. The exceptions were Dhakal et al94 who

recruited children attending as in-patients or out-patients in a medical centre, Kohler et

al99 recruited children attending community centres for screening and Sevinc and

Enoz104 recruited children attending day care centres.


Data were reported from 10 different countries, Hawaii,96 American Samoa,96 Nepal,95,

103 Fiji,107 India,92, 94, 100, 101 Micronesia,99 Korea,98 China,93 Turkey97, 104, 106 and

Ethiopia.91

The prevalence of asymptomatic GAS throat infection ranged from 1.3% (defined in the

study as carriers), in a Northern Indian study of 3591 healthy schoolchildren (aged 5 to

15 years)100 to 22.9% in a study of 266 healthy school children in Korea (aged 7 to 12

years).98

In adults the asymptomatic GAS rate in a Turkish population was reported as 5.6% by

Gϋçlϋ et al.97 Refer to Table 4.1 for further details.

Table 4.1 Prevalence of asymptomatic GAS throat infection in the community

Reference Country Year data

relates to

Number of

participants

Source of population Age range Asymptomatic

GAS infection

rate

SYSTEMATIC REVIEW

Shaikh et

al90

Spain, Korea,

Iran, Turkey,

United

States,

Canada,

Sw eden,

Australia,

Kuw ait and

India

Not

stated

18 studies Clinics, schools and emergency

departments

<5 years

Overall

3.8%

12%

EPIDEMIOLOGICAL STUDIES

Erdem et

al96

Oahu, Haw aii

2003

955

13 schools representing a cross

section of ethnicity and

socioeconomic groups

5 to 15 years

3.4%

Pago Pago,

American

Samoa

2006 106 11 schools from Oahu, in Haw aii

and 2 schools from Pago Pago in

American Samoa

5 to 15 years 13%

Rijal et al103 Nepal 2008 487 Schools (number not stated) in

Pokhara, Nepal

5 to 8 years

9 to 12 years

13 to 16 years

Overall

11.8%

7.8%

8.2%

9.2%

Dumre et

al95

Nepal 2007 350 Four schools at different

locations in the Kathmandu

valley

5 to 8 years

9 to 12 years

13 to 15 years

Overall

10.9%

12%

9.6%

10.9%

Steer et

al107

Fiji 2006

665

Four schools in Fiji representing

urban and rural populations

5 to 9 years

10 to 14 years

Overall

7.8%

4.1%

6.0%

Dhakal et

al94

India 2007 200 Children attending as in-patients

or out-patients at the Jaw aharial

Institute of Postgraduate Medical

Education and Research.

>0 to 3 years

4 to 6 years

7 to 9 years

10 to 12 years

Overall

3.8%

NA

5.6%

8%

4.5%

Kumar et

al100

India 2000 to

2002

3591 Schools in 25 to 257 villages in

Haryana District, Northern India

5 to 15 years 1.3%

Lloyd et

al101

India 2004 1173 Schools in f ive locations in

Chennai, India to try and

represent different residential

areas

5 to 17 years 8.4%


Reference Country Year data

relates to

Number of

participants

Source of population Age range Asymptomatic

GAS infection

rate

EPIDEMIOLOGICAL STUDIES

Bramhachari

et al92

India 2006 to

2008

1504 Seven municipal schools in

Mumbai, India

5 to 15 years 1.5%

Kohler et al99 Micronesia 2009 667 Children presenting to

community centres for screening.

5 to 15 years 12.4%

Kim and Lee98 Korea Not

stated

266 Elementary schools (number not

stated) in Seoul, Korea

7 to 12 years 22.9%

Chang et al93 China 2007 to

2008

4087 School children in Beijing and

Chonqing in China. No other

details

Not stated 2.3%

Sevinc and

Enoz104

Turkey 2003 to

2005

1893 13 Day care centres 1 to 7 years 2.4%

Yildirim et

al106

Turkey Not

stated

484 A primary school in Dϋzce,

Turkey

6 to 14 years 6%

Gϋçlϋ et al97

Turkey Not

stated

179 Medical students attending

Ducze University in Turkey

Adults (age

range not

specif ied)

5.6%

Abdissa et

al91

Ethiopia 2004 to

2005

937 Seven schools in three cities in

Ethiopia.

6 to 14 years 8.7%


The group discussed the importance of prevalence measures in terms of asymptomatic

carriage rates and agreed that if an intervention was planned, then all children should

be swabbed pre-and post-intervention to establish a rate.

Relationship between prevalence of asymptomatic GAS throat

infection and rheumatic fever

Research questions: This section answered two research questions.

Does asymptomatic GAS throat infection occur at a higher rate in communities with

higher rates of rheumatic fever?

Is there an association between the carriage rate and rate of rheumatic fever in

communities?

Body of evidence

Systematic reviews

Two systematic reviews of multi-country epidemiological data relating to the prevalence

of asymptomatic GAS and rheumatic fever were identified, and both were considered

to be of good quality.18, 108


Primary studies

Ten studies reported on asymptomatic GAS rates91, 92, 94-96, 99-101, 103, 107 and six studies

reported multi-country rheumatic fever rates from the same countries.91, 96, 99, 102, 107, 109,

110 These studies were summarised but were not appraised with a formal appraisal tool

due to their study design (see Appendix 1).

Summary of findings

Data on the incidence of rheumatic fever were more widely published than data on the

prevalence of asymptomatic GAS throat infection. There was a lack of published

evidence that matched the incidence of rheumatic fever and the prevalence of

asymptomatic GAS throat infection in the same country.

We attempted to match the incidence of rheumatic fever in the countries for which

asymptomatic GAS throat infection had been identified (Table 4.2). There was no

published incidence data for rheumatic fever identified for Turkey, Korea or China. Only

two studies were identified that reported both asymptomatic GAS throat infection rates

and rheumatic fever rates within the same country.91, 99 Kohler reported on 667 school

children, aged five to 15 years from Micronesia. The prevalence of asymptomatic GAS

was reported as 12.4% and the incidence of rheumatic fever in Micronesia ranged

between 50 and 134/100,000 population.99 In the second study, Abdissa reported an

asymptomatic GAS rate in 937 school children in Ethiopia, aged six to 14 years, of

8.7%. The rheumatic fever incidence rate for children (age not specified) was 4.6 to

7.1/1000.91

For a further eight studies of asymptomatic GAS prevalence, data for rheumatic fever

incidence rates were identified. It should be noted that the years for which the data

were reported do not necessarily coincide. Five countries had asymptomatic GAS

prevalence rates of less than 10% (Ethiopia, Hawaii, India, Fiji and Nepal) and three

countries had rates greater than 10%. There was no obvious relationship between the

two rates. The incidence rates of rheumatic fever varied, even when reported in the

same country over similar time frames and similar age groups (Fiji, India) and data

were often reported as ranges rather than averages. Based on the available published

evidence it is not possible to draw any inference between asymptomatic GAS throat

infection prevalence and rheumatic fever incidence.


Table 4.2 Relationship between GAS throat infection rate and rheumatic fever by country

Country Reference Year

data

relates

to

Age

range

GAS throat

infection rate

Reference Year data

relates to

Age range Rheumatic

fever rate

GAS throat infection Rheumatic fever

Oahu,

Haw aii

American

Samoa

Erdem et al96 2003

2006

3.4%

13%

Jackson et

al108

2003 and

2006

5 to 15

years

Pacif ic

Islander

9.5 to 12.4/

100,000

Micronesia Kohler et al99 2009 5 to 15

years

12.4% Kohler et

al99

2009 5 to 15

years

50 to134/

100,000

India Dhakal et

al94

Kumar et

al100

Lloyd et al101

Bramhachari

et al92

2007

2000 to

2002

2004

2006 to

2008

>0 to 12

years

5 to 15

years

5 to 17

years

5 to 15

years

4.5%

1.3%

8.4%

1.5%

Jackson et

al108

Tibazarwa et

al18

2003 and

2006

1988 to 1991

5 to 15

years

5 to 18

years

54/100,000

51/100,000

Fiji Steer et al107 2006 5 to 14

years

6.0% Parks et

al102

Cuboni et

al109

Steer et al107

2003 to 2008

1996 to 2000

2005 to 2007

4 to 20

years

All ages

5 to 14

years

5 to 15

years

24.9/ 100,000

2.3/100,000

9.8/100,000

15.2/100,000

Nepal

Rijal et al103

Dumre et al95

2008

2007

5 to 16

years

5 to 15

years

9.2%

10.9%

Limbu and

Maskey110

Not stated School

children

(ages not

specif ied)

1.2 to 1.3/

1000

Ethiopia Abdissa et

al91

2004 to

2005

6 to 14

years

8.7% Abdissa et

al91

2004 to 2005 Children

(age not

specif ied)

4.6 to 7.1/

1000


5 Community swabbing

This chapter addresses what constitutes an outbreak of ARF. It also considers whether

swabbing for GAS throat infection in asymptomatic community members following an

outbreak impacts on rates of ARF. These questions have been scoped broadly in terms

of outbreaks (ARF, GAS, GAS-induced invasive disease), population (contacts

including family members, school, residential community, workplace) and outcomes

(ARF, eradication of GAS). Note that consideration of swabbing asymptomatic contacts

does not relate to the well-established approach of prophylactic treatment of people

with a history of ARF (known as secondary prevention) although such people may be

swabbed in an outbreak of ARF.

As these questions are informed by research published over several decades, no date

restriction was applied to searching. The questions were addressed narratively,

drawing on epidemiological sources and published accounts of attempts to manage

outbreaks, with an emphasis on those occurring in the developed world.

Rheumatic fever outbreaks

Research question: What defines an outbreak of Rheumatic Fever?

Body of evidence

Factors associated with an outbreak

Outbreaks of ARF have been described from widely separated areas of the world, and

continue to be rampant in the developing world. It also persists in socially and

economically disadvantaged subpopulations within developed countries, including

indigenous Māori and Pacific Islanders descendant in New Zealand and indigenous

Aborigines in Australia. In addition, there have been several outbreaks in the

developed world in closed or semi-closed environments including warships, nursing

homes, military centres, youth detention centres, child care centres, and specific

geographical areas.

Acute rheumatic fever was a major problem in the USA until the 1960s, then largely

disappeared as a major cause of illness, arguably due to improved socioeconomic

status, reduced crowding, the advent of antibiotics, and the widespread treatment of

streptococcal throat infections.111 A resurgence of rheumatic fever occurred in the mid-

1980s among children in less crowded communities, middle-class suburbs, and people

with good access to health care, such as areas of Utah and Ohio in the USA, and

training centres for the Armed Forces. This is in stark contrast with the developing

world where socioeconomic issues are thought to be responsible for rheumatic fever

outbreaks.111


These temporally-related but geographically separated outbreaks of acute rheumatic

fever in the USA cannot be explained by host factors alone and it has been suggested

that the infecting streptococci are somehow unique.112 Group A streptococci are highly

transmissible and spread rapidly in families and communities, with the predominant M

types are constantly changing. However in reports of the outbreaks, including those in

the US in the 1980s, only a limited number of streptococcal M serotypes were obtained

from the throat cultures of children in affected communities.113 It has been conjectured

that if these streptococci have enhanced rheumatogenic potential, this characteristic

appears not to be related simply to serotype, but is probably expressed by specific

strains within several serotypes often equated with enhanced virulence.112

Determining an outbreak

An outbreak of rheumatic fever can be defined epidemiologically as a significant

increase in the incidence of newly diagnosed cases of acute rheumatic fever in a

defined geographical area over a defined period of time.114

According to the Manual for Public Health Surveillance in New Zealand115 the threshold

for reporting an outbreak may include any of the following circumstances:

two or more cases linked to a common source

a community-wide or person-to-person outbreak (except when the source has

become well-established as a national epidemic)

any other situation where outbreak investigation or control measures are

undertaken or considered.

Outbreak reporting is not required in New Zealand for single cases caused by a

specific contaminated source, and secondary cases, with the exception of secondary

cases in an institution.

In 2010 there was one outbreak of rheumatic fever reported. The outbreak occurred at

a school and involved two cases.

In practical terms, establishing whether an outbreak has occurred is more an art than a

science and several sources of information can be brought to bear on this decision. In

countries where rheumatic fever is endemic such as New Zealand, it is crucial to

establish whether new cases represent a significant increase over the ‘background’

rate. Other factors can be considered to determine whether an increase in case

incidence is unlikely to be a chance event. An example of this process is the

appearance of seven cases of invasive streptococcal disease occurring in three

adjacent counties in south-eastern Minnesota caused by a single clone of invasive

GAS infection.116 The authors argued that the seven cases represented an outbreak for

the reasons below:

cases caused by a single clone of GAS were clustered temporally and

geographically

the incidence rate of outbreak-associated cases within the outbreak area was

substantially higher than expected


four of the seven outbreak-associated cases were epidemiologically linked to

children attending one elementary school. The prevalence of streptococcal

pharyngeal carriage of the outbreak clone was substantially higher among students

attending that school than among students attending three other comparison

schools outside the outbreak area.

Summary of findings

Defined epidemiologically, an outbreak of ARF is a significant increase in the incidence

of newly diagnosed cases within a defined geographical area and over a defined time

period. However, practically applying this definition requires some detective work

drawing on several sources of information. These include the following: the incidence

of Rheumatic Fever and GAS relative to the usual background rate, the proximity of

cases geographically and socially to each other, the timing of cases, commonality of

the strain of GAS infection, and pattern of contact between people who are GAS

positive.

Swabbing asymptomatic community members and households

in areas of outbreak

Research Question: Where there is an outbreak, does swabbing of asymptomatic

community members and household reduce rates of rheumatic fever?

In New Zealand, the existing guidelines recommend that where there are three or more

cases of GAS pharyngitis confirmed within a household in a three month period,

household members should be swabbed and those found positive for GAS treated with

antibiotics, regardless of symptoms.28 This approach is consistent with

recommendations from the Infectious Disease Society of America26 and The American

Academy of Pediatrics.117 The latter does not recommend asymptomatic GAS carrier

treatment except in certain situations. Those relevant to the current research question

include the following:

when there is an outbreak of rheumatic fever or post streptococcal

glomerulonephritis

when there is an outbreak of GAS in a closed or semi-closed community

where there is an outbreak within families of multiple episodes of documented

symptomatic GAS pharyngitis which continue to occur over a period of many weeks

despite appropriate treatment.

This research question concerns whether such intervention for asymptomatic members

of an affected household or community is effective in reducing rates for rheumatic

fever.


Limitations of treating symptomatic cases only

Primary prevention of rheumatic fever involves treating people who have a confirmed

GAS infection and who are symptomatic, usually presenting with sore throat. A recent

meta-analysis of controlled studies of GAS infection treatment following sore throat

found a 60% reduction in rheumatic fever (RR 0.41 [95%CI 0.23 to 0.70, p=0.001]),

supporting a mixture of community and school-based programmes.118

However, relying on symptoms such as sore throat to target people for swabbing has

limitations, as described in the following paragraphs.

Most sore throats are viral. No microbiological test is able to differentiate between

acutely infected patients and asymptomatic carriers of GAS with viral pharyngitis.26

A

person may present with a sore throat, be swabbed as culture-positive for GAS and

treated by antibiotics, but be unresponsive to antibiotics as their sore throat is not

bacterial.

Many people who develop rheumatic fever never report having a prior sore throat and

therefore never seek medical attention. For example, in a study of an outbreak of

rheumatic fever in the inter-mountain area of Utah,119 only 46 patients (17%) sought

medical attention for a preceding sore throat.

Most significantly, symptomatic household or community members may be carriers of

GAS and able to infect or re-infect those around them, thus prolonging an outbreak and

hampering efforts to control infection. For example, it has been suggested that a cluster

of invasive streptococcal disease arising in Minnesota was related to a single virulent

clone becoming prevalent among asymptomatic carriers.116

Patterns of cross-infection

Group A streptococcal sore throat is highly infectious. It appears to be spread by

droplets, saliva, nasal secretions, food preparation, and water and is more infectious in

crowded settings.120

A systematic review120

reports on the 'ping-ponging' of infection

between members of a household. Studies suggest that where a patient has been

infected with GAS pharyngitis, the chance of another household member becoming

infected in the ensuing month is up to one in three,121 with each household member

estimated to have a 5% to 6% chance per month of contracting it from the index

case.122

Given the infectious nature of GAS pharyngitis and its potentially dangerous and

debilitating sequelae, it has been suggested that swabbing of members of households

and communities during an outbreak of GAS and treating those with positive cultures

may assist in preventing rheumatic fever. This applies to members who are

symptomatic for GAS or asymptomatic. The presence of GAS in the upper respiratory

tract (throat, nasal passage) may reflect either true infection or a carrier state. In either

state, the patient harbours the organism, but only in the case of a true infection does

the patient show a rising antibody response. In the carrier state there is no rising


antibody response.113

The carrier state for GAS is not clearly understood, but it has been suggested that

when screened and appropriately treated with antibiotics, carriers can be prevented

from spreading streptococcal infections in the community. Preventing the ping-ponging

of cross infections is aimed at reducing the incidence of life-threatening sequelae

including rheumatic fever.

Key studies attempting to control outbreaks of rheumatic fever or eradicate GAS to

prevent rheumatic fever are discussed below.

Early studies

In the early 1950s, entire regiments of US navy recruits were given courses of oral

prophylactic penicillin 123 aimed to prevent rheumatic fever. Following the administration

of 500,000U of penicillin per day there were no new cases of streptococcal infection,

with a marked reduction in the proportion of men carrying GAS in the throat, and no

more cases of ARF. However concerns about increased resistance to antibiotics, and

the resources and practical barriers associated with such intensive approaches led to

calls to investigate more targeted approaches.

In the late 1950s, a trial 124 was conducted of an intensive approach to managing GAS

infection in three Philadelphian schools. Over the school year, monthly throat swabs

were obtained from each child, from children upon presentation with upper respiratory

infections, and from family contacts of all positive cases. In one school, penicillin was

given to all positive cases (children and family members), whether GAS carriers or

cases with overt infections. In this small, preliminary study, the authors questioned

whether such an intensive therapeutic measure was justified given the high carrier

rates found generally (half the children being GAS positive at some time over the year)

and low incidence of infection. The disruption from exclusion from school of all carriers

was also problematic.

In 1960, an epidemiologic study of GAS cross-infection was conducted of families in

Cleveland, Ohio.125

Acquisition rates for GAS were highest among young

schoolchildren, and were symptomatic in 40%, with no cases of rheumatic fever.

Schoolchildren most commonly introduced a GAS into the family unit – six times as

frequently as their parents. The GAS carrier rate was 25% in families when the index

carrier was symptomatic but was only 9% when the index case was an asymptomatic

carrier. Three and four year olds had the highest risk of becoming secondary carriers

(50%). The spread of streptococci in the family unit often occurred quite slowly, and the

carrier state frequently persisted for a long time. The authors concluded that it is

desirable to administer penicillin to all members of a family once an initial streptococcal

illness is recognised.


Junior detention centre

An epidemic of streptococcal infection (40%) was the subject of intervention in a closed

community, junior detention centre in the north of England in the mid-1970s 126. The

centre received 15 to 17 year old boys for six to eight week periods, reflecting a

changing population of adolescent boys from relatively socially-deprived backgrounds.

Throats were swabbed for GAS upon entry (4% carrier rate). In an early phase of

intervention, symptomatic cases and carriers were given a course of penicillin. The

carriage-rate for GAS was reduced from 31.0% to 13.4% over several months,

however concerns about persistently high rates of acute tonsillitis (21%) and an

outbreak of rheumatic fever (three cases in two years) led to a new prophylaxis phase

being implemented. In this phase, penicillin was instituted for all boys on admission to

the centre (0.25 g orally four times per day for 10 days) before GAS status was known.

The attack rate for acute tonsillitis fell gradually over 18 months from 21.0% to 4.7%

although it was six months before any reduction occurred. The incidence of reported

sore throat fell from 67% to 3.2% over two years.

As there was no control group/centre without a programme it is not possible to observe

the natural history of the epidemic and to ascertain the degree to which the prophylaxis

intervention contributed to its management.

A follow-up investigation of the same centre 127 reported that as full prophylaxis was

difficult to administer and the epidemic seemed under control the intervention was

ceased. High rates of acute tonsillitis (over 30%) returned almost at once and

prophylaxis was recommenced for boys upon entry. Various doses were trialled over a

two-year period and fixed at 0.5 g of oral penicillin once per day for 10 days (ie, instead

of 0.25 g four times per day as previously). The attack rate for acute tonsillitis reduced

very gradually to 2.1%. The authors suggest that rates may have been reduced more

quickly if all residents had been administered the course of penicillin instead of just new

admissions. Another limitation of this study is that staff or other potential contacts were

not assessed or treated for GAS.

Navajo Indians

A three-year programme targeting ARF was administered among Navajo

schoolchildren in the USA.128 Throat swabs for GAS were taken monthly from

asymptomatic children, and upon presentation of a sore throat for any child, although

schools participated intermittently. Antibiotic treatment of GAS positive cases and

carriers was undertaken.

The ARF rate in the area covered by the programme was 39% lower in the three years

post-programme than the two years prior (13.5 cf 8.2 per 100,000, respectively)

whereas rates in the uncovered comparison area were largely unchanged at 9.5 before

and 10.1 after. However a confounding factor in the study was that there were

substantially higher attack rates of ARF in the covered areas compared with the

uncovered areas at baseline (13.5 cf 9.5, respectively). As the programme did not have

an adequate control group, any effect on ARF incidence remains uncertain.16


Child care centre in Sweden

In Sweden, day child care centres (DCC) in the county of Halland (population: 240,000)

were involved in an outbreak of erythromycin-resistant GAS (ERGAS) between 1984

and 1985, erythromycin being an antibiotic used for patients who are allergic to

penicillin.129

This represented a localised outbreak after not having had any significant

spread in the population of ERGAS before.

A prevention programme was instituted in seven DCCs where ERGAS had been

isolated and where there was more than one suspected case. Throat swabs were

taken from all children and employees at day one. On days 5 to 7, swabs were taken

from those absent on day one, from those who were culture negative on day one, and

from parents and siblings of ERGAS culture-positive subjects. All subjects with positive

swabs were treated with antibiotics and were then followed up at days 21 to 33 and re-

treated if still ERGAS-positive.

Half (49%, 112/230) the children attending the seven DCCs involved in the outbreak

were infected with ERGAS, as well as 8% of employees (7/93), 23% of parents to

ERGAS children (37/163) and 36% (22/61) of siblings to ERGAS children. In addition,

21 children also had erythromycin-sensitive GAS. It should be noted that asymptomatic

ERGAS-positive children had as many ERGAS-positive relatives as symptomatic

children, suggesting rates of infection were similar between cases and carriers for

ERGAS. However, asymptomatic children’s relatives were less likely to be symptomatic

than the relatives of symptomatic ERGAS-infected children. The authors suggest that

this may be because the symptomatic children and their symptomatic relatives were

more recently infected.

Antibiotic treatment eradicated ERGAS in 75% of cases after an initial 10-day course

and 48% of the remaining cases after a second 10-day course, leaving 13% (22/165)

still ERGAS positive. A third course was also used in one town where the outbreak

began. Treatment compliance was not assessed. None of the ERGAS-infected patients

developed clinically obvious glomerulonephritis. Over two-year follow-up, only sporadic

isolations of ERGAS arose in Halland and no case of acute glomerulonephritis

provoked by ERGAS was diagnosed.

The authors suggest that child care centres can act as epicenters for the spread of

GAS with children acting as ‘primary transmitters’, particularly as infants are known to

be ‘saliva promiscuous’. This study suggests that where a virulent strain has been

identified in a community, particularly one involving close contact of children, and

where an intervention is practical, an intensive prophylaxis programme of swabbing

close community and family contacts can be successfully managed. However it should

be cautioned that there was no comparison observation of the natural history of the

infection without an intervention programme, or a control population observed without

swabbing of asymptomatic contacts. Therefore what specific effect the programme, or

aspects of it, had on the outcomes cannot be clearly quantified.


Nursing home

Following nine outbreaks of GAS in nursing homes in Atlanta over two years, an

investigation was performed of one outbreak in the winter of 1989/1990.130 Over a six-

week period, 20% (16/80) of residents and 7% (3/45) of staff, were infected with GAS.

Eleven of the residents developed invasive disease and four died. Matched case-

control and retrospective cohort studies were performed to determine risk factors for

infection. Strong spatial clustering of cases was observed with having a roommate with

prior infection the most important risk factor. No evidence was found for common-

source transmission of infection. Following improved infection control practices and

administration of prophylactic antimicrobials to all residents and staff, no further cases

occurred.

The authors conclude that in such an outbreak of a virulent GAS strain, adherence to

infection control can prevent or control GAS outbreaks. They further suggest that

prophylactic antimicrobials may be an effective adjunct to control severe or ongoing

outbreaks. A limitation of this study is that it is not possible to determine the relative

contribution of infection control practices versus prophylactic antimicrobials in the

management of this outbreak.

Summary of findings

Several studies were identified that were published since the 1950s describing

attempts to manage outbreaks of GAS rheumatic fever through an intensive

prophylaxis programme of swabbing close community and/or household contacts.

Studies varied across factors including location, settings, population, background

infection and disease rates, strains of GAS, swabbing and GAS confirmation

techniques, treatment approaches, compliance and ability to control compliance, and

follow-up. Despite these variations, results are largely consistent. They suggest that

programmes which swab and treat GAS-positive carriers and cases are associated

with reductions in GAS infection rates and potentially rates of rheumatic fever, although

these were too small to be statistically tested. Epidemiological studies also support the

ability of carriers as well as cases to infect contacts with GAS, though it appears that

symptomatic cases are more likely to arise after contact with symptomatic index cases.

Limitations of the evidence base include that whilst some studies had the ultimate aim

of reducing incidence of rheumatic fever, study samples were too small to investigate

rheumatic fever rates as a primary outcome. Further, most studies were uncontrolled

making it difficult to isolate the contribution to reductions in infection and GAS-sequelae

of swabbing of asymptomatic carriers, as well as cases versus swabbing cases alone.

An exception was the small study (80 residents) based in a nursing home130 where a

case control design was employed.

Prophylactic treatment of cases and carriers for GAS requires practical and financial

resources, cooperation from participants and their community contacts, as well as the

careful administration and monitoring by programme staff to ensure good programme

fidelity and compliance with treatment. Such well-coordinated primary prevention

programmes may be less likely to be practical, affordable and cost-effective in

developing countries or larger communities.16 However, at least in the developed world,


the investment of resources is more likely to be cost-effective when dealing with severe

or persistent outbreaks of virulent strains within a household or community, and within

closed or semi-closed communities such as schools or nursing homes following an

outbreak of GAS.

Given the small number and methodological limitations of the studies considered here,

there is limited evidence. It is suggested that approaches involving prophylaxis of

carriers for GAS are likely to be most effective when applied in closed or semi-closed

communities where severe or persistent outbreaks of new virulent strains of GAS occur

or within households where an outbreak has occurred.


Appendix 1: Methods

This appendix describes the process undertaken by NZGG to determine the research

questions and review the evidence.

Contributors

Expert Advisory Group

Jim Vause

New Zealand College of General Practitioners

Norman Sharpe

National Heart Foundation

Louisa Ryan

Pacific Health Manager, National Heart Foundation

Lance O’Sullivan

New Zealand College of General Practitioners

Jim Miller

NZ College of Public Health Medicine

Phil Shoemack

NZ College of Public Health Medicine

Dianna Lennon

Royal Australasian College of Physicians

David Jensen

Te Ohu Rata o Aotearoa: Maori Medical Practitioners Association

Elizabeth Farrell

KidzFirst, CMDHB

Maxine Shortland

Ngati Hine Health Trust

Helen Herbert

Te Runanga o Kaikohe

Teuila Percival

Pasifika Medical Association


Melissa Kerdemelidis

Primary Health Registrar Christchurch

Bruce Arroll

University of Auckland, Department of General Practice & Primary Health Care

New Zealand Guidelines Group team

Jessica Berentson-Shaw Research Manager

Anita Fitzgerald Assistant Research Manager and lead researcher

Anne Lethaby Researcher

Catherine Coop Researcher

Julie Brown Senior Researcher

Marita Broadstock Senior Researcher

Margaret Paterson Information Specialist

Leonie Brunt Publications Manager

Declarations of competing interest

No competing interests were declared.

Research process

This section provides an overview of the research methodology utilised during the

development of this evidence review. It describes how the research questions were

developed and how the systematic and narrative reviews were undertaken.

The evidence review aimed to cover both children and adults with GAS throat infection

clinically managed within primary healthcare settings.

Research questions

The Ministry of Health suggested a list of questions, initially revised and then agreed to

by NZGG. The questions were then circulated among a specialist group, most of whom

were invited to be part of the Expert Advisory Group (EAG). Following final agreement

on the research questions, the research team prepared the questions in the PICO

(Patient, Intervention, Comparison, Outcome) format to ensure effective and focused

searches and reviews could be undertaken. Some of the research questions were able

to be subject to a formal systematic review while for the remaining questions, literature

reviews were undertaken.


Research Question PICO Type of evidence

review

Chapter 1 – Introduction and context

1. When do sore throats

occur in the natural course

of Streptococcal

Pharyngitis?

N/A Literature review. No

date restriction.

Chapter 2 - Rapid Antigen Diagnostic Tests

2. In children and adults

with sore throats, what is

the accuracy of the Rapid

Antigen Diagnostic Test

(RADT) compared to

culture to confirm GAS?

P: Children and Adults with sore throats

Index test: RADT

Ref standard: culture

Outcomes: Diagnostic accuracy, adverse

events

Subgroups: low and high risk kids

Systematic review of

diagnostic studies.

No date restriction.


presenting with a resolved

sore what is the accuracy

of the Rapid Antigen

Diagnostic Test (RADT)

compared to culture to

confirm GAS?

P: Children and Adults with resolved sore

throats

I (index test): RADT

C (ref standard): culture

Outcomes: Diagnostic accuracy, adverse

events



diagnostic studies.



presenting with a current

sore throat is immediate

RADT and/or Culture more

effective than delayed in

ensuring diagnostic

accuracy?

P: Children and adults with sore throats

I (index test): immediate RADT/culture

C (ref standard): delayed RADT/culture

O: Diagnostic accuracy, adverse events



diagnostic studies.


Chapter 3 – Antibiotic Treatment

5. What is the antibiotic of

choice for treatment of

children and adults

diagnosed GAS, when

should it be administered,

for how long and in what

dose to prevent

progression to rheumatic

fever, reduce likelihood of

antibiotic resistance and

ensure compliance?

P: Children and adults with confirmed

GAS infection

I: Antibiotics

C: No treatment, placebo, other antibiotic

O: Clinical and bacteriological resolution,

recurrence, re-infection, dose, duration,

compliance, resistance


intervention studies.

Date restriction: 2005

to May 2011.


Research Question PICO Type of evidence

review

6. In children presenting

with a current sore throat is

immediate antibiotic

treatment compared with

delayed antibiotic

treatment more effective in

eliminating a GAS infection

and preventing progression

to rheumatic fever?

P: Children and adults with sore throats

I: Immediate antibiotic treatment

C: Delayed antibiotic treatment

O: Eliminating GAS infection, progression

to ARF, resistance.


intervention studies.

Date restriction: 2005

to May 2011.

Chapter 4 - Asymptomatic Carriers

7. At what rate does

asymptomatic GAS occur

in the community?

N/A Literature review.


8. Does asymptomatic

GAS occur at a higher rate

in communities with higher

rates of rheumatic fever?



9. Is there an association

between the carriage rate

and rate of rheumatic fever

in communities?



Chapter 5 - Community swabbing

10. What defines an

outbreak of rheumatic

fever?


11. Where there is an

outbreak does swabbing of

asymptotic community

members and households

reduce rates of rheumatic

fever?


Reviewing the literature

Search strategy

Search strategies for most research questions were conducted without restrictions on

date. The questions regarding antibiotics (Chapter 3) were limited to 2005 onwards

because existing good quality systematic reviews covered the studies published prior

to 2005. Searches were completed in May 2011.

The NZGG research team in consultation with the Ministry of Health, set the inclusion

and exclusion criteria for the searches. For the questions answered by systematic

review, systematic literature searches relating to each PICO question were designed in

consultation with an information specialist. For the questions answered by literature

review, searches were also designed in consultation with an information specialist.


Studies investigating cost-effectiveness were not included.

Reviewing international guidelines

NZGG often includes the findings of international guidelines in research reports. For

the epidemiological chapters of this report, such guidelines and their findings are

referenced and described and were assessed for quality using the AGREE II tool. For

the systematic review chapters of this report, it was agreed that reporting such

guidelines would not be helpful. A study published in 2011 analysed the different

recommendations in 12 international guidelines for the management of acute

pharyngitis in children and adults.131 The study found several discrepancies in the

recommendations between countries with regard to the use of rapid antigen tests,

culture and the indications for antibiotic treatment. Most agreed that narrow-spectrum

penicillin is the first choice of antibiotic for the treatment of streptococcal pharyngitis

and that treatment should last for 10 days to eradicate the microorganism. Given the

obvious differences in recommendations, and likely differences in the evidence used to

make these decisions, NZGG has included only systematic reviews and comparative

intervention or diagnostic studies in the systematic reviews included in this evidence

review.

Search databases

The systematic review searches were conducted for the research questions noted

above. The following bibliographic, HTA and Guideline databases were included in the

search:

1. MEDLINE

2. EMBASE

3. CINAHL

4. Cochrane Library

5. Web of Science

6. DARE Database

7. HTA Database

8. CCTR

9. Current Controlled Trials (CCTR)

10. ClinicalTrials.gov

11. Web of Science

The literature review searches were conducted for the research questions noted above

using the same databases as for the systematic reviews. Other references (eg, text

book chapters, studies referenced in bibliographies) were also included where

appropriate.


Evidence appraisal

Where literature reviews were carried out (Chapters 1, 4 and 5), comparative studies

were appraised for quality and included in evidence tables. Where studies were

epidemiological (or non-comparative), no formal appraisals were carried out.

Where systematic reviews were carried out, the steps below were followed in

appraising the evidence.

Step 1: Assigning a level of evidence

Following the completion of searches, retrieved studies meeting the inclusion criteria

for each question were assigned a level of evidence. The level of evidence indicates

how well the study eliminates bias based on its design. NZGG uses a published

evidence hierarchy, designed by the National Health and Medical Research Council of

Australia (NHMRC).132

The levels of evidence are presented in Table A2.1.

Step 2: Appraising the quality of included studies

Intervention studies

Intervention study designs (systematic reviews, randomised controlled trials) that met

the inclusion criteria for each research question were appraised using an adapted

version of the GATE (Graphic Appraisal Tool for Epidemiology), which has been

validated by NZGG researchers.133

In brief, the GATE checklists are comprised of slightly different criteria depending on

the study design but all broadly address each part of the PICO framework. The case is

slightly different for systematic reviews and meta-analyses where additional criteria are

included to assess the appropriateness of combining and analysing multiple studies.

However, in general the checklists help the researcher to assess study quality in three

main areas:

1. study validity (steps made to minimise bias)

2. study results (size of effect and precision)

3. study relevance (containing applicability/generalisability).

The researcher indicates whether the criteria for quality has been met (+), is unmet (x)

or, where there is not enough information to make a judgment, is unknown (?) for each

checklist item. Researchers then assign the same quality criteria to each of three

summary sections which assess the accuracy, relevance and applicability of the

findings. Here, the researcher indicates whether the study has any major flaws that

could affect the validity of the findings and whether the study is relevant to clinical

practice. The three summary sections include:

internal validity – potential sources of bias

precision of results

applicability of results/external validity – relevance to key questions and clinical

practice.


Table A2.1 NHMRC levels of evidence

Level Intervention1 Diagnostic accuracy

2 Prognosis Aetiology

3 Screening intervention

I4 A systematic review of level II

studies

A systematic review of level II

studies


studies


studies


studies

II A randomised controlled trial A study of test accuracy with: an

independent, blinded comparison

with a valid reference standard,5

among non-consecutive persons

with a defined clinical presentation6

A prospective cohort study7 A prospective cohort study A randomised controlled trial

III-1 A pseudorandomised controlled

trail (ie, alternate allocation or some

other method)

A study of test accuracy with: an

independent, blinded comparison

with a valid reference standard,5

among non-consecutive persons

with a defined clinical presentation6

All or none8 All or none

8 A pseudorandomised controlled

trial (ie, alternate allocation or

some other method)

III-2 A comparative study with

concurrent controls:

Non-randomised, experimental

trial9

Cohort study

Case-control study

Interrupted time series with a

control group

A comparison with reference

standard that does not meet the

criteria required for Level II and III-1

evidence

Analysis of prognostic factors

amongst persons in a single

arm of a randomised

controlled trial

A retrospective cohort study A comparative study with


Non-randomised, experimental

trial

Cohort study

Case-control study

III-3 A comparative study without


Historical control study

Two or more single arm study10

Interrupted time series without a

parallel control group

Diagnostic case-control study5 A retrospective cohort study A case-control study A comparative study without


Historical control study

Two or more single arm study

IV Case series with either post-test or

pre-test/post-test outcomes

Study of diagnostic yield (no

reference standard)11

Case series, or cohort study of

persons at different stages of

disease

A cross-sectional study or

case series

Case series


Finally, researchers assign an overall assessment of the study quality based on a

summary of the checklist criteria, these are + good; x not ok, poor; ? unclear. Scores

for each of the three summary domains, and the overall score are presented as part of

the evidence tables.

Diagnostic studies

Diagnostic accuracy studies are appraised using the QUADAS tool, an internationally

recognised and validated tool.30 The QUADAS tool, developed by the NHS Centre for

Reviews and Dissemination at the University of York, aims to evaluate the presence of

spectrum bias, bias associated with the choice of reference standard, disease

progression bias, verification bias, review bias, clinical review bias, incorporation bias,

and bias associated with study withdrawals and indeterminate results. Summary scores

estimating the overall quality of a diagnostic accuracy article were not applied since the

interpretation of such summary scores is problematic and potentially misleading.32

Guidelines

Where NZGG identified existing national and international guidelines, these were

appraised for quality using the second iteration of the Appraisal of Guidelines for

Research and Evaluation (AGREE II)134 instrument and are summarised at the

beginning of each chapter. The AGREE II tool evaluates the process of practice

guideline development and the quality of reporting. The AGREE II is the currently

accepted international tool for the assessment of practice guidelines. The AGREE II is

both valid and reliable and comprises 23 items organised into six quality domains.

Evidence tables

Following the appraisal of study quality, using the different methods above, evidence

tables were developed to present the key characteristics of each of the included

studies. Different forms of the template are used for each of the different study designs.

Step 3: Expert discussion

A one-day, face-to-face meeting was held where the EAG considered the evidence.

They were unable to agree recommendations and so none are presented in this

review. Instead, key points arising from the review are provided at the start of the

document.


Appendix 2: Abbreviations and glossary

Abbreviations

AGREE Appraisal of Guidelines for Research and Evaluation

ARF Acute rheumatic fever

ARTI Acute respiratory tract infections

AUC Area under the curve

BID Twice a day

CI Confidence interval

Coeff. Coefficient

DCC Day childcare centres

dOR Diagnostic odds ratio

EAG Expert Advisory Group

ERGAS Erythromycin-resistant GAS

FP False positive

FN False negative

I2 Heterogeneity

IM intramuscular

ITT analys. Intention to treat analysis

LR+ Positive likelihood ratio

LR – Negative likelihood ratio

MD Mean difference

NHMRC National Health and Medical Research Council (Australia)

NICE National Institute for Clinical and Health Excellence

NNTB Number needed to benefit

NNTH Number needed to harm

NPV Negative predictive value

NS Not significant

NZGG New Zealand Guidelines Group

OR Odds ratio

PCR assay Polymerase chain reaction

PP analys Per protocol analysis

PPV Positive predictive value

Prev Prevalence

Q* Cochrane Q statistic

QD Once a day

QID Four times a day


RCT Randomised controlled trial

rdOR Relative diagnostic odds ratio

RHD Rheumatic heart disease

ROC Receiver operator curve

RR Relative risk

Rx Therapy/treatment

SE (AUC) Standard error (Area under curve)

SIGN Scottish Intercollegiate Guideline Network

sROC Summary receiver operator curve

Std. Err. Standard error, same as SE above

TP True positive

TN True negative

Var Variance


Glossary

Acute rheumatic fever Disease involving inflammation of joints and damage to heart

valves that follows streptococcal infection and is believed to

be autoimmune

Chronic Persisting over a long period of time

Concurrent Occurring at the same time

Heterogeneous Having a large number of variants

Holistic care Care that provides for the psychological as well as the physical

requirements of the individual

Mana Power, respect, status

Morbidity A diseased condition or state

Mortality Death

Noa Free from tapu or any other restriction

Ora Health, life, vitality

Primary care Services provided in community settings with which patients

usually have first contact (eg, general practice)

Prognosis A prediction of the likely outcome or course of a disease; the

chance of recovery or recurrence

Prognostic factors Patient or disease characteristics (eg, age and disease stage) that

influence the course of the disease under study

Prophylactic A medication or treatment designed and used to prevent a

disease

Regimen A plan or regulated course of treatment

Sequential One treatment following another

Systemic

therapy/treatment

Treatment, usually given by mouth or injection, that reaches and

affects tumour cells throughout the body rather than targeting one

specific area

Tapu Sacred, taboo

Whānau Family, community

Whānau ora The health of an extended family or community of related families

http://www.mondofacto.com/facts/dictionary?Disease

http://www.mondofacto.com/facts/dictionary?inflammation

http://www.mondofacto.com/facts/dictionary?joints

http://www.mondofacto.com/facts/dictionary?damage

http://www.mondofacto.com/facts/dictionary?heart+valves

http://www.mondofacto.com/facts/dictionary?heart+valves

http://www.mondofacto.com/facts/dictionary?follows

http://www.mondofacto.com/facts/dictionary?streptococcal

http://www.mondofacto.com/facts/dictionary?infection

http://www.mondofacto.com/facts/dictionary?autoimmune


Colorectal Cancer 95

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