Management of Group A Streptococcal Sore Throat for the Prevention of Acute

Transcription

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
The copyright owner of this publication is the Ministry of Health, which is part of the New Zealand
Crown. Content may be reproduced in any number of copies and in any format or medium
provided that a copyright acknowledgement to the New Zealand Ministry of Health is included and
the content is neither changed, sold, nor used to promote or endorse any product or service, or
used in any inappropriate or misleading context. For a full copyright statement, go to
www.health.govt.nz/about-site/copyright.
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, policymakers 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 res olved 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
Cont ribut ors .............................................................................................................. 84
Research process ..................................................................................................... 85
Research questions ................................................................................................... 85
Reviewing the literat ure ............................................................................................. 87
E vidence 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 evidencedbased 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.
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.
Management of Streptococcal A Sore Throat
1
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 days 5, 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 twothirds.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
2
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.
3
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 Set1, 2
4
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
Pacific Islands
European/Other
32
17
17
62
48
5
+98%
+185%
-168%
Total
64
115
+79%
2.0
2.9
0.3
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
NonMāori/Pacific
Rate ratio
*
Total
Mean
40.2
81.2
2.1
17.2
-95%CI
36.8
73.4
1.6
16.1
+95%CI
43.8
89.6
2.5
18.2
Māori
19.5
Pacific
39.3
15.5
24.5
31.3
49.8
CI = confidence interval
* Compared to non-Mā ori/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
5
Figure 1.2 Annual index cases and incidence rates for acute rheumatic fever in
1993–2009 for children 5 to 14 years of age
6
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.
7
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
NonMāori/
Māori
Pacific
Pacific
Total
DHBa
Counties Manukau
111
Mean annual incidence per 100,000
NonMāori/
Māori
Pacific
Pacific
Total
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
Auckland
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
10
2
0
12
43.2
51.7
0.0
22.7
20
14
7
41
18.8
29.6
3.9
12.4
372
291
37
700
64.9
96.0
7.5
51.0
332
278
28
638
75.1
104.1
8.7
61.9
95%
95%
81%
94%
Na
Na
Na
Na
81%
84%
64%
76%
Na
Na
Na
Na
b
Midcentral
Remaining 11
c
Total
Top 10 DHBs
% total cases
e
% population
d
CCDHB=Capital and Coast DHB; CMDHB=Counties Manukau DHB; DHB=District Health
Board; Na=not applicable
a
Sorted by total incidence rate
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
b
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
8
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 nonMāori 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 nonMāori/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 nonMāori/Pacific children widened both in relative terms (the ratio of incidence rates) and
in absolute terms (the difference in incidence rates) (Table 1.4).
9
Table 1.4 Changes in ethnic disparity over time for children 5 to 14 years of age during
a
the period 1993–2009
Incidence rate ratio
b
Incidence rate difference per
c
100,000 per year
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
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
b
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
10
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
11
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.
12
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?
13
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.
14
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.
15
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
16
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).
17
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.
18
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.
19
Summary of findings
Table 2.1: Characteristics of included studies
Reference
(study
design)
Rogo et al
Single-gate37
Gurol et al
Single-gate38
Sarikaya et
al
Single-gate39
Country
USA
Turkey
Prevalence
Participants
Age
Reference
standard
Type of RAD test
Sens
Spec
PPV
NPV
LR+
LR-
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)*
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%
QuickVue
64.6%
96.8%
81.0%
92.8%
81 (95%CI 20, 320)*
0.02 (0.00, 0.11)*
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%
n=453
All age
groups
Culture (5%
sheep blood
agar)
28.1%
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)
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)
Kim
Single-gate41
Korea
n=293
Children
(age not
specified)
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)
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)
Rimoin et al
Single-gate40
Turkey
28.1%
28.7%
20
66.5%
24.7%
Reference
(study
design)
Country
Participants
Age
Reference
standard
Prevalence
Tanz et al
Single-gate43
USA
n= 1848
Children 3 to
18 years
Culture (5%
sheep blood
agar)
QuickVue
Al-Najjar and
Uduman
Single-gate44
UAE
n=425
Children
(80% under
5)
Culture
Camardan et
al
Single-gate45
Turkey
n=1248
Children
Overall
Culture (7%
sheep blood
agar)
Type of RAD test
Sens
Spec
PPV
NPV
LR+
LR-
71%
97%
91.65%
88.85%
26 (95%CI 19, 36)
0.29 (95%CI 0.26,
0.34)
Diaquick
96%
99%
96%
99%
136 (95%CI 44, 419)
0.04 (0.01, 0.13)
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)
0 to 6years
89.7%
96.9%
90.8%
96.54%
29 (95%CI 18, 48)
7 to 12
years
90%
97.5%
97.67%
89.27%
36 (95%CI 16, 80)
13+ years
87.1%
97.7%
96.43%
91.49%
38 (95%CI 5.5, 261)
29.9%
14.3%
0.11 (95%CI 0.07,
0.17)
0.10 (95%CI 0.07,
0.15)
0.13 (95%CI 0.05,
0.33)
25.2%
32.4%
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)
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)
Wright et al
Single-gate48
USA
n=350
Children 0 to
18 years
Culture
(blood agar)
85.5%
97%
91%
95%
31 (95%CI 15, 65)
0.15 (95%CI 0.09,
0.25)
79.5%
95%
84.6%
93%
17 (95%CI 9.62, 30)
0.21 (95%CI 0.14,
0.33)
OSOM
QuickVue
38.1%
53.9%
41.3%
23.6%
21
24.6%
24.6%
Reference
(study
design)
Abu Sabbah
and Ghazi
Single-gate49
Prevalence
Country
Participants
Age
Reference
standard
Type of RAD test
Sens
Saudi
Arabia
n=355
Adults and
children
Culture
(horse blood
agar)
Detector Strep A
Direct
88%
Children
aged 4 to 14
Adults aged
>15
Araujo Filho
et al
Single-gate50
Forw ard et
al
Single-gate51
Brazil
Canada
n=81
Adults over
18 years
Culture (5%
goat blood
agar)
Culture (5%
sheep blood
agar)
n=818 overall
OIA MAX
Step A Rapid Test
Device (SARTD)
n=328 adults
n=490 children
Humair et al
Single-gate52
Shaheen
and Hamdan
Single-gate53
PPV
NPV
LR+
LR-
91%
70%
97%
10 (95%CI 6.90, 15)
0.13 (95%CI 0.07,
0.25)
81%
86%
67%
93%
5.93 (95%CI 3.33, 11)
93%
93%
73%
98%
14 (95%CI 8.22, 23)
93.9%
68.7%
67.4%
94.2%
3.01 (1.96, 4.61)
0.09 (0.02, 0.34)
18.9%
25.2%
16.1%
40.7%
19.6%
71.9%
94.3%
76.9%
92.7%
11 (95%CI 7.92, 14)
67.8%
93.8%
77.7%
90.2%
11 (95%CI 7.24, 17)
0.34 (95%CI 0.26,
0.45)
81.1%
94.9%
75.4%
96.3%
16 (95%CI 9.41, 27)
0.20 (95%CI 0.11,
0.35)
24.1%
16.2%
37.6%
n=372
Patients age
>15 years
Culture
(blood agar)
Amman
n=200
Adults
20 to 42
years (mean
28.3 years)
Culture
(blood agar)
Latex particle
agglutination
90.00%
98.22%
USA
n=150
Adults over
18 years
Culture
Acceava
92.1%
100%
Sw itzerland
0.21 (95%CI 0.10,
0.48)
0.08 (95%CI 0.03,
0.24)
0.25 (95%CI 0.19,
0.33)
Testpack Plus Strep
A w /OBC[On Board
Controls] II (Abbott
Laboratories)
Atlas et al
Single-gate54
Children
w ere <16
years
Spec
91.4%
95.3%
92.1%
0.09 (95%CI 0.05,
0.16)
94.9%
19.3 (95%CI 11, 34)
90.00%
98.22%
50.70 (95%CI 16.41,
156.61)
0.10 (0.03, 0.30)
100%
98%
Not estimable
0.08 (95%CI 0.03,
0.24)
15.1%
22
18.4%
Reference
(study
design)
Country
Participants
Age
Reference
standard
Type of RAD test
Ezike et al
Single-gate55
USA
n=363
Children 5 to
18 years
Culture (5%
sheep blood
agar)
OIA MAX
Culture
(Columbia
agar w ith
horse blood)
TestPack Plus
96%
86%
79.7%
Culture (5%
blood agar)
TestPack
73%
94%
85%
Lindbaek et
al
Single-gate56
Norw ay
n=306
Adults and
children
(<10 years)
Santos et al
Single-gate57
Brazil
n=50
Children age
1 to 12
years
Nerbrand et
al
Single-gate58
Sw eden
Culture (6%
defibrinised
horse blood)
n=536
All ages
n=615
All ages
Culture (6%
defibrinised
horse blood)
Chapin et al
Single-gate59
USA
n=520
Children
(age not
specified)
Culture (5%
sheep blood
agar).
Gieseker et
al
Single-gate60
USA
n=302
Children
(age not
specified)
Culture
Prevalence
Canada
n=126
All ages
Culture (5%
sheep blood
agar)
94.7%
Spec
PPV
NPV
LR+
LR-
100%
100%
96.2%
Not estimable
0.05 (95%CI 0.020.14)*
97.7%
7.0 (95%CI 4.92,9.95)
0.04 (95%CI
0.02,0.11)
88%
12 (95%CI 3.14,
14.49)
0.28 (95%CI 0.12,
0.66)
0.30 (95%CI 0.21,
0.43)
42.4%
36%
73.9%
86.8%
59.4%
92.7%
5.60 (95%CI 4.28,
7.32)
TestPack
82.8%
96.1%
92.7%
94.2%
21 (95%CI 14, 33)
0.18 (95%CI 1.02,
0.26)
Thermo Biostar OIA
86.1%
97.1%
93.7%
93.4%
28 (95%CI 15, 52)
0.13 (95%CI 0.09,
0.18)
97%
92%
82%
98%
12 (95%CI 7.4, 18)
0.04 (95%CI 0.01,
0.11)
79%
95%
84%
92%
15 (95%CI 8.29, 25)
0.252 (95%CI 0.14,
0.34)
75%
99%
96%
92%
71(95%CI 9.93, 500)
0.25 (95%CI 0.14,
0.46)
OSOM
Testpack
34%
15.3%
QuickVue
OIA Max
Rosenberg
et al
Single-gate61
Sens
23
21.1%
37.9%
28.8%
27.2%
25.4%
Reference
(study
design)
Country
Participants
Age
Reference
standard
Type of RAD test
Sens
Spec
PPV
NPV
LR+
LR-
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)
Gieseker et
al
Single-gate63
USA
n=887
Children
(age not
specified)
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)
Sheeler et al
Tw o-gate64
USA
n=211 cases
All ages
Testpack Plus
91%
96%
96%
90%
9.92 (95%CI 5.5, 18)
0.04 (95%CI 0.02,
0.11)
n=232 controls
All ages
Testpack Plus
70%
98%
92%
90%
8.88 (95%CI 5.75, 14)
0.09 (95%CI 0.04,
0.24)
Accustrip
52.6%
98.2%
52.6%
98.2%
28.9 (95%CI 13, 63)
0.48 (95%CI 0.30,
0.78)
80%
92.7%
83.1%
91.1%
10.89 (6.38, 18.59)
0.22 (95%CI 0.14,
0.34)
Overall
94.12%
89.45%
60.38%
98.89%
8.92 (95%CI 5.90, 13)
0.07 (95%CI 0.02,
0.25)
Testpack Plus
93.3%
94.7%
73.7%
98.9%
18 (95%CI 7.4, 42)
Kodak SureCell
94.7%
84.8%
52.9%
98.9%
6.22 (95%CI 3.91,
9.88)
Culture (5%
sheep blood
agar)
Culture (5%
sheep blood
agar)
Wong and
Chung
Single-gate65
Hong
Kong
n=1491
All ages
Culture (5%
horse blood
agar)
Kurtz et al
Single-gate66
USA
n=537
Children age
4 to 15
years
Culture (5%
standard)
Alesna et al
Single-gate67
Philippines
n=233
All ages
>3 years
Culture (5%
sheep blood
agar)
Prevalence
Testpac Plus
0.07 (95%CI 0.01,
0.47)
0.06 (95%CI 0.01,
0.42)
Sens = sensitivity; Spec = specificity; PPV = positive predictive value; NPV = negative predictive value; LR+ = positive likelihood ratio; LR- = negative
likelihood ratio
24
45.5%
23.7%
50.2%
20.7%
37%
31.1%
14.6%
13.8%
15.3%
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.
25
Figure 2.1 Methodological quality of individual studies
26
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.
27
Figure 2.3 Forest plot of overall study results (sensitivity and specificity)
Study
TP
FP
FN
Abu Sabbah 2006
59
25
8
263 0.88 [0.78, 0.95] 0.91 [0.87, 0.94]
Al Najjar 2008
68
3
3
422 0.96 [0.88, 0.99] 0.99 [0.98, 1.00]
Alesna 2000
14
5
1
89 0.93 [0.68, 1.00] 0.95 [0.88, 0.98]
Araujo Filho 2006
31
15
2
33 0.94 [0.80, 0.99] 0.69 [0.54, 0.81]
Atlas 2005
38
0
3
112 0.93 [0.80, 0.98] 1.00 [0.97, 1.00]
Camurdan 2008
427
22
49
751 0.90 [0.87, 0.92] 0.97 [0.96, 0.98]
Chapin 2002
173
10
24
313 0.88 [0.82, 0.92] 0.97 [0.94, 0.99]
Ezike 2005
71
0
4
102 0.95 [0.87, 0.99] 1.00 [0.96, 1.00]
Fontes 2007
49
19
5
156 0.91 [0.80, 0.97] 0.89 [0.84, 0.93]
123
48
37
610 0.77 [0.70, 0.83] 0.93 [0.90, 0.95]
Gieseker 2002
84
18
3
197 0.97 [0.90, 0.99] 0.92 [0.87, 0.95]
Gieseker 2003
184
26
26
651 0.88 [0.82, 0.92] 0.96 [0.94, 0.97]
51
12
28
362 0.65 [0.53, 0.75] 0.97 [0.94, 0.98]
Humair 2006
128
11
12
221 0.91 [0.86, 0.95] 0.95 [0.92, 0.98]
Keahey 2002
65
18
10
72 0.87 [0.77, 0.93] 0.80 [0.70, 0.88]
187
8
8
90 0.96 [0.92, 0.98] 0.92 [0.85, 0.96]
64
13
16
164 0.80 [0.70, 0.88] 0.93 [0.88, 0.96]
106
27
4
169 0.96 [0.91, 0.99] 0.86 [0.81, 0.91]
52
14
3
153 0.95 [0.85, 0.99] 0.92 [0.86, 0.95]
Maltezou 2008
121
21
25
284 0.83 [0.76, 0.89] 0.93 [0.90, 0.96]
Nerbrand 2002
107
19
22
466 0.83 [0.75, 0.89] 0.96 [0.94, 0.98]
Rimoin 2010
561 136
Forward 2006
Gurol 2010
Kim 2009
Kurtz 2000
Lindbaek 2004
Llor 2009
TN
Sensitivity
Specificity
Sensitivity
Specificity
0 0.2 0.4 0.6 0.8 1
0 0.2 0.4 0.6 0.8 1
149 1626 0.79 [0.76, 0.82] 0.92 [0.91, 0.93]
Rogo 2011
65
1
1
161 0.98 [0.92, 1.00] 0.99 [0.97, 1.00]
Rosenberg 2002
24
1
8
93 0.75 [0.57, 0.89] 0.99 [0.94, 1.00]
Santos 2003
11
2
4
32 0.73 [0.45, 0.92] 0.94 [0.80, 0.99]
Sarikaya 2010
15
8
7
70 0.68 [0.45, 0.86] 0.90 [0.81, 0.95]
Shaheen 2006
27
3
3
166 0.90 [0.73, 0.98] 0.98 [0.95, 1.00]
Sheeler 2002
165
19
4
44 0.98 [0.94, 0.99] 0.70 [0.57, 0.81]
Tanz 2009
395
36 158 1259 0.71 [0.67, 0.75] 0.97 [0.96, 0.98]
Wong 2002
10
9
9
486 0.53 [0.29, 0.76] 0.98 [0.97, 0.99]
Wright 2007
71
7
12
248 0.86 [0.76, 0.92] 0.97 [0.94, 0.99]
TP = true positive; TN – true negative; FP = false positive; FN = false negative
28
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
TP
FP
FN
TN
Gurol 2010
51
12
28
362
0.65 [0.53, 0.75]
0.97 [0.94, 0.98]
Nerbrand 2002
61
60
21
394
0.74 [0.64, 0.83]
0.87 [0.83, 0.90]
Rogo 2011
60
6
5
157
0.92 [0.83, 0.97]
0.96 [0.92, 0.99]
Sarikaya 2010
15
8
7
70
0.68 [0.45, 0.86]
0.90 [0.81, 0.95]
395
36
158
1259
0.71 [0.67, 0.75]
0.97 [0.96, 0.98]
66
12
17
243
0.80 [0.69, 0.88]
0.95 [0.92, 0.98]
Tanz 2009
Wright 2007
Sensitivity
Specificity
Sensitivity
Specificity
0 0.2 0.4 0.6 0.8 1
0 0.2 0.4 0.6 0.8 1
Sensitivity
Specificity
0 0.2 0.4 0.6 0.8 1
0 0.2 0.4 0.6 0.8 1
Sensitivity
Specificity
0 0.2 0.4 0.6 0.8 1
0 0.2 0.4 0.6 0.8 1
Sensitivity
Specificity
0 0.2 0.4 0.6 0.8 1
0 0.2 0.4 0.6 0.8 1
Sensitivity
Specificity
0 0.2 0.4 0.6 0.8 1
0 0.2 0.4 0.6 0.8 1
Sensitivity
Specificity
0 0.2 0.4 0.6 0.8 1
0 0.2 0.4 0.6 0.8 1
Sensitivity
Specificity
0 0.2 0.4 0.6 0.8 1
0 0.2 0.4 0.6 0.8 1
Sensitivity
Specificity
0 0.2 0.4 0.6 0.8 1
0 0.2 0.4 0.6 0.8 1
Sensitivity
Specificity
0 0.2 0.4 0.6 0.8 1
0 0.2 0.4 0.6 0.8 1
Acceava
Study
TP
FP
FN
TN
Atlas 2005
38
0
3
112
0.93 [0.80, 0.98]
Sensitivity
1.00 [0.97, 1.00]
Specificity
Rogo 2011
63
2
1
162
0.98 [0.92, 1.00]
0.99 [0.96, 1.00]
OSOM
Study
TP
FP
FN
TN
Sensitivity
Specificity
Gieseker 2002
84
18
3
197
0.97 [0.90, 0.99]
0.92 [0.87, 0.95]
Gieseker 2003
184
26
26
651
0.88 [0.82, 0.92]
0.96 [0.94, 0.97]
Llor 2009
52
14
3
153
0.95 [0.85, 0.99]
0.92 [0.86, 0.95]
Rogo 2011
65
1
1
161
0.98 [0.92, 1.00]
0.99 [0.97, 1.00]
Wright 2007
71
7
12
248
0.86 [0.76, 0.92]
0.97 [0.94, 0.99]
Detector Strep A Direct Kit
Study
TP
FP
FN
TN
Abu Sabbah 2006
59
25
8
263
Sensitivity
0.88 [0.78, 0.95]
Specificity
0.91 [0.87, 0.94]
Abbott Test Pack
Study
TP
FP
FN
TN
Alesna 2000
14
5
1
89
0.93 [0.68, 1.00]
0.95 [0.88, 0.98]
Humair 2006
128
11
12
221
0.91 [0.86, 0.95]
0.95 [0.92, 0.98]
64
13
16
164
0.80 [0.70, 0.88]
0.93 [0.88, 0.96]
Lindbaek 2004
106
27
4
169
0.96 [0.91, 0.99]
0.86 [0.81, 0.91]
Nerbrand 2002
107
19
22
466
0.83 [0.75, 0.89]
0.96 [0.94, 0.98]
Rosenberg 2002
24
1
8
93
0.75 [0.57, 0.89]
0.99 [0.94, 1.00]
Santos 2003
11
2
4
32
0.73 [0.45, 0.92]
0.94 [0.80, 0.99]
165
19
4
44
0.98 [0.94, 0.99]
0.70 [0.57, 0.81]
Kurtz 2000
Sheeler 2002
Sensitivity
Specificity
Strep A Rapid Test device
Study
Forward 2006
TP
FP
FN
TN
Sensitivity
Specificity
123
48
37
610
0.77 [0.70, 0.83]
0.93 [0.90, 0.95]
SD Bioline Strep A RAT
Study
Kim 2009
TP
FP
187
8
FN TN
8
90
Sensitivity
Specificity
0.96 [0.92, 0.98]
0.92 [0.85, 0.96]
Link 2 Strep A Rapid Test
Study
Maltezou 2008
TP
FP
FN
TN
Sensitivity
Specificity
121
21
25
284
0.83 [0.76, 0.89]
0.93 [0.90, 0.96]
Accustrip
Study
TP
FP
FN
TN
Wong 2002
10
9
9
486
Sensitivity
0.53 [0.29, 0.76]
Specificity
0.98 [0.97, 0.99]
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*
Sensitivity
1
sROC Curve
Symmetric sROC
AUC = 0.9672
SE(AUC) = 0.0058
Q* = 0.9153
SE(Q*) = 0.0090
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0
0.2
0.4
0.6
0.8
1
1-specificity
*Red circles indicate children, yellow circles indicate adults, green circles indicate studies that included all
age groups.
31
Table 2.2 Summary measures for children and adults
Total
children
Total
adults
Total
mixed
population
(adults and
children)
Total
Number of
participants
(number of
studies)
n=5444 (11
studies)
n=1153 (5
studies)
n=1517 (5
studies)
Pooled
sensitivity
(95%CI)
Heterogeneity
2
(I )
Pooled
specificity
(95%CI)
Heterogeneity
2
(I )
81.1 (79.1, 83.0)
91.4%
95.4 (94.7, 96.0)
73.0%
92.1 (88.9, 94.7)
72.4%
92.4 (90.3, 94.1)
86.8%
86.4 (82.2, 90.0)
92.1%
92.2 (90.5, 93.6)
95.4%
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
QuickVue
Acceava
OSOM
Detector
Strep A
Direct
Abbott
Strep A
Rapid test
device
SD Bioline
Link 2
Accustrip
Total
Number of
participants
(number of
studies)
Pooled sensitivity
n=3503 (6
studies)
n=381 (2
studies)
n=1977 (5
studies)
n=355 (1
study)
73.3 (70.3, 76.2)
76.4%
94.9 (94.0, 95.7)
92.7%
96.2 (90.5, 99.0)
55%
99.3 (97.4, 99.9)
52.2%
91.0 (88.2, 93.4)
76.6%
95.5 (94.3, 96.5)
82.2%
88 (78–95)
-
91 (87, 94)
-
n=2065 (8
studies)
n=818 (1
study)
89.7 (87.2, 91.9)
84.3%
92.9 (91.5, 94.2)
88.3%
77 (70–83)
-
93 (90–95)
-
n=293 (1
study)
n=451 (1
study)
n=514 (1
study)
n=8131 (21
studies)
96 (92, 98)
-
92 (85–96)
-
83 (76–89)
-
93 (90–96)
-
53 (29–76)
-
98 (97–99)
-
83.9 (82.3, 85.4)
90.6%
94.4 (93.8, 95.0)
89.0%
(95%CI)
Heterogeneity
(I2)
Pooled
specificity
Heterogeneity
(I2)
(95%CI)
32
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
TP
Al Najjar 2008
68
FP FN
3
TN
Sensitivity
Specificity
Sensitivity
Specificity
0 0.2 0.4 0.6 0.8 1
0 0.2 0.4 0.6 0.8 1
Sensitivity
Specificity
0 0.2 0.4 0.6 0.8 1
0 0.2 0.4 0.6 0.8 1
Sensitivity
Specificity
0 0.2 0.4 0.6 0.8 1
0 0.2 0.4 0.6 0.8 1
3 422 0.96 [0.88, 0.99] 0.99 [0.98, 1.00]
INTEX Strep A test II
Study
TP
Camurdan 2008
427
FP FN
22
TN
Sensitivity
Specificity
49 751 0.90 [0.87, 0.92] 0.97 [0.96, 0.98]
Kodak Surecell
Study
TP
FP FN TN
Alesna 2000
18
16
1
Sensitivity
Specificity
89 0.95 [0.74, 1.00] 0.85 [0.76, 0.91]
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.
33
Figure 2.8 Summary ROC plot for double sandwich immunoassay tests
Sensitivity
1
sROC Curve
Symmetric sROC
AUC = 0.9802
SE(AUC) = 0.0166
Q* = 0.9376
SE(Q*) = 0.0313
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0
0.2
0.4
0.6
0.8
1
1-specificity
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
Diaquick
Number of participants
(number of studies)
Sensitivity (95%CI)
n=496 (1 study in
96 (88, 99)
children)
INTEX Strep
n=1249 (1 study in
90 (87, 92)
A test II
children)
Kodak
n=124 (1 study in mixed
95 (74, 100)
Surecell
population)
Pooled total
n=1869 (3 studies)
90.6 (87.9, 92.9)
TP = true positive; TN – true negative; FP = false positive; FN = false
Specificity (95%CI)
99 (98, 100)
97 (96, 98)
85 (76, 91)
96.9 (95.8, 97.7)
negative
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.
34
Figure 2.9 Summary ROC plot for optical immunoassay tests
Study
TP
FP
31
15
2
33 0.94 [0.80, 0.99] 0.69 [0.54, 0.81]
173
10
24
313 0.88 [0.82, 0.92] 0.97 [0.94, 0.99]
Araujo Filho 2006
Chapin 2002
FN
TN
Sensitivity
Specificity
Ezike 2005
71
0
4
102 0.95 [0.87, 0.99] 1.00 [0.96, 1.00]
Gieseker 2002
65
12
17
208 0.79 [0.69, 0.87] 0.95 [0.91, 0.97]
Rimoin 2010
Sensitivity
Specificity
561 136 149 1626 0.79 [0.76, 0.82] 0.92 [0.91, 0.93]
0 0.2 0.4 0.6 0.8 1 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
Sensitivity
1
sROC Curve
Symmetric sROC
AUC = 0.9462
SE(AUC) = 0.0244
Q* = 0.8854
SE(Q*) = 0.0321
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0
0.2
0.4
0.6
0.8
1
1-specificity
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.
35
Table 2.5 Optical immunoassay tests by adults/children
Total
children
Total
adults
Total
Number of
participants
(number of
studies)
n=3471 (4
studies)
n=81 (1 study)
Pooled
sensitivity
(95%CI)
Heterogeneity
2
(I )
Pooled
specificity
(95%CI)
Heterogeneity
2
(I )
81.8 (79.3, 84.0)
85.1%
93.4 (92.4, 94.4)
88.3%
94 (90, 99)
-
69 (54, 81)
-
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
Cte.
S
<200
prev
children
swab
Coeff.
5.214
-0.073
-0.981
0.322
-0.212
-0.551
Std. Err.
0.4211
0.1382
0.5865
0.4667
0.4350
0.4178
p - value
0.0000
0.6037
0.1069
0.4965
0.6307
0.1994
rdOR
------0.37
1.38
0.81
0.58
[95%CI]
------(0.11; 1.25)
(0.53; 3.61)
(0.33; 1.98)
(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.
36
Table 2.7 Pooled estimates of each test
Pooled sens (95%CI)
83.9% (82.3 to 85.4)
2
I
90.6%
Chromatographic
immunoassay
Double sandwich 90.6% (87.9 to 92.9)
45.0%
immunoassay
Optical
82.1% (95%CI 79.7 to
83.5%
immunoassay
84.4)
2
sens = sensitivity; spec = specificity; I = heterogeneity
2
Pooled spec (95%CI)
94.4% (93.8 to 95.0)
I
89.0%
96.9% (95.8 to 97.7)
94.9%
93.0% (95%CI 91.9 to
93.9)
92.2%
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
37
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%.
38
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
True negative
66
69
87
False positive
3
6
5
False negative
5
4
1
Benefit from no delay in
treatment
Benefit from avoiding
unnecessary antibiotics
Detriment from
unnecessary antibiotics
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
39
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.
40
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.
41
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
42
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.
43
Table 3.1 Type of antibiotic – Bacteriologic success/eradication
Trial and
setting
Participants
Treatment 1
SYSTEMATIC REVIEWS
Pichichero
Children and
Oral
and Casey 72
adults –
cephalosporins
separate
(doses not
Setting not
analyses
reported) for:
defined –
1. four days
studies from
Also stratified
2. five days
USA and
according to
3. 10 days
Europe
w hether USA
trials or
European trials
RANDOMISED CONTROLLED TRIALS
Pichichero et
Children <12
Oral amoxicillin
al 75
years
sprinkle (475 –
775 mg once
Multicentre
daily for seven
days)
Rimoin et al76
Children 2 – 12
years
Low resource
setting in
Croatia and
Egypt
Mahakit et al74
26 centres in
Asia and
three in
Venezuela
Adolescents and
adults, aged 12
to 60 years
Oral amoxicillin
suspension (750
mg once daily)
Oral clindamycin
(300 mg BID for
10 days)
Treatment 2
Results
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
Oral penicillin
suspension (maximum
dose of 250 mg four
times a day for 10
days)
Penicillin injection
(600,000 to 1.2 million
units, according to
body w eight
Oral
amoxicillin/clavulanic
acid 1g (875 mg
amoxicillin/125 mg
clavulanic acid BID 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
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
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 significant; ITT = intention to treat; Rx = treatment/therapy; BID =
tw ice daily; MD = mean difference; PP analysis = per protocol analysis
44
Table 3.2 Type of antibiotic – Bacteriologic failure
Trial and
setting
Participants
Treatment 1
Pichichero et
Children <12
Oral amoxicillin
al 75
years
sprinkle (475 to
775 mg once
Multicentre
daily for seven
days)
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)
Treatment 2
Results
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
Oral penicillin V (250
to 500 mg BID for 10
days)
Days 38 to 45:
Amoxicillin: 43.6%
Penicillin: 40.3%
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
45
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.
46
Table 3.3 Type of antibiotic – Clinical success rates
Trial and
setting
Participants
SYSTEMATIC REVIEWS
Van Driel et
Children and
al71
adults –
separate
Mostly high
analyses
resource
countries
Treatment 1
Treatment 2
Results
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)
Pichichero
and Casey 72
Setting not
defined –
studies from
USA and
Europe
Children and
adults –
separate
analyses
Also stratified
according to
w hether USA
trials or
European trials
Oral
cephalosporins
(doses not
reported) for:
1. four days
2. five days
3. 10 days
Lennon et al
Children 5 to 12
Oral amoxicillin
73
years
(750 to 1500 mg
QD for 10 days)
Sore throat
clinic at
primary
school in NZ
Mahakit et al
74
Adolescents and
adults, aged 12
to 60 years
26 centres in
Asia and
three in
Venezuela
Pichichero et
al 75
Children <12
years
Oral clindamycin
(300 mg BID for
10 days)
Oral penicillin for 10
days
(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)
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)
days)
Days 3 to 6:
Figures not reported.
Days 12 to 16:
Figures not reported
Oral
acid 1 g (875 mg
amoxicillin/125 mg
10 days)
Days 26 to 36:
Day 12:
Clindamycin: 92.6%
P<0.003
3 months:
Clindamycin: 95.4%
NS
Days 14 to 18:
Amoxicillin: 86.1%
Penicillin: 91.9%
Rx difference: 95%CI -11.6 to -0.4%
Oral amoxicillin
Oral penicillin
sprinkle (475 to
suspension (maximum
775 mg once
dose of 250 mg four
Multicentre
daily for seven
times a day for 10
days)
days)
OR = odds ratio; CI = confidence interval; NS = not significant; ITT = intention to treat; Rx = treatment/therapy; BID =
tw ice daily; QD = once a day
47
Bacteriological relapse
Relapse was measured in two studies, one systematic review of good quality 71 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
Participants
SYSTEMATIC REVIEW
Van Driel et
Children and
al71
adults –
subgroup
Mostly high
analyses
resource
countries
Treatment 1
Treatment 2
Results
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
Children 5 to 12
Oral amoxicillin
years
(750 to 1500 mg
Sore throat
QD for 10 days)
clinic at
primary
school in NZ
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 significant; NNTB = number needed to benefit; Rx =
treatment/therapy; BID = tw ice daily; QD = once a day
48
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
Participants
Treatment 1
Rimoin et al76
Children 2 to 12
Oral amoxicillin
years
suspension
Low resource
(750 mg once
setting in
daily)
Croatia and
Egypt
Treatment 2
Results
(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
49
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
Participants
SYSTEMATIC REVIEWS
Van Driel et al Children and
71
adults –
separate
Mostly high
analyses
resource
countries
Treatment 1
Treatment 2
Results
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 Children 2 to 12
Oral amoxicillin
years
suspension
Low resource
(750 mg once
setting in
daily)
Croatia and
Egypt
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)
(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.
Oral
acid 1 g (875 mg
amoxicillin/125 mg
10 days)
≥1 adverse event:
Clindamycin: 13.8%
NS
Also NS for specific 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
50
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
51
Review findings
Bacteriological success (microbial eradication)/failure
One poor quality systematic review 77 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.
52
Table 3.7 Antibiotic dose – Bacteriological success
Trial and
setting
Participants
SYSTEMATIC REVIEWS
Casey and
Children and
Pichichero 77
adults –
separate
Setting not
analyses
specified –
trials
undertaken in
the USA and
Europe
Treatment 1
Treatment 2
Results
Oral
azithromycin (3
to 5 days)
administered at
dosages of
30 mg/kg and
60 mg/kg
Comparator antibiotics
(10 days) – dosage
not specified (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
Adolescents and Oral
adults
azithromycin
Multicentre –
(single dose 2 g)
outpatients
extended
release (AZ-ER)
Rimoin et al76
Children 2 to 12
years
Low resource
setting in
Croatia and
Egypt
Pichichero et
al75
Children <12
years
Multicentre
Oral amoxicillin
suspension
(750 mg once
daily)
Oral amoxicillin
sprinkle (475 to
775 mg once
daily for seven
days)
Oral azithromycin
(500 mg/day for
three days) immediate
release (AZ-IR)
(600,000 to 1.2 million
units, according to
body w eight
Oral penicillin
suspension (maximum
dose of 250 mg four
times a day for 10
days)
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
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
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 significant; 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
Participants
Treatment 1
Clegg et al78
Children and
Oral amoxicillin
adolescents,
(750 to1000 mg,
Single
aged 3 to 18
once daily)
paediatric
years
clinic in USA
Treatment 2
Results
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)
53
Trial and
setting
Participants
Treatment 1
Treatment 2
Results
Lennon et al73
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%)
Sore throat
clinic at
primary
school in NZ
Days 12 to 16:
Amoxicillin: 12.7%
Penicillin: 11.9%
Rx difference: (upper 95% confidence limit 6.5%)
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 26 to 36:
Amoxicillin: 10.7%
Penicillin: 11.3%
8.5%)
Days 14 to 18:
Amoxicillin: 34.7%
Penicillin: 32%
Rx difference not reported.
Amoxicillin: 43.6%
Penicillin: 40.3%
CI = confidence interval; NS = not significant; 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 review 77 and three RCTs , were identified which assessed
clinical success (one of good quality79 and two of average quality73, 75). Clinical success
54
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
Participants
setting
SYSTEMATIC REVIEW
Casey and
Children and
Pichichero 77
adults –
separate
Setting not
analyses
specified –
trials
undertaken in
the USA and
Europe
Treatment 1
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
Jorgensen79
adults, aged ≥13 azithromycin
Multicentre –
years
(single dose 2 g)
outpatients
extended
release (AZ-ER)
Treatment 2
Results
Comparator antibiotics
(10 days) – dosage
not specified (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
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%.
55
Trial and
setting
Lennon et al73
Participants
Treatment 1
Treatment 2
Results
Children 5 to 12
years
Oral amoxicillin
(750 to 1500 mg
QD for 10 days)
days)
Days 3 to 6:
Sore throat
clinic at
primary
school in NZ
Pichichero et
al 75
Days 12 to 16:
Children <12
years
Multicentre
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 26 to 36:
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 significant; 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.
56
Table 3.10 Antibiotic dose – Bacteriological relapse
Trial and
setting
Participants
Treatment 1
Clegg et al78
Children and
Oral amoxicillin
adolescents,
(750 to 1000
Single
aged 3 to 18
mg, once daily)
paediatric
years
clinic in USA
Lennon et al73
Children 5 to 12
Oral amoxicillin
years
(750 to 1500mg
Sore throat
QD for 10 days)
clinic at
primary
school in NZ
Treatment 2
Results
Visit 3 (28 to 35 days):
Rx difference -4.37 (90% CI -7.4 to -1.3)
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
Participants
Treatment 1
Clegg et al78
Children and
Oral amoxicillin
adolescents,
(750 to1000 mg,
Single
aged 3 to 18
once daily)
paediatric
years
clinic in USA
Treatment 2
Results
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.
57
Compliance
Compliance was measured by two good quality RCTs 78, 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
Participants
Treatment 1
Jorgensen79
Adolescents
Oral
and adults,
azithromycin
Multicentre –
aged ≥13
(single dose 2 g)
outpatients
years
extended
release (AZ-ER)
Clegg et al78
Children and
Oral amoxicillin
adolescents,
(750 to 1000
Single
aged 3 to 18
mg, once daily)
paediatric
years
clinic in USA
Rimoin et al76
Children 2 to
Oral amoxicillin
12 years
suspension (750
Low resource
mg once daily)
setting in
Croatia and
Egypt
Rx = treatment/therapy
Treatment 2
Results
Oral azithromycin
(500 mg/day for
three days)
immediate release
(AZ-IR)
Oral amoxicillin
(375 to 500 mg
tw ice daily)
AZ-ER: 100%
AZ-IR: 98%
(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
Visit tw o (14 to 21 days):
Amoxocillin once daily: 92%
Amoxocillin tw ice daily: 93%
Rx difference figures not reported
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.
58
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
Participants
Treatment 1
Jorgensen79
adults, aged ≥13 azithromycin
Multicentre –
years
(single dose 2 g)
outpatients
extended
release (AZ-ER)
Clegg et al78
Children and
Oral amoxicillin
adolescents,
(750 to1000 mg,
Single
aged 3 to 18
once daily)
paediatric
years
clinic in USA
Rimoin et al76
Children 2 to 12
Oral amoxicillin
years
suspension (750
Low resource
mg once daily)
setting in
Croatia and
Egypt
Rx = treatment/therapy; IM = intramuscular
Treatment 2
Results
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%
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)
(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)
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.
59
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 twicedaily 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
60
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 metaanalysis 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 (shortcourse) 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
61
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 intramuscular 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 metaanalysis 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 metaanalysis 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
62
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, shortcourse (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 shortcourse (≤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
63
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-totreat/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 shortcourse 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.
64
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).
65
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 RCTs 85-88 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.
66
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 RCTs 85, 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-
67
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.
68
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.
69
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 adults 97 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
Enoz 104 recruited children attending day care centres.
70
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
SYSTEMATIC REVIEW
Shaikh et
Spain, Korea, Not
al90
Iran, Turkey,
stated
United
States,
Canada,
Sw eden,
Australia,
Kuw ait and
India
EPIDEMIOLOGICAL STUDIES
Erdem et
Oahu, Haw aii 2003
al96
Num ber of
participants
Source of population
Age range
Asym ptomatic
GAS infection
rate
18 studies
Clinics, schools and emergency
departments
<5 years
Overall
3.8%
12%
955
13 schools representing a cross
section of ethnicity and
socioeconomic groups
5 to 15 years
3.4%
11 schools from Oahu, in Haw aii
and 2 schools from Pago Pago in
American Samoa
Schools (number not stated) in
Pokhara, Nepal
5 to 15 years
13%
5 to 8 years
9 to 12 years
13 to 16 years
Overall
5 to 8 years
9 to 12 years
13 to 15 years
Overall
5 to 9 years
10 to 14 years
Overall
>0 to 3 years
4 to 6 years
7 to 9 years
10 to 12 years
Overall
5 to 15 years
11.8%
7.8%
8.2%
9.2%
10.9%
12%
9.6%
10.9%
7.8%
4.1%
6.0%
3.8%
NA
5.6%
8%
4.5%
1.3%
5 to 17 years
8.4%
Pago Pago,
American
Samoa
Nepal
2006
106
2008
487
Dumre et
al95
Nepal
2007
350
Four schools at different
locations in the Kathmandu
valley
Steer et
al107
Fiji
2006
665
Four schools in Fiji representing
urban and rural populations
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.
Kumar et
al100
Lloyd et
al101
India
2000 to
2002
2004
3591
Schools in 25 to 257 villages in
Haryana District, Northern India
Schools in five locations in
Chennai, India to try and
represent different residential
areas
Rijal et al103
India
1173
71
Reference
Country
Year data
relates to
EPIDEMIOLOGICAL STUDIES
Bramhachari
India
2006 to
et al92
2008
Kohler et al99
Micronesia 2009
Kim and Lee98
Korea
Chang et al93
China
Sevinc and
Enoz 104
Yildirim et
al106
Gϋçlϋ et al97
Turkey
Abdissa et
al91
Ethiopia
Turkey
Turkey
Num ber of
participants
Source of population
Age range
Asym ptomatic
GAS infection
rate
1504
Seven municipal schools in
Mumbai, India
Children presenting to
community centres for screening.
Elementary schools (number not
stated) in Seoul, Korea
School children in Beijing and
Chonqing in China. No other
details
13 Day care centres
5 to 15 years
1.5%
5 to 15 years
12.4%
7 to 12 years
22.9%
Not stated
2.3%
1 to 7 years
2.4%
A primary school in Dϋzce,
Turkey
Medical students attending
Ducze University in Turkey
6 to 14 years
6%
Adults (age
range not
specified)
6 to 14 years
5.6%
667
Not
stated
2007 to
2008
266
2003 to
2005
Not
stated
Not
stated
1893
2004 to
2005
937
4087
484
179
Seven schools in three cities in
Ethiopia.
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
72
Primary studies
Ten studies reported on asymptomatic GAS rates 91, 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.
73
Table 4.2 Relationship between GAS throat infection rate and rheumatic fever by country
Country
Oahu,
Haw aii
Reference
Year
data
relates
to
Age
range
GAS throat infection
Erdem et al96 2003
GAS throat
infection rate
3.4%
2006
Reference
Year data
relates to
Age range
Rheumatic
fever rate
Rheum atic fever
Jackson et
2003 and
al108
2006
5 to 15
years
Pacific
Islander
9.5 to 12.4/
100,000
13%
American
Samoa
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
2007
>0 to 12
years
4.5%
Jackson et
al108
2003 and
2006
5 to 15
years
54/100,000
2000 to
2002
5 to 15
years
1.3%
Tibazarwa et
al18
1988 to 1991
Kumar et
al100
51/100,000
5 to 18
years
Lloyd et al101
2004
Bramhachari
et al92
8.4%
2006 to
2008
5 to 17
years
1.5%
Fiji
Steer et al107
2006
5 to 15
years
5 to 14
years
6.0%
Parks et
al102
Cuboni et
al109
2003 to 2008
4 to 20
years
24.9/ 100,000
1996 to 2000
2.3/100,000
All ages
2005 to 2007
Steer et al107
9.8/100,000
5 to 14
years
15.2/100,000
Nepal
Rijal et al103
2008
5 to 16
years
9.2%
Limbu and
Maskey 110
Not stated
Abdissa et
al91
2004 to 2005
Dumre et al95
2007
10.9%
5 to 15
years
School
children
(ages not
specified)
1.2 to 1.3/
1000
5 to 15
years
Ethiopia
Abdissa et
al91
2004 to
2005
6 to 14
years
8.7%
Children
(age not
specified)
4.6 to 7.1/
1000
74
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 mid1980s 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
75
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
76
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.
77
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
78
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.
79
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
80
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 retreated 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.
81
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 sixweek 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 casecontrol 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 commonsource 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,
82
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.
83
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
84
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
Anne Lethaby
Assistant Research Manager and lead researcher
Researcher
Catherine Coop
Julie Brown
Researcher
Senior Researcher
Marita Broadstock
Margaret Paterson
Senior Researcher
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.
85
Research Question
PICO
Type of evidence
review
Chapter 1 – Introduction and context
1. When do sore throats
N/A
occur in the natural course
of Streptococcal
Pharyngitis?
Chapter 2 - Rapid Antigen Diagnostic Tests
2. In children and adults
P: Children and Adults with sore throats
with sore throats, what is
Index test: RADT
the accuracy of the Rapid
Ref standard: culture
Antigen Diagnostic Test
Outcomes: Diagnostic accuracy, adverse
(RADT) compared to
events
culture to confirm GAS?
Subgroups: low and high risk kids
P: Children and Adults with resolved sore
presenting with a resolved
throats
sore what is the accuracy
I (index test): RADT
of the Rapid Antigen
C (ref standard): culture
Diagnostic Test (RADT)
Outcomes: Diagnostic accuracy, adverse
compared to culture to
events
confirm GAS?
P: Children and adults with sore throats
presenting with a current
I (index test): immediate RADT/culture
sore throat is immediate
C (ref standard): delayed RADT/culture
RADT and/or Culture more O: Diagnostic accuracy, adverse events
effective than delayed in
ensuring diagnostic
accuracy?
Chapter 3 – Antibiotic Treatment
5. What is the antibiotic of
P: Children and adults with confirmed
choice for treatment of
GAS infection
children and adults
I: Antibiotics
diagnosed GAS, when
C: No treatment, placebo, other antibiotic
should it be administered,
O: Clinical and bacteriological resolution,
for how long and in what
recurrence, re-infection, dose, duration,
dose to prevent
compliance, resistance
progression to rheumatic
fever, reduce likelihood of
antibiotic resistance and
ensure compliance?
Literature review. No
date restriction.
Systematic review of
diagnostic studies.
No date restriction.
diagnostic studies.
diagnostic studies.
intervention studies.
Date restriction: 2005
to May 2011.
86
Research Question
PICO
6. In children presenting
P: Children and adults with sore throats
with a current sore throat is I: Immediate antibiotic treatment
immediate antibiotic
C: Delayed antibiotic treatment
treatment compared with
O: Eliminating GAS infection, progression
delayed antibiotic
to ARF, resistance.
treatment more effective in
eliminating a GAS infection
and preventing progression
to rheumatic fever?
Chapter 4 - Asymptomatic Carriers
7. At what rate does
N/A
asymptomatic GAS occur
in the community?
8. Does asymptomatic
N/A
GAS occur at a higher rate
in communities with higher
rates of rheumatic fever?
9. Is there an association
N/A
between the carriage rate
and rate of rheumatic fever
in communities?
Chapter 5 - Community swabbing
10. What defines an
N/A
outbreak of rheumatic
fever?
11. Where there is an
N/A
outbreak does swabbing of
asymptotic community
members and households
reduce rates of rheumatic
fever?
Type of evidence
review
intervention studies.
Date restriction: 2005
to May 2011.
Literature review.
Literature review.
Literature review.
Literature review.
Literature review.
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.
87
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.
88
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.
3.
study results (size of effect and precision)
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.
89
Table A2.1
Level
NHMRC levels of evidence
Intervention1
Diagnostic accuracy2
Aetiology3
Prognosis
I4
A systematic review of level II
studies
studies
II
A randomised controlled trial
A study of test accuracy with: an
A prospective cohort study
independent, blinded comparison
with a valid reference standard,5
among non-consecutive persons
with a defined clinical presentation 6
III-1
III-2
studies
Screening intervention
studies
studies
A prospective cohort study
A randomised controlled trial
A pseudorandomised controlled
A study of test accuracy with: an
All or none 8
trail (ie, alternate allocation or some independent, blinded comparison
other method)
with a valid reference standard,5
among non-consecutive persons
with a defined clinical presentation 6
All or none 8
A pseudorandomised controlled
trial (ie, alternate allocation or
some other method)
A comparative study with
concurrent controls:
A retrospective cohort study
A comparative study with
7
Non-randomised, experimental
trial 9
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
Non-randomised, experimental
trial
Cohort study
Cohort study
Case-control study
Case-control study
Interrupted time series with a
control group
III-3
Diagnostic case-control study5
A comparative study without
A retrospective cohort study
A case-control study
Historical control study
A comparative study without
Historical control study
10
Two or more single arm study
Two or more single arm study
Interrupted time series without a
parallel control group
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 A cross-sectional study or
persons at different stages of case series
disease
90
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.
91
Appendix 2: Abbreviations and glossary
Abbreviations
AGREE
Appraisal of Guidelines for Research and Evaluation
ARF
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
2
I
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
92
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
93
Glossary
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
94
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