Acute Post-Streptococcal Glomerulonephritis in the

Acute Post-Streptococcal Glomerulonephritis
in the Northern Territory
Catherine Susan Marshall
Treatise submitted in partial fulfilment
of the requirements for the degree of
Master of Public Health
Charles Darwin University
December 2009
[C.O.U. LIBRARY!
NOTE
This treatise is presented in the form of a paper written for publication in Clinical
Infectious Diseases with additional appendices.
The boxed text is additional
information that this of relevance to local practise and is not for submission for
publication.
ABSTRACT
Background
In the past twenty years industrialised countries have reported a decline in the incidence
of acute post-streptococcal glomerulonephritis (APSGN), especially related to skin
infection. The disease remains common however in many developing countries and in
central and tropical northern Australia
Methods
Retrospectively collected data from the Northern Territory APSGN notification database
in Australia was reviewed. Streptococcal isolates from confirmed cases were emm
sequence typed to identify the strains of Streptococcus pyogenes responsible.
Results
From 1991-July 2008 there were 415 confirmed cases and 23 probable cases of APSGN
notified. 414 (94.7%) of these were Aboriginal Australians and 428 (97.7%) were people
living in remote or very remote locations. The overall annual incidence of confirmed
cases was 12.5 per 100,000 person years with an annual incidence in children under the
age of 15 of 41.4 cases per 100,000 persons and an overall rate ratio of cases in
Indigenous Australians to non-Indigenous Australians of 53.6 (95% CI 32.6-94.8). The
annual incidence in Indigenous Australian children younger than 15 years was 94.3
cases per 100,000 persons. The median age of cases was 7 years (range 0-54). Outbreaks
of disease across multiple communities occurred in 1995 (n=68), 2000 (n=55) and 2005
(n=87). Various strains of S .pyogenes were isolated from cases of APSGN including a
number not previously recognised to be nephritogenic. Strain emm55 was responsible
for a widespread outbreak in 2005.
Conclusions
APSGN continues to occur in remote Indigenous communities in Australia at rates
comparable to or higher than those estimated in developing countries. Improvements in
preventative and outbreak control strategies are needed.
ii
ACKNOWLEDGMENTS
The Menzies School of Health Research supported me to do this treatise with a Treatise
Scholarship for which I am grateful. I would also like to acknowledge the many people
that helped me, especially my supervisors. Professor Bart Currie was instrumental in
encouraging me to do this project and has been a wonderful support throughout.
Allen Cheng has also been of great assistance a,nd support. In particular I would like to
thank him for creating the maps that show geographical locations and incidence of cases.
In addition he created the graph demonstrating the number of notifications per fortnight.
From the Northern Territory Centre for Disease Control director Dr Vicki Krause and
public health physician Dr Peter Markey have also been of invaluable assistance. Peter
Markey provided up to date population statistics and advice regarding incidence
calculations.
Rebecca Towers and Leisha Richardson from the Menzies School of Health Research
laboratory also deserve a special mention. Rebecca's detailed knowledge of the
streptococcal database was of considerable help in compiling the database of APSGN
cases and Leisha completed the emm sequence typing of isolates not previously typed.
iii
TABLE OF CONTENTS
Page
Abstract
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Acknowledgments ........................................................................................................... .iii
List of Tables ..................................................................................................................... v
List of Figures .................................................................................................................. vi
Abbreviations .................................................................................................................. vii
PAPER "The Epidemiology of Acute Post-Streptococcal Glomerulonephritis
In the Northern Territory, Australia" ................................................................................. !
Appendix 1: Literature Review ........ ~·.. :........................................................................... 30
Al.l
Historical Perspective ................................................................................. 30
Al.2
Current Epidemiology and Global Burden of APSGN .............................. 33
Al.3
History of APSGN in Northern Territory and Australia ........................... .35
A1.4
Clinical Disease and Definitions ................................................................ 36
Al.5
Prognosis of APSGN .................................................................................. 38
Al.6
Streptococcus Pyogenes and Molecular Epidemiology ........................... .41
Al.7
Pathogenesis of APSGN and Nephritogenic Antigens ............................. 44
Al.8
Future Therapeutics and Vaccine Development ...................................... .47
Al.9
Skin Infection and Scabies in the Northern Territory ............................... .47
Al.lO
Public Health Management of APSGN in the NT .................................... .48
Appendix 2: Additional Methods .............................................................._. ..................... 52
A2.1
Data cleaning and Management ................................................................. 52
A2.2
APSGN Streptococcal Isolate Database ..................................................... 53
Appendix 3: Additional Results ...................................................................................... 54
REFERENCES ................................................................................................................ 68
iv
LIST OF TABLES
Page
Table 1
Demographic Characteristics of Study Population ........................................... 23
Table 2
Incidence Rates of APSGN in the Northern Territory ..................................... 24
Table 3
emmST of APSGN Isolates .............................................................................. 25
Table A 1.1 Reported epidemics of APSGN with more than 100 cases .............................. 31
Table Al.2 Reported epidemics of APSGN with less than 100 cases and
Clusters of cases ................................................................................................................. 32
Table A1.3 Definition of APSGN in the NT .......... ~ ........................................................... .37
Table A1.4 Streptococcal Serotypes previously associated with APSGN ......................... .43
TableA2.1 Cases notified in NT from Communities outside NT ....................................... 52
Table A2.2 Cases notified in an incorrect District .............................................................. 52
Table A3.1 Yearly Notifications and Incidence for all Ages .............................................. 54
Table A3.2 Yearly Notification and Incidence for Ages 0-14 years ................................... 55
Table A3.3 Yearly Notification and Incidence for those Aged 2::: 15 years ......................... 56
Table A3.4 Seasonal Distribution of Cases per District.. .................................................... 57
Table A3.5 Regional Incidence of APSGN within the NT ................................................. 58
Table A3.6 Outbreak and Sporadic Cases of APSGN in the Top End ................................ 59
Table A3.7 Outbreak and Sporadic Cases of APSGN in Central Australia ........................ 60
Table A3.8 Comparison of Outbreak versus Sporadic Cases .............................................. 60
Table A3.9 List of Individual Community Outbreaks ......................................................... 61
v
LIST OF FIGURES
Page
Figure 1
Age Distribution of Cases of APSGN ....................................................... 26
Figure 2
Local Incidence of APSGN in Children aged 0-14 years ............................ 27
Figure 3
Annual incidence of APSGN in the Northern Territory .............................. 28
Figure 4
Notifications per Month in the Top End and Central Australian regions .... 29
Figure Al.l
Pathogenesis of APSGN .............................................................................. 46
Figure A3.1
Notifications per Year and District. ............................................................. 62
Figure A3.2
Regional Incidence of APSGN .................................................................... 63
Figure A3.3
Notifications in the Top End as Outbreak of Sporadic ................................ 64
Figure A3.4
Community Locations of Cases in Outbreak Year (2005) ........................... 65
Figure A3.5
Community Locations of Cases in Non-Oubreak Year (2004) ................... 66
Figure A3.6
Notifications per Fortnight ........................................................................... 67
vi
ABBREVIATIONS
ABS
Australian Bureau of Statistics
APSGN
Acute post-streptococcal glomerulonephritis
ARF
Acute Rheumatic Fever
BPG
Benzathine Penicillin G
emmST
emm Sequence Type
GAS
Group A Streptococcus (Streptococcus Pyogenes)
MSHR
Menzies School of Health Research
NT
Northern Territory
NT CDC
Northern Territory Centre for Disease Control
SPEB
Streptococcal pyrogenic exotoxin B
zSPEB
zymogen precursor of streptococcal pyrogenic exotoxin B
vii
PAPER
Acute Post-Streptococcal Glomerulonephritis in the Northern Territory
of Australia; a review of 16 years data and comparison with the
literature
INTRODUCTION
The epidemiology of acute post-streptococcal glomerulonephritis (APSGN) has changed
substantially over the past 50 years. Prior to 1980's APGSN was relatively common
worldwide with multiple large and recurrent epidemics reported, especially in the United
States of America in the Native American population, and in Central and South America.
[1] Many of these epidemics were thought to be related to streptococcal skin rather than
throat infection, often associated with preceding scabies. [2-4]
Over the past 20 years there has been a substantial decline in the reported incidence of
APSGN, especially in industrialised countries.[!] A falling incidence in Florida was
reported to reflect a decrease in the incidence of APSGN associated with impetigo,
whereas the incidence of APSGN due to pharyngitis has remained relatively unchanged.
[5] In Chile an epidemic of APSGN associated with scabies and skin infection occurred in
the mid 1980s. However during the 1990's there was a steady decline in the number of
report cases. [4]. Similarly reductions in disease have also been reported in China,
Singapore and Europe.[6-8]
Despite this declining incidence of APSGN in many developed countries, there is still a
significant global burden of disease. Carapetis et al[9] estimated that there are more than
470,000 cases of APSGN worldwide annually with approximately 5000 deaths. 97% of
these cases occur in less developed countries. It is inevitable that APSGN is underreported
in many developing countries and these figures may be an underestimate of the true burden
of this condition.
As in most industrialised countries the southern temperate regions of Australia have
sporadic cases of APSGN, mostly related to pharyngitis.[ tO]. In contrast to other industrial
nations and southern Australia, in tropical northern Australia APSGN is more common and
outbreaks have previously been reported in Aboriginal communities.[11, 12] In the
Northern Territory (NT), which includes both an arid central Australian region and a
tropical northern region, sporadic cases occur yearly but larger outbreaks in the northern
region are documented by public health authorities around every 5-7 years.[l3] The
majority of these cases are related to pyoderma, often with underlying scabies.[14] The
overall incidence and patterns of disease in this population have not been characterized.
Currently in the Northern Territory APSGN is a notifiable condition and notifications
trigger a public health response based on local guidelines. [15] Following sporadic cases it
is recommended that household contacts be screened for signs and symptoms of APSGN
and evidence of skin sores. All contacts between the ages of 3-15 are given single dose IM
benzathine penicillin, as are contacts of other ages if they have skin sores.
A more widespread public health response occurs following a community outbreak. This is
defined as 2 unrelated clinical cases within a week or 3 unrelated clinical cases within a
month in one community. [15]. This prompts a community response with screening of all
children for edema, skin sores and scabies. Children with skin sores are treated with IM
benzathine penicillin, those with scabies are given topical permethrin 5% and children with
edema are further assessed for APSGN.
There is limited evidence regarding the best way to manage an outbreak of APSGN. The
aim of contact tracing, community screening and penicillin treatment is to reduce
transmission of the presumptive nephritogenic Streptococcus pyogenes (Group A
Streptococcus, GAS). Intramuscular benzathine penicillin has been shown to be effective
at clearing streptococcal carriage[16] and can reduce transmission within a community.
[17, 18]
There have been no randomized controlled trials assessing effectiveness of
interventions with penicillin therapy in outbreaks of APSGN. However, an observational
study in 1999 [19] supported to the use of community interventions with prophylactic
penicillin administration.
2
The ability to perform genotyping on the emm gene, which encodes the variable aminoterminus of the GAS M-protein, has allowed characterization of GAS. This is particularly
relevant in northern Australia and other parts of the world where many strains responsible
for disease were non-typeable by the older serotyping methods. [20] M serotypes and emm
sequence types (emmST) have been shown to correlate and are generally interchangeable.
It has long been recognized that certain GAS M types are associated with nephritis and
these are generally different from the strains that cause acute rheumatic fever.[21]. Some
GAS strains such as Ml, M4, M12 have traditionally been associated with APSGN
following pharyngitis, whereas other strains such as M2,M49,M55 and M57 are associated
with skin infection.[22]
Previous studies of the molecular epidemiology of GAS in Aboriginal communities of the
NT have shown that there is a wide diversity of emmST present. GAS carriage is dynamic
with high acquisition rates within households.[23-25]. Nevertheless although there is wide
diversity of stains of GAS seen in indigenous communities there may be only a limited
number of strains responsible for APSGN in the NT.
Here we review the epidemiology of APSGN within the NT over a 16 year period with the
aim of determining the current incidence, patterns of disease and diversity of strains of
GAS responsible for APSGN in the region. We document that despite declining rates of
APSGN in other industrialized countries, rates remain very high for children living in
remote Indigenous Australian communities.
There is currently a paucity of recent literature to support current management guidelines
for APSGN. It is hoped that by improving our understanding of the local epidemiology of
this condition we will be able to optimise our current guidelines, with development of
improved strategies to manage APSGN in the NT and identify further research that is
needed.
3
METHODS
Setting
The NT is sparsely populated with around 215,000 people. It occupies 15% of the land
mass of Australia but only 1% of the population. The northern third, referred to as the
''Top End" has a tropical climate with two distinct seasons being the monsoonal "wet" and
the "dry" season. The southern two-thirds are referred to as 'Central Australia' with a
much drier climate year round.
There are around 65,000 Indigenous Australians in the NT, representing around 30% of the
population. In comparison, Indigenous Australians make up only 2.4% of the total
Australian population. [26] In the NT, 80% of Indigenous Australians live in remote or
very remote locations. Indigenous Australians have poorer health outcomes than nonIndigenous Australians with a life expectancy that is estimated to be almost 20 years less
than non-Indigenous Australians. [26]
The NT is divided into 5 administrative districts: Darwin, Katherine, East Arnhem, Barkly
and Alice Springs. Each region is serviced by one hospital with Darwin and Alice Springs
acting as referral centres. In remote Aboriginal communities medical services are provided
by community clinics staffed by nurses, Aboriginal health workers and in larger clinics
resident medical practitioners. Smaller clinics may have only nurses and/or Aboriginal
health workers permanently, with nurses or medical practitioners that visit for both acute
care and public health activities.
Epidemiological Data
Epidemiological data was obtained from the Northern Territory Centre for Disease Control
(CDC) notification database. APSGN is a notifiable condition in the Northern Territory
and information is currently held in a database established in 1991. The case definition for
reported cases includes a clinically compatible illness with 2 of hematuria, hypertension
and edema (facial or peripheral). In addition laboratory evidence is required that includes
hematuria (greater than 10 red blood cells/I-LL), evidence of streptococcal infection with
either positive streptococcal serology (Anti-streptolysin 0 >250 IU/ml, anti-DNAse B
>200 IU/ml)or positive culture from throat or skin and a reduced C3 level (normal 0.861.84 gil). All confirmed cases included in the study met both the clinical and laboratory
4
criteria. Since 2005 sub-clinical cases detected during screening that presented only with
laboratory evidence have also been included in the database under a diagnosis of probable
APGSN. The database includes record of the patient's date of birth, community and
district, Indigenous status and date of diagnosis. Appendix 2.1 summarizes additional
issues of data cleaning and management.
Patients were defined as living in a remote or very remote location if their place of
residence had a score of 5.92 or more using the Accessibility/Remoteness index of
Australia(ARIA)[27]. Cases were categorized as either 'outbreak' or sporadic using a
modified definition from the NT CDC guidelines[l5]. An outbreak was defined as 2 cases
in one week or 3 cases in 1 month within one community. The available data did not
distinguish between related and unrelated cases, thus requiring in a minor variation from
the NT guidelines which specify that the cases are unrelated. Any other cases within the
community occurring within one month of an outbreak case were also defined as being
part of that outbreak.
Source of Streptococcal Isolates and Laboratory Methods
All laboratory work was completed by the staff at the Menzies School of Health Research
(MSHR) Streptococcal research laboratory in Darwin. The strepto~occal isolates used in
this study were collected between 1990-2008 from community screening projects run
through MSHR as well as passive surveillance of the Royal Darwin Hospital Pathology
Collection or the local private pathology laboratory that services many of the remote
communities (Western Diagnostic Pathology). Isolates were included in this study if they
were collected from a patient confirmed to have APSGN using the above diagnostic
criteria and confirmed using the CDC notification database and hospital patient records. If
a case had not been notified but clinical information and pathology results were available
to confirm a diagnosis, that case was included. Appendix 2.2 contains further information
pertaining to data collection, cross-checking and development of the streptococcal APSGN
database.
In addition to bacterial isolates from confirmed cases, 16 isolates were available from
contacts and community screening done in one community during the 2005 outbreak.
These were also emm sequence typed to gain further insight into the streptococcal strains
responsible for this large widespread outbreak.
5
emm sequence typing was performed on streptococcal isolates based on methods described
by the Centre for Disease Control and Prevention[28] with minor modifications that have
been described previously [23, 24]
Analytical methods
Incidences were expressed as rates per 100,000 person-years from years 1992-2007.
Population data was obtained from Northern Territory Department of Health Gains
planning and Australian Bureau of Statistics.[29] The sum of the yearly estimated
population was used as the denominator. Only confirmed cases were included in incidence
calculations given that prior to 2005 probable cases were not included in the notification
database. Notifications from 1991 were not included in incidence calculations because the
notification database was not operational for the whole year and was incomplete. 95% CI
were obtained using STATA 9. Proportions were compared using a two-sample test of
proportions. A p-value of <0.05 was used as the level of significance.
Ethics
Ethics approval was obtained from the Human Research Ethics Committee of the NT
Department of Health and Families and the Menzies School of Health Research. This
included approval from the Aboriginal Ethics Sub-Committee. Given data was collected
retrospectively and analysed in a non-identifiable form and therefore consent from
individuals was not required.
RESULTS
Epidemiology
From 1991 until July 2008 there were 415 confirmed cases and 23 probable cases of
APSGN reported. 13 notifications were made in Alice Springs District regarding people
living in communities outside the Northern Territory. (See appendix 2.1) These cases were
excluded from incidence data but included in other analysis. The demographic details of
the study population are displayed in table 1. The majority of cases occurred Indigenous
Australian children who lived in remote locations. Figure 1 shows age distribution of
cases with the 386 (88.1 %) of cases occurring in children younger than 15 years and an
overall age range of 0-54 years (median 7 years). Figure 2 shows the local incidence of
6
cases in children aged 0-14 years and geographical distribution of cases with in the NT
with a predominance seen in the Top End.
The incidence rates for different populations within the NT are shown in table 2. The
highest annual incidence of 94.3 cases per 100,000 persons (95% CI 84.2-105.3) occurred
in indigenous children under the age of 15. The rate ratio of cases in Indigenous
Australians to non-Indigenous Australians is 53.6 (95% CI 32.6-94.8).
The incidence of APSGN varied from year-to-year within the NT. This reflects the
occurrence of yearly sporadic cases and small clusters, with larger more widespread
outbreaks occurring approximately 5 yearly (see Figure 3).
These outbreaks
predominantly affect those under the age of 15. During the study period there were peaks
of notifications in 1995 (n= 68), 2000 (n= 55) and 2005 (n=102). In 2005 this figure
included 87 confirmed and 15 probable cases. The specific annual incidences for each
group are shown in tables A3.1, A3.2, A3.3 (Appendix 3).
Seasonal Distribution
The Top End of the NT has a tropical climate with two seasons. The "dry" season runs
from April to September when the weather is cooler, less humid and there is little rain. The
monsoonal "wet" season runs from October to April and during this period it is hot, humid
and rainy. In Central Australia there is a desert climate with occasional rain throughout the
year. During the period of April-September the weather is cooler than the months October
to March. In the Top End there was a peak of notifications from April to June in the early
dry season whereas in Central Australia there was no overall significant seasonal change
(see Figure 4). In the Top End 64.7% of cases occurred in the dry and 35.3% in the wet.
(p<0.0001). This seasonal distribution within the Top End may reflect a larger number of
outbreaks occurring at this time. Within Central Australia although there was no overall
significant difference in seasonal distribution, the more northern Barkly district had a
pattern similar to the Top End with 68.8% of cases occurring in the dry season. This result
was significant (p=0.034) but difficult to interpret because the numbers are small with only
16 cases being reported in this district. The difference could be attributed to a cluster of 5
cases occurring in one community in this district in the month of September. The seasonal
distribution of APSGN cases for each district is shown in table A3.4, Appendix 3.
7
Patterns of Disease
Overall across the NT 192 cases (43.8%) occurred as part of 43 community clusters or
outbreaks rather than as sporadic cases. On 4 occasions there were two or three clusters in
the same community within six months that most likely represented the same outbreak.
The outbreaks lasted an average of 21 days (range 1-65). The median number of cases per
cluster was 3 (range 2-12). There were up to 7 outbreaks occurring per year. A complete
list of individual community outbreaks is presented in table A3.9, Appendix 3. In the Top
End cases were more likely to be part of an outbreak with 183 cases( 53.4%, 95% CI 46.563.8) occurring as outbreaks or clusters compared with 9 (9.5% 95%CI 3.6-15.4) within
Central Australian (p-value <0.0001). (see tables A3.6,3.7,3.8 Appendix 3 for Details). In
the Top End 67.8% of cases occurred during the dry season.
Regional Epidemiology
Appendix 3 table A3.5 and figure A3.2 show the regional differences in incidence of
APSGN around the NT. The overall incidence of APSGN in the Top End is 13.2 cases per
100,000 person years compared with 12.2 cases per 100,00 person years in the Central
district (p=0.52). However within individual planning districts the Darwin Rural and East
Amhem regions have a significantly higher incidence of APSGN with rates of 61.2 and
53.4 cases per 100,000 person years respectively. In contrast the incidence in the Darwin
Urban region is 0.6 cases per 100,000 person years. The trend is similar when looking only
at the incidence in Indigenous Children aged 0-14 years. (Figure A3.2, Appendix 3). In
Alice Springs there is also disparity between the urban and rural districts but this is less
pronounced that in the Darwin Region.
Appendix 3, figure 3.3 shows the yearly breakdown of notifications in the Top End
defined as outbreak or sporadic. This graph demonstrates that in outbreak years there is an
increase not only in the number of cases that form part of the outbreak but also in the
number of sporadic cases that occur. This was confirmed by mapping of outbreak and
sporadic cases in both an outbreak year (2005) and a sporadic year (2004).(Figures A3.4,
A3.5 Appendix 3) The map in Figure A3.4 (Appendix 3) shows that cases defined as
sporadic (less than 3 cases in one community) occurred in neighbouring communities to 8
of the 9 communities that had outbreaks (defined as 3 or more cases) in 2005. This map
also shows that there were 32 communities in 2005 that had only 1-2 cases compared with
8
10 communities in the non-outbreak year of 2004 (Fig A3.5 Appendix 3). These cases are
not considered in the current community-based definitions of an outbreak and perhaps the
addition of a more widespread regional definition rather than a purely community-based
definition may be appropriate.
Figure A3.6 (appendix 3) shows the number of notifications over the whole study period
per fortnight. The graph suggests that a cutoff of 4 notifications per fortnight across the NT
would predict each of the large NT-wide outbreaks.
Emm Sequence Types
There were a total of 21 GAS isolates from APSGN cases that could be confirmed either
from the NT CDC notification database or clinical and pathology records. 7 cases from
1991 and 1992 were confirmed by clinical records but had not been notified to CDC. All
GAS strains were isolated from skin sores . .Two strains, one emm55 and the other a
emm68.2 were isolated from both skin sores and throat swabs. Table 3 shows the emm ST
isolated during the study.
Emm55 GAS was isolated from 4 cases during the 2005 outbreak from 4 geographically
isolated communities within the NT. In addition during community screening of one
outbreak community in this year emm55 GAS was isolated from skin sore swabs in 4 out
of 5 case contacts. Strain emm55 was also isolated from a confirmed case in 1992.
From the outbreak in 2000 there were 3 isolates of emm3.22 isolated from 3 different
communities in one district. An isolate with emm70 was also isolated from a case in one of
these communities. From a community in a different district that had 13 confirmed cases,
GAS with emm49.3, emm85 and emm86 were isolated.
From 1995, the year of the other large outbreak, strain emm19.7 was isolated from a
confirmed case in the community with the most cases. This strain was also isolated from a
suspected case that could not be confirmed retrospectively. Emml was isolated in the
same year from a sporadic case. It is not known whether they had been in contact with
people from communities involved in the outbreak.
9
DISCUSSION
Despite a decline in the incidence of APSGN seen in many parts of the industrialized
world, this study demonstrates that rates of APSGN in the NT remain high in the
Indigenous Australian population. Recent studies have estimated an annual incidence of
APSGN in underdeveloped countries of between 9.3 and 28.5 cases per 100,000
population.[!, 9] This is comparable to our overall estimated incidence in the NT of 12.5
cases per 100,000 person-years. However, the rates in the Indigenous Australian
population are significantly higher and are amongst the highest reported world-wide. The
incidence in Aboriginal Australian children under the age of 15 years is almost double the
rate of 50.5 cases per 100,000 reported in Maori children in New Zealand in the
1980's[30], and is more than three times the estimated rate for children in the developing
world calculated by Carapetis et al[9] In one small Aboriginal community the incidence
in children less than 15 years was 890.7 case per 100,000 person-years.
Indigenous
Australians have also previously been reported to have the highest rates of acute rheumatic
fever in the world. [31].
The short term prognosis for children with APSGN is generally good with a mortality of
less than 0.5% and fewer than 2% progressing to end-stage renal failure. [32] However the
long term implications of APSGN are less reassuring, especially in the Indigenous
Australian population. A recent study has found significantly higher rates of albuminuria
in Aboriginal Australians with previous APSGN compared with controls. [33] Given
albuminuria is a marker of early chronic kidney disease, this suggests that APSGN may be
contribute to the high rates of chronic renal failure seen in Indigenous Australians.
The incidence rates calculated in this study have included only confirmed cases that have
been notified. The incidence including subclinical cases would be much higher. In addition
it has been recognised that many cases are not notified by clinicians, especially from the
early 1990's. Eight GAS isolates from cases that we confirmed retrospectively were from
cases not formally notified. APSGN is not notifiable in all States of Australia and many
clinicians may not have been aware of the mandatory reporting requirements in the NT.
The true incidence of this disease is therefore likely to be considerably higher than that
calculated in this study.
10
Due to the nature of this study there is a lack of data regarding the site of underlying
infection. Nevertheless in previous reports of APSGN outbreaks within the NT the
majority of cases have been attributed to impetigo. During the outbreak in 2000, 87% of
cases were reported to have skin sores and 40% had scabies[14]. GAS were isolated from
26% of cases, all of which were skin sores. The prevalence of impetigo is very common
amongst children in Indigenous communities. In some communities it has been found in as
many as 70% of children[34]. In contrast pharyngitis has been shown to be uncommon in
indigenous communities. [35]
There is a seasonal distribution of APSGN in the Top End of the NT with a peak in the
early dry season from April-June which is likely to represent the peak of occurrence of
outbreaks. Previous studies in temperate climates have demonstrated a peak of impetigo
associated APSGN in late summer, early autumn and a peak of pharyngitis associated
APSGN in winter and spring. [5, 22, 30]. This reflects the seasonal distributions of
pyoderma and pharyngitis in these temperate regions. There is a less defined seasonal
distribution of pyoderma in the Aboriginal communities with the Top End of the NT. A
previous study has demonstrated a seasonal distribution of pyoderma in one community
[36] with a peak in the dry season however a 3 year surveillance study as part of the
'Healthy skin Program' in the East Arnhem district did not show a seasonal change in
prevalence of pyoderma or scabies.[25].
This study showed a marked difference in the patterns of disease seen in the Top End
compared to Central Australia, particularly the Alice Springs district. In the Top End over
50% of cases occur as part of outbreaks compared with less than 10% in Central Australia,
where only 5% (4 cases) in Alice Springs District were part of an outbreak. This study did
not review outcomes of APSGN cases however previous studies have suggested that
sporadic cases may have a poorer prognosis than epidemic cases. [10] The reason for this
difference in patterns is not clear but may reflect possible differences in the burden of GAS
related skin disease between the 2 regions and its associated immune response.[37]
Differences in humidity and rainfall are unlikely to be responsible given outbreak cases
within the Top End are more common in the dry season. Public health responses to cases
should be the same between regions and should not significantly explain results. These
11
differences warrant further study that might give clues to aid outbreak prevention
strategies for the future.
Thirteen different emmST from confirmed APSGN cases have been identified from this
study. Emm55 was identified as the predominant strain responsible for the widespread
outbreak in 2005 as well as a case in 1992. emm55 has also been reported from a previous
APSGN outbreak in the NT in 1983[12]as well as from outbreaks in Trinidad [38, 39] and
cases in Ethiopia[40].
A prospective household study swabbing throats and skin sores for GAS in two of the
outbreak communities, [23] performed during the period of the APSGN outbreak in 2005
demonstrated a peak of isolation of strain emm55. This study demonstrated that strain
emm55 was the predominate strain isolated in the communities during this time but only
for a short period of time. The strain was not isolated prior, or subsequently. This supports
the theory that the strain is introduced to the communities, spreads quickly and then
disappears, possibly corresponding with the development of strain-specific immunity.
Type emm3.22 was isolated from 3 cases during the 2000 outbreak in 3 different
communities in one district.
There is evidence the strain M3 has previously been
associated with pharyngitis-associated APSGN [22]but not definitively with pyodermaassociated APSGN. M3 has been recognised as a strain with a predilection for throat
rather than for skin. It was the most common strain isolated from the throat of 500 school
staff and children screened in New Zealand in 1983 in response to a cluster of cases of
acute rheumatic fever.[41] However, all the emm3.22 isolates in our collection were
isolated from the skin sores. Strains emm49, 70, 85, 86 were also isolated from individual
cases in outbreak communities during 2000. M49 has been well reported as a causative
strain of pyoderma associated APSGN and has been responsible for previous
outbreaks.[30, 42, 43].
Emm 10 and emm86 have not been previously reported to be
associated with APSGN. It is possible that unlike the outbreak in 2005, which appears to
be related to one strain of GAS, there may be multiple strains responsible for the outbreak
2000. There was only one isolate from a confirmed outbreak case in 1995 which was
strain emm19.1 which has not previously been reported in association with APSGN.
12
Of the strains found in sporadic cases of APSGN, emm57 is well recognised to cause
pyoderma associated APSGN[30, 44] and emm1 has been associated with nephritis but
usually is isolated from the throat. [4, 25, 43]. However, emm1.2 has been associated with
impetigo and APSGN in one case in Ethiopia.[40]. Strain emm68.2, 91 and 98.1, 105 have
not been reported in association with APSGN, although it is possible that these more
recently described strains were not able to be identified by the serotyping methods used in
older studies.
A limitation of this study is that, as with most other studies, it is impossible to ensure that
the isolated GAS from a patient is definitely responsible for the case of APSGN. The
majority of isolates were collected from skin swabs taken after a diagnosis of APSGN was
made, thus being up to 3 weeks after initial infection. A study by Carapetis et al[31] found
that Aboriginal children frequently have more that one strain of GAS present in skin sores,
making it possible that the strain responsible for causing APSGN is not the one isolated.
McDonald et al [23] showed that there was marked diversity and multiplicity of emmST
seen within Aboriginal communities. In this study households were followed monthly and
42% of emmST were only detected on one visit and not cultured from the same household
or community the subsequent month.
This study has GAS isolates from 21 cases of confirmed APSGN spanning 16 years, from
both outbreak and sporadic cases. A number of the strains isolated from confirmed
APSGN cases have not previously been described in association with APSGN. The use of
emm sequence typing has allowed more accurate characterisation of many isolates that
may previously have been non-typeable. This information is relevant to further research
into the pathogenesis of APSGN and relationships between M-protein characteristics and
other GAS virulence determinants and nephritogenic potential. It is also relevant to the
development of a strain specific vaccine for prevention of post-streptococcal sequelae.
APSGN remains a significant health problem in the Northern Australia. Defining the
epidemiology of this condition is important to guide further strategies for prevention and
management. This condition predominantly affects Indigenous Australian children living
in remote Indigenous communities in the tropical and sub-tropical areas of Australia. In
these communities living conditions are often poor, with marked overcrowding of
housing[45] and often inadequate water supply and sanitation facilities [46]which together
13
facilitate rapid spread of GAS. [47] Improving living conditions, housing and education in
remote communities is a thus essential to reduce the rates of APSGN and other sequelae of
GAS infection.
Relevance to Local Public Health Practice
The results of this study have been of use in revising current public health guidelines for
management of APSGN. This study has found that in outbreak years there is an increase
in the number of sporadic as well as outbreak cases and in outbreak years there are an
increase in the number of communities across the NT having only 1 or 2 cases of APSGN.
Analysing the number of notifications per fortnight suggests that four notifications per
fortnight could be added as an NT-wide outbreak definition which could trigger an alert to
communities. This could encourage identification of cases at a local level and treatment of
children with skin sores. Rapid contact tracing of all cases could be also made a priority.
The retrospective and observational nature of this study makes it difficult to assess the
efficacy of community interventions that have occurred to date. This study demonstrates
that in many outbreaks there are clusters of cases that occur within 2-3 weeks with no
further cases. In many instance the definition of an outbreak is met but then no further
cases are detected. It is difficult to assess the impact that widespread intervention has on
these outbreaks as many clusters appear self-limiting and it is unclear as to whether the
cessation of cases is due to intervention or is just the natural history of a cluster. Following
a targeted community intervention, a reduction in cases attributable to that intervention
will not be seen for at least one to two weeks. There is no evidence that treatment of
children with skin sores will prevent them from developing APSGN if they have already
been infected with a nephritogenic GAS. Treatment with penicillin aims only to decrease
transmission of the GAS to others. Because of the delays between GAS infection and onset
of APSGN it would therefore be expected that further cases of APSGN could present in
the period immediately following an intervention. Giving 1M benzathine penicillin to
uninfected contacts will however potentially provide protection from acquiring GAS
infection to those individuals for several weeks (the duration of "protective" penicillin
levels after 1M benzathine penicillin). [48]
14
Two of the larger community outbreaks during the study period were biphasic, with failure
of an initial targeted intervention to stop spread. A possible explanation for this is that
children with skin sores who were treated in the intervention had already spread the GAS
strain to other children or adults that might be harbouring the bacterium on intact skin. A
study in Native American families demonstrated that GAS are present on normal skin for
up to a month prior to development of lesions, with a mean of 10.3 days. [49].
Transmission of strains of GAS within families was rapid with the time from index case
acquisition to secondary skin acquisition of between 2 to 12 days with a mean of 4.8days.
The time from index skin infection to last skin infection within a family was 1 to 41 days
with a mean of 21 days. Thus for each child with infected skins sores that is treated with
prophylactic penicillin there are likely to be family members already colonised or infected
with the same strain who may spread the bacterium further afield.
The older intervention strategies that involved treating every child in the community
regardless of skin sore status has the advantage that it will prevent children colonised but
not yet infected with the strain of GAS developing disease. Treatment with benzathine
penicillin has been shown the prevent development of impetigo in children for at least 2-3
weeks after administration [ 18, 48]. However the disadvantage of this approach is that well
children need to be given painful injections that could be associated with complications
such as allergic reactions. It would also considerably increase resources needed to perform
interventions. Unfortunately there are no randomized controlled trials to assess the best
community intervention strategy to manage outbreaks. There is one observational study
that supports intervention with penicillin therapy and suggests that the current targeted
approach is probably effective. [19]
In the current NT APSGN guidelines all contacts of cases aged 3-15 will automatically be
treated with a dose of intramuscular benzathine penicillin. [15]. This study demonstrates
that 26 cases (6%) occurred in those aged 1-2 years and that 10 cases (2.3%) occurred in
those aged 16 years. Despite the numbers in each group being small, they are similar to
the number of cases occurring in the 14 and 15 years age group. It has therefore been
proposed that those aged 1-2 and 16 years who are contacts of a case also receive a dose of
benzathine penicillin regardless of their skin sore status in an attempt to prevent further
cases and bacterial spread.
15
Defining the epidemiology of APSGN in the NT has assisted in reviewing the current
guidelines for management of APSGN. Specifically there have been changes to age group
of contacts empirically treated with benzathine penicillin and also the introduction of a NT
wide alert when there is an increase in cases territory wide. There has also been review and
ongoing evaluation of current outbreak definitions and management strategies.
Further research is needed into the dynamics of transmission of nephritogenic strains of
GAS during outbreak periods to understand the best way of aborting outbreaks. However,
ultimately energy needs to be focused not just on managing APSGN cases and outbreaks
but on prevention. In Australia this is a disease of Indigenous Australians living in remote
areas with overcrowding, inadequate health hardware and associated poor sanitation. It is
improving the living conditions in these communities that will have the greatest impact on
reducing the burden of APSGN in Australia.
16
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Yap HK, Chia KS, Murugasu B, et al. Acute glomerulonephritis--changing patterns
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Carapetis JR, Steer A.C, Mulholland E.K, Weber M. The global burden of group
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Blyth CC, Robertson PW, Rosenberg AR. Post-streptococcal glomerulonephritis in
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Streeton CL, Hanna JN, Messer RD, Merianos A. An epidemic of acute poststreptococcal glomerulonephritis among Aboriginal children. Journal of Paediatrics
and Child Health 1995;31: 245-8.
12.
Gogna NK, Nossar V, Walker AC. Epidemic of acute poststreptococcal
glomerulonephritis in aboriginal communities. Med J Aust 1983; 1: 64-6.
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Evans C. Acute Post Streptococcal Glomerulonephritis in the Northern Territory
1980-2000. The Northern Territory Disease Control Bulletin 2001;8: 1-40.
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Keams T, Evans C, Krause V. Outbreak of Acute Post Streptococcal
Glomerulonephritis in the Northern Territory - 2000. NT Disease Control Bulletin
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15.
Northern Territroy Centre for Disease Control, Guidelines for Control of acute
post-streptococcal glomerulonephritis. 2002, Northern Territory Health Services
Darwin. p. 1-19.
16.
Peter G,Smith AL. Group A streptococcal infections of the skin and pharynx
(second of two parts). N Engl J Med 1977;297: 365-70.
17.
Reinstein CR. Epidemic nephritis at Red Lake, Minnesota J Pediatr 1955;47: 2534.
18.
Ferrieri P, Dajani AS, Wannamaker LW. Benzathine penicillin in the prophylaxis
of streptococcal skin infections: a pilot study. J Pediatr 1973;83: 572-7.
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19.
Johnston F, Carapetis JR, Patel MS, Wallace T, Spillane P. Evaluating the use of
penicillin to control outbreaks of acute post streptococcal glomerulonephritis. Paed
Infect Dis J 1999;18: 327-32.
20.
Gardiner DL,Sriprakash KS. Molecular epidemiology of impetiginous Group A
Streptococcal infection in Aboriginal communities in northern Australia J. Clin.
Microbiol1996;34: 1448-52.
21.
Rammelkamp CH, Jr.,Weaver RS. Acute glomerulonephritis, the significance of
the variations in the incidence of the disease. J Clin Invest 1953;32: 345-58.
22.
Wannamaker LW. Differences between streptococcal infections of the throat and of
the skin. I. N Engl J Med 1970;282: 23-31.
23.
McDonald MI, Towers RJ, Andrews R, et al. The dynamic nature of group A
streptococcal epidemiology in tropical communities with high rates of rheumatic
heart disease. Epidemiology and Infection 2007;136: 529-39.
24.
McDonald MI, Towers RJ, Fagan P, Carapetis JR, Currie BJ. Molecular typing of
Streptococcus pyogenes from remote Aboriginal communities where rheumatic
fever is common and pyoderma is the predominant streptococcal infection.
Epidemiol Infect. 2007;135: 1398-405.
25.
Andrews R,Keams T, East Arnhem Regional Healthy Skin Project: Final Report.
2007, Menzies School of Health Research: Darwin.
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http://www. gi sca.adelaide.edu.au/products services/ariav2 about.html.
20 October 2008.
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Accessed
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September 2008
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http://www.abs.gov .au/websitedbs/D331 0 114.nsf/home/Home.
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August 2009
30.
Lennon D, Martin D, Wong E, Taylor LR. Longitudinal study of poststreptococcal
disease in Auckland; rheumatic fever, glomerulonephritis, epidemiology and M
typing 1981-86. N Z Med J 1988;101: 396-8.
31.
Carapetis JR, Wolff DR, Currie BJ. Acute rheumatic fever and rheumatic heart
disease in the Top End of Australia's Northern Territory. Med J Aust 1996;164:
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32.
Holm SE, Nordstrand A, Stevens DL, Norgren M, Acute Postreptococcal
Glomerulonephritis, in Streptococcal Infections: Clinical Aspects, Microbiology
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University Press: New York. p. 152-62.
33.
White
AV,
Hoy
WE,
McCred
DA.
Childhood
post-streptococcal
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34.
Carapetis JR, Connors C, Yarmirr D, Krause V, Currie BJ. Success of a scabies
control program in an Australian aboriginal community. Pediatr Infect Dis J
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35.
McDonald MI, Towers RJ, Andrews RM, Benger N, Currie BJ, Carapetis JR. Low
rates of streptococcal pharyngitis and high rates of pyoderma in Australian
aboriginal communities where acute rheumatic fever is hyperendemic. Clin Infect
Dis 2006;43: 683-9.
20
36.
McDonald MI, The Epidemiology of pyoderma and pharyngitis in Aboriginal
Communities with a high prevalance of rheumatic heart disease, in Department of
Paediatrics. 2006, University of Melbourne: Parkville.
37.
McDonald M, Brown A, Edwards T, et al. Apparent contrasting rates of
pharyngitis and pyoderma in regions where rheumatic heart disease is highly
prevalent Heart Lung Circ. 2007;16: 254-9.
38.
Reid HF, Bassett DC, Gaworzewska E, Colman G, Poon-King T. Streptococcal
serotypes
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acute
glomerulonephritis. J Med Microbiol1990;32: 111-4.
39.
Potter EV, Svartman M, Mohammed I, Cox R, Poon-King T, Earle DP. Tropical
acute rheumatic fever and associated streptococcal infections compared with
concurrent acute glomerulonephritis. J Pediatr 1978;92: 325-33.
40.
Tewodros W,Kronvall G. M Protein Gene (emm Type) Analysis of Group A BetaHemolytic Streptococci from Ethiopia Reveals Unique Patterns. Journal of Clinical
Microbiology 2005;43: 4369-76.
41.
Martin DR, Meekin GE, Finch LA. Streptococci--are they different in New
Zealand? N Z Med J 1983;96: 298-301.
42.
Anthony B, Kaplan E, Chapman S, Quie P, Wannamaker L. Epidemic acute
nephritis with reappearance oftype 49 streptococcus. Lancet 1967;2: 787-90.
43.
Majeed HA, Yousof AM, Rotta J, Havlickpva H, Bahar G, Bahbahani K. Group A
streptococcal strains in Kuwait: a nine-year prospective study of prevalence and
associations. Pediatr Infect Dis J 1992; 11: 295-300; discussion -3.
44.
Potter EV, Ortiz JS, Sharrett AR, et al. Changing types of nephritogenic
streptococci in Trinidad J Clin Invest 1971;50: 1197-205.
21
45.
Bailie RS, Stevens M, McDonald E, et al. Skin infection, housing and social
circumstances in children living in remote Indigenous communities:testing and
methodological approaches. BMC Public Health 2005;5: 128.
46.
Gracey M, Williams P, Houston S. Environmental health conditions in remote and
rural aboriginal communities in western Australia Aust N Z J Public Health
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47.
Currie BJ,Carapetis JR. Skin infections and infestations in Aboriginal communities
in northern Australia Australas J Dermatol2000;41: 139-43.
48.
Ferrieri P, Dajani AS, Wannamaker LW. A controlled study of penicillin
prophylaxis against streptococcal impetigo. J Infect Dis 1974; 129: 429-38.
22
TABLES
Table 1: Demographic characteristics of the study population
Characteristic
Confirmed (n=415)
(%)
Probable (n=23)
Total(%)
(%)
7 (0-54)
5 (1-11)
7 (0-54)
Male
206 (49.6)
17 (73.9)
226 (51.6)
Female
209 (50.4)
6 (24.1)
215 (48.4)
Indigenous
392 (94.5)
23 (100)
415 ( 94.7)
Non-Indigenous
16 (3.9)
0
16 (3.7)
Unknown
7 (1.7)
0
7 (1.6)
405 (97.6)
23 (100)
428 (97.7)
Median Age (range)
Sex
Indigenous Status
Living Remote
Location
23
Table 2: Incidence Rates of APSGN in Northern Territory, Australia
Age
Total population All ages
Population Number of
Annual
Estimates
confirmed
Incidence per
(2007)*
Cases notified
100,000
1992-2007
persons
383
12.5
214,929
95%CI
(11.3-
13.8)
0-14 years
51,765
331
41.4
(37.046.1)
Aboriginal or
All ages
360
65,159
39.7
(35.744.0)
Torres Strait
Islander
0-14 years
22,540
314
94.3
(84.2105.3)
Non-Indigenous
0-14 years
29,225
17
2.3
(1.24.2)
* population estimates from Department of Health Gains Planning
24
Table 3: emmST of APSGN isolates
emm Sequence Type
number
(emmST)
(peremmST)
1995
emml9.7
1
2000
emm3.22
3
emm49.3, emm70,
1
Year
Outbreak
emm85, emm86
Sporadic
2005
emm55
4
1991
emm57.2
3
emm91
1
emm55, emm98.1,
1
1992
emm68.2
1995
emml.O
1
2001
emml05
1
25
FIGURES
Figure 1. Age Distribution of Cases of APSGN
60 , - - - - - - - - - · - - - - - - - - - - · - - - - · - · - - - - - - - - · · - - - - - · -
50
IX)
0
0
C\1I
....en
40
en
,..
1/)
Q)
1/)
30
as
u
z
Cl 20
en
D.
c(
10
o
1
2
3
4
s
6
1
8
9
10 11
12 13 14 15 16 11 18 19 20- 26- 30- 35- 40- 45- so24 29 34 39 44 49 54
age (years)
I• Aboriginal 1111 Non-Indigenous lSI Torres-Strait Islanders El Unknown I
26
Figure 2. Local community incidence of APSGN in Children Aged 0-14 years.
(Incidence per 100,000 person years)
Incidence
< 1.000
•
1 - 25
•
25- 50
•
50 - 100
•
100 - 200
•
200 - 400
•
400 - 600
•
600 - 1000
!?"·
•
•
•
27
Figure 3: Annual Incidence of APSGN in the NT
160 ·---···--·"·--·-·..- - -..- · · · · - · - - · · - · - · - - - · - · - - - - - - - - - - - - - - - - - - - - - - -
140
!
120
~
100
~
80
l
§
- A g e 0-14 years
· · • ··Age >14 years
L
1
40
year
28
Figure 4. Notifications per Month in the Top End and Central Australian regions
80
70
60
"'
Q)
"'~50
z(.!)
-
-
-
-
-
-
-
-
-
-
-
-
(/)
~ 40
~E
30
f--
20
f--
~-
•Top End
~Central Australia
---
-
-
-
-
-
-
-
:I
z
10
0
-
-
-
-
-
-
-
~
~
Jan
Feb March April
~
May
--
~-
June
July
Month
29
Aug
Sept
-
-~
Oct
·-
Nov
I
~
Dec
APPENDIX 1 -LITERATURE REVIEW
Acute post-streptococcal glomerulonephritis (APSGN) is an inflammatory condition of the
renal glomerulus that usually follows infection with group A streptococcus (GAS;
streptococcus pyogenes), although can also be associated with infection with Group C and
G Streptococcus.
Al.l Historical Perspective
The observation that kidney disease sometimes followed scarlet fever was initially made in
1836 by Richard Bright. In 1907 Schick showed that an asymptomatic interval of 12 days7 weeks preceded the onset of nephritis. [4] In 1953 a causal relationship between GAS
type 12 and glomerulonephritis was established by Rammelkamp.[21] Subsequent studies
performed during an outbreak of GAS pharyngitis in Naval training station in the 1950's
found an APSGN attack rate in those infected with type 12 GAS to be 12%.[50]. The cases
of nephritis· in this study occurred after a latent period following streptococcal infection
ranging from 6-16 days with a mean of approximately 10 days. In this study treatment of
the initial infection with penicillin appeared to decrease the incidence of APSGN although
the numbers were small. Penicillin treatment instituted later in the course of illness
because of the development of suppurative complications did not seem to be effective.
APSGN can occur following either infection of the throat or skin. The epidemiological
differences in APSGN associated with pharyngitis and pyoderma were summarized in the
1970's by Wannamaker. [22] It was shown APSGN following impetigo tends to occur in
younger children, during summer and autumn and has a latent period of around 3 weeks. In
contrast pharyngitis associated APSGN more commonly occurs in winter and spring
months with a shorter latency of around 10 days. There was also a difference noted in the
GAS strains responsible for pharyngitis and impetigo associated APSGN. Strains M1, M4
and M12 were classically associated with pharyngitis whereas M2, M49 and M55 and
M57 more likely to be associated with impetigo.
In the 1950's, 1960's and 1970's epidemics of APSGN were reported in many parts of
world, in particularly the USA, central and South America. Rodriguez-Iturbe and Musser
30
[1] summarize the major reported epidemics of APSGN in the literature.. (see table Al.1
and Al.2).
Multiple epidemics were reported to occur in Trindad, Venezuala and in
Minnesota in the USA in the Native American population in Red lake. [3, 17, 44, 51-53].
These outbreaks were commonly associated with increases in skin infection. In the 1980's
epidemic scabies was found to be associated with
further outbreaks of APSGN in
Trinidad. [3]
In the late 1970's and early 1980's clusters of APSGN were reported in New Zealand,
most commonly occurring in children of Maori or Pacific Islander background [30].
Lennon et al [30] reported annual rates of APSGN in Maori children younger than 15 years
to be 50.5 cases per 100,000 people, with rates of 46.5 per 100,000 in Pacific Island
children. During the 1980's APSGN was also reported commonly in Kuwait. [43]
Table Al.l Epidemics of APSGN with more than 100 cases [1]
Year
Location
Population
Affected
1951- Bainbridge,
Military
1952 Maryland, USA[50]
recruits
1964- San Fernando, Trinidad,
Rural and
1965 West Indies[51]
city
1968 Maracaibo,Venezuela[52]
Urban
1967- San Fernando, Trinidad,
Rural and
1968 West Indies[44]
Urban
1974 Maracaibo, Venezula
Urban
1974 Baracoa,Guantanamo,Cuba Rural
1986
1995
San Fernando,Trinidad,
West Indies[38]
Yerevan, Armenia[54]
1995
San Jose, Costa Rica
1995
Vilnius, Lithuania[55]
Nova Serrana, Minas
Gerais, Brazil [56]
1998- Lima, Peru[57]
2001
1998
Urban and
rural
Urban and
Rural
Urban and
Rural
Urban and
Rural
Rural
Urban
31
Site of
infection
Throat
No. of
Cases
180
Streptococcal
Types
M12
Skin
760
M55,M49
Throat
Skin
384
540
ND
M49,M60
Skin
Skin and
throat
Skin
200
295
ND
ND
181
Throat
196
M73,M48,M55,PT
5757
ND
Skin and
throat
Skin and
throat
103
ND
8.3
ND
cases
per
100,000
children
Unpasteurized 135
S. zooepidermicus
milk
186
ND
Throat
(clusters
A1.2. Epidemics of APSGN with less than 100 cases and clusters of cases [1]
No. of Cases
Rural
Site of
Infection
Throat
22
Streptococcal
Type
ND
Aboriginal
Skin
63
M49
Urban
Skin
57
M1, M12,M49
Aboriginal
Skin
27
M49
Eskimo
Children
Urban
Skin
75
ND
Skin and
throat
Skin
84
ND
Clusters
(autumn)
12
M49,57,60
Year
Location
Population
1952
1975-1977
Nova Scotia,
Canada[ 58]
Red Lake,
Minnesota,USA[17]
Memphis,
Tennesse,USA[59]
Red Lake,
Minnesota, USA[53]
Alaska[60]
1978-1982
Santiago, Chile[4]
1978-1983
New Zealand[61,
62]
Las Tunas,
Cuba[63]
Kuwait[43, 64]
1953
1960
1966
1980
1980-1989
1980-1998
1982-1993
1983
1992
1993
1993
2005
Northern Territory,
Australia[ 19]
Belgrade,
Yugoslavia[65]
North Yorkshire,
UK [66]
Saga, Japan[67]
North Queensland,
Australia[ 50]
Brisbane,
Australia[68]
Linkoping,
Sweden[69]
Urban and
Rural
Rural
Urban and
Rural
Rural
Military
academy
Rural
Rural
Aboriginal
Rural
Rural
Skin
Throat and
Skin
Skin and
throat
Throat
234 cases in 9 M12,M 18,M49
years
ND
Clusters
Clusters of 6
to 24
Unpasteurized Clusters
milk
Throat
42
Skin
58
Unpasteurized Clusters
milk
Cluster
Throat
32
M49, M12
ND
S.zooepidemicus
M1
ND
S.zooepidemicus
S.pyogene
S. Constellatus
A1.2 Current Epidemiology and Global Burden of APSGN
Currently worldwide there is estimated to be over 470,000 cases of APSGN annually with
approximately 5000 deaths and 97% of these cases occur in less developed countries. [9]
Carapetis et al [9] calculated a median incidence of disease in children from less developed
countries of 24.3 cases per 100,000 person-years, using 11 population studies reporting the
incidence of APSGN. In people older than 15 yrs in the same countries they calculated an
incidence of two cases per 100,000. This figure was calculated using only data from
Kuwait. Using data from an Italian biopsy study it was estimated the incidence in adults in
more developed countries to be low at around 0.3 cases per 100 000.
Rodriguez-lturbe and Musser [1] used a different approach to calculate the global burden
of APSGN. They reviewed reports of pediatric acute renal failure from underdeveloped
countries. Using the assumption that cases presenting with severe acute renal failure
represent less than 1% of total cases they estimated for every case of severe APSGN there
would be between 100 to 300 uncomplicated cases in the community. They reviewed
studies from India, Morocco, Thailand and Nigeria and estimated the overall annual
incidence of APSGN outside the industralised world to be 9.5 to 28.5 cases per 100,000
persons of all ages.
The epidemiology of APSGN has changed over the past 30 years in most of the
industralised world. A French study found that it had virtually disappeared over this
time.[70] In the Italian biopsy registry, the incidence in children younger than 15 years fell
from 2.6% to 3.7% of all primary glomerulopathies in the period 1987-1992, to only nine
cases in the period 1992-1994. [8] The case series of adults with infectious
glomerulonephritis by Monsteny et al[71] demonstrates a changing trends. Their patients
were mostly in the fourth decade and often had a background of alcoholism, diabetes, drug
addiction or cytostatic therapy. The reported glomerulonephritis following infection not
only with group A streptococcus but also with other strains of streptococci, staphylococci,
and gram negative bacteria such as E.coli and pseudomonas. Of note this study did not
include children, the population in which classical APSGN is seen.
Many other parts of the world have also recorded a decline in the incidence of APSGN
over the past 20 years. There has been a reduction in the incidence of APSGN noted in
33
China and Singapore.[6, 7]. The authors of the Singaporean study proposed that this may
be due to improvements in the socioeconomic status, health care system and urbanization
of the country.[6]
In South and Central America, where APSGN was previously common, there has been a
decrease in the yearly number of cases [1]. Berrios et al[4] report the experience with
APSGN of one health service in Santiago over 20 years from 1980-1999. They reported an
outbreak of APSGN during the mid-1980's that coincided with an outbreak of scabies and
an increased incidence of APSGN resulting from skin infections. However during the
1990's there was a steady decline in the number of APSGN cases and in 1999, the last year
of the study they had none.
A similar story has been seen in the USA. llyas and Tolaymat [5] compared a recent cohort
of patients presenting to a Florida hospital with APSGN between 1999-2006 with an
earlier cohort admitted between 1957-1973. There was a decrease in the incidence of
APSGN in Florida over this period. This was largely due to a significant decrease in the
incidence of APSGN following impetigo whilst there was no significant change in the
incidence of APSGN following pharyngitis. In the earlier cohort impetigo was the primary
cause in 66% compare with the recent cohort in which pharyngitis was the leading cause in
64%. Corresponding to this was a change in the seasonal variation. In the recent cohort
approximately 11% of cases occurred between August and October as compared to 50% in
the earlier cohort.
There was also a statistically significant change in the racial distribution of disease. The
recent cohort comprised 62% white children, 27% black children and 11% children from
other groups. The earlier cohort comprised 16% white children, 83% black children and
1% children from other racial groups. The authors of this study suggest one reason for the
changing paradigm of APSGN from impetigo related to pharyngitis related may be the
shift of pathogen responsible for impetigo. Some studies have now suggested that
Staphylococcus aureus, rather than Streptococcus pyogenes is the predominant organism
responsible for impetigo and this does not lead to APSGN. [72-74]
34
A1.3 History of APSGN in the Northern Territory and Australia
In the Northern Territory (NT) there are sporadic cases of APSGN yearly with outbreaks
occurring approximately every 5-7 years [13-15, 75, 76] This is a similar pattern as was
reported in Trinidad-Tobago during the 1960's and 1970's. [3, 38] Outbreaks of APSGN
in NT are usually associated with skin infection and often with scabies infection. [14, 76]
An outbreak of APSGN was reported in the NT in 1980.[12] This included 20 patients that
were admitted to hospital and 78 possible cases reviewed in the community who were
suspected to have disease by local health workers. Of the 78 patients reviewed in the
community it is unclear how many actually had APSGN given only 33.3% had a reduced
C3 level compared with 95% of those admitted to hospital. A reduced C3 level is normally
seen in greater than 90% of cases of APSGN.[32] In this outbreak a nephritogenic strain
of T8/25/Impl9- M55 of beta-haemolytic streptococcus was isolated in 8 outpatients but
none of the inpatients. It is unclear whether the 8 cases were confirmed to be APSGN.
Evans describes the history of APSGN outbreaks in the NT between 1980-2000, during
which period there were outbreaks in 1980, 1983/1984, 1987, 1993, 1994, 1995 and in
2000.[13] In the majority of these outbreaks more than one community was involved and
it was postulated by Evans that there was likely to have been travel links to facilitate
spread of the streptococcal strains responsible for the disease. [13] There was also a more
recent outbreak of APSGN in 2005 reported in the NT. [76] Outbreaks of APSGN have
also been reported in Aboriginal communities in other parts of Australia[ll, 77] In the
southern temperate regions of Australia the disease continues to occur sporadically but
more commonly in association with pharyngitis.[lO] In 1991 an electronic disease
notification database was established in the NT to record information about recorded cases
and outbreaks of disease.
Although many industrialized countries have noted a decline in APSGN in past 20 years,
there does not appear to have been a similar trend in Northern Australia. Although the
epidemiology APSGN in the NT has been documented in local publications it has not been
more widely reported in the mainstream literature.
The patterns of disease in the
Indigenous Australian population appear to continue to follow patterns seen in poorer
35
developing countries rather than patterns seen in the Southern population in Australia and
other parts of the developing world.
A1.4 Clinical Disease and Definitions
APSGN predominantly occurs in children under the age of 14 years although only
infrequently in children under the age of 2. [13, 78] It is much less common in adults [9].
APSGN usually becomes clinically evident 1-3 weeks following GAS pharyngitis or 3-6
weeks following GAS pyoderma. [22, 79] Clinically APSGN is characterized by features
of nephritic syndrome which are edema, hypertension and dark urine resulting from
hematuria. APSGN is associated with complement activation and a reduced C3 level is
seen almost universally. [80]. Levels usually return to normal within 6 weeks of acute
onset of disease. [81] Prior streptococcal infection can be demonstrated either with a
positive culture or with demonstration of anti- streptolysin 0 or anti-DNAase B antibodies.
Individuals with skin infection may not develop anti-streptolysin 0 antibodies as
streptolysin binds to lipids in the skin.[32] Table A1.3 represents the current diagnostic
criteria used in the Northern Territory. Prior to 2005 patients found on screening to have
hematuria plus evidence of reduced C3 and streptococcal infections but no clinical
symptoms were said to have sub-clinical disease. [15]
Following the revision of the
definitions in 2005 these patients are now referred to as having probable disease [76]
Complications reported to occur with APSGN include acute pulmonary edema, and
reversible posterior leukoencephalopathy syndrome that can be caused hypertension or an
associated cerebral vasculitis. [82-87] In one case report a patient who presented with
pulmonary edema had a normal urinalysis but APSGN was subsequently confirmed on
renal biopsy[83]
Sub-clinical disease has been found to occur in a proportion of people following
streptococcal infections who are asymptomatic. This diagnosis is based on the presence of
hematuria and a fall in serum complement 2-4 weeks after streptococcal infection,
occasionally associated with hypertension. Studies looking at sub-clinical APSGN have
found the ratio of sub-clinical to clinical disease to vary from 0.03 to 19.0.[88] Yosizhawa
et al[89] followed 12 patients with sub-clinical APSGN. Initial renal biopsies had changes
ranging from mild proliferative changes to classical pathology seen in APSGN. The
36
patients were followed for 10 years and two developed persistent/intermittent hematuria
and repeat biopsies at 4 years showed evidence of mesangial proliferative GN.
Table A1.3 Definition of APSGN in the NT [76]
Confirmed case
• Laboratory definitive evidence
OR
• Laboratory suggestive evidence
AND
clinical evidence.
Probable case
• A probable case requires laboratory suggestive evidence only.
Possible case
• A possible case requires clinical evidence only. (not notified
Laboratory definitive evidence
• Positive renal biopsy.
Laboratory suggestive evidence
• Glomerular haematuria on microscopy (RBC >10/fll)
AND
• Evidence of recent streptococcal infection (positive Gp A Streptococcal culture
from skin or throat, elevated ASO titre or AntiDNAase B)
AND
• Reduced C3 level.
Clinical evidence
• At least 2 of the following:
Facial oedema,
>=2+ dipstick haematuria,
Hypertension,
peripheral oedema.
Notes:
1. A "possible case" is the same as a "clinical case" in the NT "Guidelines for the Control of APSGN". The
guideline suggests that a community outbreak is defined as 2 unrelated clinical cases in one week (or 3 in a
month). Hence it is important to receive notification of, record and respond to, "possible cases" but these
should not be notified to NTNDS (unless confirmed by laboratory evidence).
2. If microscopy is not available then >=2+ dipstick haematuria fulfils this criteria.
3. If all other criteria have been fulfilled but the only evidence of recent streptococcal infection is isolation of
Group C or Group G Streptococci from skin or throat, this could be notified as a confirmed case after discussion
with CDC or an infectious disease physician.
37
Al.S Prognosis of APSGN
There is no specific treatment for cases of APSGN and management involves supportive
care and treatment of complications. The short term prognosis for children with APSGN is
good with a mortality of less than 0.5% and fewer than 2% progress to end-stage renal
failure.[32]. The prognosis in adults is more variable, especially in some studies from less
developed countries. One study from India reported death due to progression to endstage
renal failure to occur in 24% of adults between 2 weeks and 2 years[90] . The reason for
this poor outcome was unclear. In contrast Washio et [91] reported a series of 31 adults
with histologically and immunologically proven APSGN. On admission 57.1% of patients
older than 55 years had impaired creatinine compared with none of the patients aged 20-55
years. However in this small series none of the patients had died or developed persistent
renal failure.
International studies suggest that the long term outcomes following an episode of APSGN
are generally good, particularly in children. A study following patients with APSGN in
Trinidad for 12-17 years found only 3.5% had persistent urinary abnormalities which was
a rate no higher than similar people without prior APSGN.[92] Follow-up data from an
outbreak in Maracaibo, Venezuala found at 5-6 years after the outbreak 13.3% of people
had either reduced creatinine clearance, microscopic hematuria, proteinuria or
hypertension.[52] The rates were higher in adults. At follow-up at 11 year 12.6% of people
had reduced creatinine clearance and 11.2% had significant proteinuria.[93] These studies
had relatively high rates of loss to follow-up and no control groups.
Lien et al[94] followed 57 patients with APSGN, the majority adults, for up to 14 years. At
five years 5 had died, but only 2 of these with abnormal renal function. 11 (19%) had
either proteinuria, haematuria or abnormal renal function at follow-up. However, 3 of these
patients had repeat renal biopsy that was normal. In 5 there was incomplete resolution of
biopsy changes and obsolescent glomeruli was seen in one. Two patients were not
biopsied. This study concluded that the majority of patients with acute APSGN have a
good prognosis.
Despite the majority of patients recovering well from APSGN later progression to chronic
renal failure can occur. Schacht et al [95] report 6 patients from a cohort of 126 patients
38
with confirmed APSGN who had normalization of renal function within one year but
subsequent development of chronic renal failure.
In each of these patients clinical
remission and resolution of proliferation in glomeruli occurred prior to the development of
progressive renal failure and increasing glomerular sclerosis over a period of 2-15 years.
Five cases had persistent proteinuria from onset and in the other case it reappeared in the
8th
year after an interval of 5 years. Hypertension persisted from onset in 3 cases and
reappeared in the other 3 cases after 18mths, 4 and 5 years. It is not clear in these cases
whether progression of disease may be due to progressive renal failure due to
nephrosclerosis associated with poorly-controlled hypertension or progressive glomerular
scarring.[32]
Roderiguez-Iturbe and Musser pooled data from published series prior to 2000, which
included almost 1000 cases followed up for between 5 and 18 years.[l] They concluded
that at follow-up any abnormality was detected in 17.4%, proteinuria in 13.8%,
hypertension in 13.8% and azotemia in 1.3%. When looking at these figures it is important
to consider that they are including studies with different methods, populations and endpoints.
Follow-up studies of an outbreak of APSGN in adults in Brazil caused by streptococcus
zooepidmicus associated with consumption of unpasteurized cheese consumption reported
less favourable outcomes.[96] Of 134 confirmed cases reviewed from one hospital 10
patients required dialysis during the acute illness and three of these patients died within 1
month of disease. Three patients recovered renal function and discontinued dialysis
therapy between 2 and 10 weeks but four patients remained on chronic dialysis therapy.
An additional patient started dialysis for chronic renal failure 8 months after the onset of
disease.
A total of 69 patients were followed up a mean of 2 years following onset of disease. The
mean age of these patients was 39 years and 94% older than 15. At follow-up 42% were
hypertensive and 29% on anti-hypertensive agents (compared with 14% at admission).
Serum Creatinine was abnormal in 12% but creatinine clearance was reduced below
80ml/minl1.73 m2 in 30% of patients. Increased microalbuminuria was detected in 34% of
patients. Patients with increased microalbuminuria had a higher mean systolic and diastolic
blood pressure. Patients with a reduced creatinine clearance were older (45 years versus 36
39
years, p= 0.05) and had more frequently undergone dialysis. It was noted that the age
distribution of patients with APSGN caused by this organism appears different than GAS
which classically affects children. It was felt by the authors that different patterns of
cheese consumption did not account for the greater attack rates seen among adults.
In the Indigenous Australian population the long term outcomes of APSGN is less clear.
The recent study by White et al assessing the long term outcomes of APSGN in Indigenous
Australians found that APSGN in childhood was risk factor for albuminuria later in life.
[33] This retrospective cohort study included 473 people from one remote Aboriginal
community that experienced two epidemics of APSGN in 1980 and 1987. Follow-up data
after a mean of 14.6 years was obtained from population health screening performed in the
community between 1992 and 1999. The study showed that 13% of people with previous
APSGN compared with 4% of controls had evidence of macro-albuminuria (ACR
~
34
mg/mmol) on follow-up screening with an odds ratio adjusted for age and sex of 6.1 (95%
CI 2.2-16.9). 32% of APSGN cases versus 18% of controls had
micro-albuminuria(~
3.4
mg/mmol.) with an adjusted odds ratio of 3.2(95% CI 1.7-6.2) and 21% versus 7% had
hematuria> trace with an adjusted odds ratio of 3.7 (95% CI 1.8-8.0). Overall 30% had
either hematuria greater than a trace or macro-albuminuria compared with 11% of controls
(adjusted odds ratio 4.6 (95% CI 2.3-9.0). This study is the only reported APSGN followup study to include a control group.
A study by Hoy et al [97] looking at renal disease in an Aboriginal Community also found
a strong association between the a raised albumin-creatinine ratio and a history of APSGN.
Albuminuria is thought to be a marker of early chronic kidney disease in this population
and its progression predicts renal failure. In one cohort study the presence of albuminuria
was a predictor of mortality and cardiovascular disease, including in a the non-diabetic
cohort.[98]
The study by White et al [33] was not long enough to show progression to chronic renal
failure as albuminuria usually precedes clinical signs of chronic renal disease. It is
therefore possible that albuminuria may not have such adverse prognostic significance
after APSGN as in other circumstances. It is also possible that APSGN may only increase
the risk of chronic renal disease in combination with other insults such as diabetes. [33]
40
In summary the long term significance of APSGN in the Indigenous Australian population
remains uncertain although the evidence suggests that it may contribute to the high rates of
chronic renal failure that are seen in this population. Further studies are needed in this
population to clarify this relationship.
A1.6 Streptococcus pyogenes and Molecular Epidemiology
GAS isolates were first characterized by serotyping based on antigenic differences of the
M-protein molecule. M-proteins are dimeric, surface bound, a.-helical coiled molecules
which traverse and penetrate the cell wall and are a major somatic virulence factor of
GAS, exerting an anti-phagocytic effect.[99, 100] It was identified in the 1960's that only
certain M-types were associated with APSGN and that these were different from strains
causing rheumatic fever. [101] A problem with the originally used M protein serotyping is
that many strains responsible for disease in Northern Australia and other parts of the world
are non-typeable.[20] More recently isolates have been classified by genotype on the basis
of nucleotide differences in the emm gene which encodes the variable amino-terminus of
theM protein.[99] M serotypes and emm sequence types (emmST) have been shown to
correlate and are referred to interchangeably.[102] There are now greater than 150 emmST
identified.
GAS strains can be further classified into two classes on the basis of different antigenic
groups of M associated Protein (MAP) that matches skin and throat tropic strains.[l03]. It
was further ascertained that the skin tropic strain, MAP-II, possesses a cell surface protein
(Lipoproteinase) which causes opacity in horse serum (serum opacity factor-SOF). [104]
Since the 1950's when Rammelkamp described the association of M type 12 and nephritis
it has been recognized that certain M types are associated with nephritis, and these are
generally different from serotypes that cause acute rheumatic fever.[21]
It was
subsequently ascertained that some GAS strains such as Ml, M4 and M12 tend to be
associated with APSGN following pharyngitis whereas other strains such as M2, M49,
M55 and M57 are associated with skin infection.[22] Numerous GAS strains have
subsequently associated with APSGN and these are summarized in table Al.3. This table
includes strains associated with both sporadic and epidemic forms of APSGN. Tables
41
Al.l and A1.2 summarise major reported epidemics of APSGN and the associated types of
streptococcus, where this was known.
Previous studies looking at molecular epidemiology of GAS in Aboriginal communities of
the Northern Territory show there are a wide diversity of emmST present and that GAS
carriage is dynamic with high acquisition rates within households.[23, 24, 105]
Interestingly, during the studies by McDonald et al [23, 24] two communities studied had
outbreaks of GAS infection and colonization with emm55 (pattern type A-C) which
correlated with outbreaks of APSGN within the communities. M-serotype 55 has
previously been associated with outbreaks of APSGN in the Northern Territory, Trinidad
and elsewhere.[39] [14] A previous outbreak of APSGN in the Northern Territory in 2000
was associated with M-serotype 3.[14]
42
Table A1.4 Streptococcal Serotypes previously associated with APSGN
M Serotype
M1
M2
M4
M6
M8
Mil
Ml2
M14
Ml5
M18
M22
M25
M28
M41
M48
M49
M52
M53
M55
M57
M59
M60
M73
M74
M81
M89
M95
st206
st212
st221
st3757
st62
st6737
stg653
stL1376
Reported association with APSGN
New Zealand(T) [30, 62], Chile (T)* [4, 106],
Trinidad* [39], Kuwait *[43], Ethiopia(S emml.2) [40]
New Zealand (T) [62], Kuwait[43], Chile(T) [4]
New Zealand (T) [62] Kuwait-[43], Chile (T/S) [4, 106], Trinidad [39]
Chile (T) [4], Trinidad [39]
Trinidad [39]
Trinidad [39]
Kuwait *[43], Maryland USA[50]
Kuwait[43]
Kuwait[43], Trinidad [39]
Kuwait *[43], Ethiopia(S) [40]
New Zealand (T) [62]
Kuwait [43], Ethiopia [40]
Kuwait [43]
New Zealand (S) [62], Trinidad [39]
Trinidad [38]
New Zealand (SIT)* [30, 62] , Chile [106] Kuwait *[43] Minnesota USA
[42]
New Zealand(S) [62]
New Zealand (S) [62], Trinidad [39]
Trinidad* [38, 39] Ethiopia (S) [40], Northern Territory_[12]
New Zealand (S) *[30, 62]
Chile [106]
New Zealand (S/T)[62], Trinidad * [39], Chile [106]
New Zealand (S)[62], Trinidad [38]
Chile* [106], Ethiopia [40]
Kuwait* [43]
Ethiopia (emm89.8) [40]
Ethiopia (emm95) [40]
Ethiopia [40]
Ethiopia [40]
Ethiopia [40]
Ethiopia [40]
Ethiopia [40]
Ethiopia [40]
Ethiopia [40]
Ethiopia [40]
* reported as sigmficant association/associated with outbreak
43
A1.7 Pathogenesis and Proposed Nephritogenic Antigens
APSGN classically follows infection with groups A streptococcus (streptococcus
pyogenes) but has also been reported in association with infection with group C and G
streptococcus, particularly Streptococcus zooepidemicus which has been associated with a
number of food borne outbreaks.[96, 107]
The pathogenesis of APSGN is complex and not completely understood. Mechanisms
involving both the humoral and cellular immune system have been proposed. There are
theories that suggest a role of the humoral immune system by formation and deposition of
nephritogenic streptococcal immune complexes. It has also been proposed that delayedtype hypersensitivity may contribute to the pathogenesis. [108]
Despite early evidence that M protein and fibrinogen could localize in the glomerulus and
mild, self-limiting renal lesions were induced by injections of M protein, further evidence
has now accumulated against the primary role of the M protein in APSGN
patheogenesis.[109] It is uncommon to have a recurrence of APSGN suggesting a specifc
antigen(s) that causes lasting immunity whereas many putative nephritogenic M-protein
types do not confer lifetime immunity.[l09] More recently it has been shown that other
streptococci, such as S. zooepidemicus (Group C) which lack M protein have been shown
to cause outbreaks of APSGN.
The specific streptococcal antigen responsible for APSGN remains unknown although
there are currently two antigens currently being investigated. These are streptococcal
pyrogenic exotoxin B (SPEB) which is a cationic cysteine proteinase which is formed by
proteolysis of a zymogen precursor (zSPEP).[1]. The other antigen is nephritis-associated
plasmin-receptor (NAPlr) which is a glycolytic enzyme with glyceraldehyde-3-phosphate
dehydrogenase activity.[l 09)
It has been shown that high antibody titres to NAPlr are found in 92% of APSGN patients
and 60% of uncomplicated streptococcal infections in Japanese patients.[110, 111]. In
addition renal NAPlr deposits have been found in all renal biopsies of APSGN patients
taken within the first 14 days of disease. [111, 112] Of note the distribution of renal
deposits NAPlr did not coincide with the distribution of IgG deposits or complement.[112]
44
It has been proposed that the mechanism of nephritogenicity relates to the plasmin binding
capacity. The activated plasmin bound to NAPlr associates with the glomerular basement
membrane and mesangium and causes tissue destruction by indirect activation of procollagenases and other matrix metalo-proteinases. NAPlr also activates alternative
complement activation which leads to accumulation of inflammatory cells. The damaged
basement membrane subsequently allows in-situ formed and circulating immune
complexes to enter and accumulate as humps in the sub-epithelial space. (see fig Al.1)
[I 08] It has recently been demonstrated that the in vitro expression of NAPlr is not limited
to streptococcal strains responsible for APSGN but also from other streptococci from
groups A, C and G.
SPEB is a cationic cysteine proteinase that belongs to a group of exotoxins produced by
pyogenic bacteria. It is present in all S.pyogenes and is the predominant extracellular
protein, accounting for more than 90% of the total secreted protein. It is a plasmin binding
receptor protein.[l09] It has been shown that SPEB/zSPEP can be seen in the renal
biopsies of many patients with APSGN.[l13-115].
SPEB does co-localize with
complement deposits and within sub-epithelial electron dense deposits (humps) that are
typical of APSGN. This may be facilitated by the cationic, antigenic charge of SPEB as
postulated by Vogt et al.[116] Serological studies by Parra et al[l14] is South America
with 153 APSGN patients, 23 patients with uncomplicated streptococcal infection and 93
controls and found that anti-zSPEB titres of 1:800-1:3200 had a likelihood ratio
(sensitivity/1-specificity) for detection of streptococcal infection with glomerulonephritis
of 2.0-44.2.
Batsford et al [115]investigated the presence of both NAPlr and SPEB deposits on renal
biopsies and antibody titres in a series of patients from Venzuela, Chile and Switzerland.
They found SPEB deposits in 12 of 17 biopsies but NAPlr definitely in only one biopsy.
Serum antibodies to SPEB were found in 53 of 53 serum samples and antibodies to NAPlr
in only 5 of 47 serum samples. It was suggested by the authors that the differences noted
in this study compared with the finding of Yozhizawa et al[l10] regarding antibody
response deposition of NAPlr may be a difference in host factors, given the previous
studies of NAPlr were done in a relatively homogenous Japanese population.
45
Recently, studies looking at molecular genomics have been shedding new light on the
patheogenesis dilemmas. Beres et aJ [I 17] have sequenced the genome of a number of
GAS including a nephritogenic and non-nephritogenic M 12 strain. They found a large
segment of DNA that was Jacking in the non-nephritogenic strain. This codes a predicted
cell surface protein that is being investigated further.
The genome of strain of
S. zooepidemicus responsible for a large outbreak of APSGN in Brazil has also been
sequenced.[118] Of note this strain was missing a large block of DNA encoding SPEB,
which is present in all GAS. This suggests that if SPEB has a role in the pathogenesis of
APSGN, it can not be the sole causative molecule.
Understanding the pathogenesis of this condition is important for developing future
therapeutics and preventative strategies. Given immunity appears to develop to APSGN
the identification of the nephritogenic antigen may lead to a potential vaccine target. The
collation of an APSGN database and collection of isolates from confirmed cases will
provide a set of isolates on which further molecular analysis can be performed in further
attempts to clarify pathogenesis of this condition.
Figure Al.l. Pathogenesis of APSGN[109]
Nephritogenic Streptococcus
Nephritogenic streptococcus
zSPEB/SPEB
GAPDHf NAPlr)
1
Anti-zSPEB/SPEB antibodies
Mesangial and GBM Binding
1
1
Plasmin entrapment and sustained
activity
(SPEB-antiSPEB)
zSPEB, SPEB
Inflammatory reactivity
(PMN, Mo) and
Degradation of GBM
anti-SPEB
+
Ic penetration through damaged GBM
deposition
Circulating (SPEB-antiSPEB)
And in situ SPEB-antiSPEB formation
Immune Complex-Mediated Glomerulonephritis
46
A1.8 Future Therapeutics and Vaccine Development
One potential mechanism for control of .APSGN is the development of a vaccine.
Immunity to GAS is mediated via antibodies to the M-protein molecule. Antibodies are
serotype specific and generally only opsonise the homologous GAS isolate. There is
considerable genetic diversity within the M-protein molecule with around 180 different
known emmSTs. [119] There is clearly considerable diversity in molecular epidemiology
of GAS across different geographic locations. Any development of a strain specific
vaccine will thus need to consider the local epidemiology of GAS in that region and the
strains responsible for APSGN and other complications of streptococcal infection.
A1.9 Skin Infection and Scabies in the Northern Territory
Streptococcal skin infection, often related to scabies is thought to be a significant factor
contributing to incidence of APSGN in the NT. During the APSGN outbreak in 2000,
87% of cases had skin sores and 40% had scabies.[l4] During the outbreak children with
skin sores were 5 times more likely to acquire APSGN than those with no sores. An
association of outbreaks of APSGN and scabies has also been made in other countries [3,
4].
I
The prevalence of skin sores is very high in Aboriginal communities. In some
communities it has been found in as many as 70% of children. [34]. Scabies infection is
also common and in some communities reported to occur in up to 35% of children[120].
Scabies control programs have been shown to be effective at reducing the incidence of
both scabies infection and impetigo. [34, 120]
A Health skin program has recently been undertaken in the East Arnhem region of the NT.
The program has focused on organized screening and subsequent treatment of skin disease
within the participating communities. A formal healthy skin training program was also
developed for community workers. Over the three year period that the program ran the
prevalence of skin sores fell from 46.1% in the first 18 months to 27.6% in the last 18
months. The overall prevalence of scabies within the community did not change
significantly during the study although in the 2-14 years age group there was a significant
47
drop in monthly prevalence of scabies from 3.7% in the first 18 months to 1.5% in the last
18 months.[25]
Social and Environmental factors are thought to contribute to the high rates of skin
infection in the Northern Territory. It is likely that overcrowding, lack of access to
adequate water, heat, humidity, poor education and implementation of personal hygiene
are all contributing factors [47]. Munoz et al[121]found an association between poor social
and environmental factors in 10 rural communities and higher childhood admission rates.
In the communities they surveyed the average number of people per dwelling ranged from
5.5 to 10.1 and in some communities up to 32% of showers and toilets were not in working
order. Similarly a study of 155 Aboriginal communities in Western Australia found that
~~~~~~~~m~~oo~~~~~~~~
overcrowding and substandard housing. [46]Studies both in the NT and abroad have
demonstrated an association been overcrowding and increases in childhood skin infection.
[45, 122].
Taplin et al[123] demonstrated an association between climate and hygiene and prevalence
of skin sores. A tropical climate in low lying areas was associated with increased
prevalence of skin sores relative to temperate and cooler climates at higher altitude. Within
each climate there was also an association between level of hygiene and prevalence of skin
sores. It was not clear exactly how the investigators determined the level of hygiene of the
participants
Al.lO Public Health Management of APSGN in the NT
The Northern Territory Centre for Disease Control has developed guidelines for
management of APSGN.[15]
After individual cases close contacts are screened and
children aged 3-15 treated with a dose of benzathine penicillin. Contacts are screened for
scabies, skin sores, edema, hypertension and urinalysis performed to assess for hematuria.
Further investigations are only performed if there are signs of APSGN.[15]
Supporting this practice of screening close contacts are studies demonstrating high rates of
both clinical and sub-clinical disease in family contacts, especially siblings. A prospective
study by Rodriguez et al [124] of 141 first degree relatives in 22 families demonstrated an
48
attack rate of 37.8% in 77 sibling contacts with an sub-clinical to clinical ratio of 4. A
similar study by Tasic and Polenakovic[125]found evidence of glomerulonephritis in 9.4%
of 170 sibling contacts. 5.3% of the contacts had sub-clinical disease compared with 4.1%
with clinical disease resulting in an sub-clinical to clinical ratio including index cases of
0.11 (9/82). A disadvantage of this study was that family contacts were only screened once
within 7 days of admission of the index case.
When considering the appropriateness of treatment of contacts with benzathine penicillin it
is important to consider the natural history of impetigo and streptococcal carriage amongst
families. Ferrieri et al[49] intensely cultured 37 children from 6 families from Red Lake
Indian Reserve in USA in 1969 to determine the acquisition and spread of GAS amongst
households. They found that streptococci were usually cultured from normal skin prior to
the development of skin lesions in 74% of episodes of pyoderma with a mean interval of
10 days. Of children with positive normal skin cultures for GAS, 86% of children with
M57 streptococci on normal skin developed pyoderma and between 65-75% of children
with other serotypes. Within the families there was spread of GAS stains with a mean
interval from index skin acquisition to secondary skin acquisition of 4.8 days with a range
of 2-12 days. The interval between index skin infection to last skin infection was 21.0 days
with a range of 1-41 days. This suggests that it is possible that close contacts of an
APSGN case may be habouring GAS on their skin but have not yet developed infection.
In the NT a community outbreak is defined as 2 unrelated cases that meet the clinical
definition in one week (laboratory confirmation not required) or 3 clinical cases in one
month that are not epidemiologically linked as family, household, close contact. In a
community outbreak all children under the age of 15 are screened for signs of APSGN or
skin sores and scabies. Any child with skin sores is treated with benzathine penicillin and
scabies are treated with permethrin 5%. There are no randomized controlled trials to
support the efficacy of intervention with penicillin treatment in the outbreak setting. The
aim of contact tracing, community screening and penicillin treatment is to reduce
transmission of the nephritogenic streptococcus. Intramuscular benzathine penicillin has
been shown to be effective at clearing pharyngeal streptococcal carriage[16] and has been
shown to provide prophylaxis against the development of pyoderma. [17, 18]. In the
randomized controlled trial of penicillin prophylaxis against impetigo performed by
Ferrieri et al[48]intramuscular benzathine penicillin prevented development of impetigo
49
for 3-4 weeks. The isolation of GAS from normal skin was reduced but not completely
eradicated. The significance of this in ongoing transmission of GAS is unknown.
Johnston et al reviewed different methods of antibiotic administration used to manage
outbreaks of APSGN. This included 1) universal administration (Benzathine Penicillin G
(BPG) given to all children in the 3-15 age group, all household contacts and children less
than 3 years if they had skin sores; (2) targeted (BPG given to children up to 15 years if
they had one or more skin sore or were household contacts of cases of APSGN); (3)
household (BPG was administered to household contacts up to age 15 years). [19] The
authors of this observational study concluded that community wide administration of
penicillin is effective at halting continuing transmission of nephritogenic streptococcus and
therefore ending outbreaks of APSGN. In this study targeted intervention was difficult to
assess as it was used in only one outbreak with apparent success. The advantages of this
method are that it is less resource intense and it removes the ethical dilemma of
administering painful penicillin injections with potential complications to health children.
[19] In addition it is thought that the presence of skin sores is of greater of epidemiological
importance in outbreaks of APSGN than colonization of intact skin.[19] This is supported
by a report of NT outbreak in 2000 during which 87% of cases had skin sores and children
with skin sores were 5 times more at risk of acquiring APSGN than those with no sores
(RR 5.74 CI 1.75,18.84). Children with scabies had twice the risk of acquiring APSGN
compare with those with no scabies (RR 2.30 CI 1.13,4.68) [14]
Prior to 1997 the approach in the NT was universal treatment with penicillin. After
revision of the guidelines in 1997 a targeted approach was adopted and this was first
implemented in the 2000 outbreak.[14] In one community during this outbreak there was
an intervention in February but a further cluster of cases occurring 12 weeks later requiring
further intervention. It is not clear whether the same strain was responsible for both
clusters. Targeted interventions were carried out in 6 further communities in East Arnhem.
Two of these communities performed a second intervention after only one further case
because of perceived poor coverage of the first intervention.
The targeted approach was further used in the 2005 outbreak in the Top End. [76] During
this outbreak in one community the initial intervention failed to control the outbreak and a
second wave of cases occurred. During the stage 2 intervention all contacts, regardless of
50
age or skin status were screened and treated with penicillin. The definition of a close
contact was also interpreted more broadly; playmates and people other that household
members who spent a lot of time and had some physical contact with the case were
considered close contacts. Otherwise the second intervention was the same as the first and
eventually halted cases. It was postulated that wet and crowded conditions that occurred as
a result of a cyclone between the 2 stages of the outbreak may have contributed to
crowding, hygiene problems and circulation of the bacteria.
In 2005 an outbreak occurred at the Lockhart River community in Far North Queensland
and a community intervention with a targeted approach was used. [77]
In this outbreak
intra-muscular penicillin did not prevent the onset of APSGN in 3 cases, possibly because
presentation was too late for prevention of the immune complex process. Two children
received penicillin one week prior to onset of APSGN and another child received penicillin
5 weeks prior to onset of illness.
A disadvantage of a targeted approach in the management of community outbreaks is that
it will not to prevent treated children from developing APSGN if they are in the latent
period. There is evidence that treating children at this stage does not alter the course of
disease as was found in the Lockhart River Community in Queensland. Treatment of
children with skin sores is aimed at preventing further transmission of nephritogenic GAS.
However in many cases children with pyoderma will have already transmitted their GAS
to household contacts prior to receiving treatment given the mean time from household
acquisition of GAS to secondary acquisition is 4.8 days. In addition in the majority of
cases of pyoderma the GAS strain is present of a mean of 10 days prior to development of
infection. [49] A benefit of a more widespread approach to penicillin treatment is that
children who may habour GAS on their intact skin may be prevented from development of
skin sores and subsequent APSGN.
In summary, the current practices for the public health management of APSGN cases and
outbreaks are supported by limited observational studies only. Further assessment of these
strategies is required to define the optimal management.
51
APPENDIX 2.0 - ADDITIONAL METHODS
A2.1 Data Cleaning and Management
Community locations were checked to ensure that all cases occurred within the NT. This
was primarily an issue in the Alice Springs district where there are a number of South
Australian Communities in close proximity. These cases were included in general
epidemiological analysis but not in incidence calculations which were specific for NT.
Table A2.1 Cases notified in NT from Communities outside NT:.
Number of Cases
Year
Amata
1
1998
Emabella
4
1998.2005 x2, 2007
Fregon
4
1998, 2005
Mimili
1
2005
Indulkana
3
2005
total
13
Community
X
X
3
2, 2008
Community locations were also cross-checked against district. In some situations the cases
were entered under the district that they were notified in rather than district in which the
Community was located.
Table A2.2 Cases notified in incorrect Districts
Community
Number incorrectly
Incorrect District
Actual District
labelled cases
Ali Curong
1
Alice Springs
Barkly
Borroloola
5
Darwin
Katherine
Galiwinku
1
Darwin
EastAmhem
Gapiwiyak
1
Darwin
EastAmhem
Ramininging
1
Darwin
EastAmhem
Milingimbi
1
Darwin
EastAmhem
Tennant Creek
4
Alice Springs
Barkly
52
A2.2 APSGN Streptococcal Isolate database
Since 1990 isolates from supposed cases of APSGN have been collected by Menzies
School of Health Research(MSHR) as part of a larger collection of streptococcal isolates.
Many of these cases had been labelled as APSGN however clinical details had not been
verified. I aimed to verify the existing collection of possible APSGN cases and then crosscheck the NT Centre for disease control database with the MSHR database for further
isolates from APSGN cases that had been collected.
A Microsoft access database was established that included both demographic, clinical and
bacterial isolate characteristics for each cases. The demographic data collected included
name, date of birth, hospital record number (HRN), community and indigenous status.
Clinical data included the presence of edema, hypertension, skin sores, scabies and
whether the case was outbreak or sporadic. Results of urine microscopy, complement
levels, ASOT and anti-DNAse level and peak creatinine were also documented. Data about
the bacterial isolates included data of collection, site of collection, laboratory identifying
number, emmST and MLST if known.
Whether the case was confirmed by clinical
records, CDC notification or both was recorded. Isolates were included in final analysis
either if they had been notified to CDC as a confirmed case or if clinical details could be
collected retrospectively.
This database of APSGN can be used for future research into molecular characteristics of
GAS responsible for APSGN.
53
APPENDIX 3- ADDITIONAL RESULTS
Table A3.1 Yearly notifications and Incidence for all Ages
This includes only confirmed cases residing within the Northern Territory
Notified Confirmed
Estimated
Annual incidence per
Year
cases
Population
100,000 persons
1992
6
168086
3.6
1993
28
170734
16.4
1994
20
173375
11.5
1995
67
177552
37.7
1996
16
181843
8.8
1997
16
186912
8.6
1998
13
189880
6.8
1999
8
192735
4.2
2000
55
195561
28.1
2001
19
197768
9.6
.2002
6
199411
3.0
2003
4
200046
2.0
2004
14
202063
6.9
2005
80
206373
38.8
2006
12
210627
5.7
2007
20
214929
9.3
Total
383
3067895
12.5
54
Table A3.2 Yearly notifications and Incidence for Ages 0-14 years
Year
Number of Confirmed
Estimated
Annual
Notified cases aged
Population aged 0-
incidence per
0-14 years
14 years
100,000
persons
1992
6
46692
12.9
1993
16
47197
33.9
1994
16
47771
33.5
1995
55
48523
113.3
1996
14
49330
28.4
1997
16
50010
32.0
1998
12
50369
23.8
1999
8
50481
15.8
2000
45
50760
88.7
2001
17
51175
33.2
2002
5
51051
9.8
2003
1
51016
2.0
2004
14
51203
27.3
2005
77
51414
149.8
2006
10
51526
19.4
2007
19
51765
36.7
Total
331
800283
41.4
55
Table A3.3 Yearly notifications and Incidence in those ~ 15 years
Year
Number of
Population Aged~
Incidence in
confirmed cases Age
15 years
Population age . ~
~15year
15 years
1992
0
121394
0.0
1993
10
123537
8.1
1994
3
125604
2.4
1995
9
129029
7.0
1996
0
132513
0.0
1997
0
136902
0.0
1998
0
139511
0.0
1998
0
142254
0.0
2000
8
144801
5.5
2001
2
146593
1.4
2002
1
148360
0.7
2003
3
149030
2.0
2004
0
150860
0.0
2005
2
154959
1.3
2006
2
159101
1.3
2007
1
163164
0.6
total
41
2267612
1.8
56
Table A3.4 Seasonal Distribution of Cases per District.
District
Total
Dry Season
(April-
95%C
( %)
September)(%)
Wet
95%CI
Season
(%)
P- value
(OctoberMarch)
(%)
Darwin
168
106 (63.1)
55.8 -70.4
62 (36.9)
29.6-44.2
p<O.OOOI
East
127
84 (66.1)
57.9-74.3
43 (33.9)
25.6-42.1
p<O.OOOI
Katherine
48
32 (66.7)
53.3- 80.0
16 (33.3)
20.0-46.7
p=O.OOI
Top End
343
222 (64.7)*
59.7-69.8
121 (35.3)
30.2-40.3
p<O.OOOI
Barldy
16
11
46.0- 91.5
5 (31.2)
8.5-54
p=0.034
Alice
79
40 (50.6)
39.6-61.7
39 (49.4)
38.3-60.4
p=0.87
95
51 (53.7)*
43.6-63.7
44 (46.3)
36.3-56.3
p=0.31
438
273 (62.3)
57.8-66.9
165 (37.7)
33.1-42.2
p<O.OOOI
Am hem
(68.8)
Springs
Central
Australia
Total
* Difference between Top End and Central Australia significant with p= 0.049
57
Table A3.5 Regional Incidence of APSGN within the NT
Darwin
133,938
24,240 (18.1)
Darwin Urban
I 18,064
13,I86 (Il.2)
Confirmed Annual
Cases
Incidence
APSGNper
IOO,OOO
person
144
7.7
10
0.6
Darwin Rural
I5,874
I I,473 (72.3)
134
6I.2
East Arnhem
Katherine
Barkly
Alice Springs
15,911
10,054 (63.2)
18,765
10,061 (53.6)
118
48
6,203
40,112
4,031 (65.0)
14
53.4
17.1
" 16.2
(12.6- 22.7)
(8.9- 27.3)
16,048 (40.0)
59
9.8
(7.5- 12.7)
26,875
5684 (2I.I)
20
4.9
(3.0-7.6)
13,237
10670 (80.6)
39
20.0
(14.2-27.3)
214,929
65,159 (30.3)
383
12.5
(113 -13.8)
District
Population
2007
Indigenous
Population
(%)
Alice Springs
Urban
Alice Springs
Rural
Total
Population source: Department of Health Gains Planning
58
95%CI
(6.5- 9.0)
(0.28-I.l))
(5I.3-72.5)
(44.2- 64.0)
Table A3.6 Outbreak and Sporadic Cases of APSGN in the Top End
Outbreak
Year
Katherine
Darwin
Sporadic
East
total
Darwin
Katherine
Arnhem
East
total
Arnhem
I99I
0
0
0
0
0
0
0
0
I992
2
0
0
2
4
0
0
4
I993
0
0
2I
2I
2
4
7
I994
9
2
0
11
5
I
2
8
I995
7
5
2I
33
8
4
8
20
I996
3
0
0
3
3
2
4
9
I997
5
0
0
5
2
0
I998
0
0
2
2
I
0
2
3
I999
2
0
0
2
1
3
1
5
2000
20
0
22
42
0
6
5
11
200I
4
0
0
4
6
3
2
2002
0
0
0
0
2003
0
0
0
0
0
I
1
11
5
2
2004
2
0
2
4
2
3
6
11
2005
38
0
2
40
II
9
I7
37
2006
6
0
0
6
4
0
1
5
2007
0
0
0
0
7
4
2
13
2008
4
4
0
8
5
1
0
8
102
11
70
I83
6I
42
57
162
Total
59
3
3
Table A3.7 Outbreak and Sporadic Cases of APSGN in Alice Springs/Barkly
Outbreak
SJ!.oradic
Alice Springs Barkly
Alice Springs District
District
1
0
1991
0
0
0
1992
0
0
1993
0
0
1
1994
0
0
5
5
2
1995
4
0
0
1996
7
0
0
1997
11
0
0
1998
0
0
1999
0
2
0
0
2000
4
0
0
2001
0
2002
0
0
2
0
0
2003
2
0
2004
0
21
2
0
2005
0
0
0
2006
9
0
0
2007
6
0
0
2008
4
5
75
Total
difference between Alice Springs and Barkly p= 0.007
Year
Barkly
District
0
0
0
0
2
0
1
0
1
0
0
1
0
0
2
1
1
2
11
Table A3.8 Comparison of Outbreak Vs Sporadic cases
Region
Outbreak
95%C
Sporadic
95%CI
Cases(%)
(%)
Cases(%)
(%)
Pvalue
Darwin
163
102 (62.6)
55.1 -70.0
61 (37 .4)
30.0-44.9
p<0.0001
East Arnhem
127
70 (55.1)
46.5-63.8
57 (44.9)
36.2-53.5
p =0.10
Katherine
53
11 (20.8)
9.8-31.7
42 (79.2)
68.3-90.2
p < 0.0001
Top End
343
183 (53.4)
48.1-58.6
160(46.6)
41.4-51.9
p = 0.10
Barldy
16
5 (31.3)
8.5-54.0
11 (68.8)
46.0-91.5
p = 0.034
Alice Springs
79
4(5.1)
0.2-9.9
75 (94.9)
90.1-99.8%
p< 0.0001
Central
95
9 (9.5)
3.6-15.4
86 (90.5)
84.6-96.4
p< 0.0001
438
192 (43.8)
39.2-48.5
246 (56.2)
51.5-60.8
p = 0.0003
Australia
total
60
Table A3.9 List of Individual Community Outbreaks.
1992
1993
1993
1993
1993
1994
District
Darwin
EastAmhem
EastAmhem
EastAmhem
EastAmhem
Darwin
1994
1995
1995
1995
1995
1995
1995
1995
1995
1996
1997
1997
1998
1999
2000
2000
2000
2000
2000
2000
2000
2000
2000
2001
2004
2004
2005
2005
2005
2005
2005
2005
2005
2006
2008
2008
Katherine
Darwin
EastAmhem
EastAmhem
EastAmhem
Katherine
Barkly
Barkly
Alice Springs
Darwin
Darwin
Darwin
EastAmhem
Darwin
Darwin
Darwin
Darwin
Darwin
Darwin
EastAmhem
EastAmhem
EastAmhem
EastAmhem
Darwin
Darwin
EastAmhem
Darwin
Darwin
Darwin
Darwin
Darwin
EastAmhem
Alice Springs
Darwin
Darwin
Darwin
Year
2008 Katherine
Community
Oenpilli
Galiwinku
Gapuwiyak
Milingimbi
Yirrkala
Nguiu
Timber
Creek(Town)
Wadeye
Galiwinku
Gapuwiyak
Yirrkala
Ngukurr
Ali Curong*
Ali Curong*
Aputula
Nguiu
Nguiu
Peppimenarti
Yirrkala
Nguiu
Maningrida
Minjilang
Nguiu*
Nguiu*
Nguiu*
Galiwinku
Milingimbi
Ramingining
Yirrkala
Wadeye
Maningrida
Galiwinku
Cobourg Peninsula
Maningrida
Nguiu*
Nguiu*
Wadeye
Milingimbi
Alice Springs
Nguiu
Maningrida*
Maningrida*
Borroloola
(Communit~)
61
Number of
Cases
Length
(Days)
Additional cases
within 6mths
2
4
3
12
2
9
3
27
21
19
6
52
0
1
0
0
2
0
2
7
5
12
4
5
2
3
2
3
3
2
2
2
4
3
4
5
4
3
11
3
5
4
2
2
2
9
12
11
4
2
2
6
2
2
1
26
35
60
29
36
0
3
1
5
1
15
28
1
2
3
33
1
23
13
15
9
29
24
57
17
5
7
3
57
56
34
47
3
2
65
5
6
4
19
1
1
0
0
0
0
0
0
0
0
0
1
0
0
0
0
0
0
0
0
0
0
0
1
0
0
0
0
0
2
0
2
0
1
0
Figure A3.1 Notifications per Year and District
12 0
I
100
"C
~
0
80
I-
c:
Ill
Gl
Ill
Ill
0
I
80
•
...Gl
.0
E
40
:I
c:
20
~
n
1991
1992
1993
~ = g~
0 I!
2002
2006
-
IIIII
1994
• aR~ ~
1995
1996
1997
1998
1999
1.~
-
~
l.r.
!;";
2000
2001
:q
2003
2004
2005
Year
ID Alice Springs •
Barkly 0 Darwin 0 East Arnhem • Katherine
62
I
f.-
~
2007
2008
Figure A3.2 Regional Incidence in Indigenous Australians Aged 0-14 years
Indigenous Australians, 0-14 years
i
I
I
I
I
I
I
I
I
I
I
Darwin Overall
Darwin Urban
.__,
Darwin Remote
c
0
I
I
j
l
I
I
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Figure A3.3 Notifications in Top End as Outbreak or Sporadic
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