The epidemiology and outcomes of central nervous system infections in Far North Queensland, tropical Australia; 2000-2019.

BACKGROUND: The epidemiology of central nervous system (CNS) infections in tropical Australia is incompletely defined.
METHODS: A retrospective study of all individuals in Far North Queensland, tropical Australia, who were diagnosed with a CNS infection between January 1, 2000, and December 31, 2019. The microbiological aetiology of the infection was correlated with patients' demographic characteristics and their clinical course.
RESULTS: There were 725 cases of CNS infection during the study period, meningitis (77.4%) was the most common, followed by brain abscess (11.6%), encephalitis (9.9%) and spinal infection (1.1%). Infants (24.3%, p<0.0001) and Aboriginal and Torres Strait Islander Australians (175/666 local residents, 26.3%, p<0.0001) were over-represented in the cohort. A pathogen was identified in 513 cases (70.8%); this was viral in 299 (41.2%), bacterial in 175 (24.1%) and fungal in 35 (4.8%). Cryptococcal meningitis (24 cases) was diagnosed as frequently as pneumococcal meningitis (24 cases). There were only 2 CNS infections with a S. pneumoniae serotype in the 13-valent pneumococcal vaccine after its addition to the National Immunisation schedule in 2011. Tropical pathogens-including Cryptococcus species (9/84, 11%), Mycobacterium tuberculosis (7/84, 8%) and Burkholderia pseudomallei (5/84, 6%)-were among the most common causes of brain abscess. However, arboviral CNS infections were rare, with only one locally acquired case-a dengue infection in 2009-diagnosed in the entire study period. Intensive Care Unit admission was necessary in 14.3%; the overall case fatality rate was 4.4%.
CONCLUSION: Tropical pathogens cause CNS infections as commonly as traditional bacterial pathogens in this region of tropical Australia. However, despite being highlighted in the national consensus guidelines, arboviruses were identified very rarely. Prompt access to sophisticated diagnostic and supportive care in Australia's well-resourced public health system is likely to have contributed to the cohort's low case-fatality rate.

Introduction

Infections of the central nervous system (CNS) result in significant global morbidity and mortality, however, early diagnosis and prompt, targeted treatment can improve outcomes. While a definitive diagnosis is awaited, it is essential to ensure that optimal empirical antimicrobial therapy is administered. However, this is only possible if clinicians have a good understanding of the likely local pathogens [1].

The epidemiology of CNS infections in Far North Queensland (FNQ), in tropical Australia, is influenced by environmental, pathogen and human factors. The region’s tropical climate, vectors (including ticks, mites, and mosquitoes), amplifying intermediate hosts, significant agricultural industry and surrounding harsh environment might all be expected to contribute to the local burden of disease [2-5]. FNQ shares a maritime border with Papua New Guinea (PNG) and since the establishment of the Torres Strait treaty in 1985, residents of PNG and the outer Torres Strait Islands have been able to move freely across the border to maintain cultural ties. However, there is a higher prevalence of many infectious diseases—including tuberculosis, dengue, malaria, and Japanese encephalitis virus (JEV)—in PNG, which may be imported into Australia [6]. Although these pathogens have not become established on the Australian mainland, imported cases have been reported [7,8]. These infections have the potential to cause life-threatening disease in some of the most remote communities in Australia.

Urban expansion from recent population growth in the region (with a resulting expansion in medical services leading to more immunocompromised patients) and the area’s reputation as an international travel hub, might also be expected to affect the incidence of disease [2,3,9,10]. Approximately 17% of the local population identifies as an Aboriginal and/or Torres Strait Islander Australian [11]. Many members of these Indigenous communities experience significant socioeconomic disadvantage and, accordingly, a high burden of comorbidities, increasing their susceptibility to infection, including CNS disease [12-15].

Conversely, several recent public health interventions might be expected to lessen the local burden of CNS infections. A significant recent expansion of Australia’s national vaccination programme would be anticipated to reduce the local incidence of Streptococcus pneumoniae and Neisseria meningitidis infections, building on the progress seen against Haemophilus influenzae in the late 20th century [16]. Introduction of the herpes zoster vaccine in 2005 and expanded influenza and measles/mumps/rubella vaccine coverage might also be expected to have a salutary effect [17-19]. The local public health unit’s implementation of arbovirus vector control interventions, including surveillance and control of mosquito populations and release of Wolbachia-infected mosquitoes–which mitigate the transmission of dengue, zika and chikungunya–would be expected to have a positive impact [20-22]. Meanwhile, the Queensland State Government sponsored Aboriginal and Torres Strait Islander Environmental Health Program, introduced in 2002, aims to target deficiencies in health infrastructure for the local Aboriginal and Torres Strait Islander population, particularly in remote locations [23]. The program consists of a suite of public health interventions that address housing, water, sanitation, waste disposal and animal management, all of which have the potential to influence the burden of CNS infections [24,25].

This study was performed to define, more precisely, the temporospatial epidemiology of CNS infections in the FNQ region and to identify the association between demographic factors—including age, Indigenous status, and remote residence—and the aetiology and clinical course of the infections. It also intended to characterise the spectrum and burden of imported pathogens from neighbouring PNG. The study aimed to determine the success of recent public health interventions including changes to the national immunisation schedule and local arbovirus vector control measures on the incidence of CNS infections. These data might be used to inform public health strategies to reduce the local burden of potentially life-threatening CNS infections in the future.

Methods

This retrospective study was performed at Cairns Hospital in Far North Queensland, Australia. Cairns Hospital is a 531-bed tertiary-referral hospital serving a population of approximately 280,000 people who live in an area of over 380,000 km2 (Fig 1) [26]. All patients with a diagnosis of CNS infection between January 1, 2000, and December 31, 2019, were eligible for inclusion in the study. The Australian Society of Infectious Diseases and United States’ Center for Disease Control and Prevention guidelines were used for the case definitions of CNS infections (S1 File) [27,28]. Cases were identified by reviewing all hospital admissions during the study period with relevant International Classification of Diseases (ICD) coding. Additional cases were identified by searching Cairns Hospital’s electronic laboratory database for any cerebrospinal fluid (CSF) in which an organism was identified by culture, PCR, antigen, or antibody detection and by reviewing the infectious diseases department’s database of cases. Repeat samples were not included. Plasmodium falciparum is not considered a cause of meningitis or encephalitis, but it may have a similar clinical presentation [29]. As one of the aims of the study was to determine if CNS pathogens were being imported from PNG, a country which has one of the highest incidences of malaria in the region, patients with cerebral malaria (impaired consciousness and laboratory confirmed P. falciparum infection) were also identified [30]. As the consensus guidelines for the investigation and management of encephalitis in adults and children in Australia and New Zealand suggest that autoimmune encephalitis is responsible for up to a third of patients presenting with an encephalitis clinical syndrome [27], patients meeting the case definitions of autoimmune encephalitis from a recent consensus statement were also sought (S2 File) [31].

Fig 1

Map Far North Queensland, Australia, highlighting its proximity to Papua New Guinea.

The map was constructed using mapping software (MapInfo version 15.02, Connecticut, USA) using data provided by the State of Queensland (QSpatial). Queensland Place Names—State of Queensland (Department of Natural Resources, Mines and Energy) 2019, available under Creative Commons Attribution 4.0 International licence https://creativecommons.org/licenses/by/4.0/. ‘Coastline and state border–Queensland—State of Queensland (Department of Natural Resources, Mines and Energy) 2019, available under Creative Commons Attribution 4.0 International licence https://creativecommons.org/licenses/by/4.0/.

Laboratory data and radiology reports were retrieved from the public health system’s pathology database and imaging system. Additional clinical information–including the patients’ demographics, clinical features, comorbidities, and outcomes–were collected from the medical records of cases between January 1, 2015, and December 31, 2019. This period was chosen as it coincided with the introduction of an electronic medical record, facilitating data collection. The patients’ Indigenous status was also recorded: all individuals receiving care in Queensland’s public health system are asked whether they identify as an Aboriginal Australian, a Torres Strait Islander Australian, both, or neither. Infants were defined as those aged <1 year, children as those aged 1 to 17 years and adults as those aged ≥18 years. The Australian Statistical Geographical Classification Remoteness Area (ASGC-RA) framework was used to determine the remoteness of areas in Australia. Urban areas were defined as those within categories ASGC-RA 1 to 3, and remote areas as those within ASGC-RA 4 and 5 [11]. A patient was defined as being immunocompromised if they had confirmed human immunodeficiency virus (HIV) infection or were receiving systemic immunosuppressive therapy [32]. An unusual pathogen was defined as one that was not covered by the empirical treatment regime outlined in the Australian Therapeutic Guidelines [33]. Tropical pathogens included pathogens typically seen in tropical climates. Disability was defined as a Modified Rankin Scale score between 2 and 5 –or the requirement for an anticonvulsant medication–on hospital discharge [34]. The management of the patients was said to be appropriate if it was concordant with Australian Therapeutic Guidelines for the identified pathogen, or the clinical syndrome if no pathogen was identified [33]. Australian Bureau of Statistics population data were used to determine disease incidence [26].

Data analysis

All data were de-identified, entered into an electronic dataset (Microsoft Excel, S1 Dataset) and analysed with statistical software (Stata v 14.2). Univariate analysis was performed using the Kruskal-Wallis, Fisher’s exact and chi-squared tests where appropriate. Multivariate analysis was performed using logistic regression. Trends over time were determined, using year as a continuous variable, using an extension of the Wilcoxon rank sum test [35].

Ethics review

The Far North Queensland Human Research Ethics Committee provided ethical approval for this study (HREC/2020/QCH/59103–1428) and waived the requirement for informed patient consent given the retrospective nature of the study, and de-identified nature of the data.

Results

Between January 1, 2000, and December 31, 2019, a total of 859 potential cases of CNS infection were identified, however, after review, 134 failed to meet inclusion criteria, leaving 725 cases for analysis. This included 561 (77.4%) cases of meningitis, 84 (11.6%) cases of brain abscess, 72 (9.9%) cases of encephalitis and 8 (1.1%) cases of spinal cord disease (myelitis or intraspinal abscesses) (S1 Fig).

The incidence of CNS infections in the FNQ residents was 13.0/100,000 population in 2000 compared to 21.6/100,000 population in 2019, however the change in incidence did not reach statistical significance (p for trend = 0.09) (S1 Table). Of the 725 cases, 401 (55.3%) occurred in males; 425 (58.6%) occurred in adults and 176 (24.3%) occurred in infants (Table 1). A causative organism was identified in 513/725 (70.8%). Bacterial infection occurred in 175/725 (24.1%) cases, viral infection in 299/725 (41.2%) cases and fungal infection in 35/725 (4.8%) cases. Viral infection was most commonly responsible in infants and adults, although bacteria were more common in children (Table 1).

Table 1

The number of cases of CNS infection in infants, children and adults stratified by clinical phenotype and aetiology.

	Infant	Child	Adult	Total
All	176 (24.3%)	124 (17.1%)	425 (58.6%)	725
Clinical phenotypes
Meningitis	165 (93.8%)	100 (80.7%)	296 (69.7%)	561 (77.4%)
Encephalitis	7 (4.0%)	8 (6.5%)	57 (13.4%)	72 (9.9%)
Brain abscess	4 (2.3%)	15 (12.1%)	65 (15.3%)	84 (11.6%)
Spinal disease	0	1 (0.8%)	7 (1.7%)	8 (1.1%)
Aetiological agent
Bacterial	36 (20.4%)	44 (35.5%)	95 (22.4%)	175 (24.1%)
Viral	86 (48.9%)	43 (34.7%)	170 (40.0%)	299 (41.2%)
Fungal	0	1 (0.8%)	34 (8.0%)	35 (4.8%)
Other a	0	0	4 (0.9%)	4 (0.6%)
Not identified	54 (30.7%)	36 (29.0%)	122 (28.7%)	212 (29.2%)

a Two protozoan, one parasitic and one amoebic.

Aboriginal and Torres Strait Islander people

Aboriginal and Torres Strait Islander status was available in 702 cases, 178 (25.4%) of whom identified as Indigenous. Among the 666 local FNQ residents, 175 (26.3%) identified as Indigenous Australians compared with 49241/287107 (17.2%) of the general FNQ population at the end of the study period (p<0.0001). Local Indigenous residents with CNS infection were more likely to live in a remote location than local non-Indigenous people (55/175 (31.4%) versus 24/491 (4.9%), p<0.0001). The median (IQR) age of the Indigenous patients was 13 (0–35) years compared with 26 (3–48) years among non-Indigenous patients (p = 0.0001). Indigenous patients with CNS infection were more likely to be infants (p = 0.003). The proportion of patients with the different clinical phenotypes was similar for Indigenous Australians and non-Indigenous Australians, but viral aetiologies were diagnosed less commonly—and fungal aetiologies were diagnosed more commonly—in Indigenous Australians (Table 2). Cryptococcal and meningococcal infection were more common in Indigenous Australians than in non-Indigenous Australians. The higher rate of pneumococcal CNS infection in Indigenous Australians did not reach statistical significance. The rates of vaccine-preventable disease–including S. pneumoniae, N. meningitidis, and H. influenzae infection–were higher in Indigenous children and infants (p<0.0001) (S2 Table). There was only a single case of CNS tuberculosis in an Indigenous Australian during the entire study period (Table 3). The 5 additional cases of CNS tuberculosis in FNQ residents occurred in a non-Indigenous Australian, 2 patients born in PNG, 1 patient born in Laos and 1 patient born in England.

Table 2

The number of cases in Indigenous and non-Indigenous Australians stratified by age, clinical phenotypes and aetiological agent.

	All n = 702a	Indigenous n = 178	Non-Indigenous n = 524	p
Age group
Infants	167 (23.8%)	57 (32.0%)	110 (21.0%)	0.003
Children	117 (16.7%)	41 (23.0%)	76 (14.5%)	0.008
Adults	418 (59.5%)	80 (44.9%)	338 (64.5%)	<0.0001
Clinical phenotype
Meningitis	542 (77.2%)	137 (77.0%)	405 (77.3%)	0.93
Encephalitis	70 (10.0%)	16 (9.0%)	54 (10.3%)	0.61
Brain abscess	82 (11.7%)	21 (11.8%)	61 (11.6%)	0.96
Spinal disease	8 (1.1%)	4 (2.3%)	4 (0.8%)	0.11
Aetiological agent
Bacterial	166 (23.7%)	49 (27.5%)	117 (22.3%)	0.15
Viral	294 (41.9%)	54 (30.3%)	240 (45.8%)	<0.0001
Fungal	34 (4.8%)	19 (10.7%)	15 (2.9%)	<0.0001
No pathogen identified	204 (29.1%)	56 (31.5%)	148 (28.2%)	0.41

a This table only presents the data of the 702 cases in whom Indigenous status was available.

Table 3

The number of cases in Indigenous and non-Indigenous Australians by pathogen.

Pathogen	All n = 702a	Indigenous n = 178	Non-Indigenous n = 524	p
N. meningitidis	34 (4.8%)	14 (7.9%)	20 (3.8%)	0.03
S. pneumoniae	24 (3.4%)	10 (5.6%)	14 (2.7%)	0.06
B. pseudomallei	8 (1.1%)	2 (1.1%)	6 (1.1%)	0.98
M. tuberculosis	12 (1.7%)	1 (0.6%)	11 (2.1%)	0.31
Cryptococcus species	33 (4.7%)	18 (10.1%)	15 (2.9%)	<0.0001
Enterovirus	217 (30.9%)	45 (25.3%)	172 (32.8%)	0.06
Herpes simplex virus-2	31 (4.4%)	4 (2.2%)	27 (5.2%)	0.14
Herpes simplex virus-1	18 (2.6%)	1 (0.6%)	17 (3.2%)	0.06
Varicella zoster virus	14 (2.0%)	3 (1.7%)	11 (2.1%)	1.0

a This table only presents the data of the 702 cases in whom Indigenous status was available.

Impact of remote residence on disease incidence

A residential address was available in 679 local FNQ residents: there were 80 (11.8%) patients from remote areas; compared to 29953/286995 (10.4%) of the general FNQ population at the end of the study period (p = 0.25). B. pseudomallei was the only pathogen that was more likely to occur in a resident living a remote location (Table 4). A total of 5356 lumbar punctures were performed in FNQ during the study period: 4562 (85.2%) were performed in urban areas; 153951/279459 (55.1%) of the general FNQ population lived in an urban area in the 2016 Australian census (p<0.0001).

Table 4

The number of cases in urban and remote areas within FNQ by clinical phenotype and pathogen.

	All an = 679	Urban n = 599	Remote n = 80	p
Clinical phenotype
Meningitis	529	469 (78.3%)	60 (75%)	0.50
Encephalitis	66	60 (10.0%)	6 (8%)	0.55
Brain abscess	76	64 (10.7%)	12 (15%)	0.25
Spinal disease	8	6 (1.0%)	2 (2%)	0.24
Pathogen
N. meningitidis	34 (5.0%)	27 (4.5%)	7 (9%)	0.10
S. pneumoniae	22 (3.2%)	18 (3.0%)	4 (5%)	0.34
B. pseudomallei	8 (1.2%)	5 (0.8%)	3 (4%)	0.02
M. tuberculosis	6 (0.9%)	4 (0.7%)	2 (2%)	0.10
Cryptococcus species	31 (4.6%)	26 (4.3%)	5 (6%)	0.44
Enterovirus	216 (31.8%)	196 (32.7%)	20 (25%)	0.16
Herpes simplex virus-2	31 (4.6%)	28 (4.7%)	3 (4%)	0.71
Herpes simplex virus-1	18 (2.6%)	18 (3.0%)	0	0.12
Varicella zoster virus	14 (2.1%)	14 (2.3%)	0	0.17

a There were 679 cases with a residential address in FNQ.

The cohort contained 32 PNG residents; Mycobacterium tuberculosis was the most common isolate in these individuals (7/32, 21%), compared to only a single case of CNS tuberculosis in an Australian resident (1/679, 0.1%) (p<0.001). There were 767 imported cases of P. falciparum malaria diagnosed in FNQ during the study period, of which only 83/767 (10.8%) occurred after 2010. In the last five years of the study period, the period where clinical data were available, only 1/29 P. falciparum cases, a PNG resident, had impaired consciousness. Among these 29 P. falciparum cases, 12 (41%) were from PNG, 11 (38%) from Africa, 4 (14%) from Indonesia, 1 (3%) from the Solomon Islands and 1 (3%) was from India. Of the 29 cases, 18 (62%) were returning travelers, 8 (28%) were refugees or migrants, and 3 (10%) were PNG nationals transferred to Cairns for further management.

Meningitis

There were 561 cases of meningitis. The incidence was 8.9/100,000 population in 2000 compared to 16.7/100,000 population in 2019 (p for trend = 0.22). The patients with meningitis had a median (IQR) age of 19 (0–36) years; 302/561 (53.8%) were males. A viral aetiology was most common, with enterovirus the most frequently diagnosed. Neisseria meningitidis was the second most commonly identified. Cryptococcal meningitis occurred as commonly as pneumococcal meningitis (Table 5).

Table 5

Laboratory-confirmed aetiology of patients with meningitis.

Viral (n = 270)	Bacterial (n = 125)	Fungal (n = 24)
Enterovirus (n = 218)Herpes simplex virus-2 (n = 33)Varicella zoster virus (n = 12)Parechovirus (n = 3)Mumps (n = 2)Epstein Barr virus (n = 1)Human herpesvirus 6 (n = 1)	Neisseria meningitidis (n = 36)Streptococcus pneumoniae (n = 24)Staphylococcus aureus (n = 8)Streptococcus agalactiae (n = 8)Treponema pallidum (n = 6)Haemophilus influenzae (n = 6)Mycobacterium tuberculosis (n = 6)Salmonella species (n = 5)Escherichia coli (n = 5)Enterococcus faecalis (n = 4)Leptospira species (n = 3)Listeria monocytogenes (n = 2)Streptococcus milleri (n = 2)Burkholderia pseudomallei (n = 1)Aeromonas hydrophilia (n = 1)Elizabethkingia meningoseptica (n = 1)Enterococcus faecium (n = 1)Klebsiella pneumoniae (n = 1)Pasteurella multocida (n = 1)Propionibacterium acnes a (n = 1)Pseudomonas aeruginosa (n = 1)Staphylococcus epidermidis b (n = 1)Streptococcus pyogenes (n = 1)	Cryptococcus (n = 24) • Cryptococcus neoformans (n = 13) • Cryptococcus gattii (n = 7) • Cryptococcus spp (non-speciated (n = 4)

This pathogen was isolated in a patient with a ventriculoperitoneal shunt.

b This pathogen was isolated in a patient with a lumbar drain.

A pathogen was not identified in 142 (25.3%) meningitis cases.

Encephalitis

There were 72 cases of encephalitis. The incidence had a nadir of 0.4/100,000 population in 2003 and a peak of 2.5/100,000 population in 2018 (p for trend = 0.06); 43/72 (60%) cases occurred in males. The cases of encephalitis had a median (IQR)) age of 50 (21–66) years. Most cases had a viral aetiology, with herpes simplex virus-1 being the most common pathogen (18/72, 25%) (Table 6). There were only three cases of arboviral encephalitis, including one case of JEV imported from PNG in 2004, one case of Murray Valley encephalitis imported from PNG in 2012 and a single case of dengue. The case of dengue encephalitis was diagnosed in a local FNQ resident with no travel history during the last significant outbreak in Cairns in 2009. A case of cerebral gnathostomiasis was identified in a returning traveler from Thailand in 2019. There were 36 cases in which a pathogen was not identified; flavivirus serology was performed—and was negative—in 12 (33%) of these cases, 6 (17%) of whom also had negative PCR tests for Kunjin and Murray Valley Encephalitis. In addition to the 72 cases of encephalitis, there were 31 cases of immune-mediated encephalitis cases during the study period; 9/31 (29%) were acute disseminated encephalomyelitis and 4/31 (13%) were anti-N-methyl-D-aspartate receptor encephalitis. Increasing numbers of cases of autoimmune encephalitis were diagnosed over the course of the study period (p for trend = 0.002).

Table 6

Laboratory-confirmed aetiology of patients with encephalitis.

Viral (n = 29)	Bacterial (n = 5)	Fungal (n = 1)	Parasitic (n = 1)
Herpes simplex virus-1 (n = 18)Varicella zoster virus (n = 2)JC virus a (n = 2)Enterovirus (n = 2)JEV b (n = 1)Murray Valley encephalitis virus (n = 1)Dengue (n = 1)Parechovirus (n = 1)Influenza A (n = 1)	Burkholderia pseudomallei (n = 3)Haemophilus influenzae (n = 1)Pseudomonas stutzeri (n = 1)	Cryptococcus neoformans (n = 1)	Gnathostoma (n = 1)

a John Cunningham virus.

b Japanese encephalitis virus.

A pathogen was not identified in 36 (50%) encephalitis cases.

Brain abscess

There were 84 cases of brain abscess. The incidence was 0.9/100,000 population in 2000 compared to 3.1/100,000 population in 2019 (p for trend = 0.12). 50/84 (60%) occurred in males. The cases’ median (IQR)) age was 49 (19–61) years. Tropical pathogens such as Cryptococcus (9/84, 11%), Mycobacterium tuberculosis (7/84, 8%) and Burkholderia pseudomallei (5/84, 6%) were as common in this cohort as more classical aetiologies (Table 7).

Table 7

Laboratory-confirmed aetiology of patients with brain abscesses.

Bacterial (n = 45)	Fungal (n = 10)	Protozoan (n = 3)
Mycobacterium tuberculosis (n = 7)Streptococcus milleri (n = 6)Burkholderia pseudomallei (n = 5)Staphylococcus aureus (n = 5)Streptococcus pyogenes (n = 2)Nocardia paucivirans (n = 2)Propionibacterium acnes (n = 2)Streptococcus pneumoniae (n = 1)Peptostreptococcus (n = 1)Citrobacter freundii (n = 1)Haemophilus influenzae (n = 1)Kingella kingae (n = 1)Listeria monocytogenes (n = 1)Serratia marcescens (n = 1)Staphylococcus sciuri (n = 1)Streptococcus salivarius (n = 1)Bacteroides sp, anaerobic Gram negative bacilli aEnterococcus avium, Proteus mirabilis, Bacteroides fragilis, Bacteroides thetaiotaomicron aEscherichia coli, Staphylococcus epidermidisaProteus penneri, Streptococcus pyogenes aStaphylococcus aureus, Clostridium perfringens, Clostridium sordellii aStreptococcus milleri, Peptostreptococcus aStreptococcus sanguinis, Streptococcus parasanguinis a	Cryptococcus (n = 9) • Cryptococcus gattii (n = 6) • Cryptococcus neoformans (n = 2) • Non-speciated (n = 1)Aspergillus fumigatus (n = 1)	Toxoplasma gondii (n = 2)Acanthamoeba (n = 1)

a These pathogens were isolated from the 7 polymicrobial brain abscesses

A pathogen was not identified in 26 (31%) brain abscess cases.

Immunocompromised population

Of the 725 cases, 18 (2.5%) had confirmed human immunodeficiency virus (HIV) infection, and 20 additional cases between 2015–2019 were receiving immunosuppressive treatment. The spectrum of pathogens seen in these 38 cases was similar to those seen in temperate regions (S4 Table).

Vaccine-preventable disease

The decline in the incidence of pneumococcal CNS infection was not statistically significant (S2 Fig). Of the 25 cases of pneumococcal CNS infection that occurred during the study period, 10 (40%) occurred after 2010, only 2 of which were caused by vaccine-preventable serotypes, 1 of whom was a 3-month-old infant (S5 Table). There was no change in the incidence of N. meningitidis infection during the study period (S3 Fig). There were very low numbers of other vaccine-preventable CNS infection during the study period (8 cases of H. influenzae, 2 cases of mumps virus and 1 case of influenza virus).

Management

There were 189 cases who presented to Cairns Hospital between 2015 and 2019 for whom the data on initial management was accessible (149 cases of meningitis, 18 cases of encephalitis and 22 cases of brain abscess); the care in the emergency department of 128 (67.7%) was concordant with current national therapeutic guidelines (116/149 (77.9%) cases of meningitis, 6/18 (33%) cases of encephalitis and 6/22 (27%) cases of brain abscess) [36]. The number of cases who received appropriate management in the first 24 hours rose to 161/189 (85.2%) (136/149 (91.3%) cases of meningitis, 11/18 (61%) cases of encephalitis and 14/22 (64%) cases of brain abscess). Among the 28/189 (14.8%) who didn’t receive appropriate management in the first 24 hours, 8 (29%) had pathogens that were difficult to diagnose (2 cases of M. tuberculosis, B. pseudomallei, Nocardia paucivirans and 1 case each of Gnathostoma and Acanthamoeba). During the entire study period, 104/725 (14.3%) were admitted to the intensive care unit (ICU) for supportive care.

Outcomes

Across the cohort, there were 32/725 (4.4%) deaths; the case-fatality rate remained stable over the 20-year study period (p for trend = 0.43). There were 5 deaths in infants (4 cases of meningitis and 1 case of encephalitis). All three children that died were PNG residents (2 cases of brain abscess, 1 of meningitis). Death occurred in 24 adults (12 cases of meningitis, 7 cases of encephalitis and 5 of brain abscess) (S6 Table). Death was more common in patients who had a presentation with encephalitis or a confirmed bacterial aetiology. In contrast, patients with a meningitis presentation or confirmed viral aetiology were less likely to die (Table 8). In 12/32 (38%) deaths a pathogen was not identified–this included 5 cases of meningitis, 3 cases of encephalitis and 4 cases of brain abscess. While the case-fatality rate was higher in residents of PNG than Australian residents, the difference in case-fatality rate between Indigenous and non-Indigenous patients did not reach statistical significance. The case-fatality rate was no higher in residents in remote locations (Table 8).

Table 8

The number of cases in those who survived and died, stratified by clinical phenotypes, demographic characteristics and pathogens.

	All n = 725	Survived n = 693	Died n = 32	p
Clinical phenotypes
Meningitis	561 (77.4%)	544 (78.5%)	17 (53%)	0.001
Encephalitis	72 (9.9%)	64 (9.2%)	8 (25%)	0.004
Brain Abscess	84 (11.6%)	77 (11.1%)	7 (22%)	0.08
Spinal disease	8 (1.1%)	8 (1.1%)	0	1.0
Aetiological agent
Bacterial	175 (24.1%)	162 (23.4%)	13 (41%)	0.03
Viral	299 (41.2%)	296 (42.7%)	3 (9%)	<0.0001
Fungal	35 (4.8%)	31 (4.5%)	4 (12%)	0.06
Not identified a	212 (29.2%)	200 (28.9%)	12 (38%)	0.30
Demographic characteristics
Infant	176 (24.3%)	171 (24.7%)	5 (16%)	0.30
Child	124 (17.1%)	121 (17.5%)	3 (9%)	0.34
Adult	425 (58.6%)	401 (57.9%)	24 (75%)	0.06
Indigenous Australian b	178/702 (25.4%)	168/675 (24.9%)	10/27 (37%)	0.16
Remote residence	80/679 (11.8%)	77/654 (11.8%)	3/25 (12%)	1.0
Papua New Guinean residents	32 (4.4%)	28 (4.0%)	4 (12%)	0.047
Pathogen
N. meningitidis	36 (5.0%)	35 (5.0%)	1 (3%)	1.0
S. pneumoniae	25 (3.4%)	25 (3.6%)	0	0.62
S. aureus	13 (1.8%)	10 (1.4%)	3 (9%)	0.03
M. tuberculosis	13 (1.8%)	11 (1.6%)	2 (6%)	0.11
B. pseudomallei	9 (1.2%)	7 (1.0%)	2 (6%)	0.06
Cryptococcus species	34 (4.7%)	30 (4.3%)	4 (12%)	0.06
Enterovirus	220 (30.3%)	220 (31.7%)	0	<0.0001
HSV1	18 (2.5%)	16 (2.3%)	2 (6%)	0.19
Management
Appropriate therapy in the emergency department c	128/189 (67.7%)	127/185 (68.6%)	1/4 (25%)	0.10
Appropriate therapy in first 24 hours c	161/189 (85.2%)	158/185 (85.4%)	3/4 (75%)	0.48

a4 other pathogens (2 toxoplasma, 1 acanthamoeba, 1 gnathostomiasis) all survived.

b This includes the 702 cases in whom Indigenous status was available.

c Only the 189 patients managed at Cairns Hospital between 2015 and 2019 for whom complete data were available.

Among the 270 patients in whom function at discharge could be accurately determined (those managed during the from January 2015 to December 2019 period when an electronic record was used to document patient care), there were 65 with disability on discharge and 15 deaths (S7 and S8 Tables). Patients who received appropriate care in the emergency department were less likely to die or develop long term disability (odds ratio 0.11 (95% confidence interval (95% CI): 0.05–0.24), p<0.0001. In a multivariate analysis that controlled for the fact that unusual pathogens might increase the risk of poor outcomes, the risk of death or long-term disability was still lower among those who received appropriate care in the emergency department (OR (95%CI): 0.13 (0.06–0.30), p<0.0001).

Discussion

In this region of tropical Australia, the annual incidence of CNS infection due to tropical pathogens such as B. pseudomallei and Cryptococcus spp. is similar to that of traditional bacterial pathogens. The local Aboriginal and Torres Strait Islander people bear a disproportionate burden of CNS infections, with cryptococcal and meningococcal disease seen more commonly in these populations. However, residents of remote areas were not over-represented, despite the potentially increased risk of exposure to vectors and pathogens in these locations [27]. Pathogens reported frequently from tropical regions in Southeast Asia—including JEV, dengue and leptospirosis [37,38]—were very rare causes of CNS disease in FNQ, highlighting the success of local public health strategies in preventing these infections. There were also low rates of vaccine-preventable disease—especially influenza, measles, and mumps—with the incidence of invasive pneumococcal and meningococcal disease projected to decline further with recent changes in the national immunisation schedule [39-43]. Despite the region’s proximity to PNG—and Cairns’ reputation as an international travel hub—the burden of imported CNS infection was very low.

Cryptococcus spp. and B. pseudomallei were seen as commonly as traditional bacterial pathogens such as S. pneumoniae and N. meningitidis. It is important for local clinicians to be aware of this fact as CNS cryptococcosis and melioidosis may be rapidly fatal in the absence of early appropriate treatment; if the diagnoses are not considered, empirical regimens are unlikely to contain effective therapy [3,44]. Cryptococcal CNS infection was more common in the Indigenous population, echoing findings from a previous Australasian study [45]. In that study this was attributed to Indigenous Australians’ socioeconomic disadvantage, their higher prevalence of comorbidities and their greater exposure to the Eucalyptus trees (an environmental reservoir for Cryptococcus gattii) in the rural areas where they comprise a greater proportion of the population. The incidence of melioidosis is increasing in FNQ, and although CNS involvement is infrequent, a high index of suspicion is necessary in the appropriate clinical context [3,10,46,47]. Other tropical pathogens were not encountered as frequently; there were only three cases of leptospiral meningitis and no rickettsial CNS infections in this study, despite FNQ having the highest incidence of leptospirosis in Australia and a rising incidence of rickettsial infections [2,48].

Indigenous Australians bore a disproportionate burden of CNS infection; over 25% of the local residents in the cohort identified as Indigenous, compared with 17% of the local general population. However, in contrast to other infectious diseases in the region, the difference in CNS infection case-fatality rates between the Indigenous and non-Indigenous population did not reach statistical significance [12,49]. The absence of a difference in the case-fatality rate may be partly explained by the fact that Indigenous Australians were less likely to be diagnosed with viral CNS infection, particularly lower virulence pathogens like enterovirus and HSV-2. This may reflect a higher threshold for performing lumbar punctures in the remote locations in which Indigenous Australians represent a greater proportion of the population. Indigenous infants, in particular, were over-represented in this study, with disproportionately high rates of meningococcal infection, highlighting the ongoing need for optimal vaccine coverage and effective, practical strategies to improve the socioeconomic disadvantage affecting many Indigenous Australians [14,24,39,50,51]. Although the meningococcal vaccine can only be provided after 6 weeks of age, immunising household contacts of infants may prevent invasive meningococcal disease in this age group [52].

S. pneumoniae, N. meningitidis and H. influenzae type b (Hib) were important causes of vaccine-preventable CNS infection in the cohort. The incidence of invasive pneumococcal disease across Australia declined by up to 39% across all ages after adding the 7-valent conjugated pneumococcal vaccine and the pneumococcal polysaccharide vaccine to the National Immunisation Program in 2005 and 13-valent conjugated pneumococcal vaccine in 2011 [39,53]. Although, in this small study, the overall decline in the incidence of pneumococcal CNS infection was not statistically significant, almost 96% of 5-year-old children in the region are fully vaccinated and this may explain why there were only two cases of pneumococcal CNS infection caused by vaccine-preventable serotypes in the region after 2011 [54]. The only child to have pneumococcal CNS infection with a vaccine-preventable serotype after 2011 was 3 months old, not old enough to have completed their vaccination schedule. The Australian incidence of invasive meningococcal serogroup C declined 96% in the 10 years after the introduction of the meningococcal C conjugate vaccine in 2003 [55]. There were numerically fewer cases of meningococcal CNS infection in the last ten years—despite the growing population—however, as the ACWY vaccine was only added to the schedule in 2017 and as data on meningococcal serotypes was not collected in this study, it is not possible to comment on trends in local incidence. Introduction of the Hib vaccine in 1992 explains the low rates of this infection in the cohort [16]. Despite the region’s proximity to PNG—where the incidence of subacute sclerosing panencephalitis is high and vaccine coverage is suboptimal [56], there were no cases of measles-related encephalitis in the study. There were only two cases of mumps encephalitis during the study period locally (both occurring in adults), likely related to the high local rates of vaccine coverage in FNQ [54].

Arbovirus vector control interventions, including mosquito surveillance, population control and the introduction of the Wolbachia program, have been extremely successful in reducing the burden of mosquito-borne disease [20,21]. There has been only one local case of dengue encephalitis—which occurred during the last major outbreak of dengue in the region in 2009—and one imported case of JEV in the last 20 years [57,58]. There have been no locally acquired dengue CNS infections since deployment of Wolbachia-infected mosquitoes began in 2011, despite importation of dengue in travellers, particularly those returning from the Asia-Pacific region [6,21]. This stands in stark contrast to some Southeast Asian locations where flavivirus infections are responsible for a significant proportion of all CNS infections [37,38,58]. Incursions of JEV into FNQ occurred in 1998, 2000 and 2004, when infected mosquitoes were carried by cyclonic winds from PNG to the Torres Strait Islands and Cape York Peninsula. Although the virus was identified almost annually in sentinel pigs and mosquitoes on Badu Island in the Torres Strait until the discontinuation of these surveillance programs in 2005, there were no locally acquired cases in the study period; vaccination for residents of the outer Torres Strait Islands may have played a role [6,26]. The sole case of JEV was detected in an expatriate who was aeromedically evacuated from PNG in 2004 [57]. Despite Murray Valley encephalitis virus and Kunjin virus being endemic to northern Australia, there were no locally acquired cases of these flaviviruses diagnosed in this cohort with the only case of Murray Valley encephalitis occurring in a PNG resident. Recent cases of these flaviviruses appear confined to Western Australia and Northern Territory where rainfall conditions are optimal for vector survival and breeding [59,60]. Although emerging pathogens including Australian bat lyssavirus and Hendra virus are highlighted in the national consensus guidelines for encephalitis in Australia [27]—and have been identified in Queensland [61,62]—no cases were identified in the 20 years of this study.

Although tuberculosis was the most commonly identified CNS infection in PNG residents, it was identified in only a single Aboriginal or Torres Strait Islander Australian in the study period. Declining rates of tuberculosis have been noted among local Indigenous Australians following improved engagement with Indigenous communities, training of local healthcare workers and an enhanced specialist outreach program [63]. PNG is one of the world’s 30 high burden TB countries suggesting that early detection and contact tracing strategies in the Torres Strait are currently limiting the importation of TB into FNQ [6].

The Western Pacific region has seen a 43% decline in cases of malaria, but nearly 80% of cases in the region are reported from PNG [30]. It is notable then, that despite PNG’s proximity, the number of cases of P. falciparum malaria seen in FNQ is decreasing. Only 10.8% of all cases from the study period occurred in the second half of the study, only one of whom–a PNG resident–had impaired consciousness. Apart from tuberculosis, malaria, and the 2 cases of JEV and Murray Valley encephalitis, the other tropical pathogens seen in PNG residents were similar to those encountered in northern Australia.

The case-fatality rate in the study was far lower than that seen in contemporary international series from tropical locations [37,38] (S9 Table). This likely reflects management in the well-resourced Australian public health system in which patients are able to access care in even remote locations, and have access to efficient aeromedical retrieval service, comprehensive diagnostic services—including advanced imaging—and sophisticated ICU and neurosurgical support [47,64,65]. A pathogen was identified in 71.1% of cases, a larger proportion than that seen in a study examining encephalitis in Australia between 1979 and 2006 [66], although this is likely due to the use of ICD coding—and the pathology database—to identify cases. The difference in the spectrum of isolated pathogens—especially the greater proportion of lower virulence pathogens such as enterovirus seen in the FNQ cohort—is also likely to have contributed to the lower case-fatality rate. Although the proportion of encephalitis deaths from unidentified pathogens was reported to be high in a previous Australian study [66], there were only 12 deaths due to CNS infection from unidentified pathogens over 20 years in this series–and only 3 of these were due to encephalitis. It was notable that an autoimmune aetiology explained approximately a third of encephalitis presentations with the incidence increasing during the study period, at least in part due to greater local recognition of the syndrome [67]. Future research employing novel molecular diagnostic techniques may help identify emerging infections, guide targeted therapy, and further inform optimal management strategies [68].

This study was limited by incomplete access to medical records and imaging which precluded comprehensive data collection. The incidence of individual pathogens was relatively low increasing the likelihood of a type 2 statistical error. The Modified Rankin Scale score and requirement of an anticonvulsant medication on discharge are crude proxy measures of long-term disability [34]. Using ICD coding and searching the laboratory database for any CSF that had identified an organism may have resulted in a lower number of cases with an unidentified pathogen. Additionally, cases of mild, self-limiting CNS infection may have been missed in remote locations due to a higher threshold for performing lumbar punctures in these settings. There was no standardised testing of patients with each of the clinical syndromes and testing was not always comprehensive; it is therefore possible that the failure to identify individual pathogens—particularly flaviviruses, Hendra virus and Australian bat lyssavirus—was the result of not testing for them. Different methods used by the Australian Bureau of Statistics to define the FNQ population led to minor variations in the size of the local population in the analyses that compared characteristics of the cohort to that of the general population, although this would not be expected to influence the study’s findings. Despite these limitations, this study has identified the evolving spectrum of pathogens that are responsible for CNS infections in the region. Just as importantly, it highlights the pathogens that—despite being emphasised in national consensus statements—are actually identified infrequently.

Conclusion

In this region of Australia, tropical pathogens caused CNS infections as frequently as classical bacterial pathogens, however, only one case of locally acquired arboviral encephalitis occurred over the 20 years of the study. The case-fatality rate was very low compared to contemporary series from Southeast Asia, reflecting differences in the array of responsible pathogens and Australia’s well-resourced health care system. With effective vector control, expanding comprehensive vaccination schedules and an emphasis on prompt diagnosis and therapy, death, and disability from CNS infections in the region is expected to decline even further in the future.

Cases of CNS infection satisfying the criteria for inclusion in the study.

(TIF)

Click here for additional data file.

S. pneumoniae incidence per 100,000 population.

(TIF)

Click here for additional data file.

N. meningitidis overall incidence per 100,000.

(TIF)

Click here for additional data file.

Incidence per 100,000 local population between 2000 and 2019.

(DOCX)

Click here for additional data file.

Pathogens identified in Aboriginal and Torres Strait Islander children and infants.

(DOCX)

Click here for additional data file.

Pathogens in patients who lived outside Australia.

(DOCX)

Click here for additional data file.

Pathogens identified in immunocompromised patients.

(DOCX)

Click here for additional data file.

Serotypes identified in pneumococcal CNS infection.

(DOCX)

Click here for additional data file.

Pathogens causing CNS infection in patients who died.

(DOCX)

Click here for additional data file.

Death and disability outcomes stratified by clinical phenotypes, aetiology and demographic characteristics.

(DOCX)

Click here for additional data file.

Residual deficits in infants, children and adults after CNS infection, and associated pathogens.

(DOCX)

Click here for additional data file.

Most common pathogens causing CNS infection and case fatality rates in Far North Queensland, Vietnam and Laos [4,5].

(DOCX)

Click here for additional data file.

Case definitions of CNS infections.

(DOCX)

Click here for additional data file.

Case definitions of autoimmune encephalitis.

(DOCX)

Click here for additional data file.

(XLSX)

Click here for additional data file.

5 Jan 2022

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Reviewer #1: Overall, this is an interesting study detailing changes in the epidemiology of CNS infections in a region of Australia over the past 20 years.

Specific comments are as follows:

INTRODUCTION

- lines 80-82, there are probably additional reasons for a higher prevalence of some infectious diseases in PNG compared to Australia than the “fragile public health system.” I would just state that PNG has a higher prevalence of these infections and leave it at that.

- line 100 – I would specify here that Wolbachia blocks the insects ability to spread dengue, Zika, and chikungunya as I don’t think the average reader would be aware of this.

METHODS

- Lines 142-143 would specify that collected data were de-identified

- Lines 142-143 – the way this is worded is really confusing because earlier they mention that patients between 2000 and 2019 are included. I would re-word this to state that for the subset of patients between 2015 and 2019 additional clinical information, such as demographics etc. was collected.

RESULTS

- Lines 201-202 – it says Cryptococcal and meningococcal infection were more common in Indigenous Australians... Would add “compared to non-indigenous Australians” to that sentence.

- Lines 222-223 – I would also show the one case of TB in non-PNG individuals (with denominator) here, to highlight how different this was between groups.

- Lines 223-224 The sentence that starts with “there were 15 other patients in the cohort ...“ doesn’t really fit here. It should be deleted or moved to a different part of the paper.

- Line 235 – Even though the authors state earlier that they used CDC case definition of meningitis, I would add a sentence to clarify how they diagnosed these cases of meningitis – did they all have lumbar punctures, or were any of them diagnosed based on clinical symptoms only?

- Lines 235-240 – Were there any differences between immunocompromised and non-immunocompromised individuals? These might be interesting data to include here.

- Lines 277-280 – Were there any differences in the spectrum of diseases (meningitis vs. encephalitis) among immunocompromised and non-immunocompromised patients?

- Lines 303-304 – I would list admission to ICU as an outcome, not a treatment.

- Lines 322-323 – They say 65 had disability on discharge and “an additional 15 deaths” – does this mean 15 more subjects died following discharge? This statement is confusing.

DISCUSSION

- Lines 339-341 – They say residents of remote areas were not over-represented, despite increased risks of exposure to vectors. However, I would think it would be likely that those in remote areas may be less likely to seek care.

- Lines 354-358 – was there any information regarding the association between HIV status and cryptococcal diagnosis

- Lines 418-420 – they state that Murray Valley Encephalitis virus and Kunjin virus are endemic but there were no cases of these diagnosed – in how many cases were these viruses tested for??

TABLES

- Table 1 – for the descriptive statistics shown in the tables, I’m not sure it makes sense to include p-values. However, if you do include them (as is shown in Tables 2 and 3) they should also be listed in Table 1 then.

- Table 5 – were there no cases that had >1 pathogen?? If there were, this should be clarified in a footnote.

- Table 9 – I would not include this whole table in the discussion. You could make it a supplemental table and refer to it in text, but typically tables are not included in the discussion.

Reviewer #2: The authors try to highlight the epidemiological profiles and clinical outcomes of patients who were diagnosed with central nervous system infections in Far North Queensland, tropical Australia. The data were retrospectively collected from 1st January 2000 until 31st December 2019. I find the manuscript is too verbose and lack of novelty. The abstract was not comprehensively written. For example, the aim of the study was not properly written in the background with lack of problem statement. Methodology was not very clear in terms of the lab tests/methods used for the identification of the pathogens.

Several variables should be defined as follows: tropical pathogens, indigenous communities, not identified pathogens (Table 1), Indigenous Australians, Local Indigenous, disability outcomes, and residual deficits.

Why the first letter of “Indigenous” is capitalized, especially when it is written as Indigenous communities or Indigenous status.

Methods:

The inclusion and exclusion criteria were not clearly mentioned. Were repeat samples included? Were patients with coinfections included?

Line 142-143: “The patients’ demographics, clinical features, comorbidities, and outcomes were collected from the medical records of cases between January 1, 2015, and December 31, 2019” There is a big gap on the data collected between 2000 to 2014, which may affect the statistical analysis in general.

Line 151 -153: the statement should be cited.

Results:

The analysis was affected by different denominators used and this has created a lot of confusion to the readers.

Table 2: what is the purpose of comparing indigenous versus non-indigenous? This was not highlighted in the introduction.

Species should not be italicised.

About enterovirus, was it only one genus identified? What method was used for the identification?

There were too many tables provided, which I think some are not necessary especially the impact of residential address. It would be good if geographic information system is utilized.

Line 312-313: statistical results should be provided.

Discussion:

Line 379: Spelling error was observed, N. meningitides

Table 9 should be de-tabulated, and the authors should use all the points for the discussion. The table is more appropriate for a review paper.

Epidemiological parameters were not critically discussed in relation to CNS infections. Lack of references for the comparison was observed.

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Reviewer #1: Yes: Jesica A Herrick

Reviewer #2: No

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Submitted filename: PONE21-35660.pdf

Click here for additional data file.

19 Jan 2022

Response to Reviewers

We thank the editorial staff and reviewers for the time that they have taken to review our manuscript and the helpful comments that they have made to improve the work. Please find below our point-by-point responses to their comments. For clarity, the editorial staff and reviewers’ comments are presented in blue normal text, while our responses are in black normal text. Any modified – or highlighted – text is presented as black and italicized.

Editorial staff comments

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Response: We have checked that the manuscript meets the style requirements – including file naming – and feel that it does. We are very happy to address specific issues if any remain.

2. We note that Figure 1 in your submission contain map images which may be copyrighted. All PLOS content is published under the Creative Commons Attribution License (CC BY 4.0), which means that the manuscript, images, and Supporting Information files will be freely available online, and any third party is permitted to access, download, copy, distribute, and use these materials in any way, even commercially, with proper attribution. For these reasons, we cannot publish previously copyrighted maps or satellite images created using proprietary data, such as Google software (Google Maps, Street View, and Earth). For more information, see our copyright guidelines: http://journals.plos.org/plosone/s/licenses-and-copyright.

We require you to either (1) present written permission from the copyright holder to publish these figures specifically under the CC BY 4.0 license, or (2) remove the figures from your submission.

Response: The map in the submission was created using mapping software (MapInfo version 15.02, Connecticut, USA) using data provided by the State of Queensland (QSpatial) which are not copyrighted. Queensland Place Names — State of Queensland (Department of Natural Resources, Mines and Energy) 2019, available under Creative Commons Attribution 4.0 International licence https://creativecommons.org/licenses/by/4.0/ and ‘Coastline and state border–Queensland - State of Queensland (Department of Natural Resources, Mines and Energy) 2019, available under Creative Commons Attribution 4.0 International licence https://creativecommons.org/licenses/by/4.0/

These data - which are freely available in the public domain - are provided by the State Government of Queensland. This is similar to some of the U.S. government sources that were suggested in the decision email.

All the patients were managed in the State Government’s Public Health system. All the authors contributed to the manuscript while working or studying in the State Government’s Public Health system.

We have used these data to create maps in multiple PLoS publications in the past 4 years without any issue.

1. PLoS Negl Trop Dis. 2021 Jun 21;15(6):e0009544. doi: 10.1371/journal.pntd.0009544. eCollection 2021 Jun.

2. PLoS Negl Trop Dis. 2021 Jan 14;15(1):e0008990. doi: 10.1371/journal.pntd.0008990. eCollection 2021 Jan.

3. PLoS One. 2020 Sep 3;15(9):e0238719. doi: 10.1371/journal.pone.0238719. eCollection 2020.

4. PLoS Negl Trop Dis. 2019 Jul 18;13(7):e0007583. doi: 10.1371/journal.pntd.0007583. eCollection 2019 Jul.

5. PLoS Negl Trop Dis. 2019 Feb 13;13(2):e0007205. doi: 10.1371/journal.pntd.0007205. eCollection 2019 Feb.

6. PLoS Negl Trop Dis. 2017 Mar 6;11(3):e0005411. doi: 10.1371/journal.pntd.0005411. eCollection 2017

We have added a footnote to Figure 1 – specifically addressing this copyright issue – to make this clearer. Hopefully this addresses your concerns.

REVIEWERS COMMENTS

Reviewer #1: Overall, this is an interesting study detailing changes in the epidemiology of CNS infections in a region of Australia over the past 20 years.

Specific comments are as follows:

INTRODUCTION

- lines 80-82, there are probably additional reasons for a higher prevalence of some infectious diseases in PNG compared to Australia than the “fragile public health system.” I would just state that PNG has a higher prevalence of these infections and leave it at that.

Response: We agree with the reviewer, the original description was too simplistic. We have deleted the phrase as suggested (lines 80-81).

- line 100 – I would specify here that Wolbachia blocks the insects ability to spread dengue, Zika, and chikungunya as I don’t think the average reader would be aware of this.

Response: We thank the reviewer for highlighting this important point. We have amended the paper accordingly (line 104-105).

METHODS

- Lines 142-143 would specify that collected data were de-identified

Response: We agree that this is important. We did state that the data were de-identified in the statistics section of the original submission (line 189).

- Lines 142-143 – the way this is worded is really confusing because earlier they mention that patients between 2000 and 2019 are included. I would re-word this to state that for the subset of patients between 2015 and 2019 additional clinical information, such as demographics etc. was collected.

Response: We thank the reviewer for highlighting this source of potential confusion. We have revised the paper accordingly (lines 158-162).

RESULTS

- Lines 201-202 – it says Cryptococcal and meningococcal infection were more common in Indigenous Australians... Would add “compared to non-indigenous Australians” to that sentence.

Response: We thank the reviewer for this helpful suggestion. We have revised the paper accordingly (lines 229-230).

- Lines 222-223 – I would also show the one case of TB in non-PNG individuals (with denominator) here, to highlight how different this was between groups.

Response: This is an excellent suggestion. We have revised the paper accordingly (line 253-254).

- Lines 223-224 The sentence that starts with “there were 15 other patients in the cohort ...“ doesn’t really fit here. It should be deleted or moved to a different part of the paper.

Response: We thank the reviewer for their constructive comment. We have revised the paper accordingly (line 254).

- Line 235 – Even though the authors state earlier that they used CDC case definition of meningitis, I would add a sentence to clarify how they diagnosed these cases of meningitis – did they all have lumbar punctures, or were any of them diagnosed based on clinical symptoms only?

Response: We agree with the reviewer that the method of diagnosing CNS infections is important. This is described in detail in Supplementary File 1.

- Lines 235-240 – Were there any differences between immunocompromised and non-immunocompromised individuals? These might be interesting data to include here.

- Lines 277-280 – Were there any differences in the spectrum of diseases (meningitis vs. encephalitis) among immunocompromised and non-immunocompromised patients?

Response: We agree with the reviewer that immunocompromise is an important variable worth examining. The difference in case-fatality rate between immunocompromised and non-immunocompromised individuals did not reach statistical significance (p=0.14) and we list all the pathogens that cause infection in the immunocompromised patients in Supplementary Table 4.

However, detailed discussion of the differences in individual infections between immunocompromised (who represented only 2.5% of the cohort) and non-immunocompromised patients is beyond the scope of this paper which instead aimed to focus on long term trends and the implications for public health strategy in the region. Two manuscripts - one examining Cryptococcal infection and another examining CNS melioidosis in the region during the same time period - have been submitted to academic journals and are currently under review.

- Lines 303-304 – I would list admission to ICU as an outcome, not a treatment.

Response: The reviewer is right to note that some studies use ICU admission as an outcome. However, we feel that it is better placed in the management paragraph, as this is how patients were managed by the attending clinicians. This means that the more traditional long-term outcomes - death and long-term disability can be discussed alone in the outcome section.

- Lines 322-323 – They say 65 had disability on discharge and “an additional 15 deaths” – does this mean 15 more subjects died following discharge? This statement is confusing.

Response: We thank the reviewer for highlighting this source of potential confusion. 15 of the 32 total deaths occurred between January 2015 and December 2019. We have revised the paper accordingly to clarify this (line 360).

DISCUSSION

- Lines 339-341 – They say residents of remote areas were not over-represented, despite increased risks of exposure to vectors. However, I would think it would be likely that those in remote areas may be less likely to seek care.

Response: We agree with the reviewer that cases of mild CNS infection may have been missed in residents of remote areas. Indeed, we present data to show that lumbar punctures were performed less frequently in rural and remote settings (lines 248-251). This point has been specifically acknowledged as a limitation of the study (lines 509-510).

- Lines 354-358 – was there any information regarding the association between HIV status and cryptococcal diagnosis

Response: There were only 3 cases of Cryptococcal disease in HIV seropositive patients during the entire study period. The association between HIV infection and cryptococcal disease is well recognised and it is probably unnecessary to describe it in more detail.

As highlighted above, we have another paper under review at PLoS One examining Cryptococcal infections in the region where we discuss the issue in more detail (PONE-D-21-37969R1. The aetiology and clinical characteristics of cryptococcal infections in Far North Queensland, tropical Australia).

There were 18 episodes of CNS infection in HIV seropositive patients during the study period. This included 3 cases of Cryptococcal disease, 2 cases of Toxoplasmosis gondii, 1 case of JC virus, 1 case of TB, 1 case of Salmonella yarrabah, 1 case of Listeria monocytogenes, 1 case of Human Herpes Virus 6, 1 case of Herpes Zoster and 7 cases in which the pathogen was not identified.

These pathogens are all presented in supplementary table 4 and further detailed description of infections in this relatively small subgroup (approximately 2.5% of the cohort) is probably beyond the scope of the manuscript, however we would be happy to expand this section if the Editor thought that it would be valuable.

- Lines 418-420 – they state that Murray Valley Encephalitis virus and Kunjin virus are endemic but there were no cases of these diagnosed – in how many cases were these viruses tested for??

Response: The reviewer makes an excellent point and one that we should have presented in the initial submission. There were 36 cases of encephalitis in which no pathogen was identified. Flavivirus serology was performed - and was negative - in 12. PCR for Kunjin and Murray Valley Encephalitis was performed - and was negative - in 6. It is therefore possible that cases of either pathogen were missed in the remaining 24 cases; 2 of these cases died. We have expanded the results to highlight this point (lines 291-293) and we have also added this as a limitation of the study (lines 511-514).

TABLES

- Table 1 – for the descriptive statistics shown in the tables, I’m not sure it makes sense to include p-values. However, if you do include them (as is shown in Tables 2 and 3) they should also be listed in Table 1 then.

Response: There are no comparisons - or analyses - made in Table 1 so there are no p-values to present. We could perform an analysis, but differences in CNS infection between adults, children and infants have been described previously. Furthermore, it is more complicated to present statistical analyses between three groups succinctly. The absolute numbers presented in a descriptive manner perhaps tell their own story: meningitis occurs more commonly in infants; fungal pathogens are seen almost exclusively in adults.

This is different from Tables 2 and 3 which compare the number of cases in Indigenous and non-Indigenous Australians - using the chi-square or Fisher’s exact test - in each of the categories. There is very little data that compares the burden of CNS infections in Indigenous and non-Indigenous Australians, so we have performed a statistical analysis and presented the p values accordingly.

If the Editor feels that the paper would be stronger performing analyses comparing the incidence of the different clinical phenotypes and pathogens in adults, children and infants, we would be happy to present this.

- Table 5 – were there no cases that had >1 pathogen?? If there were, this should be clarified in a footnote.

Response: There were no cases of meningitis or encephalitis with more than one pathogen identified. Cases of polymicrobial brain abscesses are indicated by a superscript a in Table 7, as detailed in the footnote (line 313).

- Table 9 – I would not include this whole table in the discussion. You could make it a supplemental table and refer to it in text, but typically tables are not included in the discussion.

Response: We thank the reviewer for their constructive comment. We have relegated the table to supplementary material (supplementary table 9).

Reviewer #2: The authors try to highlight the epidemiological profiles and clinical outcomes of patients who were diagnosed with central nervous system infections in Far North Queensland, tropical Australia. The data were retrospectively collected from 1st January 2000 until 31st December 2019. I find the manuscript is too verbose and lack of novelty. The abstract was not comprehensively written. For example, the aim of the study was not properly written in the background with lack of problem statement.

Response: We agree with the reviewer about the importance of a clear and concise abstract. Our abstract is 294 words (6 words less than the word limit set by PLOS ONE). We would argue that we do present the aim of the study in the abstract: to define the epidemiology of central nervous system infections in Far North Queensland (lines 27-28).

We present the aims of the study, in some detail, in the introduction (as per STROBE guidelines) (lines 113-121).

Methodology was not very clear in terms of the lab tests/methods used for the identification of the pathogens.

Response: We agree with the reviewer that it is important to define the laboratory methods used to identify the pathogens. However, given the large number of pathogens assayed using a variety of different tests, we felt that describing the laboratory tests in further detail would impact significantly on the length and legibility of the article. Cryptococcal infection, for instance, may be identified by India Ink stain, antigen testing (of CSF or serum) or culture. Leptospirosis might be identified by serology, PCR, or culture. These are just two of the pathogens that were sought, and we feel that detailing all these tests for the large variety of pathogens would be unnecessarily inclusive. We would be happy to expand the current description (lines 133-134) if the Editor felt that this were appropriate.

Several variables should be defined as follows: tropical pathogens, indigenous communities, not identified pathogens (Table 1), Indigenous Australians, Local Indigenous, disability outcomes, and residual deficits.

Response: We thank the reviewer for highlighting this oversight. We have revised the paper accordingly to define Aboriginal and Torres Strait Islander Australians (lines 162-164). ‘Not identified pathogens’ includes cases where a pathogen was not identified by culture, PCR, antigen, or antibody detection. We feel that this definition is implied and unnecessary to define further, however we would be happy to do so if the Editor felt that this would improve the legibility of the text. We have added a definition for tropical pathogens in the methods (lines 180-181), however in almost every reference to tropical pathogens we do refer to the pathogens that we are discussing (lines 44-46, lines 306-308, lines 374-375, lines 399-402). We define disability in the original manuscript in lines 181-183.

Why the first letter of “Indigenous” is capitalized, especially when it is written as Indigenous communities or Indigenous status.

Response: The Australian Bureau of Statistics Standards for Statistics on Cultural and Language Diversity state that the word ‘Indigenous’ should always be capitalised, as capitalisation demonstrates respect.

Methods: The inclusion and exclusion criteria were not clearly mentioned. Were repeat samples included? Were patients with coinfections included?

Response: We thank the reviewer for highlighting this oversight. Repeat samples were not included, we have revised the paper to reflect this (line 135). The few patients with coinfections - all brain abscesses - have this highlighted in table 7.

Line 142-143: “The patients’ demographics, clinical features, comorbidities, and outcomes were collected from the medical records of cases between January 1, 2015, and December 31, 2019” There is a big gap on the data collected between 2000 to 2014, which may affect the statistical analysis in general.

Response: We completely agree with the reviewer that incomplete data collection and the inclusion of a small dataset may contribute to a type 2 statistical error. This is acknowledged as a limitation of the study (lines 504-505).

Line 151 -153: the statement should be cited.

Response: We thank the reviewer for highlighting this oversight. We have revised the paper accordingly (reference 32).

Results: The analysis was affected by different denominators used and this has created a lot of confusion to the readers.

Response: We agree with the reviewer that there are various denominators used; this was unfortunately unavoidable given the long study period and the sometimes incomplete data available for this retrospective study. We have done our best to indicate the denominators, always presenting them in any text or table. We would be happy to address any specific sources of confusion.

Table 2: what is the purpose of comparing indigenous versus non-indigenous? This was not highlighted in the introduction.

Response: Aboriginal and Torres Strait Islander Australians experience significant socioeconomic disadvantage, high rates of comorbidity and are more likely to reside in rural and remote areas, where residents may face challenges in accessing healthcare. It is intuitive that therefore that Indigenous Australians may be at greater risk of CNS infection. The reviewer may have missed that this was, in fact, discussed in the introduction in the original submission (lines 88-95 and lines 105-111).

Species should not be italicised.

Response: The PLOS ONE submission guidelines state that species names should be written in italics. We are very happy for the Editorial staff to advise of their preference.

About enterovirus, was it only one genus identified? What method was used for the identification?

Response: Cases of enterovirus infection were identified using polymerase chain reaction assays. They were not further characterised as this has no impact on clinical management of these patients, which is supportive.

There were too many tables provided, which I think some are not necessary especially the impact of residential address. It would be good if geographic information system is utilized.

Response: We thank the reviewer for their constructive comment. We have moved Table 9 to the supplementary material accordingly (S9 Table).

We feel that residence in a remote location is actually an interesting variable to examine, as there is significant diversity in the different ecosystems across the 280,000km2 of Far North Queensland. The region includes rainforest, marine environments, lush arable land and dry savannah. It also contains a modern, urban region - Cairns - which is a major international tourist hub. It might be anticipated that residents in different parts of the region would be at risk of CNS from different pathogens due to differences in environmental exposure (eg Burkholderia pseudomallei, Cryptococcus gattii, Leptospirosis, Acanthamoeba), vector exposure (flavivirus, rickettsial disease) or animal exposure (Hendra virus, Australian bat lyssa virus). However, as table 4 demonstrates there are similar rates of most CNS infections in urban and remote settings.

We believe that this is an important negative finding as national guidelines counsel clinicians to test for many exotic pathogens in people living in remote locations. Our work suggests that these pathogens are, in fact, very rare. Clinicians working in the region should not necessarily waste time and money seeking these pathogens - focussing instead on more common pathogens - in the absence of another clear indication.

We have however adjusted the heading of this paragraph to “Impact of remote residence on disease incidence” to emphasise that it is residence in a remote location, rather than residential address per se (which might suggest an analysis of spatial clustering).

Line 312-313: statistical results should be provided.

Response: The p-values for these statements are presented in Table 8. We have not presented them in the text again as we feel that it would be duplicative, although we would be happy to if the Editor felt that this improved the legibility of the paragraph.

Discussion: Line 379: Spelling error was observed, N. meningitides

Response: We thank the reviewer for highlighting this oversight. We have revised the paper accordingly (line 403).

Table 9 should be de-tabulated, and the authors should use all the points for the discussion. The table is more appropriate for a review paper.

Response: We thank the reviewer for their constructive comment. We have revised the paper accordingly and moved Table 9 to the supplementary material (S9 Table).

Epidemiological parameters were not critically discussed in relation to CNS infections.

Response: We have discussed several epidemiological parameters including age, Aboriginal and Torres Strait Islander status and geographical location throughout the text. It is true that there may be other parameters in the dataset, such as the presence of specific comorbidities that we have not analysed. However, these parameters may not add further value to the paper, and we are concerned that our simple messages may be lost if we try and present all this information in a single manuscript.

Were there any specific epidemiological parameters that the reviewer thinks it would be useful to look at?

Lack of references for the comparison was observed.

Response: We are uncertain about what aspect of the manuscript the Reviewer is referring to here. We would be happy to address this point if their specific concern could be made clearer.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

23 Feb 2022

24 Feb 2022

We thank the editorial staff and reviewers for the time that they have taken to review our manuscript and the helpful comments that they have made to improve the work. Please find below our point-by-point responses to their comments.

REVIEWERS COMMENTS

Reviewer #2: The authors have adequately addressed all the previous comments by the reviewer. The revised manuscript has some merits for the reader as the results are well presented and well-concluded. Congratulations!

Response: Thank you very much.

Reviewer #3: An important retrospective study is presented. The authors have responded well to the comments from the reviewers.

The manuscript is now acceptable for publication. I have only a few minor comments and recommendations:

Recommend change of the end of the title from " a 20 -years retrospective study" to " 2000- 2019"

In the Results section in Abstract: Remove all the quata of 725 from 561/725 etc and present only percentages. The number 725 is presented in the beginning of the results.

Remove decimals on percentages when n<100 :

Rows 268, 271, 280, 290, 292, 293, 308, 319, 321, 336 and on

Table 4 on the group Remote areas (n=80)

Table 8 on Died (n= 32)

Response: We thank the reviewer for their comments. This is really a question of style, but we have revised the text as suggested (lines 4, 36-58, 251, 256-258, Table 4, 294, 297, 306, 316, 321, 323, 324, 331, 343, 354, 356, 363, 376, Table 8).

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

2 Mar 2022

The epidemiology and outcomes of central nervous system infections in Far North Queensland, tropical Australia; 2000-2019

PONE-D-21-35660R2

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Reviewers' comments:

11 Mar 2022

PONE-D-21-35660R2

The epidemiology and outcomes of central nervous system infections in Far North Queensland, tropical Australia; 2000-2019

Dear Dr. Gora:

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