Encephalitis Sentinel Surveillance in Intensive Care Units in Brazil
Conditions: Encephalitis, Central Nervous System Infections and Inflammations, Intensive Care Neurological Disorder, Prognosis, Meningitis/Encephalitis, Meningitis
Sponsor: D'Or Institute for Research and Education

Encephalitis Sentinel Surveillance in Intensive Care Units in Brazil
-
Brazil ICU Encephalitis Surveillance -
v1.1 2019

1) Introduction
The emergence or reemergence of infectious diseases with major public health impact due to
potential severity, such as encephalitis and haemorrhagic fevers, are a challenge for the health systems
and health authorities around the world, in an increasingly globalized community, with large mass
agglomeration events, or even increased risk of bioterrorism [1,2].
It is believed that new infectious diseases begin to circulate in the population, often with severe
cases, long before they are officially described in the literature [3,4]. Thus, Intensive Care Units (ICUs)
would be an important target for sentinel syndromic surveillance tools, optimizing resource consumption
precisely by focusing on new diseases with greater potential for severe presentations and, therefore,
higher
associated
morbidity
and
mortality.
However,
health
surveillance
in
ICUs
are
still
underdeveloped, particularly in low and middle income countries [3].
A passive, vertical and disease-oriented surveillance system may let a large number of
undiagnosed cases occur, delaying recognition of outbreaks and identification of new pathogens [5].
Therefore, there is need for syndromic surveillance of cases of Undiagnosed Severe Infectious Illness
(USII) - that is, diseases that lead to ICU admission or death, with characteristics of possible infectious
etiology, but without an etiological diagnosis with the investigation routine commonly available [1,6].
Australia [3], the United States of America [1,7–9] and the United Kingdom [6] have already conducted
studies on the incidence, epidemiology and etiology of the USII and created network for the early
detection and rapid diagnosis of these cases.
Among the USII, encephalitis may be considered the hallmark: it is a severe clinical
manifestation associated with many infectious diseases, including recently identified emerging and
reemerging diseases [10–12]. Also, the true incidence of these infections is difficult to determine
because many cases are unreported, the diagnosis may not be considered, or a specific etiology is never
confirmed because the microbiological diagnosis of encephalitis is difficult and expensive, particularly
in low and middle-income countries, although these disorders occur with sufficient frequency that
clinicians should be familiar with the clinical manifestations, diagnostic techniques, and therapeutic
options [11]. In Brazil, ICUs are often without resources to perform initial diagnostic tests for etiologies
of CNS disease; frequently such testing is not available until a week or more after admission [13,14].
Our proposal is to develop a sentinel syndromic surveillance strategy to identify encephalitis
cases possibly related to emerging pathogens admitted to ICUs in Brazil. “Sentinel” to allow a
diagnostic intensive approach on a smaller number of cases, “syndromic” to guarantee a sensitive
criterion to include new or unexpected pathogens, and in ICUs to prioritize potentially severe threats. In
a resource-limited setting it won’t be possible to monitor and investigate all cases of encephalitis, so a

cost-effective algorithm for early identification of the cases that are most likely to be caused by unusual,
unexpected or emerging pathogens must be developed. As universal surveillance of encephalitis is not
recommended in Brazil, data on incidence, causes and prognosis is not available, leaving a gap in the
understanding of the epidemiology of this central nervous system disease in the country. This study will
review cases of encephalitis admitted in the last five years to ICUs in a large metropolitan area. Its
results will help understand the epidemiology of encephalitis in Brazil and will provide data to build a
strategy for early identification of outbreaks and of emerging infectious diseases.
2) Materials and methods
2.1 Study design
Retrospective cohort study in the metropolitan area of Rio de Janeiro, RJ, Brazil, from
2012-2019.
2.2 Study sample
We willuse data from 35 ICUs (600 beds) of nine hospitals in the metropolitan area of Rio de
Janeiro - Brazil (12 million inhabitants in 2018 [15]), from january 2012 to july 2019, covered with the
Epimed Monitor database, which routinely registers all admissions in ICUs: the Evandro Chagas
National Institute of Infectology (INI), Oswaldo Cruz Foundation (Fiocruz); the seven largest hospitals
of Rede D’Or private health corporation - Barra D’Or, Caxias D’Or, Copa D’Or, Niterói D’Or, Norte
D’Or, Oeste D’Or and Quinta D’Or -, and the Complexo Hospitalar de Niterói (CHN) hospital, a large
private health complex.
The Epimed Monitor system is present in more than 400 hospitals throughout Brazil, with 750
ICUs
and
11,000
monitored
beds,
reaching
over
1,000,000
patients
within
its
base
(http://www.utisbrasileiras.com.br/en/epimed/)[16]. Based on previous studies [17,18], we expect to
identify between 100 and 250 cases of encephalitis.
2.3 Inclusion and Exclusion Criteria
Identification of suspected case of central nervous system infections in the Epimed Database of
non-surgical and non-neonatal ICU admissions: risk greater or equal to 10% - sensitivity of 88.69%, a
specificity of 85.57%, area under the Receiver Operating Characteristics (ROC) curve of 0.892 (95%
confidence interval 0.864 - 0.921, P<0.0001) - by the authors` diagnostic prediction tool developed for
this study, and will be published.

Suspected cases will have their medical records reviewed. Those who fulfill the diagnostic
criteria as follows were included as a case of CNSI:
-Brain abscess or suppurative intracranial infections: diagnosis of brain abscess requires at least
one of the following criteria:
•Organism identified from brain tissue
•Abscess on gross anatomic or histopathologic exam
•Two of the following: headache, dizziness, fever, localizing neurological signs, changing level
of consciousness or confusion; and one of the following: organism on microscopic examination of brain
or abscess tissue, neuroimaging evidence of infection, or diagnostic serology.
-Encephalitis: Involvement of the brain parenchyma by the infectious agent. Diagnosis of
encephalitis by Venkatesan et al requires:
•Major criteria: Presence of decreased or altered level of consciousness, lethargy or personality
change lasting at least 24 hours and exclusion of encephalopathy due to other non-infectious aetiologies
•Two of the following for possible encephalitis, three of the following for probable or confirmed
encephalitis: fever, seizures, new onset focal neurological findings, cerebrospinal fluid (CSF) white
blood cell (WBC) count >10x106/L, abnormal neuroimaging and electroencephalography.
-Meningitis: Patients without criteria for encephalitis, and at least one of the following criteria:
•Organism identified from CSF
•The presence of two of the following: fever or headache, meningeal signs or cranial nerve signs
(and hypothermia, apnoea, bradycardia or irritability for those under <1 year of age); and one of the
following: increased WBC count (≥5 cells/mm3), increased protein and/or decreased glucose in CSF, an
organism on Gram stain or culture, or diagnostic serology.
For the purpose of this study, meningoencephalitis cases were classified as encephalitis. Also, the
CNSI were classified according to the time of disease evolution in days20: acute infection: ≤7 day;
subacute infection: 8-30 days; and chronic infection: >30 days.
•Etiological confirmation of CNSI: microbiological (direct exam/microscopy, isolation by
culture/molecular amplification methods, antigenic or serologic evidence of infection, histopathologic
exam) VERSUS clinical confirmation (clinical, epidemiological, radiological/other exams criteria, plus
cytological/biochemical analysis of CSF and empirical therapy)
The exclusion criteria were: Participants without CNSI case definition, readmissions during the
period of data collection (only the first admission was evaluated), evidence of nosocomial or
postoperative neuroinfection, diseases of inflammatory or autoimmune etiology, missing important data
for analysis or diagnosis.

2.4 Data collection
Cases classified as suspected central nervous system infections, including encephalitis, will have
the medical records reviewed and the information retrieved using the Research Electronic Data Capture
(REDCap) tool (www.project-redcap.org), an electronic form service aimed at scientific research, with
the appropriate international certification of information security for multicentric studies. Those
fulfilling the diagnostic criteria will be included in the study and will have the following clinical and
laboratory data collected:
. Age (date of birth), gender, ethnicity
. Date of onset of symptoms, date of hospital admission, date of ICU admission, date of outcome
. Postal Code (ZIP Code) of the residence and/or hotel
. History of international travel in the last 6 months
. History of travel in the country in the last 4 weeks
. Attendance at mass events (e.g. Carnival, Olympic Games, etc.)
. Contact with people with similar clinical features
. Contact with healthy or sick animals
. Consumption of unpasteurized, unusual or processed foods in a homemade way
. Clinical history, comorbidities, use of medications, vaccination history
. Initial diagnosis, final diagnosis, diagnostic tests, instituted treatments
. Etiologic agent, date of diagnosis, reason for late diagnosis (test availability, pathogen characteristics,
change in clinical features)
. Presence of organic dysfunctions: respiratory failure - arterial oxygen tension (Pa,O2) of <8.0 kPa (60
mmHg), an arterial carbon dioxide tension (Pa,CO2) of >6.0 kPa (45 mmHg) or both [19]; neurologic
deterioration - coma, defined as Glasgow coma scale (GCS) <8 points[20]; acute renal failure, defined
by RIFLE Classification System for Acute Kidney [21] - Injury 20 as serum creatinine (SCr) increased
>3 times baseline, or SCr ≥4 mg/dL or acute rise ≥0.5mg/dL, or glomerular filtration rate decreased
75%, or urine output <0.3mL/kg/h 24h (oliguria), or anuria 12h; and sepsis, defined by the Sepsis-3
Consensus in 2016 as a life-threatening organ dysfunction caused by a dysregulated host response to
infection, including septic shock. Septic shock can be clinically identified by a vasopressor requirement
to maintain a mean arterial pressure of 65 mmHg or greater and serum lactate level less than 2 mmol/L
(18 mg/dL) in the absence of hypovolemia [22].

.Severity and prognostic ICU scores: Simplified Acute Physiologic Score (SAPS) 3, Sequential Organ
Failure Assessment Score (SOFA) [23–25].
2.5 Outcome Ascertainment
The outcomes will be classified in four groups:
Early etiological diagnosis (less or equal to 72h after ICU admission);
Late etiological diagnosis;
Discharge without diagnosis;
Death without diagnosis;
We will determine if a group of signs, symptoms, lab results and epidemiological information
available in the first three days of hospitalization is associated with the outcomes evaluated.
3) Expected results/deliverables:
- Total number of encephalitis cases in a large network of ICUs; Encephalitis cases/ICU
admissions; Undiagnosed encephalitis cases/ total number of encephalitis cases.
- Description of the most common causes of encephalitis in these population and the availability
of  diagnostic procedures in the ICUs;
- A set of variables present at ICU admission associated with an undiagnosed encephalitis
outcome;
- The determination of the number and distribution of ICUs to establish a cost-effective sentinel
surveillance system.
4) Perspectives:
Our main goal is to develop an integrated endemic and emerging surveillance strategy to be
tested in a future prospective study, when cases will be selected for a deeper laboratory and
epidemiological investigation. This first retrospective study is important to support some decisions, like
what are the most suitable ICUs to be sentinel sites, how many cases we expect to test and which tests
we need to offer to complement the ICUs current etiological investigation. The case definition must
have high sensitivity and specificity but also timeliness, to identify as early as possible the cases that
should be included.
This study will develop surveillance core functions in ICU, an area underrepresented in Brazilian
and in other Latin American countries surveillance systems. It will also provide evidence-based
information on the necessary diagnostic resources for encephalitis surveillance, helping to plan support
functions like laboratory capacity in resource-limited settings.
5) Ethical aspects

This study was designed according to prevailing ethical precepts and will be submitted for
analysis in the INI-FIOCRUZ Research Ethics Committee. Medical records will be consulted by the
professionals involved in the study, but the identity of the patients will be preserved in anonymized
forms and the researchers guarantee confidentiality in any future publication. Being a retrospective study
using data collected in past ICU admissions, there are no discomforts or physical risks associated with
this project.
6) Chronogram
Time frame: February 2020 - October 2021
Activities
Period
RETROSPECTIVE COHORT STUDY
Epimed database collection and RedCap form elaboration
DONE
Epimed data analysis
DONE
Inclusion of 3 other hospitals
DONE
Review of medical records
DONE
Final analysis and results
2022
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