Meningitis Clinical Trial
Official title:
Neurovirus Emerging in the Americas Study (NEAS): Neurologic Manifestations of the Arbovirus Dengue, Chikungunya and Zika Infections in Colombia
This is a multi-center case-control study that aims to define the association between the exposure to an arbovirus infection and the development of a neurological syndrome in patients from Colombia. The study makes part of the Neurovirus Emerging in the Americas Study (NEAS) that is a collaborative effort that looks to combine the efforts of researchers, healthcare providers and patients in Colombia to establish a comprehensive registry of the clinical, radiological and laboratory profile of patients with new onset of neurological diseases associated mosquito-borne viruses, known as arboviruses.
NEAS is led by Dr. Carlos Pardo-Villamizar at Johns Hopkins University (JHU) and Drs. Beatriz
Parra and Lyda Osorio at Universidad del Valle (UV) in Colombia. They have established a
collaborative network with physicians, neurologists and experts in microbiology and
epidemiology in that country. NEAS is actively recruiting patients in seven university-based
hospitals in five Colombian cities. The protocol of the study has been approved in each of
the participating centers.
NEAS prospective case-control study aims to define the association between the exposure to
arbovirus (Zika, Dengue and Chikungunya) and the development of a neurological syndrome in
patients from Colombia, a country with endemic transmission of arbovirus. The cases are
defined as individuals that present with new onset of a neurological syndrome of unknown
etiology, including but not limited to encephalitis, myelitis, meningitis,
polyneuropathy/Guillain-Barre syndrome and cranial nerve involvement. There are two
age-matched control groups: 1) household controls and 2) controls with a febrile syndrome of
unknown etiology that do not present neurological involvement. The estimated sample size in
the study is 50 participants in each group (cases and controls 1 and 2). The time to collect
the complete sample size is between 12-24 months, and depends on the local incidence of
cases.
Each center has a coordinator team that includes a neurologist, a physician - neurology or
internal medicine resident -, and a research coordinator. The team is constantly screening
the patients admitted to the center. The patients that fulfill the criteria for cases or
controls are approached by the research coordinator who is in charge to inform the
participant about the study and complete the informed consent. Then, the medical team perform
the neurological evaluation, including the history and the physical exam according to the
NEAS forms. Samples of blood and urine are collected in all participants. If a lumbar
puncture is done as part of the standard of care, spinal fluid is also collected. Based on
resources availability, the participants are followed every week for a 4-week period and in
each visit a clinical assessment and sample collection are completed.
Demographic and clinical information, laboratory and imaging results are stored in a secured
web-based database in the platform REDcap,based at JHU. Each center has a unique combination
of a username and a password to enter the database and include the information of each
participant in real time. Each center has access to the included information by the same
center and no by other centers. Standardized forms (NEAS forms) were created by the study
team that include relevant information necessary to achieved the aims of this study and
guarantee the data consistency. Laboratory testing and imaging results are obtained from the
medical records. A permanent monitoring of the data base is done by the teams at JHU and UV.
After the samples are collected they are shipped to the study core laboratory located at UV
(Dr. Beatriz Parra). Each center has been trained in the correct handling, processing, and
shipping of the samples. Once the samples are in the core laboratory, they are aliquoted and
stored. Blood, urine and spinal fluid are tested by Real Time/Reverse Transcriptase (RT)-
Polymerase Chain Reaction (PCR) for the presence of viral RNA (Ribonucleic Acid) of Zika
virus and Dengue virus. Serum and spinal fluid are tested by ELISA for the detection of
anti-flavivirus IgM and IgG. The results are shared with the local study team and with the
medical team taking care of the participant. In addition, aliquots of samples are sent to JHU
for additional immunological and virological assessments (Dr. Carlos Pardo-Vllamizar).
Standard Operative Procedures (SOP) have been created for patient recruitment and consent,
REDcap data entering, and biosamples process and shipment. The statistical analysis will be
done by epidemiologists at UV (Dr. Lyda Osorio) and it will include frequency measures and
central tendency measures of the variables. The measure of the strength of association will
be done using Odds ratio and confidence intervals.
DATA DICTIONARY
The variables are divided in three categories: demographic, clinical and laboratory. The most
relevant variables collected in the study are described below.
Demographic variables:
- Case: Case definition
- Type of control: Control definition
- Fulfillment of the inclusion criteria: Fulfillment of the inclusion criteria established
by the protocol
- Gender: Sexual phenotype of the participant supported by the medical records or ID
- Age: Participant`s age according to the medical records or ID
- Race: Phenotype reported by the participant
- City of residence: Place where has mainly been in the last 3 months
- City of report: Place where the participant is recruited to the study
Clinical variables:
- General symptoms: Clinical manifestations consistent with decrease in the normal health
shape of the participant
- Onset of general symptoms: Date of the onset of general symptoms
- Neurological symptoms: Clinical manifestations reflecting an abnormal functioning of the
nervous system
- Temporal profile: Time (in days) between the onset of general symptoms and neurological
symptoms
- Visit to endemic regions: History of have visited during the last 4 weeks regions with
current local transmission of Zika, Dengue and/or Chikungunya virus
- Past medical history: History of a disease diagnosed by the doctor or reported in the
medical records during the past year
- Family history: Diseases suffered by first or second consanguinity degree relatives
diagnosed by the doctor or reported in the medical records
- Recent vaccination: History of vaccination during the past 4 weeks before the onset of
the neurological symptoms
- Recent infectious disease: History of an infectious disease during the past 4 weeks
before the onset of the neurological symptoms
- Recent surgical procedure: History of a major surgical procedure during the past 4 weeks
before the onset of the neurological symptoms
- Date of physical exam: Date when physical exam was completed by the study team
- Mental status: Range of own/outer consciousness
- Orientation: Awareness of time, place and person
- Dysarthria: Word articulation dysfunction secondary to a motor pathways damage
- Attention deficit: Inability to selectively concentrate in an specific portion of the
information
- Cranial nerves abnormalities: Compromise of one/more of the cranial nerves detected on
the physical exam
- Muscle strength: Amount of strength done by a muscle against resistance
- Deep tendon reflexes: Extension secondary to a deep tendon stimulus
- Sensory deficit: Absence or abnormality in the sensory function
- Romberg sign: Clinical sign suggesting sensory ataxia, secondary to dorsal columns
abnormalities
- Ataxia: Abnormal muscle coordination during voluntary movements
- Muscle tone: Muscle resistance against passive movement
- Urinary retention: Inability to complete bladder emptiness
- Low rectal muscle tone: Decrease in the strength of the rectal sphincter
- Abnormal movements: No voluntary movements, without purpose, secondary to a neurological
dysfunction
- Respiratory failure: Inability to perform an efficient gas exchange or to maintain
normal levels of oxygen and/or carbon dioxide
- Autonomic dysfunction: Abnormalities in the autonomic nervous system
- Electromyography: Electrophysiological study of the muscle activity
- Electroencephalogram: Electrophysiological study of the brain conduction
- Brain MRI: Imaging study of the brain
- Spinal cord MRI: Imaging study of the spinal cord
- Rankin score: Functional scale for patients with neurological disorders
- ASIA scale: Severity of spinal cord lesion
Laboratory variables:
- Blood analysis: Include white blood cells count, platelets, hemoglobin, hematocrit and
liver function enzymes.
- Spinal fluid analysis: Includes leukocytes, glucose, proteins, red blood cells,
oligoclonal bands, cultures, herpes virus PCR.
- Virological analysis: Includes detection or absence of detection of IgM and IgG by
ELISA, and the RNA by RT-PCR for Zika virus, Dengue virus and Chikungunya virus.
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