Clinical trial NCT03206541: Neurologic Manifestations of the Arbovirus Infection in Colombia
Official title: Neurovirus Emerging in the Americas Study (NEAS): Neurologic Manifestations of the Arbovirus Dengue, Chikungunya and Zika Infections in Colombia
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Encephalitis
Myelitis
Guillain-Barre Syndrome
Cranial Nerve Palsies
Meningitis
Zika Virus Infection
Dengue (Virus); Fever, Sandfly
Chikungunya Fever
Keywords: Neurological syndromes
Arbovirus infection
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: Universidad del Valle, Colombia
name: ZikaPLAN
First posted: 2017-07-02
Enrollment: 570
Sex: ALL
Minimum age (years): 8
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study population includes males and females over 8 years of age at risk of being infected by Dengue, Chikungunya or Zika viruses.

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Male or female
* Case or control definition
* Informed consent or assent

Exclusion Criteria:

* Known etiology for the acute neurological disorders
* History of known neurological syndrome

Primary outcomes:
measure: Neurological outcomes in arbovirus infections
timeFrame: 12-24 months
Secondary outcomes:
measure: Viral genotype
timeFrame: 24-36 months
measure: Immune response
timeFrame: 24-36 months
Other outcomes:
Locations:
city: Medellín
country: Colombia
facility: Clinica Leon XIII
state: Antioquia
city: Medellín
country: Colombia
facility: Neuroclinica
state: Antioquia
city: Barranquilla
country: Colombia
facility: Clinica La Misericordia Internacional
state: Atlantico
city: Neiva
country: Colombia
facility: Clinica Medilaser
state: Huila
city: Neiva
country: Colombia
facility: Hospital Universitario de Neiva
state: Huila
city: Pasto
country: Colombia
facility: Hospital Universitario de Narino
state: Narino
city: Cúcuta
country: Colombia
facility: Hospital Universitario Erasmo Meoz
state: Norte De Santander
city: Cali
country: Colombia
facility: Hospital Universitario del Valle
state: Valle Del Cauca
Study officials:
affiliation: Johns Hopkins University
name: Carlos A Pardo-Villamizar, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Universidad del Valle
name: Beatriz Parra, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Universidad del Valle
name: Lyda Osorio, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Munoz LS, Barreras P, Pardo CA. Zika Virus-Associated Neurological Disease in the Adult: Guillain-Barre Syndrome, Encephalitis, and Myelitis. Semin Reprod Med. 2016 Sep;34(5):273-279. doi: 10.1055/s-0036-1592066. Epub 2016 Sep 9.
citation: Rowland A, Washington CI, Sheffield JS, Pardo-Villamizar CA, Segars JH. Zika virus infection in semen: a call to action and research. J Assist Reprod Genet. 2016 Apr;33(4):435-7. doi: 10.1007/s10815-016-0684-6. Epub 2016 Mar 5. No abstract available.
citation: Parra B, Lizarazo J, Jimenez-Arango JA, Zea-Vera AF, Gonzalez-Manrique G, Vargas J, Angarita JA, Zuniga G, Lopez-Gonzalez R, Beltran CL, Rizcala KH, Morales MT, Pacheco O, Ospina ML, Kumar A, Cornblath DR, Munoz LS, Osorio L, Barreras P, Pardo CA. Guillain-Barre Syndrome Associated with Zika Virus Infection in Colombia. N Engl J Med. 2016 Oct 20;375(16):1513-1523. doi: 10.1056/NEJMoa1605564. Epub 2016 Oct 5.
citation: Zea-Vera AF, Parra B. Zika virus (ZIKV) infection related with immune thrombocytopenic purpura (ITP) exacerbation and antinuclear antibody positivity. Lupus. 2017 Jul;26(8):890-892. doi: 10.1177/0961203316671816. Epub 2016 Sep 30.