Ignite Creation Date:
2024-10-26 @ 3:37 PM
Last Modification Date:
2024-10-26 @ 3:37 PM
Study NCT ID:
NCT06539325
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-07-11
Brief Title:
Rapid Molecular Diagnosis and Detection of Emerging Infectious Diseases in Patients With Tropical Fever Tropifever
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Rapid Molecular Diagnosis and Detection of Emerging Infectious Diseases in Patients With Tropical Fever
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
Tropifever
Brief Summary:
Travellers returning from tropical countries often present to emergency departments with acute fever While systematic screening for malaria is well established in clinical practice in France further diagnostic testing for infectious diseases is less codified In addition the clinical presentation of many tropical and emerging infectious diseases is often similar making a positive diagnosis in these patients challenging
Improving the microbiological diagnostic strategy for febrile travellers is crucial because the lack of an accurate diagnosis in many of these patients prevents the implementation of appropriate diagnostic and therapeutic measures These measures include antimicrobial treatment but also additional investigations specialised monitoring and the initiation of follow-up of acute or chronic infections
In addition the current diagnostic approach to tropical fevers is poorly suited to detect outbreaks associated with a new or re-emerging infectious disease and to alert public health authorities in a timely manner
Therefore this project aims to evaluate the impact of a systematic and expanded microbiological diagnostic strategy for patients presenting to the emergency department with fever after returning from tropical countries To evaluate this testing strategy the investigators propose to conduct a multicentre cluster-randomised cross-over trial comparing standard care with a systematic microbiological diagnostic algorithm added to standard care
Improving the microbiological diagnostic strategy for febrile travellers is crucial because the lack of an accurate diagnosis in many of these patients prevents the implementation of appropriate diagnostic and therapeutic measures These measures include antimicrobial treatment but also additional investigations specialised monitoring and the initiation of follow-up of acute or chronic infections
In addition the current diagnostic approach to tropical fevers is poorly suited to detect outbreaks associated with a new or re-emerging infectious disease and to alert public health authorities in a timely manner
Therefore this project aims to evaluate the impact of a systematic and expanded microbiological diagnostic strategy for patients presenting to the emergency department with fever after returning from tropical countries To evaluate this testing strategy the investigators propose to conduct a multicentre cluster-randomised cross-over trial comparing standard care with a systematic microbiological diagnostic algorithm added to standard care
Detailed Description:
Frequently travelers returning from tropical countries seek medical advice in the emergency department ED for acute fever While the systematic search for malaria is well anchored in clinical practice in France further diagnostic testing for infectious diseases ID is less codified Besides the clinical presentation of many tropical and emerging infectious pathologies EID is often similar presenting challenges for a positive diagnosis in those patients
Indeed besides testing for malaria all patients with fever and a travel history in tropical regions in the last 3 months there are to our knowledge no French guidelines on the diagnosis strategy of fever in the returning traveler A few studies have proposed a syndromic testing strategy for patients admitted to ICU but literature still lacks data on the efficiency of syndromic testing strategies in patients without severity criteria consulting at the ED Other expert committees and literature on the topic usually recommend to collect a detailed clinical history including nature of travel relevant activities and exposure and physical findings and then prescribe laboratory tests according to each situation However this common-sense clinical approach may not be adapted to the peculiar situation of emergency departments where the expertise of clinicians in infectious and tropical diseases may vary and time constraints do not always allow clinicians to collect a detailed history and examination Moreover even a careful medical history and physical examination may mislead clinicians in case of atypical clinical presentations or unexpected infections
A recent study conducted in Spain Switzerland and Belgium has shown that among travelers with acute undifferentiated febrile illnesses 132455 290 had viral infections including 108455 237 arboviruses 96455 211 malaria and 82455 180 bacterial infections A review of travel-related infections in 103739 patients consulting in different European clinics between 1998 and 2018 reported an increase in arboviral infections over the last decade with dengue chikungunya and zika virus infections being almost as frequent as malaria between 2013 and 2018 A similar percentage of patients presented a viral syndrome with or without rash in which the etiological agent could not be identified emphasizing the gaps in our current testing strategy
The diagnosis of respiratory viruses including SARS-CoV-2 influenza and respiratory syncytial virus RSV is often overlooked in returning travelers consulting in the emergency department ED despite being transmitted either year-long in tropical countries or during the rainy season concomitantly with malaria Rickettsial diseases such as spotted fever or scrub typhus for example represented 2 of febrile returning travelers in a recent article but are exceptionally sought after in the diagnostic process of patients consulting in the emergency department Some of these patients with rickettsial diseases had no characteristic eschar Likewise hemorrhagic fevers and particularly Lassa fever whose prevalence has been increasing in recent years in Nigeria are seldomly tested
It is thus an open question whether a broader and more systematic microbiological laboratory testing strategy could enhance the number of diagnosis and thus the management of patients in this population Indeed improving our diagnostic strategy is crucial because the lack of a precise diagnosis in many of these patients prevents the implementation of appropriate diagnostic therapeutic measures These measures obviously include antimicrobial treatments but also additional investigations specialized monitoring and the initiation of a follow-up of acute or chronic infections Indeed the visit in the ED of those febrile travelers represents a unique opportunity to screen for chronic viral infections such as HIV hepatitis B and C as well as acute hepatitis due to HAV or HEV as this population of travelers is particularly at risk
Potential measures also include isolation measures or public health measures such as mandatory reporting Indeed even though epidemiological surveillance systems and mandatory reporting have been established for dengue fever chikungunya and other arboviruses the number of reported cases in metropolitan France remains low and is probably underestimated This limited testing in returning travelers impairs our ability to detect cryptic transmission of these diseases Even though most of those infections are self-limiting improving the detection of these arboviral infections is crucial as their vectors notably Aedes albopictus are now present seasonally or yearlong in different French metropolitan areas Thus infected patients could potentially fuel local transmissions of arboviruses emphasizing the need for improved diagnostic tools in metropolitan hospitals
Furthermore the current diagnosis approach for tropical fever is poorly suited to detect outbreaks linked to a new or re-emerging infectious disease and to promptly alert public health authorities Although the diagnostic of viral hemorrhagic fevers for example is unlikely in returning travelers the current diagnosis approach does not permit the early diagnosis of an outbreak especially in the case of a pauci-symptomatic patient Other emerging infectious diseases such as shown by the recent example of Monkeypox are never routinely screened before an outbreak occurs However recent data suggest that Monkeypox may have been circulating at low levels in France before the alert was given
This project thus aims to evaluate the clinical impact of a systematic diagnostic strategy for patients consulting the ED for fever after returning from the tropics To evaluate this testing strategy the investigators propose to perform a multicentric cluster-randomized trial comparing the standard of care with a systematic microbiological diagnostic algorithm added to the standard of care
As discussed above there is no well-established standard of care nor guidelines for the diagnostic approach of a returning traveler with fever in the emergency department Literature exist but mostly consist of expert advice Indeed fever in a returning traveler is a complex condition with multiple potential diagnoses The diagnostic approach in the emergency department is individualized very heterogeneous and often limited by time constraints
This is why the design proposed is a cluster randomized trial comparing Standard of Care SoC to Standard of Care plus a systematic microbiological diagnostic algorithm
During intervention periods this algorithm will be added to the SoC for every traveler returning from tropical countries and presenting with fever measured at the ED
The investigators make the hypotheses that this project will
1 improve the diagnosis of tropical and emerging infectious diseases in patients with a fever returning from tropical countries by using a systematic microbiological diagnostic approach
2 by providing microbiologically confirmed diagnosis optimize the clinical management of patients including but not limited to additional investigations specific monitoring dedicated follow-up isolation measures antimicrobial treatment thus improving patients clinical outcomes
3 increase the application of public health measures for infectious and tropical diseases including mandatory reporting to the Regional Health Agency thus improving the national surveillance of selected diseases
4 provide the participating centers with tools for the early detection of emerging infectious diseases allowing them to participate in the surveillance and early alert of any emergence Indeed this protocol by using and evaluating innovative and versatile diagnostic tools is adapted to the rapid addition of one or multiple additional pair of primers into the diagnosis strategy in case of a new emergence or a re-emerging infectious disease
Finally the proposed microbiological diagnostic strategy and the precise analysis of microbiologically confirmed positive diagnosis in this study may inform future guidelines for the screening of infectious and tropical diseases in febrile returning travellers
The investigators plan to include patients consulting in the emergency department for fever within 28 days of returning from tropical regions who do not have sepsis qSOFA 2 nor require immediate hospitalization
Patients will be included in the emergency department because they usually are less explored than in other contexts such as a dedicated ID consultation Moreover studies have shown that patients seeking the ED are usually more frail or vulnerable than other patients They visit the ED because they are often unaware of consultations dedicated to tropical pathologies and sometimes because they do not have a general practitioner So the ED visit represents an excellent opportunity to put these patients back into an appropriate care plan Patients will not be included in other contexts such as the outpatient clinic of infectious diseases because the standard of care in these structures might be different from emergency departments
Fever will be defined as a tympanic temperature above 38c measured in the emergency department
The 28 days cut-off is based on the fact that most arboviruses respiratory viruses and hemorrhagic fevers have a combined incubation and detection period below 28 days
Tropical regions will be defined as any region located between the Tropic of Cancer and the Tropic of Capricorn
Patients with sepsis qSOFA 2 or patients who require hospitalization will not be included because they usually have rapid access to a wide panel of diagnostic testing while hospitalized and are explored more than patients who do not require hospitalization Quick SOFA is widely used as a score for sepsis
Standard of care is the standard diagnostic approach for returning travelers with fever It will include the standard clinical evaluation of a patient with the collection of medical history travel history physical examination etc In addition to travel-related infections cosmopolitan causes of fever should be considered in ill travellers as well as non-infectious cause of fever including eg venous thrombosis allergic fever cancer etc The standard of care for diagnosis in a patient with fever is thus complex and heterogeneous among patients
Regarding laboratory work-up there are no specific guidelines for these patients apart from systematic malaria testing Standard of care usually includes systematic malaria thin smear - antigen test - qPCR according to each center and local capacities sample for upper respiratory tract symptoms chest X-Ray for abnormal auscultation etc
As part of this study all patients included in the control period and the intervention period will have a follow-up visit planned with an infectious diseases specialist at Day 4 -1
The follow-up visit will allow clinicians to provide a diagnosis to the patient if a diagnosis has been confirmed and to organize subsequent diagnosis and therapeutic management of the patients Day 4 -1 has been chosen for the follow-up visit because this ensures that the ID specialist will have access to most of the microbiological examinations included in the diagnostic algorithm both in the control and in the intervention periods and complies with the recommendation to see all patients with a diagnosis of malaria for the Day 3 monitoring
The testing strategy that will be evaluated during this study includes tests that will be realized in all centres in order to be available during the follow-up consultation with the ID specialist and specialized tests that will be performed retrospectively in one central hospital Bichat-Claude Bernard
Indeed besides testing for malaria all patients with fever and a travel history in tropical regions in the last 3 months there are to our knowledge no French guidelines on the diagnosis strategy of fever in the returning traveler A few studies have proposed a syndromic testing strategy for patients admitted to ICU but literature still lacks data on the efficiency of syndromic testing strategies in patients without severity criteria consulting at the ED Other expert committees and literature on the topic usually recommend to collect a detailed clinical history including nature of travel relevant activities and exposure and physical findings and then prescribe laboratory tests according to each situation However this common-sense clinical approach may not be adapted to the peculiar situation of emergency departments where the expertise of clinicians in infectious and tropical diseases may vary and time constraints do not always allow clinicians to collect a detailed history and examination Moreover even a careful medical history and physical examination may mislead clinicians in case of atypical clinical presentations or unexpected infections
A recent study conducted in Spain Switzerland and Belgium has shown that among travelers with acute undifferentiated febrile illnesses 132455 290 had viral infections including 108455 237 arboviruses 96455 211 malaria and 82455 180 bacterial infections A review of travel-related infections in 103739 patients consulting in different European clinics between 1998 and 2018 reported an increase in arboviral infections over the last decade with dengue chikungunya and zika virus infections being almost as frequent as malaria between 2013 and 2018 A similar percentage of patients presented a viral syndrome with or without rash in which the etiological agent could not be identified emphasizing the gaps in our current testing strategy
The diagnosis of respiratory viruses including SARS-CoV-2 influenza and respiratory syncytial virus RSV is often overlooked in returning travelers consulting in the emergency department ED despite being transmitted either year-long in tropical countries or during the rainy season concomitantly with malaria Rickettsial diseases such as spotted fever or scrub typhus for example represented 2 of febrile returning travelers in a recent article but are exceptionally sought after in the diagnostic process of patients consulting in the emergency department Some of these patients with rickettsial diseases had no characteristic eschar Likewise hemorrhagic fevers and particularly Lassa fever whose prevalence has been increasing in recent years in Nigeria are seldomly tested
It is thus an open question whether a broader and more systematic microbiological laboratory testing strategy could enhance the number of diagnosis and thus the management of patients in this population Indeed improving our diagnostic strategy is crucial because the lack of a precise diagnosis in many of these patients prevents the implementation of appropriate diagnostic therapeutic measures These measures obviously include antimicrobial treatments but also additional investigations specialized monitoring and the initiation of a follow-up of acute or chronic infections Indeed the visit in the ED of those febrile travelers represents a unique opportunity to screen for chronic viral infections such as HIV hepatitis B and C as well as acute hepatitis due to HAV or HEV as this population of travelers is particularly at risk
Potential measures also include isolation measures or public health measures such as mandatory reporting Indeed even though epidemiological surveillance systems and mandatory reporting have been established for dengue fever chikungunya and other arboviruses the number of reported cases in metropolitan France remains low and is probably underestimated This limited testing in returning travelers impairs our ability to detect cryptic transmission of these diseases Even though most of those infections are self-limiting improving the detection of these arboviral infections is crucial as their vectors notably Aedes albopictus are now present seasonally or yearlong in different French metropolitan areas Thus infected patients could potentially fuel local transmissions of arboviruses emphasizing the need for improved diagnostic tools in metropolitan hospitals
Furthermore the current diagnosis approach for tropical fever is poorly suited to detect outbreaks linked to a new or re-emerging infectious disease and to promptly alert public health authorities Although the diagnostic of viral hemorrhagic fevers for example is unlikely in returning travelers the current diagnosis approach does not permit the early diagnosis of an outbreak especially in the case of a pauci-symptomatic patient Other emerging infectious diseases such as shown by the recent example of Monkeypox are never routinely screened before an outbreak occurs However recent data suggest that Monkeypox may have been circulating at low levels in France before the alert was given
This project thus aims to evaluate the clinical impact of a systematic diagnostic strategy for patients consulting the ED for fever after returning from the tropics To evaluate this testing strategy the investigators propose to perform a multicentric cluster-randomized trial comparing the standard of care with a systematic microbiological diagnostic algorithm added to the standard of care
As discussed above there is no well-established standard of care nor guidelines for the diagnostic approach of a returning traveler with fever in the emergency department Literature exist but mostly consist of expert advice Indeed fever in a returning traveler is a complex condition with multiple potential diagnoses The diagnostic approach in the emergency department is individualized very heterogeneous and often limited by time constraints
This is why the design proposed is a cluster randomized trial comparing Standard of Care SoC to Standard of Care plus a systematic microbiological diagnostic algorithm
During intervention periods this algorithm will be added to the SoC for every traveler returning from tropical countries and presenting with fever measured at the ED
The investigators make the hypotheses that this project will
1 improve the diagnosis of tropical and emerging infectious diseases in patients with a fever returning from tropical countries by using a systematic microbiological diagnostic approach
2 by providing microbiologically confirmed diagnosis optimize the clinical management of patients including but not limited to additional investigations specific monitoring dedicated follow-up isolation measures antimicrobial treatment thus improving patients clinical outcomes
3 increase the application of public health measures for infectious and tropical diseases including mandatory reporting to the Regional Health Agency thus improving the national surveillance of selected diseases
4 provide the participating centers with tools for the early detection of emerging infectious diseases allowing them to participate in the surveillance and early alert of any emergence Indeed this protocol by using and evaluating innovative and versatile diagnostic tools is adapted to the rapid addition of one or multiple additional pair of primers into the diagnosis strategy in case of a new emergence or a re-emerging infectious disease
Finally the proposed microbiological diagnostic strategy and the precise analysis of microbiologically confirmed positive diagnosis in this study may inform future guidelines for the screening of infectious and tropical diseases in febrile returning travellers
The investigators plan to include patients consulting in the emergency department for fever within 28 days of returning from tropical regions who do not have sepsis qSOFA 2 nor require immediate hospitalization
Patients will be included in the emergency department because they usually are less explored than in other contexts such as a dedicated ID consultation Moreover studies have shown that patients seeking the ED are usually more frail or vulnerable than other patients They visit the ED because they are often unaware of consultations dedicated to tropical pathologies and sometimes because they do not have a general practitioner So the ED visit represents an excellent opportunity to put these patients back into an appropriate care plan Patients will not be included in other contexts such as the outpatient clinic of infectious diseases because the standard of care in these structures might be different from emergency departments
Fever will be defined as a tympanic temperature above 38c measured in the emergency department
The 28 days cut-off is based on the fact that most arboviruses respiratory viruses and hemorrhagic fevers have a combined incubation and detection period below 28 days
Tropical regions will be defined as any region located between the Tropic of Cancer and the Tropic of Capricorn
Patients with sepsis qSOFA 2 or patients who require hospitalization will not be included because they usually have rapid access to a wide panel of diagnostic testing while hospitalized and are explored more than patients who do not require hospitalization Quick SOFA is widely used as a score for sepsis
Standard of care is the standard diagnostic approach for returning travelers with fever It will include the standard clinical evaluation of a patient with the collection of medical history travel history physical examination etc In addition to travel-related infections cosmopolitan causes of fever should be considered in ill travellers as well as non-infectious cause of fever including eg venous thrombosis allergic fever cancer etc The standard of care for diagnosis in a patient with fever is thus complex and heterogeneous among patients
Regarding laboratory work-up there are no specific guidelines for these patients apart from systematic malaria testing Standard of care usually includes systematic malaria thin smear - antigen test - qPCR according to each center and local capacities sample for upper respiratory tract symptoms chest X-Ray for abnormal auscultation etc
As part of this study all patients included in the control period and the intervention period will have a follow-up visit planned with an infectious diseases specialist at Day 4 -1
The follow-up visit will allow clinicians to provide a diagnosis to the patient if a diagnosis has been confirmed and to organize subsequent diagnosis and therapeutic management of the patients Day 4 -1 has been chosen for the follow-up visit because this ensures that the ID specialist will have access to most of the microbiological examinations included in the diagnostic algorithm both in the control and in the intervention periods and complies with the recommendation to see all patients with a diagnosis of malaria for the Day 3 monitoring
The testing strategy that will be evaluated during this study includes tests that will be realized in all centres in order to be available during the follow-up consultation with the ID specialist and specialized tests that will be performed retrospectively in one central hospital Bichat-Claude Bernard
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None