Differentiating causes of febrile illness in Burkina Faso: data from an accuracy study comparing gold standard culture techniques with a haemocytometry based algorithm (IMS), procalcitonin (PCT) and C-reactive protein (CRP)

Different causes of acute febrile illness due to different infectious diseases (e.g. bacterial, viral malaria) may present with a similar clinical presentation. We performed a clinical diagnostic study to assess the diagnostic accuracy of a new tool - the Infection Manager System (IMS) - an algorithm which uses haemocytometric data to predict the cause of infection (e.g. bacterial, viral, malaria). The current dataset is a subset of data obtained during this study which was performed in a rural setting in Burkina Faso. The study was registered at ClinicalTrials.org under Identifier NCT02669823. All data used for the manuscript entitled "Infection Manager System (IMS) as a new hemocytometry-based bacteremia detection tool: a diagnostic accuracy study in a malaria-endemic area of Burkina Faso" are included in the current subset of data. To test the IMS we collected clinical and demographic data from approximately 900 patients aged between 3 months and 100 years presenting with an acute febrile illness. Upon inclusion, 2-5 ml EDTA anticoagulated blood was sampled for haemocytometry, malaria diagnostics (thick- and thin blood films and RDTs) and blood culture. A nasopharyngeal swab and aliquots of residual blood and plasma were stored at -80° for retrospective analyses. 1. A viral panel on nasopharyngeal swabs 2. PCR's for malaria, Salmonella, S. aureus, H. influenzae, S. pneumoniae on whole blood or plasma samples and 3. C-reactive protein (CRP) and procalcitonin (PCT) levels on plasma samples. Additional diagnostics such as chest X-ray, echography, urinalysis, and culture of urine, stool, pus, or cerebrospinal fluid were performed on clinical indication. In this cohort we attempted to provide a microbiologically proven diagnosis for all patients admitted with febrile illness using gold standard methods (e.g. blood culture, malaria microscopy and PCR). We then assessed the accuracy of the novel IMS to differentiate causes of infection against these conventional diagnostic methods. We furthermore assessed the accuracy of both CRP and PCT in differentiating causes of infection and compared them to the performance of the IMS. We found that the IMS had a higher diagnostic accuracy to detect bacteremia than PCT at a cut of value of 0.5 µg/L, and was comparable in sensitivity, but superior in specificity to CRP at a cut of value of 20 mg/L. Subanalysis among patients below the age of five showed that they had a slightly lower accuracy of IMS, PCT and CRP. Combining the IMS and CRP did not significantly improve accuracy due to the high level of overlap between CRP and the IMS. The high negative predictive value of IMS –also in non-bacteremic bacterial infections – suggests that the IMS holds promise to rationalize antimicrobial prescription in healthcare facilities where hematology analyzers are available. The relatively low specificity and PPV demonstrate that it is not (yet) suitable as a diagnostic for bacteremia. Data were collected on standardized case report forms (CRFs) and entered into a secure database (RedCap, Vanderbilt University, Nashville, USA) after conformity check by a medical doctor. Entered data were checked against the CRFs by a data manager. Approximately ten percent of patient study files were checked by an independent monitor. Results from PCRs and ELISAs were entered into an excel database and merged with the principal database upon completion of inclusion. Laboratory analyses were performed and interpreted by experienced laboratory technicians who were blinded to clinical data. Raw data from the haematology analyser was electronically transferred to SYSMEX company once every two weeks for storage. SYSMEX had no access to the clinical data, researchers were blinded to the haematology analyser results until all clinical data were locked into a STATA database. Quality control and quality assurance were done in accordance with Good Clinical and Laboratory Practice (GCLP) guidelines. NA: Not available Variable Explenation Labels       Age_category Age category 1: <5 years 2: 5 years or older     sexe Sexe 0: male 1: female     pretreatment_malaria Antimalaria medication past 2 weeks 0: no 1: currently taking 2: currently finished 3: do not know pretreatment_antibiotics Antibiotics taken past 2 weeks 0: no 1: currently taking 2: currently finished 3: do not know onset_fever Days since onset fever         vomiting_anamnestic Vomiting 0: no 1: yes     abd_pain abdominal pains 0: no 1: yes     diarrhoea diarrhoea 0: no 1: yes     diarrhoea_frequency number of stools per day 0: <3x per day 1: 3 or more per day     diarrhoea_duration_days Number of days since onset diarrea         runny_nose runny nose 0: no 1: yes     earpain earpain 0: no 1: yes     throat_ache throat ache 0: no 1: yes     cough cough 0: no 1: yes     productive_cough productive cough 0: no 1: yes     dyspnoa dyspnoea 0: no 1: yes     dysuria dysuria 0: no 1: yes     other_miction_problem other mictions issues         myalgia myalgia 0: no 1: yes     arthralgia arthralgia 0: no 1: yes     skin_condition_unspecified rash or other skin conditions 0: no 1: yes     iritability iritability 0: no 1: yes     convulsions convulsions 0: no 1: yes     lethargy lethargy 0: no 1: yes     pulse_enrollment heartrate at inclusion beats per minute       bldpres_enrollment_sys systolic bloodpressure at inclusion mmHg       bldpres_enroll_dia diastolic bloodpressure at inclusion mmHg       temp_enrollment temperature at inclusion celcius       rsp_rate_enrollment respiratory rate at inclusion breaths per minute       haz06 height for age Z-score         waz06 weight for age Z-score         whz06 weight for height Z-score         bmiz06 BMI Z-score         bmi BMI calculated         pulmonary_wheezing wheezing at auscultation 0: no 1: yes     pulmonary_rhonchi rhonchi at auscultation 0: no 1: yes     normal_pulmones normal chest auscultation 0: no 1: yes     chest_indrawing_enrollment chest indrawing at inclusion 0: no 1: yes     nasal_flaring_enrollment nasal flaring at inclusion 0: no 1: yes     abd_auscultation normal abdominal auscultation sound 0: no 1: yes     abd_pain_palpation pain at abdominal palpation 0: no 1: yes     hepatomegaly hepatomegaly 0: no 1: yes     splenomegaly splenomegaly 0: no 1: yes     neck_stiffness_enrollment neck stiffness  0: no 1: yes     emv_e glasgow coma scale; eye         emv_m glasgow coma scale; movement         emv_v glasgow coma scale; verbal         emv total <5 years: max 5 5 or older: max 15     Antibiotics_at_admission Antibiotics given at hospitalisation 0: no 1: yes     Antimalarials_at_admission antimalaria given at hospitalisation 0: no 1: yes     Days_of_hospitalisation Total days in hospital days       Cured Mode of exit out of the hospital 1: cured 2: referred to larger hospital 3: left against medical advise 4: died diagnosis_discharge_1 Clinical diagnosis at discharge         diagnosis_discharge_2 Clinical diagnosis at discharge (second diagnosis)         malaria_RDT_hrp rapid diagnostic test on HRP 0: negative 1: positive     malaria_RDT_pldh rapid diagnostic test on pLDH 0: negative 1: positive     malaria_thick_smear malaria microscopy (>1 parasite) 0: negative 1: positive     malaria_parasite_density microscopy parasite density parasites/ml       gametocytes gametocytes in microscopy 0: negative 1: positive     species_m___1 malaria parasite species 0: negative 1: falciparum 2: falciparum+malariae   culture_wbclt Conclusion of bloodculture 1 0: negative 1: positive     pathogen_bloodculture 1 Name pathogen culture 1         culture_wbclt_2 Conclusion of bloodculture 2         pathogen_bloodculture_2 Name pathogen culture 2         bloodcultures_conclusion Total conclusion both cultures Name pathogen       CSF_rdt Rapid diagnostic test on cerebrospinal fluid         CSF_conc conclusion of culture/RDT cerebrospinal fluid         stool_cult Stool sample culture and microscopy         stool_conc Conclusion of the stool culture and microscopy         urine_cult Urine microscopy, sediment and culture         urine_conc Conclusion of urine diagnostics         pus_cult Pus culture         pus_conc conclusion of the pus culture         other_bacterial_pathogens pathogens isolated through other cultures than blood culture         ct_malaria_PCR malaria PCR Ct-value         logstqmalaria log stq malaria PCR         ParasitesmL_PCR Conclusion malaria PCR in parasites per ml         Parasites_uL_PCR Conclusion malaria PCR in parasites per ul         PCR_Aureus_Cq Cq value of s. aureus PCR on blood         PCR_AureusTm Tm value of s. aureus PCR on blood         PCR_Haemophilus_Cq Cq value of haemophilus PCR on blood         PCR_Haemophils_Tm Tm value of haemophilus PCR on blood         PCR_Pneumoniae_Cq Cq value of s pneumoniae PCR on blood         PCR_Salmonella_Ct Ct value of Salmonella PCR on blood         PCRbacteria_conclusion Summary of positive bacterial PCR's on blood         Nasopharyngeal swab PCR done on nasopharyngeal swab 0: negative 1: positive     Nasopharyngeal_Virus Which virus isolated in nasopharyngeal swab         Nasopharyngeal_Bacteria Which bacteria isolated in nasopharyngeal swab         CRP_mgdl CRP value in mg/dl analyzed by Eliza         PCT_ugL procalcitonin value in ug/L analyzed by Eliza         Hepatitisserology Serology on hepatitits         Ultrasound Ultrasound results         Xray X-ray results         Other_diagnostic_tests Conclusion of not previsouly mentioned additional tests         Diagnosis Diagnosis group as reported in the diagnostic scheme         Diagnosis_2 Potential second diagnosis         Diagnosis_3 Potential third diagnosis         Coinfection Which type of co-infection         WBC white bloodcell count cells/L       RBC red bloodcell count cells/L       HGB hemoglobin count g/dl       PLT platelet count cells/L       NEUT_A neutrophils (absolute number) cells/L       LYMP_A lymphocytes (absolute number) cells/L       MONO_A monocytes (absolute number) cells/L       EOSI_A eosinophils  (absolute number) cells/L       BASO_A basophils  (absolute number) cells/L       NEUT_P neutrophils (percentage of leukocytes) %       LYMP_P lymphocytes (percentage of leukocytes) %       MONO_P monocytes (percentage of leukocytes) %       EOSI_P eosinophils (percentage of leukocytes) %       BASO_P basophils (percentage of leukocytes) %       NRBC_A Nucleated red blood cells (absolute number) cells/L       NRBC_P Nucleated red blood cells (percentage of red bloodcells) %       IG_A immature granulocytes (absolute number) cells/L       IG_P immature granulocytes (percentage of granulocytes) %       RET_A reticulocytes (absolute number) cells/L       RET_P reticulocytes (percentage of red blood cells) %       ASLYMP_A Antibody-synthesizing lymphocytes (absolute number) cells/L       ASLYMP_P Antibody-synthesizing lymphocytes (percentage) %       RELYMP_A reactive lymphocytes (absolute number) cells/L       RELYMP_P reactive lymphocytes (percentage) %       NEUTRI neutrophil reactivity index  cells/L       NEUTGI neutrophil granularity index %       Bactscore IMS bacterial score         Virscore IMS viral score         Malscore IMS malaria score         IMS_final_full_classification Classification of the IMS