Acute Undifferentiated Fever Research Articles

Complete Genome Sequence of Leptospira interrogans Strains FMAS_KW1, FMAS_KW2 and FMAS_AW1 Isolated from Leptospirosis Patients from Karawanalla and Awissawella, Sri Lanka.

Leptospirosis is an important cause of acute undifferentiated fever and complex multisystem febrile diseases in the tropics and subtropics. Understanding the evolution of Leptospira especially as related to the clinical pathogenesis of leptospirosis is facilitated by systematic comparative genomic analysis of human-infecting isolates. Here, we announce the complete genome sequences of three Leptospira strains that were isolated from blood of humans with undifferentiated fever in Sri Lanka.

Dengue and chikungunya among outpatients with acute undifferentiated fever in Kinshasa, Democratic Republic of Congo: A cross-sectional study.

BackgroundPathogens causing acute fever, with the exception of malaria, remain largely unidentified in sub-Saharan Africa, given the local unavailability of diagnostic tests and the broad differential diagnosis.MethodologyWe conducted a cross-sectional study including outpatient acute undifferentiated fever in both children and adults, between November 2015 and June 2016 in Kinshasa, Democratic Republic of Congo. Serological and molecular diagnostic tests for selected arboviral infections were performed on blood, including PCR, NS1-RDT, ELISA and IFA for acute, and ELISA and IFA for past infections.ResultsInvestigation among 342 patients, aged 2 to 68 years (mean age of 21 years), with acute undifferentiated fever (having no clear focus of infection) revealed 19 (8.1%) acute dengue–caused by DENV-1 and/or DENV-2 –and 2 (0.9%) acute chikungunya infections. Furthermore, 30.2% and 26.4% of participants had been infected in the past with dengue and chikungunya, respectively. We found no evidence of acute Zika nor yellow fever virus infections. 45.3% of patients tested positive on malaria Rapid Diagnostic Test, 87.7% received antimalarial treatment and 64.3% received antibacterial treatment.DiscussionChikungunya outbreaks have been reported in the study area in the past, so the high seroprevalence is not surprising. However, scarce evidence exists on dengue transmission in Kinshasa and based on our data, circulation is more important than previously reported. Furthermore, our study shows that the prescription of antibiotics, both antibacterial and antimalarial drugs, is rampant. Studies like this one, elucidating the causes of acute fever, may lead to a more considerate and rigorous use of antibiotics. This will not only stem the ever-increasing problem of antimicrobial resistance, but will–ultimately and hopefully–improve the clinical care of outpatients in low-resource settings.Trial registrationClinicalTrials.gov NCT02656862.

Clinical Spectrum of Acute Undifferentiated Fever - An Experience from a Tertiary Care Centre

Clinical Spectrum of Acute Undifferentiated Fever - An Experience from a Tertiary Care Centre

Emergence of murine typhus in La Réunion, France, 2012–2017

ObjectiveMurine typhus (MT) is an acute zoonosis caused by Rickettsia typhi, a flea-borne rickettsiosis. The first autochthonous case was reported in 2012. Once autochthonous transmission of Rickettsia typhi was proven, we performed a prospective study to describe and raise awareness of this often-misdiagnosed disease among physicians. Patients and methodsWe performed a prospective observational study of MT cases in La Réunion from 2012 to 2017. MT cases were defined as clinically compatible illnesses with a specific positive serology and/or PCR. ResultsSixty-one confirmed cases were collected. The main clinical features were prolonged fever (90%), asthenia (87%), and headaches (79%). The main biological abnormalities were elevated liver enzymes (84%) and thrombopenia (75%). Renal function was normal in 90% of cases; it was an important feature because leptospirosis is a frequent cause of acute renal failure. A seasonal factor was observed with 79% of cases reported in the warm season and most of them in the west and south of the island (i.e., the dry areas). ConclusionMT is an emerging disease in La Réunion, and local conditions could lead to an endemic situation. Cases of acute undifferentiated fever with headaches should guide to the diagnosis of MT especially in the warm season and dry areas. Leptospirosis is an alternative diagnosis, which differs from MT by its epidemiological characteristics and by the associated frequent renal dysfunction.

Clinical Manifestations and Molecular Diagnosis of Scrub Typhus and Murine Typhus, Vietnam, 2015-2017.

Rickettsioses are endemic to Vietnam; however, only a limited number of clinical studies have been performed on these vectorborne bacteria. We conducted a prospective hospital-based study at 2 national referral hospitals in Hanoi to describe the clinical characteristics of scrub typhus and murine typhus in northern Vietnam and to assess the diagnostic applicability of quantitative real-time PCR assays to diagnose rickettsial diseases. We enrolled 302 patients with acute undifferentiated fever and clinically suspected rickettsiosis during March 2015-March 2017. We used a standardized case report form to collect clinical information and laboratory results at the time of admission and during treatment. We confirmed scrub typhus in 103 (34.1%) patients and murine typhus in 12 (3.3%) patients. These results highlight the need for increased emphasis on training for healthcare providers for earlier recognition, prevention, and treatment of rickettsial diseases in Vietnam.

Study of Clinical Profile of Acute Undifferentiated Fever in a Tertiary Care Hospital

Study of Clinical Profile of Acute Undifferentiated Fever in a Tertiary Care Hospital

Seroprevalence of Tick-Borne Anaplasma phagocytophilum Infection in Healthy Adult Population and Patients with Acute Undifferentiated Fever from the Yunnan Province of China.

Anaplasma phagocytophilum-the causative agent of human granulocytic anaplasmosis (HGA)-is a tick-borne pathogen transmitted by Ixodid ticks infecting wild and domestic mammals as well as humans. Despite the availability of evidence regarding this emerging infection among vectors, host animals, and individuals in China, there is limited knowledge on the prevalence and distribution of A. phagocytophilum in the Yunnan Province. The aim of this study was to assess the seroprevalence of A. phagocytophilum in healthy adults and patients with acute undifferentiated fever from four regions in the Yunnan Province. The enzyme-linked immunosorbent assay and indirect immunofluorescence assay were used to detect immunoglobulin (Ig) G and IgM antibodies against A. phagocytophilum in sera obtained from 1185 healthy blood donors and 245 patients with acute undifferentiated fever, respectively. Demographic variables were assessed as potential risk factors using the chi-squared test. The rates of seropositivity rates were 7.59% and 4.49% in healthy donors and fever patients, respectively. Analysis of risk factors such as gender, age groups, and place of residence showed statistically significant differences. Infections with A. phagocytophilum occur widely among individuals residing in southwestern China. Our results indicate that there is serological evidence of HGA in this population and presence of acute A. phagocytophilum infections in patients with undifferentiated fever in the Yunnan Province.

Prospective case-control analysis of the aetiologies of acute undifferentiated fever in Vietnam

ABSTRACT Acute undifferentiated fever (AUF) is frequently observed in tropical settings, but diagnosing the cause of AUF is often a challenge for local physicians and the physicians treating returning travellers. We conducted a case-control study in central Vietnam in 2016. A total of 378 febrile adult patients (AUFs) with a fever for ≤21 days, no evidence of localized infection and negative screening tests for dengue and malaria, and 384 afebrile adult patients (Controls) were prospectively enrolled. Whole blood, plasma, eschar swab, throat swab and urine specimens were collected and analysed. Quantitative PCR and RT-PCR were used to test for 55 bacteria, viruses and their subtypes. Serological tests were also used to test for rickettsial agents. The most common aetiology was influenza virus (20.9% in AUFs vs. 0% in Controls), followed by rickettsial agents (mainly Orientia tsutsugamushi and Rickettsia typhi) (10.8% vs. 0.3%), dengue virus (7.7% vs. 0.5%), Leptospira (4.8% vs. 0.8%), adenovirus (4.8% vs. 1.0%), and enterovirus (2.1% vs. 0%) (p < .05). The real proportion of dengue in AUF cases was underestimated because patients with dengue-positive rapid diagnosis tests were excluded from the study. The emerging agent Rickettsia felis, which had not been previously observed in Vietnam, was detected in this study. In total, 216 patients (57.1%) were given causative diagnoses, comprising 143 (66.2%) monoinfections and 73 (33.8%) coinfections. The infections caused by these agents should be considered in clinical practice and further studies. Additionally, agents susceptible to doxycycline were detected in 15.6% of AUFs; thus, this drug should be included in the panel used to treat AUF patients.

Concurrent Coinfections in Tropics: A Hospital-Based Observational Study from Himachal Pradesh, India

India is the epicenter of tropical fever diseases. Large numbers of cases are diagnosed with scrub typhus, leptospirosis, malaria, dengue, chikungunya, and enteric fever. Coinfections as an etiology of acute undifferentiated fever (AUF) have been recently recognized. The objective of this study was to assess the prevalence of coinfections in patients admitted with AUF in a tertiary-care hospital in the rural setting of Himachal Pradesh, India. Patients with coinfections as an etiology of AUF were the subjects of the study. The clinical records of patients diagnosed with confections between July 2018 and October 2018 were analyzed retrospectively in this hospital-based cross-sectional study. Standard protocol and guidelines were followed for the case definitions. Among total patients of 1005 with AUF, 14 (1.39%) patients were found to have coinfections. The most common coinfection was scrub typhus with leptospirosis and was diagnosed in seven (50%) patients. Other coinfections were scrub typhus with dengue in four (29%) and one patient each with scrub typhus and tubercular meningitis, scrub and influenza A (H1N1/2009) infection, and scrub and malaria (P. falciparum). Scrub typhus was the most common etiological diagnosis for the AUF and was observed in 159 (15.8%) patients. All the patients with coinfections had scrub typhus as the common infection. The prevalence of coinfections among scrub typhus patients constituted 8%. In tropical regions, coinfections are not very rare. High clinical suspicion for coinfections is required. Syndromic approach in the management is justified.

Beyond Malaria: Causes of Non-Malarial Acute Undifferentiated Fever in Paediatric Out-Patient Clinics in Guinea Bissau

Background: With growing use of parasitological tests to detect malaria and decreasing incidence of the disease in Africa; it is necessary to increase our understanding of the causes of non-malarial illness, towards providing appropriate management. This research investigates causes of non-malarial undifferentiated acute fever in paediatric out-patients in Guinea Bissau. Methods: Children 0-5 years presenting acute fever (≥38o) or history of fever for less than 48 hours, negative rapid diagnostic test (RDT) and no signs of organ specific disease were recruited at the out-patient clinic of 3 facilities during 54 consecutive weeks (dry and rainy season). Medical history was recorded and blood, nasopharyngeal, stool and urine samples were collected and tested for the presence of 40 different potential aetiological causes of fever. Results: In total, 48.336 laboratory analyses were made on samples of 739 children presenting with acute fever of unknown origin and another 2.277 laboratory analysis on samples of 69 children enrolled as controls. The protocol was successful in determining a potential aetiological cause of acute fever in samples of 544 (73.61%) cases. The 544 individuals with positive samples, on average had 1.55 (sd=0.80) microorganisms identified, 333 (45.06%) had only one positive sample. Respiratory viruses were the most frequently identified pathogens, present in the nasopharynx samples of 435 (58.86%) cases, followed by bacteria detected in blood samples of 167 (22.60%) cases. Despite presenting negative RDT, P. falciparum was identified in samples of 24 (3.25%) patients and 1 (1.45%) control. Conclusions: This research provides a description of the aetiological causes of non-malarial acute fever in a West African context. Evidence of viral infections were more commonly found than bacteria or parasites. Funding: This study was entirely funded by Medecins Sans Frontieres, Barcelona-Athens Operational Centre, Insitut Pasteur Dakar and Institut Hospitalo-Universitaire Mediterranee. Declaration of Interest: Researches deny any potential conflict of interest. Ethical Approval: The protocol and its procedures were approved by two independent ethics committees (MSF's and Guinea Bissau's INASA) and are in accordance with the Declaration of Helsinki. All authors vouch for the accuracy and completeness of the data and the fidelity of the study to the protocol.

Clinical and laboratory profile of pediatric scrub typhus in a tertiary care teaching hospital in Southern India

Background: Scrub typhus is a common aetiology for an acute undifferentiated fever among children. Early recognition and prompt management help to reduce morbidity and mortality.Methods: All children who visited our pediatric out-patient department between January 2016 and February 2018, admitted with clinical suspicion of scrub typhus and having positive serum IgM by ELISA were included in the study.Results: A total of 83 cases were enrolled during the study period. Of these 55 were boys and 28 girls. The average age of presentation was seven years, and the youngest was just five months old. Majority of these patients were from rural areas (86%). Roughly, two-thirds (77%) of the study group practiced open defecation. A maximum number of cases (65;78.3%) were reported during monsoon season (between September and January).Prolonged fever (100%), gastrointestinal symptoms (76%) such as vomiting, diarrhoea and abdominal pain, lymphadenopathy (96%) and hepatosplenomegaly (61%) were common signs and symptoms of pediatric scrub typhus. Only six patients had severe illnesses. The diagnosis was based on the positive serum IgM for scrub typhus. All the patients were IgM positive. Out of these 83 patients, eschar was seen in 50 (60%) patients. Weil Felix test was positive in 15 cases out of 33 tested cases. Six children had co-infection with 2 cases of malaria and four dengue fever cases.Conclusions: Scrub typhus is one of the common causes for acute undifferentiated fever among children. A high index of clinical suspicion and a lookout for an eschar shall facilitate an early diagnosis of scrub typhus.

Epidemiological trends and molecular dynamics of dengue, chikungunya virus infection, coinfection, and other undifferentiated fever during 2015-2016 in Odisha, India.

Chikungunya virus (CHIKV) infection is spatiotemporally related to dengue virus (DENV) infection and mostly undiagnosed due to similar primary symptoms. In 2013, a high rate (36%) of coinfection of DENV and CHIKV was reported in Odisha. Hence, the hospital-based study was continued to synthesis current epidemiological understanding of their single distribution or coinfection. Suspected DENV patients serum samples were tested for DENV and CHIKV by serology and reverse-transcription polymerase chain reaction. The positive samples were used for analysis of mutation, selection pressure, and phylogenetic relationship. Clinical information was also analyzed. Among 648 (2015 and 2016) suspected DENV patients, 141 (21.7%) were positive for DENV (serotypes 1-3), 22 (3.4%) were positive for CHIKV (ECSA) and 4 (2.8%) were coinfected with both. Sequence analysis showed four consistent mutations (M104V, V112A, K166N, and F169L) in CprM gene of DENV 2 and two consistent mutations (M269V, D284E) in E1 gene of CHIKV. Interestingly, the CHIKV- E1 A226V mutation was absent in the studied population. It was also noticed that the peak incidence of both the infections occurs in August-September in 2015-16. Moreover, Plasmodium species, Salmonella typhi, and Rickettsial typhi infections were also observed in DENV patients. Different etiology was also detected in other undifferentiated fever patients as mixed infections (malaria, S. typhi, and R. typhi ). Hence, this investigation shows the significant reduction of DENV-CHIKV coinfection as compared with previous report, the burden of arboviruses and acute undifferentiated fever in Odisha in 2015-2016, highlighting the importance of epidemiological picture of febrile patients for appropriate patient management.

Scrub typhus presenting without fever

Scrub typhus may be a very a familiar reason for an acute undifferentiated fever. Although there has been an improvement in the diagnostics as well as an increased awareness regarding this disease, it still remains belatedly diagnosed and eventually turns fatal. We present a male patient who was brought to us with jaundice, tender hepatomegaly and distinctly no history fever who turned out to have a Scrub typhus infection and was salvaged owing to a diverse empirical antibiotic coverage. This represents an atypical clinical presentation of a very familiar infection: Tropical rickettsioses infection presenting with afebrile jaundice in an immunocompetent patient. It also brings into perspective the wavered nature of its disease presentation, the significant merit of procuring a good patient history and a change in empirical antibiotic policies especially in areas endemic for scrub typhus

Clinical &amp; etiological profile of acute undifferentiated fever in patients admitted to a teaching hospital in Pondicherry

Objectives: To identify the infectious aetiology and clinical features of Acute Undifferentiated Fever among patients admitted to a teaching hospital in Pondicherry. Design: Prospective observational study. Subjects: 270 cases comprising all adult patients (≥18 years) admitted to the hospital with fever of less than 14 days duration, temperature ≥38oC upon admission and non-detection of any specific foci of infection by history, physical examination and routine investigations. Previously diagnosed cases of known fevers, collagen vascular disorders, endocrine disorders, malignancies, immunodeficient states, fever of duration ≥14 days and drug induced fevers were excluded. Methods: All patients were examined and investigated according to study protocol after an informed consent to reach final diagnosis. Results: 38.1% cases were of Scrub Typhus aetiology, 20% cases tested positive for dengue, 14.1% cases came positive for Enteric fever and Malaria was found in 5.6% cases, all of P. vivax parasite. There was 1 case of TB, 1 case of candida infection and 1 case of Klebsiella pneumonia. 1 case tested positive for leptospirosis. Blood pathogens isolated were Pseudomonas and Enterococci with 1 case each. UTI was a frequent diagnosis with 7 cases of E. coli, 1 case of Enterococci and 1 case of Staphylococci. 1 case of HIV was detected. Conclusion: Scrub typhus was the most common aetiology of Acute Undifferentiated Fever followed by Dengue and Enteric fever.

Causes of acute undifferentiated fever and the utility of biomarkers in Chiangrai, northern Thailand.

BackgroundTropical infectious diseases like dengue, scrub typhus, murine typhus, leptospirosis, and enteric fever continue to contribute substantially to the febrile disease burden throughout Southeast Asia while malaria is declining. Recently, there has been increasing focus on biomarkers (i.e. C-reactive protein (CRP) and procalcitonin) in delineating bacterial from viral infections.Methodology/Principal findingsA prospective observational study was performed to investigate the causes of acute undifferentiated fever (AUF) in adults admitted to Chiangrai Prachanukroh hospital, northern Thailand, which included an evaluation of CRP and procalcitonin as diagnostic tools. In total, 200 patients with AUF were recruited. Scrub typhus was the leading bacterial cause of AUF (45/200, 22.5%) followed by leptospirosis (15/200, 7.5%) and murine typhus (7/200, 3.5%), while dengue was the leading viral cause (23/200, 11.5%). Bloodstream infections contributed to 7/200 (3.5%) of the study cohort. There were 9 deaths during this study (4.5%): 3 cases of scrub typhus, 2 with septicaemia (Talaromyces marneffei and Haemophilus influenzae), and 4 of unknown aetiologies. Rickettsioses, leptospirosis and culture-attributed bacterial infections, received a combination of 3rd generation cephalosporin plus a rickettsia-active drug in 53%, 73% and 67% of cases, respectively. Low CRP and white blood count were significant predictors of a viral infection (mainly dengue) while the presence of an eschar and elevated aspartate aminotransferase and alkaline phosphatase were important predictors of scrub typhus.InterpretationScrub typhus and dengue are the leading causes of AUF in Chiangrai, Thailand. Eschar, white blood count and CRP were beneficial in differentiating between bacterial and viral infections in this study. CRP outperformed procalcitonin although cut-offs for positivity require further assessment. The study provides evidence that accurate, pathogen-specific rapid diagnostic tests coupled with biomarker point-of-care tests such as CRP can inform the correct use of antibiotics and improve antimicrobial stewardship in this setting.

Correction: A High Malaria Prevalence Identified by PCR among Patients with Acute Undifferentiated Fever in India.

[This corrects the article DOI: 10.1371/journal.pone.0158816.].

Diagnostic Performance of Serological Tests to Detect Antibodies Against Acute Scrub Typhus Infection in Central India

Background: Differentiating scrub typhus from other acute febrile illness is difficult due to non specificity of clinical symptoms and relative absence of eschar in Indian population. The diagnosis thus relies mainly on laboratory tests. Antibody based serological tests are mainstay of scrub typhus diagnosis. Here, we evaluated the diagnostic performance of IgM ELISA, IgM IFA and ICT to detect antibodies against O. tsutsugamushi in acute serum of febrile patients. Methodology: The serum samples from 600 randomly selected patients suffering from acute undifferentiated fever were tested by all the three tests mentioned above. We used latent class analysis to generate unbiased results as all the tests for scrub typhus diagnosis are imperfect and none of them can be considered as reference standard. Results: We found that IgM ELISA with cutoff titer 0.5 OD has high diagnostic accuracy (sensitivity 99.9% and specificity 99.15) than IgM IFA (sensitivity 96.8% and specificity 99.7%) for scrub typhus diagnosis. ICT used in our study had very high specificity 100% but low sensitivity (38%) which would limit its use for acute serum samples. ICT being a screening or point of care test, has to be more sensitive while some compromise with specificity is affordable. Hence, optimal cutoff for ICT should be evaluated under different settings. Conclusion: IgM ELISA being simple and affordable could be an alternative diagnostic test to IgM IFA which is subjective and costly.

Double Trouble in a Tropical Paradise

Introduction: Leptospirosis and typhoid fever are water borne diseases. These diseases present as acute undifferentiated fever and often can be challenging to clinicians in the developing world due to limited resources. Case Presentation: A 15-year-old Malay girl presented a week after swimming in a waterfall with fever, vomiting and lethargy. Her condition deteriorated into septic shock and respiratory distress requiring mechanical ventilation. Her blood, urine and stool cultures grew pure isolates of Salmonella typhi. The leptospira serology was positive and the leptospira microscopic agglutination test revealed a high titre of 1:400. She was diagnosed with dual infections of leptospirosis and typhoid fever. With third generation cephalosporin antibiotics, she improved. There was clearance of her blood, urine and stool cultures. Her leptospira microscopic agglutination test demonstrated a fourfold reduction in titre. Conclusion: Not only do these illnesses prove challenging to physicians to diagnose and treat due to their similarity in initial presentation, they are also life threatening to the unknowing tourist or locals who went for an innocent dip in a picturesque waterfall.

Awareness of malaria and treatment-seeking behaviour among persons with acute undifferentiated fever in the endemic regions of Myanmar

BackgroundMyanmar has a high burden of malaria with two-third of the population at risk of malaria. One of the basic elements of the Roll Back Malaria Initiative to fight against malaria is early diagnosis and treatment within 24 h of fever. Public awareness about malaria is a key factor in malaria prevention and control and in improving treatment-seeking behaviour.MethodsA large community-based survey was carried out in 27 townships of malaria endemic regions in Myanmar in 2015 which reported on the knowledge, behaviour and practices around malaria in the general population. We used the data already collected in this survey to assess (i) general public awareness of malaria and (ii) treatment-seeking behaviour and associated factors among persons with acute undifferentiated fever.ResultsA total of 6597 respondents from 6625 households were interviewed (response rate of 99.5%). About 85% of the respondents were aware that mosquito bite was the mode of transmission of malaria and 90% mentioned that malaria was preventable. However, only 16% of the respondents knew about anti-malaria drug resistance. There were certain misconceptions about the transmission of malaria such as dirty water, same blood group, sharing shelter, sleeping/eating together and poor hygiene. Health facility staff were the most common source of information about malaria (80%). Nearly one-fourth (23%) of the respondents with fever resorted to self-medication. Around 28% of the respondents with fever underwent blood testing, less than half of whom (44%) were tested within 24 h. Elderly age group, females, those with poor knowledge about malaria and those residing in non-Regional Artemisinin Resistance Initiative townships were associated with poor treatment-seeking behaviour in case of fever.ConclusionAlthough there is fair knowledge on mosquito bite as a mode of transmission and prevention of malaria, there are some misconceptions about transmission of malaria. Those having poor knowledge about malaria have poor treatment-seeking behaviour. A considerable number of respondents seek care from informal care providers and seek care late. Thus, there is a need to promote awareness about the role of early diagnosis and appropriate treatment and address misconceptions about transmission of malaria.

Acute undifferentiated fever in children- an overview

Fever is one of the common reason for OPD as well as in patient admission department. Due to improvements of laboratory facilities & imaging the incidence and etiological profile of fever have drastically changed. Proper history taking and systematic examination remains the gold standard for fever evading diagnosis.