Systemic Febrile Illness Research Articles

Fever After International Travel

Fever in a child after international travel may represent a benign self-limited illness or may be a manifestation of a more severe life-threatening disease. Knowledge of these illnesses is extremely important for a clinician managing a febrile child after travel. This article presents an approach to history taking and evaluation of the febrile child after travel, stressing knowledge of diseases endemic to geographic regions, timing of symptoms, travel exposures, and specific presenting signs and symptoms. The article also discusses in detail some of the more commonly encountered systemic febrile illnesses, including malaria, dengue fever, typhoid fever, rickettsial infections, and leptospirosis.

Health Problems in Returning Travelers Consulting General Practitioners: Table 1

Over a 2-month period, 43 of 143 participating general practitioners included 97 patients with 113 health impairments, mainly gastrointestinal problems (35%), respiratory tract infections (30%), and skin diseases (11%). Systemic febrile illness or imported tropical disease accounted for less than 4% of cases.

Etiology of travel-related fever

Many potentially life-threatening infections cause fever. Several recent large studies help to define causes of fever in returned travelers. The destination of travel determines the relative likelihood of the different major causes of fever. Systemic febrile illness occurs disproportionately among ill travelers returning from sub-Saharan Africa. Malaria remains the most important overall cause of systemic febrile illness in travelers to tropical regions; dengue fever is now the most prominent cause of fever in travelers to certain regions, most notably Asia. Chikungunya fever has emerged as a major cause of fever in travelers to Indian Ocean islands off Africa and to India itself. Causes of fever vary by the time of presentation after travel. Vivax malaria is an important cause of fever with onset more than a month after return; recently studies have shown that parasites causing relapse are genetically distinct from those causing primary infection. At expert referral centers up to 25% of febrile patients have no specific cause of fever determined. Knowledge of predominant causes of febrile infections by geographic region, traveler characteristics, and time of presentation can assist the clinician in guiding posttravel diagnosis and empiric therapy of ill returned travelers and is also valuable in pretravel preparation.

Childhood scrub typhus in eastern Taiwan: ten-year experience from a medical center

Scrub typhus, a potentially fatal rickettsial infection, is endemic in western Pacific Rims including Taiwan. Most reports have been concerned about mainly adult patients, whereas serologic surveys suggested that as many as one-half of cases of scrub typhus might be in children. We conducted a retrospective study of childhood scrub typhus in our hospital from January 1997 to December 2006. Scrub typhus was diagnosed on the basis of serology tests or polymerase chain reaction (PCR) examination in fifteen children. Fever and chigger bite history were presented in all 15 cases, and eschar lesion was identified in 12 patients (80%). Nine (60%) patients had headache and six (40%) complained of abdominal pain. Three patients (20%) had meningoencephalitis, and two (13%) hemophagocytic syndrome were confirmed by bone marrow biopsy. One patient died of progressive acute respiratory distress syndrome (ARDS) and pulmonary hemorrhage. Myocarditis was revealed in autopsy. All surviving patient responded well to antibiotic therapy, and the average duration to defervescence after treatment was 1.8 days. We conclude that scrub typhus should be taken into consideration among patients of acute systemic febrile illness, especially those with suspected exposure history and typical skin lesion. Although most patients responded well to treatment, severe complications such as meningoencephalitis, interstitial pneumonia, acute respiratory distress syndrome, hemophagocytic syndrome, and myocarditis might lead to morbidity and mortality.

Fevers in Returning International Travelers

Infectious Diseases| October 01 2007 Fevers in Returning International Travelers AAP Grand Rounds (2007) 18 (4): 42–43. https://doi.org/10.1542/gr.18-4-42-a Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Fevers in Returning International Travelers. AAP Grand Rounds October 2007; 18 (4): 42–43. https://doi.org/10.1542/gr.18-4-42-a Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search nav search search input Search input auto suggest search filter All PublicationsAll JournalsAAP Grand RoundsPediatricsHospital PediatricsPediatrics In ReviewNeoReviewsAAP NewsAll AAP Sites Search Advanced Search Topics: fever, traveler Source: Wilson ME, Weld LH, Boggild A, et al. Fever in returning travelers: results from the GeoSentinal Surveillance Network. Clin Infect Dis. 2007;44:1560–1568; doi:10.1086/518173 The GeoSentinel Surveillance Network consists of clinical sites staffed by providers who are experienced in travel and tropical medicine. Practitioners from these sites contribute anonymous reports of clinical encounters with ill travelers to a large database. For this study, investigators from the GeoSentinel Network reviewed reports from 31 clinics in six continents over a 10-year period (1997–2006) to determine the frequency and causes of fever in returned travelers. To be included patients must have traveled internationally within 10 years and be seeking medical care for a presumed travel-related illness. Information collected in the database included: demographic information; reason for travel (tourism, business, research or education, visiting friends or relatives, volunteer or missionary); travel history; pre-travel clinic visit; clinical findings (including laboratory test results); and travel duration. Countries were divided into 10 regional classifications. The chief reason for seeking medical care and the presence or absence of fever (documented or by history) were recorded. Returning travelers with and without fever were compared. Of the 54,834 clinical encounters included in the database, 24,920 met inclusion criteria. Fever was the main reason for seeking medical care for 6,957 patients (28%); 429 of these were children under 20 years of age. Febrile and afebrile travelers did not differ in age. Febrile travelers were more likely to be male. For patients traveling to sub-Saharan Africa and south-central Asia, those who visited a travel clinic prior to travel were less likely to present with fever than those who did not have a pre-travel visit. Patients who were visiting friends and family in sub-Saharan Africa, south-central Asia, and Central America were more likely to present with fever compared to those traveling for other reasons. The longer the interval between return and presentation, the less likely ill patients were to present with fever. Of all returned travelers with fever, 35% had a systemic febrile illness, 15% had a diarrheal disease, and 14% had a respiratory illness. Malaria was the most common cause of fever (59%) in patients with a systemic febrile illness (n=2451). Plasmodium falciparum, which causes the most severe malaria, was identified in 66% of patients with malaria and in 14% of all patients presenting with fever. More than half of all patients with malaria required hospitalization. Vaccine-preventable infections were identified in 3% of ill returned travelers who presented with fever. Typhoid fever was the most common vaccine-preventable cause of fever. Exposures in south-central and Southeast Asia accounted for >70% of cases of typhoid fever. Travelers visiting family and friends were more likely than other travelers to be diagnosed with a vaccine-preventable disease and less likely to have sought pre-travel advice. The interval between return from travel and medical evaluation varied with type of infection. The majority (66%) of the travelers with Dengue fever were seen within one week. For travelers with malaria, 65% of those with... You do not currently have access to this content.

Fever in Returned Travelers: Results from the GeoSentinel Surveillance Network

Fever is a marker of potentially serious illness in returned travelers. Information about causes of fever, organized by geographic area and traveler characteristics, can facilitate timely, appropriate treatment and preventive measures. Using a large, multicenter database, we assessed how frequently fever is cited as a chief reason for seeking medical care among ill returned travelers. We defined the causes of fever by place of exposure and traveler characteristics. Of 24,920 returned travelers seen at a GeoSentinel clinic from March 1997 through March 2006, 6957 (28%) cited fever as a chief reason for seeking care. Of patients with fever, 26% were hospitalized (compared with 3% who did not have fever); 35% had a febrile systemic illness, 15% had a febrile diarrheal disease, and 14% had fever and a respiratory illness. Malaria was the most common specific etiologic diagnosis, found in 21% of ill returned travelers with fever. Causes of fever varied by region visited and by time of presentation after travel. Ill travelers who returned from sub-Saharan Africa, south-central Asia, and Latin America whose reason for travel was visiting friends and relatives were more likely to experience fever than any other group. More than 17% of travelers with fever had a vaccine-preventable infection or falciparum malaria, which is preventable with chemoprophylaxis. Malaria accounted for 33% of the 12 deaths among febrile travelers. Fever is common in ill returned travelers and often results in hospitalization. The time of presentation after travel provides important clues toward establishing a diagnosis. Preventing and promptly treating malaria, providing appropriate vaccines, and identifying ways to reach travelers whose purpose for travel is visiting friends and relatives in advance of travel can reduce the burden of travel-related illness.

Severe Dengue Virus Infection in Travelers

tropics and subtropics-areas that have become popular tourist destinations. In some case series, dengue is the second most frequent cause of hospitalization (after malaria) among travelers returning from the tropics [2]. GeoSentinel is a global provider-based surveillance network of travel medicine providers (available at: http://www.istm.org/geosentinel/ main.html); in its most recent update, dengue was the most frequent cause of systemic febrile illness in travelers to Asia [3]. The World Health Organization (WHO) classifies symptomatic dengue virus infections into 3 categories: undifferentiated fever, classic dengue fever, and dengue hemorrhagic fever (DHF) (figure 1) [4]. Dengue fever is defined clinically as an acute febrile illness with >2 manifesta-

Campylobacter fetus

Campylobacter fetus is an emerging human pathogen that causes a systemic febrile illness in patients with underlying medical conditions. Bacteremia is frequent and associated with a mortality rate of 17% to 43%, making proper diagnosis imperative. We present an unusual and rare manifestation of C. fetus, a case of prosthetic joint infection successfully treated by medical therapy alone.

Illness in Travelers Visiting Friends and Relatives: A Review of the GeoSentinel Surveillance Network

Travelers returning to their country of origin to visit friends and relatives (VFRs) have increased risk of travel-related health problems. We examined GeoSentinel data to compare travel characteristics and illnesses acquired by 3 groups of travelers to low-income countries: VFRs who had originally been immigrants (immigrant VFRs), VFRs who had not originally been immigrants (traveler VFRs), and tourist travelers. Immigrant VFRs were predominantly male, had a higher mean age, and disproportionately required treatment as inpatients. Only 16% of immigrant VFRs sought pretravel medical advice. Proportionately more immigrant VFRs visited sub-Saharan Africa and traveled for >30 days, whereas tourist travelers more often traveled to Asia. Systemic febrile illnesses (including malaria), nondiarrheal intestinal parasitic infections, respiratory syndromes, tuberculosis, and sexually transmitted diseases were more commonly diagnosed among immigrant VFRs, whereas acute diarrhea was comparatively less frequent. Immigrant VFRs and traveler VFRs had different demographic characteristics and types of travel-related illnesses. A greater proportion of immigrant VFRs presented with serious, potentially preventable travel-related illnesses than did tourist travelers.

A child with a systemic febrile illness – differential diagnosis and management

Fever is a common symptom in children and may sometimes be prolonged or recurrent. There are many differential diagnoses, which may lead to significant diagnostic delay. Diagnosis is based on the clinical presentation as well as a widespread panel of investigations that are necessary in order to exclude the many potential causes of fever before reaching a definite diagnosis. In particular, the physician will look for infections and malignancies before considering the disease as inflammatory. This chapter reviews the differential diagnosis of prolonged or recurrent fever, and discusses most of the inflammatory syndromes presenting with fever.

Systemic Viral Infections and Collateral Damage in the Liver

The liver is involved in infections by hepatotropic viruses that replicate in the liver and for which the liver is the main target. These include hepatitis A, hepatitis B, hepatitis C, and hepatitis E viruses. In all of these infections, hepatitis and liver damage arise as a consequence of the immune response to virus within the liver.1 In addition, the liver can be affected as part of a generalized host infection with viruses that primarily target other tissues, particularly the upper respiratory tract. Examples of this phenomenon include the herpes viruses (Epstein-Barr virus, cytomegalovirus [CMV], and herpes simplex virus), parvovirus, adenovirus,2 and severe acute respiratory syndrome (SARS)-associated coronavirus.3 Liver involvement in nonhepatotropic viral infections can range from mildly deranged liver biochemistry to fulminant liver failure. In most of these infections, hepatitis is thought to be a consequence of an immune response to viral antigens with a close topographic association between the presence of viral antigens and the associated inflammatory infiltrates in the liver. Loss of immune control may be responsible for the development of hepatitis in CMV hepatitis4 and other opportunistic viral infections such as adenovirus.4 Similar activities may also be involved in SARS-associated hepatitis, which is characterized by focal lobular lymphocytic infiltrates.5 The paper by Polakos et al6 in this issue of The American Journal of Pathology broadens the mechanism by which viruses can cause hepatitis by demonstrating that viral-specific CD8+ T cells, generated in response to a viral infection restricted to sites outside the liver, can trigger T-cell-mediated hepatitis in the absence of viral antigens in the liver. They describe the involvement of the liver during pulmonary infection with influenza virus and demonstrate that hepatitis can occur even in the absence of detectable virus in the liver. The authors describe the hepatitis in influenza infection as “collateral damage” and suggest that it occurs as a consequence of the recruitment to the liver of CD8+ effector T cells that expand systemically in response to the viral infection. These observations are of great importance for understanding the involvement of the liver in systemic infections and elucidate some of the clinical syndromes of liver inflammation that cannot be easily explained by invoking antigen-specific T-cell responses in the liver.

Spectrum of Disease and Relation to Place of Exposure among Ill Returned Travelers

Approximately 8 percent of travelers to the developing world require medical care during or after travel. Current understanding of morbidity profiles among ill returned travelers is based on limited data from the 1980s. Thirty GeoSentinel sites, which are specialized travel or tropical-medicine clinics on six continents, contributed clinician-based sentinel surveillance data for 17,353 ill returned travelers. We compared the frequency of occurrence of each diagnosis among travelers returning from six developing regions of the world. Significant regional differences in proportionate morbidity were detected in 16 of 21 broad syndromic categories. Among travelers presenting to GeoSentinel sites, systemic febrile illness without localizing findings occurred disproportionately among those returning from sub-Saharan Africa or Southeast Asia, acute diarrhea among those returning from south central Asia, and dermatologic problems among those returning from the Caribbean or Central or South America. With respect to specific diagnoses, malaria was one of the three most frequent causes of systemic febrile illness among travelers from every region, although travelers from every region except sub-Saharan Africa and Central America had confirmed or probable dengue more frequently than malaria. Among travelers returning from sub-Saharan Africa, rickettsial infection, primarily tick-borne spotted fever, occurred more frequently than typhoid or dengue. Travelers from all regions except Southeast Asia presented with parasite-induced diarrhea more often than with bacterial diarrhea. When patients present to specialized clinics after travel to the developing world, travel destinations are associated with the probability of the diagnosis of certain diseases. Diagnostic approaches and empiric therapies can be guided by these destination-specific differences.

Penicillium marneffei fungaemia in an allogeneic bone marrow transplant recipient

Penicillium marneffei is the most important thermal dimorphic fungus causing respiratory, skin and systemic mycosis in Southeast Asia.1, 2, 3 About 8% of AIDS patients in Hong Kong are infected with P. marneffei. Clinically, penicilliosis manifests as a systemic febrile illness, which results from intracellular infection of the reticuloendothelial cells by the yeast phase of the fungus. Besides HIV-positive patients, P. marneffei infections have been reported in other immunocompromised patients, such as renal transplant recipients, patients with systemic lupus erythematosus and patients who are receiving corticosteroid therapy.4, 5 Here, we describe the first case of P. marneffei infection in a bone marrow transplant recipient.

Chorioretinal lesions in nonfatal cases of West Nile virus infection

Objective West Nile virus (WNV) disease is a zoonotic infection with recent outbreaks in the United States. Recent reports have highlighted the intraocular findings associated with WNV disease. We describe the intraocular findings observed in two patients infected by the West Nile virus. Design Observational case reports. Methods During an outbreak of WNV disease in Southwest Ohio, two patients with an acute onset of a systemic febrile illness accompanied by myalgia, arthralgia, headache, and a maculopapular rash were referred for blurred vision. Complete ophthalmologic examination, fundus photographs, and fluorescein angiograms were obtained on both patients. Both patients underwent serologic testing for viruses and cultures for bacteria, viruses, and fungi. Results Ophthalmologic examination in each patient revealed anterior segment and vitreous inflammatory cells and multiple partially atrophic and partially pigmented chorioretinal lesions clustered in the peripheral fundus. Fundus examination in case 2 also revealed mild disc edema in both eyes. Intracranial pressure as measured by lumbar puncture was borderline elevated. The chorioretinal lesions in both patients showed a striking similarity and appeared hypofluorescent centrally and hyperfluorescent around the edges on a fluorescein angiogram. Serologic testing for the WNV was positive in both patients, and tests for all other bacteria, fungi, and viruses were negative. Conclusions WNV usually causes mild symptoms, but it occasionally causes neurologic illness with fatal outcome or severe morbidity. We present the cases of two patients with serology-proven WNV disease who developed chorioretinal lesions with a targetlike appearance and iridocyclitis.

Rat Bite Fever: Case Report and Review of the Literature

Rat Bite Fever: Case Report and Review of the Literature

Characterization and transcriptional analysis of gene clusters for a type IV secretion machinery in human granulocytic and monocytic ehrlichiosis agents.

Anaplasma (Ehrlichia) phagocytophila and Ehrlichia chaffeensis, the etiologic agents of granulocytic and monocytic ehrlichioses, respectively, are obligatory intracellular bacteria that cause febrile systemic illness in humans. We identified and characterized clusters of genes for a type IV secretion machinery in these two bacteria, and analyzed their gene expression in cell culture and mammalian hosts. Eight virB and virD genes were found in each bacterial genome, and all of the genes were transcribed in cell culture. Although the gene order and orientation were similar to those found in other bacteria, the eight virB and virD genes were clustered at two separate loci in each genome. Five of the genes (virB8, virB9, virB10, virB11, and virD4) were located downstream from a ribA gene. These five genes in both A. phagocytophila and E. chaffeensis were polycistronically transcribed and controlled through at least two tandem promoters located upstream of the virB8 gene in human leukemia cell lines. The virB9 gene of A. phagocytophila was transcriptionally active in peripheral blood leukocytes from human ehrlichiosis patients and experimentally infected animals. Three of the remaining genes (virB3, virB4, and virB6) of both A. phagocytophila and E. chaffeensis were arranged downstream from a sodB gene and cotranscribed with the sodB gene through one or more sodB promoters in human leukocytes. This suggests that transcription of the three virB genes in these two Anaplasma and Ehrlichia spp. is regulated by factors that influence the sodB gene expression. This unique regulation of gene expression for the type IV secretion system may be associated with intracellular survival and replication of Anaplasma and Ehrlichia spp. in granulocytes or monocytes.

Cytotoxic activities of Leptospira interrogans hemolysin SphH as a pore-forming protein on mammalian cells.

Leptospirosis is a spirochetal zoonosis that causes an acute febrile systemic illness in humans. Leptospira sp. hemolysins have been shown to be virulence factors for the pathogenesis of leptospirosis. Previously, we cloned a hemolysin SphH of Leptospira interrogans serovar lai, a homologue of L. borgpetersenii sphingomyelinase (SphA), from a genomic library (S. H. Lee, K. A. Kim, Y. K. Kim, I. W. Seong, M. J. Kim, and Y. J. Lee, Gene 254:19-28, 2000). Escherichia coli lysate harboring the sphH showed high hemolytic activities on sheep erythrocytes. However, it neither showed sphingomyelinase nor phospholipase activities, in contrast to SphA which was known to have sphingomyelinase activity. Interestingly, the SphH-mediated hemolysis on erythrocytes was osmotically protected by PEG 5000, suggesting that the SphH might have caused pore formation on the erythrocyte membrane. In the present study, we have prepared the Leptospira hemolysin SphH and investigated its hemolytic and cytotoxic activities on mammalian cells. SphH was shown to be a pore-forming protein on several mammalian cells: When treated with the SphH, the sheep erythrocyte membranes formed pores, which were morphologically confirmed by transmission electron microscopy. Furthermore, the SphH-mediated cytotoxicities on mammalian cells were demonstrated by the release of LDH and by inverted microscopic examinations. Finally, the immune serum against the full-length hemolysin could effectively neutralize the SphH-mediated hemolytic and cytotoxic activities. In conclusion, these results suggest that the virulence of Leptospira SphH was due to the pore formation on mammalian cell membranes.

Analysis of Transcriptionally Active Gene Clusters of Major Outer Membrane Protein Multigene Family in Ehrlichia canis and E. chaffeensis

Ehrlichia canis and E. chaffeensis are tick-borne obligatory intramonocytic ehrlichiae that cause febrile systemic illness in humans and dogs, respectively. The current study analyzed the pleomorphic multigene family encoding approximately 30-kDa major outer membrane proteins (OMPs) of E. canis and E. chaffeensis. Upstream from secA and downstream of hypothetical transcriptional regulator, 22 paralogs of the omp gene family were found to be tandemly arranged except for one or two genes with opposite orientations in a 28- and a 27-kb locus in the E. canis and E. chaffeensis genomes, respectively. Each locus consisted of three highly repetitive regions with four nonrepetitive intervening regions. E. canis, in addition, had a 6.9-kb locus which contained a repeat of three tandem paralogs in the 28-kb locus. These total 47 paralogous and orthologous genes encoded OMPs of approximately 30 to 35 kDa consisting of several hypervariable regions alternating with conserved regions. In the 5'-end half of the 27-kb locus or the 28-kb locus of each Ehrlichia species, 14 paralogs were linked by short intergenic spaces ranging from -8 bp (overlapped) to 27 bp, and 8 remaining paralogs in the 3'-end half were connected by longer intergenic spaces ranging from 213 to 632 bp. All 22 paralogs, five unknown genes, and secA in the omp cluster in E. canis were transcriptionally active in the monocyte culture, and the paralogs with short intergenic spaces were cotranscribed with their adjacent genes, including the respective intergenic spaces at both the 5' and the 3' sides. Although omp genes are diverse, our results suggest that the gene organization of the clusters and the gene locus are conserved between two species of Ehrlichia to maintain a unique transcriptional mechanism for adaptation to environmental changes common to them.

Inflammation is a component of neurodegeneration in response to Venezuelan equine encephalitis virus infection in mice

Infection with the mosquito-transmitted Venezuelan equine encephalitis virus (VEE) causes an acute systemic febrile illness followed by meningoencephalitis. In this communication we characterize the cytokine profile induced in the central nervous system (CNS) in response to virulent or attenuated strains of VEE using RNase Protection Assays. Virulent VEE causes an upregulation of multiple pro-inflammatory genes including inducible nitric oxide synthase (iNOS) and tumor necrosis factor alpha (TNF-α). To determine if iNOS and TNF-α contribute to the neuropathogenesis of VEE infection, iNOS and TNF receptor knockout mice were used in VEE mortality studies and exhibited extended survival times. Finally, CNS tissue sections labeled for VEE antigen, and adjacent sections double-labeled for an astrocyte marker and apoptosis, revealed that apoptosis of neurons occurs not only in areas of the brain positive for VEE-antigen, but also in areas of astrogliosis. These findings suggest that the inflammatory response, which is in part mediated by iNOS and TNF-α, may contribute to neurodegeneration following encephalitic virus infection.

“Infective” Myocardial Infarction

Four patients who developed acute myocardial infarction (AMI) in the setting of systemic febrile illness are described. They were all treated with anticoagulants or lytic agents (or both), demonstrating patient coronary arteries following infarction. We discuss the pathogenesis and therapeutic implications of AMI occurring in this setting.