Materiały źródłowe

• #1 Typhus Workup: Laboratory Studies, Imaging Studies, Histologic Findings

  https://emedicine.medscape.com/article/231374-workup

  Laboratory studies are not particularly helpful in confirming a diagnosis of flea-borne rickettsioses. These studies assist the clinician in assessing the degree of severity of the illness and in helping exclude other diseases in the differential diagnoses. […] The diagnosis of flea-borne Rickettsioses is clinically suggested when the appropriate historical elements are elicited from a patient who presents with the characteristic symptoms and signs. […] Diagnosis may be confirmed using laboratory tests; however, more than 1 week may pass before patients mount a demonstrable immune response that can be measured serologically. […] Laboratory confirmation of Rickettsioses is obtained irrespective of the clinical presentation. […] Indirect immunofluorescence assay (IFA) is the test of choice, and is used to evaluate for a rise in the antibody titer, which indicates an acute primary disease. Both acute and convalescent serum should be obtained for diagnosis.

• #2 Clinical Overview of Epidemic Typhus | Typhus Fevers | CDC

  https://www.cdc.gov/typhus/hcp/clinical-overview/clinical-overview-of-epidemic-typhus.html

  Symptoms include fever, headache, rash, and altered mental status. Laboratory confirmation is typically based on serological tests detecting IgG or IgM antibodies. […] Diagnosis is based on clinical findings and epidemiologic factors, as diagnostic tests are not reliable early in the illness course. Epidemic typhus should be considered in patients with persistent fever, a history of body louse exposure in congregate or other crowded settings, or persons who may have come in contact with flying squirrels or their nests. […] R. prowazekii can be detected via indirect fluorescent antibody (IFA) test, immunohistochemistry (IHC), polymerase chain reaction (PCR) assay of blood, plasma, or tissue samples, or culture isolation. Serologic tests are the most common means of confirmation and can be used to detect either IgG or IgM antibodies.

• #3 Clinical Overview of Murine Typhus | Typhus Fevers | CDC

  https://www.cdc.gov/typhus/hcp/clinical-overview/clinical-overview-of-murine-typhus.html

  Laboratory confirmation primarily relies on serological tests demonstrating a four-fold rise in antibody titer between acute and convalescent samples. […] Diagnosis is serologically confirmed by demonstrating a four-fold rise in antibody titer between acute and convalescent samples. […] PCR can detect R. typhi during acute illness, and is most sensitive when performed on specimens collected during the first week of illness, and prior to the start of doxycycline. […] However, PCR is insufficiently sensitive to rule out infection, and a negative PCR result should not dissuade clinicians from treating patients in whom murine typhus is suspected. […] Only demonstration of recent changes in titers between paired specimens are considered to be a reliable retrospective serologic confirmation of acute murine typhus infection.

• #4 Typhus – Wikipedia

  https://en.wikipedia.org/wiki/Typhus

  The main method of diagnosing typhus of all types is laboratory testing. It is most commonly done with an indirect immunofluorescence antibody IFA test for all types of typhus. This tests a sample for the antibodies associated with typhus. It can also be done with either immunohistochemistry (IHC) or polymerase chain reaction (PCR) tests excluding scrub typhus. Scrub typhus is not tested with IHC or PCR but is instead tested with the IFA test as well as indirect immunuoperoxidase (IIP) assays. […] Without treatment, death may occur in 10% to 60% of people with epidemic typhus, with people over age 50 having the highest risk of death. In the antibiotic era, death is uncommon if doxycycline is given. In one study of 60 people hospitalized with epidemic typhus, no one died when given doxycycline or chloramphenicol.

• #5 GroEL Chaperonin-Based Assay for Early Diagnosis of Scrub Typhus

  https://www.mdpi.com/2075-4418/12/1/136

  A point-of-care diagnostic for early and rapid diagnosis of scrub typhus caused by Orientia tsutsugamushi is required for prompt and proper treatment of patients presenting with undifferentiated febrile illnesses. […] In-house validation revealed that the ICT AgTK gave 85, 100 and 95% diagnostic sensitivity, specificity and accuracy, respectively, compared to the combined clinical features and standard IFA when tested on 40 frozen serum samples. […] The ICT AgTK is easy to perform with rapid turn-around time. It has the potential to be used as an important tool for on-site and early scrub typhus diagnosis by allowing testing of freshly collected samples (serum, plasma or buffy coat), especially in resource-limited healthcare settings. […] In this study, we offer an antigen detection test kit (AgTK) in an immunochromatographic (ICT; lateral flow) format for rapid, early and on-site diagnosis of scrub typhus.

• #6 Diagnostic evaluation of IgM ELISA and IgM Immunofluorescence assay for the diagnosis of Acute Scrub Typhus in central Nepal | BMC Infectious Diseases | Full Text

  https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-020-4861-y

  Scrub typhus is an acute febrile illness caused by the obligate intracellular bacterium, Orientia tsutsugamushi. Immunochromatography (ICT) and IgM ELISA are two of the routinely employed antibody based assays for diagnosis of Scrub typhus fever in Nepal, although the recommended gold standard diagnostic test is IgM Immunofluorescence assay (IFA). This study evaluated InBios Scrub Typhus Detect Immunoglobulin M (IgM) ELISA and IgM Immunofluorescence assays in single serum sample at the time of admission. […] Although IgM IFA is considered the gold standard test for the diagnosis of scrub typhus cases, it is relatively expensive, requires trained personal and a microscope with fluorescence filters. Scrub typhus IgM ELISA may be the best alternative test and possible viable option for resource limited endemic countries like Nepal.

• #7 Clinical Overview of Epidemic Typhus | Typhus Fevers | CDC

  https://www.cdc.gov/typhus/hcp/clinical-overview/clinical-overview-of-epidemic-typhus.html

  Diagnosis is typically confirmed by documenting a four-fold rise in antibody titer between acute and convalescent samples. […] Because IgG antibody titers may persist in some individuals for years after the original exposure, only demonstration of recent changes in titers between paired specimens can be considered reliable serological confirmation of an acute epidemic typhus infection. […] Doxycycline is the treatment of choice for suspected cases of acute epidemic typhus and Brill-Zinsser disease in adults and children of all ages.

• #7 Clinical Overview of Epidemic Typhus | Typhus Fevers | CDC

  https://www.cdc.gov/typhus/hcp/clinical-overview/clinical-overview-of-epidemic-typhus.html

  Symptoms include fever, headache, rash, and altered mental status. Laboratory confirmation is typically based on serological tests detecting IgG or IgM antibodies. […] Diagnosis is based on clinical findings and epidemiologic factors, as diagnostic tests are not reliable early in the illness course. Epidemic typhus should be considered in patients with persistent fever, a history of body louse exposure in congregate or other crowded settings, or persons who may have come in contact with flying squirrels or their nests. […] R. prowazekii can be detected via indirect fluorescent antibody (IFA) test, immunohistochemistry (IHC), polymerase chain reaction (PCR) assay of blood, plasma, or tissue samples, or culture isolation. Serologic tests are the most common means of confirmation and can be used to detect either IgG or IgM antibodies.

• #8 Flea-borne Typhus | Texas DSHS

  https://www.dshs.texas.gov/notifiable-conditions/zoonosis-control/zoonosis-control-diseases-and-conditions/flea-borne-typhus

  Many commercial laboratories offer rickettsial serology testing, but it should be noted that ELISA or EIA tests are not reliable for rickettsial disease diagnosis. Also, antibodies are typically not detectable until about 7 days after illness onset, so a negative test result on a sample taken prior to a week after illness onset does not rule out rickettsial infection (repeat testing after this time is critical to confirm or rule out infection). Molecular testing is a more definitive testing option for acute infection. Whole blood collected within a few days of illness onset may be tested by PCR in an attempt to detect Rickettsia spp. Samples may be sent to DSHS for Rickettsia Real-Time PCR.

• #8 Flea-borne Typhus | Texas DSHS

  https://www.dshs.texas.gov/notifiable-conditions/zoonosis-control/zoonosis-control-diseases-and-conditions/flea-borne-typhus

  Flea-borne (also known as murine or endemic) typhus is a rickettsial disease caused by Rickettsia typhi. Infected fleas carried by rats, opossums, cats, dogs, and other small mammals can spread these bacteria. The disease is like louse-borne typhus (R. prowazekii) but is generally milder. Disease onset is often sudden, and symptoms may include fever, headache, chills, weakness, nausea/vomiting, body aches, and rash. Flea-borne typhus can be a serious disease and can result in hospitalization. This is more likely with delayed diagnosis and treatment. […] A doctor can conduct tests to tell you if you have flea-borne typhus. […] Laboratory testing is required to confirm a diagnosis of flea-borne typhus. The most efficient and readily available diagnostic method to confirm infection with R. typhi is the detection of IgG antibodies to R. typhi using an indirect fluorescent antibody (IFA) test in acute and convalescent serum specimens collected at least 3 weeks apart. However, because antibodies for rickettsial diseases can be cross-reactive, specimens should be tested against a panel of Rickettsia antigens, including, at a minimum, R. rickettsii and R. typhi, to differentiate between the spotted fever group and non-spotted fever group Rickettsia spp.

• #9 Department of Public Health – Acute Communicable Disease Control

  http://www.publichealth.lacounty.gov/acd/TyphusTesting.htm

  Providers should consider a diagnosis of flea-borne typhus in patients with a non-specific febrile illness with headache, myalgia, rash and laboratory abnormalities including leukopenia, thrombocytopenia and elevation of hepatic transaminases, without alternate identifiable etiology. […] As symptoms are non-specific and laboratory testing is unreliable in acute phases of infection, treatment decisions should be based on clinical presentation and exposure history. […] Treatment for patients with suspected flea-borne typhus should not be delayed pending diagnostic tests. […] Laboratory diagnosis can be conducted through serologic testing for R.typhi IgG and IgM antibodies. […] Confirmation of R. typhi infection requires paired serology of acute and convalescent samples (drawn 2 weeks later) demonstrating a four-fold increase in IgG titers.

• #9 Department of Public Health – Acute Communicable Disease Control

  http://www.publichealth.lacounty.gov/acd/TyphusTesting.htm

  However, as not all patients return for additional testing, a probable diagnosis can be made with a single positive sample plus supportive clinical and laboratory criteria. […] Serological tests for both R. typhi and R. rickettsia are available at most commercial laboratories. […] The LAC DPH Public Health Laboratory (PHL) provides both serological and PCR testing for Rickettsia. […] R. typhi and R. rickettsii serum testing is available and PCR whole blood testing can detect all Rickettsia species. […] Flea-borne typhus and other rickettsial infections are reportable in California.

• #10 Typhus Workup: Laboratory Studies, Imaging Studies, Histologic Findings

  https://emedicine.medscape.com/article/231374-workup

  Brill-Zinsser disease can be confirmed in a patient with a history of primary epidemic typhus who has recurrent symptoms and signs of typhus and a rise in the immunoglobulin G (IgG) antibody titer, which indicates a secondary immune response. […] IFA and EIA tests can be used to confirm a diagnosis of Rickettsioses, but they do not identify the various rickettsial species. […] Polymerase chain reaction (PCR) amplification of rickettsial DNA of serum or skin biopsy specimens can be used for diagnosing, however test sensitivities are still to low to be considered a test of choice. […] No imaging studies are specifically indicated to aid in diagnosing typhus. Imaging studies are indicated only on a case-by-case basis to evaluate potential complications or as needed.

• #11 Rickettsia typhi – Typhus Fever | Choose the Right Test

  https://arupconsult.com/content/rickettsia-typhi

  Serologic testing of immunoglobulin G (IgG) antibodies, often by IFA, is the standard method to confirm murine typhus. […] Diagnosis by serology requires both an acute specimen, collected within a week of symptom onset, and a convalescent specimen, collected 2-10 weeks after the acute sample. […] NAAT by polymerase chain reaction (PCR) can be used to confirm an R. typhi infection and is most sensitive when conducted within a week of symptom onset. […] The sensitivity of NAAT is affected by bacterial load (ie, the severity and stage of infection), so this testing should be performed before administering treatment, ideally within the first 5 days of febrile illness. […] IHC, which like IFA can be used to detect but not identify a rickettsial infection, is limited in availability to specialized laboratories, such as the CDC.

• #11 Rickettsia typhi – Typhus Fever | Choose the Right Test

  https://arupconsult.com/content/rickettsia-typhi

  Rickettsia typhi is the fleaborne etiologic agent of murine typhus (also called endemic typhus), a leading global source of undifferentiated febrile illness. […] Infection by R. typhi is commonly diagnosed with two-step serologic testing, although other methods such as nucleic acid amplification testing (NAAT) and immunohistochemistry (IHC), when IHC is available, may also be used. […] Testing for R. typhi is indicated in patients who have symptoms consistent with infection (eg, a persistent fever accompanied by headache or a rash spreading from the trunk), particularly those who have traveled to a tropical or semitropical region and/or report exposure to common carriers (eg, rats) or their fleas. Symptoms usually occur within 7-14 days of exposure. […] Laboratory testing for R. typhi, a typhus group rickettsia, generally entails serology by immunofluorescence assay (IFA) but can also include NAAT and IHC testing.

• #12 Information for Health Care Providers

  http://med.iiab.me/modules/en-cdc/www.cdc.gov/typhus/healthcare-providers/index.html

  The most rapid and specific diagnostic assays for scrub typhus rely on molecular methods like polymerase chain reaction (PCR), which can detect DNA in a whole blood, eschar swab, or tissue sample. […] Doxycycline is the treatment of choice for suspected scrub typhus in persons of all ages. […] Treatment should never be withheld pending diagnostic tests.

• #13 Clinical Overview of Murine Typhus | Typhus Fevers | CDC

  https://www.cdc.gov/typhus/hcp/clinical-overview/clinical-overview-of-murine-typhus.html

  IHC can be used to detect infection with typhus group Rickettsia (including R. prowazekii and R. typhi) in formalin-fixed tissue samples. […] PCR of whole blood or tissue can distinguish between infection with R. typhi and R. prowazekii although the sensitivity of these assays varies considerably based on the sample type, timing of sample collection, and the severity of disease.

• #14 Epidemic Typhus – Infections – Merck Manual Consumer Version

  https://www.merckmanuals.com/home/infections/rickettsial-and-related-infections/epidemic-typhus

  To diagnose the infection, doctors test a sample of the rash and sometimes do blood tests. […] The diagnosis of epidemic typhus is suggested by the symptoms, particularly if the person has body lice or has been in an area where there was an outbreak of typhus. […] To confirm the diagnosis, doctors may do an immunofluorescence assay, which uses a sample taken from the rash (biopsy). Or they may use the polymerase chain reaction (PCR) technique to enable them to detect the bacteria more rapidly. […] Doctors may do blood tests that detect antibodies to the bacteria. However, doing the test once is not enough. The test must be repeated 1 to 3 weeks later to check for an increase in the antibody level. Thus, antibody tests do not help doctors diagnose the infection immediately after someone becomes ill but can help confirm the diagnosis later.

• #15 Typhus Fever: An Overlooked Diagnosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2761786/

  A case of typhus fever is presented. On admission, the clinical diagnosis was typhoid fever. Forty-eight hours after admission, the presence of subconjunctival haemorrhage, malena, and jaundice raised the possibility of a different aetiology, the two most likely differentials being dengue and typhus. Finally, a co-infection of typhoid and typhus was discovered. This uncommon clinical scenario should be taken into account in the management of patients with high fever on admission being treated as a case of typhoid fever. […] Epidemic and endemic typhus is sometimes misdiagnosed as typhoid fever in tropical countries. Similarly, co-infection of typhoid and typhus fever can be overlooked if not suspected clinically. High continued fever with variable associated symptoms, such as malaise, headache, and myalgia, are usually present in both typhoid and typhus fever. Jaundice and malena may also be present in some cases of both typhoid and typhus fever. However, signs such as subconjunctival haemorrhage should lead to a different aetiology of fever being considered, including typhus fever. Therefore, clinical suspicion is of paramount importance in the diagnosis of both typhoid and typhus fever. Confirmation of the diagnosis is important as the treatment is different but may not always be possible. In most cases of typhus, treatment is given based on clinical suspicion or a positive Weil-Felix test. In clinically-suspected cases of typhus fever, a rising titre of OXK, OX2, and OX19 antigens supports the diagnosis but confirmation of the diagnosis may be difficult.

• #16 Typhus – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/typhus/

  Suspect the diagnosis in patients with clinical features and relevant exposure history. […] Confirmatory tests: for acute and recrudescent infections IFA test demonstrating a four-fold rise in rickettsial antibodies when comparing a sample taken during the first week of illness to a convalescent sample taken 24 weeks later. […] Initiate treatment early in all clinically suspected cases. […] First-line: doxycycline. […] Initiate treatment early in all clinically suspected cases. […] First-line: doxycycline. […] Suspect the diagnosis in patients with clinical features and relevant exposure history.

• #17 Typhus: Causes, Symptoms, and Diagnosis

  https://www.healthline.com/health/typhus

  Typhus outbreaks usually only occur in developing countries or in regions of poverty, poor sanitation, and close human contact. […] Its important to see your doctor if you suspect that you may have typhus. […] Diagnosis is difficult because symptoms are common to other infectious diseases, including: dengue, also known as breakbone fever, malaria, an infectious disease spread by mosquitos, brucellosis, an infectious disease caused by Brucella bacterial species. […] Diagnostic tests for the presence of typhus include: skin biopsy: a sample of the skin from your rash will be tested in a lab, Western blot: a test to identify the presence of typhus, immunofluorescence test: uses fluorescent dyes to detect typhus antigen in samples of serum taken from the bloodstream, other blood tests: results can indicate the presence of infection. […] If you suspect that you have typhus, your doctor will ask about your symptoms and your medical history.

• #18 Murine Typhus | Public Health and Medical Entomology | Purdue | Biology | Entomology | Insects | Ticks | Diseases | Monitoring | Control | Hot Topics | Agriculture | Extension

  https://extension.entm.purdue.edu/publichealth/diseases/flea/typhus.html

  Difficult because initial symptoms are similar to several other diseases, including epidemic typhus fever. […] Serological tests are needed to confirm a diagnosis.

• #19 Typhus: Symptoms, Causes, Diagnosis, Treatment, Prevention

  https://www.webmd.com/a-to-z-guides/what-is-typhus/?amp=1

  If your doctor thinks you have typhus, youll get a blood test to check for typhus bacteria, especially if youve traveled to an area where typhus is common. […] It can sometimes take weeks to get those blood test results. So the doctor may recommend you start antibiotic treatment right away to be safe.

• #20 Murine (Endemic) Typhus – Infections – Merck Manual Consumer Version

  https://www.merckmanuals.com/home/infections/rickettsial-and-related-infections/murine-endemic-typhus

  Murine typhus is a rickettsial disease that is caused by Rickettsia typhi and Rickettsia felis and spread by rat fleas. […] To diagnose the infection, doctors test a sample of the rash and sometimes do blood tests. […] The diagnosis of murine typhus is suggested by symptoms. […] To confirm the diagnosis, doctors may do an immunofluorescence assay, which uses a sample taken from the rash (biopsy). Or they may use the polymerase chain reaction (PCR) technique to enable them to detect the bacteria more rapidly. […] Doctors may do blood tests that detect antibodies to the bacteria. However, doing the test only once is not enough. The test must be repeated 1 to 3 weeks later to check for an increase in the antibody level. Thus, antibody tests do not help doctors diagnose the infection immediately after someone becomes ill but can help confirm the diagnosis later.

• #21 Endemic Typhus Fever (flea-borne) – Epidemiology

  https://www.vdh.virginia.gov/epidemiology/epidemiology-fact-sheets/endemic-typhus-fever-flea-borne/

  Endemic typhus fever is a disease caused by bacteria called Rickettsia typhi or Rickettsia felis. […] The diagnosis of endemic typhus fever is based on signs and symptoms of illness, as well as laboratory tests of skin or blood.

• #22 Epidemic typhus – UpToDate

  https://www.uptodate.com/contents/epidemic-typhus

  Epidemic typhus is a potentially lethal, louse-borne, exanthematous disease caused by Rickettsia prowazekii. R. prowazekii is one of two members of the typhus group of Rickettsia known to cause human illness; the other member, Rickettsia typhi, causes murine typhus. […] The epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment of epidemic typhus will be discussed here. […] It has been estimated that epidemic typhus has caused more deaths than all the wars in history. […] Epidemic typhus is now a rare disease, but subsequent developments illustrate that an understanding of its epidemiology, clinical features, and treatment is still important to clinicians.

• #23 Epidemic Typhus Fever (louse-borne) – Epidemiology

  https://www.vdh.virginia.gov/epidemiology/epidemiology-fact-sheets/epidemic-typhus-fever-louse-borne/

  Epidemic typhus fever is a disease caused by bacteria called Rickettsia prowazekii. […] The diagnosis of epidemic typhus fever is based on signs and symptoms of illness, as well as laboratory tests of skin or blood. […] Epidemic typhus fever is treated with antibiotics. Healthcare providers choose the antibiotic based on the patients symptoms and the results of laboratory tests. […] There is currently no commercially available vaccine for epidemic typhus fever.

• #24 Diagnosis of Scrub Typhus

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2829893/

  Scrub typhus is transmitted by trombiculid mites and is endemic to East and Southeast Asia and Northern Australia. The clinical syndrome classically consists of a fever, rash, and eschar, but scrub typhus also commonly presents as an undifferentiated fever that requires laboratory confirmation of the diagnosis, usually by indirect fluorescent antibody (IFA) assay. […] Diagnosis, therefore, depends on clinical suspicion, prompting the clinician to request an appropriate laboratory investigation, and failure to diagnose the disease will likely result in treatment with ineffective -lactambased regimens. […] The mainstay in scrub-typhus diagnostics remains serology. The oldest test in current use is the WeilFelix OX-K agglutination reaction, which is inexpensive, easy to perform, and results are available overnight; however, it lacks specificity and sensitivity. The indirect fluorescent antibody (IFA) test is more sensitive, and results are available in a couple of hours; however, the test is more expensive and requires considerable training. IFA uses fluorescent anti-human antibody to detect specific antibody from patient serum bound to a smear of scrub-typhus antigen and is currently the reference standard.

• #25 Scrub Typhus Diagnostics: The Present and the Future

  https://zoonoses-journal.org/index.php/2024/02/21/scrub-typhus-diagnostics-the-present-and-the-future/

  Scrub typhus, caused by Orientia tsutsugamushi, is a vector-borne, zoonotic disease commonly occurring in a geographic region known as the tsutsugamushi triangle. Scrub typhus causes acute undifferentiated febrile illness (AUFI) with non-specific clinical features and is difficult to diagnose when a highly characteristic but not pathognomonic eschar is absent. Because the eschar is not always present, laboratory tests are required for diagnosis. Serological assays have been the mainstay of laboratory diagnosis of scrub typhus to date. Here, we present the major clinical features and clinical algorithms suggestive of this disease, to aid in better selection of diagnostic methods. The advantages and disadvantages of various scrub typhus assays are also discussed. Furthermore, we describe diagnostics, including serological and molecular assays, that may be available in the near future.

• #26 Diagnosis of Scrub Typhus

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2829893/

  All currently available serological tests for scrub typhus have limitations in which clinicians need to be aware, despite their widespread use. Although agreement exists that a 4-fold increase in antibody titer between two consecutive samples is diagnostic, such a diagnosis is retrospective and cannot guide initial treatment. Diagnosis based on a single acute-serum sample requires using a cut-off antibody titer. Cut offs ranging from 1:10 to 1:400 are quoted, often with little corroborating evidence and without establishing titers in the healthy local population (necessary to distinguish background immunity from acute infection); that cut off is then used for all patients, irrespective of whether or not they come from a scrub-typhusendemic environment. […] Most frequently, IFA uses antigen from just three serotypes: Karp, Kato, and Gilliam. Yet, enormous antigenic variation has been found everywhere where it has been sought. The Infectious Disease Surveillance Center in Japan, therefore, recommends a two-pronged approach to diagnosis. First, local strains are included in the IFA for each prefecture; second, PCR of the blood clot is performed on all specimens, although buffy coat might be preferable. This recommendation is not widely implemented outside of Japan.

• #27 Scrub Typhus Diagnostics: The Present and the Future – ScienceOpen

  https://www.scienceopen.com/hosted-document?doi=10.15212/ZOONOSES-2023-0028

  In the present review, current advances and practice in the diagnosis of scrub typhus are described. We also concisely discuss future diagnostic assays and their limitations, and provide several feasible suggestions. […] Even in the presence of an eschar and the demonstration of a response to rickettsia specific therapy, scrub typhus diagnosis requires confirmation through laboratory testing. Traditionally, four methods have been used to confirm the etiological agent of an infectious disease or syndrome: isolation of organisms, antigen detection, nucleic acid amplification tests (NAATs), and antibody detection assays. […] The best performance of serological assays for scrub typhus occurs during the second week of illness. The sensitivity is lowest for the Weil Felix test, reaching a maximum of 50%. The specificity has also been reported to be low, although we have consistently observed a specificity above 90%. A diagnosis of scrub typhus can be confirmed serologically by demonstrating a fourfold rise in titre; paired samples (acute and convalescent, taken at least 2 weeks apart) must be tested.

• #27 Scrub Typhus Diagnostics: The Present and the Future – ScienceOpen

  https://www.scienceopen.com/hosted-document?doi=10.15212/ZOONOSES-2023-0028

  Scrub typhus, caused by Orientia tsutsugamushi, is a vector-borne, zoonotic disease commonly occurring in a geographic region known as the ‘tsutsugamushi triangle’. Scrub typhus causes acute undifferentiated febrile illness (AUFI) with non-specific clinical features and is difficult to diagnose when a highly characteristic but not pathognomonic eschar is absent. Because the eschar is not always present, laboratory tests are required for diagnosis. Serological assays have been the mainstay of laboratory diagnosis of scrub typhus to date. Here, we present the major clinical features and clinical algorithms suggestive of this disease, to aid in better selection of diagnostic methods. The advantages and disadvantages of various scrub typhus assays are also discussed. Furthermore, we describe diagnostics, including serological and molecular assays, that may be available in the near future.

• #28 Diagnosis of Scrub Typhus

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2829893/

  Isolating O. tsutsugamushi requires biosafety level-3 facilities and culture on cell monolayers; median time to positivity is 27 days. Current methods of isolation are, therefore, not appropriate for the routine diagnosis of scrub typhus. There is an urgent need for alternative diagnostic methods; however, evaluation is hampered, because the current gold standard (IFA) is imperfect. […] Clinicians will remain dependent on serological methods until these issues are resolved, but work can be done to optimize their performance. Cut offs must be validated locally, and previously undiscovered serotypes must be assiduously searched for by examining rodents and chiggers, not merely patient isolates. We propose that new diagnostic assays not be validated against IFA alone but instead, be compared against a panel of both serological and antigen-detection assays (e.g., IFA with 47-kDA and/or 56-kDa PCR).

• #29 Performance of molecular and serologic tests for the diagnosis of scrub typhus | PLOS Neglected Tropical Diseases

  https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0008747

  Diagnosis of scrub typhus, caused by the bacterium Orientia tsutsugamushi, is challenging because of the overlap of its non-specific symptoms with other infections coupled with the lack of sufficient data on the performance of diagnostic tests. […] Early diagnosis of scrub typhus is crucial to improve outcomes and this study evaluates the diagnostic performance of various tests. […] The present study aims at assessing the accuracy of various rapid diagnostic tests, serologic tests, and nucleic acid amplification methods on well-characterized patient samples. […] The sensitivity and specificity of IFA were found to be 95% and 74% respectively. […] In conclusion, ELISA and RDT detecting Orientia tsutsugamushi specific IgM antibodies have excellent sensitivity and specificity while the accuracy of IFA is suboptimal for the diagnosis of scrub typhus.

• #30 Diagnostic evaluation of IgM ELISA and IgM Immunofluorescence assay for the diagnosis of Acute Scrub Typhus in central Nepal | BMC Infectious Diseases | Full Text

  https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-020-4861-y

  The overall sensitivity and specificity of the IgM ELISA was 84.0% (95% CI: 79.7387.68%) and 94.82% (CI: 93.4395.99%) respectively in our study. […] InBios IgM ELISA is a sensitive and specific test and could be substitute for the IgM IFA in resource limited countries like Nepal. ELISA is comparatively cheaper and easier test with high throughput of the specimens. […] Indirect immunofluorescence assay (IFA) is considered to be the gold standard test for the diagnosis of scrub typhus, in which the patients serum containing the antibodies to Orientia tsutsugamushi are mixed to antigen on a slide, then detected using a fluorescently labeled anti-human antibody. […] Although IFA is loosely considered the gold standard diagnostic test, it is an imperfect reference test, particularly when using only acute samples for diagnosis.

• #31 Scrub typhus point-of-care testing: A systematic review and meta-analysis | PLOS Neglected Tropical Diseases

  https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0006330

  Diagnosing scrub typhus clinically is difficult, hence laboratory tests play a very important role in diagnosis. […] Accurate point-of-care testing (POCT) for scrub typhus diagnosis would be invaluable for patient diagnosis and management. […] The quality of the studies was assessed with the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). […] Meta-analysis showed the pooled sensitivity and specificity of commercially available immunochromatographic tests (ICTs) were 66.0% (95% CI 0.370.86) and 92.0% (95% CI 0.830.97), respectively. […] Overall, the commercially available scrub typhus ICTs demonstrated better performance when ruling in the diagnosis. […] There is a need for standardised methods and reporting of diagnostic accuracy to decrease between-study heterogeneity and increase comparability among study results, as well as development of an affordable and accurate antigen-based POCT to tackle the inherent weaknesses associated with serological testing.

• #32 Orientia tsutsugamushi (Scrub Typhus) | Public Health Ontario

  https://www.publichealthontario.ca/en/Laboratory-Services/Test-Information-Index/Orientia-Tsutsugamushi

  Testing is indicated for individuals with a history of exposure to mites in endemic areas and clinical presentation compatible with suspected scrub typhus. […] For serology, collecting both an acute serum (collected early after the onset of symptoms) and a convalescent serum (collected 2-3 weeks later) may be required for laboratory confirmation of infection. […] Orientia tsutsugamushi serology is performed at NML using the commercial InBios Scrub Typhus Detect IgM and IgG assays. This duplex assay provides semi-quantitative detection of IgM and IgG antibodies to an Orientia tsutsugamushi derived recombinant antigen. […] Single acute serology sensitivity is 60% when collected within the first week of illness. IgM may become detectable 5 to 10 days following symptom onset, while IgG titres may take weeks to become detectable. Overall, IgM and IgG sensitivity is estimated at 70-100% and 58-96%, respectively, while IgM and IgG specificity is estimated at 87-100% and 92-98%, respectively.

• #32 Orientia tsutsugamushi (Scrub Typhus) | Public Health Ontario

  https://www.publichealthontario.ca/en/Laboratory-Services/Test-Information-Index/Orientia-Tsutsugamushi

  Serology may be negative in the acute stage of illness. False positive IgM results may occur and should be confirmed by collecting a convalescent serology sample. A positive IgM and IgG result does not distinguish active versus remote infection unless paired sera are collected demonstrating seroconversion. The current PCR and serology assays may not detect other rare non-tsutsugamushi Orientia species (e.g. Candidatus Orientia cholensis). […] A negative result does not exclude the diagnosis of rickettsial disease.

• #33 Scrub Typhus Workup: Approach Considerations

  https://emedicine.medscape.com/article/971797-workup

  Routine laboratory studies in patients with scrub typhus reveal early lymphopenia with late lymphocytosis. A decrease in the CD4:CD8 lymphocyte ratio may also be noted. Thrombocytopenia is also seen. […] Elevated transaminase levels may be present in 75-95% of patients. Hypoalbuminemia occurs in about 50% of cases, whereas hyperbilirubinemia is rare. These findings may be especially prevalent in children. […] Laboratory studies of choice are serologic tests for antibodies. The main confirmatory tests are the indirect immunoperoxidase test and the immunofluorescent assay. […] An infection is confirmed by a 4-fold increase in antibody titers between acute and convalescent serum specimens. A single high titer with classic clinical features is considered a probable case. Serology for all suspected subtypes should be requested.

• #34 Scrub Typhus Workup: Approach Considerations

  https://emedicine.medscape.com/article/971797-workup

  The indirect fluorescent antibody test is sensitive and provides results in a couple of hours. […] A study of 2 rapid immunochromatographic tests for detection of IgM and IgG against O tsutsugamushi determined that both assays were more sensitive and specific than the standard immune immunofluorescence assay for the early diagnosis of scrub typhus. […] O tsutsugamushi has been identified by means of the polymerase chain reaction (PCR) technique in clinical specimens. […] Performing nested PCR on the eschar might be a rapid diagnostic test for scrub typhus in the early, acute stage. […] The Weil-Felix OX-K strain agglutination reaction can be used to aid in diagnosis of scrub typhus. […] Chest radiography may reveal pneumonitis,

• #35 Highly Sensitive Molecular Diagnostic Platform for Scrub Typhus Diagnosis Using O. tsutsugamushi Enrichment and Nucleic Acid Extraction

  https://www.mdpi.com/2079-6374/14/10/493

  Highly Sensitive Molecular Diagnostic Platform for Scrub Typhus Diagnosis Using O. tsutsugamushi Enrichment and Nucleic Acid Extraction […] Scrub typhus is caused by the Gram-negative obligate intracellular bacterium Orientia tsutsugamushi, and this tick-borne disease is difficult to distinguish from other acute febrile illnesses as it typically presents with symptoms such as rash, crusting at the bite site, headache, myalgia, lymphadenopathy, and elevated liver transaminases. It can often be diagnosed clinically, but not all patients present with characteristic symptoms, so serological diagnosis and molecular techniques may be required. However, existing diagnostic tests often have low sensitivity and specificity, making early detection difficult. This study presents a nucleic acid extraction method using large volumes of plasma and buffy coat to increase sensitivity, as well as an improved detection method using two target genes.

• #36 :: JKMS :: Journal of Korean Medical Science

  https://jkms.org/DOIx.php?id=10.3346/jkms.2016.31.8.1190

  Diagnosis of scrub typhus is challenging due to its more than twenty serotypes and the similar clinical symptoms with other acute febrile illnesses including leptospirosis, murine typhus and hemorrhagic fever with renal syndrome. […] Accuracy and rapidity of a diagnostic test to Orientia tsutsugamushi is an important step to diagnose this disease. […] The sensitivity at the base of each IgM and IgG indirect immunofluorescent assay (IFA) in Korean patients was 98.6% and 97.1%, and the specificity was 98.2% and 97.7% respectively. […] ImmuneMed RDT shows superior sensitivity (98.6% and 97.1%) compared with SD Bioline RDT (84.4% at IgM and 83.3% at IgG) in Korea. […] The retrospective diagnosis of ImmuneMed RDT exhibits 94.0% identity with enzyme-linked Immunosorbent assay (ELISA) using South India patient serum samples.

• #37 :: JKMS :: Journal of Korean Medical Science

  https://jkms.org/DOIx.php?id=10.3346/jkms.2016.31.8.1190

  The sensitivity and specificity of ImmuneMed RDT was 98.6% and 97.6%, but those of SD bioline RDT was 84.4% and 96.3% respectively. […] This result indicates that the ImmuneMed RDT shows excellent performance of sensitivity and specificity to diagnose scrub typhus compared with SD Biolines. […] This means that the selected antigens from five different serotypes and other technical improvement represent to similar or better performance with InBios tsutsugamushi ELISA. […] This indicates that the ImmuneMed RDT can replace ELISA test to diagnose scrub typhus as an easy and time saving diagnostic tool with high sensitivity and specificity.

• #38 Scrub typhus point-of-care testing: A systematic review and meta-analysis | PLOS Neglected Tropical Diseases

  https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0006330

  Therefore, there is clearly a need for affordable point-of-care testing (POCT) for scrub typhus diagnosis in endemic settings with resource constraints. […] The pooled sensitivity and specificity were 66.0% (95% CI 0.370.86) and 92.0% (95% CI 0.830.97), respectively. […] The meta-analysis showed moderately low pooled sensitivity and good specificity of the current commercially available scrub typhus POCT.

• #39 Diagnosis of severe scrub typhus infection by next-generation sequencing:a case report | BMC Infectious Diseases | Full Text

  https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-020-04991-y

  Scrub typhus is an acute febrile illness, which was caused by Orientia tsutsugamushi and transmitted through the bite of chiggers. The diagnosis of scrub typhus could be missed diagnosis due to the absence of the pathognomonic eschar. […] Next-generation sequencing was a new diagnostic technology and could identify scrub typhus in accurately and fast without the pathognomonic eschar. […] The diagnosis of scrub typhus is difficult due to the absence of the pathognomonic eschar, which is the characteristic clinical manifestations and varies widely. […] Serology, biopsy, culture, and polymerase chain reaction were routine diagnostic methods and had many defects in the diagnosis. […] Polymerase chain reaction testing is only used as confirmatory test, but not as a screening test, because of multiple pathogenic bacterium in the clinic.

• #40 Diagnosis of severe scrub typhus infection by next-generation sequencing:a case report | BMC Infectious Diseases | Full Text

  https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-020-04991-y

  Next-generation sequencing (NGS) technologies have been used in the diagnosis of other pathogens. […] However, the use of NGS has not been reported in the case of Scrub Typhus. […] In the 6th day after hospitalization, Orientia tsutsugamushi was determined to be the causative pathogen by NGS. […] NGS was a new diagnostic technology which could identify Scrub typhus in accurately and fast and would be a promising critical tool to find the aetiology of multiple organs failure or septic shock.

• #41 GroEL Chaperonin-Based Assay for Early Diagnosis of Scrub Typhus

  https://www.mdpi.com/2075-4418/12/1/136

  The ICT AgTK for detecting the GroEL of O. tsutsugamushi in the frozen serum samples showed 85% diagnostic sensitivity, 100% diagnostic specificity and 92.5% accuracy, when compared with the clinical diagnosis and standard IFA. […] The ICT AgTK is easy to perform and has a rapid turn-around time. It should be used for on-site and early scrub typhus diagnosis, especially in resource-limited healthcare settings, by using the freshly collected samples, either serum, or plasma, or buffy coat.

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