An autopsy case of fatal Japanese spotted fever in Wakayama.

Japanese spotted fever (JSF) is potentially fatal infection transmitted by tick bites which vectors Rickettsia (R.) japonica. Since JSF was first described in 1984, the incidence has gradually been increased. We experienced a case of JSF of fatal outcome. A female in 70's was found dead on her bed, whose house was so called 'hoarding house' filled with many waists and unused items. The following day, the autopsy was performed. As representative symptom of external findings, skin rashes were seen on the trunk and extremities, and there were tick-bite eschars on the left upper arm. Internal findings showed no specific findings in each organ. Histopathological examination demonstrated massive inflammatory cell infiltrates mainly consisted of neutrophils in the dermis beneath the external eschar. Furthermore, destruction of glomeruli in kidney with microhemorrhage from mesangial regions was observed. The numerous inflammatory infiltrates were also observed in pulmonary interstitium, which were accompanied with histopathologic features of vasculitis. Biochemical examination showed severe systemic inflammation as monitored by elevated CRP of 16 mg/dL and renal dysfunction by BUN of 171.2 mg/dL and creatinine of 6.07 mg/dL. Subsequently polymerase chain reaction revealed specifically amplified signals for R. japonica from the samples of tick-bites eschar and blood. Thus, we diagnosed her cause of death as JSF which had been occurred multiorgan failure such as acute renal failure and possibly acute respiratory failure. (224 terms).

Spotted Fever and Typhus Group Rickettsiae in Dogs and Humans, Mexico, 2022.

We found serologic evidence of spotted fever group Rickettsia in humans and dogs and typhus group Rickettsia in dogs in Reynosa, Mexico. Our investigation revealed serologic samples reactive to spotted fever group Rickettsia in 5 community members, which highlights a potential rickettsial transmission scenario in this region.

Evaluation of tetracycline and fluoroquinolone therapy against Japanese spotted fever: Analysis based on individual data from case reports and case series.

OBJECTIVES: Although approximately 40 years have passed since Japanese spotted fever (JSF) was first reported in Japan, its treatment has not yet been standardised. As in other rickettsial infections, tetracycline (TC) is the first-line treatment, but successful instances of fluoroquinolone (FQ) combination therapy in severe cases have been reported. However, the effectiveness of TC plus FQ combined treatment (TC+FQ) remains controversial. Therefore, the antipyretic effect of TC+FQ was evaluated in this study. METHODS: A comprehensive search of published JSF case reports was conducted to extract individual patient data. In cases where it was possible to extract temperature data, after homogenising patient characteristics, time-dependent changes in fever type from the date of the first visit was evaluated for the TC and TC+FQ groups. RESULTS: The primary search yielded 182 cases, with individual data evaluations resulting in a final analysis of 102 cases (84 in the TC group and 18 in the TC+FQ group) that included temperature data. The TC+FQ group had significantly lower body temperature compared with the TC group from Days 3 to 4. CONCLUSIONS: Although TC monotherapy for JSF can eventually result in defervescence, the duration of fever is longer compared with other rickettsial infections such as scrub typhus. The results suggest that the antipyretic effect of TC+FQ was more effective, with a potential shortening of the duration that patients suffer from febrile symptoms.

Spotted fever rickettsioses. Study of cases reported in a secondary care pediatric hospital of northeastern Mexico, 2012-2022.

BACKGROUND: Spotted fever rickettsiosis is a serious disease with a high mortality rate if not timely detected. OBJECTIVE: To describe the characteristics of patients hospitalized for spotted fever rickettsiosis, as well as the risk factors associated with poor prognosis. MATERIAL AND METHODS: Data from medical records of patients hospitalized between August 2012 and July 2022 were collected. Variables were analyzed using Mann-Whitney's U-test, Fisher's exact test, and univariate or multivariate logistic regression analysis. RESULTS: Twenty-six patients were analyzed, among which a mortality of 57.6% was identified. In the between-group comparison, platelet count was lower in non-survivors (16.0 × 103/µL vs. 25.9 × 103/µL, p = 0.031). The percentage of surviving patients who received treatment more than 72 hours after fever onset was 45.5% (five patients) vs. 86.7% of non-survivors (13 patients) (p = 0.034). Receiving treatment 72 hours after fever onset increased by 7.09 times the probability of a fatal outcome (OR = 8.09, 95% CI = 1.1-55.8, p = 0.034). CONCLUSIONS: Starting adequate treatment 72 hours after the onset of fever may be an important risk factor for mortality, hence the importance of timely diagnosis and appropriate treatment of this disease.

ANTECEDENTES: La rickettsiosis de fiebre manchada es una enfermedad grave y con alta tasa de letalidad si no se identifica oportunamente. OBJETIVO: Describir las características de los pacientes hospitalizados por rickettsiosis de fiebre manchada, así como los factores de riesgo asociados a mal pronóstico. MATERIAL Y MÉTODOS: Se recabaron los datos del expediente clínico de pacientes hospitalizados entre agosto de 2012 y julio de 2022. Las variables se analizaron mediante prueba U de Mann-Whitney, prueba exacta de Fisher y regresión logística univariada y multivariada. RESULTADOS: Se analizaron 26 pacientes, en quienes se identificó una mortalidad de 57.6 %. En la comparación entre grupos, el número de plaquetas fue menor en los no supervivientes (16.0 × 103/µL versus 25.9 × 103/µL, p = 0.031). El porcentaje de pacientes supervivientes que recibieron tratamiento más de 72 horas después del inicio de la fiebre fue 45.5 % (cinco pacientes) versus 86.7 % de los no supervivientes (13 pacientes), p = 0.034. Recibir tratamiento después de 72 horas del inicio de la fiebre incrementó 7.09 veces la probabilidad de desenlace fatal (RM = 8.09, IC 95 % = 1.1-55.8, p = 0.034). CONCLUSIONES: Iniciar tratamiento adecuado posterior a 72 horas del inicio de la fiebre podría ser un factor de riesgo de mortalidad, de ahí que la importancia del diagnóstico oportuno y tratamiento adecuado de esta enfermedad.

Serological cross-reactivity between spotted fever and typhus groups of rickettsia infection in Japan.

OBJECTIVES: We examined the frequency of cross-reactions to Rickettsia typhi in patients with Japanese spotted fever (JSF) and evaluated the differences between two rickettsiae using antibody endpoint titers. METHODS: Patients' immunoglobulin (Ig)M and IgG titers against Rickettsia japonica and Rickettsia typhi in two phases were measured using an indirect immunoperoxidase assay at two reference centers for rickettsiosis in Japan. Cross-reaction was defined as a higher titer against R. typhi in convalescent sera than in acute sera among patients fulfilling the criteria for JSF diagnosis. The frequencies of IgM and IgG were also evaluated. RESULTS: Approximately 20% of cases showed positive cross-reactions. A comparison of antibody titers revealed the difficulty in identifying some positive cases. CONCLUSION: Cross-reactions of 20% in serodiagnosis may lead to the misclassification of rickettsial diseases. However, with the exception of some cases, we were able to successfully differentiate JSF from murine typhus using each endpoint titer.

Imported rickettsial infections to the United Kingdom, 2015-2020.

OBJECTIVE: The burden of imported rickettsial infection in the UK is not previously described. This retrospective review identifies rickettsial cases diagnosed at the national reference laboratory between 2015 and 2022. METHODS: Samples testing positive for spotted fever group, typhus group, and scrub typhus IgG/IgM on acute and convalescent blood samples, and/or PCR on tissue/blood were categorized as suspected, confirmed or past infection. RESULTS: 220 patients had rickettsioses, and the commonest import was acute spotted fever group infection (61%, 125/205), 54% (62/114) from South Africa. In acute typhus group cases, 60% (40/67) were from Southeast Asia. One patient with Rickettsia typhi bacteremia died. Scrub typhus group infections (5%, 10/205) were exclusively from Asia and the Western Pacific regions. Overall, 43% of confirmed cases (39/91) had not received doxycycline prior to results. CONCLUSIONS: Rickettsial infections are important and under-recognized causes of imported fever in the UK. Thorough history, examination, and timely treatment with doxycycline should be considered if there is suspicion of Rickettsia infection before testing.

The inoculation eschar of Rickettsia parkeri rickettsiosis in Brazil: Importance and cautions.

Two well characterized tick-borne rickettsioses occur in Brazil. Rickettsia rickettsii caused spotted-fever, transmitted by Amblyomma sculptum and Amblyomma aureolatum, is a severe disease with a high case-fatality rate in the southeastern region of the country. Rickettsia parkeri strain Atlantic rainforest infections transmitted by adult Amblyomma ovale ticks cause a milder non-lethal febrile disease with an eschar (necrosis) at the tick bite site. Clinical diagnosis of rickettsiosis is challenging, particularly during the early stages of the illness when signs and symptoms are non-specific. Since eschar at the tick bite site has emerged as the main clinical feature of mild R. parkeri infections and used to differentiate it from severe R. rickettsii infection, its proper recognition, distinction from other tick bite lesions, and boundaries as a clinical tool must be highlighted. Of importance, eschars induced by Rickettsia must be differentiated from dermatoses caused by other tick-borne skin infections as well from lesions caused by the tick bite itself. We herein highlight information on eschar in rickettsial diseases in Brazil and discuss the need for further research on its clinical relevance and application in the diagnosis of spotted fever caused by R. parkeri strain Atlantic rainforest. In particular, we draw attention to diagnosis of other febrile diseases in the presence of concomitant tick bites.

Clinical Forms of Japanese Spotted Fever from Case-Series Study, Zigui County, Hubei Province, China, 2021.

We report a case-series study of 5 patients with Japanese spotted fever from the Three Gorges Area in China, including 1 fatal case. Seroprevalence of Rickettsia japonica was ≈21% among the local population. Our report highlights the emerging potential threat to human health of Japanese spotted fever in the area.

Emerging tick-borne spotted fever group rickettsioses in the Balkans.

The impact of tick-borne pathogens (TBPs) on human health has increased in the last decades, since the incidence of emerging and re-emerging infectious and zoonotic tick-borne diseases has increased worldwide. Tick-borne rickettsiae of the Spotted Fever group (SFGR) are considered as emerging pathogens that can infect humans and cause a variety of non-specific clinical symptoms. Here, we report nine cases of atypical tick-borne diseases (9/460; 1.95%) that occurred over a period of four months (from 15 April 2021 to 16 August 2021) in Serbia, from which five cases were classified as confirmed SFGR infection, two cases as probable SFGR infection and two cases as suspected SFGR infection. Within cases of confirmed SFGR infection, R. helvetica was detected as the causative agent in two cases. The most common clinical finding was non-expanding persistent circular redness, followed by eschar and enlargement of regional lymph nodes, and pain at lesion site. Rickettsia outer membrane protein B (ompB) and citrate synthase (gltA) gene fragments were amplified from clinical samples and ticks attached to patients and IgG reacting with Rickettsia conorii antigen were detected in sera samples of patients, which are highly suggestive of exposure to SFGR. Surveillance and monitoring of rickettsial diseases in Serbia should continue and extended to new areas due to the increasing trend of clinical infections caused by SFGR in the country.

Evaluating the Clinical and Immune Responses to Spotted Fever Rickettsioses in the Guinea Pig-Tick-Rickettsia System.

The guinea pig was the original animal model developed for investigating spotted fever rickettsiosis (SFR). This model system has persisted on account of the guinea pig's conduciveness to tick transmission of SFR agents and ability to recapitulate SFR in humans through clinical signs that include fever, unthriftiness, and in some cases the development of an eschar. The guinea pig is the smallest animal model for SFR that allows the collection of multiple blood and skin samples antemortem for longitudinal studies. This unit provides the basic protocols necessary to establish, maintain, and utilize a guinea pig-tick-Rickettsia model for monitoring the course of infection and immune response to an infection by spotted fever group Rickettsia (SFGR) that can be studied at biosafety level 2 (BSL-2) and arthropod containment level 2 (ACL-2); adaptations must be made for BSL-3 agents. The protocols cover methods for tick feeding and colony development, laboratory infection of ticks, tick transmission of Rickettsia to guinea pigs, and monitoring of the course of infection through clinical signs, rickettsial burden, and immune response. It should be feasible to adapt these methods to study other tick-borne pathogens. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Tick transmission of SFGR to guinea pigs Support Protocol 1: Laboratory infection of ticks by injection Alternate Protocol 1: Needle inoculation of SFGR to guinea pigs Basic Protocol 2: Monitoring the course of guinea pig rickettsial infection: clinical signs Basic Protocol 3: Monitoring the course of guinea pig rickettsial infection: collection of biological specimens Support Protocol 2: Guinea pig anesthesia Basic Protocol 4: Monitoring rickettsial burden in guinea pigs by multiplex qPCR Basic Protocol 5: Monitoring guinea pig immune response to infection: blood leukocytes by flow cytometry Basic Protocol 6: Monitoring immune response to guinea pig rickettsial infection: leukocyte infiltration of skin at the tick bite site by flow cytometry Basic Protocol 7: Monitoring the immune response to guinea pig rickettsial infection: antibody titer by ELISA Support Protocol 4: Coating ELISA Plates Alternate Protocol 2: Monitoring immune response to guinea pig rickettsial infection: antibody titer by immunofluorescence assay.

Emerging Spotted Fever Rickettsioses in the United States.

Spotted fever rickettsioses are important causes of emerging infectious disease in the United States and elsewhere. Rocky Mountain Spotted Fever, caused by R. rickettsii causes a febrile, acute illness in dogs. Because it circulates in peripheral blood in low copy number and because of the acute nature of the disease, dogs may test PCR and seronegative at the time of presentation. Therefore, therapy with doxycycline must be initiated and continued based on the clinician's index of suspicion. Combining PCR with serologic testing, repeat testing of the same pre-antimicrobial blood sample, and testing convalescent samples for seroconversion facilitates diagnosis. The prognosis can be excellent if appropriate antimicrobial therapy is begun in a timely fashion. It is well established that dogs are sentinels for infection in people in households and communities. Whether R. rickettsii causes illness in cats is not well established. The role of other spotted fever group rickettsia in causing illness in dogs and cats is being elucidated. Veterinarians should keep in mind that novel and well characterized species of SFG Rickettsia are important causes of emerging infectious disease. Veterinarians can play an important role in detecting, defining, and preventing illness in their canine patients and their human companions.

Clinical Differentiation of Severe Fever with Thrombocytopenia Syndrome from Japanese Spotted Fever.

Severe fever with thrombocytopenia syndrome (SFTS) and Japanese spotted fever (JSF; a spotted fever group rickettsiosis) are tick-borne zoonoses that are becoming a significant public health threat in Japan and East Asia. Strategies for treatment and infection control differ between the two; therefore, initial differential diagnosis is important. We aimed to compare the clinical characteristics of SFTS and JSF based on symptomology, physical examination, laboratory data, and radiography findings at admission. This retrospective study included patients with SFTS and JSF treated at five hospitals in Nagasaki Prefecture, western Japan, between 2013 and 2020. Data from 23 patients with SFTS and 38 patients with JSF were examined for differentiating factors and were divided by 7:3 into a training cohort and a validation cohort. Decision tree analysis revealed leukopenia (white blood cell [WBC] < 4000/µL) and altered mental status as the best differentiating factors (AUC 1.000) with 100% sensitivity and 100% specificity. Using only physical examination factors, absence of skin rash and altered mental status resulted in the best differentiating factors with AUC 0.871, 71.4% sensitivity, and 90.0% specificity. When treating patients with suspected tick-borne infection, WBC < 4000/µL, absence of skin rash, and altered mental status are very useful to differentiate SFTS from JSF.

Effectiveness of fluoroquinolone antimicrobials in addition to tetracyclines for Japanese spotted fever: A retrospective analysis using a national inpatient database.

OBJECTIVES: This study aim to evaluate the effectiveness of fluoroquinolone (FQ) antimicrobial therapy in combination with tetracyclines (TCs) in patients with Japanese spotted fever (JSF) using a nationwide inpatient database in Japan. METHODS: We identified hospitalized patients diagnosed with JSF who were enrolled in the Japanese Diagnosis Procedure Combination inpatient database from July 2010 to March 2021. Patients who received FQ plus TC on the day of admission were compared with patients who received TC alone on the day of admission, using inverse probability of treatment weighting. The primary outcome was in-hospital mortality. Secondary outcomes were in-hospital complications, total hospitalization costs, and length of hospital stay. RESULTS: We identified 1060 eligible patients. Of these, 434 (41%) received FQ plus TC on the day of admission and 626 (59%) received TC alone on the day of admission. Inverse probability of treatment weighting showed no statistically significant differences between the groups in in-hospital mortality, in-hospital complications, total hospitalization costs, and length of hospital stay. CONCLUSION: This study did not show any significantly improved effectiveness using FQ antimicrobials in combination with TCs for treating JSF. Clinicians may need to be cautious in administering FQ and TC antimicrobials concomitantly in routine practice.

Patterns Testing for Tick-Borne Diseases and Implications for Surveillance in the Southeastern US.

Importance: Tick-borne diseases (TBD), including spotted fever group rickettsiosis (SFGR), ehrlichiosis, and, increasingly, Lyme disease, represent a substantial public health concern throughout much of the southeastern United States. Yet, there is uncertainty about the epidemiology of these diseases because of pitfalls in existing diagnostic test methods. Objective: To examine patterns of diagnostic testing and incidence of TBD in a large, academic health care system. Design, Setting, and Participants: This cross-sectional study included diagnostic test results for TBD at UNC Health, a large academic health care system with inpatient and outpatient facilities, from January 1, 2017, to November 30, 2020. Participants included all individuals seeking routine care at UNC Health facilities who had testing for SFGR, ehrlichiosis, or Lyme disease performed during the study period. Main Outcomes and Measures: Rates of test positivity, testing completeness, and incidence of TBD. Results: During the 4-year study period, 11 367 individuals (6633 [58.4%] female; 10 793 [95%] non-Hispanic individuals and 8850 [77.9%] White individuals; median [IQR] age, 53 [37-66] years) were tested for TBD. Among the 20 528 diagnostic tests performed, 47 laboratory-confirmed, incident cases of SFGR, 27 cases of ehrlichiosis, and 76 cases of Lyme were confirmed, representing incidence rates of 4.7%, 7.1%, and 0.7%, respectively. However, 3984 of SFGR tests (79.3%) and 3606 of Ehrlichia tests (74.3%) lacked a paired convalescent sample. Of 20 528 tests, there were 11 977 tests (58.3%) for Lyme disease from 10 208 individuals, 5448 tests (26.5%) for SFGR from 4520 individuals, and 3103 tests (15.1%) for ehrlichiosis from 2507 individuals. Most striking, testing for ehrlichiosis was performed in only 55% of patients in whom SFGR was ordered, suggesting that ehrlichiosis remains underrecognized. An estimated 187 incident cases of SFGR and 309 of ehrlichiosis were potentially unidentified because of incomplete testing. Conclusions and Relevance: In this cross-sectional study, most of the patients suspected of having TBD did not have testing performed in accordance with established guidelines, which substantially limits understanding of TBD epidemiology. Furthermore, the data revealed a large discrepancy between the local burden of disease and the testing performed. These findings underscore the need to pursue more robust, active surveillance strategies to estimate the burden of TBD and distribution of causative pathogens.

Diagnostic Value of IgA Antibody Measurement in Tick-Borne Spotted Fever (Astrakhan Rickettsial Fever).

Tick-borne spotted fevers caused by Rickettsia occur worldwide. The symptoms of this bacterial infection are similar to those of viral infection, and thus, diagnostic accuracy has special clinical importance. One of the commonly used methods for the diagnosis of tick-borne spotted fever is enzyme-linked immunosorbent assay (ELISA), which is based on estimation of the presence of specific IgM antibodies in blood. However, IgA analysis has not been used for the diagnosis of rickettsial diseases thus far. We investigated the diagnostic value of IgA antibody determination using patient sera collected in the Astrakhan region of Russia, where an isolated site of Astrakhan rickettsial fever (ARF) caused by Rickettsia conorii subsp. caspia is located. Our investigation was performed on serum samples collected from 185 patients diagnosed with Astrakhan rickettsial fever from May to October 2019. Western blot analysis revealed that specific IgA antibodies, as well as IgM antibodies, from patient sera bind to high-molecular-weight pathogen proteins with similar masses. The obtained data show that the determination of IgM alone allows for serological confirmation of diagnosis in only 46.5% of cases but that the determination of both IgM and IgA increases this rate to 66.5%. Taken together, the findings show an important diagnostic value of IgA evaluation for tick-borne spotted fever rickettsiosis. IMPORTANCE Tick-borne spotted fevers caused by Rickettsia occur worldwide. The symptoms of this bacterial infection are similar to the symptoms of viral infection, and thus, diagnostic accuracy has special clinical importance. The most serious spotted fever group rickettsiosis is Rocky Mountain fever in the United States, which is caused by Rickettsia rickettsii, and disease complications can lead to hemiparesis, blindness, or amputation. Rickettsia conorii subsp. caspia causes a rickettsial spotted fever named Astrakhan rickettsial fever (ARF). One of the commonly used methods for the diagnosis of tick-borne spotted fevers is ELISA, which is based on estimation of the presence of specific IgM antibodies in blood, though IgA has not been used for the diagnosis of rickettsial diseases thus far. In this study, we showed that both IgA and IgM should be analyzed in the blood serum samples of patients to significantly enhance the accuracy of diagnostics of tick-borne spotted fever rickettsiosis.