Orientia tsutsugamushi infection reduces host gluconeogenic but not glycolytic substrates.

Orientia tsutsugamushi a causal agent of scrub typhus, is an obligate intracellular bacterium that, akin to other rickettsiae, is dependent on host cell-derived nutrients for survival and thus pathogenesis. Based on limited experimental evidence and genome-based in silico predictions, O. tsutsugamushi is hypothesized to parasitize host central carbon metabolism (CCM). Here, we (re-)evaluated O. tsutsugamushi dependency on host cell CCM as initiated by glucose and glutamine. Orientia infection had no effect on host glucose and glutamine consumption or lactate accumulation, indicating no change in overall flux through CCM. However, host cell mitochondrial activity and ATP levels were reduced during infection and correspond with lower intracellular glutamine and glutamate pools. To further probe the essentiality of host CCM in O. tsutsugamushi proliferation, we developed a minimal medium for host cell cultivation and paired it with chemical inhibitors to restrict the intermediates and processes related to glucose and glutamine metabolism. These conditions failed to negatively impact O. tsutsugamushi intracellular growth, suggesting the bacterium is adept at scavenging from host CCM. Accordingly, untargeted metabolomics was utilized to evaluate minor changes in host CCM metabolic intermediates across O. tsutsugamushi infection and revealed that pathogen proliferation corresponds with reductions in critical CCM building blocks, including amino acids and TCA cycle intermediates, as well as increases in lipid catabolism. This study directly correlates O. tsutsugamushi proliferation to alterations in host CCM and identifies metabolic intermediates that are likely critical for pathogen fitness.IMPORTANCEObligate intracellular bacterial pathogens have evolved strategies to reside and proliferate within the eukaryotic intracellular environment. At the crux of this parasitism is the balance between host and pathogen metabolic requirements. The physiological basis driving O. tsutsugamushi dependency on its mammalian host remains undefined. By evaluating alterations in host metabolism during O. tsutsugamushi proliferation, we discovered that bacterial growth is independent of the host's nutritional environment but appears dependent on host gluconeogenic substrates, including amino acids. Given that O. tsutsugamushi replication is essential for its virulence, this study provides experimental evidence for the first time in the post-genomic era of metabolic intermediates potentially parasitized by a scrub typhus agent.

A case of neonatal tsutsugamushi disease diagnosed with the aid of rickettsial macrogenomic detection.

BACKGROUND: Tsutsugamushi, also known as bush typhus, is a naturally occurring disease caused by Orientia tsutsugamushi. We reported a case of vertical mother-to-newborn transmission of Orientia tsutsugamushi infection in a newborn from Yunnan (China). CASE PRESENTATION: Decreased fetal movements were observed at 39 weeks of gestation. After birth, the newborn (female) had recurrent fever, shortness of breath, and bruising around the mouth and extremities. At 5 h 58 min of age, the newborn was admitted for fever, shortness of breath and generalized rash. The liver was palpable 3 cm below the costal margin, and the limbs showed pitting edema. There was subcutaneous bleeding. Investigations suggested heavy infection, myocardial damage, decreased platelets. Treatment with cefotaxime and ampicillin failed. The mother was hospitalized at 29 weeks of gestation with a fever for 4 consecutive days, and an ulcerated crust was found in the popliteal fossa. Due to this pregnancy history, A diagnosis of Orientia tsutsugamushi infection was suspected in our index case and confirmed by macrogenomic testing and she was treated with vancomycin and meropenem, and later azithromycin for 1 week. The newborn was discharged in good general condition, gradually normalizing body temperature, and decreasing rash and jaundice. There were no abnormalities on subsequent blood macrogenomic tests for the baby. And one month later she showed good mental health, sleep, and food intake and no fever, rash, or jaundice. CONCLUSION: Determining the cause of symptoms is the key to treating diseases, especially the rare diseases that can be misdiagnosed. SUITABLE FOR PEOPLE WITH: Infectious Diseases; Neonatology; Obstetrics.

Rickettsial Disease Outbreak, Mexico, 2022.

Beginning in 2022, Nuevo Leon, Mexico, experienced an outbreak of rickettsioses that is still ongoing despite multidisciplinary control efforts. A total of 57 cases have been confirmed, particularly affecting children. We report a high mortality rate among hospitalized persons in Nuevo Leon. Continuing efforts are required to control the outbreak.

Probable African Tick Bite Fever in the United States.

African tick bite fever (ATBF) is a tick-borne rickettsial disease most often observed in North American and European tourists returning home from the southern portion of Africa. Ticks infected with Rickettsia africae transmit this parasitic bacterium to humans, who subsequently develop an influenza-like illness, one or more inoculation eschars, and in some cases, a cutaneous rash. Because ATBF often presents with non-specific symptoms that suggest other infectious diseases, establishing the diagnosis may be difficult. Confirmatory assays, including serology and nucleic acid amplification, may take weeks to return and cannot help with acute treatment decisions. We present a case of a previously healthy 60-year-old woman who developed an illness strongly suggestive of ATBF after a missionary trip to Zimbabwe and discuss the disease's diagnostic challenges. Our paper also reviews the epidemiology of this disease and the currently available diagnostic laboratory tests and recommended treatment options.

Rickettsial Illnesses as Important Causes of Febrile Illness in Chittagong, Bangladesh.

We conducted a yearlong prospective study of febrile patients admitted to a tertiary referral hospital in Chittagong, Bangladesh, to assess the proportion of patients with rickettsial illnesses and identify the causative pathogens, strain genotypes, and associated seasonality patterns. We diagnosed scrub typhus in 16.8% (70/416) and murine typhus in 5.8% (24/416) of patients; 2 patients had infections attributable to undifferentiated Rickettsia spp. and 2 had DNA sequence-confirmed R. felis infection. Orientia tsutsugamushi genotypes included Karp, Gilliam, Kato, and TA763-like strains, with a prominence of Karp-like strains. Scrub typhus admissions peaked in a biphasic pattern before and after the rainy season, whereas murine typhus more frequently occurred before the rainy season. Death occurred in 4% (18/416) of cases; case-fatality rates were 4% each for scrub typhus (3/70) and murine typhus (1/28). Overall, 23.1% (96/416) of patients had evidence of treatable rickettsial illnesses, providing important evidence toward optimizing empirical treatment strategies.

Analysis of Amblyomma sculptum haplotypes in an area endemic for Brazilian spotted fever.

Amblyomma sculptum (Ixodida: Ixodidae) Berlese, 1888, a member of the Amblyomma cajennense complex, is the major vector of Brazilian spotted fever (BSF) in southeastern Brazil. In this study, the genetic diversity of A. sculptum populations in the state of Rio de Janeiro (RJ), Brazil, was investigated because genetic variability in tick populations may be related to vector competence. Samples of A. sculptum from 19 municipalities in 7 regions of RJ were subjected to DNA extraction, amplification and sequencing of D-loop, cytochrome oxidase II and 12S rDNA mitochondrial genes. These sequences were used to map the genetic diversity of this tick. Amblyomma sculptum populations are genetically diverse in RJ, especially in the South Centre and Highland regions. Few unique haplotypes were observed in all populations, and the majority of genetic variation found was among ticks within each population. Phylogenetic reconstruction reinforced the assumption that all the haplotypes identified in RJ belong to A. sculptum. However, some RJ haplotypes are closer to A. sculptum from Argentina than to A. sculptum from elsewhere in Brazil. In RJ, A. sculptum has high genetic diversity, although little genetic differentiation. Observations also indicated a high level of gene flow among the studied populations and no evidence of population structure according to region in RJ.

Diagnosing and reintegrating traceability of infectious diseases via metagenomic next-generation sequencing: Study of a severe case of Rickettsia japonica infection.

Background: In this study, we present a case of Japanese spotted fever (JSF) caused by Rickettsia japonica and use this case to investigate the process of diagnosing and reintegrating traceability of infectious diseases via metagenomic next-generation sequencing (mNGS). Methods: From data relating to epidemiological history, clinical and laboratory examinations, and mNGS sequencing, a diagnosis of severe JSF was concluded. Results: A detailed field epidemiological investigation discovered parasitic Haemaphysalis longicornis from a host animal (dog) in the domicile of the patient, within which R. japonica was detected, along with a diverse array of other potentially pathogenic microorganisms that could cause other infectious diseases. Conclusion: The mNGS provided an efficient method to diagnose JSF infection. This methodology could also be applied to field epidemiological investigations to establish the traceability of infectious diseases.

Knowledge, attitudes, and practices (KAPs) regarding tick-borne rickettsial disease among medical staff in endemic areas of China.

Tick-borne rickettsial disease (TBRD) is a perilous acute infection that often eludes diagnosis in its early stages. The triad of knowledge, attitudes, and practices (KAPs) among medical professionals is key to reducing missed diagnosis rates. Therefore, a meticulous evaluation of KAPs is imperative. This study aimed to delve into the understanding of TBRD and explore the beliefs and practices related to personal prevention methods among individuals in Lu'an, a hotspot for TBRD. During the summer months of 2023, convenience sampling was employed by circulating a confidential questionnaire to 1,206 participants in the endemic regions of China. This questionnaire painted a comprehensive picture of the participants' sociodemographic profiles and their KAPs levels vis-à-vis TBRD. The findings revealed that participants scored a mere 55.78% in knowledge, while their attitudes and practices garnered impressive scores of 90.09% and 90.83%, respectively. Upon further analysis using multiple linear regression, several intriguing patterns emerged. Male participants, employed in the Infectious Disease Department, held vice-senior or higher titles, or had prior medical training demonstrated superior knowledge scores. On the other hand, medical personnel who were younger than 30, possessed graduate degrees or higher qualifications, and had training excelled in attitudes and practices. Notably, when employing the Boston Consulting Group (BCG) matrix, a significant distribution of medical personnel was observed across the four quadrants. Specifically, 37.43%, 13.19%, 19.61%, and 29.77% fell into the first, second, third, and fourth quadrants. This survey underscores the commendable attitudes and practices of medical staff towards TBRD in endemic regions of China. However, their knowledge level remains wanting and demands urgent improvement.

Neurological Manifestations of Scrub Typhus Infection in Pediatric Patient: A Case Report From Tertiary Care Hospital in Central India.

Scrub typhus is a neglected tropical bacterial disease endemic in central India which can manifest as meningitis/meningoencephalitis in children. It is difficult to diagnose clinically, especially in the absence of eschar or rash. Scrub typhus is seldom considered the differential diagnosis of meningitis in the Indian subcontinent. Appropriate investigations can lead to early detection of infection and initiation of correct antibiotic treatment leading to better patient prognosis even when features of meningitis supervene. Here, we report a pediatric case of scrub typhus meningitis that could be saved due to timely investigations and initiation of appropriate antimicrobial agents.

Rickettsia felis is an emerging human pathogen associated with cat fleas: A review of findings in Taiwan.

Rickettsia felis is an emerging rickettsial agent principally associated with cat fleas (Ctenocephalides felis), formerly discovered in 1990. Since then, clinical cases of R. felis infection have been identified globally by specific DNA sequences in patients with undifferentiated febrile illness, including in Taiwan, but such evidence is limited. R. felis rickettsiosis is self-limiting and easily treated with doxycycline, but its diagnosis remains a challenge. Environmental risk factors for R. felis rickettsiosis have yet to be clearly demonstrated, and its transmission biology is incompletely understood. Cat fleas are naturally infected with R. felis at varying rates, and vector competence in the transmission of R. felis has been demonstrated in animal models, including dogs, which may serve as reservoir hosts. In northern Taiwan, despite ∼20% of cat fleas infesting companion animals consistently found to be infected with R. felis, only a few cases of potential R. felis infection have been identified through a retrospective serological investigation, though without molecular confirmation. Ecological studies have identified divergent R. felis-like organisms in different arthropod hosts, but these strains appear to serve as nonpathogenic endosymbionts. Although its association with disease is limited, we believe cat flea-borne R. felis warrants increased recognition in an aging population due to immunosenescence and the proximity of companion animals to the elderly. Adopting a One Health approach involving collaboration and communication between clinicians, veterinarians, public health practitioners, and environmental scientists will improve our knowledge about this neglected pathogen and promote the prevention and control of vector-borne diseases.

An Unsuspected Case of Rocky Mountain Spotted Fever: A Lesson to Keep a Broad Differential.

Rocky Mountain spotted fever (RMSF), a tick-borne illness, can cause serious illness or death even in a healthy individual. Unfortunately, this illness can be difficult to diagnose as symptoms are nonspecific and oftentimes mimic benign viral illnesses. Delayed diagnosis can be detrimental as the timing of antibiotic administration is critical to prevent associated morbidity and mortality. A careful travel and social history can sometimes provide clues to make the diagnosis. Being aware of lesser-known objective findings such as hyponatremia, neurologic derangements, transaminitis, and thrombocytopenia may help raise suspicion for the disease. This is a case of a 72-year-old woman who presented with nonspecific symptoms and hyponatremia without known tick exposure. She was eventually diagnosed with RMSF. The timing of her presentation corresponded with a surge in COVID-19 infections throughout her area of residence, which further complicated her presentation and contributed to a delayed diagnosis.

Rickettsial neuroretinitis: A report of 2 cases.

PURPOSE: The authors present two cases of neuroretinitis caused by Rickettsia rickettsii infection. OBSERVATIONS: Case 1 is a 24-year-old male who presented with 2 months of vision loss. Case 2 is a 38-year-old female who presented with 4 weeks of eye pain and vision loss. Examination of both patients revealed neuroretinitis characterized by optic disc swelling with macular exudates, and subsequent serological analysis was positive for Rickettsia rickettsii. Both patients responded favorably to treatment with oral doxycycline and prednisone. CONCLUSIONS AND IMPORTANCE: Given the potential for neuroretinitis to cause permanent vision loss, the presence of acute vision loss, optic disc edema, and macular exudates should prompt an evaluation for Rickettsial disease in endemic areas, even in the absence of systemic symptoms or known history of a tick bite.

Ocular manifestation of rickettsial disease in South Indian population.

Purpose: The aim of this work was to study the ocular manifestations and its management in spotted fever and typhus group of rickettsial disease. Methods: A retrospective analysis of 50 patients with serologically confirmed Rickettsial disease. In all patients, relevant history, investigations and treatment details were collected and they underwent complete ophthalmic evaluation including measurement of best-corrected visual acuity, anterior segment examination and dilated fundus examination. Results: Mean age was 12.5 ± 8.99 years. Of the 50 patients, 40 patients were ≤18 years of age and 27 (54%) had ocular involvement. Out of 27 patients, bilateral involvement was seen in 10 patients. Most of the patients had no ocular symptoms. Ocular findings included, Retinal vasculitis 6 (22.22%); macular edema 4 (14.81%); vasculitis with macular edema 1 (3.7%); Retinitis 7 (25.92%); Papilloedema 6 (22.22%); Papilloedema with 6th cranial nerve palsy 1 (3.7%); Isolated 6th cranial nerve palsy 1 (3.7%) and optic neuritis 1 (3.7%). Ocular involvement was more common in double antigen group (68%) than spotted fever group (50%) or Scrub typhus group (21%) (P = 0.01). Ocular involvement was seen in 94% of the patients with CNS involvement. Cases with bilateral involvement (P = 0.01), pediatric age group (P = 0.01) and CNS involvement (P = 0.02) had poor visual outcome. Conclusion: Rickettsioses patients can have ocular manifestations with predominant posterior segment involvement during acute phase of illness. Ocular involvement was more common in the double antigen group. For any patient who presents with fever and rash living in endemic area, ophthalmic evaluation should be part of routine checkup during the acute phase of illness associated with less frequent ocular symptoms.

Halved Incidence of Scrub Typhus after Travel Restrictions to Confine a Surge of COVID-19 in Taiwan.

Scrub typhus is a rickettsial disease that is usually transmitted by mite exposure. Infected patients may present with a fever, fatigue, headache, and muscle pain. A blackish skin lesion, called eschar, is pathognomic. The mortality rate in untreated cases is high. The first case of scrub typhus in Taiwan was reported in 1908 during the Japanese colonization. In this article, using the National Infectious Disease Statistics System (NIDSS) from the Taiwan CDC, we analyzed the dynamic incidence of scrub typhus from 2016 to 2021, both seasonally and geographically. In addition, we asked whether the recent travel restrictions and social distancing policy in Taiwan (19 May to 27 July 2021), implemented due to the COVID-19 outbreak, would change the incidence of scrub typhus. The results showed that scrub typhus was most common in summer, with an incidence almost twofold greater than that in winter or spring. Most cases were identified in rural regions. Interestingly, there was a significant 52% reduction in the summer incidence in 2021, compared to the average summer incidence of the past 5 years. This reduction coincided with the countrywide lockdown measures and travel restrictions. The restricted measures for outdoor activities may have contributed to the reduced incidence of scrub typhus.

Clinical and biochemical profile of scrub typhus patients at a tertiary care hospital in Northern India.

BACKGROUND: Scrub typhus is a neglected rickettsial disease in India. Every year, we are facing outbreaks of Scrub typhus after Monsoon season. Patients present with a wide clinical spectrum ranging from pyrexia of unknown origin to multiple organ dysfunction. Some of these clinical features overlap with presentation of other tropical infections prevalent in Indian subcontinent, which leads to diagnostic dilemma and delay in diagnosis. Hence, we planned this study to know the demographic, clinical and biochemical profile of scrub typhus patients. METHODS: This was an observational study conducted in department of Medicine, King George's Medical University Lucknow, India a leading tertiary care hospital of Northern India. All scrub typhus patients were evaluated by detailed history, examination and laboratory tests. RESULTS: We enrolled 52 patients in our study. The mean age of the patients was 35.17 ± 16.90 years with majority (82.7%) of patients from rural background. All the patients had fever with an average duration of 9.6 ± 2 days. Most of the patients developed hepatitis (69.2%) followed by acute encephalitis syndrome (47%), acute kidney injury (23.1%) and acute respiratory failure (19.2%). Eschar was found in 11 patients (21.2%). CONCLUSION: Scrub typhus is often misdiagnosed or diagnosed late due to its wide clinical spectrum overlapping with clinical presentation of other commonly prevalent tropical diseases. One should always consider the differential diagnosis of scrub typhus while evaluating a young febrile patient of rural background, with features of single or multiple organ dysfunction and laboratory findings of leucocytosis, thrombocytopenia and elevation of transaminases.

Seroprevalence of scrub typhus, murine typhus and spotted fever groups in North Korean refugees.

OBJECTIVES: The aim of this study was to investigate the seroprevalence of antibodies against scrub typhus, murine typhus and spotted fever groups among North Korean refugees within 1 year of their arrival in South Korea. METHODS: We recruited North Korean refugees who had settled in South Korea after a short stay in a third country and did not have any health problems. The antibody titer was measured using a commercial indirect fluorescence assay immunoglobulin G antibody kit. RESULTS: The seroprevalence of antibodies against scrub typhus, murine typhus, and spotted fever groups among the 99 participants was 22.2%, 17.2%, and 10.1%, respectively, with 8.1% of participants testing positive for both spotted fever and murine typhus. CONCLUSIONS: Refugees may be exposed to rickettsial infections in North Korea and their journey from North Korea. This study is the first to report the seroprevalence of antibodies against the 3 common rickettsial diseases among North Korean refugees. The findings suggest that rickettsial infections should be added to the list of differential diagnoses for North Koreans with fever after entering South Korea.

Prompt defervescence after initiation of treatment for rickettsial infections - time to dispense with the dogma?

INTRODUCTION: Clinicians are commonly taught that if patients with suspected rickettsial disease have continuing fever after 48 hours of anti-rickettsial therapy, an alternative diagnosis is likely. METHODS: This retrospective study of patients hospitalised with scrub typhus and Queensland tick typhus (QTT) in tropical Australia, examined the time to defervescence after initiation of the patients' anti-rickettsial therapy. It also identified factors associated with delayed defervescence (time to defervescence >48 hours after antibiotic commencement). RESULTS: Of the 58 patients, 32 (56%) had delayed defervescence. The median (interquartile range (IQR)) age of patients with delayed defervescence was 52 (37-62) versus 40 (28-53) years in those who defervesced within 48 hours (p = 0.05). Patients with delayed defervescence were more likely to require Intensive Care Unit (ICU) admission than those who defervesced within 48 hours (12/32 (38%) versus 3/26 (12%), p = 0.02). Even among patients not requiring ICU care, patients with delayed defervescence required a longer hospitalisation than that those who defervesced within 48 hours (median (IQR): 6 (3-8) versus 3 (2-5) days, p = 0.006). CONCLUSIONS: A significant proportion of patients with confirmed scrub typhus and QTT will remain febrile for >48 hours after appropriate anti-rickettsial therapy. Delayed defervescence is more common in patients with severe disease.

Clinical characteristics and effective treatments of scrub typhus-associated hemophagocytic lymphohistiocytosis in children.

Hemophagocytic lymphohistiocytosis (HLH) is an uncommon and life-threatening disorder that may rarely complicate the clinical course of Orientia tsutsugamushi disease (scrub typhus). Here, we describe the clinical features, laboratory parameters, management, and outcome of 16 children with scrub typhus-associated HLH. All patients satisfied the HLH-2004 diagnostic criteria. All patients had fever of unknown origin and multisystem damage. Raised hepatic transaminases and abnormalities in routine blood test were observed in all children. Imaging tests showed abnormalities in 10 cases. Six patients were treated with intravenous azithromycin for 5 days, and 10 with intravenous chloramphenicol for 7-10 days because of non-response to 3-day azithromycin treatment. Five patients were treated with intravenous albumin and 3 with intravenous immunoglobulin. Two patients with severe symptoms (shortness of breath, cyanosis) were treated with dexamethasone (0.3 mg/kg/d). Fifteen patients recovered completely after 8-22 days of treatment. One patient died. The occurrence of severe complications draws attention to the need for early diagnosis and effective treatment. Anti-rickettsial antibiotic treatment (azithromycin or chloramphenicol) without the need for chemotherapy may be beneficial in such cases, instead of treatment according to the 2004 HLH protocol.

Inflammatory arthritis: a unique presentation of human anaplasmosis.

Human granulocytic anaplasmosis (HGA) is a tickborne rickettsial disease caused by the bacterium Anaplasma phagocytophilum. Reported cases have increased with the highest incidence in the Northeast. To our knowledge, this is the first report of anaplasmosis associated with an inflammatory arthritis. A 64-year-old man, with a history of Crohn's disease controlled on budesonide, presented to the emergency room in August 2017 with a week history of headache, sore throat, fever, myalgias, rash, and joint pain. There was no clinical evidence of active Crohn's disease. He lives in Nassau County and participates in outdoor activities. His exam was notable for a maculopapular rash over the trunk, arms, and thighs as well as synovitis of several proximal interphalangeal joints. Lab tests revealed transaminitis and elevated inflammatory markers. When evaluated by rheumatology, he had marked polyarthritis of wrists and hands as well as extremely painful motion of the shoulders, elbows, hips, knees, and ankles despite ibuprofen. Prednisone 20 mg daily resulted in significant improvement in his arthritis. Because of an Anaplasma phagocytophilum IgM of 1:320 (normal < 1:20; IgG < 1:64; normal < 1:64) that returned few weeks after presentation, he was prescribed 4 weeks of doxycycline. Convalescent Anaplasma serologies revealed negative IgM and IgG > 1:320. He fully recovered and was able to discontinue steroids. HGA presents acutely with a spectrum of manifestations ranging from a flu-like illness to severe complications such as respiratory failure. Myalgias and arthralgias are common, but an inflammatory arthritis has not been described.