mNGS helped diagnose scrub typhus-associated HLH in children: a report of two cases.

Background: Scrub typhus, caused by the Orientia tsutsugamushi (Ot), is a widespread vector-borne disease transmitted by chigger mites. Hemophagocytic lymphohistiocytosis (HLH) is considered to be one of the potentially severe complications. The diagnosis of scrub typhus-associated HLH may be overlooked due to the non-specific clinical characteristics and the absence of pathognomonic eschar. Case presentation: We obtained clinical data from two patients in the South of Sichuan, China. The first case involved a 6-year-old girl who exhibited an unexplained fever and was initially diagnosed with sepsis, HLH, and pulmonary infection. The other patient presented a more severe condition characterized by multiple organ dysfunction and was initially diagnosed with septic shock, sepsis, HLH, acute kidney injury (AKI), and pulmonary infection. At first, a specific examination for scrub typhus was not performed due to the absence of a characteristic eschar. Conventional peripheral blood cultures yielded negative results in both patients, and neither of them responded to routine antibiotics. Fortunately, the causative pathogen Orientia tsutsugamushi (Ot) was detected in the plasma samples of both patients using metagenomics next-generation sequencing (mNGS) and further confirmed by polymerase chain reaction. Subsequently, they both were treated with doxycycline and recovered quickly. Conclusion: The unbiased mNGS provided a clinically actionable diagnosis for an uncommon pathogen-associated infectious disease that had previously evaded conventional diagnostic approaches.

Spontaneous splenic rupture associated with scrub typhus: a case report.

BACKGROUND: Scrub typhus, an acute febrile disease with mild to severe, life-threatening manifestations, potentially presents with a variety of complications, including pneumonia, acute respiratory distress syndrome, cardiac arrhythmias (such as atrial fibrillation), myocarditis, shock, peptic ulcer, gastrointestinal bleeding, meningitis, encephalitis, and renal failure. Of the various complications associated with scrub typhus, splenic rupture has rarely been reported, and its mechanisms are unknown. This study reports a case of scrub typhus-related spontaneous splenic rupture and identifies possible mechanisms through the gross and histopathologic findings. CASE PRESENTATION: A 78-year-old man presented to our emergency room with a 5-day history of fever and skin rash. On physical examination, eschar was observed on the left upper abdominal quadrant. The abdomen was not tender, and there was no history of trauma. The Orientia tsutsugamushi antibody titer using the indirect immunofluorescent antibody test was 1:640. On Day 6 of hospitalization, he complained of sudden-onset left upper abdominal quadrant pain and showed mental changes. His vital signs were a blood pressure of 70/40 mmHg, a heart rate pf 140 beats per min, and a respiratory rate of 20 breaths per min, with a temperature of 36.8 °C. There were no signs of gastrointestinal bleeding, such as hematemesis, melena, or hematochezia. Grey Turner's sign was suspected during an abdominal examination. Portable ultrasonography showed retroperitoneal bleeding, so an emergency exploratory laparotomy was performed, leading to a diagnosis of hemoperitoneum due to splenic rupture and a splenectomy. The patient had been taking oral doxycycline (100 mg twice daily) for 6 days; after surgery, this was discontinued, and intravenous azithromycin (500 mg daily) was administered. No arrhythmia associated with azithromycin was observed. However, renal failure with hemodialysis, persistent hyperbilirubinemia, and multiorgan failure occurred. The patient did not recover and died on the fifty-sixth day of hospitalization. CONCLUSIONS: Clinicians should consider the possibility of splenic rupture in patients with scrub typhus who display sudden-onset abdominal pain and unstable vital signs. In addition, splenic capsular rupture and extra-capsular hemorrhage are thought to be caused by splenomegaly and capsular distention resulting from red blood cell congestion in the red pulp destroying the splenic sinus.

Identification of novel variants for complicating cardiac disease in the scrub typhus infection using whole genome sequencing.

BACKGROUND/AIMS: Scrub typhus infection has been known to complicate cardiovascular diseases mainly attributing to high mortality. Genetic susceptibility loci for complicating cardiac diseases such as atrial fibrillation, heart failure, and ischemic heart disease identified by genomic study have been limited in scrub typhus infection. Therefore, we investigated the genetic novel variants predicting complicating cardiac diseases in patients with confirmed scrub typhus infection using whole genome sequencing. METHODS: We performed a prospective study for eight consecutive patients with scrub typhus infection. During follow-up, six cases were clinically diagnosed with complicating cardiac diseases and two controls without complicating cardiac diseases. The whole genomes of the all patients were sequenced, and the individual sequence variants were compared between accordcase and control patients. Variant genotypes were compared and identified as a single nucleotide polymorphism (SNP) of the different genotype distributions between six cases and two controls. RESULTS: The GG genotype in SNP (rs4977397) of solute carrier 24 family member 2 (SLC24A2) gene and non-TT genotype in SNP (rs2676750) of adenosine deaminase, RNA specific, B2 (ADARB2) gene were distinctively found in the case patients with complicated cardiac disease, compared with control patents in the scrub typhus infection. CONCLUSION: We suggest that the SNPs of SLC24A2 and ADARB2 might be genetic surrogate markers for complicating cardiac diseases in the scrub typhus infection. Our study show that early detection based on individual sequence variants might be feasible to predict complicating cardiac diseases in patients with scrub typhus infection, if further studies with more participants confirm these findings.

Leukocytoclastic Vasculitis: A peculiar presentation of scrub typhus.

Scrub typhus is a disease endemic to the Indian subcontinent caused by the obligate intracellular pleomorphic organism, Orientia tsutsugamushi. Scrub typhus, among other acute febrile illnesses, manifests as prodromal symptoms of fever, malaise, myalgia and anorexia followed by a distinct maculopapular rash, hepatosplenomegaly and lymphadenopathy. We report the case of a patient presenting to tertiary care hospital in southern India in 2021 who developed a rare cutaneous vasculitis secondary to infection with Orientia tsutsugamushi. After performing the Weil-Felix test, a diagnostic titre of >1:640 against OXK was obtained. Furthermore, a skin biopsy was carried out which confirmed the diagnosis of leukocytoclastic vasculitis. The patient was treated with doxycycline and showed drastic improvement in his symptoms.

Neurological Manifestations of Scrub Typhus.

PURPOSE OF REVIEW: The occurrence of cases of scrub typhus is on the rise in South Asian and Southeast Asian countries. The present review discusses neurological complications following scrub typhus to appraise clinicians practicing in endemic regions about considering this treatable disease in the differential diagnosis of acute febrile illnesses, especially when accompanied with clinical neurological features. RECENT FINDINGS: While the association of aseptic meningitis, encephalitis, and meningoencephalitis with scrub typhus is well known, more recently described neurological syndromes associated with scrub typhus include acute disseminated encephalomyelitis, various cranial nerve palsies, cerebellitis, cerebrovascular diseases including cerebral venous sinus thrombosis, transverse myelitis, longitudinally extensive transverse myelitis, Guillain-Barré syndrome, opsoclonus-myoclonus syndrome, parkinsonism, and many more. Early diagnosis is key to successful treatment. While diagnostic confirmation is generally made by the detection of IgM antibody by either ELISA or indirect fluorescent antibody tests, conventional PCR using 56 kDa gene (cPCR) and loop-mediated isothermal amplification assay (LAMP assay), as well as a newly introduced metagenomic next-generation sequencing (mNGS), are currently available for detection of Orientia tsutsugamushi infection in clinically suspected cases. Scrub typhus is an acute febrile illness caused by Orientia tsutsugamushi. The cutaneous hallmark of the disease is the "eschar." Scrub typhus results in multisystem involvement. Neurological compromise is present in about 20% of scrub typhus patients and affects both the central nervous system and the peripheral nervous system. The postulated underlying mechanisms include direct invasion of the organism, a vasculitis-like process, or an immune-mediated injury. Diagnosis of scrub typhus is confirmed by detection of O. tsutsugamushi IgM antibody in serum. Awareness among clinicians regarding the varied presentations of this disease is very important in order to reduce morbidity and mortality. Co-infection with dengue and/or chickungunya viruses may occur in endemic regions. The history of an acute febrile illness preceding the neurological illness is crucial. A very careful search for the eschar is essential; however, the absence of the skin lesion cannot exclude the diagnosis of scrub typhus. Neurological manifestations mostly respond to doxycycline therapy.

Scrub typhus meningoencephalitis presenting as opsoclonus myoclonus syndrome: A video-based case.

Opsoclonus myoclonus syndrome secondary to scrub typhus infection is a rare clinical entity. Hence, it is important to know its clinical manifestations and complications, so that it can be properly managed. We report a 28-year-old female whose initial manifestation was only fever, which subsided in four days. Two days later, she developed opsoclonus myoclonus syndrome. This was managed with doxycycline and clonazepam, but as it persisted, intravenous immunoglobulin was added. She showed excellent response to treatment.

Association of leptospirosis and scrub typhus in acute encephalitis syndrome in a tertiary care hospital in Odisha, India.

BACKGROUND: Acute encephalitis syndrome (AES) is a major public health concern in India, causing febrile illness principally associated with viral infection. Bacteria-like scrub typhus and leptospirosis also cause acute febrile illness. Therefore, this study was conceived to address the possible etiological agents contributing to sporadic AES in a tertiary care center in Odisha, India. METHOD: This was a prospective hospital-based study that enrolled 92 consecutive patients with clinically diagnosed AES whose blood/cerebrospinal fluid samples were tested for IgM antibodies to dengue, Japanese encephalitis (JE), herpes simplex virus (HSV), Epstein-Barr virus (EBV), leptospirosis and scrub typhus. RESULTS: Viral antibodies to dengue were detected in three (3.26%) cases, HSV1 in four (4.34%) and HSV2 in three (3.26%) cases. Significantly, antibodies to EBV in 22 (23.591%) and to JE in 27 (29.34%) cases were detected. Notably, 30 (32.60%) and 11(12.0%) of patients had IgM antibodies to leptospirosis and scrub typhus, respectively. CONCLUSION: This observation indicates an association of leptospirosis and scrub typhus infection in sporadic cases of AES, besides other viruses.

Scrub typhus with secondary hemophagocytic lymphohistiocytosis in a 3-month-old child from a tertiary care hospital of Odisha.

Scrub typhus is one of the re-emerging infectious diseases in India, whereas hemophagocytic lymphohistiocytosis (HLH) results from an uncontrolled and ineffective hyperinflammatory response to a variety of triggers. HLH is categorized into primary and secondary type with infection being one of the leading causes of secondary HLH. Here, we report a case of 3-month-old girl diagnosed with scrub typhus associated with secondary HLH as both the age of presentation and the association are rarely reported in literature.

Scrub Typhus-Associated Hemophagocytic Lymphohistiocytosis: Not a Rare Entity in Pediatric Age Group.

BACKGROUND: Our goal was to study the demographic, clinical and laboratory profile and outcome of scrub typhus-associated hemophagocytic lymphohistiocytosis (HLH) in the pediatric age group. METHODS: We conducted a prospective observational study in a tertiary care teaching hospital over a period of 1 year. Children in the age group of 1 month to 12 years with IgM ELISA positive for scrub typhus were included in the study. HLH was diagnosed using HLH-2004 criteria. Demographic, clinical and laboratory profile, treatment and outcome of HLH patients were noted and also compared with non-HLH scrub typhus patients. RESULTS: Among 58 children with scrub typhus infection, 18 had HLH. The mean age of patients with HLH was 35.3 ± 44.8 months and 61% were male. Anemia, thrombocytopenia and hyperferritinemia were seen in all the patients. Hypertriglyceridemia, hypofibrinogenemia and coagulopathy were noted in 78%, 56% and 44%, respectively. All the patients were treated with intravenous doxycycline for an average duration of 9.5 days. Intravenous immunoglobulin and methylprednisolone were given in 33% and 22% cases, respectively. Complications like acute respiratory distress syndrome (ARDS) (p = 0.001) and MODS (p = 0.004) were significantly high in the HLH group. Younger age (<3 years), fever > 7 days, presence of convulsion, ARDS and MODS were the clinical predictors of scrub typhus-associated HLH. CONCLUSION: HLH in scrub typhus infected children is being increasingly recognized. Younger age, prolonged fever, presence of convulsion, ARDS and MODS should alert clinicians of the risk of HLH. Treating the primary cause usually cures the disease and immunomodulator therapy need not be routinely administered.

Application of Extracorporeal Membrane Oxygenation in Patients with Scrub Typhus Complicated with Acute Respiratory Distress Syndrome.

A 68-year-old woman was diagnosed with scrub typhus and acute pneumonia. Acute respiratory distress syndrome (ARDS) occurred on day 4 after admission and was treated with extracorporeal membrane oxygenation (ECMO). After 7 days of ECMO assistance, her respiratory condition gradually improved, and ECMO was removed. On day 20 after admission, she was discharged without any sequelae. The results suggest that ECMO should be considered as early as possible for patients with ARDS caused by scrub typhus.

Scrub typhus as a rare cause of acute pyelonephritis: case report.

BACKGROUND: Scrub typhus can present with atypical signs and symptoms such as those of acute kidney injury, gastroenteritis, pneumonitis, and acute respiratory distress syndrome. Meningitis, encephalitis, and hepatic dysfunction have also been reported, particularly in severe cases with multisystem involvement. Scrub typhus has never been reported in the literature to cause urinary tract infections (UTIs) which includes cystitis and pyelonephritis. CASE PRESENTATION: A 45-year old male presenting to the outpatient unit with fever, right flank pain, and burning micturition for three days was initially treated for UTI. However, he returned to the hospital on the fourth day of illness with persistent symptoms. He was hospitalized, with intravenous (IV) ceftriaxone. Computerized tomography scan of his abdomen-pelvis showed features of acute pyelonephritis, so his antibiotics were upgraded to meropenem and teicoplanin. Despite this, the patient's condition deteriorated. Laboratory investigations showed multisystem involvement: decreasing platelets, raised creatinine, and deranged liver panel. As Kathmandu was hit by dengue epidemic during the patient's hospitalization, on the seventh day of his illness, blood samples were sent for tropical fever investigation. All tests came out negative except for scrub typhus-IgM antibodies positive on rapid diagnostic test. The patient's symptoms subsided after 48 h of starting doxycycline and he became fully asymptomatic four days later. Fever did not recur even after discontinuing other IV antibiotics, favoring scrub typhus disease rather than systemic bacterial sepsis. CONCLUSIONS: Scrub typhus is an emerging infectious disease of Nepal. Therefore, every unexplained fever cases (irrespective of clinical presentation) should be evaluated for potential Rickettsiosis. Moreover, for cases with acute pyelonephritis, atypical causative agents should be investigated, for example scrub typhus in this case.

Scrub typhus cholecystitis.

Acute acalculous cholecystitis is usually seen in association with systemic medical illness, or after surgery, trauma or burn and is considered as a more severe disease than acute calculous cholecystitis. We recently had the opportunity of observing a patient who was admitted in a surgical emergency with clinical features of acute cholecystitis and was found to have Orientia tsutsugamushi infection after a strong clinical suspicion of acute tropical fever illness.

Acute transverse myelitis following scrub typhus: A case report and review of the literature.

Context: Scrub typhus is an acute febrile disease caused by Orientia tsutsugamushi. The disease can usually involve the lungs, heart, liver, spleen and brain through hematogenous dissemination. However, very rarely, acute transverse myelitis in the spinal cord develops from scrub typhus. We present a case of acute transverse myelitis following scrub typhus with a review of the literature. Findings: A 66-year-old male visited a hospital for general myalgia, mild headache, and fever in October. He was noted to have thick, black papule skin on his abdomen, which was highly suggestive of scrub typhus. To confirm the diagnosis, O. tsutsugamushi antibody titers were examined and detected highly in serum by an indirect fluorescence antibody assay. Doxycycline, the standard treatment for scrub typhus, was administered. However, after seven days of treatment, he rapidly developed weakness in the right leg, paresthesia in both lower limbs, and voiding difficulty. Spinal magnetic resonance imaging (MRI) revealed lesions with high signal intensity involving the spinal cord at the thoracolumbar junction. Paraparesis gradually improved following steroid pulse therapy for five days. At one-year follow-up, he could walk without cane. Conclusions:Orientia tsutsugamushi causes scrub typhus, which can affect not only the brain, but also the spinal cord. Although acute transverse myelitis develops rarely from scrub typhus, this should be considered as differential diagnosis in patients of fever with neurological deficit in endemic areas.

Misdiagnosis of scrub typhus complicated by hemophagocytic syndrome.

BACKGROUND: This study sought to analyze the cases of clinical misdiagnosis of scrub typhus complicated by hemophagocytic syndrome. METHODS: We retrospectively reviewed the medical records for diagnoses, clinical course, chest X-ray findings, laboratory data, and antibiotic therapy. RESULTS: All nine patients were misdiagnosed at the outpatient department between 07/2009 and 07/2017. They were diagnosed with septicemia and hemophagocytic syndrome, sepsis and hemophagocytic syndrome, severe infection, hepatitis and hemophagocytic syndrome, or upper respiratory tract infection. Among the nine patients, hepatic function examination showed decreased albumin and elevated C-reactive protein levels in all patients; alanine aminotransferase was increased and platelets were decreased in eight patients. Weil-Felix reaction was positive in three of nine patients. Indirect immunofluorescence demonstrated positive IgM antibody and EB virus-IgM in all nine patients; Mycoplasma pneumoniae antibody was positive in seven patients. All nine patients underwent chest computed tomography; no abnormality was found in two patients. Patch shadow with increased density was found in seven patients, including four patients with right pleural effusion and two with bilateral pleural effusion. Bone marrow biopsy was performed in all nine patients and hemophagocytic cells were seen. The nine misdiagnosed cases were given multiple broad-spectrum antibiotics either successively or concomitantly before and after admission, but no effective antibiotics against Orientis tsutsugamushi were applied. After diagnosis was corrected to scrub typhus, five patients were switched to chloramphenicol and dexamethasone, two patients were given azithromycin and dexamethasone, and two patients were treated with chloramphenicol. Body temperature returned to normal within 2-3 days and the children were quickly relieved from their condition. CONCLUSION: Hemophagocytic syndrome may be the presenting clinical feature of scrub typhus and initially mask the disease. Initial misdiagnosis is common and includes septicemia and hemophagocytic syndrome. The eschar is a useful diagnostic clue and febrile patients without any localizing signs should be thoroughly examined for its presence.

Hemophagocytic lymphohistiocytosis with neurological manifestations in an infant with scrub typhus: a rare fatal occurrence.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of unchecked activation of the immune system leading to phagocytosis of blood cells and proliferation of histiocytes in solid organs. HLH can be primary or secondary to infective, autoimmune and malignant conditions. Scrub typhus is an infective illness caused by Orientia tsutsugamushi, transmitted by mite. The illness ranges from mild fever with rash to severe multisystem illness. Scrub typhus has rarely been associated with secondary HLH. We report an infant with scrub typhus who progressed to develop HLH with central nervous system involvement with fatal outcome.

Emergence of Orientia tsutsugamushi as an important cause of Acute Encephalitis Syndrome in India.

BACKGROUND: Acute Encephalitis Syndrome (AES) is a major seasonal public health problem in Bihar, India. Despite efforts of the Bihar health department and the Government of India, burden and mortality of AES cases have not decreased, and definitive etiologies for the illness have yet to be identified. OBJECTIVES: The present study was undertaken to study the specific etiology of AES in Bihar. METHODS: Cerebrospinal fluid and/or serum samples from AES patients were collected and tested for various pathogens, including viruses and bacteria by ELISA and/or Real Time PCR. FINDINGS: Of 540 enrolled patients, 33.3% (180) tested positive for at least one pathogen of which 23.3% were co-positive for more than one pathogen. Most samples were positive for scrub typhus IgM or PCR (25%), followed by IgM positivity for JEV (8.1%), WNV (6.8%), DV (6.1%), and ChikV (4.5%).M. tuberculosis and S. pneumoniae each was detected in ~ 1% cases. H. influenzae, adenovirus, Herpes Simplex Virus -1, enterovirus, and measles virus, each was detected occasionally. The presence of Scrub typhus was confirmed by PCR and sequencing. Bihar strains resembled Gilliam-like strains from Thailand, Combodia and Vietnam. CONCLUSION: The highlights of this pilot AES study were detection of an infectious etiology in one third of the AES cases, multiple etiologies, and emergence of O. tsutsugamushi infection as an important causative agent of AES in India.

Endoscopic characteristics of infection-associated peptic ulcers.

BACKGROUND: Aside from Helicobacter pylori, another cause for the development or worsening of gastrointestinal ulcers is scrub typhus, an acute febrile disease caused by Orientia tsutsugamushi. We aimed to compare the endoscopic characteristics of peptic ulcers caused by these infectious agents. METHODS: This retrospective case-control study involved patients who underwent upper gastrointestinal endoscopy at Chosun University Hospital in Korea. We compared endoscopic features and demographic characteristics between patients with H. pylori infection and those with O. tsutsugamushi infection. RESULTS: A total of 141 patients with peptic ulcer were included in the study. Compared to patients with O. tsutsugamushi infection (n = 62; age, 63.8 ± 12.1 years; male sex, 42%), those with H. pylori infection (n = 79; age, 53.0 ± 14.8 years; male sex, 81%) were younger and more likely to be male (P < .001 for both). Patients with O. tsutsugamushi infection were more likely to have multiple lesions (40/62, 64.5% vs 37/79, 46.8%; P = .042) and irregular-shaped lesions (27/62, 43.6% vs 20/79, 25.3%; P = .031). Patients with H. pylori infection had higher incidence of hemorrhagic ulcers (26/79, 32.9% vs 8/62, 12.9%; P = .007), and lesions occurred most often in the duodenum (43.0%), followed by the antrum (36.7%), body (34.2%), and angle (12.7%) of the stomach. In patients with O. tsutsugamushi infection, lesions occurred most often in the antrum (70.97%), followed by the duodenum (35.5%), body (22.6%), and angle (14.5%) of the stomach. In both groups, gastric ulcer lesions occurred most often in the antrum, followed by the body and angle of the stomach (36.7% vs 70.97%, 34.2% vs 22.6%, and 12.7% vs 14.5% for gastric ulcers associated with H. pylori and O. tsutsugamushi infection, respectively). Patients with O. tsutsugamushi infection had significantly higher incidence of ulcers on the antrum (70.97% vs 36.7%, P < .001) and the greater curvature (45.2% vs 24.0%, P = .012). Finally, 35.5% of patients with gastric ulcer caused by scrub typhus also had duodenal ulcer. CONCLUSION: This is the first study to compare endoscopic features of peptic ulcers caused by H. pylori and O. tsutsugamushi. Peptic ulcers in patients with H. pylori infection occurred predominantly in the antrum/body/lesser curvature and presented with single, round/oval lesions, while ulcers in patients with scrub typhus occurred predominantly in the antrum/greater curvature and presented with multiple, irregular lesions. Scrub typhus should be considered as a cause of duodenal ulcer in scrub typhus-endemic areas.

Clinical significance of NGAL and KIM-1 for acute kidney injury in patients with scrub typhus.

BACKGROUND: The aim of this study is to investigate the clinical significance of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) for acute kidney injury (AKI) in patients with scrub typhus. METHODS: From 2014 to 2015, 145 patients were diagnosed with scrub typhus. Of these, we enrolled 138 patients who were followed up until renal recovery or for at least 3 months. We measured serum and urine NGAL and KIM-1 levels and evaluated prognostic factors affecting scrub typhus-associated AKI. RESULTS: Of the 138 patients, 25 had scrub typhus-associated AKI. The incidence of AKI was 18.1%; of which 11.6%, 4.3%, and 2.2% were classified as risk, injury, and failure, respectively, according to RIFLE criteria. Compared with patients in the non-AKI group, patients in the AKI group were older and showed higher total leukocyte counts and hypoalbuminemia or one or more comorbidities such as hypertension (72% vs 33%, p<0.01), diabetes (40% vs 14%, p<0.01), or chronic kidney disease (32% vs 1%, p<0.01). In addition, serum NGAL values (404± 269 vs 116± 78 ng/mL, P<0.001), KIM-1 values (0.80± 0.52 vs 0.33± 0.68 ng/mL, P<0.001), urine NGAL/creatinine values (371± 672 vs 27± 39 ng/mg, P<0.001) and urine KIM-1/creatinine values (4.04± 2.43 vs 2.38± 1.89 ng/mg, P<0.001) were higher in the AKI group than in the non-AKI group. By multivariate logistic regression, serum NGAL and the presence of chronic kidney disease were significant predictors of AKI. CONCLUSION: Serum NGAL might be an additive predictor for scrub typhus-associated AKI.