Correlation between rainfall and the prevalence of scrub typhus: an observation from a tropical endemic country / Correlación entre las precipitaciones y la prevalencia del tifus de matorral: una observación de un país endémico para enfermedades tropicales

The effect of climatological parameter on infectious disease is an interesting issue in clinical epidemiology. Of several parameters, rainfall is reported for its interrelationship with many tropical diseases such as malaria. In this short communication, the authors report the observation on correlation between rainfall and the prevalence of scrub typhus from a tropical endemic country.

El efecto del parámetro climatológico en las enfermedades infecciosas es un tema interesante en la epidemiología clínica. De varios parámetros, se reportan precipitaciones por su interrelación con muchas enfermedades tropicales como el paludismo. En esta breve comunicación, los autores informan de la observación sobre la correlación entre las precipitaciones y la prevalencia del tifus de matorral de un país endémico tropical.

Surveillance of Chigger Mite Vectors for Tsutsugamushi Disease in the Hwaseong Area, Gyeonggi-do, Republic of Korea, 2015.

Owing to global climate change, the global resurgence of vector-borne infectious diseases and their potential to inflict widespread casualties among human populations has emerged as a pivotal burden on public health systems. Tsutsugamushi disease (scrub typhus) in the Republic of Korea is steadily increasing and was designated as a legal communicable disease in 1994. The disease is a mite-borne acute febrile disease most commonly contracted from October to December. In this study, we tried to determine the prevalence of tsutsugamushi disease transmitted by chigger mites living on rodents and investigated their target vector diversity, abundance, and distribution to enable the mapping of hotspots for this disease in 2015. A total of 5 species belonging to 4 genera (109 mites): Leptotrombidium scutellare 60.6%, L. pallidum 28.4% Neotrombicula tamiyai 9.2%, Euschoengastia koreaensis/0.9%), and Neoschoengastia asakawa 0.9% were collected using chigger mite collecting traps mimicking human skin odor and sticky chigger traps from April to November 2015. Chigger mites causing tsutsugamushi disease in wild rodents were also collected in Hwaseong for the zoonotic surveillance of the vector. A total of 77 rodents belonging to 3 genera: Apodemus agrarius (93.5%), Crocidura lasiura (5.2%), and Micromys minutus (1.3%) were collected in April, October, and November 2015. The most common mite was L. pallidum (46.9%), followed by L. scutellare (18.6%), and L. orientale (18.0%). However, any of the chigger mite pools collected from rodent hosts was tested positive for Orientia tsutsugamushi, the pathogen of tsutsugamushi disease, in this survey.

Risk Factors for Scrub Typhus, Murine Typhus, and Spotted Fever Seropositivity in Urban Areas, Rural Plains, and Peri-Forest Hill Villages in South India: A Cross-Sectional Study.

Scrub typhus and spotted fever group rickettsioses are thought to be common causes of febrile illness in India, whereas they rarely test for murine typhus. This cross-sectional study explored the risk factors associated with scrub typhus, tick-borne spotted fever, and murine typhus seropositivity in three different geographical settings, urban, rural, and hill villages in Tamil Nadu, South India. We enrolled 1,353 participants living in 48 clusters. The study included a questionnaire survey and blood sampling. Blood was tested for Orientia tsutsugamushi (scrub typhus), Rickettsia typhi (murine typhus), and spotted fever group Rickettsia IgG using ELISA. The seroprevalence of scrub typhus, spotted fever, and murine typhus were 20.4%, 10.4%, and 5.4%, respectively. Scrub typhus had the highest prevalence in rural areas (28.1%), and spotted fever was most common in peri-forested areas (14.9%). Murine typhus was more common in rural (8.7%) than urban areas (5.4%) and absent in peri-forested hill areas. Agricultural workers had a higher relative risk for scrub typhus, especially in urban areas. For murine typhus, proximity to a waterbody and owning a dog were found to be major risk factors. The main risk factors for spotted fever were agricultural work and living in proximity to a forest. Urban, rural plains, and hill settings display distinct epidemiological pattern of Orientia and rickettsial infections. Although scrub typhus and spotted fever were associated with known risk factors in this study, the findings suggest a different ecology of murine typhus transmission compared with other studies conducted in Asia.

Dengue, chikungunya, and scrub typhus are important etiologies of non-malarial febrile illness in Rourkela, Odisha, India.

BACKGROUND: We conducted a diagnostic surveillance study to identify Plasmodium, dengue virus, chikungunya virus, and Orientia tsutsugamushi infections among febrile patients who underwent triage for malaria in the outpatient department at Ispat General Hospital, Rourkela, Odisha, India. METHODS: Febrile patients were enrolled from January 2016-January 2017. Blood smears and small volumes or vacutainers of blood were collected from study participants to carry out diagnostic assays. Malaria was diagnosed using rapid diagnostic tests (RDT), microscopy, and PCR. Dengue, chikungunya, and scrub typhus infections were identified using rapid diagnostic test kits and ELISA. RESULTS: Nine hundred and fifty-four patients were prospectively enrolled in our study. The majority of patients were male (58.4%) and more than 15 years of age (66.4%). All 954 enrollees underwent additional testing for malaria; a subset of enrollees (293/954) that had larger volumes of plasma available was also tested for dengue, chikungunya and scrub typhus by either RDT or ELISA or both tests. Fifty-four of 954 patients (5.7%) were positive for malaria by RDT, or microscopy, or PCR. Seventy-four of 293 patients (25.3%) tested positive for dengue by either RDT or ELISA, and 17 of 293 patients (5.8%) tested positive for chikungunya-specific IgM by either ELISA or RDT. Ten of 287 patients tested (3.5%) were positive for scrub typhus by ELISA specific for scrub typhus IgM. Seventeen patients among 290 (5.9%) with results for ≥3 infections tested positive for more than one infection. Patients with scrub typhus and chikungunya had high rates of co-infection: of the 10 patients positive for scrub typhus, six were positive for dengue (p = 0.009), and five of 17 patients positive for chikungunya (by RDT or ELISA) were also diagnosed with malaria (p < 0.001). CONCLUSIONS: Dengue, chikungunya and scrub typhus are important etiologies of non-malarial febrile illness in Rourkela, Odisha, and comorbidity should be considered. Routine febrile illness surveillance is required to accurately establish the prevalence of these infections in this region, to offer timely treatment, and to implement appropriate methods of control.

Risk Factors for Acquiring Scrub Typhus among Children in Deoria and Gorakhpur Districts, Uttar Pradesh, India, 2017.

Scrub typhus is associated with outbreaks of acute encephalitis syndrome in Uttar Pradesh, India. A case-control study indicated that children residing, playing, or visiting fields; living with firewood stored indoors; handling cattle fodder; and practicing open defecation were at increased risk for scrub typhus. Communication messages should focus on changing these behaviors.

Scrub typhus re-emergence in India: Contributing factors and way forward.

Scrub typhus is a mite borne infectious disease which has re-emerged in India in the 3rd millennium after years of quiescence. In this review, the authors hypothesize the various factors responsible for resurgence of this disease. The main drivers that could have contributed to the upsurge in scrub typhus cases in past two decades are changes in land use land cover (LULC) and urbanisation which are; as a result of the population explosion, causing a strain on sanitation and also increased diversion of forest land for agricultural use. In addition, the availability of better tests, changes in antimicrobial use, climate change also could have impacted the epidemiology, which is showing an upward trend as is evidenced by increasing reports and concomitant publications from India on scrub typhus. Scrub typhus cases are supposed to increase in the coming years as factors like global warming, urbanisation, changes in LULC and rise in AMR (anti-microbial resistance) will be difficult or impossible to control. Therefore, increasing awareness of public and health care professionals regarding scrub typhus coupled with availability of rapid diagnostic assays and implementation of appropriate treatment protocols for control of AFI (acute febrile illness) especially at the community level will help mitigate the scenario in the long run.

Prevalence and risk factors for scrub typhus in South India.

OBJECTIVE: To determine the prevalence and risk factors of scrub typhus in Tamil Nadu, South India. METHODS: We performed a clustered seroprevalence study of the areas around Vellore. All participants completed a risk factor survey, with seropositive and seronegative participants acting as cases and controls, respectively, in a risk factor analysis. After univariate analysis, variables found to be significant underwent multivariate analysis. RESULTS: Of 721 people participating in this study, 31.8% tested seropositive. By univariate analysis, after accounting for clustering, having a house that was clustered with other houses, having a fewer rooms in a house, having fewer people living in a household, defecating outside, female sex, age >60 years, shorter height, lower weight, smaller body mass index and smaller mid-upper arm circumference were found to be significantly associated with seropositivity. After multivariate regression modelling, living in a house clustered with other houses, female sex and age >60 years were significantly associated with scrub typhus exposure. CONCLUSIONS: Overall, scrub typhus is much more common than previously thought. Previously described individual environmental and habitual risk factors seem to have less importance in South India, perhaps because of the overall scrub typhus-conducive nature of the environment in this region.

The clinical characteristics of pleural effusion in scrub typhus.

BACKGROUND: The aim of this study is to identify the factors associated with the occurrence of pleural effusion and to investigate the characteristics of pleural effusion in scrub typhus. METHODS: We conducted a retrospective analysis of the medical records of scrub typhus patients between January 2004 and December 2011 at Chosun University Hospital in South Korea. A total of 445 scrub typhus patients were divided into the following two groups: without (n = 352) or with pleural effusion (n = 93). The data of 18 scrub typhus patients who underwent thoracentesis were summarized. RESULTS: Multivariate analysis demonstrated that the following factors were associated with the occurrence of pleural effusion in scrub typhus: older age (odds ratio [OR] = 1.029, P = 0.037, confidence interval [CI] = 1.002-1.056); male gender (OR = 1.924, P = 0.020, CI = 1.109-3.340); presence of heart failure (OR = 2.628, P = 0.039, CI = 1.052-6.565); and lower albumin (OR = 0.107, P ≤ 0.001, CI = 0.058-0.196). Most pleural effusion presentations were bilateral (88 %) and small (91 %). The effusion had transudate characteristics in 7 patients and exudate characteristics in 11 patients based on Light's criteria. CONCLUSIONS: This study provided the first data regarding the following four independent risk factors associated with the occurrence of pleural effusion: older age; male gender; the presence of heart failure; and lower albumin. The pleural effusion presentations in scrub typhus patients were bilateral and small in most cases, with transudate and/or exudate characteristics.

Etiologies of acute undifferentiated fever and clinical prediction of scrub typhus in a non-tropical endemic area.

Scrub typhus usually presents as acute undifferentiated fever. This cross-sectional study included adult patients presenting with acute undifferentiated fever defined as any febrile illness for ≤ 14 days without evidence of localized infection. Scrub typhus cases were defined by an antibody titer of a ≥ fourfold increase in paired sera, a ≥ 1:160 in a single serum using indirect immunofluorescence assay, or a positive result of the immunochromatographic test. Multiple regression analysis identified predictors associated with scrub typhus to develop a prediction rule. Of 250 cases with known etiology of acute undifferentiated fever, influenza (28.0%), hepatitis A (25.2%), and scrub typhus (16.4%) were major causes. A prediction rule for identifying suspected cases of scrub typhus consisted of age ≥ 65 years (two points), recent fieldwork/outdoor activities (one point), onset of illness during an outbreak period (two points), myalgia (one point), and eschar (two points). The c statistic was 0.977 (95% confidence interval = 0.960-0.994). At a cutoff value ≥ 4, the sensitivity and specificity were 92.7% (79.0-98.1%) and 90.9% (86.0-94.3%), respectively. Scrub typhus, the third leading cause of acute undifferentiated fever in our region, can be identified early using the prediction rule.

Comparative proteomic analysis of antibiotic-sensitive and insensitive isolates of Orientia tsutsugamushi.

Scrub typhus, caused by infection with Orientia tsutsugamushi, is probably the most common severe rickettsial disease. Early diagnosis followed by treatment with antibiotics such as doxycycline or chloramphenicol usually quickly decreases fever in patients, and they often recover well from other symptoms of the disease. However, poorly responsive cases have been reported from northern Thailand and southern India. In order to identify protein factors that may be partially responsible for differential drug sensitivity of isolates of Orientia, we compared the protein profiles of doxycycline sensitive (Karp) versus (vs.) insensitive (AFSC4 and AFSC7) isolates. Tryptic peptides from both total water-soluble proteins and from protein spots separated by 2D-PAGE were analyzed using LC-MS/MS. The identity of each protein was established using the published genomic sequence of Boryong strain O. tsutsugamushi. The profiles of protein released into water from these isolates were quite different. There were 10 proteins detected only in AFSC4, 3 only in Karp, and 1 only in AFSC7. Additionally, there were 2 proteins not detected only in AFSC4, 4 not found only in Karp, and 3 not found only in AFSC-7. A comparison of 2D-PAGE protein profiles of drug sensitive strain versus (vs.) insensitive isolates has led to the identification of 14 differentially expressed or localized proteins, including elongation factor Ts and Tu, DNA-directed RNA polymerase alpha-subunit, ATP synthase beta-subunit, and several hypothetical proteins. These data confirm the tremendous proteomic diversity of isolates of Orientia and suggest that drug insensitivity in this species may arise from multiple mechanisms.

Chemokine and cytokine production in susceptible C3H/HeN mice and resistant BALB/c mice during Orientia tsutsugamushi infection.

To understand the pathogenesis of scrub typhus, we examined chemokine and cytokine production in susceptible (C3H/HeN) and resistant (BALB/c) mice after infection with O. tsutsugamushi Gilliam. C3H/HeN mice produced high levels of chemokines macrophage inflammatory proteins 1 alpha (MIP-1 alpha ), MIP-2, monocyte chemoattractant protein 1 (MCP-1), and cytokines gamma-interferon (IFN-gamma ), interleukin-12 (IL-12), IL-10, and tumor necrosis factor alpha (TNF-alpha ) in response to O. tsutsugamushi infection, compared to BALB/c mice. Chemokine profiles in infected mice correlated well with the kinetics of inflammatory cell infiltration. Hyperproduction of chemokines and cytokines was observed in another susceptible-infection model (BALB/c-Karp). These results suggest that hyperproduction of chemokines and cytokines are associated with susceptibility during O. tsutsugamushi infection.

Chemokine and cytokine production during Orientia tsutsugamushi infection in mice.

Orientia tsutsugamushi, an obligate intracellular bacterium, is the causative agent of scrub typhus which is histopathologically characterized by inflammatory manifestations, indicating that rickettsiae induce mechanisms that amplify the inflammatory response. To understand the pathogenesis of scrub typhus, we examined chemokine and cytokine production after infection with O. tsutsugamushi in mice. The mRNAs that were upregulated included lymphotactin, RANTES (regulated upon activation, normal T-cell expressed and secreted), macrophage inflammatory proteins 1alpha/beta (MIP-1alpha/beta), MIP-2, monocyte chemoattractant protein 1, lymphotoxin beta, tumor necrosis factor alpha, interleukin-6, gamma-interferon, transforming growth factor beta1, and migration inhibition factor. Peak expression of these chemokines and cytokines was observed between 4 and 8 days after infection. Gene induction was followed by the secretion of chemokine and cytokine proteins. Chemokine profile in infected mice was well correlated with kinetics of inflammatory cell infiltration. Thus, O. tsutsugamushi appears to be a strong inducer of chemokines and cytokines which may, by the attraction and activation of phagocytic leukocytes, significantly contribute to inflammation observed in scrub typhus.

Induction of the gene encoding macrophage chemoattractant protein 1 by Orientia tsutsugamushi in human endothelial cells involves activation of transcription factor activator protein 1.

Human macrophage chemoattractant protein 1 (MCP-1) is a potent mediator of macrophage migration and therefore plays an essential role in early events of inflammation. In endothelial cells, at least three independent pathways regulate MCP-1 expression by NF-kappaB and AP-1. Orientia tsutsugamushi causes vasculitis in humans by replicating inside macrophages and endothelial cells. In the present study, we investigated the cis-acting and trans-acting elements involved in O. tsutsugamushi-induced MCP-1 gene expression in human umbilical vein endothelial cells (HUVEC). Although NF-kappaB activation was observed in HUVEC infected with O. tsutsugamushi, inhibition of NF-kappaB activation did not affect the MCP-1 expression. However, treatment of HUVEC with extracellular signal-regulated kinase (ERK) kinase inhibitor or p38 mitogen-activated protein kinase (MAPK) inhibitor suppressed expression of MCP-1 mRNA concomitant with downregulation of activator protein 1 (AP-1) activation. Deletion of triphorbol acetate response elements (TRE) at position -69 to -63 of MCP-1 gene abolished inducible promoter activity. Deletion of TRE at position -69 to -63-96 to -90 or deletion of NF-kappaB-binding site at position -69 to -63-88 to -79 did not affect the inducibility of promoter. Site-directed mutagenesis of the NF-kappaB binding sites at positions -2640 to -2632, -2612 to -2603 in the enhancer region, or the AP-1 biding site at position -2276 to -2270 decreased the inducible activity of the promoter. Taken together, AP-1 activation by both the ERK pathway and the p38 MAPK pathway as well as their binding to TRE at position -69 to -63 in proximal promoter and TRE at position -2276 to -2270 in enhancer region is altogether essential in induction of MCP-1 mRNA in HUVEC infected with O. tsutsugamushi. Although NF-kappaB activation is not essential per se, the kappaB site in the enhancer region is important in MCP-1 induction of HUVEC. This discrepancy in the involvement of the NF-kappaB may be due to the function of chromatin structures and other transcription cofactors in the regulation of MCP-1 gene expression in response to O. tsutsugamushi infectioin.

An unusual site of chigger bite in a patient with scrub typhus.

A 70-year-old female farmer was admitted to the hospital because of fever, headache, and diarrhea for 7 days. Hypotension, right-sided pleural effusion with respiratory distress and leukocytosis were noted. She was initially treated as systemic bacterial infection by i.v. administration of ampicillin/sulbactam and amikacin. Because fever persisted in spite of aggressive treatment, a repeat thorough physical examination was done. An eschar was found over the left-sided labium majus and an enlarged lymph node was noted over the left inguinal region. Under the impression of scrub typhus, minocycline was administered. The patient's clinical condition improved dramatically within 3 days. The diagnosis was later confirmed by a serologic test for Rickettsia tsutsugamushi.

[Tsutsugamushi fever. Rare rickettsiosis after a stay in the Philippines]. / Tsutsugamushi-Fieber. Seltene Rickettsiose nach Aufenthalf auf den Philippinen.

HISTORY AND CLINICAL FINDINGS: After returning to his native Germany from a holiday in the Philippines a 37-year-old man was admitted because of high fever, cervical lymphadenopathy, pharyngitis and conjunctivitis, transient skin rash, nausea and vomiting, leukocytosis with shift to the left, atypical lymphocytes, as well as increased transaminases, LDH and cholestasis-indicating enzymes. INVESTIGATIONS: Stool, sputum and urine cultures were negative. The chest radiogram showed bilateral mild interstitial infiltration. Antibody titres against Rickettsia tsutsugamushi were markedly raised (IgG 1:128, IgM 1:2048). DIAGNOSIS, TREATMENT AND COURSE: Empirical antibiotic treatment with ciprofloxacin (200 mg twice daily intravenously) had no effect. As the mild signs of interstitial pneumonia progressed, clarithromycin (500 mg twice daily orally) was substituted with rapid fall in fever and gradual improvement. Tsutsugamushi infection was diagnosed serologically and the antibiotic changed to doxycycline (100 mg twice daily orally), continued for 14 days. Full remission occurred. CONCLUSIONS: Tsutsugamushi fever should be included in the differential diagnosis if, in addition to a history of a visit to an endemic area, there is the clinical triad of skin necrosis at the site of a mite bite, regional lymphadenopathy and skin rash (in this case, no skin lesion). The infection can be lethal without adequate treatment. Tetracyclines and possibly also macrolide antibiotics are effective against the causative organism.

Increased levels of macrophage colony-stimulating factor, gamma interferon, and tumor necrosis factor alpha in sera of patients with Orientia tsutsugamushi infection.

Levels of macrophage colony-stimulating factor (nine of nine patients) and gamma interferon (six of nine patients) in serum were elevated above the range of normal in the acute phase of tsutsugamushi disease. Significant increases in levels of tumor necrosis factor alpha were observed during the convalescent phase in five patients, and they exceeded the levels observed during the acute phase. Hypercytokinemia appeared to be responsible for the emergence of the symptoms of tsutsugamushi disease.

Transmission of scrub typhus by needlestick from a patient receiving pefloxacin.

A nurse experience a needlestick during the care of a patient with scrub typhus, treated with pefloxacin (400 mg twice daily) and cefazolin. Seven days after the needlestick, pain and erythematous swelling developed at the tip of her left fourth finger, the site of the needlestick. Fever and headache developed 10 days later, and her skin lesion became a small vesicle surrounded by a dark erythematous area. The diagnosis of scrub typhus was made by a rising indirect immunofluorescent antibody titre, and her illness was improved with doxycycline.

Life-threatening scrub typhus in a traveler returning from Thailand.

Scrub typhus is not one of the more commonly encountered diseases in travelers returning from Asia, but it deserves more consideration in view of its severity and the availability of specific chemotherapy and chemoprophylaxis. We describe a case of scrub typhus that was associated with coma and multiorgan failure in a traveler returning to the United States from Thailand. The diagnosis was made only retrospectively despite a travel history and clinical signs that suggested infection with Rickettsia tsutsugamushi. No specific therapy was given, and marked neurological impairment persisted 6 months after the beginning of the illness. An increased awareness of scrub typhus is a prerequisite for recommending prophylaxis and instituting prompt therapy.

[Epidemiology of scrub typhus in Matsu Peikang Island].

A retrospective survey of the epidemiology of scrub typhus in 1990 in Matsu Peikang Island was made at the end of December of 1990. The diagnosis of scrub typhus was based on the presence of escar, typical clinical manifestation and good response to tetracycline treatment. There were 89 cases of scrub typhus studied, and except for one civilian, the other 88 cases were military personnel, occurring in 2.2% of the total military personnel on the island. However it occurred in 0.08% of the civilian population. Seasonal distribution of scrub typhus was limited to between June and October of 1990. The peak incidence occurred in July. Scrub typhus was distributed over the whole island. A higher incidence of scrub typhus occurred in soldiers and sergeants than in officers. A significant different incidence was found in different units. No fatalities were reported. Different units. No fatalities were reported. Different military activities, duties and the location of the military unit may affect the incidence of scrub typhus. The scrub typhus epidemic was also related to temperature.