Plasma Exchange Did Not Reduce Viral Load in a Recovered Case of Severe Fever with Thrombocytopenia Syndrome.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease caused by the SFTS virus (SFTSV). There is no specific treatment for SFTS, although several reports have indicated that plasma exchange (PE) can be an effective therapy for severe SFTS. However, whether or not PE can reduce the viral load is unclear. We herein report a woman with SFTS who had her SFTSV viral load measured just before and after PE. While the patient recovered, there was no significant difference in the SFTSV viral load after PE. Our results confirmed that PE itself does not reduce the SFTSV viral load.

Severe rhabdomyolysis associated with severe fever with thrombocytopenia syndrome in a married couple: a case report.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne infection that has recently emerged. This infectious disease is due to the transfer of SFTS virus (SFTSV) from the infected blood of animals to humans. Approximately 30% of patients who are infected with SFTS die from multiorgan failure associated with severe infection, systemic inflammatory response syndrome, or disseminated intravascular coagulation. We treated an elderly Japanese couple (husband and wife) who had genetically identical SFTSV infections and who both developed severe rhabdomyolysis. CASE PRESENTATION: An 80-year-old man presented to the clinic with a fever; his 74-year-old wife presented with a fever 9 days later. Their laboratory results at diagnosis showed severe rhabdomyolysis with significantly elevated creatinine kinase (detected levels: husband, 9546 U/L; wife, 15,933 U/L). The creatinine kinase isozyme was 100% MM type in both patients. In both the husband and wife, SFTSV was identified with real-time polymerase chain reaction analysis. The detected SFTSVs in both the husband and wife were identical according to the genome sequence analysis. The husband's bone marrow indicated macrophage activation syndrome, but he responded to supportive therapy. He was discharged after being hospitalized for 32 days. The wife was admitted to our hospital in critical condition 2 days after SFTS symptom onset. She died of multiorgan failure 8 days after onset, despite being cared for in an intensive care unit. Both of the patients presented with rhabdomyolysis following SFTS symptom onset. The patients' clinical outcomes were different from each other; i.e., the husband survived, and the wife died. CONCLUSIONS: SFTSV infection-associated rhabdomyolysis has been reported in one patient, and simultaneous onset in two related patients has not been described previously. Our findings suggest that similar biological responses occurred, but they resulted in different clinical outcomes in the patients infected by the identical SFTSV isolates. Notably, a patient's clinical outcome depends on their own immune response. We suggest that one component of viral rhabdomyolysis involves immune-mediated responses. Severe immunological responses may adversely affect the treatment outcome, as demonstrated by the wife's clinical course. Our findings demonstrate that a patient's immune response contributes to their prognosis following SFTSV infection.

Five Emerging Neuroinvasive Arboviral Diseases: Cache Valley, Eastern Equine Encephalitis, Jamestown Canyon, Powassan, and Usutu.

There are many arthropod-borne viruses (arboviruses) capable of neuroinvasion, with West Nile virus being one of the most well known. In this review, we highlight five rarer emerging or reemerging arboviruses capable of neuroinvasion: Cache Valley, eastern equine encephalitis, Jamestown Canyon, Powassan, and Usutu viruses. Cache Valley and Jamestown Canyon viruses likely circulate throughout most of North America, while eastern equine encephalitis and Powassan viruses typically circulate in the eastern half. Usutu virus is not currently circulating in North America, but has the potential to be introduced in the future given similar climate, vectors, and host species to Europe (where it has been circulating). Health care providers should contact their state or local health departments with any questions regarding arboviral disease surveillance, diagnosis, treatment, or prevention. To prevent neuroinvasive arboviral diseases, use of insect repellent and other mosquito and tick bite prevention strategies are key.

An anti-Gn glycoprotein antibody from a convalescent patient potently inhibits the infection of severe fever with thrombocytopenia syndrome virus.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease localized to China, Japan, and Korea that is characterized by severe hemorrhage and a high fatality rate. Currently, no specific vaccine or treatment has been approved for this disease. To develop a therapeutic agent for SFTS, we isolated antibodies from a phage-displayed antibody library that was constructed from a patient who recovered from SFTS virus (SFTSV) infection. One antibody, designated as Ab10, was reactive to the Gn envelope glycoprotein of SFTSV and protected host cells and A129 mice from infection in both in vitro and in vivo experiments. Notably, Ab10 protected 80% of mice, even when injected 5 days after inoculation with a lethal dose of SFTSV. Using cross-linker assisted mass spectrometry and alanine scanning, we located the non-linear epitope of Ab10 on the Gn glycoprotein domain II and an unstructured stem region, suggesting that Ab10 may inhibit a conformational alteration that is critical for cell membrane fusion between the virus and host cell. Ab10 reacted to recombinant Gn glycoprotein in Gangwon/Korea/2012, HB28, and SD4 strains. Additionally, based on its epitope, we predict that Ab10 binds the Gn glycoprotein in 247 of 272 SFTSV isolates previously reported. Together, these data suggest that Ab10 has potential to be developed into a therapeutic agent that could protect against more than 90% of reported SFTSV isolates.

Application of therapeutic plasma exchange in patients having severe fever with thrombocytopenia syndrome.

BACKGROUND/AIMS: Severe fever with thrombocytopenia syndrome (SFTS) is a viral hemorrhagic fever with a high fatality rate. However, effective treatments for SFTS cases not responded to supportive therapy have not been established. Herein, we introduced the therapeutic plasma exchange (TPE) in SFTS patients in a tertiary hospital between 2013 and 2015. METHODS: TPE was performed in patients with rapidly progressing SFTS. Clinical, laboratory, and virological parameters were compared before and after TPE. RESULTS: Among 27 confirmed SFTS patients, two patients were treated with TPE and ribavirin combination in May 2013, then, 14 patients with rapidly progressing SFTS patients were treated with only TPE from June 2013 to September 2015: their median age was 58 years (interquartile range, 50 to 70) and eight (57.1%) were male. Body temperature, pressure-adjusted heart rate, white blood cell and platelet counts, coagulation profile, serum creatinine, and multiple organ dysfunction score improved immediately after TPE. In addition, the mean cyclic threshold value of real-time reverse transcriptase polymerase chain reaction for SFTS virus after TPE (mean ± standard deviation, 31.3 ± 2.9) was significantly higher than that before TPE (26.5 ± 2.9; p < 0.001), indicating that serum viral loads decreased after TPE. Finally, 13 of 14 TPE-treated patients (92.8%) recovered from rapidly progressing SFTS without sequelae. CONCLUSION: SFTS patients treated with TPE showed improvements in clinical, laboratory, and virological parameters. These results suggest that TPE would be a therapeutic modality as rescue therapy in patients with rapidly progressing SFTS.

Case Report: Use of Plasma Exchange Followed by Convalescent Plasma Therapy in a Critically Ill Patient with Severe Fever and Thrombocytopenia Syndrome-Associated Encephalopathy: Cytokine/Chemokine Concentrations, Viral Loads, and Antibody Responses.

We describe the case of a patient with severe fever with thrombocytopenia syndrome (SFTS) complicated by SFTS-associated encephalopathy who was successfully treated with 4-day plasma exchange followed by two-time convalescent plasma therapy. During plasma exchange, the plasma cytokines interferon-α and inducible protein-10 gradually decreased without change of plasma viral load. However, plasma viral load gradually decreased after convalescent plasma therapy. This case provides important insights for understanding the mechanisms of experimental therapy in severely affected SFTS patients.

Case report: detection of the identical virus in a patient presenting with severe fever with thrombocytopenia syndrome encephalopathy and the tick that bit her.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease. Haemophysalis longicornis ticks have been considered the vector of severe fever with thrombocytopenia syndrome virus (SFTSV). However, clear data on the transmission of SFTS from ticks to humans are limited. CASE PRESENTATION: We report an 84-year-old woman who presented with fever and altered mentality, which was confirmed as SFTS with encephalopathy by reverse-transcription polymerase chain reaction in blood and cerebrospinal fluid. The SFTSV was also identified in the tick that bit her, H. longicornis. Phylogenetic analyses indicated that the SFTSV from the patient and the tick was identical. The patient gradually recovered with treatments of corticosteroids and immunoglobulin. CONCLUSION: These findings provide further evidence of SFTS viral transmission from H. longicornis to human.

Hemorrhagic fever of bunyavirus etiology: disease models and progress towards new therapies.

A growing number of bunyaviruses are known to cause viral hemorrhagic fever (VHF), a severe febrile illness which can progress to hypovolemic shock and multi-organ failure and is characterized by hematologic abnormalities and vascular leak. At present, there are no approved vaccines or antiviral therapies to effectively prevent or treat VHF caused by pathogenic bunyaviruses. Advances in the modeling of bunyaviral infections have facilitated efforts towards the development of novel post-exposure prophylactic and therapeutic countermeasures, several of which may some day be approved for human use. Here, we review recent progress in animal models of severe bunyaviral infections essential to this mission, as well as promising antivirals and biologicals that are at various stages of the development process.

Therapeutic effect of post-exposure treatment with antiserum on severe fever with thrombocytopenia syndrome (SFTS) in a mouse model of SFTS virus infection.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral disease that is endemic in China, Korea and Japan. No effective vaccine or specific treatment for SFTS is currently available. Here, we used a mouse model to examine the effects of ribavirin, site-1 protease inhibitor PF-429242, steroids, and combination of minocycline and ciprofloxacin (MC) on SFTS infection. The antiserum from a patient who recovered from SFTS was also examined for its effect on mice. Administration of antiserum completely protected mice against lethal infection with SFTSV. It could also protect mice from showing clinical signs of the disease due to non-lethal infection. MC-treatment resulted in prolonged survival times during lethal infection. Although other agents had no significant protective effects, they did not provide detrimental effects that could lead to progression of the disease in mice. Our results suggest that antiserum treatment may be clinically useful for post-exposure prophylaxis against SFTSV infection.

Severe fever with thrombocytopenia syndrome, an emerging tick-borne zoonosis.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging haemorrhagic fever that was first described in rural areas of China. The causative agent, SFTS virus (SFTSV), is a novel phlebovirus in the Bunyaviridae family. Since the first report in 2010, SFTS has been found in 11 provinces of China, with about 2500 reported cases, and an average case-fatality rate of 7·3%. The disease was also reported in Japan and Korea in 2012; Heartland virus, another phlebovirus genetically closely related to SFTSV, was isolated from two patients in the USA. The disease has become a substantial risk to public health, not only in China, but also in other parts of the world. The virus could undergo rapid evolution by gene mutation, reassortment, and homologous recombination in tick vectors and vertebrate reservoir hosts. No specific treatment of SFTS is available, and avoiding tick bites is an important measure to prevent the infection and transmission of SFTSV. This Review provides information on the molecular characteristics and ecology of this emerging tick-borne virus and describes the epidemiology, clinical signs, pathogenesis, diagnosis, treatment, and prevention of human infection with SFTSV.

Notes from the field: Heartland virus disease - United States, 2012-2013.

Heartland virus is a newly identified phlebovirus that was first isolated from two northwestern Missouri farmers hospitalized with fever, leukopenia, and thrombocytopenia in 2009. Based on the patients' clinical findings and their reported exposures, the virus was suspected to be transmitted by ticks. After this discovery, CDC worked with state and local partners to define the ecology and modes of transmission of Heartland virus, develop diagnostic assays, and identify additional cases to describe the epidemiology and clinical disease. From this work, it was learned that Heartland virus is found in the Lone Star tick (Amblyomma americanum). Six additional cases of Heartland virus disease were identified during 2012-2013; four of those patients were hospitalized, including one with comorbidities who died.

Plasma exchange and ribavirin for rapidly progressive severe fever with thrombocytopenia syndrome.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease caused by a novel bunyavirus. Although the increasing numbers of cases and deaths is of great concern, an effective treatment strategy for SFTS has not been established. We present the cases of two patients with rapidly progressing SFTS who were successfully treated with plasma exchange and ribavirin.

[Analysis on the diagnosis and treatment of a cluster of cases infected by new bunyavirus].

OBJECTIVE: To analyze and summarize the clinical characteristics, experience of diagnosis and treatment of cases infected by new bunyavirus, which occurred in Henan province in 2010. METHODS: The clinical characteristics and effect of diagnosis and treatment of 5 cases were analyzed using descriptive epidemiological method. Blood specimens were detected by RT-PCR and pathogen separation. RESULTS: PCR testing was positive for all 5 cases. New bunyavirus were isolated from 2 cases. In 5 cases, fever (5/5), the whole body aches (5/5), fatigue (5/5), anorexia (5/5), nausea (5/5), the chills (4/5), cough (4/5), expectoration (4/5), vomiting (3/5), conjunctival hyperemia (3/5); Leukocyte reduction (5/5), thrombocytopenia (5/5), elevated alanine aminotransferase (4/5), elevated aspartate aminotransferase (4/5), elevated lactate dehydrogenase (5/5), creatine kinase elevations (4/5), urinary protein (3/5). By symptomatic and supportive treatment and prophylactic antibiotics, the first case died and the other 4 cases were cured. The average course of disease was 15.4 days. CONCLUSION: Cases infected by new bunyavirus have complicated clinical feature and multiple organ damage. If symptomatic treatment is in time, prognosis will be good.

Protective immunity against acute phleboviral infection elicited through immunostimulatory cationic liposome-DNA complexes.

Cationic liposome-DNA complexes (CLDC) have been demonstrated to induce potent antitumor activities. The ability of these complexes to elicit protective immunity against viral infections has not been fully explored. Here we report findings on the use of CLDC as an antiviral agent in a mouse model of acute phleboviral (Punta Toro virus) disease. CLDC treatment of mice challenged with Punta Toro virus (PTV) resulted in dramatic increases in survival and reduced viral burden and other parameters indicative of protection against disease. CLDC were effective when administered by intraperitoneal and intravenous routes and elicited protective immunity when given within 1 day of virus challenge. Treatments administered 36 h or longer after challenge, however, were not effective in preventing mortality or disease. CLDC treatment induced release of a number of potential antiviral cytokines including IFN-gamma, IL-12, and IFN-alpha. Taken together, our findings indicate that non-specific immunotherapy with CLDC appears to be an effective treatment for blocking PTV-induced disease and suggests that further exploration in other viral disease models may be warranted.

[Vector-borne diseases. Recent advances in the diagnosis, treatment and prevention]. / Patologie a trasmissione vettoriale.

Vector borne diseases are infections transmitted by arthropods. The vector can mechanically spread the infectious disease or give hospitality to microrganisms for their biological cycle. The etiologic agents of these infections are viruses as yellow fever and Dengue, protozoans as plasmodium of malaria, Leishmania spp., bacteria as Borrelia burgdorferi, Rickettsia spp. or worms as lymphatic filariasis. They are emerging infectious diseases for the epidemiological changes of our national territory (ex. Lyme disease) but especially for the significant increase of the imported forms. Malaria is the more important infection for its clinical management but also for its remote possibility of a further transmission in Italy. In this review are illustrated the recent progresses in the diagnosis, treatment and prevention of the main vector borne infections that the clinical physicians may frequently observe. It is very important to know these diseases because an adequate preparation and continuous updating are necessarily required.

Infections by viruses of the families Bunyaviridae and Filoviridae.

Rift Valley fever is the most important bunyaviral disease of animals in Africa. The virus, transmitted by mosquitoes, causes abortions and mortality in young animals in addition to haemorrhagic fevers in humans. Although vaccines against this virus are available, the uses of these vaccines are limited because of deleterious effects or incomplete protection, justifying further studies to improve the existing vaccines or to develop others. Nairobi sheep disease is transmitted by ticks. The disease is endemic in East Africa and sporadic cases are reported in India and Sri Lanka. Other viruses transmitted by mosquitoes or midges are teratogenic in cattle or sheep, these include Akabane and related viruses in Asia, Australia and the Middle East, and Cache Valley in North America. The Marburg and Ebola viruses of the genus Filovirus are associated with epidemics in Central Africa with high fatality rates in humans; some outbreaks were related to contact with monkeys. Another subtype of Ebola virus was first described in a quarantine facility in the United States of America among cynomolgus monkeys (Macaca fascicularis) from the Philippines. The reservoir of these viruses remains unknown.

Antiviral and immunomodulating inhibitors of experimentally-induced Punta Toro virus infections.

A major component of a US Army Medical Research and Development Command-supported program to discover and develop new drugs for the treatment of Rift Valley fever, sandfly fever, and Crimean-Congo hemorrhagic fever has been to study candidate test materials against hepatotropic infections of C57BL/6 mice induced by the related but less biohazardous Punta Toro virus (PTV). The effects of 75 compounds, some of which were considered immunomodulators in their primary mechanism of activity, were studied in the PTV infection model. Of these, ribavirin, ribamidine, ribavirin 2',3',5'-triacetate, tiazofurin, tiazofurin-5'-monophosphate, tiazofurin-2',3',5'-triacetate, selenazofurin, pyrazofurin, 3-deazaguanine, and 3-deazaguanosine were considered significantly inhibitory, acting against the infection by a direct antiviral (non-immunomodulatory) fashion. These compounds had therapeutic indices (TI) ranging from > or = 5 to 65, using increased survivors as the evaluation parameter. Immunomodulators considered significantly inhibitory to this infection were poly (ICLC), ampligen, human recombinant interferon-alpha-A/D, MVE-1, MVE-2, AM-3, AM-5, mannozym, bropirimine, CL246,738, phenyleneamine, and 7-thia-8-oxoguanosine. Utilizing increased survivor numbers as measure of activity, these inhibitors had TI ranging from > or = 16 to 1000. Other antiviral effects exerted by the active compounds included reduction of hepatic icterus, lowered serum glutamic oxaloacetic and pyruvic acid transaminases, and inhibition of recoverable serum and liver virus titers. The active immunomodulators were significantly effective when therapy was initiated as late as 48 h after virus inoculation, at a time when clinical signs of the PTV disease were being manifested in the animal.

Hantavirus pulmonary syndrome: recognition and emergency department management.

Hantavirus infection with respiratory involvement is a new clinical entity. The respiratory and cardiovascular abnormalities associated with hantavirus infection define the hantavirus pulmonary syndrome (HPS). We present two cases of HPS and discuss the presentation, epidemiology, emergency department management, and differential diagnosis. Treatment of HPS involves intensive care monitoring, airway management, and cardiovascular support. Because human hantavirus infection with respiratory involvement has been recognized recently in all geographic regions of the United States, it is important for emergency physicians to recognize this syndrome's characteristic symptoms and laboratory abnormalities. The fulminant clinical course of HPS and its 65% mortality rate underscore the importance of early recognition if potentially life-saving interventions are to be initiated.