Severe Fever with Thrombocytopenia Syndrome (SFTS): Part 2
Before moving on, I thought it would be good to address the “tick issue”. There were a couple of Facebook comments about the Haemaphysalis longicornus photo from Wikipedia, and how this resembled the dog ticks that are prevalent in Singapore. I am by no means a tick expert, but I understand that the predominant tick in Singapore is the brown dog tick (Rhipicephalus sanguineus). There is a photo of an engorged brown dog tick here (which cannot be reproduced directly on this blog) which is similar to the Wikipidia image. Rhipicephalus sanguineus is fortunately not a vector for pathogens that cause human disease (except perhaps for Rickettsia conoriii – the cause of boutenneuse fever) – here is a local blog post (NUS) that discusses ticks in Singapore. Despite the identical-sounding names, Rhipicephalus microplus (Asian blue tick) is quite different from Rhipicephalus sanguineus.
Back to SFTS.
The incubation period of the SFTS virus is believed to be between 5 to 14 days. This is primarily based on the occasional documented episodes of person-to-person transmission (exposure to blood and other body secretions of infected persons in both nosocomial and intra-familial settings), and to rare cases where the time of tick bite had been documented.
A significant proportion of people exposed to the SFTS virus – either via tick bites or blood/body secretions – develop either mild infection or are asymptomatic. The exact proportion is not known. In well-investigated person-to-person clusters, the majority or even all of serologically or virologically confirmed SFTS cases were symptomatic. However, there are reports of mild infection, including this reported case of a 71-year-old Japanese lady in 2014. Serological surveys in China – summarized in this systematic review in PLoS ONE – showed that between 0.23% and 9.17% (depending on province) of the population in affected provinces were positive for antibodies against the SFTS viruss. A smaller study on leftover sera in a tertiary hospital in Korea found 2.1% antibody positivity. These suggest – despite well known problems of such studies (including specificity of the test used) – that infection dose not always lead to severe or even clinically apparent disease.
According to several publications, the clinical course of most hospitalized SFTS patients can be divided into 3 stages – fever, multi-organ dysfunction, and convalescence. The fever stage lasts up to 7 days, and the clinical features are nonspecific. It is said to be difficult to distinguish from leptospirosis, hemorrhagic fever with renal syndrome, human granulocytic anaplasmosis, or – after consideration – from most of the rickettsial diseases. The initial symptoms include fever as well as a combination of anorexia, myalgia, and gastrointestinal symptoms (especially diarrhoea). Some patients may just present with flu-like symptoms. Clinical examination may reveal the tick bite (not found in many of the hospitalized cases), and lymphadenopathy (particularly inguinal lymphadenopathy) may be present in a subset of patients. During this first phase, thrombocytopenia and leucopenia are the most common laboratory findings, occurring in over 90% of cases in large case series from both South Korea and China. Other laboratory findings include elevated C-reactive protein, liver enzymes, ferritin and creatine kinase.
Most survivors of the disease recover in the second week after the initial fever phase. However, others do not, and instead progress onto a multi-organ dysfunction phase characterized by haemorrhagic manifestations (caused by both thrombocytopenia and coagulopathy – melaena is most common in those that die from SFTS), encephalopathy, worsening hepatitis, renal failure and shock. Convalescence and recovery may still be possible from this phase. The overall mortality for SFTS is variable – the national figure for China is 5.3% (up to October 2016), but is higher in Japan (30%) and South Korea (32.6%) likely because of under-diagnosis of mild cases.
A small number of papers have been published on the pathogenesis of the SFTS virus, but perhaps this older (2011) work by Cong Jin and coworkers in PNAS is still useful to explain the thrombocytopenia – essentially overwhelming macrophage clearance of platelets with adherent virus. Endothelial dysfunction has also been postulated to contribute to the pathogenesis of the virus.
There is no specific treatment for SFTS. Ribavirin has been attempted but was not found to be useful in a large retrospective cohort in China. Plasma exchange has also been attempted in South Korea, but the results are too preliminary at present.
A high index of clinical suspicion is required, given the initial non-specific presentation. Cases are almost always from rural parts of central-eastern China, western Japan, and South Korea, presenting during the months when ticks are active in these countries. There are a variety of diagnostic tests available in these countries, including RT-PCR (during the acute/symptomatic phase of the infection), serology (after the first week of illness – the antibodies persist for at least 5 years), and viral culture in Vero or DH82 cells. In Singapore, only the RT-PCR test is available, and this is only performed at the National Public Health Laboratory (NPHL). The test is not routinely done – clinicians will have to discuss suspect cases with the NPHL laboratory officers first.
A number of small nosocomial and household outbreaks of SFTS have been reported to date. One of the better known nosocomial clusters occurred in a tertiary hospital in South Korea, where following cardiopulmonary resuscitation of the index case, 4 of 7 healthcare workers involved in the resuscitation effort contracted SFTS. Another family cluster in China involved relatives of the index that had provided bedside care or had handled her corpse subsequently. Therefore transmission of SFTS may occur after unprotected contact with blood and other body secretions of a person infected with SFTS, although the actual risk does not seem to be very high going by the reported literature. The infection prevention recommendations in South Korea, as I understand, are standard precautions (which does include putting on personal protective equipment including masks and goggles for activities that are likely to result in spraying/splashing of blood and other secretions), without any need to isolate suspect or confirmed cases.
An interesting infectious disease that seems to be on the rise in the rural parts of China and South Korea. The mortality rate is probably lower than what has been published to date. It is not clear if lifelong immunity to the virus develops after infection. The tick vectors do not seem to be prevalent – if at all present – in Singapore, as are the mammals that the virus more commonly infects (domestic livestock) as a consequence of its tick hosts. There is probably a slight risk of an imported case of SFTS, in the same way that we are at risk for a MERS-CoV importation, although the potential for nosocomial spread is far far lower than for MERS-CoV. A heightened clinical index of suspicion during the middle months of the year may help mitigate the risks.