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Kyasanur Forest Disease

Monkey Fever

Kyasanur forest disease is a viral infectious disease endemic to India whose causative agent belongs to the tick-borne encephalitis serocomplex of flaviviruses.


Presentation

Cases of KFD are only to be expected in endemic regions of southern India. Possibly, travelers who visited this area may have been exposed to infected ticks and suffer upon return to their home country, but no such case has been reported yet.

Acute onset of malaise, high-grade fever (up to 40 °C), chills and typically frontal headaches is experienced after an incubation period of 2-8 days. Fever persists for up to two weeks. Generalized pain, i.e., myalgia and limb pain, may also be noted. Some patients suffer from vomiting and diarrhea or claim a sore mouth and throat. Physical examination may reveal enlargement of cervical and axillary lymph nodes, and hepatomegaly.

Less than a week after symptom onset, hemorrhages may manifest and patients may start to present bleeding gums, epistaxis, hemoptysis, hematemesis, melena and/or hematochezia. Of note, although KFD is sometimes classified as hemorrhagic fever, some patients may not show any hemorrhagic symptoms. The hemorrhagic stage of the disease may last up to a week and eventually, symptoms subside and the patient starts to recover. Although several weeks may pass until complete recovery is achieved - patients may continue to suffer fatigue and weakness for more than a month - most patients don't develop additional symptoms.

Less than one out of five KFD patients, however, demonstrates neurological symptoms shortly after remission of hemorrhages. Mental disturbances, tremors, and abnormal reflexes are most commonly observed. Aspiration pneumonia may result from a disturbed swallowing reflex. Generalized seizures, nuchal rigidity, and visual impairment have been reported. Reduced levels of awareness are associated with a poor outcome.

Fever
  • […] of recovery followed by a li stage of fever in some cases. 2.[ncbi.nlm.nih.gov]
  • Pathologic and hematologic investigations emphasized similarities with Omsk hemorrhagic fever.[ncbi.nlm.nih.gov]
  • Kyasanur forest disease (KFD) is a tick-borne viral haemorrhagic fever endemic to South India. The disease is caused by a virus belonging to the family Flaviviridae, which also includes yellow fever and dengue fever.[en.wikipedia.org]
  • (inanition) (of unknown origin) (persistent) (with chills) (with rigor) R50.9 ICD-10-CM Diagnosis Code R50.9 Fever, unspecified 2016 2017 2018 2019 Billable/Specific Code Applicable To Fever NOS Fever of unknown origin [FUO] Fever with chills Fever with[icd10data.com]
  • Flaviviruses are typically transmitted by arthropods and this also applies to the etiologic agents of yellow fever, dengue fever, West Nile fever and tick-borne encephalitis.[symptoma.com]
High Fever
  • The disease is characterised by high fever, pain in the joints, bleeding in nose and gums. In the last 58 years, 531 persons have died of KFD in the State. S.K.[thehindu.com]
  • Symptoms and Signs Kyasanur forest disease-inflicted individuals usually present the following manifestations: * Headache * High fever * Bleeding originating from the nasal cavity and throat. * Vomiting During the convalescent period the patient may experience[medigest.uk]
  • Prakash said that high fever, bleeding in teeth and gums, and joint pain are some of the symptoms of KFD.[thehindu.com]
  • The KFD infection, which starts with high fever and bodyache, results in hemorrhage, similar to that in dengue. It has a mortality rate of 5 per cent to 10 per cent, said a state-level medical officer.[indianexpress.com]
  • The symptoms of the disease include a high fever with frontal headaches, followed by haemorrhagic symptoms, such as bleeding from the nasal cavity, throat, and gums, as well as gastrointestinal bleeding.[en.wikipedia.org]
Ascitic Fluid
  • Titers of all viral stocks were determined as tissue culture infective dose 50 (TCID 50 ) on VeroE6 cells and visualized by indirect fluorescent-antibody assay (IFA) using anti-KFDV hyperimmune mouse ascitic fluid (HMAF) primary antibody.[doi.org]
  • The slides were incubated with mouse ascites fluid antibodies against KFDV strain P9605 (R157 HMAF) and AHFV strain Zaki-1 (R204 HMAF), both kindly provided by Dr. T. Ksiazek (WRCEVA, UTMB) at a dilution of 1 1000 overnight at 4 C.[doi.org]
Veterinarian
  • After infection, each animal was observed a minimum of once per day, and its health assessed and scored by experienced CDC veterinarians or animal health technicians.[doi.org]
Hepatomegaly
  • Our study showed that KFD passes through 4 stages each lasting for about a week. i.e. a prodromal stage with fever, hypotension hepatomegaly, a stage of complication characterized by haemorrhage, neurological manifestation or bronchopneumonia, a stage[ncbi.nlm.nih.gov]
  • Physical examination may reveal enlargement of cervical and axillary lymph nodes, and hepatomegaly.[symptoma.com]
Bleeding Gums
  • Patients may cough or vomit blood, excrete blood with stools, suffer from bleeding gums and nosebleeds. Generally, symptoms subside within one or two weeks.[symptoma.com]
  • Introduction Kyasanur forest disease (KFD) is a tick-borne viral disease characterised by sudden onset of fever and/or headache followed by hemorrhagic manifestations such as conjunctival congestion, bleeding gums, epistaxis, haemoptysis, haematemesis[doi.org]
Hypotension
  • Hypotension in KFD could be of Myocardial origin. 4. Encephalopathy in KFD could be due to a metabolic cause probably of hepatic origin. 5. Lung signs could be due to intraalveolar haemorrhage and secondary infection.[ncbi.nlm.nih.gov]
  • The consequent vascular injury causes increases vascular permeability with consequent tissue edema, loss of blood volume, hypoalbuminemia, decreased osmotic pressure, hypotension, tissue hypoperfusion, and end-organ ischemia.[wuestenschiff.de]
Ulcer
  • Petra Tschakert, Vincent Ricciardi, Erica Smithwick, Mario Machado, David Ferring, Heidi Hausermann and Leah Bug , Situated knowledge of pathogenic landscapes in Ghana: Understanding the emergence of Buruli ulcer through qualitative analysis , Social[doi.org]
  • Searchable Prioritized List, Guideline Notes, Esophageal varices, Esophageal hemorrhage, ulcer with hemorrhage, perforation, gastritis, Duodenitis.Varizen ven.lechenie.v Omsk. strumpfe krampfadern elastische prellungen an den inneren krampfadern kaufen[ypujudirenereq.xpg.uol.com.br]
Flushing
  • Infectious Disease Section, Department of Medicine, New York Hospital Queens, 56–45 Main Street, Flushing, NY 11355, USA. [email protected] ; 2004 Sep 15;190(6):1084–7. pmid:15319857 View Article PubMed/NCBI Google Scholar 37.[doi.org]
Petechiae
  • In severe cases, sequelae can include encephalitis and/or a hemorrhagic syndrome, with the latter defined by petechiae, epistaxis, bleeding from gums, hematemesis, melena and hematochezia [1] – [5] .[doi.org]
Epistaxis
  • The early clinical description of the disease included severe cases with hemorrhagic manifestations, including intermittent epistaxis, hematemesis, melena, and frank blood in the stools.[ncbi.nlm.nih.gov]
  • Less than a week after symptom onset, hemorrhages may manifest and patients may start to present bleeding gums, epistaxis, hemoptysis, hematemesis, melena and/or hematochezia.[symptoma.com]
  • Introduction Kyasanur forest disease (KFD) is a tick-borne viral disease characterised by sudden onset of fever and/or headache followed by hemorrhagic manifestations such as conjunctival congestion, bleeding gums, epistaxis, haemoptysis, haematemesis[doi.org]
  • In severe cases, sequelae can include encephalitis and/or a hemorrhagic syndrome, with the latter defined by petechiae, epistaxis, bleeding from gums, hematemesis, melena and hematochezia [1] – [5] .[doi.org]
Confusion
  • However, a minor share of patients develops neurological symptoms like disorientation, confusion, tremors and abnormal reflexes. The presence of neurological complaints is an unfavorable prognostic sign.[symptoma.com]
  • Most commonly in AHFV cases, neurologic clinical signs have been described, including tremors, seizures, neck rigidity, confusion, convulsions or coma [1] – [5] .[doi.org]

Workup

To date, direct molecular biological identification of the causative pathogen is the most sensitive and specific method to confirm a tentative diagnosis of KFD. Distinct protocols for polymerase chain reaction have been designed and proven helpful even during very early stages of the disease [10]. The latter limits the applicability of serological tests like hemagglutination, complement fixation, and enzyme-linked immunosorbent assays. These methods are based on the presence of antibodies and will thus not yield positive results before an effective immune response sets in, which is typically the case about four days after symptom onset. If more than ten days have passed since symptom onset, serological tests are preferred over molecular biological methods since viremia does usually not persist beyond this time. It is currently not known how long specific antibodies remain detectable. Virus isolation from peripheral blood and subsequent culture is an alternative, specific but time-consuming diagnostic approach.

Laboratory analyses of blood samples, i.e., hemogram and blood biochemistry, should be realized in order to assess the overall condition of the patient. Common findings in KFD patients are lymphopenia and eosinopenia.

Gliosis
  • The spectrum of changes included gliosis, inflammatory response, necrosis, neural loss, and syncytium formation in mid and hind brain structures.[ncbi.nlm.nih.gov]
  • This experiment was completed by using KFDV-infected mice and discovered that KFDV caused gliosis, inflammation, and cell death in the brain.[en.wikipedia.org]
  • Areas of gliosis and perivascular cuffs sometimes also contained neutrophilic infiltrate and karyorrhectic cell debris.[doi.org]

Treatment

To date, no specific therapy for KFD is available. Patients who are diagnosed with KFD may require hospitalization, fluid therapy and possibly transfusion of blood products. Further therapeutic measures are to be adjusted to the needs and symptoms displayed by the individual patient.

Prognosis

Most patients experience an initial stage of non-specific symptoms that may last three or four days before developing hemorrhagic complications. Despite the severity of the disease, patients generally, recover from the latter. The majority of affected individuals achieve complete recovery within several weeks. Long-term sequelae are not to be expected.

However, a minor share of patients develops neurological symptoms after recovering from the hemorrhagic stage of the disease. An altered mental state, tremors, possibly seizures and reflex disturbances may be observed. The onset of neurological symptoms is an unfavorable prognostic factor.

In sum, mortality rates average 5%, but during determined outbreaks, up to 15% of affected individuals died.

Etiology

KFD is an infectious disease caused by the KFD virus. This highly virulent virus belongs to the family of Flaviviridae and the genus Flavivirus. Flaviviruses are typically transmitted by arthropods and this also applies to the etiologic agents of yellow fever, dengue fever, West Nile fever and tick-borne encephalitis. However, the pathogen that provokes KFD has been found to be more closely related to the Russian spring-summer encephalitis virus and viruses pertaining to the tick-borne encephalitis serocomplex of flaviviruses [1]. Besides the KFD virus, the Alkhumra hemorrhagic fever virus and the Nanjianyin virus form part of that serocomplex [3].

KFD is transmitted by tick species Haemaphysalis spinigera and possibly Haemaphysalis turturis, but it has also been isolated from other Haemaphysalis spp. These ticks pass through distinct developmental stages: Eggs hatch into larvae, these moult to nymphs and nymphs progress to the adult stage. It is currently assumed that larvae acquire the virus while feeding on infected animals and transmission of the KFD virus to men is most likely to occur due to a nymph bite.

The virus' natural reservoir is not known. Many mammalian and bird species have been proposed as possible carriers. According to current knowledge, macaques and langurs are accidental hosts. They are very susceptible to the virus and may therefore be used as sentinels; increased mortality rates among these non-human primate populations may indicate an imminent outbreak.

Consequently, people who belong to the frequent endemic regions in Karnataka state, India, have a high risk of contracting KFD. Due to the high virulence of the virus, local health care givers and laboratory personnel who works with this pathogen is also at risk [4]. There is no evidence for direct human-to-human transmission, although cases have been reported in patients who were presumably never exposed to ticks [5].

Epidemiology

Both the KFD virus and its vectors are endemic to southern India. However, closely related viruses have been isolated in Saudi Arabia and China [6] [7]. It has been estimated that the KFD virus, the Alkhumra hemorrhagic fever virus, and the Nanjianyin virus originated from a common ancestor as recently as in 1942 [8]. Presumably, this common ancestor has been carried over long distances, maybe by infected birds, and evolved differently in the Arabian subcontinent, in India, and in China. This hypothesis illustrates the adaptability of the pathogen, which ensures the possibility of the virus being carried to other, as of yet not affected geographic regions. Under experimental conditions, transmission of the KFD virus by Dermacentor spp., Ixodes spp. and Rhipicephalus spp. has already been shown.

With regards to the KFD virus itself, this pathogen shows low levels of genetic diversity. Isolates from early outbreaks hardly differ from those viruses that have been obtained recently.

Every year, 100 - 500 cases are reported in India [9], most of them between January and June. This part of the year corresponds to the drier season and coincides with an increased prevalence of Haemaphysalis spinigera nymphs. Adult ticks reach peak populations between July and September when KFD case numbers are already diminishing. Female adult ticks lay eggs that hatch into larvae a few weeks later. Larvae preferentially feed on small mammals and ground birds and may become infected. They molt to nymphs that pose a risk of infection to men during the following year. KFD incidence rates have been increasing during the last years.

Both men and women may be affected and most patients diagnosed with KFD are adults. This age peak is probably due to enhanced exposure in this age group since young children and elder individuals less frequently visit those areas where Haemaphysalis spp. are distributed.

Sex distribution
Age distribution

Pathophysiology

Little is known about the pathophysiological events leading to symptom onset, neurological complaints and possibly death in men. The virus is inoculated into circulation during a tick bite and causes an acute onset of fever, chills, and headaches after a few days. Viremia lasts for approximately ten days after onset of symptoms and according to experiments conducted with mice, the virus preferentially replicates in neurons and lungs [6]. Eight days after infection, extensive inflammatory infiltrates were detected in meninges.

However, only a minor share of patients eventually develops neurological symptoms. The KFD virus may or may not be primarily neurotropic in humans; symptoms like mild meningitis and encephalitis only occur during an apparent relapse after remission of initial complaints, if they occur at all. Of note, the low incidence of neurological symptoms in cases of KFD is a substantial difference to the closely related Russian spring-summer encephalitis virus [1].

Prevention

A formalin-inactivated KFD vaccine has been available for several years and systematic immunization of populations at risk is the main preventive measure applied by health caregivers in endemic regions. Ideally, all people at risk received a basic immunization consisting of two applications within nine months, and annual boosters thereafter. In reality, immunization coverage is incomplete and mass vaccinations are only carried out in areas of confirmed outbreaks, increased mortality in non-human primate populations and enhanced prevalence of KFD virus in ticks. In order to detect the latter before men are affected, surveillance systems are implemented. However, increasing KFD case numbers indicate that both vaccination regimes and monitoring of virus prevalence need to be revised [2] [11].

Prevention of tick bites, i.e. wearing long-sleeved clothes and closed shoes as well as utilization of repellents, is also recommended.

Summary

Kyasanur forest disease (KFD) is an infectious disease caused by the Kyasanur forest disease virus. The first KFD outbreak has been registered in 1957; it affected inhabitants of Karnataka state, India, who were living close to the Kyasanur forest. Although this outbreak did not claim human fatalities, a locally increased incidence of febrile diseases prompted epidemiological studies and led to the identification of a so-far undescribed virus [1].

Presumably, the virus or, more explicitly, its ancestor has been present in wildlife before, but human cases had not been registered. In fact, the outbreak coincided with high mortality rates among non-human primates pertaining to the species Macaca radiata (red-faced bonnet macaque) and Semnopithecus entellus (black-faced langur) and these species are still considered to be part of the natural reservoir of KFD virus. Subsequent studies revealed the disease to be transmitted by ticks of the genus Haemaphysalis. These ticks fall of their dying hosts and create hot spots of infection.

People who are bitten by an infected tick may develop unspecific symptoms like fever, chills and headaches after an incubation period of less than a week. Over the course of the following days, patients usually pass through a stage of hemorrhagic complications, i.e., they present with bleeding gums, epistaxis, hemoptysis, hematemesis, melena and/or hematochezia. These complications are often followed by remission; in some cases, though, apparent recovery is interrupted by renewed symptom onset and neurological complications. The overall mortality of KFD is approximately 5%, but the likelihood of death is significantly higher in those patients that develop neurological symptoms.

Only supportive treatment can be provided. However, an effective vaccine has been developed and is successfully used in endemic regions. Recent outbreaks affected non-vaccinated populations [2].

Patient Information

Kyasanur forest disease (KFD) is a viral infectious disease caused by the Kyasanur forest disease virus. It is transmitted by ticks of the genus Haemaphysalis. Both virus and ticks are endemic to Karnataka state, India, and cases of KFD have only ever been reported in this region. However, there are high similarities between the KFD virus, the Alkhumra hemorrhagic fever virus (isolated in Saudi Arabia) and the Nanjianyin virus (isolated in China).

Presumably, several mammalian and bird species inhabiting the forests of southern India constitute the natural reservoir of the KFD virus. Ticks may feed on these species, become infected with the virus and transmit it to humans. Besides men, macaques and langurs are susceptible to the virus and outbreaks are generally associated with high mortality rates in the respective non-human primate populations.

After an incubation period of less than a week, affected individuals suffer from high-grade fever (up to 40 °C), chills and typically frontal headaches. Furthermore, vomiting, diarrhea, muscle, and limb pain may be experienced. In some cases, hemorrhages may manifest a few days later. Patients may cough or vomit blood, excrete blood with stools, suffer from bleeding gums and nosebleeds.

Generally, symptoms subside within one or two weeks. However, a minor share of patients develops neurological symptoms like disorientation, confusion, tremors and abnormal reflexes. The presence of neurological complaints is an unfavorable prognostic sign.

Only supportive therapy can be provided; it comprises fluid therapy, blood transfusions, and medication to relieve symptoms.

An effective vaccine is available and is used in endemic regions.

References

Article

  1. Holbrook MR. Kyasanur forest disease. Antiviral Res. 2012; 96(3):353-362.
  2. Kiran SK, Pasi A, Kumar S, et al. Kyasanur Forest disease outbreak and vaccination strategy,Shimoga District, India, 2013-2014. Emerg Infect Dis. 2015; 21(1):146-149.
  3. Lehrer AT, Holbrook MR. Tick-borne Encephalitis Vaccines. J Bioterror Biodef. 2011; 2011(Suppl 1):3.
  4. Banerjee K, Gupta NP, Goverdhan MK. Viral infections in laboratory persnnel. Indian J Med Res. 1979; 69:363-373.
  5. Murhekar MV, Kasabi GS, Mehendale SM, Mourya DT, Yadav PD, Tandale BV. On the transmission pattern of Kyasanur Forest disease (KFD) in India. Infect Dis Poverty. 2015; 4:37.
  6. Sawatsky B, McAuley AJ, Holbrook MR, Bente DA. Comparative pathogenesis of Alkhumra hemorrhagic fever and Kyasanur forest disease viruses in a mouse model. PLoS Negl Trop Dis. 2014; 8(6):e2934.
  7. Wang J, Zhang H, Fu S, et al. Isolation of kyasanur forest disease virus from febrile patient, yunnan, china. Emerg Infect Dis. 2009; 15(2):326-328.
  8. Mehla R, Kumar SR, Yadav P, et al. Recent ancestry of Kyasanur Forest disease virus. Emerg Infect Dis. 2009; 15(9):1431-1437.
  9. Gould EA, Solomon T. Pathogenic flaviviruses. Lancet. 2008; 371(9611):500-509.
  10. Mourya DT, Yadav PD, Mehla R, et al. Diagnosis of Kyasanur forest disease by nested RT-PCR, real-time RT-PCR and IgM capture ELISA. J Virol Methods. 2012; 186(1-2):49-54.
  11. Ghosh S, Nagar G. Problem of ticks and tick-borne diseases in India with special emphasis on progress in tick control research: a review. J Vector Borne Dis. 2014; 51(4):259-270.

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Last updated: 2018-06-21 23:32