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Hemorrhagic Fever with Renal Syndrome

HFRS

Hemorrhagic fever with renal syndrome is caused by distinct virus species pertaining to the family of Bunyaviridae. There are major geographical differences in prevalence and severity, with the disease being a major public health concern in East Asia.


Presentation

As per definition, HFRS patients present with the symptom triad of fever, hemorrhages, and renal insufficiency. The first symptoms are generally noted about two weeks after exposure to the causative pathogen, but much shorter and prolonged incubation periods have been described. However, distinct symptoms set in at different points in time after infection. Individuals who contracted the disease typically pass through five stages; fever, hypotension, oliguria, diuresis, and convalescence [8].

  • Febrile stage: Symptom onset is acute; non-specific symptoms like malaise, fever, chills, headaches, myalgia, nausea, and vomiting may last up to a week. Abdominal and lower back pain may already be present. Flushing and petechial rash may indicate vascular dysfunction.
  • Hypotensive stage: Fever subsides. Patients develops hypotension and tachycardia. In severe cases, they may go into shock. This stage is much shorter than the previous one, and may only last a few hours or very few days.
  • Oliguric stage: Kidney damage manifests in form of oliguria and uremia, whereby the latter aggravates the aforedeveloped bleeding diathesis. Hypertension may be noted, and lung edema may form. This stage typically lasts four or five days.
  • Diuretic stage: Urine amounts rise again and for up to three weeks, patients may excrete up to five liters of urine per day. Dehydration and hypovolemic shock may occur if fluid resuscitation is not adequate.
  • Convalescent stage: This stage is marked by gradual resolution of symptoms. It may take several months until complete recovery is achieved, if no irreversible kidney damage occurred.

Of note, the disease will follow this exemplary course in only one out of three patients. In others, stages may not be readily distinguishable, and the characteristic signs may be absent. Stage two, the one marked by hypotension, is frequently skipped.

Fever
  • Until recent now, GBS was only reported in hemorrhagic fever patients in Europe and Asia, which termed as hemorrhagic fever with renal syndrome.[ncbi.nlm.nih.gov]
  • It is also known as Korean hemorrhagic fever, epidemic hemorrhagic fever, and nephropathia epidemica.[en.wikipedia.org]
Chills
  • We report a case of HFRS in a 24-year-old soldier presenting with fever, chills, abdominal pain and generalized myalgia. His clinical course progressed through febrile, hypotensive, oliguria and polyuria phases.[ncbi.nlm.nih.gov]
  • Initial symptoms begin suddenly and include intense headaches, back and abdominal pain, fever, chills, nausea, and blurred vision. Individuals may have flushing of the face, inflammation or redness of the eyes, or a rash.[en.wikipedia.org]
  • Hemorrhagic fever with renal syndrome: A number of diseases, also known as hemorrhagic fever, characterized by an abrupt onset of high fever and chills, headache, cold and cough, and pain in the muscles, joints and abdomen with nausea and vomiting followed[medicinenet.com]
Intermittent Fever
Pharyngitis
  • On examination, she had a normal body temperature, flushing of the face, conjunctive congestion, pharyngeal congestion, bulbar conjunctive edema, severe jaundice, petechiae and ecchymosis at sites of venipuncture, deranged liver and renal function tests[ncbi.nlm.nih.gov]
  • ., influenza, RSV, etc) or group A Streptococcus in a person with an illness compatible with streptococcal pharyngitis, a positive culture from a normally sterile site, or a presentation consistent with bacterial pneumonia.[clinicaltrials.gov]
Nausea
  • The HFRS put these women at increased risk for severe illness, despite the patients' symptomologies in the onset phase were similar to those observed in non-pregnant HFRS patients, such as fever, headache, nausea, and thrombocytopenia.[ncbi.nlm.nih.gov]
  • Initial symptoms begin suddenly and include intense headaches, back and abdominal pain, fever, chills, nausea, and blurred vision. Individuals may have flushing of the face, inflammation or redness of the eyes, or a rash.[en.wikipedia.org]
  • These illnesses typically develop within 1 to 2 weeks of exposure (sometimes later) and are characterized by acute fever, severe headache, blurred vision, and nausea.[britannica.com]
Abdominal Pain
  • Clinicians should be alert to the possibility of HFRS when examining patients who have been in endemic areas and complain of fever associated with renal dysfunction, hemorrhage or abdominal pain or both.[ncbi.nlm.nih.gov]
Hypotension
  • His clinical course progressed through febrile, hypotensive, oliguria and polyuria phases. Hantavirus infection was proven by serology at the second hospital week. The patient was successfully treated with supportive management.[ncbi.nlm.nih.gov]
  • Hypotensive stage: Fever subsides. Patients develops hypotension and tachycardia. In severe cases, they may go into shock. This stage is much shorter than the previous one, and may only last a few hours or very few days.[symptoma.com]
  • .  Thirst, edema, hemoconcentration, postural hypotension 11.[slideshare.net]
Retinal Hemorrhage
  • Two patients had congestion of retinal venules and retinal edema, and one patient had small retinal hemorrhages.[ncbi.nlm.nih.gov]
Chemosis
  • Bilateral eyelid edema, chemosis, conjunctival injection and hemorrhages, shallowing of the anterior chamber with transitory myopia, and acute glaucoma were observed in three patients with hemorrhagic fever with renal syndrome (nephropathia epidemica)[ncbi.nlm.nih.gov]
Eczema
  • Forest disease A98.3 Marburg virus disease A98.4 Ebola virus disease A98.5 Hemorrhagic fever with renal syndrome A98.8 Other specified viral hemorrhagic fevers A99 Unspecified viral hemorrhagic fever B00 Herpesviral [herpes simplex] infections B00.0 Eczema[icd10data.com]
Skin Lesion
  • With supportive care, skin lesions were improved. Ophthalmic examinations revealed conjunctival injection with epithelial defects in both eyes. Ocular complications were resolved after amniotic membrane transplantation.[ncbi.nlm.nih.gov]
Arthralgia
  • A 30-yr-old man was admitted to hospital with a 5-d history of flu-like symptoms: Headache, shivers, nausea, vomiting, backache, arthralgias, myalgias, and blurred vision.[jasn.asnjournals.org]
Headache
  • The initial presentation of HFRS is extremely variable, but generally includes fever, malaise, headache and abdominal pain.[ncbi.nlm.nih.gov]
  • Initial symptoms begin suddenly and include intense headaches, back and abdominal pain, fever, chills, nausea, and blurred vision. Individuals may have flushing of the face, inflammation or redness of the eyes, or a rash.[en.wikipedia.org]
Neurologic Manifestation
  • Eight-hundred eleven case records of patients with hemorrhagic fever with renal syndrome (HFRS) caused by Puumala virus were reviewed, and particular attention was given to data regarding severe neurological manifestations.[ncbi.nlm.nih.gov]
  • Neurological manifestations of hemorrhagic fever with renal syndrome caused by Puumala virus: review of 811 cases. Clin Infect Dis. 1995 ; 20 :255–258. Crossref Medline Google Scholar 26.[circ.ahajournals.org]

Workup

Laboratory analysis of blood and urine samples may reveal leukocytosis, thrombocytopenia, proteinuria, and microscopic hematuria as early as in the febrile stage of the disease. Coagulation tests yield the most characteristic results during the ensuing hypotensive stage of HFRS. Prolonged partial thromboplastin and prothrombin times imply a coagulopathy. During the oliguric stage of HFRS, platelet counts and urinary protein excretion normalize. However, creatinine and urea concentrations reach previously unsurpassed high values.

Although the aforementioned signs strongly support a suspicion of HFRS, they don't usually allow an early confirmation of that diagnosis. To date, the gold standard for HFRS diagnosis and identification of the causative pathogen is serological testing. ELISA, IFA and Western blot shall be mentioned as available alternatives for the detection of hantavirus-specific immunoglobulins type G and M. Their respective advantages and disadvantages have been reviewed elsewhere [7]. All serological tests are based on an established immune response and may thus yield false-negative results if applied too early. Here, molecular biological techniques like real-time RT-PCR are presumably more reliable. However, false-negative results of RT-PCR have been reported, too [9]. If renal biopsies are taken, immunohistochemical methods may be applied.

Decreased Platelet Count
  • Despite intravenous fluid resuscitation and antibiotics the patient continued to deteriorate evidenced by his worsening diarrhea and decreasing platelet count.[wehrmed.de]
Torsades De Pointes
  • We describe a 51-yr-old man presenting with syncope due to torsade de pointes. The torsade de pointes was refractory to conventional medical therapy, including infusion of isoproterenol, MgSO4, potassium, lidocaine, and amiodarone.[ncbi.nlm.nih.gov]

Treatment

Treatment is largely symptomatic. Fluid resuscitation and avoidance of hemodynamic decompensation are of utmost importance. Repeated analysis of blood samples, namely of hematocrit and electrolyte levels, allows for a reliable assessment of the patients hydration status and thus permit necessary adjustments of fluid therapy. Early initiation of therapy significantly reduces the likelihood of renal failure.

Further measures depend on the severity of the disease and those symptoms experienced by the individual patient, and may comprise:

  • Transfusion of blood products in case of severe hemorrhages.
  • Diuretics to compensate for oliguria; a symptoms shown by the majority of patients at some point in time.
  • Drug therapy to relieve specific symptoms, e.g., alterations of blood pressure.
  • In case of renal insufficiency, dialysis.

Studies regarding antiviral treatment of HFRS patients yielded contradictory results. Thus, no such compounds can be recommended at this moment.

Prognosis

Prognosis largely depends on the precise type of HFRS. Hantaan virus-induced HFRS is a severe disease and mortality rates may reach 15%. Infection with the Dobrava-Belgrade virus results in fatality in up to 10% of all cases [1] [4]. In case of Seoul virus infection, the probability of death has been reported to be approximately 2%. For the remainder of HFRS, mortality is less than 1%.

Morbidity mainly results from irreversible kidney damage and may cause the necessity for dialysis and organ transplantation. However, if adequate treatment is provided in a timely manner, most patients recover without sequelae.

Etiology

HFRS is not a homogeneous disease and may be triggered by a variety of viruses pertaining to the genus Hantavirus, which, in turn, is part of the family of Bunyaviridae. All these viruses are single-stranded RNA viruses of negative polarity; they possess a tripartite genome, i.e., their total RNA is distributed over three particles.

HFRS-inducing viruses differ largely in virulence and geographical distribution, a fact that is reflected in the many alternative, more specific designations of HFRS. In most cases, this zoonotic disease is transmitted by rodents that excrete the respective pathogen with urine, feces, and saliva. People exposed to these excretions are likely to inhale the pathogen. Bites have been reported to result in human infection and are presumably an important route of transmission from animals to animals. Human-to-human transmission has not yet been reported.

In detail, the following viruses may cause HFRS:

  • Hantaan virus provokes Korean hemorrhagic fever, i.e., the most severe form of HFRS. It's endemic in East Asian countries like China and South Korea. The main reservoir of this virus is Apodemus Agrarius, the striped field mouse.
  • Dobrava-Belgrade virus is distributed in Balkan countries, Eastern Europe, and Russia. People who suffer from HFRS due to an infection with this pathogen are often diagnosed with Balkan hemorrhagic fever, a severe disease. The virus is transmitted by Apodemus Flavicollis, the yellow-necked mouse.
  • Seoul virus originates from Eurasia but can now be found in America too, relating to its main carriers Rattus Norvegicus and Rattus Rattus, the Norway and black rats [2]. The virus is of intermediate virulence.
  • Puumala virus causes nephropathia epidemica, a mild form of HFRS that is most commonly diagnosed in Northern Europe. Cases have been reported from other European countries, too. The virus' host is Myodes Glareolus, the European bank vole.
  • Saaremaa virus is a European virus that may provoke mild HFRS. It is transmitted by the striped field mouse.
  • Amur virus has been isolated from Apodemus Peninsulae, the Korean field mouse, in Far East Russia. It is a rare cause of HFRS and little is known about its virulence [3].

Epidemiology

Although HFRS is classically considered an Eurasian disease, introduction of infected carriers into the New World allowed for virus propagation in now endemic carrier populations in America. While soldiers of the United States have indeed been the first people who were diagnosed with HFRS, during the Korean war in the 1950s and after being exposed to infected mice, it was not until decades later that the disease has been contracted in the United States itself. More recent studies indicate the presence of HFRS-associated pathogens in South America, too [2].

Nevertheless, the highest incidence rates are still reported from East Asia. In China, more than 100,000 cases are registered every year. The incidence of HFRS due to infection with Dobrava-Belgrade virus is much lower, with only about 100 cases reported per year [4]. The Puumala virus causes about 10,000 annual cases of nephropathia epidemica in Europe [5]. In Far East Russia, 100 to 200 patients contract Amur virus-induced HFRS every year [3]. Seasonal variations have been observed and presumably depend on the population dynamics of carriers [5].

According to the above described etiology of HFRS, people who are frequently exposed to carriers, their urine, feces or saliva, may be considered to have a higher risk of contracting the disease. This may apply to farmers, campers, or anyone else who works or sleeps where infected animals may have passed. This hypothesis is supported by the fact that most cases of HFRS are reported in rural areas [6].

Sex distribution
Age distribution

Pathophysiology

Hantaviruses are known to infect endothelial cells, lymphocytes, and macrophages, among other cells [1]. This explains vascular damage and hemorrhages and implies the contribution of immune mechanisms to the pathogenesis of hemorrhagic fever. Indeed, infection with such pathogens induces a strong immune reaction, cytokine and mediator release, as well as complement activation. These pathophysiological events lead to vasodilatation and increased vascular permeability, thus exacerbating vascular dysfunction and triggering fever and hypotension. Moreover, extensive endothelial damage may lead to disseminated intravascular coagulopathy and thrombocytopenia.

In case of HFRS, the initial stages of fever and low blood pressure are followed by symptoms of renal failure, most likely provoked by local effects that add to renal vascular lesions. It has been proposed that deposition of immune complexes and complements may affect the kidneys. Hantaviruses also directly damage the renal podocytes [7]. The latter may correspond to antibody-dependent cytotoxicity. However, considerable knowledge gaps remain regarding the mechanisms behind the oliguric, diuretic and convalescent stages of the disease.

Prevention

In each country, the population should be educated regarding the risks of hantavirus infection, possible carriers and their natural habitats. In general, rodents are more common in rural areas, fields, and in barns. Additionally, they may be attracted to anywhere they smell food. Thus, in order to avoid exposure to their urine, feces and saliva, people should avoid sleeping outside houses, and store their foods out of reach of animals. Campers should consider the possibility that rodents urinate on accessible tables and if properly stored food is prepared here, it may become contaminated.

In China and Korea, vaccines are used to protect from HFRS [7] [10].

Summary

Hemorrhagic fever with renal syndrome (HFRS) is a type of viral hemorrhagic fever, and thus shows some pathophysiological and clinical similarities to Dengue fever, yellow fever, as well as ebola virus disease. Only those types of viral hemorrhagic fever that are triggered by viruses of the family of Bunyaviridae and that are characterized by renal failure are designated HFRS.

HFRS is a zoonotic disease. It may be induced by at least six different species of Hantavirus, namely the Hantaan virus, the Dobrava-Belgrade virus, the Seoul virus, the Puumala virus, the Saaremaa virus, and the Amur virus, and is usually contracted upon inhalation of airborne pathogens originating from urine and feces of infected rodents. The aforementioned viruses have mainly been encountered in distinct geographical areas of Asia and Europe, but the introduction of infected carries into Americas has lead to local outbreaks. In this context, it has to be mentioned that Korean hemorrhagic fever, Balkan hemorrhagic fever, nephropathia epidemica, are all terms that refer to HFRS, but those are used in determined countries if an infection with a particular virus species is detected.

Of note, hemorrhagic pulmonary syndrome is also caused by hantaviruses but constitutes a different entity [1].

Patient Information

Hemorrhagic fever with renal syndrome (HFRS) is a zoonotic disorder. There are distinctive viruses that may trigger this disease. They are all transmitted by rodents, but differ between different geographical areas. For instance, most cases of HFRS are registered in East Asia and are caused by the Hantaan virus. Such an infection results in a severe disease also referred to as Korean hemorrhagic fever. In contrast, in Europe, severe forms of HFRS are provoked by the Dobrava-Belgrade virus, which is distributed throughout the Balkan countries and Eastern Europe. Other forms of HFRS are less severe.

Infected rodents excrete virus particles with urine, feces, and saliva. People who live, work, or stay in close proximity to those animals may be exposed to their excretions. Airborne pathogens may be inhaled and cause fever, hemorrhages and renal failure. In order to avoid this, appropriate preventive measures should be taken to reduce the exposure to rodents.

References

Article

  1. Jonsson CB, Figueiredo LT, Vapalahti O. A global perspective on hantavirus ecology, epidemiology, and disease. Clin Microbiol Rev. 2010; 23(2):412-441.
  2. Costa F, Porter FH, Rodrigues G, et al. Infections by Leptospira interrogans, Seoul virus, and Bartonella spp. among Norway rats (Rattus norvegicus) from the urban slum environment in Brazil. Vector Borne Zoonotic Dis. 2014; 14(1):33-40.
  3. Kariwa H, Yoshikawa K, Tanikawa Y, et al. Isolation and characterization of hantaviruses in Far East Russia and etiology of hemorrhagic fever with renal syndrome in the region. Am J Trop Med Hyg. 2012; 86(3):545-553.
  4. Avšič Županc T, Korva M, Markotić A. HFRS and hantaviruses in the Balkans/South-East Europe. Virus Res. 2014; 187:27-33.
  5. Khalil H, Olsson G, Ecke F, et al. The importance of bank vole density and rainy winters in predicting nephropathia epidemica incidence in Northern Sweden. PLoS One. 2014; 9(11):e111663.
  6. Lee SH, Chung BH, Lee WC, Choi IS. Epidemiology of hemorrhagic fever with renal syndrome in Korea, 2001-2010. J Korean Med Sci. 2013; 28(10):1552-1554.
  7. Zou LX, Chen MJ, Sun L. Haemorrhagic fever with renal syndrome: literature review and distribution analysis in China. Int J Infect Dis. 2016; 43:95-100.
  8. Cosgriff TM. Mechanisms of disease in Hantavirus infection: pathophysiology of hemorrhagic fever with renal syndrome. Rev Infect Dis. 1991; 13(1):97-107.
  9. Ertek M, Buzgan T. An outbreak caused by hantavirus in the Black Sea region of Turkey, January-May 2009. Euro Surveill. 2009; 14(20).
  10. Huang X, Yin H, Yan L, Wang X, Wang S. Epidemiologic characteristics of haemorrhagic fever with renal syndrome in Mainland China from 2006 to 2010. Western Pac Surveill Response J. 2012; 3(1):12-18.

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Last updated: 2019-07-11 19:59