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Nephropathia Epidemica (Ne)

Essentials

Nephropathia epidemica (NE) is an acute infectious disease in Northern Europe caused by Puumala (PUU) hantavirus.
The clinical picture varies from symptomless to severe.
NE should be suspected in patients with acute febrile disease who are found to have thrombocytopenia, haematuria, proteinuria and increased CRP concentration.
Infection confers lifelong immunity.

Epidemiology

Hantaviruses are enveloped RNA-viruses found all over the world.
In Europe and Asia, hantaviruses cause haemorrhagic fever with renal syndrome (HFRS). On the American continent, the so called hantavirus cardiopulmonary syndrome (HCPS) is encountered.
The Puumala hantavirus is transmitted to humans by the aerosols from the excretions of its carrier rodent, bank vole (Clethrionomys glareolus), by inhalation through the airways. The infection might possibly be contracted also through the gastrointestinal tract.
Smoking increases the risk of infection.
NE has not been shown to transmit between humans.
The majority of cases occur between August and January.
Two thirds of the patients are men.
In children, the disease is found rather seldom and the clinical course is usually milder than in adults.

Symptoms and signs

Incubation period is usually 2-4 weeks but may vary from one to 8 weeks.
The typical symptoms of NE are sudden high fever, headache, nausea, vomiting, abdominal pain and back ache as well as visual disturbances.
The most common symptoms and signs are presented in table T1.

The most common symptoms and signs of NE in patients treated in hospital

Symptom	Frequency (%)
Fever	98-100
Headache	62-90
Back ache	54-82
Abdominal pain	43-67
Nausea / vomiting	58-84
Myalgia	27-69
Oliguria (< 400 ml/24 hrs)	54-70
Polyuria (> 2 000 ml/24 hrs)	97
Visual disturbances	12-36
Petechiae	1-12
Diarrhoea	12-20
Cough	6-32
Vertigo*	12-25

* CNS symptoms like headache, nausea, vertigo and fatigue are commonly encountered in patients admitted to hospital. Some patients may have symptoms suggesting encephalitis, like confusion and sleepiness.

Investigations

The typical laboratory findings are leucocytosis, thrombocytopenia, proteinuria, haematuria and increased plasma CRP and creatinine concentration.
Thrombocytopenia is found in up to 90% of patients admitted to hospital. The platelet count is at its lowest on the 4th-5th day after the onset of the symptoms and returns to normal in a few days.
The most common laboratory findings in NE are presented in table T2.

The most common laboratory findings in NE in patients treated in hospital

Finding	Frequency (%)
Proteinuria	94-100
Haematuria	58-87
Increased plasma creatinine *	86-96
Thrombocytopenia	75-90
Increased CRP	52-60
Increased liver enzymes	41-60
Hypoalbuminaemia/hypoproteinaemia	24-64
Leucocytosis > 10.0 × 10⁹ /l	23-57

* Usually 3 to 7 days after the onset of fever

The result of chemical urine screening test taken at arrival at hospital predicts well how high the plasma creatinine concentration will rise during hospital care. A large sum of positive findings in the dipstick test (albuminuria, haematuria, glucosuria) predicts the emergence of severe kidney injury.

In some patients, increased haemoglobin or haematocrit values are found in the acute phase; later on, anaemia is common.

Disturbances in electrolyte balance are common but their clinical significance is usually marginal.

Chest x-ray

Abnormal chest x-ray findings are present in one third of hospitalized adult patients: pleural effusion, parenchymal infiltrates, and occasionally pulmonary oedema.

ECG

Nonspecific, transient changes are found in a half of the hospitalized patients: ST-depression and T-wave inversions.

Ultrasonography of the kidneys

Enlarged kidneys with pleural, pericardial or perirenal effusions may be found in ultrasound examination.

Diagnosis

Diagnosis is based on typical clinical picture and serology.
First-line studies in an outpatient unit include basic blood count with platelets, CRP, plasma creatinine and urinalysis.
Antibodies to Puumala hantavirus
- Diagnosis is confirmed with one serum sample using immunofluorescence and/or enzyme-linked immunological techniques. A rapid test is also available (immunochromatographic assay).
- In some patients the IgM response may be delayed. If less than 6 days have elapsed since the onset of symptoms, a negative result should be confirmed with another sample taken a few days later.

Differential diagnosis

Other viral infections
Acute bacterial infections (septicaemia, pyelonephritis)
Other types of acute nephritis

Course of the disease

There are typical phases in the clinical course; however, they are not seen in all patients.
1. Febrile phase (high fever, pains, general symptoms)
2. Hypotensive phase (haemoconcentration, shock)
3. Oliguric phase (acute kidney injury, fluid retention)
4. Polyuric phase (excessive urinary secretion)
5. Convalescence phase (days, weeks, or even months)
About 5% of hospitalized patients need dialysis.
Acute kidney injury associated with NE is more severe in smoking persons than in non-smokers.
The kidney injury is usually fully reversed.

Treatment

Mild cases may be treated in primary health care on an outpatient basis or on the observation ward of a health centre.
- Fluid therapy
- Analgesics
  - Paracetamol is a suitable analgesic; NSAIDs should be avoided because they impair renal function.
- Patient's condition and laboratory parameters should be frequently monitored: depending on the clinical picture, the situation is assessed every 2 or 3 days or even daily if necessary.
Indications for referral to hospital care
- Deteriorated general condition
- Symptoms and signs of shock
- Disturbance of fluid balance (hypo- or hypervolemia)
- Severe pains
- Acute kidney injury (increased creatinine concentration or clearly reduced urine amount)
- Albumin ++ or more in urine dipstick test
- Severe thrombocytopenia (blood platelet count below 50 x 10⁹ )
- Uncertainty about the diagnosis

Follow-up

A control visit is recommended one week to one month after hospital discharge depending on the severity of the disease, especially if acute kidney injury was associated with EN. The clinical condition and the laboratory parameters should be normalized one month after the onset of the disease.
Fatigue may continue several weeks after the acute phase.

Prognosis and compensation

Mortality with NE is low (< 0.08%).
Long-term prognosis with the disease is good.
Panhypopituitarism and chronic glomerulonephritis have been described as very rare long-term complications of NE.
In NE, treatment costs may be compensated in certain occupations (e.g. farmers) as an occupational disease. Find out about local legislation and policies.

Prevention

There is no research evidence on the possible benefit from a respirator mask in the prevention of NE.
There is no vaccine against the Puumala virus.

References

Mustonen J, Brummer-Korvenkontio M, Hedman K et al. Nephropathia epidemica in Finland: a retrospective study of 126 cases. Scand J Infect Dis 1994;26(1):7-13. [PubMed]
Lähdevirta J. Nephropathia epidemica in Finland. A clinical histological and epidemiological study. Ann Clin Res 1971;3:1-54. [PubMed]
Settergren B, Juto P, Trollfors B, Wadell G, Norrby SR. Clinical characteristics of nephropathia epidemica in Sweden: prospective study of 74 cases. Rev Infect Dis 1989 Nov-Dec;11(6):921-7. [PubMed]
Kanerva M, Paakkala A, Mustonen J, Paakkala T, Lahtela J, Pasternack A. Pulmonary involvement in nephropathia epidemica: radiological findings and their clinical correlations. Clin Nephrol 1996 Dec;46(6):369-78. [PubMed]
Paakkala A, Kallio T, Huhtala H, Apuli P, Paakkala T, Pasternack A, Mustonen J. Renal ultrasound findings and their clinical associations in nephropathia epidemica. Analysis of quantitative parameters. Acta Radiol 2002 May;43(3):320-5. [PubMed]
Mustonen J, Partanen J, Kanerva M, Pietilä K, Vapalahti O, Pasternack A, Vaheri A. Genetic susceptibility to severe course of nephropathia epidemica caused by Puumala hantavirus. Kidney Int 1996 Jan;49(1):217-21. [PubMed]
Miettinen MH, Mäkelä SM, Ala-Houhala IO, Huhtala HS, Kööbi T, Vaheri AI, Pasternack AI, Pörsti IH, Mustonen JT. Ten-year prognosis of Puumala hantavirus-induced acute interstitial nephritis. Kidney Int 2006 Jun;69(11):2043-8. [PubMed]
Mäkelä S, Kokkonen L, Ala-Houhala I, Groundstroem K, Harmoinen A, Huhtala H, Hurme M, Paakkala A, Porsti I, Virtanen V, Vaheri A, Mustonen J. More than half of the patients with acute Puumala hantavirus infection have abnormal cardiac findings. Scand J Infect Dis 2009;41(1):57-62. [PubMed]
Vaheri A, Henttonen H, Voutilainen L et al. Hantavirus infections in Europe and their impact on public health. Rev Med Virol 2013;23(1):35-49. [PubMed]
Vapalahti K, Virtala AM, Vaheri A et al. Case-control study on Puumala virus infection: smoking is a risk factor. Epidemiol Infect 2010;138(4):576-84. [PubMed]
Hautala T, Mähönen SM, Sironen T et al. Central nervous system-related symptoms and findings are common in acute Puumala hantavirus infection. Ann Med 2010;42(5):344-51. [PubMed]
Vaheri A, Strandin T, Hepojoki J et al. Uncovering the mysteries of hantavirus infections. Nat Rev Microbiol 2013;11(8):539-50. [PubMed]
Tervo L, Mäkelä S, Syrjänen J et al. Smoking is associated with aggravated kidney injury in Puumala hantavirus-induced haemorrhagic fever with renal syndrome. Nephrol Dial Transplant 2015;30(10):1693-8. [PubMed]
Outinen TK, Mäkelä S, Clement J et al. Community Acquired Severe Acute Kidney Injury Caused by Hantavirus-Induced Hemorrhagic Fever with Renal Syndrome Has a Favorable Outcome. Nephron 2015;130(3):182-90. [PubMed]
Mustonen J, Mäkelä S, Outinen T et al. The pathogenesis of nephropathia epidemica: new knowledge and unanswered questions. Antiviral Res 2013;100(3):589-604. [PubMed]
Mustonen J, Outinen T, Laine O et al. Kidney disease in Puumala hantavirus infection. Infect Dis (Lond) 2017;49(5):321-332. [PubMed]
Mantula PS, Outinen TK, Clement JPG et al. Glomerular Proteinuria Predicts the Severity of Acute Kidney Injury in Puumala Hantavirus-Induced Tubulointerstitial Nephritis. Nephron 2017;136(3):193-201. [PubMed]
Latronico F, Mäki S, Rissanen H et al. Population-based seroprevalence of Puumala hantavirus in Finland: smoking as a risk factor. Epidemiol Infect 2018;146(3):367-371. [PubMed]
Tietäväinen J, Mantula P, Outinen T et al. Glucosuria Predicts the Severity of Puumala Hantavirus Infection. Kidney Int Rep 2019;4(9):1296-1303. [PubMed]

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