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Epidemic Nephropathy

Essentials

Epidemic nephropathy (nephropathia epidemica or NE) is an acute infectious disease in Northern Europe caused by Puumala hantavirus (PUUV).
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 transient myopic phase.
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 or sign	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
Myopia	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, decreased haemoglobin 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 rarely pulmonary oedema.

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. 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.
- ECG and renal echography are not necessary for the diagnosis of epidemic nephropathy. If they have been examined for differential diagnosis, the following findings may be noted.
  - Non-specific and transient changes may be detected on ECG: ST segment depression and T wave inversion.
  - A bradycardia out of proportion to the fever is a common finding.
  - On echocardiography, an increase in the size of the kidneys and fluid accumulation around the kidneys may be found.

Differential diagnosis

Other acute viral infections
Acute bacterial infections (sepsis, 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) Acute Kidney Injury
- 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

Vial PA, Ferrés M, Vial C et al. Hantavirus in humans: a review of clinical aspects and management. Lancet Infect Dis 2023;():. [PubMed]
Koskela S, Mäkelä S, Strandin T et al. Coagulopathy in Acute Puumala Hantavirus Infection. Viruses 2021;13(8):. [PubMed]
Hautala N, Partanen T, Kubin AM et al. Central Nervous System and Ocular Manifestations in Puumala Hantavirus Infection. Viruses 2021;13(6):. [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]
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]
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]
Mustonen J, Outinen T, Laine O et al. Kidney disease in Puumala hantavirus infection. Infect Dis (Lond) 2017;49(5):321-332. [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]
Vaheri A, Strandin T, Hepojoki J et al. Uncovering the mysteries of hantavirus infections. Nat Rev Microbiol 2013;11(8):539-50. [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, 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]

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