Nephropathia epidemica (NE).

Essentials

Nephropathia epidemica (NE) is an acute infectious disease in Northern Europe caused by Puumala (PUU) hantavirus (Vapalahti et al., 2003; Muranyi et al., 2005).
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, and proteinuria.
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 pulmonary syndrome (HPS) is encountered.
The Puumala hantavirus is transmitted to humans by the excretions of a bank vole (Clethrionomys glareolus), apparently by inhalation through the airways.
The majority of cases occur between August and January.
NE has not been shown to transmit between humans.
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.

Clinical Picture

The most common symptoms and signs of NE are presented in the table below.

Table. The Most Common Symptoms and Signs of NE (Mustonen et al., 1994; Lahdevirta 1971; Settergren et al., 1989)

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

Laboratory Findings

The most common laboratory findings in NE are presented in the Table below.

Table. The Most Common Laboratory Findings in NE (Mustonen et al., 1994; Lahdevirta 1971; Settergren et al., 1989)

Finding	Frequency (%)
Proteinuria Haematuria Increased serum creatinine* Thrombocytopenia Increased C-reactive protein (CRP) Increased liver enzymes Hypoalbuminaemia/hypoproteinaemia Leucocytosis >10.0 x 10⁹/L	94–100 58–87 86–96 75 52–60 41–60 24–64 23–57

*Usually 3 to 7 days after the onset of fever

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 (Kanerva et al., 1996)

Electrocardiogram (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 (Paakkala et al., 2002).

Diagnosis

Diagnosis is based on typical clinical picture and serology.
First-line studies in an outpatient unit include basic haematological parameters (haemoglobin or haematocrit, leucocyte count, and thrombocyte count), CRP, serum creatinine, and urinalysis.
Antibodies to Puumala hantavirus
- Diagnosis is confirmed with one serum sample using immunofluorescence and/or enzyme-linked immunological techniques.
- If the result is negative and less than 6 days have elapsed since the onset of symptoms, the result should be confirmed with another sample.

Differential Diagnosis

Other viral infections
Acute bacterial infections (septicaemias, 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 (renal failure, fluid retention)
4. Polyuric phase (excessive urinary secretion)
5. Convalescence phase (days, weeks, or even months)
About 5% of hospitalized patients need dialysis.
Severe course of the disease is associated with HLA-B8 and DR3 (Mustonen et al., 1996).

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; non-steroidal anti-inflammatory drugs (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 for hospital care
- Deteriorated general condition
- Dehydration
- Fluid retention
- Renal failure (serum creatinine >150 micromol/L), oliguria
- Uncertain 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 renal failure was associated with NE. 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

Mortality with NE is low (<0.1%).
Long-term prognosis with the disease is good (Miettinen et al., 2006).
Panhypopituitarism and chronic glomerulonephritis have been described as rare long-term complications of NE.

Prevention

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

Definitions:

Levels of Evidence

Quality of Evidence: High
Further research is very unlikely to change confidence in the estimate of effect
- Several high-quality studies with consistent results
- In special cases: one large, high-quality multi-centre trial

Quality of Evidence: Moderate
Further research is likely to have an important impact on confidence in the estimate of effect and may change the estimate.
- One high-quality study
- Several studies with some limitations

Quality of Evidence: Low
Further research is very likely to have an important impact on confidence in the estimate of effect and is likely to change the estimate.
- One or more studies with severe limitations

Quality of Evidence: Very Low
Any estimate of effect is very uncertain.
- Expert opinion
- No direct research evidence
- One or more studies with very severe limitations

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