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Keywords:

  • Hantavirus;
  • glaucoma;
  • hepatitis;
  • Puumala S segment;
  • reservoir host

Summary

  1. Top of page
  2. Summary
  3. Impacts
  4. Introduction
  5. Case History
  6. Discussion
  7. Acknowledgements
  8. Conflicts of Interest
  9. References

Nephropathia epidemica (NE) caused by Puumala hantavirus (PUUV) is a mild variant of haemorrhagic fever with renal syndrome, which is endemic in Germany. We describe the case of a 67-year-old man initially presenting with acute bilateral angle-closure glaucoma, an atypical clinical presentation of PUUV infection. Subsequently, the patient developed a severe course of disease additionally complicated by profound hepatitis and interstitial nephritis, both phenomena which are rarely described in association with hantavirus infection. Serologic diagnosis was complicated by delayed antibody production until the 10th day of illness; however, PUUV RNA was detectable early in disease. To further analyse this unusual case, sequencing of the PUUV S segment was performed from the patient and regional reservoir host which showed a close relation.


Impacts

  1. Top of page
  2. Summary
  3. Impacts
  4. Introduction
  5. Case History
  6. Discussion
  7. Acknowledgements
  8. Conflicts of Interest
  9. References
  •  Human infection with hantavirus is considered an emerging zoonotic disease that causes haemorrhagic fever with severe organ impairment of either kidney (in Europe and Asia) or lung function (North and South America).
  • Puumala virus caused a hantavirus epidemic in Germany in 2010 with more than 2000 recorded cases, which is the highest number ever recorded for this area.
  •  Atypical and severe cases – which complicate the diagnosis for clinicians – should be evaluated by methods of molecular diagnosis for further analysis of the infecting strain based on PCR and sequencing to detect new variants.

Introduction

  1. Top of page
  2. Summary
  3. Impacts
  4. Introduction
  5. Case History
  6. Discussion
  7. Acknowledgements
  8. Conflicts of Interest
  9. References

Hantaviruses (Bunyaviridae family) cause two distinct zoonotic diseases in humans, hantavirus pulmonary syndrome predominantly in North and South America and haemorrhagic fever with renal syndrome (HFRS) in Europe and Asia (for an overview see Jonsson et al., 2010). In Central Europe, a mild form of HFRS, called nephropathia epidemica (NE), is mainly caused by Puumala virus (PUUV) with its reservoir host, the bank vole (Myodes glareolus) (Vapalahti et al., 2003). Hantavirus infection in Germany varies in a cyclic fashion with high case numbers recorded in 2005, 2007 and most recently in 2010 when more than 2000 cases were recorded, which is the highest number ever since mandatory registration started (Faber et al., 2010; Robert Koch Institute, 2011). However, as a large subset of infections are clinically mild or even asymptomatic and presentation can be rather unspecific, the estimated number of unreported cases is thought to be much higher.

Human infection occurs after inhalation of contaminated aerosolized excreta, urine and saliva of chronically infected bank voles. Risk areas in Germany for PUUV infection are forested areas in the south-west as most cases are reported from this area, and new genotypes associated with severe disease have been described before from this area (Zeier et al., 1992). Factors that influence the risk of human hantavirus infection are increased population size of the reservoir host, fostered by mild climate which leads to increased food supply, but also human behaviour and land-use (Schwarz et al., 2009; Tersago et al., 2009). Known behavioural risk factors for NE include occupational construction work, living close to forested areas and exposure to mice (Abu Sin et al., 2007).

The incubation period of PUUV is usually 2–3 weeks; however, it can vary considerably (Vapalahti et al., 2003). Nephropathia epidemica is generally a mild to moderate disease with initially influenza-like symptoms such as fever and headache, followed by gastrointestinal symptoms, blurred vision, back pain, acute renal failure with anuria or oliguria, proteinuria and haematuria (Huttunen et al., 2011). Owing to the extremely variable presentation of symptoms, the initial diagnosis is often not hantavirus infection, and rare findings as a result of an atypical course of disease can further complicate the diagnosis and adequate treatment (Braun et al., 2010).

Case History

  1. Top of page
  2. Summary
  3. Impacts
  4. Introduction
  5. Case History
  6. Discussion
  7. Acknowledgements
  8. Conflicts of Interest
  9. References

A 67-year-old man, living in Southern Germany, was presented to the emergency department after having been collapsed. He reported a 3-day history of fever up to 39.7°C, diarrhoea, nausea, myalgia, severe head and back pain, progressive vision disturbance and photophobia. He had no medical or travel history. The patient lives close to the forest and reported hay mowing on the forest edge as well as visits to the local golf course surrounded by forest. However, observation of mice was not remembered on any occasion.

Physical examination on admission was remarkable for conjunctival redness, photophobia and severe eye pain but otherwise normal. Main unusual findings on admission were decreased platelets (38/nl), elevated lactate dehydrogenase (LDH, 463 U/l), C-reactive protein (CRP, 142 mg/dl) and aspartate transaminase (AST, 74 U/l) (Table 1). Blood cultures and serology for leptospirosis, toxoplasmosis, Treponema pallidum, cytomegalovirus, Epstein–Barr virus, hepatitis A, B, C and E were unremarkable. Urine examination showed proteinuria and abundance of casts in the sediment. A chest X-ray was unremarkable, and abdominal ultrasound showed mild splenomegaly and normal sized, but hyperechogenic kidneys.

Table 1.   Main laboratory findings on admission
ParameterValue on admissionNormal range
Leucocytes, /nl5.54–10
Erythrocytes, /pl5.54.3–6.1
Haemoglobin, g/dl17.613–17
Haematocrit, l/l0.470.38–0.52
Platelets, /nl38150–440
Sodium, mm129135–145
Potassium, mm1.610.1–1.3
Urea, mg/dl49−45
Glucose, mg/dl13665–110
Creatinine kinase, U/l92−190
Creatinine, mg/dl1.610.3–1.3
p-Amylase, U/l188–53
Albumin, g/l34.830–50
Alkaline phosphatase, U/l7440–130
Urea, mg/dl49≤45
Lactate dehydrogenase, U/l463≤248
C-reactive protein, mg/dl142<5
Procalcitonin, ng/ml1.11<0.05
Aspartate transaminase, U/l74≤35
γ-Glutamyl transferase, U/l65≤60
Procalcitonin, ng/ml1.11<0.05
International normalized ratio1.01.2
Partial thromboplastin time, s29−35
Fibrinogen, g/l4.41.7–4.5

Owing to vision disturbance, a bedside ophthalmologic examination was immediately performed which revealed elevated intraocular pressure of 50 and 40 mmHg on the right and left eye, respectively, leading to the diagnosis of bilateral acute angle-closure glaucoma. Eye drops containing brimonidin and dorzolamid/timolol as well as latanoprost were applied immediately, and then, pilocarpin 1% was applied every 10 min. Furthermore, therapy with i.v. fluids and acetazolamide was initiated and intraocular pressure decreased to 25–20 mmHg (right) and 15 mmHg (left) after 2 h. Nausea, headache and visual acuity improved soon. Besides bilateral iris sphincter defect, no other pathologies such as optical nerve damage or visual field defect remained. Antibiotic therapy with ciprofloxacin and cefotaxime was initiated together with fluid balance. Within the next days, the patient’s general condition deteriorated with anuria and a serum creatinine rise to a maximum value of 8.5 mg/dl. On day 10 of illness, a steep rise in liver transaminases was seen. Several serologic tests were repeated, by that time antibodies against hantavirus subtype PUUV became detectable by immunoblot analysis (Mikrogen, Munich, Germany). This was confirmed by rising PUUV antibody titres in all follow-up samples (Fig. 1).

image

Figure 1.  Puumala-specific serology (IgG, IgM), RT-PCR results, over time. Creatinine, CRP, Platelets and liver enzymes. AST/ALT, aspartate aminotransferase ratio/alanine aminotransferase ratio.

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Improvement of the patient’s general state was slow, and on the 18th day of hospitalization, his creatinine rose again. A renal biopsy was performed revealing interstitial nephritis. Treatment with cortisone was started, and creatinine decreased slowly but remained elevated above the physiological value.

Puumala virus RNA was detected in the first available blood sample upon admission (day 4 of illness) (Fig. 1) by PCR (methods as recently described by Hofmann et al., 2008). To further analyse the infecting strain, sequence analysis of the PCR product was performed. Phylogenetic analysis revealed that the PUUV sequence obtained from the patient (10 H244 Wiesenbach) clustered with a human and a murine PUUV sequence and grouped in the Spessart Forest clade (Fig. 2).

image

Figure 2.  Consensus neighbour-joining phylogenetic tree (TN93 evolutionary model) of European Puumala virus (PUUV) strains based on partial sequences of the S segment (504 nt, position 397–900). Bootstrap values more than 70%, calculated from 10 000 replicates, are shown at the tree branches. PUUV-like sequences from Japan (JPN) were used as an outgroup. Sequences taken from GenBank are indicated by their accession numbers. The numbers 04 to 10 indicate the year of sampling, ○ represents human samples, while • stands for murine samples. The PUUV sequence of the presented case (10 H244 Wiesenbach) groups in the Spessart Forest clade and is marked in bold. For clarity, previously characterized PUUV clades from other parts of Europe are shown in simplified form, including the accession numbers. The complete data set of PUUV sequences as presented by Hofmann et al., 2008 was used to calculate the tree. Previously defined lineages are indicated by abbreviated names: AUT, Austrian; BAL, Balkan; BALT, Baltic; DAN, Danish; FIN, Finnish; NSCA, North Scandinavian; OMSK, Russian from Omsk region; RUS, Russian; SSCA, South Scandinavian. Scale bar indicates an evolutionary distance of 0.1 substitutions per position.

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Discussion

  1. Top of page
  2. Summary
  3. Impacts
  4. Introduction
  5. Case History
  6. Discussion
  7. Acknowledgements
  8. Conflicts of Interest
  9. References

Hantavirus infection is recognized as an emerging infectious disease and in addition, case numbers in Germany increased over the past decade, and this trend is thought to continue (Schwarz et al., 2009). While the heterogeneous clinical presentation of hantavirus can mimic a wide variety of other diseases or syndromes, diagnosis is hindered and treatment delayed. Therefore, detailed clinical description of unusual cases is necessary to document the disease spectrum and to detect potentially new variants.

In our case, the most remarkable symptom upon admission was bilateral acute angle-closure glaucoma. Acute angle-closure glaucoma is defined as a sudden rise in intraocular pressure because of closure of the Schlemm canal, which drains ocular fluid out of the anterior chamber into the vascular system. Several anatomic abnormalities predispose individuals towards acute angle-closure glaucoma. These include shallower space between the cornea and the iris, an instable iris, a thicker lens, and hyperopia. All these anatomical variations can result in a narrow iridocorneal angle. If the angle is suddenly completely closed because of forward displacement of the root of the iris against the cornea, an acute angle-closure glaucoma is the consequence. In the literature, the association between acute angle-closure glaucoma and PUUV is rarely described while ocular symptoms like transitory myopia and decreased visual acuity in PUUV infections are frequently found (Saari and Luoto, 1984; Kontkanen et al., 1995; Zimmermann et al., 2011). In studies where intraocular pressure was measured prospectively, values seemed to be rather decreased than increased. Only in a single case report, a bilateral acute angle-closure glaucoma, owing to oedema and haemorrhage in the ciliary body result in anterolateral rotation of the iris–lens diaphragm with closure of the chamber angle, is described (Zimmermann et al., 2011).

Our hypothesis for the pathology of acute angle-closure glaucoma in patients with PUUV is based on a temporary change of the lens either in its position or thickness. This hypothesis is supported by transitory myopic shift described by other authors before. An osmotic process owing to the systemic disease in the vitreous could explain an increase in vitreous volume, which could cause a forward displacement of the lens. Also, one could imagine an increase in the thickness of the lens owing to osmotic changes. Both phenomena could cause a myopic shift and an acute angle closure. While the majority of symptoms such as blurred vision or myopic shift are transient and resolve spontaneously, immediate treatment is crucial in acute glaucoma attack to prevent vision loss.

Also, severe liver involvement is not a key feature of PUUV infection, although mild liver enzyme elevation is sometimes seen during NE. Severe hepatitis with drastic liver enzyme increase as seen in the presented case has not been described in association with PUUV infection so far. Although the rise in liver enzymes could be attributed to the intake of potentially hepatotoxic drugs, this seems rather unlikely due to rather low doses of pain medication and antibiotics during the course of disease. Rapid decrease in liver function to normal values in parallel to overall improvement of kidney function and the patients’ general condition suggests a virus-related pathogenesis.

During convalescence phase, the patient additionally developed interstitial nephritis approximately 2 weeks after the onset of symptoms. As drugs are a common cause of interstitial nephritis, this is most likely in our case, too. Remarkably, during the 2010 epidemic, we observed that a large subset of patients presenting with NE report medication with potentially nephrotoxic drugs, i.e., pain killers, at some point during the course of disease (unpublished observation). Consequently, physicians taking care of hantavirus-infected patients should be alert of the risk of subsequent nephropathy caused by drugs after hantavirus infection.

In the case presented, diagnosis was hindered as the first serological response was detected 10 days after the onset of symptoms. In most settings, laboratory diagnosis of hantavirus infection is based on serological assays using the immunodominant nucleocapsid protein. By the time, patients are symptomatic, most patients have detectable antibodies; however, few cases showed delayed IgM response (Kramski et al., 2007). The IgG response is long lasting but delayed in about 10% of acute-phase IgM-positive sera. Repeated testing is therefore recommended in patients with unclear febrile illness reminiscent of hantavirus infection. For early testing or confirmation of questionable serological results, viral RNA can be detected by RT-PCR. As the viraemic period in human hantavirus infection is short with fluctuating RNA levels, molecular genetic approaches are not routinely used for the diagnosis of hantavirus infections (Kramski et al., 2007; Schilling et al., 2007). Especially for patients living in high-risk areas with symptoms indicating a hantavirus infection, molecular analysis can facilitate the identification of causative pathogen and might detect new sublineages.

In our case, phylogenetic analysis revealed that the PUUV sequence clustered with a human and a murine PUUV sequence and grouped in the Spessart Forest clade; thus, the patient was infected with a local variant of PUUV and fully recovered.

Acknowledgements

  1. Top of page
  2. Summary
  3. Impacts
  4. Introduction
  5. Case History
  6. Discussion
  7. Acknowledgements
  8. Conflicts of Interest
  9. References

Expert technical assistance by Mrs. C. Stephan (Charité Berlin) is gratefully acknowledged.

References

  1. Top of page
  2. Summary
  3. Impacts
  4. Introduction
  5. Case History
  6. Discussion
  7. Acknowledgements
  8. Conflicts of Interest
  9. References
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