The vast majority of European Hantavirus cases are caused by Puumala virus, carried by the bank vole and responsible for Nephropathia epidemica (NE) . The aim of the study was to evaluate whether clinical and laboratory findings are associated with ophthalmic involvement and disease severity in NE in Austria.
Patients examined at the emergency room of the university hospital of Graz were eligible for study inclusion. Graz is located in the south-east of Austria where a vast majority of Austrian Puumala virus infections have been identified to date . In the case of clinical suspicion of NE, diagnosis was established within 12 h after presentation using antibody testing (Point-of-care PUUMALA; Reagena, Toivala, Finland). Patients with a positive antibody test were examined by ophthalmologists within the same day. Ocular examination comprised determination of refraction (compared with baseline refraction) and best-corrected visual acuity, intraocular pressure using Goldmann applanation tonometry and split lamp examination. Patients were examined up to four times in certain cases until ocular manifestations returned to normal or to documented baseline refraction determined prior to NE. Body temperature was measured three times a day and additionally whenever the patient felt febrile. In addition, hypotension (<90 mmHG), bradycardia (<60 bpm) and tachycardia (>100 bpm) were measured three times a day. Furthermore, abnormal findings in liver function tests (AST, ALT), gamma-glutamyl transferase (GGT) and other laboratory parameters such as creatinine, urea, leukocytes, thrombocytes, CRP and LDH were assessed daily until discharge. The highest values (the lowest value for thrombocytes) were used for statistical calculations as described below.
Eighteen patients with NE (aged 18–68 years, median 40.5 years; two female, 16 male) were investigated. Patients had their first contact and investigation in the emergency room between day 1 and 14 (median, day 4) after onset of NE. Two patients had systemic symptoms (e.g. fever, cephalea, nausea) for 14 days prior to presentation and both had ophthalmic involvement. Myopic shift (=change in refraction power towards myopic direction) occurred in 9/18 (50%) patients; in eight in both eyes, in one patient in the left eye only. The average myopic shift was −2.75 diopters (maximum −3.50, minimum −1.50) in the right eye and −2.54 diopters (maximum −4.00, minimum −1.00) in the left eye. Blurred vision occurred in 14/18 (78%), conjunctival injection in 4/18 (22%), and subconjunctival haemorrhages in 1/18 (6%) patients. Intraocular pressure was normal in all eyes. All ocular manifestations were transient and did not require any treatment.
Fever (>37.8°C) was observed in 15/18 (83%) patients (median duration 7.5 days; minimum 0, maximum 15). The rates of bradycardia, tachycardia and hypotonia are depicted in Table 1. Three out of eighteen (17%) patients required haemodialysis; none of these three had myopic shift. Laboratory values are depicted in Table 2. There was no significant difference in clinical signs and symptoms and laboratory parameters between patients with and without myopic shift or with and without blurred vision (chi-square test for categorical variables; Mann–Whitney U-test for non-normally distributed continuous parameters). Only for C-reactive protein (CRP) was a difference found, with higher values measured in patients without blurred vision (p 0.03).
Table 1. Clinical signs in patients with and without myopic shift/blurred vision
| ||Patients with myopic shift, %||Patients without myopic shift, %||p-value||Patients with blurred vision, %||Patients without blurred vision, %||p-value|
|Hypotonia (<90 mmHG syst)||11 (1/9)||0 (0/9)||0.303||7 (1/14)||0 (0/4)||0.582|
|Tachycardia (>100 bpm)||11 (1/9)||33 (3/9)||0.257||21 (3/14)||25 (1/4)||0.88|
|Bradycardia (<50 bpm)||44 (4/9)||33 (3/9)||0.629||36 (5/14)||50 (2/4)||0.605|
|Fever (>37.8°C)||89 (8/9)||78 (7/9)||0.527||86 (12/14)||75 (3/4)||0.612|
Table 2. Laboratory values in patients with and without myopic shift/blurred vision
|Variable (normal range)||Patients with myopic shift (n = 9); median (range)||Patients without myopic shift (n = 9); median (range)||p-value||Patients with blurred vision (n = 14); median (range)||Patients without blurred vision (n = 4); median (range)||p-value|
|AST (<30) U/L||61 (31–93)||66 (26–193)||0.269||65 (26–193)||88.5 (53–119)||0.222|
|ALT (<35) U/L||83 (20–134)||84 (17–305)||0.353||83 (17–305)||132.5 (67–233)||0.089|
|GGT (<38) U/L||93 (27–895)||66 (16–377)||1.000||93 (16–895)||90 (32–153)||0.710|
|Creatinine (0.5–1) mg/dL||3.5 (1.1–6.7)||1.9 (0.8–10.2)||0.566||3.5 (0.8–10.2)||3.75 (1.4–8.9)||0.632|
|Urea (10–45) mg/dL||137 (30–245)||66 (21–207)||0.310||125 (21–245)||90 (61–158)||1.000|
|Leucocytes (4.4–11.3) G/L (highest value)||11.98 (5.3–22.4)||10.6 (5–13.6)||0.691||11.98 (4.98–22.41)||10.41 (8.35–13.62)||0.832|
|Thrombocytes (1140–440) G/L (lowest value)||42 (25–138)||83 (35–280)||0.122||51 (25–251)||67.5 (35–280)||0.559|
|CRP (<5) mg/L||64 (1–134)||66 (1–257)||0.791||63 (1–134)||170 (66–257)||0.026*|
|LDH (120–240) U/L||281 (190–682)||334 (165–550)||0.791||340 (165–682)||295 (240–340)||0.490|
Myopic shift was less frequent in our study (50%) compared with a Finnish study (78%) . On the other hand, the average myopic shift in our study (−2.75 diopters right eye, −2.54 diopters left eye) was more pronounced than in two other Finnish studies [3,4]. The rate of conjunctival haemorrhages in our study (6%) was similar to previous rates (2% and 4%, respectively) [3,5]. Conjunctival injection in our study (22%) resembled previous findings (27%) , but was lower compared with another Finnish study (87%) . The frequency of ocular findings in Puumala virus infections seems to be diverse in different European countries, so local epidemiological data are necessary to interpret these clinical findings correctly. It is not clear whether differences in occurrence rates and in severity of ocular symptoms in different countries are due to variant virus strains, predisposition of inhabitants or diagnostic differences. The latter, however, is unlikely as the serological tests applied in our study (i.e. Point-of-care PUUMALA; Reagena) have also been used in previous European investigations [6,7]. In contrast to recent studies , we also evaluated patients with renal failure requiring haemodialysis and none had myopic shift. Previously, shallowing of the anterior chamber, thickening of the lens, changes in osmolarity of lens and aqueous humour, length of vitreous cavity and increased tissue permeability have been considered as possible mechanisms for ocular symptoms in NE . Interestingly, one patient in our study presented myopic shift and decreased anterior chamber depth only in one eye. This is in contrast to the assumption that myopic shift is part of a systemic infection by Puumala virus . This finding may argue for a local ocular manifestation as the causative pathogenesis of myopic shift in NE or reflects differences in time of resolution of myopic shift in both eyes. In four patients with blurred vision myopic shift was not detected. It is unclear whether this was due to the fact that refraction had already normalized at the time of examination or a slightly oedematous lens was still present, or was due to non-ophthalmic reasons in Puumala virus infections; one reason could be involvement of the CNS as previously published [6,8–11].
In conclusion, ocular symptoms (especially blurred vision and myopic shift) are frequent in Puumala virus infection in Austria and may therefore be important in diagnosis of the disease. Except for higher CRP values in patients without blurred vision, there was no difference in clinical variables and laboratory parameters in patients with or without blurred vision/myopic shift, suggesting that both are independent of disease severity in Puumala virus infections.