Ocular features of hantavirus infection.

Hantavirus infections are an emerging infectious disease that is beginning to be recognized both worldwide and in India as a cause of hemorrhagic fever that may present as a pulmonary syndrome or as a renal syndrome. Reports of ocular involvement are rare and include transient myopia, low intraocular pressure, conjunctival hemorrhages and changes of intraocular dimensions. Eleven patients (10 males, one female, mean age 37.6 years) were admitted to the intensive care unit for pyrexia of unknown origin or hemorrhagic fever following exposure to flood waters. Five male patients (mean age 31.6 years) were identified as suffering from hantavirus infection. In one patient, dot and blot intraretinal hemorrhages were seen in the macula of one eye and streak hemorrhages of the disc in the other. In the remaining four, no fundus abnormalities were seen. Ophthalmologists should be aware of these features.

Hantavirus infections are increasingly recognized zoonoses. Hantaviruses are members of the virus family, Bunyaviridae and are enveloped, single-stranded RNA viruses. Several species have been identified worldwide including China, the Korean Peninsula, Russia (Hantaan, Puumala and Seoul viruses) and northern and western Europe (Puumala and Dobrava viruses). The virus is rodent-borne and transmission is via aerosols of excreta, saliva and urine.1 Following an initial pulmonary infection, there is an initial incubation period of 10 to 14 days following which dissemination occurs that leads to an acute systemic illness characterized by bleeding and shock. The common clinical patterns include hemorrhagic fever with renal syndrome (HFRS) or hantavirus pulmonary syndrome (HPS). Hemorrhagic fever with renal syndrome is marked by sudden and extreme albuminuria, due to renal medullary damage, that may lead to renal impairment and/or failure. Hantavirus pulmonary syndrome is characterized by lung involvement that manifests as an interstitial pulmonary edema. Eventually, the patient experiences hypotension, shock and respiratory distress followed by respiratory failure. In India, hantavirus infection is beginning to be recognized as a cause of pyrexia of unknown origin (PUO)2 and unexplained renal failure3 or adult respiratory distress syndrome (ARDS).

Reports of ocular involvement in hantavirus infection are rare and findings from northern European patients have described transient myopia, low intraocular pressure, conjunctival hemorrhages and changes of intraocular dimensions including shallowing of the anterior chamber and narrowing of the anterior chamber angle.4,5,6

We report the systemic and ocular findings of five patients with hantavirus infection.

Case Report

Following heavy rains on July 26, 2005, several parts of the city experienced flooding forcing residents to wade through ankle-deep or in several cases, waist-deep water. Beginning two weeks later and over the next two to three days, 11 patients were admitted to the intensive care unit for pyrexia of unknown origin (PUO) or hemorrhagic fever. There were 10 males and one female patient with ages ranging from 20 to 58 years (mean 37.6 years) and there was a positive history of wading through floodwaters in every case. An initial differential diagnosis of leptospirosis, dengue fever or hantavirus infection was considered and all patients underwent a complete physical, laboratory (hemoglobin estimation, complete blood count, renal and liver function tests and coagulation profile as well as detection of antibodies to dengue, leptospiral and hantavirus infections) and assessment of the anterior and posterior ocular segment.

Five patients were identified as suffering from hantavirus infection on the basis of positive ELISA tests to detect IgM antibodies (Focus technologies, Cypress, California, USA) with their clinical picture suggesting HPS. Four of five patients (80%) showed rising titers of IgM antibodies. They were all male, with no history of diabetes mellitus or hypertension, with ages ranging from 20 to 40 years (mean 31.6 years). The mode of presentation in every case was an acute hemorrhagic fever. There was an initial prodromal phase of a low-grade fever for two to four days (median three days) accompanied by vomiting and diarrhoea in three of the patients. This was followed by the development of increasing breathlessness and skin petechiae.

On admission, the patients were febrile, hypoxic and hypotensive. Relevant physical findings included stupor or prostration, pallor, peripheral cyanosis, icterus and the presence of bilateral coarse crepitations throughout both lung fields in these patients. Hemorrhagic manifestations were common and manifested as hematuria, hematemesis, melena or bleeding gums. Chest X-rays showed the presence of diffuse infiltrates bilaterally, consistent with adult respiratory distress syndrome (ARDS). Laboratory investigations revealed anemia (mean hemoglobin 10.3 gm/dl), renal failure (mean serum creatinine 2.7) and hepatic dysfunction (raised serum bilirubin). There was a marked thrombocytopenia (mean platelet count 28,000/mm 3 ); [normal 150,000-450,000 mm 3 ] and a markedly abnormal coagulation profile with deranged prothrombin and partial thromboplastin times.

At this time all these patients underwent torchlight examination of the anterior segment and an indirect ophthalmoscopy of dilated fundus as part of their workup. In one patient, dot and blot intraretinal hemorrhages were seen in the macula of one eye and streak hemorrhages of the optic disc in the other (Patient 1, Table 1). In the remaining four, no fundus abnormalities were seen.

Table 1

Demographic characteristics, initial fundus fi ndings and IgM values

Following their recovery (five to seven days later) three of these patients (Patients 1, 2, 3) underwent a detailed ocular evaluation. The visual acuity was 20/20 in all eyes. There were no abnormalities seen on slit-lamp examination, dilated ophthalmoscopy or tonometry. The hemorrhages identified in Patient 1 initially were not detectable at the second examination.

Tests to detect the presence of IgM antibodies, denoting recent infection, to leptospira and dengue were negative in these patients as was a polymerase chain reaction (PCR) for the detection of leptospira from the blood.

Discussion

In this small series, the only positive findings were transient intraretinal hemorrhages, bilaterally in one patient of five (20%). We observed no anterior segment or intraocular pressure abnormalities either initially or on detailed examination. These retinal hemorrhages may be due to the induced thrombocytopenia whose mechanism remains unclear but hantaviruses have been shown to specifically infect endothelial cells and to interact with platelet B-3 integrins.7 Alternatively, these hemorrhages may reflect cytopathic effects of the virus.

Several reports and case series from northern Europe describe the ocular findings in patients of hantavirus infection. Ocular lesions are seen in up to 52% of patients with common findings including transient myopia, anterior chamber angle shallowing and hypotony.4,5,6 Other anterior segment findings included lid edema, conjunctival injection and anterior uveitis. Retinal involvement was rare, with hemorrhages and edema being seen in only one of 37 (2.7%) patients in one series.6

The differing patterns of ocular involvement may be due to the fact that European series have described patients with nephropathia epidemica, which is a milder form of hantavirus infection due to the Puumala virus that is spread by Clethrionomys glareolus (red bank vole).5 This is in contrast to the hantavirus infection from South-East Asia and India which primarily involves infection with Seoul, Hantaan or Thottapalayam virii1 and possibly different patterns of ocular involvement. A MEDLINE search returned no reports of ocular involvement from Asia or India for us to confirm our hypothesis.

Hantavirus is an emerging infectious disease both worldwide and in India and ophthalmologists should be aware of the ocular features. A larger series will be needed to confirm any possible differences between Asian and European patient groups or to permit use of these findings to differentiate between various hemorrhagic fevers.