Dengue fever (DF) is a viral infection transmitted to humans by the bite of an infected female Aedes mosquito, usually the Aedes aegypti. The dengue virus belongs to the Flavivirus genus of the Flaviviridae family, and its members include the 4 antigenically related serotypes of dengue virus (DEN 1-4). With a geographic distribution spanning more than 100 countries mainly over the tropics and subtropics including America, Southeast Asia, Western Pacific, Africa, and the Eastern Mediterranean, more than 2.5 billion people are at risk, making dengue an extremely important arthropod-borne viral disease with respect to public health.1–7
The clinical features of dengue infection can be classified into 5 different presentations: (1) nonspecific febrile illnesses, (2) classic dengue, (3) dengue hemorrhagic fever, (4) dengue hemorrhagic fever with dengue shock syndrome, and (5) other unusual syndromes such as encephalitis and hepatitis.8–10 Dengue infection is characterized by an acute onset of fever associated with symptoms of malaise, headache, muscle ache, retro-orbital pain, joint pain, abdominal discomfort, and rash.1 Other clinical manifestations of dengue are related to the bleeding diathesis from thrombocytopenia.
Dengue is usually a self-limiting infection. Recovery from infection with 1 serotype provides lifelong immunity against that serotype but confers only transient and partial immunity against subsequent infection by other serotypes.11 Similarly, ophthalmic manifestations in DF have no cross-immunity, and recurrent episodes tend not to be more severe than the first episode.12 Sequential infections with other serotypes may increase the risk of more serious systemic disease such as dengue hemorrhagic fever or dengue shock syndrome, which are life-threatening.11
The diagnosis of DF is clinical but can be confirmed with laboratory tests based on the time of presentation. Frequently used tests include the polymerase chain reaction (PCR) or immunoglobin M (IgM) or immunoglobin G (IgG) enzyme immunoassays.1 During the early phase of the infection when febrile illness is within 5 days, dengue PCR is performed. If the febrile illness exceeds 5 days, the preferred tests are dengue IgM and IgG tests. It is well documented that serology is negative during the febrile phase and early infection, becoming positive after the resolution of fever. In contrast, PCR has a higher sensitivity during febrile phase, becoming negative after the fever settles.13,14
Although ocular manifestations of DF are uncommon, there have been an increasing number of reports describing a myriad of ocular signs and symptoms associated with DF.15–22 Herein, we report the ocular manifestations of DF in 11 cases from Singapore during the epidemic in 2005 to 2006.
MATERIALS AND METHODS
This case series is a retrospective review of the clinical records of 11 patients with dengue who were referred to the department for evaluation of ocular complaints after being diagnosed with DF. All patients were diagnosed to have classic DF on the basis of characteristic signs and symptoms of DF and confirmed with either a positive IgM or IgG dengue serologic test.
All patients had distance visual acuity (VA) measured with the Snellen acuity chart. All of them underwent color vision assessment, a full slit-lamp anterior segment examination, and a dilated fundi examination with the slit-lamp biomicroscopy. Retinal findings were documented with serial dilated fundi examinations and retinal photographs.
Patients underwent further testing of visual fields [Humphrey automated visual field analyzer (HVF)] and Amsler charting. Fundal fluorescein angiography and indocyanine green angiography were only performed in selected cases because of financial costs. Electrophysiologic studies were done if clinically indicated to assess and evaluate for optic nerve or macula involvement and if patients were agreeable to afford and undergo the test. Optic neuropathy was confirmed by the presence of abnormalities in amplitude and latency during visual evoked potential testing. The presence of maculopathy was diagnosed by decreased amplitudes noted on multifocal electroretinogram.
The tests (HVF and fundal fluorescein angiography) were repeated later in 7 patients based on clinical assessment of the patient’s response and clinical signs of resolution. Clinical response is defined as improvement of VA and of subjective ocular symptoms. To assess for clinical response, the tests were repeated within 1 to 2 days and then on weekly intervals. To assess for clinical resolution, the tests were repeated usually in 3 and 6 months, respectively, until the patient was discharged from the ophthalmology service. The results are presented as means (SD) unless otherwise specified.
Eleven patients were included in this case series, and 10 cases occurred in Singapore in 2005 to 2006, based on the absence of travel history 1 month before the illness. Patient 4 was initially diagnosed with DF in Kuala Lumpur, Malaysia, but came to Singapore to seek medical treatment for her blurring of vision. Three patients in this case series have been reported in an earlier case series as optic neuritis.23 We have their systemic characterization in this study, which was not elaborated earlier. There were 7 (63.6%) males and 4 (36.4%) females with ages ranging from 14 to 40 years [mean (SD), 27 (9) years]. The racial distribution was predominantly Chinese (9 patients), with 1 Malay and 1 Indian patient. Historically, DF cases are usually geographically concentrated in the northeastern and southeastern parts of Singapore. In the 2005 to 2006 dengue epidemic, large numbers of cases were also reported from the northern and southwestern parts of Singapore.24 The 5 largest clusters included areas from northern parts (Yishun Street 72, Marsiling Crescent, and Lorong 7/8 Toa Payoh), southern parts (Upper Boon Keng Road), and western parts of Singapore (Kang Ching Road).24 In our case series, the patients resided in areas where epidemic clusters were present. Five patients resided in the north (Woodlands, Yishun, Marsiling, and Teck Whye), 4 patients in the southwest (Commonwealth, Bukit Merah, Queensway), and 2 patients in the west (Joo Koon and Jurong East) of Singapore. The prevailing dengue serotype in 2005 to 2006 was DEN-1.24
We present the ocular and systemic symptoms and findings associated with DF observed at the time of admission in Supplemental Digital Content 1, http://links.lww.com/APJO/A30. The most common symptom was blurring of vision occurring in 7 patients (63.6%) followed by floaters in 2 patients (18.2%). One patient complained of unilateral central blurring, and 1 patient presented with bilateral eye redness. Of the 11 patients, 5 patients presented with bilateral involvement. Ocular symptoms occurred 1 to 2 weeks after the onset of DF. The onset of visual symptoms closely correlated with the nadir of thrombocytopenia associated with DF. All 11 cases had serial serum platelet measurements, and all presented with visual symptoms within 1 day of their lowest platelet count [mean (SD) platelet count, 68 (18) × 109/L; range, 43-99 × 109/L]. Seven (63.6%) patients complained of visual symptoms on the day of their nadir, whereas 1 (9.1%) patient presented 1 day after and 3 (2.7%) patients presented 1 day before their lowest counts. Liver function tests were performed for 8 patients, and transaminitis was noted in all patients [alanine transaminase (ALT) mean (SD) values, 440 (247)/L; aspartate transaminase (AST) mean (SD) values, 437 (272)/L.
Systemic features on initial presentation are also highlighted in Supplemental Digital Content 1, http://links.lww.com/APJO/A30. The most common systemic feature was fever (n = 11/11, 100%), followed by abdominal symptoms such as abdominal discomfort or pain (n = 6/11, 54.5%) and nausea or vomiting (n = 6/11, 54.5%). Other presenting complaints of dengue were petechial rash (n = 5/11, 45.5%), myalgia or arthalgia (n = 5/11, 45.5%), headache (n = 4/11, 36.4%), and constitutional symptoms such as loss of weight, loss of appetite, and lethargy (n = 4/11, 36.4%). Only 2 (18.2%) of 11 patients had bleeding tendencies and had associated gum bleeds, menorrhagia, and microscopic hematuria. No patient had complications of DF such as dengue hemorrhagic fever, dengue shock syndrome, or neurologic symptoms such as coma. During the episode of DF, all patients were managed conservatively with intravenous (IV) hydration and daily full blood count monitoring.
A summary of clinical findings is shown in Supplemental Digital Content 2, http://links.lww.com/APJO/A31. Common ophthalmic findings included retinal hemorrhages (15 eyes), cotton wool spots (15 eyes), retinal pigment epithelium alterations (5 eyes), optic disc swelling (3 eyes), foveolitis (3 eyes), and hyperemia (2 eyes). Foveolitis is a newly described ocular manifestation of DF and is defined as a discrete, well-circumscribed, round yellow-orange lesion localized to the fovea in patients with dengue infection.24Figure 1 is a color fundal photograph showing some of the common ophthalmic findings as listed previously. The presenting distant Snellen VA (VA) ranged from 6/6 to counting fingers (median, 6/7.5), and visual field abnormalities were noted in 5 eyes despite a normal VA. Impaired color vision was noted in 12 eyes. Color vision was not done in 1 eye because it was unrecordable because of poor vision. Visual field defects were noted in 13 eyes; 4 of these eyes were asymptomatic. Fundus fluorescein angiography was done in 9 patients; the findings include choroidal hyperfluorescence (9 eyes), blocked fluorescence (8 eyes), and capillary nonperfusion (1 eye). In 2 eyes, it was normal. Electrophysiology tests confirmed optic neuropathy in 3 eyes and maculopathy in 1 eye.
Treatment for patients with dengue ophthalmic complications varied from supportive treatment, giving oral or topical prednisolone to administering IV methylprednisolone. Most of the cases (10 patients) were treated conservatively with spontaneous resolution of clinical signs after recovery of thrombocytopenia. One patient was started on IV methylprednisolone 1 g/d for 3 days because Snellen VA at presentation was counting fingers and color vision was too poor to be assessed. This was followed by oral prednisolone at 1 mg/kg per day for 1 week and tapered off over the next 2 months in a similar manner. There were no adverse effects after steroid treatment.
Most patients recovered rapidly over a period of 1 week to 3 months with improvement of their initial VA. The follow-up period ranged from 12 days to 12 months, and the VA at the last follow-up ranged from no light perception to 6/6. By 3 months, 20/21 eyes (95.2%) had regained VA to 6/12 or better. At 1 year, the percentage of eyes that regained VA remained the same. Visual acuity of the patient that was administered IV methylprednisolone deteriorated from counting fingers in the right eye at admission to no perception to light after 12 months of follow up. Dilated fundi examination at follow up showed optic atrophy of the right optic nerve. Associated residual scotomas reflected on HVF also persisted for a longer period despite resolution of ocular signs and improvement of VA, with 4 eyes still having residual persistent scotoma and 1 eye having generalized reduction in sensitivity after 6 months and 1 year of follow-up, respectively. Figures 2 and 3 show the color fundal photographs of patient 2, who recovered with residual persistent scotoma in both eyes.
Dengue fever is the most common mosquito-borne viral disease in humans, and epidemic dengue infection has become more common in the last 2 decades with a worldwide morbidity of more than 100 million cases per year.4 The impact of dengue infection on the eye can range from minor ocular discomfort to blindness. Physicians should therefore be aware of the possible ophthalmic complications associated with this infection and comanage the patient with an ophthalmologist in cases of ocular complaints.
In our analysis of 11 patients, the presenting VA ranged from 6/6 to counting fingers. Ophthalmic findings included retinal hemorrhages (15 eyes), cotton wool spots (15 eyes), retinal pigment epithelium alterations (5 eyes), optic disc swelling (3 eyes), foveolitis (3 eyes), and hyperemia (2 eyes). Impaired color vision was noted in 12 eyes. Visual field defects were noted in 13 eyes and were asymptomatic in 4 of these eyes. The follow-up ranged from 12 days to 12 months, and the VA at the last follow-up ranged from no light perception to 6/6. The patient with a final VA of no light perception had a dilated fundi examination at 12 months of follow-up showing optic atrophy of the right optic nerve. Otherwise, prognoses of dengue-related ophthalmic manifestations were good, and most patients recovered rapidly over a period of 1 week to 3 months.
Pathophysiology for Ocular Manifestations in Dengue Fever
The pathophysiology of ocular manifestations in DF is still under debate and elucidation. However, the main hypothesis is that dengue ophthalmic complications are immune mediated.16 Studies have postulated that the dengue infection results in antigen-antibody immune complex formation, which results in an inflammatory reaction.25,26
In vivo studies have shown the activation of both humoral and cellular immune responses during the virus clearance phase, generating cluster of differentiation (CD) 4 and CD8 T lymphocytes, which are specific to dengue serotype cross-reactive epitopes.27–30 The dengue virus has also been postulated to enter human dendritic cells to induce production of interleukins, tumor necrosis factors, and interferons.31 These vasoactive and inflammatory mediators result in capillary leakage and breakdown of blood aqueous barrier, which may be the basis of dengue-induced macular edema, vasculitis, and uveitis. This immune mechanism is further substantiated by studies that showed a decrease in levels of C4 and C3 complement levels, respectively, in patients with dengue maculopathy.21,26
Foveolitis is a unique ocular entity associated with dengue infection, which is the result of an inflammatory process that leads to disruption of the outer neurosensory retina.32 It is distinguished by the presence of a discrete, well-circumscribed, round yellow-orange lesion localized to the fovea in patients with dengue infection and has been previously and newly described in a study by Loh et al.32 In our case series, foveolitis was found to be present in 3 eyes, and all underwent clinical resolution by 6 months. Ophthalmologists should be aware that foveolitis associated with DF may present with acute bilateral severe visual loss and optical coherence tomography is useful for the diagnosis and monitoring of the disease.32 Because this entity is newly described, further work is necessary to determine the effect of treatment on the course of foveolitis.
Transaminitis was noted in all 11 patients in our case series. Although the exact pathogenesis of hepatocellular damage in DF is unknown, direct invasion of hepatocytes by the dengue virus has been described, and the receptor involved is serotype specific.33 Recent studies have also found a possible role for antibodies against dengue virus nonstructural protein 1 in murine models.34 This suggests that, like maculopathy, hepatocellular damage in dengue could have an immune basis. However, there was no correlation between the likelihood of developing maculopathy and severe transaminitis, therefore suggesting that different genetic loci may be involved in different target organ disease.34
In previous studies, patients with dengue ophthalmic complications have also been found to present with visual symptoms during the nadir of thrombocytopenia.20,35,36 This is likely to explain ocular manifestations such as retinal hemorrhages given that the thrombocytopenic state induced by dengue infection increases the tendency to bleed.
Viral mutation, variance in virulence, and susceptibility of host may also contribute to the immunopathogenic mechanism of dengue ophthalmic complications and its increase in incidence.35 A cross-sectional study by Chee et al37 showed that patients who had predominantly DEN-2 serotype infection in 2007 had no dengue maculopathy, whereas it was present in 10% of the patients reported in 2005 who had predominant DEN-1 serotype.25,37 Patients in this 2005 study group were also notably younger, had complement 3 levels that were significantly lower, and were more likely to have severely raised transaminases compared with the group studied in 2007.26,37 This probably indicates that dengue ophthalmic manifestations are dependent on viral serotype as well as immune response of the host. In lieu of just a single study reporting the association of a single serotype influence, further work and population-based studies should be done to conclude the role of serotype on ophthalmic complications in general.
In our case series, the prognosis of ophthalmic involvement secondary to DF is generally good. A significant number of patients had persistent scotoma despite clinical resolution of ocular signs and improvement of VA, with 4 eyes still having residual persistent scotoma and 1 eye having generalized reduction in sensitivity after 6 months and 1 year of follow-up, respectively. In a previous study by Teoh et al,36 patients with dengue-related maculopathy had persistent central/paracentral scotoma in as much as 59.5% of 74 affected eyes at 2-year follow-up.36 This suggests that ophthalmic manifestations of DF is not as innocuous as it seems and would require follow-up with an ophthalmologist even after clinical resolution.
The first limitation of our study is the modest sample size, which may limit the representativeness of ocular manifestations in DF. However, for the first time, we have characterized systemic features in our center. With larger sample sizes, further work can be done to evaluate the relationship between dengue serotype, systemic features, and ocular manifestations.
The second limitation would be that this case series was obtained from a study population in 2005, approximately 6 years ago. However, there are several unique aspects of the 2005 dengue epidemic. The 2005 dengue outbreak in Singapore was the most severe one in the past decade, where cases peaked at approximately 14,000.38 It was also of significance because the resurgence was due to a change in dominant dengue serotype from DEN-2 to DEN-1, thereby resulting in lower herd immunity in the community.38 Subsequently, in 2007, Singapore experienced another dengue epidemic, largely from a switch in serotype from DEN-1 to DEN-2, and the DEN-2 serotype has predominated until today. The DEN-2 serotype causes less ocular manifestations and symptoms, as shown in the study by Chee et al,37 where there were no ophthalmic complications reported in the study population. This could explain why, since the 2005 outbreak, we have seen a decrease in ocular complications in patients with dengue. Although we are unable to provide more recent data (possibly due to the epidemiological change of serotype), this will be an area we are looking to further explore and to find a correlation between the different dengue serotypes and ophthalmic complications.
The third limitation is that, being a tertiary referral center, more patients in this population are likely to have more severe ocular signs and symptoms from DF. Results from population or community-based studies may yield a different spectrum of ocular manifestations that would be ideal to elucidate so as to achieve better understanding of the entire spectrum of ophthalmic complications in DF.
Lastly, although the previously described visual abnormalities are likely to be associated with dengue, these have not yet been statistically assessed to substantiate the firm association, even in other studies. It would be valuable to have future epidemiological studies to show that these visual abnormalities were not present before dengue infections or due to pre-existing comorbidities, so as to highlight the clinical and public health significance of ocular manifestations due to dengue infections.
Dengue fever is associated with a wide spectrum of ophthalmic manifestations and typically presents during the nadir of thrombocytopenia. Prognosis of ophthalmic complications in DF is generally good but can rarely result in permanent visual impairment.
Given that different dengue serotypes may result in different degree of ophthalmic manifestations, further studies are needed to properly understand the mechanism and incidence of ophthalmic complications of dengue. This is important in the background of changing epidemiological patterns and cocirculation of various dengue serotypes.
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