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Ocular manifestations of dengue fever in an East Indian epidemic
Ocular manifestations of dengue fever in an East Indian epidemic Harpreet K. Kapoor, MS (Ophthalmol); Saloni Bhai, MS (Ophthalmol); Mary John, MD (Medicine); Jai Xavier, MS (Ophthalmol) ABSTRACT • RÉSUMÉ
Background: The incidence and geographic distribution of dengue has increased dramatically in recent years. Previously, ocular findings in dengue fever were considered rare. We report a spectrum of ocular manifestations of this potentially fatal disease and its association with laboratory parameters. Methods: 134 patients hospitalized with a diagnosis of dengue fever during an epidemic were included. Systemic and ophthalmic examinations were completed on all patients. Results: The mean age was 31.3 years and 63.4% were males. All patients presented with fever. Six (4.5%) patients had retrobulbar pain and none of the patients presented with any visual complaints. Ocular findings were present in 54 (40.3%) patients. Subconjunctival haemorrhage was the commonest eye finding seen in 50 patients, of whom 84% had characteristic petechial type of haemorrhages. Fundus findings present in 10 (7.5%) patients included dilatation and tortuosity of vessels, superficial retinal haemorrhages, cotton-wool spots, and hard exudates; the macula, however, was spared in all patients. Only 6 of the patients with posterior segment involvement returned for follow-up examination and it was found that retinal changes had resolved without any specific treatment within 2 to 8 weeks time. Of all laboratory parameters evaluated, marked thrombocytopenia (platelet count <50 000/μL) emerged to be significantly associated with ocular haemorrhage. Interpretation: Multiple subconjunctival haemorrhages, especially petechial type, are a common manifestation of dengue infection. Dengue fever patients with marked thrombocytopenia are predisposed to spontaneous ocular haemorrhages. Contexte : L’incidence et la répartition géographique de la dengue, qu’on appelle aussi fièvre rouge, ont augmenté considérablement ces dernières années. Auparavant, on estimait que les effets oculaires de la fièvre rouge étaient rares. Nous faisons état d’un éventail de manifestations oculaires de cette maladie potentiellement mortelle et de son association avec les paramètres de laboratoire. Méthode : 134 patients hospitalisés avec un diagnostic de fièvre dengue lors d’une épidémie ont fait partie de l’étude. Ils ont tous subi des examens systémiques et ophtalmologiques. Résultats : La moyenne d’âge était de 31,3 ans et 63,4 % des patients étaient masculins. Tous avaient la fièvre. Six patients (4,5 %) avaient une douleur rétrobulbaire et aucuns ne se plaignaient de troubles visuels. Des problèmes oculaires ont été relevés chez 54 patients (40,3 %). L’hémorragie sousconjonctivale était le problème oculaire le plus fréquemment relevé chez 50 patients, parmi lesquels 84 % avaient des hémorragies caractérisées de type pétéchial. Les problèmes de fond d’œil présents chez 10 patients (7,5 %) comprenaient la dilatation et la tortuosité des vaisseaux ainsi que des hémorragies superficielles, des exsudats cotonneux et des exsudats secs de la rétine; la macula était cependant épargnée chez tous les patients. Seulement 6 patients sont retournés subir un examen de suivi et on a alors trouvé que les modifications de la rétine s’étaient résolues sans traitement particulier dans un délai de 2 à 8 semaines. Parmi tous les paramètres de laboratoire évalués, la thrombocytopénie marquée (compte des plaquettes inférieur à 50 000/μL) a ressorti comme étant significativement associée à l’hémorragie oculaire. Interprétation : Les hémorragies sousconjonctivales multiples, surtout de type pétéchiel, sont une manifestation commune de la dengue. Les patients atteints de la maladie avec thrombocytopénie marquée sont prédisposés aux hémorragies oculaires spontanées. From the Christian Medical College and Hospital, Ludhiana, Punjab, India Originally received Dec. 2, 2005. Revised Jun. 6, 2006 Accepted for publication Jun. 13, 2006
Correspondence to: Harpreet K. Kapoor, MS, Department of Ophthalmology, Christian Medical College & Hospital, Brown Rd., Ludhiana 141008, Punjab, India; fax 911612685816; harpreet_ [email protected] This article has been peer-reviewed. Cet article a été évalué par les pairs. Can J Ophthalmol 2006;41:741–6
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D
engue fever is one of the most common arthropodborne viral diseases of man, with an estimated 100 million cases per year and 2.5 billion people at risk worldwide.1 It has emerged as a global public health problem in the past several decades and is now endemic in most tropical and subtropical areas of Central and South America, Southeast Asia, the western Pacific, Africa, and the eastern Mediterranean.2 The number of epidemics reported from different parts of the world, including India, has risen exponentially.3–8 The principal vector of dengue infection is the mosquito Aedes aegypti, which is found worldwide between latitudes 35°N and 35°S.9 Classic dengue fever (CDF) is a self-limiting, influenza-like illness caused by any of the 4 serotypes (DEN 1–4) of dengue virus. Dengue haemorrhagic fever (DHF) is a more severe form of the disease, characterized by multisystem haemorrhagic manifestations, thrombocytopenia, increased vascular permeability, and plasma leakage. When medically unsupported, mortality is as high as 10%–20% (over 40% if shock occurs) but can be decreased to 0.2% with early diagnosis and appropriate intensive supportive therapy.9 Dengue fever is considered to be rarely associated with ocular manifestations.10 The published literature includes reports of approximately 36 patients presenting primarily with moderate to marked visual impairment due to various posterior segment alterations.10–16 This study was undertaken to document the spectrum of ocular manifestations of dengue fever, and to identify any significant laboratory parameter associations. METHODS
This study was conducted in Christian Medical College and Hospital, Ludhiana, a tertiary care hospital situated in Northern India, from October 1, 2003, to November 30, 2003. During this period, several parts of India, including Ludhiana, experienced an unprecedented epidemic of dengue fever. One hundred and thirty-four consecutive patients admitted in the medical ward with a diagnosis of dengue infection were enrolled in the study. Informed consent was obtained from the patients or their accompanying relatives. A detailed clinical history, including systemic and visual complaints, was taken. Patients with a history of diabetes mellitus, hypertension, anemia, or any other systemic or ophthalmic disorders with potential findings similar to those previously reported to be associated with dengue fever were excluded from the study. Diagnosis of dengue fever was based on clinical features and laboratory parameters. Serological evaluation was done by using the Dengue IgM Capture ELISA test kit (Panbio Limited, Brisbane, Australia).
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Table 1—World Health Organization clinical classification of dengue haemorrhagic fever (DHF) Grade DHF I DHF II
DHF III* DHF IV*
Clinical features
Laboratory findings
Fever, constitutional symptoms, positive tourniquet test Grade I + spontaneous bleeding (e.g., skin, gums, gastrointestinal tract) Grade II + circulatory failure, agitation Grade II + profound shock (blood pressure unrecordable)
Hemoconcentration, † thrombocytopenia Hemoconcentration, † thrombocytopenia Hemoconcentration, † thrombocytopenia Hemoconcentration, † thrombocytopenia
*Dengue shock syndrome. †
Platelet count <100 000/μL.
Table 2—Classic dengue fever and dengue haemorrhagic fever, grades I–IV Number of patients CDF With ocular findings Without ocular findings Total
DHF-I DHF-II DHF-III DHF-IV
Total
0
1
52
1
0
54
9
38
33
0
0
80
9
39
85
1
0
134
Note: CDF, classic dengue fever; DHF, dengue haemorrhagic fever.
Table 3—Spontaneous bleeding manifestations in patients with dengue fever Site of haemorrhage Subconjunctival haemorrhage Cutaneous haemorrhage Upper gastrointestinal bleed Lower gastrointestinal bleed Retinal haemorrhages Haemoptysis Epistaxis Hematuria Gingival bleed Menorrhagia
No. of patients 50 29 20 18 5 5 4 2 1 1
% of total, n = 134 37.3 21.6 14.9 13.4 3.7 3.7 2.9 1.5 0.8 0.8
All patients were classified into either CDF or DHF (grades I–IV) as per World Health Organization criteria (Table 1).17 Complete ocular examination, including dilated fundus examination, was carried out in all patients. Patients with ocular findings were called for weekly follow-up visits in the ophthalmology clinic after they were discharged from the hospital. Data were entered and analyzed in SPSS version 12 statistical software (SPSS Inc., Chicago, Ill.). RESULTS
One hundred and thirty-four patients hospitalized
Ocular manifestations of dengue fever—Kapoor et al
Fig. 1—Haemorrhagic manifestations of dengue fever. Left. Patient with spontaneous gingival bleed. Centre. Petechial type of subconjunctival haemorrhage. Right. Diffuse type of subconjunctival haemorrhage.
with a diagnosis of dengue fever or DHF were included in the study. The patients ranged in age from 13 to 65 years with a mean of 31.3 years; 63.4% were males. One hundred and thirty-one (97.8%) patients lived in urban areas, 85 (63.4%) patients were employed, and the rest were either students or housewives. The median duration of hospital stay was 5 days. Although only 36.6% of patients were aware that dengue spreads by mosquitoes, 65.7% were using personal protective measures like coils or mats (48.5%), mosquito nets (9.7%), and topical repellants (7.5%). All patients presented with a history of fever ranging from 37.8°C to 40.3°C. Other common presenting symptoms were vomiting (38.8%), myalgia (35.1%), headache (27.6%), abdominal pain (24.6%), and a maculopapular rash (17.2%). Only 6 (4.5%) patients presented with retrobulbar pain. None of the patients in our series had any visual complaints. The majority of patients were categorized into DHF grade II (Table 2). Spontaneous bleeding manifestations were present in 87 (64.9%) patients (Table 3 and Fig. 1). Subconjunctival haemorrhage was the commonest haemorrhagic manifestation and was found in 50 (37.3%) patients, followed by cutaneous haemorrhage in the form of petechiae and ecchymosis seen in 21.6% of patients. Ocular findings were present in 54 (40.3%) patients (Table 4), of whom 96.3% had DHF grade II. Subconjunctival haemorrhage, the commonest eye finding, was seen in 50 patients; 66% of these patients had haemorrhages in both eyes and 34% in one eye only; 42 (84%) patients had multiple, dot-like, petechial haemorrhages (Fig. 1, centre), and 8 (16%) patients had a diffuse haemorrhage (Fig. 1, right) present in 1 to 4 quadrants of one or both eyes. Fundus findings were present in 10 (7.5%) patients; 3 (2.2%) had isolated superficial retinal haemorrhages (1 unilateral, 2 bilateral), 3 (2.2%) patients had several cotton-
wool spots seen in one eye only, and 2 (1.5%) patients had dilatation and tortuosity of vessels as the only finding in both eyes. There were 2 (1.5%) patients who had a retinopathy with superficial retinal haemorrhages, hard exudates, and cotton-wool spots scattered in the fundus (1 unilateral, 1 bilateral); the macula, however, was spared in these patients. Of all the laboratory parameters evaluated, marked thrombocytopenia (platelet count less than 50 000/μL) was present in 90.7% of patients with ocular haemorrhage, and the association was statistically significant (p < 0.001) with an estimated odds ratio of 6.73 (95% CI, 2.20–20.59). Leucopenia was seen in 23 (42.6%) patients with ocular haemorrhage (p > 0.39). Prothrombin time (PT) and partial thromboplastin time (PTT) were carried out in 84 patients. Although 91.2% of patients with ocular haemorrhage had prolonged PTT values, the association was not statistically significant (p > 0.53). PT was prolonged in 67.6% of patients with ocular haemorrhage (p > 0.69). Of 102 patients who had liver function tests, only 9 (22%) patients with ocular haemorrhage had abnormal values (p > 0.50) (Table 5). After hospitalization, only 19 patients returned for follow-up ophthalmic examination. Of these 19, 16 patients had subconjunctival haemorrhages in one or both eyes at the time of admission. These had resolved within 6 to 14 days in all 16 patients. Six of the 10 patients with posterior segment involvement (3 with isolated retinal haemorrhages, 2 with cotton-wool spots, and 1 with dilatation and tortuosity of vessels) returned for follow-up evaluation. The findings in these patients had resolved without any specific treatment within 2 to 8 weeks of presentation. INTERPRETATION
The incidence, geographic distribution, and clinical severity of epidemic and endemic dengue have increased
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Table 4—Ocular findings in patients with dengue fever Ocular finding Subconjunctival haemorrhage Petechial-type haemorrhage Diffuse-type haemorrhage Posterior segment alterations Superficial retinal haemorrhages Cotton-wool spots Dilatation and tortuosity of vessels Retinopathy (hard exudates, superficial retinal haemorrhages, and cotton-wool spots)
No. of patients
% of total, n = 134
50 42 8 10 3 3 2
37.3 31.3 6.0 7.5 2.2 2.2 1.5
2
1.5
Table 5—Laboratory findings and association with ocular haemorrhage Laboratory parameter Platelet count >100 000/μL 50–100 000/μL <50 000/μL Total WBC count ≥4000/mL <4000/mL Total Prothrombin time* Normal Prolonged Total PTT* Normal Prolonged Total LFT† Normal Abnormal Total
No. (%) of patients With ocular haemorrhage 0 5 49 54
(0.0) (9.3) (90.7) (100)
Without ocular haemorrhage 9 19 52 80
(11.3) (23.7) (65.0) (100)
p value
<0.001
31 (57.4) 23 (42.6) 54 (100)
53 (66.3) 27 (33.7) 80 (100)
>0.39
11 (32.4) 23 (67.6) 34 (100)
13 (26.0) 37 (74.0) 50 (100)
>0.69
3 (8.8) 31 (91.2) 34 (100)
8 (16.0) 42 (84.0) 50 (100)
>0.53
32 (78.1) 9 (21.9) 41 (100)
52 (85.3) 9 (14.7) 61 (100)
>0.50
Note: WBC, white blood cell; PTT, partial thromboplastin time; LFT, liver function tests. *Prothrombin time and PTT were carried out in 84 patients only. † LFT was carried out in 102 patients only.
noticeably in the past few decades.9 The expansion of this flavivirus infection is linked to resurgence of the mosquito vector Aedes aegypti, population growth in the tropics, uncontrolled urbanization and overcrowding without appropriate water management, and global spread of dengue via travel and trade.18 The clinical presentation of the patients in our series was characteristic of classical dengue infection. Fever was a consistent symptom present in all patients, with vomiting, myalgia, headache, and abdominal pain being among the other common presenting symptoms. Retrobulbar pain, which has been classically described
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as a feature of dengue infection, was seen in only 4.5% patients, although its prevalence has been reported to be higher by some authors.19,20 Ocular manifestations of dengue fever have received little attention in the published literature. There are isolated reports of dengue fever patients who primarily presented with visual impairment due to posterior segment involvement (Table 6). Although none of our patients presented with visual complaints, examination revealed that a significant number (40.3%) had ocular findings, of which subconjunctival haemorrhage was the commonest, occurring in 37.3% patients. The majority of these patients had multiple, dot-like petechial haemorrhages in one or both eyes. This pattern of subconjunctival haemorrhage has been reported to be occasionally associated with systemic conditions like meningococcal septicaemia, subacute bacterial endocarditis, measles, and sandfly fever, but not yet with dengue fever.21 Since the majority of our patients had this characteristic type of subconjunctival haemorrhage, dengue infection should be an important diagnostic consideration when conjunctival petechial haemorrhages are seen in association with fever, especially in patients living in endemic areas or in travellers who have recently visited a tropical country. Ten (7.5%) patients in our series had posterior segment findings, including dilatation and tortuosity of vessels, cotton-wool spots, superficial retinal haemorrhages, and hard exudates. The macula, however, was spared in these cases and visual acuity was thus unaffected. This is in contrast to other reports, where patients presented with severe visual impairment due to choroidal effusion, optic neuritis, exudative maculopathy, or retinal thickening in the macula.10,12–15 All 4 distinct serotypes of dengue virus (DEN 1–4) can cause dengue fever. Moreover, variations in the virus strains within and between the 4 serotypes influence the disease severity.9 In our series, the majority of patients had a milder form of systemic disease, only one patient suffering from DHF grade III, no patients with DHF grade IV, and no mortality. It was also observed that, in contrast to some reports, none of our patients had impairment of vision. The difference in the severity and type of presentation in our series may be attributed to variations in the virulence and serotype of the infecting virus. The pathophysiologic mechanisms involved in dengue infection are complex and not completely understood. The various manifestations of the disease are believed to be a result of either direct viral invasion or a complex immune-mediated process. It has been speculated that viral invasion of endothelial cells, dendritic cells, monocytes, and hepatocytes causes apopto-
Ocular manifestations of dengue fever—Kapoor et al
Table 6—Summary of literature on ocular manifestations of dengue fever Author, year
No. & sex of patients
Spitznas 11 1978 [in German] Wen et al 12 1989 [in Chinese]
1F
Bilateral intraretinal haemorrhages in macula
14 F 10 M
Macular hemorrhage, 10 Maculopathy, 7 Macular and retinal haemorrhages, 5 Peripapillary haemorrhage, 3 Roth’s spot, 2 Vitreous/aqueous cells, 2 Diffuse retinal oedema, 1 Optic neuritis, 1 Ischemic optic neuropathy, 1 Intraretinal haemorrhages, retinal pigment epithelial lesions in the fovea, cotton-wool spots, maculopathy Bilateral exudative maculopathy, haemorrhages in the nerve fibre layer Bilateral choroidal effusion
Haritoglou 13 et al 2000 [in German]
2
Haritoglou 14 et al 2002
1F
CruzVillegas 10 et al 2003 Lim et al 15 2004
1M
Siqueira et 16 al 2004
1M
5F 1M
Ocular findings
Intraretinal whitish lesions with localized retinal and RPE disturbance, small dot haemorrhages, vascular sheathing around macula and papillomacular bundle Bilateral vascular sheathing, retinal haemorrhages at the equator, and cotton-wool spots in the macula
Note: RPE, retinal pigment epithelium.
sis and cellular dysfunction. This may be followed by a transient aberrant immune response, resulting in CD4/CD8 ratio inversion and cytokine overproduction, that has deleterious effects on these cells. In addition, overproduction of interleukin-6 triggers the formation of autoantibodies against platelets and endothelial cells, and this results in further immunemediated damages.22–25 Ocular findings in our patients primarily included subconjunctival haemorrhages, retinal haemorrhages, and exudates, which could be due to generalized increased capillary permeability, plasma leakage, and haemorrhagic diathesis associated with endothelial dysfunction, platelet destruction, and consumptive coagulopathy. The pathogenesis of cottonwool spots may be related to occlusion of precapillary arterioles in the retinal nerve fibre layer by immune complex deposition. Lim et al in their study suggested the possibility of specific autoantibodies being produced against retina, retinal pigment epithelium, or choroid,15 but precise mechanisms responsible for the various ocular alterations in dengue still remain unknown. Haemorrhagic manifestations of dengue fever are believed to be multifactorial in origin.
Thrombocytopenia and abnormal coagulation profiles (PT, PTT) have been reported to have a predictive value for spontaneous systemic bleeds in dengue infection.26,27 Gomber et al, however, reported that there was no significant association between thrombocytopenia and haemorrhagic manifestations, signifying that there may be other factors, like platelet dysfunction and disseminated intravascular coagulopathy, responsible for bleeding.28 There are no reports in the literature of an association of ocular haemorrhage with abnormal laboratory parameters in dengue infection. Our study revealed that 90.7% of patients with ocular haemorrhage (subconjunctival or retinal) had marked thrombocytopenia (platelet counts less than 50 000/μL) and the association was statistically significant (p < 0.001). The correlation with other parameters, like leucopenia, prolonged PT, PTT, and abnormal liver function tests, was not significant. Ocular alterations in dengue are usually self-limiting. According to Haritoglou et al, most of the findings resolve without specific treatment, but occasionally visual recovery may be prolonged or vision may remain permanently impaired in patients with a severe maculopathy.14 In our study, the 6 patients with posterior segment alterations who were reexamined resolved without any specific treatment within 2 to 8 weeks. Lim et al in a recent report suggested the use of periocular steroids for treatment of vision-threatening maculopathy in dengue patients.15 Their study, however, included 6 patients only, thus inferences regarding definitive management of such patients cannot be conclusively drawn from their observations. Further studies with a larger sample size are required to evaluate the treatment options in patients presenting with visual impairment in dengue infection. Dengue fever, and in particular life-threatening DHF, continues to be a global challenge: the pathogenesis of the disease is not completely understood, there is no specific treatment available nor any immediate prospect of a vaccine, and the mosquito control measures in most of the hyperendemic areas are inadequate. The incidence and geographic distribution of dengue has increased dramatically in the past several years, and its ocular manifestations are likely to follow this trend. Ophthalmologists should thus be aware of the various ocular manifestations of dengue, as early diagnosis and referral for appropriate supportive therapy can considerably reduce the mortality of this potentially fatal disease. Furthermore, patients of dengue fever with marked thrombocytopenia (platelet count <50 000/μL) are predisposed to spontaneous ocular haemorrhages which, while primarily subconjunctival, if present in the macula can lead to impairment of vision.
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Acknowledgements: We are most grateful to Dr. A.S. Bhatia for statistical analysis of the data. We thank Dr. Jasbir Dhanoa and Dr. Dandona for their invaluable support. We would also like to acknowledge Dr. Jude Simmons, Dr. Daya Sadiq, and Dr. Manpreet Bhullar for helping us in various ways during the course of the study.
REFERENCES 1. World Health Organization. Dengue Hemorrhagic Fever: Diagnosis, Treatment and Control. 2nd ed. Geneva, Switzerland: WHO; 1997. 2. Ramirez-Ronda CH, Garcia CD. Dengue in the Western Hemisphere. Infect Dis Clin North Am 1994;8:107–28. 3. Chaturvedi UC, Shrivastava R. Dengue haemorrhagic fever: a global challenge. Indian J Med Microbiol 2004;22:5–6. 4. McBride WJ. Deaths associated with dengue haemorrhagic fever: the first in Australia in over a century. Med J Aust 2005;183:35–7. 5. Qiu FX, Gubler DJ, Liu JC, Chen QQ. Dengue in China: a clinical review. Bull World Health Organ 1993;71:349–59. 6. Fouque F, Reynes JM, Moreau JP. Dengue in French Guiana, 1965–1993. Bull Pan Am Health Organ 1995;29:147–55. 7. Cherian T, Ponnuraj E, Kuruvilla T, Kirubakaran C, John TJ, Raghupathy P. An epidemic of dengue haemorrhagic fever and dengue shock syndrome in and around Vellore. Indian J Med Res 1994;100:54–6. 8. Aggarwal A, Chandra J, Aneja S, Patwari AK, Dutta AK. An epidemic of dengue hemorrhagic fever and dengue shock syndrome in children in Delhi. Indian Pediatr 1998;35:727–32. 9. Gibbons RV, Vaughn DW. Dengue: an escalating problem. BMJ 2002;324:1563–6. 10. Cruz-Villegas V, Berrocal AM, Davis JL. Bilateral choroidal effusions associated with dengue fever. Retina 2003; 23:576–8. 11. Spitznas M. Macular haemorrhage in dengue fever [in German; English abstract]. Klin Monatsbl Augenheilkd 1978;172:105–7. 12. Wen KH, Sheu MM, Chung CB, Wang HZ, Chen CW. The ocular fundus findings in dengue fever [in Chinese; English abstract]. Gaoxiong Yi Xue Ke Xue Za Zhi 1989;5:24–30. 13. Haritoglou C, Scholz F, Bialasiewicz A, Klauss V. Ocular manifestation in dengue fever [in German; English abstract]. Ophthalmologe 2000;97:433–6. 14. Haritoglou C, Dotse SD, Rudolph G, Stephan CM, Thurau SR, Klaub V. A tourist with dengue fever and visual loss. Lancet 2002;360:1070. 15. Lim WK, Mathur R, Koh A, Yeoh R, Chee SP. Ocular manifestations of dengue fever. Ophthalmology 2004;111: 2057–64.
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16. Siqueira RC, Vitral NP, Campos WR, Orefice F, de Moraes Figueiredo LT. Ocular manifestations in Dengue fever. Ocul Immunol Inflamm 2004;12:323–7. 17. Sanford JP. Arbovirus infections. In: Isselbacher KJ, Braunwald E, Wilson JD, et al, eds. Harrison’s Principles of Internal Medicine. New York, NY: McGraw-Hill Inc; 1994:847–8. 18. Lifson AR. Mosquitoes, models, and dengue. Lancet 1996;347:1201–2. 19. Sharp TW, Wallace MR, Hayes CG, et al. Dengue fever in U.S. troops during operation Restore Hope, Somalia, 1992–1993. Am J Trop Med Hyg 1995;53:89–94. 20. Narayanan M, Aravind MA, Thilothammai N, Prema R, Rex Sargunam CS, Ramamurthy N. Dengue fever epidemic in Chennai: a study of clinical profile and outcome. Indian Pediatr 2002;39:1027–33. 21. Duke-Elder S. Anomalies of the circulation. In: Duke-Elder S, ed. System of Ophthalmology: Diseases of the outer eye Part I. London: Henry Kimpton; 1965:36. 22. Kurane I, Rothman AL, Livingston PG, et al. Immunopathogenic mechanisms of dengue hemorrhagic fever and dengue shock syndrome. Arch Virol Suppl 1994; 9:59–64. 23. Morens DM. Antibody-dependant enhancement of infection and the pathogenesis of viral disease. Clin Infect Dis 1994;19:500–12. 24. Lei HY, Yeh TM, Liu HS, Lin YS, Chen SH, Liu CC. Immunopathogenesis of dengue virus infection. J Biomed Sci 2001;8:377–88. 25. Lin CF, Lei HY, Shiau AL, et al. Antibodies from dengue patient sera cross-react with endothelial cells and induce damage. J Med Virol 2003;69:82–90. 26. Shivbalan S, Anandnathan K, Balasubramanian S, Datta M, Amalraj E. Predictors of spontaneous bleeding in Dengue. Indian J Pediatr 2004;71:33–6. 27. Chua MN, Molanida R, de Guzman M, Laberiza F. Prothrombin time and partial thromboplastin time as a predictor of bleeding in patients with dengue hemorrhagic fever. Southeast Asian J Trop Med Public Health 1993;24:141–3. 28. Gomber S, Ramachandran VG, Kumar S, et al. Hematological observations and diagnostic markers in dengue hemorrhagic fever – a reappraisal. Indian Pediatr 2001;38:477–81. Key words: dengue, ocular, subconjunctival haemorrhage, thrombocytopenia
Background: The incidence and geographic distribution of dengue has increased dramatically in recent years. Previously, ocular findings in dengue fever were considered rare. We report a spectrum of ocular manifestations of this potentially fatal disease and its association with laboratory parameters. Methods: 134 patients hospitalized with a diagnosis of dengue fever during an epidemic were included. Systemic and ophthalmic examinations were completed on all patients. Results: The mean age was 31.3 years and 63.4% were males. All patients presented with fever. Six (4.5%) patients had retrobulbar pain and none of the patients presented with any visual complaints. Ocular findings were present in 54 (40.3%) patients. Subconjunctival haemorrhage was the commonest eye finding seen in 50 patients, of whom 84% had characteristic petechial type of haemorrhages. Fundus findings present in 10 (7.5%) patients included dilatation and tortuosity of vessels, superficial retinal haemorrhages, cotton-wool spots, and hard exudates; the macula, however, was spared in all patients. Only 6 of the patients with posterior segment involvement returned for follow-up examination and it was found that retinal changes had resolved without any specific treatment within 2 to 8 weeks time. Of all laboratory parameters evaluated, marked thrombocytopenia (platelet count <50 000/μL) emerged to be significantly associated with ocular haemorrhage. Interpretation: Multiple subconjunctival haemorrhages, especially petechial type, are a common manifestation of dengue infection. Dengue fever patients with marked thrombocytopenia are predisposed to spontaneous ocular haemorrhages. Contexte : L’incidence et la répartition géographique de la dengue, qu’on appelle aussi fièvre rouge, ont augmenté considérablement ces dernières années. Auparavant, on estimait que les effets oculaires de la fièvre rouge étaient rares. Nous faisons état d’un éventail de manifestations oculaires de cette maladie potentiellement mortelle et de son association avec les paramètres de laboratoire. Méthode : 134 patients hospitalisés avec un diagnostic de fièvre dengue lors d’une épidémie ont fait partie de l’étude. Ils ont tous subi des examens systémiques et ophtalmologiques. Résultats : La moyenne d’âge était de 31,3 ans et 63,4 % des patients étaient masculins. Tous avaient la fièvre. Six patients (4,5 %) avaient une douleur rétrobulbaire et aucuns ne se plaignaient de troubles visuels. Des problèmes oculaires ont été relevés chez 54 patients (40,3 %). L’hémorragie sousconjonctivale était le problème oculaire le plus fréquemment relevé chez 50 patients, parmi lesquels 84 % avaient des hémorragies caractérisées de type pétéchial. Les problèmes de fond d’œil présents chez 10 patients (7,5 %) comprenaient la dilatation et la tortuosité des vaisseaux ainsi que des hémorragies superficielles, des exsudats cotonneux et des exsudats secs de la rétine; la macula était cependant épargnée chez tous les patients. Seulement 6 patients sont retournés subir un examen de suivi et on a alors trouvé que les modifications de la rétine s’étaient résolues sans traitement particulier dans un délai de 2 à 8 semaines. Parmi tous les paramètres de laboratoire évalués, la thrombocytopénie marquée (compte des plaquettes inférieur à 50 000/μL) a ressorti comme étant significativement associée à l’hémorragie oculaire. Interprétation : Les hémorragies sousconjonctivales multiples, surtout de type pétéchiel, sont une manifestation commune de la dengue. Les patients atteints de la maladie avec thrombocytopénie marquée sont prédisposés aux hémorragies oculaires spontanées. From the Christian Medical College and Hospital, Ludhiana, Punjab, India Originally received Dec. 2, 2005. Revised Jun. 6, 2006 Accepted for publication Jun. 13, 2006
Correspondence to: Harpreet K. Kapoor, MS, Department of Ophthalmology, Christian Medical College & Hospital, Brown Rd., Ludhiana 141008, Punjab, India; fax 911612685816; harpreet_ [email protected] This article has been peer-reviewed. Cet article a été évalué par les pairs. Can J Ophthalmol 2006;41:741–6
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Ocular manifestations of dengue fever—Kapoor et al
D
engue fever is one of the most common arthropodborne viral diseases of man, with an estimated 100 million cases per year and 2.5 billion people at risk worldwide.1 It has emerged as a global public health problem in the past several decades and is now endemic in most tropical and subtropical areas of Central and South America, Southeast Asia, the western Pacific, Africa, and the eastern Mediterranean.2 The number of epidemics reported from different parts of the world, including India, has risen exponentially.3–8 The principal vector of dengue infection is the mosquito Aedes aegypti, which is found worldwide between latitudes 35°N and 35°S.9 Classic dengue fever (CDF) is a self-limiting, influenza-like illness caused by any of the 4 serotypes (DEN 1–4) of dengue virus. Dengue haemorrhagic fever (DHF) is a more severe form of the disease, characterized by multisystem haemorrhagic manifestations, thrombocytopenia, increased vascular permeability, and plasma leakage. When medically unsupported, mortality is as high as 10%–20% (over 40% if shock occurs) but can be decreased to 0.2% with early diagnosis and appropriate intensive supportive therapy.9 Dengue fever is considered to be rarely associated with ocular manifestations.10 The published literature includes reports of approximately 36 patients presenting primarily with moderate to marked visual impairment due to various posterior segment alterations.10–16 This study was undertaken to document the spectrum of ocular manifestations of dengue fever, and to identify any significant laboratory parameter associations. METHODS
This study was conducted in Christian Medical College and Hospital, Ludhiana, a tertiary care hospital situated in Northern India, from October 1, 2003, to November 30, 2003. During this period, several parts of India, including Ludhiana, experienced an unprecedented epidemic of dengue fever. One hundred and thirty-four consecutive patients admitted in the medical ward with a diagnosis of dengue infection were enrolled in the study. Informed consent was obtained from the patients or their accompanying relatives. A detailed clinical history, including systemic and visual complaints, was taken. Patients with a history of diabetes mellitus, hypertension, anemia, or any other systemic or ophthalmic disorders with potential findings similar to those previously reported to be associated with dengue fever were excluded from the study. Diagnosis of dengue fever was based on clinical features and laboratory parameters. Serological evaluation was done by using the Dengue IgM Capture ELISA test kit (Panbio Limited, Brisbane, Australia).
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Table 1—World Health Organization clinical classification of dengue haemorrhagic fever (DHF) Grade DHF I DHF II
DHF III* DHF IV*
Clinical features
Laboratory findings
Fever, constitutional symptoms, positive tourniquet test Grade I + spontaneous bleeding (e.g., skin, gums, gastrointestinal tract) Grade II + circulatory failure, agitation Grade II + profound shock (blood pressure unrecordable)
Hemoconcentration, † thrombocytopenia Hemoconcentration, † thrombocytopenia Hemoconcentration, † thrombocytopenia Hemoconcentration, † thrombocytopenia
*Dengue shock syndrome. †
Platelet count <100 000/μL.
Table 2—Classic dengue fever and dengue haemorrhagic fever, grades I–IV Number of patients CDF With ocular findings Without ocular findings Total
DHF-I DHF-II DHF-III DHF-IV
Total
0
1
52
1
0
54
9
38
33
0
0
80
9
39
85
1
0
134
Note: CDF, classic dengue fever; DHF, dengue haemorrhagic fever.
Table 3—Spontaneous bleeding manifestations in patients with dengue fever Site of haemorrhage Subconjunctival haemorrhage Cutaneous haemorrhage Upper gastrointestinal bleed Lower gastrointestinal bleed Retinal haemorrhages Haemoptysis Epistaxis Hematuria Gingival bleed Menorrhagia
No. of patients 50 29 20 18 5 5 4 2 1 1
% of total, n = 134 37.3 21.6 14.9 13.4 3.7 3.7 2.9 1.5 0.8 0.8
All patients were classified into either CDF or DHF (grades I–IV) as per World Health Organization criteria (Table 1).17 Complete ocular examination, including dilated fundus examination, was carried out in all patients. Patients with ocular findings were called for weekly follow-up visits in the ophthalmology clinic after they were discharged from the hospital. Data were entered and analyzed in SPSS version 12 statistical software (SPSS Inc., Chicago, Ill.). RESULTS
One hundred and thirty-four patients hospitalized
Ocular manifestations of dengue fever—Kapoor et al
Fig. 1—Haemorrhagic manifestations of dengue fever. Left. Patient with spontaneous gingival bleed. Centre. Petechial type of subconjunctival haemorrhage. Right. Diffuse type of subconjunctival haemorrhage.
with a diagnosis of dengue fever or DHF were included in the study. The patients ranged in age from 13 to 65 years with a mean of 31.3 years; 63.4% were males. One hundred and thirty-one (97.8%) patients lived in urban areas, 85 (63.4%) patients were employed, and the rest were either students or housewives. The median duration of hospital stay was 5 days. Although only 36.6% of patients were aware that dengue spreads by mosquitoes, 65.7% were using personal protective measures like coils or mats (48.5%), mosquito nets (9.7%), and topical repellants (7.5%). All patients presented with a history of fever ranging from 37.8°C to 40.3°C. Other common presenting symptoms were vomiting (38.8%), myalgia (35.1%), headache (27.6%), abdominal pain (24.6%), and a maculopapular rash (17.2%). Only 6 (4.5%) patients presented with retrobulbar pain. None of the patients in our series had any visual complaints. The majority of patients were categorized into DHF grade II (Table 2). Spontaneous bleeding manifestations were present in 87 (64.9%) patients (Table 3 and Fig. 1). Subconjunctival haemorrhage was the commonest haemorrhagic manifestation and was found in 50 (37.3%) patients, followed by cutaneous haemorrhage in the form of petechiae and ecchymosis seen in 21.6% of patients. Ocular findings were present in 54 (40.3%) patients (Table 4), of whom 96.3% had DHF grade II. Subconjunctival haemorrhage, the commonest eye finding, was seen in 50 patients; 66% of these patients had haemorrhages in both eyes and 34% in one eye only; 42 (84%) patients had multiple, dot-like, petechial haemorrhages (Fig. 1, centre), and 8 (16%) patients had a diffuse haemorrhage (Fig. 1, right) present in 1 to 4 quadrants of one or both eyes. Fundus findings were present in 10 (7.5%) patients; 3 (2.2%) had isolated superficial retinal haemorrhages (1 unilateral, 2 bilateral), 3 (2.2%) patients had several cotton-
wool spots seen in one eye only, and 2 (1.5%) patients had dilatation and tortuosity of vessels as the only finding in both eyes. There were 2 (1.5%) patients who had a retinopathy with superficial retinal haemorrhages, hard exudates, and cotton-wool spots scattered in the fundus (1 unilateral, 1 bilateral); the macula, however, was spared in these patients. Of all the laboratory parameters evaluated, marked thrombocytopenia (platelet count less than 50 000/μL) was present in 90.7% of patients with ocular haemorrhage, and the association was statistically significant (p < 0.001) with an estimated odds ratio of 6.73 (95% CI, 2.20–20.59). Leucopenia was seen in 23 (42.6%) patients with ocular haemorrhage (p > 0.39). Prothrombin time (PT) and partial thromboplastin time (PTT) were carried out in 84 patients. Although 91.2% of patients with ocular haemorrhage had prolonged PTT values, the association was not statistically significant (p > 0.53). PT was prolonged in 67.6% of patients with ocular haemorrhage (p > 0.69). Of 102 patients who had liver function tests, only 9 (22%) patients with ocular haemorrhage had abnormal values (p > 0.50) (Table 5). After hospitalization, only 19 patients returned for follow-up ophthalmic examination. Of these 19, 16 patients had subconjunctival haemorrhages in one or both eyes at the time of admission. These had resolved within 6 to 14 days in all 16 patients. Six of the 10 patients with posterior segment involvement (3 with isolated retinal haemorrhages, 2 with cotton-wool spots, and 1 with dilatation and tortuosity of vessels) returned for follow-up evaluation. The findings in these patients had resolved without any specific treatment within 2 to 8 weeks of presentation. INTERPRETATION
The incidence, geographic distribution, and clinical severity of epidemic and endemic dengue have increased
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Table 4—Ocular findings in patients with dengue fever Ocular finding Subconjunctival haemorrhage Petechial-type haemorrhage Diffuse-type haemorrhage Posterior segment alterations Superficial retinal haemorrhages Cotton-wool spots Dilatation and tortuosity of vessels Retinopathy (hard exudates, superficial retinal haemorrhages, and cotton-wool spots)
No. of patients
% of total, n = 134
50 42 8 10 3 3 2
37.3 31.3 6.0 7.5 2.2 2.2 1.5
2
1.5
Table 5—Laboratory findings and association with ocular haemorrhage Laboratory parameter Platelet count >100 000/μL 50–100 000/μL <50 000/μL Total WBC count ≥4000/mL <4000/mL Total Prothrombin time* Normal Prolonged Total PTT* Normal Prolonged Total LFT† Normal Abnormal Total
No. (%) of patients With ocular haemorrhage 0 5 49 54
(0.0) (9.3) (90.7) (100)
Without ocular haemorrhage 9 19 52 80
(11.3) (23.7) (65.0) (100)
p value
<0.001
31 (57.4) 23 (42.6) 54 (100)
53 (66.3) 27 (33.7) 80 (100)
>0.39
11 (32.4) 23 (67.6) 34 (100)
13 (26.0) 37 (74.0) 50 (100)
>0.69
3 (8.8) 31 (91.2) 34 (100)
8 (16.0) 42 (84.0) 50 (100)
>0.53
32 (78.1) 9 (21.9) 41 (100)
52 (85.3) 9 (14.7) 61 (100)
>0.50
Note: WBC, white blood cell; PTT, partial thromboplastin time; LFT, liver function tests. *Prothrombin time and PTT were carried out in 84 patients only. † LFT was carried out in 102 patients only.
noticeably in the past few decades.9 The expansion of this flavivirus infection is linked to resurgence of the mosquito vector Aedes aegypti, population growth in the tropics, uncontrolled urbanization and overcrowding without appropriate water management, and global spread of dengue via travel and trade.18 The clinical presentation of the patients in our series was characteristic of classical dengue infection. Fever was a consistent symptom present in all patients, with vomiting, myalgia, headache, and abdominal pain being among the other common presenting symptoms. Retrobulbar pain, which has been classically described
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as a feature of dengue infection, was seen in only 4.5% patients, although its prevalence has been reported to be higher by some authors.19,20 Ocular manifestations of dengue fever have received little attention in the published literature. There are isolated reports of dengue fever patients who primarily presented with visual impairment due to posterior segment involvement (Table 6). Although none of our patients presented with visual complaints, examination revealed that a significant number (40.3%) had ocular findings, of which subconjunctival haemorrhage was the commonest, occurring in 37.3% patients. The majority of these patients had multiple, dot-like petechial haemorrhages in one or both eyes. This pattern of subconjunctival haemorrhage has been reported to be occasionally associated with systemic conditions like meningococcal septicaemia, subacute bacterial endocarditis, measles, and sandfly fever, but not yet with dengue fever.21 Since the majority of our patients had this characteristic type of subconjunctival haemorrhage, dengue infection should be an important diagnostic consideration when conjunctival petechial haemorrhages are seen in association with fever, especially in patients living in endemic areas or in travellers who have recently visited a tropical country. Ten (7.5%) patients in our series had posterior segment findings, including dilatation and tortuosity of vessels, cotton-wool spots, superficial retinal haemorrhages, and hard exudates. The macula, however, was spared in these cases and visual acuity was thus unaffected. This is in contrast to other reports, where patients presented with severe visual impairment due to choroidal effusion, optic neuritis, exudative maculopathy, or retinal thickening in the macula.10,12–15 All 4 distinct serotypes of dengue virus (DEN 1–4) can cause dengue fever. Moreover, variations in the virus strains within and between the 4 serotypes influence the disease severity.9 In our series, the majority of patients had a milder form of systemic disease, only one patient suffering from DHF grade III, no patients with DHF grade IV, and no mortality. It was also observed that, in contrast to some reports, none of our patients had impairment of vision. The difference in the severity and type of presentation in our series may be attributed to variations in the virulence and serotype of the infecting virus. The pathophysiologic mechanisms involved in dengue infection are complex and not completely understood. The various manifestations of the disease are believed to be a result of either direct viral invasion or a complex immune-mediated process. It has been speculated that viral invasion of endothelial cells, dendritic cells, monocytes, and hepatocytes causes apopto-
Ocular manifestations of dengue fever—Kapoor et al
Table 6—Summary of literature on ocular manifestations of dengue fever Author, year
No. & sex of patients
Spitznas 11 1978 [in German] Wen et al 12 1989 [in Chinese]
1F
Bilateral intraretinal haemorrhages in macula
14 F 10 M
Macular hemorrhage, 10 Maculopathy, 7 Macular and retinal haemorrhages, 5 Peripapillary haemorrhage, 3 Roth’s spot, 2 Vitreous/aqueous cells, 2 Diffuse retinal oedema, 1 Optic neuritis, 1 Ischemic optic neuropathy, 1 Intraretinal haemorrhages, retinal pigment epithelial lesions in the fovea, cotton-wool spots, maculopathy Bilateral exudative maculopathy, haemorrhages in the nerve fibre layer Bilateral choroidal effusion
Haritoglou 13 et al 2000 [in German]
2
Haritoglou 14 et al 2002
1F
CruzVillegas 10 et al 2003 Lim et al 15 2004
1M
Siqueira et 16 al 2004
1M
5F 1M
Ocular findings
Intraretinal whitish lesions with localized retinal and RPE disturbance, small dot haemorrhages, vascular sheathing around macula and papillomacular bundle Bilateral vascular sheathing, retinal haemorrhages at the equator, and cotton-wool spots in the macula
Note: RPE, retinal pigment epithelium.
sis and cellular dysfunction. This may be followed by a transient aberrant immune response, resulting in CD4/CD8 ratio inversion and cytokine overproduction, that has deleterious effects on these cells. In addition, overproduction of interleukin-6 triggers the formation of autoantibodies against platelets and endothelial cells, and this results in further immunemediated damages.22–25 Ocular findings in our patients primarily included subconjunctival haemorrhages, retinal haemorrhages, and exudates, which could be due to generalized increased capillary permeability, plasma leakage, and haemorrhagic diathesis associated with endothelial dysfunction, platelet destruction, and consumptive coagulopathy. The pathogenesis of cottonwool spots may be related to occlusion of precapillary arterioles in the retinal nerve fibre layer by immune complex deposition. Lim et al in their study suggested the possibility of specific autoantibodies being produced against retina, retinal pigment epithelium, or choroid,15 but precise mechanisms responsible for the various ocular alterations in dengue still remain unknown. Haemorrhagic manifestations of dengue fever are believed to be multifactorial in origin.
Thrombocytopenia and abnormal coagulation profiles (PT, PTT) have been reported to have a predictive value for spontaneous systemic bleeds in dengue infection.26,27 Gomber et al, however, reported that there was no significant association between thrombocytopenia and haemorrhagic manifestations, signifying that there may be other factors, like platelet dysfunction and disseminated intravascular coagulopathy, responsible for bleeding.28 There are no reports in the literature of an association of ocular haemorrhage with abnormal laboratory parameters in dengue infection. Our study revealed that 90.7% of patients with ocular haemorrhage (subconjunctival or retinal) had marked thrombocytopenia (platelet counts less than 50 000/μL) and the association was statistically significant (p < 0.001). The correlation with other parameters, like leucopenia, prolonged PT, PTT, and abnormal liver function tests, was not significant. Ocular alterations in dengue are usually self-limiting. According to Haritoglou et al, most of the findings resolve without specific treatment, but occasionally visual recovery may be prolonged or vision may remain permanently impaired in patients with a severe maculopathy.14 In our study, the 6 patients with posterior segment alterations who were reexamined resolved without any specific treatment within 2 to 8 weeks. Lim et al in a recent report suggested the use of periocular steroids for treatment of vision-threatening maculopathy in dengue patients.15 Their study, however, included 6 patients only, thus inferences regarding definitive management of such patients cannot be conclusively drawn from their observations. Further studies with a larger sample size are required to evaluate the treatment options in patients presenting with visual impairment in dengue infection. Dengue fever, and in particular life-threatening DHF, continues to be a global challenge: the pathogenesis of the disease is not completely understood, there is no specific treatment available nor any immediate prospect of a vaccine, and the mosquito control measures in most of the hyperendemic areas are inadequate. The incidence and geographic distribution of dengue has increased dramatically in the past several years, and its ocular manifestations are likely to follow this trend. Ophthalmologists should thus be aware of the various ocular manifestations of dengue, as early diagnosis and referral for appropriate supportive therapy can considerably reduce the mortality of this potentially fatal disease. Furthermore, patients of dengue fever with marked thrombocytopenia (platelet count <50 000/μL) are predisposed to spontaneous ocular haemorrhages which, while primarily subconjunctival, if present in the macula can lead to impairment of vision.
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Acknowledgements: We are most grateful to Dr. A.S. Bhatia for statistical analysis of the data. We thank Dr. Jasbir Dhanoa and Dr. Dandona for their invaluable support. We would also like to acknowledge Dr. Jude Simmons, Dr. Daya Sadiq, and Dr. Manpreet Bhullar for helping us in various ways during the course of the study.
REFERENCES 1. World Health Organization. Dengue Hemorrhagic Fever: Diagnosis, Treatment and Control. 2nd ed. Geneva, Switzerland: WHO; 1997. 2. Ramirez-Ronda CH, Garcia CD. Dengue in the Western Hemisphere. Infect Dis Clin North Am 1994;8:107–28. 3. Chaturvedi UC, Shrivastava R. Dengue haemorrhagic fever: a global challenge. Indian J Med Microbiol 2004;22:5–6. 4. McBride WJ. Deaths associated with dengue haemorrhagic fever: the first in Australia in over a century. Med J Aust 2005;183:35–7. 5. Qiu FX, Gubler DJ, Liu JC, Chen QQ. Dengue in China: a clinical review. Bull World Health Organ 1993;71:349–59. 6. Fouque F, Reynes JM, Moreau JP. Dengue in French Guiana, 1965–1993. Bull Pan Am Health Organ 1995;29:147–55. 7. Cherian T, Ponnuraj E, Kuruvilla T, Kirubakaran C, John TJ, Raghupathy P. An epidemic of dengue haemorrhagic fever and dengue shock syndrome in and around Vellore. Indian J Med Res 1994;100:54–6. 8. Aggarwal A, Chandra J, Aneja S, Patwari AK, Dutta AK. An epidemic of dengue hemorrhagic fever and dengue shock syndrome in children in Delhi. Indian Pediatr 1998;35:727–32. 9. Gibbons RV, Vaughn DW. Dengue: an escalating problem. BMJ 2002;324:1563–6. 10. Cruz-Villegas V, Berrocal AM, Davis JL. Bilateral choroidal effusions associated with dengue fever. Retina 2003; 23:576–8. 11. Spitznas M. Macular haemorrhage in dengue fever [in German; English abstract]. Klin Monatsbl Augenheilkd 1978;172:105–7. 12. Wen KH, Sheu MM, Chung CB, Wang HZ, Chen CW. The ocular fundus findings in dengue fever [in Chinese; English abstract]. Gaoxiong Yi Xue Ke Xue Za Zhi 1989;5:24–30. 13. Haritoglou C, Scholz F, Bialasiewicz A, Klauss V. Ocular manifestation in dengue fever [in German; English abstract]. Ophthalmologe 2000;97:433–6. 14. Haritoglou C, Dotse SD, Rudolph G, Stephan CM, Thurau SR, Klaub V. A tourist with dengue fever and visual loss. Lancet 2002;360:1070. 15. Lim WK, Mathur R, Koh A, Yeoh R, Chee SP. Ocular manifestations of dengue fever. Ophthalmology 2004;111: 2057–64.
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16. Siqueira RC, Vitral NP, Campos WR, Orefice F, de Moraes Figueiredo LT. Ocular manifestations in Dengue fever. Ocul Immunol Inflamm 2004;12:323–7. 17. Sanford JP. Arbovirus infections. In: Isselbacher KJ, Braunwald E, Wilson JD, et al, eds. Harrison’s Principles of Internal Medicine. New York, NY: McGraw-Hill Inc; 1994:847–8. 18. Lifson AR. Mosquitoes, models, and dengue. Lancet 1996;347:1201–2. 19. Sharp TW, Wallace MR, Hayes CG, et al. Dengue fever in U.S. troops during operation Restore Hope, Somalia, 1992–1993. Am J Trop Med Hyg 1995;53:89–94. 20. Narayanan M, Aravind MA, Thilothammai N, Prema R, Rex Sargunam CS, Ramamurthy N. Dengue fever epidemic in Chennai: a study of clinical profile and outcome. Indian Pediatr 2002;39:1027–33. 21. Duke-Elder S. Anomalies of the circulation. In: Duke-Elder S, ed. System of Ophthalmology: Diseases of the outer eye Part I. London: Henry Kimpton; 1965:36. 22. Kurane I, Rothman AL, Livingston PG, et al. Immunopathogenic mechanisms of dengue hemorrhagic fever and dengue shock syndrome. Arch Virol Suppl 1994; 9:59–64. 23. Morens DM. Antibody-dependant enhancement of infection and the pathogenesis of viral disease. Clin Infect Dis 1994;19:500–12. 24. Lei HY, Yeh TM, Liu HS, Lin YS, Chen SH, Liu CC. Immunopathogenesis of dengue virus infection. J Biomed Sci 2001;8:377–88. 25. Lin CF, Lei HY, Shiau AL, et al. Antibodies from dengue patient sera cross-react with endothelial cells and induce damage. J Med Virol 2003;69:82–90. 26. Shivbalan S, Anandnathan K, Balasubramanian S, Datta M, Amalraj E. Predictors of spontaneous bleeding in Dengue. Indian J Pediatr 2004;71:33–6. 27. Chua MN, Molanida R, de Guzman M, Laberiza F. Prothrombin time and partial thromboplastin time as a predictor of bleeding in patients with dengue hemorrhagic fever. Southeast Asian J Trop Med Public Health 1993;24:141–3. 28. Gomber S, Ramachandran VG, Kumar S, et al. Hematological observations and diagnostic markers in dengue hemorrhagic fever – a reappraisal. Indian Pediatr 2001;38:477–81. Key words: dengue, ocular, subconjunctival haemorrhage, thrombocytopenia