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Clinical science
Infectious involvement in a tertiary center pediatric uveitis cohort Ymkje Marije Hettinga,1 Jolanda Dorothea Francisca de Groot-Mijnes,2 Aniki Rothova,3 Joke Helena de Boer1 1
Department of Ophthalmology, University Medical Center Utrecht, Utrecht, The Netherlands 2 Department of Virology, University Medical Center Utrecht, Utrecht, The Netherlands 3 Department of Ophthalmology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands Correspondence to Ymkje Marije Hettinga, Department of Ophthalmology, University Medical Center Utrecht, E.03-136, Heidelberglaan 100, P.O. Box 85500, 3508 CX Utrecht, The Netherlands; [email protected] Received 7 April 2014 Revised 28 May 2014 Accepted 19 July 2014 Published Online First 19 August 2014
ABSTRACT Background/aims Studies of uveitis in children have focused primarily on non-infectious causes. To date, no systematic study of infectious uveitis in children has been conducted. We investigate the prevalence of infectious causes of uveitis in children and explore the diagnostic value of analysing aqueous humour. Methods Retrospective cohort study in a tertiary referral centre for paediatric uveitis. Medical records of 345 children with uveitis presenting from 1995 through 2010 were reviewed for infectious causes (by serology and aqueous humour analysis). Results A diagnosis of infectious uveitis was established in 60/345 (17%) children. The most prevalent pathogen was Toxoplasma gondii (36/60; 60%), followed by viral infections (18/60; 30%). The most prevalent viral pathogen was varicella-zoster virus (VZV), representing 7/18 (39%) children. Viral causes were less often bilateral than other infectious causes ( p=0.04). Specific IgG serum levels determined in 42/60 (70%) patients, were positive in 41/42 (98%). Aqueous humour was analysed for 24/60 (40%) patients and was positive in 18/24 (75%). Conclusions An infectious cause of uveitis was identified in 17% of children with uveitis. T gondii and VZV were the most prevalent pathogens. We recommend analysing the aqueous humour of every child with visionthreatening uveitis of undetermined origin.
the efficacy of several diagnostic tools, including serology and analysing the aqueous humour.
MATERIALS AND METHODS Our cohort included 345 children with uveitis onset before the age of 17 years who were examined consecutively from 1995 through 2010 in the Department of Ophthalmology at the University Medical Center Utrecht, The Netherlands. We performed a retrospective study of these patients’ medical records. A diagnosis of uveitis was made in accordance with the criteria established by the International Uveitis Study Group.11 The presence of systemic diseases was assessed in accordance with current diagnostic criteria by paediatricians and/or paediatric rheumatologists. A diagnosis of infectious uveitis was based upon a combination of clinical, laboratory and imaging findings. Fuchs heterochromic uveitis syndrome (FHUS) was classified as infectious uveitis because of the established relationship between FHUS and rubella virus.12 This study was performed in accordance with the tenets of the Declaration of Helsinki, and conformed to the regulations of our centre’s institutional review board.
Aqueous humour analysis INTRODUCTION
To cite: Hettinga YM, de Groot-Mijnes JDF, Rothova A, et al. Br J Ophthalmol 2015;99: 103–107.
Uveitis encompasses a variety of inflammatory diseases of the eye. Uveitis is less prevalent in children than in adults.1 2 In previous studies, an infectious cause was identified in 6–33% of all cases of paediatric uveitis (table 1).1–9 Infectious uveitis can be caused either by the reactivation of a congenital infection, or by an acquired infection. The ability to identify infectious uveitis early is extremely important, as the treatment regimens differ significantly between infectious and non-infectious uveitis. In the Western world, the most prevalent pathogens in adult immunocompetent patients with infectious uveitis are the parasite Toxoplasma gondii and certain viruses, including herpes simplex virus (HSV), varicella-zoster virus (VZV) and rubella virus.10 Most studies of uveitis in children focus primarily on non-infectious uveitis. To date, no systematic study of infectious uveitis in children has been performed, and the diagnostic value of analysing the aqueous humour in paediatric uveitis patients has not been determined. Here, we examined the infectious causes of uveitis in children and determined
An aqueous tap was performed to obtain intraocular fluid for diagnostic purposes.13 The indication for an aqueous humour tap in our cohort was vision-threatening, active-stage uveitis of undetermined origin. The aqueous humour samples were analysed at the Netherlands Ophthalmic Research Institute (Amsterdam, The Netherlands) through 2001,14 and at the Virology Department of the University Medical Center Utrecht from 2002 onwards.15 From our patient cohort, four aqueous humour taps were performed before 2002, and 20 were performed from 2002 and after. T gondii, cytomegalovirus (CMV), HSV and VZV real-time PCR results and Goldmann-Witmer coefficient (GWC) analyses were available throughout the study period. A PCR protocol for Epstein-Barr virus (EBV) became available in 2002, rubella virus PCR and GWC analyses were implemented in 2005, and Toxocara GWC became available in 2006. Anterior chamber paracentesis was performed using a standard protocol, and all aqueous humour taps were performed under general anaesthesia and yielded 0.1–0.2 ml of aqueous fluid. We did not observe any complications following the aqueous humour taps.
Hettinga YM, et al. Br J Ophthalmol 2015;99:103–107. doi:10.1136/bjophthalmol-2014-305367
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Clinical science Table 1 Comparison of infectious uveitis in children published 1996–2013 and calculated from the original tables Cause of infectious uveitis Reference
Number of patients 55
Region
Infectious (%)*
Toxoplasmosis (%)†
Finland
13
57
14 15
Toxocariasis (%)†
Viral (%)†
Other causes
–
43
–
56 67
22 –
22 28
20 24
13 31
25 8
63 19
– Diffuse unilateral subacute neuroretinitis – Diffuse unilateral subacute neuroretinitis, Mycobacterium tuberculosis, bartonella M tuberculosis, bartonella, borrelia burgdorferi, staphylococcus, klebsiella, yersinia – M tuberculosis, borrelia burgdorferi, streptococcus, brucella undetermined
Paivonsalo-Hietanen et al1 Tugal-Tutkun et al2 de Boer et al3
130 123
Azar and Martin4 Rosenberg et al5
40 148
Boston‡ The Netherlands§ Australia Florida
BenEzra et al6
276
Israel
33
22
14
31
Kump et al7 Paroli et al8
269 257
Boston‡ Italy
6 35
60 44
7 5
33 17
Smith et al 9¶
527
11
45
–
–
Hettinga (this study)
345
USA (multicentre) The Netherlands§
17
60
3
30
Diffuse unilateral subacute neuroretinitis, M tuberculosis, borrelia burgdorferi, ascaris
*The percentage is out of the total number of uveitis patients. †The percentage is out of the total number of infectious uveitis patients. ‡The two studies from Boston had overlapping patients with each other. §The two studies from The Netherlands had overlapping patient with each other. ¶≤18 years, other ≤16 years. Fuchs heterochromic uveitis syndrome (FHUS) was classified as infectious uveitis because of the established relationship between FHUS and rubella virus.8 9
Determination of intraocular antibody titres and the GWC The total immunoglobulin G (IgG) concentrations and the titres and concentrations of specific IgGs against T gondii, VZV, HSV, EBV, rubella virus, CMV and Toxocara in patient sera and aqueous humour samples were determined as described previously.12 15 Briefly, serial dilutions of sera and ocular fluids were analysed in order to calculate the GWC, which compares the ratio of a specific antibody in the eye to the peripheral blood with the ratio of total IgG in the eye to the peripheral blood. A GWC >3 was considered positive (with the exception of VZV, for which a GWC >10 was considered positive, as low GWCs for VZV have been detected in patients with clinical features that are not consistent with an intraocular VZV infection16). If an adequate volume of aqueous humour fluid was available, all tests were performed; otherwise, only the most likely causes were tested.
Real-time PCR Eighteen samples were analysed using PCR and GWC. For three samples, PCR could not be performed due to an insufficient volume. For two cases of Toxocara and one case of Borrelia, no PCR test was available.
RESULTS The clinical diagnoses of infectious uveitis in our cohort are presented in table 2. A diagnosis of infectious uveitis was made in 60/345 (17%) of the children. Of these 60, 31 (52%) were boys 104
and 29 (48%) were girls. The mean age at the time of diagnosis was 9 years (range: 20 days to 16 years). The mean age of the children with the most prevalent infectious entities was similar (9 years in the children with ocular toxoplasmosis and 9 years in the children with viral uveitis). Thirty-eight children (63%) had unilateral uveitis, and 22 (37%) had bilateral uveitis. Fewer bilateral cases were viral compared to other infectious causes; unilateral uveitis was observed in 15/18 (83%) of viral cases compared with 23/42 (55%) of non-viral cases ( p=0.04; Fisher’s exact test). For 18 (30%) and 42 (70%) patients, infectious uveitis was diagnosed on the basis of clinical findings or specific serum IgG levels, respectively. With the exception of one case of ocular toxocariasis, 41/42 (98%) were positive for IgG against the suspected infectious agent according to the clinical diagnosis. Specifically, the clinical diagnosis was confirmed by the detection of specific IgG antibodies against T gondii (n=24 patients), VZV (n=6), rubella virus (n=2), HSV (n=2), CMV (n=3), EBV (n=1), Toxocara (n=2, positive in one case), Ascaris (n=1), and Borrelia (n= 1). The aqueous humour was analysed for 24/60 patients (40%); in 18/24 (75%) cases, the analysis yielded a positive result (table 2). In 5 cases, analysis of the anterior chamber tap confirmed our suspicion. The results of the analysis of these five patients were Toxoplasma (n=3), HSV (n=1) and VZV (n=1). In the 19 other cases the diagnosis was undetermined before analysing the aqueous humour. Of the 18 positive aqueous humour samples, 16 (89%) had a positive GWC. The
Hettinga YM, et al. Br J Ophthalmol 2015;99:103–107. doi:10.1136/bjophthalmol-2014-305367
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Clinical science Table 2 Infectious causes of uveitis in a paediatric uveitis patient cohort and the results of serology and aqueous humour analysis
Pathogen Toxoplasma gondii Viral Varicella-zoster virus Rubella virus Herpes simplex virus Cytomegalovirus Epstein-Barr virus Toxocara canis Ascaris Diffuse unilateral subacute neuroretinitis Mycobacterium tuberculosis Borrelia Total
Number of patients 36
Percentage (out of 60 patients with infectious uveitis) 60
Number of patients diagnosed on clinical grounds only
Number of patients with confirmation of specific IgG in the serum
Positive result of aqueous humour analysis
12
24
6/10
7 4 3 3 1 2 1 1
12 7 5 5 1.7 3 1.7 1.7
1 2 1 0 0 0 0 1
6 2 2 3 1 1 1 NA
6/6 2/2 2/2 NA 0/1 2/2 NA NA
1
1.7
1
NA
NA
1 60
1.7 100
0 18
1 41
0/1 18/24
NA, Not applicable.
PCR was positive in 5/18 (28%) cases tested; three samples had positive PCR and GWC results. Ocular toxoplasmosis was the most frequently diagnosed infectious disorder, representing 36 out of 60 cases (60%). All 36 patients had chorioretinal lesions that were consistent with the clinical diagnosis of ocular toxoplasmosis. Nineteen of the 36 (53%) ocular toxoplasmosis patients had unilateral involvement, and 17/36 (47%) patients had bilateral involvement. An aqueous humour tap was performed in 10 patients with ocular toxoplasmosis; 6/10 of these patients had a positive GWC for Toxoplasma, and none of these 6 children were positive for IgM antibodies. Four of the children diagnosed with ocular toxoplasmosis had negative aqueous humour findings; however, all four had Toxoplasma-specific IgG in their serum, and their clinical presentation was consistent with ocular toxoplasmosis. Moreover, all four of these children responded well to treatment with pyrimethamine and azithromycin. The second most prevalent cause of infectious uveitis in our cohort was viral infections, representing 18 of the 60 cases (30%), with VZV as the most common pathogen, affecting 7 of the 18 viral cases (39%). Six patients with VZV-associated uveitis were confirmed by aqueous humour analysis; the seventh patient had an active chickenpox infection, and aqueous humour analysis was not performed. Five VZV patients had unilateral uveitis, and two had bilateral uveitis. Additionally, five VZV patients had anterior uveitis, and two had acute retinal necrosis (ARN). Three of the VZV-associated anterior uveitis patients presented with kerato-uveitis, two of whom had a recent case of chickenpox. One additional patient had anterior uveitis with sector atrophy of the iris and a cataract. Of the two VZV-associated patients with ARN, one had acute lymphoblastic leukaemia, and the other had concurrent viral meningitis due to infection of a drain inserted to treat hydrocephalus (figure 1). Neither of these two ARN patients had evidence of recent chickenpox. The clinical manifestations at the onset of the two cases of VZV-associated retinitis were ambiguous, as illustrated by the patient depicted in figure 1. An analysis of the aqueous humour confirmed the cause of retinitis and was sufficiently decisive to facilitate early diagnosis and antiviral treatment. Later in their
disease course, both patients developed the clinical characteristics of ARN. Of the four children with a clinical diagnosis of FHUS, two were found to have an intraocular rubella virus infection by a positive GWC. The other two patients were diagnosed only clinically, as the rubella virus assays were not available at that time. Three children—all of whom were immunocompetent—had congenital CMV. One CMV patient presented with anterior uveitis and a cataract, and the other two had chorioretinal scars. All three children had a positive serum IgG test for CMV; the following pathogens were tested and were negative: T gondii, Toxocara, HSV, rubella virus, VZV and Treponema pallidum. For all three patients, the diagnosis was confirmed by examining preserved blood samples that had been collected in the first postnatal week for phenylketonuria testing. Ocular toxocariasis was diagnosed in two of the 60 patients (3%); in both cases, the diagnosis was confirmed by a positive GWC. One of these two cases had detectable Toxocara IgG in the eye only. The clinical features of these two patients included severe posterior uveitis with peripheral granuloma and retinal lesions.
DISCUSSION A diagnosis of infectious uveitis was established in 17% of our paediatric uveitis patients. Our results show that T gondii and VZV were the most prevalent causes of infectious uveitis in children based on our cohort sampled from a developed country in a temperate climate. The percentage of infectious uveitis cases among children with uveitis varies widely in previous reports. This variation might be ascribed—at least in part—to geographical differences and/or the fact that infectious uveitis was usually diagnosed solely on the basis of clinical symptoms and was rarely confirmed by specific serologic testing and/or aqueous analysis. In this study, we took a systematic diagnostic approach and performed aqueous analysis for all children who had visionthreatening uveitis of undetermined origin. An important advantage to our laboratory’s ability to diagnose infectious uveitis is
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Clinical science Figure 1 Early clinical manifestation from a 15-year-old boy with necrotising retinitis and a drain for hydrocephalus after meningitis. Based on the medical condition of this patient it was decided to perform an aqueous humour tap, which was positive for varicella-zoster virus by PCR and GWC. The patient later developed the clinical characteristics of acute retinal necrosis.
the combined approach using real-time PCR, and the detection of intraocular antibody production. We previously reported that ocular toxoplasmosis is the most prevalent cause of blindness among paediatric uveitis patients.3 A high prevalence of ocular toxoplasmosis was also found in previous studies conducted in other continents (table 1). Because necrotizing chorioretinitis is a highly common characteristic finding in toxoplasmosis, we did not perform an aqueous humour tap in all suspected patients. Additionally, four patients presented with focal chorioretinitis, typical of ocular toxoplasmosis; although their aqueous examinations were negative for toxoplasmosis, these patients responded well to treatment with antiparasitic drugs. Viruses were the second highest cause of infectious uveitis, representing 30% of infectious uveitis cases. The clinical presentation of viral uveitis was predominantly unilateral, and VZV was the most prevalent viral pathogen, representing 39% of all viral causes. However, the prevalence of VZV might be even higher, as all patients with VZV—except one—were diagnosed after 2002. Even though PCR testing and GWC analysis for VZV were available throughout this study, we cannot preclude the possibility that we may have missed cases prior to 2002, perhaps due to a lower frequency of performing aqueous analyses. Congenital and acquired VZV infections are rare causes of uveitis.6 The ocular signs of congenital VZV include cataracts, microphthalmia and chorioretinitis.17 The clinical presentation of postnatal acquired VZV uveitis can be diverse.18 19 In our cohort, two cases of VZV uveitis were related to a concurrent chickenpox infection. VZV uveitis was also reported in children after they were vaccinated with a live attenuated varicella vaccine.19 None of the children in our study were vaccinated against VZV (as the varicella vaccine is not part of our national vaccination program). Other reported causes of childhood viral uveitis include HSV type 1 and type 2, CMV, EBV and rubella virus. Viral intraocular infections can occur in healthy and immunocompromised children, and they can occur at any age.20 21 106
FHUS is diagnosed most often in the second to the fourth decade of life, although paediatric cases have been reported.12 21 22 In recent years, it has become increasingly evident that most FHUS cases in Europe are due to intraocular rubella virus infections23 Our study supports this finding, since four patients were diagnosed with FHUS, and in two of them, with indistinct presentation including mature cataract in one of them, aqueous humour analysis was performed. The question is whether FHUS should be classified as an infectious disease and justifies an aqueous humour tap since its treatment does not involve any anti-infectious therapy. Since FHUS and herpetic anterior uveitis can have comparable clinical manifestations, aqueous humour analysis can be helpful in indistinct cases to discriminate between FHUS and other causes of uveitis that requires a different treatment approach.16 Since 1987, all children in The Netherlands have been vaccinated against the rubella virus (at 14 months and 9 years of age). This might explain the relatively low prevalence of FHUS in our cohort. The diagnostic value of serological testing depends on the percentage of positive individuals in a given population. For example, 26% of the Dutch population at childbearing age has IgG antibodies against T gondii24; thus, positive serology would have a relatively high positive predictive value in this population. On the other hand, the cumulative seroprevalence of VZV approaches 95% by the age of 18 years. Thus, VZV serology does not contribute significantly to the diagnosis of VZV uveitis. Additionally, analysing the aqueous humour can be an extremely valuable diagnostic test, particularly for cases that have an inconclusive clinical presentation or are putative infectious uveitis cases, as specific antibodies in the serum can be undetectable (eg, in our patient with toxocariasis). Because confirming viral uveitis can facilitate timely and appropriate treatment, we recommend analysing the aqueous humour analysis of every child with sight-threatening uveitis of unknown cause, as well as unclear cases in which an infectious cause is suspected. Although performing an aqueous humour tap is safe,13 a major disadvantage in children is that the procedure must be performed under general anaesthesia. In our cohort, the GWC results
Hettinga YM, et al. Br J Ophthalmol 2015;99:103–107. doi:10.1136/bjophthalmol-2014-305367
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Clinical science were positive more often than the PCR results, which is consistent with observations in adult patients.15 The outcome of an aqueous analysis depends on several factors such as the patient’s immune status, the course of the disease, and the type of infection. Because these factors are usually not known beforehand, we recommend performing GWC and PCR. This is particularly important, given that herpes viral and T gondii infections are in some cases only PCR positive or only GWC positive. With respect to the rubella virus, the GWC is preferred over PCR testing, as the sensitivity of GWC for and FHUS is nearly 100%.12 23 Moreover, GWC is the preferred test when a limited volume of ocular fluid is available. An exception is severely immunocompromised children, or if ARN is suspected.25 Our study was limited by a potential bias with respect to analysing the aqueous humour, as these analyses were not performed routinely in all children with uveitis. As such, the actual prevalence of infectious uveitis in children might be even higher than reported here. In conclusion, our study systematically assessed the results of using serologic examinations and intraocular fluid analyses to determine the cause of infectious uveitis in a large cohort of children with uveitis. T gondii and VZV were the first and second most prevalent pathogens identified. Analysing the aqueous humour can be a valuable tool for rapidly establishing the precise cause of infectious uveitis, thus facilitating the early initiation of anti-infection treatment. We recommend analysing the aqueous humour analysis in all children with visionthreatening uveitis of undetermined origin.
2 3 4 5 6 7 8 9 10 11
12 13 14
15
16
17
Correction notice This article has been corrected since it was published Online First. The title has been amended from ‘Infectious involvement in a tertiary centre paediatric uveitis cohort of a tertiary referral centre’ to ‘Infectious involvement in a tertiary center pediatric uveitis cohort’. Contributors YMH: concept and design, acquisition of data, analysis and interpretation of data, drafting the article, final approval of the version to be published. JDFdGM and AR: acquisition of data, revising the article critically for intellectual content, final approval of the version to be published. JHdB: concept and design of the study, acquisition of data, revising the article critically for intellectual content; final approval of the version to be published.
18 19
20 21 22
Funding Dr. F.P. Fischer foundation, ODAS foundation and SNOO foundation. Competing interests None.
23
Ethics approval Medial ethics committee, University Medical Center Utrecht. Provenance and peer review Not commissioned; externally peer reviewed.
24
REFERENCES 1
Paivonsalo-Hietanen T, Tuominen J, Saari KM. Uveitis in children: population-based study in Finland. Acta Ophthalmol Scand 2000;78:84–8.
25
Tugal-Tutkun I, Havrlikova K, Power WJ, et al. Changing patterns in uveitis of childhood. Ophthalmology 1996;103:375–83. de Boer J, Wulffraat N, Rothova A. Visual loss in uveitis of childhood. Br J Ophthalmol 2003;87:879–84. Azar D, Martin F. Paediatric uveitis: a Sydney clinic experience. Clin Experiment Ophthalmol 2004;32:468–71. Rosenberg KD, Feuer WJ, Davis JL. Ocular complications of pediatric uveitis. Ophthalmology 2004;111:2299–306. BenEzra D, Cohen E, Maftzir G. Uveitis in children and adolescents. Br J Ophthalmol 2005;89:444–8. Kump LI, Cervantes-Castaneda RA, Androudi SN, et al. Analysis of pediatric uveitis cases at a tertiary referral center. Ophthalmology 2005;112:1287–92. Paroli MP, Spinucci G, Liverani M, et al. Uveitis in childhood: an Italian clinical and epidemiological study. Ocul Immunol Inflamm 2009;17:238–42. Smith JA, Mackensen F, Sen HN, et al. Epidemiology and course of disease in childhood uveitis. Ophthalmology 2009;116:1544–51, 1551. Rodriguez A, Calonge M, Pedroza-Seres M, et al. Referral patterns of uveitis in a tertiary eye care center. Arch Ophthalmol 1996;114:593–9. Bloch-Michel E, Nussenblatt RB. International Uveitis Study Group recommendations for the evaluation of intraocular inflammatory disease. Am J Ophthalmol 1987;103:234–5. de Groot-Mijnes JD, de Visser L, Rothova A, et al. Rubella virus is associated with fuchs heterochromic iridocyclitis. Am J Ophthalmol 2006;141:212–4. Cheung CM, Durrani OM, Murray PI. The safety of anterior chamber paracentesis in patients with uveitis. Br J Ophthalmol 2004;88:582–3. de Boer JH, Verhagen C, Bruinenberg M, et al. Serologic and polymerase chain reaction analysis of intraocular fluids in the diagnosis of infectious uveitis. Am J Ophthalmol 1996;121:650–8. de Groot-Mijnes JD, Rothova A, van Loon AM, et al. Polymerase chain reaction and Goldmann-Witmer coefficient analysis are complimentary for the diagnosis of infectious uveitis. Am J Ophthalmol 2006;141:313–8. Wensing B, Relvas LM, Caspers LE, et al. Comparison of rubella virus- and herpes virus-associated anterior uveitis: clinical manifestations and visual prognosis. Ophthalmology 2011;118:1905–10. Pastuszak AL, Levy M, Schick B, et al. Outcome after maternal varicella infection in the first 20 weeks of pregnancy. N Engl J Med 1994;330:901–5. Belfair N, Levy J, Lifshitz T. Panuveitis as presenting sign of chickenpox in a young child. Can J Ophthalmol 2006;41:97–9. Lin P, Yoon MK, Chiu CS. Herpes zoster keratouveitis and inflammatory ocular hypertension 8 years after varicella vaccination. Ocul Immunol Inflamm 2009;17:33–5. Ganatra JB, Chandler D, Santos C, et al. Viral causes of the acute retinal necrosis syndrome. Am J Ophthalmol 2000;129:166–72. Siemerink MJ, Sijssens KM, de Groot-Mijnes JD, et al. Rubella virus-associated uveitis in a nonvaccinated child. Am J Ophthalmol 2007;143:899–900. Tugal-Tutkun I, Guney-Tefekli E, Kamaci-Duman F, et al. A Cross-sectional and Longitudinal Study of Fuchs Uveitis Syndrome in Turkish Patients. Am J Ophthalmol 2009;148:510–5. Ruokonen PC, Metzner S, Ucer A, et al. Intraocular antibody synthesis against rubella virus and other microorganisms in Fuchs’ heterochromic cyclitis. Graefes Arch Clin Exp Ophthalmol 2010;248:565–71. Hofhuis A, van Pelt W, van Duynhoven YT, et al. Decreased prevalence and age-specific risk factors for Toxoplasma gondii IgG antibodies in The Netherlands between 1995/1996 and 2006/2007. Epidemiol Infect 2011;139:530–8. Tran TH, Rozenberg F, Cassoux N, et al. Polymerase chain reaction analysis of aqueous humour samples in necrotising retinitis. Br J Ophthalmol 2003;87:79–83.
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Infectious involvement in a tertiary center pediatric uveitis cohort Ymkje Marije Hettinga, Jolanda Dorothea Francisca de Groot-Mijnes, Aniki Rothova and Joke Helena de Boer Br J Ophthalmol 2015 99: 103-107 originally published online August 19, 2014
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Clinical science
Infectious involvement in a tertiary center pediatric uveitis cohort Ymkje Marije Hettinga,1 Jolanda Dorothea Francisca de Groot-Mijnes,2 Aniki Rothova,3 Joke Helena de Boer1 1
Department of Ophthalmology, University Medical Center Utrecht, Utrecht, The Netherlands 2 Department of Virology, University Medical Center Utrecht, Utrecht, The Netherlands 3 Department of Ophthalmology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands Correspondence to Ymkje Marije Hettinga, Department of Ophthalmology, University Medical Center Utrecht, E.03-136, Heidelberglaan 100, P.O. Box 85500, 3508 CX Utrecht, The Netherlands; [email protected] Received 7 April 2014 Revised 28 May 2014 Accepted 19 July 2014 Published Online First 19 August 2014
ABSTRACT Background/aims Studies of uveitis in children have focused primarily on non-infectious causes. To date, no systematic study of infectious uveitis in children has been conducted. We investigate the prevalence of infectious causes of uveitis in children and explore the diagnostic value of analysing aqueous humour. Methods Retrospective cohort study in a tertiary referral centre for paediatric uveitis. Medical records of 345 children with uveitis presenting from 1995 through 2010 were reviewed for infectious causes (by serology and aqueous humour analysis). Results A diagnosis of infectious uveitis was established in 60/345 (17%) children. The most prevalent pathogen was Toxoplasma gondii (36/60; 60%), followed by viral infections (18/60; 30%). The most prevalent viral pathogen was varicella-zoster virus (VZV), representing 7/18 (39%) children. Viral causes were less often bilateral than other infectious causes ( p=0.04). Specific IgG serum levels determined in 42/60 (70%) patients, were positive in 41/42 (98%). Aqueous humour was analysed for 24/60 (40%) patients and was positive in 18/24 (75%). Conclusions An infectious cause of uveitis was identified in 17% of children with uveitis. T gondii and VZV were the most prevalent pathogens. We recommend analysing the aqueous humour of every child with visionthreatening uveitis of undetermined origin.
the efficacy of several diagnostic tools, including serology and analysing the aqueous humour.
MATERIALS AND METHODS Our cohort included 345 children with uveitis onset before the age of 17 years who were examined consecutively from 1995 through 2010 in the Department of Ophthalmology at the University Medical Center Utrecht, The Netherlands. We performed a retrospective study of these patients’ medical records. A diagnosis of uveitis was made in accordance with the criteria established by the International Uveitis Study Group.11 The presence of systemic diseases was assessed in accordance with current diagnostic criteria by paediatricians and/or paediatric rheumatologists. A diagnosis of infectious uveitis was based upon a combination of clinical, laboratory and imaging findings. Fuchs heterochromic uveitis syndrome (FHUS) was classified as infectious uveitis because of the established relationship between FHUS and rubella virus.12 This study was performed in accordance with the tenets of the Declaration of Helsinki, and conformed to the regulations of our centre’s institutional review board.
Aqueous humour analysis INTRODUCTION
To cite: Hettinga YM, de Groot-Mijnes JDF, Rothova A, et al. Br J Ophthalmol 2015;99: 103–107.
Uveitis encompasses a variety of inflammatory diseases of the eye. Uveitis is less prevalent in children than in adults.1 2 In previous studies, an infectious cause was identified in 6–33% of all cases of paediatric uveitis (table 1).1–9 Infectious uveitis can be caused either by the reactivation of a congenital infection, or by an acquired infection. The ability to identify infectious uveitis early is extremely important, as the treatment regimens differ significantly between infectious and non-infectious uveitis. In the Western world, the most prevalent pathogens in adult immunocompetent patients with infectious uveitis are the parasite Toxoplasma gondii and certain viruses, including herpes simplex virus (HSV), varicella-zoster virus (VZV) and rubella virus.10 Most studies of uveitis in children focus primarily on non-infectious uveitis. To date, no systematic study of infectious uveitis in children has been performed, and the diagnostic value of analysing the aqueous humour in paediatric uveitis patients has not been determined. Here, we examined the infectious causes of uveitis in children and determined
An aqueous tap was performed to obtain intraocular fluid for diagnostic purposes.13 The indication for an aqueous humour tap in our cohort was vision-threatening, active-stage uveitis of undetermined origin. The aqueous humour samples were analysed at the Netherlands Ophthalmic Research Institute (Amsterdam, The Netherlands) through 2001,14 and at the Virology Department of the University Medical Center Utrecht from 2002 onwards.15 From our patient cohort, four aqueous humour taps were performed before 2002, and 20 were performed from 2002 and after. T gondii, cytomegalovirus (CMV), HSV and VZV real-time PCR results and Goldmann-Witmer coefficient (GWC) analyses were available throughout the study period. A PCR protocol for Epstein-Barr virus (EBV) became available in 2002, rubella virus PCR and GWC analyses were implemented in 2005, and Toxocara GWC became available in 2006. Anterior chamber paracentesis was performed using a standard protocol, and all aqueous humour taps were performed under general anaesthesia and yielded 0.1–0.2 ml of aqueous fluid. We did not observe any complications following the aqueous humour taps.
Hettinga YM, et al. Br J Ophthalmol 2015;99:103–107. doi:10.1136/bjophthalmol-2014-305367
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Clinical science Table 1 Comparison of infectious uveitis in children published 1996–2013 and calculated from the original tables Cause of infectious uveitis Reference
Number of patients 55
Region
Infectious (%)*
Toxoplasmosis (%)†
Finland
13
57
14 15
Toxocariasis (%)†
Viral (%)†
Other causes
–
43
–
56 67
22 –
22 28
20 24
13 31
25 8
63 19
– Diffuse unilateral subacute neuroretinitis – Diffuse unilateral subacute neuroretinitis, Mycobacterium tuberculosis, bartonella M tuberculosis, bartonella, borrelia burgdorferi, staphylococcus, klebsiella, yersinia – M tuberculosis, borrelia burgdorferi, streptococcus, brucella undetermined
Paivonsalo-Hietanen et al1 Tugal-Tutkun et al2 de Boer et al3
130 123
Azar and Martin4 Rosenberg et al5
40 148
Boston‡ The Netherlands§ Australia Florida
BenEzra et al6
276
Israel
33
22
14
31
Kump et al7 Paroli et al8
269 257
Boston‡ Italy
6 35
60 44
7 5
33 17
Smith et al 9¶
527
11
45
–
–
Hettinga (this study)
345
USA (multicentre) The Netherlands§
17
60
3
30
Diffuse unilateral subacute neuroretinitis, M tuberculosis, borrelia burgdorferi, ascaris
*The percentage is out of the total number of uveitis patients. †The percentage is out of the total number of infectious uveitis patients. ‡The two studies from Boston had overlapping patients with each other. §The two studies from The Netherlands had overlapping patient with each other. ¶≤18 years, other ≤16 years. Fuchs heterochromic uveitis syndrome (FHUS) was classified as infectious uveitis because of the established relationship between FHUS and rubella virus.8 9
Determination of intraocular antibody titres and the GWC The total immunoglobulin G (IgG) concentrations and the titres and concentrations of specific IgGs against T gondii, VZV, HSV, EBV, rubella virus, CMV and Toxocara in patient sera and aqueous humour samples were determined as described previously.12 15 Briefly, serial dilutions of sera and ocular fluids were analysed in order to calculate the GWC, which compares the ratio of a specific antibody in the eye to the peripheral blood with the ratio of total IgG in the eye to the peripheral blood. A GWC >3 was considered positive (with the exception of VZV, for which a GWC >10 was considered positive, as low GWCs for VZV have been detected in patients with clinical features that are not consistent with an intraocular VZV infection16). If an adequate volume of aqueous humour fluid was available, all tests were performed; otherwise, only the most likely causes were tested.
Real-time PCR Eighteen samples were analysed using PCR and GWC. For three samples, PCR could not be performed due to an insufficient volume. For two cases of Toxocara and one case of Borrelia, no PCR test was available.
RESULTS The clinical diagnoses of infectious uveitis in our cohort are presented in table 2. A diagnosis of infectious uveitis was made in 60/345 (17%) of the children. Of these 60, 31 (52%) were boys 104
and 29 (48%) were girls. The mean age at the time of diagnosis was 9 years (range: 20 days to 16 years). The mean age of the children with the most prevalent infectious entities was similar (9 years in the children with ocular toxoplasmosis and 9 years in the children with viral uveitis). Thirty-eight children (63%) had unilateral uveitis, and 22 (37%) had bilateral uveitis. Fewer bilateral cases were viral compared to other infectious causes; unilateral uveitis was observed in 15/18 (83%) of viral cases compared with 23/42 (55%) of non-viral cases ( p=0.04; Fisher’s exact test). For 18 (30%) and 42 (70%) patients, infectious uveitis was diagnosed on the basis of clinical findings or specific serum IgG levels, respectively. With the exception of one case of ocular toxocariasis, 41/42 (98%) were positive for IgG against the suspected infectious agent according to the clinical diagnosis. Specifically, the clinical diagnosis was confirmed by the detection of specific IgG antibodies against T gondii (n=24 patients), VZV (n=6), rubella virus (n=2), HSV (n=2), CMV (n=3), EBV (n=1), Toxocara (n=2, positive in one case), Ascaris (n=1), and Borrelia (n= 1). The aqueous humour was analysed for 24/60 patients (40%); in 18/24 (75%) cases, the analysis yielded a positive result (table 2). In 5 cases, analysis of the anterior chamber tap confirmed our suspicion. The results of the analysis of these five patients were Toxoplasma (n=3), HSV (n=1) and VZV (n=1). In the 19 other cases the diagnosis was undetermined before analysing the aqueous humour. Of the 18 positive aqueous humour samples, 16 (89%) had a positive GWC. The
Hettinga YM, et al. Br J Ophthalmol 2015;99:103–107. doi:10.1136/bjophthalmol-2014-305367
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Clinical science Table 2 Infectious causes of uveitis in a paediatric uveitis patient cohort and the results of serology and aqueous humour analysis
Pathogen Toxoplasma gondii Viral Varicella-zoster virus Rubella virus Herpes simplex virus Cytomegalovirus Epstein-Barr virus Toxocara canis Ascaris Diffuse unilateral subacute neuroretinitis Mycobacterium tuberculosis Borrelia Total
Number of patients 36
Percentage (out of 60 patients with infectious uveitis) 60
Number of patients diagnosed on clinical grounds only
Number of patients with confirmation of specific IgG in the serum
Positive result of aqueous humour analysis
12
24
6/10
7 4 3 3 1 2 1 1
12 7 5 5 1.7 3 1.7 1.7
1 2 1 0 0 0 0 1
6 2 2 3 1 1 1 NA
6/6 2/2 2/2 NA 0/1 2/2 NA NA
1
1.7
1
NA
NA
1 60
1.7 100
0 18
1 41
0/1 18/24
NA, Not applicable.
PCR was positive in 5/18 (28%) cases tested; three samples had positive PCR and GWC results. Ocular toxoplasmosis was the most frequently diagnosed infectious disorder, representing 36 out of 60 cases (60%). All 36 patients had chorioretinal lesions that were consistent with the clinical diagnosis of ocular toxoplasmosis. Nineteen of the 36 (53%) ocular toxoplasmosis patients had unilateral involvement, and 17/36 (47%) patients had bilateral involvement. An aqueous humour tap was performed in 10 patients with ocular toxoplasmosis; 6/10 of these patients had a positive GWC for Toxoplasma, and none of these 6 children were positive for IgM antibodies. Four of the children diagnosed with ocular toxoplasmosis had negative aqueous humour findings; however, all four had Toxoplasma-specific IgG in their serum, and their clinical presentation was consistent with ocular toxoplasmosis. Moreover, all four of these children responded well to treatment with pyrimethamine and azithromycin. The second most prevalent cause of infectious uveitis in our cohort was viral infections, representing 18 of the 60 cases (30%), with VZV as the most common pathogen, affecting 7 of the 18 viral cases (39%). Six patients with VZV-associated uveitis were confirmed by aqueous humour analysis; the seventh patient had an active chickenpox infection, and aqueous humour analysis was not performed. Five VZV patients had unilateral uveitis, and two had bilateral uveitis. Additionally, five VZV patients had anterior uveitis, and two had acute retinal necrosis (ARN). Three of the VZV-associated anterior uveitis patients presented with kerato-uveitis, two of whom had a recent case of chickenpox. One additional patient had anterior uveitis with sector atrophy of the iris and a cataract. Of the two VZV-associated patients with ARN, one had acute lymphoblastic leukaemia, and the other had concurrent viral meningitis due to infection of a drain inserted to treat hydrocephalus (figure 1). Neither of these two ARN patients had evidence of recent chickenpox. The clinical manifestations at the onset of the two cases of VZV-associated retinitis were ambiguous, as illustrated by the patient depicted in figure 1. An analysis of the aqueous humour confirmed the cause of retinitis and was sufficiently decisive to facilitate early diagnosis and antiviral treatment. Later in their
disease course, both patients developed the clinical characteristics of ARN. Of the four children with a clinical diagnosis of FHUS, two were found to have an intraocular rubella virus infection by a positive GWC. The other two patients were diagnosed only clinically, as the rubella virus assays were not available at that time. Three children—all of whom were immunocompetent—had congenital CMV. One CMV patient presented with anterior uveitis and a cataract, and the other two had chorioretinal scars. All three children had a positive serum IgG test for CMV; the following pathogens were tested and were negative: T gondii, Toxocara, HSV, rubella virus, VZV and Treponema pallidum. For all three patients, the diagnosis was confirmed by examining preserved blood samples that had been collected in the first postnatal week for phenylketonuria testing. Ocular toxocariasis was diagnosed in two of the 60 patients (3%); in both cases, the diagnosis was confirmed by a positive GWC. One of these two cases had detectable Toxocara IgG in the eye only. The clinical features of these two patients included severe posterior uveitis with peripheral granuloma and retinal lesions.
DISCUSSION A diagnosis of infectious uveitis was established in 17% of our paediatric uveitis patients. Our results show that T gondii and VZV were the most prevalent causes of infectious uveitis in children based on our cohort sampled from a developed country in a temperate climate. The percentage of infectious uveitis cases among children with uveitis varies widely in previous reports. This variation might be ascribed—at least in part—to geographical differences and/or the fact that infectious uveitis was usually diagnosed solely on the basis of clinical symptoms and was rarely confirmed by specific serologic testing and/or aqueous analysis. In this study, we took a systematic diagnostic approach and performed aqueous analysis for all children who had visionthreatening uveitis of undetermined origin. An important advantage to our laboratory’s ability to diagnose infectious uveitis is
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Clinical science Figure 1 Early clinical manifestation from a 15-year-old boy with necrotising retinitis and a drain for hydrocephalus after meningitis. Based on the medical condition of this patient it was decided to perform an aqueous humour tap, which was positive for varicella-zoster virus by PCR and GWC. The patient later developed the clinical characteristics of acute retinal necrosis.
the combined approach using real-time PCR, and the detection of intraocular antibody production. We previously reported that ocular toxoplasmosis is the most prevalent cause of blindness among paediatric uveitis patients.3 A high prevalence of ocular toxoplasmosis was also found in previous studies conducted in other continents (table 1). Because necrotizing chorioretinitis is a highly common characteristic finding in toxoplasmosis, we did not perform an aqueous humour tap in all suspected patients. Additionally, four patients presented with focal chorioretinitis, typical of ocular toxoplasmosis; although their aqueous examinations were negative for toxoplasmosis, these patients responded well to treatment with antiparasitic drugs. Viruses were the second highest cause of infectious uveitis, representing 30% of infectious uveitis cases. The clinical presentation of viral uveitis was predominantly unilateral, and VZV was the most prevalent viral pathogen, representing 39% of all viral causes. However, the prevalence of VZV might be even higher, as all patients with VZV—except one—were diagnosed after 2002. Even though PCR testing and GWC analysis for VZV were available throughout this study, we cannot preclude the possibility that we may have missed cases prior to 2002, perhaps due to a lower frequency of performing aqueous analyses. Congenital and acquired VZV infections are rare causes of uveitis.6 The ocular signs of congenital VZV include cataracts, microphthalmia and chorioretinitis.17 The clinical presentation of postnatal acquired VZV uveitis can be diverse.18 19 In our cohort, two cases of VZV uveitis were related to a concurrent chickenpox infection. VZV uveitis was also reported in children after they were vaccinated with a live attenuated varicella vaccine.19 None of the children in our study were vaccinated against VZV (as the varicella vaccine is not part of our national vaccination program). Other reported causes of childhood viral uveitis include HSV type 1 and type 2, CMV, EBV and rubella virus. Viral intraocular infections can occur in healthy and immunocompromised children, and they can occur at any age.20 21 106
FHUS is diagnosed most often in the second to the fourth decade of life, although paediatric cases have been reported.12 21 22 In recent years, it has become increasingly evident that most FHUS cases in Europe are due to intraocular rubella virus infections23 Our study supports this finding, since four patients were diagnosed with FHUS, and in two of them, with indistinct presentation including mature cataract in one of them, aqueous humour analysis was performed. The question is whether FHUS should be classified as an infectious disease and justifies an aqueous humour tap since its treatment does not involve any anti-infectious therapy. Since FHUS and herpetic anterior uveitis can have comparable clinical manifestations, aqueous humour analysis can be helpful in indistinct cases to discriminate between FHUS and other causes of uveitis that requires a different treatment approach.16 Since 1987, all children in The Netherlands have been vaccinated against the rubella virus (at 14 months and 9 years of age). This might explain the relatively low prevalence of FHUS in our cohort. The diagnostic value of serological testing depends on the percentage of positive individuals in a given population. For example, 26% of the Dutch population at childbearing age has IgG antibodies against T gondii24; thus, positive serology would have a relatively high positive predictive value in this population. On the other hand, the cumulative seroprevalence of VZV approaches 95% by the age of 18 years. Thus, VZV serology does not contribute significantly to the diagnosis of VZV uveitis. Additionally, analysing the aqueous humour can be an extremely valuable diagnostic test, particularly for cases that have an inconclusive clinical presentation or are putative infectious uveitis cases, as specific antibodies in the serum can be undetectable (eg, in our patient with toxocariasis). Because confirming viral uveitis can facilitate timely and appropriate treatment, we recommend analysing the aqueous humour analysis of every child with sight-threatening uveitis of unknown cause, as well as unclear cases in which an infectious cause is suspected. Although performing an aqueous humour tap is safe,13 a major disadvantage in children is that the procedure must be performed under general anaesthesia. In our cohort, the GWC results
Hettinga YM, et al. Br J Ophthalmol 2015;99:103–107. doi:10.1136/bjophthalmol-2014-305367
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Clinical science were positive more often than the PCR results, which is consistent with observations in adult patients.15 The outcome of an aqueous analysis depends on several factors such as the patient’s immune status, the course of the disease, and the type of infection. Because these factors are usually not known beforehand, we recommend performing GWC and PCR. This is particularly important, given that herpes viral and T gondii infections are in some cases only PCR positive or only GWC positive. With respect to the rubella virus, the GWC is preferred over PCR testing, as the sensitivity of GWC for and FHUS is nearly 100%.12 23 Moreover, GWC is the preferred test when a limited volume of ocular fluid is available. An exception is severely immunocompromised children, or if ARN is suspected.25 Our study was limited by a potential bias with respect to analysing the aqueous humour, as these analyses were not performed routinely in all children with uveitis. As such, the actual prevalence of infectious uveitis in children might be even higher than reported here. In conclusion, our study systematically assessed the results of using serologic examinations and intraocular fluid analyses to determine the cause of infectious uveitis in a large cohort of children with uveitis. T gondii and VZV were the first and second most prevalent pathogens identified. Analysing the aqueous humour can be a valuable tool for rapidly establishing the precise cause of infectious uveitis, thus facilitating the early initiation of anti-infection treatment. We recommend analysing the aqueous humour analysis in all children with visionthreatening uveitis of undetermined origin.
2 3 4 5 6 7 8 9 10 11
12 13 14
15
16
17
Correction notice This article has been corrected since it was published Online First. The title has been amended from ‘Infectious involvement in a tertiary centre paediatric uveitis cohort of a tertiary referral centre’ to ‘Infectious involvement in a tertiary center pediatric uveitis cohort’. Contributors YMH: concept and design, acquisition of data, analysis and interpretation of data, drafting the article, final approval of the version to be published. JDFdGM and AR: acquisition of data, revising the article critically for intellectual content, final approval of the version to be published. JHdB: concept and design of the study, acquisition of data, revising the article critically for intellectual content; final approval of the version to be published.
18 19
20 21 22
Funding Dr. F.P. Fischer foundation, ODAS foundation and SNOO foundation. Competing interests None.
23
Ethics approval Medial ethics committee, University Medical Center Utrecht. Provenance and peer review Not commissioned; externally peer reviewed.
24
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Infectious involvement in a tertiary center pediatric uveitis cohort Ymkje Marije Hettinga, Jolanda Dorothea Francisca de Groot-Mijnes, Aniki Rothova and Joke Helena de Boer Br J Ophthalmol 2015 99: 103-107 originally published online August 19, 2014
doi: 10.1136/bjophthalmol-2014-305367 Updated information and services can be found at: http://bjo.bmj.com/content/99/1/103
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