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Influence of drug therapy on the risk of recurrence of ocular toxoplasmosis
  1. Michael Reich1,2,
  2. Matthias D Becker1,2,3,
  3. Friederike Mackensen1,2
  1. 1Department of Ophthalmology, University of Heidelberg, Heidelberg, Germany
  2. 2Interdisciplinary Uveitis Center, University of Heidelberg, Heidelberg, Germany
  3. 3Department of Ophthalmology, Triemli Hospital, Zürich, Switzerland
  1. Correspondence to Michael Reich, Interdisciplinary Uveitis Center, University of Heidelberg, Im Neuenheimer Feld 400, Heidelberg D-69120, Germany; m.reich.heidelberg{at}web.de

Abstract

Background/aims Retrospective, observational case series with follow-up examination to analyse the influence of drug therapy on ocular toxoplasmosis (OT) in terms of recurrence-risk.

Methods In this one centre study an existing data set of 84 patients with active OT was used. Drug therapy for 255 active lesions was retrospectively reconstructed. Median recurrence-free survival time was calculated for the different treatment regimes using Kaplan–Meier estimates.

Results 20 different regimens were used as treatment of OT in the catchment area of the Interdisciplinary Uveitis Center, University of Heidelberg, Germany. Median recurrence-free survival time was significantly lower after using systemic corticosteroid monotherapy (0.9 years; 95% CI 0.5 to 1.3 years) compared with Toxoplasma gondii-specific antibiotic treatment (3.0 years; 95% CI 2.2 to 3.9 years; p<0.001) or compared with no therapy (3.0 years; 95% CI 2.1 to 3.9 years; p=0.006). No difference could be detected when comparing median recurrence-free survival time after using T gondii-specific antibiotics compared with no therapy (p=0.679).

Conclusions Although our study shows that drug therapy seems to influence the risk of recurrence of OT, there is no consensus regarding the choice of antiparasitic agents for treatment regimens in the catchment area of the Interdisciplinary Uveitis Center, University of Heidelberg. Survey results provide useful information for treating physicians and for clinical investigators interested in therapy.

  • Drugs
  • Infection
  • Inflammation
  • Microbiology
  • Retina
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Introduction

Toxoplasma gondii (T gondii) infection has a worldwide distributional pattern and the resulting disease of ocular toxoplasmosis (OT) is the most common cause of posterior uveitis.1–4 It is characterised by frequent reactivations due to tissue cysts remaining in the retina after initial infection with T gondii.5 ,6 Curative therapy is still not available. Therefore, patients with OT carry a lifetime risk of recurrence associated with a substantial risk of vision loss. Nevertheless, there is no consensus regarding the choice of antiparasitic agents for treatment regimes in case of toxoplasmic retinochoroiditis.7

T gondii-specific antibiotics are thought to limit proliferation of the tachyzoite form of the organism during an episode of active disease.8 Antibiotic treatment is therefore assumed to reduce the size of retinochoroidal scars occurring after toxoplasmic retinochoroiditis.9 ,10 However, none of the T gondii-specific antibiotics are able to penetrate cyst walls, and are thus not effective against the bradyzoite form.11 In consequence, traditional short-term treatments of active toxoplasmic retinochoroiditis lesions do not prevent subsequent recurrences.12–14

Corticosteroids in combination with antibiotic drug therapy are given to limit the inflammatory reaction associated with an active lesion of OT.11 However, using solely systemic corticosteroid treatment can lead to extensive and severe toxoplasmic retinochoroiditis due to excessive parasite proliferation.15 ,16 Few data are available analysing the influence of corticosteroids on the recurrence-risk of OT. de-la-Torre et al17 identified treatment with systemic steroids without antibiotics as one of the main factors being related to a higher risk of recurrence. However, the finding of this study should be interpreted with caution because of a low number of patients being treated with corticosteroid monotherapy (n=6).

In our previous study we were able to show, that the drug therapy at the time of the first active lesion (primary OT) influences the risk of recurrence in the first 10 years of disease.18 Therefore, we set out to reconstruct the drug therapy used at the time of each documented active lesion to analyse in general the influence of drug therapy at the time of any active lesion on the risk of recurrence. Additionally, the study sought to provide an understanding of existing treatment practice of active OT in the catchment area of the Interdisciplinary Uveitis Center, University of Heidelberg.

Patients and methods

Study design

This was a retrospective, observational case series with follow-up examination approved by the Local Ethical Committee and adhering to the tenets of the Declaration of Helsinki.

Data collection

A database of 4381 patients with uveitis was used. All patients consulted our Center between January 2000 and June 2012. OT was diagnosed in 156 patients. Eighty four patients fulfilled all inclusion criteria and therefore could be used for analysis (sample group). Figure 1 shows a summary of the data collection. For more detailed information regarding the data collection, inclusion or exclusion criteria as well as for further information regarding the sample group see our previous publication on a different aspect of this cohort.18

Figure 1

Flow chart of patients screened and included in the study. Drug therapy of 255 active lesions in 84 patients was retrospective reconstructable (mean 3.0 active lesions per patient, SD 2.3, median 2, range 1–11). The 255 active lesions were subdivided into groups regarding received drug therapy (see table 1).

Patients’ course of disease was reconstructed by using definitions for primary OT and recurrences based on the criteria by Holland et al.12 In this study, we used the description of an active lesion which does not differentiate between the first active lesion (primary OT) and recurrent lesions. All 84 patients were followed up at least once a year and longer when suffering a recurrence (mean follow-up 11.4 years, SD 9.5 years, median 8.8 years, range 1.3–55.6 years). As in the study of Holland et al,19 for subjects with bilateral disease, only data for the first affected eye were used in data analysis. This measure creates equal conditions for all patients and prevents bias of the results. Course of disease and treatment for each active lesion was reconstructed by chart review of the medical records of the university eye hospital, the centres electronic medical record as well as letters and chart copies from referring ophthalmologists.

A total of 289 active lesions were counted (n=84 patients, figure 1). Two hundred and eighty of them occurred in the first affected eye and could therefore be included in this study. The mean number of active lesions was 3.22 (SD 3.42, median 2, range, 1–27). None of the 84 patients of the used data set received a prophylactic, antibiotic treatment. Twenty five active lesions (8.9%) had to be excluded because drug therapy was retrospectively not reconstructable (n=22), or medication was taken <4 weeks because of side effects (n=3). The remaining 255 active lesions (still n=84 patients, figure 1) were subdivided into groups regarding received drug therapy. The following subgroups were created: (1) T gondii-specific antibiotic treatment, including therapeutic regimes of choice for typical cases of OT such as pyrimethamine, sulfadiazine, trimethoprim/sulfamethoxazole, clindamycin, azithromycin and spiramycin,7 (2) systemic corticosteroid monotherapy, (3) no therapy and (4) (antibiotic) treatment without presumed effectiveness against T gondii, such as antibiotics not listed above. Treatment—if a treatment had been chosen—of all 255 active lesions used for analysis started within the first 2 weeks after the onset of symptoms.

Statistical methods

SPSS V.20.0 was used for the statistical analysis. A probability (p) value of α<0.05 was considered statistically significant. For the descriptive data analysis means, SD, median values and minimal and maximal values were calculated. Mann–Whitney U test was used to compare differences in patient-age and duration of disease for each active lesion between the groups subdivided regarding received drug therapy at the time of an active lesion. The time intervals between consecutive active lesions and the time intervals between the last documented active lesion and the end of follow-up were used to determine the median recurrence-free survival time separately for each subgroup by using the Kaplan–Meier estimate. 95% CI was given respectively. To compare differences between the medians of the Kaplan–Meier estimators the generalised Wilcoxon test was used.

Results

Different treatment approaches used in the catchment area of the Interdisciplinary Uveitis Center, University of Heidelberg

In total, drug therapy of 255 active lesions was reconstructed retrospectively. Table 1 summarises the different treatment approaches used by ophthalmologists in the catchment area of the Interdisciplinary Uveitis Center. Twenty different regimens were used as treatment of choice after initial diagnosis of OT. The primary disease of toxoplasmosis was initially not recognised in 10 patients treated with systemic corticosteroid monotherapy. Thus, 19 active lesions were treated with systemic corticosteroid monotherapy without knowing the cause of the retinochoroiditis. The remaining three active lesions occurred after initial diagnosis of OT but were treated with corticosteroids without an antiparasitic shield anyway. Of 34 active lesions not being treated 13 active lesions occurred before the cause of the retinochoroiditis was known. The remaining 21 active lesions occurred after initial diagnosis of OT but were not treated due to a peripheral location or a low inflammatory reaction. All nine active lesions treated with (antibiotic) therapy without assumed effectiveness against T gondii occurred before diagnosis of toxoplasmosis.

Table 1

Received drug therapy at the time of an active lesion of ocular toxoplasmosis used in the catchment area of the Interdisciplinary Uveitis Center, University of Heidelberg

Examination of potential confounders

It could be shown by different studies that the risk of recurrence is influenced by the patient-age at the time of an active lesion and the duration of disease.18–20 Therefore, we compared patient-age at the time of any active lesion between the subgroups of received drug therapy (table 2). No difference was detected (p=0.119–0.424). Due to low numbers of active lesions treated by (antibiotic) treatment without assumed effectiveness against T gondii (n=9), patient-age of this subgroup was not compared. Furthermore, duration of disease for each active lesion was compared between the subgroups of received drug therapy (table 2). No difference was detected when comparing the group of active lesions without treatment versus T gondii-specific antibiotics (p=0.888) as well as versus systemic corticosteroid monotherapy (p=0.143). But when comparing T gondii-specific antibiotic treatment versus systemic corticosteroid monotherapy a significant difference was detected (p=0.038). Therefore, the duration since the first diagnosis of OT/first active lesion at the time of any active lesion seems to be a confounding factor in the following analysis. Duration of disease was not compared for the subgroup treated with the (antibiotic) therapy thought to have no effectiveness against T gondii due to low numbers of active lesions (n=9).

Table 2

Examination of potential confounders

Influence of drug therapy on the risk of recurrence

Median recurrence-free survival time of all 255 active lesions was 2.6 years (95% CI 2.1 to 3.0 years). Median recurrence-free survival time in the subgroup of active lesions treated by T gondii-specific antibiotics was 3.0 years (95% CI 2.2 to 3.9 years), 0.9 years (95% CI 0.5 to 1.3 years) in the subgroup treated with systemic corticosteroid monotherapy, 3.0 years (95% CI 2.1 to 3.9 years) in the subgroup without treatment and 2.7 years (95% CI 1.2 to 4.3 years) in the subgroup with active lesions treated with (antibiotic) treatment, which is thought to have no effectiveness against T gondii. Differences in median recurrence-free survival time between the subgroups are illustrated in figure 2. Risk of recurrence is significantly higher when treated with systemic corticosteroid monotherapy compared with T gondii-specific antibiotic treatment (p<0.001) or compared with no therapy (p=0.006). No significant difference in median recurrence-free survival time between T gondii-specific antibiotic treatment versus no therapy was detected (p=0.679). Due to low numbers of active lesions treated with (antibiotic) treatment without assumed effectiveness against T gondii (n=9; seven events, two censored), median recurrence-free survival time of this subgroup was not compared.

Figure 2

Influence of drug therapy on the risk of recurrence of ocular toxoplasmosis. Median recurrence-free survival time was analysed separately for subgroup of active lesions treated by Toxoplasma gondii-specific antibiotics (3.0 years, 95% CI 2.2 to 3.9 years, 117 events, 73 censored), by systemic corticosteroid monotherapy (0.9 years, 95% CI 0.5 to 1.3 years, 22 events, 0 censored) or being not treated (3.0 years, 95% CI 2.1 to 3.9 years, 27 events, 7 censored). To compare differences between the medians of the Kaplan–Meier estimators the generalised Wilcoxon test was used. A p value of α<0.05 was considered significant.

Discussion

OT is characterised by frequent reactivations associated with a substantial risk of vision loss. Appropriate treatment is therefore of importance. Nevertheless, a lack of consensus regarding the choice of antiparasitic agents for treatment regimes was shown by Holland et al.7 A total of 24 different regimens are used as treatments of choice for typical cases of active OT by the physician-members of the American Uveitis Society. Similar to Holland et al,7 table 1 shows that there is also no consensus of treating an active lesion of OT in the catchment area of the Interdisciplinary Uveitis Center, University of Heidelberg. Considering only treatment regimes given after initial diagnosis of OT, 20 different treatment regimens were used. In Germany, the triple drug therapy pyrimethamine, sulfadiazine and folinic acid, either with or without a corticosteroid drug, is the most commonly used treatment regime (45%).21 Clindamycin, either with or without a corticosteroid drug, is the second most common used treatment regime (38%). In contrast, in our study, clindamycin (4×300 mg/day for 4–6 weeks) in combination with oral administered prednisone (started 1 day after start of the antiparasitic treatment, initial 1 mg/kg/day, dose reduction every 5 days) was the most frequently used therapy (48%, table 1; n=122). We as well as others prefer this drug due to a lower rate of complications compared with the triple drug therapy.9

Traditional short-term treatments of active toxoplasmic retinochoroiditis lesions have been suspected to not prevent subsequent recurrences.12–14 According to our best knowledge, there only exists one study showing the influence of drug therapy on the risk of recurrence.17 However, in the study of de-la-Torre et al only 25 patients with active episodes of OT were included, thus only 80 active lesions were evaluated. Therefore, our study provides useful information with a larger sample size for treating physicians and for clinical investigators interested in therapy of OT based on the currently biggest data set in literature.

Using solely systematic treatment with corticosteroids can lead to extensive and severe toxoplasmic retinochoroiditis.15 ,16 de-la-Torre et al showed that systemic corticosteroid monotherapy is associated with a higher risk of recurrence.17 Our study confirms this result (figure 2). A higher risk of recurrence after using corticosteroid monotherapy may be explained by following hypothesis: A medical-induced immunosuppression at the time of an active episode of OT can cause an excessive parasite proliferation of T gondii.15 ,16 Thus, transition of a larger number of tachyzoite into bradyzoites will be enabled compared with the number of transitions in an immunocompetent host. Consequently, a medically induced immunosuppression may cause a larger number of retinal tissue cysts of T gondii. This leads to the conclusion that the risk of recurrence is associated with the patient-individual number of tissue cysts being formed after occurrence of an active lesion of OT.

Our study is the first study in literature at this point in time showing that there seems to be no difference in risk of recurrence after using T gondii-specific antibiotics versus no therapy (figure 2). It has to be kept in mind that the patients receiving no therapy had less severe courses of the disease. If the effect we saw is reliable, then an explanation for this could be that the transition from tachyzoites into bradyzoites can occur within days and tissue cysts can form within 2 weeks.22 ,23 Thus, transition could have already occurred by the time patients are examined by an ophthalmologist8 and therefore, keeping the hypothesis in mind that the risk of recurrence is associated with the patient-individual number of tissue cysts, short-term T gondii-specific antibiotic treatment of an active lesion has no influence on the risk of recurrence. However, this should not be interpreted to mean that antibiotic treatment has no effect. For example, the use of T gondii-specific antibiotics seems to reduce lesion size of retinochoroidal scars occurring after toxoplasmic retinochoroiditis.9 Nevertheless, our study shows that new treatment strategies are needed to prevent recurrence of OT. Antibiotic, secondary prophylaxis may be such a new treatment strategy as shown by Silveira et al24 and Felix et al.25

It remains to be mentioned, that the duration of disease is a confounder in the analysis of the influence of drug therapy on the risk of recurrence (table 2) as duration of disease has also been shown to influence the risk of recurrence, including our own study on the patient cohort, which was used for the here presented evaluation as well.18 ,19 However, 19 of 22 active lesions treated by corticosteroid monotherapy occurred before initial diagnosis of OT, tantamount to the first years of disease and younger patient-age. Therefore, duration of disease seems to be a potential confounder in our analysis but does not explain the significantly higher risk of recurrence after the use of corticosteroid monotherapy (figure 2). The same applies for patient-age, which almost reached significance between the subgroup of corticosteroid monotherapy and T gondii-specific antibiotics (table 2). In our previous study, patient-age positively correlated with the risk of recurrence. In this study, mean age at the time of active lesions in the subgroup of systemic corticosteroid monotherapy is lower than in the subgroup of T gondii-specific antibiotics. Despite this result, patients are of higher risk of recurrence when receiving systemic corticosteroid monotherapy (despite being younger when receiving this therapy) compared with T gondii-specific antibiotics. Thus, the confounder patient-age seems to be unlikely in our study.

True influence of drug therapy on the risk of recurrence may be masked by additional confounders, which were not considered in our analysis such as indication bias because of the various factors potentially affecting the choice of drug therapy, for example the severity of the uveitis. Such confounders were not considered in our study but should be considered in future studies.

Retrospective nature is another limitation of our study. Although a prospective study would have been preferable, such a study seems ethically questionable as corticosteroid monotherapy is shown to cause extensive toxoplasmotic retinochoroiditis as well as a higher risk of recurrence (figure 2).15–17 So we think that currently our study is the best possible alternative.

To conclude, although our study shows that drug therapy partly influences the risk of recurrence of OT, there is no consensus regarding the choice of antiparasitic agents for treatment regimens in the catchment area of the Interdisciplinary Uveitis Center, University of Heidelberg. More uniform treatment regimes are needed and an antibiotic, secondary prophylaxis seems to be an interesting and promising alternative as short-term T gondii-specific antibiotic treatment and no drug therapy at all, do not prevent recurrences.

Acknowledgments

MR is a recipient of a scholarship from the ‘Studienstiftung des deutschen Volkes’ and the ‘Dr Gabriele Lederle-Stiftung’ and thanks this organisations for their support.

References

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Footnotes

  • Contributors All authors contributed to this manuscript: design and conduct of the study (MR and FM), collection (MR, MDB and FM), management (MR and FM), analysis (MR). Interpretation of the data (MR), preparation (MR and FM), review or approval of the manuscript (MR, MDB and FM).

  • Competing interests FM received a limited grant for an IST from Allergan, was PI in a clinical trial from Abbvie GmBH, Esbatech and Novartis, received lecture honoraria from Heidelberg Engineering, and participated in an advisory board from Abbvie and Merck Serono; all outside the submitted work.

  • Patient consent Obtained.

  • Ethics approval Local Ethical Committee of the University of Heidelberg.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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