Epidemic retinitis during the COVID-19 pandemic

Abstract

Purpose:

To study the impact of the novel coronavirus disease-2019 (COVID-19) pandemic on incidence, seasonal variation, clinical presentation, and disease outcome of epidemic retinitis (ER) and to compare clinical outcomes with positive and negative COVID-19 serology.

Methods:

This is a retrospective, observational study conducted at a tertiary eye care hospital from August 2020 to June 2022. A graph of ER cases against the month of presentation was compared with the graph of the COVID-19 pandemic in the same region. Cases presented before COVID-19 vaccination, with positive COVID-19 serology (Group 1) were compared with cases with negative serology (Group 2).

Results:

One hundred and thirty-two cases of ER were seen. The least number of cases were seen during and immediately after the peak of the pandemic (May 2021–August 2021). COVID-19 serology was positive in 13 (22 eyes)/60 (21.6%) unvaccinated cases. Along with COVID-19, positive serology for other ER etiologies was seen in 5/13 cases (38.4%). All patients received oral doxycycline with/without steroids. Groups 1 and 2 included 22 and 21 eyes of 13 cases each. Macular edema resolved in 43.6 and 32 days in groups 1 and 2, respectively. Retinitis resolved at 1 month in both groups. Corrected distant visual acuity was 20/50 and 20/70 at the presentation, which improved to 20/20 and 20/25 in groups 1 and 2, respectively. Mean and median follow-up was 6 months and 4.5 months, respectively, in both groups. No complications or recurrences were seen.

Conclusion:

No significant impact of the COVID-19 pandemic on ER was observed.

The novel coronavirus disease-2019 (COVID-19) pandemic had an impact on various diseases and has changed the incidence and course of many diseases.[1-3] It has also caused an increase in the severity or relapse of pre-existing medical conditions.[4-6] Immune system alteration caused by coronavirus infection may have an effect on several inflammatory conditions including uveitis. It is of great interest to study the impact of COVID-19 on various inflammatory, infectious, or para-infectious diseases. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induced retinopathy or retinal vasculopathy has been frequently reported during the pandemic.[7,8] Subtle retinal lesions secondary to COVID-19, as well as the presence of SARS-CoV-2 in the retinal tissue, have been reported.[9,10] During the pandemic, we have witnessed an increase in the number of reports of a known uveitic entity being associated with COVID-19 but the causal relation is yet to be proven for many such reports. Whether SARS-CoV-2 can cause frank retinitis as that caused by herpes viruses or as seen in so-called “epidemic retinitis” (ER) or “post fever retinitis” remains to be proven in a larger series. For the first time, the isolation of the SARS-CoV-2 genome using reverse transcription-polymerase chain reaction (RT-PCR) from the vitreous fluid in a case that morphologically closely resembled ER, has been demonstrated by Hosseini et al.[11] from Iran. This raised the concern of joining SARS-CoV-2 to the list of etiological agents of ER. But mere isolation of the SARS-CoV-2 genome from ocular fluid in a single case may not confirm the cause-effect relationship. Recently, a series of “presumed” post-COVID-19 retinitis has also been reported from an endemic area, findings of which again resembled ER.[12]

ER is a uveitic entity seen after a febrile illness and has a seasonal variation. Each year the epidemic begins in post-monsoon season in August and September, peaks between November and February and gradually recedes after March-April, and is least seen in May, June, and July.[13,14] Apart from microbiological investigations, studying the wave pattern of the pandemic and the pattern of seasonal variation of ER during the pandemic is also important to deduce the cause-effect relationship. Herein, we planned our study to evaluate the impact of the COVID-19 pandemic on the incidence, seasonal variation, clinical presentation, and disease outcome of ER.

Methods

This is a retrospective, observational study of patients diagnosed with ER and presented from August 2020 to June 2022 to a tertiary care eye hospital in the South Indian state of Karnataka. The study was approved by the internal review board and adhered to the Declarations of Helsinki. Patients with a history of recent fever who presented with focal or multifocal “cotton wool spot (CWS)-like” retinitis lesions as described previously,[13,14] were diagnosed as cases of ER [Fig. 1].

Figure 1.

Fundus photo of the right eye of a patient from group 1 (Case 2, Table 3) shows cotton wool spot-like retinitis lesions along the superior arcade. (a) OCT scan passing through the lesion shows inner retinal hyper-reflectivity with back-shadowing, outer nuclear layer edema, and mild subretinal fluid. (b) Fundus photo of the right eye taken 10 days after the treatment shows resolving retinitis lesions and the formation of a macular fan. (c) OCT scan at the resolution shows an absence of macular edema and the appearance of hard exudates. (d)

The month of presentation for each patient was noted and a graph of the number of patients against months was constructed [Fig 2]. Month-wise data on the graphical representation of the COVID-19 pandemic for the state of Karnataka, India for the same study period was obtained from an interactive web-based dashboard (https://www.google.co.in/search?q = covid + graph) to track COVID-19 in real time [Fig 3].[15] Both graphs were compared for peaks and troughs.

Figure 2.

Graphical representation of the number of ER patients along the Y-axis and month of presentation along the X-axis shows a rapid increase in the number of cases from August 2020 with a peak in October-November 2020, then a transient gradual decline in December-January 2021, and again raise in February-March 2021 followed by a gradual decline. Note that the least number of cases were presented in May, June, and July 2021. The number again increased from August 2021 to reach the peak in October 2021–January 2022, followed by a gradual decline to form the trough from May 2022 to June 2022

Figure 3.

Graphical representation of the number of cases of COVID-19 seen in the state of Karnataka from June 2020 to October 2021. The graph shows the first wave of the pandemic between September 2020 and October 2020, the second wave between May 2021 and June 2021, and the third between January 2022 and February 2022

Patients with COVID-19 serology (SARS-CoV-2 RBD total IgG and IgM by chemiluminescence immunoassay) done after 2 weeks of the fever were isolated. Cases, which received COVID vaccines before presentation, were excluded. Serology-positive cases formed group 1. The remaining cases were randomized to decrease selection bias and to form group 2 with an equal number of COVID-19 serology-negative cases.

History of present illness, clinical presentation, laboratory investigations, imaging findings (Wide fields fundus photograph - Optos, ^TM Spectral-domain optical coherence tomography - SD-OCT), and treatment outcomes were studied. Resolution of ER was defined as an absence of macular edema and retinitis lesions as recorded clinically and/or on SD-OCT scan and fundus photograph. Days for resolution of the macular edema and retinitis lesions were noted and compared between groups.

Results

Hundred and thirty-two patients of ER were seen between August 2020 and June 2022. The number of patients sharply increased from mid of August 2020 to mid of October 2020, maintaining the peak through November 2020. The number then gradually decreased near to its half in January 2021 and again raised in February 2021 and March 2021. In April 2021, there was a sharp decline in the number of cases. The least number of cases (n = 7) were seen from May 2021 to August 2021. The number of cases again started increasing from August 2021 onwards, peaked between October 2021 and February 2022, then declined sharply in March 2022. Again, the least number of cases were seen in May 2022 and June 2022 [Fig. 2].

The graph of the COVID-19 pandemic for the state of Karnataka, India showed a first peak in September 2020 (the first wave of the pandemic) and a huge spike in May 2021 (the second wave of the pandemic), and a comparable spike in January 2022 (third wave of the pandemic). The least number of cases were reported from December 2020 to March 2021, July 2021 to January 2022, and February 2022 onwards [Fig. 3].

COVID-19 serology was done at the presentation in 60 cases, of which 13 (22 eyes) (21.6%) positive cases formed group 1. After randomization of remaining COVID-19 serology-negative cases, the first 13 (21 eyes) were selected to form group 2. Only one patient from each group gave a history of RT-PCR for COVID-19, done during their fever, which was negative in both. There was no history of symptoms indicating COVID infection, like shortness of breath, dry cough, or anosmia.[16]

Comparative findings for both groups were as shown in Table 1. OCT scan was available for 18 eyes in group 1 and 19 eyes in group 2 at the presentation. The comparative findings were as shown in Table 2. Seven cases were seen between May 2021 and August 2021 (during and post the second wave), of which COVID-19 serology was done in five cases. Among those, two were positive and both were vaccinated thus not included in the comparative study [Table 3]. No additional morphological features or SD-OCT findings to that of ER were observed in these cases. No complications were seen, except delayed resolution (90 days) of macular edema in a single case from group 1 [Table 3].

Table 1.

Comparison between COVID-19 serology positive and negative cases of ER

	Group 1 (22 eyes/13 patients)	Group 2 (21 eyes/13 patients)
Age (years)	32.6 (range: 11–64)	40.1 (range: 16-72)
Sex (M: F)	10:3	7:4
Mean latent period (Days)	16.8 (range: 5-40)	17.3 (range: 7-40)
Provisional diagnosis for fever by their physicians	Dengue (1), Typhoid (2), viral pneumonia (1), Measles (1)	Typhoid (4), Dengue (2)
Skin rash/joint pain	7/2	5/5
Unilateral/Bilateral	4/9	4/9
CDVA at the presentation	20/50 (range: 20/20-20/20000)	20/70 (range: 20/20-20/2000)
Anterior Uveitis	3	8
Vasculitis	1	0
Subretinal yellow precipitates	3	3
Neovascularization elsewhere	1	0
Multiple positive serology	5	1
Oral doxycycline	13	13
Oral steroids	6	4
Resolution of macular edema	43.6 (range: 20-90) (n=11)	32.5 (range: 15-60) (n=18)
Resolution of retinitis	30 (range: 15-45) (n=17)	31 (range 15-60) (n=20)
CDVA at resolution	20/20 (range 20/20-20/60) (n=17)	20/25 (range: 20/20-20/50) (n=20)
Mean, Median follow-up (Months)	6 (range: 1-16), 4.5	6 (range: 1-21), 4.5

M: Male, Female, CDVA: Corrected distant visual acuity, CMT: Central macular thickness, SRF: Subretinal fluid

Table 2.

OCT characteristics of COVID-19 serology positive and negative cases of ER

	Group 1 (n=18 eyes)	Group 2 (n=19 eyes)
Mean CMT	733.2 μm (range: 466-1068)	653.7 μm (range: 367-1053)
Inner retinal hyper-reflectivity	15	17
ONL edema	9	16
SRF	12	16
Subretinal fibrin	2	5
Retinitis within 1500 of the fovea	7	7

CMT: Central macular thickness, ONL: Outer Nuclear layer, SRF: Subretinal fluid

Table 3.

Cases presented during and after the second wave of the pandemic (May 2021–August 2021)

Age/ Sex	COVID Serology	Vaccine	COVID RT-PCR during fever	Other positive tests	Eye	Macular edema resolution (days)	Retinitis resolution (days)	Complication	Total follow-up (Months)
36/F	Neg	No	N.A.	WIDAL	OD	30	30	Nil	2.5
					OS	20	20	Nil
45/M	Pos	No	Neg	Nil	OD	90	30	Nil	18
					OS	N.A.	30	Nil
30/M	Neg	No	N.A.	Nil	OD	45	30	Nil	1.5
47/M	Pos	Yes*	N.A.	Nil	OD	30	30	Nil	3
					OS	30	30	Nil
48/M	N.A.	Yes*	N.A.	Nil	OD	N.A.	N.A.	Nil	1
28/M	N.A.	No	Neg	Nil	OD	40	20	Nil	3.5
40/M	Neg	No	N.A.	WFT	OD	20	20	Nil	14
					OS	20	20	Nil

Neg: Negative, Pos: Positive, WFT: Weil-Felix test, OD: right eye, OS: Left eye, N.A.: Not available, RT-PCR: reverse transcriptase polymerase chain reaction, *: Not included in the comparative study

In group 1, multi-positive serology was seen in five cases (Dengue IgM + Weil-Felix + COVID-19 (n = 1), Weil-Felix + COVID-19 (n = 3), WIDAL + Weil-Felix + COVID-19 (n = 1)) and in group 2, it was seen only in one (Dengue + Weil-Felix). All the patients were treated with oral doxycycline (100 mg twice a day for 3-4 weeks) with or without steroids [Table 1]. Three patients (5 eyes) in group 1 and one (1 eye) in group 2 were lost to follow-up.

SD-OCT scan was available for 11 and 18 eyes at the resolution in groups 1 and 2, respectively. Macular edema resolved in 43.6 days (range: 20-90 days) and 32.5 (range: 15-60 days) days in groups 1 and 2, respectively. Fundus photo at the resolution was available for 17 and 20 eyes in group 1 and 2 respectively. Retinitis lesions resolved in 30 days (range: 15-45 days) and 31 days (range: 15-60 days) in groups 1 and 2, respectively. Corrected distant visual acuity was 20/50 and 20/70 at the presentation, which improved to 20/20 and 20/25 in groups 1 and 2, respectively. Mean and median follow-up was 6 months and 4.5 months, respectively, in both groups. No recurrence or complications were noted, except in one eye with neovascularization elsewhere (NVE) and pre-retinal hemorrhage in group 1.

Discussion

Our study evaluated the impact of the COVID-19 pandemic on ER by studying the pattern of seasonal variation of ER during the pandemic and comparing it with the contemporary pandemic waves. It is now known that during the winter season, the maximum number of ER cases are seen in the endemic areas of India, and the incidence is least in May, June, and July.[13,14] Those 3 months during the pandemic were the key months to analyze the impact of the pandemic on ER. India (including the state of Karnataka) was worse hit by the COVID-19 pandemic in May 2021[15] [Fig. 3]. Presuming SARS CoV-2 as one of the etiological agents of ER, one would expect a high number of ER cases in subsequent months of the peak of the pandemic since the mean latent period for ER manifestations is 19-21 days,[13,14] especially when the lockdown restrictions are relaxed after a month. But as observed in our study, the peak of the pandemic graph in May 2021 corresponded with the trough of the ER graph in May 2021-July 2021 [Figs. 2 and 3]. The peak of the second pandemic wave and the peak of ER after the second wave were separated by 6 months. Taking into consideration the latent period of ER, COVID-19 appears to be not a major contributor to ER. Arguments may arise as the first and the third waves are corresponding with the peak of ER in October 2020 and January 2022. But one must remember that those are the known peaks of ER seen even in pre-pandemic studies.[13,14,17] The previously reported pattern of seasonal variation of ER, was not significantly altered during the pandemic. This observation favors against SARS-CoV-2 as a direct cause of ER. Conversely, the graph of ER correlated well with the previously reported seasonal variation of systemic rickettsial infection in the pediatric population from the same region suggesting a rickettsial etiology of ER.[18] This was an additional important observation missed in previous studies on community outbreaks and ER.[17]

We also conducted a comparative study between COVID-19 seropositive and seronegative cases, which also did not show a significant difference in terms of the history of present illness, clinical and imaging findings, and treatment outcomes except for the occurrence of anterior uveitis, outer nuclear layer edema, and subretinal fibrin less frequently in the seropositive group [Tables 1 and 2]. It has also been reported that the incidence of retinal vasculopathy and vascular occlusions has increased during the pandemic.[19,20] But in our series, vasculitis and neovascularization were observed only in one case from group 1. The occurrence of vasculitis in ER along with NVE has been reported in ER in pre-pandemic studies as well.[13] Thus, it may not necessarily suggest complications of COVID-19 in ER cases as its occurrence was uncommon in our study. During early days of the pandemic, the reported retinal findings due to COVID-19 appeared to be retinopathy rather than frank retinitis as seen in ER. The probable explanation was that hypoxia-related autonomic dysregulation of the radial peripapillary which may led to lead to acute and transient ischemia of the nerve fiber layer in systemic COVID-19 infection.[21-23] The hypothetical explanation for retinal findings in ER could be the occlusive capillaritis caused by endotheliotropic organisms such as rickettsial and dengue.[24,25]

The limitations of our study were a relatively small number of cases for a comparative study, lack of gold standard investigations to rule out reported etiologies of ER, and absence of RT-PCR for SARS CoV-2. The strength of our study was the number of ER cases seen during the pandemic, adequate enough to plot a graphical representation of seasonal variation and compare it with the contemporary pandemic graph. Along with routine serological investigations for ER, we also had a good number of patients, which underwent COVID-19 serology at the presentation. This allowed us to study the multi-positivity of serological investigations. Our study has also shown that despite the positive COVID-19 serology no change in treatment plan for ER was needed and good visual outcome can be expected. We also had good follow up which showed no long-term implications of positive COVID-19 serology on ER.

Conclusion

In conclusion, our study found no significant impact of the COVID-19 pandemic on the seasonal variation of ER. The absence of a surge of ER cases during the period of May-August 2021 may discourage the uveitis fraternity to consider SARS-CoV-2 as a major contributor to ER in contrast to rickettsial organisms. Positive COVID-19 serology detected at the presentation in unvaccinated cases may not alter the clinical presentation, course of the disease, and treatment outcomes of ER. The possibility of co-infection of SARS CoV-2 with organisms responsible for ER should not be ignored during the pandemic before considering it as yet another etiological agent of ER.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.