Classification criteria for cytomegalovirus retinitis

The Standardization of Uveitis Nomenclature (SUN) Working Group

doi:10.1016/j.ajo.2021.03.051

. Author manuscript; available in PMC: 2022 Aug 1.

Published in final edited form as: Am J Ophthalmol. 2021 May 11;228:245–254. doi: 10.1016/j.ajo.2021.03.051

Classification criteria for cytomegalovirus retinitis

The Standardization of Uveitis Nomenclature (SUN) Working Group^*,^1,^2,³

Corresponding author: Douglas A. Jabs, MD, MBA, Department of Epidemiology, the Johns Hopkins University Bloomberg School of Public Health, Room 7138, 615 N Wolfe St, Baltimore, MD, 20215 USA. Phone: 410-955-125. djabs@jhmi.edu.

CRediT roles: Douglas A. Jabs, MD, MBA: Conceptualization, Methodology, Validation, Investigation, Data curation, Writing--Original draft, Writing--Review and editing, Visualization, Supervision, Project administration, Funding acquisition. Rubens Belfort, Jr., MD, PhD, MBA^: Investigation, Writing--Review and editing. Bahram Bodaghi, PhD, FEBOph: Investigation, Writing--Review and editing. Elizabeth Graham, FRCP, DO, FRCOphth: Investigation, Writing--Review and editing. Gary N. Holland, MD: Investigation, Writing--Review and editing. Susan L. Lightman, PhD, FRCP, FRCOphth: Investigation, Writing--Review and editing. Neal Oden, PhD: Methodology, Software, Validation, Formal analysis, Investigation, Resources, Data curation, Writing--Review and editing. Alan G. Palestine, MD: Investigation, Writing--Review and editing. Justine R. Smith, FRANZCO, PhD: Investigation, Writing--Review and editing. Jennifer E. Thorne, MD, PhD: Methodology, Software, Validation, Formal analysis, Investigation, Data curation, Writing--Review and editing. Brett E. Trusko, PhD, MBA: Methodology, Software, Resources, Data curation, Investigation, Writing--Review and editing. Russell N. Van Gelder, MD, PhD: Investigation, Writing--Review and editing.

Writing committee: Douglas A. Jabs, MD, MBA^2,3; Rubens Belfort, Jr., MD, PhD, MBA⁴; Bahram Bodaghi, PhD, FEBOph⁵; Elizabeth Graham, FRCP, DO, FRCOphth⁶; Gary N. Holland, MD⁷; Susan L. Lightman, PhD, FRCP, FRCOphth^8,9; Neal Oden, PhD¹⁰; Alan G. Palestine, MD¹¹; Justine R. Smith, FRANZCO, PhD¹²; Jennifer E. Thorne, MD, PhD^2,3; Brett E. Trusko, PhD, MBA¹³; Russell N. Van Gelder, MD, PhD¹⁴

Affiliations: ¹Members of the SUN Working Group are listed online at ajo.com. From ²the Department of Epidemiology, the Johns Hopkins University Bloomberg School of Public Health, and ³the Wilmer Eye Institute, the Department of Ophthalmology, the Johns Hopkins University School of Medicine, Baltimore, MD, USA; ⁴the Department of Ophthalmology, Federal University of São Paulo, São Paulo, Brazil; ⁵the Department of Ophthalmology, Pitie-Salpetriere Hospital, IHU FOReSIGHT, Sorbonne University, Paris, France; ⁶St. Thomas Hospital Medical Eye Unit, London, UK; ⁷the UCLA Stein Eye Institute and the Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; ⁸Moorfields Eye Hospital, London, UK; ⁹Institute of Ophthalmology, University College London, London, UK; ¹⁰the Emmes Company, LLC, Rockville, MD, USA; ¹¹the Department of Ophthalmology, University of Colorado School of Medicine, Aurora, Co, USA; ¹²the Flinders University College of Medicine and Public Health, Adelaide, Australia; ¹³the Department of Medicine, Texas A&M University, College Station, TX, USA; ¹⁴the Department of Ophthalmology, University of Washington School of Medicine, Seattle, WA, USA.

Conflict of Interest: Douglas A. Jabs: none; Rubens Belfort, Jr.: none; Bahram Bodaghi: none; Elizabeth Graham: none; Gary Holland: none; Susan L. Lightman: none; Neal Oden: none; Alan G. Palestine: none; Justine R. Smith: none; Jennifer E. Thorne: Dr. Thorne engaged in a portion of this research as a consultant and was compensated for the consulting service; Brett E. Trusko: none; Russell N. Van Gelder: none.

PMCID: PMC8594755 NIHMSID: NIHMS1694771 PMID: 33845015

Abstract

Purpose:

To determine classification criteria for cytomegalovirus (CMV) retinitis.

Design:

Machine learning of cases with CMV retinitis and 4 other infectious posterior/panuveitides.

Methods:

Cases of infectious posterior/panuveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the infectious posterior/panuveitides. The resulting criteria were evaluated on the validation set.

Results:

Eight hundred three cases of infectious posterior/panuveitides, including 211 cases of CMV retinitis, were evaluated by machine learning. Key criteria for CMV retinitis included: 1) necrotizing retinitis with indistinct borders due to numerous small satellites; 2) evidence of immune compromise; and either 3) a characteristic clinical appearance or 4) positive polymerase chain assay for CMV from an intraocular specimen. Characteristic appearances for CMV retinitis included: 1) wedge-shaped area of retinitis; 2) hemorrhagic retinitis; or 3) granular retinitis. Overall accuracy for infectious posterior/panuveitides was 92.1% in the training set and 93.3% (95% confidence interval 88.2, 96.3) in the validation set. The misclassification rates for CMV retinitis were 6.9% in the training set and 6.3% in the validation set.

Conclusions:

The criteria for CMV retinitis had a low misclassification rate and appeared to perform sufficiently well for use in clinical and translational research.

PRECIS

Using a formalized approach to developing classification criteria, including informatics-based case collection, consensus-technique-based case selection, and machine learning, classification criteria for cytomegalovirus retinitis were developed. Key criteria included a necrotizing retinitis with indistinct borders due to small satellites, immune compromise, and either a characteristic clinical picture or PCR positive for cytomegalovirus from an intraocular fluid specimen. Characteristic clinical pictures included wedge-shaped, hemorrhagic, or granular retinitis. The resulting classification criteria had a low misclassification rate.

Prior to the onset of the acquired immunodeficiency syndrome (AIDS) epidemic, cytomegalovirus (CMV) was a rare disease seen primarily in patients undergoing organ transplants, with estimated frequencies of ~1% for renal transplants and ~0.5% for bone marrow transplants. The primary risk factor for CMV disease was a CMV serum antibody-positive (“seropositive”) donor organ transplanted into a CMV-seronegative recipient.¹ With the onset of the AIDS epidemic, CMV retinitis became substantially more common, and prior to the widespread use of modern combination antiretroviral therapy (ART) in the mid-1990’s, CMV retinitis was among the most common intraocular infections seen in major urban medical centers in the United States and other developed countries.^1,2 Cytomegalovirus retinitis is an AIDS-defining opportunistic infection. In that era, the lifetime risk of developing CMV retinitis after the onset of AIDS was estimated at 30%.³ The primary risk factor was a low CD4+ T cell count, with the substantial majority of cases occurring among patients with CD4+ T cell counts ≤50 cells/μL,^1-3 as CMV-seropositive rates among persons at high risk for human immunodeficiency virus (HIV) infection typically were >90%.¹ With the widespread use of modern ART, the incidence of CMV retinitis among patients with AIDS has decreased by >95%,^1,4 primarily due to immune recovery from or prevention of these levels of immunodeficiency and the attendant restoration of immunity to CMV.^1,5

Cytomegalovirus retinitis occurs in the context of a systemic infection, and CMV can be detected in the blood of the majority of patients with CMV retinitis either by culture or polymerase chain reaction (PCR) of CMV from a blood specimen.^6,7 When blood and intraocular specimens from an individual are compared at the time of diagnosis of the retinitis using sequencing of the CMV UL97 gene, there is almost perfect agreement between the two isolates.⁸ The presumed pathogenesis of CMV retinitis among patients with AIDS is reactivation of latent infection in the context of immunodeficiency, hematologic dissemination to the retina, infection of retinal vascular endothelium, infection of adjacent retina, and unless treated with anti-CMV drugs, spread across the retina.^1,9 The end result of CMV retinitis is full-thickness retinal necrosis leaving a thin, atrophic, and gliotic scar. Retinal detachments were a common complication of CMV retinitis, often due to multiple retinal tears at the border of normal retina and the atrophic scar. The incidence of retinal detachment is related to the extent of retina involved by CMV retinitis,^1,2 and its incidence has declined in the era of modern ART.¹⁰ Two clinical morphologic variants of CMV retinitis were described: 1) fulminant or hemorrhagic and 2) granular. The hemorrhagic variant presented with a more extensive area of retinal edema and necrosis, admixed with hemorrhage (Figure 1), whereas the granular variant had a “granular” appearance (Figure 2). The fulminant or hemorrhagic variant has been described as having a “pizza pie” or a “cottage cheese and ketchup” appearance. The only difference observed between the two variants was the location of the lesions – the hemorrhagic variant occurred more often in the posterior pole, whereas the granular variant occurred more often in the periphery.¹

Figure 1. — Fundus photograph of a case of cytomegalovirus retinitis with a “hemorrhagic” appearance involving the posterior pole, characterized by retinal necrosis and edema, intraretinal hemorrhage and “satellite lesions” at the border.

Figure 2. — Fundus photograph of a case of cytomegalovirus retinitis involving the periphery, characterized by a “granular” appearance and without hemorrhage.

Treatments for CMV retinitis approved by the United States Food and Drug Administration have included: intravenous ganciclovir, intravenous foscarnet, intravenous cidofovir, valganciclovir (an oral pro-drug of ganciclovir with good oral bioavailability), the sustained-release intraocular ganciclovir implant, and fomivirsen (an intravitreally administered “anti-sense” drug); with the decline in the incidence of CMV retinitis, production of the ganciclovir implant and of fomivirsen were discontinued.^1,11-17 Intravitreal injections of either ganciclovir or foscarnet have been administered as treatments for CMV retinitis.^1,18 However, because of the systemic nature of the CMV infection, absent immune recovery from ART, treatment with intraocular therapy alone is associated with in increased risk of second eye CMV retinitis (among those presenting with unilateral retinitis), visceral CMV disease, and mortality, outcomes still seen the era of modern ART.^1,18 Many patients (especially those with lesions threatening the fovea or optic nerve) in developed countries are treated with an initial series of intravitreal injections of either ganciclovir or foscarnet, combined with systemic therapy (e.g. valganciclovir). With immune recovery from ART, patients with AIDS can recover immunity to CMV and are able to discontinue anti-CMV therapy.^5,19 The United States Department of Health and Human Services guidelines include the recommendation to stop anti-CMV therapy when CMV retinitis is inactive and CD4+ T cells have risen to >100 cells/μL for at least three to six months; cohort studies suggest that discontinuation in this circumstance typically can be done safely.¹⁹ The reason for the delay after a rise in CD4+ T cells is that the recovery of immunity to CMV lags the rise in CD4+ T cells by three to six months.⁵ The rare occurrence of patients with recovered CD4+ T cells but a failure to restore immunity to CMV and ongoing problems with recurrent CMV retinitis underscores the importance of immunity specific to CMV for its control.²⁰

Patients with CMV retinitis typically have relatively mild amounts of anterior chamber and vitreous inflammation at presentation (reported median vitreous cells grade ½+ and median vitreous haze grade 0+), presumably due to the failure to mount an effective immune response to CMV, and nearly ~90% will have grade 0 vitritis after treatment with anti-CMV agents.^21,22 However, with immune recovery due to ART the new onset of or an increase in anterior chamber and/or vitreous inflammation can occur, a phenomenon termed immune recovery uveitis (IRU).^22,23 Patients diagnosed with CMV retinitis after the initiation of ART may have greater levels of anterior chamber and vitreous inflammation than those diagnosed before the initiation of ART as a consequence of IRU.

Even though much of the information on CMV retinitis comes from patients with AIDS, patients with other forms of immunosuppression, such as organ transplants and chemotherapy, may develop CMV retinitis.²⁴ Rare cases have been reported after intravitreal corticosteroid injection or sustained-release corticosteroid implantation, presumably resulting from local, ocular immune compromise.^25,26 Cases of CMV retinitis occurring in patients with other types of immune compromise appear to behave similarly to cases of CMV retinitis occurring among patients with AIDS in the modern ART era, including the occurrence of IRU when immunosuppression is reduced or discontinued.²⁴

The Standardization of Uveitis Nomenclature (SUN) Working Group is an international collaboration, which has developed classification criteria for 25 of the most common uveitides using a formal approach to development and classification. Among the diseases studied was CMV retinitis.^27-33

Methods

The SUN Developing Classification Criteria for the Uveitides project proceeded in four phases as previously described: 1) informatics, 2) case collection, 3) case selection, and 4) machine learning.^28-32

Informatics.

As previously described, the consensus-based informatics phase permitted the development of a standardized vocabulary and the development of a standardized, menu-driven hierarchical case collection instrument.²⁹

Case collection and case selection.

De-identified information was entered into the SUN preliminary database by the 76 contributing investigators for each disease as previously described.^31,32 Cases in the preliminary database were reviewed by committees of 9 investigators for selection into the final database, using formal consensus techniques described in the accompanying article.^31,32 Because the goal was to develop classification criteria,³³ only cases with a supermajority agreement (>75%) that the case was the disease in question were retained in the final database (i.e. were “selected”).^31,32

Machine learning.

The final database then was randomly separated into a training set (~85% of the cases) and a validation set (~15% of the cases) for each disease as described in the accompanying article.³² Machine learning was used on the training set to determine criteria that minimized misclassification. The criteria then were tested on the validation set; for both the training set and the validation set, the misclassification rate was calculated for each disease. The misclassification rate was the proportion of cases classified incorrectly by the machine learning algorithm when compared to the consensus diagnosis. For infectious posterior and panuveitides, the diseases against which CMV retinitis was evaluated were: acute retinal necrosis (ARN), syphilitic uveitis, tubercular uveitis, and toxoplasmic retinitis.

Comparison of cases with AIDS versus those with other immune compromise.

Cases with AIDS were compared to cases with other types of immune compromise (e.g. organ transplant, chemotherapy). For categorical variables, comparison was performed with the chi-square test or the Fisher’s exact test when the count of a variable was less than 5. Continuous variables were summarized as medians and compared with the Wilcoxon rank sum test. For characteristics with multiple categorical grades, values above and below the median were compared. P-values are nominal and two-sided.

The study adhered to the principles of the Declaration of Helsinki. Institutional Review Boards (IRBs) at each participating center reviewed and approved the study; the study typically was considered either minimal risk or exempt by the individual IRBs.

Results

Two hundred fifty-one cases of CMV retinitis were collected and 211 (84%) achieved supermajority agreement on the diagnosis during the “selection” phase and were used in the machine learning phase. These cases of CMV retinitis were compared to cases of infectious posterior/panuveitides, including 186 cases of ARN, 174 cases of toxoplasmic retinitis, 35 cases of syphilitic posterior uveitis and 197 cases of tubercular posterior or pan-uveitis. The details of the machine learning results for these diseases are outlined in the accompanying article.³² The characteristics of cases with CMV retinitis are listed in Table 1. The comparison of cases with and AIDS vs. other forms of immune compromise is listed in Table 2. The comparison of cases with AIDS vs. those with other forms of immune compromise revealed demographic differences consistent with those of the AIDS epidemic in the United States, and a statistically significant but clinically modest difference in presenting intraocular pressure (medians 13 mm Hg for cases with AIDS and 15 mm Hg for cases without). In addition, cases with AIDS had less vitritis (median vitreous haze grade 0) than did cases without AIDS (median vitreous haze grade ½+), but the difference was modest. The classification criteria developed after machine learning are listed in Table 3. Key features of the criteria include necrotizing retinitis with indistinct borders (satellites), immune compromise, and either evidence of intraocular CMV infection (e.g. PCR) or a characteristic clinical picture. Features of a characteristic clinical picture for CMV retinitis included a hemorrhagic (Figure 1), granular-appearing (Figure 2), or wedge-shaped (Figure 3) retinitis with no to mild vitritis. The overall accuracy for infectious posterior/panuveitides was 92.1% in the training set and 93.3% (95% confidence interval 88.2, 96.3%) in the validation set. The misclassification rate for CMV retinitis in the training set was 6.9% and in the validation set 6.3%. The diseases with which CMV retinitis most often was confused (i.e. misclassified) in the training set were toxoplasmic retinitis and syphilitic retinitis, and in the validation set toxoplasmic retinitis and ARN.

Table 1.

Characteristics of Cases with Cytomegalovirus Retinitis

Characteristic	Result
Number cases	211
Demographics
Age, median, years (25^th 75^th percentile)	40 (33, 47)
Gender (%)
Men	71
Women	29
Race/ethnicity (%)
White, non-Hispanic	49
Black, non-Hispanic	18
Hispanic	8
Asian, Pacific Islander	9
Other	15
Missing	1
Uveitis History
Uveitis course (%)
Acute, monophasic	54
Acute, recurrent	3
Chronic	36
Indeterminate	7
Laterality (%)
Unilateral	64
Unilateral, alternating	0
Bilateral	36
Ophthalmic examination
Keratic precipitates (%)
None	64
Fine	29
Round	2
Stellate	2
Mutton Fat	2
Other	0
Anterior chamber cells (%)
Grade 0	45
½+	26
1+	17
2+	10
3+	2
4+	1
Anterior chamber flare (%)
Grade 0	70
1+	26
2+	4
3+	0
4+	0
Iris (%)
Normal	96
Posterior synechiae	4
Iris nodules	0
Iris atrophy (sectoral, patchy, or diffuse)	0
Heterochromia	0
Intraocular pressure (IOP), involved eyes
Median, mm Hg (25^th, 75^th percentile)	13 (12, 16)
Proportion patients with IOP>24 mm Hg either eye (%)	2
Vitreous cells (%)
Grade 0	30
½+	20
1+	31
2+	16
3+	3
4+	0
Vitreous haze (%)
Grade 0	55
½+	14
1+	21
2+	7
3+	2
4+	0
Retinitis characteristics
Lesion number (%)
Unifocal (1 lesion)	23
Paucifocal (2-4 distinct lesions)	69
Multifocal (≥5 distinct lesions)	8
Lesion shape (%)
Round or ovoid	11
Placoid or ameboid	35
Wedge-shaped	31
Missing	23
Lesion character (%)
Circumferential	4
Confluent	28
Granular	36
Lesion location (%)
Posterior pole involved	38
Mid-periphery and periphery only	62
Lesion size (%)
<250 μm	5
250-500 μm	10
>500 μm	85
Other features (%)
Retinal vascular sheathing	36
Retinal hemorrhage	61
Systemic disease
Immunocompromised patients (%)
Acquired immunodeficiency syndrome (AIDS)	76
Organ transplant	3
Chemotherapy or other immunosuppression	16
Missing	5
Laboratory data (%)
Aqueous or vitreous specimen PCR^* positive for cytomegalovirus	34

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PCR = polymerase chain reaction. 71 of 71 cases tested (100%) were positive for cytomegalovirus.

Table 2.

Comparison of Cases of Cytomegalovirus Retinitis between Cases with the Acquired Immunodeficiency Syndrome and Cases with Other Immune Compromise

Characteristic	Cases with AIDS^*	Cases without AIDS	P-value
Number cases	160	51
Demographics
Age, median, years (25^th 75^th percentile)	39 (33, 44)	48 (32, 66)	0.02
Gender (%)			1.00
Men	71	71
Women	29	29
Race/ethnicity (%)			<0.001
White, non-Hispanic	42	71
Black, non-Hispanic	23	4
Hispanic	10	0
Asian, Pacific Islander	8	12
Other	16	13
Missing	1	0
Uveitis History
Uveitis course (%)			0.09
Acute, monophasic	47	45
Acute, recurrent	7	4
Chronic	35	27
Indeterminate	11	24
Laterality (%)			0.27
Unilateral	65	67
Bilateral	35	33
Ophthalmic examination
Keratic precipitates (%)			0.64
None	66	59
Fine	28	31
Other	6	10
Anterior chamber cells (%)			0.41
Grade 0	44	45
½+	28	18
≥1+	28	37
Anterior chamber flare (%)			0.17
Grade 0	73	63
1+	22	35
2+	5	2
Iris (%)			0.38
Normal	96	94
Posterior synechiae	4	6
Intraocular pressure (IOP), involved eyes
Median, mm Hg (25^th, 75^th percentile)	13 (11, 15)	15 (13, 19)	<0.001
Percent patients with IOP>24 mm Hg either eye	0	10	0.001
Vitreous cells (%)			0.52
Grade 0	32	25
½+	21	18
≥1+	48	57
Vitreous haze (%)			0.01
Grade 0	61	37
½+	12	22
≥1+	27	41
Retinitis characteristics
Lesion number (%)			0.90
Unifocal (1 lesion)	21	24
Paucifocal (2-4 distinct lesions)	70	69
Multifocal (≥5 distinct lesions)	9	7
Lesion shape (%)			0.17
Round or ovoid	13	8
Placoid	29	31
Wedge-shaped	31	33
Lesion character (%)
Circumferential or confluent	34	29	0.38
Hemorrhagic	59	63	0.40
Granular	37	33	0.39
Lesion location (%)			0.06
Posterior pole involved	39	35
Mid-periphery and periphery only	61	65
Lesion size (%)			0.72
<250 μm	5	2
250-500 μm	8	17
>500 μm	87	81
Other features (%)
Retinal vascular sheathing	37	33	0.39
Systemic disease
Laboratory data (%)
Ocular fluid specimen PCR positive for CMV^†	24	65

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AIDS = acquired immunodeficiency syndrome.

^†

PCR = polymerase chain reaction; CMV = cytomegalovirus. 38 of 38 (100%) specimens from tested cases with AIDS were PCR positive for CMV; and 33 of 33 (100%) specimens from tested cases without AIDS were PCR positive for CMV.

Table 3.

Classification Criteria for Cytomegalovirus Retinitis

Criteria (requires #1 and #2 and either #3 or #4)
1. Necrotizing retinitis with indistinct borders due to numerous small (<50 μm) satellites
AND
2. Immune compromise, either
a. Systemic (e.g. AIDS, organ transplant, chemotherapy) OR
b. Ocular (e.g. intraocular corticosteroids or chemotherapy)
AND (#3 or #4)
3. Characteristic clinical picture ([a. or b. or c.] AND d.)
a. Wedge-shaped area of retinitis OR
b. Hemorrhagic appearance of the retinitis OR
c. Granular appearance of the retinitis AND
d. Absent to mild vitritis
OR
4. Evidence of intraocular infection with cytomegalovirus
a. Positive PCR^* for cytomegalovirus from either the aqueous or vitreous specimen
Exclusions
1. Positive serology for syphilis using a treponemal test
2. Intraocular specimen PCR-positive for herpes simplex virus, varicella zoster virus or Toxoplasma gondii (unless there is immune compromise, morphologic evidence for >1 infection, the characteristic picture of cytomegalovirus retinitis, and the intraocular fluid specimen also has a positive PCR for cytomegalovirus)

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PCR = polymerase chain reaction.

Figure 3. — Fundus photograph of a case of cytomegalovirus retinitis with a wedge shaped appearance with the apex “pointing” toward the optic disc.

Discussion

Necrotizing retinitides are characterized by full thickness retinal necrosis with or without inflammation, which, upon resolution, leave an atrophic and gliotic scar in the involved areas. Clinically, the initial presentation is white to yellow retinal edema and opacity with or without hemorrhage. Necrotizing retinitides may have relatively well demarcated borders, as in the case of ARN, or have satellites extending into adjacent retina, as is seen in CMV retinitis. The classification criteria developed by the SUN Working Group for CMV retinitis have a low misclassification rate, indicating good discriminatory performance against other infectious posterior and pan-uveitides.³² Because of the similarity of the clinical presentation between cases with AIDS and those with other forms of immune compromise, these criteria appear to be applicable to both situations. The goal of the SUN project was disease classification at presentation, so that cases of active CMV retinitis were submitted, and the criteria are most applicable to active retinitis. Atrophic scars from retinitis may be non-specific, and it may be difficult to determine the original cause of such scars.

The diseases with which CMV retinitis was most often confused were two other necrotizing retinitides, ARN and toxoplasmic retinitis. In immunocompromised hosts, toxoplasmic retinitis occasionally may present as a more extensive retinitis without adjacent scars and be difficult to distinguish from CMV retinitis.³⁴ In these cases, sampling intraocular fluids for PCR for viruses and Toxoplasma gondii may be needed. Rarely, patients with immune compromise (e.g. AIDS with low CD4+ T cells) may be infected with two or more intraocular pathogens,² and the PCR result may be positive for CMV and a second pathogen. In that situation, there should be two or more morphologic presentations of retinitis, one of which is compatible with CMV retinitis, in order to diagnose CMV retinitis (as well as the positive PCR for CMV). Syphilis can produce a necrotizing retinitis that can be mistaken for CMV retinitis, and it should be excluded.

In CMV retinitis, the retinitis is due to CMV replication in the retina and the attendant retinal destruction, whereas any anterior chamber inflammation and/or vitritis may be due to the immunologic response to CMV,¹ as is seen with other infectious retinitides.³⁵ The increase in vitritis with IRU is consistent with the vitritis being largely part of the immunologic response.^22,23 Immune recovery retinitis has been proposed as an immune recovery inflammatory syndrome (IRIS), with the implication that the immune response contributes to new onset CMV retinitis or worsening of active retinitis within a three-month window after initiating ART.³⁶ However, analysis of a large cohort study of patients with AIDS provided no evidence to support immune recovery retinitis as an IRIS phenomenon,³⁷ and the amount of lesion opacity in CMV retinitis is inversely related to the degree of immune compromise, the opposite of what would be expected if there was an IRIS-type retinitis.³⁸ It is more likely that the cases cited to support the concept of immune recovery retinitis merely represented the expected behavior of CMV retinitis in the context of immune compromise observed during the three- to six-month window between the rise in CD4+ T cells after initiating ART and the restoration of immunity to CMV.⁵ The available data support the concept that active CMV retinitis is due to CMV replication in the retina.¹

Classification criteria are employed to diagnose individual diseases for research purposes.³³ Classification criteria differ from clinical diagnostic criteria, in that although both seek to minimize misclassification, when a trade-off is needed, diagnostic criteria typically emphasize sensitivity, whereas classification criteria emphasize specificity,³³ in order to define a homogeneous group of patients for inclusion in research studies and limit the inclusion of patients without the disease in question that might confound the data. The machine learning process employed did not explicitly use sensitivity and specificity; instead it minimized the misclassification rate. Because we were developing classification criteria and because the typical agreement between two uveitis experts on diagnosis is moderate at best,³¹ the selection of cases for the final database (“case selection”) included only cases which achieved supermajority agreement on the diagnosis. As such, some cases which clinicians might diagnose as CMV retinitis may not be so classified by classification criteria.

In conclusion, the criteria for CMV retinitis outlined in Table 3 appear to perform sufficiently well for use as classification criteria in clinical research.³²

Grant support:

Supported by grant R01 EY026593 from the National Eye Institute, the National Institutes of Health, Bethesda, MD, USA; the David Brown Fund, New York, NY, USA; the Jillian M. And Lawrence A. Neubauer Foundation, New York, NY, USA; and the New York Eye and Ear Foundation, New York, NY, USA.

Footnotes

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8.Hu H, Jabs DA, Forman MS, et al. Comparison of cytomegalovirus (CMV) UL97 gene sequences in the blood and vitreous of patients with acquired immunodeficiency syndrome and CMV retinitis. J Infect Dis 2002;185:861–7. [DOI] [PubMed] [Google Scholar]
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10.Jabs DA, Ahuja A, Van Natta ML, Lyon AT, Yeh S, Danis R , Studies of the Ocular Complications of AIDS Research Group. Long-term outcomes of cytomegalovirus retinitis in the era of modern antiretroviral therapy: results of a United States cohort. Ophthalmology 2015;122:1452–63. [DOI] [PMC free article] [PubMed] [Google Scholar]
11.Spector SA, Weingeist T, Pollard RB et al. A randomized controlled study of intravenous ganciclovir therapy for cytomegalovirus peripheral retinitis in patients with AIDS. J Infect Dis 1993;168:557–63. [DOI] [PubMed] [Google Scholar]
12.Palestine AG, Polis MA, De Smet MD, et al. A randomized controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS. Ann Intern Med 1991;115:665–73. [DOI] [PubMed] [Google Scholar]
13.Martin DF Sierra-Madero J, Walmsley S, et al. A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. N Engl J Med 2002;346:1119–26. [DOI] [PubMed] [Google Scholar]
14.Studies of the Ocular Complications of AIDS Research Group in collaboration with the ADIS Clinical Trials Group. Parenteral cidofovir for cytomegalovirus retinitis in patients with AIDS: the HPMPC peripheral cytomegalovirus retinitis trial. A randomized controlled trial. Ann Intern Med 1997;126:264–74. [DOI] [PubMed] [Google Scholar]
15.Musch DC, Martin DF, Gordon JF, Davis MD, Kupperman BD, the Ganciclovir Implant Study Group. Treatment of cytomegalovirus retinitis with a sustained-release ganciclovir implant. N Engl J Med 1997;337:83–90. [DOI] [PubMed] [Google Scholar]
16.Martin DF, Kupperman BD, Wolitz RA, Palestine AG, Li H, Ronbinson CA, Roche Ganciclovir Study Group. Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant. N Engl J Med 1999;340:1063–70. [DOI] [PubMed] [Google Scholar]
17.Studies of the Ocular Complications of AIDS Research Group in collaboration with the AIDS Clinical Trials Group. Foscarnet-Ganciclovir Cytomegalovirus Retinitis Trial. 4. Visual outcomes. Ophthalmology 1994;101:1250–61. [PubMed] [Google Scholar]
18.Jabs DA, Ahuja A, Van Natta ML, et al. Comparison of treatment regimens for cytomegalovirus retinitis in patient with AIDS in the era of highly active antiretroviral therapy. Ophthalmology 2013:120:1262–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Holbrook JT, Colvin R, van Natta ML, Thorne JE, Bardsley M, Jabs DA, Studies of Ocular Complication of AIDS (SOCA) Research Group. Evaluation of the United States Public Health Service guidelines for discontinuation of anticytomegalovirus therapy after immune recovery in patients with cytomegalovirus retinitis. Am J Ophthalmol 2011;152:628–37. [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Komanduri KV, Feinberg J, Hutchins, et al. Loss of cytomegalovirus-specific CD4+ T cell responses in human immunodeficiency virus type 1-infected patients with high CD4+ T cell counts and recurrent retinitis. J Infect Dis 2001;183:1285–9. [DOI] [PubMed] [Google Scholar]
21.Jabs DA, Van Natta ML, Holbrook JT, Kempen JH, Meinert CL, Davis MD, Studies of the Ocular Complications of AIDS Research Group. Longitudinal study of the ocular complications of AIDS: 2. Ocular examination results at enrollment. Ophthalmology 2007;114:787–93. [DOI] [PubMed] [Google Scholar]
22.Nguyen QD, Kempen JH, Bolton SG, Dunn JP, Jabs DA. Immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis after highly active antiretroviral therapy. Am J Ophthalmol 2000;129:634–9. [DOI] [PubMed] [Google Scholar]
23.Kempen JH, Min YI, Freeman WR, et al. Risk of immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis. Ophthalmology 2006; 113:684–94. [DOI] [PubMed] [Google Scholar]
24.Kuo IC, Kempen JH, Dunn JP, Vogelsang G, Jabs DA. Clinical characteristics and outcome of cytomegalovirus retinitis in persons without human immunodeficiency virus infection. Am J Ophthalmol 2004;138:338–46. [DOI] [PubMed] [Google Scholar]
25.Saidel MA, Berren J, Margolis TP. Cytomegalovirus retinitis after intrvitreous triamcinolone in an immunocompetent patient. Am J Ophthalmol 2005;140:1141–3. [DOI] [PubMed] [Google Scholar]
26.Ufret-Vincenty RL, Singh RP, Lowder CY, Kaiser PK. Cytomegalovirus retinitis after fluocinolone acetonide (Retisert™) implant. Am J Ophthalmol 2007;143:334–5. [DOI] [PubMed] [Google Scholar]
27.Jabs DA, Rosenbaum JT, Nussenblatt RB, the Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Report of the first international workshop. Am J Ophthalmol 2005;140:509–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
28.Jabs DA, Busingye J. Approach to the diagnosis of the uveitides. Am J Ophthalmol 2013;156:228–36. [DOI] [PMC free article] [PubMed] [Google Scholar]
29.Trusko B, Thorne J, Jabs D, et al. Standardization of Uveitis Nomenclature Working Group. The SUN Project. Development of a clinical evidence base utilizing informatics tools and techniques. Methods Inf Med 2013;52:259–65. [DOI] [PMC free article] [PubMed] [Google Scholar]
30.Okada AA, Jabs DA. The SUN Project. The future is here. Arch Ophthalmol 2013;131:787–9. [DOI] [PubMed] [Google Scholar]
31.Jabs DA, Dick A, Doucette JT, Gupta A, Lightman S, McCluskey P, Okada AA, Palestine AG, Rosenbaum JT, Saleem SM, Thorne J, Trusko B for the Standardization of Uveitis Nomenclature Working Group. Interobserver agreement among uveitis experts on uveitic diagnoses: the Standard of Uveitis Nomenclature experience. Am J Ophthalmol 2018; 186:19–24. [DOI] [PMC free article] [PubMed] [Google Scholar]
32.The Standardization of Uveitis Nomenclature (SUN) Working Group. Development of classification criteria for the uveitides. Am J Ophthalmol 2020;volume:pp. [DOI] [PubMed] [Google Scholar]
33.Aggarwal R, Ringold S, Khanna D, et al. Distinctions between diagnostic and classification criteria. Arthritis Care Res 2015;67:891–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
34.Elkins BS, Holland GN, Opremcak EM, Dunn JP, Jabs DA, Johnston WH, Green WR. Ocular toxoplasmosis misdiagnosed as cytomegalovirus retinopathy in immunocompromised patients. Ophthalmology 1994;101:499–507. [DOI] [PubMed] [Google Scholar]
35.Newman PE, Ghosheh R, Tabbara KF, O’Connor GR, Stern W. The role of hypersensitivity reactions to Toxoplasma antigens in experimental ocular toxoplasmosis in nonhuman primates. Am J Ophthalmol 1982;94:159–64. [DOI] [PubMed] [Google Scholar]
36.Ruiz-Cruz M, Alvarado-de la Barrera C, Ablanedo-Terrazas Y, Reyes-Teran G. Proposed clinical case definition for cytomegalovirus-immune recovery retinitis. Clin Infect Dis 2014;59:298–303. [DOI] [PubMed] [Google Scholar]
37.Jabs DA, Van Natta ML, Holland GN, Danis R, Studies of the Ocular Complications of AIDS Research Group. Cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome after initiating antiretroviral therapy. Am J Ophthalmol 2017;174:23032. [DOI] [PMC free article] [PubMed] [Google Scholar]
38.Holland GN, Van Natta ML, Goldenberg DT, Ritts R Jr, Danis RP, Jabs DA, Studies of the Ocular Complications of AIDS Research Group. Relationship between opacity of cytomegalovirus retinitis lesion borders and severity of immunodeficiency among people with AIDS. Invest Ophthalmol Vis Sci 2019;60:1853–62. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R1] 1.Jabs DA. Cytomegalovirus retinitis and the acquired immunodeficiency syndrome – bench to bedside: LXVI Edward Jackson Memorial Lecture. Am J Ophthalmol 2011;151:198–216. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R2] 2.Jabs DA. Ocular manifestations of HIV infection. Trans Am Ophthalmol Soc 1995;623–83. [PMC free article] [PubMed] [Google Scholar]

[R3] 3.Hoover DR, Peng Y, Saah A, et al. Occurrence of cytomegalovirus retinitis after human immunodeficiency virus immunosuppression. Arch Ophthalmol 1996;114:821–7. [DOI] [PubMed] [Google Scholar]

[R4] 4.Sugar EA, Jabs DA, Ahuja A, et al. Incidence of cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Am J Ophthalmol 2012; 153:1016–24. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R5] 5.Komanduri KV, Viswanathan MN, Wieder ED, et al. Restoration of cytomegalovirus-specific CD4+ T-lymphocyte responses after ganciclovir and highly active antiretroviral therapy in individuals infected with HIV-1. Nature Med 1999;4:953–6. [DOI] [PubMed] [Google Scholar]

[R6] 6.Jabs DA, Dunn JP, Forman M, Bressler N, Charache P, Cytomegalovirus Retinitis and Viral Resistance Study Group. Cytomegalovirus retinitis and viral resistance. Prevalence of resistance at diagnosis, 1994. Arch Ophthalmol 1996;114:809–14. [DOI] [PubMed] [Google Scholar]

[R7] 7.Jabs DA, Martin BK, Ricks MO, Forman MS, Cytomegalovirus Retinitis and Viral Resistance Study Group. Detection of ganciclovir resistance in patients with AIDS and cytomegalovirus retinitis: correlation of genotypic methods with viral phenotype and clinical outcome. J Infect Dis 2006;193:1728–37. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R8] 8.Hu H, Jabs DA, Forman MS, et al. Comparison of cytomegalovirus (CMV) UL97 gene sequences in the blood and vitreous of patients with acquired immunodeficiency syndrome and CMV retinitis. J Infect Dis 2002;185:861–7. [DOI] [PubMed] [Google Scholar]

[R9] 9.Rao NA, Zhang J, Ishimoto S. Role of retinal vascular endothelial cells in development of CMV retinitis. Trans Am Ophthalmol Soc 1998;96:111–23. [PMC free article] [PubMed] [Google Scholar]

[R10] 10.Jabs DA, Ahuja A, Van Natta ML, Lyon AT, Yeh S, Danis R , Studies of the Ocular Complications of AIDS Research Group. Long-term outcomes of cytomegalovirus retinitis in the era of modern antiretroviral therapy: results of a United States cohort. Ophthalmology 2015;122:1452–63. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R11] 11.Spector SA, Weingeist T, Pollard RB et al. A randomized controlled study of intravenous ganciclovir therapy for cytomegalovirus peripheral retinitis in patients with AIDS. J Infect Dis 1993;168:557–63. [DOI] [PubMed] [Google Scholar]

[R12] 12.Palestine AG, Polis MA, De Smet MD, et al. A randomized controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS. Ann Intern Med 1991;115:665–73. [DOI] [PubMed] [Google Scholar]

[R13] 13.Martin DF Sierra-Madero J, Walmsley S, et al. A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. N Engl J Med 2002;346:1119–26. [DOI] [PubMed] [Google Scholar]

[R14] 14.Studies of the Ocular Complications of AIDS Research Group in collaboration with the ADIS Clinical Trials Group. Parenteral cidofovir for cytomegalovirus retinitis in patients with AIDS: the HPMPC peripheral cytomegalovirus retinitis trial. A randomized controlled trial. Ann Intern Med 1997;126:264–74. [DOI] [PubMed] [Google Scholar]

[R15] 15.Musch DC, Martin DF, Gordon JF, Davis MD, Kupperman BD, the Ganciclovir Implant Study Group. Treatment of cytomegalovirus retinitis with a sustained-release ganciclovir implant. N Engl J Med 1997;337:83–90. [DOI] [PubMed] [Google Scholar]

[R16] 16.Martin DF, Kupperman BD, Wolitz RA, Palestine AG, Li H, Ronbinson CA, Roche Ganciclovir Study Group. Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant. N Engl J Med 1999;340:1063–70. [DOI] [PubMed] [Google Scholar]

[R17] 17.Studies of the Ocular Complications of AIDS Research Group in collaboration with the AIDS Clinical Trials Group. Foscarnet-Ganciclovir Cytomegalovirus Retinitis Trial. 4. Visual outcomes. Ophthalmology 1994;101:1250–61. [PubMed] [Google Scholar]

[R18] 18.Jabs DA, Ahuja A, Van Natta ML, et al. Comparison of treatment regimens for cytomegalovirus retinitis in patient with AIDS in the era of highly active antiretroviral therapy. Ophthalmology 2013:120:1262–70. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R19] 19.Holbrook JT, Colvin R, van Natta ML, Thorne JE, Bardsley M, Jabs DA, Studies of Ocular Complication of AIDS (SOCA) Research Group. Evaluation of the United States Public Health Service guidelines for discontinuation of anticytomegalovirus therapy after immune recovery in patients with cytomegalovirus retinitis. Am J Ophthalmol 2011;152:628–37. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R20] 20.Komanduri KV, Feinberg J, Hutchins, et al. Loss of cytomegalovirus-specific CD4+ T cell responses in human immunodeficiency virus type 1-infected patients with high CD4+ T cell counts and recurrent retinitis. J Infect Dis 2001;183:1285–9. [DOI] [PubMed] [Google Scholar]

[R21] 21.Jabs DA, Van Natta ML, Holbrook JT, Kempen JH, Meinert CL, Davis MD, Studies of the Ocular Complications of AIDS Research Group. Longitudinal study of the ocular complications of AIDS: 2. Ocular examination results at enrollment. Ophthalmology 2007;114:787–93. [DOI] [PubMed] [Google Scholar]

[R22] 22.Nguyen QD, Kempen JH, Bolton SG, Dunn JP, Jabs DA. Immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis after highly active antiretroviral therapy. Am J Ophthalmol 2000;129:634–9. [DOI] [PubMed] [Google Scholar]

[R23] 23.Kempen JH, Min YI, Freeman WR, et al. Risk of immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis. Ophthalmology 2006; 113:684–94. [DOI] [PubMed] [Google Scholar]

[R24] 24.Kuo IC, Kempen JH, Dunn JP, Vogelsang G, Jabs DA. Clinical characteristics and outcome of cytomegalovirus retinitis in persons without human immunodeficiency virus infection. Am J Ophthalmol 2004;138:338–46. [DOI] [PubMed] [Google Scholar]

[R25] 25.Saidel MA, Berren J, Margolis TP. Cytomegalovirus retinitis after intrvitreous triamcinolone in an immunocompetent patient. Am J Ophthalmol 2005;140:1141–3. [DOI] [PubMed] [Google Scholar]

[R26] 26.Ufret-Vincenty RL, Singh RP, Lowder CY, Kaiser PK. Cytomegalovirus retinitis after fluocinolone acetonide (Retisert™) implant. Am J Ophthalmol 2007;143:334–5. [DOI] [PubMed] [Google Scholar]

[R27] 27.Jabs DA, Rosenbaum JT, Nussenblatt RB, the Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Report of the first international workshop. Am J Ophthalmol 2005;140:509–16. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R28] 28.Jabs DA, Busingye J. Approach to the diagnosis of the uveitides. Am J Ophthalmol 2013;156:228–36. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R29] 29.Trusko B, Thorne J, Jabs D, et al. Standardization of Uveitis Nomenclature Working Group. The SUN Project. Development of a clinical evidence base utilizing informatics tools and techniques. Methods Inf Med 2013;52:259–65. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R30] 30.Okada AA, Jabs DA. The SUN Project. The future is here. Arch Ophthalmol 2013;131:787–9. [DOI] [PubMed] [Google Scholar]

[R31] 31.Jabs DA, Dick A, Doucette JT, Gupta A, Lightman S, McCluskey P, Okada AA, Palestine AG, Rosenbaum JT, Saleem SM, Thorne J, Trusko B for the Standardization of Uveitis Nomenclature Working Group. Interobserver agreement among uveitis experts on uveitic diagnoses: the Standard of Uveitis Nomenclature experience. Am J Ophthalmol 2018; 186:19–24. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R32] 32.The Standardization of Uveitis Nomenclature (SUN) Working Group. Development of classification criteria for the uveitides. Am J Ophthalmol 2020;volume:pp. [DOI] [PubMed] [Google Scholar]

[R33] 33.Aggarwal R, Ringold S, Khanna D, et al. Distinctions between diagnostic and classification criteria. Arthritis Care Res 2015;67:891–7. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R34] 34.Elkins BS, Holland GN, Opremcak EM, Dunn JP, Jabs DA, Johnston WH, Green WR. Ocular toxoplasmosis misdiagnosed as cytomegalovirus retinopathy in immunocompromised patients. Ophthalmology 1994;101:499–507. [DOI] [PubMed] [Google Scholar]

[R35] 35.Newman PE, Ghosheh R, Tabbara KF, O’Connor GR, Stern W. The role of hypersensitivity reactions to Toxoplasma antigens in experimental ocular toxoplasmosis in nonhuman primates. Am J Ophthalmol 1982;94:159–64. [DOI] [PubMed] [Google Scholar]

[R36] 36.Ruiz-Cruz M, Alvarado-de la Barrera C, Ablanedo-Terrazas Y, Reyes-Teran G. Proposed clinical case definition for cytomegalovirus-immune recovery retinitis. Clin Infect Dis 2014;59:298–303. [DOI] [PubMed] [Google Scholar]

[R37] 37.Jabs DA, Van Natta ML, Holland GN, Danis R, Studies of the Ocular Complications of AIDS Research Group. Cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome after initiating antiretroviral therapy. Am J Ophthalmol 2017;174:23032. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R38] 38.Holland GN, Van Natta ML, Goldenberg DT, Ritts R Jr, Danis RP, Jabs DA, Studies of the Ocular Complications of AIDS Research Group. Relationship between opacity of cytomegalovirus retinitis lesion borders and severity of immunodeficiency among people with AIDS. Invest Ophthalmol Vis Sci 2019;60:1853–62. [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Classification criteria for cytomegalovirus retinitis