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The Role of Ocular Fundus in Systemic Infections: Comparison
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Examining the ocular fundus demonstrates significant clinical relevance in systemic infections among inpatients. The necessity of such evaluations is not universal for all infectious cases but critical when systemic infections, notably those demonstrating a potential for ocular involvement. The utilization of a collaborative decision tree is proposed to guide clinicians in identifying patients who may derive substantial benefit from fundus examinations, thereby enhancing diagnostic accuracy and tailoring therapeutic interventions. A well-structured, interdisciplinary approach, combining systemic and ocular assessments, is crucial to establish diagnostic clarity and refine therapeutic approaches, especially in the complex clinical scenarios often presented by inpatients with systemic infections. Ultimately, adopting this strategic framework aims to promote better patient outcomes through informed and timely intervention strategies.

  • systemic infections
  • bedside diagnosis
  • ocular fundus examination
  • ophalmoscopy

1. Introduction

Ocular fundus examination offers a privileged window, providing a unique, non-invasive means of observing vasculature in vivo and subsequently uncovering numerous systemic diseases. Even though the ocular fundus is generally considered an invaluable diagnostic tool, its application can be potentially underappreciated in the context of bedside examinations for patients admitted with various systemic conditions [1]. The challenges incumbent upon the employment of the new advanced ophthalmic diagnostic technologies, particularly in bedside environments and amidst infection outbreaks, are multifaceted [2,3,4][2][3][4]. Impediments include logistical issues related to instrument transport to bedside settings and the potential for enhanced risk of cross-infection when deploying such instrumentation in infectious contexts [5,6,7][5][6][7]. Thus, the binocular indirect ophthalmoscope (BIO) remains an expedient, cost-effective diagnostic tool capable of rapid deployment in varied settings, including in situ patient care environments [8].
Numerous systemic infectious diseases can present diagnostic indicators within the ocular fundus, manifesting in both life-threatening conditions such as septicemia or endocarditis, and in infections from specific agents like Cytomegalovirus (CMV), human immunodeficiency virus (HIV), tuberculosis (TB), syphilis, and toxoplasmosis [9,10,11][9][10][11]. These agents often bear distinct signatures within the ocular fundus that may be detected during a comprehensive examination. Notably, these anomalies may present even in the absence of overt ophthalmic symptoms, meaning the ophthalmologist could, in certain instances, be pivotal in rendering initial diagnoses of these systemic conditions based on ocular findings [12].

3. Ocular Fundus Examination

Ocular fundus examination allows for the inspection of the posterior segment of the eye, including the vitreous, retina, optic nerve, macula, and retinal vessels [14][13]. Ocular fundus can be explored by direct or indirect ophthalmoscopy [15][14]. Direct ophthalmoscopy procures an upright, unreversed image with a magnification of around 15 times, whereas indirect ophthalmoscopy delivers a reversed, inverted image, magnified between two to five times. The latter, which has a longer learning curve, can be subdivided into monocular indirect ophthalmoscopy (MIO) and binocular indirect ophthalmoscopy (BIO). Direct ophthalmoscopy is suitable for swift assessments of the optic nerve head or evaluating the red reflex, and is frequently employed by non-ophthalmologist clinicians, such as neurologists and pediatricians [16,17][15][16]. Conversely, indirect ophthalmoscopy, particularly the BIO, provides a stereoscopic, extensive view of the retina, encompassing around a 40–45-degree field when utilizing a 20D lens, enabling a more detailed examination and evaluation of peripheral retinal structures, and allowing dynamic observation through lens movement and scleral depression [18][17]. Furthermore, during ophthalmoscopy, the anterior segment of the eye can also be evaluated at the bedside. Notably, signs of anterior segment involvement, such as corneal ulcers or abscesses, or the presence of synechiae can be also detected, even if in a ward context [7]. In Figure 1, two examples from real-world fundus examinations conducted in infectious disease wards using a 20D lens are shown.
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Figure 1. Examples of two real-world fundus examinations conducted in infectious disease wards and photographed using a smartphone camera. (A) shows a severe case of necrotizing herpetic retinopathy at the posterior pole. (B) despite vitreous opacity, a wide area of retinal exudate with hemorrhage at the edges near the optic nerve can be recognized. The patient was ultimately diagnosed with systemic nocardiosis.

4. Principal Systemic Infections at Bedside

.1. Systemic Bacterial Infections

Within the scope of systemic bacterial infections, ocular fundus changes are infrequent, primarily due to the protection provided by the blood-retina barrier (BRB) [22,23][18][19]. However, ocular involvement should be considered in cases of severe systemic bacterial infections, especially among immunocompromised patients [24,25,26][20][21][22]. If an infection is promptly identified within the eye, clinicians may consider changing treatment strategies such as selecting an antibiotic capable of penetrating the BRB, particularly while awaiting confirmatory blood culture results [27,28][23][24].
In certain scenarios, the identification of systemic infections, such as endocarditis or TB, might initially surface during an ophthalmologic examination [29][25]. For example, in cases where endocarditis does not present clear valvular vegetations upon transthoracic echocardiography, ocular signs, such as Roth spots (retinal hemorrhages with a central white or pale center), could serve as initial diagnostic clues, encouraging further investigations such as transesophageal echocardiogram [30,31][26][27]. Similarly, in TB, choroiditis might provide early indications of the disease, especially when other systemic signs are subtle or gradually progressive.

4.2. Systemic Viral Infections

Ocular fundus examination could uncover underlying systemic viral infections and potentially severe health conditions, providing critical insights particularly relevant in immunocompromised populations [41,42][28][29]. In naïve HIV patients, retinal microangiopathy is commonly observed. It frequently presents as cotton wool patches, which are pale, fluffy lesions on the retina, caused by microinfarctions of the retinal nerve fiber layer due to obstructed retinal capillaries [43,44][30][31]. This manifestation is especially prevalent with decreased CD4 lymphocyte counts, serving as a potential marker for monitoring disease progression and severity. Additionally, viral infections such as CMV retinitis, present with distinctive retinal findings, including vascular-distributed, hemorrhagic, or granular retinitis, providing a diagnostic marker, especially crucial in contexts of immunosuppression, whether due to HIV or other etiologies like organ transplantation [45,46][32][33]. Herpes viruses can cause serious necrotizing conditions that affect the retina. In this context, necrotizing herpetic retinopathy (NHR) is a collective term for a group of diseases that cause acute retinal necrosis due to herpes viruses, encompassing conditions such as CMV retinitis, acute retinal necrosis (ARN), and progressive outer retinal necrosis (PORN) [55][34]. CMV retinitis typically occurs in immunocompromised individuals, such as those with AIDS or undergoing immunosuppressive therapy, and presents with a distinctive appearance often described as resembling “cottage cheese with ketchup”, primarily affecting the posterior pole. Vitritis is generally absent, but signs of periphlebitis may be present [56,57][35][36]. The primary treatment for CMV retinitis is antiviral therapy, commonly with valganciclovir. In contrast, ARN can affect both immunocompetent and immunocompromised individuals and usually begins in the peripheral retina. It can present with mild hemorrhages and is often accompanied by severe vitritis. ARN typically requires systemic antiviral treatment, such as aciclovir. It is often diagnosed in an outpatient setting, as inpatients may not exhibit systemic symptoms indicative of this condition. PORN, primarily seen in severely immunocompromised patients, particularly those with advanced AIDS, is characterized by rapid progression and extensive necrosis of the outer retina, often starting at the posterior pole. Unlike CMV retinitis, PORN does not typically present with significant intraocular inflammation, which is reflected in the minimal anterior chamber reaction and vitreous cell presence. The most common causative agent is the Varicella Zoster Virus (VZV), followed by HSV. Treatment for PORN includes aggressive antiviral therapy administered both intravitreally and intravenously, along with the management of disease sequelae, such as retinal detachment. Despite therapy, the visual prognosis for PORN remains poor [41,51,55][28][34][37]. A particular discourse warrants allocation to emerging viral diseases such as SARS-CoV-2, given the proliferation of case reports delineating varied retinal findings in the context of COVID-19 [58][38]. Observations have highlighted various retinal changes, including cotton wool spots, inner retinal optical coherence tomography (OCT) hyperreflective spots, and retinal microhemorrhages, suggesting the systemic impact of SARS-CoV-2 beyond respiratory complications. The occurrence of vascular occlusions such as Central Retinal Vein Occlusion (CRVO) and Central Retinal Artery Occlusion (CRAO), and conditions like Acute Macular Neuroretinopathy (AMN) and Paracentral Acute Middle Maculopathy (PAMM) further emphasize the potential ocular involvement in infected patients. That being said, there is still no clear evidence regarding specific findings in COVID-19 infection.

4.3. Systemic Fungal Infections

In the context of systemic fungal infections, which predominantly affect immunocompromised individuals, conducting an ocular fundus examination is generally recommended, particularly in high-risk patients such as those who are immunocompromised, receiving intensive care, or with long-term catheterization [61,62][39][40]. Ocular manifestations often start with retinitis, then extend to the vitreous and ultimately evolve into endophthalmitis. Hence, early detection of initial ocular involvement can deter the progression to a more severe condition. When a systemic fungal infection is identified, clinicians may initiate an empirical fungal treatment (e.g., Caspofungin) that strategically considers drug toxicity and pharmacokinetic properties [66,67][41][42]. However, ensuring optimal therapeutic outcomes has frequently involved a comprehensive assessment of the ocular fundus, especially since identifying ocular candidiasis dictates a pivot towards utilizing agents, such as Fluconazole, that traverse the BRB effectively [68,69][43][44].

4.4. Systemic Parasitic Infections

Parasitic incursions into the ocular milieu may emanate from a diverse array of organisms, including protozoa, nematodes, and cestodes, each engendering distinct pathological sequela within the ocular fundus [71][45]. Such pathologies, whether directly attributed to parasitic activity or indirectly mediated through host immune responses, pervade both the anterior and posterior ocular segments. The latter, which encompasses choroiditis, retinichoroiditis, retinal vasculitis, and additional deleterious conditions, warrants rigorous investigation to safeguard against irreversible retinal damage and concomitant visual impairment [72][46]. Ocular toxoplasmosis, commonly resulting from T. gondii, typically presents notable retinal findings such as a distinctive white focal retinitis with concurrent vitreous inflammation, often described as a “headlight in the fog” [73,74][47][48]. Alternatively, ocular toxocariasis, often stemming from Toxocara infestation, might display as granulomatous posterior uveitis, peripheral inflammatory masses, or even, in severe cases, retinal detachment [75][49].

5. When Assessing Ocular Fundus in Systemic Infections

5.1. The Evidence about Ophthalmoscopy in Systemic Fungal Infections

Generally, ophthalmologists have been routinely consulted in hospitals to screen for intraocular infections in patients with Candida bloodstream infections. This approach originated before the advent of systemic antifungal medications and before the establishment of clear definitions of ocular disease associated with candidemia. The Infectious Diseases Society of America (IDSA) and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) have provided insights into the role of fundus examinations in the context of candidemia [84,85][50][51]. The IDSA, in 2016, specifically recommends fundoscopy screening within the first week for all patients who test positive for fungal blood cultures, highlighting the potential ocular complications that can arise from candidemia. This proactive stance is driven by the fact that many patients with candidemia can be asymptomatic or may be too systemically unwell to report visual disturbances [84,85][50][51]. In stark contrast, ESCMID’s guidelines on the Diagnosis and Management of Candida Diseases make no explicit mention of ocular involvement, indicating a more conservative stance. The Royal College of Ophthalmologists (RCOphth) has also entered the discussion, collaborating with the Intensive Care Society to recommend fundoscopy screenings for Intensive Care Unit (ICU) patients with positive fungal cultures, emphasizing that such patients are more likely to be non-verbal and, therefore, less likely to communicate visual symptoms [86][52]. More recent recommendations by the AAO aimed at eliminating low-value care practices, which not only prove inefficient but may also pose risks to patient safety. The Academy’s position on routine screening for intraocular infections resulting from Candida bloodstream infections seeks to minimize unnecessary examinations and aligns with the evidence presented in various studies on endogenous Candida endophthalmitis.[1]

 5.2. A Decision Tree for Clinicians

While the significance of routine ophthalmoscopy remains a topic of discussion, various guidelines emphasize the necessity of a personalized approach. This approach should account for the distinct clinical conditions of each patient, while also staying aligned with the latest scientific consensus. Consequently, we have formulated a comprehensive set of criteria to delineate the specific scenarios where ocular fundus examination could impact patient outcomes. To begin, even if ocular symptoms are not readily apparent, practitioners should maintain a heightened level of vigilance for patients with systemic infections known for ocular involvement or possessing a notable propensity for dissemination, such as toxoplasmosis or CMV [52,77][53][54]. Firstly, even in the absence of ocular symptoms, a high index of suspicion should be reserved for patients where the systemic infection is notorious for ocular involvement or has a propensity to disseminate, e.g., toxoplasmosis or CMV [91][55]. It is advisable to categorize patients into risk strata, considering factors such as immunosuppression, prolonged hospitalization, or the presence of a central venous catheter which are commonly associated with systemic fungal infections. Secondly, the temporality and nature of ocular symptoms, within the framework of systemic infection, must be judiciously assessed. A decision tree for assessing the ocular fundus in inpatients with systemic infections is shown in Figure 2. Figure 2. The flowchart outlines the clinical process for evaluating and treating patients with suspected systemic infections. It includes guidelines on when to conduct an ocular fundus examination. To date, comprehensive data on the implications of ocular fundus examinations for inpatients with systemic infections remain sparse, especially in terms of understanding its diagnostic efficacy, impact on treatment modifications, and ultimate contribution to patient outcomes in a hospital setting. Further retrospective studies examining historical patient data could shed light on the clinical trajectories of inpatients undergoing fundus examination versus those who were not during systemic infections.

6. Patient Management after Ocular Fundus Examination

Depending on the findings of the examination, clinical strategies will differ depending on conclusive and inconclusive findings. In scenarios with inconclusive evidence, monitoring ocular symptoms could be useful to understand whether ocular fundus could be re-evaluated based on the patient’s progress and the efficacy of systemic interventions. On the other hand, in cases with conclusive evidence pointing towards specific pathologies, the therapeutic strategy might necessitate modifications. This could involve enhancing the systemic antimicrobial regimen or incorporating specific antiviral/fungal treatments. Moreover, active collaboration with ophthalmology specialists becomes paramount to crafting a comprehensive care pathway. The utility of ocular fundus examination in guiding patient management is a nuanced topic. In the context of bacterial infections, detecting ocular involvement might suggest a systemic dissemination of the infection. Yet, conventional treatments for bacterial infections typically involve broad-spectrum antibiotics. These medications would inherently address bacterial pathogens impacting the eye. Therefore, the presence of ocular involvement might not substantially alter the foundational approach to treating bacterial infections. However, if the systemic infection is controlled, prompt treatment of the eye is crucial. Early intervention can help prevent potential vision loss, underscoring the significance of considering targeted eye therapies in such cases, such as performing aqueous/vitreous taps for antibiograms or contemplating intravitreal antibiotic injections [9]. Concerning some viral infections such as CMV, ocular changes can be instrumental in dictating treatment modalities. Detecting CMV retinitis, particularly in immunocompromised individuals, could necessitate the introduction or adjustment of specific antiviral agents. This finding may also underscore the importance of evaluating and addressing the patient’s overall immunological status [47][56]. A flowchart about patient management after ocular fundus examination is shown in Figure 3, and it emphasizes an interdisciplinary methodology that integrates diagnostic insights with the broader clinical picture to optimize patient outcomes.
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Figure 3. The flowchart visualizes the decision-making process following an ocular fundus examination in patients with systemic infections.

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