Chronic Bilateral Dacryoadenitis Associated with COVID-19: Ocular Manifestations

The novel coronavirus disease (COVID-19), caused by SARS-CoV-2 infection, has been a serious global problem affecting human health since 2019. SARS-CoV-2 is a long-stranded RNA virus positive with an outer envelope surrounding the capsid made up of the nucleocapsid protein.

The envelope contains the spike (S) glycoprotein, which is currently the primary target of common messenger RNA (mRNA) vaccines against SARS-CoV-2. The critical routes by which SARS-CoV-2 enters the human body are droplet and aerosol infection through the nasopharyngeal route and the conjunctival route.

Ocular surface infections with SARS-CoV-2 likely allow the virus to be transmitted to the nasopharyngeal epithelium via the lacrimal sac. Therefore, pathological investigations related to COVID-19 infection of periocular tissues play a crucial role in better understanding how the virus spreads throughout the body.

According to a 2020 review article, the prevalence of ophthalmic manifestations in COVID-19 ranged from 2% to 32% in different countries. Conjunctivitis is a relatively important ocular manifestation in patients with COVID-19.

However, the frequency among patients is as low as that of other ophthalmic complications, such as retinal abnormalities, because tear films could participate in protecting the conjunctival epithelium against virus adherence. Furthermore, periocular manifestations related to COVID-19, including orbital cellulitis and dacryoadenitis, are extremely rare.

Angiotensin-converting enzyme 2 (ACE2) is a critical receptor through which SARS-CoV-2 preferentially attaches to somatic cells. Expression of angiotensin-converting enzyme 2 has been confirmed in SARS-CoV-2 transmissible sites, including the conjunctiva, pathologically verifying that the virus can adhere to the ocular surface.

Importance  

The pathological characteristics of ophthalmic sequelae of COVID-19 are important for gaining new insights in the treatment of patients.

Aim  

To examine the expression of SARS-CoV-2 nucleocapsid protein and angiotensin-converting enzyme 2 (ACE2) in the lacrimal gland tissues of a patient with COVID-19 and a patient without COVID-19.

Design, environment and participants  

In this retrospective case-control study, we analyzed the case of a 35-year-old woman with positive test results for SARS-CoV-2 who had had enlarged tear glands for 6 months. A 43-year-old woman without COVID-19 who had idiopathic chronic bilateral dacryoadenitis served as a negative control.

Main results and measures  

Histopathology and immunohistochemistry with anti-SARS-CoV-2 nucleocapsid protein and ACE2 in the lacrimal glands.

Results 

Both patients were Japanese women aged 35 years (case) and 43 years (control). The histopathological findings in the patient with COVID-19 demonstrated a marked infiltration of inflammatory cells, lymphoid follicles, and formation of germinal centers in the lacrimal gland.

The inflammation consisted mainly of lymphocytes and plasma cells with several polymorphonuclear leukocytes, where the lacrimal glands were atrophic. Of note, several lacrimal gland ducts markedly contained eosinophilic materials in the lumens, indicating glandular damage.

Immunoreactivity for the SARS-CoV-2 nucleocapsid protein was observed in inflammatory cells around the ductal epithelium of the lacrimal gland. Furthermore, strong expression of ACE2 was observed in the lacrimal gland.

In the patient without COVID-19, marked inflammation was noted in the lacrimal gland; however, there were no deposits of eosinophilic material in the ductal lumens. No SARS-CoV-2 nucleocapsid protein immunoreactivity was observed, while ACE2 was expressed in the lacrimal glands.

Discussion

This case-control study demonstrated clinicopathological findings of chronic inflammation of the lacrimal glands after SARS-CoV-2 infection. The pathological features in this study were a marked infiltration of lymphoid cells in the lacrimal gland tissue, where several polymorphonuclear leukocytes infiltrated the ductal epithelium and ductal lumens that were obliterated by eosinophilic materials.

In 2021, Dermarkarian et al 4 reported on a patient with COVID-19 infection who developed acute dacryoadenitis, in whom histopathological analysis of the lacrimal gland revealed thick secretion in the ductal lumen caused by glandular epithelial damage. In contrast, IgG4-related ophthalmic disease, a cause of chronic dacryoadenitis, did not clearly show glandular damage on histological findings.

In our case, the pathological findings of the lacrimal gland were similar to dacryoadenitis in the patient with COVID-19; that is, dacryoadenitis in patients with COVID-19 could be characterized histologically by glandular damage. Furthermore, no glandular damage was observed in the patient with COVID-19-negative dacryoadenitis tissue in this study; however, ACE2 was expressed in the ductal epithelium and lacrimal gland stroma in patients with and without COVID-19.

These results suggest that the lacrimal gland ducts could be a target for SARS-CoV-2 virus attachment. Anatomically, lacrimal tears are created in the acini of the lacrimal glands, which are secreted into the ocular surface through ducts. Theoretically, retrograde spread of SARS-CoV-2 in the tear film to the lacrimal gland could cause infectious dacryoadenitis.

It is indisputable that certain levels of copies of the SARS-CoV-2 virus were detected in tears in patients with COVID-19 regardless of ocular symptoms. Based on this pathological study, the pathogenesis of COVID-19-related chronic dacryoadenitis suggests retrograde spread of lacrimal tears exposed by SARS-CoV-2 to the ACE2-positive lacrimal gland.