Meibomian Gland Disease

Etiology

The most common type of MGD is the obstructive form, resulting from obstruction of the meibomian gland terminal duct. Obstruction occurs due to ductal epithelium hypertrophy, keratinization, and the viscous nature of meibum. The result is atrophy and dropout of the meibomian glands, thus decreasing secretion.

Meibomian gland atrophy and medication effects cause meibomian sicca. Atrophy of meibomian glands results in an overall reduction in functional meibomian glands. The underlying risk factors that can lead to MGD are:

• Age
• Androgen deficiency
• History of atopy
• Sjogren syndrome
• Steven-Johnson syndrome
• Psoriasis
• Acne rosacea
• Contact lenses
• Eyelid tattooing
• Systemic antibiotic use
• Medications like isotretinoin for acne, antidepressants, or hormone replacement therapy
• Topical medications like epinephrine, beta-blockers, prostaglandin analogs, and carbonic anhydrase inhibitors
• Chronic blepharitis
• Trachoma [8][9] 

The microbiome of the ocular surface also may play a role in MGD. Infestation of the follicle of the eyelash, the sebaceous gland of Zeis, and the meibomian glands by the Demodex mite affect the functioning of the meibomian glands. Studies reveal that nearly 50% of patients with MGD also have Demodex mite infestation.[10][11][12] Causes of cicatricial MGD are trachoma, erythema multiforme, and pemphigoid. Noncicatricial MGD is often associated with acne rosacea, atopic dermatitis, seborrheic dermatitis, and psoriasis.

Epidemiology

MGD is a globally prevalent disorder. In a meta-analysis by Hassanzadeh et al, the estimated global prevalence is 35.8%, with a higher incidence in men than women.[13] Asian patients have a higher incidence of MGD and meibomian gland dropout than White patients.[13]

Clinically, MGD presents as gland atrophy, obstruction, changes in meibum quality, and eyelid vascularity. Research by Alghamdi et al reveals that 59% of participants with MGD have at least 1 abnormal meibomian gland parameter, found most commonly in older male patients.[13]

While the meibum quality does not differ significantly between races, White patients exhibit more frequent eyelid vascularity abnormalities. A study conducted by Badian et al involving patients with subjective dry eyes reveals a 93.8% prevalence of MGD without significant age or gender differences.[13]

Pathophysiology

The classification of MGD depends on meibomian gland secretion. Low-delivery states are hyposecretory or obstructive, with further subdivision into cicatricial and noncicatricial subcategories. Patients with the hyposecretory form have abnormalities in meibomian glands without obstruction, while terminal duct obstruction causes the obstructive form. In the cicatricial form, the duct orifices are dragged posteriorly into the mucosa, whereas in patients with nonscarring MGD, the duct orifices remain normal. High-delivery states represent meibomian gland hypersecretion.

Low Delivery State Meibomian Gland Dysfunction

Obstruction is the most common cause of MGD.[5] The underlying pathophysiology is epithelial hyperkeratinization causing duct obstruction, meibum stasis, cystic dilation, acinar atrophy due to disuse, and gland dropout. Meibocyte differentiation and renewal also play a role. 

• Aging: Meibomian gland acinar epithelial cell atrophy and decreased lipid production occurs with aging. These changes are likely due to reduced differentiation and cell renewal of meibocytes, decreased meibomian gland size, and increasing infiltration of inflammatory cells. The downregulation of peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor protein that regulates meibocyte differentiation and lipid biosynthesis, correlates with these changes.

• Environmental stress: Low-humidity environments cause increased cellular proliferation and turnover to increase meibum production. The long-term result may be ductal dilation and a decrease in the number of functioning meibocytes, causing gland atrophy and hyposecretion. Poorly functioning meibocytes lose the ability to remove protein from the meibum, altering the protein-to-lipid ratio. Meibum becomes viscous, disrupting the stability of the tear film. Like the cornea, aging and environmental stress over time cause the depletion of meibocyte stem cells. 

• Hormonal effects: Androgens stimulate meibum secretion and suppress inflammation, while estrogens tend to increase inflammation. Androgen-depleted states, such as patients using antiandrogen agents, those with complete androgen insensitivity syndrome, and Sjögren syndrome, may lead to the development of MGD.

• Medications: Both systemic and topical medications contribute to the low-flow form of MGD. Medications like β-blockers and carbonic anhydrase inhibitors used for glaucoma cause decreased acinar area, acinar density, and homogenous acinar wall morphology. Topical epinephrine results in hyperkeratinization of the duct epithelium, leading to meibomian gland plugging and dilation. Retinoic acid binds to nuclear receptors and changes in gene transcription. The volume of acinar tissue decreases, inhibiting the maturation of lipid-laden meibomian acinar cells.

• Microbiome: Cholesterol esters in the meibum stimulate the growth of some bacteria on the margin of the eyelid. Staphylococcus epidermidis, Staphylococcus aureus, and Propionibacterium acnes are most commonly involved. These bacteria produce lipolytic enzymes and release inflammatory mediators, causing lipolysis in the tear film and loss of tear film integrity.[14] The instability of the tear film causes increased evaporation of the aqueous layer and hyperosmolarity.[15] Changes in the tear film's flora also lead to the release of toxins, which result in eyelid inflammation.

• Contact lens use: Contact lenses result in irreversible meibomian gland dropout. The exact pathophysiology is poorly understood, but the proposed mechanisms are mechanical trauma, plugging due to aggregation of desquamated epithelial cells at gland orifices, and chronic inflammation.

• Congenital: Patients may be born with a decreased number of or absent meibomian glands. These changes may be present in patients with Turner syndrome, ectrodactyly with ectodermal dysplasia and cleft lip and palate (ECC syndrome), and anhidrotic ectodermal dysplastic syndrome. Patients with distichiasis have an extra row of eyelashes from the meibomian glands. Congenital distichiasis can occur in isolation or as part of a syndrome.

• Neoplastic: In addition to sebaceous gland tumors of the eyelids, chemotherapy, radiation, biological therapies, and hormonal therapies all contribute to MGD in patients with various malignancies. 

High Delivery State Meibomian Gland Dysfunction

The characteristic feature of the high delivery state of MGD is the release of a large lipid volume at the lid margin. Seborrheic dermatitis and acne rosacea are 2 common causes of high-delivery MGD.

Histopathology

Histopathological examination by Gutgesell et al in patients with MGD reveals obstructed and dilated ducts, enlarged acini with cystic degeneration, increased inflammatory cells, and abnormal keratinization. Additional findings are squamous metaplasia and granulation tissue formation.[16] 

In another study by Obata et al, a similar examination during the autopsy on 83 patients reported changes such as cystic dilatation of ducts and acini, thickening of the basement membrane, acini atrophy, granuloma formation, and lipogranulomatous inflammation.[17] 

History and Physical

Most patients with MGD are asymptomatic, and the degree of symptoms does not directly correlate with the amount of ocular damage. Common symptomatic complaints are dry eyes, a foreign-body sensation, photophobia, eye pain, and conjunctival injection.[2] Other potential findings are decreased visual acuity, excessive tearing, and bulbar hyperemia. Eyelid margin telangiectasia may be visible. In normal cases, meibum is clear and easily expressed; however, patients with MGD typically have opaque and viscous meibum. 

Evaluation

Clinicians diagnose MGD through a clinical examination. To aid in detecting asymptomatic MGD, all patients presenting for an eye examination should ideally undergo a rating of the expressibility and texture of the meibum by applying moderate pressure over the lower lid. Efron, in collaboration with CooperVision, developed a grading scale from 0 to 4 for MGD that describes the appearance of the eyelid margin and meibomian gland orifices as well as the presence of tearing and bulbar conjunctival redness:

• Grade 0: A pale eyelid margin, meibomian gland opening visible
• Grade 1: A pink margin, cloudy expression at some gland orifices
• Grade 2: A red margin, milky expression at gland orifices, increased tearing
• Grade 3: A red eyelid margin, yellow and continuous expression at all gland orifices (see Image. Lower Eyelid Frothing)
• Grade 4: A red eyelid margin, thick yellow and continuous expression at all gland orifices, and bulbar conjunctival redness [18]

A symptom questionnaire is helpful for symptomatic patients in quantitatively measuring symptoms resulting from MGD. Paugh et al developed a specific questionnaire using psychometric approaches among noncontact lens wearers.[19] Additional symptom assessment questionnaires include the Ocular Surface Disease Index (OSDI) and the Dry Eye Questionnaire (DEQ).[20] Following questionnaire administration, symptomatic patients should undergo a slit-lamp examination, including the following based on availability:

• Evaluation of lid morphology: Meibography using either a transillumination technique, in which the clinician everts the eyelid over a light source or an infrared video camera, to look for lid margin irregularities, pouting or plugging of the orifices, vascular engorgement, and changes in the mucocutaneous junction.[21] Note any evidence of eyelid thickening, dimpling, notching, pitting, tenderness, ridge formation between the meibomian glands, or distichiasis.[22] Meibography was first described by Tapie in 1977, using UV Wood's light to fluoresce the meibomian ducts on biomicroscopy and infrared light to illuminate the meibomian glands.[23] This imaging technique is helpful for direct in vivo visualization of the morphology of meibomian glands (see Image. MGD on Meibography). Meibography methods have evolved to include infrared meibography, visible light transillumination, laser confocal meibography, and optical coherence tomographic meibography. An example of one such system is the LipiView analyzer (Johnson and Johnson), which uses interferometry or specular reflection and allows high-resolution images of the lipid layer.[24] The average lipid layer thickness is 60 nm. A thin lipid layer is characteristic in patients with MGD and often corresponds to symptoms. Results of meibography are measured using the meiboscore, meibograde method, and Pult scale. The meiboscore for each eye's upper and lower lids is calculated separately and graded from 0 to 3; thus, a total score out of 6 is given for each eye.[25] The scoring is based on the following points:
  • The lid has partial or missing glands
  • The affected lid area is <33%
  • The affected lid area is 33% to 66%
  • The affected lid area is >66%

• Expressibility from the meibomian gland openings: Meiobiam gland openings should be patent with the expression of clear fluid.[26] Note the number of functional glands, obstructive capping or plugging, and the color and consistency of the meibum. Transillumination through everted eyelids or infrared photography detects meibomian gland dropout. 

• Calculate the blink rate and note the pattern of blinks.

• Tear film volume: The tear meniscus should be >10 mm [27]

• Tear osmolarity: Hyperosmolar tears are irritative to the ocular surface.

• Tear film break-up time: Fluorescein stain in the eye measures tear film stability. Patients are asked not to blink, and a slit-lamp visualizes the tear film. The green tear film should initially appear smooth. The patient's tear film is abnormal if blue gaps develop in less than 10 seconds. The tear film break-up time (TFBUT) of 15 to 45 seconds is normal, 10 to 15 seconds is borderline, and less than 10 seconds is abnormal.

• Schirmer test: This test quantifies the number of tears produced by each eye using Whatman number 41 strips, measuring 5 mm wide and 35 m long. Results are measured as the millimeters of tears collected over 5 minutes. Despite its common usage, this test yields variable results. Normal values typically range around 15 mm, while 5 to 10 mm is considered borderline, and <5 mm is classified as abnormal.

• Conjunctival and corneal staining: Fluorescein staining is utilized to assess the continuity in the corneal surface. Lissamine green or Rose Bengal staining highlights the dead and devitalized epithelium in the cornea.

• The Fluorescein clearance test: Detect residual fluorescein 15 minutes after instilling a drop of 2% fluorescein in the culdesac.

• Interferometry: Infererometry assesses the tear film lipid layer.

• Mass spectrometry: Looks for the presence of inflammatory cell markers and provides information regarding the overall ocular surface inflammatory status. 

Positive results on the patient symptom questionnaire, measurement of tear osmolarity, TFBUT, and conjunctival and corneal staining provide evidence of dry eye disease (see Image. MGD Induced Dry Eye Sequelae). To differentiate between evaporative dry eye disease and low flow MGD, measuring tear flow, tear meniscus height, or performing a Schirmer test is necessary. If the diagnosis of MGD remains unclear, quantifying morphologic lid features, meibum expressibility, and quality and conducting meibography to quantify gland dropout is essential.

Various imaging devices are available to evaluate the meibomian glands, many combining meibomian gland imaging with an ocular surface and adnexa evaluation. One such device combines infrared meibography with noninvasive TFBUT measurement, tear meniscus height assessment, interferometry, and conjunctival redness evaluation. Another device combines infrared and visible light transillumination imaging of the meibomian glands combined with interferometry and analysis of blink dynamics, including the number of incomplete blinks.[28]

MGD staging is based on symptoms, expressibility and secretion from the meibomian glands, and corneal staining (see Table 1. Staging of Meibomian Gland Dysfunction).[4]

Table 1. Staging of Meibomian Gland Dysfunction

Several studies, including the Dry Eye Assessment and Management (DREAM) study, attempted to interpret meibography images by categorizing morphological features of meibomian glands.[29]  Earlier studies identified meibomian gland tortuosity as an indication of MGD and upper eyelid meibomian gland tortuosity as a predictor of contact lens dropout.[30]  

Halleran et al developed a scale for meibomian gland tortuosity:[30]

• 0: no tortuous MGs
• 1: <25% tortuous MGs
• 2: 26% to 50% tortuous MGs
• 3: 51% to 75% tortuous MGs
• 4: >75% tortuous MGs

Investigators in the DREAM study identified 11 additional morphological features in addition to shortening and tortuosity.[29] These features were then assigned a severity score on a scale from 0 to 10, with 0 being the lowest severity and 10 the highest:

• Shortening (10.0)
• Tortuosity (2.67)
• Distorted (0.67)
• Hooked (4.00)
• Drop out (10.0)
• Thickened (4.67)
• Thinned (4.33)
• Overlapping (2.67)
• Ghost (8.0)
• Tadpoling (3.67)
• Abnormal gap (3.67)
• Fluffy areas (5.67)
• No extension to the lid margin (5.0)

Establishing a correlation between these scales and dry eye parameters is an active field of investigation.[31][32] This is crucial for refining diagnostic and treatment approaches for meibomian gland dysfunction.

Treatment / Management

Treatment for MGD is defined based on the signs and symptoms. The International Workshop on MGD describes treatment based on the stage of the disease.[33] 

• Stage 1 
  • Patients should optimize their work and home environment and avoid excessive screen time and direct exposure to wind, as these factors can increase the tear film evaporation rate.[34]  Regular eyelid compresses with warm water for a minimum of 4 minutes, once or twice daily, followed by a firm massage to express inspissated secretions, is a beneficial treatment. Additionally, increasing dietary omega-3 fatty acid consumption is recommended.[35][36] 
  • Artificial lubricants, topical antibiotics like azithromycin, and emollient or liposomal spray may be considered case-to-case. The topical 1.0% ophthalmic solution of azithromycin is a broad-spectrum, macrolide antibiotic with anti-inflammatory properties. Oil emulsion tear substitutes improve the lipid layer thickness and overall tear film stability.[37] Oral tetracyclines have also demonstrated clinical improvement due to their anti-inflammatory effects.
(A1)

• Stage 2 
  • Patient education is essential at each stage, emphasizing the influence of diet, home, or work environment on tear evaporation. Encouraging frequent blinking, particularly during activities like reading or computer use, is recommended. Additionally, discuss strategies for minimizing exposure to air conditioning or heating while suggesting using humidifiers in the bedroom or any space where the patient spends much time.
  • Evaluate the influence of medications taken for other systemic conditions. In this stage, warm compresses and lid expression are generally effective. Warm compresses directly heat the lid margins, melting altered meibomian secretions and providing symptomatic relief with regular treatment adherence.[33]
  • After warm compresses, digital massage of the lids facilitates the expression of thicker meibum from the glands. This manual expression clears meibomian gland duct blockages, enabling the glands to produce normal secretions. Encourage patients to maintain regular lid hygiene through warm water lid scrubs, with or without local shampoo application.[33] Emphasize cleaning the base of the eyelashes behind the lid margin to reduce bacterial load and clear meibum, thereby minimizing inflammation.

• Stage 3 
  • In addition to the treatments mentioned above, topical anti-inflammatory medications should be considered for treatment at this stage.[38][39] Lubricant eye ointment at bedtime provides symptomatic relief.
(B2)

• Stage 4 
  • The addition of additional anti-inflammatory medications is necessary in stage 4. Topical anti-inflammatory eye drops like 0.05% cyclosporine A, topical N-acetylcysteine, lifitegrast 5%, and topical steroids like loteprednol etabonate have shown to be beneficial in reducing inflammation in stage 4 MGD.[39] A selective nicotinic acetylcholine receptor agonist, varenicline, stimulates the trigeminal parasympathetic pathway in the nasal mucosa, leading to goblet cell degranulation and stimulation of meibomian gland and lacrimal gland secretions. This promotes all 3 layers of the tear film, including meibum production.[40]
(B2)

Surgical Treatment

In some patients with severe MGD, when conservative management is ineffective, mechanical opening of the terminal ducts and meibum expression may be necessary. Probing or electronic heating devices facilitate the mechanical opening of blocked ducts or assist in meibum expression by applying heat.

Intraductal Probing

Intraductal probing is a slit lamp procedure involving the mechanical opening and dilatation of the blocked meibomian gland orifices and ducts.[41] Initially, 1 to 2 mm Maskin probes penetrate the gland orifices, followed by 4 to 6 mm probes to achieve ductal patency. Probing helps by releasing the meibum, opening the blocked ducts, and improving the effectiveness of topical medications. The treatment improves TFBUT, meibum lipid levels, viscosity, lid margin abnormalities, conjunctival hyperemia, and overall patient symptoms.[42] (B2)

Syed and Sutula describe a modified technique of probing done against resistance that is beneficial in a subset of patients.[43] This method involves holding the lid with forceps and pulling in a direction opposite the movement of the probe.

Electronic Heating Devices

Heat helps by locally raising the temperature of the eyelids, melting the inspissated meibum.[6] In MGD, the altered meibomian composition leads to an increased melting point. Increased eyelid temperatures decrease the meibomian lipid viscosity while increasing the lipid levels of the tear film.

Several electronic heating devices are now available on the market, with LipiFlow (Johnson and Johnson) being widely used and effective. This device delivers heat simultaneously to the palpebral conjunctiva of both upper and lower lids. Concurrently, it also helps express meibomian gland content by providing pressure to the outer eyelid surfaces in a pulsatile manner. Interferometry studies reveal improved meibomian gland secretion, TFBUT, and increased lipid layer thickness.[44] Furthermore, decreased bulbar congestion and symptomatic relief have been reported.[45][46] However, patients must have at least 6 open meibomian glands in the lower lid to achieve effectiveness.[4] (A1)

The Systane iLux and Systane iLux MGD Thermal Pulsation Systems (Alcon) are handheld devices that enable the operator to visualize the expression of the meibum while applying heat and pressure to the meibomian glands. This system has demonstrated efficacy comparable to that of LipiFlow.[47](A1)

The MiBo Thermoflow (MIBO), another electronic heating device model, utilizes an external paddle heated to 42.2 °C and is applied with a gel buffer to the eyelids.[48] This method effectively targets the meibomian glands, aiding the liquefaction of obstructed meibum and promoting tear film stability.(A1)

Intense Pulse Laser Therapy

Intense pulse laser therapy uses a light source that generates wavelengths from 500 to 1200 nm.[49] When applied through the skin, these waves are absorbed by the blood vessels near the skin's surface, leading to local heat generation and coagulation, causing vessel thrombosis.[50] As a result, patients experience decreased redness due to abnormal telangiectatic vessels and bacteria elimination from the treated area.

Intranasal Tear Neurostimulation

Neurostimulation utilizes neural pathways connecting the nasal mucosa to structures that maintain the tear film. Stimulation of the anterior ethmoidal nerve with the help of intranasal prongs results in increased tear volume, decreased tear osmolarity, and improved lipid and protein concentrations.[51] Patients undergo treatment 3 minutes daily for 3 weeks for optimal benefit. 

Targeted Therapy

Targeted treatment may be necessary based on the specific condition associated with MGD, such as plus disease. Common examples of therapy include:

• Pulsed dose of steroids with ocular surface disease
• Steroids for phlyctenular keratitis 
• Epilation or cryotherapy for lash trichiasis 
• Intralesional steroids or incision and curettage for patients with a chalazion 
• Lid hygiene, warm compresses, topical antibiotic for anterior blepharitis 
• Tea tree oil scrubs for Demodex mite infestation 

Differential Diagnosis

The differential diagnoses that mimic meibomian gland disease include diseases that cause eyelid inflammation, conjunctival congestion, or dry eyes. These include the following:

• Staphylococcal anterior blepharitis: Characterized by hard eyelash deposits, loss of eyelashes, and distorted lashes or trichiasis, staphylococcal anterior blepharitis is often associated with ulceration or notching of the lid margin. Other related signs include dry eyes, punctate erosions, vascularization, and infiltration of the cornea. Affected patients commonly have atopic dermatitis.

• Seborrheic anterior blepharitis: This condition, associated with seborrheic dermatitis, is characterized by soft deposits, with or without the loss of distorted eyelashes. Other signs include dry eyes, punctate erosions, vascularization, and corneal infiltration.[7]  

• Demodex blepharitis: Cylindrical dandruff-like scaling or collarettes around the base of eyelashes characterize this condition, and the mites are visible under high slit lamp magnification.[52] 

• Evaporative dry eyes: Patients experiencing evaporative dry eyes exhibit irritation, a burning or stinging sensation, fatigue, blurred vision, intolerance to bright light, and discomfort with contact lenses. Clinical examination reveals decreased Schirmer's and TFBUT scores and reduced tear film height. Ocular study findings include corneal punctate epithelial erosions and positive conjunctival and corneal staining. Severe dry eyes may be associated with autoimmune diseases like Sjogren syndrome, rheumatoid arthritis, systemic lupus erythematosus, or diabetes.[53]

• Conjunctivitis: Conjunctivitis presents with redness, watering, lid edema, and intolerance to light. Signs include diffuse congestion, follicles, papillae, and matted eyelashes with or without corneal punctate epithelial erosions.

• Cicatricial conjunctivitis: Cicatrical conjunctivitis is a chronic conjunctivitis with conjunctival fibrosis. Potential causes are Stevens-Johnson syndrome, mucous membrane pemphigoid, and thermal or chemical burns.[54] 

• Contact lens-related keratoconjunctivitis: This condition presents with red, irritated eyes and is more common in patients who sleep in their contact lenses. When keratitis is significant, visual acuity is affected.[55]

• Keratitis: Neurotrophic, filamentary, interstitial, and contact lens-related corneal inflammation forms can compromise the cornea, leading to erosion, ulceration, infiltrates, or scars. Such conditions may result in reduced vision.[55]

Prognosis

The prognosis depends on the disease stage and patient compliance with the prescribed treatment. Daily eyelid hygiene, maintaining humidity in the surroundings, adequate hydration, regular lubrication, frequent blinking, and using sunglasses to shield the eyes from direct wind or sunlight are practical measures to prevent the worsening of MGD and associated evaporative dry eye symptoms. Early-stage MGD can be managed with topical medications alone and may be reversible with good patient compliance.[55]

Interventions such as probing, thermal heating devices, or intense pulsed light therapy may be necessary in advanced stages. Severe dry eyes can result in blurred vision, an inability to wear contact lenses, headaches, corneal keratinization, scarring, or corneal ulcers. Effective treatment and follow-up are crucial to prevent profound, vision-threatening complications in patients with MGD.

Complications

MGD can lead to severe evaporative dry eye disease symptoms when not treated correctly in the early stages. In addition, patients may experience inflammation of the eyelids, further predisposing them to bacterial infection, increased redness of eyelid margins, and unsatisfactory tear film quality. Demodex infestation is another complication in untreated MGD cases.[56] While treatment of MGD shows that gland regeneration is somewhat possible, the consensus is that meibomian gland loss is only partially reversible, and lack of treatment results in meibomian gland dropout and permanent loss in most cases.[57][58]

In advanced cases, corneal keratinization begins, which can be progressive and challenging to reverse with topical medications. Dilatation of acini leads to atrophy of meibomian gland ducts and the glands themselves over time. Restoring normal function to the glands is difficult.

Particular caution is necessary for patients with MGD planning on cataract surgery or any other intraocular procedure. Studies show that patients with MGD who undergo cataract surgery are at an increased risk of persistent dry eyes and meibomian gland dropout. These patients are also at risk of penetration of infection from the periocular surfaces when undergoing an intraocular procedure. For this reason, a detailed examination of the eyelids or associated dry eyes is of the utmost importance when examining a patient with a cataract to avoid severe complications like endophthalmitis.[59]

Topical antibiotic ointment with lid hygiene may be sufficient to prevent grave complications like endophthalmitis in patients with MGD. Prolonged topical corticosteroid use may cause elevated intraocular pressures or cataracts. Patients should use alternative regimens and undergo close monitoring to prevent further complications.