The Ultimate Guide to Conjunctivitis Differential Diagnosis

Nov 10, 2021
101 min read
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“Pink eye” is one of the most common complaints eyecare providers encounter. This is not surprising considering “pink eye” is a catch-all term used to describe red, watery eyes. Likewise, conjunctivitis, the clinical term for “pink eye” is also a broad classification that encompasses many different conditions with varied underlying causes but similar signs and symptoms. Conjunctivitis affects nearly six million people annually in the U.S.1 and accounts for about 1% of all primary care visits and 28% of ER visits.2,3

Clinical presentation

Conjunctivitis specifically refers to the inflammation of the bulbar and palpebral conjunctiva of the eye. This inflammation results in varying degrees of injection and edema, which gives “pink eye” its classic reddish-pink, swollen appearance and is often accompanied by some form of discharge.4 The underlying causes of conjunctivitis vary and include infectious etiologies such as bacterial, viral, fungal, and parasitic infections as well as noninfectious causes like allergies, inflammatory conditions, and mechanical irritation.

Accurately diagnosing the specific cause of conjunctivitis has been shown to be a challenge for providers, as 80% of cases of infectious conjunctivitis are treated with antibiotics, while only 30% of cases are truly bacterial in nature.5 However, while the different forms of conjunctivitis may present in similar fashions, there are key differences, although sometimes subtle, that help differentiate them.

It is critical for eyecare providers (ECPs) to identify these differences quickly and accurately, as the treatments for the various forms of conjunctivitis can differ significantly. Fortunately, there are several hallmark features that make delineating the different causes of conjunctivitis relatively straightforward.

Conjunctivitis can be caused by many underlying factors, but all forms tend to share the basic presentation of red, irritated eyes, with some form of discharge as seen in Figure 1.

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Figure 1

Making a diagnosis

Although all forms of conjunctivitis may appear similar at a superficial level, a careful history and thorough examination will often be all that is needed to determine the exact underlying cause.

Two key pieces of information will allow ECPs to quickly categorize the nature of the condition.

1) Is the patient experiencing any discharge?

  • If so, is it watery, mucoid, or stringy or ropey?
  • What color is the discharge?

2) Is there a reaction of the palpebral conjunctiva?

  • Are papillae present?
  • Are follicles present?
  • Is there a mixed reaction?

These two pieces of information–the quality of discharge and type of palpebral reaction present–will allow providers to broadly categorize the conjunctivitis as bacterial, viral, or allergic in nature, and by adding a few additional pieces of information an even more specific diagnosis can be made.

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If the patient is experiencing watery discharge with a follicular reaction, that points to a viral cause. If the discharge is more mucopurulent and is yellow-green or brownish in color along with a papillary reaction, then it is likely bacterial in nature. And if the discharge is ropey and clear with papillae, then it is likely allergic in origin, which is confirmed by the presence of itching (usually absent in other forms of conjunctivitis). However, if the patient is displaying mucoid discharge with a follicular or mixed reaction, this suggests a more systemic bacterial infection, such as chlamydia.

While the patient’s history and a few targeted questions can often broadly categorize the nature of the conjunctivitis between infectious and noninfectious, and even viral, bacterial, or allergic, clinical exam findings and pertinent patient history will provide the information required to make a specific diagnosis.

Some of the more important elements to examine include:

1) How long has the condition been going on?

  • Is it acute or chronic?

2) Is there corneal involvement? If so, what does it look like?

  • Are the lesions dendritic? Infiltrative? Ulcerative?

3) Are the lids or lashes involved?

  • Are there any lesions on the eyelids?
  • Is there any debris or discharge present on the lashes?

4) Are the lymph nodes swollen?

5) Are there any systemic symptoms?

  • Does the patient have a fever?
  • Does the patient have a rash?

6) Is the patient a contact lens wearer?

  • Do they sleep in their lenses?
  • Do they swim in their lenses or rinse them with tap water?

These additional pieces of information in conjunction with the previous broad categorization will greatly narrow the possible causes of a case and often lead to a specific diagnosis, such as a herpetic infection or contact lens-induced conjunctivitis.

There are diagnostic tests on the market that aid in differentiating the causes of conjunctivitis, including the QuickVue Adenoviral Conjunctivitis Test (Quidel), which can determine if the condition is viral in nature. While tests like these can be helpful, they may be impractical to perform in the midst of a busy clinic. Therefore, by understanding the key similarities and differences between the different forms of conjunctivitis ECPs can quickly and accurately diagnose the cause of a patient’s condition and initiate the appropriate treatment.

Included below are the broad categories of conjunctivitis such as bacterial, viral, fungal, and parasitic conjunctivitis, in addition to noninfectious forms such as allergic, inflammatory, and mechanical. These are further broken down into specific forms of conjunctivitis with a description of the hallmark signs and case history that differentiates each type.

Bacterial conjunctivitis

Overview

Bacterial conjunctivitis (BC) is the second leading cause of conjunctivitis in adults, and accounts for an estimated 30% of cases.6,5 BC primarily occurs in the winter and spring months.7 It tends to be more common in children than adults, as it accounts for 50-70% of cases of pediatric conjunctivitis.7 The hallmark sign of BC is mucoid or mucopurulent discharge, which is often colored (creamy-white or yellow-green to brown).8 In addition to eye redness, patients will typically report mild to moderate irritation or pain and light sensitivity, but discharge is routinely the main complaint as these patients will often report waking up with their eyes “crusted shut”.

Patients will also display a papillary reaction, and occasionally lid edema or chemosis. It is recommended that all cases involving copious, purulent discharge be cultured.9 There are numerous potential bacterial species that can cause conjunctivitis, but two of the most common are Haemophilus influenzae (a gram-negative bacterium), especially in children, and Staphylococcal species (gram-positive bacteria), which are more common in adults.10,11 The most common bacteria responsible for acute bacterial conjunctivitis include Haemophilus influenzae, Streptococcus pneumoniae, Pseudomonas aeruginosa, Neisseria gonorrhoeae, and Neisseria meningitides.11-13

Staphylococcus aureus and Moraxella lacunata are most frequently responsible for chronic bacterial conjunctivitis.14 Other potential bacterial species that are less commonly encountered include Streptococcus, Moraxella catarrhalis, Chlamydia trachomatis, Corynebacterium diphtheriae, and Mycobacterium tuberculosis.12,15,16

There are several potential avenues by which a bacterial infection can develop, such as touching an object or surface contaminated with bacteria and then touching or rubbing the eyes. Likewise, sharing contaminated towels, bedding, or makeup can also result in inoculation.7 Contact lens wearers are at greater risk of developing BC due to potential contamination of the lens, lens case or fingers when inserting or removing the lens.17 Another route of infection to be aware of, especially in younger adults, is oculo-genital contact that may occur during sexual activity.9

In other cases, bacterial infections arise from an overgrowth of normal microflora or transmission of bacteria between the sinuses and nasal mucosa to the conjunctiva.18 Acute cases of BC can develop within hours to days, while chronic forms take 2-7 days to develop and last at least 4 weeks.7,14

While most cases of BC are self-limiting and resolve in 1-2 weeks,6 some hyperacute forms involving particularly virulent bacteria pose significant risk and require urgent treatment.6 The use of topical antibiotics is helpful in quickening resolution and alleviating symptoms. A wide array of antibiotics can be utilized depending on the suspected organism responsible for the infection, though broad-spectrum antibiotics, such as fourth generation fluoroquinolones, are recommended to cover against a wide range of pathogens. Patients are also encouraged to launder all bedding and towels, discard any makeup, and dispose of contact lenses, lens cases, and solutions if the patient is a contact lens wearer.

As Figure 2 demonstrates, bacterial conjunctivitis is characterized by redness, papillae, and mucopurulent discharge.

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Figure 2

Acute bacterial conjunctivitis

Acute bacterial conjunctivitis can be caused by a number of bacterial species. The most common causes in children are H. influenzae, S. pneumoniae, and Moraxella catarrhalis.11 In adults, Staphylococcal species and Streptococcus pneumoniae are more common, with H. influenzae a potential culprit as well.11 Acute BC is relatively uncommon in adults and is much more likely in children.7

The typical signs and symptoms of acute BC include papillae on the palpebral conjunctiva, a scant to moderate amount of colored discharge, and mild to moderate irritation or pain and photophobia. Patients will often report waking up with their lids “crusted shut” and residual discharge may be noted on the lashes and lid margin as well.

These cases of conjunctivitis are usually self-limiting and resolve within 7-10 days;7 however, treatment with topical antibiotics can speed resolution and help alleviate symptoms.6 There are numerous antibiotics that can be successfully used to treat the condition and many broad-spectrum antibiotics are equally efficacious, so the antibiotic chosen often comes down to the suspected underlying pathogen, medication cost, availability, dosing, and any allergy concerns.

Polytrim (polymyxin B/trimethoprim) dosed QID for 7 days is an excellent option, especially for children, as are fluoroquinolones such as ciprofloxacin 0.3%, ofloxacin 0.3%, and moxifloxacin 0.5%, which have broad coverage and are also dosed QID for 7 days. These antibiotics have good coverage against both gram-positive and gram-negative bacteria, such as Staph and H. influenzae respectively, as well as relatively low dosing frequency which makes them appropriate first-line treatments.

If a significant amount of inflammation is present, a soft steroid, such as loteprednol etabonate 0.5%, dosed BID-QID for 7 days can also be used. Bacitracin or ciprofloxacin 0.3% ointment can also be used QHS as adjunct therapy to increase contact time with the ocular surface. Patients should also wash all bedding and towels and discard any makeup. It is important to note if the patient is a contact lens wearer, they should discontinue contact lens use and dispose of their lenses, lens case, and solution as each may be a potential source of contamination.

These patients should also be treated with a broad-spectrum antibiotic with good gram-negative coverage, ideally a fourth-generation fluoroquinolone, like moxifloxacin 0.5%, as they are at a higher risk of pseudomonas infection, which poses a risk to the cornea including ulceration and perforation if left untreated.19

Many consider steroid use contraindicated in the presence of infection, due to the risk of prolongment and potential worsening of the condition. However, it has been shown that when topical steroids are used for a short duration (2 weeks or less) in the treatment of bacterial conjunctivitis, these concerns are primarily theoretical and topical steroids can be used safely and effectively.20 However, if there is any sign of corneal ulceration or if the patient is a contact lens wearer, topical steroid use should be avoided.

Additionally, most cases of bacterial conjunctivitis are relatively mild, so the use of a steroid will rarely be needed. But if significant chemosis or inflammation is present, and the patient is highly symptomatic, topical steroids can be an effective adjunct therapy.

As seen in Figure 3, he discharge present in bacterial conjunctivitis is often colored rather than clear and can appear creamy-white, yellow-green, or brown

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Figure 3

Chronic bacterial conjunctivitis

Chronic bacterial blepharitis is often caused by an overgrowth of normal microflora, such as Staph bacteria. The most common causes of chronic BC are Staphylococcus aureus (and other Staph species), Moraxella lacunata, and enteric bacteria.14 These cases of conjunctivitis persist for 4 weeks or longer.14 Chronic cases may display less discharge than acute cases, but patients will often report persistently red eyes, a gritty or foreign body sensation, and crusting of the lids and lashes (scurf or debris will often be observed), especially upon waking.

A papillary reaction is also usually present. In cases of infections due to Staph bacteria patients frequently describe a burning sensation, often at the corners of the eyes. This may be due to bacterial exotoxins pooling and draining at the puncta, as the Staph bacteria that normally exist on the lids and lashes release exotoxins and waste onto the ocular surface. Cases of Staphylococcal blepharoconjunctivitis are considered noninfectious, as they are caused by the overgrowth of normal microflora (as opposed to the presence of a foreign organism).

Another sign that helps differentiate Staph conjunctivitis from other forms of conjunctivitis is the presence of saponification of the tear film. Staph bacteria produce lipases that break down the lipid layer of the tear film and give the tears a “frothy” or “foamy” appearance.21 These cases have a strong inflammatory component, so the use of a topical antibiotic-steroid combination drop such as TobraDex (dexamethasone 0.1 %/tobramycin 0.3 % ophthalmic suspension) or Zylet (loteprednol etabonate 0.5 %/tobramycin 0.3 % ophthalmic suspension, Bausch & Lomb) dosed QID for 7 days can be an excellent choice. Also, as these cases are noninfectious, the use of a topical steroid is safe in addition to being effective. While the use of a topical combination drop can successfully clear the signs and symptoms of staph blepharitis in the short-term, the condition will also require long-term treatment due to its chronic nature.

The use of hypochlorous acid sprays, such as HyClear (hypochlorous acid 0.01%, Contamac) or Avenova (hypochlorous acid 0.01%, NovaBay Pharmaceuticals) applied twice daily is the treatment of choice in these cases as it directly addresses the underlying cause of staph conjunctivitis. Hypochlorous acid is produced by the leukocytes of the immune system naturally, and it carries antiseptic and anti-inflammatory properties22 and is safe for long-term use. Application of hypochlorous acid to the lids and lashes kills the Staph bacteria present, reducing the bacterial burden, which in turn reduces the amount of exotoxin and lipase released thereby addressing the source of inflammation.

Additionally, performing in-office or at home lid debridement, such as with BlephEx (Alcon) or NuLids (NuSight Medical), respectively, can successfully remove proinflammatory debris and biofilm present in staph blepharoconjunctivitis.23

Figure 4 demonstrates the presence of “foamy” or “frothy tears,” known as saponification, is a sign of chronic blepharoconjunctivitis due to staph bacterial overgrowth.

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Figure 4

Phlyctenular keratoconjunctivitis

Phlyctenular keratoconjunctivitis (PKC) is a form of chronic conjunctivitis that is considered noninfectious in nature but is triggered by the response to a bacterial pathogen.16,24 It is thought that PKC is actually a form of Type IV hypersensitivity reaction to the presence of a bacterial antigen, rather than a direct bacterial infection.25

The most common cause of PKC in the U.S. is staphylococcus aureus, however it can also be caused by mycobacterium tuberculosis,16,26 so patients should be questioned about potential exposure to tuberculosis (TB) (such as travel to regions where TB is endemic, stays in homeless shelters or prisons), and signs and symptoms of TB assessed (including chronic cough or significant weight loss).

The condition can also be caused by chlamydia trachomatis and streptococcus viridians.25,27 It has been shown to be associated with ocular rosacea and Staph blepharitis.24,25 PKC primarily affects the pediatric population, with females being more affected than males.16 PKC also tends to be more common in the spring.28,29 The classic sign of PKC is the presence of raised, nodular lesions known as phlyctenules on the conjunctival or corneal surface. These nodular lesions are typically found near the limbus.16 The phlyctenules are prone to ulceration, often pick up stain, and display prominent injection around the lesions.

Ultimately the nodules can migrate onto the corneal surface which can lead to neovascularization and scarring.25 While conjunctival lesions typically only result in mild irritation, corneal phlyctenules often cause significant pain.24

Additionally, mucoid discharge and photophobia are a common sign and symptom of PKC, and it is worth noting that PKC due to TB tends to display more severe photophobia than that caused by staph.24 PKC is typically treated with topical steroids or steroid sparing agents, such as cyclosporine for long-term management, as inflammation is the primary driver of the condition.30 If any ulceration is noted, the concomitant use of a broad-spectrum topical antibiotic is warranted.

Lid hygiene, such as the use of hypochlorous acid, is also beneficial to decrease the number of bacteria present on the lids and lashes. Patients with high suspicion for TB should receive a Mantoux tuberculin skin test, QuantiFERON-gold testing, or chest x-ray to rule out TB as the potential cause of infection. It is also recommended the patient be tested for chlamydia if suspected. Additionally, any concomitant conditions such as ocular rosacea or staph blepharitis should be addressed.

PKC, as seen in Figure 5, displays nodules, known as phlyctenules, that appear on the conjunctiva or cornea but are often found in the limbal region.

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Figure 5

An uncommon form of chronic BC is angular blepharoconjunctivitis. This can be caused by both Staph and Moraxella lacunata and results in a scaly appearance and ulceration of the corners of the eyelid skin near the canthi, usually at the temporal canthus, in addition to conjunctival injection and mild discharge.31 When caused by moraxella, the condition can be difficult to treat and slow to heal.32 Topical fluoroquinolones are the treatment of choice in cases of angular blepharitis, especially ciprofloxacin 0.3% ointment which can be applied directly to the affected areas, providing prolonged contact time and a protective barrier for the irritated skin, which promotes healing.

Hyperacute conjunctivitis (gonococcal conjunctivitis)

Hyperacute conjunctivitis (Gonococcal conjunctivitis) is caused by Neisseria gonorrhoeae or Neisseria meningitidis and requires urgent treatment. It typically incubates over a period of 1-7 days (it remains contagious during this time as well) and then presents with a rapid onset, usually in less than 24 hours, for which it receives its name.33 The pathognomonic sign is copious, purulent milky-white discharge. This heavy discharge is often accompanied by a papillary reaction, significant conjunctival chemosis, corneal infiltrates, and lid edema.

Additionally, the eye will be tender and painful. Neisseria species are capable of perforating intact corneal tissue, and carry a risk for endophthalmitis, making urgent treatment critical.13 It is typically transmitted through sexual contact but can also be passed from infected mothers to newborns during birth which is referred to as gonococcal ophthalmia neonatorum.

Patients experiencing gonococcal conjunctivitis will require intramuscular or intravenous antibiotics depending on the degree of corneal involvement. If no ulceration is present, a patient can receive a single dose of 1 g ceftriaxone on an outpatient basis plus a topical fourth-generation fluoroquinolone, such as moxifloxacin 0.5%, dosed every waking hour until resolution (typically 5-7 days). If corneal ulceration is present, the patient will require hospital admission and should receive 1 g ceftriaxone IV twice a day for 3 days in addition to a topical fourth-generation fluoroquinolone dosed at least every waking hour (with consideration of dosing every hour around the clock for the first 1-3 days or until the ulcer has healed).

In cases of a penicillin allergy, a single dose of 2 g IM spectinomycin can be administered or an oral fluoroquinolone, such as ciprofloxacin 500 mg or ofloxacin 400 mg BID, can be given for 5 days. Patients should be instructed to frequently irrigate their eyes to reduce the bacterial burden on the ocular surface by removing the bacteria-laden discharge. It is also recommended that the patient should be treated prophylactically for chlamydial infection due to a high concomitance between the two conditions.34 The patient should also notify all sexual partners and it is recommended they be screened for other potential sexually transmitted infections (STIs), such as syphilis and HIV, as well.

Adult inclusion conjunctivitis and trachoma (chlamydial conjunctivitis)

Adult inclusion conjunctivitis (AIC) is caused by Chlamydia trachomatis (serotypes D through K).35 It accounts for 1.8 to 5.6% of cases of conjunctivitis6 and is transmitted through sexual contact, with 54% of males and 74% of females displaying concomitant genital infections.36 Chlamydial conjunctivitis is unique among BC cases as it presents more similarly to viral conjunctivitis than other bacterial infections. Both AIC and viral conjunctivitis present with follicles and both can cause preauricular lymphadenopathy and corneal subepithelial infiltrates (SEIs).37 However, AIC tends to produce thicker, colored discharge whereas viral discharge is more serous in nature. Additionally, viral conjunctivitis will resolve on its own within a few weeks whereas AIC will persist.38 The follicular reaction observed in AIC tends to develop on the lower lid. These are often giant follicles and may coexist with papillae creating a mixed reaction.39

Given its similar presentation to viral conjunctivitis, AIC often goes misdiagnosed. Additionally, it does not respond to topical antibiotics due to its underlying systemic etiology, so even when a bacterial cause is suspected standard treatment with topical antibiotics is ineffective. Given the potential difficulty of diagnosing the condition and the fact only 50-75%36 of patients have other systemic signs and symptoms, AIC often leads to chronic conjunctivitis. For this reason, in any case of chronic conjunctivitis or conjunctivitis that does not respond to topical antibiotics, especially in patients in young adulthood and in the presence of a follicular reaction, AIC should be suspected.

While cultures can be performed to confirm the diagnosis, suspected cases can be successfully treated with oral antibiotics. Treatment options include a single dose of 1 g oral azithromycin (however some patients have difficulty tolerating this high dose) or a 7-day course of doxycycline 100 mg BID, tetracycline 250 mg QID, or erythromycin 500 mg QID. Similar to hyperacute conjunctivitis, patients should also contact their sexual partners as they will also need treatment and receive testing for other concomitant STIs as well.

Trachoma is also caused by Chlamydia trachomatis, but it is caused by serotypes A through C.35 Trachoma is rare in the U.S., but it is the leading cause of infectious blindness worldwide.40 It is more common in Northern Africa and the Middle East and affects 40 million people globally.41 Infection is transmitted by flies and spread through poor hygiene conditions as well.42 Like AIC, trachoma leads to a chronic conjunctivitis with a follicular reaction. However, the follicles present in trachoma tend to appear on the upper lid as opposed to the lower lid in AIC.39

Other signs of trachoma include linear scars on the superior palpebral conjunctiva due to chronic inflammation known as Arlt’s Lines, Herbert’s Pits which are depressions in the limbus due to apposition to the superior follicles, and eventually trichiasis due to entropion secondary to the scarring of the lids which can lead to corneal scarring and opacification.39 The treatment regimen for trachoma is referred to by the acronym SAFE, which stands for surgery for advanced/scarring cases, Antibiotics for active infection (the same as those used to treat AIC), facial cleanliness, and environmental hygiene practices.43

Figure 6 demonstrates chronic follicular or mixed follicular-papillary reaction in the presence of mucoid discharge is a sign of chlamydial conjunctivitis.