Viral conjunctivitis, or pinkeye (see the image below), is a common, self-limiting condition that is typically caused by adenovirus. Other viruses that can be responsible for conjunctival infection include herpes simplex virus (HSV), varicella-zoster virus (VZV), picornavirus (enterovirus 70, Coxsackie A24), poxvirus (molluscum contagiosum, vaccinia), and human immunodeficiency virus (HIV).
Viral conjunctivitis. Image courtesy of Wikimedia Commons.
Viral conjunctivitis is highly contagious, usually for 10-12 days from onset as long as the eyes are red. Patients should avoid touching their eyes, shaking hands, and sharing towels, napkins, pillow cases, and other fomites, among other activities. Transmission may occur through accidental inoculation of viral particles from the patient's hands or by contact with infected upper respiratory droplets, fomites, or contaminated swimming pools. The infection usually resolves spontaneously within 2-4 weeks.
Signs and symptoms of viral conjunctivitis may include the following:
See Clinical Presentation for more details.
Generally, a diagnosis of viral conjunctivitis is made on the clinical features alone. Laboratory tests are typically unnecessary, but they may be extremely helpful in some cases, particularly when an epidemic of adenoviral keratoconjunctivitis threatens a community or clinic. Specimens can be obtained by culture and conjunctival cytology smear if inflammation is severe, in chronic or recurrent infections, with atypical conjunctival reactions, and in patients who fail to respond to treatment. Giemsa staining of conjunctival scrapings may aid in characterizing the inflammatory response. A rapid point-of-service immunoassay is now readily available to guide the clinician’s recommendations upon initial presentation (Adenoplus, RPS, Sarasota, FL).
See Workup for more details.
Treatment of adenoviral conjunctivitis is supportive. Patients should be instructed to use cold compresses and lubricants, such as chilled artificial tears, for comfort. Topical vasoconstrictors and antihistamines may be used for severe itching but generally are not indicated. For patients who may be susceptible, a topical astringent or antibiotic may be used to prevent bacterial superinfection. There is clinical evidence that topical ganciclovir is effective against at least Adenovirus serotype 8, thus compelling many clinicians to prescribe this agent off-label for compelling cases of epidemic keratoconjunctivitis (EKC), particularly when corneal lesions are noted.
Patients with conjunctivitis caused by HSV usually are treated with topical antiviral agents, including ganciclovir (Zirgan, Bausch & Lomb, Bridgewater, NJ), idoxuridine solution and ointment, vidarabine ointment, and trifluridine solution (Viroptic, Alcon, Fort Worth, TX).
Treatment of VZV eye disease includes high-dose oral acyclovir to terminate viral replication.
For conjunctivitis associated with molluscum contagiosum, disease will persist until the skin lesion is treated. Removal of the central core of the lesion or inducement of bleeding within the lesion usually is enough to cure the infection.
Preventing transmission of viral conjunctivitis is important. Both patient and provider should wash hands thoroughly and often, keep hands away from the infected eye and contralateral eye, and avoid sharing towels, linens, and cosmetics. Infected patients should be advised to stay home from school and work. Those who wear contact lenses should be instructed to discontinue lens wear until signs and symptoms have resolved.
See Treatment and Medication for more details.
Viruses are a common cause of conjunctivitis in patients of all ages. A variety of viruses can be responsible for conjunctival infection; however, adenovirus is by far the most common cause, and herpes simplex virus (HSV) is the most problematic. Less common causes include varicella-zoster virus (VZV), picornavirus (enterovirus 70, Coxsackie A24), poxvirus (molluscum contagiosum, vaccinia), and human immunodeficiency virus (HIV). Rarely, conjunctivitis is seen during systemic infection with influenza virus, Epstein-Barr virus, paramyxovirus (measles, mumps, Newcastle), or rubella. (See Etiology.)
Viral conjunctivitis, although usually benign and self-limited, tends to follow a longer course than acute bacterial conjunctivitis, lasting for approximately 2-4 weeks. Viral infection is characterized commonly by an acute follicular conjunctival reaction and preauricular adenopathy. (See History and Physical Examination.)
See the following for more information:
Adenoviral conjunctivitis is the most common cause of viral conjunctivitis. Particular subtypes of adenoviral conjunctivitis include epidemic keratoconjunctivitis (EKC; pink eye) and pharyngoconjunctival fever (PCF).
Viral conjunctivitis is highly contagious, usually for 10-12 days from onset as long as the eyes are red, in addition to a prodromal period of 3-7 days. Patients should avoid touching their eyes, shaking hands, and sharing towels, among other activities. Transmission may occur through accidental inoculation of viral particles from the patient's hands or by contact with infected upper respiratory droplets, fomites, or contaminated swimming pools.
Primary ocular herpes simplex infection is common in children and usually is associated with a follicular conjunctivitis. Infection usually is caused by HSV type I, although HSV type II may be a cause, especially in neonates. Recurrent infection, typically seen in adults, is often associated with superficial epithelial or deep stromal corneal involvement.
VZV can affect the conjunctiva during primary infection (chickenpox) or secondary infection (zoster). Infection can be caused by direct contact with VZV or zoster skin lesions or by inhalation of infectious respiratory secretions.
Picornaviruses cause an acute hemorrhagic conjunctivitis (AHC) that is clinically similar to adenoviral conjunctivitis but is more severe and hemorrhagic. Infection is highly contagious and occurs in epidemics.
Molluscum contagiosum may produce a chronic follicular conjunctivitis that occurs secondary to shedding of viral particles into the conjunctival sac from an irritative eyelid lesion.
Vaccinia virus has become a rare cause of conjunctivitis because, with the elimination of smallpox, the vaccination rarely is administered. Infection occurs through accidental inoculation of viral particles from the patient's hands.
HIV is the etiologic agent of acquired immunodeficiency syndrome (AIDS). Ocular abnormalities in patients with AIDS primarily affect the posterior segment, but anterior segment findings have been reported. When conjunctivitis occurs in a patient with AIDS, it tends to follow a more severe and prolonged course than in patients without AIDS. In general, patients with AIDS may develop a transient, nonspecific conjunctivitis, characterized by irritation, hyperemia, and tearing, that requires no specific treatment. Microsporidia has been isolated from the cornea and conjunctiva of several patients with AIDS and keratoconjunctivitis. In these patients, symptoms included foreign body sensation, blurred vision, and photophobia; most cases resolved without antimicrobial therapy.
Viral conjunctivitis is a common ocular disease in the United States and worldwide. Because it is so common, and because many cases are not brought to medical attention, accurate statistics on the frequency of the disease are unavailable. Viral infection frequently occurs in epidemics within families, schools, offices, shipyards, athletic teams, residential communities, and military organizations.
Viral conjunctivitis can occur equally in men and women.
Viral conjunctivitis can affect all age groups, depending on the specific viral etiology. Usually, adenovirus affects patients aged 20-40 years. HSV and primary VZV infection usually affect young children and infants. Herpes zoster ophthalmicus results from reactivation of latent VZV infection and may present in any age group. Typically, the picornaviruses affect children and young adults in the lower socioeconomic classes.
Most cases of viral conjunctivitis are acute, benign, and self-limited, although chronic infections have been reported. Long-term ocular sequelae are uncommon but may be severe and even debilitating in rare highly susceptible individuals. The infection usually resolves spontaneously within 2-4 weeks. Subepithelial infiltrates may last for several months, and, if in the visual axis, they may cause decreased vision or glare.
Complications include the following: punctate keratitis with subepithelial infiltrates, bacterial superinfection, conjunctival scarring and symblepharon, severe dry eye, irregular astigmatism, corneal ulceration with persistent keratoconjunctivitis, corneal scarring, and chronic infection.
Epithelial keratitis may accompany viral conjunctivitis. Punctate epithelial erosions that stain with fluorescein are commonly associated with viral keratitis. Rarely, these changes are sufficiently distinctive morphologically to allow identification of a specific type of virus as the etiologic agent. If the conjunctivitis persists or is severe, disturbances in the anterior stroma beneath the epithelial abnormalities may occur. In general, the stromal or subepithelial abnormalities are transient and resolve despite persistence of epithelial keratitis. However, in cases of specific adenoviral serotype infection, the stromal abnormalities may persist for months to years, long after the epithelial changes have resolved. In such cases, these subepithelial infiltrates are considered to be immunologic in origin, the result of antigen-antibody reaction. If they are in the pupillary axis, they may cause decreased vision and/or glare. Rarely, these corneal changes or the accompanying severe dry eye caused by partial obliteration of the conjunctival lacrimal ductules can lead to career-ending photophobia, eye pain, or visual disturbances.
To allay patient anxiety, it is helpful to inform patients that their symptoms may worsen during the first 4-7 days after onset before they begin to improve and may not resolve for 2-4 weeks. The contagiousness of the infection also should be emphasized. Proper isolation from the workplace or school is advisable and essential to prevent epidemics.
Patients with conjunctivitis who wear contact lenses should be instructed to discontinue lens wear until signs and symptoms have resolved.
For patient education information, see the Eye and Vision Center and the Skin, Hair, and Nails Center, as well as Pinkeye, How to Instill Your Eyedrops, and Molluscum Contagiosum.
While the manifestations of various types of bacterial conjunctivitis are fairly homogenous, those of viral conjunctivitis can vary from one disease process to another. History should focus on eliciting information that will aid in differentiating the various etiologic agents of viral infection.
Inquire about timing, onset, and duration of systemic and ocular symptoms; severity and frequency of symptoms; appropriate risk factors; and personal and environmental exposures.
Patients with adenoviral conjunctivitis may give a history of recent exposure to an individual with a red eye at home, school, or work, or they may have a history of recent symptoms of an upper respiratory tract infection. The eye infection may be unilateral or bilateral.
Patients may report ocular itching, foreign body sensation, tearing, redness, discharge, eyelids sticking (worse in the morning), and photophobia (with corneal involvement, as in epidemic keratoconjunctivitis).
Systemic manifestations are rare, except in cases of pharyngoconjunctival fever.
Primary ocular HSV infection predominantly affects young children and infants, but it may occur in individuals of all ages. Patients usually present with a red, irritated, watery eye. Often, concomitant eyelid skin involvement with multiple vesicular lesions is present.
VZV is characterized by a generalized vesicular eruption, fever, and constitutional symptoms. Ocular infection usually is unilateral and presents as small, papular lesions that erupt along the lid margin or at the limbus and may be accompanied by a mild follicular conjunctivitis.
Herpes zoster ophthalmicus represents reactivation of latent VZV infection of the trigeminal ganglion. It is characterized by a prodrome of fever, malaise, nausea, vomiting, and severe oculofacial pain and skin lesions along the ophthalmic division of the trigeminal nerve. Conjunctival involvement includes hyperemia, follicular or papillary conjunctivitis, and a serous or mucopurulent discharge.
Acute hemorrhagic conjunctivitis has been reported in epidemics in association with 2 major picornaviruses: enterovirus 70 and Coxsackievirus A24. It mostly affects children and young adults in the lower socioeconomic classes. Patients experience a rapid onset of watery discharge, foreign body sensation, burning, and photophobia within 24 hours of exposure.
Molluscum contagiosum can produce a chronic follicular conjunctivitis in association with an irritative eyelid lesion. The lesion usually is a small, elevated, pearly, umbilicated nodule near the lid margin. Multiple lesions may be present, especially in patients who are HIV positive.
Other viruses are less frequent causes of conjunctivitis. In these cases, conjunctivitis usually occurs in association with a systemic illness and includes infections caused by influenza virus, Epstein-Barr virus, paramyxovirus (measles, mumps, Newcastle), rubella, or HIV.
Typical signs of adenoviral conjunctivitis include preauricular adenopathy, epiphora, hyperemia, chemosis, subconjunctival hemorrhage, follicular conjunctival reaction, and occasionally a pseudomembranous or cicatricial conjunctival reaction. The cornea often demonstrates a punctate epitheliopathy, sometimes followed by diffuse subepithelial infiltrates, which generally occur 7-14 days after the onset of symptoms. The eyelids often are edematous and ecchymotic. In severe cases, there can be a corneal epithelial defect. The entire process typically begins in one eye and progresses to the fellow eye over a few days, albeit with less severity in the non-index eye.
With HSV infection, vesicles may be present on the eyelid or face, the eyelids may be swollen, and an ulcerative blepharitis may be present.
Corneal involvement in HSV manifests as an epithelial dendritic keratitis with typical features of linear branching and dendritic figures, as well as deeper stromal inflammation. Endothelialitis, trabeculitis with elevated intraocular pressure, and/or uveitis may also occur.
Small, papular lesions that erupt along the lid margin or at the limbus are present with varicella conjunctivitis. These lesions may resolve without sequelae, or they may become pustular and form painful, reactive conjunctival ulcers with permanent cicatrization and conjunctival pigmentation. Lid lesions may also resolve or may lead to notching, distichiasis, alopecia, hypopigmentation, or scarring.
In herpes zoster ophthalmicus, look for skin involvement with the appearance of a dermatomal pattern of vesicles. These vesicles may become necrotic, resulting in pitted scarring of the skin. Conjunctival involvement includes hyperemia, follicular or papillary conjunctivitis, and a serous or mucopurulent discharge. Preauricular adenopathy is common. Very early in the process, there may be multiple fine, dendritic corneal lesions, which disappear over a few days without treatment.
Acute hemorrhagic conjunctivitis starts unilaterally but rapidly involves the fellow eye within 1 or 2 days. Signs on examination include a swollen, edematous eyelid and pronounced hemorrhage beneath the bulbar conjunctiva.
Generally, a diagnosis of viral conjunctivitis is made on the clinical features alone. Signs of acute viral conjunctivitis include inferior palpebral conjunctival follicles, tender palpable preauricular lymph node, watery discharge, red and edematous eyelids, pinpoint subconjunctival hemorrhages, punctuate keratopathy, and membrane/pseudomembrane. Intraepithelial microcysts may be an early corneal finding, which, when present, can be helpful in the diagnosis. Subepithelial corneal infiltrates may develop 1-2 weeks after the onset of the conjunctivitis. HSV infection may demonstrate the classic corneal dendrites. Extensive multiple dendrites may suggest immunocompromise (eg, due to long-term topical steroid therapy, systemic immunosuppressive medications, HIV infection).
Conventional laboratory culture identification can be expensive and time-consuming but may be helpful in certain circumstances.[3, 4, 5, 6]
Specimens should be obtained for culture and smear if inflammation is severe, in chronic or recurrent infections, with atypical conjunctival reactions, and with failure to respond to treatment.
Giemsa staining of conjunctival scrapings may aid in characterizing the inflammatory response. Polymorphonuclear cells are prevalent in bacterial infections, whereas mononuclear cells and lymphocytes are seen with viruses.
Viral isolation methods may be helpful in the diagnosis of acute follicular conjunctivitis, but they are not indicated in chronic conjunctivitis.
Direct immunofluorescence monoclonal antibody staining and enzyme-linked immunosorbent assay (ELISA) are rapid and widely available detection techniques.
Alternative methods include the use of immunoperoxidase, electron microscopy, and polymerase chain reaction (PCR) assay. These tests are usually performed only in the context of a research program.
Serologic tests are available but generally require 2 serum samples at least 2 weeks apart, which can delay treatment decisions. The ready availability of the point-of-service Adenoplus test (RPS Diagnostics) precludes many of the traditional diagnostics owing to its relatively low cost, rapidity, patient tolerability, and accuracy.
Treatment of adenoviral conjunctivitis is supportive. No evidence exists that demonstrates the efficacy of specific antiviral agents other than topical ganciclovir. A combination topical agent that contains betadine and low-dose dexamethasone is currently in confirmatory phase III clinical trials as a broad-spectrum agent for the treatment of adenovirus, HSV, VZV, and other forms of infectious conjunctivitis. There are no oral antiviral candidates under consideration as antiadenoviral therapeutics, nor is there any evidence that oral antiherpetic drugs have any effect on ocular adenoviral disease.
Patients should be instructed to use cold compresses and lubricants, such as artificial tears, for comfort.
Topical vasoconstrictors and antihistamines may be used for severe itching but generally are not indicated, because they are minimally helpful and may cause rebounding of symptoms, as well as local toxicity and hypersensitivity.
For patients who may be susceptible, a topical astringent or antibiotic may be used to prevent bacterial superinfection.
Topical steroids may be used for pseudomembranes or when subepithelial infiltrates impair vision, although subepithelial infiltrates may recur after discontinuing the steroids. Extreme caution should be taken when using corticosteroids, as they may worsen an underlying HSV infection and may lead to long-term dependence.
A study by Wilkins et al focused on whether topical steroids improve the comfort of patients compared with hypromellose in acute presumed viral conjunctivitis. It found that the use of a short course of topical dexamethasone for patients with acute follicular conjunctivitis presumed to be viral in origin was not harmful.
An in vitro study using adenovirus 8 and A549 human epithelial cell cultures demonstrated that povidone-iodine at a concentration of 1:10 (0.8%) is highly effective against free adenovirus, less effective against intracellular adenoviral particles in already infected cells, and not significantly cytotoxic for healthy cells. Thus, povidone-iodine 0.8% may represent a potential option to reduce contagiousness in cases of adenoviral infections.
Patients with conjunctivitis caused by HSV usually are treated with topical antiviral agents, including ganciclovir gel, idoxuridine solution and ointment, vidarabine ointment, and trifluridine solution. An ophthalmologist should see any patient with ocular HSV infection.
Treatment of VZV eye disease includes oral acyclovir, 600-800 mg, 5 times daily for 7-10 days, to terminate viral replication. Valacyclovir 1000 mg or famciclovir 500 mg PO TID for 7-10 days is also approved for herpes zoster infection. Topical corticosteroids usually are not indicated for conjunctivitis or keratitis.
For conjunctivitis associated with molluscum contagiosum, disease will persist until the skin lesion is treated. Removal of the central core of the lesion or inducement of bleeding within the lesion usually is enough to cure the infection. Occasionally, surgical excision is required.
Other viral causes of conjunctivitis generally are self-limited and treated supportively with cool or warm compresses for comfort, topical antihistamines to limit redness and itching, chilled artificial tears for comfort, and topical antibiotics as necessary to prevent bacterial superinfection.
Treatment of acute hemorrhagic conjunctivitis is supportive, as in adenoviral infection, and includes bed rest, cold compresses, and analgesics. Antibiotics have no useful role unless bacterial superinfection is present.
Prevention of transmission, especially in health care facilities, is extremely important. Careful hand washing before seeing every patient, proper cleansing of instruments, and frequent changing of multiuse ophthalmic drops are vital. Using a single infective examination room, as well as educating the staff and the patient, is important.
Patients should be instructed to take contagion and isolation precautions for at least 2 weeks or as long as their eyes are red and weeping. In particular, they should avoid contact with infants, elderly persons, individuals taking immunosuppressive or chemotherapeutic agents, and immunocompromised patients.
Physicians have been sued by patients who believe they acquired viral conjunctivitis in the doctor's office. Every attempt to prevent transmission from patient to patient (not to mention to the doctor) should be made. Suggestions include not having patients with a red eye wait in the general waiting room, having a special examination room for patients with red eyes, disinfecting the examination room after seeing any patient with a red eye, not shaking hands with patients with red eye (after explaining the reason to them), touching their eyelids with cotton-tipped applicators and not your fingers, washing the hands immediately after examining the patient (even before writing in the chart or using the computer), and not giving the chart to the patient to bring to the receptionist. These patients should be escorted directly out of the clinic and instructed to make a follow-up appointment by telephone at least 2 weeks thereafter.
Viral conjunctivitis is an occupational hazard of eye care providers. Doctors, technicians, and every staff member must take all precautions possible not to become a victim.
Patients with conjunctivitis, especially those treated with medications, require follow-up care. Patients should return after the contagious period (2-3 weeks) or sooner only if the condition significantly worsens.
An important aspect of treatment is to know the proper time to refer the patient to a specialist.
Patients with hyperacute conjunctivitis or those with corneal involvement, significant visual loss, concomitant uveitis, conjunctival membrane or pseudomembrane formation, corneal ulceration, herpetic keratitis, or suspected orbital cellulitis should be referred to an ophthalmologist.
An ophthalmologist also should evaluate patients who fail to respond to appropriate therapy.
The goals of pharmacotherapy are to reduce morbidity and prevent complications.
Clinical Context: Artificial tears act to stabilize and thicken precorneal tear film and prolong tear film breakup time, which occurs with dry eye states.
These agents are used for symptomatic relief.
Clinical Context: Azelastine competes with histamine for the H1 receptor and inhibits the release of histamine and other mediators involved in the allergic response.
Clinical Context: Ketotifen is a relatively selective H1 receptor antagonist and inhibitor of histamine release from mast cells. OTC.
Clinical Context: Olopatadine is a relatively selective H1 receptor antagonist and inhibitor of histamine release from mast cells.
These agents are used to treat severe itching.
Clinical Context: This agent decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. Less potent (eg, prednisolone 0.125%, fluorometholone 0.1%) are usually sufficient to treat subepithelial infiltrates. The steroid must be tapered very carefully, often over months. Topical cyclosporine A emulsion (Restasis, Allergan, Irvine CA) may provide a viable steroid-sparing alternative for selected patients.
Clinical Context: Fluorometholone inhibits edema, fibrin deposition, capillary dilation, phagocytic migration, capillary proliferation, collagen deposition, and scar formation. It decreases inflammation and corneal neovascularization, suppresses migration of PMNs, and reverses capillary permeability. It is believed to act by inducing phospholipase A2 inhibitory proteins.
Clinical Context: Loteprednol etabonate decreases inflammation by suppressing migration of polymorphonuclear leukocytes (PMNs) and reversing increased capillary permeability.
Corticosteroids may be used for pseudomembranes and decreased vision and/or glare due to subepithelial infiltrates. They have anti-inflammatory properties and cause profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli. Extreme caution should be taken when using corticosteroids, as they may worsen an underlying HSV infection or induce dependency in the context of persistent EKC subepithelial infiltrates.
Clinical Context: The exact mechanism of the immunosuppressive activity of cyclosporine is unknown, but preferential and reversible inhibition of T lymphocytes in the G0 or G1 phase of the cell cycle has been suggested.
Immunosuppressant agents are used as adjunctive or alternative treatment when steroid use is ineffective or requires minimization.
Clinical Context: Trifluridine is a pyrimidine (thymidine) analogue drug of choice in the United States for topical antiviral therapy for HSV infection. It inhibits viral replication by incorporating into viral deoxyribonucleic acid (DNA) in place of thymidine. It is prescribed initially 9 times per day until resolution of the epithelial keratitis, then QID for another week. If the patient has no response in 7-14 days, consider other treatments. Trifluridine requires refrigeration and contains the toxic preservative thimerosal.
Clinical Context: Ganciclovir is a selective antiviral activated only within infected cells by viral thymidine kinase. It is a viral DNA chain terminator and DNA polymerase inhibitor. It is available in gel formulation and is stable at room temperature. It is prescribed 5 times per day until resolution of the epithelial keratitis, then TID for an additional week.
Clinical Context: This is a prodrug that inhibits viral replication; it is activated by phosphorylation by virus-specific thymidine kinase. The recommended dosage for acute epithelial keratitis or stromal keratitis ranges from 200 mg PO BID to 400 mg PO TID. Some clinicians recommend the highest anti-zoster strength of 800 mg owing to the variability among patients in gastric absorption and the resultant variability and unpredictability of measurable serum concentrations.
Clinical Context: Valacyclovir is a prodrug that is rapidly converted to the active drug acyclovir. It produces a greater serum concentration of acyclovir with smaller oral dosing. Valacyclovir is more expensive than acyclovir but can be as effective with a more convenient dosing regimen.
Clinical Context: This agent is a prodrug that, when biotransformed into its active metabolite, penciclovir, may inhibit viral DNA synthesis/replication. It has been used successfully in the suppression of genital herpes. Its efficacy in HSV keratitis currently is under study.
These agents are used for the treatment of HSV infection.
Clinical Context: Ofloxacin is a pyridine carboxylic acid derivative with broad-spectrum bactericidal effect. It inhibits bacterial growth by inhibiting DNA gyrase. It is indicated for superficial ocular infections of conjunctiva or cornea due to susceptible microorganisms.
Clinical Context: This combination is used for ocular infection of the cornea or conjunctiva caused by susceptible microorganisms.
Clinical Context: Ciprofloxacin has activity against Pseudomonas and Streptococcus species, methicillin-resistant Staphylococcus aureus (MRSA), S epidermidis, and most gram-negative organisms; it has no activity against anaerobes.
Clinical Context: This agent interferes with bacterial growth by inhibiting bacterial folic acid synthesis by competitively antagonizing para-aminobenzoic acid.
Therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. Antibiotics are used to prevent superinfections.