Grand Rounds at the New England Eye Center

Newborn presents with acute conjunctival injection

Exam showed left-sided conjunctival injection, eyelid edema and a near total corneal epithelial defect.

A 6-day-old male infant born full term was transferred to the Tufts Medical Center emergency department from an outside hospital with worsening redness, swelling and discharge of the left eye over the past 2 days. He was born to homeless parents, and his mother was incarcerated for the first 6 months of pregnancy. His mother had a history of intravenous drug use and was seropositive for hepatitis C. She reportedly had two negative tests for sexually transmitted infections during her pregnancy, with the most recent testing occurring 3 months before delivery. She did have trichomoniasis and recurrent yeast infections during pregnancy. The infant received erythromycin prophylaxis after delivery. The infant’s urine and serum toxicology screens were negative at birth. The infant was otherwise healthy with no known medical history. The infant was in the care of a foster mother.

Examination

Upon examination, the infant blinked to bright light with both eyes. He had no afferent pupillary defect in either eye. Extraocular movements were grossly full. IOPs were soft and equal to finger palpation. Left upper eyelid was moderately edematous and erythematous. There was a single round cystic vs. vesicular lesion with surrounding erythema on the left lower lid inferior to the lash line. The left conjunctiva was noted to have significant injection and follicles with mild yellowish mucoid discharge. The left cornea was diffusely hazy with a near total epithelial defect and a central geographic placoid lesion (Figure 1). The left anterior chamber was grossly quiet without hypopyon. Anterior segment exam of the right eye was within normal limits. Dilated fundus exam was within normal limits in both eyes.

Figure 1. Anterior segment photographs of left eye at presentation.

Source: Deborah Witkin, MD, and Mitchell B. Strominger, MD

What is your diagnosis?

See answer on next page.

Conjunctival injection

Based on the history and appearance of the left eye, the differential diagnosis included infectious etiologies such as Chlamydia trachomatis, Neisseria gonorrhoeae, herpes simplex virus (HSV), syphilis, Pseudomonas, and other bacterial or viral infections. Less likely diagnoses included chemical conjunctivitis, nasolacrimal duct obstruction, birth trauma, and congenital causes of corneal haze including Peters anomaly or congenital glaucoma. The conjunctiva was cultured for gram stain, aerobic culture, gonorrhea and HSV PCR. Due to lab processing, chlamydia testing was not available at the time of presentation. Blood cultures were also drawn at initial presentation. Based on the time course, presentation and presence of possible vesicular lesion, there was high suspicion for herpes simplex or chlamydia infection.

Workup and management

The infant was admitted to the hospital with a consult to the pediatric infectious disease service. He was started on topical erythromycin ointment and intravenous ceftazidime, clindamycin and azithromycin. Antiviral treatment was deferred initially due to risk of systemic toxicity. A chest X-ray to evaluate for Chlamydia pneumoniae was also deferred due to lack of respiratory symptoms. On the day after admission, he had no significant improvement in lid edema, mucoid discharge, conjunctival injection or corneal haze (Figure 2), so he was started on IV acyclovir and topical valganciclovir.

On the second day of admission, HSV PCR from the conjunctival swab was found to be positive. Blood cultures had no growth, and conjunctival gram stain showed normal flora. A lumbar puncture was performed for cytology and for HSV PCR of the cerebrospinal fluid. There was no sign of pleocytosis, and the PCR was negative. His serum was also tested for HSV, and he was found to be positive for HSV-1. The infant slowly improved after starting IV and topical antiviral treatment, and the epithelial defect resolved by day 9 after initial presentation. The intravenous antibiotics were discontinued on day 3 after presentation. A baseline MRI of his head was performed and showed no abnormalities.

Figure 2. Anterior segment photographs of left eye on the day after presentation.

Discussion

Neonatal conjunctivitis secondary to herpes simplex is an uncommon but potentially life-threatening illness. According to a survey of members of the American Association for Pediatric Ophthalmology and Strabismus, HSV accounted for 5.7% of the cases of neonatal conjunctivitis. The most common pathogens were Chlamydia trachomatis (35.37%), Staphylococcus aureus (19.65%) and Staphylococcus epidermidis (10.92%). The most common empiric treatments for neonatal conjunctivitis are systemic erythromycin and topical fluoroquinolones. Erythromycin ointment application is recommended after delivery for prevention of neonatal conjunctivitis.

According to National Health and Nutrition Examination Survey data, the seroprevalence for HSV in pregnant women ages 20 to 39 years between 1999 and 2014 was estimated to be 59.3% for HSV-1 and 21.1% for HSV-2. Between 0.2% and 0.39% of all pregnant women regardless of seroprevalence are shedding HSV at the time of delivery. In pregnant women with a history of recurrent genital herpes, the rate of viral shedding at delivery increases to between 0.77% and 1.4%. Factors that have been shown to increase the risk of transmitting HSV to the newborn include having a primary episode of herpes infection during pregnancy, vaginal delivery, increased duration of rupture of membranes, and use of instrumentation during labor such as forceps or fetal scalp electrode placement. In the United States, there are approximately 1,500 cases of neonatal herpes simplex infection yearly.

In order to prevent transmission of HSV during delivery, the American College of Obstetricians and Gynecologists recommends performing a cesarean section if genital herpetic lesions are present at the time of delivery. It also recommends antiviral prophylaxis with oral acyclovir or valacyclovir during later stages of pregnancy for any woman with a history of recurrent herpes simplex genital infections. However, there are numerous case reports of neonatal herpes simplex infection despite performing cesarean section and using maternal antiviral prophylaxis.

Since the introduction of effective antiviral therapies including acyclovir and valacyclovir, 45% of neonatal herpes infections are confined to the skin, eye and/or mouth. Neonatal herpes infections typically present between 10 and 12 days postpartum. Vesicular rash is a notable feature in 80% of all neonatal herpes infections. If the neonatal herpes infection progresses to involve the central nervous system or becomes disseminated, there is a significantly increased rate of morbidity and mortality. The mortality rate is 29% for disseminated disease and 4% for central nervous system disease despite the use of high-dose intravenous acyclovir. The gold standard for diagnosis of herpes simplex infection is a positive PCR from an active lesion. PCR testing of the serum and cerebrospinal fluid is recommended for cases of neonatal herpes infection.

The recommended treatment for neonatal herpes infections is high-dose intravenous acyclovir (60 mg/kg/day) for 14 days if the disease is confined to skin, eyes and/or mouth and for 21 days if there is involvement of the central nervous system. It is also recommended to treat with oral acyclovir for a minimum of 6 months after stopping intravenous treatment. Intravenous acyclovir may cause significant neutropenia, thrombocytopenia and elevated creatinine. Although the risk for toxicity is reduced with oral acyclovir, ongoing serum testing and weight checks to adjust dosing are recommended throughout treatment. While herpes strains have been reported to show resistance to acyclovir, this continues to be rare.

In this case, the newborn’s infection was confined to the eyes and skin only. He maintains a lifelong risk for recurrent herpes simplex infection, which could lead to scarring, amblyopia and other sight-threatening complications. However, due to the high suspicion for herpetic infection, he was started on antiviral treatment quickly, and the infection did not become disseminated or involve his central nervous system.

The patient remained in the hospital to complete a 14-day course of IV acyclovir and was discharged on a course of 6 months of oral acyclovir. Topical erythromycin ointment and valganciclovir were discontinued 20 days after presentation. He will continue to be monitored closely for signs of systemic toxicity due to acyclovir, recurrence of HSV and development of amblyopia.

A 6-day-old male infant born full term was transferred to the Tufts Medical Center emergency department from an outside hospital with worsening redness, swelling and discharge of the left eye over the past 2 days. He was born to homeless parents, and his mother was incarcerated for the first 6 months of pregnancy. His mother had a history of intravenous drug use and was seropositive for hepatitis C. She reportedly had two negative tests for sexually transmitted infections during her pregnancy, with the most recent testing occurring 3 months before delivery. She did have trichomoniasis and recurrent yeast infections during pregnancy. The infant received erythromycin prophylaxis after delivery. The infant’s urine and serum toxicology screens were negative at birth. The infant was otherwise healthy with no known medical history. The infant was in the care of a foster mother.

Examination

Upon examination, the infant blinked to bright light with both eyes. He had no afferent pupillary defect in either eye. Extraocular movements were grossly full. IOPs were soft and equal to finger palpation. Left upper eyelid was moderately edematous and erythematous. There was a single round cystic vs. vesicular lesion with surrounding erythema on the left lower lid inferior to the lash line. The left conjunctiva was noted to have significant injection and follicles with mild yellowish mucoid discharge. The left cornea was diffusely hazy with a near total epithelial defect and a central geographic placoid lesion (Figure 1). The left anterior chamber was grossly quiet without hypopyon. Anterior segment exam of the right eye was within normal limits. Dilated fundus exam was within normal limits in both eyes.

Figure 1. Anterior segment photographs of left eye at presentation.

Source: Deborah Witkin, MD, and Mitchell B. Strominger, MD

What is your diagnosis?

See answer on next page.

PAGE BREAK

Conjunctival injection

Based on the history and appearance of the left eye, the differential diagnosis included infectious etiologies such as Chlamydia trachomatis, Neisseria gonorrhoeae, herpes simplex virus (HSV), syphilis, Pseudomonas, and other bacterial or viral infections. Less likely diagnoses included chemical conjunctivitis, nasolacrimal duct obstruction, birth trauma, and congenital causes of corneal haze including Peters anomaly or congenital glaucoma. The conjunctiva was cultured for gram stain, aerobic culture, gonorrhea and HSV PCR. Due to lab processing, chlamydia testing was not available at the time of presentation. Blood cultures were also drawn at initial presentation. Based on the time course, presentation and presence of possible vesicular lesion, there was high suspicion for herpes simplex or chlamydia infection.

Workup and management

The infant was admitted to the hospital with a consult to the pediatric infectious disease service. He was started on topical erythromycin ointment and intravenous ceftazidime, clindamycin and azithromycin. Antiviral treatment was deferred initially due to risk of systemic toxicity. A chest X-ray to evaluate for Chlamydia pneumoniae was also deferred due to lack of respiratory symptoms. On the day after admission, he had no significant improvement in lid edema, mucoid discharge, conjunctival injection or corneal haze (Figure 2), so he was started on IV acyclovir and topical valganciclovir.

On the second day of admission, HSV PCR from the conjunctival swab was found to be positive. Blood cultures had no growth, and conjunctival gram stain showed normal flora. A lumbar puncture was performed for cytology and for HSV PCR of the cerebrospinal fluid. There was no sign of pleocytosis, and the PCR was negative. His serum was also tested for HSV, and he was found to be positive for HSV-1. The infant slowly improved after starting IV and topical antiviral treatment, and the epithelial defect resolved by day 9 after initial presentation. The intravenous antibiotics were discontinued on day 3 after presentation. A baseline MRI of his head was performed and showed no abnormalities.

Figure 2. Anterior segment photographs of left eye on the day after presentation.

Discussion

Neonatal conjunctivitis secondary to herpes simplex is an uncommon but potentially life-threatening illness. According to a survey of members of the American Association for Pediatric Ophthalmology and Strabismus, HSV accounted for 5.7% of the cases of neonatal conjunctivitis. The most common pathogens were Chlamydia trachomatis (35.37%), Staphylococcus aureus (19.65%) and Staphylococcus epidermidis (10.92%). The most common empiric treatments for neonatal conjunctivitis are systemic erythromycin and topical fluoroquinolones. Erythromycin ointment application is recommended after delivery for prevention of neonatal conjunctivitis.

According to National Health and Nutrition Examination Survey data, the seroprevalence for HSV in pregnant women ages 20 to 39 years between 1999 and 2014 was estimated to be 59.3% for HSV-1 and 21.1% for HSV-2. Between 0.2% and 0.39% of all pregnant women regardless of seroprevalence are shedding HSV at the time of delivery. In pregnant women with a history of recurrent genital herpes, the rate of viral shedding at delivery increases to between 0.77% and 1.4%. Factors that have been shown to increase the risk of transmitting HSV to the newborn include having a primary episode of herpes infection during pregnancy, vaginal delivery, increased duration of rupture of membranes, and use of instrumentation during labor such as forceps or fetal scalp electrode placement. In the United States, there are approximately 1,500 cases of neonatal herpes simplex infection yearly.

PAGE BREAK

In order to prevent transmission of HSV during delivery, the American College of Obstetricians and Gynecologists recommends performing a cesarean section if genital herpetic lesions are present at the time of delivery. It also recommends antiviral prophylaxis with oral acyclovir or valacyclovir during later stages of pregnancy for any woman with a history of recurrent herpes simplex genital infections. However, there are numerous case reports of neonatal herpes simplex infection despite performing cesarean section and using maternal antiviral prophylaxis.

Since the introduction of effective antiviral therapies including acyclovir and valacyclovir, 45% of neonatal herpes infections are confined to the skin, eye and/or mouth. Neonatal herpes infections typically present between 10 and 12 days postpartum. Vesicular rash is a notable feature in 80% of all neonatal herpes infections. If the neonatal herpes infection progresses to involve the central nervous system or becomes disseminated, there is a significantly increased rate of morbidity and mortality. The mortality rate is 29% for disseminated disease and 4% for central nervous system disease despite the use of high-dose intravenous acyclovir. The gold standard for diagnosis of herpes simplex infection is a positive PCR from an active lesion. PCR testing of the serum and cerebrospinal fluid is recommended for cases of neonatal herpes infection.

The recommended treatment for neonatal herpes infections is high-dose intravenous acyclovir (60 mg/kg/day) for 14 days if the disease is confined to skin, eyes and/or mouth and for 21 days if there is involvement of the central nervous system. It is also recommended to treat with oral acyclovir for a minimum of 6 months after stopping intravenous treatment. Intravenous acyclovir may cause significant neutropenia, thrombocytopenia and elevated creatinine. Although the risk for toxicity is reduced with oral acyclovir, ongoing serum testing and weight checks to adjust dosing are recommended throughout treatment. While herpes strains have been reported to show resistance to acyclovir, this continues to be rare.

In this case, the newborn’s infection was confined to the eyes and skin only. He maintains a lifelong risk for recurrent herpes simplex infection, which could lead to scarring, amblyopia and other sight-threatening complications. However, due to the high suspicion for herpetic infection, he was started on antiviral treatment quickly, and the infection did not become disseminated or involve his central nervous system.

The patient remained in the hospital to complete a 14-day course of IV acyclovir and was discharged on a course of 6 months of oral acyclovir. Topical erythromycin ointment and valganciclovir were discontinued 20 days after presentation. He will continue to be monitored closely for signs of systemic toxicity due to acyclovir, recurrence of HSV and development of amblyopia.