Lemons in the Arizona Sunshine: The Effects of Furocoumarins Leading to Phytophotodermatitis and Burn-like Injuries

Phytophotodermatitis is a nonimmunologic, dermatologic skin reaction mimicking a burn injury after cutaneous furocoumarin-containing plant contact followed by exposure to ultraviolet A (UV-A) radiation (320 nm–400 nm).^1,2 Furocoumarins are a tricyclic hydrocarbon with a furan ring condensed on a benzopyrone moiety with an associated methyl-group in variable locations.³ Skin exposure to furocoumarins may result in bizarre and nonuniform cutaneous patterns.^1,4 If the skin is exposed to furocoumarin and followed by UV-A radiation from sunlight, a phototoxic reaction is produced. First described by Kabler in 1942, the earliest physical examination findings include erythematous or eczema-like lesions, which then may become small blisters or subsequent large and painful bullae followed by hyperpigmented areas.^2,4 The differential diagnoses may include herpes viral infection, allergic contact dermatitis, poison oak or ivy exposure, impetigo, jelly fish envenomation, chemical and thermal burns, and nonaccidental trauma,^5-7 but none of these follow the clinical sequential triad seen with phytophotodermatitis.

The well-known 5 Cs of Arizona are climate, citrus, copper, cattle, and cotton. The first 2 Cs reveal the abundance of the sunny climate (ultraviolet solar radiation) and fruit-bearing citrus trees (Rutaceae family)⁴ in Arizona; their unfortunate combination presents annually to health care wound specialists, dermatologists, and burn surgeons.^4,8,9 Wound care specialists must be educated on phytophotodermatitis, which unfortunately has been misdiagnosed as nonaccidental trauma and can provoke a potentially embarrassing situation to the unsuspecting parent or adult caregiver who cannot recall any reasons precipitating such injuries. Easily confused with thermal burn injuries, the history as to how these injuries occurred is usually unclear; therefore, a physician’s accurate diagnosis must be made with a detailed history and physical examination.^8,9 The accuracy of the diagnosis also is directly related to clinical experience and may be missed by a clinician unfamiliar with this phototoxic reaction. The authors present a case report of a young girl injured by furocoumarin contact and subsequent solar UV-A radiation exposure that warranted an admission to a verified American Burn Association (ABA) burn center.

A 7-year-old, previously healthy girl with no past medical history was playing in her backyard when she squeezed and rubbed lemon juice, pulp, and rinds onto the skin of her face, neck, and chest as well as bilateral forearms, hands, legs, and feet. She continued to play in the hot, mid-September Arizona sunshine for several hours. The next morning the child complained of severe pain, erythema, and multiple small blisters to the aforementioned areas. She was evaluated by her pediatrician who consulted a local dermatologist who recommended various combinations of Aquaphor (Beiersdorf AG, Hamburg, Germany) and silver sulfadiazine (AGSD) cream for her blisters as well as oatmeal baths. The patient returned to the pediatrician within 2 days with worsening pain to her upper extremities and increasingly large blisters to the lower extremities. She was immediately referred to the Arizona Burn Center (Phoenix,  AZ), an ABA-verified burn center, and admitted for appropriate wound care with adequate pain control.

Upon physical examination, she was noted to be a well-nourished, well-developed 7-year-old girl with normal vital signs. Scattered first-degree (5% total body surface area [TBSA]) and second-degree burn-like lesions (10% TBSA) were found on her face, neck, chest, bilateral forearms and hands, and bilateral legs and feet (Figures 1, 2, 3, 4). These wounds were consistent with the history of lemon juice and pulp that had been smeared on the skin or had run down various aspects of her face and legs, leaving streak marks, while droplets or splatters from the lemon juice were evident on the chest and anterior thighs and legs.  All areas affected were in direct reach of her hands.

Subsequently, the blisters and wounds were debrided after administration of intravenous pain medications. The open second-degree burn-like wounds were treated with AGSD (Dr. Reddy’s Laboratories, Inc, Shreveport, LA) cream, while the first-degree burn-like wounds were treated with petroleum-based emollient (Beiersdorf Inc, Wilton, CT); sterile bandages were applied to the wounds. After receiving dressing changes every 12 hours and adequate oral pain medication (acetaminophen with codeine) over the next 3 days, the patient was discharged home with twice daily dressing changes and weekly clinic follow-up. After 21 days of home wound care, she returned to the burn clinic with well-healed wounds (Figures 5, 6, 7, 8) and no longer required oral pain medication. Hyperpigmentation was evident at the 3-week follow-up examination (Figure 9). She was discharged from the burn clinic with instructions to apply petroleum-based emollient to her wounds several times daily for the following 2 weeks and thereafter to apply sunscreen with a sun protection factor of greater than 30 when in direct sunlight for the next 3 months. 

Lemons and oranges (Rutaceae family) are the most frequent phytophotodermatitis-causing fruit substances produced in Arizona.^2,3 Generally, erythema occurs within 24 hours after initial furocoumarin contact, which may progress to blistering or tense and painful bullae formation.¹ This clinical progression eventually develops into hyperpigmentation of the affected area. The majority of these phytophototoxic injuries only require outpatient therapy and are directly related to the extent of furocoumarin contact, the depth of injury sustained after UV-A solar radiation exposure, and the symptoms experienced. Recent outpatients presenting to Arizona’s only ABA-verified burn center who were treated for their phototoxic injuries include a 60-year-old woman with painful, first-degree burn-like lesions to the dorsum of her hands and wrists after squeezing lemons and oranges to make fruit juice refreshments at a church function during the morning and afternoon hours and a 10-year-old girl who, while playing outside, presented with second-degree burn-like blisters at the hair line of her forehead, scalp, ears, and shoulders after her parent rubbed lemon juice in her dark hair to lighten the natural color. Both of these outpatients were treated with topical bacitracin for their wounds. In addition, they were told to remain out of direct sunlight, use sunscreen, and wash the affected areas with soap and water following contact with the fruit juice in the future.^10-12 Further symptomatology can be developed by the presence of moisture with sunlight, including humidity, which leads to the increased cutaneous absorption of the furocoumarins.¹²

The next step in the process of furocoumarin damage of the skin is direct sun exposure with UV-A radiation that causes the furocoumarin to covalently bind to the epidermal DNA.^2,5 Crosslinked DNA is the necessary essential pathway that results in skin injury and the subsequent development of erythema and blister formation.^2,5 In 2 studies^13,14 beginning in 1964 and progressing to publication in 1970, photosensitized furocoumarins irradiated with UV-A (365 nm) reacted with pyrimidines, resulting in a direct photochemical reaction (type 1 reaction) of a C4-cycloaddition to the 5,6-double bond of the pyrimidine base.^2,5 This reaction also included DNA and some denatured ribonucleic acid (RNA) moieties after exposure to radiation. However, the first step is noted to be the intercalation of the furocoumarin between the 2 base pairs of the DNA structure itself. It is the UV-A excitation of the 4’,5’monoadduct product and the crosslinking of the DNA in the epidermis that leads to severe cutaneous injuries.⁵ There is evidence of a type 2 reaction that may induce the peroxidation of the subcellular and cellular membranes, including the formation of radical superoxide anions.² Conclusively, this strong skin photosensitization reaction represents the most likely mechanism of action in the creation of these burn-like injuries and subsequent blister formation in any individual with adequate concentrations of the furocoumarin coupled with the appropriate UV-A wavelength.^1,15

Inflammation of the skin begins as early as 15 minutes after contact with furocoumarins and more severe cutaneous erythema and edema may develop after 24 hours.^1,2,15 Blistering is produced over the next 24 to 72 hours.^1,2 After adequate treatment, the epidermis eventually may become hyperpigmented in appearance through an unknown mechanism that leads to melanosome development starting 1 to 2 weeks after wound closure and lasting for up to 1 year before resolution.^2,16 In addition, tyrosine kinase activity increases, leading to the increased production of melanin.⁵

Children at play or individuals with occupational contact to furocoumarin-containing fruit or vegetation such as gardeners, florists, harvesters, food handlers, cannery workers, fruit juice handlers/makers, or bartenders⁵ may develop these cutaneous lesions if they are unaware of the risks of furocoumarin content (5-methoxypsoralen; 8-methoxypsoralen; 4,5’,8-trimethylpsoralen) to their exposed skin.¹ The use of gloves and protective clothing from furocoumarin contact is advisable.¹⁷ The rind contains more furocoumarins than the fruit pulp, but contact with either or both can lead to enough absorption of the furocoumarin to illicit the cutaneous response once exposed to sunlight UV-A radiation within 12 to 36 hours as in the patient in this report.^2,4

Phytophotodermatitis mistakenly has been attributed to child abuse as it simulates findings suggestive of a nonaccidental trauma and is only made worse when the unsuspecting parent cannot relate what happened to cause such injuries.^{1,2,4,5,8,9,11,12,16,18} Such an incident was described by Coffman et al⁸ from the University of Arizona, who had 2 children exposed to furocoumarins and UV-A radiation and developed unexplained burn-like injuries. A fruit juice splash or juice droplet markings leaving unusual streaks or adult hands covered in furocoumarins, which may result in cutaneous imprints on a child’s skin, could then be unjustly misconstrued as nonaccidental traumatic marks.^5,8,18 Nonetheless, physical abuse marks with intracutaneous bleeding (bruising) evolves from an initial red mark turning to a blue-colored area that then becomes a yellowish-brown, indistinct, multihued pattern as the breakdown products of hemoglobin are reabsorbed over 2 weeks.^8,11 Such injuries are different in appearance than the sequential progression of painful or itching erythematous skin, possible blistering, and final cutaneous hyperpigmentation induced by the phototoxic reaction.^8,11 The usual time for such phototoxic injuries to appear is when children are out of school on summer vacation from early June to early September, which also coincides with the maximal amount of sun overhead in the Northern Hemisphere.^11,13,18

While phytophototoxicity cases may spontaneously resolve within 3 to 5 days, wound care may be necessary for up to 3 weeks for adequate treatment before clinical wound resolution.^4,7,10 Because of the known hyperpigmentation effect, furocoumarins (also referred to as psoralens) plus the addition of UV-A radiation have been used in combination for the treatment of vitiligo, psoriasis, and atopic eczema with variable reported effects.^8,19 In a retrospective study,¹⁹ 10 children treated for vitiligo with topical meladine oil (8-methoxypsoralen and 8-isoamylene-oxypsoralen) were left unsupervised while exposed to the unlimited Saudi Arabian summer sunshine, which resulted in those children sustaining burn-like injuries over 6% to 40% TBSA. In another study,²⁰ 14 patients were taking oral psoralens for tanning purposes and sustained superficial and deep second-degree burn-like injuries after UV-A exposure requiring hospitalization for an average of 11 days.

Immediate treatment for furocoumarin exposure entails washing the affected area to remove any furocoumarins present within 30 minutes to 2 hours following contact, thereby preventing or limiting cutaneous absorption.^9-11 Washing hands with soap and water after handling citrus fruit as well as sunscreen application and clothing such as long-sleeved shirts and gloves to prevent UV-A radiation contact are important after furocoumarin exposure.^5,10,11 Application of AGSD cream to open burns once the blisters are debrided is a safe and effective treatment.^4,19,20 Educational efforts are important for parents and individuals where abundant sunshine prevails and where inadvertent furocoumarin contact would not usually cause alarm to the unsuspecting parent and/or child.

Burn-like lesions caused by furocoumarin after cutaneous absorption followed by UV-A exposure is a known clinical entity in Arizona. The sequential progression from erythematous lesions to blisters that are equivalent to second-degree burn-like lesions and then to cutaneous hyperpigmentation is a well-described, sequentially occurring clinical triad. Meticulous wound care and pain control for these injuries are essential as is the need for the wound care specialist to be well versed on this topic to quickly identify the etiology of the injury, thereby avoiding misdiagnosing the pediatric patient with nonaccidental traumatic injuries.