Purpuric Phototherapy-induced Eruption in Transfused Neonates: Relation to Transient Porphyrinemia

DISCUSSION

Visible light phototherapy is the treatment of choice for neonatal indirect hyperbilirubinemia.⁴ Daylight fluorescent bulbs emit radiance in a continuous emission spectrum from 320 nm to 700 nm, although the therapeutic wavelength is in the blue range. Shielding is included with phototherapy units to protect the infant from bulb breakage and from radiation wavelengths <380 nm during phototherapy.⁵

In this report, we describe a benign but distinct complication of phototherapy in six neonates. The characteristic clinical features of the eruption are clear demarcation, failure to blanch with diascopy, localization of purpura to sites closest to the phototherapy lamps, sparing of sites protected from phototherapy exposure, and clearing of the eruption with discontinuation of phototherapy. These features implicate the phototherapy lamps in triggering the cutaneous disorder. The relatively rare complication in transfused neonates that we call “purpuric phototherapy-induced eruption” was seen in these six neonates during a 6-year period at three different neonatal units within the Northwestern University Medical School system (five neonates) and at Children's Hospital of Philadelphia. All of these neonates received transfusions before exposure to the lights; in five of the six infants, erythroblastosis fetalis was the cause of the hemolytic anemia, whereas in the fifth, a twin–twin transfusion necessitated the blood transfusion.

The pattern of the eruption led to the initial consideration of “burn” as the diagnosis in several of these infants, yet no reason for a burn could be determined. Siegfried et al described two neonates who were treated with fluorescent daytime lamps without Plexiglass shielding.⁶ In both patients, “erythema” (not a purpuric eruption) was noted at exposed sites, with sparing; blistering was noted in one of these infants, consistent with a second degree burn. Neither neonate received a transfusion, and no skin biopsy was performed. Although the nonblanching nature of the phototherapy-induced purpura differs from the “sunburn” of ultraviolet A exposure from the fluorescent lamps, we specifically checked the shielding in all of the infants and found it to be in place. In each of our neonatal units, standard shielding for the phototherapy units is never removed, and the same units have been used by hundreds of other babies without complication. Furthermore, the biopsy examination of lesional skin of patients 1 and 3 showed focal areas of purpura without features of cutaneous ultraviolet burn (significant epidermal edema, necrotic keratinocytes, or inflammatory infiltration). We also considered the diagnosis of a heat-mediated burn. However, the lack of involvement of the skin in contact with the central metal area of the leads and the lack of epidermal damage and inflammation in the biopsy make this diagnosis unlikely.

Well-demarcated erythematous photosensitivity eruptions and purpuric lesions with sparing of shielded areas may result from the administration of phototoxic drugs and exposure to ultraviolet A radiation. The possibility of a drug-induced reaction must be considered in the neonate with phototherapy purpura. Most notorious among these photosensitizing drugs is furosemide,⁷ a medication commonly administered to sick neonates. Three of our six neonates were exposed to furosemide before the onset of the eruption. Administration of dyes may also cause photosensitivity. Intravenous fluorescein administration for angiography in a 32-week gestational age neonate resulted in a “partial thickness burn” after exposure to phototherapy for hyperbilirubinemia.⁸ The eruption was described as “erythematous and vesicular . . . with bullae.” Areas under leads were spared. The skin lesions were attributed to phototoxicity from the fluorescein, which has been shown to produce photosensitization by generation of a superoxide anion when exposed to light at a wavelength of 480 nm, in the visible light range. Slow renal clearance of the fluorescein may have led to its persistence in the skin for 6 days rather than for the usual 12 to 18 hours, as detected by Wood's lamp. In this neonate with necrotizing enteritis and surgical intervention, transfusions were likely to have been administered. Blanching of the “erythema” with compression of skin is not mentioned, nor were porphyrin levels obtained.

Although the mechanism of phototherapy purpura in our six neonates is unknown, it is intriguing to consider the possibility of circulating porphyrins as the causative agents. Porphyrins absorb light maximally in the Soret band (400 to 410 nm), with lesser bands occurring in the long visible range (580 to 650 nm).⁹ Photodistributed cutaneous erythema with purpura developed in a liver transplant recipient after exposure to a heat lamp that emitted visible light.¹⁰ Blood levels of both coproporphyrins and protoporphyrins were elevated at the time of the eruption. Neonatal blistering and photosensitivity during phototherapy for jaundice have been described in infants with congenital erythropoietic porphyria,^11,12 and purpura is an occasional feature of erythropoietic protoporphyria. Photodistributed erythema has been described occasionally in neonates treated with the experimental compound tin-protoporphyrin followed by daylight fluorescent phototherapy to treat hyperbilirubinemia,¹³ which cleared after discontinuation of the phototherapy.

Crawford et al recently described a neonate with erythroblastosis attributable to antibodies against maternal e andc blood antigens who developed a “violaceous discoloration . . . with sharp demarcation at sites of photoprotection” 31 hours after initiation of phototherapy.¹⁴ The appearance of this eruption was identical to that in our six neonates. In contrast, however, Crawford et al's patient also developed erosions at maximally affected sites and required 3 weeks to clear after discontinuation of the phototherapy. Laboratory tests on this baby showed markedly elevated levels of free erythrocyte protoporphyrin on the fifth day of life and zinc protoporphyrin levels on the 14th and 31st days; erythrocyte protoporphyrin levels were normal at 19 weeks of age. Plasma coproporphyrin levels were not described.

Blisters and erosions have been described recently in another neonate with hemolytic disease of the newborn who received phototherapy.¹⁵ This neonate had normal urine, fecal, and erythrocyte porphyrin levels, but had elevated plasma porphyrin levels [(peak total porphyrin, 27.3 μg/dL on day 15 (normal, <1 μg/dL)] when first measured 4 days after the blisters appeared. This elevated plasma porphyrin level was largely attributable to elevated plasma coproporphyrins. Similarly, the plasma porphyrin level, largely comprised of coproporphyrins, was elevated in two neonates described in our report in whom levels were obtained. Normally, plasma porphyrins are below the level of detection. Levels in the range of 10 to 15 μg/dL are usually associated with cutaneous photosensitivity, eg, the mean plasma porphyrin level in porphyria cutanea tarda is 15.8 ± 9.1 μg/dL (predominantly plasma coproporphyrins).¹⁶

The origin of the increased plasma porphyrins in the neonates that we describe is unclear. Hepatic cholestasis and poor hepatic porphyrin metabolism may have contributed to the increase in plasma porphyrins, because the direct bilirubin level was elevated in the two patients with increased plasma porphyrins. One of these patients also had an increase in transaminase levels. However, patient 3 and a patient described previously¹⁴ showed elevated erythrocyte porphyrins, which cannot be explained by hepatic dysfunction. It is unlikely that the transfused blood contained elevated levels of porphyrins. On the other hand, an unlikely but possible source of circulating porphyrins is release of porphyrins by hemolysis of young erythrocyte precursors, including reticulocytes, which contain at least a 10-fold higher protoporphyrin concentration than do mature erythrocytes.¹⁷

Purpuric light eruption should be recognized as a transient, benign, cutaneous eruption in transfused neonates who undergo phototherapy. Our discovery of significantly increased plasma porphyrin levels in the two neonates studied suggests a link with the development of cutaneous lesions after exposure to intense fluorescent radiation in the range of 400 nm. Examination of the plasma porphyrin levels in neonates affected in the future may help to elucidate the mechanism of this distinct purpuric eruption.