Statistics from Altmetric.com
Immune recovery disease results from an immunological response to circulating viral antigens in the host after bone marrow transplant (BMT) mediated immune reconstitution. It may also occur after successful antiretroviral therapy in patients with HIV and AIDS. We report a case of a child with severe combined immune deficiency (SCID) and disseminated varicella zoster virus (VZV) infection who developed interstitial keratitis and a tonic pupil after BMT.
An 8 month old male infant was referred to the ophthalmology clinic at Great Ormond Street because of suspected congenital glaucoma. The past ophthalmic and family history were unremarkable. The child was born with multiple congenital anomalies of the lower limbs which included bilateral tibial deficiencies, and an extreme talipes equinovarus of the right foot.
The child had a known history of disseminated varicella infection caused by SCID (fig 1). On examination it was noted that he had a generalised vesicular rash throughout his body extending to his eyelid margins. The eyes were white with clear corneas and he was alert, fixing and following well with full extraocular eye movements. Both pupils were reactive to light with no afferent pupillary defect. The anterior chambers were unremarkable and the intraocular pressure with the Perkins tonometer was 16 mm Hg bilaterally. Examination of the fundus, including cup to disc ratio was normal. He was reviewed periodically over the next 6 months while an inpatient undergoing treatment for SCID. During this period, he was persistently positive for VZV DNA in his blood determined by polymerase chain reaction (PCR) analysis but was negative for Epstein-Barr virus (EBV), herpes simplex virus (HSV), cytomegalovirus (CMV), and adenovirus DNA. He suffered a number of exacerbations of the varicella infection and was treated with systemic aciclovir, foscarnet, and cidofovir.
At 12 months of age he underwent allogeneic BMT from a one antigen mismatched unrelated donor following reduced intensity conditioning with fludarabine, melphalan and alemtuzumab. Engraftment was very rapid with neutrophils appearing by day 10. Before BMT the CD3+ CD4+ count was 0.04×109/l but 7 weeks after BMT the CD3+ CD4+ count was 0.47×109/l.
Four weeks after BMT his mother noted bilateral corneal haze which was more marked on the left eye. He was reviewed in his isolation cubicle with a hand held slit lamp and Perkins tonometer and was found to have bilateral corneal stromal haze and corneal vascularisation (fig 2). There was no conjunctival injection, and his intraocular pressure was 13 mm Hg in each eye. Both pupils were reactive to light. The lymphocyte count had recovered at this point to more than 1.0×109/l.
An examination under anaesthesia was arranged and a diagnosis of interstitial keratitis without epithelial involvement was made. He was treated with intensive topical prednisolone acetate 1% (one drop every 2 hours) and cyclopentolate 1% twice daily to both eyes. Betaxolol 0.5% twice daily was prescribed prophylactically to prevent raised intraocular pressure which could exacerbate the corneal haze. The child was reviewed regularly and the stromal vascularisation was seen to regress. He was thus gradually weaned off the steroid drops to one drop daily and the cycloplegics were stopped. Three months after BMT his mother reported a change in pupillary size in the right eye. On examination the right pupil was mid-dilated and oval in shape, not reactive to light and there was no evidence of posterior synechiae (fig 3). A diagnosis of a right tonic pupil was made.
At the most recent review, 6 months following BMT he had clear corneas centrally in both eyes with some persistent peripheral stromal vessels, and a right tonic pupil. Unaided visual acuity was 0.60 logMAR with both eyes using the Cardiff acuity test (Keeler Ltd, Windsor, UK). There was a left fixation preference and amblyopia therapy was commenced with occlusive patches.
Currently, the child has an ongoing mild chronic graft versus host disease affecting the skin and intestine which is controlled with low dose systemic steroids. His systemic medications also include aciclovir 120 mg four times daily.
Severe combined immune deficiencies (SCID) are a rare heterogeneous group of disorders characterised by severe T cell and B cell deficiency with low or absent antibody levels. They usually manifest in the first months of life with severe and recurring infections leading to death often by the age of 2 years.1
Since 1968 these diseases have been successfully treated with haemopoietic stem cell transplantation.2 Varicella infection has been associated with severe immune dysfunction following BMT and it has been shown that severe disseminated varicella infection causes ocular disease that mimics the sequelae of herpes zoster ophthalmicus.3 In the adult population, the commonest cause of interstitial keratitis is HSV infection whereas varicella infection is considered a rare cause.4 In children, although varicella infection is extremely common, ocular complications of this disease are rare.5
If keratitis develops in association with a childhood viral exanthem it is important to consider a number of possible infectious agents such as HSV, EBV, mumps, syphilis, Lyme disease, or tuberculosis in the differential diagnosis.4 In this setting, other documented complications in association with SCID include bilateral viral endophthalmitis,6 CMV retinitis, and optic neuritis.7 In this case the history and the physical findings were highly suggestive of the diagnosis and were confirmed by PCR testing. As far as we are aware this is the first case of varicella associated interstitial keratitis and a tonic pupil occurring in a child with SCID following BMT.
The signs of early interstitial keratitis and a right tonic pupil were noted by the child’s mother about 4 weeks after the allogeneic bone marrow transplant. We believe that an immunological response to pre-existing varicella was responsible for the development of the eye signs. This signifies a positive response from a nascent immune system in the recipient—an example of immune recovery disease.
There is experimental evidence to support this as it has been shown that whole lymphocyte and splenocyte transfer leads to herpes simplex keratitis in SCID mice.8 In other words SCID mice reconstituted with T lymphocytes of the CD4 + phenotype developed subsequent corneal lesions in relation to HSV infection. Conversely Mercadal et al have shown that unreconstituted SCID mice remained lesion free when infected with HSV.8 This suggests that herpes simplex keratitis is a T cell mediated immunopathological reaction to virus in the cornea. In our case the corneal changes occurred following bone marrow reconstitution. Before BMT the CD3+ CD4+ count was 0.04×109/l but 7 weeks following BMT the CD3+ CD4+ count was 0.47×109/l. The corneal changes become apparent at about 4 weeks after BMT. We believe that our case illustrates a similar mechanism in the human model in relation to varicella infection.
The tonic pupil developed as a consequence of a post-viral ganglionitis affecting the ciliary ganglion and the short posterior ciliary nerves, a rare but previously described complication of varicella infection.9 Other reported cases of ophthalmic immune recovery disease include a case of varicella zoster virus associated anterior stromal keratitis in a patient with AIDS10 and, in another case, in association with CMV retinitis.11
Considering BMT, varicella zoster virus associated disease can be a frequent complication following autologous and allogeneic transplantation.12 Other complications in relation to BMT include pseudomembranous conjunctivitis,13 keratoconjunctivitis sicca,14 cataracts,15 and severe graft versus host disease.16
This child did suffer a graft versus host disease-like rash at the time of the development of the keratitis. While it is possible that the keratitis was purely Graft versus host disease this seems unlikely, given that there was no conjunctival involvement and that the graft versus host disease was extremely mild. Furthermore, in this case the disseminated varicella infection preceded the BMT and formed the basis for identifying a severe immune deficiency in the child. It highlights the importance of frequent ophthalmic follow up in the immediate period following BMT as there is an increased risk of ocular disease.