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Research Letter |

Clinicopathological Findings in Persistent Corneal Cowpox Infection FREE

Sybille Graef, MD1; Andreas Kurth, PhD2; Claudia Auw-Haedrich, MD3; Niklas Plange, MD5; Winfried V. Kern, MD4; Andreas Nitsche, PhD2; Thomas Reinhard, MD3
[+] Author Affiliations
1University Eye Hospital Tuebingen, Tuebingen, Germany
2German Consultant Laboratory for Poxviruses, Centre for Biological Security, Robert Koch Institute, Berlin, Germany
3University Eye Hospital Freiburg, Freiburg im Breisgau, Germany
4Centre for Infectious Diseases and Travel Medicine, Department of Medicine, University Hospital Freiburg, Freiburg im Breisgau, Germany
5Department of Ophthalmology, RWTH Aachen University, Aachen, Germany
JAMA Ophthalmol. 2013;131(8):1089-1091. doi:10.1001/jamaophthalmol.2013.264.
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Published online

Cowpox viruses (CPXVs) belong to the genus Orthopoxvirus.1 Increasingly, CPXV infections have been reported in domestic cats, rats, and exotic zoo animals, with humans potentially being infected through direct contact with these animals.1 Typically, a CPXV infection becomes apparent through the development of small skin lesions. Healing comes with scar formation and can take several weeks. Complications and severe courses have been reported in immunocompromised individuals.2

In February 2009, a 49-year-old woman presented to a local clinic with a swollen eyelid and phlyctenular changes of the cornea in her right eye. She received antibiotics and steroid eyedrops for 2 weeks, but she developed a corneal infiltration and marginal ulceration and her best-corrected visual acuity (BCVA) decreased to 20/100.3 Because of skin lesions on her shoulder that developed after direct contact with a rat suspected of being infected with CPXV, she was also tested for a CPXV infection. That was confirmed by real-time polymerase chain reaction from conjunctival and skin swab samples. The CPXV infection of the eye was probably caused by smear infection. Involvement of Staphylococcus aureus was shown by a swab, so she was given cefuroxime sodium and local antibiotics. Corneal infiltration then resolved, but limbal ulceration worsened. Four months after the initial infection, conjunctival swabs were negative for CPXV. From then on, she received steroid eyedrops to control inflammation, ofloxacin eyedrops because of subtotal erosion, and lubricants. From her general medical history, she solely reported a 22-year history of type 1 diabetes mellitus.

In March 2010, she presented at the University Eye Hospital Freiburg because of increasing corneal melting with persistent corneal erosion (Figure 1, A and B). Her BCVA was counting fingers. Penetrating limbokeratoplasty was performed. Postoperatively, her BCVA was 10/200 (Figure 1C) and she received immunosuppressive treatment with mycophenolate mofetil.4 Three weeks later, the patient presented with scleritis, transplant erosion, and ocular hypotension. Her BCVA was reduced to 1/50. The patient received prednisolone, 100 mg/d, and cidofovir, 350 mg, intravenously once weekly because reactivation of a CPXV infection was suspected. The ocular changes improved, and the intraocular pressure values became normal, no longer hypotensive, with an epithelialized edematous transplant. Her BCVA was limited to hand movements. The cidofovir therapy was maintained. Cidofovir is, in fact, approved for Cytomegalovirus retinitis in patients with AIDS. The local therapy consisted of dexamethasone sodium phosphate, 1%, every hour. Two weeks later, the patient presented with transplant erosion and decompensated intraocular pressure due to extensive anterior synechiae. Intraocular pressure normalized after operative revision. Epithelialization took place, but the transplant remained bullous. Three months after transplantation, failure of the graft was evident. There was no inflammation.

Place holder to copy figure label and caption
Figure 1.
Preoperative and Postoperative Findings

A, Preoperative status of the right eye 18 months after primary infection with cowpox virus. B, Fluorescein staining shows widespread corneal erosion and step formation at the corneal margin (arrow). C, Postoperative finding 1 day after limbokeratoplasty. Arrows indicate the limbal part.

Graphic Jump Location

Examination of the corneal explant revealed widespread destruction of the Bowman layer. The epithelium was missing in the central part. Diffuse infiltration of lymphocytes and neutrophil granulocytes was seen. Eosinophilic granular structures were found between stromal lamellae and within some keratocytes (Figure 2A). Histological changes were congruent with chronic keratitis as well as infectious crystalline keratopathy (Figure 2B). Interestingly, the corneal explant tested positive for CPXV DNA by polymerase chain reaction. Also, electron microscopy of the corneal explant revealed numerous Orthopoxvirus particles in different stages and locations of the cornea (Figure 2, C and D).

Place holder to copy figure label and caption
Figure 2.
Histological Analysis

A, Histological overview showing local bacterial infiltrations (arrow) (hematoxylin-eosin, original magnification ×100). B, The keratocytes seem to be swollen with granular cytoplasmic material (arrow) (hematoxylin-eosin, original magnification ×400). C, Immature virions (arrows) are located in the cytoplasm of keratocytes. Co indicates collagen fibers (scale bar = 500 nm). D, Mature virions (arrows) are enclosed by collagen fibers (Co) (scale bar = 500 nm).

Graphic Jump Location

To our knowledge, this is the first report of corneal melting necessitating corneal transplantation due to a CPXV infection. Ocular complications following CPXV infection involving swelling or ulceration of eyelids, conjunctivitis, and superficial keratitis have rarely been reported.2,5 Histological changes correlate with former reports of viral-induced corneal erosion.6 It seems that if the epithelial barrier is defective, keratocytes may especially be prone to infection.

Topical and systemic immunosuppression as well as the immune privilege of the eye may have supported viral persistence and disease course. Potentially, the immunosuppressive therapy (prednisone, mycophenolate) prevented any reaction against CPXV, facilitating viral persistence and the graft failure. It is unclear whether the underlying diabetic condition had any effect on disease progression. No specific antiviral therapy exists for CPXV infection, but the application of cidofovir probably inhibited viral replication. Nevertheless, therapeutic options are limited, underscoring the potential risk of CPXV infection to humans.

Corresponding Author: Dr Graef, University Eye Hospital Tuebingen, Schleichstrasse 12-16, 72076 Tuebingen, Germany (sybille.graef@med.uni-tuebingen.de).

Published Online: June 13, 2013. doi:10.1001/jamaophthalmol.2013.264.

Conflict of Interest Disclosures: None reported.

Vorou  RM, Papavassiliou  VG, Pierroutsakos  IN.  Cowpox virus infection: an emerging health threat. Curr Opin Infect Dis. 2008;21(2):153-156.
PubMed   |  Link to Article
Baxby  D, Bennett  M, Getty  B.  Human cowpox 1969-93: a review based on 54 cases. Br J Dermatol. 1994;131(5):598-607.
PubMed   |  Link to Article
Schwarzer  H, Kurth  A, Hermel  M, Plange  N.  Severe ulcerative keratitis in ocular cowpox infection. Graefes Arch Clin Exp Ophthalmol. 2013;251(5):1451-1452.
PubMed   |  Link to Article
Birnbaum  F, Böhringer  D, Sokolovska  Y, Sundmacher  R, Reinhard  T.  Immunosuppression with cyclosporine A and mycophenolate mofetil after penetrating high-risk keratoplasty: a retrospective study. Transplantation. 2005;79(8):964-968.
PubMed   |  Link to Article
Wolfs  TF, Wagenaar  JA, Niesters  HG, Osterhaus  AD.  Rat-to-human transmission of Cowpox infection. Emerg Infect Dis. 2002;8(12):1495-1496.
PubMed   |  Link to Article
Huemer  HP, Essbauer  S, Irschick  EU.  Tissue damage caused by animal orthopoxviruses cowpox, ectromelia, vaccinia and parapoxvirus ovis in human cornea. Acta Ophthalmol. 2010;88(7):e275-e276.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
Preoperative and Postoperative Findings

A, Preoperative status of the right eye 18 months after primary infection with cowpox virus. B, Fluorescein staining shows widespread corneal erosion and step formation at the corneal margin (arrow). C, Postoperative finding 1 day after limbokeratoplasty. Arrows indicate the limbal part.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Histological Analysis

A, Histological overview showing local bacterial infiltrations (arrow) (hematoxylin-eosin, original magnification ×100). B, The keratocytes seem to be swollen with granular cytoplasmic material (arrow) (hematoxylin-eosin, original magnification ×400). C, Immature virions (arrows) are located in the cytoplasm of keratocytes. Co indicates collagen fibers (scale bar = 500 nm). D, Mature virions (arrows) are enclosed by collagen fibers (Co) (scale bar = 500 nm).

Graphic Jump Location

Tables

References

Vorou  RM, Papavassiliou  VG, Pierroutsakos  IN.  Cowpox virus infection: an emerging health threat. Curr Opin Infect Dis. 2008;21(2):153-156.
PubMed   |  Link to Article
Baxby  D, Bennett  M, Getty  B.  Human cowpox 1969-93: a review based on 54 cases. Br J Dermatol. 1994;131(5):598-607.
PubMed   |  Link to Article
Schwarzer  H, Kurth  A, Hermel  M, Plange  N.  Severe ulcerative keratitis in ocular cowpox infection. Graefes Arch Clin Exp Ophthalmol. 2013;251(5):1451-1452.
PubMed   |  Link to Article
Birnbaum  F, Böhringer  D, Sokolovska  Y, Sundmacher  R, Reinhard  T.  Immunosuppression with cyclosporine A and mycophenolate mofetil after penetrating high-risk keratoplasty: a retrospective study. Transplantation. 2005;79(8):964-968.
PubMed   |  Link to Article
Wolfs  TF, Wagenaar  JA, Niesters  HG, Osterhaus  AD.  Rat-to-human transmission of Cowpox infection. Emerg Infect Dis. 2002;8(12):1495-1496.
PubMed   |  Link to Article
Huemer  HP, Essbauer  S, Irschick  EU.  Tissue damage caused by animal orthopoxviruses cowpox, ectromelia, vaccinia and parapoxvirus ovis in human cornea. Acta Ophthalmol. 2010;88(7):e275-e276.
PubMed   |  Link to Article

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