Ocular Immunology & Inflammation, 2015; 23(1): 106–109 ! Informa Healthcare USA, Inc. ISSN: 0927-3948 print / 1744-5078 online DOI: 10.3109/09273948.2014.920510
LETTER TO THE EDITOR
Ophthalmic Manifestation of Disseminated Cutaneous Mycobacterium avium–intracellulare Complex in a Child with a Presumed Primary IL-12 Receptor Defect Cheefoong Chong, MbChB1,2, Jan Sinclair, FRACP3, Lesley Voss, FRACP3, Diana Purvis, FRACP, FNZDS3, Shuan Dai, FRANZCO1,2, and Erika M. Damato, MA, MRCP1,2 1
Department of Ophthalmology, New Zealand National Eye Centre, University of Auckland, Grafton, Auckland, New Zealand, 2Department of Ophthalmology, Auckland District Health Board, Greenlane Clinical Centre, Greenlane, Auckland, New Zealand, and 3Starship Children’s Hospital, Auckland District Health Board, Grafton, Auckland, New Zealand
Mycobacterium avium–intracellulare complex (MAC) comprises two Mycobacterium species, M. avium and M. intracellulare, and is a nontuberculous mycobacterium of little significance in the immunocompetent host, apart from cervical lymphadenopathy in young children.1 In immunocompromised individuals, however, such as those with AIDS2 or those receiving immunosuppressive medications, MAC can cause significant disease, often leading to pulmonary infection or disseminated infection. Rarely, systemic disseminated MAC can affect the eye.3 We report the case of a female pediatric patient with primary immunodeficiency, who presented with disseminated cutaneous MAC and who subsequently developed a related multifocal choroiditis and consequent choroidal neovascular membrane in the right eye, while on systemic therapy for her infection.
exacerbations of asthma, pneumonia, and recurrent ear infections. She was reported to have had past infections with wild-type measles, pertussis, and recurrent impetigo, and was unvaccinated by family choice. The patient initially developed painless, nonpruritic lesions on her upper back, scalp, chest, and thigh at the age of 8. These were managed conservatively. She remained under her local general practitioner and was referred for further investigation at the age of 12 when it was noted that the lesions had persisted (Figure 1). A skin biopsy demonstrated intense granulomatous inflammation in the dermis (Figure 2), and further testing enabled a diagnosis of cutaneous MAC. A 12-month course of treatment was commenced in May 2012 with ethambutol (15 mg/kg daily) and clarithromycin (7.5 mg/kg daily). She was referred to the ophthalmology service, shortly after commencing treatment, for regular monitoring of potential ethambutol toxicity. An initial ophthalmic examination including dilated fundus examination was normal and she had an unaided acuity of 6/6 bilaterally. Following the diagnosis of disseminated cutaneous MAC, the patient underwent a battery of systemic investigations into a primary immunodeficiency. Notably, her chest x-ray, abdominal ultrasound, HIV test, nitro-blue tetrazolium test (NBT), and T-cell function assays were normal. IgG was elevated and IgA and IgM were normal. Further testing into genetic
CASE REPORT A 12-year-old Caucasian girl was seen in pediatric services with disseminated skin lesions. She was born at full term with an uneventful newborn course. The youngest of 5 children, she had a brother who died at 8 weeks of age secondary to pneumonia, 2 older brothers with histories of recurrent boils, and an older sister with asthma. Her own childhood course was marked with several hospitalizations for
Received 19 December 2013; revised 20 March 2014; accepted 29 April 2014; published online 29 May 2014 Correspondence: Dr. Erika M. Damato, Fred Hollows NZ Ophthalmology Clinical Research Fellow, New Zealand National Eye Centre, Department of Ophthalmology, Private Bag 92019, University of Auckland, Auckland, New Zealand. E-mail: [email protected]
106
Mycobacterium avium–intracellulare Complex
107
cytokine defects revealed a normal interferon gamma (IFNg) receptor pathway but suggested a defect in interleukin (IL)-12 receptor, accounting for her presentation and previous medical history. Ten months into her treatment course, the patient developed symptoms of blurred vision and a scotoma in the right eye. She was referred to ophthalmology services for review. When seen in our clinic, best corrected visual acuity was 6/120 in the right eye and 6/6 in the left. Anterior segment examination and intraocular pressures were unremarkable, Dilated fundscopy was performed and revealed a right macular disciform scar with surrounding multifocal choroidal lesions (Figure 3). There was no vitritis. Invasive testing, such as vitreous sampling for polymerase chain reaction (PCR) testing was not felt to be warranted in view of the low perceived yield. OCT scans did not demonstrate the presence of intraretinal or subretinal fluid. A fluorescein angiogram was obtained, which showed inactive disease without any active vasculitis or choroiditis (Figure 4).
In view of her clinical presentation and recent medical history, a diagnosis of choroidal neovascularization secondary to systemic dissemination of MAC to the choroid was made. As the lesions were inactive and scarred, no additional ophthalmic treatment was prescribed. The patient remained under the care of a multidisciplinary team, including immunology, dermatology, infectious diseases, and pediatric ophthalmology teams. She completed her 12-month course of ethambutol treatment and continued on clarithromycin prophylaxis. Her cutaneous lesions improved significantly, with marked reduction in size, flattening, and increased pallor. No new lesions developed and no lymphadenitis, hepatomegaly, or splenomegaly occurred. Despite, the improvement of her cutaneous condition, vision in the right eye remained poor due to macular scarring.
FIGURE 1. Photograph of cutaneous lesion on the upper aspect of the back.
FIGURE 3. Fundus photograph showing advanced disciform scar with underlying granulomatous choroidal lesions.
FIGURE 2. (a) Cutaneous histology showing intense granulomatous inflammation in the dermis (hematoxylin and eosin stain, magnification 100). (b) The granulomata are composed of foamy histiocytes and multinucleated giant cells with a background of lymphocytes, plasma cells, and occassional eosinophils (hematoxylin and eosin stain, magnification 200). !
2015 Informa Healthcare USA, Inc.
108 C. Chong et al.
FIGURE 4. Midphase fluorescein angiogram showing blocked fluorescence and no significant leakage from a choroidal neovascular membrane. OCT scan through the lesion demonstrates scarring with no intraretinal or subretinal fluid to suggest ongoing activity.
DISCUSSION The occurrence of disseminated infection due to an organism that is not normally virulent requires investigation into an underlying immunodeficiency syndrome. Mycobacteria cause intracellular infection, which is normally under tight control by T-cell-mediated immunity and interferon gamma (IFNg) and IL-12 signaling. Inherited conditions, collectively known as Mendelian susceptibility to mycobacterial diseases (MSMD) occur due to a variety of defects, including those affecting IFNg and its receptor, IL-12 and its receptor and other molecules involved in these pathways. MSMD manifests as recurrent infection with organisms such as MAC.4 In healthy individuals, infection of macrophages by MAC leads to the display of MAC antigen on MHC class II molecules on the macrophage surface and stimulation of IL-12 release. Antigen-specific T cells respond to IL-12 by releasing cytokines, notably IFNg, and by synthesizing membrane associated proteins, such as the CD40 ligand. The process of T-cell activation results in increased genetic expression of effector cytokines and cell surface molecules. The complex of activated macrophages and surrounding T cells results in the formation of a granuloma. In addition, activated macrophages release TNFa, further stimulating other macrophages and T cells and maintaining the structure of the granuloma. Activated macrophages are equipped to kill and destroy the intracellular pathogen, in this case a mycobacterium, by mechanisms including the nitric oxide pathway.5
Genetic defects in IL-12 and the IL-12 receptor have been identified and are observed to result in an unusual susceptibility to mycobacterial infection. Such defects often lead to absent or reduced IFNg production and deficient macrophage activation.6 The diagnosis of an IL-12 receptor defect is supported by functional studies and confirmed by genetic testing. During functional studies, blood samples from the individual are exposed to IL-12 and to mycobacterial antigens, and levels of IFNg produced are measured. Affected patients will produce abnormally low levels of IFNg in response to such stimulation. IFNg signaling itself, however, is maintained. Common genetic mutations responsible for such defects are reported to include an autosomal recessive IL-12BR1 deficiency, but other mutations can exist. Treatment of acquired mycobacterial infection with conventional antibiotic regimens may be only partially effective in these patients. There is a role for recombinant IFNg treatment, which has been used very successfully in suitable patients. Partial efficacy of antibiotic therapy could account for the observation that our patient developed choroidal involvement while on appropriate treatment. In addition, an inappropriate immune response mounted in the choroid, may have contributed to this manifestation. Currently, our patient has no clinical evidence of active MAC infection. She remains visually impaired in the right eye due to macular scarring. Should her condition reactivate or involve the contralateral eye, both local treatments, including intravitreal avastin, and systemic therapy with IFNg may be warranted. Ocular Immunology & Inflammation
Mycobacterium avium–intracellulare Complex This case highlights the need to recognize underlying immunodeficiency states in children presenting with unusual infections and emphasizes that, despite seemingly adequate anti-infective therapy, infectious complications may persist, in this case leading to irreversible visual loss.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. We would like to acknowledge Mike Watson, consultant histopathologist, for the provision of the histopathology figures and legends and Roger Tuck, Shannon Brothers, and Andrew Watts, who were involved in initial management of this patient.
!
2015 Informa Healthcare USA, Inc.
109
REFERENCES 1. Howell N, Heaton P, Neutze J, Taranaki BHNP. The epidemiology of nontuberculous mycobacterial lymphadenitis affecting New Zealand children 1986–95. N Z Med J. 1997;9:171–173. 2. Horsburgh CR. Mycobacterium avium complex infection in the acquired immunodeficiency syndrome. N Engl J Med. 1991;324:1332–1338. 3. Rosenbaum PS, Mbekeani JN, Kress Y. Atypical mycobacterial panophthalmitis seen with iris nodules. Arc. Ophthalmol. 1998;116:1524–1527. 4. Haraguchi S, Day NK, Nelson RP, et al. Interleukin 12 deficiency associated with recurrent infections. Proc Natl Acad Sci U S A. 1998;95:13125–13129. 5. Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferongamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004;75:163–189. 6. Ramirez-Alejo N, Blancas-Galicia L, YamazakiNakashimada M, et al. Molecular analysis for patients with IL-12 receptor b1 deficiency. Clin Genet. 2013 Aug 16. [Epub ahead of print].
Copyright of Ocular Immunology & Inflammation is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
LETTER TO THE EDITOR
Ophthalmic Manifestation of Disseminated Cutaneous Mycobacterium avium–intracellulare Complex in a Child with a Presumed Primary IL-12 Receptor Defect Cheefoong Chong, MbChB1,2, Jan Sinclair, FRACP3, Lesley Voss, FRACP3, Diana Purvis, FRACP, FNZDS3, Shuan Dai, FRANZCO1,2, and Erika M. Damato, MA, MRCP1,2 1
Department of Ophthalmology, New Zealand National Eye Centre, University of Auckland, Grafton, Auckland, New Zealand, 2Department of Ophthalmology, Auckland District Health Board, Greenlane Clinical Centre, Greenlane, Auckland, New Zealand, and 3Starship Children’s Hospital, Auckland District Health Board, Grafton, Auckland, New Zealand
Mycobacterium avium–intracellulare complex (MAC) comprises two Mycobacterium species, M. avium and M. intracellulare, and is a nontuberculous mycobacterium of little significance in the immunocompetent host, apart from cervical lymphadenopathy in young children.1 In immunocompromised individuals, however, such as those with AIDS2 or those receiving immunosuppressive medications, MAC can cause significant disease, often leading to pulmonary infection or disseminated infection. Rarely, systemic disseminated MAC can affect the eye.3 We report the case of a female pediatric patient with primary immunodeficiency, who presented with disseminated cutaneous MAC and who subsequently developed a related multifocal choroiditis and consequent choroidal neovascular membrane in the right eye, while on systemic therapy for her infection.
exacerbations of asthma, pneumonia, and recurrent ear infections. She was reported to have had past infections with wild-type measles, pertussis, and recurrent impetigo, and was unvaccinated by family choice. The patient initially developed painless, nonpruritic lesions on her upper back, scalp, chest, and thigh at the age of 8. These were managed conservatively. She remained under her local general practitioner and was referred for further investigation at the age of 12 when it was noted that the lesions had persisted (Figure 1). A skin biopsy demonstrated intense granulomatous inflammation in the dermis (Figure 2), and further testing enabled a diagnosis of cutaneous MAC. A 12-month course of treatment was commenced in May 2012 with ethambutol (15 mg/kg daily) and clarithromycin (7.5 mg/kg daily). She was referred to the ophthalmology service, shortly after commencing treatment, for regular monitoring of potential ethambutol toxicity. An initial ophthalmic examination including dilated fundus examination was normal and she had an unaided acuity of 6/6 bilaterally. Following the diagnosis of disseminated cutaneous MAC, the patient underwent a battery of systemic investigations into a primary immunodeficiency. Notably, her chest x-ray, abdominal ultrasound, HIV test, nitro-blue tetrazolium test (NBT), and T-cell function assays were normal. IgG was elevated and IgA and IgM were normal. Further testing into genetic
CASE REPORT A 12-year-old Caucasian girl was seen in pediatric services with disseminated skin lesions. She was born at full term with an uneventful newborn course. The youngest of 5 children, she had a brother who died at 8 weeks of age secondary to pneumonia, 2 older brothers with histories of recurrent boils, and an older sister with asthma. Her own childhood course was marked with several hospitalizations for
Received 19 December 2013; revised 20 March 2014; accepted 29 April 2014; published online 29 May 2014 Correspondence: Dr. Erika M. Damato, Fred Hollows NZ Ophthalmology Clinical Research Fellow, New Zealand National Eye Centre, Department of Ophthalmology, Private Bag 92019, University of Auckland, Auckland, New Zealand. E-mail: [email protected]
106
Mycobacterium avium–intracellulare Complex
107
cytokine defects revealed a normal interferon gamma (IFNg) receptor pathway but suggested a defect in interleukin (IL)-12 receptor, accounting for her presentation and previous medical history. Ten months into her treatment course, the patient developed symptoms of blurred vision and a scotoma in the right eye. She was referred to ophthalmology services for review. When seen in our clinic, best corrected visual acuity was 6/120 in the right eye and 6/6 in the left. Anterior segment examination and intraocular pressures were unremarkable, Dilated fundscopy was performed and revealed a right macular disciform scar with surrounding multifocal choroidal lesions (Figure 3). There was no vitritis. Invasive testing, such as vitreous sampling for polymerase chain reaction (PCR) testing was not felt to be warranted in view of the low perceived yield. OCT scans did not demonstrate the presence of intraretinal or subretinal fluid. A fluorescein angiogram was obtained, which showed inactive disease without any active vasculitis or choroiditis (Figure 4).
In view of her clinical presentation and recent medical history, a diagnosis of choroidal neovascularization secondary to systemic dissemination of MAC to the choroid was made. As the lesions were inactive and scarred, no additional ophthalmic treatment was prescribed. The patient remained under the care of a multidisciplinary team, including immunology, dermatology, infectious diseases, and pediatric ophthalmology teams. She completed her 12-month course of ethambutol treatment and continued on clarithromycin prophylaxis. Her cutaneous lesions improved significantly, with marked reduction in size, flattening, and increased pallor. No new lesions developed and no lymphadenitis, hepatomegaly, or splenomegaly occurred. Despite, the improvement of her cutaneous condition, vision in the right eye remained poor due to macular scarring.
FIGURE 1. Photograph of cutaneous lesion on the upper aspect of the back.
FIGURE 3. Fundus photograph showing advanced disciform scar with underlying granulomatous choroidal lesions.
FIGURE 2. (a) Cutaneous histology showing intense granulomatous inflammation in the dermis (hematoxylin and eosin stain, magnification 100). (b) The granulomata are composed of foamy histiocytes and multinucleated giant cells with a background of lymphocytes, plasma cells, and occassional eosinophils (hematoxylin and eosin stain, magnification 200). !
2015 Informa Healthcare USA, Inc.
108 C. Chong et al.
FIGURE 4. Midphase fluorescein angiogram showing blocked fluorescence and no significant leakage from a choroidal neovascular membrane. OCT scan through the lesion demonstrates scarring with no intraretinal or subretinal fluid to suggest ongoing activity.
DISCUSSION The occurrence of disseminated infection due to an organism that is not normally virulent requires investigation into an underlying immunodeficiency syndrome. Mycobacteria cause intracellular infection, which is normally under tight control by T-cell-mediated immunity and interferon gamma (IFNg) and IL-12 signaling. Inherited conditions, collectively known as Mendelian susceptibility to mycobacterial diseases (MSMD) occur due to a variety of defects, including those affecting IFNg and its receptor, IL-12 and its receptor and other molecules involved in these pathways. MSMD manifests as recurrent infection with organisms such as MAC.4 In healthy individuals, infection of macrophages by MAC leads to the display of MAC antigen on MHC class II molecules on the macrophage surface and stimulation of IL-12 release. Antigen-specific T cells respond to IL-12 by releasing cytokines, notably IFNg, and by synthesizing membrane associated proteins, such as the CD40 ligand. The process of T-cell activation results in increased genetic expression of effector cytokines and cell surface molecules. The complex of activated macrophages and surrounding T cells results in the formation of a granuloma. In addition, activated macrophages release TNFa, further stimulating other macrophages and T cells and maintaining the structure of the granuloma. Activated macrophages are equipped to kill and destroy the intracellular pathogen, in this case a mycobacterium, by mechanisms including the nitric oxide pathway.5
Genetic defects in IL-12 and the IL-12 receptor have been identified and are observed to result in an unusual susceptibility to mycobacterial infection. Such defects often lead to absent or reduced IFNg production and deficient macrophage activation.6 The diagnosis of an IL-12 receptor defect is supported by functional studies and confirmed by genetic testing. During functional studies, blood samples from the individual are exposed to IL-12 and to mycobacterial antigens, and levels of IFNg produced are measured. Affected patients will produce abnormally low levels of IFNg in response to such stimulation. IFNg signaling itself, however, is maintained. Common genetic mutations responsible for such defects are reported to include an autosomal recessive IL-12BR1 deficiency, but other mutations can exist. Treatment of acquired mycobacterial infection with conventional antibiotic regimens may be only partially effective in these patients. There is a role for recombinant IFNg treatment, which has been used very successfully in suitable patients. Partial efficacy of antibiotic therapy could account for the observation that our patient developed choroidal involvement while on appropriate treatment. In addition, an inappropriate immune response mounted in the choroid, may have contributed to this manifestation. Currently, our patient has no clinical evidence of active MAC infection. She remains visually impaired in the right eye due to macular scarring. Should her condition reactivate or involve the contralateral eye, both local treatments, including intravitreal avastin, and systemic therapy with IFNg may be warranted. Ocular Immunology & Inflammation
Mycobacterium avium–intracellulare Complex This case highlights the need to recognize underlying immunodeficiency states in children presenting with unusual infections and emphasizes that, despite seemingly adequate anti-infective therapy, infectious complications may persist, in this case leading to irreversible visual loss.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. We would like to acknowledge Mike Watson, consultant histopathologist, for the provision of the histopathology figures and legends and Roger Tuck, Shannon Brothers, and Andrew Watts, who were involved in initial management of this patient.
!
2015 Informa Healthcare USA, Inc.
109
REFERENCES 1. Howell N, Heaton P, Neutze J, Taranaki BHNP. The epidemiology of nontuberculous mycobacterial lymphadenitis affecting New Zealand children 1986–95. N Z Med J. 1997;9:171–173. 2. Horsburgh CR. Mycobacterium avium complex infection in the acquired immunodeficiency syndrome. N Engl J Med. 1991;324:1332–1338. 3. Rosenbaum PS, Mbekeani JN, Kress Y. Atypical mycobacterial panophthalmitis seen with iris nodules. Arc. Ophthalmol. 1998;116:1524–1527. 4. Haraguchi S, Day NK, Nelson RP, et al. Interleukin 12 deficiency associated with recurrent infections. Proc Natl Acad Sci U S A. 1998;95:13125–13129. 5. Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferongamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004;75:163–189. 6. Ramirez-Alejo N, Blancas-Galicia L, YamazakiNakashimada M, et al. Molecular analysis for patients with IL-12 receptor b1 deficiency. Clin Genet. 2013 Aug 16. [Epub ahead of print].
Copyright of Ocular Immunology & Inflammation is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
