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(LUP)
[1–6] [PREPRINTER stage]
Lupus (2015) 0,
1–6
http://lup.sagepub.com
PEDIATRIC LUPUS
Cytomegalovirus in pediatric systemic lupus erythematosus: prevalence and clinical manifestations EV Rozenblyum1, DM Levy1,4, U Allen2,4, E Harvey3, D Hebert3 and ED Silverman1,4 1
Divisions of Rheumatology; 2Infectious Diseases; 3Nephrology; and 4Department of Pediatrics, and the Research Institute, Hospital for Sick Children, University of Toronto, Canada
Cytomegalovirus (CMV) is a beta-herpesvirus and antibodies to this virus are common in patients with systemic lupus erythematosus (SLE). However, few studies have examined the relationship between CMV infection and SLE. Objectives: Our objectives were: 1) to determine the prevalence of CMV infection at the time of SLE diagnosis, and 2) to determine the risk factors for CMV infection. Methods: A database review of 670 patients with pediatric SLE (pSLE) seen over a 20-year period identified seven patients with a CMV infection detected at the time of diagnosis of SLE. CMV was diagnosed by serology, urine and bronchoalveolar lavage. Clinical manifestations, laboratory findings, virology studies and treatments were reviewed. Results: CMV infection was detected in seven patients at the time of SLE diagnosis (1.04% of total cohort): six were female: mean age was 13 years. Predominant features included non-Caucasian ethnicity (p < 0.01 as compared to total SLE cohort), persistent fevers on prednisone in seven and nephrotic syndrome in four. Laboratory findings included: anemia in seven, lymphopenia in five, elevated liver enzymes in four, with anti-dsDNA and anti-RNP antibodies present in six and five, respectively. Six patients received ganciclovir and CMV hyperimmune globulin (CytogamÕ ) with the continuation of prednisone during CMV treatment. Six of seven fully recovered without sequelae (one without treatment) but one patient died with active CMV infection. Conclusions: There were 1.04% of patients with pSLE who developed CMV infection. All were of non-Caucasian ethnicity. Persistent fever despite prednisone, with concomitant anemia, may be additional clues to CMV infection in pSLE. We suggest all patients have routine testing for CMV immunity at initial presentation of pSLE. Lupus (2015) 0, 1–6. Key words: Pediatric systemic lupus erythematosus; cytomegalovirus; autoimmunity
Introduction Systemic lupus erythematous (SLE) is an autoimmune disease that can manifest in childhood, although it is more common in adulthood.1 This multisystem, heterogeneous disease has an incidence of approximately 0.9 per 100,000 children-years and a prevalence of 3.3–8.8 per 100,000 children.2 Although little is known about the etiology of this disease, it is thought to be the result of an interaction between a genetic predisposition and an environmental trigger such as an
Correspondence to: Evelyn V Rozenblyum, Hospital for Sick Children, Division of Rheumatology, 2003-25 Carlton St, Toronto, Ontario M5B 1L4, Canada. Email: [email protected] Received 1 November 2013; accepted 25 November 2014
infection that allows the manifestations of disease to emerge. Multiple bacterial and viral infections have been documented in SLE both at presentation and during the course of the illness.3–5 Recent attention has focused on the role of herpesviruses in SLE, but there have been few reports of either new-onset or reactivation of cytomegalovirus (CMV), a betaherpesvirus, in SLE.3,6–9 CMV can be categorized into infection and disease whereby infection is diagnosed when there is evidence of virus in blood, urine, or bronchoalveolar lavage (BAL), while disease requires detection of viral replication along with end organ disease. Presumed disease is evidenced by CMV infection with clinical symptoms, while confirmed disease suggests clinical symptoms with CMV-positive histopathology.10 Several mechanisms have been proposed as to how CMV infection might lead to the development
! The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
Downloaded from lup.sagepub.com at Selcuk Universitesi on January 15, 2015
10.1177/0961203314565443
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(LUP)
[1–6] [PREPRINTER stage]
CMV in pSLE EV Rozenblyum et al.
2
of SLE. These proposed mechanisms include molecular mimicry, which suggests that the similarity between CMV antigen(s) and self-antigens (in particular ribonuclear proteins) leads to persistent autoimmunity in the susceptible individual6 and can account for the presence of anti-La antibodies post-CMV infection.11 Alternatively, CMV can induce autoantigens on the surface of cells following CMV infection that leads to anti-Sm and anti-RNP antibodies in patients with latent CMV infection as compared with uninfected individuals.12 Our centre noticed several patients with newly diagnosed SLE who had an unusual clinical course, and were ultimately diagnosed with concurrent CMV infection. There was a paucity of reports in the literature linking CMV to SLE to help guide our care. The goals of the current study were to: (i) determine the prevalence of CMV infection at diagnosis and throughout the course of pSLE, and (ii) determine risk factors for CMV infection in pSLE.
be included in the analysis and report. The seven patients with CMV at the diagnosis of pSLE were then compared to the entire SLE cohort of patients with respect to the features of interest. Data collection from patients’ charts was performed at two timepoints: (i) at initial diagnosis of SLE, and (ii) at initial diagnosis of CMV. Data collected included patient’s demographic information, (i.e. age, gender, ethnicity), clinical features, physical examination findings, laboratory data including autoantibody profiles, and microbiology for CMV. SLE and CMV treatment regimens were reviewed. The data analyses primarily used descriptive statistics. Comparisons between pSLE patients with and without CMV infection were analyzed using Fisher’s exact test. Stata, version 12 (College Station, TX, USA) was used for analyses. No correction for multiple testing was performed.
Results Methods A retrospective chart review of the 670 patients with SLE followed by Pediatric Rheumatology at the Hospital for Sick Children (SickKids) between January 1984 and December 2011 was performed. This is a tertiary-quaternary 370-bed pediatric centre located in Toronto, Ontario, Canada. Information was gathered from electronic records, as all patients who attend this SLE clinic have prospective data collection using a standardized clinic form, and all clinical, laboratory and treatment data are prospectively entered into a database. This study was approved by the SickKids Research Ethics Board (study # 1000034723). The inclusion criteria were: 1) diagnosis of SLE prior to 18 years of age and followed at SickKids pSLE clinic; 2) definitive evidence of CMV infection as evident by virus isolation from urine, virus detection in blood (DNAemia), BAL and/or blood polymerase chain reaction (PCR); 3) documented CMV infection at presentation or following the diagnosis of SLE. Patients were excluded if they had no evidence of CMV infection. Using these criteria we found eight documented cases of CMV in the cohort of 540 pSLE patients (1.5%) followed during the course of this study (Table 1). Seven of these patients (88%, or 1.3% of the entire cohort) had CMV infection diagnosed within one month of pSLE diagnosis. The eighth was diagnosed with CMV five years after pSLE diagnosis and will not
Characteristics of the seven patients with CMV, compared to the sample of the other 663 patients with pSLE diagnosed over the same time period, at time of SLE diagnosis are shown in Table 1, with a prevalence of seven of 670 (1.04%). All seven patients diagnosed with CMV infection at presentation of SLE were non-Caucasian as opposed to 63% of the entire SickKids pSLE cohort (p < 0.01) (Figure 1). The typical patient with CMV infection presented with fever, nephrotic syndrome, hepatomegaly, and pneumonitis as compared to another patient without co-infection at the time of diagnosis. In patients with concomitant CMV infection, the following laboratory tests were found to be significant: anemia and severe lymphopenia (38 C) Rash Joint pain Nephrotic symptoms (edema, ascites) Hepatomegaly Pneumonitis Laboratory Pancytopenia Anemia Lymphopenia (
(LUP)
[1–6] [PREPRINTER stage]
Lupus (2015) 0,
1–6
http://lup.sagepub.com
PEDIATRIC LUPUS
Cytomegalovirus in pediatric systemic lupus erythematosus: prevalence and clinical manifestations EV Rozenblyum1, DM Levy1,4, U Allen2,4, E Harvey3, D Hebert3 and ED Silverman1,4 1
Divisions of Rheumatology; 2Infectious Diseases; 3Nephrology; and 4Department of Pediatrics, and the Research Institute, Hospital for Sick Children, University of Toronto, Canada
Cytomegalovirus (CMV) is a beta-herpesvirus and antibodies to this virus are common in patients with systemic lupus erythematosus (SLE). However, few studies have examined the relationship between CMV infection and SLE. Objectives: Our objectives were: 1) to determine the prevalence of CMV infection at the time of SLE diagnosis, and 2) to determine the risk factors for CMV infection. Methods: A database review of 670 patients with pediatric SLE (pSLE) seen over a 20-year period identified seven patients with a CMV infection detected at the time of diagnosis of SLE. CMV was diagnosed by serology, urine and bronchoalveolar lavage. Clinical manifestations, laboratory findings, virology studies and treatments were reviewed. Results: CMV infection was detected in seven patients at the time of SLE diagnosis (1.04% of total cohort): six were female: mean age was 13 years. Predominant features included non-Caucasian ethnicity (p < 0.01 as compared to total SLE cohort), persistent fevers on prednisone in seven and nephrotic syndrome in four. Laboratory findings included: anemia in seven, lymphopenia in five, elevated liver enzymes in four, with anti-dsDNA and anti-RNP antibodies present in six and five, respectively. Six patients received ganciclovir and CMV hyperimmune globulin (CytogamÕ ) with the continuation of prednisone during CMV treatment. Six of seven fully recovered without sequelae (one without treatment) but one patient died with active CMV infection. Conclusions: There were 1.04% of patients with pSLE who developed CMV infection. All were of non-Caucasian ethnicity. Persistent fever despite prednisone, with concomitant anemia, may be additional clues to CMV infection in pSLE. We suggest all patients have routine testing for CMV immunity at initial presentation of pSLE. Lupus (2015) 0, 1–6. Key words: Pediatric systemic lupus erythematosus; cytomegalovirus; autoimmunity
Introduction Systemic lupus erythematous (SLE) is an autoimmune disease that can manifest in childhood, although it is more common in adulthood.1 This multisystem, heterogeneous disease has an incidence of approximately 0.9 per 100,000 children-years and a prevalence of 3.3–8.8 per 100,000 children.2 Although little is known about the etiology of this disease, it is thought to be the result of an interaction between a genetic predisposition and an environmental trigger such as an
Correspondence to: Evelyn V Rozenblyum, Hospital for Sick Children, Division of Rheumatology, 2003-25 Carlton St, Toronto, Ontario M5B 1L4, Canada. Email: [email protected] Received 1 November 2013; accepted 25 November 2014
infection that allows the manifestations of disease to emerge. Multiple bacterial and viral infections have been documented in SLE both at presentation and during the course of the illness.3–5 Recent attention has focused on the role of herpesviruses in SLE, but there have been few reports of either new-onset or reactivation of cytomegalovirus (CMV), a betaherpesvirus, in SLE.3,6–9 CMV can be categorized into infection and disease whereby infection is diagnosed when there is evidence of virus in blood, urine, or bronchoalveolar lavage (BAL), while disease requires detection of viral replication along with end organ disease. Presumed disease is evidenced by CMV infection with clinical symptoms, while confirmed disease suggests clinical symptoms with CMV-positive histopathology.10 Several mechanisms have been proposed as to how CMV infection might lead to the development
! The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
Downloaded from lup.sagepub.com at Selcuk Universitesi on January 15, 2015
10.1177/0961203314565443
XML Template (2014) [31.12.2014–5:42pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/LUPJ/Vol00000/140273/APPFile/SG-LUPJ140273.3d
(LUP)
[1–6] [PREPRINTER stage]
CMV in pSLE EV Rozenblyum et al.
2
of SLE. These proposed mechanisms include molecular mimicry, which suggests that the similarity between CMV antigen(s) and self-antigens (in particular ribonuclear proteins) leads to persistent autoimmunity in the susceptible individual6 and can account for the presence of anti-La antibodies post-CMV infection.11 Alternatively, CMV can induce autoantigens on the surface of cells following CMV infection that leads to anti-Sm and anti-RNP antibodies in patients with latent CMV infection as compared with uninfected individuals.12 Our centre noticed several patients with newly diagnosed SLE who had an unusual clinical course, and were ultimately diagnosed with concurrent CMV infection. There was a paucity of reports in the literature linking CMV to SLE to help guide our care. The goals of the current study were to: (i) determine the prevalence of CMV infection at diagnosis and throughout the course of pSLE, and (ii) determine risk factors for CMV infection in pSLE.
be included in the analysis and report. The seven patients with CMV at the diagnosis of pSLE were then compared to the entire SLE cohort of patients with respect to the features of interest. Data collection from patients’ charts was performed at two timepoints: (i) at initial diagnosis of SLE, and (ii) at initial diagnosis of CMV. Data collected included patient’s demographic information, (i.e. age, gender, ethnicity), clinical features, physical examination findings, laboratory data including autoantibody profiles, and microbiology for CMV. SLE and CMV treatment regimens were reviewed. The data analyses primarily used descriptive statistics. Comparisons between pSLE patients with and without CMV infection were analyzed using Fisher’s exact test. Stata, version 12 (College Station, TX, USA) was used for analyses. No correction for multiple testing was performed.
Results Methods A retrospective chart review of the 670 patients with SLE followed by Pediatric Rheumatology at the Hospital for Sick Children (SickKids) between January 1984 and December 2011 was performed. This is a tertiary-quaternary 370-bed pediatric centre located in Toronto, Ontario, Canada. Information was gathered from electronic records, as all patients who attend this SLE clinic have prospective data collection using a standardized clinic form, and all clinical, laboratory and treatment data are prospectively entered into a database. This study was approved by the SickKids Research Ethics Board (study # 1000034723). The inclusion criteria were: 1) diagnosis of SLE prior to 18 years of age and followed at SickKids pSLE clinic; 2) definitive evidence of CMV infection as evident by virus isolation from urine, virus detection in blood (DNAemia), BAL and/or blood polymerase chain reaction (PCR); 3) documented CMV infection at presentation or following the diagnosis of SLE. Patients were excluded if they had no evidence of CMV infection. Using these criteria we found eight documented cases of CMV in the cohort of 540 pSLE patients (1.5%) followed during the course of this study (Table 1). Seven of these patients (88%, or 1.3% of the entire cohort) had CMV infection diagnosed within one month of pSLE diagnosis. The eighth was diagnosed with CMV five years after pSLE diagnosis and will not
Characteristics of the seven patients with CMV, compared to the sample of the other 663 patients with pSLE diagnosed over the same time period, at time of SLE diagnosis are shown in Table 1, with a prevalence of seven of 670 (1.04%). All seven patients diagnosed with CMV infection at presentation of SLE were non-Caucasian as opposed to 63% of the entire SickKids pSLE cohort (p < 0.01) (Figure 1). The typical patient with CMV infection presented with fever, nephrotic syndrome, hepatomegaly, and pneumonitis as compared to another patient without co-infection at the time of diagnosis. In patients with concomitant CMV infection, the following laboratory tests were found to be significant: anemia and severe lymphopenia (38 C) Rash Joint pain Nephrotic symptoms (edema, ascites) Hepatomegaly Pneumonitis Laboratory Pancytopenia Anemia Lymphopenia (
