Clinical Infectious Diseases Advance Access published October 9, 2014 1 Ocular Toxoplasmosis in the United States: Recent and Remote Infections
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Jeffrey L. Jones1, Valerie Bonetti2, Gary N. Holland3, Cindy Press2, Steven R. Sanislo4, Rahul N. Khurana5, Jose G. Montoya2,6 1
Parasitic Diseases Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia
2
Palo Alto Medical Foundation, Toxoplasma Serology Laboratory, Palo Alto, California
3
4
Byers Eye Institute, Stanford University School of Medicine, Stanford, California
5
Northern California Retina Vitreous Associates, Mountain View, California
6
an
Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California
M
Corresponding author: Jeffrey L. Jones, M.D., M.P.H, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA 30329‐4018, Email: [email protected], Phone: 404‐ 718‐4747, Fax: 404‐718‐4816
Ac
ce
pt ed
Alternate corresponding author: Jose G. Montoya, M.D. Toxoplasma Serology Laboratory, PAMF Research Institute, Ames Building, 795 El Camino Real, Palo Alto, CA 94301‐2302, Email: [email protected] (alternate: [email protected]), Phone: 650‐853‐4828, Fax: 650‐614‐3292
Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.
Downloaded from http://cid.oxfordjournals.org/ at Dalhousie University on October 9, 2014
us
Ocular Inflammatory Disease Center, Jules Stein Eye Institute and Department of Ophthalmology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, California
2 Abstract We tested all samples from patients with ocular toxoplasmosis sent to the Palo Alto Medical Foundation from
cr ipt
June 2004 through August 2010 for serologic evidence of recent T. gondii infection. Of 205 patients aged 10‐96
an M pt ed ce Ac
Downloaded from http://cid.oxfordjournals.org/ at Dalhousie University on October 9, 2014
us
years, 11.7% had recent infection. Many people develop ocular disease soon after T. gondii infection.
3
cr ipt
Introduction Toxoplasmosis is one of the most common causes of posterior uveitis [1] and can lead to variable
degrees of vision loss, including blindness. In the U.S., there are an estimated 21,000 persons who develop
ocular lesions from Toxoplasma gondii each year and over 4,800 who develop symptomatic ocular disease (data
burden on the U.S. health care system, with 250,000 visits to ophthalmologists for active or chronic disease over
an
a period of two years estimated from a survey in 2002 [3].
Traditional teaching has been that the majority of ocular toxoplasmosis is associated with congenital disease. Clinicians now accept the fact that the majority of reactivations are associated with post‐natally
M
acquired infections, the first episode of ocular involvement having gone unnoticed, either because it was associated with minimal symptoms or because it occurred in preverbal children [4]. It is estimated that
pt ed
approximately 2% of T. gondii infected individuals in the United States develop ocular toxoplasmosis; however, in some settings, such as epidemics with atypical genotypes, the prevalence of ocular disease soon after infection may be as high as 20% [4, 5]. Methods
Our study evaluated all T. gondii antibody‐positive serum samples from persons in the U.S. diagnosed
ce
clinically with ocular toxoplasmosis that had been sent to the Palo Alto Medical Foundation Toxoplasma
Ac
Reference Laboratory (PAMFRL) to confirm infection between June 2004 and August 2010. The PAMFRL is the only Toxoplasma testing reference laboratory in the United States. The methods for determining recent T. gondii
infection have been described, and can determine if infection occurred within the previous 6 months [6, 7]. Briefly, all samples were tested with the T. gondii Sabin‐Feldman dye test and IgM ELISA. Samples that had been
found to be both IgG and IgM antibody positive were tested further with the immunoglobulin A (IgA) ELISA,
Downloaded from http://cid.oxfordjournals.org/ at Dalhousie University on October 9, 2014
us
from a study done in the early to mid‐2000s) [2]. Care of patients with ocular toxoplasmosis causes a substantial
4 immunoglobulin E (IgE) ELISA, and differential agglutination (AC/HS) test. An acute serological profile (i.e., positive Sabin‐Feldman dye test, positive IgM ELISA, an acute pattern in the differential agglutination test, and positive IgA and IgE ELISA tests) correlates 100% with an infection acquired within 6 months in seroconversion
cr ipt
studies of pregnant women in Europe and in serological studies of patients with lymphadenopathy in the United States [6, 7]. In addition, all case patients had a low Toxoplasma avidity test result consistent with a recent
infection [8, 9]. We did not use commercial Toxoplasma IgM tests alone to determine acute T. gondii infection
because up to 27% of Toxoplasma IgM tests can remain positive for 2 or more years [10]. In analyzing our study
us
9.2, SAS Institute Inc., Cary, NC).
an
Results
Of 205 patients with serologic evidence of T. gondii infection, 110 (54%) were female. The median age
M
for those with recent infection and chronic infection were 52 years (range 15‐80 years) and 44 years (range 10‐ 96 years), respectively (p=.19, t‐test with Satterthwaite approximation). Samples from 24 (11.7%; 95%
pt ed
confidence limits 7.7%, 16.9%) patients were found to have serological test results indicating recent infection (i.e., IgG‐positive/IgM‐positive and a serologic panel including IgA, IgE, AC/HS, and avidity test consistent with recent infection); the remaining 181 (88.3%) were IgG‐positive/IgM‐negative, indicating that they had ocular disease associated with chronic infection from the more distant past.
ce
Discussion
In this referral population, 11.7% of those with ocular disease had recently acquired T. gondii infection.
Ac
Because the youngest person in the study was 10 years old, all recently acquired infections occurred after birth (in the 6 months prior to T. gondii testing, as defined in the methods), while chronic infections may have
occurred after birth or congenitally (but over 6 months previous to T. gondii testing). Those with chronic infections were probably tested by their physicians when active ocular lesions were noted (representing
Downloaded from http://cid.oxfordjournals.org/ at Dalhousie University on October 9, 2014
data, exact confidence intervals for binomial proportions and the t‐test were performed using SAS (SAS version
5 reactivations, the most common clinical presentation), but for these patients it is not known when the ocular disease first developed or over what interval reactivation occurred.
cr ipt
It has been assumed that most retinal lesions among T. gondii‐infected people are associated with remote infections [4], with clinically apparent lesions first arising from occult tissue cysts that had been present in retinal tissue since the systemic infection occurred [11]. Retinal disease can recur multiple times, as satellite lesions adjacent to retinochoroidal scars, which represent the residua of past infections. In contrast as many as
apparent toxoplasmic retinochoroiditis within a few weeks of the outbreaks [5]. These initial retinal infections present as “primary lesions” (those not arising from the borders of scars). The hypothesis is that the higher
an
incidence of early ocular involvement in epidemics versus the general population is related to infection with atypical strains of parasite [5]. Numerous genotypes are circulating in the U.S. [12], and atypical genotypes have
M
been found to be associated with ocular toxoplasmosis in the U.S., even among those with sporadic disease [13]. Our study has a number of limitations. The samples may not be representative of all people with ocular
pt ed
toxoplasmosis in the U.S. Ophthalmologists are trained to recognize the classic appearance of satellite lesions adjacent to chronic retinochoroidal scars as being diagnostic for ocular toxoplasmosis, and might be less likely to seek serologic confirmation of infection in such cases. Since other presentations of ocular toxoplasmosis are less well understood, serologic testing might be obtained more often for people with primary lesions or for those
ce
lesions that represent more severe disease. Clinicians therefore may be more likely to seek confirmation of infection for lesions that occur at the time of initial infection, because all such patients will have primary lesions; being the first episode of retinal disease, none will already have scars. It should be noted, however, that primary
Ac
lesions alone are not a reliable sign of recent infection; up to 20% of patients who present with primary lesions have serologic profiles consistent with remote T. gondii infection [14]. The PAMFRL records do not provide information about whether patients tested had satellite recurrences or primary lesions. These potential biases
could increase the observed prevalence of ocular toxoplasmosis associated with recent infection. An additional
Downloaded from http://cid.oxfordjournals.org/ at Dalhousie University on October 9, 2014
us
10‐20% of patients infected in several reported epidemics of T. gondii infection have developed clinically
6 potential limitation is that the diagnosis of ocular toxoplasmosis was made by physicians who referred serum for testing, and the authors did not independently validate the diagnosis.
cr ipt
Nevertheless, the results of our study indicate that over 10% of people with ocular disease developed it soon after acquiring T. gondii infection, a phenomenon previously thought to be uncommon in the general
population. These results also suggest that patients identified both clinically and serologically as having had a
recent T. gondii infection should be questioned about known risk factors for infection, and about close family
(i.e., persons who may have had a common exposure leading to infection). Potentially infected persons thus identified could then be examined and tested; this is particularly important for those who are pregnant or
an
immunosuppressed [15]. Household members that are infected with the same genotype as a person with ocular involvement may be at increased risk for ocular disease because, and as noted above, a higher rate of ocular
M
disease has been reported in epidemics associated with atypical genotypes [5]. Recent evidence from a study in Brazil in an area with atypical genotypes and a high rate of T. gondii‐related ocular disease suggests that
pt ed
systemic treatment of recently infected persons may decrease the occurrence of early ocular involvement [Arantes TEF, Silveira S, Holland GN, et al. Ocular involvement following post‐natally acquired Toxoplasma gondii infection: endemic disease in southern Brazil (manuscript submitted)]. However, the Arantes et al. study does not present the type, dose, or duration of treatment and clinical trials would be needed to fully establish the
Ac
ce
regimens and effectiveness of prophylactic treatment after acute T. gondii infection to prevent ocular disease.
Downloaded from http://cid.oxfordjournals.org/ at Dalhousie University on October 9, 2014
us
members or associates who may have had systemic and/or ocular symptoms similarly suggestive of infection
7 Source of funding: Funding for this study was provided to the Palo Alto Medical Foundation by the Centers for
cr ipt
Disease Control and Prevention. Conflicts of interest:
and Regeneron, and has received payment for lectures from Genentech and Regeneron. Dr. Holland reports
an
that he has been a consultant for Genentech, Novartis International, Staten, and Xoma LLC, and has received funding for clinical trial participation from Xoma LLC.
M
Standard Centers for Disease Control and Prevention Disclaimer:
pt ed
The findings and conclusions in this report are those of the authors and do not necessarily represent the official
Ac
ce
position of the Centers for Disease Control and Prevention.
Downloaded from http://cid.oxfordjournals.org/ at Dalhousie University on October 9, 2014
us
Dr. Khurana reports that he has been a consultant for Allergan and Genentech, has grants pending from Allergan
8 References
practice of ophthalmology. Am J Ophthalmol, 1996; 121: 35‐46.
cr ipt
1. McCannel CA, Holland GN, Helm CJ, Cornell PJ, Winston JV, Rimmer TG. Causes of uveitis in the general
2. Jones JL, Holland GN. Annual burden of ocular toxoplasmosis in the United States. Am J Trop Med Hyg, 2010;
3. Lum FL, Jones JL, Holland GN, Liesegang TJ, 2005. Survey of ophthalmologists about ocular toxoplasmosis. Am
an
J Ophthalmol, 2005; 140: 724‐726.
4. Holland GN. Ocular toxoplasmosis: a global reassessment. Part 1: epidemiology and course of disease . Am J
M
Ophthalmol, 2003; 136: 973‐988.
5. Holland GN. An epidemic of toxoplasmosis: lessons from Coimbatore, India. Arch Ophthalmol, 2010; 128: 126‐
pt ed
128.
6. Montoya JG, Remington JS. Studies on the serodiagnosis of toxoplasmic lymphadenitis. Clin Infect Dis 1995; 20: 781‐789.
7. Montoya JG. Laboratory diagnosis of Toxoplasma gondii infection and toxoplasmosis. J Infect Dis, 2002; 185
ce
Suppl 1: S73‐S82.
8. Hedman K, Lappalainen M, SeppaiaI, Maela O. Recent primary Toxoplasma infection indicated by a low avidity
Ac
of specific IgG. J Infect Dis, 1989; 159: 736‐740. 9. Montoya JG, Huffman HB, Remington JS. Evaluation of the immunoglobulin G avidity test for diagnosis of
toxoplasmic lymphadenopathy.J Clin Microbiol, 2004; 42: 4627‐4631.
Downloaded from http://cid.oxfordjournals.org/ at Dalhousie University on October 9, 2014
us
82: 464‐465.
9 10. Gras L, Gilbert RE, Wallon M, et al. Duration of the IgM response in women acquiring Toxoplasma gondii during pregnancy: implications for clinical practice and cross‐sectional incidence studies. Epidemiol Infect 2004;
cr ipt
132: 541‐548. 11. Holland GN, Muccioli C, Silveira C, Weisz JM, Belfort R Jr, O'Connor GR. Intraocular inflammatory reactions
without focal necrotizing retinochoroiditis in patients with acquired systemic toxoplasmosis. Am J Ophthalmol, 1999; 128: 413‐440.
an
13. Grigg ME, Ganatra J, Boothroyd JC, Margolis TP. Unusual abundance of atypical strains associated with human ocular toxoplasmosis. J Infect Dis, 2001; 184: 633‐639.
M
14. Bosch‐Drissen LEH, Berendschot TTJM, Ongkosuwito JV, Rothova A. Ocular toxoplasmosis: clinical features and prognosis of 154 patients. Ophthalmology, 2002; 109: 869‐878.
pt ed
15. Contopoulos‐Ioannidis DG, Maldonado Y, Montoya JG. Acute Toxoplasma gondii infection among family
Ac
ce
members in the United States. Emerg Infect Dis, 2013; 19: 1981‐1984.
Downloaded from http://cid.oxfordjournals.org/ at Dalhousie University on October 9, 2014
(NCCCTS, 1981‐2009). Clin Infect Dis, 2012; 54: 1595‐1605.
us
12. McLeod R, Boyer KM, Lee D, et al. Prematurity and severity are associated with Toxoplasma gondii alleles
cr ipt
Jeffrey L. Jones1, Valerie Bonetti2, Gary N. Holland3, Cindy Press2, Steven R. Sanislo4, Rahul N. Khurana5, Jose G. Montoya2,6 1
Parasitic Diseases Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia
2
Palo Alto Medical Foundation, Toxoplasma Serology Laboratory, Palo Alto, California
3
4
Byers Eye Institute, Stanford University School of Medicine, Stanford, California
5
Northern California Retina Vitreous Associates, Mountain View, California
6
an
Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California
M
Corresponding author: Jeffrey L. Jones, M.D., M.P.H, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA 30329‐4018, Email: [email protected], Phone: 404‐ 718‐4747, Fax: 404‐718‐4816
Ac
ce
pt ed
Alternate corresponding author: Jose G. Montoya, M.D. Toxoplasma Serology Laboratory, PAMF Research Institute, Ames Building, 795 El Camino Real, Palo Alto, CA 94301‐2302, Email: [email protected] (alternate: [email protected]), Phone: 650‐853‐4828, Fax: 650‐614‐3292
Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.
Downloaded from http://cid.oxfordjournals.org/ at Dalhousie University on October 9, 2014
us
Ocular Inflammatory Disease Center, Jules Stein Eye Institute and Department of Ophthalmology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, California
2 Abstract We tested all samples from patients with ocular toxoplasmosis sent to the Palo Alto Medical Foundation from
cr ipt
June 2004 through August 2010 for serologic evidence of recent T. gondii infection. Of 205 patients aged 10‐96
an M pt ed ce Ac
Downloaded from http://cid.oxfordjournals.org/ at Dalhousie University on October 9, 2014
us
years, 11.7% had recent infection. Many people develop ocular disease soon after T. gondii infection.
3
cr ipt
Introduction Toxoplasmosis is one of the most common causes of posterior uveitis [1] and can lead to variable
degrees of vision loss, including blindness. In the U.S., there are an estimated 21,000 persons who develop
ocular lesions from Toxoplasma gondii each year and over 4,800 who develop symptomatic ocular disease (data
burden on the U.S. health care system, with 250,000 visits to ophthalmologists for active or chronic disease over
an
a period of two years estimated from a survey in 2002 [3].
Traditional teaching has been that the majority of ocular toxoplasmosis is associated with congenital disease. Clinicians now accept the fact that the majority of reactivations are associated with post‐natally
M
acquired infections, the first episode of ocular involvement having gone unnoticed, either because it was associated with minimal symptoms or because it occurred in preverbal children [4]. It is estimated that
pt ed
approximately 2% of T. gondii infected individuals in the United States develop ocular toxoplasmosis; however, in some settings, such as epidemics with atypical genotypes, the prevalence of ocular disease soon after infection may be as high as 20% [4, 5]. Methods
Our study evaluated all T. gondii antibody‐positive serum samples from persons in the U.S. diagnosed
ce
clinically with ocular toxoplasmosis that had been sent to the Palo Alto Medical Foundation Toxoplasma
Ac
Reference Laboratory (PAMFRL) to confirm infection between June 2004 and August 2010. The PAMFRL is the only Toxoplasma testing reference laboratory in the United States. The methods for determining recent T. gondii
infection have been described, and can determine if infection occurred within the previous 6 months [6, 7]. Briefly, all samples were tested with the T. gondii Sabin‐Feldman dye test and IgM ELISA. Samples that had been
found to be both IgG and IgM antibody positive were tested further with the immunoglobulin A (IgA) ELISA,
Downloaded from http://cid.oxfordjournals.org/ at Dalhousie University on October 9, 2014
us
from a study done in the early to mid‐2000s) [2]. Care of patients with ocular toxoplasmosis causes a substantial
4 immunoglobulin E (IgE) ELISA, and differential agglutination (AC/HS) test. An acute serological profile (i.e., positive Sabin‐Feldman dye test, positive IgM ELISA, an acute pattern in the differential agglutination test, and positive IgA and IgE ELISA tests) correlates 100% with an infection acquired within 6 months in seroconversion
cr ipt
studies of pregnant women in Europe and in serological studies of patients with lymphadenopathy in the United States [6, 7]. In addition, all case patients had a low Toxoplasma avidity test result consistent with a recent
infection [8, 9]. We did not use commercial Toxoplasma IgM tests alone to determine acute T. gondii infection
because up to 27% of Toxoplasma IgM tests can remain positive for 2 or more years [10]. In analyzing our study
us
9.2, SAS Institute Inc., Cary, NC).
an
Results
Of 205 patients with serologic evidence of T. gondii infection, 110 (54%) were female. The median age
M
for those with recent infection and chronic infection were 52 years (range 15‐80 years) and 44 years (range 10‐ 96 years), respectively (p=.19, t‐test with Satterthwaite approximation). Samples from 24 (11.7%; 95%
pt ed
confidence limits 7.7%, 16.9%) patients were found to have serological test results indicating recent infection (i.e., IgG‐positive/IgM‐positive and a serologic panel including IgA, IgE, AC/HS, and avidity test consistent with recent infection); the remaining 181 (88.3%) were IgG‐positive/IgM‐negative, indicating that they had ocular disease associated with chronic infection from the more distant past.
ce
Discussion
In this referral population, 11.7% of those with ocular disease had recently acquired T. gondii infection.
Ac
Because the youngest person in the study was 10 years old, all recently acquired infections occurred after birth (in the 6 months prior to T. gondii testing, as defined in the methods), while chronic infections may have
occurred after birth or congenitally (but over 6 months previous to T. gondii testing). Those with chronic infections were probably tested by their physicians when active ocular lesions were noted (representing
Downloaded from http://cid.oxfordjournals.org/ at Dalhousie University on October 9, 2014
data, exact confidence intervals for binomial proportions and the t‐test were performed using SAS (SAS version
5 reactivations, the most common clinical presentation), but for these patients it is not known when the ocular disease first developed or over what interval reactivation occurred.
cr ipt
It has been assumed that most retinal lesions among T. gondii‐infected people are associated with remote infections [4], with clinically apparent lesions first arising from occult tissue cysts that had been present in retinal tissue since the systemic infection occurred [11]. Retinal disease can recur multiple times, as satellite lesions adjacent to retinochoroidal scars, which represent the residua of past infections. In contrast as many as
apparent toxoplasmic retinochoroiditis within a few weeks of the outbreaks [5]. These initial retinal infections present as “primary lesions” (those not arising from the borders of scars). The hypothesis is that the higher
an
incidence of early ocular involvement in epidemics versus the general population is related to infection with atypical strains of parasite [5]. Numerous genotypes are circulating in the U.S. [12], and atypical genotypes have
M
been found to be associated with ocular toxoplasmosis in the U.S., even among those with sporadic disease [13]. Our study has a number of limitations. The samples may not be representative of all people with ocular
pt ed
toxoplasmosis in the U.S. Ophthalmologists are trained to recognize the classic appearance of satellite lesions adjacent to chronic retinochoroidal scars as being diagnostic for ocular toxoplasmosis, and might be less likely to seek serologic confirmation of infection in such cases. Since other presentations of ocular toxoplasmosis are less well understood, serologic testing might be obtained more often for people with primary lesions or for those
ce
lesions that represent more severe disease. Clinicians therefore may be more likely to seek confirmation of infection for lesions that occur at the time of initial infection, because all such patients will have primary lesions; being the first episode of retinal disease, none will already have scars. It should be noted, however, that primary
Ac
lesions alone are not a reliable sign of recent infection; up to 20% of patients who present with primary lesions have serologic profiles consistent with remote T. gondii infection [14]. The PAMFRL records do not provide information about whether patients tested had satellite recurrences or primary lesions. These potential biases
could increase the observed prevalence of ocular toxoplasmosis associated with recent infection. An additional
Downloaded from http://cid.oxfordjournals.org/ at Dalhousie University on October 9, 2014
us
10‐20% of patients infected in several reported epidemics of T. gondii infection have developed clinically
6 potential limitation is that the diagnosis of ocular toxoplasmosis was made by physicians who referred serum for testing, and the authors did not independently validate the diagnosis.
cr ipt
Nevertheless, the results of our study indicate that over 10% of people with ocular disease developed it soon after acquiring T. gondii infection, a phenomenon previously thought to be uncommon in the general
population. These results also suggest that patients identified both clinically and serologically as having had a
recent T. gondii infection should be questioned about known risk factors for infection, and about close family
(i.e., persons who may have had a common exposure leading to infection). Potentially infected persons thus identified could then be examined and tested; this is particularly important for those who are pregnant or
an
immunosuppressed [15]. Household members that are infected with the same genotype as a person with ocular involvement may be at increased risk for ocular disease because, and as noted above, a higher rate of ocular
M
disease has been reported in epidemics associated with atypical genotypes [5]. Recent evidence from a study in Brazil in an area with atypical genotypes and a high rate of T. gondii‐related ocular disease suggests that
pt ed
systemic treatment of recently infected persons may decrease the occurrence of early ocular involvement [Arantes TEF, Silveira S, Holland GN, et al. Ocular involvement following post‐natally acquired Toxoplasma gondii infection: endemic disease in southern Brazil (manuscript submitted)]. However, the Arantes et al. study does not present the type, dose, or duration of treatment and clinical trials would be needed to fully establish the
Ac
ce
regimens and effectiveness of prophylactic treatment after acute T. gondii infection to prevent ocular disease.
Downloaded from http://cid.oxfordjournals.org/ at Dalhousie University on October 9, 2014
us
members or associates who may have had systemic and/or ocular symptoms similarly suggestive of infection
7 Source of funding: Funding for this study was provided to the Palo Alto Medical Foundation by the Centers for
cr ipt
Disease Control and Prevention. Conflicts of interest:
and Regeneron, and has received payment for lectures from Genentech and Regeneron. Dr. Holland reports
an
that he has been a consultant for Genentech, Novartis International, Staten, and Xoma LLC, and has received funding for clinical trial participation from Xoma LLC.
M
Standard Centers for Disease Control and Prevention Disclaimer:
pt ed
The findings and conclusions in this report are those of the authors and do not necessarily represent the official
Ac
ce
position of the Centers for Disease Control and Prevention.
Downloaded from http://cid.oxfordjournals.org/ at Dalhousie University on October 9, 2014
us
Dr. Khurana reports that he has been a consultant for Allergan and Genentech, has grants pending from Allergan
8 References
practice of ophthalmology. Am J Ophthalmol, 1996; 121: 35‐46.
cr ipt
1. McCannel CA, Holland GN, Helm CJ, Cornell PJ, Winston JV, Rimmer TG. Causes of uveitis in the general
2. Jones JL, Holland GN. Annual burden of ocular toxoplasmosis in the United States. Am J Trop Med Hyg, 2010;
3. Lum FL, Jones JL, Holland GN, Liesegang TJ, 2005. Survey of ophthalmologists about ocular toxoplasmosis. Am
an
J Ophthalmol, 2005; 140: 724‐726.
4. Holland GN. Ocular toxoplasmosis: a global reassessment. Part 1: epidemiology and course of disease . Am J
M
Ophthalmol, 2003; 136: 973‐988.
5. Holland GN. An epidemic of toxoplasmosis: lessons from Coimbatore, India. Arch Ophthalmol, 2010; 128: 126‐
pt ed
128.
6. Montoya JG, Remington JS. Studies on the serodiagnosis of toxoplasmic lymphadenitis. Clin Infect Dis 1995; 20: 781‐789.
7. Montoya JG. Laboratory diagnosis of Toxoplasma gondii infection and toxoplasmosis. J Infect Dis, 2002; 185
ce
Suppl 1: S73‐S82.
8. Hedman K, Lappalainen M, SeppaiaI, Maela O. Recent primary Toxoplasma infection indicated by a low avidity
Ac
of specific IgG. J Infect Dis, 1989; 159: 736‐740. 9. Montoya JG, Huffman HB, Remington JS. Evaluation of the immunoglobulin G avidity test for diagnosis of
toxoplasmic lymphadenopathy.J Clin Microbiol, 2004; 42: 4627‐4631.
Downloaded from http://cid.oxfordjournals.org/ at Dalhousie University on October 9, 2014
us
82: 464‐465.
9 10. Gras L, Gilbert RE, Wallon M, et al. Duration of the IgM response in women acquiring Toxoplasma gondii during pregnancy: implications for clinical practice and cross‐sectional incidence studies. Epidemiol Infect 2004;
cr ipt
132: 541‐548. 11. Holland GN, Muccioli C, Silveira C, Weisz JM, Belfort R Jr, O'Connor GR. Intraocular inflammatory reactions
without focal necrotizing retinochoroiditis in patients with acquired systemic toxoplasmosis. Am J Ophthalmol, 1999; 128: 413‐440.
an
13. Grigg ME, Ganatra J, Boothroyd JC, Margolis TP. Unusual abundance of atypical strains associated with human ocular toxoplasmosis. J Infect Dis, 2001; 184: 633‐639.
M
14. Bosch‐Drissen LEH, Berendschot TTJM, Ongkosuwito JV, Rothova A. Ocular toxoplasmosis: clinical features and prognosis of 154 patients. Ophthalmology, 2002; 109: 869‐878.
pt ed
15. Contopoulos‐Ioannidis DG, Maldonado Y, Montoya JG. Acute Toxoplasma gondii infection among family
Ac
ce
members in the United States. Emerg Infect Dis, 2013; 19: 1981‐1984.
Downloaded from http://cid.oxfordjournals.org/ at Dalhousie University on October 9, 2014
(NCCCTS, 1981‐2009). Clin Infect Dis, 2012; 54: 1595‐1605.
us
12. McLeod R, Boyer KM, Lee D, et al. Prematurity and severity are associated with Toxoplasma gondii alleles
