AUTHOR REPLY
crossm
Ronald G. Hauser,a,b Sheldon M. Campbell,a,b Cynthia A. Brandt,b Shiyi Wangc Yale University School of Medicine, New Haven, Connecticut, USAa; Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USAb; Yale University School of Public Health, Department of Chronic Disease Epidemiology, New Haven, Connecticut, USAc
W
e appreciate the correspondence from Dr. Galen (1) about our study and value his interest in expanding the discussion of the cost-effectiveness of screening herpes simplex virus (HSV) in cerebrospinal fluid (CSF) (2). He raises a number of important assertions upon which we feel compelled to elaborate. First, the adoption of Reller’s criteria will likely reduce rather than increase patient exposure to acyclovir. Our rationale relates to the turnaround time of the tests involved. The laboratory instruments that perform the CSF white blood cell (WBC) counts and determine protein levels have rapid turnaround times on the order of an hour in nearly all inpatient settings. In contrast, turnaround times for HSV PCR have greater variability. We estimated an average of 1 day in the model. The addition of an hour for patients with abnormal CSF WBC counts or protein levels will likely not affect even a single dose of acyclovir given every 8 h. However, for patients with normal CSF WBC counts and protein levels that rely on a negative HSV PCR to stop acyclovir, the addition of an extra day would add three additional doses of acyclovir when dosed every 8 h. If we accounted for the added exposure to acyclovir and its subsequent nephrotoxicity in the model, Reller’s criteria would become even more cost-effective (3). Second, an increase in the number of HSV PCR false-negative results would also improve the cost-effectiveness of Reller’s criteria. With Reller’s criteria, fewer HSV PCR tests are performed. Thus, if the test performs worse, application of Reller’s criteria is comparatively better than a strategy that tests all patients with HSV PCR. Third, the numbers cited in support of missed cases of HSV encephalitis (HSV-E) may mislead the reader. For example, Gilden et al. state in a review article of HSV-E without reference to a primary source, “CSF pleocytosis is observed in over 90% of [HSV-E] patients” (4). In his letter, Dr. Galen cites this to quantitatively estimate “the rate of initially normal CSF WBC in herpes simplex encephalitis at closer to 10%.” In a second example from the work of Saraya et al., six cases of HSV-E with normal CSF WBC counts are provided as evidence against Reller’s criteria (5). However, as noted in Saraya et al.’s Table 2, Reller’s criteria would have tested at least four of these patients due to an elevation in CSF protein level. Reller’s criteria may or may not have tested the remaining two cases. The exact CSF protein (⬎50 or ⱕ50 mg/dl), HIV status, and patient age (⬍2 or ⱖ2 years) are needed to specify the number (6). Both examples report the probability of normal CSF WBC counts given the presence of HSV-E, which differs from the parameter in our model, the probability of HSV infection given the presence of normal CSF WBC counts and protein levels. We maintain a belief in the cost-effectiveness of Reller’s criteria (2). Our study concluded that the screening criteria proved cost-effective when less than 1 in 200 patients deferred from testing truly had HSV CNS infection. No data presented here nor October 2017 Volume 55 Issue 10
Journal of Clinical Microbiology
Citation Hauser RG, Campbell SM, Brandt CA, Wang S. 2017. Reply to Galen, “Screening cerebrospinal fluid prior to herpes simplex virus PCR testing might miss cases of herpes simplex encephalitis.” J Clin Microbiol 55:3144 –3145. https://doi.org/10.1128/JCM .01144-17. Editor Alexander J. McAdam, Boston Children's Hospital Copyright © 2017 American Society for Microbiology. All Rights Reserved. Address correspondence to Ronald G. Hauser, [email protected]. This is a response to a letter by Galen (https:// doi.org/10.1128/10.1128/JCM.01129-17).
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Reply to Galen, “Screening Cerebrospinal Fluid Prior to Herpes Simplex Virus PCR Testing Might Miss Cases of Herpes Simplex Encephalitis”
Author Reply
Journal of Clinical Microbiology
any we have seen to date suggest that the real rate in the deferred population is so high. In our paper, we outlined an implementation strategy that would allow clinicians the option of bypassing the rule. Even if clinicians bypassed the criteria 10% of the time, we estimate that Reller’s criteria would still save well over $100,000,000 annually in the United States.
REFERENCES
October 2017 Volume 55 Issue 10
of the nervous system. Nat Clin Pract Neurol 3:82–94. https://doi.org/10 .1038/ncpneuro0401. 5. Saraya AW, Wacharapluesadee S, Petcharat S, Sittidetboripat N, Ghai S, Wilde H, Hemachudha T. 2016. Normocellular CSF in herpes simplex encephalitis. BMC Res Notes 9:95. https://doi.org/10.1186/s13104-016 -1922-9. 6. Hauser RG, Brandt CA, Martinello RA. 2017. Criteria to screen molecular tests for the diagnosis of herpes simplex virus in the central nervous system have no propensity to harm. J Pathol Inform 8:4. https://doi.org/ 10.4103/2153-3539.201113.
jcm.asm.org 3145
Downloaded from http://jcm.asm.org/ on September 29, 2017 by EAST CAROLINA UNIV
1. Galen BT. 2017. Screening cerebrospinal fluid prior to herpes simplex virus PCR testing might miss cases of herpes simplex encephalitis. J Clin Microbiol 55:3142–3143. https://doi.org/10.1128/JCM.01129-17. 2. Hauser RG, Campbell SM, Brandt CA, Wang S. 2017. Cost-effectiveness study of criteria for screening cerebrospinal fluid to determine the need for herpes simplex virus PCR testing. J Clin Microbiol 55:1566 –1575. https://doi.org/10.1128/JCM.00119-17. 3. Tucker WE, Jr. 1982. Preclinical toxicology profile of acyclovir: an overview. Am J Med 73:27–30. https://doi.org/10.1016/0002-9343(82)90058-4. 4. Gilden DH, Mahalingam R, Cohrs RJ, Tyler KL. 2007. Herpesvirus infections
crossm
Ronald G. Hauser,a,b Sheldon M. Campbell,a,b Cynthia A. Brandt,b Shiyi Wangc Yale University School of Medicine, New Haven, Connecticut, USAa; Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USAb; Yale University School of Public Health, Department of Chronic Disease Epidemiology, New Haven, Connecticut, USAc
W
e appreciate the correspondence from Dr. Galen (1) about our study and value his interest in expanding the discussion of the cost-effectiveness of screening herpes simplex virus (HSV) in cerebrospinal fluid (CSF) (2). He raises a number of important assertions upon which we feel compelled to elaborate. First, the adoption of Reller’s criteria will likely reduce rather than increase patient exposure to acyclovir. Our rationale relates to the turnaround time of the tests involved. The laboratory instruments that perform the CSF white blood cell (WBC) counts and determine protein levels have rapid turnaround times on the order of an hour in nearly all inpatient settings. In contrast, turnaround times for HSV PCR have greater variability. We estimated an average of 1 day in the model. The addition of an hour for patients with abnormal CSF WBC counts or protein levels will likely not affect even a single dose of acyclovir given every 8 h. However, for patients with normal CSF WBC counts and protein levels that rely on a negative HSV PCR to stop acyclovir, the addition of an extra day would add three additional doses of acyclovir when dosed every 8 h. If we accounted for the added exposure to acyclovir and its subsequent nephrotoxicity in the model, Reller’s criteria would become even more cost-effective (3). Second, an increase in the number of HSV PCR false-negative results would also improve the cost-effectiveness of Reller’s criteria. With Reller’s criteria, fewer HSV PCR tests are performed. Thus, if the test performs worse, application of Reller’s criteria is comparatively better than a strategy that tests all patients with HSV PCR. Third, the numbers cited in support of missed cases of HSV encephalitis (HSV-E) may mislead the reader. For example, Gilden et al. state in a review article of HSV-E without reference to a primary source, “CSF pleocytosis is observed in over 90% of [HSV-E] patients” (4). In his letter, Dr. Galen cites this to quantitatively estimate “the rate of initially normal CSF WBC in herpes simplex encephalitis at closer to 10%.” In a second example from the work of Saraya et al., six cases of HSV-E with normal CSF WBC counts are provided as evidence against Reller’s criteria (5). However, as noted in Saraya et al.’s Table 2, Reller’s criteria would have tested at least four of these patients due to an elevation in CSF protein level. Reller’s criteria may or may not have tested the remaining two cases. The exact CSF protein (⬎50 or ⱕ50 mg/dl), HIV status, and patient age (⬍2 or ⱖ2 years) are needed to specify the number (6). Both examples report the probability of normal CSF WBC counts given the presence of HSV-E, which differs from the parameter in our model, the probability of HSV infection given the presence of normal CSF WBC counts and protein levels. We maintain a belief in the cost-effectiveness of Reller’s criteria (2). Our study concluded that the screening criteria proved cost-effective when less than 1 in 200 patients deferred from testing truly had HSV CNS infection. No data presented here nor October 2017 Volume 55 Issue 10
Journal of Clinical Microbiology
Citation Hauser RG, Campbell SM, Brandt CA, Wang S. 2017. Reply to Galen, “Screening cerebrospinal fluid prior to herpes simplex virus PCR testing might miss cases of herpes simplex encephalitis.” J Clin Microbiol 55:3144 –3145. https://doi.org/10.1128/JCM .01144-17. Editor Alexander J. McAdam, Boston Children's Hospital Copyright © 2017 American Society for Microbiology. All Rights Reserved. Address correspondence to Ronald G. Hauser, [email protected]. This is a response to a letter by Galen (https:// doi.org/10.1128/10.1128/JCM.01129-17).
jcm.asm.org 3144
Downloaded from http://jcm.asm.org/ on September 29, 2017 by EAST CAROLINA UNIV
Reply to Galen, “Screening Cerebrospinal Fluid Prior to Herpes Simplex Virus PCR Testing Might Miss Cases of Herpes Simplex Encephalitis”
Author Reply
Journal of Clinical Microbiology
any we have seen to date suggest that the real rate in the deferred population is so high. In our paper, we outlined an implementation strategy that would allow clinicians the option of bypassing the rule. Even if clinicians bypassed the criteria 10% of the time, we estimate that Reller’s criteria would still save well over $100,000,000 annually in the United States.
REFERENCES
October 2017 Volume 55 Issue 10
of the nervous system. Nat Clin Pract Neurol 3:82–94. https://doi.org/10 .1038/ncpneuro0401. 5. Saraya AW, Wacharapluesadee S, Petcharat S, Sittidetboripat N, Ghai S, Wilde H, Hemachudha T. 2016. Normocellular CSF in herpes simplex encephalitis. BMC Res Notes 9:95. https://doi.org/10.1186/s13104-016 -1922-9. 6. Hauser RG, Brandt CA, Martinello RA. 2017. Criteria to screen molecular tests for the diagnosis of herpes simplex virus in the central nervous system have no propensity to harm. J Pathol Inform 8:4. https://doi.org/ 10.4103/2153-3539.201113.
jcm.asm.org 3145
Downloaded from http://jcm.asm.org/ on September 29, 2017 by EAST CAROLINA UNIV
1. Galen BT. 2017. Screening cerebrospinal fluid prior to herpes simplex virus PCR testing might miss cases of herpes simplex encephalitis. J Clin Microbiol 55:3142–3143. https://doi.org/10.1128/JCM.01129-17. 2. Hauser RG, Campbell SM, Brandt CA, Wang S. 2017. Cost-effectiveness study of criteria for screening cerebrospinal fluid to determine the need for herpes simplex virus PCR testing. J Clin Microbiol 55:1566 –1575. https://doi.org/10.1128/JCM.00119-17. 3. Tucker WE, Jr. 1982. Preclinical toxicology profile of acyclovir: an overview. Am J Med 73:27–30. https://doi.org/10.1016/0002-9343(82)90058-4. 4. Gilden DH, Mahalingam R, Cohrs RJ, Tyler KL. 2007. Herpesvirus infections
