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Kevin,
I have responded to some of your questions & comments. We may just have to agree to disagree on the role of acyclovir in a 35 d old with fever and aseptic meningitis. It's Todd's problem.!.:-) Glad the infant had a + ve enteroviral PCR and did well!
Jay

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From: Kevin Powell [log in to unmask]


Yes, but only 3 of these 10 had meningoencephalitis. The other 7 had  disseminated or SEM diease. My point was that with such a small sample of HSV meningitis in a  study of febrile infants from just one center, I would be reluctant to draw any meaningful conclusions about CSF analysis in HSV meningoencephalitis. 

"She notes an Ohio colleague would not empirically treat past 14 days and that Kimberlin (in the editorial just before Long's) would empirically start acyclovir only for clear signs of HSV, signs of sepsis, or CSF mononuclear pleocytosis outside of enteroviral season."

The index patient that was being discussed  was a 35 d old with fever and CSF pleocytosis. I would at least consider HSV in this patient. We all know that overreliance on clinical appearance in this age group, particularly early in the course of the illness is fraught with pitfalls. That was presumably why the patient received a spinal tap in the first place.   

"I would not argue with treating proven HSV CNS disease in a 5 week old, but you would needsomething beside CSF WBCs. Any articles you can cite to the contrary supporting something beyond 21 days as a typical age cutoff?"

I would refer you to two sources. In a recent prospective study of neonates with HSV infection of those withknown age at diagnosis (n = 55), 51 were diagnosed withinthe first 28 days of life; the remaining 4 cases were diagnosedat 29, 30, 33, and 45 days.[Neonatal Herpes Simplex Virus Infections in Canada: Results of a 3-Year National Prospective Study Pediatrics, Jun 2006; 117: 1955 - 1962}. The other source I had alluded to was the chapter in Nelson's text book edited by Whitley et al where there are several supporting citations for the age range of 4-55 d. Unfortunately, these are older references. My point was that this disease can occur and has been well described beyond the typical 21 d cut off. Hope these are helpful.
 

Effectiveness of therapy

"JaPe says "We know that early treatment with Acyclovir makes all the difference" and ...."the risk benefit ratio would overwhelmingly favor overtreatment ." Both statements are incorrect. Acyclovir helps but is not highly effective against HSV. That is why Kimberlin pushed the limits throughout the 1990's and early part of this century. He increased dose and increased duration of therapy. He urged earlier empiric therapy, hoping it would improve outcome, without full consideration of the cost or number-needed-to-harm when expanding use of empiric therapy on those without the disease." 

On the contrary, Dave Kimberlin was not just hoping that it would improve outcome but his study, that was the basis for the higher dose that is now also listed in the Red Book, showed that patients treatedwith high dose acyclovir were 6.6 times (adjusted OR) as likely to be developmentally normal at 12 months of age aspatients treated with standard dose therapy.  

Safety

"Using the high dose regimen for 3 weeks, 20% of infants will have neutropenia below 1000. Renal toxicity is frequent but can be reduced byscrupulous attention to providing hydration. Both toxicities are less if the acyclovir can be stopped in less that 48 hours by a rule out HSV PCR test coming back that fast. It should be noted, however that false negative HSV PCR tests on the CSF are common, as much as 30%, so therapy should be continued if clinical suspicion is very high. Ampicillin is very safe, with only the occasional severe allergic reaction. Acyclovir is different. That changes the risk-benefit calculation."

Exactly the point..whether the test (PCR or culture)  takes 48 hrs or 72 hrs ...in my judgment, emperic therapy for a potentially devastating illness like meningoencephalitis is justified. Your potrayal of 48 hrs as a timeline for acyclovir toxicity was confusing to me. Besides, in the Kimberlin trial you alluded to, in the 6 cases that had neutropenia, the ANC recovered after completion of acyclovir therapy, andthere were no apparent adverse sequelae of the transient neutropenia. It peaked at day 7-10 into therapy. The renal toxicity was noted in the children with disseminated disease and it was unclear if this was related to sepsis induced dysfunction vs. medication. Again, this resolved with correction of volume status.

Cost

"Caviness found that empiric treatment with acyclovir in febrile infants without other signs/symptoms of HSV is cost prohibitive. ....So the cost-benefit ratio is not highly in favor of empiric therapy."

You have misinterpreted the conclusions of this analysis. Emperic  therapy for all febrile neonates is indeed cost prohibitive. However, this study concluded that when considering febrile neonates with meningitis emperic therapy is cost effective along with early HSV PCR testing. 

RBCs

"I'm not sure what 3 cases you are talking about. Can you cite any research supporting a correlation of CSF RBCs with HSV in the neonatal population? I've never seen it. Then calculate the PPV and NPV of considering the RBC count given all the traumatic taps. The specificity of a CSF RBC count is simply too low and will only mislead.

I was referring to the 3 cases of HSV meningitis in the Caviness study that you initially cited, as the basis for your dumping the RBC in CSF rule. I would be reluctant to change my practice with a study of three cases. At the same time, with the overall prevalence being so low, I doubt that we will have a study anytime soon addressing your question of predictive value of RBC's in CSF in HSV meningitis. I am unable to cite any current research other than the chapter in Nelson's textbook of Pediatrics ( the listed references I am afraid are from the 1980's). 

My general approach here is that the lack of evidence is not the same as evidence of absence of the disease or a reason to ignore the test. 



Kevin Powell MD PhD FAAP

Saint Louis, MO





 

Age of onset

"All 10 of the cases in Caviness's study were under 21 days of age, 9/10 under 14 days." 

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