December 2012 FAQs
December 2012 FAQs Heading link
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What alternatives to codeine are available for post-tonsillectomy and post-adenoidectomy analgesia?
What alternatives to codeine are available for post-tonsillectomy and post-adenoidectomy analgesia?
Background
In August 2012, the US Food and Drug Administration (FDA) released a drug safety communication regarding the questionable safety of codeine for pain relief in some children following tonsillectomy and/or adenoidectomy for obstructive sleep apnea (OSA).1,2 The FDA warning followed reports of 4 cases of death or nonfatal life-threatening respiratory depression in children who received codeine. In all 4 cases, a genetic variation in the children’s ability to metabolize codeine led to toxic levels of morphine.3,4 Codeine alone or in combination with non-opioid analgesics is widely used to manage mild to moderate pain in children, especially following tonsillectomy.5,6 However, the recently documented pediatric fatalities and release of the FDA safety communication may cause clinicians to question what therapeutic options other than codeine are available for the postoperative management of pain following tonsillectomy and/or adenoidectomy.
Tonsillectomy, adenoidectomy, and pain
Tonsillectomy alone, adenoidectomy alone, and adenotonsillectomy (AT) are common surgical procedures in children.7 Indications for tonsillectomy include recurrent throat infections and sleep-disordered breathing (SDB), which is a general term that refers to a variety of conditions ranging from snoring to OSA. Indications for adenoidectomy include chronic nasal infections, refractory sinus infections, and recurrent otitis media.8 The major indication for AT is upper airway obstruction due to adenotonsillar hypertrophy.
The most common complications following all of the previously mentioned procedures are throat pain, nausea, vomiting, dehydration, and hemorrhage.7,9,10 Throat pain, especially when swallowing, is common. The mean duration of postoperative pain following adenoidectomy is about one day. 11 In contrast, the mean duration of postoperative pain following tonsillectomy or AT is approximately 5 to 6 days but some children may not have complete resolution of pain for 2 weeks or longer.6,11-14 During this time, oral analgesics are the cornerstone of pain management.5 Codeine is often prescribed for postoperative AT pain while combination codeine/acetaminophen is typically used for postoperative tonsillectomy pain.4,6
Codeine metabolism and CYP2D6 polymorphism
Codeine has minimal affinity for mu-opioid receptors and its analgesic effect depends on metabolism to morphine by cytochrome P450 2D6 (CYP2D6). 5,15 Genetic polymorphisms of CYP2D6 are well characterized.5,16 Individuals with 2 nonfunctional alleles of CYP2D6 are considered poor metabolizers.5 Poor metabolizers are present in approximately 10% of the Caucasian population and 30% of the Chinese population.5,16 These patients have little to no CYP2D6 conversion of codeine to morphine, thus codeine is generally ineffective at producing analgesia in these subsets of the population.5,15,16 An individual with 1 or 2 CYP2D6 functional alleles with full or reduced activity is considered an extensive metabolizer (EM) and CYP2D6 conversion of codeine to morphine is typically normal in these patients.5,15 Lastly, individuals with duplicated CYP2D6 genes or genes with amplified activity have an ultrarapid metabolizer (UM) phenotype. It is estimated that 1 to 7 per 100 people have the UM phenotype but the prevalence may be as high as 28 per 100 people in some ethnic groups (see Table 1 below).1
Table 1. Prevalence of Ultrarapid Metabolizers in Different Ethnic Populations.1
Ethnic population Prevalence African/Ethiopian 29% African American 3.4- 6.5% Asian 1.2-2% Caucasian 3.6-6.5% Greek 6% Hungarian 1.9% Northern European 1-2% Increased conversion of codeine to morphine in patients with the CYP2D6 UM phenotype may lead to toxic levels of morphine despite the administration of an appropriate dose of codeine.15 In most patients, approximately 10% of codeine is converted to morphine; however, patients with the UM phenotype produce up to 75% more morphine than an individual with the EM phenotype.4 Excessive levels of morphine may result in serious adverse events such as potentially fatal respiratory depression.
Case reports leading to FDA safety communication
Variations in CYP2D6 codeine metabolism were common to all 4 recently reported cases of death or nonfatal life-threatening respiratory depression in children who received codeine after tonsillectomy and/or adenoidectomy.3,4 The published case reports are summarized below. Of note, the reports were generally brief and did not consistently provide information about inpatient postoperative pain regimens or the complete timeline of events following hospital discharge.
A 2-year-old male with a history of snoring and sleep study-confirmed OSA underwent elective AT.3 The outpatient procedure was uncomplicated, and the patient received intramuscular doses of 10 mg of meperidine and 12.5 mg of dimenhydrinate 6 hours after surgery. The patient was then sent home with instructions for the oral administration of 10 to 12.5 mg of codeine and 120 mg of acetaminophen syrup every 4 to 6 hours as needed for postoperative pain. On the evening of postoperative day 2, the child developed a fever accompanied by wheezing. The following morning the child’s vital signs were absent and efforts to resuscitate were unsuccessful. Toxic blood levels of morphine were detected post-mortem. Genotyping revealed a CYP2D6 UM phenotype. The child also had bronchopneumonia which may have played a role in his death since this condition can increase the risk of hypoxemia. Recurrent episodes of hypoxemia may lead to changes in mu-opioid receptors that increase sensitivity to morphine.
A 4-year-old male of First Nations’ descent with OSA and recurrent tonsillitis underwent AT.4 The surgery was uncomplicated and the patient’s overnight hospital stay was uneventful.The patient was discharged on an age-appropriate dose of 8 mg of codeine orally up to 5 times per day as needed. The child became lethargic and sedated the day after discharge and the following afternoon the patient was brought to the hospital without vital signs. The patient received a total of 4 codeine doses; a post-mortem codeine blood level was within normal limits while the morphine serum concentration was almost 3 times the upper limit of normal. Genotyping revealed a CYP2D6 UM phenotype.
A 5-year-old male with recurrent tonsillitis and snoring underwent AT. The child was prescribed postoperative acetaminophen and an age-appropriate dose of 12 mg of codeine every 4 hours.4 The patient was discharged after an uneventful hospital stay but was found without vital signs 24 hours following the procedure. Codeine and morphine blood levels were obtained post-mortem. Pharmacokinetic modeling determined that the codeine level was appropriate for the dose of codeine received while the morphine level was excessively high. Confirmative genotyping was not conducted; however, based on the morphine level relative to codeine the authors concluded that there is a high likelihood the child had a CYP2D6 UM phenotype.
A 3-year-old female of Middle Eastern descent with OSA underwent tonsillectomy.4 The surgery was without complication and the child remained inpatient for 24 hours. During hospitalization, the patient received two 15-mg doses of codeine syrup which were well tolerated. Upon discharge the patient was prescribed 15 mg of codeine and 150 mg of acetaminophen every 4 to 6 hours as needed. The child was found unresponsive and febrile several hours after receiving the final codeine dose. The patient presented to the hospital with an oxygen saturation of 65% and required resuscitation, mechanical ventilation, and administration of naloxone. Twenty-four hours following these interventions, the patient was extubated. She recovered fully. CYP2D6 genotyping indicated an EM phenotype, but the patient’s morphine levels were suggestive of a UM phenotype. According to the case report authors, prior literature reports have noted an overlap in the EM and UM phenotypes.
The patients in these cases all received codeine doses within the recommended weight-adjusted dosing range.3,4 However, the patients in the second and third cases were labeled overweight by the authors (27.6 and 29 kg, respectively).4 The authors postulated that due to the limited distribution of morphine into adipose tissue, dosing based on total body weight rather than lean body mass may have contributed to morphine accumulation in these patients.
Management options for clinicians
The previously summarized case reports indicate that there is an inherent risk for serious adverse events when codeine is used in children following tonsillectomy and/or adenoidectomy. Therefore, clinicians should consider all possible therapeutic strategies when approaching the postoperative management of pain in children who have undergone these procedures.
Preemptive CYP2D6 genotyping
Although the 2011 clinical practice guideline for tonsillectomy in children published by the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) does not address CYP2D6 genotype testing, a number of tests are currently available.7,15 AmpliChip CYP450 Test (Roche) and xTAG CYP2D6 (Luminex Corporation) are FDA-approved for use.17,18 Clinical genotyping services for CYP2D6 are also available from multiple companies including LabCorp, Quest Diagnostics, Mayo Medical Laboratories, ARUP, and PGx Lab.15 The potential benefit of preemptive genotyping is the ability to identify patients who have UM or poor metabolizer phenotypes so that safe and effective analgesic regimens can be prescribed. A 2011 guideline from the National Institutes of Health Clinical Pharmacogenetics Implementation Consortium (CPIC) on codeine therapy in the context of known CYP2D6 genotype recommends avoidance of codeine in CYP2D6 UM patients and consideration of alternatives such as morphine or nonopioid analgesics.
One concern with CYP2D6 genotype testing is the potential for incorrect genotype and subsequent phenotype assignment.14 The structure of the CYP2D6 gene is complex and there are several factors that lead to potential uncertainty in phenotype predictions. Some of these factors include exclusion of rare variants in the genotype test used and the existence of the same single nucleotide polymorphisms on multiple alleles. As previously mentioned, there can be overlap between the EM and UM phenotypes which may make it difficult to predict a patient’s response to codeine.4 Genotype results may be difficult to obtain preoperatively and some parents may not consent to having their child tested. However, the biggest barrier to routine CYP2D6 genotyping appears to be cost.5 A recent review article noted that genotyping of CYP2D6 is not routinely done in the clinical setting because it is expensive. Additionally, the test may not be covered by insurance companies as it may be considered experimental, investigational, or unproven. 19
Give codeine and monitor
The widespread use of codeine in pediatric patients following tonsillectomy and/or adenoidectomy is likely due to prescriber perception that weak opioids like codeine have a lower likelihood of side effects compared to more potent opioids like morphine.5 There is little evidence, however, to support this view and there are compelling reasons to avoid postoperative codeine in children. Randomized, controlled trials in pediatric patients undergoing tonsillectomy with or without other procedures have found that combination codeine/acetaminophen is no more effective at providing postoperative pain control than acetaminophen or the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen.20,21 The AAO-HNS guideline states that combination codeine/acetaminophen does not provide superior pain control following tonsillectomy compared to acetaminophen alone.8 Also, up to one-third of children with OSA remain symptomatic after AT which may lead to recurrent episodes of hypoxemia.3 As mentioned earlier, recurrent episodes of hypoxemia may increase sensitivity to morphine. Thus, an increased risk of respiratory depression with codeine use may be observed in children with CYP2D6 UM phenotypes who also have refractory apnea symptoms following AT.
Although the literature suggests that codeine may not be an effective and safe analgesic for use in children following tonsillectomy and/or adenoidectomy and the FDA has urged prescribers to consider alternative analgesics after these procedures, some clinicians may still want to prescribe codeine in this setting.1,3,4 In this case, the FDA recommends using the lowest effective dose of codeine-containing drugs for the shortest period of time.1 The recommended dose of codeine for pediatric analgesia is 0.5 to 1 mg/kg (maximum 60 mg/dose) every 4 to 6 hours.22 Dosing based on lean body mass in obese patients should be considered due to the limited distribution of morphine into adipose tissue. 4 As needed (PRN) dosing is preferred over around-the-clock (ATC) dosing.1 Caregivers of children who receive postoperative codeine should be counseled to not administer the drug unless the child is in pain, to adhere to prescribed dosing instructions, and to monitor for decreased alertness or problems with breathing. The AAO-HNS guideline neither supports nor discourages the use of codeine but notes that codeine may be ineffective in some children while causing an increased risk of side effects in others due to CYP2D6 polymorphism.7
Avoid codeine and use alternative postoperative analgesics
The AAO-HNS guideline only addresses postoperative pain control in general terms, stating that clinicians should advocate for pain management and educate caregivers regarding the management and assessment of pain following tonsillectomy, including the need for fluid intake since inadequate hydration has been associated with increased pain post-tonsillectomy.7 Over-the-counter (OTC) analgesics are preferred due to their efficacy in treating postoperative pain, but the authors state that acetaminophen alone may not provide adequate analgesia. The authors also state that ibuprofen can be safely used for postoperative pain and that ketorolac should be avoided. An increased perceived risk of postoperative hemorrhage has made many clinicians hesitant to prescribe NSAIDs for postoperative pain management. However, data from several analyses indicate that NSAIDs, with the exception of ketorolac, do not significantly alter postoperative bleeding rates compared with placebo or other analgesics in pediatric patients following tonsillectomy.23-25postoperative analgesic pain medications are often prescribed in an ATC manner but this dosing strategy has not been proven to be better than PRN dosing, with the exception of combination hydrocodone/acetaminophen.7 Medication dosing based on a child’s weight and monitoring subsequent pain levels is the best method of analgesia management regardless of the dosing strategy utilized. Though the AAO-HNS guideline addresses only postoperative pain management in the setting of tonsillectomy, it would be reasonable to adopt a similar approach for the management of pain following adenoidectomy or TA.
If initial analgesic regimens fail
Since the mean duration of postoperative pain following adenoidectomy is about one day, simple OTC analgesics like ibuprofen are likely to provide adequate pain relief.11 However, after tonsillectomy or AT, which have a longer duration of postoperative pain, the use of simple analgesics alone may not suffice and the addition of an opioid to provide further pain relief may be warranted.
To avoid complications from opioid treatment, the CPIC guidelines recommend the use of opioids that are not metabolized by CYP2D6 in patients with a confirmed poor metabolizer or UM phenotype.7 Since genotyping is not currently a standard of care, extrapolating this recommendation to patients who have unknown CYP2D6 phenotype would be beneficial. Opioids not metabolized by CYP2D6 include buprenorphine, fentanyl, morphine, methadone, oxymorphone, and hydromorphone. Of these, hydromorphone, methadone, and morphine are available as liquid formulations.26 However, methadone is not approved for use in children and the safety and effectiveness of hydromorphone in children have yet to be established.27 Morphine is also not approved for use in children but it has been used off-label in this population with efficacy and relative safety when used appropriately.5,27 If an opioid is added to a failing initial analgesic regimen the lowest effective dose should be used for the shortest amount of time and caregivers should receive the same counseling as that described for codeine above.
Conclusion
Genetic variations in CYP2D6 may put children at increased risk of adverse events including life-threatening respiratory depression and death when codeine is used to manage postoperative pain following tonsillectomy and/or adenoidectomy. Four case reports of pediatric death or nonfatal life-threatening respiratory depression prompted the FDA to issue a safety statement alerting prescribers and consumers to the potential dangers of codeine use in children, especially those who have undergone tonsillectomy and/or adenoidectomy. Clinicians have a number of options to consider when approaching the postoperative management of tonsillectomy and/or adenoidectomy pain in children. These options include preemptive CYP2D6 genotype testing, prescribing codeine with close monitoring, or using alternate analgesics such as ibuprofen with or without the addition of a non-CYP2D6 metabolized opioid such as morphine. Until further guidance is available, treatment decisions in this setting should be made after consideration of patient-specific factors and the likely risks and benefits of each treatment option.
References
1. FDA drug safety communication: codeine use in certain children after tonsillectomy and/or adenoidectomy may lead to rare, but life-threatening adverse events or death. U.S. Food and Drug Administration Web site. http://www.fda.gov/Drugs/DrugSafety/ucm313631.htm. Updated August 16, 2012. Accessed November 11, 2012.
2. Is post-surgery codeine a risk for kids? U.S. Food and Drug Administration Web site.
http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm315497.htm. Updated August 29, 2012. Accessed November 11, 2012.3. Ciszkowski C , Madadi P,Phillips MS,Lauwers AE, Koren G. Codeine, ultrarapid-metabolism genotype, and postoperative death. N Engl J Med. 2009;361(8):827-828.
4. Kelly LE, Rieder M, van den Anker J , et al. More codeine fatalities after tonsillectomy in North American children. Pediatrics . 2012;129(5):e1343-1347.
5. Wong C, Lau E, Palozzi L, Campbell F. Pain management in children: part 2 – a transition from codeine to morphine for moderate to severe pain in children. Can Pharm J. 2012;145(6):276-279.
6. Isaacson G. Tonsillectomy care for the pediatrician. Pediatrics. 2012;130(2):324-34.
7. Baugh RF, Archer SM, Mitchell RB, et al. American Academy of Otolaryngology-Head and Neck Surgery Foundation . Clinical practice guideline: tonsillectomy in children. Otolaryngol Head Neck Surg . 2011;144(1 Suppl):S1-S30.
8. Wetmore RF. Tonsils and adenoids. In: Behrman RE, Kliegman RM, Stanton B, St. Geme J, Schor N, eds. Nelson Textbook of Pediatrics. 19 th ed. Philadelphia PA: W.B. Saunders; 2011. http://www.mdconsult.com. Accessed November 11, 2012.
9. Statham MM, Myer CM 3rd. Complications of adenotonsillectomy. Curr Opin Otolaryngol Head Neck Surg . 2010;18(6):539-543.
10. Randall DA, Hoffer ME. Complications of tonsillectomy and adenoidectomy. Otolaryngol Head Neck Surg. 1998;118(1):61-68.
11. Paradise JL,Bluestone CD, Colborn DK, et al. Adenoidectomy and adenotonsillectomy for recurrent acute otitis media: parallel randomized clinical trials in children not previously treated with tympanostomy tubes. JAMA. 1999;282(10):945-953.
12. Paradise JL,Bluestone CD, Bachman RZ, et al. Efficacy of tonsillectomy for recurrent throat infection in severely affected children: results of parallel randomized and nonrandomized clinical trials. N Engl J Med. 1984;310(11):674-683.
13. Paradise JL,Bluestone CD, Colborn DK, et al. Tonsillectomy and adenotonsillectomy for recurrent throat infection in moderately affected children. Pediatrics. 2002;110(1 Pt 1):7-15.
14. Jones DT,Yoon MJ, Licameli G. Effectiveness of postoperative follow-up telephone interviews for patients who underwent adenotonsillectomy: a retrospective study. Arch Otolaryngol Head Neck Surg . 2007;133(11):1091-1095.
15. Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium. Clinical pharmacogenetics implementation consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther . 2012;91(2):321-326.
16. Yaksh TL, Wallace MS. Opioids, analgesia, and pain management. In: Chabner BA, Brunton LL, Knollmann BC, eds.Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill; 2011. http://www.accesspharmacy.com. Accessed November 12, 2012.
17. AmpliChip CYP450 Test. Roche Molecular Systems Inc. Web site. http://molecular.roche.com/ assays/Pages/AmpliChipCYP450Test.aspx. Accessed November 12, 2012.
18. Luminex Corporation Web site. http://www.luminexcorp.com/. Accessed November 12, 2012.
19. Drug Metabolizing Enzyme Genotyping Systems. Cigna Web site. http://www.cigna.com/assets/docs/health-care-professionals/coverage_positions/mm_0381_coveragepositioncriteria_AmpliChip.pdf . Accessed November 12, 2012.
20. St Charles CS , Matt BH,Hamilton MM, Katz BP. A comparison of ibuprofen versus acetaminophen with codeine in the young tonsillectomy patient. Otolaryngol Head Neck Surg . 1997;117(1):76-82.
21. Moir MS, Bair E, Shinnick P, Messner A. Acetaminophen versus acetaminophen with codeine after pediatric tonsillectomy. Laryngoscope. 2000;110(11):1824-1827.
22. Lee CKK, Tschudy MM, Arcara KM. Drug doses. In: Tschudy MM, Arcara KM, eds. The Harriet Lane Handbook. 19th edition. Philadelphia, PA: Elsevier Mosby; 2011. http://www.mdconsult.com/. Accessed November 11, 2012.
23. Cardwell ME, Siviter G, Smith AF. Non-steroidal anti-inflammatory drugs and perioperative bleeding in paediatric tonsillectomy. Cochrane Database Syst Rev. 2005;(2):CD003591.
24. Judkins JH, Dray TG, Hubbell RN. Intraoperative ketorolac and posttonsillectomy bleeding. Arch Otolaryngol Head Neck Surg. 1996;122(9):937-940.
- Bailey R, Sinha C, Burgess LP. Ketorolac tromethamine and hemorrhage in tonsillectomy: a prospective, randomized, double-blind study. Laryngoscope. 1997;107(2):166-169.
- Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2012. http://clinicalpharmacology-ip.com. Accessed November 11, 2012.
- Wickersham RM, ed. Drug Facts and Comparisons. St. Louis, MO: Wolters Kluwer Health; 2012. http://online.factsandcomparisons.com/. Accessed November 11, 2012.
Written by:
Richard DeBartolo, PharmD Candidate,
University of Illinois at Chicago,
December 2012. -
How do the 2 factor VIII concentrations, Xyntha and Advate, differ?
How do the 2 factor VIII concentrations, Xyntha and Advate, differ?
Overview of hemophilia
Hemophilia is an inherited disorder of blood coagulation manifesting with severe, sometimes spontaneous bleeding. Two types of hemophilia can occur—either hemophilia A (deficiency of factor VIII) or hemophilia B (deficiency of factor IX).1 Both hemophilia A and B are rare, X-linked disorders, occurring in 1 in 5000 and 1 in 25 000 male births, respectively. Deficiency of factor VIII or IX results in a disorder of hemostasis manifesting as uncontrolled or severe bleeding following trauma. In the case of severe factor deficiencies, bleeding can be spontaneous.2 Most patients with hemophilia have a severe deficiency of the factor, <1% of normal or <1 IU/dL. Bleeding from hemophilia may occur at any site of the body, but is most often seen in a hinged joint (knees, ankles, and/or elbows), referred to as hemarthrosis; 70% to 80% of bleeding episodes with hemophilia are hemarthroses. Bleeding can also occur in the muscles and mucous membranes. Although less common, intracranial bleeding and bleeding in the neck or throat, or in the gastrointestinal tract can occur and be life-threatening. Appropriate and immediate treatment of bleeding is essential to prevent long-term complications of the disorder, primarily joint and muscle deterioration and loss of function. Treatment of bleeding is generally done with administration of the deficient coagulation factor. These agents are infused intravenously to achieve levels of circulating factor high enough for the cessation of bleeding. This review will discuss the agents used for treatment of hemophilia A, referred to as antihemophilic factor products or factor VIII products, with a focus on 2 specific products—Xyntha and Advate.
Antihemophilic factor products
The available antihemophilic factor or factor VIII products are listed in Table 1. Currently both plasma-derived (pdFVIII) and recombinant-derived (rFVIII) factor VIII products are marketed. Plasma-derived factor VIII products are made from source plasma (pooled, paid donor plasma from apheresis). To ensure safety, donor plasma is held for 60 days or more and undergoes serologic and/or nucleic acid testing for the presence of potentially pathogenic organisms, such as hepatitis A or B virus and human immunodeficiency virus.3 The plasma then undergoes fractionation to separate factor VIII from other plasma proteins. Viral inactivation and purification methods are then used to further ensure the safety of pdFVIII products.
Factor VIII produced by recombinant technologies (either Chinese hamster ovary [CHO] or Baby hamster kidney [BHK] cell lines) also undergoes purification and/or viral inactivation methods.3 Recombinant factor VIII products have been classified as first, second, and third generation based on exposure to human or animal proteins during manufacture or in the final product. First generation rFVIII products have exposure to bovine serum albumin in the culture medium used for the CHO or BHK cell lines. In addition, albumin is added to the final product as a stabilizer. Only one first generation product, Recombinate, is available. There are 2 second generation rFVIII products—Helixate FS and Kogenate FS. Both of these rFVIII products are manufactured by Bayer. Human plasma protein solution is used in culture medium during production; however, sucrose is added to the final product as a stabilizer, reducing exposure of the factor to human or animal proteins. Third generation products—Advate and Xyntha—have no exposure to human or animal proteins either during manufacture or in the final product.
Table 1. Characteristics of available coagulation factor products.3
Brand name Factor source Fractionation/purification/ viral inactivation methods Stabilizer Specific activity of final product Factor VIII, plasma-derived Hemofil M (Baxter) Human plasma Paid apheresis Monoclonal antibody affinity and ion exchange chromatography TNBP/oxtoxynol 9 Albumin 2 to 22 AHF IU/mg total protein Koate-DVI (Kedrion Biopharma) Human plasma Paid apheresis Multiple precipitation and size exclusion chromatography TNPB/polysorbate 80 Dry heat Albumin 9 to 22 AHF IU/mg total protein Monoclate-P (Baxter) Human plasma Paid apheresis Monoclonal antibody affinity chromatography Pasteurization Albumin 5 to 10 AHF IU/mg total protein Factor VIII, recombinant (full-length) First generation Recombinate (Baxter) Recombinant Immunoaffinity and ion exchange chromatography Albumin (Bovine serum albumin used in culture medium) 1.65 to 19 AHF IU/mg total protein Second generation Helixate FS (CSL Behring) Kogenate FS (Bayer) Recombinant Ion exchange and immunoaffinity chromatography TNBP/polysorbate 80 Sucrose (Human plasma protein solution used in culture medium) 4000 AHF IU/mg total protein Third generation Advate (Baxter) Recombinant Immunoaffinity and ion exchange chromatography TNBP/polysorbate 80 Triton X 100 Trehalose (Free of human- and animal-derived plasma proteins) 4000 to 10,000 AHF IU/mg total protein Factor VIII, recombinant (B-domain deleted) Third generation Xyntha (Wyeth) Recombinant TNPB/Triton X 100 Nanofiltration Sucrose (Free of human- and animal-derived plasma proteins) 5500 to 9900 AHF IU/mg total protein Abbreviations: AHF=antihemophilic factor; DEAE=diethylaminoethyl cellulose; NA=not available; TNBP=tri (n-butyl) phosphate detergent. B-domain deleted factor VIII
In addition to classifying rFVIII products by exposure to human or animal proteins, these products also differ in regards to the structure of the factor VIII protein. Factor VIII is a large complex glycoprotein comprised of a single chain of amino acids.4 Three distinct domains have been identified (A, B, and C), each thought to have a specific function within the glycoprotein. Two of the domains—A and C—have been shown to share amino acid sequences similar to another factor protein (factor V) and are thought to be essential to the procoagulant activity of factor VIII. However, for domain B, the amino acid sequence is dissimilar to other factor proteins. Although the role of domain B is not fully understood, it is not thought to be directly involved with coagulation and likely associated with intracellular processing of the protein. Deletion of this domain results in a smaller protein, with no loss of procoagulant activity.5 This smaller protein then allows for an increased yield during manufacture, with a more efficient expression of the recombinant-derived protein from host cells.6
Full-length versus B-domain deleted recombinant factor VIII
Currently one B-domain deleted (BDD) rFVIII product is available, Xyntha, a third generation rFVIII product.7 Compared to Advate, a third generation full-length (fl) rFVIII, Xyntha is a smaller protein, with 1438 amino acids versus 2332.7,8
Table 2. Comparison of Xyntha and Advate.7,8
Factor product Availability Elimination half-life In vivo incremental recoverya Xyntha (Wyeth) 250, 500, 1000, and 2000 IU lyophilized powder in single-use vials 11.2 to 11.8 h 2.15 to 2.47 IU/dL/IU/kg Advate (Baxter) 250, 500, 1000, 1500, 2000, 3000, and 4000 IU lyophilized powder in single-use vials 10.27 to 11.70 h (children and adolescents <16 y) 12.03 h (adults >16 y) 2.05 to 2.26 IU/dL/IU/kg (children and adolescents <16 y) 2.57 IU/dL/IU/kg (adults >16 y) a Measured at maximum post-infusion concentration (Cmax) and calculated as (Cmax-baseline)/dose (IU/kg).
Few clinical trials are available comparing the efficacy of Xyntha and Advate. For all of the factor products, most available trials enroll a small number of patients evaluating factor VIII as treatment of bleeding episodes or as prophylaxis. Additionally, studies that are available often evaluate only the pharmacokinetics of factor VIII, since these parameters vary between individuals and dosing is adjusted based on individual patient values.
Gruppo and colleagues conducted a meta-analysis of published trials comparing BDD-rFVIII to full-length factor VIII for prophylaxis of bleeding episodes among patients with hemophilia A.9 The primary endpoint for the analysis was the incidence of breakthrough bleeding. The BDD-rFVIII available at the time of the analysis was a second generation rFVIII (Refacto); the comparator full-length product was either recombinant (fl-rFVIII) or plasma-derived (fl-pdFVIII). Thirteen observational studies were included in the analysis, enrolling 540 patients; 324 received full-length factor VIII and 216 were given BDD-rFVIII. The cumulative weekly dose of full-length factor VIII was 60 IU/kg versus 81.3 IU/kg for BDD-rFVIII (p=0.11). However, the bleeding incidence with full-length factor was 6.6 episodes per year compared with 16.8 episodes with BDD-rFVIII (p<0.0005), for an incidence rate ratio of 2.10 (95% confidence interval [CI] 1.98 to 2.24). The pooled elimination half-life of BDD-rFVIII was also shorter compared to full-length FVIII—11.3 hours versus 13.7 hours for plasma-derived and 14.3 hours for recombinant factors (p=0.004 and p=0.001, respectively). However, the authors noted that the assay method used to determine the half-life could not be factored into the analysis for differences.
Recht and colleagues reported the results of 2 clinical evaluations of Xyntha, one of which was a pharmacokinetic comparison of Xyntha and Advate. 10 Ninety-four patients (mean age, 24 years) with hemophilia A and at least 150 prior exposure days to a factor VIII product and no inhibitors were randomized to a single 50-IU/kg infusion of either Xyntha or Advate at 50 IU/kg. After a 72-hour washout period, the alternate factor product was administered. The 2 factor products were considered pharmacokinetically equivalent if the 90% CI of the ratio of the geometric least squares means of the primary pharmacokinetic parameters were within the window of 80% to 125%. Based on data for 30 patients, the 2 factor products were considered pharmacokinetically equivalent, with the described ratios meeting the equivalence window. The in vivo recovery percentages were 112 and 114 for BDD-rFVIII and fl-rFVIII, respectively, with corresponding incremental recoveries of 2.35 and 2.39 IU/dL/IU/kg and areas under the time curve (AUC) of 13.8 and 15.0 IU·h/mL.
Risk of inhibitor formation
Inhibitor formation is a serious complication of hemophilia, since development of inhibitors or antibodies to exogenous factor VIII can impact treatment of bleeding episodes. Inhibitors are more commonly seen among patients with severe factor VIII deficiencies, likely due to repeated and early exposure to factor concentrates.2
One meta-analysis has been conducted to determine if the rate of inhibitor formation differs between full-length factor VIII products and BDD-rFVIII. 11 A total of 29 clinical trials (primarily noncomparative, observational trials) were included in the analysis—19 for fl-rFVIII products and 10 for a BDD-rFVIII product (either a second or third generation product). Most trials were small (median, 59 patients), however, 5 trials included between 200 and 400 patients. For all treated patients, the pooled rate of de novo inhibitors was 0.83%; for those given BDD-rFVIII, the rate was 2.61% versus 0.42% for fl-rFVIII (odds ratio 6.30; 95% CI 2.07 to 19.1). For both products, the risk of inhibitor increased with exposure days, with risks remaining higher for BDD-rFVIII. The authors did note that the clinical trials included in the analysis were limited to nonrandomized, observational designs and use of a single factor product in a single cohort; however, several steps were taken by the authors to reduce bias of the analysis.
Summary
Currently, the National Hemophilia Foundation recommends use of a recombinant factor VIII product as first-line for treatment of hemophilia A. 12 Although no one recombinant factor product is recommended by the Foundation, a previous statement regarding formulary development and restrictions advocates that a “diverse range of therapies” be available to patients.13 Additionally, restriction to one factor product within a class of products solely for cost containment is not supported by the organization.
In regards to Xyntha and Advate, both are effective for treatment and prophylaxis of bleeding associated with hemophilia A, and the 2 products have similar pharmacokinetic properties. However, the 2 factors are structurally different and currently there are no head-to-head comparisons of the products to assess efficacy for bleeding episodes in patients with hemophilia A. Although limited, some data suggest that the risk of inhibitor formation may be higher with the B-domain deleted product. Additional study is needed to confirm this finding.
References
1. National Hemophilia Foundation. Types of Bleeding Disorders. http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=179&contentid=45&rptname=bleeding . Accessed November 26, 2012
2. Srivastava A, Brewer AK, Mauser-Bunshocten EP, et al. Guidelines for the management of hemophilia. Haemophilia. 2012. DOI: 10.1111/j.1365-2516.2012.02909.x.
3. Brooker M. Registry of clotting factor concentrates. Ninth edition, 2012. World Federation of Hemophilia. http://www.wfh.org/en/page.aspx?pid=1270. Accessed November 26, 2012.
4. Pipe SW. Functional roles of the factor VIII B domain. Haemophilia. 2009;15(6):1187-1196.
5. Kessler CM, Gill JC, White GC, et al. B-domain deleted recombinant factor VIII preparations are bioequivalent to a monoclonal antibody purified plasma-derived factor VIII concentrate: a randomized, three-way crossover study. Haemophilia. 2005;11(2):84-91.
6. Miao HZ, Sirachainan N, Palmer L, et al. Bioengineering of coagulation factor VIII for improved secretion Blood. 2004;103(9):3412-3419.
7. Advate [package insert]. Westlake Village, CA: Baxter Healthcare; 2012.
8. Xyntha [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals; 2012.
9. Gruppo RA, Brown D, Wilkes MM, Navickis RJ. Comparative effectiveness of full-length and B-domain deleted factor VIII for prophylaxis—a meta-analysis. Haemophilia. 2003;9(3):251-260.
10. Recht M, Nemes L, Matysiak M, et al. Clinical evaluation of moroctocog alfa (AF-CC), a new generation of B-domain deleted recombinant factor VIII (BDDrFVII) for treatment of haemophilia A: demonstration of safety, efficacy, and pharmacokinetic equivalence to full-length recombinant factor VIII. Haemophilia. 2009;15(4):869-880.
11. Aledort LM, Navickis RJ, Wilkes MM. Can B-domain deletion alter the immunogenicity of recombinant factor VIII? A meta-analysis of prospective clinical studies. J Thromb Haemost. 2011;9(11):2180-2192.
12. National Hemophilia Foundation. MASAC recommendations concerning products licensed for the treatment of hemophilia and other bleeding disorders. MASAC Document #210. http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=57&contentid=693 . Accessed November 26, 2012.
13. National Hemophilia Foundation. MASAC recommendation regarding factor concentrate prescriptions and formulary development and restrictions. MASAC Document #159. http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=57&contentid=179 . Accessed November 26, 2012.
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What is the most recent information on West Nile Virus?
What is the most recent information on West Nile Virus?
In 2012 the United States experienced a dramatic increase in the incidence of West Nile virus (WNV) infections.1 As of November 6, 5054 cases have been reported in 48 states. There were 2559 (51%) cases classified as neuroinvasive disease and 228 deaths. These numbers are vastly increased compared to 2011when there were 712 total reported cases; 486 cases of neuroinvasive disease and 43 total deaths. Due to the stark increase in the number of infections and the potential for complications and mortality, it is important for clinicians to gain understanding of the diagnostic and treatment modalities for WNV.
The first cases of WNV disease in North America appeared in 1999 in New York City.2 During this epidemic, 40% of the reported 28,805 cases were neuroinvasive, with a mortality rate of 4%. The actual mortality rate, however, is likely to be falsely elevated due to a reporting bias. It is estimated that 80% of all WNV infections remain asymptomatic, 20% develop a flu-like illness called West Nile fever (WNF), and less than 1% of all estimated cases go on to develop a neuroinvasive type of infection. Despite these statistics, WNV remains one of the most common causes of viral encephalitis in the United States.
The WNV is a single-stranded RNA virus belonging to the Flaviviridae family of the genusFlavivirus.3 This virus belongs to the Japanese encephalitis serocomplex, which includes other viruses such as yellow fever, the St Louis encephalitis virus, the Kunjin virus, and the Japanese encephalitis virus. WNV is maintained in a transmission cycle through involvement of mosquitoes and birds. The birds, in particular robins and sparrows, serve as amplifying hosts, while the Culex pipiens, the common house mosquito, is often what spreads the disease. Transmission of virus can also occur through person-to-person transmission. There have been case reports of transmission via organ transplantation of an infected donor, blood transfusions, and even from a mother to child during pregnancy or through breast feeding.2Blood donations are routinely screened for WNV; however, organ and tissue donations are not at this time.1 As these routes of transmission are rare, the disease typically follows a seasonal pattern influenced by the life cycle of mosquitoes. Most cases of WNV are seen from spring to early fall as a result of a higher prevalence of mosquitoes during this time.4
Once an infected mosquito bites a human host, the WNV from the saliva begins to replicate in the Langerhans dendritic cells.5 Within 1 or 2 days of the initial bite, the dendritic cells migrate through the lymph system and eventually enter the blood stream where primary viremia occurs. Viremia typically precedes symptoms and lasts for approximately 1 week. Serum IgM antibodies can usually be detected early in response to the virus (usually days 2 to 7 of disease) while serum IgG can be detected days 8 to 20 of disease; both antibodies can persist in the body and may last more than 2 months. There is a strong correlation between resolution of viremia and presence of serum antibodies; in contrast, a delay in developing antibodies to the virus seems to increase the chances of central nervous system (CNS) involvement and worsening disease.3
The incubation period for WNV is usually 2 to 14 days, and the spectrum of disease ranges from asymptomatic infection to paralysis and death from the West Nile neuroinvasive diseases (WNND).3 See Table 1 for symptoms associated with each WNV manifestation. Surveillance data from California suggest that risk factors for developing WNND include an age > 64 years, diabetes, hypertension, and the male sex.6 Immunosuppression, a past medical history (PMH) of cancer, chronic renal disease, and chronic alcohol abuse are also cited as risk factors in other studies.5,7 These patients tend toward a longer, more severe course of illness and carry a worse prognosis. Those who develop WNF and West Nile meningitis have a <1% mortality rate. However, this mortality rate rapidly increases with development of West Nile encephalitis (20%) and acute flaccid paralysis (10-50%).8
Table 1. Symptoms of Various Manifestations of West Nile Disease.5
Manifestation Typical Symptoms West Nile fever Abrupt onset of fever, headache, fatigue, malaise, anorexia, nausea, myalgia, lymphadenopathy, cognitive impairment, and non-pruritic generalized maculopapular rash West Nile Neuroinvasive Disease
Meningitis Fever, stiff neck, headache, photophobia, cerebral spinal fluid pleocytosis without altered mental status or focal weakness Encephalitis
(evidence of brain parenchyma involvement required)Common: Fever, diffuse weakness, fatigue, headache, confusion, altered mental status, uncoordinated gait Less common:gastrointestinal complaints, rash, arthralgia, myalgia, cranial nerve palsies Uncommon: pharyngitis, lympadenopathy, conjunctivitis, tremor (at rest or kinetic), seizure Acute flaccid paralysis (AFP) or poliomyelitis
(can be concurrent with encephalitis or meningitis)Abrupt and progressive asymmetric weakness that involves 1 or more extremities; back or muscle pains tend to occur just prior to onset of weakness Other symptoms include: areflexia, hyporeflexia, loss of bladder and bowel function, respiratory distress, paresthesias It has also been shown that there are long-term consequences resulting from WNV disease.8Up to half of the symptomatic patients will continue to have persistent cognitive and motor deficits up to as long as 18 months after resolution of viral disease; some patients are unable to return to baseline. It is important to note, however, that severity of initial paralysis does not predict future outcomes. There have been cases of mild disease persisting and cases of profound quadriplegia making full recovery of strength.
Diagnosis of WNV disease can be challenging. Patients have either normal complete blood counts or exhibit only a mild leukocytosis.2 For those with WNND, the clinical picture directly overlaps with other sources of meningitis, often times delaying the diagnosis of WNV. Neuroimaging studies and neuropathology studies often appear normal. The definitive diagnosis for WNV disease is the detection of WNV-specific IgM by enzyme linked immunosorbent assays (ELISA) either in the serum or cerebrospinal fluid (CSF). Special attention must be given to those who have recently received the yellow fever vaccine or Japanese encephalitis vaccine as cross-reactivity among different flaviviruses can occur, creating false positives on the assays. In order to confirm the ELISA results, plaque reduction neutralization assays need to be performed when one suspects cross-reactivity.5
Treatment
As a result of limited clinical evidence, there is no accepted pharmacologic agent to date for the treatment of WNV disease; the current standard of care is purely supportive in nature.1There has been in vitro testing of several compounds. Ribavirin and interferon α-2b both show activity in vitro, and studies in mice generally support the use of interferon but not ribavirin.9This may possibly be due to the low lipid solubility of ribavirin and its inability to sufficiently pass through the blood brain barrier. There is a 2001 report that describes the use of ribavirin in humans during a WNV outbreak in Israel.10 Thirty-seven patients were treated with ribavirin. Forty-one percent of those who received ribavirin died; no details of doses or specific outcomes in those who survived were provided. No additional trials using ribavirin in humans have been published since this report.
Interferon α-2b therapy has more promising data in both mice and humans.9 There have been a handful of case reports in humans supporting improved outcomes with a 2-week course of interferon α-2b.11,12 The most common dosing regimen was an initial dose of 3 million units IV, followed by 3 million units subcutaneously for the next 13 days. Within 2 to 3 days of therapy, most clinicians in the case reports saw clinical improvement in their patients. However, further studies need to be conducted before definitively claiming a benefit with interferon therapy.
Pooled immunoglobulin G (IVIG) from people with circulating antibodies to WNV is a potential treatment option. In a report of 8 patients by Makhoul and colleagues, patients with a confirmatory WNV IgM test were given IVIG.13 The IVIG WNV antibody concentration was 1:1600, and the prescribed dose of IVIG was 0.4 grams/kg/dose for 5 days (total dose 2 grams/kg). In this report, 6 out of 8 patients recovered. Those who survived in this study were administered IVIG prior to day 6 on admission, while those who died were administered IVIG on hospital day 6 and day 19. Study authors commented that time to treatment was a significant factor in patient recovery—the earlier the treatment was started, the faster the patient was able to resolve neurologic symptoms. It may also be important to note that case reports in Canada using IVIG has not shown much success.14 There may be differences in WNV antibody concentration in the pool of immunoglobulin gathered, leading to location-specific outcomes.
As treatments are currently limited, prevention of disease becomes essential. The Centers for Disease Control and Prevention (CDC) recommends prevention by protection against mosquito bites. They recommend applying insect repellent to exposed skin and clothing, wearing long sleeved shirts and pants when outdoors, using mosquito nets, and draining standing water.16 In addition, there were 2 phase 1 clinical trials published showing the safety and efficacy of an inactivated WNV DNA vaccine.16,17 It is possible that this vaccine will be available in the upcoming years, minimizing future epidemics and reducing mortality from this disease.
A summary of case reports can be found in Table 2.
Table 2. Summary of Case Reports.4,10,11,13,14,18,19
Citation Patients (n) Patient Description Treatment Outcome Chowers102001 Israel 37 This was a subset of 325 patients hospitalized with WNF Ribavirin 22/37 survived Kalil11 2005United States 2 43 year old male with PMH of lymphoblastic lymphoma 54 year old female with PMH of rheumatoid arthritis Interferon α-2b 3 million units IV x 1, then 3 million units SC daily x 13 days On day 2 of therapy, both patients became alert and oriented. One patient continued to have mild leg weakness 9 months after discharge. Lewis4 2007United States 1 83 year old male Interferon α-2b 3 million units SC q12 hours x 1 day, then daily x 13 days Four days after finishing his 2 week course of therapy, patient was able to walk. Fan14 2004Canada 3 78 year old male 57 year old female IVIG No clinical improvement; both patients died. 83 year old male Unknown – supportive care Patient showed evidence of resolving encephalitis on day 65 but died on day 122. Makhoul132009 Israel 8 All experienced progressive headaches, high fever, confusion, nausea and vomiting. WNV IgM test was positive in all patients prior to therapy IVIG 0.4 g/kg/day containing high WNV antibodies obtained from healthy blood donors 6/8 patients recovered Average hospital stay between 8-15 days. Rhee18 2011United States 1 51 year old male with PMH of hepatitis C and cirrhosis IVIG 0.4 g/kg was given on hospital day 4; a second dose of IVIG 0.4 g/kg was given on hospital day 8 Improved signs and symptoms after first dose of IVIG; discharged with baseline mental status Anticona192012 United States 2 70 year old male with PMH of hypertension and coronary disease 81 year old male with PMH of hypertension, diabetes, atrial flutter and sick sinus syndrome Supportive Care Both patients remained in hospital > 30 days; > 15 of which were in the ICU. Both patients had residual extremity paresis on discharge. Abbreviations: ICU = intensive care unit, PMH = past medical history, SC = subcutaneous, WNF = West Nile fever, WNV = West Nile virus
Conclusion
As the incidence of WNV infections increases in the current nationwide epidemic, recognition of the disease as well as its potential for neurologic complications may lead to faster diagnosis and improved patient outcomes. Prevention of WNV is key based on the lack of treatment options currently available. There is limited evidence that interferon α-2b or IVIG may be beneficial for patients with WNV disease. A WNV vaccine has been shown to be safe and effective in phase I trials.
References
1. CDC. Questions and Answers. Centers for Disease Control and Prevention Web site. Available at: http://www.cdc.gov/ncidod/dvbid/westnile/qa/prevention.htm. Accessed November 14, 2012.
2. Khabbaz RF, Ostroff SM, LeDuc JW, et al. Emerging and reemerging infectious disease threats. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. Philadelphia, Pa: Elsevier Inc.; 2010:199-210.
3. Petersen LR, Marfin AA, Gubler DJ. West Nile virus. JAMA. 2003;290(4):511-515.
4. Lewis M, Amsden JR. Successful treatment of West Nile virus infection after approximately 3 weeks into the disease course. Pharmacotherapy. 2007;27(3):455-458.
5. Davis LE, DeBiasi R, Goade DE, et al. West Nile virus neuroinvasive disease. Ann Neurol. 2006;60(3):286-300.
6. Jean CM, Honarmand S, Louie JK, Glaser CA. Risk factors for West Nile virus neuroinvasive disease, California, 2005. Emerg Infect Dis. 2007;13(12):1918-1920.
7. Lindsey NP. Medical risk factors for severe West Nile virus disease, United States, 2008-2010. Am J Trop Med Hyg. 2012;87(1):179-184.
8. Sejvar JJ. The long-term outcomes of human West Nile virus infection. Clin Infect Dis.2007;44(12):1617-1624.
9. Engle MJ, Diamond MS. Antibody prophylaxis and therapy against West Nile virus in wild-type and immune-deficient mice. J Virol. 2003;77(24):12941-12949.
10. Chowers MY, Lang R, Nassar F, et al. Clinical characteristics of the West Nile fever outbreak, Israel, 2000. Emerg Infect Dis. 2001;7(4):675-678.
11. Kalil AC, Devetten MP, Singh S, et al. Use of interferon-alpha in patients with West Nile encephalitis: report of 2 cases. Clin Infect Dis. 2005; 40(5):764-766.
12. Sayao AL, Suchowersky O, al-Khathaami A, et al. Calgary experience with West Nile virus neurological syndrome during the late summer of 2003. Can J Neurol Sci. 2004;31(2):194-203.
13. Makhoul B, Braun E, Herskovitz M, Ramadan R, Hadad S, Norberto K. Hyperimmune gammaglobulin for the treatment of West Nile virus encephalitis. Isr Med J Assoc. 2009; 11(3):151-153.
14. Fan E, Needham DM, Brunton J, Kern RZ, Stewart TE. West Nile virus infection in the intensive care unit: a case series and literature review. Can Respir J. 2004;11(5):354-358.
15. Centers for Disease Control. Fight the bite. Centers for Disease Control and Prevention Web site. Available at: http://www.cdc.gov/ncidod/dvbid/westnile/index.htm. Accessed September 19, 2012.
16. Ledgerwood JE, Pierson TC, Hubka SA. A West Nile virus DNA vaccine utilizing a modified promoter induces neutralizing antibody in younger and older healthy adults in a phase I clinical trial. J Infect Dis. 2011;203(10):1396-1404.
17. Martin JE, Pierson TC, Hubka S. A West Nile virus DNA vaccine induces neutralizing antibody in healthy adults during a phase 1 clinical trial. J Infect Dis. 2007;196(12):1732-1740.
18. Rhee C, Eaton EF, Concepcion W, Blackburn BG. West Nile virus encephalitis acquired via liver transplantation and clinical response to intravenous immunoglobulin: case report and review of the literature. Transpl Infect Dis. 2011;13(3):312-317.
19. Anticona EMF, Zainah H, Ouellette DR, Johnson LE. Two case reports of neuroinvasive West Nile virus infection in the critical care unit. Case Rep Infect Dis. 2012;2012:839458.
Written by:
Linda Lei, PharmD, PGY-1,
University of Illinois at Chicago,
December 2012.