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Varicella encephalitis and pneumonia in a patient with end stage renal failure

Varicella encephalitis and pneumonia in a patient with end stage renal failure We describe a patient with end stage renal failure (ESRF) on hemodialysis who was admitted to our department for primary varicella infection complicated by varicella pneumonia and encephalitis. Varicella infections results in serious morbidity and mortality in ESRF dialysis and transplant patients. Evidence published thus far suggests that live attenuated varicella vaccines are effective and safe in ESRF and renal transplant patients. Worldwide a few countries have instituted guidelines for the varicella immunisation in ESRF patients. However, in the Asia Pacific Region, it has not been widely given due to the lack of national consensus guidelines. Our case depicts that primary varicella infection can occur at any time in immunosupressed patients and thus suffer serious consequences from it. With increasing burden of chronic kidney disease, Renal Physicians and Family Physicians in the Asia Pacific Region should meet and study the epidemiological data in each individual country and decide on the consensus guidelines on how the varicella vaccination can be targeted for those at risk. Keywords: End stage renal failure, Varicella, Vaccination Background and Emergency Department to Singapore General Our case report illustrates the serious complications of Hospital Department of Family Medicine and Con- varicella in a patient with end stage renal failure and em- tinuing Care for fever, chills and non productive cough of phasizes the need for consensus guidelines on varicella two days duration. There was no travel or contact history. vaccinations in such patients in the Asia Pacific region. On examination, he was alert, non-toxic looking and ori- Although evidence in literature show that live attenuated entated to time, place and person. He had a temperature vaccines can be safe & effective, these vaccines are still of 38.4 degree Celsius, blood pressure of 140/90 mmHg, generally avoided due to lack of consensus guidelines on pulse rate of 80 per minute and respiratory rate of 16 per vaccinations in patients with end stage renal failure. Lit- minute. His respiratory examination revealed reduced erature review provides evidence on the safety and effi- chest expansion over the left lung base associated with cacy of varicella vaccination in end stage renal failure dullness to percussion, bronchial breath sounds and patients. With the increasing burden of chronic kidney crackles. His cardiovascular, abdominal and neurological disease, family physicians also need to be alert for these examination was unremarkable. A chest radiograph con- complications of varicella and can play a big role in fa- firmed consolidation in the left lower zone with milder air cilitating varicella vaccination in patients with end stage space opacity in the right lower zone. He was initially di- renal failure. agnosed with healthcare associated pneumonia in view of recent hospitalization and started on intravenous tazocin. Respiratory viruses multiplex PCR (Polymerase Chain Case presentation Reaction) was negative. Our patient is a 58 year old construction supervisor with On the fourth day of admission, he developed vesiculo- background of hypertension and ESRF on haemodialysis papular pruritic lesions mainly over the trunk. Varicella three times per week. He was admittted via the Accident Zoster Virus (VZV) IgM was positive. He was isolated to- gether with air-borne and contact precautions, and started * Correspondence: low.lian.leng@sgh.com.sg on oral Valacyclovir 500 mg daily later on that day. The Department of Family Medicine and Continuing Care, Singapore General Hospital, Bowyer Block A, Level 2, 169608 Outram Road, Singapore Full list of author information is available at the end of the article © 2014 Low et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. Low et al. Asia Pacific Family Medicine 2014, 13:4 Page 2 of 4 http://www.apfmj.com/content/13/1/4 next day, his oxygen saturation decreased, and worsening The cerebrospinal fluid contains lymphocytes and elevated of the consolidation was noted on repeat chest radiograph. levels of protein but normal glucose concentration, allow- He also developed vivid visual hallucinations, became rest- ing differentiation from bacterial meningitis. Cerebrospinal less and agitated and disorientated to time, place and per- fluid polymerase chain reaction (CSF PCR) can be used to son. A diagnosis of varicella zoster infection complicated detect VZV DNA, and has a specificity of greater than 95%, by varicella pneumonia and encephalitis was made. Vala- but the sensitivity is 30% or less in some studies [7]. Re- cyclovir was switched to intravenous acyclovir. A lumbar peated mortality rates approach 10% and long-term neuro- puncture showed increased protein and lymphocytes and logic sequelae are reported in up to 15% of survivors [8-10]. was negative for cryptococcal antigen and neurotropic vi- There is no proven effective therapy once encephalitis oc- ruses. A magnetic resonance imaging scan of the brain curs, and supportive care remains the mainstay of manage- showed no evidence of acute infarct, intracranial bleed, ment. Acyclovir has been used with anecdotal success space-occupying lesion or hydrocephalus. The frequency [11-13]. However, acyclovir neurotoxicity should always be of dialysis was increased with continuation of the renal ad- considered in patients with prolonged or worsening neuro- justed dose of acyclovir. logical symptoms. Throughout the admission, his hemodialysis continued Varicella pneumonia is the most serious complication and he completed 2 weeks of IV acyclovir. His functional following varicella, develops more commonly in adults status improved back to the pre-morbid levels on discharge. (up to 20% of cases) than in children, and accounts for the majority of morbidity and mortality seen in adults Discussion with varicella [11]. Risk factors linked to the develop- The incidence of varicella in Singapore has been increasing ment of varicella pneumonia include cigarette smoking, since 1984 [1] and increased from 14,999 in 2003 to 24,031 pregnancy and an immunosuppressed state [9]. Varicella in 2006. Mandatory notification of varicella ceased since pneumonia typically develops insidiously with symptoms 27th August 2007 [2]. Thus the latest reported figures are of progressive dyspnea and dry cough. Patients demon- not known. strate impaired gas exchange with progressive hypox- Primary infection with varicella is usually a benign and emia and are at high risk for respiratory failure and need self-limiting illness in immunocompetent children. How- for admission to intensive care for mechanical ventila- ever, patients with end stage renal failure have lympho- tion [14,15]. Mortality rates approach 50% in patients cytopenia and impaired lymphocyte function and are with respiratory failure who require mechanical ventilation, susceptible for disseminated varicella and its complications, despite institution of aggressive therapy and appropriate with more severe morbidity and mortality rates [3,4]. support measures [16,17]. Chest radiographs typically re- Our patient suffered severe complications of varicella veal diffuse bilateral infiltrates. Prompt administration of infection that is pneumonia and viral encephalitis. Other intravenous acyclovir has been associated with clinical im- known complications include myocarditis, corneal lesions, provement and resolution of pneumonia in selected series nephritis, arthritis, bleeding diatheses, acute glomerulo- [17,18]. Resolution of pneumonitis parallels improvement nephritis, hepatitis and secondary bacterial superinfection of the skin rash, although fever and compromised pulmon- of the skin. ary function may persist for weeks [11]. The use of steroids The central nervous system is the most common extra as adjunctive therapy for treatment of life-threatening vari- cutaneous site of involvement, manifesting as acute cerebel- cella pneumonia is still controversial and should be further lar ataxia or diffuse encephalitis. These disorders typically examined in rigorous controlled trials [19]. developtowardthe endofthe firstweek of theexanthem, In immunosuppressed hosts such as ESRF patients or but can also precede the rash [5,6]. Diffuse encephalitis immunocompetent patients with disseminated disease such most often occurs in adults and clinical manifestations in- as pneumonia or encephalitis, varicella should be treated with IV acyclovir [20]. IV acyclovir reduces the occurrence clude delirium, seizures, loss of consciousness and focal neurological signs including cranial nerve palsies, hemipar- of visceral complications but has no effect on healing of esis. Varicella encephalitis is more severe in immunosup- skin lesions or pain [11]. The recommended dose is 10 mg/ kg Q8h for 7 days. pressed hosts who typically have a fulminant course with seizures, mental status changes and focal deficits including In December 2012, the FDA approved varicella zoster stroke syndromes. However verylittledataexist regarding immune globulin (VariZIG) for administration to high risk individuals within 4 days of varicella exposure. the occurrence of varicella encephalitis in patients with end stage renal failure or those undergoing dialysis. Acyclovir is an effective agent for the treatment of VZV In the workup for VZV encephalitis, computed tomog- infections but renal impairment results in high serum drug levels with resultant neurotoxicity. In renal failure, raphy or magnetic resonance imaging may or may not demonstrate abnormal radiographic findings, although elec- the half-life of acyclovir is increased from a maximum of troencephalography is often abnormal in acute encephalitis. 3.8 to 20 hours, and dosage reduction is required using Low et al. Asia Pacific Family Medicine 2014, 13:4 Page 3 of 4 http://www.apfmj.com/content/13/1/4 the interval extension method [21]. Even the adminis- patient coming in contact with varicella patients [37], the tration of recommended reduced doses can result in use of immunglobulins has risks and is expensive. Immuno- high serum levels and neurotoxicity, due to poor removal globulins should be reserved for those with imminent ex- of acyclovir by peritoneal dialysis [4]. Tremors, disorienta- posure to the virus. Varicella vaccination is a cheaper and tion, agitation, hallucinations, and delirium are common more effective way for prevention of varicella. presentations of acyclovir-induced encephalopathy, whereas seizures, cerebellar ataxia, sensory symptoms, speech disor- Role of family physicians ders, fever and cranial nerve palsies are much less frequent. There were 4,169 patients on dialysis in Singapore by 2008. Features distinguishing acyclovir neurotoxicity from VZV This number represented a 89% increase since end 1998, encephalitis include a temporal association between the when there were 2,209 patients on dialysis. The incidence symptoms and acyclovir use, as well as acellular CSF exam- of new ESRF patients requiring dialysis increases every ination. However, acyclovir neurotoxicity should always year, from 564 new cases in 1998 to 1,212 cases in 2008. be considered in patients with prolonged or worsening This represents a 115% increase during this 10-year period neurological symptoms for which daily hemodialysis is [38-40]. In addition, patients are getting more elderly. In required often. 2006, 52.1% and 5.1% of incident dialysis patients were Studies show that many ESRF and kidney transplant pa- over the age of 60 and 80 respectively. With a rapidly age- tients do not have immunity to varicella [22-25]. Primary ing population, Singapore can expect an increasing burden varicella infection is common, up to 1.9% of renal of end stage renal disease Family physicians should advise transplant recipients are admitted in the first year post- their ESRF patients of the life-threatening complications of transplant [26]. The infection can have serious compli- varicella and urgent need for review if they develop fever cations and be lethal in these ESRF and renal transplant or rash after coming in contact with varicella patients. patients who are immunosuppressed [24,26-29]. Currently, there are no local data on the seropositivity Live attenuated varicella vaccine is generally contraindi- against varicella antibody in ESRF patients in Singapore cated in immunosuppressed patients but has been proven or consensus guidelines for varicella vaccination. With an to be safe when administered to both pediatric [23,24,29] increasing burden of chronic kidney disease, Renal Physi- and adult end stage renal failure patients on dialysis, [27] cians and Family Physicians in the Asia-Pacific region as well as renal transplant patients on immunosuppressive should meet and study the epidemiological data in each treatment [25]. individual country and decide on consensus guidelines Despite the general suppression of the immune system and how the varicella vaccination program can be targeted associated with uremia, patients with ESRF have high for those at risk. Research on the seroprevalence of vari- seroconversion rates to a two-dose varicella vaccination cella in ESRF patients should be conducted if such data is regimen. Seroconversion rates ranged from 87-100% not currently available in Asia-Pacific countries. [23,29-31] in ESRF pediatric patients waiting for transplant and 64% in adult ESRF patients [24]. 66.6% of pediatric Conclusions renal transplant recipients seroconverted after a one–two Evidence supports the safety and efficacy of varicella vac- dose varicella vaccination regimen [25]. Immunization cination in patients with end stage renal failure. Guidelines guidelines in New Zealand recommend a two dose vari- for varicella vaccination for ESRF patients are available in a cella vaccination regimen for children with deteriorating few countries [33,34]. The intent of our paper is to stimu- renal function, as early as possible before transplantation late more research in the area of generating the need of [32]. In the United States, the Centers for Disease Control consensus guidelines for universal vaccinations of ESRF pa- and Prevention (CDC) adult immunization schedule rec- tients on dialysis. Serious consequences of primary varicella ommend a two dose varicella vaccination regimen and a infection can be avoided with appropriate vaccinations. single dose zoster vaccination for patients with ESRF and recipients of hemodialysis [33,34]. However, ESRF patients Consent have an inability to maintain adequate antibody titers over Written informed consent was obtained from the patient time [35,36]. Reports describe several patients in whom im- for publication of this case report and any accompanying munity to varicella waned in chronic renal insufficiency and images. A copy of the written consent is available for re- in the post-transplant period [26,27]. Hence there is a need view by the Editor-in-Chief of this journal. for yearly surveillance of antibody titre as are done for Hepatitis B & C virus and cytomegalovirus. Special consid- Abbreviations eration for vaccination should also be given to persons who ESRF: End stage renal failure; VZV: Varicella-Zoster virus. have close contact with or are at high risk of transmission to ESRF patients [32]. Although there are recommendations Competing interests to administer varicella immunoglobulin to transplant The authors declare that they have no competing interests. Low et al. Asia Pacific Family Medicine 2014, 13:4 Page 4 of 4 http://www.apfmj.com/content/13/1/4 Authors’ contributions 22. Genc G, Ozkaya O, Aygun C, Yakupoglu YK, Nalcacioglu H: Vaccination LLL, FFV and SMS participated in the proposal, design, and drafted the status of children considered for renal transplant: missed opportunities manuscript. All authors read and approved of the final manuscript. for vaccine preventable diseases. Exp Clin Transplant 2012, 10(4):314–318. 23. Prelog M, Pohl M, Emisch B, Fuchshuber A, Huzly D, Jungraithmayr T, Forster J, Zimmerhackl LB: Demand for evaluation of vaccination antibody titers in children considered for renal transplantation. Pediatr Transplant Acknowledgements 2007, 11(1):73–76. We would like to thank Associate Professor Lee Kheng Hock for his support. 24. Geel AL, Landman TS, Kal JA, Van Doomum GJ, Weimar W: Varicella Zoster virus serostatus before and after kidney transplantation, and vaccination Author details of adult kidney transplant candidates. Transplant Proc 2006, Department of Family Medicine and Continuing Care, Singapore General 38(10):3418–3419. Hospital, Bowyer Block A, Level 2, 169608 Outram Road, Singapore. 25. Chaves Tdo S, Lopes MH, De Souza VA, Dos Santos SS, Pereira LM, Reis AD, Department of Renal medicine, Singapore General Hospital, Outram Road, David-Neto E: Seroprevalance of antibodies against Varicella-zoster virus Singapore. and response to the varicella vaccine in pediatric renal transplant patients. Pediatr Transplant 2005, 9(2):192–196. Received: 18 June 2013 Accepted: 17 February 2014 26. Furth SL, Sullivan EK, Neu AM, Tejani A, Fivush BA: Varicella in the first year Published: 21 February 2014 after renal transplantation: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Pediatr Transplant 1997, 1(1):37–42. References 27. Verena W, Judith S, Meinrad B, Benedikt W, Stefan G, Girschick HJ, 1. Ooi PL, Goh KT, Doraisingham S, Ling AE: Prevalence of varicella-zoster Johannes L, Schlegel PG, Matthias E: Varicella-zoster virus infections in virus infection in Singapore. Southeast Asian J Trop Med Public Health 1992, immunocompromised patients - a single centre 6-years analysis. 23(1):22–25. BMC Pediatr 2011, 11:31. 2. Ernest WH, Imelda LE, Masitah I, Yeo CL: Knowledge, attitudes, and 28. Fardrowski JJ, Furth SL: Varicella zoster virus: vaccination and implications practices regarding chickenpox disease and its prevention in Singapore: in children with renal failure. Expert Rev Vaccines 2004, 3(3):291–298. comparison between parents and medical students. Proc Singapore 29. Nicholas JA W, Fitzpatrick MM, Highes DA, Brocklebank TJ, Judd BA, Healthc 2012, 21(4):257–264. Lewis MA, Postlethwaite RJ, Smith PA, Gerald Corbitt on behalf of the 3. Heininger U, Seward JF: Varicella. Lancet 2006, 368:1365. Trans-pennine Paediatric Nephrology Study Group: Immunization against 4. Kim CE, De Fijter CW: Herpes Zoster-associated encephalitis in a patient varicella in end stage & pre-end stage renal failure. Arch Dis Child 2000, undergoing CAPD: Case report and literature review. Perit Dial Int 2007, 82:141–143. 27(4):391–394. 30. Geel A, Zuiderma W, Van Gelder T, Van Doorman G, Weimar W: Successful 5. Dangond F, Engle E, Yessayan L, Sawyer MH: Pre-eruptive varicella vaccination against varicella zoster virus prior to kidney transplantation. cerebellitis confirmed by PCR. Pediatr Neurol 1993, 9(6):491–493. Transplant Proc 2005, 37(2):952–953. 6. Hausler M, Schaade L, Kemeny S, Schweizer K, Schoenmackers C, Ramaekers VT: 31. Furth SL, Hogg RJ, Tarver J, Moulton LH, Chan C, Fivush BA: Varicella Encephalitis related to primary varicella-zoster virus infection in immuno- vaccination in children with chronic renal failure. A report of the competent children. JNeurol Sci 2002, 195(2):111–116. Southwest Pediatric Nephrology Study Group. Pediatr Nephrol 2003, 7. David Beckham J, Tyler KL: Encephalitis. Mandell, Douglas, and Bennett’s 18(1):33–38. Principles and practice of infectious disease 2010, 2:1243–1264. 32. Ministry of Health: Immunisation Handbook 2011. Wellington: Ministry of 8. Preblud SR: Age specific risks of varicella complications. Pediatrics 1981, Health; 2011. http://www.moh.govt.nz. 68(1):14–17. 33. U.S. Department of Health and Human Services. Centers for Disease Control 9. Fleisher G, Henry W, McSorley M, Arbeter A, Plotkin S: Life threatening and Prevention: Recommended Adult Immunization Schedule – United States complications of varicella. Am J Dis Child 1981, 135(10):896–899. 2013; 2013. http://www.cdc.gov/vaccines/schedules/downloads/adult/adult- 10. Fairley CK, Miller E: Varicella Zoster virus epidemiology – a changing schedule.pdf. scene? J Infect Dis 1996, 174(3):314–319. 34. Soni R, Horowitz B, Unruh M: Immunization in end stage renal disease: 11. Longo, Fauci, Kasper, Hansen, Jameson: Varicella-Zoster virus infections. opportunity to improve outcomes. Semin Dial 2013, 26(4):416–426. Harrison’s principles of internal medicine 2011, 18:2426–2432. 35. Rodby RA, Trenholme GM: Vaccination of the dialysis patient. Semin Dial 12. Poscher ME: Successful treatment of varicella zoster virus 1991, 4(2):102–105. meningoencephalitis in patients with AIDs: report of four cases and 36. Dinits-Pensy M, Forrest GN, Cross AS, Hise MK: The use of vaccines in adult review. AIDS 1994, 8(8):1115–1117. patients with renal disease. Am J Kidney Dis 2005, 46(6):997–1011. 13. Cinque P, Bossolasco S, Vago L, Fornara C, Lipari S, Racca S, Lazzarin A, 37. Barril G, Teruel JL: Vaccination scheme in advanced chronic kidney Linde A: Varicella-zoster virus (VZV) DNA in cerebrospinal fluid of disease. Nefrol 2008, 28(Suppl 3):95–99. patients infected with human immunodeficiency virus: VZV disease of 38. Ministry of Health: Kidney Dialysis. MOH Information Papers. Statistics, the central nervous system in subclinical reactivation of VZV infection? Publications and Resources. Singapore: Ministry of Health; 2006. Clin Infect Dis 1997, 25(3):634–639. http:// www.moh.gov.sg. 14. Mohammed A: Varicella pneumonia in adults: 13 years’ experience with 39. Vathsala A: Twenty-five facts about kidney disease in Singapore: in review of literature. Ann Thorac Med 2007, 2(4):163–165. remembrance of world kidney day. Ann Acad Med 2007, 36(3):157–160. 15. Chiner E, Ballester I, Betlloch I, Blanquer J, Aguar MC, Blanquer R, 40. Choong HL: Seventh report of the Singapore Renal Registry 2007/2008; 2008. Fernandez-Fabrellas E, Andreu AL, Briones M, Sanz F: Varicella-zoster virus pneumonia in an adult population: Has mortality decreased? Scand J doi:10.1186/1447-056X-13-4 Infect Dis 2010, 42(3):215–221. Cite this article as: Low et al.: Varicella encephalitis and pneumonia in a 16. Feldman S: Varicella-zoster virus pneumonitis. Chest 1994, 106(1):22S–27S. patient with end stage renal failure. Asia Pacific Family Medicine 17. Haake DA, Zakowski PC, Haake DL, Bryson YJ: Early treatment with acyclovir 2014 13:4. for varicella pneumonia in otherwise healthy adults: retrospective controlled study and review. Rev Infect Dis 1990, 12(5):788–798. 18. Schlossberg D, Littman M: Varicella pneumonia. Arch Intern Med 1988, 148(7):1630–1632. 19. Mer M, Richards GA: Corticosteroids in life-threatening varicella pneumonia. Chest 1998, 114(2):426–431. 20. Drugs for non-HIV viral infections. Treat Guidel Med Lett 2005, 3(32):23–32. 21. Bennett VM, Aronoff GR, Morrison G, Golper TA, Pulliam J, Wolfson M, Singer I: Drug prescribing in renal failure: dosing guidelines for adults. Am J Kidney Dis 1983, 3(3):155–193. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Asia Pacific Family Medicine Springer Journals

Varicella encephalitis and pneumonia in a patient with end stage renal failure

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Copyright © 2014 by Low et al.; licensee BioMed Central Ltd.
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Medicine & Public Health; General Practice / Family Medicine; Primary Care Medicine
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Abstract

We describe a patient with end stage renal failure (ESRF) on hemodialysis who was admitted to our department for primary varicella infection complicated by varicella pneumonia and encephalitis. Varicella infections results in serious morbidity and mortality in ESRF dialysis and transplant patients. Evidence published thus far suggests that live attenuated varicella vaccines are effective and safe in ESRF and renal transplant patients. Worldwide a few countries have instituted guidelines for the varicella immunisation in ESRF patients. However, in the Asia Pacific Region, it has not been widely given due to the lack of national consensus guidelines. Our case depicts that primary varicella infection can occur at any time in immunosupressed patients and thus suffer serious consequences from it. With increasing burden of chronic kidney disease, Renal Physicians and Family Physicians in the Asia Pacific Region should meet and study the epidemiological data in each individual country and decide on the consensus guidelines on how the varicella vaccination can be targeted for those at risk. Keywords: End stage renal failure, Varicella, Vaccination Background and Emergency Department to Singapore General Our case report illustrates the serious complications of Hospital Department of Family Medicine and Con- varicella in a patient with end stage renal failure and em- tinuing Care for fever, chills and non productive cough of phasizes the need for consensus guidelines on varicella two days duration. There was no travel or contact history. vaccinations in such patients in the Asia Pacific region. On examination, he was alert, non-toxic looking and ori- Although evidence in literature show that live attenuated entated to time, place and person. He had a temperature vaccines can be safe & effective, these vaccines are still of 38.4 degree Celsius, blood pressure of 140/90 mmHg, generally avoided due to lack of consensus guidelines on pulse rate of 80 per minute and respiratory rate of 16 per vaccinations in patients with end stage renal failure. Lit- minute. His respiratory examination revealed reduced erature review provides evidence on the safety and effi- chest expansion over the left lung base associated with cacy of varicella vaccination in end stage renal failure dullness to percussion, bronchial breath sounds and patients. With the increasing burden of chronic kidney crackles. His cardiovascular, abdominal and neurological disease, family physicians also need to be alert for these examination was unremarkable. A chest radiograph con- complications of varicella and can play a big role in fa- firmed consolidation in the left lower zone with milder air cilitating varicella vaccination in patients with end stage space opacity in the right lower zone. He was initially di- renal failure. agnosed with healthcare associated pneumonia in view of recent hospitalization and started on intravenous tazocin. Respiratory viruses multiplex PCR (Polymerase Chain Case presentation Reaction) was negative. Our patient is a 58 year old construction supervisor with On the fourth day of admission, he developed vesiculo- background of hypertension and ESRF on haemodialysis papular pruritic lesions mainly over the trunk. Varicella three times per week. He was admittted via the Accident Zoster Virus (VZV) IgM was positive. He was isolated to- gether with air-borne and contact precautions, and started * Correspondence: low.lian.leng@sgh.com.sg on oral Valacyclovir 500 mg daily later on that day. The Department of Family Medicine and Continuing Care, Singapore General Hospital, Bowyer Block A, Level 2, 169608 Outram Road, Singapore Full list of author information is available at the end of the article © 2014 Low et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. Low et al. Asia Pacific Family Medicine 2014, 13:4 Page 2 of 4 http://www.apfmj.com/content/13/1/4 next day, his oxygen saturation decreased, and worsening The cerebrospinal fluid contains lymphocytes and elevated of the consolidation was noted on repeat chest radiograph. levels of protein but normal glucose concentration, allow- He also developed vivid visual hallucinations, became rest- ing differentiation from bacterial meningitis. Cerebrospinal less and agitated and disorientated to time, place and per- fluid polymerase chain reaction (CSF PCR) can be used to son. A diagnosis of varicella zoster infection complicated detect VZV DNA, and has a specificity of greater than 95%, by varicella pneumonia and encephalitis was made. Vala- but the sensitivity is 30% or less in some studies [7]. Re- cyclovir was switched to intravenous acyclovir. A lumbar peated mortality rates approach 10% and long-term neuro- puncture showed increased protein and lymphocytes and logic sequelae are reported in up to 15% of survivors [8-10]. was negative for cryptococcal antigen and neurotropic vi- There is no proven effective therapy once encephalitis oc- ruses. A magnetic resonance imaging scan of the brain curs, and supportive care remains the mainstay of manage- showed no evidence of acute infarct, intracranial bleed, ment. Acyclovir has been used with anecdotal success space-occupying lesion or hydrocephalus. The frequency [11-13]. However, acyclovir neurotoxicity should always be of dialysis was increased with continuation of the renal ad- considered in patients with prolonged or worsening neuro- justed dose of acyclovir. logical symptoms. Throughout the admission, his hemodialysis continued Varicella pneumonia is the most serious complication and he completed 2 weeks of IV acyclovir. His functional following varicella, develops more commonly in adults status improved back to the pre-morbid levels on discharge. (up to 20% of cases) than in children, and accounts for the majority of morbidity and mortality seen in adults Discussion with varicella [11]. Risk factors linked to the develop- The incidence of varicella in Singapore has been increasing ment of varicella pneumonia include cigarette smoking, since 1984 [1] and increased from 14,999 in 2003 to 24,031 pregnancy and an immunosuppressed state [9]. Varicella in 2006. Mandatory notification of varicella ceased since pneumonia typically develops insidiously with symptoms 27th August 2007 [2]. Thus the latest reported figures are of progressive dyspnea and dry cough. Patients demon- not known. strate impaired gas exchange with progressive hypox- Primary infection with varicella is usually a benign and emia and are at high risk for respiratory failure and need self-limiting illness in immunocompetent children. How- for admission to intensive care for mechanical ventila- ever, patients with end stage renal failure have lympho- tion [14,15]. Mortality rates approach 50% in patients cytopenia and impaired lymphocyte function and are with respiratory failure who require mechanical ventilation, susceptible for disseminated varicella and its complications, despite institution of aggressive therapy and appropriate with more severe morbidity and mortality rates [3,4]. support measures [16,17]. Chest radiographs typically re- Our patient suffered severe complications of varicella veal diffuse bilateral infiltrates. Prompt administration of infection that is pneumonia and viral encephalitis. Other intravenous acyclovir has been associated with clinical im- known complications include myocarditis, corneal lesions, provement and resolution of pneumonia in selected series nephritis, arthritis, bleeding diatheses, acute glomerulo- [17,18]. Resolution of pneumonitis parallels improvement nephritis, hepatitis and secondary bacterial superinfection of the skin rash, although fever and compromised pulmon- of the skin. ary function may persist for weeks [11]. The use of steroids The central nervous system is the most common extra as adjunctive therapy for treatment of life-threatening vari- cutaneous site of involvement, manifesting as acute cerebel- cella pneumonia is still controversial and should be further lar ataxia or diffuse encephalitis. These disorders typically examined in rigorous controlled trials [19]. developtowardthe endofthe firstweek of theexanthem, In immunosuppressed hosts such as ESRF patients or but can also precede the rash [5,6]. Diffuse encephalitis immunocompetent patients with disseminated disease such most often occurs in adults and clinical manifestations in- as pneumonia or encephalitis, varicella should be treated with IV acyclovir [20]. IV acyclovir reduces the occurrence clude delirium, seizures, loss of consciousness and focal neurological signs including cranial nerve palsies, hemipar- of visceral complications but has no effect on healing of esis. Varicella encephalitis is more severe in immunosup- skin lesions or pain [11]. The recommended dose is 10 mg/ kg Q8h for 7 days. pressed hosts who typically have a fulminant course with seizures, mental status changes and focal deficits including In December 2012, the FDA approved varicella zoster stroke syndromes. However verylittledataexist regarding immune globulin (VariZIG) for administration to high risk individuals within 4 days of varicella exposure. the occurrence of varicella encephalitis in patients with end stage renal failure or those undergoing dialysis. Acyclovir is an effective agent for the treatment of VZV In the workup for VZV encephalitis, computed tomog- infections but renal impairment results in high serum drug levels with resultant neurotoxicity. In renal failure, raphy or magnetic resonance imaging may or may not demonstrate abnormal radiographic findings, although elec- the half-life of acyclovir is increased from a maximum of troencephalography is often abnormal in acute encephalitis. 3.8 to 20 hours, and dosage reduction is required using Low et al. Asia Pacific Family Medicine 2014, 13:4 Page 3 of 4 http://www.apfmj.com/content/13/1/4 the interval extension method [21]. Even the adminis- patient coming in contact with varicella patients [37], the tration of recommended reduced doses can result in use of immunglobulins has risks and is expensive. Immuno- high serum levels and neurotoxicity, due to poor removal globulins should be reserved for those with imminent ex- of acyclovir by peritoneal dialysis [4]. Tremors, disorienta- posure to the virus. Varicella vaccination is a cheaper and tion, agitation, hallucinations, and delirium are common more effective way for prevention of varicella. presentations of acyclovir-induced encephalopathy, whereas seizures, cerebellar ataxia, sensory symptoms, speech disor- Role of family physicians ders, fever and cranial nerve palsies are much less frequent. There were 4,169 patients on dialysis in Singapore by 2008. Features distinguishing acyclovir neurotoxicity from VZV This number represented a 89% increase since end 1998, encephalitis include a temporal association between the when there were 2,209 patients on dialysis. The incidence symptoms and acyclovir use, as well as acellular CSF exam- of new ESRF patients requiring dialysis increases every ination. However, acyclovir neurotoxicity should always year, from 564 new cases in 1998 to 1,212 cases in 2008. be considered in patients with prolonged or worsening This represents a 115% increase during this 10-year period neurological symptoms for which daily hemodialysis is [38-40]. In addition, patients are getting more elderly. In required often. 2006, 52.1% and 5.1% of incident dialysis patients were Studies show that many ESRF and kidney transplant pa- over the age of 60 and 80 respectively. With a rapidly age- tients do not have immunity to varicella [22-25]. Primary ing population, Singapore can expect an increasing burden varicella infection is common, up to 1.9% of renal of end stage renal disease Family physicians should advise transplant recipients are admitted in the first year post- their ESRF patients of the life-threatening complications of transplant [26]. The infection can have serious compli- varicella and urgent need for review if they develop fever cations and be lethal in these ESRF and renal transplant or rash after coming in contact with varicella patients. patients who are immunosuppressed [24,26-29]. Currently, there are no local data on the seropositivity Live attenuated varicella vaccine is generally contraindi- against varicella antibody in ESRF patients in Singapore cated in immunosuppressed patients but has been proven or consensus guidelines for varicella vaccination. With an to be safe when administered to both pediatric [23,24,29] increasing burden of chronic kidney disease, Renal Physi- and adult end stage renal failure patients on dialysis, [27] cians and Family Physicians in the Asia-Pacific region as well as renal transplant patients on immunosuppressive should meet and study the epidemiological data in each treatment [25]. individual country and decide on consensus guidelines Despite the general suppression of the immune system and how the varicella vaccination program can be targeted associated with uremia, patients with ESRF have high for those at risk. Research on the seroprevalence of vari- seroconversion rates to a two-dose varicella vaccination cella in ESRF patients should be conducted if such data is regimen. Seroconversion rates ranged from 87-100% not currently available in Asia-Pacific countries. [23,29-31] in ESRF pediatric patients waiting for transplant and 64% in adult ESRF patients [24]. 66.6% of pediatric Conclusions renal transplant recipients seroconverted after a one–two Evidence supports the safety and efficacy of varicella vac- dose varicella vaccination regimen [25]. Immunization cination in patients with end stage renal failure. Guidelines guidelines in New Zealand recommend a two dose vari- for varicella vaccination for ESRF patients are available in a cella vaccination regimen for children with deteriorating few countries [33,34]. The intent of our paper is to stimu- renal function, as early as possible before transplantation late more research in the area of generating the need of [32]. In the United States, the Centers for Disease Control consensus guidelines for universal vaccinations of ESRF pa- and Prevention (CDC) adult immunization schedule rec- tients on dialysis. Serious consequences of primary varicella ommend a two dose varicella vaccination regimen and a infection can be avoided with appropriate vaccinations. single dose zoster vaccination for patients with ESRF and recipients of hemodialysis [33,34]. However, ESRF patients Consent have an inability to maintain adequate antibody titers over Written informed consent was obtained from the patient time [35,36]. Reports describe several patients in whom im- for publication of this case report and any accompanying munity to varicella waned in chronic renal insufficiency and images. A copy of the written consent is available for re- in the post-transplant period [26,27]. Hence there is a need view by the Editor-in-Chief of this journal. for yearly surveillance of antibody titre as are done for Hepatitis B & C virus and cytomegalovirus. Special consid- Abbreviations eration for vaccination should also be given to persons who ESRF: End stage renal failure; VZV: Varicella-Zoster virus. have close contact with or are at high risk of transmission to ESRF patients [32]. Although there are recommendations Competing interests to administer varicella immunoglobulin to transplant The authors declare that they have no competing interests. Low et al. Asia Pacific Family Medicine 2014, 13:4 Page 4 of 4 http://www.apfmj.com/content/13/1/4 Authors’ contributions 22. Genc G, Ozkaya O, Aygun C, Yakupoglu YK, Nalcacioglu H: Vaccination LLL, FFV and SMS participated in the proposal, design, and drafted the status of children considered for renal transplant: missed opportunities manuscript. All authors read and approved of the final manuscript. for vaccine preventable diseases. Exp Clin Transplant 2012, 10(4):314–318. 23. 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Asia Pacific Family MedicineSpringer Journals

Published: Feb 21, 2014

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