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2 "When I had chickenpox it was really boring because I had no one to play with. It was really itchy and not nice at all." "I learned not to scratch chickenpox because it can make things worse." "The day I got chickenpox it was a special day at our school and I missed it. It was very annoying." "I got chickenpox when I was 7."

Varicella Zoster virus Chickenpox and herpes zoster  Pathophysiology  Complications  Diagnosis  Treatment Vaccination Case scenario 3

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Varicella-zoster virus (VZV) is a DNA virus belongs to the herpes virus family It is the cause of chickenpox and herpes zoster Chickenpox follows initial exposure to the virus and is typically mild, self-limited 5

Maternal infection during the first 28 weeks of pregnancy may result in transmission of VZV to the fetus and cause congenital varicella syndrome 6

Congenital varicella syndrome comprises of a number of abnormalities, some of which scarring of the skin and hypoplasia of one or more limbs are characteristic. Other abnormalities include CNS and eye abnormalities, abnormalities of the GI and GU tract. Death occurs in infancy in many cases. It had been postulated that the principal manifestations of varicella embropathy are not caused by primary infection of the fetus but by in utero reactivation of virus whose period of latency in the fetal nervous system has been shortened by immunological immaturity. The incidence of embryopathy is difficult to determine. For a start, the syndrome is ill defined. Scarring of the skin and hypoplasia of a limb are characteristic but CNS and eye abnormalities may be due to other causes. The risk had been reported to be 3% but this is likely to be an over-estimate. There are at least eight case reports of infants suggestive of congenital infection born to mothers with a history of zoster during the first 4 months of pregnancy, however this association may be coincidental and to date, there is no firm data linking maternal zoster to congenital infection. Specific IgM can be detected from the cord blood in many, but not all cases of suspected congenital varicella syndrome. 7

VZV is spread by direct contact with virus shed from the characteristic skin lesions or in oral secretions. Airborne spread also occurs. Individuals with varicella can spread infection from 1 to 2 days prior to onset of the rash, up until the last lesion has crusted. However, the period of greatest infectivity is from the day before rash onset through the first few days of the rash. VZV is highly contagious, with an attack rate of 61% to 87% or higher among susceptible individuals exposed in a household setting. The incubation period, defined as the interval between exposure to VZV and onset of symptoms, ranges from 10 to 21 days and in most cases is 14 to 16 days. There may or may not be prodromal symptoms of fever, malaise, and upper respiratory tract infection prior to rash onset. The characteristic lesions appear in successive crops during the first 3 to 4 days of illness. Lesions progress rapidly from macules to vesicles to pustules, and scab over within a few days. Disease severity increases with age and with immunosuppression 8 After primary infection, VZV remains dormant in sensory nerve roots for life. Upon reactivation, the virus migrates down the sensory nerve to the skin

Herpes zoster Airborne spread Direct contact Incubation period day Incubation period day 2 days Fever Malaise URTI Fever Malaise URTI Rash Macules Vesicles Pustules Scab Sensory ganglia VZV Cell-mediated immunity Advanced age Lymphoma AIDS Pain Flu-like Swelling Redness Unilateral blister & Vesicles Unilateral blister & Vesicles Chickenpox (varicella) 9

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11 Chickenpox

The term aseptic is frequently a misnomer, implying a lack of infection. On the contrary, many cases of aseptic meningitis represent infection with viruses or mycobacteria that cannot be detected with routine methods. While the advent of polymerase chain reaction has increased the ability of clinicians to detect viruses such as enterovirus, cytomegalovirus, and herpes virus in the CSF, many viruses can still escape detection. Additionally, mycobacteria frequently require special stains and culture methods that make their detection difficult. When CSF findings are consistent with meningitis, and microbiologic testing is unrevealing, clinicians typically assign the diagnosis of aseptic meningitis—making it a relative diagnosis of exclusion. 12

Aseptic meningitis Cerebellar ataxia Encephalitis Arterial ischemic strokes 13

Incidence 1/4000 cases of varicella Presentation Ataxia usually begins with rash accompanied by Headache, vomiting, lethargy, fever, nuchal rigidity, nystagmus Prognosis Self-limited disease, most patients improve in 1-3 weeks virtually all recover without complications 14

Incidence 1-2/10,000 cases of varicella Presentation  Symptoms usually appear about one week after rash  Fever, headache, vomiting, altered mental status, focal neurologic findings, hemiparesis, sensory changes and seizures Prognosis  Mortality about 5-10%  10-20% of survivors will have neurologic complication 15

Immunocompetent children (median age = 5 yr) present with acute hemiplegia Median interval between varicella and onset of hemiplegia = 2 months Ref: Moriuchi et al. Pediatr Infect Dis J.2000; 19:648 Post-varicella angiopathy may account for 1/3 of all childhood strokes Ref: Askalan et al Stroke.2001; 32:1257 DeVerber et al Sem Ped Neurol.2000; 7:309 Ref: Askalan et al Stroke.2001; 32:1257 DeVerber et al Sem Ped Neurol.2000; 7:309 16

17 Chickenpox Herpes Zoster

Postherpetic neuralgia 18

Most common complications of zoster, which is pain that persists more than six weeks after the development of rash TCA Anticonvulsant Amitriptyline mg daily Carbamazepine mg daily Phenytoin mg daily Carbamazepine mg daily Phenytoin mg daily Relieve pain in some patients 19

20 Steroid Prednisone mg daily for 3-5 days Reduce inflammation

Molecular Methods: PCR assays for VZV are use in the diagnosis of VZV meningoencephalitis from CSF samples Detection of VZV specific IgM: VZV IgM is produced in primary varicella and herpes zoster and it is not possible to distinguish between the two conditions 21 PCR: Polymerase Chain Reaction

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Thymidine kinase (TK) Acyclovir Acyclovir monophosphate Acyclovir diphosphate Acyclovir triphosphate cellular kinases Inactivation of the viral DNA polymerase Competitive inhibition of viral DNA polymerase Incorporation into and termination of the growing viral DNA chain 24

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Treatment with Acyclovir Shortened the time to 50% healing Reduced the maximum number of lesions and vesicles Decreased fever, anorexia, and lethargy by day 2 26

Treatment was begun within 48 hours of rash onset Reduced the duration of new lesion formation Shortened the times to complete lesion scabbing, healing, and cessation of pain Reduced the prevalence of localized zoster-associated neurologic symptoms 27

Nausea, vomiting and diarrhea Headache and malaise Thrombocytopenia Renal failure and hepatitis Stevens-Johnson syndrome Coadministration of probenecid with acyclovir has been shown to increase the mean acyclovir half-life 28

Patients should be advised to maintain adequate hydration Dosage adjustment is recommended when administering in renal impairment Caution should also be exercised when administering to patients receiving potentially nephrotoxic agents 29

Valacyclovir (Valtrex), Famciclovir (Famvir)Drug Name Prodrug rapidly converted to the active drug. More expensive but has a more convenient dosing regimen than acyclovir Description Documented hypersensitivityContraindications Probenecid, zidovudine, or cimetidine coadministration prolongs half-life and increases CNS toxicity of valacyclovir Interactions Caution in renal failure and coadministration of nephrotoxic drugs; associated with onset of hemolytic uremic syndrome Precautions 30

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A live attenuated varicella virus vaccine (VARIVAX ® ) was licensed in 1995 in the United States and is manufactured by Merck & Co., Inc The vaccine contains more than 1,350 plaque forming units of Oka/Merck VZV in each 0.5 ml dose 32

The vaccine has proven to be effective for more than 10 years in preventing varicella. However, breakthrough infection (i.e., cases of chickenpox after vaccination) can occur (less than 1%-4.4%), usually resulting in mild illness 33

VARIVAX ® is a highly heat sensitive vaccine To maintain potency, the vaccine must be kept frozen at or below -15 o C Vaccine efficacy will be reduced if the vaccine is not handled and transported as recommended. Reconstituted vaccine must be discarded if not used within 30 minutes, because of possible loss of potency 34

Healthy vaccinated persons have a minimal risk for transmitting vaccine virus to their contacts; this may be higher in vaccinees in whom a varicella-like rash develops following vaccination The incidence of herpes zoster after vaccination among otherwise healthy children is 18 per 100,000 person years of follow-up 35

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Samah & Manar37 A six-year-old male was admitted to the hospital complaining of: Vomiting Headache Decreased level of consciousness Convulsion two days ago History of present illness: Chickenpox seven days ago

Samah & Manar38 Vital signs: Temp36.8 o C BP85/53 mmHg Pulse95 beats/min RR28 breath/min Height120 cm Weight21 kg IBW23.75 kg

Samah & Manar39 WBC15.4 X 10 9 /L Hb126 g/L Na139 mmol/L K3.8 mmol/L Glucose6 mmol/L Bilirubin5 umol/L

MRI was negative CSF was negative for all EEG showed Parietal epileptic activity CBC showed Left Shift Kering was positive Brudzinski was positive Encephalitis 40

EEG showed Parietal epileptic activity CBC showed Left Shift Kering was positive Brudzinski was positive CBC showed Left Shift Kering was positive Brudzinski was positive Vomiting Ondansetron 2.4 mg IV stat Omeprazole 10 mg PO BID Ondansetron 2.4 mg IV stat Omeprazole 10 mg PO BID Not improve Empirically start on Acyclovir IV 30 mg/kg/day Vancomycin IV 40mg/kg/day Ceftriaxone IV 100 mg/kg/day Empirically start on Acyclovir IV 30 mg/kg/day Vancomycin IV 40mg/kg/day Ceftriaxone IV 100 mg/kg/day Culture PCR for varicella Culture PCR for varicella Carbamazepine 200 mg PO BID Vomited Varicella PCR was positive Rectal Domperidone 10 mg TID Clonazepam 0.2mg TID Rectal Domperidone 10 mg TID Clonazepam 0.2mg TID Switch to phenytoin LD : 100 mg IV MD : 50 mg IV BID Switch to phenytoin LD : 100 mg IV MD : 50 mg IV BID Stop vancomycin and ceftriaxone Stop vancomycin and ceftriaxone Not improved Bradycardia Varicella Encephalitis 41

Neoplastic disease, radiation sickness, opioids, cytotoxic drugs and general anaesthetics Treat post-operative and cytotoxic drug nausea & vomiting 5HT 3 Receptor Antagonist (ondansetraon) Dopamine Antagonists (metoclopramide) Antihistamines (diphenhydramine) Cannabinoids (nabilone) Benzodiazepines (lorazepam) Anticholinergics (hyoscine) Steroids (dexamethasone) NK1 Receptor Antagonists (aprepitant) NK1 Receptor Antagonists (aprepitant) Motion sickness and severe morning sickness in pregnancy Cytotoxic nausea, and vomiting, or vomiting unresponsive to other agents Post-operative nausea and vomiting Radiation and chemotherapy induced nausea and vomiting Chemotherapy induced nausea and vomiting Diphenhydramine 15 mg IV every 8 hours Metoclopramide 6 mg IV every 8 hours Clonazepam 0.2 mg PO every 8 hours 42

Samah & Manar43 Phenytoin follows zero order kinetics TOXICITY – Dose Related: drowsiness, confusion, nystagmus, ataxia, slurred speech, nausea, unusual behavior, mental changes – Non-Dose Related: hirsutism, acne, gingival hyperplasia, folate deficiency, osteomalacia, hypersensitivity reactions

Samah & Manar44 Phenytoin Serum Levels: (10-20 mg/L) – Loading Dose: – 2-4 hours post IV or 24 hours post PO load – Maintenance Dose: – Steady state trough levels (5-10 days)

Acyclovir 400 mg PO QID Clonazepam 0.2 mg PO TID Phenytoin Sodium 50 mg PO BID On 25/4/

Samah & Manar46 Varicella-zoster virus (VZV) is a DNA virus belongs to the herpes virus family that may cause chickenpox and herpes zoster Aseptic meningitis, cerebellar ataxia, encephalitis and arterial ischemic strokes are the main complications of chickenpox

Samah & Manar47 Postherpetic neuralgia is the main complication of herpes zoster Acyclovir remains the treatment of choice of varicella zoster virus Immunization against the virsu helps in preventing varicella

Helms R, Quan D, Herfindal E eds. Textbook of therapeutics. Drug and disease management. Eighth Edition. Philadelphia, PA. Lippincott Williams & Wilkins; 2006: Nahata M, Mara N, Benavide S. Viral infections. In: Koda-Kimble M, Young L, Kradjan W eds. Applied therapeutics. The clinical use of drugs. Eighth Edition. Philadelphia, PA. Lippincott Williams & Wilkins; 2006: Anderson P, Knoben J, Troutman W. Handbook of clinical drug data. Tenth Edition. New York, NY. McGraw Hill; 2002: Askalan et al. Stroke. 2001; 32:1257 Moriuchi et al. Pediatr Infect Dis J 19:648, 2000

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