Case discussion Presenter: R1 鄭雋蒔 2017/03/24

Patient Profile Name:蔡O和 Age: 15 year old Birthday : 2002/03/08 Gender: male Admission date: 2017/03/16 Chief Complaint Fever up to 38.5 'C off and on for 4 days 09854335 蔡立和 , 生日 : 2002/03/08 , 性別 : 男 , 血型 : O+, 初診時間 : 2003/07/31

Present Illness Past history Hemophilia B (factor IX deficiency) with 生物製劑(weekly) 3/12 Fever to 38’C Rhinorrhea, nausea, dizziness Multiple skin rash over face and extremities 3/14 3/15 This 15 years old male with congenital factor IX disorder, was admitted to our hospital due to fever up to 38.5 'C off and on for 4 days with general vesicles for 1 day. He was in his usual status until 4 days ago when he complained of fever up to 38.5 'C. Associated symptoms was cough, throat pain, rhinorrhea, nausea, poor appetite, and mild dizziness. There was no chills, fatigue, abdominal pain, frequency when voiding, diarrhea, skin rash, and TOCC history. He then went to LMD, and common cold was diagnosed. He took some antipyretics and the symptoms was relieved. However, fever was still noted and mutiple skin rashes over face and abdominal wall since yesterday, so he came to our ER for further examination. At our ER, there was no fever but some papular rash with some vesicle lesions over face, trunk. back and extrtemities was found. Varicella was suspected that VZV-IgG was sent, and supportive care was ordered. He went home then. The next day, the vesicles progressed and bilateral eye redness was found. He also complained of throat pain but no dyspnea and skin itching. He came to our ER again today. At our ER, the vital sign showed BT: 37.9 'C, HR: 92/mm , RR: 20/min , BP: 156/100 mmHg. His consciousness was alert and there was no respiratory distress. Physical examination showed injected conjunctiva, injected throat and tonsil, 2 cm x 1cm lymph node behind bilateral ears, and multiple vesicles (over trunk, face and limbs). The lab showed thrombocytopenia, mild leukopenia with left shifting, elevated liver enzyme, and mild elevated CRP (22.4mg/L). We consulted ophthalmologist and they suggested oph oint using for suspected vacicella with bilateral corneal involvement. Under the impression of chickenpox, he was admitted to our ward for further treatment. Our ER BT: 37.2’ C , HR: 72/mm , RR: 24/min , BP: 156/92 mmHg PE: multiple papulomacular with vesicles over the trunk and extremity 疑似Varicella WBC 3500/μL ↓ seg 64% band 3% PLT 99000/μL ↓ CRP 33mg/L ↑

Present Illness Our ER 3/16 Vital Sign: WBC 3900/μL ↓ seg 51% band 12% PLT 70000/μL ↓ CRP 22.4mg/L ↑ Our ER Vital Sign: BT: 37.9’ C , HR: 92/mm , RR: 20/min , BP: 156/100 mmHg Progression of vesicle to face and trunk Red eyes with swelling Mass: 2X1cm over bilateral posterior ears 3/16 Progression of vesicle to face and trunk. red eyes with swelling seansation was noted since midnight. Large lymph node about 2cmX1cm behind bilateral ears was noted, tenderness. Still mild fever(37~38 degree ) 會診診斷 : Vacicella with bilateral corneal involvement 會診回覆 : Dear doctor: OE(OU) Cornea: PEE (OU) over inferior cornea Conjunctiva: injection (OU) EOM: no limitation Eyelid: vesicle over face and eyelid AC: deep and clear Pupil: L/R +/+ Imp: Vacicella with bilateral corneal involvement Suggestion: 1. Devirus (Acyclovir) oph oint QID (OU)-->一次點下眼瞼約0.5cm即可，勿太大量 2. Gentamycin oph solution QID (OU) 3. Vidisic QID (OU) 4. 每瓶藥物之間至少隔10分鐘 5. OPH OPD F/U 3/20 W1 AM VS 黃奕勛醫師; 如果住院，請一般照會追蹤 6. 已向家屬解釋目前狀況，眼部感染可能會擴大或是變嚴重，須持續追蹤 Thanks for your consultation!

Present Illness Treatment : Medication : Consult Oph. 3/16 Consult Oph. Varicella with bilateral corneal involvement Treatment : Acyclovir oph, Gentamycin oph, Vidisic oph Medication : Zovirax(Acyclovir) 680.00 mg STAT IVD  Admission

Past history Past History: G2P2, NSD BW: 68kg(85-97th percentile) BL:167cm(15-50th percentile ) 123 Vaccination: As schedule Growth and Development: BW: 68kg(85-97th percentile) BL:167cm(15-50th percentile ) Developmental milestones: WNL Past History: 1. Congenital factor IX disorder 2. hepatectomy at one month due to suspect liver tumor Social History: Nothing particular Travel History: Nil Current Medications: Nil TOCC:Travel history(-),Occupation(-),Contact history(-),Cluster(-)(2017/03/17) Past History: Hemophilia B (factor IX deficiency) with 生物製劑(weekly) OP history: hepatectomy at birth TOCC history: (-) Allergy history: (-)

Past history Vaccination : As schedule, but no self-paid vaccine Birth: 2002/03/08 BW: 68kg(85-97th percentile) BL:167cm(15-50th percentile ) G2P2, NSD Vaccination: As schedule Growth and Development: BW: 68kg(85-97th percentile) BL:167cm(15-50th percentile ) Developmental milestones: WNL Past History: 1. Congenital factor IX disorder 2. hepatectomy at one month due to suspect liver tumor Social History: Nothing particular Travel History: Nil Current Medications: Nil TOCC:Travel history(-),Occupation(-),Contact history(-),Cluster(-)(2017/03/17)

Review of Systems

Physical Examination Conscious: alert, general appearance: well-appearing HEENT: Chest: symmetric expansion, no chest retraction Breath sounds: clear breathing sound, rales(-),wheezing(-) Heart: regular heart beat without murmur T 37.7°C P 93/min R 22/min BP 149/100 mmHg Vital Signs: T: 37.7°C(03/16 23:20) P: 93/min(03/16 23:20) R: 22/min(03/16 23:20) BP: 149/100mmHg(03/16 23:20) Consciousness: clear, E4V5M6. HEENT: Head: no trauma, no scar, general vescles Eyes: redness over bilateral cornea, conjunctiva: not pale sclera: not icteric Throat: injected(+) with vesicles, tonsil swelling with vesicles Neck: supple, JVE (-), lymph(+), 1cm*1cm over bilateral postauricular area Chest: symmetric expansion, deformity (-) Auscultation: clear breathing sound Heart: regular beat normal S1, S2 no murmur, no pericardial friction rub. Abdomen: soft, a healed 5cm scar over RUQ Auscultation: normoactive bowel sound no renal bruits liver and spleen: not palpable shifting dullness (-) Extremities: freely movable, no pitting edema skin: generalized blister lesions with some scabs, as picture

Physical Examination Abdomen: soft, no distended, no tenderness, no rebound pain Hepatomegaly(-) Splenomegaly(-) normoactive bowel sound Extremities: freely movable, no edema Skin Clusters of vesicles on a red base Generalized blister lesions with some scabs Pustular vesicles Pustular vesicles pustular (meaning they contain a thick, yellow fluid).  clusters of vesicles on a red base.  a vesicle on a red base also known as "a dew drop on a rose petal."

Lab data CXR

Tentative diagnosis Varicella with bilateral corneal involvement Congenital factor IX disorder

Clinical course ValacIclovir (valtrex) 1000mg Q8H PO 使用本類製劑應以下列條件為限： (1) 疱疹性腦炎。 (2) 帶狀疱疹或單純性疱疹侵犯三叉神經第一分枝 VI 皮節，可能危及眼角膜者。 (3) 帶狀疱疹或單純性疱疹侵犯薦椎 S2 皮節，將影響排泄功能者。 (4) 免疫機能不全、癌症、器官移植等病患之感染帶狀疱疹或單純性疱疹者。 (5) 新生兒或免疫機能不全患者的水痘感染。 (6) 罹患水痘，合併高燒 (口溫38℃以上) 及肺炎 (需Ｘ光顯示) 或腦膜炎，並須住院者 (7) 帶狀疱疹或單純性疱疹所引起之角膜炎或角膜潰瘍者。 (8) 急性視網膜壞死症 (acute retina necrosis)。 (9) 帶狀疱疹發疹三日內且感染部位在頭頸部、生殖器周圍之病人，可給予五日內之口服或外用藥品 (10) 骨髓移植術後病患得依下列規定預防性使用acyclovir A. 限接受異體骨髓移植病患。 B. 接受高劑量化療或全身放射治療 (TBI) 前一天至移植術後第卅天為止。 2. 使用療程原則以十天為限，疱疹性腦炎得使用 14 至 21 天，口服、注射劑及外用藥膏擇一使用，不得合併使用。

Following data IgM Negative (reported as negative or positive) IgG Vaccinated: positive (> or =1.1 AI) Unvaccinated: negative (< or =0.8 AI) Interpretation A positive IgG result coupled with a positive IgM result suggests recent infection with varicella-zoster virus (VZV). This result should not be used alone to diagnose VZV infection and should be interpreted in the context of clinical presentation. A positive IgG result coupled with a negative IgM result indicates previous vaccination to or infection with VZV. These individuals are considered to have protective immunity to reinfection. A negative IgG result coupled with a negative IgM result indicates the absence of prior exposure to VZV and nonimmunity. However, a negative result does not rule out a VZV infection. The specimen may have been drawn before the appearance of detectable antibodies. Negative results in suspected early VZV infections should be followed by testing a new serum specimen in 2 to 3 weeks.

After 5 days treatment Scar formation

Final diagnosis Varicella with bilateral corneal involvement Congenital factor IX disorder

Varicella Zoster Virus

Varicella Zoster Virus Herpes virus (DNA) Herpes virus (DNA) Primary infection results in varicella (chickenpox) Recurrent infection results in herpes zoster (shingles) Short survival in environment Short survival in environment

Jon Lieff, "The Remarkable Intelligent Varicella Virus," www Jon Lieff, "The Remarkable Intelligent Varicella Virus," www.jonlieffmd.com, Feb. 23, 2014

Chickenpox Incubation period : 10-21 days (average: 14-16 days) Infectivity : Childhood : begins with exanthem Adults and adolescents: nausea, myalgia, anorexia, and headache 48 hours Onset of rash Fully crusted The triad of rash, malaise, and a low-grade fever can signal disease onset, though the typical patient is infectious for 1-2 days prior to the development of rash.

"a dew drop on a rose petal" Chickenpox a vesicle on a red base "a dew drop on a rose petal" Pustular Blister   a vesicle on a red base also known as "a dew drop on a rose petal." crusting  Small, erythematous macules appear on the scalp, face, trunk, and proximal limbs, with rapid sequential progression over 12-14 hours to papules, clear vesicles, and pustules and subsequent central umbilication and crust formation. Vesicles may appear on the palms and the soles and on the mucous membranes, together with painful, shallow, oropharyngeal or urogenital ulcers. Intense pruritus commonly accompanies the vesicular stage of the rash. The typical patient remains infectious for 4-5 days after the rash develops, by which time the last crop of vesicles has usually crusted over. Crusting Scar formation 

Chickenpox a vesicle on a red base also known as "a dew drop on a rose petal." crusting  Small, erythematous macules appear on the scalp, face, trunk, and proximal limbs, with rapid sequential progression over 12-14 hours to papules, clear vesicles, and pustules and subsequent central umbilication and crust formation. Vesicles may appear on the palms and the soles and on the mucous membranes, together with painful, shallow, oropharyngeal or urogenital ulcers. Intense pruritus commonly accompanies the vesicular stage of the rash. The typical patient remains infectious for 4-5 days after the rash develops, by which time the last crop of vesicles has usually crusted over.

Varicella Complications Infection of lesions: 40~45% Cellulitis, myositis, necrotizing fasciitis, and toxic shock syndrome  CNS manifestations Encephalitis, Reye syndrome Pneumonia (rare in children) High risks : cigarette smoking, pregnancy, immunosuppression, and male sex 死亡原因: 在成人以原發性肺炎，小孩以敗血症和腦炎最常見 Bacterial infection of lesions CNS manifestations Pneumonia (rare in children) Hospitalization ~3 per 1000 cases Death ~ 1 per 60,000 cases

Varicella treatment For healthy children ≤12 years For individuals with/high risk for complications Antivital therapy: acyclovir, valacyclovir, famciclovir Dose of acyclovir for VZV & HSV  VZV : 10-fold higher levels than HSV ANTIVIRAL THERAPY — Acyclovir and its analogues (valacyclovir, famciclovir) are effective for the treatment of primary varicella in both healthy and immunocompromised hosts [4-11]. Higher doses of acyclovir are used to treat VZV compared with herpes simplex virus (HSV). VZV is less susceptible to acyclovir, and 50 percent inhibition of VZV replication requires about 10-fold higher levels of acyclovir than those typically required for HSV [8,12]. Acyclovir and its analogues are dependent upon renal function for clearance and dose adjustment is needed in moderate to severe renal insufficiency. Oral agents are generally very well tolerated, especially in adults; however, gastrointestinal side effects or headache may occur. Acyclovir is also available in an intravenous form which can cause local reactions (phlebitis) and reversible acute kidney injury. Risk factors for acute kidney injury include dehydration, failure to dose adjust for reduced kidney function, and overly rapid infusion (eg, <1 hour) [13]. In addition, for obese patients, weight-based dosing should be scaled to ideal body weight (IBW) rather than actual body weight (ABW) to avoid an increased risk of toxicity (calculator 1). Additional discussions on the use of acyclovir and its analogues are found in the Lexicomp drug information topics within UpToDate and within individual topic reviews.

Without complication Immunocompetent children and adolescents Unvaccinated adolescents (≥13 years of age) Secondary cases in household contacts History of chronic cutaneous or pulmonary disorders Intermittent oral or inhaled steroid therapy. Taking chronic salicylates Oral form Acyclovir – 20 mg/kg per dose 4 times/day for 5 days Valacyclovir – 20 mg/kg per dose 3 times/day for 5 days If antiviral therapy is initiated, treatment should be started within 24 hours after the rash develops, if possible.

Without complication Immunocompetent adults Suggest oral antiviral therapy Oral form Acyclovir – 800 mg per dose 5 times/day for 5 days Valacyclovir – 1g per dose 3 times/day for 5 days Famciclovir – 500mg per dose We typically administer oral valacyclovir (1 g three times per day) because it can be given in fewer doses compared with acyclovir and has equivalent activity. Famciclovir can also be used, but valacyclovir provides higher antiviral drug concentrations compared with famciclovir. If oral acyclovir is used, it should be administered as 800 mg five times per day. We treat such patients with uncomplicated varicella for five to seven days; however, the course should be extended if there is delayed crusting of lesions.

Without complication Immunocompromised hosts Suggest initial therapy with intravenous acyclovir Adults – Acyclovir 10 mg/kg IV every 8 hours For adults with mild disease (ie, <50 lesions) and normal lab    Valacyclovir as an outpatient. Children ≥1 year of age and adolescents – Acyclovir 1500 mg/m2 per day in three divided doses  or 30 mg/kg/day in three divided doses. Low risk : valacyclovir (20 mg/kg per dose, three times daily) as an outpatient. For most patients, we suggest initial therapy with intravenous acyclovir. However, the antiviral regimen varies with age, disease severity, and baseline laboratories, as follows: ●Adults – Acyclovir 10 mg/kg IV every 8 hours (using ideal body weight [IBW] if obese (calculator 1)). For adults with mild disease (ie, <50 lesions) and normal baseline laboratories (ie, complete blood count, liver function tests, renal function), initiating therapy with valacyclovir is an option if the patient can be followed closely as an outpatient. ●Children ≥1 year of age and adolescents – Acyclovir 1500 mg/m2 per day in three divided doses or 30 mg/kg/day in three divided doses. Initiating therapy with valacyclovir (20 mg/kg per dose [maximal dose 1000 mg] three times daily) may be reasonable in selected immunocompromised children considered to be at low risk of developing severe varicella if the patient can be followed closely as an outpatient. Additional dosing recommendations for individuals with reduced kidney function, as well as children <1 year of age, are provided in the Lexicomp drug information topics within UpToDate and within individual topic reviews. (See "Acyclovir: An overview", section on 'Dose adjustments' and "Varicella-zoster infection in the newborn".) The typical duration of treatment is 7 to 10 days. Intravenous therapy is continued until no new lesions are occurring. Patients can then be transitioned to oral therapy until all of the lesions have crusted.

With complication Acyclovir Intravenous (IV) antiviral therapy Adults – 10 mg/kg IV Q8H Children ≥1 year and adolescents – 1500 mg/m2 per day in three divided doses  or 30 mg/kg/day in three divided doses 7 to 10 days Monitor kidney function

If antiviral therapy is initiated, treatment should be started within 24 hours after the rash develops, if possible.

使用本類製劑應以下列條件為限： 疱疹性腦炎。 帶狀疱疹或單純性疱疹侵犯三叉神經第一分枝 VI 皮節，可能危及眼角膜者。 帶狀疱疹或單純性疱疹侵犯薦椎 S2 皮節，將影響排泄功能者。 免疫機能不全、癌症、器官移植等病患之感染帶狀疱疹或單純性疱疹者。 新生兒或免疫機能不全患者的水痘感染。 罹患水痘，合併高燒 (口溫38℃以上) 及肺炎 (需Ｘ光顯示) 或腦膜炎，並須住院者

使用本類製劑應以下列條件為限： 帶狀疱疹或單純性疱疹所引起之角膜炎或角膜潰瘍者。 急性視網膜壞死症 (acute retina necrosis)。 帶狀疱疹發疹三日內且感染部位在頭頸部、生殖器周圍之病人，可給予五日內之口服或外用藥品 骨髓移植術後病患得依下列規定預防性使用acyclovir A. 限接受異體骨髓移植病患。 B. 接受高劑量化療或全身放射治療 (TBI) 前一天至移 植術後第卅天為止。 使用療程原則以十天為限，疱疹性腦炎得使用 14 至 21 天，口服、注射劑及外用藥膏擇一使用，不得合 併使用。

本院有 Acyclovir IV form 250mg/vial (578元) Oral susp 40mg/mL, 125mL/btl (928元) Valacyclovir Oral form 500mg /tab(84元) Famciclovir  Oral form 500mg /tab (97.2元)

水痘疫苗 (Varicella) 水痘疫苗: 活性減毒疫苗 接種時程: 出生滿12個月 （針對92年1月1日以後出生(14歲)幼兒實施） 接種劑量與接種間隔: >= 12個月至12歲: 單一劑量 >13歲: 兩劑，間隔四至八週 建議接種: ◎ 疾病簡介 水痘是一普遍之兒童疾病，通常症狀輕微，亦可能嚴重，好發於幼童，近來水痘發生的年齡層則有延後的趨勢，一般年齡愈大，症狀愈嚴重。水痘是由水痘-帶狀疱疹病毒（varicella-zoster virus）感染所引起的傳染病，具有高度傳染力，可經由飛沫在人與人間散佈，或經由接觸水痘的液體傳染，感染後會引發紅疹、水泡、發癢、發燒及疲倦等，可能併發嚴重的皮膚感染、疤痕、肺炎、腦炎或死亡，亦可能因病毒再活化而得到帶狀疱疹。 ◎ 認識疫苗 水痘疫苗是一種活性減毒疫苗，可有效避免嚴重之水痘症狀，接種水痘疫苗後若仍感染水痘，其症狀亦較輕微，可能會產生較少的水痘，且較不會發燒，復原較快。 ◎ 接種時程 ＊ 出生滿12個月（針對92年1月1日以後出生幼兒實施）。 ◎ 接種劑量與接種間隔 ＊ 建議施打於12個月以上之幼童，12個月至12歲兒童注射單一劑量。13歲以上應注射兩劑，間隔四至八週。 ◎ 接種禁忌 ＊ 先前接種本疫苗或對本疫苗任何成分曾發生嚴重過敏反應者。 ＊ 已知患有嚴重免疫缺失者（包括嚴重免疫不全的愛滋病毒陽性個案、先天性免疫缺失症與白血病、淋巴癌等惡性腫瘤病人或接受化療、免疫抑制藥物治療及高劑量類固醇者）。 ＊ 孕婦。 ◎ 注意事項 ＊發燒或正患有急性中重度疾病者，宜待病情穩定後再接種。 ＊最近曾輸血或接受其他血液製劑者（如免疫球蛋白），應詢問原診治醫師何時可接種水痘疫苗。 ＊接種前24小時內曾接受特定抗病毒藥物者（如：acyclovir、famciclovir或valacyclovir），於接種後間隔14天以後再重新開始服用這些藥物。 ＊女性接種後4週內應避免懷孕。 ＊接種後皮膚出現紅疹者，應避免接觸嚴重免疫不全者。 ＊18歲以下兒童接種水痘疫苗後6週內宜避免使用水楊酸類藥品(salicylates)。 ◎ 接種免疫球蛋白、輸血後之接種間隔： ＊接受一般肌肉注射免疫球蛋白治療或B型肝炎免疫球蛋白（HBIG）者，宜間隔3個月後再接種。 ＊輸過血或接受靜脈注射血液製品者，宜間隔6個月後再接種。小於1歲之麻疹個案接觸者，如已施打肌肉注射免疫球蛋白(IMIG)，應間隔6個月以上再接種MMR或水痘疫苗。 ＊曾靜脈注射高劑量（≧1g/kg）免疫球蛋白治療時，宜間隔11個月後再接種。 ◎ 接種後可能發生的反應及注意事項 ＊接種部位可能有發紅、疼痛或腫脹等局部反應。 ＊可能有輕微的發燒，偶有發生高燒、抽搐之現象。 ＊接種後5-26天於注射部位或身上可能出現類似水痘的水泡。 ＊與自然感染水痘病毒一樣，疫苗的病毒可能潛伏在體內，在免疫功能低下時，病毒再活化而表現成帶狀疱疹，但其發生率與症狀都低於自然感染。 可能親密接觸高危險族群者（醫療人員、家中有免疫缺陷成員者） 就學及工作環境有可能容易傳播水痘病毒者（軍營、幼兒園、學校、機構) 育齡婦女懷孕前一個月 旅遊或國際商務人員

Back to our patient Diagnosis Varicella with bilateral corneal involvement Congenital factor IX disorder Immunocompetent adolescents Unvaccinated adolescents (≥13 years of age) Without complication  ValacIclovir (valtrex) 1000mg Q8H