Fatal varicella with an initial presentation as severe abdominal pain with esophageal lesions, a case report and a review of the literature

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1 Cherng-Jyr Lim et al. Fatal varicella with an initial presentation as severe abdominal pain with esophageal lesions, a case report and a review of the literature Cherng-Jyr Lim 1, Yo-Spring Lin 2, Wei-Lung Chen 1,3, Jiann-Hwa Chen 1,3, Su-Hen Chang 1,3 Abstract Varicella (chickenpox) is a well-known benign infection of childhood, but it is sometimes associated with more serious complications such as pneumonitis, meningitis/encephalitis or hepatitis. We present here a fatal case of primary varicella in a previously healthy and immunocompetent foreign worker from Vietnam, the initial presentation of which was abdominal pain and esophageal lesions that preceded the disease's typical vesicular skin lesions. The patient was afebrile throughout the course of the disease, which progressed rapidly towards the development of fulminant hepatic failure, disseminated intravascular coagulation and death. Key Words: varicella, chickenpox, abdominal pain, esophagus disorders, hepatitis Introduction Varicella, or as it is more generally known, chickenpox, is a common and contagious infection of childhood that is caused by the varicellazoster virus (VZV). It is most often mild and selflimited. Sometimes it reactivates as herpes zoster or shingles later in life. Rarely, this disease can behave aggressively in certain human populations, including immunocompromised individuals, patients with human immunodeficiency virus infection, users of corticosteroid users, transplant patients, acute leukemia patients, pregnant women, and rarely even immunocompetent patients; these persons are at risk and can suffer high mortality. As an emergency physician, it is important that the early signs and symptoms of fulminant varicella and its complications are recognized so that anti-viral therapy and aggressive treatment can be started early in the course of the disease as this can prove to be life-saving. We report here a fatal case of primary varicella in a previously healthy and immunocompetent patient that serves as a reminder that varicella is able to manifest atypically, progress rapidly and become lethal in healthy individuals. Case Report A 22-year-old Vietnamese male patient presented at our emergency room with acute abdominal pain. He had up to this time been Correspondence: Dr. Su-Hen Chang Department of Emergency Medicine, Cathay General Hospital; 280, Section 4, Jen-Ai Road, Taipei 106, Taiwan (R.O.C.) Tel: ext.3761; Fax: ; chang_su_hen@hotmail.com Department of Emergency Medicine, Cathay General Hospital, Taipei, Taiwan 1, Department of Pediatrics and Infection, Ton- Yen General Hospital, Hsinchu, Taiwan 2, School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan 3 70

2 Fatal varicella initially presenting as severe abdominal pain and an esophageal lesion healthy and was without any remarkable medical history. He denied taking any type of medication or illicit drugs, and denied that he drank alcohol. He had suffered from progressive epigastric pain since the night before and this had became intolerable, which prompted his visit to the hospital at around 5 am. The pain was sharp, constant and without radiation. He had vomited once the night before and the gastric contents had been without coffee grounds. He did not have diarrhea. There were no relieving or aggravating factors to his pain. Upon arrival, he was fully conscious and alert; afebrile, and had a temperature of 36.7 C, tachycardia with a heart rate of 114 beats/min, a respiration rate of 20 breaths/min, a blood pressure (BP) of 140/71 mmhg, and on a visual analogue scale (VAS) his pain was 8. A physical examination found a soft abdomen with epigastric and right upper quadrant tenderness together with an equivocal Murphy s sign without rebounding pain. All other physical examinations were essentially normal with nonicteric sclera, intact oral mucosa, a supple neck without lymphadenopathy, clear breathing sounds and no skin rash. A review of his systems was unremarkable and no fever, headache, cough, coryza, sore throat, chest pain or urinary symptoms were present. Initial imaging of the abdomen showed a non-specific bowel gas pattern and a radiopaque ureteral calculus at the left side of 4th lumbar spine level (Figure 1). A chest X-ray was normal without subphrenic free air. Initial blood tests showed leukocytosis with a left shift, and elevated liver enzymes (hemoglobin 16.7 g/dl, white blood cells 14300/μl with 1% band, 82% neutrophils, 15% lymphocytes and 2% monocytes, platelets /μl, glucose 108 mg/dl, sodium 139 mmol/ L, potassium 3.4 mmol/l, creatinine 1.06 mg/ dl, AST/ALT 179/159 IU/L, total bilirubin 0.6 mg/dl, gamma-gt 21 U/L, alkaline phosphatase 73 IU/L, lipase 27 U/L, PT/aPTT 12.7/32.6 sec, INR 1.31). Abdominal computed tomography with intravenous contrast was arranged and the results were unremarkable for the liver, biliary tract, pancreas, spleen, intestines, and vascular Figure 1. KUB showing a non-specific bowel gas pattern and a radiopaque ureteral calculus on the left side at the 4th lumbar spine level. system, except for a left upper ureter stone with obstructive uropathy. Due to the unexplained epigastric pain, panendoscopy was arranged and this showed multiple esophageal ulcers and vesicles (Figure 2) from which biopsies were taken. Unfortunately, the unexplained epigastric pain was attributed to the left ureteral stone, and the patient was referred for extracorporeal shock wave lithotripsy, discharged with analgesics and an appointment with the hepatology clinic for follow up. On the same afternoon, vesiculopapular skin eruptions started to appear on the chest and abdomen and these spread to the face and limbs. Hemoptysis, hematemesis and hematochezia was noted the next morning along with persisted abdominal pain. He returned to the emergency room with his vital signs now being BP 136/88mmHg, a temperature of 36 C, a heart rate 118 beats/min and a respiratory rate of 20. Hemorrhagic vesicles on the face and oral mucosa were also noted. Follow up 71

3 Cherng-Jyr Lim et al. Figure 2. A panendoscopic examination showed multiple esophageal ulcerations less than 4 mm in diameter with red spots in upper portion. These occurred starting from about 25 cm to 30 cm from the oral incisor. A biopsy was carried out. blood tests showed thrombocytopenia, a marked elevation of liver enzymes, and coagulopathy. (Hb 16 mg/dl, WBC 35070/μl with 4.7% band, 81.7% neutrophils, platelet 41000/μl, AST/ALT 1660/1086 IU/L, PT > 50s, INR > 4.5, aptt 41.2s, FDP > 340 μg/ml, fibrinogen 31 mg/ dl, D-Dimer > 35.2 mg/l). Blood products, including fresh frozen plasma and platelets, were transfused, along with supplemental vitamin K1 and tranexamic acid. Empirical antibiotics and acyclovir were prescribed. However, his condition rapidly deteriorated during the following day with progressive dyspnea and massive persistent gastrointestinal bleeding. He was intubated and transferred to the intensive care unit. A followup chest X-ray was clear of abnormal infiltrations. Despite mechanical ventilation, aggressive resuscitation, administration of vasopressors, antibiotics, anti-viral agents, and cardiopulmonary resuscitations, the patient died on the second day of admission. Bacterial cultures from the blood that had been obtained on admission were negative. The patient was tested for HIV and VDRL and was negative for both. Serological testing for hepatitis A, B and C were also negative. A number of other serological tests for other viral markers were carried out, including cytomegalovirus (CMV) and Epstein-Barr virus; these were negative for IgM antibodies but positive for IgG antibodies. Testing for the presence of IgG and IgM antibodies against VZV were both negatives as well. Nevertheless, the blood samples drawn on the day of admission were sent for testing by polymerase chain reaction and this assay was positive for VZV. The biopsies from the esophageal lesions (Figure 3) showed necrotic debris, fibrinous exudate and inflammatory cell infiltration with multi-nucleation and nuclear inclusion bodies with cytoplasmic vacuolation; these are indicative of a serious infection by a member of herpesviridae at a high viral load. Periodic Acid-Schiff staining was negative and neither fungal spores nor fungal hyphae are identified. Herpes simplex virus type I antigen and CMV antigen tests were also negative. This patient received a final diagnosis of fulminant varicella complicated by acute hepatitis with liver failure and disseminated intravascular coagulation. The patient s dormitory mates and colleagues, some of whom subsequently 72

4 Fatal varicella initially presenting as severe abdominal pain and an esophageal lesion Figure 3. Pathology of an esophageal ulcer showing necrotic debris, fibrinous exudate and inflammatory cell infiltration into the esophageal mucosa (left upper). Some ground-glass nuclei with focal nuclear molding and intranuclear inclusions can be seen (black arrows). Some fibrin microthrombo-emboli (white arrows) are also visible in some capillaries (right lower). The features are compatible with virus caused cytopathic effect and disseminated intravascular coagulation. contracted the disease one to two weeks later, had the usual benign course of primary varicella and recovered completely. None developed any complications. Discussion Primary varicella is usually a benign illness of childhood and often merely requires symptomatic treatment. However, it sometimes can cause serious and unusual complications. Aside from the most obvious complication, namely bacterial infection of the patient's skin lesions, which may include infection with Staphylococcus and/or Streptococcus and can potentially result in toxic shock syndrome, VZV itself can produce some other serious complications. Of these, pneumonitis is the most common. Others such complications include acute respiratory distress syndrome, aseptic meningitis/encephalitis, rhabdomyolysis, hepatitis, disseminated intravascular coagulation, myocarditis, acute glomerulonephritis and arthritis. 1-4 High-risk groups for these complications include teenagers and adults, pregnant women, immunocompromised individuals, steroid users, and newborns/infants whose mother have never had chickenpox or have never been vaccinated. Varicella hepatitis with acute liver failure is uncommon but is frequently fatal. 5,6 The few patients who have survived this complication received early treatment with acyclovir and liver transplantation. Most of the patients who suffered from varicella hepatitis have been described as being immunocompromised. Primary varicella presenting initially with acute abdominal pain has been reported in the literature, mostly among the immunocompromised hosts such as person who are infected with HIV, bone 73

5 Cherng-Jyr Lim et al. marrow or solid organ transplantation patients, steroid users and chemotherapy patients; 5-15 rarely has it been described in an immunocompetent patient. 3,4 The other gastrointestinal symptoms associated with varicella hepatitis include nausea and vomiting. These symptoms may appear preceding or concomitantly with the cutaneous lesions caused by the virus, but alternatively they can precede them by hours, or even by as long as 9 days. 7 Even more rarely no skin lesions have been noted throughout the entire clinical course of the disease. 10,17 Abdominal pain as part of varicella infection has been thought to be caused by hepatic distention due to hepatitis, pancreatitis or neurogenic pain, and a poor prognosis is often made when this occurs in transplant patients. 18 Primary varicella infections in immunocompetent hosts with multisystem complications have been described in the literature. 2-4 However, this case is unusual and differs from the reported cases in the literature in that this patient lacked the cardinal sign of fever despite being immunocompetent. Afebrile or low grade fever typically is found when there is varicella breakthrough (varicella in vaccinated individuals) as compared to primary varicella. The involvement of the esophagus, along with acute abdominal pain, as the first manifestation of VZV infection, has also been reported, albeit in an allogeneic bone marrow transplant patient during the course of tacrolimus therapy. 9 Our case highlights that this manifestation can also occur in immunocompetent individuals. Early recognition of the severity of the disease might have altered the clinical outcome in this case. At the time of presentation at the emergency room, the potential differential diagnoses were considerable in number, including acute gastric ulcer, acute gastroenteritis, ileus/mesenteric artery thrombosis or dissection, acute pancreatitis, acute cholecystitis, and even urinary calculus. Unfortunately, this patient had a concurrent urinary calculus of left collecting system, which further complicated the task of reaching a correct diagnosis in this case. The fact that some of the patient s co-workers and dormitory mates developed varicella without complications and recovered uneventfully indicates that a particularly virulent strain of the virus did not cause his death, but rather it can be postulated that his allogeneic immune response had failed to contain the virus. Conclusion Atypical and serious complications of VZV infection are not just limited to the immunosuppressed patients, but also occur in the immunocompetent individuals. However, we found that these two groups of patients share many similarities on reviewing the case series. Varicella should be considered as a differential diagnosis for abdominal pain in all immunocompromised patients. On the other hand, abdominal pain may be the first manifestation of dissemination of varicella in healthy individuals too and in such cases this indicates a serious illness that requires aggressive treatment. Clinicians must be aware of such atypical presentations and complications of varicella in order to treat such patients successfully. This case reminds us once again not to overlook this seemingly common and usually benign disease, especially in populations where vaccination against VZV is not a common practice such as developing nations. By the same token, it is also worth noting the importance of vaccination because this helps to prevent serious complications when there is varicella infection. References 1. Gnann JW Jr. Varicella-Zoster Virus. Atypical Presentations and Unusual Complications. J Infect Dis 2002;186:S91-S Bajaj N, Joshi J, Bajaj S. Chicken Pox with Multisystem Complications. Med J Armed Forces India 2010;66: Lee S, Ito N, Inagaki T, et al. Fulminant Varicella Infection Complicated with Acute Respiratory Distress Syndrome, and Disseminated Intravscular Coagulation 74

6 Fatal varicella initially presenting as severe abdominal pain and an esophageal lesion in an Immunocompetent Young Adult. Intern Med 2004;43: Ahamed SP, Balkhair A, Krishnan R. Fulminant Varicella Zoster Infection with Multiorgan Involvement, A Case Report. Sultan Qaboos Univ Med J 2008;8: Dits H, Frans E, Wilmer A, et al. Varicella-Zoster Virus Infection Associated with Acute Liver Failure. Clin Infect Dis 1998;27: Roque-Afonso AM, Bralet MP, Ichai P, et at. Chickenpox-Associated Fulminant Hepatitis That Led to Liver Transplantation in a 63-year-old Woman. Liver Transpl 2008;14: Balkis MM, Ghosn S, Sharara AI, Atweh SF, Kanj SS. Disseminated varicella presenting as acute abdominal pain nine days before the appearance of the rash. Int J Infect Dis 2009;13:e93-e Muñoz L, Balmaña J, Martino R, Sureda A, Rabella N, Brunet S. Abdominal pain as the initial symptom of visceral varicella zoster infection in bone marrow transplant recipients. Med Clin 1998;111: Takatoku M, Muroi K, Kawano-Yamamoto C, Nagai T, Komatsu N, Ozawa K. Involvement of the Esophagus and Stomach as a First Manistestation of Varicella Zoster Virus Infection after Allogeneic Bone Marrow Transplantation. Intern Med 2004;43: Yagi T, Karasuno T, Hasegawa T, et al. Case report: Acute abdomen without cutaneous signs of varicella zoster virus infection as a late complication of allogeneic bone marrow transplantation: importance of empiric therapy with acyclovir. Bone Marrow Transplant 2000;25: David DS, Tegtmeier BR, O Donnell MR, Paz IB, McCarty TM. Visceral varicella-zoster after bone marrow transplantation: report of a case series and review of the literature. Am J Gastroenterol 1998;93: Pishvaian AC, Bahrain M, Lewis JH. Fatal Varicella- Zoster Hepatitis Presenting with Severe Abdominal Pain: A Case Report and Review of the Literature. Dig Dis Sci 2006;51: Kim SH, Haycox C. Primary disseminated varicella presenting as an acute abdomen. Pediatr Dermatol 1999;16: Os I, Strom EH, Stenehjem A, et al. Varicella infection in a renal transplant recipient associated with abdominal pain, hepatitis and glomerulonphritis. Scand J Urol Nephrol 2001;35: Schiller GJ, Nimer SD, Gajewski JL, Golde DW. Abdominal presentation of varicella-zoster infection in recipients of allogeneic bone marrow transplantation. Bone Marrow Transplant 1991;7: Feldhoff CM, Balfour HH Jr, Simmons RL, Najarian JS, Mauer SM. Varicella in children with renal transplants. J Pediatr 1981;98: Grant RM, Weitzman SS, Sherman CG, Sirkin WL, Petric M, Tellier R. Fulminant disseminated Varicella Zoster virus infection without skin involvement. J Clin Virol 2002;24: Strauss SE, Ostrove KM, Inchauspe G, et al. Varicellazoster virus infection. Biology, natural history, treatment, and prevention. Ann Intern Med 1988; 109:

7 林成值等 以嚴重腹痛及食道病灶為初始表現的致命水痘病毒感染 : 一病例報告及文獻回顧 林成值 1, 林玉春 2, 陳威龍 1,3, 陳健驊 1,3 1,3, 張思恆 摘要水痘是一種常見於幼兒時期的感染, 有時會引起肺炎 腦炎 食道炎及肝炎等併發症 本文介紹一位越南外勞, 查無任何免疫抑制情形 他在皮膚病灶出現前, 僅以急性腹痛及食道病灶為初始臨床表徵, 且在整個水痘感染病程無發燒, 之後並迅速進展至肝衰竭及瀰漫性血管內凝血病變而死亡 關鍵詞 : 水痘, 腹痛, 食道病灶, 肝炎 通訊作者 : 張思恆醫師 106 台北市仁愛路 4 段 280 號 ; 國泰綜合醫院急診醫學科電話 : 轉 3761; 傳真 : ; chang_su_hen@hotmail.com 國泰綜合醫院急診醫學科 1, 東元綜合醫院兒童感染科 2 3, 天主教輔仁大學醫學系 76