EBV Serology Research Articles

Herpes Hepatitis Causing Fulminant Liver Failure in a Crohnʼs Disease Patient

A 24-year old non pregnant white woman with history of Crohn's disease, started on azathioprine and mesalamine, one month prior to admission, presented with a five day history of fever, chills, diarrhea and abdominal pain. Her physical examination revealed temperature of 102.4 F, abdominal distension and epigastric tenderness. Initial labs showed normal CBC, Klebsiella pneumoniae positive urine culture, ALT 104 units/L (U/L), AST 120 U/L, and normal amylase and lipase levels. She was started on levofloxacin for UTI, and methyl prednisone and metronidazole for possible Crohn's flare. On day 2 of hospitalization, she developed vesiculopapular rash on her chest and abdomen which later spread to her extremities. Her ALT and AST increased to 1401 U/L and 2386 U/L respectively. Hepatitis A IgM, hepatitis B surface antigen, hepatitis core IgM antibody, hepatitis C antibody, ANA, chlamydia/gonococcal PCR test, ASMA, AMA and EBV serology were negative. Imaging studies including RUQ ultrasound, CT scan of abdomen/pelvis, and HIDA scan were normal. Her condition declined with fulminant hepatitis, coagulopathy, and pancytopenia. She admitted to having unprotected sex and contracting herpes simplex virus (HSV) in the past. She was empirically started on intravenous acyclovir and subsequently found positive for HSV type 2 IgM antibodies with titer >1:160. Acyclovir was continued for 14 days with near complete normalization of liver enzymes, coagulation studies, and blood counts. HSV viral load decreased from 500 million to 158,000 in 3 weeks. She was discharged on lifelong maintenance dose of acyclovir. HSV is a rare cause of fulminant hepatitis and at risk individuals include neonates, pregnant women, patients like those on steroids, immunosuppressant medications and HIV and cancer patients. Clinical features include fever, nausea, vomiting, abdominal pain, leukopenia, and coagulopathy with or without mucocutaneous lesions. Serum HSV PCR is the diagnostic modality of choice, although liver biopsy remains the gold standard. When HSV hepatitis is suspected or diagnosed, acyclovir should be empirically started, since delay in initiation of antiviral therapy leads to rapid development of sequelae and poor outcomes. To our knowledge, this is the second reported case of HSV hepatitis in a Crohn's disease patient. Hence, HSV hepatitis should be considered in the differential diagnosis of fulminant hepatitis in immunocompromised patients.

An Infectious Cause of Liver Dysfunction and Rhabdomyolysis

Introduction: Leptospirosis is a widespread zoonotic disease. Human infection occurs from exposure to environmental sources, such as animal urine, contaminated water or soil, or infected animal tissue. Most cases of leptospirosis are mild to moderate but when severe, case fatality rate can be as high as 50%. We present a case of leptospirosis which presented as nonspecific symptoms, elevated liver enzymes, hyperbilirubinemia and rhabdomyolysis. Case presentation: A 40 year old male, referred to our hepatologist for further workup of transaminitis and hyperbilirubinemia. His symptoms started 5 days prior to presentation as arthralgias, fevers, chills, night sweats, generalized weakness and coffee colored urine which progressively got worse. He denied exposure to sick contacts, recent medication changes, illegal substance abuse or high risk sexual behavior. He denied any animal bites including ticks or exposure to animal waste.Vital signs were stable. Laboratory testing demonstrated an indirect and direct hyperbilirubinemia, elevated liver enzymes (ALT 247 and AST 721), normal alkaline phosphatase, INR of 1.2 suggesting a hepatocellular injury. Urine analysis showed large blood. His CK was elevated at 17,911 suggesting rhabdomyolysis. Acute hepatitis panel, HIV, CMV, HSV type 1 and 2, FANA were negative. A respiratory viral panel including Influenza A and B was negative. EBV serology suggested past infection. Acetaminophen level and ammonia level were checked and were normal, urine drug screen was normal. CT abdomen and pelvis showed a few prominent lymph nodes in the retroperitoneum and inguinal region. RUQ US was normal other than mild fatty changes in the liver. On further questioning into other etiologies of liver dysfunction, he reported that he swam frequently at a nearby lake. Leptospira IgM was ordered, which came back positive. Patient was started on doxycycline. Discussion: As clinical and laboratory findings are nonspecific a high index of suspicion is required to make the diagnosis of leptospirosis based on epidemiologic exposure and clinical manifestations. Transaminitis can occur in up to 40% cases, usually < 200. In our case liver enzymes were much higher secondary to rhabdomyolysis which was caused by leptospirosis. Oral doxycycline is used for mild illness and intravenous penicillin or ceftriaxone are used for severe illness. Prevention measures include avoiding potential sources of infection and animal vaccination.

EBV DNA detection in the diagnosis of Epstein-Barr virus infection realated diseases in children

Objective To investigate the clinical significance of Epstein-Barr virus EBV DNA in children with Epstein-Barr virus infection realated diseases. Methods A retrospective cohort study was performed. Totally 222 blood samples were collected from children who were diagnosed as EBV infection in Shandong Provincial Hospital from June 2012 to August 2013. Fluorescent quantitative PCR(FQ-PCR)was used to analyze the EBV DNA in peripheral blood lymphocytes. ELISA was used to analyze the four EBV serology antibodies in the serum. Two groups of tested results were compared. Heart, hepatic impairment and renal function were analyzed through detecting AST, ALT, BUN, CREA, CK, CKMB. The results were grouped by EBV DNA copy number, and then non-parametric test together with correlation analysis was performed using SPSS21.0 analytics software. Results The positive rate of EBV-CA IgM and EBV DNA was 51.35% (114/222) and 72.97% (162/222) respectively, χ2=24.01, P 1×106 copies/ml, Ⅱ1×105-1×106 copies/ml, Ⅲ 1×104-1×105 copies/ml, Ⅳ 5×103-1×104 copies/ml, Ⅴ<5×103 copies/ml), and ALT(χ2=10.14, P<0.05), BUN(χ2=18.17, P<0.05), CK(χ2=13.09, P<0.05), CKMB(χ2=17.93, P<0.01) had a statistically significant difference between each group. Well, the log value of EBV DNA copy number had a positive correlation relationship with AST(r=0.357, P=0.001), ALT(r=0.376, P=0.001), BUN(r=0.329, P=0.000), CK(r=0.235, P=0.035). Conclusions Detection of EBV DNA can be used for the early diagnosis and assessment of process of the EBV infection related disease in children. The detection of liver, kidney function and myocardial enzymes can be used for evaluating the severity of EBV infection.(Chin J Lab Med, 2016, 39: 256-261) Key words: Epstein-barr virus infections; DNA, viral; Early diagnosis; Child

Ulcus vulvae acutum — A case of genital ulcers in adolescent girl

Ulcus vulvae acutum is a rare clinical condition characterized by the presence of multiple acute painful genital ulcers of non-venereal origin associated with systemic symptoms in young women. The aetiopathogenesis of the disease is not fully understood, although recent reports have associated it with the Epstein–Barr virus. Diagnosis is difficult and generally made by exclusion after venereal diseases, and autoimmune, inflammatory, traumatic, and neoplastic causes. We describe a case of adolescent female with an episode of ulcus vulvae acutum associated with infectious mononucleosis. The diagnosis was supported by the clinical symptoms, elevated circulating levels of liver enzymes, positive EBV serology, cervical and inguinal lymphadenomegaly, and hepatosplenomegaly. The patient presented a history of aphthous stomatitis. Negative Pathergy test and the absence of any other related symptoms allowed us to exclude the Behçhet syndrome. Lesions healed with no sequelae or recurrences.

Differences of Antithymocyte Globulin (ATG) Side Effects during Allogeneic Stem Cell Transplantation

Introduction: Due to its production and mechanism of action, antithymocyte globulin (ATG) is associated with two main side effects: immunological responses and infections.Objective: We evaluate the incidence and differences of ATG infusion reactions and fungal and viral infections in patients who receive SCT across a period of 10 years.Patients and methods: From January 2005 to December 2014, 100 patients who underwent and allogeneic stem cell transplantation (SCT) in our center received ATG (Thymoglobulin [TG] or ATG-Fresenius [ATG-F]) as part of conditioning regimen. Because an out of trend had been noted in stability profiling of TG finished product lots manufactured since December 2009 and since July 2012, TG was switched by ATG-F, patients were divided into three groups (TG-1: 45 patients; TG-2: 31 patients; ATG-F: 24 patients). Total median dose of TG was 7.5 mg/Kg in both groups.Results: Patients transplanted with ATG-F were significantly older than those who received TG (p=0.009). In addition, the use of an unrelated donor and GVHD prophylaxis with calcineurin inhibitor combined with mycophenolate mofetil was more frequent in ATG-F group (p=0.04 and p <0.0001 respectively). There were no differences between the groups in the underlying disease and its status at the transplant, the intensity of the conditioning regimen and the recipient/donor CMV and EBV serology. The majority of patients engrafted (93.3%, 93.5% and 95.8%) and neutrophil and platelet recovery was similar between three groups. Although there were no statistical differences, TG-2 showed less acute and chronic GVHD compared with TG-1 and ATG-F. All patients received premedication with corticoids. In all groups, pyrexia and chills were the most frequent symptom associated with ATG administration. All patients in TG-2 group showed infusion reaction (p= 0.006) and compared with TG-1 and ATG-F, they presented more peripheral edema (p=0.003), diarrhea (p=0.001), pulmonary edema (p=0.002) and dyspnea (p=0.005).Fungal infection was more frequent in TG-1 (30.2% vs 13.3% and 4.3%,p=0.024). CMV reactivation and BK viruria was more frequent in ATG-F (p=0.048 and 0.005, respectively). In contrast, EBV reactivation and Post Transplant Lymphoproliferative Disorder (PTLD) was more frequent in TG-2 group (33.3% vs 2.6% and 16.7%, p=0.003 and 25.8% vs 0% and 4.2%, p<0.0001, respectively).ConclusionDuring ATG infusion, pyrexia and chills are the most common side in SCT. The screening and prophylaxis of fungal infections may be associated with the diminishing of the incidence of this complication during the studied period. The use of older patients and the mycophenolate may be associated with an increasing incidence of CMV reactivation. By contrast, it is unclear if the out of trend noted in stability profiling of TG finished product lots manufactured since December 2009 has had influence in the type of infusion reactions and the incidence of EBV reactivations and PTLD observed in the TG-2 group. DisclosuresNo relevant conflicts of interest to declare.

Autoimmune Hepatitis Masquerading as Wilsonʼs Disease

Introduction: Wilson disease (WD) results from a copper (Cu) transport mutation. Initial presentation of WD can be as acute liver failure (ALF) necessitating an urgent liver transplant. Autoimmune hepatitis (AIH) is an inflammatory disease with elevated antibodies and interface hepatitis on liver biopsy. ALF from AIH can be treated with immunosuppression, thereby, preventing the need for liver transplant. Differentiation between acute WD and AIH represents a diagnostic challenge. Case presentation: A 19 year old asymptomatic male had routine labs showing ALT: 512 U/L and AST: 529 U/L. He denied personal or family history of liver disease, recent medication use, alcohol or recreational drug use, or sexual activity. Repeat labs revealed ALT: 1002 U/L, AST: 336 U/L, ALP: 178 U/L, TB: 0.77 mg/dL, DB: 0.43 mg/dL, INR: 1.1, albumin: 3.6 g/dL, IGA: 177 mg/dL and IGG: 1164 mg/dL. Acute hepatitis panel, CMV and EBV serologies, ANA, ASMA, AMA and gamma globulins on serum protein electrophoresis were negative. Iron studies showed iron deficiency anemia. Liver MRI showed hepatomegaly with periportal tracking. His ALT and AST rose and he developed fatigue, jaundice, dark urine, and pale stools. Ceruloplasmin (CPN) was normal and his 24 hour urinary Cu was elevated at 236 μg. The patient was transferred to a transplant center for listing for presumed acute WD. Physical exam revealed jaundice without Kayser-Fleischer rings. Labs showed ALT: 1925 U/L, AST: 1203 U/L, ALP: 448 U/L, GGT: 232 U/L, TB: 8.7 mg/dL, DB: 5.8 mg/dL, INR: 0.97, albumin: 3.8 g/dL, alpha-1 antitrypsin: 219 mg/dL, and ASMA: 25.3 units. Repeat 24 hour urinary Cu was 85 μg. Liver biopsy showed portal triads with dense lympho-plasmacytic infiltrates with moderate to severe interface hepatitis and negative copper staining, suggestive of AIH. Prednisone was started with notable clinical improvement. Discussion: Our patient had a normal CPN level and an elevated 24 hour urinary Cu suggestive of WD, but was misleading. During the acute icteric phase of hepatitis, metabolism of Cu can be altered leading to a false suggestion of WD. Low CPN levels, increased urinary Cu, and normal or increased serum Cu levels can occur in liver injury regardless of etiology. Interestingly, his ALP/TB ratio was not less than 2, a lab finding typically seen in ALF from WD. This case highlights the importance of considering AIH in a case of ALF even when the patient has an abnormally high urinary Cu level.

Obliterative Portal Venopathy Masquerading Large Bile Duct Obstruction in a Patient on Oral Contraceptive Pills

Introduction: Oral contraceptives pills (OCP) are generally safe but can cause wide range of side effects. We report a case of obliterative portal venopathy (OPV) causing large bile duct obstruction picture from OCP use and slow resolution after discontinuation of the medication. Case: A 19-year-old woman with medical history of Down's syndrome and hypothyroidism presented with acute jaundice, pruritus and RUQ abdominal pain. She denied any fever, alcohol use, recent travel, sick contacts, new medications or herbal supplements. Her medications included levothyroxine, fexofenadine and OCP. Physical exam was remarkable for icterus and RUQ tenderness with positive Murphy's sign. Labs showed a total bilirubin of 8.0 with direct bilirubin of 5.1, alk phos of 245, AST of 50, ALT of 100 and lipase of 23. Acute and chronic hepatitis work up was negative for acetaminophen toxicity, viral hepatitis, EBV, CMV and HSV serologies, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson disease, hemochromatosis, α1 antitrypsin deficiency, and HIV. Urine toxicology was negative. Ultrasound showed no evidence of cholecystitis, cholelithiasis or choledocholithiasis. There was no intra or extra hepatic biliary obstruction on EUS and MRCP. CT scan was unremarkable. Alk phos progressively increased to 500 and the bilirubin slowly improved. The liver biopsy showed histologic features of large bile duct obstruction, and features suggestive of OPV and nodular regenerative hyperplasia. This was most likely thought to be due to OCP use in the absence of other etiologies. OCP was discontinued and LFT's slowly improved with normalization in 5 months. Discussion: OCPs are currently prescribed to 62 million women of reproductive age in the US. While deemed mostly safe, they can cause hepatic and biliary dysfunction, and a small subset of women develop intrahepatic cholestasis. Liver biopsy shows bland cholestasis without significant inflammation. Obstructive picture with OPV has not been described. A prothrombotic state caused by OCP probably resulted in OPV-induced large duct injury and obstruction picture in the biopsy. This report highlights that OCP can present with OPV and secondary changes such as large duct injury due to their prothrombotic effects. OPV should be considered as a differential diagnosis if the labs and biopsy show findings suggestive of large bile duct obstruction before proceeding with invasive procedures like ERCP.

Haloperidol-induced Cytolytic Hepatitis

Introduction Contrary to phenothiazines, butyrophenones are very seldom associated with hepatitis. In particular, the incidence of hepatitis on haloperidol is about 0.002%. Almost all these cases consisted of cholestatic hepatitis. Cytolytic hepatitis induced by haloperidol seems to be exceptional. Objective To outline the occurrence of haloperidol-induced cytolytic hepatitis. Methods Case report and review Results We report the case of a male patient aged 22, with a family history of schizophrenia in two cousins and with a personal history of generalized epilepsy on carbamazepine. The patient was admitted to our department for behavioral disturbances. Psychiatric interview found mystical and grandiosity delusions as well as auditory and visual hallucinations. The patient was started on haloperidol 5mg bid. Routine liver enzymes obtained on day-10 revealed eight-fold elevated transaminases with no associated biological signs of cholestasis. The patient did not report any symptoms suggestive of hepatitis. Serology for viral hepatitis (A, B, and C), EBV and CMV was negative. Hepatic ultrasound examination was normal. Antinuclear, anti-LMK and anti-mitochondrial antibodies were negative. Serum and urine copper levels were normal. The diagnosis of a drug-induced hepatitis was made. Haloperidol was withdrawn and switched to olanzapine. Transaminase levels slowly dropped then normalized within two months, thus consolidating our diagnosis. Conclusions Cytolytic hepatitis induced by haloperidol is very rare and can be asymptomatic. Routine liver tests when starting antipsychotics are crucially important to diagnose this possibly hazardous side effect.

Proton Nuclear Magnetic Resonance (NMR) Metabolomics: Future in Etiological Diagnosis of Encephalomyelitis.

Encephalomyelitis is relatively rare (10.5–13.8/100,000 children) but may be fatal, and frequently causes permanent disability. The cause remains unknown in more than half the cases [1,2]. Cardinal symptoms of encephalitis include fever, headache, neck stiffness, photophobia, confusion and seizures. Clinical examination will reveal altered mental status ranging from somnolence to lethargy and coma. Delirium, cranial nerve palsies, ataxia, rash and sign of increased intracranial pressure may be seen. It is not always possible to ascertain the specific cause of encephalitis from clinical presentation alone. However there are features that can give some clue to possible etiology. Arbovirus encephalitis often heralds with a flu-like syndrome followed by increasing confusion and stupor. Herpes simplex encephalitis often presents with an abrupt change in behavior, memory loss, focal or generalized seizures, and speech concerns. West Nile encephalitis may present with flaccid, asymmetric motor weakness with altered sensorium of variable degree. Varicella may manifest with cerebellar features as Japanese encephalitis presenting with basal ganglia symptoms. The current evaluation of encephalomyelitis requires a battery of tests including neuroimaging, expensive and often limited by the inability to obtain enough specimens in pediatric population along with unacceptable turnaround time. It is warranted to explore newer methodologies to establish early diagnosis, which is detrimental to favorable clinical outcome. Proton NMR Metabolomics The concept that biological fluids reflect the health of an individual has existed for a long time. Nuclear Magnetic Resonance (NMR) spectroscopy is based on measuring the absorption of light (radio waves) due to changes in nuclear spin orientation of molecules of different metabolites. Proton nuclear magnetic resonance (NMR) metabolomics can be used to study metabolic profile of cerebrospinal fluid and urine. NMR is fully quantitative, highly reproducible, and detects all metabolites simultaneously in one snapshot. The samples are completely recoverable. Distinct Cerebro Spinal Fluid (CSF) metabolomics profile for normal controls, human rabies,6 West Nile encephalitis, and Lyme meningitis have been well described. One can correlate CSF and urine metabolomics with clinical course, imaging, and laboratory findings, to develop a rapid screen to differentiate infectious from auto-inflammatory and autoimmune causes of encephalomyelitis by cluster analysis. We have already used proton nuclear magnetic resonance (H+-NMR) to identify and quantify 56 metabolites from normal and diseased CSF using 0.5 ml of CSF in under 2 hours, and discriminate a CSF metabolomics profile by unsupervised (unbiased) cluster analysis. Contrast this with the standard diagnostic approach –almost a century old– of quantifying two (2) substances (glucose and protein) from the same CSF volume with similar turn-around time. Preliminarily, we can with high accuracy discriminate 6 central nervous system (CNS) diseases using NMR metabolomics. Contrast this with turn-around time of 4–7+ days for conventional encephalitis testing for oligoclonal bands, serology for EBV, Varicella Zoster Virus (VZV) or Lyme disease, and N-methyl-D-aspartate receptor (NMDAR), Voltage –gated potassium channel (VGKC) or aquaporin-4 autoantibodies. We conducted a study of CSF metabolomics comparing persons under treatment for rabies encephalitis, to normal controls. We were able to describe a metabolomic profile for human rabies across a number of weeks of illness. We also identified metabolic changes that correlated with clinical worsening or, alternatively, with survival. More recently, we compared CSF metabolomics profiles from patients without infection, rabies encephalitis, West Nile encephalitis, Lyme meningitis, fungal meningitis, malaria encephalopathy, and multiple sclerosis. CSF profiles clustered well and were surprisingly distinct between diseases. We hypothesize that these same findings may hold true for other forms of infectious encephalitis and will cleanly distinguish these from (ADEM) acute disseminated encephalomyelitis (approximating MS) We do not intend to supplant highly accurate and definitive testing for specific viruses or autoantibodies, but NMR might accelerate and focus initiation of effective therapies, to improve outcomes, and improve patient safety and financial risk by limiting expensive, CSF- or blood-consuming diagnostics.

An Unusual Case of CMV Gastritis in a Healthy Adult

Case Report: A 24-year-old obese female presented with a 2-week history of abdominal pain, nausea, vomiting, and dark stools. Her past medical history was significant for menorrhagia and iron deficiency anemia. Her abdomen was soft, moderately tender with normal bowel sounds. Superficial lymph nodes, including cervical, axillary, and inguinal were not palpable. Lab results revealed hemoglobin of 7.8 g/dL, MCV of 75.8 fL, WBC of 5.38 k/uL with lymphocytes at 61%, and monocytes at 7%. CT of the abdomen revealed an enlarged spleen. Monospot test was negative. Screening for HSV, syphilis, parvovirus, ova, and parasites was unremarkable. Serology for HIV 1 and 2 was negative. Her CD4 count was 615 cells/uL, CD8 count was 727 cell/uL, and the CD4:CD8 ratio was 0.85. Serology for EBV was positive for IgG and IgM antibodies against viral capsid antigens and IgG antibodies against nuclear antigen and early antigen. An EGD was done, which revealed a normal esophagus, moderate gastritis with edematous gastric folds, many non-bleeding superficial gastric ulcers spread on the entire stomach, with the largest measuring 3 mm, and a normal duodenum (Figure 1). The biopsy of the lesion revealed scattered cells with characteristic CMV inclusion bodies, and immune-histochemical staining was positive for CMV and negative for H.pylori (Figures 2A, 2B). Culture of the gastric biopsy also yielded CMV. She was treated with ganciclovir and omeprazole. Follow-up 4 weeks later revealed complete resolution of her symptoms.Figure 1Figure 2Discussion: Primary CMV infection in normal hosts is aymptomatic, but can lead to a mononucleosislike syndrome and, rarely, severe organ specific complications. This case shows the occurrence of classical CMV gastritis lesions in a normal healthy and young host, and emphasizes the need to include CMV in the differential when multiple, shallow gastric ulcers are found on upper endoscopy, even in immunocompetent hosts.

Bosentan-Induced Autoimmune Hepatitis

Introduction: Bosentan is an endothelin receptor antagonist used for pulmonary arterial hypertension (PAH). Drug-induced liver injury (DILI) is 1 of the reported side effects. However, the mechanism of the injury is not well understood. A 56-year-old female with PAH on bosentan from 2 months ago was found to have an INR of 12.8 in the lab work. She was started on Coumadin from 2 weeks prior to admission for DVT. Inpatient lab works showed AST: 592, ALT: 194, and Alk-P: 273. Total protein was 7.7, albumin 2.6, globulin 5.1, and total bilirubin 16.1. She also had of dark urine, pruritus, and yellowing of the eyes and skin. She denied abdominal pain, nausea, or vomiting. PMH: sickle cell disease, PAH, pulmonary embolism, and migraine. Home medications were bosentan, ASA, tramadol, synthroid, Lasix, folic acid, and hydroxyurea. She denied any tobacco, ETOH, or illicit drug use. Physical exam was significant for icteric sclera. There was no abdominal tenderness and the bowel sounds were present. LFTs from 1 month ago were normal. Further labs showed normal LDH, AMA, DIC panel, and hepatitis panel. CMV PCR, EBV serology, and HSV PCR were negative too. IgG was 2,600 and ASMA was positive. Imaging showed cholelithiasis without evidence of choledocholithiasis or biliary dilatation. Liver biopsy showed mild diffuse portal lobular chronic inflammation composed of lymphocytes, plasma cells, and rare eosinophils. Focal hepatic necrosis, cholestasis, and ballooning degeneration without significant steatosis or portal fibrosis was observed (Image 1). Bosentan was discontinued for this patient, and after 1 month, LFTs normalized. Mechanism of DILI in bosentan is not clear. In the presented case, the positive ASMA and the pathology findings indicating the dominance of plasma cells and lymphocytes and scarcity of eosinophils represent an autoimmune-induced mechanism. This autoimmune-induced hepatitis was most likely secondary to bosentan, and less likely AIH, given the age and also the fact that liver function improved when the patient stopped taking bosentan.Figure 1: Liver biopsy showing hepatic necrosis, cholestasis, and ballooning degeneration without significant steatosis or portal fibrosis.

Epidemiology of Post-Transplant Lymphoproliferative Disorders in Solid Organ Transplant Recipients in a Single Canadian Centre.

Objective: Many epidemiologic studies of post-transplant lymphoproliferative disorder (PTLD) in solid organ transplant (SOT) populations have limited follow-up, incomplete pre-transplant viral serology and PTLD histology, and study only adults or children. We describe a single center study of the PTLD cases in all adult and pediatric (ped) SOT recipients from January 1, 1984 to June 30, 2013. Methods: Patients (n=4750, 475 age < 18, 4275 age ≥ 18) included 724 heart (15.2%), 551 lung or heart/lung (11.6%), 1298 liver (27.3%), 2099 kidney (44.2%), 66 pancreas or kidney/pancreas (1.4%), and 12 multivisceral or small bowel (.3%). Yearly cumulative incidence (CI) was calculated using the patient-year variant of the incidence definition: number of cases/amount of patient-time at risk each year. PTLD risk factors were analyzed using univariate Cox regression analyses, ped and adult patients were analyzed separately. Results: 134 cases of PTLD occurred over a median follow-up (FU) of 5.98 yrs (standard error (SE) 0.09, range 0-29.5 yrs). Ped SOT recipients developed more early lesions and polymorphic PTLD than adults (44 vs. 10%); adults had more monomorphic PTLD (68 vs. 38%). CI of PTLD was 1.31% PY at 1 year, 2.25% PY at 5 years, 3.04% at 10 years, and 3.93% PY at 20 years. Median overall survival (OS) of the entire cohort was 13.8 years (SE .36); PTLD adversely impacted OS in adult (p=.000, HR 1.3 (95% C.Int. 1.1-1.4), but not ped recipients (p=.23). Factors that significantly increased PTLD risk were: younger age at transplant, less time post-transplant, REBV -, and RCMV- (adult only). Risk of early (≤ 1 year) and late (> 1 year) PTLD, early/late EBER+ PTLD, and PTLD localized to CNS, GI, allograft and >1 extranodal (EN) site decreased with increased age at transplant. Risk of early PTLD and allograft PTLD in adults was higher from 1984-1991 compared to 2002-13. Being REBV- conferred significantly higher risk of early and late PTLD, early and late EBER+ PTLD, and PTLD localized in the CNS, GI tract, allograft, and over 1 EN site in adults. Conclusions: PTLD cases continued to arise 20 yrs post-transplant, and risk was increased by younger age, shorter duration post-transplant, and negative EBV serology. Negative EBV serostatus also increased risk of all PTLD subgroups in adults, including CNS involvement.

Belatacept Based Immunosuppression For Renal Dysfunction Post Intestinal Transplantation.

Calcineurin inhibitors have been linked to a higher incidence of acute renal failure due to its nephrotoxic effects, which may be related to its erratic area under the curve immediately after intestinal transplantation in patients with caval drainage of the grafts. We identified the patients demonstrating a significant decline in their pre-transplant glomerular filtration rate (eGFR) after transplantation. The decline was quantified using the MDRD equation. EBV status of the patient was documented before the switch. Any episodes of rejection after the switch were recorded. From October 2008 to November 2013, 24 patients underwent intestinal transplantation. All had Campath induction and Tacrolimus monotherapy. Six (25%) demonstrated a mean decline of 45mls/min (range 25-70mls/min) in their eGFR from pre-transplant values. Decline was noted at a mean of 45 days (range 7-720 days) post transplantation. All 6 patients were switched to Belatacept. All patients had a positive EBV serology at the time of the switch. Mean time post-transplant to switch was 208 days (range 23-1195 days). The switch was accompanied with Azathioprine (50mg OD) and Prednisolone (10mg OD) n=2, Low dose tacrolimus (levels<3) n=2, No other maintenance therapy n=2. One patient (17%) demonstrated moderate rejection, 15 days post switch to Belatacept. This patient was switched to Belatacept monotherapy at 5mg/kg. This patient later succumbed to an Aspergillus brain abscess related to the step up in immunosuppression to treat rejection. Majority of patients demonstrated a significant improvement of their eGFR. One patient demonstrated moderate rejection. Belatacept may be a valid option for patients demonstrating significant decline in their eGFR after transplantation. Belatacept as monotherapy may be a high-risk strategy for rejection.

Dermatopathic Lymphadenitis Associated With Human Papilloma Virus Infection and Verruca Vulgaris

Here we present a pediatric case of human papilloma virus associated with dermatopathic lymphadenitis (DL). A 5-year-old boy presented to the pediatric oncology clinic with swelling of the neck and warts on his lower jaw. His blood chemistry and complete blood count were normal, as was chest x-ray. HIV, EBV, CMV, and parvovirus serologies were negative. The patient was investigated for malignancy and lymphoma but no association was found. Histopathologic examination of the lymph node and the lesion revealed DL and verruca vulgaris, respectively. DL represents a benign form of reactive lymph node hyperplasia and described in patients with HIV and EBV infections. It is a rare entity described in patients with human papilloma virus infection. To our knowledge, this is the first report of DL in a patient with human papilloma virus infection.

P507 EBV serology status and azathioprine-associated complications: a single centre study

P507 EBV serology status and azathioprine-associated complications: a single centre study

Recurrent thrombocytopenia and Lyme disease

Case report We present the case of a 24 year-old man admitted to the Hospital of Infectious Diseases for headache, myalgia, arthralgia and a previous unrepeated episode of moderate fever. Physical examination at the admission revealed a poor general status, loss of appetite, difficulties in maintaining orthostatic position due to the hypotonia of the lower limbs muscles, absence of meningeal irritation syndrome. He denied any tick bites in the past. Lumbar puncture, cranio-cerebral computed tomography were normal, as well as different serology for EBV, Mycoplasma, HIV, syphilis. The most prominent hematologic feature was a severe thrombocytopenia (29,000/cmm). He received ampicillin and dexamethasone and the level of platelets increased progressively to normal during a period of eight days. He was discharged without any complaints, but he returned after 5 days with the same symptoms, and thrombocytopenia (37,000/cmm). A serology test for Borrelia was performed and it was positive revealing the diagnosis of Lyme disease. The complete remission of thrombocytopenia under the same association of drugs was very rapid – in 4 days. He was discharged after having been treated for three weeks with antibiotic and two weeks of corticotherapy. Authors’ details “Gr.T.Popa” University of Medicine and Pharmacy, Iasi, Romania. Hospital of Infectious Diseases, Iasi, Romania.

Epidemiology Of Post-Transplant Lymphoproliferative Disorders Following Solid Organ Transplant In a Major Canadian Transplant Centre

Post-transplant lymphoproliferative disorder (PTLD) is a consequence of organ transplantation with a high risk of mortality. We analyzed records of all patients who received a solid organ transplant at the University of Alberta between 1984 and 2011 (n=4525). 133 patients developed PTLD over the follow up period of January 1984 to November 2012, including 61 cases that occurred less than 2 years after transplant ( early), 33 cases between 2 and 7 years after transplant (late), and 39 cases more than 7 years after transplant (very late). We calculated the cumulative incidence rate for PTLD. We also used Cox regression analysis to determine whether variables year of transplant, age at transplant, organ, and EBV serology mismatch influenced the risk of development of any PTLD, early and very late PTLD, and central nervous system (CNS) PTLD (any PTLD and early PTLD shown in Table 1). The cumulative incidence of any PTLD occurrence was 1.4% at 1 year, 2.6% at 5 years, 4.3% at 10 years, 6.6% at 15 years, and 7.9% at 20 years. Univariate analyses showed that year of transplant (1984-92 vs. 1993-2001 vs. 2002-2011) was not predictive of PTLD development (p=0.27, HR 0.88, CI 0.68-1.12). Patients aged 0-5 years at transplant had significantly higher risk of PTLD development (mean freedom from disease (FFD) 18.90 yrs, 95% CI 17.52-20.28) followed by patients over 60 (mean FFD 25.49 yrs, 95% CI 24.97-26.0; p value 0.000, hazard ratio (HR) 0.57, 95% CI 0.49-0.68). Among organs transplanted, multivisceral transplant conferred the highest risk (mean FFD 5.94, 95% CI 4.19-7.69, n=12) followed by lung transplant (mean FFD 15.45 yrs, 95% CI 17.76-19.83), whereas kidney transplant conferred the lowest risk (mean FFD 27.52 yrs, 95% CI 27.15-27.88; p=0.000, HR 0.57, 95% CI 0.49-0.68). Patients with EBV serology recipient to donor mismatch (ie. recipient negative, donor positive) also had a higher risk of PTLD development (mean FFD 22.9 yrs, 95% CI 21.2-24.6 vs. mean FFD 27.2 yrs, 95% CI 26.90-27.54, p=0.000, HR 8.79, 95% CI 5.83-13.24). Variables associated with increased risk of early PTLD development were year of transplant, with the highest risk in patients transplanted between 1984-1991 (mean FFD 27.88 yrs, 95% CI 27.51-28.24) and the lowest risk in those transplanted in 2002-2011 (mean FFD 10.7 yrs, 95% CI 10.69-10.79, p=0.002, HR 0.68, 95% CI 0.49-0.94); age, with the highest risk in patients 0-5 yrs (mean FFD 20.66, 95% CI 19.68-21.63), followed by over 60 yrs (mean FFD 26.17 yrs, 95% CI 25.98-26.36, p=0.000, HR 0.55, 95% CI 0.45-0.68); organ, with the highest risk in lung transplant (mean FFD 16.50 yrs, 95% CI 16.21-16.80), and the lowest risk in kidney transplant (mean FFD 28.40 yrs, 95% CI 28.30-28.96; p=0.000, HR 0.58, 95% CI 0.46-0.74), and EBV serologic mismatch (p=0.000, HR 18.62, 95% CI 10.45-33.20). In contrast, only organ significantly predicted development of late PTLD, with lung conferring the highest risk (mean FFD 16.27 yrs, 95% CI 15.6-16.94; p= 0.002, HR 0.53, 95% CI 0.39-0.73). Risk of development of CNS PTLD (n=10, either primary or secondary) was greater in patients with EBV serology mismatch (p=0.000, HR 19.95, CI 4.98-79.92), but no other variables significantly predicted its development. In conclusion, the risk of PTLD after solid organ transplant is increased even 20 years after transplant, but the risk of early PTLD is declining over time. The risk of PTLD is highest in patients 0-5 years of age at transplant, patients receiving lung transplant, and patients with EBV serologic mismatch.Total n (%)PTLD Cases (n=133) (%)p valueHazard ratio95% CIEARLY PTLD Cases (n=61) (%)p valueHazard ratio95% CIYear of transplant0.270.880.68-1.120.020.680.49-0.941984-92655 (14.5)33 (24.8)14 (23.0)1993-20011558 (34.4)55 (41.3)24 (39.3)2002-20112312 (51.1)45 (33.8)23 (37.7)Age category0.0000.6450.55-0.750.0000.550.45-0.680-5231 (5.1)23 (17.3)13 (21.3)5-18225 (5.0)9 (6.8)7 (11.5)18-603242 (71.6)31 (23.3)34 (55.7)Over 60827 (18.3)16 (12.0)7 (11.5)Organ0.0000.570.49-0.680.0000.580.46-0.74Heart701 (15.5)35 (26.3)17 (26.9)Lung(18 Heart/Lung)512 (11.3)28 (21.0)16 (26.2)Kidney1983 (43.8)41 (30.8)12 (19.7)Liver1219 (26.9)28 (21.0)16 (26.2)Multivisceral (6 small bowel)12 (0.3)1 (0.75)0Pancreas98 (2.2)00EBV Serology Mismatch0.0008.795.83-13.240.00018.6210.45-33.20No3832 (84.7)75 (56.3)23 (37.7)Yes231 (5.1)33 (24.8)23 (37.7)Unknown460 (10.2)25 (18.8)15 (24.6) Disclosures:Peters:Lundbeck Canada: Honoraria; Hoffman LaRoche: Research Funding.

Hepatitis and Pancreatitis Associated with the Use of Trimetropim Sulfamethoxazole: A Case Report

Purpose/Introduction: Trimetropim sulfamethoxazole (TMP-SMX) is a widely prescribed antibiotic. Both hepatitis and pancreatitis are uncommon side effects, and reports in non-immunosuppressed patients are rare. To our knowledge, there are only two previous case reports of concomitant hepatitis and pancreatitis occurring in an inmunocompetent patient. Case Presentation: A 65-year-old male with previous history of coronary artery disease, hypertension and dyslipidemia presented to the emergency room with abdominal pain, jaundice and a skin rash. The patient had been started on TMP-SMX for otitis media two weeks before arriving to the emergency department. During this period of time, the patient presented with nausea, vomiting, weight loss and fever. On physical examination, he was found to be jaundice, and a generalized non-pruritic macular rash was noticed. There was no history of alcohol use. On admission, liver function test and pancreatic markers were elevated. ALT peaked to 510, AST to 445 U/L, total and direct bilirubin to 19 and 8.9 mg/dL respectively, lipase to 578 U/L and amylase 102 U/L, albumin was decreased and coagulation studies were normal, and remained normal during and after hospitalization. Other causes of pancreatitis were rule out. Triglycerides were within normal limits and calcium and SPEP were normal. Acute viral hepatitis, CMV and EBV serology were negative, and titers of autoimmune markers were normal. Abdominal CT did not show hepatic or pancreatic abnormalities, and the abdominal ultrasound did not show gallstones or dilation of the intrahepatic ducts. Upper endoscopy showed esophagitis and gastritis. Pancreatitis and hepatitis were managed with fluid resuscitation and supportive care. The patient improved clinically, a decrease in lipase and aminotransferase was noted during hospitalization and a gradual decrease of bilirubin occurred after hospitalization. Discussion: Clinical observation is an important tool to identify adverse effects from medications. In this particular case, we have a Naranjo score of six (probable drug reaction). The mechanism of idiosyncratic adverse effects to TMP-SMX is not clearly understood, but inmuno-allergic mechanisms have been proposed. This case underlines the importance of considering commonly used medications as the causative event of severe medical conditions.

Case report: Auto-immune polymyositis secondary to EBV-infection

Introduction: Polymyositis is an immune-mediated syndrome secondary to defect in cellular immunity, frequently associated with other autoimmune diseases, maybe idiopathic, or known etiology which have the most frequent cancer or infection. In the case of viral infections, an agent can cause an injury uprightly muscle tissue, also damaging the vascular endothelium to release cytokines, which leads to a defect in expression of major histocompatibility complex and the susceptibility of muscle to destruction. In the clinical case which is described below, as an etiological factor for polymyositis arises an acute Epstein–Barr virus. Case report: Man, 45 years old, leucodermic firefighter with a history of chronic sinusitis and a former smoker. Without chronic medication. Appealed to the U.S. by frame with a month of evolution of generalized and progressive myalgia, generalized decrease in muscle strength with predominantly distal, anorexia, night sweats and weight loss quantified in about 10 kg. No fever or other symptoms. On admission he had noted the general decline in muscle mass, flaccid tetraparesia 3/3 predominantly distal — grade 3 in lower limbs, sensitively maintained. AST 708 UI/L, ALT 577 UI/L, LDH 4015 UI/L, and rhabdomyolysis with CK 25,129 UI/L. Serial serology for EBV was indicative of recent infection, TC-chest revealed consolidated nonspecific changes and pathological results of muscle biopsy revealed an extensive area of necrosis with inflammatory infiltrate with eosinophils and B lymphocytes. Described neurogenic EMG signs of active denervation in distal muscles of the lower limbs. The study to autoimmunity, Ac. Anti-SRP positive and initially positive ANA,with subsequent negative. Microbiological, serological to zoonoses, thyroid function and neoplasm were negative. For worsening muscle atrophy, the patient developed a restrictive ventilatory framework, diffusion of CO2 decreased and elevated markers of myocardial necrosis (without electrocardiographic or ecocardiographic changes) was transferred to Unit of Intensive Therapy and was subjected to non-invasive ventilation and initiated therapy 3 mg/kg/day with methylprednisolone. Despite on the poor prognosis associated with anti-SPR, the patient had a good clinical outcome in physical rehabilitation program, with the interference myopathy secondary to corticosteroids; did complete weaning of corticosteroids. Complaints about pain remained reasonably controlled with pregabalin. She was discharged with diagnosis of polymyositis with Ac anti-SRP secondary to EBV infection, followed in Outpatient Internal Medicine and Autoimmune Diseases.

The Accelerated Phase of Chediak-Higashi Syndrome: The Importance of Hematological Evaluation

To the Editor Chediak-Higashi syndrome is a rare autosomal recessive disease that was first described in 1943 by Bequez-Cesar in 3 siblings that bore the primary clinical features. In 1952 Chediak (a Cuban hematologist) and in 1954 Higashi (a Japanese pediatrician) described a series of cases characterized by misdistribution of myeloperoxidase in the patients’ neutrophilic granules [1,2]. Mean age of onset is 5.85 years; however, most patients die before age 10 years. In patients that do survive beyond childhood the neurologic problems persist and/or increase in magnitude [3]. Most cases are diagnosed clinically based on partial albinism and recurrent pyogenic infections. Both of our patients had hypopigmentation of the skin with patchy grey hairs, mild coagulation defects identified via the presence of petechial rashes on the skin, and a history of recurrent infections since birth. The characteristic hematological finding is massive lysosomal inclusions in all white cells, formed via a combined process of fusion, cytoplasmic injury, and phagocytosis due to a microtubular defect [3]. These granules exhibit both azurophilic and specific granular markers (Figure 1), and are strongly myeloperoxidase positive. Approximately 85% of cases develop a fatal accelerated phase characterized by pancytopenia, hemophagocytosis, and marked infiltration of organs by lymphocytes, leading to multi-organ dysfunction [4]. Herein we present 2 cases in the accelerated phase of Chediak-Higashi syndrome. Both were born to apparently healthy non-consanguineous parents. Figure 1 Large intracytoplasmic granules in a granulocytic cell (Giemsa stained bone marrow aspirate film; 1000×). Case 1 was a 2.5-year-old female that presented with a 6-month history of abdominal distension and moderate pallor, and a 5-d history of cough. General physical examination showed that she was thin built, and had normal facies with patchy grey hair and hypopigmentation of the skin. Systemic examination showed hepatosplenomegaly; the liver was 6 cm below the right costal margin and the spleen was 13 cm below the left costal margin. The cardiovascular and respiratory systems were normal. She also had bilateral cervical lymphadenopathy. Case 2 was a 3-year-old female that presented with a 3-month history of fever, and a 1-month history of abdominal distension, itching over the body, and moderate pallor. Physical examination showed patchy gray hair and generalized albinism with petechial spots on the thighs and abdomen. The patient weighed 7.6 kg, was of average build with normal facies and significant hepatosplenomegaly; the liver was 4 cm below the right costal margin and the spleen was 7 cm below the left costal margin. Both patients underwent bone marrow aspiration due to peripheral blood pancytopenia and organomegaly. Hemogram findings in cases 1 and 2 were, respectively, as follows: Hb: 4.2 g/dL and 3.9 g/dL; WBC: 4 × 109/L and 3 × 109/L; platelet count: 8 × 109/L and 6 × 109/L. Bone marrow aspiration findings in both cases are shown in the Table 1. Both patients had hematological findings characteristic of the accelerated phase of Chediak-Higashi syndrome-peripheral blood pancytopenia and marked hemophagocytosis (Figure 2) on bone marrow aspirate, along with lymphocyte infiltration on trephine biopsy section. Both cases were negative for HIV, CMV, and EBV serology. Table 1 Bone marrow aspirate findings in cases 1 and 2. Figure 2 Hemophagocytosis in bone marrow smear (Giemsa stain; 1000×). The genetic hallmark of Chediak-Higashi syndrome is mutations in the CHS1/LYST gene. The gene product is known to regulate lysosomal organelle function and size. The mutations could not be characterized in the presented cases because the DNA material for analysis was insufficient in one case and the other died due to the fulminant accelerated phase before hematological diagnosis was established. It is well known that Chediak-Higashi syndrome patients with deletions in the LYST gene usually present with a fulminant accelerated phase early in life, whereas those with missense mutations have a relatively better prognosis characterized by the absence of an accelerated phase and no neurological involvement [5]. The hematological findings of pancytopenia and hemophagocytosis suggest a possible deletion in the LYST gene in both of the presented cases, but ethnicity data and complete DNA analysis are needed to further substantiate the findings; nonetheless, both cases presented with the characteristic clinical and hematological profiles diagnostic of Chediak-Higashi syndrome. Careful examination of peripheral blood film in suspected cases can facilitate early diagnosis and further evaluation. In addition, recognition of early cytopenias should alert clinicians and hematologists of an impending accelerated phase. Furthermore, bone marrow aspiration is a useful diagnostic procedure for identifying tissue hemophagocytosis in such patients. Conflict of Interest Statement The authors of this paper have no conflicts of interest, including specific financial interests, relationships, and/ or affiliations relevant to the subject matter or materials included.