Aslıhan Demirel

Secondary Infections in Febrile Neutropenia in Hematological Malignancies: More Than Another Febrile Neutropenic Episode.

Objective: Febrile neutropenic episodes (FNEs) are among the major causes of mortality in patients with hematological malignancies. Secondary infections develop either during the empirical antibiotic therapy or 1 week after cessation of therapy for a FNE. The aim of this study was to investigate the risk factors associated with secondary infections in febrile neutropenic patients. Materials and Methods: We retrospectively analyzed 750 FNEs in 473 patients between January 2000 and December 2006. Results: Secondary infections were diagnosed in 152 (20%) of 750 FNEs. The median time to develop secondary infection was 10 days (range: 2-34 days). The duration of neutropenia over 10 days significantly increased the risk of secondary infections (p<0.001). The proportion of patients with microbiologically documented infections was found to be higher in primary infections (271/750, 36%) compared to secondary infections (43/152, 28%) (p=0.038). Age; sex; underlying disease; antibacterial, antifungal, or antiviral prophylaxis; blood transfusion or bone marrow transplantation; central venous catheter; and severity of neutropenia did not differ significantly between primary and secondary infections (p>0.05). While fever of unknown origin (p=0.005) and catheter-related bacteremia (p<0.001) were less frequently observed in secondary infections, the frequency of microbiologically (p=0.003) and clinically (p<0.001) documented infections, fungal pneumonias (p<0.001), infections related to gram-positive bacteria (p=0.04) and fungi (p<0.001), and 30-day mortality rate (p<0.001) were significantly higher in cases of secondary infections (p<0.001). Conclusion: Secondary infections should be regarded as life-threatening complications of febrile neutropenia. Secondary infections represent a more severe and mortal complication and cannot be regarded just as another FNE.

A case of nocardiasis complicated with meningitis in a patient with immune thrombocytopenic purpura.

Nocardia infection is a well recognized complication of the immunocompromised hosts. It is mostly a primary pulmonary infection, which may disseminate to other organs. The central nervous system (CNS) involvement of nocardiosis is usually manifested as brain abscesses. We report a 25-year-old male patient who presented with nocardial pneumonia and meningitis without brain abscess. He was diagnosed as immune thrombocytopenic purpura and methyl prednisolone was started 5 weeks previously. Nocardia spp. was obtained from his cerebrospinal fluid culture, but he died at the 7th day of intensive care. Nocardia meningitis is a rare manifestation of systemic disease. Nocardia meningitis should be considered in the differential diagnosis of meningitis with the coexisting nodular pulmonary lesions in the immunocompromised patient and medications other than co-trimoxazole may be required.

Recognizing Acute Hepatitis C in Hemodialysis Patients

Dear Sir, Hepatitis C virus (HCV) infection is common in hemodialysis patients and the relatively lower alanine aminotransferase (ALT) values in acute [1] and chronic hepatitis C infections [2, 3] of these patients make the diagnosis more difficult. Acute hepatitis C in hemodialysis patients can be treated by interferon (IFN) therapy [4], although the response rates are lower than in patients with normal renal function [5]. Lampe et al. [6] emphasized the role of recognizing acute HCV infection in hemodialysis patients by comparing the ALT level to the patient’s ALT baseline values. A 53-year-old male was under hemodialysis for 10 years due to hypertensive nephropathy. Hemodialysis was applied 3 times weekly and the serology of HCV and hepatitis B virus (HBV) and biochemistry were checked monthly. When his ALT level was measured as 29 U/l, which seemed significantly higher than his previous measurements (4, 5, 7, 4, and 6 IU/l, respectively), HCV and HBV serology was repeated. Although antiHCV remained negative and anti-HBs was positive, his ALT level was serially checked. Within 1 month, his ALT level increased to 114 U/l and anti-HCV was detected as positive. He remained symptomless. HCV ribonucleic acid (RNA) by polymerase chain reaction (PCR) was measured as 7,130 IU/l and the genotype study remained an indeterminate result. HCV RNA studies obtained 2 weeks apart gave comparable results of 5,150 and 6,120 IU/l. His ALT level increased to a maximum level of 155 U/l and then tended to decrease (Fig. 1). He was initiated with pegylated IFN alpha-2a 135 lg weekly. The study of Lemos et al. [7] emphasized the role of monitoring ALT for recognizing acute HCV infection, since the patients are almost always asymptomatic, as in our case. They observed ALT elevation in all patients and the median peak ALT was 4.79 the upper limit of normal (range: 1.1–47.4). The median interval between ALT elevation and anti-HCV seroconversion was 1 month. What is the upper limit of normal of ALT in hemodialysis patients? Espinosa et al. [1] reported the upper limit for ALT in hepatitis-free hemodialysis patients as 27 IU/l. The sensitivity of a mean ALT value C27 IU/l in the diagnosis of HCV viremia was 50% and the specificity was 100%. They reported the positive predictive value of this test in the diagnosis of hepatitis C viremia as 100% and concluded that a high ALT level can constitute an excellent tool in predicting viremia in hemodialysis patients, once other causes of liver disease have been excluded. In two studies including 19 and 32 patients with acute hepatitis C under hemodialysis, the peak median ALT levels of the patients were 345 IU/l (range: 24–1,473) [8] and 169 IU/l (range: 22–325), respectively. Another study used the definition of acute HCV infection as ‘‘a rise of twice the normal or more of serum ALT level compared to baseline in addition to a positive serum anti-HCV antibody’’ [4]. To conclude, recognizing acute HCV infection is critical, since treatment can prevent progressive liver damage by a considerable part. The ALT levels are not expected to increase by several times, so any increase compared to his/ her ‘‘normal’’ values should be considered as a warning. R. Ozaras (&) M. Yilmaz B. Mete A. Demirel Department of Infectious Diseases, Cerrahpasa Medical Faculty, University of Istanbul, Aksaray, Istanbul 34303, Turkey e-mail: rozaras@yahoo.com

On hepatitis B virus and vasculitis

We have read the paper of Lee et al. with great interest [1]. They examined whether resolved hepatitis B virus (HBV) infection was associated with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and affected AAV activity at diagnosis and prognosis. Fifty patients had antiHBc, and 61 had anti-HBs. In eosinophilic granulomatosis with polyangiitis (EGPA) patients, those with HBsAg negative/anti-HBc positive showed the higher initial mean Birmingham vasculitis activity score (BVAS) and five factor scores (FFS) than those without, significantly increased risk of relapse of EGPA than those having not and meaningfully lower cumulative relapse-free survival rates than those without during the follow-up duration. They included HBsAg-negative and anti-HBc-positive patients to represent resolved HBV infection and compared with HBsAg-negative and anti-HBc-negative patients. The data presented in the study are enough to pick and organize groups considering anti-HBs status with corresponding patient numbers (Fig. 1). Among anti-HBc (+) group, those with anti-HBs (+) (A in the Fig. 1) represent resolved HBV, while anti-HBs (−) ones (B) are named anti-HBc-only. Anti-HBc-only, as discussed in the paper, is a heterogeneous group potentially including acute, resolved, chronic HBV, and occult HBV infections [2]. Among anti-HBc (−) individuals, anti-HBs (+) ones (C) represent vaccinated ones, while anti-HBs (−) ones (D) are neither vaccinated nor infected individuals. A and B denote exposure to the virus, while C represents exposure to a recombinant HBsAg. Only D is free of exposure to neither viral nor recombinant antigens and provides an opportunity to test the HBsAg–vasculitis association as a control group. HBV and vasculitis association has been attributed to the development through immune-complex reactions; immune complexes of HBsAg with anti-HBs precipitate and become entangled in the walls of small-to-medium-sized vessels, resulting in both injuries in adjacent tissues and aneurysmal dilatation or occlusion of affected vessels [3]. Beside numerous papers reporting vasculitides associated with HBV infection, there have been some reports with recombinant HBV vaccination [4–10]. In the presented study, among anti-HBc negative individuals, further differential analysis of C and D may probably contribute to understanding of any effect of HBsAg on development and clinical course of vasculitides. Rheumatology INTERNATIONAL

Future Drugs in the Treatment of HBV

Chronic hepatitis B (CHB) virus infection, a major cause of cirrhosis and hepatocellular carcinoma (HCC), is a global public health problem. The treatment of CHB progressed during the last decades. Beginning with IFN and Peg-IFN, hepatitis B virus (HBV) treatment improved with the use of potent and safe antivirals. The newer antiviral agents, entecavir and tenofovir, are more potent and, with higher resistance barrier, have provided lifelong suppression of HBV replication. However, long-term use of HBV antivirals does not provide eradication.

Does resolved HBV or anti-HBc-only carry the same risk of HBV reactivation?

We have read the study of Yeo et al. with great interest. They reviewed 75 lymphoma patients with resolved hepatitis B virus (HBV) infection over a two-year period for HBV reactivation. They defined resolved HBV as documented positive anti-HBc, negative HBsAg, and negative HBV DNA prior to initiation of rituximab or within six months of rituximab initiation. The resolved HBV infection is defined by clearance of HBsAg with development of antibody to HBsAg. The definition in the study (positive anti-HBc, negative HBsAg, and negative HBV DNA) can be either ‘‘resolved’’ hepatitis (if the HBs antibodies are positive) or anti-HBc-only (if the HBs antibodies are negative). The HBs antibodies were tested in 65 patients and reported positive in 54. The patients in the study include 10 undetermined (resolved or anti-HBc-only), 54 resolved, and 11 anti-HBc-only. They reported three reactivations: one in undetermined group and two in anti-HBc-only. Anti-HBc-only represents a heterogeneous group of acute, resolved, chronic HBV, and occult HBV infections. Measurement of serum anti-HBs responses after the administration of a booster HBV vaccination can be useful to further distinguish this serological profile. Anti-HBc-only represents a much higher risk of reactivation after chemotherapy or immunosuppressive therapy. In a recent meta-analysis, in 20 studies involving 1672 patients not receiving antiviral prophylaxis, the reactivation risk was 14% (95% confidence interval (CI) 9.4%–19%) in 388 patients who had antiHBc-only versus 5.0% (95% CI: 3.0%–7.0%) in 1284 patients who also had anti-HBs. It was also shown that anti-HBs reduced reactivation risk with a pooled OR of 0.21 (95% CI: 0.14–0.32) versus patients with antiHBc-only. Similar results were found when limiting the analysis to rituximab chemotherapy (OR1⁄4 0.19, 95% CI: 0.11–0.32) and lymphoma (OR1⁄4 0.18, 95% CI: 0.11–0.28). The protective effect of anti-HBs against HBV reactivation was also reported in solid organ transplanted patients. Anti-HBc-only represents a much higher risk of reactivation after chemotherapy or immunosuppressive therapy compared to resolved HBV infection. The risk of reactivation should be studied separately.

Successful Treatment of Disseminated Fusariosis with the Combination of Voriconazole and Liposomal Amphotericin B

3. Gentile G, Broccoli A, Brunocilla E, Schiavina R, Borghesi M, Romagnoli D, Bianchi L, Derenzini E, Agostinelli C, Franceschelli A, Colombo F, Zinzani PL. An isolated penile mass in a young adult turned out to be a primary marginal zone lymphoma of the penis. A case report and a review of literature. Anticancer Res 2013;33:2639-2642. 4. Gong Z, Zhang Y, Chu H, Lian P, Zhang L, Sun P, Chen J. Priapism as the initial symptom of primary penile lymphoma: a case report. Oncol Lett 2014;8:1929-1932.

The Evaluation of Clostridium difficile Toxin A ve B Positivity Rates and Epidemiological Characteristics in Febrile Neutropenic Patients with Diarrhea

Yazışma Adresi/Address for Correspondence: Dr. Nur Efe İris, Bilim Üniversitesi Tıp Fakültesi, Enfeksiyon Hastalıkları ve Klinik Mikrobiyoloji Anabilim Dalı, İstanbul, Türkiye Tel.: +90 532 652 53 73 E-posta: nurefeiris@yahoo.com Geliş Tarihi/Received: 04.11.2015 Kabul Tarihi/Accepted: 19.02.2016 Giriş: Clostridium difficile (C. difficile), antibiyotik ile ilişkili ishallerin en sık nedenidir. Özellikle immünsüpresyon önemli bir risk faktörü olduğu için diyare yakınması olan febril nötropenik hastalarda toksin A ve B araştırılması önerilir. Çalışmamızda febril nötropenik dönemde ishal gelişen maligniteli hastaların dışkılarında C. difficile toksini sıklığını araştırmayı ve toksin pozitif hastaların epidemiyolojik özelliklerini irdelemeyi amaçladık. Gereç ve Yöntem: Hastanemize başvuran hematolojik maligniteli ve solid organ tümörlü hastalarda febril nötropenik dönemde diyare gelişen olguların dışkı örnekleri incelendi. C. difficile toksin A ve B sıklığı kromatografik immünoassay yöntemi ile C. difficile toksin A ve B’nin aynı anda kalitatif olarak belirlenmesini sağlayan ticari kit (MonlabTest, İspanya) ile çalışılmıştır. Bulgular: Bir Ocak 2012 ile 15 Ağustos 2015 arasındaki dönemde febril nötropenik hastalara ait toplam 197 dışkı örneğinde (%4,6) C. difficile toksin A+B pozitifliği saptandı. Ayrıca 14 olguda Ascaris yumurtası görüldü (%7) ve bir olgunun da dışkı kültüründe Salmonella spp. üredi. Toksin olumluluğu bulunan hastaların altısı kadın, üçü erkek, yaş ortalaması 63,5 olup, yedisi hematolojik maligniteli (%78), ikisi solid organ tümörlü (%22) idi. Tüm olgularda çoklu antibiyotik kullanımı mevcuttu. Yedi olguda kinolon profilaksisi, iki olguda yoğun bakım ünitesinde yatış öyküsü ve tüm olgularda daha önce uzun süreli olarak, ortalama 46 gün hastanede yatış öyküsü mevcuttu. Sonuç: Diyaresi olan febril nötropenik olgularda C. difficile toksin A+B pozitifliği %4,6 oranında saptanmıştır. Kemoterapi almış olmak, kinolon profilaksisi, karbapenem kullanımı, daha önceden uzun süreli hastanede yatış ve çoklu antimikrobiyal kullanımı öyküsü ortak epidemiyolojik özellikler olarak görülmektedir. Anahtar kelimeler: Clostridium difficile, toksin, diyare, Ascaris, epidemiyoloji Öz Nur EFE İRİS1, Aslıhan DEMİREL1, Safiye KOÇULU1, Esin ÇEVİK1, Aylin ORDU2, Reyhan DİZ KÜÇÜKKAYA3