Cytomegalovirus reactivation and its clinical impact in patients with solid tumors

Cytomegalovirus reactivation can be life threatening. However, little evidence on its incidence in solid cancers is available. Therefore our single center Cytomegalovirus polymerase chain reaction database with altogether 890 CMV positive blood serum samples of mainly hematological and oncological patients was retrospectively analyzed to examine the occurrence of Cytomegalovirus reactivation in patients with solid tumors, resulting in 107 patients tested positive for Cytomegalovirus reactivation. Seventeen patients with solid cancer and a positive CMV-PCR test were identified, of which eight patients had clinically relevant CMV disease and received prompt antiviral treatment. Five patients fully recovered, but despite prompt antiviral treatment three patients died. Among these three patients two had significant co-infections (in one case EBV and in the other case Aspergillus) indicating that that CMV reactivation was at least one factor contributing to sepsis. The patient with the EBV co-infection was treated in an adjuvant therapy setting for breast cancer and died due to Cytomegalovirus and Epstein-Barr virus associated pneumonia despite intensive therapy. The other two patients had progressive disease of an underlying pancreatic cancer at the time of CMV diagnosis. One patient died due to attendant uncontrollable Aspergillus pneumonia, the other patient most likely died independent from CMV disease because of massively progressive underlying disease.Cytomegalovirus reactivation and disease might be underestimated in routine clinical practice. In our retrospective analysis we show that approximately 50 % of our patients suffering from solid cancers with a positive Cytomegalovirus polymerase chain reaction also had clinically relevant Cytomegalovirus disease requiring antiviral therapy.     

Cytomegalovirus Retinitis and Retinal Detachment following Chimeric Antigen Receptor T Cell Therapy for Relapsed/Refractory Multiple Myeloma

Cytomegalovirus (CMV) retinitis is a rare end-organ disease of CMV infection and is a marker of severe immunosuppression, especially in human immunodeficiency virus (HIV)-positive patients. In multiple myeloma (MM) patients, CMV retinitis has been reported in the post-transplant setting, with an incidence lower than 0.2%, and in patients receiving lenalidomide. Here, we describe the first case of CMV retinitis in myeloma patients following B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor T (BCMA CAR-T) cell therapy. In addition to CMV, the patient developed multiple infections including a mouth ulcer, pneumonia, and fungal enteritis. While the complete remission (CR) status of MM was maintained, he regained a visual acuity of 20/1000 after appropriate ophthalmologic treatment. This single case illustrates the potential of BCMA CAR-T therapy to induce profound humoral immunosuppression, and demonstrates an imperative need for an established standard of monitoring and prophylaxis of post-CAR-T infections.     

Pulmonary complications occurring after allogeneic bone marrow transplantation. A study of 130 consecutive transplanted patients

This report deals with 81 pulmonary episodes occurring in 130 consecutive patients who underwent allogeneic bone marrow transplantation for hematologic malignancy in the same unit over a 5-year period. These episodes observed in 69/130 patients (53%) were mostly of infectious origin, and were investigated by bronchoalveolar lavage (BAL). The main causes of pneumonia were: cytomegalovirus (CMV) (n = 25), bacterial pneumonia (n = 17), invasive aspergillosis (n = 11) and pulmonary hemorrhage (n = 9). The overall mortality due to or associated with pneumonia was 26/130 (20%). Graft-versus-host disease clearly increased the incidence of infectious pneumonia and the mortality due to or associated with pneumonia. Granulocyte transfusions did not influence the incidence of CMV pneumonitis. The main causes and risk factors for pneumonia are discussed. The role of BAL as a noninvasive procedure is stressed.     

Pneumocystis pneumonia in a patient with non-small cell lung cancer (NSCLC) treated with pemetrexed containing regimen

Pneumocystis pneumonia is typically life-threatening in immunocompromised patients. It is relatively uncommon in patients with lung cancer. We report a case of pneumocystis pneumonia in a patient with advanced stage non-small cell lung cancer (NSCLC) following treatment with concurrent chemoradiation with a pemetrexed containing regimen. To our knowledge, this is the first report on pneumocystis pneumonia following administration of pemetrexed containing regimen.     

高原地区肺癌患者放疗后发生放射性肺损伤的危险因素

目的：探讨影响高原肺癌患者发生放射性肺损伤的危险因素。方法：采用回顾性病例对照研究分析我院183例肺癌患者接受放射治疗后发生 RILI 的危险因素。运用单因素χ2检验和多因素 Logistic 回归分析独立影响因素,Kaplan - Meier 分析比较两组患者的生存情况及血液毒性变化。结果：经单因素分析发现民族、常住地、合并慢性肺炎、合并慢性病和V 20有统计学意义（χ2=8.548、40.539、6.941、8.117、41.79,P <0.05）。多因素分析发现民族、常住地、合并慢性肺炎和 V20是独立的危险因素（P <0.05）。放疗开始对患者的血液变化影响较大,尤其是 WBC 等。生存分析显示对照组中位生存期16个月明显高于病例组11个月（P<0.05）。结论：影响患者发生 RILI 因素很多,应该根据患者基本情况适当调整放射治疗方案,以降低 RILI的发病风险。     

Filgrastim and alemtuzumab (Campath-1H) for refractory chronic lymphocytic leukemia.

Alemtuzumab (anti-CD52; Campath-1H) is effective in fludarabine-refractory chronic lymphocytic leukemia (CLL), but is associated with infection and early onset neutropenia. To reduce toxicity, filgrastim (G-CSF) was administered concurrently with alemtuzumab. In total, 14 CLL patients (median age 59) with a median of 3.5 prior regimens (range 1--12) received i.v. alemtuzumab, stepped up from 3 to 30 mg the first week, then 30 mg thrice weekly for 12 weeks. Filgrastim 5 microg/kg was administered daily 5 days before and throughout alemtuzumab therapy. Six patients developed cytomegalovirus (CMV) reactivation 3--6 weeks into treatment; six patients developed fever, three neutropenia, and one pneumonia. The patient with CMV pneumonia died; ganciclovir cleared CMV in the other patients. Five patients developed early neutropenia (weeks 2--5). Four patients developed delayed neutropenia (weeks 10--13) unassociated with CMV reactivation. Nine patients ceased therapy because of infectious and hematologic toxicity. Five partial responses were noted, all in patients with lymph nodes>cm, lasting a median of 6.5 months (range 5--13). Filgrastim and alemtuzumab were given concurrently with manageable infusion toxicity and clinical activity, but the efficacy of this regimen was limited by delayed neutropenia of unclear etiology and CMV reactivation. Filgrastrim should not be administered prophylactically during alemtuzumab therapy outside clinical trials.     

Updated guidelines on the management of cytomegalovirus reactivation in patients with chronic lymphocytic leukemia treated with alemtuzumab

The anti-CD52 monoclonal antibody alemtuzumab is highly active in the treatment of chronic lymphocytic leukemia (CLL) in patients with previously treated, relapsed, and/or refractory CLL as well as in patients with previously untreated disease. The general immunosuppressive impact and toxicities associated with alemtuzumab therapy are largely predictable and manageable. In particular, cytomegalovirus (CMV) reactivation is now a well-documented complication in patients receiving alemtuzumab. This article discusses several strategies for monitoring and treating CMV reactivation in patients with CLL receiving alemtuzumab-based therapy and provides practical recommendations for CMV management by building upon the guidelines published previously in 2004.     

Cytomegalovirus: detection in human colonic and circulating mononuclear cells in association with gastrointestinal disease

The specificity and strength of the reported association between cytomegalovirus (CMV) and colonic adenocarcinoma were tested by analysis of a consecutive series of surgically resected colons for: CMV-DNA by a DNA-DNA reassociation kinetics (hybridization) procedure; latent virus by co-cultivation of fresh tissue with indicator fibroblasts; and CMV viral antigens by immunofluorescence. Ten of 13 cancer patients whose colonic tissue was able to be examined by all techniques showed evidence of active or prior CMV infection. Four cancer specimens were CMV-DNA (hybridization)- positive; an additional specimen from a cancerous colon was culture-positive. In six instances, CMV DNA was detected in mucosal cells adjacent to colon adenocarcinoma. In tissue from one of three patients with ulcera tive colitis and two of seven patients with other non-neoplastic colonic disease, CMV DNA was also detected. No fresh colonic tissues were demonstrated to have CMV surface or nuclear antigens when examined by immunofluorescence. Culture of peripheral lymphocytes was positive for CMV in three of 14 cancer patients. A CMV specific defect in humoral immunity could not be documented in that most cancer patients, as well as cancer-free patients, exhibited circulating specific antibody to CMV and had a normal capacity for CMV-specific antibody-dependent cellular cytotoxicity. We conclude that CMV, probably in a latent form, is readily detectable in colonic cells of man, including those derived from malignant, pre-malignant and non-malignant tissues. Neither preferential replication in damaged tissue nor carriage of CMV by peripheral lymphocytes homing to gut appear to explain the presence of CMV in colon cells.     

Severe Organizing Pneumonia after Two Cycles of Docetaxel as Fourth-Line Chemotherapy for Advanced Non-Small Cell Carcinoma of the Lung

Organizing pneumonia (formerly known as bronchiolitis obliterans organizing pneumonia, BOOP) is an inflammatory process of the bronchioles that can lead to the destruction of small airways and surrounding lung tissue. Although the majority of cases are idiopathic, certain chemicals and drugs can induce OP. Here, we report a 54-year-old male patient with advanced non-small cell lung cancer (NSCLC) who developed therapy-associated OP. He had undergone several other chemotherapies before being switched to docetaxel as monotherapy (75 mg/m²). Treatment was initially well tolerated, but after the second cycle the patient developed increasing shortness of breath. Computed tomography (CT) for staging after the second cycle showed bilateral predominantly interstitial infiltration highly suggestive of acute lung fibrosis. Bronchoscopy revealed signs of chronic bronchitis and watery discharge from both lungs. Bronchoalveolar lavage and transbronchial needle biopsy was performed. Based on histopathologic examination, diagnosis of OP was made. After cessation of docetaxel and initial high dose steroids, the infiltration ameliorated rapidly. This is the second case in the literature that associates docetaxel with rapid onset of bronchiolitis obliterans. Therefore, patients with lung cancer receiving docetaxel who develop respiratory symptoms should be suspected to develop OP.Key Words: Docetaxel, Taxane, Bronchiolitis obliterans organizing pneumonia, BOOP, Organizing pneumonia, OP     

Cytomegalovirus pneumonia prior to engraftment following T-cell depleted bone marrow transplantation

CMV pneumonia is a frequent complication of allogeneic bone marrow transplantation (BMT). It usually appears 23 months following transplantation and is associated with a high mortality rate. The incidence of CMV pneumonia in our T-lymphocyte depleted allogeneic BMT recipients, transplanted between 1987–1991, was 18 out of 197 (9.2%) patients. In 3 patients (1.5% of allogeneic BMT recipients), pneumonia occurred prior to marrow engraftment, on days 12–16 post BMT. These patients did not develop acute GVHD in contrast to 9/11 patients who had acute GVHD in addition to developing CMV pneumonia between engraftment and day +100 (p<0.03). Furthermore, these three patients did not receive steroid therapy as opposed to 14/15 patients who were treated with steroids and eventually contracted CMV pneumonia post-engraftment (p<0.01). The three patients did not have two additional risk factors known for the development of CMV pneumonia: increasing age and a diagnosis of acute myeloblastic leukemia (AML) as the primary disease. Despite prompt diagnosis and therapy with ganciclovir and high doses of intravenous immunoglobulin (IVIG), two of the patients died. Tcell depleted BMT may be a risk factor for development of CMV pneumonia occurring prior to engraftment. In the era of post-BMT anti CMV prophylaxis, one should be aware that life-threatening CMV pneumonia may appear prior to engraftment and consider aggressive CMV prophylaxis.     

Successful treatment of cytomegalovirus colitis with ganciclovir in a patient with adult T cell leukemia lymphoma: case report.

An 84-year-old patient with adult T cell leukemia lymphoma (ATLL) developed diarrhea on day 5 of chemotherapy and was diagnosed with cytomegalovirus (CMV) colitis. Sigmoidoscopy revealed multiple superficial erosions surrounded by a flare. Computed tomography (CT) and ultrasonogram of the abdomen revealed marked thickening of the colonic mucosa. There were 186 CMV antigen-positive leukocytes per 31,000 white blood cells (WBC). A colonic biopsy specimen showed typical CMV nuclear inclusions. Immunohistological study of the specimen was positive for CMV antigen. Administration of ganciclovir (DHPG) 500 mg/day for 14 days improved the diarrhea and other symptoms. On day 30 of the chemotherapy, the patient developed diarrhea again but was diagnosed with pseudomembranous colitis instead of CMV colitis. At that time, CMV antigenemia and a histologic study for CMV were negative. The stool was positive for Clostridium difficile toxin antigen. ATLL patients are believed to be immunocompromised hosts and often develop opportunistic infections such as CMV infection. Most suffer from CMV pneumonia at the end of their course of therapy. Few gastrointestinal (GI) CMV infections are seen in ATLL patients and details of CMV colitis have never been reported. When an ATLL patient develops diarrhea that barely responds to conventional therapy, CMV colitis and pseudomembranous colitis should be listed in the differential diagnosis.     

美国国家健康及营养普查人群巨细胞病毒与癌症发生的相关性

目的 研究巨细胞病毒（CMV）的存在与癌症的关系。方法 回顾性分析1988—1994年参加国家健康及营养普查（NHANES Ⅲ）人群（年龄≥17岁）感染巨细胞病毒与患癌症的关系。结果 在来自NHANES Ⅲ的14 718名美国居民（≥17岁）中,CMV存在于有癌症史的患者中,皮肤癌及结直肠癌患者中稍高。CMV的加权流行率,女性较男性高出10%甚至更多,尤其在女性乳腺癌、宫颈癌及子宫癌等相关癌症中,CMV存在率稍高。且该流行率随着年龄的增长逐渐增加（P<0.01）。未经校正的逻辑回归分析表明,CMV的存在与癌症发生、皮肤癌和乳腺癌有相关性（P<0.01）,但校正性别、年龄、教育背景、种族、贫困收入比率、身体质量指数及吸烟和饮酒状况等混杂因素后,该相关性不再显著。结论 巨细胞病毒的存在与癌症相关性不显著。     

膦甲酸钠预防及抢先治疗造血干细胞移植中巨细胞病毒感染的临床研究

目的 观察膦甲酸钠用于异基因造血干细胞移植(allo-HSCT)预防及抢先治疗巨细胞病毒(CMV)感染的疗效及安全性.方法 回顾性分析2014年10月至2016年12月96例接受allo-HSCT患者临床资料.采用实时荧光定量聚合酶链反应(RQ-PCR)监测患者血浆巨细胞病毒(CMV)-DNA情况至移植后6个月,预防及抢先治疗分别采用膦甲酸钠每天60 mg/kg和每天120 mg/kg.观察CMV血症、CMV病发生情况,分析CMV感染的影响因素,分析膦甲酸钠治疗效果和安全性,评估患者生存情况.结果96例患者中42例(43.8%)移植后发生CMV感染,中位感染时间42 d.膦甲酸钠治疗的42例CMV感染患者中,疗效显著36例(85.7%),进展为CMV病6例(14.3%),其中CMV转阴5例,因CMV间质性肺炎死亡1例.半相合移植及Ⅱ~Ⅳ度移植物抗宿主病(GVHD)患者CMV血症发病率升高(χ2=3.834,P<0.05;χ2=16.807,P<0.001).膦甲酸钠不良反应轻微,无明显中性粒细胞减少.发生CMV血症42例中,死亡12例(28.6%),未发生CMV血症54例中,死亡6例(11.1%),两组总生存率差异无统计学意义(χ2=3.546,P=0.06).结论 应用膦甲酸钠对allo-HSCT患者预防及抢先治疗CMV感染的疗效确切,耐受性良好,尤其适用于造血未完全恢复的患者.     

Prevention of CMV infection after BMT in high-risk patients using CMV hyperimmune globulin

Prophylactic administration of an intravenous cytomegalovirus hyperimmune globulin in bone marrow transplant recipients provided protection against primary as well as reactivated CMV infection in patients considered to be at high risk for cytomegalovirus infections. Forty-one patients were divided in six subgroups according to factors considered to increase the incidence and severity of CMV infections following bone marrow transplantation. All of these patients received blood products from donors not screened for active or latent CMV infections. In spite of this, patients undergoing intensified conditioning therapy or mismatch transplantation, as well as those transplanted in relapse of their leukemia and even patients receiving granulocyte transfusions from donors unscreened for CMV serostatus, were found not to develop primary or secondary CMV infections. Only in the group of patients older than 35 years and among those suffering from severe GVHD six patients were found to have CMV infections, only two a symptomatic form. Intravenous administration of CMV hyperimmune globulin effectively protected even patients at high risk for CMV infection against severe complications of primary infection or reactivation of this virus.     

Three cases of necrotizing pneumonia by pseudomonas aeruginosa infection in hematological malignancy, including dead and alive cases

Pseudomonas aeruginosa (P. aeruginosa) is a common nosocomial pathogen that often causes pneumonia, especially in immunocompromised patients including cancer bearing-hosts. In cancer patients who have great risk of gram-negative bacteria leading to fatal infection, P. aeruginosa bacteremia easily results in septicemia with shock and life-threatening complications such as vital organ failure. Among those complications, necrotizing pneumonia is an infectious disease of lung caused by P. aeruginosa characterized by rapid cavitation and progressive clinical course, which is fatal not only in cancer patients but also in healthy hosts. P.aeruginosa is one of the pathogens targeted for empirical therapy neutropenic patients. Three case series of necrotizing pneumonia were reviewed in this report. All three had hematological malignancies and were immunocompromised. One of the three cases,a 30-year-old man with malignant lymphoma, recovered from pneumothorax and pyothorax complicated with lung cavitation. The other two patients died with a short course; a 55-year-old man with chronic myelogeneous leukemia within 7 hours, and a 54-year-old man with malignant lymphoma within 2 days after the onset of pneumonia, respectively. In these 3 cases, there were no obvious associations between prognosis and neutrophil counts, duration of neutropenia and steroid administration.     

Detection of Epstein-Barr Virus and Cytomegalovirus in Gastric Cancers in Kerman,Iran

Gastric cancer (GC) is a multifactorial disease with different factors having roles in its genesis. Helicobacter pylori and Epstein-Barr virus (EBV) are known infectious agents that could contribute. In addition, there is evidence of a relationship with cytomegalovirus (CMV). Since data on CMV prevalence in gastric cancer are limited, we here evaluated the frequency of EBV and CMV in Iranian patients. Ninety paraffin blocks of GC tissues from patients in Kerman were evaluated for the presence of EBV and CMV genomes by real-time polymerase chain reaction. EBV was detected in 10 cases (11.1%) and CMV in seven. One out of 17 female patients (5.88%) and nine out of 73 male patients (12.3%) were positive for EBV, while one out of 17 female patients (5.88%) and six out of 73 male patients (8.22%) were positive for CMV. The mean age for EBV-positive patients was 60.514.9 years and the mean age for CMV-positive patients was 67.912.3years. This study shows that the frequency of EBV-associated GC is high in Kerman. It also indicates that further studies of associations between GC and CMV are warranted, covering larger samples and populations from different areas of the world.     

Fatal adenovirus infection during alemtuzumab (anti-CD52 monoclonal antibody) treatment of a patient with fludarabine-refractory B-cell chronic lymphocytic leukemia

Alemtuzumab (Campath-1H) is a humanized CD52 monoclonal antibody that targets normal as well as malignant B- and T-lymphocytes. Alemtuzumab has significant antitumor activity in chronic lymphocytic leukemia (B-CLL) but also induces immunosuppression. We describe a case of fatal adenovirus infection in a heavily pretreated patient with fludarabine-refractory B-CLL receiving alemtuzumab therapy, drawing attention to the fact that also viruses other than cytomegalovirus (CMV) and herpes simplex (HSV) need to be considered in B-CLL patients with fever of unknown origin while on alemtuzumab treatment.     

Cytomegalovirus colitis after administration of docetaxel-5-fluorouracil-cisplatin chemotherapy for locally advanced hypopharyngeal cancer.

We present the case of a patient with a locally advanced hypopharyngeal carcinoma who developed a severe cytomegalovirus (CMV) colitis after his first chemotherapy course with 5-fluorouracil (5-FU), docetaxel and cisplatin. The most probable cause of his CMV colitis is the impaired immunity during a phase of neutropenia after the chemotherapy. Although there was amelioration of the colitis and clinical status after treatment with ganciclovir, the patient later deteriorated and died due to recurrent bacterial infections. This is the third reported case of CMV colitis treated with ganciclovir in a patient with a solid tumour. It is the first report of CMV colitis after docetaxel containing chemotherapy.Although CMV colitis is most frequently observed in immunosuppressed patients such as those with acquired immune deficiency syndrome (AIDS), transplants and corticosteroid treatment, it has also been reported in less immunosuppressed (elderly, malnourished, ...) and even non-immunosuppressed patients. CMV infection should therefore be included in the differential diagnosis of GI disease in all patients, and when suspected, the clinician should pursue appropriate diagnostic and therapeutic interventions.     

A randomized trial of open lung biopsy versus empiric antimicrobial therapy in cancer patients with diffuse pulmonary infiltrates

Twenty-four cancer patients with diffuse interstitial pneumonitis (DIP) were randomized to undergo an open lung biopsy (OLB) within 8 hours of presentation (12 patients) or to receive empiric antimicrobial therapy (ET) with trimethoprim-sulfamethoxazole (TMP-SMX) erythromycin for a minimum of 4 days (12 patients). Patients whose condition deteriorated underwent an OLB on day 4. Eight of 12 patients (67%) having OLB survived versus 10 of 12 (83%) receiving ET (P = .64). Morbidity occurred in nine of 12 (75%) having OLB versus eight of 12 (67%) receiving ET (P = 1.0). Concurrently, there were 14 additional cancer patients with DIP who were not randomized (nine refused, three had a coagulopathy contraindicating surgery, two were excluded by primary care physicians) and who were comparable demographically to the randomized group. Two received OLB and 12 ET. Combining the randomized and nonrandomized groups, eight of 14 (57%) having an initial OLB survived versus 18 of 24 (75%) of ET-treated patients (P2 = .19). Results of the OLB were seven Pneumocystis carinii pneumonia (PCP), five nonspecific pneumonitis (NSP), one cytomegalovirus, and one lymphoma. Results of OLB led to discontinuation of antibiotics in three patients. Of the 24 ET patients, eight failed to improve by day 4 and had an OLB. Results were two NSP, two PCP, two cancer, one blastomycosis, and one Candida pneumonia. Complications were seen in 10 of 14 (72%) initial OLB patients versus 14 of 24 (58%) patients on the ET arm (P = .65). When the complication rate between patients receiving only empiric antibiotics was compared with all patients having an OLB (initially or on day 4), the difference was greater in patients undergoing OLB (37% v 72%, respectively) (P2 = .14). ET with TMP-SMX plus erythromycin and broad spectrum antibiotics in granulocytopenic patients appeared to be as successful and potentially less toxic than an OLB in this study. Although the number of patients in this study was small, these data suggest that a trial of empiric antibiotic management may be reasonable in cancer patients presenting with DIP, especially if they are nonneutropenic.     

Effect of previous and concomitant lung pathology on the postoperative complications in patients with lung cancer

The Institute's data on postoperative complication development in 247 lung cancer patients with previous or concomitant lung pathology and 206 patients suffering from lung cancer alone were compared for the period of 1975-1984. It was found that after radical surgery pulmonary complications and lethality were much more frequent in lung cancer patients with concomitant lung disease and/or pulmonary pathology in case history (17 and 9.3%) than in patients free from such pathology (8.7 and 3.7%). To illustrate, postoperative pneumonia, bronchial fistula and pleural empyema and acute pulmonary failure were observed in 11.3, 4.9 and 2.4% of cases of concurrent lung pathology, respectively, to match respective 5.3, 2.4 and 0% in the other study group, with pneumonia being the most frequent complication, particularly, after partial resection (13.6%).