Human herpesviruses (HHVs) remain latent after primary infection and can be reactivated in response to immunosuppression and chemotherapy. Little is known about their incidence, potential relationships, risk factors and clinical impact in non-transplant leukemia patients. This study investigated prospectively incidence, risk factors, clinical impact and possible association of HHVs-(1–7) infections in patients with newly diagnosed acute leukemia. Study design involved longitudinal sampling before chemotherapy and in different phases of chemotherapy: post-induction, post-remission, and post-salvage during 2016–2018. A total of 734 plasma samples from 95 patients were analyzed by a qualitative, multiplex PCR for HHVs detection and a quantitative real-time PCR was used for cytomegalovirus (CMV) quantification. HHVs-(1–6) IgG and IgM antibodies were tested using immunoassays. Risk factors were analyzed by binary logistic regression and relationships between viruses were analyzed using the Chi-square or Fisher’s exact test as appropriate. The overall seroprevalences of HHV-(1–6) IgG were high (> 80%). At least one herpes viral agent was detected in 60 patients (63.3%). CMV was the most commonly detected virus in the different phases of chemotherapy (19.4%), followed by HHV-6 (9.7%), HHV-7 (5.2%) and EBV (2.7%). HSV-1/2 and VZV DNA were not detected. Twenty-seven patients (28.4%) had more than one virus detected in the follow-up, with 23 who were co-infected. CMV/HHV-6 was the most frequent co-infection (69.5%, 16/23). HHV-6 infection (p = 0.008) was identified as a risk factor for CMV infection while salvage treatment (p = 0.04) and CMV infection (p = 0.007) were found to be independent risk factors for HHV-6 infection. CMV co-infection was associated with severe lymphopenia with an absolute lymphocyte count (ALC) (< 500/μL) (p = 0.009), rash (p = 0.011), pneumonia (p = 0.016) and opportunistic infections [bacteremia, p < 0.001 and invasive fungal infection, (p = 0.024)] more frequently than CMV mono-viral infections. Our data suggest that co-infection with HHVs, especially CMV and HHV-6, may contribute to the development of serious clinical manifestations with profound lymphopenia, pneumonia rash and increased risk for bacterial and fungal co-infections. These findings may suggest the synergistic effect of HHVs associated infection.

中文翻译：

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人疱疹病毒（CMV，HHV-6，HHV-7和EBV）在接受化疗的非移植急性白血病患者中的合并感染。

人疱疹病毒（HHV）在初次感染后仍保持潜伏状态，可以响应免疫抑制和化学反应而重新激活。关于它们在非移植性白血病患者中的发生率，潜在关系，危险因素和临床影响知之甚少。这项研究调查了新诊断为急性白血病的患者的前瞻性发病率，危险因素，临床影响以及HHVs-（1-7）感染的可能关联。研究设计涉及在化疗之前以及在化疗的不同阶段进行的纵向采样：2016-2018年期间的诱导后，缓解后和挽救后。通过定性，多重PCR进行HHV检测，对来自95例患者的总共734个血浆样本进行了分析，并使用实时定量PCR进行了巨细胞病毒（CMV）定量。使用免疫测定法检测了HHVs-（1-6）IgG和IgM抗体。通过二进制逻辑回归分析风险因素，并根据需要使用卡方检验或费舍尔精确检验分析病毒之间的关系。HHV-（1-6）IgG的总体血清阳性率很高（> 80％）。在60例患者中检测到至少一种疱疹病毒制剂（63.3％）。在化学疗法的不同阶段，CMV是最常见的病毒（19.4％），其次是HHV-6（9.7％），HHV-7（5.2％）和EBV（2.7％）。未检测到HSV-1 / 2和VZV DNA。在随访中，有27名患者（28.4％）检测出一种以上的病毒，其中23例是同时感染的。CMV / HHV-6是最常见的合并感染（69.5％，16/23）。在挽救治疗时，将HHV-6感染（p = 0.008）确定为CMV感染的危险因素（p = 0。04）和CMV感染（p = 0.007）被发现是HHV-6感染的独立危险因素。CMV合并感染与严重淋巴细胞减少症相关，绝对淋巴细胞计数（ALC）（<500 /μL）（p = 0.009），皮疹（p = 0.011），肺炎（p = 0.016）和机会性感染[菌血症，p < 0.001和侵袭性真菌感染（p = 0.024）]比CMV单病毒感染更常见。我们的数据表明，与HHV尤其是CMV和HHV-6共同感染可能导致严重的临床表现的发展，包括严重的淋巴细胞减少，肺炎皮疹以及细菌和真菌共同感染的风险增加。这些发现可能提示HHV相关感染的协同作用。CMV合并感染与严重淋巴细胞减少相关，绝对淋巴细胞计数（ALC）（<500 /μL）（p = 0.009），皮疹（p = 0.011），肺炎（p = 0.016）和机会感染[菌血症，p < 0.001和侵袭性真菌感染（p = 0.024）]比CMV单病毒感染更常见。我们的数据表明，与HHV尤其是CMV和HHV-6共同感染可能导致严重的临床表现的发展，包括严重的淋巴细胞减少，肺炎皮疹以及细菌和真菌共同感染的风险增加。这些发现可能提示HHV相关感染的协同作用。CMV合并感染与严重淋巴细胞减少症相关，绝对淋巴细胞计数（ALC）（<500 /μL）（p = 0.009），皮疹（p = 0.011），肺炎（p = 0.016）和机会性感染[菌血症，p < 0.001和侵袭性真菌感染（p = 0.024）]比CMV单病毒感染更常见。我们的数据表明，与HHV尤其是CMV和HHV-6共同感染可能导致严重的临床表现的发展，包括严重的淋巴细胞减少，肺炎皮疹以及细菌和真菌共同感染的风险增加。这些发现可能提示HHV相关感染的协同作用。024）]比CMV单病毒感染更常见。我们的数据表明，与HHV尤其是CMV和HHV-6共同感染可能导致严重的临床表现的发展，包括严重的淋巴细胞减少，肺炎皮疹以及细菌和真菌共同感染的风险增加。这些发现可能提示HHV相关感染的协同作用。024）]比CMV单病毒感染更常见。我们的数据表明，与HHV尤其是CMV和HHV-6共同感染可能导致严重的临床表现的发展，包括严重的淋巴细胞减少，肺炎皮疹以及细菌和真菌共同感染的风险增加。这些发现可能提示HHV相关感染的协同作用。