key: cord-0948962-w0syxe9u authors: Naimi, Adel; Yashmi, Ilya; Jebeleh, Reza; Imani Mofrad, Mohammad; Azimian Abhar, Shakiba; Jannesar, Yasaman; Heidary, Mohsen; Pakzad, Reza title: Comorbidities and mortality rate in COVID‐19 patients with hematological malignancies: A systematic review and meta‐analysis date: 2022-04-06 journal: J Clin Lab Anal DOI: 10.1002/jcla.24387 sha: 29e09b5d205f3c17d75109e301c70ee01c648d8c doc_id: 948962 cord_uid: w0syxe9u INTRODUCTION: The global pandemic of coronavirus disease 2019 (COVID‐19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). It seems that there is an association between blood cancer and an increased risk of severe COVID‐19. This study aimed to review the literature reporting the COVID‐19 outcomes in patients with hematological malignancies. MATERIAL AND METHODS: In this systematic review and meta‐analysis, Pubmed, Embase, and Web of Science databases were searched using the following keywords: COVID‐19, SARS‐CoV‐2, blood cancer, myeloma, lymphoma, and leukemia. All the published articles in English from January 1, 2019, until March 10, 2021 were collected and evaluated. RESULTS: In total, 53 studies with 2395 patients were included based on inclusion criteria. Most of these studies took place in Spain (14.81%), followed by the USA (11.11%), China (9.26%), and the UK (9.26%). More than half of COVID‐19 patients with hematological malignancy were male (56.73%). Oxygen therapy played an important role in COVID‐19 treatment. Moreover, anticoagulant therapies such as enoxaparin and heparin were two great assists for these patients. Fever (74.24%), cough (67.64%), and fatigue (53.19%) were the most reported clinical manifestations. In addition, hypertension and dyslipidemia were the most common comorbidities. The mortality rate due to COVID‐19 in patients with hematological malignancies was 21.34%. CONCLUSION: This study demonstrated that hematologic cancer patients were more susceptible to a severe COVID‐19 than patients without blood cancer. Thus, the management of COVID‐19 in these patients requires much more attention, and their screening should perform regularly. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the current global pandemic of coronavirus disease 2019 . Although most patients with COVID-19 have mild symptoms, some have more severe manifestations. 1 Recent findings have suggested an association between cancer and an increased risk of developing severe symptoms of COVID-19. [2] [3] [4] Dai et al. reported that about 39% of the COVID-19 patients with cancer had severe events such as intensive care unit admission, the need for mechanical ventilation, and even death. They showed that only 8% of the COVID-19 patients without cancer had those severe symptoms. 5 In addition, hematologic cancer patients with COVID-19 had a high frequency of severe events like a higher mortality rate and a more severe COVID-19 course. 6 The immune system dysfunction is one of the main reasons that confirm patients with hematological malignancies are more vulnerable. 7 Moreover, anti-cancer therapies such as chemotherapy, radiotherapy, and immunosuppressive drugs worsen the condition of these patients. 8 There are a limited number of studies on the prevalence of comorbidities and mortality rate in COVID-19 patients with hematological malignancies. Therefore, in this systematic review and meta-analysis, we will comprehensively review the available published literatures reporting the COVID-19 outcomes and underlying diseases in patients with hematological malignancies from around the world. This study was performed following the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses" (PRISMA) statements. 9 The Pubmed/Medline, Embase, and Web of Science databases, from January 1, 2019, until March 10, 2021, were searched to collect the potentially relevant articles reporting COVID-19 disease in patients with hematological malignancies. The search was limited solely to publications in English. The following keywords or Medical Subject Headings (MESH) terms were used in text, title, or abstract with the help of Boolean operators ("and," "or"): "COVID-19," "severe acute respiratory syndrome coronavirus 2," "SARS-CoV-2," "nCoV disease," "2019-nCoV," "coronavirus disease 2019," "bone marrow cancer," "blood cancer," "myeloma," "lymphoma," "Waldenstrom macroglobulinemia," "leukemia," "hematological malignancy," "myelodysplastic syndrome," and "myeloproliferative disorder." All the articles reporting COVID-19 positive patients with at least one type of hematological malignancies were included. In other words, patients with blood cancer infected with the SARS-CoV-2 were enrolled in the study. The allogeneic stem cell transplantation patients were included as well. According to World Health Organization (WHO) guidelines, COVID-19 cases are defined as patients whose reverse transcription-polymerase chain reaction (RT-PCR) is positive. Duplicate publications, narrative reviews, meta-analyses, systematic reviews, editorials, correspondences, guidelines, articles published in languages other than English, and publications without enough data or available only in abstract form were also excluded. The included studies were screened in two stages for eligibility. First, title/abstract screening was done, and then, the full text of those that had the inclusion criteria was retrieved. It is worth noting that although we reviewed case-report articles to evaluate some variables, only research articles and case series were included for meta-analysis. The extracted data included the first author's name, country of the study, published time, type of study, number of patients, median age, gender, hematological malignancy type, blood cancer therapy, the median duration of blood cancer, COVID-19 diagnosis method, COVID-19 therapy, clinical manifestations, laboratory findings, comorbidities, and outcome. Two authors independently applied the inclusion criteria to the potentially relevant article, and discrepancies between the authors were resolved by consensus discussion. The quality assessment of the studies was carried out through the critical appraisal checklist provided by the Joanna Briggs Institute (JBI). 10 Data were analyzed using STATA software, version 17.0. The fixedeffects model and random-effects model were used to compute pooled estimates of the relative risk. The heterogeneity was quantified by the Cochran Q statistic and I 2 statistical methods. The pvalue <.05 was considered statistically significant. 11 Initially, a total of 1169 articles were collected from databases. After removing the duplicates, 704 studies remained. In the screening phase, 548 of them were excluded through the title and abstract evaluation. Out of these studies, 53 met the inclusion pellucid criteria based on the full-text screening. At the final stage, 15 eligible articles were included in the meta-analysis ( Figure 1 ). Characteristics of the selected articles are summarized in Table 1 . Most of the studies took place in Spain (8/53, 14.81%), followed by the United States (6/53, 11.11%), China (5/53, 9.26%) , and the United Kingdom (5/53, 9.26%). The demographic information, clinical features, and laboratory find- The treatment options for COVID-19 patients with hematological malignancies are summarized in Tables 2 and 3 . Hydroxychloroquine (69.3%), oxygen therapy (65.3%), and anticoagulant therapies (64.0%) such as enoxaparin and heparin were the most administrated treatments options for COVID-19. On the contrary, proteasome inhibitors (30.71%) and chemotherapy (23.46%) were the most used therapeutics to cure different types of blood cancer among patients with hematological malignancies. with COVID-19 and hematological malignancy were survived during hospitalization. In addition, Figure 3 shows the prevalence of comor- CoV-2 infection. The most prevalent comorbidity was hypertension (44.61%; 95% CI: 39.94 to 49.28), and the less one was liver disease (1.96%; 95% CI: 0.05 to 3.88). The prevalence of other comorbidities is shown also in Figure 2 . We were interested in assessing the effect of age on the death rate in patients with COVID-19 and malignancy ( Figure 4) . The meta-regression demonstrated no significant association between death rate with age (p = 0.513). The results of the critical appraisal (JBI checklist) of included studies are summarized in Table S1 . Overall, 53 articles were identified as having a low risk of bias (quality assessment score > 7). Since the onset of the COVID-19 outbreak, several studies have reported the effects of COVID-19 on cancer patients. In this regard, there is growing evidence that patients with a history of cancer have a higher rate of COVID-19 mortality than individuals without cancer. In addition, it has been reported that patients with hematological cancers had the highest frequency of major adverse events. 5, 12 Yeo et al. indicated that the cancer was associated with a 2.84fold increased risk of severe illness in COVID-19 patients and a 2.60fold increased risk of death. 13 The prevalence of cancer in COVID-19 patients is very low. In a recent study, the pooled prevalence of cancer in COVID-19 patients was 2%. 14, 15 Also, the results of the same studies from China and the United States of America reported that about 1-2% and 6% of COVID-19 patients had cancer, respectively. 14,16 The prevalence of hematological malignancies among COVID-19 patients has not yet been well studied. In a related study conducted In the other study conducted by Mehta et al. 18 in New York, the mortality rate in lymphoid neoplasms was higher than the myeloid malignancies (35% vs. 43%). Our results estimated that the mortality rate in COVID-19 patients with hematological malignancies was 21.34%. This discrepancy observed in the results of these studies can be due to different sizes of studies. Therefore, the results of studies conducted in all areas highlight the urgent need to pay special attention to patients with hematologic malignancy infected with COVID-19. The progression of blood malignancies is usually accompanied by a weakening of the immune system, which is initiated by the disease and continues through the strategy of anti-tumor therapies such as chemotherapy and radiation therapy Therefore, the suppressed immune system may lead to a greater vulnerability of cancer patients to COVID-19. A previous study showed that anti-tumor therapy increased the risk of dangerous symptoms within 14 days of the diagnosis of COVID-19 and recommended that cancer patients with COVID-19 avoid treatments that suppress the immune system. 19 On the hand, cytotoxic chemotherapies cause neutropenia and lymphocytopenia that aggravate the immunosuppressive status. This status leads to high infection rates and poor prognosis. [20] [21] [22] There is currently no advice on the effectiveness of conventional and targeted treatment strategies in these patients. 23 Hence, the risk-benefit ratio of these treatment strategies remains a challenge. In this regard, it has been demonstrated that radiation therapy has no higher risk of severe events related to the COVID-19 for these patients. 5 For example, Krengli et al. 24 Therefore, the existence of publication bias should be considered. Third, this study included patients whose RT-PCR tests were positive for SARS-CoV-2. However, it is confirmed that false-negative and false-positive RT-PCR may occur due to low amounts of SARS-CoV-2 concentrations and cross-reaction with something that's not SARS-CoV-2, respectively. Forth, heterogeneity in the study population selection and the retrospective characteristics was observed in the studies. Although the random-effects model was assumed to reflect the similarity, there may still be differences of opinion. Fifth, all included studies have reported hospitalized patients. Due to these cases usually having a severe or moderate stage of disease, mild cases may be missed. In this study, we reviewed the literatures reporting the COVID-19 outcomes in patients with hematological malignancies. Our study reveals that about one-quarter of patients with COVID-19 and hematological malignancy have died during hospitalization. One of the most important reasons that confirm these patients are more vulnerable is their immune system dysfunction. Furthermore, anticancer therapies may worsen their conditions. Therefore, the management of COVID-19 in patients with hematological malignancies requires much more attention. The authors declare that they have no competing interests. Adel Naimi, Ilya Yashmi, Reza Jebeleh, Mohammad Imani Mofrad, Shakiba Azimian Abhar, Yasaman Jannesar, and Mohsen Heidary contributed in revising and final approval of the version to be published. All authors agreed and confirmed the study for publication. The authors confirm that the data supporting the results of this study is available within the article. 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