COVID-19 in Patients with Cancer: Insights from a Tertiary Care Intensive Care Unit Nissar Shaikh Hamad Medical Corporation Mohammad Al Wraidat Hamad Medical Corporation Anood A. Al-Assaf Hamad Medical Corporation Salma K. Al-Kaabi Ministry of Public Health Ahmad A. Abujaber Hazm Mebaireek General Hospital, Hamad Medical Corporation Samar Jasim Hamad Medical Corporation Salha Bujassoum Hamad Medical Corporation Muna A. Almaslamani Hamad Medical Corporation Mohamad Y. Khatib Hamad Medical Corporation Mohamed A. Yassin Hamad Medical Corporation Abdulqadir J. Nashwan (  anashwan@hamad.qa ) Hazm Mebaireek General Hospital, Hamad Medical Corporation Research Article Keywords: Acute kidney injury, cancer, COVID-19, invasive and noninvasive ventilation, ICU, secondary infections, shock Posted Date: April 17th, 2023 DOI: https://doi.org/10.21203/rs.3.rs-2779474/v1 License:   This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/16 Additional Declarations: No competing interests reported. Page 2/16 Abstract Background & Aim: Since The emergence of the COVID-19, patients with cancer have been among the most vulnerable patients, as this infection can be severe and mostly requires intensive care therapy. Literature discussing the risk factors and the outcome of these patients in intensive care units (ICU) is accumulating. Our study aims to search for the incidence of COVID-19 infection in cancer patients and analyses their associated comorbidities, possible risk factor for infections, and their outcomes. Methods: Patients with active cancer under treatment and those recently diagnosed with cancer and had confirmed COVID-19 infection requiring ICU admission were included in our study over 8 months, from March to October 2022. Patient demographic data, comorbidities, ICU stay, duration of hospital stay, oxygenation/ventilatory requirements, treatment, secondary bacterial infection, and outcome were collected from the COVID-19 patients' registry in the ICU. Data were entered into the SPSS program version 23, and results were considered statistically significant at p ≤ 0.05. Results: A total of 24 patients with cancer and COVID-19 infection required intensive care therapy. The most common type of malignancy in those patients was solid organ tumor (13 vs. 11 patients), and most of the study sample were males (20/ 83.3%). Seventy-five percent (18 patients) required intubation and invasive ventilation. Twenty-nine percent (7 patients) had secondary bacterial pneumonia and bacteremia. In addition, 70% had septic shock and required vasopressors. Acute kidney injury (AKI) due to rhabdomyolysis (P<0.001), secondary bacterial infection (P<0.006), bacteremia and pneumonia (P<0.02), invasive ventilation (P<0.02) and requiring muscle relaxant (P<0.02), the requirement for High flow nasal cannula and prone position (P<0.03 and 0.01) respectively, shock (P<0.004) were significantly associated with increased mortality. Patients with cancer and COVID-19 had higher severity scores (P<0.003), longer ventilation duration (P<0.002), and ICU stay (P<0.002). Overall mortality was 45%.8, there was no significant difference in mortality rate between patients with solid organ tumors and hematological malignancy with COVID-19 infection requiring intensive care therapy (P<0.68). Conclusion: Cancer patients requiring ICU were more prone to develop AKI, rhabdomyolysis, secondary infection, requiring ventilation and prone position, and septic shock. These patients had a significantly high mortality rate and were severely ill, requiring prolonged ventilation and ICU stays. Background COVID-19 has emerged as a serious worldwide infection with a high fatality rate. It originated in China and quickly spread to the world, leading to more than 5 million deaths by 2021. Cancer patients are more susceptible to COVID-19 infection and its complication than the general population due to their immunosuppressed status and associated comorbid conditions. Up to date there are few original studies and metanalyses about cancer patients with COVID-19 infections from the western part of the world. These studies were inconsistent in their conclusions. More extensive studies have concluded that cancer patients have a higher risk of COVID-19 infection with worse outcomes [1]. Subsequent studies disagreed Page 3/16 with the former and mentioned that cancer diagnosis and treatment were not associated with any worse results [2]. More recent studies stated that the outcome of COVID-19 infection in cancer patients is determined by the patients’ pre-existing condition, not the specific type of malignancy [3]. Moreover, these studies have investigated patients with mild and moderate cases admitted to hospital medical wards, not high acuity patients in intensive care units. Up to date, Medical literature from the Middle East region regarding cancer patients with COVID-19 infection is lacking, especially data about patients in critical care units and their outcomes. Patients And Methods All the patients in this study were admitted to the intensive care unit of Hazm Mebaireek Hospital (The main COVID-19 designated facility in Qatar), Hamad Medical Corporation in Qatar with severe COVID-19 infection. Data was collected from the ICU patients’ registry. This is a secondary analysis of a previously approved study (MRC:01-20-607) by the medical research center at Hamad Medical Corporation (Doha, Qatar) [15]. A total of 1660 patients with severe COVID-19 infection were admitted to ICU (Intensive care unit) between March and October 2020. Of these 1660 patients, 24 had a history of cancer (on treatment or newly diagnosed). The records for these 24 patients with a background of cancer and COVID-19 infection admitted to the ICU were reviewed. Data about the demographic parameters, type of cancer, stage of cancer, associated diseases and underlying comorbidities, type of cancer treatment, the severity of COVID-19 disease, SOFA (Sequential organ failure assessment) score, length of intensive care unit stay(ICU stay), hospital length of stay, and patients’ outcome were collected from the hospital ICU COVID19 patients’ registry. Data was entered and analyzed using SPSS version 23. Categorical variables were reported using numbers (n) and percentages (%). Continuous variables are reported as mean ± SD, and categorical variables are represented as frequency and percentage. Due to the small sample size, we opted to conduct a univariate non-parametric analysis to measure the correlation between the variables and the patients' mortality, namely Chi2 and Man Whitney (U) test. Differences were considered statistically significant at p ≤ 0.05. Results During the study, 24 cancer patients were admitted to the intensive care unit with COVID-19 infection and related complications. Most patients had solid organ tumors (13/ 54.16%,) with lung cancer being the most common cancer in this group. The remainder of the patients had hematological malignancies (11/ 45.84%), and chronic lymphocytic leukemia was the most common type among these patients. Most of these cancer patients received treatment with chemotherapy (Table 1). Page 4/16 Table 1 Type and treatment of carcinoma and out come Type of Carcinoma (Ca) Ca treatment Outcome Type of tumor {n (%)} Ca Colon Surgery and Chemotherapy Therapy Survived Solid organ tumors Ca Colon Surgery, Radiotherapy, and Chemotherapy Therapy Survived 13(54.16) Renal cell Ca None Survived Brain Tumor Surgery Survived Hepatocellular Ca Chemotherapy Survived Hepatocellular Ca Palliative care Died Lung Ca Surgery + Chemotherapy Died Lung Ca Chemotherapy + radiotherapy and Immunotherapy Died Lung Ca Chemotherapy Survived Ca Breast Surgery, Radiotherapy, and Chemotherapy Therapy Survived Ca esophagus Chemotherapy Died Ca Stomach None Survived Ca Prostate Chemotherapy Died Multiple myeloma Chemotherapy Died Acute promyelocytic leukemia None Died Acute promyelocytic leukemia None Survived Chronic myelocytic leukemia Chemotherapy Survived Chronic myelocytic leukemia Chemotherapy Died Chronic myelocytic leukemia Chemotherapy Survived Chronic Lymphocytic Leukemia Chemotherapy Died Chronic Lymphocytic Leukemia Chemotherapy Survived Chronic Lymphocytic None Survived Page 5/16 Hematological Malignancies 11(45.84) Leukemia Chronic Lymphocytic Leukemia Chemotherapy Died T-cell lymphoma Chemo and Hormonal therapy Died Overall, most patients were male (20) (83.3%) and expatriate people (22/91.7%. The mean age was 53.92 years, and the most common comorbidity was hypertension (12/ 56%) (Table 2). Page 6/16 Table 2 Demographic and clinical variables Variable Gender Nationality Diabetes Mellitus Hypertension Coronary artery disease Chronic Kidney disease Chronic obstructive pulmonary disease Chronic liver disease Acute kidney injury Rhabdomyolysis Secondary infections Source of secondary infections *MDRO infection Number(n) Percentage (%) Male 20 83.3 Female 4 16.7 Qataris 2 8.3 Non-Qataris 22 91.7 No 13 54.2 Yes 11 45.8 No 12 50 Yes 12 50 No 20 83.3 Yes 4 16.7 No 23 95.8 Yes 1 4.2 No 23 95.8 Yes 1 4.2 No 22 91.7 Yes 2 8.9 No 14 58.3 Yes 10 41.7 No 17 70.8 Yes 7 29.2 No 9 37.5 Yes 15 62.5 No 9 37.5 Blood 7 29.2 Lung 7 29.2 Urine 1 4.2 No 16 66.7 Page 7/16 Variable Intubation Muscle relaxant Non-invasive ventilation High-flow nasal cannula Proning *ECMO Methylprednisolone Tocilizumab Vasopressor Convalescent plasma ICU Mortality Number(n) Percentage (%) Yes 8 33.3 No 6 25 Yes 18 75 No 8 33.3 Yes 16 66.7 No 17 70.8 Yes 7 29.2 No 20 83.3 Yes 4 16.7 No 11 45.8 Yes 13 54.2 No 23 95.8 Yes 1 4.2 No 7 29.2 Yes 17 70.8 No 15 62.5 Yes 19 37.5 No 7 29.2 Yes 17 70.8 No 18 75 Yes 6 25 No 13 54.2 Yes 11 45.8 Following COVID-19 infection, acute kidney injury occurred in 10 patients (41%) and rhabdomyolysis in 7 patients (29.2%). Secondary infections complicated the course of 15 patients (62.5%), and the most frequent sources of secondary infection were lung and blood (29.2%) each (Table 2). Seventeen patients (70.8%) developed sepsis and required vasopressors to support their hemodynamic status. Six patients (25%) required convalescent plasma therapy for primary COVID-19 virus infection. Page 8/16 Respiratory-wise, seven patients (29.2%) required non-invasive ventilatory support, four patients (16.7%) were managed with high flow nasal cannula (HFNC), eighteen patients (75%) required intubation and invasive ventilation, and 16 patients (66.7%) required muscle relaxants to facilitate their ventilation. Thirteen patients (54.2%) required prone ventilation to improve their oxygenation (Table 2), and one patient (4.2%) required ECMO support (Extra-corporal membrane oxygenation). Laboratory results revealed elevated D-dimer, fibrinogen, and CPR for all patients [6.59, 5.21, 171, respectively]. The initial SOFA score was around 4 (3.92), and the worst SORA score was 11.83. The average number of days on mechanical ventilation was 15.83 +- 16.34, the mean ICU stay was 18.88 +-16.12 days, and the mean hospital stay was 31.33 +- 16.51 days (Table 3). Table 3 Descriptive Statistics: Age, inflammatory markers, the severity of the illness, and length of stay Variables Mean Std. Deviation Age(years) 53.92 18.717 D-Dimer (mcg/mL) 6.59 23.560 Fibrinogen (Grams/L) 5.21 2.132 CRP (mg/L) 171.15 108.040 Mechanical Ventilation days 15.83 16.343 Ventilator free days 7.14 4.979 Worst SOFA During ICU STAY 11.83 5.585 SOFA SCORE Admission 3.92 2.948 TOTAL HOSPITAL DAYS 31.33 16.518 TOTAL ICU DAYS 18.88 16.128 The Table 4 shows the variables' impact on the patients' mortality rate (outcome). The AKI (acute kidney injury) was significantly associated with higher mortality in COVID-19 cancer patients (P < 0.001). Other variables that have detrimentally affected the mortality rate in these patients were rhabdomyolysis (P < 0.04), the presence of secondary infections (P < 0.006), and sepsis (P < 0.02) (Table 4). Patients requiring intubation, invasive ventilation, and muscle relaxants had a significantly higher death rate (P < 0.02). Moreover, the mortality rates were higher in patients with shock requiring vasopressor (P < 0.004), prone position (P < 0.01), and high-flow nasal cannula (P < 0.03) (Table 4). Page 9/16 Table 4 Clinical and demographic variables and outcome Variable Gender Nationality Diabetes Mellitus Hypertension Coronary artery disease Chronic Kidney disease Chronic obstructive pulmonary disease Chronic liver disease Acute kidney injury Rhabdomyolysis Secondary infections Source of secondary infections Mortality P Value No {n (%)} Yes {n (%)} Male 11(84.6%) 9(81.8) Female 2(15.4) 2(18.2) Qataris 1(7.7) 1(9.1) Non-Qataris 12(92.3) 10(90.9) No 8(61.5) 5(45.5) Yes 5(38.5) 6(54.5) No 8(61.5) 4(36.4) Yes 5(38.5) 7(63.6) No 12(92.3) 8(72.7) Yes 1(7.7) 3(27.3) No 12(92.3) 11(100) Yes 1(7.7) 0(0) No 12(92.3) 11(100) Yes 1(7.7) 0(0) No 12(92.3) 10(90.9) Yes 1(7.7) 1(9.1) No 12(92.3) 2(18.2) Yes 1(7.7) 9(81.8) No 12(92.3) 5(45.5) Yes 1(7.7) 6(54.5) No 8(61.5) 1(9.1) Yes 5(38.5) 10(90.9) No 8(61.5) 1(9.1) Blood 2(15.4) 5(45.5) Lung 3(23.1) 4(36.4) Urine 0(0) 1(9.1) Page 10/16 0.63 0.71 0.35 0.20 0.23 0.54 0.36 0.71 < 0.001 0.01 0.006 0.02 *MDRO infection No 10(76.9) 6(54.5) Yes 3(23.1) 5(45.5) No 6(46.2) 0(0) Yes 7(53.8) 11(100) No 7(53.8) 1(9.1) Yes 6(46.2) 10(90.9) No 5(38.5) 2(18.2) Yes 8(61.5) 9(91.8) No 13(100) 7(63.6) Yes 0(0) 4(36.4) No 9(69.2) 2(18.2) Yes 4(30.8) 9(81.3) No 7(53.8) 0(0) Yes 6(46.2) 119100) No 11(84.6) 7(63.6) Yes 2(15.4) 4(36.4) No 8(61.5) 7(63.6) Yes 5(38.5) 4(36.4) Hematological malignancies No 5(38.5) 6(54.5) Solid organ malignancies Yes 8(61.5) 5(45.5) Intubation Paralysis Methylprednisolone High-flow nasal cannula Prone position Vasopressor Convalescent plasma Tocilizumab 0.26 0.018 0.02 0.26 0.03 0.01 0.004 0.23 0.62 0.68 The overall number of fatalities in our group of patients was 11 (45.84%). Five of these patients (20.84%) had a solid organ tumor, whereas 6 patients (25%) had a hematological malignancy (Tables 1 and 2). Table 5 shows the variables and their association with patients’ outcomes (mortality rate). Age was more advanced in patients who died; however, it was not statistically significant (P0.08). The SOFA score on admission (sequential organ failure assessment), CRP, d-dimer, and fibrinogen levels were not statistically significant in association with higher patients’ mortality rates (Table 5). The main correlations were found to be associated to the total ICU days, mechanical ventilation days, and SOFA scores during ICU stay as they were significantly higher in patients who died (P 0.002, 0.002, 0.003, respectively) (Table 5). Page 11/16 Table 5 Age, inflammatory markers, disease severity, hospital stay, and patients' outcomes Variable Mortality Number Mean Rank Sum of Ranks P value Age (years) No 13 10.15 132.00 0.08 Yes 11 15.27 168.00 No 13 12.27 159.50 Yes 11 12.77 140.50 No 13 8.62 112.00 Yes 11 17.09 188.00 No 13 11.65 151.50 Yes 11 13.50 148.50 No 13 11.00 143.00 Yes 11 14.27 157.00 No 13 11.65 151.50 Yes 11 13.50 148.50 No 13 12.54 163.00 Yes 11 12.45 137.00 No 7 4.64 32.50 Yes 11 12.59 138.50 No 13 12.42 161.50 Yes 9 10.17 91.50 No 13 8.50 110.50 Yes 11 17.23 189.50 Total hospital stays (days) Total ICU stay (days) SOFA Score admission D-Dimer Fibrinogen(g/L) CRP(Mg/L) Mechanical ventilation (days) Ventilator free days Worst SOFA 0.86 0.002 0.53 0.27 0.53 0.90 0 .002 0.42 0.003 Discussion Oncology patients are more susceptible to COVID-19 infection and its adverse sequelae than non-cancer patients. In those patients, COVID-19 caused by coronavirus 2 (SARS-COV2) leads to acute respiratory failure, a fatal complication that disproportionately affects vulnerable patients with underlying medical or surgical comorbidities [4]. In addition, cancer patients with COVID-19 infection can rapidly deteriorate and develop serious organ dysfunction requiring intensive care admission (ICU). Page 12/16 In this pandemic, ICU utilization may need triage and prioritization of patient's admission based on patient’s outcomes. There is scarce data about COVID-19 complications and the requirement for intensive care therapy in cancer patients, which will help in the appropriate triaging of intensive care therapy requirements. Cancer patients requiring intensive care therapy mortality was 45%, much lower than the mortality described by Nadkarni et al. in their metanalysis, which was 60%. Whereas another study dictates a mortality of 56% in their population [5]. Solid organ malignancies were common in our population. Joerger et al. also had most solid organ cancer patients requiring intensive care therapy [7]. In other studies, solid organ malignancies are common in the patient population [4]. In comparison to solid organ malignancies, it’s reported in the literature that hematological malignancies require more ICU admission and significantly higher mortality [8]. In our study, the hematological malignancy patients were slightly higher in number, but there was no statistical significance. Joerger M et al. also did not find a significant difference in the outcome of patients with both malignancies. However, their solid organ malignancies were more than those of hematological malignancies [7]. Most of the literature about cancer patients with comorbidities and COVID-19 infection mentioned hypertension as the most frequent comorbidity [9]. In our patient’s population also, hypertension was the most common comorbidity. In our patient population, hypertension was the most prevalent comorbidity in COVID-19 patients [10]. Secondary bacterial infections occurred in 62.6% of our cancer patients, including pneumonia and bacteremia. Maki et al. also reported that secondary bacterial infection in COVID-19 cancer patients increased with the severity of COVID-19, and with severe infection, 81% of patients had secondary bacterial infections [11]. De Costa et al. reported that 57.9% of these ICU COVID-19 patients had secondary bacterial ventilatory-associated pneumonia, and 49.5% had MDRO bacterial infections (multi-drug resistant organism. More cancer patients required oxygen supplementation, non-invasive and invasive ventilation, and proning, as they had severe COVID-19 infection. Comparing the age of the cancer patients with COVID-19 infection requiring intensive care admission, outpatients were younger, with an average of 53 years, the mean was higher, and the severity of the disease increased from admission to ICU. Moreover, the patient population's AKI (Acute Kidney Injury) is most probably due to rhabdomyolysis, secondary bacterial infection, bacteremia, pneumonia, a requirement of non-invasive and invasive ventilation, and requirement of vasopressor due to shock were significantly associated with mortality. It's well described in the literature the requirement of oxygen supplementation and ventilation, either noninvasive or invasive ventilation, increased the risk of death in COVID-19 cancer patients [13]. However, AKI and rhabdomyolysis are not described in the literature to increase mortality in COVID-19 cancer patients. Secondary bacterial infection and multi-drug resistant pneumonia in general COVID-19 patients were reported to increase mortality [12]. Still, our study confirms that COVID-19 cancer patients with secondary bacterial infection, bacteremia, pneumonia, and vasopressor requirement due to septic shock significantly increase the risk of death. Fortunately, MDRO (multi-drug resistance organism) infections in our cancer patients did not show any significant increase in mortality. Page 13/16 The age of our COVID-19 patients did not have a significant impact on the outcome, sepsis markers (CRP, D-dimer, fibrinogen) were also not significantly differ for mortality with cancer, but those cancer patients who died had significant progress of the disease (higher SOFA score), mechanical ventilation days and more prolonged ICU stay. Pathania et al. also described that the cancer patients requiring intensive care had more extended ICU stays, more ventilator days, and worst outcomes [13]. Biovana et al., in their study, concluded that CRP and D-dimer levels are useful for the severity of COVID-19 in general. Still, nothing was mentioned about its comparison impact on patient outcomes [14]. Conclusion In our patients, solid organ malignancies overnumbered hematological malignancies; mortality was lower than mentioned in the literature. Secondary infection, pneumonia, bacteremia, AKI, rhabdomyolysis, invasive, non-invasive ventilation, and shock were significant risk faction for mortality in COVID-19 cancer patients. The patient's age and sepsis markers were raised but not significantly associated with COVID-19 cancer patients' mortality. COVID-19 cancer patients with mortality were sicker and had longer ICU stay and ventilator days than the surviving patients. Declarations Statement of Ethics: This study has been approved by the IRB at the Medical Research Center in Hamad Medical Corporation (Doha, Qatar) (MRC:01-20-607). The study has been conducted in accordance with the ethical standards noted in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. IRB of Hamad Medical Corporation waived the need for informed consent due to retrospective nature of the study. Consent for publication Not applicable. Availability of data and material All generated data is included in this published article. Competing interests The authors declare that they have no competing interests. Funding Sources: None. Page 14/16 Author Contributions: All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. 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