Clinical characteristics and outcomes of COVID-19 infection in Chinese patients with hematologic malignancies in the Omicron era

ABSTRACT

Patients with hematologic malignancies are often immunodeficient and therefore have a higher risk of severe symptoms from coronavirus disease 2019 (COVID-19). We retrospectively examined a cohort of 289 patients from 16 hospitals in Zhejiang Province who had hematologic malignancies and COVID-19 during a period when the Omicron variant was predominant. Univariate analysis showed that some clinical characteristics, including elder age (P = 0.014), multiple comorbid conditions (P = 0.011), and receipt of active antineoplastic therapy (P = 0.018) were associated with an increased risk of severe COVID-19. Patients with severe/critical COVID-19 had significantly lower levels of lymphocytes and serum albumin, and significantly higher levels of D-dimer, lactate dehydrogenase, C-reactive protein, and interleukin-6 (all P < 0.05). Fifty-four patients (18.7%) had symptoms lasting ≥3 weeks, suggesting that persistent long-term COVID-19 infection is likely present in a significant proportion of patients. Receipt of the inactivated vaccine was unrelated to disease severity (P = 0.143), which indicated that many patients with hematologic malignancies may not have effective humoral immunity to inactivated vaccines.

KEYWORDS:

• COVID-19
• hematologic malignancy
• Chinese
• severe infection
• clinical characteristics
• outcome

To the Editor,

Patients who have hematological malignancies are more likely to be immunodeficient and therefore have a higher risk of developing more severe coronavirus disease 2019 (COVID-19). He et al. studied patients with hematologic malignancies during the initial COVID-19 outbreak in Wuhan and reported that the incidence of COVID-19 was 10% and the mortality rate was 62% [1]. Even after the emergence of the less virulent Omicron variant of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in November 2021 [2], immunocompromised patients still have high rates of hospitalization and death due to COVID-19.

The many patients who have hematologic malignancies and risk factors for severe COVID-19 deserve special attention. In particular, patients receiving treatment for hematologic malignancies who are also elderly, have chronic diseases and have other comorbidities or risk factors face an increased risk for severe COVID-19 [3,4]. However, to date, there is limited data regarding COVID-19 in patients with hematologic malignancies in China, especially during the epidemic of the Omicron virus strain.

In this context, we performed a retrospective multicenter study of a cohort of 289 patients from 16 hospitals in Zhejiang Province (East China) who had baseline non-Hodgkin lymphoma (NHL) or multiple myeloma (MM) and COVID-19. All observations were from December 2022 to February 2023, a period when Omicron was by far the most prevalent variant in China and worldwide [2,5]. The main epidemic strains were BA.5.2 (70.2%) and BF.7 (28.3%) according to the data from China Chinese Center for Disease Control and Prevention [5]. Our aim was to identify the potential risk factors for severe COVID-19 in Chinese populations with hematologic malignancies and to provide a clinical basis for improving the management of these patients.

We used a real-time reverse transcription polymerase chain reaction (RT–PCR) test or a rapid antigen test to confirm SARS-CoV-2 infection in all 289 patients who had hematological malignancies (Table 1). Due to the zero-covid policy in China, all of the patients in this study were infected for the first time. Their median age was 67 years (range 21–89), 73 patients (25.3%) received vaccination prior to COVID-19, and 70 patients (24.2%) were current or former smokers. The most common symptoms following confirmation of COVID-19 were cough (66.4%), fever (59.9%), fatigue (43.3%), and shortness of breath (32.9%). The most common COVID-19-directed therapies were glucocorticoids (n = 181, 62.6%) and nirmatrelvir/ritonavir (n = 63, 21.8%). Due to national regulatory issues regarding drug use, the therapeutic options in China were relatively limited during the observation period, as shown in Table S1 (Additional file 1: Table S1). Although there was no standard treatment for COVID-19 patients with hematologic malignancies, these conventional treatments appeared to be effective in this population.

Table 1. Univariate analysis of the association of severe/critical COVID-19 status with baseline characteristics.

	Total N = 289	Mild/moderate^# N = 213	Severe/critical^# N = 76	P value*	OR (95%CI)^†
Median age (range)—years	67(21–89)	66.5(21–82)	69(37–89)
Age—n (%)
≤75-years-old	264(91.3)	210(98.6)	54(71.1)
>75-years-old	25(8.7)	3(1.4)	22(28.9)	0.014	2.145 (1.158, 3.974)
Sex—n (%)
Female	178 (61.6)	76 (35.7)	35 (46.1)	0.110	1.539 (0.905, 2.617)
Male	111 (38.4)	137 (64.3)	41 (53.9)
Comorbidities—n (%)
Cardiac disease	101 (34.9)	69 (32.4)	32 (42.1)	0.127	1.518 (0.886, 2.600)
Pulmonary disease	48 (16.6)	31 (14.6)	17 (22.4)	0.116	1.692 (0.874, 3.274)
Renal disease	23 (8.0)	12 (5.6)	11 (14.5)	0.015	2.835 (1.194, 6.730)
Hypertension	10 (3.5)	6 (2.8)	4 (5.3)	0.316	1.917 (0.526, 6.986)
Diabetes	30 (10.4)	20 (9.4)	10 (13.2)	0.355	1.462 (0.651, 3.283)
Other cancer	44 (15.2)	35 (16.4)	9 (11.8)	0.339	0.683 (0.312, 1.497)
HBV infection	23 (8.0)	16 (7.5)	7 (9.2)	0.639	1.249 (0.493, 3.164)
No comorbidities	100 (34.6)
Number of Comorbidities—n (%)
<2	221(76.5)	171 (80.3)	50 (65.8)
≥2	68(23.5)	42 (19.7)	26 (34.2)	0.011	2.117 (1.183, 3.788)
Diagnosis—n (%)
MM	97(33.6)	65 (30.5)	32 (42.1)
NHL	192(66.4)	148 (69.5)	44 (57.9)	0.066	0.604 (0.352, 1.037)
Smoking status—n (%)
Current	17 (5.9)	11 (5.16)	6 (7.89)	0.559	1.574 (0.561, 4.414)
Former	53 (18.3)	40 (18.8)	13 (17.1)
Never	219 (75.8)	162 (76.1)	57 (75.0)
Doses of inactivated vaccine—n (%)
0	160 (55.4)	110 (65.9)	50 (75.8)
≥1	73 (25.3)	57 (34.1)	16 (24.2)	0.143	0.618 (0.323, 1.180)
Unknown	56 (19.4)
Malignancy status—n (%)
Remission	69 (23.9)	57 (26.8)	12 (15.8)	0.054	1.949 (0.980, 3.874)
Non-remission	220(76.1)	156(73.2)	64(84.2)
Last/ongoing chemotherapy before COVID-19—n (%)
>3 months		34 (16)	4 (5.3)
≤3 months		179 (84)	72 (94.7)	0.018	3.419 (1.171, 9.983)
Active antineoplastic treatment—n (%)
Cytotoxic chemotherapy	116 (40.1)	87 (40.8)	29 (38.2)	0.682	0.894 (0.522, 1.530)
Molecular targeted therapy	115 (39.8)	84 (39.4)	31 (40.8)	0.836	1.058 (0.620, 1.804)
Immunomodulatory drug	63 (21.8)	45 (21.2)	18 (23.7)	0.643	1.159 (0.622, 2.160)
Monoclonal antibody	143 (49.5)	105 (49.3)	38 (50.0)	0.916	1.029 (0.609, 1.737)
After CAR-T therapy	5 (1.7)	5 (2.3)	0 (0.0)	0.404	0.977 (0.956, 0.997)
After stem cell transplantation	29 (10.0)	22 (10.3)	7 (9.2)	0.781	0.881(0.360, 2.153)

^# Disease severity was based on the U.S. NIH COVID-19 treatment guidelines: mild (no shortness of breath, dyspnea, or abnormal chest imaging); moderate (lower respiratory disease and SpO₂ ≥ 94% in room air at sea level); severe (SpO₂ < 94%, PaO₂/FiO₂ < 300 mmHg, or lung infiltrates > 50%), and critical (patients admitted to intensive care for respiratory failure, septic shock, or multiple organ dysfunction).

*Chi-square test or Fisher’s exact test, as appropriate.

^† 95% profile confidence interval in the logistic model.

SARS-CoV-2: severe acute respiratory syndrome coronavirus 2, HBV: hepatitis B virus, MM: multiple myeloma, NHL: non-Hodgkin lymphoma, CAR-T: chimeric antigen receptor T-cell immunotherapy.

Based on the guidelines for treatment of COVID-19 from the U.S. National Institutes of Health (NIH) [6], we classified 26.3% of our patients as having severe/critical disease and the other 73.7% as having moderate/mild disease. Overall, 242 patients (83.7%) were admitted to the general ward of a hospital, 34 (11.8%) received ambulatory care, and 13 (4.5%) were admitted to an intensive care unit (ICU). Sixteen patients (5.5%) died within 30 days after diagnosis of COVID-19 (Additional file 2: Table S2).

Severe COVID-19 in patients with hematologic malignancies is likely to have a multifactorial etiology (Table 1). Our univariate analysis indicated an increased risk for severe/critical COVID-19 in patients who were older than 75 years (OR = 2.145, 95% CI: 1.158–3.974), had renal disease (OR = 2.835, 95% CI = 1.194–6.730), had two or more comorbidities (OR = 2.117, 95% CI = 1.183–3.788), and received active antineoplastic therapy within 3 months of COVID-19 onset (OR = 3.419, 95% CI = 1.171–9.983). In particular, comorbidities were present in 65.4% of these patients, and the three most common ones were hypertension (34.9%), diabetes (16.6%), and another cancer (15.2%). Our findings are similar to those from previous studies [7,8]. However, there was no difference in the type of prior antineoplastic therapy (P > 0.05) or disease status (remission or not) of hematologic malignancy (P = 0.054) between the severe and non-severe groups. Thus, these four significant factors (advanced age, renal disease, two or more comorbidities, and recent antineoplastic therapy) could be utilized to predict prognosis and stratify patients with hematologic malignancies, and possibly guide the implementation of preventive strategies or treatments during similar clinical situations in the future.

We also analyzed laboratory indicators in our patients, which were measured at the time of COVID-19 diagnosis (Additional file 3: Table S3). Patients with severe/critical COVID-19 had significantly lower levels of lymphocytes and serum albumin, and significantly higher levels of D-dimer, lactate dehydrogenase, C-reactive protein, and interleukin-6 (all P < 0.05). These markers indicate the presence of increased inflammation, decreased immune function, and poor nutritional status.

Several studies of patients with hematologic malignancies who had COVID-19 showed that up to 44% of these patients had severe COVID-19, and the mortality rate ranged from 29% to 55% [3,9–11]. However, our real-world data showed that the mortality rate of patients with MM or NHL was much lower than in these previous reports. In particular, at 30 days after diagnosis of COVID-19, the overall mortality was 5.5% and the mortality of those with severe/critical disease was 21.1% (Additional file 2: Table S2). Our lower rates of severe disease and mortality may be related to the reduced pathogenicity of the Omicron variant [12]. During the observation period, the dominant variant in Zhejiang Province was the BA.5.2 lineage. When compared to BA.1 and BA.2, the replicability and pathogenicity of the BA.5 variants in the lower respiratory tract continuously decreased, indicating a clinical tendency towards a reduction in the occurrence of severe infections [13]. However, the overall rate of severe COVID-19 (26.3%) was greater in our patients than in the general population [14].

The SARS-CoV-2 virus can persist for weeks or months in immunocompromised patients, especially in those with hematologic malignancies, and virus-induced and cancer-associated lymphopenia are closely related to an increased magnitude and duration of virus shedding [15]. A prolonged viral positivity will also delay antineoplastic therapy and adversely affect patient prognosis. In our study, 54 patients (18.7% overall and 35.5% in the severe COVID-19 cohort) had symptoms that persisted for 3 or more weeks (from time of onset to resolution or death). This indicates a high index of suspicion for long-COVID, a topic that deserves further investigation in larger cohorts with longer-term follow-up.

Vaccination is the best way to protect vulnerable patients from COVID-19. Since the emergence of the Omicron variant, the protection from vaccination has declined, and breakthrough infections have increased significantly. A randomized clinical trial has shown that inactivated SARS-CoV-2 vaccines significantly reduced the risk of symptomatic COVID-19 in the general population, resulting in a vaccine efficacy of 72.8%–78.1%, and serious adverse events were rare [16]. Given the good safety and immunogenicity, inactivated vaccines are most often recommended for patients with hematological disorders in China. Nevertheless, our results showed that COVID-19 vaccination status was unrelated to disease severity (P = 0.143; OR = 0.618, 95% CI: 0.323–1.180), indicating that many patients with hematologic malignancies may not have effective humoral immunity to inactivated vaccines. Booster vaccination for COVID-19 could improve the positive rate of antibody in immunosuppressed patients. According to previous reports, in patients with B-cell malignancies who were seronegative after initial vaccination, booster vaccination resulted in elevated antibody levels in 65% of patients [17]. In addition to immunization, for these vulnerable patients, the pre-exposure prophylaxis use of neutralizing monoclonal antibodies had the potential to prevent severe SARS-CoV-2 infection [18]. Among these, anti-spike neutralizing monoclonal antibodies can accelerate the viral clearance process [19]. Of course, as subtype strains evolve, further investigation regarding sensitivity-based neutralizing antibody selection is worthwhile in clinical practice. In conclusion, as recently suggested a combined protective strategy consisting of booster vaccination plus neutralizing monoclonal antibodies may help individuals in this vulnerable patient population to overcome immune escape and block virus transmission.

The limitations of the study included its retrospective nature, small sample size, short observation time, and lack of some laboratory monitoring data. However, our findings provided several key recommendations for the clinical management of Chinese patients with hematologic malignancies in the epidemic of the Omicron virus strain. We illustrated the clinical characteristics and high-risk factors for severe/critical COVID-19 infection in patients with hematologic malignancies. The potential persistent long-term COVID infection and poor response to inactivated COVID-19 vaccination were observed in our cohort, which deserves further investigation in a larger cohort and longer-term follow-up.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the Major Project of Enze Medical Center: [Grant Number 17EZZDC06].