Clinical Outcomes of COVID-19 in Mycosis Fungoides and Sezary Syndrome

Between 2020 and 2022, COVID-19 affected more than 70% of the Israeli population [1]. Patients with haemato-oncologic neoplasms are more susceptible to developing severe infections, including persistent COVID-19 [2‒5]. Moreover, they have a lower immune response to COVID-19 vaccines in comparison to the general population [6, 7]. This is mostly related to patients with B-cell malignancies, who suffer from immune-deficiency which is associated with the disease itself and its treatment, particularly B-cell aplasia related to B-cell receptor-targeting therapies [6, 8].

Primary cutaneous lymphomas are non-Hodgkin lymphomas in which 75% are of T-cell origin, with Mycosis Fungoides and Sezary Syndrome (MF/SS) being the most commonly encountered forms [9]. MF/SS are rare diseases accounting for 4% of non-Hodgkin lymphomas and generally present with various cutaneous manifestations that may precede the diagnosis [10]. As such, a skin biopsy is essential for definitive pathological diagnosis and is typically performed by dermatologists or plastic surgeons. While early-stage disease is treated topically, more advanced or refractory MF/SS disease may require systemic therapies such as total-skin electron-beam therapy, chemotherapy or monoclonal antibodies and bone marrow transplantation [10].

Some studies have evaluated risk factors for severe COVID-19 among patients with MF/SS, which included lymphopenia, chronic organ failure, Sezary syndrome, or active aggressive disease [11]. Moreover, initial reports indicate that clinical outcomes of patients with MF/SS that were infected with COVID-19 were not significantly different from the general population [12, 13]. However, most of these studies were conducted at the beginning of the pandemic and included only the SARS-CoV-2 Alpha variant and non-vaccinated patients. In the current study, we aimed to assess the clinical outcomes of COVID-19 among patients with MF/SS from 2020 through 2022.

This cohort study was based on anonymized data obtained from electronic medical records of Maccabi Healthcare Services (MHS), the second-largest healthcare organization in Israel, with over 2.6 million insured patients. The Institutional Review Board (IRB) reviewed and approved the study protocol in accordance with the Declaration of Helsinki (ethics approval no. 134/21).

Patients aged 18 or older members of MHS were included if they received a diagnosis of MF/SS by:

• 1.

  A dermatologist, hematologist, or plastic surgeon according to the International Classification of Disease, Ninth Revision (ICD-9) coding system [14] that is added to the patient’s medical record after confirmation of the diagnosis by an expert.

Or

• 2.

  An electronic pathology report confirms the diagnosis.

The study period began on March 1, 2020, and ended on December 31, 2022. Figure 1 presents the dominant variants in Israel during the study period.

COVID-19 nasopharyngeal swabs RT-PCR test results were analyzed. To note, these PCR results for SARS-CoV-2 are centrally recorded for all members of MHS, regardless of whether the tests were conducted within MHS clinics or at external locations such as drive-in/walk-in test centers or the airport test center, and the final result is recorded as positive, negative, or borderline.

Moreover, we analyzed clinical variables (comorbidities), as well as sociodemographic variables including age, gender, and socioeconomic status, which were extracted from the electronic medical records of the patients. The socioeconomic status was defined as the residential socioeconomic performance. In Israel, the socioeconomic performance index is determined by the Israel Central Bureau of Statistics through a scoring system ranging from 1 (lowest) to 10. This is a comprehensive calculation based on 14 variables that assess social and economic factors across various domains such as demographics, education, standard of living, and employment [15].

The primary outcome was the association between COVID-19 infection and hospitalization among patients with MF/SS. The secondary outcomes included the effects of COVID-19 treatment, vaccination status, and SARS-CoV-2 variants on hospitalization and mortality rates.

The Kaplan-Meier method was used to compare the proportion of patients hospitalized for SARS-CoV-2 infection within 30 days according to the variant. Using a multivariate Cox proportional-hazards regression model, the association between patient’s factors and COVID-19 outcomes was estimated with adjustments to covariates. Given that there are many potential confounders, a two-step test for selecting the relevant covariates was used. Schoenfeld’s global test was applied to the survival curves to test the proportional-hazards assumption for those variables. Finally, a multivariate Cox proportional-hazards regression model was used to estimate the association between each covariate that met the two abovementioned testing criteria. All statistical analyses were performed using the R statistical software 4.2.2 (2022-10-31).

A total of 1,472 patients diagnosed with MF/SS between 2020 and 2022 were included in the study. Among them, 768 patients (52%) had PCR-confirmed outpatient SARS-CoV-2 infection during the study period. Table 1 presents the characteristics of these patients according to their COVID-19 PCR status. A higher rate of at least one positive PCR result during the study period was detected among younger patients (p < 0.001) and patients with comorbidities such as hypertension (p = 0.009), overweight (p = 0.001), kidney failure (p = 0.046), osteoporosis (p = 0.003), or dementia (p = 0.046).

The hospitalization rate was 2.9%, and the 30-day mortality rate from any cause after SARS-CoV-2 infection was 1.2% during the study period. Table 2 presents the number of positive PCR cases in each variant wave, along with the number of hospitalizations and mortality. SARS-CoV-2 Delta had the highest hospitalization rate (7.7%), among the three main COVID-19 variants, followed by Alpha (2.4%) and then Omicron (2.0%) (Fig. 2).

The association between various factors and COVID-19-related hospitalization during the Omicron surge was tested using a multivariable Cox proportional-hazard regression model. According to the results, fewer fully and recently vaccinated patients (i.e., received the last vaccine dose up to 3 months preinfection) required hospitalization due to SARS-CoV-2 infection compared to non-vaccinated or non-updated (HR = 0.27, 95% CI: 0.081; 0.90, p = 0.033). This represents a 73% relative risk reduction in COVID-19-related hospitalization (Fig. 3). However, the hospitalization rate was higher among patients older than 65 (HR = 1.12, 95% CI: 1.06; 1.18, p < 0.001) and patients with SS (vs. MF) (HR = 25.04, 95% CI: 4.57; 137.5, p < 0.001) or those suffering from chronic obstructive pulmonary disease (COPD) (HR = 4.44, 95% CI: 0.081; 0.90, p = 0.024).

Since January 2, 2022, the first-day nirmatrelvir was available for all MHS patients, nirmatrelvir/ritonavir (an antiviral drug used for patients with an increased risk of progression to severe COVID-19) was administered to 76 (11%) of the study MF/SS patients. There was a tendency for decreased hospitalization among patients treated within 5 days of infection, with a 79% risk reduction, although it was not statistically significant (HR = 0.21, 95% CI: 0.022; 1.90, p = 0.164).

Table 3 presents the vaccination uptake and antibody response rate. The vaccination uptake was defined as the percentage of patients receiving each dose of COVID-19 vaccine, and the antibody response rate as the percentage of patients tested for CoV-2 antibodies after vaccination that had positive immune response for the Architect AdviseDx SARS-CoV-2 IgG II kit, which is indicated by an RBD-IgG titer value greater than 50?U/mL [6]. More than 99% of the patients received the Pfizer mRNA vaccine and the rest received the Moderna mRNA vaccine. Vaccine uptake significantly decreased in the consecutive rounds of vaccination (p < 0.01) – while in the 1st round that started in December 2020, 82% of MF/SS patients were vaccinated, in the second round or first booster (starting in July 2021), 76% were vaccinated, in the third round (second booster) starting in January 2022, 39% were vaccinated, and in the fourth round (Omicron booster) that started in September 2022, only 14% were vaccinated (Table 3). Due to the small number of CoV-2 IgG tests, we could not conclude how additional doses affected the antibody response rate.

This nationwide cohort study demonstrates the impact of the COVID-19 pandemic on patients with MF/SS. The study reveals that approximately half of the patients were infected with COVID-19 during 2020–2022, 3% were hospitalized, and 1% died from any cause in the 30 days following COVID-19 diagnosis, with Delta being the most virulent variant, followed by Alpha and then Omicron. Previous studies in the general population showed similar variant rank by hospitalization rate [16]. However, it is important to note that previous studies in the hemato-oncological population reported much higher rates of hospitalization and mortality [5, 17].

Indeed, the severity of COVID-19 in hematologic patients seems to be related to the reduced immune response to severe SARS-CoV-2, which is mainly affected by the subtype of malignancy and B-cell depletion associated with the disease and its treatment [17]. Specifically, MF/SS is not associated with B-cell depletion. While the rare advanced stage MF/SS is characterized by a T-cell-related immunosuppression with an increased Th2 cytokine release of interleukin (IL)-4, IL-5, IL-10, or IL-13, early-stage disease shows increased expression of Th1 cells with IL-2, IL-12 and interferon-gamma release, with less susceptibility to infections [18]. Moreover, the microenvironment of MF/SS is mainly characterized by immature antigen-presenting, myeloid, and T-regulatory cells which may be involved in the pathogenesis of immunosuppression [19]. On the other hand, B cells seem to be over-expressed in MF/SS [20], which may explain the more benign COVID-19 course in these patients as compared to other hematological malignancies. While topical therapies that are generally used in this disease are not associated with immunosuppression, the frequently used interferon has immunomodulating effects. Finally, more modern therapies such as monoclonal antibodies (mogamulizumab, brentuximab vedotin) are not directed against B cells and do not lead to B-cell depletion [10]. Only the rare patients that are still treated with low-dose chemotherapy seem to be at increased risk of severe COVID-19 infections [17].

According to our study results, the risk factors of severe COVID-19 in MF/SS patients are similar as previously related [11] and include older age, Sezary syndrome, and COPD. As described in previous studies since the beginning of the pandemic [21], older patients with comorbidities, especially cardiovascular and respiratory, are more at risk for severe COVID-19 disease. The current study still shows that the clinical outcomes were much improved among vaccinated patients. Therefore, although the immune response of SARS-CoV-2 vaccination in MF/SS cannot yet be stated from the present results, at-risk patients should be recommended to get updated vaccination as described earlier. Following our results on the significant decrease of vaccine uptake over time among MF/SS patients, preventive measures should be emphasized, especially among older patients with COPD or Sezary syndrome.

The cohort is limited to Israeli patients that are members of MHS, which may affect its generalizability to the whole MF/SS Israeli population. Further studies should prospectively collect the clinical outcomes of COVID-19 among MF/SS patients as compared to the general population. Moreover, the diagnosis of COVID-19 was based only on PCR results and not rapid antigen tests, so some of the COVID-19 patients might have been missed. Finally, we had no data on the different stages of MF; therefore, we were not able to provide analyses on this point.

As opposed to most hematological malignancies, MF/SS patients suggest a relatively benign disease course compared to other hematological malignancies, closer to that of the general population. However, SARS-CoV-2 vaccination remains an important measure of prevention in these patients and should be emphasized in at-risk populations, including older patients and those with Sezary syndrome or respiratory diseases. Further studies are needed to evaluate the effects of the different MF/SS treatments on COVID-19 severity and antibody response to vaccination.

The Institutional Review Board (IRB) of Maccabi Health Services reviewed and approved the study protocol in accordance with the Declaration of Helsinki (ethics approval no. 134/21). Since the data were collected retrospectively, the study has been granted an exemption from requiring written informed consent by the same IRB (ethics approval no. 134/21).

The authors declare that there is no conflict of interest regarding the publication of this paper.

The research was supported by a grant from Maccabi Healthcare Services, which had no role in the preparation of data or the manuscript.

I.L. and T.T. organized and wrote the manuscript. H.A. prepared the data and preprocessed the data. L.R. designed, organized, wrote the manuscript, and performed the statistical analysis. G.M., T.P., and S.G. critically reviewed the manuscript. T.P. and S.G. supervised the research.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.