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Risk Factors for Pneumocystis jirovecii Pneumonia in Non-HIV Patients Hospitalized for COVID-19: A Case-Control Study
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Preprints on COVID-19 and SARS-CoV-2
Submitted:
15 June 2023
Posted:
16 June 2023
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Abstract
Background
Very few cases of Pneumocystis jirovecii pneumonia (PCP) have been reported in COVID-19 so far, mostly in patients with concomitant HIV infection or in solid organ transplant recipients. Despite COVID-19 is associated with lymphopenia and use of steroids, there are no studies specifically aimed to investigate risk factors for PCP in COVID-19
Methods
retrospective case-control study in a cohort of patients with confirmed COVID-19. Direct immunofluorescence assay on respiratory samples was used to diagnose PCP.
Results
We enrolled 54 patients. Patients with PCP had significant lower median lymphocyte values (p=0.033), longer COVID-19 disease duration (p=0.014), higher cumulative dose of steroid received (p=0.026), higher CRP values (p=0.005) and lower SARS-CoV-2 vaccination rate than controls (p=0.029). Cumulative steroid dose (p=0.042) and the highest CRP value during the stay (p=0.012) were identified as risk factor for PCP, while SARS-CoV-2 vaccination with one (p=0.029) and two doses (p=0.049) as a protective factor for PCP, although not independently associated.
Conclusions
PCP develops in COVID-19 patients regardless of immunosuppressive conditions. However, a higher rate of PCP is significantly associated with the cumulative steroidal dose, high CRP values and lack of vaccination.
Keywords:
Subject: Biology and Life Sciences - Immunology and Microbiology
BACKGROUND
Coronavirus Infectious Disease 19 (COVID-19) is the diseases caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), characterized by a clinical picture ranging from pauci-symptomatic illness to interstitial pneumonia leading to respiratory failure and intensive care unit (ICU) admission.[1]
Differently from influenza pandemics, respiratory co-infections and superinfections are not very common in COVID-19 patients: according to a 2020 meta-analysis by Lansbury and colleagues, in fact, bacterial co-infections account for a 7% of COVID-19 overall, with only sporadically reported fungal infections.[2]
On the other hand, a most recent meta-analysis by Nurra and colleagues, published in 2022, has shown that the pooled prevalence of opportunistic infections in COVID-19 patients is 16%, with the highest prevalence of secondary infections among viruses at 33%, 16% among the bacteria subgroup and 6% among the fungi subgroup.[3]
Thus, invasive fungal infections (IFIs), are a not-negligible complications of COVID-19, especially among critically ill patients, and are also associated with a significant higher mortality: 53% in patients with fungal diseases and 31% in patients without fungal diseases (p = 0.0387).[3]
The most common IFIs complicating the course of COVID-19 are invasive candidiasis and pulmonary aspergillosis, with the latter that became a specific clinical syndrome: the COVID-19 associated pulmonary aspergillosis (CAPA), defined by the 2020 ECMM/ISHAM consensus criteria.[4]
Other IFIs, such as Pneumocystis jirovecii pneumonia (PCP), are only sporadically reported, almost exclusively in case series and case reports, and mainly in previously immunocompromised hosts (concomitant HIV infection or solid organ transplant recipients).[5] Unfortunately, no definite consensus about COVID-associated PCP, nor any definite diagnostic criteria have been published, so far, and the existence of the PCP associated with COVID-19 has been questioned by the scientific community. While the diagnostic criteria for IFIs published by the European Organization for Research and Treatment of Cancer and the Mycoses Study Group (EORTC/MSGERC), that are designed for immunocompromised hosts, have been modified to permit the diagnosis of CAPA also in immunocompetent patients, the same has never been done for PCP.[6]
PCP is an opportunistic infection causing interstitial pneumonia and variable severity of respiratory failure, especially in patients with specific risk factors, i.e.: HIV infection with CD4+ lymphocyte count lower than 200 cells/mm3; solid organ transplantation and hematologic or rheumatic conditions treated with lymphocyte depleting agents and/or high dose steroids.[7]
Similarly to CAPA, patients with COVID-19, even if previously immunocompetent, may develop risk factors for PCP, such as severe lymphopenia ore use of high dose of steroids or other immunomodulating drugs, together with COVID-19-associated pathological mechanisms (i.e., epithelial barrier damage and immune system dysregulation).[8]
It is difficult to establish a true incidence of PCP among hospitalized COVID-19 patients, according to the published studies, since not all the available reports adopt standardized diagnostic criteria for PCP definition and most of them are based on molecular detection of Pneumocystis jirovecii on respiratory samples instead of direct detection of the fungus with immunofluorescence assay or direct staining. In fact, the two largest and most recent systematic reviews aimed to describe clinical features and risk factors for PCP in COVID-19, both published between the end of January and the beginning of February 2023, consider a different number of cases: specifically, Amstutz et al. describes 69 cases of PCP in COVID-19 in 29 articles, while Sasani et al. 30 cases. [9,10] Considering both the reviews, half of the patients were found to have at least one immunosuppressive condition before COVID-19 onset that predispose them to PCP, most commonly HIV infection, while the remaining patients had no classic risk factors for PCP development.[9,10]
Moreover, Amstutz and colleagues have found that 45% of patients with PCP received long term corticosteroids before and during COVID-19 and discovered a median absolute lymphocyte count (IQR) of 610 (280–920) cells/mm3 (n = 23) and CD4 count (IQR) of 66 (33–291.5) cells/mm3 (n = 20) in the studied population. Interestingly, Beta-D-Glucan assay (BDG) was positive only in 66.7% (26/39) of patients tested, in contrast to the estimated sensitivity of the assay of 94% in HIV patients and 83% in non-HIV patients.[10,11].
Although these results, also confirmed by Sasani and colleagues and by the previous experience at our center, shed a light on the rare and complex COVID-associated PCP, no study in literature is available to specifically assess risk factors for PCP development in COVID-19, using rigorous diagnostic criteria for case definition. Accordingly, we conducted a case-control study to identify risk factors for PCP in HIV-negative patients hospitalized for COVID-19 at our institution.
METHODS
Study design
The study was conducted in “Federico II” University Hospital, located in Naples, Italy: the largest University Hospital of Southern Italy and the referral center for COVID-19 in pregnancy for the Campania Region.
We retrospectively evaluated clinical data of the patients admitted for COVID-19 at Infectious Disease ward and Intensive Care Unit of “Federico II” University Hospital from 1st November 2021 to 30th September 2022 and diagnosed with PCP during the admission. Controls were selected among patients admitted for COVID-19 in the same period who did not develop PCP. For each case, two controls were matched, based on age+10 years, presence of solid organ transplantation (SOT) and hematological malignancies or not and setting of PCP development (ICU vs. non-ICU).
Definitions
The diagnosis of PCP was considered according to the EORTC/MSGERC criteria: “proven” if P. jirovecii was detected with direct immunofluorescence assay (DFA) on respiratory samples; “probable” in the presence of host factors, clinical features and microbiological evidence; “possible” in the presence of host and clinical features with the absence of microbiological evidence.[6] According to EORTC/MSGERC criteria, host factors were defined as: receipt of therapeutic doses of corticosteroids for at least 2 weeks within the past 60 days; antineoplastic, anti-inflammatory, or immunosuppressive treatment; and low CD4 lymphocyte counts due to a medical condition, included, but not limited, to patients with primary immuno-deficiencies, hematologic malignancies, SOTs, and allogeneic HSCT recipients.
Clinical features were considered as follows: any consistent radiographic features, particularly bilateral ground glass opacities, consolidations, small nodules or unilateral infiltrates lobar in-filtrate, nodular infiltrate with or without cavitation, multifocal infiltrates, miliary pattern and/or respiratory symptoms with cough, dyspnea, and hypoxemia accompanying radiographic abnormalities including consolidations, small nodules, unilateral infiltrates, pleural effusions, or cystic lesions on chest X-ray or computed tomography scan.
Microbiological evidence was defined as: detection of Pneumocystis jirovecii DNA by quantitative real-time polymerase chain reaction (PCR) in a respiratory tract specimen or Beta-D-glucan ≥80 ng/L (pg/mL) detection in ≥2 consecutive serum samples provided other etiologies have been excluded.[6]
PCP severity was classified according to the 1996 classification by Miller at al. in mild, moderate and severe, based on clinical features, peripheral oxygen saturation, chest radiology and arterial oxygen tension (PaO2) on room air.[12] Cut-off for arterial oxygen tension (PaO2) at rest, room air were: >11.0 kPa (>82.5 mmHg) for mild disease; 8.1–11.0 kPa (60.75–82.5 mmHg) for moderate disease and <8.0 kPa (<60 mmHg) for severe disease.[12]
Charlson Comorbidity Index comorbidities were calculated to evaluate patient’s comorbidity.[13] Steroid dose was calculated as equivalent to dexamethasone, since dexamethasone was the most frequently used steroid drug in the studied population. Chronic steroidal treatment was defined as a daily dose > 0.3 mg/kg of prednisone or equivalent for >2 weeks taken by the patient in the past 60 days, according to the EORTC/MSGERC criteria for host factors.[6]
COVID-19 severity was assessed with the World Health Organization 9-point severity scale as follows: 0: no clinical or virological evidence of infection; 1: ambulatory, no activity limitation; 2: ambulatory, activity limitation; 3: hospitalized, no oxygen therapy; 4: hospitalized, oxygen mask or nasal prongs; 5: hospitalized, noninvasive mechanical ventilation (NIMV) or high-flow nasal cannula (HFNC); 6: hospitalized, intubation and invasive mechanical ventilation (IMV); 7: hospitalized, IMV + additional support such as pressors or extracardiac membranous oxygenation (ECMO); 8: death.[14]
Statistical analysis
The statistical analysis was performed using SPSS version 27 (SPSS Inc. Chicago, IL). Continuous variables were reported as median and interquartile range and categorical variables as frequency and percentages. Categorial variables were confronted with Chi-squared test and Fisher’s exact test when appropriate. Continuous variables were confronted with logistic regression. A significance level of 0.05 was set for the interpretation of the results.
RESULTS
We enrolled 54 patients (18 cases and 36 matched controls) on a total of 380 patients admitted during the study period (14%). The median age of the included patients was 60 years (95% IQR 51-68), with 34.5% of females and 12.7% of pregnant women and a median Charlson index of 3 (95% IQR 1-5). The largest part of the patients (60%) had received at least one dose of SARS-CoV-2 vaccination and stayed at hospital for a median of 16 days (95% IQR 12-34). During hospital stay, the patients received a median of 85 mg (95% IQR 55-180) cumulative dexamethasone dose for a median of 15 days (95% IQR 12-27) and only 6 out of 54 of them (11%) received immunomodulatory therapies for COVID-19, in detail: 4 baricitinib and 2 tocilizumab. Half of the studied population (53%) was immunocompromised for hematologic malignancies, with the most common condition represented by non-Hodgkin lymphoma. Detailed clinical and demographic features of the population are displayed in Table 1.
Among 18 cases of PCP, 16 were diagnosed as “proven”, of which 10 were diagnosed with DFA on BAL, while 6 with DFA on non-bronchoscopic obtained lower respiratory tract samples (bronchial aspiration or mini-BAL). Regarding the two patients diagnosed as having “possible” PCP, they presented both host and radiological factors and no minor microbiological criteria (PCR on respiratory samples or serum BDG). Seven of the 18 cases were immunocompromised, of which 5 (27.8%) for hematologic conditions and 2 (11%) for SOT, while the other patients had no previous immunological impairment. Nine out of 18 cases of PCP required ICU admission; among them, 4 were diagnosed before ICU admission and 5 during ICU stay. (Table 2)
All patients but one were diagnosed with moderate-to-severe course of PCP according to Miller criteria and treated with intravenous trimethoprim-sulfamethoxazole (TMP-SMX) at the dose of 15-20 mg/kg divided in 3-4 daily doses for 21 days (with switch to oral drug whenever it was feasible after reaching clinical improvement) plus prednisone 40 mg (or dexamethasone at equivalent dose) twice daily for the first 5 days, followed by 40 mg daily for 5 days and 20 mg daily for the remaining 11 days. One patient presented with mild disease and was treated with oral TMP-SMX 2 double strength tabs three times daily for 21 days with no adjunctive steroids. Only one patient diagnosed with PCP had detectable serum BDG in two samples obtained in different days (>523 pg/mL in both determinations). The patient had follicular lymphoma treated with rituximab, a severe course of PCP requiring ICU admission and died 22 days after PCP diagnosis; he didn’t develop any concurrent IFIs during hospital stay, to our knowledge. Conversely, two patients developed concurrent IFIs, namely one case of Aspergillus tracheobronchitis and one case of invasive pulmonary aspergillosis. They were both pregnant patients in their early thirties, both requiring ICU admission and both died. No patients developed drug adverse reaction that required cessation of the therapy with TMP-SMX and 6 of them (33%) died.
Patient diagnosed with PCP had similar comorbidity index, WHO grade, and number of days of highest O2 support received than controls; conversely, length of stay, mortality and ICU admission were higher in cases compared to controls, although non-significantly. Also, the nadir of lymphocyte count and of PaO2/FiO2 ratio recorded were lower in PCP patients compared to controls. (Table 2)
Compared to controls, patients with PCP had significant lower median lymphocyte values (540 vs. 780 cells/mm3, p=0.033), longer COVID-19 disease duration (25 vs. 16 days, p=0.014), higher cumulative dose of steroid received (178.5 vs. 78 mg, p=0.026), higher CRP values (14.4 vs. 6.3 mg/dL, p=0.005) and lower SARS-CoV-2 vaccination rate than controls (7 patients with at least one dose vs. 26 patients with no history of vaccination, p=0.029). (Table 2)
At the univariate analysis, cumulative steroid dose received during hospital stay (OR 1.004, 95%CI 1-1.008, p=0.042) and the highest CRP value recorded during the admission (OR 1.076, 95%CI 1.016-1.140, p=0.012) were identified as risk factor for PCP, while SARS-CoV-2 vaccination with one (OR 0.269, 95%CI 0.083-0.877, p=0.029) and two doses (OR 0.304, 95%CI 0.093-0.994, p=0.049) as a protective factor for PCP, although not independently associated, according to the multivariate analysis.
By considering the clinical differences between vaccinated (at least one dose) and unvaccinated patients, unvaccinated patients had significant lower recorded P/F ratio (p=0.015) and received significantly higher dose of steroids (p=0.031) than vaccinated. (Table 3)
Discussion
Compared to controls, patients with PCP had significant lower median lymphocyte values, longer COVID-19 disease duration, higher cumulative dose of steroid received, higher CRP values and lower SARS-CoV-2 vaccination rate than controls, although only steroid dose and CRP value were identified as risk factor for PCP, while SARS-CoV-2 vaccination as a protective factor, even though not independently associated.
Despite the limitations of this study, namely the small sample size and its retrospective nature, according to our results, the risk of developing PCP in patients hospitalized for COVID-19 seems to be independent from previous immunosuppressive conditions but to be associated with the severity of the disease itself and to a complex and still not well understood combination of host susceptibility factors, iatrogenic immunosuppression, and COVID-related damage.
As we know from years of study about PCP, the main risk factors for its development are: HIV infection with CD4+ lymphocyte count <200 cells/mm3 and high HIV viral loads; certain hematologic conditions (graft versus host diseases, use of prolonged lymphopenia in the context of other hematologic malignancies, use of lymphocyte-depleting agents for lymphomas or lymphoblastic leukemia etc.); autoimmune conditions treated with lymphocyte-depleting agents, especially when combined with high and prolonged doses of steroids; solid organ transplantation, especially if lung or small bowel or complicated by lymphopenia or use of anti-thymocyte agents.[15,16,17]
It is also well described how the occurrence of a severe acute respiratory illness (SARI), especially when it ends up in acute respiratory distress syndrome (ARDS) requiring ICU admission, become an ideal breeding ground for PCP development due to lung damage, sepsis-induced immune-paralysis and iatrogenic immunosuppression in otherwise immunocompetent hosts, as reported by Beumer and colleagues during the influenza A epidemic of 2015, when 2% of non-ICU and 7% of ICU patients developed PCP as a complication of viral infection.[18]
Similar mechanisms have been called upon the development of IFIs in COVID-19 patients, together with the use of corticosteroids and immunomodulatory agents as part of COVID-19 therapy and with the absolute and CD4+ lymphopenia associated with COVID-19, which level correlate with disease severity and poor prognosis.[19,20,21]
Nonetheless, despite in our population we identified higher steroidal dose, higher CRP values and lower vaccination rate as risk factors for PCP development, we couldn’t establish which of these factors resulted to be independently associated with PCP, since they appear to influence each other. This could be explained by the fact that unvaccinated patients had more severe disease than vaccinated, as we demonstrated in Table 3 and, probably because of that, reached higher value of CRP than vaccinated and received higher steroid doses. This can be also related to the fact that most patients in our cohort developed COVID-19 during the first waves of the pandemic (at the beginning of vaccination campaign), when most of them could not have completed vaccination cycle; it was also a time in which general practitioners used to prescribe prolonged corticosteroids therapy at COVID-19 symptoms onset irrespective of the need of oxygen supplementation. These patients might have influenced the evaluation of the risk factors in our cohort due to multicollinearity among variables, exacerbated by the small sample size.
Despite such considerations, it seems that other element, independent from the universally accepted risk factors, must be considered to explain the development of PCP in COVD-19 patients. One of them could be the presence of prior colonization of the respiratory tract by Pneumocystis jirovecii spores before hospitalization or the airborne transmission from infected patients to susceptible ones, as it occurred in the past with PCP outbreaks in transplantation hospital units.[22,23] The clustering transmission of Pneumocystis jirovecii in the hospital setting can explain why the report of PCP cases are so heterogeneous in literature, with some centers like ours reporting higher numbers of cases than others, but such hypothesis must be confirmed with ad-hoc studies.
Surprisingly, despite all but two patients received a “proven” diagnosis of PCP and only two a “possible” diagnosis, no patient in our cohort but one had detectable BDG on repeated serum samples, in line with the findings of Amstutz and colleagues, which report a positive BDG only in 66.7% of patients in the studied included in their meta-analysis.[10] This findings are apparently in contrast to the high negative predictive value of BDG to rule out the diagnosis of PCP, as reported in multiple studies.[24] Nonetheless, according to the meta-analysis published in 2020 by Del Corpo and colleagues, the BDG test is more sensitive in patients with HIV than in those without (94% versus 86%) and a negative BDG is only associated with a low post-test probability of PJP (≤5%) when the pre-test probability was low to intermediate (≤20% in non-HIV and ≤50% in HIV).[11] The low rate of BDG positivity in COVID-19 patients can be related to a lower fungal burden in such population, compared to HIV patients, but this hypothesis need to be confirmed with specific studies.
Conclusions
PCP develops in COVID-19 patients regardless of previous immunosuppressive conditions. High corticosteroid dose received before and during hospital admission, high CRP values and lack of vaccination are significantly associated with PCP development in COVID-19 patients, although not independently. BDG assay seems to have a poor performance in ruling out PCP in COVID-19 patients, therefore, bronchoscopy must not be withheld in case of high suspicion of pulmonary IFI in these patients.
Further studies are needed to establish the incidence and risk factor of Pneumocystis jirovecii colonization among patients hospitalized for COVID-19 and the risks for the development of symptomatic infection among colonized hosts, also aiming to identify high-risk patients that might benefit from PCP chemoprophylaxis.
Author Contributions
Conceptualization, Giulio Viceconte, Antonio Riccardo Buonomo and Ivan Gentile; Data curation, Maria Foggia; Formal analysis, Riccardo Scotto; Investigation, Alessia D'Agostino, Antonio di Fusco, Carmine Iacovazzo, Luca Fanasca, Gaetana Messina and Francesco Cacciatore; Methodology, Luca Fanasca and Paola Salvatore; Resources, Maria Foggia; Supervision, Biagio Pinchera, Paola Salvatore and Ivan Gentile; Writing – original draft, Giulio Viceconte and Alessia D'Agostino; Writing – review & editing, Antonio Riccardo Buonomo and Ivan Gentile.
Funding
This research was supported by EU funding within the NextGenerationEU-MUR PNRR Extended Partnership initiative on Emerging Infectious Diseases (Project no. PE00000007, INF-ACT) and POR Campania FESR 2014-2020 - Asse 1 - Obiettivo Specifico 1.3. - Azione 1.3.1.
Data Availability Statement
The data that support the findings of this study are available Federico II University Hospital, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of Federico II University Hospital.
Conflicts of Interest
All authors declare no conflict of interest with respect to the main topic of the paper.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the Ethical Committee of the University of Naples Federico II (protocol n. 180/21).
Consent for publication
Not applicable.
References
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Table 1.
Demographic and clinical characteristics of the population. ICU: intensive care unit; HSCT: hematogenous stem cell transplant; MMF: mycophenolate; CRP: C-reactive protein.
Table 1.
Demographic and clinical characteristics of the population. ICU: intensive care unit; HSCT: hematogenous stem cell transplant; MMF: mycophenolate; CRP: C-reactive protein.
| N=54 | |
|---|---|
| Age, years, median (IQR) | 60 (51-68) |
| Females, n (%) | 19 (34.5) |
| Pregnant, n (%) | 7 (12.7) |
| Charlson Comorbidity Index, median (IQR) | 3 (1-5) |
| Deaths, n (%) | 14 (25.5) |
| Rehabilitation at discharge, n (%) | 3 (5.5) |
| ICU admission, n (%) | 20 (37) |
| SARS-CoV-2 vaccination, n (%) | |
| 1 dose | 33 (60) |
| 2 doses | 29 (52) |
| 3 doses | 16 (29) |
| 4 doses | 2 (3.6) |
| Pneumocystis jirovecii prophylaxis recipients, n (%) | 8 (14.5) |
| Pneumocystis jirovecii pneumonia (PJP) cases, n (%) | 18 (33) |
| Proven diagnosis | 16 (29) |
| Possible diagnosis | 2 (3) |
| PJP diagnosed in ICU PJP diagnosed before ICU admission |
5 (9) 4 (7) |
| Length of stay, days, median (IQR) | 16 (12-34) |
| Days of SARS-Cov-2 positivity, median (IQR) | 20 (14-26) |
| Days from admission to PJP diagnosis, median (IQR) | 22 (5-35) |
| Days from COVID-19 symptoms to PJP diagnosis, median (IQR) | 39 (22-52) |
| Use of immunomodulatory drug for COVID-19, n (%) | 6 (11) |
| Hematologic malignancy, n (%) | 29 (53) |
| Acute leukemia | 1 (1.8) |
| Hodgkin lymphoma | 1 (1.8) |
| Non-Hodgkin lymphoma | 9 (16.4) |
| Chronic lymphatic leukemia | 4 (7.3) |
| Multiple myeloma | 3 (5.5) |
| Myelodysplastic syndrome | 1 (1.8) |
| HSCT | 1 (1.8) |
| Use of anti-CD20, n (%) | 6 (11) |
| Chronic steroidal treatment, n (%) | 8 (14.5) |
| Solid organ transplant recipients, n (%) | 6 (11) |
| Use of steroids | 3 (5.5) |
| Use of calcineurin inhibitors | 5 (9.1) |
| Use of mTOR inhibitors | 2 (3.6) |
| Use of MMF | 4 (7.3) |
| Cumulative steroid dose during admission, milligrams, median (IQR) | 84 (55-190) |
| Number of days of steroid, median (IQR) | 15 (12-27) |
| Worst WHO severity grade, median (IQR) | 4 (4-6) |
| Lowest PaO2/FiO2 ratio, median (IQR) | 135 (89-235) |
| Highest O2 support, n (%) | |
| Nasal cannula | 11 (20) |
| Venturi mask | 16 (29) |
| HFNC | 4 (7.3) |
| CPAP | 4 (7.3) |
| NIV | 6 (11) |
| IMV | 14 (25.5) |
| Days of highest O2, n (%) | 7 (5-10) |
| Lowest lymphocyte value, cells/mm3, median (IQR) | 620 (320-1480) |
| Highest CRP value, mg/dL, median (IQR) | 10 (2.9-20) |
| Highest LDH value, IU/mL, median (IQR) | 384 (289-524) |
| Ferritin on admission, median (IQR) | 595 (246-1335) |
| Highest D-dimer value, median (IQR) | 765 (533-1524) |
Table 2.
Univariate and multivariate analysis. ICU: intensive care unit; CRP: C-reactive protein.
| Cases n=18 |
Controls n=36 |
p-value | OR (95%CI), p-value | aOR (95%CI), p-value | |
|---|---|---|---|---|---|
| Age, years, median (IQR) | 60 (49.75-70) | 60 (49-78) | 0.98 | 0.994 (0.995-1.034), p=0.754 | |
| Females, n (%) | 7 (39) | 12 (32) | 0.764 | 0.754 (0.234-2.433), p=0.637 | |
| Pregnant, n (%) | 4 (22) | 3 (8) | 0.2 | 3.2 (064-16.32), P=0.155 | |
| Charlson Comorbidity Index, median (IQR) | 3 (0.75-5) | 3 (1-5) | 0.389 | 0.876 (0.685-1.12), p=0.291 | |
| Deaths, n (%) | 6 (33) | 8 (21.6) | 0.51 | 1.81 (0. 517-6.353), P=0.353 |
|
| Rehabilitation at discharge, n (%) | 2 (11) | 1 (2.7) | 0.247 | 4.5 (0.38-53), P=0.233 | |
| ICU admission, n (%) | 9 (50) | 11(30) | 0.232 | 2.36 (0.739-7.55), P=0.147 | |
| SARS-CoV-2 vaccination, n (%) | |||||
| 1 dose | 7 (39) | 26 (70) | 0.027 | 0.269 (0.083-0.877), p=0.029 | 0.367 (0.086-1.573), p=0.177 |
| 2 doses | 6 (33) | 23 (62) | 0.042 | 0.304 (0.093-0.994), p=0.049 | 0.806 (0.064-10.143), p=0.867 |
| 3 doses | 3 (16.7) | 13 (35) | 0.135 | 0.369 (0.9-1.5), p=0.166 | |
| 4 doses | 0 (0) | 2 (5.4) | 1 | 0 (0-0) | |
| Pneumocystis jirovecii prophylaxis recipients, n (%) | 1 (5.6) | 7 (19) | 0.25 | 0.252 (0.029-2.226), p=0.215 | |
| Length of stay, days, median (IQR) | 20.5 (14.5-50.25) | 15 (10.5-27) | 0.058 | 1.033 (0.998-1.068), p=0.062 | |
| Days of SARS-Cov-2 positivity, median (IQR) | 25 (20-37) | 16 (13-23) | 0.014 | 1.141 (0.993-1.322), p=0.062 | |
| Use of immunomodulatory drug for COVID-19, n (%) | 3 (16.7) | 3 (8) | 0.381 | 2.267 (0.0409-12.5), P=0.349 | |
| Hematologic malignancy, n (%) | 5 (27.8) | 10 (27) | 0.39 | 0.564 (0.166-1.915), p=0.359 | |
| Use of anti-CD20, n (%) | 3 (16.7) | 3 (8) | 0.381 | 2.267 (0.409-12.5), p=0.349 | |
| Chronic steroidal treatment, n (%) | 3 (16.7) | 5 (13.5) | 1 | 1.28 (0.270-6), p=0.756 | |
| Solid organ transplant recipients, n (%) | 2 (11) | 4 (10.8) | 1 | 1.031 (0.171-6.23), p=0.973 | |
| Cumulative steroid dose during admission, milligrams, median (IQR) | 178.5 (68-513) | 78 (46-158) | 0.026 | 1.004 (1-1.008), p=0.042 | 1.003 (0.999-1.007), p=0.2 |
| Number of days of steroid, median (IQR) | 15 (12-20) | 16.5 (12-29.25) | 0.718 | 0.984 (0.929-1.043), p=0.596 | |
| Worst WHO grade, median (IQR) | 5 (4-6) | 4 (4-6.5) | 0.434 | 1.287 (0.7-2.378), p=0.421 | |
| Lowest PaO2/FiO2 ratio, median (IQR) | 100 (65-191) | 150 (100-269) | 0.081 | 0.995 (0.988-1.002), p=0.13 | |
| Days of highest O2, n (%) | 7 (5-10) | 6 (4.75-10) | 0.849 | 0.965 (0.873-1.068), p=0.5 | |
| Lowest lymphocyte value, cells/mm3, median (IQR) | 540 (217-772) | 780 (415-2313) | 0.033 | 1 (0.999-1), p=0.732 | |
| Highest CRP value, mg/dL, median (IQR) | 14.4 (10-28.6) | 6.3 (2.3-15) | 0.005 | 1.076 (1.016-1.140), p=0.012 | 1.052 (0.987-1.121), p=0.123 |
| Highest LDH value, IU/mL, median (IQR) | 368 (289-452) | 384 (258-533) | 0.788 | 0.999 (0.996-1.002), p=0.4 | |
| Ferritin on admission, median (IQR) | 740 (279-1342) | 520 (205-1073) | 0.332 | 1 (0.999-1.001), p=0.588 | |
| Highest D-dimer value, median (IQR) | 761 (497-1392) | 1051 (570-1526) | 0.554 | 1 (1), p=0.641 | |
Table 3.
Differences in vaccinated and non-vaccinated patients in variables associated with COVID-19 severity.
Table 3.
Differences in vaccinated and non-vaccinated patients in variables associated with COVID-19 severity.
| Vaccinated N=32 |
Non-vaccinated N=22 |
p-value | |
| Cumulative steroid dose during admission, milligrams, median (IQR) | 78 (50-163) | 168.5 (80-568) | 0.031 |
| Highest CRP value, mg/dL, median (IQR) | 8.26 (2.34-21.59) | 12.36 (3.33-17.37) | 0.223 |
| Worst WHO grade, median (IQR) | 5 (5-6.5) | 6 (5-7) | 0.089 |
| Lowest PaO2/FiO2 ratio, median (IQR) | 183 (100-275) | 100 (75-140) | 0.015 |
| Days of highest O2, n (%) | 6.5 (4.25-9.75) | 7 (5-10) | 0.739 |
| Highest LDH value, IU/mL, median (IQR) | 348 (221-528) | 390 (305-505) | 0.460 |
| Lowest lymphocyte value, cells/mm3, median (IQR) | 600 (315-1635) | 680 (355-1065) | 0.945 |
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