Severe pneumonia in patients with systemic lupus erythematosus admitted to the intensive care unit.

Background: The aim of this study was to investigate clinical characters and prognosis of patients with systemic lupus erythematosus (SLE) and severe pneumonia admitted to the intensive care unit (ICU). Materials and methods: We conducted a retrospective study that reviewed all clinical records of patients with SLE and severe pneumonia admitted to the ICU between 2008 and 2020. Results: A total of 86 SLE patients with severe pneumonia during their first ICU admission were enrolled in this study. Most patients were female (n = 71, 82.5%), and the median age was 42.3 ± 14.7 years. The most common organisms were gram-positive bacteria (20.9%), followed by gram-negative bacteria (18.6%) and fungi (10.4%). A total of 31 patients died within 30 days of ICU admission, and the 30-day mortality was 36%. In binary logistic regression analysis, Acute Physiologic and Chronic Health Evaluation II (APACHE II) score, Sequential Organ Failure Assessment (SOFA) score and mechanical ventilation were dependently associated with 30-day mortality (odds ratio [OR] 2.97, P = 0.016; OR = 4.02, P = 0.023; OR = 1.52, P = 0.036; respectively). Among the other 55 patients, 5 patients died after discharge from the ICU during the long-term follow-up. Conclusions: Mortality was high in SLE patients with severe pneumonia admitted to the ICU, and most of the patients died within 30 days of ICU admission.

Zusammenfassung: Hintergrund: Ziel der vorliegenden Studie war es, die klinischen Merkmale und die Prognose von auf die Intensivstation aufgenommenen Patienten mit systemischem Lupus erythematosus (SLE) und schwerer Pneumonie zu untersuchen. Material und Methoden: Dazu wurde eine retrospektive Studie durchgeführt, in der sämtliche klinischen Aufzeichnungen von Patienten mit SLE und schwerer Pneumonie, die zwischen 2008 und 2020 auf der Intensivstation behandelt worden waren, ausgewertet wurden. Ergebnisse: In die Studie aufgenommen wurden 86 SLE-Patienten mit schwerer Pneumonie während ihrer ersten Aufnahme auf die Intensivstation. Die meisten waren Frauen (n = 71; 82,5%), und das Durchschnittsalter betrug 42,3 ± 14,7 Jahre. Als häufigste Erreger fanden sich grampositive Bakterien (20,9%), gramnegative Bakterien (18,6%) und Pilze (10,4%). Innerhalb von 30 Tagen nach Aufnahme auf die Intensivstation starben 31 Patienten, und die 30-Tage-Mortalität betrug 36%. In der binären logistischen Regressionsanalyse waren die Scores Acute Physiologic and Chronic Health Evaluation II (APACHE II) und Sequential Organ Failure Assessment (SOFA) sowie mechanische Beatmung in abhängiger Weise mit der 30-Tage-Mortalität verknüpft (Odds Ratio, OR: 2,97; p = 0,016; OR = 4,02; p = 0,023 bzw. OR = 1,52; p = 0,036). Von den übrigen 55 Patienten starben 5 nach Entlassung von der Intensivstation während der Langzeitnachbeobachtung. Schlussfolgerung: Bei SLE-Patienten mit schwerer Pneumonie, die auf der Intensivstation behandelt wurden, war die Mortalität hoch, und die meisten der Patienten starben innerhalb von 30 Tagen nach Aufnahme auf die Intensivstation.

Keywords: Systemic lupus erythematosus; Severe pneumonia; Intensive care unit; APACHE II; Mortality; Systemischer Lupus erythematosus; Schwere Pneumonie; Intensivstation; Mortalität

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Systemic lupus erythematosus (SLE) is an autoimmune disorder with multiorgan involvement affecting mainly women of childbearing age [[1]]. With the advent of new immunosuppressive therapies, patients have benefited from improved outcomes [[2]]. However, various life-threatening conditions requiring intensive care unit (ICU) management can occur at any stage in the course of SLE [[3]]. Recent data suggest that SLE is the leading cause of ICU admissions in patients with autoimmune rheumatic conditions [[4]], accounting for approximately 13.8–37.1% of SLE hospitalizations [[6]].

Infections and lupus flares are the most common causes of admission to the ICU in patients with SLE [[8]]. In terms of infectious complications, pulmonary infections are typically more severe and more frequent [[9]]. Although risk factors for pneumonia have been identified in patients with SLE, prognostic factors of those with pneumonia requiring treatment in the ICU have not been well described, and there is a lack of information about the microbiology of these episodes, warranting further research in this area.

The main objective of our study was to describe a cohort of patients with SLE and severe pneumonia who were admitted to the ICU, to analyze their short- and long-term survival and identify which patient characteristics may influence the prognosis.

This retrospective cohort study was conducted in three ICUs, including a general ICU, a respiratory ICU and an emergency ICU, at the First Affiliated Hospital of Wenzhou Medical University from January 2008 to January 2020. If the patient was admitted more than once, only the first admission was selected for data collection. All patients fulfilled the criteria for SLE revised by the American Rheumatism Association in 1997 [[10]], and showed the clinical manifestations of pneumonia. Severe pneumonia was diagnosed according to the American Thoracic Society (ATS) criteria of severe pneumonia published in 2007 [[11]].

This study was performed after receiving approval from the First Affiliated Hospital of Wenzhou Medical University Research Ethics Committee and with the informed consent of all patients.

Demographic, medical, and laboratory data were collected, including age and gender; SLE duration, Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2k) [[12]], immunosuppressive drugs, particularly glucocorticoids and cytotoxic agents; comorbidities; pulmonary manifestations, microbiological findings, pneumonia severity assessment including the confusion, urea nitrogen, respiratory rate, blood pressure, 65 years of age and older (CURB-65) and Pneumonia Severity Index (PSI) scales, ICU parameters, such as the Acute Physiologic and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) [[13]], were calculated on the first day in the ICU. Treatments and patient outcomes were short-term mortality, defined as death within 30 days of ICU admission, and long-term mortality, was defined as death until December 2020.

Data were analyzed using SPSS 22 software (IBM, Armonk, NY, USA) and presented as mean ± standard deviation (SD), median (range), or n (%). Chi-square or student's t‑test was used to compare differences between survivors and nonsurvivors, depending on which was appropriate. Binary logistic regression was used to determine the independent risk factors associated with prognosis. We considered a 2-tailed P value < 0.05 statistically significant.

We included 86 SLE patients with severe pneumonia during their first ICU admission. Table 1 presents the demographic and main clinical characteristics of the patients. Most patients were female (n = 71, 82.5%), and the median patient age was 42.3 ± 14.7 years. Lupus nephritis (LN) was the main organ involvement observed in 33 (38.3%) patients at admission. The SLEDAI was 8.9 ± 7.4. Most patients had received prednisone (n = 80, 93%), and cyclophosphamide was the most common immunosuppressive agent (n = 29, 33.7%) before ICU admission.

Table 1 Demographic and clinical characteristics of SLE patients with severe pneumonia admitted to ICU (n = 86)

Data are shown as mean ± standard deviation (SD), median (range), or n (%) SLE systemic lupus erythematosus, ICU intensive care unit, SLEDAI SLE Disease Activity Index, CTX cyclophosphamide, MMF mycophenolate mofetil

Clinical features at presentation of those patients are were shown in Table 2. Most of the patients had fever, cough, sputum, and dyspnea. Most of the patients (89.5%) had acute respiratory failure, and 26 patients (30.2%) had acute renal failure. Fifteen patients (17.4%) had sepsis and 20 patients (23.2%) had shock.

Table 2 Clinical presentation of SLE patients with severe pneumonia admitted to ICU (n = 86)

Data are shown as mean ± standard deviation (SD), median (range), or n (%) SLE systemic lupus erythematosus, ICU intensive care unit, CURB-65 confusion, urea nitrogen, respiratory rate, blood pressure, 65 years of age and older, PSI Pneumonia Severity Index

Causative microorganisms in the 86 patients with SLE are shown in Table 3. Most of the patients (70.4%) had a culture of respiratory secretions (sputum, endotracheal aspirate or bronchoalveolar lavage), and isolation of a potential causative microorganism was achieved in 24 patients (27.9%). Microorganisms were isolated from blood specimens in 6 other patients (6.9%). The presence of a pathogen was confirmed by antigen antibody reaction or gene detection in another 20 patients (23.2%). However, no pathogen was isolated in 36 patients (41.8%), 11 of whom had no specimen to be tested. Overall, 50 patients (58.1%) had a positive result and the most common organisms were gram-positive bacteria (20.9%), followed by gram-negative bacteria (18.6%) and fungi (10.4%).

Table 3 Laboratory data of SLE patients with pneumonia admitted to ICU (n = 86)

Data are shown as mean ± standard deviation (SD), median (range), or n (%) SLE systemic lupus erythematosus, ICU intensive care unit, ESR erythrocyte sedimentation rate, CRP C-reactive protein

As shown in Table 4, the median length of ICU hospitalization was 17.9 ± 13.5 days, and mean APACHE II and SOFA scores were 29.6 ± 6.7 and 8.1 ± 3.7, respectively. Mechanical ventilation was needed in 49 (57%) patients, vasoactive drugs were administered in 39 (45.3%) patients, inotropic support was needed in 16 (18.6%) patients, and renal replacement treatment was required in 21 (24.4%) patients. A total of 31 patients died within 30 days of ICU admission, and the 30-day mortality was 36%. In the other 55 patients who were alive 30 days after admission, at the time of last follow-up, the median follow-up time was 46.3 months (range 3–147 months). Among these 55 patients, 5 patients died after discharge from the ICU during the follow-up period. Three patients died of another infection at 3 months, 1 year and 3 years, respectively, 1 patient died of heart failure at 6 months, and 1 patient receiving hemodialysis died of a stroke at 3 years.

Table 4 ICU parameters, treatment, and outcomes of SLE patients with pneumonia admitted to ICU (n = 86)

Data are shown as mean ± SD, median (range), or n (%) SLE systemic lupus erythematosus, ICU intensive care unit, APACHE II Acute Physiology and Chronic Health Evaluation II, SOFA Sepsis-related Organ Failure Assessment

When comparing survivors and nonsurvivors (Table 5), the following four variables were found to be statistically significant (P < 0.05): cyclophosphamide (CTX) usage, APACHE II score, SOFA score and mechanical ventilation. We also performed a binary logistic regression analysis which showed that APACHE II score, SOFA score and mechanical ventilation were dependently associated with 30-day mortality (odds ratio [OR] = 2.97, P = 0.016; OR = 4.02, P = 0.023; OR = 1.52, P = 0.036; respectively; Table 6).

Table 5 Possible risk factors associated with 30-day mortality of SLE patients with severe pneumonia admitted to ICU (n = 86)

Data are shown as mean ± standard deviation (SD), median (range), or n (%) SLE systemic lupus erythematosus, ICU intensive care unit, SLEDAI SLE Disease Activity Index, CTX cyclophosphamide, MMF mycophenolate mofetil, APACHE II Acute Physiology and Chronic Health Evaluation II, SOFA Sepsis-related Organ Failure Assessment *p < 0.05

Table 6 Binary logistic regression analysis with 30-day mortality as the dependent variable (R2 = 0.73)

CTX cyclophosphamide, APACHE II Acute Physiology and Chronic Health Evaluation II, SOFA Sepsis-related Organ Failure Assessment, B partial regression coefficients, OR odds ratios, CI confidence interval *p < 0.05

We divided these patients into three groups according to years they were admitted to the ICU (2008–2011, 2012–2015, 2016–2020): the 30-day mortalities were 50% (9/18), 36.5% (15/41) and 25.9% (7/27), respectively. Although there was no significantly statistical difference (P = 0.256), the mortality rate improved over time.

Previous studies have shown that the main reasons that SLE patients are admitted to an ICU were infections and lupus flare. Han et al. found that in 25 SLE patients with infection admitted to the ICU, pneumonia was the most common finding in 10 patients [[15]]. Zamir et al. investigated the causes and outcomes of ICU-admitted patients with SLE [[16]]. In 18 patients with infection, pneumonia was found in 10 patients. Aragón et al. found that infection was the leading cause of admission in 77 (27.60%) patients, with respiratory infection being the most common diagnosis (22 patients) [[17]]. These findings indicate that the lung was the most common site of infection in SLE patients admitted to the ICU. However, these studies had small numbers of patients with pneumonia, and did not elaborately analyze the specific infection subtype.

In our study, the most common organisms were gram-positive bacteria (20.9%), followed by gram-negative bacteria (18.6%) and fungi (10.4%). This was similar to some, but not all, previous studies. In a multicenter study with 381 patients diagnosed with systemic rheumatic disease (primarily SLE) who required ICU management, infection accounted for 39.3% of these ICU admissions. Among 87 patients (57.2%) with a positive culture, gram-negative bacteria (36.7%) were the most common, followed by gram-positive bacteria (26.4%) and fungi (12.6%) [[18]]. In a Thai population with SLE and pneumonia, the causative organisms identifiable in 40 of 56 patients (71.5%), and the main isolates were Mycobacterium tuberculosis (30%), followed by nocardia (15%) and aspergillus (12.5%) [[19]]. In another retrospective study, 187 SLE patients with pneumonia were studied [[20]]. A microorganism was isolated in 48 patients (25.7%), and the most common organism was Staphylococcus aureus (18.7%), followed by Pneumocystis jirovecii (16.7%) and aspergillus (14.6%).

In our study, the mortality rate of SLE patients with severe pneumonia admitted to ICU was 36%, which was similar to that reported in previous studies. In a systematic review, the median mortality rate based on the series reviewed was approximately 29.6% [[21]]. Before 2010, it was higher, with a median of 46.7%, but over the last decade, there was a reduction to 25% [[21]]. In a large national 10-year population-based follow-up study from Taiwan conducted on 2870 patients with SLE admitted to the ICU, the mortality rate decreased from 42.6% in 1999–2000 to 31.2% in 2007–2008 [[22]]. In a recent evaluation by Aragón et al. of 188 SLE patients admitted to the ICU, a total of 38 patients (20.21%) died [[17]]. These findings indicate that if the prognosis of severe pneumonia is similar to that of other conditions in SLE patients in the ICU, then the relative lower mortality rate may be the result of recent advances in diagnostic and therapeutic strategies in these patients.

Concerning prognosis, several studies have highlighted factors that are associated with ICU mortality, mainly APACHE, SOFA, SLEDAI, mechanical ventilation and vasopressor support [[18], [23]]. In our study, we also found that APACHE score, SOFA score, and mechanical ventilation were associated with poorer outcomes. In relation to SLEDAI, our findings differed from those reported in other studies. Nonsurvivors presented with lower scores, but no significant differences were found in SLEDAI when compared with survivors, which indicates that SLE activity may be a risk factor for infection, but not an adverse prognostic factor in these patients [[17]].

In summary, in this retrospective observational study across three ICUs in a single center, we investigated the clinical characteristics and outcomes of SLE patients with severe pneumonia who were admitted to the ICU. The main findings were that the 30-day mortality was 36% and that APACHE II score, SOFA score and mechanical ventilation were dependently associated with 30-day mortality.

This study was supported by the grants from the National Science Foundation of Zhejiang (LQ17H030005), the Wenzhou Committee of Science and Technology (Y2020267), and 2019 Jiaxing Key Discipiline of Medcine-Rheumatology and Autoimmunology(Supporting Subject) (2019-zc-03).

B. Zhang, L. Zheng and Y. Huang declare that they have no competing interests.

For this article no studies with human participants or animals were performed by any of the authors. All studies performed were in accordance with the ethical standards indicated in each case.