Severe diffuse alveolar hemorrhage related to autoimmune disease: a multicenter study

We conducted a retrospective French multicenter study in 11 ICU. This study was approved by the local ethics committee. All adult patients (≥ 18 years old) with a severe DAH related to an autoimmune disease admitted in the participating ICUs between January 1, 2000, and January 1, 2017, were included. Patients were identified with the International Disease Classification 10 code for auto-immune diseases (lupus, vasculitis, inflammatory myopathy, systemic sclerosis, overlap autoimmune diseases, rheumatoid arthritis) and DAH. DAH was defined as (1) hemoptysis and/or macroscopically hemorrhagic broncho-alveolar lavage, (2) new pulmonary infiltrates, and (3) anemia. DAH was defined as severe if DAH management required ICU admission. Autoimmune diseases included were small-vessel vasculitis and connective tissue disorders. Autoimmune diseases were diagnosed according to international diagnosis criteria [17‐19]. Patients were excluded if DAH at admission was related to a non-immune condition such as heart failure or infection. Patients were identified from the ICU databases using codes for acute respiratory failure and for autoimmune diseases. All patients’ medical records were reviewed by 2 investigators (AM and DS).

Demographic data, comorbidities, treatments, medical history, and clinical, biological, and radiological findings were abstracted from medical charts. Comorbidities were assessed with the Charlson comorbidity index [20]. Autoimmune diseases manifestations at ICU admission were collected including skin, neurological, joint, gut, and kidney manifestations. Physiological variables, laboratory data, and radiographic findings (chest X-ray and computed tomography [CT] when available) at ICU admission were also reported. Disease severity was assessed using the Simplified Acute Physiology Score (SAPS II) [21]. Patients were classified as having acute respiratory failure if they met the following criteria: severe dyspnea at rest, respiratory rate greater than 30 breaths per minute or clinical signs of respiratory distress, and oxygen saturation less than 92% or PaO2 less than 60 mmHg on room air [22]. Hypoxemia severity was assessed using the PaO₂/FiO₂ ratio. Fiberoptic bronchoscopy, bronchoalveolar lavage, and the use of life-sustaining treatments (i.e., noninvasive or invasive mechanical ventilation, renal replacement therapy, and vasopressors) were recorded. Diagnosis of the autoimmune disease was made according to the clinical, biological, immunological, and histological findings. Acute respiratory distress syndrome (ARDS) was defined according to the Berlin definition [23]. Acute kidney injury was defined according to the Kidney Disease Improving Global Outcomes definitions [24]. Therapeutic regimens were reported including red blood cell transfusions, standard dose steroids, high-dose steroid pulses, other immunosuppressive therapies, and plasma exchange therapy. ICU-acquired infections were recorded. The diagnosis of infection was confirmed if patients met both following criteria: microbiological identification of a pathogen and administration of related antibiotic treatment.

Mechanical ventilation weaning was defined as extubation without reintubation during the following 48 h. ICU and hospital length of stays and vital status at ICU and hospital discharge were obtained for all patients.

Patients’ characteristics were described using medians and interquartile ranges for quantitative variables and counts and percentages for qualitative variables. Characteristics of patients requiring mechanical ventilation during their ICU stay were compared to those of patients without mechanical ventilation using either the Wilcoxon rank sum test or Fishers’ exact test. Comparisons between patients having received plasma exchanges and not, between those being deceased and being discharged alive, and between those having developed a vasculitis and a connective tissue disorder were performed in the same way. To assess variables associated with the weaning of mechanical ventilation, clinical relevant baseline characteristics significantly associated with the weaning from mechanical ventilation, as well as treatments provided during ICU stay, were included in a multivariate Cox model, where treatment variables are time-varying covariates and death in ICU is considered as a competing event of discharge alive from ICU. The same procedure was used for assessing variables associated with ICU discharge.

During the study period, we identified 104 patients (54% of men) admitted to the ICU for severe DAH associated with autoimmune disease (Table 1 and supplementary e-Table 1). The median age was 56 [32–68] years old. DAH was associated with an autoimmune disease relapse in 28 (27%) patients. DAH was the first autoimmune disease manifestation in 35 (34%) patients. A pneumo-renal syndrome was present in 83 (81%) patients. The median time from onset of respiratory symptoms to ICU admission was 5 [1–21] days. On admission, patients were severely hypoxemic with a PaO₂/FiO₂ ratio of 150 [87–229] mmHg. Hemoptysis was present in 53 (51%) patients, and acute respiratory failure was reported in 78 (75%) patients. Lactate dehydrogenase (LDH) elevation was present in 65 (63%) patients. Bronchoscopy was performed in 83 (80%) patients and demonstrated macroscopic pulmonary hemorrhage in all cases.

A diagnosis of autoimmune disease was made 5 [2–11] days after hospital admission and 0 [− 1 to 2] days after ICU admission. A small-vessel vasculitis was diagnosed in 79 (76%) patients, and a connective tissue disorder in 25 (24%). Organ involvement of the autoimmune disease was histologically confirmed in 49 (47%) cases. Comparison between patients with connective tissue disorder and vasculitis is shown in Table 1. Patients with vasculitis were older (61 [39–71] vs. 42 [27–55] years old, p = 0.003) and were more often males (61% vs. 29%, p = 0.01). Pneumo-renal syndrome was more frequent in patients with a vasculitis diagnosis (89% vs. 56%, p = 0.0009). Dyspnea evolution was more acute in patients with a connective tissue disorder (time from dyspnea onset to ICU admission 1 [0–10] day vs. 6 [1–24] days, p = 0.018). Patients with a connective tissue disorder had lower platelet counts and higher LDH levels on ICU admission.

All patients but one received a specific treatment based on steroids, and 93 (89%) patients received adjunctive steroid pulse therapy. An immunosuppressive therapy based on cyclophosphamide or rituximab was initiated in 72 (69%) and 12 (11.5%) patients, respectively. Cyclophosphamide and rituximab were associated in 6 (6%) patients. PLEX was initiated in 57 (55%) patients. Patients who received PLEX tended to be more severe at ICU admission (SAPS II: 37.5 [28–49.5] vs. 32.5 [22–41.75], p = 0.073). In univariate analysis, there was no difference in mortality between patients treated or not with PLEX (supplementary eTable-2).

Noninvasive mechanical ventilation was implemented in 33 (32%) patients, failing in 18 (55%) who were subsequently intubated. Invasive mechanical ventilation was required in 52 (50%) patients overall, of whom all fulfilled the ARDS criteria. Patients were intubated 0 [0–2] days after ICU admission. Univariate analysis of factors associated with mechanical ventilation requirement is displayed in Table 2. Duration of mechanical ventilation was 12 [6–22] days. Univariate analysis of factors associated with mechanical ventilation weaning is shown in supplementary e-Table 3. In multivariate analysis, factors associated with a longer mechanical ventilation weaning were age (HR [95%CI] 0.97 [0.96–0.99] per 10 years, p < 0.0001), vasculitis (0.52 [0.27–0.98], 0.04), and time from dyspnea onset to ICU admission (0.99 [0.99–1] per day, p = 0.03) (Fig. 1). The median ICU length of stay was 11 [7–18.8] days.

Sixteen (15%) patients died in ICU. Death was attributed directly to refractory autoimmune disease in 5 (31%) cases, to refractory ARDS in 4 (25%) cases, to multi-organ failure in 4 (25%) cases, and to septic shock in 3 (19%) cases. In univariate analysis, factors associated with ICU mortality are displayed in Table 3 and supplementary e-Table 4. In multivariate analysis, factors associated with alive status at ICU discharge were chronic heart failure (HR [95%CI] 0.37 [0.15–0.94], p = 0.037), APS-related DAH (3.17 [1.89–5.32], p < 0.0001), SAPS II (0.98 [0.97–0.99], p = 0.007), and oxygen flow at ICU admission (0.95 [0.91–0.998], p = 0.04) (Fig. 2).

After ICU discharge, 48 (55%) patients were followed up with a median duration of 19 [8–38] months. At the end of follow-up, 22 (65%) of these patients had a chronic kidney disease and 8 (24%) still required renal replacement therapy. Twenty-two (47%) patients had a lung CT-scan evaluation during follow-up showing lung fibrosis for 8 (36%) patients. Pulmonary function testing was performed in 15 (32%) patients and showed a restrictive pulmonary disorder in 6 (40%) cases.