|Ahead of print publication
Predictors of mortality in diffuse alveolar hemorrhage in systemic lupus erythematosus
Phani Kumar Devarasetti1, Sravan Kumar Appani2, Rajendra Vara Prasad Irlapati3, Liza Rajasekhar1
1 Department of Clinical Immunology and Rheumatology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
2 Consultant Rheumatologist, Rishi Rheumatology Hospital, Karimnagar, India
3 Consultant Rheumatologist, Yashoda Hospitals, Somajiguda, Hyderabad, India
|Date of Submission||28-Apr-2021|
|Date of Acceptance||28-May-2021|
|Date of Web Publication||27-Aug-2022|
Department of Clinical Immunology and Rheumatology, Nizam's Institute of Medical Sciences, Hyderabad - 500 082, Telangana
Source of Support: None, Conflict of Interest: None
Background: Diffuse alveolar hemorrhage (DAH) in systemic lupus erythematosus (SLE) is not very common but is associated with high mortality. No studies from India report on DAH in SLE.
Materials and Methods: From the electronic database of SLE patients, data of those with unequivocal DAH between January 2008 and March 2017 were retrieved. Clinical, laboratory, treatment, and outcome details were noted. Univariate analysis and multivariate analysis were carried out with survival as an outcome measure.
Results: Twenty-four (1.31%) of 1828 SLE patients had DAH. Ten patients had DAH at diagnosis of lupus. The median interquartile range age was 23 (19.7–30) years, the median duration of hospital stay was 14 (10–22) days, and the mean SLE disease activity index was 19.5 ± 8.29. The most common clinical symptom was dyspnea followed by hemoptysis. Nephritis was the most common extrapulmonary organ involvement in 18. Hypocomplementemia was noted in 19/20, double-stranded DNA positivity in 20 patients. The mean erythrocyte sedimentation rate (ESR) was 62.17 ± 39.92 mm 1st h. Concomitant infection was seen in eight patients and raised serum procalcitonin in four/15 patients. All patients received intravenous (IV) methylprednisolone pulses, cyclophosphamide in 20, IV immunoglobulin in 4, rituximab in 2, and plasmapheresis in 2. Twelve patients (50%) died. High ESR and mechanical ventilation were independent risk factors for mortality in patients with DAH.
Conclusion: DAH in SLE is infrequent but is often associated with infection and high mortality. Mechanical ventilation and high ESR are associated with higher mortality.
Keywords: Diffuse alveolar hemorrhage, immunosuppression, lupus, systemic lupus erythematosus disease activity index, survivors, systemic lupus erythematosus
| Introduction|| |
Diffuse alveolar hemorrhage (DAH) is a rare, life-threatening manifestation of systemic lupus erythematosus (SLE) with a reported incidence of 0.63%–5.4%. Mortality rates range from 50% to 60%.,,
DAH is typically characterized by dyspnea, cough, hemoptysis, new drop-in hemoglobin, new diffuse infiltrates on chest imaging, and bronchoscopy showing bloody aspirate., It is usually associated with high disease activity, and an association with lupus nephritis is reported in 60%–80% of patients. Cohort studies from various parts of the world have shown that mechanical ventilation,,,,, renal failure,,,, and infection,,, are associated with mortality in DAH. No such data are available on Indian SLE patients.
The use of high-dose steroids and cyclophosphamide (CYC) is supported by previous studies,, as the mainstay of therapy. Other therapies used include plasmapheresis, intravenous immunoglobulin (IVIg), Rituximab, recombinant factor VII, and stem cell transplantation.
The present study aimed to describe the clinical and laboratory characteristics and identify factors associated with mortality in Indian SLE patients developing DAH.
| Materials and Methods|| |
This was an observational retrospective cohort study conducted in the department of clinical immunology and rheumatology in a tertiary care hospital, South India.
Participants and data source
We searched the electronic medical record database of our hospital between January 2008 and March 2017 with search terms such as SLE, DAH, and pulmonary hemorrhage. Patients with SLE with secondary antiphospholipid syndrome, primary systemic vasculitis with DAH, and coagulopathies were excluded. The diagnosis of DAH was confirmed in the presence of the following three parameters (1) symptoms (dyspnea, cough, and hemoptysis) or signs (bronchoscopy with bloody aspirate) of pulmonary hemorrhage, (2) new drop in hemoglobin (typically 1.5–2 g/dL), and (3) new diffuse infiltrates on chest imaging. Follow-up details were retrieved from case files maintained for lupus patients.
The demographic data and clinical details (age, sex, interval between disease onset and DAH, mean hospital stay and DAH as initial manifestation of SLE), symptomatology (dyspnea, cough, hemoptysis, and fever), and organ involvement (nephritis, mucocutaneous involvement, arthritis, serositis, acute renal failure, pulmonary arterial hypertension, myocarditis, central nervous system involvement, autoimmune hemolytic anemia) were noted. Laboratory parameters noted were hemoglobin, total leukocyte count, platelet count, erythrocyte sedimentation rate (ESR), serum creatinine, double-stranded DNA antibodies, complement level, anticardiolipin antibody positivity, and serum procalcitonin. Acute renal failure was defined as an absolute increase in serum creatinine of 0.3 mg/dl within 48 h or 50%–99% creatinine rise from baseline within 7 days. Patients with clinical features suggestive of infection and isolation of organisms from sputum, bronchoalveolar lavage (BAL) fluid, and blood and urine culture were considered to have an infection. Therapy details and survival data were recorded. Unit's protocol for the treatment of DAH includes sequential escalation of therapy based on achieving a target of stopping the process. This includes initial pulse high-dose steroids for 3–5 days followed by CYC and later rituximab. Plasmapheresis/IVIg is considered by 48 h of no response to therapy. Disease activity was measured using SLE Disease Activity Index (SLEDAI). Patients were divided into two groups: survivors or nonsurvivors. The clinical and laboratory variables, disease activity (SLEDAI), and treatment modalities were compared between the two groups. The Institutional Ethics Committee approved the protocol for the present study (EC/NIMS/1181/2009).
Statistical analysis of data was done using a statistical package for the social sciences (SPSSs) software version 21.0 (IBM SPSS Inc., Chicago, IL, USA). Survival was used as the independent variable. Independent sample t-test or the Wilcoxon Mann–Whitney U-test was used in continuous variables, and Fisher exact test was used for categorical variables. Multivariate analysis was carried out using the MANOVA test. P < 0.05 was considered statistically significant.
| Results|| |
Among 1828 records of SLE patients reviewed, 24 (1.31%) satisfied the definition of DAH. Themedian interquartile range (IQR) age was 23 (19.7–30) years. All patients with DAH were females. The median (IQR) interval between disease onset and DAH was 9.5 (4.5–24) months with a range of 1–204 months (one patient developed DAH 17 years after SLE diagnosis DAH at initial diagnosis of SLE seen in 10 patients). The median duration of hospital stay was 14 (10–22) days. The mean (standard deviation) SLEDAI was 19.50 ± 8.29.
Clinical profile and laboratory parameters are summarized in [Table 1].
|Table 1: Clinical profile and laboratory parameters of diffuse alveolar hemorrhage patients|
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Chest radiographs revealed bilateral diffuse or patchy alveolar infiltrates in all patients. Computer tomography of the chest was included diffuse ground-glass opacities in 15, patchy infiltrates in 5, and consolidations in 8.
Of 14 patients who developed DAH during a flare, six received low-dose steroid and hydroxychloroquine, four azathioprine, and four high-dose steroids and CYC. At the onset of DAH, all patients received IV methylprednisolone pulses followed by high-dose steroids. IV CYC was given in 20. All 12 survivors completed six pulses of CYC. Twenty-one patients required oxygen supplementation, and 13 patients required mechanical ventilation support. All patients received antibiotics from the start of critical illness.
Concomitant infection was noted in eight patients. The organisms isolated were Klebsiella pneumonia in 2, Escherichia coli in 2, Acinetobacter baumannii in 1, and Strongyloides stercoralis in 1 on BAL fluid culture. Blood culture positivity was noted for Klebsiella pneumonia in two and Enterococcus faecalis in one patient. One patient had a dual infection with A. baumannii in BAL and K. pneumonia in blood culture. Serum procalcitonin was elevated in 4/15 patients; among them, three patients had proven infection by culture.
The mortality rate was 50%. The cause of death included respiratory failure due to massive bleed into the respiratory tract in 10, concomitant infection (five/eight patients), and high disease activity. Two patients were lost to follow-up.
The median follow-up of survivors was 32 months (range: 2–56 months). Clinical, laboratory, and treatment variables were compared between survivors and nonsurvivors in [Table 2]. Among survivors, mean ESR was 42.83 ± 33.13, and nonsurvivors mean ESR was 81.50 ± 37.67 mm in the 1st h (P = 0.014). Only one of 13 ventilated patients survived. Univariate analysis showed high ESR and requirement of mechanical ventilation as independent predictors of mortality; the same parameters were found to be significant on multivariate analysis. Although thrombocytopenia, acute renal failure, and infection were higher in the nonsurvivor group, there was no statistical difference.
|Table 2: Comparison of survivors and nonsurvivors in systemic lupus erythematosus-diffuse alveolar hemorrhage|
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| Discussion|| |
We report our experience with 24 episodes of DAH in SLE patients seen and followed up at a tertiary care center in India over 9 years. While many authors have described their experience with the largest series being from China, this is the first such report from India. We report that the incidence of this complication is low but consistent with previous reports, it is associated with high mortality rates. It is seen both during the first presentation to the hospital and as part of a flare in patients on follow-up. DAH is always associated with high disease activity and commonest association is with lupus nephritis. Infection, either pulmonary or systemic, is often co-existent.
High disease activity has been reported by other cohorts.,,,,, Similarly, nephritis has been the most common associated organ reported previously.,, Hypocomplementemia in all patients with SLE DAH suggests that DAH in SLE occurs due to immune complex activation. This has been a proposed hypothesis of DAH.,,,
Diffuse or patchy infiltrates seen in DAH cannot be differentiated from infection, pulmonary edema, or lupus pneumonitis. Patients with DAH may also have these conditions coexisting in the lung. Systemic or pulmonary infection is also commonly observed in lupus due to disease or immunosuppressive medication. Hence in this context, extensive investigations included blood and sputum cultures, high-resolution computed tomography of the chest, sequential hemoglobin level, and BAL for pathological and microbiological analysis. If possible, a lung biopsy is often needed to rule out infection. In our cohort, 33% had the concomitant infection, whereas others have reported concomitant infection rates as high as 60%.,,,, Often, it is difficult to decide whether infection triggered or followed DAH.
In previous reports, factors associated with mortality in DAH were mechanical ventilation, azotemia, and infection,, A recent meta-analysis reporting on 250 lupus DAH episodes older age at the diagnosis, longer disease duration, concurrent infection, plasmapheresis, and mechanical ventilation was related to increased mortality. We also report that mechanical ventilation and high ESR are associated with mortality in a patient with lupus DAH. [Table 3] presents a comparison of the present DAH lupus cohort with published cohorts.
|Table 3: Comparison of various studies reporting on systemic lupus erythematosus-diffuse alveolar hemorrhage|
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In the absence of randomized trials, choice of therapeutic modalities in SLE DAH is often individualized. Since DAH has most often been reported in high SLEDAI, all cohorts mentioned using high-dose IV pulses of methylprednisolone. Some cohorts report a survival benefit with CYC.,,,, In our study, CYC was used in all 12 survivors and 8 of 12 nonsurvivors. Although IVIg, rituximab, and plasmapheresis were used in patients with DAH unresponsive to steroids and CYC, none survived. Limited evidence is available with the use of IVIg in SLE DAH. Shen et al., in their SLE DAH cohort (10/29 patients), did not observe survival benefit with the use of IVIg. Plasmapheresis also provides no clear survival benefit in the previous cohorts.,,, The recent meta-analysis also did not show a survival benefit with plasmapheresis, CYC, and IVIgs in lupus DAH.
Evidence of success with rituximab in SLE DAH is limited to case reports and case series.,,, The efficacy of rituximab in an acute event like DAH may be explained by circulating B-cell depletion occurring within 48 h accompanied by suppression of cytokine production, antigen presentation, and interaction with T-cell.,
A systematic review covering all DAH episodes in SLE patients from 1980 to 2014 170 episodes in 140 patients was reported. Therapies utilized were corticosteroids in 98%, CYC in 54%, plasmapheresis in 31%, azathioprine in 7.4%, IVIgs in 4.6%, mycophenolate mofetil in 2.9%, and stem cell transplantation in 2.3% episodes. Of eight patients who received Rituximab, 5 survived. DAH being an uncommon, life-threatening emergency in lupus, randomized controlled trials are unlikely, and therapy will continue to be guided by this level of evidence.
While this is the first report on SLE DAH from India, it adds to literature on therapeutic options based on anecdotal evidence to treat lupus DAH. It is retrospective in nature and hence subject to nonavailability of some information such as complements, antiphospholipid antibodies. Treatment decisions are often based on financial considerations like out-of-pocket expenditure; hence, some patients may not have received plasmapheresis despite being the part of treatment protocol of the unit.
| Conclusion|| |
DAH is rare, occurs in patients with high disease activity, and is associated with high mortality in Indian SLE patients. The requirement of mechanical ventilation and high ESR is associated with increased mortality. This underscores the importance of early diagnosis of alveolar hemorrhage as a cause of pulmonary symptoms or signs in a lupus patient before they progress to respiratory insufficiency requiring invasive ventilation.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]