Acute lupus pneumonitis as the initial presentation of systemic lupus erythematosus

Abstract

Systemic lupus erythematosus is a multisystem autoimmune disease with wide-ranging pleuropulmonary manifestations. Acute lupus pneumonitis is one of its uncommon complications. We report a 36-year-old woman with acute lupus pneumonitis as the initial presentation of systemic lupus erythematosus. Clinical, biological, radiological and functional improvements were noticed with the administration of steroids, hydroxychloroquine and immunoglobulin.

Background

Systemic lupus erythematosus is a systemic autoimmune disease that can involve any organ. Pleuropulmonary manifestations of systemic lupus erythematosus can include pleuritis (with or without pleural effusion), acute lupus pneumonitis, diffuse alveolar haemorrhage, interstitial lung disease, bronchiolitis obliterans, pulmonary hypertension, pulmonary embolism and shrinking lung syndrome.^1–3 Very few cases of acute lupus pneumonitis have been reported due to its rare presentation and diagnostic challenge. We describe the case of a 36-year-old woman with acute lupus pneumonitis manifesting as dense multiple and bilateral lung opacities.

Case presentation

A 36-year-old South American woman treated for a Hashimoto’s disease, with irrelevant family history, was referred to the emergency department due to intermittent fever, fatigue, mild dyspnoea and dry cough with infrequent clear sputum for the past 2 weeks. Six weeks prior to onset of these symptoms, hair loss, myalgia and weight loss (5 kg) were noticed. She had also been diagnosed, on a clinical basis, with herpetic gingivostomatitis and treated with an oral antiviral therapy (valaciclovir) without improvement.

Physical examination revealed fever (38.8°C), tachycardia (125 beats/min), tachyponea (20 breaths/min) and hypoxia on room air (89%). There were diffuse crackles over both lungs, oral ulcers (figure 1) and non-scarring alopecia.

Figure 1.

Image showing oral ulcers.

Investigations

Laboratory findings showed pancytopenia with lymphopenia (leucocyte count: 2.41 g/L, normal: 4–11 g/L; lymphocyte 0.05 g/L, normal: 1–4.5 g/L; haemoglobin: 95 g/L, normal: 120–160 g/L; platelet count: 99 10⁹/L, normal: 150–350 10⁹/L). C-reactive protein and procalcitonin levels were normal (5.10 mg/L, normal: 0–10 mg/L; 0.46 µg/L, normal: <0.5 µg/L, respectively) and erythrocyte sedimentation rate was elevated (40 mm/hour, normal: 0–20 mm/hour). Liver function tests showed mild cytolysis (aspartate aminotransferase: 153 U/L, normal: 11–42 U/L; alanine aminotransferase: 57 U/L, normal: 9–42 U/L) and renal function tests including urinalysis were normal.

Her latest routine laboratory test showed a normal complete blood count and liver function tests (leucocyte count: 7.8 g/L, lymphocyte 1.04 g/L, haemoglobin: 129 g/L, platelet count: 191 10⁹/L, aspartate aminotransferase: 33 U/L, alanine aminotransferase: 37 U/L).

Multiple and bilateral pulmonary opacities were present on chest X-ray (figure 2). High-resolution CT of the lungs revealed numerous areas of alveolar condensation with air bronchograms predominant in the upper right lobe and the lower lobes (figure 3A–C).

Figure 2.

Posteroanterior view of a chest X-ray showing pulmonary opacities in the right upper lobe and lower lobes.

Figure 3.

High-resolution CT of the lungs showing numerous areas of alveolar condensation with air bronchogram predominant in the upper right lobe (A) and the lower lobes (B and C).

Patient was diagnosed with community-acquired multilobar pneumonia treated with amoxicillin/clavulanic acid and clarithromycin. At day 3, antibiotics were replaced by levofloxacin due to the appearance of skin lesions raising the suspicion of an allergic reaction. Skin biopsy allowed diagnosis of fixed pigmented erythema with cutaneous lupus being excluded (figure 4). Despite empirical antibiotic coverage, patient remained febrile with persistent fatigue, mild dyspnoea and dry cough.

Figure 4.

Image showing skin lesion proximal to the right armpit with skin biopsy confirming diagnosis of fixed pigmented erythema.

Standard microbiological investigations including nasopharyngeal swab for respiratory viruses (human metapneumovirus, influenza A and B virus, parainfluenza virus 1–3, respiratory syncytial virus, rhinovirus), throat swab for atypical pneumonia agents (Chlamydia pneumoniae, Mycoplasma pneumoniae), urinary antigen tests (Streptococcus pneumoniae, Legionella pneumophila), oral swab (enteroviruses, herpes simplex virus 1 and 2, varicella zoster virus) and cultures (blood, urine and sputum) showed no evidence of pathogen. Extended microbiological workup testing for bacteria (Bartonella henselae, Brucella sp, Coxiella burnetii, Francisella tularensis, Treponema pallidum), viruses (HIV, hepatitis B, C and E viruses, cytomegalovirus, Epstein-Barr virus), fungi (Cryptococcus sp, Histoplasma capsulatum) and parasites (Leishmania sp, Fasciola sp, Strongyloides stercoralis, Toxocara sp, Toxoplasma gondii, Trichinella sp, Trypanosoma cruzi) were all negative.

After completion of a 7-day course of antibiotics, autoimmune markers were measured, revealing highly elevated antinuclear antibodies with a homogeneous pattern (titre 1:5000, normal: <1:80) and elevated anti-double-stranded (ds) DNA antibodies (1044 UI/mL, normal: <36 UI/mL). Serum C3 and C4 levels were decreased to 0.28 g/L (normal: 0.66–1.35 g/L) and 0.03 g/L (normal: 0.08–0.34 g/L), respectively. Antiphospholipid antibodies were also positive: anticardiolipin antibodies and anti-beta-2-glycoprotein I (anti-β2GPI) antibodies were elevated up to 58.4 U/mL (normal: 0–14 U/mL) and >100.0 U/mL (normal: 0–17 U/mL), respectively. Lupus anticoagulant was positive.

According to the European League Against Rheumatism and the American College of Rheumatology (EULAR/ACR) 2019 criteria,⁴ patient was diagnosed with systemic lupus erythematosus presenting with acute lupus pneumonitis. Haematologic and mucocutaneous manifestations were also present (pancytopenia with lymphopenia, oral ulcers and non-scarring alopecia) as well as acute lupus hepatitis, the latter being a diagnosis of exclusion.

Indeed, worsening of cytolysis appeared during the first week of hospitalisation, without hepatocellular insufficiency. Viral hepatitis (hepatitis A, B, C, D, E; herpes simplex virus; varicella zoster virus; Epstein-Barr virus; cytomegalovirus), alcoholic hepatitis, drug toxicity, HELLP syndrome (Haemolysis, Elevated Liver enzymes, Low Platelets), toxin exposure and malignant liver infiltration (normal liver ultrasound) were excluded.

Due to the wide variety of aetiologies causing new-onset pancytopenia, further investigations were carried out to exclude serious haematologic disorders. Peripheral blood smear and bone marrow biopsy did not demonstrate suggestive findings of haemolytic anaemia, haematological malignancies or haemophagocytic lymphohistiocytosis. Moreover, biological findings did not suggest haemolytic anaemia (reticulocyte count: 23 g/L, normal: 20–120 g/L; lactate dehydrogenase: 154 U/L, normal: 87–210 U/L; haptoglobin: 1830 mg/L, normal: 412–1693 mg/L; unconjugated bilirubin: 4.5 µmol/L, normal: 0.5–9.5 µmol/L) nor haemophagocytic lymphohistiocytosis due to its low probability according to the HScore (76 points, less than 1%), despite slightly elevated ferritin (560 µg/L, normal: 7–171 µg/L) and triglyceride (2.39 mmol/L, normal:<2.0 mmol/L) levels.⁵

Before initiating immunosuppressive therapy and due to patient’s lymphopenia, bronchoscopy with bronchoalveolar lavage (BAL) was performed and ruled out opportunistic infections (Aspergillus sp, Actinomyces sp, Cryptococcus sp, Mycobacterium tuberculosis, Nocardia sp and Pneumocystis jirovecii). BAL allowed exclusion of diffuse alveolar haemorrhage (hemosiderin: 0; normal: 0–25), an alternative pulmonary manifestation of systemic lupus erythematosus. BAL showed increased cellularity with monocytic predominance (total cell count: 600 m/L, normal: 30–350 m/L; cell viability: 99%; macrophage: 73%, normal: 55%–97%; lymphocyte: 21%, normal: 2%–34%; neutrophil: 6%, normal: 0%–3%). No malignant cells were found in the BAL.

Results of pulmonary function test revealed severe restrictive ventilatory defect (total lung capacity: 2.31 L being 63% of the predicted, forced expiratory volume in 1 s: 0.89 L being 38% of the predicted).

Treatment

Systemic steroid treatment was initiated with high-dose intravenous methylprednisolone for 3 days (10 mg/kg/day) and continued with oral prednisone (1 mg/kg/day), in association with hydroxychloroquine (4 mg/kg/day). Despite lack of evidence, intravenous immunoglobulin (0.5 g/kg/day) was also given for 4 days due to the severity of the pulmonary involvement.

Antimicrobial prophylaxis was initiated (trimethoprim–sulfamethoxazole and valaciclovir) following introduction of immunosuppressive therapy. Due to an indeterminate result of interferon-gamma-release assay (lymphopenia) and patient having lived in an area of high prevalence of tuberculosis, 4 months of rifampicin preventive therapy were recommended for the treatment of possible latent tuberculosis. Rifampicin was favoured to isoniazid due to the abnormal liver function tests.

Acetylsalicylic acid in primary prevention (100 mg/day) was suggested due to the presence of antiphospholipid antibodies.

Outcome and follow-up

After introduction of systemic lupus erythematosus therapy (figure 5A), there was immediate clinical and biological improvement, less than 24 hours, with resolution of fever (figure 5B), dyspnoea and cough associated with normalisation of aspartate aminotransferase and alanine aminotransferase values (figure 5C) as well as platelet and leucocyte counts (figure 5D). Pulmonary function test and high-resolution CT of the lungs were repeated 6 weeks after treatment initiation. Pulmonary function test showed major improvement of the restrictive ventilatory defect (forced expiratory volume in 1 s: 1.70 L being 72% of the predicted) (figure 6A, B) and radiological findings revealed a significant decrease of the numerous areas of alveolar condensation (figure 7A–C). Cardiac and ophthalmological investigations were normal. The patient is currently followed up on an outpatient basis with clinical, biological, radiological and functional monitoring.

Figure 5.

(A–D) Clinical and biological improvement after introduction of systemic lupus erythematosus therapy. ALAT, alanine aminotransferase; ASAT, aspartate aminotransferase; IVIg: intravenous immunoglobulin.

Figure 6.

Pulmonary function test before treatment revealing severe restrictive ventilatory defect (A) and 6 weeks after treatment showing mild restrictive ventilator defect (B).

Figure 7.

High-resolution CT of the lungs showing significant decrease of the numerous areas of alveolar condensation in the upper right lobe (A) and the lower lobes (B, C).

Discussion

Acute lupus pneumonitis is often described as being a rare manifestation of systemic lupus erythematosus, affecting 1%–4% of cases, with poor prognosis.¹ However, its prevalence and mortality rate are rarely estimated, partly due to unreported or misdiagnosed cases. Histopathologic studies reveal alveolar-capillary unit damage appearing to be mediated by immune complex formation produced by autoantibodies, however, pathologic findings are neither diagnostic nor pathognomonic of acute lupus pneumonitis.⁶ Its clinical presentation is similar to pneumonia and characterised by fever, cough and dyspnoea with physical examination revealing tachyponea, tachycardia, hypoxia and lung crackles. As it was found in our patient, typical radiological sign of acute lupus pneumonitis is multiple and bilateral lung opacities, with predominance in the lower lung zones.⁷ Abnormal high-resolution CT findings seem to be associated with low complement levels and high anti-dsDNA levels and also present in our patient.⁷ Bronchoscopy with BAL and lung biopsy have no value in establishing diagnosis of acute lupus pneumonitis. However, BAL allows to exclude infection and differentiate acute lupus pneumonitis from diffuse alveolar haemorrhage, another rare and mortal pulmonary presentation of systemic lupus erythematosus.

Several studies have observed that many patients with active systemic lupus erythematosus had normal C-reactive protein levels, this being the case of our patient (day 1: 5.10 mg/L, day 4: 2.10 mg/L, day 10: 4.20 mg/L and day 11: 2.80 mg/L).⁸ Marked C-reactive protein elevation in these patients was only seen during confirmed infectious episodes.⁹ Recent data also suggest the absence of correlation between procalcitonin levels and systemic lupus erythematosus disease activity with raised procalcitonin levels (≥0.5 µg/L) strongly suggestive of bacterial infection in the context of systemic lupus erythematosus.¹⁰

Acute lupus pneumonitis should be suspected in patients with known systemic lupus erythematosus presenting acute constitutional and respiratory symptoms. Being a diagnosis of exclusion, investigations must first focus on ruling out infection, pulmonary embolism, drug-induced lung toxicity, organising pneumonia, alveolar haemorrhage, heart failure and malignancy. In patients without known systemic lupus erythematosus, a high index of suspicion for acute lupus pneumonitis must be maintained, particularly in case of non-response to conventional treatment for pneumonia and when extrapulmonary characteristics of systemic lupus erythematosus are noted.

Despite no randomised-controlled trials, systemic steroids associated with immunosuppressive therapy (cyclophosphamide, rituximab, hydroxychloroquine and intravenous immunoglobulin) are until the mainstream treatment of acute lupus pneumonitis.

Learning points.

• Acute lupus pneumonitis is a rare manifestation of systemic lupus erythematosus with a poor prognosis.

• Its clinical presentation is similar to pneumonia, explaining its misdiagnosis and diagnostic delay.

• Bronchoscopy with bronchoalveolar lavage (BAL) and lung biopsy have no value in establishing diagnosis of acute lupus pneumonitis but BAL allows to exclude infection and diffuse alveolar haemorrhage.

• Acute lupus pneumonitis must be suspected in case of non-response to conventional treatment for pneumonia and when extrapulmonary characteristics of systemic lupus erythematosus are noted.