STING-Associated Vasculopathy with Onset in infancy (SAVI) Presenting as Massive Intra Alveolar Hemorrhage

Type I interferons (IFNs) play a critical role in the innate immune response to pathogens, and abnormal activation of IFN signaling underlies a group of autoinflammatory diseases referred to as the type I interferonopathies. Stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) is a monogenic type I interferonopathy first described in 2014, caused by gain-of-function mutations in STING1 (previously named TMEM173) encoding STING, a key adaptor of the DNA recognition pathway [1]. Constitutive activation of STING triggers systemic inflammation, most typically resulting in skin damage (purplish scaly lesions of the extremities exacerbated by cold), pulmonary disease (recurrent cough, interstitial lung disease), and polyarthritis. Laboratory indices can be consistent with multisystem inflammation, with anemia, thrombocytosis, and elevated CRP. Non-specific markers of autoimmunity can also be positive [1]. SAVI-associated pulmonary involvement presents as diffuse interstitial lung disease that progresses to fibrosis. It is present in most patients, with, or in the absence of, other disease features [2]. Of note, to date, no case of SAVI manifesting as life threatening intra-alveolar hemorrhage has been described. Studies are in favor of a promising effect of JAK 1/2 inhibitors [2, 3] on all aspects of the SAVI clinical phenotype. Data suggest that baricitinib improves disease signs and symptoms and allows for a reduction of corticosteroid treatment. Here we describe a female child diagnosed with SAVI at the age of 4 years after an episode of severe diffuse alveolar hemorrhage, successfully treated with the JAK 1/2 inhibitor baricitinib and corticosteroids. She is the first child of an unrelated healthy couple. She had been followed from the age of 2.5 years for severe chronic anemia (lowest hemoglobin (Hb) 3 g/dl) attributed to iron deficiency after extensive investigation. She also had a diagnosis of reactive airway disease because of chronic dry cough exacerbated during viral infections treated with inhaled steroids. Growth was impaired, height being one standard deviation (SD) below her target height, and body mass index (BMI) in the third percentile. At the age of 3.5 years she presented with life-threatening acute respiratory distress requiring admission to an intensive care unit. Tests showed a poorly regenerative microcytic anemia (Hb 6.4 g/dL, mean corpuscular volume (MCV) 64 fl, reticulocytes 95 G/L [25–100 G/L]) without involvement of other lineages. Hemolytic anemia was ruled out. High resolution CT scan (HRCT) showed patchy alveolar condensation with ground glass opacities, and some centrilobular emphysema images (Fig. 1, B1). Bronchoscopy revealed profuse macroscopic intra-bronchial bleeding. Bronchoalveolar lavage (BAL) fluid analysis was noncontributory due to high contamination with bronchial cells. Extensive testing was negative, including basic immunologic tests of B and T cell function, microbiological exploration of sputum (bacterial, viral, fungal, and parasite) and research for cow’s milk allergy, and coeliac disease. Antinuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies (ANCA), anti-double stranded DNA antibodies (anti DNA), rheumatoid factor (FR), and anti-glomerular basement membrane (anti GBM) were all negative. Of note, no lung biopsy * Léa Roditis roditis.l@chu-toulouse.fr

To the Editor, Type I interferons (IFNs) play a critical role in the innate immune response to pathogens, and abnormal activation of IFN signaling underlies a group of autoinflammatory diseases referred to as the type I interferonopathies. Stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) is a monogenic type I interferonopathy first described in 2014, caused by gain-of-function mutations in STING1 (previously named TMEM173) encoding STING, a key adaptor of the DNA recognition pathway [1].
Constitutive activation of STING triggers systemic inflammation, most typically resulting in skin damage (purplish scaly lesions of the extremities exacerbated by cold), pulmonary disease (recurrent cough, interstitial lung disease), and polyarthritis. Laboratory indices can be consistent with multisystem inflammation, with anemia, thrombocytosis, and elevated CRP. Non-specific markers of autoimmunity can also be positive [1]. SAVI-associated pulmonary involvement presents as diffuse interstitial lung disease that progresses to fibrosis. It is present in most patients, with, or in the absence of, other disease features [2]. Of note, to date, no case of SAVI manifesting as life threatening intra-alveolar hemorrhage has been described. Studies are in favor of a promising effect of JAK 1/2 inhibitors [2,3] on all aspects of the SAVI clinical phenotype. Data suggest that baricitinib improves disease signs and symptoms and allows for a reduction of corticosteroid treatment.
Here we describe a female child diagnosed with SAVI at the age of 4 years after an episode of severe diffuse alveolar hemorrhage, successfully treated with the JAK 1/2 inhibitor baricitinib and corticosteroids. She is the first child of an unrelated healthy couple. She had been followed from the age of 2.5 years for severe chronic anemia (lowest hemoglobin (Hb) 3 g/dl) attributed to iron deficiency after extensive investigation. She also had a diagnosis of reactive airway disease because of chronic dry cough exacerbated during viral infections treated with inhaled steroids. Growth was impaired, height being one standard deviation (SD) below her target height, and body mass index (BMI) in the third percentile.
At the age of 3.5 years she presented with life-threatening acute respiratory distress requiring admission to an intensive care unit. Tests showed a poorly regenerative microcytic anemia (Hb 6.4 g/dL, mean corpuscular volume (MCV) 64 fl, reticulocytes 95 G/L [25-100 G/L]) without involvement of other lineages. Hemolytic anemia was ruled out. High resolution CT scan (HRCT) showed patchy alveolar condensation with ground glass opacities, and some centrilobular emphysema images ( Fig. 1, B1). Bronchoscopy revealed profuse macroscopic intra-bronchial bleeding. Bronchoalveolar lavage (BAL) fluid analysis was noncontributory due to high contamination with bronchial cells. Extensive testing was negative, including basic immunologic tests of B and T cell function, microbiological exploration of sputum (bacterial, viral, fungal, and parasite) and research for cow's milk allergy, and coeliac disease. Antinuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies (ANCA), anti-double stranded DNA antibodies (anti DNA), rheumatoid factor (FR), and anti-glomerular basement membrane (anti GBM) were all negative. Of note, no lung biopsy was performed. A final diagnosis of diffuse alveolar hemorrhage of unknown etiology was given. The patient initially received three daily intravenous pulses of steroids with rapid clinical improvement.
Four months after this acute episode she remained clinically asymptomatic but was still anemic. HRCT scan showed the persistence of the previously observed pattern. Bronchoscopy was repeated and BAL confirmed the diagnosis of intra alveolar hemorrhage, with the identification of hemoglobin-laden macrophages and a Golde score of 296. Monthly intravenous steroids pulses were initiated, together with prophylactic azithromycin and sulfamethoxazole/trimethoprim. Increased expression of a 24 interferon-stimulated gene (ISG) panel in blood was recorded on two different serum samples at the age of 4 years (7.85 and 5.81, respectively; cut-off value 2.758). The panel included IFI27, IFI44L,  IFIT1, ISG15, RSAD2, SIGLEC1, CMPK2, DDX60,  EPSTI1, FBXO39, HERC5, HES4, IFI44, IFI6, IFIH1,  IRF7, LAMP3, LY6E, MX1, NRIR, OAS1, OASL, OTOF, and SPATS2L. Targeted Sanger sequencing of STING1 and COPA genes identified a previously described heterozygous mutation in STING1 c.842G > A; p.(Arg281Gln). The same mutation was present in her mother, in whom ISG expression was within normal limits (2.02; cut-off value 2.758) on the one occasion tested. Notably, one year after this, the mother presented with arthralgia and inflammatory alopecia.
On steroid pulses, the proband remained clinically asymptomatic, her hemoglobin normalized and the reticulocyte count decreased from 84 to 45 G/L. She showed no features of other autoimmune or inflammatory dysfunction. Brain MRI revealed one right cerebellar micro-calcification in the context of a normal neurological examination. HRCT scan showed a reduction of ground glass opacities, a complete regression of alveolar condensations, and the persistence of interlobular septal thickening, diffuse micronodules, and cystic lesions (Fig. 1, B2). In order to limit prolonged steroid usage, at the age of 4 years and 6 months we introduced baricitinib according to a published dosing schedule (2 mg three times a day, 0.4 mg/kg/day) [3], enabling weaning off of corticosteroids one month later. Twelve months after the initiation of baricitinib, clinical evaluation revealed no respiratory signs and symptoms, a catch-up in height and BMI, and correction of anemia (Hb increasing from 11.8 g/dl to 13.6 g/dl, stable MCV around 80 fl and low reticulocytes (ranging between 45 and 64 G/L)). HRCT scan was stable. Pulmonary function tests were normal. Echocardiography showed no signs of pulmonary arterial hypertension. The interferon signature normalized (2.37; cut-off value 2.758) and immunological testing remained normal.
Twenty-four months after the initiation of baricitinib, clinical and biological evaluations were stable. Chest X-ray was unchanged compared to the time at treatment initiation. The 6-min walking test was within normal limits. Tolerance was good with no side effects, although asymptomatic BK virus was detected in the urine without BK viremia.
We report here the first case of SAVI presenting as massive, life-threatening intra-alveolar hemorrhage (and in the absence of other disease manifestations). Tang et al. [4] reported the first case of diffuse alveolar hemorrhage associated with SAVI in a patient who presented with pulmonary disease and failure to thrive. Respiratory symptoms included cough, tachypnea, dyspnea, wheezing, without hypoxemia, cyanosis, or retractions. The diagnosis was made based on the bronchoalveolar lavage fluid analysis. This patient secondarily showed positive ANCA and ANA (1/80).
Melki et al. [5] described three cases of SAVI, one of which carried the same de novo mutation seen in our patient. Clinical expression in this case was of acute respiratory distress in a 7-year-old patient from an outbred European couple. Computed tomography showed diffuse ground glass opacities, and lung biopsy revealed evidence of interstitial fibrosis with signs of vasculitis. This patient did not present intra-alveolar hemorrhage or chronic anemia.
Frémond et al. [2] reported data on 21 patients with SAVI, with the majority exhibiting symptoms during the first year of life. In this series, ll patients demonstrated pulmonary involvement. The main radiological patterns were ground glass opacities, cysts, and a mosaic appearance. The patient previously described by Tang et al. [4] was included in the report and was the only one for whom bronchoalveolar lavage fluid analysis was consistent with alveolar hemorrhage. As opposed to the case reported here, 86% of patients demonstrated skin involvement, three patients exhibited basal ganglia calcification in the absence of any clinical neurological involvement, and seven patients presented a polyarthritis. In this study, long term follow-up of eight patients treated with the JAK 1/2 inhibitor ruxolitinib identified variable improvement in pulmonary disease features and a reduction in inflammatory biomarkers. None of these patients were treated with barcitinib.
In a series reported by Sanchez et al., the safety and efficacy of baricitinib were studied in 18 patients, of whom four had SAVI [2,3]. The 6-min walking test, quality of life scores, and chest CT suggested stabilized to improved pulmonary involvement with baricitinib, allowing a reduction in daily steroid therapy. While inflammatory biomarkers fell, indices of interferon signaling remained elevated.
The interest of the clinical case presented here is threefold. First, to our knowledge it is the first case of SAVI presenting as isolated life-threatening intra-alveolar hemorrhage. Intraalveolar hemorrhage as the exclusive sign of pulmonary involvement has been described in COPA syndrome [6], another type I interferonopathy with autosomal dominant inheritance and clinical expression associating arthritis, lung involvement, and autoimmune features. Second, while in most cases of SAVI the responsible mutation occurs de novo, in our report the disease-associated mutation was inherited from an asymptomatic mother. Indeed, there are only four reports in the literature of familial transmission of a STING gain-of-function, and no clinically asymptomatic individual has been previously described. Finally, our report further emphasizes the potential efficacy of baricitinib in improving the clinical and biological features of the SAVI with good tolerance.