Aiko Masunaga

Galectin-9 Attenuates Acute Lung Injury by Expanding CD14– Plasmacytoid Dendritic Cell–like Macrophages

RATIONALE Galectin (Gal)-9 plays a crucial role in the modulation of innate and adaptive immunity. OBJECTIVES To investigate whether Gal-9 plays a role in a murine acute lung injury (ALI) model. METHODS C57BL/6 mice were pretreated with Gal-9 by subcutaneous injection 24 and 48 hours before intranasal LPS inoculation. MEASUREMENTS AND MAIN RESULTS Gal-9 suppressed pathological changes of ALI induced by LPS. Gal-9 reduced levels of proinflammatory cytokines and chemokines, such as tumor necrosis factor (TNF)-α, IL-1β, IL-6, and keratinocyte-derived cytokine; decreased neutrophils; and increased IL-10 and CD11b(+)Gr-1(+) macrophages in the bronchoalveolar lavage fluid of ALI mice. In Gal-9-deficient mice, pathological changes of ALI were exaggerated, and the number of neutrophils and the TNF-α level were increased. CD11b(+)Gr-1(+) cells were increased in the spleen of both Gal-9-treated and phosphate-buffered saline (PBS)-treated ALI mice, but only Gal-9 increased the ability of CCR2-expressing macrophages to migrate toward monocyte chemoattractant protein-1. Transfer of CD11b(+)Gr-1(+) macrophages obtained from Gal-9-treated mice ameliorated ALI. CD11b(+)Gr-1(+) macrophages obtained from Gal-9-treated but not PBS-treated mice suppressed TNF-α and keratinocyte-derived cytokine production from LPS-stimulated macrophages, and down-regulated Toll-like receptor-4 (TLR4) and TLR2 expression on thioglycollate-elicited macrophages. Fluorescence-activated cell-sorting analysis revealed that CD14 is negligible on CD11b(+)Gr-1(+) macrophages obtained from Gal-9-treated mice, although those from both groups resembled plasmacytoid dendritic cells (pDCs). Gal-9 down-regulated CD14 on pDC-like macrophages from PBS-treated mice independently of Gal-9/Tim-3 (T-cell immunoglobulin- and mucin domain-containing molecule-3) interaction, resulting in the acquisition of suppressive function, suggesting that the loss of CD14 by Gal-9 is critical for the suppression of pDC-like macrophages. CONCLUSIONS Gal-9 attenuates ALI by expanding CD14(-)CD11b(+)Gr-1(+) pDC-like macrophages by preferentially suppressing macrophage functions to release proinflammatory cytokines through TLR4 and TLR2 down-regulation.

Favorable outcome with hemoperfusion of polymyxin B-immobilized fiber column for rapidly progressive interstitial pneumonia associated with clinically amyopathic dermatomyositis: report of three cases

We present 3 cases of rapidly progressive interstitial pneumonia (RPIP) associated with clinically amyopathic dermatomyositis (C-ADM) that were treated with two courses of direct hemoperfusion with polymyxin B-immobilized fiber column (PMX-DHP). Despite initial treatment with high-dose corticosteroids, pulsed cyclophosphamide, and cyclosporine, the lung disease and hypoxemia deteriorated in all the patients. After PMX-DHP treatment, the PaO2/FiO2 ratio and serum LDH and KL-6 were improved, the abnormal shadows in chest high-resolution computed tomography (HRCT) scans gradually decreased, and, finally, all patients survived. These findings indicate that PMX-DHP treatment could be effective in the management of RPIP in patients with C-ADM in combination with conventional therapy.

Successful Treatment of Severe Amiodarone Pulmonary Toxicity With Polymyxin B-Immobilized Fiber Column Direct Hemoperfusion

Amiodarone pulmonary toxicity (APT) is the most serious side effect of amiodarone. Although severe APT, such as ARDS, is rare, mortality of severe APT is high. Polymyxin B-immobilized fiber column direct hemoperfusion (PMX-DHP) is a medical device that reduces blood endotoxin levels in sepsis. Recent reports have shown that PMX-DHP improves oxygenation in patients with acute exacerbation of idiopathic pulmonary fibrosis and drug-induced severe interstitial pneumonia. Here, we present a case study of a patient with severe APT treated with PMX-DHP with complete recovery. The patient rapidly developed respiratory failure and required mechanical ventilation. Despite corticosteroid pulse therapy, no clinical improvement was noted. PMX-DHP was then started, and severe respiratory failure improved with reduction of serum levels of amiodarone and its metabolite monodesethylamiodarone. The patient was weaned from mechanical ventilation and has done well without recurrence. To our knowledge, this is the first reported case of PMX-DHP therapy for severe APT. We speculate that PMX-DHP could be a new treatment strategy for severe APT.

Efficacy of direct hemoperfusion using polymyxin B-immobilized fiber column (PMX-DHP) in rapidly progressive interstitial pneumonias: results of a historical control study and a review of previous studies:

Background: Direct hemoperfusion using polymyxin B-immobilized fiber column (PMX-DHP) therapy has been approved for sepsis-associated acute respiratory distress syndrome, but its efficacy for other rapidly progressive interstitial pneumonias (RPIPs) is unclear. The purpose of this study was to examine the efficacy of PMX-DHP therapy for acute respiratory failure in patients with RPIPs, when compared with a historical control receiving conventional treatment without PMX-DHP. Methods: This study comprised 77 patients with RPIPs in our institute between January 2002 and December 2015. The initial 36 patients between January 2002 and March 2007 were treated without PMX-DHP (historical control group), and the following 41 patients between April 2007 and December 2015 were treated with PMX-DHP (PMX-DHP group) once daily for two successive days concurrently with corticosteroids and/or immunosuppressive agents. The 90-day mortality and clinical factors were compared between the groups. Cox proportional hazards models were constructed to analyze 90-day mortality and identify predictors. Results: The 90-day mortality rate was significantly lower in the PMX-DHP group than in the controls (41.5% versus 66.7%, p = 0.019). PMX-DHP therapy was significantly associated with mortality (hazard ratio 0.505; 95% confidence interval, 0.270–0.904; p = 0.032). There were significant differences in the serial changes in the PaO2/FiO2 ratio, SOFA score, and blood neutrophil counts from days 0–5 after PMX-DHP between the survivor and non-survivor groups (p = 0.015, p < 0.001, p = 0.035, respectively). The improved PaO2/FiO2 ratio on day 3 significantly correlated with the change in blood neutrophil counts (rs = −0.431, p = 0.006). Conclusions: PMX-DHP therapy may be effective in RPIPs patients accompanied by acute respiratory failure and is expected to reduce mortality rates.

Symptomless Pulmonary Cryptococcosis in a Psoriatic Arthritis Patient during Infliximab Therapy

Dear Editor: Pulmonary cryptococcosis is a common opportunistic infection in immunosuppressed patients1. To our knowledge, this is the first reported case of pulmonary cryptococcosis in a psoriasis patient undergoing treatment with biologics. A 55-year-old man presented with an itching eruption on his head for 2 years. His skin condition got progressively worse and he reported polyarticular pain. At the initial visit, he had a systemic psoriatic eruption (Psoriasis Area and Severity Index [PASI] 14.8) and swollen joints of the shoulders, left wrist, left digitus minimus, and left knee (Disease Activity Score 28 including C-reactive protein [DAS 28-CRP]). Although he had been treated with topical steroids and vitamin D3 ointment, the treatment was not effective. Infliximab therapy (5 mg/kg) was started for both the psoriatic skin lesions and arthritis in December 2012. The screening examination for infliximab therapy revealed normal laboratory data and chest computed tomography (CT), as well as a serum Krebs von den Lungen (KL)-6 level of 266 U/ml (normal is less than 401 U/ml). A raised serum level of KL-6 is known to exist in interstitial pneumonia2. He was then treated with 5 mg/kg of intravenous infliximab that was administered at weeks 2 and 6, and then every 8 weeks thereafter. At 7 months after initiation of the infliximab therapy, although the patient denied cough or sputum or fever, and his β-D glucan, cryptococcal antigen and QuantiFERON-TB Test (Cellestis Ltd., Carnegie, Victoria, Australia) were all within the normal range, his serum KL-6 level was elevated at 585 U/ml. The patients chest CT showed ground glass opacities bilaterally in the lower lobes and multiple small nodules in the right middle lobe (Fig. 1A). The cytology of the bronchoalveolar lavage fluid revealed encapsulated yeast, indicating the presence of cryptococcus (Fig. 1B). Thus, the patient was diagnosed with pulmonary cryptococcosis. The infliximab therapy was discontinued and oral fluconazole (200 mg/day) treatment was initiated. After 3 months, the abnormal chest CT shadow and the serum KL-6 level improved. Fig. 1 (A) Chest computed tomography showed multiple small nodules at the right middle lobe (circle). (B) Cytology of bronchoalveolar lavage fluid showed encapsulated yeasts (arrows), which is consistent with cryptococcosis species (Papanicolaou stain, ×400). ... Infliximab is a tumor necrosis factor-α (TNF-α) inhibitor for the treatment of psoriasis and other inflammatory diseases. The main, severe adverse events related to anti TNF-α therapy are infectious diseases. Cryptococcosis species infections have been reported at a rate of 5.08 per 100,000 in infliximab-treated patients3. Although there are several case reports of pulmonary cryptococcosis in patients treated with infliximab, one of them is a case of pulmonary cryptococcosis in a Crohns disease patient who was receiving infliximab monotherapy without other immunosuppressive drugs4. There are no reports of pulmonary cryptococcal infection in psoriasis patients treated with biologics. It is generally accepted that cryptococcosis usually occurs as an opportunistic infection in a compromised host. We speculated that the immunosuppression caused by infliximab treatment must have resulted in pulmonary cryptococcosis in the previously reported in vivo cases5. Dermatologists recognize that continual careful monitoring of unexpected side effects is necessary in psoriasis patients treated with biological drugs. Pulmonary cryptococcosis must now be recognized as a potential severe complication of treatment with biologics in psoriasis patients.