Suppression of Type I Interferon Signaling in Myeloid Cells by Autoantibodies in Severe COVID-19 Patients.

PURPOSE: Auto-antibodies (auto-abs) to type I interferons (IFNs) have been identified in patients with life-threatening coronavirus disease 2019 (COVID-19), suggesting that the presence of auto-abs may be a risk factor for disease severity. We therefore investigated the mechanism underlying COVID-19 exacerbation induced by auto-abs to type I IFNs. METHODS: We evaluated plasma from 123 patients with COVID-19 to measure auto-abs to type I IFNs. We performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from the patients with auto-abs and conducted epitope mapping of the auto-abs. RESULTS: Three of 19 severe and 4 of 42 critical COVID-19 patients had neutralizing auto-abs to type I IFNs. Patients with auto-abs to type I IFNs showed no characteristic clinical features. scRNA-seq from 38 patients with COVID-19 revealed that IFN signaling in conventional dendritic cells and canonical monocytes was attenuated, and SARS-CoV-2-specific BCR repertoires were decreased in patients with auto-abs. Furthermore, auto-abs to IFN-α2 from COVID-19 patients with auto-abs recognized characteristic epitopes of IFN-α2, which binds to the receptor. CONCLUSION: Auto-abs to type I IFN found in COVID-19 patients inhibited IFN signaling in dendritic cells and monocytes by blocking the binding of type I IFN to its receptor. The failure to properly induce production of an antibody to SARS-CoV-2 may be a causative factor of COVID-19 severity.

Pneumonia due to Achromobacter xylosoxidans with a chronic course resembling non-tuberculous mycobacterial infection.

Achromobacter xylosoxidans is a common bacterium that rarely causes pneumonia. Determining whether A. xylosoxidans is the cause of lung infection in patients suspected of having chronic infectious lung disease is challenging because it can present with colonization. We report a case of a 56-year-old immunocompetent woman suspected of having non-tuberculous mycobacteria (NTM) infection on imaging examination and monitored for 3 years. Sputum examinations revealed A. xylosoxidans several times, and it was determined to be a colonization. A. xylosoxidans was isolated from bronchial lavage fluid and aspirated sputum, but no evidence of NTM was observed. She was diagnosed with A. xylosoxidans infection and given ceftazidime for 2 weeks. Her symptoms and imaging findings improved rapidly after treatment, without recurrences. A. xylosoxidans rarely causes chronic lower respiratory tract infections similar to NTM in immunocompetent patients. A. xylosoxidans may be a target for treatment when detected in lower respiratory tract specimens.

Elevated Myl9 reflects the Myl9-containing microthrombi in SARS-CoV-2-induced lung exudative vasculitis and predicts COVID-19 severity.

The mortality of coronavirus disease 2019 (COVID-19) is strongly correlated with pulmonary vascular pathology accompanied by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-triggered immune dysregulation and aberrant activation of platelets. We combined histological analyses using field emission scanning electron microscopy with energy-dispersive X-ray spectroscopy analyses of the lungs from autopsy samples and single-cell RNA sequencing of peripheral blood mononuclear cells to investigate the pathogenesis of vasculitis and immunothrombosis in COVID-19. We found that SARS-CoV-2 accumulated in the pulmonary vessels, causing exudative vasculitis accompanied by the emergence of thrombospondin-1-expressing noncanonical monocytes and the formation of myosin light chain 9 (Myl9)-containing microthrombi in the lung of COVID-19 patients with fatal disease. The amount of plasma Myl9 in COVID-19 was correlated with the clinical severity, and measuring plasma Myl9 together with other markers allowed us to predict the severity of the disease more accurately. This study provides detailed insight into the pathogenesis of vasculitis and immunothrombosis, which may lead to optimal medical treatment for COVID-19.

Temporal characteristics of aspiration pneumonia in elderly inpatients: From resumption of oral intake to onset.

BACKGROUND: Elderly inpatients who develop fevers after resumption of oral intake are often considered to have aspiration pneumonia (AP) and be tentatively fasted. Fasting has been associated with prolonged hospital stays and decreased swallowing ability. The purpose of this study was to compare AP and other infections after resumption of oral intake in elderly inpatients and to identify the clinical characteristics. PATIENTS AND METHODS: The records of patients who were admitted to a public tertiary hospital and referred for evaluation of swallowing disability were retrospectively reviewed to identify those who had developed AP, non-AP, or urinary tract infection (UTI) after resumption of oral intake. Eligible patients were enrolled consecutively in the study. The patient characteristics, physical findings, laboratory data, oral intake status at the time of onset of symptoms, and rate of discontinuation of oral intake after onset of infection were compared between the three types of infection. RESULTS: A total of 193 patients developed an infectious illness after resuming oral intake. Among them, 114 patients had a diagnosis of AP (n = 45), non-AP (n = 24), or UTI (n = 45). There were no significant differences in patient characteristics, physical findings or laboratory data between the group with AP and the other two groups. AP developed at a median of 6 (range 1-16) days after resumption of oral intake. The rate of discontinuation of oral intake was 91.1% in the AP group, 58.3% in the non-AP group, and 26.7% in the UTI group, respectively. CONCLUSION: Infectious diseases other than AP should be considered in the differential diagnosis when nosocomial fever develops in elderly inpatients more than 17 days after resuming oral intake. Furthermore, nosocomial fever after resuming oral intake has many causes other than AP, and discontinuation of oral intake should be carefully considered.

Yellow nail syndrome with massive chylothorax after esophagectomy: A case report.

Yellow nail syndrome (YNS) is a rare condition characterized by the triad of yellow nails, lymphedema, and respiratory manifestations. Diuretics and thoracic drainage are often not effective in YNS, and the most effective treatments are pleurodesis and decortication/pleurectomy. A 66-year-old man was admitted to our hospital for YNS after esophagectomy with gastric tube reconstruction for esophageal cancer. The patient presented with yellow nails and lymphedema. Chest X-rays and computed tomography showed massive pleural effusions and ascites that were both chylous. The patient was considered to have YNS that became apparent after surgery. He recovered with diuretics and a low-fat diet without pleurodesis and decortication/pleurectomy. Thoracic surgery can exacerbate the functional impairment of lymphatic drainage in patients with asymptomatic and undiagnosed YNS, and can lead to further development of YNS-related clinical symptoms. Despite relatively massive chylothorax following thoracic surgery, chylothorax related to YNS could be successfully controlled with conservative treatment without pleurodesis and decortication/pleurectomy.

Voriconazole treatment of pulmonary mycosis caused by Chrysosporium zonatum after treatment for pulmonary tuberculosis.

Chrysosporium zonatum is a soil-dwelling fungus that rarely causes pulmonary infections, and a small number of cases have been reported to date. A 74-year-old man, who had previously been treated for tuberculosis, presented with symptoms of low-grade fever, anorexia, cough, and bloody sputum. Chest computed tomography (CT) showed a thick-walled cavitary lesion in the right upper lobe, in which there was a suspected mycotic mass. Initially, the patient was suspected to have chronic aspergillosis due to positive serum anti-Aspergillus antibodies. However, bronchoscopic culture revealed the growth of C. zonatum. Symptoms and imaging findings improved with administration of voriconazole for 18 months. Infection by C. zonatum is very rare and is difficult to differentiate from aspergillosis by clinical features. Clinicians should be aware of the possibility of coinfection with C. zonatum and Aspergillus sp. Voriconazole may be an effective treatment option.

Short-Term Corticosteroid Therapy for Early Exacerbation of COVID-19 Pneumonia: A Case Report.

BACKGROUND The effect of corticosteroids in the management of patients with coronavirus disease 2019 (COVID-19) is unclear. CASE REPORT A 67-year-old man who tested positive for COVID-19 by reverse-transcription PCR (RT-PCR) analysis was admitted to our hospital. On admission, he had no dyspnea and his oxygen saturation (SpO2) level was normal. Chest imaging revealed ground-glass opacities (GGO) distributed in both lung fields. Four days after admission, bilateral lung shadows worsened, with a slight reduction in SpO2 levels. Short-term corticosteroid therapy was initiated, and SpO2 and radiographic findings promptly improved without use of antiviral agents. CONCLUSIONS More data are required to ascertain the role of corticosteroids in the management of COVID-19 pneumonia.

Pulmonary Cryptococcosis in a Nurse Initially Suspected of Having Pulmonary Tuberculosis.

BACKGROUND Pulmonary cryptococcosis can be associated with various imaging findings and can occur in immunocompetent hosts. It is sometimes difficult to distinguish pulmonary cryptococcosis from pulmonary tuberculosis based on imaging findings. CASE REPORT A 34-year-old female nurse who worked in an endoscopy examination room visited our hospital because of an abnormal lung shadow. At her workplace, a gastrointestinal endoscopy had been performed on a patient with infectious tuberculosis. The nurse was asymptomatic, and acid-fast staining and culture of her sputum were negative. Chest computed tomography depicted multiple nodules distributed along the bronchi. An acid-fast smear test of bronchial lavage was negative and cytological investigations revealed many yeast-like fungi. Fluconazole was administered and the computed tomography findings improved. CONCLUSIONS It is important to consider cryptococcosis, even in patients suspected of having tuberculosis.

A Fatal Case of Atypical Disseminated Herpes Zoster in a Patient with Meningoencephalitis and Seizures Associated with Steroid Immunosuppression.

BACKGROUND Herpes zoster is caused by the reactivation of the varicella zoster virus (VZV) and usually presents with vesicular skin lesions with a dermatomal distribution. Disseminated herpes zoster (DHZ) infection is characterized by non-dermatomal skin eruptions, often with involvement of other organs, and occurs in immunocompromised patients. CASE REPORT A 69-year-old man who was treated with prednisolone for amiodarone-associated interstitial lung disease, presented with seizures and altered consciousness. He had an erythematous rash with raised vesicles involving the skin of the genital region, left thigh, and abdomen. Following a diagnosis of DHZ with herpes zoster meningoencephalitis, he was treated with intravenous acyclovir. However, his level of consciousness did not improve, and he died of respiratory failure due to aspiration pneumonia. CONCLUSIONS A diagnosis of DHZ should be considered in immunosuppressed patients treated with steroids who present with seizures. A detailed search for skin eruptions should be conducted to enable early diagnosis and treatment.

Lung Mycobacterium avium developed after removing an acupuncture needle from the lung.

Acupuncture needles can cause non-tuberculosis mycobacteria (NTM) infection on the skin, but there are no reports that acupuncture needles inserted into the lung have caused lung NTM infection. A 63-year-old woman, who underwent removal of a broken acupuncture needle inserted into the lung nine years ago, was admitted with nodules in the right lung. The shadow was positioned where the needle had existed. Partial lung resection of the right lower lobe was performed, and the resected area showed caseous necrosis histopathologically. Furthermore, Mycobacterium avium was cultured from the specimen. When abnormal lung shadows are located where a resected foreign body appeared, NTM infection should be considered.

Repeated Diffuse Alveolar Hemorrhage in a Patient with Hemophilia B.

Diffuse alveolar hemorrhage (DAH) is a life-threatening complication that occurs in association with various diseases including coagulation disorders. In rare cases, it is caused by hemophilia. A 48-year-old man was admitted to our hospital for a third time due to DAH. Although the cause of DAH could not be identified by bronchoscopy or laboratory tests, a good response to corticosteroids suggested idiopathic DAH with pulmonary capillaritis. The patient was diagnosed with hemophilia B based on the results of a detailed inquiry, a mildly prolonged activated partial thromboplastin time, and low factor IX activity. Hemophilia may be an underlying factor that exacerbates the bleeding of patients with DAH, even when they show a good response to corticosteroids.

Prognostic and pathophysiological marker for patients with chronic thromboembolic pulmonary hypertension: Usefulness of diffusing capacity for carbon monoxide at diagnosis.

BACKGROUND AND OBJECTIVE: Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease in some patients, despite improved treatments. Microvasculopathy has been implicated in the poor outcomes of patients with CTEPH. A reduction in the diffusing capacity for carbon monoxide (DLCO ) was previously suggested to indicate microvasculopathy in CTEPH patients; therefore, we assessed DLCO /alveolar ventilation (DLCO /VA ) as a prognostic and pathophysiological marker in CTEPH. METHODS: We performed a retrospective cohort study of 214 CTEPH patients consecutively diagnosed between 1986 and 2011. After exclusion of 24 patients because of missing DLCO data or severe obstructive impairment, the mortality rates of medically treated patients classified with normal or decreased DLCO values were compared, and prognostic factors were determined. The relationship between long-term surgical outcomes and DLCO /VA was also investigated. RESULTS: Ninety-one inoperable patients were treated medically, two of whom underwent balloon pulmonary angioplasty. Ninety-nine underwent pulmonary endarterectomy. The 5-year survival rate of medically treated patients was significantly lower in patients with decreased DLCO /VA than in those with normal values (61.4% vs 90.4%, P = 0.017). Decreased preoperative DLCO /VA was associated with a smaller percent decrease in post-operative pulmonary vascular resistance, but not with the extent of proximal thrombi; these results may support our hypothesis that DLCO reflects microvascular involvement. CONCLUSION: Decreased DLCO /VA was associated with poor outcomes of medically treated CTEPH patients; and may be useful for identifying high-risk patients, potentially leading to earlier and more appropriate interventions.

Prominin-1/CD133 expression as potential tissue-resident vascular endothelial progenitor cells in the pulmonary circulation.

Pulmonary vascular endothelial cells could contribute to maintain homeostasis in adult lung vasculature. "Tissue-resident" endothelial progenitor cells (EPCs) play pivotal roles in postnatal vasculogenesis, vascular repair, and tissue regeneration; however, their local pulmonary counterparts remain to be defined. To determine whether prominin-1/CD133 expression can be a marker of tissue-resident vascular EPCs in the pulmonary circulation, we examined the origin and characteristics of prominin-1/CD133-positive (Prom1(+)) PVECs considering cell cycle status, viability, histological distribution, and association with pulmonary vascular remodeling. Prom1(+) PVECs exhibited high steady-state transit through the cell cycle compared with Prom1(-) PVECs and exhibited homeostatic cell division as assessed using the label dilution method and mice expressing green fluorescent protein. In addition, Prom1(+) PVECs showed more marked expression of putative EPC markers and drug resistance genes as well as highly increased activation of aldehyde dehydrogenase compared with Prom1(-) PVECs. Bone marrow reconstitution demonstrated that tissue-resident cells were the source of >98% of Prom1(+) PVECs. Immunofluorescence analyses revealed that Prom1(+) PVECs preferentially resided in the arterial vasculature, including the resistant vessels of the lung. The number of Prom1(+) PVECs was higher in developing postnatal lungs. Sorted Prom1(+) PVECs gave rise to colonies and formed fine vascular networks compared with Prom1(-) PVECs. Moreover, Prom1(+) PVECs increased in the monocrotaline and the Su-5416 + hypoxia experimental models of pulmonary vascular remodeling. Our findings indicated that Prom1(+) PVECs exhibited the phenotype of tissue-resident EPCs. The unique biological characteristics of Prom1(+) PVECs predominantly contribute to neovasculogenesis and maintenance of homeostasis in pulmonary vascular tissues.

Endothelial-to-mesenchymal transition in lipopolysaccharide-induced acute lung injury drives a progenitor cell-like phenotype.

Pulmonary vascular endothelial function may be impaired by oxidative stress in endotoxemia-derived acute lung injury. Growing evidence suggests that endothelial-to-mesenchymal transition (EndMT) could play a pivotal role in various respiratory diseases; however, it remains unclear whether EndMT participates in the injury/repair process of septic acute lung injury. Here, we analyzed lipopolysaccharide (LPS)-treated mice whose total number of pulmonary vascular endothelial cells (PVECs) transiently decreased after production of reactive oxygen species (ROS), while the population of EndMT-PVECs significantly increased. NAD(P)H oxidase inhibition suppressed EndMT of PVECs. Most EndMT-PVECs derived from tissue-resident cells, not from bone marrow, as assessed by mice with chimeric bone marrow. Bromodeoxyuridine-incorporation assays revealed higher proliferation of capillary EndMT-PVECs. In addition, EndMT-PVECs strongly expressed c-kit and CD133. LPS loading to human lung microvascular endothelial cells (HMVEC-Ls) induced reversible EndMT, as evidenced by phenotypic recovery observed after removal of LPS. LPS-induced EndMT-HMVEC-Ls had increased vasculogenic ability, aldehyde dehydrogenase activity, and expression of drug resistance genes, which are also fundamental properties of progenitor cells. Taken together, our results demonstrate that LPS induces EndMT of tissue-resident PVECs during the early phase of acute lung injury, partly mediated by ROS, contributing to increased proliferation of PVECs.

Effects of Surgical and Medical Treatment on Quality of Life for Patients With Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: This study aimed to investigate the predictors of quality of life (QOL) in patients with chronic thromboembolic pulmonary hypertension (CTEPH), changes in QOL after surgical and medical treatments, and the relationship between baseline QOL and survival. METHODS AND RESULTS: QOL was measured in 128 patients with CTEPH (male/female: 42/86, age: 56±12 years, surgical/medical: 65/63) using the Short-Form 36 (SF-36) questionnaire. Multiple regression analysis showed pulmonary vascular resistance (PVR) and 6-min walking distance (6MWD) were associated with physical functioning (PF) (P<0.01) and physical component summary (PCS) (P<0.01). In the surgical group, 7 subscales and 2 summary scores improved significantly, and in the medical group 6 subscales and the mental component summary, although the change in QOL was greater in the surgical group. The patients in the conventional therapy group with higher PF had significantly better survival than those with lower PF (5-years survival: 89.5% vs. 50.8%, P=0.002). This difference in survival was not observed in the group receiving pulmonary arterial hypertension (PAH)-specific therapy (100% vs. 100%, P=0.746). CONCLUSIONS: PVR and 6MWD were associated with PF or PCS in CTEPH patients. QOL improved after surgical or medical therapy, with a greater change in the surgical group. PAH-specific therapy improved survival in patients with lower PF at diagnosis.

Vascular Repair by Tissue-Resident Endothelial Progenitor Cells in Endotoxin-Induced Lung Injury.

Vascular disruption is one of the pathological hallmarks in acute respiratory distress syndrome. Bone marrow (BM)-derived circulating endothelial progenitor cells (EPCs) and lung tissue-resident EPCs have been considered to play a pivotal role in pulmonary vascular repair; however, which population is predominant in local pulmonary vasculogenesis remains to be clarified. We therefore examined the origin of EPCs participating in the regenerative process of pulmonary vascular endothelial cells (PVECs) in experimental acute respiratory distress syndrome. Lung samples from mice administered LPS intratracheally were investigated for cell dynamics and EPC functions. Quantitative flow cytometric analysis demonstrated that the number of PVECs decreased by roughly 20% on Day 1 and then recovered on Day 7 of LPS challenge. Bromodeoxyuridine-incorporation assays and immunofluorescence microscopy demonstrated that proliferating PVECs preferentially located in the capillary vessels. Experiments using BM chimera mice revealed that most of the regenerating PVECs were tissue-resident cells, and BM-derived cells hardly engrafted as PVECs. The population of circulating putative phenotypical EPCs decreased during the first week after LPS challenge. The regenerating PVECs were characterized by high colony-forming and vasculogenic capacities, intracellular reactive oxygen species scavenging and aldehyde dehydrogenase activites, and enhanced gene expression of Abcb1b (a drug-resistant gene), suggesting that the population of PVECs included tissue-resident EPCs activated during regenerative process of PVECs. The proliferating PVECs expressed CD34, Flk-1/KDR, and c-kit more strongly and Prom1/CD133 less strongly on the surface than nonproliferating PVECs. Our findings indicated that lung tissue-resident EPCs predominantly contribute to pulmonary vascular repair after endotoxin-induced injury.

Hypoxia-induced proliferation of tissue-resident endothelial progenitor cells in the lung.

Exposure to hypoxia induces changes in the structure and functional phenotypes of the cells composing the pulmonary vascular wall from larger to most peripheral vessels. Endothelial progenitor cells (EPCs) may be involved in vascular endothelial repair. Resident EPCs with a high proliferative potential are found in the pulmonary microcirculation. However, their potential location, identification, and functional role have not been clearly established. We investigated whether resident EPCs or bone marrow (BM)-derived EPCs play a major role in hypoxic response of pulmonary vascular endothelial cells (PVECs). Mice were exposed to hypoxia. The number of PVECs transiently decreased followed by an increase in hypoxic animals. Under hypoxic conditions for 1 wk, prominent bromodeoxyuridine incorporation was detected in PVECs. Some Ki67-positive cells were detected among PVECs after 1 wk under hypoxic conditions, especially in the capillaries. To clarify the origin of proliferating endothelial cells, we used BM chimeric mice expressing green fluorescent protein (GFP). The percentage of GFP-positive PVECs was low and constant during hypoxia in BM-transplanted mice, suggesting little engraftment of BM-derived cells in lungs under hypoxia. Proliferating PVECs in hypoxic animals showed increased expression of CD34, suggesting hypoxia-induced gene expression and cell surface antigen of EPC or stem/progenitor cells markers. Isolated PVECs from hypoxic mice showed colony- and tube-forming capacity. The present study indicated that hypoxia could induce proliferation of PVECs, and the origin of these cells might be tissue-resident EPCs.

Association of plasma fibrinogen and plasminogen with prognosis of inoperable chronic thromboembolic pulmonary hypertension.

BACKGROUND: It is unclear whether abnormalities of coagulation or fibrinolysis are associated with disease progression of chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study was to investigate the association of these factors with the severity and prognosis of CTEPH. METHODS AND RESULTS: Between 1986 and 2011, plasma fibrinogen and plasminogen were measured in 89 of 106 consecutive patients with inoperable CTEPH (17 men; mean age, 55.9±14.1 years old; mean pulmonary arterial pressure, 44.0±12.4 mmHg) and the association of level with severity and prognosis were also examined. Seventeen patients had high fibrinogen and low plasminogen (medians, ≥291 mg/dl and <101%, respectively). These patients had significantly lower cardiac index (2.26±0.68 vs. 2.70±0.57 L·min(-1)·m(-2), P=0.007), higher pulmonary vascular resistance (PVR; 13.29±7.54 vs. 9.15±4.14 Wood units, P=0.003), and poor survival (5-year survival, 35.3% vs. 88.0%, P<0.001) compared to the other 72 patients. Additional analysis showed significantly poor survival in these patients compared with the other patients who did not have modern therapy. On multivariate analysis plasma fibrinogen, plasminogen and PVR were independent predictors of survival in medically treated patients. CONCLUSIONS: High plasma fibrinogen and low plasminogen are associated with poor survival in CTEPH patients without modern therapy.