Successful Avoidance of Cicatricial Tracheobronchial Stenosis in a Patient With Endobronchial Tuberculosis by Early Administration of Systemic High-Dose Corticosteroids: A Case Report.

A 63-year-old Japanese woman was referred to our hospital due to dry cough, fever, hoarseness, stridor, and difficulty breathing. Chest computed tomography showed circumferential wall thickening in the trachea, carina, right main bronchus, and right upper lobe bronchus, and granular and nodular shadows in right S2. Flexible laryngofiberscopy showed yellowish dry respiratory secretions adhering to the subglottis. Bronchoscopic findings showed that the tracheobronchial mucosa was swollen, hyperemic, and covered with yellowish-white, cheese-like materials, and ulcerative lesions with white coatings were observed from the subglottis to the trachea, carina, right main bronchus, and right upper lobe bronchus. A diagnosis of endobronchial tuberculosis (EBTB) was confirmed by polymerase chain reaction testing, and cultures were positive for Mycobacterium tuberculosis. In addition to anti-tuberculosis chemotherapy, intravenous high-dose methylprednisolone reduced her severe respiratory symptoms and prevented cicatricial tracheobronchial stenosis. Early administration of systemic high-dose corticosteroids may be effective for EBTB patients with severely active tracheobronchial mucosal and submucosal lesions.

Anti-MDA5 Antibody-positive Clinically Amyopathic Dermatomyositis with Rapidly Progressing Interstitial Lung Disease Successfully Treated by Initiation of Combined Immunosuppressive Therapy Plus Plasma Exchange and Subsequently Switching Tacrolimus to Tofacitinib.

A 36-year-old man with inverse Gottron's sign was admitted for clinically amyopathic dermatomyositis (CADM) with rapidly progressive interstitial lung disease (RP-ILD). Early addition of plasma exchange (PE) to triple therapy improved severe respiratory failure and transiently decreased serum ferritin levels and anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab) titers. Furthermore, switching from tacrolimus to tofacitinib resulted in disease remission. Recognition of the inverse Gottron's sign may allow for the earlier diagnosis of anti-MDA5 Ab-positive dermatomyositis, and early addition of PE to triple therapy and administration of tofacitinib in refractory cases may be effective for anti-MDA5 Ab-positive CADM with RP-ILD under life-threatening conditions.

Atezolizumab-Induced Lambert-Eaton Myasthenic Syndrome in a Patient With Small-Cell Lung Cancer.

The case of a 70-year-old man who developed Lambert-Eaton myasthenic syndrome (LEMS) while receiving atezolizumab treatment for extensive-stage small-cell lung cancer (SCLC) is presented. He started receiving maintenance immunotherapy with atezolizumab following four cycles of combination therapy with atezolizumab, carboplatin, and etoposide. After five cycles of maintenance atezolizumab therapy, he complained of muscle weakness in the lower limbs and fatigue. Electromyographic findings and positive results for anti-P/Q-type voltage-gated calcium channel antibody made a diagnosis of LEMS. Based on the onset time of LEMS and the state of his underlying cancer at the time of the appearance of neurological symptoms, he was diagnosed with LEMS as an immune-related adverse event (irAE) induced by atezolizumab. After discontinuing atezolizumab treatment and initiating combination therapy with steroid pulse plus intravenous immunoglobulin, his neurological symptoms improved. Although 18 months have passed since the discontinuation of atezolizumab treatment, there has been neither recurrence of neurological symptoms nor a progression of his cancer without salvage chemotherapy. This is a rare case of LEMS as a neurological irAE induced by atezolizumab. Clinicians must be aware of the potential for LEMS to develop in SCLC patients taking atezolizumab treatment.

Autoimmune Pulmonary Alveolar Proteinosis during the Treatment of Idiopathic Inflammatory Myopathy.

Approximately 50% of idiopathic inflammatory myopathies (IIMs) are associated with interstitial lung disease (ILD). Typically, IIM-ILD manifests as nonspecific interstitial pneumonia. We herein report a rare case of a 78-year-old man with autoimmune pulmonary alveolar proteinosis (PAP) that developed during IIM treatment. The diagnosis of autoimmune PAP was based on detecting anti-granulocyte-macrophage colony-stimulating factor antibodies. We postulated that PAP may have been induced by IIM treatment with prednisolone. Our case suggests that the possibility of autoimmune PAP should be considered in patients with lung lesions during the clinical course of IIM.

Alveolar Hemorrhage Caused by the Combination of Immune Checkpoint Inhibitors (ICIs) and Angiogenesis Inhibitors: The Underlying Long-Term Vascular Endothelial Growth Factor (VEGF) Inhibition.

The combination of immune checkpoint inhibitors (ICIs) and other anticancer agents is the standard of care for various cancers. Bevacizumab, an anti-angiogenesis inhibitor, causes serious adverse events such as pulmonary hemorrhage (PH). Here, we present a case of drug-induced diffuse alveolar hemorrhage (DAH), an adverse event, in a patient with hepatocellular carcinoma who was treated with a combination of ICIs and anti-angiogenesis inhibitors after long-term use of lenvatinib, which inhibits vascular endothelial growth factor (VEGF). An 85-year-old man with hepatocellular carcinoma initially received lenvatinib, a multi-kinase inhibitor, but the drug was later switched to bevacizumab-atezolizumab combination therapy owing to disease progression. After five cycles, he developed dyspnea and diffuse ground-glass opacities, which improved with discontinuation of the combination therapy and initiation of steroid pulse therapy. Our case findings indicate that both ICIs and anti-angiogenesis inhibitors cause drug-induced DAH, and their combination may increase the severity of DAH. Moreover, long-term VEGF inhibition may induce the development of DAH. Clinicians need to be aware that long-term VEGF inhibition may be associated with DAH and should consider the risk management of such adverse events while using this combination therapy.

[A case of pulmonary nontuberculous mycobacteriosis caused by Mycobacterium branderi].

The patient was a 56-year-old man, who was found to have a cavitary lesion surrounded by small nodules in the left upper lobe (S(1+2)) on the chest computed tomography (CT) scan prior to surgery for oropharyngeal cancer. Both sputum and bronchial lavage smears for acid-fast bacilli were positive, but a polymerase chain reaction for Mycobacterium tuberculosis and Mycobacterium avium complex failed to identify the isolates. Mycobacterium species were cultured in 4 weeks. Mycobacterium branderi was identified by determining the nucleic acid sequences of the 16S ribosomal RNA (16S rRNA) and RNA polymerase B (rpoB) genes. Chemotherapy and radiotherapy for esophageal cancer were started 5 months after the surgery for oropharyngeal cancer. The patient developed fever during the second round of chemotherapy. After chemotherapy and radiotherapy, the wall of the cavitary lesion thickened and a consolidation shadow was noted in the lower portion of the cavitary lesion on the chest CT scan. Combined therapy with clarithromycin, ciprofloxacin, and ethionamide improved the clinical symptoms; further, the abnormal chest shadows disappeared, and the sputum smears and cultures for acid-fast bacilli were negative. Although, currently, there are no recommended therapeutic regimens for pulmonary nontuberculous mycobacteriosis caused by M. branderi, combined therapy including the drugs used in this case may have a beneficial effect on this disease.

Pulmonary collectins protect macrophages against pore-forming activity of Legionella pneumophila and suppress its intracellular growth.

Pulmonary collectins, surfactant proteins A (SP-A) and D (SP-D), play important roles in innate immunity of the lung. Legionella pneumophila is a bacterial respiratory pathogen that can replicate within macrophages and causes opportunistic infections. L. pneumophila possesses cytolytic activity, resulting from insertion of pores in the macrophage membrane upon contact. We examined whether pulmonary collectins play protective roles against L. pneumophila infection. SP-A and SP-D bound to L. pneumophila and its lipopolysaccharide (LPS) and inhibited the bacterial growth in a Ca(2+)-dependent manner. The addition of LPS in the culture blocked the inhibitory effects on L. pneumophila growth by the collectins, indicating the importance of LPS-collectin interaction. When differentiated THP-1 cells were infected with L. pneumophila in the presence of SP-A and SP-D, the number of permeable cells was significantly decreased, indicating that pulmonary collectins inhibit pore-forming activity of L. pneumophila. The number of live bacteria within the macrophages on days 1-4 after infection was significantly decreased when infection was performed in the presence of pulmonary collectins. The phagocytosis experiments with the pH-sensitive dye-labeled bacteria revealed that pulmonary collectins promoted bacterial localization to an acidic compartment. In addition, SP-A and SP-D significantly increased the number of L. pneumophila co-localized with LAMP-1. These results indicate that pulmonary collectins protect macrophages against contact-dependent cytolytic activity of L. pneumophila and suppress intracellular growth of the phagocytosed bacteria. The promotion of lysosomal fusion with Legionella-containing phagosomes constitutes a likely mechanism of L. pneumophila growth suppression by the collectins.

Pulmonary surfactant protein D binds MD-2 through the carbohydrate recognition domain.

Pulmonary surfactant protein D (SP-D) is a member of the collectin family and plays crucial roles in the innate immunity of the lung. We have previously shown that surfactant protein A (SP-A), a homologous collectin, interacts with MD-2 and alters lipopolysaccharide signaling. In this study, we examined and characterized the binding of SP-D to MD-2 using a soluble form of recombinant MD-2 (sMD-2). SP-D bound in a concentration- and Ca(2+)-dependent manner to sMD-2 coated onto microtiter wells. Excess mannose abolished the binding of SP-D to sMD-2. In solution, SP-D cosedimented with sMD-2 in the presence of Ca(2+). The direct binding of SP-D to sMD-2 was confirmed by BIAcore analysis. Anti-SP-D monoclonal antibody that recognizes the carbohydrate recognition domain (CRD) of SP-D significantly inhibited the binding of SP-D to sMD-2, indicating the involvement of the CRD for the binding to sMD-2. Ligand blot analysis revealed that SP-D bound to N-glycopeptidase F-treated sMD-2. In addition, the biotinylated SP-D pulled down the mutant sMD-2 with Asn(26) --> Ala and Asn(114) --> Ala substitutions, which lacks the consensus for N-glycosylation. Furthermore, the sMD-2 mutant cosedimented SP-D. These results demonstrate that SP-D directly interacts with MD-2 through the CRD.

Pulmonary surfactant protein D inhibits lipopolysaccharide (LPS)-induced inflammatory cell responses by altering LPS binding to its receptors.

Pulmonary surfactant protein D (SP-D) is a member of the collectin family that plays an important role in regulating innate immunity of the lung. We examined the mechanisms by which SP-D modulates lipopolysaccharide (LPS)-elicited inflammatory cell responses. SP-D bound to a complex of recombinant soluble forms of Toll-like receptor 4 (TLR4) and MD-2 with high affinity and down-regulated tumor necrosis factor-alpha secretion and NF-kappaB activation elicited by rough and smooth LPS, in alveolar macrophages and TLR4/MD-2-transfected HEK293 cells. Cell surface binding of both serotypes of LPS to TLR4/MD-2-expressing cells was attenuated by SP-D. In addition, SP-D significantly reduced MD-2 binding to both serotypes of LPS. A chimera containing the N-terminal region and the collagenous domain of surfactant protein A, and the coiled-coil neck and lectin domains of SP-D, was a weak inhibitor of LPS-induced cell responses and MD-2 binding to LPS, compared with native SP-D. The collagenase-resistant fragment consisting of the neck plus the carbohydrate recognition domain of SP-D also was a very weak inhibitor of LPS activation. This study demonstrates that SP-D down-regulates LPS-elicited inflammatory responses by altering LPS binding to its receptors and reveals the importance of the correct oligomeric structure of the protein in this process.

[A case of severe airflow limitation markedly improved by inhalation therapy in non-smoking woman with chronic obstructive pulmonary disease].

A 67-year old woman who had never smoked presented with dyspnea on effort and general fatigue, which had first appeared 4 years ago. She had lived for 35 years with her husband who was a heavy smoker. Chest roentgenogram showed pulmonary over-inflation, but chest CT scans didn't demonstrate emphysematous changes. Neutrophil-dominant sputum cytology, a PaO2 of 69.5 Torr, and combined ventilatory impairment on respiratory function test were revealed. FEV1.0 improved 80 ml after beta2-agonist inhalation. Although the respiratory symptoms were improved by inhaled anti-cholinergic drug, residual volume increased minimally. After the use of inhaled steroid drug (HFA-BDP) and salmeterol, the symptoms and residual volume were markedly improved. One year later, FEV1.0 increased by 450 ml. The low attenuation area detected by CT scans decreased, mainly in the lower lung field. Passive smoking might have contributed to her airflow limitation.

[A case of pyogenic spondylitis mimicking a spinal invasion of lung cancer].

A 58-year old man was admitted to our hospital complaining of right back pain, fever, abdominal fullness and epigastralgia. Chest CT revealed a mass shadow in the right S6 together with destruction of the thoracic vertebrae. These findings suggested lung cancer and its spinal invasion. A transbronchial lung biopsy specimen showed inflammatory lymphocyte infiltration. MRI T2 image of the spine showed a high intensity at the Th7/8 disc space, suggesting pyogenic spondylitis. After broad-spectrum antibiotics including PAMP/BP and CLDM were administered, both the spinal lesion and the pulmonary lesion improved gradually. The clinical course suggested that the pulmonary inflammatory lesion had spread from pyogenic spondylitis. In our case, the pyogenic spondylitis was mimicking a spinal invasion of lung cancer. In addition, MRI is thought to be useful for diagnosing spinal lesions.