COVID-19 mRNA Vaccine-induced Pneumonitis.

A 65-year-old man experienced cough and shortness of breath 3 days after receiving the first dose of the Pfizer-BioNTech coronavirus disease 2019 (COVID-19) vaccine. Chest X-ray revealed bilateral infiltrates, and the desaturation deteriorated rapidly. The symptoms and radiographic abnormalities rapidly improved after the initiation of corticosteroid therapy. Intradermal testing of the Pfizer-BioNTech COVID-19 vaccine showed a delayed positive reaction. Based on these findings, the patient was diagnosed with COVID-19 vaccine-induced pneumonitis. The timing of the onset of pneumonitis after vaccination and the results of intradermal testing suggest that Type IV hypersensitivity against COVID-19 vaccine may have been responsible for this clinical condition.

Patients with MAC Lung Disease Have a Low Visceral Fat Area and Low Nutrient Intake.

OBJECTIVE: This study aimed to examine the nutritional status and nutrient intake of patients with MAC lung disease with a focus on visceral fat area. PATIENTS AND METHODS: Among 116 patients of our hospital with nontuberculous mycobacteriosis who were registered between May 2010 and August 2011, 103 patients with MAC lung disease were included in this study. In all patients, nutritional status and nutrient intake were prospectively examined. RESULTS: Patients were 23 men and 80 women (mean age, 72.3±10.9 years). BMI (kg/m2) at the time of registration was 20.4±2.7 in men and 19.2±2.9 in women. Visceral fat area (cm2) was significantly lower in women (35.7±26.6) than in men (57.5±47.4) (p=0.0111). The comparison with general healthy adults according to age revealed a markedly reduced visceral fat area among patients with MAC lung disease. With respect to nutrient intake, energy adequacy (86.1±15.7%), protein adequacy (82.4±18.2%), lipid adequacy (78.1±21.8%), and carbohydrate adequacy (89.6±19.2%) ratios were all low at the time of registration. BMI was significantly correlated with protein adequacy (p=0.0397) and lipid adequacy (p=0.0214) ratios, while no association was found between visceral fat area and nutrient intake. CONCLUSION: Patients with MAC lung disease had a low visceral fat area and low nutrient intake.

[A CASE OF PULMONARY MYCOBACTERIUM ABSCESSUS INFECTION SUCCESSFULLY TREATED WITH SHORT-TERM CAM, AMK, AND IPM/cs FOLLOWED BY LONG-TERM ORAL CAM AND LVFX].

A 78-year-old woman who had been treated for two years with ITCZ for chronic pulmonary aspergillosis associated with prior pulmonary tuberculosis was admitted to our hospital because of general fatigue and hemosputum along with deterioration of her chest radiographic findings. Mycobacterium abscessus had been isolated once from her sputum one year before admission. We performed fiberoptic bronchoscopy (FOB) in order to help establish a final diagnosis. Sputum aspirated from her bronchus on FOB stained positive for acid-fast bacilli and was negative for Tbc and MAC using PCR. From these results, we diagnosed the patient with pulmonary M. abscessus infection. Chemotherapy with AMK, IPM/cs, and CAM was initiated. Because her symptoms rapidly improved, we switched the chemotherapy to long-term oral CAM and LVFX, and she has been in a good condition at 12 months after the initiation of the therapy. Recently, subtypes of M. abscessus complex, such as M. massiliense, have been recognized, which are more sensitive to chemotherapy. Considering the good response to therapy, there is a possibility that is the patient in the current case had a M. massiliense infection.

Transcriptional events during the recovery from MRSA lung infection: a mouse pneumonia model.

Community associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is an emerging threat to human health throughout the world. Rodent MRSA pneumonia models mainly focus on the early innate immune responses to MRSA lung infection. However, the molecular pattern and mechanisms of recovery from MRSA lung infection are largely unknown. In this study, a sublethal mouse MRSA pneumonia model was employed to investigate late events during the recovery from MRSA lung infection. We compared lung bacterial clearance, bronchoalveolar lavage fluid (BALF) characterization, lung histology, lung cell proliferation, lung vascular permeability and lung gene expression profiling between days 1 and 3 post MRSA lung infection. Compared to day 1 post infection, bacterial colony counts, BALF total cell number and BALF protein concentration significantly decreased at day 3 post infection. Lung cDNA microarray analysis identified 47 significantly up-regulated and 35 down-regulated genes (p<0.01, 1.5 fold change [up and down]). The pattern of gene expression suggests that lung recovery is characterized by enhanced cell division, vascularization, wound healing and adjustment of host adaptive immune responses. Proliferation assay by PCNA staining further confirmed that at day 3 lungs have significantly higher cell proliferation than at day 1. Furthermore, at day 3 lungs displayed significantly lower levels of vascular permeability to albumin, compared to day 1. Collectively, this data helps us elucidate the molecular mechanisms of the recovery after MRSA lung infection.

Linezolid Exerts Greater Bacterial Clearance but No Modification of Host Lung Gene Expression Profiling: A Mouse MRSA Pneumonia Model.

BACKGROUND: Linezolid (LZD) is beneficial to patients with MRSA pneumonia, but whether and how LZD influences global host lung immune responses at the mRNA level during MRSA-mediated pneumonia is still unknown. METHODS: A lethal mouse model of MRSA pneumonia mediated by USA300 was employed to study the influence of LZD on survival, while the sublethal mouse model was used to examine the effect of LZD on bacterial clearance and lung gene expression during MRSA pneumonia. LZD (100mg/kg/day, IP) was given to C57Bl6 mice for three days. On Day 1 and Day 3 post infection, bronchoalveolar lavage fluid (BALF) protein concentration and levels of cytokines including IL6, TNFα, IL1ß, Interferon-γ and IL17 were measured. In the sublethal model, left lungs were used to determine bacterial clearance and right lungs for whole-genome transcriptional profiling of lung immune responses. RESULTS: LZD therapy significantly improved survival and bacterial clearance. It also significantly decreased BALF protein concentration and levels of cytokines including IL6, IL1ß, Interferon-γ and IL17. No significant gene expression changes in the mouse lungs were associated with LZD therapy. CONCLUSION: LZD is beneficial to MRSA pneumonia, but it does not modulate host lung immune responses at the transcriptional level.

A Staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice.

Staphylococcus aureus is a major cause of human disease, responsible for half a million infections and approximately 20,000 deaths per year in the United States alone. This pathogen secretes α-hemolysin, a pore-forming cytotoxin that contributes to the pathogenesis of pneumonia. α-hemolysin injures epithelial cells in vitro by interacting with its receptor, the zinc-dependent metalloprotease ADAM10 (ref. 6). We show here that mice harboring a conditional disruption of the Adam10 gene in lung epithelium are resistant to lethal pneumonia. Investigation of the molecular mechanism of toxin-receptor function revealed that α-hemolysin upregulates ADAM10 metalloprotease activity in alveolar epithelial cells, resulting in cleavage of the adherens junction protein E-cadherin. Cleavage is associated with disruption of epithelial barrier function, contributing to the pathogenesis of lethal acute lung injury. A metalloprotease inhibitor of ADAM10 prevents E-cadherin cleavage in response to Hla; similarly, toxin-dependent E-cadherin proteolysis and barrier disruption is attenuated in ADAM10-knockout mice. Together, these data attest to the function of ADAM10 as the cellular receptor for α-hemolysin. The observation that α-hemolysin can usurp the metalloprotease activity of its receptor reveals a previously unknown mechanism of pore-forming cytotoxin action in which pathologic insults are not solely the result of irreversible membrane injury and defines ADAM10 inhibition as a strategy to attenuate α-hemolysin-induced disease.

Clinical efficacy and safety of cefepime in febrile neutropenic patients with lung cancer.

Fever often occurs along with chemotherapy-induced neutropenia. This condition is referred to as febrile neutropenia (FN). Excellent guidelines for FN treatment have recently been published; however, there has so far been insufficient research concerning FN associated with solid tumors, especially in Japan. A multi-institution prospective study of cefepime for the treatment of FN in lung cancer patients was conducted. The objective of this study was to determine the efficacy and safety of cefepime for FN in lung cancer patients. Cefepime (2 g x 2/day) was administered to patients with FN after treatment for lung cancer. The therapeutic response rate, the effect of the drug on pathogen populations, and the incidence of adverse effects were statistically analyzed. Twenty-one patients with FN were registered for this study. One case was excluded because of protocol violation; therefore, a total of 20 cases were analyzed. Three days after the administration of cefepime, improvement was evident in 15 cases. The response rate was 75%, 95% CI: 53.1-88.8. After 7 days, 17 patients experienced improvement in their condition (85%, 95% CI: 64.0-94.8). Carbapenem was eventually substituted for cefepime in three cases, and all cases finally displayed improvement. There was no mortality. Pathogens for FN were detected in three cases and they disappeared in one case. Four patients experienced adverse side effects, including skin eruption, serum bilirubin elevation, neutrophil depletion, and anterior chest pain. There were no severe adverse events. In this study, cefepime demonstrated a high degree of clinical efficacy and safety in the treatment of FN. Empiric monotherapy using cefepime is a recommended regimen for FN in patients with lung cancer in Japan.

Amphiregulin attenuates bleomycin-induced pneumopathy in mice.

Amphiregulin, an EGF receptor (EGFR) ligand, is essential for epithelial development in various organs. A recent report suggested that amphiregulin acts as a protective factor in a liver injury model. Little is known about the roles of amphiregulin in lung injury and pulmonary fibrosis. The purpose of the present study was to investigate the role of amphiregulin in an experimental model of bleomycin-induced pneumopathy in mice. C57BL/6 mice were administered a bleomycin hydrochloride solution intratracheally. Recombinant human amphiregulin was injected intraperitoneally at 6, 8, 10, and 12 days after the bleomycin instillation. The grades of inflammation and fibrosis were assessed histologically and biochemically, and the numbers of apoptotic cells were counted after TdT-mediated dUTP nick end labeling (TUNEL) staining in the lung tissues. We also examined downstream survival signals of EGFR, namely phosphorylated Akt and phosphorylated Erk, in lung tissues by Western blotting analysis and immunohistochemistry. Expression of intrinsic amphiregulin was increased in murine lung tissues after bleomycin instillation. Administration of recombinant amphiregulin improved the survival rate and suppressed the degrees of inflammation and fibrosis and the number of TUNEL-positive cells in lung tissues. Amphiregulin treatment enhanced the activation of Akt and Erk in lung epithelial cells. Amphiregulin may play a protective role in bleomycin-induced pneumopathy in mice, probably through the activation of survival signals. Administration of amphiregulin may be a novel therapeutic strategy against lung injury and fibrosis.

[A case of secondary pulmonary alveolar proteinosis associated with myelodysplastic syndrome, complicated with disseminated M. abscessus infection].

A 27-year-old man was admitted to our hospital complaining of a persistent high fever since August 2007. Chest radiography showed infiltration shadows in the right lower lung field. Chest CT revealed scattered small nodular shadows and patchy consolidations in the right lower lobe. He was diagnosed as secondary pulmonary alveolar proteinosis (sPAP) associated with myelodysplastic syndrome (MDS), confirmed by video-assisted thoracic surgery (VATS) and bone marrow aspiration. Sera were negative for anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody. He developed a subcutaneous abscess and meningitis caused by M. absessus after VATS. After a long-course of antibiotic therapy, an allogenic peripheral blood stem cell transplantation was performed. But he died of graft versus host disease and M. abscessus sepsis 87 days after transplantation.

TNF receptor 1 and 2 contribute in different ways to resistance to Legionella pneumophila-induced mortality in mice.

Legionella pneumophila is one of the most important pathogens which cause community-acquired pneumonia. Although TNF-alpha is considered to play an important role in response to bacteria, the role of the TNF-alpha receptor on L. pneumophila infection remains to be elucidated. To investigate this, we infected TNF receptor deficient mice with L. pneumophila. L. pneumophila was inoculated intranasally into TNF receptor (TNFR)-1-knock-out mice or TNFR2-knock-out mice. The mortality rate, histology of the lung, bacterial growth in the lung, and bronchoalveolar lavage (BAL) fluids were investigated. The bacterial growth of L. pneumophila in the macrophages was also studied. Almost all the mice survived after an intranasal inoculation of 1x10(6)CFU/head of L. pneumophila, but more than 90% mice were killed after inoculation of 1x10(8)CFU/head of L. pneumophila. In the case of TNFR1-knock-out mice and TNFR2-knock-out mice, a high mortality rate was observed after inoculation of 1x10(7)CFU/head of L. pneumophila in comparison to wild-type mice. The lung histology from both the TNFR1-knock-out mice documented severe lung injury at day 3 after inoculation. The clearance of L. pneumophila in the lung of the TNFR1-knock-out mice was slower than those from both the TNFR2-knock-out mice and the wild-type mice. Moreover, L. pneumophila growth in the peritoneal macrophages from the TNFR1-knock-out mice was observed. Interestingly, a lack of neutrophils accumulation in the BAL fluids and a dysregulation of cytokines (IFN-gamma, interleukin-12, and TNF-alpha) were observed in the TNFR1-knock-out mice. On the contrary, large accumulation of neutrophils in BAL fluids was observed in TNFR2-knock-out mice. These data suggested that a TNFR1 deficiency led to a compromise of the innate immunity against L. pneumophila, while a TNFR2 deficiency induced an excessive inflammatory response and resulted in death. The present study confirmed that TNFR1 and TNFR2 play a crucial, but different role in the control of L. pneumophila-induced mortality.

Biphasic effects of free radical scavengers against bleomycin-induced pulmonary fibrosis.

Oxidative stress plays a critical role in the development of pulmonary fibrosis. However, the effects of treatment with anti-oxidant agents against pulmonary fibrosis have not yet been thoroughly investigated. In this study, the effect of MCI-186, a novel free radical scavenger, on bleomycin-induced pulmonary fibrosis was investigated. Bleomycin (0.05units/mouse) was administered intratracheally into C57Bl/6 mice. MCI-186 was given to bleomycin-treated mice intraperitoneally from (i) day -3 to day 7, or from (ii) day 10 to day 28 after bleomycin administration in successive days. At 28 days after bleomycin administration, pulmonary fibrosis was then assessed by lung histology and hydroxyproline. MCI-186 inhibited H(2)O(2)-induced DNA damage in bronchial epithelium in vitro. MCI-186 decreased the lipid peroxide content, a marker for DNA damage, in the lung and reduced 8-OHdG positive cells in the lung in vivo. During the early period (day -3 to day 7) administration, MCI-186 partially attenuated bleomycin-induced pulmonary fibrosis. However, during the late period (day 10 to day 28) MCI-186 exacerbated pulmonary fibrosis, based on the histology and hydroxyproline content. In this condition, MCI-186 in the late period decreased the number of apoptosis cells induced by bleomycin, and therefore it might contribute to the deterioration of pulmonary fibrosis. These data indicate that MCI-186, radical scavenger, has a biphasic effect on bleomycin-induced pulmonary fibrosis in mice. Careful attention should be paid before clinical application of new remedies for pulmonary fibrosis.

Tubulointerstitial nephritis and IgA nephropathy in a patient with advanced lung cancer treated with long-term gefitinib.

A 52-year-old Japanese female was admitted to our hospital for microhematuria, proteinuria and progressive renal dysfunction. Two years prior to admission, she was diagnosed with lung adenocarcinoma and multiple bone and brain metastases, and was treated with gefitinib (250 mg/day). Treatment for 6 months induced partial response with 30% regression of the primary lung tumor, and resolution of metastatic tumors. After confirmation of the partial remission state, we performed percutaneous renal biopsy. Glomeruli showed mild to moderate mesangial proliferation, segmental endocapillary proliferation and occasional fibrocellular crescent formation. In addition, severe interstitial fibrosis and tubular atrophy relative to the degree of glomerular sclerosis were noted. Immunofluorescence microscopy showed predominant IgA deposition in the mesangial area. Electron microscopy revealed subepithelial and paramesangial electron-dense deposits. In consideration of the prognosis of lung cancer and complication of immunosuppressive treatment, we continued gefitinib only and closely followed-up the clinical course in the outpatient clinic. Sixteen months later, she continued to have proteinuria and microhematuria, and the severity of renal dysfunction was still the same. However, the lung cancer started to increase in size. This is quite an unusual case presenting histologically with tubulointerstitial nephritis and IgA nephropathy in a patient on long-term treatment with gefitinib.

Attenuation of pulmonary hypertension, but not emphysematous change, by breeding emphysema model mice at sea level.

Tumor necrosis factor (TNF)-alpha is a key pro-inflammatory cytokine, thought to be important in the pathogenesis of pulmonary emphysema. TNF-alpha overexpression in the lung leads to the phenotypic features of pulmonary emphysema, pulmonary hypertension, and right ventricular hypertrophy in mice bred in Denver, 5240 feet/1600 m of altitude. This study hypothesized that the altitude could affect the development of pulmonary emphysema as well as pulmonary hypertension. To investigate the effect of the altitude, TNF-alpha transgenic mice were bred at sea level, Fukuoka, Japan. The pulmonary physiology and histology demonstrated similar development of pulmonary emphysema, compared to the mice bred in Denver. With respect to pulmonary hypertension, right ventricular hypertrophy was attenuated. Interestingly, mortality rate was significant lower in the mice bred at sea level. In contrast with the results in Denver, a significant decrease of vascular endothelial growth factor (VEGF) and its receptors expression was not found. From these data, we consider that the altitude affects development of pulmonary hypertension through the expression of VEGF and its receptors. In contrast, the effect of altitude was not clear regarding the development of pulmonary emphysema.

The role of collagenases in experimental pulmonary fibrosis.

Matrix metalloproteinases (MMPs) expression plays a critical role in extracellular matrix deposition. Although several pieces of evidence have so far indicated that gelatinase contributes to the development of pulmonary fibrosis, the role of collagenase remains uncertain. In this study, we attempted to determine the role of collagenase using a bleomycin-induced pulmonary fibrosis model. Bleomycin was instilled into mice intratracheally. Bronchoalveolar lavage fluid (BAL) specimens were analyzed for gelatin and casein zymography, as well as by immunoblotting. The histology of the lungs and hydroxyproline contents were also assessed. MMPs inhibitor, CGS27023A, was simultaneously orally administered. Collagenases were induced in BAL fluids after bleomycin administration based on the data of zymography and immunohistochemistry. The co-administration of MMPs inhibitor, CGS27023A, with bleomycin resulted in worsening pulmonary fibrosis with inhibition of collagenase. The worsening of pulmonary fibrosis was mainly induced by CGS27023A administration in the late phase of bleomycin-induced pulmonary fibrosis development, but not in the early phase. The present data indicated that collagenase plays an anti-fibrotic role in the bleomycin-induced pulmonary fibrosis model. Collagenase has a greater effect on fibrosis phase than inflammatory phase in the bleomycin-induced pulmonary fibrosis in the mice.

Successful treatment of refractory chronic necrotizing pulmonary aspergillosis with micafungin.

A 63-year-old man was admitted to our hospital because he complained of fever and productive cough; this was associated with cavitary infiltrates on his chest X-ray. Although several antibiotics were given, his symptoms did not improve. Bronchofiberscope investigation yielded Aspergillus fumigatus; thus, he was diagnosed with chronic necrotizing pulmonary aspergillosis. Itraconazole, 200 mg/day, was given, and his symptoms and infiltrates on chest X-ray gradually improved. After 2 months of treatment, new infiltrates appeared on a chest X-ray. Antibacterial agents had also shown no effect, and voriconazole was substituted for itraconazole. However, the infiltrates progressed in spite of the voriconazole administration. We added micafungin to the voriconazole treatment. Both his symptoms and the infiltrates on chest X-rays improved. Because voriconazole is thought to be the most effective agent against Aspergillus spp., it is difficult to treat cases that are refractory to voriconazole. The treatment of this case provides invaluable information on how to treat pulmonary aspergillosis related to diseases other than hematologic malignancies.

[A case of pulmonary nocardiosis diagnosed five years after hemoptysis].

A 73-year-old man complaining of bloody sputum was admitted to our hospital in August 2000. His giant left lower lung field bulla had been removed in 1997, at which time atelectasis in left S10 was pointed out. Production of bloody sputum was stopped by the emergency bronchial artery embolization, and Nocardia species was found in the sputum. Because of both spontaneous disappearance of Nocardia species and no evidence of Nocardia infection, he was followed carefully by chest radiography every few months. Consolidation appeared in the left lower lung field and right upper lung field in 2005. Nocardia asteroides was frequently obtained from his sputa and lavage fluid under bronchoscopy. Therefore, we diagnosed pulmonary nocardiosis. Oral cotrimoxazole (Trimetoprim 15 mg/kg) was started, the dosage was halved because of adverse effects. Six months of treatment with cotrimoxazole resulted in improvement of the Nocardiosis.

Doxycycline attenuated lung injury by its biological effect apart from its antimicrobial function.

Antibiotics can have a biological effect apart from their anti-bacterial effect. We hypothesized that doxycycline could attenuate acute lung injury through its biological effect. Lipopolysaccharide or doxycycline-resistant Streptococcus pneumoniae was administered intratracheally into mice with the co-administration of doxycycline. Thereafter, the lung pathology, intraalveolar inflammatory cells, bacterial number, and matrix metalloproteinases were investigated. Matrix metalloproteinases, neutrophil migration, and alveolar destruction were induced by lipopolysaccharide. Doxycycline was thus found to improve all of these symptoms. In addition, an inhibitor of matrix metalloproteinases, CGS27023A, attenuated lipopolysaccharide-induced lung injury. Doxycycline also attenuated the lung injury induced by doxycycline-resistant S. pneumoniae and improved the mortality rate although the bacterial number in the lung did not change. Our data indicated that doxycycline could attenuate acute lung injury through a biological effect that was different from its antibiotic effect.

Doxycycline attenuated pulmonary fibrosis induced by bleomycin in mice.

The administration of doxycycline prior to bleomycin in mice attenuated pulmonary fibrosis. Bronchoalveolar neutrophil influx and gelatinase activity, but not caseinolytic activity, were attenuated by doxycycline. Established fibrosis was not affected by doxycycline. Thus, doxycycline might be useful for slowing down pulmonary fibrosis by biological activity other than antibacterial activity.

Gorham's disease of the chest wall: CT and MR characteristics.

We report a case of Gorham's disease of the chest wall in a 29-year-old man. A chest radiograph showed osteolysis of the left first, second, and third ribs. CT and MR images revealed a soft tissue mass around the affected ribs. The mass presented as having heterogeneous high signal intensity on T2-weighted MR images, and it showed minimal enhancement on contrast-enhanced MR images. A histologic specimen obtained by incisional biopsy from the left third rib revealed proliferation of lymphangiomatous tissue in the bone marrow. A diagnosis of Gorham's disease was made based on these clinical, radiologic, and histologic findings.

[A case of pulmonary mycobacterium intracellulare infection complicated with pneumothorax and pleurisy].

A 74 year-old female complaining of increased cough and sputum was admitted to our hospital on June 14th 2004. She had been diagnosed as Mycobacterium intracellulare (M. intracellurare) infection since 2002 and had been treated from March to October 2003 in the Department of General Medicine in our hospital. Chest CT on admission showed diffuse small nodular shadows in the lung, a cavity, pneumothorax, and pleural effusion in the right lung. The sputum smear was positive for acid-fast bacilli and sputum PCR examination was positive for M. intracellulare. She was diagnosed as the recurrence of non-tuberculous mycobacterium (NTM) infection and treatment of NTM infection was started. No other infections were suspected and the pneumothorax and pleural effusion gradually improved with the treatment. We concluded that the pneumothorax and pleural effusion were caused by NTM infection. Since pneumothorax is an extremely rare complication in NTM infections we thought it is worth-while to report our case.