Immunomodulatory Effects of Fluoroquinolones in Community-Acquired Pneumonia-Associated Acute Respiratory Distress Syndrome.

Community-acquired pneumonia is reported as one of the infectious diseases that leads to the development of acute respiratory distress syndrome. The innate immune system is the first line of defence against microbial invasion; however, its dysregulation during infection, resulting in an increased pathogen load, stimulates the over-secretion of chemokines and pro-inflammatory cytokines. This phenomenon causes damage to the epithelial-endothelial barrier of the pulmonary alveoli and the leakage of the intravascular protein into the alveolar lumen. Fluoroquinolones are synthetic antimicrobial agents with immunomodulatory properties that can inhibit bacterial proliferation as well as exhibit anti-inflammatory activities. It has been demonstrated that the structure of fluoroquinolones, particularly those with a cyclopropyl group, exerts immunomodulatory effects. Its capability to inhibit phosphodiesterase activity leads to the accumulation of intracellular cAMP, which subsequently enhances PKA activity, resulting in the inhibition of transcriptional factor NF-κB and the activation of CREB. Another mechanism reported is the inhibition of TLR and ERK signalling pathways. Although the sequence of events has not been completely understood, significant progress has been made in comprehending the specific mechanisms underlying the immunomodulatory effects of fluoroquinolones. Here, we review the indirect immunomodulatory effects of FQs as an alternative to empirical therapy in patients diagnosed with community-acquired pneumonia.

PGE2 Produced by Exogenous MSCs Promotes Immunoregulation in ARDS Induced by Highly Pathogenic Influenza A through Activation of the Wnt-ß-Catenin Signaling Pathway.

Acute respiratory distress syndrome is an acute respiratory failure caused by cytokine storms; highly pathogenic influenza A virus infection can induce cytokine storms. The innate immune response is vital in this cytokine storm, acting by activating the transcription factor NF-κB. Tissue injury releases a danger-associated molecular pattern that provides positive feedback for NF-κB activation. Exogenous mesenchymal stem cells can also modulate immune responses by producing potent immunosuppressive substances, such as prostaglandin E2. Prostaglandin E2 is a critical mediator that regulates various physiological and pathological processes through autocrine or paracrine mechanisms. Activation of prostaglandin E2 results in the accumulation of unphosphorylated ß-catenin in the cytoplasm, which subsequently reaches the nucleus to inhibit the transcription factor NF-κB. The inhibition of NF-κB by ß-catenin is a mechanism that reduces inflammation.

Interleukin-1ß and Interleukin-10 Profiles and Ratio in Serum of COVID-19 Patients and Correlation with COVID-19 Severity: A Time Series Study.

Background: Coronavirus disease-19 (COVID-19) can, in severe cases, lead to cytokine-release syndrome owing to an excessive immune response. The release of different cytokines aggravates disease severity. IL-1ß is a pro-inflammatory cytokine, while IL-10 is an anti-inflammatory cytokine, and both are involved in the human immune response to infection. This study aimed to determine whether serum levels of IL-1ß and IL-10 and the ratio of the two over time in patients with COVID-19 could facilitate early identification of disease severity. Methods: An analytical, observational time-series design was employed. Fifty participants were enrolled between May and October 2020 and were divided into two groups-non-severe (n = 20), and severe (n = 30). IL-1ß and IL-10 were analyzed using BD cytometric bead array sets. Association of the IL-1ß:IL-10 ratio with COVID-19 severity was analyzed using a Mann-Whitney test and Fisher's exact test. Optimal cut-off values to predict disease severity were determined by Youden's index. Results: In non-severe and severe groups, the median serum levels of IL-1ß decreased on day 3 (1.72 ng/mL and 2.10 ng/mL, respectively), then increased on day 6 (2.05 ng/mL and 3.31 ng/mL, respectively). However, the median of IL-10 increased on day 3 (1.88 ng/mL and 2.30 ng/mL, respectively) and day 6 (2.02 ng/mL and 2.39 ng/mL, respectively). There was no significant association between the IL-1ß:IL-10 ratio and COVID-19 severity at any time-point (p>0.05). The cutoff value of serum IL-10 between the two groups on days 0, 3, and 6 was 1.09 pg/mL (sensitivity: 66.6%; PPV: 71.4%), 2.11 pg/mL (sensitivity: 67.7%; PPV: 50.0%), and 2.08 pg/mL (sensitivity: 78.6%; PPV: 70.9%), respectively. Conclusion: The IL-1ß:IL-10 ratio was not correlated to COVID-19 severity. However, owing to its high sensitivity, IL-10 may be a potential biomarker for disease severity in severe COVID-19.

Association of soluble receptor for advanced glycation end-products (sRAGE) serum on COVID-19 severity: A cross-sectional study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a new health problem discovered in 2019 thus requires biomarkers that can detect early tissue damage. Soluble receptor for advanced glycation end-products (sRAGE) is a biomarker that can be used to identify early lung damage. OBJECTIVE: Analyzing the association of serum sRAGE on COVID-19 severity. METHODS: This study employed a cross-sectional design with a consecutive sampling method. It was conducted from May 2020-October 2021. The number of participants in this study was 145 participants which were divided into 2 groups (non-severe = 47 and severe = 98). Association of sRAGE serum on COVID-19 severity was analyzed using the chi-square test, Fisher's exact test, independence t-test, Mann Withney test, and Spearman's rank test with p-value <0.05. RESULTS: The results of blood analysis showed several blood components such as leukocytes (9896.51 ± 4949.64/µL; z = 2.431; p = 0.015), lymphocytes (13.55 ± 8.48%; z = 2.256; p = 0.024), neutrophils (78.91 ± 10.50%; z = 2.464; p = 0.014), procalcitonin (0.92 ± 3.22 ng/mL; z = 3.323; p = 0.001), CRP (8.59 ± 7.62 mg/L; z = 2.114; p = 0.034), D-dimer (4360.29 ± 7797.81 ng/mL; z = 2.186; p = 0.029), and fibrinogen (474.58 ± 168.90 mg/dL; t = 0.383; p = 0.703). There was a significant comparison in serum sRAGE values in the non-severe group (0.78 [0.63-1.00] ng/mL) and severe group (1.47 [0.97-2.25] ng/mL; r = 7.154; p <0.001). There was a significant association between serum sRAGE and COVID-19 severity (r = 0.598; p <0.001). The cut-off value for serum sRAGE between the severe and non-severe groups was 0.985 ng/mL. This study obtained sensitivity of 73.5%, specificity of 74.5% OR 8.077 and AUC 0.868 95% CI. CONCLUSION: There is a significant association between serum sRAGE and COVID-19 severity and there is also a significant difference in serum sRAGE in the two groups.

Association between serum PGE2 levels and degree of acid-fast bacilli positivity in sputum of pulmonary tuberculosis patients.

BACKGROUND: Mycobacterium tuberculosis that infected apoptotic macrophages is triggered by PGE2. Apoptosis suppresses the growth of Mycobacterium tuberculosis bacteria, which is shown in the results of acid-fast bacilli (AFB) in the sputum that becomes a marker of the number of bacteria. OBJECTIVE: Analyzing the association between serum PGE2 levels and the positivity of AFB in the sputum of tuberculosis patients. METHODS: A cross-sectional study was carried out from August 2019-July 2020. Serum PGE2 levels and AFB levels in sputum were collected from participants. Data analysis used the Chi-square test and Spearman's correlation with p < 0.05. RESULTS: The average participants' serum PGE2 levels were 446.37 ± 510.27 pg/ml, with a median value of 216.95 pg/ml. Most participants had normal serum PGE2 levels (62.9%). Most participants had a high positivity of AFB in sputum (58.1%). Analysis of the association between serum PGE2 levels and the degree of AFB positivity in sputum obtained r = -0.036 and p-value = 0.780. CONCLUSION: There is a weak negative association between serum PGE2 levels and the degree of AFB positivity in sputum but not statistically significant.

Association of serum KL-6 levels on COVID-19 severity: A cross-sectional study design with purposive sampling.

BACKGROUND: The main target of SARS-CoV2 is the alveolar type II (AT2) cells of the lung. SARS-CoV2 evades the innate immune system resulting in the release of proinflammatory cytokines (IL-1ß, IL-6, TNF-α) which causes AT2 cell damage. Krebs von den Lungen (KL-6) is a specific biomarker of AT2 cell damage. KL-6 is produced in AT2 cells that are injured/regenerated. OBJECTIVE: Research that discusses the role of KL-6 in COVID-19 is still being debated and not much has been done in Indonesia. METHODS: This study was an analytical study with a prospective design on 75 COVID-19 patients who were treated. Subjects were divided into two large groups according to their degree of severity, 57 subjects with severe degrees and 18 subjects with non-severe degrees. The serum KL-6 levels were measured on days 0 and 6. Data were analyzed using paired t-test and independent t-test for data were normally distributed and Wilcoxon test and Mann Whitney test for data that were not normally distributed. RESULT: In this study, the mean serum KL-6 for day 0 in the severe group was higher than the non-severe group with values of 45.70 U/mL and 44.85 U/mL. On day 6, the mean serum KL-6 in the severe group was lower than that in the non-severe group with values of 41.3 U/mL and 41.95 U/mL. Serum KL-6 in the severe group experienced an even greater decrease than the non-severe group. CONCLUSION: There was no significant association between serum KL-6 values on 0 days in the severity of COVID-19.

Bilateral primary spontaneous pneumothorax with multiple bleb performed by VATS and wedge resection: A rare case in Indonesian adult and review article.

BACKGROUND: Bilateral primary spontaneous pneumothorax (PSP) is a rare case of lung disease. CASE PRESENTATION: A 20-year-old man with a complaint of shortness of breath is suspected of having PSP and tuberculosis. The patient underwent water seal drainage installation in both lung cavities, but showed no improvement. Multiple blebs were found after a few days. A wedge resection with VATS became an option. The patient had improved lung function after the procedure. DISCUSSION: The WSD installation showed lungs improvement. However, when trained for lung expansion, the lung condition became bad. After wedge resection with the help of VATS on multiple blebs, the lung had a significant improvement. CONCLUSION: Wedge resection could be considered in PSP patients with multiple blebs.

Secondary pleuropulmonary amoebiasis due to liver abscess rupture: A complication case report in low resource setting.

BACKGROUND: Pleuropulmonary amoebiasis caused by complications of amoebic liver abscess (ALA) is rare. CASE PRESENTATION: A 23 years old male, presented with shortness of breath, cough with yellowish phlegm, right chest pain, fever, bulging stomach, yellow eyes, and swelling of both legs. Abdominal ultrasound and CT scan thorax and abdomen revealed right fluidopneumothorax and liver abscess. Serological testing leads to Entamoeba histolytica infection, which was treated with metronidazole but no significant improvement on empyema and abscess liver size. Surgery was performed after percutaneous aspiration drainage failed to evacuate the abscess. HE and PAS staining from surgical tissue showed Entamoeba hystolitica infection. DISCUSSION: Serological testing and radiological examination will be more useful in the early detection of cases of Entamoeba hystolitica infection. Surgery may be considered when purulent drainage does not show improvement in the patient's condition. CONCLUSION: ALA complication that causes pulmonary empyema can be surgically treated if the pus cannot be drained.

Bone marrow-derived mesenchymal stem cells attenuate pulmonary inflammation and lung damage caused by highly pathogenic avian influenza A/H5N1 virus in BALB/c mice.

BACKGROUND: The highly pathogenic avian influenza A/H5N1 virus is one of the causative agents of acute lung injury (ALI) with high mortality rate. Studies on therapeutic administration of bone marrow-derived mesenchymal stem cells (MSCs) in ALI caused by the viral infection have been limited in number and have shown conflicting results. The aim of the present investigation is to evaluate the therapeutic potential of MSC administration in A/H5N1-caused ALI, using a mouse model. METHODS: MSCs were prepared from the bone marrow of 9 to 12 week-old BALB/c mice. An H5N1 virus of A/turkey/East Java/Av154/2013 was intranasally inoculated into BALB/c mice. On days 2, 4, and 6 after virus inoculation, MSCs were intravenously administered into the mice. To evaluate effects of the treatment, we examined for lung alveolar protein as an indicator for lung injury, PaO2/FiO2 ratio for lung functioning, and lung histopathology. Expressions of NF-κB, RAGE (transmembrane receptor for damage associated molecular patterns), TNFα, IL-1ß, Sftpc (alveolar cell type II marker), and Aqp5+ (alveolar cell type I marker) were examined by immunohistochemistry. In addition, body weight, virus growth in lung and brain, and duration of survival were measured. RESULTS: The administration of MSCs lowered the level of lung damage in the virus-infected mice, as shown by measuring lung alveolar protein, PaO2/FiO2 ratio, and histopathological score. In the MSC-treated group, the expressions of NF-κB, RAGE, TNFα, and IL-1ß were significantly suppressed in comparison with a mock-treated group, while those of Sftpc and Aqp5+ were enhanced. Body weight, virus growth, and survival period were not significantly different between the groups. CONCLUSION: The administration of MSCs prevented further lung injury and inflammation, and enhanced alveolar cell type II and I regeneration, while it did not significantly affect viral proliferation and mouse morbidity and mortality. The results suggested that MSC administration was a promissing strategy for treatment of acute lung injuries caused by the highly pathogenic avian influenza A/H5N1 virus, although further optimization and combination use of anti-viral drugs will be obviously required to achieve the goal of reducing mortality.

Comparison of Virulence and Lethality in Mice for Avian Influenza Viruses of Two A/H5N1 and One A/H3N6 Isolated from Poultry during Year 2013-2014 in Indonesia.

In Indonesia, the highly pathogenic avian influenza A/H5N1 virus has become endemic and has been linked with direct transmission to humans. From 2013 to 2014, we isolated avian influenza A/H5N1 and A/H3N6 viruses from poultry in Indonesia. This study aimed to reveal their pathogenicity in mammals using a mouse model. Three of the isolates, Av154 of A/H5N1 clade 2.3.2.1c, Av240 of A/H5N1 clade 2.1.3.2b, and Av39 of A/H3N6, were inoculated into BALB/c mice. To assess morbidity and mortality, we measured body weight daily and monitored survival for 20 d. Av154- and Av240-infected mice lost 25% of their starting body weight by day 7, while Av39-infected mice did not. Most of the Av154-infected mice died on day 8, while the majority of the Av240-infected mice survived until day 20. A 50% mouse lethal dose was calculated to be 2.0 × 101 50% egg infectious doses for Av154, 1.1 × 105 for Av240 and > 3.2 × 106 for Av39. The Av154 virus was highly virulent and lethal in mice without prior adaptation, suggesting its high pathogenic potential in mammals. The Av240 virus was highly virulent but modestly lethal, whereas the Av39 virus was neither virulent nor lethal. Several mammalian adaptive markers of amino acid residues were associated with the highly virulent and lethal phenotypes of the Av154 virus.

Immunoregulatory Property of C-Type Lectin-Like Receptors in Fibrosing Interstitial Lung Diseases.

The innate immune system identifies exogenous threats or endogenous stress through germline-encoded receptors called pattern recognition receptors (PRRs) that initiate consecutive downstream signaling pathways to control immune responses. However, the contribution of the immune system and inflammation to fibrosing interstitial lung diseases (ILD) remains poorly understood. Immunoreceptor tyrosine-based motif-bearing C-type lectin-like receptors (CTLRs) may interact with various immune cells during tissue injury and wound repair processes. Dectin-1 is a CTLR with dominant mechanisms manifested through its intracellular signaling cascades, which regulate fibrosis-promoting properties through gene transcription and cytokine activation. Additionally, immune impairment in ILD facilitates microbiome colonization; hence, Dectin-1 is the master protector in host pulmonary defense against fungal invasion. Recent progress in determining the signaling pathways that control the balance of fibrosis has implicated immunoreceptor tyrosine-based motif-bearing CTLRs as being involved, either directly or indirectly, in the pathogenesis of fibrosing ILD.

The comparison of pleural fluid TNF-α levels in tuberculous and nontuberculous pleural effusion.

BACKGROUND: Tuberculous pleural effusion is the manifestation of Mycobacterium tuberculosis infection in pleura. With existing means, it is difficult to establish the diagnosis of tuberculosis (TB) and non-TB pleural effusions; thus, establishing the diagnosis of TB pleural effusion and non-TB pleural effusion is still a clinical problem. Tumour necrosis factor alpha (TNFα) is a potent inflammatory cytokine that plays an important role in immunity to Mycobacterium tuberculosis infections, this level of cytokine increases in pleural effusion due to tuberculosis. OBJECTIVE: To compare the TNF-α level of pleural fluid in TB and non-TB pleural effusion. METHODS: The samples in this study that fulfilled the inclusion criteria were patients with non-TB pleural tuberculosis effusion in the inpatient ward in Pulmonology Unit Dr. Soetomo General Hospital Surabaya, male and female, aged between 15 and 60 years. The data is divided into two: primary data and secondary data of patients who fulfilled inclusion and exclusion criteria. The data with normal distribution was analyzed using independent t2 test and if the data distribution is abnormal, it was analyzed using Fisher's exact test. RESULTS: There were 22 subjects divided into 2 groups that were 11 patients with TB pleural effusion and 11 patients with non-TB pleural effusion. The TNF-α level of pleural fluid in TB pleural effusion was 25.43±13.55pg/mL. The TNF-α level of pleural fluid in non-TB was 5.98±1.89pg/mL. The serum TNF-α level in TB pleural effusion was 83.22±88.15pg/mL. The serum TNF-α level in non-TB was 68.54±57.88pg/mL. There was higher level of TNF-α pleural fluid in TB pleural effusion than in non-TB pleural effusion (25.43±13.55pg/mL vs 5.98±1.89pg/mL, p value <0.05). The serum TNF-α level in patients with TB pleural effusion was higher than TNF-α serum level of non-TB pleural effusion. There was no significant difference between TNF-α level of pleural fluid and serum TNF-α levels in the TB pleural effusion group (p value >0.05). CONCLUSION: The TNF-α level of pleural fluid in TB pleural effusion was higher than non-TB pleural effusions and there was no significant difference between serum TNF-α levels in the TB pleural effusion group and in the non-TB pleural effusion group.

Effect of yoga on FEV1, 6-minute walk distance (6-MWD) and quality of life in patients with COPD group B.

INTRODUCTION: Yoga is used in the treatment of various diseases, including chronic obstructive pulmonary disease. However, no studies have assessed the effect of yoga on COPD patients in Indonesia. The difference between this study and similar studies completed in other countries lies in the type of yoga exercises completed, the method in which they were completed, and in certain, unique demographic characteristics. This study aims to analyze the effect of yoga on FEV1, 6-minute walk distance, and quality of life in patients with COPD group B in Indonesia. MATERIAL AND METHODS: This article reflects research done in the form of an experimental study using arandomized controlled trial with pre and post-test control group design. The samples were divided into 2 groups: the treatment group (yoga practice for 1 hour, 2 times aweek for 12 weeks) and the control group (untreated with yoga, given lung rehabilitation brochure). Assessment of the effect of yoga exercises on lung function parameters (FEV1), 6-minute walk distance and quality of life were used using SGRQ questionnaires in COPD group B. RESULTS: 33 COPD patients fulfilled the inclusion criteria. 30 patients completed the study. Pre and post yoga results were evalu-ated in the treatment group versus the control group and then further assessed using statistical tests. There was asignificant in-crease in FEV1, 6-MWD and quality of life using aSGRQ questionnaire after 12 weeks of yoga (p < 0.05) as well as aasignificant change in FEV1, 6-MWD and quality of life in the treatment group (p < 0.05) when compared with the control group (p > 0.05). CONCLUSIONS: Yoga affects FEV1, 6-MWD, and quality of life in patients with Group B COPD.

Seroevidence for a High Prevalence of Subclinical Infection With Avian Influenza A(H5N1) Virus Among Workers in a Live-Poultry Market in Indonesia.

BACKGROUND: In Indonesia, highly pathogenic avian influenza A(H5N1) virus has become endemic in poultry and has caused sporadic deadly infections in human. Since 2012, we have conducted fixed-point surveillance of avian influenza viruses at a live-poultry market in East Java, Indonesia. In this study, we examined the seroprevalence of avian influenza A(H5N1) virus infection among market workers. METHODS: Sera were collected from 101 workers in early 2014 and examined for antibody activity against avian A(H5N1) Eurasian lineage virus by a hemagglutination-inhibition (HI) assay. RESULTS: By the HI assay, 84% of the sera tested positive for antibody activity against the avian virus. Further analysis revealed that the average HI titer in 2014 was 2.9-fold higher than in 2012 and that seroconversion occurred in 44% of paired sera (11 of 25) between 2012 and 2014. A medical history survey was performed in 2016; responses to questionnaires indicated that none of workers had had severe acute respiratory illness during 2013. CONCLUSIONS: This study provides evidence of a high prevalence of avian A(H5N1) virus infection in 2013 among workers at a live-poultry market. However, because no instances of hospitalizations were reported, we can conclude the virus did not manifest any clinical symptoms in workers.

Protease-dependent hemagglutinin cleavage contributes to alteration in chicken hemagglutination by the H3N2 influenza A virus.

The human influenza A virus (H3N2) has been the predominant influenza strain since 1992, and one property of this virus is non-agglutination of chicken erythrocytes [Ch(-) virus]. The Ch(-) virus in our study was able to acquire chicken hemagglutination [Ch(+)] by trypsin passage but not by chymotrypsin passage. Moreover, the trypsin-passaged Ch(+) viruses reacquired the Ch(-) property after a further chymotrypsin passage. In particular, genetic analysis showed no evidence of mutations in the hemagglutinin (HA) gene during either trypsin or chymotrypsin passages: the only differences found were in the HA cleavage sites between the trypsin-passaged virus and the chymotrypsin-passaged virus as determined by the N-terminal amino acid sequence. These results suggested that protease-dependent differences at the viral HA cleavage site, rather than genetic mutations, are likely to have a significant effect on the viral ability to produce chicken hemagglutination.

An H5N1 highly pathogenic avian influenza virus isolated from a local tree sparrow in Indonesia.

The isolation of an H5N1 influenza A virus from a tree sparrow (Passer montanus) captured in East Java, Indonesia in 2010 is reported here. Its hemagglutinin and neuraminidase were genetically similar to those of human isolates from 2006-2007 in Indonesia. The finding of a tree sparrow H5N1 virus that possesses genetically similar surface molecules to those of human viruses highlights the importance of monitoring resident wild birds, as well as migratory birds, for pandemic preparedness.

Virological surveillance of human influenza in Indonesia, October 2008-March 2010.

Despite the high prevalence of highly pathogenic H5N1 influenza A viruses in Indonesia, epidemiology information on seasonal human influenza is lacking. The present authors, therefore, conducted virologic surveillance in Surabaya, East Java from October 2008 to March 2010. Influenza viruses, including pandemic (H1N1) 2009 viruses, were isolated from 71 of 635 individuals tested. Seasonal influenza peaked in the rainy season. Compared with seasonal influenza viruses, pandemic 2009 viruses were isolated from younger patients with milder symptoms. Given the high prevalence of H5N1 infections in humans, continued influenza surveillance is essential for pandemic preparedness.