Pneumonia and Related Conditions in Critically Ill Patients-Insights from Basic and Experimental Studies.

Pneumonia is an acute infectious disease with high morbidity and mortality rates. Pneumonia's development, severity and outcome depend on age, comorbidities and the host immune response. In this study, we combined theoretical and experimental investigations to characterize pneumonia and its comorbidities as well as to assess the host immune response measured by TREC/KREC levels in patients with pneumonia. The theoretical study was carried out using the Columbia Open Health Data (COHD) resource, which provides access to clinical concept prevalence and co-occurrence from electronic health records. The experimental study included TREC/KREC assays in young adults (18-40 years) with community-acquired (CAP) (n = 164) or nosocomial (NP) (n = 99) pneumonia and healthy controls (n = 170). Co-occurring rates between pneumonia, sepsis, acute respiratory distress syndrome (ARDS) and some other related conditions common in intensive care units were the top among 4170, 3382 and 963 comorbidities in pneumonia, sepsis and ARDS, respectively. CAP patients had higher TREC levels, while NP patients had lower TREC/KREC levels compared to controls. Low TREC and KREC levels were predictive for the development of NP, ARDS, sepsis and lethal outcome (AUCTREC in the range 0.71-0.82, AUCKREC in the range 0.67-0.74). TREC/KREC analysis can be considered as a potential prognostic test in patients with pneumonia.

Genetic dissection of host immune response in pneumonia development and progression.

The role of host genetic variation in pneumonia development and outcome is poorly understood. We studied common polymorphisms in the genes of proinflammatory cytokines (IL6 rs1800795, IL8 rs4073, IL1B rs16944), anti-inflammatory cytokines (IL10 rs1800896, IL4 rs2243250, IL13 rs20541) and toll-like receptors (TLR2 rs5743708 and rs4696480, TLR4 rs4986791, TLR9 rs352139, rs5743836 and rs187084) in patients with community-acquired pneumonia (CAP) (390 cases, 203 controls) and nosocomial pneumonia (355 cases, 216 controls). Experimental data were included in a series of 11 meta-analyses and eight subset analyses related to pneumonia susceptibility and outcome. TLR2 rs5743708 minor genotype appeared to be associated with CAP/Legionnaires' disease/pneumococcal disease. In CAP patients, the IL6 rs1800795-C allele was associated with severe sepsis/septic shock/severe systemic inflammatory response, while the IL10 rs1800896-A allele protected against the development of these critical conditions. To contribute to deciphering of the above results, we performed an in silico analysis and a qualitative synthesis of literature data addressing basal and stimulated genotype-specific expression level. This data together with database information on transcription factors' affinity changes caused by SNPs in putative promoter regions, the results of linkage disequilibrium analysis along with SNPs functional annotations supported assumptions about the complexity underlying the revealed associations.

Genetic susceptibility to nosocomial pneumonia, acute respiratory distress syndrome and poor outcome in patients at risk of critical illness.

Genetic susceptibility may partially explain the clinical variability observed during the course of similar infections. To establish the contribution of genetic host factors in the susceptibility to critical illness, we genotyped 750 subjects (419 at high risk of critical illness) for 14 single nucleotide polymorphisms (SNPs) in the xenobiotics detoxification/oxidative stress and vascular homeostasis metabolic pathways. In the group of nosocomial pneumonia (NP; 268 patients) the risk of acute respiratory distress syndrome (ARDS) is significantly higher for the carriers of CYP1A1 rs2606345 T/T genotypes and AhR rs2066853 G/A-A/A genotypes. AGTR1 rs5186 allele C is more common among NP non-survivors. The duration of stay in intensive care units (ICU) is higher for NP patients with ABCB1 rs1045642-T allele. The cumulative effect of the risk alleles in the genes comprising two sets of genes partners (xenobiotics detoxification: CYP1A1, AhR and RAS family: ACE, AGT, AGTR1) is associated with the development of both NP and ARDS.

CYP1A1, GCLC, AGT, AGTR1 gene-gene interactions in community-acquired pneumonia pulmonary complications.

This study was conducted to establish the possible contribution of functional gene polymorphisms in detoxification/oxidative stress and vascular remodeling pathways to community-acquired pneumonia (CAP) susceptibility in the case-control study (350 CAP patients, 432 control subjects) and to predisposition to the development of CAP complications in the prospective study. All subjects were genotyped for 16 polymorphic variants in the 14 genes of xenobiotics detoxification CYP1A1, AhR, GSTM1, GSTT1, ABCB1, redox-status SOD2, CAT, GCLC, and vascular homeostasis ACE, AGT, AGTR1, NOS3, MTHFR, VEGFα. Risk of pulmonary complications (PC) in the single locus analysis was associated with CYP1A1, GCLC and AGTR1 genes. Extra PC (toxic shock syndrome and myocarditis) were not associated with these genes. We evaluated gene-gene interactions using multi-factor dimensionality reduction, and cumulative gene risk score approaches. The final model which included >5 risk alleles in the CYP1A1 (rs2606345, rs4646903, rs1048943), GCLC, AGT, and AGTR1 genes was associated with pleuritis, empyema, acute respiratory distress syndrome, all PC and acute respiratory failure (ARF). We considered CYP1A1, GCLC, AGT, AGTR1 gene set using Set Distiller mode implemented in GeneDecks for discovering gene-set relations via the degree of sharing descriptors within a given gene set. N-acetylcysteine and oxygen were defined by Set Distiller as the best descriptors for the gene set associated in the present study with PC and ARF. Results of the study are in line with literature data and suggest that genetically determined oxidative stress exacerbation may contribute to the progression of lung inflammation.

Functional polymorphisms in the CYP1A1, ACE, and IL-6 genes contribute to susceptibility to community-acquired and nosocomial pneumonia.

OBJECTIVES: To establish the contribution of genetic host factors to the risk of community-acquired pneumonia (CAP) and nosocomial pneumonia (NP) in the population of the Russian Federation. METHODS: A total of 796 subjects (CAP: 334 patients, 134 controls; NP: 216 critically ill patients with NP, 105 critically ill patients without NP) were included in two case-control studies. We analyzed 13 polymorphisms in 11 genes (IL-6, TNF-α, MBL2, CCR5, NOS3, CYP1A1 (three sites), GSTM1, GSTT1, ABCB1, ACE, and MTHFR) using a tetra-primer allele-specific PCR method. RESULTS: Individual single nucleotide polymorphism (SNP) analysis revealed a strong association between CYP1A1 rs2606345 and CAP (p=3.9 × 10(-5), odds ratio (OR) 0.42, 95% confidence interval (CI) 0.27-0.63). Three genes (CYP1A1, ACE, and IL-6) were identified that account for part of the increase in vulnerability to both diseases, CAP and NP. The carriage of three predisposing genotypes versus protective genotypes increased the CAP risk (p=0.001, OR 7.01, 95% CI 1.99-24.70) and NP risk (p=0.028, OR 4.34, 95% CI 1.15-16.45). CONCLUSIONS: Genetic predisposition to CAP and NP is attributed to the cumulative contribution of polymorphisms at the CYP1A1, IL-6, and ACE genes, independently of age, gender, causative pathogen, and the use of mechanical ventilation, in patients in the Russian Federation.

Host genetic risk factors for community-acquired pneumonia.

This study was conducted to establish the contribution of genetic host factors in the susceptibility to community acquired pneumonia (CAP) in the Russian population. Patients with CAP (n=334), volunteers without a previous history of CAP, constantly exposed to infectious agents, control A group (n=141) and a second control group B consisted of healthy persons (n=314) were included in the study. All subjects were genotyped for 13 polymorphic variants in the genes of xenobiotics detoxification CYP1A1 (rs2606345, rs4646903, and rs1048943), GSTM1 (Ins/del), GSTT1 (Ins/del), ABCB1 rs1045642); immune and inflammation response IL-6 (rs1800795), TNF-a (rs1800629), MBL2 (rs7096206), CCR5 (rs333), NOS3 (rs1799983), angiotensin-converting enzyme ACE (rs4340), and occlusive vascular disease/hyperhomocysteinemia MTHFR (rs1801133). Seven polymorphic variants in genes CYP1A1, GSTM1, ABCB1, NOS3, IL6, CCR5 and ACE were associated with CAP. For two genes CYP1A1 and GSTM1 associations remained significant after correction for multiple comparisons. Multiple analysis by the number of all risk genotypes showed a highly significant association with CAP (P=2.4×10(-7), OR=3.03, 95% CI 1.98-4.64) with the threshold for three risk genotypes. Using the ROC-analysis, the AUC value for multi-locus model was estimated as 68.38.