Background: Sepsis is a life-threatening condition causing significant morbidity and mortality worldwide. Respiratory dysfunction is a common and serious complication of sepsis. Elucidating the intricate mechanisms underlying sepsis-induced respiratory complications is crucial for improving patient outcomes. 

Purpose: This review provides a comprehensive overview of recent advances across the epidemiology, pathogenesis, clinical management, and diagnostic approaches pertaining to sepsis-related respiratory dysfunction. 

Main body: Sepsis triggers both direct lung injury from pathogens as well as indirect systemic inflammation mediated by cytokines, immune cells, and vascular changes. These convergent mechanisms can lead to acute respiratory distress syndrome (ARDS) and other hypoxemic complications. Certain populations like the elderly and those with chronic illnesses are at higher risk. Timely antibiotic therapy and hemodynamic stabilization are essential to prevent respiratory deterioration. Supportive ventilation strategies and adjuvant treatments like prone positioning may be employed for severe cases. Ongoing research has focused on modulating inflammatory and molecular targets involved in lung injury as potential preventive approaches. Emerging tools utilizing genomics, biomarkers, and artificial intelligence hold promise for early risk assessment, diagnosis, and personalized treatment strategies.

Conclusion: This review highlights recent advances across the spectrum of sepsis-induced respiratory dysfunction. Integrating molecular mechanisms with clinical translation and leveraging new technologies is key to improving early detection, optimizing management, and ultimately reducing the burden of sepsis-related respiratory morbidity and mortality.

Sepsis, a life-threatening syndrome characterized by organ dysfunction, is a global health concern with alarmingly high morbidity and mortality rates [1]. In understanding sepsis, particularly its association with respiratory complications, we gain valuable insights into improving patient outcomes [2]. Early detection of sepsis-induced respiratory complications plays a critical role in guiding clinical management and treatment strategies. In this comprehensive overview, we delve into the epidemiology, pathogenesis, clinical management, and future directions pertaining to biomarkers and diagnostic tools for early detection of sepsis-induced respiratory complications. Sepsis, often triggered by a severe infection, leads to a dysregulated immune response and organ dysfunction [3]. Its association with an alarming rate of morbidity and mortality emphasizes the urgent need for effective diagnostic tools and timely intervention. By understanding the intricate nature of sepsis as a syndrome causing life-threatening organ dysfunction, we can unravel its complex respiratory complications. Sepsis poses a significant burden on global health, accounting for a substantial number of hospital admissions and healthcare costs [4]. The prevalence of sepsis-induced respiratory complications, such as acute respiratory distress syndrome (ARDS), further intensifies the gravity of the situation. Identifying risk factors that contribute to the development of respiratory complications in sepsis patients enables targeted interventions and improved patient care [5]. Unveiling the mechanisms underlying respiratory complications in sepsis is fundamental in advancing diagnostic and therapeutic approaches. Cytokines, chemokines, and immune cells contribute to respiratory dysfunction, requiring a deeper understanding of both direct and indirect injuries involved [6]. Timely treatment of underlying sepsis is essential to prevent or mitigate respiratory complications. Early identification of patients at risk of developing respiratory complications allows targeted interventions and better prognostic outcomes [7]. Current treatment strategies, along with emerging preventive approaches based on molecular and genetic research, hold promise for improved patient care. Identifying biomarkers and developing diagnostic tools creates opportunities for early detection and prognosis of sepsis-induced respiratory complications [8]. Gene biomarker panels hold potential to revolutionize diagnosis, allowing for swift intervention and personalized treatment strategies. Network analysis and bioinformatics further aid in biomarker discovery, facilitating a comprehensive understanding of sepsis pathogenesis [9]. The international guidelines for sepsis and septic shock management, such as the Surviving Sepsis Campaign, provide a standardized approach to clinical management [10]. Emphasizing the importance of timely administration of antimicrobials and their association with mortality rates, these guidelines also provide recommendations for managing sepsis-induced respiratory complications [11]. Recapping the key findings and insights on respiratory complications in sepsis, we recognize the need for further research to unravel the intricacies of pathogenesis and develop novel therapies [12]. Integrated approaches combining molecular research and clinical translation hold immense potential in transforming sepsis management, improving patient outcomes, and ultimately reducing the global burden of sepsis-induced respiratory complications [13-16]. 

While prior reviews have examined respiratory complications in sepsis, this article provides a comprehensive overview of recent advances across pathogenesis, risk factors, clinical management, and emerging diagnostic biomarkers and tools. The review offers novel insights into the intricate mechanisms underlying sepsis-induced respiratory dysfunction. It emphasizes the importance of early identification of patients at risk to enable targeted preventive strategies and personalized treatments. 

I. Sepsis and its Association with High Morbidity and Mortality Rates

Sepsis is a complex syndrome with varying manifestations, making its definition crucial for diagnosis and treatment. The association between sepsis and high morbidity and mortality rates is well-established, emphasizing the importance of timely recognition and intervention. In this review, we will delve into the definition of sepsis and explore its implications on morbidity and mortality rates [17]. The definition of sepsis has evolved over the years to improve accuracy and enhance clinical management. According to Sepsis-3, sepsis is now defined as a dysregulated host response to infection, resulting in life-threatening organ dysfunction. This definition places emphasis on organ dysfunction rather than just infection and incorporates clinical and laboratory parameters for identification [18]. Sepsis often leads to a range of complications and long-term consequences, contributing to its high morbidity rates. Organ dysfunction caused by sepsis can result in multi-organ failure, leading to prolonged hospital stays, increased risk of secondary infections, and the development of chronic health conditions. Additionally, sepsis survivors often experience long-lasting physical, emotional, and cognitive impairments, impacting their quality of life [19]. Sepsis remains a significant global public health concern due to its high mortality rates. Despite advances in medical care, sepsis-associated mortality remains alarmingly high. Studies have shown that early recognition and timely intervention greatly affect patient outcomes [20]. However, delayed or inappropriate therapy can escalate organ dysfunction, culminating in septic shock, which significantly increases the risk of death. Additionally, certain patient populations, such as the elderly, immunocompromised individuals, and those with pre-existing conditions, are particularly vulnerable to sepsis-related mortality [21].

‌ II. Sepsis through unlocking the Understanding of a Life-Threatening Syndrome

Sepsis, a potentially fatal medical condition, is a syndrome that triggers widespread inflammation and organ damage throughout the body. Recognizing the importance of understanding sepsis and its devastating consequences is crucial for medical professionals and the general public alike. In this review, we delve deep into the complexities of sepsis, exploring its causes, symptoms, diagnostic techniques, and life-saving treatments [22]. Sepsis is often referred to as the body's extreme response to an infection. Although infections can be caused by various sources such as bacteria, viruses, fungi, or parasites, sepsis occurs when the immune system's response goes haywire, leading to severe complications. This cascading response leads to widespread inflammation and dysfunctional organ behavior, ultimately posing a severe threat to the patient's life [23]. Sepsis can be triggered by infections stemming from various sources, including pneumonia, urinary tract infections, abdominal infections, or skin infections. Additionally, individuals with weakened immune systems, chronic illnesses, or those undergoing invasive medical procedures are at an increased risk for developing sepsis. Early recognition and prompt treatment are crucial to preventing its progression [24]. Recognizing the symptoms of sepsis is vital for timely intervention. Common indicators include fever, rapid heart rate, breathing difficulties, disorientation, decreased urine output, and a significant drop in blood pressure. A comprehensive diagnostic approach combines physical examination, blood cultures, imaging tests, and measurement of biomarkers to confirm sepsis and its severity [25]. Sepsis primarily damages vital organs, such as the lungs, heart, kidneys, liver, and brain, as a result of blood circulation impairment and inadequate oxygen delivery [26-34]. This dysfunction can potentially lead to acute respiratory distress syndrome (ARDS), myocardial dysfunction, acute kidney injury (AKI), liver dysfunction, and neurological complications [35-36]. The severity of organ dysfunction determines the patient's prognosis and guides the intensity of medical interventions [37].

III. Importance of understanding the relationship between sepsis and respiratory complications

The respiratory system acts as a gateway for pathogens, making it particularly susceptible during cases of sepsis. The compromised immune response allows microorganisms to invade the lower respiratory tract, leading to respiratory complications such as pneumonia, acute respiratory distress syndrome (ARDS), and ventilator-associated pneumonia (VAP). Understanding the bidirectional relationship between sepsis and respiratory complications is paramount. While sepsis can lead to respiratory problems, it is equally important to recognize how respiratory conditions can predispose individuals to sepsis. Conditions such as chronic obstructive pulmonary disease (COPD), pneumonia, and ventilator-associated lung injury can serve as potential triggers for sepsis, accentuating the need for early intervention [38]. The intertwining relationship between sepsis and respiratory complications can be attributed to shared pathophysiological mechanisms [39]. Inflammatory mediators, endothelial dysfunction, alveolar damage, impaired gas exchange, and the activation of coagulation pathways play pivotal roles in both sepsis and respiratory dysfunction. Understanding these mechanisms can provide clinicians with the knowledge necessary for accurate diagnosis and tailored therapeutic interventions [40]. Recognizing the relationship between sepsis and respiratory complications is crucial for timely and appropriate medical intervention [41]. Early identification, immediate administration of appropriate antibiotics, ventilatory support, hemodynamic stabilization, and infection control measures are pivotal in enhancing patient outcomes and reducing mortality rates [42-43].

IV. Epidemiology and Risk factors for developing respiratory complications in sepsis patients

The global burden of sepsis is significant, with more than 19 million sepsis cases and 5 million sepsis-related deaths estimated to occur annually. The majority of sepsis cases and deaths occur in low and middle-income countries. Epidemiology is crucial for understanding the distribution and determinants of sepsis, including risk factors, incidence, and mortality rates [44]. Respiratory complications are a common and serious consequence of sepsis, and identifying the risk factors. Sepsis is most commonly caused by infections, such as pneumonia, urinary tract infections, and skin infections. These infections can directly or indirectly lead to respiratory complications. Older adults are more susceptible to respiratory complications in sepsis due to age-related changes in the immune system and a higher prevalence of comorbidities. The severity of sepsis, including the presence of septic shock, is associated with an increased risk of developing respiratory complications [45]. In some cases, pneumonia or other lung infections can directly injure the lungs and lead to respiratory complications. Sepsis can cause indirect injury to the lungs through the release of inflammatory mediators, leading to lung inflammation and subsequent respiratory complications. Smoking is a risk factor for respiratory complications in sepsis patients, as it can worsen lung function and increase the risk of lung injury. Alcohol abuse can weaken the immune system and increase the risk of respiratory complications in sepsis patients. Patients with pre-existing chronic health conditions, such as diabetes, cancer, and kidney disease, are at a higher risk of developing respiratory complications in the setting of sepsis [46].

V. Pathogenesis of Sepsis-Induced Respiratory Complications

Sepsis is a life-threatening condition caused by the body's response to an infection. It can lead to respiratory complications and organ failure.

V.1. Mechanisms underlying the development of respiratory complications in sepsis

Sepsis triggers a cascade of complex inflammatory responses in the body. When the body detects infections, the immune system releases cytokines to help fight the infection as depicted in table 1. However, in severe cases of sepsis, the immune response becomes uncontrolled and dysregulated, leading to a cytokine storm. The overproduction of pro-inflammatory cytokines like interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) contributes to the pathological changes in sepsis.   This cytokine storm can damage the lungs and airways in sepsis patients, causing respiratory complications. The pro-inflammatory cytokines can activate neutrophils and cause them to accumulate in the lungs, resulting in acute lung injury and acute respiratory distress syndrome (ARDS). This neutrophil infiltration worsens pulmonary edema and inflammation [47]. The cytokine storm also increases microvascular permeability in the lungs, leading to leakage of fluids into the air spaces and impairment of gas exchange. The fluid buildup in the alveolar air spaces and interstitium further exacerbates pulmonary edema and hypoxemia in sepsis patients. The pro-inflammatory mediators produced during sepsis impair the function of pulmonary surfactant, a mixture of proteins and lipids that helps keep the alveoli open. Decreased production and inactivation of surfactant contribute to atelectasis formation and worsened lung compliance in sepsis. Increased mucus secretion from the goblet cells of the airway epithelium also occurs during sepsis, narrowing the airway lumen and making breathing difficult. This mucus plugging, together with microatelectasis from surfactant dysfunction, impedes oxygenation and gas exchange in the lungs. All of these pathological changes mediated by the cytokine storm can lead to sepsis-induced respiratory complications like ARDS, pneumonia, and other types of hypoxemic respiratory failure. The mechanisms mentioned aim to provide insight into the complex pathogenesis behind these serious lung complications in sepsis [48]. Acute respiratory distress syndrome (ARDS) can develop as a consequence of sepsis originating from either a direct lung infection or an indirect extrapulmonary source. In both scenarios, the host immune response to the inciting pathogen results in a cascade of inflammatory events that ultimately disrupt the integrity of the alveolar-capillary barrier in the lungs. This barrier is formed by the lining of the alveoli (epithelial cells) and the adjacent capillary endothelium. When sepsis triggers inflammatory cells like neutrophils and macrophages to accumulate in the lungs, they release a flood of proinflammatory signaling molecules called cytokines. Additionally, the immune system recognizes pathogen- and damage-associated molecular patterns through pattern recognition receptors. These manifold signaling pathways converge to inflict injury to the alveolar and capillary cells. The ensuing loss of barrier integrity enables an influx of protein-rich edema fluid into the airspaces, producing the hallmark pulmonary edema seen in sepsis-induced ARDS. Therefore, regardless of the sepsis source, an uncontrolled inflammatory response damages the crucial alveolar-capillary membrane, leading to life-threatening lung injury and respiratory failure as represented in figure 1 [49].

Figure 1: From Infection to Inflammation to Injury: The Multifactorial Pathogenesis of Sepsis-Associated ARDS [49].

Table 1: Key mechanisms underlying sepsis-induced respiratory complications

V.2. Role of cytokines, chemokines, and immune cells in respiratory dysfunction

Sepsis leads to an uncontrolled inflammatory response that damages the lungs and causes respiratory complications. Cytokines, chemokines, and immune cells work together to drive this pathological process [50]. Cytokines like IL-1, IL-6 and TNF-α are overproduced during the sepsis-induced cytokine storm. They increase vascular permeability, impair surfactant function, and damage the lung epithelium [51]. This contributes to acute lung injury and dysfunction. While anti-inflammatory cytokines like IL-10 also rise, they fail to balance the effects of pro-inflammatory cytokines [52].  Chemokines are released that recruit neutrophils and other immune cells to the lungs. Chemokines like IL-8 activate and migrate neutrophils, exacerbating lung inflammation [53]. Neutrophils accumulate in large numbers in the lungs due to cytokines and chemokines. The activated neutrophils release proteolytic enzymes and reactive oxygen species that oxidize lipids and proteins, damaging lung tissues and worsening injury [54]. Macrophages in the alveolar space are also activated during sepsis and produce more pro-inflammatory cytokines. They amplify the cytokine storm and promote persistent lung inflammation [55]. Intravenous immunoglobulin (IVIG) therapy has potential roles in modulating the dysregulated immune response in sepsis and septic shock. IVIG contains antibodies like IgG, IgM, and IgA that can interact with various components of the innate and adaptive immune system. Experimental evidence indicates IVIG can neutralize toxins, opsonize pathogens, activate complement, and regulate pro- and anti-inflammatory cytokines. Particular formulations enriched in IgM and IgA have shown promise in pneumonia and toxic shock syndrome figure 2 [56].

Figure 2: The Unrealized Promise of IVIG as an Immunomodulator in Sepsis [56].

V.3. Differentiating direct and indirect injuries in sepsis-induced respiratory complications

Direct injuries in sepsis-induced respiratory complications refer to the damage inflicted directly on the lungs by the infection itself. When the infection enters the lungs, it can lead to inflammation and tissue damage, impairing the ability of the lungs to efficiently exchange oxygen and carbon dioxide. This can result in respiratory distress, characterized by symptoms such as rapid breathing, shortness of breath, and low oxygen levels. Direct injuries can also lead to the development of conditions like pneumonia or acute respiratory distress syndrome (ARDS), further exacerbating respiratory complications in sepsis [57]. 

Indirect injuries, on the other hand, are not caused directly by the infection but rather by the body's response to the infection. During sepsis, the immune system goes into overdrive, releasing excessive amounts of inflammatory molecules called cytokines. These cytokines can cause widespread inflammation throughout the body, including the lungs. This inflammation can lead to injury and dysfunction of the lung tissues, contributing to respiratory complications. Indirect injuries may result in conditions such as acute lung injury and ARDS, where the lungs become stiff and cannot effectively oxygenate the blood [58].

Distinguishing between direct and indirect injuries in sepsis-induced respiratory complications can be challenging due to their overlapping features. Both types of injuries can cause similar symptoms, such as difficulty breathing and low oxygen levels. However, there are some key differences that can help in their differentiation. Direct injuries are commonly associated with infections localized in the lungs, and imaging studies such as chest X-rays or CT scans may reveal signs of pneumonia or lung consolidation. Indirect injuries, on the other hand, are typically characterized by a systemic inflammatory response affecting multiple organs, including the lungs [59].

Clinical evaluation and monitoring play a crucial role in differentiating between direct and indirect injuries. Healthcare providers may assess the patient's medical history, conduct a thorough physical examination, and order various diagnostic tests to identify the underlying cause of respiratory complications in sepsis. Blood tests can help determine markers of infection, inflammation, and organ dysfunction. Imaging studies may reveal specific lung abnormalities, aiding in the diagnosis. Additionally, advanced techniques such as bronchoscopy or lung tissue biopsy may be performed in certain cases to confirm the presence and nature of injuries [60].

Accurately distinguishing between direct and indirect injuries in sepsis-induced respiratory complications is essential for guiding appropriate treatment strategies. While both types of injuries contribute to respiratory compromise, their management approaches may differ. Direct injuries often require targeted antibiotic therapy to combat the underlying infection, along with supportive care to optimize lung function. Indirect injuries, on the other hand, focus on controlling the systemic inflammatory response through interventions like fluid management, vasopressor support, and corticosteroids. Individualized treatment plans should be tailored based on the underlying cause and severity of respiratory complications [61].

IV. Clinical Management and Treatment

IV.1. Timely treatment of underlying sepsis to prevent or mitigate respiratory complications

In sepsis, the immune response to an infection can lead to the release of chemicals into the bloodstream, causing widespread inflammation. This inflammatory response can impact the functions of various organs, including the lungs. If left untreated or if treatment is delayed, sepsis can progress to severe sepsis, where organ dysfunction becomes evident. Respiratory complications, such as acute respiratory distress syndrome (ARDS), are common in severe sepsis and can contribute to a higher risk of mortality [62]. Early identification and treatment of sepsis are crucial to prevent the progression of the condition and the subsequent development of respiratory complications. Healthcare professionals play a vital role in recognizing the signs and symptoms of sepsis, such as fever, increased heart rate, rapid breathing, and altered mental status. Once sepsis is suspected, prompt action should be taken to initiate appropriate treatment [63]. Timely treatment of underlying sepsis involves a multifaceted approach. The first step is identifying the source of infection, which may require various diagnostic tests, including blood cultures, imaging studies, and urine or sputum analysis. Antibiotics are administered promptly to target the specific infection causing the sepsis. This early administration of antibiotics is crucial in preventing the infection from spreading and reducing the overall inflammatory response [64].

Alongside antibiotic therapy, supportive care is essential in managing sepsis and preventing respiratory complications. Adequate fluid resuscitation helps maintain blood pressure and organ perfusion. Additionally, oxygen therapy may be necessary to support respiratory function and prevent hypoxia. In severe cases, mechanical ventilation might be required to ensure sufficient oxygenation and ventilation. It is worth noting that appropriate treatment should not only focus on managing the acute symptoms but also on addressing any underlying conditions that may have predisposed the patient to sepsis. Identifying and treating the root causes, such as pneumonia or urinary tract infections, can aid in preventing recurrences or the development of chronic conditions [65].

IV.2. Current treatment strategies for sepsis-induced respiratory complications

In recent years, there have been significant advancements in the treatment strategies for sepsis-induced respiratory complications as depicted in table 2. 

Table 2: Emerging preventive strategies for sepsis-induced respiratory complications

IV.2.1. Early recognition and prompt treatment:

Early recognition and timely initiation of treatment are crucial in managing sepsis-induced respiratory complications. This involves identifying the signs and symptoms of sepsis early on and initiating appropriate interventions promptly. This includes administering antibiotics, ensuring adequate fluid resuscitation, and providing respiratory support if necessary [66].

‌IV.2.2. Antibiotic therapy:

In sepsis-induced respiratory complications, prompt administration of appropriate antibiotics is essential. Broad-spectrum antibiotics are often initiated empirically until culture results guide the selection of targeted antibiotics. The choice of antibiotic depends on the suspected source of infection and the local antimicrobial resistance patterns [67].

IV.2.3. Hemodynamic support:

Sepsis-induced respiratory complications can lead to hemodynamic instability and organ dysfunction. Hemodynamic support is a key component of treatment, which involves maintaining adequate blood pressure, optimizing fluid balance, and using vasopressor medications to support cardiac output in severe cases [68-69].

IV.2.4. Mechanical ventilation and supportive care:

In patients with severe respiratory compromise, mechanical ventilation is often necessary. Lung-protective ventilation strategies, which aim to minimize further lung injury, are employed. Positive end-expiratory pressure (PEEP) is used to improve oxygenation and recruit collapsed lung regions. Supportive care includes close monitoring of fluid balance, electrolyte management, and nutritional support [70].

IV.2.5. Adjunctive therapies:

Several adjunctive therapies have shown promise in sepsis-induced respiratory complications. These include prone positioning, which improves oxygenation in ARDS patients by redistributing lung perfusion [71]. Extracorporeal membrane oxygenation (ECMO) may be considered in refractory cases as a bridge to recovery or lung transplantation [72].

IV.2.6. Targeted therapies:

Recent research has focused on identifying specific targets in the inflammatory cascade of sepsis-induced respiratory complications. Agents such as corticosteroids, anti-inflammatory cytokines, and mesenchymal stem cells are being studied for their potential to modulate the immune response and improve outcomes [73].

‌IV.2.7. Supportive management:

Alongside these targeted treatment strategies, supportive management plays a critical role in optimizing outcomes. This includes ensuring appropriate pain control, preventing complications like pressure ulcers and deep vein thrombosis, and managing any concurrent infections or organ dysfunctions [74].

IV.3. Emerging preventive strategies based on molecular and genetic research

There has been a growing focus on molecular and genetic research to develop innovative preventive strategies for sepsis-induced respiratory complications, delving into seven key emerging preventive strategies [75]. Firstly, one promising approach involves targeting the molecular mechanisms underlying sepsis-induced lung injury [76]. Extensive research has identified various molecules, such as cytokines and chemokines that play critical roles in the inflammatory response during sepsis. By developing targeted therapies to modulate the expression or activity of these molecules, it may be possible to attenuate lung damage and improve respiratory outcomes [77]. Secondly, genetic research has shed light on the genetic predisposition to sepsis and its complications. Identifying specific genetic markers associated with an increased susceptibility to respiratory complications in sepsis patients could enable early risk assessment and personalized preventive strategies [78]. Advances in genome-wide association studies and gene sequencing technologies have contributed significantly to this field, offering valuable insights into the genetic determinants of sepsis-induced lung injury [79]. Thirdly, the use of biomarkers holds great promise in predicting and preventing sepsis-induced respiratory complications. Biomarkers are measurable indicators of physiological or pathological processes occurring within the body. By identifying specific biomarkers that are associated with the development or progression of lung injury in sepsis, clinicians can effectively monitor patients and intervene at early stages to prevent or mitigate respiratory complications [80]. Fourthly, pharmacogenomics, the study of how individual genetic variations influence responses to medications, could revolutionize sepsis management. By analyzing a patient's genetic profile, it may be possible to predict their response to specific drugs used for the prevention or treatment of sepsis-induced respiratory complications [81]. This personalized approach could help optimize therapeutic regimens, minimize adverse effects, and enhance treatment efficacy [82-83].

Fifthly, immunomodulatory therapies offer a potential preventive strategy for reducing respiratory complications in sepsis. The dysregulated immune response in sepsis plays a crucial role in lung injury. Novel immunotherapies, such as immune checkpoint inhibitors or cell-based therapies, could modulate the immune system and restore its equilibrium, preventing excessive lung inflammation and subsequent respiratory damage [84]. Sixthly, advances in nanomedicine have opened up new possibilities for targeted drug delivery and precision medicine in sepsis-induced respiratory complications. Nanoparticles can be engineered to carry therapeutic agents specifically to the inflamed lungs, maximizing treatment efficacy while minimizing systemic side effects. Nanotechnology-based approaches offer great potential for personalized preventive strategies in sepsis management [85]. Lastly, the emergence of artificial intelligence (AI) and machine learning is revolutionizing medical research and healthcare [86-87]. AI algorithms can rapidly analyze vast amounts of molecular and genetic data, identifying complex patterns and predicting patient outcomes [88]. 

‌V. Biomarkers and Diagnostic Tools

Recent advances in genomics offer new hope for early identification of high-risk patients through biomarker discovery as depicted in table 3. 

Table 3: Biomarkers for early detection of sepsis-induced respiratory complications

Procalcitonin (PCT), C-reactive protein (CRP), and interleukin-6 (IL-6) are commonly used inflammatory markers that can indicate the presence of sepsis. Elevated levels of these markers in the blood can help clinicians identify patients who are at risk of developing sepsis-induced respiratory complications.

Pulmonary markers: KL-6 and MMP-7 are markers of lung injury and repair, respectively. Elevated levels of these markers in the blood can help clinicians identify patients who are at risk of developing acute respiratory distress syndrome (ARDS) or other pulmonary complications.

Oxidative stress markers: F2-isoprostanes and 8-isoprostane are markers of oxidative stress, which is a key component of sepsis pathophysiology. Elevated levels of these markers can help clinicians identify patients who are at risk of developing sepsis-induced respiratory complications [89].

Cellular apoptosis markers: HSP70 and caspase-3 are markers of cellular apoptosis, which can occur in response to sepsis-induced inflammation and tissue damage. Elevated levels of these markers can help clinicians identify patients who are at risk of developing sepsis-induced respiratory complications.

MicroRNA (miRNA) markers: miRNAs are small non-coding RNAs that play a critical role in regulating gene expression. Specific miRNAs, such as miR-15a, miR-16, and miR-29b, have been altered in sepsis and may serve as potential biomarkers for early diagnosis and prognosis [90].

VI. Role of AI and network analysis and bioinformatics in biomarker discovery

Artificial intelligence (AI), network analysis, and bioinformatics are powerful tools that can aid in the discovery of new biomarkers for sepsis diagnosis and monitoring. 

AI-driven biomarker discovery: Machine learning algorithms can analyze large datasets of patient information, including demographics, medical history, laboratory results, and clinical outcomes. AI can identify patterns and correlations between variables that might not be apparent to human analysts, allowing for the identification of novel biomarkers.

Network analysis: Sepsis is a complex condition involving multiple organ systems and biological pathways. Network analysis can help uncover relationships between different biological molecules, such as proteins, genes, and metabolites, and how they interact in sepsis. This approach can reveal new biomarker candidates and provide insights into the underlying mechanisms of sepsis [91].

Bioinformatics: The abundance of genomic, transcriptomic, and proteomic data offers opportunities for bioinformatic analysis. Bioinformatics tools can help identify genes or proteins that are differentially expressed between healthy individuals and those with sepsis. Additionally, bioinformatics can aid in the prediction of protein structures and functions, facilitating the understanding of molecular interactions and potential therapeutic targets.

Integration of multi-omics data: By integrating data from different omics technologies, such as genomics, transcriptomics, proteomics, and metabolomics, researchers can gain a comprehensive view of the molecular landscape of sepsis. AI and machine learning techniques can then be applied to this integrated dataset to identify patterns and correlations that could lead to new biomarker discoveries [92].

Personalized medicine approaches: AI and bioinformatics can also contribute to personalized medicine approaches by identifying subpopulations within sepsis patients based on their molecular profiles. This stratification can help tailor treatments to individual patients, improving outcomes and minimizing adverse reactions.

Drug repurposing and target identification: AI and bioinformatics can aid in drug repurposing by analyzing databases of known drugs and their mechanisms of action. This approach can identify potential drug candidates that could be effective in treating sepsis, accelerating the drug development process and reducing costs compared to developing new drugs from scratch.

Validation and verification: Once potential biomarkers are identified, AI and bioinformatics can assist in validating and verifying their efficacy using large datasets and statistical models. These tools can help assess the accuracy, specificity, and sensitivity of the biomarkers, ensuring that only the most promising candidates move forward to clinical validation.

Streamlining clinical trials: AI and bioinformatics can optimize clinical trial design and execution, making them more efficient and cost-effective. For instance, AI can simulate clinical trials, predicting patient outcomes and identifying the most suitable patient populations for enrollment.

Precision medicine strategies: AI and bioinformatics can support precision medicine strategies by incorporating genomic, epigenetic, and transcriptomic data to better understand patient variability and tailor treatments to individual responses [93].

Continuous learning and improvement: AI and machine learning algorithms can continuously learn from real-world data, adapting to changes in patient populations, treatment protocols, and emerging scientific knowledge. This enables a feedback loop where biomarker discovery and validation are refined over time, leading to improved diagnostic accuracy and patient outcomes [94].

‌IX. Conclusion:

Sepsis-induced respiratory dysfunction is a serious clinical concern associated with significant morbidity and mortality. This review synthesizes current knowledge on the intricate mechanisms, from direct lung injury to indirect systemic inflammation, that contribute to conditions like ARDS in sepsis patients. Identifying those at high risk and promptly intervening with appropriate antibiotics, lung-protective ventilation, and hemodynamic support are crucial for mitigating respiratory complications. Emerging tools utilizing genomics, biomarkers, and artificial intelligence hold immense promise for early diagnosis and personalized preventive strategies. Taken together, an integrated approach combining molecular research, clinical management, and translational bioinformatics is key to unraveling the pathogenesis, improving early detection, and developing innovative therapies to transform care and reduce the burden of sepsis-related respiratory complications.

X. Recommendations

Further research should focus on comprehensively elucidating the molecular pathways and genetic determinants influencing susceptibility to sepsis-induced lung injury. This could aid in developing targeted immunomodulatory or anti-inflammatory therapies. Refining existing biomarkers and identifying novel indicators of early lung damage through multi-omics approaches can enable risk stratification and timely intervention. Machine learning and AI methodologies should be leveraged to rapidly analyze complex datasets and derive clinically valid diagnostic, prognostic, and predictive models. Translating cutting-edge tools like gene expression panels and nanotechnology platforms from bench to bedside can facilitate personalized care. Fostering integrated collabo­ration between laboratory scientists and clinicians will be pivotal in advancing impactful innovations to transform sepsis management and mitigate respiratory complications.

Abbreviations list:

- SIRS - Systemic inflammatory response syndrome - ARDS - Acute respiratory distress syndrome - PCT – Procalcitonin - CRP - C-reactive protein - IL-6 - Interleukin 6 - ICU - Intensive care unit - MODS - Multiple organ dysfunction syndrome - DIC - Disseminated intravascular coagulation - PEEP - Positive end-expiratory pressure - PaO2 - Partial pressure of arterial oxygen - FiO2 - Fraction of inspired oxygen - VAP - Ventilator-associated pneumonia - ALI - Acute lung injury - ROS - Reactive oxygen species - RNS - Reactive nitrogen species - TLRs - Toll-like receptors - PAMPs - Pathogen-associated molecular patterns - DAMPs - Damage-associated molecular patterns - HMGB1 - High mobility group box 1 - NETs - Neutrophil extracellular traps - SOFA - Sequential Organ Failure Assessment - qSOFA - Quick SOFA - BNP - Brain natriuretic peptide - cTn - Cardiac troponin - KL-6 - Krebs von den Lungen-6 - MMP-7 - Matrix metalloproteinase-7 - miR – microRNA - SCCM - Society of Critical Care Medicine - ESICM - European Society of Intensive Care Medicine

Declarations:

Ethics approval and consent to participate: Not Applicable

Consent for publication:Not Applicable

Availability of data and materials: all data are available and sharing is available as well as publication.

Competing interests: The authors hereby that they have no competing interests.

Funding: Corresponding author supplied all study materials. There was no further funding for this study.

Authors' contributions: The authors completed the study protocol and were the primary organizers of data collection and the manuscript's draft and revision process. Tamer A. Addissouky wrote the article and ensured its accuracy. All authors contributed to the discussion, assisted in designing the study and protocol and engaged in critical discussions of the draft manuscript. Lastly, the authors reviewed and confirmed the final version of the manuscript.

Acknowledgements: The authors thank all the researchers, editors, reviewers, and the supported universities that have done great efforts on their studies. Moreover, we are grateful to the editors, reviewers, and reader of this journal.