Infection risk and management in patients with cirrhosis: A critical overview

Abstract

In this paper, we analyze the article published by El Labban et al, which explores the impact of cirrhosis on patients with necrotizing fasciitis. The authors conclude that cirrhosis is a significant risk factor for increased in-hospital morbidity and mortality in this patient population. Building upon their final observation regarding the importance of understanding this association, we will delve into the topic of infections in patients with liver cirrhosis. These patients exhibit intrinsic characteristics that make them particularly susceptible to infections, both bacterial and fungal. This heightened risk not only increases the likelihood of severe infections but also makes them a common trigger for acute decompensations, including the development of acute-on-chronic liver failure, which markedly worsens prognosis and mortality. Infections in patients with cirrhosis often require a more aggressive and rapid diagnostic and therapeutic approach due to the higher risk of nosocomial infections, multidrug-resistant organisms, and atypical clinical presentations. Delayed or inadequate management can lead to unfavorable outcomes, further complicating the course of their underlying liver disease. The aim of this article is to emphasize the importance of early and appropriate management in patients with cirrhosis with infections. Evidence supports that timely and tailored interventions not only improve clinical outcomes but also reduce mortality. By raising awareness among clinicians about the complexity of these cases, we hope to contribute to optimizing the care of this high-risk population.

Key Words: Infections; Cirrhosis; Necrotizing fasciitis; Sepsis; Acute-on-chronic liver failure; Multidrug resistant organism

Core Tip: Patients with cirrhosis face a significantly higher risk of infections, which often trigger acute decompensations and worsen their prognosis. The study by El Labban et al emphasizes the need for early detection and understanding of the complex pathophysiology of patients with cirrhosis, including immune dysfunction, intestinal permeability, and the risk of multidrug-resistant organisms. Recognizing these factors and adopting multidisciplinary, patient-tailored approaches are critical to mitigating the heightened morbidity and mortality observed in this population.

INTRODUCTION

Liver cirrhosis is a major cause of mortality worldwide, ranking as the 11^th most common cause of death[1,2]. Infections are among the main complications, not only due to the infectious process itself but also because they have the potential to trigger decompensation in patients with cirrhosis[3]. Approximately one-third of these patients who are hospitalized will develop some form of infection, representing a risk 4-5 times higher than that of the general population, particularly in those with gastrointestinal bleeding[4]. Consequently, it is essential to consider the possibility of an infectious process in every hospitalized patients with cirrhosis, as it may be responsible for the decompensation[3,5]. The most common infections are soft tissue infections, respiratory infections, urinary tract infections, and spontaneous bacterial peritonitis (SBP), with the latter being the most frequent (Table 1)[5,6]. Furthermore, about 15% of patients with cirrhosis will develop a nosocomial infection after hospitalization[7].

Table 1 Summary of the most common bacterial infections in cirrhosis[5,6,19,71].

Infection	Community-acquired, most common bacteria	Community-acquired, first line treatment	Community-acquired, second line treatment	HCA/nosocomial, most common bacteria	HCA/nosocomial, first line treatment	HCA/nosocomial, second line treatment
Soft tissue and skin	Streptococcus pyogenes and Staphylococcus aureus	Amoxicillin/clavulanic acid third-generation cephalosporin NF: Meropenem + daptomycin + clindamycin	Piperacillin/tazobactam	MRSA, Enterococci	Meropenem ceftazidime + penicillinase, resistant penicillin	Piperacillin/tazobactam + glycopeptide daptomycin or linezolid should be considered if VRE high prevalence
Respiratory tract	Gram positives (Streptococcus pneumoniae and Staphylococcus aureus)	Quinolones amoxicillin/clavulanic acid cephalosporin + macrolide	Piperacillin/tazobactam	Gram negatives (Pseudomonas aeruginosa, Escherichia coli), ESBL, MRSA, Acinetobacter baumannii	Piperacillin/tazobactam if low MDRO risk meropenem or ceftazidime + quinolone if high MDRO risk	Consider vancomycin or linezolid if MRSA
Urinary tract	Escherichia coli and Klebsiella pneumoniae	Ciprofloxacin cotrimoxazole third-generation cephalosporin or amoxicillin/clavulanic acid (if sepsis)	Piperacillin/tazobactam	Enterobacteriae (ESBL), Enterococci (VRE), Pseudomonas aeruginosa	Fosfomycin or Nitrofurantoin for uncomplicated infections piperacillin/tazobactam or for sepsis/complicated infection	Meropenem ± glycopeptide, especially if high prevalence MDRO
SBP	Escherichia coli and Klebsiella pneumoniae	Third-generation cephalosporin amoxicillin/clavulanic acid can be considered	Quinolones oral or intravenous injection if no norfloxacin treatment	Escherichia coli (ESBL), Klebsiella pneumoniae (MDR), Enterococci (VRE), MRSA	Piperacillin/tazobactam (low MDRO prevalence) meropenem ± glycopeptide (high MDRO prevalence)	Consider linezolid or daptomycin

Fungal infections should always be considered. ESBL: Extended spectrum β-lactamase; HCA: Healthcare-associated infection; MDRO: Multidrug resistant organism; MRSA: Methicillin-resistant Staphylococcus aureus; NF: Necrotizing Fasciitis; VRE: Vancomycin-resistant Enterococci; SBP: Spontaneous bacterial peritonitis.

The presence of infection in these patients significantly impacts their prognosis. In the study by Arvaniti et al[8], 30-day mortality was estimated at 30% in patients who experienced an infectious process, with another 30% dying within a year of the event. Those who develop a nosocomial infection also have a worse prognosis, with an estimated 30-day mortality rate of around 24%[7]. Although the overall incidence of nosocomial infections is lower, their mortality rate is considerably high, emphasizing the importance of prompt detection and management. The study conducted by the North American Consortium for the Study of End-Stage Liver Disease yielded similar results, reporting a 30-day mortality rate of approximately 24% in patients who developed a second infection[9]. Mortality due to infections has been extensively studied, particularly in patients with acute-on-chronic liver failure (ACLF). In these cases, infections have been identified as an independent risk factor for mortality, with rates exceeding 70% at 30 days, as reported by Mücke et al[10]. Early detection of infections and the prompt use of broad-spectrum antibiotics have proven to be crucial for patient outcomes[11,12]. A randomized trial conducted by Merli et al[13] demonstrated that early administration of broad-spectrum antibiotics significantly reduced mortality in these patients, particularly in those who developed sepsis compared to those receiving standard treatment.

As highlighted, infections in patients with cirrhosis present a significant challenge that requires efficient and multidisciplinary management. This has implications both in terms of survival and quality of life[14]. The study by El Labban et al[15] is particularly relevant as it identifies a worse prognosis for necrotizing fasciitis in patients with cirrhosis in terms of mortality (9.5% vs 3%), underscoring the need for more tailored management to reduce it. Necrotizing fasciitis is a severe and rapidly progressive infection affecting soft tissues, characterized by necrosis of the fascia and subcutaneous tissue, with a high risk of progression to sepsis and death if not promptly treated, particularly in patients with cirrhosis[16].

This study retrospectively included approximately 15000 patients, of whom just over 2% had cirrhosis. The identification of risk factors, such as a poor Child-Pugh score, low albumin levels, and coagulation abnormalities, should serve as a reminder to clinicians to optimize treatment. In the following sections, we briefly discuss the reasons why patients with cirrhosis are at higher risk of infections and the early measures that should be taken for their treatment.

RISK FACTORS FOR THE DEVELOPMENT OF INFECTIONS

Despite the term “liver cirrhosis”, cirrhosis is not a disease that only affects the liver but should be considered a systemic disease. Among the wide range of organs it affects, one of them is the immune system. Patients with cirrhosis present an immune dysfunction known as cirrhosis-associated immune dysfunction (CAID)[17]. This acquired immune deficiency, which affects both innate and acquired immunity, is a complex continuum between a low and high inflammatory load phenotype that changes depending on the degree of cirrhosis and decompensation, as well as external factors such as proton pump inhibitor (PPI) use, infections, invasive procedures, or alcohol consumption[18,19]. In addition to immune changes, such as a decrease in complement, a reduction in leukocytes and their malfunctioning, or the release of cytokines, the gut-liver axis also plays a fundamental role in CAID[6,17]. Patients with cirrhosis have increased intestinal permeability primarily due to alterations in the tight junctions of the intestinal barrier[20], a reduction in the mucus layer[21], and the pro-inflammatory state that leads to greater activation of intestinal macrophages, releasing nitric oxide and interleukins (ILs) that damage this barrier[22]. Increased intestinal permeability, along with slowed intestinal transit, causes bacterial translocation with the passage of endotoxins into the bloodstream. It should be noted that the intestinal microbiota in these patients is altered, with bacterial overgrowth, particularly of Enterobacteriaceae and Enterococcaceae, leading to real intestinal dysbiosis[23,24]. The proliferation of these types of bacteria, together with increased intestinal permeability and bacterial translocation makes these patients more susceptible to infections.

CAID also involves a degree of immunodeficiency. The cirrhosis stage leads to hepatic macrophages overexpressing immune exhaustion-related proteins, such as programmed cell death ligand 1, which reduces their phagocytic capacity and antimicrobial activity[25]. The previously mentioned microbial translocation also induces the production of type I interferons and IL-10 by hepatic myeloid cells, resulting in systemic immunosuppression. Excessive IL-10 production impairs the antibacterial immunity of myeloid cells and T lymphocytes[26,27]. Additionally, the high inflammatory state associated with cirrhosis decompensation leads to immune paralysis, further increasing susceptibility to infections, as well as sepsis and septic shock, especially in those with increased portal hypertension[17,28].

In addition to this, these patients have greater contact with the hospital environment and are more frequently subjected to invasive procedures. It is estimated that, of the total infections in patients with cirrhosis, between 25% and 40% are healthcare-associated[29]. This term refers to an infection acquired by a patient in any healthcare setting and associated with the receipt of medical care[30]. It should be distinguished from nosocomial infection, which specifically refers to infections occurring 48 hours or more after hospital admission[31]. This fact increases the risk of infections caused by multidrug-resistant organisms (MDROs) compared to the general population, as well as the occurrence of severe infections[5,32]. In addition, it is necessary to analyze the different risk factors for infection development by groups (Table 1).

Soft tissue and skin

These infections are favored by malnutrition, decompensation, peripheral edema, and anasarca, which contribute to skin fragility and secondary infection[33]. Patients with diabetes and cirrhosis are at higher risk of severe infections, particularly those caused by Streptococcus pyogenes and Staphylococcus aureus[34]. Patients who use parenteral drugs have an increased risk of bacteremia and deep abscesses. Furthermore, those with a history of recent surgery or hospitalization are at greater risk of developing MDRO infections, particularly those caused by Pseudomonas[33,35].

Respiratory tract

In addition to an advanced Child-Pugh stage, exposure to healthcare settings, and diabetes mellitus, malnutrition and sarcopenia further increase the risk by impairing immune function and reducing secretion clearance[36]. The use of PPIs has also been identified as a potential risk factor due to microbiota alterations, which promote colonization by respiratory tract bacteria, including MDROs[18]. The presence of ascites can alter respiratory physiology, predisposing patients to infections[37]. Hepatic encephalopathy, due to aspiration risk, and mechanical ventilation have also been described as potential contributors to these infections[38].

Urinary tract

In addition to factors already mentioned, such as advanced liver dysfunction, older age, diabetes mellitus, and antibiotic use, urinary tract infections are also associated with female sex, acute kidney injury secondary to obstruction, and the use and duration of urinary catheterization as key risk factors[33,39].

SBP

SBP is the hallmark infection in cirrhosis due to its specificity in these patients. The diagnosis is established by the presence of more than 250 polymorphonuclear cells per mm³ in ascitic fluid, regardless of culture results. All patients admitted with ascites should undergo at least one diagnostic paracentesis to screen for SBP, regardless of the presence of infection-related symptoms. Likewise, any hospitalized patient with ascites who presents signs of infection, hepatic decompensation, or acute kidney injury should undergo a diagnostic paracentesis to assess the presence of SBP[37,40]. The main risk factors for developing SBP include the use of PPIs and antibiotics, Child-Pugh class C or Model for End-Stage Liver Disease score ≥ 22, persistent hyponatremia, polymorphonuclear cell count above 100 cells/mm³, bilirubin levels ≥ 3 mg/dL, hypoalbuminemia, absence of beta-blocker therapy, and a previous episode of SBP[41-43]. Recent advances have improved early detection of SBP. The use of polymerase chain reaction in ascitic fluid for bacterial DNA detection has demonstrated a sensitivity of 80.5% and a specificity of 95.3% for SBP diagnosis, outperforming both culture and polymorphonuclear cell count[44]. Another study employing machine learning techniques found that the ferritin/neutrophil ratio, albumin levels, and the neutrophil/Lymphocyte ratio are useful predictors of SBP, achieving an area under the curve of 0.808[45]. Additionally, a recent study by Wejnaruemarn et al[46] has demonstrated that procalcitonin is a reliable biomarker for SBP confirmation.

MANAGEMENT OF INFECTIONS IN PATIENTS WITH CIRRHOSIS

The first step, and the most important, is to maintain a high clinical suspicion and actively search for infection, especially in the context of decompensated cirrhosis[47]. Although it may seem obvious, this is not always straightforward, as typical signs of infection may not be present in the early stages[48]. Another important aspect to consider is the origin of the infection. That is, whether it is community-acquired, healthcare-associated or nosocomial[3]. This factor is crucial in the initial antibiotic management due to the risk of MDROs, as well as the use of antibiotics in the 3 months prior to hospitalization[29].

It is important to keep in mind that the presentation is highly variable, ranging from asymptomatic patients to those presenting with severe sepsis, along with typical symptoms depending on the type of infection, or even a simple worsening of renal function. There are also situations or risk factors that should alert us to this possibility, such as gastrointestinal bleeding, ascites, low protein levels in ascitic fluid, or a history of infection[49]. In any case, it is essential to maintain a low threshold of suspicion. The initial evaluation requires a thorough medical history and a comprehensive physical examination to identify potential sources of infection. In addition to a complete blood test with infection markers such as C-reactive protein, procalcitonin, and liver parameters to update the stage of cirrhosis, it is essential to perform blood and urine cultures, a chest X-ray, and diagnostic paracentesis for the detection of SBP or secondary bacterial peritonitis, along with cultures of the ascitic fluid[50,51].

An important aspect is also to assess the severity of the infection. In this evaluation, it should be considered that the systemic inflammatory response syndrome criteria are not particularly useful in this situation due to the presence of CAID[52]. Although both share common characteristics such as systemic inflammation and the potential to develop multiorgan failure, there are differences between them. In summary, systemic inflammatory response syndrome can be triggered by any cause and requires specific clinical criteria for its diagnosis, whereas CAID is exclusively associated with cirrhosis and involves a degree of immunodeficiency that predisposes patients to infections, in addition to chronic systemic inflammation[17,53,54]. For this reason, the use of the quick Sepsis Related Organ Failure Assessment score has been proposed in patients with cirrhosis. These criteria assess the number of breaths per minute, with a cutoff point of > 22; systolic blood pressure, with a cutoff point of < 100 mmHg; and the level of consciousness assessed using the Glasgow Coma Scale, considering it when it is < 15. The presence of ≥ 2 quick Sepsis Related Organ Failure Assessment criteria is considered to have a high probability of sepsis[55]. As a final consequence of the high inflammatory process triggered by infections, although not the only cause, patients with cirrhosis have the peculiarity of being able to develop ACLF. There are several definitions according to different clinical guidelines, but in general terms, it can be defined as a severe form of decompensation characterized by the failure of one or more of the major organ systems and systemic inflammation, which can be triggered by an acute cause, including infections[33,56,57]. This situation leads to a 28-day mortality rate between 20% and 50% of patients, depending on the severity and the number of organs affected[58].

Therefore, the management of patients should be as early and accurate as possible. Along with close monitoring to assess progression, early measures must be adopted. The patient’s medication should be carefully reviewed to determine what is necessary and what may cause harmful effects, such as beta-blockers at certain times. PPIs should also be carefully evaluated, as they are widely used in these patients and have been shown to increase the risk of infections, decompensation, and long-term mortality[59]. The use of broad-spectrum antibiotics, guided by clinical suspicion, site of acquisition, and local resistance patterns, is essential. Geographic differences in the prevalence of MDRO infections are significant. For example, in Asia, the prevalence is around 34%, whereas in Europe, it ranges between 23% and 29%[29,32]. Economic factors also play a role, as countries with low and lower-middle income populations have a higher risk of MDRO infections[60]. Additionally, in Europe, extended-spectrum beta-lactamase-producing Enterobacteriaceae are predominant, while in the United States, vancomycin-resistant Enterococci are more common[3,32]. Moreover, early antibiotic use has been shown to reduce mortality and the development of septic shock and ACLF[13,61]. Another important aspect to consider is attempting to maintain enteral nutrition to avoid intestinal bacterial translocation[36]. It should not be overlooked that these patients, especially those who develop ACLF and those admitted to the intensive care unit, have a risk of fungal infections in up to 10% of cases[62]. As expected, patients with invasive fungal infections have a significantly high mortality risk, approaching 55%[63].

Fluid resuscitation management should be restrictive due to the underlying pathophysiological changes in these patients (e.g., splanchnic vasodilation, low effective circulating volume) combined with the acute changes secondary to the infectious process, with the aim of avoiding further complications. An accepted goal is to achieve a mean arterial pressure ≥ 60 mmHg, considering both the use of intravenous fluids and blood products[64,65]. The use of albumin is also controversial. Although it is routinely used by gastroenterologists and hepatologists, it does not always have a positive effect on patients with cirrhosis. There are clear indications for its use, such as in large-volume paracentesis, hepatorenal syndrome, or SBP[66]. However, in patients with sepsis, the effect is not always positive due to the potential risk of developing complications such as bleeding or acute pulmonary edema[67]. Properly selecting the patient profile who could benefit from its use in this context is complex. Some subgroups, such as those with hypoalbuminemia or renal failure, may benefit from its use[68]. Early detection of these infections should be distinguished from the use of prophylactic measures to prevent their development. For example, in the clinical trial conducted by Fricker et al[69], which evaluated the use of ceftriaxone in patients with advanced cirrhosis to prevent infections, it was found to be an ineffective measure to justify its systematic use. Similarly, the study by Kutmutia et al[70] on the use of antibiotics in patients with decompensated cirrhosis without evidence of infection also demonstrated the futility of this approach.

CONCLUSION

Patients with liver cirrhosis have a higher risk of infections than the general population. Their management is complex due to the present pathophysiological changes and the presence of CAID. In addition to common microorganisms, these patients also face an increased risk of MDROs, which must be considered when making decisions. It is important to mention that the study presented by El Labban et al[15] has limitations, such as its retrospective design, the number of patients with liver cirrhosis within the total sample, the manner in which results were presented, and the fact that data collection was not specifically designed for the study’s objective. However, it is a work that should be considered due to the lack of high-level scientific evidence on the topic and the conclusions drawn from it. This should encourage the scientific community to investigate this important issue and to develop specific prospective studies that explore the various infection scenarios, the risk factors influencing their progression, and to raise awareness among healthcare providers about the specific management required for these patients. Research into pathophysiology, risk factors associated with the development of infections, specific biomarkers for early detection, and the development of new antibiotics are future research lines that should be pursued for these patients.

ACKNOWLEDGEMENTS

This article was sponsored by Virgen de la Luz Hospital and Chair of Artificial Intelligence by Bayer.