CLINICAL AND PROGNOSTIC FEATURES OF CHRONIC CRITICAL ILLNESS/ PERSISTENT INFLAMMATION IMMUNOSUPPRESSION AND CATABOLISM PATIENTS: A PROSPECTIVE OBSERVATIONAL CLINICAL STUDY

— Objective: The aims of this study were to investigate and compare the clinical features and prognosis of chronic critical illness (CCI)/persistent inflammation immunosuppression and catabolism (PICS). Methods: This is a prospective obser- vational clinical study. During this study period, we collect intensive care unit patients' data from Suzhou Municipal Hospital and Suzhou Ninth People's Hospital. All patients older than 18 years were included, and according to the corresponding exclusion and diagnostic criteria, they were divided into four groups: PICS group, CCI group, CCI and PICS group (CCI + PICS), and neither CCI nor PICS group (NCCI + NPICS) and collected and recorded age, sex, hospital time, hospital diagnosis, Acute Phys- iology and Chronic Health Evaluation II score, Sequential Organ Failure Assessment score, C-reactive protein, absolute value lymphocyte count, serum albumin, white bloodcell count, absolutevalueneutrophil count, secondary infection, and28-day case fatality rate separately. Results: A total of 687 patients were admitted to the intensive care unit during the study period. The hospitalization timeless than 14 days wereexcluded,and168patients were eventually included. There are17inthe PICSgroup, 71 in the CCI group, 50 in the CCI + PICS group, and 30 in the NCCI + NPICS group. Baseline characteristics showed statistically significant differences in Sequential Organ Failure Assessment, length ofhospital stay, and28-day mortality among four groups. Baseline main indicator and multiple comparisons showed that the CCI + PICS group had longer hospital stay, worse prognosis, and more adverse outcomes. Multivariate analysis showed that final age, C-reactive protein on days 14 and 21, and serum al- bumin on days 1 and 21 had an impact on the prognosis ( P < 0.05). Conclusion: The clinical prognosis of the four groups decreased in order of NCCI + NPICS, CCI, PICS, and CCI + PICS. Our finding of clinically isolated PICS may indicate that PICS acts as an inducement or independent factor to worsen the prognosis of CCI.


INTRODUCTION
With the development and progress of medicine, many diseases that previously caused death can be treated with the majority of patients alive, and the loss of one phenotype is accompanied by the emergence of another (1) . Patients who survive death generally experience two different trajectories, namely, rapid recovery (RAP) or progression to chronic critical illness (CCI) (2)(3)(4). In the intensive care unit (ICU), patients are admitted to hospitals who may have or have life-threatening conditions; for example, after surgery, patients with severe infection or circulatory and respiratory instability are mostly characterized by advanced age, multiple comorbidities, and poor basic conditions in the past. Most of these patients have a long hospital stay, poor prognosis, and serious decline in quality of life after discharge, which is currently named as CCI. Chronic critical illness patients have a poor prognosis, serious decline in quality of life, huge medical costs, and increased burden on individuals and families (5)(6)(7)(8). To improve the above situation of CCI, it is necessary to understand the pathogenesis and potential pathophysiology of these patients, to fundamentally treat or even prevent the development of disease in these patients.
After persistent inflammation immunosuppression and catabolism (PICS) was proposed by Gentile et al. (9) in 2012, most people believed that pathophysiology mechanism of CCI was related to PICS (10)(11)(12)(13), namely, persistent inflammation and immunosuppression catabolism. The importance and value of PICS are that it provides an overall mechanism to explain persistent low-level inflammation and adaptive immunosuppression (14). Chronic critical illness is similar to PICS and is a pathophysiological state that is very difficult to treat (15); that is, the two are similar but not identical and can be further developed into PICS in CCI. Mira et al. (14) proposed whether PICS was the cause of increased morbidity and long-term mortality in CCI patients or merely a reflection of the long-term consequences of CCI, whether PICS is involved as an independent factor of CCI (as in the relationship between infection and heart failure), or that persistent organ dysfunction in CCI leads to further PICS within CCI (as are coronary atherosclerosis and coronary heart disease).
At present, the relationship between CCI and PICS is not clear: whether the long-term injury to CCI leads to the internal occurrence of PICS or whether PICS is involved in CCI as inducement or independent factor and eventually to promote and reinforce each other, resulting in the prolonged illness of the patients. To try to solve the above conjecture, data of patients admitted to the ICU of three departments of our hospital and Suzhou Ninth People's Hospital between July 2021 and March 2022 were collected in this study. The aim of this study was to evaluate the occurrence and development of CCI/PICS during the study period, as well as their relationship, clinical features, secondary infections, and prognosis, to provide a certain basis of further understanding and treatment of CCI/PICS.

Study design and population
This is a prospective, observational clinical study that enrolled ICU patients whose data were collected from three districts and Suzhou Municipal Hospital and Suzhou Ninth People's Hospital from July 2021 to March 2022.
Patients with duration of ICU stay ≥14 days and age ≥18 years were included. Exclusion criteria included the following: (1) duration of ICU stay is less than 14 days; (2) long-term use of immunosuppressants and/or corticosteroids; (3) congenital and/or acquired immunodeficiency diseases; (4) pregnant women; and (5) those who did not agree to sign the informed consent.

Main outcome measures
Each patient's data were collected, recorded, and analyzed (age, sex, hospital time, hospital diagnosis, Acute Physiology and Chronic Health Evaluation II score, Sequential Organ Failure Assessment [SOFA] score, C-reactive protein [CRP], absolute value lymphocyte count, serum albumin [Alb], white blood cell count, absolute value neutrophil count, secondary infection and 28-day mortality rate).

Diagnostic criteria and grouping
Patients were divided into four groups according to the diagnostic criteria: PICS group, CCI group, CCI + PICS group, and NCCI + NPICS (neither CCI nor PICS group) group.
Statistical analysis SPSS 25.0 software (IBM Corp, Armonk, NY) was used to analyze the data. The measurement data conforming to normal distribution were expressed as mean ± SD; single-factor ANOVA (F test) was used for the analysis between groups; M (P25, P75) was used for measurement data conforming to normal distribution, and Kruskal-Wallis multivariate rank sum test was used for comparison between groups. The counting data are expressed as case number or constituent ratio, chi-square test was used to compare the ratio between groups. Logistic regression analysis was used to clarify the relationship between study factor and outcome. First, each factor was analyzed by univariate logistic regression, and then the influencing factors were analyzed by multiple logistic regression. Power analysis was conducted to calculate the sample size and effect value. P < 0.05 was considered as statistically significant difference.

Distribution and characteristics of patients
Data of a total of 687 patients admitted to the ICU of three departments in our hospital and Suzhou Ninth People's Hospital from July 2021 to March 2022 were collected. According to the exclusion diagnostic criteria, 168 patients were eventually included. There are 17 in the PICS group, 71 in the CCI group, 50 in the CCI + PICS group, and 30 in the NCCI + NPICS group (Fig. 1).
The patient characteristics of the included cases are shown in Table 1. There were statistical differences in length of hospital stay, 28-day mortality rate, and SOFA score among the four groups ( P < 0.05), whereas the rest were not statistically significant. Multiple comparisons among groups with statistically different indicators showed that the CCI + PICS group (36.5 [24.8-

The comparison of main indicators in patients
The comparison of the main indicator of the included cases is shown in Table 2, among which neutrophils on day 1, white blood cells on days 1 and 14, lymphocyte and albumin on days 14 and 21, and CRP on day 21 difference between the four groups were statistically evident ( P < 0.05). Multiple comparisons among groups showed that the absolute count of lymphocyte in the PICS group and the CCI + PICS group was lower than those in the CCI group and the NCCI + NPICS group on days 14

Reasons for ICU admission and multiple-comparisons results
The main reasons for patients' admission to the ICU are shown in Table 3. Among them, more patients were admitted to the ICU for heart and lung reason than for other organ systems in all four groups. Multiple comparisons between statistically different groups showed that the CCI + PICS group had a longer hospital stay and worse prognosis and was more prone to adverse outcomes among the four groups ( Table 4).

The analysis of prognostic factor of patients
To analyze the factors influencing prognosis, univariate and multivariate logistic regression analyses were performed on each variable. The univariate and multivariate analyses of the four groups are shown in Table 5. Univariate analysis showed statistically significant differences in age; group; CRP at day 14; lymphocyte and Alb at days 1 and 14; and neutrophils, Alb, and CRP at day 21; indexes with P < 0.05 were selected for multivariate analysis. Finally, age, CRP on days 14 and 21, and Alb on days 1 and 21 had an impact on the prognosis. For lymphocytes, P > 0.05. According to the results of the power analysis, the possibility of insufficient sample size was excluded, indicating that there was no significant difference in the lymphocyte level among the groups. This may cast doubt about the use of lymphocytes as an indicator of immunosuppression in the diagnosis of PICS, but more experiments are still needed for further verification.

DISCUSSION
Outcomes of patients who experience early injury can generally be divided into three, namely, early death, RAP, and CCI (13,17,20). With better understanding and proper medical care, the proportion of patients who survive is significantly higher than before and eventually develops into RAP or CCI. Compared with CCI, RAP patients are mostly younger, with fewer comorbidities, better prognosis and quality of life, and less burden (21).
Since Gentile et al. (9) first proposed PICS in 2012, it is accumulating evidence that CCI and PICS are common in the critically ill patients, which often occur in the elderly with comorbidity, resulting in difficult treatment, complex diseases, prolonged course of disease, and high use of medical resource and poor clinical outcomes (8,13,20,22,23). Although increasing evidence suggests that CCI and PICS share many clinical, laboratory, and pathologic features, the relationship between CCI and PICS has not been firmly established in critically ill patients. The aim of the present study was to assess the clinical features and clinical outcomes of CCI and PICS patients. In our study, we observed that clinically isolated PICS may indicate that PICS acts as an inducement or an independent factor to worsen the prognosis of CCI, and many clinical similarities between the two may be their association with persistent organ dysfunction.
Rosenthal et al. (15) defined CCI as length of ICU stay ≥14 days with persistent organ dysfunction (persistent SOFA ≥2), which is an appropriate, but somewhat abstract and broad term. For most patients admitted to the ICU, most of them are life-threatening diseases, usually with ≥1 organ dysfunction. In such cases, it is difficult to get out of the ICU early without proper treatment or even with appropriate treatment. Such patients often finally meet the definition of CCI and are diagnosed with CCI. The above definition of CCI should be interpreted as persistent organ dysfunction leading to ICU stay ≥14 days and should emphasize on persistent or a longer period, because for some young and    middle-aged patients or patients admitted to the ICU after surgery, their organ dysfunction may often be transient. After some adjuvant treatment and self-regulation, the organ dysfunction can recover to normal at a faster speed and be admitted to the general ward, different from CCI and PICS patients.
In addition, we also found that not all patients initially present with CCI had PICS at the end of the study and that some patients maintained CCI status throughout the study, which may be because the disease course is shorter than that of patients with PICS or the current treatment is effective, the disease has not deteriorated, or the body still has a certain compensation ability, and these patients have better outcomes than CCI + PICS. Whether PICS in the CCI + PICS group is the result of chronic organ dysfunction of CCI that finally leads to persistent inflammation immunosuppression catabolism, that is, PICS, is a manifestation of long-term organ dysfunction of CCI, or is PICS involved in the development of CCI as an inducement or independent factor in the course of CCI disease has not been cleared. As both, PICS and CCI can lead to organ dysfunction; they have similar clinical characteristics in many aspects, such as prone population, clinical manifestations, and prognosis. Chronic critical illness and PICS can promote and reinforce each other and eventually lead to a vicious cycle with prolonged illness.
There are several guesses about the relationship between CCI and PICS: PICS is a potential pathological mechanism of CCI (9), or PICS is a reflection or further enhancement of long-term organ dysfunction of CCI (15), or PICS is a subset of CCI (14,24). For the above speculation, it may be possible to distinguish CCI from PICS by the time of diagnosis. If PICS is a potential pathological mechanism of CCI, PICS should occur before CCI. If it is a   reflection or further enhancement of long-term organ dysfunction of CCI, PICS should occur after CCI, and there should be no isolated PICS. If it is a subset of CCI, then all of the PICS should be included in the CCI, focusing on finding characteristics that the CCI has but the PICS does not. The time of attention should start from the patient's admission to the ICU, and the observation of related indicators of patients with hospital stay <14 days may help to judge the relationship between CCI and PICS, because the longer the disease duration, the more difficult it is to distinguish CCI from PICS. For CCI and PICS, both of them present persistent organ dysfunction, but the difference in the number, degree, and duration of organ dysfunction may lead to the different clinical prognosis of CCI and PICS patients. When an individual is threatened by the outside world, such as pathogens or burns, the body, to maintain a steady state, will react accordingly, such as inflammation (In) and/or catabolism (Ca) and/or immunosuppression (Im); if the response is appropriate at this time, the individual quickly recovers (RAP). If the body's response is too strong or too weak, the condition may lead to organ disorders, that is, SOFA ≥2. If the body is not properly treated and own compensatory ability is decreased, this can cause the length of time to be too long, namely, persistent (P), so as to meet the diagnosis of CCI. Chronic critical illness is not only the result of long-term organ dysfunction, but also can aggravate organ dysfunction, leading to PICS. Finally, patients were diagnosed with CCI + PICS, which can aggravate inflammation, immunosuppression, and catabolism, further worsening the prognosis. To sum up, it is that the external threat → In ± Im ± Ca → SOFA ≥2 + P → CCI → [In → Im → Ca → In] vicious cycle ↔ CCI + PICS. Another special point of the above pathway is that the external threat is too strong or the patient's own condition is poor; it will show inflammation, immunosuppression, and catabolism complete the phenotype at the beginning, then it will become external threat, and/or own compensation mechanism is too weak → In + Im + Ca → SOFA ≥2 + P → CCI + PICS ↔ [In → Im → Ca → In] vicious cycle (Fig. 2).
We finally concluded that age, CRP, and albumin were related to the prognosis of patients. The age distribution of CCI and PICS patients is more common in the elderly. Age is a natural physiological process, but the human tissues have a certain service life; as one ages, the more serious the damage and degeneration, and the slower the body repair mechanism and the efficiency; with the attack from the outside world, the compensatory ability and range are relatively weak. It indicates that aging is a prerequisite for the development of CCI and PICS, because the elderly will experience "immunosenescence," a state of age-related changes into the immune system (25). Moreover, Mankowski et al. (26) found that elderly (relatively young) and elderly CCI (relatively elderly RAP) patients had more persistent aberrations in many biomarkers within 14 days after sepsis. All these reflect that the compensatory mechanism of the body deteriorates seriously with age, which has a certain impact on the prognosis. The above mechanisms may lead to the correlation between age and prognosis.
C-reactive protein and albumin represent markers of inflammation and synthesis, respectively, under normal circumstances; their values fluctuate within the reference range. When subjected to external stimuli, corresponding changes will occur, which is a kind of body's stress response. If the external stimuli disappear, the condition can return to normal, but if it is always in the abnormal range, damage factors still exist. The duration and extent of both determined patient outcome and prognosis. As a common indicator of infection in the clinic, CRP is actually an emergency reactive protein synthesized by the liver to protect the body. Therefore, as long as the body is in a state of emergency, the value of CRP can be increased theoretically, but the degree and duration of the increase may be different. As an index of anabolism, the decrease in albumin is related to the imbalance of synthesis and catabolism. When the body is under threat, the liver theoretically increases the synthesis of albumin to cope with emergencies, and the half-life of albumin is long (approximately 15-19 days), and the compensatory ability of the liver is strong; if damage is slight, the amount of albumin will not change in the short term. However, it is often observed that the albumin of CCI and PICS patients is below normal clinically, indicating that the increase in its decomposition is far greater than the synthesis; it means that the body is in a high catabolic state, and the course of the disease has been long. Soeters et al. (27) proposed that hypoalbuminemia may be related to vascular permeability, increased interstitial volume, and increased hepatic degradation, indicating that there are many factors causing hypoalbuminemia in addition to the high decomposition state, which have adverse effects on the prognosis of patients. In conclusion, among the three prognostic factors, age is an irresistible factor, and the long-term distortion of CRP and albumin indicates that the duration and degree of systemic inflammation determine the outcome and prognosis. At present, with the extension of human life span, the population is aging, and the medical burden on the elderly is increasing. Based on the characteristics of CCI and PICS, active treatment and prevention are of great significance. However, the current understanding of them is not very thorough. For each disease, the best way is to prevent more than to cure, followed by early detection, early diagnosis, and early treatment. Patients who have been admitted to the ICU only achieve the latter. For early detection and early diagnosis, the first thing to have is a keen eyesight and appropriate diagnostic criteria, whereas early treatment requires multidisciplinary physician and multiple treatment measures simultaneously (7), such as treating the primary disease and comorbidities, nutritional support, physical exercise, and control of infection and complications (28).
There are some limitations to the current study. First, single-center studies, small data, observational study, the impact on DNR status, clinical relevance, and study populations are not adequately representative of ICU care in many institutions, such as lack of trauma patients and severe surgical sepsis with organ dysfunction. Second, the current diagnostic indicators related to CCI and PICS are not represented in the strict sense. There may be deficiencies in quality and quantity of diagnostic criteria (28)(29)(30)(31), and more experimental and clinical data may be needed for further screening and validation.
In short, our findings suggest that the CCI + PICS group has the worst prognosis compared with the other three groups. How to identify patients with CCI early (by age, previous comorbidities, the compensatory capacity of the organism, preliminary assessment of the disease) and take appropriate measures to prevent further development of PICS in CCI is crucial to break the vicious cycle and improve patient outcomes and prognosis.