Aggravated sepsis,acute kidney injury,and microbiological resistance: Four year’s pre

Abstract

Introduction:

The aim of our study was to compare the prevalence, etiology, and outcomes of sepsis and associated AKI in pre- and post-COVID-19 pandemic.

Methods:

We conducted a retrospective observational analysis in 144 patients with sepsis and AKI, in two periods of time, 2 years before and after COVID-19 pandemic, with 2 years’ washout period.

Results:

The comparative analysis between the two periods demonstrated more severe forms of sepsis with septic shock dominating in the post pandemic period (5 (10%) vs 23 (25%), p = 0.037). According AKI staging we found AKI stage 3 more frequently present after pandemic and more patients needed dialysis in the post COVID-19 pandemic (35 (70%) vs 79 (84%), p = 0.04; 31 (62%) vs 78 (54%), p = 0.02; 16 (32%) vs 51% (54%), p = 0.018), respectively. Patients in post COVID-19 era survived less longer (22.66 ± 11.32 vs 17.132 ± 12.66, p = 0.021) with almost doubled risk for mortality HR: 1.977; 95% CI (1.127 ± 3.469), p = 0.018. Regarding causative agents’ there was similar distribution in both periods, but the multiple antibiotic resistance index (MAR) was significantly higher in the post COVID-19 period for Staphylococcus coagulase negative (0.48 vs 0.62, p = 0.001).

Conclusion:

Sepsis and associated AKI occurrence, morbidity and mortality are significantly higher in the post COVID-19 pandemic and the increased MAR of the germs can be one of the main reason for it.

Keywords

AKI dialysis sepsis multiple antibiotic resistance COVID-19

Introduction

COVID-19 pandemic dramatically changed the world. Although the pandemic has been declared over, SARS-CoV-2 virus is still active in human population causing more or less severe infections all over the world, we are at the stage of understanding and experiencing the long-term consequences on general health globally.^1,2 A number of studies confirmed that COVID-19 pandemic did make permanent dysregulations and dysfunctions of the immune and vascular system and by that influenced each organic system.^3,4 Rising trends of antimicrobial resistance and its threat to public health, has been of interest for researchers worldwide and many studies are dedicated to it, including scientists and data form North Macedonia.⁵ It is believed that the inappropriate and uncontrolled use of antibiotics in the pandemic era substantially changed microorganisms and triggered expansion of the antimicrobial resistance (AMR) globally, influencing its’ clinical and therapeutic features.⁶

Since the first consensus definitions for sepsis was established (1991), its incidence is constantly rising, posting considerable burden to health systems worldwide.⁷ According to the latest consensus definition, sepsis is defined as a life-threatening organ dysfunction due to an inappropriate host reaction to infection, with septic shock being the most severe form.⁸ Kidneys are one of the many affected organs and acute kidney injury (AKI) due to sepsis is common manifestation. Kellum et al. emphasizes that AKI can be early sign of sepsis, considering that half of patients with sepsis included in the study, presented with AKI even before consulting the emergency departments.⁹ Despite continues improvements in recognizing and managing sepsis, sepsis-related mortality remains very high, and according to latest World Health Organization (WHO) statements, it represents 20% of all global deaths, especially in lower-middle- income countries.¹⁰ Although these rising numbers can be partially explained by the new developed tools for fast and prompt diagnosis like the quick sequential organ failure assessment (qSOFA) score, especially useful for outpatients, it seems that there are other contributing factors that need to be analyzed yet.^7,8

The aim of this study was to estimate how the COVID-19 pandemic changed prevalence, etiology, and outcomes of sepsis associated with AKI, comparing the pre- and post-COVID-19 pandemic period and also to address the distribution of different microorganisms as causative agents including their antimicrobial resistance.

Methods

Study design

We conducted a single-center retrospective, observational, comparative study in 144 patients with sepsis and associated AKI, hospitalized in our University Hospital of Nephrology in Skopje during period of 2 years before (2017–2019) and 2 years after (2022–2024) COVID-19 pandemic, with 2 year’s washout period. All patients with age over 18 that full-fielded sepsis-3 criteria, according to the latest consensus definition for sepsis in 2016,¹¹ were included in the analysis. Patients with kidney transplants, primary glomerulopathies, and vascular access related sepsis in patients with end stage kidney disease (ESKD) that require renal replacement therapy, were excluded from the study. This retrospective study was conducted as claimed by the principles of the Declaration of Helsinki, in agreement with institutional policy for obtaining informed consent at hospital admission.

Data collection and definitions

Population

The University Hospital of nephrology—Skopje, as a unique tertiary public hospital for kidney diseases provides care for referred patients from all over the state, covering approximatively two million citizens. It continually provides best practice recommended medicine, with all diagnostic and therapeutically possibilities, obtained by highly skilled personnel. All hospitalized patients from July 1, 2017 to July 31, 2024, excluding those in wash out period of COVID-19 pandemic (2019–2022) were reevaluated through sepsis criteria.

Sampling septic patients

Patients with clinical manifestation for infection prior hospitalization and with blood cultures obtained in the first 3 days of hospital stay were included in the analysis. All data were obtained from National Electronic Health Records—“Moj termin” and from patients’ medical charts. We analyzed patients’ demographics (gender and age) and comorbidities (diabetes, obstructive nephropathy malignant and non-malignant, hypertension, pre-existing chronic kidney disease (CKD)) data. Also, laboratory results, admission, and clinical features, especially those related with organ dysfunction variables for sepsis detection and gradation (body temperature, respiration and hearth rate, oxygen blood saturation, systolic blood pressure, neurological affection, white blood cells and platelets count, C-reactive protein, creatinine levels, inotrope usage),¹² were included in the analysis. Based on sepsis-3 criteria, patients with clinical suspicion of infection and ΔSOFA score ⩾2 were defined as sepsis and were included in the analysis.¹¹ Regarding clinical stage of sepsis patients were divided in three groups, sepsis, severe sepsis, and septic shock.¹¹ The primary entrance site was ratified by thorough evaluation of clinical observations, comorbidities, radiology findings, and microbiological data. A comparation of blood culture results regarding causative agents and multiple antibiotics resistance index (MAR) was performed in both periods. MAR index was calculated as the ratio of the number of antibiotics to which the isolated microorganism is resistant, to the total number of antibiotics to which the isolated microorganism was exposed.¹³

Acute kidney injury

Serum creatinine levels were monitored during first 30 days from start of hospitalization, including those from the hospital discharge day. According to KDIGO* criteria patients were assessed for AKI and were classified accordingly in stages 1, 2, and 3.¹³ Due to the insufficient data for urine output, the classification relied on increase of serum creatinine levels and patients with increase in serum creatinine of ⩾26.5 µmol/l or 1.5–1.9 times baseline creatinine were classified as stage 1, those with increase to 2.0–2.9 times from baseline as stage 2 or stage 3 with increase greater than three times baseline serum creatinine or a peak serum creatinine ⩾353.6 μmol/l or initiation of renal replacement therapy (RRT).¹⁴ Some patents required transfer to intensive care unit and those hospitalizations were reviewed as one.

AKI outcome and need of replacement therapy, as well as 30-days survival were analyzed.

Outcomes

AKI outcomes and need of replacement therapy were notified. Recovery from AKI was defined as returning to baseline kidney function, which was estimated by the most frequent serum creatinine level from 90 to 365 days prior acute illness.¹⁵ This was made in order to distinguish non-recovery AKI from pre-existing CKD. Also, we evaluated the number of patients that required renal replacement therapy during and after hospitalization (the one that did not recover kidney function). An analysis of mortality and 30-day survival was performed.

Statistical analysis

The patients were grouped as hospitalized in pre- and post-COVID-19 pandemic period. Continuous variables were expressed as mean with standard deviation (SD). An absolute number with percentage was used for presentation of nominal data. We performed a comparative analysis and used chi-square or Fisher exact test for the comparison of the categorical variables and Wilcoxon rank test or Student’s t-test for the numerical data. p < 0.05 was counted as significant. We conducted a time-to-event analysis for 30-day mortality using Cox proportional hazards regression. In order to present the impact of sepsis on outcome, we used hazard ratios (HRs), 95% CI, and Kaplan–Meier survival curves. SPSS statistical package version 21 was used for analysis.

MAR index was calculated for each causative agent isolated from blood cultures as the ratio of the number of antibiotics to which the isolated microorganism is resistant, to the total number of antibiotics to which the isolated microorganism was exposed and for their comparison a Kolmogorov–Smirnov one sample test was used performed.

Results

Periodic prevalence of sepsis

Out of 3801 hospitalizations, 50 (1.3%) in the pre-COVID-19 pandemic period and 94 (2.5%) from 3760 hospitalizations in the post-COVID-19 pandemic period, were diagnosed as sepsis, indicating twice higher prevalence of sepsis in the post-COVID-19 pandemic period, out of almost same number hospitalizations annually as it is demonstrated in the population chart flow diagram below (Figure 1).

Figure 1.

Flow diagram of the comparative analysis of demographics, clinical, and laboratory data between the two periods.

When the pre- and post-COVID-19 group were compared, no difference was found regarding the age, gender, diabetes, and hypertension (67.68 ± 11.43 vs 67.12 ± 11.54, p = 0.780; 25 (50%) vs 49 (52%), p = 0.946; 18 (36%) vs 42 (44%), p = 0.409; 34 (68%) vs 60 (63%), p = 0.752), respectively. According to sepsis staging, in the post-COVID-19 period there were more patients with septic shock (5 (10%) vs 23 (25%), p = 0.037), compared to pre-COVID-19 period, where the percentage of less severe sepsis was significantly higher (8 (16%) vs 2 (2%), p = 0.006), respectively. When all clinical features included in the sepsis staging were addressed separately, it was shown that in post-COVID-19 period there were more patients with lower blood saturation and mental status alteration (15 (28%) vs 48 (51%), p = 0.0014; 15 (30%) vs 66 (70%), p = 0.0001); respectively, also more patients had higher values of CRP (192.23 ± 91.70 vs 268.26 ± 12.38, p = 0.001) and required vasopressor and/or inotropes therapy more frequent (6 (12%) vs 30 (32%), p = 0.016), respectively. The overall number of patients with affection of two or more organ system was significantly higher in the post-COVID-19 period (26 (52%) vs 68 (72%), p = 0.025), as shown in Table 1.

Table 1.

Patients demographics, clinical, and laboratory data.

variable	Pre-COVID-19 (N = 50), mean ± SD (%)	Post-COVID-19 (N = 94), mean ± SD (%)	p
Age (years)	67.68 ± 11.43	67.12 ± 11.54	0.780
Male (%)	25 (50)	49 (52)	0.946
Diabetes (%)	18 (36)	42 (44)	0.409
Hypertension (%)	34 (68)	60 (63)	0.752
Sepsis (%)	8 (16)	2 (2)	0.006
Severe sepsis (%)	37 (74)	69 (73)	0.904
Septic shock (%)	5 (10)	23 (25)	0.037
SBP <100 mmHg (%)	24 (49)	56 (61)	0.212
SpO₂ <90% (%)	15 (28)	48 (51)	0.014
T >38 °C (%)	40 (80)	47 (50)	0.001
HR >90/min (%)	25 (53)	58 (65)	0.248
WBC >12/<4 × 10¹² (%)	60 (86)	64 (85)	0.891
PLT <60 × 10⁹ (%)	7 (14)	23 (24)	0.210
CRP (mg/dl)	192.23 ± 91.70	268.26 ± 12.38	0.001
Vasopressor/inotropes (%)	6 (12)	30 (32)	0.016
Mental alteration (%)	15 (30)	66 (70)	0.0001
More than one organ affection (%)	26 (52)	68 (72)	0.025

SBP: systolic blood pressure; SpO₂: blood oxygen level, T: body temperature; HR: heart rate; WBC: white blood count; PLT: platelet blood count, CRP: C-reactive protein.

Kidney function affection and outcomes

Kidney function affection and outcomes are presented in Table 2. No difference was found regarding overall AKI incidence and pre-existing CKD between the two groups (94% vs 98%, p = 0.238; 60% vs 57%, p = 0.622), but there were more patients in the post-COVID-19 group with AKI stadium 3 (35 (70%) vs 79 (84%), p = 0.04) and more of them required renal replacement therapy (31 (62%) vs 74 (78%), p = 0.02).

Table 2.

Kidney function and outcomes.

variable	Pre-COVID-19 (N (%))	Post-COVID-19 (N (%))	p
AKI (%)	47 (94)	93 (98)	0.238
AKI stadium 1 (%)	6 (12)	3 (3)	0.080
AKI stadium 2 (%)	9 (18)	11 (11)	0.433
AKI stadium 3 (%)	35 (70)	79 (84)	0.040
RRT (%)	31 (62)	74 (78)	0.020
Pre-existing CKD (%)	30 (60)	54 (57)	0.622
RRT after discharge (%)	12 (50)	19 (51)	0.875

AKI: acute kidney injury; RRT: renal replacement therapy; CKD: chronic kidney disease.

The post pandemic period was endured by more clinically aggravated septic conditions as septic shock and increased severity of AKI with need of renal replacement therapy as in AKI stage 3 (Figure 2).

Figure 2.

Sepsis and AKI staging before and after COVID-19 period.

The length of hospital stay of septic patients after COVID-19 was with significantly less duration than in the pre-COVID-19 period and those patients had also significantly shorter survival with death occurring almost twice more frequently (Table 3).

Table 3.

Hospital stay duration and survival.

Variable	Pre-COVID-19 (N = 50), mean ± SD	Post-COVID-19 (N = 94), mean ± SD	p
In-hospital stay (days)	13.32 ± 7.39	10.12 ± 5.2	0.016
30-Day survival (days)	22.16 ± 1.58	17.81 ± 1.31	0.021
Death (%)	16 (32)	51 (54)	0.018

Cumulative survival percentages at the 10th day were 33% higher pre pandemic (0.8 cumulative survival) in comparison to the post pandemic percentage (0.6 cumulative survival), as shown in Figure 3. Numerically, there was an extra death in every three patients post pandemic. Nearly half of patients did not survive at 20th day post pandemic and consistently remained <50% to the end of follow up. Overall, compared to the septic patients’ survival in the pre-pandemic period, there was a significantly shorter survival in post pandemic period, as shown in with Kaplan Meier analysis (log rank, p = 0.013). The Cox regression analysis confirmed 1.97 times higher risk of deaths in septic post pandemic patients (HR 1.977, 95% CI 1.127–3.469, p = 0.018).

Figure 3.

Kaplan–Meier survival curve illustrating shorter survival and higher mortality risk for patients with sepsis after the COVID-19 period.

Etiology of sepsis and multiple antibiotic resistance (MAR) indexing

Blood culture results were analyzed for the two periods. The number of positive blood cultures was around 70% and did not differ between the two groups (36 (72%) vs 52 (70%), p = 0.927). Regarding etiology of sepsis, the dominant door of entrance in both periods was the urinary tract (34 (68%) vs 57 (61%), p = 0.547), but the number of patients with obstructive nephropathy was significantly higher in the pre-pandemic group (31 (62%) vs 32 (34%), p = 0.001). When calculated the multiple antibiotics resistance (MAR) index in order to assess the association of the antibiotic resistance of the isolated causative agents of sepsis with the level of antibiotic use in analyzed periods, an important rise of MAR for Staphylococcus coagulase negative (0.48 vs 0.62, p = 0.001) and borderline rise for Escherichia coli (0.29 vs 0.35, p = 0.005) isolates in the post-pandemic group was noted (Table 4).

Table 4.

Blood cultures, causative agents, and MAR index.

variable	Pre-COVID-19 (N (%))	Post-COVID-19 (N (%))	p
Positive HC (%)	36 (72)	52 (70)	0.927
Urosepsis (%)	34 (68)	57 (61)	0.547
Obstructive nephropathy (%)	31 (62)	32 (34)	0.001
MAR coagulase neg. Staphylococcus	0.48	0.62	0.001
MAR Escherichia coli	0.29	0.35	0.005

MAR: multiple antibiotic resistance; HC: blood culture.

Regarding causative agents, distribution was similar in both periods with slight increase in the percentage of patients with coagulase-negative Staphylococci after pandemic, evidence of appearance of Enterobacter cloacae and fungal septicemia in four patients in the post-pandemic period was observed (Figure 4(a) and (b)).

Figure 4.

Causative agents in the (a) pre-pandemic period and (b) post-pandemic period.

Discussion

Our comparative analysis included 144 patients with sepsis and associated AKI. Almost all of them presented with AKI before admission, what was the reason for their initial hospitalization and treatment at our Nephrology Clinic. The number of patients with sepsis and associated AKI was twice higher in the post pandemic period which is consistent with the rising incidence of sepsis globally.¹⁶ There are a lot of studies that analyze factors that are responsible for these higher numbers of patients diagnosed with sepsis and many of them implicate COVID-19 pandemic and its consequences as important contributing factor.^17–20 COVID-19 pandemic did improve the awareness for prompt and early recognition of infection diseases and sepsis in general, but also permanently influenced our immunological systems and microbiological profile and distribution of the germs.^18–20 Although there was no difference between the two groups regarding their comorbidities, age and gender, the clinical presentation and severity of sepsis and AKI itself was significantly worse in the post-COVID-19 group patients. Respectively, there were more patients with AKI stadium 3, septic shock, and multiorgan affection. Patients in the post-COVID-19 group also had higher values of inflammatory markers, so we assume that the well described long-lasting alterations of the immune system after COVID-19 infection, like immunosuppression and hyper inflammation with their consequent increase of susceptibility to bacterial and fungal infections can partly explain the incidence and severity of sepsis in the post pandemic period.^19,20 Even though it did not reach statistical significance, it was evident that patients in the post pandemic group had lower platelets count. It is well known that platelets have important role in sepsis and many pathophysiological mechanisms can lead to low platelet count.²¹ There are several published studies that suggest that the frequency of thrombocytopenia in sepsis may have been increased after pandemic.^21–23 The exact cause of this is not well understood, but the post-COVID-19 immune dysregulation, long-term endothelial damage end residual effects of COVID-19-associated coagulopathy are numbered as possible significant contributing factors.^21–23 Also, the vaccine-induced immune thrombocytopenia and thrombosis (VITT) linked to adenoviral vector in COVID-19 vaccines is recognized in some patients, although there is no strong evidence for a clinically relevant difference in VITT occurring after Ad26 or ChAdOx1.²⁴ Regardless of the underlying mechanism, thrombocytopenia is recognized as independent predictive factor for worse outcome and mortality from sepsis in general, which is consistent with the shorter survival observed in our post pandemic group, that presented with lower platelet values.^25,26 Patients in the post pandemic group with sepsis had significantly shorter in-hospital stay and experienced death more often and this correlates with a multicentric German study where an observation of increased 30-day mortality from sepsis in hospitals in Germany, after the pandemic was analyzed.²⁷ One of the main cause for this was the impact that pandemic had on health care resources and capacities, public health policies, leading to delayed hospitalizations in more advanced and severe form of the disease.²⁸ In our analysis the risk of mortality was significantly higher for the post pandemic group and these is consistent with the excessive mortality rates observed in the post-pandemic period worldwide.^28–31 Latest published study highlights the lasting mortality impact of pandemic among vulnerable populations, specifically in the older population, possibly due to the post-COVID-19 conditions and an excessive mortality after the pandemic due to cardiovascular events was reported in younger patients.²⁸ Also, there is a study from Japan that indicates that there are serious adverse effects after repetitive m-RNA vaccine against COVID-19 that could lead to increased morbidity and mortality after the pandemic.²⁹

Factors of limitation of our study were the small number of patients included in the study, the fact that it was a single center study, also the insufficient data for patients regarding their previous COVID-19 disease experience or vaccination, but it is certainly worth thinking about it and investigating in the future.

Beside not well understood contributing factors for this state, what is for sure is that a lot of studies and reports from national and international agencies document the persistence of this phenomenon of long-lasting excessive mortality in a lot of countries and according to the report of Swiss Re institute report it’s predicted that the excess mortality will gradually tail off by 2033.^30–32

In order to understand the rising prevalence, severity, and increased mortality from sepsis in the post- pandemic period we compared blood culture isolates between the two periods. A positive isolate was obtained in around 70% of study population with sepsis and 30% had negative blood cultures, with almost equal distribution between the two periods. This percentage is in line with numbers in studies that demonstrate that the proportion of negative blood cultures in septic patients ranges from 28% to 49%^33,34 and this is partly explained by the fact that some of them were previously treated with antibiotics in local medical centers and they got sterile results on the analysis. The urinary tract remained dominant door of entrance in both periods, but in less number of cases in the post pandemic period was complication of an obstructive nephropathy. When we addressed the most common isolated causative agents and their MAR indexes, we did find increased index of antibiotic resistance for coagulase-negative Staphylococcus and Escherichia coli. A MAR index of 0.2 or greater suggests association with high antibiotic use. These corresponds with recent published literature that emphasizes the importance of the rising trends od multidrug resistance of some bacteria as a result of the antibiotics overuse during the COVID-19 pandemic and its impact on incidence and course of infection diseases in general.^35–37 What was also of big significance for our study was the occurrence of fungal sepsis only in the post pandemic period, indicating more immunocompromised state of the patients in these group as a result of the numerous direct and indirect effects of the virus itself. Centers for Disease Control and Prevention (CDC) reports from 2022 determined that COVID 19 did create a perfect storm by increasing antibiotic-resistant infections and death in hospital for 15%, putting an alert for potential new epidemic on the rise.³⁸

Conclusion

Sepsis and associated AKI occurrence and mortality are significantly higher in the post-COVID-19 pandemic period. The increased multidrug resistance of causing microorganisms is evidential, and provides some of the explanation for to the rising incidence and mortality of sepsis. Further studies on larger groups of patients are needed to evaluate additional contributing factors to this state, to upgrade our knowledge and expertise in early recognizing and management with this alarm condition and by that improve quality of care and survival from sepsis in general.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Aleksandra Canevska Taneska

Nikola Gjorgjievski

References

WHO. WHO COVID-19 dashboard (including Macedonia (monthly bulletin on the movement of infectious diseases for July 2025, Bilten 7_2025.pdf)), https://data.who.int/dashboards/covid19/summary (2025, accessed 9 August 2025).

CDC. Long COVID or post-COVID conditions, https://www.cdc.gov/covid/long-term-effects/index.html (2022, accessed 10 August 2025).

Memorial Sloan Kettering Cancer Center. COVID impacts, https://libguides.mskcc.org/CovidImpacts (2025, accessed 10 August 2025).

Davis

McCorkell

Vogel

, et al. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol 2023; 21: 133–146.

Munk

Brinch

Møller

, et al. Genomic analysis of sewage from 101 countries reveals global landscape of antimicrobial resistance. Nat Commun 2022; 13: 7251.

Boccabella

Palma

Abenavoli

, et al. Post-coronavirus disease 2019 pandemic antimicrobial resistance. Antibiotics 2024; 13(3): 233.

Mellhammar

Wollter

Dahlberg

, et al. Estimating sepsis incidence using administrative data and clinical medical record review. JAMA Netw Open 2023; 6(8): e2331168.

Sprung

Schein

RMH

Balk

RA.

The new sepsis consensus definitions: the good, the bad and the ugly. Intensive Care Med 2016; 42: 2024–2026.

Kellum

Chawla

Keener

, et al. The effects of alternative resuscitation strategies on acute kidney injury in patients with septic shock. Am J Respir Crit Care Med 2016; 193(3): 281–287.

10.

Rudd

Johnson

Agesa

, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. Lancet 2020; 395(10219): 200–211.

11.

Singer

Deutschman

Seymour

, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 2016; 315(8): 801–810.

12.

Martin

GS.

Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes. Expert Rev Anti Infect Ther 2012; 10(6): 701–706.

13.

Ayandele

Oladipo

Oyebisi

, et al. Prevalence of multi-antibiotic resistant Escherichia coli and Klebsiella species obtained from a Tertiary Medical Institution in Oyo State, Nigeria. Qatar Med J 2020; 2020(1): 9.

14.

Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2012; 2: 1–138.

15.

Forni

Darmon

Ostermann

, et al. Renal recovery after acute kidney injury. Intensive Care Med 2017; 43(6): 855–866.

16.

La Via

Sangiorgio

Stefani

, et al. The global burden of sepsis and septic shock. Epidemiologia 2024; 5(3): 456–478.

17.

AlRahmoun

Sabaté-Elabbadi

Guillemot

, et al. Impacts of the COVID-19 pandemic on sepsis incidence, etiology and hospitalization costs in France: a retrospective observational study. BMC Infect Dis 2024; 25(1): 627.

18.

Knight

Glover

McQuaid

, et al. Antimicrobial resistance and COVID-19: intersections and implications. Elife 2021; 10: e64139.

19.

Kratzer

Gattinger

Trapin

, et al. Differential decline of SARS-CoV-2-specific antibody levels, innate and adaptive immune cells, and shift of Th1/inflammatory to Th2 serum cytokine levels long after first COVID-19. Allergy 2024; 79(9): 2482–2501.

20.

Lage

Bricker-Holt

Rocco

, et al. Persistent immune dysregulation and metabolic alterations following SARS-CoV-2 infection. medRxiv [Preprint]. 2025 Apr 17:2025.04.16.25325949. doi:10.1101/2025.04.16.25325949. PMID:40321289; PMCID:PMC12047922

21.

Karim

Akhter

Karim

Thrombocytopenia in post Covid era: puzzle in the diagnosis. Bangladesh J Med 2024; 35(20): 147–148.

22.

Ranucci

Baryshnikova

Anguissola

, et al. The long term residual effects of COVID-associated coagulopathy. Int J Mol Sci 2023; 24(6): 5514.

23.

Mehandru

Merad

Pathological sequelae of long-haul COVID. Nat Immunol 2022; 23: 194–202.

24.

Van Rampelbergh

Pavord

Anaya-Velarde

, et al. Comparison of vaccine-induced immune thrombocytopenia and thrombosis cases following two adenovirus-vectored COVID-19 vaccines. Commun Med 2025; 5: 168.

25.

Cheng

Zeng

Chen

, et al. Current knowledge of thrombocytopenia in sepsis and COVID-19. Front Immunol 2023; 14: 1213510.

26.

Schupp

Weidner

Rusnak

, et al. Diagnostic and prognostic role of platelets in patients with sepsis and septic shock. Platelets 2023; 34(1): 2131753.

27.

Unterberg

Rahmel

Rump

, et al. The impact of the COVID-19 pandemic on non-COVID induced sepsis survival. BMC Anesthesiol 2022; 22: 12.

28.

Wei

Hung

, et al. Post-pandemic excess mortality of COVID-19 in Hong Kong: a retrospective study. Lancet Reg Health West Pac 2025; 58: 101554.

29.

Kakeya

Nitta

Kamijima

, et al. Significant increase in excess deaths after repeated COVID-19 vaccination in Japan. JMA J 2025; 8(2): 584–586.

30.

Pearson-Stuttard

Caul

McDonald

, et al. Excess mortality in England post COVID-19 pandemic: implications for secondary prevention. Lancet Reg Health Eur 2023; 36: 100802.

31.

Swiss Re Institute. The future of excess mortality after COVID-19, https://www.swissre.com/institute/research/topics-and-risk-dialogues/health-and-longevity/covid-19-pandemic-synonymous-excess-mortality.html#:~:text=Our%20general%20population%20forecasts%20suggest,%E2%80%938%25%20in%20the%20UK (accessed 1 September 2025).

32.

Eurostat. Excess mortality statistics, https://ec.europa.eu/eurostat/statistics-explained/index.php?title (2025, accessed 10 September 2025).

33.

Guo

Yang

, et al. Comparison of culture-negative and culture-positive sepsis or septic shock: a systematic review and meta-analysis. Crit Care 2021; 25(1): 167.

34.

Rhodes

Evans

Alhazzani

, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 2017; 43(3): 304–377.

35.

Abdelaziz Abdelmoneim

Mohamed Ghazy

Anwar Sultan

, et al. Antimicrobial resistance burden pre and post-COVID-19 pandemic with mapping the multidrug resistance in Egypt: a comparative cross-sectional study. Sci Rep 2024; 14(1): 7176.

36.

Falasca

Vetrugno

Borrelli

, et al. Antimicrobial resistance in intensive care patients hospitalized with SEPSIS: a comparison between the COVID-19 pandemic and pre-pandemic era. Front Med 2024; 11: 1355144.

37.

Peconi

Martini

Sarti

, et al. Impact of the COVID-19 pandemic on healthcare-associated infections and multidrug-resistant microorganisms in Italy: a systematic review. J Infect Public Health 2025; 18(5): 102729.

38.

Centers for Disease Control and Prevention (U.S.). COVID-19 reverses progress in fight against antimicrobial resistance in U.S.: hospitalization related infections grew 15% from 2019 to 2020: media statement for immediate release: Tuesday, July 12, 2022. CDC, 2022, https://stacks.cdc.gov/view/cdc/119024 (accessed 10 December 2025).

Aggravated sepsis,acute kidney injury,and microbiological resistance: Four year’s pre–post COVID-19 outcome study