Extremely elevated erythrocyte sedimentation rates: Associations with patients’ diagnoses and clinical characteristics

The erythrocyte sedimentation rate (ESR) is a standardized, accurate, widely available, and cost-effective method for measuring inflammation. When venous blood is placed in an upright tube, erythrocytes, being heavier than plasma, settle to the bottom under the influence of gravity. ESR is defined as the distance erythrocytes fall in one hour [1]. In the presence of elevated proteins such as fibrinogen or globulins, erythrocytes clump together more easily, forming rouleaux that settle at the bottom. Acute phase reactants (APR) refer to molecules in the blood whose levels rise or fall in response to infection, inflammatory rheumatic diseases, allergic drug reactions, surgical interventions, or trauma [2]. ESR reflects the concentration of APRs and serves as an overall measure of inflammation. However, its sensitivity and specificity are low [3].

Studies in adults have shown that while moderate ESR elevations can occur without a known cause, ESR levels exceeding 100 mm/hour are associated with serious conditions and have a low rate of false positives [4]. The differential diagnosis of markedly elevated ESR has been extensively studied since Zacharski et al.’s work in 1967, with infections, hematologic or oncologic diseases, and rheumatologic diseases consistently emerging as primary considerations [5,6]. However, variables such as the clinical setting and patient population can influence the frequency of these diagnoses and lead to differences in clinical outcomes [7].

This study aims to investigate the etiological distribution, comorbidities, and clinical outcomes of patients admitted to a tertiary hospital’s internal medicine clinic with excessive ESR values, and to explore the associations among these factors.

This retrospective, observational clinical study included patients aged 18 and older with ESR values over 100 mm/hour, admitted to the internal medicine inpatient clinic of Istanbul Medeniyet University Göztepe Training and Research Hospital between May 1, 2015, and June 1, 2021. Patients without discharge summaries or those with missing clinical, laboratory, or imaging data were excluded. The study was approved by the Ethics Committee of Istanbul Medeniyet University Göztepe Training and Research Hospital on December 8, 2021 (decision no: 2021/0620) and followed the principles of the Declaration of Helsinki. Patients’ informed consent was waived due to the retrospective study design.

STUDY DESIGN

From 8,082 patients admitted to the internal medicine inpatient clinic and who had ESR measurements during the study period, the discharge summaries of patients with ESR values over 100 mm/hour were reviewed using the hospital’s electronic database (n = 481). After excluding cases where the elevated ESR etiology was not investigated (n = 13), cases with insufficient discharge summary data (n = 16), and cases where patients or their relatives declined further investigation into the cause of ESR elevation (n = 11), 441 patients were included in the analysis. The study flow diagram is presented as Figure 1. For patients with multiple admissions, data from the admission in which the diagnosis related to the elevated ESR was made were used. Demographic data, comorbidities, laboratory parameters (C-reactive protein, ferritin, hemoglobin, leukocytes, platelets, neutrophils, lymphocytes, neutrophil/lymphocyte ratio), imaging results, and histopathological findings were recorded. Mortality data, including in-hospital and post-discharge deaths, were obtained from the hospital’s electronic system and the national health system (e-Nabız) on February 1, 2022, which served as the index date for data collection.

Figure 1.

Flow diagram for inclusion and exclusion.

A total of 441 patients, aged between 20–100 years, were included in the study. The mean age was 72.6 years and 52.6% of the patients were female. Most of the cases (72.5%) were aged 65 and older.

The most common etiological causes of extremely elevated ESR were infectious diseases (34%), malignancies (31.5%), undiagnosed cases (15.9%), renal diseases (9.8%), other causes (5%), and rheumatologic diseases (3.8%). When examining sub-diagnoses within each group, pneumonia accounted for 40% of the infectious diseases, multiple myeloma for 13.7% of the malignancies, chronic kidney injury for 51.2% of the renal diseases, and rheumatoid arthritis for 64.7% of the rheumatologic diseases (Table 1).

When comparing the six etiological categories, there were no significant differences in terms of gender (p=0.261), age groups (p=0.198), or ESR levels (p=0.507). The malignancy group had a significantly higher mortality rate compared to the other groups (p<0.001). Ferritin levels were also notably higher in the malignancy group (p<0.001). Hemoglobin levels were significantly lower in the undiagnosed group compared to the other groups (p<0.001). In the infectious disease group, leukocyte counts (p=0.001), neutrophil levels (p<0.001), neutrophil-to-lymphocyte ratio (NLR) (p<0.001), and CRP levels (p<0.001) were significantly higher than those in the malignancy and undiagnosed groups (Table 2).

Patients with ESR >120 mm/hour had significantly lower hemoglobin levels (8.33±1.84 g/dL) compared to those with ESR between 100–120 mm/hour (9.31±2.11 g/dL) (p<0.001).

When evaluating comorbidities independent of their relationship with elevated ESR, the most frequent comorbid conditions were hypertension (51%), diabetes mellitus (40.1%), coronary artery disease (22.4%), chronic kidney disease (20.9%), malignancies (19.5%), congestive heart failure (11.8%), cerebrovascular disease (10.7%), and chronic obstructive pulmonary disease (9.3%) (Table 3).

It was observed that 16 patients (3.6%) died during hospitalization, 56 (12.7%) were transferred to the intensive care unit (ICU), and 369 (83.7%) were discharged. Up to the data collection date of the study, 54 (96.4%) of those initially transferred to the ICU and 214 (58%) of those discharged were found to have died. In total, 284 patients (64.4%) had died.

Patients who died had a higher mean age (p<0.001), a greater proportion of those aged 65 and above (p<0.001), and higher rates of diabetes mellitus (p=0.043), congestive heart failure (p=0.021), and malignancies (p<0.001). Additionally, ferritin levels were higher (p=0.002), while hemoglobin (p<0.001) and lymphocyte levels (p=0.021) were lower in the deceased group compared to survivors (Table 3).

The findings of this study revealed that the average age of hospitalized patients with significantly elevated ESR was high, with nearly three-quarters being 65 years or older. The leading etiologic causes, in descending order, were infectious diseases, malignancies, undiagnosed conditions, renal diseases, other causes, and rheumatologic diseases. The most common comorbidities included hypertension, diabetes mellitus, and coronary artery disease. Although in-hospital mortality rates were low, a notably high mortality rate was observed from discharge to the data collection date. Mortality was most prevalent among patients aged 65 and older, with the highest rates occurring in those with malignancies.

ESR is a well-established laboratory test used in clinical diagnosis and monitoring. Although moderate elevations can occasionally occur without an obvious cause, our study confirmed that extreme ESR levels, particularly those exceeding 100 mm/hour, are mostly associated with an identifiable underlying disease, providing important clinical insights for physicians. A 1967 study by Zacharski and colleagues was one of the first to report that 58% of patients with elevated ESR had malignancies, which influenced clinicians to conduct extensive diagnostic investigations when faced with high ESR levels [5]. However, it is important to consider that this study was conducted in a referral center, and subsequent studies have not consistently shown malignancies to be the most frequent cause [8]. In fact, in our study, only one in three patients had malignancies. These findings suggest that while extreme ESR elevations should be taken seriously, it is prudent to first screen for benign causes before pursuing more extensive diagnostic evaluations.

One of the most comprehensive studies on excessive ESR elevation, conducted by Daniels et al. with 4807 patients, found that the underlying cause was infectious diseases in 40%, inflammatory diseases in 38%, and malignancies in 36% of patients with ESR >100 mm/hour [6]. Similarly, in a study by Cengiz et al. of 110 geriatric patients with ESR ≥80 mm/hour, infectious diseases were the most common cause (48.2%), followed by oncological diseases (17.3%) [9]. Yousuf and colleagues, in a study of 508 patients with ESR ≥100 mm/hour, also found infectious diseases to be the most frequent cause (38.6%) [10]. Despite variations in results due to study design differences, the two most common causes across these studies align with our findings: infectious diseases and malignancies.

In our study, the most frequent infectious diseases were pneumonia (40%), and urinary tract infections (23.3%). Similarly, Daniels and colleagues identified pneumonia as the most common cause, followed by cellulitis, bacteremia, abscesses, and osteomyelitis [6]. However, the etiology of elevated ESR, particularly for infectious causes, can vary significantly by geographic region. For example, Levay et al., in a study conducted at a tertiary hospital in South Africa, identified Mycobacterium tuberculosis as the most common infective organism, influenced by the high prevalence of HIV-positive patients in their cohort [11]. This highlights the impact of regional factors on the distribution of ESR etiologies.

Malignancies ranked second in etiological distribution in our study. In a study by Uguz et al. involving 205 patients over 65 years of age, the malignancies most associated with marked ESR elevations were acute myeloid leukemia, multiple myeloma, and lung cancer [12]. Although the frequency of diseases causing extremely elevated ESR varies across the literature, multiple myeloma and acute leukemias are among the most common. However, our findings, along with similar studies, suggest that in cases of extreme ESR elevations, solid tumors should also be considered as potential underlying causes, alongside hematologic malignancies.

Studies examining mortality in patients with elevated ESR levels show that very high ESR is associated with increased mortality. In the prospective, population-based Rotterdam cohort study (1990–2014), which included 5,226 participants with a mean age of 70.3 years, a 14.9-year follow-up revealed that individuals with baseline ESR levels of 20–50 mm/hour had a 27% higher risk of mortality, while those with ESR levels exceeding 50 mm/hour faced an 89% increased risk. These findings suggest that even moderate ESR elevations serve as an independent prognostic factor for mortality [13]. In our study, although the inhospital mortality rate was low (3.6%), we observed a high post-discharge mortality rate of 63.4%, consistent with existing literature. The highest mortality was observed in the malignancy group, as expected. Since only patients with ESR ≥100 mm/hour were included in this study and no control group was used, we cannot conclude that elevated ESR is an independent prognostic factor for mortality. However, based on our findings and previous research, we believe that severe underlying diseases and comorbidities contribute to ESR values exceeding 100 mm/hour, which in turn is associated with high mortality.

Patients with ESR levels between 100–120 mm/hour were found to have higher hemoglobin levels compared to those with ESR >120 mm/hour, in line with the known inverse relationship between hemoglobin and ESR [14]. CRP and NLR levels were higher in the infectious diseases group, consistent with the literature [15,16].

The retrospective and single-center design, the inclusion of only patients with ESR ≥100 mm/hour, and the absence of a control group are the main limitations of this study. Accepting the most likely diagnosis that could cause elevated ESR as the final diagnosis is another limitation, which could introduce bias due to potential inaccuracies or misattributions in diagnosis. The retrospective nature of the study may also result in data completeness issues, as some clinical or laboratory data may be missing or inconsistently recorded. Furthermore, although most patients were observed to have died post-discharge, we were unable to access cause-of-death information from the National Database, and thus no causal relationship between elevated ESR and mortality can be inferred from this study. Finally, it is worth noting that the etiology of elevated ESR can vary significantly across geographic regions due to differences in the prevalence of infectious, inflammatory, or malignant diseases, which may limit the generalizability of our findings to other populations.

The results of this study suggest that the detection of extremely elevated ESR values in hospitalized patients, particularly the elderly, may indicate the presence of serious underlying conditions. Infectious diseases and malignancies should be considered as primary causes.