A study on proadrenomedullin as a marker of severity and prognosis in community-acquired pneumonia

INTRODUCTION

Community-acquired pneumonia (CAP) is a prevalent condition, with an incidence ranging from 20% to 30% in developing nations compared to 3–4% in developed countries.^[1-3] In Western countries, CAP remains the leading cause of mortality due to infectious diseases and accounts for substantial healthcare resource utilization.^[4] Despite advances in diagnostic methodologies, the etiology of CAP often remains indeterminate. Even with comprehensive laboratory investigations and invasive techniques, a definitive etiological diagnosis is established in only 45–70% of cases.^[5] Streptococcus pneumoniae is the most frequently identified pathogen, accounting for 35–60% of cases^[6,7] with the highest detection rates observed in studies utilizing urinary antigen tests.^[8] Biomarkers such as procalcitonin (PCT) and C-reactive protein (CRP) are commonly employed to indicate acute inflammation, but both exhibit significant limitations. Multiple studies have demonstrated that neither PCT nor CRP effectively differentiates between varying severities of CAP, as classified by scoring systems such as the pneumonia severity index or confusion, urea, respiratory rate, blood pressure, and age 65 (CURB-65), nor are they reliable predictors of mortality risk.^[9] However, PCT has shown elevated levels in cases of CAP of bacterial origin compared to non-bacterial etiologies. Conversely, CRP, as a non-specific marker, is influenced by numerous other factors, reducing its diagnostic specificity. Adrenomedullin (ADM), a potent vasodilator, also possesses immunomodulatory and metabolic properties.^[10-13] It exhibits bactericidal activity, augmented by its regulation of complement pathways and immune responses.^[14-16] Unsurprisingly, ADM levels are significantly elevated during sepsis.^[17] Its multifunctional roles include vasodilatory, antimicrobial, and anti-inflammatory effects.^[18] Increased circulating proADM levels in infections, including CAP, may be attributed to two mechanisms: (1) the enhanced synthesis of ADM as a member of the calcitonin gene family during infections, and (2) reduced clearance via renal and pulmonary pathways.^[17,19-21] Accurate measurement of ADM is challenging due to its rapid clearance from the bloodstream.^{[10,11,22,23]} However, the mid-regional proadrenomedullin (MR-proADM), a more stable precursor fragment, reliably reflects ADM levels and is not subject to the same degradation.^[24] MR-proADM has recently emerged as a valuable prognostic biomarker for assessing individual risk in sepsis.^[22] To date, no studies from India have focused on the prognostic role of MRproADM in CAP, with the exception of a study by Kannan et al., which explored this biomarker in pediatric sepsis.^[25] Hence, we conducted this pioneering research to evaluate the prognostic significance of MR-proADM in patients diagnosed with CAP.

MATERIAL AND METHODS

RESULTS

A total of 50 patients were included in the study, with a mean age of 62 years. The majority of the participants were over 60 years of age (n = 24, 48%). Of 50 patients, 56% were male and 44% were female, with a male-to-female ratio of 1.27:1. Most patients resided in rural areas (n = 37, 74%). Table 1 provides a detailed overview of the demographic and clinical characteristics of the study population. Cough was the most frequently reported symptom, present in 98% (n = 49) of cases, followed by fever and dyspnea. A classic symptom triad of fever, cough, and dyspnea was observed in 50% (n = 25) of patients. 58% of the patients had underlying comorbidities, with the most common comorbidity being hypertension (n = 20, 69%), followed by type 2 diabetes (n = 9, 31%).

The severity of disease, assessed using the CURB-65 score, revealed that 46% (n = 23) of patients had moderate disease, 36% (n = 18) had mild disease, and 18% (n = 9) were classified as having severe disease. The patients were followed for 4 weeks. At follow-up, 78% (n = 39) of patients demonstrated favorable outcomes and recovered, while 22% (n = 11) succumbed to the condition. Among patients who improved on follow-up, 53.8% were males and 46.2% were females, and among those who expired, 63.6% were males and 36.4% were females. The mean age of patients who improved at follow-up was 54.13 years, and that of patients who died was 66 years. Correlation of age with outcome in our study population was found statistically significant (P = 0.036). Among those who expired, 6% (n = 3) each belonged to the mild and moderate disease categories, while 10% (n = 5) were in the severe disease category. The CURB-65 score was found to be a statistically significant predictor of patient outcomes (P = 0.026), as illustrated in Figure 1.

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Figure 1:

Bar diagram depicting correlation of grading of the severity of community-acquired pneumonia as per confusion, urea, respiratory rate, blood pressure, and age 65 (CURB-65) score with outcome of the disease.

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The association of ProADM levels with various parameters, including CAP severity (based on the CURB-65 score), lobar involvement, and patient outcomes, was analyzed. ProADM levels were found to increase with greater CAP severity as categorized by the CURB-65 score (P = 0.021). Furthermore, patients with multilobar pneumonia exhibited significantly higher ProADM levels (1.49 nmol/L) compared to those with unilobar pneumonia (1.00 nmol/L, P = 0.017). Among patients who died during follow-up, admission ProADM levels were significantly elevated compared to those in survivors (1.95 nmol/L vs. 0.85 nmol/L, P < 0.001) [Table 2].

In addition, we examined the relationship between CAP severity (classified according to the CURB-65 score) and patient outcomes with ESR and TLC. However, no statistically significant associations were identified in these parameters [Tables 3 and 4].

DISCUSSION

With this objective, we conducted a study analyzing 50 patients hospitalized with CAP of varying severity, classified according to the CURB-65 score. Among these, 39 patients demonstrated clinical improvement, whereas 11 patients succumbed to the disease. The mean age of patients who died was 66 years, consistent with findings from Lim et al. (2003) ^[26] who examined 1,068 patients with a mean age of 64 years and identified age ≥65 years as an independent risk factor for mortality. Our study also found no significant association between sex, place of residence, co-morbidities, or smoking status and patient outcomes, aligning with findings from Courtais et al. (2012).^[27]

To address these challenges, our study employed the CURB-65 score, which involves fewer variables and allows for rapid severity stratification in emergency scenarios. In our study, 18 patients had mild disease, 23 had moderate disease, and 9 had severe disease based on the CURB-65 score. Among the 11 patients who died, 3 were from the mild category, 3 from the moderate category, and 5 from the severe category. The CURB-65 score was found to be a statistically significant predictor of patient outcomes (P = 0.026), consistent with findings by Lim et al.^[26] Our findings indicate that ProADM levels at the time of admission were strongly associated with disease severity (P = 0.021), demonstrating superior prognostic accuracy compared to traditional laboratory markers such as ESR and TLC. These results are consistent with a study by Christ-Crain et al. (2006)^[28] which analyzed data from 302 patients and reported that ProADM levels increased with CAP severity (P < 0.001).

Moreover, ProADM levels were significantly higher in patients who succumbed to the disease compared to those who recovered (P < 0.0001), reinforcing its utility in predicting mortality risk. This aligns with the findings of both Christ-Crain et al.^[29] and Courtais et al.^[30] Notably, ProADM levels were significantly elevated in cases of multilobar pneumonia (1.5 nmol/L) compared to unilobar pneumonia (1.0 nmol/L, P = 0.017), further supporting its value as a biomarker for severe disease, as reported by Christ-Crain et al.^[29]

CAP progressing to sepsis remains a significant contributor to morbidity and mortality worldwide.^[28] Detecting sepsis is particularly challenging due to its non-specific clinical presentation, necessitating reliable laboratory tests for diagnosis. Conventional investigations such as TLC, ESR, and CRP lack specificity for sepsis.^[31] Therefore, there is a critical need for biomarkers with enhanced sensitivity, specificity, and predictive value. ProADM, a biomarker that rises significantly in sepsis, has shown promise in both the prognostic and diagnostic evaluation of CAP-associated sepsis.

CONCLUSION

Our study highlights the significant association between ProADM levels and CAP severity, as well as patient outcomes, including mortality. Elevated admission ProADM levels were predictive of worse outcomes, making it a potentially valuable biomarker for prognosis, particularly in emergency settings. ProADM demonstrated superior prognostic utility compared to traditional inflammatory markers such as ESR and TLC.

Future studies with larger and more diverse populations are essential to confirm these findings and to further explore the relationship between ProADM levels and other prognostic factors in CAP. ProADM has the potential to enhance the clinical management of CAP, aiding in the early identification of high-risk patients and improving outcomes.