Procalcitonin: “To Follow or Not to Follow” That's the Question

How to cite this article: Todi SK. Procalcitonin: “To Follow or Not to Follow” That''s the Question. Indian J Crit Care Med 2021;25(5):484–485.

Sepsis has been recognized as an important cause of mortality globally, more so in resource-limited regions.¹ It accounts for 19.7% of all global deaths. Timely antibiotic therapy in patients with septic shock is associated with a significant decrease in mortality in observational studies.² Though this has not been uniformly noted in patients with sepsis without shock. Moreover, empirical use of appropriate antibiotic therapy has also been associated with a significant decrease in infection-related and all-cause mortality in critically ill patients.³ This has led to a widespread use of early broad-spectrum antibiotics in patients with septic shock. Unfortunately, despite the lack of robust evidence, similar practice is usually followed in patients with infection without organ dysfunction or shock. This has resulted in the emergence of multidrug-resistant (MDR) bacterial infections not only in hospitals but also in the community, which leads to a vicious cycle of prescribing further empirical broad-spectrum antibiotics for a new infection especially hospital-acquired. In the absence of a reliable method to “rule in” or “rule out” infection, it will be difficult to curb the upfront use of antibiotics. Decreasing antibiotic burden in the intensive care unit (ICU) and in the individual patient will be possible by sending appropriate microbiological cultures and deescalating antibiotics wherever possible and to decrease the duration of antibiotic therapy. As cultures are often negative and may only yield colonizing organisms, the scope of de-escalation may be limited especially in settings with MDR infection with limited options for de-escalation. Shortening the duration of antibiotics without compromising the efficacy may be the only way to achieve the goal of decreasing antibiotic exposure. Assessment of clinical improvement is the current prevalent practice of deciding on the duration of antibiotic therapy. This practice is based predominantly on a subjective assessment, which has led to a widely variable practice of antibiotic duration, which on an average is longer than what is probably desirable. Utilizing biomarkers like Procalcitonin has been recommended for decreasing the duration of antibiotic therapy.⁴To discuss the impact of a biomarker on the duration of antibiotic therapy, one needs to ascertain what should be an “ideal” duration of therapy. This will depend on multiple factors, with some situations requiring “prolonged” therapy like immunosuppressed state, the severity of infection (debatable), sites of infection like endocarditis, and microbiological factors like staphylococcal bacteremia and MDR gram-negative infection. Even in these situations exact duration of therapy is arbitrary and is dependent on the clinical response of the patient. On the other hand, in most other situations duration of antibiotic therapy may be “shorter”. The current practice of prescribing antibiotics for a certain minimum number of days, usually seven days is not based on sound evidence. There is a growing literature of evidence that the duration of antibiotic therapy can be shortened even further in most infections including severe infection. Recent trials in intra-abdominal infections requiring surgery have compared four days of antibiotics with seven days and have found equivalent results.⁵ The generalizability of these results is not possible in many situations and also clinical trials on the duration of antibiotic therapy are not available for many infections encountered in clinical practice in ICU. It is evident that the duration of antibiotic therapy requires individualization and is a field where personalized medicine can be readily practiced. Procalcitonin is the biomarker most commonly studied in this regard. Earlier studies on procalcitonin use in various infectious diseases had shown a decrease in duration of antibiotic therapy without any harmful effect with the use of this biomarker. This was achieved by serially measuring procalcitonin values and stopping the antibiotic when the level came below a certain percentage of baseline (usually 80%) or below a certain cutoff value usually less than 0.5 µg/mL. Relapse of infection was not noticed in these trials, with some trials even showing a decrease in mortality.⁶ Thus, the use of procalcitonin was recommended in sepsis guidelines to decrease the duration of antibiotic therapy.In a study published this issue, the author randomized 90 patients (45 in each arm) admitted with sepsis/septic shock to a procalcitonin-guided duration of antibiotic therapy or institutional protocol-based therapy. Procalcitonin value of <0.1 µg/mL was taken as the cut-off for stopping antibiotic therapy. Clinical response was also considered in both arms while considering the duration of antibiotic therapy. Patients requiring a short course of therapy like elective surgery or prolonged course of therapy like endocarditis, immunocompromised patients were excluded from the study. Duration of antibiotic therapy was significantly shorter in the procalcitonin group of 5 days vs 8 days in the control group. ICU length of stay, duration of mechanical ventilation, and duration of inotrope requirement were also significantly higher in the control group. Secondary infection defined as the occurrence of a new infection at another site was significantly higher in the control group, probably due to longer ICU stay and longer duration of mechanical ventilation. Reinfection rate which was defined as recurrence of infection at the same site was similar in both the group and also there were no significant differences in mortality between the groups. There were baseline differences in the groups, with septic shock patients being significantly higher in the control group, though the severity of score markers like SOFA and APACHE II and lactate levels were surprisingly similar between the two groups and bacteremia was more common in the procalcitonin group, which could be due to less robust randomization due to small sample size. Historically, clinicians are reluctant to shorten the duration of therapy in patients with sepsis and septic shock, which leads to prolonged antibiotic therapy and the authors should be commended to undertake this study in the septic shock population. Despite limitations, this study emphasizes the scope of safely decreasing the duration of antibiotic therapy in these groups of patients.Similar to the present study most of the studies on duration of antibiotic therapy have used clinical response along with procalcitonin levels to adjudicate duration of antibiotic justifying shortening the duration only in patients with positive clinical response. In practice, “positive clinical response” is an not all-or-none phenomenon with various parameters like fever, leukocytosis showing favorable or unfavorable trends that might be concordant or discordant and the composite response assessment remains a subjective impression. Moreover, the duration of antibiotic therapy in the control arm in many studies on procalcitonin has been of more than seven days duration which is contrary to the present evidence of shorter duration even in a sicker group of patients. Studies comparing the use of procalcitonin where the control arm had a shorter duration of antibiotic have not yielded significant results. The use of the procalcitonin strategy in infections with MDR organisms or immunosuppressed patients has also not been well studied as these were excluded from many procalcitonin studies. Despite these limitations, the current trend of prescribing a longer duration of antibiotics can only be curbed by judicious use of biomarkers like procalcitonin along with antibiotic stewardship practices. In the absence of a willingness to shorten the duration of antibiotics based on the procalcitonin result, the utility of this biomarker will not be realized. Moreover, the need for serial measurement of this expensive test also adds to the cost of care in ICU. Future research agenda on the utility of procalcitonin would be to compare this molecule with a relatively inexpensive biomarker like C-reactive protein on decreasing duration of therapy and total antibiotic burden in a critically ill patient with sepsis and septic shock and its effect on other important clinical and economic parameters like resource utilization, secondary bacterial and fungal infection, incidence of MDR bacterial infection and Clostridium difficle infection. This should be achieved without increasing the incidence of relapse or reinfection. The utility of the use of this biomarker in patients infected with MDR infection or immunosuppressed patients also needs to be studied. It might even be prudent to study the negative impact of the use of this molecule which may lead to unnecessary prolongation of antibiotic duration in patients who have clinically responded but not yet reached the procalcitonin cutoff. The control arm duration of antibiotic therapy in procalcitonin should be shorter in accordance with the recent guidelines. Approach to the duration of antibiotic therapy in patients with initial norma procalcitonin values and what should be the ideal frequency of repeating this marker need also be studied. Last but not the least, compliance with antibiotic stewardship practices of deescalating or stopping antibiotic based on a protocolized algorithm of procalcitonin value need to be studied in critically ill patient population.⁷     

Regulatory Role of Vitamin D Receptor Gene Variants of BsmI, ApaI, TaqI, and FokI Polymorphisms on Macrophage Phagocytosis and Lymphoproliferative Response to Mycobacterium tuberculosis Antigen in Pulmonary Tuberculosis

The regulatory role of vitamin D receptor (VDR) gene variants of Bsm I, Apa I, Taq I, and Fok I polymorphisms on vitamin D(3)-modulated macrophage phagocytosis with live Mycobacterium tuberculosis and lymphoproliferative response to M. tuberculosis culture filtrate antigen (CFA) was studied in patients with pulmonary tuberculosis (n = 46) and in normal healthy subjects (NHS) (n = 64). Vitamin D(3) at a concentration of 1 x 10(-7) M enhanced the phagocytic potential of normal subjects who had a phagocytic index of less than 20%. This increase was seen in subjects with the genotypes BB (p = 0.017), AA (p = 0.016), tt (p = 0.034), and FF (p = 0.013) and the extended genotype BBAAtt (p = 0.034). Normal subjects with BBAAtt performed better phagocytosis than individuals with bbaaTT genotype (p = 0.034). Vitamin D(3) at 10(-9), 10(-8), and 10(-7) M concentrations suppressed the lymphoproliferative response to CFA antigen in normal subjects. This decreased lymphocyte response was observed in normal individuals with the genotypes BB (p = 0.0009), tt (p = 0.016), and FF (p = 0.008) and the extended genotype BBAAtt (p = 0.02). Addition of vitamin D(3) had no significant effect on macrophage phagocytosis and lymphoproliferative response to CFA in pulmonary TB patients. This may be due to the unresponsive nature of the cells to the action of vitamin D(3) or the downregulated VDR expression by virtue of the disease, which renders them inactive. The genotypes BB, tt, and the extended genotype BBAAtt may be associated with increased expression of VDR which in turn regulate the action of vitamin D(3) and modulate the immune functions to M. tuberculosis in NHS.     

Morphine stimulates superoxide formation by glomerular mesangial cells

Focal glomerulosclerosis is the predominant glomerular lesion in heroin addicts. We studied whether morphine, a metabolite of heroin, could directly affect the formation of superoxide by glomerular mesangial cells. Mesangial cells preincubated with morphine (10^–8 M) showed a higher (P<0.001) production of superoxide when compared to control cells (control) 401±21 vs. morphine 610±41 nM/mg protein/h). This effect of morphine on mesangial cells was dose dependent. Naloxone, an opiate antagonist, attenuated morphine-induced formation of Superoxide by mesangial cells [control, 317±4; morphine (10^–8 M), 573±9; and naloxone (10^–8 M) + morphine (10^–8 M), 333±6 nM/mg protein/h]. We conclude that morphine enhances formation of superoxide by mesangial cells and this effect of morphine seems to be mediated through opiate receptors. Since superoxide has been demonstrated to cause mesangiolysis, we propose that morphine may be playing a role in the induction of mesangial injury in patients with opiate abuse.This work was supported by National Institute of Health Grant R01-DA-06753.     

Extramedullary hematopoiesis in the liver in sudden infant death syndrome

Liver extramedullary hematopoiesis was examined in 54 victims of sudden infant death syndrome and in 21 infants who died of other causes in an attempt to confirm Naeye's findings of increased extramedullary hematopoiesis in cases of sudden infant death syndrome. Our data showed greater extramedullary hematopoiesis in victims of sudden infant death syndrome (F = 23.52), supporting Naeye's hypothesis that victims of sudden infant death syndrome have suffered a subtle, chronic hypoxemic condition before death.     

A randomized trial of intravenous tissue plasminogen activator for acute myocardial infarction with subsequent randomization to elective coronary angioplasty

Patients presenting within four hours of the onset of acute myocardial infarction were randomly assigned to receive 80 to 100 mg of recombinant human-tissue plasminogen activator (t-PA) intravenously over a period of three hours (n = 72) or placebo (n = 66). Administration of the study drug was followed by coronary arteriography, and candidates for percutaneous transluminal coronary angioplasty were randomly assigned either to undergo angioplasty on the third hospital day (n = 42) or not to undergo angioplasty during the 10-day study period (n = 43). The patency rates of the infarct-related arteries were 66 percent in the t-PA group and 24 percent in the placebo group. No fatal or intracerebral hemorrhages occurred, and episodes of bleeding requiring transfusion were observed in 7.6 percent of the placebo group and 9.8 percent of the t-PA group. As compared with the use of placebo, administration of t-PA was associated with a higher mean (+/- SEM) ejection fraction on the 10th hospital day (53.2 +/- 2.0 vs. 46.4 +/- 2.0 percent, P less than 0.02), an improved ejection fraction during the study period (+3.6 +/- 1.3 vs. -4.7 +/- 1.3 percentage points, P less than 0.0001), and a reduction in the prevalence of congestive heart failure from 33 to 14 percent (P less than 0.01). Angioplasty improved the response of the ejection fraction to exercise (+8.1 +/- 1.4 vs. +1.2 +/- 2.2 percentage points, P less than 0.02) and reduced the incidence of postinfarction angina from 19 to 5 percent (P less than 0.05), but did not influence the ejection fraction at rest. These data support an approach to the treatment of acute myocardial infarction that includes early intravenous administration of t-PA and deferred cardiac catheterization and coronary angioplasty.     

Effect of gossypol in association with chromium protoporphyrin on heme metabolic enzymes

Gossypol prevents the liberation of oxygen from oxyhemoglobin and exerts a hemolytic effect on erythrocytes. In excessive dosages of gossypol, an extreme burden is placed upon the respiratory and circulatory organs owing to the reduced oxygen carrying capacity of blood. Chromium protoporphyrin (CrPP) has been shown to either competitively suppress or to significantly ameliorate a variety of naturally occurring or experimentally induced forms of jaundice in animals and man. In this communication, a novel tissue dependent response to gossypol (50 micromol/kg bw) and gossypol in association with CrPP (50 micromol/kg bw) is described. Our results revealed that gossypol stimulated the hepatic, splenic, and renal delta-aminolevulinic acid synthase (ALA-S) activity, the heme biosynthetic enzyme, and simultaneous administration of CrPP and gossypol synergized the gossypol-mediated increase of ALA-S activity. Gossypol was found to be a potent stimulator of heme oxygenase (HMOX) activity in rat liver and kidney to varying degrees. This tissue response contrasted with that of the spleen, where gossypol decreased the activity of the enzyme. In consonance with the increased hepatic and renal HMOX activity, a marked increase was observed in total serum bilirubin concentration in gossypol treated rats. When rats were given CrPP simultaneously with gossypol, the gossypol mediated increase in hepatic and renal HMOX activity was effectively blocked. Furthermore, the increase in enzymatic activity was accomplished by a decline in the total microsomal protein content on gossypol administration. These findings emphasize the toxic effect of gossypol in eliciting increased heme degradation by stimulating HMOX activity in the liver and the kidney and the potential usefulness of CrPP in experimental and perhaps clinical conditions in which hyperbilirubinemia occurs.     

Mechanism of fluconazole resistance in Candida albicans biofilms: phase-specific role of efflux pumps and membrane sterols

Candida albicans biofilms are formed through three distinct developmental phases and are associated with high fluconazole (FLU) resistance. In the present study, we used a set of isogenic Candida strains lacking one or more of the drug efflux pumps Cdr1p, Cdr2p, and Mdr1p to determine their role in FLU resistance of biofilms. Additionally, variation in sterol profile as a possible mechanism of drug resistance was investigated. Our results indicate that parent and mutant strains formed similar biofilms. However, biofilms formed by double and triple mutants were more susceptible to FLU at 6 h (MIC = 64 and 16 microg/ml, respectively) than the wild-type strain (MIC > 256 microg/ml). At later time points (12 and 48 h), all the strains became resistant to this azole (MIC > or = 256 microg/ml), indicating lack of involvement of efflux pumps in resistance at late stages of biofilm formation. Northern blot analyses revealed that Candida biofilms expressed CDR and MDR1 genes in all the developmental phases, while planktonic cells expressed these genes only at the 12- and 48-h time points. Functionality of efflux pumps was assayed by rhodamine (Rh123) efflux assays, which revealed significant differences in Rh123 retention between biofilm and planktonic cells at the early phase (P = 0.0006) but not at later stages (12 and 48 h). Sterol analyses showed that ergosterol levels were significantly decreased (P < 0.001) at intermediate and mature phases, compared to those in early-phase biofilms. These studies suggest that multicomponent, phase-specific mechanisms are operative in antifungal resistance of fungal biofilms.     

Evidence of linkage and association on 18p11.2 for psychosis.

The genetic basis of bipolar disorder (BPD) and schizophrenia (SCZ) has been established through numerous clinical and molecular studies. Although often considered separate nosological entities, evidence now suggests that the two syndromes may share some genetic liability. Recent studies have used a composite phenotype (psychosis) that includes BPD, SCZ, psychosis not otherwise specified, and schizoaffective disorder, to identify shared susceptibility loci. Several chromosomal regions are reported to be shared between these syndromes (18p, 6q, 10p, 13q, 22q). As a part of our endeavor to scan these regions, we report a positive linkage and association finding at 18p11.2 for psychosis. Two-point linkage analysis performed on a series of 52 multiplex pedigrees with 23 polymorphic markers yielded a LOD score of 2.02 at D18S37. An independent set of 159 parent offspring trios was used to confirm this suggestive finding. The TDT analysis yielded support for association between the marker D18S453 and the disease allele (chi2 = 4.829, P < 0.028). This region has been implicated by several studies on BPD [Sjoholt et al. (2004); Mol Psychiatry 9(6):621-629; Washizuka et al. (2004); Biol Psychiatry 56(7):483-489; Pickard et al. (2005); Psychiatr Genet 15(1):37-44], SCZ [Kikuchi et al. (2003); J Med Dent Sci 50(3):225-229; Babovic-Vuksanovic et al. (2004); Am J Med Genet 124(3):318-322] and also as a shared region between the two diseases [Ishiguro et al. (2001); J Neural Transm 108(7):849-854; Reyes et al. (2002); Mol Psychiatry 7(4):337-339; Craddock et al. (2005); J Med Genet 42(3):193-204]. Our findings provide an independent validation of the above reports, and suggest the presence of susceptibility loci for psychoses in this region.