High Procalcitonin in a Patient with Drug Hypersensitivity Syndrome

Case Report

An 18-year-old male was admitted to the hospital with a fever lasting for 10 days, nausea, diarrhea, abdominal pain, and a 2-day history of maculopapular rash with facial edema. Prior to his hospitalization, the patient self-treated with amoxicillin 500 mg three times daily. He had a past medical history of grand mal epilepsy for which he was treated with phenobarbital, which was replaced by valproate 5 years later. Due to inadequate disease control, carbamazepine therapy was added approximately 3 weeks prior to the onset of high fever.

On admission, laboratory results revealed leukocytosis and eosinophilia. Serum procalcitonin (PCT) was highly elevated at 2.64 ng/mL (normal level < 0.1 ng/mL) alongside C-reactive protein at 59 mg/L (normal < 5 mg/L). He was misdiagnosed with sepsis and treated with broad-spectrum antibiotics clindamycin and ceftriaxone alongside continuing carbamazepine therapy.

Five days later, the patient developed a high-grade fever with a PCT increase to 3.84 ng/mL and C-reactive protein to 72 mg/L. During fever spikes, the patient experienced seizures and altered mental status. Hepatotoxicity was suspected for which carbamazepine was replaced by phenobarbital.

A week after admission, drug rash, eosinophilia, and systemic symptoms (DRESS) diagnosis was confirmed for which phenobarbital and valproate therapy were immediately discontinued. The patient was treated with IV methylprednisolone (120 mg/day) and topical steroids. Three days later, the PCT level decreased to 0.8 ng/mL. A week later the patient restarted valproate (500 mg twice daily) and had a full recovery 2 months after carbamazepine discontinuation. 

Procalcitonin under normal conditions is produced in the C cells of the thyroid and is typically released from all types of cells throughout the body in cases of infection. Although the diagnosis of DRESS is often nonspecific and includes symptoms such as high fever, morbilliform rash, and facial edema, various proinflammatory markers have also been found to be elevated in DRESS which can induce synthesis of serum PCT.

This patient was diagnosed with sepsis based on presentation and PCT values, despite negative blood cultures; it was thought the negative cultures were due to his previous antibiotic treatment.

The authors report this to be the first case of carbamazepine-induced DRESS associated with elevated PCT. However, they also state that biomarkers such as PCT should only be a part of a clinical assessment of critically ill patients. Additionally, DRESS should be included in the differential diagnosis of patients presenting with similar symptoms to this patient. 

Elevated procalcitonin levels in patients with acetaminophen intoxication: two case reports. A CARE-compliant article 

Case report

A 24-year-old woman was admitted to the emergency department after consuming approximately 8,000 mg of acetaminophen between the hours of 0800 and 2200. Upon admission, the patient was cognizant but she was experiencing nausea, vomiting, and epigastric pain. At the time of admission, her vital signs were unremarkable. The patient reported tenderness around the upper part of her abdomen; no signs of rebound tenderness or costovertebral angle tenderness were noted.

The patient was treated with N-acetylcysteine for 20 hours which was given ~13 h after her first dose of acetaminophen. C-reactive protein (CRP), aspartate transaminase (AST), and white blood cell (WBC) counts were within normal limits. Her procalcitonin (PCT) was elevated, measuring at 31.89 ng/mL ~60 h after her first dose of acetaminophen.

Approximately 27 hours after the first dose of acetaminophen, her acetaminophen drug level measured at <5.0 µg/mL. Ultrasound imaging did reveal any hepatic or bile duct abnormalities. Additionally, there were no concerns for infection. The patient was discharged four days later without complications.

A 51-year-old man was admitted to the emergency department (ED) after consuming 23,600 mg of acetaminophen (279.6 mg/kg). Upon admission, the patient was cognizant with general weakness. His vital signs on arrival to ED were within normal limits. The patient’s physical exam was normal as well.

The patient was treated with N-acetylcysteine for 20 hours which was given ~8 h after his first dose of acetaminophen. His initial CRP, AST, ALT, and WBC count were within normal limits. On the second day of admission, AST and ALT levels increased substantially to 2508 and 1473 IU/L, respectively. PCT levels elevated to 44.66 ng/mL after ~56 h after first acetaminophen consumption. Acetaminophen drug level was measured at 116.9 µg/mL.

On the third day, AST and ALT decreased to 1382 and 1370 IU/L, respectively. Ultrasound imaging showed mild fatty liver and hepatomegaly without bile duct distention. No signs of possible infection were noted during his hospital stay. On day six, his AST and ALT levels further decreased to 53 and 357 IU/L, respectively. The patient was discharged since no unusual symptoms noted and due to the daily decrease in liver enzymes. The patient was seen the next day at outpatient gastroenterology for a follow-up examination. His liver enzymes were within normal levels and no unusual symptoms were noted.

Although infections are the most common cause of elevated PCT levels, other causes may include severe and prolonged cardiogenic shock, heart shock, trauma, severe pancreatitis, rhabdomyolysis, autoimmune disorders, severe renal and liver dysfunction. 

The authors suggested other mechanisms such as cytokine stimuli or other organ involvement may be associated with the production of PCT in patients with acetaminophen intoxication. The authors suppose that these case reports may be useful in determining the pathophysiology of the correlation between PCT and acetaminophen levels.

Serum procalcitonin level in chronic hemodialytic patients with no evidence of bacterial infection 

Design

Non-randomized, non-controlled prospective observational study

N= 125

Objective

To verify the reference range of procalcitonin (PCT) and parameters affecting its value in patients receiving chronic hemodialysis

Study Groups

Adult patients with end-stage renal disease (N= 125)

Inclusion Criteria

Adult patients with end-stage renal disease (ESRD) undergoing chronic intermittent hemodialysis (HD) or hemodiafiltration (HDF), clinically stable, free from clinical signs of systemic infection, no history of surgery during in previous 1 month

Exclusion Criteria

Not explicitly stated

Methods

Patients received dialysis via high-flux membrane with routine clinical and laboratory evaluation every 2 weeks to detect signs of infection. If findings suggested possible infection, systemic computed tomography was conducted to rule out infection. Plasma and serum samples were obtained 2 days after dialysis sessions and prior to the next session to determine the static state of the patients. Electrochemiluminescence immunoassay was used to measure PCT levels. 

Duration

Duration of trial: not clearly stated 

Mean duration of treatment: 6 years

Outcome Measures

Correlation of variables associated with dialytic efficiency and nutrition index with PCT levels

Baseline Characteristics

ESRD (N= 125)

Age, years

Male

Duration of dialysis, years

Primary disease

Diabetes mellitus (DM) nephropathy

Non-DM nephropathy

Chronic glomerular nephritis

Immunoglobulin A nephritis

Nephrosclerosis

57 (45.6%)

68 (54.4%)

19 (15.2%)

11 (8.8%)

9 (7.2%)

Modality of dialysis

HD

HDF

112 (89.6%) 

13 (10.4%)

Dialysis time, hours

3.9 ± 0.5

Baseline laboratory parameters

Mean PCT, ng/mL

Median PCT, ng/mL (range)

PCT > 0.3 ng/mL

PCT > 0.5 ng/mL

C-reactive protein, mg/dL

Serum creatinine

White blood cell counts, x10³/μL

β2 microglobulin

Kt/V equivalent

0.24 ± 0.22

0.18 (0.05 to 1.73)

27 (21.6%)

9 (7.2%)

0.3 ± 0.8

9.5 ± 2.3

5.55 ± 2.16

25.7 ± 6.2

1.23 ± 0.26

Results

PCT mean, median (range)

R (range) 

p-value

Sex

Male (n= 82)

Female (n= 43)

0.238, 0.185 (0.05 to 0.95)

0.264, 0.17 (0.05 to 1.73)

-

-

0.4397

Primary disease

DM nephropathy (n= 57)

Non-DM (n= 68)

0.222, 0.18 (0.05 to 0.84)

0.268, 0.185 (0.05 to 1.73)

-

-

0.433

Modality of hemodialysis

HD (n= 112)

HDF (n= 13)

0.24, 0.18 (0.05 to 1.73)

0.308, 0.24 (0.11 to 0.95)

-

-

0.0831

Age

-

Duration of dialysis

-

Urine volume/day (n= 64)

-

Dialysis time

-

Serum creatinine

-

White blood cell counts

-

C-reactive protein

-

β2 microglobulin

-

Kt/V equivalent

-

Adverse Events

Common Adverse Events: N/A

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: Not disclosed 

Study Author Conclusions

Most of the patients with hemodialysis showed normal PCT. However, a not negligible number of them had higher baseline PCT level than those in healthy individuals. In 7.2 % of them, serum PCT exceeded the cutoff point for sepsis in healthy individuals. Impairment of renal function and hemodialytic status may affect the PCT level.

InpharmD Researcher Critique

Although systemic bacterial infection could be ruled out in this study due to the absence of fever and other clinical signs, it was difficult to determine if patients were free of localized infections. Further investigation would be needed to clarify the relationship between elevated serum PCT in dialysis patients with localized infection. Additionally, the sample size in this study was relatively small, which may limit the generalizability of the results.

Extreme Procalcitonin Elevation without Proven Bacterial Infection Related to Amphetamine Abuse

Case Study

A 21-year-old male with no significant past medical history was brought to the emergency department by paramedics after being found unconscious by his parents. He was found to be severely hypoglycemic for which he was stabilized with IV glucose infusion and supplemental oxygen. Upon further examination, he was found to be tachypneic (30 breaths/minute) and tachycardic (135 beats/minute) with a blood pressure of 96/67 mmHg. Arterial blood gases revealed severe metabolic acidosis and hyperkalemia, for which a hemodialysis catheter was inserted and intermittent venous-venous hemodiafiltration was initiated. His procalcitonin level on day 1 was 1432 ng/mL.

The patient was transferred to the intensive care unit after requiring endotracheal intubation with rapid sequence induction. He was initiated on fluid resuscitation with crystalloid infusion and continued to receive intensive care with mechanical ventilation and continuous propofol and morphine sedation. Imipenem (500 mg TID) and amikacin (1000 mg daily) were initiated.

Cerebrospinal fluid samples revealed no leukocytosis and microbiology results did not confirm infection for which antibiotics were stopped after 24 hours. Toxicology reports detected levels of amphetamine in the urine sample. Additionally, routine laboratory tests showed signs of acute kidney injury (creatinine: 395 μmol/L, blood urea nitrogen: 21.5 mmol/L) and elevated creatinine kinase levels indicative of rhabdomyolysis. On day 3, the patient’s condition stabilized and he was extubated. On days 2 and 4, his PCT were 1640 and 1007, respectively.

His agitation was successfully treated with IV haloperidol bolus doses, however he remained anuric and required daily intermittent venovenous hemodialysis filtration (IVVHDF) for the remainder of his stay. By day 6, his PCT decreased to 170.6 ng/mL. He was discharged on day 10, when his PCT was 15.18 ng/mL.

Procalcitonin (PCT) is a biomarker generally known for the diagnosis of sepsis as well as differentiating bacterial infection from systemic inflammation. Elevated PCT levels have been found in various surgical and trauma patients due to the systemic inflammatory response syndrome (SIRS). Similarly, severe SIRS has been noted in various medical conditions including amphetamine intoxication.

The authors report this to be the first case demonstrating elevated PCT related to amphetamine intoxication in this case, since there were no signs of infection, the authors suggest that the increased PCT was due to tissue injury, which resulted in severe rhabdomyolysis and acute renal failure.

Aprotinin reduces the procalcitonin rise associated with complex cardiac surgery and cardiopulmonary bypass

Design

Pre-post, quazirandomized, clinical study

N=60

Objective

To investigate the effects of Aprotinin on post-operative procalcitonin (PCT) in patients undergoing major cardiac surgery, in the form of pulmonary artery endarterectomy (PEA)

Study Groups

Aprotinin (n=30)

Tranexamic acid (n=30)

Inclusion Criteria

Patients with chronic thromboembolic pulmonary hypertension scheduled for isolated pulmonary endarterectomy surgery (PEA)

Exclusion Criteria

PEA combined with another procedure; severe postoperative bleeding requiring resternotomy; local and systemic infection with SIRS score ≥2 (defined according to the Society of Critical Care Medicine Consensus Conference and guidelines of the Center for Disease Control and Prevention)

Methods

Prior to January 2008, Aprotinin 2,000,000 IU was given prior to induction of anesthesia, then 2,000,000 IU in cardiopulmonary bypass (CPB) prime, and 50,000 IU per hour continuously intravenously throughout the whole procedure. From January 2008 onwards, patients received Tranexamic acid 1g before skin incision, 1g after heparin dose, and 2g in CPB prime.

*Due to a recommendation from the European Medicines Agency published in November 2007, Aprotinin was discontinued and withdrawn from hospital formularies. Thus, starting in January of 2008, Tranexamic Acid was used to continue the clinical trials.

Duration

Trial duration: January 2007 to June 2011

Outcome Measures

Aprotinin and Tranexamic Acid influence on Procalcitonin (PCT) levels

Baseline Characteristics

Aprotinin (n=30)

Tranexamic acid (n=30)

Age, years

Male

Results

Aprotinin (n=30)

Tranexamic acid (n=30)

PCT, ng/mL (interquartile range)

Before surgery

After separation from CPB 12h

After separation from CPB 18h

0.18 (0.13-0.23)

0.18 (0.11-0.24)

1.52 (1.26-1.84)

0.16 (0.11-0.21)

0.30 (0.19-0.44)

2.18 (1.90-2.62)*

Adverse Events

None reported

Study Author Conclusions

This study concludes that aprotinin attenuates the post-surgical increase of PCT following major cardiac surgery with CPB and deep hypothermic circulatory arrest (DHCA), in a similar manner to other pro-inflammatory cytokines. These results also support previous findings that a rise of tumor necrosis factor-a, interleukin-6, and interleukin-8 post-surgery is significantly altered by the use of aprotinin. Significant correlation between PCT and IL-6 post-surgery may be indicative of an indirect IL-6-mediated pathway of PCT alteration.

InpharmD Researcher Critique

One of the weaknesses of this study is the change in the drug used during this clinical trial. It was discontinued due to a recommendation from the European Medicines Agency in November 2007 which made this trial have to continue with another drug, tranexamic acid. The study stated that tranexamic acid served as the control group versus aprotinin-treated patient since tranexamic acid has been shown to have no significant effects on cytokine activation or cytokine-mediated inflammatory activities.