BRIEF COMMUNICATION Serum Procalcitonin Levels in Patients with Primary Pulmonary Coccidioidomycosis Kenneth K. Sakata1, Thomas E. Grys3, Yu-Hui H. Chang2, Holenarasipur R. Vikram4, and Janis E. Blair4 1
Departments of Internal Medicine and 2Biostatistics, Mayo Clinic, Scottsdale, Arizona; and 3Department of Laboratory Medicine and Pathology and 4Division of Infectious Diseases, Mayo Clinic Hospital, Phoenix, Arizona
Abstract Rationale: The serum procalcitonin assay has emerged as a promising biomarker to distinguish between bacterial and viral respiratory tract infections but has not been used to differentiate coccidioidomycosis from bacterial infection. A correlation between procalcitonin serum levels and coccidioidomycosis has never been reported. Objective: To determine any association between serum procalcitonin levels and primary pulmonary coccidioidomycosis. Methods: We identified and enrolled 20 immunocompetent patients with symptomatic primary pulmonary coccidioidomycosis of , 8 weeks’ duration and performed a one-time procalcitonin assay, with a cutoff of , 0.25 mg/L indicating a nonbacterial infection.
Measurements and Main Results: Nineteen of 20 patients (95%) had serum procalcitonin of , 0.25 mg/L. The median procalcitonin level was 0.05 mg/L (range, , 0.05–0.87 mg/L; interquartile range, 0.05–0.05 mg/L). Sixteen of 20 patients (80%) had undetectable procalcitonin of , 0.05 mg/L. The four patients with detectable procalcitonin had a median value of 0.2 mg/L (range, 0.09–0.87 mg/L). Conclusions: In this pilot study, procalcitonin was not elevated in immunocompetent patients with primary pulmonary coccidioidomycosis at a median of 32 days after symptom onset. Larger prospective studies are needed to confirm this finding. Keywords: coccidioidomycosis; community-acquired pneumonia; immunocompetent; procalcitonin; respiratory tract infections
(Received in original form April 28, 2014; accepted in final form August 1, 2014 ) This work was supported by funds from the Mayo Clinic. Author Contributions: K.K.S.: grant and IRB application, study protocol and design, patient consent and enrollment, data collection, and manuscript preparation. T.E.G.: coordinating procalcitonin testing with the researchers’ manuscript preparation. Y.-H.H.C.: statistical analysis and manuscript preparation. H.R.V.: manuscript preparation. J.E.B.: grant and IRB application, study protocol and design, patient enrollment and consent, data collection, and manuscript preparation. Correspondence and requests for reprints should be addressed to Janis E. Blair, M.D., Division of Infectious Diseases, Mayo Clinic Hospital, 5777 E Mayo Blvd, Phoenix, AZ 85054. E-mail: [email protected] Ann Am Thorac Soc Vol 11, No 8, pp 1239–1243, Oct 2014 Copyright © 2014 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201404-180BC Internet address: www.atsjournals.org
Growing evidence supports the use of procalcitonin as a biomarker to reliably predict lower respiratory tract infections (RTIs) with an underlying bacterial etiology. Procalcitonin is a precursor hormone to calcitonin that becomes elevated in bacterial but not in viral infections (1–3). Such information can be useful in determining (1) which patients may benefit from antibacterial treatment and (2) the duration of antibacterial therapy for RTIs (4–6). Algorithmic approaches to RTIs using procalcitonin rely on data from randomized
controlled trials (4, 5). Their application has resulted in less antibiotic initiation and shorter duration of antimicrobial therapy without significant negative effects on outcomes (4, 5, 7). Proinflammatory mediators specific to bacterial infections, particularly IL-1b, tumor necrosis factor, and IL-6, stimulate the release of procalcitonin (8). Many tissues and organs synthesize and release procalcitonin in the presence of bacterial infections or endotoxins (1, 9, 10). Conversely, in viral and coccidioidal
Sakata, Grys, Chang, et al.: Serum Procalcitonin in Coccidioidomycosis
infections, IFN-g is released, blocking procalcitonin up-regulation (1, 11). Our search of the English-language medical literature identified no studies evaluating an association between procalcitonin levels and coccidioidomycosis. Coccidioidomycosis is caused by the fungus Coccidioides, which is endemic to the southwestern United States (12). Annually, an estimated 150,000 infections are reported, 60% in Arizona (12). Coccidioidomycosis typically results from inhalation of airborne arthroconidia. An 1239
BRIEF COMMUNICATION RTI of varying intensity follows a 1- to 3-week incubation period. In Arizona, 15 to 29% of all cases of community-acquired pneumonia (CAP) are due to primary coccidioidal pneumonia (12–14). Presenting symptoms are usually indistinguishable from—and often mistaken for—those of viral and/or bacterial causes. The diagnosis of coccidioidomycosis is frequently entertained only after a prolonged clinical course or nonresponse to empiric antibacterial therapy (13). Because primary pulmonary coccidioidomycosis accounts for many cases of CAP in Arizona, we sought to determine whether procalcitonin levels might distinguish between bacterial and coccidioidal causes of pneumonia. We conducted a prospective pilot study to measure serum procalcitonin levels in patients with primary pulmonary coccidioidomycosis. Some of the results of this study have been reported previously in the form of an abstract (15).
serologic or microbiologic results. Eligible patients were contacted for possible participation. Table 1 summarizes study inclusion and exclusion criteria. A study investigator interviewed participants to document active symptoms within 24 hours of phlebotomy by telephone or in face-toface interviews. Patients on antifungal therapy when the procalcitonin assay was performed were included if they otherwise met inclusion criteria. Patients who received corticosteroid therapy were not excluded. Patients were recruited and enrolled from inpatient and outpatient settings and provided informed consent. This study was approved by the Mayo Clinic Institutional Review Board. A one-time blood draw for procalcitonin was performed. We abstracted the following data from the patient history and medical records: demographics, clinical illness details (including symptoms and physical findings), diagnostic evaluation results (including serology, microbiology, and radiography results), and treatment (including antibacterial or antifungal antimicrobials).
Methods
Definitions
Our tertiary care academic medical institution is in Maricopa County, Arizona, an area highly endemic for Coccidioides posadasii. Prospective patients were identified by referring providers (primary medical practitioners or infectious diseases or pulmonary medicine specialists) or by reviewing medical records of patients at our institution who had positive coccidioidal
The a priori definitions of inclusion criteria matched those of the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group for invasive fungal infections (16). Patients were considered to have proven coccidioidomycosis with a positive fungal culture, cytology, or histopathology specimen. Probable infection required three conditions:
Table 1. Inclusion and exclusion criteria for pilot study of association between serum procalcitonin levels and acute primary pulmonary coccidioidomycosis Inclusion Criteria
Exclusion Criteria
Age > 18 yr Receipt of any of the following immunosuppressive agents: therapeutic Proven or probable pulmonary interferon preparations, tumor necrosis coccidioidomycosis factor and interleukin inhibitors, At least one symptom* of chemotherapy, azathioprine, methotrexate, coccidioidomycosis, in addition to fatigue, calcineurin inhibitors, or mycophenolate manifested at the time of phlebotomy mofetil Time from symptom onset to procalcitonin ANC , 1,000 cells/mm3 blood draw of < 8 wk Concurrent or recent† bacterial infection Unable or unwilling to provide consent Definition of abbreviation: ANC = absolute neutrophil count. *Symptoms included (but were not limited to) fever, chills, night sweats, anorexia, weight loss, cough, dyspnea, chest or other infection-related pain, headache, swelling, and rash. † Defined as duration of < 4 wk.
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compatible symptoms, positive serology, and typical radiographic abnormalities. Positive serology required coccidioidal IgG by any methodology (complement fixation, immunodiffusion, or enzyme immunoassay) or IgM by immunodiffusion. An isolated IgM seropositivity by enzyme immunoassay was considered insufficient evidence of seropositivity because of concerns about potential false positivity (17, 18). After phlebotomy, serum was separated from blood and stored at 2708 C until procalcitonin was measured using the miniVIDAS BRAHMS PCT (bioM´erieux Inc., Durham, NC) assay on the miniVIDAS analyzer per the manufacturer’s instructions. This test is approved by the U.S. Food and Drug Administration to aid in the diagnosis of sepsis, with values of > 0.50 mg/L indicating increased risk of severe sepsis or septic shock (VIDAS B.R.A.H.M.S. PCT Product Insert 30 450–1 rev 2007/08). The assay is useful for discriminating among bacterial causes of lower RTIs, with a cutoff of > 0.25 mg/L commonly indicating a bacterial cause (4, 5). Simple statistical descriptive measurements were used. The primary end point was estimation of the proportion (with 95% CIs) of patients with nonbacterial procalcitonin values (, 0.25 mg/L).
Results A total of 274 patients with positive coccidioidomycosis serology between January 1, 2013 and January 31, 2014 were identified from our institution; nine patients met study inclusion criteria. Thirteen other patients were referred from inpatient and outpatient providers at our institution, for a total of 22 initially eligible. Two patients were later excluded because they met exclusion criteria. The final cohort (n = 20) with a diagnosis of primary pulmonary coccidioidomycosis met study inclusion criteria and provided consent (Figure 1). Table 2 summarizes key demographics and characteristics of their illness. Most patients were male (12/20 [60%]) outpatients (14/20 [70%]) with probable coccidioidomycosis (17/20 [85%]) and a median age of 62 years (range, 28–92 yr; interquartile range [IQR], 49–70 yr). Median time from symptom onset to blood draw for procalcitonin assay was 32 days (range, 17–56 d; IQR, 25–52 d).
AnnalsATS Volume 11 Number 8 | October 2014
BRIEF COMMUNICATION
13 Patients referred from inpatient and outpatient providers
274 Patients identified with positive coccidioidomycosis serology 265 Patients excluded • Onset of symptoms to procalcitonin assay >8 weeks • Immunosuppressive medication • Asymptomatic • Preimmunosuppressive therapy surveillance testing • Absence of compatible radiographic findings • Chronic coccidioidal infection surveillance serologic results
13 Patients met study inclusion criteria
9 Patients met study inclusion criteria
22 Patients eligible for study inclusion 2 Patients excluded • Immunosuppressive medication • Onset of symptoms to procalcitonin assay >8 weeks 20 Patients consented for enrollment and had serum procalcitonin assays
Figure 1. Flowchart of patient screening and enrollment in pilot study of serum procalcitonin levels in patients with primary pulmonary coccidioidomycosis.
The time from symptom onset to phlebotomy in patients with detectable and undetectable procalcitonin was 17 to 30 days (median, 19.5 d; IQR, 18–25 d) and 18 to 56 days (median, 39.5 d; IQR, 28–54 d), respectively. There was no statistically significant difference between patients with detectable and undetectable procalcitonin who underwent phlebotomy , 30 days from symptom onset (3/4 [75%] and 5/16 [31%], respectively; P =0.26 by Fisher exact test). Other than fatigue, cough was the most common (13/20 [65%]) symptom at the time of the procalcitonin test. All patients had radiographic findings consistent with pneumonia. Before diagnosis with pulmonary coccidioidomycosis, 17 patients (85%) had a presumptive diagnosis of CAP or unspecified RTI. Fourteen patients (70%) received at least one course of empiric antibacterial therapy before diagnosis of coccidioidomycosis. The procalcitonin levels ranged from , 0.05 mg/L to 0.87 mg/L (median, 0.05 mg/L; IQR, 0.05–0.05 mg/L). Nineteen patients (95%) had levels , 0.25 mg/L. Sixteen patients (80%) had undetectable procalcitonin (, 0.05 mg/L, the limit of
detection), and one patient had a level of 0.87 mg/L. The four patients with detectable procalcitonin had a median level of 0.2 mg/L (range, 0.09–0.87 mg/L). Fourteen patients (70%) were on fluconazole when the procalcitonin assay was conducted; 13 were treated orally with fluconazole 400 mg/d. Median time from fluconazole initiation to procalcitonin assay was 9.5 days (range, 1–30 d; IQR, 7–16 d). Twelve of 14 treated patients had undetectable procalcitonin (, 0.05 mg/L). The two patients with detectable procalcitonin had levels of 0.22 and 0.87 mg/L. The six patients not on fluconazole had procalcitonin levels of , 0.25 mg/L. Two patients had detectable procalcitonin levels of 0.09 and 0.18 mg/L.
Discussion Pulmonary coccidioidomycosis is commonly acquired through inhalation of airborne Coccidioides arthroconidia. Similar to viral or bacterial illnesses, coccidioidomycosis produces a wide spectrum of nonspecific symptoms, and
Sakata, Grys, Chang, et al.: Serum Procalcitonin in Coccidioidomycosis
distinguishing it from other respiratory illnesses is difficult early on. In Arizona, Coccidioides accounts for about one fourth of CAP cases (12–14). Nonetheless, clinicians frequently do not consider the diagnosis when patients initially present with RTI signs and symptoms (13). Chang and colleagues (14) and Valdivia and colleagues (19) have reported that up to 81% of persons with coccidioidomycosis may receive unnecessary empiric antibacterial therapy, which increases the risk of antibioticrelated complications and adverse effects, the emergence of multidrug-resistant pathogens, and increased health care costs (20). Our preliminary data indicate that procalcitonin may help discriminate coccidioidal from bacterial causes of CAP and thus may reduce unnecessary use of antibiotics (5), although further study in a larger cohort is required. The diagnosis of coccidioidomycosis is problematic, especially in early infection, when the typical dry cough impedes obtaining sputum for culture and when inadequate time has passed for a serologic response. Serologic testing has long been used for the diagnosis of coccidioidomycosis (21, 22). The most 1241
BRIEF COMMUNICATION Table 2. Characteristics of 20 patients with primary pulmonary coccidioidomycosis who had serum procalcitonin assays Characteristic Age, yr Median IQR Range Sex Male Female Treatment setting Outpatient Inpatient Diagnosis Proven Highly probable Time from symptom onset to phlebotomy, d Median IQR Range Symptoms† Cough Fatigue Dyspnea Chest pain Positive serology at time of procalcitonin assay EIA IgM EIA IgG ID IgM ID IgG CF‡ Peripheral eosinophilia Detectable procalcitonin Undetectable procalcitonin Prior diagnosis of CAP or unspecified respiratory infection Antibiotics Empiric antibiotics >2 courses of antibiotics Chest radiographs Nonspecific opacity Consolidation Chest CT Consolidation Cavitation
No. (%)*
62 49–70 28–92 12 (60) 8 (40) 14 (70) 6 (30) 3 (15) 17 (85) 32 25–52 17–56 13 8 5 5
(65) (40) (25) (25)
17 19 7 8 8 12 2/4 10/16 17
(85) (95) (35) (40) (40) (60) (50) (63) (85)
14 8 18 9 7 10 7 4
(70) (40) (90) (50)
Definition of abbreviations: CAP = communityacquired pneumonia; CF = complement fixation; CT = computed tomography; EIA = enzyme immunoassay; ID = immunodiffusion; IQR = interquartile range. *Values are number (percentage) unless indicated otherwise. † The mean number of symptoms was 2. ‡ The range of CF titers was 1:2 to 1:32.
commonly used methods include enzyme immunoassay (IgM and IgG), immunodiffusion (IgM and IgG), and complement fixation (IgG). These assays have poor sensitivity for detection of Coccidioides in early stages (23); thus, 1242
finding alternate means of correctly identifying coccidioidomycosis early on is a high priority for future research. Recently, serum procalcitonin has been studied rigorously in patients with bacterial or viral RTIs. We undertook this study to assess its value in patients with pulmonary coccidioidomycosis. The nonbacterial range cutoff of , 0.25 mg/L was based on published clinical algorithms on procalcitonin in RTIs (4, 5). Nineteen of 20 patients had procalcitonin in the nonbacterial range. The median time from symptom onset to phlebotomy was 32 days. A recent study documented the median time from symptom onset to 50% reduction and to complete resolution in treated and nontreated patients as 9.9 and 9.1 weeks, respectively, and as 18.7 and 17.8 weeks, respectively (24). Thus, identifying patients with coccidioidal illness within 32 days from symptom onset is early in the course of infection. In addition, our cohort included four patients with a procalcitonin assay performed < 21 days from symptom onset (i.e., even earlier in infection), and all four patients had procalcitonin levels of , 0.25 mg/L. Whether identifying these patients earlier than 21 days into their clinical course would have changed the procalcitonin levels is unknown. One 92-year-old woman had an elevated procalcitonin of 0.87 mg/L on Day 30 of her coccidioidal illness. She was hospitalized at another hospital for 7 days after presenting with dyspnea, fever, and bilateral infiltrates on chest radiographs. She was diagnosed with CAP and discharged on a 10-day course of azithromycin and cefaclor. She presented to our hospital 2 days later with new confusion and continued dyspnea and fever. On hospital Day 2, her coccidioidomycosis was diagnosed after positive IgM and IgG by enzyme immunoassay, and treatment was initiated. Three of the four patients with detectable procalcitonin were hospitalized. The only common finding among these patients was that their time from symptom onset to procalcitonin assay was < 30 days. At the time of the procalcitonin assay, these three patients had recently undergone placement of catheters, intravenous lines, invasive procedures, or instrumentation; whether such instrumentation, or its accompaniment by an occult bacterial infection, influenced their procalcitonin levels is not known. Three other inpatients had undetectable procalcitonin.
Cell-mediated immunity plays a critical role in the host defense against Coccidioides, as evidenced by the increased risk of severe coccidioidomycosis among patients with depressed cellular immune function (11, 25). Induction of the T-helper type 1–associated immune response to produce IFN-g and other cytokines protects against coccidioidomycosis (11). IFN-g impedes procalcitonin up-regulation (1). Thus, low procalcitonin in symptomatic patients with active coccidioidomycosis is consistent with a T-helper type 1 response. The procalcitonin response in immunocompromised hosts is not well defined. One study demonstrated decreases in positive and negative predictive values of procalcitonin with severe neutropenia (26). Thus, we excluded any patients with an absolute neutrophil account of , 1,000 cells/mm3. Whether procalcitonin is useful in distinguishing coccidioidal from bacterial RTIs in immunosuppressed patients requires research. Our study had several limitations. First, this study had a small sample size. Second, the use of serologic tests for diagnosis delays recognition (and inclusion) of patients with coccidioidomycosis. Thus, the earliest time from symptom onset to procalcitonin assay was 17 days. Whether procalcitonin is higher earlier on is not known. In addition, 14 patients (70%) were on antifungal therapy when the procalcitonin assay was conducted, and its effect on procalcitonin in patients with coccidioidomycosis is not known. Furthermore, patients who received empiric antibacterial therapy were enrolled in the study. Although unlikely, antibacterial therapy may have masked a potential recent undetected bacterial infection.
Conclusions In this small pilot study, our data identified the possibility that patients with proven or probable active pulmonary coccidioidal infection do not have elevated procalcitonin a median of 32 days after symptom onset. Larger prospective studies are needed to confirm this trend and to assess the utility of procalcitonin in early primary pulmonary coccidioidomycosis when the sensitivity of coccidioidal serologic tests is low. n Author disclosures are available with the text of this article at www.atsjournals.org.
AnnalsATS Volume 11 Number 8 | October 2014
BRIEF COMMUNICATION References 1 Linscheid P, Seboek D, Nylen ES, Langer I, Schlatter M, Becker KL, Keller U, Muller ¨ B. In vitro and in vivo calcitonin I gene expression in parenchymal cells: a novel product of human adipose tissue. Endocrinology 2003;144:5578–5584. 2 Chua AP, Lee KH. Procalcitonin in severe acute respiratory syndrome (SARS). J Infect 2004;48:303–306. 3 Cuquemelle E, Soulis F, Villers D, Roche-Campo F, Ara Somohano C, Fartoukh M, Kouatchet A, Mourvillier B, Dellamonica J, Picard W, et al.; A/H1N1 REVA-SRLF Study Group. Can procalcitonin help identify associated bacterial infection in patients with severe influenza pneumonia? A multicentre study. Intensive Care Med 2011; 37:796–800. 4 Schuetz P, Amin DN, Greenwald JL. Role of procalcitonin in managing adult patients with respiratory tract infections. Chest 2012;141: 1063–1073. 5 Schuetz P, Chiappa V, Briel M, Greenwald JL. Procalcitonin algorithms for antibiotic therapy decisions: a systematic review of randomized controlled trials and recommendations for clinical algorithms. Arch Intern Med 2011;171:1322–1331. 6 Schuetz P, Christ-Crain M, Thomann R, Falconnier C, Wolbers M, Widmer I, Neidert S, Fricker T, Blum C, Schild U, et al.; ProHOSP Study Group. Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 2009;302:1059–1066. 7 Soni NJ, Samson DJ, Galaydick JL, Vats V, Huang ES, Aronson N, Pitrak DL. Procalcitonin-guided antibiotic therapy: a systematic review and meta-analysis. J Hosp Med 2013;8:530–540. 8 Becker KL, Nylen ´ ES, White JC, Muller ¨ B, Snider RH Jr. Clinical review 167: Procalcitonin and the calcitonin gene family of peptides in inflammation, infection, and sepsis: a journey from calcitonin back to its precursors. J Clin Endocrinol Metab 2004;89:1512–1525. 9 Morgenthaler NG, Struck J, Chancerelle Y, Weglohner ¨ W, Agay D, Bohuon C, Suarez-Domenech V, Bergmann A, Muller ¨ B. Production of procalcitonin (PCT) in non-thyroidal tissue after LPS injection. Horm Metab Res 2003;35:290–295. 10 Muller ¨ B, White JC, Nylen ´ ES, Snider RH, Becker KL, Habener JF. Ubiquitous expression of the calcitonin-i gene in multiple tissues in response to sepsis. J Clin Endocrinol Metab 2001;86:396–404. 11 Cox RA, Magee DM. Coccidioidomycosis: host response and vaccine development. Clin Microbiol Rev 2004;17:804–839. 12 Sunenshine RH, Anderson S, Erhart L, Vossbrink A, Kelly PC, Engelthaler D, Komatsu K. Public health surveillance for coccidioidomycosis in Arizona. Ann N Y Acad Sci 2007;1111: 96–102. 13 Kim MM, Blair JE, Carey EJ, Wu Q, Smilack JD. Coccidioidal pneumonia, Phoenix, Arizona, USA, 2000-2004. Emerg Infect Dis 2009;15:397–401.
14 Chang DC, Anderson S, Wannemuehler K, Engelthaler DM, Erhart L, Sunenshine RH, Burwell LA, Park BJ. Testing for coccidioidomycosis among patients with community-acquired pneumonia. Emerg Infect Dis 2008;14:1053–1059. 15 Sakata KK, Grys TE, Chang Y-H, Vikram H, Blair J. Serum procalcitonin levels in acute coccidioidomycosis infections [abstract]. Am J Respir Crit Care Med 2014;189:A1694. 16 De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, Pappas PG, Maertens J, Lortholary O, Kauffman CA, et al.; European Organization for Research and Treatment of Cancer/ Invasive Fungal Infections Cooperative Group; National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/ MSG) Consensus Group. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008;46: 1813–1821. 17 Blair JE, Currier JT. Significance of isolated positive IgM serologic results by enzyme immunoassay for coccidioidomycosis. Mycopathologia 2008;166:77–82. 18 Kuberski T, Herrig J, Pappagianis D. More false-positive immunoglobulin (Ig) M antibody test results: coccidioidomycosis. In Literature 2010;51:i–iv. 19 Valdivia L, Nix D, Wright M, Lindberg E, Fagan T, Lieberman D, Stoffer T, Ampel NM, Galgiani JN. Coccidioidomycosis as a common cause of community-acquired pneumonia. Emerg Infect Dis 2006;12: 958–962. 20 Roberts RR, Hota B, Ahmad I, Scott RD II, Foster SD, Abbasi F, Schabowski S, Kampe LM, Ciavarella GG, Supino M, et al. Hospital and societal costs of antimicrobial-resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship. Clin Infect Dis 2009;49:1175–1184. 21 Pappagianis D, Zimmer BL. Serology of coccidioidomycosis. Clin Microbiol Rev 1990;3:247–268. 22 Pappagianis D. Serologic studies in coccidioidomycosis. Semin Respir Infect 2001;16:242–250. 23 Blair JE, Coakley B, Santelli AC, Hentz JG, Wengenack NL. Serologic testing for symptomatic coccidioidomycosis in immunocompetent and immunosuppressed hosts. Mycopathologia 2006;162:317–324. 24 Blair JE, Chang YH, Cheng MR, Vaszar LT, Vikram HR, Orenstein R, Kusne S, Ho S, Seville MT, Parish JM. Characteristics of patients with mild to moderate primary pulmonary coccidioidomycosis. Emerg Infect Dis 2014;20:983–990. 25 Blair JE, Logan JL. Coccidioidomycosis in solid organ transplantation. Clin Infect Dis 2001;33:1536–1544. 26 Svaldi M, Hirber J, Lanthaler AI, Mayr O, Faes S, Peer E, Mitterer M. Procalcitonin-reduced sensitivity and specificity in heavily leucopenic and immunosuppressed patients. Br J Haematol 2001; 115:53–57.
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Departments of Internal Medicine and 2Biostatistics, Mayo Clinic, Scottsdale, Arizona; and 3Department of Laboratory Medicine and Pathology and 4Division of Infectious Diseases, Mayo Clinic Hospital, Phoenix, Arizona
Abstract Rationale: The serum procalcitonin assay has emerged as a promising biomarker to distinguish between bacterial and viral respiratory tract infections but has not been used to differentiate coccidioidomycosis from bacterial infection. A correlation between procalcitonin serum levels and coccidioidomycosis has never been reported. Objective: To determine any association between serum procalcitonin levels and primary pulmonary coccidioidomycosis. Methods: We identified and enrolled 20 immunocompetent patients with symptomatic primary pulmonary coccidioidomycosis of , 8 weeks’ duration and performed a one-time procalcitonin assay, with a cutoff of , 0.25 mg/L indicating a nonbacterial infection.
Measurements and Main Results: Nineteen of 20 patients (95%) had serum procalcitonin of , 0.25 mg/L. The median procalcitonin level was 0.05 mg/L (range, , 0.05–0.87 mg/L; interquartile range, 0.05–0.05 mg/L). Sixteen of 20 patients (80%) had undetectable procalcitonin of , 0.05 mg/L. The four patients with detectable procalcitonin had a median value of 0.2 mg/L (range, 0.09–0.87 mg/L). Conclusions: In this pilot study, procalcitonin was not elevated in immunocompetent patients with primary pulmonary coccidioidomycosis at a median of 32 days after symptom onset. Larger prospective studies are needed to confirm this finding. Keywords: coccidioidomycosis; community-acquired pneumonia; immunocompetent; procalcitonin; respiratory tract infections
(Received in original form April 28, 2014; accepted in final form August 1, 2014 ) This work was supported by funds from the Mayo Clinic. Author Contributions: K.K.S.: grant and IRB application, study protocol and design, patient consent and enrollment, data collection, and manuscript preparation. T.E.G.: coordinating procalcitonin testing with the researchers’ manuscript preparation. Y.-H.H.C.: statistical analysis and manuscript preparation. H.R.V.: manuscript preparation. J.E.B.: grant and IRB application, study protocol and design, patient enrollment and consent, data collection, and manuscript preparation. Correspondence and requests for reprints should be addressed to Janis E. Blair, M.D., Division of Infectious Diseases, Mayo Clinic Hospital, 5777 E Mayo Blvd, Phoenix, AZ 85054. E-mail: [email protected] Ann Am Thorac Soc Vol 11, No 8, pp 1239–1243, Oct 2014 Copyright © 2014 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201404-180BC Internet address: www.atsjournals.org
Growing evidence supports the use of procalcitonin as a biomarker to reliably predict lower respiratory tract infections (RTIs) with an underlying bacterial etiology. Procalcitonin is a precursor hormone to calcitonin that becomes elevated in bacterial but not in viral infections (1–3). Such information can be useful in determining (1) which patients may benefit from antibacterial treatment and (2) the duration of antibacterial therapy for RTIs (4–6). Algorithmic approaches to RTIs using procalcitonin rely on data from randomized
controlled trials (4, 5). Their application has resulted in less antibiotic initiation and shorter duration of antimicrobial therapy without significant negative effects on outcomes (4, 5, 7). Proinflammatory mediators specific to bacterial infections, particularly IL-1b, tumor necrosis factor, and IL-6, stimulate the release of procalcitonin (8). Many tissues and organs synthesize and release procalcitonin in the presence of bacterial infections or endotoxins (1, 9, 10). Conversely, in viral and coccidioidal
Sakata, Grys, Chang, et al.: Serum Procalcitonin in Coccidioidomycosis
infections, IFN-g is released, blocking procalcitonin up-regulation (1, 11). Our search of the English-language medical literature identified no studies evaluating an association between procalcitonin levels and coccidioidomycosis. Coccidioidomycosis is caused by the fungus Coccidioides, which is endemic to the southwestern United States (12). Annually, an estimated 150,000 infections are reported, 60% in Arizona (12). Coccidioidomycosis typically results from inhalation of airborne arthroconidia. An 1239
BRIEF COMMUNICATION RTI of varying intensity follows a 1- to 3-week incubation period. In Arizona, 15 to 29% of all cases of community-acquired pneumonia (CAP) are due to primary coccidioidal pneumonia (12–14). Presenting symptoms are usually indistinguishable from—and often mistaken for—those of viral and/or bacterial causes. The diagnosis of coccidioidomycosis is frequently entertained only after a prolonged clinical course or nonresponse to empiric antibacterial therapy (13). Because primary pulmonary coccidioidomycosis accounts for many cases of CAP in Arizona, we sought to determine whether procalcitonin levels might distinguish between bacterial and coccidioidal causes of pneumonia. We conducted a prospective pilot study to measure serum procalcitonin levels in patients with primary pulmonary coccidioidomycosis. Some of the results of this study have been reported previously in the form of an abstract (15).
serologic or microbiologic results. Eligible patients were contacted for possible participation. Table 1 summarizes study inclusion and exclusion criteria. A study investigator interviewed participants to document active symptoms within 24 hours of phlebotomy by telephone or in face-toface interviews. Patients on antifungal therapy when the procalcitonin assay was performed were included if they otherwise met inclusion criteria. Patients who received corticosteroid therapy were not excluded. Patients were recruited and enrolled from inpatient and outpatient settings and provided informed consent. This study was approved by the Mayo Clinic Institutional Review Board. A one-time blood draw for procalcitonin was performed. We abstracted the following data from the patient history and medical records: demographics, clinical illness details (including symptoms and physical findings), diagnostic evaluation results (including serology, microbiology, and radiography results), and treatment (including antibacterial or antifungal antimicrobials).
Methods
Definitions
Our tertiary care academic medical institution is in Maricopa County, Arizona, an area highly endemic for Coccidioides posadasii. Prospective patients were identified by referring providers (primary medical practitioners or infectious diseases or pulmonary medicine specialists) or by reviewing medical records of patients at our institution who had positive coccidioidal
The a priori definitions of inclusion criteria matched those of the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group for invasive fungal infections (16). Patients were considered to have proven coccidioidomycosis with a positive fungal culture, cytology, or histopathology specimen. Probable infection required three conditions:
Table 1. Inclusion and exclusion criteria for pilot study of association between serum procalcitonin levels and acute primary pulmonary coccidioidomycosis Inclusion Criteria
Exclusion Criteria
Age > 18 yr Receipt of any of the following immunosuppressive agents: therapeutic Proven or probable pulmonary interferon preparations, tumor necrosis coccidioidomycosis factor and interleukin inhibitors, At least one symptom* of chemotherapy, azathioprine, methotrexate, coccidioidomycosis, in addition to fatigue, calcineurin inhibitors, or mycophenolate manifested at the time of phlebotomy mofetil Time from symptom onset to procalcitonin ANC , 1,000 cells/mm3 blood draw of < 8 wk Concurrent or recent† bacterial infection Unable or unwilling to provide consent Definition of abbreviation: ANC = absolute neutrophil count. *Symptoms included (but were not limited to) fever, chills, night sweats, anorexia, weight loss, cough, dyspnea, chest or other infection-related pain, headache, swelling, and rash. † Defined as duration of < 4 wk.
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compatible symptoms, positive serology, and typical radiographic abnormalities. Positive serology required coccidioidal IgG by any methodology (complement fixation, immunodiffusion, or enzyme immunoassay) or IgM by immunodiffusion. An isolated IgM seropositivity by enzyme immunoassay was considered insufficient evidence of seropositivity because of concerns about potential false positivity (17, 18). After phlebotomy, serum was separated from blood and stored at 2708 C until procalcitonin was measured using the miniVIDAS BRAHMS PCT (bioM´erieux Inc., Durham, NC) assay on the miniVIDAS analyzer per the manufacturer’s instructions. This test is approved by the U.S. Food and Drug Administration to aid in the diagnosis of sepsis, with values of > 0.50 mg/L indicating increased risk of severe sepsis or septic shock (VIDAS B.R.A.H.M.S. PCT Product Insert 30 450–1 rev 2007/08). The assay is useful for discriminating among bacterial causes of lower RTIs, with a cutoff of > 0.25 mg/L commonly indicating a bacterial cause (4, 5). Simple statistical descriptive measurements were used. The primary end point was estimation of the proportion (with 95% CIs) of patients with nonbacterial procalcitonin values (, 0.25 mg/L).
Results A total of 274 patients with positive coccidioidomycosis serology between January 1, 2013 and January 31, 2014 were identified from our institution; nine patients met study inclusion criteria. Thirteen other patients were referred from inpatient and outpatient providers at our institution, for a total of 22 initially eligible. Two patients were later excluded because they met exclusion criteria. The final cohort (n = 20) with a diagnosis of primary pulmonary coccidioidomycosis met study inclusion criteria and provided consent (Figure 1). Table 2 summarizes key demographics and characteristics of their illness. Most patients were male (12/20 [60%]) outpatients (14/20 [70%]) with probable coccidioidomycosis (17/20 [85%]) and a median age of 62 years (range, 28–92 yr; interquartile range [IQR], 49–70 yr). Median time from symptom onset to blood draw for procalcitonin assay was 32 days (range, 17–56 d; IQR, 25–52 d).
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13 Patients referred from inpatient and outpatient providers
274 Patients identified with positive coccidioidomycosis serology 265 Patients excluded • Onset of symptoms to procalcitonin assay >8 weeks • Immunosuppressive medication • Asymptomatic • Preimmunosuppressive therapy surveillance testing • Absence of compatible radiographic findings • Chronic coccidioidal infection surveillance serologic results
13 Patients met study inclusion criteria
9 Patients met study inclusion criteria
22 Patients eligible for study inclusion 2 Patients excluded • Immunosuppressive medication • Onset of symptoms to procalcitonin assay >8 weeks 20 Patients consented for enrollment and had serum procalcitonin assays
Figure 1. Flowchart of patient screening and enrollment in pilot study of serum procalcitonin levels in patients with primary pulmonary coccidioidomycosis.
The time from symptom onset to phlebotomy in patients with detectable and undetectable procalcitonin was 17 to 30 days (median, 19.5 d; IQR, 18–25 d) and 18 to 56 days (median, 39.5 d; IQR, 28–54 d), respectively. There was no statistically significant difference between patients with detectable and undetectable procalcitonin who underwent phlebotomy , 30 days from symptom onset (3/4 [75%] and 5/16 [31%], respectively; P =0.26 by Fisher exact test). Other than fatigue, cough was the most common (13/20 [65%]) symptom at the time of the procalcitonin test. All patients had radiographic findings consistent with pneumonia. Before diagnosis with pulmonary coccidioidomycosis, 17 patients (85%) had a presumptive diagnosis of CAP or unspecified RTI. Fourteen patients (70%) received at least one course of empiric antibacterial therapy before diagnosis of coccidioidomycosis. The procalcitonin levels ranged from , 0.05 mg/L to 0.87 mg/L (median, 0.05 mg/L; IQR, 0.05–0.05 mg/L). Nineteen patients (95%) had levels , 0.25 mg/L. Sixteen patients (80%) had undetectable procalcitonin (, 0.05 mg/L, the limit of
detection), and one patient had a level of 0.87 mg/L. The four patients with detectable procalcitonin had a median level of 0.2 mg/L (range, 0.09–0.87 mg/L). Fourteen patients (70%) were on fluconazole when the procalcitonin assay was conducted; 13 were treated orally with fluconazole 400 mg/d. Median time from fluconazole initiation to procalcitonin assay was 9.5 days (range, 1–30 d; IQR, 7–16 d). Twelve of 14 treated patients had undetectable procalcitonin (, 0.05 mg/L). The two patients with detectable procalcitonin had levels of 0.22 and 0.87 mg/L. The six patients not on fluconazole had procalcitonin levels of , 0.25 mg/L. Two patients had detectable procalcitonin levels of 0.09 and 0.18 mg/L.
Discussion Pulmonary coccidioidomycosis is commonly acquired through inhalation of airborne Coccidioides arthroconidia. Similar to viral or bacterial illnesses, coccidioidomycosis produces a wide spectrum of nonspecific symptoms, and
Sakata, Grys, Chang, et al.: Serum Procalcitonin in Coccidioidomycosis
distinguishing it from other respiratory illnesses is difficult early on. In Arizona, Coccidioides accounts for about one fourth of CAP cases (12–14). Nonetheless, clinicians frequently do not consider the diagnosis when patients initially present with RTI signs and symptoms (13). Chang and colleagues (14) and Valdivia and colleagues (19) have reported that up to 81% of persons with coccidioidomycosis may receive unnecessary empiric antibacterial therapy, which increases the risk of antibioticrelated complications and adverse effects, the emergence of multidrug-resistant pathogens, and increased health care costs (20). Our preliminary data indicate that procalcitonin may help discriminate coccidioidal from bacterial causes of CAP and thus may reduce unnecessary use of antibiotics (5), although further study in a larger cohort is required. The diagnosis of coccidioidomycosis is problematic, especially in early infection, when the typical dry cough impedes obtaining sputum for culture and when inadequate time has passed for a serologic response. Serologic testing has long been used for the diagnosis of coccidioidomycosis (21, 22). The most 1241
BRIEF COMMUNICATION Table 2. Characteristics of 20 patients with primary pulmonary coccidioidomycosis who had serum procalcitonin assays Characteristic Age, yr Median IQR Range Sex Male Female Treatment setting Outpatient Inpatient Diagnosis Proven Highly probable Time from symptom onset to phlebotomy, d Median IQR Range Symptoms† Cough Fatigue Dyspnea Chest pain Positive serology at time of procalcitonin assay EIA IgM EIA IgG ID IgM ID IgG CF‡ Peripheral eosinophilia Detectable procalcitonin Undetectable procalcitonin Prior diagnosis of CAP or unspecified respiratory infection Antibiotics Empiric antibiotics >2 courses of antibiotics Chest radiographs Nonspecific opacity Consolidation Chest CT Consolidation Cavitation
No. (%)*
62 49–70 28–92 12 (60) 8 (40) 14 (70) 6 (30) 3 (15) 17 (85) 32 25–52 17–56 13 8 5 5
(65) (40) (25) (25)
17 19 7 8 8 12 2/4 10/16 17
(85) (95) (35) (40) (40) (60) (50) (63) (85)
14 8 18 9 7 10 7 4
(70) (40) (90) (50)
Definition of abbreviations: CAP = communityacquired pneumonia; CF = complement fixation; CT = computed tomography; EIA = enzyme immunoassay; ID = immunodiffusion; IQR = interquartile range. *Values are number (percentage) unless indicated otherwise. † The mean number of symptoms was 2. ‡ The range of CF titers was 1:2 to 1:32.
commonly used methods include enzyme immunoassay (IgM and IgG), immunodiffusion (IgM and IgG), and complement fixation (IgG). These assays have poor sensitivity for detection of Coccidioides in early stages (23); thus, 1242
finding alternate means of correctly identifying coccidioidomycosis early on is a high priority for future research. Recently, serum procalcitonin has been studied rigorously in patients with bacterial or viral RTIs. We undertook this study to assess its value in patients with pulmonary coccidioidomycosis. The nonbacterial range cutoff of , 0.25 mg/L was based on published clinical algorithms on procalcitonin in RTIs (4, 5). Nineteen of 20 patients had procalcitonin in the nonbacterial range. The median time from symptom onset to phlebotomy was 32 days. A recent study documented the median time from symptom onset to 50% reduction and to complete resolution in treated and nontreated patients as 9.9 and 9.1 weeks, respectively, and as 18.7 and 17.8 weeks, respectively (24). Thus, identifying patients with coccidioidal illness within 32 days from symptom onset is early in the course of infection. In addition, our cohort included four patients with a procalcitonin assay performed < 21 days from symptom onset (i.e., even earlier in infection), and all four patients had procalcitonin levels of , 0.25 mg/L. Whether identifying these patients earlier than 21 days into their clinical course would have changed the procalcitonin levels is unknown. One 92-year-old woman had an elevated procalcitonin of 0.87 mg/L on Day 30 of her coccidioidal illness. She was hospitalized at another hospital for 7 days after presenting with dyspnea, fever, and bilateral infiltrates on chest radiographs. She was diagnosed with CAP and discharged on a 10-day course of azithromycin and cefaclor. She presented to our hospital 2 days later with new confusion and continued dyspnea and fever. On hospital Day 2, her coccidioidomycosis was diagnosed after positive IgM and IgG by enzyme immunoassay, and treatment was initiated. Three of the four patients with detectable procalcitonin were hospitalized. The only common finding among these patients was that their time from symptom onset to procalcitonin assay was < 30 days. At the time of the procalcitonin assay, these three patients had recently undergone placement of catheters, intravenous lines, invasive procedures, or instrumentation; whether such instrumentation, or its accompaniment by an occult bacterial infection, influenced their procalcitonin levels is not known. Three other inpatients had undetectable procalcitonin.
Cell-mediated immunity plays a critical role in the host defense against Coccidioides, as evidenced by the increased risk of severe coccidioidomycosis among patients with depressed cellular immune function (11, 25). Induction of the T-helper type 1–associated immune response to produce IFN-g and other cytokines protects against coccidioidomycosis (11). IFN-g impedes procalcitonin up-regulation (1). Thus, low procalcitonin in symptomatic patients with active coccidioidomycosis is consistent with a T-helper type 1 response. The procalcitonin response in immunocompromised hosts is not well defined. One study demonstrated decreases in positive and negative predictive values of procalcitonin with severe neutropenia (26). Thus, we excluded any patients with an absolute neutrophil account of , 1,000 cells/mm3. Whether procalcitonin is useful in distinguishing coccidioidal from bacterial RTIs in immunosuppressed patients requires research. Our study had several limitations. First, this study had a small sample size. Second, the use of serologic tests for diagnosis delays recognition (and inclusion) of patients with coccidioidomycosis. Thus, the earliest time from symptom onset to procalcitonin assay was 17 days. Whether procalcitonin is higher earlier on is not known. In addition, 14 patients (70%) were on antifungal therapy when the procalcitonin assay was conducted, and its effect on procalcitonin in patients with coccidioidomycosis is not known. Furthermore, patients who received empiric antibacterial therapy were enrolled in the study. Although unlikely, antibacterial therapy may have masked a potential recent undetected bacterial infection.
Conclusions In this small pilot study, our data identified the possibility that patients with proven or probable active pulmonary coccidioidal infection do not have elevated procalcitonin a median of 32 days after symptom onset. Larger prospective studies are needed to confirm this trend and to assess the utility of procalcitonin in early primary pulmonary coccidioidomycosis when the sensitivity of coccidioidal serologic tests is low. n Author disclosures are available with the text of this article at www.atsjournals.org.
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