Candidemia in pediatric outpatients receiving home total parenteral nutrition

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1 Medical Mycology May 2005, 43, 219/225 Candidemia in pediatric outpatients receiving home total parenteral nutrition M. V. CANO*$, J. F. PERZ$%, A. S. CRAIG%, M. LIU*, G. M. LYON*$, M. E. BRANDT*, T. J. LOTT*, B. A. LASKER*, F. F. BARRETT, M. M. McNEIL*, W. SCHAFFNER% & R. A. HAJJEH* *Division of Bacterial and Mycotic Diseases and $Epidemic Intelligence Service Epidemiology Program Office, Centers for Disease Control and Prevention, Atlanta, GA, %Tennessee Department of Health, Nashville, TN, Department of Preventive Medicine, Vanderbilt University School of Medicine, Nashville, TN and University of Tennessee Health Science Center, Memphis, TN, USA Introduction This is a cohort study of pediatric outpatients receiving total parenteral nutrition (TPN) and follow-up care in a Tennessee hospital between January and June The study was conducted following an increase in the incidence of candidemia. Of 13 children receiving home TPN, five had candidemia; three were due to Candida parapsilosis. Case patients were more likely to have an underlying hematologic disease (P/ 0.02) as well as previous history of fungemia (P/ 0.02). Two case patients had successive candidemia episodes 3 months apart; karyotypes and RAPD profiles of each patient s successive C. parapsilosis isolates were similar. Candida spp. were frequently detected in hand cultures from cohort members (four of 10) and family member caregivers (nine of 11); C. parapsilosis was isolated from five caregivers. Our findings underscore the challenges of maintaining stringent infection control practices in the home health care setting and suggest the need for more intensive follow-up and coordination of home TPN therapy among pediatric patients. Keywords Candida parapsilosis has emerged as a leading cause of fungal bloodstream infection (BSI) in hospitalized children [1,2]. Outbreaks of C. parapsilosis BSI in hospitals have been associated with intravascular devices and administration of intravenous fluids and Received 20 January 2004; Accepted 8 May 2004 Correspondence: Maria V. Cano, Division of Global Migration and Quarantine, Centers for Disease Control and Prevention, Mailstop- E03, 1600 Clifton Road NE, Atlanta, GA 30333, USA. Tel: / ; Fax: / ; mcano@cdc.gov Present addresses: M. V. Cano: Division of Global Migration and Quarantine, Centers for Disease Control and Prevention, Atlanta, GA, USA. J. F. Perz: Division of Viral Hepatitis, National Centers for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA. G. M. Lyon: Infectious Disease Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. M. M. McNeil: National Immunization Program, Centers for Disease Control and Prevention, Atlanta, GA, USA. R. A. Hajjeh: US Naval Medical Research Unit, Cairo, Egypt. candidemia, outpatient, risk factors, total parenteral nutrition total parenteral nutrition (TPN) [3,4]. As a result of changes in health care delivery and advances in medical technology, infections such as fungal BSI that previously occurred almost exclusively among hospitalized patients are now increasingly evident in the community setting [5 /8]. Information on risk factors for BSI due to Candida spp. in outpatients is lacking. We sought to identify potential risk factors for candidemia in the outpatient setting by investigating an apparent cluster of C. parapsilosis BSI in pediatric outpatients receiving home TPN. Between January and June 1999, an increase in the number of C. parapsilosis BSI was noted in children who received care at a 150-bed pediatric hospital in Tennessee (Hospital A). Of five patients with C. parapsilosis BSI, three had acquired the infection as outpatients and all had received TPN through a central venous catheter at home prior to their onset of symptoms. In 1998, only one case of outpatient-acquired C. parapsilosis BSI was reported 2005 ISHAM DOI: /

2 220 Cano et al. among children receiving home TPN and follow-up care at Hospital A. Preliminary investigation by the hospital s infection control personnel suggested no epidemiologic link among the cases. An investigation was undertaken by a team from the Centers for Disease Control and Prevention (CDC) and the Tennessee Department of Health. Materials and methods Case ascertainment We sought to identify cases of outpatient candidemia occurring among pediatric patients seen in the outpatient clinics of Hospital A. Potential cases were identified by reviewing the following data sources: (i) medical records of all patients with positive blood cultures for Candida spp. detected from Hospital A microbiology laboratory data, and (ii) a list of Hospital A admissions and discharges with the diagnosis of disseminated candidiasis (ICD-9 Code 112.5). Cohort study Because all but one of the potential cases identified occurred in children receiving home TPN, we performed a cohort study of Hospital A pediatric patients (B/16 years old) receiving home TPN from 1 December 1998 through 30 June A list of all Hospital A pediatric patients receiving home TPN was obtained from the Hospital A parenteral nutrition nurses. Thirteen patients were identified and enrolled. A case was defined as BSI due to Candida spp. occurring from 1 January through 30 June 1999, in a pediatric patient in the Hospital A outpatient clinic who was not hospitalized within the previous 30 days, or was hospitalized for B/48 h. Because we were interested in examining exposures that could have occurred in the 30 days prior to infection, risk factors were examined for the period beginning on 1 December 1998 through 30 June 1999, or the date on which Candida spp. were first isolated from a blood culture. To determine risk factors for outpatient-acquired candidemia, the following information was obtained by reviewing patient medical records: demographics, medical history, underlying illnesses, medications, hospitalizations, outpatient visits, central venous lines and non-intravascular devices (e.g. gastrostomy tube, tracheostomy, ureter stent), surgical and nonsurgical invasive procedures (e.g. cardiac catheterization, bronchoscopy) and laboratory data. The Hospital A parenteral nutrition nurses were interviewed for information regarding training provided to the family in home TPN administration and central venous line care. Family members who were primarily involved in TPN administration and central line care were interviewed in their homes. Information was collected regarding procedures associated with TPN administration, maintenance of the central line for TPN, training in the administration of parenteral nutrition and infection control, educational level of the family member interviewed and the home health agency involved in follow-up care of the patients at home. Using standardized forms, we interviewed the home health agency nurses and pharmacies by telephone regarding their practices during the previous year. Information on services such as distribution of educational materials, demonstration of line care to the family members, blood draws and frequency of home visits, was obtained from the home health agency nurses. Details on preparation, storage and handling of the TPN solution and nutritional additives were obtained from the pharmacies. Environmental studies Using the handiwipe method [9], hand cultures were obtained from the patients and from family members administering home TPN and providing central line care. The patients and family members were instructed to wipe their hands with sterile handiwipes soaked in Tween-80, which were then placed in sterile containers. Culturette swabs of the central line exit site were also performed. All the samples were sent to CDC for culture and identification. A representative colony of each morphologic type of Candida was selected for species identification and molecular subtyping. C. parapsilosis isolates were subtyped by electrophoretic karyotyping (clamped homogeneous electric field and transverse alternating field electrophoresis) [10] and random amplified polymorphic DNA (RAPD) using primers PAO3, T3B, M13core and RP-2 [11]. Karyotype and RAPD patterns were analyzed using BioRad FlorS imager with Diversity database 2 TM software (Biorad Corporation, Hercules, CA). Statistical analysis Data were analyzed using Epi-Info version 6.04b (Centers for Disease Control and Prevention). Categorical variables were compared with the Fisher s exact test, while continuous variables were compared with the Wilcoxon two-sample test. Univariate analysis was performed to determine risk factors for outpatient candidemia, and relative risks (RR) and 95% confidence

3 Candidemia in pediatric outpatients 221 intervals (CI) were calculated. Multivariate analysis was not performed due to the small sample size. Results Case-patient characteristics A total of 13 pediatric patients of Hospital A were receiving home TPN. Of these, five (38%) had outpatient candidemia during the study period. Selected characteristics of the patients with candidemia are shown in Table 1. The median age was 10 years, with a range of 1 to 14 years. Except for case no. 5, all had a history of short bowel syndrome. Three of the patients had C. parapsilosis BSI, one had Candida albicans BSI, and one had a dual infection (C. albicans and Candida glabrata). Two case-patients (cases nos 1 and 3) each had successive candidemia episodes 3 months apart during the study period. In addition, cases nos 2 and 3 had prior episodes of outpatient-acquired C. parapsilosis BSI in 1997 and 1998, respectively. The median duration of hospitalization for candidemia during the study period was 15 days (range, 5/74 days). One of the patients (case no. 4) died during the study period; no information on the immediate cause of death was available. Cohort study There were no significant differences between casepatients and non-case patients with respect to age, sex, race, presence of more than one central line, number of years on TPN, prosthetic devices, medications (including antibiotics) or isolation of Candida spp. from sites other than from blood (Table 2). However, casepatients were significantly more likely than non-case patients to have an underlying hematologic disorder; all five case-patients had an underlying hematologic disorder (sickle cell trait: two; chronic thrombocytopenia: one; iron deficiency anemia: two) versus two of the eight non-case patients (Von Willebrand s disease and sickle cell trait, respectively, P/0.02). In addition, case-patients were significantly more likely to have a history of fungal BSI (P /0.02). The differences in the mean numbers of hospitalizations, hospital days and outpatient visits during the study period between casepatients and non-case patients were not statistically significant (3.4 vs 2.5 hospitalizations; 57 vs 42 hospital days; 3.4 vs 6.8 outpatient visits). Information on TPN administration and central line care was available for 12 patients (four cases and eight non-cases). Methods of TPN storage and administration (e.g. equipment used), hand washing practices, central line care and maintenance, total number of days of TPN training, educational level of the family members caring for the patients and frequency of home health agency visits did not differ significantly between the two groups. Case-patients tended to have their fingernails cut less frequently than did the noncase patients (B/once per week for 4/4 case-patients vs 3/ 8 non-cases, P / 0.08). Other activities, such as pulling or scratching the central line site by the patient, swimming, exposure to pets and frequency of hand washing and bathing did not differ significantly between case-patients and non-case patients. Instruction in TPN administration and central line care technique to the family members was provided by the Hospital A parenteral nutrition nurses before the patients were initially discharged. Family members all reported they had received adequate training in TPN administration and central line care. The number of days of training reported ranged from 1 to 21 (median 7.5 days for family members of cases and 6.0 days for family members of non-cases). The instructions Table 1 Characteristics of patients receiving home total parenteral nutrition who developed outpatient candidemia, Hospital A, Memphis, Tennessee, 1 January through 30 June 1999 Case Age (years) Sex Underlying Illnesses Candida blood culture species 1 1 M Short bowel syndrome, GERD 1, iron deficiency anemia 2 10 F Short bowel syndrome, sickle cell trait, megacystic colon, seizure disorder 3 9 F Short bowel syndrome, sickle cell trait, asthma 4 14 F Short bowel syndrome, seizure disorder thrombocytopenia 5 14 M Idiopathic intestinal pseudo-obstruction, iron deficiency anemia Length of hospitalizations (days) Outcome Candida parapsilosis 20 Survived Candida parapsilosis 15 Survived Candida parapsilosis 11 Survived Candida albicans 74 Expired Candida glabrata Candida albicans 5 Survived 1 Gastroesophageal reflux disease.

4 222 Cano et al. Table 2 Selected characteristics for cases and non-cases among the cohort of pediatric outpatients receiving home total parenteral nutrition, Hospital A, Memphis, Tennessee, 1 January through 30 June Characteristic Cases n/5 (%) Non-cases n/8 (%) RR 95% CI p Male sex 2 (40) 4 (50) / Age 5/3 years 1 (20) 4 (50) / Race Black 5 (100) 5 (62) Undefined / 0.2 White 0 3 (37) Medical history Hematologic disease 5 (100) 2 (25) Undefined / 0.02 Short bowel syndrome 4 (80) 6 (75) / Bacteremia 5 (100) 6 (75) Undefined / 0.5 Fungemia 5 (100) 2 (25) Undefined / 0.02 Other candidiasis 2 2 (40) / Gastrostomy tube 5 (100) 5 (62) Undefined / 0.2 Other non-intravascular devices 2 (40) 2 (25) / Central venous line (/1) 2 (40) 2 (25) / Blood culture positive for bacteria 2 (40) 2 (25) / Nonblood culture positive for Candida species 3 (60) 1 (12) / Antibiotic 2 (40) 3 (38) / Hospitalizations (/2) 3 (60) 3 (38) / Outpatient visits (/4) 3 (60) 4 (50) / Except for demographic data and medical history, pertains to study period. 2 Information unknown for 4 cohort members. regarding the need to observe strict aseptic technique for central line care and TPN administration were uniform for case and non-case families and consistent with current recommendations of the Centers for Disease Control Healthcare Infection Control Practices Advisory [12]. However, on specific questioning, only two family members (one for a case-patient and another for a non-case) reported following the recommendation of changing the needleless devices every 3 days. All family members reported following the instructions given by the Hospital A parental nutrition nurses for use of aseptic technique for exit site dressing changes and preparation of the TPN prior to administration. During the home visits, three family members were observed changing the dressing at the central line exit site and did so appropriately. Only one family of a non-case reported changing home health care agencies since December The four pharmacies providing the TPN solutions reported no changes in the preparation and delivery of the TPN to study households in the year prior to the investigation. The seven home health agencies also noted no changes in services provided to the patients. After demonstrating the administration of TPN and central line care on initial visits, the frequency of visits by the home health agencies varied from five times a week to twice a month. None of the home health agencies was directly affiliated with Hospital A, while one agency was affiliated with one of the pharmacies providing TPN. Environmental study Hand and central line exit site cultures were obtained from three case-patients and seven non-cases; hand cultures were obtained from 11 family members (Table 3). Candida spp. were detected in the hand cultures of one case-patient and three non-cases. C. parapsilosis was not isolated from any of the cohort members hands, and no cultures from the central line exit sites showed fungal growth. Candida spp. were detected in the hand cultures of nine family members; C. parapsilosis was isolated from the hand cultures of five family members, including four family members of non-cases. For each of the two case-patients (nos 1 and 3) who had successive C. parapsilosis BSI 3 months apart, the isolates from the first and subsequent episodes showed similar karyotypes. Representative RAPD profiles and karyotypes from case-patient no. 3 are shown in Fig. 1. The karyotypes of the case-patients blood C. parapsilosis isolates differed from each other. In addition, C. parapsilosis isolates from family members hand cultures showed different karyotypes than the casepatients isolates.

5 Candidemia in pediatric outpatients 223 Table 3 Results of cultures from patients receiving home total parenteral nutrition and family members, Hospital A, Memphis, Tennessee, 1 January to 30 June 1999 Patient Blood Patient hand Central line exit site Family member* hand Case 1 Candida parapsilosis No yeast No growth Not available Case 2 Candida parapsilosis No yeast No growth Candida albicans, Aureobasidium sp., Rhodotorula glutinis Case 3 Candida parapsilosis Candida famata, No growth Candida parapsilosis Aureobasidium sp. Non-case 1 Not applicable No yeast No growth 1: No yeast 2: Aureobasidium sp. Non-case 2 Not applicable Candida albicans, No growth Candida glabrata Candida glabrata Non-case 3 Not applicable No yeast No growth Candida parapsilosis Non-case 4 Not applicable Aureobasidium pullulans Aureobasidium sp., Rhodotorula rubra Non-case 5 Not applicable Candida albicans, Aureobasidium pullulans Non-case 6 Not applicable Candida famata, Aureobasidium pullulans Discussion Developments in medical technology now allow patients to obtain specialized care as outpatients, although with less stringent infection control [8] than No growth No growth Not available Candida parapsilosis, Cryptococcus sp., Aureobasidium pullulans, Rhodotorula rubra 1: Candida parapsilosis 2: Candida parapsilosis, Candida lusitaniae Candida kefyr, Aureobasidium pullulans Aureobasidium sp. Non-case 7 Not applicable No yeast No growth Candida kefyr *Single family member unless noted. used in a hospital setting. In this study of Candida BSI among children receiving long-term TPN, we found that a high proportion of the children acquired the infection in the outpatient setting. The infections were caused by several species of Candida; no common Fig. 1 Representative patterns of Candida parapsilosis isolates by (A) RAPD using primer PAO3, and (B) electrophoretic karyotyping. S (size standard) for (A) is a combination of Lambda HindIII Digest and Roche marker VI. For (B), S is S. cervisiae chromosomes. Similar patterns observed for one patient are shown by brackets.

6 224 Cano et al. source was identified. Significant findings from our study included the association of Candida BSI with underlying hematologic disease and a history of fungemia. Previous studies have reported hematologic malignancies, particularly acute leukemia and lymphoma to be risk factors for the development of inpatient candidemia [13]. Patients with hematologic malignancy are considered predisposed to develop candidemia because of increased colonization with Candida spp. and severe, prolonged granulocytopenia [14]. Underlying hematologic diseases, such as sickle cell anemia, thrombocytopenia and iron deficiency anemia, are possibly a marker for poor health status, or they may have a more specific role in the pathogenesis of candidemia. Increased colonization with Candida spp. has been reported for candidemic patients [15], and prior infections such as candiduria [1] and candidemia may predispose them to recurrent invasive fungal disease. Administration of TPN has been recognized as a risk factor for candidemia [2,4,8,16], particularly infection with C. parapsilosis [17 /19]; this was the predominant Candida spp. isolated from our patients. C. parapsilosis is very commonly isolated from the subungual space and cutaneous lesions [16]; the introduction of infection into the bloodstream may occur via traumatic skin breaks or central venous lines when strict aseptic technique is not followed during routine TPN administration. The environmental component of our investigation demonstrated that Candida spp. were commonly detected on the hands of the patients and their family members. This underscores the importance of maintaining good hygiene and appropriate technique in the administration of TPN in the home setting. Our molecular epidemiological findings did not reveal a mode of transmission between patients and family members. However, molecular correlation of repeated isolates from two case-patients was demonstrated. The similar profiles among repeated isolates from two of our case-patients may indicate inadequate resolution of their previous C. parapsilosis infection, though the lack of clinical signs and symptoms of BSI during the 3-month intervals between infection makes this unlikely. Alternatively, the patients may have been repeatedly exposed to C. parapsilosis from a persistent source, such as a resident strain present on the patient s skin or periodic seeding from an affected catheter. This investigation had several limitations. The relatively small sample size reduced the power of our study to identify potential risk factors. The collection of hand and central line exit site cultures was delayed relative to the period of acquisition of Candida infection, making it difficult to relate these findings to cases fungemic episodes. During the home visits, the family members were aware that they were being observed and may have performed central line care differently from their usual practices. We consider that routine periodic follow-up or re-evaluation of these practices by trained parenteral nutrition staff is warranted. The children in our cohort required frequent medical attention as a result of BSI or other complications relating to their underlying illnesses and/or conditions; during the study period, approximately one-quarter of their collective person-time time occurred in the hospital. In contrast to the intensive medical attention these patients received as inpatients, management of their conditions in the outpatient setting was uneven. In this study, as in previous studies [19,20], home TPN administration and central venous line care and maintenance were provided almost exclusively by a family member with home health agencies providing only intermittent support. The frequency of home visits and type of services provided also differed considerably, and there was no clearly delineated home follow-up coordination between the hospitals and home health agencies to monitor infection rates and problems with TPN administration and central line care encountered by family members. As advanced medical treatment is increasingly being provided on an outpatient basis, the incidence of serious complications, such as bloodstream infections, is also likely to increase. For children maintained on home TPN, more intensive follow-up and coordination involving their physicians, hospitals, home health agencies and families [21] are essential to ensure that central line care and TPN administration consistent with infection control guidelines are followed and maintained to prevent recurrent BSI. Acknowledgements We thank Althea Grant, Geri Grandberry, Yvonne Davis and Steve Buckingham. References 1 MacDonald L, Baker C, Chenoweth C. Risk factors for candidemia in a children s hospital. Clin Infect Dis 1998; 26: 642/ Levy I, Rubin LG, Vasishtha S, Tucci V, Sood SK. Emergence of Candida parapsilosis as the predominant species causing candidemia in children. Clin Infect Dis 1998; 26: 1086/ Sherertz RJ, Gledhill KS, Hampton KD, et al. Outbreak of Candida bloodstream infections associated with retrograde medication administration in a neonatal intensive care unit. J Pediatr 1992; 120: 455/ Solomon SL, Khabbaz RF, Parker RH, et al. An outbreak of Candida parapsilosis bloodstream infections in patients receiving parenteral nutrition. J Infect Dis 1984; 149: 98/102.

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