Abstract
Background
Newborn screening (NBS) for cystic fibrosis (CF) has become standard practice in many countries. Consequently, the prevalence of infants with intermediate/equivalent sweat test results has increased. This study examined clinical practices in the United States (US) related to intermediate sweat test results subsequent to NBS.
Methods
Telephone surveys were conducted with staff from 77 (47% response rate) US CF centers documenting clinical practices related to intermediate/equivalent sweat chloride levels (30–59 mmol/L) following abnormal NBS.
Results
Thirty percent of centers followed CF Foundation guidelines for classifying intermediate/equivalent results. There was much variability in sweat testing procedures, diagnostic labels, additional diagnostics, addressing prognosis, and services offered to parents. CF center staff identified a need for resources to better address the uncertainty associated with intermediate/equivalent results.
Conclusion
Findings warrant evaluation of barriers to adherence with existing guidelines and establishment of internationally accepted, evidenced-based, clinical standards for infants with intermediate/equivalent CF NBS results.
Keywords: cystic fibrosis, newborn screening, intermediate/equivocal sweat test, genetic counseling, uncertainty
Newborn Screening and Diagnosis of Cystic Fibrosis
Newborn screening (NBS) programs test neonates for treatable genetic and metabolic disorders to prevent or minimize complications. NBS for cystic fibrosis (CF) has been implemented in Australia, Europe, New Zealand, North America, and many Latin American countries (1–3). Following an abnormal NBS result for CF, infants require sweat testing to diagnose or rule out CF (4, 5). In the United States (US), sweat chloride analysis using pilocarpine iontophoresis is typically conducted at accredited or affiliate pediatric CF Centers (5). According to recommendations from the US Cystic Fibrosis Foundation (CFF) and the European Cystic Fibrosis Society (ECFS), sweat chloride results for infants ≤ six months of age are classified as normal (chloride levels ≤ 29 mmol/L), abnormal (chloride levels ≥ 60 mmol/L), or intermediate/equivocal (chloride levels 30–59 mmol/L) (4, 1, 6). If results fall within the intermediate/equivocal diagnosis range, the CFF recommends a repeat sweat test within 2 months (4). Additional testing may include comprehensive Cystic Fibrosis Transmembrane Receptor (CFTR) analysis, fecal elastase evaluation, and pulmonary cultures (7).
Intermediate/Equivocal Results
The intermediate/equivocal classification is a relatively new category arising largely from the inclusion of genetic testing in NBS. Variability in CFTR gene mutations produces intermediate/equivocal sweat test results (8) and uncertainty about the severity and onset of CF symptoms. This uncertainty creates challenges for clinicians in communicating results to parents (4) and leads to concerns for parents about the health status of their infants (9). Parent anxiety is fueled by the association of CF with a shortened lifespan. Although practice guidelines offer direction for clinical management of infants with intermediate/equivocal results (7), there is no internationally accepted protocol that addresses psychosocial aspects of intermediate/equivocal results. This study documented current practices associated with intermediate/equivocal CF results including sweat testing procedures, diagnostic labels, parameters used to classify intermediate/equivocal results, additional diagnostic tests prescribed, how providers address prognosis, and services offered to parents.
METHODS
Design
This descriptive study used a telephone survey to investigate how CF center care providers in the US address intermediate/equivocal sweat test results following abnormal NBS for CF. The Health Sciences Institutional Review Board at University of Wisconsin – Madison approved this study.
Recruitment
Using telephone contact information obtained from the Cystic Fibrosis Foundation, we recruited participants from all 164 pediatric CF care centers in the US between 11/23/2009 and 3/4/2010. Staff persons were included if they self-identified as the most knowledgeable provider at their site regarding clinical management of intermediate/equivocal sweat tests. Because the survey was confined to US CF centers, we used the term “intermediate” rather than “equivocal” sweat test results to be consistent with the language found in the CFF recommendations (4). A script guided verbal consent procedures which involved a description of the study, measures to protect participant confidentiality, and the voluntary nature of participation. When initial attempts to reach the appropriate staff person were unsuccessful, we made 1–3 additional attempts.
Sample
The final sample included 77 (47%) of the 164 accredited and affiliate pediatric CF care facilities. Respondents represented 56 accredited and 21 affiliate pediatric CF centers in 38 states. Participant’s job titles included nurses (n=33), clinic coordinators (n=24), CF center directors (n=17), genetic counselors (n=14), physicians (n=4), social workers (n=2), respiratory therapists (n=2), pulmonary diagnosticians (n=2), nutritionist (n=1), and pediatric pulmonary clinic director (n=1). Several participants reported more than one title. Most respondents were highly experienced in CF care (M= 15.7 ± 9.98 years of experience, range= 2–43 years). The mean length of time NBS for CF had been mandated in participants’ states was 4.4 years (SD=4.8). The mean number of intermediate sweat tests in the last 12 months was 7.1.
Data Collection
The telephone survey was developed by a team of content and methodology experts. Four board-certified CF center genetic counselors reviewed the survey for appropriateness of content and ease of administration. After incorporating their feedback, the final 48-item questionnaire incorporated 2 clinical scenarios, 41 close-ended questions, and 7 open-ended questions. Content included respondent demographic information, state NBS protocols, clinic procedures, and follow-up services/referrals offered to parents of infants with intermediate results. Interviews were scheduled at the convenience of the participant and lasted about 20 minutes. Responses were entered into a password protected Excel file for coding and analysis. To ensure confidentiality, each participating CF center was assigned a six-digit code.
ANALYSIS AND RESULTS
Closed-ended questions were coded, responses summarized, and percentages calculated. We conducted a directed and summative content analysis using procedures described by Krippendorff (10) for open-ended questions. Resulting codes were based on consensus ratings of major themes derived from the data.
Representativeness of Sample
We obtained data from the CFF regarding the number of patients receiving services at each CF center from 2006 to 2008. We compared the mean patient volume of our sample (M=84.9) to the mean of the non-participating centers (M=80.2). Results of the T-test showed no significant difference (t-test value = −0.477 and p = 0.63). As illustrated in Figure 1, most participants reported NBS algorithms that involve some combination of measuring immunoreactive trypsinogen (IRT) followed by DNA testing.
Figure 1.
Major Categorical Themes for Discussing Prognosis
Sweat Testing Procedures
Most respondents (84%) reported bilateral collection of sweat and 90% use the pilocarpine iontophoresis method. Fifty-eight percent reported parents were informed about the possibility of intermediate results before sweat testing, 22% said their center did not inform parents of this possibility, 10% only informed parents sometimes, and 10% did not respond. Seventy-one percent of centers informed parents of the sweat test results the same day as testing. The remaining 29% did not indicate when they parents about sweat test results.
Genetic Counseling
Seventy-five percent of CF centers offered genetic counseling to parents either all or most of the time. These centers also described a high uptake rate by parents (74%). Providers of genetic counseling services included genetic counselors (79%), CF center physicians (27%), nurses (6%), and CF center directors or coordinators (2%). The timing of genetic counseling varied: after results were known (52%), during sweat collection (17%), after sweat testing was completed, but before results were known (16%), before sweat testing was conducted (13%), and whenever the family wished to receive counseling (4%) More than one response was accepted.
Parameters for Intermediate Classification
There was a wide range of definitions for the sweat test intermediate result with some reporting the use of more than one term. The lower limit for an intermediate classification was reported as 30 mmol/L (71%) or 40 mmol/L (17%). The remaining centers reported lower limits of 0 mmol/L (1%), 20 mmol/L (3%), 25 mmol/L (3%), 31 mmol/L (1%), or 35 mmol/L (1%). The “0 mmol/L” response was associated with a NBS protocol requiring two mutations for a sweat test referral. Three percent did not respond. The majority of centers (53%) used 60 mmol/L as the upper limit of the intermediate range. Other upper limits included 59 mmol/L (32%), 40 mmol/L (5%), 30 mmol/L (3%), 29 mmol/L (1%), and 25 mmol/L (1%). Five percent did not respond.
The most commonly reported terms used to classify intermediate sweat test results included “CFTR-related metabolic syndrome” (CRMS; 57%), “atypical CF” (40%), and “non-classic CF” (12%). Other labels (34%) were “CFTR- related abnormality”, “abnormal sweat chloride level”, “some CFTR dysfunction”, “variant CF”, “abnormal NBS with two CFTR mutations”, “borderline”, “elevated IRT”, and “CF-like”. Eight percent did not use a label until a definite diagnosis was determined.
Follow-Up Assessment
We created two clinical scenarios to offer participants opportunities to illustrate how they would approach follow-up assessment and care for newborns with intermediate test results. The first scenario involved an infant with a high IRT and a single 508del mutation. The second scenario was similar, but NBS results detected two mutations, F508del and R117H-7T. Each scenario was modified as needed during surveys to fit each center’s definition of the intermediate range. As noted in Table 1, the most common response (73%) to the first scenario was to repeat the sweat test, but not to proceed with genetic testing using a larger mutation panel or gene sequencing, nor to have the child evaluated in the CF clinic. Time frame for repeating the sweat test included infant age 2 months (44%); infant age 3–6 months (17%), and 12% within a month of original sweat test (12%), Other centers individualized the follow-up testing, e.g., repeating the sweat test when the infant’s weight reached 8–10 pounds or when insurance approval was obtained.
Table 1.
Follow-Up Procedures for Intermediate Sweat Test Results
| 1st scenario | Yes N (%) | No N (%) | No Response N (%) |
|---|---|---|---|
| Repeat Sweat Test | 56 (73%) | 13 (17%) | 8 (10%) |
| Clinical Work-Up | 24 (31%) | 45 (58%) | 8 (10%) |
| Gene Sequencing | 23 (30%) | 46 (60%) | 8 (10%) |
| Other | 12 (16%) | 56 (73%) | 9 (12%) |
| Larger Mutation Panel | 10 (13%) | 59 (77%) | 8 (10%) |
|
| |||
| 2nd scenario | Yes N (%) | No N (%) | No Response N (%) |
|
| |||
| Repeat Sweat Test | 46 (60%) | 19 (25%) | 12 (16%) |
| Clinical Work-Up | 35 (46%) | 30 (39%) | 12 (16%) |
| Other | 10 (13%) | 54 (70%) | 13 (17%) |
| Gene Sequencing | 5 (7%) | 60 (78%) | 12 (16%) |
| Larger Mutation Panel | 2 (3%) | 63 (82%) | 12 (16%) |
For the second scenario, most respondents (60%) reported they would repeat the sweat test at either two months of age (34%) or 3–6 months of age (25%). Centers were much less likely to proceed with additional genetic analysis using a larger mutation panel or gene sequencing. Centers were divided about whether the child should be evaluated in the CF clinic.
The R117H-7T gene change was considered to be a symptom-causing mutation by 12% of respondents and not symptom-causing by another 12%. Most centers (55%) said the allele is “sometimes” considered a symptom-causing mutation.
Prognosis
We asked providers to describe how they would address the infant’s prognosis with parents in each scenario. As illustrated in Figure 2, a content analysis of provider responses to the first scenario revealed five content areas: (a) uncertainty of clinical implications, (b) hopeful prognosis, (c) chronic nature of the condition, (d) no discussion of prognosis, and (e) CFF guidelines for care. Respondents who offered parents a hopeful prognosis (34%) included some combination of the following five points: (a) infant would be healthy (42%), (b) infant is probability just a CF carrier (27%), (c) CF is a spectrum disorder (23%), (d) advances in treatment continue to improve prognosis (12%), and (e) longevity of people with CF continues to increase (8%). Providers who offered a hopeful prognosis for the second scenario emphasized the same points, except for the probability that the child was just a carrier.
Factors influencing the prognosis conversation included infant genotype and health, as well as parental anxiety and knowledge. Other variables involved the timing of the discussion, family history of CF, parents’ stress level, parents’ social support, parents’ state of denial, sweat chloride levels, previous clinical experiences with particular mutations, information parents reported reading, infant age, and provider’s expectations about parent adherence to follow-up recommendations (Table 2). One respondent stated that all patients received the same counseling regardless of other factors.
Table 2.
Factors that Influence How Prognosis is Described
| Factors | Yes N (%) | No N (%) | No Response N (%) |
|---|---|---|---|
| CFTR Mutations | 58 (75%) | 16 (21%) | 3 (4%) |
| Health of Newborn | 53 (69%) | 21 (27%) | 3 (4%) |
| Symptoms Present | 60 (78%) | 14 (18%) | 3 (4%) |
| Parental Anxiety | 35 (45%) | 39 (51%) | 3 (4%) |
| Parental Knowledge | 56 (73%) | 18 (23%) | 3 (4%) |
| Other | 20 (26%) | 54 (70%) | 3 (4%) |
Additional Resources
Respondents identified a need for additional resources to more effectively address the needs of infants with intermediate sweat test results and their parents. Multiple responses were accepted for needed resources including educational materials (47%), clinical personnel (18%), parent-to-parent services (4%), funding for more definitive testing (4%), follow-up telephone contact with parents and parent-to-parent support (4%). Several respondents were uncertain about needing additional resources (4%) or stated none were needed (9%) and 10% did not respond.
Follow-up Contact with Families
Thirty-eight percent of respondents stated they contacted parents between initial intermediate results and follow-up testing or clinical visits; 31% said they did not initiate contact with parents; and 26% reported contacting parents only some of the time and 5% did not respond. An average of 31% (range 0–100%) reported parents called their centers with questions or concerns about their infant following intermediate sweat test results.
Additional Referrals and Resources
Most respondents (75%) reported that they direct parents to internet sites to answer questions, typically the CFF site, www.cff.org. When asked if they had adequate resources for parents dealing with the uncertainty of intermediate sweat tests, respondents stated yes (35%), sometimes (34%), and no (28%). We also asked participants if their centers provided parents access to various services. Using a logistic regression model (11) centers were clustered into two mutually exclusive groups: standard service and standard plus service (Figure 3). The difference between these two groups was the availability of on-site mental health services, patient advocacy, benefits specialists, and financial assistance programs at the standard plus service centers, but not the standard service centers. We assessed whether group membership was associated with reported adequacy of services. Results showed that standard service centers were 1.88 times more likely than standard plus service centers to report having inadequate resources. This odds ratio was based on a 95% confidence interval with limits of 0.018 to 1.25.
DISCUSSION
The results of this study illustrate the vast variability in US clinical practices associated with intermediate/equivocal sweat test result. Only 30% of respondents reported following CFF guidelines for classifying sweat chloride results within the intermediate/equivocal range. When an infant’s results fell within the intermediate/equivocal classification, follow-up evaluation and care varied. Most centers repeated the sweat test, but at varying ages. Consequently, infants with the same sweat chloride levels received different standards of care across sites. There was also much variability in lexicons used to describe the intermediate classification.
CFF and ECFS guidelines for infants with CRMS were published in 2009 (7, 6). Our findings might reflect the short period of time between the publication of that article and the data collection for this study. Standardization is crucial to provision of consistent and optimal clinical interventions, communication with parents and among colleagues, as well as development of research protocols.
Results suggest a paucity in parent educational materials and availability of specific resources for families with infants who have intermediate results, particularly centers in the standard service cluster. Parent educational materials describing the intermediate/equivocal classification should be based on empirical evidence, use consistent terms, be written at low literacy, and available in multiple languages. Given the ever-increasing complexity of the genetics of CF, especially for the relatively new intermediate classification, it is essential that genetic counseling services be incorporated into a comprehensive approach to follow-up care.
Several CF centers offered parents opportunities to speak with or read stories about other parents whose children had intermediate results. Evidence suggests that such referrals could alleviate parental anxiety and sense of isolation, while providing a network of support (9). While knowing that they are not alone in their experience may be helpful to some parents, such referrals should be used cautiously with the caveat that all infants are unique and the experiences of a particular family might not be the same for others.
About 51% of responses to our second scenario described hopefulness as a central ingredient in counseling parents about their infant’s prognosis. Hope has been associated with increase quality of life in patients with various medical conditions (12). Uncertainty can be framed as having the potential for favorable outcomes. The challenge for providers is striking a balance between hopeful optimism and the unknown potential for symptom development.
About 38% of respondents reported that they initiated contacts with families between the time of intermediate sweat test results and follow-up clinical appointments. Such contacts could help families cope with the uncertainty of intermediate results by answering their questions and providing emotional support. Hamilton and Grant (13) integrated telephone contacts into a model of care for patients waiting for cancer treatment. These phone contacts with patients reportedly offered patients anticipatory guidance about clinical procedures, created an advocate within the complex health care system, and reduced patient anxiety. Incorporating this type of follow-up service might address many of the psychosocial needs parents of infants with intermediate results have identified thus far.
We acknowledge several limitations of the current study. We relied on the initial contact person at each CF center to direct us to the most appropriate staff member to complete the survey. Perhaps the results would have been different if we had only interviewed the CF center directors. Although data collection procedures were standardized and scripted, there could have been subtle stylistic, gender, or age differences in the interviewers that could have affected some participant responses. Despite these limitations, this report is the first to systematically document clinical practices in the care of infants with intermediate sweat results following abnormal NBS for CF.
CONCLUSION
With the international expansion of NBS to include CF, the number of parents who will receive intermediate sweat test results for their infant will increase. The results of this survey suggest the need for international consensus about the classification and clinical follow-up of infants with intermediate/equivocal sweat test results and their families. Findings warrant further evaluation of reasons for the high rate of non-adherence to existing guidelines and additional empirical evidence to develop best clinical practices regarding intermediate/equivocal sweat test results.
Supplementary Material
Acknowledgments
We extend our gratitude to the CF Center participants who generously participated in this study. We thank Roger Brown PhD for his excellent assistance with statistical analysis. Special thanks to Peggy Modaff, MS, CGC, Dania Stachiw-Hitpas, MS, CGC, Angela Tess, MS, CGC and Sumedha Ghate, MS, CGC for assistance in the development of the study survey. We are deeply grateful to Philip Farrell, MD, PhD, Michael Rock, MD, Peggy Modaff, MS, CGC and Laura Hogan, PhD for their comments and insights regarding manuscript preparation. This project was partially supported by grant 1UL1RR025011 from the Clinical and Translational Science Award (CTSA) program of the National Center for Research Resources, National Institutes of Health.
Footnotes
Institute where work was conducted: University of Wisconsin, Madison, WI
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