Discussion
This overall sample result in this study would appear to suggest that
steroids positively alter FEV1pp trajectory when there is initial
failure to progress during APE when we examine all eligible encounters
(Table 1). This assumes that all CF admissions were 12-14 days in length
and that persons not showing improved FEV1pp after 5-7 days of treatment
do not return to baseline lung function after two weeks of conventional
treatment. Those assumptions are incorrect and highlight the limits of
retrospective cohort studies. To address this limitation, we then used
propensity score matching within our data set. This allows the
construction of a non-steroid treated control group against the steroid
treated group by matching characteristics such as gender, lung function
at baseline, or CFTR mutation (Model 1, Table 2). This PS-matching
approach has been called a “retrospective randomization” by some
authors as it seeks to reduce assignment bias and mimic randomization13. Thus in Models 1 and 2, we found no significance
difference in FEV1pp at baseline or discharge. Moreover, extended
analysis including FEV1pp at follow-up visit and time to next
exacerbation were not significantly different.
Although our data showed a non-significant trend in time to next
exacerbation requiring antimicrobial therapy, this is likely due to size
of sample. The median time to next antibiotics is 99 (IQR: 51, 123.5) in
the steroid group versus 70.5 (IQR: 37-152). The Kaplan-Meier graph
(Figure 3) shows that for the first 80 days, the no-steroid group is
more likely to need antimicrobial treatment, however beyond 80 days, the
steroid group is more likely. The factors such as low number of patients
(n=34) in the PS-matched sample, as well as the retrospective nature of
the study and non-standardized follow up appointments could contribute
to the non-significance.
When FEV1pp or clinical health fails to improve as expected during APE
treatment, providers and patients alike look for alterations in the
treatment plan to improve lung function to baseline and overall
well-being. At our center, approaches might include changing the
antimicrobial regimen, increasing the total days of IV therapy,
increasing airway clearance therapy frequency from 4 to 5 session per
day, or adding corticosteroids. These options are presented to the
patient and family. Our center generally utilizes a “rescue” dose of
oral prednisone 2 mg/kg/day up to 60 mg given for 5-7 days.
Considerations for steroid therapy include: positive response on
previous use, suspected asthma, and physical exam finding including
wheezing. Although not reviewed in the study, management of
hyperglycemia can be a concern even in short term rescue use. Currently,
there is no published guidance or recommendation concerning steroid use
during CF exacerbations.
There has been previous interest in oral steroid therapy in CF.
Long-term (12 week) prednisolone therapy in 24 clinically stable
children with CF demonstrated decreased concentration of inflammatory
markers including IL-1α, sIL-2R, and IgG 14. This
study protocol dosed prednisolone at 2 mg/kg/day for the first week,
then tapered to 1 mg/kg every other day for the following 10 weeks. FEV1
benefit was associated with the steroid group at day 14, however
significance was not maintained at week 12. While there is some data
that alternate-day steroid use for three weeks to four years improves
pulmonary function 14-16, adverse events such as poor
glucose tolerance, insufficient linear growth, and Pseudomonas
aeruginosa colonization are noted after long-term administration of
steroids in CF.
Short-term use of systemic high dose steroids appears to have even less
evidence for use. CF pulmonary exacerbation treatment guidelines report
that there is insufficient evidence for use of oral corticosteroids
during APEs 2. Three studies show that short term
therapy for three to ten days show modest efficacy in improving
pulmonary function. In a pilot placebo-controlled study of oral
prednisone therapy (2 mg/kg, max 60 mg) administration for the first
five days of hospitalization in patients with APE, FEV1pp was
consistently higher in the steroid-treated group, however the FEV1
difference did not reach statistical significance in this small study of
24 patients 17. A case report of four young patients
under age six with no clinical improvement after IV antimicrobial
therapy for APE showed dramatic improvement in respiratory distress and
oxygen requirements after IV methylprednisolone burst (1 g/1.73
m2 per day for 3 days) 18. A study
of 20 infants with APE demonstrated a statistically significant increase
in forced expiratory flows after treatment with hydrocortisone in
addition to standard therapy, with no significant increase in placebo
treated group 19. Additionally, several of the infants
given placebo in this study, and none of the steroid-treated infants,
had a recurrence in respiratory symptoms between discharge and
outpatient follow up. Overall, studies remain poorly powered and larger
clinical trials would be needed to better elucidate the role of steroids
used during treatment of pulmonary exacerbations.
An alternate approach when failure to improve is noted during APE is to
increase the number of treatment days. However, in our experience most
families and their children are opposed to longer hospital stays.
Antimicrobial therapy in CF exacerbation ranges from 10-21 days with
most individuals treated between 10 and 14 days. 20Studies examining length of IV therapy suggest diminishing returns after
14 days of therapy 21. Treatment durations of 10
versus 14 versus 21 days of conventional therapy has also been recently
been studied by the CF Foundation and is also uncertain benefit
(NCT02781610) [Goss]. The longer length of stay noted in our overall
study cohort was primarily due to initiating steroid after poor response
to 10- 14 days of therapy. As our conventional therapy duration is 10-14
days, the providers’ intent was to reassess lung function prior to
steroid therapy. This often resulted in at least five more days of
hospital care and additional spirometry at the end of the steroid
treatment while continuing other treatments including antimicrobial
therapy. Despite anecdotal reports of improvement, our Models 1 and 2
suggest no benefit overall to acute rescue steroids. Waiting until day
12-14 to start steroid treatment may only add unnecessary hospital days.
To our knowledge, there are no trials showing the effectiveness of
switching antimicrobial therapy when using respiratory culture-based
guided therapy when patients fail to progress. As summarized by Chmiel
et al current thinking of CF airway pathogens is based on the recovery
of a known cohort on surveillance cultures 22.
Extended culturing techniques have demonstrated previously undocumented
species in the CF microbiome including anaerobic species, however, these
techniques are not in use in routine care. While diverse in youth, the
CF microbiome diversity narrows as the patient ages23, suggesting the ability to tightly narrow
antimicrobial coverage. Importantly, considering agents against MRSA orPseudomonas aeruginosa when not treated might be an alternate
when confronted with failure to progress.
There is conflicting evidence that corticosteroid use is a risk factor
for nontuberculous mycobacteria (NTM) colonization. Review of the
literature notes that isolation of Aspergillus spp or Allergic
Bronchopulmonary Aspergillosis (ABPA) diagnosis more common in NTM
positive patients. Corticosteroid therapy is the mainstay of ABPA
treatment 24. In a study of 139 patients with CF in
Israel, six developed NTM lung disease 25. Five of the
six patients had prolonged steroid treatments, four of which were
treatment for an ABPA diagnosis prior to NTM acquisition. Of the 133
patients without NTM, only one had ABPA and prolonged steroids
(p<0.001), therefore suggesting steroids as a risk factor for
NTM. Conversely, a nested-cohort study found there was less steroid
exposure days patients with NTM disease meeting ATS criteria than those
who were NTM negative (p<0.05) 26. This
study included 159 patients. Sixty were NTM positive, 22 of which had
NTM disease meeting ATS criteria. A multicenter study in Israel reviewed
186 patients, 42 of which had NTM isolation 27. A
multivariate analysis found an increased odds of Aspergillus sppin the NTM positive cohort (odds ratio 5.14, 95% CI 1.87–14.11). In a
retrospective database review in the US, NTM was noted in 166
individuals of the 1216 28. Aspergillus
fumigatus was more frequently found in NTM positive patients 13.9% vs.
7.2%, respectively, p<0.01. It appears that the Aspergillus
colonization, not the steroids themselves may be the association with
NTM positivity. Of the studies concerning for steroids, they include
prolonged use, thus short “rescue” dosing regimens of steroids may not
warrant alarm for development of NTM infection.
Our analysis is limited by sample size and retrospective nature, these
data suggest a prospective trial with clear criteria for starting
“rescue” treatment should be undertaken. There continues to be
interest in the use of steroids in CF APE and a clear understanding of
their use is warranted. A current randomized, double blind, placebo
controlled trial of prednisone for patients failing to recover their
FEV1 baseline at 7 days into IV antibiotic treatment for APE underway
(NCT03070522) [Waters].
1. Bhatt JM. 2013. Treatment of pulmonary exacerbations in cystic
fibrosis. Eur Respir Rev. 22(129):205-216.
2. Flume PA, Mogayzel PJ, Jr., Robinson KA, Goss CH, Rosenblatt RL, Kuhn
RJ, Marshall BC. 2009. Cystic fibrosis pulmonary guidelines: Treatment
of pulmonary exacerbations. American journal of respiratory and critical
care medicine. 180(9):802-808.
3. Sanders DB, Hoffman LR, Emerson J, Gibson RL, Rosenfeld M, Redding
GJ, Goss CH. 2010. Return of fev1 after pulmonary exacerbation in
children with cystic fibrosis. Pediatric pulmonology. 45(2):127-134.
4. Flume PA, O’Sullivan BP, Robinson KA, Goss CH, Mogayzel PJ, Jr.,
Willey-Courand DB, Bujan J, Finder J, Lester M, Quittell L et al. 2007.
Cystic fibrosis pulmonary guidelines: Chronic medications for
maintenance of lung health. American journal of respiratory and critical
care medicine. 176(10):957-969.
5. Cogen JD, Oron AP, Gibson RL, Hoffman LR, Kronman MP, Ong T,
Rosenfeld M. 2017. Characterization of inpatient cystic fibrosis
pulmonary exacerbations. Pediatrics. 139(2).
6. West NE, Beckett VV, Jain R, Sanders DB, Nick JA, Heltshe SL,
Dasenbrook EC, VanDevanter DR, Solomon GM, Goss CH et al. 2017.
Standardized treatment of pulmonary exacerbations (stop) study:
Physician treatment practices and outcomes for individuals with cystic
fibrosis with pulmonary exacerbations. Journal of cystic fibrosis :
official journal of the European Cystic Fibrosis Society. 16(5):600-606.
7. Flynn TN. 2001. Design and analysis of cluster randomization trials
in health research.: Allan donner and neil klar. London: Arnold, 2000,
pp.178, £35.00. Isbn: 0-340-69153-0. International Journal of
Epidemiology. 30(2):407-408.
8. Newson R. 2006. Confidence intervals for rank statistics: Somers’ d
and extensions. The Stata Journal. 6(3):309-334.
9. MacDonald KD, Vesco KK, Funk KL, Donovan J, Nguyen T, Chen Z, Lapidus
JA, Stevens VJ, McEvoy CT. 2016. Maternal body mass index before
pregnancy is associated with increased bronchodilator dispensing in
early childhood: A cross-sectional study. Pediatric pulmonology.
51(8):803-811.
10. Bellera CA, MacGrogan G, Debled M, de Lara CT, Brouste V,
Mathoulin-Pélissier S. 2010. Variables with time-varying effects and the
cox model: Some statistical concepts illustrated with a prognostic
factor study in breast cancer. BMC Med Res Methodol. 10:20-20.
11. Adelson JL, McCoach DB, Rogers HJ, Adelson JA, Sauer TM. 2017.
Developing and applying the propensity score to make causal inferences:
Variable selection and stratification. Front Psychol. 8:1413.
12. Arpino B, Cannas M. 2016. Propensity score matching with clustered
data. An application to the estimation of the impact of caesarean
section on the apgar score. Stat Med. 35(12):2074-2091.
13. Jupiter DC. 2017. Propensity score matching: Retrospective
randomization? J Foot Ankle Surg. 56(2):417-420.
14. Greally P, Hussain MJ, Vergani D, Price JF. 1994. Interleukin-1
alpha, soluble interleukin-2 receptor, and IgG concentrations in cystic
fibrosis treated with prednisolone. Archives of disease in childhood.
71(1):35-39.
15. Auerbach HS, Williams M, Kirkpatrick JA, Colten HR. 1985.
Alternate-day prednisone reduces morbidity and improves pulmonary
function in cystic fibrosis. Lancet (London, England). 2(8457):686-688.
16. Eigen H, Rosenstein BJ, FitzSimmons S, Schidlow DV. 1995. A
multicenter study of alternate-day prednisone therapy in patients with
cystic fibrosis. Cystic fibrosis foundation prednisone trial group. The
Journal of pediatrics. 126(4):515-523.
17. Dovey M, Aitken ML, Emerson J, McNamara S, Waltz DA, Gibson RL.
2007. Oral corticosteroid therapy in cystic fibrosis patients
hospitalized for pulmonary exacerbation: A pilot study. Chest.
132(4):1212-1218.
18. Ghdifan S, Couderc L, Michelet I, Leguillon C, Masseline B, Marguet
C. 2010. Bolus methylprednisolone efficacy for uncontrolled exacerbation
of cystic fibrosis in children. Pediatrics. 125(5):e1259-1264.
19. Tepper RS, Eigen H, Stevens J, Angelicchio C, Kisling J, Ambrosius
W, Heilman D. 1997. Lower respiratory illness in infants and young
children with cystic fibrosis: Evaluation of treatment with intravenous
hydrocortisone. Pediatric pulmonology. 24(1):48-51.
20. Plummer A, Wildman M, Gleeson T. 2016. Duration of intravenous
antibiotic therapy in people with cystic fibrosis. Cochrane Database
Syst Rev. 9:CD006682.
21. Collaco JM, Green DM, Cutting GR, Naughton KM, Mogayzel PJ, Jr.
2010. Location and duration of treatment of cystic fibrosis respiratory
exacerbations do not affect outcomes. American journal of respiratory
and critical care medicine. 182(9):1137-1143.
22. Chmiel JF, Aksamit TR, Chotirmall SH, Dasenbrook EC, Elborn JS,
LiPuma JJ, Ranganathan SC, Waters VJ, Ratjen FA. 2014. Antibiotic
management of lung infections in cystic fibrosis. I. The microbiome,
methicillin-resistant staphylococcus aureus, gram-negative bacteria, and
multiple infections. Ann Am Thorac Soc. 11(7):1120-1129.
23. Stokell JR, Gharaibeh RZ, Hamp TJ, Zapata MJ, Fodor AA, Steck TR.
2015. Analysis of changes in diversity and abundance of the microbial
community in a cystic fibrosis patient over a multiyear period. Journal
of Clinical Microbiology. 53(1):237-247.
24. Janahi IA, Rehman A, Al-Naimi AR. 2017. Allergic bronchopulmonary
aspergillosis in patients with cystic fibrosis. Ann Thorac Med.
12(2):74-82.
25. Mussaffi H, Rivlin J, Shalit I, Ephros M, Blau H. 2005.
Nontuberculous mycobacteria in cystic fibrosis associated with allergic
bronchopulmonary aspergillosis and steroid therapy. Eur Respir J.
25(2):324-328.
26. Olivier KN, Weber DJ, Lee JH, Handler A, Tudor G, Molina PL,
Tomashefski J, Knowles MR. 2003. Nontuberculous mycobacteria. Ii:
Nested-cohort study of impact on cystic fibrosis lung disease. American
journal of respiratory and critical care medicine. 167(6):835-840.
27. Levy I, Grisaru-Soen G, Lerner-Geva L, Kerem E, Blau H, Bentur L,
Aviram M, Rivlin J, Picard E, Lavy A et al. 2008. Multicenter
cross-sectional study of nontuberculous mycobacterial infections among
cystic fibrosis patients, israel. Emerg Infect Dis. 14(3):378-384.
28. Esther CR, Jr., Esserman DA, Gilligan P, Kerr A, Noone PG. 2010.
Chronic mycobacterium abscessus infection and lung function decline in
cystic fibrosis. Journal of cystic fibrosis : official journal of the
European Cystic Fibrosis Society. 9(2):117-123.