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Introduction
Plastic bronchitis is a rare disorder characterized by the formation of extensive endobronchial
casts[1]. A diagnosis is usually made when casts are expectorated or removed by
bronchoscopy[2]. Many cases of plastic bronchitis in children have
been published[3]. The processes associated with bronchial cast formation include
asthma[4], allergy[5],
infection[6],
bronchiectasis[1], cystic
fibrosis[6], and acute chest syndrome of sickle cell
disease[7], and as a complication after many different
congenital cardiac defects, such as the Fontan
procedure[8,9].
One published
study[10] showed the classification of casts based on their composition. Type 1 or inflammatory casts
consist predominantly of fibrin with dense eosinophilic, lymphocyte or neutrophilic inflammatory infiltration, and are
associated with underlying inflammatory diseases of the lung. Type 2 or acellular casts are composed primarily of mucin with no
acute inflammatory infiltration and sometimes a few mononuclear cells. The latter casts are found more commonly in children.
However Seear et al[10] did not address whether this classification aids in the treatment of these patients, apart from indicating
that acellular casts carry a poorer prognosis than inflammatory casts. Because plastic bronchitis is a rare disorder associated
with variable disease states, specific therapeutic options are based primarily on anecdotal experience, such as
acetylcysteine[10], low-dose oral
azithro-mycin[11,12],
urokinase[13], extracorporeal membrane oxygenation
(ECMO)[2], nebulised recombinant human
Dnase[14],
corticosteroids[10,15] and tissue plasminogen activator
(t-PA)[16]. At present, therapy for bronchial casts
remains limited[17].
Corticosteroids have recently been employed preferentially in plastic bronchitis, but this has only been reported in case
reports[10,15,18], not in clinically controlled trials. In the present study, we provide a special case series of thirty-two plastic
bronchitis patients with
hemoptysis[18,19] in Chinese adults admitted to West China Hospital between 1996 April and 2005
June, in order to explore the clinical features and the role of corticosteroids in treatment.
Materials and methods
Patients and ethics From April 1996 to June 2005, West China Hospital's databases were searched for patients who were
treated for plastic bronchitis, and a retrospective review was performed of the patients' medical records. Forty six episodes
were searched but the diagnosis of plastic bronchitis with hemoptysis was made in only thirty-five patients. Two out of 35
were excluded because of incomplete data. The remaining 33 patients were divided into a steroid group and a non-steroid
group. The patients in the steroid group (n=18) were treated with corticosteroids within 4 d of the onset of plastic bronchitis
with hemoptysis, and only one patient who was treated with corticosteroids on d 6 was excluded. Those in the non-steroid
group (n=14) were not treated with corticosteroids during the 8 d after onset
(Figure 1). Furthermore, none of the patients with plastic bronchitis in either the steroid group or the non-steroid group had
received any inhaled, injected, or oral corticosteroids or any immune inhibitors in the previous four
weeks.
The Medical Ethics Committee of West China Hospital at Sichuan University approved this study in accordance with the
recent principles of the Declaration of
Helsinki[20]. The efficacy of corticosteroids in plastic bronchitis is not confirmed and
this is a retrospective case-control study.
Standard interventions Patients with plastic bronchitis were immediately admitted to the medical care unit. The eight
major goals in therapy were addressed uniformly in both groups: (1) monitoring temperature, pulse, respiration, blood
pressure and the arterial oxygen saturation of the hemoglobin using pulse oximetry
(SpO2) (Oxisensor, Nellcor, Hayward, CA,
USA); (2) hemostatic agents; (3) the elimination of any identifiable underlying problem; (4) bronchodilators; (5) improved
clearance of tracheobronchial secretions; (6) infection control; (7) greater rest and/or sedation; (8) mechanical ventilation for
respiratory failure.
In the steroid group, patients were treated with
hydrocortisone , prednisone, or methylprednisolone. A fibreoptic
bronchoscopy (FOB) was performed within 3 days after hemoptysis desisted in both groups, and a biopsy was done if necessary.
Clinical variables The volume of hemoptysis and bronchitis casts of all patients who coughed up were recorded in detail.
The volume of hemoptysis was calculated in a
measuring cup with a scale and later blood expectoration was placed in a basin with normal saline for over 4 h, and normal
saline was replaced every hour. After a few hours, bronchial casts distinctly appeared, and were delivered to the department
of pathology for microscopic evaluation and the analysis of cellular composition. The bronchial casts were fixed in 10%
formalin, dehydrated, mounted in paraffin, sectioned, and stained with hematoxylin and eosin (HE). Four hundred cells of a
HE-stained slide preparation were counted for determination of the cellular composition.
White blood cell counts, red blood cell counts, neutrophil, eosinophil, and platelet, hemoglobin, prothrombin time (PT),
activated partial thromboplastin time (APTT) in blood were determined as soon as patients arrived at our hospital.
Mycobacterium and fungal stains (including pulmonary aspergillus) and cultures of the cast, purified protein derivative (PPD) skin
testing, and erythrocyte sedimentation rate (ESR) were measured in the lab. Chest radiograph and computed tomographies
(CT) or high resolution computed tomogram (HRCT) were also performed to identify the underlying problem after hemoptysis
stopped.
Statistical analysis All continuous values were expressed as mean±SEM, and compared using the Mann Whitney
U-test. Categorical data were compared using the Chi-squared test or Fisher's exact test. Statistical analysis was performed
using SPSS software for windows (Version 11.5, SPSS Inc, Chicago, IL, USA). A double sided P-value of less than 0.05 was considered to be statistically significant.
Results
Patient characteristics There were thirteen men and five women aged 20_77 years (mean 53.7 years) in the steroid group,
and ten males and four females aged 26_67 years (mean 47.4 years) in the non-steroid group. The demographic data and
identifiable underlying problems of those patients are listed in Tables 1 and 2, respectively. Clinical variables, such white
blood cell count, neutrophil, eosinophil, platelet, hemoglobin, SpO2, PPD skin testing, ESR, mycobacterium and fungal stains
and cultures of the casts, are listed in Table 1. Fungal stains and cultures of the cast, especially aspergillus, were negative in
both groups. The homogeneity test between the two groups at baseline indicated that the two groups were comparable in all
aspects (all P>0.05).
Volume of hemoptysis and bronchial
casts The volume of hemoptysis was recorded in detail from when plastic
bronchitis took place. On d 2, the volume of hemoptysis in both the steroid group and the non-steroid group began to decrease, but
the decrease was much slower in the non-
steroid group from d 2. After the 8 d treatment, the volume of hemoptysis was much more decreased in the steroid group
compared with that in the non-steroid group (43±15 mL vs 117±33 mL on d 5, 29±12 mL vs 97±23 mL on d 6, 18 ±10 mL vs 80±20 mL on d 7, and 13±8 mL vs 66±14 mL on d 8, P=
0.033, P=0.016, P=0.01, and P=0.002, respectively) (Figure 2).
After blood was expectorated, it was placed into normal saline solution and bronchial casts eventually appeared in all
cases. Bronchial casts were always with concomitant hemoptysis. The bronchial casts observed had varying consistencies
and were usually soft, hollow, often ramified and white or yellowish (Figure 3A). Microscopic evaluation of the bronchial
cast from every patient found that the cast consists of fibrin with eosinophils, neutrophils, lympho-cytes, and macrophages
(Figure 3B). There was no statistically significant difference in cellular composition of bronchial casts between the two
groups (Table 1). Until d 10, FOB had been performed in eighteen patients in whom hemoptysis had desisted, but no
bronchial casts were found in bronchi except for bloodstain. The cases with any bronchial casts made significant reductions
in the steroid group in comparison to those in the non-steroid group (4 of 18 vs 10 of 14, P=0.005, odds ratio=7.75, 95%
CI=[1.76, 43.60]) (Figure 4).
Efficacy and safety of corticosteroids Hydrocortisone, prednisone, or methylprednisolone was used in the steroid group,
but corticosteroids were administered in only three patients on d 1, possibly because the diagnosis of plastic bronchitis was
not made in other patients at that time. In light of the different anti-inflammation effects, all doses of hydrocortisone,
prednisone or methylprednisolone were used daily in the steroid group and were calculated as the dose of dexamethasone.
On d 3, the initial dose of corticosteroids had reached its peak (8.3 milligrams) and was then decreased to 7.0 milligrams as
dexamethasone was main-tained. At the same time, the resultant volume of hemoptysis was approximately consistent with the
administration of the corticosteroid dose. Three out of 18 in the steroid group and two out of 14 in the non-steroid group
received invasive mechanical ventilation for respiratory failure
(P=0.62), but no deaths were found in both groups (Table 1).
During the
8 d of treatment with corticosteroids, no gastrointestinal hemorrhage or other adverse events related with corticosteroids
occurred in the steroid group.
Follow-up Since d 9, some patients in the non-steroid group were treated with corticosteroids because of their limited
efficacy. Fifteen days later, hemoptysis stopped and no bronchial casts were found in all patients except one with
bronchiectasis in the steroid group and two with undefined states in the non-steroid group. These three patients were later
prematurely discharged. The dose of corticosteroids was lowered one-half every 7 d if used over 5 d.
Discussion
Plastic bronchitis is a clinical entity characterized by the expectoration of casts, which could cause obstruction of the
tracheobronchial tree and respiratory
distress[19]. The casts are of variable size and take the shape of the bronchi in which
they form. This condition can occur at any
age[10], but the majority of published reports regarding plastic
bronchitis are in pediatric patients, except for a few adult
patients[3,21]. In this study, 84.4% of patients had identifiable underlying problems
such as bronchiectasis (53.2%), tuberculosis
(15.6%) and pneumonia (15.6%), but the etiology of cast formation in a few patients (15.6%) could not be
defined[22].
Plastic bronchitis with hemoptysis has been reported much more in China perhaps because of underlying problems as a
developing country. The present report is different from many published reports in that we could not see the casts directly.
Blood expectoration was placed into a container with normal saline for over 4 h, and normal saline was replaced every hour.
Several hours later, bronchial casts distinctly appeared. Hemoptysis of large volumes (eg mean 216 mL on d 1) in those
patients occurred while bronchial casts were expectorated. Usually, it was too difficult for this kind of hemoptysis to be cured
with common hemostatics. Furthermore, most patients with plastic bronchitis in our study could cough out bronchial casts
formed in their tracheobron-chus without the help of bronchoscopic
removal[7], perhaps because of the fact that they are all of the
adult population and possess good pulmonary functions.
Until now, no specific therapy for bronchial casts has been shown to be effective. Different therapies have been applied
in various case reports, depending on the nature of the cast or identifiable underlying disease. Since 1997, bronchial casts
were separated into two well-defined types: type 1 (inflammatory) and type 2
(acellular)[10]. However, its importance in the
treatment of plastic bronchitis was not presented in recent studies. In our study, microscopic
examination of these casts in all patients revealed fibrinous exudates mixed with mucin, exfoliated epithelial cells, and
inflammatory cells, which were consistent with type 1 casts. Although plastic bronchitis is an uncommon disease, bronchial
casts with hemoptysis could result in life-threatening airway obstruction and
asphyxiation[23]. In recent studies,
corticosteroids have been employed preferentially in plastic
bronchitis[2,15], but without any controlled study results the efficacy of this
therapy remains to be established. According to our clinical experience we put forward the hypothesis that corticosteroids
were effective and safe in the treatment of plastic bronchitis with hemoptysis. In this retrospective study, the results showed
that on d 2 the volume of hemoptysis in the steroid group began to decrease sharply, but in the non-steroid group the
decrease was much slower. On
d 5, 6, 7, and 8, the volume of hemoptysis was significantly decreased in the steroid group compared to the non-steroid group
(all P<0.05). Furthermore, the cases with bronchial casts decreased evidently in the steroid group compared with the
non-steroid group (OR=7.75, 95% CI=[1.76, 43.60]) until d 10. Although the volume of hemoptysis and plastic casts could be
improved by corticoids, no statistical difference was found in some endpoints such as mechanical ventilation and mortality
between two groups in this study.
Multiple factors are likely to interplay in the pathogenesis of bronchial casts. These include airway inflammation caused
by acute respiratory tract infections as documented in our cases. This was different between our study and Western
countries. Bronchiectasis and tuberculosis are
common diseases in the developing world, especially in
China[24, 25]. Some studies have reported that the addition of corticosteroids is effectively used in the treatment of bronchiectasis and
tuberculosis[26,27]. In this study, corticosteroids have been shown to be effective on the basis of common supportive therapy, but its
mechanism of hemostasia or inhibiting casts formation was unclear. As mentioned above, all bronchial casts of the patients
in the two groups were inflam-matory. After corticosteroids were administered, hemoptysis with bronchial casts in patients
of the steroid group was reduced markedly. Thus, we speculate that hemoptysis may be related to bronchial inflammation as
it was not cured with common hemostatics except for corticosteroids, which could reduce inflammatory cytokine
expression[28]. But the detailed correlation between hemoptysis and inflammation remains to be determined. Although plastic bronchitis,
especially with type 1 casts, is described as usually a self-limited
illness[29], our study suggested that corticosteroids might
at least shorten the course of this disease. Unfortunately it is to be determined whether corticosteroids could decrease the
risk of mechanical ventilation in plastic bronchitis patients with hemoptysis.
Because this is a retrospective case-control study with a small sample size, the differences in outcome between the steroid
and non-steroid groups may be exaggerated (type 2 error). In evidence-based medicine (EBM), Dave Sackett generated
"levels of evidence" for ranking the validity of evidence about the value of preventive manoeuvres, and then tied them as
"grades of recommendations" to the
advice[30]. Moreover, the dictates of EBM suggest that when the ideal study is not
available, one falls back on the strongest evidence that one can
access[31]. Therefore, although the present study had some
limitations, it would be the best evidence thus far for the treatment of plastic bronchitis with hemo-ptysis.
Conclusion
In the present study, we proved that routine doses of corticosteroids as an anti-inflammatory drug would be effective and
safe for plastic bronchitis in a clinically controlled study in China. Clinicians should intervene early with corticosteroids if
bronchial casts are found in patients with large volumes of hemoptysis. Although improvement after the administration of
corticosteroids was observed in this study, a multi-centre, prospective, clinically controlled trial is warranted.
Acknowledgements
We thank Xiao-dong CHEN, a medical student, for assistance with recording data, Mrs Xiao-ling WU and Mrs Lan YUAN
of the medical care unit for major contributions in the daily care of these patients, and Prof Guan-jian LIU at Chinese
Evidence-based Medicine and Clinical Epidemiology Centre and Prof Michael SEEAR at British Columbia's Children's Hospital in
Canada for helpful suggestions. We also thank Jon P COLIAS at San Francisco State University for assistance with editing
this manuscript.
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