Bleomycin Lung Injury: A Case Report and Review of the Literature-Juniper Publishers
Juniper Publishers-Journal of Anesthesia
Abstract
Bleomycin is a drug used to in the treatment of
Hodgkin's Lymphoma, amongst other tumours. Bleomycin has been implicated
in causing pneumonitis and pulmonary fibrosis, now termed Bleomycin
Lung Injury (BLI). BLI is a much debated subject, in terms of both its
pathogenesis and management of patients after diagnosis.
In this paper, we reviewed the current knowledge of
Bleomycin-Induced Lung Injury from a case report perspective. We will
describe the case of a patient with BLI presenting to our ICU and
discuss the available literature.
Keywords: Bleomycin; Acute Lung Injury, Chronic Lung Injury, Pneumonitis, Drug Toxicities, Free radicals Abbreviations: BLI: Bleomycin Lung Injury; ARDS: Acute Respiratory Distress Syndrome; ICU: intensive care unit
Introduction
Bleomycin is a glycopeptide antibiotic, originally
isolated from Streptomyces verticillus, and discovered to have
antitumour cytotoxic activity in 1966 [1].
It is now commonly used as a chemotherapeutic agent for germ cell
tumours, lymphoma, squamous cell tumours of the head, neck and axilla,
Kaposi's sarcoma and cervical cancer. However, Bleomycin has also been
associated with pulmonary toxicity, causing in some cases pneumonitis,
pulmonary fibrosis, and fatal acute respiratory distress syndrome (ARDS)
[2-4]. Lung damage associated with Bleomycin is termed Bleomycin Lung Injury (BLI).
In 1990 it was estimated that approximately 10%
patients who have treatment with Bleomycin develop some form of lung
injury, with 1% developing fatal pulmonary fibrosis [5]. However, since then, incidences of lung injury of between 0 and 46% of all patients who take the drug had been reported [6].
Mortality rates range between 2 and 10% of those affected, although
some studies report up to 27% mortality, and in mechanically ventilated
patients mortality rates of up to 33% have been reported [2,6-8].
There has been put forward a suggestion that oxygen therapy following Bleomycin exposure potentiates lung damage [9-11].
This is due to the supposed mechanism of action of Bleomycin involving
oxygen-free radicals, combined with a number of studies on animals
indicating an association.
Other drugs may also exacerbate or protect against this unwanted side effect. [12].
For this reason, the management of a patient following Bleomycin
therapy, whether presenting with or without symptoms of lung damage, is
crucial.
It is important to note that patients treated with
Bleomycin are immunosuppressed, and hence more likely to develop various
infections. Bacterial, viral and fungal infections will all produce
lung injury and have similar clinical presentations to BLI, i.e.
hypoxia. These infections are more common than Bleomycin Lung Injury
and, in these circumstances, lack of oxygen as part of the sepsis
syndrome increases mortality and should be treated promptly. Hence, when
treating these patients infectious causes of hypoxia/lung injury should
be considered and treated first.
The benefits versus the risks of oxygen therapy
should be considered on an individual patient basis, depending on the
index of suspicion of BLI (presence or absence of an alternative cause),
Bleomycin dose and time since last dose and the presence of other risk
factors.
The following is a case report of a patient admitted
to the intensive care unit (ICU) with ARDS following chemotherapy with
Bleomycin.
Case Presentation
A 39 year-old man presented to the Accident and
Emergency Department complaining of shortness of breath. He had a known
history of Hodgkin's Lymphoma for which he had been treated with 5%
cycles of ABVD chemotherapy (Doxorubicin, Vinblastine, Bleomycin and
Dacarbazine), including 17.500 units of Bleomycin per cycle. His last
cycle had finished 10 days before the acute episode of shortness of
breath.=
He also had known pulmonary hypertension and had a
pericardial effusion that required drainage three months before this
presentation. He had had multiple pulmonary emboli and was previously
noted on echocardiogram to have a dilated right heart. The patient had
no other notable medical history except that of smoking tobacco,
cannabis and heroin, and previous history of intravenous drug use.
On admission the patient was alert and conscious,
pulse was 124 beats per minute, temperature 36.2 °C, respiratory rate
was 28 breaths per minute, and oxygen saturation was 94% on air. He was
noted to have a Skin Tunnelled Central Venous Catheter (Hickman®) in
situ, and on examination of his chest bibasal crepitations. Initial
differential diagnosis was that of pneumonia, pulmonary oedema (in light
of his known cardiac pathology), or pulmonary embolism (in light of his
relevant history).
Chest X-ray showed bibasal infiltrates. He was
started on empirical antibiotic treatment with Co-amoxiclav and
Clarithromycin. Investigations found a high white blood cell count but
there was no growth on blood or sputum cultures, and the patient
remained apyrexial.
Four days after admission to hospital he was admitted
to the Intensive Care Unit (ICU) with progressive respiratory failure
and hypoxia. An initial target of paO2 of 7kPa was set and, due to his
background of exposure to Bleomycin, when he failed to respond to low
flow oxygen at 40% FiO2 he was started on steroids at a dose of 1 mg/kg
of Prednisolone (later tapered down by 10 mg every third day), and
received an early trial non-invasive bilevel positive airway pressure
(BIPAP®) ventilation. His oxygen saturation target was set at 82 - 85%
corresponding to a PaO2 of 7-7.5 kPa as he had initially a single organ
failure with no signs of systemic sepsis, rather than the recommended
SaO2 of 88-92% (i.e. PaO2 8-8.5) [13].
This was a difficult clinical decision made after taking into
consideration the patient’s previous history of Bleomycin therapy and
the deleterious effects oxygen has in lungs previously exposed to this
drug, as we will discuss later. The possibility of an already existent
Bleomycin Induced Lung Injury causing the current respiratory failure
was also considered. The risk/benefit balance between permissive hypoxia
versus the potential toxic effects predisposed by Bleomycin was
carefully considered. Unfortunately, there is no suggestion from the
literature as to what is the optimal saturation target in this patients.
The patient did not have any other concomitant organ failures and he
was carefully monitored for any signs of developing end organ hypoxia
(acidosis, hyperlactatemia...). It was worsening hypoxemia that led to
intubation and ventilation and not other organ dysfunctions.
In spite of this, the patient continued to
deteriorate, requiring intubation and mechanical ventilation 24 hours
after admission to the ICU. Decision was made to limit his inspired
oxygen fraction in light of his Bleomycin exposure. With the above PaO2
as a target, he was ventilated using a lung protective strategy,
initially 6 ml per kilogram of IBW (Ideal Body Weight), pressure
controlled ventilation with a 10 cmH2O PEEP level, thus limiting the
plateau pressure at 30 cmH2O and was started on nitric oxide at 10-15
ppm; with FiO2 limited to 0.4 immediately following intubation.
Broncho-alveolar lavage was performed, but the
microbiological samples were negative for all the respiratory viruses
including CMV, and showed no bacterial or fungal growth. Pneumocystis
jiroveci and Aspergillus antigen were also negative. An
echocardiographic study did not show significant changes with respect to
previous studies.
CT chest appearance was recognised (by method of
exclusion) as that of a drug-induced lung injury. Opinion from
respiratory specialists agreed BLI as the most likely cause of lung
injury.
Over the following four days his respiratory failure
deteriorated further and he progressed into multi-organ failure
requiring vasopressor and inotropic support. On the 5th day after
admission to ICU his lung injury worsened with no response to any
treatment. After consulting his family treatment was withdrawn and he
was kept comfortable.
Discussion
This patient's history of exposure, the clinical
progression, the absence of any other alternative diagnosis along with
the CT appearances makes Bleomycin-induced Lung Injury the most likely
diagnosis in this case. In view of the index of suspicion and the
potential harm due to oxygen therapy this patient was managed
differently from other patients with ARDS in the ICU, particularly
regarding oxygen therapy.
Bleomycin exerts its cytotoxic effects by induction
of free radicals. Bleomycin forms a complex with Fe (II), which is
oxidized to Fe (III). This causes reduction of oxygen to free radicals,
which causes single and double-strand breaks in cellular DNA leading to
genomic instability of damaged cells. It also inhibits tumour
angiogenesis [2,14,15].
Bleomycin causes an increase in reactive oxygen
species resulting in oxidative stress and pulmonary fibrosis. It has
been found to induce apoptosis and senescence in lung cells [6].
It has also been suggested that Bleomycin induces oxygen sensitivity,
and in animal studies oxygen has been shown to augment lung injury from
Bleomycin exposure [13-17]. Previous studies cited.
Bleomycin-induced synthesis of pro-collagen by
fibroblasts as one of the key mechanisms of action of Bleomycin-induced
fibrosis, however recent data indicate the role of pro- inflammatory
cytokines IL-18 and IL-1 beta, as well as scaffold proteins such as
caveolin-1 as more important in the mechanism of injury [14-18].
This is then followed by collagen deposition by fibroblasts, which are
both directly and indirectly stimulated by Bleomycin itself [19]. Bleomycin is broken down by an enzyme found in most tissues called Bleomycin Hydrolase [5,20].
This enzyme has been shown to be involved in post-
proteasomal processing of peptides for antigen presentation; the
proteasome generates some precursor peptides which are extended at their
N-termini with the exact ligands for presentation on MHC class I
molecules [21,22].
It is thought that relative lack of this enzyme in lungs and skin
causes Bleomycin to accumulate in these organs, causing toxicity [6,20,23].
This higher concentration of drug in the lungs, combined with the high
availability of oxygen, may contribute to the propensity of the lungs to
Bleomycin-induced damage [6,21].
Among patients who have Bleomycin pulmonary toxicity
there appears to be three distinct reactions. The normal clinical
manifestation of Interstitial Pneumonia occurs weeks to months after
initiation of chemotherapeutic treatment; however a hypersensitivity
reaction and a delayed response reaction have both been described. The
hypersensitivity reaction was termed such in light of lung biopsy
results and the pathologic appearance, whereas delayed onset reaction
has occurred between two and ten years after initiation of treatment [23-25].
These distinctions are clinically important because of the response of
the pneumonitis to steroids: the Hypersensitivity Pneumonitis having a
markedly favourable response to corticosteroids, compared to the
Interstitial Pneumonitis, with a non-hypersensitive pathogenesis, for
which response to steroids is variable [2,25,26].
There are number of recognised risk factors for
developing lung injury in response to Bleomycin. The most commonly
described in the literature are dose, age, route of administration,
kidney function, and a history of smoking [27].
Cumulative dose of over 450mg was identified as an
independent risk factor for BLI27. In patients treated with Bleomycin at
doses lower than 450mg there was a 3to5% incidence of BLI. This is
increased by 13% with doses of 450-549 mg and by 17% with more than
550mg [27,28].
However, BLI has been described in patients even with low doses of
Bleomycin, and fatalities have been reported amongst them [29,30].
Patients over the age of 70 years were found to be at
higher risk of BLI, however this may be confounded by the decrease in
kidney function with advancing age [2,27,31,32].
Route of administration has been looked at as a risk
factor, and found that intravenous bolus was more likely to induce
injury than continuous intravenous infusions [33,34].
Reduced kidney function is another factor likely to increase the risk of BLI [2,27].
One study found creatinine clearance to be the most important risk
factor for decrease in lung function by a particular method of
monitoring.
Cisplatin, a nephrotoxic agent, has been extensively studied as a synergistic factor in the production of BLI [35-38]. As well as other drugs such as the granulocyte colony-stimulating factor (G-CSF) [39,40].
A history of smoking has also been shown to increase the risk of BLI [2,22,27]
Lower et al; showed radiographic alterations suggestive of BLI in 55%
of patients receiving Bleomycin who were smokers, compared with 0% of
the non-smokers, while animal studies have shown that cigarette smoke
potentiates the deleterious effect of Bleomycin on the lungs [41,42].
Some drugs have been found to minimise lung injury
induced by Bleomycin. In older literature, studies on animals showed
soluble Fas antigen, IL-1-receptor antagonists, Keratinocyte Growth
Factor, Cyclosporin, antibodies against TNF-CD3 receptor, Dexrazoxane
and Amifostine to be effective.[2] Dexrazoxane and Amifostine block Bleomycin-induced free radicals [2].
More recent animal studies have shown N-acetylcysteine combined with
Dexrazoxane to be effective as an antioxidant therapy, as well as
PG-490-88, a water-soluble derivative of Triptolide, and
Dimethyl-Prostaglandin E2. However, evidence from human studies is not
readily available in the literature [43-45].
Because of the mechanism of Bleomycin involving
oxygen- free radicals, the association between BLI and oxygen therapy
has been studied. In animal studies oxygen was found to potentiate the
effects of Bleomycin induced Lung Injury. [8,9,11,17].
It is generally accepted that high levels of FiO2 should be avoided in
patients with previous exposure to Bleomycin, although the restriction
of oxygen therapy intra and perioperatively has been debated [46,47].
Interestingly, nitric oxide has been shown to improve
lung architecture and pulmonary hypertension in animals; however the
evidence base in humans is limited [48].
Conclusion
Bleomycin is an effective chemotherapeutic drug for a
number of different tumours, including Hodgkin's lymphoma. Because of
its efficacy and because of the relatively low incidence of lung injury,
it is not feasible to discontinue its use, even in the face of a
guaranteed number of fatalities as a result of BLI.
What is important for patients who are exposed to
Bleomycin is how they are managed after initiation of chemotherapy
treatment. Firstly, monitoring of lung function and lung appearance on
radiography is important. A high index of clinical suspicion is crucial
in any patient who has undergone a treatment regimen including Bleomycin
presenting with respiratory symptoms. Identifying patients with other
risk factors such as old age, renal failure, smoking history and skin
toxicity; and careful follow up is essential. While maintaining said
index of suspicion, investigating for and treating other more common
causes of hypoxia in immunosuppressed patients, such as bacterial,
fungal or viral infections; is essential.
Patients exposed to Bleomycin and presenting with
severe respiratory failure represent a unique scenario in Critical Care
where we need to tightly control oxygen delivery to maintain the minimal
acceptable tissue oxygenation that allows survival and functionality at
a cellular level, as opposed to trying to maximise it.
Until further evidence surrounding Bleomycin and
oxygen therapy is produced, in patients requiring oxygen therapy a
careful evaluation of risks and benefits should be undertaken and
decisions should be made on an individual case-by-case basis. Early
input from oncologists, radiologists, respiratory physicians and
critical care physicians is essential in this decision-making process.
Further research into drugs attenuating BLI may aid
prognosis of future patients, however the single most important thing
remains to expand the currently limited evidence base on Bleomycin Lung
Injury, and formally follow up all patients who are treated with this
drug.
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