Netherlands Journal

netherlands journal of critical care
Figure 3. (400X HE) postmortem lung microscopy showing characteristic signs of lung
fibroses.
Figure 4. (400x, HE) postmortem lung microscopy showing characteristic signs of cytotoxic
therapy: atypical type II pneumocyte (arrow).
this patient’s group is poor, with a 5 year progression-free survival of
40% [20,21] and a 5 year-survival of 48 %[20,21].
Because of its infrequent occurrence and often complicated multidisciplinary
treatments, the best results are obtained in specialized
centres [21].
Bleomycin therapy is associated with Bleomycin Induced Pneumonitis
(BIP) which can lead to potentially lethal pulmonary fibrosis
[3].
The incidence of BIP is, depending on the criteria used for the
diagnosis, 0-46% [1], the mortality of all the patients treated with
bleomycin is 3%. Clinical diagnosis of BIP is difficult due to its
resemblance to other conditions such as pneumonia and pulmonary
metastases. Clinical signs are non-productive cough, exert
ional dyspnoea and fever. Physical examination is not conclusive,
and chest radiographs often show bilateral infiltrates and/or lobar
consolidations[1,2]. Lung function changes are found in half of the
patients treated with bleomycin [3], but it is not possible to use these
symptoms to accurately predict patients likely to develop BIP [1,3,6].
The diagnosis of BIP is therefore only made by the exclusion of other
diseases.
The pathogenesis of BIP has mainly been investigated in animals.
The antitumour effect of bleomycin works through inhibition of
tumour angiogenesis and induction of tumour cell death. The mechanisms
of the toxic effect are not known in detail, but the formation
of free radicals and cytokines may lead to endothelial damage. Free
radicals that are produced directly after oxidation of the Bleomycin-
Fe II complex cause dysfunction of the antioxidant system activity
and subsequently lead to DNA damage from unopposed endogenous
super oxide production [1,3,14]. Bleomycin also has some potential
for direct DNA-cleaving [1,5,15] and this damaging effect on DNA
might be involved in late-onset, previously asymptomatic lung
damage following bleomycin administration[1]. A five fold increase
has been shown with 70% supplemental oxygen versus ambient air
in animal studies [8]. However in humans, clear data showing an
increased risk of BIP with concomitant oxygen supplementation are
lacking [1].
Bleomycin is mainly eliminated by the kidneys and deactivated
by the enzyme bleomycin hydrolase, which is produced in the liver,
spleen, bone marrow and intestine, but not in the lungs or skin. This
is why toxicity occurs mainly in these organs [1,3,8,12]. Genetic variance
in the enzyme setup may partially explain individual difference
in susceptibility [12,19].
Risk factors for development of BIP are: cumulative doses of bleomycin
(> 400 U), age >40 years, a creatinine clearance