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...nlvn110n:mcmucacar leucocytes into the lower
This mechanism is probably important
large boluses of infectious material such
aspiration. In animal studies it is also
the clearance of Gram-negative organisms.
can also be recruited by interaction of
with organisms opsonized wilh antibody.
antibOdy mediated neutrophil recruitment
to be of vital importance in lhe control
specifically those caused by Graml16J. Finally, neutrophil function
by interaction of these cells with the
ine tumour necrosis factor [17] .
pncumonias are relatively rare. lhus lung
echanisms must function well. These
involve clearance of foreign material via
which are harmless to the delicate epilhelium
Mechanisms which are anatomic (airway
or physiologic (cough) can clear particles
y noxious, inflammatory response.
associated with lgA antibody are probably
~&IIJl""""'t inflammation and tissue destruction.
can phagocytose small numbers
without compromising significant amounts
In general, these mechanisms are active
' .airwli•Oill and/or for a relatively small inoculum
By contrast, with a large inoculum or
cenain types of bacter.ia, a significant
process must ensue for clearance. In
requires recruitment of polymorphonuclear
and some injury to the gas exchange
may occur with occasional scarring and/or
References
HY, Merrill WW. - Lung immunology: the
in lung parenchyma. Curr PulmoMI,
HY. - Host defense inpairmenls that may
.JUnu,mrn•· v infections. Clin Chest Med, 1987, 8,
WW, Naegel GP, Olchowski JJ, Reynolds HY. a subclass proteins in serum and lavage fluid
Quantitation and comparison with
A and E. Am Rev Respir Dis, 198S, 131,
373
4. Pennington JE., Ehrie MG, Hickcy WP. - Host
defen:se mechanisms against pneumonia due to Pseuddmonas
aer1~ginosa. Rev Infect Dis, 1984, 6 (Suppl . 3), 657-666.
5. Dunn MM, Toews GB, Hart D, Pierce AK. - The
effects of systemic immunization of pulmonary clearance of
PseudomoMs aeruginosa. Am Rev Respir Dis, 1985, 131,
426-431.
6. Toews GB, Vial WC. - The role of C5 in
polymorphonuclear leukocyte recruitment in response to
Streptococcus pneumoniae. Am Rev Respir Dis, 1984, 129,
82-86.
7. Hansen EJ, Hart DA, McGehee JL, Toews GB. Immune enhancement of pulmonary clearance of nontypable
Haemophilus influenzae. Infect lmmun., 1988, 56, 182-190.
8. Toews GB, Pierce AK. - The fifth component of
complement is not required for the clearance of Staphylococcus
aureus. Am Rev Respir Dis, 1984, 129. 597-601.
9. Coonrod JD. - The role of extracellular bactericidal factors in pulmonary host defense. Semin Respir Infect, 1986, 1,
118--129.
10. Shephard VL. - The role of the respiratory burst of
phagocytes in host defensc. Semin Respir Infect, 1986, 1,
99- 106.
11. Toews GB. - Determinants of bacterial clearance from
the lower respiratory tract. Semin Respir Infect, 1986, 1,
68-78.
12. Breiman RP, Horwitz MA. - Guinea pigs sublethally
infected with aerosolized Legionella pneumophila develop
humoral and cell-mediated immune responses and are protected
against lethal aerosol challenge. A model for studying host
defense against lung infections caused by intracellular pathogens.
J Exp Med, 1987, 165. 799-81 1.
.
13. Black CM, Catterall IR, Remington JS. - In vivo and
in vitro activation of alveolar macrophages by recombinant
interferon-gamma. J lmmuMI, 1987, 138, 491-495.
14. Debs RI, Fuch.s HJ, Philip R, Montgomery AB, Brunene
EN, Liggitt D, Patton JS, Shellito JE. - Lung-specific
delivery of cytokines induces sustained pulmonary and
systemic immunomodulation in rats. J lmmuMI, 1988, 140,
3482-3488.
15. Sibille Y, Naegel GP, Merrill WW, Young KR Jr, Care
SB, Reynolds HY. - Neu trophi l chemotactic activity
produced by normal and activaled human bronahoalveolar lavage
cells. J Lab Clin Med, 1987, l lO, 624--633.
16. Toews GB, Hart DA, Hansen EJ. - Effect of sysaemic
immunization on pulmonary clearance of
Haemophilus influenzoe type B. Infect Jmmun, 1985, 48,
343--349.
17. Blanchard DK, Djeu JY, Klein TW, Friedman H, Stewart
WE 2nd. - Protective effects of tumor necrosis factor in
experimental Legionella pneumophila infections of mice via
activation of PMN function. J Leukoc Bioi, 1988, 43, 429-435.
Role of bronchoalveolar lavage in the assessment of
pulmonary complications following bone marrow
and organ transplantation
S.l. Rennard
lion is a major lherapy for many diseases.
and non-neoplastic diseases are treated with
ha& LrunsplantaLion. Failure of parenchyma!
been treated with specific organ transplant.
Combination transplantations have been undertaken.
Transplantation stresses the lung and pulmonary
complications frequently develop. Bronchoalveolar
lavage (BAL) is valuable in assessment and management
374
W . MERRILL
of transplant patients. Pulmonary complications arising
from transplantation include: 1) e ffects of
immunosuppression; 2) immunological reactions; 3) drug
toxicity; and 4) "special problems".
Immunosuppression is generally required for
transplantation and infecLions, including those by
opportunisti c organisms. are frequent. BAL is
important in assessment of puJmonary infection because:
1) each lavage can sample approximately one million
alveoll and a wedged lavage can be performed in several
different segments during llle same procedure, providing
effective assc.<>Smcm of inlr.t·alveoJar infection; 2) BAL
is rehu.ively safe and easily performed compared to oilier
invasive methods used to obtain diagnostic material sucn
as transbronchial or open lung biopsy. Use of BAL is
important in thrombocytopenic patients where bleeding
represents a potential hazard; with BAL, bleeding
seldom occurs eveQ in severe cases [1]. No serious
bleeding complication occurred in over 1,000 BAL
performed in bone marrow transplant patients, many of
whom were severely thrombocytopenic.
We perfonn bronchoscopy and BAL at an "early" stage
in transplant patients, i.e. when their clinical condition
suggests possible lower respiratory tract infection. This
aggressive use of BAL oflen yields a diagnosis before
respiratory failure develops, i.e. when the patient can
better tolerate lhe procedure and when antibiotic lhcrapy
is most helpful. TransbronchiaJ biopsy is not generally
performed as it increases morbidity and mortality
wilhout dramatically increasing yield. Results of initial
BAL are available within hours and the procedure can be
repeated wilh or wilhout transbconchial biopsy when
required. If no diagnosis is obtained. open lung biopsy
can follow. Aggressive use of BAL causes little delay
in proceeding to open lung biopsy if nee{!ed, which is
rare with this approach.
Various techniques increase lhc diagnostic power of
BAL [2]. Cytological evaluation using a rapid silver
staining tcchniquc is highly effective in diagnosis of
Pnewnocystis carinii and fungal infections. However,
aspergiUus is frequently present in llle vascular spaces of
the lung but not the alveoli and, lllus, often not recovered
by BAL . Candida is often found in BAL as a
contaminant from the oropharynx. A,.llhough diagnosis of
candida pneumonia by BAL is difficult, llle number of
organisms seen cytologically, clinical circumstances and
tests such as quantification of candida antigen in SAL
are helpfu l [3]. Cytology using PAP techniques can
assist in diagnosis of a variety of viral infections. Special
diagnostic studies are available including immunohistochemical sta.ins and probes using viral specific cDNA.
With the advent of antiviral antibiotics, accurate
diagnosis and prompt Lreatmem of viml pneumonias can
greatly aid lhc clinical management of transpl:uu patients.
BAL yields a diagnosis of bacterial pneumonia [4, 51
of comparable accuracy to ihat of shc.:uh catheter culture,
transtracheal and transthoracic needle aspiration and
endotracheal suclioning. Use of quantitative culture may
be helpful in confirming lhe cliagnosis particularly in a
COIT1plex transplant patient wilh a severely abnorm:tl chest
X-ray and several potential non-infectious processes.
Quantitative BAL may have implications 8
of quantitative urine cultures.
lmmunologicaJiy mediated lung disease
at least two analogous seu ings. Fol
transplantation, llle host immune system
the donor lung as foreign leading to rc JClCii•..,
may be acute, hyperacute or a chronic form
leading to bronchiolitis obliterans [6J . rn
boJ}e llUlJTOW transplantation, the donor mm•""~' ~
cells can attack lhe host lung. Although tl]e
not normally appear to be involved in classic
versus host disease (GVHD), Lhe syndrome .
interstitial pneumonitis developing within
allogeneic transplantation is much more
patients with GVHD [7]. Chronic disease can
these patients and lead to the development o£
litis obliterans [8]. This may be a major
long-term morbid.ity and monality in bolll
allogeneic bone marrow transplantation.
It has been suggested that Lhe bronchiolar
participates in the response to infection by
lymphocytes expressing MHC antig~ns [9] and
Perhaps such ·"activation" of the epithelial
their recognition by non-identicallvnlnhtv''""o
help in exploring such concepts. The major
at present is to exclude a treatable infeclion.
be used to monitor Lhe severity of lower rest)i(SQI
inflammation by lavage differenLjal or quan
antigen specific lymphocyte activation [6) and,
in detennining anti-inflammatory lherapy.
Drugs used in transplantation can cause
toxicity, e.g. GMCSF, used to speed
marrow function following transplantation,
used to treat acute rejection, have been a~DCilll!GCI
symptoms like those of adult respi
syndrome (ARDS). Cytotoxic anti-cancer
used in bone marrow transplantation can injure
of non-neoplastic cells including those of lhe
A syndrome characterized by
diffuse alveolar haemorrhage developing
after autologous bone marrow transplantation
be a major cause of mortality. The prominent
features of the syndrome have led to the use
DAH (diffuse alveolar haemorrhage). The
parenchyma and that of other organs
affected. The condition resembles
topenic purpura but wilh no evidence of
thic intravascular haemolysis. No cong
present but platelet consumption is prom i
renal failure, CNS dysfunction and diffuse
infiltrates progressing to respiratory failure are
No infectious agents arc identified. The find.ings
are characteristic: each successive al iquot
lavaged at a single wedged site yields rctull\S
progressively bloodier. Successive aliquoLS are
in alveolar material and liule or no blood is
a bronchial wash, hence llle bleeding is al
has been confirmed at autopsy. The proc~ss
since lavages in separate lobes yield idenucal
often despite normal chest X-ray in the
region.
WORKSHOP REPORT
injuries BAL assists in exclusion of any
; recognition of the syndrome from
ings; development of therapies for these
e.g. in diffuse alveolar haemorrhage,
ilic inflammation is occasionally observed
when there are no detectable neutrophils in
blood; this has led to trials of glucocortiplace special stress on the lung.
pleural space can lead to severe
transplantation is associated with the
of right-sided pleural effusions and right
atelectasis, presumably due to subdissection. Most transplantation patients
volumes of intravenous fluids and
have some underlying disease which can
directly or indirectly. The ability of BAL
lung is helpful in assessment of the
of pulmonary complications following
Management of such complications is
important and BAL will play a
References
Finley TN, Golde DW. - Diagnostic lavage
pulmonary hemorrhage in thrombocytopenic
mtWt'lnl ii ~e.d patients. Am Rev Respir Dis, 1977, 116,
375
2. Linder J, Rennard S . - In: Bronchoa\veolar Lavage.
American Society of Clinical Pathology Press, Chicago, 1988.
3. Ness MJ, Rennard SI, Yaughan WP, Ghafouri MA, Lindcr
J. - Detection of candida antigen in bronchoalveolar lavage
fluid. ACTA 9ytologica, 1988,_32, 347- 352.
4. Thorpe ffi, Baughman RP, Frame PT, Wesseler TA,
Staneck JL. - Bronchoalveo\ar lavage for diagnosing acute
bacterial pneumonia. J Infect Dis, 1987, 155, 855- 861.
5. Kahn FW, Jones JM. - Diagnosing bacterial respiratory
infection by bronchoalveolar lavage. J Infect Dis, 1987, 155,
862- 869.
6. Dauber JH, Ze.evi A. - Lung transplantation: local
immune fwlction and pulmonary defense mechanisms. In: Lung
Immunology. R. Daniels ed., 1988, pp. 625-665.
7 . Weiner RS, Bort.in MM, Gale RP, Gluckman E, Kay HEM,
Kolb HJ, Hartz AJ, Rimm AA. - Interstitial pneumonitis
after bone marrow transplantation. Ann Intern Med, 1986, 104,
168-175.
8. Chan CK, Hyland RH, Hucheon MA, Minden MD,
Alexander MA, Kossakowslca AE, Urbanski SJ, Fyles
GM, Fraser IM, Curtis JE. - Small airways disease in
recipients of allogeneic bone marrow transplants. An analysis
of 11 cases and review of the literature. Medicine, 1987, 66,
327-340.
9. Glanville AR, Tazelaar HD, Theodore J, Imoto E, Rouse
RV, Baldwin JC, Robin ED.- The distribution of MHC class
I and II antigens on bronchial epithelium. Am Rev Respir Dis,
1989, 139, 330-334.
10. Rossi GA, Sacco 0, Lapertosa G, Corte G, Ravazzoni C,
Allergra L. - Human ciliated bron chial epithelial cells
express HLA DR antigens and HLA DR genes. Am Rev Respir
Dis, 1988, 137, SA.
Pulmonary toxicity induced by chemical agents
W.J. Martin
toxins include a spectrum of agents from
drugs to environmental pollutants. Many
lung damage at a cellular level in a
(table 1). Beuer understanding of this
improves the diagnostic and therapeutic
lo patients with serious pulmonary reactions to
oxygen is a well-known therapeutic agent,
significant pulmonary toxicity when used
anllmli,,"' " exceeding 50--60% for a long period.
i3 has been shown to be directly toxic
'11111"'"~... . ..__ _ , cells [1] there is clear evidence to
mmatory response in the mediation of
l2, 3), There is increasing evidence for
mechanisms operating in the de.veloptoxicity.
~mon~ry .~nd
US~~n•
Critical Care Medicine, Dept of Tntcma1
UniVersity School of Medidne, lndianapolls,
Oxygen is the ultimate electron acceptor in aerobic
metabolism; with its eventual reduction to water. The
cell must "handle" 0 2 carefully using a divalent
reductive process in the cytochrome system, since
univalent reduction of 0 2 results in generation of potentially lethal 0 2-derived species such as superoxide, hydrogen peroxide and the hydroxyl radical. The cell has
derived a variety of defences to prevent damage from
inadvertent generation of toxic 0 2 -deri ved species. These
include superoxide dismutase, catalase, glutathione etc.,
which detoxify these species and protect the cell.
Normally the antioxidant defences are available in excess
and generation of occasional 0 2-derived radicals is no
risk. In conditions where their generation is facilitated,
i.e. hyperoxia, paraquat toxicity. bleomycin toxicity etc.,
antioxidant defences are overwhelmed and oxidants
induce a variety of biochemical insults to the ceU such as
lipid peroxidation (cell membrane damage), DNA
damage (inhibited or altered replication) or attack of
sulphydryl bonds (protein destruction). A large variety