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1. Editorials
Am J Respir Crit Care Med Vol 162. pp 2017–2022, 2000
Internet address: www.atsjournals.org
Targeting Tuberculosis Prevention
Much of tuberculosis control is based on the current under-
standing of factors that influence transmission of Mycobacte-
rium tuberculosis and that lead to active tuberculosis among
persons who acquire the infection (1). One of these activities,
contact investigation, is intended to identify persons (con-
tacts) who have acquired tuberculosis infection from a newly
discovered active case, thereby enabling targeting of preven-
tive treatment to a group at high risk of developing active tu-
berculosis, this being the main goal of the activity. The study
by Marks and coworkers (2) in this issue of the American
Journal of Respiratory and Critical Care Medicine (pp. 2033–
2038) presents an assessment of the current status of contact
investigation and treatment of latent tuberculosis infection
among contacts in tuberculosis control programs in the United
States. The data suggest that programs are only moderately
successful in identifying, evaluating, and, when indicated,
treating infected contacts. The study also implicitly makes the
point that there is still much to learn about this component of
tuberculosis control and that both new sociobehavioral in-
sights and technologic innovations are needed to make this in-
tervention most efficient and effective.
The need to focus efforts to prevent tuberculosis in popula-
tions and individuals, such as contacts, at high risk for devel-
oping the disease is strongly emphasized in the recent Institute
of Medicine report, Ending Neglect: The Elimination of Tuber-
culosis in the United States (3). Even stronger emphasis is pro-
vided in the new statement by the American Thoracic Society
and the Centers for Disease Control and Prevention (4), “Tar-
geted Tuberculin Testing and Treatment of Latent Tuberculo-
sis Infection.”
The principle that underlies the emphasis on contact inves-
tigation is that a person is most likely to develop active tuber-
culosis soon after being infected, although the potential ex-
tends throughout the person’s lifetime (5). Inferences from
epidemiological studies conducted since the early 1990s, using
molecular methods, suggest that the risk soon after infection
might be greater than was determined to be the case in the
early 1960s (6–8). Molecular epidemiological data also have
shown that, especially among persons with human immunode-
ficiency virus (HIV) infection, outbreaks, including outbreaks
of multiple drug-resistant tuberculosis, may occur with fright-
ening speed (9, 10). The implication of these findings is that
contact investigation can no longer be undertaken at a lei-
surely pace but must be accomplished rapidly if it is to have its
full benefit. It is encouraging to note that Marks and col-
leagues reported that the interval between diagnosis and initi-
ation of treatment of latent tuberculosis infection was 30 days.
However, the time of diagnosis was not defined, leaving room
for unreported delays, and all the patients were in public sec-
tor tuberculosis control programs. It would be useful to know
if there were differences between public sector and private
sector patients, given that it is likely that, increasingly, patients
will be managed by private physicians.
It is increasingly evident that “close and prolonged” con-
tact is not necessary for transmission of M. tuberculosis to oc-
cur. The weight of evidence is strong that transmission may
occur with casual contact, as may be inferred from molecular
epidemiological studies (8, 11). In a report from San Fran-
cisco, among a group of patients with tuberculosis caused by
organisms having the same DNA fingerprint, some had easily
found exposures to one another, whereas others had expo-
sures that were identified only after exhaustive review of hos-
pital and clinic records and hotel and shelter registries (8).
Findings such as these indicate that the “concentric circle”
paradigm for contact investigation is inadequate (12). Yet, in
the data from Marks and colleagues, a full one-third of the in-
dex cases identified only household contacts. It might be in-
ferred that the fact that such a high proportion had only
household contacts identified was a consequence of insuffi-
cient probing on the part of the interviewer.
Under current circumstances, in-depth cultural under-
standing is required to identify the broad group of contacts
that might have been infected by a given index case. For ex-
ample, Marks and coworkers found that, although foreign-
born patients did not identify more close contacts, they had
more household contacts. This seems contradictory but may
be a function of different family and household structures.
The finding does, however, clearly indicate that cultural un-
derstanding is needed to conduct and interpret contact inter-
views with foreign-born patients. Given that in 1999, 42% of
the new cases nationally were among persons born outside of
the United States, competence in conducting interviews with
foreign-born patients is and will be increasingly important.
Homeless persons, a group at very high risk of tuberculosis,
also serve as an example of the need for specialized contact in-
terviewing. Marks and coworkers found homelessness to be
significantly correlated with having no contacts identified. In
San Francisco in the early 1990s this was the case as well.
However, because of concerns that the contact interview was
not being conducted in a way to elicit contacts from homeless
persons when in fact there were significant exposures occur-
ring, staff were retrained and provided with information on
the homeless lifestyle. The number of new cases with no con-
tacts identified decreased from 25 to 5% between 1990 and
1997 (13).
A number of studies have shown that index patients having
acid-fast bacilli in their sputum, cavitation on chest films, and
severe cough are more infectious for their contacts than pa-
tients who do not meet these criteria. Rarely do children have
these characteristics (1). Priority in contact investigation is
generally given to the contacts of more highly infectious pa-
tients (12). Reports, however, have described tuberculosis in
an embalmer who handled the body of a person who died of
tuberculosis, an outbreak the source for which was a 9-year-
old child, and an assessment that estimated approximately
20% of the new tuberculosis cases in San Francisco resulted
from transmission from a sputum-negative source case (14–
16). Each of these studies calls into question the traditional
approaches to priority assignment in contact investigation and
suggests that the investigative base must be broadened, a rec-
ommendation contained in the Institute of Medicine report (3).

2. 2018 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 162 2000
The shortcomings of our current diagnostic tools for identi-
fying latent tuberculosis infection were also illustrated in the
foreign-born contacts as reported by Marks and coworkers.
High rates of initial tuberculin skin test positivity and skin test
conversions from an initially negative to a positive test at the
time of follow up were found among foreign-born contacts. As
the authors note, it cannot be determined whether the initial
positive test was the result of recent or prior infection with M.
tuberculosis that occurred in their country of origin, cross-sen-
sitization caused by bacillus Calmette-Guèrin (BCG) vaccina-
tion, or infection with nontuberculous mycobacteria. Like-
wise, the apparent conversions could be due to “boosting” of a
waned reaction but being indistinguishable from a new infec-
tion. The need for new tools with which to make a more accu-
rate diagnosis of latent tuberculosis infection is a point empha-
sized strongly in the Institute of Medicine report (3). The
inefficiency and inaccuracy of the tuberculin skin test limit the
usefulness of the whole prevention strategy.
There is no value in identifying infected contacts if there is
not a good mechanism for ensuring that treatment of latent in-
fection is provided. In the report by Marks and colleagues,
only 56% of those who started treatment completed it. Given
the high-risk status of close contacts (all of those in the study
were close contacts), this is a sorry result. Perhaps the comple-
tion rate would have been better if the newly recommended
2-month regimen of rifampin and pyrazinamide had been
used, although its effectiveness has been documented only in
persons with HIV infection (4). With a short-course regimen,
treatment could be administered under direct observation to
ensure completion of therapy as in treating active tuberculosis.
In summary, data from the assessment conducted by Marks
and coworkers suggest that many improvements are needed if
contact investigation is to provide a major contribution to tu-
berculosis elimination in the United States. The data also sug-
gest that we are addressing only the “easy” parts of contact
investigation and are doing that only moderately well. To real-
ize the potential of this crucial element of tuberculosis control
there must be increased emphasis on eliciting contacts in a
more comprehensive way, completing the evaluation more
rapidly, and being more effective in completing treatment of
latent infection. At the same time there needs to be intensified
research to identify a more accurate test for the diagnosis of
latent tuberculosis infection. Advances such as these will pro-
vide the wherewithal to move more rapidly toward the elimi-
nation of tuberculosis in the United States, as called for in the
Institute of Medicine report.
PHILIP C. HOPEWELL
San Francisco General Hospital
University of California San Francisco
San Francisco, California
References
1. Hopewell PC. Factors influencing the transmission and infectivity of My-
cobacterium tuberculosis: implications for clinical and public health
management. In: Sande MA, Hudson LD, Root RK, editors. Respira-
tory infections. New York: Churchill Livingstone; 1986. p. 191–216.
2. Marks SM, Taylor ZT, Qualls NL, Shrestha-Kuwahara, RJ, Wilce MA,
Nguyen, CH. Outcomes of contact investigations of infectious tuber-
culosis patients. Am J Respir Crit Care Med 2000;162:2033–2038.
3. Institute of Medicine. Ending neglect: the elimination of tuberculosis in
the United States. Washington DC: National Academy Press; 2000.
4. American Thoracic Society/Centers for Disease Control and Prevention.
Targeted tuberculin testing and treatment of latent tuberculosis infec-
tion. Am J Respir Crit Care Med 2000;161:S221–S247.
5. Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis: general
review. Adv Tuberc Res 1970;17:28–106.
6. Genewein A, Telenti A, Bernasconi C, Mordasini C, Weiss S, Maurer
AM, Rieder HL, Schopfer K, Bodmer T. Molecular approach to iden-
tifying route of transmission of tuberculosis in the community. Lancet
1993;342:841–844.
7. Alland D, Kalkut GE, Moss AR, McAdam RA, Hahn JA, Bosworth W,
Drucker E, Bloom BR. Transmission of tuberculosis in New York
City: an analysis by DNA fingerprinting and conventional epidemio-
logic methods. N Engl J Med 1994;330:1710–1716.
8. Small PM, Hopewell PC, Singh SP, Paz EA, Parsonnet J, Ruston DC,
Schechter GF, Daley CL, Schoolnik GK. The epidemiology of tuber-
culosis in San Francisco: a population-based study using conventional
and molecular methods. N Engl J Med 1994;330:1703–1709.
9. Daley CL, Small PM, Schecter GF, Schoolnik GK, McAdam RA, Jacobs
WR Jr, Hopewell PC. An outbreak of tuberculosis with accelerated
progression among persons with human immunodeficiency virus. An
analysis using restriction-fragment-length polymorphisms. N Engl J
Med 1992;326:231–235.
10. Edlin BR, Tokars JI, Grieco MH, Crawford JT, Williams J, Sordillo EM,
Ong KR, Kilburn JO, Dooley SW, Castro KG, et al. An outbreak of
multidrug-resistant tuberculosis among hospitalized patients with the
acquired immunodeficiency syndrome. N Engl J Med 1992;326:1514–
1521.
11. Dwyer B, Jackson K, Raios K, Sievers A, Wilshire E, Ross B. DNA
restriction fragment analysis to define an extended cluster of tuber-
culosis in homeless men and their associates. J Infect Dis 1993;167:
490–494.
12. Etkind SC, Veen J. Contact follow-up in high- and low-prevalence coun-
tries. In: Reichman LB, Hershfield ES, editors. Tuberculosis: a com-
prehensive international approach. New York: Marcel Dekker; 2000.
p. 377–399.
13. Jasmer RM, Hahn JA, Small PM, Daley CL, Behr MA, Moss AR,
Creasman JM, Schechter GF, Paz EA, Hopewell PC. A molecular ep-
idemiologic analysis of tuberculosis trends in San Francisco, 1991–
1997. Ann Intern Med 1999;130:971–978.
14. Sterling TR, Pope DS, Bishai WR, Harrington S, Greshon RR, Chaisson
RE. Transmission of Mycobacterium tuberculosis from a cadaver to an
embalmer. N Engl J Med 2000;342:246–248.
15. Curtis AB, Rizdon R, Vogel R, McDonough S, Hargreaves J, Ferry J,
Valway S, Onorato IM. Extensive transmission of Mycobacterium tu-
berculosis from a child. N Engl J Med 1999;341:1491–1495.
16. Behr MA, Warren SA, Salamon H, Hopewell PC, Ponce de Leon A,
Daley CL, Small PM. Transmission of Mycobacterium tuberculosis
from acid-fast bacilli smear-negative patients. Lancet 1999;353:444–
449.
Fibrinogen, Stroke, and Obstructive Sleep Apnea
An Evolving Paradigm of Cardiovascular Risk
Obstructive sleep apnea (OSA) has been linked increasingly
to cardiovascular disease. Disturbances in inflammatory and
coagulation profiles, particularly cytokines and fibrinogen,
have emerged as possible mediators of cardiovascular patho-
physiology in OSA. In the current issue of the Journal (pp.
2039–2042) Wessendorf and colleagues provide further insight
into possible interactions between plasma fibrinogen and is-
chemic stroke in patients with OSA (1).
Fibrinogen, a plasma protein synthesized in the liver, is in-
timately involved in blood coagulation. Fibrinogen is also an
acute-phase protein, increasing in response to infection and
inflammation (2). Thrombosis superimposed on atherosclero-

3. Editorials 2019
sis contributes importantly to cardiovascular events (2). Fi-
brinogen enhances thrombosis and atherosclerosis by effects
on platelet aggregation, blood rheology, and endothelial cell
injury (3). Fibrinogen and its degradation products may also
damage blood vessel walls by stimulating smooth muscle pro-
liferation and migration (4).
Notwithstanding these theoretical constructs linking fibrin-
ogen to vascular disease, what is the evidence that high fibrin-
ogen is associated with increased cardiovascular events? The
first clear epidemiologic data, from the Northwick Park Heart
Study, showed that initial fibrinogen levels were associated with
cardiovascular mortality independent of other risk factors (5).
These early findings have been echoed by a series of other
studies (2, 6). The data implicating fibrinogen are especially strik-
ing for myocardial infarction and stroke (7). In patients with un-
stable angina or non-Q wave myocardial infarction, high fi-
brinogen predicts subsequent myocardial infarction and death
(8). A cerebrovascular correlate to this is that in stroke survi-
vors hyperfibrinogenemia is an independent risk factor for
subsequent stroke, heart attack, and cardiovascular death (9).
Like fibrinogen, OSA may also be implicated as a risk fac-
tor for first stroke, recurrent stroke, and poststroke mortality
(1, 10–12). OSA patients have increased morning levels of fi-
brinogen (13). Elevated fibrinogen may be one mechanism
linking OSA to stroke. The present study by Wessendorf and
coworkers (1) of patients with ischemic stroke, describes first
that stroke patients have a high prevalence of OSA, and sec-
ond that stroke patients with OSA also have higher fibrinogen
levels. The authors suggest that high fibrinogen may contrib-
ute to increased vascular morbidity in OSA patients, and
make the important point that OSA should be considered
when examining fibrinogen as a vascular risk factor.
As with any cross-sectional study, there are clear but un-
derstandable constraints and limitations regarding their data.
Single measurements of fibrinogen in the morning leave open
the question of whether fibrinogen rises after untreated OSA
(13), or whether patients with OSA and stroke have persis-
tently high prevailing levels of fibrinogen. There is a paucity of
patients with severe sleep apnea, so that the regression slopes
described are dependent on a small number of subjects with
the most severe apnea. Nor does the study provide any sugges-
tion as to what we are to make of those patients with compara-
tively severe apnea, but in whom fibrinogen levels were at the
lower limits of measurements. Last, the strength of association
described between OSA and fibrinogen is only modest, and no
causality is demonstrated. Any etiologic link to stroke is ex-
trapolation, pending more robust data.
Nevertheless, this study raises a number of interesting
questions. First, the lack of severe apnea in their patient sam-
ple encourages speculation that patients with more severe ap-
nea did not survive the stroke. Second, it is widely held that
body mass index (BMI) and other measures of obesity are de-
terminants of fibrinogen (14). Obesity is linked to a higher
prevalence of sleep apnea. It is notable that Wessendorf and
colleagues found that OSA, but not BMI, was independently
associated with elevated fibrinogen (1). Perhaps if OSA were
factored into epidemiologic studies of fibrinogen, the associa-
tion with BMI would be weaker and less consistent. This ca-
veat may be relevant to a host of measures of cardiovascular
risk presently ascribed to obesity per se, and obtained without
adjusting for the potential influence of OSA.
A third question concerns why patients with OSA should
have high fibrinogen. It is conceivable that the myriad of bio-
chemical, neurohumoral, inflammatory, and metabolic distur-
bances induced by OSA may elicit increases in fibrinogen.
Less biologically plausible is that high fibrinogen may induce
OSA. Could the high fibrinogen be merely a reflection of the
acute-phase reaction to the stroke insult, with stroke being
worse and fibrinogen consequently higher in those patients
with preexisting OSA? Fibrinogen is itself highly variable, be-
ing influenced by behavioral, environmental, seasonal, phar-
macologic, and other factors (3). Fibrinogen levels are high af-
ter stroke, and remain significantly elevated for at least 6 wk
after a stroke (15). Data showing plasma cell infiltration and
interstitial edema in the uvula mucosa of patients with OSA
may also be relevant (16). The investigators postulate that soft
palate inflammation may contribute to upper airway occlusion
during sleep. These data also raise the speculative but provoc-
ative possibility that airway inflammation associated with
OSA may induce increases in plasma fibrinogen.
A fourth issue is the difference between men and women
not only in the prevelance of OSA, but also in the measure-
ments and implications of fibrinogen. Average fibrinogen lev-
els are higher in women (17). Plasma fibrinogen rises after
menopause and may be reduced by hormone replacement
(18), variables not addressed in the present study (1). Mecha-
nisms linking fibrinogen to the development of cerebrovascu-
lar disease may be different in males and females. In the
Framingham Heart Study, fibrinogen was linked to heart at-
tack and stroke in men (6). In women, fibrinogen was also
strongly linked to heart attack, but there was only a weak as-
sociation with stroke.
Finally, and perhaps most important, can a reduction in fi-
brinogen be achieved, and will this affect cardiovascular out-
comes in patients with OSA? Treatment of OSA with nasal
continuous positive airway pressure (CPAP) may elicit small
decreases in fibrinogen (13). A number of pharmacologic agents,
many directed at lipid lowering, have serendipitously been found
to also lower plasma fibrinogen (19). In the Bezafibrate In-
farction Prevention Study (20), baseline fibrinogen was con-
firmed as an independent predictor of cardiovascular events
in patients with coronary artery disease. Preliminary data sug-
gest that in patients with high baseline fibrinogen levels, re-
duction of fibrinogen by bezafibrate therapy was linked to
decreased cardiac death and ischemic stroke. Whether fibrino-
gen represents a surrogate for other more direct mediators of
cardiovascular risk remains to be determined. This will be im-
portant for understanding the pathophysiologic interactions
between fibrinogen, OSA, and stroke.
Acknowledgment: The authors appreciate the helpful suggestions and com-
ments of Dr. John Greenwood, MBChB, PhD.
ABU S. M. SHAMSUZZAMAN
VIREND K. SOMERS
Divisions of Hypertension and Cardiovascular Diseases
Department of Internal Medicine
Mayo Clinic and Mayo Foundation
Rochester, Minnesota
References
1. Wessendorf T, Thilmann A, Wang Y, Schreiber A, Konietzko N, Teschler
H. Fibrinogen levels and obstructive sleep apnea in ischemic stroke.
Am J Respir Crit Care Med 2000;162:2039–2042.
2. Ernst E. Fibrinogen as a cardiovascular risk factor—interrelationship
with infections and inflammation. Eur Heart J 1993;14(Suppl K):82–87.
3. Eber B, Schumacher M. Fibrinogen: its role in the hemostatic regulation
in atherosclerosis. Semin Thromb Hemost 1993;19:104–107.
4. Smith EB, Keen GA, Grant A, Stirk C. Fate of fibrinogen in human ar-
terial intima. Arteriosclerosis 1990;10:263–275.
5. Meade TW, North WR, Chakrabarti R, Stirling Y, Haines AP, Thomp-
son SG, Brozovie M. Haemostatic function and cardiovascular death:
early results of a prospective study. Lancet 1980;1:1050–1054.

4. 2020 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 162 2000
6. Kannel W, Wolf P, Castelli W, D’Agostino R. Fibrinogen and risk of car-
diovascular disease: The Framingham Study. JAMA 1987;258:1183–
1186.
7. Di Minno G, Mancini M. Measuring plasma fibrinogen to predict stroke
and myocardial infarction. Arteriosclerosis 1990;10:1–7.
8. Toss H, Lindahl B, Siegbahn A, Wallentin L, FRISC Study Group. Prog-
nostic influence of increased fibrinogen and C-reactive protein levels
in unstable coronary artery disease: fragmin during instability in coro-
nary artery disease. Circulation 1997;96:4204–4210.
9. Resch KL, Ernst E, Matrai A, Paulsen HF. Fibrinogen and viscosity as
risk factors for subsequent cardiovascular events in stroke survivors.
Annu Intern Med 1992;117:371–375.
10. Dyken ME, Somers VK, Yamada T, Ren ZY, Zimmerman MB. Investi-
gating the relationship between stroke and obstructive sleep apnea.
Stroke 1996;27(3):401–407.
11. Palomaki H, Partinen M, Erkinjuntti T, Kaste M. Snoring, sleep apnea
syndrome, and stroke. Neurology 1992;42(7, Suppl 6):75–81.
12. Bassetti C, Aldrich MS, Chervin RD, Quint D. Sleep apnea in patients
with transient ischemic attack and stroke: a prospective study of 59
patients. Neurology 1996;47(5):1167–1173.
13. Chin K, Ohi M, Kita H, Noguchi T, Otsuka N, Tsuboi T, Mishima M,
Kuno K. Effects of NCPAP therapy on fibrinogen levels in obstruc-
tive sleep apnea syndrome. Am J Respir Crit Care Med 1996;153(6, Pt
1):1972–1976.
14. Barasch E, Benderly M, Graff E, Behar S, Reicher-Reiss H, Caspi A, Pelled
B, Reisin L, Roguin N, Goldbourt U. Plasma fibrinogen levels and their
correlates in 6457 coronary heart disease patients: the Bezafibrate Infarc-
tion Prevention (BIP) Study. J Clin Epidemiol 1995;48:757–765.
15. Beamer NB, Coull BM, Clark WM, Briley DP, Wynn M, Sexton G. Per-
sistent inflammatory response in stroke survivors. Neurology 1998;50:
1722–1728.
16. Sekosan M, Zakkar M, Wenig BL, Olopade CO, Rubinstein I. Inflam-
mation in the uvula mucosa of patients with obstructive sleep apnea.
Laryngoscope 1996;106:1018–1020.
17. Kannel WB. Influence of fibrinogen on cardiovascular disease. Drugs
1997;54:32–40.
18. Meade TW, Dyer S, Howarth DJ, Imeson JD, Stirling Y. Antithrombin
III and procoagulant activity: sex differences and effects of the meno-
pause. Br J Haematol 1990;74:77–81.
19. Cook NS, Ubben D. 1990. Fibrinogen as a major risk factor in cardiovas-
cular disease. Trends Pharmacol Sci 11:444–451.
20. Behar S. Lowering fibrinogen levels: clinical update. BIP Study Group.
Bezafibrate Infarction Prevention. Blood Coagul Fibrinolysis 1999;10
(Suppl 1):S41–S43.
Hypertensive Pulmonary Vascular Disease
Dawn of the Age of Prevention?
In this month’s issue of AJRCCM (pp. 2252–2259), Faul and
colleagues present data that a compound extracted from a tra-
ditional Chinese herb (Tripterygium wilfordii Hook. f.) atten-
uates neointimal reaction and pulmonary hypertension in rats
that underwent pneumonectomy and were given monocrota-
line to cause lung vascular injury (1). The compound, triplotide,
has antiproliferative effects perhaps related to inhibition of
NF-␬B activation and enhanced apoptosis. Models of hyper-
tensive pulmonary vascular disease (HPVD) resulting in changes
similar to those in the small pulmonary arteries seen in primary
pulmonary hypertension have been difficult to develop, and
monocrotaline is a well-known but poorly understood stimu-
lus involving injury and repair of the resistance vessels. Pneu-
monectomy in the study by Faul and coworkers presumably
enhanced the response by causing a doubling of flow and an
increase in pressure in the remaining lung. The authors con-
clude that it is time to think of therapies for HPVD that are
based on the pathogenic abnormalities that result in neointimal
formation, and we, along with many others in the field, agree.
Major advances in the management of patients with HPVD
have occurred in the last two decades (2). The first break-
through was the observation that chronic vasodilator therapy
could cause prolonged clinical remission in the 25% of pa-
tients with persistent pulmonary hypertension (PPH) who
have a reversible vasoconstrictor component to the disease.
The mid-1980s brought the landmark discovery that intrave-
nous prostacyclin markedly improves functional status and
survival in a high percentage of patients with PPH regardless
of vasodilator effect. The mechanism of the beneficial effect of
prostacyclin independent of vasodilation is not known, but
speculation is that an antiproliferative, antiplatelet, or remod-
eling effect is responsible. A new wave of clinical trials is un-
derway in a search for alternative methods of delivery of pros-
tacyclin, including oral, inhaled, and subcutaneous. Inhaled
nitric oxide and oral endothelin antagonists are under study as
well. How these therapies may affect neointimal formation re-
mains to be determined.
The second major area of progress has involved insights
into the pathogenesis of HPVD. The era of subsetting PPH by
pathological type was effectively brought to an end by the
finding that all variations of vascular pathology could be found
in the lungs of patients with familial PPH, and that other forms
of HPVD including scleroderma, cirrhosis, and that associated
with human immunodeficiency virus (HIV) shared these patho-
logical subsets. Beginning in the 1990s a number of investiga-
tors have found that abnormalities of multiple endogenous
mediators can be found in PPH and other forms of HPVD (2).
These mediator abnormalities include excessively high levels
of circulating thromboxanes, endothelin, and coagulation prod-
ucts, and low levels of NO and prostacyclin. What has remained
unclear is whether these abnormalities represent responses of
the vascular wall to injury, or whether one or more of these
observed abnormalities promotes primary pathogenesis. All
potentially are involved in the proliferative lesions of HPVD.
While these clinical observations have been accumulating,
studies of the biology of the vascular wall have yielded insights
into the abnormalities seen in HPVD. Surprisingly, the endot-
helium of the plexiform lesion becomes monoclonal in PPH
(3). What this means mechanistically is tantalizingly unclear.
Endothelial dysfunction with reduced prostacyclin synthase
and transforming growth factor ␤ (TGF-␤) receptor mRNA
has been found. Clearly a variety of proliferative and fibro-
blastic genes must be active in HPVD, because the pathologi-
cal condition of the vessels displays this phenotype. The initi-
ating stimulus (or stimuli) for disease activation is unknown
and the sequence of the cascade leading to the vasculopathy is
unknown. When the mystery of this process is unraveled, at-
tempts to intercede with drugs that inhibit neointimal prolifer-
ation will be easier to apply.
The gene that causes familial primary pulmonary hyperten-
sion has been discovered to be bone morphogenetic protein
receptor 2 (BMPR2) (4, 5). This gene is part of the TGF-␤ re-
ceptor superfamily. It was tested because of its potential as a
vascular growth receptor and thus was considered an excellent
positional candidate. Of further interest, we have found that at
least 25% percent of patients tested with “sporadic” PPH also
possess a mutation in BMPR2 (6). We do not yet know
whether patients with HPVD from other associations such as

5. Editorials 2021
liver disease, HIV, anorexigens, or scleroderma will have simi-
lar mutations, but the finding that this gene is a common fea-
ture in PPH should propel investigations into pathogenesis to
the next phase. Mutations in BMPR2 have been found in in-
tra- and extracellular domains and we suspect may all result in
altered and reduced signal transduction. Work is underway to
define the functional abnormalities of BMPR2 in transfected
cells and transgenic species. It seems likely that a second hit,
either as an environmental event or activation of a second
gene, may be necessary for abnormalities in BMPR2 to ini-
tiate HPVD. Studies of BMPR2 in monocrotaline-treated rats,
in other models of HPVD, and in affected vessels of patients
with PPH should yield insights into the pathologic changes
and pave the way for treatment and, more powerfully, preven-
tive therapies. This is an exciting time to be involved in the
problem of pulmonary vascular disease.
JOHN H. NEWMAN
KIRK B. LANE
Center for Lung Research
Department of Medicine
Vanderbilt University School of Medicine
Nashville, Tennessee
References
1. Faul JL, Nishimura T, Berry GJ, Benson GV, Pearl RG, Kao PN. Trip-
tolide attenuates pulmonary arterial hypertension and neointimal for-
mation in rats. Am J Respir Crit Care Med 2000;162:2252–2259.
2. Rich S, editor. Primary pulmonary hypertension: executive summary
from the world symposium. Geneva, Switzerland: World Health Or-
ganization; 1998. Available via the Internet (http://www.who.int/ncd/
cvd/pph.html).
3. Lee SD, Shroyer KR, Markham NE, Cool CD, Voelkel NF, Tuder
RM. Monoclonal endothelial cell proliferation is present in primary
but not secondary pulmonary hypertension. J Clin Invest 1998;101:
927–934.
4. The International PPH Consortium, Lane KB, Machado VC, Pauciulo
MW, Thomson JR, Phillips JA III, Loyd JE, Nichols WC, Trembath
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Lung-protective Ventilation in Acute Respiratory
Distress Syndrome
Protection by Reduced Lung Stress or by Therapeutic Hypercapnia?
Mechanical ventilation using inappropriate settings can pro-
duce acute parenchymal lung injury and an acute inflamma-
tory response in the lung. The associated release of cytokines
into alveoli and the systemic circulation (1, 2) may contribute
to multiple organ dysfunction (3, 4) and mortality in acute re-
spiratory distress syndrome (ARDS). “Lung-protective” ven-
tilation strategies attempt to avoid these consequences by lim-
iting peak lung distension and preventing end-expiratory
collapse, accepting the hypercapnia that often results; such
strategies reduced mortality rate in ARDS in two randomized
trials (5, 6). Hypercapnia is generally regarded as an undesir-
able consequence of limiting alveolar stress, but in a series of
studies, Laffey, Kavanagh and colleagues have questioned
whether hypercapnic acidosis per se may contribute to the
benefits of lung-protective ventilation. They showed that in
isolated perfused rabbit lungs, respiratory acidosis protected
the lung from ischemia–reperfusion injury (7), whereas respi-
ratory alkalosis potentiated the injury (8). The protective ef-
fect of respiratory acidosis was associated with inhibition of
xanthine oxidase (7), and was prevented by buffering the aci-
dosis (9); i.e., the protection resulted from the acidosis rather
than hypercapnia. In this issue of the Journal (pp. 2287–2294)
(10), they extend these observations to intact anesthetized
rabbits. The control and study groups received identical venti-
lation, but in the study group the inspired CO2 concentration
was increased, producing “therapeutic hypercapnia” (PaCO2
approximately 105 mm Hg, pH 7.05). Left lung ischemia and
reperfusion were then induced by clamping the left hilum for
75 min, then releasing the left hilum and ligating the right hi-
lum. After a further 90 min, the left lung was evaluated. The
hypercapnic group showed substantially lower concentrations
of protein and tumor necrosis factor-alpha (TNF-␣) in lung la-
vage fluid, less pulmonary edema, better lung compliance,
lower lung 8-isoprostane and nitrotyrosine concentrations
(suggesting less lipid peroxidation and peroxynitrite-induced
injury, respectively), and less apoptosis than the control group.
The study group also showed less increase in blood lactate
concentration, but the cause and significance of the elevated
lactate concentration are not clear. The animals were not se-
verely hypoxemic, but cardiac output could have fallen (it was
not measured) after reperfusion of the left lung, and could
have been better maintained in the hypercapnic group (11).
Tissue oxygen unloading may also have been facilitated in the
hypercapnic group (12). However, as the authors acknowl-
edge, the rate of lactate production and clearance are both af-
fected by acid–base disturbances (13), and the animals re-
ceived infusions of lactated Ringer’s solution. Therefore, the
difference between groups may have been caused by different
lactate kinetics resulting from the pH difference. We should
be cautious in attributing it to the prevention of dysoxia or
other systemic “protective” effects of hypercapnic acidosis, as
suggested by the authors.
However, other studies have suggested cytoprotective ef-
fects from acidosis. In a series of experiments, Lemasters and
colleagues showed that cultured cells remained viable during 5 h
of total anoxia providing the intracellular pH remained low. If
the intracellular pH increased during anoxia or after reoxy-
genation, cell death occurred (14). These effects were inde-
pendent of changes in intracellular Ca2⫹
, and also occurred in
an isolated perfused heart model (14). Acidosis suppresses the
respiratory burst (15) and cytokine expression (16) in mac-
rophages. Laffey and Kavanagh have discussed other studies
suggesting cytoprotection by hypercapnic acidosis (17). There-
fore, although it seems improbable that all of the apparent
benefit of lung protective ventilation is a direct consequence
of hypercapnia, the hypothesis addressed by Laffey and col-

6. 2022 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 162 2000
leagues is an important and reasonable one. If “lung-pro-
tective ventilation” in ARDS does reduce pulmonary and
systemic inflammation (2), and perhaps multiple organ dys-
function (3, 4), hypercapnic acidosis per se could conceivably
be partly responsible, perhaps by downregulating inflamma-
tory cells (15, 16), and possibly other mechanisms, as well as
by inhibition of xanthine oxidase. This possibility deserves fur-
ther study.
The intriguing findings in the study of Laffey and cowork-
ers (10) raise a number of important questions. Would hyper-
capnia provide similar protection in other models of lung in-
jury, and what other mechanisms may be involved? Would
protection still occur if hypercapnia was induced after isch-
emia–reperfusion (or other insults) rather than before, as in
this study? How long will the effect persist? The inhibition of
xanthine oxidase appeared to result mainly from extracellular
acidosis, and so may persist until renal compensation occurs.
However, other effects of acidosis, including suppression of
the respiratory burst and cytokine expression by macrophages
(15, 16), probably result from intracellular acidosis. Intracellu-
lar acidosis is corrected much more rapidly during hypercap-
nia (within a few hours) than the extracellular acidosis, by ac-
tive membrane ion exchangers that protect intracellular pH.
Would metabolic acidosis produce the same effect? Finally, if
the protective effect does occur in models of lung injury other
than ischemia–reperfusion, and in patients, would it result in
improved outcome? Would any possible adverse systemic ef-
fects of acute hypercapnia offset the benefit? Apart from its
contraindication in intracranial hypertension and, perhaps, se-
vere cardiac disease, the greatest concern most clinicians have
about hypercapnia appears to be the possibility of acidosis-
induced myocardial depression. Yet in clinical studies, almost
all patients managed with permissive hypercapnia have sus-
tained an increase in cardiac output after hypercapnia, associ-
ated with increased endogenous plasma catecholamine con-
centrations (11).
Acute hypercapnia causes extremely complex physiologic de-
rangements, probably affecting all cells and organ systems. Al-
though these are poorly understood, some (including possible
downregulation of inflammatory cells) could be detrimental, and
the degree of harm or benefit could vary in different clinical cir-
cumstances. Until we have a better understanding of the cellular
and systemic effects of hypercapnia, including the apparent cyto-
protective effects and their mechanisms, we can not consider a
clinical trial of therapeutic hypercapnia (the intentional eleva-
tion of PaCO2
above that resulting from lung-protective ventila-
tion). However, a clinical trial of buffering of the acidosis during
lung-protective ventilation in ARDS with permissive hypercap-
nia could be justified now. Buffering may have adverse effects
on gas exchange and tissue oxygenation (12) and, perhaps, could
eliminate or reduce the protective effects suggested by Laffey
and coworkers (10). A clinical trial is due.
KEITH G. HICKLING
Department of Intensive Care
University of Otago
Dunedin, New Zealand
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