corticoids for arf

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State of the Art

Am JRespir Crit Care Med Vol 160. pp 10791100, 1999Internet address: www.atsjournals.org

Corticosteroids in Acute Respiratory Failure

MICHAEL A. JANTZ and STEVEN A. SAHN

Division of Pulmonary and Critical Care Medicine, Allergy and Clinical Immunology, Medical University of South Carolina,

Charleston, South Carolina

CONTENTS

Introduction

Pharmacology

and Me chanisms of A ctionCorticosteroids in A cute Respiratory Failure

Acute R espiratory Distress SyndromeStatus Asthmat icus

COPD

Pneum ocystis carinii

Pneumonia

Acute Eo sinophilic PneumoniaAlveolar Hemor rhage Syndromes

Systemic Lupus E rythematosusWegeners G ranulomatosis

Microscopic Po lyangiitisAntiGlomerular Basement Membrane Disease

(Go odpastures Syndrome)Bone Marro w Transplantation

Acute Lup us Pneumonitis

Bronchiolitis Obliterans O rganizing Pneumonia (Crypto-genic Organizing Pneumonia)

Radiation PneumonitisMiliary Tuberculosis

Pulmonary Toxicity Secondary to Drugs or ToxinsBleomycin Pneumonitis

Mitomycin

AmiodaroneCocaineAcute Complications of Corticosteroid Ther apy

Corticosteroids have been advocated for a h ost of conditionswhich the pulmonologist/intensivist may encounter as causes

of acute respiratory failure. The purpose of this article is to ex-amine the data and rationale for use of corticosteroids in con-

ditions that are most likely to cause acute respiratory failure

requiring admission to the intensive care unit (ICU). At theconclusion o f each section discussing a specific disease or con-

dition, we provide our recommendation for corticosteroidtreatment of that entity, cognizant that randomized, double-

blind, placebo-controlled trials may be lacking. We focus pri-marily on human studies and not in vitro

or animal model

studies. In the following section on the mechanisms of actionof corticosteroids, we provide a general overview and do not

cite each individual study as our focus is the clinical treatmentof conditions encountered in the ICU . For additional in-depth

discussion of the molecular actions of corticosteroids, the reader

is referred to the excellent discussions provided by Stellato andcoworkers (1) and by Barn es and A dcock (2).

PHARMACOLOGY AND M ECHANISMS OF ACTION

Corticosteroids are mainly transported in the blood com-

plexed to transcortin (corticosteroid-binding globulin) and al-bumin, although a small portion is in a free, metabolically ac-

tive state. The free corticosteroid molecules readily cross the

plasma membrane into the cytoplasm. Once in the cytoplasm,

corticosteroids bind to their specific receptor, the glucocorti-coid receptor (GR). The GR is located in the cytoplasm ofnearly all human cells. In the cytoplasm, the GR exists as a

heterocomplex that contains the GR in association with twosubunits of the heat shock protein hsp90, one subunit of the

heat shock protein hsp56, one subunit of the heat shock pro-tein hsp70, and an acidic 23 kD protein (3, 4). After hormone

binding, the GR complex undergoes dissociation and theligand-activated GR translocates to the nucleus. In the nu-

cleus, the activated GR can bind to glucocorticoid responseelements on DNA or can interact with transcription factors

(510). Depending on the specific glucocorticoid regulatoryelement to which the GR binds, the tra nscription rate of a spe-

cific proteins messenger RNA (mRNA) can be induced (up-

regulated) or suppressed (downregulated) (11). In addition toeffects mediated through glucocorticoid response elements lo-

cated in promoter r egions of DNA and interactions with othertranscription factors, the activated GR can alter mRN A stabil-

ity (12, 13).Corticosteroids inhibit the transcription of several cyto-

kines that are relevant to inflammatory conditions includinginterleukin (IL)-1, IL-3, IL-4, IL-5, IL-6, IL-8, tumor necrosis

factor (TNF)-

, and granulocytemacrophage colony stimu-lating factor (GM-CSF) (14). Corticosteroids interact with the

transcription factors activator protein ( AP) -1 and nuclear fac-tor (NF)-

B (7, 9, 10). The transcription factors AP-1 and/or

NF-

B are known to be involved in the u pregulation of a num-ber of gene products that play a central role in inflammation

including IL-1, IL-2, IL-3, IL-6, IL-8, TNF-

, GM-CSF, and

RANTES (Regulated upon Activation, Normal T-cell Ex-pressed and Secreted) (15). By interfering with these tran-

scription factors, corticosteroids can inhibit expression of the segenes. Transcription of the IL-2 gene is predominantly regu-

lated by nuclear factor of activated T cells (NF-AT), which isdependent on a nuclear factor thought to be AP-1, to form a

transcriptional complex (16, 17). Thus, corticosteroids may in-hibit IL-2 gene transcription indirectly by binding to AP-1

(18). Corticosteroids have also bee n dem onstrated to increasethe degradation of mRNA encoding for IL-1

, IL-6, and G M-

CSF (12, 13).Corticosteroids have an effect on a variety of inflammatory

mediators. Nitric oxide synthase may be induced by various

(

Received in original form January 21, 1999 and in revised form May 17, 1999

)

Correspondence and requests for reprints should be addressed to Steven A.

Sahn, M.D., Professor of Medicine and Director, Division of Pulmonary and Criti-cal Care Medicine, Allergy and Clinical Immunology, Medical University of South

Carolina, 96 Jonathan Lucas St., P.O. Box 250623, Charleston, SC 29425.


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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 160 1999

cytokines, resulting in increased nitric oxide production (19,

20). The induction of the inducible form of nitric oxide syn-thase is inhibited by corticosteroids (21, 22), presumably by

effects on NF-

B which is an important transcription factorin regulating inducible nitric oxide synthase (23). Corticoste-

roids inhibit the gene encoding for inducible cyclo-oxygenase(CO X-2), which also appears to be depende nt on NF -

B acti-

vation (2426). Gene transcription of cytosolic phospholipaseA

2

, which is induced by cytokines and cleaves arachidonic acid

providing precursors for the leukotriene and prostaglandinmediators of the COX and lipoxygenase pathways, is inhibited

by corticosteroids (27, 28). Platelet-activating factor activates

AP-1 binding in inflammatory cells, and this may be inhibitedby steroids. In addition, corticosteroids inhibit the synthesis of

endothelin-1, a pept ide with potent bronchoconstrictor prop-ert ies, in lung and a irway epithelial cells (29, 30).

Corticosteroids increase transcription of the

2

-receptorgene. Desensitization of

2

-adrenergic receptors is prevented

by corticosteroids, and downregulated receptors are restoredto normal levels by corticosteroids (31). Corticosteroids also

have effects on the IL-1 surface receptor, as they induce a sol-uble form of the IL-1 receptor, known as the IL-1 RII or

decoy receptor, which reduces the functional activity of IL-1(32, 33). In addition, corticosteroids have effects on adhesion

molecules. Corticosteroids inhibit the gene transcription of in-tercellular adhesion molecule-1 (ICAM-1) and E-selectin (34,

35). ICAM-1 expression is dependent on NF-

B activation

(36). Lastly, corticosteroids increase the synthesis of secretoryleukocyte protease inhibitor (SLPI) by airway epithelial cells.

SLPI is thought to be the predominant antiprotease in con-ducting airways and may be important in reducing airway in-

flammation (37).There are a number of cellular effects of corticosteroids.

Steroids cause an expansion in the number of circulating neu-trophils secondary to diminished adheren ce to the vascular en -

dothelium (demargination) and stimulation of bone marrowproduction. It ha s been r eported that corticosteroids stabilize

lysosomes, inhibit the release of lysosomal enzymes, and in-

hibit chemotaxis and other neutrophil functions; however,these studies used extremely high concentrations of steroidsand may not be p harmacologically or physiologically meaning-

ful (38). Levels of circulating mononuclear cells, eosinophils,

and b asophils are decreased after steroid administration. IL-1and TNF-

release by macrophages is inhibited by corticoste-

roids (3943). Inhibition of genes encod ing for the chemokinesmacrophage inflammatory protein-1

(MIP-1

) and mono-

cyte chemotactic protein-1 (MCP-1) by steroids is also ob-served (44, 45). Corticosteroids have a direct inhibitory effect

on mediator release from eosinophils and suppress the per mis-sive action of the cytokines IL-3, IL-5, and GM-CSF that pro-

long eosinophil survival (4649). The downregulation of IL-1

and IL-2 by steroids affects T lymphocytes as they act as

growth factors for these cells (5052). The release of various

cytokines by T lymphocytes is also inhibited by corticosteroids

(1). Although steroids do not appear to have a direct inhibi-tory effect on mast cell mediator release in the lung, chronic

steroid treatment is associated with a marked reduction inmucosal mast cell number (53). Mucus secretion is stimulated

by several inflammatory mediators and cytokines. Corticoste-roids have been noted to decrease mucus secretion in the a ir-

ways (54, 55). Finally, corticosteroids appear t o have an inhib-itory effect on leakage in the microvasculature. This effect is

thought to be du e to diminishing the cellular sources of proin-flammatory and vasoactive mediators, and possibly by a direct

antipermeability effect on the microvasculature (5659).

Some investigators have proposed that corticosteroids maynot simply inhibit immune responses but may enhance some

immune functions and optimize the biologic response to vari-ous immunologically related stressors (60, 61). Upregulation

of receptors for IL-1, IL-2, IL-4, interferon-

(IFN-

), GM-CSF, and TNF in various cell types by glucocorticoids has

been demonstrated (60). Glucocorticoids also strongly poten-tiate the IL-1- and IL-6-induced expression of acute phase

proteins as part o f the acute p hase response to tissue injury orinfection, which is important in limiting local and systemic in-

flammation (60, 61). In human B cells, glucocorticoids are syn-ergistic with IL-1 and IL-6 in inducing production of IgM and

IgG (60). Further study is needed to und erstand the seeminglyparadoxical effects of corticosteroids in decreasing cytokine

production while upregulating cytokine receptors, and how cor-

ticosteroids optimize the immune response. Further researchis also needed in assessing potential differences between the

effects of endogenous corticosteroids at physiologic concen-trations and the effects of exogenous, synthetic corticosteroids

at pha rmacologic doses on the immune response.Cortisol is the major endogenous glucocorticoid, whereas

aldosterone is the major mineralocorticoid. Cortisol is pro-duced by the zona fasciculata and zona reticularis in the adre-

nal cortex; aldosterone is produced in the zona glomerulosa.The effects on immune and inflammatory modulation by glu-

cocorticoids have previously been discussed. In addition to

these effects, effects on glucose and lipid are seen with gluco-corticoids. The primary action of the mineralocorticoids is tofacilitate sodium reabsorption an d excretion of p otassium a nd

hydrogen ions in the renal tubular cell. The normal un stressed

daily production of cortisol is estimated to be 13 to 20 mg/d;the maximum stress-induced output of cortisol is estimated to

be 200 to 300 mg/d (62).The properties of the corticosteroids commonly prescribed

in the I CU are listed in Table 1. Because many of the e ffects ofcorticosteroids are mediated through gene transcription and

protein synthesis, the biologic half-lives of the various prepa-rations may not directly correlate with plasma levels and, thus,

are only estimates. Hydrocortisone is the synthetic equivalentto cort isol. Because of its mineralocorticoid effects in addition

to its glucocorticoid effects, it is the preferred agent for phy-

TABLE 1

PROPERTIES OF COMMONLY PRESCRIBED CORTICOSTEROIDS IN THE ICU*

Agent

Equivalent Dose

(

mg

)

Glucocorticoid

Potency

Mineralocorticoid

Potency

Plasma t

1/2

(

min

)

Biologic t

1/2

(

h

)

Hydrocortisone 25.0 1 1 80115 812

Prednisone 5.0 4 0.8 160 1236

Prednisolone 5.0 4 0.8 115250 1236

Methylprednisolone 4.0 5 0.5 80180 1236

Dexamethasone 0.75 25 0 110120 3672

* Adapted from Chin and coworkers (62).


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State of the Art 1081

siologic replacement. This same property, however, increases

the possibility of fluid and electrolyte imbalances. Prednisone,in contrast to prednisolone, requires he patic hydroxylation to

become active. Methylprednisolone may be better concen-trated in the lungs than prednisolone because it has a larger vol-

ume of distribution, longer mean residence time, and greaterretention in the epithelial lining fluid of the alveoli (63). Be-

cause of its negligible mineralocorticoid activity, dexametha-

sone may be the agent of choice in situations in which fluidand sodium rete ntion is undesirable, such as treatmen t of ce-

rebral edema.

CORTICOSTEROIDS IN ACUTE RESPIRATORY FAILURE

Acute Respiratory Distress Syndrome (ARDS)

A number of trials have demonstrated that patients with

ARDS do not benefit from a short course of large doses ofcorticosteroids administered early in the disease. Weigelt and

coworkers performed a prospective, double-blind, random-ized study of early methylprednisolone therapy in 81 acutely

ill, mechanically ventilated patients felt to be at high risk forARDS (64). Patients were given methylprednisolone 30 mg/kg

every 6 h for 48 h. AR DS developed in 25 of 39 (64% ) of the

steroid-treated patients and 14 of 42 (33% ) of the placebo-

treated patients (p

0.008). Mortality was 46% in the ste roid-and 31% for placebo-treated patients (p

0.18). Infectiouscomplications occurred in 77% of the steroid group versus

43% in the placebo group (p

0.001). Luce and coworkersconducted a prospective, double-blind, randomized trial eval-

uating the efficacy of methylprednisolone to pre vent A RD S inpatients with septic shock (65). Patients received 4 doses of

methylprednisolone 30 mg/kg every 6 h or placebo. In the me-thylprednisolone group, 13 of 38 (34%) d eveloped AR DS

compared with 14 of 37 (38% ) in the placebo group (p

no tsignificant [NS]). Morta lity was 58% in the steroid group ver-

sus 54% in the placebo group (p

NS).Bone an d coworkers also performed a prospective, double-

blind, randomized study to determine if early treatment with

corticosteroids would decrease the incidence of A RD S in pa-tients at risk from sepsis (66). Patients were treated with either

meth ylprednisolone 30 mg/kg every 6 h for 24 h or placebo . Atrend toward an increased incidence of ARDS was observed

in the steroid-treate d group, 50 of 152 (32%) compared withthe p lacebo-treated group, 38 of 152 (25%) (p

0.10). Mor-

tality at 14 d for patients who developed A RD S was 52% (26of 50) in the steroid group and 21% (8 of 38) in the placebo

group (p

0.004), while reversal of ARDS was noted in 31%of the steroid-treated pa tients versus 61% in the placebo-

treated patients (p

0.005). A greater mortality from second-ary infections was also noted in the steroid group. Bernard and

coworkers conducted a prospective, double-blind, randomizedcontrolled trial of methylprednisolone in 99 patients with early

ARDS (67). Patients were administered methylprednisolone30 mg/kg every 6 h for a total of 4 doses or placebo. Mortality

at 45 d was 60% (30 of 50) in the steroid group and 63% (31 of

49) in the placebo group (p

0.74). Reversal of ARDS was36% (18 of 50) in the steroid group and 39% (19 of 49) in the

placebo group (p

0.77). Infectious complications were simi-lar between the two groups, 16% versus 10% in the steroid

and placebo groups, respectively (p

0.60).In contrast to early ARDS, there is evidence that cortico-

steroids may be beneficial in the fibroproliferative phase, orlate phase, of ARDS. Ashbaugh and Maier described 10 pa-

tients who did not respond to conventional treatment (68).Ope n lung biopsies demonstrated cellular proliferation, oblit-

eration of alveoli, and fibrosis. Patients were treated with me-

thylprednisolone 125 mg every 6 h beginning 6 to 22 d after

onset of ARDS. Following a clinical response, the dose of ste-roids was then tapered over 3 to 6 wk. Of the 10 patients, eight

recovered. Two patients died from sepsis. Hooper and Kearlinitially reported 10 patients followed by an additional 16 pa-

tients who were treated with corticosteroids for establishedARDS (69, 70). Established ARDS was defined as ARDS

where the causative process had resolved and the duration of

ARDS was greater than 72 h. Clinically, patients were notthought to have active infections and patients with positive

blood or wound cultures were excluded from the study. Bron-choalveolar lavage (BA L) o r lung biopsy was not pe rformed.

ARDS was present 3 to 40 (mean 9.2) d before steroid ther-apy. The initial dose of methylprednisolone was 125 to 250 mg

every 6 h based on the severity of respiratory compromise.The initial dose was maintained for 72 to 96 h before t apering

was begun based on clinical response with the dosage reducedapproximately 50% every 2 to 3 d. A ll patients showed im-

provement in respiratory parameters. Overall survival was81% (21 of 26). Three patien ts died of multisystem organ fail-

ure, one died of a cardiac arrhythmia, and one died of systemiccandidiasis. Biffl and coworkers utilized corticosteroids in six

patients with persistent, severe ARDS who were failing con-

ventional therapy (71). BAL was performed before initiating

steroid therapy to exclude infection. Patients were treatedwith methylprednisolone 1 to 2 mg/kg every 6 h starting 12 to26 (mean 15.8) d after ventilatory support was initiated. The

ratio of arterial oxygen pressure to fraction of inspired oxygen(Pa

O2

/F

IO2

) improved from 84 to 172 (p

0.01) and the lung

injury score ( LIS) decreased from 3.6 to 2.9 (p

0.01) by Da y7. Overall survival was 83% ( 5 of 6). The mean dur ation o f

corticosteroid therapy was 21.3 d (range 13 to 42). One patientdeveloped a Staphylococcus aureus

lung abscess and two pa-

tients had catheter-related sepsis.Meduri and colleagues have published a nu mber o f studies

reporting the efficacy of corticosteroids for the fibroprolifera-tive phase of ARDS. They initially described eight patients

followed by an additional 17 patients (72, 73). Patients were

given an initial bolus of 200 mg followed by 2 to 3 mg/kg/d individed doses every 6 h of methylprednisolone. Bronchoscopy

with bilateral BAL and protected brush sampling was per-formed before initiation of steroid treatme nt to exclude infec-

tion. Weekly bronchoscopy with BAL was also done for earlydetection of nosocomial pneumonia. Patients required me-

chanical ventilation for 5 to 23 (mean 15) d before initiation ofsteroid therapy. By Day 7 of treatme nt, the Pa

O2

/F

IO2ratio in-

creased from 164 to 234 (p

0.0004) and LIS decreased from3.0 to 2.1 (p

0.001). Three patterns o f response were note d.

Rapid responders showed improvement by Day 7 (n

15),delayed responders showed improvement by D ay 14 (n

6),

and nonr esponders exhibited no improvement by Day 14 (n

4). Overa ll survival rate was 72% (18 of 25). ICU survival was

87% (13 of 15) in the rapid re sponders, 83% (5 of 6) in the de-layed responders, and 25% (1 of 4) in the nonre sponders. The

average duration of corticosteroid treatment was 36 d. Pneu-

monia developed in 38% o f responders and 75% of nonre-sponders.

Meduri and coworkers recently published the results of arandomized, double-blind, placebo-controlled trial of cortico-

steroids for unresolving ARDS (74). Patients were eligible forthe study if they had required mechanical ventilation for 7 d

with a LIS of

2.5 and less than a 1-point reduction in the LISfrom Day 1 of their ARDS, as well as no evidence of un-

treated infection. Sixteen patients were randomized to treat-ment with methylprednisolone while eight patients received

placebo. Enrollment was stopped after 24 patients based on


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interim statistical analysis. The treatment protocol for methyl-

pred nisolone was a loading dose of 2 mg/kg, followed by 2 mg/kg/d from D ay 1 to D ay 14, 1 mg/kg/d from D ay 15 to Day 21,

0.5 mg/kg/d from Day 22 to Day 28, 0.25 mg/kg/d on Days 29and 30, and 0.125 mg/kg/d on Days 31 and 32. If the patient

was extubated b efore Day 14, treatme nt was advanced to D ay15 of drug therapy. One-fourth of the total daily methylpred-

nisolone dose was given every 6 h. Bronchoscopy with bilat-eral BA L was performed prior to initiation of steroid therap y

as well as weekly to exclude ventilator-associated pneumonia.Infections were identified in 10 patients prior to study entry,

eight in the methylprednisolone arm and two in the control

group. These patients were t reated with an tibiotics for at least3 d before treatment r andomization.

Weekly bronchoscopy with bilateral BAL was included inthe p rotocol because the two p revious uncontrolled studies by

Meduri and coworkers had shown that ventilator-associatedpneumonia may develop in the absence of fever (72, 73). Thus,

surveillance bronchoscopy was performed to allow for earlydetection of occult pneumonia. Significant changes were ob-

served for Pa

O2

/F

IO2

ratio (262 versus 148, p

0.001), LIS (1.7versus 3.0, p

0.001), mean pulmonary artery pressure (22.5

versus 30.0 mm H g, p

0.01), and mu ltiple-organ dysfunctionsyndrome (MO DS) score (0.7 versus 1.8, p

0.001) in the cor -

ticosteroid-treated group versus the placebo group. In accor-dance with the study protocol, four patients in the placebo

arm were blindly crossed over to the m ethylprednisolone arm

when no improvement was observed 10 d after tre atment. O fthe four patients who were blindly crossed over from placebo

to methylprednisolone, only one survived. ICU survival was100% (16 of 16) in the steroid group versus 37% (3 of 8) in the

placebo group (p

0.002); overall survival was 87% ( 14 of 16)versus 37% ( 3 of 8), respectively (p

0.03). The two death s in

the met hylprednisolone arm occurred after ICU discharge andwere related to a cardiac arrhythmia in one patient and recur-

rent aspiration in the other patient with neurologic dysfunc-tion. An increased incidence of infections was noted in the ste-

roid group with a risk ratio of 1.80 compared with placebo,

although the 95% confidence interval was 0.86 to 3.76. Four of16 surveillance bronchoscopies in patients without fever iden-tified a significant growth o f pathogens.

Meduri has written an excellent review of the host defenseresponse in the progression of ARDS and how that response

may be affected by corticosteroid therapy, which we will sum-

marize (75). Fibroproliferation is a stereotypical reparative re-action to tissue injury and is characterized by the replacement

of damaged epithelial cells by accumulation of mesenchymalcells and their connective tissue products in the airspaces and

walls of the intra-acinar microvessels. This process occurswithin 7 d of the onset of ARDS with a rapid increase in the

second and third week of respiratory failure. Unchecked fi-broproliferation results in extensive fibrotic remodeling of the

lung parenchyma. A n umber of cytokines mediate the host de-fense response to injury. Nonsurvivors of ARDS have been

reported to have higher initial plasma and BAL levels ofTNF-

, IL-1

, IL-2, IL-4, IL-6, and IL-8 compa red with survi-

vors (76, 77). Persistent elevation of plasma and BAL cyto-kines TNF-

, IL-1

, IL-6, and IL-8 has also been reported in

nonsurvivors of AR DS (76, 77). Similar observations have been

noted in patients with sepsis, and it is postulated that disrup-tion of the alveolocapillary membrane in patients with A RD S

allows the release of cytokines into the systemic circulation,which may contribute to t he development and/or m aintenance

of the systemic inflammatory response syndrome (SIRS) an dMODS (75, 78, 79). In the absence of inhibitory signals, these

mediato rs of the host defense re sponse sustain ongoing inflam-

mation with tissue injury and stimulate proliferation of mesen-

chymal cells with deposition of extracellular matrix productsand collagen, resulting in fibrosis. Thus, an overaggressive

and prot racted host defense response, rather than the incitingcondition, is likely the major factor influencing outcome in

ARDS.It is hypothesized that activity of glucocorticoids produced

by the hypothalamicpituitaryadrenal (H PA ) axis as well asanti-inflammatory cytokines such as IL-4, IL-10, IL-1 receptor

antagonist, and soluble TN F receptors, are necessary to regu-late termination of the host defense response (75). Cortico-

steroids inhibit the host defense response at many levels and

inhibit the transcription of TNF, IL-1, IL-2, and IL-6. Corti-costeroids also suppress the synthesis of phospholipase-A

2

,

COX-2, and nitric oxide synthase-1 genes, decreasing the pro-duction of prostanoids, platelet-activating factor, and nitric

oxide, three additional key molecules in the inflammatorypathway. In addition, corticosteroids have an inhibitory effect

on fibrogenesis and the expression of adhesion molecules. Cy-tokines can produce resistance to glucocorticoids by reducing

their receptor binding affinity which may offset the modula-tory activity of the HPA axis in limiting the host defense re-

sponse in some pat ients (80, 81).Thus, there appears to be some rationale for use of corti-

costeroids in the fibroproliferative phase in A RD S. In a sepa-rate study by Meduri and coworkers, the effects of corticoste-

roid treatment on plasma and BAL cytokine levels in nine

patients with late A RD S were compared with 12 previous non-survivors from ARDS who had undergone cytokine concen-

tration measurements (82). Baseline plasma and BAL cyto-kine levels in the nine corticosteroid-treated patients were

similar to the comparison group. The surviving patients trea tedwith corticosteroids were found to have significant reductions

in plasma and BAL TNF-

, IL-1

, IL-6, and IL-8 concentra-tions. The decreases in the various cytokine levels were seen

only after 5 to 14 d of steroid administration. Meduri and co-workers also examined the effects of cort icosteroids on plasma

and BA L levels of procollagen aminoterminal propeptide type I

(PINP) and type III (PIIINP) in patients with nonresolvingAR DS (83). PINP and PIIINP are secreted by fibroblasts andreflect collagen synthesis at the site of disease. Previous stud-

ies reported that nonsurvivors of AR DS had per sistent eleva-tions of plasma and BAL PIIINP levels (8486). Meduri and

coworkers found elevated plasma levels of PINP a nd PII INP

in their patients at t he time of study enrollment and o bservedthat the concentrations of PINP and PIIINP increased over

time in nonsurvivors as opposed to survivors in whom the lev-els did not change significantly (83). BAL concentrations of

PINP and PIIINP were also noted to be higher in nonsurvivorscompared with survivors, although the differences were not

statistically significant. In that study 11 patients who had notshown an improvement in LIS greater tha n 1 point were ran-

domized to receive methylprednisolone using the same prot o-col as in their previous randomized trial (74), and six patients

received placebo. In the patients treated with methylpred-nisolone, significant decreases in plasma and BAL PINP and

PIIINP levels were observed, whereas no changes in theseconcentrations were seen in patients receiving placebo. De-

creases in plasma and BA L PINP and PIII NP levels correlated

with improvements in LIS and Pa

O2

/F

IO2

ratios.Timing and duration of corticosteroid therapy are also

likely important. In experimental acute lung injury, corticos-teroid administra tion was effective in decreasing lung collagen

and edema formation as long as treatment was prolonged,whereas steroid withdrawal rapidly negated this positive effect

(8789). Limiting corticosteroid therapy to the first 6 d after


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acute lung injury was also shown to enhance accumulation of

collagen after discontinuing treatment in an experimentalmodel (88). These observations, together with the apprecia-

tion of the role of an exaggerated and prot racted host defenseresponse in producing nonresolving ARDS, may explain the

difference between initial studies using a short course of corti-costeroids early in AR DS versus the r esults of later studies re-

porting benefit with prolonged corticosteroid administration

in the late, or fibroproliferative phase, of ARDS. In addition,the use of corticosteroids after a certain period of time may

not be effective in changing the outcome of A RD S. In an ear-lier study by Meduri and coworkers, open lung biopsies were

obtained in 12 patients before tr eatment with me thylpredniso-lone for late AR DS (73). Histology from the responders dem-

onstrated myxoid cellular fibrosis, preserved alveolar architec-ture, and absence of arteriolar subintimal fibroproliferation;

whereas nonresponders had dense acellular fibrosis, distortedalveolar architecture, and arteriolar subintimal proliferation.

Thus, it appears a therapeutic window exists for treating fibro-proliferative A RD S and treatment will be ineffective once end-

stage fibrosis has developed.Given the current data o f case series and one, albeit small,

double-blind ran domized controlled trial, it appears t hat t here

may be a role for corticosteroids in the fibroproliferative phase

of AR DS, as opposed to ear ly in the course or as preventativetherapy for ARDS. Additional double-blind, randomized trialsare needed before making a firm recommendat ion for treating

all patients with corticosteroids. Nevertheless, in patients whohave not exhibited clinical improvement after 7 to 14 d of con-

ventional therapy, we think that it is reasonable to initiate atrial of corticosteroids after excluding sources of ongoing in-

fection, including bronchoscopy to evaluate for lower respira-tory tract infection, recognizing that ARDS and SIRS may

clinically simulate infection. In the a bsence of any tr ials evalu-ating dosage or duration of steroid treatment, we would rec-

ommend the pr otocol used by Meduri and colleagues includ-ing weekly surveillance bronchoscopy. In their studies, weekly

surveillance bronchoscopy with bilateral BAL was performed

and believed to be useful in detecting early, occult pneumonia.It is beyond the scope of this article to discuss the role of bro n-

choscopy in evaluating ventilator-associated pneumonia, al-beit controversial. A low thr eshold in evaluating patients for

development of a new infection while undergoing corticoster-oid therapy should be maintained. A National Institutes of

Health (NIH)-sponsored multicenter randomized, controlledtrial using Meduri and coworkers protocol is planned to fur-

ther assess the efficacy of corticosteroid therapy for fibropro-liferative AR DS.

Status Asthmaticus

Although not all studies have reported a benefit, the majoritysupport the efficacy of corticosteroids in treating acute, severe

asthma or status asthmaticus. Fanta a nd coworkers conducteda randomized, double-blind, placebo-controlled trial in 20 pa-

tients who were refractory to 8 h of treatment with

-agonists

and am inophylline (90). E leven patients were rando mized t o a2 mg/kg bolus followed by a 0.5 mg/kg/h infusion of hydrocor -

tisone, and nine patients received placebo. At 24 h the FEV

1

increased by 118% from baseline (p

0.025) in the corticos-

teroid group, whereas FEV

1

increased b y 36% from baseline(p

NS) in the placebo group. All of the patients who re-

ceived corticosteroids had at least a 10% improvement inFE V

1

, whereas only four patients who received placebo had

similar improvement (p

0.025). Younger and coworkersevaluated the use of corticosteroids in a pediatric population

in a double-blind, randomized, placebo-controlled fashion (91).

After no improvement with three bronchodilator treatments,

patients were randomized to an initial bolus of 2 mg/kg ofmethylprednisolone followed by 1 mg/kg every 6 h or placebo.

By 24 h the patients in the methylprednisolone arm (n

15)had a significant improvement in a clinical pulmonary index

score compared with patients in the p lacebo arm (n

13) (p

0.02), as well as FEF

2575

at 36 h (p

0.05). However, no dif-

ferences were observed in changes in peak expiratory flow

rate (PEFR), FEV

1

, or FVC between the t wo groups. Piersonand coworkers also conducted a double-blind, randomized,

placebo-controlled trial in pediatric patients (92). Patientswere randomized to receive hydrocortisone, dexamethasone,

betamethasone, or placebo. A significantly greater increase inPa

O2

was noted in the steroid-treated patients (all three ste-

roid groups combined) compared with the patients who re-ceived placebo, 58.5 to 78.1 mm Hg and 57.9 to 64.4 mm Hg,

respectively (p

0.005). No differences in changes in FEV

1

were seen. Seven of 15 patien ts in the placebo group, however,

required re assignment to a steroid group. No differences wereobserved between the three steroid groups. Other studies

have been published reporting efficacy for corticosteroids intreating acute, severe asthma ( 93).

Other researchers have reported no benefit with cortico-

steroids in treating acute, severe asthma or status a sthmaticus

(94). Corticosteroids are known not to ha ve any immediate ef-fect on pulmonary mechanics in acute asthma, with a numberof studies noting a 6-h or greater de lay from administration t o

a measurable effect on pulmonary function (90, 92, 93, 95).This initial delay most likely reflects the time necessary for the

actions of corticosteroids on the

2

-receptor including synthe-sis of new

2

-receptors with increased receptor density and re-

versal of

2

-receptor desensitization a nd downregulation ( 31,96). Given these observations on the delayed effect of corti-

costeroids, some studies may be discounted for having obser-vation times that were too short (97, 98). Morell and cowork-

ers found no difference in pulmonary function in patientstreated with 10 mg/kg of methylprednisolone or 2 mg/kg of

methylprednisolone every 4 h for 48 h versus placebo (99).

However, a significant portion of e ach of the t hree groups whowere on maintenance steroids prior to study entry continued

to receive oral steroids at undisclosed doses. A negative studywas reported by Luksza in comparing 1,200 mg/d and 400

mg/d of hydrocortisone to n o steroid tr eatment as assessed byPEF R (100). The study was not randomized or b linded, how-

ever, and six of 30 (20% ) pat ients not r eceiving steroids re -quired mechanical ventilation compared with seven of 60

(12% ) of patients treated with hydrocortisone. In addition totoo short observation times, other potential factors may ex-

plain studies finding no benefit for corticosteroids in acuteasthma. The presence of airway remodeling with a componen t

of fixed a irway obstruction secondary to previous undertreat -ment or lack of tre atment is one possibility. Some pa tients in

the adult studies may have had a component of chronic ob-

structive pulmonary disease (COPD) that would tend to ne-gate the effect of steroid therapy. Some patients may simply

have had a particularly severe a nd prolonged episode of statusasthmaticus that requires a more extended course of cortico-

steroids. Finally, it has become appreciated that some patientswith asthma exhibit corticosteroid resistance owing to various

mechanisms (101, 102).A number of studies have evaluated various doses of corti-

costeroids in treating status asthmaticus. Haskell and cowork-ers randomized eight patients each to 15 mg (low), 40 mg

(medium), and 125 mg (high) of methylprednisolone every6 h for 3 d in a double-blind fashion (103). Compared with

initial spirometry, the high-dose group significantly improved


6/22

1084


(p

0.01) in the first day, the medium-dose group signifi-

cantly improved (p

0.01) in the second day, and the low-dose group did not show significant improvement. Ma rquette

and coworkers conducted a double-blind, randomized trial of1 mg

kg/d versus 6 mg/kg/d of methylprednisolone in 45 pa-

tients (104). No differences in improvements in FEV

1

wereobserved. Bowler and coworkers performed a double-blind,

randomized trial comparing three different doses of hydrocor-tisone (105). Patients received 50 mg (n

22), 100 mg (n

20), or 500 mg (n

24) of hydrocortisone every 6 h for 48 hfollowed by oral prednisone. PEFR and FEV

1

improved with

no significant differences between t he t hree groups. Raimondi

and coworkers randomized 20 patients to treatment with 80mg/kg/d of hydrocortisone and 20 patients to 6 mg/kg/d of hy-

drocortisone given in divided doses every 6 h (106). No dif-ferences in spirometry were noted between the two groups.

Ra tto and coworkers conducted a t rial in 70 patients compar-ing 80 mg or 160 mg twice a day of oral me thylprednisolone to

125 mg or 250 mg of methylprednisolone given intravenouslyfour times a day (107). Improvements in PEFR and FEV

1

were similar between the oral and intravenous groups. Stud-ies comparing different corticosteroid preparations have not

shown any significant differences in efficacy (92, 95).We think that corticosteroids should be used in all patients

admitted to the ICU for status asthmaticus. Given less miner-alocorticoid effects with methylprednisolone compared with

hydrocortisone, we favor the former. G iven th e available dat a,

we would recommend a dose of at least 40 mg every 6 h al-thou gh some clinicians prefer a dose o f 60 mg every 6 h. Doses

above that range probably do not confer additional benefit.Given the lack of data , we do not recommend a specific taper-

ing protocol; dose reduction should be based on clinical re-sponse.

COPD

Although corticosteroids are used by many clinicians in treat-ing acute respiratory failure from CO PD, few controlled stud-

ies exist to support its use. The most widely referenced trial is

by Albert and colleagues who studied 44 patients with CO PDand acute respiratory insufficiency (defined as Pa

O2

65 mmHg on room air or Pa

CO 2

50 mm Hg with pH

7.35 or

both) in a double-blind, random ized, placebo-controlled trialwith 0.5 mg

kg of methylprednisolone every 6 h for 72 h or

placebo (108). Patients also received intravenous aminophyl-

line, inhaled isoproterenol, and antibiotics. Bedside spirome-try was done before and after br onchodilator inhalation three

times daily. At e ach time interval, the percent change in FE V

1

was greater in the methylprednisolone group (p

0.0001).

Twelve of 22 (55% ) patients in the methylprednisolone ar mhad 40% or more improvement in prebronchodilator FEV

1

compared with three of 21 (14% ) in the placebo arm (p

0.01). For the po stbronchodilator FEV

1

, nine of 22 (41%) pa-

tients receiving methylprednisolone improved by at least 40%compared to three of 21 patients (14%) receiving placebo (p

0.05). However, the statistical methods and analysis used inthe study by Albert and colleagues have been questioned. In

an editorial, Glenny challenged the study on t he basis that theuse of absolute spirometric volumes, rather than percent

changes, should be used to assess differences between the

methylprednisolone and placebo groups (109). When analyzedwith this method, Glenny concluded that there was no effect

of corticosteroid treatm ent. In addition, although not statisti-cally significant, the admitting FEV

1

levels for the steroid

group were lower than the placebo group, 602

240 ml versus675

267 ml (p 0.1), which may have affected the resultsbecause of the effect of regression to the mean.

Rubini and coworkers have recently published a study eval-

uating the effects of corticosteroids on respiratory mechanicsin eight patients requiring mechanical ventilation for acute re-

spiratory failure secondary to CO PD (110). Patients were given0.8 mgkg of methylprednisolone and respiratory mechanicswere measured before and 90 min after steroid administration.Bronchodilators were withheld at least 12 h before beginning

the study. Maximal inspiratory resistance decreased from 20.3to 15.3 cm H 2O/L/s and minimal airway resistance decreased

from 16.2 to 11.9 cm H2O/L/s (p 0.01). Self-contr olled posi-

tive end-expiratory pressure (auto-PEEP) also decreased by

16% from the b aseline of 9.0 cm H2O (p 0.05). Given thetime course for effects of corticosteroids observed in statusasthmaticus, we are surprised at the results of this study.

A study often cited for showing no efficacy for corticoste-roids in treating acute exacerbations of COPD is that of Emer-

man and coworkers (111). In their study, 96 patients with COPDwho presented to th e emergency department with acute respi-

ratory distress were randomized to receive either 100 mg ofmethylprednisolone or placebo in a double-blind fashion. Pa-

tients also received hourly inhaled isoetharine and intrave-nous aminophylline. Spirometry per formed after the t hird and

fifth aerosol treatments revealed no difference in improve-ment in FEV1 between the met hylprednisolone group (37%)

and the control group (43%) ( p NS). There was also no dif-ference in the rat e of hospitalization between the two groups

(33% in the steroid group and 30% in the placebo group). A s

the treatment effect was only assessed for an average of 4.5 h,the negative results may reflect insufficient time to observe an

effect for corticosteroid therapy.Given the available data, it is problematic to make a firm

recommendation either for or against the use of corticoste-roids in acute re spiratory failure secondary to COPD and the

appropriate dose. In our practice, we tend to use corticoste-roids for patients who are severely ill and require admission to

the ICU , particularly if they require me chanical ventilation. Inthe absence of any controlled da ta, we use 40 to 60 mg of meth -

ylprednisolone every 6 to 12 h for 72 h.

Pneumocystis cariniiPneumonia

It is beyond the scope of this article to discuss the clinical fea-

tures ofPneum ocystis carinii pneumonia (PCP) and the vari-ous treatment modalities. The reader is referred to several re-

cent excellent reviews of the subject (112114). This section

will focus specifically on the use of corticosteroids for PCP-induced respiratory failure. Although t he incidence of PCP has

decreased with the u se of chemoprophylaxis, PCP r emains themost common opportunistic infection associated with huma n

immunodeficiency virus (HIV) infection. In the MulticenterAI DS Cohort Study the incidence of PCP as the acquired im-

munodeficiency syndrome (AIDS) index diagnosis was 15%among those receiving chemopr ophylaxis, with 28% develop-

ing PCP at some point during their illness. For those not re-ceiving chemopro phylaxis, 46% d eveloped PCP as their initial

AIDS-related illness (115). PCP continues to be the most com-mon diagnosis among HIV-infected patients requiring ICU

admission (116).Prior to the u se of corticosteroids, the survival for patients

with AIDS-related PCP who required admission to the ICU

for mechanical ventilation was below 15% ( 117, 118). The firstsuggestion that corticosteroids might be beneficial in PCP was

note d in case reports in 1985 and 1987 (119121). A number ofcase series were then pub lished be tween 1987 and 1990 repo rt-

ing a beneficial effect of corticosteroids in PCP-induced acuterespiratory failure. MacFadden and coworkers described 10

patients with acute re spiratory failure (Pa O2 60 mm Hg with


7/22


FIO2 0.6) who were treated with methylprednisolone 40 mgintravenously every 6 h for 7 d compared with eight patientswho received conventional treatment (122). Nine of the 10

(90% ) steroid-treated patients survived whereas only two ofthe e ight ( 25% ) conventionally treated patients survived (p 0.01). Walmsley and colleagues reported on treatment of 21episodes of PCP in 20 patients with corticosteroids compared

with 12 retrospective controls who were similar to the steroid

treatme nt group except for being less hypoxemic (PaO2 47 mmHg steroid group versus 56 mm Hg controls) (123). Six pa-

tients were treat ed with 20 to 120 mg/d of predn isone or meth-ylprednisolone for 4 to 20 d, and 15 patients were treated with

80 mg/d of either steroid for 5 d. Corticosteroid tr eatment wasassociated with a significantly greate r improvement in oxygen-

ation and a trend t oward lower mortality (10% versus 25% ).Five patients worsened after the 5-d regimen of steroids was

suddenly discontinued with a repeat course resulting in im-provement of three of the five patients.

Two additional nonrando mized trials were t hen p ublishedsuggesting decreased mortality and decreased need for me-

chanical ventilation in patients treated with corticosteroids(Table 2). A fter these case series, additional randomized trials

were performed to evaluate the role of corticosteroid treat-

ment in PCP (Table 3). These trials demonstrated that th e use

of corticosteroids within 48 to 72 h after initiating anti-Pneu-mocystis therapy decreased the incidence of early deteriora-tion in oxygenation as well as lowered mortality and the de-

velopment of respiratory failure. The beneficial effects ofcorticosteroids as adjunctive treatment for PCP have also been

demonstrated in children (Table 4).In add ition to causing infection in t he H IV-positive patient,

PCP m ay occur in solid organ transplant recipients, bone mar-row transplant recipients, patients undergoing chemotherapy

for hematologic and solid organ malignancies, and patientswith chronic inflammatory diseases requiring prolonged use of

corticosteroids or other immunosuppressives (e.g., methotrex-ate) (133138). The mort ality of PCP in these pat ient popula-

tions is higher than the HIV population, ranging from 34 to

58% (133137). Pare ja and coworkers conducted a retro spec-tive review examining the effects of adjunctive corticosteroids

in cases of severe PCP in non-HIV patients (139). Thirty pa-tients were identified who had a PaO2 5 mm Hg or O 2 satu-ration 90% on roo m air. Sixteen patients received increasedsteroids ( 60 mg prednisone or equivalent daily) while 14patients were maintained on a low dose of steroid ( 30 mg

prednisone or equivalent daily) or had steroid therapy tapered.

The increased high-dose steroid group demonstrat ed a shorterduration of mechanical ventilation (6.3 versus 18.0 d, p 0.047), a shorter durat ion of ICU stay (8.5 versus 15.8 d, p 0.025), and a shorter duration of supplemental oxygen re-

quirement (10.0 versus 32.2 d, p 0.05). No difference in mor -tality was noted (44% versus 36% , p NS).

Although there has been some concern about precipitating

serious infections or worsening opportunistic infections inHI V patients with the use of corticosteroids based upon case

reports in the literatur e, analysis of a number of series is notsupportive. In the largest series of 251 patients, there was an

excess of localized her pes infections (26% versus 15% in thestandard ther apy group), but no o ther op portunistic infections

(129). In a retrospective analysis of 23 patients treated withcorticosteroids versus 16 patients treated without corticoster-

oids, Lambertus and coworkers did not find an excess toxicityin the steroid-treated group with one patient developing cryp-

tococcal meningitis 3 wk after completing treatment (140). Ina study by Gallant and coworkers (141) of 53 patients who re-

ceived adjunctive corticosteroids and 121 patients who did notreceive steroid th erapy, no differences were seen be tween the

two groups in the incidence of cytomegalovirus (CMV), My-

cobacterium avium complex, cryptococcal meningitis, toxo-

plasmosis, Kaposis sarcoma, herpes simplex, herpes zoster, ornon-Hodgkins lymphoma. Esophageal candidiasis was morecommon among the patients who received corticosteroids.

Comparing 94 patients receiving corticosteroids with 50 pa-tients who did not, Jones and coworkers found that use of cor-

ticosteroids did not increase the morbidity from undiagnosedtuberculosis (n 8) or increase the frequency of reactivationtuberculosis (142). No increase in risk of developing tubercu-losis or nontuberculous mycobacterial infection was noted by

Martos and coworkers in 72 patients treated with corticoster-oids versus 57 patients who did not receive steroid therapy

(143). Jensen and colleagues did note a trend toward highermortality in 21 patients with PCP t reated with corticosteroids

versus 21 patients not treated with corticosteroids who also

had CMV cultured from BAL fluid; however, this differencewas not statistically significant (p 0.08) (144).

Based upon the available literature, we concur with the rec-ommendations for adjunctive corticosteroid t herapy as stated

by the National Institutes of H ealthUniversity of CaliforniaExpert Panel consensus statement with th e regimen of 40 mg

of prednisone twice a day on D ays 15, 40 mg/d on D ays 610,

TABLE 2

NONRANDOMIZED STUDIES EVALUATING CORTICOSTEROIDS IN ADULTS WITH PCP

Authors (Ref. no.) Study Type Entry Criteria Steroid Therapy Results

MacFadden et al.,

1987 (122)

NR, NB (n 18) PaO2 60 with

FIO2 0.6

Methylprednisolone 40 mg

IV Q 6 h 7 d

ST mortality 10%, n 10;

CT mortality 75%, n 8;ST MV requirement 30%;

CT MV requirement 75%

Walmsley et al.,

1988 (123)

NR, NB Retrospective

(n 33)

PaO2 70 on

room air

Prednisone 80 mg QD 5 d (n 15);

20 to 120 mg QD 5 d (n 6)


CT mortality 25% n 12;

ST MV requirement 10%;

CT MV requirement 25%;

5 relapses after steroids D/C

Montaner et al.,

1989 (124)

NR, NB Retrospective

(n 24)

ARF requiring M V Hydrocortisone 400 to 1,000 mg/ d in

divided doses during ARF


CT mortality 84%, n 6

Schiff et al.,

1990 (125)

NR, NB (n 20) PaO2 60 with FIO2 0.6;

16 required MV

Methylprednisolone 20 to 40 mg IV

Q 6 h 7 to 10 d

Mortality 60% (no controls);

9 relapses after steroids D/C

Definition of abbreviations: ARF acute respiratory failure; CT conventional therapy; D/C discontinued; IV intravenously; M Vmechanical ventilation; NB nonblinded; NR

nonrandomized; Q every; QD every day; ST steroid therapy.


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1086 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 160 1999

and 20 mg/d on Days 1121 (145). Intravenous methylpred-

nisolone can be given at 75% of the a forementioned doses inpatients unable to take oral therapy. Most patients requiring

ICU care will meet t he definition of moderatesevere pulmo-nary dysfunction for which corticosteroids are recommended

(PaO2 70 mm Hg or alveolararterial O2 gradient 35 mmHg). To obtain maximal benefit, corticosteroids should be ini-

tiated within 24 to 72 h of the diagnosis of PCP. Based on thelimited data, we would also recommend corticosteroid treat-

ment for non-HIV patients with respiratory failure. To limitthe possibility of an adverse outcome, we would r ecommend

obtaining appropriate studies to evaluate for coexisting bacte-

rial or opportunistic pathogens.

Acute Eosinophilic Pneumonia

Idiopathic acute eosinophilic pneumonia (AEP) was first de-

scribed by Allen and Davis (146) as well as Badesch and co-workers in 1989 (147). AEP is a clinical entity distinct from

other eosinophilic lung diseases. Based on their observationsAllen and Davis proposed the following clinical criteria for

the diagnosis of AEP: (1) acute febrile illness less than 5 d du-ration; (2) hypoxemic respiratory failure; (3) diffuse alveolar

or mixed alveolarinterstitial infiltrates on chest radiograph;(4) BA L eosinophils greater than 25%; (5) absence of para-

sitic, fungal, or other infection; (6) prompt and complete re-

sponse to corticosteroids; and (7) failure of relapse after dis-

continuation of corticosteroids.Since then additional cases of AEP have been reported in

the literature (148157). The average age at presentation inthe two largest series was 28.4 and 37.2 yr (n 15 and 13, re-spectively) (152, 155). The youngest patient reported was 13yr old (149) while the oldest was 86 yr old (153). In general,

the mea n age at onset is lower for AE P than for chronic eosi-nophilic pneumonia (CEP). The mean duration of symptoms

has been reported to be from 2.8 d and 7.8 d (152, 155). Theprogression of symptom s may be very rap id with less than 24 h

from time of symptom onset to respiratory failure requiring

mechanical ventilation. A duration of symptoms ranging from

15 to 22 d prior to presentation has also been repo rted in t wosmaller series (150, 156). Cough, fever, and dyspnea are theprominent symptoms with pleuritic chest pain and myalgias

also reported.Most patients with AEP are febrile on presentation with

temperatures ranging from 99.0 to 104.0 F. On auscultationthe majority of patients have inspiratory crackles; however, a

normal exam may be noted in some patients (146, 155). Al-though not originally described by Allen and coworkers, the

presence of wheezes has been noted (151, 153, 155). The vastmajority of patients demonstrate hypoxemia with PaO2 less

than 60 mm Hg on r oom air with the rema inder having an in-creased alveolararterial gradient. Per ipheral white blood cell

TABLE 3

RANDOMIZED STUDIES EVALUATING CORTICOSTEROIDS IN ADULTS WTIH PCP


Clement et al., 1989

(abstract) (126)

R, PC, DB (n 41) PaO2 50 on RA Methylprednisolone 60 mg

IV Q 6 h 2 d, 60 mg

Q 12 h 2 d, 60 mg QD, 40 mg

QD, 20 mg QD


CT mortality 41%, n 22; only 11

patients treated 48 h following

anti-PCP therapy

Montaner et al.,

1990 (127)

R, PC, DB (n 37) SpO2 85% but 90%

on RA or SpO2 5%

with exercise

Prednisone 80 mg PO QD 7 d,

40 mg QD 2 d,

30 mg QD 2 d,20 mg QD 2 d, 15 mg

QD 2 d, 10 mg QD 2 d

ST deterioration 5.6%, n 18;

CT deterioration 42.1%, n 19;

deterioration 10%decrease in baseline SpO2;

study terminated early

Gagnon et al., 1990

(128)

R, PC, DB (n 23) PaO2 75 on FIO2 0.35

but 60 on FIO2 1.0

Methylprednisolone 40 mg IV

Q 6 h 7 d


CT mortality 82%, n 11;

ST respiratory failure 25%;

CT respiratory failure 82%; study

terminated early; 4 relapses after

steroids D/C

Bozzette et al., 1990

(129)

R, NB (n 251) Excluded if PaO2/FIO2 75

or required M V

Prednisone 40 mg Q 12 h 5 d,

40 mg QD 5 d, 20 mg QD

for total of 1421 d



ST respiratory failure 14%;

CT respiratory failure 30%

Definition of abbreviations:CT conventional therapy; DB double-blind; D/C discontinued; IV intravenously; MV mechanical ventilation; PC placebo-controlled; Q

every; QD every day; R randomized; RA room air; SpO2 pulse oximetry; ST steroid therapy.

TABLE 4

NONRANDOMIZED STUDIES EVALUATING CORTICOSTEROIDS IN CHILDREN WTIH PCP


Sleasman et al.,

1993 (130)

NR, NB (n 11) MV wtih PaO2/FIO2 150 Methylprednisolone 1 mg/kg Q 6 h 7 d,

0.5 mg/kg Q 12 h 2 d, 1 mg/kg QD 3 d



McLaughlin et al.,

1995 (131)

NR, NB Retrospective (n 20) M V wit h PaO2 75

on FIO2 0.5

Methylprednisolone 24 mg/ kg/d in

4 divided doses 14 d then 7 d taper



Byeet al.,

1994 (132)

NR, NB Retrospective (n 88) All patients Methylprednisolone 1 mg/kg

Q 12 h 5 d, 0.5 mg/kg

Q 12 h 5 d, 0.5 mg/kg QD 7 d



ST MV requirement 42%;

CT MV requirement 64%

For definition of abbreviations, seeTable 2.


9/22


(WBC) counts are usually elevated with a neutrophilic pre-

dominance. In contrast to patients with CEP, patients withAEP typically do not have peripheral blood eosinophilia, al-

though some patients have been reported with peripheralblood eosinophilia either initially or during the course of their

illness (151, 152, 156). Pulmonary function testing in nonintu-bated patients has demonstrated the presence of either ob-

structive or restrictive defects with a decrease in diffusion ca-

pacity being seen in all pat ients (149, 151, 153).Most patients pr esent with bilateral infiltrates on chest ra-

diograph, although two patients have presented with unilat-eral findings (154). In their review of 15 patients, Pope-Har-

man an d coworkers found that 27% had interstitial infiltrates,27% had alveolar infiltrates, and 46% h ad mixed alveolar and

interstitial infiltrates (155). The progression of findings wasusually one of increased interstitial markings followed by the

development of alveolar infiltrates. Small pleural effusions werealso common, being seen bilaterally in 67% o f patients at some

time during their illness. In an analysis of computed tomo-graphic (CT) scans obtained on five patients, Cheon and co-

workers found that patchy areas of ground glass opacity wasthe most common finding with areas of consolidation being

seen in two patients (154).

BAL fluid obtained in AEP is most remarkable for an in-

crease in eosinophil percentages. The average percentage ofBAL eosinophils has been reported as 36.9 2.5% and 40.327.5% (152, 155). Transbronchial biopsies or open lung biopsies

reveal infiltration of the alveoli and interstitium by eosinophils(151, 153, 156). The appearance of acute and organizing diffuse

alveolar damage was also noted on open lung biopsies (156).The diagnosis of AE P should be considered in all patients

with acute respiratory failure accompanied by unexplaineddiffuse pulmonary infiltrates, and BAL should be performed

immediately because it is the only method of establishing thediagnosis of AEP. Other conditions that may produce BAL

eosinophilia include CEP, idiopathic pulmonary fibrosis, sar-coidosis, Churg-Strauss syndrome, bronchiolitis obliterans or-

ganizing pneumonia (BOOP), idiopathic hypereosinophilic

syndrome, drug reactions, PCP, parasitic infections, and fun-gal infections (158, 159). In particular, fungal pneumonia can

resemble AEP and BAL fluid should be stained and culturedfor fungi when A EP is suspected. Fatal invasiveA spergillus in-

fection in immunocompetent patients has been reported tocause BAL eosinophilia as has infection with Coccidiodes im-

mitis (160, 161). CEP has rarely been reported to cause respi-ratory failure requ iring mechanical ventilation (162, 163).

Corticosteroids are the cornerstone of treatment for AEP.A number of case series and reports have demonstrated the

efficacy of corticosteroids (146, 149, 151, 152, 155, 157). Intheir original report and in their subsequent larger series of 15

patients, Allen and Davis treated patients with methylpred-nisolone at a dose of 60 mg to 125 mg every 6 h (146, 155). Ba-

desch and colleagues trea ted their patient with 125 mg of meth-

ylprednisolone every 6 h (147). The pediatric patient treatedby Buchheit and coworkers was given 2 mg/kg of methylpred-

nisolone every 6 h (149). In Tazelaar and coworkers series ofnine patients, all patients were treated with high-dose corti-

costeroids, although the dose was not specified (156). Most pa-tients demonstrated rapid improvement within 1 to 2 d with

some patients showing improvement in several hours. A ll pa-tients responded by 6 to 7 d. After resolution of hypoxemia

and t ermination of me chanical ventilation, patients were thentreated with 40 to 60 mg of prednisone a day which was then

tapered over 4 to 12 wk (146, 147, 149, 155). Corticosteroidshave been tapered as quickly as 10 d and 14 d in two patients

(146, 157). Although spontaneous improvement without the

use of corticosteroids has been reported (150152), these pa-

tients likely had less severe disease. We recommend the use ofcorticosteroids for any patient with AE P req uiring admission

to the ICU and certainly for any patient re quiring mechanicalventilation for A EP. Based on t he available literature, we sug-

gest the use of intravenous methylprednisolone at an initial

dose of 60 mg to 125 mg every 6 h and then switching to oralprednisone at a dose of 40 to 60 mg a day after the patient has

stabilized. This may then be tapered over a 2- to 6-wk time pe-riod depending on the clinical course.

Alveolar Hemorrhage Syndromes

Alveolar hemorr hage has been associated with a wide varietyof disorde rs, including connective tissue diseases, vasculitides,

coagulopathies, cardiac disease, and drug or toxin exposure.The alveolar hemorrhage syndromes are often misdiagnosed

initially on presentation as pulmonary edema or pneumonia.To discuss all of these entities is beyond the scope of this arti-

cle, thus we will focus on those conditions most likely to be en-countered and in which benefit from corticosteroid therapy

has been reported.Systemic lupus erythematosus (SL E) . Alveolar hemorrhage

is a well-recognized complication of SLE with acute, life-

threatening hemorrhage described in the literature. The inci-

dence of massive pulmonary he morrhage in SLE is unknown,but Marino a nd Pertschuk noted that o f their 140 patients fol-lowed for 2 yr, three (2% ) developed diffuse alveolar hemo r-

rhage (164). D iffuse alveolar hemor rhage may be the pr esent-ing manifestation of SLE (165). Mortality greater than 50%

has been reported with alveolar hemorrhage at any time dur-ing the course of SLE (164, 166168). In a recent series by

Zamora and coworkers of 15 patients with 19 episodes of dif-fuse alveolar hemorrhage, 13 of whom required mechanical

ventilation, mor tality was 42% (169). Schwab and coworkers,however, reported a mor tality of 25% (1 of 8) despite four pa-

tients requiring mechanical ventilation (170).No prospective or controlled trials assessing therapy have

been performed, although high-dose corticosteroids have been

advocated by many investigators (171, 172). In the series byZamora and coworkers, 18 of the 19 episodes were treated with

methylprednisolone at doses ranging from 500 to 2,000 mg/d for2 to 6 d followed by a taper (169). Cyclophosphamide was used

in 10 episodes and plasmapheresis in 12 episodes, in addition tocorticosteroids. In Schwabs series of eight patients, methyl-

prednisolone 1,000 mg/d was given for 3 d with cyclophospha-mide in five patients (170). Given these data and observations

with treatment for other causes of alveolar hemorrhage, wewould recommend a course of pulse methylprednisolone at a

dose of 1,000 mg/d followed by a taper based on clinical course.It is beyond the scope of this article to discuss the merits of

treatment with cyclophosphamide and plasmapheresis.Wegeners granulomatosis (WG). Although the lung is the

most common organ system involved in WG (173), diffuse al-

veolar hemorrhage is uncommon (174). Between 5 and 15%of patients presenting with diffuse alveolar hemorrhage will

have WG as the underlying condition (174), and in patientswith WG who develop alveolar hemorr hage, alveolar hemor-

rhage is often the initial presentation of their disease (175,176). Patients with WG presenting with alveolar he morrhage

have a more fulminant course and a higher mortality com-pared with patients with a more typical presentation (175,

177182). Acute renal failure is often associated with alveolarhemorrhage in these pat ients.

Corticosteroids alone are not sufficient therapy for WG(173, 183). The current standard tre atment of WG, developed

at the NIH, consists of prednisone 1 mg/kg/d and cyclophos-


10/22


phamide 2 mg/kg/d based on ideal body weight (173, 183). Af-

ter 4 weeks, the prednisone is tapered over 1 to 2 months to 60mg every other day. In patients with fulminant disease, 2 mg/

kg/d of prednisone and 3 to 5 mg/kg/d of cyclophosphamidehave been used. Some have suggested the use of pulse methyl-

prednisolone at a dose of 1,000 mg/d for 3 d for life-threaten-ing alveolar hemorrhage due to WG (184, 185). We concur

with these re commendations. Other immunosuppressives havebeen u sed but t he discussion of these therap ies is beyond the

scope of this art icle.Microscopic polyangiitis (M PA ). MPA is a systemic necro-

tizing vasculitis that clinically and histologically affects small

vessels (capillaries, venules, or arterioles) without formationof granulomas, as is seen with WG . Like WG , MPA is an an-

tineutrophil cytoplasmic antibody (ANCA)-associated vascu-litis. MPA has the same spectrum of manifestations as WG

and is thought to be the most common cause of the pulmo-naryrenal syndrome (186). A number of patients have been

described with d iffuse alveolar hemor rhage due to MP A (187189). Pulmonary capillaritis is thought to be common with

MPA . In their series of 18 patients with MPA , Gaudin and co-workers found that 11 (61%) had capillaritis and 12 (67%) had

acute alveolar hemorrhage (190). In the series of 34 patientswith MP A described by Savage and coworkers, 10 (29%) had

pulmonary hemorrhage (191). Respiratory failure requiringmechanical ventilation has been reported (188, 191).

For tre atment of MPA, Savage and coworkers used a regi-

men of prednisolone 60 mg/d, and cyclophosphamide 3 mg/kg/das initial therapy (191). Azathioprine at a dose of 3 mg/kg/d

was used as additional therapy in 17 patients, and instead ofcyclophosphamide in three patients. Plasma exchange was

also performed in 18 patients. The success with this regimenwas 79%. Th e predn isolone dose was reduced at weekly inter-

vals to 20 mg/d by 4 wk and then to a maintenance dose of 5 to10 mg/d for 1 yr o r longer. Cyclopho sphamide was given for

8 wk and the azathioprine was continued for 1 yr or longer.Relapses were observed in 12 patients. Treatment similar to

that for fulminant WG with pulse methylprednisolone and cy-

clophosphamide have been advocated by others (186, 192).Given the lack of available data and clinical similarities be-tween MPA and WG, such recommendations seem appro-

priate. A ntiglomerular basement mem brane disease (G oodp as-

tures syndrome). Pulmonary involvement by antiglomerular

basement membrane (anti-GBM) disease ranges from 60 to80% (184). Virtually all patien ts with an ti-GBM disease will

have evidence of glomerulonephritis with microscopic hema-turia or proteinuria although frank renal failure may be pres-

ent in o nly 50% (193). Glomerulonephritis alone may be seenin 20 to 40% of patients, whereas anti-GBM disease limited t o

the lung alone occurs in less than 10% of pat ients (194). Pa-tients may exhibit hemoptysis ranging from blood-streaked

sputum to massive life-threatening hemorrha ge. A small num-ber o f patients may require mechanical ventilation for severe

alveolar he morrhage.Pulse methylprednisolone at a dose o f 1,000 mg/d for 1 to

3 d has been reported to be effective in controlling alveolar

hemorrhage in patients with anti-GBM disease (195, 196).However, corticosteroids as monotherapy have not changed

overall mortality owing to their inability to prevent progres-sion to end-stage renal disease (194, 197). Combination therapy

with cytotoxic agents and corticosteroids (prednisone 1 to 2mg/kg/d) coupled with the use of plasmapheresis has been re-

ported to achieve the best results (195, 197, 198). We concur thatpulse methylprednisolone should be used for patients with life-

threat ening alveolar hemorrhage caused by anti-GBM disease.

Bone marrow transplantation (BMT). Diffuse alveolar hem-

orrhage has been reported in patients undergoing autologousand allogeneic BMT. In a study of 141 consecutive patients

undergoing autologous BMT, Robbins and coworkers foundthat 29 (21%) patients developed alveolar hemorrhage (199).

The median time of onset of alveolar hemorrhage was 12 dwith a range of 7 to 40 d after transplantation. Two patients

developed alveolar hemorrhage before transplantation. Mor-tality was 79% in their series. In an a nalysis of 77 pat ients

treated with a utologous BMT, Jules-Elysee and coworkers re-

ported that 10 (13%) cases of acute re spiratory failure causedby diffuse alveolar hemorrhage occurred with a mortality of

100% (200). Crilley and coworkers found that of 84 patien tsundergoing allogeneic BMT, five (6% ) patien ts died of alveo-

lar hemorrh age (201). In a review of 111 open lung biopsies of109 BMT recipients with diffuse infiltrates, Crawford and co-

workers noted n ine (8% ) cases with extensive alveolar hemor-rhage (202). In a postmortem study of 47 patients who had re-

ceived allogeneic BMTs and died of pulmonary complications,Agusti and coworkers noted that 11 (23% ) patients had evi-

dence of diffuse alveolar hem orrhage (203). In a postmorte mstudy of 21 pediatric patients who developed hypoxemic respi-

ratory failure, Bojko and coworkers reported th at two patients(10% ) had p ulmonary hemorrhage (204).

Administration of corticosteroids to patients with diffusealveolar hemorr hage after BMT ma y improve outcome. Chaoand coworker s reporte d successfully trea ting four pa tients with

alveolar hemo rrhage after aut ologous BMT, two of whom re-quired mechanical ventilation (205). Patients were treated with

meth ylprednisolone 1,000 mg/d for 3 d, th en 500 mg/d for 3 d,then 250 mg/d, followed by 60 mg/d with a taper over 2 mo. In

a retrospective analysis, Metcalf and coworkers studied 65 ep-isodes of alveolar hemorrhage in 63 of 603 consecutive pa-

tients who had undergone BMT (206). Patients were dividedinto three groups according to the therapy they received.

Twelve patients received supportive care alone, 10 patientsreceived low-dose corticosteroids (30 mg/d or less of methyl-

prednisolone or its equivalent), and 43 patients received high-

dose corticosteroids (more than 30 mg/d of methylpredniso-lone or its equivalent). The need for endotracheal intubation

was 100% in the group that did not r eceive steroids, 80% inthe low-dose steroid group, and 45% in the high-dose steroid

group. Mortality was 92% in the non steroid group, 90% inthe low-dose steroid group, and 67% in the high-dose steroid

group. In the high-dose steroid group, most patients weretreated with 125 to 250 mg of methylprednisolone every 6 h

for 4 to 5 d followed by a taper over 2 to 4 wk based on clinicalimprovement. No increased risk of infection was noted be-

tween the steroid- and nonsteroid-treated groups.In the absence of other data, and if the presence of infec-

tion has been sufficiently excluded, we recommend treatmentfor BMT-associated alveolar hemorrhage with methylpred-

nisolone at a dose of 125 to 250 mg every 6 h for 4 to 5 d fol-lowed by a taper over 2 to 4 wk.

Acute Lupus Pneumonitis

The syndrome of acute lupus pneumo nitis occurs in 1 to 4% of

patients with SLE (171). Patients typically present with abrupt

onset of dyspnea, fever, cough, and pleuritic chest pain. Lupuspneumonitis may be the presenting manifestation in some

patients. Matthay and coworkers described 12 patients withacute lupus pneumonitis, representing 12% of their SLE pa-

tients who were hospitalized during a 6-yr period (207). Mor-tality was 50% in their series despite treat ment with cortico-

steroids and the addition of azathioprine in some patients.


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Other fulminant cases of acute lupus pneumonitis have been

reported (208212).Little data exists for the optimal treatment of acute lupus

pneumonitis. In their series of 12 patients, Matthay and co-workers specified the dose of corticosteroids in only three pa-

tients, which was 100 mg/d of prednisone in two patients and400 mg/d of hydrocortisone in one p atient. A zathioprine at a

dose of 2 mg/kg/d was used in seven patients (207). Inoue and

coworkers successfully treated two patients with corticoste-roids alone, one with 80 mg/d of prednisone and one with 200

mg/d of prednisone (213). In a patient requiring mechanicalventilation, D omingo-Pedrol a nd coworkers reported success-

ful treatment with 1,000 mg/d of methylprednisolone for 5 dfollowed by 60 mg/d of prednisone (212). Freter and cowork-

ers also used pulse methylprednisolone at a dose of 750 mg/dfor 3 d followed by prednisone 60 mg/d to successfully treat a

patient with fulminant lupus pneumonitis (211). Cyclophos-phamide an d plasmapheresis have also been used in conjunc-

tion with methylprednisolone 250 mg every 6 h in a patientwho was failing corticosteroid therapy alone (210).

Based on the case series and data available for alveolarhemorrhage caused by SLE, we recommend initial treatment

with 1 mg/kg/d of prednisone or equivalent. Pulse methylpred-

nisolone of 1,000 mg/d for 3 d followed by 1 mg/kg/d of pred-

nisone may be o f benefit in patients with life-threatening lupuspneumonitis. The adjunctive use of cytotoxic agents and plas-mapheresis has been advocated by some investigators, although

their role is undefined.

Bronchiolitis Obliterans Organizing Pneumonia (BOOP)(Cryptogenic Organizing Pneumonia)

The clinical syndrome of idiopathic bronchiolitis obliterans or-

ganizing pneumonia (BOOP), also known as cryptogenic or-ganizing pneumonitis (COP), was initially described in eight

patien ts by Davison and coworker s in 1983 (214) and in 50 pa-tients by Epler and coworkers in 1985 (215). BOOP has also

been associated with a variety of conditions including infec-tions, drugs and toxins, irradiation, organ and bone marrow

transplantation, collagen vascular diseases, malignancies, andinflammatory bowel disease (216, 217). Patients with BOOP

typically have a subacute presentation with dyspnea, cough,fever, malaise, weight loss, and a flulike syndrome (215, 218

220). On chest radiograph multiple patchy alveolar opacities,diffuse inter stitial infiltrates, or a focal pulmonary opacity may

be seen. The clinical presentations of idiopathic BOOP andsecondary BO OP are similar (220).

The overall prognosis for BOO P is good, however progres-

sion to deat h occurs in 6 to 15% of cases (215, 218, 221223);patients with BOOP secondary to connective tissue diseases

may have a worse outcome (215, 220). Fulminant and life-threatening BOOP has been reported. Cohen and coworkers

described 10 patients with rapidly progressive BO OP and se-vere respiratory failure requiring mechanical ventilation in

nine patients (224). Of these 10 patients, seven died despiteaggressive therapy with corticosteroids and the use of cyto-

toxic therapy in four. The doses of corticosteroids used werenot specified. Nizami and coworkers reported five patients

with life-threatening BOOP causing hypoxemic respiratoryfailure (225). Four patients required mechanical ventilation,

and two subsequently died. All patients were treated with cor-ticosteroids, although the dose was reported for only one pa-

tient (methylprednisolone 80 mg every 12 h). Fulminant respi-

ratory failure in a patient with BOOP unsuccessfully treatedwith 250 mg of methylprednisolone every 6 h for 3 d followed

by 60 mg/d was described by Iannuzzi and coworkers (226).Schwarz, however, successfully treated a patient requiring me-

chanical ventilation with 2 g/d of methylprednisolone for 5 d

followed by an unspecified taper (227). Bellomo and cowork-ers also reported successful treatment of two patients having

severe hypoxemia with 50 to 60 mg/d of prednisolone (228).Corticosteroids are considered the t reatment of choice for

BO OP although the ideal dose and duration of treatment have

not bee n clearly defined. Given the lack of data re garding thetreatme nt of life-threatening BO OP, extrapolation from treat-

ment of non -ICU patients is necessary. A number of case se-ries have reported successful treatment with corticosteroids

(214, 215, 217, 219, 229). Doses ranged from 20 mg/d to 1 mg/kg/d of prednisone. Patients were trea ted for several months.

Relapses were noted when therapy was discontinued or ste-roids were rapidly tapered during the first months of treat-

ment. King and Mortenson have recommended a dose ofpred nisone of 1.5 mg/kg/d (using ideal body weight) n ot to ex-

ceed 100 mg/d for 4 to 8 wk followed by a dose of 0.5 to 1.0mg/kg/d for 4 to 6 wk (222). After 3 to 6 mo, if the patients

condition is stable or improving, the pred nisone m ay be grad-ually tapered. For rapidly progressive, severe cases of BOO P

they recommend 250 mg of methylprednisolone intravenouslyevery 6 h for 3 to 5 d followed by oral prednisone. Cor dier has

recommended a regimen of m ethylprednisolone 60 mg every

12 h for 3 to 5 d followed by daily prednisone at a dose of 1 mg/

kg (216). After clinical and radiographic improvement thedose is decreased to 0.5 mg/kg/d for 1 to 2 mo followed by agradual taper. Although spontaneous improvement has been

noted in some patients (218, 219, 223), for patients with mod-erate to severe BOOP we recommend treatment with corti-

costeroids. Based on the current case series, we would suggestan initial dose of 1 mg/kg/d of prednisone or equivalent, not to

exceed 100 mg/d. After 4 to 8 wk, if clinical response is seen,this may be de creased to 0.5 mg/kg/d for 4 to 8 wk followed by

a gradual taper. Patients should probably be treated for atleast 6 mo, although some patients may require 12 mo of ther-

apy. In patients with life-threaten ing BOO P, an initial pulse of1,000 mg/d of methylprednisolone for 3 to 5 d may be appro-

priate.

Radiation Pneumonitis

Radiation lung injury presents as two distinct clinical syndromes,radiation pneumonitis and radiation fibrosis. This section will

focus on the former as it may result in respiratory failure. Theestimated incidence of symptomatic radiation pneumonitis is 7

to 8% , although the percentage of patients who develop radio-logic changes is substantially higher, averaging 43% across

several studies (230, 231). The typical time course for the on-set of radiation pneumonitis is 2 to 3 mo after completion of

radiation ther apy, although some patients develop symptomsas late as 6 mo (232). Presentations as early as 1 to 2 wk after

receiving radiation therapy have been reported (233235),usually in association with previous chemotherapy or high-

dose, short-course radiothera py. The cardinal symptom of ra-diation pneumonitis is dyspnea, which can vary from mild to

severe. Patients may also have cough and fever, thus simulat-

ing an infectious process. In a small numbe r of patient s, the ra-diation pneumonitis may produce acute r espiratory failure re-

quiring mechanical ventilation, and in some patients, fatalrespiratory insufficiency and acute cor pulmonale (236238).

The development of ARDS with diffuse bilateral infiltratesfollowing limited thoracic irradiation has also been reported

(234, 239).Corticosteroids are the mainstay for tre atment of radiation

pneumonitis, although data from large human studies arelacking. However, a number of animal models have shown ef-

ficacy. In a mouse model, Philips and coworkers demonstrated


12/22


that p rednisolone (1 mg/kg) given at the time of irradiation re-

duced mortality, as did administration when animal deaths be-gan to appear in another cohort group (100 to 160 d) (240).

Gross found that methylprednisolone given 80 d postirradia-tion increased survival in mice; and when the steroid was later

discontinued, morta lity increased to that of the control group(241). These findings were confirmed by Gross and coworkers

in a subsequent study (242). In a 30 to 40 kg sheep model ofradiation pneumonitis, Loyd and coworkers observed that

treatme nt with 1 g of methylprednisolone every 6 h preventedacute lung dysfunction as measured by increases in lung lymph

protein clearance, mean pulmonary artery pressures, lung

lymph thromboxane concentrations, and arterial oxygen ten-sions (243).

Although t here are no controlled clinical trials in humans,there is some evidence that corticosteroids are beneficial in

treating radiation pneum onitis. Ab rupt d iscontinuation of cor-ticosteroids in patients receiving corticosteroids as part of a

chemotherapeutic regimen was reported to precipitate se-vere radiation pneumonitis in some patients (244246). When

seven of 10 of these p atients resumed prednisone, at doses of20 mg to 120 mg daily, all showed clinical improvement. Rubin

and Casarett summarized eight studies in humans publishedbefore 1960 (247). In patients treate d at the on set of acute ra-

diation pneumonitis, seven of nine (78%) patients respondedas opposed to seven of 13 (54%) who were treated after radia-

tion pneumonitis had been established. Four of these studies

demonstrated no ben efit with pr ophylactic use of corticoster-oids. Yamada and coworkers reported that 16 of 17 patients

with mo derate to severe radiation p neumonitis improved withsteroid therapy, although doses were not provided (248).

Ot her case reports and case series have reported ben efit withcorticostero ids (233, 238, 249); however, some cases o f severe

radiation pneum onitis may be u nresponsive to corticosteroids(234, 237).

Based on th e available data, we recommend the use of cor-ticosteroids for moderat e or severe ra diation pneumonitis. In

the absence of clinical trials, we would suggest the use of at

least 60 mg of prednisone per day or equivalent. Gross hassuggested a dose range of 60 to 100 mg daily of prednisone(232). Following a satisfactory response, this dose should be

decreased to 20 to 40 mg a day followed by a gradual taper

over several weeks to pr event recurrence.

Miliary Tuberculosis

Miliary tuberculosis (TB) may occasionally lead to respiratory

failure requiring ICU admission. A number of cases of AR DShave been reported in association with miliary TB (250253).

Miliary TB with respiratory failure has also been reported inthe H IV-infected patient p opulation (254, 255). A numb er of

investigators have advocated the use of corticosteroids in thisclinical setting. To our knowledge, only one controlled trial

exists examining the utility of corticosteroids for miliary TB.Tongnian and coworkers treated 28 patients with isoniazid

(INH), streptomycin (STM), and para-aminosalicylic acid (PAS)alone, whereas 27 patients were treated with prednisone in

addition to antituberculous therapy ( 256). The corticosteroidregimen consisted of prednisone 10 mg four times a day for

1 wk, then 20 mg daily for 2 to 7 wk, followed by a gradual

taper for a total course of 3 to 5 mo. Mortality was 7% in thecorticosteroid group compared with 18% in the control group.

With the pa ucity of data, no firm recommendations for theuse of corticosteroids in miliary TB can be given. We believe

that corticosteroids should be given in conjunction with antitu-berculous chemotherapy in patients with miliary TB and hy-

poxemic respiratory failure or ARDS. The possibility of coex-

isting adrenal insufficiency in patients with disseminated TB

should be kept in mind.

Pulmonary Toxicity Secondary to Drugs or Toxins

Bleomycin pneum onitis . Bleomycin is an ant itumor an tibiotic

with activity against a variety of tumors including squamouscell carcinoma o f the head and neck, cervix, and esopha gus, as

well as germ cell tumors, Hodgkins lymphoma, and non-Hodgkins lymphoma (257). Interstitial pneumonitis is the

most serious adverse effect, leading to respiratory compro-mise and death in some patients. The incidence of bleomycin

interstitial pneumonitis has ranged from 3 to 11% and the

overall mortality from interstitial pneumonitis

corticoids for arf

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