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					INFECTIONS IN THE COMPROMISED HOST                        0891-5520/01 $15.00   + .OO

                        STEROID USE
                               Natalie C. Klein, MD, Chi Hiong-U Go, MD,
                                                  and Burke A. Cunha, MD


     Corticosteroid use has dramatically increased in the last decade.
Cortisone was first isolated from the adrenal cortex in 1935, and first
synthesized in the mid 1940s. In 1948, cortisone was first used for the
treatment of rheumatoid arthritis (RA). In the 1950s, steroid use for the
treatment of asthma became widespread. Steroids are widely used for
the treatment of many rheumatologic diseases including systemic lupus
erythematosus (SLE), RA, sarcoidosis, temporal arteritis, and other vas-
culitides. Steroids also play an important role in the treatment of many
pulmonary diseases including asthma, chronic obstructive pulmonary
disease, and interstitial fibrosis. Steroids are used in ophthalmology for
treatment of uveitis, and in hematology for the treatment of idiopathic
thrombocytopenic purpura and autoimmune hemolytic anemia. Steroids
play an important role in immunosuppressive therapy in organ trans-
plantation. In addition, steroids are useful as antiinflammatory agents in
the treatment of a number of infectious diseases including Pneurnocystis
curinii pneumonia (PCP) and tuberculous meningitis.'*, 13, 30, 38, 45, 6o Al-
though corticosteroids are useful in the treatment of a wide spectrum of
diseases, chronic steroid use also is associated with an increased risk of
developing certain infectious diseases. This review will focus on the
infectious complications occurring in patients on chronic corticosteroids.

From the State University of New York School of Medicine, Stony Brook, New York; and
    Infectious Disease Division, Winthrop-University Hospital, Mineola, New York


VOLUME 15 NUMBER 2 JUNE 2001                                                     423
424     KLEIN et a1


       Corticosteroids are biologically active synthetic analogs of the ste-
roid hormones produced in the adrenal cortex and have both glucocorti-
coid (metabolic) and mineralocorticoid (electrolyte regulating) effects.
Steroids are used in clinical practice both for replacement therapy and
for treatment of a wide array of diseases, because of their antiinflamma-
tory or immunosuppressive action.
       Corticosteroids inhibit superoxide production that results in a de-
crease in hydrogen peroxide generation and diminution in release of the
antibacterial lysosomal hydrolases within the phagocytic vacuole, thus
interfering with the killing of microorganisms. For these reasons, steroids
permit multiplication of the microorganism within the phagocytes while
alleviating inflammation.
       Chronic steroid use predisposes patients to a variety of infections by
interfering with host defense mechanisms. Steroids affect most aspects of
the immune system (Table 1). Corticosteroids cause a weakening of
collagen, and fibrous tissue support proteins in the skin and soft tissue
leading to atrophy, easy bruising, and delayed wound healing. The
resulting striae seen in individuals receiving chronic steroids makes the
skin more susceptible to traumatic breaks, and infections caused by
Staphylococcus uureus, Streptococcus pyogenes, and some gram-negative ba-
       A single dose of corticosteroid produces a neutrophilic leukocytosis
which peaks 4 to 6 hours after giving the steroid. This leukocytosis
results from an increased release of neutrophils from the bone marrow,

      Effect on 1st Line of Defense (Skin/Mucous Membranes)
        Delayed healing
      Effect on Neutrophils
        Neutrophilic leukocytosis
        Increased release of neutrophils from bone marrow
        Decrease migration of neutrophils to inflammatory sites
        Inhibition of chemotaxis
        Very high steroid doses inhibit phagocytosis and intracellular killing
      Effect on Lymphocytes
        Selective depletion of circulating T-lymphocytes by redistribution
        Suppression of delayed hypersensitivity
      Effect of Monocyte-Macrophage
        Decreased chemotaxis
        High-dose steroids inhibit phagocytosis and bactericidal activity
        Decreased production of proinflammatory cytokines (interleukin 1, TNF-a)
                             INFECTIONS ASSOCIATED WITH STEROID USE   425

and a decreased migration of neutrophils to inflammatory sites. High-
dose steroids inhibit phagocytosis and intracellular killing of patho-
     A single dose of steroid causes a marked lymphocytopenia from
redistribution of lymphocytes out of the circulation. There is selective
depletion of circulating T-lymphocytes. Steroids cause a suppression of
delayed hypersensitivity and skin testing, and suppression of lympho-
cyte proliferation to antigens.
     Monocytopenia and eosinopenia also occur 4 to 6 hours after admin-
istration of corticosteroids. Steroids cause decreased migration of mono-
cytes/macrophages at inflammatory sites, decreased production of pro-
inflammatory cytokines, and decreased bactericidal activity.19, 74

     Infections associated with corticosteroids are dependent on the route
of administration, dose, and duration of therapy. Inhaled steroids have
the lowest risk of causing infection. The most common infectious compli-
cation is oropharyngeal candidiasis. Candida albicans and non-C. albicans
species are the most common isolates from the oropharynx of patients
on inhaled steroid preparations.6,51, 70 Some systemic absorption can
occur by way of absorption from the lungs, and secondary to ingestion
of steroids deposited in the oropharynx. Systemic absorption can be
minimized by use of a spacer and by thoroughly rinsing the mouth
after use.
     Clearly, the likelihood of infectious complications increases with
increase in steroid dose and duration of therapy. Short acting prepara-
tions such as hydrocortisone are the least potent, while dexamethasone,
a long acting steroid, is 25 times more potent.
     With systemically administered steroids, the risk of infection is
related to the dose of steroid and the duration of therapy as demon-
strated in a meta-analysis of 71 controlled trials.60The overall rate of
infectious complications was 12.7% in steroid-treated patients compared
to 8.0% in the control group (relative risk 1.6).60  The rate of infection
was not increased in patients receiving less than 10 mg/day or a cumula-
tive dose of less than 700 mg of prednisone. Patients with neurologic
diseases had a much higher rate of infection compared to patients with
intestinal, hepatic, or renal diseases.
     Limiting steroid administration for less than 21 days also decreases
infectious complications. Prolonged suppression of T-lymphocyte-medi-
ated cellular immunity appears necessary for opportunistic infection to
occur. The host’s underlying disease state, which dictates the dosage
and duration of steroid therapy, largely accounts for variable and dose-
dependent infectious complications seen in pra~tice.~, 55
                                                        36, 39,

     Patients receiving chronic steroids have an increased susceptibility
to all types of infection. Although a wide spectrum of both common
426    KLEIN et a1

and opportunistic infection have been reported, the largest number of
infections are caused by the pyogenic bacteria (Table 2). The most com-
mon pathogens are Staphylococcus, streptococci, and the Enterobacteria-
ceae. Patients on chronic steroids are at increased risk of developing
surgical wound infections and wound dehiscence since steroids interfere
with fibroblast proliferation and collagen synthesis?
    Chronic steroid use increases the risk of infection with intracellular
pathogens. Infections caused by Listevia monocytogenes, Salmonella species,
Brucella, and Legionella occur more frequently in patients receiving
chronic steroids.'O, 31, 34
    Nocardia asteroides, a filamentous gram-positive bacterium causes
central nervous system infection, subcutaneous abscesses, and pulmo-
nary infection in immunocompromised patients on steroids. Nocardial

                      Legionella micdadei
                      Listeria monoytogenes
                      Mycobacterium tuberculosis
                      Nontuberculous mycobacteria
                      Nocardia asteroides
                      Rhodococcus equi
                      Salmonella sp.
                      Staphylococcus aureus
                      Candida albicans and nonalbicans sp.
                      Coccidioides immitis
                      Cyptococcus neofomans
                      Fusarium sp.
                      Histoplasma capsulatum
                      Penicillium marneffei
                      Pseudallescheria boydii
                      Z ygomycoses
                      Herpes simplex virus
                      Human papillomavirus
                      Respiratory syncytial virus
                      Varicella zoster
                      Cryptosporidiosis/lsospora belli
                      Pneumocystis carinii
                      Strongyloides stercoralis
                      Toxoplasma gondii
                              INFECTIONS ASSOCIATED WITH STEROID USE   427

infection presents most often as a brain abscess or acute necrotizing
pneumonia, and is an important cause of morbidity and mortality in
transplant patients and patients with malignancie~.~~,   47, 4x, 52,
     Mycobacterium tuberculosis infects 1.7 billion people worldwide and
3% to 4% will develop active tuberculosis during the first year of tuber-
culin conversion. Prolonged corticosteroid therapy increases the risk of
developing active mycobacterial disease. Individuals receiving chronic
steroid therapy, defined as the equivalent of greater than or equal to
15 mg/day prednisone for at least 1 month, should receive isoniazid
prophylaxis if they have a positive Mantoux tuberculin skin test.3,32
     TB occurring in the setting of chronic steroid use is often miliary or
disseminated, has a high mortality rate, and may have an atypical
pre~entation.~~ are numerous reports of extrapulmonary TB, in-
cluding TB arthritis, intestinal TB, central nervous system TB, and TB
involving the bone and liver developing in patients receiving chronic
steroids.57, 74 Chronic steroid use also increases the risk of developing
disseminated nontuberculous mycobacterial infections. Most cases have
occurred in organ transplant recipients who are also receiving other
immunosuppressive therapy.44, 64 The most common presentation was
the development of cutaneous lesions.
     Legionella pneumophila is the most common species accounting for
approximately 85% of Legionella infections. Risk factors for legionnaires'
disease include cigarette smoking, chronic lung disease, advanced age,
and immunosuppression. Sixty percent of nonpneumophila Legionella
infections are caused by L. micdadei and 10% by L. bozemanii.18 Most cases
o nonpneumophila Legionella infections are associated with malignancy,
organ transplantation, or chronic corticosteroid use.l', 18, 26, 53
     Rhodococcus equi, a cause of bronchopneumonia in horses, is an
intracellular pathogen causing pulmonary infections primarily in AIDS
patients but also in immunosuppressed patients receiving corticoste-
roids. Extrapulmonary infections with R. equi include subcutaneous ab-
scesses, intra-abdominal infection, disseminated abscesses, osteomyelitis,
paraspinal abscess, and bacteremia.21, 59
     Fungal infections, both endemic mycoses and nosocomially ac-
quired, are an important cause of morbidity and mortality in patients
receiving chronic corticosteroids. Besides steroids, other factors contrib-
uting to the development of nosocomial invasive fungal disease include
the use of broad spectrum antibiotics, presence of indwelling central
venous catheters, hyperalimentation, diabetes mellitus, and multiple
surgical procedures.8, l5
     Patients receiving chronic steroids may develop primary fungal
infection or reactivation of infection with the endemic mycoses, His-
toplasma capsulatum, Coccidioides immitis, Cyptococcus neoformans, or Blas-
tomyces dermatitidis. Candida and Aspergillus species are the most common
cause of nosocomial fungal infections, but in the last decade, infection
with unusual fungal organisms has become an increasing concern in
immunocompromised patients. Some of these newer fungi reported to
cause infection in patients on steroids include Pseudalleschevia boydii,
428    KLEIN et a1

Penicillium marnefei, Fusarium species, Trichosporon species, Exophiala,
Alternaria, and X y l ~ h y p h a .33, 49 ,
     Aspergillosis is the most common cause of invasive fungal infec-
tion worldwide and has a high mortality rate. Post-transplant patients
receiving greater than 1.25 mg of prednisone/kg/day for longer than
1 month are at high risk of invasive Aspergillus. Since steroid immuno-
suppression effect is delayed and cumulative, most invasive Aspergil-
lus infection usually is seen after the first month of transplantation.
Although other factors such as graft rejection and broad spectrum
antibiotic use may contribute to the development of disseminated
aspergillosis, the dose of corticosteroids seems to be the most important
fa~for.25~29, 58. 71

     Patients receiving chronic steroids are at increased risk of devel-
oping localized and disseminated infections with herpes zoster virus,
herpes simplex virus (HSV), cytomegalovirus (CMV), Epstein-Barr virus
(EBV), adenovirus, influenza and parainfluenza virus. Herpes zoster in
the normal host usually is manifested as a painful vesicular eruption
limited to one dermatome. Patients receiving chronic steroids are at
increased risk of developing multidermatomal shingles, cutaneous dis-
semination and varicella zoster pneumonitis.2, 16, 20, 28, 56 There are also
data that low-dose steroid therapy, nasal steroids, and short course
steroid therapy for asthmatics, if given during the incubation period,
may increase the severity and risk of varicella dissemination.
     HSV occurring in patients receiving chronic steroids is characterized
by more extensive mucocutaneous involvement and atypical presenta-
tions, including perianal ulceration and recurrent glos~itis.~,  Dissemina-
tion to visceral organs and prolonged excretion of HSV-1 in saliva occur
primarily in organ or bone marrow transplant recipients. The use of
acyclovir prophylaxis is recommended in these patients.
     CMV, like HSV infections, tends to be more prolonged and severe
in immunosuppressed hosts. Patients receiving chronic steroids may
develop disseminated disease. The most common clinical manifestations
include pneumonia, retinitis, hepatitis, colitis, esophagitis, and central
nervous system in~olvement?~,67 Most cases of disseminated CMV
occur in transplant patients receiving other immunosuppressive drugs
such as cyclophosphamide, azathioprine, or cyclosporine. Steroids act
synergistically with other immunosuppressive agents to enhance reacti-
vation of CMV. The addition of high-dose steroids to azathioprine results
in a high incidence of reactivation of CMV in renal transplant patients.50
Immunocompromised patients receiving chronic steroids are also at in-
creased risk o developing severe infections caused by adenovirus, respi-
ratory syncytial virus, influenza and parainfluenza viruses.17
     Immunosuppressed patients are susceptible to a number of parasitic
infections including Pneumocys tis carinii (PCP), Toxoplasma gondii, Cryp-
tosporidium, and Strongyloides stercoralis. Both endogenous and exogenous
sources of steroids predispose to PCP. PCP has been reported in Cush-
ing's syndrome, in asthmatics receiving steroids, in patients with acute
lymphatic leukemia receiving high-dose steroids, and in transplant recip-
         7,22,    72 The corticosteroid rat and mouse models have been used
                                   INFECTIONS ASSOCIATED WITH STEROID USE           429

to study the pathogenesis of PCP.27, PCP prophylaxis is recommended
for patients receiving chronic steroids.
     Corticosteroids are a major risk factor for disseminated Stroqyloides.
Disseminated Strongyloides has occurred after less than 10 days of high-
dose steroid treatment.27, Therefore it is important to screen patients
from endemic areas for Strongyloides and treat this infection prior to
initiating immunosuppressive therapy.


     The use of low-dose trimethoprim-sulfamethoxazole in organ trans-
plantation markedly reduces the risk of developing Pneumocystis pneu-
monia, Listeria infection, toxoplasmosis, nocardiosis, and urinary tract
infections. Acyclovir prophylaxis decreases the incidence of HSV and
herpes zoster infection in bone marrow transplant recipients. Adminis-
tration of CMV hyperimmune globulin and ganciclovir has been used
to prevent CMV reactivation in renal transplant recipients. Patients with
positive tuberculin skin tests, who require chronic steroids, should re-
ceive a minimum of a 6-month course of isoniazid prophylaxis. Patients
with eosinophilia should be screened for parasitic infection and treated
prior to initiating chronic steroid therapy. Patients receiving steroids
who have negative varicella titers should receive zoster immunoglobulin
if exposed to chickenpox. The risk of fungemia in immunosuppressed
patients can be reduced by minimizing the use of broad spectrum
antibiotics and indwelling central line catheters. Finally, and most im-
portantly, the use of the lowest possible effective dose of steroids for the
shortest possible time will decrease the risk of infection. Clinicians
should maintain a high index of suspicion for the development of
common and unusual opportunistic infections in patients receiving
chronic high-dose steroid therapy.


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                                                                 Address reprint requests to
                                                                     Natalie C. Klein, MD
                                                               Infectious Disease Division
                                                             Winthrop-University Hospital
                                                                Mineola, New York, 11501

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