# Presentation: 142161

## Spotlight Case

**Empiric Steroids: the Good, the Bad, and the Ugly**

## Source and Credits

- This presentation is based on the September 2008 AHRQ WebM&M Spotlight Case
- See the full article at _[http://webmm.ahrq.gov](http://webmm.ahrq.gov/)_
- CME credit is available
- Commentary by: **Edward D. Harris, Jr, MD, Stanford University**
- Editor, AHRQ WebM&M: Robert Wachter, MD
- Managing Editor: Erin Hartman, MS

## Objectives

*	**At the conclusion of this educational activity, participants should be able to:*
- Describe appropriate indications for use of steroids
- Appreciate contraindications for use of empiric steroids
- Understand which chronic illnesses and systemic diseases can benefit from glucocorticoid use

## Case A: Part 1

*	**A 55-year-old male immigrant with no significant past medical history came to the emergency department for evaluation of a 3-day history of dyspnea, non-productive cough, and fever. Physical examination revealed tachypnea, bibasilar crepitations, and diffuse, end expiratory wheezes. The patient was started empirically on a cephalosporin and a macrolide for community-acquired pneumonia. Given the diffuse wheezing on exam, he was also treated with intravenous corticosteroids.*

## Community-Acquired Pneumonia (CAP)

- Diagnosis often made without evidence of causative agent
- Antibiotic coverage initiated
- Glucocorticoids often added because many of these patients also have chronic obstructive pulmonary disease (COPD)
- Systemic steroids reportedly promote resolution of symptoms and reduce mortality in CAP patients

*See Notes for references.*

## Etiologic Agents in CAP

- How aggressively should physicians search for a specific etiologic agent in CAP?
- When there are risk factors for “atypical” causes, such as the patient being an immigrant, closer look is warranted
- Specific therapies for parasitic diseases often found in immigrant populations
- In patient such as this one, using glucocorticoids for “expiratory wheezing” is questionable without better sense of causative agent

## Case A: Part 2

*	**Over subsequent days, the patient deteriorated, developing respiratory failure and requiring transfer to the intensive care unit. Diffuse wheezing persisted. Subsequent chest radiographs and CT scans revealed progressive bilateral diffuse granular opacities. More extensive work-up pursued to evaluate for atypical and fungal pneumonia revealed no culprit organism. Bronchoscopy revealed thick yellow mucus and cultures were sent. Ultimately, bronchial washings demonstrated the larvae of strongyloides stercoralis.*

## The Presented Case

- Glucocorticoids not helpful in *Strongyloides stercoralis*
- Proper therapeutic regimen would have included discontinuing glucocorticoids, and providing appropriate anti-infectives for *S. stercoralis:* thiabendazole and ivermectin

## Glucocorticoids

- Should be considered essentially for acute use, with plans to taper or replace with other medications
- Exceptions are chronic or prolonged diseases for which there are no more therapeutic options

## Empiric Steroids

- Whenever initiating glucocorticoid therapy empirically without certainty of the underlying illness, ask yourself:
- Are there any conditions remaining on the differential diagnosis that could get much worse on glucocorticoids?
- If yes, consider withholding steroids, empirically treating the other condition, or pursuing more aggressive diagnostic testing to rule out the condition

## Case B: Part 1

*	**A 49-year-old woman had onset over 3 weeks of morning stiffness, pain, and swelling bilaterally in her proximal interphalangeal (PIP) joints, metacarpophalangeal (MCP) joints, wrists, and knees. She is post-menopausal, has an unremarkable past medical history and no allergies, and her only medications are a statin drug for high LDL and gabapentin for sleep. She has not left her home for the past 6 months. She is fatigued and finds that she cries more easily. She sees you, her primary care physician, 31⁄2 weeks after symptoms began.*

## 	Examination reveals bilateral tenderness and soft tissue swelling in the finger joints except for distal interphalangeal (DIP) joints and the palmar aspect of the wrists. Both knees are swollen, with a particularly large effusion on the right. A right popliteal cyst is present, and full extension lacks 20 degrees. MCP joints 1-3 are tender on the right foot. Full extension of the left elbow is limited. No subcutaneous nodules or skin rash are found. Eye exam is normal, as is examination of the cardiorespiratory system.

**Case B: Part 1 (cont.)**

## While awaiting the results of laboratory tests, would it be appropriate to begin treatment with 15 mg prednisone each morning because of concern about the right knee?

**Case B: Question**

## While awaiting lab tests and definitive diagnosis, it would be inappropriate to start therapy with prednisone 15 mg daily

**Case B: Answer**

## Diagnosis

- The history suggests a diagnosis of early rheumatoid arthritis (RA)
- Morning stiffness is *sine qua non* for joint inflammation
- Patient’s joint distribution typical for RA: distal interphalangeal (DIP) joints rarely affected

## Steroids in Present Case

- Although initiating low-dose therapy may lead to improvement in patient’s symptoms, it would lead to conflict later: low dose is “forgotten” by physician, but patient cannot bear stopping it
- If daily dose continued for more than month, this post-menopausal woman would be at greater risk for glucocorticoid-induced osteoporosis

*See Notes for reference.*

## Steroids for RA

- Historically, tendency was for physicians to treat RA with oral, daily glucocorticoids
- Such treatment now recognized as inappropriate, especially since efficacy of methotrexate has clearly been demonstrated
- Early intervention could include
- Non-steroidal anti-inflammatory drugs
- Tetracycline derivatives found to have small but definite efficacy in early RA

*See Notes for reference.*

## Options for This Patient

- Oral daily glucocorticoids contraindicated
- Appropriate to aspirate as much fluid as possible from patient’s right knee
- Aspiration itself alleviates symptoms
- Fluid should be sent for cell count and culture
- Can inject 40 mg triamcinolone (an injectable glucocorticoid) or an equivalent
- Intraarticular route of administration approximately twice as effective as intramuscular injection of similar doses

*See Notes for reference.*

## Case B: Part 2

*	**Let’s assume glucocorticoids were *_*not*_* initiated. *
*	**The joint fluid contained 23,000 polymorphonuclear leukocytes (PMNs)/mm3 and culture was negative. Her hemoglobin was 10.2 g/dL, plasma WBC 9500/****L with 3% eosinophils and 80% PMNs. Urinalysis and a comprehensive serum screen were normal. The C-reactive protein was 6.8 mg/dL, and both rheumatoid factor and anti-citrullinated antibody (highly specific for RA) were present in serum. Now, almost 5 weeks after symptoms began, the patient is not improved and probably is worse. *

## Case B: Part 2—Question

**Should oral glucocorticoids be used empirically **_**now**_** to suppress the presumed RA?**

## Case B: Part 2—Answer

- Although appropriate to diagnose RA in this woman, it is _**not**_ appropriate to begin oral glucocorticoids unless there is a definitive plan to discontinue them relatively soon

## Treatment of RA

- Randomized trial compared treatment strategies:
- Initial combination therapy with methotrexate, sulfasalazine, and rapidly tapered high-dose prednisone therapy
- Initial combination therapy with methotrexate and infliximab (a monoclonal antibody directed against TNF alpha)
- Patients on either of these regimens
- More likely to achieve clinical remission and have significantly less joint damage progression after 2 years than those on sequential monotherapy or step-up to combination therapy
- Those on protocol with initial prednisone did not have more toxicity than those who were not given prednisone

*See Notes for reference.*

## Empiric Glucocorticoids in RA 

- Empiric use of glucocorticoids in RA should be limited to one of three scenarios:
- For acute symptom relief, administration of single high dose of intramuscular glucocorticoids very early in disease process before other therapies are given
- To relieve single painful, inflamed joint, use of intraarticular glucocorticoids at 2- to 3-month intervals
- Use of oral glucocorticoids only in protocols where tapered to zero dose within a month (e.g., glucocorticoid combined with other disease-modifying agents such as methotrexate)

## Case C: Part 1

*	**A 43-year-old man developed a skin eruption believed to be an allergy to a diuretic (his only medication) that he was taking for hypertension. Within several weeks, he became profoundly tired, had spiking fevers during the day, and began to lose weight. He noted stiffness in knees and hands, especially in the morning. His wife noted that he seemed ‘pale.’*

## Case C: Part 1 (cont.)

*	**On examination he appeared ill and was mildly tachypneic. Oral temperature was 39.4°C. Blood pressure was 117/75, pulse 112 (regular). He had a faint serpiginous skin eruption on his trunk. Cardiac examination revealed tachycardia and prominent heart sounds. Liver and spleen were palpable, the latter extending 6 cm below the left costal margin. Mild pitting edema of the lower extremities was found, but he had no joint effusions. Neurologic examination was reported as “non-focal.” Stool was negative for occult blood.*

## Case C: Part 1—Initial Test Results

| Test | Result |
| --- | --- |
| WBC [white blood cell count] | 2100/L |
| band forms | 40% |
| lymphocytes | 10% |
| Platelets | low |
| Smear exam | multiple fragmented RBC |
| Hemoglobin  | 8.3 g/dL |
| Urinalysis | numerous WBC |
| ESR [erythrocyte sedimentation rate] | 120 mm/h |
| C-reactive protein (CRP) | 28.8 mg/dL |

## Case C: Part 1—Other Test Results

| Test | Result |
| --- | --- |
| BUN | 56 mg/dL |
| Bilirubin | 4.2 mg/dL |
| AST/GGT (liver function tests) | elevated |
| Blood glucose | normal |
| Creatine kinase | slight elevation |
| Sodium | 132 mEq/L |
| Potassium | 5.4 mEq/L |
| Albumin | 2.8 g/dL |
| Globulin | 2.4 g/dL |
| Tests for tick-borne diseases | negative |

## Case C: Question

**While awaiting other tests, would it be appropriate to begin 80 mg prednisone/day in divided doses?**

## Case C: Answer

- The physicians should consider, but then reject, this course of treatment until most possibilities of infection have been ruled out
- Patient is very ill with systemic process that could be generating an excess inflammatory cytokine release, “cytokine storm”

## Illness and Empiric Steroids

- Steroids should not be administered unless infection has been excluded by appropriate studies
- After infection seems unlikely, malignancy (most often lymphoma) and systemic vasculitis are the most probable diagnoses
- In a patient who is continuing to worsen, empiric steroids 80-100 mg/day intravenously is appropriate while workup continues

## Case C: Part 2

*The blood smear showing fragmented RBC led to other tests*
*Fibrinogen: low*
*Fibrin degradation products: high*
*Serum ferritin: 1120 ****g/L*

## Case C: Part 2 (cont.)

*	**As the patient was stabilized, but not improved, with glucocorticoid administration 3 days later, a subsequent bone marrow examination revealed phagocytosis of hematopoietic cells by invasive macrophages. A protocol for treatment of aggressive lymphoma was added to the prednisolone, and the patient improved.*

## The Present Case

- Extremely high ferritin levels, in association with fever, splenomegaly, cytopenias, and hypofibrinogenemia suggest a diagnosis of hemophagocytic lymphohistiocytosis

*See Notes for reference.*

## Lesson from Case

- “Don’t use steroids unless you cannot help it!”
- Even though diagnosis was not clear, most causes of infection had been ruled out
- Severe multi-system disease without a clear diagnosis is more often caused by infection, malignancy, or systemic vasculitis

## When Diagnosis is Unclear

- In absence of infection, appropriate to test hypothesis that problem is “steroid-responsive disease”
- Drug can be stopped if patient does not improve, or if cause for which there are specific therapies emerges
- For example, *Strongyloides* in Case A

## When to Use Glucocorticoids

- Certain forms of arthritis respond to glucocorticoids, usually given intra-articularly
- Rheumatoid arthritis, acute gouty arthritis, juvenile arthritis, osteoarthritis, pseudogout, psoriatic arthritis, rheumatic fever
- Glucocorticoids often used in oral doses for systemic vasculitis and other connective tissue diseases, including:
- Dermatomyositis/polymyositis, mixed connective tissue disease, polymyalgia rheumatica, systemic lupus erythematosus

## When to Avoid Empiric Steroids

- Steroids may exacerbate underlying disease processes
- Therefore, certain comorbidities should preclude use of glucocorticoids unless specifically indicated

## When to Avoid Use (cont.)

- Physicians should be very cautious about prescribing glucocorticoids for periods longer than several weeks to patients with following:
- Infection—all forms
*Exception to rule is when high doses of glucocorticoids are indicated to diminish severe inflammatory manifestations of the infections (e.g., Pneumocystis carinii lung disease and tuberculous pneumonia)*
- Diabetes mellitus
- Poorly controlled hypertension
- Post-menopausal women, especially those with other risk factors for osteoporosis

## Take-Home Points

- For a patient with a glucocorticoid-responsive chronic illness that has flared, administering glucocorticoids intramuscularly or, less frequently, intravenously, will often suppress the disease flare and spare the patient the long-term risks of continued oral therapy, even in small doses
- Infection with aggressive bacteria or mycobacteria is the primary contraindication for use of glucocorticoids, unless the principal manifestation of infection is the inflammatory response to the inciting agent

## Take-Home Points (cont.)

- In severely ill patients with an undiagnosed systemic disease in whom most forms of infection have been ruled out, a therapeutic trial of high-dose glucocorticoids gives useful information, and may help the patient
- With advances in the treatment of multi-system chronic diseases (including rheumatoid arthritis, inflammatory bowel disease, systemic vasculitis), addition of other medications to supplement glucocorticoids is almost always indicated