by Sheila Rodriguez Gonzalgo1, M.D., Samuel Ejadi1, M.D., and Colleen Christmas2, M.D.
1Clinical Fellow and 2Associate Professor, Johns Hopkins Geriatric Medicine
- History of Present Illness
- Social History
- Physical Examination
- Laboratory Studies
- Radiology Studies
- Differential Diagnosis
- Clinical Course
- Case Discussion
A 35 year-old male kickboxer was in good health until 6 months prior to presentation to our service, when he developed a chronic cough productive of blood-tinged white sputum, flu-like symptoms, a decrease in appetite, and subsequent weight loss. Two months prior to admission, he was incarcerated, and his symptoms worsened. A TB skin test was placed and was found to be negative. Upon his release one month prior to admission, he became so short of breath that he could no longer continue kickboxing. He presented to the emergency room, was found to have a right upper lobe infiltrate, given a prescription for azithromycin and was discharged home. He then developed several painless subcutaneous nodules. The largest nodule, however, was associated with pain in his left lower leg and eventually hindered his ambulation which prompted admission to Johns Hopkins Bayview Medical Center. Review of systems was significant for subjective fevers, chills, night sweats, and a 10-kg weight loss. He denied prior pneumonia, sinus infections, acne, arthritis, hematuria, high blood pressure, paresthesias or numbness, and muscle weakness.
Previous employment included slaughtering chickens in rural Virginia, traveling on the East Coast as a professional mover, and most recently, installing home insulation, but no exotic travel or pets. Again, he was recently incarcerated for one of many knife fights, and he mentioned a sick contact in prison who had “knots” of unclear etiology. He had no history of intravenous drug use and had been in a monogamous relationship for four years.
This was a young robust gentleman who was afebrile and nontoxic-appearing. Firm, non-fluctuant subcutaneous nodules, ranging from 1 X 1 cm to 10 X 4 cm, were found on his anterior left tibia, left wrist, right second metacarpal, upper back, face, and occipital scalp. The lesion at the left tibia exhibited ulceration. (Figure 1) With the exception of his left tibia and right hand, the nodules were non-tender but erythematous. Joint exam revealed nontender swelling of the right second metacarpal that limited flexion (Figure 2) of that finger and bone tenderness associated with the left anterior tibial nodule. The remainder of the joint exam was unremarkable. The chest, cardiovascular, and abdominal exams were unremarkable.
White blood cell count was 10,590 #/cu mm, with a normal differential; hematocrit 31.3 %; platelets 573,000 .
ESR 123 mm/hr, total protein 8.4 gm/dl, albumin 3.6 gm/dl, protein gap 4.8.
C-ANCA negative, p-ANCA negative, ANA negative, RF negative .
RPR negative. HIV negative. Urinalysis revealed too numerous to count white blood cells with moderate leukocyte esterase.
A PPD skin test was negative, but a Candida control was positive. Bacterial, acid fast bacillus, and fungal cultures were sent of the blood, sputum, and urine. Incision and drainage of several nodules expressed purulent material, which was sent for pathologic examination and cultures, along with biopsies of the nodules. All initial cultures were negative for any organisms.
CT of the chest showed right upper, middle, and lower lung infiltrates with air bronchograms (Figure 5). Bone scan demonstrated increased radiotracer activity in the left tibia and calcaneous, and multiple ribs (Figure 6).
- Multifocal infectious osteomyelitis
- Fungal-cryptococcus, histoplasmosis, blastomycosis, coccidiomycosis
- Other bacteria, such as Staphylococcus aureas (endocarditis)
- Polyarteritis nodosa
- Acne arthritis variant with polyfocal inflammatory bone lesions
- Malignancy with bony metastasis
This is a previously healthy immunocompetent 35 year-old man who presented with a chronic systemic inflammatory process, as evidenced by anemia, elevated ESR, increased globulins, and weight loss. The primary organs involved include lung, skin, bone, and genitourinary tract.
The expression of frankly purulent material from the left leg nodule suggested that this was most likely an infectious process. Fungus is a probable source, given the chronicity of the patients symptoms. The most likely fungal causes of infection are the endemic mycoses, which are usually seen in immunocompetent hosts-histoplasmosis, blastomycosis, and coccidiomycosis. This patient had never traveled to the west and was not exposed to coccidiomycosis. Histoplasmosis most commonly presents as a flu-like pulmonary illness, with erythema nodosum and arthritis or arthralgias, but dissemination to bone is rare. Blastomycosis disseminates to the lung, skin, bone, and genitourinary tract, which is consistent with the pattern of organ involvement seen in this patient. Cryptococcus is usually seen as an opportunistic infection in an immunocompromised host.
A bacterial source would have caused a more typical pneumonia, and this patient appeared too healthy to have mycobacteria or Staphylococcus infection. The chronicity of his symptoms, the lack of a murmur on cardiac exam, and persistently negative blood cultures all argued against Staphylococcus endocarditis. Skin and lung are common sites for Nocardia infection, but has been reported in bone less often (1 of 36 in a case series by Kontoyiannis et al. 1998). Nocardia is also associated with immunosuppression, such as those patients undergoing transplantation, steroid therapy, and cancer.
There are also rheumatologic or vasculitic illnesses that cause nodules. Polyarteritis nodosa can cause pulmonary infiltrates and subcutaneous nodules but usually not bony lesions. Severe skin diseases, such as acne fulminans and hidadrenitis suppurtiva are associated with multiple bone lesions that can resemble osteomyelitis but may be sterile on culture. However, this patient had no history of acne or sinus tracts. Sarcoidosis is also associated with skin and lung lesions, but the granulomas in bone do not erode into skin, and the erythema nodosum do not erode into bone.
He was initially treated with intravenous antibiotics for empiric therapy for osteomyelitis, pneumonia, and urinary tract infection. Subsequently, he developed high-grade fevers and new nodules on his face, and he continued to have nightsweats and wasting. After four days of negative cultures, antibiotics were discontinued. A bronchoscopy was nondiagnostic. Because of dramatic clinical deterioration with persistently negative cultures, empiric amphotericin B was initiated. He then defervesced (Figure 7) with recovery of function in his right hand and left leg, and diminution of the skin nodules. After two weeks, a fungus was found in the cultures of the nodule biopsy, bronchoalveolar lavage, and later the urine.
This fungus was identified by DNA probe to be Blastomyces dermatitidis (Figure 8). Thirteen months later, the patient is doing well without evidence of recrudescence.
This patients presentation was consistent with disseminated blastomycosis, with involvement of the lungs, skin, bones, and genitourinary system. Blastomyces dermatitidis is a dimorphic fungus that resides in soil and wood of the Ohio and Mississippi River valleys and the southeastern United States. The portal of entry is the respiratory tract and is associated with occupational and recreational activities in wooded areas along waterways, where there is moist soil with a high content of organic matter and spores. The incubation period ranges from 21 to 106 days. Most likely, this patient inhaled conidia in the soil while crawling underneath houses installing insulation. He used only a t-shirt to cover his mouth and nose.
Initial pulmonary infection is often subclinical and may mimic symptoms of influenza or bacterial infection, with myalgias, arthralgias, fevers, and chills. Subsequent extrapulmonary involvement occurs through hematogenous spread to skin, bones, genitourinary tract, and rarely the central nervous system. Chronic pulmonary disease is characterized by productive cough, hemoptysis, weight loss, and pleuritic chest pain, with variable radiologic findings. Skin disease, which may be a marker for multiorgan infection, can take the form of verrucous lesions on exposed body areas, ulcerative lesions, or subcutaneous nodules. Skeletal blastomycosis usually presents as a well-circumscribed osteolytic lesion in the long bones, vertebrae, and ribs. Prostatic blastomycosis is also common and can present with urinary obstructive symptoms.
One series reported a case fatality rate of 11% when blastomycosis was inadequately treated. Itraconazole has been shown to be more effective than ketoconazole and fluconazole in the treatment of blastomycosis, and it is commonly used to treat uncomplicated focal, nonmeningeal, non-life-threatening blastomycosis on an outpatient basis. However, itraconazole has been associated with treatment failure in studies of dogs with CNS infection; thus, amphotericin B is first-line therapy for CNS blastomycosis. Amphotericin B should also be used as initial therapy in immunocompromised populations – those with AIDS, long-term glucocorticoid use, hematologic malignancy, solid organ transplantation, and pregnancy – since mortality in these patients exceeds 30%. These patients may later require chronic suppressive therapy with itraconazole.
- The Centers for Disease Control and Prevention: Morbidity and Mortality Weekly Report. Blastomycosis acquired occupationally during prairie dog relocation – Colorado 1998. JAMA 282(1):21-22, 1999.
- The Centers for Disease Control and Prevention: Morbidity and Mortality Weekly Report. Blastomycosis – Wisconsin, 1986-1995. JAMA 276(6):444, 1996.
- Kaufman CA. Newer developments in therapy for endemic mycoses. Clinic Infectious Diseases Aug;19 Supply 1:S28-32, 1994.
- Kontoyiannis D, Ruoff K, Hooper D. Nocardia Bacteremia: Report of 4 Cases and Review of the Literature. Medicine 77(4):255-267, 1998.
- Legendre AM, Rohrbach BW, Toal RL, Rinaldi MG, Grace LL, Jones JB. Treatment of blastomycosis with itraconazole in 112 dogs. Journal of Veterinary Internal Medicine 10(6):365-71, 1996.
- Nijhawan P, Elkin PL. 59-year-old with right hip pain. Mayo Clinic Proceedings 73(6):541-544, 1998.
- Pappas PG. Blastomycosis in the Immunocompromised patient. Seminars in Respiratory Infections 12(3):243-51, 1997.
- Paul DS, Kaminsky DA. A New England logger with a diffuse pneumonia. Chest 117:244-247, 2000.
- Pettersson T. Sarcoid and erythema nodosum arthropathies. Best Practice & Research in Clinical Rheumatology 14>(3):461-76, 2000.
- Seo R, Oyasu R, Schaeffer A. Blastomycosis of the epididymis and prostate. Urology 50(6):980-2, 1997.
- Saccente M, Abernathy RS, Pappas PG, Shah HR, Bradsher RW. Vertebral blastomycosis with paravertebral abscess: report of eight cases and review of literature. Clin Infect Dis 26(2):413-8, 1998.
- Wheat J. Histoplasmosis: experience during outbreaks in Indianapolis and review of the literature. Medicine 76(5):339-354, 1997.