A forty-year-old woman who had no history of trauma was seen
with tenderness and effusion of four months’ duration in the
right knee. She had also noted transient migratory arthralgias in
the left knee and left foot during that time-period. However, the
right knee was the only joint affected at the time of presentation.
Her medical history included human immunodeficiency virus, diagnosed
eleven years earlier; genital herpes simplex virus; polycystic kidney
disease; and hypertension. Pulmonary histoplasmosis had been diagnosed eight
months earlier and treated with oral itraconazole intermittently
because of the patient’s noncompliance. The last CD4 count,
three months earlier, was 104 (20%), and the human immunodeficiency
viral load was 56,000 (decreased from >1,000,000 five months
earlier).
The knee was warm, with minimal erythema, moderate effusion,
and generalized tenderness to palpation, especially at the suprapatellar
area and the medial and lateral joint lines. The range of motion
was 0 to 45, and there was pain at the extremes of extension and
flexion.
Aspiration of knee-joint fluid revealed 671 white blood cells, 13,310
red blood cells, and 71% neutrophils. Histoplasma
capsulatum was identified by DNA probe. No other joint
was aspirated. The erythrocyte sedimentation rate was elevated to
102, the level of antinuclear antibodies was slightly elevated,
and the rheumatoid factor was negative.
Radiographs made three weeks earlier had revealed a suprapatellar
effusion and soft-tissue swelling. A magnetic resonance image had
then revealed soft-tissue edema along the posterior aspect of the
knee, a moderate-sized joint effusion, and two focal areas within
the joint, showing low signal on both T1 and long fast-spin-echo
T2-weighted images (Fig. 1). This finding was interpreted
as probable pigmented villonodular synovitis.
A percutaneous synovial biopsy was performed six weeks after
the knee aspiration. Staining of biopsy sections with hematoxylin
and eosin showed fibrotic synovial tissue with numerous inflammatory
cells, consisting predominantly of histiocytes, with a few plasma
cells and lymphocytes (Figs. 2-A and 2-B). The histiocytes had a vacuolated
cytoplasm, which contained ill-defined round-to-oval bodies (Fig. 2-C). A Grocott
stain for fungi highlighted these bodies, confirming the diagnosis
of fungal yeast forms. These intracellular organisms measured approximately
half the size of a red blood cell (2 to 4 m) and showed narrow-based
budding (Fig. 2-D).
The findings were consistent with a diagnosis of histoplasmosis.
Concomitantly, a workup beginning four weeks after the first aspiration
confirmed that the pulmonary histoplasmosis had recurred, and systemic
antifungal therapy was begun. Knee-joint fluid obtained by repeat
aspiration contained 45,300 red blood cells and 3500 nucleated cells,
with 53% granulocytes, 22% lymphocytes, and 25% tissue
cells. A mycology smear was negative, but culture was positive,
with 1+ Histoplasma capsulatum. A Gram
stain showed 4+ white blood cells and 4+ red blood cells;
no organisms were seen. There was no growth on routine culture of
joint fluid.
While hospitalized, the patient received liposomal amphotericin
B for seven days, and she was discharged with instructions to take
oral itraconazole. At the time of her last visit, approximately
eight months after the diagnosis of the knee infection, she was
continuing to take oral itraconazole (300 mg/day). The
knee had no effusion, and the range of motion was 0 to 130 without
pain. A repeat magnetic resonance image demonstrated resolution
of the previous inflammatory changes and a possible incidental small
tear involving the anterior horn of the lateral meniscus. Plain
radiographs showed a normal right knee.
After having done well for a year, the patient had renewed swelling
of the right knee. Cultures of specimens obtained with arthrocentesis
were again positive for Histoplasma capsulatum. She
received liposomal amphotericin B for eight days and continued to
take oral itraconazole. The swelling of the right knee subsided,
and, at the time of this writing, the infection was again quiescent.
Although it is an opportunistic organism, histoplasmosis has been
seen both in patients with the human immunodeficiency virus and
in those without it. A literature review revealed eight cases in
which Histoplasma capsulatum grew on culture of
material from the affected joints of adults (Table I). Four of these
cases involved the knee, and the others involved parts of the upper
extremity. Only one of these patients was described as having the
human immunodeficiency virus; the status of the other patients was
not reported. Of the seven patients for whom the treatment was described, three
were managed with antifungal medications5-7.
Another patient was treated with amputation between the middle and
distal two-thirds of the thigh8.
Two other patients were treated with both surgery and antifungal
medications. One of these patients had exploration of the left forearm,
wrist, and palm, with removal of granulomatous tissue, the involved
part of the triquetrum, and the proximal one-third of the lumbrical
muscles10. The other patient had
resection of granular synovitis surrounding the flexor tendons in
the forearm and of nongranular thickened synovial tissue14. Another patient was treated by
surgical excision of a mass in the flexor sheath on the volar aspect
of the left wrist and then with antifungal medication11 after recurrence and possible adrenal
involvement. The disease was eradicated in five patients, the patient
treated by amputation died from postoperative complications, and
the disease was eventually eradicated in the patient who had the recurrence
after the medical regimen.
There have been sporadic findings of arthritis in patients with histoplasmosis
even when no organisms were grown on culture of synovial fluid1,3,9,12. Nightingale et al. reviewed
the cases of 980 patients with acquired immunodeficiency syndrome
who had disseminated histoplasmosis, but the authors did not mention
whether there were findings of arthritis9.
Allen reported on two patients who had bone involvement with disseminated
histoplasmosis, but no clinical evidence of joint involvement was
noted in either patient1. Class
and Cascio reported on a patient who had histoplasmosis presenting
as acute polyarthritis; they did not examine the joint fluid since
they believed that the joint involvement was an allergic manifestation3.Rosenthal
et al. discussed the rheumatologic manifestations of histoplasmosis,
which occurred in 6.3% of patients with symptomatic histoplasmosis
diagnosed during an epidemic in Indianapolis12.
Cultures were negative for joint disease, and histologic studies
did not reveal fungal organisms. Wheat et al. noted that, while
cultures of specimens from patients who have chronic pulmonary and
disseminated histoplasmosis are often positive, they are rarely
positive in epidemics, when the disease is in an acute phase15.
Localized bone involvement may be seen in conjunction with a
normal appearance of the joint space on radiographs; however, there
may be atrophy of articular surfaces and secondary changes of surrounding
bone13. Darouiche et al. reported
that histopathological examination of surgical specimens often revealed
caseating and/or noncaseating granulomas5.Cuellar et al. stated that Histoplasma
may be detected in tissues or exudates in only 70% of cases
and it takes two to three weeks for complement-fixation antibodies
to histoplasmin and Histoplasma yeast antigens to become positive4.
The 1997 edition of The Medical Letter on Drugs and Therapeutics lists
the drug of choice for histoplasmosis as itraconazole (200 mg orally,
twice a day) or amphotericin B (0.5 to 0.6 mg/kg intravenously
for four to twelve weeks)16. Amphotericin
B is recommended for patients with severe illness. Alternative choices
are ketoconazole (400 mg orally, once or twice a day) and fluconazole
(400 mg, twice a day). Itraconazole (200 mg orally, once or twice
a day) and amphotericin B (0.1 to 0.5 mg/kg intravenously,
once a week) are listed as alternatives for chronic suppression
in patients with human immunodeficiency virus16.
Wheat stated that patients with acquired immunodeficiency syndrome
have a high rate of recurrence of disseminated histoplasmosis17. He therefore thought that a high-dosage
initial course of amphotericin is unwarranted. He suggested, as
a general approach to the treatment of disseminated histoplasmosis,
1.0 to 1.5 g of amphotericin B over a six-to-eight-week period of induction
therapy followed by ketoconazole (400 mg/day) or amphotericin
B (50 to 100 mg/wk) over an indefinite maintenance period.
He stated that ketoconazole cannot be recommended for immunocompromised
patients because it is ineffective for them17.
In 1993, Drew extensively reviewed the pharmacotherapy for disseminated
histoplasmosis in patients with acquired immunodeficiency syndrome18. He concluded that amphotericin
B is the drug of choice for induction therapy and that it should
be followed by maintenance therapy with either amphotericin B or
an oral azole antifungal agent that is active against Histoplasma
capsulatum for the prevention of recurrence. Itraconazole
may be used instead for both induction and maintenance treatment18.
In summary, histoplasmosis is an opportunistic fungal infection
that is not commonly seen in patients who are not immunocompromised.
The diagnosis should be considered in a patient with unexplained
erythema, pain, and swelling in the knee. Radiographic findings
may be inconclusive, and a biopsy is necessary. Treatment options
include medical management with itraconazole or amphotericin B.