Thyrotoxicosis Induced by Thyroid Involvement of Disseminated Aspergillus fumigatus Infection

Abstract

Aspergillus fumigatus is increasingly recognized as an important nosocomial pathogen in severely immunocompromised patients. Infection is difficult to diagnose antemortem and typically has a fatal outcome. Here we report the case of a cardiac transplant recipient with disseminated A. fumigatus infection which clinically presented as thyrotoxicosis due to massive involvement of the thyroid gland.

Aspergillus fumigatus is increasingly recognized as an important nosocomial pathogen in severely immunocompromised patients. Infection is difficult to diagnose antemortem and typically has a fatal outcome (2, 5). Aspergillosis was found in 13.8% of cardiac transplant recipients at Stanford University Medical Center, and all patients with disseminated disease (4.8%) died (3). Although involvement of the thyroid gland is reported at autopsy for 9 to 15% of patients with disseminated disease, very few individual case reports have been published (2, 6, 7).

Here we report a case of disseminated A. fumigatus infection in a cardiac transplant recipient. The patient was a 65-year-old man who underwent transplantation because of end-stage ischemic cardiomyopathy. The immunosuppressive regimen included prednisone (7.5 mg twice a day), mycophenolate mofetil (1,000 mg twice a day), and tacrolimus (5 mg plus 6 mg daily). Postoperative evaluation revealed coronary heart disease of the transplanted organ but demonstrated good ventricular function. Low-grade rejection of the organ (Ib according to the International Society for Heart and Lung Transplantation classification) was shown by myocardial biopsy. Weight loss and moderate elevation of the serum C-reactive protein level (in the range of 5 to 6 mg/liter) were repeatedly documented in postoperative outpatient exams. Routine respiratory cultures repeatedly grew A. fumigatus 7 to 15 weeks after transplantation. However, negative culture results were also noted, and physical examination and chest radiography revealed no sign of infection. Laboratory tests showed normal thyroid function (thyroid-stimulating hormone, free 3,5,3′-triiodothyronine [T₃], and free 3,5,3′,5′-tetraiodothyronine [T₄] within the normal range).

Six months after transplantation the patient was admitted to the hospital for decreasing renal function thought to be caused by elevated serum tacrolimus levels (23.4 ng/ml). Physical examination revealed that the patient was cachectic and dehydrated. The systolic blood pressure was 110 mm Hg, the pulse rate was 80, and the respiratory rate was 20 per minute; temperature was normal. His white blood cell (WBC) count was 8,100/mm³, and the level of serum C-reactive protein was 24.8 mg/liter. A leukocyte esterase test suggested urinary tract infection. Treatment with tacrolimus was discontinued and antibiotic therapy was initiated (200 mg of ciprofloxacin twice a day).

The following day, physical examination revealed fever (38.5°C), altered mental status with stupor, and progressive respiratory distress (partial O₂ pressure of 55 mm Hg). The patient was transferred to the intensive care unit for intratracheal intubation and mechanical ventilation. Thyroid function tests confirmed the clinical suspicion of thyrotoxicosis (thyroid-stimulating hormone, 0.0 mU/liter [normal range, 0.3 to 3.0 mU/liter]; free T₃, 5.7 pg/ml [normal range, 2.2 to 5.5 pg/ml]; and free T₄, 7.7 ng/dl [normal range, 0.6 to 1.8 ng/dl]). The WBC count was 4,500/mm³ and the level of serum C-reactive protein was 28.1 mg/liter. Chest radiography demonstrated mild pulmonary congestion without signs of infection. Culture of respiratory specimens grew few organisms of the normal flora of the upper respiratory tract, Escherichia coli and Candida glabrata. The urine culture grew >10⁵ E. coli organisms (resistant to ciprofloxacin) per ml. Antithyroid therapy with methimazole (40 mg four times a day) and propylthiouracil (50 mg three times a day) was introduced and antibiotic treatment was switched to ceftriaxone (2 g daily), vancomycin (2 g daily), and diflucan (200 mg daily).

Fever (38.5°C), tachycardia (125/min), and an increasing demand for dopamine were seen the following day. Laboratory studies showed a WBC count of 4,700/mm³ and a level of serum C-reactive protein of 21 mg/liter. An increased blood urea nitrogen (117.9 mg/dl) despite good diuresis as well as coagulation disturbances (prolonged partial thromboplastin time [PTT], 61.8 s, and platelets, 114,000/mm³) were documented. Thyroid function tests demonstrated increasing levels of free T₃ (9.4 pg/ml) and free T₄ (10.3 ng/dl), and an ultrasound showed a nonhomogenous enlarged thyroid gland (volumes of 35 and 27 ml for the right and left lobes, respectively). Mycophenolate mofetil was reduced (500 mg twice a day).

Frozen sections of tissue from a thyroid biopsy performed the next day revealed infectious thyroiditis with suppurative inflammation, abscess formation, and considerable tissue destruction (Fig. 1). Septate hyphae less than 5 μm in thickness and branching at acute angles were identified (Fig. 1, inset). Blood vessels were often thrombosed and invaded by hyphae of the fungus. After intraoperative diagnosis of a fungal thyroiditis caused by Aspergillus, a total thyroidectomy was performed. A culture of an intraoperative swab grew A. fumigatus, confirming the histopathological diagnosis. A serum sample taken the same day had a positive result in an Aspergillus antigen (galactomannan) enzyme-linked immunosorbent assay, and the microbiology laboratory reported growth of A. fumigatus from a tracheal secretion taken two days earlier. Diflucan was replaced by amphotericin B (60 mg daily) and itraconazole (200 mg twice a day by nasogastric tube), which was later switched to amphotericin B plus flucytosine (2.5 g four times a day). The galactomannan enzyme-linked immunosorbent assay is one of the most sensitive tests available for the diagnosis of invasive aspergillosis. Since antigen detection occurs rather late during the clinical course for most patients, weekly determinations are required (5, 8).

FIG. 1.

Periodic acid-Schiff stain showing infectious thyroiditis with suppurative inflammation and destruction of follicles. Arrows indicate the area of inflammation and tissue destruction. (Inset) Branching (asterisk) and septate (arrowhead) hyphae consistent with Aspergillus species. Magnification, ×125 (×291 for inset).

Low-grade fever (38.0 to 38.5°C) was seen the following 10 days, and laboratory studies revealed the following data: increased WBC counts from 5,400 to 20,200/mm³, a decreased platelet count to 70,000/mm³, and an increase in blood urea nitrogen to 159.3 mg/dl. Thyroid tests showed rapidly decreasing function, and thyroid hormone replacement was started 5 days after the operation. Two days postoperation, chest radiography for the first time showed signs of inflammation in the lower left lobe, and diffuse pulmonary involvement developed. A cerebral computed tomography scan was negative. Cultures of endotracheal secretions again grew A. fumigatus. Despite further reduction of the immunosuppressive regimen (mycophenolate mofetil was interrupted and prednisone was reduced to 12.5 mg twice a day), the patient deteriorated progressively and died 14 days after hospitalization. No autopsy was performed.

Early diagnosis of invasive aspergillosis is a challenge in posttransplant patient monitoring. Positive culture results for A. fumigatus during the routine postoperative exams were not regarded diagnostic at that time, although persistent elevation of serum C-reactive protein levels and weight loss were documented. Neither treatment nor additional diagnostic investigation was initiated. Localized infection might have developed at that time and exacerbation of disseminated disease might have been caused by the immunosuppression. A longer subclinical course and the lack of radiographically overt pulmonary disease have been described as characteristic features of aspergillosis in transplant recipients (3).

As reported by Berger et al., thyroid function tests suggested hyperthyroidism in 12 of 56 episodes during bacterial thyroiditis although clinical overt disease was rarely seen (1). These data are difficult to assess, since preexisting thyroid disease had been present in most cases. Leakage of the hormone may be induced by local inflammation and direct tissue destruction. Although involvement of the thyroid gland was reported at autopsy for 9 to 15% of patients with disseminated aspergillosis, hyperthyroidism was rarely reported (2, 6, 7). Only one case of thyrotoxicosis induced by thyroid involvement in disseminated aspergillosis has been described; the case involved a pediatric patient with chronic granulomatous disease (4).

As in the case described here, diagnosis is delayed in most cases, and frequently the fungal infection is first revealed at autopsy (2). The significance of recovery of Aspergillus spp. from respiratory specimens is a matter of debate. However, a highly predictive value of isolation of Aspergillus spp. from respiratory secretions in high-risk patients was found by Yu et al. (9). Prospective studies are necessary, but it might be reasonable to initiate oral itraconazole and weekly determination of Aspergillus antigen in sera of high-risk patients with Aspergillus spp. repeatedly grown from respiratory specimens.