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Departments of Internal Medicine
Laboratory Medicine
Pathology, National Taiwan University Hospital
School of Medical Technology, National Taiwan University College of Medicine, Taipei, Taiwan
ABSTRACT
We present a case of fatal histoplasmosis in a patient with Addison's disease and long-term use of corticosteroid. The patient acquired Histoplasma capsulatum in China and initially presented with a laryngeal mass. He developed fulminant pneumonia and respiratory failure 9 years later. Nucleotide sequences of internal transcribed spacer regions of rRNA genes of the H. capsulatum isolate recovered from biopsied lung tissue and of the extracted fungal DNA from the laryngeal lesion were identical, indicating the recurrent nature of infection.
CASE REPORT
An 86-year-old male retired engineer from Taiwan was a heavy smoker. Before his retirement in 1983, he visited several countries in Asia, including Indonesia, Thailand, and Saudi Arabia. After his retirement, he continued to live in Taiwan but visited mainland China every 2 to 3 years. Addison's disease was diagnosed in 1992, and he began lifelong corticosteroid treatment (7.5 mg every day). Pulmonary tuberculosis was diagnosed in 1993, and he remained well after a 9-month course of antituberculosis agents. A laryngeal tumor was found in 1994, and culture of the laryngeal tissue grew Histoplasma capsulatum. A chest radiograph showed no active lung lesions. Surgical removal of the laryngeal mass was performed, and ketoconazole (400 mg every day) was given for 2 months postoperatively. No evidence of recurrence of histoplasmosis was found thereafter.
In early December 2002, a progressive cough with yellowish sputum developed 3 weeks after he returned from a 1-month visit to China. He did not have fever, dyspnea, or sore throat. A chest radiograph taken after arrival at the emergency department on 3 January 2003 showed bilateral pneumonia with multiple cavities (Fig. 1A). Gram- and acid-fast-stained smears of sputum collected on 5 January 2003 were negative for significant pathogens. Recurrence of tuberculosis was suspected, and empirical treatment with antituberculosis agents (isoniazid, rifampin, ethambutol, and pyrazinamide) was administered. However, aggravated dyspnea and intermittent fever (up to 38.2°C) occurred despite therapy with these agents. His white blood cell count was 10.50 x 109/liter (neutrophils, 92.0%; lymphocytes, 2.3%). Intravenous ampicillin/sulbactum (1.5 g every 6 h) was added. Chest computed tomography showed multiple ill-defined consolidations and cavitations in all of the lobes of both lungs and absence of mediastinal lymphadenopathy. Transthoracic lung aspiration and a biopsy were performed on 7 February. Pathology study showed many budding yeasts within and outside the histiocytes (Fig. 1B). Recurrent histoplasmosis with severe pneumonia was suspected. No abnormality was found other than the previously excised laryngeal lesion. A Gram-stained smear of the sputum specimen collected on 5 January 2003 was rechecked, and many unstained yeasts with hyphae were found (Fig. 1C). Cultures of sputum specimens and the biopsied lung tissue both grew H. capsulatum 10 days after inoculation.
Amphotericin B (30 mg/day) was started on 10 February 2003 but exacerbated dyspnea and hypoxemia persisted, and a follow-up chest radiograph showed nearly total whiteout of both lungs. Although Gram-stained sputum specimens collected repeatedly 2 weeks after the start of amphotericin B treatment showed a marked decrease in the amount of yeasts, the patient died of superimposed nosocomial pneumonia and respiratory failure on 25 February. The result of a human immunodeficiency virus antibody test was negative.
The nucleotide sequences of the internal transcribed spacer (ITS) regions of rRNA genes (including ITS1, the 5.8S rRNA gene, and ITS2) of the H. capsulatum isolate recovered from biopsied lung tissue and the extracted fungal DNA from the laryngeal tumor were examined using two sets of primers according to a previous description (5, 6). The sequences obtained were analyzed using GCG software (Wisconsin package; version 10.1 for Unix) and the BLASTN program (National Center for Biotechnology Information Internet homepage). Both sequences showed 99% identity to H. capsulatum (accession number AB055244). The similarity between the two sequences was analyzed further using the BL2SEQ program (NCBI Internet homepage). Results showed 100% identity in the 515-bp fragment produced by PCR. Comparison of the ITS sequences of a set of H. capsulatum isolates obtained from the GenBank (NCBI Internet homepage) and those found in this study failed to disclose 100% identity (accession numbers AB055248 [97.52% identity], AB055247 [97.11%], AB055246 [98.17%], AB055242 [98.58%], AB055239 [98.78%], AB055237 [98.37%], AB055230 [96.53%], AB055228 [96.52%], AB071770 [96.52%], AB071835 [98.1%], AB061781 [98.17%], and AB055243 [98.3%]).
Discussion. Previous study demonstrated that ITS typing by reading nucleotide sequences, not by analysis of DNA banding patterns using restriction fragment length polymorphism of mitochondrial DNA or randomly amplified polymorphic DNA, could provide a sufficient tool for classifying H. capsulatum isolates (6). Although the isolate from the laryngeal lesion was not preserved for this study, the genetic relationship between the ITS regions of the isolate and of the laryngeal lesion has clearly established the recurrent nature of infection.
Recurrent histoplasmosis is rare even in AIDS patients (4, 12). Recurrence or reactivation of histoplasmosis has been reported for patients with antifungal therapy of inadequate duration and dosage (1, 2, 9, 10, 13). Patients treated with infliximab and corticosteroid may be at increased risk of reactivation of latent histoplasmosis (3, 9-11, 13). This patient had undergone long-term corticosteroid treatment, which might have contributed to the recurrence of histoplasmosis. Misinterpretation of the stained smear of the initial sputum specimen led to a delay in diagnosis. A large burden of yeasts in the lung and delayed administration of antifungal agents also seem likely to have contributed to the poor outcome for the patient (8).
Histoplasmosis is a rare disease in Taiwan, and few microbiologically documented cases have been previously reported (7). A seroepidemiological study using a histoplasmin skin test in Taiwan in 1953 suggested that histoplasmosis did not exist in Taiwan at that time (7). This is the first reported case of recurrent and fatal histoplasmosis presenting with acute pneumonia in a non-AIDS patient from Taiwan. A previous study showed that histoplasmosis was endemic in China, particularly in the southeast region (14). The seropositivity rate was 25.5% overall but was significantly higher (31.7%) in patients with tuberculosis. Review of our patient's travel history and clinical course suggested that the first H. capsulatum strain was acquired either in China or in one of the other Asian countries that he had visited at least 9 years prior to this admission. The latency between initial presentation and clinical recurrence of histoplasmosis has been reported to be up to 13 years (3).
Histoplasmosis is commonly diagnosed in areas of endemicity but frequently overlooked in areas of nonendemicity due to a low index of suspicion among physicians (7, 8). Because of increasing intercontinental travel and also the possibility of recurrence after several years of latency, physicians in areas of nonendemicity should be alert to the possibility of the presence of H. capsulatum, which can cause localized infection, acute and life-threatening pneumonia, and disseminated diseases. Immunocompromised patients with a recent history of travel to or exposure to areas of endemicity are at the highest risk of such infection. Prompt microbiological investigation should be undertaken to make an accurate diagnosis and provide early and appropriate antifungal treatment.
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