Differences in clinical characteristics and prognosis of Penicilliosis among HIV-negative patients with or without underlying disease in Southern China: a retrospective study

Penicilliosis has been reported in immunocompromised patients with HIV infection, but also in patients free of HIV infection. Certain diseases can cause immune function decline and immune disorders, such as haematological malignancies, colon cancer, myasthenia gravis, mixed connective tissue disease, transplant rejection, systemic lupus erythematosus, diabetes mellitus, as well as the use of corticosteroids or immunosuppressive agents, even in HIV-negative [ 3, 4]. The incidence of Penicillium marneffei infection in patients without HIV infection has shown a marked increased in recent years [ 3, 5– 8]. In our study, during an 11-year period, Penicillium marneffei infection was present in 43 (43/109, 39.45 %) patients without HIV infection. Among these patients, 41.86 % had underlying diseases, with diabetes being the most common; 58.14 % had no underlying diseases, which suggests that Penicillium marneffei infection is not a rare entity, but is also common in HIV-negative individuals and even healthy hosts.

The common clinical manifestations among HIV-negative patients were similar to those in previous reports [ 6]. However, there were no statistically significant differences between Group D and Group ND in clinical manifestations and laboratory findings, with the exception of thoracalgia, which was more common in HIV-negative patients with underlying disease ( P < 0.05).

Previous work has postulated that deficiency of CD4+ T-cell-mediated immunity plays a key pathogenic role in AIDS patients and may also be involved in immunocompromised HIV-negative patients, potentially leading to Penicillium marneffei infection [ 6– 9]. In our study, CD8 T-cell counts, CD8 T-cell percentages, and serum immunoglobulin levels did not differ between the two groups ( P > 0.05). However, HIV-negative patients without underlying disease had higher lymphocyte cell counts, CD4 cell counts, and CD4 T-cell percentages than those with underlying disease. The mean CD4 cell count was below normal levels in HIV-negative patients with underlying disease. In addition, in the univariate analysis, only underlying disease, CD4 cell percentage, and T lymphocyte cell percentage were significantly associated with overall survival. Thus, HIV-negative patients with underlying disease, such as cancer, mixed connective tissue disease, transplant rejection, systemic lupus erythematosus, diabetes mellitus, and Langerhans cell histiocytosis, and those taking corticosteroids or immunosuppressive agents, exhibited worse CD4 T-cellular immunodeficiency during the course of the disease than HIV-negative patients without underlying disease. Browne et al. and Lee et al. reported that autoantibody to interferon-ɤ is associated with the new clinical syndrome of adult-onset immunodeficiency [ 8, 10, 11]. This may be another cause of cell-mediated immunity defects in patients who are not infected with HIV. This also suggests that underlying disease, CD4 cell percentage, and T lymphocyte cell percentage may be potential risk factors affecting prognosis.

Specifically, 32.5 % of patients had osteolytic lesions, and all of these were HIV-negative individuals; no HIV-positive patients exhibited such lesions. Thus, osteolytic lesions are one of the most common and important clinical characteristics of Penicillium marneffei infection, which can easily be neglected in HIV-negative patients [ 12]. Serous effusions are often thought to reflect hypoalbuminaemia, connective tissue disease, or tuberculosis. However, in our study, 81.39 % of patients had multi-exudate effusion, which suggests that exudate effusions are equally common in Penicillium marneffei infection in HIV-negative individuals. However, the mechanism by which effusion is generated is unclear; the cause may be inflammation initiated by disseminated Penicillium marneffei infection, or may directly involve the thoracic cavity.

There were relatively few cases of Penicillium marneffei infection among HIV-negative patients with and without underlying disease. The current recommendation for severe disease in HIV-positive patients is intravenous amphotericin B at a dosage of 0.6 mg∙kg ⁻¹∙d ⁻¹ for 2 weeks, followed by oral itraconazole 200 mg twice daily for 10 weeks. For mild disease, the recommendation is oral itraconazole at a dose of 200 mg twice daily for 8–12 weeks [ 6].

In this study, we found that HIV-negative patients with underlying disease had a worse prognosis and greater treatment difficulty than those without underlying disease. The reason for this is that HIV-negative patients with underlying disease have more obvious immune deficiency and CD4+ T cell-mediated immune deficiency than patients without underlying disease. Some diseases have the potential to damage immune function, especially CD4 T-cellular immune function. The majority of patients in this study received treatment for Penicillium marneffei infection with intravenous amphotericin B at a dosage of 0.6 mg∙kg ⁻¹∙d ⁻¹ for 4–8 weeks, followed by oral itraconazole or fluconazole 200 mg twice daily for 6–12 months, even treated for up to 2 years, which was significantly longer than the current recommendation for severe disease in HIV-positive patients. Oral itraconazole at a dosage of 200 mg once daily has been recognised as secondary prophylaxis. Thus, timely, effective, and longer courses of antifungal treatment, combined with support of the immune system, are important to improve patient prognosis. The longest duration for relapse was 4 years in this study; therefore, longer-term secondary prophylaxis and follow-up may be necessary to prevent relapse and improve prognosis. The important factors to assess when to discontinue secondary prophylaxis treatment include lymphocyte cell counts, CD4 cell counts, CD4 T-cell percentages, lung and bone imaging, and negative culture of clinical specimens.