Effect of combination antiretroviral therapy on the clinical manifestations,radiological characteristics,and disease severity of HIV-associated Talaromyces marneffei infection

Abstract

The objective of this study was to evaluate whether combination antiretroviral therapy (cART) has an effect on the clinical manifestations, radiological characteristics, and disease severity of human immunodeficiency virus (HIV)-associated Talaromyces marneffei infection. The clinical manifestations, chest computed tomography (CT) images, and disease severity were compared between 14 patients with culture-confirmed T. marneffei infections who received cART and 38 patients who did not receive cART. Clinical manifestations included high fever (>38°C), cough, shortness of breath, chills, and skin rash. Chest CT scans were evaluated for the presence of ground-glass opacities, consolidation, miliary nodules, nodules, masses, cavitation, pericardial effusion, pleural effusion, mediastinal lymphadenitis, and the distribution of parenchymal abnormalities. Disease severity was estimated by clinical manifestations and chest CT findings. Fever (>38°C), cough, shortness of breath, and chills were significantly less frequent in patients who received cART than in those who did not receive cART (P < 0.05). The frequencies of miliary nodules, mediastinal lymphadenitis, and the proportion of diffuse lesions were significantly lower in patients who received cART than in those who did not receive cART (P < 0.05). The disease severity was significantly decreased in patients who received cART compared with patients who did not receive cART (P < 0.001). T. marneffei-infected patients who received cART had fewer clinical manifestations and decreased disease severity compared with those who did not receive this treatment. The use of cART is associated with modified chest CT characteristics in HIV-associated T. marneffei infections.

Keywords

HIV combination antiretroviral therapy clinical manifestation chest imaging

Introduction

Opportunistic infections (OIs) have always been common complications in people living with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS). In southern China and Southeast Asia, Mycobacterium tuberculosis, Cryptococcus, and Talaromyces (Penicillium) marneffei (T. marneffei) are the three main epidemic opportunistic pathogens that cause most HIV-associated deaths.^1,2

Combination antiretroviral therapy (cART) is an effective treatment for HIV/AIDS and has been shown to affect the clinical and radiological characteristics of HIV-associated pulmonary tuberculosis, toxoplasmic encephalitis, and cryptococcal meningoencephalitis.^3–7 However, the effect of cART on the clinical manifestations and radiological characteristics of T. marneffei infections remains unknown. In addition, a decreased incidence and mortality of HIV-associated OIs^8–10 and an increased survival rate¹¹ have been observed with cART, but it remains unclear whether cART can reduce the disease severity of HIV-associated OIs. Disease severity, which can be reflected and measured by clinical and radiological manifestations, is to some extent closely related to hospitalization and mortality rates. Thus, we hypothesized that cART could have an effect on reducing the disease severity of HIV-associated T. marneffei infections.

To address these issues, we performed a retrospective study evaluating the clinical manifestations and chest computed tomography (CT) findings of HIV-associated T. marneffei infections. Our objective was to evaluate the impact of cART on the clinical manifestations, chest CT characteristics, and disease severity of HIV-associated T. marneffei infections.

Patients and methods

Study population

This study was designed retrospectively and was performed in accordance with the Declaration of Helsinki. Eighty-four people living with HIV (PLHIV) admitted to Shanghai Public Health Clinical Center with T. marneffei infections confirmed by blood cultures or bone marrow cultures were eligible for the study and were observed from January 2011 to December 2016. Our exclusion criteria were as follows: (a) patients with other confirmed fungal infections, mycobacterial infections, and tumors and (b) those who received therapeutic antifungal therapy before admission. Thirty-two patients were excluded, and 52 patients were enrolled in the study. According to whether or not they received cART before admission, they were divided into two groups, namely the cART group and the non-cART group.

Information was collected from the patients’ medical records, including age, gender, course of disease before admission, duration from HIV diagnosis to admission in both groups, and duration of cART before admission in the cART group. According to available reports that HIV-associated T. marneffei infection usually causes respiratory symptoms, skin and soft tissue lesions, weight loss, and lymphadenopathy, we collected data regarding the main clinical symptoms and signs, including fever (>38°C), cough, shortness of breath, chills, and skin rash.^12–14 The adverse outcomes, including acute respiratory distress syndrome (ARDS), requirement for mechanical ventilation, and in-hospital death, were also recorded. All medical charts were reviewed by a physician who specializes in infectious diseases (TQ).

Imaging examinations

The scanner was a multidetector CT (Somatom Plus 16, Siemens, Germany), and the protocol was as follows: automatic tube current, 120 kV; slice thickness, 5 mm; interval, 5 mm; pitch, 1; collimation, 0.75 mm; rotation time, 0.5 s; matrix, 512 × 512; and breath-holding following inspiration. All examinations were performed with the range from the apex of the lung to the diaphragmatic surface and were obtained within one day of hospital admission. A mediastinal (width, 350 HU; level, 40 HU) B40f window and a lung (width, 1200 HU; level, −600 HU) B70f window were used. Diffuse miliary nodules were observed on a lung B70f window with reconstruction thickness of 1.0 mm and a reconstruction interval of 0.5 mm.

Image analysis

The chest CT findings were reviewed by two senior radiologists (YS and FS, with approximately 30 and 15 years of experience in thoracic imaging, respectively) who were blinded to the clinical information. The CT scans were analyzed according to the presence and distribution of the parenchymal abnormalities, including ground-glass opacities (GGOs), which were defined as densities with opacity greater than that of the normal pulmonary parenchyma but less than that of pulmonary blood vessels; consolidation, which was defined as opacification of the lung parenchyma obscuring the underlying vessels; miliary nodules, which were defined as focal round opacities with a maximum diameter of 0.3 cm; nodules, which were defined as round opacities with a minimum diameter of 0.3 cm and a maximum diameter of 3.0 cm; masses, which were defined as round opacities with a minimum diameter of 3.0 cm; cavitation, which was defined as a nonbronchial air-containing cavity; and mediastinal lymphadenitis, which was defined as a lymph node ≥1.0 cm in short-axis diameter.

By referring to the classification system used by Grieser et al.¹⁵ and Feng et al.,¹⁶ the CT findings were graded on a scale of 1–3 points: grade 1, normal attenuation; grade 2, GGO; and grade 3, consolidation. Each lung was divided into three zones as follows: upper (above the carina), middle (below the carina and above the inferior pulmonary vein), and lower (below the inferior pulmonary vein). In each zone, the degree of pulmonary abnormalities was scored on a 4-level scale by estimating the percentage of affected pulmonary parenchyma: 0, normal; 1, <25% abnormality; 2, 25–50% abnormality; 3, 50–75% abnormality; and 4, >75% abnormality. The score for each zone was calculated by multiplying the point value by the scale value. The CT score of each patient was calculated by adding the scores of six zones and yielded a value ranging from 0 to 72. Diffuse pulmonary lesions were defined as parenchymal abnormalities in each lung segment affecting >75% of the segment; otherwise, lesions were defined as scattered lesions.

Data analysis

Data are presented as the mean±standard deviation, median and interquartile range, or numbers (%), as appropriate. Student’s t-test or the Mann–Whitney U test was used to compare differences in continuous data. The distribution of the variables was evaluated with the Kolmogorov–Smirnov test for normality. The frequencies of categorical variables were compared by Pearson’s Chi square or Fisher’s exact tests, and the data are expressed as numbers (%). All analyses were considered statistically significant at a P value of less than 0.05 (two-tailed). The data were analyzed with SPSS version 18.0 for Windows (SPSS Inc., Chicago, IL, USA).

Results

In the non-cART group, one patient had been diagnosed with HIV for three years, and the others were diagnosed with HIV due to T. marneffei infection. In the cART group, all patients started taking cART after the diagnosis of HIV, and the average duration of cART before admission was 14.2 months. During the hospital stay, the same antifungal agents were used in both groups. The demographics, course of disease before admission, and clinical presentation for patients treated with or without cART are shown in Table 1. Patients who did not receive cART represented 73.1% (38/52) of the entire study population. They were older than patients who received cART, but there were no significant differences between the two groups (P > 0.05) in terms of gender or course of disease before admission. The most common clinical manifestation in the non-cART group was fever (35/38, 92.1%), followed by cough (25/38, 65.8%), chills (18/38, 47.4%), skin rash (20/38, 52.6%), and shortness of breath (11/38, 28.9%). In the cART group, fever (7/14, 50%) was the most common clinical manifestation observed, followed by skin rash (5/14, 35.7%), cough (2/14, 14.3%), chills (1/14, 7.1%), and shortness of breath (0/14, 0%). The occurrences of all the collected clinical manifestations were observed more frequently in the non-cART group than in the cART group. The frequencies of clinical manifestations, including high fever (>38°C), cough, shortness of breath, and chills, were significantly different between the two groups (P < 0.05). Three patients experienced ARDS, four patients required mechanical ventilation, and four patients died in the hospital in the non-cART group, while no patients experienced these adverse outcomes in the cART group.

Table 1.

Demographics, course of disease before admission, and clinical manifestations of T. marneffei infections among PLHIV treated with or without cART.

Variable	Without cART(n = 38)	With cART (n = 14)
Male, no.	36 (94.7)	14 (100)
Age, years	35.7 ± 10.7	32.2 ± 8.9
Course of disease before admission, weeks	3 (2–7)	4 (2–5)
Clinical manifestations
Fever (>38°C)	35 (92.1)	7 (50)***
Cough	25 (65.8)	2 (14.3)***
Shortness of breath	11 (28.9)	0 (0)*
Chills	18 (47.4)	1 (7.1)**
Skin rash	20 (52.6)	5 (35.7)
Adverse outcome
ARDS	3 (7.9)	0 (0)
Requirement for mechanical ventilation	4 (10.5)	0 (0)
In-hospital death	4 (10.5)	0 (0)

ARDS: acute respiratory distress syndrome; cART: combination antiretroviral therapy; PLHIV: people living with HIV.

Data are expressed as numbers (%), the mean ± standard deviation (SD), or median (IQR) (*P < 0.05; **P < 0.01; ***P < 0.001).

The most commonly observed pulmonary parenchymal abnormality on chest CT in the non-cART group was miliary nodules (22/38, 57.9%), followed by GGOs (15/38, 39.5%), nodules (14/38, 36.8%), consolidation (6/38, 5.8%), cavitation (6/38, 5.8%), and masses (1/38, 2.6%) (Table 2). In the cART group, GGOs (4/14, 28.6%) were the most commonly observed pulmonary parenchymal abnormality, followed by miliary nodules (3/14, 21.4%), nodules (2/14, 14.3%), consolidation (1/14, 7.1%), cavitation (1/14, 7.1%), and masses (0/14, 0%). When we analyzed the chest CT findings between the two groups, we found that the frequency of each radiological abnormality in patients in the cART group was lower than that in the non-cART group. Furthermore, the incidences of miliary nodules (Figure 1) and mediastinal lymphadenitis (Figure 2) were significantly lower in the cART group than in the non-cART group (P < 0.05). When all 52 patients were considered, lesions were found to be distributed bilaterally in most patients in both groups. The proportion of patients with T. marneffei infections with normal lung imaging in the cART group (5/14, 35.7%) was significantly greater than that in the non-cART group (1/38, 2.6%) (P < 0.01), and receiving cART was significantly associated with a decreased occurrence of diffuse lesions (P < 0.05).

Table 2.

Chest CT findings associated with T. marneffei infection among PLHIV treated with or without cART.

Variable	WithoutcART (n = 38)	With cART (n = 14)
Lesions
GGOs	15 (39.5)	4 (28.6)
Miliary nodules (≤0.3 cm)	22 (57.9)	3 (21.4)*
Nodules (>0.3 cm, ≤3 cm)	14 (36.8)	2 (14.3)
Masses (>3 cm)	1 (2.6)	0 (0.00)
Consolidation	6 (15.8)	1 (7.1)
Cavitation	6 (15.8)	1 (7.1)
Pleural effusion	10 (26.3)	1 (7.1)
Pericardial effusion	5 (13.2)	0 (0)
Mediastinal lymphadenitis	28 (73.7)	4 (28.6)**
Distribution of pulmonary lesions
Normal lung imaging	1 (2.6)	5 (35.7)**
Diffuse lung lesions	17 (44.8)	1 (7.1)*
Scattered lung lesions	20 (52.6)	8 (57.1)
Anatomic side distribution
Unilateral lung	6 (15.8)	2 (14.3)
Bilateral lungs	31 (81.6)	7 (50.0)

cART: combination antiretroviral therapy; CT: computed tomography; GGOs: ground-glass opacities; PLHIV: people living with HIV.

Data are expressed as numbers (%) (*P < 0.05; **P < 0.01).

Figure 1.

T. marneffei infection in a 25-year-old HIV-seropositive man who did not receive cART and presented with a high fever, cough, and chills at admission. The chest CT shows bilateral diffuse pulmonary miliary nodules involving both lungs.

Figure 2.

T. marneffei infection in a 49-year-old HIV-seropositive man who received cART and presented with a high fever at admission. Both lungs were clear on chest CT, but mediastinal lymphadenitis was present.

To determine differences in disease severity, we compared the number of symptoms or signs, the number of pulmonary segments with parenchymal abnormalities, and the CT scores between the two groups (Table 3). From a clinical perspective, the number of symptoms or signs was significantly lower in the cART group than in the non-cART group at both the individual and general levels (P < 0.001). From a radiological perspective, the number of pulmonary segments involved and the number of pulmonary zones involved were also significantly lower in the cART group than in the non-cART group at both the individual and general levels (P < 0.001). The mean CT score in the cART group was lower than that in the non-cART group (P < 0.001).

Table 3.

Disease severity of T. marneffei infections among PLHIV treated with or without cART.

Variable	Without cART (n = 38)	With cART (n = 14)
Symptom or sign in each patient	3 (2–3)	1 (0–2)***
Symptom or sign in all patients	105 (55.3%)	15 (21.4%)***
Pulmonary segment involved in each patient	18 (5.5–18)	4 (0–7)***
Pulmonary segment involved in all patients	486 (71.1%)	63 (25.0%)***
Pulmonary zone involved in each patient	6 (3.75–6)	3 (0–4.5)***
Pulmonary zone involved in all patients	180 (78.9%)	34 (40.1%)***
CT score	29.5 ± 19.2	8.5 ± 10.3***

cART: combination antiretroviral therapy; CT: computed tomography; PLHIV: people living with HIV.

Data are expressed as numbers (%), the mean ± standard deviation (SD), or the median (IQR) (***P < 0.001).

Discussion

cART has been shown to affect the clinical and radiological characteristics of HIV-associated OIs, but its effects on the clinical manifestations and chest imaging findings in patients with HIV-associated T. marneffei infections have not been previously discussed. In the present study, we found that there were significant decreases in the frequencies of clinical manifestations and changes in chest CT characteristics of HIV-associated T. marneffei infections since cART came into clinical use. Moreover, when we compared the disease severity reflected by clinical symptoms, pulmonary parenchymal abnormalities, and CT scores between the two groups, we found that patients who received cART were significantly more likely to present with decreased disease severity than those who did not receive cART.

cART has been shown to be effective following immediate initiation in PLHIV with a low immunological status,^17,18 even during the early stages of treatment.¹¹ In our study, patients who received cART less frequently had clinical symptoms including fever, cough, shortness of breath, chills, and skin rash and achieved better outcomes than patients who did not receive cART. In addition, our data showed an association between the use of cART and the chest CT imaging characteristics of HIV-associated T. marneffei infections. Patients who received cART less often had chest CT appearances of mediastinal lymphadenitis and miliary nodules, and we observed a decreased proportion of diffuse lung lesions and an increased proportion of normal lung imaging findings in patients in the cART group. We were unable to explore the immune status of the two groups, as CD4 cell counts of some patients were not available, but these changes in clinical manifestations and chest CT characteristics probably reflect the fact that patients treated with cART are less immunosuppressed than untreated patients.¹⁹

Clinical manifestations including fever, cough, and skin rash and chest CT appearances including miliary nodules, GGOs, and mediastinal lymphadenitis were frequently observed in both groups. These clinical features can help to improve the accuracy of clinical diagnosis of T. marneffei infection in PLHIV. The appearance of miliary nodules is usually seen on chest CT scans in PLHIV with T. marneffei infections and should be noted by radiologists. In particular, the appearance of diffuse miliary nodules (11 patients in the non-cART group and 1 in the cART group in our study) is not a characteristic sign of miliary pulmonary tuberculosis, and misdiagnosis usually delays appropriate treatment. Therefore, this condition is an important differential diagnosis for pulmonary tuberculosis. In addition, some patients in our study who were treated with or without cART had normal lung imaging findings. These patients always had accompanying clinical signs or symptoms, suggesting that the diagnosis of T. marneffei infection cannot be ruled out in patients without pulmonary abnormalities.

The results of our study also showed an association between the use of cART and the disease severity of T. marneffei infection in PLHIV, suggesting that cART reduces the disease severity of HIV-associated T. marneffei infection. This finding may help to increase the understanding of the clinical benefits of cART for PLHIV, including for decreasing hospitalization^20,21 and increasing the survival rates of patients with OIs.^22,23 Disease severity is to some extent closely related to mortality, suggesting that the decreased mortality in cART-treated populations may be attributed to a reduction in disease severity.

The present study does have some limitations. First, patients enrolled in our study were diagnosed at a single clinical center, and the number of patients treated with cART was relatively small. These factors may limit the extent to which our findings can be generalized. Second, we only reviewed the clinical presentations and CT images of the respiratory system because T. marneffei infection mainly manifests as respiratory symptoms, lymphadenopathy, and hepatomegaly.¹² Some patients in our study were admitted to the hospital with abdominal pain, but the clinical and radiological findings regarding the abdomen were not included in the analysis but should also be collected to more comprehensively evaluate the effect of cART on T. marneffei infection.

Conclusions

Our study regarding the clinical manifestations and chest CT characteristics of T. marneffei infection in PLHIV who received cART demonstrated a decreased frequency of clinical manifestations, modified chest CT characteristics, and decreased disease severity in those treated with cART.

Footnotes

Ethical approval

This study was approved by the Institutional Review Board of Shanghai Public Health Clinical Center.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The work was supported by the Shanghai Municipal Science and Technology Commission Program (1541196900).

ORCID iD

Yuxin Shi

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