Clinical characteristics of disseminated cryptococcosis in previously healthy children in China

Cryptococcus belongs to capsulated yeast and can cause an invasive and fatal disease. Most occurs in adults aged 20 to 50 years old, approximately 1%–5% of the population, while in children the incidence is less than 1% [1]. When cryptococcus is inhaled into the respiratory tract, it might localize in immunocompetent hosts. Once individuals show immune defects, cryptococcus could disseminate hematogenously to any part of the body, including the central nervous system (CNS), lymph nodes, liver, spleen, kidney, and skin, especially in patients with profound cellular immune deficiency [2]. If 2 or more are invaded, patients would be diagnosed with disseminated cryptococcosis [3]. Joshi et al. [4] reported that cryptococcosis usually occurs in immunocompromised subjects, accounting for nearly 80% of patients with cryptococcal infection, especially in those with human immunodeficiency virus (HIV) infection. This is followed by primary immunodeficiencies, diabetes, and requiring glucocorticosteroid therapy or organ transplantation. On the contrary, studies [5, 6] in China demonstrated that 50–77% of patients with cryptococcal meningitis exhibited normal immune function. However, disseminated cryptococcosis is rare in immunocompetent children, and is mostly localized in the brain or lungs [7]. It is usually misdiagnosed as tuberculosis or other diseases. Some studies were limited to case reports or only several cases [8]. Furthermore, the spectrum of clinical manifestations and laboratory tests were not reported systematically. Therefore, we conducted this study to analyze the clinical characteristics of disseminated cryptococcosis in previously healthy children in China.

Cryptococcosis is a rare and fatal disease that preferentially infects immunosuppressed hosts. A previous study [1] reported that the rate of cryptococcal infection in immunosuppressed patients (5–10%, up to 30% in patients with AIDS) was higher than in immunocompetent patients (less than 5% in adults, and less than 1% in children). However, Zhu et al. [9] reported that more than 60% of pediatric patients with cryptococcosis in China had normal immune functions. Luo et al. [10] also reported that nearly 70% of children with cryptococcosis were immunocompetent subjects and had no underlying illness or risk factors. Furthermore, Yuchong et al. [11] analyzed 8796 patients with cryptococcosis in mainland China from 1985 to 2010 and found that only 15.7% were HIV positive. This finding is interesting because the patients in our study were all HIV negative with no obvious immune deficiency. Additionally, Thompson and Chan [12‐14] demonstrated that serotype A and D are more commonly detected in immunocompromised individuals or patients with a history of exposure to pigeon droppings, while serotype B and C (common seen in China) are usually observed in patients without significant immunosuppression. However, whether these previously healthy children in this study with normal levels of IgA, IgG, and IgM, and normal numbers of CD4 + T cells, CD8 + T cells, B cells, and NK cells in our study were real immunocompetent individuals is unknown and need further investigation.

In our study, the median age of children with disseminated cryptococcosis was 4.7 years old, and 63.5% of patients were less than 5 years old. This was similar to Luo et al.’s [10] study, but different from the study conducted by Joshi et al. [4] (where the median age was 12 years old). In addition, Goldman et al. [15] showed that most cases with cryptococcosis had pigeon dropping exposure; conversely, in our study, only 19.2% of patients had pigeon exposure. Therefore, if pediatric patients do not have a history of pigeon dropping exposure, the pediatrician should not omit a diagnosis of disseminated cryptococcosis.

In our study, fever, cough, and hepatomegaly were the 3 most common manifestations, while in the study by Severo et al. [16], headache, fever, vomiting, and neck pain were more common because most cases were cryptococcal meningitis. The lung was the most commonly invaded organ in our study, but respiratory symptoms were not obvious. This was inconsistent with chest X-ray or CT scan. Similar results were demonstrated by Suwatanapongched et al. [17]. Diffused miliary or scattered small nodules mainly in subpleural areas were the most common imaging features in our study, which is consistent with the results by Qu et al. [18]. In addition, studies by Xie et al. [19, 20] showed that cavitations within nodules/masses were more commonly seen in immunocompromised patients, especially in AIDS patients, while air bronchograms were more commonly seen in immunocompetent patients. Hilar or mediastinal lymphadenopathy was another common imaging finding in our study, which is relatively rare in immunocompetent patients and was reported in a previous case study [21]. Since diffused miliary and hilar or mediastinal lymphadenopathy are also 2 typical features of tuberculosis, pediatricians should pay attention to distinguishing between chronic pulmonary cryptococcosis and tuberculosis. The second most commonly invaded organ was the CNS (69.2%, 36/52) in our study. In contrast, Kaur et al. [22] showed that the CNS was the most commonly invaded site in pediatric AIDS with cryptococcosis, and it was related to CNS tissue tropism of cryptococcus. Therefore, when considering disseminated cryptococcosis, lumbar puncher should be done even if there are no significant signs of CNS invasion. Additionally, Shih et al. [23] reported that because of robust immune responses, immunocompetent patients exhibited more severe neurological complications than immunocompromised patients, such as hydrocephalus and seizure. They also showed that immunocompetent patients usually presented with longer symptom durations, typical meningeal signs, and neuroimaging findings. Meanwhile, immunocompromised patients usually manifested with high fever and parenchymal lesions in the brain. In our study, common neuroimaging findings were hydrocephalus, multiple intraparenchymal lesions, and ventricular dilatation; these findings are similar to those by Tan et al. [24]. In addition, Zhu et al. [25] showed that more than 70% of patients with cryptococcal meningitis were misdiagnosed, most as tuberculosis-associated diseases. However, different from tubercular meningitis, obliteration of basilar cistern and meningeal enhancement were less common in cryptococcal meningitis. Furthermore, cranial nerve impairment and intracranial venous sinus thrombosis were detected in our study, which was rarely reported before [6].

Besides lung and brain invasion, Dromer [26] demonstrated that the incidence of abdominal, renal, lymph node, and skin invasion (1.2%, 1.9%, 1.7%, and 0.4%, respectively) were lower than the results of the present study. However, in our study, nearly 67.3% of patients had abdominal lymph nodes invasion, including of the mesentery, hepatic portal, and abdominal para-aortic lymph nodes, and some of them were accompanied with calcification, which is rarely reported [27]. Several cases presented with abdominal pain or discomfort were misdiagnosed as tuberculosis because abdominal cryptococcosis has similar symptoms or pathologic results as tuberculosis. The incidence of the invasion of the liver, spleen, peripheral lymph nodes, and skin were relatively rare in our study. Poojary et al. [28] showed that cutaneous cryptococcosis may be present for 2 to 8 months before development of systemic signs of infection, and therefore this time period could provide a window of opportunity for treatment before fatal effects of dissemination occur. Furthermore, invasion of bone marrow, the intestinal tract, kidney, and pericardium by cryptococcal infection can be found in our study.

In this study, increased WBC (especially more than 20 × 10⁹/L), and high levels of CRP and ESR were common in patients with disseminated cryptococcosis. Furthermore, 42.3% and 51.9% of patients had elevated eosinophil and IgE, which is similar to results by Bassetti et al. [29, 30]. However, after treatment with anti-fungal drugs, levels of eosinophil and IgE decreased quickly; this was in line with results by Zhu et al. [9]. This could be explained by Th2 cell-mediated immune response [31]. Cryptococcal antigen tests, ink smears, culture, or pathological methodologies to confirm cryptococcus existence in specimens of blood, CSF, other tissues or body fluids were important diagnostic evidence. Antinori et al. [32] demonstrated that the sensitivity and specificity of cryptococcal capsular polysaccharide antigens in the diagnosis of cryptococcosis can reach to 96%. In our study, the positive rate of serum cryptococcal capsular polysaccharide antigens was 73.1%, which was even higher in patients with CNS invasion (reaching 83.3%). However, the positive rate of other methods was lower. Therefore, once disseminated cryptococcosis is suspected, these methods should be done repeatedly and combined. However, Lee et al. [33] showed that immunocompromised patients had higher serum cryptococcal antigen titers, and higher positive rates of fungal cultures from blood and CSF.

In our study, the clinical isolates in Chinese pediatric patients were sensitive to amphotericin B, fluconazole, itraconazole and 5-flucytosine. Chan et al. [13, 34] found that Cryptococcus neoformans predominantly infected immunocompetent individuals. The 2010 IDSA Clinical Practice Guidelines for the management of cryptococcal meningitis in non-HIV infected and non-transplant patients recommend induction therapy with amphotericin B (0.7–1.0 mg/kg/d) plus 5-flucytosine (100 mg/kg/d) for 2 weeks, followed by fluconazole (6 mg/kg) for a minimum of 8 weeks, and then maintenance therapy with fluconazole for at least 6 to 12 months [35]. Zhu et al. [9] pointed out that intrathecal administration of amphotericin B was an effective adjunctive treatment for many cryptococcosis patients in China. However, there are no well-controlled studies to clarify the role of intrathecal amphotericin B in the management of cryptococcal meningitis. Furthermore, the usage of intrathecal amphotericin B is not recommended in the 2010 IDSA guidelines. Patients with CNS invasion usually have a longer-term therapy than those without CNS invasion, which is consistent with these recommendations [35]. However, managing cryptococcosis remains a challenging issue, and how to determine the course of treatment remains unknown. Additionally, Zhu et al.’s [9] study demonstrated that immunocompetent individuals with cryptococcosis exhibited similar treatment responses and prognosis as immunocompromised patients; however, this should be confirmed by studies using a larger sample size. Most patients were cured in the present study. The mortality rate (11.5%) in our study was lower than that reported in a previous study (39.13%) [10]. This might be attributed to the lung being the most commonly invaded organ in our study. During follow-up, we found that some of the patients had severe sequela, including hydrocephalus, cirrhosis, and blindness. Liao et al. [36] reported that initial consciousness level, hydrocephalus, high CSF antigen titers, underlying diseases, non-amphotericin, B-based initial therapy, and delayed diagnosis (>120 days) were risk factors of poor prognosis. Therefore, pediatricians should pay attention to these indexes.

Disseminated cryptococcosis can be seen in previously healthy or immunocompetent children in China. The lung and CNS were the 2 most commonly invaded organs in this study. Most cases showed no specific clinical manifestations, or were misdiagnosed as tuberculosis or other diseases. The prognosis of children with disseminated cryptococcosis is poor, but if diagnosed early, the majority cases could be managed successfully.