Acute histoplasmosis is a rare fungal disease. Staffolani et al. [12] once reviewed the literatures on acute histoplasmosis in immunocompetent travelers. They found most reported travelers were from America and Europe to Africa and South America. The only exception they found was traveling from Taiwan to Indonesia. By then, no immunocompetent travelers from Chinese mainland was found by them. In recent years, an increasing number of sporadic and chronic histoplasmosis cases occur in Chinese mainland, 90–95% of which are asymptomatic in immunocompetent persons.
The infection of acute histoplasmosis is usually mild and self-limited in immunocompetent people, however, in rare cases, the disease can progress to severe form with high morbidity [13,14,15,16]. The most frequent symptoms are fever, cough, headache and chest pains. Constitutional symptoms (myalgia, sweats, weight loss, anorexia etc.) are also commonly reported. All 10 patients in this study had accordant clinical symptoms with those in literatures, but the condition of these patients especially No.1 patient was apparently much worse than those in literatures [2, 17,18,19,20,21,22,23,24,25,26,27]. This is possibly because China is a non-endemic country and most Chinese are unimmune to acute histoplasmosis, Moreover, those patients did not take any respiratory protection when they were exposed for long time inside the tunnel, as a result they had to inhaled a large amount of pathogen in these days. In addition, due to the limitation of local healthcare facilities, they did not receive timely diagnosis and treatment, as a result they were already very seriously infected when they were back in China, already 8–18 days after the onset.
The most common sign of chest CT imaging in literatures is nodular infiltrates [28]. In this study, CT images in chests of patient No.1-No.4 showed diffuse miliary nodules in both lungs, while the images of patient No.5-No.10 showed only scattered nodular shadows. This difference is probably related to the difference in their jobs, and accordingly in their exposure conditions. Patients No.1-No.4 were soil cleaners who underwent longer exposure and inhaled more pathogenic fungi, consequently, their disease conditions were much worse than the others. Thus obviously not only the pulmonary nodules, but also the severity and manifestations of the acute histoplasmosis, are closely related to the inhaled fungi amount and the exposure time.
The abdominal CT manifestations in literatures include splenomegaly (sometimes with focal splenic lesions) and lymph node enlargement [29]. Although diffuse hypodense lesions are less common in spleen, they are regarded as specific signs of histoplasmosis infection [30]. As none of imaging manifestations of hepatosplenomegaly was found previously in these patients, the reason for the current hepatosplenomegaly of the patients maybe relevant to the spread of histoplasm along the reticuloendothelial system after respiratory infection. But we did not take further histological examination of liver and spleen for the verification, because of the disagreement of the patients.
It’s reported 5–20% of disseminated histoplasmosis can affect the central nervous system, especially in immunosuppressive patients [31], or sometimes in patient with normal immunity [32]. In this study, the No.1 patient was firstly in drowsiness and then in coma all the time. Although his cerebrospinal fluid was cultured and was negative, unfortunately no further relevant examination was allowed by his families at that time, thus we can hardly exclude the possibility of the spreading of histoplasm over the central nervous system. It is possible that not only the brain parenchyma but also the meninges had been damaged when the histoplasm spread into the nervous system.
From the laboratory test results of the 10 patients, we could find the ratio of CD4/CD8 was < 1, and the CRP, PCT, G-test, LDH, CysC, β2-MG were mostly elevated by varying degrees. However, none of them showed specificity in the diagnosis of acute histoplasmosis. However, we must note that, microbiological diagnosis methods (e.g. culture), and histopathology are still unsubstitutable. The gold standards for the diagnosis of histoplasmosis are still direct microscopic examination and culture. In this study, even the result of mNGS test was also taken as a reference, while the final definitive diagnosis was still based on the fungi growth in cultures, as the sensitivity of mNGS test was reported to possibly vary widely from 36 to 100% [33]. For infections with unknown pathogens, detailed investigation of epidemiological history is very important. The patients in this study were all infected when they were working in an endemic area of histoplasmosis, As the 10 patients had the similar clinic symptoms, and also the results of their imaging examination, blood laboratory test and blood mNGS test all hinted the existence of H. capsulatum, so all of them were considered as acute histoplasmosis patients and were treated accordingly. The final microbiological evidence also verified this diagnosis.
The CRP and PCT are inflammation indicators showing more specificity to the acute infections, not only bacterial but also fungal [34, 35]. The G-test is often employed in the diagnosis of fungal infection, and it should be gradually decreased by anti-infective therapy [36, 37], because the fungal (1–3)-β-Dglucan is a primary composition of fungal cytoderm and is released via hydrolyzation during fungal infection [38]. Thus it might be reasonable that, a decrease of fungal (1–3)-β-Dglucan along with the anti-infective therapy possibly indicates a fungal infection [37]. In this study, according to the variation of disease conditions of the patients, the CRP, PCT and the G-test all show consistent trends with the disease conditions that, they were all high at the admission but significantly decreased 3 weeks later when disease conditions of patients turned better. Besides, with regard to other factors, we can find 1) the CysC, β2-MG, LDH also show very consistent trends with the PCT and CRP, and find 2) the rank correlation coefficients between CysC, N/L, β2-MG, LDH and G-test, CRP, PCT are all positive. In this case, although it is not solidly suggested, it can to some extent be indicated that the CysC, N/L, β2-MG, LDH can reflect the possibility of airway inflammation, and have certain with the disease condition. We’d suggest that it worths trying to include those factors in the condition monitoring of acute histoplasmosis patients, which might also help in the prognosis and follow up.
Cytokines, particularly chemokines, are key recruitment mediators of leukocytes and other inflammatory cells leading to pulmonary damage. They have been implicated in the pathogenesis of ARDS/diffuse alveolar damage [39]. Now the monitoring of cytokines/hemokines is commonly applied in sepsis [40], severe acute respiratory syndrome (SARS) [41] and 2019 novel coronavirus infection disease (COVID-19) [42]. But there are not many studies about the monitoring and correlation analysis of cytokines/chemokines in acute histoplasmosis patients. In this study, we measured 15 cytokines/chemokines in 10 patients during hospitalization. Perhaps this is the first study on continuous monitoring of cytokines/chemokines in acute histoplasmosis.
For the No.1 patient, all cytokines/chemokines other than IL-4 were elevated more highly (around 10 times) than other patients, which may be due to his serious illness and the septic shock, ARDS and cardiopulmonary resuscitation he once experienced in the early stage. In the following treatment course those factors fluctuated, but after 3 weeks’ treatment, those factors returned close to normal, most of his symptoms disappeared, and the infection of his lungs remitted as well. The other 9 patients’ most cytokines/chemokines (other than IL-4, IL-12, INF-α, TNF-α) varied widely with patients and time. The general trend of those factors is highest at admission, decreasing rapidly in the first 4 days of hospitalization, and decreasing gradually thereafter. This trend holds especially for the IL-6, IL-8, IL-10 and IFN-γ. In addition, the IL-6, IL-8, IL-10 and IFN-γ all show positive rank correlation coefficients with the CRP and PCT, thus it could be kind of indication for that the IL-6, IL-8, IL-10 and IFN-γ can somewhat reflect the condition of airway inflammation, and may be relevant with the prognosis as well. Although IL-27 has moderate associations to CRP and PCT as well, it’s not taken into this discussion because it was mostly within normal range.
Despite some characteristics of those laboratory test factors in acute histoplasmosis patients were found in this study, due to the limitation of the number of samples, and due to the special condition of patients, our study is mainly a qualitative observational study. In this case, the results and conclusions of this study still require further verification by studies with more samples and with randomized controlled trials, or by in vitro cell experiments and animal experiments.