Acute histoplasmosis is a rare fungal disease. Staffolani S, et al[10] reviewed the literatures on acute histoplasmosis in immunocompetent travelers. They found most of the 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 reported by them. In recent years, an increasing number of sporadic and chronic histoplasmosis cases started to occur in Chinese mainland, with 90%~95% of the reported patients were asymptomatic in immunocompetent persons. This outbreak reported in our paper is so far the biggest collective exposure in Chinese, with the most 10 acute histoplasmosis patients.
The infection of acute histoplasmosis is usually mild and self-limiting in immunocompetent people, however, apparently in rare cases, the disease can progress to a severe form with high morbidity[11-14]. The most frequent symptoms were fever, cough, headache and chest pains. Constitutional symptoms (myalgia, sweats, weight loss, anorexia etc.) were also commonly reported. All the 10 patients we reported had accordant clinical symptoms with the literatures. But the conditions of the severer one of the 10 were significantly much worse than those reported in literatures[2,15-25]. This is possibly because China is a non-epidemic country of histoplasmosis, so most Chinese had no immunity to acute histoplasmosis. The 10 patients, with neither any immunity nor any protective measures, entered the abandoned tunnel and inhaled a large amount of pathogenic fungi in a short time, thus doubtlessly, their conditions are likely to be much worse.
The chest CT manifestations of acute histoplasmosis were various. The most common signs were nodular infiltrates[26]. In the study, chest CT images of 4 patients (case No.1~4) showed diffuse miliary nodules in both lungs of them, as they were soil cleaners who underwent longer exposure and inhaled more pathogenic fungi. The pulmonary nodules of the 4 were plenty and tiny, with diameters mostly less than 5 mm. Conversely, CT images of the other 6 patients doing other jobs showed scattered nodular shadows in both lungs, because they were exposed shorter and inhaled fewer fungi. Their pulmonary nodules were few and big in the subpleural and bipulmonary lobes, diameters of which ranged from 2~15mm. Thus apparently the manifestations of pulmonary nodules were closely related to the inhaled fungi amount and exposure time.
The abdominal CT manifestations of acute histoplasmosis include splenomegaly sometimes with focal splenic lesions, and lymph node enlargement[27]. Although diffuse hypodense lesions were found less common in spleen, they were taken as specific signs of histoplasmosis infection[28]. Of the 10 patients we reported, splenomegalies were found in 8 as per their abdominal CT images, analogous to those reported in literatures. The splenomegaly might be attributed to the spread of H. capsulatum infection along the reticuloendothelial system.
It's reported 5%~20% of disseminated histoplasmosis can affect the central nervous system, especially in immunosuppressive patients[29]. Once there was even a rare case of brain abscess with histoplasmosis in an adult with normal immune function[30]. As for the case No.1 patient we reported, when he was admitted, he was in deep coma with his cranial CT image showing apparent meningitis inside, which indicates the histoplasmosis affects not only the brain parenchyma but also the meninges when it spreads to nervous system.
As H. capsulatum culture growth is often shown at more than 1 week, histoplasma antigen is a useful tool and rapid detection for diagnosis of acute histoplasmosis[6], however, it's likely unavailable in non-epidemic countries like China. As when the 10 patients we reported at admission, their CRP, PCT, LDH, β2-MG, Cysc, and G-test were increased, their CD4/CD8 was decreased, their WBC and N/L kept relatively constant, and their cytokines and chemokines were increased except for IL-4, IL-12, INF-a, TNF-a, and their CT images were presented as nodular infiltrates in lungs. In this case, comprehensive multi-analysis by incorperating more indicators might help the diagnosis of histoplasmosis. Thus if any other patient was exposed to histoplasma recently and showed similar conditions on the foregoing manefestation, it might be reasonable to be considered as histoplasmosis.
β2-MG is concerned with the presentation and stabilization of major histocompatibility complex (MHC) I antigen on the cell surface, which is important in adjusting antigen presentation and immunity[31]. It has been reported that β2-MG is an independent predictor of pulmonary infection in hemodialysis patients[32], which was found increased in 9 of the 10 patients we reported, consistently. With the progress of treatment and the remission of conditions, β2-MG got back into normal range, and during this remission β2-MG showed positive moderate rank correlation to the CRP and PCT, which were significantly correlated to the disease severity as well. Therefore, it sounds reasonable to take β2-MG as another potential predictor of acute histoplasmosis. Besides, when the lungs were damaged, LDH was found increased in serum in former study[33], and in all patients we reported as well, consistently. Likewise, LDH also showed positive rank correlation to CRP and PCT, thus LDH in serum may also be taken as a potential predictor. Similar conclusions could be drawn to the N/L, but not to WBC, which suggested that N/L may be more sensitive than WBC in acute histoplasmosis infection. As for the CysC, it showed positive rank correlation to not only CRP, PCT but also G-test, N/L, β2-MG and LDH, thus similarly it’s also a potential predictor. Of the 10 patients we reported, although their urea nitrogen and creatinine were in the normal range, their CysCs were increased to a certain extent. With the administration of liposome amphotericin B, some patients experienced kidney damage but their CysCs did not increase significantly, indicating that histoplasmosis infection might have potential damage to kidney and CysC might be insensitive to drugs. However, considering about limitation from the number of cases we reported, more case studies and verifications are still required for the applicability of those potential predictors.
Cytokines, particularly chemokines, are key recruitment mediators of leukocytes and other inflammatory cells leading to pulmonary damage, and have been implicated in the pathogenesis of ARDS/diffuse alveolar damage[34]. At present, the monitoring of cytokines and chemokines in sepsis is commonly applied besides ARDS[35]. In addition, in Severe Acute Respiratory Syndrome (SARS)[36] and 2019 novel coronavirus infection disease (COVID-19)[37], the monitoring of cytokines and chemokines were usually employed. For the COVID-19 patients, the serum IL-6, IL-8, and TNF-α were significantly increased, and were taken as independent predictors for survivals[37]. But so far there were few studies about the monitoring and correlation of cytokines and chemokines in histoplasmosis patients. Hirayama T, et al[38], found that the serum IL-2 receptor (sIL-2R) were increased and well correlated to the disease status in acute histoplasmosis patients, although sIL-2R is actually nonspecific to inflammation. In this study, we tested the IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-17, IL-27, IL-33, TNF-a, IFN-r, and HMGB1 of the 10 patients, totally 12 cytokines and chemokines, regularly for 8 months. This is perhaps the first study based on a continuous monitoring of a series of cytokines and chemokines in histoplasmosis. We found that all the patients’ serum IL-4 were lower than the reference range. Their IL-12, INF-a, TNF-a were always lower than the reference range except for those of No.1 patient at early stage. Other cytokines and chemokines increased at begining but gradually decreased with the disease remission. The IL-6, IL-8, and IL-10 increased relatively consistently and they all had positive rank correlation to CRP, PCT, G-test, N/L, β 2-MG, CysC, and LDH. Thus the IL-6, IL-8, IL-10 were reasonably sensitive to the severity of acute histoplasmosis. However, due to the limitations from the number of cases, the examination intervals, inconsistency of some of the control conditions (e.g. severity, immunity, therapy of individuals, etc.), more case studies and verifications are still required.
While pulmonary due to histoplasma in immunosuppressed patients is more common in Epidemic area, systemic representation of this fungal infection in immunocompetent patients is rare and self-limiting in China. To our knowledge, this is the first collective acute histoplasmosis infection in immunocompetent patients, and with the largest number of patients in Chinese. Physicians should think of acute histoplasmosis when people had fevers, cough in histoplasma endemic regions. More examinations and imaging tests should be employed, and more relevant indicators should be taken into account for improving the accuracy of diagnosis and differential diagnosis.