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An Outbreak of Febrile Histoplasmosis Among Chinese Manganese-Mine Workers in Cooperative Republic of Guyana in 2019

What is already known on this topic? Cases of histoplasmosis have been reported in every continent except Antarctica but are fairly rare in China. High prevalence of histoplasmosis has been observed in Central America, Caribbean, and South America. Infections of Histoplasma are acquired through a respiratory route, particularly inhalation of aerosols from disturbed soils enriched with excreta from birds and bats. These infections are most common in persons involved with removing soil, visiting caves, cleaning old houses, or felling trees, etc. What is added by this report? This is the first report of cluster infections of Histoplasmaamong overseas Chinese workers. A strong dose-dependent association of illness onset and disease severity with the exposure intensity to the soils and wastes possibly contaminated by the Histoplasmahas been proposed. Long labor times, repeated entering of contaminated tunnels, working in high-dust environments are likely to result in earlier illness onsets, more severe clinical courses, and even fatal outcomes. More importantly, none of the patients used reliable personal protection equipment (PPE), such as common masks while working, that would prevent the inhalation of more Histoplasmaspores. What are the implications for public health practice? The epidemiological findings of this outbreak investigation highlight a probable risk of infection with Histoplasma when entering without PPE into the environment with bats living around, such as caves or mines. Effective education and communication might be needed among residents and travelers. This outbreak expands our knowledge of the control and prevention of fungal disease in China.

At the beginning of April 2019, China National Health Commission (NHC) and China Center for Disease Control and Prevention (China CDC) received reports of a cluster of febrile illness involving about ten Chinese workers in a manganese ore in Cooperative Republic of Guyana. The enterprise applied to NHC for permission for evacuating the patients back to China for further treatment. A special Chinese medical team composed of the experts of epidemiology, medical bacteriology, clinical and emergency medicines was deployed to Georgetown, Guyana on April 6, 2019 to provide the support in clinical and public health, to identify the potential etiology and to assess the potential threat, especially the risk of international transmission.

Outbreak Recognition and Initial Response
On March 28, 2019, six Chinese males with fever visited the local Pakera District Hospital (PDH) in Matthews Ridge. They complained of non-productive coughing, headaches, weakness and joint pain, and two of them had severe symptoms. All of them came from a manganese ore mine nearby. After hospitalization, the District Medical Officer (DMO) notified this event to the Chief Medical Officer (CMO) of the Ministry of Public Health (MOPH) of Guyana immediately and MOPH operationalized its emergency responses operations quickly. One day later, a patient's condition suddenly deteriorated and died with a manifestation of hemorrhagic and multi-organ failure. The rest of the five patients were further transferred to Georgetown Public Hospital (GPH) on March 30, 2019. In the following days, eight more cases including seven Chinese workers and one Guyanese worker were successfully identified and transferred to GPH. Two other mild cases with only mild fever stayed in PDH. Another severe patient displayed multi-organ failure and died in GPH on April 3, 2019.
Based on the signs and symptoms of the six patients, the MOPH of Guyana issued a working case searching definition: a person who had fever, with or without any one of the below symptoms with unexplained reasons such as cough, headaches, weakness, muscle, and/or joint pains since March 1, 2019 in Matthews Ridge. Healthy miners in the manganese ore mine who had entered the same abandoned tunnels and the close contacts of the patients were placed under medical observation. Up to April 15, 2019, a total of 16 patients were identified. Two Chinese patients died, and two cases (one Chinese patient and one Guyanese patient) were discharged. Because the Guyanese patient showed negative laboratory test results and had no exposure to the abandoned mines, he was excluded from the final case-list. A total of 24 miners including 10 healthy co-exposed miners and 14 close contacts were under medical observations in Matthews Ridge.

Pathogen Detection
Various tissue specimens from the two fatal cases and blood samples from surviving patients were transferred to the laboratories of China CDC. Nextgeneration sequencing (NGS) technology based on Illumina MiSeq platform identified different lengths of specific gene sequences of Histoplasma capsulatum in seven different samples of two fatal cases and one severe case, including lung and blood samples. Up to April 15, 7 cases were laboratory confirmed as being infected with Histoplasma capsulatum. Therefore, 7 of 15 patients were laboratory confirmed cases and the remaining 8 patients were clinically diagnosed cases (Table 1).

Epidemiological Investigation on the Field
The investigation was conducted by carefully interviewing the patients and their healthy co-workers. The median age of 15 Chinese male patients was 43.5 years old (range: 23-56). The first case displayed clinical manifestation on March 22, 2019 and the peak of disease was on March 30, 2019 (Table 1 and Figure 1). Fever was the most frequent symptom (n=15, 100%), while other symptoms were also noticed including headache (n=10, 67%), muscle pains (n=8, 53%), joint pains (n=8, 53%), weakness (n=7, 47%), cough (n=3, 20%), skin rash (n=3, 20%), and dizziness (n=1, 7%). A clinical evaluation score (range: 0.5 to 100) was assigned to each of the 15 Chinese cases by clinical experts according to illness severity. The more severe the illness was, the higher score was assessed. Among the 15 cases, 2 were fatal cases, 4 were severe cases, and 9 were milder cases ( Table 1). The median incubation period of all 15 cases was estimated as 10 days (range 2-11.5 days). The median incubation period of 6 severe and fatal cases [4 days (range 1.5-10 days)] was estimated significantly higher than that of 9 milder cases [12.5 days (range 8.5-13.5 days)].
It was found that all 15 Chinese patients worked in 4 short tunnels (less than 20 meters long) during March 16 and 29, 2019, with varying labor hours. The tunnels were abandoned for more than 50 years. Bats were observed to live inside, and the feces of bats were observed on the ground during the field investigation. The workers entered the tunnels for waste clearance, including shoveling soil and crushing the concrete of the ground without any PPE. Neither the 10 coworkers who had also entered in those tunnels nor the 14 close contacts got sick, resulting an attack rate of 38.5%, and the exposure's odds ratio (OR) of 2.4 (1.495-3.853) (p<0.0001). This strongly highlights that all patients in this event were exposed to the same pathological agent, and the possibility of human-tohuman transmission is extremely limited.

The Relationship Between Exposure Intensity and Disease Severity
As shown in Table 1, the frequency of entry and duration of stay inside of the tunnels among the 15 Chinese patients varied largely. To evaluate the exposure intensity of cases, an equation was used as below: Of note, n was the number of abandoned tunnels (range: 1-4), F was the times of entry, t was hours of stay per entry, w was the type of work including shovel (score=1.5), crush (score=1), and inspection (score=0.5), T was the date of entry including Period 1 (score=1.5) from March 13 to 22 and Period 2 (score=1) from March 23 to 29, L was the place of work including the bottom (score=1.5), middle (score=1) and entrance (score=0.5) of the tunnels, and E indicated whether other work was performed during the stay (Yes scoring 1, No scoring 0.5).
Two distinct profiles of exposure intensity among the patients were clearly noticed. One was above 170 and the other was below 15. A logistic regression   (Table 1). These data indicate a close relationship between the exposure intensity and disease severity.

Comments
In this overseas investigation among Chinese workers, a closely dose-dependent association of illness onset and disease severity with the exposure intensity to soil and waste possibly contaminated by the Histoplasma has been proposed. Long labor times, repeated entering of contaminated tunnels, working in dustier environments are likely to result in earlier illness onsets, more severe clinical courses and even fatal outcomes. More importantly, none of the patients used reliable PPE, such as common masks while working, that would prevent the inhalation of more Histoplasma spores. Finally, ten patients were successfully evacuated from Guyana to China with a Chinese medical aid aircraft without causing any further transmission. This outbreak practiced and exercised the Chinese medical emergency response overseas, but this investigation was limited because the environmental risk of the mines could not be evaluated. Environmental specimens collected in the mines were not been shipped to China on time due to restricted cooperation on specimen transportation between the countries.
The infection of Histoplasma has been reported in some countries in Southern America(1-2), including Guyana (3). During an interview with the staff in the local hospital, we learned that there was a local farmer who underwent similar but mild pathogenesis after entering the same tunnels and collecting feces of bats as fertilizer, highlighting the possibility of a long-term circulation of Histoplasma in this region. Although the clinical features of this cluster disease are similar to that of acute infections of Histoplasma described elsewhere(4-7), such a cluster outbreak is fairly rare in China. To our knowledge, no definitively confirmed cluster infection of Histoplasma in China has been reported. Despite that, there have been a few similar events that occurred in travelers in the caves in the southwestern region of China, inhabited various species of bats, though no reliable pathogen evidence has been obtained. The clinical findings of the cases provide valuable experience to Chinese clinicians to 3     understand the clinical features of acute infection of Histoplasma and will help achieve early detection and efficient treatment for patients. Although information on the miners' reference level of health is not available for further comparative analysis, the epidemiological findings of this outbreak investigation highlight a probable risk of infection with Histoplasma when entering without PPE into environments inhabited by bats such as caves or mines. Education and communication initiatives might benefit residents and travelers in this region. This outbreak expands our knowledge of the control and prevention of fungal disease in China. Due to worldwide industrial collaborations and traveling, we to need watch closely for emerging pathogens(8).