key: cord-1003562-9k01pq6z
authors: Kolivand, Pirhossein; Fathi, Mohammad; Kheyrati, Leila; Lak, Mehran
title: Exposure to sulfur mustard increases the risk for mortality in patients with COVID-19 infection: A cohort study
date: 2021-09-25
journal: Am J Emerg Med
DOI: 10.1016/j.ajem.2021.09.053
sha: ce254edeb5519f8dbd98a46e8a1ddce2fe1cb640
doc_id: 1003562
cord_uid: 9k01pq6z

OBJECTIVE: This study aims to assess the prognosis of inpatients with COVID-19 infection who have a history of sulfur mustard exposure. METHODS: We started a cohort study in October 2020 and ended in May 2021 on inpatients with COVID-19 infection who had been admitted to university healthcare centers. The analytic sample included 960 inpatients having COVID-19 infection (192 with; and 768 without sulfur mustard exposure). The exposed patients were male war veterans, and the unexposed patients were male individually age-matched people. All patients had a positive RT-PCR test and a positive chest CT for COVID-19. The outcome was death within 28 days of admission, and the predictors were clinical features recorded at patients' bedsides. RESULTS: There was a significantly higher prevalence for asthma (p = 0.026) and pulmonary disease other than asthma (p < 0.001) in patients with the exposure. Sulfur mustard exposure was associated with increased risk for mortality of COVID-19 [hazard ratio (95% CI) = 1.92 (1.14,3.24), p = 0.013]. Early intubation signified a poor prognosis [hazard = 7.34 (4.65,11.58), p < 0.001]. However, individuals with higher PaO2 [hazard = 0.97 (0.95,0.98), p < 0.001], or people undergoing O2 therapy early upon admission [hazard = 0.58 (0.38,0.89), p = 0.011] showed lower risks for mortality. Individuals with asthma were at higher risk for mortality [hazard = 3.76 (1.69,8.36), p = 0.001]. CONCLUSION: Individuals with COVID-19 infection and sulfur mustard exposure should be considered high-risk patients and that, healthcare settings should be ready to provide critical care for them, including O(2) therapy. They are more likely to have asthma or other pulmonary diseases.

As of 25 May 2021, there has been about 3.5 million death caused by the global pandemic of COVID-19 according to the World Health Organization dashboard for Coronavirus. The infection manifests within an average of 11.5 days from exposure in 97.5% of symptomatic people [1] . Early in the course of COVID-19, typical findings on chest computerized tomography (CT) include ground-glass opacities with bilateral peripheral involvement in multiple lobes and consolidation [2] . The disease is commonly diagnosed using reverse transcription-polymerase chain reaction (RT-PCR) test with 20% to 67% false-negative based on time since exposure as reported in the literature [3] . In patients with clinical suspicion of COVID-19, the negative test result should be interpreted with other clinical and paraclinical evidence [3] . Overall, inpatient mortality is 15-20%, and 40% of hospitalized patients require intensive care [1] .

Meanwhile, reports from different populations show variability in mortality rates. Hospital mortality is estimated to be less than 5% for individuals younger than 40 years, 35% for patients aged 70 to79 years, and more than 60% for people 80 to 89 years of age [4] . Concerning sex, a similar mortality pattern was reported in Europe, while a study carried out in the US showed that male sex was independently associated with death, hospitalization, and intensive care unit admissions [5, 6] . Individuals undergoing kidney transplants or dialysis; and patients with cancer, diabetes, and neurologic or cardiovascular diseases are suggested to be at increased risk for mortality [7] [8] [9] [10] [11] .

People exposed to chemical weapons experience severe acute and chronic health problems.

Sulfur Mustard (SM) is a chemical agent which was commonly used by Iraq in the 1980s as a J o u r n a l P r e -p r o o f Journal Pre-proof weapon against Iran. It is believed that thousands of unprotected people living in Iran, Iraq, and Syria have been exposed to SM [12, 13] . Late in the course of the disease, SM exposure (SME) is associated with pulmonary complications (Mustard lung) such as asthma, emphysema, chronic bronchitis, obliterative bronchiolitis syndrome, chronic obstructive pulmonary disease, and tracheobronchomalacia [14] [15] [16] [17] [18] [19] . Other long-term effects of SME include cancer, hematologic, immunological, neuropsychiatric, and reproductive problems [12, [20] [21] [22] . Patients experience eye and skin complications [23, 24] and also social isolation [15] .

In an observational study, about 34,000 patients who had sustained SME during the Iran-Iraq war of 1980-1988 were screened for the complications of the exposure [25] . Overall, 23 to 37% had mild, 1.5% to 4.5% had moderate, and 0.023-1.0% had severe health problems. In a crosssectional study of 197 veterans with SME, asthma was diagnosed in 21 (10.65%), chronic bronchitis in 116 (58.88%), bronchiectasis in 17 (8.62%), airway narrowing in 19 (9.64%), and pulmonary fibrosis in 24 (12.18%) patients [26] . It was concluded that SM is associated with developing a series of chronic destructive pulmonary sequelae in the long term.

In another cross-sectional study of chronic SME complications, patients commonly complained of cough and dyspnea [27] . They had wheezing and coarse rale in chest auscultation. However, in about one-third of patients, clinical examination and radiographic findings were not conclusive for pulmonary complications of SME. Meanwhile, spirometry showed an obstructive pattern, and the pulmonary function test implied normal or restrictive patterns. Bronchospasms typically followed lung infections, asthma, environmental allergens, and cold air [26, 27].

There is no quantitative study in the literature to deal with the effects of coexisting SME and COVID-19 on patients' mortality. The aim of conducting this study was to assess the prognosis of inpatients with a history of SME who have COVID-19 infection and thereby, enable the triage officer to rapidly evaluate the necessity of more critical care for the patient. 

We carried out a study to assess the risk for mortality of COVID-19 among patients with a history of SME. Our cohort study started in October 2020 and ended in May 2021. The target population was people with COVID-19 infection who were admitted to university healthcare centers. Patients were managed according to the instructions given by World Health 

We included all people who were hospitalized with a diagnosis of COVID-19 infection. All 

All the patients with SME were male war veterans. Therefore, to eliminate any possible confounding effect of sex we included male inpatients with a positive RT-PCR test and a positive chest CT for COVID-19. The total number of patients was 67871 of which 192 had SME. Because of severe imbalance in exposure variable, we randomly under-sampled the Non-SME group to provide a 1:4 ratio of SME: Non-SME patients in the final sample. However, to cancel out possible age confounding effect, each Non-SME patient was randomly selected as an individually age-matched to 4 SME patients. At the end of the process, the analytic sample included 960 patients (192 SME and 768 age-and sex-matched Non-SME patients) and had 49 missing data. The missing data included respiratory rate (46; 4.8%) and O2 therapy at admission (3; 0.3%). The missing data were imputed using predictive mean matching. We excluded highly imbalanced predictors from the analysis, including seizure, paresis, plegia, dermatologic and hematologic problems, liver diseases, HIV/AIDS, chemotherapy or immune deficiency, and dialysis. Figure 1 shows the flow of data in the study, and Figure 2 illustrates initial variable importance for predicting mortality, estimated with random forest technique. Based on the selected features, Table 1 shows the characteristics of the two groups of patients. The

We conducted the current study to investigate the effects of exposure to SM on the risk of mortality among inpatients with COVID-19 infection. The infection was confirmed with both RT-PCR test and positive chest CT findings for COVID-19. Clinical features on admission significantly affected the death risk of the patients. Our results showed that SME is associated with a nearly two-fold increased risk for mortality. Patients with SME showed accelerated mortality within three weeks of admission compared with well-matched Non-SME people. In addition, early intubation signifies a poor prognosis. However, individuals with higher PaO2 or people undergoing O2 therapy early upon admission showed lower risks for mortality.

Our data suggest that the percentage of patients with SME who have received O2 therapy at admission was significantly higher than the Non-SME group. Patients with SME have likely been triaged correctly as requiring critical care services and consequently have been admitted to hospital and received O2. This also might lower the risk of mortality for the SME group than what has been previously thought. Also, our results implied there is a significantly higher prevalence of asthma and pulmonary disease other than asthma in patients with SME and that individuals with asthma are at higher risk for mortality. These findings show that people with SME should be considered as high-risk patients and a more serious clinical approach should be planned for them. Our results are consistent with some findings reported in the literature regarding the impacts of SME on respiratory health. SM [bis-(2-chloroethyl) sulfide] is a vesicating electrophilic alkylating agent that has mutagenic, cytotoxic, and carcinogenic effects on living tissues causing significant morbidity [32] . The mortality rate is 2% to 3% with lethal exposure of approximately 100 mg/kg or 5 to 7 mL. Death J o u r n a l P r e -p r o o f Journal Pre-proof is usually from pulmonary complications. The mechanism for late pulmonary complications of SME is still unknown [33] . However, the pulmonary renin-angiotensin system has been suggested as an underlying process of lung damage through engaging in inflammatory and fibrotic responses. Variable concentrations of angiotensin-converting enzyme (ACE) have been reported to be associated with the severity of chronic respiratory problems following SME. A study on 208 patients with previous SME suggested that genotypes of ACE are associated with Our results showed that 5.7% of patients with SME and 1.2% without SME had asthma. Also, 25.0% of SME and 2.3% of Non-SME group had non-asthma pulmonary disease. Bronchitis was the most commonly reported pulmonary disease for our SME sample. However, due to inconsistent recording of verbal data, we were not able to estimate its prevalence among our patients.

To our knowledge, this is the only cohort study describing the effect of SME on mortality of COVID-19. We selected strict inclusion criteria (positive RT-PCR test result plus CT findings).

This allowed us to be more confident regarding the diagnosis of COVID-19 infection. We 

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PaO2: Partial Pressure of Oxygen; SME: Sulfur Mustard Exposure