key: cord-0836216-28ujm8bz
authors: Almaghlouth, Nouf K; Davis, Monique G; Davis, Michelle A; Anyiam, Felix E; Guevara, Roberto; Antony, Suresh J
title: Risk factors for mortality among patients with SARS‐CoV‐2 infection: A longitudinal observational study
date: 2020-09-28
journal: J Med Virol
DOI: 10.1002/jmv.26560
sha: b2aa84d4ff1a34e15f3773bceaddb5bb83742a27
doc_id: 836216
cord_uid: 28ujm8bz

BACKGROUND: Recent literature suggests that approximately 5‐18% of patients diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) may progress rapidly to a severe form of the illness and subsequent death. We examined the relationship between sociodemographic, clinical, and laboratory findings with mortality among patients. METHODS: In this study, 112 patients were evaluated from February‐May 2020 and 80 patients met the inclusion criteria. Tocilizumab (TCZ) was administered, followed by methylprednisolone to patients with pneumonia severity index (PSI) score ≤ 130 and CT scan changes. Demographic data and clinical outcomes were collected. Laboratory biomarkers were monitored during hospitalization. Statistical analyses were performed with significance p≤ 0.05. RESULTS: Eighty (80) patients: 45 males (56.25%) and 35 females (43.75%) met the study inclusion criteria. Seven patients (8.75%) were deceased. An increase in mortality outcome was statistically significantly associated with higher average levels of IL‐6 with P value (0.050), and D‐dimer with P value (0.024). Bivariate logistics regression demonstrated a significant increased odds for mortality for patients with bacterial lung infections (OR: 10.83, 95% CI: 2.05 – 57.40, P=0.005) and multi‐organ damage (OR: 103.50, 95% CI: 9.92 – 1079.55, P=0.001). Multivariate logistics regression showed a statistically significant association for multi‐organ damage (AOR: 94.17, 95% CI: 7.39 ‐ 1200.78, P=0.001). CONCLUSIONS: We identified three main predictors for high mortality. These include interleukin‐6 (IL‐6), D‐dimer, and multi‐organ damage. The latter was the highest potential risk for in‐hospital deaths. This warrants aggressive health measures for early recognition of the problem and initiation of treatment to reverse injuries. This article is protected by copyright. All rights reserved.

Multivariate analysis was also done to adjust for the effect of confounders. An observation is said to be statistically significant if P-value is less than or equal to 0.05 (P ≤ 0.05).

One hundred and twelve (112) patients were evaluated of which 80 positive patients (45 males, 56.25%; 35 females, 43.75%) met the study criteria. Table 1 summarized the general sociodemographic characteristics, medical history, and clinical presentations of patients with SARS-CoV-2 treated with TCZ. Most of the patients were within the ages 30-64 years (39, 48.75%) and ≥ 65 years (37, 46.25%), with a median (IQR) age of 63 (51, 72) years. The least were those <30 years (4, 5.0%). Patients with Hispanic ethnicity were the majority in the study (44, 57.14%), followed by White/Hispanic (25, 32.47%), which can be mainly attributed to the fact that the population of El Paso is predominately Hispanic. Comorbidities observed most among the patients were Hypertension (47, 65.28%), type II diabetes mellitus (37, 51.39%), and hyperlipidemia (18, 25%). Other comorbidities presenting was (31, 43.05%), with the total number of presenting comorbidities on admission noted to be ≤2 symptoms on presentation in (46, 63.89%) of our patients, and those with 3 or more comorbidities (26, 36.11%), with a median of 2 comorbidities (1 -3). The most common presenting symptom was Shortness of breath (62, 86.11%), followed by fever (53, 73.61%), cough (49, 68.06%), and other associated symptoms (42, 58.33%), with a median (IQR) number of symptoms 3 (2-5). A limited number of patients had lung bacterial coinfection (12, 15%) and multi-organ damage (10, 12.50%). Multi-organ damage was identified as the development of potentially reversible This article is protected by copyright. All rights reserved.

physiologic derangement involving two or more organ systems not involved in the primary admission disease. 11 Recent travel history was reported in 11 patients (15.71%), and 34 patients had positive contact history (48.43%). The primary clinical outcome was mortality among SARS-CoV-2 patients, as summarized in Table 2 . A total of seven patients (8.7%) were deceased during the study period. The duration of hospital stays ranged from five to ten days for all patients.

Using the Mann-Whitney U test, we noted statistically significant results between average IL-6 and mortality and D-dimer level with mortality. An increase in mortality outcome was noted among those with higher average levels of IL-6 with P value (0.050).

A similar finding was observed with D-dimer, as the higher the average D-dimer, the significant correlated increase in the risk of mortality with P value (0.024). However, no statistically significant relationship with mortality was observed among CRP, procalcitonin, ferritin, and LDH levels in our study population, as illustrated in Table 3 .

From the bivariate logistics regression model (Table 4) , there were statistically significant associations between bacterial lung infections, multi-organ damage, and mortality. Those with a bacterial lung infection were 10.83 times more likely to die from SARS-CoV-2 than those with no bacterial lung infection (OR: 10.83, 95% CI: 2.05 -57.40, P=0.050). Also, those with multi-organ damage were 103.50 times more likely to die from SARS-CoV-2 than those with no multi-organ damage (OR: 103.50, 95% CI: 9.92 -1079.55, P=0.001).

After adjusting for possible confounders, the multivariate logistics regression model was only statistically significant for multi-organ damage, although with a slightly This article is protected by copyright. All rights reserved. 

Seven patients (8.7%) of our study population (total of 80) were deceased during our study period. All our patients have had hypoxemia with higher oxygen requirement > 3L and PSI score ≤ 130 and significant radiological changes. The majority of our patients have shown elevation in levels of CRP, ferritin, LDH, and D-dimer on initial presentation. After examining the association between all independent variables and mortality outcomes, we noted that mortality rates were higher among those patients with higher D-dimer and higher levels of IL-6 throughout their hospitalization period.

Nevertheless, the sequential use of TCZ and methylprednisolone within 72 hours of admission and its effect on the cytokine release syndrome (CRS) as used in our study protocol was examined in our previous study by Antony et al. 12 Moreover, in this study we discovered that the occurrence of multi-organ damage in the presence of SARS-CoV-2 infection accounted for the highest risk of mortality as compared to all other examined variables. Nevertheless, the coexistence of bacterial lung infection was a confounding factor in the presence of multi-organ failure.

On the molecular level, SARS-CoV-2 is considered more closely related to the severe acute respiratory syndrome coronavirus (SARS-CoV) than the Middle East respiratory syndrome-related coronavirus (MERS-CoV) in its sequence identity. 13 Moreover, SAR-CoV-2 shares the same cellular receptor as SARS-CoV which is the ACE2 receptor 14 that commonly found in alveolar epithelial type II cells of lung tissues 15 and also seen in other extrapulmonary tissues such as the cardiac endothelium, kidneys, and intestines, 16, 17 which might play a key role in the multi-organ damage in SARS-CoV-2 infection.

In a prospective cohort study conducted by Rong-Hui et al 18 to examine mortality predictors, the presence of a secondary bacterial infection led to higher concentrations of CRP and procalcitonin. 18 Their study noted that deceased patients had higher levels of inflammatory biomarkers than those who survived the SARS-CoV-2 infection, which might go in favor of possible increased risk of mortality with a secondary bacterial infection. Moreover, another study found that 81.7% of patients who died with SARS-CoV-2 disease were associated with bacterial infections. 19 Also, Martins-Filho et al 20 found that sepsis was associated with a 2.5-fold increase in death risk among these patients. 20 Our study examined the relationship between superimposed bacterial lung infection and mortality; however, our current result did not support the findings of previous literature.

A study published earlier in the Lancet has provided further insight into the clinical course and mortality risks for severe SAR-CoV-2 infection among patients in Wuhan. 4 In-hospital mortality was associated with older age, a higher SOFA score, and This article is protected by copyright. All rights reserved.

D-dimer level greater than 1 μg/mL, representing findings known to be associated with severe pneumonia. 4 The rate of in-hospital mortality was noted to be high (28%). 4

Furthermore, several studies have reported that pulmonary embolism and coagulopathy are frequently observed in SARS-CoV-2 patients. 8,21-23 Zhang et al 8 reported that initial D-dimer level ≥2.0 µg/mL (equivalent to 4-fold increase) was correlated with a higher incidence of mortality, compared to those with D-dimer level of <2.0 µg/mL and therefore, could effectively predict in-hospital mortality in SARS-CoV-2 patients. 8 In the meta-analysis study conducted by Martins-Filho et al 20 to assess for mortality risks, dyspnea at the onset of disease, decreased gas exchange, increased IL-6 levels, coagulation abnormalities including increased D-dimer levels and multi-organ damage such as cardiac injury, acute kidney disease, acute respiratory distress syndrome (ARDS), and sepsis were considered important mortality predictors among SARS-CoV-2 positive patients. 20 Their results were relatively similar to our conclusion in regard to significant laboratory markers and multi-organ damage with outcome mortality. Therefore, closer attention must be paid during hospitalization to these factors to minimize the risk of multi-organ damage and possibly reverse it as soon as possible.

Our study noted that the most potential risk factor for mortality that demands immediate intervention, as discussed earlier, was the multi-organ damage. The presence of extrapulmonary organ failure was widely influencing the rapid progression of the illness and subsequent death. These observed injuries include ARDS, heart failure, renal failure, shock, and multi-organ failure. Therefore, the coexistence of these findings will precipitate higher mortality rates among the SARS-CoV-2-positive population. Full 

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Abbreviations: n, Number of patients; %, Percentage of patients; R, Reference