Part Ⅱ Angiotensin Converting Enzyme Inhibitors May Increase While Active Vitamin D May Decrease The Risk Of Severe Pneumonia in SARS-CoV-2 Infected Patients With Chronic Kidney Disease On Maintenance Hemodialysis

Results

1. Patients Characteristic

During the study period, 133 patients were hospitalized for COVID-19. Of these, we achieved access to complete admission data, along with a chest CT scan, and records of 85 individuals who were finally included in the study. Among them, 52.94% were male, and 47.06% were female. The mean age of the cohort was 69.74 (13.19), and the median dialysis vintage was 38 (14–84) months. Overall, 62 (72.94%) were recovered and discharged from the hospital, while 23 (27.06%) died during their hospital stay. The mean time to discharge was 17.77 (7.37) days, while the median time to death was 10 (3–16) days. Tables 1 and S1 (Supplementary Material) present the characteristics of patients and their chronic home treatment.

2. Clinical Presentation on Admission

On admission, 29.14% of patients had no symptoms. In these patients, the diagnosis was accidental when they were tested for SARS-CoV-2 after prior contact with infected individuals. The most common presenting symptom in all of the cohorts was fatigue (70.59%), followed by fever (44.71%), shortness of breath (40.0%), and cough (30.59%).

In the first 24h of presentation, mean (SD) finger oxygen saturation was 93.47 (5.62)%, body temperature was 36.92 (0.68) ◦C, and mean systolic blood pressure 140.76 (24.54) mmHg. Seventeen (20.0%) patients had a finger oxygen saturation of less than 90%. Laboratory investigation revealed a mean WBC count of 6.13 (2.87) with a median (IQR) lymphocyte count of 0.87 (0.63–1.27). Forty-nine (57.65%) patients were lymphopenic. All patients showed raised serum C-reactive protein and D-dimers with a median level of 53 (13.6–117.4) mg/L, and 1161.8 (685.89–1842.2) ng/mL, respectively. The mean arterial partial pressure O2 was 67.04 (22.94) mmHg. Twelve (14.13%) patients presented with arterial partial pressure O2 value below 60 mmHg on admission. Detailed findings on admission are presented in Table 2.

3. Imaging Evaluation

Among 85 patients included in the study, 66 (77.65%) had CT evidenced COVID-19 pneumonia on admission. The predominant chest CT features in patients with confirmed pneumonia included ground-glass opacities 63 (74.12%), crazy paving pattern 53 (62.35%), consolidation 35 (41.18%), pleural effusion 34 (40%), and linear opacities 24 (28.24%). Typical radiographic changes observed in our patients are shown in Figure 1. These changes had mainly a bilateral distribution—61 (92.42%) in lower lobes. In 25 (37.88%) and 22 (33.33%) patients, pulmonary parenchyma was involved in 1–5% and 5–25%, respectively. In 14 (21.21%) and 5 (7.6%) patients, pulmonary parenchyma was involved in 25–50% and >50%, respectively. The median TSS in all cohorts was 7 (4–11) (Table 3).

4. Factors Associated with Severe COVID-19 Pneumonia

The factors associated with extensive inflammatory changes in the lungs (severe pneumonia) at diagnosis of COVID-19 include chronic treatment with angiotensin-converting enzyme inhibitors (ACEI) (p = 0.02), while chronic treatment with active vitamin D was associated with limited changes (mild pneumonia) (p < 0.011) (Table 1). The clinical features on the admission of fever (p = 0.01), low finger oxygen saturation (p < 0.001), low arterial partial pressure of oxygen (p = 0.02), increased indicators of inflammation including serum C-reactive protein (p < 0.001) and ferritin (p = 0.03), and low count of lymphocytes (p < 0.001) were associated with severe pneumonia expressed by a higher TSS score. Detailed results are presented in Tables 1 and 2.

Discussion

In this study, we retrospectively analyzed the clinical presentation of HD patients with newly diagnosed SARS-CoV-2 infection. The most common early clinical symptoms at admission included fatigue, fever, dyspnea, and cough which did not differ from those seen in other studies in HD patients [25–27]. At the time of diagnosis, nearly one-third of the patients were completely asymptomatic, while the remaining subjects usually reported single symptoms much less frequently than in the general population, which may be due to numerous immune disturbances and impaired reactivity [28]. At the same time, as many as 20% of patients presented with reduced blood oxygenation requiring urgent oxygen therapy. Similar to other reports, more than half of the cases were lymphopenic and frequently had increased markers of inflammation [26,27,29,30].

Consistently in several previous reports on COVID-19 individuals from the general population, our results showed that COVID-19 pneumonia in HD patients features predominant ground glass opacities, mainly bilateral, with lower lung zones being mostly involved [31,32]. Ground-glass opacities refer to the area of increased attenuation in the lung on computed tomography with preserved bronchial and vascular markings and can be taken as an indicator of the early stage of pneumonia [33]. A crazy-paving pattern, defined as a linear pattern superimposed on GGO resembling irregularly shaped paving stones was observed in 62% of the cohort and 82% in the group with a severe course. This is important given the fact that this appearance can be considered an indicator of disease progression [34]. In the general population, these changes are observed in a much smaller percentage ranging from 5 to 36% [35]. The area of the increased lung opacity with obscuration of underlying broncho vascular markings refers to consolidation, which is also an indicator of disease progression and appears in the general population at a later stage of the disease [36]. This mixed pattern, showing a per lobular and peripheral distribution, suggests the presence of secondary organizing pneumonia [33]. In our cohort, it was observed in over 40% of patients were already on admission. Importantly, all these changes were observed in nearly 78% of all patients diagnosed with SARS-CoV-2 infection, including those who did not report any symptoms. The remaining cases also presented opacities, which, however, did not exceed 1% of lung parenchyma and were not treated as pneumonia for this study. In the study of Turgutalp et al. in a Turkish HD population, this percentage was 89.6% [27]. These results indicate that chest CT may be a valuable method for diagnosing COVID-19 in HD patients. Fang et al. found that the sensitivity of chest CT for COVID-19 diagnosis was even greater than RT-PCR (98% versus 71%) [37]. In nearly 30% of our patients, the changes at the time of diagnosis covered more than 25% of the lung parenchyma. All this data indicates a frequent occurrence of serious lung lesions yet at the time of diagnosis and a very rapid course of the inflammatory process in HD patients, closely corresponding to the extremely high mortality rate in this group of patients. Of note, the mean time of hospital admission was 2.2 days from the onset of symptoms, and the median time to death in the severe course group was 4 days after admission. The pleural effusion usually not seen in COVID-19 turned out to be a common (40%) CT chest finding similar to the study of Turgutalp et al. [27]. It may be related to the specificity of dialysis patients, more specifically to fluid overload and concomitant heart failure.

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Identifying patients with rapidly developing pneumonia and a high risk of developing acute respiratory distress syndrome (ARDS) as soon as possible might help individualize pharmacological treatment and optimal utilization of medical resources. It was demonstrated that the sooner pharmacological treatment is started in such patients, the greater the chances of survival [15–18]. We found that patients with more extensive lung changes on admission objectified by a higher TSS were likely to present with fever, had decreased finger oxygen saturation and arterial oxygen partial pressure, increased laboratory indicators of inflammation including serum c-reactive protein and ferritin, and decreased lymphocytes count. The predictive value of inflammation level and lymphopenia concerning the progression of COVID-19 and a poor outcome was reported in previous studies [20,38]. In our recent study, high CRP and D-dimer levels upon admission were strongly associated with a 3-month mortality risk in HD patients [39]. Other studies also show a predictive value of blood oxygenation indices for the severity of pneumonia and mortality of COVID-19 patients [21,40,41].

An important part of the study was the assessment of potentially modifiable factors that could affect the patient outcome. Chronic home treatment might affect susceptibility and prognosis. In particular, it was postulated that ACE inhibitors could act as a potential risk factor for SARS-CoV-2 infection and poor outcome by upregulating ACE2, a viral entry co-receptor for the virus [42,43]. The results of our study seem to confirm this hypothesis. Patients who received chronic ACEI treatment were more likely to have more extensive lung lesions. However, there is also enough evidence that allows stating the opposite hypothesis [42]. Firstly, there are limited findings showing changes in serum or pulmonary ACE2 levels after ACEI. Secondly, ACE2 and angiotensin (1–7) are protective in several different acute lung injury models [44]. For instance, a large population-based study revealed an association of ACE inhibitors with lower COVID-19 incidence. Variations between different ethnic groups observed in this study raise the possibility of ethnic-specific effects of ACE inhibitors on COVID-19 disease susceptibility and severity, which deserves further study [45]. The relationship between the use of ACEI and the incidence and severity of COVID-19 should be investigated in further studies, especially in vaccinated HD patients. Determination of ACE2 expression could help confirm such a relationship and our hypothesis [46].

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Low 25-hydroxy vitamin-D (25-OH D) level is associated with proinflammatory cytokines levels and was demonstrated to be an independent predictor of COVID-19 severity in the general population [47]. However, research into vitamin D supplementation in the prevention and treatment of COVID-19 provides inconsistent results [48,49]. In the recent study, we originally found that in HD patients who were treated with active vitamin D, there may be a lower risk of 3-month death from COVID-19 [39]. There was substantial clinical and methodological heterogeneity in the conducted studies, mainly because of different supplementation strategies, formulations, vitamin D status of participants, and reported outcomes [50]. Our cases did not have determined 25-OH-D levels. Following the KDIGO guidelines, some of them received 1-alpha-hydroxyvitamin D3 (Alfacalcidol), aimed to normalize calcium and phosphorus levels and maintain parathormone within two to nine times the normal upper limit [51]. Such treatment turned out to be a significant factor associated with less extensive inflammation in the lungs, thus supporting the hypothesis of a beneficial effect of vitamin D on the prognosis of patients. It may be based on the anti-inflammatory effect of active vitamin D and the prevention of a cytokine storm in COVID-19. Very recent data suggest that proinflammatory interleukin-6 functions may be redirected to the production of anti-inflammatory interleukin-10 by vitamin D in activated human helper T cells [52]. Vitamin D also plays an important role in the innate and acquired defense against infections [53]. The active form of vitamin D3 was shown to upregulate the production of antimicrobial peptides, i.e., cathelicidin LL-37 in macrophages and lymphocytes involved in the process of autophagy, i.e., the intracellular killing of pathogens in infected cells [54]. Vitamin D is also required for acquired immunity and antimicrobial activity mediating by Th1 and Th2 cells [55]. Finally, it may promote the stabilization of the endothelium and the barrier function in the presence of inflammatory mediators [56]. Following this lead, numerous preclinical studies have demonstrated that vitamin D suppresses the replication of Mycobacterium tuberculosis in vitro, which may translate to preventing and developing the disease [53]. The hypothetical antibacterial effect of vitamin D may also contribute to its potential protective effect on the extent of lung lesions in the course of SARS-CoV-2 pneumonia. Multiple studies reported an unexpectedly high incidence of multidrug-resistant gram-negative, gram-positive bacteria, and fungi infections among patients with COVID-19 admitted to the intensive care unit [57].

The question remains whether the potentially beneficial effects of vitamin D in HD patients apply only to its active formulations or also to its native form, i.e., cholecalciferol and ergocalciferol. A nonrandomized trial of 158 patients on hemodialysis demonstrated reduced inflammation markers, serum-intact parathyroid hormone, and erythropoietin stimulating agent dose after 6 months of cholecalciferol supplementation [58]. On the contrary, other research that has measured inflammation in patients on hemodialysis after vitamin D supplementation has not found reductions in cytokines or T-cell or monocyte mediators [59,60]. It is known that more than half of the patients on hemodialysis are deficient in total serum 25-hydroxy vitamin D [25 (OH) D], and administration of native vitamin D corrects these levels without significant increases in serum calcium or phosphorus. On the other hand, impaired 1-α hydroxylation in the kidney and non-fully investigated extrarenal vitamin activation raises doubts about the effectiveness of nutritional forms of vitamin D in this patient group [61].

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The study, to our best knowledge, is the first to analyze potential predictors of COVID-19 pneumonia in HD patients. The study’s strengths include representing the entire spectrum of the disease, from asymptomatic to severe cases, and detailed quantitative artificial intelligence-assisted assessment of the extent of inflammatory changes in the lungs. A limitation of the study is its observational design, which only permits the description of associations. Secondly, the relatively small sample of cases with CT chest images allows for concluding an exploratory character only.

Conclusions

Even though nearly one-third of the patients were completely asymptomatic, with the remaining usually reporting only single symptoms, a large percentage of them had extensive inflammatory changes at diagnosis with SARS-CoV-2 infection. Fever, elevated markers of inflammation, and decreased blood oxygenation are predictors of the extent of the inflammatory changes in the lungs expressed by a high TSS score in CT. Chronic treatment with ACE inhibitors may increase the risk, while the use of active vitamin D may reduce the risk of developing severe pneumonia. The potential risks of ACEI therapy in the context of SAR-CoV-2 infection and the well-known cardioprotective properties of ACEI need to be weighed. Until more substantial data is available to define recommendations, chronic treatment of heart failure with ACEI in dialysis patients should not be interrupted. The use of active vitamin D in dialysis patients may improve their prognosis during the COVID-19 pandemic. However, it should be carried out by the current KDIGO recommendations [51], taking into account the levels of calcium, phosphorus, and the concentration of the parathyroid hormone.

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Piotr Tylicki 1, Karolina Polewska 1, Aleksander Och 1,Anna Susmarska 2 , Ewelina Puchalska-Regli ´nska 3 , Aleksandra Parczewska 3 , Bogdan Biedunkiewicz 1 , Krzysztof Szabat 3 , Marcin Renke 4 , Leszek Tylicki 1,* and Alicja D ˛ebska-´Slizie ´n 1

1. Department of Nephrology Transplantology and Internal Medicine, Medical University of Gdansk, 80-210 Gdansk, Poland; ptylicki@gumed.edu.pl (P.T.); kpolewska@gumed.edu.pl (K.P.); aleksanderoch@gumed.edu.pl (A.O.); bogdan.biedunkiewicz@gumed.edu.pl (B.B.); adeb@gumed.edu.pl (A.D.-´S.)

2. Department of Radiology, University Center for Maritime and Tropical Medicine, 81-519 Gdynia, Poland; anna.susmarska@gmail.com

3. 7th Naval Hospital in Gdansk, 80-305 Gdansk, Poland; e.puchalska@7szmw.pl (E.P.-R.); puchola@gmail.com (A.P.); k.szabat@7szmw.pl (K.S.)

4. Department of Occupational, Metabolic and Internal Diseases, Faculty of Health Science, Medical University of Gdansk, 81-519 Gdynia, Poland; mrenke@gumed.edu.pl