The goal of this study was to investigate the time profile of arterial oxygen saturation in Covid 19 in IVM treated versus NIVM treated individuals. Secondly, we set out to explore correlates and determinants of change in digital arterial oxygen saturation measured by pulse oximeter in covid 19 patients.
In this propensity- matched study utilizing patients on room air with SPO2% < 94, our results demonstrate a significantly greater increase in SPO2% in the IVM containing regime than the NIVM group. (P = 0.000 RMANOVA).
SPO2% increased from baseline by + 7.9% on IVM but by only + 2.2% on NIVM regimen by day 5. There was also a temporal correspondence between the SPO2% time profile, with the fall in viral load ( increase in Cycle threshold Ct of genes E and N) .
These findings confirm our previous reports on ivermectin virucidal pharmacodynamics against SARS - CoV − 2 and the concomitant increase in arterial oxygen saturation in Covid 19 disease. [15, 16]. Other workers have also reported a rapid rise in SPO2% within 24 hours in severe Covid 19 patients, when treated with ivermectin in the US and Zimbabwe [17, 24].
With the data at our disposal, we investigated statistically which factors may be associated with this increase in SPO2%. As above, absolute Cycle threshold figures correlated strongly with absolute SPO2 figures, and trends in both parameters also correlated, although less strongly.
This suggests a quantitative relationship between the drug regimen induced virucidal effect and the increased arterial oxygen saturation in individual patients. To our knowledge, this is a novel report.
Change in inflammatory indices such as C reactive protein, ESR, Neutrophil count and Neutrophil/lymphocyte ratio were poorly correlated with change in SPO2%.
By contrast, there was a significant correlation between increased platelet count and increase in SPO2%. This change is accentuated when the analysis is limited to IVM using patients but reversed with NIVM patients. Change in D dimer levels did not significantly correlate with change in SPO2. Absolute day 7 hemoglobin correlates very weakly with day 7 SPO2, although delta hemoglobin did not correlate with delta SPO2. These results suggests that changes in hematological/thrombotic variables may play a role in the increase in oxygen saturation reported in this study.
Gender may also contribute to the magnitude of the increase in SPO2%. Our findings suggest that the noticeable increase in SPO2 in the IVM arm is accentuated by male sex. It is established that female gender by innate immunological and or ACE2 or Transmembrane Serine Protease 2 (TMPRSS2) viral entry receptors, which are under androgenic regulation, are less prone to severe Covid 19 than men [25]. There was a significantly greater increase in SPO2% on NIVM in female than in Male patients, whilst this gender difference was not seen in the IVM group. Speculatively, this may indicate an interaction between IVM to mitigate the androgen mediated platelet hypercoagulability in men [26] and thus cause similar SPO2% increase.
Collectively, our findings strongly suggest that diminution in SARS- CoV-2 viral load (inverse of Ct), platelet count changes and gender are significant contributors to the increased SPO2% in these patients.
The molecular mechanisms of these findings, however, remain unexplained by this study.
The hypoxemia and reduced SPO2% in Covid 19 patients follows SARS - CoV-2 viral invasion of alveolar macrophages, which cause elaboration of the NF kappa B transcription and production of the pro inflammatory cytokines ( IL − 1B and NLRP3 inflammasome) [27]. This is succeeded by a feed forward release of IL- 6, Tumor Necrosis Factor TNF alpha, massive release of neutrophils and Neutrophil Extracellular Traps ( NETs). The neutrophils cause activation of coagulation, platelet sequestration and thrombin activation, clot and fibrin formation, with virucidal activity [28]. The resultant cytokine induced "immunothrombosis" cause a bidirectional mutual activation of alveolar microvascular thrombosis and inflammation with inflammatory cell infiltrates, necrosis and perfusion of unventilated alveoli, V/Q mismatch and fall in arterial oxygenation [29]. A contribution from bronchial nicotinic cholinergic mediated inflammation has also been suggested [29].
The greater beneficial effect of Ivermectin containing regimen ( IVM ) than IVM on SPO2% in Covid 19 may conceivably be attributed to the inhibition by ivermectin of pro- inhibitors cytokines by its suppression of the JAK - STAT pathway [30], competitive interaction with SARS - CoV − 2 spike protein S reducing viral binding and entry [31] and direct activation of neuronal acetylcholine receptor and the vagus nerve [32] causing reduced bronchial inflammation and dilation.
A limitation of our study was the unavailability of inflammatory cytokine measurements. Although viral load ( Ct) may serve as a surrogate for cytokines, the actual blood or breath levels of IL- 1B, IL − 6, TNF would have provided a direct assessment of their kinetics and oxygenation impact.
Owing to the fact that ivermectin increases SPO2% at least in part by cytokine suppression, it is attractive to speculate that it might also enhance arterial oxygenation in non infectious chronic respiratory disorders such as bronchial asthma or chronic obstructive pulmonary disease ( COPD) where inflammation and cytokines also play a role [18, 32]. This should be a subject of future inquiry.
In conclusion, Ivermectin regime ( IVM) caused a more rapid onset and greater increase in SPO2%, than the NIVM arm, in hypoxemic covid 19 patients breathing room air.
The rise in SPO2% was concomitant with a fall in SARS - CoV − 2 viral load (increased Ct) with a temporal correspondence and correlation.
The SPO2% correlated significantly with changes in platelet count.
Males not receiving ivermectin ( NIVM) had a blunted increase in SPO2% compared to the females in the same group. By contrast, ivermectin (IVM) conferred similar increase in SPO2% in Males and females.
Ivermectin may increase arterial oxygenation mainly through its virucidal action.
Table 1
Propensity matched baseline variables in the IVM and NIVM groups. (SPO2% <94)
Variable | IVM only | NON IVM | Overall | P value (test) |
Total Numbers | 21 | 26 | 47 | |
Mean Age (SD)years. | 39.8 | 44.8 | 42.6 | 0.219 (ttest) |
Sex (Male %) | 13(61.9) | 17(65.4) | 30(63.8) | 0.805 (chi2) |
Oxygen use | 2(9.5) | 7(29.2) | 9(20) | 0.100(chi2) |
Ventilator | 2(9.5) | 1(5.0) | 3(7.3) | 0.578 (chi2) |
Vaccination | 0(0.0) | 7(53.9) | 7(31.8) | 0.008(chi2) |
Hematology |
Hemoglobin g/dl | 12.03 | 12.49 | 12.30 | 0.490 |
WBC X109cells/liter | 9.82 | 8.90 | 9.31 | 0.175 |
Lymphocyte X109 cells/liter | 32.67 | 45.65 | 39.85 | 0.0010 |
Neutrophils X109 cells/liter | 61.14 | 57.84 | 59.32 | 0.422 |
Neutrophil to Lymphocyte ratio(NLR) | 2.90 | 1.21 | 2.01 | 0.0046 |
Platelet count X109 cells/liter | 193.7 | 183.2 | 187.9 | 0.534 |
Viral Load Cycle Threshold Ct. |
N-gene CT | 27.33 | 18.25 | 22.31 | 0.0000 |
E-gene CT | 21.18 | 15.50 | 18.03 | 0.0000 |
Inflammatory markers |
ESR ml/h Westergren | 12.62 | 12.15 | 12.36 | 0.442 |
C-reactive Protein mg/l | 15.13 | 11.51 | 13.13 | 0.010 |
D-dimer ng/ml FEU (Fibrinogen equivalent Unit) | 218.9 | 207.5 | 212.6 | 0.067 |
SpO2% | 89.1 | 87.1 | 88.0 | 0.961 |
Symptoms at baseline (%) |
Diarrhea | 3(15.8) | 2(8.0) | 5(11.3) | 0.420 |
Anosmia | 7(35.0) | 15(57.7) | 22(47.8) | 0.127 |
Ageusia | 5(23.8) | 8(30.8) | 13(27.7) | 0.596 |
Dyspnea | 3(15.0) | 4(15.4) | 7(15.2) | 0.971 |
Headache | 12(60.0) | 6(23.1) | 18(39.1) | 0.011 |
Cough | 17(80.9) | 7(26.9) | 24(51.1) | 0.000 |
Myalgia scores | 1.57 | 2.00 | 1.80 | 0.0062 |
Table 2
Linear regression table showing pairwise correlation (r) between Day5-SPO2, Day7-SPO2, DeltaSPO2_Day5 and DeltaSPO2_Day7 and other parameters (P values).
Parameter | Day5spo2 | Day7spo2 | Deltaspo2 (7) (Day7-baseline) | Deltaspo2(5) (Day5-baseline) |
Day5 N-Ct | 0.769 (0.0000)* | 0.772(0.0000)* | 0.337(0.0031)** | 0.397(0.0002)** |
Day5 E-Ct | 0.646(0.0000)* | 0.620(0.0000)* | 0.315(00059)** | 0.401(0.0002)** |
Delta N-Ct (Day5-baseline) | | | 0.206(0.0758)# | 0.076(0.492) |
Delta E-Ct (Day5-baseline) | | | 0.207(0.0743)# | 0.225 (0.0396)** |
Delta-CRP (Day7-baseline) | | | -0.082(0.485) | |
Delta-ESR (Day7-Baseline) | | | 0.0071(0.952) | |
Delta-DDimer (Day7-Baseline) | | | 0.129(0.269) | |
Day7 CRP | | -0.034(0.773) | | |
Day7 D_Dimer | | 0.0111(0.925) | | |
Day7 ESR | | 0.388(0.0006)* | | |
Day7 Platelet | | 0.076(0.5151) | | |
Day7 Hb | | 0.0194(0.096)* | | |
Day7 Lymphocyte | | -0.387 (0.0006)* | | |
Delta platelet (Day7-baseline) | | | 0.252(0.029)** | |
Delta Hb (Day7-baseline) | | | 0.169(0.147) | |
Delta lymphocyte (Day7-baseline) | | | 0.659(0.615) | |
Delta Neutrophil (Day7-baseline) | | | 0.125(0.287) | |
Day7NLR | | 0.208 (0.073)# | | |
Delta NLR | | | -0.098 (0.399) | |
Key:
*Significant association against SPO2 absolute values
**Significant association against change in SPO2 values
# Strong trend towards significant association