SARS-CoV-2 causes placental changes that can lead to embryonic/foetal death. However, the pregnant woman who in other diseases is considered (e.g., H1N1) a risk group for the development of severe forms of the disease, in COVID-19 rarely evolves with severity, except when childbirth occurs, and the woman loses the bond with the placenta. The answer for the pregnant woman is in the immunosuppression promoted by the placenta, in the metabolism of tryptophan and phenylalanine (Try) and functions of furins and cathepsins. This article discusses at crucial points the main pathophysiological mechanisms that can explain the events observed during pregnancy and the peri-and postpartum phenomena. It also shows the vital role of the placenta in this period of gestation, which is one of the most significant evolutionary adaptations that humans have in the face of SARS-CoV-2 infection. The studies for the elaboration of this article could also bring to light theories about the formation of the syncytial lung in COVID-19, about the physiology of the Faget's Sign and justify new therapeutic approaches that should be carried out seeking a better outcome for patients in this case aimed at pregnant and postpartum women. This article names the main clinical manifestations of COVID-19 as the thrombometabolic and immune tolerant syndrome induced by SARS-CoV-2 infection (TMITSy-CoV-2). Finally, this article aims to bring to light a host-parasite interaction that, if well understood, can help in the management of the pregnant woman and the first postpartum moments, because even without specific medications, we can perform better clinical management, resulting in a good outcome for the pregnant woman and the foetus. Reading the Appendix is essential as it complements the general pathophysiology of COVID-19.
Coronaviruses (CoVs) are a family of positive-stranded RNA viruses with envelopes widely distributed among mammals and birds that cause respiratory and intestinal infections in animals and humans. Brazil reported a disproportionately large number of maternal deaths attributed to COVID-19, particularly during the postpartum period. There were 160 notified deaths associated with COVID-19 among pregnant and 106 deaths among postpartum hospitalized women considering data from the Brazilian Ministry of Health's Influenza Epidemiological Surveillance Information System. The high maternal death rates in Brazil are accompanied by large racial, geographic, and socioeconomic disparities. The COVID-19 mortality rate among pregnant and postpartum women is 7.2% in Brazil (data published in 2021/June). This percentage is 2.5 times higher than the national rate of 2.8%. According to the Covid-19 Observatory of the Oswaldo Cruz Foundation (Fiocruz) [1].
Pregnant women are not part of the risk group for hospital admission, but they present risks due to the pregnant woman's status and because there are cases of placental changes that may lead to the embryo or foetus death. Maternal mortality rate by COVID-19 increased and Brazil is responsible for an important portion of cases. This rate may be even higher due to underreporting, and it is necessary to consider "The Long COVID-19" as the greatest causes of mortality that is underreported. A recent study published COVID-19 is diagnosed in the third trimester. Thus, women with COVID-19 diagnosis or whose pregnancy ended earlier in pregnancy are underrepresented either because our study was exclusively hospital based or earlier infection may manifest with mild symptoms, which are either ignored or managed in primary care [2] (Tables 2, Table 3, Table 4 and Table 5 in the Appendix).
This article based on praxis aims to bring Hypotheses that allows physicians to have more possibilities to perform better management of the pregnant women facing a reality that show us no active antiviral to avoid COVID-19. Understanding the pathophysiology of COVID-19 is the way that we have to improve medical conduct and offer more safety to pregnant women and foetus.
Performing a search for articles in PubMed and SciELO databases - Scientific Electronic Library Online, Articles published in the last 20 years were considered valid. The search for articles was based on the following descriptors: (mj :( "Coronavirus Infections" OR "Pregnant Women") AND mha ("Infectious Complications in Pregnancy/MO" OR "Infectious Complications in Pregnancy/PA" OR "Infectious Complications in Pregnancy/PP")), considering all types of articles published on COVID-19 and pregnancy, as only 71 articles were found to be considered to perform the idea inside this manuscript. Only articles published between 2001 and 2021 and in English were considered, totalling 67 articles. Official sites of the Brazilian government and sites of universities were accepted to complement information and research. More information about mechanisms that may happen during the gestational period were complemented by search on Google Scholar. Articles in Russian were also included, mainly because they addressed the shock in COVID-19, as many articles present interesting and unique views that help in understanding the pathophysiological mechanisms. Overall, considering all the subjects covered, 202 articles were selected based on the quality of publication and relevance to the subject, but 101 are in the main text. Many other articles were used to support the pathophysiology of SARS-CoV-2 and host hospitalization. The figures used from sources other than those drawn by the author himself had their origins duly identified. Figures modified or constructed by the author were performed using the platform www.biorrender.com (Created with BioRender).
amh: document subject descriptors mh: The search result was N records. N = number of found records. mj: primary descriptors of the document - example: mj: The search result was N records.
bAPCs: Antigen-presenting cells BALF: Broncho alveolar lavage fluid FGF-β: Basic fibroblast growth factor CLIP: Class II-associated invariant chain COPD: Chronic obstructive pulmonary disease cTEC: Cortical thymus epithelial cells DPPI: Dipeptidyl aminopeptidase I ECM: Extracellular matrix EMT: Epithelial-mesenchymal transition ER: Endoplasmic reticulum Ets: Erythroblast transformation-specific transcription factor GAGs: Glycosaminoglycan hCATL: human cathepsin L HMWK: High-molecular-weight kininogens IFN: Interferon IL: Interleukin IR: Insulin receptor IRES: Internal ribosomal entry site L: Left-hand domain LMP: Lysosomal membrane permeabilisation LMWK: Low-molecular-weight kininogens M6PR: Mannose-6-phosphate receptor MMPs: Matrix metalloproteinase MOMP: Mitochondrial outer membrane permeabilisation PAI: Plasminogen activator inhibitor R: Right-hand domain ROS: Reactive oxygen species SMA: Smooth muscle actin TGF: Transforming growth factor TGN: Trans-Golgi network TIMP: Tissue inhibitors of metalloproteinase TNF: Tumour necrosis factor UTR: Untranslated regions VEGF: Vascular endothelial growth factor XIAP: X-chromosome-linked inhibitor of apoptosis
The maternal organism only tolerates the foetus because the placenta develops an immune tolerance mechanism in the pregnant woman's body, so the embryo is not recognized as not proper. About four days after fertilization, the morula reaches the uterus and fluid from the uterine cavity passes through the pellucid zone to form - the blastocystic cavity. Blastomeres are separated into two parts with increasing fluid, and two structures arise due to this separation 1) Trophoblast: External cell layer that will form the embryonic part of the placenta and 2) Embryoblast: A group of centrally located blastomeres that will give rise to the embryo. After six days of fertilization, the embryo base is adhered to the uterine wall and physiologically by the embryoblast structure by the action of proteolytic metalloproteinases of the endometrium. On the opposite side, the trophoblast starts differentiation to 1) Cytotrophoblast: Inner cell layer and 2) Syncytiotrophoblast: Outer cell layer [3-5]. The Syncytiotrophoblast is highly invasive and responsible for producing the hormone hCG that maintains hormonal activity in the corpus luteum during pregnancy and forms the basis for pregnancy tests. More about placental development, immune response and vasculogenesis, about changes in placental physiology in the face of gestational or Sars-CoV-2 induced diabetes are more detailed in the Appendix. Figures numbered 1 through 22 remain in the main text as they are self-explanatory, but more details are presented in the Appendix in supplementary material [6-8] (Figure 1, Figure 2, Figure 3 and Figure 4).
Cathepsins [9-13] identified as a lysosomal protease that degrades substrates in acidic compartments, Furins [14-16] ubiquitous proprotein convertase cleaves substrates at the consensus sequence -Arg-X-Lys/Arg-Arg↓. For these two proteins to have their actions guaranteed, they need the microenvironment where they act to be acidic. Cathepsin and Furins are induced to be expressed mainly in environments with low oxygen tension, that is, in a hypoxemic environment. Both proteins are related to mental diseases, cardiovascular diseases and the development of neoplasms and metastasis. However, they also participate essentially and fundamentally in protein processing when patients are in homeostasis. They also play an essential role in placental implantation and the process of invasive waves related to placental development and implantation, and these reasons justify their presence, in high concentrations, in syncytiotrophoblast. Cathepsin L [16-18] and the rasHa oncogene are expressed in two coincident waves corresponding to periods during which the placenta is invasive and just before parturition. Large amounts of cathepsin L in the placenta suggest that the proteinase has a significant function there. Expression of cathepsin L in the placenta is potentially under the control of the ras product gene p21; both are under developmental control [19-21] (Table 1 and Figure 5).
The performance of autopsies has shown that some lungs that progress with severity from COVID-19 have pneumocytes II modified to syncytium formation, and this phenomenon occurs mainly in cases where the disease has evolved into severe or critical forms [22-24].
This article shows that lesion caused by SARS-CoV-2 promotes a highly hypoxemic environment that induces the expression of cathepsins and furins which, in addition to their usual functions, also help in the viral replication of the coronavirus [16,25-27].
There is, in this process, a tendency to acidification of cell environment so that the functions of cathepsins and furins occur optimally. So, this justifies the difficulty in maintaining, in critically ill patients, an adequate pH in the blood gases and what happens is that, in the usual management of the severely ill patient COVID-19, the hypoxemic environment is allowed to be allowed, conduct called permissive hypercapnia [28].
This permissive hypercapnia has been allowed. Nevertheless, this article shows that this conduct must be proscribed. The critically ill patient should not remain with arterial blood gases showing acidosis due to elevated PCO2, allowing the cellular environment to remain acidified means allowing more cathepsins and Furins to be expressed, facilitating viral replication and dissemination, and enabling syncytium formation in lung cells. In other words, the syncytium formation process in lung cells shows that the hypoxemia of the disease intensified by the tendency of the cell medium to try to acidify so that cathepsin and furin act efficiently is how COVID-19 perpetuates viral replication forms syncytia that also help SARS-COV-2 in its infection and is the phenomenon that is presented to us to manage in critically ill patients. The acidosis presented by many intubated patients is very difficult to reverse, justifying the medical management of permissive hypercapnia. The problem with this approach is that we are permissive with something that keeps the virus in replication and dissemination, in addition to allowing a severe tendency to immunosuppression and tolerance in these critically ill patients, justifying opportunistic infections and providing a highly tumorigenic environment [29-31].
Permissive hypercapnia must be proscribed in patients COVID-19, and the patient should be managed with improved mechanical ventilation and the use of 8.4% sodium bicarbonate in order to adjust the pH to the most physiological possible so that expression induction of Cathepsins and Furins, as well as the maintenance of a medium with optimal pH to carry out their functions, are blocked [32,33].
This article shows the vital role of Methylprednisolone in attenuating the inflammatory manifestations promoted by SARS-CoV-2. More than this drug acting on classical inflammation pathways, corticosteroids seem to act on proteins that directly favour COVID-19 severity, that is, on furins and cathepsins [34].
The effect of Methylprednisolone (MTP), an anti-inflammatory drug, upon purified calpain and the Ca2+-mediated degradation of endogenous proteins of spinal cord homogenate in vitro has been examined. The activity of calpain purified from rabbit muscle was greatly inhibited in a dose-dependent fashion by MTP. Calpain-mediated degradation of myelin basic protein (MBP) was also inhibited by MTP and cathepsin B-mediated MBP breakdown. MTP acts as a proteinase (calpain) inhibitor and defines a new mechanism for its actions.
Cathepsin B-like activity was measured in lung secretions. The enzyme had a pH optimum of approximately 5.5 and had the characteristics of an alkaline-stable cysteine proteinase. Enzyme activity in the sputum from ten subjects with chronic bronchitis was significantly reduced after 5 days of treatment with prednisolone. A pharmacologic dose of Methylprednisolone (50 mg/kg) significantly delayed the subcellular redistribution of cathepsin D and the other hydrolases in the ischemic heart. Unlike untreated hearts, no evidence of enzyme diffusion from lysosomes could be demonstrated immunohistochemically in corticosteroid-treated ischemic hearts for over 45 min. This study demonstrates that corticosteroid pre-treatment does not prevent alterations in cardiac lysosomes during severe ischemia indefinitely, but it does significantly delay their development.
Cathepsins increased in cystic fibrosis and have a role in airway remodelling during fibrogenesis in pulmonary fibrosis. An association has led to the hypothesis that emphysema in subjects with normal serum alpha-antitrypsin concentrations arises as a result of an imbalance between the enzymes and inhibitors within the lung such that enzyme activity persists. The main serum and alveolar inhibitor of proteolytic enzymes are alpha-antitrypsin3, and severe deficiency of this protein is associated with the development of pulmonary emphysema. The sputum-to-serum concentration ratios of alpha-antichymotrypsin rose during corticosteroid treatment, and steroid treatment may increase protection against these proteolytic enzymes, which could benefit some patients, particularly those with recurrent bacterial infections [35,36].
Furin inhibits inflammatory responses in the myeloid cells by reducing the production of pro-inflammatory cytokines. The function of Furin in immunoregulation is not entirely clear, but its expression in immune cells is critical for the functional maturation of anti-inflammatory pro-TGF-β1 cytokine and the suppressive function of regulatory T cells.
Furin levels were significantly elevated in Peripheral Blood (PB) and Synovial Fluid in some Rheumatic Disorders. Mononuclear cells, T cells, and monocytes from Rheumatoid Arthritis patients compared to healthy controls had Furin levels significantly associated with the prevailing prednisolone treatment, higher prednisolone doses, and increased C-reactive protein levels and Health and with functional maturation of anti-inflammatory protransforming growth factor-β1 (pro-TGF-β1) cytokine and the suppressive function of regulatory T cell. Some cytokines as IL-1β, IL-2, IL-4, IL-6, IL-7, IL-10, IFN-γ, and TNF-α levels in plasma were correlated with Furin.
Recently a study showed differences in ACE2, TMPRSS2, and furin epithelial and airway gene expression are unlikely to confer enhanced COVID-19 pneumonia risk in patients with asthma across all treatment intensities and severity. ACE2 expression was inversely correlated with markers of type 2 immunity, with no influence of sex or use of nasal corticosteroids. The same article showed that segmental bronchial allergen challenge in adults with mild asthma led to decreases in ACE2 expression and that IL-13 reduces ACE2 expression on cultured bronchial epithelial cells. The data shows the importance of understanding the effects of TH2 and IL-17-driven inflammation, inhaled corticosteroids on airway epithelial cell ACE2 expression, and the susceptibility of these cells to infection and replication by SARS-CoV-2 [37,38].
This article highlights the importance of using corticosteroids in COVID-19, including pulse therapy. The use of corticosteroids deserves further clinical studies. However, in a situation in which we do not have specific medications, it is essential to show that corticosteroids have a fundamental role because they have nonspecific anti-inflammatory actions and can act in numerous ways, contributing to the improvement of the patient COVID-19 in moderate, severe and critical illness [39-41].
NAD/NADH+ and the warburg effect: Perhaps the placental buffering in SARS-CoV-2 infection (full text is in the Appendix)
Mitochondria are multifunctional organelles, and their primary role is in ATP generation by oxidative phosphorylation (OXPHOS) using substrates derived from β-oxidation and the tricarboxylic acid cycle, and are also involved in cell signalling via the production of reactive oxygen species (ROS). ROS are a normal by-product of OXPHOS but, when produced in excess, e.g., during disrupted oxygen (O2) or substrate supply, they can cause oxidative stress and damage DNA, lipids, and proteins [42-45].
Hypoxia is the main cause of foetal growth restriction at high altitudes and is a common feature of sea-level pregnancy complications. Some studies in rodents show that inhalation hypoxia adapts placental morphology and nutrient transport to the foetus depends upon the degree, timing, and length of O2 restriction by the low oxygen environment and that, even as oxygen becomes available, glycolysis would be preferred to oxidative phosphorylation. Since oxidative phosphorylation has a more significant potential to produce free radicals, supporting glycolysis may act as a protective mechanism in preventing teratogenesis in a tissue that is undergoing rapidly (Figure 6 and Figure 7).
The placenta is compared with tumours and other proliferating or developing cells, the rate of glucose uptake dramatically increases and lactate is produced, even in the presence of oxygen and fully functioning mitochondria [46,47]. This pathway, known as The Warburg Effect (Figure 5 and Figure 6), is the regeneration of NAD+ from NADH in the pyruvate to lactate step that completes aerobic glycolysis. In this scenario, NADH produced by glyceraldehyde phosphate dehydrogenase (GAPDH) must be consumed to regenerate NAD+ to keep glycolysis active. This high rate of glycolysis allows supply lines to remain open that can, for example, siphon 3-phosphoglycerate (3PG) to serine for one-carbon metabolism-mediated production of NADPH nucleotides. The Warburg Effect might support a metabolic environment that allows for rapid biosynthesis to support growth and proliferation [17,48,49].
A first publication based on observations of COVID-19 patients already indicated to us a possibility that the infection by SARS-CoV-2 is responsible for autoimmune and immunosuppressive events and for causing a tolerant and tumorigenic environment. Time has come to say that this idea is, unfortunately, something real and that COVID-19 also causes dysmetabolism due to the need for oxygen that is almost always, in severe cases, not overcome due to intense hypoxemia and lack of substrates for aerobic respiration to be appropriately performed. Furins, cathepsins, Tryptophan metabolism shifted from the hepatic enzyme TDO to the inflammatory IDO-1 are examples of the multiple pathways that affect inflammation and immunosuppression in COVID-19, pathways that go far beyond the internalisation of ACE-2 and its impact on the Renin-Angiotensin-Aldosterone pathway [30,50].
In general, we are beginning to understand why even asymptomatic or mildly symptomatic patients may present some persistent inflammatory aftermath or symptoms of hypertension and dysglycemia, in addition to psychiatric conditions, after the infection. The virus passed through the human body at some point (with high or low inoculum), and some modification, no matter how small, was caused. Multiple pathways are responsible for controlling inflammation, so there are many possibilities of sequelae after infection by SARS-CoV-2 because it acts on these vias.
The inflammation in COVID-19 is multicausal: Direct tissue injury or metabolic and molecular changes, the parasite-host relationship, viral inoculum, patient comorbidities, time of exposure to hypoxemia (for the most symptomatic cases) and autoimmune events induced by autoantibodies and immune complex formation.
TMITSy-CoV-2 is a viral aetiology syndrome caused by SARS-CoV-2, with variable spectrum due to the multiple pathways influencing its clinical presentation. These factors depend on 1) The specific points of intersection of each patient concerning their genetic factors and their comorbidities, especially those considered to have an inflammatory profile, 2) On viral mutations that can direct the different variants to one or the other route, preferentially and 3) The hypoxemic environment, whose intensity and time of exposure to this environment have a directly proportional impact on the magnitude of the Syndrome.
It is clinically characterised by:
a) Thrombosis due to multiple causes: cathepsins impacting factor VIII, adenosine and platelet activation, changes in the endothelial response due to changes in tryptophan metabolism and the action of IDO-1, vasospasm due to angiotensin and aldosterone, or autoimmune events (Takotsubo Syndrome and Takayasu's Arteritis). Catastrophic events usually occur at multiple sites [51-54].
b) Generalised lymphocytic apoptosis: generalised apoptosis by cathepsins, by the action of hypoxemia and Kynurenin products, inducing cell death of CD4+ cells, CD8+ cells, B cells and mainly natural killer cells (NK cells). This fact justifies the existence of cases with reactivation of latent infectious diseases [55-58].
- Rapid growth of neoplasms: the magnitude of the disease can cause intense lymphopenia; the SARS-CoV-2 infection causes a highly tumorigenic environment.
- Immunoparalysis with the sustained presence of recurrent bacteremias, most of them by dermatological and mainly intestinal translocation (which, as an inflammatory site, is the leading site of bacterial dissemination due to barrier break).
c) Variable eosinophilia dependent on adenosine and tryptophan metabolites, in addition to inflammatory stimulation by IL-6 [30,59,60].
d) Basophilia [61].
e) Neuropsychiatric manifestations due to alterations in tryptophan metabolism, due to the action of Kynurenine by-products and adenosine excess. It includes peripheral pain and difficulty in sedation [13,62,63].
f) Anemia due to the use of pyrrolic rings to build enzymes in the inflammatory pathways, to a decrease in serotonin in the bone marrow and general consumption of iron used for the metabolism of the intracellular airways [63-66].
Inflammation "de novo": Every time there is an increased need for oxygen supply, there is a stimulus for the inflammatory pathways of oxidative stress to be reactivated. This fact is real and reflects the high prevalence of the event "failure to extubate". Patients have worsening neurological and respiratory status, in addition to systemic repercussions with neutrophilia and generalized inflammation, causing bacterial translocation and refractory vasoplegic shock.
The extubation guidelines do not consider COVID-19 as a disease that presents different demands and as long as this disease is seen as an already known disease, we will be doomed to new inflammation and failures.
The relationship between SARS-CoV-2 and the pregnant woman deserves essential considerations.
Had it been thought that pregnant and postpartum women should be a risk group for severity, plenty of hospital admissions would happen. However, there were few admissions concerning pregnant women, as they usually present with no symptoms or oligosymptomatic, especially in early pregnancy; however, the embryo/foetus is not necessarily saved from suffering from SARS-CoV-2 infection.
Intriguingly, the closer to term, the more symptomatic the pregnant woman becomes due to coronavirus infection. Perhaps the common thinking has considered that, because the placenta naturally immunosuppresses pregnant women, the usual thing would be to be more susceptible to infections, which can reactivate latent viral diseases. However, COVID-19 has three distinct phases similar to other biphasic diseases such as yellow fever. COVID-19 has a viremic phase, followed by a period of defervescence, which may be the resolution of the disease or proceed to an immune-mediated inflammatory phase which, in the case of COVID-19, starts around 8 days after the patient perceives the first symptoms [2,67].
So far, there is no specific antiviral drug that is effective. Even in the face of many controversies, Corticosteroid is an essential [2,68] option in alleviating the symptoms caused by the cytokine storm, responsible for the period in which many orotracheal intubations occur (OTI), especially in people with predictors of severity (mainly obese, diabetic, and elderly) because they already have an inflammatory profile related to their comorbidities [40,69-71].
This article shows that the placenta plays a similar role to the Corticosteroids immunosuppressing the patient in COVID-19, reducing the magnitude of the inflammatory storm and its consequences. Thus, the treatment for a disease that progresses with inflammation - and being biphasic (second phase without viral presence) - is to perform immunosuppression. The placenta naturally immunosuppresses pregnant women.
The structural and molecular changes that trigger specific diseases in pregnancy are based on changes in the formation of blood vessels, changes in invasive waves and changes that promote premature placental ageing mediated by multiple pathways, but with oxidative stress being one of the most critical factors and determinants of molecular and biochemical changes leading to structural ones.
SARS-CoV-2 infection promotes alterations based on the magnification of hypoxia and, more directly, aggression to the vascular endothelium. These changes simulate or are superimposed on pre-existing conditions such as diseases such as HELLP Syndrome, preeclampsia and eclampsia [72]. Furthermore, oxidative stress promotes [46,73] an environment of insulin resistance and the internalisation of ACE-2, an environment that allows pregnant women to develop a hypertensive period (Figure 8, Figure 9, Figure 10, Figure 11, Figure 12 and Figure 13) [74-76].
Once the virus infects the human cell, there is a trace of the internalisation of ACE-2 and for each person. The time for this protein to be expressed again is variable and very individual.
The materno-foetal interface presents syncytial cells with many Furins and Cathepsins, molecules that act under acidic pH. SARS-CoV-2 needs these proteins to be able to perform better during the infection. Extreme hypoxia can lead to syncytium formation in pneumocytes II, as cathepsins and furins are induced by hypoxia. Perhaps this fact justifies the formation of syncytium in the lungs. This hypothesis raises an essential issue in the management of the COVID-19 patient, as there is permissiveness in the face of higher pCO2, conduct called permissive hypercapnia, however allowing the acidic and hypoxemic environment causes more cathepsins and furins to be expressed in a way that facilitates viral replication and protein processing. Based on this idea, the behaviour of permissive hypercapnia should be proscribed, and mechanical ventilation should be better managed, including the intravenous administration of 8.4% sodium bicarbonate, despite the current protocols.
COVID-19 provides a deficient cellular environment for aerobiosis. The internalisation of ACE-2 in enterocytes causes fewer amino acids to be absorbed, and among the most important for the proposed pathophysiology, we have Tryptophane (Try) and Phenylalanine (Phe). The Try deficit will cause a deficit of NAD/NADH+, of serotonin (5-HT) presenting a shift in metabolism for the production of Kynurenine and its derivatives, many of them toxic to the central nervous system, which explains the difficulty in sedating patients [77-79]. Try during inflammatory processes has been metabolised by IDO-1 [80-82], produced mainly by dendritic cells, macrophages and monocytes, mainly when stimulated by IFN-gamma. In physiological normality, Try is metabolised by the hepatic enzyme TDO. With the switch to IDO-1, the Kynurenine pathway is prioritised (Figure 14, Figure 15, Figure 16 and Figure 17).
Kynurenine has an immunosuppressive [83-85] role by acting on AhR receptors, promoting a tendency for lymphocytes to differentiate into Treg. Cathepsins and Furins also induce the tolerance pathway as well as promote apoptosis of lymphocytes. These facts explain much of what we see in patients who exhibit intense lymphopenia associated with the severity of hypoxia (Figure 18 and Figure 19).
Phe is a substrate for the formation of catecholamines; when Phe is in deficit, the chronic stress of COVID-19 can deplete catecholamine reserves and justify the difficulty in suspending the intravenous administration of norepinephrine in patients.
The production of Kynurenine and IDO-1 is altered so that in the first trimester, there is a tendency towards the formation of 5-HT involved in fetal development and blood vessels. By the action of IDO-1, the Try metabolism tends towards the KYN pathway, generating both protective and toxic metabolites to the Central Nervous System. During inflammatory processes, the preference for the KYN pathway is orchestrated to decrease inflammation, as KYN binds to AhR receptors, down-regulating IL-6 production by inhibiting two MyD88-dependent LPS signalling pathways (Figure 19 and Figure 20) [86-88].
Figure 20: Cerebral angiography: AVM and aneurysm are not determined and the right recurrent artery of Heubner is normal. View Figure 20As pregnancy progresses, the placenta loses its immunosuppressive strength and perhaps the increase in oxygen tension is an explanation for this phenomenon since hypoxia makes the environment more tolerant. Furthermore, the ageing process of the placenta tends to a natural increase in oxidative stress indicating that the pathways that activate inflammation are gradually increased as the placenta ages. Thus, in the third trimester and after 34 weeks, the pregnant woman is more symptomatic when the SARS-CoV-2 infection occurs during this period [88,89].
There are many cases of acute COVID-19 that start with psychiatric manifestations, especially depression. The deficit of 5-HT and dopamine can explain these changes due to low intestinal absorption, which can have repercussions in more intense puerperal melancholia [87,90,91].
Added to the 5-HT and dopamine deficits, cell damage due to intense hypoxia generates Adenosine as a product whose function is initially cellular protection, acting in an immunosuppressive way.
Hypoxia induces ATP release via ATP-binding cassette (ABC) transporters, pannexin 1 or connexins. Accumulated ATP can stimulate purinergic P2 receptors (P2XRs and P2YRs) or be further degraded to Adenosine by the sequential action of CD39 and CD73 ectonucleotidases. In situations of great metabolic stress, in this case, the magnitude of hypoxia produced in SARS-CoV-2 infection in a cellular medium depleted of NAD/NADH+ [58,92-94], requiring tissue lysis to guarantee amino acids for gluconeogenesis, Adenosine is produced in large quantities. It may reflect metabolic exhaustion in the face of cell damage. This article theorises that Adenosine [95-97] promotes bradycardia even in a febrile state, a fact known as the Faget's Sign (Figure 21 and Appendix). This phenomenon is also a known sign of other illnesses, for example, yellow fever. The tendency towards bradycardia is related to tissue hypoxia with implications for aerobic metabolism [98-101]. An electrocardiogram must be performed whenever a pregnant woman (or any patient) is admitted to the hospital. A baseline comparison is necessary to have a better assessment of the possible causes of bradycardia. Another essential role of Adenosine is to cause peripheral vasodilation, adding points for refractory shock COVID-19.
This article shows that exposure to hypoxia is linked to the magnitude of the patients' phenomena since cell responses tend towards tolerance. Patients with predictors of severity (T2DM, obese, elderly, heart diseases) gets immunosuppressed by SARS-CoV-2 and can rapidly induce tumour growth due to apoptosis of all lineages of lymphocytes. The activation of latent diseases of any infectious etiologies [102-104], which can, in pregnant women, cause secondary damage to the foetus, is a fact. Publications showing activation of the virus of the Herpesviridae family [105-107] in the face of lymphopenia in COVID-19 has not been rare [108-110]. Considering the role of neutrophils and the formation of immune complexes in COVID-19, tolerance also allows for autoimmune diseases.
In pregnant women, the placenta acts as a buffer by immunosuppressing the pregnant woman, preventing her from progressing to an inflammatory phase with intense symptoms. At the same time, pregnant women with T2DM and obesity are more symptomatic because they present placental changes that prevent them from performing adequate immunosuppression.
Soon after placental separation, postpartum women rapidly progress to respiratory failure (depending on comorbidities and the extent of pulmonary involvement). This phenomenon may occur because, without the placenta, the postpartum woman's homeostasis returns to the basal level. Inflammation occurs quickly and generates the cytokine storm that drives them to Acute Respiratory Distress Syndrome (ARDS). For this reason, it is necessary to perform a chest tomography immediately after placental separation (see guide in the Appendix).
Due to COVID-19 has a viral phase and another one almost (most cases) inflammatory exclusively, immunosuppression by the placenta is the natural treatment against cytokine storm.
T2DM or obese patients have a high chance of progressing to severe or critical forms of COVID-19, as they already have a comorbidity profile that stimulates inflammation. Even in early pregnancy, pregnant women with diabetes or obesity will be more symptomatic, as the metabolic pathways of the placenta are already altered, tending to premature ageing and more significant oxidative stress (Figure 22).
The placenta acts as a buffer against SARS-CoV-2 infection: 1) Immunosuppression prevents the pregnant woman from presenting symptoms resulting from an inflammatory storm, 2) The placenta is initially supported in an oxygen-poor environment, and its energy metabolism prioritises via an anaerobic route, a fact that can mitigate the effects of hypoxia caused by SARS-CoV-2, 3) The materno-foetal interface is a syncytium, a site that can be tropic for the coronavirus since this environment has high expression of cathepsins and furins; however, it is the place where maternal macrophages and neutrophils are stimulated to contain the infection. In this case, syncytium would have a protective role against SARS-CoV-2 infection, functioning as a trap.
Given the pandemic and, in the case of something that I had never seen before, a virus for which we do not have adequate treatment, the only solution was to study the virus-host relationships to establish better medical practices on an understanding of the pathophysiology involved in infection.
I am aware that all of these are hypotheses, but hypotheses based on observation of almost two years dealing with the clinical management of COVID-19 patients. I am fully convinced that tomorrow all this can change, as we are talking about science. The important thing is that we are not static in the face of the new. Our knowledge is limited, and we need to expand it to understand acute SARS-CoV-2 infection and the consequences of chronic inflammation that has a terrible impact on people's quality of life, a situation called "Long COVID-19". So far, the main approaches have a more palliative than curative bias. We are acting on the symptoms and not on the essence that causes the presented clinical phenomena. With that, we have a polymedication that often causes more problems in the patient's life than benefits.
Understanding the disease is the best way to know how to treat it.
-To Syomara Regina de Almeida, an Obstetrician with who I have the pleasure of sharing plenty of doubts facing the pregnant women that Syomara trusted me to follow-up considering each patient as unique in their individualities.
I had the obligation (with a grateful satisfaction) of studying deeply each pregnant woman to find options to offer facing the real life, considering my professional and human ethics.
-To Maria Luiza Benício. An Obstetrician and a friend of mine who believed in my opinion when I explained by phone, what I was thinking about COVID-19 and pregnancy relationship. It happened about 1 year ago.
-To All patients that allow me to grow up as a human being, as a physician, as a researcher. All this work has been developed to offer better choices when no other option has already been available.
-To the hospital do servidor público (public servants) in the state of São Paulo (HSPE). My eternal gratitude.
-To my friends, parents and family who supported me to continue, even in the face of storms: Be they cytokine storms or human storms.
-And to Andrea Lúcia Silva Ladeira de Almeida, clinical manager of the HSPE, for understanding that these studies have value not only for me, who grows with the doubts and with the search for solutions in the face of doubts, but that the most significant value is the outcome we can achieve for the COVID-19 patients when we understand that SARS-CoV-2 does not behave like a known virus.
Luiz Zanella: I wrote this article based on my nearly two years of clinical experience and studies focused on the management of the patient COVID-19. The experience and existing doubts in the management of pregnant patients originated both from consultations carried out at the HSPE and from outpatients for which I was appointed a specialist in infectious diseases to perform care in conjunction with the Obstetricians.
Miriane Marques: My friend and an Obstetrician who helped me searching for articles about pregnant women's pathophysiology.
This work does not require authorization and there is no identification of patients. There was no need for a consent form to this review according to the National Ethics Committee.
All data are available in the electronic medical record system of Hospital do Servidor Estadual (Sao Paulo-Brazil) and in the authors' research files.
The authors report on conflict of interest.
Luiz Gonzaga Francisco de Assis 'Barros D'Elia Zanella is a physician specialised in Infectious Diseases. I work fully in Public Health (SUS-Sistema Único de Saúde) in Brazil, providing private care in my own clinic. Also, I conduct clinical research at the "Hospital do Servidor Público do Estado de São Paulo (HSPE)". I have been dealing with COVID-19 patients in COVID-19 wards, Intensive Care Units, and I work with the training of medical residents. I have no conficts of interest and I do not have founds that.
Miriane Marques Borges is a Gynecologist and Obstetrician. She provides private care and to the Public Health System. She does not receive any funding that conflicts with the article's proposal.
This article did not receive funding from any kind of sources to be written.
The recent publication by Nóbrega-Cruz, et al. [74], favouring the idea that COVID-19 needs a different understanding of its pathophysiology, addresses the molecular relationships that lead pregnant women to be more symptomatic in the final stages of pregnancy. Adding to the ideas proposed in Nóbrega-Cruz, et al. this article shows changes in metabolic pathways by the action of SARS-Cov-2. Changes related to ACE-2 internalization associated with the cellular injury caused by SARS-CoV-2 triggering intense hypoxia indicate that the pathophysiology of COVID-19 needs reconsiderations every moment. COVID-19 is a new disease, and hypoxia has differences that make it something serious, whose management requires a different view concerning other diseases that course with respiratory severity. Together, the two articles highlight the need for clinical approaches to be modified for all COVID-19 patients. However, this article focuses on pregnant and postpartum women.
It is important to emphasize that the conduct of pregnant and postpartum women is necessarily Obstetric, a speciality focused on improvements in this area. My role, as an Infectious Diseases specialist, is to expose situations where I was involved by jointly conducting obstetric cases, which supplied me moments of learning and study.
It is essential to consider that pregnant and postpartum women need improvement in Clinical, Obstetrical, and Intensive Care management, which a joint inter-clinical specialities discussion is essential, adding ideas and knowledge facing a new disease makes possible to achieve better and targeted approaches for each patient.
From the contact with specialists in obstetrics, conducting patients at the Hospital do Servidor Público do Estado de São Paulo (HSPE), where I work as an Infectious disease specialist/emergency physician and intensive care physician helping in the care in COVID-19, I expose the result after studies triggered by the necessity of better management of COVID-19 pregnant women.
Due to this confidence in joint management, I nurtured an essential desire for a study to improve conduct based on understanding the virus-pregnant woman relationship.
The following key points summarize what I consider essential given the conditions that make the placenta the exceptional protection for pregnancy to come close to term (about 280 days or 40 weeks) during SARS-CoV-2 infection.
1. The placenta is an organ that provides the woman with immunosuppression due to vasculogenesis, which tends the microenvironment to tolerance so that the embryo is not recognised as not proper by the maternal immune system (Figure 1, Figure 2, Figure 3, Figure 4 and Appendix).
2. The tolerant microenvironment occurred by the action of cytokines that act systemically, providing the pregnant woman with a status of physiological immunosuppression. However, SARS-CoV-2 infection has handled saving women from symptoms in the early stages of pregnancy (until the end of the second trimester).
3. When the placenta is still a highly active organ, from the third trimester onwards, the placenta shows more intense and rapid ageing, the mechanisms that maintain immunosuppression are less and less intense, allowing the standard tools of inflammation to come back. The pregnant woman becomes more symptomatic in diseases that progress with inflammatory processes such as COVID-19. For this reason, the placenta is an organ that protects the pregnant woman during COVID-19, allowing a normal pregnancy when thrombosis in placental vessels does not occur during SARS-CoV-2 infection in the first trimester of pregnancy.
4. The placenta allows the woman to be a safe environment for the embryo and foetus, but the woman is more symptomatic in the third trimester and manifests symptoms linked to endothelial damage by SARS-CoV-2.
5. Symptoms related to endothelial damage caused by the coronavirus simulate classic diseases of pregnant women such as HELLP syndrome, preeclampsia, and eclampsia. The internalization of ACE-2 by the virus causes an increase in systemic blood pressure, simulating Gestational Diabetes mellitus (GDM). At the same time, the general metabolism has a hyperglycaemic environment, affecting GDM, in oxidative stress (Figure 1, Figure 2 and Figure 3) and aldosterone elevation. Placenta has mechanisms that can compensate the oxidative stress under normal hypoxia (Figure 8, Figure 9, Figure 10, Figure 11, Figure 12, Figure 13 and Figure 18) via The Warburg effect (Appendix).
6. Deficient tryptophan can generate significant symptoms of puerperal blues. Try replacement associated with Bupropion or Citalopram can bring good results to be studied in clinical protocols of specific and necessary clinical studies. So far, I only present hypotheses and experiences (Figure 2 and Figure 3).
7. The placenta produces tryptophan, an amino acid deficient in patients with SARS-CoV-2 infection of the gastrointestinal system, as ACE-2 absorbs it in enterocytes. Phenylalanine is also absorbed by ACE-2 in the intestines and becomes deficient in COVID-19. The lack of tryptophan promotes a more tolerant environment due to immunosuppression by lymphocyte apoptosis (via caspase, CD4+, CD8+, NK and B cells). Some latent infections can be reactivated due to lymphopenia, such as Herpes zoster, other viral diseases, in addition to mycobacteriosis, fungal diseases.
8. Lack of tryptophan (Try) and phenylalanine (Phe) has caused acute psychiatric symptoms and catecholamine deficiency.
9. The lack of vitamin B3 due to the shift to Kynurenine (via IDO1) promotes deficient cellular respiration, generating hypoxemia and adenosine in response to this environment of cellular aggression. However, all this pathophysiology is alleviated in pregnant women with the intraplacental production of Try and a hypoxemic buffering (Figure 5, Figure 6, Figure 7, Figure 8, Figure 13, Figure 14, Figure 15, Figure 16, Figure 17, Figure 18 and Figure 19).
10. When it is necessary to induce the delivery due to signs and symptoms of gestational diseases mimicked by SARS-CoV-2, the woman loses the organ that supported her as a marvellous shield to the foetus. There is, at this time, a considerable acute hormonal variation, in addition to the temporary organ loss that allows an infection in the third trimester to be sustained until the symptoms of gestational diseases reach the criteria for resolution of childbirth.
11. With the loss of the placenta, the woman progressively becomes symptomatic, and, in about 10 to 12 hours after the delivery, she can progress to respiratory failure with orotracheal intubation (in cases where infection occurred near this period).
12. Symptoms related to endothelial damage caused by the coronavirus mimic classical diseases of pregnant women such as HELLP syndrome, preeclampsia, and eclampsia. ACE-2 internalization by the virus causes an increase in systemic blood pressure, simulating GHD, and metabolic syndrome.
13. Furins and Cathepsins are present in large quantities in syncytiotrophoblast and act in the process of placental implantation (Figure 5). Usually, the expressions of these proteins are related to hypoxia in the environment. Thus, the hypoxia developed in COVID-19 can promote important changes in the invasive waves of the placenta, impacting the development of diseased pregnancies and foetal/embryo death. Perhaps the high expression of furins and cathepsins contribute to the process of "symptom buffering" of COVID-19 in pregnant women, associated with the fact that the placenta can meet metabolic needs due to the lack of tryptophan.
14. The uteroplacental location of Ang-(1-7) and ACE2 in pregnancy suggests an autocrine function of Ang-(1-7) in the vasoactive regulation that characterizes placentation and established pregnancy. ACE2 at the maternal–foetal interface a prerequisite for transplacental transmission. Strong and diffuse membranous staining of cytotrophoblast and syncytiotrophoblast (ST) cells of placental villi, as well as a membranous expression in extra villous trophoblast. ACE2 expression was detected in villous stroma, Hofbauer cells, or endothelial cells. TMPRSS2 expression was only present weakly in the villous endothelium and rarely in the ST.
15. In COVID-19 patients, endothelial activation has been shown to be associated with elevated circulating markers of coagulation (e.g., D-dimers) and inflammation (e.g., TNF-a, IL-6, IL-2, and MCP-1). COVID-19 patients usually present with elevated platelet numbers, highly increased fibrinogen and slightly prolonged prothrombin and activated partial thromboplastin time.
16. Placentas from pregnancies complicated with chorioamnionitis (ChA), exhibited increased expression of ACE2 mRNA. Placental ACE2 protein localized to syncytiotrophoblast, in foetal blood vessels and M1/M2 macrophage and neutrophils within the villous stroma. Increased numbers of M1 macrophage and neutrophils were present in the placenta of ChA pregnancies. Placentas from pregnant women with COVID-19 and uninfected neonates show significant variability in the spectrum of pathology findings. Placentas from infected maternal-neonatal dyads are characterized by the finding of mononuclear cell inflammation of the intervillous space, termed chronic histiocytic intervillositis, together with syncytiotrophoblast necrosis.
17. Perhaps because the infection induces greater expression of ACE-2, attenuating the effects of internalization of ACE-2 itself. The virus finds an environment rich in cathepsins and furins, and with syncytial cells ready, the placenta acts as a buffer for the adverse effects of SARS-CoV-2 infection. However, both the pregnant woman and the placenta are not exempt from suffering thrombotic events, or even the foetus is exempt from suffering an infection.
18. The fact that M1 macrophages express more ACE-2 and mediate an inflammatory response offers a break in the immunosuppression offered by the placenta, which can be harmful to the foetus, but which can be located in the ST region, allowing viral containment to this site.
19. Never belittle the unknown opponent. We don't know of his strength. For outpatient management, consider that any symptom with pain in the hypochondria and epigastrium should be considered an urgency, and obstetric ultrasonography is necessary. We had a patient with acute loss of amniotic fluid, which could be signs of low (lung base) pneumonia with referred ipsilateral abdominal pain. The guidance to go to the hospital in the face of signs and symptoms caused by a virus, whose pathophysiology is unknown, was crucial for the excellent evolution of the pregnant woman and the foetus (Figure 19, Figure 20, Figure 21 and Figure 22).
20. In summary, SARS-CoV-2 has a high performance to infect individuals of Homo sapiens, of any population, due to the presence of receptors that allow the infection to occur in different tissues. At the same time, the placenta offers specific mechanisms that favour protection for most pregnancies to generate viable foetuses.
The placenta buffers the effects of SARS-CoV-2 infection by:
a) Immunosuppression - acting as corticosteroids, inhibiting the exacerbated inflammatory phase.
b) Syncytiotrophoblast and trophoblast that "trap" the virus in an optimal environment, but that allows the action of macrophages and neutrophils that will act to eliminate the virus.
c) The anaerobic glycolytic pathway very preserved in the first months of pregnancy.
d) Perhaps due to the exchange of deficient substances resulting from the internalization of ACE-2, but which the placenta produces, attenuating the nutritional demands related to Tryptophan and Phenylalanine.