COVID-19 survivors are at higher risk of post-acute sequelae involving pulmonary and several extrapulmonary organ systems

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COVID-19 survivors are at higher risk of post-acute sequelae involving pulmonary and several extrapulmonary organ systems — generally referred to as long COVID. However, a detailed assessment of kidney outcomes in long COVID is not yet available.

Here we show that beyond the acute phase of illness, 30-day survivors of COVID-19 exhibited higher risks of AKI, eGFR decline, ESKD, major adverse kidney events (MAKE), as well as steeper longitudinal decline in eGFR.

The risks of kidney outcomes increased according to the severity of the acute infection (categorized by care setting into non-hospitalized, hospitalized, and admitted to intensive care).

The findings provide insight into the long-term consequences of COVID-19 on kidney outcomes and suggest that post-acute COVID-19 care should include attention to kidney function and disease.

Discussion:

In this work, we characterize post-acute kidney outcomes in a cohort of 89,216 30-day survivors of COVID-19. The results show that beyond the fir

st 30 days of infection, COVID-19 survivors exhibited increased risk (and burden) of AKI, eGFR decline, ESKD, and MAKE. The risks (and burdens) of kidney outcomes increased according to the severity of the acute infection. While AKI during the acute phase contributed to the increased risk of post-acute kidney outcomes, our analyses also suggest that increased risk of post-acute kidney

outcomes was evident even among those who did not experience AKI in the acute phase. Examination of intra- individual longitudinal change in eGFR suggested that COVID-19 survivors experienced greater loss of eGFR than non-infected controls and that eGFR loss was more profound as the severity of the acute COVID-19 infection increased.

Taken together, these results suggest that beyond the acute phase of COVID-19 infection, people with COVID-19 experience higher risk adverse kidney outcomes. Post-acute care of people with COVID-19 should involve attention and care for acute and chronic kidney disease.

The implications of our findings are clear. Given the large number of people infected with COVID-19 (>34 million people in the US, and > 193 million globally), and given that estimates by the World Health Organization suggest that 10% of people infected with COVID-19 may experience post-acute sequelae, the numbers of people with long COVID in need of post COVID care will likely be staggering and will present substantial strain on already overwhelmed health systems.

Governments and health systems around the world are establishing post-acute COVID clinics to attend to the needs of people with post-acute COVID sequelae.

The optimal composition of those clinics is not yet clear. The higher risks of adverse kidney outcomes reported in this study highlights the need for integration of kidney care as a component of the multidisciplinary post-acute COVID care. Our estimates of burden of kidney sequelae may also be useful to inform capacity planning.

While our analyses suggest that AKI during the acute phase contributes to the increased risk of post-acute kidney outcomes (in that the risk of post-acute kidney outcomes was higher in those hospitalized with an AKI than those hospitalized without an AKI during the acute phase of the infection), it is also evident that the risk was increased in those who did not experience an AKI during the acute phase.

Furthermore, our analyses of risks and burdens of post-acute kidney outcomes by care setting of the acute infection highlight two key messages: (1) that the risk and associated burden of post-acute kidney outcomes was evident even among individuals whose acute disease was not severe enough to necessitate hospitalization (this will likely have broad implications because this group represents the majority of people with COVID-19) and (2) that the risk

and associated burden increased across the severity spectrum of the acute COVID-19 infection (from non- hospitalized to hospitalized individuals, to those admitted to intensive care).

The mechanism or mechanisms of increased risk of acute kidney injury, eGFR decline, ESKD, and MAKE in the post-acute phase of COVID-19 infection are not clear. While initial observations suggested that SARS- CoV-2 may have kidney tropism, more recent evidence does not endorse the earlier assessment(31).

Other potential explanations include dysregulated immune response or autoimmunity, persistent inflammation, disturbances in endothelial function and the coagulation system, and disturbances in the autonomic nervous system. Mechanisms related to changes in the broader economic and social conditions in the context of the global pandemic that may have differentially impacted people with COVID-19 may be also at play(32-38).

A deeper understanding of the mechanistic and epidemiologic drivers of the post-acute kidney sequelae of SARS-CoV-2 infection (and more broadly the entire spectrum of post-acute sequelae of SARS-CoV-2) is urgently needed to help inform care strategies.

This study has several strengths. To build our cohort, we capitalized on the breadth and depth of the electronic health databases of the US Department of Veterans Affairs which operates the largest nationally integrated healthcare delivery system in the US. We broadened our covariate specification approach to include a set of 29 predefined variables selected based on prior evidence as well as 100 algorithmically selected variables from several VA high dimensional data domains including diagnostic codes, prescription records, and laboratory test results.

We evaluated several kidney outcomes including AKI, eGFR decline, the terminal endpoint of ESKD, as well assessing intra-individual longitudinal changes in eGFR. Our outcomes (for AKI, eGFR decline, and longitudinal eGFR changes) were defined based on laboratory values rather than relying on ICD codes.

We tested for potential presence of spurious biases by applying positive and negative outcome controls. We not only provided estimates of risks on the ratio scale (hazard ratios), but also reported estimates of excess burden per 1000 persons due to COVID-19 on the absolute scale; this measure additionally reflects

the contribution of baseline risk and provides a useful estimate of potential harm and would be more easily understood by a broader public than relative risk (e.g. hazard ratio).

This study has several limitations. The demographic and health characteristics of our VA cohort (older white males) may limit generalizability of the findings. Although we adjusted (through weighting) for both predefined and algorithmically selected high dimensional covariates, and although covariate balance assessment suggested small standardized mean differences even in the covariates that were not directly included in the propensity score model, residual confounding may not be completely ruled out. Our datasets did not include individual data on urine measures for incorporation in AKI definitions.

Although we provide estimates of risk and excess burden by intensity of care during the acute phase of the disease (non-hospitalized, hospitalized, and admitted to intensive care), our analyses did not adjust for other markers of severity within these categories.

Finally, as the pandemic continues to evolve, as the impact of vaccinations and new variants (e.g. delta variant) is realized, as long-term follow-up of COVID-19 survivors extends, and as treatment strategies of the acute disease improves, it is possible that the epidemiology of post-acute COVID-19 kidney outcomes will change as time progresses.

In sum, we show that 30-survivors of COVID-19 exhibited higher risk of AKI, eGFR decline, ESKD, and MAKE than those not infected by COVID-19. Greater longitudinal eGFR loss was observed in COVID-19 survivors (compared to non-infected controls). The risk of adverse kidney outcomes increased according to the severity of the acute infection as proxied by the care setting (non-hospitalized, hospitalized, and admitted to intensive care).

The totality of the evidence suggests that substantial risk of kidney outcomes in people with COVID-19 and highlights the need to integrate a kidney care component in post-acute COVID care pathways.

reference link https://jasn.asnjournals.org/content/early/2021/08/25/ASN.2021060734


With the corona virus disease 2019 (COVID-19) still looming large, it is becoming increasingly evident that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is accountable for previously unexpected long-term health consequences. Unlike originally thought, the novel SARS-CoV-2 virus affects not just the lungs but multiple organ systems, including heart, brain, liver, kidneys and gastrointestinal tract.

While the majority of patients are either asymptomatic or present with mild disease that recovers within a couple of weeks, some patients with severe disease require hospitalization and intensive care with associated mortality. At the same time, clinicians are increasingly seeing cases of those who exhibit chronic, diverse and ongoing disease symptoms even after their initial recovery from viral infection.

Critical illnesses are known to be causally associated with longer-term outcomes. Likewise, chronic cases of COVID-19, especially those with lingering disease collectively termed as “long-haulers”, are re-defining the whole COVID-19 pandemic.

A wide array of names is used to refer to this subset of COVID-19 survivors, including long COVID, chronic COVID, post-acute COVID syndrome, post-acute COVID-19, long-term effects of COVID, long-haul COVID, late sequelae, as well as the research terminology post-acute sequalae of COVID-19 or SARS-COV-2 infection (1).

A sizeable subset of COVID-19 patients continues to experience chronic persistent symptoms even after recovery from acute infection, such as extreme fatigue, shortness of breath, joint pains, brain fogs and mood swings (2–4). These symptoms persist beyond the acute presentation of the disease and appear to be independent of disease severity (Figure 1).

These long-haulers present with a disease portrait distinct from the typical acute COVID-19 disease. They broadly represent patients who have failed to return to their baseline health post-acute COVID-19 infection.

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Figure 1
Development of post-acute sequelae of COVID-19 (PASC). This figure illustrates the development of PASC with time across the spectrum of severities presented by COVID-19. DM, diabetes mellitus; HTN, hypertension; IHD, ischemic heart disease; COPD, chronic obstructive pulmonary disease; CKD, chronic kidney disease.

The chronic symptoms in these patients are suggestive of ongoing pathophysiological processes post-COVID-19 infection. Besides the virus itself, the immune response to SARS-CoV-2 could be held responsible for the appearance of these lasting symptoms, possibly through triggering an ongoing inflammatory process (Figure 1).

The diverse symptomatic manifestations of post-acute COVID-19, the potential underlying immunopathological mechanisms and evidence of multi-organ clinical sequelae of COVID-19 will be discussed in this review.

Manifestation of Symptoms in Post-Acute Sequelae of COVID-19

Patients with post-acute sequalae of COVID-19 (PASC) develop significant limitations in activities of daily living (ADLs) such as walking, bathing, or dressing with multi-factorial causes of this functional decline (18). This physical weakness can be attributed to myopathy, neuropathy, cardio-respiratory impairments, cognitive impairment, or a combination of these conditions.

COVID-19 long-haulers thus, show multiple diverse symptoms affecting different parts of the body, such as nausea, extreme fatigue, dyspnea or shortness of breath, cough, chest pain, brain fog, short-term memory loss, palpitations, excessive bruising, joint pain, light and sound sensitivity, coagulation, neurological, gastrointestinal and gynecological problems (3, 19). These lingering chronic symptoms reflect damage across multiple organs.

A recent study that investigated the long-term health consequences of COVID-19 in patients discharged from hospital found fatigue or muscle weakness in 63%, sleep difficulties in 26%, and anxiety or depression in 23% of the cohort (10). In this study, the patients with severities during their hospital stay demonstrated more severe impaired pulmonary diffusion capacities and abnormal chest imaging manifestations.

Additionally, dermatological manifestations in PASC included papulosquamous eruptions, in particular pernio- or chilblain-like lesions (20). Neurological manifestations, such as impaired consciousness, acute cerebrovascular diseases and skeletal muscle injury, were demonstrated in COVID-19 patients with more severe infection (21). In addition to posing as risk factors for the disease itself, factors such as age, frailty and presence of comorbidities, they also modulate the long-term impact of the disease.

Interestingly, similar observations of long-term sequelae has been reported following the SARS-CoV-1 outbreak of 2003 (22), and Middle East Respiratory Syndrome (MERS) outbreak of 2012 as well (23). The survivors from the previous two CoV epidemics were found to experience persistent shortness of breath, fatigue, mental health problems and reduced quality of life that constituted a kind of post-acute viral syndrome (23).

A one-year follow-up study of SARS survivors reported a significant reduction in mental health (24). Another 15-year follow-up study showed partially reversible femoral head necrosis, pulmonary interstitial damage and associated functional decline that remained stable after an initial improvement in SARS patients (25). In addition, chronic widespread musculoskeletal pain, persistent fatigue, weakness, depression and disordered sleep characterized chronic post-SARS syndrome (26).

These characteristic symptoms overlapped with those observed in chronic fatigue syndrome and fibromyalgia syndrome (26). Similarly, MERS survivors reported reduced overall quality of life and quality of physical health at approximately 14 months of follow-up (27). As seen with SARS survivors, high levels of chronic fatigue symptoms and psychiatric disorders, including post-traumatic stress disorder (PTSD), anxiety, and depression, were noted at one-year follow-up of MERS patients (28).

Intriguingly, similar findings were also observed among non-CoV-related ARDS survivors (29) and in those who required critical care (30). These post-acute variants of COVID-19, SARS and MERS thus show similarities to other illnesses, such as chronic fatigue syndrome (myalgic encephalomyelitis), sepsis and dysautonomia.

Collectively, dyspnea, fatigue, sleep disorders and psychological issues, including anxiety, depression, PTSD and concentration problems, constituted the most commonly reported persistent symptoms across majority of the COVID-19 study participants at follow-up.

These clinical manifestations of PASC could be a result of viral invasion directly into the tissues possibly facilitated by its receptor angiotensin-converting enzyme 2 (ACE2) expression, immune system dysregulation, hyperinflammation and cytokine storm syndrome, immune-mediated multi-system damage, maladaptation of ACE2-related pathways, endothelial damage and microvascular injury, hypercoagulable states associated with COVID-19, critical care-associated sequelae or a combination of these (31, 32).

Since dysregulation of immune response is central to the etiopathogenesis of the acute phase of COVID-19, we hypothesize possible immunopathological mechanisms that may contribute to the pathophysiology of post-acute sequelae of COVID-19.

Potential Immunopathological Mechanisms Underlying Post-Acute Sequelae of COVID-19

Aberrant cellular or humoral immune responses are believed to be the primary culprit responsible for the lasting symptoms associated with PASC. Herein, we summarize several hypotheses backed by literature to explain the long-term outcomes of COVID-19 infection (Figure 2):

a) COVID-19 survivors with persistent symptoms may harbor the virus in several potential tissue reservoirs across the body, which may not be identified by nasopharyngeal swabs,

b) delayed viral clearance due to immune exhaustion resulting in chronic inflammation and impaired tissue repair,

c) cross reactivity of SARS-CoV-2-specific antibodies with host proteins resulting in autoimmunity,

d) mitochondrial dysfunction and impaired immunometabolism,

e) alterations in microbiome, and

f) imbalance in renin-angiotensin system leading to the long-term health consequences of COVID-19.

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Figure 2
Potential immunopathological mechanims underlying multi-organ sequelae of post-acute sequelae of COVID-19 (PASC).

Hidden Viral Reservoirs & Non-Infectious Viral Fragments

The lingering disease symptoms post viral infection may relate to the significant molecular and cellular damage caused by the virus. This widespread damage in turn can be due to the wide distribution pattern of ACE2 (33), the cellular entry receptor for SARS-CoV-2 (34), and to the indirect effects of the inflammatory mediators triggered by the virus. One study provided evidence for the persistence of residual virus in the lungs, suggesting the likelihood of SARS-CoV-2 virus to cause lasting lung damage (35).

Although SARS-CoV-2 preferentially infects the respiratory tract (36), the broad organotropism of this virus is fast emerging. For instance, one autopsy study of 22 COVID-19 patients detected viral presence in multiple organs, including the heart, brain, liver, kidneys and blood, in addition to the respiratory system (33).

In another study of 14 asymptomatic patients that underwent small intestinal biopsies 4 months after COVID-19 onset, persistent SARS-CoV-2 was detected in half of them (37). As such, several studies have shown the presence of gastrointestinal reservoirs of infectivity post viral infection (37–39). Human body fluids, including bronchoalveolar lavage, sputum, saliva, blood, urine, feces, tears, and semen, from organs expressing the ACE2 receptor may also harbor the virus (40, 41).

This multiorgan tropism is a potential explanation for the lingering long-term symptoms of COVID-19, where the virus or viral fragments could hide in reservoirs beyond the respiratory tract and hence go undetected in a nasal swab test. Another evidence in support of the reservoir theory is the observation of long-term SARS-CoV-2 viral shedding among COVID-19 patients, which extended over 3 months in some patients (42, 43).

This viral persistence could then trigger chronic inflammation which may underlie the chronic COVID-19 symptoms. A similar pattern has been observed in chronic viral arthritis caused by the chikungunya virus (44), where viral RNA was found to persist in myofibers, dermal and muscle fibroblasts resulting in chronic musculoskeletal pain months to years post the initial acute infection (45).

Additionally, there also exists the possibility that these reservoirs could be established in immune-privileged sites that are less accessible to the immune system such as the eye, testes, placenta, brain and central nervous system, resulting in festering infection (46). Several SARS-CoV-2 proteins have high homology with similar proteins of SARS-CoV-1 virus (47), which have been shown to play a role in evasion of the immune system (48).The viral organ reservoirs could thus go unnoticed possibly leading to the establishment of a chronic disease state.

A recent study also hinted at an unexpected hiding spot for fragments of SARS-CoV-2 genetic material within human chromosomes (49). Chimeric transcripts comprising of viral sequences fused to cellular sequences were detected in published data sets of SARS-CoV-2-infected cultured cells and patient-derived tissues.

The possibility of SARS-CoV-2 retro-integration into human cellular genome and subsequent transcription of these integrated viral sequences was demonstrated in this study. This may explain SARS-CoV-2 PCR positivity in COVID-19 survivors in the absence of true infection.

SARS-CoV-2 re-infection in COVID-19 patients is another matter of emerging concern (50). SARS-CoV-2 being a novel coronavirus, the duration of protective immunity to re-infection is largely uncertain (51). To add to this, the genetic makeup of the re-infected viral strain was found to be divergent from the original one (52) and re-infection could be associated with more severe outcomes (53).

The original virus hiding away in tissues and undergoing mutations could offer a potential explanation by leading to a viral strain with a different genetic background. This different strain could be responsible for re-infection or rather a reactivation of the pre-existing virus, as observed in the case of human immunodeficiency virus (HIV) (54, 55).

The residual low level of virus may be responsible for at least some of the clinical manifestations of PASC, such as the persistent loss of smell and taste (55). Viral persistence and its associated genetic mutations are capable of provoking anti-viral “antibody waves” leading to immune exhaustion which may further explain SARS-CoV-2 re-infections.

reference link :https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278217/

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