Multiomic characterisation of the long-term sequelae of SARS survivors: a clinical observational study, 2023, Li et al

[rvallee]

(SARS-1)

Multiomic characterisation of the long-term sequelae of SARS survivors: a clinical observational study
Open Access: https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00061-5/fulltext
Published: February 27, 2023
DOI: https://doi.org/10.1016/j.eclinm.2023.101884

Background
We aimed to characterise the long-term health outcomes of survivors of severe acute respiratory syndrome (SARS) and determine their recovery status and possible immunological basis.

Methods
We performed a clinical observational study on 14 health workers who survived SARS coronavirus infection between Apr 20, 2003 and Jun 6, 2003 in Haihe Hospital (Tianjin, China). Eighteen years after discharge, SARS survivors were interviewed using questionnaires on symptoms and quality of life, and received physical examination, laboratory tests, pulmonary function tests, arterial blood gas analysis, and chest imaging. Plasma samples were collected for metabolomic, proteomic, and single-cell transcriptomic analyses. The health outcomes were compared 18 and 12 years after discharge. Control individuals were also health workers from the same hospital but did not infect with SARS coronavirus.

Findings
Fatigue was the most common symptom in SARS survivors 18 years after discharge, with osteoporosis and necrosis of the femoral head being the main sequelae. The respiratory function and hip function scores of the SARS survivors were significantly lower than those of the controls. Physical and social functioning at 18 years was improved compared to that after 12 years but still worse than the controls. Emotional and mental health were fully recovered. Lung lesions on CT scans remained consistent at 18 years, especially in the right upper lobe and left lower lobe lesions. Plasma multiomics analysis indicated an abnormal metabolism of amino acids and lipids, promoted host defense immune responses to bacteria and external stimuli, B-cell activation, and enhanced cytotoxicity of CD8+ T cells but impaired antigen presentation capacity of CD4+ T cells.

Interpretation
Although health outcomes continued to improve, our study suggested that SARS survivors still suffered from physical fatigue, osteoporosis, and necrosis of the femoral head 18 years after discharge, possibly related to plasma metabolic disorders and immunological alterations.

Funding
This study was funded by the Tianjin Haihe Hospital Science and Technology Fund (HHYY-202012) and Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-063B, TJYXZDXK-067C).

 

[Hutan]

The report of osteoporosis and necrosis of the femoral head is, I think, the first I have seen related to bone health in people with ME/CFS. Is anybody else aware of any other reports related to this? The paper notes:

Osteoporosis and necrosis of the femoral head may result from host metabolic and immunological alterations, as well as high pulse administration of glucocorticoids.

So, it sounds as though a treatment regime specific to this group may be largely responsible. I suppose a reduction in weight bearing exercise and perhaps lower vitamin D due to not getting outside often might contribute to osteoporosis in some cases.

These survivors, during the acute SARS episode, received an average dose of 5167 mg methylprednisolone for an average of 35 days.

A one-off treatment of prednisone - is that likely to be enough to make a difference to later osteoporosis? There does seem to be a real difference (10/14 of cases with osteoporosis, only 1/14 controls.)

The median age was 61.0 (54, 69) years, and ten patients (71.4%) were women (Table 1). Two (15.4%) had a history of smoking. Eight (57.1%) survivors had hypertension and six (42.9%) survivors had type 2 diabetes. Fatigue was the most common symptom in SARS survivors (50%) and was significantly higher than that in the control group (7.1%) (p = 0.04).

The rates of type 2 diabetes seem very high at 6/14, but 3/14 of the controls also had it. Rates of coronary heart disease are more than double that of the controls (5/14 vs 2/14). Fatigue wasn't affecting everyone in the post-SARS group.

Of 31 SARS survivors, they say 10 refused follow-up visits and 7 could not complete assessments due to Covid restrictions, hence the 14 participants. It would be interesting to know the health status of the 10 who refused to participate. The sample is very small, so some things might just be chance findings.

 

[Hutan]

Metabolites

Most amino acid metabolic pathways, including tyrosine metabolism, arginine biosynthesis, lysine degradation, and arginine and proline metabolism, were upregulated in SARS survivors at 18 years after discharge compared to those in controls (Fig. 1B).

However, the lipid metabolic pathways, including metabolism of glycerophospholipid, sphingolipid, alpha-linolenic acid, linoleic acid, and arachidonic acid, were downregulated (Fig. 1B).

In particular, an increase in ornithine and a decrease in its product N-methylputrescine, an important component of the urea cycle, were observed in the plasma of SARS survivors at 18 years after discharge compared to those in controls (Fig. 1A and B). As ornithine is a metabolic biomarker of osteoporosis,
23 these data provide a possible explanation for osteoporosis as the most common complication of SARS survivors 18 years after infection. Because ornithine increases growth hormone levels and accelerates muscle tissue production, elevated plasma ornithine levels may be a restorative response to fatigue in these survivors.
24

FWIW in such a small sample with substantial co-morbidities

Upregulated : ornithine, N2-Methylguanine, L-Dopa, Glutaric acid, 3-nitrotyrosine, aspartyl glutamate,

Downregulated: Gluconolactone, stearoyl sphingomyelin, phosphorylcholine, N-(gamma-glutamyl)ethanolamine, N-methylputrescine, N-methylalanine,

 

[Mij]

https://www.frontiersin.org/articles/10.3389/fpsyg.2020.612366/full

Other Disorders
Chronic Fatigue
Chronic fatigue syndrome (CFS) is a complex neurological disorder associated with persistent, overwhelming fatigue that affects > 3% of the population in Western countries and is more prevalent in women (Griffith and Zarrouf, 2008). Diagnostic criteria include severe, persistent fatigue for at least 6 months, exclusion of other medical disorders, and observation of at least four minor symptoms, including impaired memory, nausea, extreme post-exertion fatigue, headaches, muscle pain, sore throat, and poor sleep (Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome et al., 2015). There remains a lack of treatment and diagnostics tools for CFS, although glucocorticoids have been used (McKenzie et al., 2000). Bone loss and increased fracture risk have been reported in individuals with CFS, independent of glucocorticoid use. Hoskin et al. found that hip BMD was approximately 7% lower in women with CFS (Hoskin et al., 2006). A prospective study reported a 1.16-fold increased risk of fracture in the CFS cohort without osteoporosis compared to the non-CFS cohort (Chen C.-S. et al., 2014). However, no mechanistic insights were provided in these studies. Other studies have reported that IGF-1 levels are altered in CFS patients (Buchwald et al., 1996; Berwaerts et al., 1998; Cleare et al., 2000; Nijs et al., 2003). IGF-1 is essential for osteoblast proliferation, thus impaired secretion could lead to bone loss. Studies are needed to further characterize those CFS patients with low serum IGF-1 to determine if these subgroups have increased fracture risk compared to CFS patients with normal or high levels of IGF-1. High prevalence of mycoplasma infections has also been reported in CFS patients (Choppa et al., 1998; Nasralla et al., 1999), which can stimulate macrophage activation and release of pro-inflammatory cytokines that enhance osteoclast activity. M. fermentans has been shown to produce 2-kDa macrophage-activating lipopeptide (MALP-2), which stimulates macrophages and bone resorption in a dose-dependent manner and is increased with CFS (Piec et al., 1999). Thus, chronic fatigue may induce bone loss or increase fracture risk through increased inflammation and/or dysregulation of growth factors.

 

[Hutan]

Proteomics

Thirty-two differentially expressed proteins (DEPs) were identified between SARS survivors at 18 years after discharge and controls, including 22 up-regulated and 10 down-regulated proteins

There were no significant enrichments in GO analysis based on the downregulated DEPs. However, the GO terms of upregulated DEP enrichment were classified into eight types of biological processes (BPs). B cell activation and humoral immune response-related BP types, including “Phagocytosis”, “Complement activation”, “B cell activation and immunoglobin-mediated humoral immune response”, “Immune effector process” and “Lymphocyte activation”, were annotated in the functional classification of GO enrichments of upregulated DEPs (Fig. 2B). Similarly, the levels of immunoglobulin heavy variable (IGH) IGHV1-2 (p = 0.037), IGHV2-26 (p = 0.037), IGHV3-64D (p = 0.0046), IGHV4OR15-8 (p = 0.0029), and IGHV5-10-1 (p = 0.037) were elevated in SARS survivors at 18 years after discharge compared to that in controls (Fig. 2C), suggesting that B cell activation and immunoglobin-mediated humoral immune responses remain in SARS survivors at 18 years after discharge.

It was tempting to go through the 32 proteins, finding out what each one does. But, I think we would need to have the data run for just the people reporting fatigue, and that's just 7/14 people, so the sample would be very small indeed.