Hypocortisolism in survivors of severe acute respiratory syndrome (SARS), 2005. Khee Shing-Leow et al

[Hutan]

Publication date: 2005

https://pmc.ncbi.nlm.nih.gov/articles/pmid/16060914/
Summary
Objective
Following the severe acute respiratory syndrome (SARS) outbreak, many survivors were observed to suffer from psychosomatic symptoms reminiscent of various endocrine disorders. Hence, we sought to determine the existence of any chronic endocrine sequelae in SARS survivors.

Design, patients, measurements
Sixty-one survivors of SARS prospectively recruited were analysed for hormonal derangements 3 months following recovery. Patients with pre-existing endocrine disorders were excluded. Any endocrine abnormalities diagnosed were investigated and treated where indicated up to a year. Serial evaluation facilitated characterization of trends and prognostication of any endocrinological aberrations.

Results
Twenty-four (39·3%) patients had evidence of hypocortisolism. The hypothalamic–pituitary–adrenal (HPA) axis dysfunction of the majority resolved within a year. Two (3·3%) of the hypocortisolic cohort had transient subclinical thyrotoxicosis. Four (6·7%) were biochemically hypothyroid, being comprised of three with central hypothyroidism and one with primary hypothyroidism. Two of the three with central hypothyroidism had concomitant central hypocortisolism. Eight had subnormal DHEAS levels.

Conclusions
These preliminary findings highlight a possible aetiologic role of SARS-associated coronavirus in causing a reversible hypophysitis or direct hypothalamic effect, with the HPA axis affected more frequently than the HPT axis.

 

[Hutan]

I've put this thread in Long Covid research, although it relates to the SARS-CoV-1 outbreak in Singapore, not the latest Corona virus.
This paper has been cited as evidence of hypocortisolism in survivors of SARS-CoV infections.

There were 238 people infected with SARS and 33 of them died. People with pre-existing endocrine disorders were excluded form this study. They studied 6 1 survivors. 8 of the participants had had severe SARS and had been in ICU.

Twenty-four-hour urinary free cortisol (UFC) was done to assess integrated cortisol secretion. Subjects with serum cortisol below 275 nmol/l as cut-off underwent dynamic HPA axis evaluation using low dose (1 µg), short Synacthen (ACTH-1-24) test (SST). Subjects with 0800 h serum cortisol below 138 nmol/l and/or poststimulation serum cortisol under 550 nmol/l at 30 min were deemed hypocortisolic. SST assessment for HPA axis recovery was repeated at about three to six monthly intervals. Although the study was terminated at 1 year, reviews were extended for those with persistent hypocortisolism as medically appropriate. Symptomatic patients with orthostatic hypotension were prescribed physiological doses of hydrocortisone replacement until their SST normalized.

Twenty-four (39·3%) patients had hypocortisolism, of which 20 (83·3%) had unequivocal central hypocortisolism as evidenced by concomitant low or inappropriately normal ACTH levels (Table 2).

Four (16·7%) had hypocortisolism associated with plasma ACTH above the upper reference limit of 11 pmol/l (50 pg/ml). Although this may superficially suggest primary hypocortisolism, the levels of ACTH were not elevated sufficiently to be diagnostic of primary hypocortisolism. In the absence of renin–aldosterone data and overt addisonian crisis, primary adrenal insufficiency was most unlikely, whereas secondary hypocortisolism appear to be the main form of HPA axis dysfunction encountered here. Indeed, the raised ACTH may in fact be a reflection of a recovering HPA axis following steroid-induced suppression. Among these four patients, one who was given systemic steroids during SARS was probably a case of central hypocortisolism rather than primary hypocortisolism, being recruited at a time when the hypothalamo-pituitary unit was recovering from transient HPA axis suppression, while the other three with elevated ACTH who had no steroids exposure during SARS or prior to SARS could arguably be cases of SARS-induced central hypocortisolism showing evidence of early hypothalamo-pituitary recovery rather than primary adrenal insufficiency.

There's a bit to unpick there.

24 of the 61 patients are reported as having hypocortolism.

10 of the patients had been given corticosteroids during their acute care and the authors note that some of the cases are likely to be a result of steroid-induced suppression.

It is possible that some of the patients had an underlying issue before becoming unwell (perhaps it made them more susceptible to infection), and that it is just the subsequent investigations that have identified it.

There's also the possibility that the illness has perturbed hormone systems.

 

[Hutan]

Because the treatment protocol for critically ill SARS patients managed in the ICU included the use of high-dose systemic glucocorticoids, HPA axis suppression as a cause of central hypocortisolism from exogenous steroid exposure remains a possibility. Of the 24 patients with hypocortisolism, six received systemic glucocorticoids during SARS while one was an asthmatic on inhaled corticosteroids. Among the six patients treated with systemic glucocorticoids, three were on prednisolone up to a dose of 60 mg given for 2–5 days; the other three patients had intravenous methylprednisolone 200 mg for 3 days, followed by hydrocortisone 100 mg 8 hourly for about a week before being switched to oral prednisolone tapered over 10 days. Notably, the majority (18 patients) of those with hypocortisolism were glucocorticoid naïve. Four of six patients treated with high-dose parenteral glucocorticoids who escaped hypocortisolism post-SARS demonstrated the lack of prolonged suppression on the HPA axis with the corticosteroid regimen and doses utilized.

Six of the 24 patients termed as having hypocortolism were given systemic glucocorticoids during the SARS infection and one was taking inhaled corticosteroids for asthma.

 

[Hutan]

Hopefully, I can have a look at this a bit more tomorrow. I note though that a significant proportion of the patients with a normal 'HPA axis' reported fatigue and orthostatic issues:

only 37·8% (14/37) of those with normal HPA axis compared with 87·5% (21/24) of those with impaired HPA axis volunteered having experienced fatigue and/or orthostatic dizziness at the point of recruitment.

 

[SNT Gatchaman]

I'll add these technical references to this thread —

Advances in wearable electrochemical antibody-based sensors for cortisol sensing (2023)
Khumngern, Suntisak; Jeerapan, Itthipon

Cortisol is a crucial hormone involving many physiological processes. Hence, cortisol detection is essential.

This review highlights the key progress made on wearable electrochemical sensors using antibodies. It covers the design, principle, and electroanalytical methodology for detecting cortisol noninvasively. This article also analyzes and collects the analytical performances of electrochemical cortisol sensors. The development of these sensors continues to face challenges such as biofouling, sample management, sensitivity, flexibility, stability, and recognition layer performance. It is also necessary to develop a sensitive electrode and material.

This article also presents potential strategies for designing antibody electrodes and provides examples of sensing systems. Additionally, it discusses the challenges in translating research into practical applications.

Link | PDF (Analytical and Bioanalytical Chemistry)


Portable biosensor for monitoring cortisol in low-volume perspired human sweat (2017)
Kinnamon, David; Ghanta, Ramesh; Lin, Kai-Chun; Muthukumar, Sriram; Prasad, Shalini

A non-faradaic label-free cortisol biosensor was demonstrated using MoS2 nanosheets integrated into a nanoporous flexible electrode system. Low volume (1–5 μL) sensing was achieved through use of a novel sensor stack design comprised of vertically aligned metal electrodes confining semi-conductive MoS2 nanosheets. The MoS2 nanosheets were surface functionalized with cortisol antibodies towards developing an affinity biosensor specific to the physiological relevant range of cortisol (8.16 to 141.7 ng/mL) in perspired human sweat. Sensing was achieved by measuring impedance changes associated with cortisol binding along the MoS2 nanosheet interface using electrochemical impedance spectroscopy. The sensor demonstrated a dynamic range from 1–500 ng/mL with a limit of detection of 1 ng/mL. A specificity study was conducted using a metabolite expressed in human sweat, Ethyl Glucuronide. Continuous dosing studies were performed during which the sensor was able to discriminate between four cortisol concentration ranges (0.5, 5, 50, 500 ng/mL) for a 3+ hour duration. Translatability of the sensor was shown with a portable form factor device, demonstrating a comparable dynamic range and limit of detection for the sensor. The device demonstrated a R2 correlation value of 0.998 when comparing measurements to the reported impedance values of the benchtop instrumentation.

Link | PDF (Nature Scientific Reports)

 

[Hutan]

Ever since Singapore was stricken in March 2003 with severe acute respiratory syndrome (SARS), it became apparent that many survivors experienced chronic pulmonary morbidities and a multitude of psychosomatic manifestations.

We hypothesize that an endocrinological basis could account for some of these extrapulmonary symptoms due to their resemblance to various hormonal and metabolic disorders that frequently feature nonspecific symptomatology. 1 Studies have linked aberrations in the hypothalamic–pituitary–adrenal (HPA) axis to psychiatric conditions. 2Moreover, correlations of hypothalamo–pituitary–thyroid (HPT) axis dysfunction with certain psychosomatic syndromes have been described. 3

I'm not sure if the authors understood 'psychosomatic' in the same way that I do. If an endocrinological basis resulting from a disease process accounts for psychosomatic manifestations, are they really psychosomatic manifestations? It all gets quite circular, but I think one bit of semi-solid ground is 'can the problem be fixed by thinking about things differently?

 

[Hutan]

238 people infected with SARS, 33 died.
205 people survived, 2 with pre-existing hypothyroidism excluded
Of the 203, 60 met inclusion criteria and agreed to participate, enrolled at 3 months post-discharge

So, quite a lot of people did not participate. I suspect that the authors would have known the endocrinological status of some of the infected people, and probably would have encouraged those with 'interesting' endocrinology to participate. People who participated got followup treatment if needed.

The 60 enrolled people includes 8 who had severe SARS (admitted to ICU), 10 used corticosteroids during the acute illness

Blood samples were collected at 0800 h by venepuncture into EDTA and plain tubes for: 1) full blood count, 2) electrolytes, 3) cortisol, 4) ACTH, 5) free T4, 6) free T3, 7) TSH and 8) dehydroepiandrosterone sulphate (DHEAS). Twenty‐four‐hour urinary free cortisol (UFC) was done to assess integrated cortisol secretion. Subjects with serum cortisol below 275 nmol/l as cut‐off underwent dynamic HPA axis evaluation using low dose (1 µg), short Synacthen (ACTH‐1‐24) test (SST).

Subjects with 0800 h serum cortisol below 138 nmol/l and/or poststimulation serum cortisol under 550 nmol/l at 30 min were deemed hypocortisolic.

 

[Hutan]

Among the 24 patients with hypocortisolism, three were deemed hypocortisolic based on 0800 h serum cortisol below 138 nmol/l, while 21 patients with borderline values underwent low‐dose SST for evaluation of HPA axis integrity.

So, actually only three had 8 am cortisol levels below the cut-off level. Also, I don't believe an 8 am cortisol level less than 138 mol/l necessarily means that the person is hypocortisolic. As we have discussed elsewhere, cortisol levels vary a lot over a day, and someone who is not working, who has disrupted sleep and who may be napping during the day may well not have a pronounced morning peak cortisol level.

I don't think we have enough evidence here to conclude that the SARS-CoV-1 survivors had unusually low serum cortisol, especially with the complication of steroid medicines.

Because the treatment protocol for critically ill SARS patients managed in the ICU included the use of high‐dose systemic glucocorticoids, HPA axis suppression as a cause of central hypocortisolism from exogenous steroid exposure remains a possibility. Of the 24 patients with hypocortisolism, six received systemic glucocorticoids during SARS while one was an asthmatic on inhaled corticosteroids. Among the six patients treated with systemic glucocorticoids, three were on prednisolone up to a dose of 60 mg given for 2–5 days; the other three patients had intravenous methylprednisolone 200 mg for 3 days, followed by hydrocortisone 100 mg 8 hourly for about a week before being switched to oral prednisolone tapered over 10 days.

So, 7 of the 24 'patients with hypocortisolism' had been exposed to steroids.

Of the 21 people whose data is given in Table 2 (because they underwent ACTH testing), only 4 out of 17 patients with 24-hour urinary free cortisol results had low levels. I can't tell if these patients had been treated with steroids.

I'm finding the ACTH testing results harder to understand, or explain away.

Four (16·7%) had hypocortisolism associated with plasma ACTH above the upper reference limit of 11 pmol/l (50 pg/ml). Although this may superficially suggest primary hypocortisolism, the levels of ACTH were not elevated sufficiently to be diagnostic of primary hypocortisolism. In the absence of renin–aldosterone data and overt addisonian crisis, primary adrenal insufficiency was most unlikely, whereas secondary hypocortisolism appear to be the main form of HPA axis dysfunction encountered here. Indeed, the raised ACTH may in fact be a reflection of a recovering HPA axis following steroid‐induced suppression. Among these four patients, one who was given systemic steroids during SARS was probably a case of central hypocortisolism rather than primary hypocortisolism, being recruited at a time when the hypothalamo‐pituitary unit was recovering from transient HPA axis suppression, while the other three with elevated ACTH who had no steroids exposure during SARS or prior to SARS could arguably be cases of SARS‐induced central hypocortisolism showing evidence of early hypothalamo‐pituitary recovery rather than primary adrenal insufficiency.

So, 4 had mildly raised ACTH. Of those, 1 had been given systemic steroids during their illness. All the others had ACTH in the normal range.

Twenty‐four (39·3%) patients had hypocortisolism, of which 20 (83·3%) had unequivocal central hypocortisolism as evidenced by concomitant low or inappropriately normal ACTH levels

How do you know if someone has 'inappropriately normal' ACTH?
The stimulated ACTH levels in the first test (shown in Table 2) do look low, with the figures in later tests increasing substantially.


A severe illness might indeed cause hypocortisolism, as might the steroids or other medicines the patients were given. That doesn't mean hypocortisolism is part of ME/CFS symptomology. I wonder if there are other studies that measured cortisol in SARS-Cov-1 and MERS.

 

[rvallee]

I'm not sure if the authors understood 'psychosomatic' in the same way that I do. If an endocrinological basis resulting from a disease process accounts for psychosomatic manifestations, are they really psychosomatic manifestations? It all gets quite circular, but I think one bit of semi-solid ground is 'can the problem be fixed by thinking about things differently?

One interpretation, which seems oddly but low-key popular, is the use of this term as a replacement for "we don't understand this but won't admit it". I think this interpretation of psychosomatic would likely be shockingly high if it could be polled.