WORLD’s first case of YELLOW NAIL SYNDROME (YNS) associated
with COVID, PT & DM is reported from India by Dr. T. Rama Prasad
in the Journal of Medicine & Surgery, THE ANTISEPTIC of March 2023 –
Indexed in IndMED; www.theantiseptic.in
Rama Prasad. T., Yellow Nail Syndrome and COVID-19 : a case report and discussion. The Antiseptic,2023 March, Vol. 120, No. 03; ; P:07-14, Indexed in IndMED – www.theantiseptic.in
Rama Prasad. T., https://journal.chestnet.org/article/S0012-3692(16)40458-7/fulltext -- Yellow Nail Syndrome - Chest (U.S.A.), Vol. 77, p.5, 1980
Rama Prasad. T., Yellow Nail Syndrome - The Indian Journal of Chest Diseases & Allied Sciences, Vol. 22, pp. 69-72, 1980.
“Incidentally, Dr. T. Rama Prasad holds the WORLD RECORD in medical journalism of authoring 28 articles related to a single disease, COVID-19 which were published in a single medical journal, THE ANTISEPTIC, in a time span of 30 months. This article titled ‘Yellow Nail Syndrome (YNS) and COVID-19 …’ is one of them.” For details about Yellow Nail Syndrome, please go to :
https://drtramaprasad.blogspot.com/2017/04/yellow-nail-syndrome_28.html
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An anecdote
During my childhood, one of my schoolmates had huge nails. Her name was Gowri. We nicknamed her as ‘Goru’ (meaning nail of a finger or toe in Telugu). They used to say that her huge nails caused a problem in her heart. It might be a case of ‘Digital Clubbing’ (abnormal nails present in some ‘Congenital Heart Diseases’). After one summer vacation, ‘Goru’ didn’t come back to the school. It was learnt that she died due to the nail / heart problem, and that treatment couldn’t be given as they didn’t have money to pay for it.
Perhaps, this incident prompted me to look at everyone’s nails from that time which might have led me to report the first case of ‘Yellow Nail Syndrome (YNS)’ from India in 1980 and the first case in the world of ‘Yellow nails & Covid’now in 2023. And perhaps, the preventable death of ‘Goru’ due to inability to pay for the treatment motivated me to start my ‘PAY WHAT YOU CAN’ Clinic (PWYCC) half-a-century ago where patients may pay whatever they can. There is no fixed fee. The money received is mostly spent to help people in one way or the other. The credit for these case reports on YNS and the starting of my PWYCC should go to ‘Goru’.
-- T. Rama Prasad
Please go to the LINKS below to know more :
http://drtramaprasad.blogspot.com/2017/06/pay-what-you-can-clinic.html
https://drtramaprasad.blogspot.com/2017/04/dr-t-rama-prasad.html
http://drtramaprasad.blogspot.com or www.rama-scribbles.in
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The FIRST case from INDIA
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| Representative photo |
There is another abnormal manifestation of nails called 'Digital Clubbing' ... nails may look like 'parrot beaks' or fingers may look like 'drumsticks' ! In most of the cases, the disease is not in nails ... it may be due to birth defects of heart, diseases in lungs, or cancer. We do not exactly know why the nails are affected when the main disease is elsewhere. More than 40 years ago (1979), I wrote an article in a medical journal on what could be the causes for development of these changes -- Digital clubbing and Hypertrophic Pulmonary Osteoarthropathy -- Pathogenesis -- The Antiseptic, Vol. 76. pp. 213-215, 1979. Even today, in 2023, we are not sure of the cause !!
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| YELLOW beauty !! |
Diseases & Allied Sciences, Vol. 22, pp. 69-72, 1980
COVID world: To date, 27 of my articles on COVID-related matters were published in The Antiseptic over 29 months (a sort of World Record in medical journalism – one subject; one author; one monthly medical journal; 27 articles in 29 months).
-- Dr. T. Rama Prasad, ‘PAY WHAT YOU CAN’ Clinic, Perundurai, India
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. Yellow Nail Syndrome and COVID-19 :
a case report and discussion .
RAMA PRASAD T.
Dr. T. Rama Prasad,
Formerly: Medical Superintendent (Special) of RTS & IRT Perundurai Medical College and Research Centre,
Perundurai, Tamil Nadu, India.
Presently: Director of ‘PAY WHAT YOU CAN’ Clinic, Perundurai, Erode District, TN – 638052. drtramaprasad@gmail.com WhatsApp +91 98427 20393 BLOG https://drtramaprasad.blogspot.com
WEBSITE www.rama-scribbles.in Twitter @DrRamaprasadt Facebook T Rama Prasad
Telegram Dr T Rama Prasad
A MONTHLY JOURNAL OF MEDICINE AND SURGERYSN
Vol. 120 No. 03 March 2023 ISSN 0003 5998
Indexed in IndMED Email: admin@theantiseptic.in www.theantiseptic.in
Yellow Nail Syndrome and COVID-19 : a case report and discussion .
RAMA PRASAD T.
.
Dr. T. Rama Prasad,
Formerly: Medical Superintendent (Special) of RTS & IRT Perundurai Medical College and Research Centre,
Perundurai, Tamil Nadu. Presently: Director of ‘PAY WHAT YOU CAN’ Clinic, Perundurai, Erode District, TN – 638052.
Specially Contributed to “The Antiseptic” Vol. 120, No. 3
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ABSTRACT
‘Yellow Nail Syndrome’ (YNS) is usually and simply described as a rare manifestation of a troika of yellow nails, lymphedema and pleural effusion. The syndrome is known to be associated with some diseases. A case of its association with a triple whammy of COVID-19, pulmonary tuberculosis and diabetes mellitus is reported here which is the first of its kind in the world. This gains significance especially as the patient contracted COVID-19 sometime before the manifestations developed. The associations, features and the pathogenesis are briefly discussed.
Key words: Yellow Nail Syndrome, COVID-19, Long COVID
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Introduction and background
The world’s first case of Yellow Nail Syndrome (YNS) associated with COVID-19, pulmonary tuberculosis (PT) and diabetes mellitus (DM), is documented here. YNS itself is a very rare manifestation, and its development in a case of COVID-19 is exceptionally uncommon. Much more, the simultaneous detection of PT and DM in this case makes it more unique. This case, arguably, is the first incidence of YNS developing in a COVID-19 patient.
The presentation of the case here may not be in the formal ‘case report’ format – a distinct deviation from the customary documentation. I would like to introduce this subject with a ‘background’ by reprinting hereunder a paragraph from my article titled “Post-Omicron Peregrination” which was published in April 2022 in The Antiseptic, ‘a premier monthly Journal of Medicine and Surgery’ established in 1904 -- Vol. 119, No.4, P. 10; ISSN 0003 5998; Indexed in IndMED; www.theantiseptic.in 1
“ … Yellow Nail Syndrome
The nail changes (‘digital clubbing’) I wrote above prompt me to mention about a COVID-19 case I had seen with ‘Yellow Nail Syndrome’ (RT-PCR positive, pleural effusion and yellow nails). The case is yet to be documented. This may be the first COVID-19 case in the world to be associated with ‘Yellow Nail Syndrome’. In this context, I recall the first documented case of ‘Yellow Nail Syndrome’ from India which was reported by me and published more than 40 years ago, in 1980, in an American medical journal (Chest, April 1980, Vol. 77, Issue 4, P. 580; https://journal.chestnet.org/article/S0012-3692(16)40458-7/fulltext ). 49, 48 In the same year, I reported the second case of ‘Yellow Nail Syndrome’ in India which was published in the Indian Journal of Chest Diseases and Allied Sciences (1980, Vol. 22, No. 1, P. 69-72 https://drtramaprasad.blogspot.com/2017/04/yellow-nail-syndrome_28.html ). 48 I wrote in this article: “The pathogenesis of this syndrome is yet to be elucidated, particularly of the enigmatic yellow discolouration of the nails.” Four decades on, the pathogenesis is still an enigma, and many of the happenings occurred in the Covid pandemic period would remain an enigma for ever. …”
This ‘Yellow Nail Syndrome’ case was preliminarily mentioned in the article cited above nine months ago as a prelude to this report. 1 The full report is presented here of the case which is the first of its kind. In this case, a hitherto undescribed association of YNS, COVID-19, PT and DM was observed. The enigmatic association is discussed in this paper. As the discourse on YNS centres around its causation, a little on the pathogenesis is also written in this report.
The subjects of YNS and COVID-19 revolve around uncertainties – as confounding as Heisenberg’s uncertainty principle. Brain boners indeed.
Overview
n Definition:
‘Yellow Nail Syndrome’ is generally recognized as comprising of at least two of the following triad: (1) slow-growing, thickened, dystrophic and yellow nails, (2) primary lymphedema, and (3) respiratory tract disease manifestations. Some academicians added bronchiectasis as a fourth criterion. Diagnostic problems arise because patients rarely present all the three manifestations concurrently.
Samman and White who described in 1964 the first series of 13 cases who had slow-growing yellow discoloured nailsand primary lymphedema. 2 Emerson in 1966 added pleural effusion to the diagnostic criteria. Nordkild et al. documented an extensive historical review of the YNS. 3 Probably, Heller reported the first case in 1927.
n The first and the second case from India:
‘Yellow Nail Syndrome’ is considered to be a very rare and poorly recognised disorder, with only around 500 cases published in the world medical literature so far. When I reported the first case from India in 1980, in the American journal, Chest, four decades ago, the total number of cases reported in the world was below 50. 4 This first case had a very rare mix of yellow nails, pulmonary tuberculosis, tuberculous liver abscess and diabetes mellitus. My second reported case of ‘Yellow Nail Syndrome’, published in the same year in Indian Journal of Chest Diseases and Allied Sciences (IJCDAS), had a combination of yellow nails, lymphedema and bilateral bronchiectasis. 5 Interestingly, the founder of IJCDAS (the publishing arm of Vallabhbhai Patel Chest Institute - VPCI, Delhi, founded in 1959) Dr. R. Viswanathan reviewed (mentioned in the ‘acknowledgement’ of the article) the manuscript of the article of this second case. Dr. R. Viswanathan (1899 – 1982 ; https://en.wikipedia.org/wiki/Raman_Viswanathan ) , the founder director of VPCI, is considered as ‘The Father of Chest Medicine in India’. Incidentally, I was the recipient of ‘Dr. R. Viswanathan Prize’ of Andhra University, Visakhapatnam, about half-a-century ago
n Prevalence:
The exact prevalence of the syndrome is not known. Reports of YNS have been few and far between. According to one estimate, it is less than 1 / 1,000,000. I suspect the prevalence to be much higher, if not for underreporting. Only a handful of YNS cases were reported from India with a population of 1.4 billion, whereas in the rest of the world with a population of 6.6 billion as many as about 500 cases were reported. The causes for the low figures are: lack of awareness of YNS, even among doctors; people may not care for the visible manifestations as they are mostly painless and not uncomfortable; rural folk manage with native remedies without approaching healthcare professionals; the yellow discolouration may not be very visible in dark-skinned populations. A high clinical suspicion is the key.
n Cause
The specific underlying cause for YNS remains obscure, although a role of lymphatic dysfunction, specifically of lymphatic drainage, is usually evoked. Titanium dioxide (used in dental and joint implants, surgical staples, cosmetics and toothpastes, etc.) is a suspect in the causation of YNS. If a toothpaste can cause YNS, what can’t ! Curiously, one case of YNS was reported where the commonly and widely used anti-hypertensive drug amlodipine was incriminated as a cause for YNS. 6 The syndrome, an acquired one mostly, affects people above the age of 50 years though children and new born babies had it. Genetic predisposition was reported in some cases. A few cases of familial and congenital YNS were reported. Its association with cancer gained it the qualification ‘paraneoplastic syndrome’. Whether associated diseases like COVID-19, malignancies, autoimmune diseases, immunodeficiency diseases, etc. play a causative role is a matter of conjecture. Various theories have been put forth, but they are like a Schrodinger’s cat – both alive and dead !
n Cure
The symptoms, signs and treatment may vary from case to case depending upon the manifestations and the associated diseases. There is no cure. Oftentimes, spontaneous attenuation or remission of the manifestations of YNS was noted, in up to 30% of the cases. Complications like cellulitis, pneumonia, empyema, etc. may occur. Basically, treatment is directed to alleviate symptoms and to cure or control the various associated disorders / diseases, on general lines. Vitamin E, triazole antifungal drugs, zinc, corticosteroids, clarithromycin, etc. were used, with inconsistent efficacy, to reduce nail abnormalities. 7 In the case reported in this paper, vitamin E was used but to no avail. Octreotide, a somatostatin analogue, was used in some cases of chylous effusion with positive response.
n Yellow nails
Yellow colour of the nails (xanthonychia) is the most conspicuous clinical manifestation of this syndrome, at least in the fair-coloured people. The discolouration varies from pale yellow to dark green. Other changes in the nails may be: increased curvature, transverse ridging, slow growing, brittleness, loss of cuticles and lunulae, dystrophy, thickening, hardening, opacity, onycholysis, etc. The manifestations are commonly misdiagnosed as those of onychomycosis due to some common features. Vitamin E ameliorated the symptoms in some cases.
n Lymphedema
Lymphedema is the first one to appear in 30% of the cases. It occurs in both lower limbs or in other dependent areas, and does not differ in appearance from primary lymphedema but can be differentiated by ‘dynamic lymphatic imaging’ (lymphoscintigraphy). Pitting oedema in YNS may be confused with that of congestive cardiac failure, especially when concurrent bilateral pleural effusions are present. Treatment may involve, as in primary lymphedema – massage, compression dressing, manual lymph drainage, exercises and rarely surgical intervention.
n Respiratory manifestations
More than half of the YNS patients have respiratory system problems like chronic cough, bilateral exudative pleural effusions with lymphocyte predominance, bronchiectasis, recurrent pneumonias, sinusitis, pulmonary fibrosis, etc. Pulmonary function tests and biopsies usually contribute little. Recurrent infections are to be treated according to the situation. Decortication / pleurectomy or pleurodesis may have to be considered in some cases.
n Associated morbidities
YNS is a syndrome, not a disease per se. It is associated with morbidities as different as diseases implicated in the areas of lymphatic disorders, autoimmune afflictions, malignant maladies, etc. COVID-19 / long COVID is also following its footsteps in affecting varied body systems. We do not yet know whether these two are mutually aggravating or collectively contributing factors in the evolution of varied manifestations.
It is observed that YNS may be associated with a myriad of morbidities -- chronic respiratory and lymphatic diseases, recurrent pneumonias, bronchiectasis, chronic sinusitis, malignancies, immunodeficiency diseases, connective tissue diseases, protein-losing enteropathy, nephrotic syndrome, thyroid disease, rheumatoid arthritis, use of some drugs, etc. Association of Yellow Nail Syndrome with COVID-19, PT and DM in a case as reported in this article is a hitherto undescribed entity. The possible relationship between these varied manifestations is discussed in this paper. Of course, it may be a matter for conjecture.
n COVID-19
I do not find the need to write an overview on COVID-19, because, at this point of time of the Covid pandemic, everyone from a layperson to a luminary is loaded with the knowledge of‘known unknowns’ about the much-hyped Covid !!! All these three years, the news channels were like ‘Covid channels’ !!! It is sufficient to say that, three years on, there are too many gaps in our knowledge about COVID-19 which upended the world with 6.8 million human deaths and an unfathomable degree of global economic death. COVID-19 has been associated with a myriad of diseases and disorders of which YND could be one. Both the maladies seem to have chosen an eclectic mix of manifestations !
Case summary
In November 2021, a 54-year-old South Indian man tested positive for ‘RT-PCR Covid’ test at his native place. He had mild symptoms and ‘recovered’ with symptomatic treatment at a local medical facility. No other investigations were done at that point of time. Later, he was apparently active with his usual manual agricultural work for a month after which he felt fatigued and developed cough, left-sided chest pain and mild fever. He ignored the symptoms for more than a month and in February 2022, he sought medical help.
He also had a history of being treated for tuberculosis (TB) some 20 years ago. He didn’t have any records of the past illness, and he was leading a normal life later for two decades without medical check-ups and medicines. He was not aware of having any other disease. Investigations carried out in February 2022 revealed that he had left-sided pleural effusion, pulmonary tuberculosis and diabetes mellitus. It was noticed that some of the nails of his fingers and toes had yellow discolouration, and were excessively curved along both axes, having the appearance of ‘parrot beak’ as in digital clubbing, and were slightly thickened and dystrophic with a bit of ridging and loss of cuticles and lunulae (Figures 1 and 2). There was no onycholysis. ‘Leading questions’ revealed that the patient was not aware of the changes in the nails.
Figure 1 : Right and left thumb nails
Figure 2 : Right and left big toe nails
Chest radiography and computed tomographic imaging of the chest revealed left-sided pleural effusion, areas of infiltration and consolidation, and fibrotic changes in the lower lobes, mostly on the left side (Figure 3). Sputum examination (CB-NAAT) indicated detection of TB bacilli which were sensitive to rifampicin. Thoracentesis and examination of the pleural fluid didn’t reveal confirming evidence of tuberculosis as a cause for the effusion. Cultures of the fluid for TB bacilli and other microbes were negative. Adenosine deaminase (ADA) was less than 40 U/L. It’s an exudate by Light’s criteria with a predominance of lymphocytes, and the LDH was low relative to the protein level of > 3g/dL. ‘Serum / effusion albumin gradient’ study was not done. Plasma glucose levels were elevated (FPG: 123; PPPG: 210). He was not a known diabetic. Pulmonary function tests revealed a restrictive pattern. ‘40+15 Hypoxia Test’ (a kind of ‘Walk Test’ combined with ‘Step Climbing Test’, described by me in an article titled “40+15 Hypoxia Test in COVID-19” which was published in The Antiseptic of December 2020) demonstrated a fall of 3% of the SpO2. 8
Figure 3 : Chest radiograph
Negative results were reported for human immunodeficiency virus, hepatitis B virus surface antigen, anti-nuclear antibody, anti-neutrophil cytoplasmic antibody, and lung cancer indicators. Results of routine blood tests including IL-6, D-dimer, Ferritin and CRP didn’t reveal any significant abnormality except elevation of ESR to 56 mm / 1 hour. Cardiac parameters including ECG and echocardiography were not significantly abnormal. Radiographically, paranasal sinuses were normal. There were no signs of lymphedema. The patient never had ‘thiol group’ of drugs or titanium prostheses / implants which are linked to YNS as causative factors by some researchers. 9
The patient was given a standard course of ‘anti-tuberculosis treatment (ATT)’ with oral drugs. He was also treated for diabetes mellitus with oral drugs. The regimen included Vitamin E of 1200 mg/day. Corticosteroids were not given. Thoracentesis was done three times at his native place with more or less the same findings as those of the first tapping. Radiologically, the pleural effusion didn’t clear, at the end of the ATT, while the images of infiltration and consolidation cleared well. The fibrotic images were unaltered, indicating that the fibrotic changes might be related to sequelae of the TB disease he had 20 years ago (stable fibrosis). Perhaps, the fibrotic changes limited the ‘expansion’ of the effusion physically. The status of the nails was more or less the same at the end of the ATT, in spite of administering vitamin E which was reported to have ameliorated the yellow colour in some cases. There was good clinical improvement and the patient got back to work. But, shockingly, it was learnt that he died of a ‘cardiac arrest’ some months after completion of the ATT. Post-mortem examination was not conducted, and no information is available about the event. Oftentimes, in India, patients’ relatives won’t cooperate for post-mortem examinations or academic investigations or sharing health information.
Discussion
In the case reported here, a hitherto undescribed association of COVID-19, pulmonary tuberculosis, and diabetes mellitus with ‘Yellow Nail Syndrome (YNS)’ was observed. The most interesting aspect of this case of YNS is its association with COVID-19, though signs of YNS (yellow nails and pleural effusion) and other manifestations (diabetes mellitus and tuberculosis) were detected about three months after the patient was tested positive for COVID-19. From the history, it seems likely that the manifestations occurred only after contracting COVID-19. The time lag between the time of ‘RT-PCR positivity’ and the detection of yellow discolouration of nails, pleural effusion, PT and DM may prompt one to think of ‘Post-acute Sequelae of COVID-19 (PASC)’, commonly known as ‘Long COVID’. There is a growing body of evidence that beyond the first 30 days of the acute phase of SARS-CoV-2 infection, people could experience a wide range of ‘post-acute sequelae’ –- referred to as ‘Long COVID’ which is a multifaceted syndrome associated with several pulmonary and extra-pulmonary manifestations / diseases. The time lag in this case may even be considered as the phase of “persistence” of COVID-19 during which period this patient might have had symptoms which didn’t bother him much. The nomenclature of ‘Long COVID’ is a tad arbitrary and a play of semantics. 10
‘Long COVID’ is the only disease description in the world which ‘appeared’ first in social media and later, through a rare public ‘movement’, compelled ‘Covid scientists’ to recognise it as an entity. I wrote the following in an article in the October 2022 issue of The Antiseptic under the title “The Long COVID” : “ … The reported symptoms of Long COVID are myriad, weird and odd. They may be of persistence, sequelae and other medical complications. They may start weeks and months after initial recovery, and may last for a long time. They may relapse and remit. They may belong to any system in the body including skin (skin-rashes may take many forms – vesicular, maculopapular, urticarial, chilblain-like lesions on extremities like the so-called ‘Covid toe’). They may be similar to the symptoms of some other diseases. …” 11
It is debatable as to whether the YNS in the case reported here occurred in a patient who had COVID-19 or ‘Long COVID’, and whether the SARS-CoV-2 infection is a causal factor for the development of YNS or a casual coincidental morbidity. In this context, it may be interesting to have a look into my article titled “The long and the short of COVID in India” (The Antiseptic, June 2022). 12
This case has the potential to provoke thought in a direction to find a possible causal relationship between COVID-19 and the manifestations, especially as the patient was apparently hale and healthy doing his manual work for a couple of decades before being affected by COVID-19 in November 2021, without having signs and symptoms of YNS or respiratory problems, though he had TB disease 20 years ago. YNS, diabetes mellitus and pulmonary tuberculosis were detected in February 2022, about three months after he tested positive for COVID-19. He was not a known diabetic. The tuberculous lesions were in the lower lobes which are more frequently affected by TB in diabetics. It might be a fresh infection, though there is a remote possibility of reactivation in the old healed lesions (stable fibrosis) in lower lobes. The pleural effusion could be due to TB or YNS, even after taking into consideration the results of investigations as mentioned in the ‘Case summary’ above.
All the same, some of the results of the study of pleural fluid and the persistence of pleural effusion after the completion of treatment for TB indicate that the pleural effusion is likely to be a constituent of YNS, not of TB. The unilateral effusion weighs in favour of an association with TB while the ADA which was less than 40 U/L goes against it. Pleural fluid in YNS is usually an exudate by Light’s criteria, with a predominance of lymphocytes, and the LDH tends to be low relative to the protein level. These findings, which were observed in this case (the LDH was low relative to the protein level of > 3g/dL), would support the postulation of linking the YNS with effusion, though much can be said on both sides of the aisle. At the end of the ATT, it seems that the lesions of infiltration and consolidation cleared well, presumably with ATT, while the radiological images of fibrosis and pleural effusion were unaltered. This shows that the fresh lesions due to the recently acquired TB got resolved while the old chronically stable fibrotic components of the past TB (sequelae) persisted, and that the pleural effusion which might be due to YNS persisted and stayed physically limited by the surrounding fibrotic elements. The patient felt reasonably comfortable and resumed his routine work after completing the course of ATT. He seemed to have ‘learnt to live’ with pulmonary functional compromise due to the old stable fibrosis and the ‘physically limited’ effusion. Not unexpectedly, the nail abnormalities remained more or less the same.
Another confounding facet of this case is the sudden death of the patient. Unexpectedly and unexplainably, this patient who had no history or evidence of chronic cardiac or cardio-vascular problems died at his native place suddenly, said to be due to ‘cardiac arrest’. Such unexpected and unexplainable ‘sudden cardiac deaths’ were being reported in the third year of the Covid pandemic among individuals who recovered from COVID-19. 13 A menagerie of wild morbidities seems to prevail.
n New information
Additionally, some evidence is present to connect the apparently disparate diseases in this case. COVID-19 is now known to promote TB and DM. It had also been incriminated as the cause of ‘sudden cardiac deaths’ in individuals who recovered from ‘acute Covid illness’. My articles titled ‘COVID and Tuberculosis’ , ‘The Long COVID’, ‘COVID Fear and Paranoia’, and ‘Post-Omicron Peregrination’ (published in The Antiseptic of December 2021, October 2022, May 2022, and April 2022, respectively) may throw some light on the interrelationship between COVID-19, YNS, TB, DM and the sudden death in this case. The following are some relevant excerpts from these articles : 14, 11, 15, 1
n Covid and TB
“…A scientific study has evaluated the correlation of host-expression with SARS-CoV-2 and interaction of 26 proteins of SARS-CoV-2 with 332 human proteins.4 It was found that Mycobacterium tuberculosis that causes TB shares most of the host protein interaction partners (same interactome) with SARS-CoV-2 which is of utmost importance as both the infections have high affinity towards lung tissues. Lung is commonly involved in most of the cases of COVID-TB. Both the pathogens may induce immunomodulation disorders leading to an unbalanced inflammatory response which can worsen the course of both the diseases. … Furthermore, when infected with Covid, old healed TB lesions may get activated, and the people of ‘latent TB infection’ (LTBI) may develop active TB. Past experience with SARS and MERS-CoV has shown that adverse effects of TB occurred during and after the infectious phase of the diseases. Notwithstanding our experience with similar viruses in the past, we are still groping in the dark corridors of the ominous and looming pandemic. …” (The Antiseptic of December 2021). 14
n Covid and DM
“… After recovery from Covid, many are facing increased problem of Tuberculosis, other respiratory diseases, diabetes – new and uncontrolled old cases, tachycardia, etc. Many Covid rehabilitation centres came up across India to cater to ‘Long COVID’ patients. …” (The Antiseptic, October 2022). 11 A study published in ‘The Lancet’ concluded that in the post-acute phase of COVID-19 (Long COVID), people exhibited increased risk of contracting diabetes mellitus. 16
“…It is now known that those who had even asymptomatic infection may suffer from these symptoms even long after the infection. In the UK, 1.7 million (nearly 3% of the entire population) reported ‘Long Covid’ symptoms. 45% of them contracted the infection over a year ago, and many of them had to leave their jobs due to incapacity to work. …” (The Antiseptic, May 2022). 15
n Covid and sudden cardiac deaths
“…Andhra Pradesh’s minister Goutham Reddy, 50 years, hale and healthy, died of cardiac arrest while getting ready to the gym on February 21, 2022. It’s reported that he recovered recently from Covid-19 and that ‘the doctors suspected that post-Covid complications might have led to the cardiac arrest.’ …” (The Antiseptic, April 2022). 1 More than 3,500 Americans died from ‘Long COVID-related illness’ in the first 30 months of the pandemic, and several ‘sudden cardiac deaths’ in ‘Long COVID’ are reported. 17
All this points to the possible relationship between COVID-19 and the other afflictions (YNS, PT, and DM) this patient had. All the same, the causal relationship may remain entirely speculative due to lack of robust evidence.
The discussion won’t be complete without a discourse on pathogenesis.
Pathogenesis
n Impaired lymph transport
The pathogenesis of YNS is far from clear, but lymphatic involvement, specifically lymphatic drainage, is often evoked to explain lymphedema, pleural effusion (particularly chylothorax) or nail discolouration. With the advent of lymphoscintigraphy, lymphangiography has become ‘old-fashioned’. Lymphoscintigraphy studies revealed that the underlying lymphatic flow disruption is more of impaired lymph transport than lymphatic hypoplasia / aplasia. According to Bull et al., the abnormalities observed in YNS appear to be functional and potentially reversible unlike as in primary lymphedema which is due to permanent structural lymphatic abnormalities. They opined that an inflammatory component that leads to altered capillary permeability, fluid shifts, and alterations in blood flow is likely to be the cause of the oedema in YNS. 18
n Vascular abnormalities
By extension of thought, one may wonder whether Bull’s theory of ‘alterations in blood flow’ may be applied concurrently with the ‘lymph flow’ theories advanced for YNS. It is theorised that ‘vascular abnormalities’ may form the basis for the pathogenesis of digital clubbing. A peep into the excerpt below from my article titled “Digital Clubbing and Hypertrophic Pulmonary Osteoarthropathy – pathogenesis” published more than 40 years ago (The Antiseptic, 1979) 19 may project a different pathological connectivity to YNS : “… In clubbing, the distal phalanges receive abnormally more blood supply through an abnormal increase in arterial and venous formation with abnormal arterio-venous anastomoses. The spongy feeling perceived at the base of the nail and the ‘drum stick’ appearance may be attributable to the increase in the vascular tissues. It is not clear how the increased convexity of the nail is caused, but a disproportionate increase in the vascular tissues underneath the base of the nail which lies under the skin may explain the loss of the angle between the nail and the posterior nail fold. …” 19 And, it is interesting to note that in the case presented in this article, ‘the nails were excessively curved along both axes, having the appearance of ‘parrot beak digital clubbing’.
n Microvasculopathy
Maldonado et al. thought that YNS pathophysiology might be attributable to microvasculopathy associated with protein leakage rather than functional lymphatic impairment. 20 Thickened nails and their slow growth might be due to defective lymphatic drainage caused by subungual tissue sclerosis leading to lymphatic obstruction. The normally loose subungual stroma was found to be replaced by dense fibrous tissue. 21 In a case of YNS, fibrosis and dilated lymphatic vessels were seen in the parietal pleura. 22 The yellow discolouration may be due to accumulation of lipofuscin pigment. 7
n A mix of many
The theories elucidating the pathogenesis of the components of YNS and COVID-19 are bogged down in a mire of controversial perceptions. One controversy is about the impairment of the lymphatic system in the evolution of various changes in nails. Some think that the lymphatic impairment associated with YNS is secondary, and predominantly functional in nature, rather than as a result of structural changes. Malfunction of lymphatic system (congenital or acquired hypoplasia of the lymphatic vessels, obstruction to lymph drainage, decrease in function of lymphatics, increased production and decreased draining capacity of lymphatics, etc.) is blamed also for the occurrence of lymphedema and pleural effusions. Pleural effusions may be due to defective lymphatic drainage, rather than due to excessive production of pleural fluid. Electron microscopy has revealed the presence of dilated lymphatic capillaries in the visceral pleura, suggesting an obstruction to the lymph drainage. The cause for the impaired lymph transport is not clear, however. While it is generally believed that YNS is a sporadically acquired manifestation, a genetic factor – a mutation of the FOXC2 gene which causes a disorder called lymphedema-distichiasis syndrome – may play a role in the genesis of YNS.
n Parrot beak nails
Even the pathogenesis of the ‘age-old’ related manifestation of nails, digital clubbing, is still being debated. I wrote 43 years ago the following concluding sentence in an article titled “Digital clubbing and Hypertrophic Pulmonary Osteoarthropathy - pathogenesis” which was published in The Antiseptic of April 1979 19 : “Our knowledge about the pathogenesis of digital clubbing and hypertrophic pulmonary osteoarthropathy is fragmentary and inconclusive, and the views put forth still belong to the realm of conjecture.” 19
The view expressed more than four decades ago seems to be relevant even today ! In the case described in this paper, the nails were excessively curved as in ‘parrot beak’ clubbing. The etiological and pathophysiological connection between digital clubbing, YNS and COVID-19 is yet to be studied. There is yet another rare nail-related disease called ‘Parrot Beak Nail Dystrophy (PBND)’ a case of which was reported by Parnia Forouzan et al. in 2021 – 65th reported case in the world. 23 The PBND presents as excessive forward curvature of the distal nail plate, probably caused by chronic vasoconstrictive ischemia and abnormal phospholipid distribution in the nail plate. The PBND can concurrently occur with other nail dystrophies. The field of manifestations of abnormalities of nails is so ill-understood that we don’t know how much of the known can be applied to the case documented in my article here.
An array of eclectic changes in nails is observed in a myriad of diseases including COVID-19, but we are not very certain about the pathogenesis of the protean manifestations. In a cross-sectional study of 43 hospitalized COVID-19 patients in India, many of them were found to be having ‘nail bed erythema’, ‘red half-moon sign’, ‘leukonychia’, ‘distal brown discolouration, etc. 24
Hubris and hypocrisy
While the idea of COVID-19 being the cause for YNS, PT and DM in this case seems to be no more than just theoretical, it would be naïve to brush it aside. We all thought that a little virus can’t do such a devastating damage to the world in the modern medical set up of 2020s. But it did. Anything would be possible for this coronavirus, including political manipulations ! Who knows what happens when, heaven forbid, a new deadly variant commences its global peregrination to install another pandemic ?
A conundrum
There have been a lot of ‘myopic’ studies about various aspects of YNS and COVID-19. It is possible to be seriously misled by the conclusions of narrowly focused research studies – akin to the parable, originated in the Indian subcontinent, of the ‘blind men and an elephant’. Some of them are loaded with such scientific jargon which an ordinary clinician can’t comprehend. We tend to go into a panic mode at the sight of ratios, square root signs and half-forgotten Greek letters. The devil is in the detail ! The researcher may wear an anorak but the intention is to make us understand. Obviously, the reader may have a sense of déjà vu about going back to the drawing board. A review article on YNS by Stephane Vignes and Robert Baran with 116 references makes a good reservoir of knowledge about YNS. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5327582/)
People and even Covid experts were confused with the way in which the Covid pandemic navigated and compelled authorities to revise their preventive and technical advisories, and programming strategies too often during the three-year period -- a metaphor for our ignorance. Some stepped into over-precautious routes. A glaring example is the unduly prolonged ‘zero-Covid’ policy of China which seemed like an act of monumental folly – my articles titled “Death of ‘zero-Covid”, “China and COVID uncertainties” and “Zero-COVID strategy” may provide a window to have a peep into the scenario. 25,26,27 The knowledge we gained during the past three years about this virus, let alone its association with YNS, is diverse and fragmentary, an academic Rubik’s cube with a lot of possibilities. The uncertainties and vicissitudes may be perceived in my articles on Covid published in The Antiseptic -- 27 articles in 29 months, on a single subject, by a single author, in a single journal – a sort of a world record in medical journalism. 1,8,11,12,14,15,19, 25 to 45 The transience of human life seems to be applicable to pandemics too; the present Covid pandemic seems to have come to an end with the beginning of 2023 by a fortunate stroke of serendipity, but the World Health Organization seems to be doubly cautious in not declaring it so to date. Anyway, all this is by the way.
YNS sans Y ?
While all-encompassing standardized definition of YNS remains elusive, the varied characterizations are found to have methodologic and analytic limitations. There is a lack of unanimity even on the matter of what constitutes YNS. As the name suggests, yellow colour of nails (xanthonychia) is a ‘must’ feature of YNS. However, according to the definition, yellow nails are not required to be present if the other two of the three clinical signs are found. Although it’s not a cosmetic issue, it doesn’t seem to be cogent. It is unacceptable to semantic logic. It’s like naming ‘Indian ocean’ without India nearby. But,
“What’s in a name ? That which we call a rose
By any other name would smell as sweet.”
-- Juliet / Shakespeare
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