We read with great interest the article by Marietjie Venter and Karin Richter on the diagnostic assay for COVID-19 [1]. We agree with the authors about delays in diagnoses, a severe shortage of tests and laboratory capacity for performing RT-PCR tests. This is especially true for many developing countries such as Bangladesh, which is faced with current health care crises to provide healthcare for more than 165 million population. A large number of people are being tested for COVID-19 and confirmed with the disease every day in Bangladesh, and many more remain undetected due to the lack of testing. Further, the delay to receive test results and lack of medical records cause COVID-19 patients to transmit the disease in the community and hamper proper treatments.
Prior to the COVID-19 test, several pre-conditional medical records are required to support the results. In Bangladesh, these records are generally gathered by health workers in the testing centres manually and ignoring many important symptoms and conditions. However, this
process is tedious and prone to omission, error and bias, leading to incomplete medical records. Further, participants are required to return to the centre the next day to collect test results which might increase community transmission. To mitigate such disadvantages, we developed a
smartphone-based RT-PCR record and monitoring app ‘mobEVID’.
This app has been built following Novel coronavirus RT-PCR app...
We read with great interest the article by Marietjie Venter and Karin Richter on the diagnostic assay for COVID-19 [1]. We agree with the authors about delays in diagnoses, a severe shortage of tests and laboratory capacity for performing RT-PCR tests. This is especially true for many developing countries such as Bangladesh, which is faced with current health care crises to provide healthcare for more than 165 million population. A large number of people are being tested for COVID-19 and confirmed with the disease every day in Bangladesh, and many more remain undetected due to the lack of testing. Further, the delay to receive test results and lack of medical records cause COVID-19 patients to transmit the disease in the community and hamper proper treatments.
Prior to the COVID-19 test, several pre-conditional medical records are required to support the results. In Bangladesh, these records are generally gathered by health workers in the testing centres manually and ignoring many important symptoms and conditions. However, this
process is tedious and prone to omission, error and bias, leading to incomplete medical records. Further, participants are required to return to the centre the next day to collect test results which might increase community transmission. To mitigate such disadvantages, we developed a
smartphone-based RT-PCR record and monitoring app ‘mobEVID’.
This app has been built following Novel coronavirus RT-PCR app developed by the Indian Council of Medical Research [2]. After developing a beta version of the app, we consulted with a group of national experts (including people engaged with RT-PCR testing, health policymakers,
hospital administrators, researchers and clinicians). We demonstrated the contents and designs of the app to the experts. The app was further modified based on expert recommendations. We translated the materials of the app into Bangla following a rigorous process of translation and
back-translation by two bilingual researchers. This app allows users and laboratory personals to record COVID-19 test results and individual
medical records in the app and transmit them to a secure server for storage and use by clinicians. The user account contains four parts such including: (i) add new entry, (ii) repeat test, (iii) view personal details, and (iv) incomplete records. The 'new entry' part allows to create a new patient ID and is split into two sections, A and B. In section A, test participants provide their contact information such as name, address, email, phone number etc. and select information related to collected samples. In section B, the exposure history and medical records of the test participant are entered, for example, if the participants have recently travelled abroad or had contact with COVID-19 cases/suspected cases. In addition, clinical symptoms and conditions are presented as a drop-down menu to enter the participant's medical history. Finally, the details of the participant's hospitalization information are entered. On the other hand, the app allows any participants in Bangladesh to download the app and self-register as a user freely.
If a participant is tested for COVID-19, they can receive their RT-PCR test results rapidly through this app. Data from the app are stored securely in a central repository and can be exported in different formats (excel/pdf) to the local authority. This app can be used either in Bangla or English, which makes it more user friendly and interpretable to the users.
The mobEVID is a flexible option for both test providers and users to share primary information and test results rapidly. The app also contains up to date information on COVID-19 following national recommendations and medical records of the participants. These records are also helpful for clinicians treating the cases and inform the participants about their condition immediately for contact tracing, taking necessary action and monitoring progress. This app might be useful for government and policymaker to record COVID-19 cases, maintain a patient database and help prevent rapid community transmission of COVID-19 in Bangladesh.
Acknowledgement: We are thankful to Dr. Newaz Mohammed Bahadur, Dr. Firoz Ahmed, and Koushik Chandra Howlader to support us to build this apps.
References
[1] Venter M, Richter K. Towards effective diagnostic assays for COVID-19: a review. Journal of Clinical Pathology 2020;73:370-377.
[2] NIC EGov Mobile Apps “RT-PCR - Apps on Google Play.” Google, Google, 3 June 2020, play.google.com/store/apps/details?id=nic.hp.niv_reporting&hl=en.
*Correspondence
Dr Sheikh Mohammed Shariful Islam, MBBS, MPH, PhD, FESC
NHMRC Emerging Leader and National Heart Foundation Senior Research Fellow
Institute for Physical Activity and Nutrition, Deakin University,
221 Burwood Highway, Burwood 3125, Melbourne, Australia
Telephone: +61451733373, Email: shariful.islam@deakin.edu.au
As a interested candidate for histopathology speciality training, I had the opportunity to attend a lung MDT in which roughly 25 cases were discussed. The case load was huge and some cases were rushed. The rushed cases were to be rediscussed which is a good form of safety netting although not ideal. The histopathology consultant requested reminders so immunohistology or second readings do not get missed. It would truely revolutionise MDT meetings if standard double reading could become a routine practice although already done in majority of cases.
The author has shed light on the importance of double reading of slides along with impressive figures.
A second review of slides could be a way to not only reduce error, but also improve quality of care in terms of management and immunohistology.
Thank you so much for highlighting the importance of a routine second review prior to MDT meetings. During the taster session, I asked the Histopathology consultants if they encourage second reviews and was informed that wherever there is the slightest doubt, another consultant or sub-specialist would be consulted. It was reassuring to know that histopathologists can always benefit from their colleagues expertise.
This practice safeguards patients in the sense that a correct diagnosis can be made in all cases minimising potential errors.
Dear Editor,
before COVID-19, in the era of targeted therapies, pathologists played a cornerstone role in providing information especially about cancer diagnoses.1 Therefore, scientific community felt that autopsies were out-dated. Now, in this emerging reality, we are assisting to the transformation of the pathologist’s role: instead of proceeding to the “future” of molecular diagnosis we are going back to the “past” of our “noir” connotation. This negative meaning was linked, in the popular culture, to frequent post-mortem examinations performed by pathologist forgetting the paramount value of this medical procedure in explaining pathogenetic mechanisms of all diseases.2 During COVID-19 pandemia, Italian Hospitals changed their usual health department strategy. Hospital Governments strengthened intensive care units and lung units and decreased surgical activities. Pathologists’ role shifted from microscopic diagnosis back to the original mortuary role, setting aside optical microscope, the principal pathologist’s tool, and leaving space to necropsy activity with management of dead bodies by mortuary staff and pathologists in the perspective of threat of transmission of SARS-CoV-2.2 For this reason, Government has promptly implemented extraordinary and detailed measures to restrict viral spread from this source.3 In Italy, pathologists fill in death certificate, a legal instrument and a permanent record of an individual’s death, that requires accuracy, promptness,...
Dear Editor,
before COVID-19, in the era of targeted therapies, pathologists played a cornerstone role in providing information especially about cancer diagnoses.1 Therefore, scientific community felt that autopsies were out-dated. Now, in this emerging reality, we are assisting to the transformation of the pathologist’s role: instead of proceeding to the “future” of molecular diagnosis we are going back to the “past” of our “noir” connotation. This negative meaning was linked, in the popular culture, to frequent post-mortem examinations performed by pathologist forgetting the paramount value of this medical procedure in explaining pathogenetic mechanisms of all diseases.2 During COVID-19 pandemia, Italian Hospitals changed their usual health department strategy. Hospital Governments strengthened intensive care units and lung units and decreased surgical activities. Pathologists’ role shifted from microscopic diagnosis back to the original mortuary role, setting aside optical microscope, the principal pathologist’s tool, and leaving space to necropsy activity with management of dead bodies by mortuary staff and pathologists in the perspective of threat of transmission of SARS-CoV-2.2 For this reason, Government has promptly implemented extraordinary and detailed measures to restrict viral spread from this source.3 In Italy, pathologists fill in death certificate, a legal instrument and a permanent record of an individual’s death, that requires accuracy, promptness, and completeness and therefore they must take care of this delicate and sad situation having contact with infectious dead bodies. As well as other sanitary staff working with SARS-CoV-2 infected people, pathologists must wear personal protective equipment, like a clean protective outer garment, disposable gloves, a disposable surgical mask and appropriate eye protection. Since SARS-CoV-2 has been categorized as a hazard group 3 pathogen, autopsies of suspected COVID-19 deceased have been centralized in specific Hospitals with adequate autopsy rooms (equipped with negative pressure).4 As it happened in past with the explanation of pathogenetic mechanisms of several diseases, results of COVID-19 autopsies are thought to elucidate the biological bases of this new infectious disease. The aim of this report is to underline that the pandemia of COVID-19 represents a step back to past for pathologists, confirming the gold standard role of post-mortem examination in the progress of medicine and health care, as it happened till the seventies of the 20th century. The occurrence of an emerging, new pathology like COVID-19 restored the dignity of autopsies that will remain an essential tool to learn physiopathological mechanisms of diseases.
References
1. Masood S. The changing role of pathologists from morphologists to molecular pathologists in the era of precision medicine. Breast J 2020;26(1):27-34. doi: 10.1111/tbj.13728. Epub
2. Diebold J. Clinical autopsy—its role in modern medicine. Praxis (Bern 1994) 2007;96(43):1667-71.
3. Regione Lombardia Nota Direzione Generale Welfare 12/03/2020“Emergenza da COVID-19. Indicazioni in materia di attività funebre”
4. Hanley B, Lucas SB, Youd E, Swift B, Osborn M.Autopsy in suspected COVID-19 cases. J Clin Pathol 2020 doi: 10.1136/jclinpath-2020-206522. [Epub ahead of print]
Elizabeth H Blackburn and Jack Szostak discovered that a unique DNA
sequence in the telomeres protects chromosomes from degradation. Carol
Greider and Elizabeth Blackburn identified telomerase, the enzyme that
makes telomere DNA. These discoveries explained how the ends of the
chromosomes are protected by the telomeres and that they are built by
telomerase. If the telomeres are shortened, cells age....
Elizabeth H Blackburn and Jack Szostak discovered that a unique DNA
sequence in the telomeres protects chromosomes from degradation. Carol
Greider and Elizabeth Blackburn identified telomerase, the enzyme that
makes telomere DNA. These discoveries explained how the ends of the
chromosomes are protected by the telomeres and that they are built by
telomerase. If the telomeres are shortened, cells age. Conversely, if
telomerase activity is high, telomere length is maintained, and cellular
senescence is delayed. This is the case in cancer cells, which can be
considered to have eternal life [1]. Cancer cells have the ability to
divide infinitely and yet preserve their telomeres. How do they escape
cellular senescence? One explanation became apparent with the finding that
cancer cells often have increased telomerase activity [1] Telomeres,
repeated sequences of DNA at the end of chromosomes, prevent degradation
of genetic material. Each time chromosomes replicate a small amount of
the DNA at both ends is lost, by an uncertain mechanism. Because human
telomeres shorten at a much faster rate than many lower organisms, we do
speculate that this telomere shortening probably has a beneficial effect
for humans, namely mortality. The telomere hypothesis of aging postulates
that as the telomeres naturally shorten during the lifetime of an
individual, a signal or set of signals is given to the cells to cause the
cells to cease growing (senesce). At birth, human telomeres are about
10,000 base pairs long, but by 100 years of age this telomere reduces to
about 5,000 base pairs. Scientists discovered an important enzyme that can
turn the telomere production on the DNA molecule "on" and "off." It's
called telomerase. It seems that as we get older, the amount of telomerase
in our cells decreases. Naturally, the exploration of this enzyme is now
the focus of much investigation, but unfortunately the research is aimed
at understanding how to turn telomeres "off" to limit the spread of
"immortal" cancer cells. Telomerase is actually an enzyme (a catalytic
protein) that is able to arrest or reverse this shortening process.
Normally, telomerase is only used to increase the length of telomeres
during the formation of sperm and perhaps eggs, thus ensuring that our
offspring inherit long "young" telomeres to propagate the species. The
telomere hypothesis of cancer is that the function of telomere shortening
is to cause cells that have lost normal control over growth to senesce
(i.e. stop growing) before being able to replicate enough times to become
a tumor, thus decreasing the frequency of cancer. Immortal cells like
cancer have an unfair advantage over normal human cells which are designed
to senesce. But nature seems to have planned this human telomere
shortening perhaps to prolong life by hindering the otherwise unchecked
growth of non-immortal or benign tumors. Malignant, or immortal tumors can
simply outlive the rest of the organism. Malignant cancer cells are being
studied because they appear to have altered the shortening of telomeres by
turning "on" the telomerase. Thus it appears that some cancers and aging
are both connected with the biology of telomeres. So telomerase-inhibiting
drugs would probably kill the cancer cells before much damage is done to
normal cell
Today reduction in mortality in breast cancer is due to early
detection through screening by mammography. However at least 25%
reduction in mortality could have been achieved due this screening
procedure [early-stage pre menopausal breast cancer, for example, 10-year
survival rates is today 68% for African Americans versus 77% for
Caucasians]. Besides these there played other factors also and these are
1) systemic or improved systemic treatment with chemotherapy 2) adjuduvant
therapies after surgery to eliminate micro metastasis like Her2 Nue
antagonist Herpentine and to prevent recurrences. Women with steroid
hormone receptor[ER+ or PR+] positive and negative cases are benefited by
Cyclopshomide & methotraxate & 5 FU chemotherapeutic agents. More
effective adjuduvant endocrine treatments are with variuous aromatase
inhibitors like letrozole or anastrozole.
Cases of breast cancers occur even when there is no family history or only
a few cases in elderly relatives are known as sporadic breast cancer.
Hereditary breast cancer is different from those of sporadic breast cancer
.The increased risk of breast cancer for those with a family history may
be caused by inherited factors (genes) like BRCA1 and BRCA2,[both the
genes protects breast cells from developing cancer. Certain mutations in
BRCA1 stop the gene working properly and therefore make it more likely
that breast cancer will develop],or a combination of inherited factors and
lifestyle like no breast feeding or unmarried women. Having an increased
genetic risk by mutation of these two genes can lead to breast cancer
developing even at an earlier age. BRCA1 and TP53 genes are of high
penetrance genes for breast Cancers. Mutations in the rare high
penetrance breast cancer predisposing genes are BRCA1 and BRCA2 and they
account for 16 to 25% of the inherited component of breast cancers in the
world scenario.This, in turn, can have an impact on raising your family.
So is it today possible to do BRCA1 gene test for people that know they
carry a specific mutation that predisposes them to suffer from breast
cancer. It is a real fact that most Breast cancers develop sporadically
and not related with a familial history or hereditary BRCA genes. It is
thought that less than 5% of people those develop breast or bowel cancer
do so because of an inherited fault. Unless there is a strong family
history of breast cancer in you it is unlikely that your child will
inherit a gene that increases the risk of developing cancer. So splicing
off BRCA1 gene before embryo may be an advancement for medical technology
[2]. Mutations in TP53, which at same time may cause the Li Fraumeni
syndrome, STK11 gene causing Peutz Jeghers syndrome, and PTEN causing
Cowden syndrome are however very uncommon sporadic causes of breast
cancers of NOS type, as are mutations in CDH1, although these mutations
may be highly penetrant for breast cancer The intermediate penetrance
breast cancer susceptibility genes are mutations in ATM, CHEK2, BRIP1,
BARD1, and PALB2. They can cause an increased odds ratio for breast cancer
of 2 to 4. These genes are all involved in the same DNA repair pathways,
but it is curious that they do not confer the high risk of breast cancer
seen in women who carry mutations in BRCA1 and BRCA2. Also of great
interest is that biallelic mutations in BRCA2, BRIP1, and PALB2 cause
Fanconi anaemia subtypes FANC D, J, and N respectively, further indicating
overlap in the functions of these genes. There are also good evidences now
that there are up to eight polymorphisms, which are reproducibly found to
influence breast cancer risk, particularly the FGFR2 gene. Carriers of two
low risk rs2981582 alleles at the FGFR2 locus (frequency 38% of the
population) have a relative risk of breast cancer of 0.83 compared with
the general population, carriers of one high-risk and one low-risk allele
(47%) have a relative risk of 1.05, and carriers of two high-risk alleles
(14%) have a relative risk of 1.26
Telomere crisis is also an important early event in the development
of breast cancer. In the breast, cells in a milk-collecting duct
occasionally proliferate excessively due to development of a regulatory
defect and results usual ductal hyperplasia." The chromosomes in these
growing cells lose a hundred or so base pairs of DNA every time they
divide," ,because the usual DNA replication processes don't copy DNA all
the way out to the ends of the chromosomes. This erodes the DNA sequences
that interact with proteins to form structures called telomeres, which
protect the chromosome ends. Eventually the DNA ends erode so much they
can no longer protect the chromosomes. When this happens the chromosomes
become unstable, and damage-control mechanisms kick in that kill the
unstable cells. This process, known as "telomere crisis Cells in which telomerase is activated can then proliferate indefinitely to form the next stage of cancer, known as 'ductal carcinoma in situ.' The mean telomere length is found decreased from normal tissue to carcinoma in situ, and decreased even more in invasive cancers of breast.
It was therefore proposed that breast cancer might be treated by eradicating telomerase. Several studies are underway in this area, including clinical trials evaluating vaccines directed against cells with elevated telomerase activity[1] "
Authors
Professor Pranab kumar Bhattacharya MD(cal), FIC path(Ind.)
Mr. Ritwik Bhattacharya, B.Com(cal)
Mr. Rupak Bhattacharya BSc
Mrs Dahlia Mukherjee BA (hons)
Miss Upasana Bhattacharya of Mahamyatala,
Dr. Debashis Bhattacharya Ms(cal) FRCS(Edin)
Dr. Diptendra Narayan Sarkar
Dr. Tarun Biswas MBBS(cal)-
Dr. Satyaki Mitra MD(PGT)
Dr. Avisnata Das MBBS(cal),
References
1] Press Release on the 5 October 2009 “The Nobel Prize in Physiology or
Medicine 2009� by The Nobel Assembly, consisting of at Karolinska
Institutet, Sweden
2] Response by Professor Pranab Kumar Bhattacharya Published by BMJ
on 4th feb 20009 .for the BMJ case reports Blog unnatural selection by
author Dean Jankens, published on 9th Jan 2009
Kapoor et al. (1) investigated pseudohyperkalemia in outpatients and
attributed many of the cases to hematological abnormalities or delay in
specimen centrifugation or clotting. Plasma is often recommended as the
preferred specimen in patients with leukocytosis, erythrocytosis or
thrombosis (2). Potassium released from ruptured cells during the clotting
process of serum specimens may result in false...
Kapoor et al. (1) investigated pseudohyperkalemia in outpatients and
attributed many of the cases to hematological abnormalities or delay in
specimen centrifugation or clotting. Plasma is often recommended as the
preferred specimen in patients with leukocytosis, erythrocytosis or
thrombosis (2). Potassium released from ruptured cells during the clotting
process of serum specimens may result in false-positive reporting and
unnecessary therapy (3). Others have reported on a phenomenon known as
reverse pseudohyperkalemia in patients with leukocytosis where potassium
concentrations in plasma specimens exceeded concentrations in serum (4).
We describe a similar case of reverse psuedohyperkalemia. A 87-year-
old man with chronic lymphocytic leukemia (CLL) was treated for the past 2
years as an outpatient. He received cyclophosphamide, vincristine, and
rituximab chemotherapeutic agents as part of his treatment plan. Blood was
collected in serum separator (SST) and EDTA tubes for routine metabolic
and hematology studies. The potassium concentration averaged 3.7 mmol/L on
a Beckman DXC chemistry analyzer (n=11). His white blood cell (WBC) and
platelet counts averaged 306 x 109 cells/L (94-97% lymphocytes) and 95 x
109 platelets/L over this time period. Recently, he was admitted to the
ED. Specimens were collected for metabolic (lithium-heparin specimen with
separator gel) and hematology (EDTA plasma) analyses. The specimens were
transported by pneumatic tube, and time from collection to analysis was
<60 min. The potassium concentration was 7.5 mmol/L; similar results
were obtained on a second analyzer. No hemolysis was observed. The
hematology results supported a known diagnosis of CLL but all other
laboratory data was within normal limits. Pseudohyperkalemia was
investigated. Additional venous blood specimens were collected in lithium-
heparin with a separator gel and a SST tubes. The specimens were
immediately transported to the lab by pneumatic tube (<5 min transport
time), promptly centrifuged (5 min at 3500 rpm) or allowed to clot (30
min; then centrifuged for 5 min at 3500 rpm) and analyzed. The plasma
specimen exhibited significantly higher potassium (7.4 mmol/L)
concentration compared with the serum specimen (3.9 mmol/L). A significant
layer of WBC was evident on the packed erythrocyte layer in the lithium-
heparin tube. No WBC layer was observed in the serum specimen. Four days
later, a similar occurrence (lithium-heparin potassium = 6.4; serum
potassium = 4.2 mmol/L) was observed on the same in-patient.
Some cells, especially malignant ones are susceptible to in-vitro
heparin-induced cell membrane damage during specimen processing resulting
in diffusion of potassium into the supernatant from ruptured leukocytes.
Similar cases in other leukemia patients have been observed in our
laboratory. Both laboratorians and clinicians should be aware of this
phenomenon to minimize false-positive reporting and unnecessary therapy.
1. A K Kapoor, AK, Ravi A, Twomey PJ. Investigation of outpatients
referred to a chemical pathologist with potential pseudohyperkalaemia. J
Clin Pathol 2009; 62:920-923.
2. Ifudu O, Markell MS, Friedman EA. Unrecognized pseudohyperkalemia
as a cause of elevated potassium in patients with renal disease. Am J
Nephrol. 1992;12(1-2):102-4.
3. Sevastos N, Theodossiades G, Savvas SP, Tsilidis K, Efstathiou S,
Archimandritis AJ. Pseudohyperkalemia in patients with increased cellular
components of blood. Am J Med Sci. 2006 Jan;331(1):17-21
4. Abraham B, Fakhar I, Tikaria A, Hocutt L, Marshall J, Swaminathan
S, Bornhorst JA. Reverse pseudohyperkalemia in a leukemic patient. Clin
Chem. 2008 Feb;54(2):449-51.
Of all the prospective candidates for thyroid replacement therapy(1),
even when due account is taken of the improvent in left ventricular
diastolic function attributable to this treatment modality in patients of
mean age 39.9 with subclinical hypothyroidism(SCH)(2), the over 65s with
SCH are probably the ones least likely to be at cardiovascular
disadvantage if they do not receive thyroid replacement t...
Of all the prospective candidates for thyroid replacement therapy(1),
even when due account is taken of the improvent in left ventricular
diastolic function attributable to this treatment modality in patients of
mean age 39.9 with subclinical hypothyroidism(SCH)(2), the over 65s with
SCH are probably the ones least likely to be at cardiovascular
disadvantage if they do not receive thyroid replacement therapy(3)(4). In
a longitudinal study of risk factors for development of cardiovascular
disease(CVD) in 3233 adults aged 65 or more with baseline serum
thyrotropin(TSH) levels(including 496 with SCH characterised by serum TSH
>4.5 mU/l but < 20.0 mU/l) no difference was documented between SCH
and euthyroidism for incident coronary heart disease and CVD death(3).
Likewise, among 427 subjects of mean age 73 with SCH(characterised by mean
TSH 8.1 mU/l) and coexisting type 2 diabetes, there was no relationship
between baseline TSH and cardiovascular mortality(4). Furthermore, on
follow-up of SCH for 5 or more years, this disorder was not additive to
the relatively higher cardiovascular risk attributable solely to type 2
diabetes(4). Finally, in a prospective longitudinal study evaluating
disability in daily life, depressive symptoms, cognitive function, and
mortality in 558 subjects aged 85(including 67 with TSH in the range 4.8
mU/l to 33 mU/l, some of whom were subclinically hypothyroid, and others
overtly hypothyroid), who were followed up for 4 years, all measures of
performance significantly deteriorated with time, but increasing baseline
levels of TSH were not associated with accelerated increase in disability
in activities of daily living, depressive symptoms, or cognitive decline
during follow-up. If anything, "increasing TSH levels at baseline were
associated with a significant(p=0.03) decelerated increase in disability
in instrumental ADLs(activities of daily living". Furthermore, increasing
baseline TSH levels were associated with lower mortality on 4 year follow-
up(5). Accordingly, especially in subjects aged 85 or more with SCH
characterised by TSH < 33 mU/l, there should be no "rush" to initiate
thyroid replacement therapy, because it appears to confer no improvement
in quality of life, and definitely neither cardiovascular benefit nor
survival benefit.
(2) Yazici M., Gorgulu S., Sertbas Y et al
Effects of thyroxin therapy on cardiac function in patients with
subclinical hypothyroidism: index of myocardial performance in the
evaluation of left ventricular function
International Journal of Cardiology 2004;95:135-143
(3)Cappola AR., Fried LP., Arnold AM et al
Thyroid status, cardiovascular risk, and mortality in older adults
JAMA 2006;295:1033-1041
(4)Sathyapalan T., Manuchehri AM., Atkin SL
Subclinical hypothyroidism is associated with reduced all-cause mortality
in patients with type 2 diabetes
Diabetes Care 2010;33:e37
(5)Gussekloo J., van Exel E., de Craen AJM et al
Throid status, disability and cognitive function, and survival in old age
JAMA 2004;292:2591-9
Further to our 2019 paper entitled ‘Impact and importance of a centralised review panel for lymphoma diagnostics in the WHO era: a single centre experience’, we write to report on the impact of the subsequent introduction of a centralised lymphoma review network in Ireland.
We previously described a discordance rate of 7.8% (14/179) between referral and review lymphoma diagnoses sent to St. James’s Hospital (SJH) Dublin for multi-disciplinary team (MDT) review between 2013-2016. Since then a formal lymphoma review network has been established in Ireland, resulting in a significant increase in lymphoma cases reviewed at SJH. 736 lymphoma cases were reviewed between 2017-2019, of which 0.007% had a discordant diagnosis (5/736). This rate is markedly lower than that previously reported in the published literature (6-48%) [1, 2].
This dramatic reduction in the level of discordant lymphoma diagnoses demonstrates the positive impact of centralized review networks with specialist haematopathologist input upon lymphoma diagnostics in Ireland. This trend is most likely attributable to the fact that cases are now referred directly to SJH for Specialist Haematopathologist opinion pre-diagnosis, where the necessary ancillary tests required for accurate diagnosis are available on site. Additionally, as previously discussed by Bowen et al, rates of diagnostic discrepancies tend to be higher in non-academic institutions compared to academic institutions...
Further to our 2019 paper entitled ‘Impact and importance of a centralised review panel for lymphoma diagnostics in the WHO era: a single centre experience’, we write to report on the impact of the subsequent introduction of a centralised lymphoma review network in Ireland.
We previously described a discordance rate of 7.8% (14/179) between referral and review lymphoma diagnoses sent to St. James’s Hospital (SJH) Dublin for multi-disciplinary team (MDT) review between 2013-2016. Since then a formal lymphoma review network has been established in Ireland, resulting in a significant increase in lymphoma cases reviewed at SJH. 736 lymphoma cases were reviewed between 2017-2019, of which 0.007% had a discordant diagnosis (5/736). This rate is markedly lower than that previously reported in the published literature (6-48%) [1, 2].
This dramatic reduction in the level of discordant lymphoma diagnoses demonstrates the positive impact of centralized review networks with specialist haematopathologist input upon lymphoma diagnostics in Ireland. This trend is most likely attributable to the fact that cases are now referred directly to SJH for Specialist Haematopathologist opinion pre-diagnosis, where the necessary ancillary tests required for accurate diagnosis are available on site. Additionally, as previously discussed by Bowen et al, rates of diagnostic discrepancies tend to be higher in non-academic institutions compared to academic institutions such as SJH [3]. We believe that the ongoing educational component of the centralized review network, involving regular feedback and annual teaching sessions for pathologists in referring hospitals, has further improved the initial discordance rate.
We anticipate that this new low rate of discordance will be maintained in our institution, providing patients with an accurate diagnosis with which to best direct therapeutic considerations.
Kind regards,
Dr. Kate Dinneen
Specialist Registrar in Histopathology
St. James’s Hospital, Dublin, Ireland
Trinity College Dublin, Ireland
Dr Richard Flavin
Consultant Histopathologist
St. James’s Hospital, Dublin, Ireland
Trinity College Dublin, Ireland
References
1. Lester, J.F., et al., The clinical impact of expert pathological review on lymphoma management: a regional experience. Br J Haematol, 2003. 123(3): p. 463-8.
2. LaCasce, A.S., et al., Comparison of referring and final pathology for patients with non-Hodgkin's lymphoma in the National Comprehensive Cancer Network. J Clin Oncol, 2008. 26(31): p. 5107-12.
3. Bowen, J.M., et al., Lymphoma diagnosis at an academic centre: rate of revision and impact on patient care. Br J Haematol, 2014. 166(2): p. 202-8.
In the last few months, starting from the late 2019 in the area of Wuhan, China, an enormous increase in the number of infections due to SARS-coronavirus-2 (SARS-CoV-2) has been witnessed worldwide.[1-2] So far, 16 April 2020, the Situation report of the World Health Organization (WHO) has reported 1,914,916 confirmed cases and 123,010 deaths, of which 84,607 in the European Region.[2] This data could be itself sufficient to testify the importance of the on-going pandemic, which is further confirmed by the uncertainties regarding the possibility of gaining a natural or vaccine-mediated lifelong immunity. It is a matter of fact that, until the discovery of a vaccination, and maybe beyond that, it is likely that the world will have to deal with the virus and its long-time consequences for years. This necessarily imply that measures to deal with SARS-CoV-2 in all aspects, from life until death and post-mortem examination, have to be figured out and put in place.
A growing issue regards the distinction between “died from” and died with” SARS-CoV-2, which would be fundamental in order to gain knowledge on several issues including lethality of the virus, trend of death rate, and to compare data from different countries and regions (e.g. higher SARS-CoV-2 death rate per 1,000 infections are reported for Italy, UK and Belgium, while it is very low in Germany, Turkey and South Korea.[3] A complete post-mortem examination is probably an irreplaceable mean of distinguishing bet...
In the last few months, starting from the late 2019 in the area of Wuhan, China, an enormous increase in the number of infections due to SARS-coronavirus-2 (SARS-CoV-2) has been witnessed worldwide.[1-2] So far, 16 April 2020, the Situation report of the World Health Organization (WHO) has reported 1,914,916 confirmed cases and 123,010 deaths, of which 84,607 in the European Region.[2] This data could be itself sufficient to testify the importance of the on-going pandemic, which is further confirmed by the uncertainties regarding the possibility of gaining a natural or vaccine-mediated lifelong immunity. It is a matter of fact that, until the discovery of a vaccination, and maybe beyond that, it is likely that the world will have to deal with the virus and its long-time consequences for years. This necessarily imply that measures to deal with SARS-CoV-2 in all aspects, from life until death and post-mortem examination, have to be figured out and put in place.
A growing issue regards the distinction between “died from” and died with” SARS-CoV-2, which would be fundamental in order to gain knowledge on several issues including lethality of the virus, trend of death rate, and to compare data from different countries and regions (e.g. higher SARS-CoV-2 death rate per 1,000 infections are reported for Italy, UK and Belgium, while it is very low in Germany, Turkey and South Korea.[3] A complete post-mortem examination is probably an irreplaceable mean of distinguishing between these classes of deceased, by providing a multidisciplinary study of all organs and an extensive sampling of tissues, and of lowering the risks of misdiagnosis.
Legal medicine is the field where “mors gaudet succurrere vitae” (literally, death founds pleasure in helping life), or “the dead can speak to livings”.[4] Post-mortem examinations might suggest a mechanism of health harm, prevent the spread of a novel disease, control medical quality, arise suspicion toward a sign and even hint for a specific treatment and a preventive role of post-mortem examinations has been long declared.[5-7]
For example, the identification of pulmonary thromboemboli at post-mortem examination of patients who died from SARS, together with occlusions and microthrombosis of lung vessels in SARS-CoV-2 lung dissection and D-dimer elevation in patients now suggest the possibility of a therapeutic role of anticoagulant, heparin and low molecular weight heparin (LMWH) against SARS-CoV-2 infection.[8-11] Data regarding the true mechanism leading to death with SARS-CoV-2 are lacking, and it is unknown if a major role is played by respiratory acute insufficiency, multi-organ failure, cytokine release syndrome or hyper-response of the immune system, by haematological abnormalities, triggered within a disseminated intravascular coagulation (CID) syndrome or by all these mechanisms, in a different time from the contagion.[12-14]
So far, clinical criteria, e.g. onset of relevant symptoms before the death, have been applied, limiting the postmortem examination to the only collection of tissues (e.g. lung biopsies) and biological fluids to confirm the occurred infection by SARS-CoV-2. [15] Indeed, it is fundamental to limit the risks for health care professionals. [15] However, this could be a bit limitative, since the mere presence of a SARS-CoV-2 in the body does not prove that the deceased actually died because of it, even though a certified infection is surely a strong hint. Additionally, it is not clear whether the sensitivity of swabs might be affected in the post-mortem period, if false negatives could occur, due to a death of SARS-CoV-2 when the host succumbs and the timing of this negativity with respect to the time of death.
Finally, post-mortem examination of patients affected by SARS-CoV-2, healed and later died might provide an opportunity to ass long-time effects of the virus on lungs, hearts and other tissues.
For the above-mentioned reason, we would like to remark the importance of performing post-mortem examinations in this era of SARS-CoV-2 pandemic spread, provided that guidance to limit the risks for workers are respected and appropriate precautions put in place.[16]
Given the importance of a homogenization process regarding the death numbers due to SARS-CoV-2, borrowing a concept used in forensic toxicology for novel psychoactive substances (the scientific knowledge of which, as in the case of SARS-CoV-2 is still limited),[17] we would also like to suggest the adoption of a shared scale in the evaluation of the role of SARS-CoV-2.
In the evaluation the following factors are suggested:
1. Presence and severity of the infection by SARS-CoV-2, as assessed by in vivo data, including swabs, clinical records, radiological imaging, and post-mortem samples, including once again swabs, blood lower respiratory tract or any other sample.[15] When available, in vivo data are useful to assess if the victim has been infected, possessed risk factors for mortality and was suffering from symptoms suggestive of SARS-CoV-2 or not.[18] Post-mortem examinations on the other hand might provide insights on tissues not accessible in livings and multiple samples. [15, 19]
2. Presence and severity of previous diseases. These could have a role in facilitating the accidental contact between SARS-CoV-2 and the victim, as in the case of a hospitalized person who came in tight contact with an infected patient and acquired the infection in this setting, or of an immune-depressed patient. The latter is not only characterized by a facilitated contagion, in comparison with a healthy subject, but also a different natural history of the SARS-CoV-2 infection, been on one hand less prone to an abnormal physiological response, on the other extremely more exposed to the direct harm caused by the pathogen.
3. Circumstances of the death. These are of paramount importance, especially for the exclusion of SARS-CoV-2 as a cause of death, as in road traffic fatal accidents, gunshot-wounds, asphyxia, burns etc. It is clear that an external traumatic event, occurred after the contraction of the virus, could break the chain of the even, or better substitute itself, leading to death in an independent manner with respect to CoV-2. Is this the extreme case of an infected asymptomatic patient which is struck by a vehicle or shot to dead by military forces, as recently occurred in Africa due to curfew violation.[20]
Suicides should be evaluated carefully, since they do not automatically exclude a contribution of SARS-CoV-2, even though in an indirect way. For examples, it has been reported by the news that suicides occurred due to the fear of having infected other people. Circumstances are also fundamental in order to ascertain the risk of contagion, as in the case of people in close contact with patients because co-inhabitants or due to professional setting, as for doctors. A high index of suspect should be always maintained in the latter case, given the likelihood of an infection.[21]
4. Post-mortem radiology. Especially when in vivo imaging is not disposable, chest X-ray or, even better, post-mortem computerized tomography (PMCT) or a “virtopsy” approach could facilitate the retrieval of typical features of SARS-CoV-2. Of course, the decision to submit a suspected CoV-2 victim to an expensive and time-consuming (considering the pre-scan and post-scan necessities, as to disinfect the room) PMCT should be evaluated case-by-case and is not mandatory. Most importantly, its execution should not negatively impact clinical routine and the necessities of living patients.
5. Pathologic macroscopic and microscopic findings. Lungs and respiratory airways appear as the primary target of the infection and certainly their analysis should be as accurate as possible. Some data has already been published on persons with certified infection and could be useful to assess a compatibility of cases to the described features. [15, 19, 22-24]. Though, iatrogenic damage due to medications or devices, as in the case of alveolar hyper-insufflation in the course of mechanical ventilation, is possible and should be considered carefully. Moreover, myocardial, liver and multi-organ failure has been described.[23, 25]
6. Toxicological evaluation. A toxicological screening of common drugs of abuse could be important to exclude acute intoxications. Moreover, in the cases of patients prescribed multiple drugs, an evaluation of concentrations could be useful to assess if levels were within therapeutic ranges or exceeded them, suggesting a potential overdose.
7. Additional analyses should be performed whenever suggested by circumstantial, clinical or necroscopic data.
A possible SARS-CoV-2 significance score or CSS could be classified in four-points, in order to provide a fast assessment tool, which could be used in order to help establishing the cause of death for the Judicial Authority, as follows:
• 0 when SARS-CoV-2 was merely an occasion, but does not upsurge to the role of cause of death. An occasion is classified by its insignificance with respect to the death, exchangeability, ineffectiveness, non-indispensability.[26] An example is that of a old victim, with multiple increasing episodes of acute pulmonary edema due to cardiac chronic decompensation in the last stage, whose conditions are so severe that he succumbed to the mere rhinitis manifestations of SARS-CoV-2 and would have died even in the presence of usually well-tolerated pathogens.
• 1, i.e. low, when SARS-CoV-2 was present and a causative role cannot be excluded, even though an alternative leading cause of death is likely. An example could be that of a victim with multi-organ failure due to failed transplant, who suffers of multiple opportunistic infections, including low symptomatic SARS-CoV-2.
• 2, i.e. medium SARS-CoV-2 has likely contributed to death, even if additional factors might have had a prominent role. An example could be that of a victim with past history of haemorrhages and a poor haemostatic balance, who receives LMWH or other similar medications due to massive SARS-CoV-2-induced CID and dies of cranial hemorrhage.
• 3, i.e. high: SARS-CoV-2 with all probability was the leading cause to death.
A CSS could remain U= unclassified/unclear, when not enough data is disposable, until the execution of additional analyses, e.g. of swabs or microscopical analysis, or even after that, when the role of SARS-CoV-2 is unclear.
The so-presented scale tends to over-aestimate the role of SARS-CoV-2, though this seems necessary at this historic moment due to its diffusion and to the lack of knowledge regarding time course, natural history and mechanisms of injury.
Moreover, CSS should not be intended as a mathematic simplification of the process of post-mortem evaluation, a self-explanatory and sufficient response to a complex issue. Though CSS contains several elements of judgement and could lower the inhomogeneities in forensic evaluation of SARS-CoV-2, it is to be considered as an additional concise tool to be placed side by side with full medico-legal evaluation and discussion.
6. Byard RW. Preventive pathology revisited. Forensic Sci Med Pathol 2014;10(2):155-6. doi: 10.1007/s12024-014-9534-y. Epub 2014 Jan 23.
7. Buschmann CT, Tsokos M, Kleber C. Preventive pathology: the interface of forensic medicine and trauma surgery for pre-hospital trauma management. Forensic Sci Med Pathol 2015;11(2):317-8. doi: 10.1007/s12024-014-9603-2.
8. Chong PY, Chui P, Ling AE, et al. Analysis of deaths during the severe acute respiratory syndrome (SARS) epidemic in Singapore: challenges in determining a SARS diagnosis. Arch Pathol Lab Med 2004;128(2):195-204.
9. Fox SE, Aibek A, Harbert JL, et al. Pulmonary and Cardiac Pathology in Covid-19: The First Autopsy Series from New Orleans. medRxiv 2020.04.06.20050575. doi: https://doi.org/10.1101/2020.04.06.20050575
10. Luo W, Yu H, Gou J, et al. Clinical Pathology of Critical Patient with Novel Coronavirus Pneumonia (COVID-19). Preprints 2020, 2020020407.
11. Thachil J. The versatile heparin in COVID-19. J Thromb Haemost 2020. doi: 10.1111/jth.14821. [Epub ahead of print]
12. Henderson LA, Canna SW, Schulert GS, et al. On the alert for cytokine storm: Immunopathology in COVID-19. Arthritis Rheumatol 2020. doi: 10.1002/art.41285. [Epub ahead of print]
13. Tang N, Bai H, Chen X, et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 2020. doi: 10.1111/jth.14817. [Epub ahead of print]
14. Shi Y, Wang Y, Shao C, et al. COVID-19 infection: the perspectives on immune responses. Cell Death Differ 2020. doi: 10.1038/s41418-020-0530-3. [Epub ahead of print]
15. Hanley B, Lucas SB, Youd E, et al. Autopsy in suspected COVID-19 cases. J Clin Pathol 2020. pii: jclinpath-2020-206522. doi: 10.1136/jclinpath-2020-206522.
16. Osborn M, Lucas S, Stewart R, et al. The Royal College of Pathologists. Briefing on COVID-19 Autopsy practice relating to possible cases of COVID-19 (2019-nCov, novel coronavirus from China 2019/2020). Available from: https://www.rcpath.org/uploads/assets/d5e28baf-5789-4b0f-acecfe370eee622... Access date: 18 April 2020
17. Elliott S, Sedefov R, Evans-Brown M. Assessing the toxicological significance of new psychoactive substances in fatalities. Drug Test Anal 2018;10(1):120-126. doi: 10.1002/dta.2225.
18. Li X, Xu S, Yu M, et al. Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan. J Allergy Clin Immunol 2020. pii: S0091-6749(20)30495-4. doi: 10.1016/j.jaci.2020.04.006. [Epub ahead of print]
19. Barton LM, Duval EJ, Stroberg E, et al. COVID-19 Autopsies, Oklahoma, USA. Am J Clin Pathol 2020;aqaa062. doi: 10.1093/ajcp/aqaa062
21. Zhan M, Qin Y, Xue X, et al. Death from Covid-19 of 23 Health Care Workers in China. N Engl J Med 2020. doi: 10.1056/NEJMc2005696. [Epub ahead of print]
22. Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020;8(4):420-422. doi: 10.1016/S2213-2600(20)30076-X. Epub 2020 Feb 18.
23. Tian S, Xiong Y, Liu H, et al. Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies. Mod Pathol 2020. doi: 10.1038/s41379-020-0536-x.
24. Tian S, Hu W, Niu L, et al. Pulmonary Pathology of Early-Phase 2019 Novel Coronavirus (COVID-19) Pneumonia in Two Patients With Lung Cancer. J Thorac Oncol 2020. pii: S1556-0864(20)30132-5. doi: 10.1016/j.jtho.2020.02.010. [Epub ahead of print]
25. Yang F, Shi S, Zhu J, et al. Analysis of 92 deceased patients with COVID-19. J Med Virol 2020. doi: 10.1002/jmv.25891. [Epub ahead of print]
26. Puccini C. Istituzioni di Medicina Legale. Casa Editrice Ambrosiana 2003.
given the spread of Covid-19 infection with its serious consequences and given that the phenomenon has taken on partly unexpected epidemic dimensions which have required drastic Italian government restrictive measures to counteract its spread, in Our opinion it is legitimate to think of a reclassification of the risk category to which the pathogen Covid-19 belongs.
As it is known, Covid-19 is a viral pathogen of relatively recent acquisition in the human species which in its changed forms has presented over time health problems of growing social impact in different parts of the world and currently in Italy.
The SARS-1 (SARS-CoV, 2002, China) and MERS (2012, Saudi Arabia) forms have relatively little interest in Europe while the SARS-CoV-2 (China, Wuhan, 2019; Covid-19) has importantly spread in Italy.
So far beta-coronaviruses capable of causing disease in humans have been classified by WHO in the Risk Group (RG) 3: ”viral agent with high individual risk, but with a risk of collective spread assessed as low-moderate”.
So, the probability of propagation in the community of this virus was assessed as "moderate".
Also the NIH Guidelines defines the risk groups 3 as “high risk to an individual but a low risk to the community”
Furthermore, RG3 (NIH and WHO) is defined as to have efficient therapeutic approaches .
However, the present experience has led us to realize that Covid-19 has a very hig...
given the spread of Covid-19 infection with its serious consequences and given that the phenomenon has taken on partly unexpected epidemic dimensions which have required drastic Italian government restrictive measures to counteract its spread, in Our opinion it is legitimate to think of a reclassification of the risk category to which the pathogen Covid-19 belongs.
As it is known, Covid-19 is a viral pathogen of relatively recent acquisition in the human species which in its changed forms has presented over time health problems of growing social impact in different parts of the world and currently in Italy.
The SARS-1 (SARS-CoV, 2002, China) and MERS (2012, Saudi Arabia) forms have relatively little interest in Europe while the SARS-CoV-2 (China, Wuhan, 2019; Covid-19) has importantly spread in Italy.
So far beta-coronaviruses capable of causing disease in humans have been classified by WHO in the Risk Group (RG) 3: ”viral agent with high individual risk, but with a risk of collective spread assessed as low-moderate”.
So, the probability of propagation in the community of this virus was assessed as "moderate".
Also the NIH Guidelines defines the risk groups 3 as “high risk to an individual but a low risk to the community”
Furthermore, RG3 (NIH and WHO) is defined as to have efficient therapeutic approaches .
However, the present experience has led us to realize that Covid-19 has a very high propagation ability in the community as it spreads very easily from one individual to another, this is also reflected into the containment measures issued urgently by a number of National European governments.
In addition, for Covid-19 effective and validated therapies are not currently known and there is no vaccine available against it.
It should also be considered that validated serological diagnostics for Covid-19 infection are currently unavailable.
It therefore seems necessary to review the classification of the risk associated with Covid-19 infection and with it, it seems necessary to review the consequent safety levels (bio-containment), for laboratories that have to handle potentially infected material (WHO Laboratory biosafety manual, 2004, III edition).
The topic is of considerable importance as regards the autopsy activity on subjects with Covid-19 infection or with suspected Covid-19 infection.
This activity, prudently, should be carried out in safe environments and with procedures corresponding to those relating to the safety levels suitable for the biocontainment of RG4 agents, rather than those corresponding to the containment level for RG3.
Guidelines are urgently needed to help pathologists operate in the safest way, also contributing to harmonizing approach at European level.
It is proposed to ensure that:
1. in case of an ascertained death for SARS-CoV-2 (i.e. with a positive test for Covid-19) post-mortem autopsy should be avoided, unless the procedure is performed in environment and in ways appropriate for diagnostic activities at RG4 level;
2. in each hospitalized patient, molecular assessment (nasopharyngeal swab test) should be performed to determine Covid-19 presence;
3. when this first test is negative, a second diagnostic test should be carried out in the following 24 hours as recommended by the WHO;
4. when a person dies (irrespective if hospitalized or not), in the absence of documented molecular verification on Covid-19 presence, a nasopharyngeal swab should be performed just after having ascertained the death with the usual procedures;
5. in any case, when a documented valid verification on Covid-19 presence in the subject is absent, post-mortem invasive assessments and procedures should be carried out only with the precautions indicated for RG4;
6. in any case, based on the available medical documentation, in the present Covid-19 epidemic context the pathologist should be free to decide unquestionably whether to perform a complete autopsy or to perform a minimally invasive autopsy on selected areas of the body.
It is essential to remember that the goal of clinical pathology laboratory testing is not the acquisition of information itself, but to improve patient outcome through the promotion of proper laboratory test utilization, namely an appropriate test request and result utilization [1]. Given that pathology laboratory testing is reported to play a crucial role in 70% of clinical decisions and that the overall mean rate of inappropriate over-utilization is around 20% [2], innovations that rationalise and guide appropriate testing are welcome. Mahe et al are to be commended on defining an algorithm to determine which patients to test for the myeloproliferative neoplasm (MPN)-associated JAK2 V617F mutation [3]. Such an approach is particularly pertinent given that identification of this mutation has shifted from a confirmatory test for a relatively uncommon group of diseases to an advance screening test in the initial work up of patients in whom the numerous secondary causes that result in haematological indices similar to that of MPN have not been excluded. Also, the recent revision of World Health Organization classification of myeloid neoplasms lowered the threshold of haemoglobin level for considering a diagnosis of the MPN polycythaemia vera (PV) with a subsequent perceived and real impact on the level of JAK2 V617F testing [4, 5]. Using simple complete blood count (CBC) indices, Mahe et al found that application of their JAK2-tree algorithm to a historical dataset would hav...
It is essential to remember that the goal of clinical pathology laboratory testing is not the acquisition of information itself, but to improve patient outcome through the promotion of proper laboratory test utilization, namely an appropriate test request and result utilization [1]. Given that pathology laboratory testing is reported to play a crucial role in 70% of clinical decisions and that the overall mean rate of inappropriate over-utilization is around 20% [2], innovations that rationalise and guide appropriate testing are welcome. Mahe et al are to be commended on defining an algorithm to determine which patients to test for the myeloproliferative neoplasm (MPN)-associated JAK2 V617F mutation [3]. Such an approach is particularly pertinent given that identification of this mutation has shifted from a confirmatory test for a relatively uncommon group of diseases to an advance screening test in the initial work up of patients in whom the numerous secondary causes that result in haematological indices similar to that of MPN have not been excluded. Also, the recent revision of World Health Organization classification of myeloid neoplasms lowered the threshold of haemoglobin level for considering a diagnosis of the MPN polycythaemia vera (PV) with a subsequent perceived and real impact on the level of JAK2 V617F testing [4, 5]. Using simple complete blood count (CBC) indices, Mahe et al found that application of their JAK2-tree algorithm to a historical dataset would have reduced testing for this mutation by 15%, a considerable impact on workload [3]. Co-incidentally, another group have reported a similar attempt to refine JAK2 V617F testing for suspected PV by incorporating the immature platelet fraction into a CBC-based algorithm [6]. These two studies from Canada and New Zealand suggest that JAK2 V617F over-requesting is a widespread issue.
Given the specificity of the JAK2 V617F mutation for the MPN and the distinct haematological and clinical characteristics of these malignancies, it is disappointing to realise that similar to previous studies [7], Mahe et al note that the majority of JAK2 V617F requests had no clinical details provided. While obtaining CBC data for 95% of their historical cohort it should be mentioned that not all laboratories performing JAK2 V617F mutation studies might have access to corresponding CBC results, e.g. centralised genetic or molecular diagnostic facilities. Other (uncommon) instances that preclude application of this algorithm are when a bone marrow aspirate is provided for molecular analysis or in the acknowledged clinical scenario where splanchnic vein thrombosis unveils a haematologically latent MPN [8].
For other providers of a similar molecular diagnostic service it would be valuable for the authors to discuss how they actually intend to implement this algorithm prospectively and to educate users of their service. A review after a period of operation would reveal any issues regarding barriers to adherence and provide welcome evidence for reducing unnecessary JAK2 V617F testing in a real-world setting.
REFERENCES
1. Salinas M, López-Garrigós M, Flores E, et al. Managing inappropriate requests of laboratory tests: from detection to monitoring. Am J Manag Care 2016;22:e311-6.
2. Zhi M, Ding EL, Theisen-Toupal J, et al. The landscape of inappropriate laboratory testing: a 15-year meta-analysis. PLoS One 2013;8:e78962.
3. Mahe E, Mønsted Pedersen K, Çolak Y, et al. JAK2-tree: a simple CBC-based decision rule to guide appropriate JAK2 V617F mutation testing. J Clin Pathol 2019;72:172-6.
4. Sandes AF, Gonçalves MV, Chauffaille ML. Frequency of polycythemia in individuals with normal complete blood cell counts according to the new 2016 WHO classification of myeloid neoplasms. Int J Lab Hematol 2017;39:528-31.
5. Langabeer SE. An increase in diagnostic JAK2 V617F mutation testing: is masked polycythaemia vera the explanation? Eur J Intern Med 2018;52:e37-8.
6. Johnson S, Baker B. A CBC algorithm combined with immature platelet fraction is able to identify JAK2 V617F mutation-positive polycythaemia vera patients. Int J Lab Hematol 2019, Epub ahead of print, doi: 10.1111/ijlh.12967.
7. Langabeer SE. Referral centre variation in requesting JAK2 V617F mutation analysis for the investigation of a myeloproliferative neoplasm. J Clin Pathol 2012;65:1149-50.
8. Goulding C, Uttenhal B, Foroni L, et al. The JAK2 (V617F) tyrosine kinase mutation identifies clinically latent myeloproliferative disorders in patients presenting with hepatic or portal vein thrombosis. Int J Lab Hematol 2008;30:415-9.
Dear Sir,
We read with great interest the article by Marietjie Venter and Karin Richter on the diagnostic assay for COVID-19 [1]. We agree with the authors about delays in diagnoses, a severe shortage of tests and laboratory capacity for performing RT-PCR tests. This is especially true for many developing countries such as Bangladesh, which is faced with current health care crises to provide healthcare for more than 165 million population. A large number of people are being tested for COVID-19 and confirmed with the disease every day in Bangladesh, and many more remain undetected due to the lack of testing. Further, the delay to receive test results and lack of medical records cause COVID-19 patients to transmit the disease in the community and hamper proper treatments.
Prior to the COVID-19 test, several pre-conditional medical records are required to support the results. In Bangladesh, these records are generally gathered by health workers in the testing centres manually and ignoring many important symptoms and conditions. However, this
process is tedious and prone to omission, error and bias, leading to incomplete medical records. Further, participants are required to return to the centre the next day to collect test results which might increase community transmission. To mitigate such disadvantages, we developed a
smartphone-based RT-PCR record and monitoring app ‘mobEVID’.
This app has been built following Novel coronavirus RT-PCR app...
Show MoreAs a interested candidate for histopathology speciality training, I had the opportunity to attend a lung MDT in which roughly 25 cases were discussed. The case load was huge and some cases were rushed. The rushed cases were to be rediscussed which is a good form of safety netting although not ideal. The histopathology consultant requested reminders so immunohistology or second readings do not get missed. It would truely revolutionise MDT meetings if standard double reading could become a routine practice although already done in majority of cases.
The author has shed light on the importance of double reading of slides along with impressive figures.
A second review of slides could be a way to not only reduce error, but also improve quality of care in terms of management and immunohistology.
Thank you so much for highlighting the importance of a routine second review prior to MDT meetings. During the taster session, I asked the Histopathology consultants if they encourage second reviews and was informed that wherever there is the slightest doubt, another consultant or sub-specialist would be consulted. It was reassuring to know that histopathologists can always benefit from their colleagues expertise.
This practice safeguards patients in the sense that a correct diagnosis can be made in all cases minimising potential errors.
Dear Editor,
Show Morebefore COVID-19, in the era of targeted therapies, pathologists played a cornerstone role in providing information especially about cancer diagnoses.1 Therefore, scientific community felt that autopsies were out-dated. Now, in this emerging reality, we are assisting to the transformation of the pathologist’s role: instead of proceeding to the “future” of molecular diagnosis we are going back to the “past” of our “noir” connotation. This negative meaning was linked, in the popular culture, to frequent post-mortem examinations performed by pathologist forgetting the paramount value of this medical procedure in explaining pathogenetic mechanisms of all diseases.2 During COVID-19 pandemia, Italian Hospitals changed their usual health department strategy. Hospital Governments strengthened intensive care units and lung units and decreased surgical activities. Pathologists’ role shifted from microscopic diagnosis back to the original mortuary role, setting aside optical microscope, the principal pathologist’s tool, and leaving space to necropsy activity with management of dead bodies by mortuary staff and pathologists in the perspective of threat of transmission of SARS-CoV-2.2 For this reason, Government has promptly implemented extraordinary and detailed measures to restrict viral spread from this source.3 In Italy, pathologists fill in death certificate, a legal instrument and a permanent record of an individual’s death, that requires accuracy, promptness,...
Dear Editor,
Elizabeth H Blackburn and Jack Szostak discovered that a unique DNA sequence in the telomeres protects chromosomes from degradation. Carol Greider and Elizabeth Blackburn identified telomerase, the enzyme that makes telomere DNA. These discoveries explained how the ends of the chromosomes are protected by the telomeres and that they are built by telomerase. If the telomeres are shortened, cells age....
Dear Editor:
Kapoor et al. (1) investigated pseudohyperkalemia in outpatients and attributed many of the cases to hematological abnormalities or delay in specimen centrifugation or clotting. Plasma is often recommended as the preferred specimen in patients with leukocytosis, erythrocytosis or thrombosis (2). Potassium released from ruptured cells during the clotting process of serum specimens may result in false...
Dear Editor
Of all the prospective candidates for thyroid replacement therapy(1), even when due account is taken of the improvent in left ventricular diastolic function attributable to this treatment modality in patients of mean age 39.9 with subclinical hypothyroidism(SCH)(2), the over 65s with SCH are probably the ones least likely to be at cardiovascular disadvantage if they do not receive thyroid replacement t...
Dear Editor,
Further to our 2019 paper entitled ‘Impact and importance of a centralised review panel for lymphoma diagnostics in the WHO era: a single centre experience’, we write to report on the impact of the subsequent introduction of a centralised lymphoma review network in Ireland.
We previously described a discordance rate of 7.8% (14/179) between referral and review lymphoma diagnoses sent to St. James’s Hospital (SJH) Dublin for multi-disciplinary team (MDT) review between 2013-2016. Since then a formal lymphoma review network has been established in Ireland, resulting in a significant increase in lymphoma cases reviewed at SJH. 736 lymphoma cases were reviewed between 2017-2019, of which 0.007% had a discordant diagnosis (5/736). This rate is markedly lower than that previously reported in the published literature (6-48%) [1, 2].
This dramatic reduction in the level of discordant lymphoma diagnoses demonstrates the positive impact of centralized review networks with specialist haematopathologist input upon lymphoma diagnostics in Ireland. This trend is most likely attributable to the fact that cases are now referred directly to SJH for Specialist Haematopathologist opinion pre-diagnosis, where the necessary ancillary tests required for accurate diagnosis are available on site. Additionally, as previously discussed by Bowen et al, rates of diagnostic discrepancies tend to be higher in non-academic institutions compared to academic institutions...
Show MoreIn the last few months, starting from the late 2019 in the area of Wuhan, China, an enormous increase in the number of infections due to SARS-coronavirus-2 (SARS-CoV-2) has been witnessed worldwide.[1-2] So far, 16 April 2020, the Situation report of the World Health Organization (WHO) has reported 1,914,916 confirmed cases and 123,010 deaths, of which 84,607 in the European Region.[2] This data could be itself sufficient to testify the importance of the on-going pandemic, which is further confirmed by the uncertainties regarding the possibility of gaining a natural or vaccine-mediated lifelong immunity. It is a matter of fact that, until the discovery of a vaccination, and maybe beyond that, it is likely that the world will have to deal with the virus and its long-time consequences for years. This necessarily imply that measures to deal with SARS-CoV-2 in all aspects, from life until death and post-mortem examination, have to be figured out and put in place.
Show MoreA growing issue regards the distinction between “died from” and died with” SARS-CoV-2, which would be fundamental in order to gain knowledge on several issues including lethality of the virus, trend of death rate, and to compare data from different countries and regions (e.g. higher SARS-CoV-2 death rate per 1,000 infections are reported for Italy, UK and Belgium, while it is very low in Germany, Turkey and South Korea.[3] A complete post-mortem examination is probably an irreplaceable mean of distinguishing bet...
Dear Editor,
given the spread of Covid-19 infection with its serious consequences and given that the phenomenon has taken on partly unexpected epidemic dimensions which have required drastic Italian government restrictive measures to counteract its spread, in Our opinion it is legitimate to think of a reclassification of the risk category to which the pathogen Covid-19 belongs.
As it is known, Covid-19 is a viral pathogen of relatively recent acquisition in the human species which in its changed forms has presented over time health problems of growing social impact in different parts of the world and currently in Italy.
The SARS-1 (SARS-CoV, 2002, China) and MERS (2012, Saudi Arabia) forms have relatively little interest in Europe while the SARS-CoV-2 (China, Wuhan, 2019; Covid-19) has importantly spread in Italy.
So far beta-coronaviruses capable of causing disease in humans have been classified by WHO in the Risk Group (RG) 3: ”viral agent with high individual risk, but with a risk of collective spread assessed as low-moderate”.
So, the probability of propagation in the community of this virus was assessed as "moderate".
Also the NIH Guidelines defines the risk groups 3 as “high risk to an individual but a low risk to the community”
Furthermore, RG3 (NIH and WHO) is defined as to have efficient therapeutic approaches .
However, the present experience has led us to realize that Covid-19 has a very hig...
Show MoreIt is essential to remember that the goal of clinical pathology laboratory testing is not the acquisition of information itself, but to improve patient outcome through the promotion of proper laboratory test utilization, namely an appropriate test request and result utilization [1]. Given that pathology laboratory testing is reported to play a crucial role in 70% of clinical decisions and that the overall mean rate of inappropriate over-utilization is around 20% [2], innovations that rationalise and guide appropriate testing are welcome. Mahe et al are to be commended on defining an algorithm to determine which patients to test for the myeloproliferative neoplasm (MPN)-associated JAK2 V617F mutation [3]. Such an approach is particularly pertinent given that identification of this mutation has shifted from a confirmatory test for a relatively uncommon group of diseases to an advance screening test in the initial work up of patients in whom the numerous secondary causes that result in haematological indices similar to that of MPN have not been excluded. Also, the recent revision of World Health Organization classification of myeloid neoplasms lowered the threshold of haemoglobin level for considering a diagnosis of the MPN polycythaemia vera (PV) with a subsequent perceived and real impact on the level of JAK2 V617F testing [4, 5]. Using simple complete blood count (CBC) indices, Mahe et al found that application of their JAK2-tree algorithm to a historical dataset would hav...
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