Dragi Weekly No. 278: COVID-19, LADA guidelines, vitamin D and asthma

Hello everyone! It is time for a new season of Dragi Webdo and time to go back to work for many. Here are the news that I have seen during the summer. To begin with, I can only recommend you to read the article about using placebo in chronic pain that was published in the BMJ and that shows that a placebo, even when telling it is a placebo, has a certain placebo effect and the importance of the patient-doctor relationship in the placebo effect. Have a good reading!

1/ Pharmacovigilance

The risk of lower limb amputation with canaglifozine was evaluated in the BMJ through a cohort study comparing canaglifozine to GLP-1 receptor agonist with propensity score match. The authors confirm the higher risk, but only for patients over 65 with a past medical history of cardiovascular disease. The number of patients to treat each year to cause an amputation (NNH) is 274.

The French Agency for Drug Safety informs about the risk of QT prolongation with levetiracetam, in order to prevent doctors associating it with other medications responsible for this cardiac abnormality.

2/ COVID-19

As we get closer to the end of school holidays (in the Northern hemisphere), the French association of community paediatricians and the French society of paediatrics have published guidelines building on the advice from the French Academy of medicine. They advise a reinforcement of immunization strategies: against influenza (according to the usual criteria, not for every child contrary to the USA) and against rotavirus (which is usually recommended in the USA). This last one is actually not recommended anymore in France since 2015 due to insufficient medical benefit, partly because of the risque of intussusecption. Limiting the prevalence of theses diseases may limit the burden of emergency rooms according to the authors. The press release of the Academy of medicine has only one reference, it's not much and the vaccine remains being not reimbursed. Regarding management of COVID-19 before 6 years old, the authors only recommend a screening test only for severe cases or persisting symptoms over 3 days or in case of contact with a COVID+ patient. For children over 6, all should be tested if symptomatic. The time off school should be at least 7 days and until symptoms disappear.

The BMJ has published an article regarding physical distancing, advising for 2 metres rather than 1 metre between people. They have also produced a table estimating the risk of transmission according to different situations:

An article in the JAMA has found out that, among patients hospitalized for COVID, 87% had a post-COVID syndrome, defined as symptoms persisting despite a normal PCR test. The patients had been followed for around 2 months and were presenting mostly with fatigue (53%), dyspnea (43%), joint pain (27%) and chest pain (22%).

3/ Respiratory medicine

I have already written several times about the possible benefit of vitamin D for childhood asthma (here and a bit there). In a study published in the JAMA, 200 children with vitamin D deficiency and an ICS-controlled asthma were randomized between a placebo group and a vitamin D 4,000 IU per day group. After 48 weeks, there had not been any improvement for the delay until the first severe exacerbation. One can regret that, in this article, there is not any information about the non-severe asthma attacks and the use of short-term relievers, but there was not any difference for ICS use. Overall, this study should be included in the next Cochrane meta-analysis on this topic.

In a NEJM study, the treatment with 3 days of amoxicillin was studied against placebo, for non severe pneumonias of children aged between 2 months and 5 years in Pakistan, in general practice. The reasoning was that, considering the pneumococcal vaccination, the amoxicillin was not useful anymore. As a matter of fact, with this vaccination, atypical pneumonia are the most frequent ones after 3 years old; macrolides do not have much use (see this Cochrane review). The failure rate at day 3 was significantly larger in the placebo group (NNT = 43; 4.8% vs 2.5%), no difference at day 14. So, we can draw 2 interesting findings: 3 days of amoxicillin seem to be enough, instead of 5; and even we miss a pneumonia, it seems to evolve favorably. 

4/ Diabetes

I wanted to finish with the guidelines regarding the Latent Autoimmune Diabetes in Adults (LADA), a diabetes mellitus intermediate between type 1 and type 2, affecting between 2 to 12% of the diabetic patients (quite a lot!). The diagnosis is usually made among patients over 30 years old with a low BMI and anti-GAD+ antibodies. These patients usually have a C-peptide that decreases much less faster than type 1 diabetes patients and therefore can be treated by non-insuline antidiabetic drugs. But few patients will have a low C-peptide and will require insulin. I won't discuss this further.

And that's all for the comeback ! Thanks for your loyalty. If not already done, do not hesitate to subscribe on Facebook, Twitter or to the newsletter by e-mail: you have to put your e-mail address in the top right field of this page and confirm the subscription in an e-mail entitled "FeedBurner Email Subscriptions" that will be sent to you and may land in your junk folder.

See you next week!

 

@Dr_Agibus (free translation by @carttom)

Dragi Weekly No. 277 : domestic violence (guidelines), hyperandrogenia (guidelines), diarrhea (guidelines), serological test COVID, oseltamivir, diacerein

Hello! This is the last Dragi Webdo of this season and we will be back from late August-early September. I am starting this blog post with an Irish article from the BJGP that discusses the workload of GPs and the distribution of their working hours according to duties: for around 10 hours a day of work, only 7 are dedicated to consultation (clinical consultation and prescription)!

1/ COVID-19

The BMJ has published a systematic review about the efficiency of screening serological tests. The authors find out that the sensitivity of ELISA tests is 84%, 66% for rapid tests/POC tests (LFIA) and 98% for the new techniques of chemiluminescent immunoassays (CLIA). All specificities are between 97 and 100%. A swab 3 weeks after the onset of symptoms could optimize the sensitivity of tests.

We already talked about vitamin D and the advice from the French Academy of Medicine. Finally, the BMJ confirms what I was saying: there is no proof that a supplementation would decrease the onset or the gravity of a COVID-19 infection.

And for the pleasure, as oseltamivir is not useful for the flu, some tried it for coronaviruses (not specifically for COVID). This study in the BJGP randomized patients with a positive coronavirus viral syndrome to be treated by oseltamivir or usual care. The time to recovery was 4 days with the antiviral drug versus 5 days (significant difference!). There is not enough data on the 300 included patients to study hospitalizations and adverse effects but 7 patients (5%) of the placebo group went to ED versus only 1 (1%) in the oseltamivir group. Overall, the benefit remains modest and the adverse effects were not studied to allow us to say if we should use it for COVID in general practice.

2/ Domestic violence

The French High Autority in Health has published guidelines about the screening and the management of domestic violence (against female partners only). One can think about it when the partner is too much controlling in the consultation, speaking instead of the patient or having contemptuous sayings. The guide offers some ready-made sentences, to be adapted, for example:

"Have you already been victim of any kind of violence (physical, verbal, psychological, sexual) in your life?"
"How does your partner behave with you?"
"Have you already been afraid of your partner?"

3/ Gastro-enterology

Guidelines were published about the prevention of child diarrhea due to antibiotics. The authors recommend prescribing Lactobacillus rhamnosus GG ou S. boulardii to decrease by 40% the risk of diarrhea onset with antibiotics (with an estimated NNT = 10 for amoxicillin+clavulanate and 30 for the other antibiotics). The authors say that antibiotics trigger a long-term dysbiosis, but the consequences of this are not that well evaluated and the long-term benefits of probiotics are not studied at all. I almost forgot: these guidelines are published with the support of Biocodex, a firm selling probiotics (they also produced guidelines favoring probiotics in all-cause diarrhea for kids, whereas the NEJM finds that useless). Overall, we know that for children with risk factors, probiotics decrease the risk of C. difficile infection (and this is useful) but otherwise, for the children, it is probably more useful to question the antibiotics prescription in a vast array of situations.

4/ Neurology

A BJGP article studied the association between the difference of blood pressure between the 2 arms and the cognitive decline. The authors actually find out that a systolic BP difference over 5 mmHg between the 2 arms was associated with a greater cognitive decline (>5 points on MMSE) among patients aged 66 on average with an initial MMSE score at 26. But we mostly see that patients with the greatest BP difference between the 2 arms (>10 mmHg) had an average BP 15 mmHg higher (142 vs. 158 mmHg). So, it is equally probably that it is their uncontrolled BP that increases the cognitive impairment, because of vascular dementia.

5/ Rheumatology

About osteoarthritis, a study compared the efficacy of celecoxib vs diacerein. The authors find out that diacerein 50 bd is not inferior to celecoxib 200 mg daily in this randomized tirat that used the WOMAC score at 6 month as the primary endpoint. The conclusion is, for me, always the same: it does not prove the efficacy of the diacerein, because 200 mg celecoxib is known to be a suboptimal dose allowing fewer adverse effects but without much efficacy. Therefore, diacerein is as efficient as an inefficient treatment (or celecoxib 200 mg daily is as inefficient as diacerein, which is known to be inefficient). The same team had already published the 200 mg celecoxib vs. glucosamine study with the same result and the same conclusion as the aforementioned study.

6/ Endocrinology

The French Society of Endocrinology has published guidelines about hyperandrogenism. The authors recommend to use cytoproterone acetate as a first-line treatment, associated with an estrogen. They warn that the former molecule at a dose of 35 µg does not have a market authorization as a contraceptive and that there is a higher cardiovascular risk with it, compared to the other contraceptives. The use of higher doses is not recommended because on one hand 100 mcg doses have not shown more efficacy than 35 mcg and on the other hand the ANSM reminded the risk of meningioma. The second-line drug is spironolactone (associated with a contraceptive), out of market authorization, with 100 mg dose that can be increased to 300 mg (ouch, when you see how hypertensive patients are with only 25-50 mg...).

Here come the holidays! I wish you a good summer. There might be some posts during the summer, we'll see. To be sure not to miss the back-to-school season, think about subscribing on on Facebook, Twitter or to the e-mail newsletter if not already done. You have to put your e-mail address in the top right field of this page and confirm the subscription in an e-mail entitled "FeedBurner Email Subscriptions" that will be sent to you and may land in your junk folder.

A la prochaine, passez un bon été !

See you next time, have a good summer!

@Dr_Agibus (free translation by @carttom)

Dragi Weekly No. 276 : COVID-19 (guidelines: ECDC, IDSA, Canada), HF related oedema, COPD, tramadol, lung cancer, students/GP

Hello everyone! Quite a bunch of interesting articles this week and I did not manage to stop myself... Have a good reading!

1/ Pharmacovigilance

We already talked about the superior addiction and mortality risks of tramadol. A new study, that was presented at the European congress of rheumatology, has similar findings. Indeed, patients treated with tramadol had a higher risk of death compared to NSAIDs users, and the use of tramadol was also associated to an increase in cardiovascular events, venous thrombotic events and hip fracture.

2/ COVID-19

The Infectious Diseases Society of America has developed guidelines about the diagnosis of COVID. What is emphasized is that RT-PCR on a nasopharyngeal swab is the reference and can be repeated in case of high suspicion for a symptomatic patient. For an asymptomatic patient, it is recommended to do a test in case of exposure or hospitalization for another reason if the prevalence is high in the community or if the patient is immunodeficient or before surgery and other acts with high risk of aerosolisation.

The European CDC has published guidelines regarding the use of air conditioning and fans in the context of COVID-19. A bad use of ventilation in tiny interior spaces is associated to an increase in the risk of transmission of respiratory diseases. Some studies emit the hypothesis that ventilation may increase the risk of COVID transmission but it could also be because these studies are done indoors. So, air conditioning can spread the droplets over longer distances indoors but air conditioning can also participate to air circulation which decreases the risk of transmission. However, fans that only spread particles without renewing indoor air with outdoor air are to be avoided. 

The Québec Society of Public Health has emitted advice on COVID+ patients who are deemed cured but who get a new positive PCR test. If the first positive test dates from less than 3 months ago, the patient is considered as cured with a persistence of the viral RNA and another cause for the current symptoms is to be sought. If the first positive test dates from more than 3 months and the patient is symptomatic, the test must be repeated, the number of "thermal cycles" must be counted and another cause should be looked for: in case of the absence of any other cause, the patient can be viewed as reinfected. Overall, the authors think that the immunity is protective for only 3 months after the iinital infection.

3/ Cardiovascular medicine

The BMJ offers an article regarding the management of peripheral oedema when caused by heart failure. After excluding another cause (renal failure, DVT, cellulitis, venous insufficiency, lymphoedema and medication adverse effects), the cause of the cardiac decompensation must be sought (non-adherence, insufficient treatment, acute kidney injury, BP surge, (N)STEMI, cardiac arrythmia, infection or iatrogeny such as NSAIDs). Then, one must look for other signs such as jugular venous pressure: it is measured with the patient inclined at 30-45° and the highest reflux point should not be 4 cm (= 1.57 inches) above the sternal angle of Louis (see picture). BNP dosing is only useful to establish the diagnosis of cardiac oedema, it is not useful for patients with known heart failure (see here and there).

For treatment, it is of course diuretics, especially loop diuretics. They must be started at small doses or by doubling the previous dose for patients already taking them. The efficacy is monitored 24 hours later with an increase in diuresis and a weight loss. If the diuresis does not increase, the diuretic dose can be increased (because of a threshold effect discussed here). It is advised not to go over 80 to 120 mg of furosemide daily. 40 mg of furosemide are equivalent of 1 mg of bumetanide. An increase of creatinine can be accepted up to 25% (or a GFR decrease up to 20%). After the acute episode, the diuretics have to be kept until the next consultation with the cardiologist except if the cause of the failure has been resolved.

4/ Screening

The USPSTF discusses the screening of illicit drugs use among teenagers and young adults. Its prevalence is estimated at 8% for use during the past month and 50% by the time they graduated from high school. So it is something that has been screened for a while, but it seems there is a lack of studies to evaluate the benefit-risk balance of this screening. More evidence on this topic shall be published!

This article from Annals of Family Medicine studied the applicability of community-based lung cancer screening since the American Academy of Family Physicians does not support it. Over 6,000 screenings that were performed, 15% of patients had a supplementary investigation, 6.6% an invasive procedure and 1.5% had a cancer diagnosed. There were 0.6% of adverse effects among all the patients (respectively 10% of those who had had an invasive procedure and 2% of mortality among those who had surgery performed on them). These figures are coherent with known data but overdiagnosis was not studied here.

Here is an article about a saliva test looking for high-risk HPV subtypes in order to diagnose oropharyngeal cancer. But is it relevant for larger screening procedures?

5/ Pneumology

A new study, ETHOS, compared triple therapy (ICS, LAMA and LABA) versus double therapy (LAMA+LABA) in COPD patients with CAT-score over 10 and with 2 episodes of exacerbation over the past year (only one was required if FEV1 < 50%) despite a double inhaled therapy. The authors found out that patients with triple therapy had a lower number of moderate or severe exacerbations by 24% per year for high steroid doses. It is even seen that patients with triple therapy had a lower mortality than those with double inhaled therapy (NNT=100)! The tritherapy is indeed superior for these patients and the increased risk of pneumonia (NNH=59) is not enough to decrease the mortality benefit. However, we know that ICS benefit is a staple for asthma, yet despite patients with asthma were excluded from the study, 30% patients from the study were positive for reversibility on spirometry after bronchodilatators. Morevover, the patients with an uncontrolled CAT and exacerbation episodes despite a bitherapy are classified as GOLD D stage and so have an indication for a triple therapy. Overall, this study only shows that current guidelines are adapted for patients not controlled with a double therapy (and it is one of the few times that a benefit on mortality is found out) and is absolutely not in favour of a triple therapy for patients of lower severity ; for the latter, the pneumonia risk weighs the balance in favour of the risks rather than benefits.

6/ Nephrology

A long time ago, a study was supposing that allopurinol could slow down the progress of CKD, but it was not that clear. This randomized controlled trial from the NEJM, including patients with an average GFR of 31 mL/min has not found any benefit from allopurinol on the decline of the renal function after 2 years.

7/ The qualitative study by @DrePetronille

About the choice of medical careers, this qualitative study of the week interrogated Canadian and British students during focus groups about their perception of the intellectual stimulation of general practice, in order to understand why GP positions are less chosen than other medical specialties. In favour of the choice of GP, the participants discussed the intellectual stimulation obtained thanks to the diversity of the consultations and patients, the high skill level that is required to deal with those and the incertitude about the activities of the day. They also evoked the possible career arrangements over time. On the contrary, some participants described GP as a speciality in which one does always the same thing, with the necessity to refer patients to specialists. This negative image of GP might have been favored by the image that medicine teachers project about this job across med school, the one of a speciality 'by default'. The interrogated students did not associate research with general practice, as research seemed to be more dedicated to specialists. GP teachers were seen as less visible than teachers from the other specialties by the students, who therefore do not have any role model. This study brings some leads to understand the perception of intellectual stimulation for the choice of speciality but should be completed with other studies regarding other aspects of the job: healthcare organization, administrative management.

Have a good week!

@Dr_Agibus (free translation by @carttom)

Dragi Weekly No. 275: Down syndrome, vulvovaginal candidiasis, ibuprofen, COVID-19/symptoms, aspirin/colorectal cancer, prostate cancer

Hello! To begin with, here is a simple handy guide about "healthcare professionals taking care of trans people". Have a good reading!

1/ Pharmacovigilance

A systematic review about the use of ibuprofen for children was published to produce a facts sheet, to compared with paracetamol. The main difference is an average apyrexia time of 2.5 hours with ibuprofen versus 2 hours with paracetamol, both treatments being able to lower the temperature by 1.6 °C (= 35 °F).  These treatments are responsible for rare adverse effects but there is a suspicion of a higher risk of secondary infection for ibuprofen.

2/ Infective diseases

The French Academy of Medicine discusses the unusual COVID-specific symptoms. The authors describe neurological impairments such as dysgueusia and anosmia but also memory disorders and Guillain-Barré syndromes. There is skin damage such as frostbites, dyshydrosis, urticaria, purpura and Kawazaki syndrome. Also, lymphopenia, hypokaliemia, hyperglycaemia and hyperlipidemia can be be observed.

The BMJ discusses vulvo-vaginal recurrent candidiasis that is defined by 4 episodes over 12 months (with at least 2 confirmed on a swab). Contributing factor must be sought: antibiotics, estrogens, HRT, diabetes, clothes, vaginal showers and daily pads. The clinical exam is mandatory and allows to distinguish between candidiasis, lichen sclerosus, vulvodynia, contact dermatitis and eczema (lichen simplex). The vaginal swab is required to look for both fungal and bacterial (including STI) causes. A fasting blood sugar can also be useful in this context. In case of Candida infection, a treatment by fluconazole 150 mg every third day during 6 days (3 doses total) followed by a weekly dose every week is proposed. In case of an infection with an other germ than Candida, 100,000 IU nystatin pessaries are recommended during 14 nights in a row every month for 6 months. It is not useful to screen sexual partners or to use probiotics but cetirizine can be useful in case of major itch.

	Candidiasis	Lichen sclerosus	Vulvodynia	Contact dermatitis	Lichen simplex
Erythema	+	+	+/−	+	+/−
Fissure	+/−	+/−	−	+/−	+/−
Exsudat	+	−	−	+/−	−
Oedema	+/−	−	−	+/−	+/−
Other	Satellite lesions	Palor, atrophia	Painful swabbing	Exsudat	Lichenification

Considering the current tick-borne encephalitis cluster in Auvergne-Rhône-Alpes, this disease has become a disease with mandatory notification.

3/ Oncology

I have already spoken about faecal calprotectin which seemed to be efficient to rule out an inflammatory or cancerous origin for intestinal transit disorders (see here). The French High Autority in Health re-evaluated its use to answer a query from professionals. Calprotectin might be useful for the initial investigations of transit disorders for patients with normal CRP and no red flags. A negative faecal calprotectin could allow to diagnose IBS, a colonoscopy being required if the test is positive. However, the HAS does not align totally with guidelines from other countries, finding that evidence is lacking and French studies must be conducted. This decision is partly due to disagreements about thresholds.

A Lancet study was published about the prescription of aspirin in prevention of colorectal cancer among very high-risk patients, with a Lynch syndrome (the topic is indeed in debate, see here). As their patients were having a regular follow-up because of their condition, we can assume that both groups were having systematic colonoscopies. In this article, the patients were followed up during 10 years and 9% of patients with aspirin have had a cancer vs 13% without. But there is no data about mortality.

Regarding prostate cancer, a new "PREDICT" algorithm allows to evaluate the mortality risk for the affected patients in order to discuss possible treatments.

On this topic as well, one can find in this NEJM article the graphs showing a decreased mortality for prostate cancer from the 90's. This trend is comparable to the ones for breast and lung cancer (without any screening available for the latter). We can also see that the numbers of patient to screen to avoid 1 death by lung cancer is between 380 and 570, whereas the number of patients to screen that can lead to overdiagnosis is between 11 and 18! Overall, around 30 overdiagnoses to reduce the specific (and not global) mortality of 1 patient.

4/ Genetics

Here is now a very comprehensive review article from the NEJM about Down syndrome. I will focus on the most common associated conditions and complications needed to be known for the regular follow-up of affected patients. 44% of patients have a cardiac malformation, 30% to 40% infections linked to immunodeficiency, more than 80% hearing impairment, 50% visual impairment, 50% thyroid disorder. Also, there are iron-deficiency anemias with an increased MCV and increased risk of leukemia and testicular cancer. The atlantoaxial instability is a source of complications but its screening does not yield any benefit on the risk of myelopathy.

5/ Diabetology

We already talked about it but a new Cochrane systematic review was published about metformin: there is no sound evidence for the efficacy of metformin versus no intervention, versus other antidiabetic drugs and versus behaviour changing interventions.

We were talking about the "time in range" (TIR) last week. It seems that at the #ADA2020 conference (American Diabetes Association), a study was presented with a decrease in cardiovascular events for patients with TIR >50-70% or TIR >70% versus patients with TIR <50%. But these measures were done on repeated self-tests and not on continuous glucose monitoring data.

Finished! To avoid missing anything, you should subscribe on Facebook, Twitter or to the e-mail newsletter if not already done. You have to put your e-mail address in the top right field of this page and confirm the subscription in an e-mail entitled "FeedBurner Email Subscriptions" that will be sent to you and may land in your junk folder.

See you next week !

@Dr_Agibus (free translation by @carttom)

Dragi Weekly No. 274 : Gout (guidelines), continuous glucose monitoring (guidelines), varicocele, rapid test for sore throat, bedbugs, migraine with aura

Hello!

Dragi Weekly is written by @Dr_Agibus, MD, who works and lives in France but targets an international audience (free translation by @carttom). We may only be interested by our analyses on international scientific literature and not by the content aimed at French doctors (such as French guidelines, specific medication alerts, French articles). But we still want you to have access to this content if you want to. So, to improve the clarity of blog posts between France-specific parts, links in French and English parts and links, here is a colour code:

- International content remains written in black
- Links in English remain written in blue
- France-specific content will be written in green from now on
- Links in French will be displayed in red.

Have a good reading!

1/ COVID-19

Articles about COVID are getting rarer. Here is a retrospective Chinese study of 2,800 hospitalized patients for COVID infection, which finds out that patients with HBP have a higher death risk than patients without. Among HBP patients, those treated by ACEi or ARB did not have an increased mortality risk compared to those treated with other medications. But the HBP patients without any treatment had an increased risk of death.

In concordance to the previous study, the European Medicines Agency (EMA) states as well that it is better to continue ACEi and ARB medications for COVID patients, considering the absence of evidence of more severe forms of COVID among patients taking those drugs in the most recent studies.

A BMJ study had a look at protective personal gear (PPE). 400 physicians and nurses were equipped with masks, gloves, protection glasses, facial masks and gowns to do their daily work, including invasive procedures on COVID+ patients during 2 weeks of lockdown. At the end of the 2 weeks, no health professional had any symptom or a positive test (either nasopharyngeal PCR swab or serology). I think that an additional test the week after could have been useful but the authors say that they wanted the scientific community to profit from these results as soon as possible. By the way, the serology tests that were used in this study were quite reliable with a sensibility and a specificity of 88% and 99% for IgM and 98% and 98% for IgG, respectively.

2/ Rheumatology

Few months after the US guidelines, the French guidelines for gout have been published by the French Society of Rheumatology, thanks to a Delphi method including 9 rheumatologists, 3 GPs, 1 nephrologist, 1 cardiologist and 1 patient. 2/3 of the panel being rheumatologists, not sure how the other voices could be heard. Anyway, there are general recommendations: informing the patient that gout is linked to uric acid crystals and that one needs to change its habits to decrease uricemia. The first recommendation is to treat all gout patients with a preventive treatment... This a grade D guideline, evidence level 4 = expert consensus ; that is not found in other guidelines (only if >2 attacks/year or tophus or chronic kidney disease). 2nd recommendation is to decrease uricemia under 50 µmol/L (= 300 mg/L) in the best-case scenario, under 60 µmol/L (= 360 mg/L) otherwise. 3rd recommendation is to use allopurinol as first-line preventive treatment (except if GFR<30 mL/min, in this case febuxostat is recommended). 4th recommendation is to prescribe colchine at a 0.5-1 mg daily dose for 6 months to decrease the risks of gout attacks induced by introducing a long-term treatment. 5th recommendation is to screen for renal, cardiovascular and metabolic comorbidities (expert advice as well). So these guidelines will increase the prescription of hypouricemic therapies without enough evidence about their usefulness and do not talk about the true controversy in the gout treatment: colchicine or NSAIDs as the first-line drug for gout attacks.

3/ Infective diseases

Translator's comment: the following paragraph only applies to countries where rheumatic fever is no longer a concern. Please follow your local guidelines otherwise (for New Zealand see here for example).

The Cochrane Library has published a review regarding efficacy and safety of rapid tests for strep A sore throats (we already talked about it here). I remind you the 3 main different approaches: 1/ French: rapid test before antibiotherapy ; 2/British: antibiotherapy according to McIsaac score; 3/Nordic countries: no antibiotherapy except for abscess or phlegmon. So this review finds out that using a rapid test decreases by 25% the use of antibiotics compared to clinical exam only, but does not allow to decrease their dispensation — that means people do not directly buy their antibiotics after prescription (not the case in France!). It is possible that there are less infective complications for patients who had a rapid test, but the evidence level remains uncertain as the statistical result is not significant. The British and Nordic countries approach seems to be the most coherent with evidence showing that the efficacy of antibiotics is only in reducing symptoms duration by 16 hours.

Let us talk about bedbugs thanks to this NEJM article, written by authors from the French Academic Hospital Institute 'Méditerranée Infection'. The diagnosis is evoked thanks to repeated bites and papular or vesicular lesions on uncovered areas, usually around 3 to 5 lesions (breakfast, lunch and dinner for these bugs too !), sometimes described as 'packed' or 'linear' or 'zigzag'. However the lesions are not specific of bedbugs (shoot!). Their traces can be found on mattresses, tapestries, electric cables, thanks to their faeces which look like some piles of black dots and to their exoskeletons. Patients experience a heavy psychological burden because of the bites and the associated sleeping disorders. Management of bedbugs consists in using the vacuum cleaner to aspirate the bedbugs (and then throwing the suction bag away after closing it), then wash all clothes and linen at 60 °C (= 140 °F), but only the clothes with marks of infestation, not ALL the clothes. Commercial-grade insecticides should not be used because the parasites are resistant to them. French guidelines seem to exist here on this topic.

4/ Neurology

We already talked about the increase of cardiovascular risk caused by migraines. This JAMA article discusses it through a 20-year long cohort study of women. Among these women, with an average age of 55, 8% of women had migraines without aura and 5% with. The risk of cardiovascular events related to migraines with aura was superior to the risk caused by obesity, on par with the one caused by HBP, cardiovascular hereditary predisposition and dyslipidaemia, and inferior to the one caused by diabetes and active smoking. 

5/ Urology

An article discusses varicoceles, which are present among 20% of all men. By increasing the testis temperature, they can alter the spermatogenesis, lower testosterone production and lead to infertility. Grade 1 and 2 varicoceles are usually asymptomatic. The diagnosis is mainly clinical and the ultrasound scan is rather to be used for symptomatic patients (after ruling out an infection if the main symptom is pain). The treatment (surgical or embolization) is only necessary in case of discomfort or infertility, with a success rate of around 80%. 

6/ Diabetology

International guidelines (with the help of Abbott pharmaceutical company) were published to interpret continuous glucose monitoring data (CGM). The sensors have improved and the scientific societies are now in favour of a follow-up with CGM rather than with self-monitored blood glucose levels. 3 indicators are to be used:

 - TIR: time in range: 3.9 to 10 mmol/L (= 70 to 180 mg/dL)
 - TBR: time below range (= hypoglycemia)
 - TAR: time above range (= hyperglycemia).
The most common target is for the patient to be 70% of total time in the target interval and a maximum of 4% of total time in hypoglycemia.
In the figure below, you can find these targets and their equivalence with HbA1c (but this remains quite approximative: being 70% in the normal range, but with 20% below and 10% over is not the same as being 25% over and 5% below). So, as you may have guessed, these targets are based on expert's advice and have not been evaluated on clinical criteria. I think that a maximum of 4% of total time in hypoglycemia is relevant but if we rely on the displayed correlation between HbA1c and TIR, a target of 60% TIR would me more relevant for a level of HbA1c at 7.5% (= 58 mmol/mol) than a 70% minimal target. Once again, having 70% of good values and effectively less than 4% hypoglycemia should be a "good target" but clinical studies must be performed to confirm it.

The DIRECT study showed that strict lifestyle changes could allow to obtain a remission of diabetes with a NNT figure between 2 and 3. This study has been replicated in Qatar and published in Lancet Diab&Endoc with the following protocol for 140 patients with a type 2 diabetes for less than 3 years: 12 weeks with a 800 Kcal (= 3347 kJ) daily diet then 12 weeks of diet rehabilitation, 10 000 steps to be done every day and 150 minutes of physical activity every week. The remission of diabetes was defined as an HbA1c < 48 mmol/mol (= 6.5%) but the primary outcome was the weight loss after 1 year. Weight loss was significantly more important in the intervention group (-12 kg vs -4 kg), but only 6.6 mmol/mol (= 0.6%) of difference on HbA1c (but significant difference in favour of the intervention group) and the remission rate of diabetes was 61% vs 12% (NNT=2). 

Thanks for reading me this week and see you next week!

@Dr_Agibus (free translation by @carttom)

Dragi Weekly No. 273 : COVID-19, antihypertensive medication reduction, withdrawal of ICS (ERS guidelines), hormone replacement therapy, thyroid cancer, liraglutide/obesity

Hello! I hope that, as usual, you are doing well and I thank you for your loyalty and your positive feedback. Here are the selected articles for this week, have a good reading!

1/ COVID-19

Of course, we are going to start by talking about the withdrawal of the Lancet article that we spoke about few weeks ago. I did not talk too much about the study methods simply because the week prior, 3 other studies already had shown the uselessness of the chloroquine. So this Lancet article, whether approved or withdrawn, was not changing anything.

By the way, the results of the British Recovery study were presented. It was a study randomizing hospitalized COVID patients in 5 arms: standard of care, lopinavir-ritonavir, dexamethasone, hydroxychloroquine or azithromycin. With 1,500 patients in the hydroxychloroquine arm and 3,000 in the standard of care arm, there was no difference in mortality at day 28 between the 2 groups (respectively 25.7% vs 23.5%). One can still persist with hydroxychloroquine, but at some stage, it becomes unreasonable.

A study in Lancet Public Health looked at the non-hospital cardiac arrest events in the Paris region during COVID epidemic. So, the figure speaks by itself, and mortality followed the same trend. It is probably the collateral effects of COVID, associated with the inaccessibility of some healthcare services and with the renouncement to healthcare during that time.

2/ Cardiovascular medicine

A randomized controlled trial in the JAMA evaluated deprescribing antihypertensive medication for patients over 80 y.o. with a SBP < 150 mmHg vs. control group. Respectively, in each group, there were 86% and 89% of patients with a SBP < 150 mmHg at week 12 ; medication reduction was maintained in 66% of the patients from the intervention group. I hope that the authors will soon provide data with a longer follow-up and on cardiovascular or mortality clinical outcomes.

3/ Repsiratory medicine

The European Respiratory Society provides guidelines on withdrawal of inhaled corticosteroids for COPD patients. The American society suggested this option of medication reduction as well (see here). ERS recommends deprescribing ICS for patients with no recent exacerbation and having an eosinophil count under 300 / µL. In case of medication reduction, a long-acting bronchodilatator (LABA or LAMA) should be kept as a preventer.

4/ Gynaecology

Following a Lancet article about the risks of hormone replacement therapy, the European Medicines Agency was asked to start an inquiry about the risk increase of breast cancer with HRT up to 10 years after its discontinuation (except for low dose vaginal estrogens which seemed to be safe). These suspicions were validated by the EMA and from now on, they should figure in the corresponding medicines' safety information sheets.

A randomized controlled trial evaluated the impact of a shared-decision making tool regarding the choice between vaginal birth and C-section among patients with a past history of C-section, hoping reducing the rate of unnecessary surgical procedures. The study included over 1,400 patients and the tool only managed to decrease the number of C-sections by 3% (43% vs 46%). There was no significant difference between the 2 groups regarding maternal and neonatal consequences. Overall, this tool does not work, but remains interesting (see the study appendix ; too long to be copied here unfortunately). 

5/ Endocrinology and nutrition

A new article discusses the overdiagnosis of thyroid cancer (see previous discussed article here). In France, the overdiagnosis of thyroid cancers is estimated at 83% between 2008 and 2012. The estimated mortality of this cancer is less than 1 per 100,000 patients. 

A randomized controlled trial evaluated the efficacy of liraglutide for weight reduction in non diabetic obese teenagers. The authors conclude that the treatment is efficient, with a significant BMI decrease of 0.37 SD (standard deviation) after 56 weeks: that equals to a BMI decrease of around 5 points for patients with an initial average BMI of 35. However, as soon as liraglutide was stopped, weight was going back almost up to the initial value 6 months after cessation. For the control group, after stopping the placebo, BMI also increased so there was still a difference between the 2 groups, but the result on the weight by itself remains unsatisfactory anyway...

Finished! Do not forget Facebook, Twitter and the newsletter! See you next week!

@Dr_Agibus (free translation by @carttom).

Dragi Weekly No. 272 : Guidelines for travelers, COVID (vitamin D, hydroxychloroquine), Lyme disease, mesothelioma, dementia

Hello! This is the end of the semester for our residents, I hope next semester will be more "usual", even though already short of one month. Here are the articles of the week, good reading!

1/ COVID-19

The French Academy of Medicine (link in French) takes position in favor of a vitamin D deficiency screening for COVID patients older than 60 and then a treatment if deficiency is proven ; and in favor of a treatment without prior screening for COVID patients younger than 60. This advice relies on a correlation that was found in only one study. For years, vitamin D has been promoted with many advantages but supplementation (blog post in French) does not manage to improve clinical outcomes. Only in respiratory diseases, in case of deficiency, it seems there are less complications in COPD and asthma patients (blog posts in French) after supplementation.

Following the Lancet article last week, the French High Council for Public Health (link in French) advises not to use hydroxycholoroquine to treat COVID-19 anymore.

In order to confirm this position, here is a systematic review that was published in Annals of Internal Medicine. The authors did not find any published study about using (hydroxy)chloroquine as a preventive treatment. The benefits from this medication on mortality, clinical aggravation, intubation needs and symptom resolution were globally similar to those from conventional treatment. The side effects were mainly a QT-interval increase among patients with (hydroxy)chloroquine, but without any clinical consequences. I think that, in a study, one stops the treatment and does not wait for the ventricular arrhythmia to happen.

And for those performing nasopharyngeal swabs, the best way to do it is to aim for the ear lobe.

2/ Cardiovascular diseases

For patients with infrarenal aortic aneurysms of small size (< 50 mm), a randomized controlled trial tested the use of doxycycline 100 mg daily during 2 years. And we have to admit that it does not work to slow down the progress of the aneurysm. Next time, they may try hydroxycholoroquine!
After all, both are malaria medications so why not?

3/ Infective diseases

Perfect transition to speak about 2020 health guidelines for travellers (link in French), published by the High Council for Public Health. Compared to 2019 ones (blog post in French), I have not found any changes. So, for this year, I want to speak about venous thromboembolic events prevention. Class II compression stockings are advised for people with risk factors or not able to wander in the plane during flights over 6 hours long. LMWH do not possess any valid indication but could sometimes be prescribed if stockings cannot be used or in case of very high risk, notably in case of past medical history of travel-related DVT (see here, blog post in French).

Now let us talk about Lyme disease, with a BMJ review. Erythema migrans appears between few days to few weeks after the bite, unlike the bite rash which appears between few hours to few days and disappears during the next few days (and which does not need any treatment). Erythema migrans has a clear centre only for Borellia Afzelli (which is present in Europe in 60% of cases), whereas B. Burgdorferi (in the USA) and B. garinii are responsible for homogeneous erythemas. So, in more than half of cases, if it is homogeneous, it is still a Lyme disease! Doxycycline is now the first-line treatment, as described in French and English guidelines. Chronic symptoms attributed to the Lyme borreliosis happen in 5-10% of patients who were treated and are still symptomatic. Criteria are 1/ documented infection at an early or late stage ; 2/ improvement after treatment ; 3/ onset within 6 months and for at least 6 months of musculoskeletal impairment, cognitive impairment or fatigue. In these cases, antibiotic treatment does not work and is not advised because the disease is not "active", it is only sequelae symptoms. Some scientific societies offer, on a case-by-case basis, 3 to 6 weeks of antibiotics once, suspecting an insufficient early treatment or a secondary infection. Regarding treatment after the bite, only the "International society of Lyme disease" recommends it systematically ; otherwise it is more about careful monitoring and treatment only if erythema migrans appears (for Americans, according to some criteria seen here).

4/ Respiratory medicine

European guidelines about mesothelioma management have just been published. I confess that this is not really general practice... but there is a small part about screening. And in at-risk populations, standard X-Rays were the most used. So, we now know that the existence of pleural plaques is only a sign of asbestos exposure and not an additional risk factor (even though it is correlated with cancer since mesothelioma is linked to asbestos). Injected CT-scan is to be recommended as more precise but we lack studies on the screening benefits (see French guidelines here).

5/ Neurology

My grandmother knew it: eating fish is good for memory! This article speaks about the Mediterranean diet and finds out that a diet with a lot of fish decreases the risk of dementia and slows down the progress of memory impairment. This result comes from ancillary analyses from 2 current randomized trials studying the progress of macular degeneration.

After the failure of the ASPREE study to show efficacy of aspirin in primary prevention on global and cardiovascular mortality (blog post in French), here is the ASPREE analysis about the efficacy of aspirin on the risk of cognitive disabilities: no benefit on reducing the risk of dementia either.

This is the end for this week. To avoid missing anything, you should subscribe on Facebook, Twitter or to the e-mail newsletter if not already done. You have to put your e-mail address in the top right field of this page and confirm the subscription in an e-mail entitled "FeedBurner Email Subscriptions" that will be sent to you and may land in your junk folder.

Have a good day, good luck to the new residents and see you next week!

@Dr_Agibus (free translation by @carttom)

Dragi Weekly No. 271: COVID (hydroxychloroquine, remdesivir, olfactory dysfunction), venous thromboembolic diseases (NICE guidelines), surveillance colonoscopy, PrEP, OGTT, insulin

Hello! As always, quite a few news around COVID this week, but also some other interesting papers. Have a good reading!

1/ COVID-19

To abandon hydroxcychloroquine once and for all, The Lancet published a study based on the registries of more than 600 hospitals worldwide to compare mortality and the onset of arrythmias among patients with hydroxychloroquine (or chloroquine) alone or in association with azithromycin versus patients without any of those medications. Out of 96,000 included patients, around 15,000 had one of these medications. The authors found that, after adjusting on severity and other confounding factors, patients who were treated with hydroxychloroquine had a higher risk of death (18% vs 9.3%, NNH=12) and it was even worse with hydroxychlorquine + azithromycin (22% vs 9.3%, NNH = 8). We can also observe an increase in ventricular arrythmias for patients with those medications. Overall, it is not a randomized controlled trial, but those who treated their patients with compassionate use of hydroxychloroquine should have waited for more solid data. The major risk factors associated with an increase of mortality on top of these medications were smoking, cardiovascular diseases and COPD, whereas the use of ACEi seemed to be a protective factor.

Let us move on to a randomized controlled trial regarding remdesivir, that was published in the NEJM. Firstly, it is a study that was not funded by the pharmaceutical industry. Included patients were COVID+ with a lower respiratory tract infection (so not all COVID+ patients). The main endpoint was the time to recovery (i.e. the time to get out of the necessity of an hospitalization with active care). We can also see that they modified the primary endpoint during the study, but they do not hide it. The results are intermediate results of a still ongoing study, but the authors have reached the required number of events (recovery). There was not any adjustment on the number of tests, so we only look at the primary outcome. The statistical analysis plan was using the O'Brien and Fleming method for intermediate analyses: overall the alpha-risk is at 5%, but at the first intermediate analysis the significance threshold was 0.0001 for example, then 0.001 at the next one and the last 0.0489, so all in all the sum makes 5%. But we do not know what intermediate level the authors used for the final analysis of their study. In the end, over 1,000 patients were randomized (50% with HBP, 30% with diabetes, 30% with obesity). The recovery was faster with remdesivir: 11 days versus 15 days with placebo, p-value <0.001 (apparently, low enough to be considerated valid with the statistical conditions described above for the intermediate analysis). But there was not less mortality. Overall, this treatment seems to be efficient to reduce the length of hospital stay by 4 days (which is not that much) without a proven effect on mortality now, but maybe the results at the end of the follow-up will bring more precision on this topic.

The French Health Authority (link in French here) published guidance on rapid serology tests. Regarding the rapid screening tests in pathology lab, the indications are the same than the normal serology tests (see here). Regarding the point-of-care tests, the Health Authority has not found any published study about them. Even though these latter tests could be an option for diagnosis catching-up for patients who do not have access to a pathology lab or who stay symptomatic despite a negative PCR or who could not get a PCR test, the Health authority recommends that a normal serology test should be systematically performed to confirm the result of a positive POC test (and same for a negative POC tests, but it is only advised).

So, how many people have suffered from COVID? This JAMA study, performed in Los Angeles, found out that, among a representative sample of 1,700 individuals who accepted to be screened, 13% had fever with cough, 9% fever with shortness of breath and 6% dysosmia or dysgeusia. So, authors concluded that only 4.5% of the population suffered from COVID.

Another study in the JAMA about the olfactive impairment with COVID. It allows to discover lots of words to identify olfactive impairment: orthonasal, retronasal impairements, phantosmia, parosmia, parageusia. If the impairment is acute in a viral context, COVID can be an explanation. If the impairment is progressive with a fluctuating nasal obstruction, it is probably a naso-sinusal aetiology. If the impairment is progressive, non fluctuating, in older people with loss of memory, it is probably neuro-degenerative. At last, if the impairment is post-traumatic, it is usually brutal with a severe anosmia. Regarding the management of olfactive impairment due to COVID, the authors suggest to: 1/ put smoking detectors in the house and to verify expiry dates on food before eating it; 2/ try olfactive rehabilitation by sniffing lemon, rose, eucalyptus etc, 20 seconds each, twice daily for at least 3 months; 3/ try oral omega-3 and intranasal vitamin A.

2/ Respiratory medicine

The NICE has published guidelines about venous thromoboembolic diseases. Nothing new compared to the European and French guidelines we spoke about here (link in French). The authors recommend the use of the PERC criteria to rule out a pulmonary embolism in case of low-risk and the use of D-dimers age-adjusted threshold for patients over 50. They recommend against cancer screening for idiopathic events without any other symptoms. The advised first-line treatments are apixaban and rivaroxaban, for a duration of 3 months for the events with an identified cause ; for an unknown duration, depending on the risk-benefits balance for events without. For patients refusing long-term anticoagulation, the authors suggest using low-dose aspirin.

3/ Gastro-enterology

After the discussion about bowel cancer screening (link in French here), here comes a BMJ article discussing the colonoscopy surveillance and when to stop it. So, if a colonoscopy was indicated and polyps were found, what should the surveillance be?

- For 1 or 2 sessile polyps or adenomas < 10 mm, return to non-invasive screening tests is advised.
- From 3 of them (English guidelines' threshold is at 5), a 3-year colonoscopy is recommended (if it is only sessile polyps, returning to non-invasive screening can be considered).
Going back to non-invasive testing means waiting for 10 years after the colonoscopy before restarting any test! Only American guidelines recommend a colonoscopy surveillance every 3 or 10 years, depending on the situation. The former is also what I usually see for my patients in France, but the return back to non-invasive testing is motivated by the low risk (<0.5%) of severe complications during colonoscopies that can add up with repeated colonoscopies and starts to be significant.
- In the other situations (adenomas over 10 mm or with high-grade dysplasia; or sessile polyps > 10 mm or with any grade of dysplasia): a 3-year colonoscopy surveillance is recommended.

4/ Infective diseases

In the PrEP context (link in French), a new preventive treatment of the HIV infection is currently under development: cabetogravir, which has a 8-week lasting effect. A randomized controlled trial among men (and transsexuals) who have sex with men, compared IV cabotegravir to oral Truvada, which is the current advised drug for PrEP. After around 4 years of treatment, in an intermediate analysis, 0.38% patients with cabotegravir had a seroconversion versus 1.21% with Truvada. But 80% of the patients with cabotegravir had side effects versus 30% with Truvada. Let us wait for the final publication of the results now.

5/ Diabetology

Can a biologist tell me how OGTT tubes during pregnancy are centrifugated? It is because this study finds that glucose levels are higher in case of an early centrifugation compared to a late one: early centrifugation could lead to increase the number of gestational diabetes diagnoses by 11.6%!

A JAMA article speaks about the role of the insulin in uncontrolled type 2 diabetes. The authors recommend not to delay insulin initiation when initial HbA1c is over 9% = 75 mmol/mol (and not 10% =  86 mmol/mol as guidelines say), because non-insulin treatments only lower HbA1c by 1.6%  = 5.5 mmol/mol on average. This is insufficient to go under the 8% = 64 mmol/mol threshold, that seems to be associated with less mortality and less complications (please note that the authors do not call for a strict control (link in French), which has no evident benefit).

Thanks for your loyalty, let us meet again next week for the next Dragi Webdo!

@Dr_Agibus (free translation by @carttom)