Clinical features of covid-19
BMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m1470 (Published 17 April 2020) Cite this as: BMJ 2020;369:m1470Read our latest coverage of the coronavirus pandemic
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Dear Editor,
Vetter et al describe an interesting array of clinical features in people who (hopefully) tested positive for SARS-CoV2. But how do we know if the presence of the virus was casually associated with the illness in the patient? Even with testing only a small proportion of the population, it seems that around 3% of the UK population has tested positive for the virus. Would we not expect at least 3% of patients with those conditions to test positive for the virus by chance alone?
And when we get the influenza back this winter, if we decide to test everyone who comes into hospital, what proportion of these presentations do we think will test positive for the influenza virus by chance alone? Or would we attribute a wider range of clinical features to Staph aureus when the next patient who presents with myocardial infarction has this bacterium on throat and nose swab (for whatever reason)?
COVID-19 is testing our scientific processes in many ways, including our understanding of association and causation.
Competing interests: No competing interests
Dear Editor
I am interested to see the continued debate about testing strategies for Covid-19 but I have seen no discussion about the role of testing in clinical practice.
I think that politicians and epidemiologists are looking at the epidemic in a way that does not help clinical medicine although, in time, the disease will be controlled.
I know personally 6 people who have probably contracted Corona virus in different parts of the country, 3 of them with typical symptoms and quite poorly, and one with mild symptoms.
They have all been isolated, they have all contacted GPs and or hospital and they have all received expert advice and treatment for their symptoms. Not one has been offered a test to confirm the diagnosis. How can this be? I fully support the drive to test ALL professional staff as a priority but I do not understand how the medical profession can be expected to treat patients without the application of the reliable test which is available. Why are doctors being expected to diagnose a new and potentially lethal disease without access to testing of their patients?
In addition, as far as I know, not one of these cases has been added to the national statistics.
We are more than 2 months into this epidemic and in my view all of these potential cases should have been checked by testing, their contacts traced and their numbers logged. It seems that there is a long way to go.
Kind Regards
Martin Milling
martin@mpmilling.uk
Competing interests: No competing interests
Dear Editor
I am surprised that Drs Vetter, Lan Vu and L’Huillier et al didn’t cast their net wider in reviewing covid-19 – BMJ 2020;369:m1470.
Infections caused by the SARS-CoV-2 virus have some unusual features.
Pregnant women do not usually have a serious infection – despite the fact that they are immunologically compromised. This vulnerability was seen dramatically in the H1N1/09 pandemic in 2009 – when many such women became very ill.
Neonates and infants usually suffer mild forms of the infections only – although they are considered to have a poor immune status.
Both of these immunologically compromised groups survive SARS-CoV-2 infections relatively well.
It has emerged that elderly infected people have a high mortality rate. Elderly people’s immune response is somewhat diminished – but they have a vast range of antibodies to a lifetime of infections and vaccinations.
In media reports it has appeared that people with pigmented skin also seemed to have a high mortality rate. Further media reports suggest that obese people were also dying also disproportionately.
I wondered what factors linked these three groups – the elderly, those with pigmented skin and those who are obese?
Reviewing the literature it was apparent that all three groups are commonly vitamin D deficient. Furthermore vitamin D plays a significant part in the body’s defence to respiratory infections.
I suspect many of the excess deaths due to SARS-CoV-2 infection may be due - sadly - to vitamin D deficiency. It follows that supplementary vitamin D in these people may be warranted.
There is also the possibility that high doses of the vitamin could be used as part of a treatment regimen.
01. Samefors, M, Ostgren, C J, Molstad, S et al Vitamin D deficiency in elderly people in Swedish nursing homes is associated with increased mortality. European Journal of Endocrinology, 170(5), 667–675. doi:10.1530/eje-13-0855
02. Weishaar, T, Rajan, S, & Keller, B et al Probability of Vitamin D Deficiency by Body Weight and Race/Ethnicity. The Journal of the American Board of Family Medicine, 29(2), 226–232. doi:10.3122/jabfm.2016.02.150251
03. Pereira-Santos, M, Costa, P R F, Assis, A et al Obesity and vitamin D deficiency: a systematic review and meta-analysis. Obesity Reviews, 16(4), 341–349. doi:10.1111/obr.12239
04. Ginde AA, Mansbach JM, Camargo CA Jr. Vitamin D, respiratory infections, and asthma. Curr Allergy Asthma Rep. 2009 Jan;9(1):81-7. doi: 10.1007/s11882-009-0012-7
Competing interests: No competing interests
Dear Editor,
As a junior doctor working in a large teaching hospital with personal experience of testing positive for covid-19, I felt compelled to respond to this article about the clinical features of this novel coronavirus.
I agree wholeheartedly with the statement that ‘testing strategies that exclude patients with few symptoms are likely to miss a substantial proportion of cases’, and would like to comment further on this article drawing on an interesting case report to encourage both learning and debate.
As a FY1 doctor, normally fit and well, to wake up one morning with total anosmia was a peculiar experience. Despite having read reports in the media about this being a covid-19 symptom, having then checked Public Health England’s guidelines I realised it is not currently viewed as an important enough symptom to warrant self-isolation, nor indeed NHS staff testing, as is confirmed in this article.
After much debate with the medical staff at my hospital as to whether I should work – with the HR department wanting me to come into work as per national guidelines, but my ward consultant feeling strongly that without any other reason to explain anosmia it was likely covid-19 – I ended up isolating for seven days.
Four days into isolation, during which time no further symptoms developed, I tested positive for covid-19.
As a FY1 working in a very well-staffed teaching hospital, I almost certainly saved more lives by avoiding contact with patients for a week through self-isolation, than in going to work to care for them.
Consequently, I feel very passionately that the threshold for testing should not just be lowered in vulnerable patients as this article recommends, but also in NHS staff to prevent unrecognised cases transmitting the virus.
Competing interests: No competing interests
Dear Editor,
In response to ‘Clinical features of covid-19’, we agree with the authors about common and/or early clinical findings in COVID-19 patients. In fact, clinicians all over the world are still facing, in their everyday clinical practice, accidental COVID-19 positive patients, presenting with numerous signs and symptoms of unknown origin. Atypical presentations unnecessarily increase the exposure risk of healthcare workers.
The authors clearly stated the numerous presentations of the disease. We wanted to add some key clinical elements not to be missed, and to discuss the consequences on the exposure risk of healthcare professionals.
Several studies have reported gastrointestinal symptoms such as abdominal discomfort, nausea, vomiting, and diarrhea. However, an uncommon early presentation of COVID-19 is a literally acute surgical abdomen [1]. An epigastric and right upper quadrant pain with a positive Murphy’s sign, which usually refer to cholecystitis, can be an early presentation of COVID-19. Basal pneumonia and pleural effusions could explain this finding.
SARS-CoV2 can also induce a hypercoagulable state as stated by the authors. Peripheral thrombosis and multiple cerebral infarcts were described as a late finding in COVID-19 positive patients [2]. Antiphospholipid antibodies were detected in their serum. Critical illness and various infections are known to cause a transient rise in antiphospholipid antibodies. A potential role of antiphospholipid antibodies in causing thrombosis in these select patients is yet to be determined. Moreover, acute pulmonary embolism was described with absence of major thrombo-embolic predisposing factors and diffuse bilateral COVID-19 pneumonia [3].
Taste or olfactory disorders are an important finding as well. Given that nasal obstruction or rhinorrhea can explain anosmia in many patients, isolated anosmia without other otolaryngologic features is therefore considered as highly suggestive of a COVID-19 infection. Although the pathophysiology is unknown until now, the hypothesis of a potential viral invasion of the olfactory bulb by the human coronavirus is yet to be determined.
Acute thoracic pain, chest tightness and heart palpitations related to cardiac involvement were also described as clinical manifestations of COVID-19. This relates to "myocardial injury, and in patients with severe infections myocarditis and myopericarditis with reduced ejection fraction, cardiac arrhythmias, heart failure, and misdiagnosis as acute coronary syndrome" as clearly stated by the authors. Some studies explain it by the fact that myocardial endothelial cells express Angiotensin-Converting Enzyme ACE2 (the functional receptor for SARS-CoV2) abundantly, while others by the cytokine storm; thus, the specific mechanism of myocardial injury is still uncertain. Undoubtedly, cardiac injury remains one of the most important prognostic factors in the management of patients with COVID-19.
Dermatologic manifestations have been reported and are mainly erythematous rash or widespread urticaria. These manifestations are similar to skin involvement during common viral infections. However, an interesting finding is the appearance of chickenpox-like lesions [4]. Acrosyndrome and frostbite lesions are also found in some patients but are not described in the literature until now.
Neurological (dizziness, Guillain-Barre syndrome, strokes...) and ophthalmologic (conjunctival hyperemia, chemosis...) symptoms are also reported in the literature and by the authors.
We should not forget the significant number of asymptomatic yet contagious infections [5] which are considered as a supplementary exposure risk factor for healthcare professionals.
Such diverse presentations constitute a public health burden, especially for healthcare professionals. During pandemics, the safety of the clinician and the population must be considered along with that of the individual patient [6]. Although video consultations are ongoing for multiple specialties and for non-urgent consultations [7], there is still a tremendous risk for healthcare professionals. This has led Public Health England to suggest wearing aprons, surgical masks, eye protection and gloves where there is a droplet transmission risk, when the patient’s COVID-19 status is unknown. However, an international widespread lack of personal protective equipment (PPE) makes this recommendation scantly applicable. This scandalous lack is causative of an increased morbidity and eventually mortality [8], as well as mental health degradation [9] among physicians.
To conclude, atypical presentations of COVID-19, although uncommon, have been and continue to be described in the literature. Therefore, physicians’ vigilance is needed and COVID-19 should remain in the differential diagnosis of every symptom that could not be explained by other pathologies, in our daily clinical practice. Moreover, this seems to have a huge impact on healthcare professionals’ health. We think that full PPE, although shortages continue, should be considered for all patients as community spread increases.
References
1. Sellevoll HB, Saeed U, Young VS, Sandbæk G, Gundersen K, Mala T. Acute abdomen as an early symptom of COVID-19. Tidsskr Den Nor Legeforening 2020 Apr 7; Available from: https://tidsskriftet.no/en/2020/04/kort-kasuistikk/acute-abdomen-early-s...
2. Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, et al. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. N Engl J Med. 2020 Apr 8;0(0):null.
3. Danzi GB, Loffi M, Galeazzi G, Gherbesi E. Acute pulmonary embolism and COVID-19 pneumonia: a random association? Eur Heart J. 2020 Mar 30;
4. Recalcati S. Cutaneous manifestations in COVID-19: a first perspective. J Eur Acad Dermatol Venereol JEADV. 2020 Mar 26;
5. Day M. Covid-19: four fifths of cases are asymptomatic, China figures indicate. BMJ. 2020 Apr 2;369:m1375.
6. Fritz Z, Perkins GD. Cardiopulmonary resuscitation after hospital admission with covid-19. BMJ. 2020 06;369:m1387.
7. Greenhalgh T, Wherton J, Shaw S, Morrison C. Video consultations for covid-19. BMJ. 2020 Mar 12;368:m998.
8. Seven days in medicine: 25-31 March 2020. BMJ. 2020 Apr 1;369:m1288.
9. Greenberg N, Docherty M, Gnanapragasam S, Wessely S. Managing mental health challenges faced by healthcare workers during covid-19 pandemic. BMJ. 2020 26;368:m1211.
Competing interests: No competing interests
Dear Editor,
Re: Clinical features of covid-19
In response to ‘The wide array of symptoms has implications for the testing strategy’. We concur with the authors that we are missing common symptoms of mild or early covid-19 infection. We note a specific ‘tertian’ pattern of illness in more prolonged cases with symptom clusters which go far beyond the cough, fever and shortness of breath required for testing.
We have noticed many people with mild presentation only complain of a throat symptom. This is expressed in unusual but consistent terms: “a dry throat”, “as if going to get a cold but didn’t” or “a weird throat”. This is usually followed by, “it’s not a sore throat.” This symptom appears to be common and may represent the only manifestation of infection. These may represent some of the many mild cases we are missing.
In more prolonged cases (weeks) where gradual clinical recovery occurs, we have observed a periodic pattern of recurrence every three days, like the ‘tertian fevers’ of some forms of malaria. In these cases, people seem to get lesser recurrences of their original symptom clusters.
We agree with the authors that the range of symptoms commonly seen are much wider than the original definition and should prompt testing so as not to miss cases.
We note
-headache which is often occipital and associated with spinal pain
-retrosternal tingling/pain
-hoarseness
-diarrhoea and colicky abdominal pain, which may present without the cough.
These wider symptoms will hopefully soon be recorded in national public information sources.
Competing interests: No competing interests
Dear Editor
I read with interest the variety of non-respiratory COVID-19 symptoms highlighted by Vetter et al. In the last few weeks there have been a slew of case reports outlining cutaneous presentations associated with the virus. These differed from urticarial eruptions to vasculitis, vesicles, petechiae, livedo reticularis and florid erythema(1-5).
The sudden onset of new cutaneous symptoms should also alert clinicians to the possibility of COVID-19 and trigger testing. In the absence of respiratory symptoms patients may be more likely to present in the community setting or be referred on to specialist dermatologists. Clinicians should keep a wide differential in mind when faced with acute cutaneous presentations to promptly diagnose COVID-19 and prevent transmission of the virus.
1. Henry D, Ackerman M, Sancelme E, Finon A, Esteve E. Urticarial eruption in COVID-19 infection. J Eur Acad Dermatol Venereol. 2020 Apr 15. doi: 10.1111/jdv.16472.
2. Mazzotta F., Troccoli T., Bonifazi E. A new vasculitis at the time of COVID-19. European Journal Of Pediatric Dermatology - pd online, Monday's case. https://www.ejpd.com/images/nuova-vasculite-covid-ENG.pdf
3. Joob, B, Wiwanitkit, V. COVID-19 can present with a rash and be mistaken for Dengue. J Am Acad Dermatol. 2020 Mar 22. 2020 May;82(5):e177
4. Manalo, I. F., Smith, M. K., Cheeley, J., & Jacobs, R. (2020). A Dermatologic Manifestation of COVID-19: Transient Livedo Reticularis. J Am Acad Dermatol. 2020 Apr 10. doi: 10.1016/j.jaad.2020.04.018
5. Recalcati S1. Cutaneous manifestations in COVID‐19: a first perspective J Eur Acad Dermatol Venereol. 2020 Mar 26. doi: 10.1111/jdv.16387. [Epub ahead of print]
Competing interests: No competing interests
Dear Editor
Range of symptoms and timeline needed so as not to be missing other things, especially in small children
In the Uk our leaders have proclaimed a policy of home self isolation (with no testing or contact tracing) if you meet either of the 2 criteria (cough or mild fever) with you being allowed out again at day 7 if well and clinical screening in primary care if ill but not so ill as to need hospital (again with no testing)
Those tested are about 25% positive and if this reflects the non tested there are a lot of people and their contacts being ignored by the NHS.
What is the range of illness symptomatology and how long can fever can last in covid before further investigation is needed especially in small children. Can an adult or child have a fever for 2 weeks in covid without a secondary infection? is this common? At what stage should any investigation be undertaken? How many mild cases have raised CRP D-Dimers etc or if they are raised does this point to something else or severe covid . Should we in primary care be measuring O2 sats at rest or after walking about a bit. Many questions .No guidelines beyond Stay at home ,protect the NHS ,save lives. Why
Competing interests: No competing interests
Dear Editor,
the oro-fecal route is well-documented in patients affected by SARS-Cov-19 (Wang et al., 2020; Guan et al., 2020; Lescure et al., 2020). In particular, fecal excretion persisted for 1‐11 days after sputum excretion in 23%‐82% adults (Tian et al., 2020). Oropharyngeal specimen negativity been described together with anal swab positivity up to 28 days after the onset of symptoms also in in children (Xu et al., 2020; Fan et al., 2020). This finding suggests that some patients with SARS-CoV-2 infection have viral RNA or live infectious virus in feces well after the negativization of oropharyngeal specimens.
Apart from the inference that patients test positive on rectal swabs even after nasopharyngeal swabs become negative, another deduction can be drawn that is even more important by an operative standpoint. Indeed, the available data suggest that some patients test positive on rectal swabs in the very first days of COVID-19 onset (Lescure et al., 2020). To make a few examples, in a review article, Tian et al. (2020) reported fecal PCR positivity 2‐5 days after sputum in in 36%‐53% of patients, while Xiao et al (2020) found that 39/73 hospitalized patients had viral RNA in their feces from 1 to 12 days. Therefore, the occurrence of oro-fecal route points towards the usefulness of rectal swabs at the very onset of the disease to confirm, or even diagnose, COVID-19. A rectal swab could be performed, also in absence of digestive symptoms, in persons who meet one of the two following criteria:
1) throat- or sputum-negative patients with symptoms, signs or instrumental exams that are suspicious for COVID-19;
2) throat- or sputum-negative subjects with close or casual contacts with confirmed cases.
REFERENCES
1) Fan Q, Pan Y, Wu Q, Liu S, Song X, et al. 2020. Anal swab findings in an infant with COVID‐19. Pediatric Investigation, 4 (1), https://doi.org/10.1002/ped4.12186.
2) Lescure FX, Bouadma L, Nguyen D, Parisey M, Wicky PH, et al. 2020. Clinical and virological data of the first cases of COVID-19 in Europe: a case series. Lancet Infect Dis., pii: S1473-3099(20)30200-0. doi: 10.1016/S1473-3099(20)30200-0.
3) Xiao F, Tang M, Zheng X, Liu Y. 2020. Evidence for Gastrointestinal Infection of SARS-CoV-2. Gastroenterology, in press. DOI: https://doi.org/10.1053/j.gastro.2020.02.055.
4) Xu Y, Li X, Zhu B, Liang H, Fang C, et al. 2020. Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nat Med., 26(4):502-505. doi: 10.1038/s41591-020-0817-4.
5) Tian Y, Rong L, Nian W, He Y. 2020. Review article: gastrointestinal features in COVID-19 and the possibility of faecal transmission. Aliment Pharmacol Ther. 2020 May;51(9):843-851. doi: 10.1111/apt.15731.
6) Wang W, Xu Y, Gao R, Lu R, Han K, et al. 2020. Detection of SARS-CoV-2 in Different Types of Clinical Specimens. JAMA. 2020 Mar 11. doi: 10.1001/jama.2020.3786.
Arturo Tozzi
Center for Nonlinear Science, Department of Physics, University of North Texas, Denton, Texas, USA
tozziarturo@libero.it
Arturo.Tozzi@unt.edu
Gennaro D'Amato
Division of Respiratory and Allergic Diseases, Department of Chest Diseases, High Specialty A. Cardarelli Hospital, Napoli, Italy
Medical School of Specialization in Respiratory Diseases, University on Naples Federico II
Alfredo Guarino
University of Naples Federico II, Naples, Italy
Department of Translational Medical Sciences
Competing interests: No competing interests
Re: Clinical features of covid-19
Dear Editor,
The novel coronavirus (COVID-19) pandemic started in China in December 2019 and has spread worldwide, infecting over 2 million people and causing over 275,000 deaths to date (1). Vetter and colleagues, in their editorial, summarise the wide array of clinical features associated with COVID-19 infection, from mild symptoms to severe presentations with sepsis, acute respiratory distress syndrome and coagulopathy (2). Thrombotic presentations have been associated with COVID-19, leading to a major focus on anticoagulation and venous thromboembolism (VTE) prophylaxis, particularly in critically ill patients (3). However, there is still little information on VTE risk after hospital discharge. Abnormalities in coagulation include elevated D-dimer, other fibrin degradation products and prothrombin time, which are associated with poor prognosis (4).
Physicians are turning to guidelines to advise on COVID-19 patients experiencing thrombotic events, including American College of Chest Physicians and National Institute for Health and Care Excellence (NICE) guidance. These provide comprehensive information on the management of thrombotic risk in hospitalised patients and recommend the use of risk assessment tools (RATs) such as those from Padua, Caprini and the UK Department of Health to stratify patients’ VTE risk; however, none suggest the use of thromboprophylaxis extended beyond discharge. The online Thrombosis UK guidance is specific to COVID-19 (5); although highly informative, this does not mention prophylaxis beyond hospitalisation. Extended thromboprophylaxis is delivered to surgical patients post-operatively in orthopaedic surgery or if a history of VTE is present but is not often considered in medical patients.
It is unclear whether COVID-19 patients are at increased risk of VTE compared to medical patients with chest sepsis and elevated D-dimer, and whether the risk of VTE is significant beyond discharge. COVID-19 patients share risk factors with pneumonia patients that negatively impact at least two arms of Virchow’s triad, including prolonged immobility and coagulopathy (3). In addition, endothelial dysfunction may be of importance in COVID-19 due to the presence of ACE-2 receptors on endothelial cells facilitating entry of the virus, leading to increased risk of VTE and microvascular thrombosis (6). Data emerging from Italy has shown that in COVID-19 patients screened by duplex ultrasound, the incidence of deep vein thrombosis (DVT) was 23% for patients intubated in ICU and 8% for patients breathing spontaneously, with an asymptomatic pulmonary embolism rate of 19% (7).
In the hospitalised population, the metric used to assess VTE outcomes is the 90-day Hospital Acquired Thrombosis rate. It has been previously shown that the time between 14- and 21-days post discharge is associated with the highest incidence of VTE post-surgery (8). The above raise the following questions:
1. What is the incidence of VTE following hospital discharge for patients with COVID-19?
2. Should a RAT be used to identify high-risk populations?
3. Should prolonged prophylaxis be considered in some or all patients?
At present, there are no good data on the incidence of VTE in the first 90-days following hospital discharge in COVID-19 patients, and it is not clear how long the pandemic will last for. Hence, high-quality cohort follow-up data is urgently required to map the natural history of this patient group and permit interventions to reduce avoidable deaths. Potentially, high-risk populations can be identified via existing scoring systems, however the derangement in baseline coagulation parameters should be noted when risk assessing these patients.
Due to the lack of evidence, physicians are left with a dilemma as to waiting for further data to accurately define the magnitude of the issue, with the risk of further VTE-related deaths, or offering a prophylactic regimen to patients when discharged. If of the view to offer prophylaxis, evidence would suggest that pharmacological prophylaxis is probably the best option. Another issue is whether this should be given to all COVID-19 patients or just to a pre-specified high-risk group, which is currently not clearly defined. The duration of such a prophylactic regimen is also not clearly defined but is likely to be of a minimum of 2 weeks based on evidence from surgical trials and NICE guidance. The delivery of extended prophylaxis should be balanced with the risk of bleeding in the individual patient; however, it must be acknowledged that there is no trial evidence to support the use of prolonged prophylaxis and any recommendation is based on empirical knowledge.
By appreciating this issue and probably offering some form of prolonged prophylaxis, we, as physicians, may well be able to alleviate suffering and further deaths from COVID-19.
1. Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time.[letter]. Lancet Infect Dis. 2020 Feb 19;S1473-3099(20)30120-1. doi: 10.1016/S1473-3099(20)30120-1.
2. Vetter P, Lan Vu D, L'Huiller AG, Schibler M, Kaiser L, Jacquerioz F. Clinical features of covid-19 BMJ 2020;369:m1470. https://doi.org/10.1136/bmj.m1470
3. Klok FA, Kruip MJHA, van der Meer NJM et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020. https://doi.org/10.1016/j.thromres.2020.04.013
4. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18:844-847.
5. Hunt B, Retter A, McClintock C. Practical guidance for the prevention of thrombosis and management of coagulopathy and disseminated intravascular coagulation of patients infected with COVID-19. 2020. https://thrombosisuk.org/covid-19-thrombosis.php. Accessed 20th April 2020,
6. Chen L, Li X, Chen M, Feng Y, Xiong C. The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovascular Research. 2020
7. Baccellieri D, Apruzzi L, Ardita V et al. The “Venous Perspective” in Lombardia (Italy) during the first weeks of the Covid-19 epidemic. Phlebology. 2020 (in print, awaiting publication)
8. Planes A, Vochelle N, Darmon JY, Fagola M, Bellaud M, Huet Y. Risk of deep-venous thrombosis after hospital discharge in patients having undergone total hip replacement: double-blind randomised comparison of enoxaparin versus placebo. Lancet. 1996;348:224-228.
Competing interests: No competing interests