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How to present patient cases

• Related content
• Peer review
• Mary Ni Lochlainn , foundation year 2 doctor 1 ,
• Ibrahim Balogun , healthcare of older people/stroke medicine consultant 1
• 1 East Kent Foundation Trust, UK

A guide on how to structure a case presentation

This article contains...

-History of presenting problem

-Medical and surgical history

-Drugs, including allergies to drugs

-Family history

-Social history

-Review of systems

-Findings on examination, including vital signs and observations

-Differential diagnosis/impression

-Investigations

-Management

Presenting patient cases is a key part of everyday clinical practice. A well delivered presentation has the potential to facilitate patient care and improve efficiency on ward rounds, as well as a means of teaching and assessing clinical competence. 1

The purpose of a case presentation is to communicate your diagnostic reasoning to the listener, so that he or she has a clear picture of the patient’s condition and further management can be planned accordingly. 2 To give a high quality presentation you need to take a thorough history. Consultants make decisions about patient care based on information presented to them by junior members of the team, so the importance of accurately presenting your patient cannot be overemphasised.

As a medical student, you are likely to be asked to present in numerous settings. A formal case presentation may take place at a teaching session or even at a conference or scientific meeting. These presentations are usually thorough and have an accompanying PowerPoint presentation or poster. More often, case presentations take place on the wards or over the phone and tend to be brief, using only memory or short, handwritten notes as an aid.

Everyone has their own presenting style, and the context of the presentation will determine how much detail you need to put in. You should anticipate what information your senior colleagues will need to know about the patient’s history and the care he or she has received since admission, to enable them to make further management decisions. In this article, I use a fictitious case to …

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Tools for the Patient Presentation

The formal patient presentation.

• Posing the Clinical Question
• Searching the Medical Literature for EBM

Sources & Further Reading

First Aid for the Wards

Lingard L, Haber RJ.  Teaching and learning communications in medicine: a rhetorical approach .  Academic Medicine. 74(5):507-510 1999 May.

Lingard L, Haber RJ.  What do we mean by "relevance"? A clinical and rhetorical definition with implications for teaching and learning the case-presentation format . Academic Medicine. 74(10):S124-S127.

The Oral Presentation (A Practical Guide to Clinical Medicine, UCSD School of Medicine)  http://meded.ucsd.edu/clinicalmed/oral.htm

"Classically, the formal oral presentation is given in 7 minutes or less. Although it follows the same format as a written report, it is not simply regurgitation. A great presentation requires style as much as substance; your delivery must be succinct and smooth. No time should be wasted on superfluous information; one can read about such matters later in your admit note. Ideally, your presentation should be formulated so that your audience can anticipate your assessment and plan; that is, each piece of information should clue the listener into your thinking process and your most likely diagnosis."  [ Le, et al, p. 15 ]

Types of Patient Presentations

New Patient

New patients get the traditional H&P with assessment and plan.  Give the chief complaint and a brief and pertinent HPI.  Next give important PMH, PSH, etc.  The ROS is often left out, as anything important was in the HPI.  The PE is reviewed.  Only give pertinent positives and negatives.  The assessment and plan should include what you think is wrong and, briefly, why.  Then, state what you plan to do for the patient, including labs.  Be sure to know why things are being done: you will be asked.

The follow-up presentation differs from the presentation of a new patient.  It is an abridged presentation, perhaps referencing major patient issues that have been previously presented, but focusing on new information about these issues and/or what has changed. Give the patient’s name, age, date of admission, briefly review the present illness, physical examination and admitting diagnosis.  Then report any new finding, laboratory tests, diagnostic procedures and changes in medications.

The attending physician will ask the patient’s permission to have the medical student present their case.  After making the proper introductions the attending will let the patient know they may offer input or ask questions at any point.  When presenting at bedside the student should try to involve the patient.

Preparing for the Presentation

There are four things you must consider before you do your oral presentation

• Occasion (setting and circumstances)

Ask yourself what do you want the presentation to do

• Present a new patient to your preceptor : the amount of detail will be determined by your preceptor.  It is also likely to reflect your development and experience, with less detail being required as you progress.
• Present your patient at working or teaching rounds : the amount of detail will be determined by the customs of the group. The focus of the presentation will be influenced by the learning objectives of working responsibilities of the group.
• Request a consultant’s advice on a clinical problem : the presentation will be focused on the clinical question being posed to the consultant.
• Persuade others about a diagnosis and plan : a shorter presentation which highlights the pertinent positives and negatives that are germane to the diagnosis and/or plan being suggested.
• Enlist cooperation required for patient care : a short presentation focusing on the impact your audience can have in addressing the patient’s issues.

Preparation

• Patient evaluation : history, physical examination, review of tests, studies, procedures, and consultants’ recommendations.
• Selected reading : reference texts; to build a foundational understanding.
• Literature search : for further elucidation of any key references from selected reading, and to bring your understanding up to date, since reference text information is typically three to seven years old.
• Write-up : for oral presentation, just succinct notes to serve as a reminder or reference, since you’re not going to be reading your presentation.

Knowledge (Be prepared to answer questions about the following)

• Pathophysiology
• Complications
• Differential diagnosis
• Course of conditions
• Diagnostic tests
• Medications
• Essential Evidence Plus

Template for Oral Presentations

Chief Complaint (CC)

The opening statement should give an overview of the patient, age, sex, reason for visit and the duration of the complaint. Give marital status, race, or occupation if relevant.  If your patient has a history of a major medical problem that bears strongly on the understanding of the present illness, include it.  For ongoing care, give a one sentence recap of the history.

History of Present Illness (HPI)

This will be very similar to your written HPI. Present the most important problem first. If there is more than one problem, treat each separately. Present the information chronologically.  Cover one system before going onto the next. Characterize the chief complaint – quality, severity, location, duration, progression, and include pertinent negatives. Items from the ROS that are unrelated to the present problem may be mentioned in passing unless you are doing a very formal presentation. When you do your first patient presentation you may be expected to go into detail.  For ongoing care, present any new complaints.

Review of Systems (ROS)

Most of the ROS is incorporated at the end of the HPI. Items that are unrelated to the present problem may be briefly mentioned.  For ongoing care, present only if new complaints.  

Past Medical History (PMH)

Discuss other past medical history that bears directly on the current medical problem.  For ongoing care, have the information available to respond to questions.

Past Surgical History

Provide names of procedures, approximate dates, indications, any relevant findings or complications, and pathology reports, if applicable.  For ongoing care, have the information available to respond to questions.

Allergies/Medications

Present all current medications along with dosage, route and frequency. For the follow-up presentation just give any changes in medication.  For ongoing care, note any changes.

Smoking and Alcohol (and any other substance abuse)

Note frequency and duration. For ongoing care, have the information available to respond to questions.

Social/Work History

Home, environment, work status and sexual history.  For ongoing care, have the information available to respond to questions.

Family History Note particular family history of genetically based diseases.  For ongoing care, have the information available to respond to questions.

Physical Exam/Labs/Other Tests

Include all significant abnormal findings and any normal findings that contribute to the diagnosis. Give a brief, general description of the patient including physical appearance. Then describe vital signs touching on each major system. Try to find out in advance how thorough you need to be for your presentation. There are times when you will be expected to give more detail on each physical finding, labs and other test results.  For ongoing care, mention only further positive findings and relevant negative findings.

Assessment and Plan

Give a summary of the important aspects of the history, physical exam and formulate the differential diagnosis. Make sure to read up on the patient’s case by doing a search of the literature. 

• Include only the most essential facts; but be ready to answer ANY questions about all aspects of your patient.
• Keep your presentation lively.
• Do not read the presentation!
• Expect your listeners to ask questions.
• Follow the order of the written case report.
• Keep in mind the limitation of your listeners.
• Beware of jumping back and forth between descriptions of separate problems.
• Use the presentation to build your case.
• Your reasoning process should help the listener consider a differential diagnosis.
• Present the patient as well as the illness .
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• Last Updated: Jul 19, 2023 10:52 AM
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• Taylor and Francis - PMC COVID-19 Collection

Epidemiology, pathogenesis, clinical presentations, diagnosis and treatment of COVID-19: a review of current evidence

Sayeeda rahman.

School of Medicine, American University of Integrative Sciences (AUIS), Bridgetown, Barbados

Maria Teresa Villagomez Montero

Kherie rowe, rita kirton, frank kunik, jr, introduction.

The COVID-19 pandemic has created a public health crisis, infected millions of people, and caused a significant number of deaths. SARS-CoV-2 transmits from person to person through several routes, mainly via respiratory droplets, which makes it difficult to contain its spread into the community. Here, we provide an overview of the epidemiology, pathogenesis, clinical presentation, diagnosis, and treatment of COVID-19.

Areas covered

Direct person-to-person respiratory transmission has rapidly amplified the spread of coronavirus. In the absence of any clinically proven treatment options, the current clinical management of COVID-19 includes symptom management, infection prevention and control measures, optimized supportive care, and intensive care support in severe or critical illness. Developing an effective vaccine is now a leading research priority. Some vaccines have already been approved by the regulatory authorities for the prevention of COVID-19.

Expert opinion

General prevention and protection measures regarding the containment and management of the second or third waves are necessary to minimize the risk of infection. Until now, four vaccines reported variable efficacies of between 62–95%, and two of them (Pfizer/BioNTech and Moderna) received FDA emergency use authorization. Equitable access and effective distribution of these vaccines in all countries will save millions of lives.

1. Introduction

Coronavirus disease 2019 (COVID-19) is a highly contagious and infectious disease caused by the novel coronavirus, severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) [ 1 , 2 ]. It is well documented that the initial cases of COVID-19 related infection were first reported in Wuhan, Hubei Province of China in December 2019, and were linked to the Huanan Seafood Market [ 3 ]. Since then, the infection has spread to over 216 countries and territories. The World Health Organization (WHO) announced that COVID-19 reached pandemic status on 30 January 2020 [ 4 , 5 ] and subsequently, declared a global pandemic in March 2020 [ 6 ]. It has since been referred to be ‘the most crucial global health calamity of the century and the greatest challenge that humankind faced since the 2nd World War’ [ 7 ]. As of 26 December 2020, there were approximately 80,500,000 confirmed COVID-19 cases worldwide, including 1,700,000 related deaths [ 8 ], with a case fatality rate of 2.2%. The case fatality rate varies among countries, estimated from 0 to more than 20% [ 9 ]. A second wave of COVID-19 infection has already been recorded in many countries, which may be due to premature relaxation of government-enforced lockdown rules in many parts of the world [ 10 , 11 ]. Several countries have reported a new rise in daily cases higher than the first wave in March 2020 [ 12 , 13 ]. Although there is no shortage of information on this pandemic virus presented in everyday practice, this paper presents a comprehensive review of the latest information on SARS-CoV-2 highlighting the epidemiology, pathogenesis, and clinical aspects of SARS-CoV-2 infection.

We searched and reviewed literature published since November 2019, which focused on the epidemiology, pathogenesis, diagnosis, treatment, and prevention of COVID-19. Original studies, reviews, editorials, commentaries, perspectives, short or special communications, and position/policy papers on the COVID-19 pandemic were also searched. Information from websites of different professional associations and national or international organizations was extracted. Reference lists from the retrieved articles were also manually examined for relevant information. PubMed, Scopus, and Google Scholar were also searched using specific keywords, including ‘SARS-CoV-2ʹ, ‘COVID-19 infection’, ‘epidemiology’, ‘pathogenesis’, ‘diagnosis’, ‘treatment’, and ‘prevention’.

3. Origin, history, and epidemiology of COVID-19

Coronaviruses are a large family of viruses that are common in humans and many different species of animals (e.g. cats, bats). Most people are infected with these viruses at some point in their lives. Common human coronaviruses typically cause upper respiratory tract infections (URTIs) such as the common cold. However, some variants can cause mild influenza-like symptoms. Initially, cases related to SARS-CoV-2 were associated with high mortality rates, especially in people with chronic diseases, such as diabetes and cardiovascular diseases [ 14 , 15 ].

There are four main genres of coronaviruses: alpha (α), beta (β), gamma (γ), and delta (δ). The first human coronaviruses were identified in the mid-1960s. Common variants that affect people around the world include 229E, NL63, OC43, and HKU1. Among them, 229E and NL63 are α-coronaviruses, and OC43 and HKU1 are β-coronaviruses [ 16 ]. The usual signs and symptoms generated by these coronaviruses are similar to those of the common cold, accompanied by mild to moderate URTI. It is also of note that some coronaviruses that infect animals can undergo mutation and adaptation, thereby driving the co-evolution of coronaviruses that can become a new human coronavirus (HCoV) [ 17 ]. Therefore, these HCoV infections are zoonotic, and their symptoms are accompanied by more severe respiratory tract syndromes than those of the aforementioned ones. Three recent examples of these are: (i) SARS-CoV-2 (the novel coronavirus, causing coronavirus disease in 2019 or COVID-19), (ii) SARS-CoV (the β-coronavirus, causing severe acute respiratory syndrome, or SARS), and (iii) MERS-CoV (the β-coronavirus, causing Middle East respiratory syndrome, or MERS) [ 17 , 18 ].

COVID-19 was initially thought to be a zoonotic disease originating in bats, which may have undergone several cross-species events, first crossing the species barrier to pangolins and subsequently to humans. The outbreak appeared to have started from single or multiple zoonotic transmission events in the wet market in Wuhan [ 19 ]. As such, it was initially suspected that direct contact with intermediate host animals or the consumption of wild animals was the main route of SARS-CoV-2 transmission [ 5 ]. Its epidemiological link was first demonstrated by the appearance of several reported cases of severe respiratory distress, which had a typical characteristic radiological pattern (e.g. initial chest images demonstrated multifocal airspace opacities and consolidation in 70–80% of coronavirus-infected patients [ 20 ]). SARS-CoV-2 is highly transmissible and preliminary reports have suggested that the reproductive number (R 0 ) of people that an infected person could potentially infect is approximately 2.2 [ 21 ]. The R 0 is used to reflect contagious disease, and the higher the number, the more infectious the disease. If SARS-CoV-2 is compared to influenza and other diseases, the high R 0 , which varies from to 3–5, is representative of a more contagious infection [ 22 , 23 ] ( Table 1 ). The number of COVID-19 cases increased at a rapid rate, partly due to the highly infectious nature of the virus as well as the lack of awareness and availability of diagnostic kits in the initial stages of the pandemic [ 24 ].

Reproduction number (R 0 ) of some selected viruses [ 22 , 23 ]

Mortality for COVID-19 appears to be higher than that for influenza, especially seasonal influenza. Early estimates relied heavily on genetic tests, which are the gold standard for diagnosing COVID-19, from either sputum or nose swabs from the back of the nose [ 25 ]. However, these tests only provide a clear picture of active infection; they are not an accurate reflection of possible past infective events. In addition to the genetic tests, serological studies are now also used, and can indicate whether the individual has been infected in the past, based on antibody response [ 26 ].

4. Structural and molecular features of SARS-CoV-2

SARS-CoV-2 belongs to the genus Betacoronavirus of the subfamily Orthocoronavirinae in the family Coronaviridae, and the order Nidovirales [ 27–30 ]. The viral particle is pleomorphic, as confirmed by cryo-electron tomography, and possesses non-segmented, single-stranded, positive-sense ribonucleic acid (ssRNA+) as its genome [ 31 , 32 ]. A coronavirus contains four structural base proteins: spike (S), envelope (E), membrane (M), and nucleocapsid (N) [ 32 , 33 ]. Among them, the S protein plays the most important role in viral attachment, fusion, and entry [ 34 ]. Its 30 kb genome RNA is large enough to produce a positive sense to be read directly by ribosomes in the cell [ 33 ]. The genome is coated with an N protein, which forms a helical nucleocapsid [ 35 ]. The N protein-coated genome is enclosed in a lipid envelope, and the viral lipid envelope is speckled by viral proteins [ 35 , 36 ]. As viruses cannot make their own lipids, they use the host’s lipids for replication and morphogenesis [ 37 ]. The N protein plays a crucial role in the morphogenesis phase of the viral life cycle during virion formation [ 35 ]. In addition to the lipid envelope, coronaviruses have a membrane glycoprotein called the matrix protein on its outer layer [ 38 ]. This transmembrane protein has a significant C-terminal domain that makes contact with the N protein [ 39 ]. Another minor envelope protein, E, is also an important component at the end of the viral life cycle [ 38 ].

Coronaviruses get their name from the characteristic feature of their S protein, which resembles a halo effect seen in solar eclipse or a crown-like appearance under an electron microscope [ 34 ]. The S protein has a roughly cylindrical shape and is heavily glycosylated [ 40 ], and encodes and possesses both receptor-binding and-fusion functions. Coronavirus uses its S protein, a main target for neutralizing antibodies, to bind with specific receptors and mediate membrane fusion and virus entry. It is a trimeric protein [ 34 ], composed of three intertwined chains that have identical amino acid sequences, each of which is called a protomer. However, the protomers do not have identical three-dimensional conformations. The monomer of the trimeric S protein is approximately 180 kDa and contains two distinct functional subunits, S1 and S2, both necessary for mediating attachment and membrane fusion, respectively. In its structure, N- and C-terminal portions of the S1 fold are two independent domains, the N-terminal domain (NTD) and C-terminal domain (CTD). Depending on the virus, either NTD or CTD can serve as the receptor-binding domain (RBD). The S protein induces successful infusion into the cell by first binding to the host receptor through the RBD of the S1 subunit, resulting in viral genomic fusion; the second stage by S2 facilitates the fusion of the cell and host membranes, which contains amino acid sequences necessary for continuing infiltration [ 41–43 ]. The RBD in the S protein is the most mutable part of the coronavirus genome and tends to be common for general viruses [ 44 ].

During viral replication, SARS-CoV-2 uses host protease enzymes to covalently attach sugars to asparagine side chains near the protein surface [ 45 ]. To achieve fusion, the S protein needs to be cleaved by proteases present in the host cell. The hosts own peptide bond breaking proteases cut the S protein at specific sites, and conformational changes enable fusion to occur [ 46 ]. Moreover, the availability of proteases on target cells largely determines whether coronaviruses enter cells through the plasma membrane or by endocytosis [ 47 ]. Proteolytic cleavage of the S glycoprotein also determines whether the virus can cross species, for example, from bats to humans [ 48 ]. The process is critical because it allows the fusion sequences to be exposed. The nature of the cell protease that cleaves the S glycoprotein varies according to the coronavirus [ 31 ]. Coronavirus proteins may be cleaved by one or several host proteases based on virus strains and cell types, including trypsin, cathepsins, transmembrane protease serine protease-2 (TMPRSS-2), TMPRSS-4, or human airway trypsin-like protease (HAT) [ 43 , 49 ]. However, the specific proteases that promote virus entry into SARS-CoV-2 remain elusive [ 43 , 49 , 50 ]. This cleavage is generally mediated by furin [ 50 ], an enzyme belonging to the subtilisin-like proprotein convertase family. It cleaves precursor proteins and facilitates their conversion to a biologically active state; thus, it plays a vital role in viral protein processing [ 51 ]. The S1/S2 cleavage site is the target site of furin during infection. The RBD of the S1 subunit contacts angiotensin-converting enzyme 2 (ACE2), which is facilitated by furin cleavage [ 52 , 53 ]. Furin proteases are found in significant amounts in the lungs. Therefore, viruses that attack the respiratory tract make use of this enzyme to convert and activate their own surface glycoproteins. Basically, it is like a lock-and-key mechanism, where viral glycoprotein and cellular receptor represent key and lock, respectively. Other influenza pathogens that have similar cleavage sites can also be acted upon by furin and other cellular proteases. The prevalent expression of cellular proteases across cell types increases the potential for the virus to successfully infiltrate the host [ 53 ]. It should be mentioned here that all other β-coronaviruses, including SARS-CoV, which is the closest to the SARS-CoV-2 strain, do not contain this cleavage site [ 54 ]. A study showed that the S protein of SARS-CoV-2 is 10 to 20 times more likely to bind to human ACE2 than the S protein of the early 2000s SARS-CoV strain [ 55 ]. The heightened affinity for a prevalent cellular receptor may be a factor that increases transmission [ 56 ].

5. Mechanism of SARS-Cov-2 transmission

5.1. mechanisms of transmission.

The transmissibility of an infection is determined by the basic R 0 , with a value above the threshold of 1 implies continuous and sustained human-to-human transmission [ 23 , 57 ]. The rapid spread of SARS-CoV-2 is due, in part, to the transmission mechanisms of the viral agent. An understanding of the transmission dynamics of infectious spread is critical, providing insights into the epidemiologic spread, implementation of outbreak control measures, and determination of the efficacy of such control measures [ 23 ].

The transmission characteristics of SARS-CoV-2 are very similar to those of SARS-CoV and pandemic influenza. Riou et al . [ 57 ] stated that this was an indicator of the potential for sustained human-to-human transmission and the risk of global spread. More recently, a mean R 0 range of 2.24 to 3.58 [ 58 , 59 ] was determined. With transmissibility on par with that of SARS-CoV, pandemic influenza, and HIV, but much lower than measles and chickenpox ( Table 1 ), SARS-CoV-2 presented a moderate to severe infectious threat [ 57 ].

The first evidence of potential person-to-person transmission was reported by Chan et al . [ 60 ]. They investigated the transmission of the virus in a group of family members who had recently visited Wuhan. They had no history of contact with animals, visits to markets, or eating game meat, but stayed in the same hotel throughout their travel. With no direct zoonotic involvement, this was the first indication that the virus could be spread by human contact. These initial findings were subsequently confirmed with increasing evidence demonstrating sustained human-to-human transmission [ 57 , 61 ].

SARS-CoV-2 uses the same receptor, ACE2, as SARS-CoV, and mainly spreads through the respiratory tract [ 62 ]. As a respiratory infectious disease, the virus is transmitted primarily by droplets, respiratory secretions, and direct contact [ 63 ]. However, viral particles have been isolated from fecal swabs and blood, implying several alternative routes for transmission [ 64–66 ]. It is worth noting that the ACE2 protein is also expressed by enterocytes in the small intestine [ 67 ]. Previous Chinese reports have shown no evidence of vertical transmission of the virus by blood products or the fecal-oral route [ 64 , 68–70 ]. However, some recent studies from the United Kingdom (UK) and other countries have confirmed a low rate of vertical transmission due to COVID-19 [ 71–75 ].

5.2. Incubation period

The incubation period on average is 1–14 days, however, generally is 3–7 days. SARS-CoV-2 may be present in the throat or the nose a few days before symptom onset. Interestingly, completely asymptomatic subjects may have viral loads similar to those of symptomatic patients [ 76 ]. This implies that asymptomatic individuals may be possible sources of infection. After the incubation period, patients present with similar symptoms, including fever, cough, and malaise. A small percentage of patients also manifest gastrointestinal symptoms, such as diarrhea and vomiting. The elderly and those with underlying disorders rapidly develop acute respiratory distress syndrome (ARDS), septic shock, metabolic acidosis, and coagulation dysfunction, which may ultimately lead to multiple organ failure and even death [ 5 , 77 , 78 ].

6. Clinical and pathological characteristics of COVID-19

SARS-CoV-2 targets the respiratory system, and transmission occurs via contact droplets and fomites from an infected person who may be symptomatic or asymptomatic [ 79 ]. During the incubation period, the virus triggers a slow response in the lungs. SARS-CoV-2 mainly invades alveolar epithelial cells, resulting in respiratory symptoms [ 80 ].

The S-glycoprotein on the surface of SARS-CoV-2 binds to ACE2 [ 80 ]. The receptor and the enzyme on the surface of type 2 alveolar cells induce a conformational change in S-glycoprotein initiating proteolytic digestion by host cell proteases (TMPRSS2 and furin), ultimately leading to internalization of the virion [ 81 ]. This implies that SARS-CoV-2 has a pathogenesis similar to that of SARS-CoV [ 82 ]. Coronaviruses generally enter via endocytosis or direct fusion of the viral envelope with the host membrane. Once internalized by the host cell, the viral particle is uncoated, and its genome enters the cell cytoplasm. Coronaviruses have an RNA genome from which they can directly produce their proteins and new genomes in the cytoplasm by attaching to the host ribosomes [ 83 ]. The host ribosomes translate viral RNA into RNA polymerase proteins. This RNA polymerase then reads the positive strand again to generate single-stranded, negative-sense RNA (ssRNA-) strands.

The ssRNA- strands are then used as a template by RNA polymerase to make additional ssRNA+ strands. The small RNA strands are read by host ribosomes in the endoplasmic reticulum to make the structural components of the virus. These structural components are then transferred from the endoplasmic reticulum to the Golgi apparatus. Within the Golgi apparatus, ssRNA+ genomes are packaged in the nucleocapsids to create new virion particles. These progeny viruses are then released from the host cell via exocytosis through secretory vesicles. The replication of the virus in alveolar cells mediates damage and induces an inflammatory response in the tissues. Cellular entry of the virus triggers an inflammatory response by recruiting T-helper cells that produce interferon (IFN)-gamma (IFN-γ), interleukin (IL)-2, and IL-12 [ 84 ]. The injured alveolar cells also release interferons, cytokines, and other intracellular components. The subsequent recruitment of other inflammatory cells leads to the development of a ‘ cytokine storm ’ which can precipitate the organ damage and multi-organ failure seen in severe disease [ 84 ]. COVID-19 infected patients have shown higher concentrations of peripheral blood immune mediators [ 85 ]. IL-6, interferon gamma-induced protein (IP)-10, and IFN-γ were markedly elevated in all three highly pathogenic HCoV infections [ 3 , 85 ]. Interferons act in a paracrine manner and can have numerous effects on the surrounding cells, preparing them against viral infection [ 86 ]. The alveolar macrophages detect cell injury and respond to cytokines released by injured alveolar cells. The alveolar macrophages respond by secreting cytokines and chemokines [ 87 ]. The inflammatory process occurring within the lung parenchyma stimulates nerve endings responsible for initiating the cough reflex, thus, people often present with an early dry cough [ 87 ]. Tumor necrosis factor (TNF)-α and IL-1β are proinflammatory cytokines that cause an increase in vascular permeability, increase in adhesion molecule expression, and induce recruitment of more immune cells, including neutrophils and monocytes. They bind to adhesion proteins on the surface of tissues and enter the site of injury [ 88 ]. IL-8 recruits neutrophils, and other chemokines attract monocytes [ 89 ]. The increase in vascular permeability causes leakage of fluid into the interstitial space and alveoli, resulting in interstitial and pulmonary edema. This can lead to dyspnea, impaired oxygenation, or hypoxemia. The clinicopathological characteristics of coronaviruses are shown in Figure 1 .

Viral replication of SARS-coV-2 in alveolar cells

Neutrophils engulf viruses and other debris around the area, which can be detrimental because this activity also results in the release of chemical by-products that damage the surrounding tissue [ 90 ]. Consequently, when there are damaged alveolar cells all over, less surfactant is produced. The alveoli can easily collapse, resulting in impaired oxygenation or hypoxemia [ 91 ] ( Figure 1 ). White blood cells (WBCs) and damaged endothelial cells release other inflammatory mediators, including arachidonic acid metabolites, including leukotrienes and prostaglandins. Leukotrienes cause bronchoconstriction, leading to impaired ventilation, and subsequent hypoxemia [ 92 ]. Prostaglandins, IL-1, IL-6 and TNF-α are responsible for causing fever, a primary feature of COVID-19 [ 93 , 94 ]. Decreased oxygen levels in the blood stimulate chemoreceptors in the cardiopulmonary center in the brain, which causes an increased inspiratory rate to increase oxygen levels in the blood and also initiate the heart to pump faster to deliver oxygen to the body [ 95 ]. For this, patients with hypoxemia usually develop tachypnea and tachycardia [ 96 ]. However, some patients may be asymptomatic because their immune system keeps it in check or only minor symptoms, such as cough accompanied by shortness of breath and some fever. The alveolar macrophages can also detect the virus using its special toll like receptor-4 (TLR-4) receptors, which engulf viral particles through phagocytosis [ 97 ].

A common finding in COVID-19 is lymphopenia, which is assumed to be due to the release of interferons [ 98 ]. IL-6 stimulates hepatocytes to produce acute phase reactants such as C-reactive protein (CRP), fibrinogen, and hepcidin [ 99 ]. CRP is a good inflammatory marker, and a high level in the blood is a marker of inflammation [ 100 ]. Therefore, the damaged alveolar tissue, accumulation of the fluid, ventilation/perfusion mismatch, and hypoxemia, which are not related to heart function, leads to the presentation of ARDS, which is considered to be the leading cause of mortality in COVID-19 [ 101 ].

6.1. Clinical manifestations

Patients with COVID-19 experience varying degrees of severity, and 80% of them have mild infection [ 102 ]. Approximately 15% of cases develop severe disease characterized by dyspnea, hypoxia, and lung changes on imaging; 5% are critically ill, with respiratory failure from ARDS, shock, and/or multi-organ dysfunction [ 3 , 103 , 104 ]. As ACE2 is expressed not only in the lungs but also in the heart, endothelium, renal tubular epithelium, intestinal epithelium, and the pancreas, SARS-CoV-2 may possess the potential to invade these tissues, to proliferate and destroy these organs, causing multiple organ dysfunction syndrome (MODS) [ 105 , 106 ]. Excessive activation of lymphocytes and increased pro-inflammatory mediators in patients with COVID-19 promotes immune-mediated damage. The process causes a mild disease to increase in severity and single organ involvement to progress to MODS. In severe cases, the disease can lead to ARDS, septic shock, metabolic acidosis, coagulation dysfunction, and MODS. Elderly individuals with reduced immunity and comorbidities are more susceptible to severe infections [ 107 ].

The median age of individuals affected by severe complications related to COVID-19 ranges from 49 to 56 years of age [ 108 ]. As symptoms progress, patients may develop pneumonia with ARDS, which requires intensive care. Children are typically asymptomatic or present with mild symptoms. Men and women have the same susceptibility to infection; however, male patients are more at risk for worse outcomes and death [ 109 ]. The symptoms include fever, fatigue, dry cough, anorexia, myalgia, dyspnea, and sputum production [ 110 ]. Mortality rate increases with age, with a significant increase above 80 years of age. The mortality rate also increased with comorbidities, including diabetes, heart disease, chronic kidney disease, chronic lung disease, and other socio-demographic factors ( Table 2 ). An increased risk of infection due to SARS-CoV-2 is also found to be associated with other comorbidities such as hypertension (27–30%), diabetes (19%), and coronary heart disease (6–8%) [ 104 , 111 ]. Studies have also demonstrated that patients with severe COVID-19 develop ARDS (67.3%), acute kidney injury (28.9%), abnormal hepatic function (28.9%), and cardiac injury (23.1%) [ 112 ]. An overview of the effect of COVID-19 on different pathophysiological conditions is presented in Table 2 [ 109 , 113–124 ].

Effect of COVID-19 on different pathophysiological conditions

7. COVID-19 diagnostic techniques

The rapid and accurate detection of COVID-19 has become vital for effective response and prevention of further spread in large populations. Contact tracing has also been shown to be of extreme importance. It has allowed the systematic encapsulation of specific points of caseload increase, giving governments the opportunity to protect the health of the population without completely shutting down their economies. The American Center for Disease Control and Prevention (CDC) has been utilized since the initial identification of SARS-CoV-2 molecular assays for its detection, mostly using real-time polymerase chain reaction (PCR) methods [ 125 ]. The PCR for COVID-19 can only diagnose whether a person is currently infected with this particular coronavirus. It cannot provide information on other diseases or symptoms [ 126 ] and could miss patients who have cleared the virus and recovered from the disease [ 126 , 127 ]. Serology tests are also important as they can help assess the immune response [ 128 ], follow up on the progression of the disease, and the length of immune protection present after patients have recuperated from COVID-19 [ 129 ]. The serologic test is an enzyme-linked immunosorbent assay (ELISA)-based test that detects SARS-CoV-2 antibodies (IgG and IgM) in serum or plasma. The ELISA used by the CDC utilizes purified SARS-CoV-2 S protein (no live virus) as an antigen [ 130 ]. The problem with serologic tests is that the cross-reactivity to antibodies generated by other coronaviruses cannot be completely ruled out [ 130 ]. Comparative information on the use of different diagnostic techniques for COVID-19 is presented in Table 3 [ 131–134 ].

Viral test for COVID-19

8. Treatment and preventive measures

In the absence of any clinically proven treatment options, the treatment is symptomatic, and current clinical management includes infection prevention and control measures as well as supportive care [ 135 ]. Available therapeutic drugs include antiviral agents (e.g. remdesivir, hydroxychloroquine, chloroquine) and supporting agents (vitamin C, azithromycin, corticosteroids, IL-6 antagonists) [ 136 , 137 ]. Developing an effective COVID-19 vaccine is currently the world’s leading research priority [ 138 ]. Some vaccines have already been approved by the regulatory authorities for the prevention of COVID-19 [ 139–141 ].

8.1. Public health and preventive measures

Public health and preventive approaches are the current strategies to curb the transmission of COVID‐19 and focus on testing, case tracing, isolation, social distancing, and personal hygiene [ 142 ]. Important COVID-19 prevention and control measures in the community include hand hygiene, personal protective equipment (PPE), crowd avoidance, social distancing, isolation, school measures/closures, workplace measures/closures, quarantine, and travel restrictions [ 143 , 144 ].

A study conducted in Singapore recommended closing schools, maintaining effective social distancing in the workplace, and adopting quarantine measures to contain the pandemic once community transmission had been established [ 145 ]. Such measures were also found to reduce infection, mortality, and intensive care unit (ICU) admissions [ 58 , 146 , 147 ]. Social distancing reduces interactions between people and is effective in preventing community transmission [ 142 ]. The use of face masks is strongly indicated to reduce COVID-19 transmission in potentially asymptomatic or pre-symptomatic people [ 148 , 149 ]. The widespread use of face masks has been found to be effective in preventing SARS-CoV-2 transmission in highly affected areas in Italy and New York City [ 150 ]. Studies have demonstrated that a surgical mask could reduce virus exposure by an average of six times (range: 1.1 to 55 times) and should be worn by the potentially infected subject [ 151 ]. The WHO recommended the use of PPE by health care workers as they are more likely to be increasingly exposed to the virus and should wear medical/surgical masks, gowns, gloves, and face shields when treating infected patients or collecting samples [ 152 ].

Quarantine was found to be the most effective method for reducing the number of infected cases and decreasing mortality rates [ 22 , 153 , 154 ]. A review of 29 COVID-19 related studies found that quarantine can decrease the rate of infected cases (from 81% to 44%) and mortality (from 61% to 31%) [ 155 ]. Travel restrictions and lockdown in the early phase of the pandemic in Australia [ 156 ] and China [ 157 ] helped to decrease transmission effectively. Testing, isolation, and contact tracing were found to be effective in controlling the spread of the virus in countries such as South Korea, Singapore, Taiwan, and Hong Kong [ 158–161 ]. In contrast, Italy witnessed a wider outbreak as the country failed to employ such preventive measures during the early phase of the pandemic [ 161 ].

8.2. Management strategies based on symptoms

Management strategies of COVID-19 patients depend on the severity of the symptoms of the patients [ 162 , 163 ]:

• Mild cases:
• SpO 2 levels of 94%–97% in room air
• Symptomatic treatment
• O 2 therapy via nasal canula
• (2) Moderate cases:
• SpO 2 levels of 90%–94% in room air
• High-flow nasal oxygen (HFNO) therapy or noninvasive ventilation (NIV) in case of no improvement
• (3) Severe cases:
• SpO 2 levels ≤ 90% in room air or patients with ARDS
• O 2 therapy via HFNO/NIV with helmet
• Invasive ventilation via endotracheal intubation for patients with ARDS in cases of falling SpO 2 levels
• ARDS management

8.3. Pharmacological treatments

8.3.1. antiviral agents.

Extensive research is ongoing regarding antiviral therapies for the treatment of COVID-19. Although several antiviral therapies are being investigated by scientists, no treatments have been shown to be effective in treating COVID-19 [ 164 , 165 ]. Preliminary results are available from The Adaptive COVID-19 Treatment Trial (ACTT-1) from hospitalized COVID-19 patients. This double-blind randomized control trial (RCT) conducted in 60 trial sites and 13 subsites (United States of America [USA] (45 sites), Denmark (8), UK (5), Greece (4), Germany (3), Korea (2), Mexico (2), Spain (2), Japan (1), and Singapore (1)] showed that remdesivir was associated with a shorter median recovery time compared with placebo (11 vs. 15 days) with evidence of lower respiratory tract infection [ 165 ]. The trial also showed a significant mortality benefit (remdesivir group 4.0% vs. control group 12.7%). A study conducted in China, prematurely terminated due to adverse events of remdesivir, found that COVID-19 patients, with symptom duration of ≤ 10 days, improved faster compared to that of the placebo group, but this finding was not statistically significant [ 166 ]. A study conducted in the USA, Europe, and Canada showed clinical improvement among severe COVID-19 hospitalized patients (36 of 53 patients; 68%) who were treated with compassionate use of remdesivir [ 167 ]. Another RCT that included 584 patients with moderate COVID-19 at 105 hospitals in the United States, Europe, and Asia found those who took a 5-day course of remdesivir compared with those randomized to standard care had a statistically better outcome [ 168 ]. However, the WHO Solidarity Trial [ 169 ], conducted in 30 countries, found that remdesivir (including hydroxychloroquine, lopinavir/ritonavir, and interferon) had little or no effect on overall mortality, ventilation need, and duration of hospital stay.

Although the preliminary findings of the ACTT-1 study supported the use of remdesivir, the researcher recommended that remdesivir or any other antiviral drug alone is not effective, as the mortality rate is higher with the use of remdesivir. Another randomized, controlled, open-label trial with lopinavir/ritonavir treatment demonstrated no benefit compared to standard care [ 170 ]. Similarly, the UK RECOVERY (Randomized Evaluation of COVID-19 therapy) reported no benefit of lopinavir/ritonavir on survival, the clinical course, or the length of hospital stay [ 171 ]. After interim analysis of the trial results, the WHO SOLIDARITY and UK RECOVERY trials discontinued the lopinavir/ritonavir arms as the trials produced little or no reduction in the mortality of hospitalized COVID-19 patients in comparison to the standard of care [ 172 , 173 ]. Remdesivir received conditional marketing authorization by the European Commission on 3 July 2020, to treat COVID-19 patients [ 174 ]. Several anti-flu drugs, such as oseltamivir [ 175 ] and arbidol [ 176 ], have been used to treat COVID-19 patients and demonstrated a certain efficacy. Although the WHO recommended against the use of remdesivir in COVID-19 patients [ 177 ], the U.S. Food and Drug Administration (FDA) approved remdesivir on 22 October 2020, for the treatment of COVID-19 patients requiring hospitalization [ 178 ]. Remdesivir (Veklury) was the first drug approved by the FDA and indicated ‘for the treatment of COVID-19 disease in hospitalized adults and children aged 12 years and older who weigh at least 40 kg’ [ 178 ].

8.3.2. Corticosteroids

Corticosteroids have received considerable attention for the treatment of COVID-19 [ 179 , 180 ] and were found to be beneficial in several COVID-19-related conditions such as sepsis, pneumonia, and ARDS [ 181–183 ]. The RECOVERY trial found that dexamethasone reduced mortality by one-third in critically ill COVID-19 patients [ 184 , 185 ]. The medication was most helpful for patients on a ventilator or those who needed extra oxygen, but no benefit was noted for those with less severe symptoms. However, other studies reported conflicting results, with some showing benefits [ 186–188 ], while others demonstrated potential harm [ 189 , 190 ]. A meta-analysis of 15 studies [ 191 ] identified an increased risk of mortality and multi-organ dysfunction, no mortality benefit, and possibly an increased risk of death with the use of corticosteroids among COVID-19, SARS, and MERS patients. A recent WHO report suggested that systemic corticosteroids likely reduced 28-day mortality in patients with critical COVID-19 but may have increased the risk of death in non-severe patients [ 174 ]. The report recommended the use of systemic corticosteroid therapy for 7 to 10 days in patients with severe and critical COVID-19 and no corticosteroid treatment for non-severe patients in whom it may cause harm.

8.3.3. Antiviral/immunomodulatory drugs

Chloroquine and hydroxychloroquine are usually used as immunomodulatory therapies. Both drugs are approved by the FDA for the treatment or prevention of malaria. Recently, the FDA has approved the use of chloroquine and hydroxychloroquine to treat COVID-19 patients ‘only in hospitalized patients with COVID-19 when clinical trials are not available, or participation is not feasible, through an Emergency Use Authorization (EUA)’ [ 192 ]. According to ClinicalTrials.gov, 212 hydroxychloroquine trials (179 randomized) and 38 chloroquine trials (31 randomized trials) were registered until 3 September 2020 [ 193 ].

However, the outcomes of treatment with chloroquine (500 mg every 12 h) and hydroxychloroquine are not encouraging. The RECOVERY trial found that hydroxychloroquine did not reduce 28-day mortality when compared to the usual standard of care. In addition, patients who received hydroxychloroquine had a longer median hospital stay and increased risk of progressing to invasive mechanical ventilation or death than those who received the standard of care [ 194 ]. In a multicenter, randomized, open-label, three-group, controlled trial involving hospitalized patients in Brazil, no positive outcomes were reported with hydroxychloroquine alone or with hydroxychloroquine plus azithromycin among hospitalized patients with mild to moderate COVID-19 [ 195 ]. The occurrence of an adverse event (e.g. elevation of liver enzyme levels, and prolongation of the QTc interval) was more frequent among patients who received hydroxychloroquine or hydroxychloroquine plus azithromycin than among those who did not receive either agent [ 195 ]. Another open-label, randomized clinical trial at 57 centers in Brazil involving hospitalized patients with severe COVID-19 also failed to show the effectiveness of hydroxychloroquine plus azithromycin over hydroxychloroquine alone [ 196 ]. Large retrospective observational studies in hospitalized patients suffering from COVID-19 also showed no evidence of benefit for hydroxychloroquine with or without azithromycin [ 197 , 198 ]. However, a large, multicenter, retrospective, observational study in the USA reported that treatment with hydroxychloroquine alone and in combination with azithromycin reduced COVID-19 associated mortality [ 199 ]. Several randomized trials conducted among non-hospitalized patients with COVID-19 failed to demonstrate a clinical benefit of hydroxychloroquine treatment [ 200 , 201 ].

The COVID-19 Treatment Guidelines of National Institutes of Health, USA recommends against the use of high-dose chloroquine to treat COVID-19 due to severe toxicities, such as higher rates of mortality and QTc prolongation [ 202 , 203 ]. It has been warned that the combination of hydroxychloroquine and azithromycin should be used with caution as the combination is associated with QTc prolongation in patients with COVID-19 [ 204 ].

8.3.4. Immune-based therapy

The agents that modulate the immune response are used for the management of moderate to critical COVID-19, including human blood-derived products and immunomodulatory therapies. Human blood-derived products are collected from patients who have recovered from COVID-19 infection (e.g. convalescent plasma and immunoglobulin products) [ 205 , 206 ]. Other agents approved to treat other immune and/or inflammatory syndromes are also considered to treat COVID-19 patients, including corticosteroids (e.g. glucocorticoids) [ 207 ], interleukin inhibitors [ 208 , 209 ], interferons [ 210 ], and kinase inhibitors [ 211 ].

It has been suggested that convalescent plasma may help suppress the virus and modify the inflammatory response [ 205 ]. At present, there is limited evidence from clinical trials to evaluate the efficacy and safety of convalescent plasma for the treatment of COVID-19 [ 212 ]. A retrospective evaluation conducted by the FDA and the Mayo Clinic (USA) in >70,000 patients who received COVID-19 convalescent plasma demonstrated that plasma with high antibody titers may be more effective than low-titer plasma in non-intubated patients [ 213 , 214 ]. The FDA also evaluated 20,000 hospitalized patients with COVID-19 convalescent plasma and reported that transfusion is safe in patients with COVID-19 and found low overall rates of serious adverse events (SAEs) [ 215 ]. It is important to note that the FDA approved EUA on 23 August 2020, to use convalescent plasma in hospitalized patients with COVID-19 [ 216 ].

Interferon β was found to be effective against coronaviruses [ 217 ]. The WHO Solidarity Trial [ 169 ] found that interferon had little or no effect on overall mortality, ventilation need, and duration of hospital stay. However, a randomized, double-blind, placebo-controlled phase 2 trial conducted in the UK [ 218 ] demonstrated that hospitalized patients infected with SARS-CoV-2 received inhaled nebulized interferon β-1a had significantly greater odds of clinical improvement and rapid recovery on the WHO ordinal scale for clinical improvement [ 219 ]. Further studies should be conducted to evaluate the effectiveness of high-risk COVID-19 populations such as elderly, comorbid, or immunosuppressed patients [ 169 , 218 ].

8.3.5. Adjunctive therapy

Adjunctive therapies are used in patients with COVID-19, and some clinical trials are ongoing to identify the effects of these agents [ 202 ]. It was observed that COVID-19 patients were associated with a prothrombotic state and had a higher incidence of venous thromboembolism [ 220 , 221 ]. A French prospective multicenter study among ICU patients (n = 150) demonstrated that 16.7% of patients with ARDS secondary to COVID-19 developed life-threatening thrombotic complications despite prophylactic anticoagulation [ 221 ]. Another study conducted in the Netherlands found a 31% incidence of thrombotic complications in critically ill ICU patients with COVID-19 (n = 184) [ 222 ]. Therefore, patients with COVID-19 admitted to the ICU should receive pharmacological thrombosis prophylaxis [ 222 ].

Vitamin and mineral supplements are typically used to treat respiratory viral infections. Several studies have examined the effectiveness of vitamin and mineral supplements for the treatment and prevention of SARS-CoV-2 infection. High doses of vitamin C are recommended for the treatment of sepsis [ 223 ] and ARDS in patients with serious COVID-19. Several recent studies have examined the impact of vitamin D on COVID-19. One study of 489 people found that those who had a deficient vitamin D status were 1.77 times more likely to be infected with the virus than people with normal vitamin D status [ 224 ]. Despite the lack of evidence of whether vitamin D treatment may decrease the incidence of COVID-19, the use of vitamin D treatment is advocated due to its low risk and low cost [ 225 , 226 ]. Some clinical trials are ongoing with zinc supplementation alone or in combination with hydroxychloroquine for the prevention and treatment of COVID-19 [ 227–230 ]. A single-institution retrospective study in the USA showed ‘a lack of a causal association between zinc and survival in hospitalized patients with COVID-19’ [ 231 ].

8.4. A vaccine

Scientists are conducting research on the development of COVID-19 vaccines. At present, there are >100 COVID-19 vaccine candidates under development, some of which are in the human trial phase [ 138 ]. The WHO is working through the Access to COVID-19 Tools (ACT) accelerator to speed up the pandemic response and distribute vaccines via the COVID-19 Vaccines Global Access (COVAX) [led by WHO, Global Alliance for Vaccines and Immunization (GAVI) and Coalition for Epidemic Preparedness Innovations (CEPI)] to facilitate equitable access and distribution [ 138 ]. The WHO announced the launch of the WHO COVID-19 Solidarity vaccine trial on 28 May 2020, which is an international, randomized controlled phase III trial of different vaccine candidates [ 232 ]. It is one of the largest trials that enrolled almost 280,000 patients from 470 hospital sites in over 34 countries [ 232 , 233 ]. The trial aims to examine the efficacy of multiple vaccines (within a short period of vaccine introduction into the study), so that weakly effective vaccines are not deployed to treat patients with COVID-19 [ 232–235 ].

Until October 2020, there were 42 COVID-19 candidate vaccines in the clinical evaluation, of which 10 were in phase 3 trials ( Table 4 ) [ 232 , 236 ]. There are 151 candidate vaccines for preclinical evaluation [ 232 ]. So far, four vaccines have been reported to be effective for the prevention of COVID-19: Pfizer/BioNtech, Moderna, Oxford, and Sputnik V vaccines. The details of these vaccines are presented in Table 4 [ 232 , 236 ] and Table 5 [ 139 , 141 , 237 , 238 ]. The first two vaccines received emergency approval for use in the prevention of COVID-19 [ 139–141 ]. Whether these vaccines are effective against new strains of SARS-CoV-2, which were recently identified in the UK and other countries, needs further investigation.

COVID-19 vaccine candidates in phase III trials [ 231 , 235 ]

* Single dose schedule. ** S – Spike protein

Vaccines found to be effective in preventing COVID-19 [ 139 , 141 , 237 , 238 ]

*Intra-muscular

8.4.1. Pfizer/biontech vaccine

On 9 November 2020, Pfizer and its German partner BioNTech announced that their experimental vaccine was found to be more than 90% effective in preventing COVID-19 in participants without evidence of prior SARS-CoV-2 infection, based on initial data from Phase 3 trials [ 239 ]. According to Pfizer, the vaccine prevented COVID-19 symptoms in 90% of 94 patients who received the vaccine compared to the placebo. As of 8 November 2020, a total of 38,955 participants had received a second dose of the vaccine, of which 42% of global participants and 30% of U.S. participants had diverse racial and ethnic backgrounds [ 239 ]. Approximately 21% of the participants had at least one underlying comorbidity, that is, obesity, diabetes, or pulmonary disease [ 240 ]. On 16 November 2020, Pfizer released updated information concerning the observed efficacy of its vaccine in adults over 65 years of age, which was more than 94% [ 241 ]. On 11 December 2020, the FDA authorized the Pfizer/BioNTech vaccine for emergency use for individuals aged 16 years and older in the USA. This is the first COVID-19 vaccine approved by the FDA [ 139 ]. The European Medicines Agency (EMA) has also approved the Pfizer-BioNTech vaccine as the first COVID-19 vaccine to be used in EU countries [ 140 ].

The Pfizer/BioNTech vaccine is a messenger RNA (mRNA) vaccine, also known as BNT162b2, based on the SARS-CoV-2 S glycoprotein antigen and formulated in lipid nanoparticles (LNPs) [ 240 ]. It is a highly purified single-stranded, 5ʹ-capped mRNA produced by cell-free in vitro transcription from the corresponding DNA templates [ 242 ]. Its mechanism of action consists of nucleoside-modified mRNA (modRNA) encoding the viral S glycoprotein of SARS-CoV-2, which is formulated in lipid particles. This allows the delivery of RNA into host immune cells to enable the expression of the SARS-CoV-2 S antigen.

8.4.2. Moderna vaccine

On 16 November 2020, Moderna, Inc., a US pharmaceutical company, announced that its vaccine was 94.5% effective (Phase 3 COVE study) at preventing COVID-19 related illness, including severe cases, and is generally well tolerated [ 243 ]. An interim analysis of 95 cases (90 COVID-19 in the placebo group versus 5 cases in the mRNA-1273 group) demonstrated ‘a point estimate of vaccine efficacy of 94.5% (p < 0.0001)’ [ 243 ]. The Coronavirus Efficacy and Safety (COVE) trial, a randomized and placebo-controlled study, recruited 30,000 participants in the USA, aged 18 and above [ 243 ]. Unlike the Pfizer vaccine, it can be stored at standard refrigerator temperatures, which are available in doctors’ offices, pharmacies, and hospitals [ 244 ]. On 18 December 2020, the FDA issued an EUA for the Moderna vaccine for use in individuals 18 years of age and older in the USA [ 141 ].

The Moderna vaccine also used a similar technology to Pfizer/BioNTech. The active ingredient of the Moderna vaccine is a synthetic mRNA encoding the pre-fusion stabilized S glycoprotein of SARS-CoV-2. Both vaccines differ in their composition of LNP that encase the RNA; additionally, the RNA in both vaccines encodes a slightly modified form of the SARS-CoV-2 S protein [ 245 ]. Moderna’s formulation allows the vaccine to be stored at a higher temperature than Pfizer’s, which must be kept at −70°C, much colder than a normal freezer. Moderna’s vaccine can be stored in a − 20°C freezer for 6 months, and in a refrigerator (at approximately 4°C) for 30 days [ 141 , 237 ].

8.4.3. Oxford vaccine

Another vaccine developed by the University of Oxford, UK, and another pharmaceutical giant AstraZeneca was found highly effective – two full doses gave 62% protection (n = 8,895), a half dose followed by a full dose 90% (n = 2,741). Overall, the trial showed 70% protection (n = 11,636) [ 246 ]. The trial participants (n = 23,000) were from the UK and Brazil. The vaccine is cheaper than Pfizer and Moderna and does not require an ultra-cold storage and transport system [ 247 ]. As the vaccine was found to be more effective in trial participants who received a lower dose, AstraZeneca is now planning to run a new global trial [ 247 ].

Unlike the mRNA vaccines of Pfizer-BioNTech and Moderna, this vaccine uses double-stranded DNA. The mechanism of the vaccine is based on its effect on the S protein of SARS-CoV-2. The Oxford-AstraZeneca team used a modified version of the cold-causing chimpanzee adenovirus, known as ChAdOx1. Adenovirus derived from chimpanzee with E1 and E3 deletions encoding full-length S protein with a tissue plasminogen activator signal peptide [ 248 ]. With the use of genetic engineering methods, a portion of the DNA that is used for viral replication was deleted, so the adenovirus can no longer replicate and cause infection in the human body [ 249 ].

8.4.4. Sputnik V vaccine

The Russian vaccine Sputnik V was developed by the Gamaleya Research Institute in coordination with the Russian Defense Ministry. It was administered to 18,794 volunteers who received both the first and second doses of the vaccine or placebo. It showed very high efficacy; higher than 95% [ 238 ]. It is an adenovirus vector-based vaccine that uses a two-shot model with two different human adenoviral vectors, Ad5 and Ad26, for each shot [ 250 ]. When the first vaccine containing the vector with the S protein of SARS-CoV-2 is introduced into the human body, it synthesizes the S protein and initiates an immune response. After 21 days, the booster dose of the vaccine, based on another adenovirus vector unknown to the host cell, is administered. The body reacts by generating a further immune response that provides longlasting immunity [ 251 ].

9. The ethics of epidemics: ethical and moral issues associated with COVID-19

When it comes to global pandemics such as COVID-19, there are numerous issues in medical ethics that must be addressed and adhered to in order to ameliorate the human condition [ 252 , 253 ]. One of the most important issues to consider is patient confidentiality [ 254 ]. While confidentiality must be maintained between physicians and patients during standard medical care, when it comes to the treatment of a patient diagnosed with COVID-19, an exception has to be made. Since COVID-19 is considered a reportable illness, the type of illness that poses a threat to another person, doctors must follow Tarasoff’s Law of duty to warn and protect [ 255 ]. In other words, physicians are required to report quarantine and follow-up contact tracing [ 256 ].

Another ethical issue, autonomy, must be considered when a patient is diagnosed with COVID-19. A legally competent adult patient (18 years of age and older) may exercise their autonomous right to refuse treatment [ 257 ]. In such a case, a physician’s duty is to notify the patient about the possible health outcomes of refusing the treatment. However, COVID-19 is considered to be a quarantinable disease; thus, physicians could detain infected individuals during the infectious period.

In addition, informed consent is not required in the case of an emergency, such as in the case of a life-saving procedure for a patient diagnosed with COVID-19. Another example of an exception to obtaining informed consent is when the COVID-19 patient waived his or her right receiving information related to COVID-19 [ 254 ]. If a physician has to treat a patient diagnosed with COVID-19 who is incapacitated because he or she is either psychotic, unconscious, suicidal/homicidal, or under the influence, obtaining informed consent is not necessary [ 257 ]. Furthermore, physicians can invoke therapeutic privilege if physicians agree that the COVID-19 patient is unable to make good decisions for himself or herself. In this case, beneficence trumps the adult patient’s autonomy; hence, informed consent is not required during treatment [ 255 ].

In the case of minor health care (persons younger than 18 years of age), legally competent adult caregivers give consent for treatment [ 256 ]. Thus, when it comes to treating a minor diagnosed with COVID-19, the same rule applies as in the case of an adult patient. While physicians must always obtain informed consent from legal guardians when treating a minor, lifesaving treatment is always an exception [ 234 ]. Hence, legally competent adult guardians cannot refuse the lifesaving treatment of COVID-19 minors. On the other hand, when it comes to legally competent emancipated minors who are diagnosed with COVID-19, the physician must apply Tarasoff’s Law of duty to warn and protect [ 256 ]. In other words, the physicians must report, and quarantine emancipated minors diagnosed with COVID-19 since they pose a threat to another person and community. Furthermore, physicians could override their autonomous rights to refuse therapy by invoking therapeutic privileges, just in the case of adult patients [ 257 ].

10. Conclusion

The COVID-19 pandemic is the greatest global public health crisis since the pandemic influenza outbreak of 1918. Since its origin in Wuhan, the COVID-19 pandemic has now spread around the world, causing significant morbidity and mortality. Direct person-to-person respiratory transmission has rapidly amplified the spread of the virus, making it difficult to contain its spread within the community. Moreover, some patients are completely asymptomatic with a mild influenza-like illness and a positive swab test, and some present with serious symptoms that require immediate hospitalization. Currently, there is no effective antibody test available, and an effective, rapid, and sensitive serological test for COVID-19 is urgently needed for rapid diagnosis. Moreover, there is no effective approved therapy for COVID-19. Personal hygiene is fundamental for preventing transmission. Current treatment and management are mainly supportive of oxygen therapy, antivirals, steroids, hydroxychloroquine, immunomodulators, and plasma exchange therapy. We need to keep a close eye on human clinical trials for optimistic news on vaccine development.

10.1. Limitations

The information presented in this review paper must be considered in the context of potential limitations. There has been an overwhelming amount of information published since the outbreak of COVID-19, and most of the journal papers published, mainly in the early phase of pandemics, were not based on clinical/scientific research. The evidence-based information garnered for this review was obtained after careful review of currently published journal papers, reports, policy guidelines.

Another drawback of this paper is its narrative nature, which may limit the critical analysis of the information. A systematic review using appropriate protocols [ 258 ] of the current literature would help to draw reliable and accurate scientific information, improve the generalizability and consistency of findings, and increase the precision of the conclusion presented to formulate policy guidelines. However, the present review covers the most updated information on the anniversary of the COVID-19 pandemic, and such documentation is necessary for keeping readers, researchers, scientists, and policymakers appraised of the current status of the pandemic [ 259 ].

11. Expert Opinion

The COVID-19 pandemic has created a public health crisis, taking an enormous toll on humanity, disrupting lives and livelihoods [ 4 , 77 , 259 ]. The scale and severity of COVID-19 is unprecedented, and millions of people have been infected with large numbers of morbidities and mortalities [ 4 , 57 ]. Genetic sequencing suggests that the virus belongs to the family Coronaviridae and genus Betacoronavirus, which is closely linked to the SARS virus [ 27–30 ]. Epidemiological and virologic studies have reported that COVID-19 usually transmits from person to person through several routes, mainly via respiratory droplets [ 260–263 ]. Evidence of virological assessment of transmission of infection from people with presymptomatic stage is limited due to the lower number of samples collected [ 264 , 265 ]. Some infected persons can be contagious during the presymptomatic phase, from to 1–3 days before symptom onset [ 266 , 267 ]. For individuals, transmission risk is found to be greatest on the day of symptom onset in symptomatic patients [ 264 , 265 , 268 , 269 ]. Ferretti et al. analyzed five datasets and demonstrated that approximately 10% of transmissions may occur two days before the manifestation of symptoms [ 270 ]. Another review identified that 31% of infected individuals remain asymptomatic [ 271 ].

While most people with COVID-19 show only mild (40%) or moderate (40%) symptoms, approximately 15% of patients exhibit severe symptoms (requiring oxygen therapy), and 5% develop critical disease with complications (e.g. respiratory failure, ARDS, sepsis, septic shock) [ 135 ]. The WHO reported that the crude mortality ratio (the number of reported deaths divided by the reported cases) is 3–4%; however, the true mortality of COVID-19 will take some time to determine [ 271 ]. Elderly people, smokers, and patients with comorbid diseases (such as diabetes, hypertension, cardiac disease, chronic lung disease, and cancer) have an increased risk of severe disease and death [ 272 , 273 ].

The host response to SARS-CoV-2 is a key factor in the presentation of disease severity; however, variations in viral strain phenotypes, specifically those associated with the glycoprotein components of the virus, have contributed to the efficient transmission of the virus during the current pandemic [ 274 ].

Although the sequence diversity of SARS-CoV-2 is low, its global spread has resulted in several thousand viral variants due to mutations in the native strain over time [ 259 , 275 ]. The most notable of these, as first documented by Korber et al . [ 277 ], is a viral variant with an amino acid substitution in the S glycoprotein spike. The mutation, which causes a substitution of the amino acid aspartate (D-biochemical symbol), at the 614 th amino acid position of the spike protein with glycine (G), has overtaken the native SARS-CoV-2 virus as the most prevalent infective strain [ 277 ]. This variant, termed D614G, is associated with increased transmissibility and higher viral loads in COVID-19 patients, has not been demonstrated to cause an increase in disease severity [ 276 , 278 ]. The substitution enhances viral replication within the respiratory tract of infected individuals and affects neutralization susceptibility [ 274 ].

Compared with other highly mutable viruses, such as HIV, SARS-CoV-2 has a low mutation rate; however, as pandemics progress, it is possible that antigenic drift events, which slowly accumulate mutations over time, can lead to increased fitness as well as immunological and drug resistance [ 279 ]. This is a key consideration for current and future vaccine development.

Case detection, contact tracing, surveillance, infection prevention and control, physical distancing, and clinical management are effective strategies used to contain COVID-19 cases [ 280 , 281 ]. Early detection and reporting can prove to be useful, and contact tracing is a widely used surveillance system to fight the ongoing epidemic of COVID-19 [ 282 ]. Contact tracing provides information that also helps to better understand the transmission and epidemiology of COVID-19 [ 158 , 281 ]. Moreover, some countries are now experiencing the ‘second’ or ‘third’ waves of coronaviruses [ 283 ]. Scientists have proposed using app-based contact tracing to keep the epidemic in control as an alternative [ 284 ]. A digital technological system, called ‘proximity tracking ’ is now a widely used surveillance system for COVID-19 [ 285 ].

Currently, PCR, the gold standard for detecting SARS-CoV-2, is used to detect the virus in specialized laboratories [ 2 , 125 , 127 , 286 ]. The test has high sensitivity and specificity for the detection of viral ribonucleic acid (RNA) [ 2 , 286 ]. The high volume of samples could lead to a shortage of reagents and may increase the turn-around time of the tests. Alternatively, rapid antigen tests provide multiple benefits, including ease of use, quick results (10 to 30 minutes), low cost, and can be performed both in the laboratory and at the point of patient care [ 280 ]. Although rapid antigen testing has a lower sensitivity, the WHO recommends the use of this test where PCR is unavailable or where reduced turnaround-time is clinically necessary [ 287 ]. Antigen tests are immunoassays that are used to determine if the person has an active disease [ 288 ], whereas a positive antibody test indicates that the patient is likely infected with COVID-19 at some time in the past [ 289 ]. Antibody tests can be conducted in laboratory settings (e.g. enzyme-linked immunosorbent assays, chemiluminescence immunoassays) or point of care (e.g. Abbott SARS-CoV-2 assay, Roche Elecsys assay) [ 290 ].

To date, no effective specific drug therapy or vaccine has been found to limit the spread of this pathogen. Infection prevention and control measures, supportive needs, and intensive care support are the main strategies for clinical management of COVID-19 infection [ 136 ]. General prevention and protection measures regarding the containment and management of the second or third waves are necessary to minimize the risk of infection. There is some promising news regarding COVID-19 vaccines. Several phase 3 clinical trials are in progress or are being planned in some countries. As of 24 November 2020, four vaccines were reported to be 62–95% effective ( Table 5 ) [ 139 , 141 , 237 , 238 ]. These promising results have fueled optimism around the world, as we may be a step closer to defeating this deadly virus. Certainly, there is light at the end of the tunnel. Equitable access and effective distribution of these vaccines in all countries will save millions of lives.

ABBREVIATIONS

Funding Statement

This paper was not funded.

Article highlights

• The COVID-19 pandemic has created a public health crisis, infected millions of people, and caused a large number of morbidities and mortalities.

• COVID-19 transmits from person to person through several routes, mainly via respiratory droplets, which makes it difficult to contain its spread into the community.

• Currently, there is no effective antibody test available, and an effective, rapid, and sensitive serological test for COVID-19 is urgently needed for rapid diagnosis.

• In the absence of any clinically proven treatment options, the current clinical management of COVID-19 includes symptom management, infection prevention and control measures, optimized supportive care, and intensive care support for severe or critical illness, and general prevention and protection measures regarding the containment and management of the second or third waves are necessary to minimize the risk of infection.

• There is some promising news regarding COVID-19 vaccines as large-scale (Phase 3) clinical trials are in progress. As of 24 November 2020, four vaccines were reported to be 62–95% effective. Equitable access and effective distribution of these vaccines in all countries will save millions of lives.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

3 types of medical presentations (and how to give them)

Here are some tips for presenting the top three types of medical presentations: lectures, research presentations, and case reports.

Derek Murray

Building presentations

With your long to-do list as a medical professional, giving presentations is probably not a high priority. Yet, medical presentations are inevitable. Are you ready to give them when your job requires it? If so, where do you even start?

We want to make it a little easier for you to present data-heavy medical topics in an easy-to-understand way.

So, let’s dive right in with the top three types of medical presentations.

Key Takeaways:

• Structure your medical presentation into a story to make it memorable.
• Medical presentations can be lectures, research, or case presentations.
• Customize the presentation based on the type and goal.

1. Lectures

Medical lectures educate an audience about a medical topic. They’re one of the most challenging presentations. According to the Learning Pyramid , lectures are the most passive learning techniques, which is also why they have the lowest retention rates.

There are several settings for educational lectures, including:

• Conferences
• University or school lectures

Medical lectures help students or an audience comprehend complex medical information and then turn what they learned into actionable strategies.

For example, you may teach students with little medical knowledge about a new medical concept. But they must understand the topic and be able to recall it for examinations.

Tips for giving medical lectures

How can you turn one of the most challenging presentations into an engaging, memorable lecture? Here are a few tips to ace your educational medical lectures:

• Be interactive : Use Q&As, activities, and open discussions.
• Hand out resources: Give physical booklets students can review after the presentation.
• Use multimedia: Add audio-visual elements like images, video, and audio clips.
• Use simple language: Your audience is learning, so they need simple language and plenty of definitions to understand the topic.
• Make it entertaining: Keep your audience’s attention with a more engaging and entertaining presentation.

UnitedHealth Group incorporated imagery and movement to show rather than tell about mental health in 2022 to boost their engagement on the topic.

2. Research presentations

The most information-heavy medical presentation is the research presentation. Research presentations share findings with experienced medical professionals, usually in conference settings. Some of the audience includes:

• Investigators
• Ph.D. students
• Medical professionals and experienced doctors

Research presentations can also be part of healthcare marketing . You may have to introduce a new process, pharmaceutical, or device to encourage other healthcare professionals to adopt it in their practices.

Tips for giving research presentations

Use these tips to improve your research presentations :

• Speak on a higher level: You’re talking to a knowledgeable audience, so they expect a higher level of research.
• Back all facts with data: Use statistics and research to back all claims.
• Use power poses: Build authority with a confident presentation.
• Grab the audience’s attention: Start your presentation by giving your audience a reason to care, like a problem you want to solve.
• Build up the conclusion: Structure the research in a natural, progressive order that builds up to your conclusion.
• Look at the future: Conclude with how the research findings will impact the future of medicine.
• Visualize data : Simplify findings and data with visuals and charts.

Cardinal Health transformed the complex research for Smart Compression into understandable slides using a mix of graphics and storytelling in their medical presentation.

3. Case reports

Medical professionals must give oral case reports when transferring information between providers or a team. These presentations are very brief and often don’t require visuals.

Sometimes a case is especially unique and offers educational value to others. In that case, presenters should transform their quick oral case reports into a longer presentation that incorporates data and visuals.

Tips for giving case reports

Case reports use a similar structure to oral patient presentations, except with more details about each point. You’ll still want to pack as much information in a short presentation as possible.

• Begin the presentation with a patient overview: Start by introducing the patient, including all relevant demographic details in summarized graphics and lists.
• Present the history of the patient: Describe the patient’s history, why they sought care, and the symptoms they presented in charts and visuals.
• Explore medical information: Dive into the medical details, like treatment and history, using a storytelling structure to connect the information.
• Offer a plan: Outline a treatment plan alongside proof.

Summarize details in charts: You’ll pack a large amount of information in a concise presentation, so use plenty of charts and diagrams to summarize data and simplify outcomes.

Tips for preparing engaging medical presentations

Your medical presentations have highly complex topics rich with data. These topics can easily feel overwhelming or even boring if they don’t have the right structure and appearance.

Here are three medical presentation tips we’ve learned to help you prepare and present high-quality medical presentations that engage AND inform.

Know your audience’s knowledge level

Before building and presenting a medical topic, you must know your audience’s knowledge level. A lecture to a class of first-year college students will sound far different from a presentation to doctors with 10+ years of industry experience.

Build a presentation around your audience’s knowledge, so it’s understandable yet challenging. By taking this extra step, you’ll know what points need more explanation and what topics you can dig deeper into based on your audience’s experience.

Build a structured story

A complex topic becomes easy to understand and follow if you use a storytelling structure . You might ask, “How can a lecture on a new treatment be a story?”

Any time you communicate, it’s a story: You have the challenge to solve, potential solutions to try, and a final winner (like when presenting medical research). You can structure that story in a progressive order or by announcing one primary outcome and providing a list of proofs (like with patient case studies).

Focus on a goal

The goal of medical presentations can be educating, training, or persuading the audience, depending on the type of medical presentation. Knowing your goal guides which data is most relevant to bring your desired outcome.

Communicate at the speed of healthcare with Prezent

Whether you’re preparing a lecture, research presentation, or case report, creating presentation slides is probably far down your priority list. The fast-paced healthcare industry has enough duties vying for attention. So how are you supposed to squeeze in hours to build an engaging presentation?

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Type 2 Diabetes Mellitus Clinical Presentation

• Author: Romesh Khardori, MD, PhD, FACP; Chief Editor: George T Griffing, MD  more...
• Sections Type 2 Diabetes Mellitus
• Practice Essentials
• Pathophysiology
• Epidemiology
• Patient Education
• Physical Examination
• Approach Considerations
• Glucose Studies
• Glycated Hemoglobin Studies
• Urinary Albumin Studies
• Diabetes Testing in Asymptomatic Patients
• Tests to Differentiate Type 2 and Type 1 Diabetes
• Pharmacologic Therapy
• Management of Glycemia
• Dietary Modifications
• Activity Modifications
• Bariatric Surgery
• Laboratory Monitoring
• Monitoring for Diabetic Complications
• Management of Hypertension
• Management of Dyslipidemia
• Management of Coronary Heart Disease
• Management of Ophthalmologic Complications
• Management of Diabetic Neuropathy
• Management of Infections
• Management of Intercurrent Medical Illness
• Management of Critical Illness
• Pharmacologic Considerations in Surgery
• Prevention of Type 2 Diabetes Mellitus
• Stroke Prevention in Diabetes
• Consultations
• Medication Summary
• Antidiabetics, Biguanides
• Antidiabetics, Sulfonylureas
• Antidiabetics, Meglitinide Derivatives
• Antidiabetics, Alpha-Glucosidase Inhibitors
• Antidiabetics, Thiazolidinediones
• Antidiabetics, Glucagonlike Peptide-1 Agonists
• Dual GIP/GLP-1 Agonists
• Antidiabetics, Dipeptidyl Peptidase IV Inhibitors
• Antidiabetics, Amylinomimetics
• Selective Sodium-Glucose Transporter-2 Inhibitors
• Bile Acid Sequestrants
• Antidiabetics, Rapid-Acting Insulins
• Antidiabetics, Short-Acting Insulins
• Antidiabetics, Intermediate-Acting Insulins
• Antidiabetics, Long-Acting Insulins
• Dopamine Agonists
• Questions & Answers
• Media Gallery

The diagnosis of diabetes mellitus is readily entertained when a patient presents with classic symptoms (ie, polyuria, polydipsia, polyphagia, weight loss). Other symptoms that may suggest hyperglycemia include blurred vision, lower extremity paresthesias, or yeast infections, particularly balanitis in men. However, many patients with type 2 diabetes are asymptomatic, and their disease remains undiagnosed for many years.

In older studies, the typical patient with type 2 diabetes had diabetes for at least 4-7 years at the time of diagnosis. [ 152 ] Among patients with type 2 diabetes in the United Kingdom Prospective Diabetes Study, 25% had retinopathy; 9%, neuropathy; and 8%, nephropathy at the time of diagnosis. (For more information, see Diabetic Neuropathy .)

Patients with established diabetes

In patients with known type 2 diabetes, inquire about the duration of the patient's diabetes and about the care the patient is currently receiving for the disease. The duration of diabetes is significant because the chronic complications of diabetes are related to the length of time the patient has had the disease.

A focused diabetes history should also include the following questions:

Is the patient's diabetes generally well controlled (with near-normal blood glucose levels) - Patients with poorly controlled blood glucose levels heal more slowly and are at increased risk for infection and other complications

Does the patient have severe hypoglycemic reactions - If the patient has episodes of severe hypoglycemia and therefore is at risk of losing consciousness, this possibility must be addressed, especially if the patient drives or has significant underlying neuropathy or cardiovascular disease

Does the patient have diabetic nephropathy that might alter the use of medications or intravenous (IV) radiographic contrast material

Does the patient have macrovascular disease, such as coronary artery disease (CAD) that should be considered as a source of acute symptoms

Does the patient self-monitor his or her blood glucose levels - If so, note the frequency and range of values at each time of day

When was the patient's hemoglobin A1c (HbA1c; an indicator of long-term glucose control) last measured, and what was it

What is the patient’s immunization history - Eg, influenza, pneumococcal, hepatitis B, tetanus, herpes zoster

As circumstances dictate, additional questions may be warranted, as follows:

Does the patient give a history of recent polyuria, polydipsia, nocturia, or weight loss - These are symptoms of hyperglycemia

Has the patient had episodes of unexplained hypoglycemia - If so, when, how often, and how does the patient treat these episodes

Does the patient have hypoglycemia unawareness (ie, does the patient lack the adrenergic warning signs of hypoglycemia) - Hypoglycemia unawareness indicates an increased risk of subsequent episodes of hypoglycemia

Regarding retinopathy, when was the patient's last dilated eye examination, and what were the results

Regarding nephropathy, does the patient have known kidney disease; what were the dates and results of the last measurements of urine protein and serum creatinine levels

Does the patient have hypertension (defined as a blood pressure of 130/80 mm Hg or higher); what medications are taken

Does the patient have CAD

Regarding peripheral vascular disease, does the patient have claudication or a history of vascular bypass

Has the patient had a stroke or transient ischemic attack

What are the patient's most recent lipid levels; is the patient taking lipid-lowering medication

Does the patient have a history of neuropathy or are symptoms of peripheral neuropathy or autonomic neuropathy present (including impotence if the patient is male)

Does the patient have a history of foot ulcers or amputations; are any foot ulcers present

Are frequent infections a problem; at what site

Dawn phenomenon

The Dawn phenomenon, defined as a blood glucose increase of over 20 mg/dL occurring at the end of the night, appears to be common in type 2 diabetes. In a study of 248 noninsulin-treated patients with type 2 diabetes who underwent continuous glucose monitoring for 2 consecutive days, approximately half were found to have the dawn phenomenon. [ 153 , 154 ] Patients with the dawn phenomenon had HbA1c levels and 24-hour mean glucose values that were significantly higher than in other patients, the mean differences being 4.3 mmol/mol for HbA1c (0.39%) and 12.4 mg/dL for average 24-hour glucose concentrations. Mean 24-hour glucose did not significantly differ between patients treated with diet alone and those treated with oral antihyperglycemic agents (ie, oral antidiabetic drugs did not eliminate the dawn phenomenon). [ 153 , 154 ]

Early in the course of diabetes mellitus, the physical examination findings are likely to be unrevealing. Ultimately, however, end-organ damage may be observed. Potential findings are listed in the image below.

A diabetes-focused examination includes vital signs, funduscopic examination, limited vascular and neurologic examinations, and a foot assessment. Other organ systems should be examined as indicated by the patient's clinical situation.

Assessment of vital signs

Baseline and continuing measurement of vital signs is an important part of diabetes management. In addition to vital signs, measure height, weight, and waist and hip circumferences.

In many cases, blood pressure measurement will disclose hypertension, which is particularly common in patients with diabetes. Patients with established diabetes and autonomic neuropathy may have orthostatic hypotension. Orthostatic vital signs may be useful in assessing volume status and in suggesting the presence of an autonomic neuropathy.

If the respiratory rate and pattern suggest Kussmaul respiration, diabetic ketoacidosis (DKA) must be considered immediately, and appropriate tests ordered. DKA is more typical of type 1 diabetes, but it can occur in type 2.

Funduscopic examination

The funduscopic examination should include a careful view of the retina. The optic disc and the macula should be visualized. If hemorrhages or exudates are seen, the patient should be referred to an ophthalmologist as soon as possible. Examiners who are not ophthalmologists tend to underestimate the severity of retinopathy, especially if the patients' pupils are not dilated.

Whether patients develop diabetic retinopathy depends on the duration of their diabetes and on the level of glycemic control maintained. [ 155 , 156 ] Because the diagnosis of type 2 diabetes often is delayed, 20% of these patients have some degree of retinopathy at diagnosis. The following are the 5 stages in the progression of diabetic retinopathy:

Dilation of the retinal venules and formation of retinal capillary microaneurysms

Increased vascular permeability

Vascular occlusion and retinal ischemia

Proliferation of new blood vessels on the surface of the retina

Hemorrhage and contraction of the fibrovascular proliferation and the vitreous

The first 2 stages of diabetic retinopathy are known as background or nonproliferative retinopathy. Initially, the retinal venules dilate, then microaneurysms (tiny red dots on the retina that cause no visual impairment) appear. As the microaneurysms or retinal capillaries become more permeable, hard exudates appear, reflecting the leakage of plasma.

Larger retinal arteriolar and venular calibres have been associated with lower scores on memory tests but not with lower scores on other cognitive tests. [ 157 ] This association was strong in men. Impaired arteriolar autoregulation may be an underlying mechanism of memory decrements.

Rupture of intraretinal capillaries results in hemorrhage. If a superficial capillary ruptures, a flame-shaped hemorrhage appears. Hard exudates are often found in partial or complete rings (circinate pattern), which usually include multiple microaneurysms. These rings usually mark an area of edematous retina. The patient may not notice a change in visual acuity unless the center of the macula is involved.

Macular edema can cause visual loss; therefore, all patients with suspected macular edema must be referred to an ophthalmologist for evaluation and possible laser therapy. Laser therapy is effective in decreasing macular edema and preserving vision but is less effective in restoring lost vision. (For more information, see Macular Edema in Diabetes .)

Preproliferative and proliferative diabetic retinopathy are the next stages in the progression of the disease. Cotton-wool spots can be seen in preproliferative retinopathy. These represent retinal microinfarcts caused by capillary occlusion; they appear as patches that range from off-white to gray, and they have poorly defined margins.

Proliferative retinopathy is characterized by neovascularization, or the development of networks of fragile new vessels that often are seen on the optic disc or along the main vascular arcades. The vessels undergo cycles of proliferation and regression. During proliferation, fibrous adhesions develop between the vessels and the vitreous. Subsequent contraction of the adhesions can result in traction on the retina and retinal detachment. Contraction also tears the new vessels, which hemorrhage into the vitreous.

Patients with preproliferative or proliferative retinopathy must immediately be referred for ophthalmologic evaluation because laser therapy is effective in this condition, especially before actual hemorrhage occurs.

Often, the first hemorrhage is small and is noted by the patient as a fleeting, dark area, or "floater," in the field of vision. Because subsequent hemorrhages can be larger and more serious, the patient should be referred immediately to an ophthalmologist for possible laser therapy. Patients with retinal hemorrhage should be advised to limit their activity and keep their head upright (even while sleeping), so that the blood settles to the inferior portion of the retina, thus obscuring less central vision.

Patients with active proliferative diabetic retinopathy are at increased risk of retinal hemorrhage if they receive thrombolytic therapy; therefore, this condition is a relative contraindication to the use of thrombolytic agents.

One study has shown that individuals with gingival hemorrhaging have a high prevalence of retinal hemorrhage. [ 158 ] Much of this association is driven by hyperglycemia, making it possible to use gingival tissue to study the natural course of microvascular disease in patients with diabetes.

Foot examination

The dorsalis pedis and posterior tibialis pulses should be palpated and their presence or absence noted. This is particularly important in patients who have foot infections, because poor lower-extremity blood flow can slow healing and increase the risk of amputation.

Documenting lower-extremity sensory neuropathy is useful in patients who present with foot ulcers because decreased sensation limits the patient's ability to protect the feet and ankles. This can be assessed with the Semmes Weinstein monofilament or by assessment of reflexes, position, and/or vibration sensation.

If peripheral neuropathy is found, the patient should be made aware that foot care (including daily foot examination) is very important for preventing foot ulcers and avoiding lower-extremity amputation. (For more information, see Diabetic Foot and Diabetic Foot Infections .)

Differentiation of type 2 from type 1 diabetes

Type 2 diabetes mellitus can usually be differentiated from type 1 diabetes mellitus on the basis of history and physical examination findings and simple laboratory tests (see Workup: Tests to Differentiate Type 2 and Type 1 Diabetes ). Patients with type 2 diabetes are generally obese, and may have acanthosis nigricans and/or hirsutism in conjunction with thick necks and chubby cheeks.

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• Simplified scheme for the pathophysiology of type 2 diabetes mellitus.
• Prevalence of type 2 diabetes mellitus in various racial and ethnic groups in the United States (2007-2009 data).
• Prevalence of diabetes mellitus type 2 by age in the United States (2007 estimates).
• Possible physical examination findings in patients with type 2 diabetes mellitus.
• Diagnostic criteria (American Diabetes Association) for diabetes mellitus type 2.
• Major findings from the primary glucose study in the United Kingdom Prospective Diabetes Study (UKPDS).
• Results from metformin substudy in the United Kingdom Prospective Diabetes Study (UKPDS).
• Findings from the blood pressure substudy in the United Kingdom Prospective Diabetes Study (UKPDS).
• Laboratory monitoring guidelines for patients with type 2 diabetes mellitus.
• American Diabetes Association guidelines for low-density lipoprotein cholesterol in diabetes mellitus type 2.
• Treatment of type 2 diabetes mellitus.
• Types of insulin. Premixed insulins can be assumed to have a combination of the onset, peak, and duration of the individual components.
• Simplified scheme for using insulin in treating patients with type 2 diabetes mellitus.
• Simplified scheme of idealized blood glucose values and multiple dose insulin therapy in type 2 diabetes mellitus.

Contributor Information and Disclosures

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Anne L Peters, MD, CDE Director of Clinical Diabetes Programs, Professor, Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, California, Los Angeles County/University of Southern California Medical Center

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Don S Schalch, MD is a member of the following medical societies: American Diabetes Association , American Federation for Medical Research , Central Society for Clinical Research , and Endocrine Society

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Stable Angina Pectoris: Definition, Clinical Presentation and Pathophysiologic Mechanisms

• First Online: 02 August 2016

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• Juan Carlos Kaski 2  

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Angina is usually caused by coronary artery disease; atherosclerotic plaques in the coronary arteries cause progressive narrowing of the arterial lumen and symptoms occur when the restricted blood flow does not provide adequate amounts of oxygen to the myocardium during oxygen demand increases (such as during exercise). Angina can also, less commonly, be caused by: valve disease (for example aortic stenosis), hypertrophic obstructive cardiomyopathy, or hypertensive heart disease. This classical definition of angina pectoris is applicable, essentially and almost exclusively, to myocardial ischaemia caused by obstructive coronary atherosclerosis. Therefore, it does not necessarily encompass all of the various presentations of angina pectoris identified over the past five decades. Dynamic, functional mechanisms may play a key role in the genesis of angina both in the presence and the absence of epicardial coronary artery obstructions. This chapter will discuss the different forms of clinical presentation of angina pectoris and the various pathophysiological mechanisms responsible for the occurrence of myocardial ischaemia. In addition, the concept of coronary flow reserve, haemodynamic assessment of coronary artery stenosis and the role that abnormalities in cardiac metabolism can play in exacerbating myocardial ischaemia will be also addressed in this chapter.

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Kaski, J.C. (2016). Stable Angina Pectoris: Definition, Clinical Presentation and Pathophysiologic Mechanisms. In: Essentials in Stable Angina Pectoris. Springer, Cham. https://doi.org/10.1007/978-3-319-41180-4_2

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Osteoporosis

Definition and clinical presentation.

Glaser, David L. MD * ; Kaplan, Frederick S. MD *†

From the Departments of * Orthopaedic Surgery and † Medicine, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.

Acknowledgment date: June 17, 1997.

Acceptance date: June 17, 1997.

Device status category: 1.

Address reprint requests to: Frederick S. Kaplan, MD; Department of Orthopaedic Surgery: Silverstein Two; Hospital of the University of Pennsylvania; 3400 Spruce Street; Philadelphia, PA 19104.

Osteoporosis is a skeletal condition characterized by decreased density (mass/volume) of normally mineralized bone. The reduced bone density leads to decreased mechanical strength, thus making the skeleton more likely to fracture. Postmenopausal osteoporosis (Type I) and age-related osteoporosis (Type II) are the most common primary forms of bone loss seen in clinical practice. Secondary causes of osteoporosis include hypercortisolism, hyperthyroidism, hyperparathyroidism, alcohol abuse, and immobilization. In the development of osteoporosis, there is often a long latent period before the appearance of the main clinical manifestation, pathologic fractures. The earliest symptom of osteoporosis is often an episode of acute back pain caused by a pathologic vertebral compression fracture, or an episode of groin or thigh pain caused by a pathologic hip fracture. In the diagnostic process, the extent and severity of bone loss are evaluated and secondary forms of bone loss are excluded. A careful diagnostic work-up that includes clinical history, physical examination, laboratory evaluation, bone densitometry, and radiographic imaging will allow the clinician to determine the cause of osteoporosis and to institute medical interventions that will stabilize and even reverse this frequently preventable condition.

Osteoporosis is a skeletal condition characterized by decreased density (mass/unit volume) of normally mineralized bone. The reduced density impairs the mechanical strength of the bone, thus making it more vulnerable to fracture.

The World Health Organization has established diagnostic criteria for osteoporosis that are based on bone density measurements determined by dual-energy x-ray absorptiometry (DXA). A patient is classified as having low bone mass if the bone mineral density measures between 1 and 2.5 standard deviations below the mean value in a young reference population. The diagnosis of osteoporosis is made if a patient's bone density is 2.5 standard deviations or more below the mean for young normal people 2 ( Table 1 ).

In this definition, it is recognized that there is a strong association between bone mineral density and the likelihood of fracture. 4,22,28 According to the criteria, approximately 0.6% of young women have osteoporosis and approximately 16% have low bone mass. By age 75, an estimated 38% of white women will have osteoporosis and 94% will have low bone mass. 20,21,25,26 Although the definition is useful for establishing the prevalence of osteoporosis, it is inadequate as a guide to treatment, because other factors influence bone quality and fracture risk. Treatment should be determined for each patient after consideration of these other factors in addition to bone density. Because the risk of osteoporotic fracture during the remaining lifetime of many elderly patients is sufficiently low, aggressive treatment is usually not needed. Conversely, many patients who do not meet the World Health Organization's criteria for osteoporosis might have other risk factors and circumstances that justify treatment. Therefore, the World Health Organization's criteria has made physicians aware of the prevalence of osteoporosis but should not be used to dictate absolute thresholds for diagnosis and treatment.

Osteoporosis has been classified into two categories, primary and secondary. Primary osteoporosis is further divided into three types- postmenopausal osteoporosis (Type I), age-related osteoporosis (Type II), and idiopathic osteoporosis. Postmenopausal (Type I) osteoporosis develops in women who have estrogen deficiency, whereas age-related (Type II) osteoporosis occurs in men and women as their bone density decreases with aging. Secondary osteoporosis refers to those patients in whom a causative factor or disease process is identifiable. 18

Osteoporosis is less common in men than in women, probably reflecting that men have greater bone mass than women at all ages, and experience no physiologic equivalent of menopause. 24 Nonetheless, severe Type II (age-related) and idiopathic osteoporosis occurs in men. Secondary osteoporosis caused by excessive alcohol in-take, hypogonadism, hypercortisolism, and hyperthyroidism also occur in men and can lead to varying degrees of clinically significant osteoporosis. 7,9,12,13,16

Clinical Signs and Symptoms

In osteoporosis, as in hypertension, there is often a long latent period before clinical symptoms or complications develop. The most prevalent sequelae are compression fractures of the vertebral bodies and fractures of the ribs, proximal femurs, humeri, and distal radiuses.

Pathologic fractures are among the most obvious clinical manifestations of osteoporosis. 14,17 In patients with osteoporosis, as well as in older persons, fractures are often the result of a fall. 11,29 Results reported in recent studies on falls in the elderly have identified numerous predisposing factors. Intrinsic causes include neurologic and musculoskeletal disorders, cardiovascular disorders, and visual disturbances, all common in this population. Extrinsic factors that increase the risk of falls are the use of sedatives, excessive use of prescription medications, dim lighting, cluttered floors, and various other obstructions (scatter rugs, curbs, and stairs). 21,23,29-31 Reduced resistance to trauma caused by a decrease in soft tissue padding that can help absorb and deflect the kinetic energy at sites of impact, as well as low bone mass, may contribute to the high incidence of fracture. Hip fractures in thin patients are probably related to decreased resistance and low bone mass. Therefore, persons with ample body fat or well-developed muscles are less likely to sustain a fracture during a fall. 14

Vertebral Compression Fractures

The earliest symptom of osteoporosis is often an episode of acute back pain occurring when the person is at rest or during such routine activity as bending, standing from a seated position, lifting a heavy object, or opening a window. Although most compression fractures are painless, pain can occur suddenly. Most patients can recall the exact moment the pain began but may have difficulty identifying the vertebral site involved. Spinal movement is severely restricted, with flexion reduced more than extension. Pain intensifies with sitting or standing and is relieved by bed rest in the fully recumbent position. Coughing, sneezing, and straining to move the bowels can exacerbate the pain. Sitting or standing for prolonged periods may be impossible because of severe pain. The patient walks slowly, but the gait is otherwise normal.

Anterior compression fractures in the thoracic spine may cause thoracic kyphosis (dowager's hump), the stooped posture characteristic of osteoporosis. Loss of vertebral height is usually insidious and painless and is accompanied by loss in height of the intervertebral discs. Involvement of the lumbar spine may lead to progressive loss of the normal lumbar lordosis. Axial height decreases after each fracture, and there is a discrepancy between the standing height and arm span. Patients with severe, progressive spinal compression may have an acquired short trunk and short stature. This is easily identified with the patient in the standing position. Normally the finger tips should come to the mid thigh. In advanced osteoporosis, with loss of axial height, the finger tips come to the lower thigh or knee when the patient is standing. Once the spine has collapsed to the point at which the lower ribs rest on the iliac crest, height remains stable, although bone density may continue to diminish.

After acute vertebral fractures, spasms of the paravertebral muscles are palpable and often visible. The spine and paravertebral muscles may be tender to deep palpation and to percussion at the level of the fracture.

Acute fractures are usually not associated with abnormal neurologic findings, in that they are usually stable injuries. When present, radiculopathy, can cause unilateral or bilateral pain that radiates along the costal margin of the affected spinal nerve. Involvement of the spinal cord or cauda equina is extremely uncommon, and should suggest other conditions, including infection, metastatic or primary bone tumors, myeloma, Paget's disease, or lymphoma.

During intervals between compression fractures, most patients remain pain free. However, some patients continue to be plagued by dull, aching back pain, especially with prolonged standing. This pain can often be relieved with intermittent bed rest throughout the day.

It is important to distinguish chronic back pain from the incapacitating pain of temporally clustered fractures. For a significant number of patients with cluster fractures, the severe pain initiated by the first vertebral compression fracture barely subsides before the occurrence of equally severe pain with the next fracture. Typically, these patients will have multiple fractures in a period of months, followed by gradual recovery. Such patients are able to recall each exacerbation and tend to have more severe pain of longer duration than those with isolated compression fractures. When cluster fractures are suspected in a patient, evaluation for secondary causes of osteopenia is warranted. Exacerbation of a preexisting chronic illness in a severely osteopenic, steroid-dependent patient, or an increase in the glucocorticoid medication often precipitates temporal clustering of fractures. 15

Some permanent side effects of progressive vertebral compression fractures are related to decreases in the size of the thoracic and abdominal cavities. Postural changes diminish exercise tolerance. After ingesting even small amounts of food, the patient often feels full and bloated. Severe vertebral collapse in the lumbar spine causes the abdomen to protrude. Circumferential pachydermal skin folds may develop at the rib and pelvic margins as the spinal deformity progresses.

Appendicular Fractures

In some persons, osteoporosis is first manifested by a pathologic fracture of the proximal femur or distal radius, sustained after a fall. The incidence of fractures of the femoral neck increase with age. 19 Fractures of the proximal femur are among the most feared complications of osteoporosis and are solely responsible for catapulting the disease into the category of a life-threatening disorder. These fractures often occur in patients with several preexisting comorbidities that contribute to more complicated postoperative recovery, including pneumonia, deep vein thrombosis, and fat embolus syndrome. Although reduced bone density is a critical component leading to a fractured hip, other intrinsic and extrinsic factors-cardiac disease, neurologic disorders, and medications that cause dizziness-may be equally important.

Patients typically complain of hip pain and the hip's inability to bear weight. Physical examination reveals a shortened, externally rotated leg. In cases of occult fractures, the patient complains of severe pain when the hip is in a weight-bearing position. Occult hip fractures can be observed in patients who have risk factors for osteoporosis and tend to be more active. Magnetic resonance imaging or a bone scan is often useful in diagnosing occult fractures.

Diagnostic Evaluation

The diagnostic work-up of osteoporosis focuses on evaluating the cause and magnitude of bone loss and on excluding secondary causes of bone loss. In many patients, the diagnosis of osteoporosis is made only after a pathologic fracture has occurred. To avoid the potentially devastating effects of osteoporosis, it may be clinically warranted and cost-effective to assess bone density in patients at high risk before fractures or deformities occur. These low-cost, usually available techniques are valuable diagnostic tools. Serial bone density measurements are extremely useful for monitoring the effectiveness of therapy or preventive interventions.

History and Laboratory Studies

Postmenopausal osteoporosis in women and age-related osteoporosis in men and women are the most common forms of symptomatic bone loss seen in clinical practice. A detailed history, however, may suggest that the low bone density is secondary to hyperthyroidism, primary hyperparathyroidism, hypercortisolism, myeloma, or osteomalacia ( Tables 2 and 3 ).

Risk factors for low bone density have limited value in estimating a person's actual bone density. 27 However, determining risk factors for fracture can be useful in identifying those at high risk, and treatment can be initiated to reduce the risk. 6 In women, several common, important, and clinically useful risk factors have been identified recently in the Study of Osteoporotic Fractures. These include low bone mineral density; history of a fracture after age 40; history of a fracture of the hip, wrist, or vertebra in a first-degree relative; or current cigarette smoking. 5

Obtaining a thorough history facilitates selection of appropriate baseline tests. Routine laboratory tests include complete blood count with leukocyte differential measurement; a 24-hour urine collection to measure calcium and creatinine excretion; and determination of serum levels of calcium, albumin, phosphorus, alkaline phosphatase, blood urea nitrogen, and creatinine ( Table 2 ). In asymptomatic postmenopausal osteoporosis, results of routine laboratory tests are normal and do not assess the extent or rate of bone loss or indicate the prognosis. Even in severe postmenopausal osteoporosis, the serum levels of calcium, inorganic phosphorus, and alkaline phosphatase are usually normal, although alkaline phosphatase levels may rise transiently for several weeks after a fracture. Measurement of biochemical markers appears helpful in assessing bone turnover and aids in monitoring therapy. Total alkaline phosphatase, osteocalcin, Type I collagen propeptides, urinary collagen cross-links, and collagen telopeptides are several markers that may be useful. A complete description of these tests is summarized by Erye in this issue. 1,3,8,10

Additional tests are warranted if bone loss caused by conditions other than aging and menopause is suspected. Diagnosis of primary or iatrogenic hyperthyroidism requires measurement of serum triiodothyronine resin uptake (T 3 RU), and thyroxine (T 4 ) levels, and calculation of the free thyroxine index (FTI). Serum thyroid-stimulating hormone (TSH) levels are markedly suppressed in all forms of hyperparathyroidism and are a sensitive indicator of thyroid status. Serum protein electrophoresis, urinary immunoelectrophoresis and bone marrow aspirate may be needed to detect multiple myeloma. In patients who have hypercalcemia, parathyroid hormone levels must be determined. The serum level of 25-hydroxyvitamin D, an excellent indicator of total body reserves of vitamin D, may be measured to evaluate a possible vitamin D deficiency, the most common biochemical abnormality associated with hip fractures. All men with osteopenia or osteoporosis should have an evaluation of serum testosterone level, in that asymptomatic hypogonadism is a common cause of osteopenia in men.

Differential Diagnosis

Osteoporosis and osteomalacia are commonly confused osteopenic conditions in adults. Whereas osteoporosis is characterized by a decreased density of normally mineralized bone matrix, osteomalacia is a qualitative rather than a quantitative disorder of bone metabolism. In osteomalacia, bone density may be increased, normal, or (most commonly) decreased, and bone matrix is insufficiently mineralized.

Unlike its more easily recognized childhood counterpart, rickets, adult osteomalacia may be difficult to diagnose clinically. The incidence is evenly distributed throughout all age groups. The most common causes are chronic renal failure, malabsorption, vitamin D deficiency, abnormalities of the vitamin D pathway, and hypophosphatemic syndromes. Rarer causes are renal tubular acidosis, aluminum intoxication, and hypophosphatasia.

In contrast to osteoporosis, which does not become evident until fractures occur, osteomalacia may cause generalized bone pain, tenderness, and generalized myopathy. Osteomalacia caused by vitamin D deficiency is suggested by bone pain or pathologic fracture in a patient taking anticonvulsants, by a history of malabsorption syndrome in a patient, or by a femoral neck fracture in an older patient. The levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D must be determined when osteomalacia is suspected. The diagnosis can be confirmed with fluorescent microscopic examination of nondecalcified trabecular bone tissue obtained by transiliac bone biopsy after administration of time-separated double tetracycline labeling.

Although the radiographic features of osteoporosis and osteomalacia may be similar, axial changes predominate in osteoporosis, whereas appendicular changes predominate in osteomalacia. Osteomalacia is suggested by symmetric pathologic fractures and traumatic fractures. Pseudofractures (Looser zones) are characteristic of osteomalacia. These small, incomplete cortical fractures develop perpendicular to the long axis of a bone and are often bilaterally symmetric. Common areas of involvement include medial borders of the scapulas, ribs, ischiopubic rami, femoral necks, lateral borders of the femur, and distal radiuses.

Results of routine laboratory studies, typically normal in osteoporosis, may be abnormal in osteomalacia. Osteomalacia should be suspected when the product of the serum calcium level and serum phosphate level is chronically below 25 (with normal serum albumin), especially if accompanied by an elevated bone-specific alkaline phosphatase level and a urinary calcium excretion of less than 50 mg per 24 hours.

Conclusions

The effectiveness of current treatment methods for osteoporosis relies on the accurate diagnosis and classification of the disease process that results in low bone density and fractures. A careful diagnosis that is based on clinical history, physical examination laboratory evaluation, bone densitometry, and radiographic imaging will allow the clinician to enact preventive measures and medical interventions that can even reverse this frequently preventable disorder.

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The 1st EoETALY Consensus on the Diagnosis and Management of Eosinophilic Esophagitis - Definition, Clinical Presentation and Diagnosis

Affiliations.

• 1 Gastroenterology Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
• 2 Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.
• 3 Department of Medical-Surgical Sciences and Translational Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome 00189, Italy.
• 4 Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
• 5 Endoscopy Unit, IRCCS CROB, Rionero in Vulture, Italy.
• 6 Gastroenterology Unit ASLTO4, Chivasso - Ciriè - Ivrea, Italy.
• 7 Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia 27100, Italy; First Department of Internal Medicine, IRCCS San Matteo Hospital Foundation, Pavia 27100, Italy.
• 8 Digestive Endoscopy Unit - Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
• 9 Department of Advanced Medical and Surgical Sciences, University of Campania "L. Vanvitelli", Naples, Italy.
• 10 Digestive Pathophysiology Unit and Digestive Endoscopy Unit, Azienda Ospedaliero Universitaria di Modena, Ospedale Civile di Baggiovara, Modena, Italy.
• 11 Division of Gastroenterology, Department of Internal Medicine, University of Genoa, Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
• 12 Gastroenterology and Digestive Endoscopy Unit,' Santa Chiara' Hospital, Trento, Italy.
• 13 Gastrointestinal Unit, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Baronissi 84084, Italy.
• 14 Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia 27100, Italy.
• 15 Gastroenterology and Endoscopy Unit, Fondazione IRCCS Policlinico San Matteo, Pavia 27100, Italy.
• 16 Maternal and Child Health Department, Pediatric Gastroenterology and Liver Unit, Sapienza - University of Rome, Italy.
• 17 Endoscopic Unit, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy.
• 18 Department of clinical medicine and surgery, University of Naples Federico II, Naples, Italy.
• 19 Inflammatory Bowel Disease Unit, "Cannizzaro" Hospital, Catania, Italy.
• 20 Immunoallergology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy.
• 21 Personalized Medicine, Asthma and Allergy Clinic, IRCCS Humanitas Research Hospital, Rozzano - Milan, Italy.
• 22 Unit of Gastroenterology and Digestive Endoscopy, Campus Bio Medico University, Rome, Italy.
• 23 Allergy Unit, Department of Internal Medicine, University Hospital of Parma, Parma, Italy.
• 24 Gastroenterology and Digestive Endoscopy Unit, Azienda Ospedaliera Universitaria of Modena, Modena, Italy.
• 25 Division of General, Oncological, Mini-Invasive and Obesity Surgery, University of Campania "Luigi Vanvitelli", Naples 80131, Italy.
• 26 Division of Gastroenterology, Department of Internal Medicine, University of Genoa, Genoa, Italy.
• 27 Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, Via Giustiniani 2, Padua 35128, Italy.
• 28 Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, Via Giustiniani 2, Padua 35128, Italy. Electronic address: [email protected].
• PMID: 38423918
• DOI: 10.1016/j.dld.2024.02.005

Eosinophilic esophagitis (EoE) is a chronic type 2-mediated inflammatory disease of the esophagus that represents the most common eosinophilic gastrointestinal disease. Experts in the field of EoE across Italy (i.e., EoETALY Consensus Group) including gastroenterologists, endoscopists, allergologists/immunologists, and paediatricians conducted a Delphi process to develop updated consensus statements for the management of patients with EoE and update the previous position paper of the Italian Society of Gastroenterology (SIGE) in light of recent evidence. Grading of the strength and quality of the evidence of the recommendations was performed using accepted GRADE criteria. The guideline is divided in two documents: Part 1 includes three chapters, namely 1) definition, epidemiology, and pathogenesis; 2) clinical presentation and natural history, and 3) diagnosis, while Part 2 includes two chapters: 4) treatment and 5) monitoring and follow-up. This document has received the endorsement of three Italian national societies including the SIGE, the Italian Society of Neurogastroenterology and Motility (SINGEM), and the Italian Society of Allergology, Asthma, and Clinical Immunology (SIAAIC). With regards to patients' involvement, these guidelines involved the contribution of members of ESEO Italia, the Italian Association of Families Against EoE.

Keywords: EoE; EoETALY; Eosinophilic esophagitis; Guidelines.

Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.

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Conflict of interest statement

Declaration of competing interest Nicola de Bortoli: Advisory board member for: AlfaSigma, Sanofi Genzyme, Dr Falk; Lecture grants from Reckitt-Benkiser, Malesci, Dr. Flak, Sofar, Alfa-Sigma, Pharma-Line. Pierfrancesco Visaggi: Has served as speaker for Dr Falk, JB Pharmaceuticals, Malesci. Roberto Penagini: Has served as speaker for Dr Falk, Sanofi. Edda Battaglia: has served as consultant for NZP, GUNA Gaia Pellegatta has served as speaker for Dr Falk, Sanofi Genzyme, Malesci. Paola Iovino: Has served as consultant for Dr Falk Giovanni Marasco: Served as an advisory board member for AlfaSigma, EG Pharma, Monteresearch srl, Recordati, Cineca. Received lecture grants from Agave, AlfaSigma, Bromatech, Clorofilla, Echosens, Ferring, Mayoly Spindler, Menarini and Schwabe Pharma. Salvatore Oliva: Has served as speaker for Sanofi, Medtronic; Has served as consultant for: Sanofi, Medtronic, Brystol; Has received research support from Alfa Sigma, Medtronic. Francesca Racca: has served as speaker for Sanofi; has served as consultant for Dr Falk, Sanofi, GSK Erminia Ridolo: has served as consultant for Dr Falk Edoardo Vincenzo Savarino: has served as speaker for Abbvie, Agave, AGPharma, Alfasigma, Aurora Pharma, CaDiGroup, Celltrion, Dr Falk, EG Stada Group, Fenix Pharma, Fresenius Kabi, Galapagos, Janssen, JB Pharmaceuticals, Innovamedica/Adacyte, Malesci, Mayoly Biohealth, Omega Pharma, Pfizer, Reckitt Benckiser, Sandoz, SILA, Sofar, Takeda, Tillots, Unifarco; has served as consultant for Abbvie, Agave, Alfasigma, Biogen, Bristol-Myers Squibb, Celltrion, Diadema Farmaceutici, Dr. Falk, Fenix Pharma, Fresenius Kabi, Janssen, JB Pharmaceuticals, Merck & Co, Nestlè, Reckitt Benckiser, Regeneron, Sanofi, SILA, Sofar, Synformulas GmbH, Tssakeda, Unifarco; he received research support from Pfizer, Reckitt Benckiser, SILA, Sofar, Unifarco, Zeta Farmaceutici. Bruno Annibale, Federica Baiano Svizzero, Giovanni Barbara, Brigida Barberio, Ottavia Bartolo, Antonio Di Sabatino, Ludovico Docimo, Marzio Frazzoni, Manuele Furnari, Matteo Ghisa, Andrea Iori, Marco Vincenzo Lenti, Elisa Marabotto, Aurelio Mauro, Marcella Pesce, Antonino Carlo Privitera, Ilaria Puxeddu, Mentore Ribolsi, Salvatore Russo, Giovanni Sarnelli, Salvatore Tolone, Patrizia Zentilin, Fabiana Zingone: None.

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Revised Criteria for Alzheimer's Diagnosis, Staging Released

Megan Brooks

June 28, 2024

A work group convened by the Alzheimer's Association has released revised biology-based criteria for the diagnosis and staging of Alzheimer's disease (AD), including a new biomarker classification system that incorporates fluid and imaging biomarkers as well as an updated disease staging system. 

"Plasma markers are here now, and it's very important to incorporate them into the criteria for diagnosis," senior author Maria C. Carrillo, PhD, Alzheimer's Association chief science officer and medical affairs lead, told Medscape Medical News . 

The revised criteria are the first updates since 2018 .

"Defining diseases biologically, rather than based on syndromic presentation, has long been standard in many areas of medicine — including cancer, heart disease and diabetes — and is becoming a unifying concept common to all neurodegenerative diseases," lead author Clifford Jack, Jr, MD, with Mayo Clinic, Rochester, Minnesota, said in a news release from the Alzheimer's Association. 

"These updates to the diagnostic criteria are needed now because we know more about the underlying biology of Alzheimer's and we are able to measure those changes," Jack added. 

The 2024 revised criteria for diagnosis and staging of AD were published online on June 28 in Alzheimer's & Dementia . 

Core Biomarkers Defined

The revised criteria define AD as a biologic process that begins with the appearance of AD neuropathologic change (ADNPC) in the absence of symptoms. Progression of the neuropathologic burden leads to the later appearance and progression of clinical symptoms.

The work group organized AD biomarkers into three broad categories: (1) core biomarkers of ADNPC, (2) nonspecific biomarkers that are important in AD but are also involved in other brain diseases, and (3) biomarkers of diseases or conditions that commonly coexist with AD.

Core Alzheimer's biomarkers are subdivided into Core 1 and Core 2. 

Core 1 biomarkers become abnormal early in the disease course and directly measure either amyloid plaques or phosphorylated tau (p-tau). They include amyloid PET; cerebrospinal fluid (CSF) amyloid beta 42/40 ratio, CSF p-tau181/amyloid beta 42 ratio, and CSF total (t)-tau/amyloid beta 42 ratio; and "accurate" plasma biomarkers, such as p-tau217. 

"An abnormal Core 1 biomarker result is sufficient to establish a diagnosis of AD and to inform clinical decision making [sic] throughout the disease continuum," the work group wrote. 

Core 2 biomarkers become abnormal later in the disease process and are more closely linked with the onset of symptoms. Core 2 biomarkers include tau PET and certain soluble tau fragments associated with tau proteinopathy (eg, MTBR-tau243) but also pT205 and nonphosphorylated mid-region tau fragments. 

Core 2 biomarkers, when combined with Core 1, may be used to stage biologic disease severity; abnormal Core 2 biomarkers "increase confidence that AD is contributing to symptoms," the work group noted. 

The revised criteria give clinicians "the flexibility to use plasma or PET scans or CSF," Carrillo told Medscape Medical News . "They will have several tools that they can choose from and offer this variety of tools to their patients. We need different tools for different individuals. There will be differences in coverage and access to these diagnostics." 

The revised criteria also include an integrated biologic and clinical staging scheme that acknowledges the fact that common co-pathologies, cognitive reserve, and resistance may modify relationships between clinical and biologic AD stages. 

Formal Guidelines to Come 

The work group noted that currently, the clinical use of AD biomarkers is intended for the evaluation of symptomatic patients, not cognitively unimpaired individuals.

Disease-targeted therapies have not yet been approved for cognitively unimpaired individuals. For this reason, the work group currently recommends against diagnostic testing in cognitively unimpaired individuals outside the context of observational or therapeutic research studies. 

This recommendation would change in the future if disease-targeted therapies that are currently being evaluated in trials demonstrate a benefit in preventing cognitive decline and are approved for use in preclinical AD, they wrote. 

They emphasize that the revised criteria are not intended to provide step-by-step clinical practice guidelines for clinicians. Rather, they provide general principles to inform diagnosis and staging of AD that reflect current science.

"This is just the beginning," said Carrillo. "This is a gathering of the evidence to date and putting it in one place so we can have a consensus and actually a way to test it and make it better as we add new science."

This also serves as a "springboard" for the Alzheimer's Association to create formal clinical guidelines. "That will come, hopefully, over the next 12 months. We'll be working on it, and we hope to have that in 2025," Carrillo said. 

The revised criteria also emphasize the role of the clinician. 

"The biologically based diagnosis of Alzheimer's disease is meant to assist, rather than supplant, the clinical evaluation of individuals with cognitive impairment," the work group wrote in a related commentary published online on June 28 in Nature Medicine . 

Recent diagnostics and therapeutic developments "herald a virtuous cycle in which improvements in diagnostic methods enable more sophisticated treatment approaches, which in turn steer advances in diagnostic methods," they continued. "An unchanging principle, however, is that effective treatment will always rely on the ability to diagnose and stage the biology driving the disease process."

Funding for this research was provided by the National Institutes of Health, Alexander family professorship, GHR Foundation, Alzheimer's Association, Veterans Administration, Life Molecular Imaging, Michael J. Fox Foundation for Parkinson's Research, Avid Radiopharmaceuticals, Eli Lilly, Gates Foundation, Biogen, C2N Diagnostics, Eisai, Fujirebio, GE Healthcare, Roche, National Institute on Aging, Roche/Genentech, BrightFocus Foundation, Hoffmann-La Roche, Novo Nordisk, Toyama, National MS Society, Alzheimer Drug Discovery Foundation, and others. A complete list of donors and disclosures is included in the original article. 

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